WO2008022467A1

WO2008022467A1 - 2-substituted azain doles and 2 substituted thienopyrroles, their precursors and novel processes for the preparation thereof

Info

Publication number: WO2008022467A1
Application number: PCT/CA2007/001499
Authority: WO
Inventors: Mark Lautens; Josephine Yuen; Yuanqing Fang
Original assignee: Mark Lautens; Josephine Yuen; Yuanqing Fang
Priority date: 2006-08-25
Filing date: 2007-08-24
Publication date: 2008-02-28

Abstract

The present invention relates generally to processes for the chemical synthesis of azaindole and thienopyrrole compounds, in particular azaindole and thienopyrrole compounds that are substituted at the 2-position of the azaindole or thienopyrrole ring, and optionally at additional locations of the azaindole or thienopyrrole ring such as the 1- and/or 3-position, compounds prepared by such processes, and synthetic precursors of such processes. More particularly, the present invention relates to the preparation of 2- substituted azaindoles from an ortho-gem-dihalovinylaminopyridine or from an ortho- gem-dihalovinylaminopyridine N-oxide compound and an organoboron reagent using a palladium metal pre-catalyst, base and a ligand. The present invention also relates to the preparation of 2-substituted thienopyrroles from an ortho-gem-dihalovinylthiophene compound and an organoboron reagent using a palladium metal pre-catalyst, base and a ligand. The present invention also relates to processes for the production of ortho-gem- dihalovinylaminopyridines which are useful as starting materials in the production of 2- substituted azaindoles, and novel compounds prepared by the processes. The present invention also relates to processes for the production of ortho-gem-dihalovinylthiophenes which are useful as starting materials in the production of 2-substituted thienopyrroles, and novel compounds prepared by the processes. Formulae (V) and (VII).

Description

2-Substituted Azaindoles and 2-Substituted Thienopyrroles, their Precursors and Novel Processes for the Preparation Thereof

1. Field of the Invention

The present invention relates generally to processes for the chemical synthesis of azaindole and thienopyrrole compounds, in particular azaindole and thienopyrrole compounds that are substituted at the 2-position of the azaindole or thienopyrrole ring, and optionally at additional locations of the azaindole or thienopyrrole ring such as the 1- and/or 3-position, compounds prepared by such processes, and synthetic precursors of such processes. More particularly, the present invention relates to the preparation of 2- substituted azaindoles from an ortAo-g-e/n-dihalovinylaminopyridine or from an ortho- gem-dihalovinylaminopyridine N-oxide compound and an organoboron reagent using a palladium metal pre-catalyst, base and a ligand. The present invention also relates to the preparation of 2-substituted thienopyrroles from an ort/ϊø-gem-dihalovinylthiophene compound and an organoboron reagent using a palladium metal pre-catalyst, base and a ligand. The present invention also relates to processes for the production of ortho-gem- dihalovmylammopyridines which are useful as starting materials in the production of 2- substituted azaindoles, and novel compounds prepared by the processes. The present invention also relates to processes for the production of ortho-gem-dihalovinylthiophenes which are useful as starting materials in the production of 2-substituted thienopyrroles, and novel compounds prepared by the processes.

2. Brief Description of the Related Art

By replacing one of the benzo carbons with nitrogen, four possible isomeric forms of azaindole^' result (see formulae below). Since they are bioisosteric structures of indoles, azaindoles enjoy great attention in designing pharmaceutically important agents. Even though naturally occurring azaindoles are rare, their presence in biologically active compounds is widespread in recent patents and publications, as discussed below.

Indole 4-azaindole 5-azaindole 6-azaindole 7-azaindole or or or or

Pyrrolo[3,2-b]pyridine Pyrrolo[3,2-c]pyridine Pyrrolo[2,3-c]pyridine Pyrrolo[2,3-jb]pyridine

Azaindole compounds have been used as tubulin^inhibitory, antimitotic agents for potential cancer treatment (Mahboobi, S.; Pongratz, H.; Hufsky, H.; Hockemeyer, J.; 5 Frieser, M.; Lyssenko, A.; Paper, D. H.; Buergermeister, J.; Boehmer, F.-D.; Fiebig, H.- H.; Burger, A. M.; Baasner, S.; Beckers, T. J. Med. Chem. 2001, 44, 4535).

Azaindole compounds have also been used as selective potent Dopamine D₄ antagonists as potential anti-psychotic agents (Curtis, N. R.; Kulagowski, J. J.; Leeson, P. D.; Ridgill, M. P.; Emms, F.; Freedman, S. B.; Patel, S.; Patel, S. Bioor. Med. Chem. Lett. 10 1999, 9, 585).

Azaindoles have been used as Transforming Growth Factor (TGF)-βl antagonists for the potential treatment of pulmonary fibrosis, scleroderma, systemic scleroderma, and nephritis (Maruyama, Y.; Hirabayashi, K.; Hori, K. In. PCT Int. AppL; (Nippon Shinyaku Co., Ltd., Japan) WO 03037862, 2003; Jinnin, M.; Ihn, H.; Tamaki, K. MoI. Pharmacol. 15 2006, 69, 597).

Azaindole compounds have been used as antithrombotics and anticoagulants (Bastian, J. A.; Fisher, M. J.; Harper, R. W.; Lin, H.-S.; McCowan, J. R.; Sail, D. J.; Smith, G. F.; Takeuchi, K.; Wiley, M. R.; Zhang, M. In Eur. Pat. AppL; (Eli Lilly, USA). EP 997465, 2000).

20 Azaindole compounds have also been utilized as NKl receptor antagonists for potential treatment of migraine, cystitis, asthma, depression and cytotoxininduced emesis (Cooper, L. C; Chicchi, G. G.; Dinnell, K.; Elliott, J. M.; Hollingworth, G. J.; Kurtz, M. M.; Locker, K. L.; Morrison, D.; Shaw, D. E.; Tsao, K. L.; Watt, A. P.; Williams, A. R.; Swain, C. J. Bioorg. Med. Chem. Lett. 2001, 11, 1233). Azaindole compounds have been used as CB1/CB2 receptor agonists in pain management (Wei, Z.; Dolaine, R.; Walpole, C; Yang, H. In PCT Int. Appl; (Astrazeneca Ab, Swed.). WO 04087704, 2004.)

Azaindole compounds have also been used as ITK kinase inhibitors (Aadal Nielsen, P.; 5 Brimert, T.; Kristoffersson, A.; Linnanen, T.; Sjoe, P. hi PCT Int. Appl; (Astrazeneca AB, Swed.). WO 04016609, 2004. Aadal Nielsen, P.; Brimert, T.; Kristoffersson, A.; Linnanen, T.; Sjoe, P. In PCT Int. Appl; (Astrazeneca AB, Swed.). WO 04016610, 2004.)

Azaindole compounds have also found utility as potent inhibitors of the MAP kinase p38, which can be used as new methods of treatment for inflammatory diseases such as 10 rheumatoid arthritis and inflammatory bowel disease (Henry, J. R.; Rupert, K. C; Dodd,

J. H.; Turchi, I. J.; Wadsworth, S. A.; Cavender, D. E.; Schafer, P. H.; Siekierka, J. J.

Bioorg. Med. Chem. Lett. 1998, 8, 3335; Henry, J. R.; Dodd, J. H. Tetrahedron Lett.

1998, 39, 8763; Dodd, J. H.; Henry, J. R.; Rupert, K. In PCT Int. Appl; (Ortho-McNeil

Corporation, Inc., USA). WO 9847899, 1998; Henry, J. R.; Rupert, K. C; Dodd, J. H.; 15 Turchi, I. J.; Wadsworth, S. A.; Cavender, D. E.; Fahmy, B.; Olini, G. C; Davis, J. E.;

Pellegrino-Gensey, J. L.; Schafer, P. H.; Siekierka, J. J. J. Med. Chem. 1998, 41, 4196).

Azaindole compounds have also been used as p38 kinase α inhibitors (Mavunkel, B. J.; Perumattam, J. J.; Lu, Q.; Dugar, S.; Goyal, B.; Wang, D. X.; Chakravarty, S.; Luedtke, G. R.; Nashashibi, L; Tester, R.; Tan, X. In U.S. Pat. Appl Publ; (USA). US 05288299, 20 2005).

In other examples, azaindole compounds have been used as the antagonists of gonadotropin releasing hormone (GnRH) for the treatment and the prevention of disturbances of calcium, phosphate and bone metabolism (Walsh, T. F.; Ujjainwalla, F.; Goulet, M. T.; Bugianesi, R. L. In PCT Int. Appl; (Merck & Co., Inc., USA). WO

25 9951596, 1999; Walsh, T. F.; Ujjainwalla, F.; Goulet, M. T. In PCT Int. Appl; (Merck & Co., Inc., USA). WO 5591595, 1999; Walsh, T. F.; Ujjainwalla, F.; Goulet, M. T.; Young, J. R. In PCT Int. Appl; (Merck & Co., Inc., USA). WO 5591234, 1999; Walsh, T. F.; Ujjainwalla, F.; Goulet, M. T. In PCT Int. Appl; (Merck & Co., Inc., USA). WO 9951233, 1999; Walsh, T. F.; Ujjainwalla, F.; Goulet, M. T.; Young, J. R. In PCT Int.

30 Appl; (Merck & Co., Inc., USA). WO 5591232, 1999.; Walsh, T. F.; Ujjainwalla, F.; Goulet, M. T.; Young, J. R. In PCT Int. AppL; (Merck & Co., Inc., USA). WO 9951231, 1999.

Azaindoles have been used as as endothelin receptor antagonists (Elliott, J. D.; Leber, J. D. In PCT Int. AppL; (SmithKline Beecham Corp., USA). WO 9533748, 1995)

Azaindoles have also been used as c-Jun N-terminal kinases (JNKs) inhibitors for the treatment of neurodegenerative disorders (Graczyk, P.; Khan, A.; Bhatia, G.; Iimura, Y. In PCT Int. AppL; (Eisai London Research Laboratories Limited, UK). WO 04078756, 2004).

Azaindole compounds have been used as G-protein-coupled chemoattractant receptor (CRTh2) receptor antagonists for treatment of an inflammatory or allergic condition (BaIa, K.; Leblanc, C; Sandham, D. A.; Turner, K. L.; Watson, S. J.; Brown, L. N.; Cox, B. In PCT Int. AppL; (Novartis AG, Switz.; Novartis Pharma GmbH). WO 05123731, 2005).

In other examples, azaindole compounds have been used as Janus kinase 3 (JAK3 kinase) inhibitors for potential treatment of T-cell proliferative disorders such as transplant rejection and autoimmune diseases (David, L.; Hansen, P. In PCT Int. AppL; (Astrazeneca AB, Swed.). WO 04099205, 2004).

Azaindoles have been used as inhibitors of glycogen phosphorylase and are useful in the prophylactic or therapeutic treatment of diabetes, hyperglycemia, hypercholesterolemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis or tissue ischemia e.g. myocardial ischemia, or as cardioprotectants or inhibitors of abnormal cell growth (Bradley, S. E.; Krulle, T. M.; Murray, P. J.; Procter, M. J.; Rowley, R. J.; Sambrook Smith, C. P.; Thomas, G. H. In PCT Int. AppL; (Osi Pharmaceuticals, Inc., USA; Schofield, Karen Lesley). WO 04104001, 2004).

Azaindole compounds have also been used as MTP ApoB inhibitors, which are useful for the treatment of hypercholesterolemia, hyperlipidemia (Guevel, A. C; Vidal, C; Roux, B.; Chevreuil, O. In PCT Int. AppL; (Merck Patent GmbH, Germany). WO 06010423, 2006). Azaindole compounds have also been used as protein kinase inhibitors and antiproliferative agents, particularly for tumor treatment (Wentzler, S.; El Ahmad, Y.; Filoche Romme, B.; Nemecek, C; Venot, C. In Fr. Demande; (Aventis Pharma S. A., Fr.) FR 2868422, 2005; (Nemecek, C; Metz, W.; Wentzler, S.; Lesuisse, D. In Fr. Demande; (Aventis Pharma S. A., Fr.) FR 2876103, 2006).

By replacing the annulated benzene ring of indole with an aromatic thiophene ring, three possible isomeric forms of thienopyrroles result (see formulae below). Thieno[2,3- bjpyrrole and thieno[3,2-b]pyrrole isomers are also bioisoteric structures of indoles, therefore, frequently used in pharmaceutical agents. Due to its instability, thieno[3,4- b]pyrrole isomer is rarely used.

Thieno[2,3-6]pyrrole Thieno[3,2-b]pyrrole Thieno[3,4-jb]pyrrole

Thienopyrrole compounds have been used as sPLA2 inhibitors, which may be useful for inflammatory disease treatment (Beight, D. W.; Morin, J. M.; Sawyer, J. S.; Smith, E. C. R. (Eli Lilly & Company, USA) WO 2002012249, 2002).

Thienopyrrole compounds have also been used as potent non-steroidal anti-inflammatory agents for pain management (Kumar, P. R.; Raju, S.; Goud, P. S.; Sailaja, M.; Sarma, M. R.; Reddy, G. O.; Kumar, M. P.; Reddy, V. V. R. M. K.; Suresh, T.; Hegde, P. Bioorg. Med. Chem. 2004, 12, 1221).

Thienopyrrole compounds have been used as MCP-I inhibitors, which may be useful for anti-inflammatory agents and immunomodulators (Barker, A. J.; Kettle, J. G.; Faull, A. W.; (Zeneca Ltd, UK) WO 9940914, 1999).

In other examples, thienopyrrole compounds have been used as inhibitors of glycogen phosphorylase, which are useful for treatment of type-II diabetes (Birch, A. M.; Morley, A. D.; Stacker, A.; Whittamore, P. R. O. (Astrazeneca) WO 2003074532, 2003).

.IBSTiTUTE SHEET (RULE 26} Thienopyrrole compounds have also been used as gonadotropin releasing hormone antagonists (Arnould, J. C. (Astrazeneca) WO 2004018479, 2004).

Thienopyrrole compounds have also found utility as antiviral agents in particular against hepatitis C. (Attenni, B.; Hernando, J. I. M.; Malancona, S. N. F.; Ontoria Ontoria, J. M.; Rowley, M. (Istituto di Ricerche di Biologia Molecolare P Angeletti S.p.A., Italy) WO 2005023819, 2005).

Previous work in the field has led to the development of numerous processes for the synthesis of azaindoles and thienopyrroles and derivatives thereof, several of which are shown below with the reported yields for the preparation of various azaindoles and thienopyrroles.

Methods of constructing azaindoles are very similar to those of indoles. Many of the prior art processes are reported to have numerous drawbacks such as being inefficient, requiring multiple steps, requiring commercially unavailable or expensive starting materials, requiring the use of harsh reaction conditions, and/or are challenging to adapt to an industrial scale. They usually suffer from low yields, limited reaction scope, and low accessibility of the starting materials Many of the methods are summarized in a review in 2002 (Hyaric, M.; Viera de Almeida, M.; Nora de Souza, M. V. Quim. Nova 2002, 25, 1165). A general description of several prior art processes is set out below in Schemes 1-16, additional details of which are set out in the references as indicated.

Fischer indole synthesis is the most commonly used method in indole synthesis, however, it fails to give the corresponding azaindoles due to the deactivating effect of the pyridine ring (Molina, A.; Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-Builla, J.; Pascual-Teresa, B.; Gago, F.; Rodrigo, M. M.; Ballesteros, M. J. Org. Chem. 1996, 61, 5587).

Madelung-type cyclization is very commonly used in azaindole synthesis from picolines in moderate yields (Scheme 1) (Fisher, M. H.; Schwartzkopf, G., Jr.; Hoff, D. R. J. Med. Chem. 1972, 15, 1168). Another drawback is that the reaction suffers from harsh reaction conditions (NaOH, 250-300 °C). Therefore, the product cannot bear any sensitive functionalities (Hands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.; Cottrell, I. F.; Wright, S. H. B. Synthesis, 1996, 877). A modified Madelung-type cyclization by Lorenz uses slightly milder conditions (200 ⁰C instead of 300 °C) to give 7-azaindoles in good yield (Lorenz, R. R.; Tullar, B. F.; Koelsch, G. F.; Archer, S. J. Org. Chem. 1965, 30, 2531).

Scheme 1

Gassman indole synthesis was used to give A-, 6-, and 7-azaindoles in moderate to good yield (Scheme 2) (Debenham, S. D.; Chan, A.; Liu, K.; Price, K.; Wood, H. B. Tetradedron Lett. 2005, 46, 2283).

Scheme 2

I Q R = Ue, CF₃, Br, H, NO₂, OMe, Cl

In another example, Bartoli cyclization was used to synthesize various 4-and 6- azaindoles from various nitropyridines (Scheme 3) (Zhang, Z.; Yang, Z.; Meanwell, M. A.; Kadow, J. F.; Wang, T. J. Org. Chem. 2002, 67, 2345). However, the yields are 15 generally low (11 -50%).

Scheme 3

R = OMe, Cl, 0-2-F-Ph In another example, cyclization of a reactive nitrene intermediate generated from nitro reduction or thermo decomposition of azide provided 5- or 6-azaindoles in low yield (Scheme 4) (Fisher, M. H.; Schwartzkopf, G., Jr.; Hoff, D. R. J. Med. Chem. 1972, 15, 1168).

i Scheme 4

In another example, an iodoaminopyridine was treated with an enolate under UV irradiation to result in a ketone, which cyclized to give corresponding 5-, 6-, or 7- azaindoles (Scheme 5) (Estel, L.; Marsais, F.; Queguiner, G. J. Org. Chem. 1988, 53, 10 2740).

Scheme 5

R = H, Me liquid NH₃ 7 ^A0^J-Q^ysW^/ _o ^o

R¹= Me, ffiu

In another example, an ort/jo-alkynylaminopyridine cyclized under various conditions.

Examples of such conditions include KH or KOt-Bu in NMP (4- or 7- azaindoles 15 (Scheme 6): Koradin, C; Dohle, W.; Rodriguez, A. L.; Schmid, B.; Knochel, P.

Tetrahedron 2003, 59, 1571; Rodriguez, A. L.; Koradin, C; Dohle, W.; Knochel, P.

Angew. Chem., Int. Ed. 2000, 39, 2488; McLaughlin, M.; Palucki, M.; Davies, I. W. Org.

Lett. 2006, 8, ASAP (ol061232r); CuI in DMF (5-azaindole: Tetrahedron Lett. 1998, 39,

5159); Pd(PPh₃)₄ and aryl, alkenyl halides or triflates (4-, 7-azaindoles: Cacchi, S.; 20 Fabrizi, G.; Parisi, L.M. J. Comb. Chem. 2005, 7, 510). Scheme 6

I) Pd(OAc)₂

2) fBuOK R² = alkyl _R3 _{= Phi} alky,, _alkeny| 83-91%

In another example, a Pd-catalyzed annulation of internal alkyne with iodoaminopyridines afforded various 5-, 6-, 7- azaindoles (Scheme 7) (Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998, JP, 5355; Curtis, N. R.; Kulagowski, J. J.; Leeson, P. D.; Ridgill, M. P.; Emms, F.; Freedman, S. B.; Patel, S.; Patel, S. Bioorg. Med. Chem. Lett. 1999, P, 585).

Scheme 7

R¹ = H₁ Me, CO₂Me, Cl, CF₃ 47-77%

In another example, a Pictet-Spengler reaction of a histidine derivative followed by dehydrogenation provided 6-azaindoles in a multi-step synthesis (Scheme 8) (Rousseau, J.-F.; Dodd, R. H. J. Org. Chem. 1998, 63, 2731), However, only a limited number of 6- azaindole derivatives can be prepared using this method.

Scheme 8

In another example, a Pd-catalyzed annulation of chloroaminopyridine with ketones provided azaindoles. However, the yield was only moderate and only 4-azaindoles and 7- azaindoles are shown in the paper (Scheme 9) (Nazare, M.; Schneider, C; Lindenschmidt, A.; Will, D. W. Angew. Chem., Int. Ed. 2004, 43, 4526).

Scheme 9

R², R³ = alkyl, H, CONEt₂, CO₂H

In another example, a Pd-catalyzed direct arylation of azaindoles with arylhalide afforded 2-arylazaindoles (Scheme 10). (Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897; Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050; Sames, D.; Sezen, B.; Lane, B. S. In PCT Int. Appl.; (the Trustees of Columbia University, USA). WO 04069394, 2004). However, only 7-azaindoles were demonstrated to undergo the reaction.

Scheme 10

Methods of constructing thienopyrroles are also similar to those of indoles, however, they also suffer from low yields, limited reaction scope, and low accessibility of the starting materials. Again, thienopyrroles are not accessible through Fischer indole synthesis approach. One of the most commonly used approaches is the condensation of an ort/zo-methoxycarbonylmethylamino thiophenecarboxyaldehydes under basic conditions (Scheme 11) (Soth, S.; Farmer, M.; Paulmier, C. Can. J. Chem. 1978, 56, 1429). Scheme 11 CO₂Et

In another example, thienopyrroles were synthesized using Reissert-type reductive condensation of ørt/zø-nitrothienyl pyruvate using SnCl₂ 2H₂O (Scheme 12). However, the yield is low and only thienopyrrole carboxylic esters are accessible (Gale, W. W.; Scott, A. N.; Snyder, H. R. J. Org. Chem. 1964, 29, 2160).

Scheme 12

47% (2 steps)

In another example, thienopyrroles were synthesized via thiocyanation of pyrrole, followed by alkylation with bromoacetic acid, electrophilic aromatic substitution cyclization, and reduction (Scheme 13) (Matteson, D. S.; Snyder, H. R. J. Am. Chem. Soc. 1957, 79, 3610).

Scheme 13

In another example, thienopyrroles were synthesized via cyclization insertion reaction of suitable nitrene species into the C-H bond either from reduction of ortho- nitrostyrylthiophene (Scheme 14) (Srinivasan, K.; Srinivasan, K. G.; Balasubramanian, K. K.; Swaminathan, S. Synthesis 1973, No. 5, 313), or thermo-decomposition of azidovinylthiophene (Hemetsberger, H.; Knittel, D. Monatsh. Chem. 1972, 103, 194), or photo-decomposition of ørt/jo-azidovinylthiophene (Gairns, R. S.; Moody, C. J.; Rees, C. W. J. Chem. Soc, Chem. Commun. 1985, 1818).

Scheme 14

In another example, thienopyrroles were synthesized via an intramolecular Heck reaction of an ortΛo-iodo-TV-allylaminothiophene (Scheme 15) (Wensbo, D.; Annby, U.; Gronowitz, S. Tetrahedron 1995, 51, 10323).

Scheme 15

In another example, thienopyrroles were synthesized from 3-(thieno-2-yl)-3-oxo-2- diazopropanoates via a Rh(II)-mediated Wolff rearrangement (Scheme 16). (Lee, D. J.; Kim, K.; Park, Y. J. Org. Lett. 2002, 4, 873).

Scheme 16

In view of the above, there remains a need for novel and versatile processes for synthesizing all four azaindole isomers and the two thienopyrrole isomers, in particular 2-substituted azaindole and thienopyrrole compounds, such as 1,2-substituted azaindoles, 1,2-substituted thienopyrroles, 2,3-substituted azaindoles, 2,3 -substituted thienopyrroles, 1, 2,3-substituted azaindoles and 1, 2,3-substituted thienopyrroles. The development and implementation of such processes could simplify the preparation of commercially important azaindole and thiophene compounds.

One such commercially important azaindole compound is the Smad3 inhibitor SIS3, shown below, which can potentially be used for the treatment for systematic sclerosis or scleroderma (Jϊnnin, M.; Ihn, H.; Tamaki, K. MoI Pharmacol 2006, 69, 597 Maruyama, Y.; Hirabayashi, K.; Hori, K. (Nippon Shinyaku Co., Ltd., Japan) PCT Int. Appl. WO 2003037862 (2003) ).

Another commercial application is the KDR kinase inhibitor, which is potentially useful for the treatment of cancer (Fraley, M. E.; Hartman, G. D.; Hungate, R. W. In PCT Int. Appl.; (Merck & Co., Inc., USA). WO 01062252, 2001).

Scheme 17

Summary of the Invention

Li one aspect, the invention provides a process for the preparation of a 2-substituted azaindole compound selected from the group of azaindole isomers consisting of: 5-

13

5UDGTiTUTE SHEET (RULE 26) azaindole, 6-azaindole, or 7-azaindole, wherein the 2-substituent comprises a R₄ group which is bonded to the 2-position of the azaindole ring via a C-C bond, the process comprising reacting an ort/20-ge/n-dihalovinylaminopyridine compound of the formula (II) wherein the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (II):

wherein

Halo comprises Br or Cl

R₂ comprises alkyl, cycloalkyl, aryl, heteroaryl, aryl-lower alkyl-, heteroaryl-lower alkyl-, or alkoxycarbonyl all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and

R₃ comprises H, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aryl-lower alkyl-, or heteroaryl-lower alkyl-, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents;

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R₄, a boronic acid anhydride of R₄, a trialkylborane Of R₄ and a 9-BBN derivative of R4;

in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted azaindole compound.

In another aspect, the invention provides a process for the preparation of a 2-substituted thienopyrrole compound selected from isomeric forms wherein the sulphur occupies the 4 or 6 position of the 2-substituted thienopyrrole compound, wherein the 2-substituent comprises a R₄ group which is bonded to the 2-position of the thienopyrrole ring via a

C-C bond, the process comprising reacting an ørt/zo-gew-dihalovinylthiophene compound of the formula (FV) wherein the sulphur occupies any one of the positions of the aromatic ring that are marked by an asterisk:

IV

wherein

Halo comprises Br or Cl

R₂ is alkoxycarbonyl which is optionally substituted at one or more substitutable positions with one or more suitable substituents;

with an organoboron reagent selected from the group consisting of a boronic ester OfR₄, a boronic acid of R₄, a boronic acid anhydride of R₄, a trialkylborane OfR₄ and a 9-BBN derivative OfR₄;

in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted thienopyrrole compound.

In yet another aspect, the invention provides a process for the preparation of a compound comprising within its structure a 2-substituted azaindole moiety of formula (I) selected from the group of azaindole isomers consisting of: 5-azaindole, 6-azaindole and 7- azaindole,

(I)

wherein

R₄ is selected from the group consisting of aryl, heteroaryl, 1 ° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2-position of the azaindole ring via a C-C bond;

R₂ comprises alkyl, cycloalkyl, aryl, heteroaryl, aryl-lower alkyl-, heteroaryl-lower alkyl-, or alkoxycarbonyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and

the process comprising reacting an ort/20-gem-dihalovinylaminopyridine compound of formula (II) whereby the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (II):

(H)

wherein

Halo comprises Br or Cl and R₂ and R₃ are as defined above, with an organoboron reagent selected from the group consisting of a boronic ester of R4, a boronic acid of R₄, a boronic acid anhydride of R₄, a trialkylborane Of R₄ and a 9-BBN derivative Of R₄;

in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted azaindole compound of formula (I).

In one aspect, when R₂ of formula (II) is benzyloxycarbonyl (Cbz), the Cbz group is partially or fully deprotected in situ to yield a compound of formula (I) wherein R₂ is H.

In another aspect, the invention provides a process for the preparation of a compound comprising within its structure a 2-substituted thienopyrrole moiety of formula (III) including two isomeric forms wherein the sulphur occupies the 4 or 6 position of the thienopyrrole ring:

wherein

R₂ is alkoxycarbonyl, which is optionally substituted at one or more substitutable positions with one or more suitable substituents, and

R₃ comprises H, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aryl-lower alkyl-, or heteroaryl-lower alkyl-, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents; the process comprising reacting an ørt/zo-gem-dihalovinylaminothiophene compound of formula (FV) wherein the sulphur occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (IV):

(IV)

wherein

Halo comprises Br or Cl and R₂ and R₃ are as defined above:

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R₄, a boronic acid anhydride of R₄, a trialkylborane of R₄ and a 9-BBN derivative OfR₄;

in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted thienopyrrole compound of formula (III).

In one aspect, when R₂ of formula (IV) is benzyloxycarbonyl (Cbz), the Cbz group is partially or fully deprotected in situ to yield a compound of formula (III) wherein R₂ is H.

In another aspect, the invention provides a process for the preparation of a 2-substituted azaindole compound of formula (V) including azaindole isomers selected from the group consisting of: 5-azaindole, 6-azaindole and 7-azaindole

(V)

wherein each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of formula (V); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

R₂ comprises alkyl, cycloalkyl, aryl, heteroaryl, aryl-lower alkyl-, heteroaryl-lower alkyl- or alkoxycarbonyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents,

R₃ comprises H, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aryl-lower alkyl-, or heteroaryl-lower alkyl-, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and

R₄ is selected from the group consisting of aryl, heteroaryl, 1° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2-position of the azaindole ring via a C-C bond;

the process comprising reacting an ortho-gerø-dihalovinylaminopyridine compound of formula (VI) whereby the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VI):

wherein

Halo comprises Br or Cl, and

R₂ and R₃ are as defined above, with an organoboron reagent selected from the group consisting of a boronic ester of Rj, a boronic acid of R₄, a boronic acid anhydride of R₄, a trialkylborane of R» and a 9-BBN derivative OfR₄;

in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted azaindole compound of formula (V).

In one aspect, when R₂ of formula (VI) is benzyloxycarbonyl (Cbz), the Cbz group is partially or fully deprotected in situ to yield a compound of formula (V) wherein R₂ is H.

In still another aspect, the invention provides a process for the preparation of a 2- substituted thienopyrrole compound of formula (VII) selected from isomeric forms wherein the sulphur occupies the 4 or 6 position of the 2-susbstituted thienopyrrole compound

wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the thiophene ring of formula (VII); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

R₂ is alkoxycarbonyl, which is optionally substituted at one or more substitutable positions with one or more suitable substituents,

R_t is selected from the group consisting of aryl, heteroaryl, 1° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein Rj is bonded to the 2-position of the thienopyrrole ring via a C-C bond;

the process comprising reacting an ortho-gem-dihalovinylaminothiophene compound of formula (VIII) wherein the sulphur occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VIII):

wherein

Halo comprises Br or Cl, and

R₂ and R₃ are as defined above,

with an organoboron reagent selected from the group consisting of a boronic ester of Rj, a boronic acid of R₄, a boronic acid anhydride of Rj, a trialkylborane of R» and a 9-BBN derivative of Rj;

in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted thienopyrrole compound of formula (VII).

In one aspect, when R₂ of formula (VIII) is benzyloxycarbonyl (Cbz), the Cbz group is partially or fully deprotected in situ to yield a compound of formula (VII) wherein R₂ is H. In another aspect, the invention provides, a process for the preparation of a 2-substituted azaindole compound including azaindole isomers selected from the group consisting of: 4-azaindole, 5-azaindole, 6-azaindole, or 7-azaindole, wherein the 2-substituent comprises a R₄ group which is bonded to the 2-position of the azaindole ring via a C-C bond, the process comprising reacting an ortAo-gew-dihalovinylaminopyridine N-oxide compound wherein the nitrogen occupies any one of the positions in the aromatic ring of the formula (X) that are marked with an asterisk:

wherein

Halo comprises Br or Cl,

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R», a boronic acid anhydride of R₄, a trialkylborane of R₄ and a 9-BBN derivative of R₄;

In another aspect, the invention provides a process for the preparation of a compound comprising within its structure a 2-substituted azaindole moiety of formula (IX) including azaindole isomers selected from the group consisting of: 4-azaindole, 5- azaindole, 6-azaindole and 7-azaindole,

wherein

the process comprising reacting an ort/zo-gem-dihalovinylaminopyridine N-oxide compound of formula (X) wherein the nitrogen occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (X):

(X) wherein

Halo comprises Br or Cl, and R₂ and R₃ are as defined above,

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R₄, a boronic acid anhydride of R₄, a trialkylborane of R₄ and a 9-BBN derivative of R₄;

in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted azaindole compound of formula (IX).

In one aspect, when R₂ of formula (X) is benzyloxycarbonyl (Cbz), the Cbz group is partially or fully deprotected in situ to yield a compound of formula (IX) wherein R₂ is H.

In yet another aspect of the invention, there is provided a process for the preparation of a 2-substituted azaindole compound including azaindole isomers selected from the group consisting of: 4-azaindole, 5 -azaindole, 6-azaindole, or 7-azaindole, wherein the 2- substituent comprises a R₄ group which is bonded to the 2-position of the azaindole ring via a C-C bond, the process comprising reacting an ort/20-gem-dihalovinylaminopyridine N-oxide compound wherein the nitrogen occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (XII):

wherein

Halo comprises Br or Cl

Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R₄, a boronic acid anhydride Of R₄, a trialkylborane OfR₄ and a 9-BBN derivative OfR₄;

In another aspect, the invention provides a process for the preparation of a 2-substituted azaindole compound of formula (XI) including azaindole isomers selected from the group consisting of: 4-azaindole, 5 -azaindole, 6-azaindole and 7-azaindole

(XI)

wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine N-oxide ring of formula (XI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

the process comprising reacting an ortho-gem-dihalovinylaminopyridine N-oxide compound of formula (XII) wherein the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (XII):

wherein Ri, R₂ and R₃ are as defined above,

and Halo comprises bromo or chloro;

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R», a boronic acid anhydride of R₄, a trialkylborane of R₄ and a 9-BBN derivative of R₄; in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted azaindole compound of formula (XI).

In one aspect, when R₂ of formula (XII) is benzyloxycarbonyl (Cbz), the Cbz group is partially or fully deprotected in situ to yield a compound of formula (XI) wherein R₂ is H.

In another aspect, the invention provides a process for the palladium-catalyzed tandem intramolecular C-N bond formation and intermolecular C-C bond formation between an ortho-gem-dihalovinylaminopyridine compound of formula (VI) whereby the nitrogen occupies any one of the positions of the aromatic ring marked by an asterisk in formula (VI):

wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of formula (VI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

R₃ comprises H, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aryl-lower alkyl-, or heteroaryl-lower alkyl-, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents; and

and Halo comprises chloro, or bromo;

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R₄, a boronic acid anhydride Of R₄, a trialkylborane of R₄ and a 9-BBN derivative OfR₄, and wherein R₄ is selected from the group consisting of aryl, heteroaryl,

1° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2- position of the azaindole ring via a C-C bond, for the preparation of a 2-substituted azaindole of formula (V) including the isomers: 5-azaindole, 6-azaindole and 7-azaindole

(V)

wherein Ri, R₂, R₃ and R₄ are as defined above,

the process comprising reacting the ortho-gem-dihalovinylammopyridine compound of formula (VI) with the organoboron reagent in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to afford the tandem C-N and C-C bond formation between the ortho-gem-dihalovinylaminopyridine compound of formula (VI) and the organoboron reagent to afford the 2-substituted azaindole of formula (V).

hi still another aspect of the invention, there is provided a process for the palladium- catalyzed tandem intramolecular C-N bond formation and intermolecular C-C bond formation between an ortho-gem-dihalovinylaminothiophene compound of formula (VIII) wherein the sulphur occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VIII):

wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the thiophene ring of formula (VIII); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

and Halo comprises chloro, or bromo;

with an organoboron reagent selected from the group consisting of a boronic ester of R», a boronic acid of R₄, a boronic acid anhydride Of R₄, a trialkylborane of Rj and a 9-BBN derivative of R₄, and wherein R₄ is selected from the group consisting of aryl, heteroaryl, 1 ° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2- position of the thienopyrrole ring via a C-C bond, for the preparation of a 2-substituted thienopyrrole of formula (VII) including isomeric forms wherein the sulphur occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VII):

(VII)

wherein Ri, R₂, R₃ and R₄ are as defined above,

the process comprising reacting the ortho-gem-dihalovinylaminothiophene compound of formula (VIII) with the organoboron reagent in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to afford the tandem C-N and C-C bond formation between the ortho-gem-dihalovinylaminothiophene compound of formula (VIII) and the organoboron reagent to afford the 2-substituted thienopyrrole of formula (VII).

In one aspect, when R₂ of formula (VIII) is benzyloxycarbonyl (Cbz), the Cbz group is partially or fully deprotected in situ to yield a compound of formula (VII) wherein R₂ is H.

In another aspect of the invention, there is provided a process for the palladium-catalyzed tandem intramolecular C-N bond formation and intermolecular C-C bond formation between an ortho-gem-dihalovinylaminopyridine N-oxide compound of formula (XII) including isomers wherein the N-oxide occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (XII):

wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, lower alkenyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine N-oxide ring of formula (XII); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

and Halo comprises chloro, or bromo;

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R₄, a boronic acid anhydride of R₄, a trialkylborane of R₄ and a 9-BBN derivative OfR₄, and wherein R₄ is selected from the group consisting of aryl, heteroaryl, 1 ° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2- position of the azaindole ring via a C-C bond, for the preparation of a 2-substituted azaindole of formula (XI) comprising isomeric forms wherein the N-oxide occupies any one of the A-, 5-, 6-, or 7-positions in formula (XI):

wherein Ri, R₂, R₃ and R₄ are defined as above,

the process comprising reacting the ortho-gerø-dihalovinylaminopyridine N-oxide compound of formula (XII) with the organoboron reagent in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to afford the tandem C-N and C-C bond formation between the ortho-gem- dihalovinylaminopyridine N-oxide compound of formula (XII) and the organoboron reagent to afford the 2-substituted azaindole of formula (XI).

In one aspect, when R₂ of formula (XII) is benzyloxycarbonyl (Cbz), the Cbz group is 5 partially or fully deprotected in situ to yield a compound of formula (XI) wherein R₂ is H.

In another aspect, the invention provides a process for the preparation of an ortho-gem- dihalogen vinylaminopyridine compound of formula (VI) wherein the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula 10 (VI):

wherein each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O- lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 15 20-membered fused monocycle or polycyclic ring with the pyridine ring of Formula (VI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₃ is H, CF₃, or alkynyl optionally substituted at one or more positions with one or more suitable substituents, R₂ is H and Halo is bromo, said process comprising the steps of:

20 (a) reacting a nitropyridinecarboxaldehyde or ketone compound of formula (XIV) where the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (XIV):

(XIV)

wherein Ri is as defined above, and R₃ is as defined above, with CBr₄ and PPh₃ under conditions effective to generate in situ the ortho-gem-diha\oγiny\ compound of formula (XV)

(XV)

wherein Ri is as defined above, R₃ is as defined above, and Halo is bromo and the nitrogen occupies any one of the positions of the pyridine ring marked by an asterisk in formula (XV); and

(b) reducing the compound of formula (XV) under conditions effective to reduce the nitro group of the compound of formula (XV) without affecting the functional groups present in the compound, to afford the compound of formula (VI).

In another aspect of the invention, there is provided a process for the preparation of an ortho~gem-diha\ogen vinylaminopyridine compound of formula (XVI), wherein the nitrogen occupies any one of the positions of the aromatic ring that are marked with an asterisk in formula (XVI):

wherein each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O- lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of Formula (XVI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₃ is H, CF₃ or alkynyl, optionally substituted at one or more positions with one or more suitable substituents; R₂ is H, alkoxycarbonyl, alkyl, aryl or aryl-lower alkyl; R₅ is H, alkyl or alkoxycarbonyl, with the proviso that both R₂ and R₅ are not H; and Halo is bromo, said process comprising the steps of:

reacting an aminopyridinecarboxaldehyde or ketone compound of formula (XVII) wherein the nitrogen occupies any one of the positions of the aromatic ring that are marked with an asterisk in formula (XVII):

(XVII)

wherein Ri, R₂, R₃ and R₅ are as defined above, with CBr₄ and PPh₃ under conditions effective to generate in situ the

compound of formula (XVI) wherein the nitrogen occupies any one of the positions of the pyridine ring that are marked by an asterisk in formula (XVI):

wherein Ri, R₂, R₃ and R₅ are as defined above, and Halo is bromo. In another aspect, the invention provides a process for the preparation of an ortho-gem- dihalovinylaminothiophene compound of formula (VIII) wherein the sulphur occupies any one of the positions in the thiophene ring that are marked by an asterisk in formula (VIII):

wherein each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O- lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the thiophene ring of Formula (VIII); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₃ is H, CF_3> or alkynyl, optionally substituted at one or more positions with one or more suitable substituents; R₂ is alkoxycarbonyl, optionally substituted at one or more positions with one or more suitable substituents, and Halo is bromo, said process comprising the steps of:

reacting a aminothiophenecarboxaldehyde or ketone compound of formula (XIX) wherein the sulphur occupies any one of the positions in the thiophene ring that are marked by an asterisk in formula (XIX):

wherein Ri, R₂, and R₃ are as defined above, with CBr₄ and PPh₃ under conditions effective to generate in situ the ortho-gem-άihύovmy\ compound of formula (VIII) wherein the sulphur occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VIII):

wherein Ri, R₂, and R₃ are as defined above, and Halo is bromo.

In another aspect of the invention, there is provided a process for the preparation of an ort/zo-gem-dihalovinylaminopyridine compound of formula (XVI) wherein the nitrogen occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (XVI): .

(XVI)

wherein each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O- lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of Formula (XVI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₂ is H, alkyl, aryl, aryl-lower alkyl-, or alkoxycarbonyl, all of which are optionally substituted with one or more suitable substituents; R₅ is H, alkyl, aryl, aryl-lower alkyl-, or alkoxycarbonyl, all of which are optionally substituted with one or more suitable substituents, with the proviso that both R₂ and R₅ are not H; and R₃ is H, alkyl or alkynyl, all of which are optionally substituted at one or more positions with one or more suitable substituents, and Halo is chloro, said process comprising the steps of:

reacting a pyridinecarboxaldehyde or ketone compound of formula (XVII) where the nitrogen occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (XVII):

wherein Ri, R₂, R₃ and R₅ are as defined above, with 2 or more equivalents of CHCl₃ and PPh₃ in the presence of 2 or more equivalents of KO'Bu, wherein said equivalents are relative to formula (XVII), under conditions effective to generate in situ the ortho-gem- dichloro vinyl compound of formula (XVI), wherein the nitrogen occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (XVI):

(XVI)

wherein Ri, R₂, R₃ and R₅ are as defined above and Halo is chloro.

In another aspect, the invention provides a process for the preparation of an ortho-gem- dihalovinylaminothiophene compound of formula (VIII) wherein the sulphur occupies any one of the positions in the thiophene ring that are marked by an asterisk in formula (VIII):

wherein each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O- lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the thiophene ring of Formula

(VIII); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₂ is alkoxycarbonyl optionally substituted at one or more positions with one or more suitable substituents, and R₃ is H, alkyl, or alkynyl all of which are optionally substituted at one or more positions with one or more suitable substituents, and Halo is chloro, said process comprising the steps of:

reacting an aminothiophenecarboxaldehyde or ketone compound of formula (XIX) wherein the sulphur occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (XIX):

wherein Ri, R₂, and R₃ are as defined above, with 2 or more equivalents of CHCl₃ and PPh₃ in the presence of 2 or more equivalents of KO'Bu, wherein said equivalents are relative to formula (XIX), under conditions effective to generate in situ the ortho-gem- dichloro vinyl compound of formula (VIII). In another aspect, the invention also provides novel 2-substituted azaindoles or salts thereof selected from the group consisting of:

Also contained within the invention are the novel 2-substituted azaindoles and their salts when prepared by a process of the present invention.

In another aspect, the invention also provides novel 2-substituted thienopyrroles or salts thereof selected from the group consisting of:

Also contained within the invention are the novel 2-substituted thienopyrroles and their salts when prepared by a process of the present invention.

In another aspect, the invention also provides novel ort/zø-gem-dihalovinylaminopyridine compounds or salts thereof selected from the group consisting of:

In another aspect, the invention provides novel ort/zø-gem-dihalovinylaminothiophene compounds or salts thereof selected from the group consisting of:

Novel ortλø-gem-dihalovinylaminopyridine compounds and novel ortho-gem- dihalovinylaminothiophene compounds when prepared by a process of the present invention are likewise encompassed within the present invention. Such compounds are useful in the preparation of 2-substituted azaindoles and 2-substituted thienopyrroles as described herein.

In another aspect, the invention provides a process for the preparation of N- arylaminopyridine compounds of formula (VI) where the nitrogen occupies any one of the positions in the pyridine ring that are marked by an asterisk in formula (VI):

(VI)

wherein Halo comprises Br or Cl; R₂ comprises aryl which is optionally substituted at one or more substitutable positions with one or more suitable substituents; R₃ comprises H, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aryl-lower alkyl-, or heteroaryl-lower alkyl-, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents; and each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of Formula (VI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; said process comprising the steps of: reacting a compound of formula (XIII) wherein the nitrogen occupies any one of the positions marked by an asterisk in formula (XIII):

wherein Halo, R₁, R₃ are as defined above, with an organoboron reagent comprising a

5 boronic acid, boronic acid anhydride or BF₃ ^" salt of R₂, wherein R₂ is as defined above, in the presence of at least about 1.5 equivalent of a copper (II) catalyst relative to the compound of formula (VI), at least about 0.3 equivalents of a C₈-C₂₀ fatty acid relative to the compound of formula (VI), molecular oxygen, and a non-nucleophlic base, at a reaction temperature of between about 40 ⁰C and 60 ⁰C, under conditions effective to

10 form a C-N bond between formula (VI) and the R₂ group of the organoboron reagent, to afford the N-arylaniline compounds of formula (VI).

In yet another aspect of the invention, there is provided a process for the deprotection of the N-alkoxycarbonyl azaindoles of formula (V) where the nitrogen occupies any one of the positions of the pyridine ring marked by an asterisk in formula (V):

15 (V)

.wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to

20 20-membered fused monocycle or polycyclic ring with the pyridine ring; all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

R₂ comprises alkoxycarbonyl, which is optionally substituted at one or more substitutable positions with one or more suitable substituents,

the process comprising treating a compound of formula (V) with an acid to form the N-H azaindole wherein R₂ is H and Ri, R₃ and R₄ are as defined above for compound (V).

In another aspect, the invention provides a process for the deprotection of the N- alkoxycarbonyl thienopyrrole compounds of formula (VII) where the sulphur occupies the 4 or 6 position of the aromatic ring:

(VII)

wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the thiophene ring; all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

R₄ is selected from the group consisting of aryl, heteroaryl, 1° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents,

the process comprising treating a compound of formula (VII) with a base to form the N- H thienopyrrole wherein R₂ is H and Ri, R₃ and R₄ are as defined above for compound (VII).

In another aspect of the invention, there is provided a process for the removal of the N- oxide from a compound of formula (XI) wherein the nitrogen occupies any one of the A-, 5-, 6-, or 7- positions in formula (XI):

wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine N-oxide ring; all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

R₂ comprises H, alkyl, cycloalkyl, aryl, heteroaryl, aryl-lower alkyl-, or heteroaryl-lower alkyl- or alkoxycarbonyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents

the process comprising treating the N-oxide of formula (XI) with a reducing agent to form the reduced compound of formula (V) wherein Ri, R₂, R₃ and R» are as defined above for compound (XI) and wherein the nitrogen occupies any one of the A-, 5-, 6-, or 7- positions in formula (V).

(V)

In another aspect, the invention provides a process for the preparation of the Smad3 inhibitor SIS3 of formula (XX):

the process consisting of a Heck coupling reaction between the 3-iodoazaindole of formula (XXI) and the acrylamide of formula (XXII) in the presence of a palladium metal pre-catalyst, base and ligand:

In still another aspect, the invention provides a process for the preparation of the azaindole of formula (XXIII):

wherein R₂ is alkyl and R₄ is aryl or alkenyl, the process comprising reacting a gem-dihalovinylaminopyridine of formula (XXIV):

(XXIV) where R₂ is as defined above and Halo comprises of Br or Cl, with a boronic acid of the formula (HO)₂B-aryl or (HO)₂B-alkenyl, in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the azaindole compound.

In another aspect, the invention provides a process for the preparation of the azaindole of formula (XXV):

where R₂ comprises alkyl, cycloalkyl, heteroaryl, aryl-lower alkyl-, aryl, heteroaryl- lower alkyl- or alkoxycarbonyl all of which are optionally substituted at one or more substitutable positions, and Re comprises lower alkyl; the process comprising reacting the gem-dihalovinylaminopyridine of formula (XXVI):

(XXVI) where R₂ is as defined above, and Halo comprises Br or Cl, with a boronic acid of formula (XXVII):

(XXVII) where R^ is as defined above, in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the azaindole of formula (XXV).

In another aspect, the invention provides a process for the preparation of an ortho-gem- dihalovinylaminopyridine compound of formula (VI) wherein the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VI):

(VI)

wherein each of the one or more Ri substituents is independently selected from the group consisting of H, fluoro, loweralkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of Formula (VI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₂ is H, R₃ is H, alkyl, or alkynyl optionally substituted at one or more positions with one or more suitable substituents, and Halo comprises chloro, said process comprising the steps of: (a) reacting a nitropyridinecarboxaldehyde or ketone compound of formula (XIV) where the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (XIV)

wherein Ri and R₃ are as defined above for formula (VI), with 2 or more equivalents of CHCl₃ and PPh₃ in the presence of 2 or more equivalents of KO'Bu under conditions effective to generate in situ the ort/zo-gem-dichlorovinyl compound of formula (XV)

wherein Ri, R₃ and Halo are as defined above; and (b) reducing the compound of formula (XV) under conditions effective to reduce the nitro group of the compound of formula (XV), without affecting the functional groups present in the compound, to afford the compound of formula (VI).

Detailed Description of Embodiments

The present invention provides novel, versatile and efficient processes and conditions for the palladium-catalyzed chemical synthesis of a variety of 2-substituted azaindole and thienopyrrole compounds, including 1 ,2-disubstituted, and 1,2,3-trisubstituted azaindoles and 1 ,2-disubstituted thienopyrroles, from inexpensive starting materials that can be easily prepared in large quantities. Moreover, the palladium metal pre-catalyst loadings useful in the present invention are low, in some embodiments about 3%, and the processes typically afford yields of 2-substituted azaindoles and 2-substituted thienopyrroles in about the 70-90% range. The novel process can allow for the rapid access and the ease of production of diversified azaindoles and thienopyrroles, and their analogs and their derivatives.

The processes of the present invention further provide reaction conditions, and starting materials which are precursors for the preparation of 2-substituted azaindoles and 2- substituted thienopyrroles, as well as novel processes and conditions for the preparation of the precursor materials.

The present invention further provides a highly modular method for palladium-catalyzed tandem carbon-nitrogen/carbon-carbon bond formation between an ort/zo-gemdihalogen substituted vinylaminopyridine compound with an organoboron reagent in the presence of a palladium metal pre-catalyst and a ligand to afford 2-substituted azaindole compounds.

The present invention further provides a highly modular method for palladium-catalyzed tandem carbon-nitrogen/carbon-carbon bond formation between an ort/zø-gemdihalogen substituted vinylaminothiophene compound with an organoboron reagent in the presence of a palladium metal pre-catalyst and a ligand to afford 2-substituted thienopyrrole compounds. The present invention also provides novel 2-substituted azaindole compounds prepared by the novel processes of the present invention as well as novel ortho-gem- dihalovinylaminopyridine derivatives for the production of 2-substituted azaindoles.

The present invention also provides novel 2-substituted thienopyrrole compounds prepared by the novel processes of the present invention as well as novel ortho-gem- dihalovinylaminothiophene derivatives for the production of 2-substituted thienopyrroles.

The present invention further provides novel methods for the copper-mediated C-N coupling of anilines and arylboronic acids to prepare N-aryl-ortho-gem- dihalovinylaniline compounds that are useful as intermediates in the processes of the present invention for the preparation of 2-substituted indoles.

The present invention further provides novel methods for the preparation of ortho-gem- dihalovinylaminopyridine compounds as intermediates in the processes of the present invention for the preparation of 2-substituted azaindoles.

The present invention further provides novel methods for the preparation of ortho-gem- dihalovinylaminothiophene compounds as intermediates in the processes of the present invention for the preparation of 2-substituted thienopyrroles.

The present invention further provides a novel method for the synthesis of the 2,3- disubstitued azaindole, an Smad3 inhibitor SIS3, which can be used for the treatment of sclerosis or scleroderma.

The present invention provides methods for the synthesis of gem- dihalovinylaminopyridine N-oxides from the corresponding gem- dihalovinylaminopyridine.

The present invention also provides methods for the deprotection of an N-oxide group from an azaindole N-oxide to give the azaindole.

The present invention provides methods for the removal of an alkoxycarbonyl group from an N-alkoxycarbonyl substituted azaindole to give N-H azaindoles. The present invention further provides a novel method for the synthesis of the KDR kinase inhibitor 3-(lH-pyrrolo[2,3-c]pyridine-2-yl)-lH-quinolin-2-one which is potentially useful for the treatment of cancer.

Therefore, in one embodiment, the invention provides a process for the preparation of a 2-substituted azaindole compound selected from the group of azaindole isomers consisting of: 5 -azaindole, 6-azaindole, or 7-azaindole, wherein the 2-substituent comprises a R₄ group which is bonded to the 2-position of the azaindole ring via a C-C bond, the process comprising reacting an or/Λo-gem-dihalovinylaminopyridine compound of the formula (II) wherein the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (II):

wherein

Halo comprises Br or Cl

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R₄, a boronic acid anhydride of R4, a trialkylborane of R₄ and a 9-BBN derivative of R₄;

in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted azaindole compound. In another embodiment, the invention provides a process for the preparation of a 2- substituted thienopyrrole compound selected from isomeric forms wherein the sulphur occupies the 4 or 6 position of the 2-substituted thienopyrrole compound, wherein the 2- substituent comprises a R₄ group which is bonded to the 2-position of the thienopyrrole ring via a C-C bond, the process comprising reacting an ørt/zø-gerø-dihalovinylthiophene compound of the formula (IV) wherein the sulphur occupies any one of the positions of the aromatic ring that are marked by an asterisk:

IV

wherein

Halo comprises Br or Cl

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R₄, a boronic acid anhydride Of R₄, a trialkylborane of R_t and a 9-BBN derivative of R₄;

In another embodiment, the invention provides a process for the preparation of a compound comprising within its structure a 2-substituted azaindole moiety of formula (I) selected from the group of azaindole isomers consisting of: 5-azaindole, 6-azaindole and 7-azaindole,

(i)

wherein

Rj is selected from the group consisting of aryl, heteroaryl, 1 ° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2-position of the azaindole ring via a C-C bond;

R.₂ comprises alkyl, cycloalkyl, aryl, heteroaryl, aryl-lower alkyl-, heteroaryl-lower alkyl-, or alkoxycarbonyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and

(H)

wherein Halo comprises Br or Cl and R₂ and R₃ are as defined above,

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R₄, a boronic acid anhydride of R», a trialkylborane of R4 and a 9-BBN derivative of R₄;

In yet another embodiment, the invention provides a process for the preparation of a compound comprising within its structure a 2-substituted thienopyrrole moiety of formula (III) including two isomeric forms wherein the sulphur occupies the 4 or 6 position of the thienopyrrole ring:

wherein

R₃ comprises H, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aryl-lower alkyl-, or heteroaryl-lower alkyl-, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents; the process comprising reacting an ort/20-gem-dihalovinylaminothiophene compound of formula (IV) wherein the sulphur occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (IV):

(IV)

wherein

Halo comprises Br or Cl and R₂ and R₃ are as defined above:

In another embodiment, the invention provides a process for the preparation of a 2- substituted azaindole compound including azaindole isomers selected from the group consisting of: 4-azaindole, 5 -azaindole, 6-azaindole, or 7-azaindole, wherein the 2- substituent comprises a R₄ group which is bonded to the 2-position of the azaindole ring via a C-C bond, the process comprising reacting an ortΛo-gem-dihalovinylaminopyridine N-oxide compound wherein the nitrogen occupies any one of the positions in the aromatic ring of the formula (X) that are marked with an asterisk:

(X)

wherein

Halo comprises Br or Cl,

with an organoboron reagent selected from the group consisting of a boronic ester OfR₄, a boronic acid of R4, a boronic acid anhydride of R₄, a trialkylborane of R» and a 9-BBN derivative of R₄;

In yet another embodiment, the invention provides a process for the preparation of a compound comprising within its structure a 2-substituted azaindole moiety of formula (IX) including azaindole isomers selected from the group consisting of: 4-azaindole, 5- azaindole, 6-azaindole and 7-azaindole,

(IX) wherein

R» is selected from the group consisting of aryl, heteroaryl, 1° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2-position of the azaindole ring via a C-C bond;

the process comprising reacting an ørt/20-gem-dihalovinylaminopyridine N-oxide compound of formula (X) wherein the nitrogen occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (X):

wherein

Halo comprises Br or Cl, and R₂ and R₃ are as defined above,

with an organoboron reagent selected from the group consisting of a boronic ester of R», a boronic acid Of R₄, a boronic acid anhydride of R₄, a trialkylborane of R₄ and a 9-BBN derivative OfR₄;

in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted azaindole compound of formula (IX). In one aspect, when R₂ of formula (X) is benzyloxycarbonyl (Cbz), the Cbz group is partially or fully deprotected in situ to yield a compound of formula (IX) wherein R₂ is H.

As used in the context of the present invention, the various chemical terms are to be given their ordinary meaning as would be understood by persons skilled in the art, unless provided otherwise.

The following chemical terms presently described apply to all compounds and processes disclosed herein, unless provided otherwise.

The term "suitable substituent" as used in the context of the present invention is meant to include independently H; hydroxyl; cyano; alkyl, such as lower alkyl, such as methyl, ethyl, propyl, n-butyl, t-butyl, hexyl and the like; alkoxy, such as lower alkoxy such as methoxy, ethoxy, and the like; aryloxy, such as phenoxy and the like; vinyl; alkenyl, such as hexenyl and the like; alkynyl; formyl; haloalkyl, such as lower haloalkyl which includes CF₃, CCl₃ and the like; halide; aryl, such as phenyl and napthyl; heteroaryl, such as thienyl and furanyl and the like; amide such as C(O)N(CH₃ )₂ and the like; acyl, such as C(O)-C₆H₅, and the like; ester such as -C(O)OCH₃ the like; ethers and thioethers, such as O-Bn and the like; amino; thioalkoxy; phosphino and the like. It is to be understood that a suitable substituent as used in the context of the present invention is meant to denote a substituent that does not interfere with the formation of the desired product by the claimed processes of the present invention.

As used in the context of the present invention, the term "lower alkyl" as used herein either alone or in combination with another substituent means acyclic, straight or branched chain alkyl substituent containing from one to six carbons and includes for example, methyl, ethyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, and the like. A similar use of the term is to be understood for "lower alkoxy", "lower thioalkyl", "lower alkenyl" and the like in respect of the number of carbon atoms. For example, "lower alkoxy" as used herein includes methoxy, ethoxy, t-butoxy.

The term "alkyl" encompasses lower alkyl and also includes acyclic, straight or branched chain alkyl groups having more than 6 carbons atoms, such as, for example, acyclic straight or branched chain alkyl substituents having 7-10 carbon atoms. The term "haloalkyl" represents straight chain or branched chain alkyl, of which at least one hydrogen is substituted with halogen.

The terms "1° alkyl", "2° alkyl", and "3° alkyl" are generally understood by a person of skill in the art to mean an alkyl substituent wherein the carbon atom at the point of attachment is bonded to 1, 2, and 3 other carbon atoms, respectively.

The term "aryl" as used herein, either alone or in combination with another substituent, means an aromatic monocyclic system containing 6 carbon atoms or a polycyclic aromatic system, such as an aromatic bicyclic system containing 10 carbon atoms. For example, the term "aryl" includes a phenyl or a naphthyl ring.

The term "heteroaryl" as used herein, either alone or in combination with another substituent means a 5, 6, or 7-membered unsaturated heterocycle containing from one to 4 heteroatoms selected from nitrogen, oxygen, and sulphur and which form an aromatic system. The term "heteroaryl" also includes a polycyclic aromatic system comprising a 5, 6, or 7-membered unsaturated heterocycle containing from one to 4 heteroatoms selected from nitrogen, oxygen, and sulphur.

The term "cycloalkyl" as used herein, either alone or in combination with another substituent, means a cycloalkyl substituent that includes for example, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "cycloalkyl-alkyl-" as used herein means an alkyl radical to which a cycloalkyl radical is directly linked; and includes, but is not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopentylethyl, 2-cyclopentyl ethyl, cyclohexylmethyl, 1-cyclohexylethyl and 2-cyclohexylethyl. A similar use of the

"alkyl" term is to be understood for aryl-alkyl-, heteroaryl-alkyl-, and the like as used herein. For example, the term "aryl-alkyl-" means an alkyl radical, to which an aryl is bonded. Examples of aryl-alkyl- include, but are not limited to, benzyl (phenylmethyl),

1 -phenyl ethyl, 2-phenylethyl and phenylpropyl.

As used herein, the term "heterocycle", either alone or in combination with another radical, means a monovalent radical derived by removal of a hydrogen from a three- to seven-membered saturated or unsaturated (including aromatic) heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur. Examples of such heterocycles include, but are not limited to, azetidine, pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, thiophene, hydantoin, diazepine, imidazole, isoxazole, thiazole, tetrazole, piperidine, piperazine, homopiperidine, homopiperazine, 1,4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine, pyridine-N-oxide or pyrimidine, and the like.

The term "alkenyl", as used herein, either alone or in combination with another radical, encompasses "lower alkenyl" and is intended to mean an unsaturated, acyclic straight chain radical containing two or more carbon atoms, at least two of which are bonded to each other by a double bond. Examples of such radicals include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl, and 1-butenyl.

The term "alkynyl", as used herein encompasses "lower alkynyl" and is intended to mean an unsaturated, acyclic straight chain radical containing two or more carbon atoms, at least two of which are bonded to each other by a triple bond. Examples of such radicals include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

The term "alkoxy" as used herein, either alone or in combination with another radical, means the radical -O-(C_1-n)alkyl wherein alkyl is as defined above containing 1 or more carbon atoms, and includes for example methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy and 1,1-dimethylethoxy. Where n is 1 to 6, the term "lower alkoxy" applies, as noted above, whereas the term "alkoxy" encompasses "lower alkoxy" as well as alkoxy groups where n is greater than 6 (for example, n = 7 to 10). The term "aryloxy" as used herein alone or in combination with another radical means -O-aryl, wherein aryl is defined as noted above.

The term "alkoxycarbonyl" as used herein means the radical -C(O)OR wherein R is alkyl (such as t-butyl) or aryl-lower alkyl- (such as benzyl).

The term "lower alkylcarbonyl" as used herein means the radical -C(O)R wherein R is lower alkyl.

As used herein the term "heteroatom" means O, S or N.

Depending on the substitution on the starting material

aminopyridine compound and the organoboron reagent used in the processes of the present invention, the 2-substituted azaindole compound may bear additional substituents at various position of the azaindole ring, and it is to be understood that, in the context of the present invention, the term 2-substituted azaindoles is meant to include azaindoles that may include additional substituents at other positions in the structure. For example, in one embodiment, the present invention provides 2-substituted azaindoles that also have a substituent at the 3 -position of the azaindole ring. In another embodiment, the present invention provides 2-substituted azaindoles that also bear a substituent at the 1- position of the azaindole ring. In one embodiment, the 2-substituted azaindoles additionally contain a substituent designated Ri. In another embodiment, the invention provides a process for the preparation of a 2-substituted azaindole compound of formula (V) including azaindole isomers selected from the group consisting of: 5-azaindole, 6- azaindole and 7-azaindole

wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of formula (V); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

the process comprising reacting an ortho-gem-dihalovinylaminopyridine compound of formula (VI) whereby the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VI):

wherein

Halo comprises Br or Cl, and

R₂ and R₃ are as defined above,

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R₄, a boronic acid anhydride of R», a trialkylborane of R₄ and a 9-BBN derivative of R4;

In another embodiment, the invention provides a process for the palladium-catalyzed tandem intramolecular C-N bond formation and intermolecular C-C bond formation between an ortho-gem-dihalovinylaminopyridine compound of formula (VI) whereby the nitrogen occupies any one of the positions of the aromatic ring marked by an asterisk in formula (VI):

wherein

each of the one or more R₁ is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of formula (VI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

and Halo comprises chloro, or bromo;

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R₄, a boronic acid anhydride of R₄, a trialkylborane OfR₄ and a 9-BBN derivative OfR₄, and wherein R₄ is selected from the group consisting of aryl, heteroaryl, 1° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2- position of the azaindole ring via a C-C bond, for the preparation of a 2-substituted azaindole of formula (V) including the isomers: 5-azaindole, 6-azaindole and 7-azaindole

(V)

wherein Ri, R₂, R₃ and R4 are as defined above,

the process comprising reacting the ortho-gem-dihalovinylaminopyridine compound of formula (VI) with the organoboron reagent in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to afford the tandem C-N and C-C bond formation between the ortho-ge/w-dihalovinylaminopyridine compound of formula (VI) and the organoboron reagent to afford the 2-substituted azaindole of formula (V).

Depending on the substitution on the starting material ort/zo-gem-dihalovinyl aminopyridine N-oxide compound and the organoboron reagent used in the processes of the present invention, the 2-substituted azaindole N-oxide compound may bear additional substituents at various position of the azaindole ring, and it is to be understood that, in the context of the present invention, the term 2-substituted azaindoles is meant to include azaindoles that may include additional substituents at other positions in the structure. In one embodiment, the 2-substituted azaindoles additionally contain a substituent at the 1- position of the azaindole ring. In one embodiment, the 2-substituted azaindole N-oxides additionally contain a substituent designated Rj. hi another embodiment, the invention provides a process for the preparation of a 2-substituted azaindole compound including azaindole isomers selected from the group consisting of: 4-azaindole, 5-azaindole, 6- azaindole, or 7-azaindole, wherein the 2-substituent comprises a R₄ group which is bonded to the 2-position of the azaindole ring via a C-C bond, the process comprising reacting an ortΛo-gem-dihalovinylaminopyridine N-oxide compound wherein the nitrogen occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (XII):

wherein

Halo comprises Br or Cl

Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine N-oxide ring of formula (XII); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

R3 comprises H, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aryl-lower alkyl-, or heteroaryl-lower alkyl-, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents;

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R4, a boronic acid anhydride of R₄, a trialkylborane of R₄ and a 9-BBN derivative of R₄;

in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted azaindole compound. In another embodiment, the invention provides a process for the preparation of a 2- substituted azaindole compound of formula (XI) including azaindole isomers selected from the group consisting of: 4-azaindole, 5-azaindole, 6-azaindole and 7-azaindole

wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine N-oxide ring of formula (XI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

R4 is selected from the group consisting of aryl, heteroaryl, 1° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2-position of the azaindole ring via a C-C bond;

wherein Ri, R₂ and R₃ are as defined above,

and Halo comprises bromo or chloro;

in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted azaindole compound of formula (XI).

In still another embodiment, the invention provides a process for the palladium-catalyzed tandem intramolecular C-N bond formation and intermolecular C-C bond formation between an ortho-gem-dihalovinylaminopyridine N-oxide compound of formula (XII) including isomers wherein the N-oxide occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (XII):

wherein each of the one or more R₁ is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine N-oxide ring of formula (XII); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

and Halo comprises chloro, or bromo;

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid Of R₄, a boronic acid anhydride of Rj, a trialkylborane of Rj and a 9-BBN derivative of R₄, and wherein R₄ is selected from the group consisting of aryl, heteroaryl, 1° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2- position of the azaindole ring via a C-C bond, for the preparation of a 2-substituted azaindole of formula (XI) comprising isomeric forms wherein the N-oxide occupies any one of the A-, 5-, 6-, or 7-positions in formula (XI):

(XI)

wherein Ri, R₂, R₃ and R₄ are defined as above, the process comprising reacting the ortho-ge/M-dihalovinylaminopyridine N-oxide compound of formula (XII) with the organoboron reagent in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to afford the tandem C-N and C-C bond formation between the ortho-gem- dihalovinylaminopyridine N-oxide compound of formula (XII) and the organoboron reagent to afford the 2-substituted azaindole of formula (XI).

Depending on the substitution on the starting material ort/jo-ge/w-dihalovinyl aminothiophene compound and the organoboron reagent used in the processes of the present invention, the 2-substituted thienopyrrole compound may bear additional substituents at various position of the thienopyrrole ring, and it is to be understood that, in the context of the present invention, the term 2-substituted thienopyrroles is meant to include thienopyrroles that may include additional substituents at other positions in the structure. In one embodiment, the 2-substituted thienopyrroles additionally contain a substituent 1- position of the thienopyrrole ring. In one embodiment, the 2-substituted thienopyrroles additionally contain a substituent designated Ri. hi another embodiment, the invention provides a process for the preparation of a 2-substituted thienopyrrole compound of formula (VII) selected from isomeric forms wherein the sulphur occupies the 4 or 6 position of the 2-substituted thienopyrrole compound

wherein

R₄ is selected from the group consisting of aryl, heteroaryl, 1° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2-position of the thienopyrrole ring via a C-C bond;

wherein

Halo comprises Br or Cl, and

R₂ and R₃ are as defined above,

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid Of R₄, a boronic acid anhydride of R₄, a trialkylborane of R₄ and a 9-BBN derivative OfR₄; in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted thienopyrrole compound of formula (VII).

In another embodiment, the invention provides a process for the palladium-catalyzed tandem intramolecular C-N bond formation and intermolecular C-C bond formation between an ortho-gem-dihalovinylaminothiophene compound of formula (VIII) wherein the sulphur occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VIII):

wherein

each of the one or more R₁ is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the thiophene ring of formula (VIII); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

R₃ comprises H, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aryl-lower alkyl-, or heteroaryl-lower alkyl-, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents; and and Halo comprises chloro, or bromo;

with an organoboron reagent selected from the group consisting of a boronic ester of R4, a boronic acid Of R₄, a boronic acid anhydride Of R₄, a trialkylborane Of R₄ and a 9-BBN derivative OfR₄, and wherein R₄ is selected from the group consisting of aryl, heteroaryl, 1° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2- position of the thienopyrrole ring via a C-C bond, for the preparation of a 2-substituted thienopyrrole of formula (VII) including isomeric forms wherein the sulphur occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VII):

(VII)

wherein Rj, R₂, R₃ and R₄ are as defined above,

the process comprising reacting the ortho-ge/w-dihalovinylaminothiophene compound of formula (VIII) with the organoboron reagent in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to afford the tandem C-N and C-C bond formation between the ortho-gerø-dihalovinylaminothiophene compound of formula (VIII) and the organoboron reagent to afford the 2-substituted thienopyrrole of formula (VII).

In one embodiment of the novel processes, halo of the ortho-gem- dihalovinylaminopyridine starting material of formula (II) or formula (VI) comprises bromo or chloro. In another embodiment, halo of the ort/20-gew-dihalovinylaniline compound of formula (II) or formula (VI) comprises chloro. In other preferred embodiments, R₂ comprises alkoxycarbonyl, or benzyl which is optionally substituted at one or more substitutable positions with one or more suitable substituents; or aryl which is optionally substituted at one or more substitutable positions with one or more suitable substituents, for example optionally substituted phenyl; or R₂ comprises alkyl such as methyl or ethyl, or the like.

In one embodiment of the novel processes, halo of the ort/*o-gem-dihalovinylthiophene starting material of formula (FV) or formula (VIII) comprises bromo or chloro. In another embodiment, halo of the ortAo-gem-dihalovinylaminothiophene compound of formula (IV) or formula (VIII) comprises chloro. In other preferred embodiments, R₂ comprises alkoxycarbonyl, which is optionally substituted at one or more substitutable positions with one or more suitable substituents.

In another preferred embodiment, R₂ comprises alkoxycarbonyl and Halo of the ortho- gem-dihalovinylaminopyridine starting material of formula (II) or formula (VI) comprises chloro.

In another preferred embodiment, R₂ comprises alkyl and Halo of the ortho-gem- dihalovinylaminopyridine starting material of formula (II) or formula (VI) comprises chloro.

In another preferred embodiment, R₂ comprises benzyl and Halo of the ortho-gem- dihalovinylaminopyridine starting material of formula (II) or formula (VI) comprises chloro.

In another preferred embodiment, R₂ comprises alkoxycarbonyl and Halo of the ortho- gew-dihalovinylaminothiophene starting material of formula (IV) or formula (VIII) comprises chloro.

In one embodiment of the novel processes, halo of the ortho-gem- dihalovinylaminopyridine N-oxide starting material of formula (X) or formula (XII) comprises bromo or chloro. In another embodiment, halo of the ortho-gem- dihalovinylaminopyridine N-oxide compound of formula (X) or formula (XII) comprises chloro. In other preferred embodiments, R₂ comprises alkoxycarbonyl, or benzyl which is optionally substituted at one or more substitutable positions with one or more suitable substituents; or aryl which is optionally substituted at one or more substitutable positions with one or more suitable substituents, for example optionally substituted phenyl; or R₂ comprises alkyl such as methyl or ethyl, or the like.

In another preferred embodiment, R₂ comprises alkoxycarbonyl and Halo of the ortho- ge/w-dihalovinylaminopyridine N-oxide starting material of formula (X) or formula (XII) comprises chloro.

Methods for preparing ortΛo-gem-dihalovinylaminopyridine compounds or ortho-gem- dihalovinylaminothiophene compounds are known to those skilled in the art. Alternatively, the ortho-gem-dihalovinylaniline compounds of formula (II), (VI), (X), or (XII) or the ortΛo-gerø-dihalovinylaminothiophene compounds of formula (IV) or (VIII) may be prepared by the novel processes of the present invention as are described and claimed below.

In one embodiment, the ortΛo-gem-dihalovinylaminopyridine or ortho-gem- dihalovinylaminothiophene employed in the processes for the preparation of 2- substituted azaindoles or 2-substituted thienopyrroles comprises ortho-gem- dibromovinylaminopyridine or ort/20-gerø-dibromovinylaminothiophene.

In another embodiment, the organoboron reagent used in the processes of the invention comprises a reagent as follows:

R₄ B(OH)₂ ;

R₄ — B(ORs)₂ ;

R₄ ^°\ ^^R4

B B

R₄

(R₄)₃ B ;

R₄ BBN ; or R4 ^B(^Rs)2 In one embodiment, the organoboron reagent comprises an organoboronic acid, such as phenylboronic acid, C₆H₅-B(OH)₂, which is optionally further substituted at one or more substitutable positions with one or more substituents such as methyl, OMe, CF₃, and the like, hi another embodiment, the organoboron reagent comprises an organoboronic ester, such as a cyclic catechol ester, pinacol ester or ethylene glycol and the like. In one embodiment, R₅ of the organoboron ester may be a simple alkyl, such as methyl, ethyl, propyl and the like. Likewise, the organoboron reagent can comprise a 9-BBN derivative, such as n-HexBBN, or a trialkylboron reagent, such as Et₃B. In another embodiment, R₆ of the organoborane reagent maybe a cyclic or non-cyclic secondary alkyl group.

Many organoboron reagents are commercially available and methods for preparing organoboron reagents for use in the present invention are known to those skilled in the art. A description of general synthetic techniques used for preparing such organoboron reagents is found in Miyaura, N.; Suzuki, A., Chem. Rev. 1995, 95, 2457-2483, and Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168, the contents of which are hereby incorporated herein by reference in this regard.

In one embodiment, the palladium metal pre-catalyst used in the processes for preparing 2-substituted azaindoles or 2-substituted thienopyrroles of the present invention is any one of Pd(OAc)₂, Pd(PPh₃)₄, Pd₂(dba)₃, Pd(CH₃CN)₂Cl₂, PdCl₂, K₂PdCl₄, or Pd₂(dba)₃ -HCCl₃ but is not limited to these pre-catalysts. Palladium metal pre-catalysts are commercially available, and methods for preparing such palladium metal pre- catalysts are known to those skilled in the art. A description of general synthetic techniques used for preparing such pre-catalysts is found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, the contents of which are hereby incorporated herein by reference in this regard. In one embodiment, the pre-catalyst comprises Pd(OAc)₂ and the organoboron reagent comprises a boronic acid of R₄. In another embodiment, the pre-catalyst comprises Pd₂(dba)₃, and the organoboron reagent comprises a 9-BBN derivative OfR₄.

The quantity of pre-catalyst which can be used can be any quantity which allows for the formation of the 2-substituted azaindole product or 2-substituted thienopyrrole product.

In one embodiment, the pre-catalyst is present in an amount of about 3 mole percent to about 6 mole percent relative to the ort/20-gem-dihalovinylaminopyridine compound or ort/zø-gem-dihalovinylaminothiophene compound used in the reaction, hi another embodiment, the pre-catalyst is present in an amount of about 5 mole percent relative to the ort/zo-gem-dihalovinylaniline compound or ort/20-gem-dihalovinylaminothiophene used in the reaction.

Ligands for use in the present processes for the preparation of 2-substituted azaindoles or 2-substituted thienopyrroles comprise a phosphorous-containing ligand or a nitrogen- containing carbenoid ligand, such as s-Phos, X-Phos, Dave-Phos, P(o-tol)₃, PPh₃, P(O- CF₃-Ph)₃, BINAP, tol-BINAP, dppm, dppe, dppp, dppb, dppf, Xanphos, BIPHEP, AsPh₃, and

Mes NJ^ MΘS

+ cr , and the like. In one embodiment, the preferred ligand is s-Phos. In another embodiment the preferred ligand is X-Phos. Methods for preparing such ligands are well known to those skilled in the art. A description of general synthetic techniques used for preparing such ligands is found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, the contents of which are hereby incorporated herein by reference in this regard.

The quantity of ligand which can be used can be any quantity which allows for the formation of the 2-substituted azaindole or 2-substituted thienopyrrole. In one embodiment, the ligand is present in amount of about 6 mole % to about 10 mole % relative to the ort/20-gem-dihalovinylaminopyridine or ortho-gem- dihalovinylaminothiophene compound used in the reaction. In another embodiment, the ligand is s-Phos and it is present in amount of about 6 mole % relative to the ortho-gem- dihalovinylaminopyridine or ørt/20-ge/M-dihalovinylaminothiophene compound. The preparation of s-Phos is described and referenced in the publication of Walker et al. Angew. Chem. Int. Ed. 2004, 43, 1871-1876 and Barder et al. J. Am. Chem. Soc. 2005, 127, 4685, the details of which are herein incorporated by reference in this regard. In another embodiment, the ligand is s-Phos, used in combination with Pd(OAc)₂ as a pre- catalyst, and which are present in quantities of 6 mole % and 3 mole %, respectively. The ratio of s-Phos and Pd ranges from 1.5-2.5:1. In another embodiment of the processes of the present invention for the preparation of 2- substituted azaindoles or 2-substituted thienopyrroles, the base comprises an organic base or an inorganic base, such as a metal carbonate, a metal hydroxide, a metal alkoxide, a metal phosphate or a trialkylamine, and the like, hi one embodiment, the base comprises K₂CO₃, Na₂CO₃, Cs₂CO₃, NaOH, K₃PO₄-H₂O, KOtBu or NEt₃, or combinations thereof. In another embodiment, the base comprises K₃PO₄-H₂O. Additional bases for use with the present processes are known to those skilled in the art, for example, such as those disclosed in the publication of Miyaura et al. Chem. Rev. 1995, 95, 2457-2483, the details of which as relating to the bases is hereby incorporated herein by reference. In another embodiment, the base K₃PO₄-H₂O is used in combination with s-Phos as the ligand and Pd(OAc)₂ as a pre-catalyst. The quantity of the base which is used can be any quantity which allows for the formation of the 2-substituted azaindole compound or 2-substituted thienopyrrole. In one embodiment, the base is present in about 5 equivalents relative to the ortΛo-gew-dihalovinylaminopyridine or ortho-gem- dihalovinylaminothiophene starting material. In another embodiment, the base is present in about 3 equivalents relative to the ortΛo-gem-dihalovinylaminopyridine or ortho-gem- dihalovinylaminothiophene starting material. In another embodiment, the base is KaPO₄ with KOH and is present in about 1.5 equiv. Of KsPO₄ and 1.5 equiv. of KOH relative to the ort/zo-ge/M-dihalovinylaminopyridine or ort/20-gem-dihalovinylaminothiophene starting material.

Any solvent may be used in the processes of the present invention for the formation of 2- substituted azaindoles or 2-substituted thienopyrroles provided that it does not interfere with the formation of the 2-substituted azaindole or 2-substituted thienopyrrole product. Both protic and aprotic and combinations thereof are acceptable. A suitable solvent includes but is not limited to toluene, dioxane, benzene, THF, and the like.

In general, the reagents may be mixed together or added together in any order for the preparation of 2-substituted azaindoles or 2-substituted thienopyrroles. Air can be removed from the reaction vessel during the course of the reaction and the solvent and reaction mixtures can be purged with a non-reactive gas.

The process conditions for the preparation of 2-substituted azaindoles or 2-substituted thienopyrroles can be any operable conditions which yield the desired 2-substituted azaindole or 2-substituted thienopyrrole product. A preferred temperature for the processes for the production of 2-substituted azaindoles or 2-substituted thienopyrrole is about 100 ⁰C, although this temperature can be higher or lower depending upon the reagents, reaction conditions and the solvent used. Typical reaction times are between 1 and 14 hours, although longer or shorter times may be used if necessary.

The 2-substituted azaindole or 2-substituted thienopyrrole product can be recovered by conventional methods known to those skilled in the art, for example crystallization and silica gel chromatography. The yield of the product 2-substituted azaindole or 2- substituted thienopyrrole will vary depending upon the specific pre-catalyst, ligand, base, starting materials and process conditions used. Typically, the 2-substituted azaindole or 2-substituted thienopyrrole is provided in a yield greater than 50%, preferably in a yield of greater than 70%, more preferably in a yield greater than 80%. In a preferred embodiment, the s-Phos is present at about 6 mol %, Pd(OAc)₂ is present at about 3 mol %, the base comprises K₃PO₄-H₂O and is present at about 5 equivalents, the solvent is toluene, the ort/jo-gem-dihalovinylaminopyridine comprises ortho-gem- dichlorovinylaminopyridine which is as described for Example 2a, Table 1, and the organoboronic reagent comprises an organoboronic acid of structure R₄-B(OH)₂, and the yield is greater than 60%, preferably greater than 70%, more preferably greater than 80%.

In another embodiment of the present invention, when R₂ is alkoxycarbonyl in the final 2-substituted azaindole or 2-substituted thienopyrrole prepared by the processes of the present invention, the process may also include an additional step of cleavage of the alkoxycarbonyl group to afford a 2-substituted azaindole or 2-substituted thienopyrrole wherein R₂ is H. Methods and reaction conditions for the cleavage of alkoxycarbonyl groups are known to those skilled in the art, for example, such as those disclosed in Theodora W. Greene, Protective Groups in Organic Synthesis, Wiley Interscience Publications, John Wiley & Sons, New York, copyright 1981), the details of which are incorporated herein by reference in this regard. In one embodiment, a mixture of TFA and dichloromethane is used to effect removal of the alkoxycarbonyl group from an azaindole substrate. In another embodiment, HCl is used to afford cleavage of the alkoxycarbonyl group from an azaindole substrate. In another embodiment, NaOMe was used to effect removal of the alkoxycarbonyl group from a thienopyrrole substrate. In another embodiment of the present invention, when R₂ is benzyl, or a substituted benzyl in the final 2-substituted azaindole prepared by the processes of the present invention, the process may also include an additional step of cleavage of the optionally substituted N-benzyl group to afford a 2-substituted azaindole wherein R₂ is H. Methods and reaction conditions for the cleavage of benzyl groups are known to those skilled in the art, for example, such as those disclosed in Theodora W. Greene, Protective Groups in Organic Synthesis, Wiley Interscience Publications, John Wiley & Sons, New York, copyright 1981), the details of which are incorporated herein by reference in this regard.

The present invention also provides novel processes for the chemical synthesis of the precursor ørt/jø-gem-dihalovinylaminopyridine or ortAø-gew-dihalovinylaminothiophene compounds which are exemplified in the Examples below, for use in the novel process for the chemical synthesis of 2-substituted azaindole compounds or 2-substituted thienopyrrole compounds.

In one embodiment, the invention provides a process for the preparation of an ortho- gerø-dihalogen vinylaminopyridine compound of formula (VI) wherein the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VI):

wherein each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O- lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to

20-membered fused monocycle or polycyclic ring with the pyridine ring of Formula

(VI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₃ is H, CF₃, or alkynyl optionally substituted at one or more positions with one or more suitable substituents, R₂ is H and Halo is bromo, said process comprising the steps of: (a) reacting a nitropyridinecarboxaldehyde or ketone compound of formula (XIV) where the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (XIV):

wherein Ri is as defined above, and R₃ is as defined above, with CBr₄ and PPh₃ under conditions effective to generate in situ the ortho-gem-dihalovinyl compound of formula (XV)

(XV)

In another embodiment, the invention provides a process for the preparation of an ortho- gew-dihalogen vinylaminopyridine compound of formula (XVI), wherein the nitrogen occupies any one of the positions of the aromatic ring that are marked with an asterisk in formula (XVI):

wherein each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O- lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of Formula

(XVI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₃ is H, CF₃ or alkynyl, optionally substituted at one or more positions with one or more suitable substituents; R₂ is H, alkoxycarbonyl, alkyl, aryl or aryl-lower alkyl-; R₅ is H, alkyl or alkoxycarbonyl, with the proviso that both R₂ and R₅ are not H; and Halo is bromo, said process comprising the steps of:

reacting a aminopyridinecarboxaldehyde or ketone compound of formula (XVII) wherein the nitrogen occupies any one of the positions of the aromatic ring that are marked with an asterisk in formula (XVII):

wherein Rj, R₂, R₃ and Rs are as defined above, with CBr₄ and PPh₃ under conditions effective to generate in situ the ort&o-gem-dihalovinyl compound of formula (XVI) wherein the nitrogen occupies any one of the positions of the pyridine ring that are marked by an asterisk in formula (XVI):

wherein R₁, R₂, R₃ and R₅ are as defined above, and Halo is bromo.

In yet another embodiment, the invention provides a process for the preparation of an ort/zo-gem-dihalovinylammopyridine compound of formula (XVI) wherein the nitrogen occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (XVI):

(XVI)

wherein each of the one or more R₁ is independently selected from the group consisting of H, fiuoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O- lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of Formula (XVI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₂ is H, alkyl, aryl, aryl-lower alkyl-, or alkoxycarbonyl, all of which are optionally substituted with one or more suitable substituents; R₅ is H, alkyl, aryl, aryl-lower alkyl-, or alkoxycarbonyl, all of which are optionally substituted with one or more suitable substituents, with the proviso that both R₂ and R₅ are not H; and R₃ is H, alkyl or alkynyl, all of which are optionally substituted at one or more positions with one or more suitable substituents, and Halo is chloro, said process comprising the steps of: reacting a pyridinecarboxaldehyde or ketone compound of formula (XVII) where the nitrogen occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (XVII):

wherein Ri, R₂, R₃ and R₅ are as defined above, with 2 or more equivalents of CHCl₃ and PPh₃ in the presence of 2 or more equivalents of KO'Bu, wherein said equivalents are relative to formula (XVII), under conditions effective to generate in situ the ortho-gem- dichlorovinyl compound of formula (XVI), wherein the nitrogen occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (XVI):

(XVI)

wherein Ri, R₂, R₃ and R₅ are as defined above and Halo is chloro.

Additional methods for the preparation of ortho-gem-dibτomoviny\ compounds are known in the art, for example, see, Eymery, F.; Iorga, B, Synthesis, 2000, 185-213, the details of which are hereby incorporated herein by reference in this regard.

In another embodiment, the invention provides a process for the preparation of an ortho- gem-dihalovinylaminothiophene compound of formula (VIII) wherein the sulphur occupies any one of the positions in the thiophene ring that are marked by an asterisk in formula (VIII):

(VIII); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₃ is H, CF₃, or alkynyl, optionally substituted at one or more positions with one or more suitable substituents; R₂ is alkoxycarbonyl, optionally substituted at one or more positions with one or more suitable substituents, and Halo is bromo, said process comprising the steps of:

wherein Rj, R₂, and R₃ are as defined above, with CBr₄ and PPh₃ under conditions effective to generate in situ the ort/zo-gem-dihalovinyl compound of formula (VIII) wherein the sulphur occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VIII):

wherein Ri, R₂, and R₃ are as defined above, and Halo is bromo.

In yet another embodiment, the invention provides a process for the preparation of an ørt/20-ge/M-dihalovinylaminothiophene compound of formula (VIII) wherein the sulphur occupies any one of the positions in the thiophene ring that are marked by an asterisk in formula (VIII):

wherein each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O- lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the thiophene ring of Formula (VIII); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₂ is alkoxycarbonyl optionally substituted at one or more positions with one or more suitable substituents, and R₃ is H, alkyl, or alkynyl all of which are optionally substituted at one or more positions with one or more suitable substituents, and Halo is chloro, said process comprising the steps of: reacting an aminothiophenecarboxaldehyde or ketone compound of formula (XIX) wherein the sulphur occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (XIX):

wherein Rj, R₂, and R₃ are as defined above, with 2 or more equivalents of CHCl₃ and PPh₃ in the presence of 2 or more equivalents of KO'Bu, wherein said equivalents are relative to formula (XIX), under conditions effective to generate in situ the ortho-gem- dichloro vinyl compound of formula (VIII).

In another embodiment, the ort/zo-gemdihalovinylaminopyridines were prepared from the corresponding protected ort/20-aminopyridinecarboxyaldehydes or pyridyl ketones, wherein R₃ is H, alkynyl or CF₃. The process involves the alkylation of an N-Boc- aminopyridinecarboxaldehyde using a modified procedure (Krein, D. M.; Lowary, T. L.

J. Org. Chem. 2002, 67, 4965), followed by conversion of the aldehyde to the ortho- gemdibromovinylpyridylamines using Ramirez' conditions (CBr₄/PPh₃) (Ramiraz, F; Desal, N. B.; McKelvie, N. J. Am. Chem. Soc. 1962, 84, 1745) or other methods known to those skilled in the art. Removal of the Boc group was achieved using HCl or using an appropriate method known to those skilled in the art.

Scheme 18

The aminopyridine carboxaldehydes (and ketones), and aminothiophenecarboxaldehydes (and ketones), were prepared from the corresponding Boc or Piv-protected aminopyridines (2, 3, or 4-aminopyridines) or Boc or Piv protected aminothiophene by a directed lithiation followed by trapping the lithio species with DMF or N- formylpiperidine (aldehyde), or Weinreb amides (ketones) known to those skilled in the art (Schemes 19 and 20) (Venuti, M. C; Stephenson, R. A.; Alvarez, R.; Bruno, J. J.; Strosberg, A. M. J. Med. Chem. 1988, 31, 2136. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815). R₃ can be H, alkyl, haloalkyl but is not restricted to these substituents, R₂ is either Boc or Piv. Many of these aldehydes are also commercially available.

Scheme 19

Scheme 20

ide

In another embodiment the gem-dichlorovinylaminopyridines were synthesized from the corresponding aldehyde or ketone by using the Wittig reagent, CCl₂PPh₃ (Scheme 21)_. The CCl₂PPh₃ reagent was conveniently prepared from the reaction of chloroform, triphenylphosphine, and KO'Bu HO'Bu (Speziale, A. J.; Ratts, K. W. J. Am. Chem. Soc. 1962, 84, 854). A modified procedure was used (Speziale, A. J.; Ratts, K. W.; Bissing, D. E. Org. Syn., Coll. Vol. 5, 361). The modifications are as follows: use of 1.5 or more equivalents of CHCl₃, PPh₃, and KO'Bu HO'Bu to afford higher yields; also, H₂O₂ was used to oxidize the excess PPh₃ during the workup instead of highly toxic HgCl₂. This method is also suitable for the synthesis of both isomers of ortho-gem- dihalovinylaminothiophenes whereby the thiophene is substituted at the 2,3 positions. R₃ can be H, alkyl, haloalkyl but is not restricted to these substituents, R₂ can be H, alkyl, alkoxycarbonyl but is not restricted to these groups.

The results of substrate synthesis are summarized in Table 1.

Scheme 21

The /V-alkyl 2-amino-3-dichlorovinylpyridines can be prepared using a modified procedure in the literature (Rrein, D. M.; Lowary, T. L. J. Org. Chem. 2002, 67, 4965). By treatment of a mixture of 7V-Boc 2-amino-3-dichlorovinylpyridine and alkyl halide in anhydrous DMF with NaH, the BocNH group is alkylated and the Boc group can be deprotected under acidic conditions (Scheme 22). Scheme 22

Another method of preparation of iV-alkyl 2-amino-3-dichlorovinylpyridine is alkylation of the aldehyde followed by olefination using the method described previously and HCl Boc deprotection (Scheme 23).

Scheme 23

Examples of N-substituted gem-dihalovinylaminopyridines and N-substituted gem- dihalovinylaminothiophenes prepared using the processes as herein described are illustrated in Table 1.

Table 1

Any solvents may be used in the processes of the present invention for the formation of the starting material ort/zo-gemhalovinylaminopyridine or ortho- gemhalovinylaminothiophene compounds provided that they do not interfere with the formation of the desired ortho-gew-halovinylaminopyridine or ortho- gemhalovinylaminothiophene products. Both protic and aprotic and combinations thereof are acceptable. Suitable solvents include but are not limited to dichloromethane and ethanol, ether, dichloromethane, ethyl acetate, THF and the like which are compatible with the reaction.

The ort/jø-gem-dihalovinylaminopyridine compounds or ort/jo-gem-dihalovinyl- aminothiophene compounds can be recovered by conventional methods known to those skilled in the art, for example crystallization, silica gel chromatography, vacuum distillation and the like, where appropriate. The yield of the ortho-gem- dihalovinylaminopyridine compounds or ortAø-gerøhalovinylaminothiophene compounds will vary including depending upon the bases, starting materials and process conditions used. Typically, the ortΛo-gemdihalovinylaminopyridine or ortho- gemhalovinylaminothiophene is provided in a yield greater than about 40%. In another embodiment, the ort/?o-gem-dihalogenvinylaminopyridine compound or ortho- ge/nhalovinylaminothiophene compound is afforded in a yield of between about 40% and about 85% yield.

The process conditions for the preparation of the ortΛo-gem-dihalovinylaminopyridine or ort/zø-gem-dihalovinylaminothiophene compounds from either their respective aldehydes or ketones can be any operable conditions which yield the desired the ortho-gem- dihalovinylaminopyridine or ørtλo-gem-dihalovinylaminothiophene products. Preferred temperatures for the processes for the production of the ortho-gem- dihalovinylaminopyridine or ort/jø-gem-dihalovinylaminothiophene compounds are set out in the examples below, although temperatures can be higher or lower depending upon the reagents, reaction conditions and the solvent used. Typical reaction times are set out in the examples below, although longer or shorter times may be used if necessary.

The ort/zo-gem-dihalovinylaminopyridine or ørt/?ø-gem-dihalovinylaminothiophene compounds can be recovered by conventional methods known to those skilled in the art, for example crystallization and silica gel chromatography.

In one embodiment, the invention provides a process for the preparation of an ortho- gem-dihalovinylaminopyridine compound of formula (VI) wherein the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VI):

(VI)

wherein each of the one or more Ri substituents is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of Formula (VI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₂ is H, R₃ is H, alkyl, or alkynyl optionally substituted at one or more positions with one or more suitable substituents, and Halo comprises chloro, said process comprising the steps of: (a) reacting a nitropyridinecarboxaldehyde or ketone compound of formula (XIV) where the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (XIV)

wherein Ri and R₃ are as defined above for formula (VI), with 2 or more equivalents of CHCl₃ and PPh₃ in the presence of 2 or more equivalents of KO'Bu under conditions effective to generate in situ the ortAo-gem-dichlorovinyl compound of formula (XV)

wherein Ri, R₃ and Halo are as defined above; and (b) reducing the compound of formula (XV) under conditions effective to reduce the nitro group of the compound of formula (XV), without affecting the functional groups present in the compound, to afford the compound of formula (VI). In a preferred embodiment, the reducing agent is SnCl₂2H₂O (except where R₃ is alknyl). Other appropriate reducing conditions are known to those of skill in the art, and include those disclosed in R.C. Larock, Comprehensive Organic Transformation (2^nd Ed), Wiley- VCH, New York, 1999, pp. 821-828, the contents of which are hereby incorporated by reference in this regard.

Use of two or more equivalents of CHCl₃ and PPh₃ in the presence of 2 or more equivalents of KO'Bu is expected to afford higher yields than reported previously (Olah et al., J. Org. Chem. 1975, 40, 8, 1107-1110).

Thus, a number of ørt/zo-gem-dihalovinylaminopyridine compounds can be prepared using the processes of the invention. In one embodiment, the invention provides a novel ortAo-gem-dihalovinylaminopyridine compound or a salt thereof selected from the group consisting of:

Additionally, a number of ort/*o-gem-dihalovinylaminothiophene compounds can be prepared using the processes of the invention. In another embodiment, the invention provides a novel ort/20-gem-dihalovinylaminothiophene compound or a salt thereof selected from the group consisting of:

In yet another embodiment, the invention provides a process for the preparation of N- arylaminopyridine compounds of formula (VI) where the nitrogen occupies any one of the positions in the pyridine ring that are marked by an asterisk in formula (VI):

wherein Halo comprises Br or Cl; R₂ comprises aryl which is optionally substituted at one or more substitutable positions with one or more suitable substituents; R₃ comprises H, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aryl-loweralkyl-, or heteroaryl-lower alkyl-, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents; and each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of Formula (VI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; said process comprising the steps of:

reacting a compound of formula (XIII) wherein the nitrogen occupies any one of the positions marked by an asterisk in formula (XIII):

(XIII)

wherein Halo, Ri, R₃ are as defined above, with an organoboron reagent comprising a boronic acid, boronic acid anhydride or BF₃ ^" salt of R₂, wherein R₂ is as defined above, in the presence of at least about 1.5 equivalent of a copper (II) catalyst relative to the compound of formula (VI), at least about 0.3 equivalents of a C₈-C₂₀ fatty acid relative to the compound of formula (VI), molecular oxygen, and a non-nucleophilic base, at a reaction temperature of between about 40 ⁰C and 60 ⁰C, under conditions effective to form a C-N bond between formula (VI) and the R₂ group of the organoboron reagent, to afford the N-arylaniline compounds of formula (VI). These compounds are useful for the synthesis of 2-substituted azaindoles of the present invention. In another aspect, the fatty acid comprises myristic acid. In yet another aspect, the non-nucleophilic base comprises lutidine or collidine. This improved method is expected to afford arylation of sterically hindered aminopyridines, which can be challenging to achieve by conventional methods, in good yield with less copper (II) catalyst required than previously known in the art (Antilla et al., Organic Letters 2001, 3, 13, 2077-2079).

N-alkylated ørt/zo-gem-dihalovinylaminopyridine compounds may also be prepared via reductive amination reactions, representative examples of which are illustrated in Scheme 24 below:

Scheme 24

wherein R₁, R₃, and X (halo) are as previously defined for Formula (VI) above. The aldehyde/ketone substituents R₂' and R₂" may independently be H, alkyl, aryl, heteroaryl, alkenyl, alkynyl, or other suitable substituents. The reductive sources for such reactions include, but are not limited to, NaBH(OAc)₃, NaBH₄, Na(CN)BH₃, and the like. Standard reductive amination reaction conditions are known to the person skilled in the art, and it is understood that conditions used to effect such reactions must be compatible with the functional groups present on the substrates. The process conditions for the above embodiment can be any operable conditions which yield the desired iV-alkylated products (Richard C. Larock, Comprehensive Organic Transformation, Wiley VCH, New York, copyright 1999; Reddy, TJ. et al. Synlett, 2005, 583; Abdel-Magid, A. F. et al J. Org. Chem. 1996, 61, 3849; Bomann, M.D. et al. J. Org. Chem. 1995, 60, 5995).

2-substituted azaindole compounds synthesized by reacting the gem- dihalovinylaminopyridine or gem-dihalovinylaminopyridine N-oxide with an organoboron reagent in the presence of a palladium metal pre-catalyst, ligand, and base in a solvent are shown in Table 2. In a preferred embodiment Pd(OAc)₂ is used as the catalyst, S-Phos or X-Phos is used as the ligand, K₃PO₄-H₂O is used as the base and toluene is used as the solvent, although the reaction is not restricted to the reagents listed above. In a preferred embodiment, the S-Phos is present at about 6 mol %, Pd(OAc)₂ is present at about 3 mol %, the base comprises K₃PO₄-H₂O and is present at about 5 equivalents, the solvent is toluene, the ort/zo-gem-dihalovinylaminopyridines comprises [3-(2,2-dibromovinyl)pyridin-2-yl]methylamine which is as described for Example 2a, and the organoboronic reagent comprises phenylboronic acid of structure R₄-B(OH)₂, and the yield is greater than 50%, preferably greater than 70%, more preferably greater than 80%.

Scheme 25

Table 2

The ligands L-I to L-4 are defined as follows:

Generalized preferred ligand structure S-Phos X-Phos Dave-Phos L-4 L-1 L-2 L-3

Typically, for a coupling involving chloro functionality, an electron-rich, sterically hindered phosphine ligand, or N-heterocyclic carbene ligand are used known to those skilled in the art (for a review, see: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.). An example of such preferred ligand family is Buchwald's biphenyl-type of ligands some of which are shown above (Buchwald, S. L.; Old, D. W.; Wolfe, J. P.; Palucki, M.; Kamikawa, K. In (Massachusetts Institute of Technology, USA). US 6,307,087, 2001), many of which are commercially available (see formulae shown above). The substitution on one of the phenyl groups provides fine-tuning of the steric and electronic properties of the catalyst systems, enabling enhancement of the yield of certain azaindole preparation.

One of the crucial requirements, for a successful reaction for the azaindole synthesis is an appropriate substituent on the amino nitrogen group. Substrates with free NH₂ group gave no formation of the corresponding azaindole product, resulting in slow decomposition of the substrate, as well as catalyst poisoning. Suitable substituent on the amino group (R₂) can be alkyl, alkoxycarbonyl or alkylaryl. On the other hand, it is more advantageous to use an alkoxylcarbonyl (t-butoxycarbonyl, Boc) substituted amino group as it is required during the substrate synthesis. In a few cases, the iV-Boc- azaindoles or N-Cbz-azaindoles formed in the coupling process are partially or fully deprotected in situ. (Examples 2aa and 2z).

A preferred temperature for the processes for the production of 4, 5, 6, or 7-azaindoles is about 100 ⁰C, although this temperature can be higher or lower depending upon the reagents, reaction conditions and the solvent used. Typical reaction times are between 2 and 44 hours, although longer or shorter times may be used if necessary. The 4, 5, 6, or 7-azaindoles product can be recovered by conventional methods known to those skilled in the art, for example crystallization and silica gel chromatography. The yield of the product azaindole will vary depending upon the specific pre-catalyst, ligand, base, starting materials and process conditions used. Typically, the azaindoles were in provided in a yield greater than 50%, preferably in a yield of greater than 70%, more preferably in a yield greater than 80%.

In an attempt to synthesize 4-azaindole from N-Cbz-[2-(2,2-dichlorovinyl)-pyridin-3- yl] amine (Scheme 26), only a complex mixture was obtained. This is presumably due to the formation of a relatively stable palladium intermediate, in which the pyridyl nitrogen coordinates to the metal complex after oxidative addition. This intermediate may prevent further C-N bond formation, resulting in decomposition or undesired couplings. To prevent this, the pyridyl nitrogen was protected by an TV-oxide (Scheme 26). This strategy leads to a successful reaction to obtain the desired azaindole product in good to excellent yields (examples 2z and 2aa). In these cases, the iV-Cbz-azaindoles formed in the coupling process were completely deprotected in situ under the reaction conditions (example 2z and 2aa) due to the lability of the Cbz group under basic conditions.

Scheme 26

The halogen in the substrates can be either chloro or bromo, although chloro substrates are preferred as they typically give higher yields (Example 2a vs. Example 2b; and

Example 2e vs. Example 2f). Also, the method of preparing the chloro substrates are more highly yielding compared to bromo substrates starting from the same ortho-(t- butoxycarbamyl)pyridinecarboxaldehydes.

Various organoboron reagents comprised of electron-rich, electron-poor, sterically hindered aromatic, heteroaromatic, and alkenyl boronic acids are able to couple with the substrate to give the desired azaindoles. Typically, a slight excess to the stoichiometric amount of boronic acid (1.2-1.5 equiv. depending on the substrate) is used since the parasitic homocoupling of the boronic acid consumes part of the boronic acid.

Various palladium metal pre-catalysts including Pd(O) and Pd(II) are valid palladium metal sources known to those skilled in the art.

Also, N-alkoxylcarbonylazaindoles can be easily removed to give lH-azaindoles under conventional methods analogous to N-alkoxylcarbonylindoles known to those skilled in the art (Greene, T. W. Protective Groups in Organic Synthesis, Wiley Interscience Publications, John Wiley & Sons, New York, 1999). In one embodiment, the invention provides a process for the deprotection of the N-alkoxycarbonyl azaindoles of formula (V) where the nitrogen occupies any one of the positions of the pyridine ring marked by an asterisk in formula (V):

(V)

.wherein

each of the one or more Ri is independently selected from the group consisting of Η, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring; all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions, R₂ comprises alkoxycarbonyl, which is optionally substituted at one or more substitutable positions with one or more suitable substituents,

the process comprising treating a compound of formula (V) with an acid to form the N-H azaindole wherein R₂ is H and Ri, R₃ and R4 are as defined above for compound (V).

One example under acidic conditions is illustrated in Scheme 27, in which 1H-6- azaindole is obtained in good yield.

Scheme 27

In another example, both Boc and methoxy groups of l-Boc-2-(2-methoxyquinolin-3- yl)-6-azaindole were deprotected under acidic conditions to give 3-(lΗ-pyrrolo[2,3- c]pyridin-2-yl)-lH-quinolin-2-one (Scheme 28). The product is a KDR kinase inhibitor, which is potentially useful for the treatment of cancer. (Fraley, M. E.; Hartman, G. D.; Hungate, R. W. In PCT Int. Appl; (Merck & Co., Inc., USA). WO 01062252, 2001.) Scheme 28

4-Oxy-4-azaindoles (example 2y, 2z) obtained from this process can be deoxygenated under the conditions known to those skilled in the art.

In one embodiment, the invention provides a process for the removal of the N-oxide from a compound of formula (XI) wherein the nitrogen occupies any one of the A-, 5-, 6-, or 7- positions in formula (XI):

.wherein

the process comprising treating the N-oxide of formula (XI) with a reducing agent to form the reduced compound of formula (V) wherein R₁, R₂, R₃ and R4 are as defined above for compound (XI) and wherein the nitrogen occupies any one of the 4-, 5-, 6-, or 7- positions in formula (V).

(V)

One example is illustrated in Scheme 29, in which l-H-4-azaindole is obtained in good yield using PCl₃ conditions. Other appropriate conditions are known to those of skill in the art, and include those disclosed in Albini, A.; Pietra, S. Heterocyclic N-oxides CRC Press: Boca Raton. 1991, the contents of which are hereby incorporated by reference in this regard.

Scheme 29

Another application of this method is the synthesis of a Smad3 inhibitor SIS3, which can potentially be used for the treatment for systematic sclerosis or scleroderma (Jinnin, M.; Ihn, H.; Tamaki, K. MoI Pharmacol 2006, 69, 597 Maruyama, Y.; Hirabayashi, K.; Hori, K. (Nippon Shinyaku Co., Ltd., Japan) PCT Int. Appl. WO 2003037862 (2003) ). Such process starts from l-methyl-2-phenyl-7-azaindole, which was prepared efficiently from either [3-(2,2-dichlorovinyl)-pyridin-2-yl]-methylamine (example 11) or [3-(2,2- dibromovinyl)-pyridin-2-yl]-methylamine (example Ii) using the tandem coupling method. Iodination at the 3-position of the azaindole using 7V-iodosuccimide (NIS) gave the iodoazaindole in excellent yield (95%). A Heck reaction between the iodide and 1- (6,7-dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-propenone (Watanabe, T.; Kakefuda, A.; Kubota, H.; Masuda, N. In Jpn. Kokai Tokkyo Koho; (Yamanouchi Pharmaceutical Co., Ltd., Japan). JP 11269172, 1999, p 16 pp) under microwave radiation gave the final product in excellent yield (90%) (Scheme 30)

Scheme 30

Thus, a variety of azaindole compounds can be produced using the processes of the invention, hi one embodiment, the invention provides a novel 2-substituted azaindole or a salt thereof selected from the group consisting of:

Preparation of thieno[2,3-b]pyrrole and thieno[3,2-b]pyrrole from the corresponding ortAø-NHBoc-gemdichlorovinylthiophenes can be performed in a similar way to the azaindoles. The thienopyrrole products can be recovered by conventional methods known to those skilled in the art, for example crystallization and silica gel chromatography. The yield of the thienopyrrole product will vary depending upon the specific pre-catalyst, ligand, base, starting materials and process conditions used. Typically, the thienopyrrole in provided in a yield greater than 50%, preferably in a yield of greater than 70%, more preferably in a yield greater than 80%. In a preferred embodiment, the S-Phos is present at about 6 mol %, Pd(OAc)₂ is present at about 3 mol %, the base comprises K₃PO₄-H₂O and is present at about 5 equivalents, the solvent is toluene, the ørt/zo-NHBoc-gemdichlorovinylthiophenes comprises [3-(2,2- dichlorovinyl)thiophen-2-yl]-carbamic acid tert-butyl ester, which is described in Example 3 a, and the organoboronic reagent comprises an organoboronic acid of structure Ri-B(OH)₂, and the yield is greater than 50%, preferably greater than 70%, more preferably greater than 80%.

Scheme 31

2-Substituted thionopyrroles prepared by this method are shown below. The ligands have been previously defined.

Table 3

Similar to the azaindole synthesis, the substituents on the amino group are crucial for the success of the coupling reaction. Substrates with a free -NH₂ or -NHR (where R is an alkyl group) are unstable at rt in air, hence unsuitable for the synthesis of thienopyrroles. Suitable groups are electron-withdrawing groups, such as alkoxycarbony (e.g. Boc) to stabilize sensitive aminopyrrole substrates.

Similar to the azaindole synthesis, the halogen in the substrates can be either chloro or bromo, although chloro substrates are preferred. Also, the method for preparing the chloro substrates is more convenient.

Various organoboron reagents comprising of electron-rich, electron-poor,^' sterically hindered aromatic, heteroaromatic, alkenyl boronic acids (example 3a-3j) are able to couple with the substrate to give the desired thienopyrroles. Typically, a slight excess to the stoichiometric amount of boronic acid (1.2-1.5 equiv. depending on the substrate) is used since the parasitic homocoupling of the boronic acid consumes part of the boronic acid.

The ligand is one of the crucial factors for a successful thienopyrrole synthesis reaction. Typically, for a coupling reaction involving a chloro functionality, an electron-rich, sterically hindered phosphine ligand, or iV-heterocyclic carbene ligand known to those skilled in the art is preferred (for a review, see: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.). An example of such a preferred ligand family is Buchwald's biphenyl-type of ligands (Buchwald, S. L.; Old, D. W.; Wolfe, J. P.; Palucki, M.; Kamikawa, K. In (Massachusetts Institute of Technology, USA). US 6,307,087, 2001), many of which are commercially available (see formulae on page 101). The substitution on one of the phenyl groups provides fine-tuning of the steric and electronic properties of the catalyst systems, enabling to enhance the yield of certain azaindole preparation

111

SUBSTiTUTE SHEET (RULE ZS) Thus, a variety of thienopyrroles can be obtained using the processes of the invention. In one embodiment, the invention provides a novel 2-substituted thienopyrrole or a salt thereof selected from the group consisting of:

Analogous to the azaindoles, N-alkoxylcarbonylthienopyrroles can be easily deprotected to give H-thienopyrroles under basic conditions similar to those conditions to cleave N- alkoxylcarbonylpyrroles known to those skilled in the art (Greene, T. W. Protective Groups in Organic Synthesis, Wiley Interscience Publications, John Wiley & Sons, New York, 1999). In one embodiment, the invention provides a process for the deprotection of the N-alkoxycarbonyl thienopyrrole compounds of formula (VII) where the sulphur occupies the 4 or 6 position of the aromatic ring:

(VII)

wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the thiophene ring; all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

An example of this is shown in Scheme 32. Other suitable methods can also be used such as silica gel under high vacuum (Wensbo, D.; Gronowtiz, S. Tetrahedron 1996, 52, 14975-14988. Apelqvist, T.; Wensbo, D. Tetrahedron Lett. 1996, 37, 1471).

Scheme 32

Every reference cited herein is hereby incorporated by reference in its entirety. Examples

General Procedures: All reactions were carried out under N₂. Solvents and solutions were added with a syringe, unless otherwise noted. Analytical TLC was performed using EM separations precoated silica gel 0.2 mm layer UV fluorescent sheets. Column chromatography was carried out as "flash chromatography" as reported by Still using Merck 60 (230-400 mesh) silica gel (Still, W. C; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-5). Unless otherwise specified, extracts were dried over MgSO₄ and solvents were removed with a rotary evaporator at aspirator pressure.

Toluene was distilled under N₂ from Na/benzophenone immediately prior to use. Phosphine ligands were purchased from Strem Chemical Company and other pre- catalysts or reagents were obtained from commercial sources without further purification.

Melting points were taken on a Fisher- Johns melting point apparatus without correction. IR spectra were obtained using Nicolet DX FT IR spectrometer as thin films on NaCl plates. High-resolution mass spectra were obtained from a VG 70-250S (double focusing) mass spectrometer at 70 eV. ¹H, ¹³C, and ¹⁹F NMR spectra were obtained using Varian Unity 500, Mercury 400, Mercury 300 or Gemini 300 spectrometers. ¹H spectra were referenced to tetramethylsilane (TMS, 0 ppm) using CDCl₃ as solvent, DMSO-D₅ residue peaks (2.50 ppm) using DMSO-d₆ as a solvent, CHD₂OD residue peaks (3.30 ppm) using CD₃OD as a solvent. ¹³C spectra were referenced to solvent carbons (77.23 ppm for CDCl₃; 39.57 ppm for DMSO-d₆, 49.15 ppm for CD₃OD). When carbons are equivalent, no special notation is used.

Example 1: Synthesis of ortho-gemdihalovinylaminopyridine and ortho- gemdihalovinylaminothiophene derivatives

Example Ia: Synthesis of [3-(2,2-dichlorovinyl)pyridin-2-yl] carbamic acid tert- butyl ester

1a A modified literature procedure was applied to prepare [3-(2,2-dichlorovinyl)pyridin-2- yl] carbamic acid tert-butyl ester (Speziale, A. J.; Ratts, K. W.; Bissing, D. E. Org. Syn., Coll. Vol. 5, 361).

Preparation of KO'BU HO'BU: A mixture of KO'Bu (56 g), HO'Bu (46 g), and anhydrous 5 heptane (100 niL) was heated to 115 ⁰C (reflux) for 1 h. Heptane was distilled out at bath temperature of 115 ⁰C. The residual HO'Bu was removed under vacuum (0.3 mm Hg) for 1 h to yield a white powder (90.5 g, 97%).

General procedure: To a round-bottom flask was charged with KO'Bu HO'Bu (1.86 g, 10 mmol) and powdered PPh₃ (2.62 g, 10 mmol) and purged with argon for 10 min.

10 After heptane (15 mL) was added, the mixture was cooled to 0 ⁰C in an ice bath. To the vigrously stirred mixture, a solution of chloroform (1.19 g) in heptane (5 mL) was added dropwise so that the internal temperature was maintained under 3 ⁰C. After addition, the mixture was stirring for additional 30 min. The mixture was concentrated to about 10 mL under high vacuum at rt. To the mixture (3-formyl-pyridin-2-yl)-carbamic acid tert-butyl

15 ester (1.11 g, 5 mmol) at 0 ⁰C was added in one portion followed by dry benzene (3 mL) and the mixture was stirred overnight. The reaction was quenched by the addition of NH₄Cl solution (20 mL), extracted with DCM (3x20 mL). H₂O₂ (10%, 1 mL) was added to the aqueous phase mixture and stirred for 30 min. The organic phase was washed with H₂O (50 mL) and brine (20 mL) and dried over MgSO₄. The product was further purified

20 by flash chromatography on silica gel (33% EtOAc in hexanes) to afford the desired product (1.24 g, 86%) as a white solid, mp: 151-152 ⁰C. IR (CHCl₃, cm^"1): 3415, 2981, 1731, 1576, 1489, 1438, 1369, 1154. ¹H NMR (400 MHz, CDCl₃) δ 8.38 (IH, dd, J=4.9, 1.7 Hz), 7.94 (IH, ddd, J=7.7, 1.8, 0.7 Hz), 7.71 (IH, br), 7.14 (IH, dd, J= 7.7, 4.8 Hz), 6.85 (IH, s), 1.51 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 152.7, 149.1, 148.3, 138.5,

25 125.0, 123.9, 123.2, 120.4, 81.5, 28.3. HRMS (ESI) calc'd for C₁₂Hj₄N₂O₂NaCl₂ ([M+Na]⁺) 311.0324. Found: 311.0331.

Example Ib: Synthesis of 2-(2,2-dichlorovinyl)-pyridin-3-ylamine

The general procedure for the preparation of gemdichloro vinyl substrate was performed on a 25 mmol scale to afford the product as a white solid mixture with PPh₃(O). The mixture was taken into HCl (50 mL, 6N), and heated to 110 ⁰C overnight (12 h). The mixture was cooled to rt, extracted with Et₂O (3x20 mL). The aqueous layer was neutralized with NaOH and K₂CO₃, extracted with EtOAc (3^χ50 mL), washed with brine, and dried over Na₂SO₄. The crude product was further purified by flash chromatography to afford the product was a white crystalline solid. (3.47 g, 73% over 2 steps), mp: 79-80 ⁰C. IR (neat, cm^"1): 3332, 3206, 1613, 1582, 1449, 1313, 1264. ¹H NMR (400 MHz, CDCl₃) δ 8.09 (IH, X in ABX, J_Aχ=4.5 Hz, J_BX=1.7 Hz), 7.07 (IH, A in ABX, J_AB=8.2 Hz, J_Aχ=4.5 Hz), 7.02 (IH, B in ABX, J_AB= 8.2 Hz, J_BX=1J Hz), 6.87 (IH, s), 3.81 (2H, br). ¹³C NMR (100 MHz, CDCl₃) δ 140.7, 140.0, 138.4, 126.5, 124.9, 124.2, 123.0. HRMS (ESI) calc'd for C₇H₆N₂Cl₂ ([M+H]⁺) 188.9980. Found: 188.9983.

Example Id: Synthesis of benzyl-[3-(2,2-dichlorovinyl)-pyridin-2-yI]-amine

To a solution of the aldehyde (0.237 g, 1.17 mmol) in DMF (3 mL) was added BnBr (0.270 g, 1.58 mmol) at 0 ⁰C. To the mixture was added NaH (0.063 g, 60% mineral oil, 1.58 mmol) in three portions over 15 min and stirred for an additional 15 min. The mixture was warmed to rt and stirred for 30 min before quenched by the addition of NaHCO₃ (10 mL). The mixture was extracted with Et₂O (3x1 OmL), and the combined organic layers were washed with H₂O (10 mL), NaHCO₃ (10 mL), brine (10 mL), and dried over Na₂SO₄. The product was purified by flash chromatography (15% EtOAc in hexanes) to afford a yellowish oil (0.275, 75%), which was used directly in the olefination steps following the general procedure to afford a yellowish oil. The mixture was added to an aqueous HCl solution (10 mL, 3 M) and heated to 75 ⁰C for 2 h. The mixture was then basifϊed using K₂CO₃, extracted with Et₂O (3^χ15 mL), and dried over Na₂SO₄. The product was purified by flash chromatography (15% EtOAc in hexanes) to afford a yellow solid (0.227 g, 93% in 2 steps), mp: 57-58 ⁰C. IR (neat, cm^"1): 3438, 3316, 3027, 1588, 1498, 1407, 1274. ¹H NMR (400 MHz, CDCl₃) δ 8.14 (IH, dd, J=4.8, 1.5 Hz), 7.55 (IH, d, J=6.8 Hz), 7.38-7.27 (5H, m), 6.65 (IH, dd, J=7.2, 5.1 Hz), 6.58 (IH, s), 4.67 (2H, d, J=5.5 Hz), 4.49 (IH, br). ¹³C NMR (100 MHz, CDCl₃) δ 155.2, 148.5, 139.7, 137.3, 128.8, 128.1, 127.5, 125.3, 123.5, 114.1, 112.9, 45.9. HRMS (ESI) calc'd for C₁₄H₁₃N₂Cl₂ ([M+H]⁺) 279.0450. Found: 279.0456.

Example Ie: Synthesis of [4-(2,2-dichlorovinyr)pyridiii-3-yl]-carbamic acid tert- butyl ester

r Ii v I ^CH0 - r fi-v T— <^c c^ιi

~NHBoc N

NHBoc 1e

The general procedure for the preparation of gemdichloro vinyl substrates was performed on a 5 mmol scale to afford the product as a white solid (0.87 g, 60%). mp: 120-122 ⁰C: IR (neat, cm^'1): 3221, 2977, 1728, 1556, 1515, 1418, 1247, 1160. ¹H NMR (400 MHz, CDCl₃) δ 9.02 (IH, br), 8.39 (IH, d, J=5.1 Hz), 7.37 (IH, d, J=5.1 Hz), 6.78 (IH, s), 6.22 (IH, br), 1.54 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 152.8, 145.2, 144.9, 132.9, 132.1, 127.4, 123.0, 122.9, 81.9, 28.4. HRMS (ESI) calc'd for C₁₂H₁₅N₂O₂Cl₂ ([M+H]⁺) 289.0505. Found: 289.0514.

Example If: Synthesis of [4-(2,2-dichlorovinyl)pyridin-3-yl]-carbamic acid tert- butyl ester

1f

The general procedure for the preparation of gemdichloro vinyl substrates was performed on a 25 mmol scale to afford the product as a white solid (6.82 g, 94%). mp: 148-149 ⁰C. IR (neat, cm^"1): 3196, 2974, 1733, 1574, 1511, 1245, 1154. ¹U NMR (400 MHz, CDCl₃) δ 8.46 (IH, s), 8.45 (IH, d, J=5.7 Hz), 8.06, (IH, d, J=5.7 Hz), 6.71 (IH, s), 6.50 (IH, br), 1.55 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 151.8, 150.7, 150.4, 143.3, 127.7, 121.5, 118.2, 112.8, 82.4, 28.4. HRMS (ESI) calc'd for C₁₂H₁₅N₂O₂Cl₂ ([MH]⁺) 289.0505. Found: 289.0512.

Example Ig: [3-(2,2-Dichloro-vinyl)thiophen-2-yl]-carbamic acid tert-butyl ester

The general procedure for the preparation of gemdichloro vinyl substrate was performed on a 10 mmol scale to afford the product as a white solid (2.23 g, 76%). mp: 120-121 ⁰C. IR (neat, cm-¹): 3200, 2980, 1682, 1553, 1501, 1275, 1153. ¹H NMR (400 MHz, CDCl₃) δ 7.22 (IH, d, J=5.7 Hz), 6.88 (IH, d, J=5.7 Hz), 6.78 (IH, br), 6.66 (IH, s), 1.53 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 152.5, 138.5, 124.5, 121.5, 120.8, 118.8, 117.8, 82.4, 28.4. HRMS calc'd for C₁₁H₁₃NO₂SCl₂ ([M]⁺) 293.0044. Found: 293.0039.

Example Ih: [2-(2,2-Dichlorovinyl)thiophen-3-yl]carbamic acid tert-butyl ester

The general procedure for the preparation of gewdichlorovinyl substrates was performed on a 4.4 mmol scale to afford the product as a white solid (1.03 g, 80%). mp: 132-133 ⁰C. IR (neat, cm^"1): 3268, 2978, 1691, 1553, 1367, 1248, 1159. ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.30 (2H, m, br), 6.89 (IH, br), 6.43 (IH, br), 1.52 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 153.0, 135.8, 126.1, 123.6, 119.6, 119.2, 81.5, 28.5. HRMS calc'd for C₁₁H₁₃NO₂SCl₂ ([M]⁺) 293.0044. Found: 293.0039.

Example Ii: Synthesis of [3-(2,2-dibromovinyl)-pyridin-2-yl]methylamine

1 i

To a mixture of the aldehyde (0.222 g, 1 mmol) and DMF (3 mL) was added MeI (0.178 g, 1.25 mmol) at 0 ⁰C. NaH (0.052 g, 60% mineral oil, 1.35 mmol) was added in three portions over 15 min and the resulting yellowish suspension was stirred for an additional 60 min. The mixture was warmed to rt and quenched by the addition Of NaHCO₃ (10 mL) and H₂O (10 mL). The mixture was extracted with Et₂O (3><1 OmL), and the combined organic layers were washed with H₂O (10 mL), NaHCO₃ (10 mL), brine (10 mL), and dried over Na₂SO₄. The product was further purified by flash chromatography (25% EtOAc in hexanes) to afford an oil (0.197 g, 84%), which was used in the next step. To a solution of the methylated aldehyde (0.183 g, 0.77 mmol) and CBr₄ (0.389 g, 1.17 mmol) was added a solution of PPh₃ (0.613 g, 2.34 mmol) in DCM (~1 mL) at 0 ⁰C for 15 min before warmed to it. The mixture was poured into a Na₂CO₃ solution, extracted with Et₂O (2x5 mL), washed with brine (5 mL), dried over Na₂SO₄. After removal of the solvent, the mixture was filtered through a short column, eluting with 33% EtOAc in hexane containing 1% Et₃N to afford a yellowish oil. The oil was taken into a solution of HCl (3M, 10 mL), heated to 75 ⁰C for 30 min, cooled to rt, neutralized with solid K₂CO₃. After extraction with Et₂O, the organic layers were dried over Na₂SO₄, chromatographed with 20% EtOAc/hexanes to afford a yellowish oil (0.160 g, 71% in 2 steps). IR (neat, cm^"1): 3305 (s), 2942 (m), 1593 (s), 1517 (s), 1394 (m), 1268 (m). ¹H NMR (400 MHz, CDCl₃) δ 8.16 (IH, dm, /=5.1 Hz), 7.49 (IH, dm, /-7.5 Hz), 7.15 (IH, s), 6.62 (IH, dd, J=7.5, 5.5 Hz), 4.42 (IH, br), 3.04 (3H, d, J=4.0 Hz). ¹³C NMR (100 MHz, CDCl₃) δ 155.5, 148.1, 137.1, 132.3, 116.9, 112.3, 95.0, 29.0 HRMS (ESI) calc'd for C₈H₉Br₂N₂ ([M+H]⁺) 290.9126. Found: 290.9126.

Example Ij : Synthesis of benzyl- [3-(2,2-dibromovinyl)-pyridin-2-yl] amine

1j

The procedure for the synthesis of the methyl analogue was performed on a 1.5 mmol scale to afford a slightly yellow oil (36 % over 3 steps). IR (neat, cm^"1): 3424, 3040, 1583, 1498. ¹H NMR (400 MHz, CDCl₃) δ 8.17 (IH, dd, J= 4.8, 1.8 Hz), 7.54 (IH, ddd, J= 7.5, 1.8, 0.9 Hz), 7.44-7.28 (4H, m), 7.18 (IH, s), 6.68 (IH, dd, J= 7.5, 5.1 Hz), 4.70 (2H, d, J = 5.5 Hz), 4.52 (IH, br). ¹³C NMR (100 MHz, CDCl₃) δ 154.9, 148.6, 139.7, 137.2, 132.4, 128.9, 128.1, 127.5, 116.6, 112.9, 95.0, 45.9. HRMS (EI) calc'd for C₁₄Hi₂N₂Br₂ ([M]⁺) 365.9367. Found: 365.9367.

Example Ik: Synthesis of [3-(2,2-dichloro-l-methylvinyl)-pyridin-2-yl]-carbamic acid tert-butyl ester

1k

To a solution of 2-PivNH pyridine (2.82 g, 16 mmol) in THF (40 mL) was added n-BuLi dropwise at -78 ⁰C. After addition, the mixture was warmed to 0 ⁰C (ice bath) and stirred for 2 h. The mixture was cooled to -78 ⁰C, and a solution of 7V-methoxy-N- 5 methylacetamide (2.0 g, 19 mmol) in THF (10 mL) was added. The mixture was stirred for 10 min and warmed to rt overnight. The reaction was quenched by the addition of NH₄Cl (30 mL), extracted with Et₂O (30 mL), washed NaHCO₃, brine, and dried over Na₂SO₄. The crude product was purified by flash chromatography (50%→100% EtOAc in hexanes) to afford a white solid (1.75 g, 50%). mp: 67-68 ⁰C. IR (neat, cm^"1): 3268, 10 2967, 1710, 1694, 1663, 1580, 1504, 1450, 1263, 1153. ¹H NMR (300 MHz, CDCl₃) δ 11.53 (IH, s), 8.66 (IH, dd, J=4.7, 1.8 Hz), 8.19 (IH, dd, J=7.9, 2.0 Hz), 7.10 (IH, dd, J = 7.9, 4.8 Hz), 2.67 (3H, s), 1.37 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 201.1, 176.9, 153.7, 152.2, 140.0, 118.1, 40.7, 28.1, 27.5. HRMS (ESI) calc'd for Ci₂Hi₆N₂O₂ ([M]⁺) 220.1211. Found: 220.1211.

15 The general procedure for the preparation of gewdichloro vinyl substrate was followed on 5 mmol scale to afford a white solid (1.276 g, 89%). mp: 116-118 ⁰C. IR (neat, cm^"1): 3210, 2967, 1680, 1516, 1438, 1285, 1166. ¹H NMR (400 MHz, CDCl₃) δ 8.38 (IH, dd, J = 4.8, 1.7 Hz), 7.91 (IH, br), 7.55 (IH, dd, J = 7.7, 1.8 Hz), 7.19 (IH, dd, J=7.8, 4.8 Hz), 2.25 (3H, s), 1.32 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 177.01, 148.2, 147.6,

20 137.7, 133.2, 130.7, 121.4, 117.6, 39.7, 27.7, 21.8. HRMS (EI) calc'd for C₁₃Hi₆N₂OCl₂ ([M]⁺) 286.0640. Found: 286.0643.

A solution of the pivaloyl amide (1.265 g, 4.4 mmol) in HCl (6M, 10 mL) was heated to

110 ⁰C over night (12 h). The mixture was diluted with H₂O (10 mL), neutralized with solid K₂CO₃, extracted with Et₂O (3><20 mL), washed with brine, and dried over Na₂SO₄.

25 The crude material was purified using flash chromatography (33%->50% EtOAc in hexanes) afford a white solid (0.836 g, 94%). mp: 82-83 ⁰C. IR (neat, cm^"1): 3474, 3297, 3162, 1631, 1574, 1454. ¹H NMR (400 MHz, CDCl₃) δ 8.06 (IH, dd, J = 4.6, 1.5 Hz), 7.24 (IH, dd, J = 7.5, 1.9 Hz), 6.70 (IH, ddd, J = 7.5, 5.0, 0.5 Hz), 4.44 (2H, br), 2.14 (3H, s). ¹³C NMR (100 MHz, CDCl₃) δ 154.6, 148.2, 136.8, 132.4, 120.2, 119.7 114.4, 5 21.3. HRMS (EI) calc'd for C₈H₈N₂Cl₂ ([M]⁺) 202.0065. Found: 202.0063.

A mixture of the pyridine amine (0.102 mg, 0.5 mmol) and BoC₂O (0.120 mmol, 0.55 mmol) in t-BuOH (2 mL) was stirred at rt for 38 h to result a white suspension. The solvent was removed under vacuum and the residue was taken into a NaHCO₃/K₂CO₃ solution. The aqueous layer was extracted with EtOAc (25 mL), washed with brine, and

10 dried over Na₂SO₄. The crude material was purified using flash chromatography (25% EtOAc in hexanes) afford a white solid (0.110 g, 72%). mp: 172-174 ⁰C. IR (neat, cm^"1): 3162, 2974, 1725, 1519, 1448, 1271, 1161. ¹H NMR (400 MHz, CDCl₃) δ 8.41 (IH, dd, J= 4.8, 1.8 Hz), 7.49 (IH, dd, J= 7.7, 1.8 Hz), 7.09 (IH, dd, J= 7.5, 4.8 Hz), 7.03 (IH, br), 2.20 (3H, s), 1.52 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 152.2, 148.4, 147.8, 137.9,

15 132.3, 127.6, 120.0, 119.3, 81.3, 28.4, 21.8. HRMS (EI) calc'd for C₁₃H₁₇N₂O₂Cl₂ ([M+H]⁺) 303.0667. Found: 303.0660.

Example 11: Synthesis of [3-(2,2-dichloro-vinyl)-pyridin-2-yl]-methyl-amine

1a 11

To a suspension of [3-(2,2-dichlorovinyl)pyridin-2-yl] carbamic acid tert-butyl ester 0 (0.289 g, 1 mmol) in DMF (3 mL) was added MeI (84 μL, 1.35 mmol) at 0 ⁰C. To the mixture was added NaH (0.052 g, 60% mineral oil, 1.35 mmol) in three portions over 15 min and stirred for an additional 15 min. The mixture was warmed to rt and stirred for 30 min before quenched by the addition Of NaHCO₃ (10 mL). The mixture was extracted with Et₂O (3^χl0mL), and the combined organic layers were washed with H₂O (10 mL), 25 NaHCO₃ (10 mL), brine (10 mL), and dried over Na₂SO₄. The product was further purified by flash chromatography (15-20% EtOAc in hexanes) to afford an oil (0.296 g, 98%), which was used directly in the next step. The mixture was added to an aqueous HCl solution (10 mL, 3 M) and heated to 75 ⁰C for 2 h. The mixture was then basified using K₂CO₃, extracted with Et₂O (3x15 mL), and dried over Na₂SO₄. The product was purified by flash chromatography (20% EtOAc in hexanes) to afford a white solid (0.1704 g, 84% in 2 steps), mp: 76-77 ⁰C. IR (neat, cm^'1): 3340, 3271, 2940, 1593, 1574, 1395, 1276. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (IH, dd, ./=5.1, 1.8 Hz), 7.51 (IH, d, J=7.5 Hz), 6.62 (IH, dd, J=7.5, 5.1 Hz), 6.58 (IH, s), 4.29 (2H, br), 3.03 (3H, d, J=4.8 Hz). ¹³C NMR (100 MHz, CDCl₃) δ 156.1, 148.5, 137.0, 125.2, 123.7, 114.3, 112.4, 28.9. HRMS (ESI) calc'd for C₈H₉N₂Cl₂ ([MH]⁺) 203.0137. Found: 203.0131.

Example Im: Synthesis of [2-(2,2-dichlorovinyl)-l-oxypyridin-3-yl]-carbamic acid benzyl ester

1m Benzyl chloro formate (0.68 mL, 4.8 mmol) was added to a suspension of the aminopyridine (600 mg, 3.2 mmol) in saturated aqueous NaHCO₃ solution (6 mL) and acetone (24 mL) at 0 °C. The reaction was warmed slowly to rt and stirred for 7 h then re-cooled to 0 ⁰C and more benzyl chloro formate (1.4 mL) and saturated aqueous NaHCO₃ solution (12 mL) added. The reaction was warmed to rt and another further addition of benzyl chloroformate and NaHCO₃ solution was made after 24 h. After a further 24 h, the solvent was removed in vacuo and the aqueous layer extracted with EtOAc (3 x 50 mL). The organic layer was washed with brine, dried (Na₂SO₄), filtered and concentrated. The crude material was purified using chromatography eluting with 20% EtOAc/hexane to give an inseparable mixture of the product and benzyl alcohol. The mixture was heated to 55 ⁰C at 0.12 mm Hg until most of the benzyl alcohol had been removed. The product was obtained as a colourless oil (containing 20% BnOH), which was directly used in the next step without further purification. Corrected yield (831 mg, 80%). ¹H NMR (400 MHz, CDCl₃) δ 8.38 (IH, dd, J= 4.6, 1.3 Hz), 8.34 (IH, br s), 7.45-7.34 (6H, m), 6.89 (IH, s), 6.59 (IH, br s), 5.23 (2H, s). HRMS (ESI) calc'd for C₁₅Hi₃N₂O₂Cl₂ ([M+H]⁺): 323.0348. Found: 323.0353.

w-CPBA (1.05 g, 4.70 mmol) was added to a solution of the CBz protected substrate (831 mg, 2.6 mmol) in CH₂Cl₂ (26 mL) and stirred at rt for 14 h. The solvent was removed in vacuo then the residue taken up in MeOH and preadsorbed onto silica gel. The crude material was purified using chromatography eluting with 5% MeOH/EtOAc to give the N-oxide as a white solid (604 mg, 1.8 mmol, 69%). mp: 128-130 °C. IR (neat, cm^"1): 2921, 1728, 1541, 1432, 1242. ¹H NMR (400 MHz, CDCl₃) δ 8.08 (IH, d, J=8.6 Hz), 8.02 (IH, dd, J = 6.4, 0.9 Hz), 7.42-7.34 (5H, m), 7.23 (IH, dd, J -8.6, 6.4 Hz), 6.84 (IH, s), 6.80 (IH, s), 5.23 (2H, s). ¹³C NMR (100 MHz, CDCl₃) δ 153.2, 136.0, 135.4, 134.6, 134.5, 129.7, 128.9, 128.7, 125.3, 118.9, 117.5, 68.2. HRMS (ESI): Found [M+H]⁺ 339.0299. Ci₅H₁₃N₂O₃Cl₂ requires 339.0297.

Example In: Synthesis of [3-(2,2-Dichloro-l-methyl-vinyl)-6-methyl-pyridin-2-yl]- [2-(3,4-dimethoxy-phenyl)-ethyl]-amine

The general procedure was followed. The crude material was purified using flash chromatography, eluting with 25% EtOAc/hexane to yield the product as a yellow solid (30%).

¹H NMR (400 MHz, CDCl₃) δ 7.01 (IH, d, J 7.3), 6.84-6.74 (3H, m), 6.44 (IH, d, J 7.3), 4.14 (IH, m), 3.87 (6H, s), 3.8-3.6 (2H, m), 2.87 (2H, td, J 6.6, 2.9), 2.41 (3H, s), 1.97 (3H, s).

Example lo: Synthesis of [S-^.l-Dichloro-vinylJ-l-oxy-pyridin^-ylJ-carbamic acid tert-butyl ester

m-CPBA (639 mg, 2.86 mmol) was added to a solution of If (450 mg, 1.6 mmol) in CH₂Cl₂ (15 mL) and stirred at rt for 18 h. The solvent was removed in vacuo then the residue taken up in MeOH and preadsorbed onto silica gel. The crude material was purified using chromatography eluting with 5 to 10% MeOH/EtOAc to give the N-oxide as a white solid (308 mg, 1.0 mmol, 63%). ¹H NMR (400 MHz, CDCl₃) δ 8.18 (IH, s), 8.10 (2H, s), 6.61 (IH, s), 6.60 (IH, s), 1.54 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 151.7, 139.4, 139.0, 135.3, 129.9, 121.2, 119.2, 116.1, 83.0, 28.4. HRMS (ESI): Found [M+H]⁺ 305.0466. C₁₂H₁₅N₂O₃Cl₂ requires 305.0454. IR (neat, υ cm^"1): 2976, 1728, 1578, 1510, 1446, 1249, 1153. mp: 136-138 ⁰C.

Example 2: Synthesis of Azaindole Derivatives

Example 2a: Synthesis of l-methyl-2-phenyl-lH-pyrrolo[2,3-b]pyridine

1i

General procedure: A mixture of the gem-dibromoalkene (87.6 mg, 0.30 mmol), 2- methylphenylboronic acid (55 mg, 0.45 mmol) and K₃PO₄-H₂O (350 mg, 0.15 mmol) was purged with argon and vacuum three times. A solution Of Pd(OAc)₂ (2.3 mg, 0.010 mmol) and S-phos (8.2 mg, 0.020 mmol) in toluene (3 mL) was stirred at rt for 10 minutes then added via syringe to the solid reagents. The reaction was heated to 100 C for 2 h. The reaction was cooled to rt and saturated NaHCO₃ solution added. The mixture was extracted with Et₂O (3x10 mL), dried over Na₂SO₄ and concentrated in vacuo. The crude material was purified using chromatography eluting with 25% EtOAc/hexane to yield the product as a white solid (52.6 mg, 84%). ¹H NMR (400 MHz, CDCl₃) δ 8.35

(IH, dd, J=4.8, 1.5 Hz), 7.90 (IH, dd, J=U, 1.5 Hz), 7.56-7.54 (2H, m), 7.50-7.47 (2H, m), 7.45-7.40 (IH, m), 7.08 (IH, dd, J=U, 4.6 Hz), 6.52 (IH, s), 3.88 (3H, s).

Example 2b : Synthesis of 1 -methyl-2-phenyl-l H-pyrroIo [2,3-b] pyridine

11

The general procedure was followed. The crude material was purified using chromatography eluting with 25% EtOAc/hexane to yield the product as a white solid (62 mg, 96%).

5 Example 2c: Synthesis of l-methyl-2-(4-methoxyphenyl)-lH-pyrrolo[2,3- b]pyridine

The general procedure was followed except the catalyst loading was 5 mol%, the amount of S-Phos used was 10 mol% and 3 equivalents of base were used. The crude material

10 was purified using chromatography eluting with 25% EtOAc/hexane to yield the product as a white solid (84%). mp: 74-75 ⁰C. IR (neat, υ cm^"1): 2936, 1605, 1489, 1247. ¹H NMR (400 MHz, CDCl₃) δ 8.34 (IH, dd, J =4.6, 1.3 Hz), 7.89 (IH, dd, J =7.7, 1.5 Hz), 7.49 (2H, d, J =8.8 Hz), 7.08 (IH, dd, J =7.9, 4.8 Hz), 7.03 (2H, d, J =8.8 Hz), 6.47 (IH, s), 3.89 (3H, s), 3.88 (3H, s). ¹³C NMR (100 MHz, CDCl₃) δ 160.0, 149.3, 142.5, 142.0,

15 130.6, 128.1, 124.9, 121.0, 116.2, 114.3, 99.0, 55.6, 30.0. HRMS (EI) calc'd for C₁₅H]₄N₂O ([M]⁺): 238.1106. Found 238.1106.

Example 2d: Synthesis of l-methyl-2-(4-trifluoromethylphenyl)-lH-pyrrolo[2,3- b] pyridine

The general procedure was followed except the catalyst loading was 5 mol%, the amount of S-Phos used was 10 mol% and 3 equivalents of base were used.. The crude material was purified using chromatography eluting with 25% EtOAc/hexane to yield the product as a white solid (86%). mp: 105-106 °C. IR (neat, cm^"1): 2956, 1728, 1585, 1503, 1446. ¹H NMR (400 MHz, CDCl₃) δ 8.40 (IH, dd, J =4.8, 1.5 Hz), 7.94 (IH, dd, J =7.9, 1.5 Hz), 7.77 (2H, d, J =8.3 Hz), 7.69 (2H, d, J =8.3 Hz), 7.12 (IH, dd, J =7.9, 4.8 Hz), 6.60 (IH, s), 3.91 (3H, s). ¹³C NMR (100 MHz, CDCl₃) δ 149.7, 143.6, 140.3, 136.2, 130.4 (Jc_-F =33.0 Hz), 129.5, 128.8, 125.8 (J_c-F=3.8 Hz), 124.3 (J_c-F =272.7 Hz), 120.6, 116.6, 5 100.8, 30.1. ¹⁹F NMR (376 MHz, CDCl₃) δ -62.6. HRMS (EI) calc'd for C₁₅Hi₁N₂F₃ ([M]⁺) 276.0874. Found: 276.0870.

Example 2e: Synthesis of l-benzyl-2-phenyl-lH-pyrrolo[2,3-b]pyridine

The general procedure was followed except the catalyst loading was 5 mol%, the amount0 of S-Phos used was 10 mol% and 3 equivalents of base were used.. The crude material was purified using chromatography eluting with 25% EtOAc/hexane to yield the product as a white solid (74%). mp 110-111 ⁰C. ¹H NMR (400 MHz, CDCl₃) δ 8.34 (IH, dd,

J=4.6, 1. 5 Hz), 7.92 (IH, dd, J=7.8, 1.6 Hz), 7.40-7.35 (5H, m), 7.19-7.15 (3H, m), 7.09

(IH, dd, J= 7.7, 4.7 Hz), 6.96-6.94 (2H, m), 6.55 (IH, s), 5.57 (2H, s). ¹³C NMR (1005 MHz, CDCl₃) δ 149.5, 143.3, 142.1, 138.7, 132.6, 129.5, 128.7, 128.6, 128.6, 128.4,

127.2, 126.7, 120.8, 116.6, 100.5, 46.2. HRMS calc'd for C₂₀H₁₆N₂ (M⁺) 284.1313.

Found: 284.1315.

Example 2f: Synthesis of l-benzyl-2-phenyl-lH-pyrrolo[2,3-b]pyridine

1d 0 The general procedure was followed. The crude material was purified using chromatography eluting with 25% EtOAc/hexane to yield the product as a white solid (90%).

Example 2g: Synthesis of 2-Phenyl pyrrolo[2,3-b]pyridine-l-carboxylic acid tert- butyl ester

The general procedure was followed except the catalyst loading was 5 mol%, the amount of S-Phos used was 10 mol% and 3 equivalents of base were used. The crude material was purified using flash chromatography, eluting with 25% EtOAc/hexane to yield the product as a yellow solid (62%). mp: 121-122 °C. IR (neat, cm^"1): 2978, 1749, 1306,

1250, 1158. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (IH, dd, ./=4.8, 1.8 Hz), 7.86 (IH, dd, J

=8.4, 1.5 Hz), 7.46-7.36 (5H, m), 7.19 (IH, dd, J =1.1, 4.6 Hz), 6.49 (IH, s), 1.27 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 150.1, 148.6, 145.1, 140.9, 134.5, 128.7, 128.3, 122.0,

118.9, 106.1, 84.2, 27.6. HRMS (ESI) calc'd for C₁₈Hi₈N₂O₂Na ([M+Na]⁺): 317.1260. Found: 317.1268.

Example 2h: Synthesis of 3-methyl-2-phenyl-pyrrolo[2,3-b]pyridine-l-carboxylic acid tert-butyl ester and 3-methyl-2-phenyl-lH-pyrrolo[2,3-b] pyridine

1k 2h 2h

The general procedure was followed except the catalyst loading was 5 mol% and the amount of S-Phos used was 10 mol%. The crude material was purified using flash chromatography, eluting with 25% EtOAc/hexane to yield the Boc product as a white solid (A: 40%) and the deprotected product as a white solid (B: 57%).

A: mp: 148-150°C. IR (neat, cm^"1): 2980, 1747, 1415, 1328, 1250, 1154. ¹H NMR (300 MHz, CDCl₃) δ 8.53 (IH, dd, J =4.9, 1.4 Hz), 7.83 (IH, dd, J =7.8, 1.5 Hz), 7.48-7.34 (5H, m), 7.21 (IH, dd, J =1.6, 4.8 Hz), 2.15 (3H, s), 1.20 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 149.5, 148.7, 145.2, 136.1, 133.9, 129.8, 128.2, 127.9, 127.1, 123.2, 118.5, 113.2, 83.6, 27.5, 9.2. HRMS (ESI) calc'd for C₁₉H₂₀N₂O₂Na ([M+Na]⁺): 331.1416. Found: 331.1428.

B: mp: 199-200 °C. IR (neat, cm^"1): 3433, 2914, 1580, 1443, 1289. ¹H NMR (400 MHz, CDCl₃) δ 11.12 (IH, br), 8.22 (IH, dd, J =4.9, 1.5 Hz), 7.91 (IH, dd, J =7.8, 1.4 Hz), 7.73 (2H, d, J =7.2 Hz), 7.54 (2H, t, J -7.6 Hz), 7.41 (IH, t, J =7.4 Hz), 7.08 (IH, dd, J =7.8, 4.8 Hz), 2.49 (3H, s). ¹³C NMR (100 MHz, CDCl₃) δ 149.2, 142.4, 135.4, 133.4, 129.0, 128.4, 127.8, 127.3, 123.2, 115.4, 106.5, 9.9. HRMS (ESI) calc'd for Ci₉H₂₀N₂O₂Na ([M+Na]⁺): 209.1073. Found: 209.1072.

Example 2i: Synthesis of l-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3,6-dimethyl-2-phenyl- 1 H-pyrrolo [2,3-b] pyridine

The general procedure was followed except that the catalyst loading was 5% and 10% of S-Phos was used. The crude material was purified using flash chromatography, eluting with 25% EtOAc/hexane to yield the product as a colourless oil (30%).

¹H NMR (400 MHz, CDCl₃) δ 7.73 (IH, d, J 7.9), 7.45-7.36 (3H, m), 7.21-7.17 (2H, m), 6.95 (IH, d, J 7.9), 6.63 (IH, d, J 8.1), 6.37 (IH, dd, J 7.9, 1.7), 6.19 (IH, d, J 2.0), 4.42 (2H, t, J 7.2), 3.82 (3H, s), 3.65 (3H, s), 2.82 (2H, t, J 7.5), 2.67 (3H, s), 2.18 (3H, s).

Example 2j: Synthesis of 2-Phenyl pyrrolo[2,3-c]pyridine-l-carboxylic acid tert- butyl ester

The general procedure was followed. The crude material was purified using chromatography eluting with 33% EtOAc/hexane to yield product as a white solid

(87%). mp: 108-109 ⁰C. IR (neat, cm^"1): 2979, 1734, 1433, 1349, 1326, 1149. ¹H NMR (400 MHz, CDCl₃) δ 9.48 (IH, s), 8.42 (IH, d, J=5.3 Hz), 7.45 (IH, dd, J=5.3, 1.1 Hz), 7.43-7.40 (5H, m), 6.54 (IH, s), 1.36 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 149.5, 144.0, 142.4, 137.8, 134.6, 134.3, 133.9, 129.0, 128.5, 128.1, 114.9, 108.8, 84.7, 27.7. HRMS (ESI) calc'd for C₁₈H₁₉N₂O₂ ([M+H]⁺) 295.1441. Found: 295.1450.

Example 2k: Synthesis of 2-o-tolyl pyrroloβjS-clpyridine-l-carboxylic acid tert- butyl ester

The general procedure was followed except that the catalyst loading was 5%, 10% of S- Phos was used and 3 equivalents of base was used. The crude material was purified using chromatography eluting with 25% EtOAc/hexane to yield the product as a colorless oil (73%). IR (neat, cm^"1): 3338, 2928, 1732, 1589, 1432, 1340, 1147. ¹H NMR (400 MHz, CDCl₃) δ 9.53 (IH, s), 8.45 (IH, d, J=5.3 Hz), 7.49 (IH, dd, J=5.3, 0.9 Hz), 7.37-7.32 (IH, m), 7.29-7.23 (3H, m), 6.47 (IH, d, J= 0.6 Hz), 2.18 (3H, s), 1.30 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 149.4, 143.0, 142.4, 138.0, 137.2, 134.8, 134.2, 133.9, 129.8, 129.7, 128.9, 125.6, 114.9, 108.6, 114.5, 108.6, 84.3, 27.7, 20.1. HRMS (ESI) calc'd for C₁₉H₂₁N₂O₂ ([M+H]⁺): 309.1597. Found: 309.1605.

Example 21: Synthesis of 2-(4-trifluoromethyIphenyl) pyrrolo[2,3-c]pyridine-l- carboxylic acid tert-butyl ester

The general procedure was followed except the catalyst loading was 5 mol%, the amount of S-Phos used was 10 mol% and 3 equivalents of base were used. The crude material was purified using chromatography eluting with 50-70% EtOAc/hexane to yield the product as a colorless oil (72%). IR (neat, cm^"1): 3427, 2990, 1735, 1592, 1324, 1133. ¹H NMR (400 MHz, CDCl₃) δ 9.48 (IH, s), 8.45 (IH, d, J= 5.3 Hz), 7.70 (2H, d, J= 8.1 Hz), 7.57 (2H, d, J= 7.9 Hz), 7.49 (IH, dd, J= 5.3, 1.1 Hz), 6.61 (IH, s), 1.40 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 149.3, 142.7, 142.3, 138.2, 137.6, 134.5, 134.4, 130.7 (q, J_c-F =33.0 Hz), 129.5, 125.1 (1C, Jc_-F= 3.8 Hz), 124.2 (J_c-F = 272.2 Hz), 115.2, 109.9, 85.2, 27.9. ¹⁹F NMR (376 MHz, CDCl₃) δ -62.2. HRMS (ESI) calc'd for C₁₉H₁₈N₂O₂F₃ ([M+H]⁺): 363.1314. Found: 363.1329.

5 Example 2m: Synthesis of 2-(4-methoxyphenyl) pyrroloP-S-clpyridine-l-carboxylic acid tert-butyl ester

10 was purified using chromatography eluting with 30-40% EtOAc/hexane to give the product as a white solid (81%). mp: 103-104 °C. IR (neat, υ cm^"1): 3392, 2983, 1735, 1599, 1494, 1432, 1330, 1252, 1140. ¹H NMR (400 MHz, CDCl₃) δ 9.44 (IH, s), 8.42 (IH, d, J= 5.3 Hz), 7.46 (IH, d, J= 5.3 Hz), 7.37 (2H, d, J= 8.8 Hz), 6.97 (2H, d, J= 8.6 Hz), 6.52 (IH, s), 3.87 (3H, s), 1.44 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 160.1, 149.6,

15 144.1, 142.4, 137.8, 134.8, 134.3, 130.3, 126.2, 114.8, 113.6, 108.5, 84.8, 55.6, 28.0. HRMS (ESI) calc'd for C₁₉H₂₁N₂O₃ ([M+H]⁺): 325.1546. Found: 325.1562.

Example 2n: Synthesis of 2-naphthalen-2-yl pyrrolo[2,3-c]pyridine-l-carboxylic acid tert-butyl ester

The general procedure was followed except the catalyst loading was 5 mol%, the amount of S-Phos used was 10 mol% and 3 equivalents of base were used. The crude material was purified using chromatography eluting with 50% EtOAc/hexane to give the product as a yellow oil (70%). IR (neat, υ cm^"1): 2921, 1731, 1585, 1432, 1327, 1143. ¹H NMR 25 (400 MHz, CDCl₃) δ 9.51 (IH, s), 8.46 (IH, d, J= 5.3 Hz), 7.96 (IH, s), 7.92-7.86 (3H, m), 7.57- 7.49 (4H, m), 6.67 (IH, s), 1.34 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 149.4, 143.9, 142.3, 137.7, 134.6, 133.0, 132.9, 131.1, 128.1, 127.8, 127.6, 127.3, 126.9, 126.6, 126.6, 114.8, 109.1, 84.8, 29.7, 27.6. HRMS (ESI) calc'd for C₂₂H₂₁N₂O₂ ([M+H]⁺): 345.1597. Found: 345.1595.

5 Example 2o: Synthesis of 2-thiophen-3-yl-pyrrolo[2,3-c]pyridine-l-carboxylic acid tert-butyl ester

The general procedure was followed except the catalyst loading was 5 mol%, the amount of S-Phos used was 10 mol% and 3 equivalents of base were used. The reaction was

10 heated to 100 °C for 20 h. The crude material was purified using chromatography eluting with 10 to 25% EtOAc/hexane to give the product as an off-white solid (55%). mp 86-87 0C. IR (neat, cm⁴): 2918, 1737, 1337, 1149. ¹H NMR (400 MHz, CDCl₃) δ 9.44 (IH, s), 8.41 (IH, d, J=5.3 Hz), 7.45 (IH, dd, J = 5.3, 0.9 Hz), 7.41 (IH, dd, J - 3.1, 1.3 Hz), 7.36 (IH, dd, J= 5.1, 3.1 Hz), 7.17 (IH, dd, J= 5.1, 1.3 Hz), 6.58 (IH, s), 1.48 (9H, s).

15 ¹³C NMR (100 MHz, CDCl₃) δ 149.5, 142.4, 139.0, 137.9, 134.6, 134.2, 133.8, 129.0, 125.2, 124.5, 114.9, 109.2, 84.9, 28.0. HRMS (ESI) calc'd for C₁₆H₁₇N₂O₂S ([M+H]⁺): 301.1005. Found: 301.1016.

Example 2p: Synthesis of 2-pent-l-enyl-pyrrolo[2,3-c]pyridine-l-carboxylic acid 0 tert-butyl ester

The general procedure was followed except that 5 mol% of Pd(OAc)₂ was used, 10 mol% of S-Phos and 3 equiv. of base. The reaction was heated to 100 ⁰C for 2 h. The crude material was purified using chromatography eluting with 25 to 50% EtOAc/hexane 25 to give the product as a colourless oil (79%). IR (neat, cm^"1): 2937, 1738, 1325, 1148. ¹H NMR (400 MHz, MeOD) δ 9.20 (IH, s), 8.20 (IH, d, J 5.3), 7.49 (IH, d, J 5.3), 6.96 (IH, d, J 15.8), 6.72 (IH, s), 6.36 (IH, dt, J 15.6, 7.0), 2.54 (2H, q, J 7.3), 1.70 (9H, s), 1.54 (2H, sextet, J 7.3), 0.99 (3H, t, J 7.5). ¹³C NMR (100 MHz, MeOD) δ 151.0, 145.6, 142.1, 138.4, 137.8, 137.1, 135.0, 122.7, 116.3, 105.6, 86.8, 36.5, 28.5, 23.4, 14.2. HRMS (EI) calc'd for C_nH₂₂N₂O₂S ([M]⁺): 286.1681. Found: 286.1683.

Example 2q: Synthesis of 2-(2-methoxyquinolin-3-yl)-pyrrolo[2,3-c]pyridine-l- carboxylic acid tert-butyl ester

The general procedure was followed except that 5 mol% of Pd(OAc)₂ was used, 10 mol% of S-Phos and 3 equiv. of base. The reaction was heated to 100 ⁰C for 1 h. The crude material was purified using chromatography eluting with 40 to 50% EtOAc/hexane to give the product as a colourless oil (102 mg, 0.27 mmol, 91%). mp: 88-90 °C. IR (neat, υ cm^"1): 2976, 1742, 1623, 1582, 1456, 1344, 1266, 1147. ¹H NMR (400 MHz, CDCl₃) δ 9.50 (IH, s), 8.44 (IH, d, J= 5.3 Hz), 8.05 (IH, s), 7.89 (IH, d, J= 8.1 Hz), 7.77 (IH, dd, J= 8.13 Hz), 7.66 (IH, ddd, J= 8.6, 7.0, 1.5 Hz), 7.50 (IH, dd, J= 5.3, 1.1 Hz), 7.43 (IH, ddd, J= 8.1, 7.0, 1.1 Hz), 6.37 (IH, s), 4.05 (3H, s), 1.37 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 159.8, 149.4, 146.6, 142.2, 139.2, 137.9, 137.5, 134.5, 134.1, 130.2, 127.8, 127.4, 124.9, 124.7, 120.0, 115.1, 109.4, 84.8, 53.9, 27.9. HRMS (ESI) calc'd for . C₂₂H₂₂N₃O₃ ([M+H]⁺): 376.1655. Found: 376.1663.

Example 2r: Synthesis of 2-Phenyl-pyrroIo[3,2-c]pyridine-l-carboxylic acid tert- butyl ester

1f

The general procedure was followed except that a variety of ligands were used in separate experiments as set out in Table 2. The Pd loading was 5% in all cases and the amount of boronic acid used was 1.2 equivalents. The crude material was purified using chromatography eluting with 50% EtOAc/hexane to give the product as a yellow oil (yields, see table 2). mp 128-129 ⁰C. IR (neat, cm^"1): 2979, 1737, 1459, 1339, 1321, 1228, 1152. ¹H NMR (400 MHz, CDCl₃) δ 8.88 (IH, s), 8.49 (IH, d, J= 5.7 Hz), 8.05 (IH, d, J=5.7 Hz), 7.43-7.40 (5H, m), 6.62 (IH, s), 1.32 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 149.7, 144.3, 143.5, 141.9, 141.6, 134.2, 129.0, 128.3, 128.1, 125.8, 110.3, 180.0, 84.7, 27.7. HRMS (ESI): calc'd for C₁₈H₁₉N₂O₂ ([M+H]⁺) 295.1441. Found: 295.1453.

Example 2s: Synthesis of 2-(4-fluorophenyl)-pyrrolo[3,2-c]pyridine-l-carboxylic acid tert-butyl ester

1f

The general procedure was followed except that X-Phos was used in place of S-Phos and 1.2 equiv. of boronic acid was used at a catalyst loading of 5%. The crude material was purified using chromatography eluting with 30 to 35% EtOAc/hexane to yield the product as a white solid (88%). mp: 132-133 ⁰C. IR (neat, cm^"1): 1728, 1592, 1497, 1453, 1340, 1225, 1154. ¹H NMR (400 MHz, CDCl₃) δ 8.87 (IH, d, J=Ll Hz), 8.49 (IH, d, J = 5.7 Hz), 8.03 (IH, dt, /=5.7 Hz, /=0.9 Hz), 7.42-7.36 (2H, m), 7.12 (2H, tm, J =8.6 Hz), 6.59 (IH, d, J=0.9 Hz), 1.37 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 162.9 (1C, J_c-F 248), 149.6, 144.4, 143.6, 141.9, 140.5, 130.8 (1C, J_C-F 8.4), 130.3, 125.7, 115.2 (1C, J_C- _F 21), 110.4, 108.3, 85.0, 27.8. ¹⁹F NMR 377 MHz) δ -113.3. HRMS (EI): calc'd for C₁₈H_nN₂O₂F ([M]⁺) 312.1274. Found: 312.1280.

Example 2t: 2-(4-methoxyphenyl)-pyrrolo[3,2-c]pyridine-l-carboxylic acid tert- butyl ester

The general procedure was followed except that 1.2 equiv. of boronic acid was used at a catalyst loading of 5%. The reaction was heated to 100 C for 13.5 h then diluted in EtOAc and filtered through a pad of celite. The crude material was purified using chromatography eluting with 30 to 40% EtOAc/hexane to give the product as a colourless oil (68%). IR (neat, cm^"1): 2974, 1738, 1450, 1332, 1240, 1155. ¹H NMR (400 MHz, CDCl₃) δ 8.86 (IH, d, J = 0.6 Hz), 8.47 (IH, d, J =5.9 Hz), 8.02 (IH, d, J = 5.9 Hz), 7.34 (2H, dt, J =9.0, 2.2 Hz), 6.96 (2H, dt, / = 8.8 Hz, f = 2.2 Hz), 6.56 (IH, d, J =0.7 Hz), 3.86 (3H, s), 1.38 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 159.9, 149.8, 144.1, 143.4, 141.8, 141.6, 130.3, 126.5, 125.9, 113.6, 110.3, 107.6, 84.7, 55.6, 27.8. HRMS (ESI): calc'd for Ci₉H₂₁N₂O₃ ([M+H]⁺) 325.1546. Found: 325.1539.

Example 2u: Synthesis of Z-o-Tolyl-pyrroloP^-clpyridine-l-carboxylic acid tert- butyl ester

1f The general procedure was followed except that X-Phos was used in place of S-Phos and 1.2 equiv. of boronic acid was used at a catalyst loading of 5%. The crude material was purified using chromatography eluting with 50% EtOAc/hexane to give the product as a yellow oil (75%). mp 104-105 ⁰C. IR (neat, cm^"1): 2979, 2930, 1739, 1457, 1340, 1228, 1154. ¹H NMR (400 MHz, CDCl₃) δ 8.87 (IH, s), 8.49 (IH, d, J= 5.9 Hz), 8.11 (IH, d, J=5.7 Hz), 7.34-7.24 (4H, m), 6.52 (IH, d, J=0.7 Hz), 2.17 (3H, s), 1.29 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 149.6, 144.1, 143.4, 141.4, 140.6, 137.4, 134.4, 129.9, 129.7, 128.8, 125.9, 125.6, 110.6, 107.7, 84.3, 27.6, 20.1. HRMS (ESI): calc'd for Ci₉H₂₁N₂O₂ ([M+H]⁺) 309.1597.1441. Found: 309.1596.

Example 2v: Thiophen-3-yl-pyrrolo[2,3-c]pyridine-l-carboxylic acid tert-butyl ester

The general procedure was followed except that 1.2 equiv. of boronic acid was used at a catalyst loading of 5%. The crude material was purified using chromatography eluting with 50% EtOAc/hexane to give the product as a yellow oil (80%). mp 112-113 ⁰C. IR (neat, Cm^"1): 2980, 1739, 1459, 1338, 1152. ¹H NMR (400 MHz, CDCl₃) δ 8.86 (IH, s), 8.48 (IH, d, J= 5.9 Hz), 8.03 (IH, d, J=5.7 Hz), 7.38-7.34 (2H, m), 7.14 (IH, dd, J=4.8, 1.3 Hz), 6.63 (IH, d, J=0.7 Hz), 1.43 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 149.6, 144.3, 143.4, 141.7, 136.5, 134.0, 129.0, 125.6, 125.1, 124.0, 110.4, 108.3, 84.8, 27.8. HRMS (ESI): calc'd for Ci₆H_nN₂O₂S ([M+H]⁺) 301.1005. Found: 301.1012.

5 Example 2w: Synthesis of 5-Oxy-2-phenyl-pyrrolo[3,2-c]pyridine-l-carboxylic acid tert-butyl ester

The general procedure was followed except using half the concentration (approx. 0.05M) at a catalyst loading of 5%. The reaction was heated to 100 °C for 2 h then the reaction

10 mixture was diluted in MeOH and the solids filtered off. The crude material was purified using chromatography eluting with 10 to 15% MeOH/EtOAc to give the product as a yellow solid (33 mg, 0.11 mmol, 65%). ¹H NMR (400 MHz, CDCl₃) δ 8.53 (IH, d, J 1.8), 8.18 (IH, dd, J7.3, 1.8), 8.08 (IH, dd, J7.0), 7.47-7.38 (5H, m), 6.51 (IH, s), 1.30 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 149.1, 144.9, 135.5, 134.3, 133.2, 131.7, 129.0,

15 128.9, 128.2, 127.1, 112.5, 106.6, 85.6, 27.6. HRMS (EI): Found [M]⁺ 310.1313. Ci₈H₁₈N₂O₃ requires 310.1317. IR (neat, υ cm^"1): 1734, 1449, 1333, 1130. mp: 150- 152 ⁰C.

Example 2x: Synthesis of 2-(4-Methoxy-phenyl)-5-oxy-pyrrolo[3,2-c]pyridine-l- 0 carboxylic acid tert-butyl ester

The general procedure was followed except using half the concentration (approx. 0.05M) at a catalyst loading of 5%. The reaction was heated to 100 ⁰C for 1.5 h then the reaction mixture was diluted in MeOH and the solids filtered off. The crude material was purified using chromatography eluting with 5 to 15% MeOH/EtOAc to give the product as a colourless gum (44 mg, 0.13 mmol, 76%). ¹H NMR (400 MHz, CDCl₃) δ 8.51 (IH, d, J 1.3), 8.17 (IH, dd, J7.0, 1.7), 8.04 (IH, d, J7.3), 7.33 (2H, dt, J8.8, 2.9), 6.97 (2H, dt, J 5 8.8, 2.9), 6.46 (IH, d, J 0.4), 3.07 (3H, s), 1.37 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 160.3, 149.2, 144.9, 135.2, 134.3, 131.5, 130.3, 127.1, 125.4, 113.7, 112.4, 106.3, 85.6, 55.6, 27.7. HRMS (ESI): Found [M+H]⁺ 341.1508. Ci₉H₂iN₂O₄ requires 341.1495. IR (neat, υ cm^"1): 2924, 1739, 1447, 1335, 1132.

10 Example 2y: Synthesis of 2-(4-Methoxy-phenyl)-5-oxy-pyrrolo[3,2-c]pyridine-l- carboxylic acid tert-butyl ester

The general procedure was followed except using half the concentration (approx. 0.05M) at a catalyst loading of 5%. The reaction was heated to 100 °C for 1 h then the reaction

15 mixture was diluted in MeOH and the solids filtered off. The crude material was purified using chromatography eluting with 5 to 15% MeOH/EtOAc to give the product as a colourless gum (36 mg, 0.13 mmol, 50%). ¹H NMR (400 MHz, CDCl₃) δ 8.54 (IH, t, J 0.7), 8.20 (IH, dd, J 7.3, 1.7), 8.08 (IH, d, J 7.2), 7.71 (2H, d, 7.9), 7.53 (2H, d, J 8.1), 6.55 (IH, s), 1.32 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 148.6, 142.8, 136.6, 135.9,

20 134.1, 131.7, 130.9 (J_c-F 33.0), 129.2, 126.7, 125.0 (J_c-F 3.8), 123.8 (Jc_-F 272.0), 112.5, 107.4, 86.0, 27.4.

Example 2z: 2-Phenyl-lH-pyrrolo[3,2-b]pyridine 4-oxide

The general procedure was followed except using half the concentration (approx. 0.05M) at a catalyst loading of 5%. The reaction was heated to 100 ⁰C for 2 h then the reaction mixture was diluted in MeOH and the solids filtered off. The crude material was purified using chromatography eluting with 10 to 20% MeOH/EtOAc to give the product as a yellow solid (70%). mp: 150 °C (decomp.). IR (neat, cm^"1): 3317, 1452, 1130. ¹H NMR (400 MHz, MeOD) δ 8.10 (IH, dd, J= 6.2, 0.6 Hz), 7.84-7.79 (2H, m), 7.64 (IH, dt, J = 8.3, 0.9 Hz), 7.47-7.42 (2H, m), 7.37 (IH, tt, J= 6.4, 1.3 Hz), 7.16 (IH, dd, J = 8.1, 6.1 Hz), 7.10 (IH, d, J=0.9 Hz). ¹³C NMR (100 MHz, MeOD) δ 145.1, 138.6, 135.6, 132.8, 131.9, 130.8, 130.5, 127.3, 118.7, 115.8, 93.7. HRMS (ESI): calc'd for C₁₃H_UN₂O ([M+H]⁺) 211.0865. Found: 211.0873.

Example 2aa: 2-(4-Methoxyphenyl)-lH-pyrrolo[3,2-b]pyridine 4-oxide

The general procedure was followed except using half the concentration (approx. 0.05M) at a catalyst loading of 5%. The reaction was heated to 100 ⁰C for 1 h then the reaction mixture was diluted in MeOH and the solids filtered off. The crude material was purified using chromatography eluting with 10 to 30% MeOH/EtOAc to give the product as a pale brown solid (98%). mp: 270 °C (decomp.). IR (neat, cm^"1): 3413, 1650, 1011. ¹H

NMR (500 MHz, DMSO) δ 12.32 (IH, s), 8.0 (IH, d, J = 6.2 Hz), 7.91 (2H, d, J = 8.8 Hz), 7.40 (IH, d, J = 8.2 Hz), 7.08-7.03 (4H, m), 3.37 (3H, s). ¹³C NMR (125 MHz,

DMSO) δ 159.7, 140.4, 137.1, 133.1, 130.3, 127.1, 123.1, 117.3, 114.5, 109.6, 92.0, 55.3.

HRMS (ESI): calc'd for Ci₄H_nN₂O₂ ([M+H]⁺) 241.0971. Found: 241.0977.

Example 2bb:2-(4-Methoxyphenyl)-lH-pyrrolo[2,3-c]pyridine

Trifluoroacetic acid (0.1 mL) was added to a solution of the carbamate (24 mg, 0.074 mmol) in CH₂Cl₂ (0.5 mL) at it. The reaction was stirred for 4 h at rt then diluted with CH₂Cl₂ and basified to pH 10 using 2M NaOH. H₂O was added and the layers separated. The organic layer was washed with brine, dried (Na₂SO₄), filtered and concentrated to give the product as a pale brown solid (14 mg, 0.062 mmol, 84%). mp: 222-225 °C. IR (neat, cm^"1): 1602, 1493, 1429, 1249. ¹H NMR (400 MHz, DMSO) δ 11.87 (IH, s), 8.68 5 (IH, s), 8.04 (IH, d, J 5.3), 7.85 (IH, d, J 8.6), 7.44 (IH, d, J 5.7), 7.06 (IH, d, J 8.3), 6.82 (IH, s), 3.80 (3H, s). ¹³C NMR (100 MHz, DMSO) δ 159.6, 141.5, 138.2, 134.1, 133.8, 133.0, 127.2, 123.8, 114.5, 114.1, 96.6, 55.3, 55.2. HRMS (ESI): calc'd for C₁₄H₁₃N₂O ([M+H]⁺) 225.1022. Found: 225.1013.

10 Example 2cc: 2-PhenyMH-pyrroIo[3,2-b]pyridine

Phosphorus trichloride (0.02 niL, d 1.57, 0.22 mmol) was added dropwise to a stirred solution of the pyridine N-oxide (12 mg, 0.038 mmol) in CHCl₃ (1 mL). The reaction mixture was heated to 80 °C for 7 h. Ice was added to the reaction mixture and then

15 neutralized to pH 10 using saturated aqueous NaHCO₃ solution. After stirring for 30 min, the mixture was extracted using CHCl₃ (3 x 15 mL). The organic layer was washed with brine, dried (MgSO₄), filtered and concentrated in vacuo. The crude material was purified using chromatography eluting with 100% EtOAc to 10% MeOH/EtOAc to give the product as a white solid (6 mg, 0.03 mmol, 80%). mp: 250-252 °C. ER (neat, cm^"1):

20 3439, 1642. ¹H NMR (400 MHz, MeOD) δ 7.23 (IH, s), 6.58 (IH, d, J - 5.7 Hz), 6.29 (2H, d, J = 7.7 Hz), 5.93 (2H, t, J= 7.5 Hz), 5.89 (IH, d, J= 5.9 Hz), 5.82 (IH, t, J= 7.3 Hz), 5.45 (IH, s). ¹³C NMR (100 MHz, MeOD) δ 143.5, 142.8, 141.9, 140.5, 133.2, 130.3, 129.5, 127.9, 126.8, 108.1, 99.1, 99.1. HRMS (ESI): calc'd for Ci₃H₁₀N₂ ([M]⁺) 194.0844. Found: 194.0852.

25

Example 3: Synthesis of Thienopyrrole Derivatives

Example 3a: 5-Phenyl-thieno[2,3-b]pyrrole-6-carboxylic acid tert-butyl ester

The general procedure given in example 2a was followed. The crude material was purified using chromatography eluting with 3.5% EtOAc/hexane to give the product as a colorless oil (76%). mp 88-89 ⁰C. IR (neat, υ cm^"1): 2979, 2928, 1754, 1726, 1463, 1367, 5 1315, 1164, 1140, 1121, 1044. ¹R NMR (400 MHz, CDCl₃) δ 7.43-7.30 (5H, m), 7.01 (IH, AB, J=5.5 Hz), 6.99 (IH, AB, J=5.5 Hz), 6.47 (IH, s), 1.42 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 149.1, 140.0, 136.2, 134.4, 130.6, 129.6, 127.8, 127.8, 121.7, 117.4, 108.6, 84.7, 28.0. HRMS (ESI): calc'd for C₁₇H₁₇NO₂NaS ([M+Na]⁺) 322.0872. Found: 322.0874. 0

Example 3b: 5-(4-Fluoro-phenyl)-thieno[2,3-b]pyrrole-6-carboxylic acid tert-butyl ester

The general procedure given in example 2a was followed except at a catalyst loading of5 5%. The crude material was purified using chromatography eluting with 3.5% EtOAc/hexane to give the product as a colorless oil (81%). mp 114-115 ⁰C. IR (neat, υ cm^"1): 2980, 1753, 1724, 1504, 1369, 1316, 1161, 1140, 1123. ¹H NMR (500 MHz, CDCl₃) δ 7.40-7.37 (2H, m), 7.09-7.05 (2H, m), 7.02 (IH, AB, J= 5.4 Hz), 6.99 (IH, AB, J= 5.4 Hz), 6.45 (IH, s), 1.46 (9H, s). ¹³C NMR (125 MHz, CDCl₃) δ 162.6 (J_C-_F=2470 Hz), 149.0, 138.8, 136.2, 131.4 (Jc_-F=8.2 Hz), 130.5, 130.4 (J_c-F=3.4 Hz), 121.8, 117.4, 114.8 (Jc-_F=22 Hz), 108.8, 84.9, 28.1. ¹⁹F NMR (288 MHz, CDCl₃) δ -114.4. HRMS: calc'd for C₁₇H₁₆NO₂SF ([M]⁺) 317.0886. Found: 317.0878.

Example 3c: 5-(4-Trifluoromethyl-phenyl)-thieno[2,3-b]pyrrole-6-carboxylic acid5 tert-butyl ester

The general procedure given in example 2a was followed except that Dave-Phos was used as the ligand at a Pd loading of 5%. The crude material was purified using chromatography eluting with 3.5% EtOAc/hexane to give the product as a solid (48%).

5 mp: 124-125 ⁰C. IR (neat, υ cm^"1): 2983, 1754, 1727, 1323, 1165, 1124. ¹H NMR (400

MHz, CDCl₃) δ 7.64 (2H, d, J=8.1 Hz), 7.55 (2H, d, J=7.9 Hz), 7.04 (IH, AB, J= 5.3

Hz), 7.01 (IH, AB, J= 5.3 Hz), 6.54 (IH, s), 1.47 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ

148.9, 138.4, 137.8, 137.0, 130.7, 129.8, 129.7 (q, Jc-_F=32 Hz), 124.8 (q, J_c-F=3.6 Hz),

124.4 (q, Jc-_F=272 Hz), 122.1, 117.5, 109.7, 85.3, 28.0. ¹⁹F NMR (376 MHz, CDCl₃) δ -

10 62.5. HRMS: calc'd for C₁₈H₁₆NO₂F₃S ([M]⁺) 367.0854. Found: 367.0854.

Example 3d: 5-Styryl-thieno[2,3-b]pyrrole-6-carboxylic acid tert-butyl ester

OCi -→ CCV^

1g Boc 3d Boc

The general procedure given in example 2a was followed except that Dave-Phos was 15 used as the ligand at a Pd loading of 5%. The crude material was purified using chromatography eluting with 3.5% EtOAc/hexane to give the product as a yellowish oil (71%). IR (neat, υ cm^"1): 3081, 2979, 1742, 1403, 1366, 1326, 1165, 1113. ¹H NMR (400 MHz, CDCl₃) δ 7.84 (IH, d, J=16.3 Hz), 7.50 (2H, dm, /=8.3 Hz), 7.33 (2H, t, J=7.7 Hz), 7.23 (IH, tt, J=7.5, 1.2 Hz), 6.98 (IH, AB, J= 5.3 Hz), 6.96 (IH, AB, J= 5.3 0 Hz), 6.96 (IH, d, J=15.8 Hz), 6.83 (IH, d, J=0.7 Hz), 1.70 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 149.2, 139.5, 137.6, 136.0, 130.9, 128.8, 128.6, 127.7, 126.7, 122.0, 120.1, 117.3, 104.4, 85.3, 28.4. HRMS: calc'd for C₁₉H₂₀NO₂S ([M+H]⁺) 326.1209. Found: 326. 1225.

25 Example 3e: 5-Phenyl-thieno[3,2-b]pyrrole-4-carboxylic acid tert-butyl ester

The general procedure given in example 2a was followed. The crude material was purified using chromatography eluting with 3.5% EtOAc/hexane to give the product as a white solid (73%). mp 103-104 ⁰C. IR (neat, υ cm^"1): 3379, 2921, 1731, 1585, 1432, 1327, 1143. ¹H NMR (400 MHz, CDCl₃) δ 9.51 (IH, s), 8.46 (IH, d, J= 5.3 Hz), 7.96 5 (IH, s), 7.92-7.86 (3H, m), 7.57- 7.49 (4H, m), 6.67 (IH, s), 1.34 (9H, s). ¹³C NMR (100 MHz, CDCl₃) δ 149.4, 143.9, 142.3, 137.7, 134.6, 133.0, 132.9, 131.1, 128.1, 127.8, 127.6, 127.3, 126.9, 126.6 (2C), 114.8, 109.1, 84.8, 29.7, 27.6. HRMS (ESI): Found [M+H]⁺ 345.1595. C₂₂H₂₁N₂O₂ requires 345.1597.

10 Example 3f: 5-(4-Trifluoromethyl-phenyl)-thieno[3,2-b]pyrrole-4-carboxylic acid tert-butyl ester

The general procedure given in example 2a was followed except at a catalyst loading of 5%. The crude material was purified using chromatography eluting with 3.5%

15 EtOAc/hexane to give the product as a white solid (66%). mp: 119-120 ⁰C. IR (neat, cm^" '): 2981, 1743, 1617, 1478, 1323, 1129. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (2H, dd, J= 8.6, 0.7 Hz), 7.53 (2H, dd, J=8.5, 0.7 Hz), 7.41 (IH, dd, J = 5.3, 0.7 Hz), 7.23 (H, d, J =5.3 Hz), 6.54 (IH, s), 1.43 (9H, s). ¹⁹F NMR (376 MHz, CDCl₃) δ -62.5. ¹³C NMR (125 MHz, CDCl₃) δ 149.2, 140.9, 138.1, 137.9, 129.6 (q, J_c-F=37 Hz), 129.5, 126.1, 125.5,

20 124.9 (q, J_c-F=3.8 Hz), 124.4 (q, J_c-F=272 Hz), 115.9, 108.9, 84.5, 28.0. HRMS (ESI): calc'd for C₁₈H₁₇NO₂F₃S ([M+H]⁺) 368.0926. Found: 368.0931.

Example 3g: 5-(4-Methoxycarbonylphenyl)thieno[3,2-b]pyrrole-4-carboxylic acid tert-butyl ester

The general procedure given in example 2a was followed. The crude material was purified using chromatography eluting with 5% EtOAc/hexane to give the product as a white solid (74%). mp 86-87 ⁰C. IR (neat, υ cm^"1): 2980, 1726, 1609, 1321, 1276, 1141. 1H NMR (500 MHz, CDCl₃) δ 8.05 (2H, dm, /=8.7 Hz), 7.48 (2H, dm, /=8.6 Hz), 7.41 (IH, d, J= 5.2 Hz), 7.23 (IH, d, J=5.2 Hz), 6.56 (IH, s), 3.94 (3H, s), 1.42 (9H, s). ¹³C NMR (125 MHz, CDCl₃) δ 167.1, 149.2, 141.0, 139.0, 138.4, 129.2, 129.0, 126.1, 125.4, 5 115.8, 108.9, 84.4, 52.4, 28.0. HRMS (ESI): calc'd for C₁₉H)₉NO₄NaS ([M+Na]⁺) 380.0927. Found: 380.0925.

Example 3h: 5-Thiophen-3-yl-thieno[3,2-b]pyrrole-4-carboxylic acid tert-butyl ester

The general procedure given in example 2a was followed except at a Pd loading of 5%. The crude material was purified using chromatography eluting with 3.5% EtOAc/hexane to give the product as a white solid (73%). mp: 111-112 ⁰C. IR (neat, υ cm^"1): 3099, 2978, 1731, 1486, 1319, 1131. ¹H NMR (400 MHz, CDCl₃) δ 7.40 (IH, d, J=5.1 Hz), 7.32- 15 7.30 (2H, m), 7.19 (IH, d, J=5.1 Hz), 7.16 (IH, dd, J=A.6, 1.1 Hz), 6.53 (IH, s), 1.49 (9H, s), 1.50 (2H, hexatet, J=7.4 Hz), 0.96 (3H, t, J=7.4 Hz). ¹³C NMR (125 MHz, CDCl₃) δ 149.3, 140.1, 134.7, 134.3, 129.6, 125.9, 124.6, 124.4, 123.5, 116.0, 108.1, 84.0, 28.0. HRMS: calc'd for Ci₅H₂₅NO₂S₂ ([M]⁺) 305.0544. Found: 305.0547.

20 Example 3i: 5-Pent-l-enyl-thieno[3,2-b]pyrrole-4-carboxylic acid tert-butyl ester

The general procedure given in example 2a was followed except at a Pd loading of 5%. The crude material was purified using chromatography eluting with 3.5% EtOAc/hexane to give the product as a white solid (80%). IR (neat, υ cm^"1): 2963, 1738, 1485, 1370, 25 1320, 1255, 1120. ¹H NMR (400 MHz, CDCl₃) δ 7.27 (IH, d, J=5.1 Hz), 7.08 (IH, d, J=5.1 Hz), 6.99 (IH, dd, J=15.8, 0.7 Hz), 6.59 (IH, s), 6.09 (IH, dt, /=15.8 Hz, /=6.9 Hz), 2.20 (2H, qd, J"= 7.6 Hz, /=0.4 Hz), 1.66 (9H, s), 1.50 (2H, sextet, J=7.4 Hz), 0.96 (3H, t, J=7.4 Hz). ¹³C NMR (125 MHz, CDCl₃) δ 149.6, 139.4, 139.1, 132.3, 126.4, 123.6, 122.0, 116.2, 103.4, 84.1, 35.3, 28.4, 22.7, 14.0. HRMS: calc'd for Ci₆H₂₁NO₂S ([M]⁺) 291.1293. Found: 291.1290.

5 Example 3j: 5-(4-Fluoro-phenyl)-thieno[3,2-b]pyrrole-4-carboxylic acid tert-butyl ester

The general procedure given in example 2a was followed except at a Pd loading of 5%.

The crude material was purified using chromatography eluting with 3.5% EtOAc/hexane 10 to give the product as a white solid (74%). mp: 122-123 ⁰C. IR (neat, υ cm^"1): 2979, 1746,

1479, 1323, 1300, 1132. ¹U NMR (500 MHz, CDCl₃) δ 7.40 (IH, d, J= 5.1 Hz), 7.38-

7.36 (2H, m), 7.19 (IH, d, J=5.3 Hz), 7.70 (2H, tm, /=8.4 Hz), 6.46 (IH, s), 1.43 (9H, s).

¹⁹F NMR (376 MHz, CDCl₃) δ -114.4. ¹³C NMR (125 MHz, CDCl₃) δ 162.5 (Jc-_F=247

Hz), 149.3, 140.3, 138.4, 131.1 (Jc-_F=7.7 Hz), 130.7 (J_c-F=3.4 Hz), 125.9, 124.7, 116.0, 15 114.8 (J_c-_F=22 Hz), 108.0, 84.1, 28.1. HRMS (ESI): calc'd for C₁₇H₁₆NO₂FNaS

([M+Na]⁺) 340.0778. Found: 340.0776.

Example 3k: 5-Phenyl-6H-thieno[2,3-b] pyrrole

20 In a 5-mL round-bottom flask was charged with the Boc protected thienopyrrole (36.2 mg, 0.12 mmol) and MeONa (65 mg, 1.2 mmol). After purged with Ar for 5 min, anhydrous methanol (1 mL) and THF (1 niL) were added. The mixture was stirred at rt overnight (16 h). The reaction was then quenched by the addition Of NaHCO₃, extracted with Et₂O (3x10 mL), dried over MgSO₄. The residue was chromatographed with 10%

25 EtOAc/hexanes to afford a white solid (23.1 mg, 96%). ¹H NMR (400 MHz, CDCl₃) δ 8.43 (IH, br), 7.50 (2H, dm, J=8.0 Hz), 7.37 (2H, t, J=7.9 Hz), 7.50 (IH, tm, J-7.4 Hz), 6.99 (IH, d, J= 5.3 Hz), 6.83 (IH, dd, ./=5.3, 0.5 Hz), 6.71 (IH, d, J=2.0 Hz). ¹³C NMR (100 MHz, CDCl₃) δ 138.8, 134.9, 133.2, 132.6, 129.2, 126.9, 124.3, 118.6, 118.0, 99.2. Example 4: Synthesis of Smad3 Inhibitor SIS3

Example 4a: 3-Iodo-l-methyl-2-phenyl-lH-pyrrolo[2,3-b]pyridine

To a solution of l-methyl-2-phenyl-lH-pyrrolo[2,3-b]pyridine (34.5 mg, 0.166 mmol) in DCM (1 mL) at 0 ⁰C was added N-iodosuccimide (56 mg, 0.248 mmol). The mixture was stirred for 30 min and warmed to rt and stirred for an additional 2 h before diluted with Et₂O (10 mL) and quenched by the addition of KI solution. The mixture was washed with Na₂S₂O₃, NaHCO₃, brine and dried over Na₂SO₄. The crude product was purified by silica gel column chromatograph (20% EtOAc in hexanes) to afford a white crystalline solid (53.2 mg, 96%). mp: 84-85 ⁰C. IR (neat, cm^"1): 3051, 1592, 1566, 1480, 1448, 1402, 1309, 1111. ¹H NMR (400 MHz, CDCl₃) δ 8.37 (IH, dd, J=4.6, 1.8 Hz), 7.75 (IH, dd, J=7.9, 1.5 Hz), 7.56-7.46 (5H, m), 7.16 (IH, dd, J=7.9, 4.8 Hz), 3.79 (3H, s). ¹³C NMR (100 MHz, CDCl₃) δ 148.7, 144.0, 142.1, 131.1, 130.7, 129.2, 129.1, 128.5, 123.7, 116.9, 56.5, 30.5. HRMS (ESI): calc'd for C₁₄H₁₂N₂I ([M+H]⁺) 335.0039. Found: 335.0044.

Example 4b: 3-Iodo-l-methyl-2-phenyl-lH-pyrrolo[2,3-b]pyridine

A 10-mL microwave tube was charged with the iodide (33.3 mg, 0.1 mL), acrylamide (Watanabe, T.; Kakefuda, A.; Kubota, H.; Masuda, N. In Jpn. Kokai Tokkyo Koho; (Yamanouchi Pharmaceutical Co., Ltd., Japan). JP 11269172, 1999, p 16 pp) (24.7 mg, 0.1 mmol), Bu₄NCl (28 mg, 0.1 mmol), Na₂CO₃ (0.1 mmol), and Pd(OAc)₂ (1.2 mg, 0.005 mmol). The tube was sealed and purged with Ar for 5 min before the addition of anhydrous DMF (0.5 mL) and purged for another 5 min while stirring. The reaction vessel was subjected to controlled microwave radiation at 200 ⁰C for 5 min. The mixture was diluted with H₂O (5 mL), extracted with EtOAc (3 mL), Et₂O (2x5 mL). The combined organic layers were washed with H₂O (2x5 mL), NaHCO₃ (5 mL), brine (5 mL) and dried over Na₂SO₄. The crude product was purified by silica gel column 5 chromatography (75% EtoAc in hexanes) to afford a foamy solid (40.8 mg, 90%). IR (neat, cm^"1): 2934 (m), 1644 (s), 1591 (s), 1517 (m), 1454 (s), 1270 (s), 1113 (m). ¹R NMR (400 MHz, CDCl₃) δ 8.37 (IH, dd, J=4.6, 1.8 Hz), 7.75 (IH, dd, J=7.9, 1.5 Hz), 7.56-7.46 (5H, m), 7.16 (IH, dd, J=7.9, 4.8 Hz), 3.79 (3H, s). ¹³C NMR (100 MHz, CDCl₃) (two roramers) δ 167.0, 149.1, 148.0, 144.6, 143.8, 136.2, 130.9, 130.1, 129.5, 10 129.0, 128.4, 126.2, 126.2, 126.0, 124.6, 118.7, 117.3, 114.0, 113.7, 111.8, 111.4, 109.7, 109.3, 56.2, 47.3, 44.6, 43.9, 40.2, 30.0, 29.4, 28.4. HRMS (ESI): calc'd for C₂₈H₂₈N₃O₃ ([M+H]⁺) 454.2125. Found: 454.2116.

Example 5: Synthesis of KDR Kinase Inhibitor 15

Example 5: 3-(lH-Pyrrolo[2,3-c]pyridin-2-yl)-lH-quinolin-2-one

The substrate (30 mg, 0.08 mmol), was dissolved in 3M aqueous HCl solution (2 mL) and heated to 80 °C for 13 h. The reaction was cooled to rt and basified to ~pH 9 by the

20 careful addition of solid K₂CO₃. The reaction was diluted with water then extracted using CHCl₃ (6 x 20 mL). The combined organic layers were concentrated then purified using chromatography eluting with 10 to 20% MeOH/EtOAc to give the product as a bright yellow solid (21 mg, 0.08 mmol, quantitative), mp: >290 °C. IR (neat, cm^"1): 3256, 2355, 1667, 1157. ¹H NMR (400 MHz, DMSO) δ 12.29 (IH, s), 12.0 (IH, s), 8.89 (IH, s), 8.69

25 (IH, s), 8.09 (IH, d, J = 4.9 Hz), 7.77 (IH, d, J = 7.7 Hz), 7.57 (IH, tm, J¹ = 8.3 Hz), 7.52 (IH, d, J= 5.3 Hz), 7.40 (IH, d, J= 8.1 Hz), 7.31 (IH, d, J= 0.9 Hz), 7.27 (IH, t, J = 7.3 Hz). ¹³C NMR (100 MHz, DMSO) δ 160.5, 138.0, 137.2, 136.5, 135.1, 133.5, 131.7, 130.9, 128.2, 122.5, 121.6, 119.2, 115.0, 114.2, 100.3, 100.3. HRMS (EI): calc'd for C₁₆H₁₁N₃O ([M+H]⁺) 261.0902. Found: 261.0901.

30

Claims

1. A process for the preparation of a 2-substituted azaindole moiety of formula (I) selected from the group of azaindole isomers consisting of: 5-azaindole, 6-azaindole and 7-azaindole,

(i)

wherein

R₂ comprises H, alkyl, cycloalkyl, aryl, heteroaryl, aryl-lower alkyl-, heteroaryl-lower alkyl-, or alkoxycarbonyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and

the process comprising reacting an ortΛo-gem-dihalovinylaminopyridine compound of formula (II) whereby the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (II):

(H)

wherein

Halo comprises Br or Cl and R₂ and R₃ are as defined above, except that R₂ of formula (II) is not H,

with an organoboron reagent selected from the group consisting of a boronic ester of R4, a boronic acid of R», a boronic acid anhydride of R4, a trialkylborane of R4 and a 9-BBN derivative of R»;

in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted azaindole compound of formula (I),

with the proviso that when R₂ of formula (II) is benzyloxycarbonyl (Cbz), the Cbz group is partially or fully deprotected in situ to yield the compound of formula (I) wherein R₂ is H.

2. A process for the preparation of a 2-substituted thienopyrrole moiety of formula (III) including two isomeric forms wherein the sulphur occupies the 4 or 6 position of the thienopyrrole ring:

wherein R₄ is selected from the group consisting of aryl, heteroaryl, 1 ° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2-position of the azaindole ring via a C-C bond;

R₂ is H or alkoxycarbonyl, which is optionally substituted at one or more substitutable positions with one or more suitable substituents, and

the process comprising reacting an ortλø-gem-dihalovinylaminothiophene compound of formula (FV) wherein the sulphur occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (IV):

(IV)

wherein

Halo comprises Br or Cl and R₂ and R₃ are as defined above, except that R₂ of formula (IV) is not H:

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R₄, a boronic acid anhydride of R4, a trialkylborane of R₄ and a 9-BBN derivative OfR₄;

in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted thienopyrrole compound of formula (III), with the proviso that when R₂ of formula (IV) is benzyloxycarbonyl (Cbz), the Cbz group is partially or fully deprotected in situ to yield the compound of formula (III) wherein R₂ is H.

3. A process for the preparation of a 2-substituted azaindole compound of formula (V) including azaindole isomers selected from the group consisting of: 5 -azaindole, 6- azaindole and 7-azaindole

(V)

wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of formula (V); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

R₂ comprises H, alkyl, cycloalkyl, aryl, heteroaryl, aryl-lower alkyl-, heteroaryl-lower alkyl- or alkoxycarbonyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents,

wherein

Halo comprises Br or Cl, and

R₂ and R₃ are as defined above, except that R₂ of formula (VI) is not H,

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R₄, a boronic acid anhydride of R4, a trialkylborane of R₄ and a 9-BBN derivative of Rj;

in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted azaindole compound of formula (V),

with the proviso that when R₂ of formula (VI) is benzyloxycarbonyl (Cbz), the Cbz group is partially or fully deprotected in situ to yield the compound of formula (V) wherein R₂ is H.

4. A process for the preparation of a 2-substituted thienopyrrole compound of formula (VII) selected from isomeric forms wherein the sulphur occupies the 4 or 6 position of the 2-substituted thienopyrrole compound

wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or Rj is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the thiophene ring of formula (VII); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

R₂ is H or alkoxycarbonyl, which is optionally substituted at one or more substitutable positions with one or more suitable substituents,

R₄ is selected from the group consisting of aryl, heteroaryl, 1 ° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein Rj is bonded to the 2-position of the thienopyrrole ring via a C-C bond;

(VIII)

wherein

Halo comprises Br or Cl, and

R₂ and R₃ are as defined above, except that R₂ of formula (VIII) is not H,

in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted thienopyrrole compound of formula (VII),

with the proviso that when R₂ of formula (VIII) is benzyloxycarbonyl (Cbz), the Cbz group is partially or fully deprotected in situ to yield the compound of formula (VII) wherein R₂ is H.

5. A process for the preparation of a 2-substituted azaindole moiety of formula (IX) including azaindole isomers selected from the group consisting of: 4-azaindole, 5- azaindole, 6-azaindole and 7-azaindole,

wherein

the process comprising reacting an ort/20-ge/M-dihalovinylaminopyridine N-oxide compound of formula (X) wherein the nitrogen occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (X):

(X)

wherein

Halo comprises Br or Cl, and R₂ and R₃ are as defined above, except that R₂ of formula (X) is not H,

with an organoboron reagent selected from the group consisting of a boronic ester OfR₄, a boronic acid of R4, a boronic acid anhydride of R₄, a trialkylborane of R₄ and a 9-BBN derivative OfR₄; in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted azaindole compound of formula (IX),

with the proviso that when R₂ of formula (X) is benzyloxycarbonyl (Cbz), the Cbz group is partially or fully deprotected in situ to yield the compound of formula (IX) wherein R₂ is H.

6. A process for the preparation of a 2-substituted azaindole compound of formula (XI) including azaindole isomers selected from the group consisting of: 4-azaindole, 5- azaindole, 6-azaindole and 7-azaindole

wherein

R₃ comprises H, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aryl-lower alkyl-, or heteroaryl-lower alkyl-, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and Rj is selected from the group consisting of aryl, heteroaryl, 1° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2-position of the azaindole ring via a C-C bond;

the process comprising reacting an ortho-gew-dihalovinylaminopyridine N-oxide compound of formula (XII) wherein the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (XII):

wherein Ri, R₂ and R3 are as defined above, except that R₂ of formula (XII) is not H,

and Halo comprises bromo or chloro;

with an organoboron reagent selected from the group consisting of a boronic ester of Rj, a boronic acid of Rj, a boronic acid anhydride of Rj, a trialkylborane of Rj and a 9-BBN derivative of Rj;

in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the 2-substituted azaindole compound of formula (XI),

with the proviso that when R₂ of formula (XII) is benzyloxycarbonyl (Cbz), the Cbz group is partially or fully deprotected in situ to yield the compound of formula (XI) wherein R₂ is H.

7. A process for the palladium-catalyzed tandem intramolecular C-N bond formation and intermolecular C-C bond formation between an oτtho-gem- dihalovinylaminopyridine compound of formula (VI) whereby the nitrogen occupies any one of the positions of the aromatic ring marked by an asterisk in formula (VI):

wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of formula (VI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

and Halo comprises chloro, or bromo;

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid Of R₄, a boronic acid anhydride Of R₄, a trialkylborane of R₄ and a 9-BBN derivative OfR₄, and wherein R₄ is selected from the group consisting of aryl, heteroaryl, 1° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2- position of the azaindole ring via a C-C bond, for the preparation of a 2-substituted azaindole of formula (V) including the isomers: 5-azaindole, 6-azaindole and 7-azaindole

(V)

wherein Ri, R₂, R₃ and R» are as defined above, except that R₂ of formula (V) may also be H,

the process comprising reacting the ortho-gem-dihalovinylaminopyridine compound of formula (VI) with the organoboron reagent in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to afford the tandem C-N and C-C bond formation between the ortho-gem-dihalovinylaminopyridine compound of formula (VI) and the organoboron reagent to afford the 2-substituted azaindole of formula (V),

8. A process for the palladium-catalyzed tandem intramolecular C-N bond formation and intermolecular C-C bond formation between an or\ho-gem- dihalovinylaminothiophene compound of formula (VIII) wherein the sulphur occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VIII):

wherein each of the one or more R₁ is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the thiophene ring of formula (VIII); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

and Halo comprises chloro, or bromo;

with an organoboron reagent selected from the group consisting of a boronic ester of Rj, a boronic acid of R₄, a boronic acid anhydride of R₄, a trialkylborane of R₄ and a 9-BBN derivative of Rt, and wherein R₄ is selected from the group consisting of aryl, heteroaryl, 1 ° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2- position of the thienopyrrole ring via a C-C bond, for the preparation of a 2-substituted thienopyrrole of formula (VII) including isomeric forms wherein the sulphur occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VII):

(VII)

wherein Ri, R₂, R3 and R4 are as defined above, except that R₂ of formula (VII) may also be H, the process comprising reacting the ortho-gem-dihalovinylaminothiophene compound of formula (VIII) with the organoboron reagent in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to afford the tandem C-N and C-C bond formation between the ortho-gem-dihalovinylaminothiophene compound of formula (VIII) and the organoboron reagent to afford the 2-substituted thienopyrrole of formula (VII),

9. A process for the palladium-catalyzed tandem intramolecular C-N bond formation and intermolecular C-C bond formation between an or\ho-gem- dihalovinylaminopyridine N-oxide compound of formula (XII) including isomers wherein the N-oxide occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (XII):

wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine N-oxide ring of formula (XII); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions, R₂ comprises alkyl, cycloalkyl, aryl, heteroaryl, aryl-lower alkyl-, heteroaryl-lower alkyl- or alkoxycarbonyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents,

and Halo comprises chloro, or bromo;

with an organoboron reagent selected from the group consisting of a boronic ester of R₄, a boronic acid of R₄, a boronic acid anhydride of R₄, a trialkylborane of R₄ and a 9-BBN derivative OfR₄, and wherein R₄ is selected from the group consisting of aryl, heteroaryl, 1° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and wherein R₄ is bonded to the 2- position of the azaindole ring via a C-C bond, for the preparation of a 2-substituted azaindole of formula (XI) comprising isomeric forms wherein the N-oxide occupies any one of the A-, 5-, 6-, or 7-positions in formula (XI):

wherein Ri, R₂, R₃ and R₄ are defined as above, except that R₂ of formula (XI) may also be H,

the process comprising reacting the ortho-gem-dihalovinylaminopyridine N-oxide compound of formula (XII) with the organoboron reagent in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to afford the tandem C-N and C-C bond formation between the oτiho-gem- dihalovinylaminopyridine N-oxide compound of formula (XII) and the organoboron reagent to afford the 2-substituted azaindole of formula (XI), with the proviso that when R₂ of formula (XII) is benzyloxycarbonyl (Cbz), the Cbz group is partially or fully deprotected in situ to yield the compound of formula (XI) wherein R₂ is H.

10. A process for the preparation of an ortho-gem-diha\ogen vinylaminopyridine compound of formula (VI) wherein the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VI):

(VI)

wherein each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O- lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of Formula (VI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₃ is H, CF₃, or alkynyl optionally substituted at one or more positions with one or more suitable substituents, R₂ is H and Halo is bromo, said process comprising the steps of:

(a) reacting a nitropyridinecarboxaldehyde or ketone compound of formula (XIV) where the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (XIV):

wherein Ri is as defined above, and R₃ is as defined above, with CBr₄ and PPh₃ under conditions effective to generate in situ the ørt/*o-gem-dihalovinyl compound of formula (XV)

(XV)

11. A process for the preparation of an

vinylaminopyridine compound of formula (XVI), wherein the nitrogen occupies any one of the positions of the aromatic ring that are marked with an asterisk in formula (XVI):

wherein each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O- lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of Formula (XVI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₃ is H, CF₃ or alkynyl, optionally substituted at one or more positions with one or more suitable substituents; R₂ is H, alkoxycarbonyl, alkyl, aryl or aryl-lower alkyl-; R₅ is H, alkyl or alkoxycarbonyl, with the proviso that both R₂ and R₅ are not H; and Halo is bromo, said process comprising the steps of:

(XVII)

wherein Ri, R₂, R₃ and R₅ are as defined above, with CBr₄ and PPh₃ under conditions effective to generate in situ the ortho-gem-dihalovinyl compound of formula (XVI) wherein the nitrogen occupies any one of the positions of the pyridine ring that are marked by an asterisk in formula (XVI):

(XVI)

wherein Ri, R₂, R₃ and R₅ are as defined above, and Halo is bromo.

12. A process for the preparation of an ort/20-gem-dihalovinylaminothiophene compound of formula (VIII) wherein the sulphur occupies any one of the positions in the thiophene ring that are marked by an asterisk in formula (VIII):

wherein each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O- lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the thiophene ring of Formula (VIII); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₃ is H, CF₃, or alkynyl, optionally substituted at one or more positions with one or more suitable substituents; R₂ is alkoxycarbonyl, optionally substituted at one or more positions with one or more suitable substituents, and Halo is bromo, said process comprising the steps of:

wherein Ri, R₂, and R₃ are as defined above, with CBr₄ and PPh₃ under conditions effective to generate in situ the ortλo-gem-dihalovinyl compound of formula (VIII) wherein the sulphur occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VIII):

(VIII)

wherein Ri, R₂, and R₃ are as defined above, and Halo is bromo.

13. A process for the preparation of an ort/20-gem-dihalovinylaminopyridine compound of formula (XVI) wherein the nitrogen occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (XVI):

wherein each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O- lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of Formula (XVI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₂ is H, alkyl, aryl, aryl-lower alkyl-, or alkoxycarbonyl, all of which are optionally substituted with one or more suitable substituents; R₅ is H, alkyl, aryl, aryl-lower alkyl-, or alkoxycarbonyl, all of which are optionally substituted with one or more suitable substituents, with the proviso that both R₂ and R₅ are not H; and R₃ is H, alkyl or alkynyl, all of which are optionally substituted at one or more positions with one or more suitable substituents, and Halo is chloro, said process comprising the steps of: reacting a pyridinecarboxaldehyde or ketone compound of formula (XVII) where the nitrogen occupies any one of the positions in the aromatic ring that are marked by an asterisk in formula (XVII):

(XVII)

(XVI)

wherein Rj, R₂, R₃ and R₅ are as defined above and Halo is chloro.

14. A process for the preparation of an ort/zo-gerø-dihalovinylaminothiophene compound of formula (VIII) wherein the sulphur occupies any one of the positions in the thiophene ring that are marked by an asterisk in formula (VIII):

wherein each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O- lower alkyl, aryl or heteroaryl, or Ri is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the thiophene ring of Formula (VIII); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; R₂ is alkoxycarbonyl optionally substituted at one or more positions with one or more suitable substituents, and R₃ is H, alkyl, or alkynyl all of which are optionally substituted at one or more positions with one or more suitable substituents, and Halo is chloro, said process comprising the steps of:

wherein Ri, R₂, and R₃ are as defined above, with 2 or more equivalents of CHCl₃ and PPh₃ in the presence of 2 or more equivalents of KO'Bu, wherein said equivalents are relative to formula (XIX), under conditions effective to generate in situ the ortho-gem- dichlorovinyl compound of formula (VIII).

15. A novel ort/*o-gem-dihalovinylaminopyridine compound or a salt thereof selected from the group consisting of:

16. A novel ort/*o-gem-dihalovinylaminothiophene compound or a salt thereof selected from the group consisting of:

17. A process for the preparation of N-arylaminopyridine compounds of formula (VI) where the nitrogen occupies any one of the positions in the pyridine ring that are marked by an asterisk in formula (VI):

wherein Halo comprises Br or Cl; R₂ comprises aryl which is optionally substituted at one or more substitutable positions with one or more suitable substituents; R₃ comprises H, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aryl-lower alkyl-, or heteroaryl-lower alkyl-, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents; and each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring of Formula (VI); all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions; said process comprising the steps of:

wherein Halo, Ri, R₃ are as defined above, with an organoboron reagent comprising a boronic acid, boronic acid anhydride or BF₃ ^" salt of R₂, wherein R₂ is as defined above, in the presence of at least about 1.5 equivalent of a copper (II) catalyst relative to the compound of formula (VI), at least about 0.3 equivalents of a Cg-C₂₀ fatty acid relative to the compound of formula (VI), molecular oxygen, and a non-nucleophilic base, at a reaction temperature of between about 40 ⁰C and 60 ⁰C, under conditions effective to form a C-N bond between formula (VI) and the R₂ group of the organoboron reagent, to afford the N-arylaniline compounds of formula (VI).

18. A process for the deprotection of the N-alkoxycarbonyl azaindoles of formula (V) where the nitrogen occupies any one of the positions of the pyridine ring marked by an asterisk in formula (V):

(V)

wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or R₁ is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the pyridine ring; all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

the process comprising treating a compound of formula (V) with an acid to form the N-H azaindole wherein R₂ is H and Rj, R₃ and R₄ are as defined above for compound (V).

19. A process for the deprotection of the N-alkoxycarbonyl thienopyrrole compounds of formula (VII) where the sulphur occupies the 4 or 6 position of the aromatic ring:

wherein

each of the one or more Ri is independently selected from the group consisting of H, fluoro, lower alkyl, lower alkenyl, lower alkoxy, aryloxy, lower haloalkyl, -C(O)O-lower alkyl, aryl or heteroaryl, or Rj is an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the thiophene ring; all of which are optionally substituted with one or more suitable substituents at one or more substitutable positions,

R₃ comprises H, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aryl-lower alkyl-, or heteroaryl-lower alkyl-, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and R₄ is selected from the group consisting of aryl, heteroaryl, 1° alkyl, and alkenyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents,

20. The process for the removal of the N-oxide from a compound of formula (XI) wherein the nitrogen occupies any one of the 4-, 5-, 6-, or 7- positions in formula (XI):

wherein

R₂ comprises H, alkyl, cycloalkyl, aryl, heteroaryl, aryl-lower alkyl-, or heteroaryl-lower alkyl- or alkoxycarbonyl, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents Ra comprises H, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aryl-lower alkyl-, or heteroaryl-lower alkyl-, all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents, and

the process comprising treating the N-oxide of formula (XI) with a reducing agent to form the reduced compound of formula (V) wherein Rj, R₂, R₃ and R₄ are as defined above for compound (XI) and wherein the nitrogen occupies any one of the A-, 5-, 6-, or 7- positions in formula (V).

(V)

21. A process for the preparation of the Smad3 inhibitor SIS3 of formula (XX):

22. A process for the preparation of the azaindole of formula (XXIII):

where R₂ is as defined above and Halo comprises of Br or Cl, with a boronic acid of the formula (HO)₂B-aryl or (HO)₂B-alkenyl, in the presence of a base, a palladium metal pre-catalyst and a ligand under reaction conditions effective to form the azaindole compound.

23. A process for the preparation of the azaindole of formula (XXV):

where R₂ comprises alkyl, cycloalkyl, heteroaryl, aryl-lower alkyl-, aryl, heteroaryl- lower alkyl- or alkoxycarbonyl all of which are optionally substituted at one or more substitutable positions, and R₆ comprises lower alkyl; the process comprising reacting the gem-dihalovinylaminopyridine of formula

(XXVI):

24. A process for the preparation of an ørt/zø-gem-dihalovinylaminopyridine compound of formula (VI) wherein the nitrogen occupies any one of the positions of the aromatic ring that are marked by an asterisk in formula (VI):

(VI)

wherein R₁ and R₃ are as defined above for formula (VI), with 2 or more equivalents of CHCl₃ and PPh₃ in the presence of 2 or more equivalents of KO'Bu under conditions effective to generate in situ the ort/zo-gem-dichlorovinyl compound of formula (XV)