WO2024064745A1

WO2024064745A1 - Synthesis of reldesemtiv

Info

Publication number: WO2024064745A1
Application number: PCT/US2023/074681
Authority: WO
Inventors: Matthew W. Peterson; Qing Lu; Bradley P. Morgan; Luke W. Ashcraft; Denise Andersen
Original assignee: Cytokinetics, Incorporated
Priority date: 2022-09-21
Filing date: 2023-09-20
Publication date: 2024-03-28

Abstract

Provided herein is a process for the preparation of reldesemtiv and salts thereof. Also provided herein are intermediates used in this process and their preparation.

Description

SYNTHESIS OF RELDESEMTIV

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63/376,567, filed September 21, 2022, the contents of which are hereby incorporated by reference in their entirety for all purposes.

FIELD

[0002] Provided herein is a process for the preparation of reldesemtiv and salts thereof.

BACKGROUND

[0003] U.S. Patent No. 8,962,632 discloses l-(2-((((trans)-3 -fluoro- 1 -(3 -fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide (reldesemtiv), a next-generation fast skeletal muscle troponin activator (FSTA) as a potential treatment for people living with debilitating diseases and conditions associated with neuromuscular or non- neuromuscular dysfunction, muscular weakness, and/or muscle fatigue. U.S. Patent No. 11,142,516 discloses alternative methods of preparing reldesemtiv.

[0004] Previous methods of preparing reldesemtiv involved reagents of high cost or low availability, such as 3 -cyanopyrrole; relied upon protecting group chemistries; required chromatographic purifications; involved hazardous reagents such as diethylaminosulfur trifluoride; and/or involved cryogenic reaction temperatures. In addition, previous methods of preparing reldesemtiv involved certain intermediate oils, which are impractical to handle and may pose challenges in purification.

[0005] There is a need for improved methods for preparing such compound with low cost, improved safety, improved processability (e.g., avoiding use of cryogenic reaction temperatures; or enabling isolation of solid intermediates, for easier handling and/or to facilitate improved purification, such as by crystallization), and scalability.

BRIEF SUMMARY

[0006] In one aspect, provided is a method of preparing a compound of Formula (1):

or a salt thereof, comprising:

(i) converting a compound of Formula (3)

or a salt thereof, to the compound of Formula (2)

or a salt thereof; and

(ii) converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof.

[0007] In another aspect, also provided is a method of preparing a compound of Formula

(2)

or a salt thereof, comprising converting a compound of Formula (3)

(3), or a salt thereof to the compound of Formula (2).

[0008] In some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof comprises reacting the compound of Formula (3) or a salt thereof with a compound of Formula (4)

or a salt thereof.

[0009] In some embodiments, the method further comprises converting a compound of

Formula (5)

or a salt thereof, to the compound of Formula (3) or a salt thereof. In some embodiments, the step of converting the compound of Formula (5) or a salt thereof to the compound of Formula (3) or a salt thereof comprises reacting the compound of Formula (5) or a salt thereof with a compound of Formula (6)

wherein X is chloro or fluoro, to obtain the compound of Formula (3) or a salt thereof.

[0010] In some embodiments, the method further comprises obtaining the compound of

Formula (5) by converting a compound of Formula (7)

to the compound of Formula (5) or a salt thereof. [0011] In some embodiments, the method further comprises obtaining the compound of Formula (7) by converting a compound of Formula (8) to the compound of Formula (7).

[0012] In some embodiments, the method further comprises obtaining the compound of Formula (8) by converting a compound of Formula (9) to the compound of Formula (8).

[0013] In some embodiments, the method further comprises obtaining the compound of

Formula (4) by converting methyl l-tosyl-lH-pyrrole-3-carboxylate to the compound of Formula (4).

Tos

[0014] In some embodiments, the method further comprises obtaining methyl 1 -tosyl- 1H- pyrrole-3 -carboxylate by converting l-tosyl-lH-pyrrole-3-carboxylic acid to methyl 1-tosyl- lH-pyrrole-3-carboxylate.

Tos

[0015] In some embodiments, the method further comprises obtaining 1-tosyl-lH- pyrrole-3 -carboxylic acid by converting l-(l-tosyl-lH-pyrrol-3-yl)ethan-l-one to 1-tosyl-lH- pyrrole-3 -carboxylic acid.

[0016] In some embodiments, the method further comprises obtaining 1-(1 -tosyl- 1H- pyrrol-3-yl)ethan-l-one by converting 1-tosyl-lH-pyrrole to l-(l-tosyl-lH-pyrrol-3-yl)ethan- 1-one.

[0017] In some embodiments, the method further comprises obtaining 1 -tosyl- IH-pyrrole by converting pyrrole to 1 -tosyl- IH-pyrrole.

[0018] In another aspect, also provided is a method of preparing a compound of Formula (2) or a salt thereof, by the methods detailed herein.

DETAILED DESCRIPTION

Definitions

[0019] As used herein and unless otherwise stated or implied by context, terms that are used herein have the meanings defined below. Unless otherwise contraindicated or implied, e.g., by including mutually exclusive elements or options, in those definitions and throughout this specification, the terms “a” and “an” mean one or more and the term “or” means and/or where permitted by context. Thus, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. [0020] At various locations in the present disclosure, e.g., in any disclosed embodiments or in the claims, reference is made to compounds, compositions, or methods that “comprise” one or more specified components, elements or steps. Embodiments also specifically include those compounds, compositions, compositions or methods that are, or that consist of, or that consist essentially of those specified components, elements or steps. The term “comprised of’ is used interchangeably with the term “comprising” and are stated as equivalent terms. For example, disclosed compositions, devices, articles of manufacture or methods that "comprise" a component or step are open and they include or read on those compositions or methods plus an additional component s) or step(s). However, those terms do not encompass unrecited elements that would destroy the functionality of the disclosed compositions, devices, articles of manufacture or methods for its intended purpose. Similarly, disclosed compositions, devices, articles of manufacture or methods that "consist of' a component or step are closed and they would not include or read on those compositions or methods having appreciable amounts of an additional component(s) or an additional step(s). Furthermore, the term “consisting essentially of’ admits for the inclusion of unrecited elements that have no material effect on the functionality of the disclosed compositions, devices, articles of manufacture or methods for its intended purpose as further defined herein. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0021] “About” as used herein when used in connection with a numeric value or range of values provided to describe a particular property of a compound or composition indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the particular property. Specifically, the term "about" when used in this context, indicates that the numeric value or range of values can vary by 5% of the recited value or range of values.

[0022] “Alkyl” refers to and includes saturated linear and branched univalent hydrocarbon structures and combination thereof, having the number of carbon atoms designated (z.e., Ci-Cio means one to ten carbons). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-C20 alkyl”). More particular alkyl groups are those having 1 to 8 carbon atoms (a “Ci-Cs alkyl”), 3 to 8 carbon atoms (a “Cs-Cs alkyl”), 1 to 6 carbon atoms (a “Ci-Ce alkyl”), 1 to 5 carbon atoms (a “C1-C5 alkyl”), or 1 to 4 carbon atoms (a “C1-C4 alkyl”). Examples of alkyl include, but are not limited to, groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0023] “Cycloalkyl” as used herein refers to a C3-C10 saturated or unsaturated nonaromatic hydrocarbon ring group. The cycloalkyl may have a bridge. Examples of the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl.

[0024] “Halo” refers to fluoro, chloro, bromo or iodo. In another embodiment, halo is fluoro. In another embodiment, halo is bromo.

[0025] “Optionally substituted” as used herein means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to 3, 2 to 4, 3 to 4, 1 to 3, 1 to 4 or 1 to 5 substituents. It is understood that where a chemical moiety here is “optionally substituted,” the disclosure includes embodiments in which the moiety is substituted and embodiments in which the moiety is unsubstituted.

[0026] “Alkylene diamine” as used herein refers to a linear or branched alkyl group or cycloalkyl group substituted by two amine groups, each of which is optionally substituted with one substituent. In one embodiment, an alklylene diamine is a linear or branched alkyl group or cycloalkyl group substituted by two unsubstituted amine groups. In one embodiment, an alklylene diamine is a linear or branched alkyl group or cycloalkyl group substituted by two amine groups, each of which is substituted. In one embodiment, an alklylene diamine is a linear or branched alkyl group or cycloalkyl group substituted by two amine groups, each of which is substituted by a Ci-Ce alkyl group. In one embodiment, an alklylene diamine is a linear or branched alkyl group or cycloalkyl group substituted by two amine groups, each of which is substituted by a C1-C3 alkyl group. In one embodiment, an alklylene diamine is a linear or branched alkyl group or cycloalkyl group substituted by two amine groups, each of which is substituted by a methyl group. In one embodiment, an alklylene diamine is a linear alkyl group or a cycloalkyl group substituted by two amine groups, each of which is substituted by a methyl group. Exemplary alkylene diamines include trans-N,N'-dimethylcyclohexane-l,2-diamine and N,N’ -dimethylethylenediamine (DMEDA).

[0027] Each compound disclosed herein may be in a salt form. The compound may contain at least one amino group, and accordingly acid addition salts can be formed with this amino group. Exemplary salts include, without limitation, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0028] A salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the salt can have multiple counter ions. Hence, a salt can have one or more charged atoms and/or one or more counterions. In some embodiments, the salt is a pharmaceutically acceptable salt.

Methods

[0029] In one aspect, provided is a method of preparing a compound of Formula (1):

or a salt thereof, comprising:

(i) converting a compound of Formula (3)

(3), or a salt thereof, to a compound of Formula (2)

or a salt thereof; and

[0030] In some embodiments, the compound of Formula (1) is not a salt. In some embodiments, the compound of Formula (1) is l-(2-((((lr,3r)-3-fluoro-l-(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide. In some embodiments, the compound of Formula (1) is a salt. In some embodiments, the compound of Formula (2) is not a salt. In some embodiments, the compound of Formula (2) is methyl l-(2- ((((lr,3r)-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH- pyrrole-3 -carboxylate. In some embodiments, the compound of Formula (2) is a salt. In some embodiments, the compound of Formula (3) is not a salt. In some embodiments, the compound of Formula (3) is 5-bromo-N-((( l r,3r)-3-fluoro- l -(3-fluoropyridin-2- yl)cyclobutyl)methyl)pyrimidin-2-amine In some embodiments, the compound of Formula (3) is a salt. In some embodiments, none of compound of Formula (1), the compound of Formula (2), and the compound of Formula (3) are salts. In some embodiments, the compound of Formula (1), the compound of Formula (2), and the compound of Formula (3) are each salts. In some embodiments, one of compound of Formula (1), the compound of Formula (2), and the compound of Formula (3) is a salt. In some embodiments, two of compound of Formula (1), the compound of Formula (2), and the compound of Formula (3) are salts.

[0031] In some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof comprises reacting the compound of Formula (2) or a salt thereof with formamide in the presence of a base. In some embodiments, the base is an organic base. Examples of organic bases include, without limitation, amine bases such as N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, ethanolamine; alkoxide bases such as methoxide, ethoxide, tert-butoxide; hydride bases such as sodium hydride; aromatic bases such as pyridine, picoline, lutidine, collidine; and the like. In some embodiments, the base is an inorganic base. Examples of inorganic bases include, without limitation, carbonate bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate; hydroxide bases such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide; phosphate bases such as potassium phosphate, sodium phosphate; and the like. In some embodiments, the base is sodium methoxide.

[0032] In some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed in the presence of an organic solvent. Examples of organic solvents include, without limitation, hexane, pentane, cyclopentane, cyclohexane, benzene, toluene, 1,4-di oxane, di chloromethane (DCM), chloroform, ethyl acetate, tetrahydrofuran (THF), acetone, acetonitrile (MeCN), dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetic acid, n-butanol, isopropanol, n-propanol, ethanol, and methanol and the like. In some embodiments, the organic solvent is any compatible mixture of organic solvent such as those given as examples herein. In some embodiments, the organic solvent is free of water. In some embodiments, the organic solvent comprises water. In some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed in DMSO. It is understood that each description of the solvent may be combined with each description of base, the same as if each and every combination were specifically and individually listed. For example, in some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed in DMSO in the presence of sodium methoxide.

[0033] In some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed at a temperature of about 180 °C, about 170 °C, about 160 °C, about 150 °C, about 140 °C, about 130 °C, about 120 °C, about 110 °C, about 100 °C, about 90 °C, about 80 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, or about 20 °C. In some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed at a temperature of less than about 180 °C, about 170 °C, about 160 °C, about 150 °C, about 140 °C, about 130 °C, about 120 °C, about 110 °C, about 100 °C, about 90 °C, about 80 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, or about 20 °C. In some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed at a temperature of at least about 180 °C, at least about 170 °C, at least about 160 °C, at least about 150 °C, at least about 140 °C, at least about 130 °C, at least about 120 °C, at least about 110 °C, at least about 100 °C, at least about 90 °C, at least about 80 °C, at least about 70 °C, at least about 60 °C, at least about 50 °C, at least about 40 °C, at least about 30 °C, or at least about 20 °C. In some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed at a temperature of between about 180 °C and about 20°C, between about 150 °C and about 20°C, between about 110 °C and about 20°C, between about 100 °C and about 20°C, between about 100 °C and about 30°C, between about 90 °C and about 30°C, between about 80 °C and about 40°C, or between about 70 °C and about 50°C. In some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed at a temperature of about 40 °C to about 80 °C. In some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed at a temperature of about 60 °C. It is understood that each description of the temperature may be combined with each description of solvent and/or base, the same as if each and every combination were specifically and individually listed. For example, in some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed in DMSO in the presence of sodium methoxide, at a temperature of about 60°C. For example, in some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed in DMSO in the presence of sodium methoxide, at a temperature of between about 80°C and about 40°C.

[0034] In some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof further comprises crystallizing the compound of Formula (1) in water. In some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof further comprises crystallizing the compound of Formula (1) in ethanol. In some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof further comprises crystallizing the compound of Formula (1) in n-propanol and water. In some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof further comprises crystallizing the compound of Formula (1) in n-propanol and water after heating to a temperature of between about 60°C and about 95°C. [0035] In some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof comprises hydrolysis of the methyl ester of the compound of Formula (2) or a salt thereof to a carboxylic acid, and further reacting said carboxylic acid with ammonium hydroxide.

[0036] In another aspect, provided is a method of preparing the compound of Formula (2) or a salt thereof, comprising converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof.

[0037] In some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof comprises reacting the compound of Formula (3) or a salt thereof with a compound of Formula (4)

or a salt thereof. It is to be understood that the use of the compound of Formula (4) in the syntheses of the compounds described herein may provide the benefit of lower cost relative to other reagents, such as cyano-lH-pyrrole. In some embodiments, the reaction of the compound of Formula (3) with the compound of Formula (4) is performed in the presence of a catalyst. In some embodiments, the catalyst is a transition metal catalyst. In some embodiments, the reaction is performed in the presence of a palladium catalyst. In some embodiments, the reaction is performed in the presence of cuprous iodide. In some embodiments, the reaction is performed in the presence of a base. In some embodiments, the reaction is performed in the presence of an organic base. Examples of organic bases include, without limitation, amine bases such as N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, ethanolamine; alkoxide bases such as methoxide, ethoxide, tert-butoxide; hydride bases such as sodium hydride; aromatic bases such as pyridine, picoline, lutidine, collidine; and the like. In some embodiments, the base is an inorganic base. Examples of inorganic bases include, without limitation, carbonate bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate; hydroxide bases such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide; phosphate bases such as potassium phosphate, sodium phosphate; and the like. In some embodiments, the second base is potassium phosphate. In some embodiments, the reaction is performed in the presence of an amine, such as mono-, di-, tri-, or tetra substituted amine. In some embodiments, the reaction is performed in the presence of an alkylene diamine. Exemplary alkylene diamines include, without limitation: ethyl- 1,2-diamine; N,N-dimethyl-ethyl-l,2- diamine; N,N-dimethyl-N’ -methyl-ethyl- 1 ,2-diamine; N,N-dibutyl-ethyl- 1 ,2-diamine; N,N,N’ ,N’ -tetramethyl-ethyl- 1 ,2-diamine; cylclohexyl- 1 ,2-diamine; trans-N,N’ - di ethylcyclohexyl- 1,2-diamine; trans-N,N’-diisopropylcyclohenxyl-l,2-diamine. In some embodiments, the alkylene diamine is trans-N,N'-dimethylcy cl ohexane- 1,2-diamine. In some embodiments, the alkylene diamine is N,N’ -dimethylethylenediamine (DMEDA). It is understood that each description of the catalyst, base, and alkylene diamine may be combined, the same as if each and every combination were specifically and individually listed. For example, in some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in the presence of cuprous iodide, a base, and an alkylene diamine; in some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in the presence of cuprous iodide, a potassium phosphate, and an alkylene diamine; in some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in the presence of cuprous iodide, a base, and DMEDA. For example, in some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in the presence of cuprous iodide, potassium phosphate, and N,N’ -dimethylethylenediamine. It is to be understood that the use of DMEDA in the syntheses of the compounds described herein may provide the benefit of higher yield and/or the benefit of lower cost relative to other reagents, such as trans-N,N'-dimethylcyclohexane- 1,2-diamine.

[0038] In some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in the presence of an organic solvent. Examples of organic solvents include, without limitation, hexane, pentane, cyclopentane, cyclohexane, benzene, toluene, 1,4-di oxane, di chloromethane (DCM), chloroform, ethyl acetate, tetrahydrofuran (THF), acetone, acetonitrile (MeCN), dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetic acid, n-butanol, isopropanol, n-propanol, ethanol, and methanol and the like. In some embodiments, the organic solvent is any compatible mixture of organic solvent such as those given as examples herein. In some embodiments, the organic solvent is free of water. In some embodiments, the organic solvent comprises water. In some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in THF. It is understood that each description of the solvent may be combined with each description of catalyst, base, and alkylene diamine, the same as if each and every combination were specifically and individually listed. For example, in some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in THF the presence of cuprous iodide, potassium phosphate, and N,N’ -dimethylethylenediamine.

[0039] In some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed at a temperature of about 110 °C, 100 °C, about 90 °C, about 80 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, or about 20 °C. In some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed at a temperature of less than about 110 °C, 100 °C, about 90 °C, about 80 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, or about 20 °C. In some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed at a temperature of at least about 110 °C, at least about 100 °C, at least about 90 °C, at least about 80 °C, at least about 70 °C, at least about 60 °C, at least about 50 °C, at least about 40 °C, at least about 30 °C, or at least about 20 °C. In some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed at a temperature of between about 110 °C and about 20°C, between about 110 °C and about 30°C, between about 110 °C and about 40°C, between about 100 °C and about 40°C, between about 90 °C and about 40°C, between about 90 °C and about 50°C, between about 90 °C and about 60°C, between about 80 °C and about 50°C, between about 80 °C and about 60°C, or between about 80 °C and about 70°C. In some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed at a temperature of about 75 °C. It is understood that each description of the temperature may be combined with each description of solvent, catalyst, base, and/or alkylene diamine, the same as if each and every combination were specifically and individually listed. For example, in some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in THF at a temperature of about between about 50 °C and about 80 °C. For example, in some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in THF in the presence of cuprous iodide, potassium phosphate, and N,N’ -dimethylethylenediamine, at a temperature of about between about 50 °C and about 80 °C. For example, in some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in THF in the presence of cuprous iodide, potassium phosphate, and N,N’ -dimethylethylenediamine, at a temperature of about 65 °C, for instance, 65 ± 5 °C. For example, in some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in THF in the presence of cuprous iodide, potassium phosphate, and N,N’ -dimethylethylenediamine, at a temperature of about 65 °C. For example, in some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in THF in the presence of cuprous iodide, potassium phosphate, and N,N’ -dimethylethylenediamine, at a temperature of about 65 °C.

[0040] In some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof further comprises crystallization of the compound of Formula (2). In some embodiments, the compound of Formula (2) is crystallized in methanol and water.

[0041] In some embodiments, the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining the compound of Formula (3) by converting a compound of Formula (5)

or a salt thereof, to the compound of Formula (3) or a salt thereof.

[0042] In some embodiments, the step of converting the compound of Formula (5) or a salt thereof to the compound of Formula (3) or a salt thereof comprises reacting the compound of Formula (5) or a salt thereof with a compound of Formula (6)

wherein X is chloro or fluoro, to obtain the compound of Formula (3) or a salt thereof. In some embodiments, X is chloro. In some embodiments, X is fluoro.

[0043] In some embodiments, the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed in the presence of a base. In some embodiments, the base is an organic base. Examples of organic bases include, without limitation, amine bases such as N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, ethanolamine; alkoxide bases such as methoxide, ethoxide, tert-butoxide; hydride bases such as sodium hydride; aromatic bases such as pyridine, picoline, lutidine, collidine; and the like. In some embodiments, the base is an inorganic base. Examples of inorganic bases include, without limitation, carbonate bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate; hydroxide bases such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide; phosphate bases such as potassium phosphate, sodium phosphate; and the like. In some embodiments, the base is sodium bicarbonate. In other embodiments, the base is diisopropylethylamine.

[0044] In some embodiments, the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed in the presence of an organic solvent. Examples of organic solvents include, without limitation, hexane, pentane, cyclopentane, cyclohexane, benzene, toluene, 1,4-di oxane, di chloromethane (DCM), chloroform, ethyl acetate, tetrahydrofuran (THF), acetone, acetonitrile (MeCN), dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), acetic acid, n-butanol, isopropanol, n-propanol, ethanol, and methanol and the like. In some embodiments, the organic solvent is any compatible mixture of organic solvent such as those given as examples herein. In some embodiments, the organic solvent is free of water. In some embodiments, the organic solvent comprises water. In some embodiments, the reaction is performed in DMAc. In some embodiments, the reaction is performed in a mixture of DMAc and water. In some embodiments, the compound of Formula (5) or a salt thereof is provided as a solution in methanol. In some embodiments, the reaction is performed in a mixture of DMAc and methanol. In some embodiments, the reaction is performed in NMP. It is understood that each description of the solvent may be combined with each description of the compound of Formula (6) and/or the base, the same as if each and every combination were specifically and individually listed. For example, in some embodiments, the compound of Formula (6) is 2-chloro-5-bromopyrimidine, and the reaction is performed in DMAc and methanol in the presence of sodium bicarbonate. In other embodiments, the compound of Formula (6) is 2-fluoro-5-bromopyrimidine, and the reaction is performed in NMP in the presence of diisopropylethylamine.

[0045] In some embodiments, the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed at a temperature of about 160 °C, about 150 °C, about 140 °C, about 130 °C, about 120 °C, about 110 °C, about 100 °C, about 90 °C, about 80 °C, about 75 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, or about 20 °C. In some embodiments, the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed at a temperature of less than about 160 °C, about 150 °C, about 140 °C, about 130 °C, about 120 °C, about 110 °C, about 100 °C, about 90 °C, about 80 °C, about 75 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, or about 20 °C. In some embodiments, the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed at a temperature of at least about 160 °C, about 150 °C, about 140 °C, about 130 °C, about 120 °C, about 110 °C, about 100 °C, about 90 °C, about 80 °C, about 75 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, or about 20 °C. In some embodiments, the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed at a temperature of between about 160 °C and about 20°C, between about 150 °C and about 30 °C, between about 120 °C and about 40°C, between about 110 °C and about 50°C, between about 100 °C and about 60°C, or between about 80 °C and about 70°C. In some embodiments, the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed at a temperature of about 75 °C. In some embodiments, the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed at room temperature or at a temperature of about 25 °C. It is understood that each description of the temperature may be combined with each description of solvent and/or base, the same as if each and every combination were specifically and individually listed. For example, in some embodiments, the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed in DMAc in the presence of sodium bicarbonate, at a temperature of about 75 °C; in some embodiments, the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed in DMAc and methanol in at a temperature of about 75 °C; in some embodiments, the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed in DMAc and methanol in the presence of sodium bicarbonate, at a temperature of about 75 °C. In some such embodiments, the compound of Formula (3) is isolated as a solid. In some such embodiments, the compound of Formula (3) is precipitated as a solid upon addition of water. In other embodiments, the compound of Formula (6) is 2-fluoro-5-bromopyrimidine, and the reaction is performed in NMP in the presence of diisopropylethylamine, at room temperature.

[0046] In some embodiments, the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining the compound of Formula (5) by converting a compound of Formula (7)

to the compound of Formula (5) or a salt thereof.

[0047] In some embodiments, the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof comprises reacting the compound of Formula (7) with H2. In some embodiments, the reaction of the compound of Formula (7) with EE is performed at a pressure of about 0.5 MPa or between about 0.45 MPa and about 0.90 MPa. In some embodiments, the reaction of the compound of Formula (7) with H2 is performed at a pressure of between about 0.45 MPa and about 0.48 MPa. In some embodiments, the reaction of the compound of Formula (7) with H2 is performed at a pressure of 0.465 MPa ±0.015 MPa. In some embodiments, the reaction of the compound of Formula (7) with H2 is performed in the presence of a hydrogenation catalyst, such as a nickel, palladium, or platinum catalyst. In some embodiments, the catalyst is Raney nickel, also known as sponge nickel. In some embodiments, the reaction is performed in the presence of a base. Examples of bases include ammonia, sodium hydroxide, or potassium hydroxide. In some embodiments, the reaction is performed in the presence of ammonia.

[0048] In some embodiments, the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof is performed in the presence of an organic solvent. Examples of organic solvents include, without limitation, hexane, pentane, cyclopentane, cyclohexane, 1,4-di oxane, tetrahydrofuran (THF), n-butanol, isopropanol, n-propanol, ethanol, and methanol and the like. In some embodiments, the organic solvent is any compatible mixture of organic solvent such as those given as examples herein. In some embodiments, the organic solvent is free of water. In some embodiments, the organic solvent comprises water. It is understood that each description of the solvent may be combined with each description of the catalyst and/or the base, the same as if each and every combination were specifically and individually listed. For example, in some embodiments, converting the compound of Formula (7) to the compound of Formula (5) comprises reacting the compound of Formula (7) with Fb with Raney nickel in the presence of ammonia in methanol. For example, in some embodiments, converting the compound of Formula (7) to the compound of Formula (5) comprises reacting the compound of Formula (7) with Fb at a pressure of between about 0.45 MPa and about 0.48 MPa with Raney nickel in the presence of ammonia in methanol.

[0049] In some embodiments, the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof is performed at a temperature of about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 0 °C, about -10 °C, or about -20 °C. In some embodiments, the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof is performed at a temperature of less than about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 0 °C, about -10 °C, or about -20 °C. In some embodiments, the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof is performed at a temperature of at least about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 0 °C, about -10 °C, or about -20 °C. In some embodiments, the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof is performed a temperature of between about 60 °C and about -20°C, between about 50 °C and about -10°C, between about 50 °C and about 0°C, between about 50 °C and about 10°C, between about 40 °C and about 20°C, or between about 35 °C and about 25 °C. In some embodiments, the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof is performed at a temperature of about 30 °C. It is understood that each description of the temperature may be combined with each description of solvent and/or base, the same as if each and every combination were specifically and individually listed. For example, in some embodiments, the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof is performed in methanol in the presence of Fb, Raney nickel, and ammonia, at a temperature of between about 40 °C and about 20°C, at a temperature of between about 35 °C and about 25°C or at a temperature of about 30 °C. For example, in some embodiments, the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof is performed in methanol in the presence of Fb at a pressure of between about 0.45 MPa and about 0.48 MPa, Raney nickel, and ammonia, at a temperature of between about 40 °C and about 20°C, of between about 35 °C and about 25 °C, or at a temperature of about 30 °C. In some embodiments, the compound of Formula (5) is obtained as a solution in methanol.

[0050] In some embodiments, the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining the compound of Formula (7) by converting a compound of Formula (8) to the compound of Formula (7).

[0051] In some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) is performed in the presence of a fluorinating agent. Examples of fluorinating agents include, without limitation, diethylaminosulfur trifluoride (DAST), 2,2- difhioro-l,3-dimethylimidazolidine (DFI), Selectfluor, N-fluorobenzenesulfonimide (NF SI), tri ethylamine trihydrofluoride (TREAT -HF), and perfluorobutane sulfonyl fluoride (PBSF). In some embodiments, the fluorinating agent is perfluorobutane sulfonyl fluoride (PBSF). In some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) is performed by subjecting the compound of Formula (8) to PBSF followed by TREAT-HF. It is to be understood that the use of PBSF in the syntheses of the compounds described herein may provide benefits relative to other reagents, such as DAST, such as lower cost, improved compatibility with glass reaction vessels, and improved safety and thermal stability, as well as improved reaction yield and selectivity. In other embodiments, the fluorinating agent is DAST.

[0052] In some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) is performed in the presence of a base. In some embodiments, the reaction is performed in the presence of an organic base. Examples of organic bases include, without limitation, amine bases such as N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, ethanolamine; alkoxide bases such as methoxide, ethoxide, tert-butoxide; hydride bases such as sodium hydride; aromatic bases such as pyridine, picoline, lutidine, collidine; and the like. In some embodiments, the base is an inorganic base. Examples of inorganic bases include, without limitation, carbonate bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate; hydroxide bases such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide; phosphate bases such as potassium phosphate, sodium phosphate; and the like. In some embodiments, the base is triethylamine. In some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) is performed in the absence of a base. It is understood that each description of the base may be combined with each description of the fluorinating agent, the same as if each and every combination were specifically and individually listed. For example, in some embodiments, converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with PBSF in the presence of triethylamine, optionally followed by reaction with triethylamine trihydrofluoride (TREAT- HF). For example, in some embodiments, converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with PBSF in the presence of tri ethylamine. For example, in some embodiments, converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with PBSF in the presence of triethylamine, followed by reaction with TREAT -HF.

[0053] In some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) is performed in the presence of an organic solvent. Examples of organic solvents include, without limitation, hexane, pentane, cyclopentane, cyclohexane, benzene, toluene, 1,4-di oxane, dichloromethane (DCM), chloroform, ethyl acetate, tetrahydrofuran (THF), acetone, acetonitrile (MeCN), dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetic acid, n-butanol, isopropanol, n-propanol, ethanol, and methanol and the like. In some embodiments, the organic solvent is any compatible mixture of organic solvent such as those given as examples herein. In some embodiments, the organic solvent is free of water. In some embodiments, the organic solvent comprises water. In some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) is performed in toluene. In some embodiments, the compound of Formula (8) is provided as a solution in toluene. In some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) is performed in dichloromethane. It is understood that each description of the solvent may be combined with each description of fluorinating agent and/or base, the same as if each and every combination were specifically and individually listed. For example, in some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with PBSF and tri ethylamine in toluene; in other embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with PBSF and triethylamine in toluene followed by reaction with TREAT -HF. In other embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with DAST in di chloromethane.

[0054] In some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) is performed at a temperature of about 110°C, about 100 °C, about 90 °C, about 80 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 0 °C, about -10 °C, about -20 °C, about -30 °C, about -40 °C, about -50 °C, about -60 °C, about -70 °C, or about -80 °C. In some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) is performed at a temperature of less than about 110°C, about 100 °C, about 90 °C, about 80 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 0 °C, about -10 °C, about -20 °C, about -30 °C, about -40 °C, about -50 °C, about -60 °C, about -70 °C, or about -80 °C. In some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) is performed at a temperature of at least about 110°C, about 100 °C, about 90 °C, about 80 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 0 °C, about -10 °C, about -20 °C, about -30 °C, about -40 °C, about -50 °C, about -60 °C, about -70 °C, or about -80 °C. In some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) is performed at a temperature of between about 110°C and about -80 °C, between about 60°C and about -80 °C, between about 30°C and about -30 °C, between about 20°C and about -20 °C, between about 15°C and about -10 °C, between about 15°C and about -5 °C, between about 10°C and about -5 °C, or between about 10°C and about 0 °C. It is understood that each description of the solvent may be combined with each description of fluorinating agent and/or base, the same as if each and every combination were specifically and individually listed. For example, in some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) is performed in toluene at a temperature of between about 10 °C and about -5 °C. For example, in some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with PBSF and tri ethylamine in toluene at a temperature of between about 10 °C and about -5 °C. In some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with PBSF and tri ethylamine in toluene at a temperature of between about 10 °C and about -5 °C, followed by reaction with TREAT -HF in toluene at a temperature of between about 10 °C and about -5 °C. In other embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) comprises combining the compound of Formula (8) with DAST in di chloromethane at a temperature of between about -5 °C and about 10°C, followed by heating to a temperature of about 40 °C.

[0055] In some embodiments, the compound of Formula (7) is obtained as a solid. In some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) is followed by crystallization of the compound of Formula (7). In some embodiments, the compound of formula (7) is crystallized in n-propanol and water.

[0056] In some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with PBSF and tri ethylamine in toluene at a temperature of between about 10 °C and about 0 °C, followed by reaction with TREAT -HF in toluene at a temperature of between about 10 °C and about 0 °C, followed by crystallization of the compound of Formula (7). In some embodiments of the foregoing, the reaction yields a mixture of the compound of Formula (7) (the cis isomer) and the trans isomer of the compound of Formula (7), wherein the mixture comprises not more than 1.5% of the trans isomer. In some embodiments of the foregoing, the reaction yields a mixture of the compound of Formula (7) (the cis isomer) and the trans isomer of the compound of Formula (7) at a ratio of about 240: 1 (cis:trans).

[0057] In some embodiments, the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining the compound of Formula (8) by converting a compound of Formula (9) to the compound of Formula (8).

[0058] In some embodiments, the step of converting the compound of Formula (9) to the compound of Formula (8) is performed by reacting the compound of Formula (9) with a reducing agent. Examples of reducing agents include, without limitation, sodium borohydride, lithium aluminum hydride, borane, triethylsilane, phenylsilane, diphenylsilane, diphenylchlorosilane, trichlorosilane, tetraphenyldisilane, tris(trimethylsilyl)silane, and the like. In some embodiments, the reducing agent is a silane. In some embodiments, the reducing agent is triethylsilane (TES). In some embodiments, the reduction of the compound of Formula (9) to the compound of Formula (8) is a stereoselective reduction. In other embodiments, the reducing agent is sodium borohydride.

[0059] In some embodiments, the step of converting the compound of Formula (9) to the compound of Formula (8) comprises a stereoselective reduction of the compound of Formula (9). In some embodiments, the reaction of the compound of Formula (9) with a reducing agent yields the compound of Formula (8) (the trans isomer) and the cis isomer of the compound of Formula (8). In some embodiments, the reaction of the compound of Formula (9) with a reducing agent yields the compound of Formula (8) (the trans isomer) and its cis isomer at a ratio of about 1.5: 1 (trans:cis). In some such embodiments, the reducing agent is sodium borohydride. In some embodiments, the reaction of the compound of Formula (9) with a reducing agent yields the compound of Formula (8) (the trans isomer) and its cis isomer at a ratio of at least about 20:1. In some such embodiments, the reducing agent is triethylsilane (TES). In some embodiments, the reaction of the compound of Formula (9) with a reducing agent yields a mixture of the compound of Formula (8) (the trans isomer) and its cis isomer, wherein the compound of Formula (8) (the trans isomer) comprises about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about 99.9% of the mixture. In some embodiments of the foregoing, the reducing agent is triethylsilane (TES). In some embodiments, the reaction of the compound of Formula (9) with a reducing agent yields a mixture of the compound of Formula (8) (the trans isomer) and its cis isomer, wherein the compound of Formula (8) (the trans isomer) comprises at least about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about 99.9% of the mixture. In some embodiments of the foregoing, the reducing agent is triethylsilane (TES). In some embodiments, the reaction of the compound of Formula (9) with a reducing agent yields the compound of Formula (8) (the trans isomer) which is substantially free of the cis isomer. In some embodiments, the reducing agent is TES and the reaction of the compound of Formula (9) with a reducing agent yields the compound of Formula (8) (the trans isomer) and its cis isomer at a ratio of between about 23: 1 and about 30:1 (trans:cis). In some embodiments, the reducing agent is TES and the reaction of the compound of Formula (9) with a reducing agent yields a mixture of the compound of Formula (8) (the trans isomer) and its cis isomer, wherein the compound of Formula (8) (the trans isomer) comprises at least about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about 99.9% of the mixture.

[0060] In some embodiments, the step of converting the compound of Formula (9) to the compound of Formula (8) is performed in the presence of a solvent. Examples of solvents include, without limitation, hexane, pentane, cyclopentane, cyclohexane, benzene, toluene, 1,4-di oxane, dichloromethane (DCM), chloroform, ethyl acetate, tetrahydrofuran (THF), acetone, acetonitrile (MeCN), dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), acetic acid, n-butanol, isopropanol, n-propanol, ethanol, and methanol and the like. In some embodiments, the solvent comprises an acid. In some embodiments, the acid is any compatible mixture of acids. In some embodiments, the acid comprises water. In some embodiments, the acid is free of water. Examples of acid solvents include hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidyl acid, trifluoroacetic acid, and the like. In some embodiments, the solvent comprises trifluoroacetic acid. It is understood that each description of the acid may be combined with each description of the reducing agent, the same as if each and every combination were specifically and individually listed. For example, in some embodiments, converting the compound of Formula (9) to the compound of Formula (8) comprises reacting the compound of Formula (9) with triethylsilane in the presence of trifluoroacetic acid. In some embodiments, converting the compound of Formula (9) to the compound of Formula (8) comprises reacting the compound of Formula (9) with triethylsilane in the presence of trifluoroacetic acid, followed by pH adjustment to basic pH. In some embodiments, converting the compound of Formula (9) to the compound of Formula (8) comprises reacting the compound of Formula (9) with triethylsilane in the presence of trifluoroacetic acid, followed by pH adjustment to pH of from about 8.5 to about 9.5 using an aqueous base. In some embodiments, converting the compound of Formula (9) to the compound of Formula (8) comprises reacting the compound of Formula (9) with triethylsilane in the presence of trifluoroacetic acid, followed by pH adjustment to pH of about 9 using an aqueous base. Examples of aqueous bases include, without limitation, carbonate bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate; hydroxide bases such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide; phosphate bases such as potassium phosphate, sodium phosphate; and the like. In some embodiments of the foregoing, the reducing agent is TES and the reaction of the compound of Formula (9) with a reducing agent yields the compound of Formula (8) (the trans isomer) and its cis isomer at a ratio of between about 23: 1 and about 30: 1. In some embodiments, the reducing agent is TES and the reaction of the compound of Formula (9) with a reducing agent yields a mixture of the compound of Formula (8) (the trans isomer) and its cis isomer, wherein the compound of Formula (8) (the trans isomer) comprises at least about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about 99.9% of the mixture. In other embodiments, the step of converting the compound of Formula (9) to the compound of Formula (8) comprises reacting the compound of Formula (8) with sodium borohydride in di chloromethane and methanol.

[0061] In some embodiments, the step of converting the compound of Formula (9) to the compound of Formula (8) is performed at a temperature of about 72 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 5 °C, about 0 °C, about -5 °C, about -10 °C, or about -15 °C. In some embodiments, the step of converting the compound of Formula (9) to the compound of Formula (8) is performed at a temperature of less than about 72 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 5 °C, about 0 °C, about -5 °C, or about -10 °C. In some embodiments, the step of converting the compound of Formula (9) to the compound of Formula (8) is performed at a temperature of at least about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 5 °C, about 0 °C, about -5 °C, about -10 °C, or about -15 °C. In some embodiments, the step of converting the compound of Formula (9) to the compound of Formula (8) or a salt thereof is performed a temperature of between about 70 °C and about -15°C, between about 60 °C and about -15°C, between about 50 °C and about -15°C, between about 40 °C and about -15°C, between about 30 °C and about -15°C, between about 25 °C and about -15°C, between about 20 °C and about -15°C, between about 15 °C and about -15°C, between about 10 °C and about -15°C, between about 5 °C and about -15°C, between about 5 °C and about -10°C, or between about 5 °C and about -5°C. In some embodiments, the step of converting the compound of Formula (9) to the compound of Formula (8) or a salt thereof is performed a temperature of about 0 °C. It is understood that each description of the temperature may be combined with each description of reducing agent and/or acid, the same as if each and every combination were specifically and individually listed. For example, in some embodiments, the step of converting the compound of Formula (9) to the compound of Formula (8) or a salt thereof is performed in the presence of triethylsilane and trifluoroacetic acid, at a temperature of about 0 °C. In some embodiments of the foregoing, the reducing agent is TES and the reaction of the compound of Formula (9) with a reducing agent yields the compound of Formula (8) (the trans isomer) and its cis isomer at a ratio of between about 23: 1 and about 30: 1. In some embodiments, the reducing agent is TES and the reaction of the compound of Formula (9) with a reducing agent yields a mixture of the compound of Formula (8) (the trans isomer) and its cis isomer, wherein the compound of Formula (8) (the trans isomer) comprises at least about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about 99.9% of the mixture. In some embodiments, the compound of Formula (8) is obtained as a solution in toluene. In other embodiments, the step of converting the compound of Formula (9) to the compound of Formula (8) comprises reacting the compound of Formula (8) with sodium borohydride in the presence of dichloromethane and methanol at a temperature of about -78° C.

[0062] In some embodiments, the compound of Formula (8) is purified by recrystallization. In some such embodiments, recrystallization yields the compound of Formula (8) (the trans isomer) and its cis isomer at a ratio of up to 241 : 1.

[0063] In some embodiments, the method of preparing the compound of Formula (1) or Formula (2) further comprises preparing the compound of Formula (9).

[0064] In some embodiments, preparation of the compound of Formula (9) comprises reacting the compound of the Formula (Al)

with an aqueous acid to obtain the compound of Formula (9). [0065] In some embodiments, preparation of the compound of Formula (9) further comprises reacting the compound of Formula (A2)

with 2-chl oro-3 -fluoropyridine to obtain the compound of Formula (Al). In some such embodiments, preparation of the compound of Formula (9) further comprises converting the compound of Formula (A3)

to the compound of Formula (A2). In some such embodiments, preparation of the compound of Formula (9) further comprises converting the compound of Formula (A4)

to the compound of Formula (A3). In some such embodiments, preparation of the compound of Formula (9) further comprises converting the compound of Formula (A5)

to the compound of Formula (A4).

[0066] In some embodiments, preparation of the compound of Formula (9) comprises reacting l,3-dibromo-2,2-dimethoxypropane with tert-butyl 2-cyanoacetate to obtain the compound of Formula (A2), and converting the compound of Formula (A2) to the compound of Formula (9).

[0067] In some embodiments, preparation of the compound of Formula (9) comprises converting a compound of Formula (Cl) to the compound of Formula (9).

[0068] In some embodiments, preparation of the compound of Formula (9) comprises converting a compound of Formula (C2)

to the compound of Formula (Cl), and converting the compound of Formula (Cl) to the compound of Formula (9).

[0069] In some embodiments, the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining the compound of Formula (4) by converting methyl l-tosyl-lH-pyrrole-3-carboxylate to the compound of Formula (4).

Tos

[0070] In some embodiments, the step of converting methyl l-tosyl-lH-pyrrole-3- carboxylate to the compound of Formula (4) comprises tosyl deprotection of methyl 1-tosyl- lH-pyrrole-3-carboxylate. In some embodiments, the step of converting methyl 1-tosyl-lH- pyrrole-3 -carboxylate to the compound of Formula (4) comprises reacting methyl 1-tosyl-lH- pyrrole-3 -carboxylate with a base. In some embodiments, the base is an alkoxide base. In some embodiments, the base is sodium methoxide. In some embodiments, the step comprises reacting methyl l-tosyl-lH-pyrrole-3-carboxylate with sodium methoxide in methanol. In some embodiments, the step comprises reacting methyl l-tosyl-lH-pyrrole-3-carboxylate with sodium methoxide in methanol at a temperature of between about 30 °C and about 20 °C.

[0071] In some embodiments, the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining methyl l-tosyl-lH-pyrrole-3-carboxylate by converting l-tosyl-lH-pyrrole-3-carboxylic acid to methyl l-tosyl-lH-pyrrole-3-carboxylate. Tos

[0072] In some embodiments, the step of converting l-tosyl-lH-pyrrole-3-carboxylic acid to methyl l-tosyl-lH-pyrrole-3-carboxylate comprises esterification of 1-tosyl-lH- pyrrole-3 -carboxylic acid. In some embodiments, the step of converting 1 -tosyl- IH-pyrrole- 3-carboxylic acid to methyl l-tosyl-lH-pyrrole-3-carboxylate comprises reacting 1-tosyl-lH- pyrrole-3 -carboxylic acid with thionyl chloride. In some embodiments, the step of converting l-tosyl-lH-pyrrole-3-carboxylic acid to methyl l-tosyl-lH-pyrrole-3-carboxylate comprises reacting l-tosyl-lH-pyrrole-3-carboxylic acid with thionyl chloride in methanol. In some embodiments, the step comprises reacting l-tosyl-lH-pyrrole-3-carboxylic acid with thionyl chloride in methanol at a temperature of between about 60 °C and about 75 °C.

[0073] In some embodiments, the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining l-tosyl-lH-pyrrole-3-carboxylic acid by converting l-(l-tosyl-lH-pyrrol-3-yl)ethan-l-one to l-tosyl-lH-pyrrole-3-carboxylic acid.

Tos

[0074] In some embodiments, the step of converting l-(l-tosyl-lH-pyrrol-3-yl)ethan-l- one to l-tosyl-lH-pyrrole-3-carboxylic acid comprises reacting l-(l-tosyl-lH-pyrrol-3- yl)ethan-l-one with sodium hypobromite. In some embodiments, the step comprises reacting l-(l-tosyl-lH-pyrrol-3-yl)ethan-l-one with sodium hypobromite in water and 1,4-dioxane. In some embodiments, the step comprises reacting l-(l-tosyl-lH-pyrrol-3-yl)ethan-l-one with sodium hypobromite in water and 1,4-dioxane at a temperature of between about 0 °C and about 10 °C. In some embodiments, the step comprises reacting l-(l-tosyl-lH-pyrrol-3- yl)ethan-l-one with sodium hypobromite in water and 1,4-dioxane at a temperature of between about -5 °C and about 10 °C.

[0075] In some embodiments, the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining l-(l-tosyl-lH-pyrrol-3-yl)ethan-l-one by converting 1 -tosyl- IH-pyrrole to l-(l-tosyl-lH-pyrrol-3-yl)ethan-l-one.

[0076] In some embodiments, the step of converting 1-tosyl-lH-pyrrole to 1-(1 -tosyl- 1H- pyrrol-3-yl)ethan-l-one comprises reacting 1 -tosyl- IH-pyrrole with acetic anhydride in the presence of aluminum trichloride. In some embodiments, the step comprises reacting 1-tosyl- IH-pyrrole with acetic anhydride in the presence of aluminum trichloride in dichloromethane. In some embodiments, the step comprises reacting 1 -tosyl- IH-pyrrole with acetic anhydride in the presence of aluminum trichloride in di chloromethane at a temperature of between about 0 °C and about 40 °C.

[0077] In some embodiments, the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining 1-tosyl-lH-pyrrole by converting pyrrole to 1-tosyl- IH-pyrrole. In some embodiments, the step of converting pyrrole to 1 -tosyl- IH-pyrrole comprises reacting pyrrole with tosyl chloride in the presence of a base. In some embodiments, the base is sodium hydroxide. In some embodiments, the step of converting pyrrole to 1 -tosyl- IH-pyrrole comprises reacting pyrrole with tosyl chloride in the presence of sodium hydroxide and dichloromethane. In some embodiments, the step of converting pyrrole to 1 -tosyl- IH-pyrrole comprises reacting pyrrole with tosyl chloride in the presence of sodium hydroxide and di chloromethane at a temperature of between about 0 °C and about 30 °C.

[0078] In some embodiments, the methods of preparing a compound of Formula (1) or a salt thereof further comprise crystallization of the compound of Formula (1). In some embodiments, crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) in an organic solvent. Examples of solvents include, without limitation, hexane, pentane, cyclopentane, cyclohexane, benzene, toluene, 1,4-di oxane, di chloromethane (DCM), chloroform, ethyl acetate, tetrahydrofuran (THF), acetone, acetonitrile (MeCN), dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetic acid, n-butanol, isopropanol, n-propanol, ethanol, and methanol and the like. In some embodiments, the solvent is any compatible mixture of solvent such as those given as examples herein. In some embodiments, the solvent is free of water. In some embodiments, the solvent comprises water. In some embodiments, the solvent is n-propanol. In some embodiments, the solvent is n-propanol and water. In some embodiments, the crystallization of the compound of Formula (1) is performed at a temperature of about 97 °C, about 95 °C, about 90 °C, about 85 °C, about 80 °C, about 75 °C, about 70 °C, or about 65 °C. In some embodiments, the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) in the solvent at a temperature of at least about 97 °C, about 95 °C, about 90 °C, about 85 °C, about 80 °C, about 75 °C, about 70 °C, or about 65 °C. In some embodiments, the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) in the solvent at a temperature of less than about 97 °C, about 95 °C, about 90 °C, about 85 °C, about 80 °C, about 75 °C, about 70 °C, or about 65 °C. In some embodiments, the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) in the solvent at a temperature of between about 97 °C and about 65 °C, between about 97 °C and about 75 °C, between about 97 °C and about 80 °C, between about 95 °C and about 80 °C, or between about 90 °C and about 80 °C. In some embodiments, the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) in the solvent at a temperature of about 85 °C. In some embodiments, the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) in the solvent, followed by stepwise cooling of the compound of Formula (1) in the solvent. In some embodiments, the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) to about 85 °C in a mixture of water and n-propanol, followed by stepwise cooling of the compound of Formula (1) in the solvent. In some embodiments, the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) to about 85 °C in a mixture of water and n-propanol, followed by cooling to about 70 °C. In some embodiments, the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) to about 85 °C in a mixture of water and n-propanol, followed by cooling to about 70 °C, followed by cooling to about 40 °C. In some embodiments, the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) to about 85 °C in a mixture of water and n- propanol, followed by cooling to about 70 °C, adding seed crystals, and cooling to about 40 °C. In some embodiments, the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) to about 85 °C in a mixture of water and n-propanol, followed by diluting with additional water and n-proppanol, cooling to about 70 °C, adding seed material of the compound of Formula (1), and cooling to about 40 °C.

[0079] In some embodiments, seed material of the compound of Formula (1) is obtained from a previous batch of crystalline compound of Formula (1). In some embodiments, seed material of the compound of Formula (1) is obtained by heating the compound of Formula (1) in ethanol. In some embodiments, seed material of the compound of Formula (1) is obtained by refluxing the compound of Formula (1) in ethanol. In some embodiments, seed material of the compound of Formula (1) is obtained by refluxing the compound of Formula (1) in ethanol followed by polish filtration. In some embodiments, seed material of the compound of Formula (1) is obtained by refluxing the compound of Formula (1) in ethanol followed by polish filtration and cooling to a temperature of 20 °C to 25 °C.

Synthetic Schemes

[0080] Certain processes provided herein are described in reference to the illustrative synthetic schemes shown below and the specific examples that follow. Certain reactions and conversions described herein can be conducted using methods known in the art. For example, U.S. Patent Nos. 8,962,632, 11,142,516, 8,969,346, 9,133,123 as well as in WO 2011/133920, WO 2011/133888, and WO 2011/133882 describe methods and reagents that can be used to synthesize certain compounds disclosed herein. Skilled artisans will recognize that, to obtain various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. In addition, one of skill in the art will recognize that protecting groups may be used to protect certain functional groups (amino, carboxy, or side chain groups) from reaction conditions, and that such groups are removed under standard conditions when appropriate.

[0081] Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g. a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described. [0082] Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.

[0083] Abbreviations used herein are explained in the following table.

Abbreviations

[0084] Scheme 1 A illustrates a scheme of synthesizing the compound of Formula (9). Scheme 1A

(A2) (A1) (9)

[0085] Scheme IB illustrates an alternative scheme of synthesizing the compound of

Formula (9).

Scheme IB

[0086] Scheme 1C illustrates a second alternative scheme of synthesizing the compound of Formula (9). Scheme 1C

[0087] Scheme 2 A illustrates a scheme converting the compound of Formula (9) to the compound of Formula (5).

Scheme 2A

[0088] Scheme 2B illustrates an alternative scheme converting the compound of Formula (9) to the compound of Formula (5).

Scheme 2B

2) selective cryst.

(9)

H₂, NH₃,

Raney Ni

[0089] Scheme 3A illustrates a scheme of converting the compound of Formula (5) to the compound of Formula (1).

Scheme 3A

[0090] Scheme 3B illustrates an alternative scheme of converting the compound of

Formula (5) to the compound of Formula (1). Scheme 3B

[0091] Scheme 4 illustrates a scheme of synthesizing a compound of Formula (4).

Scheme 4

[0092] Scheme 5 illustrates a synthetic route to the preparation of the compound of Formula (1) from the compound of Formula (9). Scheme 5

C t lli ti d

[0093] It is to be noted that the procedures depicted in Scheme 5 provide the benefit of improved cost of goods and processability, as they require isolation of only four intermediates (the compounds of Formula (7), Formula (3), Formula (2), and Formula (1)), all of which are isolated as solids which may be purified by crystallization. In comparison, previous methods of synthesis involved various oily chemical intermediates, and required purifications by column chromatography. In addition, the procedures depicted in Scheme 5 result in a 63% overall yield of crystalline compound of Formula (1) starting from the compound of Formula (9), versus 21% overall yield of non-crystalline compound of Formula (1) also starting from the compound of Formula 9 for the procedures depicted in Scheme 6.

[0094] Scheme 6 illustrates a synthetic route to the preparation of the compound of Formula (1) from the compound of Formula (9).

Scheme 6

NC

EXAMPLES

Example 1: Preparation of N-tosyl pyrrole

25 °C [0095] A reactor was charged with methylene chloride (662.5 kg), NaOH (92.4 kg, 3.1 eq.), and pyrrole (50.0 kg, 1.0 eq.). The reaction mixture was cooled to 0 - 5 °C. p- Toluenesulfonylchloride (170.5 kg, 1.2 eq.) was slowly added into the reactor while maintaining the temperature of the reaction below 25 °C. The reaction mixture was stirred for not less than 12 hours at 20 - 30 °C. The reaction was monitored by TLC (Hexane : Ethyl Acetate = 9: 1; N-tosyl pyrrole Rf = 0.7). Upon reaction completion, purified water (130.0 kg) was added and the mixture was stirred for not less than 30 minutes. Methylene chloride was removed by distillation at a temperature of not more than 70 °C. Ethyl acetate (10.0 kg) was added and the mixture was stirred for not less than 30 minutes. The layers were separated, the organic layer was recovered. Anhydrous sodium sulfate (40.0 kg) was added to the organic layer and the mixture was stirred for not less than 30 minutes. The mixture was filtered to remove solids, the solids were washed with ethyl acetate (10.0 kg), and filtrates were combined. The combined filtrates were concentrated under reduced pressure at a temperature of not more than 70 °C. Heptane (342.0 kg) was added to the residue and the mixture was stirred for 2 hours at 15 - 25 °C. The solid product was isolated by filtration and washed with additional heptane (34.2 kg). The product was dried under reduced pressure at 45 - 55 °C for about 8 hours to yield 133.5 kg of N-tosyl pyrrole (81% yield).

Example 2: Preparation of l-(l-tosyl-lH-pyrrol-3-yl)ethan-l-one

Tos

[0096] A first reactor was charged with methylene chloride (699.2 kg) and aluminum chloride (294.2 kg, 3.7 eq.). The reaction mixture was cooled to 0 - 5 °C. Acetic anhydride (158.2 kg, 2.6 eq.) was added, and the mixture was stirred for not less than 10 minutes, while maintaining a temperature of between 20 - 25 °C. A second reactor was charged with methylene chloride (349.6 kg) and N-tosyl pyrrole (131.9 kg, 1.0 eq.). The N-tosyl pyrrole solution was slowly added to the first reactor and the mixture was stirred for not less than 2 hours, while maintaining the temperature below 40 °C (Target 35 °C). The reaction was monitored by TLC (Hexane : Ethyl Acetate = 4:1; l-(l-tosyl-lH-pyrrol-3-yl)ethan-l-one Rf = 0.4). Upon reaction completion, water (13320.0 kg) was added to a third reactor and cooled to 0 - 5 °C. The reaction mixture was slowly transferred from the first reactor into the third reactor. After stirring for not less than 1 hour, the layers were separated and the organic layer was isolated. Water (13320.0 kg) and sodium hydroxide (52.8 kg, 2.2 eq.) were added to the organic layer, and the mixture was stirred for not less than 30 minutes. The layers were separated and the organic layer was isolated. The organic layer was concentrated under reduced pressure at a temperature of not more than 70 °C to yield solid l-(l-tosyl-lH-pyrrol- 3-yl)ethan-l-one. Methylene chloride (349.6 kg) was added to the solids and the mixture was heated to 30 - 35 °C to dissolve the solids. Heptane (902.4 kg) was added, and the mixture was stirred for not more than 2 hours at 20 - 25 °C to crystallize the solids. The solids were isolated by filtration and washed with heptane (90.2 kg). The solids were isolated and dried for not less than 8 hours at 45 - 55 °C to yield 123.5 kg l-(l-tosyl-lH-pyrrol-3-yl)ethan-l- one (79% yield).

Example 3: Preparation of N-tosylpyrrole-3-carboxylic acid

Tos Tos

₂ 25 °C

[0097] A first reactor was charged with water (1632.7 kg) and sodium hydroxide (301.3 kg, 15.8 eq.) and the mixture was cooled to a temperature of -5 - -10 °C. Bromine (234.2 kg, 3.0 eq.) was added over the course of approximately 4 hours, at a rate to maintain a reaction temperature below 0 °C. A second reactor was charged with 1,4-dioxane (1946.0 kg), 1-(1- tosyl-lH-pyrrol-3-yl)ethan-l-one (124.5 kg, 1.0 eq.), and water (753.6 kg) and the mixture was cooled to 0 °C. The content of the first reactor were transferred to the second reactor over the course of approximately 1.5 hours, at a rate to maintain an internal temperature below 10 °C. The mixture was stirred for 2 hours. The reaction was monitored by TLC (Hexane : Ethyl Acetate = 1 : 1; N-tosylpyrrole-3 -carboxylic acid Rf = 0.2). Hydrochloric acid (35%) (602.8 kg) was added to acidify the reaction mixture to a pH of 1 - 2. Methylene chloride (1664.1 kg) was added and the mixture was stirred for not less than 1 hour. The organic layer was isolated. Anhydrous sodium sulfate (80.0 kg) was added and the mixture was stirred for 30 minutes. The solids were removed by filtration and washed with additional methylene chloride (83.2 kg); the combined filtrates were distilled under vacuum at a temperature of not more than 70 °C. Isopropyl alcohol (195.9 kg) was then added and the mixture was stirred for not less than 2 hours at 20 - 25 °C to crystallize the product N-tosylpyrrole-3 -carboxylic acid. The solids were isolated by filtration and were washed with isopropyl alcohol (48.9 kg). The solids were dried for not less than 8 hours at a temperature of 45 - 55 °C to yield 97.0 kg of N-tosylpyrrole-3 -carboxylic acid (77%). Example 4: Preparation of methyl N-tosylpyrrole-3-carboxylate

Tos Tos

[0098] A reactor was charged with methanol (800.1 kg) and N-tosylpyrrole-3 -carboxylic acid (97.0 kg, 1.0 eq.). Thionyl chloride (65.6 kg, 1.5 eq.) was added to the reaction mixture over approximately 30 minutes, at a rate to maintain an internal temperature below 55 °C. The reaction mixture was then heated to a temperature of 65 - 75 °C for not less than 1 hour. The reaction was monitored by TLC (Hexane : Ethyl Acetate = 2: 1; N-tosylpyrrole-3 - carboxylate Rf = 0.5). Upon reaction completion, the reaction mixture was concentrated under reduced pressure at a temperature of not more than 70 °C. The crude residue containing methyl N-tosylpyrrole-3-carboxylate was used directly in the next reaction.

Example 5: Preparation of methyl-lH-pyrrole-3-carboxylate (compound of formula (4))

[0099] The reactor containing methyl N-tosylpyrrole-3 -carboxylate from Example 4 was charged with methanol (802.3 kg) and sodium methoxide (30%) (103.0 kg, 1.5 eq.), maintaining an internal temperature below 30 °C. The reaction mixture was stirred for not less than 16 hours at 20 - 30 °C. The reaction was monitored by TLC (Hexane : Ethyl

Acetate = 3:2; methyl-lH-pyrrole-3-carboxylate Rf = 0.25). Upon reaction completion, the reaction mixture was concentrated under reduced pressure at a temperature of not more than 70 °C.

[0100] Purification procedure: Ethyl acetate (900.0 kg) and water (1012.0 kg) were added and the mixture was stirred for not less than 1 hour. The organic layer was isolated.

Anhydrous sodium sulfate (80.0 kg) and activated carbon (4.1 kg) were added and the mixture was stirred for not less than 30 minutes. The solids were removed by filtration through a pad of Celite (40.0 kg), the pad was washed with ethyl acetate (22.5 kg) and the liquors were recovered. Activated carbon (4.1 kg) was added to the liquors and stirred for 30 minutes. The solids were removed by filtration through a pad of Celite, the pad was washed with ethyl acetate (22.5 kg) and the liquors were recovered and concentrated at reduced pressure at a temperature of not more than 70 °C, yielding a 29.3 kg of crude methyl-lH- pyrrole-3 -carboxylate. Ethyl acetate (150.0 kg) was added to the crude methyl-lH-pyrrole-3- carboxylate and the mixture was stirred at 60 °C to dissolve the solids. Heptane (298.2 kg) was added slowly and the mixture was cooled to 20 - 30 °C. The reactor was further cooled to 5 - 10 °C and stirred for 2 hours. The crystallized solids were isolated by filtration and washed with heptane (298.2 kg). The solids were dried for not less than 8 hours 45 - 55 °C. The product methyl- lH-pyrrole-3 -carboxylate was assayed by HPLC for purity (limit not less than 98%). In the event of lower purity, the purification procedure was repeated until purity limit was met. The procedure yielded 27.8 kg of methyl-lH-pyrrole-3-carboxylate (compound of Formula (4)) (64% over 2 steps from N-tosylpyrrole-3 -carboxylic acid).

Example 6: Preparation of methyl 3,3-dimethoxycyclobutane-l-carboxylate (compound of formula (A4))

[0101] A reactor was vacuumed to <-0.08MPa and then inerted with nitrogen to atmosphere; this was repeated 3 times. The reactor was charged with MeOH (290 kg) and stirring was started. 3 -oxocyclobutanecarboxylic acid (compound of Formula (A5)) (70.7 kg, 619.6 mol, 1.0 eq.), Amberlyst-15 ion exchange resin (7.2 kg, 10% w/w), and trimethoxymethane (164 kg, 1545 mol, 2.5 eq.) were charged to the reactor. The reaction mixture was heated to 60±5°C; the reaction was continued for 5.5 hour at 60±5°C. The reactor was sampled for HPLC 3 -oxocyclobutanecarboxylic acid < 0.2%; then the mixture was cooled to below 15°C and centrifuged. The filter cake was washed with MeOH. The filtrate was pumped to the reactor and the solution was concentrated under vacuum below 55°C until the system was not more than 2 volumes (-142 L). The reactor was charged with MeOH (113 kg) and the solution was concentrated under vacuum below 55°C until the system is not more than 2 volumes. The reactor was charged again with MeOH (113 kg) and the solution was concentrated under vacuum below 55°C until the system is not more than 2 volumes. The solution was sampled for GC: Trimethoxymethane < 0.2 %. The solution of methyl 3,3-dimethoxycyclobutane-l-carboxylate (compound of formula (A4)) was used directly in the next reaction. Example 7: Preparation of 3,3-dimethoxycyclobutane-l-carboxamide (compound of formula (A3))

[0102] The solution from Example 6 was diluted with MeOH (434 kg) and cooled below 0°C. Continued to inject NH3 gas for 6 hr. Stirred for 5 days at 20°C~25°C. Sampled for HPLC: Compound of formula (A4) < 0.6%. Concentrated the solution under vacuum below 55°C until the system is not more than 2 volumes (-142 L). Cooled to below 25°C. Charged TBME (160 kg) to reactor. Concentrated the solution under vacuum below 50°C until the system is not more than 2 volumes. Charged PE (130 kg) to reactor. Concentrated the solution under vacuum below 50°C until the system is not more than 2 volumes. Charged PE (260 kg) to reactor. Cooled to 5±5°C. Stirred for 4 hours at 5±5°C. Centrifuged; washed the filter cake with PE. Collected wet cake; sampled for HPLC purity = 99%. Put the filter cake into vacuum oven and dried the filter cake at 25±5°C for at least 10 hours to give 90.9 kg 3,3- dimethoxycyclobutane-1 -carboxamide (compound of formula (A3)) as off-white solid. Yield 84% in two steps from 3 -oxocyclobutanecarboxylic acid (compound of formula (A5)).

Example 8: Preparation of 3,3-dimethoxycyclobutane-l-carbonitrile (compound of formula (A2)) MeO OMe TFAA V Et₃N < > toluene CN 25°C

(A2)

[0103] A reactor was vacuumed to <-0.08 MPa and then inerted with nitrogen. The process was repeated for three times. The reactor was charged with toluene (394.4 kg) and stirred. 3, 3 -dimethoxy cy cl obutane-1 -carboxamide (compound of formula (A3)) (90.0 kg, 565.4 mol, 1.0 eq.) and TEA (127.7 kg, 1262 mol, 2.2 eq) were charged to the reactor. The reaction mixture was cooled to below 5°C. TFAA (127.36 kg, 606 mol, 1.07 eq.) was slowly added at 0±5°C, and the reaction mixture was stirred at 20±5°C for 10 hour. The reaction mixture was sampled for GC: 3,3-dimethoxycyclobutane-l-carboxamide (compound of formula (A3)) = 1.46%. The reaction mixture was cooled to below 10°C. H2O (92.6 kg) was charged to reactor and stirred for 30 minutes. The aqueous phase was separated and extracted with toluene twice (153 kg, 116 kg). The organic phases were combined and wash with water. H2O was removed by azeotrope until KF<0.03%. KF = 0.03% (KF = Karl Fischer titration). The toluene solution of 3, 3 -dimethoxy cyclobutane- 1 -carbonitrile (compound of formula (A2)) was collected (498.4 kg). Assay = 14.3% (by ’H-NMR) yield: 89%. The toluene solution was used in the next step without any purification.

Example 9: Preparation of l-(3-fluoropyridin-2-yl)-3,3-dimethoxycyclobutane-l- carbonitrile (compound of Formula (Al))

(A2) (A1)

Batch 1

[0104] The toluene solution of 3, 3 -dimethoxy cyclobutane- 1 -carbonitrile (compound of formula (A2)) from Example 8 (155 kg, calcd 46.19 kg of 3, 3 -dimethoxy cyclobutane- 1- carbonitrile, 157 mol, 1.0 eq.) and 2-chloro-3-fluoropyridine(19.62 kg, 149 mol, 0.95eq.) were charged to a reactor. Reactor was vacuumed to < -0.08 MPa and then inerted with nitrogen to atmosphere. The process was repeated for three times. The reaction mixture was cooled to -20±5°C slowly. NaHMDS (2M in THF) (82.17 kg, 1.14 eq) was added slowly at - 20±5°C, and the reaction mixture was sampled for HPLC each hour until the content of 2- chl oro-3 -fluoropyridine < 2 % (2-chl oro-3 -fluoropyridine = 0.6 % after 2 hours ). The reaction mixture was cooled to below -20°C. Aqueous NH4Q (10% w/w) 40 kg was added while keeping the temperature below 0°C. The reaction mixture was stirred for at least 30 minutes, settled for at least 30 minutes, and allowed to separate. The organic phase was maintained to combine with batch 2

Batch 2

[0105] The toluene solution of 3, 3 -dimethoxy cyclobutane- 1 -carbonitrile (compound of formula (A2)) (323 kg, calcd 22.17 kg of 3, 3 -dimethoxy cy cl obutane-1 -carbonitrile, 327 mol, 1.0 eq.) and 2-chloro-3-fhioropyridine(39.87 kg, 303 mol, 0.95eq.) was charged to a reactor. Reactor was vacuumed to < -0.08 MPa and then inerted with nitrogen to atmosphere. The process was repeated for three times. The reaction mixture was cooled to -20±5°C slowly. NaHMDS (2M in THF) (166.79 kg, 1.14 eq) was added slowly at -20±5°C, and the reaction mixture was sampled for HPLC each hour until the content of 2-chl oro-3 -fluoropyridine < 2 % (2-chl oro-3 -fluoropyridine = 0.6 % after 2 hours ). The reaction mixture was cooled to below -20°C. Aqueous NH4Q (10% w/w) 88.9 kg was added while keeping the temperature below 0°C. The reaction mixture was stirred for at least 30 minutes, settled for at least 30 minutes, and allowed to separate. The organic phase was combined with the organic phase in batch l.The aqueous phase was extracted with ethyl acetate (112 kg). The organic phase was washed with sat. NaCl (169.35 kg). The collected organic phases were concentrated under vacuum below 70°C until the system was not more than 2 volumes (-136 L). The organic phases were sampled for HPLC 95% and the concentrated l-(3-fluoropyridin-2-yl)-3,3- dimethoxycyclobutane-1 -carbonitrile (compound of formula (Al)) residue was used in the next step.

Example 10: Preparation of l-(3-fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile (compound of Formula (9))

(A1) (9)

[0106] A reactor was charged with water (608 kg) and stirred. The reactor was charged portionwise with cone. HC1 (176.33 kg) while maintaining the temperature below 35°C. l-(3- fluoropyridin-2-yl)-3,3-dimethoxycyclobutane-l-carbonitrile (compound of formula (Al)) from Example 9 was charged to the reactor. The reaction mixture was heated to 50±5°C and was reacted for 4.5 hours at 50±5°C after completion addition. The reaction mixture was sampled for HPLC analysis each hour until the content of l-(3-fluoropyridin-2-yl)-3,3- dimethoxycyclobutane-1 -carbonitrile (compound of formula (Al)) was <2.0% (l-(3- fluoropyridin-2-yl)-3,3-dimethoxycyclobutane-l-carbonitrile = 0.88% after reaction for 4 hour at 50±5°C). The reaction mixture was cooled to below 30°C, and extracted with EtOAc (644.5 kg). The aqueous phase was extracted with EtOAc twice (439 kg, 229 kg). The organic phases were combined and washed with a solution of NaHCOs (9% w/w) 315.5 kg and then a solution of sat.NaCl 365 kg. The organic phases were concentrated under vacuum below 60°C until the system was not more than 2 volumes (-140 L). The organic phases were cooled to below 40 °C, and the reactor was charged with i-propanol (159 kg). The organic phases were concentrated under vacuum below 55°C until the system is not more than 1 volume. The organic phases were cooled to below 25°C, and stirred for 2 hours at 25±5°C. The reactor was charged with PE(164 kg), cooled to below 10°C, and stirred for 5 hour at 5±5°C, followed by centrifugation. The wet cake was collected and sampled for HPLC anlaysis (purty 99.1%). The filter cake was placed into vacuum oven and dried at 30±5°C for at least 10 hours. A representative sample was collected for KF and LOD KF = 0.1%, LOD = 0.52%. The solid was packaged under nitrogen and stored at room temperature. 70.33 kg of 1 -(3 -fluoropyri din-2 -yl)-3 -oxocyclobutanecarbonitrile were obtained as an off-white solid. Yield 65.4% in three steps from 3,3-dimethoxycyclobutane-l-carbonitrile (compound of formula (A2)).

Example 11: Preparation of (lr,3r)-l-(3-fluoropyridin-2-yl)-3-hydroxycyclobutane-l- carbonitrile (compound of Formula (8))

[0107] Trifluoroacetic acid (1120 L, 8.0 vol.) was added to a reactor followed by l-(3- fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile (the compound of formula (9)) (140.0 kg, 0.74 kmol, 1.00 equiv.) then triethylsilane (256.8 kg, 2.21 kmol, 3.00 equiv.) was added. The mixture was stirred at 0 °C for 2 days to give (lr,3r)-l-(3-fluoropyridin-2-yl)-3- hydroxycyclobutane-1 -carbonitrile (the compound of formula (8)) and (lr,3r)-3-cyano-3-(3- fluoropyridin-2-yl)cyclobutyl 2,2,2-trifluoroacetate (intermediate I). The phases were split and most of the trifluoroacetic acid layer (lower layer) was removed by vacuum distillation at < 50 °C , and not lower than 25 °C, to a target volume of 420 L of residue. Then water (350 L, 2.5 vol.) and ^-heptane (560 L, 4.0 vol.) were charged, and the layers were separated. The desired product, (lr,3r)-l-(3-fluoropyridin-2-yl)-3-hydroxycyclobutane-l-carbonitrile (the compound of formula (8)) stayed in lower aqueous phase and residual silane was removed by two heptane washes (560 L each, 4.0 vol.). [0108] The mixture of (lr,3r)-l-(3-fluoropyridin-2-yl)-3-hydroxycyclobutane-l- carbonitrile (the compound of formula (8)) and (lr,3r)-3-cyano-3-(3-fluoropyridin-2- yl)cyclobutyl 2,2,2-trifluoroacetate (Intermediate I) was then subjected to a pH adjustment. Initially the pH was adjusted to pH 1.5 by adding 30% aqueous sodium hydroxide (216.4 L water + 93.7 kg sodium hydroxide) and then the pH was adjusted to pH 9.0 (176.6 L water + 20.4 kg sodium carbonate). Water (280 L, 2.0 vol.) was added to the crude solution of (lr,3r)- 1 -(3 -fluoropyri din-2 -yl)-3-hydroxycy cl obutane-1 -carbonitrile and the product was extracted with two portions of MIBK (560 L each, 4.0 vol.). The two MIBK layers were combined and washed with 20% aqueous potassium bicarbonate (280.0 L of water + 70.0 kg of potassium bicarbonate). The organic layer was vacuum distilled at < 50 °C, and not lower than 25 °C, to a target volume of 420 L of residue. Toluene (1400 L, 10.0 vol.) was added to the residue and the reaction mixture was vacuum distilled at < 50 °C, and not lower than 25 °C, to a target volume of 420 L. The solvent swap process to toluene was repeated by adding an additional portion of toluene (280 L, 2.0 vol.) and distilling the mixture at < 50 °C which gave a toluene solution of (lr,3r)-l-(3-fluoropyridin-2-yl)-3-hydroxycyclobutane-l- carbonitrile (the compound of formula (8)) in a trans:cis ratio of about 30: 1.

Example 12: Preparation of (ls,3s)-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutane-l- carbonitrile (compound of Formula (7))

[0109] To the toluene solution of the compound of formula (8) was added tri ethylamine (119.2 kg, 1.18 kmol, 1.6 equiv.) followed by perfluorobutyl sulfonyl fluoride (266.9 kg, 0.89 kmol, 1.20 equiv.). The reaction mixture was stirred at 0 °C for 4 hours and 30 minutes to give a mixture of (lr,3s)-3-fluoro-l-(3-fluoropyridine-2-yl)cyclobutane-l-carbonitrile (the compound of formula (7)) and (lr,3r)-3-cyano-3-(3-fluoropyridin-2-yl)cyclobutyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonate (Intermediate II). Additional triethylamine (104.3 kg, 1.03 kmol, 1.40 equiv.) was added followed by triethylamine trihydrofluoride (23.7 kg, 0.15 kmol, 0.20 equiv.) and the mixture was stirred at 10 °C for 19 hours and 20 minutes to give (lr,3s)-3-fluoro-l-(3-fluoropyridine-2-yl)cyclobutane-l-carbonitrile (the compound of formula (7)). The reaction was cooled to 0 °C and a 13.5% aqueous potassium bicarbonate (280.0 L of water + 43.6 kg of potassium bicarbonate) was added to the reaction mixture. The mixture was stirred for 10 minutes and the layers were allowed to separate for 30 minutes. The upper layer was set aside, the middle layer was discarded to waste, and the lower layer was processed further. The lower layer was extracted twice with toluene (420 L each, 3.0 vol.). The toluene layers were combined and the upper organic layer that was set aside from the extraction was added. The combined organic layer was washed twice with 5% aqueous sodium bicarbonate (420.0 L each of water + 22.1 kg each of sodium bicarbonate). The organic layer was then washed with water (420 L, 3.0 vol.). Two silica gel pressure filters were prepared with silica gel (56.0 kg, 40 wt% each) and toluene (350 L, 2.5 vol. each). The organic layer was divided in two and filtered through the prepared pressure filters and then washed through with toluene (504 L, 3.6 vol.). The filtrates were combined and concentrated under vacuum to 420 L at < 50 °C, and not lower than 25 °C. n-Propanol (980 L, 7.0 vol.) was then added and the mixture was concentrated to 400 L at < 50 °C, and not lower than 25 °C. This solvent swap step was repeated once with additional n-propanol (980 L, 7.0 vol.). Water (560 L, 4.0 vol.) was then added over one hour to the reaction mixture at 0 °C. Seed crystal material (140 g, 0.1 wt%) was added and the slurry was stirred for 3 hours at 20 °C. (The seed material can be obtained from a previous batch following the procedure of this example, or can be prepared following the procedure described in Example 18.) The slurry was cooled to 0 °C over 3 hours and water (700 L, 5.0 vol.) was added. The solid product was isolated from the heterogeneous mixture by centrifugation whereby the cake was washed twice with water (140 L each, 1.0 vol). The wet product was dried under reduced pressure at a temperature of 20 °C for 4 hours to give 111.5 kg (78.0% over two steps) of (ls,3s)-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutane-l-carbonitrile (the compound of formula (7)) in a cis Trans ratio of about 240: 1.

Example 13: Preparation of ((lr,3i')-3-fluoro-l-(3-fluoropyridin-2- yl)cyclobutyl)methanamine (compound of Formula (5))

[0110] (1 s,3 s)-3 -Fluoro- 1 -(3 -fluoropyri din-2 -yl)cy cl obutane- 1 -carbonitrile (the compound of formula (7)), (112.7 kg, 0.58 kmol, 1.00 equiv.) and methanol (789 L, 7.0 vol.) were mixed at 20 °C and a solution of 7N ammonia in methanol (338 L, 3.0 vol.) was added. Sponge Nickel (R-200, 36.1 kg, 0.62 kmol, 1.06 equiv.) was added and the heterogeneous mixture was washed with water (23 L, 0.20 vol.). The reaction vessel was vacuum purged three time with nitrogen and then three times with Eb. The vessel was pressurized to 0.465±0.015 MPa at 30 °C for 24 hours. The reaction mixture was then purged with nitrogen and the spent catalyst was then removed by filtration and washed with methanol (225 L, 2.0 vol.). The methanol fractions were combined and distilled to 338 L at < 40 °C, but not lower than 25 °C. Additional methanol (338 L, 2.0 vol.) was added and the mixture was again concentrated to 338 L at < 40 °C, but not lower than 25 °C. The methanol solution of ((lr,3r)-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutyl)methanamine (the compound of formula (5)) was used directly in the next step (see Example 3 A).

Example 14: Preparation of 5-broino-N-(((l r.3r)-3-nuoro-l-(3-nuoropyridin-2- yl)cyclobutyl)methyl)pyrimidin-2-amine (compound of formula (3))

[OHl] Sodium bicarbonate (73.1 kg, 0.87 kmol, 1.50 equiv.), 5-bromo-2- chloropyrimidine (117.9 kg, 0.61 kmol, 1.05 equiv.) and dimethylacetamide (676 L, 6.0 vol.) were added to the methanol solution of the compound of formula (5) from Example 2A. The reaction mixture was heated to 75 °C and stirred for 13 hours 30 minutes. The mixture was then cooled to 60 °C and process water (1014 L, 9.0 vol.) was added over 1 hour and the mixture was stirred for an additional two hours. The slurry was then cooled to 20 °C over 4 hours. The reaction solids were isolated by centrifugation and the wet cake was washed with a 20% aqueous solution of NA -di methyl acetamide (451 L, water + 113 L of N,N- dimethylacetamide) and then with water (240 L, 2.1 vol.). The washed solids were dried at 25 °C under vacuum for 12 hours to give 193.7 kg of 5-bromo-N-(((lr,3r)-3-fluoro-l-(3- fluoropyridin-2-yl)cyclobutyl)methyl)pyrimidin-2-amine (the compound of formula (3)) (94.0% yield over two steps from (ls,3s)-3-fhioro-l-(3-fhioropyridin-2-yl)cyclobutane-l- carbonitrile, the compound of formula (7)). Example 15: Preparation of methyl l-(2-((((lr,3 )-3-fluoro-l-(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxylate (compound of

Formula (2))

[0112] 5 -Brom o- A -((( 1 r, 3r)-3 -fluoro- 1 -(3 -fluoropyridin-2- yl)cyclobutyl)methyl)pyrimidin-2-amine (the compound of formula (3)) (204.4 kg, 0.58 kmol, 1.00 equiv.) was added to the reaction vessel, then methyl lH-pyrrole-3-carboxylate (the compound of formula (4)), (72.0 kg. 0.58 kmol, 1.00 equiv.) was added followed by potassium phosphate (267.8, 1.27 kmol, 2.20 equiv.) and copper iodide (38.4 kg, 0.20 kmol, 0.35 equiv.). The reaction vessel and charge lines were thoroughly flushed with nitrogen then THF (2044 L, 10.0 vol.) and TV, TV ’-dimethylethylene diamine (DMEDA), (60.9 kg, 0.69 kmol, 1.20 equiv.) were added. The mixture was agitated at 65 °C for 20 hours and then cooled to 40 °C. Additional THF (1022 L, 5.0 vol.) was added followed by celite (61.3 kg, 30 wt%), the suspension was cooled to 25 °C stirred at this temperature for 1 hour. The suspension was filtered. The insoluble material, reactor and filter were washed with THF (818 L, 4.0 vol.). The combined THF filtrates were concentrated at < 50 °C, and not below 25 °C, to 15.0 volumes (-3066 L) of residue. The filtrate was washed four times with 10% NH4Q aqueous solution (613 L of water each + 68.1 kg of NH4Q each) until copper content was below 100 mg/L. The reaction mixture was then washed with 10% aqueous sodium chloride solution (613 L of water + 153.3 kg of sodium chloride). The organic layer was subsequently concentrated under reduced pressure to 5.0 volumes at a temperature of < 50 °C, and not below 25 °C. Methanol (1022 L, 5.0 vol.) was then added over 30 minutes at 20 °C and the mixture was stirred at this temperature for an additional 2 hours. Water (1635 L, 8.0 vol.) was added over 1 hour at 20 °C and the heterogenous mixture was stirred for an additional 2 hours. The solids were isolated by centrifugation and washed first with a mixture of THF (153 L, 0.75 vol.), methanol (153 L, 0.75 vol.) and water (307 L, 1.5 vol.) then a mixture of methanol (675 L, 3.3 vol.) and water (552 L, 2.7 vol.). The solid was dried under vacuum < 50 °C, but not below 25 °C, until a constant weight was reached which provided 205.7 kg (89.5%) of methyl l-(2-((((lr,3r)-3-fluoro-l-(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxylate (the compound of formula (2)).

Example 16: Preparation of l-(2-((((lr,3i')-3-fluoro-l-(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide (compound of Formula (1))

fhioro-l-(3-fhioropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxylate (the compound of formula (2)), (205.7 kg, 0.52 kmol, 1.00 equiv.) was charged to a reaction vessel, followed by formamide (1029 L, 5.0 vol.) and DMSO (411.4 L, 2.0 vol.). Once the slurry was suspended, NaOMe (138.0 kg, 2.57 kmol, 5.0 equiv.) was charged and the reaction was heated to 60 °C for 2.5 hours. Water (617 L, 3.0 vol.) was charged at 45 °C over one hour and the reaction then stirred for an additional one hour. A second portion of water (1029 L, 5.0 vol.) was charged over one hour the mixture was stirred for an additional for one hour. The reaction was then cooled to 20 °C over 3 hours to and stirred for an additional 3 hours. The solid was isolated by centrifugation and the filter cake was washed with water (154 L, 0.75 vol.) and the wet cake was dried to give 192.7 kg (97.3 %) of l-(2-((((lr,3r)-3-fluoro-l-(3- fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide (crude compound of formula (1)).

Example 17. Crystallization of the compound of Formula (1)

[0114] 1 -(2-(((( 1 r,3 r)-3 -Fluoro- 1 -(3 -fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide (crude compound of formula (1)), (192.7 kg, 0.50 kmol, 1.00 equiv.) was charged to a vessel along with n- propanol (1303 L, 6.76 vol.) and water (432 L, 2.25 vol.). The mixture was heated to 85 °C to form a clear solution, filtered, and additional w-propanol (145 L, 0.75 vol.) and water (48 L, 0.25 vol.) were added. The mixture was cooled to 70 °C and seed material (193 g, 0.10 wt%) was charged. (Seed material can be obtained from a previous batch following the procedures of this example or can be prepared as described in Example 18). The reaction mixture was stirred for 5 hours and then cooled to 40 °C over 3 hours. The reaction mixture was further cooled to 20 °C over 4 hours and stirring was continued for 2 hours then the reaction mixture was cooled to 0 °C over 2 hours and stirring was continued for an additional 2 hours. The slurry was centrifuged and the wet cake was washed twice with n-propanol (145 L each, 0.75 vol.) and dried at for 12 hours to give 178.9 kg (93.0 %) of crystalline l-(2-((((lr,3r)-3- fluoro-l-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3- carboxamide (crystalline compound of Formula (1)).

Example 18: Alternate Crystallization of l-(2-((((lr,3 )-3-fluoro-l-(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide (compound of Formula (1))

[0115] 1 -(2-(((( 1 r, 3r)-3 -luoro- 1 -(3 -fluoropyri din-2 - yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide (crude compound of formula (1)) was divided into two portions for polish filtration.

[0116] Batch 1 : l-(2-((((lr,3r)-3-luoro-l-(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide (crude compound of formula (1)) (2.18 kg, 0.0057 kmol, 1.00 equiv.) was charged to a reactor and ethanol (87.7 L, 40 vol.) was added. The mixture was heated to reflux to dissolve the solids. The solution was polish filtered and then cooled to 20 °C.

[0117] Batch 2: The remaining portion of l-(2-((((lr,3r)-3-fluoro-l-(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide (compound of formula (1)) (2.17 kg, 0.0056 kmol, 1.00 equiv.) was then charged and ethanol (87.5 L, 40 vol.) was added. The heterogeneous mixture was heated to reflux and polish filtered.

[0118] The filtrates from Batch 1 and Batch 2 were combined and distilled at atmospheric pressure until the volume was 5 volumes (~ 25 L of solution). Agitation was continued at reflux to keep the solids dissolved. The solution was cooled to 25 °C over 11 hours and stirring was continued at 20 °C for 8 hours. The slurry was filtered and the filter cake was washed with ethanol (8.7 L. 2 vol.). The crystalline product was dried under vacuum at 45 °C for 16 hours.

Example 19: Alternate preparation of methyl 3,3-dimethoxycyclobutane-l-carboxylate (compound of formula (A4))

[0119] A reactor was vacuumed to 0.02 MPa or less and then inerted with nitrogen to atmosphere for three times. MeOH (339.00 kg), 3 -oxocyclobutanecarboxylic acid (85.19 kg, 746.6 mol, 1.0 eq.), Amberlyst-15 ion exchange resin (8.90 kg, 10% w/w), and trimethoxymethane (196.00 kg, 1847.3 mol, 2.5 eq.) were charged into the reactor and the resulting mixture was heated to 55±5°C and reacted for 6 hours to give methyl 3,3- dimethoxycyclobutane-1 -carboxylate (compound of formula (A4)) solution in MeOH. ’H NMR (CDCh, 400 MHz) 3 3.70 (s, 3H), 3.17 (s, 3H), 3.15 (s, 3H), 2.94-2.85 (m, 1H), 2.47- 2.36 (m, 4H).

Example 20: Alternate preparation of 3,3-dimethoxycyclobutane-l-carboxamide (compound of formula (A3))

[0120] The methyl 3,3-dimethoxycyclobutane-l-carboxylate (compound of formula

(A4)) solution in MeOH of Example 19 was cooled to below 25°C and centrifuged. The filter cake was washed with MeOH (7.00 kg) and the filtrate was pumped to the reactor. The solution was concentrated under vacuum below 55°C until the system had no more than 2 volumes (-170 L). MeOH (139.40 kg) was charged to the reactor and the solution was concentrated under vacuum below 55°C until the system had no more than 2 volumes. MeOH (130.00 kg) was charged to the reactor and the solution was concentrated under vacuum below 55°C until the system had no more than 2 volumes. Half of the resulting solution was diluted with MeOH (435.00 kg) and cooled to below 30°C. NH3 gas (133.80 kg) was injected into the reactor below 35°C for 24 hours. The mixture was stirred at 40 ± 5°C for 72 hours.

The resulting solution was concentrated under vacuum below 50°C until the system had no more than 2 volumes. MTBE (181.00 kg) was charged into the reactor. The resulting solution was concentrated under vacuum below 50°C until the system had no more than 2 volumes. PE (318.00 kg) was charged into the reactor. The resulting mixture was cooled to 5±5°C, stirred for 4 hours at 5±5°C, and centrifuged. The filter cake was washed with PE (42.00 kg) and the wet filter cake was put into a vacuum oven. The filter cake was dried at 30±5°C for at least 8 hours to give 3,3-dimethoxycyclobutane-l-carboxamide (compound of formula (A3)) as off-white solid (112.63 kg, 94.7% yield). ^XH NMR (CDCk, 400 MHz) 3 5.76 (bs, 1H), 5.64 (bs, 1H), 3.18 (s, 3H), 3.17 (s, 3H), 2.84-2.76 (m, 1H), 2.45-2.38 (m, 4H).

Example 21: Alternate preparation of 3,3-dimethoxycyclobutane-l-carbonitrile (compound of Formula (A2)) MeO OMe TFAA y

Et₃N < > toluene 25°C

(A2)

[0121] A reactor was vacuumed to 0.02 MPa or less and then inerted with nitrogen to atmosphere three times. Toluene (500.00 kg), 3,3-dimethoxycyclobutane-l-carboxamide (compound of formula (A3)) (112.54kg, 706.9 mol, 1.0 eq.), and TEA (158.00 kg, 1561.3 mol, 2.20 eq) were charged into the reactor and the resulting mixture was cooled to 0+ 5°C. TFAA (164.00 kg, 781 mol, 1.10 eq.) was added dropwise at 0±5°C. The resulting mixture was stirred for 10 hours at 20±5°C and cooled below 5±5°C. H2O (110.00 kg) was charged into the reactor at below 15 °C. The resulting mixture was stirred for 30 minutes and the water phase was separated. The aqueous phase was extracted with toluene (190.00 kg) twice. The organic phases were combined and washed with H2O (111.00 kg). H2O was removed by azeotrope until the water content was no more than 0.03%. The resulting solution was cooled to below 20°C to give 3, 3 -dimethoxy cy cl obutane-1 -carbonitrile (compound of formula (A2)) solution in toluene (492.00 kg with 17.83% assay content, 87.9% yield).

Example 22: Alternate preparation of l-(3-fluoropyridin-2-yl)-3,3- dimethoxycyclobutane-l-carbonitrile (compound of Formula (Al))

NaHMDS

(A2) (A1)

[0122] A reactor was vacuumed to 0.02 MPa or less and then inerted with nitrogen to atmosphere three times. The 3, 3 -dimethoxy cyclobutane-1 -carbonitrile (compound of formula (A2)) solution in toluene prepared as described in Example 21 (246.00 kg of a 17.8% solution of 3,3-dimethoxycyclobutane-l-carbonitrile in toluene, 1.05 eq.) and 2-chl oro-3 - fluoropyridine (39.17 kg, 297.9 mol, 1.00 eq.) were charged into the reactor. The reactor was vacuumed to 0.02 MPa and less and then inerted with nitrogen to atmosphere for three times. The mixture was slowly cooled to -20±5°C. NaHDMS (2M in THF) (165.71 kg, 1.20 eq) was added dropwise at -20±5°C. The resulting mixture was stirred at -15±5°C for 1 hour. The mixture was stirred until the content of 2-chl oro-3 -fluoropyridine is no more than 2% as measured by HPLC. Deionized water (16.00 kg) was added dropwise at below 0 °C while maintaining the reactor temperature. The resulting solution was transferred to another reactor. Aq. NH4Q (10% w/w, 88.60 Kg) was added dropwise at below 0°C while maintaining the reactor temperature. Soft water (112.00 kg) was charged into the reactor and the aqueous phase was separated and collected. The aqueous phase was extracted with ethyl acetate (70.00 kg) and an organic phase was collected. The organic phase was washed with sat. NaCl (106.00 kg) and collected. The above steps were repeated to obtain another batch of organic phase. The two batches of organic phase were concentrated under vacuum below 70°C until the system had no more than 2 volumes. The resulting solution was cooled to below 30°C to give a l-(3-fluoropyridin-2-yl)-3,3-dimethoxycyclobutane-l-carbonitrile (compound of formula (Al)) solution. 'H NMR (CDCh, 400 MHz) 3 8.42-8.38 (m, 1H), 7.50-7.45 (m, 1H), 7.38-7.33 (m, 1H), 3.28 (s, 3 H), 3.13 (s, 3H), 3.09-3.05 (m, 4H).

Example 23: Alternate preparation of l-(3-fluoropyridin-2-yl)-3- oxocyclobutanecarbonit

(A1) (9)

[0123] A reactor was vacuumed to 0.02 MPa and less and then inerted with nitrogen to atmosphere for three times. Water (603.00 kg) was added to the reactor and was stirred. Concentrated HC1 (157.30 kg) was charged into the reactor at below 35°C. The l-(3- fluoropyridin-2-yl)-3,3-dimethoxycyclobutane-l-carbonitrile (compound of Formula (Al)) solution prepared as described in Example 22 (206.00 kg) was charged into the reactor and the resulting mixture was heated to 50±5°C and reacted for 3 hours at 50±5°C. The mixture was reacted until the content of l-(3-fluoropyridin-2-yl)-3,3-dimethoxycyclobutane-l- carbonitrile was no more than 2.0% as measured by HPLC. The reaction mixture was cooled to below 30°C and extracted with ethyl acetate (771.00 kg). An aqueous phase was collected and extracted with ethyl acetate (770.00 kg). The organic phases were combined and the combined organic phase was washed with soft water (290.00 kg) and brine (385.30 kg). The organic phase was concentrated under vacuum at below 60°C until the system had no more than 2 volumes. Propan-2-ol (218.00 kg) was charged into the reactor. The organic phase was concentrated under vacuum at below 60°C until the system had no more than 1 volume. PE (191.00 kg) was charged into the reactor at 40±5 °C and the resulting mixture was heated to 60±5 °C and stirred for 1 hour at 60±5 °C. The mixture was then slowly cooled to 5±5 °C and stirred for 5 hours at 5±5 °C. The mixture was centrifuged and the filter cake was washed with PE (48.00 kg) and the wet filter cake was collected. Water (80.00 kg), concentrated HC1 (2.20 kg), propan-2-ol (65.00 kg), and the wet filter cake were charged in this order into a drum. The resulting mixture was stirred for 10 minutes at 20±5 °C. The mixture was centrifuged and the filter cake was washed with a mixture solution containing 18.00 kg of propan-2-ol, 22.50 kg of soft water, and 0.60 kg of concentrated HC1. The filter cake was put into a vacuum oven and dried at 30±5°C for at least 10 hours. The filter cake was dried until the weight did not change to give 1 -(3 -fluoropyridin-2-yl)-3 -oxocyclobutanecarbonitrile (compound of formula (9)) as off-white solid (77.15 kg, 68.0% yield). 'H N R (CDCh, 400 MHz) 3 8.45-8.42 (m, 1H), 7.60-7.54 (m, 1H), 7.47-7.41 (m, 1H), 4.18-4.09 (m, 2H), 4.02- 3.94 (m, 2H).

Example 24: Second alternate preparation of 3,3-dimethoxycyclobutane-l-carbonitrile (compound of Formula (A2))

[0124] To a flask was added l,3-dimethyl-2-imidazolidinone (DMI) (30 mL) and tertbutyl cyanoacetate (8.08 g) at room temperature. To the resulting solution was added potassium tert-butoxide (7.71 g), l,3-dibromo-2,2-dimethoxypropane (5.00 g) at 0 °C. To another flask, potassium iodide (158 mg), 2,6-di-tert-butyl-p-cresol (42 mg), DMI (25 mL) were added at room temperature and then resulting solution was heated to 165 °C. To this solution, previously prepared mixture was added dropwise at 140-165 °C, then stirred for 2 hours at 165 °C. To the reaction mixture, water (65 mL) was added. A resulting solution was extracted with toluene (40 mL, three times) and then combined organic layer was washed with water (20 mL, three times) and IN NaOH aq. (20 mL). A resulting organic layer was concentrated below 50 °C under reduced pressure to give 3,3-dimethoxycyclobutane-l- carbonitrile (compound of formula (A2)) (66% yield, GC assay) as toluene solution. ’H NMR (CDCh, 400 MHz) d 3.17 (s, 3H), 3.15 (s, 3H), 2.93-2.84 (m, 1H), 2.63-2.57 (m, 2H), 2.52- 2.45 (m, 2H).

Example 25: Preparation of l-(3-fluoropyridin-2-yl)-3-methylenecyclobutane-l- carbonitrile (compound of Formula (Cl))

(C2) (C1)

[0125] To a solution of 3 -methylenecyclobutanecarbonitrile (compound of formula (C2))

(150 g, 1.61 mol, 1 equivalent) and 2-chl oro-3 -fluoropyridine (212 g, 1.61 mmol, 1 equivalent) in toluene (1 L) was added NaHMDS (2 M in THF, 885 mL, 1.1 equivalent) dropwise at 0-10 °C. Upon completion of addition, the reaction mixture was warmed to rt, stirred overnight, and quenched with NHiClcsat.) solution. The organic layer was washed with water (2x500 mL) and brine (500 mL), dried over Na2SO4, filtered, and concentrated to give the crude 1 -(3 -fluoropyridin-2-yl)-3 -methylenecyclobutane- 1 -carbonitrile (compound of formula (Cl)) (272 g, 90%) which was used in next step without further purification. LRMS (M+H⁺) m/z 189.1.

Example 26: Second alternate preparation of l-(3-fluoropyridin-2-yl)-3-oxocyclobutane- 1-carbonitrile (compound of Formula (9))

(C1) (9)

[0126] To a mixture of l-(3-fluoropyridin-2-yl)-3-methylenecyclobutanecarbonitrile (compound of formula (Cl)) (272 g, 1.45 mol) and RUCI3.H2O (9.0 g, 0.044 mol) in DCM (1 L), acetonitrile (1 L), and water (1.5 L) mixture was added solid NalCb (1235 g, 5.8 mol) portionwise at 10-30 °C. Upon the completion of addition, the reaction was stirred 1 h at 15 °C and overnight at rt. The solid precipitate was filtered off and washed with DCM (2x1000 mL). The organic layer was washed with water (2x500 mL) and brine (500 mL), dried over Na2SO4, and concentrated to provide 1 -(3 -fluoropyridin-2-yl)-3 -oxocyclobutane- 1- carbonitrile (compound of formula (9)) as a dark solid (238 g, 86.3%). LRMS (M+H⁺) m/z 191.1.

Example 27: Preparation of l-(3-fluoropyridin-2-yl)-3-hydroxycyclobutane-l- carbonitrile

[0127] To a solution of 1 -(3 -fluoropyridin-2-yl)-3 -oxocyclobutanecarbonitrile

(compound of formula (9)) (231 g, 1.22 mol) in a mixture of DCM (2 L) and MeOH (200 mL) was added NaBHi portionwise at -78 °C. The reaction mixture was stirred at -78 °C for 1 h and quenched with a mixture of methanol and water (1/1). The organic layer was washed with water (500 mL x 3), dried over Na2SO4, and concentrated. The residue was purified on silica gel (50% EtOAc/hexanes) to provide the l-(3-fluoropyridin-2-yl)-3- hydroxycyclobutane-1 -carbonitrile as an amber oil (185.8 g, 77.5%). LRMS (M+H+) m/z 193.2.

Example 28: Alternate preparation of (ls,3s)-3-fluoro-l-(3-fluoropyridin-2- yl)cyclobutane-l-carbonitrile (compound of Formula (7))

1) cis:trans ratio 8:1

2) selective cryst.

[0128] To a solution of 1 -(3 -fluoropyridin-2-yl)-3 -hydroxy cyclobutanecarbonitrile (185 g, 0.96 mol) in DCM (1 L) was added DAST portionwise at 0-10 °C. Upon the completion of addition, the reaction was refluxed for 6 h. The reaction was cooled to rt and poured onto sat.

NaHCCh solution. The mixture was separated and the organic layer was washed with water, dried over Na2SO4, and concentrated. The residue was purified on silica gel (100% DCM) to provide the title compound as a brown oil (116 g, 62%) in a 8: 1 cis:trans mixture. The above brown oil (107 g) was dissolved in toluene (110 mL) and hexanes (330 mL) at 70 °C. The solution was cooled to 0 °C and stirred at 0 °C overnight. The precipitate was filtered and washed with hexanes to provide the cis isomer of (ls,3s)-3-fluoro-l-(3-fluoropyridin-2- yl)cyclobutane-l -carbonitrile (compound of Formula (7)) as a white solid (87.3 g, 81.6%).

LRMS (M+H⁺) m/z 195.1.

Example 29: Alternate Preparation of ((lr,3i')-3-fluoro-l-(3-fluoropyridin-2- yl)cyclobutyl)methanamine (compound of Formula (5)).

[0129] A mixture (ls,3s)-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutane-l-carbonitrile (compound of Formula (7)) (71 g, 0.37 mol) and Raney nickel (~7 g) in 7N ammonia in methanol (700 mL) was charged with H2 (60 psi) for 2 days. The reaction was filtered through a celite pad and washed with methanol. The filtrate was concentrated under high vacuum to provide ((lr,3r)-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutyl)methanamine (compound of Formula (5)) as a light green oil (70 g, 97.6%). LRMS (M+H⁺) m/z 199.2.

[0130] While the foregoing written description of the methods, compounds, and compositions described herein enables one of ordinary skill to make and use the methods, compounds, and compositions described herein, those of ordinary skill will understand and appreciate the existence of variations, combinations, and equivalents of the specific embodiment, method, schemes, and examples herein. The methods, compounds, and compositions provided herein should therefore not be limited by the above-described embodiments, methods, schemes, or examples, but rather encompasses all embodiments and methods within the scope and spirit of the methods, compounds, and compositions provided herein.

[0131] Each reference disclosed herein is incorporated by reference in its entirety.

Claims

1. A method of preparing a compound of Formula (1):

or a salt thereof, comprising:

(i) converting a compound of Formula (3)

(3), or a salt thereof, to a compound of Formula (2)

(2), or a salt thereof; and

2. The method of claim 1, wherein the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof comprises reacting the compound of Formula (2) or a salt thereof with formamide in the presence of a first base.

3. The method of claim 2, wherein the first base is sodium methoxide.

4. The method of any one of claims 1 to 3, wherein the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is conducted in a solvent which is DMSO.

5. The method of any one of claims 1 to 4, wherein the step of converting the compound of Formula (2) or a salt thereof, to the compound of Formula (1), or a salt thereof, is conducted at 40-80°C.

6. The method of any one of claims 1 to 5, further comprising crystallizing the compound of Formula (1) in water.

7. The method of any one of claims 1 to 6, further comprising crystallizing the compound of Formula (1) in n-propanol and water.

8. The method of claim 7, wherein the crystallization in n-propanol and water occurs after heating the compound of Formula (1) at 60-95°C.

9. A method of preparing a compound of Formula (2)

(2), or a salt thereof, comprising converting a compound of Formula (3)

or a salt thereof, to the compound of Formula (2) or a salt thereof.

10. The method any one of claims 1 to 9, wherein converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof comprises reacting the compound of Formula (3) or a salt thereof with a compound of Formula (4)

or a salt thereof.

11. The method of claim 10, wherein the reaction of the compound of Formula (3) with the compound of Formula (4) is performed in the presence of cuprous iodide, a second base, and an alkylene diamine.

12. The method of claim 11, wherein the alkylene diamine is N,N’- dimethylethylenediamine.

13. The method of claim 10 or 11, wherein the second base is potassium phosphate.

14. The method of any one of claims 10 to 13, wherein the reaction between the compound of Formula (3) or a salt thereof and the compound of Formula (4) or a salt thereof, is conducted in THF at 50-80°C.

15. The method of any one of claims 10 to 14, wherein the compound of Formula (2) is crystallized in methanol and water.

16. The method of any one of claims 1 to 15, further comprising obtaining the compound of Formula (3), or a salt thereof, by converting a compound of Formula (5)

or a salt thereof, to the compound of Formula (3) or a salt thereof.

17. The method of claim 16, wherein the step of converting the compound of Formula (5) or a salt thereof to the compound of Formula (3) or a salt thereof comprises reacting the compound of Formula (5) or a salt thereof with a compound of Formula (6)

(6), wherein X is chloro or fluoro, to obtain the compound of Formula (3) or a salt thereof.

18. The method of claim 17, wherein the reaction of the Formula (5) or a salt thereof with the compound of Formula (6) is performed in the presence of sodium bicarbonate.

19. The method of claim 17 or 18, wherein the reaction of the Formula (5) or a salt thereof with a compound of Formula (6) is performed in methanol and dimethylacetamide at a temperature of about 75 °C.

20. The method of any one of claims 16-19, wherein the compound of Formula (3) is isolated as a solid.

21. The method of claim 20, wherein the compound of Formula (3) is precipitated after the addition of water .

22. The method of any one of claims 16-21, further comprising obtaining the compound of Formula (5) or a salt thereof by converting a compound of Formula (7)

to the compound of Formula (5) or a salt thereof.

23. The method of claim 22, wherein the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof comprises reacting the compound of Formula (7) with H2.

24. The method of claim 23, wherein the reaction of the compound of Formula (7) with H2 is performed at an H2 pressure of 0.45 MPa to 0.48 MPa.

25. The method of claim 23, wherein the reaction of the compound of Formula (7) with H2 is performed in the presence of Raney nickel and ammonia in methanol at a temperature of 25-35 °C.

26. The method of any one of claims 22-25, wherein the compound of Formula (5) is obtained as a solution in methanol.

27. The method of any one of claims 22-26, further comprising obtaining the compound of Formula (7) by converting a compound of Formula (8)

to the compound of Formula (7).

28. The method of claim 27, wherein the step of converting the compound of Formula (8) to the compound of Formula (7) or a salt thereof comprises reacting the compound of Formula (8) with perfluorobutane sulfonyl fluoride (PBSF) in the presence of a third base.

29. The method of claim 28, wherein the reaction of the compound of Formula (8) with perfluorobutane sulfonyl fluoride (PBSF) in the presence of a third base is followed by reaction with triethylamine trihydrofluoride.

30. The method of any one of claims 27-29, wherein the step of converting the compound of Formula (8) to the compound of Formula (7) or a salt thereof is performed in toluene at -5 °C to 10 °C.

31. The method of any one of claims 27-30, wherein the step of converting the compound of Formula (8) to the compound of Formula (7) or a salt thereof results in not more than 1.5% of a trans isomer of the compound of Formula (7).

32. The method of any one of claims 27-31, wherein the third base is tri ethylamine.

33. The method of any one of claims 27-32, wherein the compound of Formula (7) is isolated as a solid.

34. The method of any one of claims 27-33, wherein the compound of Formula (7) is crystallized in n-propanol and water.

35. The method of any one of claims 27-34, further comprising obtaining the compound of Formula (8) by converting a compound of Formula (9)

to the compound of Formula (8).

36. The method of claim 35, wherein the step of converting the compound of formula (9) to the compound of formula (8) comprises reacting the compound of formula (9) with triethylsilane in the presence of trifluoroacetic acid.

37. The method of claim 36, wherein the reaction of the compound of formula (9) with triethylsilane in the presence of trifluoroacetic acid is performed at about 0 °C.

38. The method of claim 36 or 37, wherein the reaction of the compound of formula (9) with triethylsilane in the presence of trifluoroacetic acid is followed by pH adjustment to about pH 9 using an aqueous base.

39. The method of any one of claims 35-38, wherein the compound of Formula (8) is obtained as a solution in toluene.

40. The method of any one of claims 10-39, further comprising obtaining the compound of Formula (4) by converting methyl l-tosyl-lH-pyrrole-3-carboxylate

to the compound of Formula (4).

41. The method of claim 40, wherein converting methyl l-tosyl-lH-pyrrole-3-carboxylate to the compound of Formula (4) comprises reacting methyl l-tosyl-lH-pyrrole-3-carboxylate with sodium methoxide.

42. The method of claim 41, wherein the reaction of methyl l-tosyl-lH-pyrrole-3- carboxylate with sodium methoxide is performed in methanol at a temperature of between about 20 °C and about 30 °C.

43. The method of any one of claims 40-42, further comprising obtaining methyl 1-tosyl- lH-pyrrole-3-carboxylate by converting l-tosyl-lH-pyrrole-3-carboxylic acid

to methyl l-tosyl-lH-pyrrole-3-carboxylate.

44. The method of claim 43, wherein the step of converting l-tosyl-lH-pyrrole-3- carboxylic acid to methyl l-tosyl-lH-pyrrole-3-carboxylate comprises reacting 1-tosyl-lH- pyrrole-3 -carboxylic acid with thionyl chloride.

45. The method of claim 44, wherein the reaction of l-tosyl-lH-pyrrole-3-carboxylic acid with thionyl chloride is performed in the presence of methanol at a temperature of between about 60 °C and about 75 °C.

46. The method of any one of claims 43-45, further comprising obtaining 1-tosyl-lH- pyrrole-3 -carboxylic acid by converting 1-(1 -tosyl- lH-pyrrol-3-yl)ethan-l -one

to l-tosyl-lH-pyrrole-3-carboxylic acid.

47. The method of claim 46, wherein the step of converting l-(l-tosyl-lH-pyrrol-3- yl)ethan-l-one to l-tosyl-lH-pyrrole-3-carboxylic acid comprises reacting 1-(1 -tosyl- 1H- pyrrol-3-yl)ethan-l-one with sodium hypobromite.

48. The method of claim 47, wherein the reaction of l-(l-tosyl-lH-pyrrol-3-yl)ethan-l- one with sodium hypobromite is performed in the presence of water and 1,4-di oxane at a temperature of -5 °C to 10 °C.

49. The method of any one of claims 46-48, further comprising obtaining l-(l-tosyl-lH- pyrrol-3-yl)ethan-l-one by converting 1 -tosyl- IH-pyrrole

to 1 -( 1 -tosyl- lH-pyrrol-3 -yl)ethan- 1 -one.

50. The method of claim 49, wherein converting 1 -tosyl- IH-pyrrole to 1-(1 -tosyl- 1H- pyrrol-3-yl)ethan-l-one comprises reacting 1 -tosyl- IH-pyrrole with acetic anhydride in the presence of aluminum trichloride.

51. The method of claim 50, wherein the reaction of 1 -tosyl- IH-pyrrole with acetic anhydride in the presence of aluminum trichloride is performed in di chloromethane at a temperature of 0 °C to 40 °C.

52. The method of any one of claims 49-51, further comprising obtaining 1-tosyl-lH- pyrrole by converting pyrrole to 1-tosyl-lH-pyrrole.