Synthesis of pyrrolo [3, 4-C] pyrrole

Abstract

Novel synthetic processes for preparing pyrrolo [3, 4-c] pyrrole, derivatives thereof, and intermediates thereof are provided. Also provided are methods of using pyrrolo [3, 4-c] pyrroles in processes of making biologically active compounds (e.g., PKR activating compounds).

Description

Technical Field

[0001] The present disclosure relates to novel synthetic methods for preparing pyrrolo[3,4-c]pyrrole, its derivatives and intermediates thereof. The present disclosure further relates to synthetic methods for preparing bioactive compounds using pyrrolo[3,4-c]pyrrole, its derivatives and intermediates thereof. Background Art

[0002] Pyrrolo[3,4-c]pyrrole can be used as a bioactive compound, for example, as a dual inhibitor of autotaxin and carbonic anhydrase (WO 2017 / 050791, WO 2017 / 050792), an inhibitor of stearoyl-CoA desaturase (WO 2008 / 135141, WO 2010 / 028761), an agonist of the κ-opioid receptor (WO 2016 / 181408), an inhibitor of dipeptidyl peptidase-IV (WO 2014 / 061031) and a pyruvate kinase R activating compound (WO2018 / 175474). Currently, the methods for synthesizing pyrrolo[3,4-c]pyrrole utilize mono-protected and / or bis-protected pyrrolo[3,4-c]pyrrole, such as N-Boc-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole: However, the synthesis of mono-protected pyrrolo[3,4-c]pyrrole faces several challenges, including difficulties in large-scale production, poor atom economy, generation of a large amount of bromine and low yields (Heterocycles 1995, 41, 1291; WO 2016 / 046837). Therefore, there is a need for improved methods for synthesizing pyrrolo[3,4-c]pyrrole. Summary of the Invention

[0003] In a first aspect, the present disclosure provides a novel method for preparing a compound of formula (III-Y) or a salt thereof, which compound can be used as a key intermediate for synthesizing pyrrolo[3,4-c]pyrrole, particularly for preparing pyrrolo[3,4-c]pyrrole substituted with different groups on each nitrogen: Wherein: R12 is -CR2R3-(C6-C 10 aryl), wherein the C6-C 10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C1-C6 alkyl; and R4 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; and R5 and R6 are each independently a halogen, such as chlorine, bromine, iodine, or -OSO2R7, where each R7 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 aryl, where C6-C 10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0004] The intermediate compound of formula (III-Y) can be used to prepare bioactive compounds, such as PKR activation compounds. Such PKR activation compounds can enhance the activities of wild-type and mutant PKR enzymes.

[0005] In some embodiments, the present disclosure relates to a method for preparing a compound of formula (III-Y).

[0006] In some embodiments, the method further comprises the further step of converting the compound of formula (III-Y) into a compound of formula (III-Z) by reacting with R1-Cl, where R1 is -C(O)C1-C6 alkoxy:

[0007] In some embodiments, the method further comprises converting the compound of formula (III-Z) into a compound of formula (V-Z) by reacting the compound of formula (III-Z) with a sulfonamide:

[0008] In a second aspect, the present disclosure relates to a key intermediate in the synthesis of pyrrolo[3,4-c]pyrrole, where the intermediate is a compound of formula (III-Y) or a salt thereof.

[0009] In a third aspect, the present disclosure relates to a key intermediate in the synthesis of pyrrolo[3,4-c]pyrrole, where the intermediate is a compound of formula (III-Z) or a salt thereof.

[0010] In a fourth aspect, the present disclosure relates to a key intermediate in the synthesis of pyrrolo[3,4-c]pyrrole, where the intermediate is a compound of formula (V-Z) or a salt thereof.

[0011] In a fifth aspect, the present disclosure relates to the use of intermediate compounds of formula (III-Y), (III-Z) or (V-Z), which can be used for the synthesis of a compound of formula (I) - (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one, also known as etavopivat: or for the synthesis of a compound of formula (II) - (2R)-2-hydroxy-2-phenyl-1-[5-(pyridin-2-ylsulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one: Detailed Embodiments

[0012] As used herein, the term "C1-C6 alkyl" refers to a saturated, branched or straight-chain hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of C1-C6 alkyl include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, isopentyl, 2-methylbutyl, neopentyl, 3-methylbutyl, tert-pentyl, 1-hexanol, 2-hexanol, 3-hexanol, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-methyl-3-pentyl, 3-methyl-3-pentyl, 2,2-dimethyl-1-butanyl, 2,3-dimethyl-1-butyl, 3,3-dimethyl-1-butyl.

[0013] As used herein, the term "C6-C 10 aryl" refers to a cyclic aromatic group containing 6-10 carbon atoms. Such aryl can be substituted or unsubstituted. Examples of C6-C 10 aryl include, but are not limited to, phenyl, naphthyl, etc.

[0014] As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0015] As used herein, the term "C1-C6 haloalkyl" refers to a C1-C6 alkyl as defined herein that contains at least one halogen group as defined herein. Specific examples of C1-C6 haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0016] As used herein, the term "C1-C6 alkoxy" refers to the group -OC1-C6 alkyl. Examples of C1-C6 alkoxy include, but are not limited to, methoxy, ethoxy, 1-propoxy, isopropoxy, n-butoxy, tert-butoxy, and the like.

[0017] As used herein, the term "C1-C6 haloalkoxy" refers to a C1-C6 alkoxy as defined herein that contains at least one halogen group as defined herein. Specific examples of C1-C6 haloalkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethyl, trichloromethyl, and the like.

[0018] As used herein, the term "6-10 membered heteroaryl" refers to a 6-10 membered cyclic aromatic ring system having ring carbon atoms and 1-3 heteroatoms selected from O, N, or S. Such 6-10 membered heteroaryl can be substituted or unsubstituted. Examples of 6-10 membered heteroaryl include, but are not limited to, 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-benzofuranyl, 6-benzofuranyl, 6-benzoxazolyl, 6-benzothiazolyl.

[0019] In one aspect, the present disclosure describes synthetic methods, intermediates, and reaction parameters for the efficient preparation of pyrrolo[3,4-c]pyrrole. The present disclosure also encompasses the recognition that the intermediate compounds of formulas (III-Y), (III-Z), and (III): (i) can be efficiently synthesized from commercially available starting materials; (ii) can be purified without chromatography; and (iii) can be used to synthesize pyrrolo[3,4-c]pyrrole having differentially substituted nitrogen atoms.

[0020] The intermediate compounds of formulas (III-Y), (III-Z), and (III) can be used to prepare bioactive compounds such as PKR (pyruvate kinase R) activating compounds. Such PKR activating compounds can enhance the activity of wild-type and mutant PKR enzymes.

[0021] In some embodiments, the PKR activating compound prepared using the intermediate compound of formula (III-Y), (III-Z), or (III) is a compound of formula (I): It can also be referred to as (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one or etavopivat.

[0022] The compound of formula (I) is a selective, orally bioavailable PKR activator that reduces 2,3-DPG (diphosphoglycerate), increases ATP, and has an anti-sickling effect on red blood cells (RBCs) in disease models, with a wide therapeutic window relative to preclinical toxicity. The compound of formula (I) is a potent activator of PKR and a multimodal metabolic regulator of RBCs. Activation of PKR simultaneously decreases the 2,3-DPG concentration, thereby increasing hemoglobin-oxygen affinity and reducing sickling, while also increasing intracellular ATP, thereby improving RBC health and reducing hemolysis or RBC death.

[0023] The compound of formula (I) is an allosteric activator of recombinant wild-type (WT) PKR and the mutant enzyme PKR R510Q, which is one of the most prevalent PKR mutations in North America. PKR exists in both dimeric and tetrameric states, but is most functionally effective in the tetrameric state. PKR is an isoform of pyruvate kinase expressed in RBCs and is a rate-limiting enzyme in the glycolytic pathway. The compound of formula (I) stabilizes the tetrameric form of PKR, thereby reducing the Michaelis constant (Km) for its substrate phosphoenolpyruvate (P).

[0024] In some embodiments, the PKR activator compound prepared using the intermediate compounds of formula (III-Y), (III-Z), or (III) is a compound of formula (II): It may also be referred to as (2R)-2-hydroxy-2-phenyl-1-[5-(pyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one. The intermediate compounds of the present disclosure and methods for their preparation

[0025] In one aspect, the present disclosure relates to a method for preparing a compound of formula (III-Y) according to Scheme A1. The compound of formula (III-Y) can be further used in the efficient synthesis of pyrrolo[3,4-c]pyrrole. The reaction according to Scheme A1 involves reacting an azomethine precursor of formula (III-W) with an electron-deficient alkyne of formula (III-X) in the presence of an acid: Scheme A1 wherein R12 is -CR2R3-(C6-C 10 aryl), wherein the C6-C 10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C1-C6 alkyl; and R4 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; and R5 and R6 are each independently halogen, such as chlorine, bromine, iodine, or -OSO2R7, where each R7 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C6-C 10 aryl, where C6-C 10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; and R9 is a suitable silyl protecting group selected from trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS) or dimethylisopropylsilyl (DMIPS); and R10 is C1-C6 alkyl.

[0026] In some embodiments, R12 of the azomethine precursor of formula (III-W) is -CH2-Ph (benzyl) or 4-methoxybenzyl. In one embodiment, R12 of formula (III-W) is benzyl. In some embodiments, the suitable silyl group R9 of (III-W) is selected from TMS, DMPS, TES, TBS or DMIPS. In one embodiment, the suitable silyl group R9 is TMS. In some embodiments, R10 of formula (III-W) is C1-C6 alkyl or straight-chain C1-C6 alkyl. In one embodiment, R10 is selected from methyl, ethyl, 1-propyl, 1-butyl. In some embodiments, R10 is methyl.

[0027] In some embodiments, R5 and R6 of the electron-deficient alkyne of formula (III-X) are each independently selected from chlorine, bromine, iodine or -OSO2R7. In one embodiment, R5 and R6 are each chlorine. In one embodiment, R5 and R6 are each bromine.

[0028] In some embodiments, the reaction according to Scheme A1 is carried out in the presence of an acid. In some embodiments, the acid is selected from TFA, TMSOTf, TMSI, a combination of TMSOTf and CsF, or a combination of TMSI and any one of CsF, LiF, ZnCl2, or a combination thereof. In one embodiment, the acid is TFA. In some embodiments, the acid is present in a substoichiometric amount or catalytic amount of about 0.01-0.2 equivalent, such as 0.03-0.07 equivalent or about 0.05 equivalent.

[0029] In some embodiments, the reaction of Scheme A1 is carried out in a nonpolar solvent selected from, for example, toluene, DCM, or a mixture thereof. In one embodiment, the solvent is toluene. In some embodiments, about 1 equivalent of the compound of formula (III-W) is reacted with about 1.1 to 3 equivalents, such as 1.5 - 2 equivalents, of the compound of formula (III-X).

[0030] In one embodiment, the reaction according to Scheme A1 is carried out in a nonpolar solvent selected from DCM, toluene, or a mixture thereof using about 0.01 - 0.2 equivalent of an acid, about 1 equivalent of the compound of formula (III-W), and 1.1 to 3 equivalents of the compound of formula (III-X), the acid being selected from TFA, TMSOTf, TMSI, a combination of TMSOTf and CsF, or a combination of TMSI and any one of CsF, LiF, ZnCl2, or a combination thereof.

[0031] In some embodiments, the reaction of Scheme A1 is carried out according to Scheme A1’ using the compound of formula (III-W1) and results in the preparation of the compound of formula (III-Y1), wherein R5, R6, R9, R10 are as defined above: Scheme A1’

[0032] In a specific embodiment, the method according to Scheme A1 is the method according to Scheme A, wherein the compound of formula (III-Y) is the compound of formula (III-B), which can be prepared, for example, via the method depicted in Scheme A and more fully described in Examples 1 and 2. Scheme A

[0033] In some embodiments, Step 1 A In the presence of a sub-stoichiometric amount (e.g., 0.1 equivalent or 0.05 equivalent) of a suitable acid (e.g., trifluoroacetic acid (TFA)) in a suitable solvent (e.g., toluene or dichloromethane (DCM)), an azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-deficient alkyne (e.g., dichlorobutyne, III-C) are used. In some embodiments, Step 1 A In the presence of a sub-stoichiometric amount (e.g., 0.1 equivalent or 0.05 equivalent) of trimethylsilyl trifluoromethanesulfonate (i.e., Me3SiOTf) in a suitable solvent (e.g., toluene or DCM), an azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-deficient alkyne (e.g., dichlorobutyne, III-C) are used. In some embodiments, Step 1 AIn the presence of sub-stoichiometric amounts (e.g., 0.1 equivalent or 0.05 equivalent) of trimethylsilyl trifluoromethanesulfonate (i.e., Me3SiOTf) and CsF, an azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-deficient alkyne (e.g., dichlorobutyne, III-C) are used in a suitable solvent (e.g., toluene or DCM). In some embodiments, step 1 A In the presence of sub-stoichiometric amounts (e.g., 0.1 equivalent or 0.05 equivalent) of trimethylsilyl iodide (i.e., Me3SiI), an azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-deficient alkyne (e.g., dichlorobutyne, III-C) are used in a suitable solvent (e.g., toluene or DCM). In some embodiments, step 1 A In the presence of sub-stoichiometric amounts (e.g., 0.1 equivalent or 0.05 equivalent) of trimethylsilyl iodide (i.e., Me3SiI) and an additive selected from CsF, LiF, ZnCl2, and combinations thereof, an azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-deficient alkyne (e.g., dichlorobutyne, III-C) are used in a suitable solvent (e.g., toluene or DCM). One of ordinary skill in the art can determine the suitable acid and the suitable solvent without undue experimentation.

[0034] While not wishing to be bound by any particular theory, it is believed that the selection of electron-deficient alkynes can be used to avoid by-products and reduce the number of steps in the method. In some aspects of the present disclosure, the stoichiometric ratio between the azomethine precursor and the electron-deficient alkyne is selected to avoid by-products and facilitate purification. In some embodiments, 1.0 equivalent of the azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and 2.0 equivalents of the electron-deficient alkyne (e.g., dichlorobutyne, III-C) are used. In other embodiments, 1.0 equivalent of the azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and 1.5 equivalents of the electron-deficient alkyne (e.g., dichlorobutyne, III-C) are used.

[0035] In some embodiments, the method for preparing a compound of formula (III-Y), (III-Y1), or (III-B) may include separating the product in the form of a salt. In some embodiments, the method for preparing a compound of formula (III-Y), (III-Y1), or (III-B) may include transferring the product to a further reaction step without prior purification.

[0036] In some embodiments, the method further comprises the step of converting a compound of formula (III-Y) to a compound of formula (III-Z), for example by contacting the compound of formula (III-Y) with R1-Cl according to Scheme A2: Scheme A2 wherein R1 is selected from C1-C6 alkoxycarbonyl (such as tert-butoxycarbonyl or methoxycarbonyl), benzyloxycarbonyl (i.e., Cbz), C6-C 10 aryloxycarbonyl (such as phenoxycarbonyl), C1-C6 alkylcarbonyl (such as acetyl), haloalkylcarbonyl (such as trifluoroacetyl), and -SO2-(C6-C 10 aryl) (such as tosyl). In one embodiment, R1 is -C(O)(C1-C6 alkoxy). In one embodiment, R1 is -C(O)(C1-C6 alkoxy), wherein the C1-C6 alkoxy is a straight-chain C1-C6 alkoxy selected from methoxy, ethoxy, 1-propoxy, 1-butoxy, 1-pentyloxy, or 1-hexyloxy. In one embodiment, R1 is -C(O)OCH3.

[0037] In some embodiments, a method that includes both Scheme A1 and A2 is represented by Scheme B1, where R9, R10, R12, R5, R6, and R1 are as defined above for Schemes A1 and A2: Scheme B1

[0038] In some embodiments, the method of Scheme A2 is according to Scheme A2': Scheme A2' Or a method that includes both Scheme A1' and A2' is represented by Scheme B2, where R9, R10, R5, R6, and R1 are as defined above for Schemes A1' and A2': Scheme B2

[0039] In a specific embodiment, the method according to Scheme B1 or B2 is the method depicted in Scheme B, where the compound of formula (III-A) can be prepared, for example, as more fully described in Examples 1 and 2. Scheme B

[0040] In some embodiments, Step 1 B is substantially the same as described above for Step 1 A as described above.

[0041] In some embodiments, Step 2 B is accomplished by contacting a compound of formula (III-B) with methyl chloroformate in the presence of a suitable solvent (e.g., toluene or DCM). Without wishing to be bound by any particular theory, it is believed that the choice of methyl carbamate (e.g., as opposed to benzyl carbamate or phenyl carbamate) as the protecting group facilitates purification, increases the stability of intermediate compound (III-A), and simplifies the deprotection of late-stage intermediate (V-A) (e.g., removal of the methyl carbamate to afford the free secondary amine).

[0042] In some embodiments, Step 1 B and 2 B are carried out in the same reaction vessel. In some embodiments, Step 1 B and 2 B are carried out without any intermediate isolation or purification steps. In other embodiments, Step 1 B and 2 B are carried out sequentially in different vessels. In other embodiments, Step 1 B and 2 B are carried out sequentially in different vessels without any intermediate isolation or purification steps. In other embodiments, Step 1 B and 2 B are carried out sequentially in different vessels, wherein Step 1 B is carried out in a first vessel, and the product of Step 1 B is transferred to a second vessel containing a C1-C6 alkyl chloroformate to complete Step 2 B .

[0043] Specific examples and more detailed experimental conditions for the preparation of compounds of formula (III-A) and (III-B) are shown in Examples 1 and 2 below.

[0044] In another aspect, the present disclosure relates to a method for preparing a compound of formula (III-Z) wherein R1 is –C(O)(C1-C6 alkoxy), as shown in Scheme C below. Scheme C Wherein: R5 and R6 are each independently halogen or –OSO2R7; each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C6-C 10 aryl, wherein said C6-C 10 aryl is optionally substituted with 1 to 3 R8; and Each R8 is independently a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0045] In some embodiments, each of R5 and R6 is a halogen. In some embodiments, each of R5 and R6 is chlorine. In some embodiments, each of R5 and R6 is bromine. In some embodiments, each of R5 and R6 is iodine. In some embodiments, each of R5 and R6 is –OSO2R7. In some embodiments, R7 is C1-C6 alkyl. In some embodiments, R7 is methyl. In some embodiments, R7 is a C6-C 10 aryl substituted by one R8. In some embodiments, R8 is C1-C6 alkyl. In some embodiments, R8 is methyl. In some embodiments, R7 is a phenyl substituted by one methyl. In some embodiments, the compound of formula (III-X) is 1,4-dichloro-2-butyne. In some embodiments, the compound of formula (III-X) is 1,4-dibromo-2-butyne. In some embodiments, the compound of formula (III-X) is 1,4-diiodo-2-butyne. In some embodiments, the compound of formula (III-X) is but-2-yne-1,4-diyl bis(methanesulfonate). In some embodiments, the compound of formula (III-X) is but-2-yne-1,4-diyl bis(4-methylbenzenesulfonate).

[0046] In some embodiments, Step 1 C is substantially completed as described above for Step 1 A described.

[0047] In some embodiments, Step 2 C is completed by contacting a compound of formula (III-Y1) with ClC(O)(C1-C6 alkoxy) (i.e., C1-C6 alkyl chloroformate) in the presence of a suitable solvent (such as toluene or DCM).

[0048] In some embodiments, a method for preparing a compound of formula (III-Z) in which R1 is –C(O)(C1-C6 alkoxy) includes the step of converting 1-benzyl-3,4-di(substituted)-2,5-dihydro-1H-pyrrole (III-Y1) (such as 1-benzyl-3,4-di(chloromethyl)-2,5-dihydro-1H-pyrrole (III-B)) into a compound of formula (III-Z) (i.e., Step 2 C)(e.g., compound (III)). In some embodiments, the step of converting a compound of formula (III-Y1) to a compound of formula (III-Z) comprises contacting the compound of formula (III-Y1) with ClC(O)(C1-C6 alkoxy) (i.e., C1-C6 alkyl chloroformate). In some embodiments, R1 is –C(O)OCH3. In some embodiments, the compound of formula (III-Z) is methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (i.e., compound III-A, where R1 is methoxycarbonyl and R5, R6 are each chloro). In some embodiments, for example, where R1 is –C(O)OCH3 and / or the compound of formula (III-Z) is compound (III-A), the step of converting the compound of formula (III-Y1) to the compound of formula (III-Z) comprises contacting the compound of formula (III-Y1) with methyl chloroformate.

[0049] In some embodiments, a method for preparing a compound of formula (III-Z) wherein R1 is –C(O)(C1-C6 alkoxy) comprises the step of contacting dichlorobutyne (III-C, (III-X), where each of R5, R6 is chloro) with N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (III-D) to obtain a compound of formula (III-Y1), where R5, R6 are each chloro (i.e., (III-B)) (i.e., step 1 C ). In some embodiments, the contacting of the compound of formula (III-C) with the compound of formula (III-D) is carried out in the presence of an acid. In some embodiments, the acid is TFA. In some embodiments, the contacting of the compound of formula (III-C) with the compound of formula (III-D) is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is toluene.

[0050] In some embodiments, step 1 C and 2 C are carried out in the same vessel. In some embodiments, step 1 C and 2 C are carried out without any intermediate isolation or purification. In other embodiments, step 1 C and 2 C are carried out sequentially in different vessels. In other embodiments, step 1 C and 2 C are carried out sequentially in different vessels without any intermediate isolation or purification steps. In other embodiments, step 1 C and 2 C are carried out sequentially in different vessels, where step 1 C is carried out in a first vessel, and step 1 CThe product is transferred to a second container containing a C1-C6 alkyl chloroformate to complete Step 2 C 。

[0051] In some embodiments, the method further comprises the step of converting a compound of formula (III-Z) to a compound of formula (V-Z) by reacting a compound of formula (III-Z) with a compound of formula (IV-Y) in the presence of a base according to Scheme A3: Scheme A3 wherein R11 is a C6-C 10 aryl or a 6-10-membered heteroaryl containing 1-3 O, N, S atoms, wherein the C6-C 10 aryl and 6-10-membered heteroaryl are each optionally substituted with one or more substituents selected from R13 and -OR13; each R13 is independently -H, a -C1-C6 alkyl optionally substituted with one or more substituents selected from oxo, -F, -Cl, -Br, -I, -CN, -NO2; or two R13 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring; wherein R1 is selected from C1-C6 alkoxycarbonyl (e.g., tert-butoxycarbonyl or methoxycarbonyl), benzyloxycarbonyl (i.e., Cbz), C6-C 10 aryloxycarbonyl (e.g., phenoxycarbonyl), C1-C6 alkylcarbonyl (e.g., acetyl), haloalkylcarbonyl (e.g., trifluoroacetyl), and -SO2-(C6-C 10 aryl) (e.g., tosyl), and R5 and R6 are each independently a halogen, such as chlorine, bromine, iodine, or -OSO2R7, wherein each R7 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 aryl, wherein the C6-C 10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0052] In some embodiments, R11 is a 6-10-membered heteroaryl as defined above, such as, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, R1 is C1-C6 alkoxycarbonyl, and R5, R6 are each a halogen. In one embodiment, R11 is a 6-10-membered heteroaryl as defined above, such as, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl; R1 is C1-C6 alkoxycarbonyl, and R5, R6 are each chlorine.

[0053] In some embodiments, the reaction according to step 1 A3 is carried out in the presence of a base such as K2CO3 or Cs2CO3. In one embodiment, the base is K2CO3. In some embodiments, the reaction according to Scheme A3 is carried out in a suitable solvent selected from DMSO, toluene, or a mixture thereof.

[0054] In some embodiments, the method according to Scheme A3 involves a method for preparing a compound of formula (V) according to Scheme A3': Scheme A3' which comprises the following steps: Contacting a compound of formula (III-Z), such as a compound of formula (III): with 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV): to obtain a compound of formula (V), wherein R1 is a protecting group. In some embodiments, R1 is a protecting group, wherein the protecting group is –C(O)(C1-C6 alkyl), –C(O)(C1-C6 haloalkyl), -C(O)(C1-C6 alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)2(tolyl). In some embodiments, R1 is –C(O)(C1-C6 alkoxy). In some embodiments, R1 is –C(O)OCH3.

[0055] In some embodiments, the step of contacting a compound of formula (III) with a compound of formula (IV) is carried out in the presence of a base. In some embodiments, the base is Cs2CO3 or K2CO3. In some embodiments, the base is Cs2CO3. In some embodiments, the base is K2CO3. In some embodiments, the compound of formula (V) is formed in the presence of a suitable solvent. In some embodiments, the suitable solvent is DMSO, toluene, or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is a combination of DMSO and toluene.

[0056] In some embodiments, the compound of formula (III) is a compound of formula (III-A): which may also be referred to as methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate.

[0057] In some embodiments, the compound of formula (V) is a compound of formula (V-A): It may also be referred to as methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.

[0058] In some embodiments, the present disclosure relates to intermediate compounds of formula (III): Wherein: R1 is H, –CR2R3-(C6-C 10 aryl), or a protecting group, wherein the C6-C 10 aryl is optionally substituted with 1 to 3 R4; R2 and R3 are each independently H or C1-C6 alkyl; and R4 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. The compound of formula (III) can be used to prepare bioactive compounds, for example, PKR activating compounds. In some embodiments, the compound of formula (III) is used in a method for preparing a compound of formula (I). In other embodiments, the compound of formula (III) is used in a method for preparing a compound of formula (II).

[0059] In some embodiments, R1 is H. In some embodiments, R1 is a protecting group. In some embodiments, R1 is –CR2R3-(C6-C 10 aryl). In some embodiments where R1 is –CR2R3-(C6-C 10 aryl), R2 and R3 are each H. In some embodiments where R1 is –CR2R3-(C6-C 10 aryl), R2 is C1-C6 alkyl and R3 is H. In some embodiments where R1 is –CR2R3-(C6-C 10 aryl), R2 is methyl and R3 is H. In some embodiments where R1 is –CR2R3-(C6-C 10 aryl), the C6-C 10 aryl is unsubstituted. In some embodiments where R1 is –CR2R3-(C6-C 10 aryl), the C6-C 10 alkyl is substituted with one C1-C6 alkoxy. In some embodiments where R1 is –CR2R3-(C6-C 10 aryl), the C6-C10 The aryl group is substituted by a methoxy group. In some embodiments where R1 is –CR2R3-(C6-C 10 aryl), the C6-C 10 aryl is phenyl. In some embodiments where R1 is –CR2R3-(C6-C 10 aryl), the C6-C 10 aryl is 4-methoxyphenyl. In some embodiments, R1 is benzyl (i.e., –Bn, which can also be shown as –CH2-Ph). In some embodiments, R1 is 4-methoxybenzyl.

[0060] As used herein, the term "protecting group" for R1 refers to any group that can prevent the amine group of the compound of formula (III) from participating in or affecting reactions on other parts of the molecule (such as reactions with any one or both of the chloromethyl groups of the compound), while being removable under conditions that do not have an adverse effect on the remainder of the molecule. Examples of amine protecting groups that may be suitable for the disclosed methods include alkoxycarbonyl (such as tert-butoxycarbonyl or BOC and methoxycarbonyl), benzyloxycarbonyl (i.e., Cbz), C6-C 10 aryloxycarbonyl (such as phenyloxycarbonyl), C1-C6 alkylcarbonyl (such as acetyl), haloalkylcarbonyl (such as trifluoroacetyl), and toluenesulfonyl. Those skilled in the art will understand that other compounds of formula (III) in which other amine protecting groups are used are also considered to be within the scope of the compounds of formula (III).

[0061] In some embodiments, R1 is a protecting group, where the protecting group is –C(O)(C1-C6 alkyl), –C(O)(C1-C6 haloalkyl), –C(O)(C1-C6 alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)2(tolyl). In some embodiments, R1 is a protecting group, where the protecting group is –C(O)(C1-C6 alkoxy). In some embodiments, R1 is a protecting group, where the protecting group is –C(O)OCH3.

[0062] In some embodiments, the present disclosure relates to a compound of formula (III), where the compound is: (i) methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate; or (ii) 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole.

[0063] In some embodiments, the compound of formula (III) is a compound of formula (III-A): It can also be referred to as methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate.

[0064] In some embodiments, the compound of formula (III) is a compound of formula (III-B): It can also be referred to as 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole.

[0065] In some embodiments, the present disclosure relates to an intermediate compound of formula (V): wherein R1 is a protecting group.

[0066] In some embodiments, R1 is –C(O)(C1-C6 alkyl), –C(O)(C1-C6 haloalkyl), –C(O)(C1-C6 alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)2(tolyl). In some embodiments, R1 is –C(O)OCH3.

[0067] In some embodiments, the compound of formula (V) is a compound of formula (V-A): It can also be referred to as methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.

[0068] In some embodiments, the present disclosure relates to a compound of formula (V-A): wherein the compound is prepared by a method comprising the following steps: Contacting methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A) with 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV) in the presence of a base. In some embodiments, the base is Cs2CO3 or K2CO3. In some embodiments, the base is Cs2CO3. In some embodiments, the base is K2CO3. In some embodiments, the compound of formula (V-A) is formed in the presence of a suitable solvent. In some embodiments, the suitable solvent is dimethyl sulfoxide (DMSO), toluene, or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is a combination of DMSO and toluene.

[0069] In another aspect, the present disclosure relates to an intermediate compound of formula (IV): which may also be referred to as 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide.

[0070] In another aspect, the present disclosure relates to a method for preparing a compound of formula (IV), as depicted in Scheme D and more fully described in Example 3. In some embodiments, the compound of formula (IV) is obtained by the method depicted in Scheme D and more fully described in Example 3. Scheme D

[0071] In some embodiments, the method for preparing a compound of formula (IV) comprises the step of converting a compound of formula (IV-D) to a compound of formula (IV-C) (i.e., Step 1 D ). In some embodiments, Step 1 D comprises contacting a compound of formula (IV-D) with 1,2-dibromoethane to obtain a compound of formula (IV-C). In some embodiments, Step 1 D is carried out in the presence of a base. Those of ordinary skill in the art will understand that there are many bases compatible with the process of Step 1 D . For example, in some embodiments, the base is potassium carbonate. In some embodiments, Step 1 D is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is water, ethanol (EtOH), or a combination thereof. In some embodiments, the suitable solvent is a mixture of EtOH and water. In some embodiments, the suitable solvent is a mixture of EtOH and water in a ratio of about 80:20 to 98:2, such as about 85:15 or about 95:5.

[0072] In some embodiments, the method for preparing a compound of formula (IV) comprises the step of converting a compound of formula (IV-C) to a compound of formula (IV-B) (i.e., Step 2 D ). In some embodiments, Step 2 D comprises contacting a compound of formula (IV-C) with a brominating reagent. Those of ordinary skill in the art will understand that there are many brominating reagents compatible with the process of Step 2 D . For example, in some embodiments, the brominating reagent is N-bromosuccinimide (NBS). In some embodiments, Step 2 D is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is ethyl acetate (EtOAc), N,N-dimethylformamide (DMF), or a combination thereof.

[0073] In some embodiments, the method for preparing the compound of formula (IV) includes the step of converting the compound of formula (IV-B) into the compound of formula (IV-A) (i.e., step 3 D ). In some embodiments, step 3 D includes contacting the compound of formula (IV-B) with a Grignard reagent, C 1- 6 alkyllithium, and sulfonyl chloride. In some embodiments, step 3 D includes contacting the compound of formula (IV-B) with isopropylmagnesium chloride, butyllithium, and sulfonyl chloride. In some embodiments, step 3 D includes first contacting the compound of formula (IV-B) with a Grignard reagent to obtain a first metallated intermediate compound, contacting the first metallated intermediate compound with C1-C6 alkyllithium (such as butyllithium, n-butyllithium, or hexyllithium) to obtain a second metallated intermediate compound, and subsequently contacting the second metallated intermediate compound with sulfonyl chloride to obtain the compound of formula (IV-A). In some embodiments, step 3 D includes first contacting the compound of formula (IV-B) with isopropylmagnesium chloride to obtain a first metallated intermediate compound, subsequently contacting the first metallated intermediate compound with butyllithium to obtain a second metallated intermediate compound, and then contacting the second metallated intermediate compound with sulfonyl chloride to obtain the compound of formula (IV-A). In some embodiments, the butyllithium is selected from n-butyllithium, sec-butyllithium, and tert-butyllithium. In some embodiments, the butyllithium is n-butyllithium. In some embodiments, the butyllithium is sec-butyllithium. In some embodiments, the butyllithium is tert-butyllithium. In some embodiments, step 3 D is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is tetrahydrofuran (THF).

[0074] In some embodiments, the method for preparing the compound of formula (IV) includes the step of converting the compound of formula (IV-A) into the compound of formula (IV) (i.e., step 4 D ). In some embodiments, step 4 D includes contacting the compound of formula (IV-A) with ammonia to obtain the compound of formula (IV). In some embodiments, step 4 D is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is methanol (MeOH).

[0075] In another aspect, the present disclosure relates to a method for preparing the compound of formula (IV), as depicted in Scheme E and more fully described in Example 4. In some embodiments, the compound of formula (IV) is obtained by the method depicted in Scheme E and more fully described in Example 4. Scheme E

[0076] In some embodiments, the method for preparing a compound of formula (IV) includes the step of converting a compound of formula (IV-F) into a compound of formula (IV-E) (i.e., step 1 E ). In some embodiments, step 1 E includes contacting the compound of formula (IV-F) with bromine, a hydrohalic acid (such as hydrochloric acid or hydrobromic acid), and sulfamic acid. In some embodiments, step 1 E includes first contacting the compound of formula (IV-F) with a first portion of bromine, then contacting the compound of formula (IV-F) with hydrochloric acid, then contacting the compound of formula (IV-F) with a second portion of bromine, and finally contacting the compound of formula (IV-F) with sulfamic acid. In some embodiments, step 1 E includes first contacting the compound of formula (IV-F) with a first portion of bromine, then contacting the compound of formula (IV-F) with hydrobromic acid, then contacting the compound of formula (IV-F) with a second portion of bromine, and finally contacting the compound of formula (IV-F) with sulfamic acid. In some embodiments, step 1 E includes first contacting the compound of formula (IV-F) with a first portion of bromine to obtain a first intermediate compound, then contacting the first intermediate compound with hydrochloric acid to obtain a second intermediate compound, then contacting the second intermediate compound with a second portion of bromine to obtain a third intermediate compound, and finally reacting the third intermediate compound with sulfamic acid to obtain the compound of formula (IV-E). In some embodiments, step 1 E includes first contacting the compound of formula (IV-F) with a first portion of bromine to obtain a first intermediate compound, then contacting the first intermediate compound with hydrobromic acid to obtain a second intermediate compound, then contacting the second intermediate compound with a second portion of bromine to obtain a third intermediate compound, and finally contacting the third intermediate compound with sulfamic acid to obtain the compound of formula (IV-E). In some embodiments, step 1 E is carried out in a suitable solvent. In some embodiments, the suitable solvent is water.

[0077] In some embodiments, the method for preparing a compound of formula (IV) includes the step of converting a compound of formula (IV-E) into a compound of formula (IV-B) (i.e., step 2 E ). In some embodiments, step 2 E includes contacting the compound of formula (IV-E) with 1,2-dibromoethane to obtain the compound of formula (IV-B). In some embodiments, step 2 E is carried out in the presence of a base. Those of ordinary skill in the art will understand that there are many bases for step 2 Eis compatible with the process. For example, in some embodiments, the base is potassium carbonate. In some embodiments, step 2 E is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is water, EtOH, or a combination thereof. In some embodiments, the suitable solvent is a combination of water and EtOH. In some embodiments, the suitable solvent is a combination of water and EtOH in a ratio of about 1 to about 1.

[0078] In some embodiments, the method for preparing the compound of formula (IV) includes the step of converting the compound of formula (IV-B) into the compound of formula (IV-A) (i.e., step 3 E ). In some embodiments, step 3 E includes contacting the compound of formula (IV-B) with a Grignard reagent, C 1- 6 alkyllithium, and sulfonyl chloride. In some embodiments, step 3 E includes contacting the compound of formula (IV-B) with isopropylmagnesium chloride, butyllithium, and sulfonyl chloride. In some embodiments, step 3 E includes first contacting the compound of formula (IV-B) with a Grignard reagent (such as isopropylmagnesium chloride) to obtain a first metallated intermediate compound, contacting the first metallated intermediate compound with a C1-C6 alkyllithium (such as butyllithium, n-butyllithium, or hexyllithium) to obtain a second metallated intermediate compound, and then contacting the second metallated intermediate compound with sulfonyl chloride to obtain the compound of formula (IV-A). In some embodiments, step 3 E includes first contacting the compound of formula (IV-B) with isopropylmagnesium chloride to obtain a first metallated intermediate compound, subsequently contacting the first metallated intermediate compound with butyllithium to obtain a second metallated intermediate compound, and then contacting the second metallated intermediate compound with sulfonyl chloride to obtain the compound of formula (IV-A). In some embodiments, the butyllithium is selected from n-butyllithium, sec-butyllithium, and tert-butyllithium. In some embodiments, the butyllithium is n-butyllithium. In some embodiments, the butyllithium is sec-butyllithium. In some embodiments, the butyllithium is tert-butyllithium. In some embodiments, step 3 E is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is THF.

[0079] In some embodiments, the method for preparing the compound of formula (IV) includes the step of converting the compound of formula (IV-A) into the compound of formula (IV) (i.e., step 4 E ). In some embodiments, step 4 E includes contacting the compound of formula (IV-A) with ammonia to obtain the compound of formula (IV). In some embodiments, step 4 EIt is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is MeOH.

[0080] On the other hand, the present disclosure relates to an intermediate compound of formula (VII): It may also be referred to as (S)-tropic acid. (S)-Tropic acid can be prepared as described below, or alternatively, it can be prepared by optical resolution from racemic tropic acid, for example, by forming diastereomeric salts using (1R,2S)-2-amino-1,2-diphenylethanol ((1R,2S)-ADPE), using, for example, EtOH, isopropanol (IPA), or an EtOH / water or IPA / water mixture, as described in Tetrahedron 70(2014)7923 - 7928.

[0081] On the other hand, the present disclosure relates to a method for preparing an intermediate compound of formula (VII), as depicted in Scheme F and more fully described in Example 5. In some embodiments, the compound of formula (VII) is obtained by the method depicted in Scheme F and more fully described in Example 5. Scheme F

[0082] In some embodiments, the method for preparing the compound of formula (VII) includes the step of converting the compound of formula (VII-C) into the compound of formula (VII-B) (i.e., step 1 F ). In some embodiments, step 1 F includes contacting the compound of formula (VII-C) with methyl formate to obtain the compound of formula (VII-B). In some embodiments, step 1 F is carried out in the presence of a base. Those of ordinary skill in the art will understand that there are many bases compatible with the process of step 1 F . In some embodiments, the base is sodium tert-butoxide or sodium methoxide. In some embodiments, the base is sodium tert-butoxide. In some embodiments, the base is sodium methoxide. In some embodiments, step 1 F is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is toluene, THF, or methyl tert-butyl ether (MTBE). In some embodiments, the suitable solvent is toluene. In some embodiments, the suitable solvent is THF. In some embodiments, the suitable solvent is MTBE.

[0083] In some embodiments, the method for preparing the compound of formula (VII) includes the step of converting the compound of formula (VII-B) into the compound of formula (VII-A) (i.e., step 2 F ). In some embodiments, step 2 FComprising contacting a compound of formula (VII-B) with a reducing agent. Step 2 F Comprising contacting a compound of formula (VII-B) with a reducing agent in the presence of an enzyme. In some embodiments, the reducing agent is an enzyme. In some embodiments, the reducing agent is NADPH. In some embodiments, the enzyme is a carbonyl reductase (CRED). In some embodiments, the enzyme is an engineered form of CRED. In some embodiments, Step 2 F Is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is phosphate buffer, toluene, MTBE, or a combination thereof. In some embodiments, the suitable solvent is phosphate buffer. In some embodiments, the suitable solvent is a combination of phosphate buffer and toluene. In some embodiments, the suitable solvent is a combination of phosphate buffer and MTBE. In some embodiments, the pH of the phosphate buffer is about 6.5 - 7. In some embodiments, the phosphate buffer comprises one or more additional reagents and enzyme cofactors. In some embodiments, the one or more additional reagents and enzyme cofactors comprise thiamine ·HCl, L-lysine, GDP, NADP, or a combination thereof. In some embodiments, the one or more additional reagents and enzyme cofactors comprise each of thiamine·HCl, L-lysine, GDP, and NADP. In some embodiments, Step 2 F Comprises a step of separating or purifying methyl (S)-tropate. In some embodiments, Step 2 F Comprises a step of separating or purifying methyl (S)-tropate from a mixture of methyl (R)-tropate and methyl (S)-tropate. The separation or purification step can be carried out by any method commonly known to those of ordinary skill in the art. For example, in some embodiments, the separation or purification step comprises a chromatographic step (e.g., chiral resolution by HPLC, UPLC, or SFC). In other embodiments, the separation or purification step comprises a recrystallization step. In some embodiments, the separation or purification step may comprise derivatizing a mixture of (R)-tropic acid and (S)-tropic acid to form a mixture of diastereomers, and then separating the derivatized diastereomers by any method commonly known to those of ordinary skill in the art.

[0084] In some embodiments, the method for preparing a compound of formula (VII) comprises a step of converting a compound of formula (VII-A) into a compound of formula (VII) (i.e., Step 3 F ). In some embodiments, Step 3 F Comprises contacting a compound of formula (VII-A) with a base or an enzyme. In some embodiments, Step 3 Fcomprising contacting a compound of formula (VII-A) with a base. Those of ordinary skill in the art will understand that many bases are compatible with the process of step 3 F In some embodiments, the base is sodium hydroxide (i.e., NaOH). In some embodiments, step 3 F is carried out in the presence of an enzyme. In some embodiments, step 3 F is carried out in the presence of a lipase. In some embodiments, step 3 F is carried out in the presence of Candida antarctica lipase B (CALB). In some embodiments, step 3 F is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is toluene or MTBE. In some embodiments, the suitable solvent is toluene. In some embodiments, the suitable solvent is MTBE.

[0085] In yet another aspect, the present disclosure relates to a composition comprising a compound of formula (III) or a pharmaceutically acceptable salt thereof: wherein R1 is a protecting group.

[0086] In some embodiments, the composition comprising a compound of formula (III) further comprises a compound of formula (IV): or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the composition comprising a compound of formula (III) further comprises a base. In some embodiments, the base is Cs2CO3 or K2CO3. In some embodiments, the base is Cs2CO3. In some embodiments, the base is K2CO3.

[0088] In some embodiments, the composition comprising a compound of formula (III) further comprises a compound of formula (V): or a pharmaceutically acceptable salt thereof, wherein R1 is a protecting group.

[0089] In some embodiments of the composition comprising a compound of formula (III), the R1 group present on the compound of formula (III) and / or the compound of formula (V) is –C(O)(C1-C6 alkyl), -C(O)(C1-C6 haloalkyl), –C(O)(C1-C6 alkoxy), –C(O)(benzyloxy), -C(O)(phenoxy) or –S(O)2(tolyl). In some embodiments, R1 is –C(O)(C1-C6 alkoxy). In some embodiments, R1 is –C(O)OCH3.

[0090] In some embodiments of the composition comprising the compound of formula (III), the compound of formula (III) is a compound of formula (III-A): It may also be referred to as methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate.

[0091] In some embodiments of the composition comprising the compound of formula (III), the compound of formula (V) is a compound of formula (V-A): It may also be referred to as methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. Method for preparing PKR activating compounds

[0092] In another aspect, the present disclosure relates to a method for preparing a compound of formula (I), the compound of formula (I) being (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one, also known as etavopivat: As depicted in Scheme G and more fully described in Examples 6 to 12. Scheme G

[0093] In some embodiments, the method for preparing the compound of formula (I) comprises the steps of: contacting a compound of formula (III) with 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV) to obtain a compound of formula (V); and converting the compound of formula (V) into the compound of formula (I), wherein R1 is a protecting group (i.e., step 1 G , followed by step 2 G and 3 G ). In some embodiments, step 1 G is carried out in the presence of a base. In some embodiments, the base is Cs2CO3 or K2CO3. In some embodiments, the base is Cs2CO3. In some embodiments, the base is K2CO3. In some embodiments, step 1 GIt is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is DMSO, toluene, or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is a mixture of DMSO and toluene.

[0094] In some embodiments, R1 is –C(O)(C1-C6 alkyl), –C(O)(C1-C6 haloalkyl), –C(O)(C1-C6 alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or -S(O)2(tolyl). In some embodiments, R1 is –C(O)(C1-C6 alkoxy). In some embodiments, R1 is –C(O)OCH3.

[0095] In some embodiments, the compound of formula (III) is obtained by the method depicted in Scheme C. In some embodiments, the compound of formula (III) is a compound of formula (III-A). In some embodiments, the compound of formula (III) is a compound of formula (III-A), wherein the compound of formula (III-A) is obtained by the method depicted in Scheme B and more fully described in Examples 1 and 2.

[0096] In some embodiments, the compound of formula (IV) is obtained by the method depicted in one of Scheme D or E and more fully described in Examples 3 and 4, respectively.

[0097] In some embodiments, the compound of formula (V) is obtained by the method described above for preparing the compound of formula (V). In some embodiments, the compound of formula (V) is a compound of formula (V-A).

[0098] In some embodiments, the method for preparing the compound of formula (I) includes the step of converting the compound of formula (V) into the compound of formula (VI) (i.e., step 2 G ). In some embodiments, step 2 G includes deprotecting the compound of formula (V) to obtain the compound of formula (VI). In some embodiments, deprotecting the compound of formula (V) to obtain the compound of formula (VI) includes contacting the compound of formula (V) with an acid. Those of ordinary skill in the art will understand that there are many acids compatible with the process of step 2 G . In some embodiments, the acid includes HBr and acetic acid. In other embodiments, the acid includes dibutyl sulfide and methanesulfonic acid (MSA). In other embodiments, the acid includes dibutyl sulfide, TFA, and MSA. In some embodiments, step 2 G further includes the step of neutralizing the acid with a suitable base. In some embodiments, the suitable base is ammonium hydroxide. In some embodiments, step 2 GFurther comprising contacting the compound of formula (VI) with (S)-tropic acid (VII) to form a complex of compounds (VI) and (VII). In some embodiments, step 2 G is carried out pure, in the absence of additional solvents (e.g., dibutyl sulfide and MSA are present in an amount sufficient to dissolve the compound of formula (VI)). It will be appreciated that step 2 G can be run in the presence of a suitable solvent or co-solvent.

[0099] In some embodiments, the method for preparing the compound of formula (I) comprises the step of contacting (VI) with (S)-tropic acid (VII) to obtain the compound of formula (I) (i.e., step 3 G ). In some embodiments, step 3 G comprises coupling the compound of formula (VI) with (S)-tropic acid (VII) to obtain the compound of formula (I). In some embodiments, step 3 G is carried out in the presence of a coupling reagent. In some embodiments, the coupling reagent is a carbodiimide coupling reagent. In some embodiments, step 3 G is carried out in the presence of a coupling reagent and an additive. Step 3 G is carried out in the presence of a carbodiimide coupling reagent and an additive. Those of ordinary skill in the art will understand that there are many coupling reagents (such as carbodiimide coupling reagents, such as EDC (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide) or HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), etc.) and additives (such as ethyl (hydroxyamino)cyanoacetate 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine N-oxide (HOPO), etc.) that are compatible with the process of step 3 G . In some embodiments, for example, the coupling reagent comprises EDC. In some embodiments, the coupling reagent comprises propylphosphonic anhydride In some embodiments, the coupling reagent comprises and EDC. In some embodiments, step 3 G is carried out in the presence of EDC and an additive, wherein the additive is In some embodiments, step 3 G is carried out in the presence of EDC and an additive, wherein the additive is HOPO. In some embodiments, step 3 G is carried out in and EDC and an additive, wherein the additive is In some embodiments, step 3 G is carried out in It is carried out in the presence of EDC and an additive, wherein the additive is HOPO. In some embodiments, step 3 G In the presence of and an additive, wherein the additive is In some embodiments, step 3 G In the presence of and an additive, wherein the additive is HOPO. In some embodiments, step 3 G It is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is DMSO, N,N-dimethylacetamide (DMAc), EtOH, DCM, 2-methyltetrahydrofuran (2-MeTHF) or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is DMAc. In some embodiments, the suitable solvent is EtOH. In some embodiments, the suitable solvent is DCM. In some embodiments, the suitable solvent is a combination of DMAc and EtOH. In some embodiments, the suitable solvent is 2-MeTHF. In some embodiments, the suitable solvent is a combination of 2-MeTHF and DMAc. In some embodiments, the suitable solvent is a combination of 2-MeTHF and EtOH. In some embodiments, the suitable solvent is a combination of EtOH, DMAc and 2-MeTHF.

[0100] In yet another aspect, the present disclosure relates to a method for preparing a compound of formula (II) — (2R)-2-hydroxy-2-phenyl-1-[5-(pyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one: As depicted in Scheme H and more fully described in Example 13. Scheme H

[0101] In some embodiments, the method for preparing a compound of formula (II) comprises the following steps: contacting a compound of formula (III) with pyridine-2-sulfonamide (VIII-A) to obtain a compound of formula (VIII); and converting the compound of formula (VIII) into a compound of formula (II), wherein R1 is a protecting group (i.e., step 1 H , followed by step 2 H and 3 H ). In some embodiments, step 1 HIt is carried out in the presence of a base. In some embodiments, the base is Cs2CO3 or K2CO3. In some embodiments, the base is Cs2CO3. In some embodiments, the base is K2CO3. In some embodiments, step 1 H It is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is DMSO, toluene, or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is a mixture of DMSO and toluene.

[0102] In some embodiments, R1 is –C(O)(C1-C6 alkyl), –C(O)(C1-C6 haloalkyl), –C(O)(C1-C6 alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or -S(O)2(tolyl). In some embodiments, R1 is –C(O)(C1-C6 alkoxy). In some embodiments, R1 is –C(O)OCH3.

[0103] In some embodiments, the compound of formula (III) is obtained by the method depicted in Scheme C. In some embodiments, the compound of formula (III) is a compound of formula (III-A). In some embodiments, the compound of formula (III) is a compound of formula (III-A), wherein the compound of formula (III-A) is obtained by the method depicted in Scheme B and more fully described in Examples 1 and 2.

[0104] In some embodiments, the method for preparing the compound of formula (II) includes the step of converting the compound of formula (VIII) into the compound of formula (IX) (i.e., step 2 H ). In some embodiments, step 2 H includes deprotecting the compound of formula (VIII) to obtain the compound of formula (IX). In some embodiments, deprotecting the compound of formula (VIII) to obtain the compound of formula (IX) includes contacting the compound of formula (VIII) with an acid. Those of ordinary skill in the art will understand that there are many acids compatible with the process of step 2 H . In some embodiments, the acid includes HBr and acetic acid. In other embodiments, the acid includes dibutylsilane, TFA, and MSA. In other embodiments, the acid includes dibutylsilane and MSA. In some embodiments, step 2 H further includes the step of neutralizing the acid with a suitable base. In some embodiments, the suitable base is ammonium hydroxide. In some embodiments, deprotecting the compound of formula (VIII) to obtain the compound of formula (IX) includes contacting the compound of formula (VIII) with a strong base. In some embodiments, the strong base is potassium hydroxide. In some embodiments, step 2 HFurther includes contacting the compound of formula (IX) with (R)-2-hydroxy-2-phenylacetic acid (XI) to form a complex of compounds (IX) and (XI). In some embodiments, step 2 H is carried out pure, without the presence of additional solvents (e.g., dibutyl sulfide and MSA are present in an amount sufficient to dissolve the compound of formula (VI)). It is understood that step 2 H can be run in the presence of a suitable solvent or co-solvent. For example, in some embodiments, step 2 H is carried out in the presence of water.

[0105] In some embodiments, the method for preparing the compound of formula (II) includes the step of contacting (IX) with (R)-2-hydroxy-2-phenylacetic acid (XI) to obtain the compound of formula (II) (i.e., step 3 H ). In some embodiments, step 3 H includes coupling the compound of formula (IX) with (R)-2-hydroxy-2-phenylacetic acid (XI) to obtain the compound of formula (II). In some embodiments, step 3 H is carried out in the presence of a coupling reagent. In some embodiments, the coupling reagent is a carbodiimide coupling reagent. In some embodiments, step 3 H is carried out in the presence of a coupling reagent and an additive. Step 3 H is carried out in the presence of a carbodiimide coupling reagent and an additive. Those of ordinary skill in the art will understand that there are many coupling reagents (e.g., carbodiimide coupling reagents such as EDC or HATU, or etc.) and additives (e.g., ((hydroxyamino)cyanoacetic acid ethyl ester), HOBt, HOSu or HOPO etc.) that are compatible with the process of step 3 H . In some embodiments, for example, the coupling reagent includes EDC. In some embodiments, the coupling reagent includes In some embodiments, the coupling reagent includes and EDC. In some embodiments, step 3 G is carried out in the presence of EDC and an additive, where the additive is In some embodiments, step 3 G is carried out in the presence of EDC and an additive, where the additive is HOPO. In some embodiments, step 3 G is carried out in the presence of and an additive, where the additive is In some embodiments, step 3 G is carried out in the presence of and EDC and an additive, where the additive is In some embodiments, the coupling reagent comprises and EDC·HCl. In some embodiments, the coupling reagent comprises HOBt and EDC. In some embodiments, the coupling reagent comprises HOPO and EDC. In some embodiments, step 3 H is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is DMSO, DMAc, EtOH, DCM, 2-MeTHF, or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is DMAc. In some embodiments, the suitable solvent is EtOH. In some embodiments, the suitable solvent is DCM. In some embodiments, the suitable solvent is 2-MeTHF. In some embodiments, the suitable solvent is a combination of DMAc and EtOH. In some embodiments, the suitable solvent is a combination of 2-MeTHF and DMAc. In some embodiments, the suitable solvent is a combination of 2-MeTHF and EtOH. In some embodiments, the suitable solvent is a combination of EtOH, DMAc, and 2-MeTHF. In some embodiments, the suitable solvent is DMSO. List of embodiments

[0106] The present invention is further described by the following non-limiting embodiments: 1. A compound of formula (III): or a salt thereof, wherein: R1 is H, –CR2R3-(C6-C 10 aryl), or a protecting group, wherein the C6-C 10 aryl is optionally substituted with 1 to 3 R4; R2 and R3 are each independently H or C1-C6 alkyl; and R4 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. 2. The compound of embodiment 1, wherein R1 is –CR2R3-(C6-C 10 aryl). 3. The compound of embodiment 1 or 2, wherein R2 and R3 are each H. 4. The compound of embodiment 1, wherein R1 is a protecting group. 5. The compound of embodiment 1 or 4, wherein R1 is –C(O)(C1-C6 alkyl), -C(O)(C1-C6 haloalkyl), –C(O)(C1-C6 alkoxy), –C(O)(benzyloxy), -C(O)(phenoxy), or –S(O)2(tolyl). 6. A compound according to any one of embodiments 1, 4 or 5, wherein R1 is –C(O)(C1-C6 alkoxy). 7. A compound according to any one of embodiments 1 or 4 to 6, wherein the compound is: Methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate, or a salt thereof. 8. A compound according to any one of embodiments 1 to 3, wherein the compound is: 1-Benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole, or a salt thereof. 9. A method for preparing a compound of formula (III): wherein R1 is –C(O)(C1-C6 alkoxy), the method comprising step (i): (i) converting a compound of formula (III-B): into a compound of formula (III). 10. The method of embodiment 9, wherein converting the compound of formula (III-B) into the compound of formula (III) comprises contacting the compound of formula (III-B) with ClC(O)(C1-C6 alkoxy). 11. The method of embodiment 9, wherein R1 is –C(O)OCH3. 12. The method of embodiment 11, wherein converting the compound of formula (III-B) into the compound of formula (I) comprises contacting the compound of formula (III-B) with methyl chloroformate. 13. The method according to any one of embodiments 9 to 12, wherein the compound of formula (III-B) is obtained by step (ii), which comprises: (ii) contacting a compound of formula (III-X) with a compound of formula (III-D): to obtain a compound of formula (III-B), wherein: R5 and R6 are each independently halogen or –OSO2R7 each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C6-C 10 aryl, wherein the C6-C 10 aryl is optionally substituted with 1 to 3 R8; and Each R8 is independently a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. 14. The method of embodiment 13, wherein R5 and R6 are each a halogen. 15. The method of embodiment 14, wherein R5 and R6 are each chlorine, i.e., the compound of formula (III-C). 16. The method of any one of embodiments 13 to 15, wherein the contacting of the compound of formula (III-C) or (III-X) with the compound of formula (III-D) is carried out in the presence of an acid. 17. The method of embodiment 16, wherein the acid is trifluoroacetic acid. 18. The method of any one of embodiments 13 to 15, wherein the contacting of the compound of formula (III-C) or (III-X) with the compound of formula (III-D) is carried out in the presence of trimethylsilyl trifluoromethanesulfonate. 19. The method of any one of embodiments 13 to 15, wherein the contacting of the compound of formula (III-C) or (III-X) with the compound of formula (III-D) is carried out in the presence of trimethylsilyl trifluoromethanesulfonate and CsF. 20. The method of any one of embodiments 13 to 15, wherein the contacting of the compound of formula (III-C) or (III-X) with the compound of formula (III-D) is carried out in the presence of trimethylsilyl iodide. 21. The method of any one of embodiments 13 to 15, wherein the contacting of the compound of formula (III-C) or (III-X) with the compound of formula (III-D) is carried out in the presence of trimethylsilyl iodide and an additive selected from CsF, LiF, ZnCl2, and combinations thereof. 22. The compound of formula (III-A): It is prepared by a method consisting essentially of the following steps: (i) Contacting the compound of formula (III-C): with the compound of formula (III-D): in the presence of an acid to obtain the compound of formula (III-B): (ii) Contacting the compound of formula (III-B) with methyl chloroformate to obtain the compound of formula (III-A). 23. The compound of embodiment 22, wherein the acid is trifluoroacetic acid. 24. The compound of formula (IV): or a salt thereof. 25. A method for preparing a compound of formula (IV): which comprises contacting a compound of formula (IV-A): with ammonia to obtain a compound of formula (IV). 26. The method of embodiment 25, wherein the compound of formula (IV-A) is obtained as follows: A compound of formula (IV-B): is converted into a compound of formula (IV-A). 27. The method of embodiment 26, wherein converting the compound of formula (IV-B) into the compound of formula (IV-A) comprises contacting the compound of formula (IV-B) with a Grignard reagent, a C1-C6 alkyllithium, and a sulfonyl chloride. 28. The method of embodiment 26 or 27, wherein converting the compound of formula (IV-B) into the compound of formula (IV-A) comprises the following steps: Contacting the compound of formula (IV-B) with a Grignard reagent to obtain a first metallated intermediate compound (IV-B1); Contacting the first metallated intermediate (IV-B1) compound with a C1-C6 alkyllithium (such as butyllithium, n-butyllithium or hexyllithium) to obtain a second metallated intermediate compound (IV-B2); and Contacting the second metallated intermediate compound (IV-B2) with a sulfonyl chloride to obtain a compound of formula (IV-A). 29. The method of embodiment 27 or 28, wherein the Grignard reagent is isopropylmagnesium chloride. 30. The method of any one of embodiments 27 to 29, wherein the C1-C6 alkyllithium is butyllithium, such as n-butyllithium. 31. The method of any one of embodiments 26 to 30, wherein the compound of formula (IV-B) is obtained by converting a compound of formula (IV-C): into a compound of formula (IV-B). 32. The method of embodiment 31, wherein converting the compound of formula (IV-C) into the compound of formula (IV-B) comprises contacting the compound of formula (IV-C) with a brominating reagent. 33. The method of embodiment 32, wherein the brominating reagent is N-bromosuccinimide. 34. The method according to any one of embodiments 31 to 33, wherein the compound of formula (IV-C) is obtained by contacting a compound of formula (IV-D): with 1,2-dibromoethane to obtain a compound of formula (IV-C). 35. The method according to embodiment 34, wherein the contacting of the compound of formula (IV-D) with 1,2-dibromoethane is carried out in the presence of a first base. 36. The method according to embodiment 35, wherein the first base is K2CO3. 37. The method according to any one of embodiments 26 to 30, wherein the compound of formula (IV-B) is obtained by contacting a compound of formula (IV-E): with 1,2-dibromoethane to obtain a compound of formula (IV-B). 38. The method according to embodiment 37, wherein the contacting of the compound of formula (IV-E) with 1,2-dibromoethane is carried out in the presence of a first base. 39. The method according to embodiment 38, wherein the first base is K2CO3. 40. The method according to any one of embodiments 37 to 39, wherein the compound of formula (IV-E) is obtained by converting a compound of formula (IV-F): into a compound of formula (IV-E). 41. The method according to embodiment 40, wherein converting the compound of formula (IV-F) into the compound of formula (IV-E) comprises contacting the compound of formula (IV-F) with bromine, hydrohalic acid, and sulfamic acid. 42. The method according to embodiment 40 or 41, wherein converting the compound of formula (IV-F) into the compound of formula (IV-E) comprises the following steps: Contacting the compound of formula (IV-F) with a first portion of bromine to obtain a first intermediate compound (IV-F1); Contacting the first intermediate compound (IV-F1) with hydrohalic acid to obtain a second intermediate compound (IV-F2); Contacting the second intermediate compound (IV-F2) with a second portion of bromine to obtain a third intermediate compound (IV-F3); and Contacting the third intermediate compound (IV-F3) with sulfamic acid to obtain a compound of formula (IV-E). 43. The method according to embodiment 41 or 42, wherein the hydrohalic acid is hydrochloric acid. 44. The method according to embodiment 41 or 42, wherein the hydrohalic acid is hydrobromic acid. 45. Compound of formula (IV): It is prepared by a method consisting essentially of the following steps: (i) Contacting a compound of formula (IV-D): with 1,2-dibromoethane in the presence of a base to obtain a compound of formula (IV-C): (ii) Contacting the compound of formula (IV-C) with a brominating reagent to obtain a compound of formula (IV-B): (iii) Contacting the compound of formula (IV-B) with a Grignard reagent, a C1-C6 alkyllithium, and a sulfonyl chloride to obtain a compound of formula (IV-A): (iv) Contacting the compound of formula (IV-A) with ammonia to obtain the compound of formula (IV). 46. The compound of embodiment 45, wherein step (iii) further comprises the following steps: Contacting the compound of formula (IV-B) with a Grignard reagent to obtain a first metallated intermediate compound (IV-B1); Contacting the first metallated intermediate (IV-B1) compound with a C1-C6 alkyllithium (such as butyllithium, n-butyllithium or hexyllithium) to obtain a second metallated intermediate compound (IV-B2); and Contacting the second metallated intermediate compound (IV-B2) with a sulfonyl chloride to obtain the compound of formula (IV-A). 47. The compound of embodiment 45 or 46, wherein the base is K2CO3. 48. The compound of any one of embodiments 45 to 47, wherein the brominating reagent is N-bromosuccinimide. 49. The compound of any one of embodiments 45 to 48, wherein the Grignard reagent is isopropylmagnesium chloride. 50. The compound of any one of embodiments 45 to 49, wherein the C1-C6 alkyllithium is butyllithium, such as n-butyllithium. 51. Compound of formula (IV): It is prepared by a method consisting essentially of the following steps: (i) Contacting a compound of formula (IV-F): Contact with bromine, hydrohalic acid and sulfamic acid to obtain a compound of formula (IV-E): (ii) Contact the compound of formula (IV-E) with 1,2-dibromoethane in the presence of a base to obtain a compound of formula (IV-B): (iii) Contact the compound of formula (IV-B) with a Grignard reagent, C1-C6 alkyllithium and sulfonyl chloride to obtain a compound of formula (IV-A): (iv) Contact the compound of formula (IV-A) with ammonia to obtain a compound of formula (IV). 52. The compound of embodiment 51, wherein step (i) further comprises the following steps: Contact the compound of formula (IV-F) with the first portion of bromine to obtain a first intermediate compound (IV-F1); Contact the first intermediate compound (IV-F1) with hydrohalic acid to obtain a second intermediate compound (IV-F2); Contact the second intermediate compound (IV-F2) with the second portion of bromine to obtain a third intermediate compound (IV-F3); and Contact the third intermediate compound (IV-F3) with sulfamic acid to obtain a compound of formula (IV-E). 53. The compound of embodiment 51 or 52, wherein step (iii) further comprises the following steps: Contact the compound of formula (IV-B) with a Grignard reagent to obtain a first metallated intermediate compound (IV-B1); Contact the first metallated intermediate (IV-B1) compound with C1-C6 alkyllithium (such as butyllithium, n-butyllithium or hexyllithium) to obtain a second metallated intermediate compound (IV-B2); and Contact the second metallated intermediate compound (IV-B2) with sulfonyl chloride to obtain a compound of formula (IV-A). 54. The compound of any one of embodiments 51 to 53, wherein the hydrohalic acid is hydrochloric acid. 55. The compound of any one of embodiments 51 or 53, wherein the hydrohalic acid is hydrobromic acid. 56. The compound of any one of embodiments 51 to 55, wherein the base is K2CO3. 57. The compound of any one of embodiments 51 to 56, wherein the Grignard reagent is isopropylmagnesium chloride. The compound of any one of embodiments 51 to 57, wherein the C1-C6 alkyllithium is butyllithium, such as n-butyllithium. 59. A method for preparing a compound of formula (V): which comprises contacting a compound of formula (III): with a compound of formula (IV): to obtain a compound of formula (V), wherein R1 is a protecting group. 60. The method of embodiment 59, wherein the contacting of the compound of formula (III) with the compound of formula (IV) is carried out in the presence of a base. 61. The method of embodiment 60, wherein the base is Cs2CO3 or K2CO3. 62. The method of any one of embodiments 59 to 61, wherein R1 is –C(O)(C1-C6 alkyl), –C(O)(C1-C6 haloalkyl), –C(O)(C1-C6 alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy) or –S(O)2(tolyl). 63. The method of any one of embodiments 59 to 62, wherein R1 is –C(O)(C1-C6 alkoxy). 64. The method of any one of embodiments 59 to 63, wherein R1 is –C(O)OCH3. 65. A compound of formula (V-A): or a salt thereof. 66. A compound of formula (V-A): or a salt thereof, which is prepared by a method consisting essentially of the following steps: contacting methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate: with 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide: in the presence of a base. 67. The compound of embodiment 66, wherein the base is Cs2CO3 or K2CO3. 68. A method for preparing a compound of formula (I): It includes reacting a compound of formula (III): with a compound of formula (IV): to obtain a compound of formula (V): converting the compound of formula (V) into a compound of formula (I), wherein R1 is a protecting group. 69. The method of embodiment 68, wherein the contacting of the compound of formula (III) with the compound of formula (IV) is carried out in the presence of a first base. 70. The method of embodiment 69, wherein the first base is Cs2CO3 or K2CO3. 71. The method of any one of embodiments 68 to 70, wherein converting the compound of formula (V) into a compound of formula (I) includes: deprotecting the compound of formula (V) to obtain a compound of formula (VI): or a salt thereof. 72. The method of embodiment 71, wherein deprotecting the compound of formula (V) to obtain a compound of formula (VI) includes contacting the compound of formula (V) with a first acid. 73. The method of embodiment 72, wherein: the first acid includes HBr and acetic acid; or the first acid includes dibutyl sulfide, trifluoroacetic acid and methanesulfonic acid; or the first acid includes dibutyl sulfide and methanesulfonic acid. 74. The method of any one of embodiments 68 to 73, wherein converting the compound of formula (V) into a compound of formula (I) further includes: coupling the compound of formula (VI) with a compound of formula (VII): to obtain a compound of formula (I). 75. The method of embodiment 74, wherein the coupling of the compound of formula (VI) with the compound of formula (VII) is carried out in the presence of a coupling reagent. 76. The method of embodiment 74 or 75, wherein the coupling reagent includes EDC. 77. The method of embodiment 75 or 76, wherein the coupling of the compound of formula (VI) with the compound of formula (VII) is further carried out in the presence of an additive. 78. The method of embodiment 77, wherein the additive is ethyl (hydroxyimino)cyanoacetate or 2-hydroxypyridine-N-oxide. The method according to any one of embodiments 68 to 78, wherein R1 is –C(O)(C1-C6 alkyl), –C(O)(C1-C6 haloalkyl), –C(O)(C1-C6 alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)2(tolyl). 80. The method according to any one of embodiments 68 to 79, wherein R1 is –C(O)(C1-C6 alkoxy). 81. The method according to any one of embodiments 68 to 80, wherein R1 is –C(O)OCH3. 82. The method according to any one of embodiments 68 to 79, wherein R1 is –C(O)(C1-C6 alkoxy), and the compound of formula (III) is obtained by step (i): (i) A compound of formula (III-B): is converted to a compound of formula (III). 83. The method of embodiment 82, wherein converting the compound of formula (III-B) to the compound of formula (III) comprises contacting the compound of formula (III-B) with ClC(O)(C1-C6 alkoxy). 84. The method of embodiment 82, wherein R1 is –C(O)OCH3. 85. The method of embodiment 84, wherein converting the compound of formula (III-B) to the compound of formula (I) comprises contacting the compound of formula (III-B) with methyl chloroformate. 86. The method according to any one of embodiments 82 to 85, wherein the compound of formula (III-B) is obtained by step (ii): (ii) contacting a compound of formula (III-C) with a compound of formula (III-D): to obtain a compound of formula (III-B), wherein: R5 and R6 are each independently halogen or –OSO2R7; each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 aryl, wherein the C6-C 10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. 87. The method of embodiment 86, wherein R5 and R6 are each halogen. 98. The method of embodiment 87, wherein R5 and R6 are each chlorine. 89. The method of any one of embodiments 86 to 88, wherein the contact of the compound of formula (III-C) with the compound of formula (III-D) is carried out in the presence of a second acid. 90. The method of embodiment 89, wherein the second acid is trifluoroacetic acid. 91. The method of any one of embodiments 86 to 88, wherein the contact of the compound of formula (III-C) with the compound of formula (III-D) is carried out in the presence of trimethylsilyl trifluoromethanesulfonate. 92. The method of any one of embodiments 86 to 88, wherein the contact of the compound of formula (III-C) with the compound of formula (III-D) is carried out in the presence of trimethylsilyl trifluoromethanesulfonate and CsF. 93. The method of any one of embodiments 86 to 88, wherein the contact of the compound of formula (III-C) with the compound of formula (III-D) is carried out in the presence of trimethylsilyl iodide. 94. The method of any one of embodiments 86 to 88, wherein the contact of the compound of formula (III-C) with the compound of formula (III-D) is carried out in the presence of trimethylsilyl iodide and an additive selected from CsF, LiF, ZnCl2, and combinations thereof. 95. The method of any one of embodiments 68 to 94, wherein the compound of formula (IV) is obtained by contacting a compound of formula (IV-A): with ammonia to obtain the compound of formula (IV). 96. The method of embodiment 95, wherein the compound of formula (IV-A) is obtained by: converting a compound of formula (IV-B): into the compound of formula (IV-A). 97. The method of embodiment 96, wherein converting the compound of formula (IV-B) into the compound of formula (IV-A) comprises contacting the compound of formula (IV-B) with a Grignard reagent, a C1-C6 alkyllithium, and a sulfonyl chloride. 98. The method of embodiment 96 or 97, wherein converting the compound of formula (IV-B) into the compound of formula (IV-A) comprises the following steps: contacting the compound of formula (IV-B) with a Grignard reagent to obtain a first metallated intermediate compound (IV-B1); contacting the first metallated intermediate (IV-B1) compound with a C1-C6 alkyllithium (such as butyllithium, n-butyllithium, or hexyllithium) to obtain a second metallated intermediate compound (IV-B2); and Contact the second metallization intermediate compound (IV-B2) with sulfonyl chloride to obtain the compound of formula (IV-A). The method of embodiment 97 or 98, wherein the Grignard reagent is isopropylmagnesium chloride. The method of any one of embodiments 97 to 99, wherein the C1-C6 alkyllithium is butyllithium, such as n-butyllithium. The method of any one of embodiments 96 to 100, wherein the compound of formula (IV-B) is obtained by converting the compound of formula (IV-C): into the compound of formula (IV-B). The method of embodiment 101, wherein converting the compound of formula (IV-C) into the compound of formula (IV-B) comprises contacting the compound of formula (IV-C) with a brominating reagent. The method of embodiment 102, wherein the brominating reagent is N-bromosuccinimide. The method of any one of embodiments 101 to 103, wherein the compound of formula (IV-C) is obtained as follows: contacting the compound of formula (IV-D): with 1,2-dibromoethane to obtain the compound of formula (IV-C). The method of embodiment 104, wherein the contact of the compound of formula (IV-D) with 1,2-dibromoethane is carried out in the presence of a second base. The method of embodiment 105, wherein the second base is K2CO3. The method of any one of embodiments 96 to 100, wherein the compound of formula (IV-B) is obtained as follows: contacting the compound of formula (IV-E): with 1,2-dibromoethane to obtain the compound of formula (IV-B). The method of embodiment 107, wherein the contact of the compound of formula (IV-E) with 1,2-dibromoethane is carried out in the presence of a second base. The method of embodiment 108, wherein the second base is K2CO3. The method of any one of embodiments 107 to 109, wherein the compound of formula (IV-E) is obtained by converting the compound of formula (IV-F): into the compound of formula (IV-E). The method of Embodiment 110, wherein converting the compound of formula (IV-F) to the compound of formula (IV-E) comprises contacting the compound of formula (IV-F) with bromine, hydrohalic acid, and sulfamic acid. The method of Embodiment 110 or 111, wherein converting the compound of formula (IV-F) to the compound of formula (IV-E) comprises the following steps: Contacting the compound of formula (IV-F) with a first portion of bromine to obtain a first intermediate compound (IV-F1); Contacting the first intermediate compound (IV-F1) with hydrohalic acid to obtain a second intermediate compound (IV-F2); Contacting the second intermediate compound (IV-F2) with a second portion of bromine to obtain a third intermediate compound (IV-F3); and Contacting the third intermediate compound (IV-F3) with sulfamic acid to obtain the compound of formula (IV-E). The method of Embodiment 111 or 112, wherein the hydrohalic acid is hydrochloric acid. The method of Embodiment 111 or 112, wherein the hydrohalic acid is hydrobromic acid. The method of any one of Embodiments 74 to 114, wherein the compound of formula (VII) is obtained by converting the compound of formula (VII-A): to the compound of formula (VII). The method of Embodiment 115, wherein converting the compound of formula (VII-A) to the compound of formula (VII) comprises contacting the compound of formula (VII-A) with a third base. The method of Embodiment 116, wherein the third base is NaOH. The method of Embodiment 115, wherein converting the compound of formula (VII-A) to the compound of formula (VII) comprises contacting the compound of formula (VII-A) with an enzyme. The method of Embodiment 118, wherein the enzyme is lipase. The method of Embodiment 119, wherein the lipase is CALB. The method of any one of Embodiments 115 to 120, wherein the compound of formula (VII-A) is obtained by converting the compound of formula (VII-B): to the compound of formula (VII-A). 122. The method of embodiment 121, wherein converting the compound of formula (VII-B) to the compound of formula (VII-A) comprises contacting the compound of formula (VII-B) with a reducing agent. 123. The method of embodiment 122, wherein the compound of formula (VII-B) is contacted with the reducing agent in the presence of an enzyme. 124. The method of embodiment 123, wherein the enzyme is a carbonyl reductase (CRED). 125. The method of any one of embodiments 121 to 124, wherein the compound of formula (VII-B) is obtained as follows: contacting a compound of formula (VII-C): with methyl formate to obtain the compound of formula (VII-B). 126. The method of embodiment 125, wherein the contacting of the compound of formula (VII-C) with methyl formate is carried out in the presence of a fourth base. 127. The method of embodiment 126, wherein the fourth base is sodium tert-butoxide or sodium methoxide. 128. A composition comprising a compound of formula (III) or a salt thereof: wherein R1 is a protecting group. 129. The composition of embodiment 128, which further comprises a compound of formula (IV): or a salt thereof. 130. The composition of embodiment 128 or 129, which further comprises a base. 131. The composition of embodiment 130, wherein the base is Cs2CO3 or K2CO3. 132. The composition of any one of embodiments 128 to 131, which further comprises a compound of formula (V): or a salt thereof. 133. The composition of any one of embodiments 128 to 132, wherein R1 is -C(O)(C1-C6 alkyl), –C(O)(C1-C6 haloalkyl), –C(O)(C1-C6 alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy) or –S(O)2(tolyl). 134. The composition of any one of embodiments 128 to 133, wherein R1 is –C(O)(C1-C6 alkoxy). 135. The composition of any one of embodiments 128 to 134, wherein the compound of formula (III) is: Methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate. The composition of any one of embodiments 132 to 135, wherein the compound of formula (V) is: Methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. List of additional specific embodiments:

[0107] The following are alternative non-limiting embodiments of the present invention: 1. A method for preparing a compound according to formula (III-Y): which comprises, according to step 1 A1 Scheme A1 Reacting an azomethine precursor according to formula (III-W) with an electron-deficient alkyne according to formula (III-X), wherein step 1 A1 is carried out in the presence of an acid: Scheme A1 wherein R12 is -CR2R3-(C6-C 10 aryl), wherein the C6-C 10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C1-C6 alkyl; and R4 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; and R5 and R6 are each independently halogen, such as chlorine, bromine, iodine, or -OSO2R7, wherein each R7 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C6-C 10 aryl, wherein the C6-C 10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; and R9 is a suitable silyl protecting group selected from trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS) or dimethylisopropylsilyl (DMIPS); and R10 is a C1-C6 alkyl group. 2. The method according to embodiment 1, wherein R12 is -CH2Ph (benzyl) or 4-methoxybenzyl. 3. The method according to any one of the foregoing embodiments, wherein R12 is benzyl. 4. The method according to any one of the foregoing embodiments, which comprises step 1 A1’ Scheme A1' reacting an azomethine precursor according to formula (III-W1) with an electron-deficient alkyne according to formula (III-X), wherein step 1 A1’ is carried out in the presence of an acid: Scheme A1' wherein R5 and R6 are each independently a halogen, such as chlorine, bromine, iodine, or -OSO2R7, wherein each R7 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C6-C 10 aryl, wherein C6-C 10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; and R9 is a suitable silyl protecting group selected from trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS) or dimethylisopropylsilyl (DMIPS); and R10 is a C1-C6 alkyl group. 5. The method according to any one of the foregoing embodiments, wherein R9 is trimethylsilyl (TMS). 6. The method according to any one of the foregoing embodiments, wherein R10 is a straight-chain C1-C6 alkyl group selected from methyl, ethyl, 1-propyl, 1-butyl, 1-pentyl or 1-hexyl. 7. The method according to any one of the foregoing embodiments, wherein R10 is a C1-C4 alkyl group selected from methyl, ethyl, 1-propyl or 1-butyl. 8. The method according to any one of the foregoing embodiments, wherein R10 is methyl. 9. The method according to any one of the foregoing embodiments, wherein R5 and R6 are each a halogen. 10. The method according to any one of the foregoing embodiments, wherein R5 and R6 are each selected from chlorine, bromine or iodine. 11. The method according to any one of the foregoing embodiments, wherein R5 and R6 are each chlorine. 12. A method according to any one of the foregoing embodiments, wherein the compound of formula (III-Y) or (III-Y1) is transferred to a further reaction step without prior purification. 13. A method according to any one of embodiments 1-11, wherein the compound of formula (III-Y) or (III-Y1) is isolated as a salt. 14. A method according to any one of the foregoing embodiments, wherein about 1 equivalent of the compound of formula (III-W) or (III-W1) is reacted with about 1.1 - 3 equivalents of the compound of formula (III-X). 15. A method according to embodiment 14, wherein about 1 equivalent of the compound of formula (III-W) or (III-W1) is reacted with about 1.5 - 2 equivalents of the compound of formula (III-X). 16. A method according to embodiments 14-15, wherein about 1 equivalent of the compound of formula (III-W) or (III-W1) is reacted with about 1.5 or about 2 equivalents of the compound of formula (III-X). 17. A method according to any one of the foregoing embodiments, wherein the acid is present in a sub-stoichiometric amount of about 0.01 - 0.2 equivalents. 18. A method according to any one of the foregoing embodiments, wherein the acid is present in a sub-stoichiometric amount of about 0.03 - 0.07 equivalents, such as about 0.05 equivalents. 19. A method according to any one of the foregoing embodiments, wherein the acid is selected from TFA, TMSOTf, TMSI, a combination of TMSOTf and CsF, or a combination of TMSI and any one of CsF, LiF, ZnCl2, or a combination thereof. 20. A method according to any one of the foregoing embodiments, wherein the acid is TFA. 21. A method according to any one of the foregoing embodiments, wherein the reaction of the compound of formula (III-W) or (III-W1) and the compound of formula (III-X) is carried out in a non-polar solvent selected from, for example, toluene, DCM, or a mixture thereof. 22. A method according to embodiment 21, wherein the non-polar solvent is toluene. 23. A method according to any one of embodiments 21-22, wherein the compound of formula (III-X) is dissolved in a non-polar solvent such as toluene, and the mixture is cooled to a temperature of about -10°C to 10°C, followed by the addition of an acid, such as TFA. 24. A method according to any one of embodiments 21-23, wherein the compound of formula (III-X) is dissolved in a non-polar solvent such as toluene, and the mixture is cooled to a temperature of about -5°C to 5°C, followed by the addition of TFA. 25. According to the method of any one of embodiments 23-24, wherein a compound of formula (III-W) or (III-W1) is subsequently added. 26. According to the method of any one of embodiments 23-25, wherein a compound of formula (III-W) or (III-W1) is subsequently added, and the temperature is maintained at about -10°C to 20°C during the addition. 27. According to the method of any one of the foregoing embodiments, which further comprises step 2 A2 : Converting the compound of formula (III-Y) or (III-Y1) into the compound of formula (III-Z) according to Scheme A2: Scheme A2 wherein R1 is selected from C1-C6 alkoxycarbonyl (such as tert-butoxycarbonyl or methoxycarbonyl), benzyloxycarbonyl (i.e., Cbz), C6-C 10 aryloxycarbonyl (such as phenoxycarbonyl), C1-C6 alkylcarbonyl (such as acetyl), haloalkylcarbonyl (such as trifluoroacetyl) and -SO2-(C6-C 10 aryl) (such as tosyl). 28. According to the method of embodiment 27, wherein the compound of formula (III-Y) is the compound of formula (III-Y1). 29. According to the method of any one of embodiments 27-28, wherein R1 is -C(O)(C1-C6 alkoxy). 30. According to the method of any one of embodiments 27-29, wherein R1 is -C(O)OCH3. 31. According to the method of any one of embodiments 27-30, wherein step 2 A2 is carried out by contacting the compound according to formula (III-Y) or (III-Y1) with R1-Cl. 32. According to the method of any one of embodiments 27-31, wherein step 2 A2 is carried out by contacting the compound of formula (III-Y) or (III-Y1) with ClC(O)(C1-C6 alkoxy). 33. According to the method of any one of embodiments 27-32, wherein step 2 A2 is carried out by contacting the compound of formula (III-Y) or (III-Y1) with methyl chloroformate. 34. According to the method of any one of embodiments 27-33, wherein step 2 A2 is carried out in a second non-polar solvent. 35. The method according to embodiment 34, wherein the second non-polar solvent is selected from toluene, DCM, n-heptane, or a combination thereof. 36. The method according to any one of embodiments 34-35, wherein the second non-polar solvent is toluene, n-heptane, or a combination of toluene and n-heptane. 37. The method according to any one of embodiments 27-36, wherein step 2 A2 is carried out as follows: adding the reaction mixture containing the compound of formula (III-Y) or (III-Y1) from step 1 A1 or step 1 A1’ to a mixture of R1-Cl in n-heptane at a temperature of -20 °C to -5 °C, while maintaining this temperature during the addition. 38. The method according to embodiment 37, wherein R1-Cl is ClC(O)(C1-C6 alkoxy), such as methyl chloroformate. 39. The method according to any one of embodiments 27-38, wherein step 2 A2 is carried out as follows: adding R1-Cl to the reaction mixture containing the compound of formula (III-Y) or (III-Y1) from step 1 A1 or step 1 A1’ at a temperature of -10 °C to 0 °C, while maintaining this temperature during the addition. 40. The method according to any one of embodiments 37-39, wherein R1-Cl is ClC(O)(C1-C6 alkoxy), such as methyl chloroformate. 41. The method according to any one of the foregoing embodiments, wherein the compound of formula (III-W) is a compound of formula (III-D): 42. The method according to any one of the foregoing embodiments, wherein the compound of formula (III-X) is a compound of formula (III-C): 43. The method according to any one of the foregoing embodiments, wherein the compound of formula (III-Y) or (III-Y1) is a compound of formula (III-B): 44. The method according to any one of the foregoing embodiments, wherein the compound of formula (III-Z) is a compound of formula (III-A): 45. The method according to any one of embodiments 27-44, which further comprises step 3 A3:React the compound of formula (III-Z) with the compound of formula (IV-Y) according to Scheme A3 to form the compound of formula (V-Z): Scheme A3 wherein R11 is C6-C 10 aryl, 6-10-membered heteroaryl containing 1-3 O, N, S, wherein the aryl and heteroaryl are each optionally substituted by one or more substituents selected from -R13 and -OR13; each R13 is independently -H, -C1-C6 alkyl optionally substituted by one or more substituents selected from oxo, -F, -Cl, -Br, -I, -CN, -NO2; or two R13 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring; wherein the reaction is carried out in the presence of a base. 46. The method according to embodiment 45, wherein R11 is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl. 47. The method according to any one of embodiments 45-46, wherein R11 is 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl. 48. The method according to any one of embodiments 45-47, wherein the base is selected from Cs2CO3 and K2CO3. 49. The method according to any one of embodiments 45-48, wherein the base is K2CO3. 50. The method according to any one of embodiments 45-49, wherein the reaction according to Scheme A3 is carried out in a suitable solvent selected from DMSO, toluene or a mixture thereof. 51. The method according to any one of embodiments 45-50, wherein about 1 equivalent of the compound of formula (IV-Y) and about 1-2 equivalents of the base are mixed in DMSO and heated to a temperature of about 75-110 °C, and then about 1 equivalent of the compound according to formula (III-Z) in toluene, DMSO or a mixture thereof is added. 52. The method according to embodiment 51, wherein the mixture of the compound of formula (IV-Y) and the base in DMSO is heated to a temperature of about 85-100 °C. 53. The method according to any one of embodiments 51-52, wherein the mixture of the compound of formula (IV-Y) and the base in DMSO is heated to a temperature of about 100 °C. 54. The method according to any one of embodiments 45-53, wherein the compound of formula (III-Z) is in toluene. 55. A method according to any one of embodiments 45 - 53, wherein the compound of formula (III-Z) is in DMSO. 56. A method according to any one of embodiments 45 - 55, wherein the compound of formula (IV-Y) is a compound according to formula (IV) or a compound of formula (VIII-A): 57. A method for preparing a compound of formula (V-Z), comprising the steps of: a. Reacting an azomethine precursor of formula (III-W) with an electron-deficient alkyne of formula (III-X) according to Scheme A1, wherein the reaction is carried out in a first non-polar solvent in the presence of an acid: Scheme A1 wherein R12 is -CR2R3-(C6-C 10 aryl), wherein the C6-C 10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C1-C6 alkyl; and R4 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; and R5 and R6 are each independently halogen, such as chlorine, bromine, iodine, or -OSO2R7, wherein each R7 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C6-C 10 aryl, wherein the C6-C 10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; and R9 is a suitable silyl protecting group selected from trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS) or dimethylisopropylsilyl (DMIPS); and R10 is C1-C6 alkyl; b. Converting the compound of formula (III-Y) to the compound of formula (III-Z) by reacting with R1-Cl in a second non-polar solvent according to Scheme A2: Scheme A2 wherein R1 is selected from C1-C6 alkoxycarbonyl (such as tert-butoxycarbonyl or methoxycarbonyl), benzyloxycarbonyl (i.e., Cbz), C6-C 10 aryloxycarbonyl (such as phenoxycarbonyl), C1-C6 alkylcarbonyl (such as acetyl), haloalkylcarbonyl (such as trifluoroacetyl) and -SO2-(C6-C 10 aryl) (such as tosyl); c. According to Scheme A3, in the presence of a base in a suitable solvent, reacting a compound of formula (III-Z) with a compound of formula (IV-Y) to form a compound (V-Z): Scheme A3 wherein R11 is C6-C 10 aryl, a 6-10-membered heteroaryl containing 1-3 O, N, S, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents selected from -R13 and -OR13; each R13 is independently -H, a -C1-C6 alkyl optionally substituted with one or more substituents selected from oxo, -F, -Cl, -Br, -I, -CN, -NO2; or two R13 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring. 58. The method according to embodiment 57, wherein R12 is benzyl. 59. The method according to any one of embodiments 57-58, wherein R10 is methyl. 60. The method according to any one of embodiments 57-59, wherein R9 is trimethylsilyl. 61. The method according to any one of embodiments 57-60, wherein R5 and R6 are each chlorine. 62. The method according to any one of embodiments 57-61, wherein the first polar solvent is selected from DCM, toluene or a mixture thereof. 63. The method according to any one of embodiments 57-62, wherein the acid is TFA. 64. The method according to any one of embodiments 57-63, wherein R1-Cl is ClC(O)(C1-C6 alkoxy). 65. The method according to any one of embodiments 57-64, wherein R1-Cl is methyl chloroformate. 66. The method according to any one of embodiments 57-65, wherein the second non-polar solvent is n-heptane, DCM, toluene or a mixture thereof. 67. The method according to any one of embodiments 57-66, wherein the compound of formula (IV-Y) is a compound of formula (IV) or (VIII-A): 68. According to the method of any one of embodiments 57 - 67, wherein the suitable solvent is selected from DMSO, toluene, or a mixture thereof. 69. According to the method of any one of embodiments 57 - 68, wherein the base is K2CO3. 70. A compound of formula (III - Y) or a salt thereof: wherein R12 is -CR2R3-(C6 - C 10 aryl), wherein the C6 - C 10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C1 - C6 alkyl; and R4 is halogen, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 alkoxy, or C1 - C6 haloalkoxy; and R5 and R6 are each independently halogen, such as chlorine, bromine, iodine, or -OSO2R7, wherein each R7 is independently selected from C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 alkoxy, C1 - C6 haloalkoxy, or C6 - C 10 aryl, wherein the C6 - C 10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halogen, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 alkoxy, or C1 - C6 haloalkoxy. 71. The compound according to embodiment 70, wherein the compound is a compound of formula (III - Y2) or a salt thereof: wherein R12 is -CR2R3-(C6 - C 10 aryl), wherein the C6 - C 10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C1 - C6 alkyl; and R4 is halogen, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 alkoxy, or C1 - C6 haloalkoxy. 72. The compound according to any one of embodiments 70 - 71, wherein R12 is benzyl, i.e., a compound of formula (III - B): (1 - benzyl - 3,4 - bis(chloromethyl)-2,5 - dihydro - 1H - pyrrole - 1 - carboxylate). 73. The compound of formula (III) or a salt thereof: wherein R1 is -C(O)(C1-C6 alkyl), -C(O)(C 1- 6 haloalkyl), -C(O)(C1-C6 alkoxy), -C(O)(benzyloxy), -C(O)(phenoxy) or –S(O)2(tolyl). 74. The compound according to embodiment 73, wherein R1 is –C(O)(C1-C6 alkoxy). 75. The compound according to any one of embodiments 73-74, wherein the compound is a compound of formula (III-A): (methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate), or a salt thereof. 76. The compound of formula (V-Z): wherein R1 is –C(O)(C1-C6 alkyl), –C(O)(C1-C6 haloalkyl), –C(O)(C1-C6 alkoxy), -C(O)(benzyloxy), –C(O)(phenoxy) or –S(O)2(tolyl); and R11 is C6-C 10 aryl, a 6-10-membered heteroaryl containing 1-3 O, N, S, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents selected from -R13 and -OR13; each R13 is independently -H, -C1-C6 alkyl optionally substituted with one or more substituents selected from oxo, -F, -Cl, -Br, -I, -CN, -NO2; or two R13 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring. 77. The compound according to embodiment 76, wherein the compound is a compound of formula (V): wherein R1 is –C(O)(C1-C6 alkyl). 78. The compound according to any one of embodiments 76-77, wherein the compound is a compound of formula (V-A): 79. The compound according to embodiment 76, wherein the compound is a compound of formula (VIII): wherein R1 is –C(O)(C1-C6 alkyl). 80. A compound according to any one of embodiments 76 or 79, wherein the compound is a compound of formula (VIII-B): 81. Use of a compound according to any one of embodiments 70 - 80 for the preparation of a compound according to formula (I) or (II). 82. A method for preparing a compound according to formula (I): which comprises the following steps: a. According to step 1 of Scheme B1’ B1’ , in the presence of a first acid and in a first non-polar solvent, reacting a compound of formula (III-D) with a compound of formula (III-C) to obtain a compound of formula (III-B): Scheme B1’ b. According to step 2 of Scheme B1’ B1’ , by reacting with R1-Cl in a second non-polar solvent, converting the compound of formula (III-B) into a compound of formula (III), wherein R1 is -C(O)C1-C6 alkoxy (e.g., methoxycarbonyl); c. According to Scheme G1, in the presence of a first base and in a suitable solvent, reacting a compound of formula (III) wherein R1 is C1-C6 alkoxycarbonyl (e.g., methoxycarbonyl) with a compound of formula (IV) to form compound (V): Scheme G1 d. Deprotecting the compound of formula (V) wherein R1 is C1-C6 alkoxycarbonyl (e.g., methoxycarbonyl) with a second acid, and then neutralizing with a second base to obtain a compound of formula (VI), or forming a salt of compounds of formula (VI) and (VII) by adding compound (VII): Scheme G2 e. Performing a coupling reaction of the compound of formula (VI) with the compound of formula (VII) according to Scheme G3, or according to Scheme G3’, using a coupling reagent and additives in a second suitable solvent to perform a coupling reaction starting from the salt of formula (VI)·(VII) to obtain a compound of formula (I): Scheme G3 or Scheme G3’ 83. The method according to embodiment 82, wherein the compound of formula (III-D) in step a is the rate-limiting reagent. 84. The method according to any one of embodiments 82-83, wherein in step a, about 1.5-2.0 equivalents of the compound of formula (III-C) react with about 1 equivalent of the compound of formula (III-D). 85. The method according to any one of embodiments 82-84, wherein in step a, the compound of formula (III-C) is mixed with a first non-polar solvent and cooled to about -5 to 5 °C, a first acid is added, and then the compound of formula (III-D) in the first non-polar solvent is added while maintaining this temperature. 86. The method according to any one of embodiments 82-85, wherein the first acid is TFA. 87. The method according to any one of embodiments 82-86, wherein the first acid is TFA and about 0.05 equivalent is used. 88. The method according to any one of embodiments 82-87, wherein the first non-polar solvent is toluene. 89. The method according to any one of embodiments 82-88, wherein the reaction mixture from step a is used in the next step b without further purification. 90. The method according to any one of embodiments 82-89, wherein the second non-polar solvent is toluene or a mixture of toluene and n-heptane. 91. The method according to any one of embodiments 82-90, wherein R1-Cl is mixed with n-heptane before adding the reaction mixture containing the compound of formula (III-B) from step a. 92. The method according to any one of embodiments 82-91, wherein step b is carried out at a temperature of about -15 °C to about -5 °C. 93. The method according to any one of embodiments 82-92, wherein R1-Cl is added to the reaction mixture from step a at a temperature of about -15 °C to about -5 °C. 94. The method according to any one of embodiments 82-93, wherein R1-Cl is methyl chloroformate. 95. The method according to any one of embodiments 82-94, wherein in step c, the first base is K2CO3. 96. The method according to any one of embodiments 82-95, wherein about 1.1 equivalents of the first base are used in step c. 97. The method according to any one of embodiments 82-96, wherein a suitable solvent in step c is DMSO, toluene or a mixture thereof. 98. The method according to any one of embodiments 82 - 97, wherein the suitable solvent in step c is a mixture of DMSO and toluene. 99. The method according to any one of embodiments 82 - 98, wherein in step c, the compound of formula (IV), the first base and a suitable solvent are mixed and heated to about 100 °C, and then the compound of formula (III) in a suitable solvent is added. 100. The method according to any one of embodiments 82 - 99, wherein in step c, the compound of formula (IV), K2CO3 and DMSO are mixed and heated to about 100 °C, and then the compound of formula (III) in toluene is added. 101. The method according to any one of embodiments 82 - 100, wherein in step c, the compound of formula (III) is a compound of formula (III - A). 102. The method according to any one of embodiments 82 - 101, wherein the suitable solvent in step c is DMSO, toluene or a mixture thereof. 103. The method according to any one of embodiments 82 - 102, wherein in step d, the compound of formula V is a compound of formula (V - A). 104. The method according to any one of embodiments 82 - 103, wherein in step d, the second acid is a mixture of Bu2S and MSA. 105. The method according to any one of embodiments 82 - 104, wherein in step d, the mixture of the compound of formula (V) and the second base is heated to about 70 °C. 106. The method according to any one of embodiments 82 - 105, wherein in step d, the second base is an aqueous solution of NH4OH. 107. The method according to any one of embodiments 82 - 106, wherein in step d, when forming the salts of the compounds of formula (VI) and (VII), about 1 equivalent of (VI) and about 1 equivalent of (VII) are mixed in DCM or MeCN. 108. The method according to any one of embodiments 82 - 107, wherein in step e, the reaction is carried out using the salt of (VI)·(VII) according to Scheme G3’. 109. The method according to any one of embodiments 82 - 108, wherein in step e, the coupling reagent is selected from EDC, DCC, propylphosphonic anhydride and HATU. 110. The method according to any one of embodiments 82 - 109, wherein in step e, the coupling reagent is EDC·HCl. 111. The method according to any one of embodiments 82 - 110, wherein in step e, the additive is selected from ethyl (hydroxyamino)cyanoacetate HOBt, HOSu, HOPO. 112. The method according to any one of embodiments 82 - 111, wherein in step e, the additive is ethyl (hydroxyamino)cyanoacetate or HOPO. 113. The method according to any one of embodiments 82 - 112, wherein in step e, the coupling reagent is EDC·HCl and the additive is ethyl (hydroxyamino)cyanoacetate 114. The method according to any one of embodiments 82 - 112, wherein in step e, the coupling reagent is EDC·HCl and the additive is HOPO. 115. The method according to any one of embodiments 82 - 114, wherein in step e, the second suitable solvent is selected from DMAc, 2 - MeTHF, EtOH or a combination thereof. 116. The method according to any one of embodiments 82 - 115, wherein in step e, the second suitable solvent is a combination of DMAc and EtOH. 117. The method according to any one of embodiments 82 - 116, wherein in step e, the second suitable solvent is a combination of DMAc, EtOH and 2 - MeTHF. 118. Compounds of formula (VI)·(VII): 119. Use of the compound according to embodiment 118 for the preparation of Etavopivat (I). 120. A method for preparing a compound according to formula (II): which comprises the following steps: a. According to Scheme B1’ step 1 B1’ , in the presence of a first acid in a first non - polar solvent, reacting a compound of formula (III - D) with a compound of formula (III - C): b. According to Scheme B1’ step 2 B1’ , converting a compound of formula (III - B) into a compound of formula (III) by reacting with R1 - Cl in a second non - polar solvent, wherein R1 is - C(O)C1 - C6 alkoxy (e.g., methoxycarbonyl); c. According to Scheme H1, in the presence of a first base in a suitable solvent, a compound of formula (III) in which R1 is C1-C6 alkoxycarbonyl (such as methoxycarbonyl) is reacted with a compound of formula (VIII-A) to form a compound of formula (VIII): Scheme H1 d. Deprotect the compound of formula (VIII) in which R1 is C1-C6 alkoxycarbonyl (such as methoxycarbonyl) with a fourth base or a third acid to obtain a compound of formula (IX) or a salt thereof: e. According to Scheme G4, in a third suitable solvent using a coupling reagent and an additive, a coupling reaction of the compound of formula (IX) or a salt thereof with a compound of formula (XI) is carried out to obtain a compound of formula (II): Scheme G4 121. The method according to embodiment 120, wherein the compound of formula (III-D) in step a is the rate-limiting reagent. 122. The method according to any one of embodiments 120-121, wherein in step a, about 1.5-2.0 equivalents of the compound of formula (III-C) are reacted with about 1 equivalent of the compound of formula (III-D). 123. The method according to any one of embodiments 120-122, wherein in step a, the compound of formula (III-C) is mixed with a first nonpolar solvent and cooled to about -5 to 5 °C, a first acid is added, and then the compound of formula (III-D) in the first nonpolar solvent is added while maintaining this temperature. 124. The method according to any one of embodiments 120-123, wherein the first acid is TFA. 125. The method according to any one of embodiments 120-124, wherein the first acid is TFA and about 0.05 equivalent is used. 126. The method according to any one of embodiments 120-125, wherein the first nonpolar solvent is toluene. 127. The method according to any one of embodiments 120-126, wherein the reaction mixture from step a is used in the next step b without further purification. 128. The method according to any one of embodiments 120-127, wherein the second nonpolar solvent is toluene or a mixture of toluene and n-heptane. 129. The method according to any one of embodiments 120-128, wherein R1-Cl is mixed with n-heptane, and then the reaction mixture containing the compound of formula (III-B) from step a is added. 130. The method according to any one of embodiments 120-129, wherein step b is carried out at a temperature of about -15°C to about -5°C. 131. The method according to any one of embodiments 120-130, wherein R1-Cl is added to the reaction mixture from step a at a temperature of about -15°C to about -5°C. 132. The method according to any one of embodiments 120-131, wherein R1-Cl is methyl chloroformate. 133. The method according to any one of embodiments 120-132, wherein in step c, the first base is K2CO3. 134. The method according to any one of embodiments 120-133, wherein about 1.1 equivalents of the first base are used in step c. 135. The method according to any one of embodiments 120-134, wherein a suitable solvent in step c is DMSO, toluene, or a mixture thereof. 136. The method according to any one of embodiments 120-135, wherein a suitable solvent in step c is DMSO. 137. The method according to any one of embodiments 120-136, wherein in step c, the compound of formula (VIII-A), the first base, and a suitable solvent are mixed and heated to about 80-100°C, and then the compound of formula (III) in a suitable solvent is added. 138. The method according to any one of embodiments 120-137, wherein in step c, the compound of formula (VIII-A), K2CO3, and DMSO are mixed and heated to about 80-100°C, and then the compound of formula (III) in DMSO is added. 139. The method according to any one of embodiments 120-138, wherein in step c, the compound of formula (III) is the compound of formula (III-A). 140. The method according to any one of embodiments 120-139, wherein a suitable solvent in step c is DMSO. 141. The method according to any one of embodiments 120-140, wherein in step d, the compound of formula (VIII) is the compound of formula (VIII-B): 142. The method according to any one of embodiments 120 - 141, wherein in step d, the fourth base is KOH. 143. The method according to embodiment 142, wherein the fourth base is KOH, and the reaction is carried out in MeOH. 144. The method according to any one of embodiments 142 - 143, wherein about 3M KOH in MeOH is used. 145. The method according to any one of embodiments 142 - 144, wherein step d is carried out by heating, such as by heating to reflux. 146. The method according to any one of embodiments 120 - 141, wherein in step d, the third acid is selected from the group consisting of HBr / AcOH mixture, Bu2S / MSA mixture, and a mixture of Bu2S, TFA, and MSA. 147. The method according to embodiment 146, wherein the third acid is a mixture of HBr and AcOH. 148. The method according to embodiment 147, wherein the dihydrobromide salt of compound (IX) is formed. 149. The method according to embodiment 148, wherein the dihydrobromide (X) is neutralized with a base such as NH4OH or NaOH to form the compound of formula (IX). 150. The method according to any one of embodiments 120 - 149, wherein in step e, the coupling reagent is selected from EDC, DCC, propylphosphonic anhydride and HATU. 151. The method according to any one of embodiments 120 - 150, wherein in step e, the coupling reagent is EDC or EDC·HCl. 152. The method according to any one of embodiments 120 - 151, wherein in step e, the additive is selected from ethyl (hydroxyamino)cyanoacetate HOBt, HOSu, HOPO. 153. The method according to any one of embodiments 120 - 152, wherein in step e, the additive is HOBt. 154. The method according to any one of embodiments 120 - 153, wherein in step e, the coupling reagent is EDC and the additive is HOBt. 155. The method according to any one of embodiments 120 - 154, wherein in step e, the third suitable solvent is DMSO. Examples

[0108] The compounds described in this application are prepared using the methods of the present invention described in detail below. Embodiments of the claimed methods are illustrated below. Those skilled in the art will recognize that other embodiments falling within the scope of the claimed methods can be practiced using the examples below with some modifications within the skill of the art. Intermediate compounds and any final products are analyzed using conventional analytical techniques. List of Abbreviations: 1 H NMR Proton Nuclear Magnetic Resonance 2,3-DPG 2,3-Diphosphoglyceric Acid 2-MeTHF 2-Methyltetrahydrofuran Bn Benzyl CALB / Cal B Candida antarctica Lipase B CDCl3 Deuterochloroform CRED Carbonyl Reductase d Chemical Shift DCC Dicyclohexylcarbodiimide DCM Dichloromethane DMAc N,N-Dimethylacetamide DMF N,N-Dimethylformamide DMSO Dimethyl Sulfoxide DMSO-d6 Deuterated Dimethyl Sulfoxide EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Eq Equivalent EtOAc Ethyl Acetate EtOH Ethanol GC Gas Chromatography GDH Glucose Dehydrogenase h Hour HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HOBt Hydroxybenzotriazole HOPO 2-Hydroxypyridine N-Oxide HOSu N-Hydroxysuccinimide HPLC High Performance Liquid Chromatography HCl Hydrochloric Acid IPA Isopropyl Alcohol iPr Isopropyl iPrAc Isopropyl Acetate KF Karl Fischer LCMS Liquid Chromatography / Mass Spectrometry LOD Loss on Drying Me Methyl MeCN Acetonitrile MeOH Methanol MHz Megahertz Min Minute MSA Methanesulfonic acid MTBE Methyl tert-butyl ether NADP Nicotinamide adenine dinucleotide phosphate NBS N-Bromosuccinimide n-BuLi n-Butyllithium NLT Not less than NMH Not more than NMMNTB N-(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine PKR Pyruvate kinase R ppm Parts per million QNMR Quantitative NMR RBC Red blood cell rt Room temperature SFC Supercritical fluid chromatography Propylphosphonic anhydride TfO Trifluoromethanesulfonate, trifluoromethanesulfinate TFA Trifluoroacetic acid THF Tetrahydrofuran TMS Trimethylsilyl UPLC Ultra performance liquid chromatography UPLCMS Ultra performance liquid chromatography / mass spectrometry vol Volume Example 1 Synthesis of methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A) and 1-benzyl-3,4-bis (chloromethyl)-2,5-dihydro-1H-pyrrole (III-B)

[0109] Step 1: 1-Benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole (III-B)

[0110] 1,4 - dichloro - 2 - butyne (1.163 kg, 1.5 eq) and toluene (2.84 L, 1.9 vol) were added to the first reactor under a nitrogen atmosphere, and the mixture was cooled to a temperature of -5 °C to 5 °C. While maintaining the temperature at -5 °C to 5 °C, TFA (0.036 kg, 0.05 eq) was added to the reactor. The feed line was rinsed with toluene (0.075 L, 0.05 vol), and the rinse was added to the reactor. While maintaining the temperature at -5 °C to 10 °C, N-(methoxymethyl)-N-(trimethyl-silylmethyl)benzylamine (NMMNTB) (1.496 kg, 1.0 eq, 1.0 vol; rate-limiting reagent) was added to the reactor in portions over 1 - 2 h. The feed line was rinsed with toluene (0.075 L, 0.05 vol), and the rinse was added to the reactor. Then the reaction mixture was stirred at -7 °C to 10 °C for approximately 1 h. 2 mL aliquots of the reaction mixture were taken, quenched with 4 mL of saturated ice-cold aqueous sodium bicarbonate, and evaluated by 1 1H NMR, confirming the completion of Step 1 and the formation of 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole, the intermediate compound (III-B).

[0111] 1 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.34 - 7.14 (m, 5H), 4.27 (s, 4H), 3.80 (s, 2H), 3.59 (s, 4H) ppm.

[0112] Step 2: Methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A)

[0113] n-Heptane (1.35 L, 0.9 vol) was added to the second reactor, followed by methyl chloroformate (0.834 kg, 1.4 eq). The feed line was rinsed with n-heptane (0.15 L, 0.1 vol), and the rinse was added to the second reactor. Then the second reactor was cooled to a temperature of -15 °C to -10 °C, and while maintaining the temperature at -15 °C to -10 °C, the contents of the first reactor were added to the second reactor over 1 - 2 h. The feed line was rinsed with n-heptane (0.15 L, 0.1 vol), and the rinse was added to the second reactor. The reaction mixture was stirred at a temperature of -15 °C to -5 °C for approximately 40 min. The progress of the reaction was monitored by HPLC analysis, and stirring was continued until the reaction was complete.

[0114] Then, deionized water (3.0 L, 2 vol) was added to the second reactor while maintaining the temperature of the reaction mixture < 20 °C during the addition. The reaction mixture was stirred overnight at 10 °C. Then, n-heptane (13.5 L, 9.0 vol) was added to the second reactor over at least 1 h, causing precipitation of the product. The reaction mixture was cooled to -5 °C to 2 °C over at least 1 h and then stirred for at least 1 h while maintaining the temperature at -5 °C to 2 °C. Then, the reaction mixture was filtered to obtain a solid product, which was then rinsed with deionized water (6 × 3.9 L; 6 × 2.6 vol), with stirring for at least 15 min during each wash. Then, the filter cake was rinsed with n-heptane (2 × 3.9 L; 2 × 2.6 vol), with stirring for at least 15 min during each wash. Then, the filter cake was dried in vacuo at 40 °C to give methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A, 1.3 kg, 70% yield) as a white to light pink / cream solid, with a purity > 95% as evaluated by HPLC.

[0115] 1 1H NMR (CDCl3, 300 MHz) δ (ppm): 4.38 (m, 2H), 4.35 (m, 2H), 4.19 (s, 4H), 3.75 (s, 3H) ppm. Example 2 Alternative synthesis of methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A) and 1-benzyl-3,4-bis (chloromethyl)-2,5-dihydro-1H-pyrrole (III-B) Step 1: 1-Benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole (III-B)

[0116] Under a nitrogen stream, 1,4-dichlorobut-2-yne (556 mL, 2.0 eq) and toluene (1.35 L, 2 vol) were added to a 4 L reactor, and the solution was cooled to 0 °C. TFA (10.9 mL, 0.05 eq) was added at -2 °C, and the mixture was stirred for 18 min. Then, at -3 °C, NMMNTB (750.0 g, 675.0 g pure, 1.0 eq) was added to the reactor over 2 h 39 min. An exothermic reaction was observed at the end of the addition, with a maximum temperature reaching 14 °C. The mixture was stirred while cooling at -5 - 0 °C, and the conversion was monitored by 1 1H NMR after 1 h 20 min, showing 91.3% conversion to 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole (III-B). The product was carried on to the next step without further purification.

[0117] 1 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.34 - 7.14 (m, 5H), 4.27 (s, 4H), 3.80 (s, 2H), 3.59 (s, 4H) ppm. Step 2: Methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A)

[0118] Cool the product mixture from the first step to -8 °C and add methyl chloroformate (208 mL, 1.4 eq) over 36 min. During the addition, the maximum temperature reached in the reactor was -3 °C. Continue the contact at -5 °C. After 40 min, monitor the product conversion by HPLC and 1 1H NMR, showing a conversion of 100% to give methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A).

[0119] Transfer the reaction mixture to a 15 L reactor (cooled to a temperature of -5 °C) for work-up. Add n-heptane (675 mL, 1 vol), followed by deionized water (1.35 L, 2 vol). An exothermic reaction was observed, with a maximum temperature of 10 °C, and the mixture was warmed to a temperature of 15 - 20 °C to facilitate phase separation. After decantation, three layers were observed: an upper organic layer (turbid, slightly yellow), a middle aqueous layer (turbid, white), and a bottom organic layer (thick, oily, orange). Discard the bottom and middle layers. The upper layer was washed first with deionized water (675 mL, 1 vol), then with saturated aqueous sodium bicarbonate (675 mL, 1 vol), and finally with brine (675 mL, 1 vol). After sequentially discarding the aqueous layers, the organic layer was cooled to 5 °C and stored overnight in the reactor without stirring. No change in appearance was observed.

[0120] Drain the contents of the reactor into a clean bucket (Note: Treatment of the solution with anhydrous sodium sulfate may be included at this stage to ensure no aqueous layer remains in the separation step), wash the reactor with deionized water (2 L) and then with acetone (1 L), and dry under vacuum.

[0121] The resulting solution was filtered through a glass fiber and then added to a clean 15 L reactor. At 18 - 20 °C, n - heptane (6.1 L, 9 vol) was added over 8 min, and then the mixture was cooled to - 20 °C over 1 hour and 45 minutes. After stirring at - 20 °C for 1 hour and 50 minutes, the resulting white suspension was filtered, washed with ice - cold n - heptane (2 x 1 L, 2 x 1.5 vol), and dried in vacuo at 40 °C overnight to give 361.8 g of the product (57% yield, QNMR = 103%).

[0122] The crude solid product (50.1 g) and toluene (100 mL, 2 vol) were added to a 1 L reactor purged with nitrogen, and the mixture was heated to 25 - 30 °C to obtain a brown solution. Then n - heptane (50 mL, 1 vol) and deionized water (100 mL, 2 vol) were added, and the mixture was stirred at about 25 °C for 9 min.

[0123] The aqueous layer (pH = 2 - 3) was decanted and discarded. The organic layer was washed with saturated aqueous sodium bicarbonate (50 mL, 1 vol) and brine (50 mL, 1 vol). The 1 L reactor was washed and dried with water and acetone. Then the organic layer was filtered through a glass fiber and transferred under nitrogen to a clean 1 L reactor. At 23 °C, n - heptane (450 mL, 9 vol) was added over 2 min. Crystallization occurred at about half of the addition, and the suspension initially thickened and then became more fluid at the end of the addition.

[0124] The suspension was cooled to about - 15 °C and stirred at this temperature for 17 min. The solid was filtered, washed with cold n - heptane (2 x 50 mL, 2 x 1 vol), and dried in vacuo. The product (III - A, 23.2 g) as a fine white solid was obtained with an HPLC purity of 99.5%.

[0125] 1 1H NMR (CDCl3, 300 MHz) δ (ppm): 4.38 (m, 2H), 4.35 (m, 2H), 4.19 (s, 4H), 3.75 (s, 3H) ppm. Example 3 Synthesis of 2,3 - dihydro - [1,4] dioxino[2,3 - b]pyridine - 7 - sulfonamide (IV)

[0126] Step 1: 2,3 - dihydro - [1,4] dioxino[2,3 - b]pyridine (IV - C)

[0127] EtOH (9.87 L, 8.5 vol) was added to the reactor, followed by 2,3-dihydroxypyridine (1.16 kg, 10.45 mol, 1 eq), and then deionized water (1.74 L, 1.5 vol). Then K2CO3 (3.61 kg, 2.5 eq) was added to the reactor through the manway. Then 1,2-dibromoethane (3.93 kg, 2.0 eq) was slowly added to the reactor. The feed line was rinsed with EtOH (about 1 L), and the washings were added to the reactor. The resulting suspension was heated to 75 - 85 °C (reflux) and agitated at this temperature for 12 h. A sample of the reaction mixture was taken and analyzed by HPLC to confirm the complete formation of the desired product.

[0128] EtOH (about 7 vol) in the reaction mixture was azeotropically distilled off at a temperature of 80 - 90 °C until the residual volume was 3 - 4 vol. Deionized water (5.81 L, 5 vol) was added to the reactor, and distillation was continued until the material temperature reached 99 - 100 °C. Additional deionized water (2.31 L, 2 vol) was added to the reactor, and distillation was continued until the material temperature reached 99 - 100 °C. Then the mixture was cooled to <30 °C. EtOAc (5.81 L, 5 vol) was added to the reactor, and the mixture was agitated at <30 °C for 30 min. Agitation was stopped, and the layers were allowed to separate for 30 min, and the bottom aqueous layer was drained into a clean container. The first organic top layer was drained into another clean container.

[0129] The aqueous layer was added back to the reactor, then EtOAc (5.81 L, 5 vol) was added, and the resulting mixture was agitated at <30 °C for 30 min. Agitation was stopped, and the layers were allowed to separate for 30 min, and the bottom aqueous layer was drained into a clean container. Then the first organic top layer was added to the reactor, followed by brine (about 5 vol, 4.35 L of water and 1.45 kg of sodium chloride, about 25 wt% brine solution). Then the mixture was agitated for 30 min, at which point agitation was stopped, and the layers were allowed to separate for 30 min, and the bottom aqueous layer was drained into a clean container.

[0130] Then the combined organic extracts remaining in the reactor were concentrated by distillation to about 2-fold volume. Then the mixture was cooled to 25 °C and drained into a clean container. The reactor was rinsed with additional EtOAc and combined with the concentrated organic extracts. The resulting 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-C) was stored as a concentrated solution in EtOAc and transferred to the next step.

[0131] 11H NMR (DMSO-d6, 300 MHz) δ (ppm): 7.73 (dd, J = 4.8, 1.5 Hz, 1H), 7.28 (dd, J = ddd, 7.8, 1.5, 0.6 Hz, 1H), 6.95 (ddd, J = 7.8, 4.8, 0.3 Hz, 1H), 4.40 - 4.38 (m, 2H), 4.26 - 4.24 (m, 2H) ppm.

[0132] Step 2: 7-Bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-B)

[0133] A concentrated solution of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-C) (919.1 g pure, 1.0 eq) prepared in the first step was added to a reaction vessel together with DMF (4.5955 L, 5.0 vol). Then N-bromosuccinimide (NBS) (1.5506 kg, 1.3 eq) was added to the reactor through a hopper at 20 - 30 °C. The resulting mixture was heated to 55 - 60 °C and stirred at this temperature for 8 h. The mixture was cooled to 25 °C and evaluated by HPLC to confirm complete conversion to the desired product. Then the mixture was further cooled to a temperature of <5 °C, and a solution of sodium metabisulfite (1.274 kg, 1.0 eq) in deionized water (9.191 L, 10 vol) was added to the reactor while maintaining the temperature <15 °C. The resulting mixture was further cooled to a temperature of 0 - 5 °C and stirred for at least 2 h. The product precipitated from the solution and was then separated by filtration. The filter cake was washed with deionized water (5 x 4.5955 L, 5 x 5 vol) and then dried in vacuo at 55 °C for 16 h to give 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-B, 1.8900 kg, 62% yield) as an off-white to pale yellow powder.

[0134] 1 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 7.85 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 4.44 - 4.41 (m, 2H), 4.29 - 4.27 (m, 2H) ppm.

[0135] Step 3: 2,3-Dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV)

[0136] Add THF (14.051 L, 9 vol) to the first reactor, and add 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-B, 1.8900 kg, 1.5612 kg pure) produced in step 2 into the reactor through the manhole. Stir the mixture at 25 °C for 15 min. Evaluate the water content of the mixture, and proceed to the next step after determining that the water content < 0.1% v / v.

[0137] Then cool the reaction mixture to -25 °C to -18 °C, and add isopropylmagnesium chloride in THF (0.8696 kg, 1.17 eq) to the reactor while maintaining the temperature between -25 °C and -5 °C. Rinse the feed line with THF (1.5612 L, 1 vol), and add the rinse to the reactor. Then add n-butyllithium in hexane (0.7268 kg, 1.57 eq) to the reactor while maintaining the temperature between -25 °C and -5 °C. Rinse the feed line with THF (1.5612 L, 1 vol), and add the rinse to the reactor. Stir the mixture at a temperature of -25 °C to -5 °C for 15 - 25 min.

[0138] Add toluene (4.6836 L, 3 vol) to the second reactor, and then add sulfuryl chloride (2.9262 kg, 3 eq) while maintaining the temperature < 25 °C. Rinse the feed line with toluene (1.5612 L, 1 vol), and add the rinse to the second reactor. While maintaining the temperature between -25 °C and -5 °C, slowly add the reaction mixture from the first reactor to the second reactor. Rinse the first reactor with THF, and add the rinse to the second reactor. While maintaining the temperature between -25 °C and 0 °C, stir the reaction mixture obtained in the second reactor for at least 30 min. After 30 min, take a portion of the reaction mixture, quench it with ice water, and analyze it by HPLC to confirm complete conversion to the desired product - intermediate compound 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride (IV-A).

[0139] While maintaining a temperature < 0 °C, deionized water (6.2448 L, 4 vol) was added to the second reactor. The mixture was agitated at a temperature of -10 °C to 0 °C for 20 min. After agitation, the layers were allowed to separate for at least 15 min, and the bottom aqueous layer was transferred back to the first reactor while maintaining the temperature < 0 °C. A 20% w / w solution of sodium chloride (1.5612 kg) in deionized water (brine, 6.2448 L, 4 vol) was prepared in a separate container, and half of it (approximately 2 vol) was added to the second reactor while maintaining the temperature < 0 °C. Then the mixture was agitated at a temperature < 0 °C for 20 min. After agitation, the layers were allowed to separate for at least 15 min, and the bottom aqueous layer was transferred back to the first reactor while maintaining the temperature < 0 °C. The other half of the brine solution (approximately 2 vol) was added to the second reactor while maintaining the temperature < 0 °C. Then the mixture was agitated at a temperature < 0 °C for 15 min. After agitation, the layers were allowed to separate for at least 15 min, and the bottom aqueous layer was transferred back to the first reactor while maintaining the temperature < 0 °C.

[0140] While maintaining a temperature < 5 °C, DCM (7.0860 L, 5 vol) was added to the reactor containing the aqueous wash solution and agitated for 15 min. After agitation, the layers were allowed to separate for approximately 60 min. The remaining organic layer in the second reactor was cooled to -15 °C, and the bottom organic layer from the first reactor was added to the second reactor. The combined organic extract in the second reactor was cooled to -20 °C.

[0141] While maintaining a temperature < 5 °C, the MeOH solution of ammonia (0.9846 kg, 8.0 eq) was added to the second reactor over a period of 1 h. The feed line was rinsed with MeOH, and the wash solution was added to the second reactor. Then the reaction mixture was agitated at a temperature < 0 °C for 1 - 3 h. A sample of the reaction mixture was taken and evaluated by HPLC to confirm complete conversion to the desired product 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV).

[0142] The reaction mixture was cooled to -10 °C, and deionized water (7.806 L, 5 vol) was added to the reactor while maintaining the temperature between -10 °C and 0 °C. The solid product was collected by vacuum filtration. DCM (7.0860 L, 5 vol) was added to the reactor, and the collected solid was washed by allowing the wash solution from the reactor to permeate the filter for 15 min, agitating the solid, and then vacuum filtering again. Deionized water (3.122 L, 2 vol) was added to the reactor, and the collected solid was washed by allowing the wash solution from the reactor to permeate the filter for 15 min, agitating the solid, and then vacuum filtering again.

[0143] Transfer the wet filter cake to a clean third reactor, and then add deionized water (15.6 L, 10 vol) thereto. Stir the resulting mixture under reflux for 1 - 2 h. After stirring, cool the slurry to 15 - 25 °C and stir for another 30 min. Collect the solid product by vacuum filtration, and add deionized water (3.1 L, 2 vol) to the reactor. Wash the collected solid by allowing the wash liquor from the reactor to permeate the filter for 15 min, stirring the solid, and then vacuum filtering again. Take a portion of the solid product and evaluate it by HPLC to confirm the product purity.

[0144] Add DCM (3.750 L, 2.4 vol) together with the wet cake collected by filtration in the previous step to the reactor. Add MeOH (1.250 L, 0.8 vol) to the reactor, and stir the mixture at a temperature of 15 - 20 °C for at least 30 min. Separate the solid product by vacuum filtration, and add DCM (2.000 L, 1.3 vol) to the reactor. Wash the collected solid by allowing the wash liquor from the reactor to permeate the filter for 15 min, stirring the solid, and then vacuum filtering again. Take a portion of the solid product and evaluate it by HPLC to confirm the product purity. Dry the solid under vacuum at 50 °C for 16 h to obtain 2,3 - dihydro - [1,4]dioxino[2,3 - b]pyridine - 7 - sulfonamide as a white to grey / beige powder (IV, 0.94 kg, 60% yield, purity 99.4% as measured by HPLC).

[0145] 1 1H NMR (DMSO - d6, 300 MHz) δ (ppm): 8.15 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.47 (br s, 2H), 4.52 - 4.50 (m, 2H), 4.35 - 4.32 (m, 2H) ppm. Example 4 Alternative synthesis of 7 - bromo - 2,3 - dihydro - [1,4]dioxino[2,3 - b]pyridine (IV - B)

[0146] Step 1: 5 - bromopyridine - 2,3 - diol (IV - E)

[0147] Furfural (IV-F, 5.8 g, 0.06 mol) in 70 g of water was cooled to 0 °C, and bromine (9.7 g, 0.06 mol) was added dropwise while maintaining the temperature between 0 - 5 °C. After stirring for 30 min, HBr (concentrated, 3 mL) was added in one portion, and stirring was continued for 30 min at a temperature of 0 - 5 °C. Then the resulting solution was cooled to -10 °C. While maintaining the temperature below 0 °C, bromine (9.7 g, 0.06 mol) was added dropwise to the reaction solution. The reaction solution was stirred at -5 °C for 1 h, and then while maintaining the temperature between 45 - 55 °C, it was added to a solution of sulfamic acid (6 g, 0.062 mol) in water (23 g). The reaction was stirred at 50 - 55 °C for 30 min. Then the reaction mixture was cooled to 0 - 10 °C, stirred for 1 h, and finally filtered to collect the desired product in the form of a precipitate. The precipitated product was then dried at 50 °C for 18 h to collect the crude product as a gray solid - 5 - bromopyridine - 2,3 - diol (IV - E) (65% yield).

[0148] 1 H NMR (400 MHz, DMSO - d6) δ (ppm): 11.84 (brs, 1H), 9.55 (br s, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H).

[0149] Step 2: 7 - bromo - 2,3 - dihydro - [1,4]dioxino[2,3 - b]pyridine (IV - B)

[0150] To a solution of 5 - bromopyridine - 2,3 - diol (IV - E, 1.0 eq) in EtOH / H2O (10 vol / 10 vol) was added K2CO3 (1.41 eq) and BrCH2CH2Br (1.76 eq). The mixture was heated to a temperature of 70 - 75 °C and maintained for 44 h. Additional K2CO3 (0.35 eq) and BrCH2CH2Br (0.35 eq) were added, and heating was continued for 10 h. The progress of the reaction was monitored by HPLC to confirm the complete consumption of the starting material. Subsequently, the reaction solution was concentrated to remove EtOH. EtOAc (20 vol) was added, and the desired product was extracted. The solution of the product in EtOAc was concentrated. DMF (1.5 vol) was added, followed by H2O (7.5 vol). The precipitate was filtered and dried to obtain the desired product - 7 - bromo - 2,3 - dihydro - [1,4]dioxino[2,3 - b]pyridine (IV - B) (45% yield). 11H NMR (DMSO-d6, 300 MHz) δ (ppm): 7.85 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 4.44 - 4.41 (m, 2H), 4.29 - 4.27 (m, 2H) ppm. Example 5 (S)-Tropic acid (VII) synthesis

[0151] Step 1: Methyl 2-formylphenylacetate (VII-B)

[0152] Under nitrogen, sodium methoxide (1.3 eq) was added to a clean, dry reactor, and then MTBE (6 vol) was added. The reactor contents were then heated to a temperature of 15 - 25 °C, and while maintaining the temperature between 15 - 20 °C, methyl phenylacetate (3.0 kg, 1 eq) was added over at least 20 min. The feed line was rinsed with additional MTBE (0.5 vol), and the rinse was added to the reactor. The reactor contents were maintained and agitated at a temperature of 15 - 25 °C for 30 - 60 min. Then, while maintaining the temperature between 15 - 25 °C, methyl formate (1.80 kg, 1.5 eq) was added to the reactor over at least 1 h. The feed line was rinsed with additional MTBE (0.5 vol), and the rinse was added to the reactor. The reactor contents were then heated to a temperature of 15 - 25 °C and agitated for at least 5 h while maintaining the above temperature. The reaction progress was monitored by taking a sample of the reaction mixture and evaluating the content of methyl phenylacetate via 1 1H NMR.

[0153] Subsequently, the reaction mixture was cooled to -10 °C to 5 °C, and water (4 vol) was added to the reactor while maintaining the reactor temperature between -10 °C and 5 °C. The reactor contents were then agitated for at least 15 min while maintaining the temperature between -10 °C and 5 °C. The pH of the aqueous layer was measured and adjusted with sodium hydroxide or citric acid until the pH was in the range of 11.5 to 12.5.

[0154] The reactor contents were allowed to stand for at least 15 min, the bottom aqueous layer containing the desired product was drained into a suitable container and stored at a temperature of -10 °C to 5 °C. Subsequently, the upper organic layer was drained from the reactor. The aqueous layer was added back to the reactor and maintained at a temperature of -10 °C to 5 °C. MTBE (4 vol) was added to the reactor, and the mixture was agitated while maintaining the temperature between -10 °C and 5 °C. While maintaining the temperature between -10 °C and 5 °C, a 25% w / w aqueous solution of citric acid (3 vol) was added to the reactor, and the resulting mixture was agitated for at least 15 min.

[0155] Let the reaction mixture stand for at least 40 min to separate into layers. Set aside the top organic layer containing the desired product and add the bottom aqueous layer back to the reactor. Monitor the pH of the aqueous layer and adjust it to the range of 4 - 5. While maintaining the temperature between 5 - 20 °C, add MTBE (1.5 vol) to the reactor containing the aqueous layer and stir for at least 10 min. Let the reactor contents stand for at least 15 min, then remove the bottom aqueous layer.

[0156] Add the combined organic layers to the reactor, followed by adding 20% w / w sodium chloride solution (1.5 vol). Then, while maintaining the temperature between 5 - 20 °C, stir the mixture for at least 10 min. Let the reactor contents stand for at least 15 min, then remove the bottom aqueous layer. Then heat the reactor contents under reduced pressure to a temperature of 28 - 35 °C until the combined organic layers are concentrated to approximately 4.5 vol.

[0157] Cool the reactor contents, drain the final product solution into a clean container, and store it at -20 °C to obtain methyl 2 - formylphenylacetate (VII - B; 3.31 kg of active substance, 93% yield). Determine the final product solution by 1 1H NMR to confirm the product identity and purity.

[0158] 1 1H NMR, enol form (500 MHz, CDCl3) δ (ppm): 12.0 (br s, 1H), 7.20 - 7.40 (m, 5H), 3.78 (s, 3H).

[0159] 1 1H NMR, hydrated aldehyde form (500 MHz, CDCl3) δ (ppm): 7.90 (s, 1H), 7.20 - 7.40 (m, 5H), 3.70 (s, 3H).

[0160] 1 1H NMR, aldehyde form (500 MHz, CDCl3) δ (ppm): 9.83 (s, 1H), 7.20 - 7.40 (m, 5H), 3.60 (s, 3H).

[0161] Alternative Step 1: Methyl 2 - formylphenylacetate (VII - B)

[0162] Sodium methoxide (30 g, 0.56 mol) was added to a 1 L flask equipped with overhead stirring, followed by toluene (415 ml). Methyl phenylacetate (VII-C, 79 mL, 0.56 mol) was added dropwise over 30 min, and the mixture was stirred for an additional 10 min at room temperature. Methyl formate was added dropwise, and the addition rate was adjusted to keep the reaction temperature below 31 °C. After all of the methyl formate had been added, the reaction mixture was stirred at room temperature for 3.5 h and cooled to 5 °C. A 0.4 M citric acid solution (540 mL, 0.22 mol) was added dropwise with stirring. The layers were separated, and the aqueous layer was extracted with toluene (415 ml). The combined toluene extracts were washed with brine and concentrated in vacuo to give 105.5 g of a colorless liquid that partially solidified on standing. The crude product contained 77% of methyl 2-formyl-2-phenylacetate (VII-B, 81.2 g; 82% yield) and 14% of methyl phenylacetate.

[0163] 1 H NMR, enol form (500 MHz, CDCl3) δ (ppm): 12.0 (br s, 1H), 7.20 - 7.40 (m, 5H), 3.78 (s, 3H).

[0164] 1 H NMR, hydrated aldehyde form (500 MHz, CDCl3) δ (ppm): 7.90 (s, 1H), 7.20 - 7.40 (m, 5H), 3.70 (s, 3H).

[0165] 1 H NMR, aldehyde form (500 MHz, CDCl3) δ (ppm): 9.83 (s, 1H), 7.20 - 7.40 (m, 5H), 3.60 (s, 3H).

[0166] Step 2: Crude (S)-tropic acid (VII)

[0167] Water (8.75 vol), KH2PO4 (0.178 eq), and glucose monohydrate (2.5 eq) were added to the reactor and agitated at a temperature of 20 - 28 °C for at least 5 min. The pH of the solution was adjusted to a value of 6.75 ± 0.25 with 3 M NaOH, and the temperature of the solution was adjusted to 25 - 28 °C. CRED-A231M165-GDH-102 lyophilized cell-free extract (0.138 wt%) was added to the reactor, and the solution was agitated at a temperature of 25 - 28 °C for at least 15 min. A 2.2 - 2.6 wt% enzyme-glucose solution was removed and stored under ambient conditions for subsequent addition.

[0168] Then, NADP disodium salt (0.002265 eq) and MTBE (7.25 vol) were added to the reactor, and the solution was stirred while maintaining the temperature between 25 - 28 °C. Then, while maintaining the pH within the range of 6.75 ± 0.25 using 3M NaOH and keeping the reaction temperature between 25 - 28 °C, the product solution containing methyl 2 - formyl - 2 - phenylacetate (VII - B) generated in the above step 1 was added to the reactor at a constant rate over 4.5 - 5.5 h. After the complete addition of methyl 2 - formyl - 2 - phenylacetate (VII - B), the previously removed enzyme - glucose solution was added to the reactor in one portion. Then, while maintaining the pH within the range of 6.75 ± 0.25 using 3M NaOH and keeping the reaction temperature between 25 - 28 °C, the remaining methyl 2 - formyl - 2 - phenylacetate (VII - B) solution (1.51 - 1.81 vol) was added to the reactor at a constant rate over 5.5 - 6.5 h. The reactor contents were stirred for an additional 4 h at a temperature of 25 - 28 °C and pH 6.75 ± 0.25. The completion of the reaction was evaluated by NMR to confirm the conversion to the desired product, methyl (S) - tropate (VII - A).

[0169] 1 1H NMR (500 MHz, CDCl3) δ (ppm): 7.36 - 7.26 (m, 5H), 4.08 - 4.18 (m, 1H), 3.87 - 3.80 (m, 2H), 3.71 (s, 3H), 2.35 (br s, 1H).

[0170] While maintaining the temperature below 40 °C, the reactor contents were concentrated under reduced pressure to a total of 10 vol to 11.25 vol. After concentration, the reactor contents were heated to a temperature of 40 - 50 °C and stirred for 5 - 15 min. Liquid CALB (0.5 wt%) was added to the reactor in one portion, and the resulting solution was stirred for 24 h while maintaining the temperature between 40 - 50 °C and pH 7.25 ± 0.25. The pH of the reaction mixture was adjusted with 3M aqueous NaOH as needed. The progress of the reaction was evaluated by HPLC, and after determining that the reaction was complete, the reactor contents were cooled to a temperature of 10 - 15 °C and stirred for 5 - 15 min.

[0171] While maintaining the temperature between 10 - 15 °C, the pH of the reactor contents was adjusted to a value between 1.0 - 1.5 using 25% hydrochloric acid (about 1.4 vol). After pH adjustment, while maintaining the temperature between 10 - 15 °C, the reactor contents were stirred for at least 4 h. The reactor contents were filtered and the solid product was collected in the form of a filter cake. Water (1.0 vol) was added to the reactor, cooled to a temperature of 10 - 15 °C, and then the wet filter cake was washed with water. The wet filter cake gave crude (S)-tropic acid (VII, 1.51 kg of active substance, 81% yield), and its purity (99.32%) and enantiomeric purity (99.3%) were evaluated by HPLC.

[0172] 1 H NMR (500 MHz, MeOD) δ (ppm): 7.25 - 7.35 (m, 5H), 4.90 (br s, 1H), 4.05 - 4.15 (m, 1H), 3.69 - 3.77 (m, 2H).

[0173] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.17 - 7.27 (m, 5H), 6.90 (br s, 2H), 3.82 - 3.77 (m, J = 1H), 3.42 - 3.56 (m, 2H).

[0174] Alternative Step 2a: Methyl (S)-tropate (VII-A)

[0175] In a 1 L flask equipped with overhead stirring, glucose monohydrate (57.8 g, 1.3 eq), L-lysine hydrochloride (8.2 g, 0.2 eq), and thiamine hydrochloride (7.6 g, 0.1 eq) were dissolved in 0.1 M potassium phosphate buffer (430 ml). The resulting solution was heated to 30 °C and the pH was adjusted to 6.5 using aqueous K2CO3 solution (20% w / w). NADP (0.6 g), GDH-102 (0.8 g, 2 wt%), and CRED-41 (4 g, 10 wt%) were added to the reaction mixture, and then toluene (40 ml) was added. While maintaining the reaction temperature at 30 °C and the pH at 6.5, a solution of methyl 2-formyl-2-phenylacetate (40 g, 1 eq) in 40 ml of toluene was added over 10 h via an injection pump. 5 h after the start of the addition, more GDH-102 (0.8 g, 2 wt%) and CRED-41 (4 g, 10 wt%) were added.

[0176] After stirring for 16 h, 100 ml of toluene was added and the reaction mixture was filtered through a layer of Celite. The layers were separated and the aqueous phase was extracted with toluene (2 x 75 ml). The organic layers were combined and washed with brine (1 x 100 ml). Concentration under reduced pressure gave 45.2 g of a crude reaction mixture which contained 57% methyl (S)-tropate (VII-A, ee 87% (S), yield 64%).

[0177] 1 H NMR (500 MHz, CDCl3) δ (ppm): 7.36 - 7.26 (m, 5H), 4.08 - 4.18 (m, 1H), 3.87 - 3.80 (m, 2H), 3.71 (s, 3H), 2.35 (br s, 1H).

[0178] Alternative Step 2b: Crude (S)-tropic acid (VII)

[0179] In a 1 L flask equipped with overhead stirring, a solution of 1 M NaOH in 15% aqueous NaCl was prepared (NaOH: 15 g (2 eq); NaCl: 58 g; H2O: 393 ml). The solution was cooled to -10 °C. With vigorous stirring, a solution of crude methyl (S)-tropate (VII-A, 33 g, 1 eq) in toluene (200 ml) was added dropwise over 2 h while maintaining the reaction temperature at -10 °C. After all of the toluene solution had been added, stirring was continued for 1 h.

[0180] While maintaining the temperature below 0 °C, aqueous hydrochloric acid (28%) was added to adjust the pH of the reaction mixture to 8. MTBE (100 ml) was added with stirring, the phases were separated and the organic layer was discarded. The aqueous phase was washed again with 100 ml of MTBE (organic layer discarded).

[0181] Aqueous sulfuric acid (50%) was added to adjust the pH to 2, followed by extraction with 2-MeTHF (3 x 100 ml). The combined organic layers were concentrated under reduced pressure to give crude (S)-tropic acid (VII, ee 86% (S), 27 g).

[0182] 1 H NMR (500 MHz, MeOD) δ (ppm): 7.25 - 7.35 (m, 5H), 4.90 (br s, 1H), 4.05 - 4.15 (m, 1H), 3.69 - 3.77 (m, 2H).

[0183] 11H NMR (400 MHz, DMSO-d6) δ (ppm): 7.17 - 7.27 (m, 5H), 6.90 (br s, 2H), 3.82 - 3.77 (m, J = 1H), 3.42 - 3.56 (m, 2H).

[0184] Step 3: Recrystallization of (S)-tropic acid (VII)

[0185] Add the crude (S)-tropic acid (VII, 1 eq) prepared in the previous step to a clean reactor. Add THF (6 vol, based on the input of Step 2) to the reactor. Heat the reactor contents to a temperature of 35 - 45 °C and maintain for at least 1 h.

[0186] Then filter the reactor contents and wash the filter cake twice with THF (3 vol). Discard the undissolved material remaining on the filter. Determine the (S)-tropic acid content in each solution by 1 1H NMR of the filtrate and THF washings.

[0187] Condition the reactor by rinsing with THF. Then add back the THF filtrate and washings prepared in the initial filtration step to the reactor and concentrate the mixture to approximately 2-fold volume by vacuum distillation at a temperature of 35 - 45 °C.

[0188] After concentration, heat the reactor contents to a temperature of 35 - 45 °C and add water (4 vol) to the reactor. Then, at a temperature of 35 - 45 °C, concentrate the reactor contents to approximately 4-fold volume by vacuum distillation. Determine the THF content of the reaction mixture by 1 1H NMR and confirm that it is between 3 - 10%.

[0189] Then heat the reactor contents to a temperature of 35 - 45 °C and add toluene (2 vol) while maintaining the temperature between 35 - 45 °C. Then cool the reactor contents to a temperature of 0 - 10 °C over at least 5 h and maintain at this temperature for at least 15 h. Then filter the reactor contents while maintaining the temperature between 0 - 10 °C. Visually inspect the reactor for any residual solids, rinse the reactor with the mother liquor and collect any residual solid material.

[0190] Subsequently, while maintaining the temperature between 0 - 10 °C, the filter cake was washed with toluene (2 vol). After washing, the filter cake was pull-dried under vacuum for at least 2 h. Then, the purity, enantiomeric purity, and protein content of the resulting semi-dry filter cake were evaluated by HPLC. After HPLC analysis, the filter cake was further dried by heating at a temperature of 35 - 45 °C under reduced pressure for at least 24 h. The water content and solvent content of the dried filter cake were evaluated by KF and GC, respectively. The dry product material was collected to obtain (S)-tropic acid (VII, 92% yield), with a purity of 99.8% and an enantiomeric purity of 99.7%.

[0191] 1 H NMR (500 MHz, MeOD) δ (ppm): 7.25 - 7.35 (m, 5H), 4.90 (br s, 1H), 4.05 - 4.15 (m, 1H), 3.69 - 3.77 (m, 2H).

[0192] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.17 - 7.27 (m, 5H), 6.90 (br s, 2H), 3.82 - 3.77 (m, J = 1H), 3.42 - 3.56 (m, 2H).

[0193] Alternative Step 3: Recrystallization of (S)-Tropic Acid (VII)

[0194] The crude (S)-tropic acid (10 g, ee 86% (S)) was suspended in a 1:4 mixture of 50 ml of n-heptane:iPrAc, and the suspension was heated to 60 °C. After stirring at this temperature for 1 h, the mixture was cooled to room temperature and equilibrated with stirring (about 20 h). It was filtered and washed with 10 ml of cold n-heptane:iPrAc mixture (1:4) to obtain (S)-tropic acid (ee 98.3%, 7 g after drying under reduced pressure).

[0195] 1 H NMR (500 MHz, MeOD) δ (ppm): 7.25 - 7.35 (m, 5H), 4.90 (br s, 1H), 4.05 - 4.15 (m, 1H), 3.69 - 3.77 (m, 2H).

[0196] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.17 - 7.27 (m, 5H), 6.90 (br s, 2H), 3.82 - 3.77 (m, J = 1H), 3.42 - 3.56 (m, 2H). Example 6 (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo Synthesis of (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I)

[0197] Step 1: Methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (V-A)

[0198] Add 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV, 31.00 g), K2CO3 (21.15 g, 1.1 eq), and DMSO (300 mL, 10 vol) to a 1 L jacketed reactor. Heat the contents to 100 °C. Slowly add a toluene (270 mL, 9 vol) solution of methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A, 31.91 g, 1.0 eq) over 2.5 h through an in-line filter. Rinse the vessel with toluene (30 mL, 1 vol) and add the rinse over 10 min to the reaction vessel. Stir the contents of the reactor at 100 °C for 1 h. Take a sample of the reaction mixture and monitor by HPLC, showing 0.1% of III-A remaining.

[0199] Then cool the reaction mixture to room temperature over 6 h. Remove toluene by distillation with a jacket temperature of 60 °C. Cool the contents of the reactor to room temperature. While maintaining the temperature below 30 °C, add water (300 mL, 10 vol) to the resulting thick mixture over 1 h. Let the mixture age for 30 min.

[0200] Filter the solid and wash with water (2 × 300 mL, 10 vol) and MeCN (4 × 150 mL, 5 vol). Then dry the solid on the filter for 16 h to obtain a white solid (42.219 g, 82.8%) with an HPLC purity of 97.8%.

[0201] A solid (42 g) was added to a 1 L jacketed reactor containing MeCN (420 mL, 10 vol). The mixture was heated to 80 °C and stirred at this temperature for 1 h. The slurry was cooled to room temperature over 4 h and then stirred overnight at this temperature. The solid was collected by filtration and washed with MeCN (210 mL, 5 vol). The solid was dried on the filter for 2 h to give a white solid (40.21 g, recovery rate 95.7%, total recovery rate 78.9%), with an HPLC purity of 99.4%.

[0202] 1 1H NMR (300 MHz, CDCl3) δ (ppm): 8.30 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 4.54 - 4.51 (m, 2H), 4.34 - 4.32 (m, 2H), 4.13 - 4.07 (m, 8H), 3.72 (s, 3H) ppm.

[0203] Step 2: 7 - ((3,4,5,6 - Tetrahydropyrrolo[3,4 - c]pyrrol - 2(1H) - yl)sulfonyl) - 2,3 - dihydro - [1,4]dioxino[2,3 - b]pyridine (VI)

[0204] A mixture of methyl 5 - ((2,3 - dihydro - [1,4]dioxino[2,3 - b]pyridin - 7 - yl)sulfonyl) - 3,4,5,6 - tetrahydropyrrolo[3,4 - c]pyrrole - 2(1H) - carboxylate (V - A, 29.4 g, 80 mmol), Bu2S (88.2 mL, 3 vol) and MSA (58.8 mL, 2 vol) was heated at 70 °C for 19 h. LCMS indicated completion of the reaction. The mixture was cooled to 10 °C and diluted with water (240 mL) at ≤25 °C and extracted with n - heptane (3 × 120 mL). The aqueous solution was divided into two equal portions.

[0205] The first portion was cooled to 10 °C and neutralized with 28 - 30% NH4OH (120 mL) at ≤25 °C. The mixture was stirred at room temperature for 1 h and extracted with DCM (3 × 120 mL, 60 mL and 60 mL). The combined DCM extracts were washed with 1N NaOH (120 mL) and water (120 mL) and added to another flask containing (S) - tropic acid (VII, 6.65 g, 40 mmol, 1.0 eq) and DCM (80 mL). The mixture was stirred at room temperature over the weekend. The solid was filtered, washed with DCM (30 mL) and dried in a vacuum oven at 40 °C for 6 h. 17.3 g was obtained (yield, 91.0%)

[0206] Cool the second portion to 10 °C and neutralize with 28 - 30% NH4OH (120 mL) at ≤25 °C. Stir the mixture at room temperature for 20 min, heat to 70 °C, and stir for 1 h. Cool the mixture to 15 °C and stir for 0.5 h. Collect the solid by filtration and wash with water (30 mL). Repulp the free amine in water (120 mL) at 70 °C for 20 h, then cool to 15 °C and stir for 0.5 h. Collect the solid by filtration, wash with water (60 mL), and dry in a vacuum oven at 45 °C for 6 h. 10.1 g (yield, 81.6%) of 7 - ((3,4,5,6 - tetrahydropyrrolo[3,4 - c]pyrrol - 2(1H) - yl)sulfonyl)-2,3 - dihydro - [1,4]dioxino[2,3 - b]pyridine (VI) is obtained.

[0207] Stir 7 - ((3,4,5,6 - tetrahydropyrrolo[3,4 - c]pyrrol - 2(1H) - yl)sulfonyl)-2,3 - dihydro - [1,4]dioxino[2,3 - b]pyridine and (S)-tropic acid (VII, 5.7 g, 34.3 mmol, 1.05 eq) in MeCN (202 mL) / water (2.0 mL) at room temperature for 18 h. Collect the solid by filtration, wash with MeCN (60 mL), and dry in a vacuum oven at 40 °C overnight. This process gives 14.5 g (yield, 93.5%; overall yield, 76.2%)

[0208] 1 1H NMR (300 MHz, DMSO - d6) δ (ppm): 8.18 (d, J = 3 Hz, 1H), 7.65 (d, J = 3 Hz, 1H), 7.27 - 7.18 (m, 5H), 7.0 - 6.2 (br, 3H) 4.53 - 4.50 (m, 2H), 4.35 - 4.32 (m, 2H), 4.03 (br s, 4H), 3.90 - 3.92 (m, 1H), 3.60 - 3.50 (m, 6H).

[0209] Step 3: (S)-1-(5 - ((2,3 - dihydro - [1,4]dioxino[2,3 - b]pyridin - 7 - yl)sulfonyl)-3,4,5,6 - tetrahydropyrrolo[3,4 - c]pyrrol - 2(1H) - yl)-3 - hydroxy - 2 - phenylpropan - 1 - one (I)

[0210] Add to a 10 dram scintillation vial (2.500 g), EDC·HCl (1.058 g, 0.525 eq), (0.300 g, 0.2 eq) and DMAc (10 mL, 2 vol). Stir the contents of the vial at 20 ± 5 °C for 1 h. Add the remaining (2.500 g) and EDC·HCl (1.058 g), and the reaction mixture was stirred for 3 h. Samples were taken and analyzed by LCMS, indicating 0% remaining of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI). 2-MeTHF (15 mL, 3 vol) was added to the reactor, and the contents of the vial were passed through a 0.45 μm inline filter. The vial was rinsed with DMAc (1 mL, 0.2 vol), and this solution was passed through the inline filter. EtOH (2.5 mL, 0.5 vol) and 2-MeTHF (10 mL, 2 vol) were added to the vial, and the mixture was stirred overnight at room temperature.

[0211] Water (60 mL, 12 vol) was added to the reaction mixture. The slurry was aged at room temperature for 30 min, after which the solid was collected by filtration. The solid was washed with water (3 × 20 mL, 4 vol) and EtOH (1 × 20 mL, 4 vol). The solid was dried on the filter for 2 h to give (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I) (4.29 g, 89.2% yield) as a white solid with an HPLC purity of 98.6%.

[0212] 1 1H NMR (400 MHz, CDCl3) δ (ppm): 8.24 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.35 - 7.23 (m, 5H), 4.51 - 4.50 (m, 2H), 4.32 - 4.30 (m, 2H), 4.28 - 3.93 (m, 8H), 3.78 - 3.67 (m, 3H), 3.15 - 3.13 (m, 1H) ppm. Example 7 Reslurrying of (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I)

[0213] The crude (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)- 3,4,5,6-Tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I, 13.7 g) was suspended in EtOH (205.5 mL, 15 vol) and water (13.7 mL, 3 vol). The mixture was heated to reflux for 30 min, then cooled to 70 °C and aged at this temperature for 3 h. Then the slurry was cooled to 50 °C over 4 h and stirred at this temperature for 14 h. Then the slurry was cooled to 20 °C over 1 h and stirred at this temperature for 1 h. The solid was collected by filtration and washed with EtOH (41.1 mL, 3 vol). The solid was dried on the filter for 2 h and then dried under a full vacuum with a nitrogen stream for 20 h. The isolated white solid was 12.561 g (recovery 91.7%, overall yield 81.6%), and the HPLC purity was 99.6%.

[0214] 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.24 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.35 - 7.23 (m, 5H), 4.51 - 4.50 (m, 2H), 4.32 - 4.30 (m, 2H), 4.28 - 3.93 (m, 8H), 3.78 - 3.67 (m, 3H), 3.15 - 3.13 (m, 1H) ppm. Example 8 5-((2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo [3,4-c]pyrrole-2(1H)-carboxylic acid methyl ester (V-A) on a large scale synthesis

[0215] To a 10 L jacketed reactor was added 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV, 516.5 g) and K2CO3 (352 g, 1.1 eq) and DMSO (5 L, 10 vol). The contents were heated to 100 °C. A toluene (3 L, 6 vol) solution of 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid methyl ester (III-A, 531.3 g, 1.0 eq) was slowly added over 2.5 h through an in-line filter. The vessel was rinsed with toluene (0.5 L, 1 vol) and the rinse was added to the reaction vessel over 10 min. The contents of the reactor were stirred at 100 °C for 1 h. A sample of the reaction mixture was taken and monitored by HPLC, indicating 0.2% of III-A remaining.

[0216] The reaction mixture was cooled to room temperature over 6 h. Toluene was removed by distillation with a jacket temperature of 65 °C.

[0217] The contents of the reactor were cooled to room temperature. While maintaining the temperature below 30 °C, water (5 L, 10 vol) was added to the thick mixture over 1 h. The mixture was aged for 30 min.

[0218] The solid was collected by filtration and washed with water (2 × 5 L, 10 vol) and MeCN (4 × 2.5 L, 5 vol). The solid was dried on the filter for 2 h and then dried at 45 °C under full vacuum for 16 h to give a white solid (702 g, 82.6%), with an HPLC purity of 99.5% and a KF of 0.7%.

[0219] The crude solid (700 g) was added to a cleaned 10 L jacketed reactor and suspended in MeCN (7 L, 10 vol). The slurry was heated to 80 °C and stirred at this temperature for 1 h. The contents of the reactor were cooled to 20 °C over 4 h and stirred at this temperature for 14 h. The solid was collected by filtration and washed with MeCN (3.5 L, 5 vol). The solid was dried on the filter for 2 h and then dried overnight in a vacuum oven at 45 °C. The isolated solid was 676 g of methyl 5 - ((2,3 - dihydro - [1,4]dioxino[2,3 - b]pyridin - 7 - yl)sulfonyl) - 3,4,5,6 - tetrahydropyrrolo[3,4 - c]pyrrole - 2(1H) - carboxylate (V - A), with a recovery of 96.3% and an overall yield of 79.5%, an HPLC purity of 99.6% and a KF of 0.5%.

[0220] 1 1H NMR (CDCl3, 300 MHz): δ (ppm): 8.30 (s, 1H), 7.59 (s, 1H), 4.55 - 4.50 (m, 2H), 4.35 - 4.30 (m, 2H), 4.15 - 4.05 (m, 8H), 3.72 (s, 3H). Example 9 Large - scale synthesis of 7 - ((3,4,5,6 - tetrahydropyrrolo[3,4 - c]pyrrol - 2(1H) - yl)sulfonyl) - 2,3 - dihydro - [1,4]dioxino[2,3 - b]pyridine (VI)

[0221] Methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (V-A, 300.0 g, 0.817 mol; obtained by the method of Example 8), Bu2S (900 mL, 3 vol), and MSA (600 mL, 2 vol) were added to a 10 L jacketed reactor. The mixture was heated to 70 °C and stirred for 19 h. LCMS indicated completion of the reaction (V-A = 0.6%). The mixture was cooled to <10 °C, diluted with water (2.4 L) at ≤25 °C, and extracted with n-heptane (3 × 1.2 L).

[0222] The aqueous solution was cooled to 10 °C and neutralized with 28 - 30% NH4OH (2.4 L) at ≤25 °C to obtain 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI).

[0223] The mixture was stirred at room temperature for 1 h and extracted with DCM (2.4 L, 1.2 L, and 1.2 L). The combined DCM extracts were washed with 1N NaOH (2.4 L) and water (2.4 L), and added to another flask containing (S)-tropic acid (VII, 135.7 g, 0.817 mol, 1.0 eq) and DCM (1.55 L). The mixture was stirred at room temperature (23 °C) for 20 h. The solid was collected by filtration, washed with DCM (600 mL), and dried overnight in a vacuum oven at 40 °C to obtain 360.2 g of (VI)·(VII) (yield, 92.8%), with a purity of 99.76%. LOD: 0.16%.

[0224] 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 8.18 (d, J = 3 Hz, 1H), 7.65 (d, J = 3 Hz, 1H), 7.27 - 7.18 (m, 5H), 7.0 - 6.2 (br, 3H) 4.53 - 4.50 (m, 2H), 4.35 - 4.32 (m, 2H), 4.03 (br s, 4H), 3.90 - 3.92 (m, 1H), 3.60 - 3.50 (m, 6H). Example 10 Alternative large-scale synthesis of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI)

[0225] Methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (V-A, 300.0 g, 0.817 mol; obtained by the method of Example 8), Bu2S (900 mL, 3 vol), and MSA (600 mL, 2 vol) were added to a 10 L jacketed reactor. The mixture was heated to 70 °C and stirred for 19 h. LCMS indicated completion of the reaction (V-A = 0.5%). The mixture was cooled to <10 °C, diluted with water (2.4 L) at ≤25 °C, and extracted with n-heptane (3 × 1.2 L).

[0226] The aqueous solution was cooled to 10 °C and neutralized with 28 - 30% NH4OH (2.4 L) at ≤25 °C.

[0227] The mixture was stirred at room temperature for 20 min, then heated to 70 °C and stirred for 1 h. The mixture was cooled to 12 °C and stirred for 0.5 h. The solid was filtered and washed with water (600 mL). Then the free amine was repulped in water (2.4 L) at 70 °C for 18 h. The mixture was cooled to 12 °C and stirred for 0.5 h. The solid was filtered, washed with water (600 mL), and dried overnight in a vacuum oven at 50 °C to give 216.1 g of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI, yield, 85.5%; LOD, 0.20%).

[0228] A suspension of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine and (S)-tropic acid (121.9 g, 0.734 mol, 1.05 eq) in MeCN (4.32 L) / H2O (43 mL) was stirred at room temperature (20 °C) for 21 h. The solid was collected by filtration, washed with MeCN (600 mL), and dried overnight in a vacuum oven at 40 °C to give 320.6 g of (VI)·(VII) (yield, 96.5%; overall yield, 82.6%), with a purity of 99.66%. LOD: 0.14%.

[0229] 11H NMR (300 MHz, DMSO-d6) δ (ppm): 8.18 (d, J = 3 Hz, 1H), 7.65 (d, J = 3 Hz, 1H), 7.27 - 7.18 (m, 5H), 7.0 - 6.2 (br, 3H) 4.53 - 4.50 (m, 2H), 4.35 - 4.32 (m, 2H), 4.03 (br s, 4H), 3.90 - 3.92 (m, 1H), 3.60 - 3.50 (m, 6H). Example 11 (S)-1-(5-((2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I) on a large scale synthesis

[0230] Add (VI)·(VII) (175.20 g; obtained by the method of Example 9), EDC·HCl (73.85 g, 0.525 eq), OxymaPure (20.99 g, 0.2 eq) and DMAc (700 mL, 2 vol) to a 3 L round bottom flask. Stir the contents of the flask at 20 ± 5 °C for 1 h. Add the remaining (VI)·(VII) (175.49 g) and EDC·HCl (74.18 g), and stir the reaction mixture for 4 h. Take a sample and analyze it by HPLC, indicating 1.8% remaining of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI). Add 2-MeTHF (700 mL, 2 vol) to the flask, and pass the contents of the flask through a 0.45 μm inline filter into a 10 L jacketed reactor. Rinse the flask with DMAc (80 mL, 0.23 vol), and pass this solution through the inline filter into the reactor.

[0231] Add EtOH (175 mL, 0.5 vol) and 2-MeTHF (1.05 L, 3 vol) to the reactor, and stir the mixture at room temperature overnight. Take a sample and analyze it by HPLC, indicating 0.1% remaining of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI).

[0232] Water (4.2 L, 12 vol) was added to the reaction mixture. The slurry was aged at room temperature for 30 min and then the solid was collected by filtration. The solid was washed with water (3 × 1.4 L, 4 vol) and EtOH (1 × 1.4 L, 4 vol). The solid was dried on the filter for 2 h to give crude (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I) (306.0 g, 90.9% yield) as a white solid with an HPLC purity of 98.8%.

[0233] Crude (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I) (300 g), EtOH (4.5 L, 15 vol) and water (300 mL, 1 vol) were charged into a cleaned 10 L jacketed reactor. The contents of the reactor were heated to reflux (∼78 °C) and stirred at this temperature for 1 h. The contents of the reactor were cooled to 70 °C and aged at this temperature for 3 h. The contents of the reactor were cooled to 50 °C over 5 h and aged over the weekend at this temperature. The contents of the reactor were cooled to 20 °C and stirred at this temperature for 1 h, followed by filtration. The filter cake was rinsed with EtOH (900 mL, 3 vol). The solid was dried on the filter for 2 h and then dried at 45 °C under a nitrogen stream in full vacuum for 16 h. The isolated solid was 288.7 g of (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I, recovery 96.2%, overall recovery 85.7%) with an HPLC purity of 99.8%.

[0234] 1 1H NMR (400 MHz, CDCl3) δ (ppm): 8.24 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.35 - 7.23 (m, 5H), 4.51 - 4.50 (m, 2H), 4.32 - 4.30 (m, 2H), 4.28 - 3.93 (m, 8H), 3.78 - 3.67 (m, 3H), 3.15 - 3.13 (m, 1H) ppm. Example 12 Alternative large-scale synthesis of (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I)

[0235] (VI)·(VII) (150.01 g; obtained by the method of Example 10), EDC·HCl (63.49 g, 0.525 eq), (17.93 g, 0.2 eq) and DMAc (600 mL, 2 vol) were added to a 2 L jacketed reactor. The contents of the reactor were stirred at 20 ± 5 °C for 1 h. The remaining (VI)·(VII) (150.11 g) and EDC·HCl (63.85 g) were added, and the reaction mixture was stirred for 3 h. Samples were taken and analyzed by HPLC, indicating 1.0% remaining of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI). 2-MeTHF (600 mL, 2 vol) was added to the reactor, and the contents of the flask were passed through a 0.45 μm in-line filter into a 10 L jacketed reactor. The flask was rinsed with DMAc (60 mL, 0.2 vol), and this solution was passed through the in-line filter into the reactor.

[0236] EtOH (150 mL, 0.5 vol) and 2-MeTHF (900 mL, 3 vol) were added to the reactor, and the mixture was stirred overnight at room temperature. Samples were taken and analyzed by HPLC, indicating 0.0% remaining of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI).

[0237] Water (3.6 L, 12 vol) was added to the reaction mixture. The slurry was aged at room temperature for 30 min, after which the solid was collected by filtration. The solid was washed with water (3 × 1.2 L, 4 vol) and EtOH (1 × 1.2 L, 4 vol). The solid was dried on the filter for 2 h and then dried at 45 °C under a full vacuum with a nitrogen stream to give crude (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I) (248.7 g, 86.2% yield) as an off-white solid with an HPLC purity of 98.8%.

[0238] Crude (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I, 248.7 g), EtOH (3.75 L, 15 vol) and water (250 mL, 1 vol) were added to a cleaned 10 L jacketed reactor. The contents of the reactor were heated to reflux (∼78 °C) and stirred at this temperature for 1 h. The contents of the reactor were cooled to 70 °C and aged at this temperature for 3 h. The contents of the reactor were cooled to 50 °C over 5 h and aged overnight at this temperature. The contents of the reactor were cooled to 20 °C and stirred at this temperature for 1 h, after which filtration was carried out. The filter cake was rinsed with EtOH (750 mL, 3 vol). The solid was dried on the filter for 2 h and then dried at 45 °C under a full vacuum with a nitrogen stream for 16 h. The isolated solid was 237.75 g of (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I, recovery 95.6%, overall recovery 82.4%) with an HPLC purity of 99.7%.

[0239] 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.24 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.35 - 7.23 (m, 5H), 4.51 - 4.50 (m, 2H), 4.32 - 4.30 (m, 2H), 4.28 - 3.93 (m, 8H), 3.78 - 3.67 (m, 3H), 3.15 - 3.13 (m, 1H) ppm. Example 13 (2R)-2-Hydroxy-2-phenyl-1-[5-(pyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo Synthesis of [3,4-c]pyrrol-2-yl]ethan-1-one (II) Step 1: Methyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (VIII-B)

[0240] Add K2CO3 (90 g, 648 mmol) and DMSO (750 mL, 15 vol) to the reaction vessel. Then add a yellow solution of pyridine-2-sulfonamide (VIII-A, 52.6 g, 316 mmol) in DMSO (100 mL, 2 vol) to the reaction vessel within NLT 5 min. Then rinse the vessel with DMSO (50 mL, 1 vol) and add the solution to the reaction vessel. Heat the reaction mixture to 85 - 90 °C, at which point a light slurry forms.

[0241] Add a solution of methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A, 70.8 g, 316 mmol) in DMSO (100 mL, 2 vol) to the reaction vessel, maintaining the temperature at 85 - 90 °C. Rinse the vessel with DMSO (50 mL, 1 vol) and add the solution to the reaction vessel. Evaluate the reaction mixture by UPLC analysis and observe complete conversion after 1 hour 20 minutes.

[0242] Cool the reaction mixture to 20 - 25 °C and quench with water (500 mL) while maintaining the temperature at 20 - 30 °C. Stir the resulting solution at 20 - 25 °C for 3 h, then filter through a sintered funnel. Wash the filter cake with water (2 x 250 mL; 2 x 5 vol) to remove residual inorganic salts. Dry the solid under vacuum at 40 - 45 °C for 16 h to obtain 53 g of methyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (VIII-B, 54.2% yield), UPLCMS purity >99%.

[0243] 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.81 - 8.70 (m, 1H), 8.18 - 8.06 (m, 1H), 8.01 - 7.92 (m, 1H), 7.77 - 7.65 (m, 1H), 4.23 (br s, 4H), 4.00 (br s, 4H), 3.59 (s, 3H). Step 2: 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (IX)

[0244] Methyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (VIII-B, 15 g, 48.5 mmol) and MeOH (118 mL, 2909 mmol) were added to a reaction vessel. The suspension was stirred at room temperature for 5 min, and 3 M aqueous potassium hydroxide solution (64.7 mL, 194 mmol) was added to the reaction vessel.

[0245] The resulting solution was heated to reflux (about 75 °C) and maintained at this temperature for 23 h. Then the solution was concentrated under reduced pressure and extracted with DCM (4 x 65 mL). The combined extracts were concentrated under reduced pressure, and the resulting light brown solid was slurried with MTBE. The resulting slurry was concentrated under reduced pressure and dried at room temperature to give 6.18 g of 2-(pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (IX, 50.7% yield), which was carried on to the next step without further purification.

[0246] 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.78 - 8.72 (m, 1H), 8.16 - 8.08 (m, 1H), 7.95 (dt, J = 7.8 Hz), 1H, 7.70 (ddd, J = 7.4, 4.7, 1.2 Hz, 1H), 4.15 (s, 4H), 3.50 (s, 4H), 3.32 (br s, 1H). Alternative Step 2a: 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole dihydrobromide (X)

[0247] Methyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (VIII-B, 4.13 g, 13.35 mmol) was added to a reaction vessel, and HBr in acetic acid (33 wt%; 19.87 mL, 113 mmol) was added. The resulting solution was stirred at 20 - 25 °C for 5 min. Then the solution was heated to 45 - 50 °C over 30 min and stirred at this temperature for approximately 3 h.

[0248] The solution was cooled to 20 - 25 °C, and EtOAc (40 mL) was slowly added to the reaction mixture. The resulting solution was stirred at room temperature for 2 h, and then the solid was filtered. The filter cake was washed with additional EtOAc (2 x 10 mL) and rinsed with IPA (2 x 10 mL). The resulting brown solid was suction dried on the filter overnight to give 5.5 g of 2-(pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole dihydrobromide (X, 100% yield).

[0249] 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 10.15 - 9.90 (br s, 1H), 8.80 - 8.70 (m, 1H), 8.16 - 8.06 (m, 1H), 8.00 - 7.90 (m, 1H), 7.75 - 7.20 (m, 1H), 7.25 - 6.35 (br s, 1H), 4.20 (s, 4H), 3.90 (s, 4H). Alternative Step 2b: 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (IX)

[0250] 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole dihydrobromide (X, 1 g, 2.421 mmol) was added to a reaction vessel and diluted with water (12.5 mL). DCM (7.5 mL) was added to the reaction vessel, followed by IPA (3 mL). The resulting solution was stirred for 5 min, and then the solid was filtered.

[0251] The filtrate was washed with DCM (1 mL), and then rinsed with water (1 mL). The resulting layers were separated, and the aqueous layer was extracted with DCM (5 mL). The aqueous layer was then basified to pH 14 with 2.5 M NaOH (3 mL). The aqueous layer was then extracted with DCM (3 x 5 mL). The organic layers were combined and concentrated under reduced pressure to give 0.58 g of 2-(pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (IX, 95% yield), which was used in the next step without further purification.

[0252] 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.78 - 8.72 (m, 1H), 8.16 - 8.08 (m, 1H), 7.95 (dt, J = 7.8 Hz), 1H, 7.70 (ddd, J = 7.4, 4.7, 1.2 Hz, 1H), 4.15 (s, 4H), 3.50 (s, 4H), 3.32 (br s, 1H). Step 3: (2R)-2-Hydroxy-2-phenyl-1-[5-(pyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one (II)

[0253] 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (IX, 0.5 g, 1.990 mmol) was added to a reaction vessel containing (R)-2-hydroxy-2-phenylacetic acid (0.318 g, 2.089 mmol) and HOBt (0.096 g, 0.497 mmol). DMSO (4 mL, 8 vol) was then added to the reaction vessel.

[0254] A dilute suspension of EDC (0.115 g, 2.388 mmol) in degassed DMSO (2 mL, 4 vol) was added to the reaction vessel. The vessel was rinsed with degassed DMSO (1 mL, 2 vol) and added to the reaction vessel. The resulting solution was stirred overnight at 20 - 25 °C.

[0255] After stirring overnight, UPLCMS analysis showed that approximately 50% of the pyrrolidine (IX) had been converted to the product. Additional EDC (0.34 g) was added, and the resulting mixture was stirred at room temperature for 2 h, at which point UPLCMS analysis showed complete conversion to the product.

[0256] Water (35 mL) was slowly added to the reaction mixture over 1 h, and the resulting solution was stirred for 16 h. The resulting solid was filtered through a funnel, and the filter cake was washed with water (2 x 3 mL, 1 x 6 vol), then rinsed with EtOH (6 mL, 12 vol). The solid was suction dried under an air aspirator for 30 min and then dried in a vacuum oven at 40 - 45 °C for 5 h to give 0.61 g of (2R)-2-hydroxy-2-phenyl-1-[5-(pyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one (II, 80% yield).

[0257] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (d, J = 4.4 Hz, 1H), 8.12 - 8.05 (m, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.68 (dd, J = 7.6, 4.4 Hz, 1H), 7.40 - 7.25 (m, 5H), 5.65 (d, J = 6.2 Hz, 1H), 5.18 (d, J = 6.2 Hz, 1H), 4.30 - 3.90 (m, 8H).

[0258] All patents and publications cited herein are hereby incorporated by reference in their entirety.

[0259] Any composition disclosed herein may comprise, consist of, or consist essentially of any compound or component disclosed herein. According to the present disclosure, the phrase "consist essentially of" and like terms limit the scope of a claim to the specified materials or steps and those materials or steps that do not materially affect the basic and novel characteristics of the claimed invention.

[0260] The reagents and conditions described herein are for illustrative purposes only and not limiting. Those skilled in the art will understand that various analogs can be prepared by modifying the synthetic reactions, for example, using different starting materials, different reagents, and different reaction conditions (e.g., temperature, solvent, concentration, etc.).

[0261] The present disclosure enables those skilled in the relevant art to implement and use the invention provided herein according to a plurality of different embodiments. Various changes, modifications, and improvements to the present disclosure that are readily envisioned by those skilled in the art, including certain changes, modifications, substitutions, and improvements, also fall within the scope of the present disclosure. Accordingly, the foregoing description and drawings illustrate the discoveries provided herein by way of example.

[0262] As used herein, the term "about" means within the error range caused by the standard deviation found in their respective test measurements for the recited values, and if such errors cannot be determined, "about" means within 10% of the recited value.

[0263] Unless otherwise expressly stated, the use of the term "a" is intended to include "at least one" or "one or more". For example, "a compound" is intended to include "at least one compound" or "one or more compounds".

[0264] Any range given in absolute or approximate terms is intended to cover both, and any definitions used herein are intended to clarify and not limit. Although the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors, which are necessarily caused by the standard deviation found in their respective test measurements. In addition, all ranges disclosed herein should be understood to cover any and all sub-ranges subsumed therein (including all fractional and integral values).

[0265] In addition, the present invention encompasses any and all possible combinations of some or all of the various embodiments described herein. It should also be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the invention and without diminishing its intended advantages. Accordingly, such changes and modifications will be covered by the appended claims.

Claims

1. A method for preparing a compound according to formula (III-Y): It includes according to step 1 A1 Scheme A1 makes an azomethine precursor according to formula (III-W) react with an electron-deficient alkyne according to formula (III-X), where step 1 A1 is carried out in the presence of an acid: Scheme A1 wherein R12 is -CR2R3-(C6-C 10 aryl), wherein the C6-C 10 aryl is optionally substituted with 1 to 3 R4s; wherein R2 and R3 are each independently H or C1-C6 alkyl; and R4 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; and R5 and R6 are each independently a halogen, such as chlorine, bromine, iodine, or -OSO2R7, where each R7 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 aryl, where C6-C 10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; and R9 is a suitable silyl protecting group selected from trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS) or dimethylisopropylsilyl (DMIPS); and R10 is C1-C6 alkyl.

2. The method according to claim 1, which comprises step 1 A1’ Scheme A1' reacting an azomethine precursor according to formula (III-W1) with an electron-deficient alkyne according to formula (III-X), wherein step 1 A1’ is carried out in the presence of an acid: Scheme A1' wherein R5 and R6 are each independently a halogen, such as chlorine, bromine, iodine, or -OSO2R7, wherein each R7 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C6-C 10 aryl, wherein C6-C 10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; and R9 is a suitable silyl protecting group selected from trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS) or dimethylisopropylsilyl (DMIPS); and R10 is C1-C6 alkyl.

3. The method according to any one of the preceding claims, wherein R5 and R6 are each chlorine.

4. The method according to any one of the preceding claims, wherein the acid is selected from TFA, TMSOTf, TMSI, a combination of TMSOTf and CsF, or a combination of TMSI and any one of CsF, LiF, ZnCl2, or a combination thereof.

5. The method according to any one of the preceding claims, further comprising step 2 A2 : converting the compound of formula (III-Y) into the compound of formula (III-Z) according to Scheme A2: Scheme A2 wherein R1 is selected from C1-C6 alkoxycarbonyl (such as tert-butoxycarbonyl or methoxycarbonyl), benzyl Oxycarbonyl (i.e., Cbz), C6-C 10 Aryloxycarbonyl (e.g., phenyloxycarbonyl), C1-C6 alkylcarbonyl (e.g., acetyl), haloalkylcarbonyl (e.g., trifluoroacetyl), and -SO2-(C6-C 10 Aryl) (e.g., tosyl).

6. The method according to claim 5, wherein R1 is –C(O)(C1-C6 alkoxy), such as -C(O)OCH3.

7. The method according to any one of claims 5-6, further comprising step 3 A3 : reacting the compound of formula (III-Z) with the compound of formula (IV-Y) according to Scheme A3 to form the compound of formula (V-Z): Scheme A3 wherein R11 is C6-C 10 aryl, 6- to 10-membered heteroaryl containing 1 to 3 O, N, S, wherein the aryl and heteroaryl are each optionally substituted by one or more substituents selected from -R13 and -OR13; each R13 is independently -H, -C1-C6 alkyl optionally substituted by one or more substituents selected from oxo, -F, -Cl, -Br, -I, -CN, -NO2; or two R13s on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring; wherein the reaction is carried out in the presence of a base.

8. The method according to claim 7, wherein R11 is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl.

9. A method for preparing a compound of formula (V-Z), which comprises the following steps: a. Reacting an azomethine precursor of formula (III-W) with an electron-deficient alkyne of formula (III-X) according to Scheme A1, wherein the reaction is carried out in a first non-polar solvent in the presence of an acid: Scheme A1 wherein R12 is -CR2R3-(C6-C 10 aryl), wherein the C6-C 10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C1-C6 alkyl; and R4 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; and R5 and R6 are each independently a halogen, such as chlorine, bromine, iodine, or -OSO2R7, where each R7 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 aryl, where C6-C 10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; and R9 is a suitable silyl protecting group selected from trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS) or dimethylisopropylsilyl (DMIPS); and R10 is C1-C6 alkyl; b. According to Scheme A2, the compound of formula (III-Y) is converted to the compound of formula (III-Z) by reaction with R1-Cl in a second non-polar solvent: Scheme A2 wherein R1 is selected from C1-C6 alkoxycarbonyl (such as tert-butoxycarbonyl or methoxycarbonyl), benzyloxycarbonyl (i.e., Cbz), C6-C 10 aryloxycarbonyl (such as phenyloxycarbonyl), C1-C6 alkylcarbonyl (such as acetyl), haloalkylcarbonyl (such as trifluoroacetyl) and -SO2-(C6-C 10 aryl) (such as toluenesulfonyl); c. According to Scheme A3, the compound of formula (III-Z) is reacted with the compound of formula (IV-Y) in a suitable solvent in the presence of a base to form compound (V-Z): Scheme A3 wherein R11 is C6-C 10 aryl, 6-10 membered heteroaryl containing 1-3 O, N, S, wherein the aryl and heteroaryl are each optionally substituted by one or more substituents selected from -R13 and -OR13; each R13 is independently -H, -C1-C6 alkyl optionally substituted by one or more substituents selected from oxo, -F, -Cl, -Br, -I, -CN, -NO2; or two R13s on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring.

10. The compound of formula (III-Y) or a salt thereof: wherein R12 is -CR2R3-(C6-C 10 aryl), wherein said C6-C 10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C1-C6 alkyl; and R4 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; and R5 and R6 are each independently a halogen, such as chlorine, bromine, iodine, or -OSO2R7, where each R7 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 aryl, where C6-C 10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

11. The compound according to claim 10, wherein R12 is benzyl, i.e., the compound of formula (III-B): (1-Benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate).

12. The compound of formula (III) or a salt thereof: wherein R1 is -C(O)(C1-C6 alkyl), -C(O)(C 1- 6 haloalkyl), -C(O)(C1-C6 alkoxy), -C(O)(benzyloxy), -C(O)(phenoxy) or –S(O)2(tolyl).

13. The compound according to claim 12, wherein the compound is the compound of formula (III-A): (Methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate), or a salt thereof.

14. The compound of formula (V-Z): wherein R1 is –C(O)(C1-C6 alkyl), –C(O)(C1-C6 haloalkyl), –C(O)(C1-C6 alkoxy), -C(O)(benzyloxy), –C(O)(phenoxy) or –S(O)2(tolyl); and R11 is C6-C 10 aryl, 6-10 membered heteroaryl containing 1-3 O, N, S, wherein the aryl and heteroaryl are each optionally substituted by one or more substituents selected from -R13 and -OR13; each R13 is independently -H, -C1-C6 alkyl optionally substituted by one or more substituents selected from oxo, -F, -Cl, -Br, -I, -CN, -NO2; or two R13s on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring.

15. The compound according to claim 14, wherein the compound is the compound of formula (V): wherein R1 is –C(O)(C1-C6 alkyl).

16. The compound according to claim 14, wherein the compound is the compound of formula (VIII): wherein R1 is –C(O)(C1-C6 alkyl).

17. Use of the compound according to any one of claims 14-16 for the preparation of a compound according to formula (I) or (II).

18. A method for preparing a compound according to formula (I): which comprises the following steps: a. According to Step 1 of Scheme B1' B1’ , in the presence of a first acid and in a first non-polar solvent, reacting a compound of formula (III-D) with a compound of formula (III-C) to obtain a compound of formula (III-B): Scheme B1’ b. According to Step 2 of Scheme B1’ B1’ , by reacting with R1-Cl in a second non-polar solvent, Converting the compound of formula (III-B) to the compound of formula (III), wherein R1 is -C(O)C1-C6 alkoxy (e.g., methoxycarbonyl); c. According to Scheme G1, in the presence of a first base and in a suitable solvent, the compound of formula (III) wherein R1 is C1-C6 alkoxycarbonyl (e.g., methoxycarbonyl) is reacted with the formula (IV) compound to form compound (V): Scheme G1 d. Deprotecting the compound of formula (V) wherein R1 is C1-C6 alkoxycarbonyl (e.g., methoxycarbonyl) with a second acid, followed by neutralization with a second base to obtain the compound of formula (VI), or forming a salt of the compounds of formula (VI) and (VII) by adding compound (VII): Scheme G2 e. Performing a coupling reaction of the compound of formula (VI) and the compound of formula (VII) according to Scheme G3 ​ ​ react, or carry out a coupling reaction from the salts of formula (VI)·(VII) using a coupling reagent and an additive in a second suitable solvent according to Scheme G3’ to obtain a compound of formula (I): Scheme G3 or Scheme G3’ 19. Compounds of formula (VI)·(VII):

20. Use of the compound according to claim 19 for the preparation of Etavopivat (I).

21. A method for preparing a compound according to formula (II): which comprises the following steps: a. According to step 1 of Scheme B1' B1’ , in the presence of a first acid in a first non-polar solvent reacting a compound of formula (III-D) with a compound of formula (III-C): Scheme B1’ b. According to step 2 of Scheme B1' B1’ , the compound of formula (III-B) is converted to the compound of formula (III) by reaction with R1-Cl in a second nonpolar solvent, where R1 is -C(O)C1-C6 alkoxy (e.g., methoxycarbonyl); c. According to Scheme H1, in the presence of a first base in a suitable solvent, reacting a compound of formula (III) in which R1 is C1-C6 alkoxycarbonyl (such as methoxycarbonyl) with a compound of formula (VIII- A) to form a compound of formula (VIII): Scheme H1 d. Deprotecting the compound of formula (VIII) in which R1 is C1-C6 alkoxycarbonyl (such as methoxycarbonyl) with a fourth base or a third acid to obtain a compound of formula (IX) or a salt thereof: e. According to Scheme G4, carrying out a coupling reaction of the compound of formula (IX) or a salt thereof with a compound of formula (XI) in a third suitable solvent using a coupling reagent and an additive to obtain a compound of formula (II): Scheme G4

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