Processes and intermediates for preparing MCL1 inhibitors

Abstract

To provide methods for treating diseases.SOLUTION: The present disclosure provides methods for preparing MCL1 inhibitors or a salt thereof and related key intermediates. The present disclosure relates to methods and intermediates for the synthesis of certain compounds which inhibit MCL1, for use in the treatment of cancers. The present disclosure provides methods for making compounds according to Formula (A), as shown above. In some embodiments, the present disclosure provides compounds according to Formula (I).SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 62 / 940,387, filed November 26, 2019, the entire contents of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THE INVENTION The present disclosure relates to methods and intermediates for synthesizing certain compounds that inhibit MCL1 for use in the treatment of cancer. [Background technology]

[0003] Apoptosis (programmed cell death) is a process for eliminating unwanted or potentially dangerous cells from an organism. Avoiding apoptosis is important for tumor development and sustained growth. Myeloid cell leukemia 1 protein (MCL1) is an anti-apoptotic member of the Bcl-2 family of proteins. MCL1 is overexpressed in many cancers. Overexpression of MCL1 prevents cancer cells from undergoing apoptosis. Studies have shown that MCL1 inhibitors can be used to treat cancer. Although compounds that inhibit MCL1 have been disclosed, there remains a need for synthetic methods for preparing such compounds on a production scale.

[0004] International Application No. PCT / US2019 / 032053 (WO 2019 / 222112) discloses novel compounds useful as MCL1 inhibitors. This patent publication includes compounds according to formula (A): [ka] and pharmaceutically acceptable salts thereof are disclosed to be effective as inhibitors of MCL1 and useful in the treatment of cancer.

[0005] Currently, there is a need for synthetic methods and intermediates that can be used to prepare compounds of Formula I and their salts. There is also a need for methods for preparing intermediate compounds that can be used to prepare compounds of Formula I and their salts. Summary of the Invention

[0006] The present disclosure provides methods for making a compound according to formula (A) as shown above. In some embodiments, the present disclosure provides a compound according to formula (I): [ka] (In the formula, [ka] is a single or double bond; R 12 is hydrogen or -C(O)R 1 and; R 1 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -OR 7 , or -NR 8 R 9 and the C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl optionally contain 1 to 5 R 10 substituted with a group; R 2 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 cycloalkyl, or 3- to 12-membered heterocycloalkyl, 1~6 Alkyl, C1~6 Haloalkyl, C 3~10 Cycloalkyl and 3- to 12-membered heterocycloalkyl optionally contain 1 to 5 R 10 substituted with a group; R 3 is hydrogen, C 1~6 Alkyl, -OR 7 , C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 3- to 12-membered heterocycloalkyl, -C(O)R 7 , or -CN, and the C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl and 3- to 12-membered heterocycloalkyl optionally contain 1 to 5 R 10 substituted with a group; R 4 is hydrogen; R 5 is C 1~6 Alkyl, -(CH2CH2O) p R 7 , C 1~6 Haloalkyl, or C 3~10 is cycloalkyl, and the C 1~6 Alkyl, C 1~6 Haloalkyl, or C 3~10 Cycloalkyl optionally has 1 to 5 R 10 substituted with a group; R 6 is hydrogen or halogen; Each R 7 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl optionally contain 1 to 5 R 10 substituted with a group; Each R 8 and R9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocycle together with the atom to which they are bonded, and the C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl optionally contain 1 to 5 R 10 substituted with a group; Each R 10 independently, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -S(O) q R a , -S(O)NR a R b , -NR a S(O)2R b , -N3, -CN, or -NO2, or two R 10 The group is a fused, spiro, or bridged C 3~10 cycloalkyl or 3- to 12-membered heterocycloalkyl, 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6Alkynyl, C 3~10 Cycloalkyl, C 6~10 The aryl, 3- to 12-membered heterocycle, and 5- to 10-membered heteroaryl may optionally have 1 to 5 R 20 substituted with a group; Each R a and R b are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or R a and R b form a 3- to 12-membered heterocycloalkyl together with the atom to which they are attached, and the C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 The aryl and 5- to 10-membered heteroaryl may optionally contain 1 to 5 R 20 substituted with a group; Each R 20 independently, C 1~6 Alkyl, C3- 10 Cycloalkyl, C1-6 haloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, hydroxyl, C 1~6 Alkoxy, amino, -CN, -C(O)H, -C(O)NH2, -C(O)NH(C- 1~6 alkyl), -C(O)N(C- 1~6 alkyl), -COOH, -C(O)C 1~6 Alkyl, -C(O)OC 1~6 alkyl, or halogen; p is 0, 1, or 2; q is 0, 1, or 2) and pharmaceutically acceptable salts thereof. In some embodiments, the compound of Formula I is a compound according to Formula Ia: [ka]

[0007] In certain embodiments, the present disclosure provides a method of making Compound 1: [ka]

[0008] Compounds of Formula A (and Formulas I and I(a)) can be roughly divided into four functional regions, each separated by one of four key synthetic bonds (dotted lines), as shown below: [ka]

[0009] Thus, compounds of Formula A (and Formulas I and I(a)) can be considered to contain four main submoieties: a tetracyclic core (TC), specifically a 6'-substituted-3,4-dihydro-2H,2'H,4H-5λ 2 -spiro[benzo[b][1,4]oxazepane-3,1'-naphthenylene-7-acyl moiety; disubstituted cyclobutane moiety (CB); polysubstituted sulfonimidamide moiety (SNO); and sn N-linked side chain (SC).

[0010] In this structure, the TC and CB moieties are connected by a single N-C alkylamine bond (numbered 1), the TC and SNO moieties are connected by a single N-C acylamido bond (numbered 2), the CB and SNO moieties are connected by a C-C alkyl or C=C alkenyl bond (numbered 3), and the SC and SNO moieties are connected by an R 12 Depending on the identity of the , they are connected by an N-H or N-C single bond (numbered 4).

[0011] WO 2019 / 222112 discloses a process for preparing compounds of Formula A (including Formulas I and I(a)). In this process, key synthetic bonds are formed in the order 1, 2, 4, and then 3. Thus, the process can be roughly abbreviated as follows: [ka]

[0012] In this nomenclature, when discussing synthetic routes that build and connect key fragments stepwise, it is understood that there may be protecting groups and other temporary substituents present in many intermediates that do not match the ultimate substituents or structural motifs found in the final compound of formula A. The process disclosed in WO 2019 / 222112 [ka]

[0013] Disclosed herein are methods for making compounds of Formula A (e.g., compounds of Formula I or I(a)), as well as methods for making key intermediates therefor. Specifically, in some embodiments, a method for making a compound of Formula A (e.g., compounds of Formula I or I(a)), in which key synthetic bonds are formed in one or more of the following order: 1, 2, 3, then 4; 2, 1, 3, then 4; 1, 2, 4, then 3; 2, 1, 4, then 3; 2, 3, 1, then 4; or 3, 2, 1, then 4; with the proviso that when the order of the key synthetic bond formation steps is 1, 2, 3, 4, the process can proceed to intermediate 1-J or 1-K (wherein R 5 This does not include the use of

[0014] In some embodiments, the fragment TC is fully formed before being incorporated into the process steps described above. In other embodiments, the fragment TC is first prepared as a bicyclic phenoxy fragment, carried through one or more steps in a protected state, and subsequently subjected to deprotection and ring closure to form the tetracyclic TC fragment. For example, [ka] (wherein PG represents a protected aldehyde, for example, PG is CH(OC) 1~6 alkyl)(OC) 1~6alkyl) or -O(C 2~10 alkyl)O-). DETAILED DESCRIPTION OF THE INVENTION

[0015] Thus, in a first aspect, the present disclosure provides a method (Method A) for making a compound of Formula A above (e.g., a compound of Formula I or I(a)), the method comprising the steps of: (a) (1) synthesizing fragment TC (or BC); (2) synthesizing fragment CB; (3) joining fragment TC (or BC) to fragment CB by forming bond 1; (4) synthesizing fragment SNO; (5) joining fragment TC-CB (or BC-CB) to fragment SNO by forming bond 2; (6) connecting the CB and SNO portions of the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 3 intramolecularly; and (7) joining the SC portion to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4 to form a compound of formula A; provided that in the process, the TC-CB fragment, i.e., a compound of formula intermediate 1-J or 1-K as defined herein (wherein R 5 is H) is not at any time, or (b) (1) synthesizing fragment SNO; (2) synthesizing fragment TC (or BC); (3) joining fragment SNO to fragment TC (or BC) by forming bond 2; (4) synthesizing fragment CB; (5) joining fragment TC-SNO (or BC-SNO) to fragment CB by forming bond 1; (6) connecting the CB and SNO portions of the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 3 intramolecularly; and (7) joining the SC portion to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4 to form a compound of formula A; or (c) (1) synthesizing fragment TC (or BC); (2) synthesizing fragment CB; (3) joining fragment TC (or BC) to fragment CB by forming bond 1; (4) synthesizing fragment CNO; (5) joining fragment TC-CB (or BC-CB) to fragment CNO by forming bond 2; (6) joining the SC portion to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4; and (7) connecting the CB and SNO portions of the SC-SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 3 intramolecularly to form a compound of formula A; or (d) (1) synthesizing fragment SNO; (2) synthesizing fragment TC (or BC); (3) joining fragment SNO to fragment TC (or BC) by forming bond 2; (4) synthesizing fragment CB; (5) joining fragment TC-SNO (or BC-SNO) to fragment CB by forming bond 1; (6) joining the SC portion to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4; and (7) joining SC-SNO-TC-CB by forming bond 3 within the molecule. connecting the CB and SNO moieties of the B (or SC-SNO-BC-CB) fragment to form a compound of formula A; or (e) (1) synthesizing fragment TC (or BC); (2) synthesizing fragment SNO; (3) joining fragment TC (or BC) to fragment SNO by forming bond 2; (4) synthesizing fragment CB; (5) joining fragment TC-SNO (or BC-SNO) to fragment CB by forming bond 3; (6) connecting the CB and SNO portions of the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 2 intramolecularly; and (7) joining the SC portion to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4 to form a compound of formula A; or (f) (1) synthesizing fragment SNO; (2) synthesizing fragment CB; (3) joining fragment SNO to fragment CB by forming bond 3; (4) synthesizing fragment TC (or BC); (5) joining fragment SNO-CB to fragment TC (or BC) by forming bond 2; (6) connecting the CB and TC (or BC) portions of the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 1 intramolecularly; and (7) joining the SC portion to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4 to form a compound of formula A; Optionally, any of the foregoing processes further comprise converting any intermediate comprising fragment BC to the same intermediate comprising fragment TC, for example; If fragment SNO is joined to fragment BC by forming bond 2 in step (3) (e.g., in process (b) or process (d)), fragment SNO-BC may be converted to fragment SNO-TC in step (3') followed by the remaining steps; or If (e.g., in process (f)) in step (5) fragment SNO-CB is joined to fragment BC to form fragment SNO-BC-CB, then in step (5') fragment SNO-BC-CB may be converted to fragment SNO-TC-CB (without bond 1) followed by the remaining steps, or in step (6') fragment SNO-BC-CB may be converted to fragment SNO-TC-CB (with bond 1) followed by the remaining steps; (Wherein fragment BC is [ka] and the fragment TC is [ka] and the fragment CB is [ka] and the fragment SNO is [ka] and the fragment SC is R 12 PG is a protecting group (e.g., CH(OC) 1~6 alkyl)(OC 1~6 alkyl) or -O(C 2~10 alkyl)O—), and All other substituents are as defined herein for compounds of formula A).

[0016] In some embodiments, the product of Method A is Compound I, Compound I(a), or Compound 1, as defined herein. In some embodiments, Method A can include one or more steps, in any order and in any combination, as provided in any embodiment of Method 1, Method 2, Method 3, Method 4, and Method 5 herein.

[0017] In a second aspect, the present disclosure provides a method (Method 1) for making a compound selected from one or more of the above compounds 1-B, 1-C, 1-D, 1-E, 1-F, 1-G, 1-H, 1-I, 1-J, 1-K, 2-B, 2-C, 2-D, 2-E, 3-A, 3-B, 3-C, 3-D, 9-A, 9-B, 9-C, 9-D, 9-E, and compound I or I(a), comprising reacting a precursor compound with one or more reagents in a suitable solvent for a time and under conditions effective to form a product compound. Method 1 generally comprises the step of reacting a precursor compound with one or more reagents in a suitable solvent for a time and under conditions effective to form a product compound. Method 1 generally comprises the step of reacting a precursor compound with one or more reagents in a suitable solvent for a time and under conditions effective to form a product compound. ), and the evolution of these intermediates to Compound 1. Without being limited to the order or combination of steps used, possible embodiments of Method 1 can include any of the steps shown in Schemes 1, 2, and 3. [ka] [ka]

[0018] In certain embodiments, the present disclosure provides Method 1 as follows: 1.1 Method 1, comprising reacting compound 1-A with a suitable protecting reagent in a suitable solvent, optionally with a suitable base and / or catalyst, for a time and under conditions effective to provide compound 1-B, wherein R' is C 1~6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, or t-butyl), optionally where R' is methyl; 1.2 The substituent PG is a silyl group, an alkylcarbonyl group (e.g., -C(=O)-C 1~6 alkyl (e.g., acetyl, isobutyryl, pivaloyl, adamantanecarbonyl), arylcarbonyl (e.g., benzoyl), alkoxycarbonyl (e.g., -C(=O)-OC 1~6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl), aryloxycarbonyl groups (e.g., phenoxycarbonyl), tertiary alkyl groups (e.g., t-butyl or trityl), alkoxyalkyl groups (e.g., methoxymethyl or ethoxymethyl), or C 1~6 Method 1.1, wherein the alkylaryl group is selected from alkylaryl groups (e.g., benzyl, 3,5-dimethoxybenzyl); 1.3 Method 1.2, wherein the substituent PG is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., t-butyldiphenylsilyl), and triarylsilyl groups (e.g., triphenylsilyl); 1.4 Method 1.3, wherein the substituent PG is a tert-butyldiphenylsilyl group, and optionally the protecting agent is tert-butyldiphenylsilyl chloride; 1.5 The protecting reagent may be a silyl chloride (e.g., chlorotrimethylsilane, chlorotriethylsilane, chlorotripropylsilane, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, chlorodimethylphenylsilane, chlorotriphenylsilane), a silyl trifluoromethanesulfonate (e.g., trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate), bromotrimethylsilane, bromotriethylsilane, bromotripropylsilane, triisopropylsilyl bromide, tert-butyldimethylsilyl bromide, bromodimethylphenylsilane, bromotriphenylsilane), N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-( any of Methods 1.1-1.4, wherein the alkoxy group is selected from (trimethylsilyl)trifluoroacetamide, benzyl halides (e.g., 3,5-dimethoxybenzyl chloride, 3,5-dimethoxybenzyl bromide), dibenzyl carbonate, acid chlorides (e.g., pivaloyl chloride, 1-adamantanecarbonyl chloride), anhydrides (e.g., di-tert-butyl carbonate), chloroformates (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate), alkyl chlorides (e.g., trityl chloride), and alkoxymethyl chlorides (e.g., methoxymethyl chloride); 1.6 Any of Methods 1.1-1.5, wherein the reaction includes a base; 1.7 Method 1.6, wherein the base is selected from tertiary amines (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, 1-methylimidazole), and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monobasic, dibasic, or tribasic), sodium phosphate (monobasic, dibasic, or tribasic)); 1.8 Method 1.7, wherein the base is triethylamine; 1.9 Any of Methods 1.1-1.8, wherein the reaction includes a catalyst; 1.10 Method 1.9, wherein the catalyst is selected from 4-(dimethylamino)pyridine, N-methylimidazole, 4-pyrrolidinopyridine, 4-piperidinopyridine, and 9-azajulolidine; 1.11 Method 1.10, wherein the base is 4-(dimethylamino)pyridine; 1.12 Any of Methods 1.1-1.11, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent; 1.13 Method 1.12, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.14 Method 1.12, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, and a nitrile (e.g., acetonitrile); 1.15 Method 1.12, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane; 1.16 Any of Methods 1.1 to 1.15, wherein the reaction temperature is −30 to 40° C., for example, −10 to 30° C. or about 0 to 25° C.; 1.17 Method 1, or any of 1.1-1.16, comprising reacting compound 1-B with an organometallic reagent in a suitable solvent for a time and under conditions effective to form 1-hydroxycyclopropane compound 1-C, where R' is defined as in Method 1.1 and PG is defined as provided in Methods 1.2, 1.3, or 1.4; 1.18 Substituent R x But H, C 1~6 Alkyl (e.g., methyl), and C 6~10 aryl (e.g., phenyl), and alkyl is optionally selected from C 6~10 aryl (e.g., phenyl) substituted, Method 1.17; 1.19 R x ,where H is,Method 1.18; 1.20 Organometallic reagents are often used in combination with organolithium reagents (e.g., C 1~6 alkyllithium) or Grignard reagents (e.g., C 1~6 alkylmagnesium halide), Methods 1.17, 1.18, or 1.19; 1.21 The organometallic reagent is selected from ethylmagnesium bromide, ethylmagnesium chloride, n-propylmagnesium bromide, and 2-phenylethylmagnesium bromide, each optionally provided as a solution in an ethereal solvent (e.g., tetrahydrofuran, methyl tert-butyl ether, diethyl ether, dibutyl ether, dioxane). , method 1.20; 1.22 Any of methods 1.17-1.21, wherein the reaction further comprises a transition metal promoter, such as a titanium(IV) compound; 1.23 Method 1.22, wherein the promoter is a titanium(IV) alkoxide (e.g., titanium(IV) methoxide, titanium(IV) ethoxide, titanium(IV) propoxide, titanium(IV) isopropoxide, or titanium(IV) butoxide); 1.24 Any of Methods 1.20-1.23, wherein the organometallic reagent is ethylmagnesium bromide and the promoter is titanium(IV) isopropoxide; 1.25 Any of Methods 1.17-1.24, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent; 1.26 Method 1.25, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene); 1.27 Method 1.25, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, and a nitrile (e.g., acetonitrile); 1.28 Method 1.25, wherein the non-polar solvent is an ethereal solvent, optionally the solvent is tetrahydrofuran; 1.29 Any of Methods 1.17 to 1.28, wherein the reaction temperature is −20 to 30° C., for example, −5 to 15° C. or about 0 to 5° C.; 1.30 Compound 1-C is reacted in a suitable solvent to form beta-haloketone compound 1-D, where PG is defined as provided in Method 1.2, 1.3, or 1.4, and R x with a halogenating agent for a time and under conditions effective to form (wherein R is defined as in Method 1.18 or 1.19); 1.31 Method 1.30, wherein the substituent X is selected from bromo, chloro, and iodo; 1.32 Method 1.31 where X is bromo; 1.33 Method 1.30, 1.31, or 1.32, wherein the halogenating agent is selected from N-bromosuccinimide, N-bromophthalimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosaccharin, hypobromous acid, N-chlorophthalimide, N-chlorosuccinimide, N-chlorosaccharin, 1,3-dichloro-5,5-dimethylhydantoin, N-iodosuccinimide, N-iodophthalimide, and iodine; 1.34 Method 1.33, wherein the halogenating agent is selected from N-bromosuccinimide, N-bromophthalimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosaccharin, and hypobromous acid; 1.35 Method 1.34, wherein the halogenating agent is N-bromosuccinimide; 1.36 Any of Methods 1.30-1.35, wherein the suitable solvent is a non-polar solvent; 1.37 Method 1.36, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.38 Method 1.37, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane; 1.39 Any of Methods 1.30 to 1.38, wherein the reaction temperature is −20 to 30° C., for example, −5 to 15° C. or about 0 to 5° C.; 1.40 Any of Methods 1.30-1.39, wherein compound 1-C is mixed (e.g., stirred or agitated) with a halogenating agent in a suitable solvent for 0.25-5 hours, e.g., 0.5-3 hours, or 1-2 hours, or about 1.5 hours; 1.41 Compound 1-D is reacted with an alpha, beta-unsaturated ketone compound 1-E (wherein PG is defined as provided in Method 1.2, 1.3, or 1.4, and R xis defined as in Method 1.18 or 1.19, and X is chloro, bromo, or iodo; 1.42 Method 1.41, in which the base is selected from tertiary amines (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, DABCO), and aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, 1-methylimidazole); 1.43 Method 1.42, wherein the base is selected from triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and 1,8-diazabicyclo[5.4.0]undec-7-ene; 1.44 Method 1.43, in which the base is triethylamine; 1.45 Any of Methods 1.41-1.44, wherein the suitable solvent is a non-polar solvent; 1.46 Method 1.45, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.47 Method 1.46, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane; 1.48 Any of Methods 1.41 to 1.47, wherein the reaction temperature is −20 to 30° C., for example, −5 to 15° C. or about 0 to 5° C.; 1.49 Any of Methods 1.30-1.48, wherein the conversion of Compound 1-C to Compound 1-D and the conversion of Compound 1-D to Compound 1-E are carried out sequentially in the same vessel without isolating Compound 1-D; 1.50 The alpha, beta-unsaturated ketone compound 1-E is reacted with the allylic alcohol compound 1-F and its stereoisomer 1-F' (wherein PG is defined as provided in Method 1.2, 1.3, or 1.4, and R x is defined as in Method 1.18 or 1.19); 1.51 Method 1.50, wherein the reduction is carried out by reacting compound 1-E with a reducing agent and a Lewis acid catalyst in a suitable solvent; 1.52 Method 1.51, in which the reducing agent is selected from borane agents (e.g., borane, borane complexes [e.g., BH3-THF, BH3-DMS, BH3-CBS], 9-BBN), borohydride agents (e.g., sodium borohydride, lithium borohydride, lithium triethylborohydride), aluminum hydride agents (e.g., lithium aluminum hydride, diisobutylaluminum hydride), transfer hydrogenation agents (e.g., RuCl[(R,R)-Tsdpen](p-cymene), RuCl[(S,S)-Tsdpen](p-cymene) with a hydrogen source (e.g., isopropanol), aluminum alkoxide agents in alcoholic solvents (e.g., aluminum triisopropoxide in ethanol), and reducing enzymes (e.g., ketoreductases); 1.53 Method 1.52, in which the reducing agent is sodium borohydride; 1.54 Method 1.51, 1.52, or 1.53, wherein the Lewis acid is selected from cerium(III) chloride, magnesium bromide, magnesium chloride, magnesium iodide, calcium chloride, calcium bromide, and calcium iodide; 1.55 Method 1.54, wherein the Lewis acid is cerium(III) chloride, e.g., cerium(III) chloride heptahydrate or anhydrous cerium(III) chloride; 1.56 Any of Methods 1.50-1.55, wherein the suitable solvent is a polar protic solvent or a non-polar solvent; 1.57 Method 1.56, in which the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol, butanol); 1.58 Method 1.56, in which the non-polar solvent is an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), a hydrocarbon solvent (e.g., toluene, n-hexane, n-heptane), or a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.59 Method 1.56, in which the solvent is ethanol; 1.60 Any of Methods 1.50 to 1.59, wherein the reaction temperature is −30 to 30° C., for example, −20 to 20° C. or −10 to 0° C.; 1.61 Any of Methods 1.50-1.60, wherein Products 1-F and 1-F' are not separated prior to the next step in the method; 1.62 Any of Methods 1.50-1.60, wherein products 1-F and 1-F' are separated prior to the next step in the method; 1.63 A method comprising treating a mixture of allylic alcohol compounds 1-F and 1-F′ with an acyl donor and an esterase enzyme, wherein PG is defined as provided in Method 1.2, 1.3, or 1.4, and R x is defined as in Method 1.18 or 1.19, and the acyl donor is an ester of an acid of formula RCOOH; 1.64 Method 1.63, in which an esterase enzyme selectively esterifies the (R)-allylic alcohol moiety of compound 1-F' to form ester 1-F''; 1.65 Method 1.64, wherein the esterase is a bacterial esterase, e.g., Pseudomonas stutzeri lipase; 1.66 R, H, C 1~6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), haloC 1~6 Alkyl (e.g., trifluoromethyl, trichloromethyl), C 1~6Method 1.63, 1.64, or 1.65, wherein the aryl is selected from alkyl carboxylate (e.g., 3-propionate, 4-butyrate), optionally substituted aryl (e.g., phenyl, 4-bromophenyl), and optionally substituted heteroaryl (e.g., 2-pyridyl); 1.67 Any of Methods 1.63-1.66, wherein the acyl donor is a vinyl ester, isopropenyl ester, methyl ester, ethyl ester, 2,2,2-trifluoroethyl ester, 2,2,2-trichloroethyl ester, or methoxyvinyl ester of an acid RCOOH, or an anhydride of an acid RCOOH (including mixed and unmixed linear anhydrides and cyclic anhydrides of dicarboxylic acids), and R is defined as in Method 1.66; 1.68 Method 1.67, wherein the acyl donor is selected from succinic anhydride, vinyl acetate, isopropenyl acetate, ethyl acetate, isopropyl acetate, acetic anhydride, 2,2,2-trifluoroethyl acetate, 2,2,2-trichloroethyl acetate, methoxyvinyl acetate, vinyl propionate, vinyl valerate, vinyl isobutyrate, vinyl trifluoroacetate, vinyl trichloroacetate, vinyl benzoate, 4-bromovinyl acetate, vinyl picolinate, glutaric anhydride, vinyl formate, vinyl butyrate, and butyric anhydride; 1.69 Any of Methods 1.63-1.68, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent; 1.70 Method 1.69, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane) and hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane); 1.71 Method 1.69, in which the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, and a nitrile (e.g., acetonitrile); 1.72 The non-polar solvent is an ethereal solvent, optionally the solvent is methyl tert-butyl ether. t-butyl ether, Method 1.69; 1.73 Any of Methods 1.63-1.72, wherein the reaction temperature is 0-50°C, e.g., 10-30°C or about 20°C; 1.74 Any of Methods 1.63-1.73, wherein upon completion of the reaction, the product mixture is purified to isolate compound 1-F and / or remove and discard compound 1-F″; 1.75 Compound 1-F is reacted in a suitable solvent to form ether compound 1-G (where PG is defined as provided in Method 1.2, 1.3, or 1.4, and R x is defined as in Method 1.18 or 1.19, and R 5 is C 1~6 Alkyl, -(CH2CH2O) p R 7 , C 1~6 Haloalkyl, and C 3~10 cycloalkyl, wherein C 1~6 Alkyl, C 1~6 Haloalkyl, or C 3~10 Cycloalkyl optionally contains 1 to 5 R 10 substituted with a group (R 7 and R 10 with an alkylating agent, and optionally a base, for a time and under conditions effective to form (wherein R is as defined for compounds of Formula I); 1.76 R 5 But C 1~6 Alkyl and C 1~6 haloalkyl, each optionally selected from halogen, oxo, C 3~6 Method 1.75, substituted with 1 to 3 groups selected from cycloalkyl, and 4- to 6-membered heterocycloalkyl; 1.77 R 5 C optionally substituted with 1 to 3 halogens (e.g., fluoro) 1~6 alkyl (e.g., methyl, ethyl, isopropyl, propyl, tert-butyl), Method 1.76; 1.78 R 5 is methyl, Method 1.77; 1.79 An alkylating agent is a compound of formula R 5-X (wherein X is Cl, Br, I, OS(O)OR 5 and OSO2-L (wherein L is C 1~6 alkyl, optionally substituted aryl, or haloC 1~6 any of methods 1.75-1.78, wherein the compound is selected from the group consisting of alkyl; 1.80 Method 1.79, wherein the alkylating agent is selected from alkyl bromides, alkyl chlorides, alkyl iodides, alkyl triflates, alkyl tosylates, alkyl mesylates, alkyl nosylates, alkyl benzene sulfonates, and dialkyl sulfates; 1.81 Method 1.80, wherein the alkylating agent is selected from methyl iodide, methyl triflate, methyl tosylate, and dimethyl sulfate; 1.82 Any of methods 1.75-1.81, wherein the reaction further comprises a base selected from an inorganic hydride (e.g., sodium hydride, potassium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, or lithium hydroxide), and an amide base (e.g., sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, or potassium diisopropylamide); 1.83 Method 1.82, in which the base is sodium t-butoxide; 1.84 Any of Methods 1.75-1.83, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent; 1.85 Method 1.84, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene); 1.86 Method 1.84, wherein the polar protic solvent is an alcohol solvent (e.g., tert-butanol or tert-amyl alcohol), optionally in combination with water; 1.87 Polar aprotic solvents include N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and dichloromethane, optionally in combination with water. methyl sulfoxide, Method 1.84; 1.88 Method 1.84, where the preferred solvent is tetrahydrofuran; 1.89 Any of Methods 1.75 to 1.88, wherein the reaction temperature is −80 to 50° C., e.g., −45 to 10° C., or −10° C. to 10° C., or about 0° C.; 1.90 Compound 1-G is reacted with alcohol Compound 1-H (wherein PG is defined as provided in Method 1.2, 1.3, or 1.4, and R x is defined as in Method 1.18 or 1.19, and R 5 Method 1, or any of Methods 1.1-1.89, comprising treating with a deprotecting reagent for a time and under conditions effective to form a 2-amino-2-methyl-1-propanol group (wherein 1.91 R 5 C optionally substituted with 1 to 3 halogens (e.g., fluoro) 1~6 alkyl (e.g., methyl, ethyl, isopropyl, propyl, tert-butyl), Method 1.90; 1.92 R 5 is methyl, ethyl, or isopropyl, and optionally R 5 is methyl, Method 1.91; 1.93 Any of methods 1.90-1.92, wherein the deprotecting reagent is selected from an inorganic base (e.g., an aqueous solution thereof), an acid (e.g., an aqueous or organic solvent solution thereof), a fluoride agent (e.g., in an organic solvent), a hydrogenation agent (e.g., hydrogen in combination with a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex), or a phase transfer hydrogenation system), optionally further comprising a phase transfer agent; 1.94 Any of methods 1.90-1.93, wherein the deprotecting reagent is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrochloric acid (e.g., aqueous HCl, HCl in ether, HCl in methanol, HCl in isopropanol), sulfuric acid, acetic acid, trifluoroacetic acid, phosphoric acid, methanesulfonic acid, 4-toluenesulfonic acid, hydrofluoric acid, pyridine hydrogen fluoride, triethylamine hydrogen fluoride, potassium fluoride, sodium fluoride, lithium fluoride, cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, hydrogen in combination with a catalyst (e.g., Pd, Pd / C, Pt, Ru / C, Raney nickel, Ru complexes, Rh complexes, PtO2, Pt complexes, Pd complexes, Ir complexes), and ammonium formate in combination with a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt, PtO2); 1.95 Any of Methods 1.90-1.94, wherein the substituent PG is a silyl group and the deprotecting agent is a fluoride agent; 1.96 Method 1.95, wherein the substituent PG is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., t-butyldiphenylsilyl), and triarylsilyl groups (e.g., triphenylsilyl), and the deprotecting reagent is selected from hydrofluoric acid, hydrogen fluoride pyridine, hydrogen fluoride triethylamine, potassium fluoride, sodium fluoride, lithium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, and tetrabutylammonium fluoride; 1.97 Method 1.96, wherein the substituent PG is tert-butyldiphenylsilyl and the deprotecting agent is selected from tetramethylammonium fluoride, tetraethylammonium fluoride, and tetrabutylammonium fluoride; 1.98 Any of Methods 1.90-1.97, wherein the suitable solvent is a non-polar solvent, a polar protic solvent, or a polar aprotic solvent; 1.99 Method 1.98, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.100 The polar protic solvent is an alcohol solvent ( Method 1.98, where the polar protic solvent is water, or the polar protic solvent is methanol, ethanol, propanol, isopropanol, tert-butanol, tert-amyl alcohol; 1.101 Method 1.98, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide, optionally in combination with water; 1.102 Method 1.98, where the preferred solvent is tetrahydrofuran; 1.103 Any of Methods 1.90 to 1.102, wherein the reaction temperature is −15 to 50° C., for example, −5 to 40° C., or 0 to 30° C., or 10 to 30° C.; 1.104 Compound 1-H is treated with an oxidizing agent in a suitable solvent to give aldehyde compound 1-I (wherein R x is defined as in Method 1.18 or 1.19, and R 5 Method 1 or any of Methods 1.1-1.103, comprising forming a crystalline solid (a crystalline solid, wherein the crystalline solid is defined as in any of Methods 1.75-1.78); 1.105 Method 1.104, wherein the reaction further comprises an additive, a catalyst, and / or a base; 1.106 Method 1.104 or 1.105, wherein the oxidizing agent is selected from sodium hypochlorite, sulfur trioxide / pyridine, dimethyl sulfoxide / oxalyl chloride, DMSO / acetic anhydride, DMSO / trifluoroacetic anhydride, diacetoxyiodobenzene (DAIB), tetrapropylammonium perruthenate (TPAP) / N-methylmorpholine oxide, Dess-Martin periodinane, pyridinium chlorochromate, N-chlorosuccinimide / dimethyl sulfide, iodosylbenzene, DMSO / dicyclohexylcarbodiimide, bis(trifluoroacetoxy)iodobenzene, and manganese dioxide; 1.107 Method 1.106, wherein the oxidizing agent is selected from diacetoxyiodobenzene (DAIB), Dess-Martin periodinane, iodosylbenzene, and bis(trifluoroacetoxy)iodobenzene; 1.108 Method 1.107, in which the oxidizing agent is diacetoxyiodobenzene (DAIB); 1.109 Any of methods 1.104-1.108, wherein the reaction further comprises a catalyst selected from TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl), 4-hydroxy-TEMPO, polymer-supported TEMPO, 2-azaadamantane N-oxyl, 9-azabicyclo[3.3.1]nonane N-oxyl, and 9-azanoradamantane N-oxyl; 1.110 Any of methods 1.104-1.109, wherein the reaction further comprises an additive selected from sodium bromide, lithium bromide, and potassium bromide; 1.111 Any of methods 1.104-1.110, wherein the reaction further comprises a base selected from inorganic bases (e.g., dibasic sodium phosphate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide) and organic amine bases (e.g., triethylamine, N,N-diisopropylethylamine, pyridine, DBU, DBN); 1.112 Any of methods 1.104-1.109, wherein the oxidant is diacetoxyiodobenzene, the catalyst is TEMPO, and the reaction does not further comprise a base or additive; 1.113 Any of methods 1.104-1.112, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent; 1.114 Method 1.113, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.115 Method 1.113, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide, optionally in combination with water; 1.116 Method 1.113, wherein the preferred solvent is dichloromethane; 1.117 Any of Methods 1.104 to 1.116, wherein the reaction temperature is −80 to 50° C., e.g., −40 to 40° C. or 10 to 30° C.; 1.118 Compound 1-I is reacted with a tertiary amine compound 1-J (wherein R x is defined as in Method 1.18 or 1.19, and R 5 is defined as in any of methods 1.75-1.78, and R z is defined as in any of methods 2.129-2.131, and R 6 wherein R is hydrogen or a halogen. x is H. In one embodiment, R 5 is methyl; 1.119 R 6 is selected from chloro, bromo, fluoro, and iodo; method 1.118; 1.120 R 6 is chloro, Method 1.119; 1.121 Any of methods 1.118-1.120, wherein the reducing agent is selected from hydride reducing agents, silane reducing agents, and zinc in acid (e.g., zinc in acetic acid); 1.122 Method 1.121, in which the reducing agent is a hydride reducing agent; 1.123 Method 1.122, wherein the hydride reducing agent is selected from sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride; 1.124 Method 1.123, wherein the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride; 1.125 Any of methods 1.122-1.124, in which a hydride reducing agent is combined with a reagent to adjust the hydride reduction activity (e.g., titanium isopropoxide, magnesium perchlorate, or zinc chloride); 1.126 Method 1.121, wherein the reducing agent is selected from silane (such as triisopropylsilane, triphenylsilane, diethylsilane), sodium borohydride, sodium borohydride / acetic acid, sodium triacetoxyborohydride, sodium cyanoborohydride, titanium isopropoxide / sodium cyanoborohydride, zinc / acetic acid, sodium borohydride / magnesium perchlorate, zinc borohydride / zinc chloride, tetramethylammonium triacetoxyborohydride. In one embodiment, the reducing agent is triethylsilane; 1.127 Any of methods 1.121-1.126, wherein the reaction further comprises an acid (e.g., selected from acetic acid, trifluoroacetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid). In one embodiment, the acid is trifluoroacetic acid; 1.128 Any of methods 1.118-1.128, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent; 1.129 Method 1.128, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), acetonitrile, and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.130 Method 1.128, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; 1.131 Method 1.128, wherein the suitable solvent is dichloromethane. In one embodiment, the solvent is acetonitrile; 1.132 Any of methods 1.118-1.131, wherein the temperature of the reaction is −30 to 50° C., e.g., −30 to 0° C., or −30 to −10° C., or about −20° C. In one embodiment, the temperature is −10 to 30° C.; 1.133 Compound 1-J is reacted with carboxylic acid compound 1-K (wherein R x teeth , defined as in Method 1.18 or 1.19, and R 5 is defined as in any of methods 1.75-1.78, and R z is defined as in any of methods 2.129-2.131, and R 6 wherein R is hydrogen or a halogen; 1.134 The reaction may involve treating compound 1-J with an aqueous acid or base solution in an organic and / or aqueous solvent; or treating compound 1-J with an enzyme (e.g., a bacterial or fungal lipase, e.g., a lipase from a Rhizopus species), or treating compound 1-J with magnesium dibromide in a non-polar solvent, or treating compound 1-J with a fluoride source (e.g., hydrofluoric acid, hydrogen fluoride pyridine, hydrogen fluoride triethylamine, potassium fluoride, sodium fluoride) in a non-polar solvent. Method 1.133, which comprises treating compound 1-J with hydrogen in combination with a catalyst (e.g., Pd, Pd / C, Pt, Ru / C, Raney nickel, Ru complexes, Rh complexes, PtO2, Pt complexes, Pd complexes, Ir complexes), or ammonium formate in combination with a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt, PtO2); 1.135 Method 1.134, wherein the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid; 1.136 Method 1.134, wherein the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, tetrabutylammonium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, tetramethylammonium hydroxide, alkoxides (lithium, sodium, potassium, magnesium, or calcium salts of methoxide, ethoxide, isopropoxide, t-butoxide, or t-pentoxide), trimethyltin hydroxide, sodium trimethylsilanolate, potassium trimethylsilanol, and pyridine; 1.137 Any of methods 1.133-1.136, wherein the solvent is selected from one or more of water, alcohols (e.g., methanol, ethanol, isopropanol, propanol, butanol, tert-butanol, tert-amyl alcohol), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, acetonitrile), ethers (e.g., 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.138 Any of methods 1.133-1.137, wherein the temperature of the reaction is from -10 to 100°C, e.g., from 10 to 80°C, or from 20 to 80°C, or from 20 to 50°C. In one embodiment, the temperature is from 20 to 100°C. In one embodiment, the temperature is from 50 to 70°C; 1.139 (1S,5R)-3-oxabicyclo[3.2.0]heptan-2-one (compound 2-A) is reacted with 1-hydroxycyclopropane compound 2-B (wherein the substituent R x is H, C 1~6 Alkyl (e.g., methyl), and C 6~10 with an organometallic reagent for a time and conditions effective to form an alkyl group selected from an optionally substituted aryl (e.g., phenyl) and an alkyl group selected from an optionally substituted aryl (e.g., phenyl); 1.140 R x but H, Method 1.139; 1.141 Organometallic reagents are organolithium reagents (e.g., C 1~6 alkyllithium) or Grignard reagents (e.g., C 1~6 alkylmagnesium halide), method 1.139 or 1.140; 1.142 The organometallic reagents are ethylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium iodide, n-propylmagnesium bromide, and 2-phenylethylmagnesium bromide. magnesium, each optionally provided as a solution in an ethereal solvent (e.g., tetrahydrofuran, methyl tert-butyl ether, diethyl ether, dibutyl ether, dioxane); 1.143 Any of methods 1.139-1.142, wherein the reaction further comprises a transition metal promoter, such as a titanium(IV) compound; 1.144 Method 1.143, in which the promoter is a titanium(IV) alkoxide (e.g., titanium(IV) methoxide, titanium(IV) ethoxide, titanium(IV) propoxide, titanium(IV) isopropoxide, titanium(IV) n-butoxide, titanium(IV) t-butoxide, titanium(IV) benzoxide); 1.145 Any of methods 1.139-1.144, wherein the organometallic reagent is ethylmagnesium bromide and the promoter is titanium(IV) isopropoxide; 1.146 Any of methods 1.139-1.145, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent; 1.147 Method 1.146, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene), or the polar aprotic solvent is a nitrile (e.g., acetonitrile); 1.148 Method 1.147, wherein the nonpolar solvent is an ethereal solvent, optionally the solvent is tetrahydrofuran; 1.149 Any of Methods 1.139 to 1.148, wherein the reaction temperature is −20 to 50° C., for example, −10 to 10° C. or about 0 to 5° C.; 1.150 Compound 2-B is reacted with compound 2-C (wherein R x any of Methods 1, or 1.1 through 1.149, comprising reacting with a suitable protecting reagent for a time and under conditions effective to obtain (as defined as in Method 1.139 or 1.140) 1.151 The substituent PG is a silyl group, an alkylcarbonyl group (e.g., -C(=O)-C 1~6 alkyl (e.g., acetyl, isobutyryl, pivaloyl, adamantanecarbonyl), arylcarbonyl (e.g., benzoyl), alkoxycarbonyl (e.g., -C(=O)-OC 1~6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl), aryloxycarbonyl groups (e.g., phenoxycarbonyl), tertiary alkyl groups (e.g., t-butyl or trityl), alkoxyalkyl groups (e.g., methoxymethyl or ethoxymethyl), and C 1~6 alkylaryl groups (e.g., benzyl, 3,5-dimethoxybenzyl), Method 1.150; 1.152 Method 1.151, in which the substituent PG is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., t-butyldiphenylsilyl), and triarylsilyl groups (e.g., triphenylsilyl); 1.153 Method 1.152, wherein the substituent PG is a tert-butyldiphenylsilyl group, and optionally the protecting agent is TBDPS chloride; 1.154 The protecting reagent is a silyl chloride (e.g., chlorotrimethylsilane, chlorotriethylsilane, chlorotripropylsilane, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, chlorodimethylphenylsilane, or chlorotriphenylsilane), a silyl trifluoromethanesulfonate (e.g., trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, dimethylphenylsilyl trifluoromethanesulfonate), nate, or triphenylsilyl trifluoromethanesulfonate), silyl bromides (e.g., bromotrimethylsilane, bromotriethylsilane, bromotripropylsilane, triisopropylsilyl bromide, tert-butyldimethylsilyl bromide, bromodimethylphenylsilane, or bromotriphenylsilane), N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, benzyl halides (e.g., any of methods 1.150 to 1.153, wherein the alkoxymethyl chloride is selected from, for example, 3,5-dimethoxybenzyl chloride, 3,5-dimethoxybenzyl bromide, dibenzyl carbonate, acid chlorides (e.g., pivaloyl chloride or 1-adamantanecarbonyl chloride), anhydrides (e.g., di-tert-butyl carbonate), chloroformates (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate, or phenyl chloroformate), alkyl chlorides (e.g., trityl chloride), and alkoxymethyl chlorides (e.g., methoxymethyl chloride); 1.155 Any of methods 1.150-1.154, wherein the reaction includes a base; 1.156 Method 1.155, wherein the base is selected from a tertiary amine (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (e.g., pyridine, 2,6-lutidine, collidine, imidazole, or 1-methylimidazole), and an inorganic base (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monobasic, dibasic, or tribasic), or sodium phosphate (monobasic, dibasic, or tribasic)); 1.157 Method 1.156, in which the base is triethylamine; 1.158 Any of methods 1.150-1.157, wherein the reaction involves a catalyst; 1.159 Method 1.158, wherein the catalyst is selected from 4-(dimethylamino)pyridine, 2,6-dimethylpyridine, N-methylimidazole, imidazole, 4-pyrrolidinopyridine, 4-piperidinopyridine, and 9-azajulolidine; 1.160 Method 1.159, wherein the base is 4-(dimethylamino)pyridine; 1.161 Any of methods 1.150-1.160, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent; 1.162 Method 1.161, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, or dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, or n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene); 1.163 Method 1.161, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, and a nitrile (e.g., acetonitrile); 1.164 Method 1.161, wherein the non-polar solvent is a halogenated solvent, and optionally the solvent is dichloromethane; 1.165 Any of methods 1.150 to 1.161, wherein the reaction temperature is −30 to 40° C., e.g., −10 to 30° C. or 0 to 25° C.; 1.166 Compound 2-C is reacted in a suitable solvent with beta-haloketone compound 2-D, where PG is defined as in any of methods 1.151-1.153, and R x with a halogenating agent for a time and under conditions effective to form (wherein R is defined as in Method 1.139 or 1.140); 1.167 Method 1.166, wherein the substituent X is selected from bromo, chloro, and iodo; 1.168 Method 1.167 where X is bromo; 1.169 The halogenating agent is N-bromosuccinimide, N-bromophthalimide, Method 1.166, 1.167, or 1.168, wherein the cation is selected from bromine, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosaccharin, hypobromous acid, N-chlorophthalimide, N-chlorosuccinimide, N-chlorosaccharin, 1,3-dichloro-5,5-dimethylhydantoin, N-iodosuccinimide, N-iodophthalimide, and iodine; 1.170 Method 1.169, wherein the halogenating agent is selected from N-bromosuccinimide, N-bromophthalimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosaccharin, and hypobromous acid; 1.171 Method 1.169, in which the halogenating agent is N-bromosuccinimide; 1.172 Any of methods 1.166-1.171, wherein the suitable solvent is a non-polar solvent; 1.173 Method 1.172, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.174 Method 1.172, wherein the non-polar solvent is a halogenated solvent, optionally the solvent is dichloromethane; 1.175 Any of Methods 1.166 to 1.174, wherein the reaction temperature is −20 to 30° C., e.g., −5 to 15° C. or 0 to 5° C.; 1.176 Any of Methods 1.166-1.175, wherein compound 2-C is mixed (e.g., stirred or agitated) with a halogenating agent in a suitable solvent for 0.1-3 hours, e.g., 0.2-2 hours, or 0.3-1 hour, or about 0.5 hours; 1.177 Compound 2-D is reacted with an alpha, beta-unsaturated ketone compound 2-E (wherein PG is defined as provided in any of Methods 1.151-1.153, and R x is defined as in Method 1.139 or 1.140, and X is chloro, bromo, or iodo), with a base for a time and under conditions effective to form 1.178 Method 1.177, wherein the base is selected from tertiary amines (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, DABCO), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, 1-methylimidazole), and inorganic bases (e.g., alkali metal carbonates such as sodium carbonate, potassium carbonate, and lithium carbonate, alkali metal phosphates such as monobasic, dibasic, or tribasic sodium, potassium, or lithium phosphate); 1.179 Method 1.178, wherein the base is selected from triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and 1,8-diazabicyclo[5.4.0]undec-7-ene; 1.180 Method 1.179, in which the base is triethylamine; 1.181 Any of methods 1.177-1.180, wherein the suitable solvent is a non-polar solvent; 1.182 Method 1.181, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, or dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, or n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene); 1.183 Method 1.182, wherein the non-polar solvent is a halogenated solvent, and optionally the solvent is dichloromethane; 1.184 The reaction temperature is -20 to 30°C, for example, -5 to 15°C or 0 to 5°C. Any of methods 1.177-1.183; 1.185 Any of methods 1.166-1.184, wherein the conversion of compound 2-C to compound 2-D and the conversion of compound 2-D to compound 2-E are carried out sequentially in the same vessel without isolating compound 2-D; 1.186 Compound 2-E is reacted in a suitable solvent to give epimerized alpha, beta-unsaturated ketone compound 1-E (where PG is defined as provided in any of methods 1.151-1.153, and R x Method 1, or any of Methods 1.1 through 1.185, comprising reacting with a promoter for a time and under conditions effective to form a hydroxybenzoate (wherein 1.187 Method 1.186, wherein the accelerator is selected from tertiary amines (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, or DABCO), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, or 1-methylimidazole), inorganic bases (e.g., alkali metal carbonates such as sodium carbonate, potassium carbonate, and lithium carbonate, or alkali metal phosphates such as monobasic, dibasic, or tribasic sodium, potassium, or lithium phosphates), inorganic halides (e.g., lithium chloride, magnesium bromide, magnesium chloride), and acids (e.g., titanium tetraisopropoxide, benzenesulfonic acid, toluenesulfonic acid, or methanesulfonic acid); 1.188 Method 1.187, wherein the accelerator is selected from triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); 1.189 Method 1.188, in which the accelerator is DBU; 1.190 Any of methods 1.186-1.189, wherein the suitable solvent is a nonpolar solvent, a polar aprotic solvent, or a polar protic solvent; 1.191 Method 1.190, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene); 1.192 Method 1.190, wherein the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile); 1.193 Method 1.190, wherein the polar protic solvent is an alcohol solvent (e.g., methanol, ethanol, propanol, or isopropanol); 1.194 Method 1.190, wherein the non-polar solvent is a halogenated solvent, optionally the solvent is dichloromethane; 1.195 Any of Methods 1.186-1.194, wherein the temperature of the reaction is −10 to 50° C., e.g., 0 to 40° C., or 10 to 30° C., or about 25° C.; 1.196 thiolating compound 1-E by reacting compound 1-E with a thiol and a base in a suitable solvent for a time and under conditions effective to form compound 3-A, wherein PG is defined as provided in Method 1.2, 1.3, or 1.4, and R x is defined as in Method 1.18 or 1.19, or any of Methods 1.1 to 1.195; 1.197 R S optionally replaced by C 1~6 Method 1.196, wherein the alkyl is selected from alkyl (e.g., methyl) and optionally substituted aryl (e.g., phenyl); 1.198 R S But C 1~6 Alkoxy, halogen, C 1~6 C optionally substituted with one or more groups selected from alkyl, and aryl (e.g., phenyl). 1~6 alkyl, and optionally R S is methyl, ethyl, or isopropyl; Method 1.197; 1.199 R S But C 1~6 Alkoxy, halogen, C 1~6 Alkyl and aryl aryl optionally substituted with one or more groups selected from aryl (e.g., phenyl), and optionally R S is phenyl or tolyl, method 1.197; 1.200 R S is 4-tril, Method 1.197; 1.201 Thiol is R S any of methods 1.196-1.200, wherein —SH (e.g., methanethiol, benzenethiol, or 4-methylbenzenethiol); 1.202 Any of methods 1.196-1.201, wherein the base is selected from tertiary amines (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or 1,4-diazabicyclo[2.2.2]octane) and aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, imidazole, or 1-methylimidazole); 1.203 Method 1.202, wherein the base is triethylamine or N,N-diisopropylethylamine; 1.204 Any of methods 1.196-1.203, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent; 1.205 Method 1.204, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, or dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene); 1.206 Method 1.204, wherein the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, or isopropyl acetate) and nitriles (e.g., acetonitrile); 1.207 Method 1.204, wherein the non-polar solvent is a halogenated solvent, and optionally the solvent is dichloromethane; 1.208 Any of Methods 1.196-1.207, wherein the temperature of the reaction is from -20 to 50°C, e.g., from 0 to 30°C, or from 10 to 20°C, or about 25°C; 1.209 The unsaturated thio compound 3-A is converted into an alcohol compound 3-B, where PG is defined as provided in Method 1.2, 1.3, or 1.4, and R x is defined as in Method 1.18 or 1.19, and R S Method 1 or any of Methods 1.1 to 1.208, comprising reducing to (wherein 1.210 Method 1.209, wherein the reduction is carried out by reacting compound 3-A with a reducing agent and a Lewis acid catalyst in a suitable solvent; 1.211 Method 1.210, wherein the reducing agent is selected from a borane agent (e.g., borane, a borane complex [e.g., BH3-THF, BH3-DMS, BH3-CBS], or 9-BBN), a borohydride agent (e.g., sodium borohydride, lithium borohydride, or lithium triethylborohydride), an aluminum hydride agent (e.g., lithium aluminum hydride, diisobutylaluminum hydride, or lithium tri-t-butoxyaluminum hydride), a transfer hydrogenation agent (e.g., RuCl[(R,R)-Tsdpen](p-cymene), RuCl[(S,S)-Tsdpen](p-cymene) with a hydrogen source (e.g., isopropanol), an aluminum alkoxide agent in an alcohol solvent (e.g., aluminum triisopropoxide in ethanol), and a reducing enzyme (e.g., ketoreductase); 1.212 Method 1.211, in which the reducing agent is sodium borohydride; 1.213 Any of methods 1.209-1.212, wherein the Lewis acid is selected from cerium(III) chloride, magnesium bromide, magnesium chloride, magnesium iodide, calcium chloride, calcium bromide, and calcium iodide; 1.214 Method 1.213, wherein the Lewis acid is cerium(III) chloride, e.g., cerium(III) chloride heptahydrate or anhydrous cerium(III) chloride; 1.215 Method 1.20, wherein the suitable solvent is a polar protic solvent or a non-polar solvent. Any of 9 to 1.214; 1.216 Method 1.215, wherein the suitable solvent is a polar protic solvent, such as an alcohol (e.g., methanol, ethanol, propanol, isopropanol, or butanol); 1.217 Method 1.215, wherein the suitable solvent is a non-polar solvent, such as an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), a hydrocarbon solvent (e.g., toluene, n-hexane, n-heptane), or a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.218 Method 1.215, in which the solvent is ethanol; 1.219 Any of Methods 1.209 to 1.218, wherein the reaction temperature is −30 to 30° C., e.g., −20 to 20° C. or −10 to 10° C.; 1.220 Compound 3-B is reacted in a suitable solvent to form the ether compound 3-C, where PG is defined as provided in Method 1.2, 1.3, or 1.4, and R x is defined as in Method 1.18 or 1.19, and R S is defined as in any of methods 1.197-1.200, and R 5 is hydrogen, C 1~6 Alkyl, -(CH2CH2O) p R 7 , C 1~6 Haloalkyl, and C 3~10 cycloalkyl, wherein C 1~6 Alkyl, C 1~6 Haloalkyl, and C 3~10 Cycloalkyl optionally contains 1 to 5 R 10 substituted with a group (R 7 and R 10 with an alkylating agent and optionally a base for a time and under conditions effective to form (wherein R is as defined for compounds of formula I); 1.221 R 5 But C 1~6 Alkyl and C 1~6 haloalkyl, each optionally selected from halogen, oxo, C 3~6 Method 1.220, substituted with 1 to 3 groups selected from cycloalkyl, and 4- to 6-membered heterocycloalkyl; 1.222 R5 C optionally substituted with 1 to 3 halogens (e.g., fluoro) 1~6 alkyl (e.g., methyl, ethyl, isopropyl, propyl, tert-butyl), Method 1.221; 1.223 R 5 is methyl, Method 1.222; 1.224 The alkylating agent is a compound of formula R 5 -X (wherein X is Cl, Br, I, OS(O)OR 5 and OSO2-L (wherein L is C 1~6 alkyl, optionally substituted aryl, or haloC 1~6 any of methods 1.220 to 1.223, wherein the compound is selected from the group consisting of alkyl; 1.225 Method 1.224, wherein the alkylating agent is selected from alkyl bromides, alkyl chlorides, alkyl iodides, alkyl triflates, alkyl tosylates, alkyl mesylates, alkyl nosylates, alkyl benzene sulfonates, and dialkyl sulfates; 1.226 Method 1.224, wherein the alkylating agent is selected from methyl iodide, methyl triflate, methyl tosylate, and dimethyl sulfate; 1.227 Any of methods 1.220-1.226, wherein the reaction further comprises a base selected from an inorganic hydride (e.g., sodium hydride, potassium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), and an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, or potassium diisopropylamide); 1.228 Method 1.227, in which the base is sodium hydride; 1.229 Any of methods 1.220-1.228, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent; 1.230 Non-polar solvents are ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, Method 1.229, wherein the solvent is selected from hydrocarbon solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene), hydrocarbon solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene); 1.231 Method 1.229, in which the polar protic solvent is an alcohol solvent (e.g., tert-butanol, tert-amyl alcohol), optionally in combination with water; 1.232 Method 1.229, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide, optionally in combination with water; 1.233 Method 1.229, where the preferred solvent is tetrahydrofuran; 1.234 Any of methods 1.220 to 1.233, wherein the reaction temperature is −80 to 50° C., e.g., −45 to 10° C., or −10° C. to 10° C., or 10 to 20° C.; 1.235 Compound 3-C is reacted with N-tosylsulfinimidoyl compound 3-D (wherein R s is defined as per any of Methods 1.197-1.200, PG is defined as per Methods 1.2, 1.3, or 1.4, and R x is defined as in Method 1.18 or 1.19, and R 5 Method 1, or any of Methods 1.1 through 1.234, comprising treating with an S-oxidizing reagent for a time and under conditions effective to form a methyl group (as defined as in any of Methods 1.220 through 1.223); 1.236 R 5 C optionally substituted with 1 to 3 halogens (e.g., fluoro) 1~6alkyl (e.g., methyl, ethyl, isopropyl, propyl, tert-butyl), Method 1.235; 1.237 R 5 is methyl, ethyl, or isopropyl, and optionally R 5 is methyl, Method 1.236; 1.238 Any of methods 1.235 to 1.237, wherein the S-oxidizing agent is selected from N-chloro-4-methylbenzenesulfonamide or a salt thereof, N-chlorobenzenesulfonamide or a salt thereof, (tosylimido)iodobenzene, and p-tosylamido / phenyliodine diacetate; 1.239 Method 1.238, in which the agent is sodium N-chloro-4-methylbenzenesulfonamide (chloramine-T); 1.240 Any of methods 1.235-1.239, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent; 1.241 Method 1.240, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, or n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene); 1.242 Method 1.240, wherein the polar protic solvent is an alcohol solvent (e.g., methanol, ethanol, isopropanol, n-butanol, tert-butanol, or tert-amyl alcohol); 1.243 Method 1.240, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, and a nitrile (e.g., acetonitrile); 1.244 Method 1.240, wherein the preferred solvent is acetonitrile; 1.245 Any of Methods 1.235-1.244, wherein the temperature of the reaction is 0-50°C, e.g., 10-30°C or about 25°C; 1.246 Compound 3-D is pyrolyzed in a suitable solvent to give allyl ether compound 1-G, where PG is defined as provided in Method 1.2, 1.3, or 1.4, and R x is defined as in Method 1.18 or 1.19, and R 5 Method 1 or any of Methods 1.1 through 1.245, comprising forming a crystalline solid (a crystalline solid, wherein the crystalline solid is defined as in any of Methods 1.220 through 1.223); 1.247 R 5 C optionally substituted with 1 to 3 halogens (e.g., fluoro) 1~6 alkyl (e.g., methyl, ethyl, isopropyl, propyl, or tert-butyl), Method 1.246; 1.248 R 5 is methyl, ethyl, or isopropyl, and optionally R 5 is methyl, Method 1.247; 1.249 Any of methods 1.246-1.248, in which heat is applied in the absence of any chemical reagent; 1.250 Any of methods 1.246-1.249, wherein the suitable solvent is a non-polar solvent, a polar protic solvent, or a polar aprotic solvent, optionally wherein the solvent has a boiling point of at least 60°C; 1.251 Method 1.250, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-heptane), and halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene); 1.252 Method 1.250, wherein the polar protic solvent is an alcohol solvent (e.g., methanol, ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, or any mixture thereof); 1.253 Method 1.250, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, nitriles (e.g., acetonitrile), and esters (e.g., ethyl acetate, methyl acetate, or isopropyl acetate); 1.254 Method 1.250, wherein the preferred solvent is isopropyl acetate; 1.255 Any of methods 1.246-1.254, wherein the temperature of the reaction is 70-150°C, e.g., 80-100°C or about 90°C; 1.256 Method 1 or any of Method 1.255, wherein a compound according to any one or more of Compounds 1-B, 1-C, 1-D, 1-E, 1-F, 1-G, 1-H, 1-I, 1-J, or 1-K is produced; 1.257 In one or more of the compounds, R' is methyl and R x is H, X is Cl or Br (e.g., Br), PG is trialkylsilyl or dialkylarylsilyl (e.g., TBDPS), and R z But C 1~3 alkyl (e.g., methyl), and R 5 But C 1~3 alkyl (e.g., methyl), and / or R 6 is a halogen (e.g., chloro); method 1.256; 1.258 Method 1 or any of Methods 1.1 through 1.257, wherein a compound is produced by any one or more of Compounds 2-B, 2-C, 2-D, or 2-E; 1.259 In one or more of the compounds, R x is H, PG is trialkylsilyl or dialkylarylsilyl (e.g., TBDPS), and / or X is Cl or Br (e.g., Br); 1.260 Method 1 or any of Methods 1.1 through 1.259, in which a compound is produced by any one or more of Compounds 3-A, 3-B, 3-C, or 3-D; 1.261 In one or more of the compounds, R xis H, PG is trialkylsilyl or dialkylarylsilyl (e.g., TBDPS), and R S is aryl (e.g., 4-tolyl), and / or R 5 But C 1~3 alkyl (e.g., methyl), Method 1.260; 1.262 Method 1 or any of methods 1.1 to 1.261, in which one or more of compounds 9-A, 9-B, 9-C, 9-D, and 9-E are produced; 1.263 Method 1.262, wherein one or more of compounds 9-A, 9-B, 9-C, 9-D, or 9-E are made according to any one or more of Method 4 or Method 4.1, see below, or Method 5 or Method 5.1, see below; 1.264 In one or more of the compounds, R x is H and R y But, H Yes, R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R 4 is H and R 5 But C 1~3 alkyl (e.g., methyl), and R 6 is halogen (e.g., chloro), and / or R 12 is H or -C(O)-R 1 (In the formula, R 1 is an optionally substituted C 1~6 Alkyl (e.g., methyl), optionally substituted C 1~6 Method 1.262 or 1.263, wherein the aryl group is selected from alkoxy (e.g., (S)-1-phenylethoxy), or optionally substituted 5-10 membered heteroaryl (e.g., 1-methyl-3-methoxy-1H-pyrazol-4-yl); 1.265 In one or more of the compounds, R x is H and R y is H and R 2 and R 3 are independently H or methyl, and R 4is H and R 5 is methyl, and R 6 is chloro, Method 1.264; 1.266 Method 1.265, wherein in one or more of the compounds, R 2 and R 3 is H or R 2 and R 3 1.267 is methyl or R 2 is H and R 3 is methyl; 1.268 In one or more of the compounds, R 2 is H and R 3 is methyl, Method 1.266; 1.269 In compound 9-C, R 12 But C(O)-R 1 and R 1 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and —NR 8 R 9 C is selected from 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are optionally joined by 1 to 5 R 10 substituted with groups; each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocyclic ring together with the atom to which they are attached, and each R 8 and R9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocycle together with the atom to which they are bonded, and the C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl optionally contain 1 to 5 R 10 substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a , and -NR a R b Selected from;R a and R b are independently hydrogen or C 1~6 any of methods 1.262 to 1.267, which is alkyl; 1.270 In compound 9-C, R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10 5-10 membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl) substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, C 1~6 Method 1.268, selected from alkoxy, and halogen; 1.271 In compound 9-C, R 12 But -C(O)-R1 and R 1 However, optionally 1 to 5 R 10 pyrazolyl or imidazolyl substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl (e.g., methyl) or C 1~6 alkoxy (e.g., methoxy), Method 1.269; 1.272 In compound 9-C, R 12 But -C(O)-R 1 and R 1 However, you can optionally select 1 to 3 C 1~6 Alkyl (e.g., methyl) or C 1~6 pyrazolyl substituted by alkoxy (e.g., methoxy), e.g., R 1 is 3-methoxy-1-methyl-1H-pyrazolyl, Method 1.269; 1.273 Compound I is produced by Method 1 or Methods 1.1 to 1.27 Either 1; 1.274 Method 1.272, wherein compound I is compound I(a); 1.275 Method 1.272 or 1.273, wherein compound I or I(a) is made according to any one or more of Method 4 or Method 4.1, see below, or Method 5 or Method 5.1, see below; 1.276 In compound I or I(a), R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R 4 is H and R 5 But C 1~3 alkyl (e.g., methyl), and R 6 is halogen (e.g., chloro), and / or R 12 But -C(O)-R 1 and R 1 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10Aryl, 3- to 12-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and —NR 8 R 9 C is selected from 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are optionally joined by 1 to 5 R 10 substituted with groups; each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocyclic ring together with the atom to which they are attached, and each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocycle together with the atom to which they are bonded, and the C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl optionally contain 1 to 5 R 10 substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a , and -NR aR b Selected from;R a and R b are independently hydrogen or C 1~6 alkyl, any of methods 1.272-1.274; 1.277 In compound I or I(a), R 2 and R 3 are independently H or methyl, and R 4 is H and R 5 is methyl, and R 6 is chloro, Method 1.275; 1.278 In compound I or I(a), R 2 and R 3 is H or R 2 and R 3 is methyl, or R 2 is H and R 3 is methyl, Method 1.276; 1.279 In compound I or I(a), R 2 is H and R 3 is methyl, Method 1.277; 1.280 In compound I or I(a), R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10 a 5- to 10-membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl) substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, C 1~6 any of methods 1.275-1.278, wherein the alkyl group is selected from alkoxy, and halogen; 1.281 In compound I or I(a), R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10 pyrazolyl or imidazolyl substituted with a group; 10 Each of the groups is independently C1~6 Alkyl (e.g., methyl) or C 1~6 alkoxy (e.g., methoxy), Method 1.279; 1.282 In compound I or I(a), R 12 But -C(O)-R 1 and R 1 However, you can optionally select 1 to 3 C 1~6 Alkyl (e.g., methyl) or C 1~6 pyrazolyl substituted by alkoxy (e.g., methoxy), e.g., R 1 is 3-methoxy-1-methyl-1H-pyrazolyl, Method 1.280; 1.283 Any of Methods 1.262-1.281, wherein in one or more of Compound 9-E, Compound I, or Compound I(a), is a double bond; 1.284 Method 1 or any of Methods 1.1-1.282, in which Compound 1 is produced; 1.285 Method 1 or any of Methods 1.1 through 1.283, further comprising any step of any of Method 2, see below, Method 3, see below, Method 4, see below, and Method 5, see below.

[0019] In a third aspect, the present disclosure provides a method (Method 2) for making a compound selected from one or more of compounds 4-B, 4-C, 4-D, 4-E, 5-A, 5-B, 5-C, 5-D, 5-E, 5-E', 5-F, 5-G, 5-G', 5-H, 5-I, 1-J, 1-K, 9-A, 9-B, 9-C, 9-D, 9-E, and compound I or I(a) described herein, comprising reacting a precursor compound with one or more reagents in a suitable solvent for a time and under conditions effective to form a product compound. Method 2 generally relates to the ongoing formation of a tetracyclic moiety (TC) comprising intermediates 5-F and 5-I, and the evolution of these intermediates to compound 1. While not limited to the order or combination of steps used, possible embodiments of Method 2 can include any of the steps shown in Schemes 4 and 5.

[0020] In certain embodiments, the present disclosure provides Method 2 as follows: 2.1 Method 2, comprising reacting compound 4-A (6-hydroxy-3,4-dihydronaphthalen-1(2H)-one) with a suitable triflating reagent in a suitable solvent and with a suitable base for a time and under conditions effective to provide compound 4-B; 2.2 Method 2.1, wherein the triflating reagent is selected from trifluoromethanesulfonyl anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonyl fluoride, trifluoromethanesulfonic acid, N-trifluoromethanesulfonylimidazole, and N-phenyltrifluoromethanesulfonimide; 2.3 Method 2.1 or 2.2, wherein the base is selected from tertiary amines (e.g., N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine), and inorganic bases (e.g., lithium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, sodium phosphate (monobasic, dibasic, or tribasic), potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic, dibasic, or tribasic), potassium fluoride, lithium carbonate, cesium carbonate); [ka] 2.4 Any of Methods 2.1-2.3, wherein the reagent is trifluoromethanesulfonyl anhydride and the base is pyridine; 2.5 Any of Methods 2.1-2.4, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent; 2.6 Method 2.5, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.7 Method 2.5, wherein the polar aprotic solvent is selected from nitriles (e.g., acetonitrile) and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate); 2.8 Method 2.5, wherein the non-polar solvent is dichloromethane; 2.9 Any of Methods 2.1 to 2.8, wherein the reaction temperature is −80 to 40° C., for example, −30 to 20° C., or −10 to 10° C., or about 0° C.; 2.10 Method 2, or any of Methods 2.1-2.9, comprising reacting compound 4-B with a halide source for a time and under conditions effective to form compound 4-C, wherein R6 is fluoro, chloro, bromo, or iodo; 2.11 R 6 is selected from chloro and bromo (e.g., R 6 is chloro), Method 2.10; 2.12 The halide source may be a chloride salt (e.g., lithium chloride, potassium chloride, cesium chloride, tetrabutylammonium chloride), triphenylphosphine dichloride, copper(II) chloride, copper(I) chloride, phosphorus oxychloride, thionyl chloride, sulfuryl chloride, cyanuric chloride, methanesulfonyl chloride, phosgene, triphosgene, bromide salt (e.g., lithium bromide, potassium bromide, cesium bromide, tetrabutylammonium bromide), triphenylphosphine dibromide, Method 2.10 or 2.11, wherein the iodide is selected from iodine, copper(II) bromide, copper(I) bromide, phosphorus tribromide, phosphorus oxybromide, thionyl bromide, sulfuryl bromide, iodide salts (e.g., potassium iodide, cesium iodide, tetrabutylammonium fluoride), copper(II) iodide, copper(I) iodide, fluoride salts (e.g., lithium fluoride, potassium fluoride, cesium fluoride, tetrabutylammonium fluoride), copper(II) fluoride, and copper(I) fluoride; 2.13 Method 2.12, wherein the halide source is a chloride salt, e.g., lithium chloride; 2.14 Any of Methods 2.10-2.13, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent; 2.15 Method 2.14, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene); 2.16 Method 2.14, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, nitriles (e.g., acetonitrile), and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate); 2.17 Method 2.14, in which the polar aprotic solvent is N-methyl-2-pyrrolidinone; 2.18 Any of Methods 2.10 to 2.17, wherein the reaction temperature is 50 to 250°C, e.g., 100 to 220°C, or 130 to 150°C, or about 140°C; 2.19 Compound 4-C is converted to compound 4-D (wherein R 6 is defined as provided in Method 2.10 or 2.11); 2.20 R 6 is chloro, Method 2.19; 2.21 Method 2.19 or 2.20, wherein the reaction comprises treating compound 4-C with a trimethylsulfonium salt and a base in a polar aprotic solvent; 2.22 Trimethylsulfonium salts include trimethylsulfonium chloride, trimethylsulfonium bromide, trimethylsulfonium iodide, and trimethylsulfonium tetrafluoroborate. phonium, or trimethylsulfonium methylsulfate, Method 2.21; 2.23 Methods 2.21 or 2.22, wherein the base is an inorganic base (e.g., sodium hydroxide, potassium hydroxide, or lithium hydroxide); 2.24 Any of Methods 2.21-2.23, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, and a nitrile (e.g., acetonitrile); 2.25 Any of Methods 2.21 to 2.24, wherein the reaction temperature is 0 to 50°C, for example, 10 to 40°C or 20 to 30°C; 2.26 Any of Methods 2.19-2.25, wherein the stereoisomers of compound 4-D are not separated prior to the next step in the method; 2.27 Compound 4-E (wherein R 6 Method 2, or any of Methods 2.1-2.26, comprising rearranging compound 4-D for a time and under conditions effective to form (wherein R is defined as provided in Method 2.10 or 2.11); 2.28 R 6 is chloro, Method 2.27; 2.29 Method 2.27 or 2.28, wherein the reaction comprises treating compound 4-D with a Lewis acid in a non-polar solvent; 2.30 Method 2.29, wherein the Lewis acid is selected from boron trifluoride, boron trichloride reagent, boron tribromide, magnesium dibromide, indium chloride, bismuth triflate, and copper triflate; 2.31 Method 2.30, wherein the boron trifluoride is boron trifluoride diethyl etherate, boron trifluoride dimethyl sulfide, or boron trifluoride tetrahydrofuran complex; 2.32 Any of Methods 2.29-2.31, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.33 Method 2.32, in which the nonpolar solvent is tetrahydrofuran; 2.34 Any of Methods 2.27 to 2.33, wherein the reaction temperature is −10° C. to 50° C., for example, 0° C. to 30° C. or 0° C. to 10° C.; 2.35 Any of Methods 2.27-2.34, wherein the stereoisomers of compound 4-E are not separated prior to the next step in the method; 2.36 Compound 4-E is converted to compound 5-A (wherein R 6 is defined as provided in Method 2.10 or 2.11); 2.37 R 6 is chloro, Method 2.36; 2.38 Method 2.35 or 2.36, wherein the reaction comprises treating compound 4-E with formaldehyde and a base in a polar protic solvent; 2.39 Method 2.38, in which formaldehyde is provided as an aqueous solution; 2.40 Method 2.38 or 2.39, wherein the base is a hydroxide base (e.g., sodium, potassium, lithium, magnesium, barium, calcium, zinc, or aluminum hydroxide); 2.41 Any of methods 2.38-2.40, wherein the solvent is selected from methanol, ethanol, propanol, isopropanol, t-butyl alcohol, t-amyl alcohol, ethylene glycol, diethylene glycol, triethylene glycol, and water, or a combination thereof; 2.42 Method 2.41, wherein the solvent further comprises one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, and dioxane; 2.43 The reaction is carried out using aqueous formaldehyde, sodium hydroxide, or potassium hydroxide. any of Methods 2.38-2.42, including a solution and diethylene glycol solvent; 2.44 Any of Methods 2.36 to 2.43, wherein the reaction temperature is 0°C to 90°C, for example, 5 to 50°C or 10 to 40°C; 2.45 Compound 5-A is reacted with compound 5-B (wherein R 6Method 2, or any of Methods 2.1-2.44, comprising acylating with an acylating agent for a time and under conditions effective to form a methyl group (wherein R is defined as provided in Method 2.10 or 2.11); 2.46 R 6 is chloro, Method 2.45; 2.47 R m But H, C 1~6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), haloC 1~6 Alkyl (e.g., trifluoromethyl, trichloromethyl), carboxy C 1~6 Method 2.45 or 2.46, wherein the aryl is selected from alkyl (e.g., 3-carboxypropyl), optionally substituted aryl (e.g., phenyl, 4-bromophenyl), or optionally substituted heteroaryl (e.g., pyridyl, such as 2-pyridyl); 2.48 R m C 1~6 alkyl, and optionally R m is methyl, Method 2.47; 2.49 Any of Methods 2.45-2.48, wherein the acylation is asymmetric, e.g., the acylation produces a product with greater than 50% ee (e.g., greater than 75% ee, or greater than 85% ee, or greater than 90% ee, or greater than 95% ee) before any purification. 2.50 Any of methods 2.45-2.49, wherein the acylation is enzymatic and the acylating agent is a combination of an enzyme and an acyl donor; 2.51 The acyl donor is a compound of formula R m -C(=O)-OZ or an ester of formula R m -C(=O)-OC(=O)-R m anhydride of (wherein Z is C 1~6 Alkyl (e.g., methyl, ethyl, isopropyl), C 2~6 Alkenyl (e.g., vinyl, allyl, methoxyvinyl, isopropenyl), and haloC 1~6 alkyl (e.g., selected from trifluoromethyl, 2,2,2-trichloroethyl); 2.52 Method 2.50, wherein the acyl donor is selected from vinyl acetate, ethyl acetate, isopropyl acetate, acetic anhydride, 2,2,2-trifluoroethyl acetate, 2,2,2-trichloroethyl acetate, methoxyvinyl acetate, isopropenyl acetate, vinyl propionate, vinyl valerate, vinyl isobutyrate, vinyl trifluoroacetate, vinyl trichloroacetate, vinyl benzoate, vinyl 4-bromoacetate, vinyl picolinate, glutaric anhydride, and vinyl formate; 2.53 The enzyme is a lipase, e.g., a bacterial or fungal enzyme such as Candida species. any of methods 2.50 to 2.52, wherein the lipase is Lipozyme TL IM or Novozym 435; 2.54 Any of Methods 2.45-2.53, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent; 2.55 Method 2.54, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane) and hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane); 2.56 Method 2.54, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, nitriles (e.g., acetonitrile), and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate); 2.57 Method 2.54, in which the polar aprotic solvent is ethyl acetate; 2.58 Any of Methods 2.45 to 2.57, wherein the reaction temperature is −10° C. to 110° C., for example, 0 to 80° C., or 10 to 40° C., or 20 to 30° C.; 2.59 Compound 5-B is reacted with an aldehyde compound 5-C (wherein R 6 is defined as provided in Method 2.10 or 2.11, and R m Method 2.47 or 2.4 with an oxidizing agent for a time and under conditions effective to form a methyl group (as defined as ##STR1##); 2.60 R 6 is chloro and R m is methyl, Method 2.59; 2.61 Method 2.59 or 2.60, wherein the reaction further comprises an additive, a catalyst, and / or a base; 2.62 Any of methods 2.59-2.61, wherein the oxidizing agent is selected from sodium hypochlorite, sulfur trioxide-pyridine, dimethyl sulfoxide with an activator (e.g., oxalyl chloride), tetrapropylammonium perruthenate (TPAP) / N-methylmorpholine oxide, Dess-Martin periodinane, pyridinium chlorochromate, N-chlorosuccinimide / dimethyl sulfide, iodosylbenzene, chromium trioxide, 2-iodoxybenzoic acid, bis(trifluoroacetoxy)iodobenzene, diacetoxyiodobenzene (DAIB), and manganese dioxide; 2.63 Method 2.62, wherein the DMSO activator is selected from oxalyl chloride, trifluoroacetic anhydride, cyanuric chloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, N-chlorosuccinimide, benzoic anhydride, methanesulfonic anhydride, tosylic anhydride, triflic anhydride, methyl chloroglyoxylate, thionyl chloride, diphosgene, triphosgene, methanesulfonyl chloride, tosyl chloride, benzenesulfonyl chloride, trichloroacetonitrile, 2-chloro-1,2-dimethylimidazolinium chloride, polyphosphoric acid, phosphorus trichloride, phosphorus pentoxide, triphenylphosphine dichloride, triphenylphosphine dibromide, phosphorus oxychloride, acetyl chloride, benzoyl chloride, acetyl bromide, phenyl dichlorophosphate, diphenyl chlorophosphate, diethyl chlorophosphate, and ethoxyacetylene; 2.64 Any of Methods 2.61-2.63, wherein the reaction further comprises a catalyst selected from TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl), 4-hydroxy-TEMPO, polymer-supported TEMPO, 2-azaadamantane N-oxyl, 9-azabicyclo[3.3.1]nonane N-oxyl, and 9-azanoradamantane N-oxyl; 2.65 Any of methods 2.61-2.64, wherein the reaction further comprises an additive selected from sodium bromide, lithium bromide, and potassium bromide; 2.66 Any of Methods 2.61-2.65, wherein the reaction further comprises a base selected from a tertiary amine (e.g., N,N-diisopropylethylamine, N-methylmorpholine, tri-n-propylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2]octane), an aromatic amine (e.g., pyridine, 2,6-lutidine, collidine), an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium phosphate (monobasic, dibasic, or tribasic), sodium acetate, potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic, dibasic, or tribasic), potassium acetate, potassium fluoride, lithium carbonate, lithium acetate, cesium carbonate), and a hydroxide base (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium hydroxide); 2.67 Any of Methods 2.59-2.66, wherein the oxidizing agent is sulfur trioxide-pyridine; 2.68 Method 2.67, in which the base is N,N-diisopropylethylamine; 2.69 Any of Methods 2.59-2.68, wherein the suitable solvent is water, a nonpolar solvent, and / or a polar aprotic solvent; 2.70 Method 2.69, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.71 Polar aprotic solvents include N-methyl-2-pyrrolidinone, N,N-dimethyl Method 2.69, wherein the amine is selected from acetamide, N,N-dimethylformamide, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), nitriles (e.g., acetonitrile), and ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone); 2.72 Method 2.69, where the preferred solvent is a mixture of ethyl acetate and dimethyl sulfoxide; 2.73 Any of Methods 2.59 to 2.72, wherein the reaction temperature is −80 to 50° C., for example, −40 to 40° C. or −10 to 10° C.; 2.74 Compound 5-C is reacted with acetal compound 5-D (wherein R 6 is defined as provided in Method 2.10 or 2.11, and R m Method 2, or any of Methods 2.1 through 2.73, comprising treating with a protecting agent for a time and under conditions effective to form a protective layer (wherein 2.75 R 6 is chloro and R m is methyl, Method 2.74; 2.76 each R n But independently, C 1~6 alkyl (e.g., methyl, ethyl, or isopropyl), or two R n The parts are joined together to form a C 2~10 Alkyl or C 2~10 forming an alkenyl bridge (i.e., a cyclic acetal), the bridge optionally containing 1 to 4 C 1~6 substituted by alkyl, halogen, or aryl, or two Rn Method 2.74 or 2.75, where the moieties are joined together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge); 2.77 each R n But independently, C 1~6 alkyl, and optionally, each R n is methyl, Method 2.76; 2.78 Two R n Method 2.76, wherein the moieties are joined together to form a bridge selected from -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(Ph)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(Ph)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(C6H5)CH(C6H5), -CH2CH(C6H5)CH2-, and -(o-C6H4)-; 2.79 Two R's n Method 2.78, wherein the moieties are joined together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-, -CH(CH3)CH(CH3)-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH2CH3)2CH2-, -CH(C6H5)CH(C6H5), and -CH2CH(C6H5)CH2-; 2.80 each R n But the same C 1~6 an alkyl moiety (e.g., methyl, ethyl, or isopropyl), and the protecting agent is C 1~6 Alcohol or Tri(C 1~6 alkyl) orthoformate, e.g., each R n is methyl and the protecting agent is methanol or trimethyl orthoformate; 2.81 Two R's n The part is C2~10 Alkyl or C 2~10 The protecting agent forms an alkenyl bridge, and 2~10 Alkyl-diol or C 2~10 Alkenyl-diol (e.g., ethylene glycol, propylene glycol), Method 2.76; 2.82 The protecting agent is selected from the group consisting of trimethyl orthoformate, trimethyl orthoacetate, triethyl orthoacetate, triethyl orthoformate, alcohols (e.g., MeOH), and diols (e.g., ethylene glycol, pinacol, propylene glycol, butanediol, 2,2-dimethyl-1,3-propanediol, catechol, HOCH2CH2OH, HOCH(CH3)CH(CH3)OH, HOCH2CH(CH3)OH, HOCH2CH(Ph)OH, HOC(CH3)2C(CH3)2OH, HOCH2CH2CH2OH, HOCH2CBr2CH2OH, HOCH2(C=CH)CH2OH, HOCH2CH(Ph)CH2OH, HOCH(CH3)CH2CH(CH3)OH, HOCH2CH(CH3) CH2OH, HOCH2C(CH3)2CH2OH, HOCH2C(CH2CH3)2CH2OH, HOCH2CH2CH2CH2OH, HOCH2CH2CH2CH2CH2OH), Method 2.81; 2.83 Any of Methods 2.74-2.82, wherein the reaction further comprises, for example, a catalytic amount (e.g., 0.001-0.10 equivalents or 0.01-0.05 equivalents) of an acid; 2.84 Method 2.83, wherein the acid is selected from p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonate, sulfuric acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, trichloroacetic acid, phosphoric acid, oxalic acid, fumaric acid, phthalic acid, and formic acid, or the acid is an immobilized acidic resin (e.g., Amberlyst resin); 2.85 each R n is methyl, the protecting agent is trimethyl orthoformate, and the acid catalyst is p-toluenesulfonic acid; 2.86 Any of Methods 2.74-2.85, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent; 2.87 Method 2.86, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.88 Method 2.86, wherein the polar protic solvent is selected from alcohols (e.g., methanol, ethanol, propanol, isopropanol) and diols (e.g., ethylene glycol, propylene glycol), or combinations thereof, and optionally the solvent alcohol is the same as the protecting agent; 2.89 Method 2.86, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 2.90 Method 2.86, wherein the preferred solvent is methanol; 2.91 Any of Reactions 2.74-2.87 in which the reaction involves refluxing in a hydrocarbon solvent (e.g., toluene) with azeotropic removal of water; 2.92 Any of Methods 2.74 to 2.91, wherein the reaction temperature is 0 to 150°C, e.g., 25 to 120°C, 0 to 60°C, or 35 to 55°C; 2.93 Compound 5-D was reacted with acetal compound 5-E (wherein R 6 is defined as provided in Method 2.10 or 2.11, and R m is defined as in Method 2.47 or 2.48, and R n Method 2, or any of Methods 2.1-2.92, comprising hydrolyzing with a base, optionally a suitable co-solvent, for a time and under conditions effective to form a methyl group (wherein m is defined as in any of Methods 2.76-2.79); 2.94 R6 is chloro and R m is methyl and R n are each methyl, Method 2.93; 2.95 Method 2.93 or 2.94, wherein the base is an inorganic base, e.g., hydroxide, bicarbonate, or carbonate; 2.96 Method 2.95, wherein the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate; in one embodiment, the base is potassium carbonate; 2.97 Any of Methods 2.93-2.96, wherein the suitable co-solvent is selected from a non-polar solvent, a polar protic solvent, a polar aprotic solvent, or a combination thereof; 2.98 Non-polar solvents include ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, Method 2.97, wherein the solvent is selected from hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.99 Method 2.98, in which the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol); 2.100 Method 2.98, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, and a nitrile (e.g., acetonitrile); 2.101 Method 2.97, where the preferred solvent is a combination of tetrahydrofuran and water; 2.102 Any of methods 2.93-2.101, wherein the reaction further comprises a phase transfer catalyst, such as a quaternary ammonium halide salt (e.g., chloride or bromide salts of tetrabutylammonium, tetraethylammonium, benzyltriethylammonium, methyltricaprylammonium, methyltributylammonium, or methyltrioctylammonium); 2.103 Any of Methods 2.93 to 2.102, wherein the reaction temperature is −10 to 70° C., for example, 10 to 30° C. or 20 to 30° C.; 2.104 Any of Methods 2.74-2.103, wherein compound 5-C is converted to compound 5-E in two steps without isolating or purifying intermediate compound 5-D; 2.105 comprising treating compound 5-E with a transacetalization agent in a suitable solvent for a time and under conditions effective to form acetal compound 5-E'; 6 is defined as provided in Method 2.10 or 2.11, and each R of Compound 5-E n But independently, C 1~6 alkyl (e.g., methyl, ethyl, or isopropyl), and both R n R of compound 5-E n Not the same as Method 2 or any of Methods 2.1 through 2.104; 2.106 R 6 is chloro, Method 2.105; 2.107 Both R of compound 5-E n is methyl, Method 2.105 or 2.106; 2.108 Each R in compound 5-E' n But independently, C 2~6 alkyl (e.g., ethyl or isopropyl), or the two R n The parts are joined together to form a C 2~10 Alkyl or C 2~10 forming an alkenyl bridge (i.e., a cyclic acetal), which bridge is optionally substituted with 1 to 4 aryls, or two R nAny of methods 2.105-2.107, wherein the moieties are joined together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge); 2.109 Each R in compound 5-E' n But independently, C 2~6 alkyl, and optionally, each R n is ethyl, Method 2.108; 2.110 The two R's in compound 5-E' n Method 2.108, wherein the moieties are joined together to form a bridge selected from -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(Ph)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(Ph)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(C6H5)CH(C6H5), -CH2CH(C6H5)CH2-, and -(o-C6H4)-; 2.111 The two R in compound 5-E' n the moieties joined together are selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-, -CH(CH3)CH(CH3)-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH2CH3)2CH2-, -CH(C6H5)CH(C6H5), and -CH2CH(C6H5)CH2-; forming crosslinks, method 2.110; 2.112 Each R in compound 5-E' n But the same C 2~6 alkyl moiety (e.g., ethyl or isopropyl), and the transacetalization agent is C 2~6 For example, each R n Method 2.108, where is ethyl and the agent is ethanol; 2.113 The two R in compound 5-E' nThe part is C 2~10 Alkyl or C 2~10 The alkenyl bridge is formed, and the transacetalization agent is C 2~10 Alkyl-diol or C 2~10 Alkenyl-diol (e.g., ethylene glycol, propylene glycol), method 2.108; 2.114 Method 2.113, wherein the transacetalization agent is selected from alcohols (e.g., ethanol and propanol), or diols (e.g., ethylene glycol, 2,3-butanediol, pinacol, propylene glycol, 2,4-pentanediol, 2-methyl-1,3-propanediol, 2,2-dimethyl-1,3-propanediol, 2,2-diethyl-1,3-propanediol, 2-phenyl-1,3-propanediol, meso-1,2-diphenyl-1,2-ethanediol, and catechol); 2.115 Any of methods 2.105-2.114, wherein the reaction further comprises a Lewis acid (e.g., boron trifluoride, titanium isopropoxide) or a Bronsted acid (e.g., p-toluenesulfonic acid); 2.116 Method 2.115, wherein the Lewis acid is selected from boron trifluoride, boron trichloride, boron tribromide, magnesium dibromide, indium chloride, aluminum chloride, tin(IV) chloride, zinc chloride, bismuth triflate, copper triflate, titanium(IV) chloride, and titanium(IV) alkoxides (e.g., titanium(IV) methoxide, titanium(IV) ethoxide, titanium(IV) propoxide, titanium(IV) isopropoxide, or titanium(IV) butoxide); 2.117 Method 2.116, in which the boron trifluoride is boron trifluoride diethyl etherate, boron trifluoride dimethyl sulfide, or boron trifluoride tetrahydrofuran complex; 2.118 Method 2.115, wherein the Bronsted acid is selected from p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonate, sulfuric acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, trichloroacetic acid, phosphoric acid, oxalic acid, fumaric acid, phthalic acid, and formic acid, or the acid is an immobilized acidic resin (e.g., Amberlyst resin); in one embodiment, the acid is boron trifluoride diethyl etherate (BF3·OEt2); 2.119 Any of methods 2.105-2.118, wherein the suitable solvent is a non-polar solvent, a polar protic solvent, or a polar aprotic solvent, optionally a non-polar solvent or a polar aprotic solvent in combination with a trace amount of a polar protic solvent (e.g., less than 10% v / v); 2.120 Method 2.119, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.121 Method 2.119, wherein the polar protic solvent is selected from alcohols (e.g., ethanol, propanol, isopropanol), and diols (e.g., ethylene glycol, propylene glycol), or combinations thereof, and optionally the solvent alcohol is the same as the transacetalization agent; 2.122 Method 2.119, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 2.123 Method 2.119, where the preferred solvent is 2-methyltetrahydrofuran; 2.124 Any of Reactions 2.105-2.120 in which the reaction involves refluxing in a hydrocarbon solvent (e.g., toluene) with azeotropic removal of water; 2.125 Any of Methods 2.105 to 2.124, wherein the reaction temperature is 0 to 100°C, e.g., 25 to 120°C, or 50 to 100°C, or 70 to 80°C; 2.126 Compound 5-E or 5-E′ is reacted with the ether adduct compound 5-F (wherein R 6 is defined as provided in Method 2.10 or 2.11, and each R n Method 2, or any of Methods 2.1-2.125, comprising treating with 4-fluoro-3-nitrobenzoic acid or ester for a time and under conditions effective to form (wherein R is defined as provided in any of Methods 2.76-2.79 or 2.108-2.111); 2.127 R 6 is chloro, Method 2.126; 2.128 Both R of compound 5-E or 5-E' n The moiety is methyl or ethyl, or the two R n Method 2.126 or 2.127, wherein the moieties are joined together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-; 2.129 R z is H or optionally substituted C 1~6 any of methods 2.126 to 2.128, wherein the alkyl is 2.130 R z H, unsubstituted C 1~6 Alkyl (e.g., methyl), C 1~6 Alkoxy-substituted C 1~6 Alkyl (e.g., methoxyethyl, methoxymethyl), C 1~6 Alkoxy-substituted C 1~6 Alkoxy-substituted C 1~6 Alkyl (e.g., methoxyethoxyethyl, methoxyethoxymethyl), 5-6 membered heterocycloalkyl substituted C 1~6 Alkyl (e.g., 2-N-(morpholino)ethyl, 2-tetrahydropyranyl), aryloxy-substituted C 1~6 Alkyl (e.g., benzyloxymethyl), halogen-substituted C1~6 Alkyl (e.g., 2,2,2-trichloroethyl), trialkylsilyl-substituted C 1~6 Alkyl (e.g., 2-(trimethylsilyl)ethyl, triisopropylsilylmethyl), trialkylsilyl-substituted C 1~6 Alkoxy-substituted C 1~6 Alkyl (e.g., 2-(trimethylsilyl)ethoxymethyl), and aryl-substituted C 1~6 alkyl (e.g., benzyl, 4-methylbenzyl, 4-nitrobenzyl), Method 2.129; 2.131 R z is H or unsubstituted C 1~6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, or tert-butyl), Method 2.130; 2.132 Any of methods 2.126-2.131, wherein compound 5-E or 5-E' is dissolved or suspended in a suitable solvent and treated with a strong base and, optionally, a promoter (e.g., sodium iodide, tetrabutylammonium iodide); 2.133 Method 2.132, wherein the base is selected from inorganic hydrides (e.g., sodium hydride, potassium hydride), alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide), inorganic hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), amide bases (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate (mono-, di-, or tribasic), sodium phosphate (mono-, di-, or tribasic)); 2.134 The base is selected from sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, and potassium diisopropylamide, and optionally a salt Method 2.133, in which the group is potassium t-butoxide; 2.135 Methods 2.132, 2.133, or 2.134, wherein 4-fluoro-3-nitrobenzoic acid or ester is added to the reaction about 1 to 60 minutes, e.g., about 1 to 30 minutes, or 1 to 20 minutes, or 1 to 15 minutes, or 1 to 10 minutes, or 1 to 5 minutes, after addition of the base; 2.136 4-Fluoro-3-nitrobenzoic acid or ester of the formula 4-F-3-NO2-C6H4-COOR z any of methods 2.126 to 2.135; 2.137 Any of methods 2.126-2.136, wherein the suitable solvent is a non-polar solvent; 2.138 Method 2.137, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.139 Method 2.138, in which the nonpolar solvent is tetrahydrofuran; 2.140 Any of Methods 2.126 to 2.139, wherein the reaction temperature is −80 to 100° C., e.g., −45 to 10° C., or −30 to 10° C., or −10 to 5° C., or about 0° C., or −10 to 50° C., or −10 to 30° C., or 10 to 30° C., or 30 to 80° C.; 2.141 Nitro compound 5-F or 5-G′ is reacted with aniline compound 5-G or 5-H, respectively, in a suitable solvent, where R 6is defined as provided in Method 2.10 or 2.11, and each R n is defined as provided in either Methods 2.76-2.79 or 2.108-2.111, and R z Method 2, or any of Methods 2.1 through 2.140, comprising treating with a reducing agent for a time and under conditions effective to obtain a compound (C14, C24, C34, C42, C54, C64, C72, C82, C9 ... 2.142 R 6 is chloro, Method 2.141; 2.143 Both R of compound 5-F or 5-G' n The moiety is methyl or ethyl, or the two R n Method 2.141 or 2.142, wherein the moieties are joined together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-; 2.144 R z But unsubstituted C 1~6 any of methods 2.141-2.143, wherein the alkyl is alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, or tert-butyl); 2.145 Any of methods 2.141-2.144, wherein the reducing agent is selected from zinc, tin, or iron in acid (e.g., formic acid or acetic acid or HCl in a suitable solvent); 2.146 Any of methods 2.141-2.144, wherein the reducing agent is a hydrogenation agent (e.g., hydrogen in combination with a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex), or a phase transfer hydrogenation system); 2.147 Method 2.146, in which the hydrogenation agent is hydrogen gas in combination with a palladium, platinum, rhodium, iridium, ruthenium, or nickel catalyst (e.g., Pd, Pd / C, Pd(OAc)2, Pt / C, PtO2, Ru / C, Raney nickel, Ru complex, Rh complex, PtO2, Pt complex, Pd complex, Ir complex), or ammonium formate in combination with a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt, PtO2); 2.148 Method 2.147, wherein the hydrogenation agent is hydrogen gas, optionally in combination with a Pd, Pd / C, Pd(OAc)2, Pt / C, or PtO2 catalyst, at a pressure of 1 to 5 bar (e.g., 1 to 2 bar); 2.149 Method 2.145, in which the reducing agent is iron in acetic acid; 2.150 Any of methods 2.141-2.149, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent; 2.151 Method 2.150, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.152 Method 2.150, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or an acid (e.g., formic acid, acetic acid); 2.153 Method 2.150, wherein the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile); 2.154 Method 2.150, wherein the suitable solvent is ethyl acetate or isopropyl acetate or acetic acid; 2.155 Any of Methods 2.141 to 2.154, wherein the reaction temperature is 0 to 100°C, e.g., 20 to 50°C, or 20 to 30°C, or 50 to 80°C; 2.156 The acetal compound 5-F or 5-G is reacted in a suitable solvent to give the aldehyde compound 5-G′ or 5-H, respectively, where R 6 is defined as provided in Method 2.10 or 2.11, and each R n is defined as provided in either Methods 2.76-2.79 or 2.108-2.111, and R zMethod 2, or any of Methods 2.1-2.155, comprising treating with a deprotecting agent for a time and under conditions effective to obtain a compound (III) (wherein X is defined as in any of Methods 2.129-2.131); 2.157 R 6 is chloro, Method 2.156; 2.158 R n is methyl or ethyl, or two R n Method 2.156 or 2.157, wherein the moieties are joined together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-; 2.159 R z But unsubstituted C 1~6 any of methods 2.156-2.158, wherein the aryl group is alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, or tert-butyl); 2.160 Any of methods 2.156-2.159, wherein the deprotecting agent comprises an acid; 2.161 Method 2.160, wherein the acid is selected from HCl (e.g., aqueous HCl, or HCl / methanol, HCl / isopropanol, or HCl / dioxane), HBr (e.g., aqueous HBr or HBr / acetic acid), sulfuric acid, phosphoric acid, p-toluenesulfonic acid, pyridinium tosylate, trifluoroacetic acid, methanesulfonic acid, trichloroacetic acid, Lewis acids (e.g., erbium triflate), and acidic resins (e.g., Amberlyst); 2.162 Method 2.161, wherein the acid is selected from HCl (e.g., HCl / dioxane), p-toluenesulfonic acid, methanesulfonic acid, and an acidic resin (e.g., Amberlyst); 2.163 Any of methods 2.156-2.162, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, a polar aprotic solvent, or a combination thereof; 2.164 Method 2.163, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.165 Method 2.163, wherein the polar protic solvent is water and / or an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or an acid (e.g., formic acid, acetic acid); 2.166 When the polar aprotic solvent is a ketone (e.g., acetone, methyl ethyl ketone), Method 2.163, wherein the carboxylic acid is selected from esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 2.167 Method 2.163, wherein the suitable solvent is acetone or dioxane; 2.168 Any of Methods 2.156-2.167, wherein the reaction temperature is 0-100°C, e.g., 20-50°C or 20-30°C; 2.169 Optionally, any of Methods 2.141-2.168, in which the intended product compound 5-H undergoes spontaneous condensation to partially or completely form the intermediate imine 5-H', and a mixture of 5-H and 5-H' is carried forward to the next step, or the isolated product is 5-H', which is used in the next step; 2.170 The aniline / acetal compound 5-H (and / or 5-H′) is reacted with a secondary amine compound 5-I (wherein R 6 is defined as provided in Method 2.10 or 2.11, and R z Method 2, or any of Methods 2.1 through 2.169, comprising treating with a reducing agent for a time and under conditions effective to obtain a compound (C14, C24, C34, C42, C54, C64, C76, C86, C96, C97, C98, C99, C99, C100, C111, C122, C131, C142, C151, C152, C161, C162, C163, C164, C171, C175, C176, C177, C178, C179, C180, C181, C182, C183, C184, C185, C186, C187, C188, C189, C190, C191, C192, C193, C194, C195 2.171 R 6 is chloro, Method 2.170; 2.172 R z But unsubstituted C1~6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, or tert-butyl), method 2.170 or 2.171; 2.173 Any of methods 2.170-2.172, wherein the reducing agent is selected from hydride reducing agents, silane reducing agents, and zinc in acid (e.g., zinc in acetic acid); 2.174 Method 2.173, wherein the reducing agent is a hydride reducing agent; 2.175 Method 2.174, wherein the hydride reducing agent is selected from sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride; 2.176 Method 2.175, wherein the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride; 2.177 Any of methods 2.174-2.176, in which a hydride reducing agent is combined with a reagent to adjust the hydride reduction activity (e.g., titanium isopropoxide, magnesium perchlorate, or zinc chloride); 2.178 Method 2.173, wherein the silane reducing agent is triethylsilane; 2.179 Any of methods 2.173-2.178, wherein the reaction further comprises an acid (e.g., selected from acetic acid, trifluoroacetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid); 2.180 Any of methods 2.170-2.179, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent; 2.181 Method 2.180, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.182 Method 2.180, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; 2.183 Method 2.180, wherein the suitable solvent is dichloromethane or dichloroethane; 2.184 Any of Methods 2.170-2.183, wherein the reaction temperature is −30 to 80° C., e.g., 0 to 50° C., or 20 to 30° C., or about 20° C.; 2.185 Any one or more of compounds 4-B, 4-C, 4-D, and 4-E Method 2 or any of Methods 2.1 to 2.184, wherein the compound is produced by 2.186 In one or more of the compounds, R 6 is a halogen (e.g., chloro); Method 2.185; 2.187 Method 2, or any of methods 2.1 through 2.186, wherein any one or more of compounds 5-A, 5-B, 5-C, 5-D, 5-E, 5-E', 5-F, 5-G, 5-G', 5-H, and 5-I is produced; 2.188 In one or more of the compounds, R m But C 1~3 alkyl (e.g., methyl), and both R n is methyl or ethyl, or two R n the moieties are joined together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-; R z But C 1~3 alkyl (e.g., methyl), and / or R 6 is a halogen (e.g., chloro); Method 2.187; 2.189 Method 2 or any of Methods 2.1 through 2.188, wherein a compound according to any one or more of Compounds 1-J or 1-K is produced; 2.190 In one or more of the compounds, R x is H and R z But H or C 1~3alkyl (e.g., methyl), and R 5 But C 1~3 alkyl (e.g., methyl), and / or R 6 is a halogen (e.g., chloro); Method 2.189; 2.191 Method 2 or any of Methods 2.1 through 2.190, wherein a compound is produced by any one or more of Compounds 9-A, 9-B, 9-C, 9-D, or 9-E; 2.192 Method 2.191, wherein one or more of compounds 9-A, 9-B, 9-C, 9-D, or 9-E are made according to any one or more of Method 4 or Method 4.1, see below, or Method 5 or Method 5.1, see below; 2.193 In one or more of the compounds, R x is H and R y is H and R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R 4 is H and R 5 But C 1~3 alkyl (e.g., methyl), and R 6 is halogen (e.g., chloro), and / or R 12 is H or -C(O)-R 1 (In the formula, R 1 is an optionally substituted C 1~6 Alkyl (e.g., methyl), optionally substituted C 1~6 Method 2.191 or 2.192, wherein the aryl group is selected from alkoxy (e.g., (S)-1-phenylethoxy), or optionally substituted 5-10 membered heteroaryl (e.g., 1-methyl-3-methoxy-1H-pyrazol-4-yl); 2.194 In one or more of the compounds, R x is H and R y is H and R 2 and R 3 are independently H or methyl, and R 4 is H and R 5 is methyl, and R 6is chloro, Method 2.193; 2.195 In one or more of the compounds, R 2 and R 3 is H or R 2 and R 3 is methyl, or R 2 is H and R 3 is methyl, Method 2.194; 2.196 In one or more of the compounds, R 2 is H and R 3 is methyl, Method 2.195; 2.197 In compound 9-C, R 12 But C(O)-R 1 and R 1 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and —NR 8 R 9 C is selected from 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are optionally joined by 1 to 5 R 10 substituted with groups; each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocyclic ring together with the atom to which they are attached, and each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C1~6 haloalkyl, 3- to 12-membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocycle together with the atom to which they are bonded, and the C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl optionally contain 1 to 5 R 10 substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a , and -NR a R b Selected from;R a and R b are independently hydrogen or C 1~6 any of methods 2.191 to 2.196, wherein the alkyl is 2.198 In compound 9-C, R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10 5-10 membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl) substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, C 1~6 Method 2.197, selected from alkoxy, and halogen; 2.199 In compound 9-C, R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10pyrazolyl or imidazolyl substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl (e.g., methyl) or C 1~6 alkoxy (e.g., methoxy), Method 2.198; 2.200 In compound 9-C, R 12 But -C(O)-R 1 and R 1 However, you can optionally select 1 to 3 C 1~6 Alkyl (e.g., methyl) or C 1~6 pyrazolyl substituted by alkoxy (e.g., methoxy), e.g., R 1 is 3-methoxy-1-methyl-1H-pyrazolyl, Method 2.198; 2.201 Method 2 or any of methods 2.1 to 2.200, in which a compound according to Compound I is produced; 2.202 Method 2.201, wherein compound I is compound I(a); 2.203 Method 2.201 or 2.202, wherein compound I or I(a) is made according to any one or more of Method 4 or Method 4.1, see below, or Method 5 or Method 5.1, see below; 2.204 In compound I or I(a), R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R 4 is H and R 5 But C 1~3 alkyl (e.g., methyl), and R 6 is halogen (e.g., chloro), and / or R 12 But -C(O)-R 1 and R 1 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and —NR 8 R 9 C is selected from1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are optionally joined by 1 to 5 R 10 substituted with groups; each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocyclic ring together with the atom to which they are attached, and each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocycle together with the atom to which they are bonded, and the C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl optionally contain 1 to 5 R 10 substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a , and -NR a R b Selected from;R a and R b are independently hydrogen or C 1~6 any of methods 2.201 to 2.203, wherein the alkyl is 2.205 In compound I or I(a), R 2 and R 3 are independently H or methyl, and R 4 is H and R 5 is methyl, and R 6 is chloro, Method 2.204; 2.206 In compound I or I(a), R 2 and R 3 is H or R 2 and R 3 is methyl, or R 2 is H and R 3 is methyl, Method 2.205; 2.207 In compound I or I(a), R 2 is H and R 3 is methyl, Method 2.206; 2.208 In compound I or I(a), R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10 a 5- to 10-membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl) substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, C 1~6 any of methods 2.204 to 2.207, wherein the alkoxy group is selected from alkoxy and halogen; 2.209 In compound I or I(a), R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10 pyrazolyl or imidazolyl substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl (e.g., methyl) or C 1~6alkoxy (e.g., methoxy), Method 2.208; 2.210 In compound I or I(a), R 12 But -C(O)-R 1 and R 1 However, you can optionally select 1 to 3 C 1~6 Alkyl (e.g., methyl) or C 1~6 pyrazolyl substituted by alkoxy (e.g., methoxy), e.g., R 1 is 3-methoxy-1-methyl-1H-pyrazolyl, Method 2.209; 2.211 Any of Methods 2.191-2.210, wherein in one or more of Compound 9-E, Compound I, or Compound I(a), is a double bond; 2.212 Method 2 or any of Methods 2.1-2.211, in which Compound 1 is produced; 2.213 Method 2 or any of Methods 2.1-2.212, further comprising any step of any of Method 1, see below, Method 3, see below, Method 4, see below, and Method 5, see below.

[0021] In a fourth aspect, the present disclosure provides a method (Method 3) for making a compound selected from one or more of compounds 6-B, 6-B', 6-C, 6-D, 6-E, 6-F, 6-G, 6-H, 6-I, 6-J, 6-K, 6-L, 6-L', 7-A, 8-A, 8-B, 9-A, 9-B, 9-C, 9-D, 9-E, and compounds I or I(a) described herein, comprising reacting a precursor compound with one or more reagents in a suitable solvent for a time and under conditions effective to form a product compound. Method 3 generally relates to the ongoing formation of sulfonimidamide moieties (SNOs) containing intermediates 6-H, 6-L, and 8-B, and the evolution of these intermediates to compound 1. While not limited to the order or combination of steps used, possible embodiments of Method 3 can include any of the steps shown in Schemes 6, 7, and 8. [ka] [ka]

[0022] In certain embodiments, the present disclosure provides Method 3 as follows: 3.1 Method 3, comprising reacting alcohol compound 6-A with an activating agent in a suitable solvent with a suitable base for a time and under conditions effective to provide activated compound 6-B; 3.2 R y But H, C 1~6 Method 3.1, wherein the aryl is selected from alkyl (e.g., methyl), and optionally substituted aryl (e.g., phenyl); 3.3 R y ,is H,Method 3.2; 3.4 R 2 But hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cyclo alkyl, or 3- to 12-membered heterocycloalkyl, 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl and 3- to 12-membered heterocycloalkyl optionally contain 1 to 5 R 10 substituted with a group (R 10 is as defined for Compound I), any of Methods 3.1 to 3.3; 3.5 R 2 is hydrogen or C 1~6 alkyl (e.g., methyl), Method 3.4; 3.6 R 3 But hydrogen, C 1~6 Alkyl, -OR 7 , C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 3- to 12-membered heterocycloalkyl, -C(O)R 7 , or -CN, and the C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl and 3- to 12-membered heterocycloalkyl optionally contain 1 to 5 R 10 substituted with a group (R 7 and R10 is as defined for Compound I), any of Methods 3.1 to 3.5; 3.7 R 3 But hydrogen, C 1~6 alkyl (e.g., methyl), or -OR 7 (In the formula, R 7 is C 1~6 alkyl (e.g., methyl), Method 3.6; 3.8 R 3 is hydrogen or C 1~6 alkyl (e.g., methyl), Method 3.7; 3.9 R 2 and R 3 are both hydrogen or R 2 is hydrogen and R 3 C 1~6 alkyl (e.g., methyl) or R 2 and R 3 Both are C 1~6 any of Methods 3.1-3.9, wherein the alkyl group is alkyl (e.g., methyl); 3.10 R 2 is hydrogen and R 3 C 1~6 alkyl (e.g., methyl), Method 3.9; 3.11 Any of Methods 3.1-3.10, wherein the group X of compound 6-B is selected from halide (e.g., chloride, bromide, iodide), sulfonate (e.g., 4-toluenesulfonate, mesylate, nosylate, benzenesulfonate, triflate), and oxyphosphonium (e.g., oxytriphenylphosphonium), optionally wherein the group X is 4-toluenesulfonate; 3.12 Any of Methods 3.1-3.11, wherein the activating agent is selected from p-toluenesulfonyl chloride, p-toluenesulfonyl fluoride, p-toluenesulfonic anhydride, benzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride, triflic anhydride, N-phenyltriflimide, triphenylphosphine dihalide, triphenylphosphine with tetrahalomethanes (e.g., tetrabromomethane), and metal halide salts (e.g., sodium bromide, potassium iodide), and combinations thereof; 3.13 Method 3.12, where the activating agent is p-toluenesulfonyl chloride; 3.14 Any of Methods 3.1-3.13, wherein the base is selected from tertiary amines (e.g., triethylamine, N-methylmorpholine, N-ethylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, picoline, indole, isoindole, quinoline, isoquinoline), and inorganic bases (e.g., lithium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, sodium phosphate (monobasic, dibasic, or tribasic), potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic, dibasic, or tribasic), potassium fluoride, lithium carbonate, cesium carbonate); 3.15 Method 3.14, in which the base is triethylamine; 3.16 Any of Methods 3.1-3.15, wherein the reaction further comprises a catalyst; 3.17 Method 3.16, wherein the catalyst is selected from 4-dimethylaminopyridine, N-methylimidazole, 4-pyrrolidinopyridine, 4-piperidinopyridine, and 9-azajulolidine, optionally wherein the catalyst is 4-dimethylaminopyridine; 3.18 Any of Methods 3.1-3.17, wherein the activating agent is p-toluenesulfonyl chloride, the base is triethylamine, and the catalyst is 4-dimethylaminopyridine; 3.19 Any of Methods 3.1-3.18, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent; 3.20 Method 3.19, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.21 Method 3.19, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, nitriles (e.g., acetonitrile), and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate); 3.22 Method 3.19, in which the nonpolar solvent is dichloromethane; 3.23 Any of Methods 3.1 to 3.22, wherein the reaction temperature is −20 to 80° C., for example, −10 to 30° C. or 0 to 20° C.; 3.24 Compound 6-B is converted to thioether compound 6-C (wherein R y is defined as in Method 3.2 or 3.3, and R 2 and R 3 wherein X is as defined in any of Methods 3.4-3.10 and X is as defined in Method 3.11; 3.25 R e is optionally substituted 5-10 membered heteroaryl (e.g., optionally substituted pyridyl or pyrimidinyl), -C(=NH)NH(C 1~6 alkyl), - C(=NH)N(C 1~6 -C(=NH)NH2, Method 3.24; 3.26 R eis a 5-10 membered heteroaryl, for example a 6 membered heteroaryl (e.g., 2-pyridyl or 2-pyrimidinyl); 3.27 Thiols are reacted with thiols of formula R e Any of Methods 3.24-3.26, wherein the compound has —SH, optionally in its salt form (e.g., lithium, sodium, or potassium), or its tautomeric equivalent (e.g., thiourea or thiopyridone); 3.28 Method 3.27, wherein the thiol is selected from 2-mercaptopyrimidine, 2-mercaptopyridine, thiourea, N-methylthiourea, N,N-dimethylthiourea, each optionally in the form of a salt (e.g., sodium or potassium salt); 3.29 Reactions involving inorganic hydrides (e.g., sodium hydride, potassium hydride, lithium hydride, calcium hydride), alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide), inorganic hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), amide bases (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropyl methyl silazide), any of Methods 3.24-3.28, comprising a base selected from a tertiary amine (e.g., triethylamine, N-methylmorpholine, N-ethylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), quinoline, isoquinoline), and an inorganic base (e.g., lithium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, sodium phosphate (monobasic, dibasic, or tribasic), potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic, dibasic, or tribasic)); 3.30 The base is an inorganic hydride (e.g., sodium hydride or potassium hydride) or is an alkoxide base (e.g., sodium ethoxide or sodium methoxide), Method 3.29; 3.31 Any of Methods 3.27-3.29, wherein the thiol is 2-mercaptopyrimidine and the base is sodium ethoxide; 3.32 Any of Methods 3.24-3.31, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent; 3.33 Method 3.32, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.34 Method 3.32, in which the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol); 3.35 Method 3.32, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.36 Method 3.32, wherein the suitable solvent is methanol or ethanol, optionally wherein the suitable solvent is ethanol; 3.37 Any of Methods 3.24 to 3.36, wherein the reaction temperature is 0 to 100°C, e.g., 20 to 80°C, or 55 to 75°C, or about 65°C; 3.38 Thioether compound 6-C is reacted with sulfone compound 6-D (wherein R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R eMethod 3, or any of Methods 3.1 through 3.37, comprising the step of oxidizing with an oxidizing agent for a time and under conditions effective to form (wherein 3.39 Method 3.38, wherein the oxidizing agent is selected from peroxides (e.g., hydrogen peroxide, sodium peroxide, potassium peroxide), organic peroxides and peroxy compounds (e.g., tert-butyl hydroperoxide, peracetic acid, trifluoroperacetic acid, meta-chloroperoxybenzoic acid, magnesium monoperoxyphthalate), hypochlorites (e.g., sodium hypochlorite, potassium hypochlorite, calcium hypochlorite), periodates (e.g., sodium periodate, potassium periodate), perborates (e.g., sodium perborate), peroxymonosulfates (e.g., potassium peroxymonosulfate, Oxone), permanganates (e.g., potassium permanganate), tetramethyl perruthenate (TPAP), and any combination thereof; 3.40 Method 3.39, in which the oxidizing agent is a peroxide (e.g., hydrogen peroxide); 3.41 Any of methods 3.38-3.40, wherein the reaction further comprises a catalyst selected from, for example, sodium tungstate, tungsten oxytetrachloride, tetrabutylammonium hexapolytungstate, ammonium molybdate, vanadyl acetylacetonate, manganese sulfate, phosphotungstic acid, ammonium cerium nitrate, ruthenium trichloride, methyltrioxorhenium, scandium triflate, iron, and any combination thereof; 3.42 Any of methods 3.38-3.41, wherein the oxidant is hydrogen peroxide and the catalyst is sodium tungstate; 3.43 Any of Methods 3.38-3.42, wherein the reaction optionally further comprises a catalytic amount (e.g., 0.01-0.1 equivalents) of an acid, e.g., phosphoric acid; 3.44 Method 3.43, wherein the phosphoric acid is selected from phenylphosphonic acid, methylphosphonic acid, phenylphosphinic acid, methylphosphinic acid, phosphoric acid, polyphosphoric acid (PPA), phosphonic acid, phosphinic acid, and combinations thereof; 3.45 The reaction may optionally involve catalytic amounts (e.g., 0.01–0.1 equivalents) of phase transfer reagent. Any of Methods 3.38-3.44, further comprising a drug, e.g., a tetraalkylammonium salt (e.g., a tetraethylammonium or tetrabutylammonium salt); 3.46 Method 3.45, wherein the phase transfer reagent is selected from tetrabutylammonium hydrogen sulfate, tetrabutylammonium sulfate, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, and tetrabutylammonium iodide; 3.47 Any of Methods 3.42-3.46, wherein the reaction optionally further comprises catalytic amounts (e.g., 0.01-0.1 equivalents) of each of phenylphosphonic acid and tetrabutylammonium hydrogen sulfate; 3.48 Any of Methods 3.38-3.47, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent; 3.49 Method 3.48, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.50 Method 3.48, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol), water, or a combination thereof; 3.51 Method 3.48, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.52 Method 3.48, where the preferred solvent is toluene; 3.53 Any of Methods 3.38 to 3.52, wherein the reaction temperature is 0 to 100°C, e.g., 0 to 60°C or 10 to 30°C; 3.54 Compound 6-D is reacted with compound 6-E (wherein R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R e Method 3, or any of Methods 3.1 through 3.53, comprising reacting with a base for a time and under conditions effective to form a methyl group (wherein 3.55 Method 3.54, wherein M is selected from hydrogen and an alkali metal or alkaline earth metal, e.g., M is selected from H, Li, Na, K, Mg, and Ca; 3.56 The base may be an inorganic hydride (e.g., sodium hydride, potassium hydride, lithium hydride, calcium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide), an inorganic hydroxide (e.g., sodium hydroxide, Method 3.54 or 3.55, wherein the base is selected from an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), an organic lithium base (e.g., methyllithium, ethyllithium, propyllithium, n-butyllithium, s-butyllithium, t-butyllithium), and an inorganic carbonate (e.g., sodium carbonate, potassium carbonate, cesium carbonate); 3.57 Method 3.56, wherein the base is selected from inorganic hydrides, alkoxides, and inorganic hydroxides; 3.58 Method 3.57, wherein the base is selected from sodium methoxide and potassium methoxide; 3.59 The preferred solvent may be a non-polar solvent, a polar protic solvent, or a polar aprotic solvent. any of methods 3.54 to 3.58; 3.60 Method 3.59, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.61 Method 3.59, in which the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol), or water, or a mixture of the two, and optionally the base is an alkoxide corresponding to the alcohol (e.g., methoxide base and methanol solvent), or the base is a hydroxide base and the solvent is water; 3.62 Method 3.59, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.63 Any of Methods 3.58-3.61, wherein the base is sodium methoxide or potassium methoxide and the solvent is methanol; 3.64 Any of Methods 3.54 to 3.63, wherein the reaction temperature is 0 to 100°C, e.g., 0 to 60°C or 10 to 30°C; 3.65 Any of Methods 3.54-3.64, where the solvent is removed from the reaction and the crude compound 6-E is washed with water and / or an organic solvent and then carried on to the next step without further purification; 3.66 Compound 6-E is oxidized with a suitable oxidizing agent and base in a suitable solvent to give sulfonamide compound 6-F (wherein R y is defined as in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4 to 3.10, and M is as defined in Method 3.55; 3.67 Method 3.66, in which the oxidizing agent is hydroxylamine-O-sulfonic acid, or the oxidizing agent is a combination of ammonia and an oxidizing agent selected from iodine, N-chlorosuccinimide, N-bromosuccinimide, tert-butyl hydroperoxide, and m-chloroperoxybenzoic acid; 3.68 Method 3.67, in which the oxidizing agent is hydroxylamine-O-sulfonic acid; 3.69 Any of methods 3.66-3.68, wherein the base is selected from an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, tetrabutylammonium hydroxide), an inorganic base (e.g., lithium acetate, sodium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, sodium phosphate (monobasic, dibasic, or tribasic), potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic, dibasic, or tribasic), lithium carbonate, cesium carbonate), other alkali metal carboxylates (e.g., potassium propionate), and combinations thereof; 3.70 Method 3.69, wherein the base is sodium acetate or potassium acetate; 3.71 Any of Methods 3.66-3.70, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent; 3.72 Method 3.71, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.73 Method 3.71, in which the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol), or water, or a mixture of the two; 3.74 Method 3.71, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.75 Method 3.71, where the preferred solvent is water; 3.76 Any of Methods 3.66-3.71, wherein the temperature of the reaction is 0-100°C, e.g., 20-80°C, or 35-55°C, or about 45°C; 3.77 Compound 6-F is reacted with N-protected compound 6-G (wherein R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 with a protecting agent for a time and under conditions effective to form a protecting group (wherein R is as defined in any of Methods 3.4-3.10); 3.78 Protecting group R k is a silyl group, an alkylcarbonyl group (e.g., -C(=O)-C 1~6 Alkyl, for example, acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1~6 Alkyl (aryl), for example, 2-phenylethylcarbonyl or 1-phenylethylcarbonyl, arylcarbonyl group (for example, benzoyl), alkoxycarbonyl group (for example, -C(=O)-OC 1~6 Alkyl, for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl, or -C(=O)-OC 1~6 Alkyl (aryl), for example, 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl), aryloxycarbonyl group (for example, phenoxycarbonyl), tertiary alkyl group (for example, t-butyl or trityl), C 1~6 Alkoxy C1~6 Alkyl groups (e.g., C 1~6 alkoxymethyl, for example, methoxymethyl or ethoxymethyl), C 1~6 Alkylaryl groups (e.g., benzyl, 3,5-dimethoxybenzyl, 1-methylbenzyl), diarylalkyl groups (e.g., C 1~6 Alkyl(aryl) groups (e.g., diphenylmethyl), alkylsulfonyl groups (e.g., SO2C 1~6 alkyl, e.g., methanesulfonyl or isopropylsulfonyl), and arylsulfonyl groups (e.g., SO2-aryl, e.g., benzenesulfonyl, toluenesulfonyl), Method 3.77; 3.79 R k is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., t-butyldiphenylsilyl), and triarylsilyl groups (e.g., triphenylsilyl); 3.80 R k is selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, dimethylphenylsilyl, trimethylsilyl, triethylsilyl, and triisopropylsilyl; 3.81 R k is tert-butyldimethylsilyl, Method 3.80; 3.82 The protecting reagent is a silyl chloride (e.g., chlorotrimethylsilane, chlorotriethylsilane, chlorotripropylsilane, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, chlorodimethylphenylsilane, chlorotriphenylsilane), a silyl trifluoromethanesulfonate (e.g., trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate), bromotrimethylsilane, bromotriethylsilane, bromotripropylsilane, triisopropylsilyl bromide, tert-butyldimethylsilyl bromide, bromodimethylphenylsilane, bromotriphenylsilane), N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N- any of Methods 3.77-3.81, wherein the alkoxy group is selected from (trimethylsilyl)trifluoroacetamide, benzyl halides (e.g., 3,5-dimethoxybenzyl chloride, 3,5-dimethoxybenzyl bromide), dibenzyl carbonate, acid chlorides (e.g., pivaloyl chloride, acetyl chloride, benzoyl chloride), anhydrides (e.g., di-tert-butyl carbonate), chloroformates (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, 1-phenylethyl chloroformate), alkyl halides (e.g., trityl chloride, tert-butyl chloride, benzyl bromide, benzyl chloride, 2-chloro-2-phenylpropane), and alkoxymethyl halides (e.g., methoxymethyl chloride); 3.83 Any of methods 3.77-3.82, wherein the reaction further comprises a base; 3.84 The base may be a tertiary amine (e.g., trimethylamine, triethylamine, N-methylmorpholine, N-ethylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine), an inorganic hydride (e.g., sodium hydride, potassium hydride), or a tertiary amine (e.g., methylisopropylamine ... Method 3.83, wherein the base is selected from: lithium hydride, lithium amide bases (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), organolithium bases (e.g., n-butyllithium, s-butyllithium, t-butyllithium), and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monobasic, dibasic, or tribasic), sodium phosphate (monobasic, dibasic, or tribasic)); 3.85 Method 3.84, wherein the protecting agent is tert-butyldimethylsilyl chloride and the base is triethylamine; 3.86 Any of methods 3.77-3.85, wherein the reaction further comprises a catalyst selected from 4-(dimethylamino)pyridine, 2,6-dimethylpyridine, N-methylimidazole, imidazole, 4-pyrrolidinopyridine, 4-piperidinopyridine, and 9-azajulolidine; 3.87 Any of Methods 3.77-3.86, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent; 3.88 Method 3.87, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.89 Method 3.87, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.90 Method 3.87, wherein the nonpolar solvent is an ether, and optionally the solvent is tetrahydrofuran or 2-methyltetrahydrofuran; 3.91 Any of Methods 3.77 to 3.90, wherein the reaction temperature is −30 to 100° C., e.g., −10 to 30° C., 0 to 25° C., or 0 to 100° C., e.g., 20 to 80° C., or 35 to 55° C., or about 45° C.; 3.92 Protected sulfonamide 6-G can be converted to compound 6-H, where R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R k (1) treating with a chlorinating agent and a base in a suitable solvent for a time and under conditions effective to form a chlorinating agent (wherein R is as defined in any of Methods 3.78-3.81); followed by (2) treating with a source of ammonia in a suitable solvent; 3.93 Method 3.92, wherein the chlorinating agent is selected from triphenylphosphine dichloride (Ph3PCl2) (optionally prepared in situ from triphenylphosphine and oxalyl chloride), phosphorus oxychloride (optionally prepared in situ from phosphorus pentoxide and a chloride salt, e.g., sodium chloride, potassium chloride, or tetrabutylammonium chloride), phenyl dichlorophosphate, triphenyl dichlorophosphorane, phenylphosphonic acid dichloride, oxalyl chloride, thionyl chloride, sulfuryl chloride, triphenyl phosphite dichloride complex ((PhO)3PCl2) (optionally prepared in situ from chlorine and triphenyl phosphite), phosphorus(V) oxychloride, phosphorus trichloride, phosphorus pentachloride, and hydrogen chloride; 3.94 Method 3.93, wherein the chlorinating agent is triphenylphosphine dichloride, optionally prepared in situ from triphenylphosphine oxide and oxalyl chloride; 3.95 Any of Methods 3.92-3.94, wherein the base is selected from tertiary amines (e.g., trimethylamine, triethylamine, N-methylmorpholine, N-ethylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), and aromatic amines (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine); 3.96 Method 3.95, wherein the base is N,N-diisopropylethylamine; 3.97 Any of Methods 3.92-3.96, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent; 3.98 Method 3.97, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.99 Method 3.97, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.100 Method 3.97, in which the nonpolar solvent is dichloromethane; 3.101 Any of Methods 3.92-3.100, wherein the ammonia source is selected from ammonia gas dissolved in any of the solvents provided in Methods 3.97-3.100, aqueous ammonia, inorganic ammonium salts (e.g., ammonium chloride, ammonium bromide, ammonium sulfate, ammonium acetate), ammonia surrogates (e.g., hexamethyldisilazane), amides (e.g., acetamide), and carbamates (e.g., tert-butyl carbamate); 3.102 Method 3.101, wherein the ammonia source is ammonia dissolved in a solvent, optionally the solvent is the same solvent as the reaction solvent from step (1) (e.g., the reaction solvent is dichloromethane and the ammonia source is ammonia gas dissolved in dichloromethane); 3.103 Any of Methods 3.92 to 3.102, wherein the reaction temperatures in Step (1) and Step (2) are independently selected from −40 to 60°C, −25 to 30°C, −20 to 30°C, −20 to 10°C, −10 to 30°C, −10 to 10°C, −20 to 0°C, −10 to 0°C, and 0 to 30°C; 3.104 Step (1) comprises combining compound 6-G with a base and a suitable solvent at a temperature of −20 to 0° C., followed by adding a chlorinating agent (or forming the chlorinating agent in situ) and stirring the reaction for a period of 0.5 to 10 hours (e.g., 1 to 5 hours), followed by Any of Methods 3.92-3.103, wherein step (2) comprises cooling the reaction to -40 to -10°C, adding an ammonia source, and stirring the reaction at a temperature ranging from -10°C to 10°C for a period of 0.1 to 5 hours (e.g., 0.1 to 2 hours); 3.105 The mono-protected sulfonimidamide compound 6-H is reacted with the di-protected sulfonimidamide compound 6-I (wherein R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R k is as defined in any of Methods 3.78-3.81, except that R p is R kwith a protecting agent for a time and under conditions effective to obtain (which is not the same as 3.106 R k is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., t-butyldiphenylsilyl), and triarylsilyl groups (e.g., triphenylsilyl); 3.107 R k is selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, dimethylphenylsilyl, trimethylsilyl, triethylsilyl, and triisopropylsilyl; method 3.106; 3.108 R k is tert-butyldimethylsilyl, Method 3.107; 3.109 Protecting group R p is a silyl group, an alkylcarbonyl group (e.g., -C(=O)-C 1~6 Alkyl, for example, acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1~6 Alkyl (aryl), for example, 2-phenylethylcarbonyl or 1-phenylethylcarbonyl, arylcarbonyl group (for example, benzoyl), alkoxycarbonyl group (for example, -C(=O)-OC 1~6 Alkyl, for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl, or -C(=O)-OC 1~6 Alkyl (aryl), for example, 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl), aryloxycarbonyl group (for example, phenoxycarbonyl), tertiary alkyl group (for example, t-butyl or trityl), C 1~6 Alkoxy C 1~6 Alkyl groups (e.g., C 1~6 alkoxymethyl, for example, methoxymethyl or ethoxymethyl), C 1~6Alkylaryl groups (e.g., benzyl, 3,5-dimethoxybenzyl, 1-methylbenzyl), diarylalkyl groups (e.g., C 1~6 alkyl(aryl)(aryl), e.g., diphenylmethyl), alkylsulfonyl groups (e.g., SO2C 1~6 any of methods 3.105-3.108, wherein the aryl group is selected from alkyl (e.g., methanesulfonyl or isopropylsulfonyl), and arylsulfonyl groups (e.g., SO2-aryl, e.g., benzenesulfonyl, toluenesulfonyl); 3.110 R p But -C(=O)-C 1~6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1~6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1~6 Method 3.109, selected from alkyl(aryl) (e.g., 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl), and —C(═O)—O-aryl (e.g., phenoxycarbonyl); 3.111 R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; method 3.110; 3.112 R p is optionally 1-phenylethoxycarbonyl in (R) or (S) form; 3.113 The protecting reagent is a silyl chloride (e.g., chlorotrimethylsilane, chlorotriethylsilane, chlorotripropylsilane, triisopropylsilyl chloride, tert-butylsilane ... t-butyldimethylsilyl chloride, chlorodimethylphenylsilane, chlorotriphenylsilane), silyl trifluoromethanesulfonates (e.g., trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, dimethylphenylsilyl trifluoromethanesulfonate, triphenylsilyl trifluoromethanesulfonate), silyl bromides (e.g., bromotrimethylsilane, bromotriethylsilane, bromotripropylsilane, triisopropylsilyl bromide, tert-butyldimethylsilyl bromide, bromodimethylphenylsilane, bromotriphenylsilane), N,O-bis(trimethylsilyl)acetamide, N,O- any of methods 3.105-3.112, wherein the aryl group is selected from bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, benzyl halides (e.g., 3,5-dimethoxybenzyl chloride, 3,5-dimethoxybenzyl bromide), dibenzyl carbonate, acid chlorides (e.g., pivaloyl chloride, acetyl chloride, benzoyl chloride), anhydrides (e.g., di-tert-butyl carbonate), chloroformates (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, 1-phenylethyl chloroformate), alkyl halides (e.g., trityl chloride, tert-butyl chloride, benzyl bromide, benzyl chloride, 2-chloro-2-phenylpropane), and alkoxymethyl halides (e.g., methoxymethyl chloride); 3.114 The protecting agent is optionally prepared by reacting the corresponding C 1~6 Alkyl alcohol or C 1~6 C, which is prepared in situ by reacting an alkyl (aryl) alcohol with carbonyldiimidazole (CDI) followed by the addition of compound 6-H. 1~6 Alkyl or C 1~6 any of methods 3.105 to 3.112, wherein the compound is an alkyl(aryl) 1H-imidazole-1-carboxylate; 3.115 The protecting agent is a symmetrical or unsymmetrical carbonate (e.g., di-tert-butyl dicarbonate or 4-nitrophenyl(1-phenylethyl) carbonate), C 1~6 Alkyl or C 1~6 Alkyl (aryl) chloroformates (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, 1-phenylethyl chloroformate), or C 1~6 Alkyl or C 1~6 alkyl(aryl) 1H-imidazole-1-carboxylates; 3.116 Method 3.115, wherein the protecting agent is selected from 1-phenylethyl-1H-imidazole-1-carboxylate (optionally made in situ from 1-phenylethanol and CDI), 4-nitrophenyl-(1-phenylethyl)carbonate, and 1-phenylethyl chloroformate, each of which is optionally in the (R) or (S) form; 3.117 Any of methods 3.105-3.116, wherein the reaction further comprises a base; 3.118 The base may be a tertiary amine (e.g., trimethylamine, triethylamine, N-methylmorpholine, N-ethylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine), an inorganic hydride (e.g., sodium hydride), lithium hydride, potassium hydride, lithium hydride), amide bases (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), organic lithium bases (e.g., n-butyllithium, s-butyllithium, t-butyllithium), and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monobasic, dibasic, or tribasic), sodium phosphate (monobasic, dibasic, or tribasic), sex)) selected from method 3.117; 3.119 Method 3.118, wherein the base is an inorganic hydride (e.g., sodium hydride, potassium hydride, lithium hydride), an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), or an organic lithium base (e.g., n-butyllithium, s-butyllithium, t-butyllithium); 3.120 Method 3.119, wherein the protecting agent is (S)-1-phenylethyl 1H-imidazole-1-carboxylate (optionally made in situ from (S)-1-phenylethanol and CDI) and the base is lithium hexamethyldisilado; 3.121 Any of methods 3.105-3.120, wherein the reaction further comprises a catalyst selected from 4-(dimethylamino)pyridine, 2,6-dimethylpyridine, N-methylimidazole, imidazole, 4-pyrrolidinopyridine, 4-piperidinopyridine, and 9-azajulolidine; 3.122 Any of methods 3.105-3.121, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent; 3.123 Method 3.122, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.124 Method 3.122, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.125 Method 3.122, wherein the nonpolar solvent is an ether, and optionally the solvent is tetrahydrofuran or 2-methyltetrahydrofuran; 3.126 Any of Methods 3.105 to 3.125, wherein the reaction temperature is −30 to 100° C., e.g., −20 to 60° C., −20 to 10° C., 0 to 25° C., or 0 to 100° C., e.g., 20 to 80° C. or 35 to 55° C.; 3.127 Compound 6-I is reacted with compound 6-J (wherein R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R k is as defined in any of Methods 3.78-3.81, and R p is as defined in any of Methods 3.109-3.112, except that R p is R kwith a deprotecting agent for a time and under conditions effective to form a methyl group (which is not the same as 3.128 R k is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., t-butyldiphenylsilyl), and triarylsilyl groups (e.g., triphenylsilyl); 3.129 R k is selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, dimethylphenylsilyl, trimethylsilyl, triethylsilyl, and triisopropylsilyl; 3.130 R k is tert-butyldimethylsilyl, Method 3.129; 3.131 R p But -C(=O)-C 1~6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1~6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1~6 Alkyl (aryl) (e.g., 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl) any of methods 3.127-3.130, wherein the alkyl group is selected from -C(=O)-O-aryl (e.g., phenoxycarbonyl), and -C(=O)-O-aryl (e.g., phenoxycarbonyl); 3.132 R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; method 3.131; 3.133 R pis optionally 1-phenylethoxycarbonyl in (R) or (S) form; 3.134 R k is tert-butyldimethylsilyl, and R p is optionally 1-phenylethoxycarbonyl in (R) or (S) form; 3.135 Any of methods 3.127-3.134, wherein the deprotecting reagent is selected from an inorganic base (e.g., an aqueous solution thereof), an inorganic acid (e.g., an aqueous or organic solvent solution thereof), a fluoride agent (e.g., in an organic solvent), a hydrogenation agent (e.g., hydrogen in combination with a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex), or a phase transfer hydrogenation system), optionally further comprising a phase transfer agent; 3.136 The deprotecting reagent may be sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, lithium carbonate, sodium phosphate (mono-, di-, or tribasic), potassium phosphate (mono-, di-, or tribasic), hydrochloric acid (e.g., aqueous HCl, HCl in ether, HCl in methanol, HCl in isopropanol), sulfuric acid, acetic acid, trifluoroacetic acid, phosphoric acid, methanesulfonic acid, hydrofluoric acid, hydrogen fluoride pyridine, hydrogen fluoride triethylamine, potassium fluoride, sodium fluoride, lithium fluoride Method 3.135, wherein the catalyst is selected from ammonium, cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, triethylamine trihydrofluoride, tetrabutylammonium difluorotriphenylsilicate, hydrogen in combination with a catalyst (e.g., Pd, Pd / C, Pt, Ru / C, Raney nickel, Ru complexes, Rh complexes, PtO2, Pt complexes, Pd complexes, Ir complexes), and ammonium formate in combination with a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt, PtO2); 3.137 R k any of methods 3.127 to 3.136, wherein is a silyl group and the deprotecting agent is a fluoride agent or an inorganic base; 3.138 R kis a trialkylsilyl group (e.g., tripropylsilyl, triisopropylsilyl, t-butyldiethylsilyl, t-butyldimethylsilyl) and the deprotecting reagent is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, monobasic sodium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, potassium bicarbonate, potassium carbonate, monobasic potassium phosphate, dibasic potassium phosphate, tribasic potassium phosphate, lithium carbonate, cesium carbonate, sodium fluoride, potassium fluoride, cesium fluoride, triethylamine trihydrofluoride, tetrabutylammonium fluoride, tetrabutylammonium difluorotriphenylsilicate, and tetrabutylammonium difluorotriphenylsilicate; 3.139 R k is t-butyldimethylsilyl and the deprotecting agent is selected from sodium carbonate, potassium carbonate, and cesium carbonate; 3.140 Any of methods 3.127-3.139, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent, or a combination thereof; 3.141 Method 3.140, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.142 The polar protic solvent is an alcohol solvent (e.g., ethanol), optionally in combination with water. Method 3.140, wherein the polar protic solvent is water, or the polar protic solvent is methanol, ethanol, propanol, isopropanol, tert-butanol, tert-amyl alcohol; 3.143 Method 3.140, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile), optionally in combination with water; 3.144 Method 3.140, wherein the suitable solvent is tetrahydrofuran or 2-methyltetrahydrofuran, optionally in combination with water; 3.145 Any of Methods 3.127 to 3.144, wherein the reaction temperature is −15 to 70° C., for example, −5 to 40° C., or 0 to 30° C., or 10 to 30° C., or 20 to 70° C., 40 to 60° C., or about 50° C. 3.146 Compound 6-J is reacted with compound 6-K (wherein R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R e Method 3, or any of Methods 3.1 to 3.145, comprising acylating with an acylating agent and a base for a time and under conditions effective to form a methyl group (wherein 3.147 R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; method 3.146; 3.148 R p is optionally 1-phenylethoxycarbonyl in (R) or (S) form; 3.149 R'' is H, C 1~6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), haloC 1~6any of methods 3.146-3.148, wherein R is selected from alkyl (e.g., trifluoromethyl, trichloromethyl), optionally substituted aryl (e.g., phenyl, 4-bromophenyl), and optionally substituted heteroaryl (e.g., 2-pyridyl); 3.150 R'' is C 1~6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), Method 3.149; 3.151 Method 3.150, wherein R'' is methyl; 3.152 Any of methods 3.146-3.151, wherein the acylating agent is an acid chloride (e.g., R″—C(═O)—Cl), an acid anhydride (e.g., R″—C(═O)—O—(C═O)—R″), or a carboxylic acid (e.g., R″—COOH) in combination with an activating or coupling reagent (e.g., oxalyl chloride, thionyl chloride, phosphoryl chloride, 1,1-carbonyldiimidazole, a carbodiimide reagent (e.g., DCC or EDC), or any other peptide coupling reagent (e.g., HATU, T3P, isobutyl chloroformate); 3.153 R'' is C 1~6 alkyl (e.g., methyl) and the acylating agent is an acid chloride (e.g., R″—C(═O)—Cl) or an acid anhydride (e.g., R″—C(═O)—O—(C═O)—R″), Method 3.152; 3.154 Any of methods 3.146-3.153, wherein the base is selected from tertiary amines (e.g., trimethylamine, triethylamine, N-methylmorpholine, N-ethylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), and aromatic amines (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine); 3.155 Method 3.154, wherein the base is pyridine; 3.156 The reaction is carried out using, for example, 4-dimethylaminopyridine, imidazole, N-methyl Any of methods 3.146-3.155, further comprising a catalyst selected from imidazole, triphenylphosphine oxide, 1-hydroxy-7-azabenzotriazole, and N,N-dimethylformamide; 3.157 Any of methods 3.146-3.156, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent; 3.158 Method 3.157, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.159 Method 3.157, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.160 Method 3.157, in which the nonpolar solvent is dichloromethane; 3.161 Any of methods 3.146 to 3.160, wherein the reaction temperature is −20 to 60° C., e.g., −5 to 40° C., or 0 to 30° C., or 10 to 30° C., or about 25° C.; 3.162 Compound 6-K is reacted with a mixture of hydrolyzed stereoisomer 6-L and unreacted stereoisomer 6-L′ (wherein R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R eMethod 3, or any of Methods 3.1 to 3.161, comprising stereoselectively (e.g., enantioselectively or diastereoselectively) hydrolyzing, for a time and under conditions effective to obtain (wherein R is defined as in any of Methods 3.109 to 3.112) 3.163 R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; method 3.162; 3.164 R p is optionally 1-phenylethoxycarbonyl in (R) or (S) form; 3.165 R'' is C 1~6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), Method 3.164; 3.166 Method 3.165, where R'' is methyl; 3.167 Any of methods 3.162-3.166, wherein the reaction comprises treating compound 6-K with an enzyme such as a lipase or protease, e.g., a bacterial or fungal lipase or protease; 3.168 Method 3.167, wherein the lipase or protease is derived from a Candida species (e.g., Candida rugosa), a Pseudomonas species (e.g., Pseudomonas stutzeri), or a Rhizomucor species (e.g., Rhizomucor miehei); 3.169 Any of methods 3.162-3.168, wherein the reaction optionally further comprises an aqueous buffer solution having a pH between 5 and 8 (e.g., a pH of about 7), such as a sodium phosphate buffer or a potassium phosphate buffer; 3.170 Any of methods 3.162-3.169, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent, water, or a combination thereof; 3.171 Nonpolar solvents include ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chloroform). Method 3.170, selected from: 3.172 Method 3.170, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), and nitriles (e.g., acetonitrile); 3.173 Method 3.170, in which the nonpolar solvent is methyl isobutyl ketone in combination with aqueous sodium phosphate buffer (pH about 7); 3.174 Any of methods 3.162-3.173, wherein the temperature of the reaction is 0-50°C, e.g., 10-40°C, or 10-30°C, or about 20°C; 3.175 Any of methods 3.162-3.174, wherein compound 6-L and compound 6-L' are purified and isolated separately; 3.176 comprising converting compound 6-B to compound 6-B' by replacing group X with a different group X, wherein R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4 to 3.10, and the group X of compound 6-B is a sulfonate (e.g., 4-toluenesulfonate, mesylate, nosylate, benzenesulfonate, triflate); 3.177 Method 3.176, in which group X of compound 6-B' is a halide (e.g., chloride, bromide, or iodide); 3.178 Method 3.177, in which the group X in compound 6-B is 4-toluenesulfonate and the group X in compound 6-B′ is bromine; 3.179 Method 3.176, 3.177, or 3.178, comprising treating compound 6-B with an inorganic halide salt (e.g., lithium, sodium, potassium, or cesium salt of chloride, bromide, or iodide) in a suitable solvent; 3.180 Method 3.179, in which the inorganic halide is lithium bromide; 3.181 Any of methods 3.176-3.180, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent; 3.182 Method 3.181, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.183 Method 3.181, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, nitriles (e.g., acetonitrile), and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate); 3.184 Method 3.181, in which the polar aprotic solvent is N-methyl-2-pyrrolidinone; 3.185 Any of methods 3.176 to 3.184, wherein the reaction temperature is 20 to 120°C, e.g., 20 to 100°C or 40 to 60°C; 3.186 Compound 6-B or 6-B′ is reacted with sulfonic acid 7-A (wherein R y is as defined in Method 3.2 or 3.3, and R 2 and R 3with a sulfite source for a time and under conditions effective to obtain compound 6-B, wherein the group X of compound 6-B is selected from halide (e.g., chloride, bromide, iodide), sulfonate (e.g., 4-toluenesulfonate, mesylate, nosylate, benzenesulfonate, triflate), and oxyphosphonium (e.g., oxytriphenylphosphonium), or wherein the group X of compound 6-B′ is halide (e.g., bromide, chloride, or iodide); 3.187 The group X in compound 6-B or 6-B' is a halide, optionally Method 3.186, wherein the halide is bromide or iodide; 3.188 Method 3.186 or 3.187, in which the sulfite source is an inorganic sulfite or bisulfite, e.g., lithium, sodium, potassium, or cesium sulfite or bisulfite; 3.189 Method 3.188, in which the sulfite source is sodium sulfite; 3.190 Any of methods 3.186-3.189, wherein the suitable solvent is a nonpolar solvent, a polar aprotic solvent, water, or a combination thereof; 3.191 Method 3.190, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.192 Method 3.190, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, nitriles (e.g., acetonitrile), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate); 3.193 Method 3.190, in which the solvent is a mixture of acetone and water; 3.194 Any of methods 3.186 to 3.193, wherein the reaction temperature is 20 to 120°C, e.g., 40 to 100°C or 50 to 70°C; 3.195 The sulfonic acid 7-A is reacted with the sulfonamide compound 6-F, where R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 Method 3, or any of Methods 3.1 through 3.194, comprising the steps of (1) treating with a chlorinating agent and optionally a catalyst in a suitable solvent, for a time and under conditions effective to form a chlorinated amine, wherein X is as defined in any of Methods 3.4 through 3.10, followed by (2) treating with an ammonia source in a suitable solvent; 3.196 Method 3.195, wherein the chlorinating agent is selected from oxalyl chloride, thionyl chloride, sulfuryl chloride, phosphorus(V) oxychloride, phosphorus trichloride, and phosphorus pentachloride; 3.197 Method 3.196, wherein the chlorinating agent is oxalyl chloride; 3.198 Any of methods 3.195-3.197, wherein reacting step (1) further comprises a catalyst, e.g., 4-dimethylaminopyridine or N,N-dimethylformamide; 3.199 Any of Methods 3.195-3.198, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent, or the solvent is neat chlorinating agent (e.g., thionyl chloride). 3.200 Method 3.199, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.201 Method 3.199, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.202 Method 3.199, in which the solvent is tetrahydrofuran; 3.203 Any of Methods 3.195-3.302, wherein the ammonia source is selected from ammonia gas dissolved in any of the solvents provided in Methods 3.199-3.202, gaseous ammonia, aqueous ammonia, and an ammonia surrogate (e.g., hexamethyldisilazane); 3.204 Method 3.203, in which the ammonia source is aqueous ammonia; 3.205 Methods 3.195 to 3.2, wherein the reaction temperatures in steps (1) and (2) are independently selected from -10 to 100°C, 0 to 50°C, 0 to 30°C, and 20 to 30°C. Any of 04; 3.206 Any of Methods 3.195-3.205, wherein step (1) comprises combining compound 7-A with a catalyst and a suitable solvent at a temperature in the range of 0-30°C, followed by adding a chlorinating agent and stirring the reaction for a period of 0.1 hours to 2 hours (e.g., 0.5-1 hour), followed by step (2) comprising adding the reaction mixture from step (1) to a reactor containing an ammonia source and stirring the reaction for a period of 0.1 hours to 2 hours (e.g., 0.1-0.5 hours) at a temperature in the range of 10°C to 30°C; 3.207 Compound 6-H is reacted with diacyl compound 8-A (wherein R y is defined as in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R k acylation with an acylating agent and a base for a time and under conditions effective to form a silyl group; 3.208 R kis selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., t-butyldiphenylsilyl), and triarylsilyl groups (e.g., triphenylsilyl); 3.209 R k is selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, dimethylphenylsilyl, trimethylsilyl, triethylsilyl, and triisopropylsilyl; 3.210 R k is tert-butyldimethylsilyl, Method 3.209; 3.211 R'' is H, C 1~6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), haloC 1~6 any of methods 3.207-3.210, wherein R is selected from alkyl (e.g., trifluoromethyl, trichloromethyl), optionally substituted aryl (e.g., phenyl, 4-bromophenyl), and optionally substituted heteroaryl (e.g., 2-pyridyl); 3.212 R'' is C 1~6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), Method 3.211; 3.213 Method 3.212, where R'' is methyl; 3.214 Any of methods 3.207-3.213, wherein the acylating agent is an acid chloride (e.g., R″—C(═O)—Cl), an acid anhydride (e.g., R″—C(═O)—O—(C═O)—R″), or a carboxylic acid (e.g., R″—COOH) in combination with an activating or coupling reagent (e.g., oxalyl chloride, thionyl chloride, phosphoryl chloride, 1,1-carbonyldiimidazole, a carbodiimide reagent (e.g., DCC or EDC), or any other peptide coupling reagent (e.g., HATU, T3P, isobutyl chloroformate); 3.215 R'' is C 1~6 alkyl (e.g., methyl) and the acylating agent is an acid chloride (e.g., R″—C(═O)—Cl), an acid anhydride (e.g., R″—C(═O)—O—(C═O)—R″), Method 3.214; 3.216 Method 3.215, where R'' is methyl and the acylating agent is acetyl chloride; 3.217 The base is a tertiary amine (e.g., trimethylamine, triethylamine, N-methylmorpholine, N-ethylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (e.g., pyridine, pyrimidine, pyridazine, pyrazine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine), an amide base (e.g., sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), or a tertiary amine (e.g., pyridine, pyrimidine, pyridazine, pyrazine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine), an amide base (e.g., sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide). any of Methods 3.207-3.216, wherein the alkoxide is selected from a methyl methyl ester, a propyl amide, and an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide); 3.218 Method 3.217, wherein the base is an aromatic amine selected from pyridine, pyrimidine, pyridazine, and pyrazine; 3.219 Any of methods 3.207-3.218, wherein the reaction further comprises a catalyst selected from, for example, 4-dimethylaminopyridine, imidazole, N-methylimidazole, triphenylphosphine oxide, 1-hydroxy-7-azabenzotriazole, and N,N-dimethylformamide; 3.220 Any of methods 3.207-3.219, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent; 3.221 Method 3.220, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.222 Method 3.220, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.223 Method 3.220, in which the solvent is acetonitrile; 3.224 Any of Methods 3.207 to 3.223, wherein the reaction temperature is −20 to 50° C., e.g., −5 to 40° C., or 0 to 30° C., or 10 to 30° C., or about 20° C.; 3.225 Compound 8-A is converted to the hydrolyzed stereoisomer 8-B (wherein R y is defined as in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R″ is as defined in any of Methods 3.211-3.213; 3.226 R'' is C 1~6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), Method 3.225; 3.227 Method 3.226, where R'' is methyl; 3.228 Any of methods 3.225-3.227, wherein the reaction comprises treating compound 8-B with an enzyme such as a lipase or protease, e.g., a bacterial or fungal lipase or protease; 3.229 Method 3.228, wherein the lipase or protease is derived from a Carica species (e.g., Carica papaya); 3.230 Any of methods 3.225-3.229, wherein the reaction optionally further comprises an aqueous buffer solution having a pH between 5 and 8 (e.g., a pH of about 7), such as a sodium phosphate buffer or a potassium phosphate buffer; 3.231 Any of methods 3.225-3.230, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent, water, or a combination thereof; 3.232 Nonpolar solvents include ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halides. Method 3.231, wherein the halogenated solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, and chlorobenzene; 3.233 Method 3.231, in which the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), and nitriles (e.g., acetonitrile); 3.234 Method 3.231, in which the nonpolar solvent is methyl isobutyl ketone in combination with aqueous sodium phosphate buffer (pH about 7); 3.235 Any of Methods 3.225-3.234, wherein the temperature of the reaction is 0-50°C, e.g., 10-40°C, or 20-40°C, or about 30°C; 3.236 Method 3, or any of methods 3.1 through 3.235, wherein any one or more of compounds 6-B, 6-B', 6-C, 6-D, 6-E, 6-F, 6-G, 6-H, 6-I, 6-J, 6-K, 6-L, 6-L', 7-A, 8-A, and 8-B is produced; 3.237 In any one or more of the compounds, R y is H and R 2 But H or C 1~3 alkyl (e.g., methyl), and R 3 But H or C 1~3 alkyl (e.g., methyl), X is 4-toluenesulfonyl or bromo, and R e is 2-pyrimidyl, M is Na, and R k is trialkylsilyl (e.g., tert-butyldimethylsilyl), and R p But -C(=O)-OC 1~6 alkyl(aryl) (e.g., 1-phenylethoxycarbonyl, optionally in the (R) or (S) form), where R″ is C 1~3 alkyl (e.g., methyl), Method 3.236; 3.238 In one or more of the compounds, R 2 and R 3 is H or R 2 and R 3 is methyl, or R 2 is H and R 3 is methyl, Method 3.237; 3.239 In one or more of the compounds, R 2 is H and R 3 is methyl, Method 3.238; 3.240 Method 3, or any of Methods 3.1 through 3.239, in which a compound is produced by any one or more of Compounds 9-A, 9-B, 9-C, 9-D, or 9-E; 3.241 Method 3.240, wherein one or more of compounds 9-A, 9-B, 9-C, 9-D, or 9-E is made according to any one or more of Method 4 or Method 4.1, see below, or Method 5 or Method 5.1, see below; 3.242 In one or more of the compounds, R x is H and R y is H and R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R 4 is H and R 5 But C 1~3 alkyl (e.g., methyl), and R 6 is halogen (e.g., chloro), and / or R 12 is H or -C(O)-R 1 (In the formula, R 1 is an optionally substituted C 1~6 Alkyl (e.g., methyl), optionally substituted C 1~6 Method 3.240 or 3.241, wherein R is selected from alkoxy (e.g., (S)-1-phenylethoxy), or optionally substituted 5-10 membered heteroaryl (e.g., 1-methyl-3-methoxy-1H-pyrazol-4-yl); 3.243 In one or more of the compounds, R x is H and R y is H and R 2 and R 3 are independently H or methyl, and R 4 is H and R 5 is methyl, and R 6 is chloro, Method 3.242; 3.244 In one or more of the compounds, R 2 and R 3 is H or R 2 and R 3 is methyl, or R 2 is H and R 3 is methyl, Method 3.243; 3.245 In one or more of the compounds, R 2 is H and R 3 is methyl, Method 3.244; 3.246 In compound 9-C, R 12 But C(O)-R1 and R 1 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 cycloalkyl , C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and —NR 8 R 9 C is selected from 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are optionally joined by 1 to 5 R 10 substituted with groups; each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocyclic ring together with the atom to which they are attached, and each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocycle together with the atom to which they are bonded, and the C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl optionally contain 1 to 5 R 10 substituted with a group; 10 Each of the groups is independently C 1~6Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a , and -NR a R b Selected from;R a and R b are independently hydrogen or C 1~6 any of methods 3.240 to 3.245, which is alkyl; 3.247 In compound 9-C, R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10 5-10 membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl) substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, C 1~6 Method 3.246, selected from alkoxy, and halogen; 3.248 In compound 9-C, R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10 pyrazolyl or imidazolyl substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl (e.g., methyl) or C 1~6 alkoxy (e.g., methoxy), Method 3.247; 3.249 In compound 9-C, R 12 But -C(O)-R 1 and R 1 However, you can optionally select 1 to 3 C 1~6 Alkyl (e.g., methyl) or C 1~6 pyrazolyl substituted by alkoxy (e.g., methoxy), e.g., R 1is 3-methoxy-1-methyl-1H-pyrazolyl, Method 3.247; 3.250 Method 3 or any of Methods 3.1 to 3.249, wherein a compound according to Compound I is produced; 3.251 Method 3.250, wherein compound I is compound I(a); 3.252 Method 3.251 or 3.251, wherein compound I or I(a) is made according to any one or more of Method 4 or Method 4.1, see below, or Method 5 or Method 5.1, see below; 3.253 In compound I or I(a), R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R 4 is H and R 5 But C 1~3 alkyl (e.g., methyl), and R 6 is halogen (e.g., chloro), and / or R 12 But -C(O)-R 1 and R 1 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and —NR 8 R 9 C is selected from 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are optionally joined by 1 to 5 R 10 substituted with groups; each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocyclic ring together with the atom to which they are attached, and each R 8 Reach BiR 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocycle together with the atom to which they are bonded, and the C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl optionally contain 1 to 5 R 10 substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a , and -NR a R b Selected from;R a and R b are independently hydrogen or C 1~6 any of methods 3.250 to 3.252, wherein the alkyl is 3.254 In compound I or I(a), R 2 and R 3 are independently H or methyl, and R 4 is H and R 5 is methyl, and R 6 is chloro, Method 3.253; 3.255 In compound I or I(a), R 2 and R 3 is H or R 2 and R3 is methyl, or R 2 is H and R 3 is methyl, Method 3.254; 3.256 In compound I or I(a), R 2 is H and R 3 is methyl, Method 3.255; 3.257 In compound I or I(a), R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10 a 5- to 10-membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl) substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, C 1~6 any of methods 3.253 to 3.256, wherein the alkoxy group is selected from alkoxy and halogen; 3.258 In compound I or I(a), R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10 pyrazolyl or imidazolyl substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl (e.g., methyl) or C 1~6 alkoxy (e.g., methoxy), Method 3.257; 3.259 In compound I or I(a), R 12 But -C(O)-R 1 and R 1 However, you can optionally select 1 to 3 C 1~6 Alkyl (e.g., methyl) or C 1~6 pyrazolyl substituted by alkoxy (e.g., methoxy), e.g., R 1 is 3-methoxy-1-methyl-1H-pyrazolyl, Method 3.258; 3.260 Any of Methods 3.240-3.259, wherein in one or more of Compound 9-E, Compound I, or Compound I(a), is a double bond; 3.261 Method 3 or any of Methods 3.1-3.260 to produce Compound 1; 3.262 Method 3 or any of Methods 3.1-3.261, further comprising any step of any of Method 1, see below, Method 2, see below, Method 4, see below, and Method 5, see below.

[0023] In a fifth aspect, the present disclosure provides a method (Method 4) for making a compound selected from one or more of compounds 9-A, 9-B, 9-C, 9-D, 9-E, and compounds I or I(a) described herein, comprising reacting a precursor compound with one or more reagents in a suitable solvent for a time and under conditions effective to form a product compound. Method 4 generally relates to the formation of the SNO-CB-TC cyclic fragment (including a ring-closing metathesis step) and the subsequent attachment of side chain fragments (SC) including intermediates 9-B, 9-C, and 9-E, and the further evolution of these intermediates to compound 1. While not limited to the order or combination of steps used, possible embodiments of Method 4 can include any of the steps shown in Scheme 9. [ka]

[0024] In certain embodiments, the present disclosure provides Method 4 as follows: 4.1 Compound 6-L′ is converted to the opposite stereoisomer 8-B (wherein R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R p Method 4, comprising deprotecting with a deprotecting agent for a time and under conditions effective to obtain (R" is as defined in any of Methods 3.109-3.112 and R" is as defined in any of Methods 3.211-3.213); 4.2 R pis selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; 4.3 R p is optionally 1-phenylethoxycarbonyl in (R) or (S) form; 4.4 R'' is C 1~6 any of Methods 4.1-4.3, wherein the alkyl is alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl); 4.5 Method 4.4, where R'' is methyl; 4.6 The deprotection reagent may be an inorganic base (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, lithium carbonate, sodium phosphate (mono-, di-, or tribasic), potassium phosphate (mono-, di-, or tribasic), optionally as an aqueous solution thereof), an inorganic acid (e.g., an aqueous solution thereof or an organic solvent thereof), solution), a fluoride agent (e.g., hydrofluoric acid, hydrogen fluoride pyridine, hydrogen fluoride triethylamine, potassium fluoride, sodium fluoride, lithium fluoride, cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, triethylamine trihydrofluoride, tetrabutylammonium difluorotriphenylsilicate, optionally in an organic solvent), a hydrogenation agent (e.g., a heterogeneous catalyst (e.g., any of Methods 4.1-4.5, wherein the catalyst is selected from a homogeneous catalyst (e.g., a soluble transition metal complex), e.g., hydrogen in combination with Pd, Pd / C, Pt, Ru / C, Raney nickel, Ru complexes, Rh complexes, PtO, Pt complexes, Pd complexes, Ir complexes, or a phase transfer hydrogenation system such as ammonia formate in combination with a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt, PtO)), optionally further comprising a phase transfer agent or enzyme; 4.7 Method 4.6, wherein the deprotecting agent is an acid selected from, for example, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonate, sulfuric acid, hydrochloric acid (e.g., aqueous HCl, HCl in ether, HCl in methanol, HCl in isopropanol), hydrobromic acid, acetic acid, formic acid, phosphoric acid, and oxalic acid, and optionally the acid is trifluoroacetic acid; 4.8 Any of Methods 4.1-4.7, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent; 4.9 Method 4.8, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 4.10 Method 4.8, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 4.11 Method 4.8, where the solvent is dichloromethane; 4.12 Any of Methods 4.1 to 4.11, wherein the reaction temperature is −50 to 50° C., for example, 0 to 40° C., or 10 to 30° C., or about 20° C.; 4.13 Sulfonimide amide compound 8-B or sulfonimide amide compound 6-L is converted into N-acylsulfonimide amide compound 9-A (wherein R y is defined as in Method 3.2 or 3.3, and R 2 and R 3 R of compound 6-L is as defined in any of Methods 3.4-3.10) with carboxylic acid 1-K for a time and under conditions effective to form pis defined as in any of Methods 3.109-3.112, R″ of compound 8-B is defined as in any of Methods 3.211-3.213, and R x is defined as in Method 1.18 or 1.19, and R 5 is defined as in any of methods 1.75 to 1.78, and R 6 is hydrogen or halogen; 4.14 R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; Method 4.13; 4.15 R p is optionally 1-phenylethoxycarbonyl in the (R) or (S) form; 4.16 R'' is C 1~6 any of Methods 4.13-4.15, wherein the alkyl is alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl); 4.17 Method 4.16, where R'' is methyl; 4.18 The acid activator is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC-HCl), carbonyldiimidazole (CDI), propylphosphine Sulfonic anhydride (T3P), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM), thionyl chloride, oxalyl chloride, (chloromethylene)-dimethyliminium chloride, isobutyl chloroformate, N,N,N,N',N'-tetramethylchloride any of Methods 4.13-4.17, wherein the chloroformamidinium hexafluorophosphate (TCFH), N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, diphenyl chlorophosphate, 2,4,6-trichlorobenzoyl chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), (PhO)2POCl, oxalyl chloride ((COCl)2), and thionyl chloride (SOCl)2); 4.19 Method 4.18, wherein the acid activator is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC HCl); 4.20 Any of Methods 4.13-4.19, wherein the base is selected from tertiary amines (e.g., N-methylmorpholine, triethylamine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, DABCO), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, 1-methylimidazole), inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, and bicarbonate derivatives, monobasic, dibasic, or tribasic potassium and sodium phosphates); 4.21 Method 4.20, wherein the base is imidazole; or, in one embodiment, the base is 1-methylimidazole; 4.22 Any of Methods 4.13-4.21, wherein the reaction includes a promoter selected from 4-dimethylaminopyridine (DMAP), N-methylimidazole, 1-hydroxy-7-azabenzotriazole (HOAt), and 1-hydroxybenzotriazole (HOBt); 4.23 Any of Methods 4.13-4.22, wherein the acid activator is EDC-HCl, the base is 1-methylimidazole, and the promoter is DMAP; 4.24 Any of Methods 4.13-4.23, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent, or a combination thereof with water; 4.25 Method 4.24, wherein the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 4.26 Method 4.24., wherein the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), esters (e.g., ethyl acetate, isopropyl acetate), polar aprotic solvents (e.g., N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP)), nitriles (e.g., acetonitrile), hydrocarbon solvents (e.g., toluene), ketones (acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (2-propanol); halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 4.27 Method 4.24, wherein the solvent is N,N-dimethylformamide. In one embodiment, the solvent is acetonitrile; 4.28 The reaction temperature is -50 to 50°C, for example, 0 to 40°C, or 10 to 30°C. or 0°C to 80°C, or about 20°C; 4.29 Deprotecting compound 9-A with a deprotecting agent in a suitable solvent for a time and under conditions effective to form compound 9-B or deprotecting compound 9-D for a time and under conditions effective to form compound 9-E; y is defined as in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R p is defined as in any of Methods 3.109 to 3.112 or as —C(═O)—R″, where R″ is as defined in any of Methods 3.211 to 3.213, and R x is defined as in Method 1.18 or 1.19, and R 5 is defined as in any of methods 1.75 to 1.78, and R 6 is hydrogen or halogen; 4.30 R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; Method 4.29; 4.31 R p is optionally 1-phenylethoxycarbonyl in (R) or (S) form; 4.32 R p is -C(=O)-R'', and R'' is C 1~6 Any of Method 4.31, wherein the alkyl is alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl); 4.33 Method 4.32, where R'' is methyl; 4.34 Any of Methods 4.29-4.33, wherein the deprotecting reagent is selected from an inorganic base (e.g., an aqueous solution thereof), an inorganic acid (e.g., an aqueous or organic solvent solution thereof), a fluoride agent (e.g., in an organic solvent), a hydrogenation agent (e.g., hydrogen in combination with a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex), or a phase transfer hydrogenation system), optionally further comprising a phase transfer agent or an enzyme; 4.35 The deprotecting reagent may be sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, lithium carbonate, sodium phosphate (mono-, di-, or tribasic), potassium phosphate (mono-, di-, or tribasic), methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonate, sulfuric acid, hydrochloric acid, hydrobromic acid, acetic acid, formic acid , phosphoric acid, oxalic acid, citric acid, hydrochloric acid (e.g., aqueous HCl, HCl in ether, HCl in methanol, HCl in isopropanol), methanesulfonic acid, hydrofluoric acid, hydrogen fluoride pyridine, hydrogen fluoride triethylamine, potassium fluoride, sodium fluoride, lithium fluoride, cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, triethylamine trihydrofluoride, tetrabutylammonium difluorotriphenylsilicate, catalysts (e.g., Pd, Pd / C, Pt, Ru / C, Raney nickel, Ru complexes, Rh complexes, PtO 2、 Method 4.34, wherein the deprotecting reagent is selected from hydrogen in combination with a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt, PtO2), and ammonium formate in combination with a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt, PtO2); in one embodiment, the deprotecting reagent is sodium isopropoxide; in one embodiment, the deprotecting reagent is trifluoroacetic acid; 4.36 Method 4.34, wherein the deprotecting agent is an enzyme such as a lipase or protease, e.g., a bacterial or fungal lipase or protease; 4.37 Method 4.36, wherein the lipase or protease is derived from a Candida species (e.g., Candida rugosa), a Pseudomonas species (e.g., Pseudomonas stutzeri), or a Rhizomucor species (e.g., Rhizomucor miehei); 4.38 Method 4.37, in which the enzyme is a lipase from Pseudomonas stutzeri; 4.39 Methods 4.36-4.38, wherein the reaction optionally further comprises an aqueous buffer solution having a pH of 5-8 (e.g., pH about 7), such as a sodium phosphate buffer or a potassium phosphate buffer; 4.40 Any of Methods 4.29-4.39, wherein the suitable solvent is a nonpolar solvent, a polar aprotic solvent, a polar protic solvent, water, or a combination thereof; 4.41 Method 4.40, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); in one embodiment, the non-polar solvent is tolune; 4.42 Method 4.40, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), and nitriles (e.g., acetonitrile); 4.43 Method 4.40, wherein the polar protic solvent is selected from alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol), and water, or combinations thereof; 4.44 Method 4.40, wherein the non-polar solvent is methyl tert-butyl ether in combination with an aqueous sodium phosphate buffer solution (pH about 7). In one embodiment, the solvent is a combination of tetrahydrofuran (THF) and 2-propanol (IPA); 4.45 Any of Methods 4.29-444, wherein the temperature of the reaction is 0-100°C, e.g., 10-80°C, or 20-60°C, or 20-40°C, or 40-80°C, or 60-80°C, or about 30°C; in one embodiment, the temperature of the reaction is 10-30°C. In one embodiment, the temperature of the reaction is 60-80°C; 4.46 A method for producing a compound I comprising the steps of: acylating compound 9-B for a time and under conditions effective to form compound I9-C; or acylating compound 9-E for a time and under conditions effective to form compound I, wherein the step comprises treating the starting material compound with a suitable acylating agent and base in a suitable solvent; R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R x is defined as in Method 1.18 or 1.19, and R 5 is defined as in any of methods 1.75 to 1.78, and R 6 is hydrogen or halogen; 4.47 R 12 is as defined for compound I or I(a), Method 4.46; 4.48 R 12 But C(O)-R 1 and R 1 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and —NR 8 R 9 C is selected from 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are optionally joined by 1 to 5 R 10 substituted with groups; each R 8 and R9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocyclic ring together with the atom to which they are attached, and each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocycle together with the atom to which they are bonded, and the C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl optionally contain 1 to 5 R 10 substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, rogen, oxo, -OR a , and -NR a R b Selected from;R a and R b are independently hydrogen or C 1~6 alkyl, Method 4.46; 4.49 R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 105-10 membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl) substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, C 1~6 Method 4.48, selected from alkoxy, and halogen; 4.50 R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10 pyrazolyl or imidazolyl substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl (e.g., methyl) or C 1~6 alkoxy (e.g., methoxy), Method 4.49; 4.51 R 12 But -C(O)-R 1 and R 1 However, you can optionally select 1 to 3 C 1~6 Alkyl (e.g., methyl) or C 1~6 Method 4.50, which is a pyrazolyl substituted with alkoxy (e.g., methoxy); 4.52 R 12 But -C(O)-R 1 and R 1 is 3-methoxy-1-methyl-1H-pyrazolyl, Method 4.51; 4.53 R 12 But -C(O)-R 1 and R 1 is replaced by any optional C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 aryl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, and the acylating agent is an acid chloride (e.g., R 1 -C(=O)-Cl), acid anhydrides (e.g., R 1-C(=O)-O-(C=O)-R 1 ), or carboxylic acids (e.g., R 1 -COOH) in combination with an activating or coupling reagent (e.g., oxalyl chloride, thionyl chloride, phosphoryl chloride, 1,1-carbonyldiimidazole, a carbodiimide reagent (e.g., DCC or EDC), or any other peptide coupling reagent (e.g., HATU, T3P, isobutyl chloroformate); any of Methods 4.46-4.52; 4.54 The activating agent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC HCl), carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM), thionyl chloride, oxalyl chloride, (chloromethylene)-dimethyl Method 4.53, wherein the chloroformate is selected from chloroformium chloride, isobutyl chloroformate, N,N,N,N'N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH), N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, diphenyl chlorophosphate, 2,4,6-trichlorobenzoyl chloride, and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT); 4.55 Method 4.54, in which the activating agent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC HCl); 4.56 R 12 But -C(O)-R 1 and R 1 replaced by any optional -OR 7 and the acylating agent is a chloroformate (e.g., R 7 —OC(═O)—Cl) or carbonates (e.g., R 7 -OC(=O)-OR 7 ) Methods 4.46 to 4.52. 4.57 R 12 But -C(O)-R 1 and R 1 is any optionally substituted -NR 8 R 9 and the acylating agent is an isocyanate (e.g., R 8 R 9 -NC(=O)) in any of Methods 4.46 to 4.52; 4.58 The base is a tertiary amine (e.g., N-methylmorpholine, triethylamine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2. 2.2]octane, DABCO), aromatic amines (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine), inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monobasic, dibasic, or tribasic), sodium phosphate (monobasic, dibasic, or tribasic)), amide bases (e.g., sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, Any of Methods 4.46-4.57, wherein the base is selected from methyl disilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), and alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, sodium isopropoxide, potassium isopropoxide, and lithium isopropoxide). In one embodiment, the base is 1-methylimidazole; 4.59 Any of Methods 4.46-4.58, wherein the reaction further comprises a catalyst / accelerator selected from, for example, 4-dimethylaminopyridine, imidazole, N-methylimidazole, triphenylphosphine oxide, 1-hydroxy-7-azabenzotriazole, N,N-dimethylformamide, N,N-dimethylacetamide, and dichloromethylene-dimethyliminium chloride; in one embodiment, the catalyst / accelerator is 4-dimethylaminopyridine; 4.60 Any of Methods 4.46-4.59, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent, optionally further comprising water; 4.61 Method 4.60, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, and chlorobenzene); 4.62 Method 4.60, wherein the solvent is selected from esters (e.g., ethyl acetate, isopropyl acetate), carbonates (e.g., dimethyl carbonate), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), chlorinated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform), hydrocarbon solvents (e.g., toluene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone), and nitriles (e.g., propionitrile); 4.63 Method 4.60, in which the solvent is acetonitrile; 4.64 Any of Methods 4.46 to 4.63, wherein the reaction temperature is −20 to 60° C., for example, −5 to 40° C., or 0 to 30° C., or 10 to 30° C., or about 20° C.; 4.65 The reaction comprises performing ring-closing metathesis on compound 9-A under conditions and for a time effective to form compound 9-D, or on compound 9-B under conditions and for a time effective to form compound 9-E, or on compound 9-C under conditions and for a time effective to form compound I, in a suitable solvent and using a suitable catalyst; R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R x is defined as in Method 1.18 or 1.19, and R 5 is defined as in any of methods 1.75 to 1.78, and R 6 Method 4 or any of 4.1 to 4.64, wherein is hydrogen or halogen and is a double bond; 4.66 R x and R y but both are hydrogen, Method 4.65; 4.67 R 12 is as defined for compound I or I(a); 4.68 R 12 But C(O)-R 1 and R 1 But C 1~6 Alkyl, C 1~6 Ha Roalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and —NR 8 R 9 C is selected from 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are optionally joined by 1 to 5 R 10 substituted with groups; each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocyclic ring together with the atom to which they are attached, and each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocycle together with the atom to which they are bonded, and the C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl optionally contain 1 to 5 R 10 substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a , and -NR a R b Selected from;R a and R b are independently hydrogen or C 1~6 alkyl, Method 4.67; 4.69 R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10 5-10 membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl) substituted with a group; 10 Each of the groups is independently C 1~6Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, C 1~6 Method 4.68, selected from alkoxy, and halogen; 4.70 R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10 pyrazolyl or imidazolyl substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl (e.g., methyl) or C 1~6 alkoxy (e.g., methoxy), Method 4.69; 4.71 R 12 But -C(O)-R 1 and R 1 However, you can optionally select 1 to 3 C 1~6 Alkyl (e.g., methyl) or C 1~6 Method 4.70, which is a pyrazolyl substituted with alkoxy (e.g., methoxy); 4.72 R 12 But -C(O)-R 1 and R 1 is 3-methoxy-1-methyl-1H-pyrazolyl, Method 4.71; 4.73 Any of methods 4.65-4.72, wherein the catalyst is a ruthenium catalyst or a molybdenum catalyst; 4.74 The catalyst is dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II), dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), dichloro[1 ,3-bis(2-methylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][3-(2-pyridinyl)propylidene]ruthenium(II), [1,3-dimesityl-2-imidazolidinylidene]dichloro(phenylmethylene)bis(3-bromopyridine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](3-methyl-2-butenylidene)(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinylidene]( 2-Isopropoxyphenylmethylene)ruthenium(II), [1,3-Dimesityl-2-imidazolidinylidene]dichloro[3-(2-pyridinyl)propylidene]-ruthenium(II), (1,3-Dimesityl-imidazolidin-2-ylidene)dichloro(2-isopropoxy-5-nitrobenzylidene)ruthenium(II), Tricyclohexylphosphine[4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][2-thienylmethylene]ruthenium(II) dichloride, Tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][2-thienylmethylene]ruthenium(II) dichloride, Tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][2-thienylmethylene]ruthenium(II) dichloride, Tri Method 4.73, wherein the aryl group is selected from cyclohexylphosphine[2,4-dihydro-2,4,5-triphenyl-3H-1,2,4-triazol-3-ylidene][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][3-phenyl-1H-inden-1-ylidene]ruthenium(II) dichloride, dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), and bis(tricyclohexylphosphine)-3-phenyl-1H-inden-1-ylideneruthenium(II) dichloride; 4.75 Method 4.73, wherein the catalyst is selected from 2,6-diisopropyl-phenylimido-neophyllidene[(S)-(-)-BIPHEN]molybdenum(VI), dichlorobis[(2,6-diisopropylphenyl)imido](1,2-dimethoxyethane)molybdenum(VI), and (T-4)-chloro(2,2-dimethylpropylidene)[2,2”,4,4′,6,6′-hexakis(1-methylethyl)[1,1′:3′,1-terphenyl]-2′-olato][2-methyl-2-propaneaminoato(2-)]molybdenum(VI); 4.76 Method 4.73, in which the suitable catalyst is Hoveyda-Grubbs II catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II)); 4.77 Any of Methods 4.65-4.76, wherein the solvent is a nonpolar solvent or a polar aprotic solvent; 4.78 Method 4.77, wherein the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); in one embodiment, the solvent is toluene; 4.79 Method 4.77, wherein the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-pentanone), and carbonates (e.g., dimethyl carbonate, diethyl carbonate, diisopropyl carbonate); 4.80 Any of Methods 4.65-4.79, wherein the temperature of the reaction is 0-150°C, e.g., 20-90°C, or 40°C-90°C, or 20°C-60°C, or 40°C-80°C, or about 80°C; in one embodiment, the temperature of the reaction is 70°C-90°C; 4.81 Method 4, or any of Methods 4.1-4.80, further comprising the step of reducing the double bond of compound 9-D, 9-E, I, or I(a) (wherein is a double bond) for a time and under conditions effective to form compound 9-D, 9-E, I, or I(a), respectively (wherein is a double bond), which step comprises treating the compound with hydrogen gas over a suitable catalyst (e.g., Pd / C, Pt, PtO2, Raney nickel, nickel boride, RhCl(Ph3P)3) in a suitable solvent (e.g., acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran, toluene); 4.82 Method 4, or any of Methods 4.1-4.81, wherein compounds 8-B, 9-A, 9-B, 9-C, 9-D, 9-E, or compounds according to one or more of Compounds I or I(a) are produced; 4.83 In any one or more of the compounds, R x is H and R y is H and R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R 4 is H and R 5 But C 1~3 alkyl (e.g., methyl), and R 6 is halogen (e.g., chloro), and R p But -C(=O)-OC 1~6 alkyl(aryl) (e.g., 1-phenylethoxycarbonyl, optionally in the (R) or (S) form), where R″ is C 1~3 alkyl (e.g., methyl), and / or R 12 is H or -C(O)-R 1 (In the formula, R 1 is an optionally substituted C 1~6 Alkyl (e.g., methyl), optionally substituted C 1~6 Method 4.82, wherein the aryl group is selected from alkoxy (e.g., (S)-1-phenylethoxy), or optionally substituted 5-10 membered heteroaryl (e.g., 1-methyl-3-methoxy-1H-pyrazol-4-yl); 4.84 In one or more of the compounds, R 2 and R 3 is H or R 2 and R 3 is methyl, or R 2 is H and R 3 is methyl, Method 4.83; 4.85 In one or more of the compounds, R 2 is H and R 3 is methyl, Method 4.84; 4.86 In one or more of Compound 9-C, Compound I, and Compound I(a), R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10 5-10 membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl) substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, C 1~6 any of methods 4.82 to 4.85, wherein the alkyl group is selected from alkoxy and halogen; 4.87 R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10 pyrazolyl or imidazolyl substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl (e.g., methyl) or C 1~6 alkoxy (e.g., methoxy), Method 4.86; 4.88 R 12 But -C(O)-R 1 and R 1 However, you can optionally select 1 to 3 C 1~6 Alkyl (e.g., methyl) or C 1~6 pyrazolyl substituted by alkoxy (e.g., methoxy), e.g., R 1 is 3-methoxy-1-methyl-1H-pyrazolyl, Method 4.87; 4.89 Any of Methods 4.82-4.88, wherein in one or more of Compound 9-D, 9-E, Compound I, or Compound I(a), is a double bond; 4.90 Method 4 or any of Methods 4.1 through 4.89, wherein the product of the method is Compound 1; 4.91 Method 4, or any of Methods 4.1-4.90, further comprising any step of any of Method 1, see below, Method 2, see below, Method 3, see below, and Method 5, see below.

[0025] In a sixth aspect, the present disclosure provides a method (Method 5) for making a compound selected from one or more of compounds 5-F, 5-F', 10-A, 10-B, 10-C, 10-C', 10-D, 10-E, 9-A, and 9-D described herein, comprising reacting a precursor compound with one or more reagents in a suitable solvent for a time and under conditions effective to form a product compound. Method 5 generally relates to the formation of SNO-CB-TC cyclic fragments (including ring-closing metathesis steps) and alternative routes for the attachment of side chain fragments, including intermediates 10-C, 10-C', and 10-E, and the further evolution of these intermediates to Compound 1. While not limited to the order or combination of steps used, possible embodiments of Method 5 can include any of the steps shown in Scheme 10. [ka]

[0026] In certain embodiments, the present disclosure provides Method 5 as follows: 5.1 Method 5, comprising any of the steps described in any of Method 1, see below, Method 2, see below, Method 3, see below, and Method 4, see below; 5.2 (1) Compound 5-F (wherein R 6 , R n , and R z (2) reacting compound 5-E or 5-E′ with 4-fluoro-3-nitrobenzoic acid or ester for a time and under conditions effective to form compound 5-F′ (wherein R z is H) by treating compound 5-F as provided in any of Methods 1.134-1.138 with compound 5-F for a time and under conditions effective to form z is not H) to the corresponding compound 5-F'; in one embodiment, nare each independently CH3, or two R n the moieties joined together form a bridge selected from -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(Ph)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(Ph)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(C6H5)CH(C6H5), -CH2CH(C6H5)CH2-, and -(o-C6H4)-; 5.3 R of compound 5-F z But unsubstituted C 1~6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, or tert-butyl) ), Method 5.2; 5.4 R of Compound 5-F or 5-F' z ,is H,Method 5.3; 5.5 acylation of compound 6-L with 4-fluoro-3-nitrobenzoic acid in a suitable solvent using an acid activator and a base for a time and under conditions effective to form compound 10-A, or acylation of compound 6-L with benzoic acid compound 5-F / 5-F′ for a time and under conditions effective to form compound 10-B; 6 is defined as provided in Method 2.10 or 2.11, and each R n is defined as provided in any of Methods 2.76-2.79 or 2.108-2.111, and R of compound 5-F or 5-F′ z is H and R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R p is as defined in any of Methods 3.109 to 3.112, or any of Methods 5.1 or 5.2; 5.6 R 6 is chloro, Method 5.5; 5.7 Both R n is methyl or ethyl, or two R n Method 5.5 or 5.6, wherein the moieties are joined together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-, -CH(CH3)CH(CH3)-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH2CH3)2CH2-, -CH(C6H5)CH(C6H5), and -CH2CH(C6H5)CH2-; 5.8 R p any of Methods 5.5-5.7, wherein is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; 5.9 R p is optionally 1-phenylethoxycarbonyl in (R) or (S) form; 5.10 Any of Methods 5.5-5.9, wherein the acid activator is selected from N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC HCl), (PhO)2POCl, carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM), thionyl chloride, oxalyl chloride, and sulfuryl chloride; 5.11 Method 5.10, wherein the acid activator is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC HCl); 5.12 Any of Methods 5.5-5.11, wherein the base is selected from tertiary amines (e.g., trimethylamine, triethylamine, N-methylmorpholine, N-ethylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine), and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monobasic, dibasic, or tribasic), sodium phosphate (monobasic, dibasic, or tribasic)); 5.13 Method 5.12, wherein the base is imidazole or 1-methylimidazole; 5.14 Any of Methods 5.5-5.13, wherein the reaction further comprises a promoter selected from, for example, 4-dimethylaminopyridine (DMAP), N-methylimidazole, 1-hydroxy-7-azabenzotriazole (HOAt), and 1-hydroxybenzotriazole (HOBt); 5.15 Any of Methods 5.5-5.14, wherein the acid activator is EDC-HCl, the base is 1-methylimidazole, and the promoter is DMAP; 5.16 Any of Methods 5.5-5.15, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent; 5.17 Method 5.16, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 5.18 Method 5.16, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 5.19 Method 5.16, in which the solvent is acetonitrile; 5.20 Any of Methods 5.5 to 5.19, wherein the reaction temperature is −50 to 50° C., e.g., 0 to 40° C., or 10 to 30° C., or about 20° C.; 5.21 Fluorophenyl compound 10-A is reacted with the ether adduct compound 10-B (wherein R 6 is defined as provided in Method 2.10 or 2.11, and each R n is defined as provided in either Methods 2.76-2.79 or 2.108-2.111, and R y is defined as in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R p with alcohol compound 5-E or 5-E' under conditions and for a time effective to form (wherein R is as defined in any of Methods 3.109-3.112); 5.22 R 6 is chloro, Method 5.21; 5.23 Both R of compound 5-E n is methyl or ethyl, or two R n Method 5.21 or 5.22, wherein the moieties are joined together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-; 5.24 R pis selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; 5.25 R p is optionally 1-phenylethoxycarbonyl in the (R) or (S) form, Method 5.24; 5.26 Any of Methods 5.21-5.25, wherein compound 5-E or 5-E' is dissolved or suspended in a suitable solvent and treated with a strong base and, optionally, a promoter (e.g., sodium iodide, tetrabutylammonium iodide); 5.27 Method 5.26, wherein the base is selected from inorganic hydrides (e.g., sodium hydride, potassium hydride), alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide), inorganic hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), amide bases (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate (mono-, di-, or tribasic), sodium phosphate (mono-, di-, or tribasic)); 5.28 The base is sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, Method 5.27, wherein the base is selected from potassium t-butoxide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, and potassium diisopropylamide; and optionally the base is potassium t-butoxide; 5.29 Any of Methods 5.21-5.28, wherein compound 10-A is added to the reaction about 1-60 minutes, e.g., about 1-30 minutes, or 1-20 minutes, or 1-15 minutes, or 1-10 minutes, or 1-5 minutes, after the addition of the base; 5.30 Any of Methods 5.21-5.29, wherein the suitable solvent is a non-polar solvent; 5.31 Method 5.30, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 5.32 Method 5.30, in which the nonpolar solvent is tetrahydrofuran; 5.33 Any of Methods 5.21 to 5.32, wherein the reaction temperature is −80 to 100° C., for example, −45 to 10° C., or −30 to 10° C., or −10 to 5° C., or about 0° C., or −10 to 50° C., or −10 to 30° C., or 10 to 30° C., or 30 to 80° C.; 5.34 The acetal compound 10-B or 10-C′ is reacted in a suitable solvent to give the aldehyde compound 10-C or 10-D, respectively, where R 6 is defined as in Method 2.10 or 2.11, and each R n is defined as provided in either Methods 2.76-2.79 or 2.108-2.111, and R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R p Method 5, or any of Methods 5.1 to 5.33, comprising treating with a deprotecting agent for a time and under conditions effective to form a methyl group (wherein 5.35 R 6 is chloro, Method 5.34; 5.36 Both R of compound 5-E nis methyl or ethyl, or two R n Method 5.34 or 5.35, wherein the moieties are joined together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-; 5.37 R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; 5.38 R p is optionally 1-phenylethoxycarbonyl in the (R) or (S) form; Method 5.37; 5.39 Any of Methods 5.34-5.38, wherein the acid is selected from HCl (e.g., aqueous HCl, or HCl / methanol, HCl / isopropanol, or HCl / dioxane), HBr (e.g., aqueous HBr or HBr / acetic acid), sulfuric acid, phosphoric acid, p-toluenesulfonic acid, pyridinium tosylate, trifluoroacetic acid, methanesulfonic acid, trichloroacetic acid, Lewis acids (e.g., erbium triflate), and acidic resins (e.g., Amberlyst); 5.40 Method 5.39, in which the acid is methanesulfonic acid; 5.41 Any of Methods 5.34-5.40, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, a polar aprotic solvent, or a combination thereof; 5.42 Method 5.41, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 5.43 The polar protic solvent is water and / or alcohol (e.g., methanol, ethanol). Method 5.41, where the solvent is ethanol, propanol, isopropanol) or an acid (e.g., formic acid, acetic acid); 5.44 Method 5.41, wherein the polar aprotic solvent is selected from ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 5.45 Method 5.41, where the preferred solvent is tetrahydrofuran and water; 5.46 Any of Methods 5.34 to 5.45, wherein the reaction temperature is 0 to 100°C, e.g., 20 to 50°C, or 20 to 30°C, or 60 to 70°C; 5.47 R by Method p The protecting group is cleaved, resulting in the reaction product, compound 10-C or 10-D, where R p becomes hydrogen, in any of methods 5.34 to 5.46; 5.48 Reducing the nitro / aldehyde compound 10-C to the aniline / aldehyde compound 10-D or reducing the nitro / acetal 10-B to the aniline / acetal 10-C', wherein R 6 is defined as provided in Method 2.10 or 2.11, and each R n is defined as provided in either Methods 2.76-2.79 or 2.108-2.111, and R y is defined as in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R p is as defined in any of Methods 3.109-3.112, or R p is hydrogen, and each R n is defined as provided in any of Methods 2.76-2.79 or 2.108-2.111, Method 5, or any of Methods 5.1-5.47; 5.49 R 6 is chloro, Method 5.48; 5.50 R pis selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; Method 5.48 or 5.49; 5.51 R p is optionally 1-phenylethoxycarbonyl in the (R) or (S) form; 5.52 R p is hydrogen, Methods 5.48 or 5.49; 5.53 Any of Methods 5.48-5.52, wherein the reducing agent is selected from zinc, tin, or iron in an acid (e.g., formic acid or acetic acid or HCl, or ammonium chloride in a suitable solvent); 5.54 Method 5.53, in which the reducing agent is iron (e.g., powder) in acetic acid; 5.55 Any of methods 5.48-5.52, wherein the reducing agent is a hydrogenation agent (e.g., hydrogen in combination with a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex), or a phase transfer hydrogenation system); 5.56 Method 5.55, wherein the hydrogenation agent is hydrogen gas in combination with a palladium, platinum, rhodium, iridium, ruthenium, or nickel catalyst (e.g., Pd, Pd / C, Pd(OAc)2, Pt / C, PtO2, Ru / C, Raney nickel, Ru complex, Rh complex, PtO2, Pt complex, Pd complex, Ir complex), or ammonium formate in combination with a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt, PtO2); 5.57 Method 5.56, wherein the hydrogenation agent is hydrogen gas, optionally in combination with a Pd, Pd / C, Pd(OAc)2, Pt / C, or PtO2 catalyst, at a pressure of 1 to 5 bar (e.g., 1 to 2 bar); 5.58 Any of Methods 5.48-5.57, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent; 5.59 Method 5.58, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 5.60 Polar protic solvents are alcohols (e.g., methanol, ethanol, propane, etc.). propanol, isopropanol) or acid (e.g., formic acid, acetic acid) or aqueous acid (e.g., aqueous HCl), Method 5.58; 5.61 Method 5.58, wherein the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile); 5.62 Method 5.58, where the preferred solvent is acetic acid; 5.63 Any of Methods 5.48 to 5.62, wherein the reaction temperature is 0 to 100°C, e.g., 20 to 50°C, or 20 to 30°C, or 50 to 90°C, or 65 to 85°C; Any of Methods 5.34-5.63, in which the intended product compound 10-D of Step 5.64 undergoes spontaneous condensation to partially or completely form intermediate imine 10-D', and a mixture of 10-D and 10-D' is carried forward to the next step, or product 10-D' is isolated and used in the next step; 5.65 The aniline / acetal compound 10-D (and / or 10-D′) is reacted with a secondary amine compound 10-E (wherein R 6 is defined as provided in Method 2.10 or 2.11, and R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R p is as defined in any of Methods 3.109-3.112, or R pwith a reducing agent for a time and under conditions effective to obtain (wherein R is hydrogen); 5.66 R 6 is chloro, Method 5.65; 5.67 R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; Method 5.65 or 5.66; 5.68 R p is optionally 1-phenylethoxycarbonyl in the (R) or (S) form; Method 5.67; 5.69 R p is hydrogen, Method 5.65 or 5.66; 5.70 Reducing agents include hydride reducing agents, silane reducing agents, hydrogenation, iron powder (Fe) in combination, sodium triacetoxyborohydride (NaBH(OAc)3), tin or zinc in combination with an acid (e.g., hydrochloric acid, acetic acid, ammonium chloride), transition metals (e.g., Pd, Pt, or Rh) in combination with H2 or formate, poisoned heterogeneous catalysts (e.g., Pt / S / C), silanes (e.g., triisopropylsilane, triphenylsilane, diethylsilane), sodium borohydride, hydrogen Any of Methods 5.65-5.69, wherein the reducing agent is selected from sodium borohydride / acetic acid, sodium cyanoborohydride, titanium isopropoxide / sodium cyanoborohydride, zinc / acetic acid, sodium borohydride / magnesium perchlorate, zinc borohydride / zinc chloride, tetramethylammonium triacetoxyborohydride; in one embodiment, the reducing agent is iron powder (Fe) in combination with sodium triacetoxyborohydride (NaBH(OAc)3); 5.71 Method 5.70, wherein the reducing agent is a hydride reducing agent; 5.72 Method 5.71, wherein the hydride reducing agent is selected from sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride; 5.73 Method 5.72, wherein the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride; 5.74 Any of Methods 5.71-5.73, combining a hydride reducing agent with a reagent to adjust the hydride reduction activity (e.g., titanium isopropoxide, titanium ethoxide, borate, magnesium perchlorate, or zinc chloride); 5.75 Method 5.70, wherein the silane reducing agent is triethylsilane; 5.76 Reactions involving acids (e.g., formic acid, acetic acid, trifluoroacetic acid, citric acid, pivalic acid) any of Methods 5.70-5.75, further comprising an acid selected from p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid; 5.77 Any of Methods 5.65-5.76, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent; 5.78 Method 5.77, in which the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 5.79 Method 5.77, wherein the polar protic solvent is selected from alcohols (e.g., methanol, ethanol, propanol, isopropanol) and acids (e.g., acetic acid, formic acid, trifluoroacetic acid); 5.80 Method 5.77, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 5.81 Method 5.77, where the preferred solvent is acetic acid; 5.82 Any of Methods 5.65 to 5.81, wherein the reaction temperature is −30 to 100° C., e.g., 0 to 80° C., or 20 to 30° C., 20 to 50° C., 50 to 90° C., or 60 to 80° C.; 5.83 Compound 10-E is reacted with a tertiary amine compound 9-A (wherein R 6 is defined as provided in Method 2.10 or 2.11, and R y is as defined in Method 3.2 or 3.3, and R 2 and R 3 is as defined in any of Methods 3.4-3.10, and R p is as defined in any of Methods 3.109-3.112, or R p is hydrogen and R x is defined as in Method 1.18 or 1.19, and R 5 Method 5, or any of Methods 5.1-5.82, comprising reducing and treating with compound 1-I for a time and under conditions effective to form (wherein 5.84 R 6 is chloro, Method 5.83; 5.85 R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; method 5.83 or 5.84; 5.86 R p is optionally 1-phenylethoxycarbonyl in the (R) or (S) form; 5.87 R p is hydrogen, Method 5.83 or 5.84; 5.88 Any of methods 5.83-5.87, wherein the reducing agent is selected from a hydride reducing agent, a silane reducing agent, or hydrogenation; 5.89 Method 5.88, in which the reducing agent is a hydride reducing agent; 5.90 Method 5.89, wherein the hydride reducing agent is selected from sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride; 5.91 Method 5.90, wherein the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride; 5.92 Any of Methods 5.89-5.91, combining a hydride reducing agent with a reagent to adjust the hydride reduction activity (e.g., titanium isopropoxide, titanium ethoxide, borate, magnesium perchlorate, or zinc chloride); 5.93 Method 5.88, in which the silane reducing agent is triethylsilane; 5.94 The reaction is carried out with an acid (e.g., acetic acid, trifluoroacetic acid, citric acid, pivalic acid, p- Any of Methods 5.83-5.93, further comprising an acid selected from toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid; 5.95 Any of Methods 5.83-5.94, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent; 5.96 Method 5.95, in which the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 5.97 Method 5.95, wherein the polar protic solvent is selected from alcohols (e.g., methanol, ethanol, propanol, isopropanol) and acids (e.g., acetic acid, formic acid, trifluoroacetic acid); 5.98 Method 5.95, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 5.99 Method 5.95, wherein the preferred solvent is dichloromethane; 5.100 Any of Methods 5.83 to 5.95, wherein the reaction temperature is −30 to 80° C., e.g., 0 to 80° C. or 10 to 30° C.; 5.101 Method 5, or any of Methods 5.1 through 5.100, wherein a compound according to one or more of Compounds 10-A, 10-B, 10-C, 10-C', 10-D, 10-E, or 9-A is produced; 5.102 Method 5, or any of 5.1-5.101, wherein compound I, compound I(a), or compound 1 is further synthesized from product compound 9-A, as provided by any step described in method 4.

[0027] In a further aspect, the disclosure provides compounds 1-A, 1-B, 1-C, 1-D, 1-E, 1-F, 1-G, 1-H, 1-I, 2-A, 2-B, 2-C, 2-D, 2-E, 3-A, 3-B, 3-C, 3-D, 4-E, 5-F, 6-H, 7-I, 8-I, 9-I, 10-I, 11-I, 12-I, 13-I, 14-I, 15-I, 16-I, 17-I, 18-I, 19-I, 20-I, 21-I, 22-I, 23-I, 24-I, 25-I, 26-I, 27-I, 28-I, 29-I, 30-I, In certain embodiments, the present disclosure provides each of: 4-A, 4-B, 4-C, 5-A, 5-B, 5-C, 5-D, 5-E, 5-E', 5-F, 5-G, 5-G', 5-H, 5-I, 6-A, 6-B, 6-B', 6-C, 6-D, 6-E, 6-F, 6-G, 6-H, 6-I, 6-J, 6-K, 6-L, 6-L', 7-A, 8-A, 8-B, 9-A, 9-B, 9-C, 9-D, 9-E, 10-A, 10-B, 10-C, 10-C', 10-D, or 10-E. 6.1 Compound 9-A (wherein R x and R y are each independently H, C 1~6 Alkyl or C 6~10 aryl, wherein the alkyl is optionally C 6~10 substituted with aryl, R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R 5 is C1~6 alkyl (e.g., methyl), and R 6 is halogen (e.g., chloro), and R p represents an alkylcarbonyl group (e.g., -C(=O)-C 1~6 Alkyl, for example, acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1~6 Alkyl (aryl), for example, 2-phenylethylcarbonyl or 1-phenylethylcarbonyl, arylcarbonyl group (for example, benzoyl), alkoxycarbonyl group (for example, -C(=O)-OC 1~6 Alkyl, for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl, or -C(=O)-OC 1~6 alkyl(aryl), for example, 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl, and aryloxycarbonyl groups, for example, phenoxycarbonyl; 6.2 R p But C(=O)-C 1~6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1~6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1~6 Compound 9-A as provided in formula 6.1, selected from alkyl(aryl) (e.g., 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl), and —C(═O)—O-aryl (e.g., phenoxycarbonyl); 6.3 R p But -C(=O)-OC 1~6 Compound 9-A as provided in formula 6.2, which is alkyl(aryl); 6.4 R pis selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; 6.5 R p is optionally 1-phenylethoxycarbonyl in (R) or (S) form; 6.6 R p is 1-phenylethoxycarbonyl in the (S) form, compound 9-A as provided in formula 6.5; 6.7 R x and R y Compound 9-A as provided in any of formulas 6.1-6.6, wherein each is H; 6.8 R 2 is H and R 3 Compound 9-A as provided in any of formulas 6.1-6.7, wherein is methyl; 6.9 R 5 Compound 9-A as provided in any of formulas 6.1 to 6.8, wherein is methyl; 6.10 R 6 Compound 9-A as provided in any of formulas 6.1-6.9, wherein is chloro; 6.11 Compound 9-B (wherein R x and R y are each independently H, C 1~6 Alkyl or C 6~10 aryl, wherein the alkyl is optionally C 6~10 substituted with aryl, R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R 4 is H and R 5 is C 1~6 alkyl (e.g., methyl), and R 6 is a halogen (e.g., chloro); 6.12 R x and R yCompound 9-B as provided in formula 6.11, wherein each is H; 6.13 R 2 is H and R 3 Compound 9-B as provided in formula 6.11 or 6.12, wherein is methyl; 6.14 R 5 Compound 9-B as provided in any of formulas 6.11-6.13, wherein is methyl; 6.15 R 6 Compound 9-B as provided in any of formulas 6.11-6.14, wherein is chloro; 6.16 Compound 9-C (wherein R x and R y are each independently H, C 1~6 Alkyl or C 6~10 aryl, wherein the alkyl is optionally C 6~10 substituted with aryl, R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R 4 is H and R 5 is C 1~6 alkyl (e.g., methyl), and R 6 is halogen (e.g., chloro), and R 12 is -C(O)-R 1 and R 1 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and —NR 8 R 9 C is selected from 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl optionally contain 1 to 5 R 10 substituted with groups; each R 8 and R9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 along with the atoms to which they are bonded form a 3- to 12-membered heterocycle, and each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, or R 8 and R 9 form a 3- to 12-membered heterocycle together with the atom to which they are bonded, and the C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl optionally contain 1 to 5 R 10 substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a , and -NR a R b Selected from;R a and R b are independently hydrogen or C 1~6 a compound that is alkyl; 6.17 R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 105-10 membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl) substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, C 1~6 Compound 9-C as provided in formula 6.16, selected from alkoxy, and halogen; 6.18 R 12 But -C(O)-R 1 and R 1 However, optionally 1 to 5 R 10 pyrazolyl or imidazolyl substituted with a group; 10 Each of the groups is independently C 1~6 Alkyl (e.g., methyl) or C 1~6 Compound 9-C as provided in formula 6.17, which is alkoxy (e.g., methoxy); 6.19 R 12 But -C(O)-R 1 and R 1 However, you can optionally select 1 to 3 C 1~6 Alkyl (e.g., methyl) or C 1~6 Compound 9-C as provided in formula 6.18, which is a pyrazolyl substituted with alkoxy (e.g., methoxy); 6.20 R 12 But -C(O)-R 1 and R 1 is 3-methoxy-1-methyl-1H-pyrazolyl, compound 9-C as provided in formula 6.19; 6.21 R x and R y Compound 9-C as provided in any of formulas 6.16-6.20, wherein each is H; 6.22 R 2 is H and R 3 Compound 9-C as provided in any of formulas 6.16-6.21, wherein is methyl; 6.23 R 5 Compound 9-C as provided in any of formulas 6.16-6.22, wherein is methyl; 6.24 R 6 Compound 9-C as provided in any of formulas 6.16-6.23, wherein is chloro; 6.25 Compound 9-E (wherein R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R 4 is H and R 5 is C 1~6 alkyl (e.g., methyl), and R 6 is a halogen (e.g., chloro); Compound 9-E as provided in formula 6.25, where 6.26 is a double bond; 6.27 R 2 is H and R 3 Compound 9-E as provided in formula 6.25 or 6.26, wherein is methyl; 6.28 R 5 Compound 9-E as provided in any of formulas 6.25-6.27, wherein is methyl; 6.29 R 6 Compound 9-E as provided in any of formulas 6.25-6.28, wherein is chloro; 6.30 Compound 10-E (wherein R y is H or C 1~6 alkyl (e.g., methyl), and R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R 6 is halogen (e.g., chloro), and R p represents an alkylcarbonyl group (e.g., -C(=O)-C 1~6 Alkyl, for example, acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1~6 Alkyl (aryl), for example, 2-phenylethylcarbonyl or 1-phenylethylcarbonyl, arylcarbonyl group (for example, benzoyl), alkoxycarbonyl group (for example, -C(=O)-OC 1~6 Alkyl, e.g. For example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl, or -C(=O)-OC 1~6 alkyl(aryl), for example, 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl, and aryloxycarbonyl groups, for example, phenoxycarbonyl; 6.31 R p But C(=O)-C 1~6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1~6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1~6 Compound 10-E as provided in formula 6.30 selected from alkyl(aryl) (e.g., 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl), and —C(═O)—O-aryl (e.g., phenoxycarbonyl); 6.32 R p But -C(=O)-OC 1~6 Compound 10-E as provided in formula 6.30 or 6.31, which is alkyl(aryl); 6.33 R p Compound 10-E as provided in any of formulae 6.30-6.32, wherein is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; 6.34 R p is optionally 1-phenylethoxycarbonyl in (R) or (S) form; 6.35 R p is 1-phenylethoxycarbonyl in the (S) form, compound 10-E as provided in formula 6.34; 6.36 R yis H, compound 10-E as provided in any of formulas 6.30-6.35; 6.37 R 2 is H and R 3 Compound 10-E as provided in any of formulas 6.30-6.36, wherein is methyl; 6.38 R 6 Compound 10-E as provided in any of formulas 6.30-6.37, wherein is chloro; 6.39 Compound 10-B or 10-C′ (wherein R y is H or C 1~6 alkyl (e.g., methyl), and R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R 6 is halogen (e.g., chloro), and each R n independently, C 1~6 alkyl (e.g., methyl, ethyl, or isopropyl), or two R n The parts are joined together to form a C 2~10 Alkyl or C 2~10 forming an alkenyl bridge (i.e., a cyclic acetal), which bridge is optionally substituted with 1 to 4 halogens or aryls, or two R n The moieties are joined together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge), and R p represents an alkylcarbonyl group (e.g., -C(=O)-C 1~6 Alkyl, for example, acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1~6 Alkyl (aryl), for example, 2-phenylethylcarbonyl or 1-phenylethylcarbonyl, arylcarbonyl group (for example, benzoyl), alkoxycarbonyl group (for example, -C(=O)-OC 1~6 Alkyl, for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl, or -C(=O)-OC 1~6alkyl(aryl), for example, 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl, and aryloxycarbonyl groups, for example, phenoxycarbonyl; 6.40 R p But C(=O)-C 1~6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1~6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1~6 alkyl(aryl) (e.g., 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl), and —C(═O)—O-aryl (e.g., phenoxycarbonyl); Compound 10-B or 10-C' as provided in formula 6.39; 6.41 R p But -C(=O)-OC 1~6 Compound 10-B or 10-C' as provided in formula 6.39 or 6.40, which is alkyl(aryl); 6.42 R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; 6.43 R p is optionally 1-phenylethoxycarbonyl in (R) or (S) form; 6.44 R p is 1-phenylethoxycarbonyl in the (S) form, compound 10-B or 10-C' as provided in formula 6.43; 6.45 R y is H; 6.46 R 2 is H and R 3 Compound 10-B or 10-C' as provided in any of formulas 6.39-6.45, wherein is methyl; 6.47 each R n But independently, C 1~6 alkyl, and optionally, each R n Compound 10-B or 10-C' as provided in any of formulas 6.39-6.46, wherein is methyl; 6.48 Two R's n Compound 10-B or 10-C' as provided in Formula 6.47, wherein moieties are joined together to form a bridge selected from -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(Ph)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(Ph)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -(o-C6H4)-; 6.49 Two R's n Compound 10-B or 10-C' as provided in formula 6.48, wherein the moieties are joined together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-; 6.50 R 6 is chloro; 6.51 Compound 10-C or 10-D (wherein R y is H or C 1~6 alkyl (e.g., methyl), and R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R 6 is halogen (e.g., chloro), and R p represents an alkylcarbonyl group (e.g., -C(=O)-C1~6 Alkyl, for example, acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1~6 Alkyl (aryl), for example, 2-phenylethylcarbonyl or 1-phenylethylcarbonyl, arylcarbonyl group (for example, benzoyl), alkoxycarbonyl group (for example, -C(=O)-OC 1~6 Alkyl, for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl, or -C(=O)-OC 1~6 alkyl(aryl), for example, 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl, and aryloxycarbonyl groups, for example, phenoxycarbonyl; 6.52 R p But -C(=O)-C 1~6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1~6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1~6 Compound 10-C or 10-D as provided in formula 6.51 selected from alkyl(aryl) (e.g., 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl), and —C(═O)—O-aryl (e.g., phenoxycarbonyl); 6.53 R p But -C(=O)-OC 1~6 Compound 10-C or 10-D as provided in formula 6.51 or 6.52, which is alkyl(aryl); 6.54 R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; 6.55 R pis optionally 1-phenylethoxycarbonyl in (R) or (S) form; 6.56 R p is 1-phenylethoxycarbonyl in the (S) form, compound 10-C or 10-D as provided in formula 6.55; 6.57 R y is H; Compound 10-C or 10-D as provided in any of formulas 6.51-6.56; 6.58 R 2 is H and R 3 Compound 10-C or 10-D as provided in any of formulas 6.51-6.57, wherein is methyl; 6.59 R 6 Compound 10-C or 10-D as provided in any of formulas 6.51-6.58, wherein is chloro; 6.60 Compound 10-A (wherein R y is H or C 1~6 alkyl (e.g., methyl), and R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R p represents an alkylcarbonyl group (e.g., -C(=O)-C 1~6 Alkyl, for example, acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1~6 Alkyl (aryl), for example, 2-phenylethylcarbonyl or 1-phenylethylcarbonyl, arylcarbonyl group (for example, benzoyl), alkoxycarbonyl group (for example, -C(=O)-OC 1~6 Alkyl, for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl, or -C(=O)-OC 1~6 alkyl(aryl), for example, 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl, and aryloxycarbonyl groups, for example, phenoxycarbonyl; 6.61 R p But C(=O)-C 1~6Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1~6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1~6 Compound 10-A as provided in formula 6.60, selected from alkyl(aryl) (e.g., 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl), and —C(═O)—O-aryl (e.g., phenoxycarbonyl); 6.62 R p But -C(=O)-OC 1~6 Compound 10-A as provided in formula 6.61, which is alkyl(aryl); 6.63 R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; Compound 10-A as provided in formula 6.62; 6.64 R p is optionally 1-phenylethoxycarbonyl in (R) or (S) form, compound 10-A as provided in formula 6.63; 6.65 R p is 1-phenylethoxycarbonyl in the (S) form, compound 10-A as provided in formula 6.64; 6.66 R y Compound 10-A as provided in any of formulas 6.60-6.65, wherein is H; 6.67 R 2 is H and R 3 Compound 10-A as provided in any of formulas 6.60-6.66, wherein is methyl; 6.68 Compound 5-F (wherein R 6 is halogen (e.g., chloro), and each R n independently, C 1~6 alkyl (e.g., methyl, ethyl, or isopropyl) Or two R's n The parts are joined together and 2~10 Alkyl or C 2~10 forming an alkenyl bridge (i.e., a cyclic acetal), which bridge is optionally substituted with 1 to 4 halogens or aryls, or two R n The moieties are joined together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge), and R z is H, and unsubstituted C 1~6 alkyl (e.g., methyl or ethyl), and one C 1~6 Alkoxy, aryloxy, trialkylsilyl, aryl, or haloC 1~6 C substituted by alkyl 1~6 alkyl (e.g., methyl or ethyl); 6.69 each R n But independently, C 1~6 alkyl, and optionally, each R n is methyl, compound 5-F as provided in formula 6.68; 6.70 Two R n Compound 5-F as provided in formula 6.69, wherein moieties are joined together to form a bridge selected from -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(Ph)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(Ph)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -(o-C6H4)-; 6.71 Two R's n Compound 5-F as provided in formula 6.70, wherein the moieties are joined together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-; 6.72 R zis H; Compound 5-F as provided in any of formulas 6.68-6.71; 6.73 R z But unsubstituted C 1~6 Compound 5-F as provided in any of formulas 6.68-6.72, which is alkyl (e.g., methyl or ethyl); 6.74 R 6 Compound 5-F as provided in any of formulas 6.68-6.73, wherein is chloro; 6.75 Compound 5-E (wherein R 6 is a halogen (e.g., chloro), and two R n The parts are joined together to form a C 2~10 Alkyl or C 2~10 forming an alkenyl bridge (i.e., a cyclic acetal), which bridge is optionally substituted with 1 to 4 halogens or aryls, or two R n the moieties are joined together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge); 6.76 Two R n Compound 5-E as provided in formula 6.75, wherein moieties are joined together to form a bridge selected from -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(Ph)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(Ph)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -(o-C6H4)-; 6.77 Two R n Compound 5-E as provided in formula 6.76, wherein the moieties are joined together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-; 6.78 R 6Compound 5-E as provided in any of formulas 6.75-6.77, wherein is chloro; 6.79 Compound 8-A or 8-B (wherein R y is H or C 1~6 alkyl (e.g., methyl), and R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R 6 is halogen (e.g., chloro), and R'' is C 1~6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl); 6.80 R y is H, compound 8-A or 8-B as provided in formula 6.79; 6.81 R 2 is H and R 3 Compound 8-A or 8-B as provided in formula 6.79 or 6.80, wherein is methyl; 6.82 Compound 8-A or 8-B as provided in any of formulae 6.79-6.81, wherein R″ is methyl; 6.83 Compound 6-K (wherein R y is H or C 1~6 alkyl (e.g., methyl), and R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R'' is H, C 1~6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), haloC 1~6 is selected from alkyl (e.g., trifluoromethyl, trichloromethyl), optionally substituted aryl (e.g., phenyl, 4-bromophenyl), and optionally substituted heteroaryl (e.g., 2-pyridyl); R p represents an alkylcarbonyl group (e.g., -C(=O)-C 1~6 Alkyl, for example, acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1~6Alkyl (aryl), for example, 2-phenylethylcarbonyl or 1-phenylethylcarbonyl, arylcarbonyl group (for example, benzoyl), alkoxycarbonyl group (for example, -C(=O)-OC 1~6 Alkyl, for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl, or -C(=O)-OC 1~6 alkyl(aryl), for example, 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl, and aryloxycarbonyl groups, for example, phenoxycarbonyl; 6.84 R p But C(=O)-C 1~6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1~6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1~6 Compound 6-K as provided in formula 6.83 selected from alkyl(aryl) (e.g., 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl), and —C(═O)—O-aryl (e.g., phenoxycarbonyl); 6.85 R p But -C(=O)-OC 1~6 Compound 6-K as provided in formula 6.84, which is alkyl(aryl); 6.86 R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; compound 6-K as provided in formula 6.85; 6.87 R p is optionally 1-phenylethoxycarbonyl in (R) or (S) form, compound 6-K as provided in formula 6.86; 6.88 R pis 1-phenylethoxycarbonyl in the (S) form, compound 6-K as provided in formula 6.87; 6.89 R y Compound 6-K as provided in any of formulas 6.83-6.88, wherein is H; 6.90 R 2 is H and R 3 Compound 6-K as provided in any of formulas 6.83-6.89, wherein is methyl; 6.91 R'' is C 1~6 Compound 6-K as provided in any of formulas 6.83-6.90, which is alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl); 6.92 Compound 6-K as provided in any of formulae 6.83-6.91, wherein R'' is methyl; 6.93 Compound 6-L (wherein R y is H or C 1~6 alkyl (e.g., methyl), and R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R p represents an alkylcarbonyl group (e.g., -C(=O)-C 1~6 Alkyl, for example, Acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1~6 Alkyl (aryl), for example, 2-phenylethylcarbonyl or 1-phenylethylcarbonyl, arylcarbonyl group (for example, benzoyl), alkoxycarbonyl group (for example, -C(=O)-OC 1~6 Alkyl, for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl, or -C(=O)-OC 1~6 alkyl(aryl), for example, 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl, and aryloxycarbonyl groups, for example, phenoxycarbonyl; 6.94 R p But C(=O)-C 1~6Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1~6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1~6 Compound 6-L as provided in formula 6.93 selected from alkyl(aryl) (e.g., 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl), and —C(═O)—O-aryl (e.g., phenoxycarbonyl); 6.95 R p But -C(=O)-OC 1~6 Compound 6-L as provided in formula 6.94, which is alkyl(aryl); 6.96 R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; compound 6-L as provided in formula 6.95; 6.97 R p is optionally 1-phenylethoxycarbonyl in (R) or (S) form, compound 6-L as provided in formula 6.96; 6.98 R p is 1-phenylethoxycarbonyl in the (S) form, compound 6-L as provided in formula 6.97; 6.99 R y is H, compound 6-L as provided in any of formulas 6.93-6.98; 6.100 R 2 is H and R 3 Compound 6-L as provided in any of formulas 6.93-6.99, wherein is methyl; 6.101 Compound 6-J (wherein R y is H or C 1~6 alkyl (e.g., methyl), and R 2 and R 3 are independently H or C 1~6alkyl (e.g., methyl), and R p represents an alkylcarbonyl group (e.g., -C(=O)-C 1~6 Alkyl, for example, acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1~6 Alkyl (aryl), for example, 2-phenylethylcarbonyl or 1-phenylethylcarbonyl, arylcarbonyl group (for example, benzoyl), alkoxycarbonyl group (for example, -C(=O)-OC 1~6 Alkyl, for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl, or -C(=O)-OC 1~6 alkyl(aryl), for example, 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl, and aryloxycarbonyl groups, for example, phenoxycarbonyl; 6.102 R p But C(=O)-C 1~6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1~6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1~6 Compound 6-J as provided in formula 6.101 selected from alkyl(aryl) (e.g., 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl), and —C(═O)—O-aryl (e.g., phenoxycarbonyl); 6.103 R p But -C(=O)-OC 1~6 Compound 6-J as provided in formula 6.102, which is alkyl(aryl); 6.104 R p However, 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxy Compound 6-J as provided in formula 6.103, selected from dimethylcarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl; 6.105 R p is optionally 1-phenylethoxycarbonyl in (R) or (S) form, compound 6-J as provided in formula 6.104; 6.106 R p is 1-phenylethoxycarbonyl in the (S) form, compound 6-J as provided in formula 6.105; 6.107 R y is H; Compound 6-J as provided in any of formulas 6.101-6.106; 6.108 R 2 is H and R 3 Compound 6-J as provided in any of formulas 6.101-6.107, wherein is methyl; 6.109 Compound 1-H (wherein R 5 is C 1~6 alkyl (e.g., methyl), and R x is H, C 1~6 Alkyl or C 6~10 aryl, wherein the alkyl is optionally C 6~10 aryl-substituted); 6.110 R x is H, compound 1-H as provided in formula 6.109; 6.111 R 5 Compound 1-H as provided in formula 6.109 or 6.110, wherein is methyl; 6.112 Compound 1-E or 1-F (wherein R x is H, C 1~6 Alkyl or C 6~10 aryl, wherein the alkyl is optionally C 6~10 aryl-substituted, where PG is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., t-butyldiphenylsilyl), and triarylsilyl groups (e.g., triphenylsilyl); 6.113 Compound 1-E or 1-F as provided in formula 6.112, where PG is an alkyldiarylsilyl group (e.g., t-butyldiphenylsilyl); 6.114 Compound 1-E or 1-F as provided in formula 6.113, wherein PG is tert-butyldiphenylsilyl; 6.115 R x is H; 6.116 Compound 1-D (wherein R x is H, C 1~6 Alkyl or C 6~10 aryl, wherein the alkyl is optionally C 6~10 aryl-substituted, X is Br, Cl, or I, and PG is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., t-butyldiphenylsilyl), and triarylsilyl groups (e.g., triphenylsilyl); 6.117 Compound 1-D as provided in formula 6.116, where PG is an alkyldiarylsilyl group (e.g., t-butyldiphenylsilyl); 6.118 Compound 1-D as provided in formula 6.117, wherein PG is tert-butyldiphenylsilyl; 6.119 R x Compound 1-D as provided in any of formulas 6.116-6.118, wherein is H; 6.120 Compound 1-D as provided in any of formulas 6.116-6.119, wherein X is Br; 6.121 Compound 1-D as provided in any of formulas 6.116-6.119, wherein X is I; 6.122 Compound 1-D as provided in any of formulas 6.116-6.119, where X is Cl; 6.123 Compound 1-C (wherein PG is a trialkylsilyl group (e.g., trimethylsilyl) arylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., t-butyldiphenylsilyl), and triarylsilyl groups (e.g., triphenylsilyl); 6.124 Compound 1-C as provided in formula 6.123, where PG is an alkyldiarylsilyl group (e.g., t-butyldiphenylsilyl); 6.125 Compound 1-C as provided in formula 6.124, wherein PG is tert-butyldiphenylsilyl; 6.126 Compound 1-B, wherein PG is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., t-butyldiphenylsilyl), and triarylsilyl groups (e.g., triphenylsilyl), and R' is C 1~6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, or t-butyl); 6.127 Compound 1-B as provided in formula 6.126, where PG is an alkyldiarylsilyl group (e.g., t-butyldiphenylsilyl); 6.128 Compound 1-B as provided in formula 6.127, wherein PG is tert-butyldiphenylsilyl; 6.129 Compound 1-B as provided in any of formulae 6.126-6.128, wherein R' is methyl; 6.130 Compound 5-D (wherein R 6 is halogen (e.g., chloro), and R m is H, C 1~6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), haloC 1~6 Alkyl (e.g., trifluoromethyl, trichloromethyl), carboxy C 1~6alkyl (e.g., 3-carboxypropyl), optionally substituted aryl (e.g., phenyl, 4-halophenyl), or optionally substituted heteroaryl (e.g., pyridyl, such as 2-pyridyl), and each R n independently, C 1~6 alkyl (e.g., methyl, ethyl, or isopropyl), or two R n The parts are joined together to form a C 2~10 Alkyl or C 2~10 forming an alkenyl bridge (i.e., a cyclic acetal), which bridge is optionally substituted with 1 to 4 halogens or aryls, or two R n the moieties are joined together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge); 6.131 Two R's n Compound 5-D as provided in Formula 6.130, wherein moieties are joined together to form a bridge selected from -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(Ph)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(Ph)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -(o-C6H4)-; 6.132 Two R's n Compound 5-D as provided in formula 6.131, wherein the moieties are joined together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-; 6.133 each R n But independently, C 1~6 Compound 5-D as provided in formula 6.132, which is alkyl (e.g., methyl, ethyl, or isopropyl); 6.134 each R nis methyl, compound 5-D as provided in formula 6.133; 6.135 R m But C 1~6 Compound 5-D as provided in any of formulas 6.130-6.134, wherein the alkyl is 6.136 R m is methyl, compound 5-D as provided in formula 6.135; 6.137 R 6 Compound 5-D as provided in any of formulas 6.130-6.136, wherein is chloro; 6.138 Compound 5-B or 5-C (wherein R 6 is halogen (e.g., chloro), and R m is H, C 1~6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), haloC 1~6 Alkyl (e.g., trifluoromethyl, trichloromethyl), carboxy C 1~6 selected from alkyl (e.g., 3-carboxypropyl), optionally substituted aryl (e.g., phenyl, 4-halophenyl), or optionally substituted heteroaryl (e.g., pyridyl, such as 2-pyridyl); 6.139 R m But C 1~6 Compound 5-B or 5-C as provided in formula 6.138, which is alkyl; 6.140 R m is methyl; 6.141 R 6 is chloro; 6.142 Compound 7-A (wherein R y is H or C 1~6 alkyl (e.g., methyl), and R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl); 6.143 R yis H, compound 7-A as provided in formula 6.142; 6.144 R 2 is H and R 3 Compound 7-A as provided in formula 6.142 or 6.143, wherein is methyl; 6.145 Compound 6-F (wherein R y is H or C 1~6 alkyl (e.g., methyl), and R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl); 6.146 R y is H, compound 6-F as provided in formula 6.145; 6.147 R 2 is H and R 3 Compound 6-F as provided in formula 6.145 or 6.146, wherein is methyl; 6.148 Compound 6-C (wherein R y is H or C 1~6 alkyl (e.g., methyl), and R 2 and R 3 are independently H or C 1~6 alkyl (e.g., methyl), and R e is an optionally substituted 5-10 membered heteroaryl (e.g., optionally substituted pyridyl or pyrimidinyl), —C(═NH)NH(C 1~6 alkyl), -C(=NH)N(C 1~6 alkyl)2, and —C(═NH)NH2; 6.149 R y is H, compound 6-C as provided in formula 6.148; 6.150 R 2 is H and R 3 Compound 6-C as provided in formula 6.148 or 6.149, wherein is methyl; 6.151 R e is a 5- to 10-membered heteroaryl, for example a 6-membered heteroaryl (e.g., 2-pyridyl or 2-pyrimidinyl); 6.152 R e is 2-pyrimidinyl, compound 6-C as provided in formula 6.151; 6.153 Compound 5-I (wherein R 6 is halogen (e.g., chloro), and R z is H, and unsubstituted C 1~6 alkyl (e.g., methyl or ethyl), and one C 1~6 Alkoxy, aryloxy, trialkylsilyl, aryl, or haloC 1~6 C substituted by alkyl 1~6 alkyl (e.g., methyl or ethyl); 6.154 R z is H, compound 5-I as provided in formula 6.153; 6.155 R z But unsubstituted C 1~6 Compound 5-I as provided in formula 6.153, which is alkyl (e.g., methyl or ethyl); 6.156 R 6 is provided in any of formulas 6.153 to 6.155, where Compound 5-I as shown; 6.157 A compound according to any of formulas 6.1 to 6.156, selected from: [ka] 6.158 A compound according to any of formulas 6.1 to 6.156, selected from: [ka] 6.159 A compound according to any of formulas 6.1 to 6.156, selected from: [ka] 6.160 A compound according to any of formulas 6.1 to 6.156, selected from: [ka] 6.161 A compound according to any of formulas 6.1 to 6.156, selected from: [ka] 6.162 A compound according to any of formulas 6.1 to 6.156, selected from: [ka] 6.163 A compound according to any of formulas 6.1 to 6.156, selected from: [ka] 6.164 A compound according to any of formulas 6.1 to 6.156, selected from: [ka] a compound according to any one of formulas 6.1 to 6.156, wherein: [ka] a compound according to any one of formulas 6.1 to 6.156, wherein: [ka] 6.167 A compound according to any of formulas 6.1 to 6.156, selected from: [ka] 6.168 A compound according to any of formulas 6.1 to 6.156, selected from: [ka] 6.169 A compound according to any one of formulas 6.1 to 6.156, wherein: [ka] 6.170 A compound according to any of formulas 6.1 to 6.156, selected from: [ka]

[0028] In one embodiment, the present disclosure provides a method for making a compound selected from 13-A, 13-B, 13-C, 13-D, 13-E, and 9-B, as shown in Scheme 13, comprising: x and R y However, independently, H, C 1~6 Alkyl or C 6~10 aryl, wherein the alkyl is optionally C 6~10 aryl-substituted, C 6~10 aryl (e.g., phenyl), and optionally substituted aryl (e.g., phenyl); R 2 and R 3 are independently H or C 1~6 alkyl, and R 5 But C 1~6 alkyl, and R 6 is a halogen, and each R n But independently, C 1~6 alkyl or two R n The parts are joined together to form a C 2~4 forming alkyl bridges, the bridges optionally independently containing C 1~3 substituted with 1 to 4 groups selected from alkyl and phenyl; R p H, -C(=O)-C 1~6 Alkyl, -C(=O)-heteroaryl, -C(=O)-OC 1~6 Alkyl, and -C(=O)-OC 1~6 alkyl-phenyl, wherein each phenyl or heteroaryl is optionally independently selected from C 1~3 Alkyl and -OC 1~3 alkyl, each heteroaryl having 1 to 4 heteroatoms, each heteroatom independently selected from N, O, and S, and each heteroaryl having 5 to 10 ring members. [ka]

[0029] In one embodiment, the present disclosure provides a method for preparing compound 13-A from compound 1-I, comprising: x But H, C 1~6 Alkyl or C 6~10 aryl, wherein the alkyl is optionally C 6~10 substituted with aryl, R 5 But C 1~6 In one embodiment, R x is H and R 5 is methyl.

[0030] In one embodiment, the method includes reacting compound methyl 3-amino-4-fluorobenzoate with compound 1-I under reductive amination conditions using an acid, a reducing agent, and a dehydrating agent in a suitable solvent for a time and under conditions effective to form compound 13-A.

[0031] In one embodiment, the acid is selected from citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, and trifluoroacetic acid (TFA). In one embodiment, the acid is trifluoroacetic acid (TFA).

[0032] In one embodiment, the reducing agent is a silane (such as triisopropylsilane, triphenylsilane, diethylsilane, etc.), sodium borohydride, sodium borohydride / acetic acid, sodium cyanoborohydride, titanium isopropoxide / sodium cyanoborohydride, The reducing agent is selected from zinc / acetic acid, sodium borohydride / magnesium perchlorate, zinc borohydride / zinc chloride, tetramethylammonium triacetoxyborohydride, and triethylsilane (EtSiH). In one embodiment, the reducing agent is triethylsilane (EtSiH).

[0033] In one embodiment, the dehydrating agent is selected from molecular sieves, sodium sulfate, and magnesium sulfate (MgSO4). In one embodiment, the dehydrating agent is magnesium sulfate (MgSO4).

[0034] In one embodiment, the solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), hydrocarbon solvents (e.g., toluene, n-heptane), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide), and acetonitrile (MeCN). In one embodiment, the solvent is acetonitrile (MeCN).

[0035] In one embodiment, the temperature of the reaction is 0 to 40°C. In one embodiment, the temperature of the reaction is about 20°C.

[0036] In one embodiment, the present disclosure provides a method for preparing compound 13-B from compound 13-A and compound 5-E, comprising: 6 is a halogen, and each R n But independently C 1~6 alkyl or two R n The parts are joined together to form a C 2~4 forming alkyl bridges, the bridges optionally independently containing C 1~3 In one embodiment, R 6 is Cl. In one embodiment, each R n are independently CH3.

[0037] In one embodiment, the method comprises reacting compound 13-A with compound 5-E in a suitable solvent using a base for a time and under conditions effective to form compound 13-B. 6 is Cl, and each R nare independently CH3.

[0038] In one embodiment, the base is selected from the group consisting of alkoxides (such as sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, and sodium methoxide), tertiary amines (such as triethylamine, tri-n-butylamine, N,N,N',N'-tetramethylethylenediamine, N-methylmorpholine, N-methylpiperidine, 1,4-diazabicyclo[2.2.2]-octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,5-diazabicyclo-4.3.0]non-5-ene), inorganic bases (such as sodium bicarbonate, sodium carbonate, monobasic sodium phosphate, dibasic sodium phosphate, potassium bicarbonate, potassium carbonate, monobasic potassium phosphate, and dibasic potassium phosphate), lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and sodium tert-pentoxide (NaO t -pentoxide). In one embodiment, the base is selected from sodium tert-pentoxide (NaO t -pentoxide).

[0039] In one embodiment, the solvent is an ester (such as ethyl acetate, butyl acetate, isobutyl acetate), an ether (such as methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), an aromatic solvent (such as toluene, benzene, xylene, trifluorotoluene), a polar aprotic solvent (such as N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, butyronitrile), a chlorinated solvent (such as 1,2-dichloroethane, chlorobenzene), or a methyl ether (such as methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane). , N,N-dimethylformamide (DMF), or any combination of the listed solvents. In one embodiment, the solvent is N,N-dimethylformamide (DMF).

[0040] In one embodiment, the temperature of the reaction is 50-100°C. In one embodiment, the temperature of the reaction is about 70°C.

[0041] In one embodiment, the present disclosure provides a method for preparing compound 13-C from compound 13-B.

[0042] In one embodiment, the method comprises treating compound 13-B with a base or acid in a suitable solvent for a time and under conditions effective to form compound 13-C.

[0043] In one embodiment, the base is selected from inorganic bases (hydroxides such as sodium, potassium, lithium, and cesium; carbonates such as lithium, sodium, potassium, and cesium; tribasic phosphates, e.g., sodium, potassium). In one embodiment, the base is lithium hydroxide (LiOH).

[0044] In one embodiment, the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid.

[0045] In one embodiment, the solvent is selected from alcohols (e.g., methanol, ethanol, and isopropanol), miscible or immiscible with water, ethers (e.g., 2-methyltetrahydrofuran, tetrahydrofuran, and 1,4-dioxane), polar aprotic solvents (e.g., N,N-dimethylformamide and N,N-dimethylacetamide). In one embodiment, the solvent is a mixture of tetrahydrofuran and water. In one embodiment, the solvent is a mixture of tetrahydrofuran and water in a 1:1 volume ratio.

[0046] In one embodiment, the temperature of the reaction is 30 to 100°C. In one embodiment, the temperature of the reaction is about 70°C.

[0047] In one embodiment, the present disclosure provides a method for preparing compound 13-D from compound 13-C and compound 6-L. p is -C(=O)-C 1~6 Alkyl, -C(=O)-phenyl, -C(=O)-OC 1~6 Alkyl, -C(=O)-OC 1~6In one embodiment, R is selected from alkyl-phenyl, and —C(═O)—O-phenyl. 2 is H. In one embodiment, R 3 is methyl. In one embodiment, R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form. In one embodiment, R p is the (S) form of 1-phenylethoxycarbonyl.

[0048] In one embodiment, the method comprises reacting compound 13-C with compound 6-L using an acid activator, a promoter, and a base in a suitable solvent for a time and under conditions effective to form compound 13-D.

[0049] In one embodiment, the acid activator is carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM), thionyl chloride, oxalyl chloride, (chloromethylene)-dimethyliminium chloride, isobutyl chloroformate, N,N,N,N'N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH), The acid activator is selected from N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, diphenylchlorophosphate, 2,4,6-trichlorobenzoyl chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC·HCl). In one embodiment, the acid activator is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC·HCl).

[0050] In one embodiment, the accelerator is selected from N-methylimidazole, 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), N,N-dimethylacetamide, N-methylimidazole, and 4-dimethylaminopyridine (DMAP). In one embodiment, the accelerator is 4-dimethylaminopyridine (DMAP).

[0051] In one embodiment, the base is selected from tertiary amines (e.g., N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, DABCO), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, 1-methylimidazole, N-methylimidazole), inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate and bicarbonate derivatives, mono-, di-, and tribasic potassium and sodium phosphates). In one embodiment, the base is N-methylimidazole (NMI).

[0052] In one embodiment, the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), esters (e.g., ethyl acetate, isopropyl acetate), polar aprotic solvents (e.g., N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide), nitriles (e.g., acetonitrile), hydrocarbon solvents (e.g., toluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene). In one embodiment, the solvent is acetonitrile (MeCN).

[0053] In one embodiment, the reaction temperature is -50 to 50°C. In one embodiment, the reaction temperature is 10 to 30°C.

[0054] In one embodiment, the present disclosure provides a method for preparing compound 13-E from compound 13-D.

[0055] In one embodiment, the me...

Claims

1. A compound selected from the following: 【Chemistry 1】 or its salt wherein R y is H or C 1-6 alkyl; R 2 and R 3 are independently H or C 1-6 alkyl; R p is selected from H, —C(═O)—C 1-6 alkyl, —C(═O)-heteroaryl, —C(═O)—O—C 1-6 alkyl, and —C(═O)—O—C 1-6 alkyl-phenyl, where each phenyl or heteroaryl is optionally substituted with 1 to 4 groups independently selected from C 1-3 alkyl and —OC 1-3 alkyl; R″ is selected from H, C 1-6 alkyl, haloC 1-6 alkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; wherein each heteroaryl has 1 to 4 heteroatoms, and each heteroatom is independently selected from N, O, and S; and wherein each heteroaryl has 5 to 10 ring members.

2. The following: 【Chemistry 2】 The compound or salt thereof according to claim 1, selected from:

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