Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([O:22][C:20]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:15])[CH:21]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: Clc1cc(Cl)nc(-c2ccc(Cl)s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Clc1cc(Oc2cc(Cl)nc(-c3ccc(Cl)s3)n2)ccn1

Procedure:
0.4 g 2-(5-Chloro-2-thienyl)-4,6-dichloropyrimidine, 0.2 g 2-Chloro-4-hydroxypyridine, and 0.3 g potassium carbonate are refluxed in 30 mL dry acetonitril for 16 hours. The mixture is poured into water, and the product is extracted with toluene and purified by flash chromatography (0.38 g, m.p. 154°-156° C.).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9](#[N:11])[CH3:10].[C:12]1([C:18](=[CH2:23])[C:19]([O:21][CH3:22])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>C1CCCCC1.O1CCCC1>[C:9]([CH2:10][CH2:23][CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:19]([O:21][CH3:22])=[O:20])#[N:11]
Reactant: C=C(C(=O)OC)c1ccccc1
Reactant: CC#N
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COC(=O)C(CCC#N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Lithium diisopropylamide (3.67 ml of a 1.5 molar solution in cyclohexane) was added to acetonitrile (0.26 ml) in tetrahydrofuran (10 ml) at -78° C. After 1 hour, methyl 2-phenyl-acrylate (see Preparation 22) (0.81 g) in tetrahydrofurn (10 ml) was added and the mixture was stirred for 1 hour, allowed to warm to room temperature then treated with saturated ammonium chloride solution. The resulting mixture was partitioned between ethyl acetate and water, the organic phase dried over magnesium sulphate and evaporated to give a residue which was partitioned between ether and 10% aqueous sodium carbonate. The organic layer was dried over magnesium sulphate and evaporated to leave the title compound (0.5 g, 75%) as an oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([Cl:25])=[CH:20][CH:21]=2)[N:16]=1.C(#N)C>O>[Cl:25][C:19]1[N:18]=[C:17]2[C:22]([CH:23]=[CH:24][C:15]([NH:14][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=3)=[N:16]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc(C(F)(F)F)cc1
Temperature: 4 °C
Yield: 77.9 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 4-trifluoromethylbenzoic acid (10 g), N,N'-carbonyldiimidazole (8.4 g) and 2-amino-7-chloro-1,8-naphthyridine (5.9 g). The product obtained by precipitation in water (11.5 g; m.p. 236° C.) is dissolved in boiling acetonitrile (250 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (2×20 cc) and dried at 45° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-4-trifluoromethylbenzamide (9 g), m.p. 236° C., is obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH:25](OCC)=[O:26]>C(O)C>[CH:25]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26]
Reactant: NCc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Reactant: CCOC=O
Solvent: CCO
Product: O=CNCc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1

Procedure:
A mixture of phenylmethyl [2-[5-(aminomethyl)-1H-indol-3-yl]ethyl]carbamate (0.25 g), ethyl formate (5 ml) and ethanol (1 ml) was heated under reflux for 9 h. The solvent was evaporated in vacuo and the residue was evaporated with ethanol (2×5 ml) to give the title compound (0.27 g) as cream crystals m.p. 114°-6°.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C@@H:3](/[N:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:4][O:5][Si](C)(C)C.[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:1][CH:2]([CH3:18])[C@@H:3]([NH:10][C@H:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:4][OH:5]
Reactant: CC(C)[C@H](CO[Si](C)(C)C)/N=C/c1ccccn1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)[C@H](CO)N[C@H](c1ccccc1)c1ccccn1
Temperature: -78 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
The silylated imine from the previous step, e.g. (2R)-3-methyl-N—[(E)-2-pyridinylmethylidene]-1-[(trimethylsilyl)oxy]-2-butanamine was dissolved in dry THF (500 ml) and the solution was cooled down to −78° C. A 1 M solution of phenylmagnesiumbromide in THF (200 ml, 200 mmol, 2 eq) was added dropwise while the mixture was stirred by a magnetic bar. The mixture was further stirred 2 hours at −78° C. The temperature was then slowly increased up to room temperature overnight. A sample of the reaction mixture was quenched with aqueous NaHCO3 and analysed by LC-MS to detect the O-silylated products. After one night, the mixture was quenched with HCl 1M (250 ml) and the mixture was stirred at room temperature until the desilylation was complete (after 1 h, LC/MS analysis). The aqueous phase was further acidified with the addition of 5M HCl solution (20 ml). The aqueous phase was washed with 300 ml cyclohexane/Et2O (2:1), then made basic with 60 ml NaOH 5M at 0° C., and the organic products were extracted with Et2O, dried (MgSO4) and concentrated to give the desired product (XX*), e.g. (2R)-3-methyl-2-{[(R)-phenyl(2-pyridinyl)methyl]amino}-1-butanol as a yellowish oil (22.9 g, 85% yield, d.e.=99%, determined by 1H NMR).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C:5]=1[C:20]1[N:24]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[N:23]=[CH:22][CH:21]=1.I[CH3:34].O>C1COCC1>[CH3:34][N:6]1[C:5]([C:20]2[N:24]([C:25]3[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=3)[N:23]=[CH:22][CH:21]=2)=[C:4]([CH3:3])[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]1=[O:19]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
Sodium hydride (10 mg of a 60% dispersion in mineral oil, 0.25 mmol) was added to a stirred suspension of 4-(5-{5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (Example 1) (70 mg, 0.17 mmol) in THF (2.0 mL) under a nitrogen atmosphere. This resulted in degassing and the formation of a yellow solution. Iodomethane (0.031 mL, 0.5 mmol) was added and the mixture was stirred for 3 h. Water (10 mL) was added and the mixture was extracted with DCM (2×10 mL). The combined organic phase was dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash column chromatography (2 g Si II SPE eluted with 0-50% EtOAc in DCM in 10% increments). Concentration of the appropriate fractions in vacuo gave the title compound which was freeze-dried from acetonitrile/water to afford a fluffy white solid (50 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:20].[C:21]([C:25]1[CH:29]=[C:28]([N:30]=[C:31]=[O:32])[N:27]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=2)[N:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:29]=[C:28]([NH:30][C:31]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:16]4[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:20])=[O:32])[N:27]([C:33]2[CH:38]=[N:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[N:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cn1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Product: COc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)cnc34)cc2F)cn1
Yield: 7 %

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 5-(3-tert-butyl-5-isocyanato-1H-pyrazol-1-yl)-2-methoxypyridine to afford the title compound (6 mg, 7%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH2:25][S:26]([OH:29])(=O)=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:30]P(Cl)(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH2:25][S:26]([Cl:30])(=[O:29])=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)CCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Solvent: ClCCl
Product: O=S(=O)(Cl)CCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Yield: 17.1 %

Procedure:
3-({1-[1-(4-Chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)propane-1-sulfonic acid (8.4 g) were dissolved in dichloromethane (70 mL). Pentachloro-λ5-phosphane (6.05 g, 29 mmol) were added at room temperature and the reaction mixture was heated under reflux for 3 h. The reaction mixture was poured on ice water and the aqueous layer was extracted with dichloromethane. The combined organic layers were concentrated in vacuo (11 g). The crude product was used for the next step without further purification. For test purposes a sample of the crude product (3.8 g) was purified by flash chromatography (silica, methanol:acetonitrile=1:1) to yield a pale yellow foam (1.5 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C=O.C[C:10](O)([C:12]#[N:13])C.P(=O)(O)(O)O.[CH3:20][C:21]1([CH3:40])[CH2:26][CH:25]([NH:27][C:28](=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:24][C:23]([CH3:39])([CH3:38])[NH:22]1>C(=O)([O-])[O-].[K+].[K+].C(O)C>[C:12]([CH2:10][N:22]1[C:21]([CH3:20])([CH3:40])[CH2:26][CH:25]([NH:27][C:28](=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:24][C:23]1([CH3:39])[CH3:38])#[N:13]
Reactant: CC(C)(O)C#N
Reactant: CCCCCCCCC(=O)NC1CC(C)(C)NC(C)(C)C1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Solvent: CCO
Product: CCCCCCCCC(=O)NC1CC(C)(C)N(CC#N)C(C)(C)C1
Yield: 82.3 %

Procedure:
15 ml of ethanol saturated with potassium carbonate, 18 g of paraformaldehyde, 1.43 g of potassium carbonate and 51 g of acetonecyanohydrin were stirred at 25° C. for 2 h and then brought to pH 6 with 85% strength phosphoric acid. 75 ml of ethanol and 88 g of N-[2,2,6,6-tetramethyl-4-piperidinyl]pelargonamide were added, and the mixture was refluxed for 6.5 h. The reaction mixture was filtered, the filtrate was concentrated and the residue was recrystallized from n-heptane to give 82 g of N-[1-cyanomethyl-2,2,6,6-tetramethyl-4-piperidinyl]pelargonamide having a melting point of 68° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:34]=[C:35]([CH2:39][C:40](O)=[O:41])[CH:36]=[CH:37][CH:38]=1.CCN(C(C)C)C(C)C>>[OH:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:43])([F:31])[F:44])[CH:34]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:29])[CH3:30]
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)c2cnccc21

Procedure:
Prepared according to Method 1 (Example 19) using (5-aminopyridin-3-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Preparation 28), 3-trifluoromethylphenylacetic acid and DIPEA. The residue was purified using silica gel column chromatography eluting with 80% EtOAc in hexane followed by acid deprotection using 10% HCl in dioxane at room temperature for 18 hours. The reaction was concentrated in vacuo and purified using preparative HPLC to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:17]([CH2:23][CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C=CC=CC=1>C1COCC1>[CH2:23](/[C:17](=[CH:4]\[C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:24]
Reactant: CCOC(=O)C(CC)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1F
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1ccccc1F)CC

Procedure:
A solution of 2-fluorobenzaldehyde (6.2 g, 50 mmol) and ethyl 2-(triphenylphosphoranylidene)butanoate (18.8 g, 50 mmol) in THF (200 mL) was refluxed for 2 hrs. The reaction mixture was concentrated and the residue was triturated with 1:1 hexane:ethyl acetate. The precipitate was removed by filtration through silica gel and the filtrate was concentrated. The residue was purified by chromatography on silica gel eluting with 8:2 hexane:ethyl acetate to give ethyl (E)-2-ethyl-3-(2-fluorophenyl)propenoate.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)[C:10]([CH2:19][CH3:20])([CH3:18])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[CH:15]1([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]2([CH2:19][CH3:20])[CH3:18])[CH2:17][CH2:16]1
Reactant: CCC1(C)CN(Cc2ccccc2)CCC1NC1CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CNCCC1NC1CC1

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.5 g) and 1-benzyl-4-cyclopropylamino-3-ethyl-3-methylpiperidine (3.54 g, 13.00 mmol) in methanol (70 ml) was stirred in hydrogen atmosphere (1 atm.) at 60° C. for 48 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-cyclopropylamino-3-ethyl-3-methylpiperidine. Yield 2.3 g (93%), C11H22N2, m/z 183 (M+1).
Reaction SMILES: C([O:4][C@H:5]([C@H:21]1[O:26][CH2:25][CH2:24][N:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:22]1=[O:37])[C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18]C(=O)O[N:15]=2)=[CH:10][CH:9]=1)(=O)C.N.CO.Cl>CCOCC>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:6](=[O:20])[C@H:5]([OH:4])[C@H:21]2[O:26][CH2:25][CH2:24][N:23]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[C:22]2=[O:37])=[CH:9][CH:10]=1)(=[NH:15])[NH2:18]
Reactant: CC(=O)O[C@@H](C(=O)Nc1ccc(-c2noc(=O)[nH]2)cc1)[C@H]1OCCN(c2ccc(C(F)(F)F)cc2)C1=O
Agent: Cl
Agent: N
Solvent: CCOCC
Solvent: CO
Product: N=C(N)c1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(C(F)(F)F)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound 96-1 (110 mg) was treated with 7 M NH3/MeOH (1 mL) and the mixture was stirred at RT for 1 h. After removal of the volatile materials on the rotavap, the residue was dissolved in MeOH (1 mL) and 3M HCl (0.25 ml). The resulting suspension was treated with a balloon of H2 over 10% Pd/C (30 mg) and stirred at RT for 2 h. The resulting mixture was filtered through Celite® and concentrated. The residue was purified by reverse phase HPLC to give EXAMPLE 96 which was converted to the HCl salt (88 mg) by treating with one equivalent HCl in ether and concentration on a rotavap.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]([OH:52])[CH3:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:54]([O:56][CH2:57][CH3:58])=[O:55].C(N(CC)CC)C>ClCCl>[C:54](=[O:55])([O:52][CH:50]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:51])[O:56][CH2:57][CH3:58]
Reactant: CCOC(=O)Cl
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)OC(C)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 30 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 1m (0.2 g, 0.28 mmol, obtained from the synthetic method described in step 11 of example 1) in dichloromethane (20 mL) were added ethyl chloroformate (0.26 mL, 2.8 mmol), triethylamine (0.78 mL, 5.60 mmol) and 4-dimethyl aminopyridine (cat. 5 mg) in turn at room temperature. The mixture was heated to 30° C. and stirred for 16 hours. The resulting mixture was quenched with 20 mL of saturated ammonium chloride, and then extracted with dichloromethane (40 mL×2). The combined organic layers were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=15/1 to give the title compound 12a as a light yellow solid (73.6 mg, 33.5%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.44 (s, 1H), 7.39-7.29 (m, 10H), 7.22 (dd, 5H), 7.08 (d, 2H), 6.91 (d, 2H), 6.77 (d, 2H), 5.10 (m, 1H), 4.97 (d, 1H), 4.90 (s, 1H), 4.81 (d, 2H), 4.33 (s, 1H), 4.21 (s, 1H), 4.20-4.09 (m, 2H), 4.07 (s, 1H), 4.04 (d, 2H), 4.00-3.92 (m, 3H), 3.86-3.76 (m, 2H), 3.66 (d, 1H), 1.41 (t, 3H), 1.29 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:13])[CH3:12])=[O:4].[C:20]([O:23][C@H:24]1[CH2:29][C@H:28]([CH3:30])[CH2:27][CH2:26][C@H:25]1[C:31](Cl)=[O:32])(=[O:22])[CH3:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])(O)=O.[Na+]>ClCCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:9]=1[N:10]([CH:11]([CH3:13])[CH3:12])[C:31]([C@@H:25]1[CH2:26][CH2:27][C@@H:28]([CH3:30])[CH2:29][C@@H:24]1[O:23][C:20](=[O:22])[CH3:21])=[O:32])=[O:4]
Reactant: CC(=O)O[C@H]1C[C@H](C)CC[C@H]1C(=O)Cl
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@@H]1CC[C@@H](C)C[C@@H]1OC(C)=O)C(C)C
Temperature: 90 °C
Reaction time: 20 h
Yield: 48.1 %

Procedure:
To a solution of 3-Isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (136 mg, 0.50 mmol) in 1,2-dichloroethane (1.0 ml) was added (1R,2S,4R)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid chloride (119 mg, 0.54 mmol) dissolved in 1,2-dichloroethane (0.6 ml) followed by PPh3 (136 mg, 0.52 mmol). The resulting solution was stirred for 20 h at 90° C. and then cooled to room temperature. It was then diluted with ethyl acetate (10 ml) and a solution of saturated NaHCO3 (10 ml). The aqueous phase was separated and washed with ethyl acetate (2×10 ml) and the combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0% to 25% EtOAc/Hexane) to obtain 110 mg (45%) of (1R,2S,4R)-3-[Isopropyl-(2-Acetoxy-4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 1.5:1.0 mixture of rotamers 7.73-7.70 ppm (m, 2H, Haro); 7.69-7.63 ppm (m, 1H, Haro); 7.51-7.41 ppm (m, 4H, Haro); 7.13 ppm (s, 0.6H, Haro, major rotamer); 5.79 ppm (s, 0.4H, minor rotamer); 5.21 ppm (s, 0.6H, major rotamer); 4.95-4.88 ppm (m, 1H); 3.88 ppm (s, 1.8H, major rotamer); 3.87 ppm (s, 1.2H, minor rotamer); 2.40-2.36 ppm (m, 0.6H, major rotamer); 2.11 ppm (s, 3H); 1.78-0.77 ppm (m, 16H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[C:6]([O:31][CH3:32])[CH:7]=3)[N:12]=[CH:11][CH:10]=2)=[C:17]([C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:18]=1
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (50 mg), morpholine (29 mg), and potassium carbonate (76 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (35 mg, yield 64%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:4]=1[S:18]([NH:21][C@H:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([N:28]2[CH:32]=[N:31][N:30]=[CH:29]2)[CH2:23]1)(=[O:20])=[O:19])[CH3:2].Br[C:34]1[C:35]2[N:36]([CH:40]=[CH:41][N:42]=2)[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.CCOC(C)=O.CCO>[CH2:1]([C:3]1[CH:8]=[C:7]([C:34]2[C:35]3[N:36]([CH:40]=[CH:41][N:42]=3)[CH:37]=[CH:38][CH:39]=2)[CH:6]=[CH:5][C:4]=1[S:18]([NH:21][C@H:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([N:28]2[CH:29]=[N:30][N:31]=[CH:32]2)[CH2:23]1)(=[O:19])=[O:20])[CH3:2]
Reactant: CCc1cc(B2OC(C)(C)C(C)(C)O2)ccc1S(=O)(=O)N[C@H]1CCC[C@@H](n2cnnc2)C1
Reactant: Brc1cccn2ccnc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CCc1cc(-c2cccn3ccnc23)ccc1S(=O)(=O)N[C@H]1CCC[C@@H](n2cnnc2)C1
Temperature: 120 °C

Procedure:
Compound 2c (1.50 mL of a 0.1 M DME solution, 0.150 mmol) was added to a mixture of 8-bromoimidazo[1,2-a]pyridine (29.6 mg, 0.150 mmol), sodium carbonate (150 μL of a 2 M aq. solution, 0.300 mmol) and tetrakistriphenylphosphine palladium(0) (17.3 mg, 0.015 mmol) in DME:water:EtOH (2.00 mL of a 12:4:3 mixture, respectively). The reaction mixture was placed in a sealed tube and heated in a microwave reactor at 120° C. for 15 min. After cooling to rt, the mixture was diluted with EtOAc and filtered through a short column Celite®, eluting copiously with EtOAc. The combined organics were concentrated in vacuo, and the resulting crude residue was purified by preparative thin layer chromatography on silica gel (10% MeOH/DCM as eluent) to afford the title compound, 2d. m/z (ES) 453 (MH)+. IC50=3.9 nM
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Cl:9][CH2:10][C:11](=N)OC>C(Cl)Cl>[Cl:9][CH2:10][C:11]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: COC(=N)CCl
Reactant: Nc1ccccc1S
Solvent: ClCCl
Product: ClCc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a solution of aminothiophenol (8.3 g) in methylene chloride at 0° C. is added methyl chloroacetimidate hydrochloride1 (8.6 g). The reaction is allowed to warm to room temperature while stirring overnight. The mixture is washed with water three times; dried over magnesium sulfate and concentrated to an oil. The oil is distilled (120°-135° C. at 0.5 mm Hg) to give 7.8 g (71% yield) of product.