Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[NH2:23][CH:24]1[C:46](=[O:47])[N:26]2[CH:27]([C:36]([O:38]CC3C=CC=CC=3)=[O:37])[C:28]3([S:35][C@H:25]12)[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3.[H][H]>C(O)C.[Pd]>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[C:12]1([CH3:22])[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1.[NH2:23][CH:24]1[C:46](=[O:47])[N:26]2[CH:27]([C:36]([OH:38])=[O:37])[C:28]3([S:35][C@H:25]12)[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3
Reactant: CN1CCC2(CC1)S[C@@H]1C(N)C(=O)N1C2C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CN1CCC2(CC1)S[C@@H]1C(N)C(=O)N1C2C(=O)O
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
A solution of 2.5 g (0.00354 mole) of benzyl 6-amino-1'-methyl-spiro[penam-2,4'-piperidine]-3-carboxylate di-p-toluenesulfonate (obtained in 8.1) in 1.5 liter of ethanol is subjected to hydrogenolysis in a Parr's apparatus under 3.2 kg/cm2 of hydrogen in the presence of 2 g of palladium on carbon (10% Pd). After 90 minutes, the reaction mixture is filtered and the filtrate is evaporated to dryness and lyophilized in 600 ml of water. 1.8 g of 6-amino-1'-methyl-spiro[penam-2,4'-piperidine]-3-carboxylic acid di-p-toluenesulfonate is obtained; yield: 83%; M.P. approx 155°-160° C. (start of decomposition).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:6][CH:5]=1.[OH-].[K+]>C1COCC1.O>[CH2:21]([S:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][CH2:11][NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][N:6]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(NCCCc2ccccc2SCc2ccccc2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(NCCCc2ccccc2SCc2ccccc2)nc1
Temperature: 50 °C

Procedure:
To a solution of the ester of Example 6 in THF (0.8 mL) was added a solution of KOH (14 mg, 0.255 mmol) in H2O (0.2 mL). The mixture was stirred at 50° C., then concentrated to remove THF. The aqueous phase was washed with ethyl ether, then the aqueous phase was acidified until pH 3–4 was reached. The acidified solution was extracted with Et2O or EtOAc (3×), dried over MgSO4, filtered and concentrated in vacuo to give a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br-].[CH3:24][O:25][C:26]1[N:31]=[C:30]([Zn+])[CH:29]=[CH:28][CH:27]=1>>[C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[N:31]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc([Zn+])n1
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
Agent: [Br-]
Product: COc1cccc(-c2cncc(N(C(=O)OC(C)(C)C)c3ccc(Cl)cc3)n2)n1

Procedure:
Was prepared according to Example 5 from (4-chloro-phenyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl ester and 6-methoxy-2-pyridylzinc bromide.
Reaction SMILES: Cl.[CH3:2][NH2:3].[C:4](=[O:7])([O-])[O-].[K+].[K+].C(=O)=O.[F:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][C:15]=1[N:27]1[C:32](=[O:33])C2CCCC(=C2)C1=O.Cl>C(#N)C>[F:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([O:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:16][C:15]=1[NH:27][C:32](=[O:33])[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=1[C:4]([NH:3][CH3:2])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: CN
Reactant: O=C1C2=CC(CCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Yield: 107.5 %

Procedure:
Methylamine hydrochloride (0.200 g, 2.96 mmol) and potassium carbonate (0.400 g, 2.89 mmol), and acetonitrile (5 ml) as a solvent were placed into a round bottom flask (25 cc), followed by stirring at room temperature. After confirming the generation of carbon dioxide gas, N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide (0.650 g, 1.79 mmol) was added thereto, followed by stirring overnight at room temperature. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (20 ml), and the mixture was extracted with ethyl acetate (40 ml x 3 portions). After drying the organic layer over anhydrous magnesium sulfate, the drying agent was removed, and the solvent was distilled off under reduced pressure. The precipitated crystals were isolated by filtration, thoroughly washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-methyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.380 g, 53.8% yield). The melting point and the spectral data thereof are shown in Example 37.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:23]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:23])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)C(=O)Nc1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: CC(C)C(=S)Nc1ccc(Br)cc1
Temperature: 120 °C
Yield: 136.1 %

Procedure:
In a 500 mL three-neck flask were put 18 g (74 mmol) of N-(4-bromophenyl)isobutyramide obtained in Step 1, 15 g (37 mmol) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent), and 120 mL of toluene, and the mixture was heated and refluxed at 120° C. for 3 hours. After that, toluene was distilled off to give a yellow oily substance. This oily substance was purified by silica gel column chromatography. Toluene was used as a developing solvent. The resulting fraction was concentrated to give a yellow solid. The resulting solid was collected by suction filtration, and the collected solid was washed with a small amount of methanol to give 13 g of a white solid of N-(4-bromophenyl)isobutyrthioamide in a yield of 70%. The reaction scheme of Step 2 is shown in (b-2) below.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[N:11][C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[CH:27]=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[CH2:27][NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[N:11][C:10]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccsc1C=O
Reactant: CSc1nc(-c2ccncc2)nn1-c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CSc1nc(-c2ccncc2)nn1-c1ccc(NCc2sccc2C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A stirred solution of 1-(4-aminophenyl)-5-methylthio-3-(4-pyridyl)-1H-1,2,4-triazole (Example 1) (100 mg, 0.35 mmol) and 3-methylthiophene-2-carboxaldehyde (44 mg, 0.35 mmol) in 5% acetic acid in MeOH (4 mL) at room temperature was treated with sodium cyanoborohydride (55 mg, 0.88 mmol) and the reaction mixture was further stirred at room temperature for 48 h. The reaction mixture was concentrated, diluted with EtOAc, washed with NaHCO3 solution, brine and dried (MgSO4). The residue obtained on concentration was flash chromatographed on silica gel and eluted with a gradient of dichloromethane/acetone (9/1 to 3/1). The title compound was obtained as a white solid (85 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:13][C@H:12]3[C@:14]4([CH2:18][N:17]([CH2:19][C:20]([F:23])([F:22])[F:21])[S:16](=[O:25])(=[O:24])[NH:15]4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8][C:7]=2[CH:26]=1)#[CH:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[N+:35]=[N-:36])=[CH:30][CH:29]=1>CC1C=CC(C)=CC=1>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:2]=[C:1]([C:3]3[CH:4]=[CH:5][C:6]4[CH2:13][C@H:12]5[C@:14]6([CH2:18][N:17]([CH2:19][C:20]([F:21])([F:22])[F:23])[S:16](=[O:25])(=[O:24])[NH:15]6)[C@H:9]([CH2:10][CH2:11]5)[CH2:8][C:7]=4[CH:26]=3)[N:36]=[N:35]2)=[CH:30][CH:29]=1
Reactant: C#Cc1ccc2c(c1)C[C@H]1CC[C@@H](C2)[C@]12CN(CC(F)(F)F)S(=O)(=O)N2
Reactant: [N-]=[N+]=Nc1ccc(F)cc1
Solvent: Cc1ccc(C)cc1
Product: O=S1(=O)N[C@@]2(CN1CC(F)(F)F)[C@@H]1CC[C@H]2Cc2ccc(-c3cn(-c4ccc(F)cc4)nn3)cc2C1

Procedure:
A solution of the alkyne from Step 2 (0.075 g, 0.195 mmol) and 4-fluorophenylazide (0.035 g, 0.25 mmol) in p-xylene (5 mL) was refluxed under nitrogen for 21 hr. The solution was evaporated to dryness. Preparative HPLC on a normal phase column, eluting with an ethyl acetate-isohexane gradient gave the major cycloadduct (0.022 g). Further purification by reverse phase HPLC, eluting with an acetonitrile-pH3 buffer gradient, gave the triazole as yellow solid, which was rinsed with diethyl ether and dried to give a pale yellow powder (0.010 g, 10%).
Reaction SMILES: [CH:1]12[NH:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:7]2[CH:4]3[CH2:5][CH2:6][CH:1]2[CH:2]([NH:8][C:9]2[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]4)[CH2:3]3)=[CH:21][CH:20]=1
Reactant: c1cc2[nH]ncc2cc1NC1CC2CCC1N2
Reactant: Cc1ccc(C=O)cc1
Product: Cc1ccc(CN2C3CCC2C(Nc2ccc4[nH]ncc4c2)C3)cc1

Procedure:
Reaction of Intermediate 24 with 4-methylbenzaldehyde affords the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][N:15]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH2:14][C:13]([CH3:28])([CH3:27])[C:12]=3[N:11]=[C:10]([CH:29]([CH3:31])[CH3:30])[C:9]=2[CH2:32][OH:33])=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][N:15]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])=[O:19])[CH2:14][C:13]([CH3:28])([CH3:27])[C:12]=3[N:11]=[C:10]([CH:29]([CH3:30])[CH3:31])[C:9]=2[CH:32]=[O:33])=[CH:4][CH:3]=1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1CO)CN(C(=O)OCC[Si](C)(C)C)CC2(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C=O)CN(C(=O)OCC[Si](C)(C)C)CC2(C)C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
To a stirred mixture of 2-(trimethylsilyl)ethyl 4-(4-fluorophenyl)-3-(hydroxymethyl)-2-isopropyl-8,8-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (4.73 g, 10 mmol), N-methylmorpholine-N-oxide (1.29 g, 11.00 mmol) and 4 Å molecular sieves (2 g) in CH2Cl2 (100 mL) was added tetrapropylammonium perruthenate (0.09 g, 0.25 mmol) at rt. After 5 h, the reaction mixture was diluted with hexanes (100 mL), filtered through a plug of silica gel using 1:1 Et2O/hexanes (500 mL) and concentrated under reduced pressure to afford 2-(trimethylsilyl)ethyl 4-(4-fluorophenyl)-3-formyl-2-isopropyl-8,8-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (4.28 g, 91% yield) as a pale yellow pasty solid. 1H NMR (500 MHz, CDCl3) δ ppm: 9.79 (1H, s), 7.18 (4H, d, J=6.4 Hz), 4.24 (2H, br. s.), 4.16 (2H, t, J=8.1 Hz), 3.54 (2H, br. s.), 1.36 (6H, s), 1.28 (6H, d, J=6.7 Hz), 1.22-1.27 (1H, m), 0.93-1.05 (1H, m), 0.84-0.93 (1H, m), 0.02 (9H, br. s.). LCMS (M+H) calcd for C26H36N2O3Si: 471.25. found: 471.3.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:12][CH:13]([CH2:16][CH2:17][CH3:18])[CH:14]=O.C1(C)C=CC=CC=1>O>[CH3:11][O:10][C:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[N:4]=[CH:12][CH:13]([CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)c1ccccc1N
Reactant: CCCC(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC(C)C=Nc1ccccc1C(=O)OC

Procedure:
226.5 g (= 1.5 g mole) of methyl anthranilate, 150 g (= 1.5 g mole) of 2-methylpentanal and 400 g of toluene are brought into a 2 liter reaction flask. Then the mixture is agitated under reflux for about 5 hours at a bottom temperature of 100°-120°C, 20 g of water being taken off through the reflux head. Then the solution is concentrated at a 30 cm Vigreux column under reduced pressure (about 20 mm Hg) to a bottom temperature of 110°C. 360 g of toluene are obtained and 347 g of evaporation-residue. The evaporation residue is fractionated at a 30 cm Vigreux column to obtain:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][C:10]([CH2:15][N:16]4[C:24](=[O:25])[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17]4=[O:26])([CH3:14])[C:9]=3[O:27][C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[F:43][C:44]1[CH:45]=[C:46]([SH:50])[CH:47]=[CH:48][CH:49]=1>[Cu]I>[F:43][C:44]1[CH:45]=[C:46]([S:50][C:2]2[CH:7]=[CH:6][C:5]3[C:8]4[CH2:13][CH2:12][NH:11][C:10]([CH2:15][N:16]5[C:24](=[O:25])[C:23]6[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=6)[C:17]5=[O:26])([CH3:14])[C:9]=4[O:27][C:4]=3[CH:3]=2)[CH:47]=[CH:48][CH:49]=1
Reactant: CC1(CN2C(=O)c3ccccc3C2=O)NCCc2c1oc1cc(I)ccc21
Reactant: Fc1cccc(S)c1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: CN(C)C=O
Product: CC1(CN2C(=O)c3ccccc3C2=O)NCCc2c1oc1cc(Sc3cccc(F)c3)ccc21
Temperature: 120 °C
Reaction time: 72 h

Procedure:
To 2-(7-iodo-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl)-isoindole-1,3-dione (0.192 g, 0.406 mmol) was added sodium tert-butoxide (117 mg, 1.22 mmol), copper (I) iodide (7.74 mg, 0.0406 mmol), 1,2-ethanediol (45.3 μL, 0.812 mmol), N,N-dimethylformamide (4.00 mL, 51.6 mmol), and finally 3-fluorobenzenethiol (36.0 μL, 0.427 mmol). The reaction mixture was flushed with N2 and heated at 120° C. under a N2 atmosphere. After 72 h, the reaction was cooled to room temperature and concentrated. The residual solid was partially dissolved into a 5% MeOH in DCM solution and flushed through a plug of Celite. The concentrated filtrate was chromatographed on silica gel using DCM-MeOH—NH4OH to afford a brownish yellow gum. MS m/z 473 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=O)=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[O:16][CH3:17].CC1[C:24](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=C(OC)C(OC)=C(OC)C=1OC>>[CH3:1][C:2]1[C:7](/[CH:8]=[C:26](\[CH2:25][CH3:24])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[O:16][CH3:17]
Reactant: CCOC(=O)/C=C/c1c(C)c(OC)c(OC)c(OC)c1OC
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Product: CCOC(=O)/C(=C/c1c(C)c(OC)c(OC)c(OC)c1OC)CC

Procedure:
Compound 8c was prepared from 7 (0.437 g, 1.82 mmol) as described above for 8a to give 0.258 g (0.762 mmol, 42%) of the product as a colorless oil following flash chromatography (1:3 EtOAc:hexanes).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[S:21][CH:20]=[N:19][CH:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CS(C)=O>[S:21]1[C:17]([C:14]2[N:13]=[CH:12][C:11]3[CH:10]=[N:9][N:8]([C:6]4[N:7]=[C:2]([N:32]5[CH2:31][CH2:30][N:29]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:34][CH2:33]5)[CH:3]=[CH:4][CH:5]=4)[C:16]=3[CH:15]=2)=[CH:18][N:19]=[CH:20]1
Reactant: Fc1cccc(-n2ncc3cnc(-c4cncs4)cc32)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cncs5)cc43)n2)CC1
Temperature: 95 °C

Procedure:
A solution of 5-[1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridin-6-yl]thiazole (50 mg, 0.17 mmol) and 1-N-boc-piperazine (175 mg, 0.921 mmol) in dimethyl sulfoxide; 2.0 mL was heated at 95° C. for 8 h. The reaction was quenched with water and extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum to give tert-butyl 4-[6-(6-thiazol-5-ylpyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]piperazine-1-carboxylate:
Reaction SMILES: [C:1]([CH2:3][C:4](O)=O)#[N:2].O1CCOC[CH2:8]1.[CH:13]1([CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C=O>O>[CH:13]1([CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH2:8][C:3](=[CH2:4])[C:1]#[N:2])[CH2:24][CH2:25]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: C1CCC(CC2CCNCC2)CC1
Reactant: C1COCCO1
Reactant: N#CCC(=O)O
Agent: C=O
Solvent: O
Product: C=C(C#N)CN1CCC(CC2CCCCC2)CC1
Reaction time: 0.25 h

Procedure:
Cyanoacetic acid (0.9 g., 0.01 mole) was dissolved in 6 ml. of dioxane and 1 ml. of water. In a 15 minute period, 4-cyclohexylmethylpiperidine (1.8 g., 0.01 mole) was added. After an additional 15 minutes, 37% aqueous formaldehyde (1.8 g., 0.02 mole) was dripped in over a two minute period. The reaction mixture was agitated twelve hours at 20°-25° C., extracted with 200 ml. of ether, water washed, dried over anhydrous sodium sulfate, filtered and stripped. A yield of 1.2 g. of high purity product was obtained as a residue.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[CH3:15][O:16][C:17](=[O:40])[C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:27][CH:26]=2)=[C:20](N)[CH:19]=1.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>CC(O)=O.O>[CH3:15][O:16][C:17](=[O:40])[C:18]1[CH:19]=[CH:20][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])=[CH:27][CH:26]=2)=[C:22]([NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[N:5][C:4]=3[N:10]=[CH:11][N:12]=2)[CH:23]=1
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C)ccc23)c1
Temperature: 120 °C
Yield: 62 %

Procedure:
A suspension of N′-(3-cyano-6-methyl-pyridin-2-yl)-N,N-dimethyl-formamidine (1.00 g, 5.3 mmol) and 3-amino-4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-benzoic acid methyl ester (prepared in Example 385C) (1.99 g, 5.3 mmol) in AcOH (20 mL) was heated at 120° C. for 30 minutes under N2. After cooling to room temperature, the reaction mixture was portioned between AcOEt (250 mL) and H2O (200 mL), and then made basic to pH 9 with K2CO3 under stirring. The organic layer was separated, washed with 10% NaHCO3, H2O and brine, dried over MgSO4, and evaporated to give pale brown oil. The oily residue was separated by silica gel column chromatography (AcOEt) to yellow amorphous, which was solidified by the treatment of i-Pr2O. The resulting solid was collected by filtration, washed with i-Pr2O, and dried at 40° C. overnight under reduced pressure to give the title compound as pale yellow crystal (1.70 g, 62%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:31]2([CH3:32])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH:21]([C:23](OC)=[O:24])[CH3:22])[CH2:12][C@@H:11]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C(OC)=O)C)C[C@@H](OC(OC)=O)C1)=O>>[Si:1]([O:8][C@@H:9]1[C@@:31]2([CH3:32])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH:21]([CH3:22])[CH2:23][OH:24])[CH2:12][C@@H:11]([O:34][Si:35]([C:38]([CH3:39])([CH3:41])[CH3:40])([CH3:36])[CH3:37])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)OC)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: CC(CO)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 67.9 %

Procedure:
The procedure of Example 11 was repeated except that 85 mg of methyl 1α,3β-bis(t-butyldimethylsilyloxy)pregna-5,7-diene-20-carboxylate was used in lieu of 70 mg of methyl 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carboxylate to give 55 mg of 1α,3β-bis(t-butyldimethylsilyloxy)-20-methylpregna-5,7-diene-21-ol, whose 1H NMR spectrum was identical with that obtained in Example 9.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([OH:14])[C:7]([CH3:13])([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([O:14][Si:24]([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25])[C:7]([CH3:12])([CH3:13])[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)COc2cc(Br)ccc2C1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)COc2cc(Br)ccc2C1O[Si](C)(C)C(C)(C)C
Yield: 54226.5 %

Procedure:
To a solution of 7-bromo-3,3-dimethyl-chroman-4-ol (300 mg, 1.44 mmol) in DMF (3.33 mL) was added imidazole (119 mg, 1.75 mmol) followed by TBDMS-Cl (263 mg, 1.75 mmol). The next day, the reaction was diluted with ethyl acetate and washed with water (3×) and saturated sodium bicarbonate (1×). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude material was purified using silica gel chromatography (100% pentane to 50% pentane in ethyl acetate) to yield the desired product (290 g, 65% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C@@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)[OH:8].C(N(CC)CC)C.[Cl:28][C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[OH:8][C@@:7]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:29]([Cl:28])=[O:31])[CH2:10]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)Cl)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 159.1 %

Procedure:
A solution of (S)-5-methoxy-1-phenyl-1-((R)-piperidin-3-yl)pentan-1-ol (455.6 mg, 1.8 mmol) and triethylamine (1.50 mL, 10.7 mmol) in CH2Cl2 (100 mL) was cooled to 0° C. A solution of triphosgene (278.6 mg, 1.0 mmol) in CH2Cl2 (10 mL) was added with fast dropwise addition. The solution was stirred for 30 min at 0° C. and then for 2 h at rt. The reaction mixture was cooled to 0° C., washed with ice-cold satd aq NaHCO3 (3×10 mL) and ice-cold brine (3×10 mL), dried (Na2SO4), decanted, and siripped to afford (R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbonyl chloride (540.8 mg, 99%) as a yellow oil. This material was carried on directly to the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][C:26]1([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:29][CH2:28][CH2:27]1)[C:9]1[N:14]=[N:13][C:12]([C:15]2[S:16][C:17]([C:20]([O:22]CC)=O)=[CH:18][N:19]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:37]>CO>[C:20]([C:17]1[S:16][C:15]([C:12]2[N:13]=[N:14][C:9]([N:8]([CH2:25][C:26]3([C:30]4[C:35]([F:36])=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:27][CH2:28][CH2:29]3)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:11]=2)=[N:19][CH:18]=1)(=[O:22])[NH2:37]
Reactant: CCOC(=O)c1cnc(-c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)s1
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(C(N)=O)s2)nn1
Temperature: 120 °C

Procedure:
To a solution of ethyl 2-(6-(tert-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)thiazole-5-carboxylate (162 mg, 0.32 mmol) in MeOH (8 mL) was purged with NH3 gas for 5 min. The reaction mixture was sealed and heated in a microwave reactor for 30 min at 120° C. The reaction mixture was concentrated and used in next step without purification, LRMS (M+H+) m/z 484.2.