Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH3:27])([CH3:26])[CH2:12][N:13]2[Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[CH:9][C:8]=1[F:28].[C:29]1([S:35](F)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[C:29]1([S:35]([C:7]2[CH:15]=[C:14]3[C:10]([C:11]([CH3:27])([CH3:26])[CH2:12][N:13]3[Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[CH:9][C:8]=2[F:28])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)N1CC(C)(C)c2cc(F)c(Br)cc21
Reactant: O=S(=O)(F)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)N1CC(C)(C)c2cc(F)c(S(=O)(=O)c3ccccc3)cc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
BuLi (2.2 M solution in Et2O. 2.4 mL, 5.4 mmol) was slowly added to a solution of 6-bromo-5-fluoro-3,3-dimethyl-1-triisopropylsilanyl-2,3-dihydro-1H-indole (1.8 g, 4.5 mmol) in THF (20 mL) at −78° C. under nitrogen. The solution was stirred for 15 minutes at −78° C. and then phenylsulfonyl fluoride (541 μL, 4.5 mmol) was slowly added. Stirring was maintained for 1 h at the same temperature. The reaction was quenched by adding saturated aqueous NH4Cl and the product was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated. The crude material was purified by SiO2 chromatography (10% EtOAc in petrol) to give the title compound (1.4 g) as a yellow solid. 1H NMR (CDCl3): 7.98 (2H, d), 7.64-7.56 (1H, m), 7.56-7.48 (2H, m), 7.23 (1H, d), 6.68 (1H, d), 3.50 (2H, s), 1.55-1.45 (3H, m), 1.24 (6H, s), 1.21-1.11 (18H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C@@H:9]2[CH:16]3[CH2:17][N:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)=[N:6][CH:7]=1.[NH:19]1[C:27]2[C:22](=[CH:23][C:24](B(O)O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.N>>[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([C:2]3[CH:3]=[CH:4][C:5]([O:8][C@@H:9]4[CH:16]5[CH2:17][N:12]6[CH2:13][CH:14]([CH2:18][CH:10]4[CH2:11]6)[CH2:15]5)=[N:6][CH:7]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Brc1ccc(OC2C3CC4CC2CN(C4)C3)nc1
Agent: N
Product: c1cc2cc(-c3ccc(OC4C5CC6CC4CN(C6)C5)nc3)ccc2[nH]1

Procedure:
Prepared from the product of Example 10C (45 mg, 0.14 mmol) and 5-indolylboronic acid (33 mg, 0.204 mmol; Maybridge) according to Method G: MS (DCI/NH3) m/z=346 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C.C1COCC1>O>[CH2:1]([O:8][C:9]([N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:17]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccc(CNCC2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(CNCc2ccccc2)CC1
Reaction time: 3 h
Yield: 49.7 %

Procedure:
Under ice-cooling, 3.46 g of benzyloxycarbonyl chloride was added dropwise to a mixed solution of 4.15 g of N-(4-piperidylmethyl)-N-benzylamine, 2.10 g of triethylamine and 200 ml of THF. After stirring the mixture at the same temperature for 3 hours and then at room temperature for 2 hours, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; chloroform:methanol=19:1) to give 3.41 g of N-(1-benzyloxycarbonylpiperidin-4-ylmethyl)-N-benzylamine (yield: 50%, IR: 1702 cm-1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:13]=1[C:14](OC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]([CH:19]=[CH:18][C:13]=1[CH2:14][OH:15])[C:22]#[N:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C#N)cc1OCCNC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.15 g (12.95 mmol) of methyl 2-(2-(t-butoxycarbonylamino)ethoxy)-4-cyano-benzoate was dissolved in 60 ml of tetrahydrofuran (dehydrated). 8.6 ml (17.2 mmol) of 2 M lithium borohydride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. The solvent was evaporated, and the residue was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:33]=[CH:32][C:12]([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=[CH:24][C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)[S:3]1.C([O-])=O.[NH4+]>C(O)(=O)C.[Pd]>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][C:14]3[CH:15]=[CH:16][C:17]([C:20](=[CH:24][C:25]4[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=4)[C:21]([OH:23])=[O:22])=[CH:18][CH:19]=3)=[CH:32][CH:33]=2)[S:3]1
Reactant: Cc1ccc(C=C(C(=O)O)c2ccc(Oc3ccc(C=C4SC(=O)NC4=O)cc3)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1ccc(C=C(C(=O)O)c2ccc(Oc3ccc(CC4SC(=O)NC4=O)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
To a solution of 40 (1.0 g, 2.2 mmol) and ammonium formate (8.32 g, 132 mmol) in 25 mL glacial acetic acid was added 5% Pd/C (1.0 g). The mixture was refluxed for 7.5 h, cooled to room temperature and filtered over Celite. The mixture was concentrated in vacuum then added to 200 mL water. The product was filtered and washed with hexanes. The solid was recrystallized out of toluene, cooled to room temperature and sonicated until the solid was observed. The mixture was then stirred at room temperature for 16 h. The precipitate was collected and washed with hexanes to yield a white solid (0.609 g, 59.1%). 1H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 12.05 (br s, 1H), 7.72 (s, 1H), 7.30 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.99 (d, J=9.2 Hz, 2H), 6.98 (d, J=8.0 Hz, 2H), 4.92 (dd, J=4.4 and 9.6 Hz, 1H), 3.38 (dd, J=4.4 and 14.0 Hz, 1H), 3.21 (dd, J=9.2 and 14.0 Hz, 1H), 2.24 (s, H).
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][CH2:16][C@H:17]([N:27]([CH3:40])[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[F:39])=[O:29])[CH2:18][O:19][Si](C(C)(C)C)(C)C)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[P:1]([O:13][CH2:14][CH2:15][CH2:16][C@H:17]([N:27]([CH3:40])[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[F:39])=[O:29])[CH2:18][OH:19])([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCOP(=O)(OC(C)(C)C)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1F)[C@H](CO)CCCOP(=O)(OC(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a solution of (S)-di-tert-butyl 5-(tert-butyldimethylsilyloxy)-4-(3-(2,3-difluorobenzyl)-1-methylureido)pentyl phosphate (4.1 g, 7.95 mmol) in THF (40 mL) was added TBAF (1.0 M in THF, 8.0 mL, 8.0 mmol). The resulting solution was stirred at RT for 1 h. The mixture was quenched with sat. NH4Cl and diluted with EtOAc. The organic layer was washed with sat. NH4Cl (×2) and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-di-tert-butyl 4-(3-(2,3-difluorobenzyl)-1-methylureido)-5-hydroxypentyl phosphate (2.52 g, 61%) as a colorless oil. LRMS (M+H+−2 tBu) m/z 383.0.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[CH:14]4[C:18]([CH3:20])([CH3:19])[C:11]([CH3:21])([CH2:12][CH2:13]4)[C:10]=3[N:9]2[CH3:22])[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:22][N:9]1[C:10]2[C@@:11]3([CH3:21])[C:18]([CH3:19])([CH3:20])[C@H:14]([CH2:13][CH2:12]3)[C:15]=2[C:16](=[O:17])[N:8]1[C:4]1[CH:3]=[C:2]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[CH:29]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Cn1c2c(c(=O)n1-c1cccc(I)c1)C1CCC2(C)C1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1cccc(-c2cccc(-n3c(=O)c4c(n3C)[C@]3(C)CC[C@H]4C3(C)C)c2)c1
Yield: 20.1 %

Procedure:
A mixture of 2-(3-iodo-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Example 23; 80 mg, 0.2 mmol), 3-methyl-phenyl-boronic acid (41 mg, 0.29 mmol), potassium carbonate (66 mg, 0.47 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 0.014 mmol) in dimethoxyethane (4 mL) was sealed under argon and heated at 80 degrees overnight and then at 90 degrees over the weekend. The reaction mixture was diluted with dichloromethane, filtered through a cotton plug and frit, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an RS-12 column, eluting with 0-35% ethyl acetate/hexanes to give (4S,7R)-1,7,8,8-tetramethyl-2-(3′-methyl-biphenyl-3-yl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (15 mg, 20%) as a brown solid. ES(+)-MS (M+H) 373.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>O>[N+:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: C1CCNCC1
Solvent: O
Product: O=[N+]([O-])c1cccc(N2CCCCC2)c1
Temperature: 110 °C
Reaction time: 72 h
Yield: 93.7 %

Procedure:
A mixture of 3-fluoronitrobenzene (10.0 g, 70.9 mmol) and piperidine (14 ml, 141 mmol) was stirred at 110° C. for 3 days. After cooling water (200 ml) was added and the mixture was extracted with dichloromethane (3×100 ml). The combined organic extracts were washed with saturated aqueous sodium carbonate, dried over sodium sulfate and evaporated to dryness to leave 1-(3-nitrophenyl)piperidine (13.7 g, 93%) as an oil. This oil was dissolved in ethanol (150 ml) and was hydrogenated at ambient pressure using palladium on activated carbon as the catalyst to yield 2a (11.7 g, 100%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]1([CH3:27])[CH:15]=[CH:14][C:13]([C:16](=O)[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=O)=[CH:12][CH:11]=1>CCO>[Cl:1][C:2]1[CH:7]=[N:6][C:5]2=[N:8][C:16]([C:13]3[CH:12]=[CH:11][C:10]([CH3:27])=[CH:15][CH:14]=3)=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Reactant: Nc1cc(Cl)cnc1N
Solvent: CCO
Product: Cc1ccc(-c2nc3cc(Cl)cnc3nc2-c2ccc(C)cc2)cc1

Procedure:
A mixture comprising 5-chloropyridine-2,3-diamine (1 g, 6.9 mmol) and 1,2-di-p-tolylethane-1,2-dione (1.6 g, 6.9 mmol) in EtOH (15 ml) under argon was stirred at 70° C. overnight. The mixture was heated for a further 8 hours and the solvent was removed under reduced pressure. The resulting crude material was purified by chromatography on silica eluting with 5% EtOAc in hexane to afford the titled compound;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=1.[OH:23][CH:24]1[CH2:27][NH:26][CH2:25]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.[Cl-].[Na+].O>[CH2:9]([S:8][C:6]1[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=[C:2]([N:26]2[CH2:27][CH:24]([OH:23])[CH2:25]2)[N:7]=1)[CH3:10]
Reactant: CCSc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Reactant: OC1CNC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCSc1nc(N2CC(O)C2)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 110 °C
Yield: 15 %

Procedure:
A mixture of 439 mg (1.2 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2), 284 mg (2.6 mmol) 3-hydroxy-azetidine, 2.1 g (6.5 mmol) Cs2CO3 and 149 mg (0.13 mmol) Pd(PPh3)2 in 1,4-dioxane (4 ml) was heated at 110° C. for 16 h. Subsequently the RM was diluted with brine (30 ml) and extracted with EtOAc (3×40 ml). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 1:1) and subsequent crystallization (hexane/EtOAc) provided 66 mg (0.18 mmol, 15%) 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(3-hydroxy-azetidin-1-yl)-4-methyl-pyridine-3-carboxylic acid amide (example 7). [M+H]+ 376.1.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][CH:23]=[C:22]([C:25](O)=[O:26])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3][CH2:2]1.C(OC(=O)[NH:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([C:41](=[O:46])[NH:42][CH:43]2[CH2:45][CH2:44]2)[CH2:37][CH2:36]1)(C)(C)C>>[CH:43]1([NH:42][C:41]([C@H:38]2[CH2:39][CH2:40][C@H:35]([NH:34][C:25]([C:22]3[C:18]4[N:19]=[CH:20][N:21]=[C:16]([C:8]5[C:9]6[O:13][CH2:12][O:11][C:10]=6[CH:14]=[CH:15][C:7]=5[O:6][CH2:5][CH:1]5[CH2:2][CH2:3][CH2:4]5)[C:17]=4[NH:24][CH:23]=3)=[O:26])[CH2:36][CH2:37]2)=[O:46])[CH2:45][CH2:44]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)NC2CC2)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12
Product: O=C(N[C@H]1CC[C@H](C(=O)NC2CC2)CC1)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A68) and trans-(4-cyclopropylcarbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (A195) the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:18]([NH2:28])[C:19]1[CH:27]=[CH:26][C:25]2[O:24][CH2:23][O:22][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[CH2:23]1[O:24][C:25]2[CH:26]=[CH:27][C:19]([CH2:18][NH:28][C:2]3[C:11]4[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:20][C:21]=2[O:22]1
Reactant: COc1cc2c(Cl)ncnc2c(OC)c1OC
Reactant: NCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: COc1cc2c(NCc3ccc4c(c3)OCO4)ncnc2c(OC)c1OC
Yield: 69.5 %

Procedure:
21.2 g (0.083 mol) of 4-chloro-6,7,8-trimethoxyquinazoline, 17.0 g (0.112 mol) of piperonylamine and 13.5 g (0.127 mol) of sodium carbonate were mixed with 400 ml of isopropyl alcohol. The obtained mixture was heated under reflux for 24 hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate to give 21.3 g of the title compound as a pale-yellow needle.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@:22](Br)([C@@H:23]([OH:27])[CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:29])[CH:18]=[CH:19]2)[C@@H:14]([CH3:30])[CH2:13]3)[CH2:10][C@@H:9]1[CH3:31])[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@@:22]4([O:27][C@H:23]4[CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:29])[CH:18]=[CH:19]2)[C@@H:14]([CH3:30])[CH2:13]3)[CH2:10][C@@H:9]1[CH3:31])[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(C)=O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@@]3(Br)[C@@H](O)C[C@@]21C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)O[C@]1(C(C)=O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@]34O[C@H]4C[C@@]21C
Yield: 71.8 %

Procedure:
A suspension of 800 mg of 17α-acetoxy-9α-bromo-11β-hydroxy-6α,16β-dimethyl-1,4-pregnadiene-3,20-dione in 8 ml of acetone is stirred with 1.2 g of finely triturated potassium carbonate for 22 hours at room temperature. The potassium carbonate is suctioned off and the filtrate concentrated to dryness under vacuum. The crude product is purified on 100 g of silica gel with a hexane-ethyl acetate gradient (0-50% ethyl acetate), thus isolating 480 mg of 17α-acetoxy-9,11β-epoxy-6α,16β-dimethyl-1,4-pregnadiene-3,20-dione, mp 248°-250° C.
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S(=O)(=O)(O)O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]3[CH:33]=2)=[CH:20][CH:19]=1>C(O)(=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:25]=[C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]3[C:33]=2[CH2:2][NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:22][CH:23]=1
Reactant: Cc1ccc2nc(-c3ccc(Cl)cc3)cn2c1
Reactant: O=C(NCO)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1ccc2nc(-c3ccc(Cl)cc3)c(CNC(=O)c3ccccc3)n2c1
Temperature: 50 °C

Procedure:
To a solution of 4.54 g (0.03 mol) of N-(hydroxymethyl)benzamide in 50 ml of glacial acetic acid, 2 g of concentrated sulphuric acid are added, and then, after 15 minutes' heating at 50° C., 4.8 g (0.02 mol) of 2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridine are added.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[NH2:27].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:27][NH:26][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: NNc1ccncc1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNc1ccncc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask was charged with (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g) and EtOAc (10.0 mL). 4-Hydrazinylpyridine hydrochloride (0.16 g, 1.2 eq.) was added at −40° C. followed by the simultaneous addition of T3P (50% in EtOAc, 0.85 mL, 2.0 eq.) and DIPEA (0.49 mL, 4.0 eq.). The reaction mixture was stirred for 30 min at −40° C. before being concentrated under reduced pressure (35° C., 20 mmHg) to afford 0.35 g of crude material. Purification by column chromatography using MeOH:CH2Cl2 as a mobile phase (compound was eluted with 4% MeOH in CH2Cl2) afforded 80 mg (yield: 29.85%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyridin-4-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ, 10.53 (br s, NH exchangeable, 1H), 9.58 (s, 1H), 8.88 (br s, NH exchangeable, 1H), 8.84 (s, 2H), 8.29 (s, 1H), 8.09-8.11 (d, 2H), 7.52-7.54 (d, J=10.4 Hz, 1H), 6.66-6.69 (m, 2H), 6.06-6.10 (d, J=14.4 Hz, H); LCMS for C18H13F6N6O [M+H]+ 443.33. found 443.24 (RT 2.241 min, purity: 90.17%).
Reaction SMILES: [CH2:1]([C:3]1([C:35]([O:37]CC)=[O:36])[CH2:8][CH2:7][N:6]([C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:15]=[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:17]4[S:21][C:20]([NH:22][C:23](=[O:27])[NH:24][CH2:25][CH3:26])=[N:19][C:18]=4[CH:28]=3)[N:13]=2)[CH2:5][CH2:4]1)[CH3:2].[OH-].[Na+]>CCO>[CH2:1]([C:3]1([C:35]([OH:37])=[O:36])[CH2:8][CH2:7][N:6]([C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:15]=[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:17]4[S:21][C:20]([NH:22][C:23](=[O:27])[NH:24][CH2:25][CH3:26])=[N:19][C:18]=4[CH:28]=3)[N:13]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3csc(N4CCC(CC)(C(=O)OCC)CC4)n3)cc(-c3ccccn3)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3csc(N4CCC(CC)(C(=O)O)CC4)n3)cc(-c3ccccn3)c2s1
Temperature: 70 °C

Procedure:
To a solution of ethyl 4-ethyl-1-[4-[2-(ethylcarbamoylamino)-7-(2-pyridyl)-1,3-benzothiazol-5-yl]thiazol-2-yl]piperidine-4-carboxylate (20 mg, 0.035 mmol) in EtOH (1 mL) was added aqueous NaOH (0.3 mL, 3.5 M). The solution was heated to 70° C. for 22 h then cooled to rt and the pH of the solution adjusted to 4-5. The mixture was extracted with EtOAc (3×1 mL) and the combined organic layer combined, dried over Na2SO4, filtered then evaporated under reduced pressure. The residue was adsorbed to a 0.5 g silica plug then purified using a 4 g silica column and a MeOH:DCM elution gradient. Compound 209 was isolated as an off-white solid (3.4 mg, 18% yield). 1H NMR (MeOD) δ 8.75 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 8.38 (d, J=1.5 Hz, 1H), 8.22 (d, J=8.2 Hz, 1H), 8.18 (d, J=1.4 Hz, 1H), 7.97-7.91 (m, 1H), 7.37 (ddd, J=7.5, 4.9, 0.9 Hz, 1H), 7.16 (s, 1H), 3.95 (dt, J=13.1, 3.7 Hz, 2H), 3.36 (t, J=7.2 Hz, 2H), 3.25 (td, J=13.3, 2.9 Hz, 2H), 2.24 (d, J=13.2 Hz, 2H), 1.70-1.53 (m, 4H), 1.24 (td, J=7.2, 2.0 Hz, 3H), 0.92 (td, J=7.5, 4.2 Hz, 3H). MS: 537.12 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7](/[C:8](=[CH:14]/[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)/[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1.O>CO.CS(C)=O>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
Sodium borohydride (3.0 g, 79 mmol) (Aldrich) was added in small portions to a suspension of 6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one (19 g, 66 mmol) (from example 76a supra) in methanol (200 mL) and DMSO (50 mL) at such a rate that gas evolution was not too vigorous. When the addition was complete, mixture was stirred at room temperature for 0.5 h-1 h. After water (200 mL) was added, the resulting precipitate was collected and dried to give 18.3 g of rac-6-chloro-3-(4-chloro-benzyl)-1,3-dihydro-indol-2-one as a light yellow solid. MS: 293 (M+H)+.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([N+:17]([O-])=O)[CH:16]=1)[NH:13][C:12]([C:20]1[S:21][CH:22]([CH:25]([O:28][CH3:29])[O:26][CH3:27])[CH2:23][N:24]=1)=[CH:11]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O.[Cl-].[Ca+2].[Cl-].C(=O)([O-])O.[Na+]>C(O)C.[Fe]>[C:1]([O:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([NH2:17])[CH:16]=1)[NH:13][C:12]([C:20]1[S:21][CH:22]([CH:25]([O:26][CH3:27])[O:28][CH3:29])[CH2:23][N:24]=1)=[CH:11]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COC(OC)C1CN=C(c2cc3cc(OC(=O)C(C)(C)C)cc([N+](=O)[O-])c3[nH]2)S1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Ca+2]
Solvent: CCO
Solvent: O
Product: COC(OC)C1CN=C(c2cc3cc(OC(=O)C(C)(C)C)cc(N)c3[nH]2)S1
Temperature: 90 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
To a solution of 2-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-7-nitro-1H-indol-5-yl pivalate (4.32 g) in ethanol (100 mL) were added water (10 mL), calcium chloride (1.13 g) and iron (3.42 g), and the mixture was stirred at 90° C. for 2 hr. The mixture was allowed to cool, and basified with saturated aqueous sodium hydrogencarbonate, and the insoluble substance was filtered off. The filtrate was extracted with ethyl acetate, and the combined organic layers were washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=4:1-1:3) to give the title compound (2.55 g, yield 64%) as a pale-yellow amorphous powder. MS: 392 (MH+).