Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1.CC(C)([O-])C.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[N:29]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1nccnc1-c1ccc(Cn2ccc3ccccc32)cc1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 68 %

Procedure:
N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzene sulfonamide (intermediate 26) (854 mg, 2 mmol, 1 eq) and 1H-Indole (234 mg, 2.0 mmol, 1 eq) were shaken in tetrahydrofuran (20 mL) and heated up to 50 degrees for 10 minutes. To the reaction mixture was added potassium tert-butoxide (4.5 mL of a 1M solution in THF). The reaction mixture was maintained to 50 degrees for 5 h, and then cooled down to room temperature. The reaction mixture was treated with 10 ml of an aqueous citric acid solution (20 g in 100 mL of water) and extracted with AcOEt. The organic layer was dried over MgSO4 and evaporated. The crude was purified similarly to Method A to give pure N-{3-[4-(1H-indol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide as a yellow solid (691 mg, 1.36 mmol, yield: 68%, 98% HPLC purity).
Reaction SMILES: CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([C:35](OCC)=[O:36])[C:30](OCC)=[O:31].[OH-].[Na+]>O.O1CCCC1>[OH:31][CH2:30][CH:29]([CH2:35][OH:36])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:14]1[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:17][C:13]=1[CH3:12]
Reactant: CCOC(=O)C(CCCCCc1nc(-c2ccccc2)oc1C)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCCCCC(CO)CO
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To 15 ml of dry ether, 637 mg of lithium aluminium hydride was added, and 2.6 g of diethyl [5-(5-methyl-2-phenyloxazol-4-yl)pentyl]malonate/10 ml of dry ether was added dropwise. After 2-hour-stirring at room temperature, the mixture was cooled with ice-cold water, and 14 ml of tetrahydrofuran/0.8 ml of water was added dropwise gradually. To the mixture were added 0.8 ml of an aqueous solution of 1 N sodium hydroxide and 2.3 ml of water, and stirred for 15 minutes and filtrated to remove insolubles. The filtrate was concentrated to provide 2.0 g of the objective compound as white crystals. M.p. 71–74° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:12][C:13]([C@H:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@H:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[CH:10]=[CH2:11].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)C.[Ag-]=O>[CH2:9]([O:12][C:13]([C@H:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@H:16]([O:21][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:14])[CH:10]=[CH2:11]
Reactant: C=CCOC(=O)[C@H](CC(C)C)[C@H](O)C(=O)OC
Reactant: BrCc1ccccc1
Agent: O=[Ag-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOC(=O)[C@H](CC(C)C)[C@H](OCc1ccccc1)C(=O)OC
Reaction time: 24 h

Procedure:
0.51 g of silver(I) oxide and 0.33 ml of benzyl bromide were added to a solution of 0.27 g of methyl 3(R)-(allyloxycarbonyl)-2(S)-hydroxy-5-methylhexanoate in 5 ml of dimethylformamide. After stirring the mixture for 24 hours, 0.36 g of cesium carbonate were added and stirring was continued for 3 hours. The mixture was diluted with diethyl ether and filtered. The filtrate was then washed in succession with 5% aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate, water and brine. The diethyl ether phase was dried over anhydrous magnesium sulphate and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel using ethyl acetate/hexane (1:19) for the elution. There was obtained 0.16 g of methyl 3(R)-(allyloxycarbonyl)-2(S)-benzyloxy-5-methylhexanoate in the form of a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16](F)[CH:15]=3)=[CH:12][N:11]=[C:10]([NH2:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:22].C(O)C.N>C(O)C>[NH2:22][C:16]1[CH:15]=[C:14]([C:13]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][C:10]([NH2:21])=[N:11][CH:12]=2)[CH:19]=[CH:18][N:17]=1
Reactant: Nc1ncc(-c2ccnc(F)c2)c(-c2cccc(F)c2)n1
Reactant: N
Solvent: CCO
Product: Nc1cc(-c2cnc(N)nc2-c2cccc(F)c2)ccn1
Temperature: 150 °C
Yield: 12 %

Procedure:
A mixture of 4-(3-fluorophenyl)-5-(2-fluoro-4-pyridyl)-2-pyrimidinylamine (100 mg, 0.352 mmol) and ammonia/ethanol (ethanol saturated with an ammonia gas under ice-cooling) (20 mL) was sealed in a test tube and stirred at 150° C. for 2 weeks. After cooling as it was, the reaction solution was concentrated. The residue was dissolved by adding ethyl acetate and water thereto. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate and concentrated. The residue was purified by TLC plate (eluting solvent: dichloromethane/methanol=10/1), to give the title compound (12 mg, 12%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1>O.[Rh]>[CH2:4]1[CH:5]2[C:6]([NH:1][CH:2]([CH2:10][CH2:9]2)[CH2:3]1)=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Rh]
Solvent: O
Product: O=C1NC2CCC1CC2
Reaction time: 96 h

Procedure:
Suspend 5% rhodium/carbon (2 g) in water (50 mL) and add 4-aminobenzoic acid (27.4 g, 200 mmol) and dilute to 200 mL with water. Shake the mixture at 50 psi for 4 days, filter through glass fiber and evaporate the solvent in vacuo to a white solid. Mix the solid with diphenyl ether and heat quickly to reflux for 20 minutes. Cool and partition between hexane and water. Separate the organic phase and wash with water. Combine the aqueous phases, treat with sodium hydrogen carbonate and subject to continuous extraction with methylene chloride overnight. Evaporate the methylene chloride extracts in vacuo to give 3-isoquinuclidone as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.N1C=CC=CC=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:38]([F:41])([F:40])[F:39])[O:27][N:26]=[C:25]([C:28]3[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[C:30]([CH3:37])[CH:29]=3)[CH2:24]2)[CH:19]=[C:20]([Cl:22])[CH:21]=1>ClCCl>[Br:8][C:4]1[N:3]=[C:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:25]3[CH2:24][C:23]([C:18]4[CH:19]=[C:20]([Cl:22])[CH:21]=[C:16]([Cl:15])[CH:17]=4)([C:38]([F:41])([F:40])[F:39])[O:27][N:26]=3)=[CH:29][C:30]=2[CH3:37])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Br)n1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1cccc(Br)n1
Yield: 63.5 %

Procedure:
In a solution of 0.13 g of 2-amino-6-bromopyridine and 0.16 g of pyridine in 5 mL of dichloromethane, a solution of 0.30 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 in 5 mL of dichloromethane was added at room temperature with stirring. After the completion of the addition dropwise, it was stirred at the same temperature further for 2 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, and precipitated insoluble material was removed through silica gel column, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.25 g of the aimed product as colorless resinous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:5]=[CH:6][CH:7]=1.[F:33][C:34]1[CH:35]=[CH:36][C:37]([C:40](O)=[O:41])=[N:38][CH:39]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)C(C)CN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl.C(=O)(O)[O-].[Na+].CN(C)C=O>[C:25]([NH:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@:8]2([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:40]([C:37]3[CH:36]=[CH:35][C:34]([F:33])=[CH:39][N:38]=3)=[O:41])[CH:3]=2)[N:9]=1)(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cccc(N)c2)C1
Reactant: O=C(O)c1ccc(F)cn1
Agent: CCN=C=NCC(C)N(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cccc(NC(=O)c3ccc(F)cn3)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
A slurry of tert-butyl (4aR,7aS)-7a-(3-aminophenyl)-2-benzamido-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (93 mg, 0.21 mmol), 5-fluoropyridine-2-carboxylic acid (31.9 mg, 0.23 mmol), 1-hydroxybenzotriazole hydrate (56.7 mg, 0.41 mmol) and 1-(2-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol) in dichloromethane (4 mL) containing dimethylformamide (1 ml) is treated with diisopropylethylamine (179.2 μL, 1.03 mmol) and the resulting mixture is stirred at room temperature overnight. The reaction mixture is diluted with dichloromethane (5 mL) and saturated aqueous sodium bicarbonate (15 mL). The organic layer is separated and washed with saturated aqueous sodium chloride (10 mL), dried over sodium sulfate, filtered, and the solvent removed in vacuo to give the crude title compound (105 mg, 89%). ES/MS (m/e): 576 (M+H).
Reaction SMILES: [O:1]1[C:5]([CH:6]=O)=[CH:4][N:3]=[CH:2]1.[CH3:8][C:9]([S:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[CH3:8][C:9]([S:12](/[N:14]=[CH:6]/[C:5]1[O:1][CH:2]=[N:3][CH:4]=1)=[O:13])([CH3:11])[CH3:10]
Reactant: O=Cc1cnco1
Reactant: CC(C)(C)S(N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C/c1cnco1
Temperature: 65 °C
Yield: 58.7 %

Procedure:
Oxazole-5-carbaldehyde (1.0 g, 10.30 mmol), 2-methylpropane-2-sulfinamide (2.247 g, 18.54 mmol; CASRN 146374-27-8), and tetraethoxytitanium (8.460 g, 37.09 mmol) were stirred in THF (15 mL) and heated to 65° C. for 12 h under nitrogen. The reaction was cooled and poured onto water. The solids were filtered off and the filtrate was extracted with EtOAc. The layers were separated and the organic layer was dried (MgSO4), filtered and concentrated. The resulting residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (20 to 25% EtOAc) to afford 1.211 g (58.7%) of (E)-2-methyl-N-(oxazol-5-ylmethylene)propane-2-sulfinamide (20).
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH2:11])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1[N:3]([NH:11][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2ccccc2n1N
Reactant: Clc1ccncc1
Agent: Cl
Product: Cc1cc2ccccc2n1Nc1ccncc1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-1-amine and 4-chloropyridine hydrochloride at 120° C. for 30 minutes in substantially the same manner as in Example 1, m.p. 75°-78° C.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:25][CH2:26][CH2:27][CH3:28])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29](O)([C:31]([F:34])(F)F)=O>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([NH:11][C:14]4[CH:23]=[CH:29][C:31]([F:34])=[CH:16][CH:15]=4)=[O:5])[CH2:9][CH2:10]3)=[CH:15][C:16]([NH:25][CH2:26][CH2:27][CH3:28])=[N:17]2)=[CH:22][CH:21]=1
Reactant: CCCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCNc1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloro-2-(n-propylamino)quinoline (25 mg, 0.06 mmol) is deprotected with TFA in CH2Cl2 and transformed into the title product according to method C using 4-fluorophenyl isocyanate (10 μL, 0.09 mmol) and triethylamine (60 μL, 0.43 mmol) to give a colorless solid.
Reaction SMILES: Cl[O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].[CH2:13]=[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:17])[O:15]1>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:4]1[CH2:13][C:14]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16](=[O:17])[O:15]2)[O:2][N:3]=1
Reactant: ClON=Cc1ccc(Cl)cc1Cl
Reactant: C=C1OC(=O)c2ccccc21
Product: O=C1OC2(CC(c3ccc(Cl)cc3Cl)=NO2)c2ccccc21

Procedure:
By a method similar to the procedure of Example 2, a reaction of 2,4-dichlorobenzaldehyde chlorooxime and 3-methylenephthalide was carried out. The solid collected from the reaction mixture afforded 12.2 g of the desired product after workup, and the ether solution gave 4 g of the desired product (yield 70.2%). Recrystallization from chloroform led to pure white crystals of the desired product, m.p. 158°-161° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[O:12][C@H:11]1[CH2:17][OH:18])([O-])=O.[N+](C1C=CC=CC=1[C@H]1OC(C)(C)O[C@@H]1CO)([O-])=O>>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[O:14][C:13]([CH3:15])([CH3:16])[O:12][C@H:11]1[CH2:17][OH:18]
Reactant: CC1(C)O[C@@H](CO)[C@H](c2ccccc2[N+](=O)[O-])O1
Agent: CC1(C)O[C@H](c2ccccc2[N+](=O)[O-])[C@@H](CO)O1
Product: CC1(C)O[C@@H](CO)[C@H](c2ccccc2N)O1
Yield: 70 %

Procedure:
The substantially same method as described in Example 47 was conducted, except that (4S,5S)-methyl-5-(2-nitrophenyl)-2,2-dimethyl-1.3-dioxolane-4-carboxylate (Preparation example 50) was used instead of (4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1.3-dioxolane-4-yl)methanol (Preparation example 46), to obtain the title compound (11 g, 70˜95%)
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][N:8]=1.[F:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH:18]=[O:19].[Cl-].[NH4+]>O1CCCC1>[F:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH:18]([OH:19])[C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: COc1cccnc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccnc1C(O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol) of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran (2 ml) solution of 2-bromo-3-methoxypyridine (564 mg, 3 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 60 minutes. Under ice cooling, 2,5-difluorobenzaldehyde (328 μl, 3 mmol) was added dropwise to the resulting brown solution. The temperature of the reaction mixture was raised gradually to room temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The solvent was dried, followed by concentration under reduced pressure to yield needle crystals. The resulting needle crystals were triturated with hexane, whereby the title compound (660 mg, 88%) was obtained.
Reaction SMILES: [CH2:1]([S:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@:20]([F:24])([C@@H:21]([OH:23])[CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH:16]=[CH:17]1)[CH2:12][CH2:11]3)[CH3:2].ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)(Cl)Cl>[CH2:1]([S:3]([C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@:20]([F:24])([C@@H:21]([OH:23])[CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH:16]=[CH:17]1)[CH2:12][CH2:11]3)=[O:34])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCS[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Solvent: ClC(Cl)Cl
Product: CCS(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Yield: 95.4 %

Procedure:
To a solution of (11β,17β)-17-(ethylthio)-9-fluoro-11-hydroxyandrosta-1,4-dien-3-one (700 mg, 1.92 mmole; see example 6) in chloroform (30 ml) was added a solution of 86% m-chloroperbenzoic acid (390 mg, 1.95 mmole) in chloroform (15 ml). An instantaneous reaction was noted (tlc). The solution was then washed with a 10% potassium carbonate solution and water, dried (anhydrous magnesium sulfate) and evaporated to afford the title compound (697 mg) as a solid. One crystallization of this from ethyl acetate followed by drying (100° C., 0.3 mm of Hg, 10 hours) gave the analytical specimen of the title compound (600 mg), melting point 247°-250° C., with consistent spectral data.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8].[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:14]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=c1ccn(CCCCO)c(=O)[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=c1ccn(CCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Yield: 86 %

Procedure:
1-(4′-Hydroxybutyl)uracil (0.083 g, 0.45 mmol), trityl chloride (0.140 g, 0.50 mmol) and DMAP (5 mg, 0.05 mmol) were stirred in dry pyridine (6 mL) at 50° C. under nitrogen for 64 h. The reaction mixture was left to cool to room temperature and then partitioned between cold water (20 mL) and DCM (15 mL, 2×10 mL). The organic extracts were combined, washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo. Further purification by silica gel column chromatography (Isolute SI column) using a gradient elution of 0→3% CH3OH in CHCl3. The fractions with Rf=0.58 (10% CH3OH/CHCl3) yielded the title compound as a white solid (0.165 g, 86%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]([N:20]2[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21]2)=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]([N:20]3[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21]3)=[O:19])[CH2:16][CH2:17]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C2CCNCC2)C1
Reactant: FC(F)(F)c1cccc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C2CCN(c3cccc(C(F)(F)F)n3)CC2)C1
Yield: 29.7 %

Procedure:
A solution of 2-chloro-6-(trifluoromethyl)pyridine (1.8 g, 9.9 mmol), tert-butyl [(3S)-1-(piperidin-4-ylcarbonyl)pyrrolidin-3-yl]carbamate (2.97 g, 10.0 mmol) and triethylamine (4.1 mL, 30 mmol) in DMF (50 mL) was heated at 100° C. for 4 hrs. After cooling down, ethyl acetate was added. The resulting solution was washed with brine several times, dried over Na2SO4 and concentrated. The residue was chromatographed on silica gel to give the title compound (1.3 g) as a yellow solid. MS (M+H) 443.2.
Reaction SMILES: Br[C:2]1[CH:28]=[C:27]([F:29])[C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[O:30]1[CH2:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH2:32][CH2:31]1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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].O>[O:30]1[CH2:31][CH:32]=[C:33]([C:2]2[CH:28]=[C:27]([F:29])[C:5]3[N:6]([CH2:9][C:10]4[CH:26]=[CH:25][C:13]5[N:14]=[C:15]([NH:17][C@@H:18]6[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]6[OH:24])[S:16][C:12]=5[CH:11]=4)[CH:7]=[N:8][C:4]=3[CH:3]=2)[CH2:34][CH2:35]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cc(F)c43)cc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(C5=CCOCC5)cc(F)c43)cc2s1
Temperature: 100 °C
Yield: 36.4 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (150 mg, 0.316 mmol) from Example 203, 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (133 mg, 0.632 mmol), sodium carbonate (67 mg, 0.0632 mmol), 1,4-dioxane (2 mL), and water (0.5 mL) was purged with a stream of argon. To the mixture was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) DCM adduct (35 mg, 0.0474 mmol) and the mixture was heated in a sealed vessel at 100° C. for 3 h. The mixture was cooled to rt and purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((5-(3,6-dihydro-2H-pyran-4-yl)-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (55 mg, 36%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.49-7.56 (m, 2H), 7.29 (d, J=8.1 Hz, 1H), 7.21 (d, J=13.0 Hz, 1H), 7.09 (m, 1H), 6.27 (br m, 1H), 5.51 (s, 2H), 4.72 (d, J=5.2 Hz, 1H), 4.21 (d, J=2.5 Hz, 2H), 4.06 (m, 1H), 3.81 (t, J=5.4 Hz, 2H), 3.61 (m, 1H), 3.51 (br m, 1H), 3.30 (br m, 1H), 2.00 (m, 1H), 1.88 (m, 1H), 1.55-1.67 (m, 2H), 1.11-1.32 (m, 4H); LCMS (ESI) m/z 479 (M+H)+.
Reaction SMILES: C(O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)C=C.[CH2:19]([O:22][C@H:23]1[C:31]2[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=2)[C@@H:25]([NH2:33])[CH2:24]1)[CH:20]=[CH2:21].[F:34][C:35]1[CH:36]=[C:37]([CH2:42][C@H:43]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C@H:44]2[CH2:46][O:45]2)[CH:38]=[C:39]([F:41])[CH:40]=1>>[CH2:19]([O:22][C@H:23]1[C:31]2[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=2)[C@@H:25]([NH:33][CH2:46][C@@H:44]([OH:45])[C@@H:43]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:52])([CH3:51])[CH3:53])[CH2:42][C:37]2[CH:36]=[C:35]([F:34])[CH:40]=[C:39]([F:41])[CH:38]=2)[CH2:24]1)[CH:20]=[CH2:21]
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Agent: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c2cc(Br)ccc21
Yield: 76 %

Procedure:
Step BE (1). (1S,3R)-3-(Allyloxy)-6-bromo-2,3-dihydro-1H-inden-1-amine from Step Z(1) was reacted with tert-butyl (S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethylcarbamate following a procedure analogous to Step AW (1) to afford 1.5 g (76% yield) of tert-butyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-bromo-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate. LC-MS (M+H)+ 568.97. 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (s, 9H) 1.79-1.90 (m, 2H) 2.64-2.82 (m, 4H) 3.03 (dd, J=14.09, 4.21 Hz, 1H) 3.36-3.44 (m, 1H) 3.68-3.80 (m, J=8.42, 4.03 Hz, 1H) 4.01-4.12 (m, 3H) 4.50 (d, J=9.51 Hz, 1H) 4.73 (t, J=6.04 Hz, 1H) 5.18 (dd, J=10.43, 1.28 Hz, 1H) 5.24-5.34 (m, J=17.20, 1.46 Hz, 1H) 5.92 (ddd, J=22.60, 10.52, 5.67 Hz, 1H) 6.63 (tt, J=9.01, 2.33 Hz, 1H) 6.70-6.78 (m, 2H) 7.25 (d, J=8.05 Hz, 1H) 7.39 (dd, J=7.87, 1.65 Hz, 1H) 7.49 (s, 1H).