Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[Br:29][CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>CCCCC.O1CCCC1>[Br:29][CH2:30][CH2:31][CH2:32][C:33]([O:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:34]
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reactant: O=C(Cl)CCCBr
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OC(=O)CCCBr)c1coc([Si](C)(C)C)c1
Reaction time: 0.33 h

Procedure:
tert-Butyl lithium (a 1.7 M solution in pentane; 0.25 ml, 0.43 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (120.4 mg, 0.36 mmol) in tetrahydrofuran (6 ml) at 0° under argon. After 20 minutes, a solution of 4-bromobutyryl chloride (66 mg, 0.43 mmol) in tetrahydrofuran (1 ml) was added. Stirring was continued at room temperature for 16 hours and the mixture was quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative TLC (20×20 cm, 500μ silica plate; developed with 10% ethyl ether/hexane). The title ester was obtained as a yellow oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[NH:24][C:23](=[O:26])[C:22]([CH3:27])=[CH:21]2>CC(C)=O>[CH2:1]([O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[NH:24][C:23](=[O:26])[C:22]([CH3:27])=[CH:21]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc2cccc(O)c2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc2cccc(OCc3ccccc3)c2[nH]c1=O

Procedure:
Benzyl bromide (1.28 mL) is added to a suspension of potassium carbonate (2.98 g) in a solution of 8-hydroxy-3-methyl-1H-quinolin-2-one (1.26 g) in acetone (36 mL) at room temperature. The reaction mixture is refluxed for 18 hours, filtered, evaporated and purified by flash column chromatography on silica gel, eluting with 2% methanol in dichloromethane.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:33])[C@H:10]([NH:13][C:14]([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)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:41](Cl)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C@H:9]([CH3:33])[C@H:10]([NH:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:11][O:12][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](OCc1ccccc1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A solution of (2R,3R)-3-(benzyloxy)-2-(tritylamino)butan-1-ol (4.33 g, 9.91 mmol) dissolved in 150 mL of CH2Cl2 was treated with triethylamine (1.52 mL, 10.9 mmol), tert-butyldimethylsilyl chloride (1.65 g, 10.9 mmol) and DMAP (122 mg, 1.00 mmol) and the reaction mixture was stirred under N2 overnight. The reaction mixture was then concentrated and the resulting material was dissolved in 50 mL of CH2Cl2 and washed successively with H2O and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 5-10% ethyl acetate/hexanes) gave 3.26 g of (2R,3R)-3-(benzyloxy)-1-{[tert-butyl(dimethyl)silyl]oxy-}-N-tritylbutan-2-amine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH2:10][C:11](O)([CH2:13][S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:22]3[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[CH:10]=[C:11]([CH2:13][S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(CSc3ccccc3)N=C2c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(CSc3ccccc3)nc2-c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-[(phenylthio)methyl]-4,5-dihydro-1H-imidazole (1 mmol) and p-toluenesulfonic acid monohydrate (100 mg) in toluene (70 mL) is heated to reflux for 48 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude residue is redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture is purified by chromatography on silica gel using hexane/ethyl acetate to give 2-(4-chlorophenyl)-4-[(phenylthio) methyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2C(OC(C)(C)C)=O)[CH:6]=[N:7][C:8]=1[Cl:9])#N.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC[O:33]CC>>[ClH:9].[C:1]([C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][NH:13]2)[CH:6]=[N:7][C:8]=1[Cl:9])(=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(C#N)c1
Product: Cl
Product: O=C(c1ccccc1)c1cc(OC[C@@H]2CCN2)cnc1Cl

Procedure:
The 5-cyano-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine of example 92a in anhydrous Et2O at 0° C. is treated with 1.5 equivalents of phenylmagnesium bromide in Et2O and stirring is maintained at 0 to 35° C. until the nitrile is largely consumed. The solvent is evaporated and the residue is treated with 2M aqueous potassium hydrogen sulfate to hydrolyze the intermediate imine. The solution is made basic with potassium carbonate and extracted with EtOAc. The combined extracts are dried (Na2SO4) and concentrated to a residue which is chromatographed (silica gel) to afford the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4][NH:3]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@@H](C)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of (2R,5S)-2,5-dimethylpiperazine (commercially available) (3.495 g, 30 mmol) in dichloromethane (25 mL) at 0° C. was added triethylamine (3.76 mL, 27 mmol) followed by dropwise benzyl chloroformate (4.0 mL, 27 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was then evaporated to dryness. The residue was taken up in aqueous 1N HCl solution and washed with EtOAc. The organic layer was extracted with 1N HCl solution twice and the combined aqueous layers were basicified with 6N NaOH to ˜pH 11. The resulting basic aqueous solution was extracted with EtOAc three times. The combined organic layers were washed with brine, dried (MgSO4) and evaporated to yield phenylmethyl trans-2,5-dimethyl-1-piperazinecarboxylate (enantiomeric mixture) (1.35 g, 18%). LCMS: (M+H)+: 249.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]=[N+]=[N-].O1CCCCC1OCCNC(N)=O.CCOCC.[OH:30][C@H:31]1[CH2:51][C@@:50]2([CH3:52])[C@@H:42]([CH2:43][C@@H:44]([OH:54])[C@:45]2([OH:53])[C:46](=[O:49])[CH2:47][OH:48])[C@H:41]2[C@H:32]1[C@:33]1([CH3:56])[C:38]([CH2:39][CH2:40]2)=[CH:37][C:36](=[O:55])[CH:35]=[CH:34]1>CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:54][C@@H:44]1[CH2:43][C@@H:42]2[C@:50]([CH3:52])([CH2:51][C@H:31]([OH:30])[C@H:32]3[C@H:41]2[CH2:40][CH2:39][C:38]2[C@:33]3([CH3:56])[CH:34]=[CH:35][C:36](=[O:55])[CH:37]=2)[C@@:45]1([OH:53])[C:46](=[O:49])[CH2:47][OH:48]
Reactant: [N-]=[N+]=CCOC1CCCCO1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CO
Agent: NC(=O)NCCOC1CCCCO1
Solvent: CO
Solvent: CCOCC
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCCOC1CCCCO1)[C@]2(O)C(=O)CO

Procedure:
A solution of 2-(tetrahydropyran-2-yl)oxy-1-diazoethane (prepared from 69.1 g of N-[2-(tetrahydropyran-2-yl-oxy)ethyl]urea by the procedure described in Example 18) in 600 ml of 3:1 ether-pentane is stirred with 200 ml each of ether and methanol at 0°C. 14 g of 11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate is added in portions. After nitrogen evolution ceases the solvents are removed in vacuo and the residue is dissolved in chloroform and chromatographed on a 150 g-silica gel column. Elution with chloroform and then 1:1 chloroform-ethyl acetate gives 4.0 g of TLC pure 16α-[2-(tetrahydropyran-2-yloxy)ethoxy]11β,17,21-trihydroxypregna-1,4-diene-3,20-dione.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[O:16])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([Mg]Br)#[CH:18]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:17]#[CH:18])([OH:16])[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC1(O)CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure A. I In a solution of 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.25 g, 10 mmol) in tetrahydrofuran (20 mL) was dropped in ethynyl magnesium bromide (60 mL, 30 mmol) at −0° C. Then the solution was stirred overnight at room temperature. Then the reaction mixture was quenched with saturated NH4Cl and extracted with dichloromethane, dried with anhydrous sodium sulfate to afford 3-Ethynyl-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.8 g, 32%). 1H NMR: (DMSO-d6, 400 MHz) δ 5.43 (s, 1H), 3.98 (s, 2H), 3.24 (s, 1H), 2.08-1.91 (m, 8H), 1.37 (s, 9H).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([C@H:10]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[NH:11][C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3]>CO.[Pd]>[CH2:1]([C:4]1[C:5]([C@H:10]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=2)[NH:11][C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: C=CCc1cccnc1[C@@H](NC(=O)Nc1cccnc1)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Product: CCCc1cccnc1[C@@H](NC(=O)Nc1cccnc1)c1ccc(C(F)(F)F)cc1

Procedure:
A solution of (S)-1-((3-allylpyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)-3-(pyridin-3-yl)urea (Example 43) (0.055 g, 0.133 mmol) and Pd (10 wt % on carbon, 0.020 g, 0.133 mmol) in MeOH was hydrogenated under H2 (1 atm) at rt for 4 h. The catalyst was filtered off, and the filtrate was concentrated to give the title compound as a white solid. 1H NMR (300 MHz, d4-MeOH): δ ppm 8.60-8.38 (m, 2H), 8.12 (d, J=4.4 Hz, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.74-7.43 (m, 5H), 7.40-7.21 (m, 2H), 6.42 (s, 1H), 2.89-2.51 (m, 2H), 1.74-1.35 (m, 2H), 0.95 (t, J=7.2 Hz, 3H). MS (ESI pos. ion) m/z: 415.0 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[CH:14](C(OC)=O)[C:15]([O:17]C)=O)=[O:4]>Cl>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[CH2:14][C:15](=[O:17])[NH:11]2)([OH:2])=[O:4]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C(C(=O)OC)C(=O)OC
Agent: Cl
Product: O=C1Cc2c(cccc2C(=O)O)N1
Yield: 38.1 %

Procedure:
Dimethyl 2-methoxycarbonyl-6-nitrophenylmalonate (3.0 g) was refluxed in 50 mL of 6 N hydrochloric acid overnight. The mixture was concentrated to dryness, 20 mL ethanol and 1.1 g of tin(II) chloride were added and the mixture was refluxed for 2 hours. The mixture was filtered through Celite, concentrated and chromatographed on silica gel using ethyl acetate:hexane:acetic acid as eluent to give 0.65 g (37%) of 4-carboxy-2-oxindole as a white solid.
Reaction SMILES: [Si]([O:8][CH:9]([C:23]([CH3:27])([CH3:26])[CH2:24]O)[CH:10]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:11])(C(C)(C)C)(C)C.C(N(CC)CC)C.S(Cl)(C)(=O)=O.O>C1COCC1>[OH:8][CH:9]1[C:23]([CH3:24])([CH3:26])[CH2:27][N:12]([C:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:22])[CH:10]1[CH3:11]
Reactant: CC(NC(=O)OCc1ccccc1)C(O[Si](C)(C)C(C)(C)C)C(C)(C)CO
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1C(O)C(C)(C)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 91.7 %

Procedure:
A solution (20 mL) of benzyl [2-(tert-butyldimethylsilyloxy)-4-hydroxy-1,3,3-trimethylbutyl]carbamate (1.38 g) and triethylamine (0.73 mL) in THF was added mesyl chloride (0.352 mL) at 0° C., and the mixture was stirred at 0° C. for 45 min. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a solution (20 mL) of the residue in THF was added 1M potassium tert-butoxide—THF solution (3.8 mL). After stirring at room temperature for 1 hr, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a solution (10 mL) of the residue in THF was added 1M tetrabutylammonium fluoride—THF solution (4 mL), and the mixture was stirred at room temperature for 17 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/2) to give the title compound as a colorless solid (yield: 842 mg, yield: 92%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([OH:19])[C:6]2[N:11]=C(C3C=CC=C(C)C=3)O[C:7]=2[N:8]=1.[CH3:20][O:21][C:22]1[C:30]([CH3:31])=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[CH3:32]>>[CH3:20][O:21][C:22]1[C:30]([CH3:31])=[CH:29][C:25]([C:26]2[O:27][C:7]3[N:8]=[C:3]([S:2][CH3:1])[N:4]=[C:5]([OH:19])[C:6]=3[N:11]=2)=[CH:24][C:23]=1[CH3:32]
Reactant: CSc1nc(O)c2nc(-c3cccc(C)c3)oc2n1
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Product: COc1c(C)cc(-c2nc3c(O)nc(SC)nc3o2)cc1C

Procedure:
2-(4-Methoxy-3,5-dimethyl-phenyl)-5-methylsulfanyl-oxazolo[5,4-d]pyrimidin-7-ol was prepared according to the procedure described in example 1, steps (a) to (d), using 4-methoxy-3,5-dimethylbenzoyl chloride in step (a).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][CH3:30])[CH:23]=3)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH:36]=[C:35]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[N:33]1>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH3:30])[S:37]([C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)(=[O:39])=[O:38])[CH:23]=3)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CNCc1cccc(C(CNC(=O)OC(C)(C)C)C2(c3ccc(Cl)cc3)CCC2)c1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(Cc1cccc(C(CNC(=O)OC(C)(C)C)C2(c3ccc(Cl)cc3)CCC2)c1)S(=O)(=O)c1cnn(C)c1
Temperature: 25 °C

Procedure:
tert-Butyl (2-[1-(4-chlorophenyl)cyclobutyl]-2-{3-[(methylamino)methyl]phenyl}ethyl)carbamate (35 mg, 0.082 mmol) was dissolved in dichloromethane (0.8 mL). 4-Dimethylaminopyridine (10 mg, 0.082 mmol) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (16 mg, 0.09 mmol) was added. The reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with aqueous hydrochloric acid (1 N, 5 ml, twice) and sodium bicarbonate. The organic layer was dried (magnesium sulfate) and concentrated in vacuo. The crude product was purified by preparative thin layer chromatography (silica, ethyl acetate, n-heptane). Yield: 36 mg (0.063 mmol, 77%)
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH:9]2[O:13][CH:12]([CH:14]([OH:24])[CH2:15][CH2:16][NH:17]C(=O)C(F)(F)F)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N.CO.C(Cl)Cl>>[NH2:17][CH2:16][CH2:15][CH:14]([CH:12]1[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:13]1)[OH:24]
Reactant: O=C(NCCC(O)C1CCC(CCC2CCCCC2)O1)C(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CO
Product: NCCC(O)C1CCC(CCC2CCCCC2)O1

Procedure:
Deprotection of N-(3-(5-(2-cyclohexylethyl)tetrahydrofuran-2-yl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide following the method used in Example 14 gave after flash chromatography purification (4%-16% 7N NH3/MeOH—CH2Cl2 gradient) Example 15 as a colorless oil. Yield (0.033 g, 40%); 1H NMR (400 MHz, CD3OD) δ 3.62-3.84 (m, 2H), 3.45-3.57 (m, 2H), 2.71-2.88 (m, 2H), 1.80-2.05 (m, 2H), 1.39-1.80 (m, 10H), 1.09-1.37 (m, 6H), 0.87-0.99 (m, 2H); RP-HPLC tR=9.75 min; ESI-MS m/z 256.3 [M+H]+.
Reaction SMILES: [H-].[Na+].O=[C:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@H:13]([CH:14]([CH3:24])[C:15](=[O:23])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3.[Cl:25][C:26]1[CH:40]=[CH:39][CH:38]=[CH:37][C:27]=1[CH2:28]P(=O)(OCC)OCC.Cl>CN(C=O)C.C(Cl)Cl.CC(C)=O>[Cl:25][C:26]1[CH:40]=[CH:39][CH:38]=[CH:37][C:27]=1[CH:28]=[C:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@H:13]([CH:14]([CH3:24])[C:15](=[O:23])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3
Reactant: CC1C(=O)CC[C@@]2(C)[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CCOP(=O)(Cc1ccccc1Cl)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC1C(=O)CC[C@@]2(C)[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=Cc3ccccc3Cl)CC[C@@H]12
Temperature: 70 °C
Reaction time: 1.83 h

Procedure:
Sodium hydride (60%, 26 mg, 0.66 mmole) was added to a solution of 101 mg. (0.33 mol) of 17-keto-4-methyl-5α-androstan-3-one (F) and 173 mg (0.66 mol) of diethyl 2-chlorobenzylphosphonate in 1.0 ml of dry DMF at room temperature. The mixture was heated at 70° C. in a nitrogen atmosphere with stirring for 110 minutes, cooled, poured into 0.5N HCl (20 ml) and extracted with methylene chloride (3×). The organic phases were combined, washed with water (3×), saturated NaCl solution and dried over magnesium sulfate. The organic phase was concentrated under reduced pressure to yield a tan, gummy solid. Flash chromatography of the crude solid was conducted on a silica gel 60×20 mm column, and eluted with 4:1 methylene chloride/acetone in 6 ml. fractions. Fractions 18-24 contained the product which were combined and evaporated to yield a white solid, mp 205°-208° C., yielding one spot on silica gel TLC using 4:1 methylene chloride/acetone. The proton NMR confirmed the assigned structure for 39.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][C:26]([F:39])=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][C:26]([F:39])=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:3]=12
Reactant: COc1cccc(-c2nn(C(C)c3oc4ccc(F)cc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1)n1nc(-c2cccc(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.2 %

Procedure:
To a solution of Example 121 (0.180 g, 0.324 mmoles) in dichloromethane (15 ml), BBr3 (1M in dichloromethane, 1.6 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as grey solid (0.045 g, 27% yield). MP: 193-196° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.74 (s, 1H), 8.17 (s, 1H), 7.83-7.70 (m, 4H), 7.63 (m, 1H), 7.35 (t, J=8.2 Hz, 1H), 7.31 (m, 1H), 7.12 (m, 4H), 6.99 (m, 2H), 6.08 (q, J=6.8 Hz, 1H), 1.90 (d, J=7.0 Hz, 3H). Mass: 511.87 (M+).
Reaction SMILES: Cl[CH2:2]Cl.C[N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14](=[O:23])[NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:13][C:8]=2[N:7]=[CH:6]1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(N(CC)CC)C>[C:24]1([S:30]([N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14](=[O:23])[NH:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:13][C:8]=3[N:7]=[C:6]2[CH3:2])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCCl
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cn1cnc2cc(C(=O)NCc3ccccn3)ccc21
Solvent: CCN(CC)CC
Product: Cc1nc2cc(C(=O)NCc3ccccn3)ccc2n1S(=O)(=O)c1ccccc1
Reaction time: 3 h

Procedure:
Dichloromethane (10 ml) and triethylamine (0.760 g) are added to 1-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (1.00 g). Furthermore, benzenesulfonyl chloride (0.994 g) is dripped into the solution. After stirring for three hours, the reaction solution is washed with water three times, and once more washed with a sodium bicarbonate aqueous solution. An organic layer is concentrated under reduced pressure, purified through silica gel column chromatography (eluate: ethyl acetate/ethanol=9/1) and thus, a mixture of 1-benzenesulfonyl-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole and 1-benzenesulfonyl-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (1.38 g) is obtained. Further, this mixture is purified through medium pressure silica gel column chromatography (eluate: ethyl acetate/methanol=100/3) and thus, 0.550 g of oily 1-benzenesulfonyl-2-Methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (189) and 0.540 g of oily 1-benzenesulfonyl-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (190) are obtained. The oily materials are dissolved using methylene chloride (1.5 ml), and then crystallized by adding diethylether. 1H-NMR (CDCl3, δ): 2.84 (3H, s), 4.81 (2H, d, J=4.8 Hz), 7.24 (1H, dd, J=5.1 and 7.3 Hz), 7.37 (1H, d, J=7.7 Hz), 7.53 (2H, dd, J=7.9 and 7.5 Hz), 7.63-7.74 (2H, m), 7.85 (1H, dd, J=8.4 and 1.2 Hz), 7.97 (2H, dd, J=9.6 and 1.1 Hz), 8.58-8.61 (2H, m).