Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH3:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[C:11]=1[OH:20]>C1(C)C(C)=CC=CC=1>[CH3:16][O:15][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][CH:19]=[C:10]([O:9][CH3:8])[C:11]=1[O:20][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3]
Reactant: COC(=O)c1cccc(OC)c1O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1C
Product: COC(=O)c1cccc(OC)c1OS(=O)(=O)N=C=O
Temperature: 140 °C

Procedure:
3.4 g (0.024 mol) of chlorosulfonyl isocyanate are added dropwise to a solution of 3.6 g (0.02 mol) of methyl 3-methoxy-salicylate in 20 ml of xylene at 25° C. When the dropwise addition has ended, the temperature is slowly increased to 140° C. and the mixture is heated under reflux for 2.5 hours. It is cooled and the solvent and excess chlorosulfonyl isocyanate are removed on a rotary evaporator. The yellow oil which remains (5.4 g=1004 of theory) is used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]=[CH:11][C@H:12]([C@@H:14]([C@@H:16]([C@H:18]([CH3:20])[OH:19])[OH:17])[OH:15])[OH:13]>N1C=CC=CC=1>[CH3:20][C@@H:18]1[O:19][CH:11]([O:10][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[C@@H:12]([O:13][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:14]([O:15][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[C@H:16]1[O:17][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: C[C@@H]1OC(OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)C(OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzoyl chloride (21.4 g, 152.3 mmol; 17.7 mL) was added dropwise to a cooled solution of L-fucose (5.0 g, 30.5 mmol) in pyridine (100 mL), at 0-5° C., and the mixture was stirred for three hours at room temperature. The mixture was poured onto ice water and extracted with ethyl acetate (EtOAc). The extracts were successively washed with ice cold dilute HCl, aqueous NaHCO3, and brine, dried over anhydrous MgSO4, and concentrated. The product was used for the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[N:4]1)[CH3:2].BrC1C=NN([CH:23]2CC[O:25][CH2:24]2)C=1>>[O:25]1[CH2:24][CH2:23][CH:1]([N:3]2[CH:7]=[C:6]([B:8]3[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])([CH3:16])[O:9]3)[CH:5]=[N:4]2)[CH2:2]1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnn(C2CCOC2)c1
Product: CC1(C)OB(c2cnn(C3CCOC3)c2)OC1(C)C

Procedure:
The title compound was prepared in the same manner as 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole starting with 4-bromo-1-(tetrahydrofuran-3-yl)-1H-pyrazole.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CN(C)c1ccccc1N
Reactant: O=C(O)CCCCc1ccc([N+](=O)[O-])cc1
Product: CN(C)c1ccccc1NC(=O)CCCCc1ccc([N+](=O)[O-])cc1

Procedure:
The experimental protocol used is the same as that described for intermediate 5.1), N,N-dimethyl-1,2-benzenediamine replacing 4-(N-methylpiperazinyl)aniline and 5-(4-nitropheny)pentanoic acid replacing 4-(4-nitrophenyl)butanoic acid.
Reaction SMILES: [OH:1][N:2]=[CH:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[O:19])=[CH:13][CH:12]=1.[CH3:29][O:30][C:31](=[O:44])[CH:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][C:34]#[CH:35].C(N(CC)CC)C.Cl[O-].[Na+]>ClCCl>[CH3:29][O:30][C:31](=[O:44])[CH:32]([NH:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:33][C:34]1[O:1][N:2]=[C:3]([CH:4]2[CH2:8][CH2:7][CH2:6][N:5]2[C:9](=[O:28])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])=[O:19])=[CH:15][CH:16]=2)[CH:35]=1
Reactant: C#CCC(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)N2CCCC2C=NO)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Cc1cc(C2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)no1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
A solution of 1-(4-{2-[2-(hydroxyimino-methyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-phenyl)-3-o-tolyl-urea (300 mg, 0.789 mmol), 2-tert-butoxycarbonylamino-pent-4-ynoic acid methyl ester (359 mg, 1.182 mmol, crude mixture) and triethyl amine (12.9 μL) in dichloromethane (2 mL) was stirred 5 minutes. A sodium hypochlorite solution (5.25%, 2 mL) was added. The reaction was stirred at room temperature overnight. The aqueous portion was extracted 4 times with dichloromethane. The combined organic portions were washed with brine, dried over magnesium sulfate and concentrated. Chromatography of the crude mixture on a Biotage Flash 40S column eluting with ethyl acetate/hexane 1:5 gave the title compound (66 mg, 14%). MS (CI) m/z 604.5 (M−1), 505.9 (M-99)
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11].Br[CH2:19][CH2:20]Br>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([C:13]2([C:14]([O:16][CH3:17])=[O:15])[CH2:20][CH2:19]2)[CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11]
Reactant: COC(=O)Cc1cc(F)c(OC)c(F)c1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(c2cc(F)c(OC)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
Sodium hydride (0.326 g, 8.14 mmol) was added in one portion to methyl 2-(3,5-difluoro-4-methoxyphenyl)acetate (1.76 g, 8.14 mmol) in DMF (46.3 mL) at 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes. Following this 1,2-dibromoethane (0.772 mL, 8.96 mmol) was added to the reaction mixture and the solution was stirred for 5 minutes. Additional sodium hydride (0.326 g, 8.14 mmol) was then added and the reaction allowed to stir for 2 hours. The reaction mixture was quenched with saturated NH4Cl (50 mL). The reaction mixture was diluted with EtOAc (75 mL), and washed sequentially with water (4×50 mL) and saturated brine (50 mL). The organic layer was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution at 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(3,5-difluoro-4-methoxyphenyl)cyclopropanecarboxylate (1.540 g, 78%) as a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.Cl[CH2:19][O:20][CH3:21]>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH2:9][O:10][CH2:19][O:20][CH3:21])=[CH:5][N:6]=1
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOCc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (5,6-dichloropyridin-3-yl)methanol (commercially available) in CH2Cl2 (0.2 M) at 0° C. was added triethylamine (3 eq.) and chloro(methoxy)methane (2 eq.). After stirring at 0° C. for 3 hours the reaction mixture was concentrated and the crude was purified by chromatography (silica gel, 20-50% EtOAc in hexanes) to afford 2,3-dichloro-5-((methoxymethoxy)methyl)pyridine as a colorless oil.
Reaction SMILES: [CH2:1](O)C.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([N+:15]([O-])=O)[CH:7]=1>[Fe].C(O)(=O)C>[CH3:1][CH2:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][C:8]=1[NH2:15])=[O:14]
Reactant: CCO
Reactant: COc1ccc(C(C)=O)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCC(=O)c1ccc(OC)cc1N
Reaction time: 1 h
Yield: 85 %

Procedure:
To a 1:1 mixture of ethanol and acetic acid was added 1-(4-methoxy-2-nitrophenyl)ethanone (1 eq) and Fe dust (3 eq) was added in portions. The reduction was complete in 1 h. The reaction mixture was filtered and then concentrated and partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate and dried and concentrated to give methyl 1-(4-methoxy-2-aminophenyl)ethanone in 85% yield. ES/MS m/z 196 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CN(C=O)C>[C:8]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([CH3:11])([CH3:10])[CH3:9]
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1ccnc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 28.5 %

Procedure:
A solution of imidazole (253 mg, 3.72 mmol) in DMF (2 mL) was added to a suspension of NaH (60% in mineral oil, 164 mg, 4.10 mmol) in DMF (8 mL), and the mixture was stirred at room temperature for 45 minutes. A solution of toluene-4-sulfonic acid 2-tert-butoxycarbonylamino-ethyl ester (1.29 g, 4.09 mmol) in DMF (6 mL) was added, and the mixture was stirred at room temperature for 16 h then concentrated in vacuo. The residue was partitioned between H2O (25 mL) and EtOAc (25 mL), and the aqueous phase was extracted with EtOAc (25 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (200:5:1-100:5:1 CH2Cl2/MeOH/NH4OH) gave a colourless oil (224 mg, 29%). 1H NMR (CDCl3) δ 1.44 (s, 9H), 3.43 (m, 2H), 4.08 (m, 2H), 4.64 (br s, 1H), 6.92 (s, 1H), 7.09 (s, 1H), 7.46 (s, 1H).
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1.[OH-].[Na+]>O1CCOCC1.CO>[F:1][CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:35][CH:36]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCF)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCF)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 48 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.059 g, 0.100 mmol) in 1,4-dioxane (2 mL) was added NaOH (1N) (0.5 mL, 0.500 mmol). The mixture was heated to 85° C. for 15.25 h, was cooled to rt, then was diluted with methanol and 1,4-dioxane and was purified by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to give 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (29.2 mg, 0.048 mmol, 48.2% yield) as a white solid. LCMS: m/e 576.6 (M+H)+, 1.74 min (method 2). 1H NMR (400 MHz, Acetic acid d4) δ 7.99 (d, J=8.53 Hz, 2H), 7.26 (d, J=8.28 Hz, 2H), 5.33 (d, J=4.77 Hz, 1H), 4.73-4.99 (m, 3H), 4.70 (s, 1H), 3.41-3.73 (m, 2H), 2.83-2.94 (m, 1H), 1.73 (s, 3H), 1.19 (s, 3H), 1.11 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H), 0.82-2.27 (m, 22H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH2:7]Cl)[CH:6]=1.[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH2:7][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])[CH:6]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(F)(F)c1nn(CCl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(Br)c(C(F)(F)F)n1
Yield: 39.3 %

Procedure:
1.67 g of 4-bromo-1-(chloromethyl)-3-trifluoromethyl-1H-pyrazole and 1.03 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 18 ml of N,N-dimethylformamide. 1.74 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.97 g of [(4-bromo-3-trifluoromethyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (15), hereinafter) shown by below formula.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]([NH2:32])[CH3:31]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:8][NH:32][CH:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[CH3:31])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C=O
Reactant: CC(N)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNC(C)c1ccccn1

Procedure:
Using General Procedure B: Reaction of 3-methyl-pyridine-2-carbaldehyde in CH2Cl2 and 1-pyridin-2-yl-ethylamine with NaBH(OAc)3 gave (3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amine as a pale yellow oil. 1H NMR (CDCl3)δ1.48 (d, 3H, J=6.9 Hz), 2.19 (s, 3H), 3.70-3.83 (m, 2H), 4.02 (q, 1H, J=6.9 Hz), 7.06 (dd, 1H, J=5.4, 7.5 Hz), 7.13-7.18 (m, 1H), 7.36-7.40 (m, 1H), 7.47 (d, 1H, J=7.8 Hz), 7.66 (dt, 1H, J=1.8, 7.8 Hz), 8.40 (d, 1H, J=3.9 Hz), 8.55-8.57 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH:12]=[CH:13][C:9]=2[CH:8]=[C:7]([Cl:14])[CH:6]=1)([O:3]C)=[O:2].[OH-].[K+]>CO>[Cl:14][C:7]1[CH:6]=[C:5]([C:1]([OH:3])=[O:2])[C:10]2[O:11][CH:12]=[CH:13][C:9]=2[CH:8]=1
Reactant: COC(=O)c1cc(Cl)cc2ccoc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Cl)cc2ccoc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A solution of 7-carbomethoxy-5-chlorobenzo[b]furan (6c) (3.02 g, 14.3 mmol) containing potassium hydroxide (3.22 g) in 100 ml of aqueous methanol (CH3OH/H2O=3/2) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was acidified with conc. HCl to pH of about 1, cooled in freezer for several hours and filtered to give 7c as an off-white solid (2.65 g, 94.3%), mp 212°-215° C. NMR (DMSO-d6) δ 8.0-6.87 (m, 5H, aromatic protons and OH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[CH2:11]([S:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:30]([OH:40])[CH:29]=2)=[CH:21][C:20]=1[O:41][CH3:42])(=[O:17])=[O:16])[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[CH2:11]([S:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:30]([O:40][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:29]=2)=[CH:21][C:20]=1[O:41][CH3:42])(=[O:17])=[O:16])[CH2:12][CH2:13][CH3:14]
Reactant: COc1cccc(CCl)c1
Reactant: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)OC)c(O)c2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)OC)c(OCc3cccc(OC)c3)c2)cc1OC
Temperature: 70 °C
Yield: 41 %

Procedure:
68 μl (0.5 mmol) of 3-methoxybenzyl chloride are added to a solution of 200 mg (0.5 mmol) of methyl 3-(4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-2-hydroxyphenyl)propanoate and 89 mg (0.5 mmol) of potassium carbonate in 5 ml of methyl ethyl ketone, and the reaction medium is then heated at 70° C. for 48 hours. After cooling, water is added and the reaction medium is then extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 120 mg (48%) of methyl 3-[4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-2-(3-methoxybenzyloxy)phenyl]propanoate are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]([NH:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)=[O:9].[F:30][C:31]([F:43])([F:42])[C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1.CCN(CC)CC>C(Cl)Cl>[N:24]1([CH2:23][C:21]([C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[CH:11]([NH:10][C:8](=[O:9])[CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][N:1]2[S:38]([C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:42])[F:43])[CH:33]=2)(=[O:40])=[O:39])[CH2:12][CH2:13][CH2:14]3)=[CH2:22])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: C=C(CN1CCCCC1)c1ccc2c(c1)CCCC2NC(=O)CC1CCCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(CN1CCCCC1)c1ccc2c(c1)CCCC2NC(=O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-piperidin-2-yl-N-[6-(1-piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide (155.8 mg, 0.39 mmol) in CH2Cl2(2 mL) was added 3-(trifluoromethyl)benzenesulfonyl chloride (Fluka, 0.1 mL, 0.59 mmol) and Et3N (Aldrich, 0.1 mL, 0.79 mmol). The mixture was stirred at rt overnight, diluted with CH2Cl2 (30 mL), washed with 10% Na2CO3 (twice) and brine. The organic solution was dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography (3%–10% MeOH—CH2Cl2) to provide the title compound. MS (ESI): 604 (M+H)+. Calc'd for C32H40F3N3O3S—603.27.
Reaction SMILES: C(OO)(=[O:3])C.[Cl:6][C:7]1[C:8]([O:22][CH:23]2[CH2:26][CH2:25][CH2:24]2)=[N:9][CH:10]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:12]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.O>[Cl:6][C:7]1[CH:12]=[C:11]([OH:3])[CH:10]=[N:9][C:8]=1[O:22][CH:23]1[CH2:26][CH2:25][CH2:24]1
Reactant: CC1(C)OB(c2cnc(OC3CCC3)c(Cl)c2)OC1(C)C
Reactant: CC(=O)OO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Oc1cnc(OC2CCC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Acetic acid solution of peracetic acid (35%, 4.2 mL, 21.3 mmol) was added to a solution of 3-chloro-2-cyclobutoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 20, 4.4 g, 14.2 mmol) in glacial acetic acid (26 mL) and water (13 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. Aqueous solution of sodium thiosulfate (0.5 M, 80 mL) was added and the mixture was stirred for 30 minutes at room temperature. The aqueous layer was extracted with EtOAc (3×40 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 10% EtOAc in heptane to afford the title compound as a clear oil (2.05 g, 72%):
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)([O-:5])=[O:4].[Br:15]Br>O1CCOCC1>[Br:15][C:14]1[C:8]2[C:9](=[N:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=2)[NH:12][N:13]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1cnc2[nH]ncc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc2[nH]nc(Br)c2c1
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
4N NaOH (5.12 mL, 20.5 mmol) was added to a cold (0° C.) solution of 5-nitro-1H-pyrazolo[3,4-b]pyridine (0.84 g, 5.12 mmol) in dioxane (30 mL), followed by bromine (1.05 mL, 20.5 mmol). The cold bath was removed, and the reaction mixture was left at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and quenched with saturated Na2S2O3 (50 mL) The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (9:1) to give 3-bromo-5-nitro-1H-pyrazolo[3,4-b]pyridine (1.10 g, 88%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]3[O:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[CH:25][N:26]=3)[S:21][C:14]=12>>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[O:23][C:22]([C:20]3[S:21][C:14]4[C:15](=[N:16][CH:17]=[CH:18][C:13]=4[NH:11][C:7]4[CH:8]=[C:9]5[C:4](=[CH:5][CH:6]=4)[NH:3][C:2]([CH3:1])=[CH:10]5)[CH:19]=3)=[N:26][CH:25]=2)=[CH:28][CH:29]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: COc1ccc(-c2cnc(-c3cc4nccc(Cl)c4s3)o2)cc1
Product: COc1ccc(-c2cnc(-c3cc4nccc(Nc5ccc6[nH]c(C)cc6c5)c4s3)o2)cc1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 7-chloro-2-[5-(4-methoxy-phenyl)-oxazol-2-yl]-thieno[3,2-b]pyridine by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ11.00 (s, 1H), 8.79 (s, 1H), 8.21 (d, 1H), 7.98 (s, 1H), 7.79 (m, 2H), 7.76 (s, 1H), 7.24 (m, 2H), 7.08 (s, 1H), 7.06 (s, 1H), 6.85 (d, 1H), 6.60 (d, 1H), 6.10 (s, 1H), 3.79 (s, 3H), 2.42 (s, 3H); RP18-HPLC RT: 6.55 minutes; API MS: 453 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].[OH-:25].[Na+].O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:25])[C:8]=1[CH3:24]
Reactant: [OH-]
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Yield: 41.7 %

Procedure:
2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then, mcpba (70.2% purity; 8.95 g (36.4 mmol)) was added gradually so that the internal temperature did not exceed −15° C. 10% Aqueous sodium hydroxide solution (70.8 ml) was then added, and after stirring and still standing the water layer was separated. The separated water layer was washed with dichloromethane (48 ml) twice. After addition of a 2N-ammonium acetate aqueous solution, the water layer was extracted with dichloromethane (48 ml) twice. The dichloromethane layer was washed with water (48 ml) twice, concentrated under a reduced pressure, crystallized with dichloromethane (28 ml) and ethyl acetate (184 ml), and filtered to obtain 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (10.9 g) (HPLC purity 99.7%, yield 41.7%).