Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.F[C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][C:33]=1[CH3:40].[H-].[Na+].[Cl-].[NH4+]>CS(C)=O>[CH3:12][O:11][CH2:10][C@H:9]([CH3:13])[O:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([C:14]2[NH:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=1)[O:1][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][C:33]=1[CH3:40]
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Reactant: Cc1cc(C=O)ccc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C=O)cc2C)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 53.8 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (150 mg, 0.348 mmol) synthesized in Example (38d) and commercially available 4-fluoro-3-methylbenzaldehyde (0.14 mL, 1.148 mmol) were dissolved in dimethyl sulfoxide (5.0 mL), and sodium hydride (60%, 40 mg, 1.00 mmol) was added, followed by stirring at 100° C. for 4 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (30 mL) was added, and extraction was carried out with diethyl ether (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=25%-30%) to afford the desired compound (84 mg, yield 54%) as a yellow solid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[Cl-].C(N(CC)CC)C.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=O.C(=O)(O)[O-].[Na+]>O>[Br:2][C:1]([Br:5])=[CH:19][C:15]1[O:14][CH:18]=[CH:17][CH:16]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccco1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: BrC(Br)=Cc1ccco1
Reaction time: 0.08 h
Yield: 54.7 %

Procedure:
To a stirred solution of 9.6 g (29 mmol) of carbon tetrabromide in 120 mL of dry me hylene chloride at 0° was added 15.2 g (58 mmol) of tripheiiylphosphine. After 15 min 3.0 mL (22.5 mmol) of triethylamine was added, and after stirring another 5 min at 0°, the reaction mixture was cooled to -780°. At this temperature 1.50 mL (22.5 mmol) of 2-furaldehyde was added quickly dropwise, and after addition was complete, the mixture was stirred a -70° for 30 min. The reaction mixture was poured onto a rapidly stirring saturated solution of sodium bicarbonate in water. The methylene chloride phase was removed and the aqueous layer was extracted with additional methylene chloride. The combined extracts were evaporated to a solid which was stirred in 500 mL of hexanes for 2 h. After filtration, the filtrate was concentrated to a volume of 50 mL and the filtered again to remove precipitated solid. Final evaporation of the filtrate afforded 3.1 g (58%) of the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20]([CH2:24][C:25]5[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=5[C@@H:32]([NH:37][S@](C(C)(C)C)=O)[C:33]([F:36])([F:35])[F:34])=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[C:12]([F:44])=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1.Cl>CO>[N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20]([CH2:24][C:25]5[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=5[C@@H:32]([NH2:37])[C:33]([F:34])([F:35])[F:36])=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[C:12]([F:44])=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: CC(C)(C)[S@](=O)N[C@H](c1ccc(F)cc1Cc1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12)C(F)(F)F
Agent: Cl
Solvent: CO
Product: N[C@H](c1ccc(F)cc1Cc1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12)C(F)(F)F
Yield: 89.9 %

Procedure:
Stir a mixture of (S)—N—((R)-1-(2-((2-(2-(2-(1H-1,2,3-Triazol-1-yl)ethylamino)-5-fluoropyrimidin-4-yl)benzo[b]thiophen-7-yl)methyl)-4-fluorophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (10.5 g, 16.52 mmol) and HCl (16.52 mL, 66.07 mmol, in dioxane) in methanol (100 mL) for 2 h. Concentrate the mixture and dilute with NaOH (1 N). Extract the product with ethyl acetate (150 mL×3). Wash the organic layer with 1:1 water/aqueous saturated sodium chloride and aqueous saturated sodium chloride. Dry over Na2SO4, filter, and concentrate. Dissolve the material with heat in DCM/hexanes and solidify the material in 3 h upon cooling. Filter the solid to give the title compound (8.1 g tan solid, 92%). MS (ES) m/z 546 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[CH2:10](I)[CH3:11]>C(#N)C>[CH2:10]([N:7]1[CH2:8][CH:9]=[C:4]([CH2:3][O:2][CH3:1])[CH2:5][CH2:6]1)[CH3:11]
Reactant: COCc1ccncc1
Reactant: CCI
Solvent: CC#N
Product: CCN1CC=C(COC)CC1

Procedure:
6.5 g (0.053 mol) of 4-methoxymethyl pyridine and 9.9 g of ethyl iodide are refluxed in 65 ml of acetonitrile for 1 hour. After the solvent has been distilled off the quaternary salt remaining is taken up in methanol and reduced with sodium borohydride analogously to Example 1 b). 7.8 g (95.2% of theory) of the title compound are obtained (b.p. 85° C./20 mbar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[C:10]=1[OH:11])[CH:6]=O.[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])[CH3:17]>>[C:19]1([C:16](=[O:18])[CH:17]=[CH:6][C:5]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[C:10]([OH:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(C=O)cc(C(F)(F)F)c1O
Reactant: CC(=O)c1ccccc1
Product: COc1cc(C=CC(=O)c2ccccc2)cc(C(F)(F)F)c1O

Procedure:
The procedure described in Example 8 was repeated using 1.7 g of 3-methoxy-4-hydroxy-5-trifluoromethylbenzaldehyde and 1.0 g of acetophenone. Yield 1.1 g (45%), m.p. 166°-168° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CON(C)[C:23]([CH:25]1[CH2:28][CH2:27][CH2:26]1)=[O:24]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:23]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[O:24])[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Br)cc21
Reactant: CON(C)C(=O)C1CCC1
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(C(=O)C3CCC3)cc21

Procedure:
Prepared from 6-bromo-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester and cyclobutanecarboxylic acid methoxy-methyl-amide using a procedure analogous to that of Preparation 263. MS: [M+H]+=331.
Reaction SMILES: C([O:4][C:5]1[C:13]2[O:12][C@@H:11]3[CH2:14][C@H:15]([OH:27])[C@@H:16]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C@@H:10]3[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=O)C.[OH-].[K+].CO.[Cl-].[NH4+]>CO>[C:21]1([S:18]([NH:17][CH:16]2[CH:10]3[CH:11]([O:12][C:13]4[C:5]([OH:4])=[CH:6][CH:7]=[CH:8][C:9]=43)[CH2:14][CH:15]2[OH:27])(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)Oc1cccc2c1O[C@@H]1C[C@H](O)[C@@H](NS(=O)(=O)c3ccccc3)[C@H]21
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Product: O=S(=O)(NC1C(O)CC2Oc3c(O)cccc3C21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
The (1S, 2S, 3aR, 8bS)-1-benzenesulfonamido-2-hydroxy-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-yl acetate (1.14 g), produced according to the process described above, was dissolved in methanol (15 ml) followed by the addition of 0.61N potassium hydroxide/methanol solution (5.0 ml) and stirring for 30 minutes at room temperature. The reaction mixture was added to a 5% aqueous solution of ammonium chloride and extracted with ethyl acetate (60 ml+30 ml×2). The organic layer was washed with saturated brine (30 ml) and concentrated to a solid after drying with anhydrous sodium sulfate. The residue was purified with column chromatography (silica gel: chloroform/methanol 20:1-10:1) to obtain (1SR, 2S, 3aR, 8bS)-1-benzenesulfonamido-2-hydroxy-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-ol (940 mg).
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]=[N:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21])([O-])=[O:4].C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1.C=O.N(C1C=CC=CC=1)=NC1C=CC=CC=1>C(O)C.O>[OH:21][C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[N:13]1[N+:3]([O-:4])=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=[N:12]1
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: C=O
Agent: O=C1c2ccccc2-c2ccccc21
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1

Procedure:
95% potassium hydroxide 17.7 g was added and dissolved in a mixture of ethyl alcohol 80 ml and water 10 ml. 2-nitro-2'-hydroxy-5'-methylazobenzene 12.9 g was then added to the resultant solution at 50° to 60° C. for 30 minutes while stirring, and thereafter 9-fluorenone 0.6 g and 35% formalin 5.6 g were added to the solution in 30 minutes. The resultant mixture was stirred for 1 hour at 65° to 70° C., and was further reacted at the boiling point (85° C.) for 4 hours, thus almost all of the azobenzene having disappeared to produce 2-(2-hydroxy-5-methylphenyl)benzotriazole-N-oxide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][C@@H:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[N+:49]([C:52]1[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][C:53]=1[C:62]([F:65])([F:64])[F:63])([O-:51])=[O:50].O>ClCCl>[N+:49]([C:52]1[CH:57]=[CH:56][C:55]([S:58]([O:1][CH2:2][CH2:3][CH2:4][C@H:5]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][C@@H:7]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[NH:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:60])=[O:59])=[CH:54][C:53]=1[C:62]([F:65])([F:63])[F:64])([O-:51])=[O:50]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)[C@@H](CCCO)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H](CCCOS(=O)(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.1 %

Procedure:
To a solution of di-tert-butyl (4S)-4-(3-hydroxypropyl)-N-trityl-L-glutamate (439 mg, 0.78 mmol) and triethylamine (330 μL, 2.35 mmol) in dichloromethane (7.0 mL) was added 4-nitro-3-(trifluoromethyl)benzenesulfonyl chloride (340.7 mg, 1.18 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 45 min and then water was added. Organic layer was separated, and aqueous layer was extracted with dichloromethane. Combined organic solution was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/n-hexane=15/85) to give the desired product (4 h, 470 mg, 74%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[CH3:11][O:12][C:13]1[CH:49]=[CH:48][C:16]([CH2:17][N:18]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([C:26]3[CH:27]=[C:28]([CH:33]([OH:38])[C:34]([F:37])([F:36])[F:35])[CH:29]=[N:30][C:31]=3F)[N:20]=2)=[CH:15][CH:14]=1.C1COCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)[C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([C:26]3[CH:27]=[C:28]([CH:33]([OH:38])[C:34]([F:35])([F:36])[F:37])[CH:29]=[N:30][C:31]=3[NH:10][C:4]3[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[N:20]=2)=[CH:48][CH:49]=1
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)C(F)(F)F)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)C(F)(F)F)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a stirred mixture of 5-fluoro-6-methoxypyridin-3-amine (2.427 g, 17.07 mmol) and 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)-2,2,2-trifluoroethanol (4.64 g, 8.54 mmol) in THF (50.00 mL, 610 mmol) was added LiHMDS (1.0 M in THF, Aldrich; 42.7 mL, 42.7 mmol) dropwise at −10° C. and the mixture was stirred at the same temperature for 30 min. The reaction was quenched with water and saturated NH4Cl(aq)(25 mL each) and diluted with EtOAc (25 mL). The separated aqueous layer was extracted with ethyl acetate (2×50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude residue which was purified by flash column chromatography (ISCO Combiflash system, 0% to 50% ethyl acetate in hexanes) to obtain the desired product 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-2,2,2-trifluoroethanol (5.1428 g, 7.73 mmol, 91% yield) as a brown foam.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:11][S@@](C(C)(C)C)=O)[CH3:10].Cl>O1CCOCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([NH2:11])[CH3:10]
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1cccc(F)c1F
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
To a round bottom flask containing (R)—N—((S)-1-(2,3-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (786.8 mg, 3.01 mmol) was added Dioxane (10.000 mL). To this solution was added HCl in dioxane 4.0M (1.505 mL, 6.02 mmol) and the solution was allowed to stir 15 min at room temperature. The reaction mixture was concentrated, dissolved in Et2O 10 ml, and concentrated again. Et2O was again added and resulting mixture sonnicated and a solid material was filtered and dried to afford (S)-1-(2,3-difluorophenyl)ethanamine (0.4213 g, 2.176 mmol, 72.3% yield) as a white crystalline HCl salt. 1H NMR (400 MHz, <d2o>) d ppm 1.55 (d, J=6.99 Hz, 3H) 4.71 (q, J=6.96 Hz, 1H) 7.10-7.26 (m, 3H); MS m/z 158.0 (M+H)+; Rt-0.37 min.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][CH:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:29][CH3:30])[N:20]2C2CCCCO2)=[C:16]([NH2:31])[N:15]=1)[CH2:10][O:11][CH3:12]>CO>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH3:8][CH:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:29][CH3:30])[NH:20]2)=[C:16]([NH2:31])[N:15]=1)[CH2:10][O:11][CH3:12]
Reactant: COCC(C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COCC(C)Oc1nc(N)c2nc(OC)[nH]c2n1
Reaction time: 24 h

Procedure:
TFA (7.5 ml) was added to a solution of 2-{[1-methyl-2-(methoxy)ethyl]oxy}-8-(methoxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (4.7 g, 13.9 mmol) in MeOH (30 ml) with stirring. The mixture was left to stand at room temperature for 1 day. A white solid formed which was filtered off and washed with ethyl acetate. This gave product (3.7 g, 76.1%)
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH:18]=O)=[CH:11][CH:10]=2)[CH2:4][O:3]1.[C:21]([S:25]([NH2:27])=[O:26])([CH3:24])([CH3:23])[CH3:22]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17]/[CH:18]=[N:27]/[S:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:26])=[CH:11][CH:10]=2)[CH2:4][O:3]1
Reactant: CC(C)(C)S(N)=O
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCC=O)cc2)O1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](COc2ccc(CCC/C=N/S(=O)C(C)(C)C)cc2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-[4-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-butyraldehyde (4.28 g, 15.4 mmol) in THF (150 ml) is added tert-butyl sulfinamide (2.05 g, 16.9 mmol) followed by titanium ethoxide (6.5 ml, 30.8 mmol). The yellow solution formed is stirred at room temperature overnight. The solution is quenched with 1 N NaOH (200 ml) and EtOAc (100 ml) and stirred for 30 minutes at room temperature. The resultant mixture is filtered through Celite™ (filter material) and the organic phase is separated and dried (MgSO4). Concentration in vacuo gives 2-Methyl-propane-2-sulfinic acid [4-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-but-(E)-ylidene]-amide as a yellow oil; [M+H]+ 382.23
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([O:16][CH2:17][C:18]23[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]2)[CH2:20][CH2:19]3)(=O)=O)=CC=1.O[C:28]1[CH:45]=[CH:44][C:31]([O:32][CH2:33][CH:34]([OH:43])[CH2:35][CH2:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[CH:30][CH:29]=1.[C:46]([OH:51])(=[O:50])[C:47]([OH:49])=[O:48]>CN(C)C=O.[Cl-].[Na+].CCOCC.O>[C:46]([OH:51])(=[O:50])[C:47]([OH:49])=[O:48].[C:18]12([CH2:17][O:16][C:28]3[CH:45]=[CH:44][C:31]([O:32][CH2:33][CH:34]([OH:43])[CH2:35][CH2:36][C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[CH:30][CH:29]=3)[CH2:19][CH2:20][CH:21]([CH2:22][CH2:23]1)[CH2:24][CH2:25]2
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(CC2)CC3)cc1
Reactant: Oc1ccc(OCC(O)CCc2cccnc2)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: OC(CCc1cccnc1)COc1ccc(OCC23CCC(CC2)CC3)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Anhydrous potassium carbonate (0.100 g) was added to a solution of bicyclo[2,2,2]oct-1-ylmethyl para-toluenesulfonate (0.180 g) and (±)-1-(4-hydroxyphenoxy)-4-(3-pyridyl)-2-butanol (0.115 g) in anhydrous dimethylformamide (3 ml). The mixture was heated at reflux under nitrogen, with stirring for 6 hours then cooled to room temperature before being poured into water (20 ml). The mixture was diluted with saturated aqueous sodium chloride solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with acetone:hexane (2:3) to give an oil. This oil was treated with oxalic acid (excess) in ether to give the title compound as a solid (0.167 g) which was recrystallised from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[C:13]([CH3:42])([CH3:41])[C@H:14]2[C@:27]([CH3:30])([CH2:28][CH:29]=1)[C@@H:26]1[C@:17]([CH3:40])([C@@:18]3([CH3:39])[C@H:23]([CH2:24][CH2:25]1)[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([CH:37]=O)[CH2:20][CH2:19]3)[CH2:16][CH2:15]2)[C:5]([O:7]C)=[O:6].[NH2:43][CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][S:50](=[O:54])(=[O:53])[CH2:49][CH2:48]1>>[O:53]=[S:50]1(=[O:54])[CH2:49][CH2:48][N:47]([CH2:46][CH2:45][CH2:44][NH:43][CH2:37][C@:21]23[CH2:33][CH2:32][C@@H:31]([C:34]([CH3:36])=[CH2:35])[C@@H:22]2[C@@H:23]2[C@@:18]([CH3:39])([CH2:19][CH2:20]3)[C@@:17]3([CH3:40])[C@@H:26]([C@:27]4([CH3:30])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:41])([CH3:42])[C:12]([C:11]3[CH:10]=[CH:9][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=3[F:1])=[CH:29][CH2:28]4)[CH2:25][CH2:24]2)[CH2:52][CH2:51]1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: NCCCN1CCS(=O)(=O)CC1
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following steps 5 and 6 using methyl 3-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-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 and 4-(3-aminopropyl) thiomorpholine 1,1-dioxide as the reactant amine. The product was isolated as a white solid (70 mg, 68.0%). LCMS: m/e 737.5 (MH+), 2.59 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.77 (d, J=7.8 Hz, 1H), 7.67 (d, J=9.8 Hz, 1H), 7.19-7.31 (m, 1H), 5.38 (d, J=4.8 Hz, 1H), 4.78 (br. s., 1H), 4.67 (br. s., 1H), 3.41 (br. s., 4H), 3.30-3.38 (m, 4H), 3.27 (d, J=12.5 Hz, 1H), 3.21 (br. s., 2H), 3.00 (t, J=6.4 Hz, 2H), 2.90 (br. s., 1H), 2.53 (br. s., 1H), 2.10 (br. s., 4H), 1.84 (br. s., 3H), 1.75 (br. s., 7H), 1.54 (br. s., 8H), 1.36 (br. s., 3H), 1.20 (br. s., 5H), 1.11 (br. s., 3H), 1.07 (br. s., 3H), 0.98 (br. s., 3H), 0.94 (br. s., 3H). 19F NMR (376 MHz, MeOD) δ ppm −113.31 (s, 1 F).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]=[CH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)[CH2:11][CH2:10]1.[H][H]>CO.[Pt]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(CC=Cc2ccc3c(c2)CCC(=O)N3)CC1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: COc1ccccc1N1CCN(CCCc2ccc3c(c2)CCC(=O)N3)CC1

Procedure:
2.3 Grams of 6-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-1-propenyl}-3,4-dihydrocarbostyril and 0.2 g of platinum black were suspended in 100 ml of methanol and the suspension was catalytically hydrogenated under 2 to 4 atmospheric pressure of hydrogen gas at a normal temperature. After the catalyst was removed by filtration, the filtrate was dried under a reduced pressure. The residue was recrystallized from isopropanol-diisopropyl ether to obtain 6-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-3,4-dihydrocarbostyril in colorless prism-like crystals. Yield: 1.3 g. Melting point: 145°-146° C.
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]2[N:6]([C@@H:10]3[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]3[OH:12])[C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.[OH-].[NH4+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)Cl.CO>O>[CH2:24]([S:9][C:7]1[N:6]([C@@H:10]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]2[OH:12])[C:5]2[CH:19]=[C:20]([Cl:21])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: OC[C@H]1O[C@@H](n2c(=S)[nH]c3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](n2c(SCc3ccccc3)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Reaction time: 5 h

Procedure:
Compound 53 (0.5 g) was dissolved in cold water (10 ml) containing concentrated ammonium hydroxide (2.5 ml). Benzyl chloride (0.5 ml) was added to this solution with stirring and the stirring continued at room temperature for 5 hours. The white solid (0.41 g) which had separated from solution was collected by filtration, washed with cold water. The solid was extracted with ethyl acetate (100 ml) and the ethyl acetate phase was dried over anhydrous Na2SO4 and then evaporated by aspirator to give a syrup. The syrup was subjected to a flash column of silica gel with CH2Cl2 --MeOH (15:1) as eluant. Fractions were collected (25 ml each) and fractions containing the desired compound were combined and evaporated to afford 54 which was crystallized from CH2Cl2 --MeOH (15:1), mp. 149° C., Yield 0.223 g (35.5%).