Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].[Cl-].[NH4+]>ClCCl.O>[CH3:19][S:20]([O:9][CH2:8][C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:22])=[O:21]
Reactant: OCc1ccc(Br)nc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(6-Bromopyridin-3-yl)methanol (2.45 g, 13.0 mmol) was dissolved in dichloromethane (20 mL), cooled to 0° C. and treated successively with N,N-diisopropylethylamine (2.73 mL, 15.6 mmol, 1.2 equiv) and methanesulfonyl chloride (1.17 mL, 15.0 mmol, 1.15 equiv). After stirring for 30 minutes, the mixture was treated with ammonium chloride (10 mL, aqueous saturated) and warmed to ambient temperature. The mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:23])=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.O>ClCCl>[CH2:1]([N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[NH:23][C:32]1=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(NCc2ccccc2)cccc1OCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c2c(OCc3ccccc3)cccc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 263.1 %

Procedure:
To a solution of N*1*-Benzyl-3-benzyloxy-benzene-1,2-diamine (4.60 g, 15.11 mmol) in 100 mL dichloromethane at 0° C. was added triethylamine (4.201 mL, 30.22 mmol) followed by portionwise addition of triphosgene (1.57 g, 5.29 mmol). The resulting solution was stirred for 2 hours at 0° C. The reaction mixture was allowed to warm to room temperature and was then added to 200 mL water. The organic phase was separated, washed with 100 mL 10% aqueous HCl, 100 mL saturated aqueous sodium bicarbonate, and 100 mL brine, dried over sodium sulfate, and concentrated in vacuo to give 4.60 g (13.92 mmol, 92%) of 1-benzyl-4-benzyloxy-1,3-dihydro-benzoimidazol-2-one as a tan solid. MS: 331 (M+H)+.
Reaction SMILES: N([C@@H:4]1[C@@H:8]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[O:7][C@@H:6]([N:18]2[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:5]1)=[N+]=[N-].[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H]([OH:29])C1.C(N(CC)CC)C.[Si](Cl)(C(C)(C)C)(C)C>CN(C)C1C=CN=CC=1.ClCCl.CN(C=O)C>[Si:11]([O:10][CH2:9][C@H:8]1[O:7][C@@H:6]([N:18]2[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:5][C@@H:4]1[OH:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
3'-azido-5'-O-(tert-butyldimethylsilyl)-2',3'-dideoxyuridine, 1du. 2'-Deoxyuridine (11.4 g, 50 mmol) was thoroughly dried by coevaporating in vacuo with anhydrous DMF (2×100 mL). DMF (100 mL) was then added, followed by triethylamine (8.36 mL, 60 mmol), 4-dimethylaminopyridine (0.31 g, 2.5 mmol), and tert-butyldimethylsilyl chloride (8.29 g, 55.0 mmol). The reaction mixture was stirred for 1 h at RT, diluted with dichloromethane (600 mL) and extracted with H2O (3×200 mL), and saturated aq. NaCl (200 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified on silica (2-10% MeOH/CH2Cl2) to afford 80% yield (13.7 g, 40.0 mmol) of 5'-O-(tert-butyldimethylsilyl)-2'-deoxyuridine. Triphenylphosphine (16.8 g, 64.0 mmol) and DMF (100 mL) were added, and to this stirring mixture was added a solution of diisopropylazodicarboxylate (12.6 mL, 64.0 mmol) in DMF (20 mL). After stirring 2 h at RT, the reaction mixture was concentrated in vacuo to ca. 30 mL, and poured into Et2O (1200 mL). The desired 2,3'-anhydro-5'-O-(tert-butyldimethylsilyl)-2'-deoxyuridine began precipitating out after 10 min of rapid stirring. The resulting mixture was placed in the refrigerator overnight, the precipitate was collected by filtration, washed with additional cold Et2O (2×300 mL), and dried in vacuo to afford 90% yield (11.7 g, 36.0 mmol) of 2,3'-anhydro-5'-O-(tert-butyldimethylsilyl)-2'-deoxyuridine as a white solid, which was not purified further. The 2,3'-anhydro-5'-O-(tert-butyldimethylsilyl)-2'-deoxyuridine (33.8 g, 104.2 mmol) was then reacted with LiN3 (7.65 g, 156.3 mmol) in DMF (300 mL) at 95°-100° C. for 48 h. The resulting brown, homogeneous mixture was then cooled to RT, concentrated in vacuo to an oil, dissolved in EtOAc (800 mL), and extracted with H2O (200 mL). The aqueous layer was extracted twice more with EtOAc (75 mL), and the combined organics were washed with H2O (3×250 mL) and once with saturated. aq. NaCl (250 mL). The EtOAc solution was dried over Na2SO4, filtered, and concentrated in vacuo, to afford 87% yield (33.2 g, 90.3 mmol) of 3'-azido-5'-O-(tert-butyldimethylsilyl)-2',3'-dideoxyuridine, 1du, as a brownish foam, which was taken on directly to hydrogenation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:21](O)=[O:22])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CN(C)C=O>[C:58]1([NH:57][C:21]([C:15]2[C:14]3[C:18](=[CH:19][CH:20]=[C:12]([NH:11][S:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)(=[O:9])=[O:10])[CH:13]=3)[NH:17][N:16]=2)=[O:22])[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Yield: 12.7 %

Procedure:
N-Phenyl-5-(3-fluorobenzenesulfonylamino)-1H-indazole-3-carboxamide can be obtained as described in Example 18 from 0.45 g of 5-(3-fluorobenzenesulfonylamino)-1H-indazole-3-carboxylic acid, 11 ml of dimethylformamide, 0.56 g of 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 0.38 g of diisopropylethylamine and 0.14 g of aniline. 70 mg of N-phenyl-5-(3-fluorobenzenesulfonylamino)-1H-indazole-3-carboxamide are thus obtained in the form of a brown solid melting above 260° C. (Analysis: C20H15FN4O3S.0.73H2O % calculated C, 58.54; H, 3.68; F, 4.63; N, 13.65; O, 11.69; S, 7.81. % found C, 58.09; H, 3.18; N, 13.58; S, 7.43).
Reaction SMILES: O[CH2:2][C@@H:3]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F.F.F.C(N(CC)CC)C.[F:31]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.CCN(C(C)C)C(C)C>C1(C(F)(F)F)C=CC=CC=1>[F:31][CH2:2][C@@H:3]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@H](CO)c1ccccc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Solvent: FC(F)(F)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1[C@H](CF)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of (S)-2-(2-hydroxy-1-phenylethyl)isoindoline-1,3-dione (1.5 g, 5.61 mmol) in PhCF3 (18.71 mL) was added triethylamine trihydrofluoride (5.48 mL, 33.7 mmol), perfluorobutanesulfonyl fluoride (1.019 mL, 5.67 mmol), DIEA (14.70 mL, 84 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h, then more perfluorobutanesulfonyl fluoride (1.019 mL, 5.67 mmol) was added. After 5 h, the reaction mixture was quenched with NaHCO3 and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo. The crude product was purified by flash chromatography (0-10% EtOAC in heptane) yielding (S)-2-(2-fluoro-1-phenylethyl)isoindoline-1,3-dione (30% yield). LCMS (m/z): 270.1 (MH+), 0.96 min.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[NH2:23][CH2:24][CH:25]1[C:29](=[N:30][O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][NH:27][CH2:26]1>>[NH2:23][CH2:24][CH:25]1[C:29](=[N:30][O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][N:27]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:26]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(C)(C)ON=C1CNCC1CN
Agent: Cl
Product: CC(C)(C)ON=C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1CN
Temperature: 25 °C
Yield: 67.3 %

Procedure:
141 mg (0.5 mmole) of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 143 mg (0.55 mmole) of 3-aminomethyl-4-t-butyloxyiminopyrrolidine dihydrochloride were refluxed for 2.5 hours under heating according to the same manner as Example 89 and cooled down to room temperature. Then, the resulting product was then separated and purified with preparative HPLC to obtain 151 mg (Yield: 67%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:24]=[C:25]=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:18]([NH:24][C:25](=[O:26])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: CCCCCCN=C=O
Product: CCCCCCNC(=O)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (35.0 mg, 0.155 mmol) using the same procedure employed for Example 2 (2), but with n-hexylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (16.7 mg, 30%) having the following characteristics.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[C:24](=O)(O)[O-].[Na+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:24])=[O:13]
Reactant: O=C([O-])O
Reactant: COc1ccccc1Sc1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccccc1Sc1ccccc1OC
Temperature: 25 °C

Procedure:
Dissolve 115 g of the acid of Step A in 3.5 liters of methanol and add slowly 25 ml of sulfuric acid. Stir under reflux for 72 hours. Cool the reaction mixture to room temperature and add 100 g of sodium bicarbonate in portions. Stir for an additional hour and strip to dryness. Dissolve the residue in methylene chloride and wash the solution three times with water. Dry the solution and strip to an oil which solidifies. (m.p. 82°-84° C.)
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[N+:21]([O-])([OH:23])=[O:22].CCC1(C2C=CC=CC=2)C(=O)NC(=O)NC1=O>C(O)(=O)C>[OH:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: O=[N+]([O-])O
Agent: CCC1(c2ccccc2)C(=O)NC(=O)NC1=O
Solvent: CC(=O)O
Product: C[C@]12CC[C@@H]3c4ccc(O)c([N+](=O)[O-])c4CC[C@H]3[C@@H]1CCC2=O
Temperature: 120 °C
Yield: 13 %

Procedure:
To a suspension of estrone (11, 8.11 g, 30 mmol) in acetic acid (250 mL) was heated to 120° C. and cooled to 50° C. To the reaction mixture was added 70% nitric acid (2.27 mL, 36 nunol, in an acetic acid (8.0 mL) solution) at 50° C., and stirred for 20 h at room temperature. The precipitate was filtered and washed with acetic acid, H2O, Et2O to afford 1.18 g of 76a (13% yield) mp: >250° C. To the filtrate was added H2O; it was then extracted with Et2O. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:EtOAc (2:1, v/v) to afford 3.25 g of 76b (34% yield) mp: 178-180° C.
Reaction SMILES: [OH-:1].[Na+].[OH:3][CH:4]([C:8]1[N:9]=[C:10]([CH2:34][CH2:35][CH3:36])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([C:30]([O:32]C)=[O:31])=[O:29])=[CH:18][CH:17]=2)[C:12]=1[C:13]#[N:14])[CH:5]([CH3:7])[CH3:6]>C(O)C>[OH:3][CH:4]([C:8]1[N:9]=[C:10]([CH2:34][CH2:35][CH3:36])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([C:30]([OH:32])=[O:31])=[O:29])=[CH:18][CH:17]=2)[C:12]=1[C:13]([NH2:14])=[O:1])[CH:5]([CH3:7])[CH3:6]
Reactant: CCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1nc(C(O)C(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1

Procedure:
4 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 170 mg of 4-(1-hydroxy-2-methylpropyl)-1-[(2'-methoxalylbiphenyl-4-yl)methyl]-2-propylimidazole-5-carbonitrile [prepared as described in step (a) above] dissolved in 3 ml of hot ethanol, and the resulting mixture was stirred under reflux for 2.5 hours. At the end of this time, the ethanol was removed by evaporation under reduced pressure, and ethyl aceate was added to the residual aqueous solution. 4 ml of 1N aqueous hydrochloric acid were added to the mixture, after which the ethyl acetate layer was separated. This extract was then dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure to give 140 mg of the title compound as crystals, softening at 150° C., and melting at 165°-170° C. (with decomposition).
Reaction SMILES: C(O[C:4](=[O:15])[CH:5]([CH3:14])[C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])C.C(OC(O[CH2:22][CH3:23])=C)C.[CH3:24][NH2:25]>C(OCC)C.C[O-].[Na+]>[CH2:11]([O:10][C:8]([C:7]1[C:6]([OH:13])=[C:5]([CH3:14])[C:4](=[O:15])[N:25]([CH3:24])[C:22]=1[CH3:23])=[O:9])[CH3:12]
Reactant: CN
Reactant: C=C(OCC)OCC
Reactant: CCOC(=O)CC(=O)C(C)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)c1c(O)c(C)c(=O)n(C)c1C
Temperature: 85 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
A mixture of 2-methyl-3-oxo-pentanedioic acid diethyl ester (10.0 g, 46.3 mmol), 1,1-diethoxy-ethene (12.8 mL, 92.5 mmol) and sodium methoxide (0.026 mg, 0.481 mmol) was heated to 85° C. for nine hours. The reaction mixture was cooled to room temperature and concentrated. To the resulting residue was added methylamine (1.91 mL, 55.5 mmol, 40% H2O). After stirring at room temperature for 16 hours, the reaction mixture was diluted with diethyl ether and washed with water. The aqueous phase was acidified to pH 1 with 10% HCl solution and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated. Trituration of the resulting residue with diethyl ether and flash column chromatography (3% MeOH in methylene chloride) gave 3.55 g (34%) desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[O:31]C(=O)C)=[CH:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[OH:31])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3OC)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccnc3OC)c2)=C(C)C1=O
Yield: 81.7 %

Procedure:
N-(2-Methoxypyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.150 g, 0.312 mmol) was dissolved in methanol (5 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=3:1) to obtain the titled compound (0.112 g, 0.255 mmol, 82%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:18][C:19]2([C:24]#[N:25])[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[F:17])=[N:7][CH:8]=1.[CH:26]1([CH:29]([C:36]2[C:41]([F:42])=[CH:40][N:39]=[C:38]([OH:43])[CH:37]=2)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][CH2:27]1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[C:24]([C:19]1([CH2:18][C:5]2[CH:4]=[C:3]([CH2:2][O:43][C:38]3[CH:37]=[C:36]([CH:29]([CH:26]4[CH2:28][CH2:27]4)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:41]([F:42])=[CH:40][N:39]=3)[CH:8]=[N:7][C:6]=2[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[F:17])[CH2:20][CH2:21][CH2:22][CH2:23]1)#[N:25]
Reactant: COc1ccc(F)c(-c2ncc(CBr)cc2CC2(C#N)CCCC2)c1
Reactant: CCOC(=O)CC(c1cc(O)ncc1F)C1CC1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(CC3(C#N)CCCC3)c2)ncc1F)C1CC1
Yield: 16.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of 1-((5-(bromomethyl)-2-(2-fluoro-5-methoxyphenyl)pyridin-3-yl)methyl)cyclopentanecarbonitrile (48 mg) and ethyl 3-cyclopropyl-3-(5-fluoro-2-hydroxypyridin-4-yl)propanoate (40 mg) obtained in Example 42, step E, in toluene (1 mL) was added silver carbonate (48 mg), and the mixture was refluxed for 2 hr. The reaction mixture was filtered, and the solvent in the filtrate was evaporated under reduced pressure and the residue was purified by preparative HPLC (water/acetonitrile, TFA added) to give the title compound (11 mg) as a yellow oil.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[N:30]=[CH:31][C:24]=12>C1COCC1.C(OCC)(=O)C>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:29]1[C:25]2=[N:26][CH:27]=[N:28][C:23]([O:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[C:24]2[CH:31]=[N:30]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: COC[C@@H](C)OC[C@H](O)C(=O)Nc1cnc(C)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1cnc(C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.8 %

Procedure:
Sodium hydride (14.26 mg, 0.36 mmol) was added to (S)-2-hydroxy-3-((R)-1-methoxypropan-2-yloxy)-N-(5-methylpyrazin-2-yl)propanamide (Intermediate Y12) (64 mg, 0.24 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting mixture was stirred for 10 minutes at 0° C. and 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (86 mg, 0.32 mmol) was added and the reaction was allowed to warm up to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (75 mg, 63.4%). 1H NMR (400 MHz, CDCl3) δ 1.16 (d, 3H), 2.52 (s, 3H), 3.33-3.48 (m, 5H), 3.80-3.89 (m, 1H), 4.16-4.27 (m, 2H), 6.01 (t, 1H), 7.45-7.55 (m, 3H), 7.60-7.64 (m, 1H), 8.11-8.12 (m, 1H), 8.41 (s, 1H), 8.59 (s, 1H), 8.94 (s, 1H), 9.42 (d, 1H). m/z (ESI+) (M+H)+=498.36; HPLC tR=2.19 min.
Reaction SMILES: F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)[N:10]1CCC[CH2:11]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([O:38][C:39]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:40]=2[C:41](O)=[O:42])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN>C(Cl)Cl>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([O:38][C:39]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:40]=2[C:41](=[O:42])[NH:10][CH3:11])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2C(=O)O)CC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cc(Cl)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
Bromo-tris-pyrrolidinophosphonium hexafluorophosphate (1.57 g, 3.37 mmol) was added to a vigorously stirred mixture of 2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]oxy}-5-chlorobenzoic acid (1.00 g, 2.8 mmol) and 40% aq methylamine (2 ml) in DCM (10 ml). Stirring was continued for 30 min. before partitioning between 1N hydrochloric acid (10 ml) and dichloromethane (10 ml). The organic layer was separated and washed with saturated sodium bicarbonate solution (20 ml) and water (20 ml), then dried over sodium sulfate and the solvent removed under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetate:isohexane (1:1) to give the title compound as a colourless solid (0.84 g).
Reaction SMILES: [3H]C1C=C2OCOC2=CC=1OC[C@H:10]1[C@H:15]([C:16]2[CH:17]=[CH:18][C:19](F)=[CH:20][CH:21]=2)CC[NH:12][CH2:11]1.[Na+].[Cl-].[C-:28]#[N:29].[K+].CN(CCCC1(C2C=CC(F)=CC=2)[O:45]CC2C=C(C#N)C=CC1=2)C>>[CH:19]1[C:18]([OH:45])=[CH:17][C:16]2[C:15]([CH2:10][CH2:11][NH2:12])=[CH:28][NH:29][C:21]=2[CH:20]=1
Reactant: [3H]c1cc2c(cc1OC[C@@H]1CNCC[C@H]1c1ccc(F)cc1)OCO2
Reactant: [C-]#N
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Product: NCCc1c[nH]c2ccc(O)cc12
Reaction time: 2 h

Procedure:
The affinity was determined by competition experiments using [3H]-paroxetine. The membranes are prepared from the frontal cortex of the rat and are incubated in triplicate with 0.25 nM [3H]-paroxetine and the compound being tested in a final volume of 0.4 ml, for 2 hours at 25° C. The incubation buffer contains 50 mM TRIS-HCl (pH 7.4), 120 mM NaCl and 5 mM KCN. The non-specific binding is determined using 10 μM citalopram.
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.N[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:18]#[N:19]>>[Cl:23][C:22]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[S:8]([Cl:11])(=[O:10])=[O:9]
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Reactant: N#Cc1ccc(Cl)c(N)c1
Product: N#Cc1ccc(Cl)c(S(=O)(=O)Cl)c1

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 3-amino-4-chloro-benzonitrile.
Reaction SMILES: [S].[N+:2]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH3:15])=[CH:7][CH:6]=1)([O-])=O.[OH-:16].[Na+]>C(O)C.C(OCC)(=O)C>[NH2:2][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:16])=[CH:7][CH:6]=1
Reactant: Cc1ccc([N+](=O)[O-])c2ccccc12
Reactant: [OH-]
Agent: [Na+]
Agent: [S]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(C=O)c2ccccc12

Procedure:
To a stirring boiling solution of sulfur (3.7 g) in 12% aqueous NaOH (50 mL) was added a solution of 4-nitro-1-methylnaphthalene (8 g) in ethanol (50 mL). After refluxing the solution for one hour, the reaction was diluted with 500 mL of ethyl acetate and washed with water and brine, dried over MgSO4, and concentrated. The product was purified via silica gel column chromatography using ethyl acetate:hexane (5:95 to 10:90). The product (2.54 g, 34%) was stored at −78° C.