Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=[CH:11]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[NH2:25].C(=O)([O-])O.[Na+]>C(O)(C)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:17]2[C:18]3[N:10]([CH2:9][CH2:8][NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=[CH:12][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Yield: 85.2 %

Procedure:
A solution of tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (712 mg) and 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (830 mg) in isopropyl alcohol (7.1 mL) was stirred at 80° C. for 12 hrs. Aqueous sodium hydrogen carbonate was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→ethyl acetate) to give the title compound (1.12 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:28])([C@@H:14]([C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1.[CH3:29][Mg]Br.[Cl-].[NH4+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:28])([C@@H:14]([C@@:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)([OH:22])[CH3:29])[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1
Reactant: C[C@]12Cn3cnc(-c4ccc(F)cc4)c3C=C1CCC[C@@H]2C(=O)c1cccs1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: C[C@]12Cn3cnc(-c4ccc(F)cc4)c3C=C1CCC[C@@H]2[C@](C)(O)c1cccs1
Yield: 49 %

Procedure:
To a stirred solution of the above ((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)(thiophen-2-yl)methanone was added methylmagnesium bromide solution (3 M in diethyl ether, 2 mL, 6 mmol) dropwise at −78° C. under argon. The reaction mixture was then stirred at RT for 2.5 hr before saturated aqueous ammonium chloride solution (6 mL) was added slowly with water bath cooling. The mixture was extracted with ethyl acetate (3×5 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Silica gel flash chromatography (10-100% ethyl acetate in hexanes) gave (S)-1-((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)-1-(thiophen-2-yl)ethanol (58 mg, 0.14 mmol, 49% yield for steps (h)+(i)+(j)) as a solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][C:31]1[N:35]([C@H:36]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]2)[C:34]2[CH:48]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:50]=[CH:51][C:33]=2[N:32]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:49]3[CH:50]=[CH:51][C:33]4[N:32]=[C:31]([CH3:30])[N:35]([C@H:36]5[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:37]5)[C:34]=4[CH:48]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2n1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nc(C)n([C@H]5CCN(C(=O)OC(C)(C)C)C5)c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (50 mg, 0.10 mmol), (S)-tert-butyl 3-(2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate (181 mg, 0.42 mmol), then Pd(PPh3)4 (23 mg, 0.02 mmol). The vial was flushed with argon, diluted with dioxane (2 mL) and to this was added 2M aqueous K2CO3 (0.2 mL, 0.4 mmol). The vial was sealed then heated to 100° C. for 16 hours and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (0-100% THF/CH2Cl2 gradient) to afford the desired product. LCMS-ESI+: calc'd for C39H46ClN4O5S: 717.3 (M+H+); Found: 717.1 (M+H+).
Reaction SMILES: O[C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[C:30]4[CH:29]=[C:28]([C:31]5[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=5)[N:27]=[CH:26][C:25]=4[CH:24]=[N:23]3)[N:17]=2)[CH2:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C(N(S(F)(F)[F:43])CC)C>C(Cl)Cl>[F:43][C:2]1([C:16]2[N:17]=[C:18]([N:22]3[C:30]4[CH:29]=[C:28]([C:31]5[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=5)[N:27]=[CH:26][C:25]=4[CH:24]=[N:23]3)[CH:19]=[CH:20][CH:21]=2)[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(C3(O)CCCN(C(=O)OC(C)(C)C)CC3)n2)cn1
Solvent: ClCCl
Product: Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(C3(F)CCCNCC3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.7 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azepane-1-carboxylate (150 mg, 0.3 mmol) in DCM (5 mL) was added diethylaminosulfur trifluoride (DAST, 0.12 mL, 0.9 mmol). The mixture was stirred at room temperature for 1 hour, which was monitored by LCMS. After completion of the reaction, it was concentrated under reduced pressure to afford 1-(6-(4-fluoroazepan-4-yl)pyridin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine as a light yellow oil (130 mg, 87%). MS (ESI) m/z: 493 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[N:13]1([CH2:19][CH2:20][O:21][C:22]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[CH:26][C:23]=2[CH:24]=O)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C[O-].[Li+]>CN(C=O)C.CO>[CH3:31][O:30][C:28]1[C:27]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[CH:26][C:23](/[CH:24]=[CH:2]/[C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=2)=[O:3])=[C:22]([O:21][CH2:20][CH2:19][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[CH:29]=1
Reactant: CC(=O)c1ccc(C(N)=O)cc1
Reactant: COc1cc(OCCN2CCOCC2)c(C=O)cc1-c1cccs1
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(OCCN2CCOCC2)c(/C=C/C(=O)c2ccc(C(N)=O)cc2)cc1-c1cccs1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
To a solution of 4-acetyl-benzamide (Ex-92A, 0.25 g, 1.53 mmol) and 2-(2-morpholin-4-yl-ethoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-60A, 0.53 g, 1.53 mmol) in DMF (7 mL) and methanol (3 mL) was added lithium methoxide. The solution was allowed to stir at ambient temperature. The reaction was quenched with water after 2 hours. The aqueous solution was extracted with ethyl acetate. The combined extract was washed with NaHCO3, NH4Cl, brine, dried (Na2SO4) and concentrated. The residue was stirred in ethanol overnight to afford the title compound as a yellow solid (0.43 g, 57%), mp 183–184° C. 1H-NMR (CDCl3) δ 8.09–8.04 (m, 3H), 7.93 (d, J=8.3 Hz, 2H), 7.87 (s, 1H), 7.57 (d, J=15.7 Hz, 1H), 7.42 (d, J=3.9 Hz, 1H), 7.32 (d, 4.4 Hz, 1H), 7.11–7.08 (m, 1H), 6.55 (s, 1H), 6.25 (bs, 1H), 5.75 (bs, 1H), 4.25 (t, J=5.9 Hz, 2H), 3.98 (s, 3H), 3.71 (t, J=4.2 Hz, 4H), 2.92 (t, J=5.7 Hz, 2H), 2.59 (t, J=4.6 Hz, 4H). MS m/z=493 ([M+H]+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.C1COCC1.[CH3:18][NH2:19]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[N:19][CH3:18]
Reactant: O=Cc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN=Cc1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
3-Chloro-4-nitrobenzaldehyde (251 mg 1.35 mmole) was dissolved in dichloromethane (2 mL) and methylamine, 2M in THF (0.88 mL, 1.76 mmole) was added along with 3A Sieves (400 mg). The reaction was stirred at room temperature for 18.5 hours. The sieves were filtered and washed with more dichloromethane. The filtrate was evaporated, however only partial conversion to the imine was observed. The residue was redissolved in dichloromethane (2 mL) and methylamine. 2M in THF (1.0 mL, 2.0 mmole) was added along with powdered 3A Sieves (400 mg). The reaction was stirred at room temperature for a further 16.5 hours. The sieves were filtered and washed and the filtrate evaporated to give the title compound as an oil which quickly crystallised (199 mg). 1H-NMR (CDCl3, 500 MHz): δ 3.60 (d, J=1.89 Hz, 3H), 7.73 (dd, J=1.89, 8.51 Hz, 1H), 7.93 (m, 2H), 8.30 (q, J=1.58 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][C:7]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[CH2:10][NH:9][C:8]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:34]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][C:7]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[CH2:10][NH:9][C:8]1=[S:34]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)C1(Cc2ccc(OC)c(OC)c2)C(=O)NCC1c1ccc(OC)c(OC)c1
Solvent: c1ccccc1
Product: CCOC(=O)C1(Cc2ccc(OC)c(OC)c2)C(=S)NCC1c1ccc(OC)c(OC)c1
Reaction time: 1 h
Yield: 130.6 %

Procedure:
A mixture of 6 g of ethyl 3-(3,4-dimethoxybenzyl)-4-(3,4-dimethoxyphenyl)-2-oxo-3-pyrrolidinecarboxylate, 4 g of diphosphorus pentasulfide and 120 ml of anhydrous benzene is refluxed with stirring for one hour. While it is hot, the insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue is washed with water and recrystallized from ethanol to give 5.4 g of ethyl 3-(3,4-dimethoxybenzyl)-4-(3,4-dimethoxyphenyl)-2-thioxo-3-pyrrolidinecarboxylate as white crystalline powder, melting at 166°-169°C.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S([O-])([O-])=O.[Na+].[Na+].[C:27](=O)(O)[O-].[Na+].IC>O>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([S:15]([CH3:27])(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)CCN(C(C)=O)CC2
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cc2c(cc1S(C)(=O)=O)CCN(C(C)=O)CC2
Temperature: 70 °C

Procedure:
3-Acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (18 g, 0.056 m) was added in portions to a mixture of sodium sulfite (8.8 g, 0.069 m) and sodium bicarbonate (10.8 g, 0.115 m) in water (36 ml) stirred at 70° C. There was a vigorous evolution of gas after each addition. The mixture was stirred for fifteen minutes, treated with iodomethane (8.5 ml, 0.136 m) and refluxed for forty-five minutes. The mixture was partitioned between methylene chloride and water. The methylene chloride phase was washed with water, dried with sodium sulfate and concentrated in vacuo to give 3-acetyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 159°-162° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH:12]=O)[C:3]1=[O:14].[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([CH3:28])([NH2:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([NH:27][CH2:12][C:4]2[C:3](=[O:14])[N:2]([CH3:1])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)([CH3:28])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC1(N)CCN(Cc2ccccc2)C1
Reactant: Cn1c(=O)c(C=O)cc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1c(=O)c(CNC2(C)CCN(Cc3ccccc3)C2)cc2ccccc21
Reaction time: 0.5 h

Procedure:
1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (956 mg, 5.11 mmol), 1-benzyl-3-methylpyrrolidin-3-amine (972 mg, 5.11 mmol), and acetic acid (0.877 ml, 15.32 mmol) were combined in CH2Cl2 (25 ml) and stirred for 30 min. Sodium triacetoxyborohydride (3248 mg, 15.32 mmol) was added and the reaction stirred for 2.5 hours before being partitioned between CH2Cl2 and satd. bicarb. The aqueous portion was extracted 3×CH2Cl2, and the organic portion dried (Na2SO4) then concentrated in vacuo. The resulting material was carried on crude.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH:9]=O)[C:5]([CH2:11][OH:12])=[CH:4][N:3]=1.[ClH:13].[C:14]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[ClH:13].[OH:8][C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[C:5]([CH2:11][OH:12])[C:6]=1[CH:9]=[CH:19][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ncc(CO)c(C=O)c1O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C=Cc1c(CO)cnc(C)c1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 23.8 %

Procedure:
To a suspension of 10.0 g of pyridoxal hydrochloride in 400 ml of ethanol, 17.2 g of (carbethoxymethylene)triphenylphosphorane is added under cooling in an ice-water bath, and the mixture is stirred at room temperature for 17 hours. The reaction mixture is concentrated to half in volume and cooled in an ice-water bath. The precipitate is collected and washed with a small amount of cold ethanol to give 3.2 g of ethyl 3-(3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridyl)acrylate hydrochloride.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[C:9]2[C:10]([CH3:25])=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[C:13]([CH3:14])[C:8]=2[O:7][CH:6]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[CH:11]=[C:10]([CH3:25])[C:9]2[C:5]([CH2:4][C:3]([OH:26])=[O:2])=[CH:6][O:7][C:8]=2[C:13]=1[CH3:14]
Reactant: COC(=O)Cc1coc2c(C)c(OCc3ccc(Cl)cc3Cl)cc(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(OCc2ccc(Cl)cc2Cl)cc(C)c2c(CC(=O)O)coc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a mixture of methyl(6-((2,4-dichlorobenzyl)oxy)-4,7-dimethyl-1-benzofuran-3-yl)acetate (147 mg), MeOH (2.0 mL) and THF (dry) (2.0 mL) was added 1N NaOH (1.12 mL) at room temperature. The mixture was stirred at room temperature for 2 h, and then concentrated in vacuo. The residue was neutralized with 1N HCl, and the mixture was extracted with EtOAc. The organic layer was washed with brine and, dried over MgSO4, and concentrated in vacuo. The precipitate was collected by filtration, and crystallized from EtOAc-hexane to give the title compound (118 mg).
Reaction SMILES: C[C:2]1[CH:11]=[C:10]([CH2:12][N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:28]([OH:30])=[O:29].[OH-].[Na+]>C1COCC1.CO>[C:21]([N:13]([CH2:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:28]([OH:30])=[O:29])=[CH:2][CH:11]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: Cc1cc(CN(Cc2ccccn2)C(=O)OC(C)(C)C)c2ccccc2c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
The compound obtained in Example 43-1 (1.60 g) was dissolved in THF (16 ml) and methanol (16 ml). After the addition of 1 mol/l aqueous solution of sodium hydroxide (16 ml), the mixture was stirred for 16 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was dissolved in distilled water and 1 mol/l aqueous solution of hydrochloric acid was added to produce a precipitate. The precipitate was collected by filtration and dried to obtain the title compound (1.3537 g) as a white solid.
Reaction SMILES: [CH2:1]1[O:17][C:4]2([C:12]3[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[C:10](Br)[CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[SH:26].[OH-].[K+]>N1C=CC=CC=1.O>[CH2:1]1[O:17][C:4]2([C:12]3[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[C:10]([S:26][C:20]4[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=4[F:18])[CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc2c(cc1Br)C1(CC2)OCCO1
Reactant: Fc1ccc(S)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1cc2c(cc1Sc1ccc(F)cc1F)C1(CC2)OCCO1
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a mixture of 5-nitro-6-bromo-1-indanone ethylene ketal (600 mg, 2.0 mmol) and 2,4-difluorothiophenol (F. Klages and K. Bott Chem. Ber. 97,735 (1964)) (440 mg, 3.0 mmol) in pyridine (4.0 mL) was added a solution of 8M aqueous potassium hydroxide (375 μL, 3.0 mmol) at room temperature. The mixture was stirred for 2 h, diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed successively with 1M aqueous NaOH (2x),0.5M aqueous HCl (1x), brine, dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography over silica gel and eluted with toluene: ethyl acetate (10:1) afforded the title compound (590 mg, 81%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14]CC)=O)=[CH:6]2.[H-].[Na+].[CH2:19]([O:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH3:20]>C1(C)C=CC=CC=1>[O:14]=[C:12]1[C:7]2=[CH:6][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=3[N:8]2[CH2:24][CH:23]1[C:22]([O:21][CH2:19][CH3:20])=[O:25]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1Cn2c(cc3cc(OC)ccc32)C1=O

Procedure:
A stirred solution of ethyl 5-methoxy-indole-2-carboxylate (30 g, 137 mmol) in 1.5 L of toluene under N2 was treated with sodium hydride (6.7 g of 60% in oil, 167 mmol) and ethylacrylate (16.3 ml, 150 mmol). The mixture was heated to reflux. After 3 hours (hr), additional ethyl acrylate (3 ml) and sodium hydride (3.3 g) were added. After a total of 8 hr, the starting material was consumed completely and the mixture was quenched with ethanol and treated with water and dilute HCl and methylene chloride. The organic layer was washed with brine, dried and concentrated to give 2,3-dihydro-1-oxo-7-methoxy-2-ethoxycarbonyl-1H-pyrrolo[1,2-a]indole, which was used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[C@H:35]1[CH2:40][CH2:39][C@H:38]([CH2:41][CH3:42])[CH2:37][CH2:36]1)(=O)=O>C(O)(C)(C)C.CC(=O)CC>[CH2:41]([C@@H:38]1[CH2:39][CH2:40][C@H:35]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:6]=[CH:5]3)[CH2:36][CH2:37]1)[CH3:42]
Reactant: CC[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: CC(C)(C)O
Product: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@@H](CC)CC4)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 1-((6-hydroxynaphthalen-2-yl)methyl)piperidine-4-carboxylate (2.43 g, 8 mmol, 1.0 eq) in the co-solvent t-butanol/2-butanone (40 mL/20 mL) was added cesium carbonate (5.0 g, 16 mmol, 2.0 eq). The mixture was stirred at 80° C. for 10 min and then trans-4-ethylcyclohexyl methanesulfonate (3.2 g, 16 mmol, 2.0 eq) was introduced. The suspension was stirred at 80° C. under N2 for 15 h. Then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (EtOAc/PE=1:5) to give ethyl 1-((6-(cis-4-ethylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylate as a slight yellow solid (1.6 g, yield: 46%). ESI-MS (M+H)+: 424.3. 1H NMR (400 MHz, CD3OD) δ: 7.63-7.56 (m, 3H), 7.30 (dd, J=8.4, 1.6 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 7.03 (dd, J=8.8, 2.4 Hz, 1H), 4.68-4.66 (m, 1H), 4.01 (q, J=7.2 Hz, 2H), 3.66 (s, 2H), 2.85-2.80 (m, 2H), 2.25-2.22 (m, 1H), 2.11-2.08 (m, 2H), 1.96-1.92 (m, 2H), 1.81-1.77 (m, 2H), 1.65-1.45 (m, 6H), 1.33-1.30 (m, 2H), 1.22-1.12 (m, 3H), 1.13 (t, J=7.2 Hz, 3H), 0.82 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][S:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)#[N:2].C[Si]([N:19]=[N+:20]=[N-:21])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:19]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([CH2:7][S:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=2)=[N:2][N:21]=[N:20]1
Reactant: N#Cc1ccc(CSCC(=O)O)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(O)CSCc1ccc(-c2nnn[nH]2)cc1
Reaction time: 6 h

Procedure:
(4-Cyanobenzylthio)acetic acid (from Example 3; 207 mg, 1 mmol) was added to a stirred solution of trimethylsilylazide (400 μL, 3 mmol) and dibutyltin oxide (25 mg, 100 μmol) in toluene (0.5 mL) at 110° C. After 6 hours, the reaction was quenched with MeOH (1 mL) and evaporated. The residue was purified by flash chromatography (silica gel; 1000:100:3 to 1000:100:13 CHCl3 /MeOH/HOAc) to give the title compound. Rf (silica; 1000:100:6 CHCl3 /MeOH/HOAc)=0.2 compared to the nitrile starting material of Rf =0.67. 1H NMR (d6DMSO); δ3.15 (s, 2H), 3.88 (s, 2H), 7.51 (d, 2H, J=8.1 Hz), 7.99 (d, 2H, J=8.1 Hz). FAB mass spectrum m/z=251 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])O.[Na+]>C1COCC1>[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:32][CH2:31]1
Reactant: OC1CCNCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCC(O)CC4)cc2)CC3)cc1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
In THF (10 ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (300 mg), and to the mixture was added 4-hydroxypiperidine (235 mg). The mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N-[4-(4-hydroxypiperidinomethyl)phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 49) (271 mg) as colorless crystals.