Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1)=[O:4].[CH3:14][NH:15][CH3:16].[OH-].[Na+]>O1CCOCC1>[CH3:14][N:15]([CH3:16])[C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:4])=[CH:6][CH:7]=1)=[O:12]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
A solution of 5 g (25.2 mmol) of methyl 4-chlorocarbonyl benzoate in 20 ml of dioxane was added to 30 ml of 50% aqueous dimethylamine solution under cooling with ice. After stirring for 30 minutes, 50 ml of 1 N aqueous sodium hydroxide solution was added to the resultant mixture, and they were stirred at room temperature for 2 days. The reaction liquid was washed with ethyl acetate and made acidic with hydrochloric acid. After the extraction with ethyl acetate, the extract was washed with saturated Aqueous NaCl solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was washed with hexane and dried to obtain the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[NH2:6].I[CH3:15]>O1CCCC1>[Cl:3][C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[NH:6][CH3:15]
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 33.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 1.2 g, 30 mmol) in tetrahydrofuran (100 ml), cooled in an ice bath, was added slowly a solution of 2-chloro-5-nitroaniline (5 g, 29 mmol) in tetrahydrofuran (10 ml) followed by a solution of iodomethane (1.8 ml, 29 mmol) in tetrahydrofuran (10 ml). After stirring at room temperature for 20 hours, the mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (100 ml) and water (100 ml). The organic layer was washed with saturated aqueous sodium chloride solution (50 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane-hexane (1:3) and recrystalized (ethyl ether) to provide (2-chloro-5-nitro-phenyl)-methyl-amine (1.8 g, 33% yield) as orange crystals.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([C:20]1[NH:21][C:22]([CH2:27][OH:28])=[C:23](CO)[N:24]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(O)C>[CH2:9]([C:20]1[NH:21][C:22]([CH2:27][OH:28])=[C:23]([Cl:1])[N:24]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCCCCCCCCc1nc(CO)c(CO)[nH]1
Solvent: CCO
Product: CCCCCCCCCCCc1nc(Cl)c(CO)[nH]1
Reaction time: 2 h

Procedure:
1.10 Grams (8.3 mmol) of the N-chlorosuccinimide was added little by little to a solution consisting of 2.15 g (7.6 mmol) of a 2-undecyl-4,5-bis(hydroxymethyl) imidazole and 200 ml of ethanol at a temperature of 40° to 45° C. over a period of about 23 minutes. The mixture was stirred at the same temperature for two hours to effect the reaction and, then, ethanol was distilled off under reduced pressure. The resulting reaction product was washed with water and was then recrystallized from acetone to obtain a creamy-white fine crystalline 2-undecyl-4-chloro-5-(hydroxymethyl) imidazole in an amount of 1.16 g (yield, 53.1%). By using acetonitrile, furthermore, the recrystallization was effected twice to obtain a colorless crystalline product in pure form. The TLC and spectra of this compound were the same as the properties exhibited the above-mentioned 2-undecyl-4-chloro-5-(hydroxymethyl) imidazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([CH2:12][CH2:13][C:14]([OH:16])=O)[O:9][N:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:14](=[O:16])[CH2:13][CH2:12][C:10]2[O:9][N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:11]=2)[CH2:38][CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)CCc1nc(-c2ccccn2)no1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(CCc1nc(-c2ccccn2)no1)NC1CCN(Cc2ccccc2)CC1
Reaction time: 0.25 h

Procedure:
To a solution of 3-(3-Pyridin-2-yl-[1,2,4]oxadiazol-5-yl)-propionic acid (1 g) in tetrahydrofuran (5 ml), was added carbonyldiimidazole (0.74 g). The mixture was stirred for 10 minutes before addition of 1-benzyl-piperidin-4-ylamine (1 ml) in tetrahydrofuran (5 ml). The reaction mixture was stirred for 15 minutes then partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated, dried (MgSO4) and solvent removed by evaporation. Purification by Biotage® 40S eluting 3%MeOH/0.5% 880 ammonia/dichloromethane gave the title compound (0.93 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5](=O)[CH2:6][CH:7]([P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])[P:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH3:3].B.CSC.Cl>C1COCC1>[CH2:19]([O:18][P:16]([CH:7]([P:8]([O:10][CH2:11][CH3:12])(=[O:9])[O:13][CH2:14][CH3:15])[CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:25][CH2:26][CH3:27])(=[O:17])[O:21][CH2:22][CH3:23])[CH3:20]
Reactant: CCCN(CCC)C(=O)CC(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CCCN(CCC)CCC(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58.9 %

Procedure:
A solution of N,N-dipropyl-3,3-bis(diethoxyphosphinyl)propionamide (1.25 g, 2.9 mmol) in THF (7.1 ml) was cooled to 0° C., and borane-methylsulfide (0.71 ml, 7.1 mmol) was added via syringe. The reaction was stirred at 0° C. for 20 minutes, then warmed at 65 C. for 3 hours. The reaction mixture was cooled to 0° C. and 6N HCl (6 ml) was added carefully. The solvent was removed m vacuo, and the residue was treated with methanol (5 ml) and concentrated. The residue was dissolved in water (10 ml) and extracted with Et2O (3×10 ml). The aqueous layer was made basic to phenolphthalein with solid KOH and saturated with NaCl. The product was extracted into dichloromethane (5×20 ml), dried (Na2SO4) and concentrated to give the title compound (0.71 g, 60%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH3:25]O>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([O:16][CH3:25])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CO
Reactant: CN1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(S(=O)(=O)N2CCN(C)CC2)c1

Procedure:
3-((4-methylpiperazin-1-yl)sulfonyl)benzoic acid (250 mg, 0.879 mmol) was refluxed in the presence of concentrated sulfuric acid (5.68 mg, 0.044 mmol) in methanol at 70° C. for overnight. Reaction was monitored by TLC. After completion of the reaction, solvent was removed by vacuum and the crude material was used for further reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][S:9]1(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][C@@H:29]1[O:31][CH2:30]1>CC(C)=O.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]([CH2:27][CH2:28][C@H:29]2[CH2:30][O:31]2)[S:9]1(=[O:19])=[O:18]
Reactant: BrCC[C@H]1CO1
Reactant: O=S1(=O)NCc2ccccc2N1c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=S1(=O)N(CC[C@H]2CO2)Cc2ccccc2N1c1ccccc1F
Temperature: 40 °C
Reaction time: 14 h
Yield: 87.7 %

Procedure:
A solution of 1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.20 g, 0.72 mmol) in acetone (3 mL) was treated with potassium carbonate (0.11 g, 0.81 mmol), (S)-(−)-4-Bromo-1,2-epoxybutane (0.15 mL, 1.46 mmol) and was heated to 40° C. for two h then at room temperature for 14 h. The reaction mixture was diluted with ethyl ether (40 mL) and washed with 2 N sodium hydroxide (2×20 mL), the organic layer was isolated, dried with MgSO4 and evaporated. The crude reaction product was purified by flash chromatography (SiO2, 3-50% ethyl acetate/heptane) to provided 1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.22 g, 86%) as a white solid.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[N:7][N:8]([CH2:10][CH2:11][NH2:12])[CH:9]=1)([O-:4])=[O:3].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>O1CCCC1>[N+:2]([C:5]1[CH:6]=[N:7][N:8]([CH2:10][CH2:11][NH:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH:9]=1)([O-:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1cc([N+](=O)[O-])cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)NCCn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-nitro-1H-pyrazol-1-yl)ethanamine hydrochloride (1.0 g) obtained in Step B of Example 348 in tetrahydrofuran (30 mL) were added triethylamine (2.2 mL) and methanesulfonyl chloride (0.60 mL) in an ice bath, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized (hexane/ethyl acetate) to give the title compound (880 mg).
Reaction SMILES: FC(F)(F)C(O)=O.O.[CH2:9]([O:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([O:31][CH2:32][C@H:33]3[CH2:36][CH2:35][N:34]3C(OC(C)(C)C)=O)[CH:30]=2)[CH2:21][CH2:20]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[NH:34]1[CH2:35][CH2:36][C@@H:33]1[CH2:32][O:31][C:29]1[CH:28]=[N:27][CH:26]=[C:25]([N:22]2[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17][O:16][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:24][CH2:23]2)[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1COc1cncc(N2CCC(CCOCc3ccccc3)CC2)c1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COCCC2CCN(c3cncc(OC[C@H]4CCN4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
Trifluoroacetic acid (1.5 mL) and water (0.15 mL) were added to CH2Cl2 (7.5 mL). This mixture was added to 3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[[1-(tert-butoxycarbonyl)-2(R)-azetidinyl]methoxy]pyridine (260 mg, 0.54 mmol) in a 25 mL round-bottom flask with a magnetic stirrer under N2. After stirring overnight at room temperature, TLC analysis of the crude reaction mixture indicated that the starting material had disappeared. The mixture was concentrated, and the residue was purified by preparative HPLC (column: SunFire Prep C18, 150×19 mm, 5 μm particle size; UV detection at 270 nm; mobile phase: A, water with 0.05% CF3COOH; B, methanol; 40-50% B in A in 6 min, up to 100% in 1 min, back to 40% in 1 min). The eluate was partially evaporated under reduced pressure (bath 30° C.) to remove CH3OH. The residue was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine and dried. After concentrated in vacuo, the free base (130 mg, 63%) was obtained as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 7.97 (s, 1H), 7.79 (s, 1H), 7.38-7.28 (m, 5H), 6.78 (s, 1H), 4.53 (s, 2H), 4.43-4.41 (m, 1H), 4.15-4.09 (m, 2H), 3.85-3.82 (m, 1H), 3.70-3.66 (m, 2H), 3.58-3.50 (m, 2H), 2.79-2.71 (dd, 2H, J=7.2 Hz, 2.1 Hz), 2.47-2.39 (m, 2H), 1.82-1.78 (d, 2H, J=1.2 Hz), 1.64-1.58 (m, 3H), 1.40-1.27 (m, 3H). LC-MS (ESI) m/z 382 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[O:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27]>C1COCC1.CCOC(C)=O>[CH3:13][C:12]([Si:9]([CH3:11])([CH3:10])[O:8][C:4]1[CH:3]=[C:2]([C:25](=[O:26])[CH2:24][CH2:23][C:22]([OH:27])=[O:21])[CH:7]=[CH:6][CH:5]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Reactant: O=C1CCC(=O)O1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)CCC(=O)O)c1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
Under argon, to a solution of [(3-bromophenyl)oxy](1,1-dimethylethyl)-dimethylsilane (1.5 g, 5.22 mmol) in THF (60 mL) at −78° C., was added dropwise n-BuLi (3.6 mL, 1.6 M in hexanes), 20 min after the addition, this solution was added to a solution of dihydro-2,5-furandione (630 mg, 6.26 mmol) in THF (10 mL) under argon at −78° C. 15 min later, the reaction mixture was slowly warmed to rt overnight. The reaction mixture was diluted with EtOAc (50 mL), then extracted with NaOH (20 ml, 1.0 N). Aquaous layer was acidified with HCl (1.0N) until pH=2, then extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a colorless crystal (546 mg, 54%). MS (ES+) m/e 195 [M+H]+.
Reaction SMILES: CC([O:4][C@@H:5]([CH2:10][N+:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][C:7]([O-:9])=[O:8])=O.[As:15](=[O:19])([OH:18])([OH:17])[OH:16].[CH2:20]([OH:22])[CH3:21]>>[As:15](=[O:16])([OH:19])([OH:18])[OH:17].[C:20]([C@@:5]([CH2:6][C:7](=[O:8])[O-:9])([CH2:10][N+:11]([CH3:12])([CH3:13])[CH3:14])[OH:4])(=[O:22])[CH3:21]
Reactant: CCO
Reactant: CC(=O)O[C@H](CC(=O)[O-])C[N+](C)(C)C
Agent: O=[As](O)(O)O
Product: CC(=O)[C@@](O)(CC(=O)[O-])C[N+](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Acetyl L-carnitine (35.3 g) was weighted and put in a flask (250 ml), into which 80 ml ethanol was added. The mixture was heated to dissolve completely. An ethanol solution containing 31.0 g arsenic acid was slowly and dropwise added into the solution of acetyl L-carnitine, continued to stir for a further 1 h after the addition, cooled to room temperature, and white crystals were precipitated. After grinding, 64.4 g of white powder was obtained. Yield: 97.1%. Melting temperature: 150.6° C.-152.1° C. 1H-NMR (DMSO, 500 MHz), δ 2.28 (m, 2H), 3.16 (m, 9H), 3.35 (m, 2H), 4.36 (m, 1H), 9.51 (s, 3H); IR: 3423 cm−1, 2975 cm−1, 2399 cm−1, 1723 cm−1, 1477 cm−1, 1302 cm−1, 1191 cm−1, 1106 cm−1, 879 cm−1, 769 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:24])[C:12]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:24])[C:12]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:56][CH:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)=[O:21])=[CH:17][N:16]=1
Reactant: Cn1nnc(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccc2F)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of 6-((4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (98 mg, 0.3 mmol) and TBTU (105 mg, 0.33 mmol) in DMF (1 mL) was added DIPEA (261 μL, 1.49 mmol). Then 4-aminotetrahydropyran (34 μL, 0.33 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (108 mg, 88%) as a white solid after recrystallisation from ethyl acetate/heptane. MS: m/e=412.3 [M+H]+.
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[Cl:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33]>>[CH3:36][O:35][C:31](=[O:34])[CH2:32][CH2:33][N:21]1[C:22]2[C:17](=[CH:16][CH:15]=[C:14]([Cl:13])[CH:23]=2)[CH:18]=[C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:24]
Reactant: O=c1[nH]c2cc(Cl)ccc2cc1-c1ccccc1
Reactant: C=CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: COC(=O)CCn1c(=O)c(-c2ccccc2)cc2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
1 ml of benzyltrimethylammonium hydroxide is added to a suspension of 8 g of 7-chloro-1,2-dihydro-2-oxo-3-phenylquinoline in 21.3 ml of methyl acrylate at 40° to 50° C., under nitrogen, the mixture is stirred at this temperature for 31/2 hours and the excess methyl acrylate is then distilled off in vacuo. The solid residue is dissolved in 100 ml of methylene chloride and the solution is washed with 2 N acetic acid, sodium bicarbonate solution and water. After drying the organic phase over sodium sulphate and distilling off the solvent, the residue is recrystallised from cyclohexane. 8.0 g of the title compound of m. 122°-124° C. are obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:23](=[O:24])[C:22]4[C:21]5[C:16](=[CH:17][C:18]([C:25]#[N:26])=[CH:19][CH:20]=5)[NH:15][C:14]=4[C:13]([CH3:28])([CH3:27])[C:12]=3[CH:29]=2)[CH2:4][CH2:3]1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+].COC1CCCC1>C(Cl)Cl.CN(C=O)C>[CH3:27][C:13]1([CH3:28])[C:14]2[NH:15][C:16]3[C:21](=[CH:20][CH:19]=[C:18]([C:25]#[N:26])[CH:17]=3)[C:22]=2[C:23](=[O:24])[C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]3)=[CH:29][C:12]1=2
Reactant: CC1(C)c2cc(N3CCC(O)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: COC1CCCC1
Product: CC1(C)c2cc(N3CCC(=O)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8-(4-Hydroxy-piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound B2-7-1, 210 mg, 0.545 mmol), was dissolved in the DCM (2 mL) and DMF (0.6 mL) mixture solvent, added with 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (300 mg, 1.3 eq.), and the mixture was stirred at room temperature for 2 hr. To the reaction solution, 0.25 mol/L aqueous solution of sodium thiosulfate, saturated sodium bicarbonate solution and CPME were added followed by further stirring at room temperature for 1 hr. The reaction solution was filtered and the filtrate was subjected to liquid separation. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the target compound (yellowish white powder, 109 mg, 52%).
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[CH2:15]([Mg]Br)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:15]([CH:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)CC2
Reactant: Br[Mg]CCc1ccccc1
Product: CCOC(=O)c1cc2c([nH]1)C(CCc1ccccc1)CC2

Procedure:
The title compound was synthesized from ethyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.3 g, 1.55 mmol) and phenethylmagnesium bromide (7.5 mL, 0.5 M in THF, 3.7 mmol) according to General Procedure 3 to afford 96.5 mg of (E/Z)-ethyl 6-(2-phenylethylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by General Procedure 6 to give 87.3 mg of ethyl 6-phenethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate in 90% purity. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.55 (br. s., 1H), 7.29-7.35 (m, 2H), 7.19-7.26 (m, 3H), 6.64 (d, J=1.59 Hz, 1H), 4.23-4.33 (m, 2H), 3.02-3.13 (m, 1H), 2.51-2.82 (m, 5H), 1.94-2.14 (m, 2H), 1.78-1.90 (m, 1H), 1.34 (t, J=7.13 Hz, 3H).
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:13]O>>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([O:5][CH3:13])=[O:4]
Reactant: O=C(O)C(Br)c1ccc(F)cc1
Reactant: CO
Product: COC(=O)C(Br)c1ccc(F)cc1
Yield: 87 %

Procedure:
The α-bromo-4-fluorophenylacetic acid from Part 1 was dissolved in methanol (100 ml) and was added Dowex-50X-400® (2.7 g) to the solution. The mixture was refluxed for 6 hours and the resin was removed by filtering through Celite® after cooling. The filtrate was evaporated to give an oily residue, which was purified by column chromatography on silica gel with elution by 1:9 ethyl acetate-hexane to afford methyl α-bromo-4-fluorophenylacetate (87% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][C:5]([F:18])=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:26][NH2:27]>C(O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:27][NH:26][C:13](=[O:14])[C:6]=2[C:5]([F:18])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NN
Reactant: CCOC(=O)c1c(F)nc(-c2ccccc2)c(N)c1C(=O)OCC
Solvent: O
Solvent: CCO
Product: Nc1c(-c2ccccc2)nc(F)c2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 1 ml of ethanol was dissolved 90 mg of 3-amino-6-fluoro-4,5-diethoxycarbonyl-2-phenylpyridine, followed by addition of 2 ml of hydrazine monohydrate. The mixture was stirred at room temperature for 4 hours. After the solvent was distilled off, the resulting crystals were collected by filtration with ethanol. Water was added to the crystals, and the mixture was neutralized with 1N hydrochloric acid, followed by collection by filtration. A methanol solution of the crystals was mixed with silica gel and purified by silica gel column chromatography (eluent:ethyl acetate→ethyl acetate/methanol 1:1), followed by collection by filtration with water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:16]=[CH:17][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([CH3:13])[CH3:12].ClS([N:30]=[C:31]=O)(=O)=O.CN(C=O)C>C(OCC)(=O)C>[C:31]([C:16]1[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([F:1])[CH:3]=2)[NH:9][C:8](=[O:11])[C:7]3([CH3:13])[CH3:12])=[CH:18][CH:17]=1)#[N:30]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cc(F)c2c(c1)C(C)(C)C(=O)N2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1cc(F)c2c(c1)C(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
To a stirred solution of tert-butyl 2-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrole-1-carboxylate (1.0 g, 2.9 mmol) was added chlorosulfonylisocyanate (0.28 mL, 3.2 mmol). The mixture was stirred at 25° C. for 2 h then DMF (0.21 mL, 2.9 mmol) was added and the mixture was stirred for an additional 1 h. The mixture was diluted with ethyl acetate and washed with NaHCO3, water, saturated aqueous NaCl, dried over MgSO4, and concentrated. Flash chromatography (2% MeOH/CH2Cl2) afforded 0.23 g (21%) of the title compound as a white solid.