Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=1)([O-])=O>CO.[Pd]>[F:17][C:15]([F:16])([F:18])[C:11]1[CH:10]=[C:9]([N:6]2[CH:7]=[N:8][C:4]([NH2:1])=[N:5]2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ncn(-c2cccc(C(F)(F)F)c2)n1
Agent: [Pd]
Solvent: CO
Product: Nc1ncn(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.7 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 3-nitro-1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (1 g, 3.88 mmol, 1.00 equiv) in methanol (20 mL). The mixture was treated with Pd/C (1 g) and stirred under an atmosphere of hydrogen for 3 h at 25° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 900 mg of crude product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[NH3:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: N
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Product: NS(=O)(=O)c1ccc(Br)c(F)c1
Reaction time: 16 h

Procedure:
According to general procedure A, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and ammonia (20 mL, ca. 7N in methanol) were stirred together for 16 hours. 4-bromo-3-fluorobenzenesulfonamide was provided after purification (0.23 g, 61%). HRMS: calcd for C6H5BrFNO2S, 252.92084; found (EI, M+), 252.9201. HPLC purity 100.0% at 210-370 nm, 7.5 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]3[O:20][C:19]([C:21]([O:23]C)=[O:22])=[CH:18][CH:17]=3)[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:11]([CH3:36])=[C:10]2[C:37]([C:39]2[O:40][CH:41]=[CH:42][CH:43]=2)=[O:38])=[CH:5][CH:4]=1)#[N:2].[OH-].[Li+].Cl.CO>O1CCCC1.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]3[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=3)[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:11]([CH3:36])=[C:10]2[C:37]([C:39]2[O:40][CH:41]=[CH:42][CH:43]=2)=[O:38])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)c3ccco3)C2c2ccc(C#N)cc2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(Cc2ccc(C(=O)O)o2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl 5-{[6-(4-cyanophenyl)-5-(2-furoyl)-4-methyl-2-oxo-3-[3-(trifluoro-methyl)-phenyl]-3,6-dihydropyrimidin-1(2H)-yl]methyl}-2-furoate (Example 51) (30 mg, 0.51 mmol) in tetrahydrofuran (1.5 ml) is added a solution of lithium hydroxide (2.4 mg, 0.10 mmol) in water (1.5 ml). The reaction is stirred at room temperature overnight (16 h), then acidified with 1 N hydrochloric acid. A precipitate is obtained. Methanol (7 ml) is added, and the crude product is purified by preparative HPLC(RP18 column; eluent: acetonitrile/0.1% aq. formic acid 30:70→90:10).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.N1C2C(=CC=CC=2)C=C1.C[O-].[Na+]>CO>[Cl:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: O=C1CCCCC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1Cl
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc2[nH]ccc2c1
Solvent: CO
Product: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1Cl
Yield: 88.1 %

Procedure:
To a one liter round bottom flask equipped with a reflux condenser was added 26.3 grams (0.135 mol) of 7-chloro-1H-indole-6-carboxylic acid and 200 mL of dry methanol. Three equivalents (41.8 mL, 0.404 mol) of cyclohexanone was added in one portion. The heterogeneous mixture was heated to 60° C. at which point all of the indole went into solution. 6.1 equivalents of a methanolic sodium methoxide solution (0.820 mol, 187 mL) was then added in two portions. The solution was heated at reflux overnight. In the morning, the reaction mixture was cooled and evaporated to dryness. The crude mixture was diluted with 75 mL of ethyl acetate and acidified with 1M HCl. The resulting solid was filtered, washed with cold ethyl acetate and dried overnight in a vacuum desiccator to yield 32.8 grams (88%) of a powder. 1H NMR (300 MHz, CD3OD) δ 7.73 (d, J=8.42 Hz, 1H), 7.61 (d, J=8.42 Hz, 1H), 7.37 (s, 1H), 6.16 (br s, 1H), 2.42 (m, 2H), 2.24 (m, 2H), 1.79 (m, 2H), 1.68 (m, 2H), MS m/z 276.01 (M+H).
Reaction SMILES: FC1[C:7]([OH:8])=C(F)C(F)=C(F)C=1F.C(N=C=NCCCN(C)C)C.C(O)=O.[N:27]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:31][NH:30][CH:29]([C:33]([O:35][CH3:36])=[O:34])[CH2:28]1.C(N(CC)CC)C.Cl>CCOCC.C(Cl)Cl>[CH:7]([N:30]1[CH2:31][CH2:32][N:27]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:28][CH:29]1[C:33]([O:35][CH3:36])=[O:34])=[O:8]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of pentafluorophenol in 520 mL of anhydrous ether at 0° C. there are added in succession 49 g of 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (286 mmol) in portions and 12 mL of formic acid (312 mmol). The whole is stirred at ambient temperature for 2 hours. There is subsequently added a mixture of 32 g of 1-tert-butyl 3-methyl 1,3-piperazinedicarboxylate (130 mmol) and 18 mL of triethylamine (130 mmol) in solution in 520 mL of CH2Cl2. The whole is stirred overnight at ambient temperature. The reaction mixture is hydrolysed with an 1N aqueous HCl solution and extracted with CH2Cl2. The organic phases are subsequently combined and then washed with a saturated aqueous NaHCO3 solution and then with a saturated aqueous NaCl solution until neutral. After drying over MgSO4, filtration and concentration to dryness, the product is isolated by chromatography over silica gel (petroleum ether/AcOEt gradient: 0-30%). The title product is obtained in the form of an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][SH:4].[H-].[Na+].[CH2:7]([CH:10]1[C:14](O)([CH3:15])[CH:13]=[CH:12][C:11]1=[O:17])[CH:8]=[CH2:9]>O1CCCC1>[CH2:7]([C:10]1[C:11](=[O:17])[CH2:12][CH:13]([S:4][CH2:3][CH2:2][OH:1])[C:14]=1[CH3:15])[CH:8]=[CH2:9]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: OCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1=C(C)C(SCCO)CC1=O
Reaction time: 1 h
Yield: 96.2 %

Procedure:
Into the same flask as used in Example 1, 2-hydroxyethylmercaptan (35 g) and tetrahydrofuran (10 g) were charged, and sodium hydride (0.6 g) was added thereto at a temperature of 10° to 20° C. At the same temperature, the reaction mixture was stirred for 1 hour. Thereafter, 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g) was dropwise added thereto at a temperature of 15° to 30° C. for 1 hour, followed by stirring at the same temperature for 2 hours and at a temperature of 40° to 70° C. for 3 hours. After completion of the reaction, the mixture was treated in the same manner as in Example 1 to obtain 2-allyl-3-methyl-4-(2'-hydroxyethylthio)-2-cyclopentenone (20.4 g). Yield, 96 %. nD20 1.5243.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH:14]2[CH2:20][CH:19]3[N:21]([CH3:22])[CH:16]([CH2:17][CH2:18]3)[CH2:15]2)=[C:9]([Cl:23])[CH:8]=1)(=O)=O.[Cl-].[Li+].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)CCC.[OH-].[Na+]>CN1CCCC1=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:23][C:9]1[CH:8]=[C:7]([C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)[CH:12]=[CH:11][C:10]=1[S:13][CH:14]1[CH2:20][CH:19]2[N:21]([CH3:22])[CH:16]([CH2:17][CH2:18]2)[CH2:15]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: CN1C2CCC1CC(Sc1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CN1CCCC1=O
Product: CN1C2CCC1CC(Sc1ccc(-c3cccnc3)cc1Cl)C2
Temperature: 100 °C
Yield: 30.3 %

Procedure:
A mixture of 3-chloro-4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl trifluoromethanesulfonate (215 mg), lithium chloride (70 mg), triphenylarsine 32 mg) and tris(dibenzylideneacetone)-dipalladium (0) (20 mg) was stirred in N-methylpyrrolidinone (10 ml) under nitrogen for 5 minutes. To this was added 3-tributylstannylpyridine (200 mg) and the solution heated to 100° C. for 2 hours. The solution was cooled to room temperature and aqueous sodium hydroxide (10%) added to quench the reaction. The mixture was extracted three times with dichloromethane, the combined organics dried (MgSO4), filtered and evaporated to dryness. The material was purified on an SCX cartridge eluting sequentially with methanol and 2M ammonia in methanol, followed by preparative LC-MS yielding 3-{[2-chloro-4-(3-pyridinyl)phenyl]thio}-8-methyl-8-azabicylo[3.2.1]octane (54 mg)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH:3]1[C:15]([OH:17])=O.C([N:20](CC)CC)C.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[NH4+]>CN(C)C=O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH:3]1[C:15]([NH2:20])=[O:17]
Reactant: O=C(O)C1CN(Cc2ccccc2)CCC1O
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: NC(=O)C1CN(Cc2ccccc2)CCC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a solution of 4-hydroxy-1-(phenylmethyl)-3-piperidinecarboxylic acid (12 g) and triethylamine (3.53 mL, 25.5 mmol) in N,N-dimethylformamide (60 mL) was added 1-hydroxy-7-azabenzotriazole (3.48 g, 25.6 mmol) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (8.54 g, 56.2 mmol). After stirring for 5-10 min. ammonium bicarbonate (15.3 g, 204 mmol) was added. The reaction mixture was stirred at room temperature for overnight. The solvent was then removed under reduced pressure and the residue was dissolved in aqueous sodium bicarbonate and dichloromethane. The aqueous phase was extracted with 9:1 dichloromethane:methanol. The organic layer was dried and evaporated. The residue was chromatographed on silica gel, eluting with 10-20% methanol/dichloromethane, to give the desired compound (4.15 g, 35%). Impure fractions were chromatographed again to give further product (1.02 g).
Reaction SMILES: C(=O)[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1.C(O)C.[CH:14]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])OCC>[Cl-].[NH4+]>[CH2:22]([O:21][CH:14]([O:18][CH2:19][CH3:20])[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH3:23]
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1cccc(C=O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(OCC)c1cccc(C=O)c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
A mixture of isophthalaldehyde (21.44 g, 160 mmol), ammonium chloride (0.34 g, 6.38 mmol) in anhydrous ethanol (23.2 g, 480 mmol) was cooled to 0° C., then triethyl orthoformate was added drop-wise. After the addition, the mixture was warmed to 40° C. and stirred for two days. The mixture was filtered and the filtrate was concentrated to give crude product. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=200:1 to 100:1) to give 3-(diethoxymethyl)benzaldehyde (25.4 g, yield 76%) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.23-1.27 (m, 6H), 3.53-3.67 (m, 4H), 5.58 (s, 1H), 7.52-7.56 (t, J=7.6 Hz, 1H), 7.74-7.77 (dd, J1=7.6 Hz, J2=3.6 Hz, 1H), 8.00 (s, 1H), 10.04 (s, 1H); LC-MS (ESI) m/z: 209 (M+1)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]([CH2:23][C:24]([NH:26][C@@H:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][OH:29])=[O:25])[C:13](=[O:37])[CH:12]1[CH:38]([CH3:40])[CH3:39])(=[O:10])[CH3:9].O>CS(C)=O>[C:8]([N:11]1[CH:16]=[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:14]([CH2:23][C:24]([NH:26][C@@H:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[O:29])=[O:25])[C:13](=[O:37])[CH:12]1[CH:38]([CH3:40])[CH3:39])(=[O:10])[CH3:9]
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@H](CO)Cc2ccccc2)C(=O)C1C(C)C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@H](C=O)Cc2ccccc2)C(=O)C1C(C)C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
Triethylamine (2.60 ml) is added to a solution of (2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol (1.37 g, Compound No. 6-1) in dimethyl sulfoxide (16 ml). A sulfur trioxide-pyridine complex (1.7 g) is added to the mixture, and the whole is stirred overnight. Water is added to the reaction mixture, and the whole is stirred for one hour and extracted with ethyl acetate. The extract is washed with a saturated aqueous ammonium chloride solution, water and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (631 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:26]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:27])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a solution of (1RS,2RS)-2-amino-1,3-bis(4-fluorophenyl)-1-propanol (450 mg, 1.71 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (342 ml, 2.56 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred at room temperature for 3 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (553 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1(N)CCCCC1.C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2cccc(Cl)c2)cc1
Solvent: CO
Solvent: NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(O)CCC(O)c1ccc(-c2cccc(Cl)c2)cc1
Yield: 65 %

Procedure:
Prepared analogous to Example 25 from 4-(3'-chloro-4-biphenylyl)-4-oxo-butyric acid. Melting point of the cyclohexylamine salt: 160°-161° C. (from ethyl acetate by addition of methanol). Yield: 65% of theory.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH2:15][C:14](=[O:16])[N:13]3[C:9](=[N:10][C:11]4[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:12]=43)[CH2:8]2)=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC(C2CC(=O)N3C(=[N:37]C4C=CC(Cl)=CC=43)C2)=CC=1.N>O1CCOCC1.O>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:8][C:9]2[NH:10][C:11]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:12]=3[N:13]=2)[CH2:15][C:14]([NH2:37])=[O:16])=[CH:3][CH:2]=1
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)Cc2nc3ccc(Cl)cc3n21
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)Cc2nc3cc(Cl)ccc3n21
Agent: N
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)CC(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(-c2ccccc2)cc1

Procedure:
The 1:1-mixture of 3-(biphenyl-4-yl)-7-chloro-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one and 3-(biphenyl-4-yl)-8-chloro-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one (200 mg) was dissolved in 1,4-dioxane (3 ml) at reflux temperature. A 25% solution of ammonia in water (1 ml) was added to give a light red solution. Refluxing was continued for 2 h while addition of 25% ammonia solution in 1 ml portions was repeated every half an hour (3 times). Then all volatiles were removed at the water aspirator and the residue was triturated with acetone to leave 3-(biphenyl-4-yl)-4-(5-chloro-2-benzimidazolyl)butyramide (165 mg) as light yellowish solid.
Reaction SMILES: BrCCBr.[Mg].[CH2:6]1[O:14][CH:9]([CH:10]([CH3:13])[CH2:11]Br)[O:8][CH2:7]1.CON(C)[C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:6]1[O:14][CH:9]([CH:10]([CH3:13])[CH2:11][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=2)[O:8][CH2:7]1
Reactant: CC(CBr)C1OCCO1
Reactant: CON(C)C(=O)c1ccc(C)c(C)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Cc1ccc(C(=O)CC(C)C2OCCO2)cc1C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
0.29 ml (3.4 mmol) of 1,2-dibromoethane was added to a suspension of 1.66 g (68.1 mmol) of magnesium in 5 ml of anhydrous tetrahydrofuran under a stream of nitrogen. 9.96 g (51.1 mmol) of 3-bromo-2-methylpropionaldehyde ethylene acetal [prepared as described in step (i) above] were then added dropwise to the resulting mixture, whilst ice-cooling, after which the mixture was stirred for 1 hour. A solution of 6.58 g (34.1 mmol) of N-methoxy-N-methyl-3,4-dimethylbenzamide in 30 ml of tetrahydrofuran was then added dropwise to the mixture, and the resulting mixture was stirred, whilst ice-cooling for 1 hour. A saturated aqueous solution of ammonium chloride was then added to the mixture, and the resulting mixture was extracted twice with ethyl acetate. The organic extracts were combined and washed with a saturated aqueous solution of sodium chloride, after which they were dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 6:1 by volume mixture of hexane and ethyl acetate, to give 3.26 g (yield 39%) of the title compound as a colorless oily substance.
Reaction SMILES: C([O:4][C:5]1[C:6]([O:24][CH3:25])=[CH:7][C:8]2[NH:9][C:10]3[C:15]([S:16](=[O:21])(=[O:20])[C:17]=2[C:18]=1[Br:19])=[CH:14][C:13]([O:22][CH3:23])=[CH:12][CH:11]=3)(=O)C.[OH-].[Na+].C(O)(=O)C>CO>[Br:19][C:18]1[C:17]2[S:16](=[O:20])(=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH3:23])[CH:14]=3)[NH:9][C:8]=2[CH:7]=[C:6]([O:24][CH3:25])[C:5]=1[OH:4]
Reactant: COc1ccc2c(c1)S(=O)(=O)c1c(cc(OC)c(OC(C)=O)c1Br)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2c(c1)S(=O)(=O)c1c(cc(OC)c(O)c1Br)N2
Reaction time: 0.33 h

Procedure:
To a suspension of 3-acetoxy-4-bromo-2,7-dimethoxy-10H-phenothiazine-5,5-dioxide (10.0 g) in methanol (105 ml) was added a solution of 2N aqueous sodium hydroxide (74 ml) under a nitrogen atmosphere. After 20 minutes, the mixture was acidified with 10% v/v aqueous acetic acid (250 ml), causing a large amount of compound to precipitate. The mixture was then diluted with water (105 ml) and the solid filtered, washed with water and ether and dried in a dessicator to afford quantitatively the title compound, m.p. 252°-260° C. (dec).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[O-][CH2:19]C.[K+].C1(C)C=CC(S(OC)(=O)=O)=CC=1.[Cl-].[Na+].[BH4-].[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:19][O:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C1CCCc2ccccc2C1=O
Reactant: CC[O-]
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [BH4-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(OC)c2ccccc2CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
A mixture of ethyl 6,7,8,9-tetrahydro-5-oxo-5H-benzocycloheptene-6-carboxylate (12.0 g, 51.7 mmol), potassium ethoxide (4.78 g, 56.8 mmol) and toluene (200 ml) was stirred at room temperature for 0.5 hour and then distilled under reduced pressure to remove the solvent. The residue was dissolved in N-methylpyrrolidinone (150 ml), followed by adding thereto methyl p-toluenesulfonate (10.6 g, 56.8 mmol), and the resulting mixture was stirred at 55-60° C. for 1 hour. The reaction mixture was poured into a cold aqueous sodium chloride solution and extracted twice with ethyl acetate, and the extract solution was washed twice with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was dissolved in ethanol. The resulting solution was cooled to 0° C., followed by adding thereto sodium tetrahydroborate (0.98 g, 25.8 nmol), and the resulting mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was poured into a cold aqueous ammonium chloride solution and extracted twice with ethyl acetate, and the extract solution was washed twice with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/98) to obtain 6.66 g of ethyl 9-methoxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.[C:44]1([C:50]2([C:56]([OH:58])=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CO.ClCCl>[N:36]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:28][CH2:29][N:53]3[CH2:52][CH2:51][C:50]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)([C:56]([OH:58])=[O:57])[CH2:55][CH2:54]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Agent: NC(=O)N1CCCC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 88.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid pyrrolidine-amide hydrochloride to give, after chromatography on silica gel eluting sequentially with 1% methanol/dichloromethane, 1.5% methanol/dichloromethane, 2% methanol/dichloromethane, and then 1.5% methanol/dichloromethane, the title compound: Rf =0.27 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: [ClH:1].O.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[Al+3].[Cl-].[Cl-].[Cl-].O.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:1].[C:15]1([C:6]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
A mixture of 4-piperidone monohydrate hydrochloride (15.0 g, 97.6 mmol, 1.00 equiv) and AlCl3 (130 g, 976 mmol, 10.0 equiv) in anhydrous benzene (600 mL) was stirred at reflux for 4 hours. The mixture was cooled to room temperature, poured into ice (300 g) and water (50 mL), and filtered. The solid was washed with toluene and dried to afford 19.2 g (72%) of off-white solid, which was characterized spectroscopically.