Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:21](=[C:22]3[CH2:27][CH2:26][N:25](C)[CH2:24][CH2:23]3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]=2[CH:29]=1.C(N(CC)CC)C.C>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:21](=[C:22]3[CH2:23][CH2:24][N:25]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:26][CH2:27]3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]=2[CH:29]=1
Reactant: CCOC(=O)Cl
Reactant: CN1CCC(=C2c3ccc(F)cc3CCc3cccnc32)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(=C2c3ccc(F)cc3CCc3cccnc32)CC1
Temperature: 80 °C
Yield: 62.9 %

Procedure:
Ethyl chloroformate (8.5 mL, 9.65 g, 0.089 mole) is slowly added at 80° C. to a solution of 8-fluoro11-(1-methyl-4-piperidylidene)-6,ll-dihydro-5H-benzo[5,6)cyclohepta[1,2-b]pyridine (5.4 g, 0.0175 mole) and triethylamine (3.6 mL, 2.61 g, 0.026 mole) in 60 mL of toluene. Following complete addition, the temperature is maintained at 80° C. for 1 hour. The reaction mixture is treated with charcoal, filtered, and concentrated to a residue. Following purification by silica gel chromatography and crystallization from pentane, 4.10 g (0.011 mole) of 8-fluoro-6,11-dihydro-11-(1- ethoxycarbonyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine is obtained in 63% yield. 8-bromo, 8,9-dichloro, 9-chloro, and 9-fluoro analogs of this 8-fluoro-11-(1-ethoxycarbonyl-4piperidylidene) compound can be prepared.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C([Li])CCC.Cl[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31]>C1COCC1.CCCCCC>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
804 mg (3.2 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) is dissolved in 16 ml dry THF and cooled to −78° C. After the addition of 2.21 ml butyl lithium in hexane (1.59 M), the yellow solution is stirred at −78° C. for 30 min. Subsequently, 680 l (640 mg=3.84 mmol) (2-chloromethoxyethyl)-trimethylsilane (SEM-Cl) is added and stirring is continued at −20° C. for 5 h. The mixture is then allowed to warm up to room temperature overnight. The reaction is then quenched by addition of 10 ml saturated NH4Cl solution followed by 10 ml water and extracted with 2×40 ml isopropyl acetate. The layers are separated and the organic layer dried over MgSO4, filtered and evaporated. The resulting residue (1.33 g) is purified using column chromatography (dichloromethane:triethylamine=99.5:0.5→dichloromethane:methanol:triethylamine=98.5:1:0.5) to give (S)-5-Biphenyl-4-ylmethyl-1-(2-trimethylsilanylethoxymethyl)pyrrolidin-2-one (1-a, R1=SEM) as a yellow oil. NMR (400 MHz, CDCl3, /ppm): 7.58 (m, 4H); 7.47 (m, 2H); 7.37 (m, 1H); 7.30 (m, 2H); 5.04 (d, J=10.6, 1H); 4.70 (d, J=10.6, 1 H); 4.03 (m, 1H); 3.59 (m, 2H); 3.24 (dd, J=4.2, 13.4, 1H); 2.67 (dd, J=9.1, 13.4, 1H); 2.33 (t, J=8.2, 2 H); 2.10 (m, 1H); 1.81 (m, 1H); 1.00 (m, 2H); 0.06 (s, 9H). MS (ESI, m/e) 382 [M+H]+; 763 [2M+H]+. IR (solution in CH2Cl2, /cm−1): 3057; 2951; 1702; 1487; 1414; 1249; 1073; 859; 836; 759; 697.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][CH:13]1[CH2:18][NH:17][C:16](=O)[CH2:15][N:14]1[C:20]([O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Br:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[N:17]3[CH2:18][CH:13]([CH3:12])[N:14]([C:20]([O:22][CH2:23][CH:24]4[C:36]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[C:30]5[C:25]4=[CH:26][CH:27]=[CH:28][CH:29]=5)=[O:21])[CH2:15][C:16]3=[N:1]2)=[CH:7][CH:8]=1
Reactant: CC1CNC(=O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1cc(Br)ccc1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC1Cn2c(nc3cc(Br)ccc3c2=O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 2-amino-4-bromobenzoic acid (2.8 g, 13.1 mmol, 1.1 equiv), (9H-fluoren-9-yl)methyl 2-methyl-5-oxopiperazine-1-carboxylate (4 g, 11.9 mmol, 1 equiv), and phosphoryl trichloride (4 mL) in 1,4-dioxane (100 mL) was stirred at 80° C. for two hours. After it was cooled to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: [O:1]=[CH:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Cl:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[CH:21][C:22]=1[F:23]>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:2]([OH:1])[CH2:3][C@H:4]2[CH2:8][CH2:7][CH2:6][N:5]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Fc1ccc([Mg]Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CC=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CC(O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of (R)-tert-butyl 2-(2-oxoethyl)pyrrolidine-1-carboxylate (A. Furstner and J. W. L. Kennedy, Chem.—Eur. J. 2006 12(28):7398-7410) in THF cooled to −78° C. was added (3-chloro-4-fluorophenyl)magnesium bromide (0.720 mL, 0.360 mmol) and the reaction was warmed to RT for 1 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated to afford an oil which was purified by SiO2 chromatography to afford 0.0745 g (72%) of (2R)-tert-butyl 2-(2-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)pyrrolidine-1-carboxylate (301) as a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[C:8]2[CH:13]=[N:12][C:11](OC)=[N:10][C:9]=2[N:16]([CH2:18][CH3:19])[CH:17]=1)=[O:5])[CH3:2].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C1(C)C=CC=CC=1>O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[C:8]2[CH:13]=[N:12][C:11]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:10][C:9]=2[N:16]([CH2:18][CH3:19])[CH:17]=1)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cn(CC)c2nc(OC)ncc2c1=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2nc(N3CCCC3)ncc2c1=O

Procedure:
5.9 g of 6-ethoxycarbonyl-8-ethyl-2-methoxy-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine, 4.6 g. of pyrrolidine and 12 g of toluene are heated for 2 hours at 90° C. After cooling, 100 cm3 of water are added to the mixture. The precipitate is filtered off and washed with water. After drying, 5.5 g of 6-ethoxycarbonyl-8-ethyl-5-oxo-2-pyrrolidino-5,8-dihydro-pyrido[2,3-d]pyrimidine are obtained. After recrystallisation from ethanol, it melts at 202° C and is identical to the product described in the literature.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:15])=[CH:9][C:8]=1[F:22].[Si:23]([O:30][CH:31]1[CH2:35][CH2:34][O:33][C:32]1=[O:36])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C(=O)(O)[O-].[Na+]>O1CCCC1>[Si:23]([O:30][CH:31]([CH2:35][CH2:34][OH:33])[C:32]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:15])=[CH:9][C:8]=1[F:22])=[O:36])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OC1CCOC1=O
Reactant: O=C(Nc1ccc(Br)c(F)c1)c1ccccn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC(CCO)C(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.1 ml of n-butyl lithium (2.66 M hexane solution) was dropwise added to a tetrahydrofuran (100 ml) solution of 1.1 g of N-(4-bromo-3-fluorophenyl)pyridine-2-carboxamide at −78° C., and the reaction liquid was stirred at the same temperature for 15 minutes. 1.21 g of 3-((t-butyl(dimethyl)silyl)oxy)dihydrofuran-2 (3H)-one was added to the reaction liquid, and the reaction liquid was stirred at the same temperature for 1 hour. Aqueous saturated sodium bicarbonate solution was added to the reaction liquid at the same temperature, then heated up to room temperature and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=100/1) to obtain the entitled compound as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH3:15])[C:8]([OH:10])=[O:9])[N:6]=1.[C:16](OC(=O)C)(=[O:18])C>C(O)=O>[CH:16]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH3:15])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: CCCON=C(C(=O)O)c1csc(N)n1
Solvent: O=CO
Product: CCCON=C(C(=O)O)c1csc(NC=O)n1
Yield: 78.5 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-n-propoxyiminoacetic acid (syn isomer, 21.8 g.), acetic anhydride (38.8 g.) and formic acid (17.5 g.) were treated in a similar manner to that of Example F-(5), and then the obtained oil was triturated with diisopropyl ether to give 2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetic acid (syn isomer, 19.2 g.), mp. 164° C. (dec.).
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[S:13][C:14]=1[CH3:15])(OCC)=O)C.[H-].[Na+].[CH3:31][O:32][CH2:33][O:34][C:35]1[C:39]([CH:40]=O)=[CH:38][N:37]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:36]=1.O>O1CCCC1>[CH3:31][O:32][CH2:33][O:34][C:35]1[C:39](/[CH:40]=[CH:9]/[C:10]2[N:11]=[C:12]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[S:13][C:14]=2[CH3:15])=[CH:38][N:37]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:36]=1
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To a solution of tert-butyl 4-{4-[(diethoxyphosphoryl)methyl]-5-methyl-1,3-thiazol-2-yl}piperazine-1-carboxylate (2.0 g) in tetrahydrofuran (50 mL) was added sodium hydride (60% in oil, 0.20 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (1.1 g) was added to the reaction mixture, and the mixture was heated under reflux for 4 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (5:95-25:75, v/v) to give tert-butyl 4-(4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-5-methyl-1,3-thiazol-2-yl)piperazine-1-carboxylate as a yellow oil (1.3 g, yield 57%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1([NH2:12])[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.CN([CH:25]=[O:26])C>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2]([C:25](=[O:26])[NH:12][C:9]32[CH2:11][CH2:10]3)=[CH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: NC1(c2cc(Cl)ccc2Br)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C1NC2(CC2)c2cc(Cl)ccc21
Temperature: 130 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
A mixture of 1-(2-bromo-5-chlorophenyl)cyclopropanamine (2 g, 8.1 mmol), Pd(dppf)Cl2 (0.2 g), DIPEA (3.1 g, 24.3 mmol) in DMF (20 mL) was stirred in an autoclave under 2 MPa of CO (g) at 130° C. for 16 hours. The reaction mixture was diluted with EtOAc (300 mL), and washed with brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated under reduced pressure to give a crude product which was purified by chromatography to afford title compound (700 mg, yield 44.6%) as a yellow solid. MS: 193.8 (M+H+, 1C1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[C:16]2[S:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[C:16]2[S:23]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:9]
Reactant: Cc1[nH]c2ccc(Cl)cc2c1SC1CCNCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1[nH]c2ccc(Cl)cc2c1S(=O)C1CCNCC1
Reaction time: 4 h

Procedure:
Metachloroperbenzoic acid (2.79 g) is added in portions to a solution of 5-chloro-2-methyl-3-(piperidin-4-ylthio) -1H-indole (3 g, prepared in Example 15) in dichloromethane (25 ml) at -40° C. After 4 hours at room temperature, the insoluble material is filtered off. The filtrate is washed with sodium hydroxide and then with water. The aqueous phases are extracted with ether and then with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and concentrated. The oily residue obtained is chromatographed on silica gel (eluent: CH2Cl2 /MeOH/NH4OH : 90/10/1) to give 5-chloro-2-methyl-3-(piperidin-4-yl-sulfinyl)-1H-indole in the form of an oil, which crystallizes on the addition of ether (0.4 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([OH:15])=[C:10]([C:12](O)=[O:13])[N:11]=[C:6]2[CH:5]=[N:4]1)[CH3:2].S(Cl)([Cl:18])=O>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([OH:15])=[C:10]([C:12]([Cl:18])=[O:13])[N:11]=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2nc(C(=O)O)c(O)nc21
Reactant: O=S(Cl)Cl
Product: CCn1ncc2nc(C(=O)Cl)c(O)nc21

Procedure:
31.3 g. of 1-ethyl-6-hydroxy-1H-pyrazolo[3,4-b]-pyrazine-5-carboxylic acid (0.15 mol.) are carefully added in portions to 300 ml. of thionyl chloride. As soon as the gas evolution has ceased, the mixture is heated at reflux for 3 hours. After removal of excess thionyl chloride under vacuum, the residue is dissolved in benzene. Evaporation of the benzene provides 30.5 g. (90%) of amorphous 1-ethyl-6-hydroxy-1H-pyrazolo[3,4-b]pyrazine-5-carbonyl chloride which is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[N+:18]([O-])=O.[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH2:18]
Reactant: COc1ccc(CSc2ccc([N+](=O)[O-])c(F)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(CSc2ccc(N)c(F)c2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a vigorously stirred ice-cold mixture of 2-fluoro-4-(4′-methoxy-benzylmercapto)nitrobenzene and NiCl2.6H2O (6.08 g, 25.6 mmol) in CH3OH was added NaBH4 (1.93 g, 51.1 mmol) in portions. The reaction mixture was stirred for 1 h at 0° C., then poured into cold water. The whole was extracted with CH2Cl2 (3×100 ml) and the combined organic layers were dried (Na2SO4), filtered, and evaporated to give 2-fluoro-4-(4′-methoxybenzylmercapto)aniline. MS (Cl) m/e 264 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][CH3:16])=[CH:13][C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>O1CCOCC1.CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][CH3:16])=[CH:13][C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1COCCO1
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
1-(4-Nitrophenyl)-3-(3-pyridinyl)-5-ethylpyrazole (18.0 g, 61.2 mmol) was dissolved in dioxane (200 mL) and MeOH (200 mL). The solution was treated with ammonium formate (38.6 g, 612 mmol) and 5% Pd/C (1.8 g) at room temperature for 6 hr. It was then filtered through a pad of diatomaceous earth and the cake was washed with CH3CN. The filtrate was concentrated and the residue was treated with water (200 mL). The resulting slurry was stirred at room temperature for 3 hr, and collected by filtration. The solid was washed with water and dried in an oven under house vacuum to give 1-(4-aminophenyl)-3-(3-pyridinyl)-5-ethylpyrazole (15.5 g, 95%). %). 1H NMR (CDCl3, 400 MHz) 9.05 (s, 1H), 8.53 (d, J=4.7 Hz, 1H), 8.16 (d, J=7.2 Hz, 1H), 7.30 (m, 1H), 7.23, 6.75 (ABq, J=8.1 Hz, 4H) 6.54 (s, 1H), 3.83 (bs, 2H), 2.63 (q, J=7.6 Hz, 2H), 1.25 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH2:13][C:14]([OH:16])=O)[C:10](=[O:17])[CH2:9]2)=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([CH2:13][C:14]([N:21]3[CH2:22][CH2:23][NH:18][C:19](=[O:24])[CH2:20]3)=[O:16])[C:10](=[O:17])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CC(c2ccc(Cl)cc2)CC1=O
Reactant: O=C1CNCCN1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: ClCCl
Product: O=C1CN(C(=O)CN2CC(c3ccc(Cl)cc3)CC2=O)CCN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
82.5 g (325 mmol) of 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid, 32.5 g (325 mmol) of piperazin-2-one (ketopiperazine) and 100.8 g (325 mmol) of freshly distilled triphenyl phosphite are melted at 180°. The whole is allowed to cool to 130° and left to stand for 5 hours. The solidified reaction mass is cooled to room temperature and stirred for 1 hour with 300 ml of dichloromethane. The whole is filtered with suction, washed three times with 150 ml of dichloromethane each time and allowed to dry in the air. 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-3-oxopiperazine having a melting point of 208°-210° is obtained and can be purified further by dissolving in 200 ml of hot acetic acid, adding 800 ml of water and crystallising in an ice bath.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH3:25])[CH3:26])[CH2:20][CH2:19]2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]
Reactant: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@H](N(C)C)CC4)c3c2)cc(Cl)c1O

Procedure:
Following general procedure F, {6-bromo-4-[trans-4-(dimethylamino)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (50 mg, 0.120 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (51 mg, 0.180 mmol) to afford the desired product (22 mg, 37%) as a yellow-green solid: 1H NMR (300 MHz, CD3OD) δ 9.18 (s, 1H), 8.36 (s, 1H), 8.09 (d, J=10.4 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 4.24 (s, 1H), 3.99 (s, 3H), 3.35 (s, 1H), 2.86 (s, 7H), 2.46 (s, 2H), 2.21 (s, 2H), 1.73 (d, J=10.4 Hz, 4H), 1.28-1.06 (m, 4H); ESI MS m/z [C28H32ClN3O3+H]+; HPLC 97.5% (AUC), tR=10.92 min.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[C:20]3[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=3[CH:18]([CH2:29][CH3:30])[C:17]([CH3:31])=[N:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]>O1CCOCC1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[C:20]3[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=3[CH:18]([CH2:29][CH3:30])[C:17]([CH:31]=[O:2])=[N:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: O=[Se]=O
Reactant: CCC1C(C)=NN=C(c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Solvent: C1COCCO1
Product: CCC1C(C=O)=NN=C(c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Yield: 97.4 %

Procedure:
6.05 g of selenium dioxide are added within 1.5 hours to a stirred suspension of 19.1 g (0.05 mole) of 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine in 150 ml of 80% aqueous dioxane at an inner temperature of 84° to 87° C. The metallic selenium is removed from the mixture by clarification, and the yellow solution is evaporated in vacuo. The thick, honey-like residue is stirred with 100 ml of water, whereupon the title compound separates as a yellow powder. The product is filtered off, washed five times with 10 ml of water each and dried in vacuo. 19.3 g (96%) of crude 1-(3,4-dimethoxyphenyl)-4-formyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine are obtained; m.p.: 103°-105° C. When recrystallized from acetone and cyclohexane the product melts at 108°-110° C. C22H24N2O5 =396.45.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:69])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH3:68])[N:64]=[C:65]([CH2:66][CH3:67])[C:52]3=[CH:51][CH:50]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:78]>CO.O>[ClH:78].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:69])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH3:68])[N:64]=[C:65]([CH2:66][CH3:67])[C:52]3=[CH:51][CH:50]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CCc1nn(C)c2c1ccc1c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CCc1nn(C)c2c1ccc1c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 43 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(3-ethyl-1-methyl-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (2 mL), water (3 mL) and 1 M HCl (0.1 mL) and chromatographed on a 2 g C18 cartridge {gradient 40 to 65% MeOH in water+1 M HCl (60 μL in each 5 mL of eluent)} to give the title compound (9 mg, 43%, 3 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.38 (br s, 3H), 7.80 (d, J=8.6 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.55-7.53 (m, 2H), 7.50-7.43 (m, 3H), 7.41-7.37 (m, 2H), 7.32 (d, J=8.3 Hz, 2H), 4.34 (s, 3H), 2.99 (q, J=7.6 Hz, 2H), 2.63-2.52 (m, 4H), 2.22-2.11 (m, 1H), 1.87-1.76 (m, 1H), 1.35 (t, J=7.6 Hz, 3H). LCMS (Method E): RT=3.79 min, [M+H]+=450.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C[O-].[Na+].[CH2:24](I)[CH3:25]>CN(C)C=O>[C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:24][CH3:25])[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCI
Reactant: CC(=O)c1cccc(NS(=O)(=O)c2ccc(C)cc2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1cccc(C(C)=O)c1)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C

Procedure:
A 29 g portion of N-(3-acetylphenyl)-4-methylbenzenesulfonamide was dissolved in 250 ml of dimethylformamide with stirring. This mixture was treated with 6.5 g of sodium methoxide and stirred for 30 minutes, then 20 g of ethyl iodide was added. This mixture was stirred at room temperature for one hour, then at reflux for 5 hours. The dimethylformamide was removed in vacuo, the residue shaken with 150 ml of water, the mixture adjusted to pH 4 with 10N sodium hydroxide and then cooled to 0° C. The precipitate was collected, washed twice with water and then air dried, giving 31.5 g of N-(3-acetylphenyl)-N-ethyl-4-methylbenzenesulfonamide.