Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:21][O:22][C:23](=[O:25])[N:24]=2)[CH:15]=1.[CH2:28]([N:31]([CH2:35][CH:36]=[CH2:37])[C:32](Cl)=[O:33])[CH:29]=[CH2:30]>N1C=CC=CC=1>[F:27][C:13]([F:12])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[N:24]([C:32]([N:31]([CH2:35][CH:36]=[CH2:37])[CH2:28][CH:29]=[CH2:30])=[O:33])[C:23](=[O:25])[O:22][N:21]=2)[CH:15]=1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCN(CC=C)C(=O)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To 1 ml of pyridine were added 0.28 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.29 g of N,N-diallylcarbamoyl chloride was added at room temperature. After stirring for 8 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.34 g of 3-(4-trifluoromethylpyridin-2-yl)-N,N-diallyl-1,2,4-oxadiazol-5-one-4-carboxamide (present compound (17)).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[NH:6]2.[CH2:12]([O:19][C:20](=[O:23])[CH2:21]Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:19][C:20](=[O:23])[CH2:21][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[NH:6]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc2c(O)cccc2[nH]1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc2c(OCC(=O)OCc3ccccc3)cccc2[nH]1

Procedure:
A mixture of 4-hydroxy-2-methylindole (3.0 g, 0.02 mole), bromo-acetic acid benzyl ester (4.6 g, 0.02 mole), potassium carbonate (2.8 g, 0.02 mole) in acetone was refluxed for 48 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (10:1 Hex:EtOAc) to afford intermediate (2). Yield: 3.5 g, 58%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17](O)=[O:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[F:38][C:39]([F:49])([F:48])[O:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1>C(#N)C>[F:38][C:39]([F:48])([F:49])[O:40][C:41]1[CH:42]=[CH:43][C:44]([NH:45][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])[CH2:16][CH2:15]2)=[O:18])=[CH:46][CH:47]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(C(=O)O)CC2)cc1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)N2CCC(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
1-[(4-Methylphenyl)sulfonyl]-4-piperidinecarboxylic acid (0.283 g) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in acetonitrile (40 ml) were treated at RT and under an argon atmosphere with N-methyl-morpholine (0.2 g) and the mixture was stirred for 2 h at RT. 4-trifluoromethoxy-aniline (0.176 g) was then added and stirring was continued for 20 h at RT until completion of the reaction. The reaction mixture was partitioned between ethyl acetate and aqueous 1M HCl, the layers were separated and the organic layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (AcOEt/heptane, gradient from 0 to 30%) to give 1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.298 g) as a white solid. MS (ESI): 443.1 (MH+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11](=[N:24][CH:25]1[CH2:29][CH2:28][O:27][C:26]1=[O:30])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][CH:32]=1>C1COCC1>[C:11](=[N:24][C:25]1([CH2:37][C:34]2[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=2)[CH2:29][CH2:28][O:27][C:26]1=[O:30])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccncc1
Reactant: O=C1OCCC1N=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1OCCC1(Cc1ccncc1)N=C(c1ccccc1)c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
Potassium bis-(trimethylsilyl)amide (2.67, 13.4 mMol) was dissolved in anhydrous THF (50 mL) under an atmosphere of dry N2. The mixture was cooled to -40° C. to which was added a solution of 3-(benzhydrylidene-amino)-dihydro-furan-2-one (3.38 g, 12.7 mMol) in THF (30 mL). The mixture was warmed to ambient temperature and stirred at this temperature for 30 minutes. The solution was then cooled to -40° C. and a solution of 4-picolyl chloride (1.70 g, 13.4 mMol) in THF (20 mL) was added. The reaction mixture was warmed to ambient temperature and stirred for 18 hours. The mixture was partitioned between ethyl acetate-(EtOAc) and water. The organic layer was dried over sodium sulfate (Na2SO4), filtered and concentrated under vacuum to give a yellow oil. The oil was chromatographed on flash silica gel eluting with a gradient of EtOAc-hexanes (50:50) to EtOAc-hexanes (60:40 ) to give 2.26 g of the titled compound as an oil which crystallizes to a white solid upon standing.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.[H-].[Na+].I[CH3:25].[OH-].[Na+]>CN(C)C=O.O>[CH3:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH3:25])[C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1
Reactant: Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccccn2)c2c1c(=O)c1ccccc1n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
To an ice-cold solution of 3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one (1.11 g, 4.0 mmol) in N,N-dimethylformamide (16 mL), sodium hydride (oiliness, content 60%, 0.19 g, 4.8 mmol) was added and the mixture was stirred at room temperature for 1 hour. Subsequently, iodomethane (2.5 mL, 40.2 mmol) was added thereto at 0° C., and the mixture was stirred at room temperature for additional 16 hours. To the mixture was added iced water, and the mixture was made basic by the addition of an aqueous sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:ethyl acetate:chloroform=3:1:1) to give the title compound (0.47 g, 40% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]2)=[CH:4][C:5]([NH:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[Cl:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][NH:27][C:28]([C:30]2([C:33]([F:36])([F:35])[F:34])[CH2:32][CH2:31]2)=[O:29])=[CH:24][C:23]=1[N:39]=[C:40]=S.CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][NH:27][C:28]([C:30]2([C:33]([F:36])([F:35])[F:34])[CH2:32][CH2:31]2)=[O:29])=[CH:24][C:23]=1[NH:39][C:40]1[N:9]([CH3:10])[C:5]2[CH:4]=[C:3]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]([F:19])([F:20])[F:18])[CH2:13][CH2:12]3)[C:2]([F:1])=[CH:8][C:6]=2[N:7]=1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(F)cc1N
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)nc2cc(F)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound was prepared in analogy to Example 76 using 5-fluoro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (175 mg, 0.60 mmol), N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (200 mg; 0.60 mmol), DIC (76 mg, 0.60 mmol) and DMF (3 mL).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH2:16][CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=1
Reactant: Cn1c(CN2C(=O)c3ccccc3C2=O)nc(-c2ccncn2)cc1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cn1c(CN)nc(-c2ccncn2)cc1=O
Yield: 54.3 %

Procedure:
To a solution of 5.3 g (15.26 mmol) of 2-(1-Methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-isoindole-1,3-dione in 40 ml of ethanol was added 2.37 mL (76.30 mmol) of hydrazine hydrate and the resulting mixture was heated under reflux for 3 h. The mixture was filtered and the solid obtained was triturated with dichloromethane for 24 h, filtered, and the resulting filtrates were evaporated to dryness, the residue was triturated with diethyl ether and filtered to give 1.8 g of pure compound as a solid.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([OH:13])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][CH:7]=1.[CH3:14][C@@:15]12[C@@H:23](O)[CH2:22][CH2:21][C@H:20]1[C@@H:19]1[CH2:25][CH2:26][C:27]3[C@@:33]([CH3:34])([C@H:18]1[CH2:17][CH2:16]2)[CH2:32][CH2:31][C:29](=[O:30])[CH:28]=3>>[CH3:14][C@@:15]12[C@@H:23]([O:12][C:5]([C:6]3[CH:11]=[CH:10][CH:9]=[N:8][CH:7]=3)=[O:13])[CH2:22][CH2:21][C@H:20]1[C@@H:19]1[CH2:25][CH2:26][C:27]3[C@@:33]([CH3:34])([C@H:18]1[CH2:17][CH2:16]2)[CH2:32][CH2:31][C:29](=[O:30])[CH:28]=3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: O=C(O)c1cccnc1
Solvent: O=S(Cl)Cl
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC(=O)c1cccnc1
Reaction time: 3 h

Procedure:
Thionyl chloride (2 ml) was added to 0.7 g (5.7 mmol) of nicotinic acid and the mixture was refluxed for 3 hrs. Excess thionyl chloride was distilled under vacuum. To the cold residue 10 ml of dry pyridine was added followed with 1.44 g (5.0 mmol) of testosterone. The mixture was heated while stirring over a boiling water bath for 3 hrs. Pyridine was distilled under vacuum and 5 ml of methanol was added to the oily residue. The mixture was cooled and the solid crystallized out was filtered and recrystallized from methanol/acetone mixture. Yield, 1.4 g (71%), m.p. 187°-188°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:17]([O:20][CH:21]([CH:23]=[CH2:24])[CH3:22])(=[O:19])[CH3:18].C(N)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>[C:17]([O:20][CH:21]([CH3:22])[CH:23]=[CH:24][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: C=CC(C)OC(C)=O
Reactant: CCOc1cnc(-c2ccc(Br)cc2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: CC(C)(C)N
Product: CCOc1cnc(-c2ccc(C=CC(C)OC(C)=O)cc2)nc1
Yield: 67 %

Procedure:
12 g of 2-(4-bromophenyl)-5-(ethoxy)pyrimidine, 12 g of 2-acetoxy-3-butene, 10 g of N-tert.butylamine, 20 ml of N-methylpyrrolidone, 0.12 g of palladium(II) acetate and 0.3 g of triphenylphosphine were reacted in analogous manner to Example 1(d) to give 9 g of 2-[4-(3-acetoxy-1-butenyl)phenyl]-5-ethoxypyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:14])[C:7]([OH:13])=[C:8]([N+:10]([O-])=O)[CH:9]=1)([O-])=O.[H][H]>[Ni].CO>[NH2:10][C:8]1[CH:9]=[C:4]([NH2:1])[CH:5]=[C:6]([CH3:14])[C:7]=1[OH:13]
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Agent: [Ni]
Solvent: CO
Product: Cc1cc(N)cc(N)c1O

Procedure:
11.0 g (50.0 mmol) 4,6-dinitro-o-cresol were hydrogenated with 2.0 g Raney nickel in 100 mL MeOH under a 5 bar hydrogen atmosphere for 4 h at RT. Then the catalyst was suction filtered and the filtrate was concentrated by rotary evaporation.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([N:18]1[CH:22]=CC=N1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[N:30]1([C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[CH2:35]CN[CH2:32][CH2:31]1>CO>[CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:32][CH2:31][N:30]([C:36]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[CH2:35][CH2:22]1)=[N:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[O:7])([CH3:3])[CH3:4]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCN(C(=O)OCc2ccccc2)CC1
Yield: 50.3 %

Procedure:
Following the procedure described in Example 7, the reaction of N,N′-bis{[(2-methyl-2-propanyl)oxy]carbonyl}-1H-pyrazole-1-carboximidamide (0.25 g, 1.1 mmol), triethylamine (0.5 mL, 3.4 mmol) and benzyl piperazine-1-carboxylate (0.422 g, 1.36 mmol) in methanol (10 mL) gave the title compound (0.256 g, 50%) as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH2:5][CH2:6][C:7]([OH:9])=O.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)=[O:9])[CH:10]=[CH:11][C:12]=1[OH:13]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)CCc1ccc(O)c(O)c1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)CCc2ccc(O)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 22 %

Procedure:
To a solution of 3,4-dihydroxyhydrocinnamic acid (723 mg, 3.97 mmol) in anhydrous THF (20 mL) were added N-methylmorpholine (0.44 mL, 3.97 mmol) and isobutylchloroformate (0.52 mL,3.97 mmol) at 0° C. After 45 min, at 0° C., a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anhydrous THF (4 mL) was added to the reaction mixture. After 5 min the temperature was allowed to warm up to rt and stir overnight. After extraction with EtOAc (100 mL), washing with HCl (0.1N, 50 mL) and a saturated aqueous solution of NaHCO3 (50 mL), the organic layer was dryed over sodium sulfate and evaporated under vacuo to give a yellow oil. Purification by flash chromatography using DCM/MeOH (95/5) as eluant gave the title compound as a colourless oil (22%) in a 94.8% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([OH:24])[CH:10]=[C:11]([C:13]2[NH:14][C:15]([C:18]3[O:19][CH2:20][C@@H:21]([CH3:23])[N:22]=3)=[CH:16][CH:17]=2)[CH:12]=1)[CH3:5].Br[C:26]1[CH:31]=[N:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:10]=[C:11]([C:13]2[NH:14][C:15]([C:18]3[O:19][CH2:20][C@@H:21]([CH3:23])[N:22]=3)=[CH:16][CH:17]=2)[CH:12]=1)[O:24][C:26]1[CH:31]=[N:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=1)[CH3:5]
Reactant: CS(=O)(=O)c1cnc(Br)cn1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=N[C@H](C)CO3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H](C)CO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 91 %

Procedure:
3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (340 mg, 1.03 mmol) synthesized in Example (107c) was dissolved in acetonitrile (10 mL), and 2-bromo-5-(methylsulfonyl)pyrazine (300 mg, 1.27 mmol) synthesized in Example (107d) and cesium carbonate (850 mg, 2.61 mmol) were added at room temperature, followed by stirring at room temperature for 4.5 hours under nitrogen atmosphere. To this reaction solution, water (20 mL) was added, and extraction was carried out with methylene chloride (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate=100%) to afford the desired compound (456 mg, yield 91%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]2[CH:14]=[C:13]([CH:15]([NH2:17])[CH3:16])[O:12][N:11]=2)=[CH:8][N:9]=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]2[CH:14]=[C:13]([CH:15]([NH:17][C:31](=[O:33])[CH3:32])[CH3:16])[O:12][N:11]=2)=[CH:8][N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(Oc2ncc(-c3cc(C(C)N)on3)s2)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2ncc(-c3cc(C(C)NC(C)=O)on3)s2)c(Cl)c1
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
To a solution of Example 37A (358 mg, 1.02 mmol) and triethylamine (426 μL, 3.06 mmol) in dichloromethane (5 mL) was added acetic anhydride (116 μl, 1.22 mmol) at ambient temperature. The reaction was stirred for 10 minutes and was then concentrated on a rotary evaporator. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 30% to 80% ethyl acetate in hexanes to give 338 mg (94%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.42 (d, J=7.35 Hz, 3H) 1.87 (s, 3H) 3.82 (s, 3H) 4.98-5.18 (m, 1H) 6.89 (s, 1H) 7.05 (dd, J=9.19, 2.94 Hz, 1H) 7.27 (d, J=2.94 Hz, 1H) 7.56 (d, J=9.19 Hz, 1H) 7.94 (s, 1H) 8.51 (d, J=7.72 Hz, 1H); MS (ESI) m/z 394.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C(C1N(CC2C=CC(C(OCC)=O)=CC=2Cl)C(C=O)=CN=1)CCC.[C:47]1([CH2:53][CH2:54][C:55]([O:57]C(C)(C)C)=[O:56])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)[C:7](/[CH:10]=[C:54](\[CH2:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)/[C:55]([OH:57])=[O:56])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: CC(C)(C)OC(=O)CCc1ccccc1
Agent: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OCC)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ncc(/C=C(\Cc2ccccc2)C(=O)O)n1Cc1ccc(C(=O)OC)cc1

Procedure:
The title compound was prepared using 2-n-butyl-1-[(4-carbomethoxyphenyl)methyl]imidazole-5-aldehyde, prepared by the method described for the preparation of 2-n-butyl-1-[(4-carboethoxy-2-chlorophenyl)methyl]imidazole-5-aldehyde in Example 44, and t-butyl 3-phenylpropanoate by the procedure of Example 27, except, instead of basic hydrolysis, trifluoroacetic acid hydrolysis of the t-butyl ester is employed.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[C:3]=1[CH3:21]
Reactant: CN1CCNCC1
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1c(-c2ccc(N3CCN(C)CC3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 80 °C
Reaction time: 19 h

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.1 g, 0.324 mmol) in dmf (0.025 mL, 0.32 mmol) was added 1-methylpiperazine (0.036 g, 0.356 mmol) followed by potassium carbonate (0.090 g, 0.65 mmol). The reaction was stirred at 80° C. and stirring continued for 19 h. After which, the reaction mixture was cooled to rt and water was added. The crude reaction mixture was extracted with EtOAc, dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-3-methyl-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=389.1 (M+1).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][O:36][CH3:37])[N:30]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:37][O:36][CH2:35][C:31]1[N:30]=[C:29]([CH2:28][N:11]([CH:9]2[C:10]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][CH2:8]2)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:34]=[CH:33][CH:32]=1
Reactant: COCc1cccc(CBr)n1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCc1cccc(CN(CCCCN2C(=O)c3ccccc3C2=O)C2CCCc3cccnc32)n1

Procedure:
Using General Procedure A: Reaction of 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione, 2-bromomethyl-6-methoxymethyl-pyridine (Gillespie, R. J. et al. PCT Int. Appl. (2002), WO 2002055083), and DIPEA in CH3CN gave 2-{4-[(6-methoxymethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione as a yellow oil. Deprotection with H2NNH2.H2O following General Procedure E gave the free base. Conversion to the HBr salt using General Procedure D gave COMPOUND 356 as a white solid. 1H NMR (D2O) δ 1.52-1.70 (m, 4H), 1.75-1.89 (m, 1H), 1.98-2.10 (m, 1H), 2.16-2.22 (m, 1H), 2.39-2.43 (m, 1H), 2.59-2.68 (m, 1H), 2.84-3.02 (m, 5H), 3.53 (s, 3H), 4.28 (d, 1H, J=15.9 Hz), 4.36 (d, 1H, J=15.9 Hz), 4.49 (dd, 1H, J=5.7, 10.5 Hz), 4.88 (s, 2H), 7.80 (dd, 1H, J=5.7, 7.8 Hz), 7.91 (d, 1H, J=7.8 Hz), 8.08 (d, 1H, J=7.8 Hz), 8.26 (d, 1H, J=8.1 Hz), 8.47 (dd, 1H, J=7.8, 8.1 Hz), 8.57 (d, 1H, J=5.7 Hz); 13C NMR (D2O) δ 20.42 (2 carbons), 24.93, 25.01, 27.62, 39.53, 51.42, 53.24, 59.28, 60.01, 70.38, 125.20, 125.72, 126.27, 140.04, 140.29, 146.84, 146.93, 151.24, 153.50, 153.82; ES-MS m/z 355 (M+H). Anal. Calcd. for C21H30N4O.3.4HBr.1.2H2O: C, 38.73; H, 5.54; N, 8.60; Br, 41.72. Found: C, 39.06; H, 5.54; N, 8.44; Br, 41.42.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][C:3]=2[O:2]1.C([Mg]Br)C.Br[C:18]1[C:23](=[O:24])[NH:22][C:20](=[O:21])[C:19]=1[Br:25].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[Br:25][C:19]1[C:20]([NH:22][C:23](=[O:24])[C:18]=1[C:6]1[C:5]2[C:9](=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[NH:8][CH:7]=1)=[O:21]
Reactant: O=C1NC(=O)C(Br)=C1Br
Reactant: c1cc2cc3c(cc2[nH]1)OCO3
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2c[nH]c3cc4c(cc23)OCO4)=C1Br
Yield: 56.8 %

Procedure:
6.44 g (40 mmol) 5,6-methylenedioxyindole are dissolved in 300 ml anhydrous toluene and mixed dropwise at 60° C. with 20 ml of a 2M solution of ethyl magnesium bromide in tetrahydrofuran (Aldrich). After completion of the addition, there is added dropwise thereto a solution of 1.7 g (6.67 mmol) dibromomaleinimide in 50 ml toluene, with the addition of the minimum amount of tetrahydrofuran required for solution, and then heated under reflux for 18 hours. After cooling, the reaction mixture is mixed with a saturated aqueous solution of ammonium chloride, the organic phase is separated off and the aqueous phase is extracted three times with toluene and once with ethyl acetate. The combined organic phases are dried, rotary evaporated and chromatographed in silica gel (elution agent: dichloromethane/ethyl acetate 30:1 v/v). There is obtained 1.27 g (56% of theory) 2-bromo-3-(5,6-methylenedioxy-1H-indol-3-yl)-maleinimide; m.p. about 185° C. (decomp.); RF=0.50 (dichloromethane/ethyl acetate 3:1 v/v); and 0.63 g (22.5% of theory) 2,3-bis-(5,6-methylenedioxy-1H-indol-3-yl)-maleinimide in the form of red crystals; m.p, about 270° C. (decomp.), after recrystallisation from propanol; RF=0.36 (dichloromethane/ethyl acetate 3:1 v/v).