Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][C:15]([CH:28]([N:36]=C(C2C=CC=CC=2)C2C=CC=CC=2)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:51])([CH3:4])([CH3:3])[CH3:2].Cl.O>CC(C)=O>[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][C:15]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)([C:16]([F:18])([F:17])[F:19])[CH:28]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[N:36]=2)=[CH:9][C:8]=1[CH3:51])=[O:52])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=O)CC(c2cc(Cl)cc(Cl)c2)(C(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C2=NC(C(=O)OC(C)(C)C)C(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
Similarly, the reaction was carried out under similar conditions: To a solution of 4-[3-[(Benzhydrylidene-amino)-tert-butoxycarbonyl-methyl]-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoic acid tert-butyl ester (426 mg, one diastereoisomer, obtained in example P12) in acetone (12 mL) was added hydrochloric acid (6 mL, 10%) and the solution was stirred at ambient temperature for 3 hours. Water was then added and the reaction mixture was extracted with ethylacetate and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 05% dichloromethane in heptane) to afford tert-butyl 5-(4-tert-butoxycarbonyl-3-methyl-phenyl)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4-dihydropyrrole-2-carboxylate (248 mg) as a white solid. 19F NMR (376 MHz, CDCl3) δ −75.20 ppm (1 diastereoisomers). Chiral HPLC analysis (Chiralpack AS-RH, acetonitrile:water:methanol=55:5:40, 1 ml/min, retention time 22.87 minutes (minor enantiomer) and 25.52 minutes (major isomer) indicated that the reaction proceeded with little enantioselectivity.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Cl:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[CH:4][CH:3]=1.[F:21][C:22]([F:27])([F:26])[S:23]([O-])=O.[Na+].S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Cl:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[CH:4][C:3]=1[S:23][C:22]([F:27])([F:26])[F:21]
Reactant: Nc1ccnn1-c1cc2c(cc1Cl)C(F)(F)OC2(F)F
Reactant: O=S([O-])C(F)(F)F
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1c(SC(F)(F)F)cnn1-c1cc2c(cc1Cl)C(F)(F)OC2(F)F
Temperature: 55 °C
Yield: 38.6 %

Procedure:
To a suspension wherein 5-amino-1-(6-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)pyrazole (391 mg, 1.27 mmol), sodium trifluromethanesulfinate (397 mg, 2.54 mmol) and dimethylamine tosylate (690 mg, 3.17 mmol) are in toluene (4 ml), thionyl chloride (302 mg, 2.54 mmol) was added dropwise under ice cooling over a period of about 10 minutes and then stirred under heating at 50 to 60° C. for 14 hours. After allowing to cool, the reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 200 mg of 5-amino-1-(6-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-4-trifluoromethylsulfenylpyrazole.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:9]1[C:18]2[N:19]=[CH:20][NH:21][C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:31][CH2:32][CH2:33][CH2:34][CH2:35]I>CN(C)C=O>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:35][CH2:34][CH2:33][CH2:32][Cl:31])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCCCCI
Reactant: c1ccc(CN(Cc2ccccc2)c2nc3ccccc3c3[nH]cnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCCCn1cnc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, N,N-dibenzyl-1H-imidazo[4,5-c]quinolin-4-amine (20.0 g, 55.04 mmol), sodium hydride (3.3 g, 60% dispersion, 82.56 mmol), and anhydrous dimethyl formamide (275 mL) under a nitrogen atmosphere. After the reaction mixture had stirred at ambient temperature for 2 hours, 4-chloro-1-iodobutane (19.23 g, 88.06 mmol) was added and the resulting homogeneous solution was stirred at ambient temperature for 48 hours at which time the starting material was consumed. The solution was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a light yellow solid. The material was recrystallized from ethyl acetate and hexanes to give N,N-dibenzyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (20.7 g, 45.49 mmol) as white needles. MS (CI) for C28H27ClN4 m/z 455 (MH+), 365, 329, 239
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:3].[P:25]([O:30]C)([O:28][CH3:29])[O:26][CH3:27]>>[CH2:5]([O:4][C:2]([P:25](=[O:30])([O:28][CH3:29])[O:26][CH3:27])=[O:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCCCCCOC(=O)Cl
Reactant: COP(OC)OC
Product: CCCCCCCCCCCCCCCCCCCCOC(=O)P(=O)(OC)OC
Reaction time: 8 h
Yield: 97 %

Procedure:
1-Eicosanyl chloroformate (6.0 g, 16.6 mmol) was added slowly to refluxing P(OMe)3 30 (mL), and after 2 hours the mixture was left at room temperature overnight. Excess P(OMe)3 was removed by vacuum distillation, and the remaining white solid was collected, washed with cold hexane, and recrystallized from hexane to obtain colorless crystals from which traces of hexane were not fully removed (7.0 g, 97% yield); mp 53-54° C.; TLC: Rf 0.39 (silica gel, 98:2 CHCl3—MeOH); IR (KBr): υ 2950, 2915, 1705, 1540, 1280, 1220 cm−1; 1H NMR (CDCl3) δ0.8-1.8 (m, >39H, CH3(CH2)18), 3.9 (d, 6H, P(OCH3)2), 4.3 (t, 2H, CH2O). Anal. Calcd. for C23H47O5P.0.15C6H14: C, 64.13, H, 11.08; P, 6.92. Found: C, 63.91; H, 10.91; P, 6.62.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10](CC3C=CC=CC=3)[CH2:9]2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc([C@H]2CN(Cc3ccccc3)CCO2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc([C@H]2CNCCO2)cc1
Yield: 95.8 %

Procedure:
A suspension of (2S)-2-(4-fluorophenyl)-4-(benzyl)morpholine (250 mg) and 5% Pd—C (0.106 g) in ethanol (5 mL) was treated with hydrogen for 1 hr at 33-35° C. The suspension was filtered through celite and washed with ethanol. The solvent was evaporated to give (2S)-2-(4-fluorophenyl)morpholine (160 mg, 94%) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:16]([O-])=O)[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].Cl.[H][H]>C(O)C.CO.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH2:16])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: COc1c(OC(C)=O)cc(C(=O)O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: COc1c(N)cc(C(=O)O)cc1OC(C)=O
Yield: 103.4 %

Procedure:
3-Acetoxy-4-methoxy-5-nitro-benzoic acid (4.50 g, 17.6 mmol) (R. T. Borchardt et al., J. Med. Chem. 25 (1982), 312-323; F. Tiemann et al., Ber. dt. Chem. Ges. 9 (1876), 937) was dissolved in ethanol (180 ml) and 0.5 M hydrogen chloride in methanol (4 ml) and hydrogenated in an H-Cube™ hydrogenation reactor with 100 bar hydrogen at 40° C. over a 10% palladium on charcoal cartridge. The mixture was evaporated to dryness to give 4.1 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:15])[C@@H:11]1[O:14][C@@H:12]1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].CCCCCC.C(OCC)(=O)C>O1CCCC1.C(Cl)Cl>[C:1]([O:5][C:6]([C@H:8]1[N:9]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:15])[C@@H:11]1[C@H:12]([OH:14])[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1O[C@H]1C(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N(CC(=O)OC(C)(C)C)[C@@H]1C(=O)OC(C)(C)C

Procedure:
A solution of 13.18 g of (2R,3R)-N,N-bis-(tert-butoxycarbonylmethyl)-2,3-epoxybutyramide in 100 ml of tetrahydrofuran is cooled with stirring to -15°, and 100 ml of a 0.5-molar solution of lithium hexamethyldisilazide in tetrahydrofiran is added at temperatures between -15° and -10°. The progress of the reaction is followed by thin layer chromatography (solvent: a 1:1 mixture of hexane and ethyl acetate); the reaction is complete after stirring for about 4 hours at the temperature indicated above. The reaction mixture is diluted with methylene chloride and poured onto ice, and the organic layer is washed successively with water, twice with 0.1N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and water. The wash water is extracted twice with methylene chloride, and the combined organic phases are dried over sodium sulfate and evaporated under a water pump vacuum. After flash chromatography over 750 g of silica gel 60 (0.040-0.063 mm, Merck; elution with a 6:4 mixture of hexane and ethyl acetate), the crude product obtained gives (3S,4S,1R)-4-tert-butoxycarbonyl-1-tert-butoxycarbonylmethyl-3-(1'-hydroxyethyl)-azetidin-2-one, which melts at 79°-81°; [α]D -22.6° (c=0.574% in chloroform).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH:25]1[CH2:2][CH:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCNCC1CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 95.1 %

Procedure:
A mixture of 7.7 g of 2-chloromethyl-1,4-bis(phenylmethyl)piperazine, 12 g of N-methylpiperazine, 3.5 g of potassium carbonate, 150 ml of dioxane and 60 ml of water was heated overnight at 80°-90° C. and then evaporated. The residual gum was dissolved in dichloromethane, washed with water, dried, filtered and evaporated, giving 8.8 g of 2-[(N-methylpiperazinyl)methyl]-1,4-bis(phenylmethyl)piperazine.
Reaction SMILES: C[O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[NH2:14][C@@H:15]1[C:20](=[O:21])[O:19][C:17](=[O:18])[CH2:16]1.N[C@H](C(O)=O)CC1C=CC=CC=1.C(N[C@@H]1C(=O)OC(=O)C1)=O>C(O)(=O)C>[NH2:14][C@H:15]([C:20]([NH:5][C@H:4]([C:3]([OH:2])=[O:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:21])[CH2:16][C:17](=[O:18])[OH:19]
Reactant: N[C@H]1CC(=O)OC1=O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=CN[C@H]1CC(=O)OC1=O
Solvent: CC(=O)O
Product: N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
In known methods for producing α-AMP, an N-protected-L-aspartic anhydride is reacted with L-phenylalanine methyl ester in an organic solvent, and then the protecting group is eliminated by a conventional method (U.S. Pat. No. 3,786,039); and addition salt of L-aspartic anhydride with a strong acid is directly reacted with L-phenylalanine methyl ester (Japanese Patent Publication No. 14,217/74); or L-phenylalanine is reacted with N-formyl-L-aspartic anhydride in glacial acetic acid, and the formyl group is eliminated from the product to give α-L-aspartyl-L-phenylalanine (hereinafter referred to as α-AP), which is then esterified with methanol (U.S. Pat. No. 3,933,781).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[NH:28]1[CH2:31][CH2:30][CH2:29]1.CCCP(=O)=O>O1CCCC1>[C:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:28]4[CH2:31][CH2:30][CH2:29]4)=[O:27])=[O:24])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (4.5 g, 12.4 mmol), azetidine (2.53 ml, 37.3 mmole), N-diisopropylethylamine (6.51 ml, 37.3 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 18.3 ml, 31 mmol) in tetrahydrofurane (220 ml) is stirred for 2 hours at 70° C. The turbid solution is concentrated to about 100 ml, cooled, poured on cooled sat. aqueous sodium bicarbonate solution (1000 ml) and the suspension is stirred for 20 minutes. The solid is collected by filtration, washed with little water and dried affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (5 g, 100%) as a white solid. mp.: 243-5° C. MS: m/z=402.3 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[S:14][CH:15]=[C:16]([Br:18])[CH:17]=2)[CH:10]([C:19](Cl)=[O:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH:11]2[CH:10]([C:19](=[O:20])[C:17]3[C:16]([Br:18])=[CH:15][S:14][C:13]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CN(Cc2ccccc2)CC1c1cc(Br)cs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1c2c(Br)csc2C2CN(Cc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72 %

Procedure:
A solution of the product from step d) (4.04 g, 9.59 mmol) in CH2Cl2 (13.7 ml) was added dropwise to a slurry of AlCl3 (3.83 g, 28.77 mmol) in CH2Cl2 (36 ml) at 22° C. After 45 minutes, the reaction mixture was poured into ice cold 2 M NaOH (100 ml) and extracted with CH2Cl2 (300 ml). The organic layer was dried (MgSO4) and solvent evaporated in vacuo to give a residue that was purified by silica-gel chromatography using a ethyl acetate/hexanes gradient (0% to 50% ethyl acetate) to give the subtitle compound (2.4 g, 72%). MS calculated for C16H14BrNOS+H 348, observed 348, 350.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][O:11][CH2:12][CH2:13][CH2:14]OS(C)(=O)=O>CN(C=O)C>[CH3:10][O:11][CH2:12][CH2:13][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: COCCCOS(C)(=O)=O
Solvent: CN(C)C=O
Product: COCCCOc1cccc(C=O)c1

Procedure:
Alkylation of 3-hydroxybenzaldehyde (11) with methanesulfonic acid 3-methoxypropyl ester following the method used in Example 34 except that the reaction solvent was DMF gave 3-(3-methoxypropoxy)benzaldehyde as a clear oil. Yield (1.32 g, 55%): 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 7.40-7.47 (m, 3H), 7.15-7.20 (m, 1H), 4.12 (t, J=6.4 Hz, 2H), 3.56 (t, J=6.2 Hz, 2H), 3.35 (s, 3H), 2.05-2.11 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].O>C(#N)C>[C:19]([NH:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[O:21])[CH3:20]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(=O)NNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
In 100 ml of acetonitrile were dissolved 15.3 g of p-nitrophenylhydrazine and 10.1 g of triethylamine, and 7.9 g of acetyl chloride was added dropwise to the solution under ice-cooling over a period of 15 minutes. Thereafter, the mixture was stirred for 1 hour at 25° C., 100 ml of water was added therreto, and crystals thus deposited were collected by filtration and washed with acetonitrile to provide 16.6 g of 1-acetyl-2-(4-nitrophenyl)hydrazine. The melting point was 209°-214° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[CH:22][NH:21][C:20]=1[CH:33]=O>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:20]2[NH:21][CH:22]=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3cccc(Br)c3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.6 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(3-bromo-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (61.4 mg, 49%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)CCC>>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[O:9][C:10]3[C:2]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[CH:3][C:4]([OH:19])=[CH:5][C:6]=3[N:7]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Product: Oc1ccc(-c2nc3cc(O)cc(-c4cccs4)c3o2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 53, Step a, from 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole and 2-(tributylstannyl)thiophene. The product was obtained as a white solid (95% yield), m.p. 95–100° C.); MS m/e 338 (M+H).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:20]Br)=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[C:10]([Br:22])=[C:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(OC(C)(C)C)=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Br:22][C:10]1[C:11]2[C:16](=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([CH2:20][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:12]=2)[NH:8][C:9]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccccc2)c(Br)c2cc(CBr)cc([N+](=O)[O-])c21
Product: O=[N+]([O-])c1cc(CN2CCOCC2)cc2c(Br)c(-c3ccccc3)[nH]c12

Procedure:
1-BOC-3-bromo-5-bromomethyl-7-nitro-2-phenyl-indole obtained in Step 2 of Preparation 63 and morpholine were reacted to give the title compound, according to the same procedures as Step 3 and 4 of Preparation 63.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10]([C:12]3=[CH:13][CH:14]=[CH:15][C:3](=[C:4]23)[CH:2]=1)=[O:11])=[O:8].[OH-].[Na+].Br[CH:19]1[CH2:23][CH2:22][O:21][C:20]1=[O:24].[Na].O=C1C(N2CC3C=CC=C4C=3C(=CC=C4)C2)CCO1>CN(C)C=O.C(O)C>[O:24]=[C:20]1[CH:19]([N:9]2[C:10](=[O:11])[C:12]3[CH:13]=[CH:14][CH:15]=[C:3]4[C:4]=3[C:5](=[CH:6][CH:1]=[CH:2]4)[C:7]2=[O:8])[CH2:23][CH2:22][O:21]1
Reactant: O=C1OCCC1Br
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Agent: O=C1OCCC1N1Cc2cccc3cccc(c23)C1
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C1OCCC1N1C(=O)c2cccc3cccc(c23)C1=O

Procedure:
10 g. (0.0507 moles) of naphthalimide is dissolved in 200 ml. of hot (90°) dimethylformamide with stirring. 2.06 g. (0.0507 moles) of sodium hydroxide dissolved in 50 ml. of hot ethanol is added causing the naphthalimide sodium salt to precipitate. The sodium salt is filtered off at room temperature, washed with ethanol, and is taken up in 200 ml. of hot (90 °) dimethylformamide. 8.37 g. (0.0507 moles) of 3-bromo-4,5-dihydro-2(3H)-furanone in a small amount of dimethylformamide is added to the sodium salt solution. This mixture is heated at from 80° to 100° for an hour and crude organic material is precipitated by the addition of 500 ml. of water. This material is filtered off, washed with water and recrystallized from 600 ml. of dioxane. Additional recrystallization from 25 ml. of dimethylformamide/25 ml. of isopropyl alcohol yields 3.1 g. of 2-(tetrahydro-2-oxo-3-furanyl)-1H-benz[de]isoquinoline-1,3(2H-dione; m.p. 310°-312°.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][N:7]=1)=O)C.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[F:12][C:11]1[C:6]([CH2:4][OH:3])=[N:7][CH:8]=[C:9]([F:13])[CH:10]=1
Reactant: CCOC(=O)c1ncc(F)cc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: OCc1ncc(F)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 3,5-difluoro-pyridine-2-carboxylic acid ethyl ester of Step A (2.5 g, 12.6 mmol) in ethanol (10 mL), cooled using an ice water bath, was added sodium borohydride (1.43 g, 37.8 mmol) in a portion wise manner. The solution was stirred at 0° C. for thirty minutes and at ambient temperature for two hours. The reaction was returned to 0° C. and saturated ammonium chloride was added dropwise. The solvent was removed in vacuo and the resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated ammonium chloride, water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the alcohol as a yellow oil (1.8 g, 98%). MS (M+H): 146
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=1>CN(C=O)C>[CH3:20][S:19][C:15]1[N:16]=[C:17]([N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[CH:4]2)[CH:18]=[CH:13][N:14]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-n2cnc3ccccc32)n1
Temperature: 100 °C
Yield: 38.6 %

Procedure:
A mixture of NaH (0.548 mg, 22.8 mmol), benzimidazole (0.52 g, 21.3 mmol) and 4-chloro-2-methylthiopyrimidine (2.48 mL, 21.3 mmol) in 30 mL of DMF was heated to 100° C. for 30 min. The reaction was quenched with H2O and extracted with EtOAc. The combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography (silica, 0-10% MeOH:CH2Cl2) to give 1.99 g of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.69 (s, 1H); 8.64 (d, J=5.5 Hz, 1H); 8.22 (dd, J=1.4, 7.3 Hz); 7.89 (dd, J=1.6, 7.3 Hz); 7.44 (m, 2H); 7.23 (d, J=5.7 Hz, 1H); 2.69 (s, 3H).