Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:6].CS(Cl)(=O)=O>C(Cl)Cl>[C:5]1(=[O:6])[C:4]2[C:3](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:2][N:7]1[CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: O=C(NCCSc1ccncc1)c1ccccc1CO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: O=C1c2ccccc2CN1CCSc1ccncc1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
To a solution of 1.153 g (4.0 mmol) of 4-[2-(2-hydroxymethylbenzoyl)aminoethylthio]pyridine and 1.68 ml (12.1 mmol) of triiethylamine in 50 ml of methylene chloride, 0.62 ml (8.0 mmol) of methanesulfonyl chloride was added with stirring at room temperature, and the mixture was stirred at room temperature for 30 minutes. The mixture was washed with saturated aqueous sodium bicarbonate, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) to give 623 mg of the desired compound (57.6% yield, colorless crystals), mp. 86°-87° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O.O>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH2:20][CH2:19]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 122 °C
Reaction time: 24 h
Yield: 53.6 %

Procedure:
To a suspension of 1-fluoro-3-nitrobenzene (3.77 mL, 35.4 mmol) and potassium carbonate (10 g, 71 mmol) in DMSO (30 mL) was added 1-methyl piperazine (59 mL, 53.2 mmol). The mixture was stirred at 122° C. for 24 hours. After cooing down, the mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried with sodium sulfate (Na2SO4), and concentrated in vacuo to afford an orange oil. Recrystallization from EtOAc/hexanes gave 4.2 g of 1-(4-methyl-piperazin-1-yl)-3-nitrobenzene, which was reduced via hydrogenation to give the title compound (beige solid, 3 g). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.04 (t, J=8.0 Hz, 1H), 6.38 (dd, J=2.3, 8.2 Hz, 1H), 6.26 (t, J=2.2 Hz, 1H), 6.22 (dd, J=2.3, 8.2 Hz, 1H), 3.60 (br, 2H), 3.18 (t, J=4.9 Hz, 4H), 2.55 (t, J=4.9 Hz, 4H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N>ClCCCl>[Br:21][CH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2)nn1
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: ClCCCl
Product: BrCc1ccc(-c2ccccc2)nn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a solution of 3-methyl-6-phenylpyridazine (925 mg, 5.43 mmol) in 1,2-dichloroethane (28 ml) were added NBS (1.07 g, 6.01 mmol) and 2,2′-azobis(2,4-dimethylvaleronitrile) (67.3 mg, 0.271 mmol), followed by stirring at 80° C. for 1 hour. During the reaction, 2,2′-azobis(2,4-dimethylvaleronitrile)(134 mg, 0.540 mmol) was additionally added in two portions. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=5:1→0:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (449 mg) as a slightly brown solid. (Yield: 33%)
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].[OH-].[Na+].[Br-].[Na+]>>[N:1]([C:2]([CH3:6])([CH3:5])[C:3]#[N:4])=[N:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4]
Reactant: CC(C)(N)C#N
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C#N)N=NC(C)(C)C#N

Procedure:
By method of Example 2, 2-amino-2-methylpropanenitrile (of 78.5% purity) was dichlorinated and coupled with further 2-amino-2-methylpropanenitrile in the presence of caustic soda and the following combinations of tetra alkyl quaternary ammonium chloride surfactant and added sodium bromide. The yields of title compound obtained were as shown.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.[Cl:21]CCCl>>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:21])=[O:14])=[CH:11][N:10]=1)[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)cn1
Reactant: ClCCCl
Agent: CN
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(tert-Butoxycarbonyl-methyl-amino)-nicotinic acid (12.5 g, 47.0 mmol) (prepared analogously to A-08 using methyl amine instead of ethylamine) is taken up in 300 mL DCE, 1-chloro-N,N-2-trimethylpropenyl-amine (10.0 mL, 74.8 mmol) is added and the reaction mixture is stirred overnight at RT. The reaction mixture is concentrated under reduced pressure and the crude product is used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12](=O)([O-])[O-].[K+].[K+].CI.ClCCl>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of 3-fluoro-4-nitro-phenol (25.3 g, 0.16 mol) in acetone (160 ml), potassium carbonate (41.7 g, 0.30 mol) and methyl iodide (20.0 ml, 0.32 mol) are added at ambient temperature. The reaction mixture is stirred at 40 C.° for 3 h. After cooling down to room temperature, dichloromethane is added to the reaction mixture, which is filtrated and evaporated. Dichloromethane is added to the residue and the organic phase is washed with H2O and brine, dried over sodium sulfate and evaporated down to give 2-fluoro-4-methoxy-1-nitro-benzene in 98% yield.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[CH2:6][CH2:5][NH:4]1.[H][H]>C(O)C>[ClH:1].[CH3:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5][NH:4]1
Reactant: [H][H]
Reactant: CC1NCCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: CCO
Product: CC1NCCc2ccc(N)cc21

Procedure:
A suspension of 1-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.0 g, 8.75 mmol) in ethanol (100 ml) and a catalytic quantity of 10% Pd--C was hydrogenated until no more hydrogen was taken up. The catalyst was filtered off, the solvent was concentrated to a small volume, ether was added and the precipitated solid was collected and dried: 1.39 g (78%), MS (M+H)+ 163.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[C:16]#[N:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(O)(=O)C.[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[CH2:16][NH2:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C#N)CC1
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN)CC1
Reaction time: 22 h
Yield: 99.5 %

Procedure:
Platinum oxide (200 mg) was added to a solution of 2-[4-(t-butoxycarbonyl)piperazin-1-yl]benzonitrile (2.01 g, 7 mmol) in ethanol-acetic acid (95:5, 35 mL) and the mixture was shaken under hydrogen (50 psi) for 22 h, adding further platinum oxide (1 g) after 4 h. The mixture was filtered through Hyflo, further ethanol (85 mL), acetic acid (15 mL) and platinum oxide (1 g) were added and the mixture was shaken under hydrogen (50 psi) for 6 h., adding further platinum oxide (200 mg) after 2 h. and 4 h. The mixture was filtered through Hyflo and the solvent was evaporated under reduced pressure. Water (50 mL) was added, the pH was adjusted to 10.0 with aqueous potassium carbonate (saturated) and the mixture was extracted with ether (3×50 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the crude title compound as a pale yellow oil (2.03 g, 100%), δH (360 MHz, CDCl3) 7.34-7.08 (4H, m), 3.91 (2H, s), 3.57 (4H, t, J 4.9 Hz), 2.87 (4H, t, J 4.9 Hz), 1.60 (2H, br s), and 1.49 (9H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:23])[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17]OS(C)(=O)=O)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:24]#[N:25].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][C:24]#[N:25])[CH2:13][CH2:12]1)[CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CN(CC[C@H]1CC[C@H](COS(C)(=O)=O)CC1)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC[C@H]1CC[C@H](CC#N)CC1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To 12.64 g (36.17 mmol) of trans-methanesulfonic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester in 100 mL of DMF were added 4.51 g (92 mmol, 2.6 eq) of sodium cyanide, and the solution was stirred at 80° C. for 2 hours. After cooling the reaction mixture to RT, it was partitioned between ether and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 10.14 g (quantitative) of crude trans-[2-(4-cyanomethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester as colorless oil, MS: 298 (M+NH4+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1)=[N+]=[N-].[ClH:16].[H][H]>CO.[Pd].O.C(O)C>[ClH:16].[NH2:1][CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])cc1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(CN)cc1O
Temperature: 25 °C
Yield: 65 %

Procedure:
Crude methyl 4-(azidomethyl)-2-hydroxybenzoate was dissolved in methanol (750 mL) in a 2 L Parr hydrogenation flask. Palladium on carbon catalyst (10% [w/w], 3.8 g) in water (25 mL) was added, followed by concentrated hydrochloric acid (35 mL). The flask was affixed to a Parr hydrogenator, and the mixture was shaken at room temperature under 40 psi of hydrogen for 16 hours. The reaction mixture was then filtered through a 0.45 mm nylon filter. The retained solid was then washed with methanol (150 mL), water (100 mL), and methanol again (150 mL). The combined filtrates were evaporated to dryness to afford a tan solid. This solid was dissolved in hot denatured ethanol (150 mL) and the solution was allowed to cool to room temperature. White crystals formed quickly. Finally, the mixture was then chilled for 16-18 hours at 4° C. to complete crystallization. The solid was filtered, washed with a little cold ethanol (50 mL) and then diethyl ether (150 mL), and dried in vacuo over potassium hydroxide pellets to afford 51.5 g (65% yield based on methyl 4-bromomethyl-2-hydroxybenzoate) of methyl 4-aminomethyl-2-hydroxybenzoate hydrochloride (m.p. 225-227° C., open capillary, uncorrected).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1>N1C=CC=CC=1>[F:21][C:18]([F:19])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cn1)Oc1ccccc1
Temperature: 21 °C
Reaction time: 0.5 h

Procedure:
Phenyl chloroformate (1.92 g, 12.3 mmol) was added to a stirring solution of 2-amino-5-trifluoromethylpyridine (2.0 g, 12.3 mmol) in pyridine (20 mL) at a rate which maintained the temperature at 21° C. The mixture was stirred for an additional 0.5 hr and the resulting precipitate was collected by filtration, extracted with ether, then dried to obtain 2.33 g (67 percent of theory) of the title compound as white crystals melting at 203° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:12](O)[CH2:13][OH:14]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]1[O:14][CH2:13][CH2:12][O:5]1
Reactant: OCCO
Reactant: COc1ccc(Br)c(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Br)c(C2OCCO2)c1
Yield: 95.2 %

Procedure:
A mixture of 2-bromo-5-methoxy-benzaldehyde (45.25 g), ethylene glycol (52.22 g) and 4-toluenesulphonic acid (0.4 g) in toluene (400 mL) is heated at reflux for 5 hours using a Dean and Stark apparatus to remove water formed in the reaction. The reaction mixture is washed five times with water (500 mL) and evaporated giving 2-(2-bromo-5-methoxyphenyl)-[1,3]dioxolane (51.9 g) as a yellow liquid.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](O)=[O:4].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH2:25]([O:32][C:33](=[O:44])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39](=[O:43])[C@H:40]([CH3:42])[NH2:41])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.C(Cl)(Cl)Cl>[CH2:25]([O:32][C:33](=[O:44])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39](=[O:43])[C@H:40]([CH3:42])[NH:41][C:3](=[O:4])[C@@H:2]1[CH2:6][CH2:7][CH2:8][NH:1]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 2.5 h

Procedure:
Ac-L-proline (3.05 g, 19.41 mmol) was dissolved in dry tetrahydrofuran (100 ml) under an argon atmosphere in a flask fitted with an overhead stirrer and an internal thermometer. The solution was cooled to -15° C. and N-methylmorpholine (2.13 ml, 19.41 mmol) was added followed by isobutylchloroformate (2.51 ml, 19.41 mmol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. Five minutes after the addition was completed, a solution of L-alanyl-L-proline benzyl ester hydrochloride (6.08 g, 19.41 mmol) in chloroform (70 ml) was added followed by a second portion of N-methylmorpholine (2.13 ml, 19.41 mmol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. The reaction mixture was then allowed to slowly warm to room temperature and stirred at room temperature for 2.5 hours. The reaction mixture was concentrated to a small residue on a rotary evaporator, diluted with chloroform (500 ml) and poured into a separatory funnel where it was washed with 0.2 N hydrochloric acid (3×200 ml) and 5% sodium bicarbonate (200 ml). The organic layer was dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and chromatographed using methylene chloride-methanol as an eluent to give Ac-L-prolyl-L-alanyl-L-proline benzyl ester; Rf: 0.35 (CH3OH/CH2Cl2 --7:93).
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1.[CH:41]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH2:42].CCO>CC(O)C>[CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:42][CH2:41][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:33][CH2:34]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Reactant: C=CS(C)(=O)=O
Solvent: CCO
Solvent: CC(C)O
Product: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(CCS(C)(=O)=O)CC2)C4)c(C)c1
Temperature: 100 °C
Yield: 77.6 %

Procedure:
A mixture of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (3.04 g, 5.6 mmol) and methyl vinyl sulfone (5.94 g, 56 mmol) in a mixed solvent of EtOH (70.0 mL) and 2-propanol (70.0 mL) was heated at 100° C. for 22 h and then evaporated. Chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (190:10:1) afforded title compound (2.82 g, 78%). 1H NMR (DMSO-d6) δ 1.68-1.85 (4H), 2.15 (m, 2H), 2.18 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.75 (m, 2H), 3.05 (m, 2H), 3.08 (s, 3H, CH3), 3.54 (m, 1H), 3.70 (m, 1H), 3.93-4.19 (4H), 4.43 (s, 1H), 4.47 (s, 1H), 5.48 (d, J=6 Hz, 0.5H, NH), 5.53 (d, J=6 Hz, 0.5H, NH), 6.20 (m, 1H), 6.81 (m, 1H), 6.90-6.99 (2H), 7.31-7.37 (1.5H), 7.67 (s, 0.5H), 7.80 (s, 0.5H), 7.94 (s, 0.5H), 11.14 (br d, J=6 Hz, 1H, NH), 11.22 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 649.5 (MH+); Anal. Calcd for C33H40N6O6S: C, 61.09; H, 6.21; N, 12.95, S 4.94; Found: C, 60.85; H, 6.17; N, 12.87, S 4.85.
Reaction SMILES: [C:1]1(=[N:10]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([NH:10][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: ON=C1CCc2ccccc21
Solvent: c1ccncc1
Product: CC(=O)NC1=CCc2ccccc21
Reaction time: 2.5 h

Procedure:
1-Indanone oxime (7.02 g, 0.048 moles), pyridine (250 ml) and acetic anhydride (170 ml) were stirred and heated under nitrogen at reflux for 16.5 hours. The cooled mixture was evaporated in vacuo and the residue agitated thoroughly with 1N sodium carbonate solution and ether (250 ml each). The liquid was filtered through filter-aid and the black solid treated again with sodium carbonate/ether and filtered. The combined ether extracts and washes were dried (MgSO4) and evaporated to a black-orange oil (8.6 g). This was applied to a column of basic alumina, allowed to stand for 2.5 hours and eluted with ethyl acetate/hexane 1:2 v/v. The appropriated fractions were evaporated to leave a crude solid (3 g). This was recrystallized from ethyl acetate/hexane to give the title product, mp. 139° C., (1.44 g, 17%) with the same IR spectrum as in Example 1.
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)[CH2:3][C:4]#[N:5].[NH2:13][NH2:14].CCO.OP(O)(O)=O>O.CO>[Br:12][C:8]1[CH:7]=[C:6]([C:2]2[CH:3]=[C:4]([NH2:5])[NH:13][N:14]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: N#CCC(=O)c1cccc(Br)c1
Reactant: NN
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: O
Solvent: CO
Product: Nc1cc(-c2cccc(Br)c2)n[nH]1

Procedure:
Ten vials were each charged with 3-oxo-3-(3-bromophenyl)propionitrile (1.0 g, 4.5 mmol), hydrazine (0.2 mL) and EtOH (1 mL), and subject to microwave irradiation at 120° C. for 60 min. The contents of all vials was pooled and the solvent was evaporated in vacuo. The crude product was dissolved in ethanol (approx. 200 mL) and acidified by the addition of 4N HLC in dioxane, after 0.5 h the precipitate was collected, washed with additional ethanol and dried to yield 9.60 g. LC/MS (10% MeOH, 90% H2O, 0.2% H3PO4 to 90% MeOH, 10% H2O, 0.2% H3PO4, 2 minute gradient with an Exterra C18 S-5 column 4.6×30 mm): [M+H]+ m/z=239.0, 241.0; retention time=0.85 min.
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[C:19][C:20]([OH:22])=O)[CH2:13][CH2:12]1)[CH3:10].CN1CCOCC1.[NH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][C:35]([C:41]#[N:42])=[C:34]2[NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Br:50])[CH:45]=1>O1CCCC1.N1C=CC=CC=1>[Br:50][C:46]1[CH:45]=[C:44]([NH:43][C:34]2[C:33]3[C:38](=[CH:39][CH:40]=[C:31]([NH:30][C:20](=[O:22])[C:19]#[C:18][CH2:17][N:14]4[CH2:13][CH2:12][N:11]([CH2:9][CH3:10])[CH2:16][CH2:15]4)[CH:32]=3)[N:37]=[CH:36][C:35]=2[C:41]#[N:42])[CH:49]=[CH:48][CH:47]=1
Reactant: CCN1CCN(CC#CC(=O)O)CC1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: CCN1CCN(CC#CC(=O)Nc2ccc3ncc(C#N)c(Nc4cccc(Br)c4)c3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Isobutyl chloroformate (0.785 g, 5.75 mmol) was dropwise added into an ice cold solution of 4-(N-ethylpiperazino)-2-butynoic acid (1.75 g, 8.85 mmol) and N-methylmorpholine (1.3453 g, 13.3 mmol) in 50 mL of tetrahydrofuran under N2. After stirring for 30 min, a solution of 1.5 g (4.42 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by flash column chromatography. The product fractions were collected, and dried in vacuo to give 1.07 g (46%) of light brown solid; ESMS m/z 517.1, 519.1 (M+H+); mp 161° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9](OC)=[O:10])[CH:7]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:17][C:9](=[O:10])[CH:8]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1C(=O)Nc2ccc(F)cc21
Temperature: 42.5 °C
Yield: 118.4 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a gas inlet tube and having an inner volume of 500 ml were charged 60.0 g (0.22 mol) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate synthesized according to Example 1 with a purity of 98% and 228 g of methanol under argon atmosphere. Under stirring, while maintaining the temperature of the mixture to 40 to 45° C., 3.0 g (0.72 mmol in terms of the palladium atom) of 5% by weight palladium/carbon (49% hydrated product) was added to the mixture. Then, while blowing hydrogen with a flow rate of 123 ml/min. and a normal pressure, the mixture was reacted at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered to remove the catalyst, the filtrate was concentrated under reduced pressure, and 80 ml of methanol and 240 ml of water were added to the resulting concentrate and cooled to 10° C. Then, after filtration of the precipitated crystals, they were dried to obtain 54.5 g (isolation yield: 94%) of 5-fluoro-3-methoxycarbonyloxindole as white crude crystals with a purity of 80% (analytical value by high performance liquid chromatography).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[C:4]([N+:9]([O-])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1>[Fe]>[Br:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Br)c1Cl
Agent: [Fe]
Product: Nc1cc(Cl)cc(Br)c1Cl

Procedure:
3-Bromo-2,5-dichloro nitrobenzene (D9) was treated with iron powder in the manner described in Description 7 to give the title compound (D10) as a solid (77%), MH+ 240/242.
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1.CO.C(Cl)(Cl)Cl>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:3][C:4]1[C:13]([I:1])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1
Reactant: II
Reactant: COC(=O)c1ccc(N)nc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: COC(=O)c1cnc(N)c(I)c1
Temperature: 25 °C
Yield: 62.2 %

Procedure:
To a solution of iodine (3.55 g, 14.0 mmol) in 100 mL absolute ethanol at room temperature was added silver sulfate (4.37 g, 14.0 mmol) and methyl 6-aminonicotinate (1.52 g, 10.0 mmol). After 42 hours the reaction was filtered to isolate a tan precipitate. The solid was heated with 20% MeOH/CHCl3 then cooled to room temperature, filtered, and rinsed with MeOH and CHCl3. The filtrate was evaporated, dissolved in hot MeOH, filtered to remove brownish impurities, and then crystallized from MeOH to give the title compound as a light tan solid (1.73 g, 62%).