Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:17]([O:19]C)=[O:18])=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[C:10]([C:17]([OH:19])=[O:18])=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(OC)ccc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(OCc2ccccc2)c(C(=O)O)n1
Reaction time: 3 h
Yield: 63.2 %

Procedure:
Methyl 3-benzyloxy-6-methoxy-picolinate (20 mg) was dissolved in 1 ml of methanol. A 1 N aqueous sodium hydroxide solution (0.33 ml) was added to the solution, and a reaction was allowed to proceed at room temperature for 3 hr. The reaction solution was then adjusted to pH 3 by the addition of 1 N hydrochloric acid. The precipitate was collected by filtration to give 12 mg (yield 63%) of the title compound.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:37][CH2:36][CH2:35][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]1[CH2:34][CH2:33][CH2:32][C@H:17]1[C:18]([NH:20][CH2:21][C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])=[O:19])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].CCOCC>Cl.O1CCOCC1>[NH:1]1[CH2:37][CH2:36][CH2:35][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]1[CH2:34][CH2:33][CH2:32][C@H:17]1[C:18]([NH:20][CH2:21][C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])=[O:19])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.75 h

Procedure:
3.02 g (5.8 mmol) of Boc-Pro-Arg-Pro-Gly-Pro were suspended in 10 ml of 2N hydrochloric acid in dioxane and were incubated at room temperature for 45 min. Then, dry ether was added, and the precipitate was washed by decantation with dry ether. It was reprecipitated with ether from absolute methanol. The resulting precipitate was dissolved in 7.5 ml of 30% ethanol and applied to Amberlyst A-21 (Aco−-form) column for acetate/hydrochloride salt exchange. Peptide was eluted with 200 ml of 30% ethanol, evaporated to dryness under vacuum and precipitated with absolute ether from methanol.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Br:15][C:16]1[N:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[Br:15][C:16]1[N:21]=[CH:20][C:19]([NH:22][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(Br)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a mixture of tert-butyl 4-oxopiperidine-1-carboxylate (1.15 g, 5.78 mmol) and 6-bromopyridin-3-amine (0.5 g, 2.89 mmol) in dichloroethane (20 mL), acetic acid (8 mL, 2.89 mmol) was added and the contents were stirred at room temperature for 3 h. Sodium triacetoxy borohydride (1.225 g, 5.78 mmol) was added and the contents were stirred at room temperature for 12 h. The reaction was diluted with ethyl acetate and washed with brine; the organic layer was separated and concentrated in vacuo. The resulting residue was purified by flash column chromatography to give tert-butyl 4-((6-bromopyridin-3-yl)amino)piperidine-1-carboxylate (0.638 g, 62%); MS: 357.1 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([NH:14]C(=O)OC(C)(C)C)[CH3:13])[C:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[C:5]2[C:28]1[O:32][N:31]=[C:30]([CH3:33])[N:29]=1.O1CCOCC1>C(Cl)Cl.Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([NH2:14])[CH3:13])[C:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[C:5]2[C:28]1[O:32][N:31]=[C:30]([CH3:33])[N:29]=1
Reactant: Cc1noc(-c2c(-c3ccccn3)c(C(C)NC(=O)OC(C)(C)C)nc3ccc(F)cc23)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1noc(-c2c(-c3ccccn3)c(C(C)N)nc3ccc(F)cc23)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of tert-butyl 1-(6-fluoro-4-(3-methyl-1,2,4-oxadiazol-5-yl)-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate (0.246 g, 0.547 mmol) in DCM (1.095 mL) and hydrochloric acid, 4M solution in 1,4-dioxane (2.74 mL, 10.95 mmol) was stirred at rt. After 2.5 h, the mixture was partitioned between DCM (50 mL) and water (50 mL). The acidic aq mixture was washed with DCM (30 mL×2) to remove organic impurities. The aq layer was basified to ˜pH 13 with 10 N NaOH (1.5 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with water (100 mL×1), dried over MgSO4, filtered, and concentrated in vacuo to give 1-(6-fluoro-4-(3-methyl-1,2,4-oxadiazol-5-yl)-3-(pyridin-2-yl)-quinolin-2-yl)ethanamine as a light yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59-8.64 (1H, m), 8.29 (1H, dd, J=9.3, 5.6 Hz), 7.83-7.92 (2H, m), 7.76 (1H, dd, J=10.0, 2.7 Hz), 7.50 (1H, d, J=7.8 Hz), 7.44 (1H, ddd, J=7.6, 4.9, 1.2 Hz), 4.03 (1H, q, J=6.7 Hz), 2.38 (3H, s), 2.03 (2H, br. s.), 1.24 (3H, d, J=6.5 Hz); LC-MS (ESI) m/z 350.1 [M+H]+. The light yellow syrup was carried on crude without purification for the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])ccn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccnc(CBr)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 24.8 %

Procedure:
A solution of 2-methyl-4-nitropyridine (1.79 g, 13.0 mmol) in CCl4 (30 mL) was treated with N-bromosuccinimide (2.31 g, 13.0 mmol) and benzoyl peroxide (420 mg, 1.30 mmol), stirred at 80° C. for 16 h, cooled to room temperature, filtered through Celite, concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (15:1)] to give the title compound (700 mg, 25%) as a colourless oil; NMR δH (400 MHz, CDCl3) 8.89 (1H, d, J 5.0 Hz), 8.19 (1H, d, J 2.0 Hz), 7.96 (1H, dd, J 5.0, 2.0 Hz) and 4.66 (2H, s).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH:10]([CH2:28][CH3:29])[CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[CH2:34][CH2:35][NH2:36]>>[CH2:28]([CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:36][CH2:35][CH2:34][C:33]3[CH:37]=[CH:38][CH:39]=[C:31]([F:30])[CH:32]=3)[N:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:29]
Reactant: NCCc1cccc(F)c1
Reactant: CCC1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CCC1CNCCN1Cc1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1

Procedure:
Intermediate 130 was coupled with 3-fluorophenethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 420. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.25-8.4 (m, 2H) 7.8 (d, 1H) 7.7 (t, 1H) 7.5 (d, 1H) 7.18-7.35 (m, 2H) 7.05-7.15 (m, 2H) 6.9 (m, 1H) 4.72 (d, 1H) 4.1 (d, 1H) 3.92 (br s, 2H) 3.65 (m, 1H) 3.3-3.5 (m, 6H) 3.12 (m, 1H) 3.05 (m, 2H) 2.18 (m, 1H) 1.92 (m, 1H) 1.1 (t, 3H).
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([N+:19]([O-])=O)[CH:7]=1>O.[Fe]>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([NH2:19])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Oc1ccccc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(Br)ccc1Oc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
Iron powder (3 g, 53.4 mmol) and acetic acid (10 mL) were added to a stirred suspension of 4-bromo-2-nitro-1-phenoxybenzene (3.1 g, 9.5 mmol) in water (25 mL) of 60° C. The reaction mixture was heated to 80° C. and stirred for 30 min. After cooling to room temperature the reaction mixture was filtered and extracted with toluene. The toluene solution was washed with water (3×) and brine, dried (Na2SO4) and evaporated to give the crude compound (2.3 g, 87%). Data: (m/z)=264+266 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:23][O:24][CH3:25])=[C:10](/[CH:19]=[CH:20]/[CH2:21]O)[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C1(P(=[CH:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O-2].[O-2].[Mn+4].C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:23][O:24][CH3:25])=[C:10](/[CH:19]=[CH:20]/[CH:21]=[CH:45]/[C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(/C=C/CO)c(COC)nc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)/C=C/C=C/c1c(COC)nc2c(cnn2CC)c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.3 %

Procedure:
A mixture of (2E)-3-[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-propen-1-ol (40 mg), ethyl (triphenylphosphanylidene)-acetate (49 mg), manganese dioxide (103 mg) and DCM (2 ml) was stirred at room temperature for 1 h. The reaction mixture was filtrated through celite pad. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel (CHCl3-MeOH 95:5) to give ethyl (2E,4E)-5-[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-2,4-pentadienoate (53 mg) as a colorless solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([CH:26]([OH:29])[CH2:27][CH3:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:30][O:31][N:32]=[C:33]([N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1O.N(C(OCC)=O)=NC(OCC)=O>CCOCC.C1COCC1>[CH3:30][O:31][N:32]=[C:33]([N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:29][CH:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:27][CH3:28]
Reactant: CON=C(c1ccccc1O)n1ccnc1
Reactant: CCC(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(Oc1ccccc1C(=NOC)n1ccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
Triphenylphosphine (1.05 g), 1-phenylpropyl alcohol (0.54 g) and THF (20 ml) were added to 2-hydroxy-α-(1-imidazolyl)benzaldehyde O-methyloxime (0.43 g), and diethyl azodicarboxylate (0.70 g) was added under ice-cooling over 10 minutes. Then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, ether (100 ml) was added, the mixture was washed with water (80 ml) twice, and the ether layer was concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography to give α-(1-imidazolyl)-2-(1-phenylpropyloxy)benzaldehyde O-methyloxime (0.63 g) as a colorless oil.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Cl[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C.CC(N(C)C)=O>O1CCOCC1>[N:20]1[CH:21]=[CH:22][CH:23]=[N:24][C:19]=1[N:8]1[CH2:7][CH2:6][C:5]2([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]2)[CH2:10][CH2:9]1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ncccn3)CC2)C1
Yield: 51 %

Procedure:
A stirred mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (0.2 mmol, 1 eq.), 2-chloropyrimidine (0.4 mmol, 2 eq.), DIPEA (2 eq.), DMA (2 eq.) in 1,4-dioxane (0.5 ml) was subjected to microwave radiation in a 10 ml pressure tube at 120° C. for 30 min. After concentration, the crude product was purified by column chromatography (silica gel, 20% ethyl acetate in hexane) in order to obtain the desired product. Yield: 51%
Reaction SMILES: O.O.[Sn](Cl)Cl.[N:6]([CH:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[S:34])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[O:28])=[CH:22][CH:21]=2)=[CH:13][C:12]=1[Cl:35])[CH3:10])=[N+]=[N-]>CO.C(OCC)(=O)C>[NH2:6][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[S:34])[NH:19][C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[O:28])=[CH:24][CH:25]=2)=[CH:13][C:12]=1[Cl:35])[CH3:10]
Reactant: CC(N=[N+]=[N-])c1ccc(NC(=S)Nc2ccc(NC(=O)c3ccco3)cc2)cc1Cl
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(N)c1ccc(NC(=S)Nc2ccc(NC(=O)c3ccco3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of tin(II) chloride dihydrate (0.25 g) in methanol (2.5 mL) is added furan-2-carboxylic acid (4- {3-[4-(1-azido-ethyl)-3-chloro-phenyl]-thioureido}-phenyl)-amide (0.22 g) and the solution is stirred for approximately 15 hours at room temperature. The solution is then diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate then saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate. After removal of the solvent by evaporation under reduced pressure the residue is chromatographed over silica gel (8% methanol in dichloromethane containing 1% triethylamine is used as the eluant) to provide the desired product as a yellow solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH2:19][C:20](Cl)=[O:21]>C1COCC1>[C:4]1([C@H:7]2[NH:10][C:20](=[O:21])[CH2:19][O:9][CH2:8]2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: NC(CO)c1ccccc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1COC[C@@H](c2ccccc2)N1
Reaction time: 1 h

Procedure:
(R)-Phenylglycinol (0.20 g, 1.46 mmol) in dry THF (10 mL) was treated with triethylamine (0.18 g, 1.75 mmol) in one portion at 0°, under an atmosphere of nitrogen. Chloroacetylchloride (0.20 g, 1.75 mmol) was added dropwise over 15 minutes at 0°. The mixture was allowed to reach room temperature over 1 hour then quenched with water (5 mL) and EtOAc (5 mL). The organic layer was washed with brine (10 mL), dried (MgSO4) and evaporated in vacuo to a white solid. NMR shows the precursor to the product (non ring closed). The solid was dissolved in dry THF (5 mL) and 10M NaOH was added slowly at 0°. The suspension was allowed to reach room temperature over 1.5 hours. The suspension was diluted with water (10 mL) and EtOAc (10 mL) and the organic layer was further washed with water (10 mL), then dried (MgSO4) and evaporated in vacuo to a crude yellow solid, which was taken to the next step without any purification.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=3[CH2:25][N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH:8]=2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3C=O)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: O
Product: CN1CCN(Cc2ccc(F)cc2-c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)CC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
114 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4-fluorobenzaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 97 μl of 1-methylpiperazine and 50 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 195 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:2][C:3]1[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[CH:7]=1
Reactant: CC(C)(C)c1nn(CCl)cc1Cl
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1nn(CC(C#N)(C#N)CCC(F)(F)F)cc1Cl
Yield: 30 %

Procedure:
0.98 g of 4-chloro-3-t-butyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 0.65 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 12 ml of N,N-dimethylformamide. 1.11 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.40 g of [(4-chloro-3-t-butyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (13), hereinafter) shown by below formula.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8].[H-].[Na+].[CH3:22][C:23]1([CH3:26])[CH2:25][O:24]1>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:22][C:23]([OH:24])([CH3:26])[CH3:25])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC1(C)CO1
Reactant: N#Cc1cc(F)ccc1Oc1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
A solution of 5-fluoro-2-(1H-indazol-5-yloxy)-benzonitrile (0.100 g, 0.395 mmol) in DMF (4 mL) was treated with NaH (0.022 g, 60%, 056 mmol) and stirred for 5 minutes. 2,2-Dimethyloxirane (0.035 g, 0.48 mmol) was added and the solution was stirred at room temperature for 1 hour. The reaction mixture was then heated to 80° C. for 1.5 hours. The solution was cooled to room temperature, diluted with ether (50 mL), washed with water (3×5 mL), brine, dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed eluting with ethyl acetate/hexanes (1:1) to afford 0.070 g of product (47% yield).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:30])[C:11]([F:29])([F:28])[C:12]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])([OH:19])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl.O.C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:30])[C:11]([F:29])([F:28])[C:12]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])([OH:19])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: COc1ccccc1NC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCS
Product: O=C(Nc1ccccc1O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 38.8 %

Procedure:
In 4 ml of methylene chloride was dissolved 80 mg of N-(2-methoxyphenyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide. To the resulting solution were added 120 mg of ethanethiol and 130 mg of aluminum chloride at -5° to 0° C. The resulting mixture was subjected to reaction at 20°-25° C. for 20 hours. Then, the reaction mixture was introduced into a mixed solvent consisting of 10 ml of chloroform and 5 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform/methanol=20/1) to obtain 30 mg of N-(2-hydroxyphenyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccccc1Cl
Product: O=C(O)Cc1ccccc1Nc1ccccc1Cl

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 2-chloroaniline to yield 2-[(2-chlorophenyl)amino]phenylacetic acid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[N:23]1([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:26]1[CH2:25][CH2:24][N:23]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27]1)[CH:11]=[CH:10]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: CCOC(=O)CN1CCNCC1
Product: CCOC(=O)CN1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1
Yield: 64.2 %

Procedure:
Prepared according to the method of example 30, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (200 mg) and 1-piperazineacetic acid, ethyl ester (310 mg) to afford the sub-title compound as a solid (180 mg).
Reaction SMILES: [N+:1]([C:4](=[CH2:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[CH3:13][N:14]([CH3:18])[C:15](=[S:17])[S-:16].C[NH2+]C>C(=S)=S>[CH3:13][N:14]([CH3:18])[C:15](=[S:16])[S:17][CH:5]([CH:4]([N+:1]([O-:3])=[O:2])[CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)C(=S)[S-]
Reactant: C=C(Cc1ccccc1)[N+](=O)[O-]
Agent: C[NH2+]C
Solvent: S=C=S
Product: CC(C(SC(=S)N(C)C)c1ccccc1)[N+](=O)[O-]

Procedure:
As in Example 17, reaction of (2-nitro-2-propenyl)benzene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide, gave α-(1-nitroethyl)benzyl dimethyldithiocarbamate melting at 92° - 94° C. when recrystallized without heating from acetone-ethanol solution.