Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1)=O.[CH3:17][NH:18][CH2:19][CH2:20][NH2:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[C:37](=[O:39])[CH3:38])(=O)C>C1(C)C=CC=CC=1.N1C=CC=CC=1.C(Cl)Cl>[C:37]([N:21]1[CH2:20][CH2:19][N:18]([CH3:17])[CH:1]1[C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1)(=[O:39])[CH3:38]
Reactant: COC(=O)c1cc(C=O)cnc1C(=O)OC
Reactant: CNCCN
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C2N(C)CCN2C(C)=O)cnc1C(=O)OC
Temperature: 0 °C
Reaction time: 66 h
Yield: 57.1 %

Procedure:
A solution of dimethyl 5-formylpyridine-2,3-dicarboxylate (0.75 g, 0.0036 mol), N-methylethylene diamine (0.38 mL, 0.0044 mol) and a catalytic amount of para-toluenesulfonic acid in toluene (10 mL) is heated at reflux temperature for 3 hours. During this process, water is removed by placement of an addition funnel containing 3 angstrom molecular sieves between the reaction flask and the reflux condensor. The reaction mixture is concentrated in vacuo, dissolved in methylene chloride (30 mL) and is washed with saturated aqueous sodium bicarbonate solution. The organic solution is dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. The residue is dissolved in pyridine (10 mL) at 0° C. and treated with acetic anhydride (0.34 mL, 0.0036 mol). The reaction mixture is stirred for 1 hour at 0° C. and for 66 hours at room temperature. The pyridine is removed in vacuo to yield an oil. The oil is dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate. The organic solution is dried over anhydrous magnesium sulfate, concentrated in vacuo and purified by chromatography using silica gel and 10% triethylamine in ethyl acetate as eluant to yield the title compound (0.66 g, 56%) as a yellow oil, identified by IR and NMR spectral analyses.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:6]=1[C:7]([CH3:31])=[C:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:9]([O:16][CH:17]([F:19])[F:18])=[N:10]2.CO.[OH-].[Li+].O>C(O)(=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:5]([CH2:4][C:3]([OH:32])=[O:2])=[C:6]2[C:11]=1[N:10]=[C:9]([O:16][CH:17]([F:19])[F:18])[C:8]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1)=[C:7]2[CH3:31]
Reactant: COC(=O)Cc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1c(Cc2ccc(S(C)(=O)=O)cc2)c(OC(F)F)nc2c(Cl)ccc(CC(=O)O)c12
Reaction time: 2 h

Procedure:
A solution of [8-chloro-2-difluoromethoxy-3-(4-methanesulfonylbenzyl)-4-methylquinolin-5-yl]acetic acid methyl ester (0.030 g), methanol (2.0 mL), saturated aqueous lithium hydroxide solution (0.20 mL) and water (0.40 mL) was stirred at room temperature for 2.5 hours and then at 40° C. for 2 hours. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the solvent removed under reduced pressure. The residue was diluted with water and the solid collected by filtration, washed with water and methanol and then dried to afford title compound as a white solid, 0.016 g.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:5]([C:19](OC)=[O:20])=[C:4]([CH3:23])[N:3]=1.O>C1(C)C=CC=CC=1.O1CCCC1>[OH:9][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:23])=[C:5]([CH2:19][OH:20])[C:6]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1
Reactant: COC(=O)c1c(C)nc(C)c(C(=O)OC)c1-c1ccc(F)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nc(C)c(CO)c(-c2ccc(F)cc2)c1CO
Temperature: 25 °C
Reaction time: 6 h

Procedure:
25 ml (87.5 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene are added under nitrogen to a solution of 7.9 g (25 mmol) of the compound from Example 19 in 100 ml of dry tetrahydrofuran at 0° C. The mixture is stirred at room temperature for 6 h, cooled again to 0° C. and 200 ml of water are slowly added dropwise. The mixture is extracted three times using 150 ml of ethyl acetate each time, the combined organic phases are washed once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is stirred with ether, filtered off with suction and dried in a desiccator.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O.[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1.S(Cl)(Cl)=O>C(Cl)Cl>[N:27]1([C:18](=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=3)[N:4]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=C(Nc1ccccc1)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1C(=Nc1ccccc1)n1nnc2ccccc21
Yield: 58.1 %

Procedure:
A solution of 4-oxo-N-phenyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (0.153 g, 0.426 mmol), 1H-benzo[d][1,2,3]triazole (0.201 g, 1.69 mmol) and thionyl chloride (0.06 mL, 0.82 mmol) in methylene chloride (2 mL) was heated under microwave heating conditions at 80 watts of power for 10 min. After that time, the reaction was concentrated and the crude product purified by flash column chromatography (silica gel, hexanes to ethyl acetate) to give 0.114 g (58%) of 3-[1H-benzotriazol-1-yl(phenylimino)methyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale red solid that was used without further characterization.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[C:28]=2[CH:27]=[CH:26][N:25]=1>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][S:34]([C:29]3[C:28]4[CH:27]=[CH:26][N:25]=[CH:24][C:33]=4[CH:32]=[CH:31][CH:30]=3)(=[O:35])=[O:36])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NS(=O)(=O)c3cccc4cnccc34)cc2)COC1(C)C
Temperature: 50 °C
Reaction time: 6 h
Yield: 64.7 %

Procedure:
(S)-4-[2-(4-Amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (150 mg) was dissolved in tetrahydrofuran at room temperature before treatment with triethylamine (129.8 μl) and isoquinoline-5-sulfonyl chloride (141.4 mg), the reaction mixture was then warmed to 50° C. and stirred for 6 hours. Upon evaporation of the solvent in vacuo the residue was purified by flash column chromatography (SiO2; hexane/EtOAc 3:1) to afford title compound (S)-4-{2-[4-(isoquinoline-5-sulfonylamino)-phenyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (155 mg) as a white solid. MS (ISP): 512.3 ([M+H]+).
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9]CN2CCCC2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH3:18]OC1C=CC(N)=C(C)C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[CH:16][C:17]=1[CH3:18])=[C:2]=[S:3]
Reactant: COc1ccc(N)c(C)c1
Reactant: S=C=Nc1ccc(OCCN2CCCC2)cc1
Product: COc1ccc(N=C=S)c(C)c1

Procedure:
The title compound is prepared as described in Example 1 for 1-[2-(4 isothiocyanato-phenoxy)-ethyl]-pyrrolidine but using 4-methoxy-2-methylaniline. Title compound: ES-MS: 180.9 [M+H]+; single peak at tR=5.56 min (System 2).
Reaction SMILES: [CH3:1][S:2]C1C=C(C=CC=1)N.[CH3:10][S:11][C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][CH:25]=1)[NH:15][CH:16]=[C:17](C)[C:18]([O:20]C)=S.C([O-])(=O)C=C>>[CH3:1][S:2][CH:17]1[C:18](=[O:20])[C:23]2[C:14](=[CH:13][C:12]([S:11][CH3:10])=[CH:25][CH:24]=2)[N:15]=[CH:16]1
Reactant: CSc1cccc(N)c1
Reactant: COC(=S)C(C)=CNc1cccc(SC)c1
Agent: C=CC(=O)[O-]
Product: CSc1ccc2c(c1)N=CC(SC)C2=O

Procedure:
Using the methods described in Example 11 and Example 12, 3-methylthioaniline was converted to methyl 3-(3-methylthioanilino)-2-methylthioacrylate, m.p. 90°-92°. This acrylate was cyclised to give 3,7-bis(methylthio)4-quinolone, m.p. 197°-200°, containing the corresponding 5-methylthio isomer. This product was methylated with dimethyl sulphate in aqueous potassium hydroxide at room temperature to give a mixture of 1-methyl-3,7-bis (methylthio)-4-quinolone and 1-methyl-3,5-bis(methylthio)-4-quinolone. This mixture was separated by high pressure liquid chromatography to give 1-methyl-3,7-bis(methylthio)-4-quinolone, m.p. 154°-155° (from ethanol). Oxidation of this compound with 3-chloroper benzoic acid gave 1-methyl-3-methylsulphinyl-7-methylthio-4-quinolone, m.p. 196°-198° (from ethanol).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50]O)[CH:46]([O:52]O)[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2].B(F)(F)F.CCOCC.[N+](=[C:68]([CH3:70])[CH3:69])=[N-]>C(OCC)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:52][CH:68]([CH3:70])[CH3:69])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CC(C)=[N+]=[N-]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OO)C(OO)C3)C(C)CCC1=O)C(C)CC2OC
Agent: FB(F)F
Solvent: CCOCC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4",3"-dihydroxyoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg) in diethyl ether (6 ml) is added boron trifluoride etherate (10 ml) followed by freshly prepared 2-diazopropane (100-fold excess). The mixture is stirred at room temperature for 15 min. and quenched with sat'd aqueous sodium bicarbonate solution. The organic layer is separated, washed with sat's NaCl and dried over sodium sulfate. Removal of solvent followed by preparative TLC on silica gives the title compound and its 4" isomer.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([N+:24]([O-])=O)[CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.Cl.C(O)C.[CH3:31][N:32]1[C:36]([C:37](Cl)=[O:38])=[CH:35][C:34]([CH3:40])=[N:33]1>C(=O)([O-])O.[Na+].O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[C:22]([NH:24][C:37]([C:36]5[N:32]([CH3:31])[N:33]=[C:34]([CH3:40])[CH:35]=5)=[O:38])[CH:23]=[C:2]([F:1])[CH:3]=4)=[CH:11][N:10]3[N:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(Nc1nc2ccc(Oc3cc(F)cc([N+](=O)[O-])c3)cn2n1)C1CC1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)Nc2cc(F)cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n(C)n1
Reaction time: 1 h
Yield: 27.5 %

Procedure:
A mixture of N-[6-(3-fluoro-5-nitrophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (130 mg, 0.364 mmol), reduced iron (150 mg), concentrated hydrochloric acid (300 μL), ethanol (3 mL) and water (3 mL) was stirred under refluxing conditions for 1 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylacetamide (3 mL). 1,3-Dimethyl-1H-pyrazole-5-carbonyl chloride (69.3 mg, 0.437 mmol) was added thereto with stirring under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate to give the title compound (45.0 mg, 28%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22]CC)=[O:21])[CH2:16][C@H:15]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:12])=[CH:5]2.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[C:20]([C@H:17]1[CH2:18][CH2:19][C@@H:14]([NH:13][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:12])[C@H:15]([NH:25][C:26]([C:28]2[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=2)=[O:27])[CH2:16]1)([OH:22])=[O:21]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 12 h
Yield: 78.4 %

Procedure:
(1R,2R,4S)-N1-[(5-Chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine (1.6 g) was suspended in a mixed solvent of ethanol (20 ml) and tetrahydrofuran (15 ml), and a 1N aqueous solution (5.9 ml) of sodium hydroxide was added at room temperature to stir the mixture for 12 hours at the same temperature. After adding 1N hydrochloric acid (5.9 ml), the solvent was distilled off under reduced pressure, and the residue was washed with water and ether to obtain the title compound (1.19 g) as a colorless solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([NH2:17])[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[C:1]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([NH2:17])=[CH:11][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
Benzoyl chloride (10.7 ml, 92.5 mmol) was added to a stirred solution of 1,4-phenylenediamine (10.0 g, 92.5 mmol) and triethylamine (14.2 ml, 102 mmol) in dichloromethane (250 ml) at 0° C. The reaction was allowed to warm to ambient temperature over 3 hours, the solid was filtered off and water (100 ml) was added to the filtrate, causing precipitation of a second solid. Collection of this solid by suction filtration and drying in vacuo yielded N-benzoyl 4-aminoaniline (5.55 g, 28% yield) as a white solid:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:12]=[C:11]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:37]=[CH:36]3)[C:10]=1[CH2:49][CH3:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:54][B:55](OC(C)C)[O:56]C(C)C)(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=[C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:12]=[C:11]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[N:38]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[C:37]([B:55]([OH:56])[OH:54])=[CH:36]3)[C:10]=1[CH2:49][CH3:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCc1c(-c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1c(-c2ccc3c(c2)cc(B(O)O)n3C(=O)OC(C)(C)C)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Yield: 24 %

Procedure:
To a solution of tert-butyl 5-(4,6-bis(benzyloxy)-5-((benzyloxy)carbonyl)-3-ethylpyridin-2-yl)-1H-indole-1-carboxylate, prepared according to the protocol described in Example 412, step 3 (3.07 g, 4.59 mmol), triisopropylborate (1.17 mL, 5.51 mmol) in THF (15 mL), at −78° C. was added while stirring, LDA (3.67 mL, 1.5 M in cyclohexane, 5.51 mmol). The mixture was stirred for 0.5 h after the addition and the cooling bath was removed to allow the reaction mixture to warm to room temperature and stirred for an additional 0.5 h. The reaction was quenched with 6 N HCl at 0° C. and acidified to pH 4 and the mixture was diluted with DCM and water. The organic layer was separated, washed with water, brine and dried over anhydrous Na2SO4. The filtrate was concentrated and chromatographed (ethyl acetate in DCM, 0-40%) to give the boronic acid intermediate as light yellow powder (0.78 g) in 24% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.[CH2:16]([CH2:18][NH2:19])[OH:17].C(N(CC)CC)C.CO>>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:19]([CH2:18][CH2:16][OH:17])[CH:6]=[CH:5]2
Reactant: NCCO
Reactant: O=c1occc2c([N+](=O)[O-])c(Cl)ccc12
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1c2ccc(Cl)c([N+](=O)[O-])c2ccn1CCO
Reaction time: 1 h

Procedure:
A microwave vial was charged with 6-chloro-5-nitro-1H-isochromen-1-one (1.0 g, 0.00443 mol), ethanolamine (0.401 mL, 0.00665 mol), triethylamine (1.24 mL, 0.00886 mol) and methanol (30 mL, 0.7 mol) and the reaction was subjected to microwave at 100° C. for 1 hour. the solvent was removed under reduced pressure and the residue purified by flash chromatography to afford the product as a yellow solid. MS m/z=269.4 (M+H). 1H NMR (400 MHz; CDCl3) 8.41 (d, J=8.56 Hz, 1H), 7.52 (d, J=8.56 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.31 (d, J=8.56 Hz, 1H), 4.17 (t, J=44.88 Hz, 2H), 3.99 (t, J=5.11 Hz, 2H), 2.55 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6](Cl)[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1.Cl.[F:22][C:23]([F:28])([F:27])[C@@H:24]([NH2:26])[CH3:25].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([NH:26][C@@H:24]([CH3:25])[C:23]([F:28])([F:27])[F:22])[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ncnn3c2Cl)c(F)c1
Reactant: C[C@H](N)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncnn12)C(F)(F)F
Temperature: 25 °C
Reaction time: 13 h
Yield: 95.7 %

Procedure:
A mixture of 5,7-dichloro-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine (3.0 g, 9.4 mmol), (1S)-2,2,2-trifluoro-1-methylethylamine hydrogen chloride (4.2 g, 28.2 mmol), and N,N-diisopropylethylamine (4.9 mL, 28.2 mmol) in 100 mL of N,N-dimethylformamide is stirred at room temperature under nitrogen atmosphere for 13 h. The reaction mixture is diluted with ethyl acetate. The organic layer is washed with 1 N hydrochloric acid (2×) and saturated sodium chloride (2×), dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with 20% ethyl acetate in hexanes. Concentration provides 5-chloro-6-(2,4,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine as a light yellow solid (3.56 g). MS: m/z 396.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3[N:11]=[C:12]([CH3:14])O[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:17]=1.[CH3:18][NH2:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3[N:11]=[C:12]([CH3:14])[N:19]([CH3:18])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:17]=1
Reactant: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2o1
Reactant: CN
Product: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2n1C
Temperature: 40 °C

Procedure:
A mixture of the product from step (i) (3.33 g), and 40% w/v aqueous methylamine solution was heated at 40° C. for 4 h. The solid was filtered and washed with water then dried under vacuum to give the subtitled product as a cream powder.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].ClC(Cl)=C(Cl)C(Cl)=C(Cl)Cl.[CH3:16][N:17]([Si:19]([CH3:22])([CH3:21])Cl)[CH3:18]>>[CH3:16][N:17]([Si:19]([CH3:22])([CH3:21])[C:1]#[C:2][C:3]#[C:4][Si:19]([N:17]([CH3:18])[CH3:16])([CH3:22])[CH3:21])[CH3:18]
Reactant: CN(C)[Si](C)(C)Cl
Reactant: [Li]CCCC
Agent: ClC(Cl)=C(Cl)C(Cl)=C(Cl)Cl
Product: CN(C)[Si](C)(C)C#CC#C[Si](C)(C)N(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A flame dried 250 ml Schlenk flask containing THF (20 ml) was cooled to −78°C. and n-butyl lithium (20 ml of 2.4 M in hexane, 48.0 mmol) was added by syringe. After several minutes hexachlorobutadiene (1.88 ml, 12.0 mmol) was added dropwise via syringe over a 10 minute period. After completion of addition, the cold bath was removed and the mixture stirred at room temperature for 3 hours. The resulting 1,4-dilithio-1,3-butadiyne was used without further purification. The flask was then recooled to −78° C., and dimethylaminodimethylchlorosilane (3.6 ml, 24 mmol) was added by syringe. The flask was removed from the cold bath and the reaction mixture stirred at room temperature for 16 hours. At this time 1H NMR analysis indicated complete disappearance of dimethylaminodimethylchlorosilane and formation of 1,4-bis-(dimethylaminodimethylsilyl)-butadiyne. The THF was removed in vacuo, and the mixture was taken up in a minimum amount of pentane and filtered. The pentane was removed in vacuo to give 2.91 g (96%) of 1,4-bis(dimethylaminodimethylsilyl)butadiyne.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1OC1C.COC1C(OCCCCCCCC2C=CC=CC=2)=C2C(=C([N+]([O-])=O)C=1)N=CC=C2C>CCOCC.CCN(CC)CC.CN(P(N(C)C)(N(C)C)=O)C>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[C:4]2[CH3:17]
Reactant: BrCCCCc1ccccc1
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Agent: CC1CO1
Agent: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCc1ccccc1
Reaction time: 5 h

Procedure:
To a stirred mixture of 5-hydroxy-6methoxy-4-methyl-8-nitroquinoline (5.9 g, 0.025 mol), 1-bromo-4-phenylbutane (4.3 g, 0.02 mol) and HMPA (15 ml), at 110°-115° C., was added dropwise, during 1 h, a mixture of propylene oxide (6 ml) and Et3N (1 ml). The reaction was continued for 5 h, allowed to cool and extracted successively with pet ether, Et2O and Me2CO leaving 1.1 g of insoluble starting material, 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline. The pet ether and Et2O fractions were worked up as described above for 6-methoxy-4-methyl-8-nitro-5-(7-phenylheptoxy)quinoline (see example 1, part b) to give crude 6-methoxy-4-methyl-8-nitro-5(4-phenylbutoxy) quinoline as an oil. This material was dissolved in CHCl3, placed on a silica gel column and eluted with CHCl3. The eluates were concentrated to an oil which on trituration with pet ether gave 3.2 g (43%) of 6-methoxy-4-methyl-8-nitro-5-(4-phenylbutoxy) quinoline as yellow-green crystals, mp 88°-89° C. Recrystallization from hexane provided the analytical sample, mp 90°-91° C.