Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH2:23][F:24])([CH2:21][F:22])[CH:9]=1)=O)#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1C=CC=CC=1>[C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH2:23][F:24])([CH2:21][F:22])[CH:9]=1)=[S:34])#[N:2]
Reactant: N#CCCNC(=O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: N#CCCNC(=S)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Yield: 36.4 %

Procedure:
A mixture of 0.11 g of N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-nitro-2H-1-benzopyran-4-carboxamide and 0.17 g of a Lawesson's reagent and 10 ml of benzene was refluxed with heating for 2 hours. The solvent was distilled and the obtained residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) and further recrystallyzed by a mixed solvent of ethyl acetate and hexane to obtain 42 mg of N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-nitro-2H-1-benzopyran-4-carbothioamide with a melting point of 114°-116° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:28][OH:29].O>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]([NH:28][OH:29])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2Cc3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A mixture of 3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (15.0 g, 42.7 mmol) and N,N′-carbonyldiimidazole (7.27 g, 44.8 mmol) in tetrahydrofuran (50 mL) under nitrogen was stirred at room temperature for 2 hours. To the resulting solution was added hydroxylamine hydrochloride (3.86 g, 55.5 mmol). The resulting suspension was stirred for 18 hours. To the suspension was added water (150 mL) and stirring was continued for 1 hour. The suspension was filtered, the solid was washed with water (5×30 mL) and ether (2×20 mL), and then was dried in a vacuum oven overnight (60° C., <1 torr) to give 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propion-amide as a white solid (13.0 g, 82% yield): mp, 167-168° C.; 1H NMR (DMSO-d6) δ1.29 (t, J=6.9 Hz, 3H, CH3) 2.81-2.86 (m, 2H, CH2), 3.72 (s, 3H, CH3), 3.96-4.04 (m,2H, CH2), 4.13 (d, J=17.5 Hz, 1H, CHH), 4.54 (d, J=17.5 Hz, 1H, NCHH), 5.73 (t, J=7.9 Hz, 1H, NCH), 6.84-6.92 (m, 3H, Ar), 7.43-7.68 (m, 4H, Ar), 8.83 (br.s, 1H, OH), 10.61 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.68, 35.04, 46.22, 51.20, 55.44, 63.73, 111.85, 112.19, 119.21, 122.78, 123.43, 127.83, 131.29, 131.85, 132.27, 141.67, 147.85, 148.42, 165.99, 166.82. Anal. Calcd for C20H22N2O5: C, 64.85; H, 5.99; N, 7.56. Found: C, 64.73; H, 6.17; N, 7.36.
Reaction SMILES: C(O[C:4]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([C:12]#[N:13])[S:6](=[O:15])(=[O:14])[N:5]=1)C.[NH3:16]>C(O)C>[NH2:16][C:4]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([C:12]#[N:13])[S:6](=[O:15])(=[O:14])[N:5]=1
Reactant: N
Reactant: CCOC1=NS(=O)(=O)C(C#N)=C1OCC
Solvent: CCO
Product: CCOC1=C(C#N)S(=O)(=O)N=C1N
Reaction time: 2 h

Procedure:
To a suspension of 3,4-diethoxy-5-cyanoisothiazole-1,1-dioxide (0.85 g, 0.0037 mol) in 40 ml of ethanol was added 2.6 ml of 1.7M ammonia in ethanol (0.0044 mol) with stirring. A clear yellow solution formed and a white precipitate separated in 5 minutes. After 2 hours at room temperature, the title compound (0.61 g, 82%, mp 232°-233.5°) was collected and a sample recrystallized from ethanol to give analytically pure material, mp 236°-238.5°, Rf 0.26 (10% methanol-chloroform, silica gel).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1.[O:20]1CCCC1>CSC>[OH:20][CH:8]1[CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccccn2)CC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCC(c2ccccn2)C(O)C1
Temperature: 50 °C
Reaction time: 6 h
Yield: 24 %

Procedure:
A solution of 1.30 g (5.0 mmol) of tert-butyl 3',6'-dihydro-2'H-[2,4']bipyridine-1'-carboxylate in 15 ml of absolute tetrahydrofuran was treated dropwise at 0° C. under argon with 1.0 ml (801 mg, 10.0 mmol) of borane-dimethyl sulphide complex (95%) in dimethyl sulphide. The mixture was heated to boiling such that a slow distillation of the solvent took place (about 1 drop per minute). After 3 hours 3 ml of 2N sodium hydroxide solution and 2 ml of hydrogen peroxide solution (30%) were added dropwise at 0° C. The mixture was stirred at 50° C. for 6 hours, then cooled to room temperature and, for working-up, poured into a mixture of 200 ml of ether, 200 ml of water and 25 ml of sodium pyrosulphite solution (10%) while stirring vigorously. The organic phase was separated and the aqueous phase was extracted three times with 50 ml of ether each time. The combined organic phases were washed twice with 25 ml of water each time, dried over magnesium sulphate and finally the solvent was distilled off under reduced pressure. The crude product was purified by flash chromatography on silica gel with a 1:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 354 mg (24% of theory) of tert-butyl (3'RS,4'RS)-3'-hydroxy-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridine-1'-carboxylate as a yellow oil; MS: 279 (M+H)+.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[N:16]=[C:15](Cl)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[CH:13]=2)[N:8]=1.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33]([OH:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1>C1COCC1>[Cl:6][C:7]1[N:16]=[C:15]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]([OH:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[CH:13]=2)[N:8]=1
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: NCc1ccc(-c2ccccc2C(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1-c1ccc(CNc2nc(Cl)nc3ccc(Cl)cc23)cc1

Procedure:
A mixture of sodium acetate (0.56 g), 2,4,6-trichloroquinazoline (0.40 g) and 4'-aminomethyl (1,1'-biphenyl)-2-carboxylic acid (0.43 g) was stirred at room temperature in 10 mL of THF for 5 days. All solvents were removed by evaporation and the resulting residue was partitioned between ethyl acetate and brine. The ethyl acetate fraction was dried over anhydrous magnesium sulfate, filtered and evaporated. The crude material was purified using silica gel chromatography to yield 0.15 g (21%) of an off white solid (m.p.=210°-240° C.): 1H NMR (DMSO-d6, 400 MHz) δ9.45 (t, J=6.2 Hz, 1H), 8.52 (d, J=2.3 Hz, 1H), 7.83 (dd, J=2.3, 8.9 Hz, 1H), 7.66 (m, 2H), 7.49 (m, 1H), 7.35 (m, 7H), 4.77 (d, J=5.2 Hz); negative FAB MS m/e 422(M-H). Anal. calcd for C22H15Cl2N3O2 : C, 62.28; H,3.56; N, 9.90. Found: C, 62.44; H, 3.52; N, 9.95.
Reaction SMILES: C([O:4][CH:5]([CH2:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:29]=[CH:30][C:31]3[N:35]=[CH:34][N:33]([CH3:36])[C:32]=3[CH:37]=2)[CH:23]=1)[C:19](=[O:21])[CH3:20])[CH2:6][N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)(=O)C.[OH-].[Li+]>CCO.O>[CH2:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:16][N:7]1[CH2:6][CH:5]([OH:4])[CH2:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:29]=[CH:30][C:31]3[N:35]=[CH:34][N:33]([CH3:36])[C:32]=3[CH:37]=2)[CH:23]=1)[C:19](=[O:21])[CH3:20]
Reactant: CC(=O)OC(CN1CCc2ccccc2C1)CN(C(C)=O)c1cccc(-c2ccc3ncn(C)c3c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)N(CC(O)CN1CCc2ccccc2C1)c1cccc(-c2ccc3ncn(C)c3c2)c1
Temperature: 25 °C
Yield: 6.7 %

Procedure:
To a solution of 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(N-(3-(1-methyl-1H-benzo[d]imidazol-6-yl)phenyl)acetamido)propan-2-yl acetate (60 mg, 0.121 mmol) in EtOH (2 ml) and H2O (1 mL) was added lithium hydroxide (10 mg, 0.238 mmol). The mixture was stirred at 25° C. until LCMS indicated completion of the reaction. Solvents were evaporated and the residue dissolved in 30 mL DCM, washed with aq. NaHCO3 and water then dried over anhydrous Na2SO4, and filtrated. Solvent was removed from this filtrate leaving a residue which was then purified by prep-HPLC to afford the desired product as colorless oil (3.7 mg, 6.7%). 1H NMR (400 MHz, METHANOL-d4) δ 8.49 (br. s., 1H), 8.20 (s, 1H), 7.84 (s, 1H), 7.70-7.81 (m, 3H), 7.49-7.67 (m, 2H), 7.33-7.41 (m, 1H), 7.13-7.27 (m, 3H), 7.09 (d, J=6.90 Hz, 1H), 4.31 (br. s., 1H), 4.20 (s, 2H), 4.03 (dd, J=5.21, 13.99 Hz, 1H), 3.96 (s, 3H), 3.73-3.84 (m, 1H), 3.32-3.39 (m, 2H), 2.98-3.19 (m, 4H), 1.97 (s, 3H) LCMS (m/z): 455.2 [M+H]+
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=[O:2].[Cl:11][C:12]1[CH:13]=[N+:14]([O-:32])[CH:15]=[C:16]([Cl:31])[C:17]=1[CH2:18][C@@H:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)O.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[Cl:31][C:16]1[CH:15]=[N+:14]([O-:32])[CH:13]=[C:12]([Cl:11])[C:17]=1[CH2:18][C@H:19]([O:9][C:8]([C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)=[O:10])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Reactant: O=Cc1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)s2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
A stirred solution of 5-formyl-2-thiophenecarboxylic acid (400 mg, 2.56 mmol) in dichloromethane (20 mL) was added with (1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethanol I-1/A (881 mg, 2.56 mmol) followed by 4-(dimethylamino)-pyridine (156 mg, 1.28 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (983 mg, 5.12 mmol). The resulting mixture was stirred at room temperature for 18 h. The reaction was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, passed through a hydrophobic fit and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography, eluting with 0-100% EtOAc in DCM, to afford the title compound (488 mg, 39%) as yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([N+:18]([O-])=O)[C:5]=1[CH:21]=[CH:22][C:23]([O:25]C)=O)(=[O:3])[CH3:2].[H][H]>C(O)C.[Ni]>[C:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]2[C:5]=1[CH2:21][CH2:22][C:23](=[O:25])[NH:18]2)(=[O:3])[CH3:2]
Reactant: COC(=O)C=Cc1c(C(C)=O)cc(OCc2ccccc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(=O)c1cc(OCc2ccccc2)cc2c1CCC(=O)N2
Reaction time: 6 h

Procedure:
A suspension of methyl 3-(2-acetyl-4-benzyloxy-6-nitrophenyl)acrylate (5.0 g, 14.07 mmol) in ethanol (100 mL) is hydrogenated with Raney nickel (3 g) at ambient temperature and 4 bar hydrogen pressure. After 6 hours, more Raney nickel (2 g) is added and the mixture is hydrogenated for a further 2 hours. The catalyst is separated off and the filtrate is combined with 2 M aqueous hydrochloric acid (15 mL). The product that crystallizes out is filtered off and dried. Yield: 1.0 g (24%); mass spectroscopy: [M+H]+=296.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[F:12][C:13]([C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27])([F:23])[C:14]([F:22])([F:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[F:12][C:13]([C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[CH2:26][OH:27])([F:23])[C:14]([F:22])([F:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccccc1C(F)(F)C(F)(F)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCc1ccccc1C(F)(F)C(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium aluminum hydride, 530 mg. (0.0139 mole), is weighed under nitrogen, transferred to a dry-nitrogen-flushed reaction flask, and suspended in 15 ml. of absolute ether. A solution of 4.15 g. (0.0139 mole) of 2-(α,α,β,β-tetrafluorophenethyl)benzoic acid in 35 ml. of absolute ether is added dropwise. The mixture is stirred at room temperature for 30 minutes and allowed to stand overnight in a nitrogen atmosphere. Hydrolysis is effected by the dropwise addition of 1 ml. of water. The precipitate is removed by filtration, and washed with ether. Evaporation of the dried ethereal filtrate under reduced pressure leaves the product as a white solid, m.p. 80°-81° C. A sample for analysis is sublimed at 70° C. and 0.1 mm.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8](O)=[O:9])[CH2:4][CH2:3]1.C[N:13]1CCOCC1.CC(COC(Cl)=O)C.[OH-].[NH4+]>C1COCC1>[F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([NH2:13])=[O:9])[CH2:4][CH2:3]1
Reactant: CN1CCOCC1
Reactant: O=C(O)C1CCC(F)(F)CC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)C1CCC(F)(F)CC1
Temperature: 0 °C
Yield: 53.1 %

Procedure:
To a solution of compound 4,4-difluorocyclohexanecarboxylic acid (3.5 g, 21 mmol) in 80 mL THF, 4-methylmorpholine (2.51 g, 21 mmol) was added at −70° C., followed by isobutyl chloridocarbonate (2.85 g, 21 mmol). 30 min later, 10 mL ammonium hydroxide was added. The resulting mixture was allowed to warm up to 0° C. After removal of all solvents, the residue was washed with water, PE to afford the compound 4,4-difluorocyclohexanecarboxamide (1.82 g, 40%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][CH2:3][CH3:4].[Li]CCCC.[CH2:15]1[O:17][CH2:16]1>C1COCC1>[CH2:1]([C:5]1[O:6][C:7]([CH2:15][CH2:16][OH:17])=[CH:8][CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CO1
Reactant: CCCCc1ccco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCc1ccc(CCO)o1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
To a solution of 2-butylfuran (3.00 g, 24.2 mmol) in THF (24 mL) at −78° C. was added n-BuLi (11.6 mL, 2.5 M, 29.0 mmol) dropwise over 10 min. The reaction was warmed to rt and stirred for 3.5 h. After cooling to 0° C., ethylene oxide (1.81 mL, 36.2 mmol) was added, the reaction was warmed to rt and stirring was continued for 19 h. The reaction was then cooled to 0° C. and quenched with sat. NH4Cl (20 mL), followed by extraction with diethyl ether (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 4.07 g (100%) compound 502A as a bright orange oil. This material was used without further purification. HPLC: 96% at 3.23 min (retention time) (YMC Combiscreen ODS-A column, 4.6×50 mm, eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over 4 min, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 169.22 [M+H]+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[CH:16]/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]([O:25][CH3:26])=[O:24])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: COC(=O)/C=C/C=C/C=C/C=C/c1ccc(OC)c(OC2CCCC2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCCCc1ccc(OC)c(OC2CCCC2)c1

Procedure:
To a solution of 0.22 g (0.62 mmol) of methyl 9-(3-cyclopentoxy-4-methoxyphenyl)-2,4,6,8-E,E,E,E-nontetraenoate in 75 mL of methanol is added 0.05 g of 5% palladium on carbon black. The suspension is shaken under a 50 psi atmosphere of hydrogen for 20.9 hours after which time the excess gas is dissociated and the solution is filtered over Celite 545. The mixture is concentrated to dryness followed by liquid chromatography of the crude product over 100 g of silica gel eluting with 5% ethyl acetate in hexane. The final product is dried in vacuo and is found to be analytically pure as an oil.
Reaction SMILES: Cl[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3](=O)[CH3:4].[C:16]([NH2:19])(=[S:18])[CH3:17]>C(O)C.CCCCC>[CH3:17][C:16]1[S:18][C:2]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[C:3]([CH3:4])[N:19]=1
Reactant: CC(N)=S
Reactant: CC(=O)C(Cl)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: CCCCC
Product: Cc1nc(C)c(Cc2ccc([N+](=O)[O-])cc2)s1
Yield: 68.3 %

Procedure:
4.7 g of 3-chloro-4-(4-nitrophenyl)butan-2-one and 2.4 g of thioacetamide are dissolved in 60 ml of ethanol and refluxed for 12 hours. The reaction medium is concentrated, the residue is taken up in water and the solution is rendered basic with sodium carbonate and extracted with chloroform. After concentration of the organic phase, the solid obtained is taken up in hot pentane to give 3.5 g of 2,4-dimethyl-5-(4-nitrobenzyl)thiazole in the form of yellow crystals melting at 66° C.
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[O:10][C@@H:11]([CH2:14][OH:15])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:43][C:33]1[CH:38]=[CH:37][C:36]([S:39]([O:15][CH2:14][CH:11]2[O:10][C:9]3[C:4]([CH2:1][CH:2]=[CH2:3])=[C:5]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: C=CCc1c(OCc2ccccc2)ccc2c1O[C@@H](CO)CO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCc1c(OCc2ccccc2)ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 15.6 g (50.0 mmole) of [(2S)-8-allyl-7-(benzyloxy)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol in 100 mL of methylene chloride was added 26.3 mL (0.15 mole) of N,N-diisopropylethylamine, 0.63 g (5 mmole) of 4-dimethylaminopyridine and 14.25 g (75.0 mmole) of p-toluenesulfonyl chloride. The mixture was stirred at room temperature under nitrogen for 15 hours. The solvent was then removed in vacuum and the residue column chromatographed on silica gel with methylene chloride as eluant. Combination of the product fractions and concentration in vacuum gave 18.0 g (77%) of the (R)-enantiomer of the title compound as a white solid, m.p. 76-77° C.
Reaction SMILES: C([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=O)C1C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>>[CH2:20]([N:12]1[C:13]2[C:18](=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:10]([OH:9])([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[C:11]1=[O:22])[CH3:21]
Reactant: COc1ccc(CCl)cc1
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Product: CCN1C(=O)C(O)(Cc2ccc(OC)cc2)c2cc(C)ccc21

Procedure:
This compound was made in an analogous fashion to 11-ethyl-3-hydroxy-5-methyl-3-(3,4,5-trimethoxybenzyl)indolin-2-one using 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate: and 4-methoxy benzyl chloride (purchased from Fisher Scientific). 1H-NMR δ 7.11 (s, 1H), 7.05 (dd, 1H), 6.83 (d, 2H), 6.65 (d, 2H), 6.56 (d, 1H), 3.72 (s, 3H), 3.64 (m, 1H), 3.40 (m, 1H), 3.24 (d, 1H), 3.12 (d 1H), 2.34 (s, 3H), 2.0 (bs, OH), 0.94 (t, 3H). Calculated mass for C19H21NO3, 311.15. Observed 334.1 (M+Na).
Reaction SMILES: CON(C)[C:4]([C@@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH3:8])=[O:5].[CH:18]1([Mg]Br)[CH2:20][CH2:19]1.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:18]1([C:4]([C@@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:7][CH3:8])=[O:5])[CH2:20][CH2:19]1
Reactant: Br[Mg]C1CC1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)C1CC1
Reaction time: 4.5 h
Yield: 94 %

Procedure:
A solution of tert-butyl {(1S)-1-[methoxy(methyl)carbamoyl]propyl}carbamate (14.3 g) in tetrahydrofuran (130 mL) was ice-cooled under a nitrogen atmosphere, and 1.0 mol/L-cyclopropylmagnesium bromide/tetrahydrofuran solution (300 mL) was added. The mixture was stirred at the same temperature for 4.5 hr, saturated aqueous ammonium chloride solution (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→16%) to give the title compound as a colorless oil (yield: 10.7 g, 94%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]2[CH:28]([OH:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([OH:30])[CH:26]=3)[O:21][CH2:20]2)[CH:13]=1>>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C@H:19]2[C@@H:28]([OH:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:30][C:2]4[CH:11]=[CH:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]=4)[CH:26]=3)[O:21][CH2:20]2)[CH:13]=1
Reactant: Oc1ccc2c(c1)C(O)C(Oc1cccnc1)CO2
Reactant: Clc1ccc2ccccc2n1
Product: O[C@H]1c2cc(Oc3ccc4ccccc4n3)ccc2OC[C@H]1Oc1cccnc1

Procedure:
By the method of Example 1, 2-chloroquinoline and 3-(3-pyridyloxy)-4,6-chromandiol (EP appln. 312,295) were converted to present title product in like yield; mp 112°-114° C.; IR (CHCl3) 3563, 1620, 1603 cm-1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1>>[Cl:19][C:18]1[C:13]([O:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)=[N:14][CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Product: O=[N+]([O-])c1cnc(Oc2ccc3ncccc3c2)c(Cl)c1

Procedure:
Quinolin-6-ol was reacted with 2,3-dichloro-5-nitro pyridine to obtain 6-(3-chloro-5-nitropyridin-2-yloxy)quinoline which was further converted to 5-chloro-6-(quinolin-6-yloxy)pyridin-3-amine as per the procedure described in preparation 1 step iii and iv.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[C:13](=[O:21])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[C:11]2=[O:33])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:41][C:42]#[N:43]>CN(C=O)C>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:41][C:42]#[N:43])=[CH:17][CH:18]=3)[C:13](=[O:21])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[C:11]2=[O:33])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: N#CCBr
Reactant: COc1ccc(Cn2c(=O)c3cc(O)ccc3n(C3CCN(C(C)=O)CC3)c2=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3cc(OCC#N)ccc3n(C3CCN(C(C)=O)CC3)c2=O)cc1OC
Yield: 72.1 %

Procedure:
0.12 g of 1-(1-acetylpiperidin-4-yl)-3-(3,4-dimethoxybenzyl)-6-hydroxyquinazoline-2,4(1H,3H)-dione obtained in stage 2.2 and 0.172 g of Cs2CO3 in 3 ml of DMF are stirred for 15 min at AT. 0.038 g of bromoacetonitrile is added and the reaction mixture is subsequently irradiated under a microwave field at 100° C. for 15 min. It is filtered and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an MeOH/DCM mixture, (1/99, v/v) as far as (4/96, v/v), to give 0.094 g of the expected product.