Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([N+:11]([O-])=O)[CH:3]=1.[CH:14]1(N)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C[CH2:23][OH:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:23](=[O:24])[N:11]([CH:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:4]=2[CH:3]=1
Reactant: CCO
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: NC1CCCCCC1
Product: O=c1[nH]c2ccc(Cl)cc2n1C1CCCCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 18.2 g of 4-chloro-1,2-dinitrobenzene and 31 g of cycloheptylamine in 55 ml of 95% EtOH is left stirring for 15 hours at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with EtOAc, washed with 1N HCl solution, with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with petroleum ether. 13 g of the expected product are obtained after crystallization from isopropanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[OH-].[K+].C(COC)OC>O.CN(C)P(N(C)C)(N(C)C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[N:3]=1
Reactant: Clc1cccc(Cl)n1
Reactant: COc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: COCCOC
Solvent: O
Product: COc1ccc(Oc2cccc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution comprising 14.8 grams (0.1 mole) of 2,6-dichloropyridine, 12.4 grams (0.1 mole) of 4-methoxyphenol and 8.4 grams (0.15 mole) of flake potassium hydroxide in 100 milliliters of a 1:1 mixture of monoglyme and hexamethylphosphoramide was stirred for 24 hours at room temperature. The resulting mixture was diluted with water and thoroughly extracted with hexane. The extract was washed with water, dried and concentrated under reduced pressure. The residue was recrystallized from pentane giving 14.5 grams (64 percent of theoretical) of 2-chloro-6-(4-methoxyphenoxy)pyridine which melted at 63°-65° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Ni]>[C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:8]2[O:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2o1
Reactant: [H][H]
Agent: [Ni]
Product: CCOC(=O)C1CC(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O1

Procedure:
A solution of 12.0 parts of 6,8-di-t-butyl-4-oxo-4H-1benzopyran-2-carboxylic acid, ethyl ester in 150 parts of ethanoo was hydrogenated, using Raney Nickel as catalyst, until one equivalent of hydrogen had been absorbed. The catalyst was removed by filtration and the ethanol was evaporated to give a residue which was chromatographed on silica gel. Careful elution with a 1:1 mixture of chloroform and light petroleum (b.p. 60°-80° C) gave 3.73 parts of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester, m.p. 61°-63° C, as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH2:13]([CH2:15][NH2:16])[OH:14]>O1CCOCC1>[NH2:6][C:5]1[CH:7]=[C:8]([NH:16][CH2:15][CH2:13][OH:14])[C:2]([Cl:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: NCCO
Solvent: C1COCCO1
Product: Nc1cc(NCCO)c(Cl)cc1[N+](=O)[O-]

Procedure:
0.11 mole (22.8 g) of 4,5-dichloro-2-nitroaniline is added to a solution of 0.55 mole (33.3 ml) of ethanolamine in 70 ml of dioxane. The reaction mixture is heated for 6 hours in refluxing dioxane. After dilution with water and neutralization with concentrated hydrochloric acid, the expected product precipitates.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:8]([CH3:9])=[CH:7][N:6]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[N:5]=1.[H-].[Na+].[CH3:18]I>C1COCC1>[CH3:18][O:1][CH2:2][CH2:3][C:4]1[C:8]([CH3:9])=[CH:7][N:6]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:11])=[O:12])[N:5]=1
Reactant: CI
Reactant: Cc1cn(S(=O)(=O)N(C)C)nc1CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1nn(S(=O)(=O)N(C)C)cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(2-hydroxyethyl)-N,N,4-trimethyl-1H-pyrazole-1-sulfonamide (compound 305.2, 636 mg, 2.73 mmol) in THF (10 mL). Sodium hydride (131 mg, 60% in mineral oil, 3.27 mmol) was added at 0° C. and stirred for 30 min at 0° C. This was followed by the addition of CH3I (204 μL, 3.28 mmol). The reaction mixture was stirred for 3 h at room temperature. The reaction was quenched with 10 mL of NH4Cl (sat.) and the aqueous phase was extracted with 3×50 mL of EtOAc. The combined organic phases were dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography with hexanes/EtOAc (15:1-8:1) as the eluent to give 452 mg (67%) of the title compound as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)=[CH:10][C:4]=2[O:3]1.CN1CCOCC1.CN(C)C=O.C(OC(Cl)=O)C(C)C.Cl.[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][C:45]2[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=2)[CH2:40][CH2:39]1>>[C:49]([C:48]1[CH:47]=[CH:46][C:45]([CH2:44][CH:41]2[CH2:42][CH2:43][N:38]([C:13](=[O:15])[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[O:1])[O:3][C:4]=4[CH:10]=3)=[O:16])[CH2:39][CH2:40]2)=[CH:52][CH:51]=1)#[N:50]
Reactant: N#Cc1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)oc2c1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)oc4c3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
To a mixture of 0.3g (1.5 mmol) of N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-oxalamic acid, 0.165 ml (1.5 mmol) of N-methyl-morpholine in 8 ml of dimethylformamid 0.2 ml (1.5 mmol) of isobutyl-chloroformate is added dropwise at 0° C. and the mixture is stirred at 0° C. for 1 hour. Then 0.333 g (1.4 mmol) of 4-piperidin-4-ylmethyl-benzonitrile hydrochloride and 0.165 ml (1.5 mmol) of N-methyl-morpholine are added and the reaction mixture is stirred at 0° C. for 1 hour, at room temperature for 16 hours. The reaction mixture is concentrated and the residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent to yield 0.045 g (8.0%) of the title compound. Rf.: 0.4. Melting Point: 259-260° C. (isopropanol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][Mg+].[Br-].OS(O)(=O)=O.O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[CH2:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg+]
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1ccccc1F
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1ccc(OCc2ccccc2)cc1)c1ccccc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Compound 1 (4.0 g, 13.1 mmol) was dissolved in dry THF (40 mL) and the solution was cooled to 0° C. CH3MgBr (15 mL, 19.5 mmol, 1.3 M) was added drop-wise. The resulting mixture was stirred at room temperature overnight. The solution was cooled to 0° C. and H2SO4 (2 mL, 98%) was added. A precipitate was formed and the inhomogeneous mixture was stirred at room temperature for 1 h. H2O (20 mL) was added and the mixture was extracted with diethyl ether (2×100 mL). The organic phase was washed with NaHCO3 (2×50 mL, saturated aqueous solution) and brine (50 mL) and dried over Na2SO4. Filtration and evaporation of the solvent under reduced pressure gave a crude material which was purified by column chromatography (heptane:ethyl acetate 6:1). Yield 2.58 g, 65% as an off-white solid. 1H-NMR (CDCl3) δ; 7.46-7.36 (m, 4H), 7.36 (m, 5H), 7.18-7.03 (m, 2H), 6.93 (d, 2H, J=8.6 Hz), 5.68 (d, 1H, J=1.0 Hz), 5.32 (s, 1H), 5.07 (s, 2H); 13C-NMR (CDCl3) δ 160.1 (d, J=248 Hz), 158.6, 143.5, 137.0, 133.4, 131.5 (d, J=3.5 Hz), 129.2 (d, J=8.1 Hz), 128.6 (2C), 128.0 (4C), 127.5 (2C), 123.9 (d, J=3.8 Hz), 115.7 (d, J=22.3 Hz), 115.3 (d, J=1.9 Hz), 114.6 (2C), 70.0.
Reaction SMILES: Br[CH2:2][C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:15]1[CH:29]=[CH:28][C:18]([CH2:19][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[CH:17][CH:16]=1.[C-:30]#[N:31].[Na+]>C(O)C.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:6]2[O:5][C:4]([C:15]3[CH:29]=[CH:28][C:18]([CH2:19][P:20](=[O:27])([O:21][CH2:22][CH3:23])[O:24][CH2:25][CH3:26])=[CH:17][CH:16]=3)=[C:3]([CH2:2][C:30]#[N:31])[C:8](=[O:9])[C:7]=2[CH:10]=1
Reactant: CCOP(=O)(Cc1ccc(-c2oc3ccc(Cl)cc3c(=O)c2CBr)cc1)OCC
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(Cc1ccc(-c2oc3ccc(Cl)cc3c(=O)c2CC#N)cc1)OCC
Temperature: 25 °C

Procedure:
A 2.0 g quantity of the compound obtained in Example 23 was dissolved in a mixture of 5 ml of ethanol and 0.6 ml of water. After addition of 0.48 g of sodium cyanide with stirring at room temperature, the reaction mixture was refluxed with heating for 12 hours. After addition of 20 ml of water, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed serially with 20 ml of water and 20 ml of brine and dried over Glauber's salt. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography (eluent: chloroform:ethyl acetate=1:1). The resulting crude crystals were recrystallized from dichloromethane-n-hexane to provide 1.0 g of the title compound as colorless crystals. Table 1 shows the structure and physical property of the compound obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[C:19]([CH2:31][CH3:32])=[C:20]([CH2:24][CH2:25][C:26](OCC)=[O:27])[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].CC(C[AlH]CC(C)C)C>ClCCl>[CH2:31]([C:19]1[C:20]([CH2:24][CH2:25][CH:26]=[O:27])=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[S:14][C:13]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[C:3]([CH:4]=2)[C:1]#[N:2])=[N:17][CH:16]=1)[CH3:32]
Reactant: CCOC(=O)CCc1cccc(-c2cnc(-c3ccc(OC(C)C)c(C#N)c3)s2)c1CC
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CCc1c(CCC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 123.2 %

Procedure:
To a solution of ethyl 3-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]propanoate (D114) (900 mg, 2.006 mmol) in Dichloromethane (DCM) (20 mL) stirred under nitrogen at −70° C. was added a solution of DIBAL-H (4 ml, 4.00 mmol) dropwise during 30 min. The reaction mixture was stirred at −70° C. for 20 minutes. The reaction mixture was quenched with cooled aqueous HCl solution (10 mL, 10%). The organic layers were washed with water twice. Then the organic layers were separated and dried over anhydrous sodium sulphate. The organic solvent was evaporated in vacuo to afford 5-{5-[2-ethyl-3-(3-oxopropyl)phenyl]-1,3-thiazol-2-yl}-2-[(1-methylethyl)oxy]benzonitrile (D115) (1 g), which was used directly without further purification. MS (ES): C24H24N2O2S requires 404.2. found 405.2 (M+H+).
Reaction SMILES: [Cl:1][CH:2]([C:10]([CH3:31])=[CH:11][CH:12]([C:22]1[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][CH2:24][C:23]=1[CH3:30])[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:3][CH2:4][C:5]([CH3:9])=[CH:6][CH:7]=O.[OH-].[K+]>O.C(Cl)Cl>[C:16]1([S:13]([CH:12]([C:22]2[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][CH2:24][C:23]=2[CH3:30])[CH:11]=[C:10]([CH3:31])[CH:2]([Cl:1])[CH2:3][CH2:4][C:5]([CH3:9])=[CH:6][CH:7]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=[CH:3][CH:2]=[C:10]([CH3:31])[CH:11]=[CH:12][C:22]2[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][CH2:24][C:23]=2[CH3:30])(=[O:15])=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=CC=O)CCC(Cl)C(C)=CC(C1=C(C)CCCC1(C)C)S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C=CC=C(C)C=CC1=C(C)CCCC1(C)C)=CC=CC=C(C)CCC(Cl)C(C)=CC(C1=C(C)CCCC1(C)C)S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A 100-ml round-bottom flask was charged with a solution of 2.14 g (6.4 mmoles) of vitamin A acetate, 1.68 g (6.4 mmoles) of triphenylphosphine and 0.64 g (6.4 mmoles) of concentrated sulfuric acid in 10 g of methanol, and the contents were stirred at 25° C. for 3 hours. Thereafter, methanol was removed by distillation in vacuo from the reaction mixture to obtain a tar-like vitamin A phosphonium salt. This was dissolved in 10 g of water and to the solution was added 10 ml of a solution of 3.0 g (6.4 mmoles) of 6-chloro-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,7-nonadien-1-al in methylene chloride. To this mixture was added gradually 10.84 g (12.8 mmoles) of a 7.7% aqueous solution of potassium hydroxide at 8° C., and the resulting mixture was stirred for 30 minutes. After completion of the reaction, an organic layer was separated from an aqueous layer and washed with water, followed by distilling off of the solvent, to give 6.72 g (purity: 40.9%, 3.85 mmoles, yield: 60.2%) of an oily substance. This substance was purified by silica gel chromatography (hexane/ethyl acetate=85/15) to give 2.05 g of 1-phenylsulfonyl-4-chloro-1,18-di(2,6,6-trimethyl-1-cyclohexen-1-yl)-3,7,12,16-tetramethyloctadeca-2,7,9,11,13,15,17-heptaene.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[CH2:22][CH2:23][O:24][C:25]4[CH:31]=[CH:30][C:29]([C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=5)=[CH:28][C:26]=4[CH:27]=3)=[O:20])=[CH:14][CH:13]=2)=[N:7][CH:8]=[CH:9][CH:10]=1.ClC1C=CC=C(C(OO)=[O:47])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:47][N+:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]2[CH2:22][CH2:23][O:24][C:25]3[CH:31]=[CH:30][C:29]([C:32]4[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=4)=[CH:28][C:26]=3[CH:27]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: COCOc1cccnc1Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc[n+]([O-])c1Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.6 %

Procedure:
To a solution of N-[4-(3-methoxymethoxypyridin-2-ylmethyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1benzoxepine-4-carboxamide (300 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.22 g) at 0° C., and the mixture was stirred at room temperature for 18 hours. To the mixture was added sodium thiosulfate, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:15→1:10), and recrystallized from ethanol to give N-[4-(1-oxido-3-methoxymethoxypyridin-2-ylmethyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 173) (203 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(=O)CC>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:9]2[CH3:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(F)ccc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)c1cn(C)c2cc(F)ccc2c1=O

Procedure:
A mixture of ethyl 7-fluoro-4-hydroxyquinoline-3-carboxylate (4.7 g), anhydrous potassium carbonate (3.0 g), dimethyl sulphate (2.52 g) and butanone (200 ml) can be boiled under reflux for 14 hours. The solvent can be evaporated and the residue can be triturated with dichloromethane (150 ml). The mixture can be filtered and the filtrate evaporated to a-small volume. Diethyl ether can be added, causing a solid to precipitate. The solid can be collected, washed with ether, dried and recrystallized from industrial methylated spirit to give the compound ethyl 7-fluoro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate, m.p. 164-166° C.
Reaction SMILES: [OH-].[Na+].FC(F)(F)C([NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11]([OH:18])[CH2:10][CH2:9]1)=O>CO.O.CO>[NH3:7].[NH2:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11]([OH:18])[CH2:10][CH2:9]1
Reactant: O=C(N[C@H]1CC[C@@H](O)c2ccccc21)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N
Product: N[C@H]1CC[C@@H](O)c2ccccc21
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 200 %

Procedure:
Sodium hydroxide (2.10 g, 53.0 mmol) was added to an ice cold solution of Intermediate 1c (3.43 g, 13.2 mmol) in MeOH/water (2:1, 50 mL) and stirred for 3.5 h. The mixture was loaded on to a SCX-2 cartridge, eluting with MeOH then 2M NH3 in MeOH, to yield the title compound (2.30 g, 13.2 mmol, 99%). 1H NMR (400 MHz, d6-DMSO): 1.66-1.90 (4H, m), 3.71-3.77 (1H, t, J=5.4 Hz), 4.46-4.54 (1H, t, J=5.4 Hz), 7.14-7.22 (2H, m), 7.32-7.38 (1H, m), 7.40-7.46 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([S:17](=[O:26])(=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:8]=1)=[O:5].[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33].C(N(CC)CC)C>C1COCC1>[C:31]([N:22]1[CH2:21][CH2:20][CH:19]([NH:18][S:17]([C:9]2[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=3[CH3:1])[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)(=[O:26])=[O:25])[CH2:24][CH2:23]1)(=[O:35])[CH:32]([CH3:34])[CH3:33]
Reactant: Cc1ccccc1C(=O)Nc1cc(S(=O)(=O)NC2CCNCC2)cc2c1CCCC2
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1cc(S(=O)(=O)NC2CCN(C(=O)C(C)C)CC2)cc2c1CCCC2
Reaction time: 18 h
Yield: 8.5 %

Procedure:
To a 25° C. mixture of sulfonamide (60) (185 mg, 0.4 mmol) in THF (10 mL) was added isobutyryl chloride (107 mg, 1 mmol) and triethyl amine (607 mg, 6 mmol). The mixture was stirred for 18 hours, followed by filtration to remove the solid. The filtrate was concentrated in vacuo and purified via chromatography, to afford the title compound as white solid (17 mg). 1H NMR (300 MHz, MeOD) δ 7.81 (s, 1H), 7.53 (m, 2H), 7.38 (m, 1H), 7.31 (m, 2H), 4.28 (m, 1H), 3.90 (m, 1H), 3.19 (m, 1H), 3.09 (m, 1H), 2.83 (m, 6H), 2.55 (s, 3H), 1.85 (m, 7H), 1.38 (m, 2H), 1.04 (m, 6H)); LC/MS (M+H)+ m/z 498.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][NH2:18])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][NH:18][C:25](=[O:27])[CH3:26])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](CNC(C)=O)NC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of methyl 2(S)-benzyloxycarbonylamino-3-aminopropionate (2.5 g) in methylene chloride was added pyridine (20 mL) and acetic anhydride (5 mL). After stirring for 2 h the solution was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was extracted w/50 mL each of 2% potassium hydrogen sulfate, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo. Upon evaporation pyridine hydrochloride precipitated and was removed by filtration. The filtrate was evaporated to obtain the title compound. 1H NMR (300 MHz, CDCl3) δ 7.28 (5H, s), 6.14 (1H, s), 5.97 (1H, d), 5.10 (2H, s), 4.41 (1H, m), 3.78 (3H, s), 1.93 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:8][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][Cl:27]>CC(C)=O>[Cl:27][CH2:26][CH2:25][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[O:8][CH:9]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:17])[N:6]=2)=[CH:11][CH:12]=1
Reactant: ClCCBr
Reactant: COC(=O)Cc1coc(-c2ccc(O)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1coc(-c2ccc(OCCCl)cc2)n1
Yield: 86.7 %

Procedure:
A mixture of methyl[2-(4-hydroxyphenyl)-1,3-oxazol-4-yl]acetate 150 (1 g, 4.29 mmol, 1 eq), potassium carbonate (2.37 g, 17.16 mmol, 4 eq) and 1-bromo-2-chloroethane (1.54 g, 10.7 mmol, 2.5 eq) in acetone (50 ml) is stirred at reflux for 140 h. Potassium carbonate is then filtered off and the solvent is evaporated. The residue is taken up in ethyl acetate and washed two times with an aqueous solution of sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum to give 1.1 g of methyl {2-[4-(2-chloroethoxy)phenyl]-1,3-oxazol-4-yl}acetate i51.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[CH:16][CH2:17][NH:18][O:19]C2CCCCO2)=[CH:4][CH:3]=1.Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[CH:16][CH2:17][NH:18][OH:19])=[CH:4][CH:3]=1
Reactant: Fc1ccc(Sc2ccccc2C=CCNOC2CCCCO2)cc1
Agent: Cl
Solvent: CO
Product: ONCC=Cc1ccccc1Sc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-[3-[2-(4-fluorophenylthio)phenyl]prop-2-enyl]-O-tetrahydropyranyl hydroxylamine (1.76 g; 4.9 mmol) in 25 ml of methanol and cooled in an ice bath was added 2.5 ml of concentrated HCl dropwise. The reaction mixture was stirred at room temperature overnight and then concentrated to dryness. The mixture was partitioned between diethyl ether and saturated NaHCO3 and the aqueous layer extracted one more time with diethyl ether. The organics were combined, washed with water and brine and dried over K2CO3 to afford the subtitle compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([NH2:12])=[S:11])=[CH:3][CH:2]=1.Br[CH2:14][C:15](=O)[C:16]([OH:18])=[O:17]>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]2[S:11][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[N:12]=2)=[CH:3][CH:2]=1
Reactant: NC(=S)NCCc1ccncc1
Reactant: O=C(O)C(=O)CBr
Solvent: CO
Product: O=C(O)c1csc(NCCc2ccncc2)n1
Yield: 57.2 %

Procedure:
2-(2-Pyridin-4-yl-ethylamino)-thiazole-4-carboxylic acid (236 mg) was prepared according to General Procedure B using (2-pyridin-4-yl-ethyl)-thiourea (300 mg) and 3-bromo-2-oxo-propionic acid (293 mg) in methanol (2 mL). The crude product was used in a subsequent step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([NH2:25])=[C:20]([NH2:26])[CH:19]=1>>[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]2[N:25]=[C:1]([C:3]3[CH:16]=[CH:15][C:6]([CH:7]=[C:8]4[S:12][C:11](=[O:13])[NH:10][C:9]4=[O:14])=[CH:5][CH:4]=3)[NH:26][C:20]=2[CH:19]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Product: Cc1cc2nc(-c3ccc(C=C4SC(=O)NC4=O)cc3)[nH]c2cc1C

Procedure:
5,6-Dimethyl-2-[4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenyl]benzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 4,5-dimethyl-1,2-phenylenediamine by following General Procedure 2.