Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([N:16]3[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]3)=[C:12]([CH:15]=2)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.[N:23]1[NH:24][N:25]=[N:26][C:27]=1[C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>>[N:26]1[NH:25][N:24]=[N:23][C:27]=1[C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([N:16]4[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]4)=[C:12]([CH:15]=3)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=2)=[CH:30][CH:29]=1
Reactant: N#Cc1cc(-c2ccnc(Cl)n2)ccc1N1CCC(O)CC1
Reactant: Nc1ccc(-c2nn[nH]n2)cc1
Product: N#Cc1cc(-c2ccnc(Nc3ccc(-c4nn[nH]n4)cc3)n2)ccc1N1CCC(O)CC1

Procedure:
5-2-(4-(2H-Tetrazol-5-yl)phenylamino)pyrimidin-4-yl)-2-(4-hydroxypiperidin-1-yl)benzonitrile was obtained by following procedure E using 5-(2-chloropyrimidin-4-yl)-2-(4-hydroxypiperidin-1-yl)benzonitrile and 4-(2H-tetrazol-5-yl)aniline. 1H NMR (DMSO-d6, 400 MHz) δ 10.09 (s, 1H), 8.61 (d, 1H), 8.50 (d, 1H), 8.38 (dd, 1H), 8.06 (d, 2H), 8.00 (d, 2H), 7.55 (d, 1H), 7.32 (d, 1H), 3.72 (m, 1H), 3.61 (m, 2H), 3.13 (m, 2H), 1.89 (m, 2H), 1.59 (m, 2H). MS (ESI) 440.10 (M+H).
Reaction SMILES: [C:1]([N:4]([N:14]1[CH:18]=[N:17][N:16]=[CH:15]1)[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H][H]>[C].[Pd].CO>[C:1]([N:4]([N:14]1[CH:15]=[N:16][N:17]=[CH:18]1)[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N(c1ccc([N+](=O)[O-])cc1)n1cnnc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N(c1ccc(N)cc1)n1cnnc1
Yield: 98.8 %

Procedure:
A proper amount of 10% palladium-carbon was added to 15 ml of a methanol solution containing 0.38 g of 4-[N-acetyl-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole and the mixture was subjected to catalytic reduction in the presence of hydrogen gas at room temperature for about 40 minutes. After completion of reaction, the catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 0.33 g of 4-[N-acetyl-N-(4-aminophenyl)amino]-4H-1,2,4-triazole from the chloroform/methanol (50/1) eluate.
Reaction SMILES: [N:1]1[C:10]2[O:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(OO)(=[O:17])C>C(O)(=O)C>[N+:1]1([O-:17])[CH:2]=[CH:3][CH:4]=[C:5]2[C:10]=1[O:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[O:6]2
Reactant: c1ccc2c(c1)Oc1cccnc1O2
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: [O-][n+]1cccc2c1Oc1ccccc1O2
Temperature: 70 °C

Procedure:
A solution of 32 g of pyrido[2,3-B][1,4]benzodioxin in 100 ml of glacial acetic acid is treated with 36 g of 40% peracetic acid in acetic acid in four equal portions. After the fourth portion is added, the mixture is heated at 70° C. for 10 minutes. Another 4 g of 40% peracetic acid in acetic acid is added and the temperature is maintained at 70° C. for 10 minutes and then heated to reflux for 10 minutes. The mixture is concentrated at reduced pressure, 100 ml of isopropanol is added and the mixture is concentrated again. The resulting oil is dissolved in 700 ml of dichloromethane and the organic layer is washed with excess cold 25% sodium hydroxide solution. The organic layer is dried and evaporated to yield the pyrido[2,3-B][1,4]-benzodioxin 1-oxide, mp 223°-226° C. after recrystallization from acetonitrile.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]2[O:12][C:11]([C:13](=[O:15])[CH3:14])=[CH:10][C:9]=2[CH:16]=1)(=[O:3])[CH3:2].[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][CH2:14][C:13]([C:11]1[O:12][C:8]2[C:7]([CH3:17])=[C:6]([CH3:18])[C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:16][C:9]=2[CH:10]=1)=[O:15]
Reactant: BrBr
Reactant: CC(=O)Oc1cc2cc(C(C)=O)oc2c(C)c1C
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc2cc(C(=O)CBr)oc2c(C)c1C
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
1-(5-Acetoxy-6,7-dimethyl-benzofuran-2-yl)-ethanone (83 mg) (prepared from 1-(5-hydroxy-6,7-dimethyl-benzofuran-2-yl)-ethanone from Example 14 with acetanhydride and pyridine), was dissolved in chloroform (10 mL). Bromine (50 mg) was added and the solution was stirred at 70° C. for 10 min. When the color of bromine disapeared, the mixture was evaporated to dryness. The residue was purified by silica gel column eluting with 30% EtOAc in hexane to give 85 mg of 2-bromo-1-(5-acetoxy-6,7-dimethyl-benzofuran-2-yl)-ethanone as a white solid. 1H NMR (CDCl3, 300 MHz) δ: 7.58 (s, 1H), 7.26 (s, 1H), 4.43 (s, 2H), 2.51, 2.37, 2.21 (3s, 9H) ppm. 13C NMR (CDCl3, 75 MHz) δ: 182.55, 170.13, 153.71, 150.74, 146.81, 131.21, 124.51, 122.92, 115.15, 113.28, 30.69, 21.27, 13.54, 12.80 ppm.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11](F)[CH:10]=1.C(N(CC)CC)C>CS(C)=O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]=[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[S:3][C:15]=2[CH:16]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CCOC(=O)CS
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2ccc(Br)cc2s1
Yield: 91.8 %

Procedure:
A solution of ethyl thioglycolate (0.65 g, 5.42 mmol), 4-bromo-2-fluorobenzaldehyde (1.0 g, 4.93 mmol) and triethylamine (1.25 mL, 12.3 mmol) in DMSO (5 mL) was heated at 75° C. for 2 h. The mixture was partitioned between H2O (50 mL) and CH2Cl2 (2×50 mL), and the combined organic layers were dried over Na2SO4. The drying agent was filtered off, and the solvent was removed in vacuo to give the title compound as an oil (1.29 g, 92%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:22]([CH3:24])[CH3:23])[CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:11]([O:13]C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[O-].[K+:30]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH:22]([CH3:24])[CH3:23])[CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:11]([O-:13])=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2].[K+:30]
Reactant: COC(=O)C(CN(C(=O)OC(C)(C)C)C(C)C)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)N(CC(C(=O)[O-])c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 104.7 %

Procedure:
Methyl 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate (133 g, 374 mmol) was dissolved in THF (1.0 L) and treated with potassium trimethylsilanolate (“KOTMS”; 56.0 g, 392 mmol) at room temperature. The mixture was allowed to stir overnight to completion by LCMS analysis of the crude. The mixture was concentrated in vacuo to afford a wet foam, which was allowed to dry under vacuum overnight to afford potassium 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate as a solid (148.7 g, 105%). LC/MS (APCI+) m/z 242.1 [M-Boc-K]+.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5](/[CH:6]=[CH:7]/[C:8](OCC)=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][OH:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: OCC=Cc1ccc(Br)cc1
Temperature: -78 °C

Procedure:
To a solution of ethyl trans-4-bromocinnamate [CAS 24393-53-1] (8 mL, 42.6 mmol) in anhydrous dichloromethane (150 mL) under N2 was added dropwise diisobutylaluminum hydride in dichloromethane (128 mL, 1M, 128 mmol) at −78° C. Following the addition, the mixture was allowed to warm from −78° C. to −30° C. over two hours. The mixture was then cooled back to −78° C. and aqueous 1 N HCl was added. The organic layer was separated, dried with MgSO4, filtered and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 1.44 (t, J=6 Hz, 1H), 4.32 (t, J=4.5 Hz, 2H), 6.37 (dt, J=16.5 Hz, J=6 Hz, 1H), 6.57 (dt, J=15 Hz, J=3 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 214 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:18]>C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][NH:18][C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]ccc(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A clear solution of 3-(benzyloxy)-2-methyl-4H-pyran-4-one (150 g, 0.69 mol), ethanol (300 mL) and ammonium hydroxide (28.0-30.0% solution, 690 mL, 10.5 mol) in a 2 L 3-necked round bottom flask equipped with a mechanical stirrer was heated to reflux for 5 h. The reaction mixture was allowed to cool to room temperature, and a further 230 mL of ammonium hydroxide (3.5 mol) was added. The resulting solution was heated to reflux for another 3.5 h, then allowed to cool to RT and stirred for overnight. A solid product had separated, and was collected by suction filtration. Thus, 95 g of 3-benzyloxy-2-methyl-1H-pyridin-4-one (64% yield) was obtained as a first crop. HPLC Method 4 (Example 24), RT=10.7 min, HPLC purity (peak percent area): 99% at λ=280 nm)). 1H NMR (DMSO-d6) δ ppm: 11.3 (br s, 1H), 7.46 (s, 1H), 7.35, (m, 5H), 6.13 (s, 1H), 5.04 (s, 2H), 2.05 (s, 3H); 1H NMR (DMSO-d6+D2O) δ ppm: 7.47 (d, J=7.0 Hz, 1H), 7.39, (m, 5H), 6.20 (d, J=7.0 Hz, 1H), 5.01 (s, 2H), 2.03 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:34])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:34])[NH:6][C:7]([C:15]1[CH:16]=[CH:17][C:18]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:19][CH:20]=1)=[N:8]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc2c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(C4CCNCC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl 4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidine-1-carboxylate (11) (0.45 mmol) in 1,4-dioxane (2 mL) was added 4 M HCl in 1,4-dioxane (1 mL). The resulting solution was stirred at room temperature for 5 hours. Then, the mixture was concentrated in vacuo and the resulting material was purified by flash chromatography on silica gel to afford compound 5,7-dimethoxy-2-(4-(piperidin-4-yl)phenyl)quinazolin-4(3H)-one (12).
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.CO[C:13](=[O:33])[CH:14]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[CH2:15][N:16]([CH3:18])[CH3:17]>C(OCC)C>[CH2:26]([O:25][C:22]1[CH:21]=[CH:20][C:19]([CH:14]([C:13]2([OH:33])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:15][N:16]([CH3:17])[CH3:18])=[CH:24][CH:23]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)C(CN(C)C)c1ccc(OCc2ccccc2)cc1
Reactant: BrCCCCCBr
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CN(C)CC(c1ccc(OCc2ccccc2)cc1)C1(O)CCCCC1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Activated magnesium turnings (8 g) and a few crystals of iodine were charged to diethyl ether (200 ml). After addition of 1,5-dibromopentane (20.7 ml; 0.15 mol), the reaction mixture was refluxed for 2 hours. The reaction mass was cooled to 0-5° C. Separately prepared solution of 2-(4-benzyloxy-phenyl)-3-dimethylamino-propionic acid methyl ester (10 g; 0.032 mol) in diethyl ether (100 ml) was added to the above reaction mass very slowly. The temperature was raised to 25-30° C. with constant stirring for 2 hours. After completion of the reaction; the reaction mass was quenched with saturated ammonium chloride solution (100 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml) and the combined organic layer was washed with water (100 ml). The organic layer was dried on sodium sulphate, concentrated under reduced pressure and the product was isolated in n-heptane (25-30 ml). The material was dried under vacuum at 45-50° C. Yield: 7 g, Efficiency: 62%.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>CCOCC>[C:26]([N:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)(=[O:28])[CH3:27]
Reactant: c1ccc(Oc2ccc(C3CCCN3)cc2)cc1
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC1c1ccc(Oc2ccccc2)cc1

Procedure:
To a solution of 10 parts of 2-(4-phenoxyphenyl) pyrrolidine in 200 parts of anhydrous ether and 4.2 parts of triethylamine, there was added a solution of 3.3 parts of acetyl chloride in 30 parts of ether. The reflux was maintained for one hour, then the reaction mixture was filtered off on cooling and the filtrate was distilled. There were obtained 13 parts of 1-acetyl-2-(4-phenoxyphenyl) pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:11]3)=[CH:4][CH:3]=1.C(=O)([O-])O.[K+].[I:25]I>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[I:25])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:11]3)=[CH:6][CH:7]=1
Reactant: II
Reactant: Clc1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: Clc1ccc(-c2nc3sc4ccccc4n3c2I)cc1
Yield: 83.2 %

Procedure:
In 100 ml of methylene chloride was dissolved 2 g of 2-(p-chlorophenyl)imidazo[2,1-b]benzothiazole and after adding thereto 20 ml of an aqueous 10% potassium hydrogencarbonate solution and 1.8 g of iodine, the mixture was stirred overnight vigorously at room temperature. The crystals which formed were recovered by filtration and recrystallized from a mixture of methylcellosolve and water to provide 2.4 g of 2-(p-chlorophenyl)-3-iodoimidazo[2,1-b]benzothiazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.[O:12]1[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:13]1>O>[OH:12][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:13][N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: c1ccc(-c2ncc[nH]2)nc1
Reactant: CCCCCCCCCCC1CO1
Solvent: O
Product: CCCCCCCCCCC(O)Cn1ccnc1-c1ccccn1
Temperature: 160 °C
Reaction time: 1 h

Procedure:
A mixture of 14.5 g (0.1 mole) 2-(2-pyridyl)imidazole, 18.4 g (0.1 mole) 1,2-epoxydodecane and 3 drops of water was heated with stirring at about 160° C. under nitrogen for about one hour. The resulting product was then extracted with hot hexane and collected as yellow crystals which had a melting point of 62°-65° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[N:22]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[N:22]1([CH2:28][CH2:29][NH:30][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: NCCN1CCOCC1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCCN3CCOCC3)cc2c1=O
Yield: 54 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (29 mg, 0.0912 mmol) is reacted with 2-morpholin-4-yl-ethylamine according to the GPA affording 21 mg (54%) of a red powder. Rt=2.33 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(C(Sc3ccc(Cl)cc3)c3cc(F)ccc3F)c(Cl)cn2)CC1
Temperature: 25 °C
Yield: 12.9 %

Procedure:
A 1,4-dioxane (2.2 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (300 mg, 0.48 mmol) obtained in Example 54 and t-butyl 4-aminopiperidine-1-carboxylate (600 mg) was stirred at 120° C. for 5 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give the title compound (36 mg, 9%) as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1>>[O:32]=[C:30]([CH3:31])[CH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:24][CH:25]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: CC(=O)Cc1ccc(O)cc1
Product: CC(=O)Cc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 1-(4-hydroxyphenyl)-2-propanone: MS (APCI) m/z 445 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[N:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.N12CCCN=C1CCCCC2.Br[CH2:24][CH2:25][CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:11]=[N:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Oc1cnc2c(n1)CCCC2
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: ClCCCCOc1cnc2c(n1)CCCC2
Temperature: 60 °C
Yield: 54.6 %

Procedure:
300 mg (2 mmol) of 2-hydroxy-5,6,7,8-tetrahydroquinoxaline was dissolved in 5 ml of DMF, and 360 μl (2.4 mmol) of 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) and 277 μl (2.4 mmol) of 1-bromo-4-chlorobutane were added thereto. The resultant mixture was stirred with heating at 60° C. for 22 hours to effect a reaction. The DMF in the resultant reaction mixture was distilled off in vacuo to thereby obtain a residue. An aqueous solution of potassium carbonate was added to the obtained residue, followed by extraction with chloroform to obtain an extract. The extract was dried over sodium sulfate anhydride, and subjected to filtration to thereby obtain a filtrate. The solvent of the filtrate was distilled off to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was charged in a column of 20 g of silica gel (Art7734, manufactured and sold by E. Merck, Darmstadt) and eluted with chloroform, to thereby obtain 263 mg of 2-(4-chlorobutoxy)-5,6,7,8-tetrahydroquinoxaline (yield: 54.7%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)[C:4]=2[CH:3]=1
Reactant: C1=COCCC1
Reactant: Brc1ccc2c(c1)[nH]c1ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1ccc2c3ccccc3n(C3CCCCO3)c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
10 mmol of 2-bromo-9H-carbazole, 0.1 mmol of pyridinium toluene-4-sulphonate, and 50 mmol of 3,4-dihydro-2H-pyran was added to dichloromethane at room temperature and let stir for 2 hours before the temperature was raised to 50° C. for 2 hours further. The solution was cooled, concentrated under reduced pressure, and subjected to column chromatography of silica with dichloromethane as the eluent. After concentrating under reduced pressure, 2-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-carbazole was isolated in 90% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)[CH:6]=[CH:7][CH:8]=1.[OH:26]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)=[O:26])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)c1
Reactant: OO
Product: COc1cccc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)c1

Procedure:
Prepared analogous to Example 2 from 6-[4-(3-methoxyphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[I:12])[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:9]=[CH:10][C:11]=1[I:12]
Reactant: COC(=O)c1ccc(I)c(Br)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: ClCCl
Product: OCc1ccc(I)c(Br)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 81.2 %

Procedure:
A solution of methyl 3-bromo-4-iodobenzoate (4.3 g, 12.6 mmol) in CH2Cl2 was cooled, under N2, to −78° C. DIBAL-H (25.2 mL of a 1M solution in CH2Cl2) was added slowly to the solution, which was stirred at −78° C. for 45 minutes and then allowed to come to room temperature. Next, the reaction mixture was diluted with 1M HCL (40 mL) and stirred for 30 minutes. The reaction was further diluted with water and extracted with CH2Cl2. The organic phase was dried (Na2SO4) and concentrated under vacuum to afford the intermediate (3.2 g, 82%) as a solid. 1HNMR (CDCl3) δ ppm: 7.85 (1H), 7.67 (1H), 7.02 (1H), 4.65 (2H), 1.76 (1H, OH).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[NH:19])[NH:17][OH:18])=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.[CH2:21]([N:23]([CH2:26][C:27]1[S:31][C:30]([C:32](O)=O)=[CH:29][C:28]=1[CH3:35])[CH2:24][CH3:25])[CH3:22].Cl>[Li+].[OH-].CO>[CH2:21]([N:23]([CH2:26][C:27]1[S:31][C:30]([C:32]2[O:18][N:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([S:7]([NH:6][CH2:5][C:4]([OH:3])=[O:20])(=[O:8])=[O:9])=[CH:15][CH:14]=3)[N:19]=2)=[CH:29][C:28]=1[CH3:35])[CH2:24][CH3:25])[CH3:22]
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(C(=N)NO)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(S(=O)(=O)NCC(=O)O)cc3)no2)cc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 1.8 %

Procedure:
{4-[5-(5-Diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzenesulfonylamino}-acetic acid ethyl ester (98 mg) is obtained starting from [4-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]-acetic acid ethyl ester (233 mg, 0.774 mmol) and 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (160 mg, 0.704 mmol) according to Method A; LC-MS: tR=0.57 min; [M+1]+=493.17. This material (98 mg, 199 μmol) is dissolved in 2 N aq. LiOH (25 mL) and methanol (25 mL). The mixture is stirred at rt for 20 h before it is acidified by adding 1 N aq. HCl and extracted twice with EA. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (6 mg) as a white solid; LC-MS: tR=0.50 min; [M+1]+=465.02.