Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[O:6]([C:13]1[C:18]([NH:19][OH:20])=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+].C(Cl)Cl>O>[OH:20][N:19]([C:18]1[C:13]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:14][CH:15]=[CH:16][CH:17]=1)[C:2](=[O:3])[O:4][CH3:5]
Reactant: ONc1cccnc1Oc1ccccc1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)N(O)c1cccnc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3 g (mmol) of methyl chloroformate were added dropwise at 0° C. to a mixture of 7.8 g (39 mmol) of N-(2-phenoxypyridin-3-yl)hydroxylamine (Example 1.b), 4 g (50 mmol) of NaHCO3 (solid) and 10 ml of methylene chloride. After 1 hour at room temperature (approximately 25° C.), the reaction mixture was treated with a further 2 g of methyl chloroformate and stirred for a further 2 hours at room temperature. The reaction mixture was subsequently treated with a further 2 g of methyl chloroformate and left for approximately 12 hours at 5° C. The resulting mixture was treated with water and extracted repeatedly using tert-butyl methyl ether. The organic phases were combined, washed and dried, and the solvent was removed under reduced pressure. The residue obtained was purified by column chromatography (cyclohexane/ethyl acetate). This gave 2.5 g of the title compound as a solid (m.p.: 140° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].C([O:17][C@@H:18]1[C@@H:22]([N:23]2[C:27]3[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:26]=3[N:25]=[C:24]2Br)[CH2:21][C@@H:20]([CH2:35][O:36]C(=O)C)[C@@H:19]1[O:40]C(=O)C)(=O)C>CN(C)C=O>[Cl:32][C:30]1[C:29]([Cl:33])=[CH:28][C:27]2[N:23]([C@@H:22]3[C@@H:18]([OH:17])[C@@H:19]([OH:40])[C@H:20]([CH2:35][OH:36])[CH2:21]3)[C:24]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:25][C:26]=2[CH:31]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)OC[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC[C@@H]1C[C@H](n2c(Oc3ccccc3)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Phenol (72 mg, 0.77 mmol) and anhydrous potassium carbonate (106 mg, 0.77 mmol) were stirred in dry N,N-dimethylformamide (5 mL) under nitrogen for 1.0 hour. (±)(1R*,2S*,3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (400 mg, 0.770 mmol) was added and the mixture stirred at 80° C. (oil bath) for 18 hours. Volatiles were removed in vacuo and the residue partitioned between chloroform and water. The chloroform layer was dried (sodium sulfate) and volatiles evaporated. The residual oil was stirred in 4N ammonia in methanol (30 mL) at ambient temperature for 18 hours. Evaporation and chromatography of the residue on silica gel with elution by 2% methanol-chloroform gave (±)-(1R*,2S*,3S*,5S*)-5-(5,6-dichloro-2-phenoxy-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol as white solid foam from ethyl acetate (215 mg, 68%); 1H-NMR(DMSO-d6) δ: 7.98 and 7.71 (both s, 2, aromatic CH), 7.6-7.3 (m, 5, C6H5), 5.07 (d, J=6.4 Hz, 1, OH), 5.0-4.75 (m overlapping t at 4.95, J=3.1 Hz, total 2, NCH and OH), 4.71 (d, J=3.9 Hz, 1, OH), 4.5-4.35 (m, 1, OCH), 3.9-3.8 (m, 1, OCH), 3.7-3.4 (m, 2, OCH2), 2.3-1.9 (m, 3, CH2 and CH); mass spectrum (CI): 409 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1>[O:22]1[CH2:23][CH2:24][N:19]([C:2]2[C:3]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1
Solvent: C1COCCO1
Product: Fc1ccc(-c2ccc3ncnc(N4CCOCC4)c3n2)cc1
Yield: 97 %

Procedure:
A mixture of 4-chloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (56 mg, 0.2 mmol) and morpholine (200 μl) in dioxane (5 ml) was refluxed for 1 hour. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane, in a volume ratio of 1:60, yielding the title compound (60 mg, yield 97%) as a white solid which was characterised by its mass spectrum as follows: MS (m/z): 311 ([M+H]+, 100).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[OH:19][C:17]1[CH:16]=[CH:15][N:14]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[C:13](=[O:12])[CH:18]=1
Reactant: Oc1ccnc(O)c1
Reactant: COC(=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Temperature: 150 °C

Procedure:
A mixture of methyl 4-iodobenzoate (0.421 g, 1.6 mmol), 2,4-dihydroxypyridine (0.174 g, 1.34 mmol), CuI (25 mg, 0.134 mmol) and K2CO3 (200 mg) in DMF (2 mL) was heated to 150° C. in a sealed vial for 4 hours, diluted with ethyl acetate (100 mL), washed with water (30 mL) and brine (30 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2:1 hexanes/ethyl acetate to provide the desired product. MS (APCI) m/e 246 (M+H)+.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:24][O:25][C:26](=[O:44])[C@@H:27]([NH2:43])[CH:28]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1>>[CH3:24][O:25][C:26](=[O:44])[C@@H:27]([NH:43][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:14]=1[NH:13][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:11])=[O:12])[CH:28]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1
Reactant: COC(=O)[C@@H](N)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Product: COC(=O)[C@@H](NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 94 %

Procedure:
The title compound (48 mg, 94%) was obtained from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid and (S)-2-amino-3,3-bis-(4-chloro-phenyl)-propionic acid methyl ester as in Example 1, Part C. 1H NMR (500 MHz, CDCl3): 11.28 (s, 1H), 8.37 (dd, J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.68 (d, J=1.9, 1H), 7.32-7.28 (m, 4H), 7.20-7.15 (m, 4H), 6.96 (d, J=8.5, 1H), 6.87 (dd, J=8.4, 2.0, 1H), 6.21 (br d, J=8.8, 1H), 5.50 (t, J=8.5, 1H), 4.48 (d, J=8.3, 1H), 3.63 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:20])[CH3:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:21]([CH2:29][CH:30]=[CH2:31])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[S:14]2)[C@H:10]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl>[C:18]([C@H:17]1[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:21]([CH2:29][CH:30]=[CH2:31])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])[S:14]2)[C@@H:10]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:20])[CH3:19]
Reactant: C=CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C(C)O)O[C@@H]2S1
Solvent: ClCCl
Product: C=CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C(C)=O)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.8 %

Procedure:
To a solution of 143 (6 g, 11 mmol) in dichloromethane (120 mL) was added DMP (6.9 g, 16 mmol). The resulting solution was stirred for 1.5 hours at room temperature, then quenched by saturated aqueous sodium bicarbonate solution (80 mL), and extracted with dichloromethane (3×100 mL). The combined organic layer was washed with brine (2×50 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography with 5%-10% ethyl acetate in petroleum ether to afford 144 as a yellow syrup (4 g, 67%). (ES, m/z): [M+H]+ 553.0; 1H NMR (300 MHz, CDCl3): 7.34-7.19 (m, 10H), 6.10 (d, J=6.9 Hz, 1H), 5.85-5.76 (m, 1H), 5.10-4.94 (m, 2H), 4.69-4.25 (m, 7H), 4.15-4.10 (m, 1H), 3.97-3.83 (m, 2H), 2.19 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [ClH:1].ClC1C=CC([NH:9][NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]3[N:19]=[N:18][N:17]([CH3:20])[C:16]=3[CH:21]=2)=CC=1.C(O)C.[OH-].[Na+].[OH:27][C@H:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29]([OH:31])=[O:30]>O>[OH:27][C@H:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29]([OH:31])=[O:30].[Cl:1][C:32]1[CH:37]=[CH:36][C:35]([CH:11]([NH:10][NH2:9])[C:12]2[CH:13]=[CH:14][C:15]3[N:19]=[N:18][N:17]([CH3:20])[C:16]=3[CH:21]=2)=[CH:34][CH:33]=1
Reactant: Cn1nnc2ccc(CNNc3ccc(Cl)cc3)cc21
Reactant: Cl
Agent: O=C(O)[C@H](O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1nnc2ccc(C(NN)c3ccc(Cl)cc3)cc21
Temperature: 14 °C
Reaction time: 0.17 h
Yield: 163.7 %

Procedure:
To a mixture of 200 g of intermediate 2-a and 479 ml of ethanol at 23° C. was added a solution of 23.94 g of sodium hydroxide in 180 ml of water. After stirring for 10 min. there were added 50.2 g of (-)-(R) α-hydroxybenzeneacetic acid. The whole was stirred for 30 min. at 60° C. and the product was crystallized by adding some product crystals obtained in a previous low-scale set-up. Then the whole was stirred for 2 hours at 50° C. and overnight at room temperature. The reaction mixture was cooled (temp. 14° C.) and stirred for 1 hour. The product was filtered off, washed with ethanol and dried in vacuo, yielding 118.8 g (87%) of (-)-6-[(4-chlorophenyl)-hydrazinomethyl]-1-methyl-1H-benzotriazole (R)-α-hydroxybenzeneacetate (1:1) monohydrate (interm. 3-a); diastereomeric excess: 92.6%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[CH:6][CH:7]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([N:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=2)[CH:16]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([N:17]=[C:18]([C:20]([NH:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:21])[N:19]=2)[CH:16]=1
Reactant: Cc1ccc(CN)cc1
Reactant: CCOC(=O)c1nc2ccc(Br)cn2n1
Product: Cc1ccc(CNC(=O)c2nc3ccc(Br)cn3n2)cc1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using p-tolylmethanamine and ethyl 6-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[CH3:30][CH:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:33]([CH:31]([CH3:32])[CH3:30])(=[O:35])=[O:34])[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
The operation is carried out as in Stage 1 of Example 10 starting from 280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methylene chloride, 0.2 ml of triethylamine and 172 mg of 1-methylethanesulphonic acid chloride in place of the 4-methyl-benzenesulphonic acid chloride then the reaction medium is agitated at ambient temperature for approximately 30 min. Then 2 ml of water is added, followed by extracting with 3×5 ml of methylene chloride, washing with 5 ml of saturated sodium chloride, drying, evaporating, impasting in 5 ml of ether then in 5 ml of pentane, separating, and drying. After chromatography on silica eluting with methylene chloride/CH3CN in a proportion of 70/30, 115 mg of expected product is thus obtained in the form of white crystals.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[Cl:14].[CH3:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(Cl)Cl>[Cl:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:19]1[CH2:20][CH2:21][CH:16]([CH3:15])[CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1ccc(OCCBr)c(Cl)c1
Reactant: CC1CCNCC1
Solvent: ClCCl
Product: CC1CCN(CCOc2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
7.80 g (27.8 mmol) of 4-(2-bromoethoxy)-3-chloronitrobenzene (III.1.a) and 10.1 mL (84.0 mmol) of 4-methylpiperidine is dissolved in 100 mL of methylene chloride and stirred for 12 hours at ambient temperature. Then the mixture is filtered through 400 g of aluminum oxide (activity 2-3) with methylene chloride/methanol 49:1 as eluant. Yield: 6.9 g (83% of theory); Rf value: 0.50 (aluminum oxide, petroleum ether/ethyl acetate=3:1); C14H19ClN2O3; EII mass spectrum: m/z=299/301 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH2:24]O)[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.C(P(CCCC)CCCC)CCC.[NH:50]1[CH:54]=[N:53][CH:52]=[N:51]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(OCC)(=O)C.O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH2:24][N:50]4[CH:54]=[N:53][CH:52]=[N:51]4)[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2cc(CO)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: c1nc[nH]n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(COc2cc(Cn3cncn3)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 85.1 %

Procedure:
To a mixture of {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}methanol (0.50 g), tributylphosphine (0.61 g), 1H-1,2,4-triazole (0.21 g) and tetrahydrofuran (80 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.75 g) at room temperature, and the mixture was stirred for 15 hrs. Ethyl acetate was added to the reaction mixture. The ethyl acetate layer was washed successively with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 1-({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}methyl)-1H-1,2,4-triazole as crystals (0.47 g, yield 85%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 95-96° C.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3]C1.Cl.[CH3:13][NH:14][CH3:15].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.Cl>ClCCCl.O>[CH3:13][N:14]([CH3:15])[CH:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCCl
Product: CN(C)C1CCC(=O)CC1
Reaction time: 0.17 h
Yield: 17 %

Procedure:
To a suspension of 1,4-cyclohexanedione monoethyleneketal (3.82 g, 24.6 mmol) and dimethylamine hydrochloride (2.00 g, 24.6 mmol) in 1,2-dichloroethane (50 ml) were dropwise added triethylamine (4.2 ml, 29.6 mmol) and DBU (1,8-diazabicyclo-[5.4.0]-7-undecene) (4.4 ml), and the mixture was stirred for 10 minutes. To the mixture was added triacetoxyborohydride (7.68 g, 34.4 mmol), and the mixture was stirred for 4.5 hours. Precipitate was filtered off, and the filtrate was concentrated to give crude product (6.34 g), which was dissolved in water (10 ml). To the mixture was dropwise added concentrated hydro-chloric acid (6 ml), and the mixture was stirred for 48 hours. The reaction mixture was diluted with water and washed twice with ether. The aqueous layer was made basic with sodium hydroxide and extracted with ether twice. The extract was washed with saturated sodium chloride solution, dried with potassium carbonate and purified by evaporation to give 4-dimethylaminocyclohexanone (0.59 g, 17%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].N1CCNCC1>O.O1CCOCC1>[CH3:15][O:14][C:12]([C:10]1[S:11][C:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][N:1]2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[CH:8][CH:9]=1)=[O:13]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1ccc(C2CCCCN2)s1
Agent: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(C2CCCCN2C(=O)OCc2ccccc2)s1
Reaction time: 4 h

Procedure:
To a mixture of EXAMPLE 28B (0.3 g), potassium carbonate (0.36 g), dioxane (20 mL) and water (5 mL) was added benzyl chloroformate (0.23 mL), and the mixture stirred for 4 hours. Piperazine was added, and the mixture stirred for 30 minutes and partitioned between ethyl acetate and brine. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated. The concentrate was flash chromatographed on silica gel with 10-50% ethyl acetate in hexane.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(F)=C(F)C=2)CCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:25]1([CH2:24][N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][N:9]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCCC2)c2ccc(F)c(F)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: Fc1ccc(NCC2CCCCC2)cc1F
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCCC2)c2ccc(F)c(F)c2)s1

Procedure:
The title compound was prepared via {2-[3-cyclohexylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclohexylmethyl-(3,4-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[CH3:17][C:18]1[NH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][N:22]=1>O>[C:1]1([NH:7][C:8]([N:19]2[C:20]([N+:23]([O-:25])=[O:24])=[CH:21][N:22]=[C:18]2[CH3:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ncc([N+](=O)[O-])[nH]1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ncc([N+](=O)[O-])n1C(=O)Nc1ccccc1
Reaction time: 4 h
Yield: 82.9 %

Procedure:
A solution of 11.9 g. (0.1 mol.) of phenylisocyanate in 75 ml. of toluene is added dropwise to the stirred suspension of 15.2 g. (0.12 mol.) of 2-methyl-5-nitroimidazole in 60 ml. of water at 10° to 12° C. When the addition is complete, the mixture is stirred for further 4 hours. The separated product is filtered off, washed and dried. 20.4 g. (82.9%) of 1-phenylcarbamoyl-2-methyl-5-nitroimidazole are obtained; m.p.: 218°-220° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[C:7](=[CH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:6]2>O=[Pt]=O.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH:7]([CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)C(=Cc1ccncc1)C2
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1)C2
Temperature: 80 °C
Reaction time: 6 h
Yield: 34.8 %

Procedure:
1.80 g of 2,3-dihydro-5,6-dimethoxy-2-((pyridin-4-yl)methylene)inden-1-one and 40 milligrams of PtO2 were added to 15 mL glacial acetic acid. The reaction mixture was stirred at 80° C., with H2 being supplied at 1 atmosphere for 6 hours. Solids were filtered off. The filtrate was concentrated. 30 mL of Na2CO3 aqueous solution were added thereto. The resulted mixture was extracted with of chloroform (5×20 mL). The extracts were combined, washed with brine, and dried over anhydrous MgSO4. The drying agent was then filtered off. Solvent was removed in vacuo to give crude product. Purification of crude product by silica gel column chromatography (CHCl3/CH3OH 95/5) afforded 0.63 g of white crystalline compound. The yield was 35%. 1H NMR (CDCl3): 8.53 (brs, 2H), 7.15-7.25 (m, 3H), 6.82 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.35 (dd, 1H, J=4.4, 14.0 Hz), 3.12 (dd, 1H, J=7.6, 16.8 Hz), 2.95-3.05 (m, 1H), 2.65-2.75 (m, 2H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)[N:24]=2)[CH:21]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[O:27]1[CH:28]=[CH:29][C:25]([C:23]2[N:24]=[C:19]3[CH:18]=[CH:17][C:16]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][OH:8])=[CH:21][N:20]3[CH:22]=2)=[CH:26]1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccccc1-c1ccc2nc(-c3ccoc3)cn2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1ccccc1-c1ccc2nc(-c3ccoc3)cn2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
250 mg of 6-[2-[(tert-butyldimethylsilanyloxy)methyl]phenyl]-2-(furan-3-yl)imidazo[1,2-a]pyridine in 6 ml of tetrahydrofuran are placed in a round-bottomed flask, and 320 mg of tetrabutylammonium fluoride are added thereto. The reaction mixture is stirred at ambient temperature for 48 h and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture. 156 mg of compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][NH:13]C(=O)OC(C)(C)C)[C:3]1=[O:21].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:13][CH2:12][CH2:11][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]([CH3:1])[C:3]1=[O:21]
Reactant: Cn1c(=O)n(CCNC(=O)OC(C)(C)C)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)n(CCN)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (2-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)carbamate (100 mg, 0.345 mmol) in DCM (3 mL) was added TFA (1.5 mL) at 0° C. to 5° C. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give the crude product, which was used in the next step without further purification (140 mg crude). MS (ESI) m/z 192.1 [M+H]+.