Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH:7]([CH2:10][C:11](O)=[O:12])[C:6]=2[CH:14]=1.B>C1COCC1>[OH:12][CH2:11][CH2:10][CH:7]1[C:6]2[CH:14]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: O=C(O)CC1COc2ccc(Br)cc21
Agent: B
Solvent: C1CCOC1
Product: OCCC1COc2ccc(Br)cc21
Reaction time: 12 h
Yield: 58.9 %

Procedure:
A solution of 5-bromo-3-(carboxymethyl)-2,3-dihydro-benzofuran (reference example 15, 1.86 g , 7.68 mmol) in THF (21 mL) is cooled to 0° C. then a solution of borane in THF (7.7 mL, 1 M). On complete addition the cold bath is removed and stirring continued for 12 h. The reaction is quenched with aq. HCl (2M) diluted with ethyl acetate washed with sat. NaHCO3 solution then brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (30% ethyl acetate in hexanes) to give the title compound (1.1 g) as an oil. 1H NMR (CDCl3) d 1.55 (bs, 1H), 1.88 (m, 1H), 2.03 (m, 1H), 3.61 (m, 1H), 3.75 (t, J=6 Hz, 2H), 4.29 (dd, J=8, 7 Hz, 1H), 4.68 (t, J=8 Hz, 1H), 6.68 (d, J=8 Hz, 1H), 7.22 (dd, J=8, 1 Hz, 1H), 7.28 (d, J=1 Hz, 1H). MS m/z242/244 Br pattern (M+).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([S:14][C:15]1[C:16]([C:21]2[N:33]([CH3:34])[C:24]3=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=[C:23]3[N:22]=2)=[N:17][CH:18]=[CH:19][N:20]=1)[CH3:13].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:12]([S:14]([C:15]1[C:16]([C:21]2[N:33]([CH3:34])[C:24]3=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=[C:23]3[N:22]=2)=[N:17][CH:18]=[CH:19][N:20]=1)=[O:6])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1nccnc1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1nccnc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
467 mg of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 425 mg of 2-(3-ethylsulfanylpyrazin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine and 8 ml of chloroform under ice cooling. The mixture was heated to room temperature and stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was poured to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 205 mg of 2-(3-ethylsulfinylpyrazin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 7) and 230 mg of 2-(3-ethylsulfonylpyrazin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 8).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:36]=[CH:35][C:19]3[NH:20][C:21]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[N:22][C:18]=3[CH:17]=2)[CH2:9][O:8]1)(C)(C)C.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1COCC1>[OH:8][CH2:9][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:36]=[CH:35][C:19]2[NH:20][C:21]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][CH:26]=3)=[N:22][C:18]=2[CH:17]=1)=[O:6]
Reactant: CC(C)(C)[Si](C)(C)OC1(c2ccccc2-c2ccc3[nH]c(COc4ccc(C(F)(F)F)cc4)nc3c2)CO1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=C(CO)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A reaction mixture of 5-{2-[2-(tert-butyl-dimethyl-silanyloxy)-oxiranyl]-phenyl}-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.072 g, 0.134 mmol) and toluenesulfonic acid monohydrate (0.031 g, 0.161 mmol) in THF (2 mL) was heated to 80° C. and stirred for 2 hours. The reaction mixture was concentrated and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:2) to afford the title compound as a brown oil (0.053 g, 92%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.64 (d, 2H, J=9.2 Hz), 7.62-7.56 (m, 2H), 7.54-7.46 (m, 4H), 7.26-7.23 (m, 3H), 5.45 (s, 2H), 4.06 (s, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C23H18F3N2O3: 427.4 (M+H), Found 427.0.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([CH2:9][Cl:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:11]([O-:20])(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]1[C:4]([CH2:9][Cl:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:11]([O:20][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][Cl:10])(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC(=O)[O-]
Agent: ClCc1ccccc1CCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)OCc1ccccc1CCl
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a glass-made three-necked flask (volume: 500 ml) with a condenser, 133.0 g (759 mmol) of α,α′-dichloro-o-xylene, 13.3 g of N,N-dimethylformamide and 42.2 g (253 mmol) of sodium octanoate (sodium caprylate) were added. After the mixture was heated and stirred at 110° C. for 2 hours, the reaction mixture was analyzed by the gas chromatography. The conversion of α,α′-dichloro-o-xylene, the yield of [2-(chloromethyl)phenyl]methyl octanoate (based on sodium octanoate), and the molar ratio of the [2- (chloromethyl)phenyl]methyl octanoate produced to the diester compound as a by-product are shown in Table 1 below.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:19][CH2:18][C:17]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH2:20]2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:19][CH2:18][C:17]4([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[O:21][CH2:20]4)[CH2:16][CH2:15]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Reactant: c1ccc2c(c1)OCC21CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC3)COc3ccccc34)nn2)n1

Procedure:
The object product (185 mg, 53%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (200 mg) obtained in Example 43(2), spiro[1-benzofuran-3,4′-piperidine] (210 mg) and potassium carbonate (150 mg).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4].[CH2:16]([S:20](Cl)(=[O:22])=[O:21])[CH2:17][CH2:18][CH3:19]>N1C=CC=CC=1>[CH2:16]([S:20]([O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4])(=[O:22])=[O:21])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCC(O)C(=O)O
Reactant: CCCCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCC(OS(=O)(=O)CCCC)C(=O)O
Reaction time: 8 h

Procedure:
2-Hydroxydodecanoic acid (1 g) dissolved in a 10% methanolic hydrochloric acid solution was stirred at room temperature for 1 hour. The mixture was then concentrated and distributed into chloroform and water, and the chloroform layer was washed with a 1% aqueous sodium hydrogen carbonate solution and water, dried with anhydrous sodium sulfate and concentrated to give the methyl ester of 2-hydroxydodecanoic acid (1.02 g). To the methyl ester of 2-hydroxydodecanoic acid dissolved in pyridine (20 ml) was added butanesulfonyl chloride (0.80 g), and the mixture was stirred for 8 hours. Then, the pyridine was removed by distillation, and the residue was distributed into chloroform and water. The chloroform layer was dried with anhydrous sodium sulfate, concentrated and subjected-to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (50:1) to give the methyl ester of 2-butanesulfonyloxydodecanoic acid (1.21 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([CH3:19])([S:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:5].C(N(CC)CC)C.[CH3:27][OH:28]>>[Cl:1][CH2:2][CH2:3][C:4]([CH3:19])([S:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:28][CH3:27])=[O:12])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:5]
Reactant: CC(C)(CCCl)Sc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(SC(C)(C)CCCl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(4-chloro-2-methylbutan-2-ylthio)-3-nitrobenzoyl chloride (3.48 g, 10.8 mmol) in MeOH (200 mL) was added triethylamine (15.05 mL, 108 mmol). The reaction was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The resulting paste was diluted with EtOAc (200 mL) and washed with saturated aqueous NaHCO3 (75 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting solid was used without further purification.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]4[O:22][CH2:23][O:24][C:17]=34)=[N:10][CH:11]=[N:12]2)=[C:7]([O:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:6]=1)(=O)C.N>>[CH2:23]1[O:22][C:18]2[C:17](=[C:16]([CH:21]=[CH:20][CH:19]=2)[NH:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([OH:4])=[CH:6][C:7]=3[O:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:12]=[CH:11][N:10]=2)[O:24]1
Reactant: CC(=O)Oc1cc(OC2CCOCC2)c2c(Nc3cccc4c3OCO4)ncnc2c1
Agent: N
Product: Oc1cc(OC2CCOCC2)c2c(Nc3cccc4c3OCO4)ncnc2c1

Procedure:
Using an analogous procedure to that described in the last paragraph of Note [22] immediately above, 7-acetoxy-4-(2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazoline was reacted with a saturated methanolic ammonia solution to give 4-(2,3-methylenedioxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline; NMR Spectrum: (DMSOd6) 1.8-1.95 (m, 2H), 2.1-2.2 (m, 2H), 3.52 (m, 2H), 3.8 (s, 3H), 3.9 (m, 2H), 4.95 (m, 1H), 6.7 (s, 1H), 6.75 (d, 1H), 6.85 (s, 1H), 7.6 (d, 1H), 7.88 (s, 1H), 8.4 (s, 1H), 9.65 (s, 1H), 10.6 (br s, 1H); Mass Spectrum: M+H+ 382.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.C([Li])CCC.[C:27]1(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[OH:33][C:27]1([CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccccn2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC(c2ccccn2)C2(O)CCCCC2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A solution of tert-butyl 4-(2-Pyridin-2-yl-ethyl)-piperazine-1-carboxylate (466 mg, 1.60 mmol) in dry tetrahydrofuran (6 mL) under nitrogen was cooled to −78° C. and treated dropwise with a solution of n-butyllithium (2.5 M in hexanes, 0.70 mL, 1.75 mmol). The resulting solution was stirred at −78° C. for 1 h. The reaction was then treated with a solution of cyclohexanone (174 mg, 1.77 mmol) in dry tetrahydrofuran (0.8 mL). The reaction was stirred at −78° C. for 45 min, after which time the reaction was then quenched by the addition of a saturated aqueous solution of sodium bicarbonate, and the tetrahydrofuran was removed in vacuo. The resulting residue was partitioned between water and ethyl acetate and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×30 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo and the product was purified via Biotage Horizon (FLASH 25 M, silica, gradient from 0% methanol/EtOAc to 10% methanol/EtOAc) to yield 484 mg (78%) tert-butyl 4-[2-(1-hydroxy-cyclohexyl)-2-pyridin-2-yl-ethyl]-piperazine-1-carboxylate as a colorless oil.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25]2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=[C:21]([NH2:28])[C:20]=2[N:19]=[C:18]1[CH3:29]>>[NH2:28][C:21]1[C:20]2[N:19]=[C:18]([CH3:29])[N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:11]([NH:10][C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:12])[C:25]=2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=1
Reactant: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Product: Cc1nc(N)c2nc(C)n(CCCNC(=O)N[C@@H]3C[C@H]3c3ccccc3)c2c1C

Procedure:
Using the methods of Examples 75-85, trans-2-phenylcyclopropyl isocyanate was reacted with 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 393.2393.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](/[CH:10]=[CH:11]/[C:12]2[N:13]([CH3:23])[N:14]=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[S:5][C:6]=1[C:7]([OH:9])=O.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[O:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:7]([C:6]2[S:5][C:4](/[CH:10]=[CH:11]/[C:12]3[N:13]([CH3:23])[N:14]=[N:15][C:16]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:3][C:2]=2[CH3:1])=[O:9])[CH2:26][CH2:27]1
Reactant: NC1CCOCC1
Reactant: Cc1nc(/C=C/c2c(-c3ccccn3)nnn2C)sc1C(=O)O
Product: Cc1nc(/C=C/c2c(-c3ccccn3)nnn2C)sc1C(=O)NC1CCOCC1
Yield: 66 %

Procedure:
As described for example 10 g, 4-methyl-2-[(E)-2-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-yl)-vinyl]-thiazole-5-carboxylic acid (56 mg, 0.17 mmol), was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (46 mg, 66%) which was obtained as a light yellow solid. MS: m/e=411.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[NH:12][NH:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:21]1([CH:27]=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)(Cl)Cl>[CH:21]1([CH2:27][N:12]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:10](=[O:20])[NH:11]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=CC1CCCCC1
Reactant: O=C1NNC(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C1NN(CC2CCCCC2)C(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3,4-Dichloro-phenyl)-5-pyridin-4-yl-pyrazolidin-3-one 0.30 g and 0.2 mL cyclohexanecarbaldehyde in chloroform 20 mL was added NaBH3(CN) 0.1 g at 0° C., the reaction was warmed 50° C. and stirred for 1 hour. The reaction was quenched with sat.NaHCO3 25 mL at 0° C. The reaction mixture was extracted with dichloromethane, 3×50 mL. The combined organic phase was washed with brine, dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained as yellow solid 0.4 g. MS (ES+): 404 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][S-:13].[Na+].O>CN(C=O)C>[Cl:11][C:4]1[N:3]=[C:2]([S:13][CH3:12])[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=1
Reactant: Clc1cc2nc[nH]c2c(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(Cl)cc2nc[nH]c12
Temperature: 120 °C

Procedure:
To a solution of 4,6-dichloro-3H-imidazo[4,5-c]pyridine (2.01 g, 10.7 mmol) in DMF (21 mL) at room temperature was added sodium methanethiolate (1.88 g, 26.8 mmol). Mixture was heated at 120° C. for eight hours. An additional 801 mg of sodium methanethiolate was added and mixture stirred at 120° C. for fifteen hours. After adding an additional 340 mg of sodium methanethiolate and heating at 120° C. for five hours, reaction mixture was cooled to room temperature and poured into 100 mL of water. This was then extracted with ethyl acetate (5×150 mL) and combined organic layers were washed with 50% Brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 6-chloro-4-(methylthio)-3H-imidazo[4,5-c]pyridine 2.01, which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[S:14]([OH:17])(=[O:16])=[O:15].[OH-].[Na+:19]>>[CH:3]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[S:14]([O-:17])(=[O:15])=[O:16])=[CH2:2].[Na+:19]
Reactant: O=S(=O)(O)c1c(CCBr)ccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: C=Cc1ccc2ccccc2c1S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Next, 2-(2-bromoethyl)naphthalenesulfonic acid (5 g) was slowly added dropwise to a 1-mol/L aqueous solution of sodium hydroxide (50 mL), and the whole was stirred for 1 hour at room temperature. After that, the resultant was refluxed for 6 hours, and was then subjected to a dehydrobromination reaction, whereby sodium 2-ethenylnaphthalenesulfonate was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[CH:22][C:21](N)=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].N([O-])=O.[Na+].[C:29](=O)(O)[O-:30].[Na+]>S(=O)(=O)(O)O.CO>[NH2:1][C:2]1[N:23]=[C:22]([O:30][CH3:29])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: O=C([O-])O
Reactant: Nc1cnc(N)c(C(=O)NCc2ccc(Oc3ccccc3)s2)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Reaction time: 0.5 h

Procedure:
2,5-Diamino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Preparation Example A+-10 (27 mg, 59 μmol), sodium nitrite (4.1 mg, 59 μmol) and sulfuric acid (several drops) were dissolved in methanol (5 mL), and the solution was stirred for 30 minutes under reflux. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, and the organic layer was washed with brine. The solvent was evaporated in vacuo, the residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), then, further by NH silica gel column chromatography (hexane:ethyl acetate=5:1), and the title compound (0.7 mg) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2[CH:23]=[CH:24][CH:25]=[N:26]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Br:1])[CH:10]=1)[C:5]([NH:26][CH:25]1[CH2:23][CH2:24]1)=[O:7]
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3,5-dibromobenzoic acid (1 eq.) in DMF (0.15 M) was added HATU (1.3 eq.), cyclopropylamine (1.1 eq.) and Hunig's base (3 eq.). The resulting yellow mixture was stirred at RT for 18 h. The reaction was then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Trituration of the crude product thus obtained in a mixture of ether and hexanes afforded the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][O:8][CH3:9])[N:6]=1.[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:9][O:8][CH2:7][N:5]1[N:4]=[N:3][C:2]([NH:1][C:17](=[O:18])[CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:6]1
Reactant: COCn1nnc(N)n1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: COCn1nnc(NC(=O)C(c2ccccc2)c2ccccc2)n1

Procedure:
The title compound, white solid, m.p. 127-128° and MS: (neg. ions): m/e=322.2 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-methoxymethyl-2H-tetrazole and diphenylacetyl chloride.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:13][CH2:12][N:11](C(OCCCC3C=CC=CC=3)=O)[C@H:10]([C:26]([O-:28])=[O:27])[CH2:9]2)[CH2:4][CH2:3]1.[H][H].[CH3:31][CH2:32]O>[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[CH2:13][CH2:12][NH:11][C@H:10]([C:26]([O:28][CH2:31][CH3:32])=[O:27])[CH2:9]2)[CH2:6][CH2:7]1
Reactant: CN1CCC(N2CCN(C(=O)OCCCc3ccccc3)[C@H](C(=O)[O-])C2)CC1
Reactant: [H][H]
Reactant: CCO
Agent: [Pd]
Product: CCOC(=O)[C@@H]1CN(C2CCN(C)CC2)CCN1
Reaction time: 2 h

Procedure:
A suspension of 2.15 g (5.52 mmol) 1-benzyl-2-ethyl(S)-4-(1-methyl-piperidin-4-yl)-piperazine-1,2-dicarboxylate and 100 mg 10% Pd/C in 50 mL EtOH was hydrogenated for 2 h at 50° C. and 3447 hPa hydrogen pressure. The catalyst was filtered off and the filtrate was evaporated to dryness. The product was reacted further without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[OH-].[Na+]>C1COCC1.C([O-])(=O)C.[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: COC(=O)CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reaction time: 8 h

Procedure:
To a slurry of methyl 3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)propanoate (0.114 g, 0.26 mmol) in 3 mL THF/1 mL water was added sodium hydroxide (0.53 mL, 0.53 mmol). The reaction mixture became light yellow and was still heterogeneous. After stirring overnight, the slightly milky solution was treated with a stream of nitrogen to remove the THF, then 0.53 mL 1N HCl to neutralize base, at which point a white precipitate formed, and diluted with 3 mL 3M pH 4.8 sodium acetate buffer. The reaction mixture was filtered and the solid rinsed with water and MeOH. The solid was collected and dried in vacuo to give 3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)propanoic acid as a white solid. MS (ESI) m/z; calculated: 418.1; Observed: 419.1 (M++1).
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:11]([CH2:12][CH2:13][OH:14])[NH:10][C:9]1=[O:15])[C:2]1C=CC=CC=1.[O:16]1CCCCC1N1C(CCOC2CCCCO2)CC1=O>>[OH:16][CH:1]([C@H:8]1[C@@H:11]([CH2:12][CH2:13][OH:14])[NH:10][C:9]1=[O:15])[CH3:2]
Reactant: O=C1N[C@@H](CCO)[C@@H]1Cc1ccccc1
Reactant: O=C1CC(CCOC2CCCCO2)N1C1CCCCO1
Product: CC(O)[C@@H]1C(=O)N[C@@H]1CCO

Procedure:
Following the procedure described for the preparation of trans-3-benzyl-4-(2'-hydroxyethyl)-2-azetidinone from 8-oxo-2,2-dimethyl-7α-benzyl-3-oxa-1-azabicyclo[4.2.0]octane and using 8-oxo-2,2-dimethyl-7β-(1'-hydroxyethyl)-3-oxa-1-azabicyclo[4.2.0]octane one obtains cis-3-(1'-hydroxyethyl)-4-(2'-hydroxyethyl)-2-azetidinone.
Reaction SMILES: [N:1]([CH3:4])=[C:2]=[S:3].[N:5]1([CH:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:15]3[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=3[N:13]=2)[CH2:7][CH2:6]1>O1CCCC1>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:16]2[C:15]3[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=3[N:13]=[C:12]2[NH:11][CH:8]2[CH2:7][CH2:6][N:5]([CH:29]3[CH2:34][CH2:33][CH2:32][N:31]([C:2](=[S:3])[NH:1][CH3:4])[CH2:30]3)[CH2:10][CH2:9]2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(C4CCCNC4)CC3)nc3ccccc32)cc1
Reactant: CN=C=S
Solvent: C1CCOC1
Product: CNC(=S)N1CCCC(N2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A mixture of 0.8 parts of isothiocyanatomethane, 4 parts of N-([1,3'-bipiperidin]-4-yl)-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine and 90 parts of tetrahydrofuran was stirred overnight at room temperature. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 3.7 parts (77%) of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-N-methyl-[1,3'-bipiperidine]-1'-carbothioamide; mp. 218.8° C. (compound 37).