Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2C(O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](=[O:26])([O-])[O-].[Na+].[Na+].O>CO>[CH:1]1([C:7]2[C:8]3[O:9][C:10]4[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:23](=[O:26])[C:19]=3[CH:20]=[CH:21][CH:22]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccccc1Oc1ccccc1C1CCCCC1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1c2ccccc2oc2c(C3CCCCC3)cccc12
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of 18.4 g (65 mmol) of 2-(2-cyclohexylphenoxy)benzoic acid and 190 g of polyphosphoric acid is kept at 100° C. for 2 hours. The reaction mixture is then diluted with 200 ml of methanol, neutralized with sodium carbonate and poured onto about 800 ml of water. The product which has precipitated is filtered off, washed with water and dried under a high vacuum. 14.6 g (77%) of 4-cyclohexylxanthone, melting point 122°-124° C., result as a beige powder.
Reaction SMILES: [C:1]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[CH2:13][OH:14])(OCC1C=CC=CC=1)=O.C([N:20]([CH2:23][CH3:24])CC)C.[CH3:25]S(C)=O>>[CH3:25][C:23]1[CH:24]=[C:13]([C@@H:12]2[CH2:15][CH2:16][CH2:17][N:11]2[CH3:1])[O:14][N:20]=1
Reactant: CS(C)=O
Reactant: CCN(CC)CC
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Product: Cc1cc([C@@H]2CCCN2C)on1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a stirred solution of N-Cbz-L-prolinol (5 g, 21.26 mmol, from steps 24b or 24c above) in 20 mL of anhydrous DMSO were added 8.89 mL (63.79 mmol) of triethylamine and 10.75 g (63.79 mmol) of SO3 -pyridine complex in 35 mL of DMSO. The reaction mixture was stirred at room temperature for 10 min, then poured into 200 mL of ice water. The mixture was extracted with ether, the extract was dried over Na2SO4 and concentrated to afford the title product, 3.058 g (70% yield).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)C>CN(C)C=O.O>[CH2:11]([O:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:13]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
Sodium hydride (4.8g. of 50% suspension in oil) was added to a solution of ethyl p-hydroxybenzoate (166g.) in dimethylformamide (1 l). Benzyl chloride (126 g.) was added dropwise to the solution and the mixture heated on a steam bath for 2 hours. The solution was allowed to cool and ethanol (100 mls.) was added and the mixture poured into water (3 l) and then extracted with chloroform. The organic layer was dried (anhydrous MgSO4), filtered and the solvent removed under high vacuum. The resulting crude product was recrystallized from ethanol to yield pure 4-ethoxycarbonylphenoxyphenyl methane (154.2g.), b.pt. 172-3 at 10mm Hg.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:27])[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:17][CH2:16]1.C(C(CC)C(O)=O)C.Cl>C1COCC1>[CH2:25]([CH:22]([CH2:23][CH3:24])[C:21]([N:18]1[CH2:17][CH2:16][CH:15]([NH:14][C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=2)=[O:11])[CH2:20][CH2:19]1)=[O:27])[CH3:26]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCC(CC)C(=O)N1CCC(N)CC1
Agent: CCC(CC)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: CCC(CC)C(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
To an ice cold solution of 4-(trifluoromethyl)phenyl isocyanate (56.1 mg, 0.3 mmol) in THF (1.5 ml) was added 1-(4-aminopiperidin-1-yl)-2-ethylbutan-1-one (59.4 mg, 0.3 mmol), prepared via Example 14 and Example 15 using 2-ethylbutanoic acid. The reaction mixture was allowed to warm to rt and stirred overnight. 1 M HCl aqueous solution was added followed by extraction with EtOAc. Flash chromatography eluted with 50:1 DCM:MeOH followed by recrystallization from acetone afforded desired compound (64 mg, 55%) as a white solid. Mp 207.9-209.3° C. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.57 (m, 4H), 6.40 (d, J=7.6 Hz, 1H), 4.28 (brd, J=12.4 Hz, 1H), 3.96 (brd, J=13.6 Hz, 1H), 3.78-3.70 (m, 1H), 3.18 (t, J=11.6 Hz, 1H), 2.82 (t, J=11.0 Hz, 1H), 2.67-2.60 (m, 1H), 1.89 (d, J=10.8 Hz, p 1H), 1.83 (d, J=10.4 Hz, 1H), 1.56-1.42 (m, 2H), 1.42-1.31 (m, 2H), 1.31-1.16 (m, 2H), 0.83-0.75 (m, 6H). F NMR (300 M Hz, DMSO-d6) −60.324 (s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:31]([CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:32])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCOCC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCOCC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using tetrahydropyran-4-yl-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 461.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1>>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[S:24][CH:25]=[C:21]([CH2:20][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH:1]3[CH2:2][CH2:3]3)[N:22]=2)=[CH:31][CH:30]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2csc(-c3ccc(Cl)cc3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 165A) and 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole: MS (ES) m/z 458 (M+1) and 460 (M+1, isotope).
Reaction SMILES: CS[C:3]1[CH:4]=[C:5]2[C:11]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[CH2:10][N:9]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C:6]2=[CH:7][CH:8]=1.Cl[C:33]1C=CC=C(C(OO)=O)C=1.[S:43]([O-:47])([O-])(=[O:45])=S.[Na+].[Na+]>C(Cl)Cl>[CH3:33][S:43]([C:3]1[CH:4]=[C:5]2[C:11]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[CH2:10][N:9]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])=[O:24])[C:6]2=[CH:7][CH:8]=1)(=[O:47])=[O:45]
Reactant: O=S([O-])([O-])=S
Reactant: CSc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)C1)CN2C(=O)OCC[Si](C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(S(C)(=O)=O)cc12
Reaction time: 0.5 h
Yield: 65 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl 5-(methylthio)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (192 mg, 0.41 mmol) was dissolved in methylene chloride (5 mL). Thereafter, meta-chloroperbenzoic acid (350 mg, 2.03 mmol) was added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred for 30 minutes. Thereafter, an aqueous solution of sodium thiosulfate was added to the reaction solution, and the mixed solution was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(methylsulfonyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (133.2 mg, 65%) in the form of a white amorphous product.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[CH:10]#[N:11]>[Ni].C(O)(=O)C>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]([OH:9])[CH2:10][NH2:11]
Reactant: C#N
Reactant: Cn1ncc(C=O)c1N
Agent: [Ni]
Solvent: CC(=O)O
Product: Cn1ncc(C(O)CN)c1N

Procedure:
The objective was to build the 3,4,5-trihydro-1,3-diazepin-5-ol moiety using as a template the 5-amino-1-methylpyrazole-4-carboxaldehyde, 6. This aldehyde may be readily prepared from the partial reduction and in situ hydrolysis of the corresponding nitrile, compound 5. ##STR5## The presentation of the aldehyde 6 involved the reduction of nitrile 5 with an activated form of Raney nickel (see Dominquez et al, J. Org. Chem. 1961, 26, 1625; T-1 Raney Nickel) in 70% aqueous acetic acid. Through a modification of the Kiliani-Fischer cyanohydrin homologation sequence, it was proposed to add hydrogen cyanide in this aldehyde and subsequently to reduce the nitrile portion of the resulting cyanohydrin 7. ##STR6## This transformation would provide the 5-amino-4-(β-amino-α-hydroxyethyl)-1-methylpyrazole, intermediate 8. This intermediate would be subsequently ring closed with triethylorthoformate to afford the requisite 4,5,6-trihydro-1-methylpyrazolo[5,4-d] [1,2] diazepin-4-ol, compound 9. ##STR7##
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH:10]([CH:12]([OH:14])[CH3:13])[CH2:9][N:8]1[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[O:6])[CH:2]=[CH2:3].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O>[C:12]([CH:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[N:8]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[CH2:9]1)(=[O:14])[CH3:13]
Reactant: C=CCOC(=O)N1CC(C(C)O)CN1C(=O)OCC=C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: C=CCOC(=O)N1CC(C(C)=O)CN1C(=O)OCC=C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 1,2-bis(allyloxycarbonyl)-4-(1-hydroxyethyl)pyrazolidine (13 g) in acetone (260 ml) was added dropwise Jones Reagent (2.67N, 34 ml) at 0° C. After stirring for 1 hour, to the reaction mixture was added dropwise 2-propanol (200 ml) and the reaction mixture was stirred at 0° C. for 1 hour. The precipitate was filtered off and the filtrate was evaporated to give a residual oil, which was extracted with ethyl acetate and the organic layer was separated, washed with brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (300 ml) eluting with a mixture of hexane and ethyl acetate (1:1, V/V) to give 4-acetyl-1,2-bis(allyloxycarbonyl)pyrazolidine (9.18 g).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([C:21]([N:15]2[CH2:16][CH2:17][C:12]([NH:11][C:10]([O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:19])([CH3:18])[CH2:13][CH2:14]2)=[O:22])=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)N2CCC(C)(NC(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) in dichloromethane (3 mL) at room temperature was added methyl 4-chlorocarbonylbenzoate (0.125 g, 0.62 mmol) and triethylamine (0.17 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 3 hours, aqueous ammonium chloride was added, and the mixture was extracted with dichloromethane (2×). The combined organic layers were washed with 10% KHSO4, sat. NaHCO3, brine, dried (MgSO4), and concentrated under reduced pressure to provide the titled compound. MS (CI) m/z 411 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.07 (d, 2H), 7.46 (d, 2H), 7.33 (m, 5H), 5.06 (s, 2H), 4.63 (m, 1H—NH), 4.18-4.13 (m, 2H), 3.95 (s, 3H), 3.36 (m, 2H), 2.09 (m, 2H), 1.78-1.42 (m, 2H), 1.41 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([C:10]2[CH:14]=[C:13]([C:15]3([OH:19])[CH2:18][O:17][CH2:16]3)[N:12]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:11]=2)[C:6]([CH3:9])=[CH:7][CH:8]=1.[C:28](=[S:30])=[S:29].I[CH3:32]>C1COCC1>[CH3:3][C:4]1[N:5]([C:10]2[CH:14]=[C:13]([C:15]3([O:19][C:28]([S:30][CH3:32])=[S:29])[CH2:16][O:17][CH2:18]3)[N:12]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:11]=2)[C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: Cc1ccc(C)n1-c1cc(C2(O)COC2)n(COCC[Si](C)(C)C)n1
Reactant: CI
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC(=S)OC1(c2cc(-n3c(C)ccc3C)nn2COCC[Si](C)(C)C)COC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
Into a 2 L 3-necked round-bottom flask under nitrogen was placed THF (800 mL), followed by the addition of NaH (10.4 g, 260 mmol, 1.50 equiv., 60% suspension) in several batches at 0° C. over 10 min. To this suspension was added a solution of 3-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-5-yl]oxetan-3-ol (63.0 g, 173.3 mmol, 1.0 equiv.) in THF (300 mL), dropwise with stirring at 0° C. over 30 min. The resulting solution was stirred at 0° C. for 30 min. To the mixture was added a solution of CS2 (19.7 g, 259.21 mmol, 1.50 equiv.) in THF (100 mL), dropwise with stirring at 0° C. over 20 min. The resulting solution was stirred at 0° C. for 1 h. To the mixture was added a solution of iodomethane (37.0 g, 260.7 mmol, 1.5 equiv.) in THF (100 mL), dropwise with stirring at 0° C. over 10 min. The resulting solution was stirred at 0° C. for 1 h, then quenched by the addition of 300 mL of satd. aq. NH4Cl, concentrated in vacuo, diluted with 1 L of water and extracted with 3×1 L of EtOAc. The combined organic layers were washed with 2×1 L of water and 2×500 mL of brine, dried (Na2SO4) and concentrated in vacuo to afford ([3-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-[[2-(trimethylsilyl)ethoxy]-methyl]-1H-pyrazol-5-yl]oxetan-3-yl]oxy)(methylsulfanyl)methanethione (80.0 g, 97% yield) as a yellow oil.
Reaction SMILES: C1(C)C=CC=CC=1.[O:8]=[C:9]1[CH2:16][C:13]([CH3:15])([CH3:14])[CH2:12][C:11]([CH3:17])=[CH:10]1.[OH2:18]>[O-]S([O-])(=O)=O.[Cu+2].CCCCCC>[CH3:17][C:11]1[C:12](=[O:18])[C:13]([CH3:15])([CH3:14])[CH2:16][C:9](=[O:8])[CH:10]=1
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC1=CC(=O)CC(C)(C)C1=O
Reaction time: 90 h

Procedure:
A 1-1 three-neck flask equipped with a gas inlet frit, a stirrer and an intensive condenser was charged with 350 ml of toluene, 350 g of isophorone, 11.4 g of H3 [P(Mo3O10)4 ]×H2O, 1.4 g of CuSO4 ·5H2O and 1.4 g of MoO3. After compressed air had been passed through at 110° C. for 90 hours, the reaction mixture was added a little at a time at 80° C. into 4 1 of boiling n-hexane. The mixture was then filtered, and the filtrate was concentrated in a rotary evaporator. The yellowish oil obtained by distillation at 97° C./13 mbar was converted into almost colorless crystals at -18° C. by addition of 10% by volume of n-hexane.
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:30][C@@H:31]([C@H:33]1[C:62](=[O:63])[N:35]2[C:36]([C:56]([O:58][CH2:59][CH:60]=[CH2:61])=[O:57])=[C:37]([C:40]3[S:44][C:43]4=[C:45]([C:48]([C:50]5[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=5)=[O:49])[N:46]=[CH:47][N:42]4[CH:41]=3)[C@H:38]([CH3:39])[C@H:34]12)[CH3:32])(C(C)(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[OH:30][C@@H:31]([C@H:33]1[C:62](=[O:63])[N:35]2[C:36]([C:56]([O:58][CH2:59][CH:60]=[CH2:61])=[O:57])=[C:37]([C:40]3[S:44][C:43]4=[C:45]([C:48]([C:50]5[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=5)=[O:49])[N:46]=[CH:47][N:42]4[CH:41]=3)[C@H:38]([CH3:39])[C@H:34]12)[CH3:32]
Reactant: C=CCOC(=O)C1=C(c2cn3cnc(C(=O)c4cccnc4)c3s2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C1=C(c2cn3cnc(C(=O)c4cccnc4)c3s2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 36 h
Yield: 53.4 %

Procedure:
Acetic acid (0.23 ml) and 0.72 ml of a 1 M tetrahydrofuran solution of tetrabutylammonium fluoride was added to a solution of 0.14 g of allyl (1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate in 2 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 36 hr. The reaction mixture was diluted with 50 ml of ethyl acetate, and the diluted reaction solution was washed with a 5% aqueous sodium bicarbonate solution and 10% brine in that order. The organic layer was dried, and the solvent was then removed by evaporation. The resultant crude product was purified by column chromatography on silica gel (eluted with 10% methanol/ethyl acetate) to give 60.3 mg of allyl (1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate. This product was analyzed by NMR. The results were in agreement with the results of analysis in Example 26.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.N1CCCC1>C(O)C>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[C:18]2[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])=[CH:25][CH:24]=1
Reactant: O=C1COC(=O)N1CCCCSc1cccc2nccn12
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CCO
Solvent: C1CCNC1
Product: O=C1OC(=Cc2ccc(Cl)cc2)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 1.527 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]oxazolidine-2,4-dione and 0.703 g (5.0 mmol) of 4-chlorobenzaldehyde in 20 ml of ethanol, 0.04 ml (0.5 mmol) of pyrrolidine was added, followed by refluxing for 23 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=3/1) to yield 0.301 g (14.1%, white crystal) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11](I)[N:10]=[N:9]1.[N:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[S:17][CH:16]=1.C([O-])(=O)C.[Na+]>CN(C=O)C.O>[N:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[S:17][C:16]=1[C:11]1[N:10]=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:12]=1[CH3:13]
Reactant: Cc1c(I)nnn1-c1ccccc1Cl
Reactant: c1cnc2scnc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2nc3cccnc3s2)nnn1-c1ccccc1Cl
Temperature: 140 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
Under nitrogen atmosphere, 344 mg of 1-(2-chlorophenyl)-4-iodo-5-methyl-[1,2,3]-triazole and 276 mg of thiazolo(5,4-b)pyridine (B. Stanovnik, Synthesis, 1974, 120) were dissolved in 3 ml of DMF. Then, 100 mg of sodium acetate and 103 mg of Herrman catalyst were added, and the mixture was stirred at 140° C. for 8 hours. After diluting the reaction solution with water, the resultant was extracted with chloroform. Organic layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The residues obtained by distilling out the solvents were separated and purified by thin-layer silicagel column chromatography (ethyl acete/hexane=1/1) to obtain 30 mg of the above compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].[N:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[CH:33][C:28]=2[NH:27][CH:26]=1>>[N:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH2:34][NH:1][C:4]3[C:5]4[CH:6]=[CH:7][C:8]([NH:20][CH2:19][C:18]5[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=5[O:16][CH3:15])=[N:9][C:10]=4[CH:11]=[CH:12][CH:13]=3)=[CH:33][C:28]=2[NH:27][CH:26]=1
Reactant: O=Cc1ccc2nc[nH]c2c1
Reactant: COc1ccccc1CN
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: COc1ccccc1CNc1ccc2c(NCc3ccc4nc[nH]c4c3)cccc2n1

Procedure:
The title compound, MS: m/e=410.1 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 2-methoxybenzylamine and 3H-benzimidazole-5-carbaldehyde as described in example 26.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:19]=[C:18]([C:20](=[O:25])[NH:21][CH:22]2[CH2:24][CH2:23]2)[CH:17]=[C:16]([Cl:26])[C:12]=1[C:13](O)=[O:14]>>[Cl:10][C:11]1[CH:19]=[C:18]([CH:17]=[C:16]([Cl:26])[C:12]=1[C:13]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1)=[O:14])[C:20]([NH:21][CH:22]1[CH2:24][CH2:23]1)=[O:25]
Reactant: c1cc2[nH]ccc2cn1
Reactant: O=C(NC1CC1)c1cc(Cl)c(C(=O)O)c(Cl)c1
Product: O=C(NC1CC1)c1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1

Procedure:
3,5-Dichloro-N-cyclopropyl-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)benzamide was prepared using 1H-pyrrolo[3,2-c]pyridine and 2,6-dichloro-4-(cycloproylcarbamoyl)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH3:19]>>[Cl-:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N+:16]2[CH:17]=[CH:18][N:14]([CH3:13])[C:15]=2[CH3:19])=[CH:4][CH:3]=1
Reactant: Cc1nccn1C
Reactant: ClCCCCc1ccc(Cl)cc1
Product: Cc1n(C)cc[n+]1CCCCc1ccc(Cl)cc1
Product: [Cl-]
Temperature: 115 °C
Reaction time: 3 h

Procedure:
To 4.77 g (0.023 mole) 1-chloro-4-(4-chlorobutyl)benzene add 2.23 g (0.023 mole) 1,2-dimethyl-1H-imidazole. Stir the solution for three hours at about 115° C. Follow the progress of the reaction by thin-layer chromatography on silica gel (MeOH:NaCl(1M), 92:8). At the completion of the reaction, cool to obtain an oil. Triturate the oil with petroleum ether until a solid precipitates. Recrystallize the solid from MeOH/acetone; filter and dry in vacuo to yield the title compound as a monohydrate.