ethyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1.78 g of crude 4-Mercapto-piperidine-1-carboxylic acid tert-butyl ester (273) were dissolved in 20 ml degassed DMF was added 1.3 g (7.1 mmol) 6-Fluoro-7-chloroisoquinoline (263) and 1.23 ml (8.2 mmol) DBU. After stirring for 90 min at 80° C. the solvent was evaporated. The residue was taken up in ethyl acetate and washed with brine. The organic phases were dried over Sodium sulfate and evaporated. Purification over silica gel (40% to 60% ethyl acetate in heptane) gave 1.98 g of the expected compound. degassed DMF was evaporated washed with brine The organic phases were dried over Sodium sulfate evaporated Purification over silica gel (40% to 60% ethyl acetate in heptane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.15 g 4-Acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (272) were dissolved in 84 ml MeOH and treated with 2.1 g (55.5 mmol) sodium borohydride at 0° C. after stirring for 2 h at RT all volatiles were removed in vacuo and to the residue was added slowly water and 2.3 g (11 mmol) citric acid monohydrate. Extraction with dichloromethane, drying with Sodium sulfate and evaporation gave 1.78 g of crude 4-Mercapto-piperidine-1-carboxylic acid tert-butyl ester were removed in vacuo and to the residue Extraction with dichloromethane drying with Sodium sulfate and evaporation

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 6 ml of dimethylformamide was dissolved 1-(tert-butoxycarbonyl)-4-mercaptopiperidine (corresponding to 2 mmol) as described in Reference example 12, and 86 mg (1.97 mmol) of 55% sodium hybride were added to the solution at 0° C. under a nitrogen atmosphere, followed by stirring of the resulting mixture at the same temperature for 20 minutes. Then, 503 mg (2.00 mmol) of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane were added to the reaction mixture and the mixture was stirred at 60° C. for 3 hours. After cooling, ethyl acetate was added to the reaction mixture to dilute it and washed successively with water and a saturated aqueous NaCl solution. An oil obtained by evaporation of the solvent was subjected to silica gel column chromatography and eluted with ethyl acetate to obtain 557 mg (yield: 53%) of the desired compound as an oil. were added to the solution at 0° C. under a nitrogen atmosphere the mixture was stirred at 60° C. for 3 hours After cooling to dilute it washed successively with water An oil obtained by evaporation of the solvent eluted with ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In dry methanol were dissolved 520 mg (2 mmol) of 4-(acetylthio)-1-(tert-butoxycarbonyl)piperidine, and 420 μl (2 mmol) of a 28% sodium methoxide-methanol solution were added to the mixture under ice-cooling and under a nitrogen atmosphere, followed by stirring of the resulting mixture for 40 minutes. Then, 173 μl of acetic acid were added to the mixture and the solvent was distilled off at room temperature, followed by diluting of the residue with ethyl acetate. The mixture was washed successively with an aqueous sodium hydrogencarbonate solution and an aqueous NaCl solution in the order and the solvent was distilled off to obtain 430 mg of reddish orange oil. This product was used for a subsequent reaction without purification. were added to the mixture under ice- cooling and under a nitrogen atmosphere the solvent was distilled off at room temperature by diluting of the residue with ethyl acetate The mixture was washed successively with an aqueous sodium hydrogencarbonate solution an aqueous NaCl solution in the order and the solvent was distilled off

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 6 ml of dimethylformamide was dissolved l-(tert-butoxycarbonyl)-4-mercaptopiperidine (corresponding to 2 mmol) as described in Reference example 12, and 86 mg (1.97 mmol) of 55% sodium hydride were added to the solution at 0° C. under a nitrogen atmosphere, followed by stirring of the resulting mixture at the same temperature for 20 minutes. Then, 503 mg (2.00 mmol) of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane were added to the reaction mixture and the mixture was stirred at 60° C. for 3 hours. After cooling, ethyl acetate was added to the reaction mixture to dilute it and washed successively with water and a saturated aqueous NaCl solution. An oil obtained by evaporation of the solvent was subjected to silica gel column chromatography and eluted with ethyl acetate to obtain 557 mg (yield: 53%) of the desired compound as an oil. were added to the solution at 0° C. under a nitrogen atmosphere the mixture was stirred at 60° C. for 3 hours After cooling to dilute it washed successively with water An oil obtained by evaporation of the solvent eluted with ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In dry methanol were dissolved 520 mg (2 mmol) of 4-(acetylthio)-1-(tert-butoxycarbonyl)piperidine, and 420 μl (2 mmol) of a 28% sodium methoxide-methanol solution were added to the mixture under ice-cooling and under a nitrogen atmosphere, followed by stirring of the resulting mixture for 40 minutes. Then, 173 μl of acetic acid were added to the mixture and the solvent was distilled off at room temperature, followed by diluting of the residue with ethyl acetate. The mixture was washed successively with an aqueous sodium hydrogencarbonate solution and an aqueous NaCl solution in the order and the solvent was distilled off to obtain 430 mg of reddish orange oil. This product was used for a subsequent reaction without purification. were added to the mixture under ice- cooling and under a nitrogen atmosphere the solvent was distilled off at room temperature by diluting of the residue with ethyl acetate The mixture was washed successively with an aqueous sodium hydrogencarbonate solution an aqueous NaCl solution in the order and the solvent was distilled off

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-mercapto-piperidine-1-carboxylic acid tert-butyl ester (1.5352 g, 7.06 mmol) and 4,6-dichloro-5-methyl-pyrimidine (1.1512 g, 7.06 mmol) in 15 mL of THF with sodium t-butoxide (1M in THF, 8.3 mL, 8.3 mmol) added dropwise. After 5 min, mixture was concentrated and residue was extracted with CH2Cl2 and H2O. Organic phase was dried over MgSO4, filtered and concentrated to give 4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester as a yellowish solid (2.3469 g, 97%). Exact mass calculated for C15H22ClN3O2S 343.11, found 344.1 (MH+). added dropwise mixture was concentrated residue was extracted with CH2Cl2 and H2O Organic phase was dried over MgSO4 filtered concentrated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of the crude tert-butyl 4-mercaptopiperidine-1-carboxylate (2.34 g, 10.78 mmol, 1.20 equiv), methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (2.33 g, 8.79 mmol, 1.00 equiv) and potassium carbonate (1.74 g, 12.39 mmol, 1.50 equiv) in N,N-dimethylformamide (23.4 mL) was stirred overnight in a 100-mL round-bottom flask at 50° C. The reaction mixture was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The organic layer was washed with 2×40 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted with ethyl acetate/petroleum ether (1:30-1:5) on a silica gel column to give 920 mg (23%) of tert-butyl 4-((2-(4-(methoxycarbonyl)phenyl)-5-methyloxazol-4-yl)methylthio)piperidine-1-carboxylate as a yellow solid. LC-MS: (ES, m/z): 447 [M+H]+, 347, 271, 146, 105. The reaction mixture was then quenched by the addition of 30 mL of water The resulting solution was extracted with 3×30 mL of ethyl acetate The organic layer was washed with 2×40 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum The residue was eluted with ethyl acetate/petroleum ether (1:30-1:5) on a silica gel column

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of the crude tert-butyl 4-mercaptopiperidine-1-carboxylate (2.34 g, 10.78 mmol, 1.20 equiv), methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (2.33 g, 8.79 mmol, 1.00 equiv) and potassium carbonate (1.74 g, 12.39 mmol, 1.50 equiv) in N,N-dimethylformamide (23.4 mL) was stirred overnight in a 100-mL round-bottom flask at 50° C. The reaction mixture was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The organic layer was washed with 2×40 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted with ethyl acetate/petroleum ether (1:30-1:5) on a silica gel column to give 920 mg (23%) of tert-butyl 4-((2-(4-(methoxycarbonyl)phenyl)-5-methyloxazol-4-yl)methylthio)piperidine-1-carboxylate as a yellow solid. LC-MS: (ES, m/z): 447 [M+H]+, 347, 271, 146, 105. The reaction mixture was then quenched by the addition of 30 mL of water The resulting solution was extracted with 3×30 mL of ethyl acetate The organic layer was washed with 2×40 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum The residue was eluted with ethyl acetate/petroleum ether (1:30-1:5) on a silica gel column