trimethyl(trimethylsilyl)silane

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:0.00; pressure:0.00; stir:

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

Procedure: To a solution of sodium nitrite (1 g, 0.02 mol), hexamethyldisilane (3 g, 0.02 mol), iodine (5 g, 0.02 mol) and benzyltriethylammonium chloride (0.3 g, 0.001 mol) in carbon tetrachloride (100 mL, 1 mol) was added a solution of (R)-2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (2.3 g, 0.0070 mol) in methylene chloride (3 mL, 0.05 mol) at 0° C. The mixture was stirred at the same temperature for 40 minutes and then warmed to room temperature overnight. The mixture was purified by flash chromatography to afford the desired product as a brown oil. The mixture was purified by flash chromatography

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At RT, 23.2 g (144 mmol) of hexamethyldisilane and 0.781 g (7.19 mmol) of chlorotrimethylsilane are added to a suspension of 10.0 g (71.9 mmol) of 2-hydroxynicotinic acid in 100 ml of toluene, and the mixture is stirred with a KPG stirrer at 110° C. for 30 min. The mixture is then cooled to −40° C., and 22.5 g (158 mmol) of a 1 molar solution of diisobutylaluminium hydride in dichloromethane are added dropwise to the solution. The mixture is thawed to RT, stirred at RT for 18 h and finally, at −10° C., adjusted to pH=4 with dilute hydrochloric acid, and 500 ml of methanol are added such that the temperature does not exceed −10° C. The precipitate formed is filtered off, 100 ml of water are added to the filtrate, the mixture is stirred at 50° C. for 1 h and the precipitate is filtered off. Concentration of the filtrate gives 8.55 g (95% of theory) of the desired compound. The mixture is then cooled to −40° C. is thawed to RT stirred at RT for 18 h at −10° C. are added such that the temperature does not exceed −10° C The precipitate formed is filtered off 100 ml of water are added to the filtrate the mixture is stirred at 50° C. for 1 h the precipitate is filtered off

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

Procedure: To as solution of ethyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate (Intermediate 21, 1.1 g, 2.79 mmol) in toluene (190 mL) was added iodine (2.9 g, 11.16 mmol) followed by hexamethyldisilane (4.65 mL, 22.33 mmol). The reaction mixture was heated to reflux for 30 h and then cooled to room temperature. The reaction mixture was treated 10% sodium thiosulphate (150 mL) and the layers were separated. The aqueous layer was extracted with toluene and the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica, 4% methanol in dichloromethane) afforded 300 mg (33%) of 4-chloro-3-cyano-5-methyl-N-[(3S,4R)-3-(prop-2-en-1-yloxy)piperidin-4-yl]-1H-pyrrole-2-carboxamide The reaction mixture was heated to reflux for 30 h the layers were separated The aqueous layer was extracted with toluene the organic layer was dried over anhydrous sodium sulphate concentrated under reduced pressure Purification by column chromatography (silica, 4% methanol in dichloromethane)

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

Procedure: To as solution of ethyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate (Intermediate 21, 1.1 g, 2.79 mmol) in toluene (190 mL) was added iodine (2.9 g, 11.16 mmol) followed by hexamethyldisilane (4.65 mL, 22.33 mmol). The reaction mixture was heated to reflux for 30 h and then cooled to room temperature. The reaction mixture was treated 10% sodium thiosulphate (150 mL) and the layers were separated. The aqueous layer was extracted with toluene and the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica, 4% methanol in dichloromethane) afforded 300 mg (33%) of 4-chloro-3-cyano-5-methyl-N-[(3S,4R)-3-(prop-2-en-1-yloxy)piperidin-4-yl]-1H-pyrrole-2-carboxamide The reaction mixture was heated to reflux for 30 h the layers were separated The aqueous layer was extracted with toluene the organic layer was dried over anhydrous sodium sulphate concentrated under reduced pressure Purification by column chromatography (silica, 4% methanol in dichloromethane)

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

Procedure: To as solution of Ethyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate (Intermediate 19, 2.5 g, 6.20 mmol) in toluene (450 mL) was added iodine (6.31 g, 24.8 mmol) followed by hexamethyldisilane (10.34 mL, 49.62 mmol and the reaction mixture was refluxed for 30 h. The reaction mixture was treated with 10% sodium thiosulphate (300 mL) and layers were separated. The aqueous layer was extracted with toluene and the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica, 4% methanol in dichloromethane) afforded 750 mg (36.54%) of 3,4-dichloro-5-methyl-N-[(3S,4R)-3-(prop-2-en-1-yloxy)piperidin-4-yl]-1H-pyrrole-2-carboxamide. the reaction mixture was refluxed for 30 h were separated The aqueous layer was extracted with toluene the organic layer was dried over anhydrous sodium sulphate concentrated under reduced pressure Purification by column chromatography (silica, 4% methanol in dichloromethane)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At RT, 23.2 g (144 mmol) of hexamethyldisilane and 0.781 g (7.19 mmol) of chlorotrimethylsilane are added to a suspension of 10.0 g (71.9 mmol) of 2-hydroxynicotinic acid in 100 ml of toluene, and the mixture is stirred with a KPG stirrer at 110° C. for 30 min. The mixture is then cooled to −40° C., and 22.5 g (158 mmol) of a 1 molar solution of diisobutylaluminium hydride in dichloromethane are added dropwise to the solution. The mixture is thawed to RT, stirred at RT for 18 h and finally, at −10° C., adjusted to pH=4 with dilute hydrochloric acid, and 500 ml of methanol are added such that the temperature does not exceed −10° C. The precipitate formed is filtered off, 100 ml of water are added to the filtrate, the mixture is stirred at 50° C. for 1 h and the precipitate is filtered off. Concentration of the filtrate gives 8.55 g (95% of theory) of the desired compound. The mixture is then cooled to −40° C. is thawed to RT stirred at RT for 18 h at −10° C. are added such that the temperature does not exceed −10° C The precipitate formed is filtered off 100 ml of water are added to the filtrate the mixture is stirred at 50° C. for 1 h the precipitate is filtered off

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At RT, 23.2 g (144 mmol) of hexamethyldisilane and 0.781 g (7.19 mmol) of chlorotrimethylsilane are added to a suspension of 10.0 g (71.9 mmol) of 2-hydroxynicotinic acid in 100 ml of toluene, and the mixture is stirred with a KPG stirrer at 110° C. for 30 min. The mixture is then cooled to −40° C., and 22.5 g (158 mmol) of a 1 molar solution of diisobutylaluminium hydride in dichloromethane are added dropwise to the solution. The mixture is thawed to RT, stirred at RT for 18 h and finally, at −10° C., adjusted to pH=4 with dilute hydrochloric acid, and 500 ml of methanol are added such that the temperature does not exceed −10° C. The precipitate formed is filtered off, 100 ml of water are added to the filtrate, the mixture is stirred at 50° C. for 1 h and the precipitate is filtered off. Concentration of the filtrate gives 8.55 g (95% of theory) of the desired compound. The mixture is then cooled to −40° C. is thawed to RT stirred at RT for 18 h at −10° C. are added such that the temperature does not exceed −10° C The precipitate formed is filtered off 100 ml of water are added to the filtrate the mixture is stirred at 50° C. for 1 h the precipitate is filtered off

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

Procedure: To a solution of sodium nitrite (1 g, 0.02 mol), hexamethyldisilane (3 g, 0.02 mol), iodine (5 g, 0.02 mol) and benzyltriethylammonium chloride (0.3 g, 0.001 mol) in carbon tetrachloride (100 mL, 1 mol) was added a solution of (R)-2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (2.3 g, 0.0070 mol) in methylene chloride (3 mL, 0.05 mol) at 0° C. The mixture was stirred at the same temperature for 40 minutes and then warmed to room temperature overnight. The mixture was purified by flash chromatography to afford the desired product as a brown oil. The mixture was purified by flash chromatography