2-bromo-2-methylpropanoyl chloride

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

Procedure: To a stirred ice-cooled solution of 290 mg of 6-amino-3-chloro-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol (Example 14, Part A) in 15 mL of dry ether was added 0.100 mL of dry pyridine and 228 mg of α-bromoisobutyryl chloride. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF, 268 mg of lithium iodide and 978 mg of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was then poured onto water and etracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated. Since TLC. showed the reaction had only gone halfway to completion, the crude product was redissloved in 15 mL of DMF and subjected to the same reaction conditions as above for another 24 h. After the same work-up, the crude product was purified by column chromatography over silica gel (elution with 5-15% ethyl acetate in hexanes) and then recrystallized from ethyl acetate/hexanes to give 45 mg of the title compound as colorless crystals: mp 167°; Anal. Calcd. for C18H17NO2F3Cl: C, 58.15; H, 4.62; N, 3.78. Found: C, 58.11; H, 4.59; N, 3.70. washed with water and aqueous sodium bicarbonate dried evaporated The residue was dissolved in 15 mL of dry DMF 268 mg of lithium iodide and 978 mg of cesium carbonate was added The reaction mixture was then poured onto water The combined extracts were washed with water and brine dried evaporated subjected to the same reaction conditions as above for another 24 h After the same work-up, the crude product was purified by column chromatography over silica gel (elution with 5-15% ethyl acetate in hexanes) recrystallized from ethyl acetate/hexanes

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

Procedure: 28 g (0.15 mol) 2-bromo-2-methyl-propionyl chloride are added dropwise to 25.7 g (0.10 mol) 1-(3-amino-4-benzyloxy-2-hydroxy-phenyl)-ethanone and 41 g (0.30 mol) potassium carbonate in 215 mL acetonitrile. After 8 hours stirring at reflux temperature the solid is filtered off, the filtrate is evaporated down and the residue is crystallised from ethanol. Yield: 11.2 g (35%); melting range=124-126° C. at reflux temperature the solid is filtered off the filtrate is evaporated down the residue is crystallised from ethanol

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

Procedure: 4.64 g (25 mmol) 2-bromo-2-methyl-propionyl chloride are added dropwise at 5 to 20° C. to a solution of 5.15 g (20 mmol) 1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone in 20 mL pyridine. After the addition has ended the mixture is stirred for 15 minutes, combined with ice water and 100 mL ethyl acetate and acidified with conc. hydrochloric acid. The organic phase is separated off, washed with water and dried with sodium sulphate. After the solvent has been distilled off the residue is crystallised from a diethyl ether/petroleum ether mixture. After the addition The organic phase is separated off washed with water dried with sodium sulphate After the solvent has been distilled off the residue is crystallised from a diethyl ether/petroleum ether mixture

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

Procedure: To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (200 mg, 0.566 mmol) in chloroform (10 mL) was added triethylamine (0.124 mL), followed by 2-bromo-2-methylpropionyl chloride (286 mg, 1.30 mmol). The resulting mixture was heated at 110° C. for 2 hours under microwave irradiation. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (35 mL), washed with brine and dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography to afford 180 mg of the title compound as a light solid (yield was 63%). After being cooled to room temperature the mixture was concentrated in vacuo The residue was diluted with ethyl acetate (35 mL) washed with brine dried over sodium sulfate concentrated in vacuo The residue was purified by flash chromatography

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

Procedure: To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (200 mg, 0.566 mmol) in chloroform (10 mL) was added triethylamine (0.124 mL), followed by 2-bromo-2-methylpropionyl chloride (286 mg, 1.30 mmol). The resulting mixture was heated at 110° C. for 2 hours under microwave irradiation. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (35 mL), washed with brine and dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography to afford 180 mg of the title compound as a light solid (yield was 63%). After being cooled to room temperature the mixture was concentrated in vacuo The residue was diluted with ethyl acetate (35 mL) washed with brine dried over sodium sulfate concentrated in vacuo The residue was purified by flash chromatography

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

Procedure: To a stirred ice-cooled solution of 290 mg of 6-amino-3-chloro-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol (Example 14, Part A) in 15 mL of dry ether was added 0.100 mL of dry pyridine and 228 mg of α-bromoisobutyryl chloride. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF, 268 mg of lithium iodide and 978 mg of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was then poured onto water and etracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated. Since TLC. showed the reaction had only gone halfway to completion, the crude product was redissloved in 15 mL of DMF and subjected to the same reaction conditions as above for another 24 h. After the same work-up, the crude product was purified by column chromatography over silica gel (elution with 5-15% ethyl acetate in hexanes) and then recrystallized from ethyl acetate/hexanes to give 45 mg of the title compound as colorless crystals: mp 167°; Anal. Calcd. for C18H17NO2F3Cl: C, 58.15; H, 4.62; N, 3.78. Found: C, 58.11; H, 4.59; N, 3.70. washed with water and aqueous sodium bicarbonate dried evaporated The residue was dissolved in 15 mL of dry DMF 268 mg of lithium iodide and 978 mg of cesium carbonate was added The reaction mixture was then poured onto water The combined extracts were washed with water and brine dried evaporated subjected to the same reaction conditions as above for another 24 h After the same work-up, the crude product was purified by column chromatography over silica gel (elution with 5-15% ethyl acetate in hexanes) recrystallized from ethyl acetate/hexanes

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

Procedure: To a stirred ice-cooled solution of 290 mg of 6-amino-3-chloro-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol (Example 14, Part A) in 15 mL of dry ether was added 0.100 mL of dry pyridine and 228 mg of α-bromoisobutyryl chloride. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF, 268 mg of lithium iodide and 978 mg of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was then poured onto water and etracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated. Since TLC. showed the reaction had only gone halfway to completion, the crude product was redissloved in 15 mL of DMF and subjected to the same reaction conditions as above for another 24 h. After the same work-up, the crude product was purified by column chromatography over silica gel (elution with 5-15% ethyl acetate in hexanes) and then recrystallized from ethyl acetate/hexanes to give 45 mg of the title compound as colorless crystals: mp 167°; Anal. Calcd. for C18H17NO2F3Cl: C, 58.15; H, 4.62; N, 3.78. Found: C, 58.11; H, 4.59; N, 3.70. washed with water and aqueous sodium bicarbonate dried evaporated The residue was dissolved in 15 mL of dry DMF 268 mg of lithium iodide and 978 mg of cesium carbonate was added The reaction mixture was then poured onto water The combined extracts were washed with water and brine dried evaporated subjected to the same reaction conditions as above for another 24 h After the same work-up, the crude product was purified by column chromatography over silica gel (elution with 5-15% ethyl acetate in hexanes) recrystallized from ethyl acetate/hexanes

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

Procedure: 4.64 g (25 mmol) 2-bromo-2-methyl-propionyl chloride are added dropwise at 5 to 20° C. to a solution of 5.15 g (20 mmol) 1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone in 20 mL pyridine. After the addition has ended the mixture is stirred for 15 minutes, combined with ice water and 100 mL ethyl acetate and acidified with conc. hydrochloric acid. The organic phase is separated off, washed with water and dried with sodium sulphate. After the solvent has been distilled off the residue is crystallised from a diethyl ether/petroleum ether mixture. After the addition The organic phase is separated off washed with water dried with sodium sulphate After the solvent has been distilled off the residue is crystallised from a diethyl ether/petroleum ether mixture

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

Procedure: 4.64 g (25 mmol) 2-bromo-2-methyl-propionyl chloride are added dropwise at 5-20° C. to a solution of 5.15 g (20 mmol) 1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone in 20 mL pyridine. After the addition has ended the mixture is stirred for 15 minutes, combined with ice water and 100 mL ethyl acetate and acidified with conc. hydrochloric acid. The organic phase is separated off, washed with water and dried with sodium sulphate. After the solvent has been distilled off the residue is crystallised from a diethyl ether/petroleum ether mixture. After the addition The organic phase is separated off washed with water dried with sodium sulphate After the solvent has been distilled off the residue is crystallised from a diethyl ether/petroleum ether mixture

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

Procedure: 4.64 g (25 mmol) 2-bromo-2-methyl-propionyl chloride are added dropwise at 5 to 20° C. to a solution of 5.15 g (20 mmol) 1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone in 20 mL pyridine. After the addition has ended the mixture is stirred for 15 minutes, combined with ice water and 100 mL ethyl acetate and acidified with conc. hydrochloric acid. The organic phase is separated off, washed with water and dried with sodium sulphate. After the solvent has been distilled off the residue is crystallised from a diethyl ether/petroleum ether mixture. After the addition The organic phase is separated off washed with water dried with sodium sulphate After the solvent has been distilled off the residue is crystallised from a diethyl ether/petroleum ether mixture

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

Procedure: 4.64 g (25 mmol) 2-bromo-2-methyl-propionyl chloride are added dropwise at 5-20° C. to a solution of 5.15 g (20 mmol) 1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone in 20 mL pyridine. After the addition has ended the mixture is stirred for 15 minutes, combined with ice water and 100 mL ethyl acetate and acidified with conc. hydrochloric acid. The organic phase is separated off, washed with water and dried with sodium sulphate. After the solvent has been distilled off the residue is crystallised from a diethyl ether/petroleum ether mixture. After the addition The organic phase is separated off washed with water dried with sodium sulphate After the solvent has been distilled off the residue is crystallised from a diethyl ether/petroleum ether mixture

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

Procedure: To a stirred ice-cooled solution of 290 mg of 6-amino-3-chloro-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol (Example 14, Part A) in 15 mL of dry ether was added 0.100 mL of dry pyridine and 228 mg of α-bromoisobutyryl chloride. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF, 268 mg of lithium iodide and 978 mg of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was then poured onto water and etracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated. Since TLC showed the reaction had only gone halfway to completion, the crude product was redissloved in 15 mL of DMF and subjected to the same reaction conditions as above for another 24 h. After the same work-up, the crude product was purified by column chromatography over silica gel (elution with 5-15% ethyl acetate in hexanes) and then recrystallized from ethyl acetate/hexanes to give 45 mg of the title compound as colorless crystals: mp 167°; Anal. Calcd. for C18H17NO2F3Cl: C, 58.15; H, 4.62; N, 3.78. Found: C, 58.11; H, 4.59; N, 3.70. washed with water and aqueous sodium bicarbonate dried evaporated The residue was dissolved in 15 mL of dry DMF 268 mg of lithium iodide and 978 mg of cesium carbonate was added The reaction mixture was then poured onto water The combined extracts were washed with water and brine dried evaporated subjected to the same reaction conditions as above for another 24 h After the same work-up, the crude product was purified by column chromatography over silica gel (elution with 5-15% ethyl acetate in hexanes) recrystallized from ethyl acetate/hexanes