3-bromoprop-1-ynyl(trimethyl)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:

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methyl-quinoline (0.28 mL, 2.09 mmol) was added dropwise to a solution of LDA (3.0 mL, 0.8 M in THF) in THF (3 mL) at −78° C. and the reaction mixture was stirred for 1 hour at −78° C. Then (3-bromo-prop-1-ynyl)-trimethyl-silane (0.39 mL, 2.51 mmol) was added to the reaction mixture, the solution was stirred for 18 hours at room temperature and was quenched with water. The aqueous phase was extracted with DCM. The organic phase was washed with water, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 338 mg (1.33 mmol, 64%) of 2-(4-trimethylsilanyl-but-3-ynyl)-quinoline as a yellow solid. the solution was stirred for 18 hours at room temperature was quenched with water The aqueous phase was extracted with DCM The organic phase was washed with water dried over MgSO4 filtered evaporated The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1)

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

Procedure: To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl]piperidin-1-yl)ethanone (150 mg) and potassium carbonate (43 mg) in DMF (8 ml) are added, at room temperature, potassium iodide (19 mg) and (3-bromoprop-1-yn-1-yl)(trimethyl)silane (64 mg). The reaction mixture is stirred at 80° C. for 9 h. Then dilute hydrochloric acid is added to the mixture, which is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-{[3-(trimethylsilyl)prop-2-yn-1-yl]oxy}phenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (8 mg). is extracted with ethyl acetate The combined organic phases are dried over sodium sulphate concentrated Purification by column chromatography

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methyl-quinoline (0.28 mL, 2.09 mmol) was added dropwise to a solution of LDA (3.0 mL, 0.8 M in THF) in THF (3 mL) at −78° C. and the reaction mixture was stirred for 1 hour at −78° C. Then (3-bromo-prop-1-ynyl)-trimethyl-silane (0.39 mL, 2.51 mmol) was added to the reaction mixture, the solution was stirred for 18 hours at room temperature and was quenched with water. The aqueous phase was extracted with DCM. The organic phase was washed with water, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 338 mg (1.33 mmol, 64%) of 2-(4-trimethylsilanyl-but-3-ynyl)-quinoline as a yellow solid. the solution was stirred for 18 hours at room temperature was quenched with water The aqueous phase was extracted with DCM The organic phase was washed with water dried over MgSO4 filtered evaporated The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1)

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

Procedure: A solution of 14.0 ml (2.0 M in THF/n-heptane/ethylbenzene, 28 mmol) LDA in 100 ml THF was treated during 15 min at −78° C. with 2.84 g (20 mmol) cyclopropanecarboxylic acid tert-butyl ester in 20 ml THF. After 6 h at −78° C., a solution of 3-(trimethylsilyl) propargyl bromide and 29 ml DMPU in 40 ml THF was added during 20 min. Over night, the solution was naturally warmed to room temperature, poured on ice/aqueous saturated NH4Cl solution and extracted with ether (three times). The organic phases were washed with aqueous 10% KHSO4, water (5×), aqueous 10% NaCl and dried (Na2SO4) to give 5.59 g of the title compound as volatile dark brown liquid. Over night poured on ice/aqueous saturated NH4Cl solution extracted with ether (three times) The organic phases were washed with aqueous 10% KHSO4, water (5×), aqueous 10% NaCl dried (Na2SO4)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Di-tert-butyl N-(tert-butoxycarbonyl)-L-glutamate (633 mg, 1.76 mmol) was dissolved in tetrahydrofuran (6 ml) and at −78° C., lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 3.87 ml) were added dropwise. After 30 min, 3-bromo-1-(trimethylsilyl)-1-propyne (370 mg, 1.94 mmol) in tetrahydrofuran (2 ml) was added dropwise and the mixture was stirred at −78° C. for 3 h. The reaction was than warmed to 0° C. and 10 ml of 1 N hydrochloric acid were added. The mixture was extracted with dichloromethane, dried and concentrated in vacuo. The residue was purified by silica gel chromatography to give the intermediate TMS-protected alkyne. The intermediate was dissolved in 30 ml dichloromethane/methanol (1:1). Potassium carbonate (1 g) was added and the mixture was stirred for 1 h. Water (20 ml) was added and the mixture was extracted with dichloromethane, dried and concentrated in vacuo. The product (416 mg, 59%) was used in the following reaction without further purification. than warmed to 0° C. The mixture was extracted with dichloromethane dried concentrated in vacuo The residue was purified by silica gel chromatography to give the intermediate TMS-protected alkyne the mixture was stirred for 1 h the mixture was extracted with dichloromethane dried concentrated in vacuo The product (416 mg, 59%) was used in the following reaction without further purification

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

Procedure: In THF (27.4 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (1.37 g). To the solution was added 60% sodium hydride (0.27 g) at 0° C., and the mixture was stirred at room temperature for 1 hour. To the mixture was added 3-bromo-1-(trimethylsilyl)-1-propyne (1.48 ml), and the mixture was stirred at 65° C. for 90 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-trimethylsilyl-2-propynyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.78 g). the mixture was stirred at 65° C. for 90 hours After cooled to room temperature the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried with magnesium sulfate The solvent was removed under reduced pressure the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/1)