3-bromoprop-1-ynylbenzene

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:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phosphorous tribromide (2.62 mL, 27.6 mmol) was added to a solution of 3-phenyl-2-propyn-1-ol (10.0 g, 76 mmol) and pyridine (0.14 mL, 1.77 mmol) in diethyl ether (22 mL) at a rate to maintain reflux. After addition, the mixture was heated at 40° C. for 2 h. The mixture was cooled and poured onto ice. The organic layer was separated and diluted with diethyl ether (100 mL), washed with saturated sodium bicarbonate (2×50 mL) and saturated sodium chloride (50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford 1-phenyl-3-bromo-1-propyn (13.4 g, 90%). to maintain reflux After addition The mixture was cooled poured onto ice The organic layer was separated diluted with diethyl ether (100 mL) washed with saturated sodium bicarbonate (2×50 mL) and saturated sodium chloride (50 mL) The organic layer was dried (MgSO4) filtered concentrated in vacuo

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phosphorous tribromide (2.62 mL, 27.6 mmol) was added to a solution of 3-phenyl-2-propyn-1-ol (10.0 g, 76 mmol) and pyridine (0.14 mL, 1.77 mmol) in diethyl ether (22 mL) at a rate to maintain reflux. After addition, the mixture was heated at 40° C. for 2 h. The mixture was cooled and poured onto ice. The organic layer was separated and diluted with diethyl ether (100 mL), washed with saturated sodium bicarbonate (2×50 mL) and saturated sodium chloride (50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford 1-phenyl-3-bromo-1-propyn (13.4 g, 90%). to maintain reflux After addition The mixture was cooled poured onto ice The organic layer was separated diluted with diethyl ether (100 mL) washed with saturated sodium bicarbonate (2×50 mL) and saturated sodium chloride (50 mL) The organic layer was dried (MgSO4) filtered concentrated in vacuo

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phosphorous tribromide (2.62 mL, 27.6 mmol) was added to a solution of 3-phenyl-2-propyn-1-ol (10.0 g, 76 mmol) and pyridine (0.14 mL, 1.77 mmol) in diethyl ether (22 mL) at a rate to maintain reflux. After addition, the mixture was heated at 40° C. for 2 h. The mixture was cooled and poured onto ice. The organic layer was separated and diluted with diethyl ether (100 mL), washed with saturated sodium bicarbonate (2×50 mL) and saturated sodium chloride (50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford 1-phenyl-3-bromo-1-propyn (13.4 g, 90%). to maintain reflux After addition The mixture was cooled poured onto ice The organic layer was separated diluted with diethyl ether (100 mL) washed with saturated sodium bicarbonate (2×50 mL) and saturated sodium chloride (50 mL) The organic layer was dried (MgSO4) filtered concentrated in vacuo

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phosphorous tribromide (2.62 mL, 27.6 mmol) was added to a solution of 3-phenyl-2-propyn-1-ol (10.0 g, 76 mmol) and pyridine (0.14 mL, 1.77 mmol) in diethyl ether (22 mL) at a rate to maintain reflux. After addition, the mixture was heated at 40° C. for 2 h. The mixture was cooled and poured onto ice. The organic layer was separated and diluted with diethyl ether (100 mL), washed with saturated sodium bicarbonate (2×50 mL) and saturated sodium chloride (50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford 1-phenyl-3-bromo-1-propyn (13.4 g, 90%). to maintain reflux After addition The mixture was cooled poured onto ice The organic layer was separated diluted with diethyl ether (100 mL) washed with saturated sodium bicarbonate (2×50 mL) and saturated sodium chloride (50 mL) The organic layer was dried (MgSO4) filtered concentrated in vacuo

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

Procedure: Using the procedure described in Example 12, 2-(3-hydroxyphenyl)-2-methoxy-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)but-1-yl methyl ether was reacted with 3-phenylprop-2-ynyl bromide to give 2-methoxy-2-[3-(3-phenylprop-2-ynyloxy)phenyl]-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)but-1-yl methyl ether in 85% yield, as an oil.

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

Procedure: Using the procedure described in Example 12, 2-(3-hydroxyphenyl)-2-methoxy-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)but-1-yl methyl ether was reacted with 3-phenylprop-2-ynyl bromide to give 2-methoxy-2-[3-(3-phenylprop-2-ynyloxy)phenyl]-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)but-1-yl methyl ether in 85% yield, as an oil.

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

Procedure: The general method described in Part A of Example 81 was followed, using 2-(8-ethoxymethyl-5,6-dimethyl-7H-imidazo [4,5-c]tetrazolo [1,5-a]pyridin-7-yl)ethanol (4.51 g, 15.5 mmol) in lieu of tert-butyl 2-hydroxyethylcarbamate and 3-bromo-1-phenylpropyne, prepared as described in Part A of Example 7, in lieu of propargyl bromide. The crude product was triturated with diethyl ether, isolated by filtration, and dried under reduced pressure to provide 5.93 g of 8-ethoxymethyl-5,6-dimethyl-7-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridine as a yellow solid. prepared The crude product was triturated with diethyl ether isolated by filtration dried under reduced pressure

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

Procedure: Sodium hydride (0.82 g, 20.48 mmol, 60% in mineral oil) and anhydrous N,N-dimethylformamide (20 mL) were combined and stirred for 5 minutes under nitrogen. A solution of 1-[2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]ethan-2-ol (5.8 g, 19.50 mmol) from Part G in N,N-dimethylformamide (30 mL) was then added to the sodium hydride over 5 minutes. After stirring the resulting reaction solution for 10 minutes at room temperature, a solution of 3-bromo-1-phenylpropyne (4.18 g, 21.45 mmol) from Part A in N,N-dimethylformamide (15 mL) was added to the reaction solution, and the resulting reaction mixture was stirred for 4 hours and 10 minutes. Sodium hydride (0.10 g, 60 % in mineral oil) and then 3-bromo-1-phenylpropyne (1 g) were added to the reaction mixture, and after stirring for 30 minutes, HPLC monitoring of the reaction mixture indicated about 7% starting material remaining. The reaction mixture was concentrated under reduced pressure, and the resulting oil was dissolved in dichloromethane. The dichloromethane solution was washed with saturated ammonium chloride (3×), water (3×), and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a brown solid, which was triturated with diethyl ether. The resulting solid was filtered off, and a second crop was collected from the mother liquor. The combined solids were passed through a column of silica (120 g, 40×200 mm) using 95/5 ethyl acetate/dichloromethane. A white solid (5.4 g) was isolated and carried on to the next step. HPLC analysis indicated the presence of about 9% starting material in the white solid. After stirring the resulting reaction solution for 10 minutes at room temperature the resulting reaction mixture was stirred for 4 hours and 10 minutes after stirring for 30 minutes The reaction mixture was concentrated under reduced pressure the resulting oil was dissolved in dichloromethane The dichloromethane solution was washed with saturated ammonium chloride (3×), water (3×), and brine (3×) dried with magnesium sulfate filtered concentrated under reduced pressure to a brown solid, which was triturated with diethyl ether The resulting solid was filtered off a second crop was collected from the mother liquor

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

Procedure: Using the procedure described in Example 12, 2-(3-hydroxyphenyl)-2-methoxy-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)but-1-yl methyl ether was reacted with 3-phenylprop-2-ynyl bromide to give 2-methoxy-2-[3-(3-phenylprop-2-ynyloxy)phenyl]-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)but-1-yl methyl ether in 85% yield, as an oil.