tetrabutylazanium;fluoride;dihydrofluoride

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a vial were added ethyl trans-4-[2-(5-bromo-1,3-thiazol-2-yl)oxiran-2-yl]-cyclohexanecarboxylate (101 mg, 0.28 mmol) and tetra-N-butylammonium dihydrogentrifluoride (422 mg, 1.34 mmol). The mixture was heated at 120° C. for 3 h 45 min. The mixture was diluted with water, and extracted with EtOAc. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated to afford racemic ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-2-fluoro-1-hydroxyethyl]cyclohexane-carboxylate which was used without further purification. MS ESI calc'd. for C14H19BrFNO3S [M+H]+ 380, 382. found 380, 382. extracted with EtOAc The organic phase was washed with water, brine dried over sodium sulfate concentrated

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3′-fluoro-4′-({4-[trans-4-(1-oxiran-2-ylethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.15 g), tetra-n-butylammonium dihydrogentrifluoride (0.49 g) and chlorobenzene (0.5 mL) was stirred at 120° C. for 24 hr and then at room temperature for 40 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.081 g, 51%). at room temperature for 40 hr The reaction mixture was concentrated under reduced pressure the residue was purified by silica gel column chromatography

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4′-[(2-methyl-4-{trans-4-[(2-methyloxiran-2-yl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.19 g), tetra-n-butylammonium dihydrogentrifluoride (0.65 g) and chlorobenzene (0.5 mL) was stirred at 120° C. for 20 hr. The reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.094 g, 46%). The reaction mixture was purified by silica gel column chromatography

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4′-{[4-(trans-4-{[2-(fluoromethyl)oxiran-2-yl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.17 g), potassium hydrogen fluoride (0.15 g), tetra-n-butylammonium dihydrogentrifluoride (0.097 g) and chlorobenzene (0.5 mL) was stirred at 120° C. for 14 hr. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.16 g, 87%). The precipitate was filtered off the filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4′-({4-[trans-4-(oxiran-2-ylmethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.25 g), potassium hydrogen fluoride (0.075 g), tetra-n-butylammonium dihydrogentrifluoride (0.015 g) and chlorobenzene (1 mL) was stirred at 120° C. for 5 hr. Potassium hydrogen fluoride (0.075 g) and tetra-n-butylammonium dihydrogentrifluoride (0.014 g) were added, and the mixture was stirred at 120° C. for 16 hr. Toluene was added, and the precipitate was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.15 g, 60%). the mixture was stirred at 120° C. for 16 hr the precipitate was filtered off The filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4′-({4-[trans-4-(oxiran-2-ylmethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.25 g), potassium hydrogen fluoride (0.075 g), tetra-n-butylammonium dihydrogentrifluoride (0.015 g) and chlorobenzene (1 mL) was stirred at 120° C. for 5 hr. Potassium hydrogen fluoride (0.075 g) and tetra-n-butylammonium dihydrogentrifluoride (0.014 g) were added, and the mixture was stirred at 120° C. for 16 hr. Toluene was added, and the precipitate was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.15 g, 60%). the mixture was stirred at 120° C. for 16 hr the precipitate was filtered off The filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography

Conditions: temp:7.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: First 200 mg of 5-(4-aminophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is added to a solution of 6 ml of hydrogen fluoride-pyridine complex (1:1) under argon, and then 51 mg of sodium nitrite is added at 0-5° C. After stirring at 5-10° C. for 40 minutes, 117 mg of tin(II) chloride and 190 mg of tetrabutylammonium dihydrogen trifluoride are added to the preparation. It is then heated for 3 hours to a bath temperature of 100° C. After cooling, it is added to ice water and extracted three times with ethyl acetate and three times with methylene chloride. The collected organic phase is dried, filtered, concentrated by evaporation and chromatographed on silica gel first with methylene chloride:ethanol=10:1, then a second time with acetone:ethyl acetate=3:1 and then a third time with methylene chloride:ethanol=95:5. 106 mg of 5-(4-fluorophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine with a melting point of 190° C. is obtained. It is then heated for 3 hours to a bath temperature of 100° C After cooling extracted three times with ethyl acetate and three times with methylene chloride The collected organic phase is dried filtered concentrated by evaporation chromatographed on silica gel first with methylene chloride

Conditions: temp:7.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: First 200 mg of 5-(4-aminophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is added to a solution of 6 ml of hydrogen fluoride-pyridine complex (1:1) under argon, and then 51 mg of sodium nitrite is added at 0-5° C. After stirring at 5-10° C. for 40 minutes, 117 mg of tin(II) chloride and 190 mg of tetrabutylammonium dihydrogen trifluoride are added to the preparation. It is then heated for 3 hours to a bath temperature of 100° C. After cooling, it is added to ice water and extracted three times with ethyl acetate and three times with methylene chloride. The collected organic phase is dried, filtered, concentrated by evaporation and chromatographed on silica gel first with methylene chloride:ethanol=10:1, then a second time with acetone:ethyl acetate=3:1 and then a third time with methylene chloride:ethanol=95:5. 106 mg of 5-(4-fluorophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine with a melting point of 190° C. is obtained. It is then heated for 3 hours to a bath temperature of 100° C After cooling extracted three times with ethyl acetate and three times with methylene chloride The collected organic phase is dried filtered concentrated by evaporation chromatographed on silica gel first with methylene chloride

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

Procedure: To a solution of (E)-[2-(3-{4-[1-(4-bromo-phenylcarbamoyl)-3-(tert-butyl-dimethyl-silanyloxy)-propyl]-phenyl}-acryloylamino)-phenyl]-carbamic acid tert-butyl ester (1.6 g, 2.26 mmol) in THF (40 mL) was added tetrabutylammonium dihydrogen trifluoride (1.36 g, 4.52 mmol). This mixture was stirred at room temperature overnight and then evaporated to remove THF. The mixture was dissolved in water and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography (CH2Cl2:EtOAc=10:1) to get yellow solid product. MS: calc'd 594 (MH+), exp 594 (MH+). evaporated to remove THF The mixture was dissolved in water extracted with ethyl acetate (3×30 mL) The combined organic layer was washed with brine dried with Na2SO4 filtered evaporated The crude product was purified by column chromatography (CH2Cl2:EtOAc=10:1) to get yellow solid product

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 0.245 gm (1.16 mmol) of 1-bromo-3-but-3-enylbenzene in CH2Cl2 at 0° C. was treated with 0.39 gm (1.74 mmol) of N-iodosuccinimide and 1.05 gm (1.74 mmol) of 50% wt/wt tetrabutylammoniumdihydrogen trifluoride in CH2Cl2, stirred at 0° C. for 2 h, warmed to room temperature over a 1 h period and poured into CH2Cl2. The resultant organic phase was washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of the concentrate on silica gel with a gradient of hexanes to 7.0% EtOAc-hexanes afforded 1-bromo-3-(3-fluoro-4-iodo-butyl)-benzene as an oil, 0.40 gm (50% yield); 1H NMR (400 MHz, CDCl3) δ: 2.03 (m, 2H), 2.74 (m, 2H), 3.29 (dd, 2H, J=5.4, 19.1 Hz), 4.47 (m, 1H), 7.12 (m, 2H), 7.32 (m, 2H). warmed to room temperature over a 1 h period The resultant organic phase was washed sequentially with water and brine dried over Na2SO4 concentrated under reduced pressure Chromatography of the concentrate on silica gel with a gradient of hexanes to 7.0% EtOAc-hexanes

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

Procedure: To a solution of (E)-[2-(3-{4-[1-(4-bromo-phenylcarbamoyl)-3-(tert-butyl-dimethyl-silanyloxy)-propyl]-phenyl}-acryloylamino)-phenyl]-carbamic acid tert-butyl ester (1.6 g, 2.26 mmol) in THF (40 mL) was added tetrabutylammonium dihydrogen trifluoride (1.36 g, 4.52 mmol). This mixture was stirred at room temperature overnight and then evaporated to remove THF. The mixture was dissolved in water and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography (CH2Cl2:EtOAc=10:1) to get yellow solid product. MS: calc'd 594 (MH+), exp 594 (MH+). evaporated to remove THF The mixture was dissolved in water extracted with ethyl acetate (3×30 mL) The combined organic layer was washed with brine dried with Na2SO4 filtered evaporated The crude product was purified by column chromatography (CH2Cl2:EtOAc=10:1) to get yellow solid product

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 0.245 gm (1.16 mmol) of 1-bromo-3-but-3-enylbenzene in CH2Cl2 at 0° C. was treated with 0.39 gm (1.74 mmol) of N-iodosuccinimide and 1.05 gm (1.74 mmol) of 50% wt/wt tetrabutylammoniumdihydrogen trifluoride in CH2Cl2, stirred at 0° C. for 2 h, warmed to room temperature over a 1 h period and poured into CH2Cl2. The resultant organic phase was washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of the concentrate on silica gel with a gradient of hexanes to 7.0% EtOAc-hexanes afforded 1-bromo-3-(3-fluoro-4-iodo-butyl)-benzene as an oil, 0.40 gm (50% yield); 1H NMR (400 MHz, CDCl3) δ: 2.03 (m, 2H), 2.74 (m, 2H), 3.29 (dd, 2H, J=5.4, 19.1 Hz), 4.47 (m, 1H), 7.12 (m, 2H), 7.32 (m, 2H). warmed to room temperature over a 1 h period The resultant organic phase was washed sequentially with water and brine dried over Na2SO4 concentrated under reduced pressure Chromatography of the concentrate on silica gel with a gradient of hexanes to 7.0% EtOAc-hexanes