[(E)-3-bromoprop-1-enyl]benzene

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

Procedure: To a stirring solution of 250 mg (0.58 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl acetamide in 3 mL of DMF at 0° C. is added 127 mg (0.70 mmol, 1.2 equiv) of sodium hydride (60% dispersion in mineral oil). The resulting solution is stirred 10 min, then 95 mL (0.64 mmol, 1.1 equiv) of trans-cinnamyl bromide is added. The reaction mixture is stirred 10 min at 0° C. then 2 h at RT and quenched with 1 mL H2O. The reaction mixture is diluted with 40 mL EtOAc and washed with 40 mL H2O. The organic layer is dried (MgSO4) and the solvents removed in vacuo. Purification of the resulting oil by silica gel flash column chromatography using hexane/EtOAc 4/1 as eluent followed by lyophilization of the product afforded 262 mg of the 2-[2,4-Dioxo-5-phenyl-3-(3-phenyl-allyl)-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.46-7.07 (m, 18H), 6.92 (dd, 1H, J=1.2, 8.1), 6.46 (d, H, J=15.9), 6.25 (m, 1H), 5.04 (m, 1H), 4.31 (d, 1H, J=16.6), 4.13 (d, 1H, J=16.6), 3.46 (dd, 1H, J=6.1, 7.8), 2.93 (m, 2H), 1.10 (2×d, 6H, J=6.9); low resolution MS (FAB) m/e 544 (MH+), 409, 223. The reaction mixture is stirred 10 min at 0° C. 2 h at RT and quenched with 1 mL H2O The reaction mixture is diluted with 40 mL EtOAc washed with 40 mL H2O The organic layer is dried (MgSO4) the solvents removed in vacuo Purification of the resulting oil by silica gel flash column chromatography

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and 1-((E)-3-bromoprop-1-enyl)benzene were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 378.2, found 378.2. cooled to RT The precipitate was collected by filtration

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and 1-((E)-3-bromoprop-1-enyl)benzene were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 378.2, found 378.2. cooled to RT The precipitate was collected by filtration

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

Procedure: To a solution of [(E)-3-bromo-1-propenyl]benzene (705 mg, 3.58 mmol) in dichloromethane (1 ml) was added rhodium (II) acetate dimer (20 mg, 0.05 mmol). To the mixture was added dropwise at room temperature over 4 h a solution of ethyl diazoacetate (0.43 ml, 0.47 g, 4.15 mmol) in dichloromethane (2.5 ml). The mixture was stirred at room temperature for 60 h. The mixture was purified by silica column (40 g) chromatography eluting with 1:1 hexane:dichloromethane then dichloromethane. Product-containing fractions were purified further by silica column (10 g) chromatography eluting with 9:1 hexane:dichloromethane then dichloromethane. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (75 mg, 8%). The mixture was purified by silica column (40 g) chromatography eluting with 1:1 hexane Product-containing fractions were purified further by silica column (10 g) chromatography eluting with 9:1 hexane concentrated in vacuo

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

Procedure: To a solution of [(E)-3-bromo-1-propenyl]benzene (705 mg, 3.58 mmol) in dichloromethane (1 ml) was added rhodium (II) acetate dimer (20 mg, 0.05 mmol). To the mixture was added dropwise at room temperature over 4 h a solution of ethyl diazoacetate (0.43 ml, 0.47 g, 4.15 mmol) in dichloromethane (2.5 ml). The mixture was stirred at room temperature for 60 h. The mixture was purified by silica column (40 g) chromatography eluting with 1:1 hexane:dichloromethane then dichloromethane. Product-containing fractions were purified further by silica column (10 g) chromatography eluting with 9:1 hexane:dichloromethane then dichloromethane. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (75 mg, 8%). The mixture was purified by silica column (40 g) chromatography eluting with 1:1 hexane Product-containing fractions were purified further by silica column (10 g) chromatography eluting with 9:1 hexane concentrated in vacuo

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6--yl)phenyl]methanesulfonamide (Preparation 53, 200 mg, 0.89 mmol) in N,N-dimethylfornamide (8 ml) was added sodium hydrogen carbonate (3 g, 36 mmol) and 1-[(E)-3-bromo-1-propenyl]benzene (0.13 ml, 0.89 mmol) and the reaction mixture was heated at 50° C. for 20 h. After cooling, diethyl ether (15 ml) and water (15 ml) were added and the reaction mixture was stirred vigorously for 5 min. The phases were separated and the aqueous layer was further extracted with diethyl ether (2×15 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual oil was purified by flash column chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford the title compound as an oil (40 mg, 12%). After cooling The phases were separated the aqueous layer was further extracted with diethyl ether (2×15 ml) The combined organic extracts were dried (Na2SO4) filtered concentrated in vacuo The residual oil was purified by flash column chromatography eluting with dichloromethane

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6--yl)phenyl]methanesulfonamide (Preparation 53, 200 mg, 0.89 mmol) in N,N-dimethylfornamide (8 ml) was added sodium hydrogen carbonate (3 g, 36 mmol) and 1-[(E)-3-bromo-1-propenyl]benzene (0.13 ml, 0.89 mmol) and the reaction mixture was heated at 50° C. for 20 h. After cooling, diethyl ether (15 ml) and water (15 ml) were added and the reaction mixture was stirred vigorously for 5 min. The phases were separated and the aqueous layer was further extracted with diethyl ether (2×15 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual oil was purified by flash column chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford the title compound as an oil (40 mg, 12%). After cooling The phases were separated the aqueous layer was further extracted with diethyl ether (2×15 ml) The combined organic extracts were dried (Na2SO4) filtered concentrated in vacuo The residual oil was purified by flash column chromatography eluting with dichloromethane

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

Procedure: To a stirring solution of 250 mg (0.58 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl acetamide in 3 mL of DMF at 0° C. is added 127 mg (0.70 mmol, 1.2 equiv) of sodium hydride (60% dispersion in mineral oil). The resulting solution is stirred 10 min, then 95 mL (0.64 mmol, 1.1 equiv) of trans-cinnamyl bromide is added. The reaction mixture is stirred 10 min at 0° C. then 2 h at RT and quenched with 1 mL H2O. The reaction mixture is diluted with 40 mL EtOAc and washed with 40 mL H2O. The organic layer is dried (MgSO4) and the solvents removed in vacuo. Purification of the resulting oil by silica gel flash column chromatography using hexane/EtOAc 4/1 as eluent followed by lyophilization of the product afforded 262 mg of the 2-[2,4-Dioxo-5-phenyl-3-(3-phenyl-allyl)-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.46-7.07 (m, 18H), 6.92 (dd, 1H, J=1.2, 8.1), 6.46 (d, H, J=15.9), 6.25 (m, 1H), 5.04 (m, 1H), 4.31 (d, 1H, J=16.6), 4.13 (d, 1H, J=16.6), 3.46 (dd, 1H, J=6.1, 7.8), 2.93 (m, 2H), 1.10 (2×d, 6H, J=6.9); low resolution MS (FAB) m/e 544 (MH+), 409, 223. The reaction mixture is stirred 10 min at 0° C. 2 h at RT and quenched with 1 mL H2O The reaction mixture is diluted with 40 mL EtOAc washed with 40 mL H2O The organic layer is dried (MgSO4) the solvents removed in vacuo Purification of the resulting oil by silica gel flash column chromatography

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

Procedure: To a stirring solution of 250 mg (0.58 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl acetamide in 3 mL of DMF at 0° C. is added 127 mg (0.70 mmol, 1.2 equiv) of sodium hydride (60% dispersion in mineral oil). The resulting solution is stirred 10 min, then 95 mL (0.64 mmol, 1.1 equiv) of trans-cinnamyl bromide is added. The reaction mixture is stirred 10 min at 0° C. then 2 h at RT and quenched with 1 mL H2O. The reaction mixture is diluted with 40 mL EtOAc and washed with 40 mL H2O. The organic layer is dried (MgSO4) and the solvents removed in vacuo. Purification of the resulting oil by silica gel flash column chromatography using hexane/EtOAc 4/1 as eluent followed by lyophilization of the product afforded 262 mg of the 2-[2,4-Dioxo-5-phenyl-3-(3-phenyl-allyl)-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.46-7.07 (m, 18H), 6.92 (dd, 1H, J=1.2, 8.1), 6.46 (d, H, J=15.9), 6.25 (m, 1H), 5.04 (m, 1H), 4.31 (d, 1H, J=16.6), 4.13 (d, 1H, J=16.6), 3.46 (dd, 1H, J=6.1, 7.8), 2.93 (m, 2H), 1.10 (2×d, 6H, J=6.9); low resolution MS (FAB) m/e 544 (MH+), 409, 223. The reaction mixture is stirred 10 min at 0° C. 2 h at RT and quenched with 1 mL H2O The reaction mixture is diluted with 40 mL EtOAc washed with 40 mL H2O The organic layer is dried (MgSO4) the solvents removed in vacuo Purification of the resulting oil by silica gel flash column chromatography

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and 1-((E)-3-bromoprop-1-enyl)benzene were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 378.2, found 378.2. cooled to RT The precipitate was collected by filtration

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

Procedure: 2-Fluoroimidazole hydrochloride was added to a suspension of powdered KOH in acetone, stirred for 10 minutes, and E-cinnamyl bromide added. After stirring 1 hour, the mixture was worked up by extraction and chromatography to give E-1-cinnamyl-2-fluoro-imidazole, having the following n.m.r. in CDCl3 : 4.6 (d, 2H); 6.1-6.4 (d of t, 1H); 6.6 (d, 1H); 6.6-6.8 (m, 2H); 7.2-7.5 (m, 5H). After stirring 1 hour the mixture was worked up by extraction and chromatography

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

Procedure: 2-Fluoroimidazole hydrochloride was added to a suspension of powdered KOH in acetone, stirred for 10 minutes, and E-cinnamyl bromide added. After stirring 1 hour, the mixture was worked up by extraction and chromatography to give E-1-cinnamyl-2-fluoro-imidazole, having the following n.m.r. in CDCl3 : 4.6 (d, 2H); 6.1-6.4 (d of t, 1H); 6.6 (d, 1H); 6.6-6.8 (m, 2H); 7.2-7.5 (m, 5H). After stirring 1 hour the mixture was worked up by extraction and chromatography