1-bromopropan-2-ylbenzene

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Bromo-1-hydroxyisoquinoline (150 mg, 0.67 mmol, 1.0 equiv), tetrabutylammonium bromide (25 mg, 0.07 mmol, 0.1 equiv), and 1-bromo-2-phenylpropane (160 uL, 0.8 mmol, 1.2 equiv) were combined in toluene (10 mL) and treated with 50% aq. NaOH (2 mL), and the resulting mixture was stirred rapidly and heated at 70° C. After heating for an additional 14 hours, the mixture was diluted with diethyl ether and washed with water and brine. The organic phase was dried over Na2SO4 and concentrated. Purification of the residue using flash silica gel chromatography (gradient of 2-15% ethyl acetate/hexanes) gave 6-bromo-2-(1-phenyl-2-propyl)-isoquinolin-1-one (74 mg, 0.22 mmol, 32%) as a colorless oil. This isoquinolinone (74 mg, 0.22 mmol) was converted, via Methods 1 and 2, to a 1:1 mixture of compound 6 and 6-hydroxy-2-(1-phenyl-2-propyl)-isoquinolin-1-one that was isolated as 44 mg of a white solid (33% of 6). [M−H]−=306.1 m/z. Activity: B After heating for an additional 14 hours washed with water and brine The organic phase was dried over Na2SO4 concentrated Purification of the residue

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Bromo-1-hydroxyisoquinoline (150 mg, 0.67 mmol, 1.0 equiv), tetrabutylammonium bromide (25 mg, 0.07 mmol, 0.1 equiv), and 1-bromo-2-phenylpropane (160 uL, 0.8 mmol, 1.2 equiv) were combined in toluene (10 mL) and treated with 50% aq. NaOH (2 mL), and the resulting mixture was stirred rapidly and heated at 70° C. After heating for an additional 14 hours, the mixture was diluted with diethyl ether and washed with water and brine. The organic phase was dried over Na2SO4 and concentrated. Purification of the residue using flash silica gel chromatography (gradient of 2-15% ethyl acetate/hexanes) gave 6-bromo-2-(1-phenyl-2-propyl)-isoquinolin-1-one (74 mg, 0.22 mmol, 32%) as a colorless oil. This isoquinolinone (74 mg, 0.22 mmol) was converted, via Methods 1 and 2, to a 1:1 mixture of compound 6 and 6-hydroxy-2-(1-phenyl-2-propyl)-isoquinolin-1-one that was isolated as 44 mg of a white solid (33% of 6). [M−H]−=306.1 m/z. Activity: B After heating for an additional 14 hours washed with water and brine The organic phase was dried over Na2SO4 concentrated Purification of the residue

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

Procedure: 6-Bromo-1-hydroxyisoquinoline (150 mg, 0.67 mmol, 1.0 equiv), tetrabutylammonium bromide (25 mg, 0.07 mmol, 0.1 equiv), and 1-bromo-2-phenylpropane (160 uL, 0.8 mmol, 1.2 equiv) were combined in toluene (10 mL) and treated with 50% aq. NaOH (2 mL), and the resulting mixture was stirred rapidly at ambient temperature for 48 hours, then heated at 60° C. for 24 h. The mixture was diluted with diethyl ether and washed with water and brine. The organic phase was dried over Na2SO4. Concentration and purification of the residue using silica gel flash chromatography (2-12% EtOAc/hex.) gave white crystals of 6-bromo-2-(2-phenylpropyl)-isoquinolin-1-one (169 mg, 0.49 mmol, 74%). This isoquinolinone (169 mg, 0.49 mmol) was converted, via Methods 1 and 2, to compound 5 (65 mg, 43%) which was isolated as white solid. [M−H]−=306.1 m/z. Activity: B heated at 60° C. for 24 h washed with water and brine The organic phase was dried over Na2SO4 Concentration and purification of the residue

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

Procedure: A solution of piperazine (344 g), β-bromoisopropylbenzene (199 g) in water (1 liter) and ethanol (0.35 liter) is refluxed for 24 hours. After cooling, the resulting amine is extracted with 3×0.5 liter methylene chloride. After washing with water and evaporation of the solvent in vacuo, the resulting 2-phenylpropyl piperazine is distilled; b.p.=163°-165° C./15 mm Hg. After cooling the resulting amine is extracted with 3×0.5 liter methylene chloride After washing with water and evaporation of the solvent in vacuo the resulting 2-phenylpropyl piperazine is distilled

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

Procedure: A solution of piperazine (344 g), β-bromoisopropylbenzene (199 g) in water (1 liter) and ethanol (0.35 liter) is refluxed for 24 hours. After cooling, the resulting amine is extracted with 3×0.5 liter methylene chloride. After washing with water and evaporation of the solvent in vacuo, the resulting 2-phenylpropyl piperazine is distilled; b.p.=163°-165° C./15 mm Hg. After cooling the resulting amine is extracted with 3×0.5 liter methylene chloride After washing with water and evaporation of the solvent in vacuo the resulting 2-phenylpropyl piperazine is distilled

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Bromo-1-hydroxyisoquinoline (150 mg, 0.67 mmol, 1.0 equiv), tetrabutylammonium bromide (25 mg, 0.07 mmol, 0.1 equiv), and 1-bromo-2-phenylpropane (160 uL, 0.8 mmol, 1.2 equiv) were combined in toluene (10 mL) and treated with 50% aq. NaOH (2 mL), and the resulting mixture was stirred rapidly and heated at 70° C. After heating for an additional 14 hours, the mixture was diluted with diethyl ether and washed with water and brine. The organic phase was dried over Na2SO4 and concentrated. Purification of the residue using flash silica gel chromatography (gradient of 2-15% ethyl acetate/hexanes) gave 6-bromo-2-(1-phenyl-2-propyl)-isoquinolin-1-one (74 mg, 0.22 mmol, 32%) as a colorless oil. This isoquinolinone (74 mg, 0.22 mmol) was converted, via Methods 1 and 2, to a 1:1 mixture of compound 6 and 6-hydroxy-2-(1-phenyl-2-propyl)-isoquinolin-1-one that was isolated as 44 mg of a white solid (33% of 6). [M-H]-=306.1 m/z. Activity: B After heating for an additional 14 hours washed with water and brine The organic phase was dried over Na2SO4 concentrated Purification of the residue

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

Procedure: 6-Bromo-1-hydroxyisoquinoline (150 mg, 0.67 mmol, 1.0 equiv), tetrabutylammonium bromide (25 mg, 0.07 mmol, 0.1 equiv), and 1-bromo-2-phenylpropane (160 uL, 0.8 mmol, 1.2 equiv) were combined in toluene (10 mL) and treated with 50% aq. NaOH (2 mL), and the resulting mixture was stirred rapidly at ambient temperature for 48 hours, then heated at 60° C. for 24 h. The mixture was diluted with diethyl ether and washed with water and brine. The organic phase was dried over Na2SO4. Concentration and purification of the residue using silica gel flash chromatography (2-12% EtOAc/hex.) gave white crystals of 6-bromo-2-(2-phenylpropyl)-isoquinolin-1-one (169 mg, 0.49 mmol, 74%). This isoquinolinone (169 mg, 0.49 mmol) was converted, via Methods 1 and 2, to compound 5 (65 mg, 43%) which was isolated as white solid. [M-H]-=306.1 m/z. Activity: B heated at 60° C. for 24 h washed with water and brine The organic phase was dried over Na2SO4 Concentration and purification of the residue

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

Procedure: 6-Bromo-1-hydroxyisoquinoline (150 mg, 0.67 mmol, 1.0 equiv), tetrabutylammonium bromide (25 mg, 0.07 mmol, 0.1 equiv), and 1-bromo-2-phenylpropane (160 uL, 0.8 mmol, 1.2 equiv) were combined in toluene (10 mL) and treated with 50% aq. NaOH (2 mL), and the resulting mixture was stirred rapidly at ambient temperature for 48 hours, then heated at 60° C. for 24 h. The mixture was diluted with diethyl ether and washed with water and brine. The organic phase was dried over Na2SO4. Concentration and purification of the residue using silica gel flash chromatography (2-12% EtOAc/hex.) gave white crystals of 6-bromo-2-(2-phenylpropyl)-isoquinolin-1-one (169 mg, 0.49 mmol, 74%). This isoquinolinone (169 mg, 0.49 mmol) was converted, via Methods 1 and 2, to compound 5 (65 mg, 43%) which was isolated as white solid. [M-H]-=306.1 m/z. Activity: B heated at 60° C. for 24 h washed with water and brine The organic phase was dried over Na2SO4 Concentration and purification of the residue

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

Procedure: The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and (2-bromo-1-methyl-ethyl)benzene as described in Example 49 and isolated by chiral separation (80/20 heptane/ethanol) (0.0033 mg, 15% yield). 1HNMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.18-7.34 (m, 4H), 7.13 (d, J=8 Hz, 2H), 7.04 (d, J=2 Hz, 1H), 6.67 (d, J=2 Hz, 1H), 6.12-6.20 (m, 1H), 4.63 (d, J=4 Hz, 2H), 4.18-4.38 (m, 2H), 3.37-3.46 (m, 1H), 2.75 (s, 3H), 1.30 (d, J=8 Hz, 3H); MS (M+H)+=418.4; Rt=1.31 min; HRMS (M+H)+=418.17.

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

Procedure: The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and (2-bromo-1-methyl-ethyl)benzene as described in Example 49 and isolated as a white solid (0.120 mg, 45% yield). 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.55 (d, J=4 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.18-7.33 (m, 4H), 7.12 (d, J=8 Hz, 2H), 7.03 (d, J=2 Hz, 1H), 6.67 (d, J=2 Hz, 1H), 6.16-6.24 (m, 1H), 4.63 (d, J=4 Hz, 2H), 4.18-4.31 (m, 2H), 3.34-3.44 (m, 1H), 2.74 (s, 3H), 1.29 (d, J=4 Hz, 3H); MS (M+H)+=418.2; Rt=1.31 min; HRMS (M+H)+=418.17.

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

Procedure: A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, (2-bromo-1-methylethyl)benzene (1.1 g) was added, and the mixture was stirred at 150° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in dimethyl sulfoxide (5 mL), and added to a mixture of hydroxylammonium chloride (0.28 g), sodium hydrogen carbonate (0.40 g) and dimethyl sulfoxide (20 mL) previously stirred at 40° C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr, and diluted with ethyl acetate. The mixture was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.078 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.066 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.12 g, 9%). the mixture was stirred at 150° C. for 16 hr washed with 5% aqueous potassium hydrogen sulfate solution with saturated brine, and dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The residue obtained by silica gel column chromatography previously stirred at 40° C. for 30 min The reaction mixture was stirred at 90° C. for 16 hr The mixture was washed with water with saturated brine, and dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The residue was dissolved in tetrahydrofuran (20 mL) N,N′-carbonyldiimidazole (0.078 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.066 mL) were added the mixture was stirred at room temperature for 2 hr The reaction mixture was diluted with ethyl acetate washed with saturated aqueous potassium hydrogen sulfate solution with saturated brine, and dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography

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

Procedure: A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, (2-bromo-1-methylethyl)benzene (1.1 g) was added, and the mixture was stirred at 150° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in dimethyl sulfoxide (5 mL), and added to a mixture of hydroxylammonium chloride (0.28 g), sodium hydrogen carbonate (0.40 g) and dimethyl sulfoxide (20 mL) previously stirred at 40° C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr, and diluted with ethyl acetate. The mixture was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.078 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.066 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.12 g, 9%). the mixture was stirred at 150° C. for 16 hr washed with 5% aqueous potassium hydrogen sulfate solution with saturated brine, and dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The residue obtained by silica gel column chromatography previously stirred at 40° C. for 30 min The reaction mixture was stirred at 90° C. for 16 hr The mixture was washed with water with saturated brine, and dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The residue was dissolved in tetrahydrofuran (20 mL) N,N′-carbonyldiimidazole (0.078 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.066 mL) were added the mixture was stirred at room temperature for 2 hr The reaction mixture was diluted with ethyl acetate washed with saturated aqueous potassium hydrogen sulfate solution with saturated brine, and dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography