3-methyl-1-phenylbutan-1-one

Conditions: temp:150.01; pressure:0.00; stir:

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

Procedure: The title compound was prepared as described in General Method 1 using 12 g methyl acetoacetate, 4.3 g of NaH 60% dispersion in oil, 64.5 mL of 1.6M n-butyl lithium in hexane, 10 g of iso-valerophenone, and 300 mL of tetrahydrofuran. After addition of the phenone, the reaction was stirred 15 minutes at -78° C. and 2 hours at room temperature. The crude reaction was flash chromatographed using hexane/ethyl acetate 6/40-40/60 as eluent. The solid was triturated from diethyl ether (m.p. 123.5°-125° C.). 1H NMR (CDCl3) δ 0.81 (d, 3 H), 0.89 (d, 3 H), 1.6-1.7 (M, 1 H), 1.91 (m, 2 H), 2.90 (d, 1 H), 2.95 (d, 1 H), 3.25 (d, 1 H), 3.35 (d, 1 H), 7.25-7.45 (m, 5 H). The crude reaction chromatographed The solid was triturated from diethyl ether (m.p. 123.5°-125° C.)

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

Procedure: Also prepared by the general method described in Example 6 utilizing phenyl cyclobutyl ketone, phenyl isopropyl ketone, phenyl methyl ketone and phenyl isobutyl ketone with the appropriate secondary amine were 1-cyclobutyl-1-hydroxy-1-phenyl-7-dimethylaminohept-5-yn-2-one, 1-cyclobutyl-1-hydroxy-1-phenyl-7-(N-ethyl-N-methylamino)hept-5-yn-2-one, 3-hydroxy-2-methyl-3-phenyl-9-dimethylaminonon-7-yn-4-one, 1-(1-methylcyclopropyl)-1-hydroxy-1-phenyl-7-dimethylaminohept-5-yn-2-one, and 4-hydroxy-2-methyl-4-phenyl-10-dimethylaminodec-8-yn-5-one. Also prepared by the general method

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

Procedure: Also prepared by the general method described in Example 6 utilizing phenyl cyclobutyl ketone, phenyl isopropyl ketone, phenyl methyl ketone and phenyl isobutyl ketone with the appropriate secondary amine were 1-cyclobutyl-1-hydroxy-1-phenyl-7-dimethylaminohept-5-yn-2-one, 1-cyclobutyl-1-hydroxy-1-phenyl-7-(N-ethyl-N-methylamino)hept-5-yn-2-one, 3-hydroxy-2-methyl-3-phenyl-9-dimethylaminonon-7-yn-4-one, 1-(1-methylcyclopropyl)-1-hydroxy-1-phenyl-7-dimethylaminohept-5-yn-2-one, and 4-hydroxy-2-methyl-4-phenyl-10-dimethylaminodec-8-yn-5-one. Also prepared by the general method

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

Procedure: A mixture of the above ketone (20.6 g, 127 mmol), hydroxylammonium chloride (17.7 g, 254 mmol) and absolute ethanol (200 ml) was heated at reflux for 1 h and then stirred at ambient temperature for 16 h. The solvent was evaporated in vacuo. The residue was suspended in water (200 ml) and the resulting mixture was extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water (50 ml) and brine (10 ml) and dried (MgSO4). The solvent was evaporated in vacuo to give 20.6 g of 3-methylbutyrophenone oxime. was heated at reflux for 1 h The solvent was evaporated in vacuo the resulting mixture was extracted with dichloromethane (2×100 ml) The combined organic phases were washed with water (50 ml) and brine (10 ml) dried (MgSO4) The solvent was evaporated in vacuo

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

Procedure: A mixture of the above ketone (20.6 g, 127 mmol), hydroxylammonium chloride (17.7 g, 254 mmol) and absolute ethanol (200 ml) was heated at reflux for 1 h and then stirred at ambient temperature for 16 h. The solvent was evaporated in vacuo. The residue was suspended in water (200 ml) and the resulting mixture was extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water (50 ml) and brine (10 ml) and dried (MgSO4). The solvent was evaporated in vacuo to give 20.6 g of 3-methylbutyrophenone oxime. was heated at reflux for 1 h The solvent was evaporated in vacuo the resulting mixture was extracted with dichloromethane (2×100 ml) The combined organic phases were washed with water (50 ml) and brine (10 ml) dried (MgSO4) The solvent was evaporated in vacuo

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

Procedure: A mixture of 3-methylbutanoic acid (20.4 g, 0.2 mol), thionyl chloride (35.7 g, 0.3 mol) and DMF (0.5 ml) was heated at reflux for 2 h. The mixture was carefully concentrated in vacuo to give the crude acid chloride. A suspension of anhydrous aluminium chloride (15.4 g, 115 mmol) in dichloromethane (100 ml) was cooled to 0° C. and a solution of the above acid chloride in dichloromethane (50 ml) was added dropwise. The mixture was stirred for 15 min and a solution of benzene (17.9 g, 0.23 mol) in dichloromethane (50 ml) was added dropwise and the resulting mixture stirred at room temperature for 16 h. The reaction mixture was poured into cold 0.05N hydrochloric acid (300 ml) and the resulting mixture extracted with dichloromethane (3×100 ml). The combined organic phases were washed with 1 hydrochloric acid (300 ml), water (300 ml) and saturated sodium hydrogen-carbonate solution (300 ml) and dried (MgSO4). The solvent was evaporated in vacuo to give 21.6 g of 3-methylbutyrophenone. was heated at reflux for 2 h The mixture was carefully concentrated in vacuo to give the crude acid chloride the resulting mixture stirred at room temperature for 16 h the resulting mixture extracted with dichloromethane (3×100 ml) The combined organic phases were washed with 1 hydrochloric acid (300 ml), water (300 ml) and saturated sodium hydrogen-carbonate solution (300 ml) dried (MgSO4) The solvent was evaporated in vacuo

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

Procedure: The procedure described for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-amine was used to convert isovalerophenone (0.484 g, 2.98 mmol) to the title compound. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 9.5-11.7 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-isopropyl-4-phenyl-1,3-thiazol-2-amine as a pink powder (0.060 g, 0.099 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 9.82 min;

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

Procedure: The title compound was prepared as described in General Method 1 using 12 g methyl acetoacetate, 4.3 g of NaH 60% dispersion in oil, 64.5 mL of 1.6M n-butyl lithium in hexane, 10 g of iso-valerophenone, and 300 mL of tetrahydrofuran. After addition of the phenone, the reaction was stirred 15 minutes at -78° C. and 2 hours at room temperature. The crude reaction was flash chromatographed using hexane/ethyl acetate 6/40-40/60 as eluent. The solid was triturated from diethyl ether (m.p. 123.5°-125° C.). 'H NMR (CDCl3) δ0.81 (d, 3H), 0.89 (d, 3H), 1.6-1.7 (M, 1H), 1.91 (m, 2H), 2.90 (d, 1H), 2.95 (d, 1H), 3.25 (d, 1H), 3.35 (d, 1H), 7.25-7.45 (m, 5H). The crude reaction chromatographed The solid was triturated from diethyl ether (m.p. 123.5°-125° C.)

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

Procedure: The title compound was prepared as described in General Method 1 using 12 g methyl acetoacetate, 4.3 g of NaH 60% dispersion in oil, 64.5 mL of 1.6M n-butyl lithium in hexane, 10 g of iso-valerophenone, and 300 mL of tetrahydrofuran. After addition of the phenone, the reaction was stirred 15 minutes at -78° C. and 2 hours at room temperature. The crude reaction was flash chromatographed using hexane/ethyl acetate 6/40-40/60 as eluent. The solid was triturated from diethyl ether (m.p. 123.5°-125° C.). 1H NMR (CDCl3) δ 0.81 (d, 3 H), 0.89 (d, 3 H), 1.6-1.7 (M, 1 H), 1.91 (m, 2 H), 2.90 (d, 1 H), 2.95 (d, 1 H), 3.25 (d, 1 H), 3.35 (d, 1 H), 7.25-7.45 (m, 5 H). The crude reaction chromatographed The solid was triturated from diethyl ether (m.p. 123.5°-125° C.)

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

Procedure: The title compound was prepared as described in General Method 1 using 12 g methyl acetoacetate, 4.3 g of NaH 60% dispersion in oil, 64.5 mL of 1.6M n-butyl lithium in hexane, 10 g of iso-valerophenone, and 300 mL of tetrahydrofuran. After addition of the phenone, the reaction was stirred 15 minutes at -78° C. and 2 hours at room temperature. The crude reaction was flash chromatographed using hexane/ethyl acetate 6/40-40/60 as eluent. The solid was triturated from diethyl ether (m.p. 123.5°-125° C.). 1H NMR (CDCl3) δ 0.81 (d, 3 H), 0.89 (d, 3 H), 1.6-1.7 (M, 1 H), 1.91 (m, 2 H), 2.90 (d, 1 H), 2.95 (d, 1 H), 3.25 (d, 1 H), 3.35 (d, 1 H), 7.25-7.45 (m, 5 H). The crude reaction chromatographed The solid was triturated from diethyl ether (m.p. 123.5°-125° C.)

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

Procedure: The title compound was prepared as described in General Method 1 using 12 g methyl acetoacetate, 4.3 g of NaH 60% dispersion in oil, 64.5 mL of 1.6M n-butyl lithium in hexane, 10 g of iso-valerophenone, and 300 mL of tetrahydrofuran.