1-phenylbutan-1-one

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

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

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

Procedure: The title compound was prepared as described in the General Method 1 using 5 mmol of methyl acetoacetate, 5.5 mmol of NaH 60% dispersion in oil, 5.5 mmol of 1.6M n-butyl lithium in hexane, 5.5 mmol of butyrophenone and 14 mL of tetrahydrofuran. After addition of the ketone, the reaction was stirred for 90 minutes at 0° C. The reaction was poured into saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated, and the residue flash chromatographed using hexane/ethyl acetate 80/20 as eluent. The aldol product was stirred at room temperature in 100 mL of 0.1N NaOH for 3.5 hours. The reaction was worked up as in General Method 1 and the product triturated from diethyl ether to afford a solid (m.p. 131.5°-132° C.). 1H NMR (CDCl3) δ 0.88 (t, 3 H), 1.1-1.4 (m, 2 H), 1.95 (m, 2 H), 2.90 (d, 1 H), 2.92 (d, 1 H), 3.25 (d, 1 H), 3.35 (d, 1 H), 7.2-7.4 (m, 5 H). extracted with ethyl acetate The organic layer was dried over MgSO4 concentrated the residue flash chromatographed The aldol product was stirred at room temperature in 100 mL of 0.1N NaOH for 3.5 hours the product triturated from diethyl ether

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

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

Procedure: About 50 grams of resin beads of polystyrene that has been copolymerized with about 1% divinylbenzene are stirred at room temperature for about 2 hours in butyryl chloride with aluminum chloride as a catalyst, namely Friedel-Crafts conditions. Reaction occurs with the benzene moieties on the resin to form butyrophenone or propylphenylketone. These resulting ketone moieties are then subjected to the Leukardt-Wallach reduction amination reaction using N-propyl formamide to produce N-propyl α-aminobenzyl moieties. The step-by-step synthesis of the nonapeptide as set forth in Example I is repeated. Cleavage, deprotection and purification are carried out under the same conditions and are found to produce the nonapeptide amide having the following formula: Reaction

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

Procedure: About 50 grams of resin beads of polystyrene that has been copolymerized with about 1% divinylbenzene are stirred at room temperature for about 2 hours in butyryl chloride with aluminum chloride as a catalyst, namely Friedel-Crafts conditions. Reaction occurs with the benzene moieties on the resin to form butyrophenone or propylphenylketone. These resulting ketone moieties are then subjected to the Leukardt-Wallach reduction amination reaction using N-propyl formamide to produce N-propyl α-aminobenzyl moieties. The step-by-step synthesis of the nonapeptide as set forth in Example I is repeated. Cleavage, deprotection and purification are carried out under the same conditions and are found to produce the nonapeptide amide having the following formula: Reaction

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

Procedure: To a 0° C. solution of EtMgBr in Et2O (3.0M, 570 mL, Aldrich) was slowly added m-tolunitrile (102 mL, Aldrich). After stirring at r.t. for 19 hr., benzene (300 mL) was added and the resulting mixture was cooled to 0° C. HCl (6N, 600 mL) was then slowly added. The organic phase was separated, washed with 5% NaHCO3 and brine, dried (MgSO4) and evaporated to afford the desired ketone as a yellow liquid. To a 0° C. the resulting mixture was cooled to 0° C The organic phase was separated washed with 5% NaHCO3 and brine dried (MgSO4) evaporated

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

Procedure: The procedure for the preparation of 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 butyrophenone (436 μL, 3.00 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 8.9-11.1 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-ethyl-4-phenyl-1,3-thiazol-2-amine as a white powder (0.022 g, 0.037 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 9.27 min;

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

Procedure: To a solution of 1-phenylbutan-1-one (203 mg, 1.37 mmol) in THF (2.5 mL) at −78° C. is added dropwise LiHMDS (1.62 mL of 1.0 M solution in THF, 1.62 mmol) over a period of 15 min. The solution is stirred at −78° C. for 1 h then a solution of 2-benzyloxy-4-bromomethyl-1-nitrobenzene (Example 83, step C) (400 mg, 1.25 mmol) in THF (2.5 mL) is added dropwise. The mixture is allowed to warm to RT and stirred there for 1 h then is quenched with saturated ammonium chloride solution. The mixture is extracted with EtOAc and the organic phase is washed with brine then dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 5-100% EtOAc/hexane as eluent to give the title compound. to warm to RT stirred there for 1 h then is quenched with saturated ammonium chloride solution The mixture is extracted with EtOAc the organic phase is washed with brine then dried over magnesium sulfate The solvent is removed under reduced pressure the residue is purified by flash chromatography

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

Procedure: To a solution of 1-phenylbutan-1-one (203 mg, 1.37 mmol) in THF (2.5 mL) at −78° C. is added dropwise LiHMDS (1.62 mL of 1.0 M solution in THF, 1.62 mmol) over a period of 15 min. The solution is stirred at −78° C. for 1 h then a solution of 2-benzyloxy-4-bromomethyl-1-nitrobenzene (Example 83, step C) (400 mg, 1.25 mmol) in THF (2.5 mL) is added dropwise. The mixture is allowed to warm to RT and stirred there for 1 h then is quenched with saturated ammonium chloride solution. The mixture is extracted with EtOAc and the organic phase is washed with brine then dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 5-100% EtOAc/hexane as eluent to give the title compound. to warm to RT stirred there for 1 h then is quenched with saturated ammonium chloride solution The mixture is extracted with EtOAc the organic phase is washed with brine then dried over magnesium sulfate The solvent is removed under reduced pressure the residue is purified by flash chromatography

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using the method described in Example 30 by employing (1-phenylbut-1-enyl)pyrrolidine (freshly prepared before use from butyrophenone (Aldrich Chemical Company), pyrrolidine and TiCl4 (1.63 g, 8.11 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.60 g, 8.11 mmol), N,N-diisopropylethylamine (1.4 mL, 8.11 mmol), piperidine (1.3 mL, 13.0 mmol), NEt3 (1.3 mL) and SnCl2 (24 mL of a 2 M soln in DMF). In this example the SnCl2 solution was added to the reaction mixture at 140° C. The mixture was stirred at 140° C. for an additional 16 h then the heating was discontinued and the mixture was allowed to cool to room temperature. The residue was purified by flash chromatography on silica gel with 100% EtOAc as eluant to give 0.42 g (16%) of 7-ethyl-2-methyl-6-phenyl-4-piperidylpyrrolo[3,2-d]pyrimidine as a beige colored solid. This compound (411 mg, 1.31 mmol) was dissolved in 5:1 EtOAc/MeOH (40 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.30 mL, 1.30 mmol). The solution was allowed to cool to room temperature. The resulting crystals were collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 34 mg (1%) of the title compound as a white colored solid. Mp: 261-263° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.05 (t, 3, J=7.5), 1.63 (br s, 6), 2.56 (s, 3), 2.69 (q, 2, J=7.2), 3.95 (br s, 4), 7.46-8.02 (m, 5), 11.90 (s, 1), 13.86 (s, 1). MS m/z: 321 (M+1 for free base). Anal. Calcd for C20H24N4.HCl.0.7H2O: C, 65.01; H, 7.20; N, 15.17; Cl, 9.59. Found: C, 65.09; H, 6.90; N, 14.98; Cl, 9.85. was added to the reaction mixture at 140° C to cool to room temperature The residue was purified by flash chromatography on silica gel with 100% EtOAc as eluant

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using the method described in Example 30 by employing (1-phenylbut-1-enyl)pyrrolidine (freshly prepared before use from butyrophenone (Aldrich Chemical Company), pyrrolidine and TiCl4 (1.63 g, 8.11 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.60 g, 8.11 mmol), N,N-diisopropylethylamine (1.4 mL, 8.11 mmol), piperidine (1.3 mL, 13.0 mmol), NEt3 (1.3 mL) and SnCl2 (24 mL of a 2 M soln in DMF). In this example the SnCl2 solution was added to the reaction mixture at 140° C. The mixture was stirred at 140° C. for an additional 16 h then the heating was discontinued and the mixture was allowed to cool to room temperature. The residue was purified by flash chromatography on silica gel with 100% EtOAc as eluant to give 0.42 g (16%) of 7-ethyl-2-methyl-6-phenyl-4-piperidylpyrrolo[3,2-d]pyrimidine as a beige colored solid. This compound (411 mg, 1.31 mmol) was dissolved in 5:1 EtOAc/MeOH (40 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.30 mL, 1.30 mmol). The solution was allowed to cool to room temperature. The resulting crystals were collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 34 mg (1%) of the title compound as a white colored solid. Mp: 261-263° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.05 (t, 3, J=7.5), 1.63 (br s, 6), 2.56 (s, 3), 2.69 (q, 2, J=7.2), 3.95 (br s, 4), 7.46-8.02 (m, 5), 11.90 (s, 1), 13.86 (s, 1). MS m/z: 321 (M+1 for free base). Anal. Calcd for C20H24N4.HCl.0.7H2O: C, 65.01; H, 7.20; N, 15.17; Cl, 9.59. Found: C, 65.09; H, 6.90; N, 14.98; Cl, 9.85. was added to the reaction mixture at 140° C to cool to room temperature The residue was purified by flash chromatography on silica gel with 100% EtOAc as eluant