674792-05-3

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

Procedure: 4-Fluoro-2-(methyloxy)-1-nitrobenzene (Example 22, step A) (0.429 g, 2.51 mmol), and K2CO3 (0.410 g, 2.97 mmol) were placed in a flask with 14 mL of DMSO and stirred with a stir bar. 1,1-Dimethylethyl (2S)-2-(1-methylethyl)-1-piperazinecarboxylate (0.521 g, 2.28 mmol) was dissolved in 6.6 mL of THF and added via syringe. The mixture was stirred for 8 days and poured into H2O and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography afforded the title compound of step D (0.515 g, 1.36 mmol, 60%). 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=9.3 Hz, 1H), 6.54 (dd, J=9.4, 2.3 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 4.01 (d, J=13.5 Hz, 1H), 3.86 (s, 5H), 3.60-3.75 (m, 1H), 3.22-3.28 (m, 1H), 3.06 (dd, J=13.6, 3.7 Hz, 1H), 2.90-3.02 (m, 1H), 1.79-1.92 (m, 1H), 1.37 (s, 9H), 0.92 (d, J=6.6 Hz, 3H), 0.75 (d, J=6.8 Hz, 3H). added via syringe The mixture was stirred for 8 days The layers were separated the organic layer was washed with brine The combined aqueous layers were extracted with EtOAc The combined organic layers were dried over MgSO4 filtered concentrated in vacuo Purification by flash chromatography

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

Procedure: To a solution of 1-tert-butyloxycarbonyl-(S)-2-isopropylpiperazine (384 mg, 1.7 mmol) in DME (10 mL) was added NaH (70 mg of 60% suspension in mineral oil, 1.6 mmol) and the mixture was stirred for 1 h at room temperature. Methyl 2-chlorobenzoxazole-4-carboxylate (368 mg, 1.6 mmol) was added to the reaction mixture and suspension formed was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography (silica gel, 0 to 80% EtOAc in CH2Cl2) to afford methyl 2-(4-(tert-butoxycarbonyl)-(S)-3-isopropylpiperazin-1-yl)benzoxazole-4-carboxylate (255 mg, 39%) as a white foam. 1H NMR and MS consistent. formed was stirred at room temperature for 17 h The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added solvent removed under reduced pressure The mixture was purified by column chromatography (silica gel, 0 to 80% EtOAc in CH2Cl2)

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

Procedure: To a solution of 1-tert-butyloxycarbonyl-(S)-2-isopropylpiperazine (384 mg, 1.7 mmol) in DME (10 mL) was added NaH (70 mg of 60% suspension in mineral oil, 1.6 mmol) and the mixture was stirred for 1 h at room temperature. Methyl 2-chlorobenzoxazole-4-carboxylate (368 mg, 1.6 mmol) was added to the reaction mixture and suspension formed was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography (silica gel, 0 to 80% EtOAc in CH2Cl2) to afford methyl 2-(4-(tert-butoxycarbonyl)-(S)-3-isopropylpiperazin-1-yl)benzoxazole-4-carboxylate (255 mg, 39%) as a white foam. 1H NMR and MS consistent. formed was stirred at room temperature for 17 h The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added solvent removed under reduced pressure The mixture was purified by column chromatography (silica gel, 0 to 80% EtOAc in CH2Cl2)

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

Procedure: A solution of tert-butyl (2S)-2-propan-2-ylpiperazine-1-carboxylate (2 g, 8.76 mmol) in a mixture of ethyl acetate (20 mL) and methanol (20.00 mL) was stirred at room temperature with 4M HCl in dioxane (30 mL) for 40 h under nitrogen. The reaction mixture was evaporated to dryness. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 3.5M NH3/MeOH and pure fractions were evaporated to dryness to afford (2S)-2-propan-2-ylpiperazine (1.052 g, 94%) as a white solid. The reaction mixture was evaporated to dryness The crude product was purified by ion exchange chromatography The desired product was eluted from the column were evaporated to dryness

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

Procedure: Prepared using the method used in the preparation of 2-[4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N,N-dimethyl-isobutyramide using (S)-2-isopropyl-piperazine-1-carboxylic acid tert-butyl ester in place of N,N-dimethyl-2-piperazin-1-yl-isobutyramide. The title compound was obtained as an off-white solid (182 mg, 80%). Prepared

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

Procedure: 4-Fluoro-2-(methyloxy)-1-nitrobenzene (Example 22, step A) (0.429 g, 2.51 mmol), and K2CO3 (0.410 g, 2.97 mmol) were placed in a flask with 14 mL of DMSO and stirred with a stir bar. 1,1-Dimethylethyl (2S)-2-(1-methylethyl)-1-piperazinecarboxylate (0.521 g, 2.28 mmol) was dissolved in 6.6 mL of THF and added via syringe. The mixture was stirred for 8 days and poured into H2O and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography afforded the title compound of step D (0.515 g, 1.36 mmol, 60%). 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=9.3 Hz, 1H), 6.54 (dd, J=9.4, 2.3 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 4.01 (d, J=13.5 Hz, 1H), 3.86 (s, 5H), 3.60-3.75 (m, 1H), 3.22-3.28 (m, 1H), 3.06 (dd, J=13.6, 3.7 Hz, 1H), 2.90-3.02 (m, 1H), 1.79-1.92 (m, 1H), 1.37 (s, 9H), 0.92 (d, J=6.6 Hz, 3H), 0.75 (d, J=6.8 Hz, 3H). added via syringe The mixture was stirred for 8 days The layers were separated the organic layer was washed with brine The combined aqueous layers were extracted with EtOAc The combined organic layers were dried over MgSO4 filtered concentrated in vacuo Purification by flash chromatography

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

Procedure: 4-Fluoro-2-(methyloxy)-1-nitrobenzene (Example 22, step A) (0.429 g, 2.51 mmol), and K2CO3 (0.410 g, 2.97 mmol) were placed in a flask with 14 mL of DMSO and stirred with a stir bar. 1,1-Dimethylethyl (2S)-2-(1-methylethyl)-1-piperazinecarboxylate (0.521 g, 2.28 mmol) was dissolved in 6.6 mL of THF and added via syringe. The mixture was stirred for 8 days and poured into H2O and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography afforded the title compound of step D (0.515 g, 1.36 mmol, 60%). 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=9.3 Hz, 1H), 6.54 (dd, J=9.4, 2.3 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 4.01 (d, J=13.5 Hz, 1H), 3.86 (s, 5H), 3.60-3.75 (m, 1H), 3.22-3.28 (m, 1H), 3.06 (dd, J=13.6, 3.7 Hz, 1H), 2.90-3.02 (m, 1H), 1.79-1.92 (m, 1H), 1.37 (s, 9H), 0.92 (d, J=6.6 Hz, 3H), 0.75 (d, J=6.8 Hz, 3H). added via syringe The mixture was stirred for 8 days The layers were separated the organic layer was washed with brine The combined aqueous layers were extracted with EtOAc The combined organic layers were dried over MgSO4 filtered concentrated in vacuo Purification by flash chromatography

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

Procedure: To a solution of 1-tert-butyloxycarbonyl-(S)-2-isopropylpiperazine (384 mg, 1.7 mmol) in DME (10 mL) was added NaH (70 mg of 60% suspension in mineral oil, 1.6 mmol) and the mixture was stirred for 1 h at room temperature. Methyl 2-chlorobenzoxazole-4-carboxylate (368 mg, 1.6 mmol) was added to the reaction mixture and suspension formed was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography (silica gel, 0 to 80% EtOAc in CH2Cl2) to afford methyl 2-(4-(tert-butoxycarbonyl)-(S)-3-isopropylpiperazin-1-yl)benzoxazole-4-carboxylate (255 mg, 39%) as a white foam. 1H NMR and MS consistent. formed was stirred at room temperature for 17 h The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added solvent removed under reduced pressure The mixture was purified by column chromatography (silica gel, 0 to 80% EtOAc in CH2Cl2)

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

Procedure: A solution of tert-butyl (2S)-2-propan-2-ylpiperazine-1-carboxylate (2 g, 8.76 mmol) in a mixture of ethyl acetate (20 mL) and methanol (20.00 mL) was stirred at room temperature with 4M HCl in dioxane (30 mL) for 40 h under nitrogen. The reaction mixture was evaporated to dryness. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 3.5M NH3/MeOH and pure fractions were evaporated to dryness to afford (2S)-2-propan-2-ylpiperazine (1.052 g, 94%) as a white solid. The reaction mixture was evaporated to dryness The crude product was purified by ion exchange chromatography The desired product was eluted from the column were evaporated to dryness

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

Procedure: A solution of tert-butyl (2S)-2-propan-2-ylpiperazine-1-carboxylate (2 g, 8.76 mmol) in a mixture of ethyl acetate (20 mL) and methanol (20.00 mL) was stirred at room temperature with 4M HCl in dioxane (30 mL) for 40 h under nitrogen. The reaction mixture was evaporated to dryness. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 3.5M NH3/MeOH and pure fractions were evaporated to dryness to afford (2S)-2-propan-2-ylpiperazine (1.052 g, 94%) as a white solid. The reaction mixture was evaporated to dryness The crude product was purified by ion exchange chromatography The desired product was eluted from the column were evaporated to dryness

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

Procedure: Prepared using the method used in the preparation of 2-[4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N,N-dimethyl-isobutyramide using (S)-2-isopropyl-piperazine-1-carboxylic acid tert-butyl ester in place of N,N-dimethyl-2-piperazin-1-yl-isobutyramide. The title compound was obtained as an off-white solid (182 mg, 80%). Prepared

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

Procedure: Prepared using the method used in the preparation of 2-[4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N,N-dimethyl-isobutyramide using (S)-2-isopropyl-piperazine-1-carboxylic acid tert-butyl ester in place of N,N-dimethyl-2-piperazin-1-yl-isobutyramide. The title compound was obtained as an off-white solid (182 mg, 80%). Prepared