(3S)-1-benzyl-3-propan-2-ylpiperazine

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

Procedure: LAH (1.87 g, 49.3 mmol) was suspended in 60 mL of THF with stirring and cooled to 0° C. under an inert atmosphere. (5S)-5-(1-methylethyl)-1-(phenylmethyl)-2,3-piperazinedione (2.43 g, 9.87 mmol) was dissolved in 50 mL of THF and added dropwise via addition funnel over 20 min. The funnel was rinsed with an additional 10 mL of THF. The reaction was warmed to rt and stirred for 2 days. The reaction was quenched by the careful sequential addition of 1.9 mL of H2O, 1.9 mL of 1N NaOH (aq.), and 5.7 mL of H2O. The slurry was stirred for 30 min and filtered. The solids were washed with DCM. The filtrate was concentrated in vacuo. Purification by flash chromatography afforded the title compound of step B (1.68 g, 7.69 mmol, 78%). 1H NMR (400 MHz, DMSO-d6) δ 7.33-7.18 (m, 5H), 3.40 (AB, ΔνAB=34.5 Hz, JAB=13.2 Hz, 2H), 2.78 (m, 1H), 2.71-2.51 (m, 3H), 2.28 (m, 1H), 1.88-1.72 (m, 2H), 1.63 (t, J=10.3 Hz, 1H), 1.45 (m, 1H), 0.83 (d, J=6.8 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H). added dropwise via addition funnel over 20 min The funnel was rinsed with an additional 10 mL of THF The reaction was warmed to rt stirred for 2 days The reaction was quenched by the careful sequential addition of 1.9 mL of H2O, 1.9 mL of 1N NaOH (aq.), and 5.7 mL of H2O The slurry was stirred for 30 min filtered The solids were washed with DCM The filtrate was 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 (2S)-4-benzyl-2-isopropylpiperazine (363 mg, 1.66 mmol) in 1,2-dimethoxyethane (10 mL) at room temperature, was added NaH (80 mg, 1.66 mmol, 60% suspension in mineral oil) and the mixture was stirred for 1 h. Methyl 2-chlorobenzoxazole-4-carboxylate (351 mg, 1.66 mmol) was added to the reaction mixture and the reaction 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 100% EtOAc in hexanes) to afford (S)-methyl 2-(4-benzyl-2-isopropylpiperazin-1-yl)benzoxazole-4-carboxylate (355 mg, 54%) as a pale yellow oil. MS consistent. the reaction 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 100% EtOAc in hexanes)

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

Procedure: To a solution of (2S)-4-benzyl-2-isopropylpiperazine (363 mg, 1.66 mmol) in 1,2-dimethoxyethane (10 mL) at room temperature, was added NaH (80 mg, 1.66 mmol, 60% suspension in mineral oil) and the mixture was stirred for 1 h. Methyl 2-chlorobenzoxazole-4-carboxylate (351 mg, 1.66 mmol) was added to the reaction mixture and the reaction 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 100% EtOAc in hexanes) to afford (S)-methyl 2-(4-benzyl-2-isopropylpiperazin-1-yl)benzoxazole-4-carboxylate (355 mg, 54%) as a pale yellow oil. MS consistent. the reaction 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 100% EtOAc in hexanes)

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

Procedure: To 100 mL tetrahydrofuran cooled to 0° C. were added 9 mL (8.9 mMol) lithium aluminum hydride (1.0 M in tetrahydrofuran) dropwise. To this was added dropwise a solution of 1.0 gm (4.06 mmol) 1-benzyl-2,5-dioxo-3(S)-isopropylpiperazine in 50 mL dichloromethane over 30 minutes. The reaction mixture was then heated at reflux over night. The reaction mixture was then cooled to 0° C. and was stirred vigorously while being treated sequentially with 1 mL water, 1 mL 5N sodium hydroxide, 2 mL water, and 5 gm sodium sulfate. After stirring for 30 minutes the reaction mixture was filtered and the filter cake washed with dichloromethane. The filtrate was concentrated under reduced pressure and the yellow waxy solid residue was subjected to silica gel chromatography, eluting with dichloromethane containing 0–3% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.38 gm (42%) of the title compound. The reaction mixture was then heated at reflux over night After stirring for 30 minutes the reaction mixture was filtered the filter cake washed with dichloromethane The filtrate was concentrated under reduced pressure eluting with dichloromethane containing 0–3% methanol Fractions containing product concentrated under reduced pressure

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

Procedure: LAH (1.87 g, 49.3 mmol) was suspended in 60 mL of THF with stirring and cooled to 0° C. under an inert atmosphere. (5S)-5-(1-methylethyl)-1-(phenylmethyl)-2,3-piperazinedione (2.43 g, 9.87 mmol) was dissolved in 50 mL of THF and added dropwise via addition funnel over 20 min. The funnel was rinsed with an additional 10 mL of THF. The reaction was warmed to rt and stirred for 2 days. The reaction was quenched by the careful sequential addition of 1.9 mL of H2O, 1.9 mL of 1N NaOH (aq.), and 5.7 mL of H2O. The slurry was stirred for 30 min and filtered. The solids were washed with DCM. The filtrate was concentrated in vacuo. Purification by flash chromatography afforded the title compound of step B (1.68 g, 7.69 mmol, 78%). 1H NMR (400 MHz, DMSO-d6) δ 7.33-7.18 (m, 5H), 3.40 (AB, ΔνAB=34.5 Hz, JAB=13.2 Hz, 2H), 2.78 (m, 1H), 2.71-2.51 (m, 3H), 2.28 (m, 1H), 1.88-1.72 (m, 2H), 1.63 (t, J=10.3 Hz, 1H), 1.45 (m, 1H), 0.83 (d, J=6.8 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H). added dropwise via addition funnel over 20 min The funnel was rinsed with an additional 10 mL of THF The reaction was warmed to rt stirred for 2 days The reaction was quenched by the careful sequential addition of 1.9 mL of H2O, 1.9 mL of 1N NaOH (aq.), and 5.7 mL of H2O The slurry was stirred for 30 min filtered The solids were washed with DCM The filtrate was concentrated in vacuo Purification by flash chromatography

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

Procedure: LAH (1.87 g, 49.3 mmol) was suspended in 60 mL of THF with stirring and cooled to 0° C. under an inert atmosphere. (5S)-5-(1-methylethyl)-1-(phenylmethyl)-2,3-piperazinedione (2.43 g, 9.87 mmol) was dissolved in 50 mL of THF and added dropwise via addition funnel over 20 min. The funnel was rinsed with an additional 10 mL of THF. The reaction was warmed to rt and stirred for 2 days. The reaction was quenched by the careful sequential addition of 1.9 mL of H2O, 1.9 mL of 1N NaOH (aq.), and 5.7 mL of H2O. The slurry was stirred for 30 min and filtered. The solids were washed with DCM. The filtrate was concentrated in vacuo. Purification by flash chromatography afforded the title compound of step B (1.68 g, 7.69 mmol, 78%). 1H NMR (400 MHz, DMSO-d6) δ 7.33-7.18 (m, 5H), 3.40 (AB, ΔνAB=34.5 Hz, JAB=13.2 Hz, 2H), 2.78 (m, 1H), 2.71-2.51 (m, 3H), 2.28 (m, 1H), 1.88-1.72 (m, 2H), 1.63 (t, J=10.3 Hz, 1H), 1.45 (m, 1H), 0.83 (d, J=6.8 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H). added dropwise via addition funnel over 20 min The funnel was rinsed with an additional 10 mL of THF The reaction was warmed to rt stirred for 2 days The reaction was quenched by the careful sequential addition of 1.9 mL of H2O, 1.9 mL of 1N NaOH (aq.), and 5.7 mL of H2O The slurry was stirred for 30 min filtered The solids were washed with DCM The filtrate was 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 (2S)-4-benzyl-2-isopropylpiperazine (363 mg, 1.66 mmol) in 1,2-dimethoxyethane (10 mL) at room temperature, was added NaH (80 mg, 1.66 mmol, 60% suspension in mineral oil) and the mixture was stirred for 1 h. Methyl 2-chlorobenzoxazole-4-carboxylate (351 mg, 1.66 mmol) was added to the reaction mixture and the reaction 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 100% EtOAc in hexanes) to afford (S)-methyl 2-(4-benzyl-2-isopropylpiperazin-1-yl)benzoxazole-4-carboxylate (355 mg, 54%) as a pale yellow oil. MS consistent. the reaction 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 100% EtOAc in hexanes)

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

Procedure: (3S)-1-(Benzyl)-3-isopropylpiperazine (358 mg) was dissolved in acetic acid (10 mL), and to the solution 10% palladium on carbon (40 mg) was added, and the mixture was then stirred at 50° C. under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:ammonia-saturated methanol=20:1) to obtain the title compound. The reaction mixture was filtered the filtrate was concentrated under reduced pressure The residue was purified by column chromatography on silica gel (chloroform:ammonia-saturated methanol=20:1)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (200 mg, 0.74 mmol) in 10 mL DMF was added (S)-1-benzyl-3-isopropylpiperazine followed by the addition of triethylamine (206 μL). The reaction was heated at 85° C. for two hours. The reaction was quenched with water after cooling it to room temperature. The aqueous layer was extracted twice with CH2Cl2, and the combined extracts were dried over MgSO4, filtered, and concentrated. The reaction was purified via silica gel chromatography using 1:1 hexanes:CH2Cl2 solvent system to yield 2-(4-((S)-4-benzyl-2-isopropylpiperazin-1-yl)-7-methylquinazolin-2-yl)phenol (230 mg, 64%). LC/MS: m/z 453.5 (M+H)+ at 2.61 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). The reaction was quenched with water after cooling it to room temperature The aqueous layer was extracted twice with CH2Cl2 the combined extracts were dried over MgSO4 filtered concentrated The reaction was purified via silica gel chromatography

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (200 mg, 0.74 mmol) in 10 mL DMF was added (S)-1-benzyl-3-isopropylpiperazine followed by the addition of triethylamine (206 μL). The reaction was heated at 85° C. for two hours. The reaction was quenched with water after cooling it to room temperature. The aqueous layer was extracted twice with CH2Cl2, and the combined extracts were dried over MgSO4, filtered, and concentrated. The reaction was purified via silica gel chromatography using 1:1 hexanes:CH2Cl2 solvent system to yield 2-(4-((S)-4-benzyl-2-isopropylpiperazin-1-yl)-7-methylquinazolin-2-yl)phenol (230 mg, 64%). LC/MS: m/z 453.5 (M+H)+ at 2.61 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). The reaction was quenched with water after cooling it to room temperature The aqueous layer was extracted twice with CH2Cl2 the combined extracts were dried over MgSO4 filtered concentrated The reaction was purified via silica gel chromatography

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

Procedure: To 100 mL tetrahydrofuran cooled to 0° C. were added 9 mL (8.9 mMol) lithium aluminum hydride (1.0 M in tetrahydrofuran) dropwise. To this was added dropwise a solution of 1.0 gm (4.06 mmol) 1-benzyl-2,5-dioxo-3(S)-isopropylpiperazine in 50 mL dichloromethane over 30 minutes. The reaction mixture was then heated at reflux over night. The reaction mixture was then cooled to 0° C. and was stirred vigorously while being treated sequentially with 1 mL water, 1 mL 5N sodium hydroxide, 2 mL water, and 5 gm sodium sulfate. After stirring for 30 minutes the reaction mixture was filtered and the filter cake washed with dichloromethane. The filtrate was concentrated under reduced pressure and the yellow waxy solid residue was subjected to silica gel chromatography, eluting with dichloromethane containing 0–3% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.38 gm (42%) of the title compound. The reaction mixture was then heated at reflux over night After stirring for 30 minutes the reaction mixture was filtered the filter cake washed with dichloromethane The filtrate was concentrated under reduced pressure eluting with dichloromethane containing 0–3% methanol Fractions containing product concentrated under reduced pressure

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

Procedure: LAH (1.87 g, 49.3 mmol) was suspended in 60 mL of THF with stirring and cooled to 0° C. under an inert atmosphere. (5S)-5-(1-methylethyl)-1-(phenylmethyl)-2,3-piperazinedione (2.43 g, 9.87 mmol) was dissolved in 50 mL of THF and added dropwise via addition funnel over 20 min. The funnel was rinsed with an additional 10 mL of THF. The reaction was warmed to rt and stirred for 2 days. The reaction was quenched by the careful sequential addition of 1.9 mL of H2O, 1.9 mL of 1N NaOH (aq.), and 5.7 mL of H2O. The slurry was stirred for 30 min and filtered. The solids were washed with DCM. The filtrate was concentrated in vacuo. Purification by flash chromatography afforded the title compound of step B (1.68 g, 7.69 mmol, 78%). 1H NMR (400 MHz, DMSO-d6) δ 7.33-7.18 (m, 5H), 3.40 (AB, ΔνAB=34.5 Hz, JAB=13.2 Hz, 2H), 2.78 (m, 1H), 2.71-2.51 (m, 3H), 2.28 (m, 1H), 1.88-1.72 (m, 2H), 1.63 (t, J=10.3 Hz, 1H), 1.45 (m, 1H), 0.83 (d, J=6.8 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H). added dropwise via addition funnel over 20 min The funnel was rinsed with an additional 10 mL of THF The reaction was warmed to rt stirred for 2 days The reaction was quenched by the careful sequential addition of 1.9 mL of H2O, 1.9 mL of 1N NaOH (aq.), and 5.7 mL of H2O The slurry was stirred for 30 min filtered The solids were washed with DCM The filtrate was concentrated in vacuo Purification by flash chromatography