(1S)-2-amino-1-(3-chlorophenyl)ethanol;hydrochloride

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

Procedure: To a solution of 2-(4-chloro-2,6-dimethoxy-pyrimidin-5-yl)-4-methyl-6-morpholin-4-yl-1H-benzoimidazole (0.075 g, 0.192 mmol) in acetonitrile (5 mL) was added triethylamine (134 μl, 0.962 mmol) and (S)-2-Amino-1-(3-chloro-phenyl)-ethanol hydrochloride (42 mg, 0.202 mmol). The crude material was purified on silicagel dry colomn using AcOEt: Hex (8:2) to give the title compound as a beige solid. (0.055 g, 55%). HPLC 98%. LCMS 20 (+ESI, M+H+) m/z 525. IR (KBr, cm−1) 3446, 2955, 1595, 1472, 1367. 1H NMR (400 MHz, DMSO) δ 11.63 (s, 1H), 11.1 (m, 1H), 7.54 (s, 1H), 7.41-7.28 (m, 3H), 6.87 (d, J=2.0 Hz, 1H), 6.78 (s, 1H) 5.85 (s. 1H), 4.88 (m, 1H), 4.05 (s, 3H), 3.91-3.84 (m, 4H), 3.79-3.77 (m, 4H), 3.73-3.69 (m, 1H), 3.09-3.07 (m, 4H), 2.50 (3H, s). HRMS calcd for C26H29ClN6O4:525.2017; found 525.2008. The crude material was purified on silicagel dry colomn

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

Procedure: To a solution of 2-(4-chloro-2,6-dimethoxy-pyrimidin-5-yl)-4-methyl-6-morpholin-4-yl-1H-benzoimidazole (0.075 g, 0.192 mmol) in acetonitrile (5 mL) was added triethylamine (134 μl, 0.962 mmol) and (S)-2-Amino-1-(3-chloro-phenyl)-ethanol hydrochloride (42 mg, 0.202 mmol). The crude material was purified on silicagel dry colomn using AcOEt: Hex (8:2) to give the title compound as a beige solid. (0.055 g, 55%). HPLC 98%. LCMS 20 (+ESI, M+H+) m/z 525. IR (KBr, cm−1) 3446, 2955, 1595, 1472, 1367. 1H NMR (400 MHz, DMSO) δ 11.63 (s, 1H), 11.1 (m, 1H), 7.54 (s, 1H), 7.41-7.28 (m, 3H), 6.87 (d, J=2.0 Hz, 1H), 6.78 (s, 1H) 5.85 (s. 1H), 4.88 (m, 1H), 4.05 (s, 3H), 3.91-3.84 (m, 4H), 3.79-3.77 (m, 4H), 3.73-3.69 (m, 1H), 3.09-3.07 (m, 4H), 2.50 (3H, s). HRMS calcd for C26H29ClN6O4:525.2017; found 525.2008. The crude material was purified on silicagel dry colomn

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-[8-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-methyl-9H-purin-2-yl]-piperazine-1-carboxylic acid t-butyl ester (200 mg, 0.448 mmol) in acetonitrile (10 mL) was added triethylamine (125 μl, 0.896 mmol) and (S)-2-amino-1-(3-chlorophenyl)-ethanol hydrochloride (99 mg, 0.493 mmol). The reaction mixture was stirred at 80° C. for 18 hours in a sealed tube and concentrated. The residue was dissolved in CH2Cl2 (50 mL) washed with H2O (2×30 mL), dried over MgSO4 and concentrated. The crude material was purified by crystallization in hot MeOH (35 mL) to give the title compound as a beige solid. (0.197 g, 76%). HPLC 98%; LCMS (+ESI, M+H+) m/z 581; IR (KBr, cm−1) 3419, 3271, 2975, 1696, 1496, 1232; 1H NMR (400 MHz, DMSO+D2O) δ 10.79 (br s, 1H), 7.59–7.32 (m, 5H), 6.22 (d, J=7.6 Hz, 1H), 5.00 (br t, 1H), 3.73 (br s, 4H, 3.60 (m, 1H), 3.44 (br s, 4H), 2.58 (s, 3H); HRMS calcd for C28H33ClN8O4: 581.2391; found 581.2389. concentrated The residue was dissolved in CH2Cl2 (50 mL) washed with H2O (2×30 mL) dried over MgSO4 concentrated The crude material was purified by crystallization in hot MeOH (35 mL)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-[8-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-methyl-9H-purin-2-yl]-piperazine-1-carboxylic acid t-butyl ester (200 mg, 0.448 mmol) in acetonitrile (10 mL) was added triethylamine (125 μl, 0.896 mmol) and (S)-2-amino-1-(3-chlorophenyl)-ethanol hydrochloride (99 mg, 0.493 mmol). The reaction mixture was stirred at 80° C. for 18 hours in a sealed tube and concentrated. The residue was dissolved in CH2Cl2 (50 mL) washed with H2O (2×30 mL), dried over MgSO4 and concentrated. The crude material was purified by crystallization in hot MeOH (35 mL) to give the title compound as a beige solid. (0.197 g, 76%). HPLC 98%; LCMS (+ESI, M+H+) m/z 581; IR (KBr, cm−1) 3419, 3271, 2975, 1696, 1496, 1232; 1H NMR (400 MHz, DMSO+D2O) δ 10.79 (br s, 1H), 7.59–7.32 (m, 5H), 6.22 (d, J=7.6 Hz, 1H), 5.00 (br t, 1H), 3.73 (br s, 4H, 3.60 (m, 1H), 3.44 (br s, 4H), 2.58 (s, 3H); HRMS calcd for C28H33ClN8O4: 581.2391; found 581.2389. concentrated The residue was dissolved in CH2Cl2 (50 mL) washed with H2O (2×30 mL) dried over MgSO4 concentrated The crude material was purified by crystallization in hot MeOH (35 mL)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of crude 4-chloro-3-(1,7-dihydro-1,2,5,7-tetraaza-s-indacen-6-yl)-1H-pyridin-2-one hydrochloric acid salt (80 mg, 0.25 mmol), (S)-2-amino-1-(3-chloro-phenyl)-ethanol hydrochloric acid salt (80 mg, 0.38 mmol), N-methyl morpholine (0.5 ml, excess), and acetonitrile (15 mL) was heated to 80° C. overnight and cooled to room temperature. After concentration in vacuo, the residue was purified by prep. HPLC to yield the titled compound (64 mg, 61%). 1H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.27–7.41 (m, 4H), 6.21 (d, J=7.6 Hz, 1H), 4.99 (m, 1H), 3.60–3.71 (m, 2H). LCMS (t=1.44 min), [M+H]+421. cooled to room temperature After concentration in vacuo the residue was purified by prep

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of crude 4-chloro-3-(1,7-dihydro-1,2,5,7-tetraaza-s-indacen-6-yl)-1H-pyridin-2-one hydrochloric acid salt (80 mg, 0.25 mmol), (S)-2-amino-1-(3-chloro-phenyl)-ethanol hydrochloric acid salt (80 mg, 0.38 mmol), N-methyl morpholine (0.5 ml, excess), and acetonitrile (15 mL) was heated to 80° C. overnight and cooled to room temperature. After concentration in vacuo, the residue was purified by prep. HPLC to yield the titled compound (64 mg, 61%). 1H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.27–7.41 (m, 4H), 6.21 (d, J=7.6 Hz, 1H), 4.99 (m, 1H), 3.60–3.71 (m, 2H). LCMS (t=1.44 min), [M+H]+421. cooled to room temperature After concentration in vacuo the residue was purified by prep

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-[8-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-methyl-9H-purin-2-yl]-piperazine-1-carboxylic acid t-butyl ester (200 mg, 0.448 mmol) in acetonitrile (10 mL) was added triethylamine (125 μl, 0.896 mmol) and (S)-2-amino-1-(3-chloro-phenyl)-ethanol hydrochloride (99 mg, 0.493 mmol). The reaction mixture was stirred at 80° C. for 18 hours in a sealed tube and concentrated. The residue was dissolved in CH2Cl2 (50 mL) washed with H2O (2×30 mL), dried over MgSO4 and concentrated. The crude material was purified by crystallization in hot MeOH (35 mL) to give the title compound as a beige solid. (0.197 g, 76%). HPLC 98%; LCMS (+ESI, M+H+) m/z 581; IR (KBr, cm−1) 3419, 3271, 2975, 1696, 1496, 1232; 1H NMR (400 MHz, DMSO+D2O) δ 10.79 (br s, 1H), 7.59-7.32 (m, 5H), 6.22 (d, J=7.6 Hz, 1H), 5.00 (br t, 1H), 3.73 (br s, 4H), 3.60 (m, 1H), 3.44 (br s, 4H), 2.58 (s, 3H); HRMS calcd for C28H33ClN8O4: 581.2391; found 581.2389. concentrated The residue was dissolved in CH2Cl2 (50 mL) washed with H2O (2×30 mL) dried over MgSO4 concentrated The crude material was purified by crystallization in hot MeOH (35 mL)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of crude 4-chloro-3-(1,7-dihydro-1,2,5,7-tetraaza-s-indacen-6-yl)-1H-pyridin-2-one hydrochloric acid salt (80 mg, 0.25 mmol), (S)-2-amino-1-(3-chloro-phenyl)-ethanol hydrochloric acid salt (80 mg, 0.38 mmol), N-methyl morpholine (0.5 ml, excess), and acetonitrile (15 mL) was heated to 80° C. overnight and cooled to room temperature. After concentration in vacuo, the residue was purified by prep. HPLC to yield the titled compound (64 mg, 61%). 1H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.27-7.41 (m, 4H), 6.21 (d, J=7.6 Hz, 1H), 4.99 (m, 1H), 3.60-3.71 (m, 2H). LCMS (t=1.44 min), [M+H]+ 421. cooled to room temperature After concentration in vacuo the residue was purified by prep

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of crude 4-chloro-3-(1,7-dihydro-1,2,5,7-tetraaza-s-indacen-6-yl)-1H-pyridin-2-one hydrochloric acid salt (80 mg, 0.25 mmol), (S)-2-amino-1-(3-chloro-phenyl)-ethanol hydrochloric acid salt (80 mg, 0.38 mmol), N-methyl morpholine (0.5 ml, excess), and acetonitrile (15 mL) was heated to 80° C. overnight and cooled to room temperature. After concentration in vacuo, the residue was purified by prep. HPLC to yield the titled compound (64 mg, 61%). 1H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.27-7.41 (m, 4H), 6.21 (d, J=7.6 Hz, 1H), 4.99 (m, 1H), 3.60-3.71 (m, 2H). LCMS (t=1.44 min), [M+H]+ 421. cooled to room temperature After concentration in vacuo the residue was purified by prep

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

Procedure: To a solution of 2-(4-chloro-2,6-dimethoxy-pyrimidin-5-yl)-4-methyl-6-morpholin-4-yl-1H-benzoimidazole (0.075 g, 0.192 mmol) in acetonitrile (5 mL) was added triethylamine (134 μl, 0.962 mmol) and (S)-2-Amino-1-(3-chloro-phenyl)-ethanol hydrochloride (42 mg, 0.202 mmol). The crude material was purified on silicagel dry colomn using AcOEt: Hex (8:2) to give the title compound as a beige solid. (0.055 g, 55%). HPLC 98%. LCMS 20 (+ESI, M+H+) m/z 525. IR (KBr, cm−1) 3446, 2955, 1595, 1472, 1367. 1H NMR (400 MHz, DMSO) δ 11.63 (s, 1H), 11.1 (m, 1H), 7.54 (s, 1H), 7.41-7.28 (m, 3H), 6.87 (d, J=2.0 Hz, 1H), 6.78 (s, 1H) 5.85 (s. 1H), 4.88 (m, 1H), 4.05 (s, 3H), 3.91-3.84 (m, 4H), 3.79-3.77 (m, 4H), 3.73-3.69 (m, 1H), 3.09-3.07 (m, 4H), 2.50 (3H, s). HRMS calcd for C26H29ClN6O4:525.2017; found 525.2008. The crude material was purified on silicagel dry colomn

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-[8-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-methyl-9H-purin-2-yl]-piperazine-1-carboxylic acid t-butyl ester (200 mg, 0.448 mmol) in acetonitrile (10 mL) was added triethylamine (125 μl, 0.896 mmol) and (S)-2-amino-1-(3-chlorophenyl)-ethanol hydrochloride (99 mg, 0.493 mmol). The reaction mixture was stirred at 80° C. for 18 hours in a sealed tube and concentrated. The residue was dissolved in CH2Cl2 (50 mL) washed with H2O (2×30 mL), dried over MgSO4 and concentrated. The crude material was purified by crystallization in hot MeOH (35 mL) to give the title compound as a beige solid. (0.197 g, 76%). HPLC 98%; LCMS (+ESI, M+H+) m/z 581; IR (KBr, cm−1) 3419, 3271, 2975, 1696, 1496, 1232; 1H NMR (400 MHz, DMSO+D2O) δ 10.79 (br s, 1H), 7.59–7.32 (m, 5H), 6.22 (d, J=7.6 Hz, 1H), 5.00 (br t, 1H), 3.73 (br s, 4H, 3.60 (m, 1H), 3.44 (br s, 4H), 2.58 (s, 3H); HRMS calcd for C28H33ClN8O4: 581.2391; found 581.2389. concentrated The residue was dissolved in CH2Cl2 (50 mL) washed with H2O (2×30 mL) dried over MgSO4 concentrated The crude material was purified by crystallization in hot MeOH (35 mL)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of crude 4-chloro-3-(1,7-dihydro-1,2,5,7-tetraaza-s-indacen-6-yl)-1H-pyridin-2-one hydrochloric acid salt (80 mg, 0.25 mmol), (S)-2-amino-1-(3-chloro-phenyl)-ethanol hydrochloric acid salt (80 mg, 0.38 mmol), N-methyl morpholine (0.5 ml, excess), and acetonitrile (15 mL) was heated to 80° C. overnight and cooled to room temperature. After concentration in vacuo, the residue was purified by prep. HPLC to yield the titled compound (64 mg, 61%). 1H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.27–7.41 (m, 4H), 6.21 (d, J=7.6 Hz, 1H), 4.99 (m, 1H), 3.60–3.71 (m, 2H). LCMS (t=1.44 min), [M+H]+421. cooled to room temperature After concentration in vacuo the residue was purified by prep