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

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-(2E and 2Z)-2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-(1-tert-butyloxycarbonyl-4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-but-2-enedioic acid diethyl ester: To a stirred solution of (2-E and 2Z)-2-methanesulfonyloxy-3-(1-tert-butyloxycarbonyl-4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-but-2-enedioic acid diethyl ester (0.012 g, 0.021 mmol) in acetonitrile (1 mL) was added (S)-2-amino-1-[3-chlorophenyl]ethanol (0.005 g, 0.031 mmol) and the mixture was stirred at 60° C. for 1 hour. The solvent was evaporated and the residue was purified by silica gel chromatography (50 to 75% ethyl acetate in hexane) to give the title material (0.010 g, 74%). HPLC: 97% (220 nm), LCMS (+ESI, M+H+) m/z 657; 1H NMR (400 MHz, acetone-d6) δ (ppm): 1.17-1.33 (15H, m), 2.51 (3H, br s), 3.14 (4H, m), 3.77 (6H, m), 4.24-4.34 (4H, m), 5.62 (1H, m), 6.80-7.52 (6H, m). The solvent was evaporated the residue was purified by silica gel chromatography (50 to 75% ethyl acetate in hexane)

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 3-[1,3]dioxolan-2-yl-4-iodo-2-methoxy-pyridine (3.07 g, 10.0 mmol), (S)-2-amino-1-(3-chloro-phenyl)-ethanol (1.71 g, 10 mmol), CuI (190 mg, 1.0 mmol), ethylene glycol (1.86 g, 30 mmol) and K3PO4 (6.3 g, 30 mmol) in 2-propanol (200 mL) was sealed and heated at 75° C. for 22 h (CuI and K3PO4 were crushed into powders before added). After cooled down to room temperature, the reaction mixture was loaded on silica gel. The chromatography with eluant CH2Cl2: MeOH=100:1 afforded the title product (1.27 g, 38%). 1H NMR (CDCl3) δ 3.30 (m, 1H) 3.45 (m, 1H), 3.87 (s, 3H), 3.96-4.05 (4H), 4.85 n (m, 1H), 6.09 (s, 1H), 6.15-6.30 (2H), 7.21-7.35 (2H), 7.41 (s, 1H), 7.82 (d, J=6 Hz, 1H). ESI-MS m/z 351.4 (MH+). was sealed After cooled down to room temperature

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 3-[1,3]dioxolan-2-yl-4-iodo-2-methoxy-pyridine (3.07 g, 10.0 mmol), (S)-2-amino-1-(3-chloro-phenyl)-ethanol (1.71 g, 10 mmol), CuI (190 mg, 1.0 mmol), ethylene glycol (1.86 g, 30 mmol) and K3PO4 (6.3 g, 30 mmol) in 2-propanol (200 mL) was sealed and heated at 75° C. for 22 h (CuI and K3PO4 were crushed into powders before added). After cooled down to room temperature, the reaction mixture was loaded on silica gel. The chromatography with eluant CH2Cl2: MeOH=100:1 afforded the title product (1.27 g, 38%). 1H NMR (CDCl3) δ 3.30 (m, 1H) 3.45 (m, 1H), 3.87 (s, 3H), 3.96-4.05 (4H), 4.85 n (m, 1H), 6.09 (s, 1H), 6.15-6.30 (2H), 7.21-7.35 (2H), 7.41 (s, 1H), 7.82 (d, J=6 Hz, 1H). ESI-MS m/z 351.4 (MH+). was sealed After cooled down to room temperature

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

Procedure: A mixture of (S)-2-Azido-1-(3-chlorophenyl)-ethanol (5.14 g, 0.026 mol), NaBH4 (1.97 g, 0.052 mol) and isopropyl alcohol (100 mL) was stirred at 80° C. for 24 h. The solvent was evaporated, the residue was separated on SiO2 (15 g) CHCl3-MeOH (0 to 30%). Colorless oil, 3.70 g (0.021 mol, 83%). The material was reacted with Boc2O in dichloromethane and NEt3 and analyzed by chiral SFC using a CHIRALPAK AD-H column, 30% MeOH and determined to be 91% ee. The solvent was evaporated the residue was separated on SiO2 (15 g) CHCl3-MeOH (0 to 30%) The material was reacted with Boc2O in dichloromethane and NEt3

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

Procedure: A mixture of (S)-2-Azido-1-(3-chlorophenyl)-ethanol (5.14 g, 0.026 mol), NaBH4 (1.97 g, 0.052 mol) and isopropyl alcohol (100 mL) was stirred at 80° C. for 24 h. The solvent was evaporated, the residue was separated on SiO2 (15 g) CHCl3-MeOH (0 to 30%). Colorless oil, 3.70 g (0.021 mol, 83%). The material was reacted with Boc2O in dichloromethane and NEt3 and analyzed by chiral SFC using a CHIRALPAK AD-H column, 30% MeOH and determined to be 91% ee. The solvent was evaporated the residue was separated on SiO2 (15 g) CHCl3-MeOH (0 to 30%) The material was reacted with Boc2O in dichloromethane and NEt3

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 3-[1,3]dioxolan-2-yl-4-iodo-2-methoxy-pyridine (3.07 g, 10.0 mmol), (S)-2-amino-1-(3-chloro-phenyl)-ethanol (1.71 g, 10 mmol), CuI (190 mg, 1.0 mmol), ethylene glycol (1.86 g, 30 mmol) and K3PO4 (6.3 g, 30 mmol) in 2-propanol (200 mL) was sealed and heated at 75° C. for 22 h (CuI and K3PO4 were crushed into powders before added). After cooled down to room temperature, the reaction mixture was loaded on silica gel. The chromatography with eluant CH2Cl2: MeOH=100:1 afforded the title product (1.27 g, 38%). 1H NMR (CDCl3) δ 3.30 (m, 1H) 3.45 (m, 1H), 3.87 (s, 3H), 3.96-4.05 (4H), 4.85 n (m, 1H), 6.09 (s, 1H), 6.15-6.30 (2H), 7.21-7.35 (2H), 7.41 (s, 1H), 7.82 (d, J=6 Hz, 1H). ESI-MS m/z 351.4 (MH+). was sealed After cooled down to room temperature

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

Procedure: A mixture of (S)-2-Azido-1-(3-chlorophenyl)-ethanol (5.14 g, 0.026 mol), NaBH4 (1.97 g, 0.052 mol) and isopropyl alcohol (100 mL) was stirred at 80° C. for 24 h. The solvent was evaporated, the residue was separated on SiO2 (15 g) CHCl3-MeOH (0 to 30%). Colorless oil, 3.70 g (0.021 mol, 83%). The material was reacted with Boc2O in dichloromethane and NEt3 and analyzed by chiral SFC using a CHIRALPAK AD-H column, 30% MeOH and determined to be 91% ee. The solvent was evaporated the residue was separated on SiO2 (15 g) CHCl3-MeOH (0 to 30%) The material was reacted with Boc2O in dichloromethane and NEt3

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 3-[1,3]dioxolan-2-yl-4-iodo-2-methoxy-pyridine (3.07 g, 10.0 mmol), (S)-2-amino-1-(3-chloro-phenyl)-ethanol (1.71 g, 10 mmol), CuI (190 mg, 1.0 mmol), ethylene glycol (1.86 g, 30 mmol) and K3PO4 (6.3 g, 30 mmol) in 2-propanol (200 mL) was sealed and heated at 75° C. for 22 h (CuI and K3PO4 were crushed into powders before added). After cooled down to room temperature, the reaction mixture was loaded on silica gel. The chromatography with eluant CH2Cl2: MeOH=100:1 afforded the title product (1.27 g, 38%). 1H NMR (CDCl3) δ 3.30 (m, 1H) 3.45 (m, 1H), 3.87 (s, 3H), 3.96-4.05 (4H), 4.85 n (m, 1H), 6.09 (s, 1H), 6.15-6.30 (2H), 7.21-7.35 (2H), 7.41 (s, 1H), 7.82 (d, J=6 Hz, 1H). ESI-MS m/z 351.4 (MH+). was sealed After cooled down to room temperature

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

Procedure: A mixture of (S)-2-Azido-1-(3-chlorophenyl)-ethanol (5.14 g, 0.026 mol), NaBH4 (1.97 g, 0.052 mol) and isopropanol (100 ml) was stirred at 80° C. for 24 h. The solvent was evaporated, the residue was separated on SiO2 (15 g) CHCl3-MeOH (0 to 30%). Colorless oil, 3.70 g (0.021 mol, 83%). The material was reacted with Boc2O in dichloromethane and NEt3 and analyzed by chiral SFC using a CHIRALPAK AD-H column, 30% MeOH and determined to be 91% ee. LCMS [M+H]+ 172.4. 1H NMR (300 MHz, DMSO) δ 7.24-7.39 (m, 4H), 4.46 (dd, J=4.3, 7.5 Hz, 1H), 2.68 (dd, J=4.3, 12.8 Hz, 1H), 2.57 (dd, J=7.5, 13.0 Hz, 1H). The solvent was evaporated the residue was separated on SiO2 (15 g) CHCl3-MeOH (0 to 30%) The material was reacted with Boc2O in dichloromethane and NEt3

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

Procedure: A mixture of (S)-2-Azido-1-(3-chlorophenyl)-ethanol (5.14 g, 0.026 mol), NaBH4 (1.97 g, 0.052 mol) and isopropanol (100 ml) was stirred at 80° C. for 24 h. The solvent was evaporated, the residue was separated on SiO2 (15 g) CHCl3-MeOH (0 to 30%). Colorless oil, 3.70 g (0.021 mol, 83%). The material was reacted with Boc2O in dichloromethane and NEt3 and analyzed by chiral SFC using a CHIRALPAK AD-H column, 30% MeOH and determined to be 91% ee. LCMS [M+H]+ 172.4. 1H NMR (300 MHz, DMSO) δ 7.24-7.39 (m, 4H), 4.46 (dd, J=4.3, 7.5 Hz, 1H), 2.68 (dd, J=4.3, 12.8 Hz, 1H), 2.57 (dd, J=7.5, 13.0 Hz, 1H). The solvent was evaporated the residue was separated on SiO2 (15 g) CHCl3-MeOH (0 to 30%) The material was reacted with Boc2O in dichloromethane and NEt3

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

Procedure: A solution of 4-Chloro-3-[6-(2,8-diaza-spiro[5.5]undec-2-yl)-4-methyl-1H-benzoimidazol-2-yl]-1H-pyridin-2-one (16 mg, 0.039 mmol), (S)-2-amino-1-(3-chlorophenyl)-ethanol (20 mg, 0.117 mmol) and Et3N (16 mg, 0.156 mmol) in EtOH (0.5 mL) was heated at 80° C. for 16 h. After it was cooled to room temperature, the reaction mixture was filtered to furnish yellow solid that was washed with MeOH (3×3 mL). The yellow solid then was mixed with 3 mL MeOH and the mixture was heated at 100° C. for 1 h. After it was cooled to room temperature, the mixture was filtered to furnish yellow solid that was washed with MeOH (3×2 mL) to afford the title compound (10 mg, 47%). ESI-MS m/z 547 (MH+). the reaction mixture was filtered to furnish yellow solid that was washed with MeOH (3×3 mL) The yellow solid then was mixed with 3 mL MeOH the mixture was heated at 100° C. for 1 h After it was cooled to room temperature the mixture was filtered to furnish yellow solid that was washed with MeOH (3×2 mL)

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

Procedure: A solution of 4-Chloro-3-[6-(2,8-diaza-spiro[5.5]undec-2-yl)-4-methyl-1H-benzoimidazol-2-yl]-1H-pyridin-2-one (16 mg, 0.039 mmol), (S)-2-amino-1-(3-chlorophenyl)-ethanol (20 mg, 0.117 mmol) and Et3N (16 mg, 0.156 mmol) in EtOH (0.5 mL) was heated at 80° C. for 16 h. After it was cooled to room temperature, the reaction mixture was filtered to furnish yellow solid that was washed with MeOH (3×3 mL). The yellow solid then was mixed with 3 mL MeOH and the mixture was heated at 100° C. for 1 h. After it was cooled to room temperature, the mixture was filtered to furnish yellow solid that was washed with MeOH (3×2 mL) to afford the title compound (10 mg, 47%). ESI-MS m/z 547 (MH+). the reaction mixture was filtered to furnish yellow solid that was washed with MeOH (3×3 mL) The yellow solid then was mixed with 3 mL MeOH the mixture was heated at 100° C. for 1 h After it was cooled to room temperature the mixture was filtered to furnish yellow solid that was washed with MeOH (3×2 mL)