ethyl 3-morpholin-4-ylpropanoate

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

Procedure: To a flask containing 3-morpholin-4-yl-propionic acid potassium salt (94 mg, 0.47 mmol, prepared from 3-morpholin-4-yl-propionic acid ethyl ester exactly as described in Example 7, 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (179 mg, 0.36 mmol, as prepared in Example 14 (b)), EDCI (83 mg, 0.43 mmol), and HOBT (68 mg, 0.5 mmol) was added DMF (4 mL). To the stirred slurry was added DIEA (157 μL, 0.9 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and the crude product was purified by silica gel preparative TLC to afford 10.4 mg (6%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 1.49-1.93 (m, 5H), 2.22-2.31 (m, 3H), 2.52 (br s, 4H), 2.58-2.63 (m, 3H), 2.74-2.76 (m, 4H), 3.10-3.17 (m, 2H), 3.72 (br s, 4H), 3.97-4.02 (m, 2H), 4.76-4.81 (m, 2H), 5.81-5.82 (m, 1H), 6.81-6.82 (m, 1H), 6.99-7.00 (m, 1H), 7.09-7.13 (m, 1H), 7.70 (s, 1H), 8.26 (d, 1H, J=8.2 Hz), 9.51 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C29H36N6O3, 517.28 M+H). found 517.3. extracted with EtOAc (2×25 mL) The combined organic extracts were dried (Na2SO4) concentrated in vacuo the crude product was purified by silica gel preparative TLC

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

Procedure: Ethyl-3-bromoproprionate (3.20 ml; 25 mmol) was added to a mixture of morpholine (2.20 ml; 25 mmol) and Na2CO3 (2.78 g; 26 mmol) in 4.5 ml of EtOH at RT. The mixture was stirred for 30 min at RT and 4 h at reflux. After cooling to RT and filtering, the filtrate was concentrated and the residue was dissolved in H2O. The pH was adjusted to ~1.5 with saturated KHSO4 and the acidic mixture was washed with Et2O. Solid K2CO3 was added to the aqueous layer until a pH of ~9 was reached. The basic mixture was extracted with CH2Cl2, dried (MgSO4) and concentrated to afford 4.75 g (100+%; contained trace solvent) of ethyl-3-morpholinoproprionate as a colorless liquid. A solution of this ester (935 mg; 5 mmol) in 20 ml of Et2O was added to a suspension of LiAlH4 (400 mg; 10 mmol) in 80 ml of Et2O at 0° C. After stirring for 30 min at 0° C., the reaction was quenched by the careful addition of 0.42 ml of H2O followed by 0.42 ml of 15% NaOH and 1.26 ml of H2O. MgSO4 was added and the suspension was filtered and concentrated to afford 531 mg (73%) of Compound 201a as a colorless liquid. at reflux After cooling to RT filtering the filtrate was concentrated the residue was dissolved in H2O the acidic mixture was washed with Et2O Solid K2CO3 was added to the aqueous layer until a pH of ~9 The basic mixture was extracted with CH2Cl2 dried (MgSO4) concentrated

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

Procedure: Ethyl-3-bromoproprionate (3.20 ml; 25 mmol) was added to a mixture of morpholine (2.20 ml; 25 mmol) and Na2CO3 (2.78 g; 26 mmol) in 4.5 ml of EtOH at RT. The mixture was stirred for 30 min at RT and 4 h at reflux. After cooling to RT and filtering, the filtrate was concentrated and the residue was dissolved in H2O. The pH was adjusted to ~1.5 with saturated KHSO4 and the acidic mixture was washed with Et2O. Solid K2CO3 was added to the aqueous layer until a pH of ~9 was reached. The basic mixture was extracted with CH2Cl2, dried (MgSO4) and concentrated to afford 4.75 g (100+%; contained trace solvent) of ethyl-3-morpholinoproprionate as a colorless liquid. A solution of this ester (935 mg; 5 mmol) in 20 ml of Et2O was added to a suspension of LiAlH4 (400 mg; 10 mmol) in 80 ml of Et2O at 0° C. After stirring for 30 min at 0° C., the reaction was quenched by the careful addition of 0.42 ml of H2O followed by 0.42 ml of 15% NaOH and 1.26 ml of H2O. MgSO4 was added and the suspension was filtered and concentrated to afford 531 mg (73%) of Compound 201a as a colorless liquid. at reflux After cooling to RT filtering the filtrate was concentrated the residue was dissolved in H2O the acidic mixture was washed with Et2O Solid K2CO3 was added to the aqueous layer until a pH of ~9 The basic mixture was extracted with CH2Cl2 dried (MgSO4) concentrated

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

Procedure: Ethyl-3-bromoproprionate (3.20 ml; 25 mmol) was added to a mixture of morpholine (2.20 ml; 25 mmol) and Na2CO3 (2.78 g; 26 mmol) in 4.5 ml of EtOH at RT. The mixture was stirred for 30 min at RT and 4 h at reflux. After cooling to RT and filtering, the filtrate was concentrated and the residue was dissolved in H2O. The pH was adjusted to ~1.5 with saturated KHSO4 and the acidic mixture was washed with Et2O. Solid K2CO3 was added to the aqueous layer until a pH of ~9 was reached. The basic mixture was extracted with CH2Cl2, dried (MgSO4) and concentrated to afford 4.75 g (100+%; contained trace solvent) of ethyl-3-morpholinoproprionate as a colorless liquid. A solution of this ester (935 mg; 5 mmol) in 20 ml of Et2O was added to a suspension of LiAlH4 (400 mg; 10 mmol) in 80 ml of Et2O at 0° C. After stirring for 30 min at 0° C., the reaction was quenched by the careful addition of 0.42 ml of H2O followed by 0.42 ml of 15% NaOH and 1.26 ml of H2O. MgSO4 was added and the suspension was filtered and concentrated to afford 531 mg (73%) of Compound 201a as a colorless liquid. at reflux After cooling to RT filtering the filtrate was concentrated the residue was dissolved in H2O the acidic mixture was washed with Et2O Solid K2CO3 was added to the aqueous layer until a pH of ~9 The basic mixture was extracted with CH2Cl2 dried (MgSO4) concentrated

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

Procedure: To a flask containing 3-morpholin-4-yl-propionic acid potassium salt (94 mg, 0.47 mmol, prepared from 3-morpholin-4-yl-propionic acid ethyl ester exactly as described in Example 7, 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (179 mg, 0.36 mmol, as prepared in Example 14 (b)), EDCI (83 mg, 0.43 mmol), and HOBT (68 mg, 0.5 mmol) was added DMF (4 mL). To the stirred slurry was added DIEA (157 μL, 0.9 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and the crude product was purified by silica gel preparative TLC to afford 10.4 mg (6%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 1.49-1.93 (m, 5H), 2.22-2.31 (m, 3H), 2.52 (br s, 4H), 2.58-2.63 (m, 3H), 2.74-2.76 (m, 4H), 3.10-3.17 (m, 2H), 3.72 (br s, 4H), 3.97-4.02 (m, 2H), 4.76-4.81 (m, 2H), 5.81-5.82 (m, 1H), 6.81-6.82 (m, 1H), 6.99-7.00 (m, 1H), 7.09-7.13 (m, 1H), 7.70 (s, 1H), 8.26 (d, 1H, J=8.2 Hz), 9.51 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C29H36N6O3, 517.28 M+H). found 517.3. extracted with EtOAc (2×25 mL) The combined organic extracts were dried (Na2SO4) concentrated in vacuo the crude product was purified by silica gel preparative TLC

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

Procedure: To a flask containing 3-morpholin-4-yl-propionic acid potassium salt (94 mg, 0.47 mmol, prepared from 3-morpholin-4-yl-propionic acid ethyl ester exactly as described in Example 7, 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (179 mg, 0.36 mmol, as prepared in Example 14 (b)), EDCI (83 mg, 0.43 mmol), and HOBT (68 mg, 0.5 mmol) was added DMF (4 mL). To the stirred slurry was added DIEA (157 μL, 0.9 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and the crude product was purified by silica gel preparative TLC to afford 10.4 mg (6%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 1.49-1.93 (m, 5H), 2.22-2.31 (m, 3H), 2.52 (br s, 4H), 2.58-2.63 (m, 3H), 2.74-2.76 (m, 4H), 3.10-3.17 (m, 2H), 3.72 (br s, 4H), 3.97-4.02 (m, 2H), 4.76-4.81 (m, 2H), 5.81-5.82 (m, 1H), 6.81-6.82 (m, 1H), 6.99-7.00 (m, 1H), 7.09-7.13 (m, 1H), 7.70 (s, 1H), 8.26 (d, 1H, J=8.2 Hz), 9.51 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C29H36N6O3, 517.28 M+H). found 517.3. extracted with EtOAc (2×25 mL) The combined organic extracts were dried (Na2SO4) concentrated in vacuo the crude product was purified by silica gel preparative TLC

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

Procedure: To a flask containing 3-morpholin-4-yl-propionic acid potassium salt (94 mg, 0.47 mmol, prepared from 3-morpholin-4-yl-propionic acid ethyl ester exactly as described in Example 7, 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (179 mg, 0.36 mmol, as prepared in Example 14 (b)), EDCI (83 mg, 0.43 mmol), and HOBT (68 mg, 0.5 mmol) was added DMF (4 mL). To the stirred slurry was added DIEA (157 μL, 0.9 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and the crude product was purified by silica gel preparative TLC to afford 10.4 mg (6%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 1.49-1.93 (m, 5H), 2.22-2.31 (m, 3H), 2.52 (br s, 4H), 2.58-2.63 (m, 3H), 2.74-2.76 (m, 4H), 3.10-3.17 (m, 2H), 3.72 (br s, 4H), 3.97-4.02 (m, 2H), 4.76-4.81 (m, 2H), 5.81-5.82 (m, 1H), 6.81-6.82 (m, 1H), 6.99-7.00 (m, 1H), 7.09-7.13 (m, 1H), 7.70 (s, 1H), 8.26 (d, 1H, J=8.2 Hz), 9.51 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C29H36N6O3, 517.28 M+H). found 517.3. extracted with EtOAc (2×25 mL) The combined organic extracts were dried (Na2SO4) concentrated in vacuo the crude product was purified by silica gel preparative TLC

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

Procedure: To a flask containing 3-morpholin-4-yl-propionic acid potassium salt (94 mg, 0.47 mmol, prepared from 3-morpholin-4-yl-propionic acid ethyl ester exactly as described in Example 7, 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (179 mg, 0.36 mmol, as prepared in Example 14 (b)), EDCI (83 mg, 0.43 mmol), and HOBT (68 mg, 0.5 mmol) was added DMF (4 mL). To the stirred slurry was added DIEA (157 μL, 0.9 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and the crude product was purified by silica gel preparative TLC to afford 10.4 mg (6%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 1.49-1.93 (m, 5H), 2.22-2.31 (m, 3H), 2.52 (br s, 4H), 2.58-2.63 (m, 3H), 2.74-2.76 (m, 4H), 3.10-3.17 (m, 2H), 3.72 (br s, 4H), 3.97-4.02 (m, 2H), 4.76-4.81 (m , 2H), 5.81-5.82 (m, 1H), 6.81-6.82 (m, 1H), 6.99-7.00 (m, 1H), 7.09-7.13 (m, 1H), 7.70 (s, 1H), 8.26 (d, 1H, J=8.2 Hz), 9.51 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C29H36N6O3, 517.28 M+H), found 517.3. extracted with EtOAc (2×25 mL) The combined organic extracts were dried (Na2SO4) concentrated in vacuo the crude product was purified by silica gel preparative TLC

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

Procedure: Ethyl-3-bromoproprionate (3.20 ml; 25 mmol) was added to a mixture of morpholine (2.20 ml; 25 mmol) and Na2CO3 (2.78 g; 26 mmol) in 4.5 ml of EtOH at RT. The mixture was stirred for 30 min at RT and 4 h at reflux. After cooling to RT and filtering, the filtrate was concentrated and the residue was dissolved in H2O. The pH was adjusted to ~1.5 with saturated KHSO4 and the acidic mixture was washed with Et2O. Solid K2CO3 was added to the aqueous layer until a pH of ~9 was reached. The basic mixture was extracted with CH2Cl2, dried (MgSO4) and concentrated to afford 4.75 g (100+%; contained trace solvent) of ethyl-3-morpholinoproprionate as a colorless liquid. A solution of this ester (935 mg; 5 mmol) in 20 ml of Et2O was added to a suspension of LiAlH4 (400 mg; 10 mmol) in 80 ml of Et2O at 0° C. After stirring for 30 min at 0° C., the reaction was quenched by the careful addition of 0.42 ml of H2O followed by 0.42 ml of 15% NaOH and 1.26 ml of H2O. MgSO4 was added and the suspension was filtered and concentrated to afford 531 mg (73%) of Compound 201a as a colorless liquid. ##STR383## at reflux After cooling to RT filtering the filtrate was concentrated the residue was dissolved in H2O the acidic mixture was washed with Et2O Solid K2CO3 was added to the aqueous layer until a pH of ~9 The basic mixture was extracted with CH2Cl2 dried (MgSO4) concentrated

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

Procedure: To a flask containing 3-morpholin-4-yl-propionic acid potassium salt (94 mg, 0.47 mmol, prepared from 3-morpholin-4-yl-propionic acid ethyl ester exactly as described in Example 7, 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (179 mg, 0.36 mmol, as prepared in Example 14 (b)), EDCI (83 mg, 0.43 mmol), and HOBT (68 mg, 0.5 mmol) was added DMF (4 mL). To the stirred slurry was added DIEA (157 μL, 0.9 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and the crude product was purified by silica gel preparative TLC to afford 10.4 mg (6%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 1.49-1.93 (m, 5H), 2.22-2.31 (m, 3H), 2.52 (br s, 4H), 2.58-2.63 (m, 3H), 2.74-2.76 (m, 4H), 3.10-3.17 (m, 2H), 3.72 (br s, 4H), 3.97-4.02 (m, 2H), 4.76-4.81 (m, 2H), 5.81-5.82 (m, 1H), 6.81-6.82 (m, 1H), 6.99-7.00 (m, 1H), 7.09-7.13 (m, 1H), 7.70 (s, 1H), 8.26 (d, 1H, J=8.2 Hz), 9.51 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C29H36N6O3, 517.28 M+H), found 517.3. extracted with EtOAc (2×25 mL) The combined organic extracts were dried (Na2SO4) concentrated in vacuo the crude product was purified by silica gel preparative TLC

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

Procedure: To a flask containing 3-morpholin-4-yl-propionic acid potassium salt (94 mg, 0.47 mmol, prepared from 3-morpholin-4-yl-propionic acid ethyl ester exactly as described in Example 7, 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (179 mg, 0.36 mmol, as prepared in Example 14 (b)), EDCI (83 mg, 0.43 mmol), and HOBT (68 mg, 0.5 mmol) was added DMF (4 mL). To the stirred slurry was added DEEA (157 μL, 0.9 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and the crude product was purified by silica gel preparative TLC to afford 10.4 mg (6%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 1.49-1.93 (m, 5H), 2.22-2.31 (m, 3H), 2.52 (br s, 4H), 2.58-2.63 (m, 3H), 2.74-2.76 (m, 4H), 3.10-3.17 (m, 2H), 3.72 (br s, 4H), 3.97-4.02 (m, 2H), 4.76-4.81 (m, 2H), 5.81-5.82 (m, 1H), 6.81-6.82 (m, 1H), 6.99-7.00 (m, 1H), 7.09-7.13 (m, 1H), 7.70 (s, 1H), 8.26 (d, 1H, J=8.2 Hz), 9.51 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C29H36N6O3, 517.28 M+H), found 517.3. extracted with EtOAc (2×25 mL) The combined organic extracts were dried (Na2SO4) concentrated in vacuo the crude product was purified by silica gel preparative TLC

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

Procedure: To a flask containing 3-morpholin-4-yl-propionic acid potassium salt (94 mg, 0.47 mmol, prepared from 3-morpholin-4-yl-propionic acid ethyl ester exactly as described in Example 7, 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (179 mg, 0.36 mmol, as prepared in Example 14 (b)), EDCI (83 mg, 0.43 mmol), and HOBT (68 mg, 0.5 mmol) was added DMF (4 mL). To the stirred slurry was added DIEA (157 μL, 0.9 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and the crude product was purified by silica gel preparative TLC to afford 10.4 mg (6%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 1.49-1.93 (m, 5H), 2.22-2.31 (m, 3H), 2.52 (br s, 4H), 2.58-2.63 (m, 3H), 2.74-2.76 (m, 4H), 3.10-3.17 (m, 2H), 3.72 (br s, 4H), 3.97-4.02 (m, 2H), 4.76-4.81 (m, 2H), 5.81-5.82 (m, 1H), 6.81-6.82 (m, 1H), 6.99-7.00 (m, 1H), 7.09-7.13 (m, 1H), 7.70 (s, 1H), 8.26 (d, 1H, J=8.2 Hz), 9.51 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C29H36N6O3, 517.28 M+H). found 517.3. extracted with EtOAc (2×25 mL) The combined organic extracts were dried (Na2SO4) concentrated in vacuo the crude product was purified by silica gel preparative TLC