1-oxaspiro[2.5]octane

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

Procedure: A mixture of N-(3-(3-aminophenyl)prop-2-ynyl)-2,2,2-trifluoroacetamide (0.75 g, 3.09 mmol) and 1-oxaspiro[2.5]octane (1.2 g, 9.2 mmol) in EtOH:H2O (9:1) was stirred under reflux for 36 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (20% to 30% EtOAc—hexanes gradient) gave 2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclohexyl)methylamino)phenyl)prop-2-ynyl)acetamide as an off white solid. Yield (0.48 g, 43%); 1H NMR (400 MHz, DMSO-d6) δ 7.28 (s, 1H), 7.00 (t, J=7.6 Hz, 1H), 6.53-6.51 (m, 2H), 6.39 (d, J=7.6 Hz, 1H), 5.28 (t, J=5.6 Hz, 1H), 4.18 (s, 1H), 4.01 (s, 2H), 2.88 (d, J=5.6 Hz, 2H), 1.60-1.47 (m, 4H), 1.39-1.34 (m, 4H), 1.22-1.14 (m, 2H). under reflux for 36 h The reaction mixture was concentrated under reduced pressure Purification by column chromatography (20% to 30% EtOAc—hexanes gradient)

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

Procedure: A mixture of (E)-N-(3-(3-aminophenyl)allyl)-2,2,2-trifluoroacetamide (0.8 g, 3.28 mmol) and 1-oxaspiro[2.5]octane (0.55 g, 4.91 mmol) in EtOH:H2O(9:1) was stirred under reflux for 36 hrs and concentrated under reduced pressure. Purification by column chromatography (20% to 30% EtOAc—hexanes gradient) gave (E)-2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclohexyl)methylamino)phenyl)allyl)acetamide as an off-white solid. Yield (0.5 g, 43%); 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.00 (t, J=8.0 Hz, 1H), 6.67 (s, 1H), 6.55 (t, J=8.8 Hz, 2H), 6.41 (d, J=16.0 Hz, 1H), 6.61-6.09 (m, 1H), 5.22 (t, J=5.2 Hz, 1H), 4.20 (s, 1H), 3.95 (t, J=5.2 Hz, 2H), 2.94 (d, J=5.6, 2H), 1.61-1.49 (m, 5H), 1.41-1.36 (m, 4H), 1.25-1.19 (m, 1H). under reflux for 36 hrs concentrated under reduced pressure Purification by column chromatography (20% to 30% EtOAc—hexanes gradient)

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

Procedure: A mixture of (E)-N-(3-(3-aminophenyl)allyl)-2,2,2-trifluoroacetamide (0.8 g, 3.28 mmol) and 1-oxaspiro[2.5]octane (0.55 g, 4.91 mmol) in EtOH:H2O(9:1) was stirred under reflux for 36 hrs and concentrated under reduced pressure. Purification by column chromatography (20% to 30% EtOAc—hexanes gradient) gave (E)-2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclohexyl)methylamino)phenyl)allyl)acetamide as an off-white solid. Yield (0.5 g, 43%); 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.00 (t, J=8.0 Hz, 1H), 6.67 (s, 1H), 6.55 (t, J=8.8 Hz, 2H), 6.41 (d, J=16.0 Hz, 1H), 6.61-6.09 (m, 1H), 5.22 (t, J=5.2 Hz, 1H), 4.20 (s, 1H), 3.95 (t, J=5.2 Hz, 2H), 2.94 (d, J=5.6, 2H), 1.61-1.49 (m, 5H), 1.41-1.36 (m, 4H), 1.25-1.19 (m, 1H). under reflux for 36 hrs concentrated under reduced pressure Purification by column chromatography (20% to 30% EtOAc—hexanes gradient)

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

Procedure: A mixture of 5-chloro-1-isopropyl-6-methyl-2-oxo-N-(piperidin-4-ylmethyl)-1,2-dihydropyridine-3-carboxamide as prepared in Example 6(2) (484 mg, 1.49 mmol) and 1-oxaspiro[2.5]octane (200 mg, 1.78 mmol, prepared according to Blake, Alexander J et al., J. Chem. Soc. Dalton Trans., 1998, 14, 2335) in methanol (5 mL) was stirred at 50° C. for 16 h. Then, the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol (v/v=20/1) to give 751 mg (99%) of the title compound as a white solid. Then, the solvent was removed in vacuo The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol (v/v=20/1)

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

Procedure: A mixture of 5-chloro-1-isopropyl-6-methyl-2-oxo-N-(piperidin-4-ylmethyl)-1,2-dihydropyridine-3-carboxamide as prepared in Example 6(2) (484 mg, 1.49 mmol) and 1-oxaspiro[2.5]octane (200 mg, 1.78 mmol, prepared according to Blake, Alexander J et al., J. Chem. Soc. Dalton Trans., 1998, 14, 2335) in methanol (5 mL) was stirred at 50° C. for 16 h. Then, the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol (v/v=20/1) to give 751 mg (99%) of the title compound as a white solid. Then, the solvent was removed in vacuo The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol (v/v=20/1)

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

Procedure: 2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}ethanol (342 mg) was dissolved in EtOH (5 mL). 1-oxaspiro[2.5]octane (363 mg) and water (5 mL) were added thereto, followed by stirring under heating at reflux for 2 days. The solvent was evaporated and water was added to the reaction liquid, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 1-({[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl](2-hydroxyethyl)amino}methyl)cyclohexanol (346 mg). under heating at reflux for 2 days The solvent was evaporated water was added to the reaction liquid followed by extraction with chloroform The extract was washed with saturated brine dried over magnesium sulfate The solvent was evaporated the resulting residue was purified by silica gel column chromatography (chloroform-MeOH)

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

Procedure: 2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}ethanol (342 mg) was dissolved in EtOH (5 mL). 1-oxaspiro[2.5]octane (363 mg) and water (5 mL) were added thereto, followed by stirring under heating at reflux for 2 days. The solvent was evaporated and water was added to the reaction liquid, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 1-({[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl](2-hydroxyethyl)amino}methyl)cyclohexanol (346 mg). under heating at reflux for 2 days The solvent was evaporated water was added to the reaction liquid followed by extraction with chloroform The extract was washed with saturated brine dried over magnesium sulfate The solvent was evaporated the resulting residue was purified by silica gel column chromatography (chloroform-MeOH)

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

Procedure: A mixture of 5-chloro-1-isopropyl-6-methyl-2-oxo-N-(piperidin-4-ylmethyl)-1,2-dihydropyridine-3-carboxamide as prepared in Example 6(2) (484 mg, 1.49 mmol) and 1-oxaspiro[2.5]octane (200 mg, 1.78 mmol, prepared according to Blake, Alexander J et al., J. Chem. Soc. Dalton Trans., 1998, 14, 2335) in methanol (5 mL) was stirred at 50° C. for 16 h. Then, the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol (v/v=20/1) to give 751 mg (99%) of the title compound as a white solid. Then, the solvent was removed in vacuo The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol (v/v=20/1)

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

Procedure: A mixture of N-(3-(3-aminophenyl)prop-2-ynyl)-2,2,2-trifluoroacetamide (0.75 g, 3.09 mmol) and 1-oxaspiro[2.5]octane (1.2 g, 9.2 mmol) in EtOH:H2O (9:1) was stirred under reflux for 36 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (20% to 30% EtOAc—hexanes gradient) gave 2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclohexyl)methylamino)phenyl)prop-2-ynyl)acetamide as an off white solid. Yield (0.48 g, 43%); 1H NMR (400 MHz, DMSO-d6) δ 7.28 (s, 1H), 7.00 (t, J=7.6 Hz, 1H), 6.53-6.51 (m, 2H), 6.39 (d, J=7.6 Hz, 1H), 5.28 (t, J=5.6 Hz, 1H), 4.18 (s, 1H), 4.01 (s, 2H), 2.88 (d, J=5.6 Hz, 2H), 1.60-1.47 (m, 4H), 1.39-1.34 (m, 4H), 1.22-1.14 (m, 2H). under reflux for 36 h The reaction mixture was concentrated under reduced pressure Purification by column chromatography (20% to 30% EtOAc—hexanes gradient)

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

Procedure: A mixture of (E)-N-(3-(3-aminophenyl)allyl)-2,2,2-trifluoroacetamide (0.8 g, 3.28 mmol) and 1-oxaspiro[2.5]octane (0.55 g, 4.91 mmol) in EtOH:H2O (9:1) was stirred under reflux for 36 hrs and concentrated under reduced pressure. Purification by column chromatography (20% to 30% EtOAc—hexanes gradient) gave (E)-2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclohexyl)methylamino)phenyl)allyl)acetamide as an off-white solid. Yield (0.5 g, 43%); 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.00 (t, J=8.0 Hz, 1H), 6.67 (s, 1H), 6.55 (t, J=8.8 Hz, 2H), 6.41 (d, J=16.0 Hz, 1H), 6.61-6.09 (m, 1H), 5.22 (t, J=5.2 Hz, 1H), 4.20 (s, 1H), 3.95 (t, J=5.2 Hz, 2H), 2.94 (d, J=5.6, 2H), 1.61-1.49 (m, 5H), 1.41-1.36 (m, 4H), 1.25-1.19 (m, 1H). under reflux for 36 hrs concentrated under reduced pressure Purification by column chromatography (20% to 30% EtOAc—hexanes gradient)

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

Procedure: A mixture of N-(3-(3-aminophenyl)prop-2-ynyl)-2,2,2-trifluoroacetamide (0.75 g, 3.09 mmol) and 1-oxaspiro[2.5]octane (1.2 g, 9.2 mmol) in EtOH:H2O (9:1) was stirred under reflux for 36 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (20% to 30% EtOAc—hexanes gradient) gave 2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclohexyl)methylamino)phenyl)prop-2-ynyl)acetamide as an off white solid. Yield (0.48 g, 43%); 1H NMR (400 MHz, DMSO-d6) δ 7.28 (s, 1H), 7.00 (t, J=7.6 Hz, 1H), 6.53-6.51 (m, 2H), 6.39 (d, J=7.6 Hz, 1H), 5.28 (t, J=5.6 Hz, 1H), 4.18 (s, 1H), 4.01 (s, 2H), 2.88 (d, J=5.6 Hz, 2H), 1.60-1.47 (m, 4H), 1.39-1.34 (m, 4H), 1.22-1.14 (m, 2H). under reflux for 36 h The reaction mixture was concentrated under reduced pressure Purification by column chromatography (20% to 30% EtOAc—hexanes gradient)

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

Procedure: A mixture of (E)-N-(3-(3-aminophenyl)allyl)-2,2,2-trifluoroacetamide (0.8 g, 3.28 mmol) and 1-oxaspiro[2.5]octane (0.55 g, 4.91 mmol) in EtOH:H2O(9:1) was stirred under reflux for 36 hrs and concentrated under reduced pressure. Purification by column chromatography (20% to 30% EtOAc—hexanes gradient) gave (E)-2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclohexyl)methylamino)phenyl)allyl)acetamide as an off-white solid. Yield (0.5 g, 43%); 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.00 (t, J=8.0 Hz, 1H), 6.67 (s, 1H), 6.55 (t, J=8.8 Hz, 2H), 6.41 (d, J=16.0 Hz, 1H), 6.61-6.09 (m, 1H), 5.22 (t, J=5.2 Hz, 1H), 4.20 (s, 1H), 3.95 (t, J=5.2 Hz, 2H), 2.94 (d, J=5.6, 2H), 1.61-1.49 (m, 5H), 1.41-1.36 (m, 4H), 1.25-1.19 (m, 1H). under reflux for 36 hrs concentrated under reduced pressure Purification by column chromatography (20% to 30% EtOAc—hexanes gradient)