ethyl pent-2-ynoate

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

Procedure: A solution of 1-aminopyridinium iodide (10 g, 40 mmol) [Aldrich 441503], ethyl 2-pentynoate (5.7 g, 45 mmol) [Aldrich 632112] and potassium carbonate (12.0 g, 90 mmol) were stirred in N,N-dimethylformamide (200 mL) at 20° C. for 16 h. The mixture was poured into water to give a tan suspension. The solid was filtered and washed with water to give the desired to compound (5.0 g, 57%). LCMS for C12H15N2O2 (M+H)+: m/z=219.1. 1H NMR (300 MHz, DMSO-d6): δ 8.77 (m, 1H), 8.00 (m, 1H), 7.52 (m, 1H), 7.05 (m, 1H), 4.28 (m, 2H), 3.00 (m, 2H), 1.33 (m, 3H), 1.24 (m, 3H). to give a tan suspension The solid was filtered washed with water to give the

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

Procedure: The title compound was prepared from (S)-5-(4-(1,1,3,3-tetramethyl-butyl) -phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (see Example 27) and pent-2-ynoic acid ethyl ester employing the procedure described in Example 95. [α]D25 −21.00 (c 0.5, CHCl3).

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

Procedure: The title compound was prepared from (S)-5-(4-tert-butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-yl-amine and ethyl 2-pentynoate according to the procedures employed for the preparation of the compound in Example 95. [α]D25 −29.20 (c 0.5, CHCl3) employed for the preparation of the compound in Example 95

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

Procedure: To a solution of 5-[4-(3,3,5,5-tetramethyl-cyclohexyl)-phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine (0.15 g, 0.454 mmol), prepared in accordance with the procedures described in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-(3,3,5,5-tetramethyl-cyclohexyl)-phenol (prepared using the same procedure as in step 1 of Example 74), in ethanol (5 mL) was added ethyl 2-pentynoate (0.086 g, 0.681 mmol). The reaction mixture was heated at reflux for 14 hrs and then cooled to room temperature. The reaction mixture was concentrated, loaded onto a silica gel column, and eluted with 4% methanol/methylene chloride to afford 23 mg of (S)-5-ethyl-2-[4-(3,3,5,5-tetramethyl-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one. prepared The reaction mixture was heated at reflux for 14 hrs The reaction mixture was concentrated eluted with 4% methanol/methylene chloride

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

Procedure: To a solution of (S)-5-(5,6,7,8,8a,9-hexahydro-4bH-fluoren-2-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine (16 mg, 0.055 mmol), prepared in accordance with the procedures in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 5,6,7,8,8a,9-hexahydro-4bH-fluoren-2-ol (prepared by the same procedure as in Step 1 of Example 19), in ethanol (2 mL) was added ethyl 2-pentynoate (4.2 mg, 0.065 mmol). The reaction mixture was heated at reflux for 14 hrs and then cooled to room temperature. The reaction mixture was concentrated and then loaded onto a silica gel column, and eluted with 2-6% methanol/methylene chloride to afford 8 mg of (S)-5-ethyl-2-(5,6,7,8,8a,9-hexahydro-4bH-fluoren-2-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one. The reaction mixture was heated at reflux for 14 hrs The reaction mixture was concentrated eluted with 2-6% methanol/methylene chloride

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

Procedure: To a solution of (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.26 g, 0.828 mmol), prepared in accordance with the procedures as set forth in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-bicyclo[3.3.1]non-9-yl phenol (prepared with the same procedure as set forth in steps 1 and 2 of Example 20), in ethanol (5 mL) was added ethyl 2-pentynoate (0.157 g, 1.24 mmol). The reaction mixture was heated at reflux for 14 hrs and then cooled to room temperature. The reaction mixture was concentrated and loaded onto a silica gel column, and eluted with 4-6% methanol/methylene chloride to afford 120 mg of (S)-2-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-5-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one. [α]D25 −36.89 (c 0.501, CHCl3). prepared with the same procedure The reaction mixture was heated at reflux for 14 hrs The reaction mixture was concentrated eluted with 4-6% methanol/methylene chloride

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

Procedure: To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (1.0 g, 3.64 mmol), prepared in accordance with the procedures as set forth in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-cyclohexylphenol, in ethanol (18.2 mL) was added ethyl 2-pentynoate (0.92 g, 7.28 mmol). The reaction mixture was heated at reflux for 14 hrs and then gradually cooled to room temperature. The resulting crystalline solid was isolated by filtration, washed with heptane 3 times, and dried under vacuum to afford 560 mg of (S)-2-(4-cyclohexyl-phenoxymethyl)-5-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as a white solid. [α]D25 −27.96 (c 0.526, CHCl3). The reaction mixture was heated at reflux for 14 hrs The resulting crystalline solid was isolated by filtration washed with heptane 3 times dried under vacuum

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (300 mg, 1.095 mmol) in ethanol (6 mL) was added ethyl 2-pentynoate (276 mg, 2.19 mmol). The reaction mixture was heated in a microwave oven at 170° C. for 70 min. The solvent was removed under vacuum, and the residue purified via flash column chromatography (silica gel, 1-12% EtOH/CH2Cl2) to afford 153 mg of 2-(4-cyclohexyl-phenoxymethyl)-5-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as a slightly yellow solid. The solvent was removed under vacuum the residue purified via flash column chromatography (silica gel, 1-12% EtOH/CH2Cl2)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6,7-dihydro-5H-cyclopenta[c]pyridin-7-ylacetonitrile (1.77 g, 11.2 mmol) in acetonitrile (22 mL) was added 1-(aminooxy)-2,4-dinitrobenzene (5.00 g, 25.1 mmol), and the mixture was stirred at 40° C. for 16 hr. The solvent was evaporated under reduced pressure. Half of the residue was dissolved in dimethylformamide (22 mL), ethyl 2-pentynoate (886 μL, 6.72 mmol) and potassium carbonate (1.55 g, 11.2 mmol) were added, and the mixture was stirred at room temperature for 16 hr. The reaction solution was diluted with water, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→40/60) to give the title compound (644 mg). The solvent was evaporated under reduced pressure Half of the residue was dissolved in dimethylformamide (22 mL) the mixture was stirred at room temperature for 16 hr the mixture was extracted with diethyl ether The extract was dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→40/60)

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

Procedure: A mixture of Ethyl 2-pentynoate (350 mg, 2.77 mmol), 1-iodo-3-(methoxymethoxy)benzene (1.46 g, 5.53 mmol), Phenylboronic acid (675 mg, 5.54 mmol) and K2CO3 (766 mg, 5.54 mmol) in DMF (8 ml)-H2O (2 ml) was stirred at room temperature for 10 min. Then PdCl2(PhCN)2 (10.6 mg, 0.0276 mmol) was added under Ar atmosphere, and the mixture was stirred at room temperature for 24 h. The reaction was quenched with H2O under ice cooling, and the whole was extracted with Et2O. The organic layer was washed with H2O, brine, dried over Na2SO4, then concentrated. Purification by Biotage HPFC (eluent: hexane to hexane/AcOEt, 10:1) gave 2a (25%). 2a: colorless oil; 1H-NMR (CDCl3) δ 1.02 (3H, t, J=7.4 Hz), 1.31 (3H, t, J=7.2 Hz), 2.65 (2H, t, J=7.4 Hz), 3.33 (3H, s), 4.29 (2H, t, J=7.2 Hz), 4.91 (2H, s), 6.65 (1H, m), 6.68 (1H, m), 6.74 (1H, ddd, J=1.0, 2.5, 8.3 Hz), 7.00-7.05 (3H, m), 7.10-7.19 (3H, m). the mixture was stirred at room temperature for 24 h The reaction was quenched with H2O under ice cooling the whole was extracted with Et2O The organic layer was washed with H2O, brine dried over Na2SO4 concentrated Purification by Biotage HPFC (eluent: hexane to hexane/AcOEt, 10:1)

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

Procedure: A mixture of Ethyl 2-pentynoate (350 mg, 2.77 mmol), 1-iodo-4-(methoxymethoxy)benzene (1.46 g, 5.53 mmol), 2-Methylphenylboronic acid (753 mg, 5.53 mmol) and K2CO3 (766 mg, 5.54 mmol) in DMF (8.5 ml)-H2O (2.2 ml) was stirred at room temperature for 10 min. Then PdCl2(PhCN)2 (10.6 mg, 0.0276 mmol) was added under Ar atmosphere, and the mixture was stirred at room temperature for 24 h. The reaction was quenched with H2O under ice cooling, and the whole was extracted with Et2O. The organic layer was washed with H2O, brine, dried over Na2SO4, then concentrated. Purification by silica gel flash column chromatography (eluent: hexane/AcOEt, 30:1) gave 2a (27%). 2a: colorless oil; 1H-NMR (CDCl3) δ 1.02 (3H, t, J=7.5 Hz), 1.33 (3H, t, J=7.1 Hz), 2.04 (3H, s), 2.56 (2H, m), 3.42 (3H, s), 4.30 (2H, m), 5.06 (2H, s), 6.72 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=8.8 Hz), 7.00-7.12 (5H, m). the mixture was stirred at room temperature for 24 h The reaction was quenched with H2O under ice cooling the whole was extracted with Et2O The organic layer was washed with H2O, brine dried over Na2SO4 concentrated Purification by silica gel flash column chromatography (eluent: hexane/AcOEt, 30:1)

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

Procedure: To a mixture of Ethyl 2-pentynoate (5.5 g, 43.6 mmol), 1-iodo-4-(methoxymethoxy)benzene (23.0 g, 87.1 mmol), Phenylboronic acid (10.6 g, 86.9 mmol) in DMF (132 ml) was added a solution of K2CO3 (12.1 g, 87.5 mmol) in H2O (33 ml) under ice cooling, then the mixture was stirred at room temperature for 10 min. PdCl2(PhCN)2 (167 mg, 0.435 mmol) was added under Ar atmosphere, and the mixture was stirred at room temperature for 24 h. The reaction was quenched with H2O under ice cooling, and the whole was extracted with Et2O. The organic layer was washed with H2O, brine, dried over Na2SO4, then concentrated. Purification by silica gel flash column chromatography (eluent: hexane/AcOEt, 30:1 to 10:1) gave 2 (29%) and the regioisomer (24%). 2: colorless oil; 1H-NMR (CDCl3) δ 1.00 (3H, t, J=7.4), 1.31 (3H, t, J=7.1 Hz), 2.63 (2H, q, J=7.4 Hz), 3.42 (3H, s), 4.28 (2H, q, J=7.1 Hz), 5.07 (2H, s), 6.75 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=8.8 Hz), 7.04 (2H, m), 7.12-7.21 (3H, m); regioisomer: H1-NMR (CDCl3) δ 1.02 (3H, t, J=7.4 Hz), 1.29 (3H, t, J=7.1 Hz), 2.64 (2H, q, J=7.4 Hz), 3.45 (3H, s), 4.27 (2H, q, J=7.1 Hz), 5.10 (2H, s), 6.81 (2H, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 7.00 (2H, m), 7.06-7.14 (3H, m). the mixture was stirred at room temperature for 24 h The reaction was quenched with H2O under ice cooling the whole was extracted with Et2O The organic layer was washed with H2O, brine dried over Na2SO4 concentrated Purification by silica gel flash column chromatography (eluent: hexane/AcOEt, 30:1 to 10:1)