ethyl 2-oxopyrrolidine-3-carboxylate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To sodium hydride in mineral oil (60%, 0.007 g, 0.33 mmol) was added tetrahydrofuran (1.8 mL) and the suspension was cooled to 0° C. Ethyl 2-oxopyrrolidine-3-carboxylate (0.044 g, 0.28 mmol) was added and the solution was stirred for 15 minutes. N-{3-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (0.100 g, 0.23 mmol) was dissolved in tetrahydrofuran (1.8 mL) and then added to the flask. The reaction was allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate, washed carefully with water, dried over magnesium sulfate, filtered and concentrated. The solid was purified by silica gel chromatography to yield ethyl 3-{[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-oxopyrrolidine-3-carboxylate (0.03 g, 27% yield). MS ESI: [M+H]+ m/z 505.7. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (d, J=5.2, 1H), 8.11 (s, 1H), 8.02-7.84 (m, 2H), 7.47 (s, 1H), 7.28 (d, J=5.2, 1H), 7.14 (s, 1H), 4.11 (q, J=7.4, 2H), 3.58 (m 1H), 3.28-3.21 (m, 2H), 3.15-3.03 (m, 1H), 2.66-2.54 (m, 1H), 2.31 (s, 3H), 2.27-2.16 (m, 1H), 1.15 (t, J=7.3, 3H). rhSYK activity=+++ added to the flask to warm to room temperature overnight washed carefully with water dried over magnesium sulfate filtered concentrated The solid was purified by silica gel chromatography

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

Procedure: Dissolved commercially available ethyl 2-oxopyrrolidine-3-carboxylate (2.50 g, 15.91 mmol) in 30 mL dichloromethane in 50 mL round bottom flask. To this solution was added trimethyloxonium tetrafluoroborate (2.59 g, 17.5 mmol) as a solid and rinsed with 20 mL dichloromethane. The resulting mixture was stirred at room temperature for two h and LC/MS indicated that the intermediate methyl 5-methoxy-3,4-dihydro-2H-pyrrole-4-carboxylate had formed. At this point, acetohydrazide (1.18 g, 15.91 mmol) was introduced as a solid to the mixture and the resulting solution was stirred at room temperature for 3 h. The solution was then concentrated under vacuum to remove all dichloromethane and the residue was then taken up in 100 mL n-butanol which was heated to reflux in an oil bath set at 120° C. overnight. The solution was cooled to room temperature and concentrated under vacuum. The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane:methanol solvent system. The product was extracted from the silica gel using 85:15 dichloromethane:methanol which afforded the title compound (454 mg, 11%). 1H NMR (500 MHz DMSO-d6) δ: 4.16-4.06 (m, 1H), 4.00-3.88 (m, 1H), 2.85-2.78 (m, 1H), 2.29 (s, 3H), 1.55 (dt, J=6.7, 13.9 Hz, 2H), 1.32 (dt, J=6.7, 14.0 Hz, 2H), 0.88 (t, J=7.5 Hz, 3H). LC-MS: m/z (ES)=196 (MH)+. rinsed with 20 mL dichloromethane had formed the resulting solution was stirred at room temperature for 3 h The solution was then concentrated under vacuum to remove all dichloromethane was heated to reflux in an oil bath The solution was cooled to room temperature concentrated under vacuum The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane The product was extracted from the silica gel using 85:15 dichloromethane

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

Procedure: Dissolved commercially available ethyl 2-oxopyrrolidine-3-carboxylate (2.50 g, 15.91 mmol) in 30 mL dichloromethane in 50 mL round bottom flask. To this solution was added trimethyloxonium tetrafluoroborate (2.59 g, 17.5 mmol) as a solid and rinsed with 20 mL dichloromethane. The resulting mixture was stirred at room temperature for two h and LC/MS indicated that the intermediate methyl 5-methoxy-3,4-dihydro-2H-pyrrole-4-carboxylate had formed. At this point, acetohydrazide (1.18 g, 15.91 mmol) was introduced as a solid to the mixture and the resulting solution was stirred at room temperature for 3 h. The solution was then concentrated under vacuum to remove all dichloromethane and the residue was then taken up in 100 mL n-butanol which was heated to reflux in an oil bath set at 120° C. overnight. The solution was cooled to room temperature and concentrated under vacuum. The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane:methanol solvent system. The product was extracted from the silica gel using 85:15 dichloromethane:methanol which afforded the title compound (454 mg, 11%). 1H NMR (500 MHz DMSO-d6) δ: 4.16-4.06 (m, 1H), 4.00-3.88 (m, 1H), 2.85-2.78 (m, 1H), 2.29 (s, 3H), 1.55 (dt, J=6.7, 13.9 Hz, 2H), 1.32 (dt, J=6.7, 14.0 Hz, 2H), 0.88 (t, J=7.5 Hz, 3H). LC-MS: m/z (ES)=196 (MH)+. rinsed with 20 mL dichloromethane had formed the resulting solution was stirred at room temperature for 3 h The solution was then concentrated under vacuum to remove all dichloromethane was heated to reflux in an oil bath The solution was cooled to room temperature concentrated under vacuum The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane The product was extracted from the silica gel using 85:15 dichloromethane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To sodium hydride in mineral oil (60%, 0.007 g, 0.33 mmol) was added tetrahydrofuran (1.8 mL) and the suspension was cooled to 0° C. Ethyl 2-oxopyrrolidine-3-carboxylate (0.044 g, 0.28 mmol) was added and the solution was stirred for 15 minutes. N-{3-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (0.100 g, 0.23 mmol) was dissolved in tetrahydrofuran (1.8 mL) and then added to the flask. The reaction was allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate, washed carefully with water, dried over magnesium sulfate, filtered and concentrated. The solid was purified by silica gel chromatography to yield ethyl 3-{[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-oxopyrrolidine-3-carboxylate (0.03 g, 27% yield). MS ESI: [M+H]+ m/z 505.7. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (d, J=5.2, 1H), 8.11 (s, 1H), 8.02-7.84 (m, 2H), 7.47 (s, 1H), 7.28 (d, J=5.2, 1H), 7.14 (s, 1H), 4.11 (q, J=7.4, 2H), 3.58 (in 1H), 3.28-3.21 (m, 2H), 3.15-3.03 (m, 1H), 2.66-2.54 (m, 1H), 2.31 (s, 3H), 2.27-2.16 (m, 1H), 1.15 (t, J=7.3, 3H). rhSYK activity=+++ added to the flask to warm to room temperature overnight washed carefully with water dried over magnesium sulfate filtered concentrated The solid was purified by silica gel chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To sodium hydride in mineral oil (60%, 0.007 g, 0.33 mmol) was added tetrahydrofuran (1.8 mL) and the suspension was cooled to 0° C. Ethyl 2-oxopyrrolidine-3-carboxylate (0.044 g, 0.28 mmol) was added and the solution was stirred for 15 minutes. N-{3-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (0.100 g, 0.23 mmol) was dissolved in tetrahydrofuran (1.8 mL) and then added to the flask. The reaction was allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate, washed carefully with water, dried over magnesium sulfate, filtered and concentrated. The solid was purified by silica gel chromatography to yield ethyl 3-{[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-oxopyrrolidine-3-carboxylate (0.03 g, 27% yield). MS ESI: [M+H]+ m/z 505.7. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (d, J=5.2, 1H), 8.11 (s, 1H), 8.02-7.84 (m, 2H), 7.47 (s, 1H), 7.28 (d, J=5.2, 1H), 7.14 (s, 1H), 4.11 (q, J=7.4, 2H), 3.58 (in 1H), 3.28-3.21 (m, 2H), 3.15-3.03 (m, 1H), 2.66-2.54 (m, 1H), 2.31 (s, 3H), 2.27-2.16 (m, 1H), 1.15 (t, J=7.3, 3H). rhSYK activity=+++ added to the flask to warm to room temperature overnight washed carefully with water dried over magnesium sulfate filtered concentrated The solid was purified by silica gel chromatography

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

Procedure: Dissolved commercially available ethyl 2-oxopyrrolidine-3-carboxylate (2.50 g, 15.91 mmol) in 30 mL dichloromethane in 50 mL round bottom flask. To this solution was added trimethyloxonium tetrafluoroborate (2.59 g, 17.5 mmol) as a solid and rinsed with 20 mL dichloromethane. The resulting mixture was stirred at room temperature for two h and LC/MS indicated that the intermediate methyl 5-methoxy-3,4-dihydro-2H-pyrrole-4-carboxylate had formed. At this point, acetohydrazide (1.18 g, 15.91 mmol) was introduced as a solid to the mixture and the resulting solution was stirred at room temperature for 3 h. The solution was then concentrated under vacuum to remove all dichloromethane and the residue was then taken up in 100 mL n-butanol which was heated to reflux in an oil bath set at 120° C. overnight. The solution was cooled to room temperature and concentrated under vacuum. The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane: methanol solvent system. The product was extracted from the silica gel using 85:15 dichloromethane:methanol which afforded the title compound (454 mg, 11%). 1H NMR (500 MHz DMSO-d6) δ: 4.16-4.06 (m, 1H), 4.00-3.88 (m, 1H), 2.85-2.78 (m, 1H), 2.29 (s, 3H), 1.55 (dt, J=6.7, 13.9 Hz, 2H), 1.32 (dt, J=6.7, 14.0 Hz, 2H), 0.88 (t, J=7.5 Hz, 3H). LC-MS: m/z (ES)=196 (MH)+. rinsed with 20 mL dichloromethane had formed the resulting solution was stirred at room temperature for 3 h The solution was then concentrated under vacuum to remove all dichloromethane was heated to reflux in an oil bath The solution was cooled to room temperature concentrated under vacuum The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane The product was extracted from the silica gel using 85:15 dichloromethane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To sodium hydride in mineral oil (60%, 0.007 g, 0.33 mmol) was added tetrahydrofuran (1.8 mL) and the suspension was cooled to 0° C. Ethyl 2-oxopyrrolidine-3-carboxylate (0.044 g, 0.28 mmol) was added and the solution was stirred for 15 minutes. N-{3-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (0.100 g, 0.23 mmol) was dissolved in tetrahydrofuran (1.8 mL) and then added to the flask. The reaction was allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate, washed carefully with water, dried over magnesium sulfate, filtered and concentrated. The solid was purified by silica gel chromatography to yield ethyl 3-{[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-oxopyrrolidine-3-carboxylate (0.03 g, 27% yield). MS ESI: [M+H]+ m/z 505.7. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (d, J=5.2, 1H), 8.11 (s, 1H), 8.02-7.84 (m, 2H), 7.47 (s, 1H), 7.28 (d, J=5.2, 1H), 7.14 (s, 1H), 4.11 (q, J=7.4, 2H), 3.58 (m 1H), 3.28-3.21 (m, 2H), 3.15-3.03 (m, 1H), 2.66-2.54 (m, 1H), 2.31 (s, 3H), 2.27-2.16 (m, 1H), 1.15 (t, J=7.3, 3H). rhSYK activity=+++ added to the flask to warm to room temperature overnight washed carefully with water dried over magnesium sulfate filtered concentrated The solid was purified by silica gel chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To sodium hydride in mineral oil (60%, 0.007 g, 0.33 mmol) was added tetrahydrofuran (1.8 mL) and the suspension was cooled to 0° C. Ethyl 2-oxopyrrolidine-3-carboxylate (0.044 g, 0.28 mmol) was added and the solution was stirred for 15 minutes. N-{3-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (0.100 g, 0.23 mmol) was dissolved in tetrahydrofuran (1.8 mL) and then added to the flask. The reaction was allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate, washed carefully with water, dried over magnesium sulfate, filtered and concentrated. The solid was purified by silica gel chromatography to yield ethyl 3-{[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-oxopyrrolidine-3-carboxylate (0.03 g, 27% yield). MS ESI: [M+H]+ m/z 505.7. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (d, J=5.2, 1H), 8.11 (s, 1H), 8.02-7.84 (m, 2H), 7.47 (s, 1H), 7.28 (d, J=5.2, 1H), 7.14 (s, 1H), 4.11 (q, J=7.4, 2H), 3.58 (m 1H), 3.28-3.21 (m, 2H), 3.15-3.03 (m, 1H), 2.66-2.54 (m, 1H), 2.31 (s, 3H), 2.27-2.16 (m, 1H), 1.15 (t, J=7.3, 3H). rhSYK activity=+++ added to the flask to warm to room temperature overnight washed carefully with water dried over magnesium sulfate filtered concentrated The solid was purified by silica gel chromatography

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

Procedure: Dissolved commercially available ethyl 2-oxopyrrolidine-3-carboxylate (2.50 g, 15.91 mmol) in 30 mL dichloromethane in 50 mL round bottom flask. To this solution was added trimethyloxonium tetrafluoroborate (2.59 g, 17.5 mmol) as a solid and rinsed with 20 mL dichloromethane. The resulting mixture was stirred at room temperature for two h and LC/MS indicated that the intermediate methyl 5-methoxy-3,4-dihydro-2H-pyrrole-4-carboxylate had formed. At this point, acetohydrazide (1.18 g, 15.91 mmol) was introduced as a solid to the mixture and the resulting solution was stirred at room temperature for 3 h. The solution was then concentrated under vacuum to remove all dichloromethane and the residue was then taken up in 100 mL n-butanol which was heated to reflux in an oil bath set at 120° C. overnight. The solution was cooled to room temperature and concentrated under vacuum. The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane:methanol solvent system. The product was extracted from the silica gel using 85:15 dichloromethane:methanol which afforded the title compound (454 mg, 11%). 1H NMR (500 MHz DMSO-d6) δ: 4.16-4.06 (m, 1H), 4.00-3.88 (m, 1H), 2.85-2.78 (m, 1H), 2.29 (s, 3H), 1.55 (dt, J=6.7, 13.9 Hz, 2H), 1.32 (dt, J=6.7, 14.0 Hz, 2H), 0.88 (t, J=7.5 Hz, 3H). LC-MS: m/z (ES)=196 (MH)+. rinsed with 20 mL dichloromethane had formed the resulting solution was stirred at room temperature for 3 h The solution was then concentrated under vacuum to remove all dichloromethane was heated to reflux in an oil bath The solution was cooled to room temperature concentrated under vacuum The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane The product was extracted from the silica gel using 85:15 dichloromethane

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

Procedure: Dissolved commercially available ethyl 2-oxopyrrolidine-3-carboxylate (2.50 g, 15.91 mmol) in 30 mL dichloromethane in 50 mL round bottom flask. To this solution was added trimethyloxonium tetrafluoroborate (2.59 g, 17.5 mmol) as a solid and rinsed with 20 mL dichloromethane. The resulting mixture was stirred at room temperature for two h and LC/MS indicated that the intermediate methyl 5-methoxy-3,4-dihydro-2H-pyrrole-4-carboxylate had formed. At this point, acetohydrazide (1.18 g, 15.91 mmol) was introduced as a solid to the mixture and the resulting solution was stirred at room temperature for 3 h. The solution was then concentrated under vacuum to remove all dichloromethane and the residue was then taken up in 100 mL n-butanol which was heated to reflux in an oil bath set at 120° C. overnight. The solution was cooled to room temperature and concentrated under vacuum. The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane:methanol solvent system. The product was extracted from the silica gel using 85:15 dichloromethane:methanol which afforded the title compound (454 mg, 11%). 1H NMR (500 MHz DMSO-d6) δ: 4.16-4.06 (m, 1H), 4.00-3.88 (m, 1H), 2.85-2.78 (m, 1H), 2.29 (s, 3H), 1.55 (dt, J=6.7, 13.9 Hz, 2H), 1.32 (dt, J=6.7, 14.0 Hz, 2H), 0.88 (t, J=7.5 Hz, 3H). LC-MS: m/z (ES)=196 (MH)+. rinsed with 20 mL dichloromethane had formed the resulting solution was stirred at room temperature for 3 h The solution was then concentrated under vacuum to remove all dichloromethane was heated to reflux in an oil bath The solution was cooled to room temperature concentrated under vacuum The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane The product was extracted from the silica gel using 85:15 dichloromethane

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

Procedure: Dissolved commercially available ethyl 2-oxopyrrolidine-3-carboxylate (2.50 g, 15.9 mmol) in 30 ml dichloromethane in 50 ml round bottom flask. To this solution was added trimethyloxonium tetrafluoroborate (2.59 g, 17.5 mmol) as a solid and rinsed in with 20 ml dichloromethane. The resulting mixture was stirred at room temperature for 2 h. Acetohydrazide (1.18 g, 15.9 mmol) was introduced as a solid to the mixture and the resulting solution was stirred at room temperature for 3 h. The solution was then concentrated under vacuum to remove all dichloromethane and the residue was then taken up in 100 ml n-butanol which was heated to reflux in an oil bath set at 120° C. overnight. The solution was cooled to room temperature and concentrated under vacuum. The residue was purified silica gel chromatography eluting with 10% dichloromethane: in methanol to afford the title compound (454 mg, 11%). 1H NMR (500 MHz DMSO-d6) δ; 4.16-4.06 (m, 1H), 4.00-3.88 (m, 1H), 2.85-2.78 (m, 1H), 2.29 (s, 3H), 1.55 (dt, J=6.7, 13.9 Hz, 2H), 1.32 (dt, J=6.7, 14.0 Hz, 2H), 0.88 (t, J=7.5 Hz, 3H). LC-MS: m/z (ES)=196 (MH)+. rinsed in with 20 ml dichloromethane the resulting solution was stirred at room temperature for 3 h The solution was then concentrated under vacuum to remove all dichloromethane was heated to reflux in an oil bath set at 120° C. overnight The solution was cooled to room temperature concentrated under vacuum The residue was purified silica gel chromatography eluting with 10% dichloromethane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To sodium hydride in mineral oil (60%, 0.007 g, 0.33 mmol) was added tetrahydrofuran (1.8 mL) and the suspension was cooled to 0° C. Ethyl 2-oxopyrrolidine-3-carboxylate (0.044 g, 0.28 mmol) was added and the solution was stirred for 15 minutes. N-{3-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (0.100 g, 0.23 mmol) was dissolved in tetrahydrofuran (1.8 mL) and then added to the flask. The reaction was allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate, washed carefully with water, dried over magnesium sulfate, filtered and concentrated. The solid was purified by silica gel chromatography to yield ethyl 3-{[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-oxopyrrolidine-3-carboxylate (0.03 g, 27% yield). MS ESI: [M+H]+ m/z 505.7. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (d, J=5.2, 1H), 8.11 (s, 1H), 8.02-7.84 (m, 2H), 7.47 (s, 1H), 7.28 (d, J=5.2, 1H), 7.14 (s, 1H), 4.11 (q, J=7.4, 2H), 3.58 (in 1H), 3.28-3.21 (m, 2H), 3.15-3.03 (m, 1H), 2.66-2.54 (m, 1H), 2.31 (s, 3H), 2.27-2.16 (m, 1H), 1.15 (t, J=7.3, 3H). rhSYK activity=+++ added to the flask to warm to room temperature overnight washed carefully with water dried over magnesium sulfate filtered concentrated The solid was purified by silica gel chromatography