3-O-tert-butyl 1-O-methyl propanedioate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A mixture of pyridine-3-carboxaldehyde (2.72 g), propanedioic acid, 1,1-dimethylethyl methyl ester (4.42 g), piperidine (0.173 g) and benzoic acid (0.155 g) in benzene (100 ml) was heated at reflux with removal of water to a Dean-Stark trap for 12 hours. The cooled mixture was washed with bicarbonate solution, concentrated under vacuum and the residue was purified by column chromatography, eluting with ethyl acetate-hexane (3:7) to afford racemic 2-pyridin-3-ylmethylene-malonic acid tert-butyl ester methyl ester as an oil (3.21 g). was heated The cooled mixture was washed with bicarbonate solution concentrated under vacuum the residue was purified by column chromatography eluting with ethyl acetate-hexane (3:7)

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

Procedure: A mixture of pyridine-3-carboxaldehyde (2.72 g), propanedioic acid, 1,1-dimethylethyl methyl ester (4.42 g), piperidine (0.173 g) and benzoic acid (0.155 g) in benzene (100 ml) was heated at reflux with removal of water to a Dean-Stark trap for 12 hours. The cooled mixture was washed with bicarbonate solution, concentrated under vacuum and the residue was purified by column chromatography, eluting with ethyl acetate-hexane (3:7) to afford racemic 2-pyridin-3-ylmethylene-malonic acid tert-butyl ester methyl ester as an oil (3.21 g). was heated The cooled mixture was washed with bicarbonate solution concentrated under vacuum the residue was purified by column chromatography eluting with ethyl acetate-hexane (3:7)

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

Procedure: To a suspension of sodium hydride (0.752 g, 29.8 mmol) in THF (18 mL) under nitrogen was added dropwise a solution of tert-butyl methyl malonate (3.18 mL, 17.9 mmol) in dry THF (15 mL) via syringe during a period of 15 min. The reaction mixture was stirred for 30 min before a solution of 2-chloro-5-(trifluoromethyl)nicotinonitrile (4.0 g, 14.5 mmol) in THF (30 mL) was added slowly. After being stirred at room temperature overnight, the reaction mixture was quenched with aqueous NH4Cl. THF was removed in vacuo and the aqueous solution was extracted with EtOAc three times. The combined organic layers were dried over MgSO4, filtered, and evaporated in vacuo. The crude brown product (7.1 g) was purified by flash chromatography (10:90 EtOAc/hexanes) to afford 4.20 g (84%) of desired product as a yellow oil. LC-MS calculated for C15H15F3N2O4: (M+H)+345; found 245.0 (M−CO2tBu+H+1)+. was added slowly the reaction mixture was quenched with aqueous NH4Cl THF was removed in vacuo the aqueous solution was extracted with EtOAc three times The combined organic layers were dried over MgSO4 filtered evaporated in vacuo The crude brown product (7.1 g) was purified by flash chromatography (10:90 EtOAc/hexanes)

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

Procedure: To a suspension of sodium hydride (0.752 g, 29.8 mmol) in THF (18 mL) under nitrogen was added dropwise a solution of tert-butyl methyl malonate (3.18 mL, 17.9 mmol) in dry THF (15 mL) via syringe during a period of 15 min. The reaction mixture was stirred for 30 min before a solution of 2-chloro-5-(trifluoromethyl)nicotinonitrile (4.0 g, 14.5 mmol) in THF (30 mL) was added slowly. After being stirred at room temperature overnight, the reaction mixture was quenched with aqueous NH4Cl. THF was removed in vacuo and the aqueous solution was extracted with EtOAc three times. The combined organic layers were dried over MgSO4, filtered, and evaporated in vacuo. The crude brown product (7.1 g) was purified by flash chromatography (10:90 EtOAc/hexanes) to afford 4.20 g (84%) of desired product as a yellow oil. LC-MS calculated for C15H15F3N2O4: (M+H)+345; found 245.0 (M−CO2tBu+H+1)+. was added slowly the reaction mixture was quenched with aqueous NH4Cl THF was removed in vacuo the aqueous solution was extracted with EtOAc three times The combined organic layers were dried over MgSO4 filtered evaporated in vacuo The crude brown product (7.1 g) was purified by flash chromatography (10:90 EtOAc/hexanes)

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

Procedure: Tert-butyl {[5-(benzyloxy)pyridin-3-yl](phenylsulfonyl)methyl}carbamate (2.2 g, 4.84 mmol) was suspended in a toluene (16.5 mL) water (13 mL) mixture. At 0° C. tert-butyl methyl malonate (1.0 mL, 5.8 mmol), cesium carbonate (1.58 g, 4.84 mmol) and 1-[3,5-bis(trifluoromethy)phenyl]-3-[(1R,2R)-(−)-2-(dimethylamino)cyclohexyl]thiourea (200 mg, 0.48 mmol) was added and the mixture was stirred for 48 hours at 0° C. After storage at 5° C. for 72 hours the mixture was diluted with water and ethyl acetate, the phases were separated and the aqueous phase extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate in hexane 0% to 60%) to yield 1.54 g of enantiomerically enriched tert-butyl methyl 2-{(1S)-[5-(benzyloxy)pyridin-3-yl][(tert-butoxycarbonyl)amino]methyl}propanedioate. the phases were separated the aqueous phase extracted with ethyl acetate The combined extracts were dried over sodium sulfate concentrated The residue was purified by chromatography on silica gel (ethyl acetate in hexane 0% to 60%)

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

Procedure: Tert-butyl {[3-(benzyloxy)phenyl](phenylsulfonyl)methyl}carbamate (3.0 g, 5.93 mmol) was suspended in a toluene (21.6 mL) water (16 mL) mixture. At 0° C. tert-butyl methyl malonate (1.2 mL, 7.1 mmol), cesium carbonate (1.94 g, 5.9 mmol) and 1-[3,5-bis(trifluoromethy) phenyl]-3-[(1R,2R)-(−)-2-(dimethylamino)cyclohexyl]thiourea (246 mg, 0.59 mmol) was added and the mixture was stirred for 72 hours at 0° C. After storage at −20° C. for 72 hours the mixture was diluted with water and ethyl acetate, after filtration the phases were separated and the aqueous phase extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate in hexane 0 to 35%) to yield 2.17 g of enantiomerically enriched tert-butyl methyl 2-{(1S)-[3-(benzyloxy)phenyl][(tert-butoxycarbonyl)amino]methyl}propanedioate. after filtration the phases were separated the aqueous phase extracted with ethyl acetate The combined extracts were dried over sodium sulfate concentrated The residue was purified by chromatography on silica gel (ethyl acetate in hexane 0 to 35%)

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

Procedure: Sodium hydride (60%, mineral oil; 0.985 g) was suspended in dimethylformamide (20 mL), and a solution of tert-butyl methyl malonate (4.29 g) in dimethylformamide (5 mL) was added dropwise thereto under ice-cooling. After foam generation is stopped, a solution of 2-bromo-4-fluoro-1-nitrobenzene (2.71 g) in dimethylformamide (5 mL) was added dropwise thereto at the same temperature, and the mixture was further stirred at 60° C. for 3 hours, and then concentrated. The residue was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel with ethyl acetate:hexane=1:4 to 1:5 to give the title compound (7.54 g) as an oil. under ice-cooling concentrated extracted with ethyl acetate The extract was washed with saturated brine dried over sodium sulfate concentrated The residue was purified by column chromatography on silica gel with ethyl acetate

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

Procedure: Sodium hydride (350 mg) was dissolved in dimethylformamide (10 mL)), and the solution was cooled to 0° C. After addition of tert-butyl methyl malonate (1.52 g), the mixture was stirred for one hour, and the 5-chloro-N,N-dimethyl-2-nitrobenzamide (1.0 g) obtained in Example 2a) was added thereto. The mixture was stirred at 70° C. for 4.5 hours and water was added thereto. The resulting solution was concentrated, diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and purified by column chromatography on silica gel with ethyl acetate:hexane=1:1 to give the title compound (1.29 g). The mixture was stirred at 70° C. for 4.5 hours The resulting solution was concentrated diluted with ethyl acetate washed with water The organic layer was dried over sodium sulfate purified by column chromatography on silica gel with ethyl acetate

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

Procedure: A mixture of pyridine-3-carboxaldehyde (2.72 g), propanedioic acid, 1,1-dimethylethyl methyl ester (4.42 g), piperidine (0.173 g) and benzoic acid (0.155 g) in benzene (100 ml) was heated at reflux with removal of water to a Dean-Stark trap for 12 hours. The cooled mixture was washed with bicarbonate solution, concentrated under vacuum and the residue was purified by column chromatography, eluting with ethyl acetate-hexane (3:7) to afford racemic 2-pyridin-3-ylmethylene-malonic acid tert-butyl ester methyl ester as an oil (3.21 g). was heated The cooled mixture was washed with bicarbonate solution concentrated under vacuum the residue was purified by column chromatography eluting with ethyl acetate-hexane (3:7)

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

Procedure: To a suspension of sodium hydride (7.8 g, 200 mmol) in tetrahydrofuran (100 mL) under nitrogen was added dropwise a solution of tert-butyl methyl malonate (20 mL, 120 mmol) in anhydrous tetrahydrofuran (100 mL) via syringe. The reaction mixture was stirred for 0.5 h before a solution of the intermediate prepared in Step D above (20.1 g, 97.6 mmol) in tetrahydrofuran (200 mL) was added slowly via syringe. The reaction was stirred at room temperature overnight, then quenched with a saturated solution of ammonium chloride. The organic layer was separated and the aqueous layer was extracted with three portions of ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo. Flash chromatography afforded the title compound. 1H NMR (500 MHz, CDCl3) δ 9.03 (d, J=1.5 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 5.25 (s, 1H), 3.86 (s, 3M), 1.52 (s, 9H). was added slowly via syringe quenched with a saturated solution of ammonium chloride The organic layer was separated the aqueous layer was extracted with three portions of ethyl acetate The combined organic layers were washed with water dried over sodium sulfate concentrated in vacuo