6-methoxy-2,3,4,5-tetrahydropyridine

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

Procedure: Following the procedure of Example 1, only substituting for cis-2-phenylcyclopentylamine hydrochloride and O-methylcaprolactim, appropriate amounts of cis-2-(cyclohexyl)cyclopentylamine hydrochloride and O-methylvalerolactim respectively the desired product was obtained. M.P. 195.5°-197° C.

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

Procedure: Following the procedure of Example 1, only substituting for cis-2-phenylcyclopentylamine hydrochloride and O-methylcaprolactim, appropriate amounts of cis-2-(cyclohexyl)cyclopentylamine hydrochloride and O-methylvalerolactim respectively the desired product was obtained. M.P. 195.5°-197° C.

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

Procedure: Following the procedure of Example 23, only substituting for cis-2-phenylcyclopentylamine hydrochloride and O-methylcaprolactim, appropriate amounts of cis-2-(cyclohexyl)cyclopentylamine hydrochloride and O-methylvalerolactim respectively the desired product is obtained, M.P. 195.5°-197° C.

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

Procedure: Following the procedure of Example 23, only substituting for cis-2-phenylcyclopentylamine hydrochloride and O-methylcaprolactim, appropriate amounts of cis-2-(cyclohexyl)cyclopentylamine hydrochloride and O-methylvalerolactim respectively the desired product is obtained, M.P. 195.5°-197° C.

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

Procedure: Following the procedure of Example 1, only substituting for cis-2-phenylcyclopentylamine hydrochloride and O-methylcaprolactim, appropriate amounts of cis-2-(cyclohexyl)cyclopentylamine hydrochloride and O-methylvalerolactim respectively the desired product was obtained. M.P. 195.5°-197° C.

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,3,4,5-tetrahydro-6-methoxypyridine (1.1 g, 9.72 mmol) and cyanoacetic acid methyl ester (1 g, 10.1 mmol) in 40 mL THF was heated at 70° C. overnight. The reaction was cooled, and solvent was removed in vacuo. The resulting residue was purified on flash column to afford cyano-2-piperidinylidene-ethanoic acid methyl ester (1.4 g, 80%). The reaction was cooled solvent was removed in vacuo The resulting residue was purified on flash column

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

Procedure: 6-Methoxy-2,3,4,5-tetrahydropyridine (102.7 g, 0.91 mole) was added over 25 min to a solution of lithium diisopropylamine (1.8 M, 505 mL, 0.91 mole) in THF (1.2 L) stirring at −60° C. under nitrogen. After stirring at −60° C. for 1 h, methyl 3-(4-fluorophenyl)-2-isobutyrylacrylate (175 g, 0.70 mole) was added over 75 min keeping the temperature below −50° C. The reaction was quenched with saturated ammonium chloride (750 mL) after the reaction had stirred at −60° C. for 35 min. After the reaction mixture had warmed to room temperature, ethyl acetate was added and the mixture transferred to a separatory funnel. The mixture was extracted with ethyl acetate (2×1 L). The combined organic layers were washed with 50% saturated ammonium chloride solution, water, and brine; dried over magnesium sulfate; and concentrated in vacuo to afford methyl 2-[(4-fluorophenyl)-(2-methoxy-3,4,5,6-tetrahydro-pyridin-3-yl)-methyl]-4-methyl-3-oxo-pentanoate (271 g). After stirring at −60° C. for 1 h the temperature below −50° C The reaction was quenched with saturated ammonium chloride (750 mL) after the reaction had stirred at −60° C. for 35 min After the reaction mixture had warmed to room temperature ethyl acetate was added the mixture transferred to a separatory funnel The mixture was extracted with ethyl acetate (2×1 L) The combined organic layers were washed with 50% saturated ammonium chloride solution, water, and brine dried over magnesium sulfate and concentrated in vacuo

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,3,4,5-tetrahydro-6-methoxypyridine (1.1 g, 9.72 mmol) and cyanoacetic acid methyl ester (1 g, 10.1 mmol) in 40 mL THF was heated at 70° C. overnight. The reaction was cooled, and solvent was removed in vacuo. The resulting residue was purified on flash column to afford cyano-2-piperidinylidene-ethanoic acid methyl ester (1.4 g, 80%). The reaction was cooled solvent was removed in vacuo The resulting residue was purified on flash column

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

Procedure: 6-Methoxy-2,3,4,5-tetrahydropyridine (102.7 g, 0.91 mole) was added over 25 min to a solution of lithium diisopropylamine (1.8 M, 505 mL, 0.91 mole) in THF (1.2 L) stirring at −60° C. under nitrogen. After stirring at −60° C. for 1 h, methyl 3-(4-fluorophenyl)-2-isobutyrylacrylate (175 g, 0.70 mole) was added over 75 min keeping the temperature below −50° C. The reaction was quenched with saturated ammonium chloride (750 mL) after the reaction had stirred at −60° C. for 35 min. After the reaction mixture had warmed to room temperature, ethyl acetate was added and the mixture transferred to a separatory funnel. The mixture was extracted with ethyl acetate (2×1 L). The combined organic layers were washed with 50% saturated ammonium chloride solution, water, and brine; dried over magnesium sulfate; and concentrated in vacuo to afford methyl 2-[(4-fluorophenyl)-(2-methoxy-3,4,5,6-tetrahydro-pyridin-3-yl)-methyl]-4-methyl-3-oxo-pentanoate (271 g). After stirring at −60° C. for 1 h the temperature below −50° C The reaction was quenched with saturated ammonium chloride (750 mL) after the reaction had stirred at −60° C. for 35 min After the reaction mixture had warmed to room temperature ethyl acetate was added the mixture transferred to a separatory funnel The mixture was extracted with ethyl acetate (2×1 L) The combined organic layers were washed with 50% saturated ammonium chloride solution, water, and brine dried over magnesium sulfate and concentrated in vacuo

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

Procedure: A solution of 33.9 g of (1A) and 36.6 g of nitromethane was refluxed for 3 days, cooled and quenched in one liter of cold ether. Filtration gave a solid crude product, m.p. 79° - 81°. Evaporation of the filtrate and trituration of the residue with cold ether give additional crude product. The crude product was continuously extracted from a Soxhlet thimble with ether for 18 hours, after which time only a small amount of dark oil remained. The solvent pot (not containing crystallized product) was cooled and the solid product was filtered, giving 2-(nitromethylene)piperidine (1B), as a pale yellow solid, m.p.: 80.5°-81°. cooled quenched in one liter of cold ether Filtration gave a solid crude product, m.p. 79° - 81° Evaporation of the filtrate and trituration of the residue with cold ether give additional crude product The crude product was continuously extracted from a Soxhlet thimble with ether for 18 hours The solvent pot (not containing crystallized product) was cooled the solid product was filtered

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

Procedure: A solution of 33.9 g of (1A) and 36.6 g of nitromethane was refluxed for 3 days, cooled and quenched in one liter of cold ether. Filtration gave a solid crude product, m.p. 79° - 81°. Evaporation of the filtrate and trituration of the residue with cold ether give additional crude product. The crude product was continuously extracted from a Soxhlet thimble with ether for 18 hours, after which time only a small amount of dark oil remained. The solvent pot (not containing crystallized product) was cooled and the solid product was filtered, giving 2-(nitromethylene)piperidine (1B), as a pale yellow solid, m.p.: 80.5°-81°. cooled quenched in one liter of cold ether Filtration gave a solid crude product, m.p. 79° - 81° Evaporation of the filtrate and trituration of the residue with cold ether give additional crude product The crude product was continuously extracted from a Soxhlet thimble with ether for 18 hours The solvent pot (not containing crystallized product) was cooled the solid product was filtered

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-methoxy-2,3,4,5-tetrahydropyridine (0.431 g, 3.80 mmol) was dissolved in THF (5 mL) in a 40 mL screw-cap vial and 2-(3,4-difluorophenyl)oxazol-5(4H)-one (0.75 g, 3.80 mmol) in THF (5 mL) was added, producing an orange solution. The vial was capped and heated to 90° C. for 3 hours. THF was removed under reduced pressure and the residue was dissolved in MeOH (10 ml) and lithium hydroxide monohydrate (0.479 g, 11.41 mmol) in water (1 mL) was added. The reaction was heated to 90° C. for 3 hours. MeOH was removed by evaporation under reduced pressure. The remaining aqueous solution was diluted with water (5 mL) and acidified to pH 2 with 5M HCl. The solution was extracted with EtOAc (3×5 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated to yield the desired product as a brown oil (742 mg, 71%) that was used without further purification. LCMS (+ESI) m/z: 279.3 [M+H]+. screw-cap vial producing an orange solution The vial was capped THF was removed under reduced pressure the residue was dissolved in MeOH (10 ml) The reaction was heated to 90° C. for 3 hours MeOH was removed by evaporation under reduced pressure The remaining aqueous solution was diluted with water (5 mL) The solution was extracted with EtOAc (3×5 mL) The combined organic extracts were dried over anhydrous sodium sulfate filtered evaporated