tert-butyl 2-cyanoacetate

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

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

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: To a suspension of NaH (60%, 0.056 g, 1.39 mmol) in TBF (3 mL) was added a solution of t-butyl cyanoacetate (0.197 g, 1.392 mmol) in THF (1 mL) in one portion. After 10 min, a solution of 1-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)-oxy]phenyl}-3,3-bis(methylsulfanyl)-2-propene-1-one (0.500 g, 1.16 mmol) in THF (3 mL) was added followed by dibenzo-18-crown-6 (0.013 g, 0.035 mmol). The resulting mixture was refluxed for 4 hrs. After cooled to room temperature, the mixture was partitioned between 0.1 N acetic acid solution and CH2Cl2. The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residual oil was dissolved in 1,2-dichloroethane (1 mL) and acetic acid (1 mL), and ammonium acetate (1.20 g, 15.57 mmol) was added. The mixture was stirred at 120° C. for 0.5 hrs. After cooled to room temperature, the mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic phase was washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (hexane/ethyl acetate 4:1 to 3:1) gave tert-butyl 2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-4-(methyl-sulfanyl)nicotinate as an pale yellow oil (0.177 g, yield; 29%). The resulting mixture was refluxed for 4 hrs the mixture was partitioned between 0.1 N acetic acid solution and CH2Cl2 The organic phase was separated dried over Na2SO4 filtered concentrated under reduced pressure The residual oil was dissolved in 1,2-dichloroethane (1 mL) After cooled to room temperature the mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution The organic phase was washed with saturated aqueous NaHCO3 solution and brine dried over Na2SO4 filtered concentrated under reduced pressure Purification by column chromatography on silica gel (hexane/ethyl acetate 4:1 to 3:1)

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

Procedure: A mixture of the starting compound 1A (3.000 g, 13.258 mmol), N-tert-butoxycarbonyl-phenylalaninal (3.305 g, 13.258 mmol), tert-butyl cyanoacetate (1.872 g, 13.258 mmol), ammonium acetate (3.066 g, 39.774 mmol) and 1,2-dimethoxyethane (5.0 mL) was heated at reflux for 6 hrs. After cooled to room temperature, the mixture was extracted with ethyl acetate and saturated NaHCO3 solution. The separated organic phase was washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with diisopropyl ether to give tert-butyl 2-amino-6-[2-(benzyloxy)phenyl]-4-{1-[(tert-butoxycarbonyl)amino]-2-phenylethyl}-1,4-dihydro-3-pyridinecarboxylate as a yellow solid (1.281 g, yield; 16%). was heated at reflux for 6 hrs the mixture was extracted with ethyl acetate and saturated NaHCO3 solution The separated organic phase was washed with water and brine successively dried over Na2SO4 filtered concentrated under reduced pressure The residue was triturated with diisopropyl ether

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-[2,6-bis(benzyloxy)phenyl]ethanone (8.00 g, 24.067 mmol) (starting compound 1E), tert-butyl 3-formyl-1-piperidinecarboxylate (5.133 g, 24.067 mmol) (starting compound 2B), tert-butylcyanoacetate (3.398 g, 24.067 mmol), and ammonium acetate (5.432 g, 72.202 mmol) in 1,2-dimethoxyethane (24 mL) was stirred at 100° C. in a sealed tube overnight. After cooled to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The separated organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was diluted with 30 mL of dichloromethane, and MnO2 was added to the mixture, and then the mixture was stirred at room temperature for 5 hrs. The mixture was filtered on Celite®, and concentrated under reduced pressure. The resulting residue (liquid) was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give tert-butyl 2-amino-6-[2,6-bis(benzyloxy)phenyl]-4-[1-(tert-butoxycarbonyl)-3-piperidinyl]nicotinate as a pale yellow oil. (2.5 g, yield; 16%) After cooled to room temperature the reaction mixture was partitioned between ethyl acetate and water The separated organic phase was washed with brine dried over MgSO4 filtered concentrated under reduced pressure The residue was diluted with 30 mL of dichloromethane, and MnO2 was added to the mixture the mixture was stirred at room temperature for 5 hrs The mixture was filtered on Celite® concentrated under reduced pressure The resulting residue (liquid) was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1)

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

Procedure: A mixture of the starting compound 1A (3.500 g, 15.47 mmol), starting compound 2B (3.299 g, 15.47 mmol), tert-butyl cyanoacetate (2.184 g, 15.47 mmol), ammonium acetate (3.577 g, 46.40 mmol) and 1,2-dimethoxyethane (17 mL) was heated at reflux for 3.5 hrs. After cooled to room temperature, the mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane: ethyl acetate, 4:1) to give tert-butyl 2-amino-6-[2-(benzyloxy)phenyl]-4-[1-(tert-butoxycarbonyl)-3-piperidinyl]nicotinate. (1.892 g, yield; 22%). was heated at reflux for 3.5 hrs the mixture was concentrated under reduced pressure the residue was partitioned between ethyl acetate and water The separated organic phase was washed with brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (hexane: ethyl acetate, 4:1)

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

Procedure: A solution of 1-{2-[(4-methoxybenzyl)oxy]phenyl}ethanone (14.2 g, 55.4 mmol)(starting compound 1D), benzyl 3-formyl-1-piperidinecarboxylate (13.7 g, 55.4 mmol)(starting compound 2C), tert-butyl cyanoacetate (7.8 g, 55.4 mmol), and ammonium acetate (9.8 g, 166.1 mmol) in 1,2-dimethoxyethane (60 mL) was stirred under reflux for 3.5 hrs. After cooled to room temperature, the mixture was partitioned between ethyl acetate and water. The separated organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane, 1:2) to give tert-butyl 2-amino-4-{1-[(benzyloxy)carbonyl]-3-piperidinyl}-6-{2-[(4-methoxybenzyl)oxy]phenyl}nicotinate as a pale yellow oil (4.89 g, yield; 14%). under reflux for 3.5 hrs the mixture was partitioned between ethyl acetate and water The separated organic phase was washed with water and brine dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by column chromatography on silica gel (ethyl acetate:hexane, 1:2)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromobenzothiophene (1 eq.) in DME were added tert-butyl cyanoacetate (1.1 eq.) and t-BuOK (2 eq.). The reaction was refluxed for 40 min. Thereto were added dichlorobis(triphenylphosphine)palladium(II) (0.02 eq.) and triphenylphosphine (0.06 eq.). The resulting mixture was refluxed for 1.5 h under argon and then cooled to 20° C. Aqueous HCl (6N) was added dropwise until pH=1 and the reaction mixture was partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/DCM: 9/1 to 1/1) to afford benzo[b]thiophen-4-yl-cyano-acetic acid tert-butyl ester. The reaction was refluxed for 40 min The resulting mixture was refluxed for 1.5 h under argon the reaction mixture was partitioned between water and EtOAc The organic layer was separated dried over MgSO4 filtered concentrated under reduced pressure The crude was purified by chromatography on silica gel (elution with heptane/DCM: 9/1 to 1/1)

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

Procedure: Into a 100-ml eggplant-shaped flask equipped with a magnetic stirrer and a reflux condenser were added 6.08 g (44 mmol) of potassium carbonate, 4.36 g (20 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine, 3.11 g (22 mmol) of tert-butyl cyanoacetate and 10 ml of N,N-dimethylformamide. The system inside was purged with nitrogen and stirred for 2 hours at 60° C. and for 4 hours at 70° C. The reaction slurry was cooled to room temperature and poured into 30 ml of a 5% aqueous hydrochloric acid solution. Thereto was added 50 ml of water, and concentrated hydrochloric acid was dropped until the system became acidic, followed by sufficient stirring. Then, filtration and washing with 30 ml of water were conducted. The crystals obtained were dried to obtain tert-butyl 2-cyano-2-(4,6-dimethoxypyrimidin-2-yl)acetate as white crystal of 5.4 g. HPLC purity: 99.3% Yield: 97% Into a 100-ml eggplant-shaped flask equipped with a magnetic stirrer and a reflux condenser The system inside was purged with nitrogen The reaction slurry was cooled to room temperature poured into 30 ml of a 5% aqueous hydrochloric acid solution Thereto was added 50 ml of water, and concentrated hydrochloric acid was dropped until the system Then, filtration washing with 30 ml of water The crystals obtained were dried

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 2-cyanoacetate (4.0 g, 28.3 mmol), 1,3-dibromopropane (6.29 g, 31.2 mmol) in methyl ethyl ketone (100 ml) was treated with potassium carbonate (11.75 g, 85 mmol). The reaction mixture was heated to 80° C. for 17 h and then NaI (catalyst) (0.21 g, 1.42 mmol) was added. The mixture was heated at 80° C. for 6 days and then allowed to cool to RT. The mixture was filtered through Celite® (filter material) and the filtrate was concentrated in vacuo. Purification by chromatography on silica eluting with 10% EtOAc in iso-hexane afforded the title product as a colourless oil; 1H NMR (400 MHz, CDCl3) δ 2.64 (4H, m), 2.22 (2H, m), 1.53 (9H, s). The mixture was heated at 80° C. for 6 days to cool to RT The mixture was filtered through Celite® (filter material) the filtrate was concentrated in vacuo Purification by chromatography on silica eluting with 10% EtOAc in iso-hexane