Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH3:11])[CH:9]=O.[CH3:12][CH:13](C(O)=O)[C:14](O)=O.[CH3:20][O:21][C:22](=[O:26])[CH2:23][C:24]#[N:25].C[O-].[Na+]>ClCCCl>[CH3:7][N:8]([CH:9]=[C:13]([CH3:14])[CH:12]=[C:23]([C:24]#[N:25])[C:22]([O:21][CH3:20])=[O:26])[CH3:11]
Reactant: COC(=O)CC#N
Reactant: CN(C)C=O
Reactant: CC(C(=O)O)C(=O)O
Agent: C[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)C(C#N)=CC(C)=CN(C)C
Temperature: 2.5 °C
Reaction time: 1.75 h
Yield: 74.2 %

Procedure:
A solution of oxalyl chloride (32.8 g, 0.258 mol) in 1,2-dichloroethane (50 mL) was added dropwise to a stirred, cooled (0° C.) solution of dimethylformamide (43.2 g, 0.591 mol) in 1,2-dichloroethane (70 mL) so that the temperature of the reaction mixture did not exceed 10° C. The resulting mixture was stirred at 0-5° C. for a further 1.75 hours then allowed to reach room temperature. 2-Methylmalonic acid (14.0 g, 0.118 mol) was added to the stirred mixture. The mixture was stirred at reflux temperature for 6 hours then at room temperature overnight. The solvent was evaporated (keeping bath temperature at 25° C. or less) and replaced with dry methanol. Methylcyanoacetate (12.9 g, 0.130 mol) was added and the mixture was stirred. Sodium methoxide (86.6 mL, 25% in methanol) was added ensuring that the reaction mixture temperature did not exceed 30° C. The cooled mixture was stirred for 30 min. then at room temperature for 3.5 hours. T solvent was removed by evaporation and replaced with dichloroethane. The mixture was washed with water, dried and evaporated. The crude product was triturated with cold methanol (30 mL) to yield the desired methyl 5-(N,N-dimethylamino)-2-cyano-4-methylpent-2,4-dienoate (17.0 g, 66.0%) as a yellow solid. MP 163-164° C. Hydrogen chloride gas was bubbled through a suspension of methyl 5-(N,N-dimethylamino)-2-cyano-4-methylpent-2,4-dienoate (17.0 g, 0.078 mol) in 1,2-dichloroethane for 6 hours. Further saturation of the suspension with HCl gas was followed by stirring at room temperature overnight. Excess HCl was blown out of the reaction mixture with nitrogen gas. The mixture was washed with water, dried and evaporated. The resulting oil crystallized on standing to yield an orange solid (14.4 g, 99%). The orange solid (14.0 g, 0.0754 mol) in anhydrous methanol (40 mL) was added to a 250 mL dry flask with reflux condenser. Sodium methoxide (31 mL, 0.14 mol, 25% in methanol) was added to the solution and the reaction was carried out at reflux overnight. Acetic acid was added to the mixture until pH 7.0 and the methanol was removed. The residue was poured into water and extracted with dichloromethane. The organic layer was further washed with water, brine and dried over sodium sulfate. Dichloromethane was removed to yield the desired intermediate (13.5 g, 98.0%). The intermediate (8.65 g, 0.048 mol) was dissolved in dry carbon tetrachloride (80 mL) and NBS (8.95 g, 0.050 mol) was added. The reaction mixture was heated to reflux under a lamp for 3 hour. After cooling, the solvent Was removed and the residue was further washed with hot water to get ride of the succinimide. The solid was purified by column (DCM: ethyl acetate 30:1) to yield the desired intermediate (7.77 g, 62.2%). The intermediate (0.85 g, 0.00327 mol), pyrrolidine (0.93 g, 0.0131 mol) and anhydrous THF (10 mL) was heated to reflux for 2 hours. The solvent was evaporated. The residue was purified by column (ethyl acetate to ethyl acetate:MeOH 9:1) to give the desired advanced intermediate (0.60 g, 73.4%). 3,5-Dimethyl-4-hydroxyacetophenone (5.3 g, 0.032 mol) and dry DMF (12 mL) was charged in a 100 mL flask. Sodium hydride (1.28 g, 0.032 mol, 60% in mineral oil) was added followed by benzyl bromide (4.0 mL, 0.032 mol) and the reaction mixture was kept stirring for overnight. The reaction mixture was poured into water (150 mL) and dichloromethane (150 mL) was added. The organic phase was separated and further washed with water (3×120 mL), brine and dried over sodium sulfate. The DCM was removed and the desired compound was solidified and further washed with hexane to yield the desired building block (7.30 g, 89.7%). The advanced intermediate from above (0.60 g, 0.0024 mol) and the building block described above (0.61 g, 0.0024 mol) were added to a 50 mL flask with anhydrous DMF (5 mL). Sodium hydride (0.2 g, 60% in mineral oil) was added and the reaction mixture was kept overnight at room temperature. The mixture was poured into water (80 mL) and extracted with DCM (3×80 mL) after pH was adjusted to 7.0. The organic phase was further washed with water, brine and dried over sodium sulfate. Evaporation of the solvent left 1.0 g (88.2%) of the crude product. The crude product (1.0 g, 0.0021 mol) and pyridine hydrogen chloride (2.0 g, 0.0169 mol) were mixed in a 50 mL flask and heat to 190° C. for 4 h. The mixture was cooled and poured into methanol (8 mL), then filtered. The collected solid was further washed with ethyl acetate and dry to get the hydrochloride 2-(4-hydroxy-3,5-dimethylphenyl)-6-(pyrrolidin-1-ylmethyl)-4H-pyrano[2,3-b]pyridin-4-one dihydrochloride (0.50 g, 58.7%); MS (ES) m/z: 351.03 (M); MP 337-338° C.