Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([NH:11][CH3:12])=[O:10])=[C:7]([CH3:13])[N:6]=[C:5]([O:14][CH3:15])[CH:4]=1.[Li]CCCC.[CH2:21]([O:28][C:29]1[C:36]([CH3:37])=[CH:35][C:32](C#N)=[CH:31][C:30]=1[CH3:38])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([O:28][C:29]1[C:36]([CH3:37])=[CH:35][C:32]([C:12]2[NH:11][C:9](=[O:10])[C:8]3[C:3]([O:2][CH3:1])=[CH:4][C:5]([O:14][CH3:15])=[N:6][C:7]=3[CH:13]=2)=[CH:31][C:30]=1[CH3:38])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cc(C#N)cc(C)c1OCc1ccccc1
Reactant: CNC(=O)c1c(OC)cc(OC)nc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCc4ccccc4)c(C)c3)cc2n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
A solution of 4,6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g, 157 mmol) in phosphorus oxychloride (60 mL, 629 mmol) was stirred at reflux for 1.5 hours. The extra phosphorus oxychloride was removed using a rotary evaporator and the reaction mixture was purred into icy water. The solid was removed by filtration. The filtrate was extracted with dichloromethane (3×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column (SiO2, Hexanes/EtOAc=5:1) to yield 4,6-dichloro-2-methyl nicotinic acid ethyl ester (16.9 g, 46%). A solution of 4,6-dichloro-2-methyl nicotinic acid ethyl ester (16.9 g, 71.3 mmol) in MeOH (60 mL) was mixed with sodium methoxide (58 mL, 257 mmol) and stirred at reflux for 12 hours. The reaction was quenched by adding AcOH (50 mL), diluted with water (200 mL), extracted with dichloromethane (3×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column (SiO2, Hexanes/EtOAc=6:1) to yield 4,6-dimethoxy-2-methyl nicotinic acid methyl ester (10 g, 67%). A solution of 4,6-dimethoxy-2-methyl nicotinic acid methyl ester (2.6 g, 12.3 mmol) and lithium hydroxide (1.0-6 g 44.1 mmol) in water (40 mL), MeOH (30 mL) and THF (20 mL) was stirred at reflux for 4 hours. The reaction mixture was concentrated using a rotary evaporator to dryness. The residue was mixed with HCl (conc.) (20 mL) and was concentrated again on high vacuum to dryness to yield crude 4,6-dimethoxy-2-methyl nicotinic acid (quantitative). To a solution of 4,6-dimethoxy-2-methyl nicotinic acid (2.5 g, 12.0 mmol) in dichloromethane (50 mL) and THF (50 mL) at room temperature was added oxalyl chloride (2.57 mL, 29.4 mmol) and DMF (3 drops). The reaction mixture was stirred at room temperature for 30 min, concentrated to dryness using a rotary evaporator to afford 4,6-dimethoxy-2-methyl nicotinic acid chloride HCl salt (2.8 g). A solution of 4,6-dimethoxy-2-methyl nicotinic acid chloride HCl salt (8.5 g, 33.73 mmol) in dichloromethane (20 mL) and THF (20 mL) at room temperature was mixed with methylamine in THF (50 mL, 98 mmol) and stirred at 20° C. for 1 hour. The reaction mixture was diluted with water (100 mL), extracted with dichloromethane (3×100 mL), and concentrated using a rotary evaporator to yield 4,6-dimethoxy-2,N-dimethyl-nicotinamide (4.2 g, 66%) as a light yellow solid. A solution of 4-hydroxy-3,5-dimethylbenzonitrile (2 g, 13.6 mmol) in DMF (20 mL) at room temperature was mixed with sodium hydride (0.706 g, 17.6 mmol) and stirred for 30 min. Benzyl bromide (1.62 mL, 13.59 mmol) was then added and the reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched by adding water (200 mL), extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column (SiO2, Hexanes/EtOAc=6:1) to yield 4-benzyloxy-3,5-dimethylbenzonitrile (3.25 g, 100%) as a white solid. To a solution of 4,6-dimethoxy-2,N-dimethyl-nicotinamide (0.54 g, 2.57 mmol) in THF (50 mL) at −20° C. was added n-BuLi (3.54 mL, 5.67 mmol). The reaction was stirred at −20° C.˜0° C. for 2 hours and then was cooled to −78° C. At −78° C. 4-benzyloxy-3,5-dimethylbenzonitrile (0.49 g, 2.057 mmol) was added, the cooling bath was removed, and the reaction was allowed to warm up gradually to room temperature. After stirring at room temperature for 14 hours the reaction was quenched by adding water (100 mL), extracted with dichloromethane (×3×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column (SiO2, Hexanes/EtOAc=1:5) to yield 7-(4-benzyloxy-3,5-dimethyl-phenyl)-2,4-dimethoxy-6H-[1,6]naphthyridin-5-one (0.32 g, 37%). A solution of 7-(4-benzyloxy-3,5-dimethyl-phenyl)-2,4-dimethoxy-6H-[1,6]naphthyridin-5-one (0.25 g, 0.6 mmol) in dichloromethane (100 mL) was mixed with BBr3 (3 mL, 3 mmol) and stirred at room temperature for 16 hours. The reaction was quenched by adding water (20 mL). The resulting solid was collected by filtration, washed with water and DCM to yield a light yellow solid. This solid was mixed with HCl in ether (10 mL, 10 mmol), stirred for 1 hour, filtered to afford 2-hydroxy-7-(4-hydroxy-3,5-dimethylphenyl)-4-methoxy-1,6-naphthyridin-5(6H)-one (70 mg, 37%) as a light yellow dihydrochloride. MS (ES) m/z 312 (M); MP >330° C.