Reaction SMILES: C[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH2:7][CH2:2][CH2:3][C:4]([Cl:19])=[O:5])[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(CC(C)CC(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1cccc(CCCC(=O)Cl)c1
Temperature: 25 °C

Procedure:
The Grignard, hydrolysis, and catalytic hydrogenation procedures described herein are analogous to those described for the preparation of similar compounds as reported by D. L. Vander Jagt et. al. (J. Med. Chem., 1998, 41, 3879-3887), with modification. To a stirred ice-water cooled solution of ethyl-3-methyl-4-oxocrotonate (50.1 g, 0.352 mol) in anhydrous THF (200 mL) was slowly added dropwise 3-methoxyphenylmagnesium bromide (1 M in THF) (352 mL, 0.352 mol, 1.0 eq) between 0-10° C. under a N2. The ice-water bath was removed and the reaction mixture was stirred at RT for 1.5 h. The reaction mixture was poured slowly into a mixture of ice (650 g) and 6 N HCl (170 mL) and then extracted with Et2O. The organic phase was separated, washed with H2O followed by brine, dried over MgSO4, filtered, and the filtrate was concentrated to give 98.4 g of crude ethyl (2E)-4-hydroxy-3-methyl-4-[3-(methyloxy)phenyl]-2-butenoate. The crude intermediate ester was dissolved in EtOH (900 mL) and KOH (44.2 g, 0.788 mol) was added followed by H2O (200 mL). The reaction mixture was heated at reflux for 3 h and allowed to cool at RT. The EtOH was removed in vacuo and the basic aqueous mixture was diluted with H2O (500 mL) and then washed with Et2O. The basic aqueous mixture was cooled in an ice-water bath and the pH was adjusted to ˜2 (litmus paper) via the slow dropwise addition of 6 N HCl. The acidic aqueous mixture was extracted with EtOAc (2×). The organic extracts were combined, washed with H2O followed by brine, dried over MgSO4, filtered, and the filtrate was concentrated to give 74.14 g of crude (2E)-4-hydroxy-3-methyl-4-[3-(methyloxy)phenyl]-2-butenoic acid as a dark orange oil. The crude butenoic acid was reduced by catalytic hydrogenation in three batches as described below. To a parr hydrogenation bottle containing 10% palladium on carbon (1.0 g) was added a solution of the crude butenoic acid (24.13 g) in acetic acid (160 mL). The reaction mixture was hydrogenated at 25-30 psi over a 1 h period as the reaction mixture was warmed to 60° C. Once the temperature reached 60° C., the pressure of H2 was increased to 55 psi for 7 h. The reaction mixture was allowed to stand overnight at RT between 40-45 psi. The reaction mixture was filtered through a pad of celite. The pad was washed with EtOH (2×) and the filtrate was concentrated to give 18.61 g of crude 3-methyl-4-[3-(methyloxy)phenyl]butanoic acid as an oil. The remaining crude (2E)-4-hydroxy-3-methyl-4-[3-(methyloxy)phenyl]-2-butenoic acid was hydrogenated in a similar manner to give a total of 61.9 g of crude 3-methyl-4-[3-(methyloxy)phenyl]butanoic acid. To a solution of crude 3-methyl-4-[3-(methyloxy)phenyl]butanoic acid (18.6 g) in CH2Cl2 (400 mL) was slowly added oxalyl chloride (24 mL) with stirring at RT under N2. The reaction mixture was allowed to stir at RT overnight. The reaction mixture was concentrated in vacuo to give crude 4-[3-(methyloxy)phenyl]butanoyl chloride as an oil. The crude acid chloride was dissolved in CH2Cl2 (400 mL) and the solution was cooled in an ice-water bath. To the cold acid chloride solution was added AlCl3 (22.4 g, 0.168 mol) portionwise between 0-5° C. over a 1 h period. The reaction mixture was stirred for an additional 3 h and then slowly poured into 400 mL of cold 6 N HCl (cooled in an ice-water bath). The mixture was transferred to a separatory funnel and the organic phase was separated. The aqueous phase was extracted with CH2Cl2. The organic extracts were combined, carefully washed with saturated NaHCO3 followed by brine, dried over MgSO4, filtered, and the filtrate was concentrated to give 15.6 g of the crude title compound as a brown-orange oil. The remaining crude 3-methyl-4-[3-(methyloxy)phenyl]butanoic acid was treated in a similar manner to provide an additional 32.8 g of the crude title compound. The crude title compound (48.4 g) was purified by chromatography over SiO2 with hexanes:EtOAc (9:1) to give 19.2 g (29% from 3-methoxyphenylmagnesium bromide) of the title compound 12 as a pale yellow solid. 1H NMR (400 MHz; CDCl3): δ 1.13 (d, J=6.2 Hz, 3H), 2.22-2.38 (m, 2H), 2.65 (m, 2H), 2.93 (m, 1H), 3.85 (s, 3H), 6.69 (d, J=2.4 Hz, 1H), 6.82 (dd, J=2.5 Hz, 8.7 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H). HRMS (ESI) Calcd for C12H15O2: 191.1072 (M+H)+. Found: 191.1064.