[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12]N2C(=O)CCC2=O)=O)=[CH:6][C:5]=1[Cl:20].Cl.[OH:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28].C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([OH:23])[CH:25]=2)=[O:12])=[CH:6][C:5]=1[Cl:20]Crude 2-chloro-4-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]benzoic acid methyl ester (Example 73; ˜35 g, 0.1 mol) was charged to a 1 L round bottom flask equipped with a magnetic stirrer, ice cooling bath and a argon inlet tube, using dimethylformamide (350 mL) to complete the transfer. The mixture was cooled to about 10° C., then with stirring in an argon atmosphere, 3-hydroxybenzylamine hydrochloride salt (Example 69; 18.35 g, 0.115 mol) and triethylamine (35 mL, 0.25 mol) were added in rapid succession. A precipitate began to form immediately. After the reaction was stirred at ambient temperature overnight, the volatiles were removed under reduced pressure (<0.5 mm). The oily residue was taken up in ethyl acetate (600 mL) and washed in turn with 0.5N hydrochloric acid (400 mL), brine (300 mL), saturated sodium bicarbonate solution (2×300 mL) and brine (300 mL). Each aqueous layer was back-extracted in turn with ethyl acetate (2×300 mL), then the combined organic extracts were dried (MgSO4) and evaporated to give crude 2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoic acid methyl ester (˜32 g) as an off-white solid.
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