Thus, the novel HNE inhibitors reported here represent potential starting points for future manipulation and optimization. Supplementary Material Supplemental MaterialClick here to view.(230K, docx) Footnotes Supplementary material available online Supplementary material, Figures S1CS6. Declaration of interest This work was supported in part by NIH IDeA Program COBRE Grant GM110732 (MTQ) and a USDA National Institute of Food and Agriculture Hatch project, and the Montana State University Agricultural Experiment Station.. CO= 7.2 Hz), 7.44 (t, 1H, Ar, = 6.8 Hz), 7.51 (d, 1H, Ar, = 7.6 Hz), 7.69 (d, 1H, Ar, = 8.0 Hz). ESI-MS calcd. for C15H19N3O3, 289.33; found: 290.05 [M + H]+. Ethyl 1-(cyclopropanecarbonyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (4) To a cooled (0 C) suspension of 330 (1.40 mmol) in anhydrous CH2Cl2 (2 mL), Et3N (0.1 mL) and 4.2 mmol of cyclopropanecarbonyl chloride were added. The mixture was stirred at 0 C for 2 h and then at room heat for an additional 2 h. The solvent was evaporated, cold water was added, and the mixture was neutralized with 0.5 N NaOH. The reaction mixture was extracted with CH2Cl2 (3 15 mL), the solvent was dried over sodium sulfate, evaporated 1.23C1.28 (m, 2H, cyclopropyl), 1.33C1.38 (m, 2H, cyclopropyl), 1.46 (t, 3H, OCH2= 7.2 Hz), 3.20C3.25 (m 1H, cyclopropyl) 4.52 (q, 2H, O= 7.2 Hz), 7.57 (t, 1H, Ar, = 7.6 Hz), 7.81 (t, 1H, Ar, = 7.2 Hz), 8.38 (d, 1H, Ar, = 9.6 Hz), 8.87 (d, 1H, Ar, = 8.8 Hz). ESI-MS calcd. for C15H14N2O4, 286.28; found: 287.10 [M + H]+. Ethyl 1-methyl-4-oxo-1,4-dihydrocinnoline-3-carboxylate (5) A mixture of 0.23 mmol of 330, 0.34 mmol of Na2CO3, and 1.15 mmol of CH3I in 1 mL of anhydrous CH3CN was refluxed for 6 h. After cooling, the precipitate was filtered, the solvent was evaporated 1.31 (t, 3H, OCH2= 7.2 Hz), 4.16 (s, 3H, CH3), 4.32 (q, 2H, O= 7.2 Hz), 7.62 (t, 1H, Ar, = 7.6 Hz), 7.89 (d, 1H, Ar, = 8.8 Hz), 7.95 (t, 1H, Ar, = 8.4 Hz), 8.19 (d, 1H, Ar, = 8.0 Hz). 13C NMR (DMSO-d6) 14.58 (CH3), 31.16 (CH), 44.94 (CH3), 61.47 (CH2), 117.85 (CH), 125.28 (CH), 126.34 (C), 127.0 (CH), 134.88 (CH), 138.84 (CH), 141.24 (C). IR: 1590 cm?1 (C = O ester), 1693 cm?1 (C = O). ESI-MS calcd. for C12H12N2O3, 232.24; found: 233.09 [M + H]+. Ethyl 1-(3-methylbenzyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (6) A mixture of 330 (0.46 mmol), K2CO3 (0.7 mmol), and 3-methylbenzyl chloride (0.80 mmol) in 2 mL of anhydrous DMF was stirred at 80 C for 1 h. After cooling, the mixture was diluted with cold water, and the precipitate was recovered by filtration. Yield = 61%: mp = 100C102 C (EtOH). 1H NMR (CDCl3) 1.47 (t, 3H, OCH2= 7.2 Hz), 2.33 (s, 3H, CH3), 4.52 (q, 2H, O= 7.2 Hz), 5.68 (s, 2H, CH2), 7.05 (s, 2H, Ar), 7.13 (d, 1H, Ar, = 6.4 Hz), 7.24 (d, 1H, Ar, = 8.0 Hz), 7.46 (t, 2H, Ar, = 8.8 Hz), 7.66 (t, 1H, Ar, = 7.2 Hz), 8.44 (d, 1H, Ar, = 8.0 Hz). 13C NMR (CDCl3) 14.29 (CH3), 21.43 (CH3), 60.82 (CH2), 61.88 (CH2), 116.16 (CH), 123.65 (CH), 126.14 (CH), 126.67 (CH), 127.13 (CH), 129.03 (CH), 129.23 (CH), 134.04 (CH), 134.68 (C), 139.04 (C), 140.50 (C). IR: 1717 cm?1 (C = O ester), 1632 cm?1 (C = O). ESI-MS calcd. for C19H18N2O3, 322.36; found: 323.14 [M + H]+. Ethyl 1-(3-methylbenzoyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (7) To a cooled (0 C) suspension of the appropriate substrate 330 (0.40 mmol) in anhydrous CH2Cl2 (2 mL), Et3N (0.1 mL), and 1.15 mmol of m-toluoyl chloride were added. The solution was stirred at 0 C for 2 h and then at room temperature for 2 h. After evaporation of the solvent, the residue was mixed with ice-cold water (20 mL) and neutralized with 0.5 N NaOH. Compound 7 was recovered by extraction with CH2Cl2 (3 15 mL) and was purified by column chromatography using cyclohexane/ethyl acetate 2:1 as eluent. Yield = 39%; mp = 81C83 C (EtOH). 1H NMR (CDCl3) 1.34 (t, 3H, OCH2= 7.2 Hz), 2.46 (s, 3H, CH3), 4.39 (q, 2H, O= 7.2 Hz), 7.41 (t, 1H, Ar, = 7.6 Hz), 7.48 (d, 1H, Ar, = 7.6 Hz), 7.60 (t, 1H, Ar, = 8.0 Hz), 7.68 (d, 1H, Ar, = 7.6 Hz), 7.74.1H NMR (CDCl3) 1.47 (t, 3H, OCH2= 7.2 Hz), 2.33 (s, 3H, CH3), 4.52 (q, 2H, O= 7.2 Hz), 5.68 (s, 2H, CH2), 7.05 (s, 2H, Ar), 7.13 (d, 1H, Ar, = 6.4 Hz), 7.24 (d, 1H, Ar, = 8.0 Hz), 7.46 (t, 2H, Ar, = 8.8 Hz), 7.66 (t, 1H, Ar, = 7.2 Hz), 8.44 (d, 1H, Ar, = 8.0 Hz). 6.8 Hz), 4.17 (s, 2H, CO= 7.2 Hz), 7.44 (t, 1H, Ar, = 6.8 Hz), 7.51 (d, 1H, Ar, = 7.6 Hz), 7.69 (d, 1H, Ar, = 8.0 Hz). ESI-MS calcd. for C15H19N3O3, 289.33; found: 290.05 [M + H]+. Ethyl 1-(cyclopropanecarbonyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (4) To a cooled (0 C) suspension of 330 (1.40 mmol) in anhydrous CH2Cl2 (2 mL), Et3N (0.1 mL) and 4.2 mmol of cyclopropanecarbonyl chloride were added. The mixture was stirred at 0 C for 2 h and then at room temperature for an additional 2 h. The solvent was evaporated, cold water was added, and the mixture was neutralized with 0.5 N NaOH. The reaction mixture was extracted with CH2Cl2 (3 15 mL), the solvent was dried over sodium sulfate, evaporated 1.23C1.28 (m, 2H, cyclopropyl), 1.33C1.38 (m, 2H, cyclopropyl), 1.46 (t, 3H, OCH2= 7.2 Hz), 3.20C3.25 (m 1H, cyclopropyl) 4.52 (q, 2H, O= 7.2 Hz), 7.57 (t, 1H, Ar, = 7.6 Hz), 7.81 (t, 1H, Ar, = 7.2 Hz), 8.38 (d, 1H, Ar, = 9.6 Hz), 8.87 (d, 1H, Ar, = 8.8 Hz). ESI-MS calcd. for C15H14N2O4, 286.28; found: 287.10 [M + H]+. Ethyl 1-methyl-4-oxo-1,4-dihydrocinnoline-3-carboxylate (5) A mixture of 0.23 mmol of 330, 0.34 mmol of Na2CO3, and 1.15 mmol of CH3I in 1 mL of anhydrous CH3CN was refluxed for 6 h. After cooling, the precipitate was filtered, the solvent was evaporated 1.31 (t, 3H, OCH2= 7.2 Hz), 4.16 (s, 3H, CH3), 4.32 (q, 2H, O= 7.2 Hz), 7.62 (t, 1H, Ar, = 7.6 Hz), 7.89 (d, 1H, Ar, = 8.8 Hz), 7.95 (t, 1H, Ar, = 8.4 Hz), 8.19 (d, 1H, Ar, = 8.0 Hz). 13C NMR (DMSO-d6) 14.58 (CH3), 31.16 (CH), 44.94 (CH3), 61.47 (CH2), 117.85 (CH), 125.28 (CH), 126.34 (C), 127.0 (CH), 134.88 (CH), 138.84 (CH), 141.24 (C). IR: 1590 cm?1 (C = O ester), 1693 cm?1 (C = O). ESI-MS calcd. for C12H12N2O3, 232.24; found: 233.09 [M + H]+. Ethyl 1-(3-methylbenzyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (6) A mixture of 330 (0.46 mmol), K2CO3 (0.7 mmol), and 3-methylbenzyl chloride (0.80 mmol) in 2 mL of anhydrous DMF was stirred at 80 C for 1 h. After cooling, the mixture was diluted with cold water, and the precipitate was recovered by filtration. Yield = 61%: mp = 100C102 C (EtOH). 1H NMR (CDCl3) 1.47 (t, 3H, OCH2= 7.2 Hz), 2.33 (s, 3H, CH3), 4.52 (q, 2H, O= 7.2 Hz), 5.68 (s, 2H, CH2), 7.05 (s, 2H, Ar), 7.13 (d, 1H, Ar, = 6.4 Hz), 7.24 (d, 1H, Ar, = 8.0 Hz), 7.46 (t, 2H, Ar, = 8.8 Hz), 7.66 (t, 1H, Ar, = 7.2 Hz), 8.44 (d, 1H, Ar, = 8.0 Hz). 13C NMR (CDCl3) 14.29 (CH3), 21.43 (CH3), 60.82 (CH2), 61.88 (CH2), 116.16 (CH), 123.65 (CH), 126.14 (CH), 126.67 (CH), 127.13 (CH), 129.03 (CH), 129.23 (CH), 134.04 (CH), 134.68 (C), 139.04 (C), 140.50 (C). IR: 1717 cm?1 (C = O ester), 1632 cm?1 (C = O). ESI-MS calcd. for C19H18N2O3, 322.36; found: 323.14 [M + H]+. Ethyl 1-(3-methylbenzoyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (7) To a cooled (0 C) suspension of the appropriate substrate 330 (0.40 mmol) in anhydrous CH2Cl2 (2 mL), Et3N (0.1 mL), and 1.15 mmol of m-toluoyl chloride were added. The solution was stirred at 0 C for 2 h and then at room temperature for 2 h. After evaporation of the solvent, the residue was mixed with ice-cold water (20 mL) and neutralized with 0.5 N NaOH. Compound 7 was recovered by.Compounds 18a,e,g were recovered by extraction with CH2Cl2 (3 15 mL), while crude 18bCd and 18f were recovered by vacuum filtration. for C15H19N3O3, 289.33; found: 290.05 [M + H]+. Ethyl 1-(cyclopropanecarbonyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (4) To a cooled (0 C) suspension of 330 (1.40 mmol) in anhydrous CH2Cl2 (2 mL), Et3N (0.1 mL) and 4.2 mmol of cyclopropanecarbonyl chloride were added. The mixture was stirred at 0 C for 2 h and then at room temperature for an additional 2 h. The solvent was evaporated, cold water was added, and the mixture was neutralized with 0.5 N NaOH. The reaction mixture was extracted with CH2Cl2 (3 15 mL), the solvent was dried over sodium sulfate, evaporated 1.23C1.28 (m, 2H, cyclopropyl), 1.33C1.38 (m, 2H, cyclopropyl), 1.46 (t, 3H, OCH2= 7.2 Hz), 3.20C3.25 (m 1H, cyclopropyl) 4.52 (q, 2H, O= 7.2 Hz), 7.57 (t, 1H, Ar, = 7.6 Hz), 7.81 (t, 1H, Ar, = 7.2 Hz), 8.38 (d, 1H, Ar, = 9.6 Hz), 8.87 (d, 1H, Ar, = 8.8 Hz). ESI-MS calcd. for C15H14N2O4, 286.28; found: 287.10 [M + H]+. Ethyl 1-methyl-4-oxo-1,4-dihydrocinnoline-3-carboxylate (5) A mixture of 0.23 mmol of 330, 0.34 mmol of Na2CO3, and 1.15 mmol of CH3I in 1 mL of anhydrous CH3CN was refluxed for 6 h. After cooling, the precipitate was filtered, the solvent was evaporated 1.31 (t, 3H, OCH2= 7.2 Hz), 4.16 (s, 3H, CH3), 4.32 (q, 2H, O= 7.2 Hz), 7.62 (t, 1H, Ar, = 7.6 Hz), 7.89 (d, 1H, Ar, = 8.8 Hz), 7.95 (t, 1H, Ar, = 8.4 Hz), 8.19 (d, 1H, Ar, = 8.0 Hz). 13C NMR (DMSO-d6) 14.58 (CH3), 31.16 (CH), 44.94 (CH3), 61.47 (CH2), 117.85 (CH), 125.28 (CH), 126.34 (C), 127.0 (CH), 134.88 (CH), 138.84 (CH), 141.24 (C). IR: 1590 cm?1 (C = O ester), 1693 cm?1 (C = O). ESI-MS calcd. for C12H12N2O3, 232.24; found: 233.09 [M + H]+. Ethyl 1-(3-methylbenzyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (6) A mixture of 330 (0.46 mmol), K2CO3 (0.7 mmol), and 3-methylbenzyl chloride (0.80 mmol) in 2 mL of anhydrous DMF was stirred at 80 C for 1 h. After cooling, the mixture was diluted with cold water, and the precipitate was recovered by filtration. Yield = 61%: mp = 100C102 C (EtOH). 1H NMR (CDCl3) 1.47 (t, 3H, OCH2= 7.2 Hz), 2.33 (s, 3H, CH3), 4.52 (q, 2H, O= 7.2 Hz), 5.68 (s, 2H, CH2), 7.05 (s, 2H, Ar), 7.13 (d, 1H, Ar, = 6.4 Hz), 7.24 (d, 1H, Ar, = 8.0 Hz), 7.46 (t, 2H, Ar, = 8.8 Hz), 7.66 (t, 1H, Ar, = 7.2 Hz), 8.44 (d, 1H, Ar, = 8.0 Hz). 13C NMR (CDCl3) 14.29 (CH3), 21.43 (CH3), 60.82 (CH2), 61.88 (CH2), 116.16 (CH), 123.65 (CH), 126.14 (CH), 126.67 (CH), 127.13 (CH), 129.03 (CH), 129.23 (CH), 134.04 (CH), 134.68 (C), 139.04 (C), 140.50 (C). IR: 1717 cm?1 (C = O Lipoic acid ester), 1632 cm?1 (C = O). ESI-MS calcd. for C19H18N2O3, 322.36; found: 323.14 [M + H]+. Ethyl 1-(3-methylbenzoyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (7) To a cooled (0 C) suspension of the appropriate substrate 330 (0.40 mmol) in anhydrous CH2Cl2 (2 mL), Et3N (0.1 mL), and 1.15 mmol of m-toluoyl chloride were added. The solution was stirred at 0 C for 2 h and then at room temperature for 2 h. After evaporation of the solvent, the residue was mixed with ice-cold water (20 mL) and neutralized with 0.5 N NaOH. Compound 7 was recovered by extraction with CH2Cl2 (3 15 mL) and was purified by column chromatography using cyclohexane/ethyl acetate 2:1 as eluent. Yield = 39%; mp = 81C83 C (EtOH). 1H NMR (CDCl3) 1.34 (t, 3H, OCH2=.for C16H12N2O2, 264.28; found: 265.09 [M + H]+. (4-Hydroxy-3,4-dihydrocinnolin-1(2H)-yl)(m-tolyl)meyhanone (19) Compound 18a (0.189 mmol) was subjected to catalytic reduction in EtOH (15 mL) for 4 h with a Parr instrument (Parr Instrument Company, Moline, IL) using 0.094 mmol of 10% Pd/C as a catalyst and a constant pressure at 30 PSI. 6.8 Hz), 7.51 (d, 1H, Ar, = 7.6 Hz), 7.69 (d, 1H, Ar, = 8.0 Hz). ESI-MS calcd. for C15H19N3O3, 289.33; found: 290.05 [M + H]+. Ethyl 1-(cyclopropanecarbonyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (4) To a cooled (0 C) suspension of 330 (1.40 mmol) in anhydrous CH2Cl2 (2 mL), Et3N (0.1 mL) and 4.2 mmol of cyclopropanecarbonyl chloride were added. The mixture was stirred at 0 C for 2 h and then at room temperature for an additional 2 h. The solvent was evaporated, cold water was added, and the mixture was neutralized with 0.5 N NaOH. The reaction mixture was extracted with CH2Cl2 (3 15 mL), the solvent was dried over sodium sulfate, evaporated 1.23C1.28 (m, 2H, cyclopropyl), Lipoic acid 1.33C1.38 (m, 2H, cyclopropyl), 1.46 (t, 3H, OCH2= 7.2 Hz), 3.20C3.25 (m 1H, cyclopropyl) 4.52 (q, 2H, O= 7.2 Hz), 7.57 (t, 1H, Ar, = 7.6 Hz), 7.81 (t, 1H, Ar, = 7.2 Hz), 8.38 (d, 1H, Ar, = 9.6 Hz), 8.87 (d, 1H, Ar, = 8.8 Hz). ESI-MS calcd. for C15H14N2O4, 286.28; found: 287.10 [M + H]+. Ethyl 1-methyl-4-oxo-1,4-dihydrocinnoline-3-carboxylate (5) A mixture of 0.23 mmol of 330, 0.34 mmol of Na2CO3, and 1.15 Lipoic acid mmol of CH3I in 1 mL of anhydrous CH3CN was refluxed for 6 h. After cooling, the precipitate was filtered, the solvent was evaporated 1.31 (t, 3H, OCH2= 7.2 Hz), 4.16 (s, 3H, CH3), 4.32 (q, 2H, O= 7.2 Hz), 7.62 (t, 1H, Ar, = 7.6 Hz), 7.89 (d, 1H, Ar, = 8.8 Hz), 7.95 (t, 1H, Ar, = 8.4 Hz), 8.19 (d, 1H, Ar, = 8.0 Hz). 13C NMR (DMSO-d6) 14.58 (CH3), 31.16 (CH), 44.94 (CH3), 61.47 (CH2), 117.85 (CH), 125.28 (CH), 126.34 (C), 127.0 (CH), 134.88 (CH), 138.84 (CH), 141.24 (C). IR: 1590 cm?1 (C = O ester), 1693 cm?1 (C = O). ESI-MS calcd. for C12H12N2O3, 232.24; found: 233.09 [M + H]+. Ethyl 1-(3-methylbenzyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (6) A mixture of 330 (0.46 mmol), K2CO3 (0.7 mmol), and 3-methylbenzyl chloride (0.80 mmol) in 2 mL of anhydrous DMF was stirred at 80 C for 1 h. After cooling, the mixture was diluted with cold water, and the precipitate was recovered by filtration. Yield = 61%: mp = 100C102 C (EtOH). 1H NMR (CDCl3) 1.47 (t, 3H, OCH2= 7.2 Hz), 2.33 (s, 3H, CH3), 4.52 (q, 2H, O= 7.2 Hz), 5.68 (s, 2H, CH2), 7.05 (s, 2H, Ar), 7.13 (d, 1H, Ar, = 6.4 Hz), 7.24 (d, 1H, Ar, = 8.0 Hz), 7.46 (t, 2H, Ar, = 8.8 Hz), 7.66 (t, 1H, Ar, = 7.2 Hz), 8.44 (d, 1H, Ar, = 8.0 Hz). 13C NMR (CDCl3) 14.29 (CH3), 21.43 (CH3), 60.82 (CH2), 61.88 (CH2), 116.16 (CH), 123.65 (CH), 126.14 (CH), 126.67 (CH), 127.13 (CH), 129.03 (CH), 129.23 (CH), 134.04 (CH), 134.68 (C), 139.04 (C), 140.50 (C). IR: 1717 cm?1 Lipoic acid (C = O ester), 1632 cm?1 (C = O). ESI-MS calcd. for C19H18N2O3, 322.36; found: 323.14 [M + H]+. Ethyl 1-(3-methylbenzoyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (7) To a cooled (0 C) suspension of the appropriate substrate 330 (0.40 mmol) in anhydrous CH2Cl2 (2 mL), Et3N (0.1 mL), and 1.15 mmol of m-toluoyl chloride were added. The solution was stirred at 0 C for 2 h and then at room temperature for 2 h. After evaporation of the solvent, the residue was mixed with ice-cold water (20 mL) and neutralized with 0.5 N NaOH. Compound 7 was recovered by extraction with CH2Cl2 (3 15 mL) and was purified by column chromatography using cyclohexane/ethyl acetate 2:1 as eluent. Yield = 39%; mp = 81C83 C (EtOH). 1H NMR (CDCl3) 1.34 (t, 3H, OCH2= 7.2 Hz), 2.46 (s, 3H, CH3), 4.39 (q, 2H, O= 7.2 Hz), 7.41 (t, 1H, Ar, = 7.6 Hz), 7.48 (d, 1H, Ar, = 7.6 Hz), 7.60 (t, 1H, Ar, = 8.0 Hz), 7.68 (d, 1H, Ar, = 7.6 Hz), 7.74 (s, 1H, Ar), 7.83 (t, 1H, Ar, = 7.5 Hz), 8.43 (t, 2H, Ar, = 8.0 Hz). ESI-MS calcd. for C19H16N2O4, 336.34; found: 337.11 [M +.for C19H18N2O3, 322.36; found: 323.14 [M + H]+. Ethyl 1-(3-methylbenzoyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (7) To a cooled (0 C) suspension of the appropriate substrate 330 (0.40 mmol) in anhydrous CH2Cl2 (2 mL), Et3N (0.1 mL), and 1.15 mmol of m-toluoyl chloride were added. 7.6 Hz), 7.69 (d, 1H, Ar, = 8.0 Hz). ESI-MS calcd. for C15H19N3O3, 289.33; found: 290.05 [M + H]+. Ethyl 1-(cyclopropanecarbonyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (4) To a cooled (0 C) suspension of 330 (1.40 mmol) in anhydrous CH2Cl2 (2 mL), Et3N (0.1 mL) and 4.2 mmol of cyclopropanecarbonyl chloride were added. The mixture was stirred at 0 C for 2 h and then at room temperature for an additional 2 h. The solvent was evaporated, cold water was added, and the mixture was neutralized with 0.5 N MADH9 NaOH. The reaction mixture was extracted with CH2Cl2 (3 15 mL), the solvent was dried over sodium sulfate, evaporated 1.23C1.28 (m, 2H, cyclopropyl), 1.33C1.38 Lipoic acid (m, 2H, cyclopropyl), 1.46 (t, 3H, OCH2= 7.2 Hz), 3.20C3.25 (m 1H, cyclopropyl) 4.52 (q, 2H, O= 7.2 Hz), 7.57 (t, 1H, Ar, = 7.6 Hz), 7.81 (t, 1H, Ar, = 7.2 Hz), 8.38 (d, 1H, Ar, = 9.6 Hz), 8.87 (d, 1H, Ar, = 8.8 Hz). ESI-MS calcd. for C15H14N2O4, 286.28; found: 287.10 [M + H]+. Ethyl 1-methyl-4-oxo-1,4-dihydrocinnoline-3-carboxylate (5) A mixture of 0.23 mmol of 330, 0.34 mmol of Na2CO3, and 1.15 mmol of CH3I in 1 mL of anhydrous CH3CN was refluxed for 6 h. After cooling, the precipitate was filtered, the solvent was evaporated 1.31 (t, 3H, OCH2= 7.2 Hz), 4.16 (s, 3H, CH3), 4.32 (q, 2H, O= 7.2 Hz), 7.62 (t, 1H, Ar, = 7.6 Hz), 7.89 (d, 1H, Ar, = 8.8 Hz), 7.95 (t, 1H, Ar, = 8.4 Hz), 8.19 (d, 1H, Ar, = 8.0 Hz). 13C NMR (DMSO-d6) 14.58 (CH3), 31.16 (CH), 44.94 (CH3), 61.47 (CH2), 117.85 (CH), 125.28 (CH), 126.34 (C), 127.0 (CH), 134.88 (CH), 138.84 (CH), 141.24 (C). IR: 1590 cm?1 (C = O ester), 1693 cm?1 (C = O). ESI-MS calcd. for C12H12N2O3, 232.24; found: 233.09 [M + H]+. Ethyl 1-(3-methylbenzyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (6) A mixture of 330 (0.46 mmol), K2CO3 (0.7 mmol), and 3-methylbenzyl chloride (0.80 mmol) in 2 mL of anhydrous DMF was stirred at 80 C for 1 h. After cooling, the mixture was diluted with cold water, and the precipitate was recovered by filtration. Yield = 61%: mp = 100C102 C (EtOH). 1H NMR (CDCl3) 1.47 (t, 3H, OCH2= 7.2 Hz), 2.33 (s, 3H, CH3), 4.52 (q, 2H, O= 7.2 Hz), 5.68 (s, 2H, CH2), 7.05 (s, 2H, Ar), 7.13 (d, 1H, Ar, = 6.4 Hz), 7.24 (d, 1H, Ar, = 8.0 Hz), 7.46 (t, 2H, Ar, = 8.8 Hz), 7.66 (t, 1H, Ar, = 7.2 Hz), 8.44 (d, 1H, Ar, = 8.0 Hz). 13C NMR (CDCl3) 14.29 (CH3), 21.43 (CH3), 60.82 (CH2), 61.88 (CH2), 116.16 (CH), 123.65 (CH), 126.14 (CH), 126.67 (CH), 127.13 (CH), 129.03 (CH), 129.23 (CH), 134.04 (CH), 134.68 (C), 139.04 (C), 140.50 (C). IR: 1717 cm?1 (C = O ester), 1632 cm?1 (C = O). ESI-MS calcd. for C19H18N2O3, 322.36; found: 323.14 [M + H]+. Ethyl 1-(3-methylbenzoyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (7) To a cooled (0 C) suspension of the appropriate substrate 330 (0.40 mmol) in anhydrous CH2Cl2 (2 mL), Et3N (0.1 mL), and 1.15 mmol of m-toluoyl chloride were added. The solution was stirred at 0 C for 2 h and then at room temperature for 2 h. After evaporation of the solvent, the residue was mixed with ice-cold water (20 mL) and neutralized with 0.5 N NaOH. Compound 7 was recovered by extraction with CH2Cl2 (3 15 mL) and was purified by column chromatography using cyclohexane/ethyl acetate 2:1 as eluent. Yield = 39%; mp = 81C83 C (EtOH). 1H NMR (CDCl3) 1.34 (t, 3H, OCH2= 7.2 Hz), 2.46 (s, 3H, CH3), 4.39 (q, 2H, O= 7.2 Hz), 7.41 (t, 1H, Ar, = 7.6 Hz), 7.48 (d, 1H, Ar, = 7.6 Hz), 7.60 (t, 1H, Ar, = 8.0.