F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[C:30]([C:37]1[NH:38]C=CN=1)([C:32]1NC=C[N:36]=1)=O.C(O)(=O)C1C=CC=CC=1.C(NCC1C=CC=CC=1)C1C=CC2OCOC=2C=1>O1CCCC1>[N:38]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:37]=[CH:30][CH:32]=[N:36]1A solution of 20 mmol of 2-fluorobezonitrile and 40 mmol of pyrrazole is mixed together in dimethylformaide with 1 equivalent of potassium hydroxide and a catalytic amount of 18-crown-6. The mixture is stirred at room temperature overnight, quenched with water and ethyl acetate and extracted with ethyl acetate. The organic extract is washed repeatedly with 1 N NaOH solution. The organic layer is then diluted with ether and washed with 1N HCl solution, dried and concentrated. 1H NMR (CDCl3) 6.55 (t, J=2 Hz, 1H), 7.42 (M, 1H), 7.65–7.82 m, 4H), 8.15 (d, J=1 Hz, 1H). 2-Pyrazol-1-yl-benzoic acid. Compound 178. A solution of compound 177 in conc HCl is refluxed overnight, cooled and concentrated. The product is precipitated by addition of 1 N NaOH until pH of 5–6, filtered and dried. 1H (CDCl3) 6.52 (t, J=3 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 7.50 (t, J=8 Hz, 1H) 7.62 (t, J=8 hz, 1H), 7.81 (m, 2H), 8.12 (d, J=8 Hz, 1H). N-Benzo[1,3]dioxol-5-ylmethyl-N-benzyl-2-pyrazol-1-yl-benzamide, Compound 179. 1.1 equiv of carbonyl diimidazole is added to a solution of benzoic acid 178 (200 mg) in tetrahydrofuran (5 mL); the reaction is stirred at room temperature for 3 h. After this time N-piperonyl-N-benzylamine (0.25 g) is added in one portion. After 30 min, the reaction is filtered, diluted with ether and washed with water. The organic layer is dried (Na2SO4) and purified over column chromatography to provide the desired product (390 mg). The proton NMR displays a typically doubled pattern. 1H (CDCl3) 3.83 and 4.32 (two doublets, J=16 Hz, 1H), 3.91 (two doublets, J=8 Hz, 1H), 4.18 two doublets (J=6 Hz, 1H), 5.0 and 5.1 (two doublets, J=14 Hz, 1H), 5.93 and 5.98 (s and doublet, J=2 Hz, 2H, OCH2O), 6.35–6.40 (m, 2H), 6.51 (d, J=4 Hz, 0.5H), 6.4 (m, 1.5H), 7.0–7.88 m, 15H). LC-MS 412.3
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