Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:6]#[N:7])#[CH:2].Cl[O:14][N:15]=[CH:16][C:17]1[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:18]=1[O:25][CH3:26].C(Cl)(Cl)Cl>C1C=CC=CC=1>[C:23]([C:21]1[CH:20]=[CH:19][C:18]([O:25][CH3:26])=[C:17]([C:16]2[CH:2]=[C:1]([C:3]3[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:10]=3[O:11][CH3:12])[O:14][N:15]=2)[CH:22]=1)#[N:24]
Reactant: C#Cc1cc(C#N)ccc1OC
Reactant: COc1ccc(C#N)cc1C=NOCl
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(C#N)cc1-c1cc(-c2cc(C#N)ccc2OC)on1

Procedure:
3-(4-cyanophenyl)-5-(4-cyano-2-nitrophenyl)isoxazole (53a) was prepared from phenylacetylene 51b and chlorooxime 52a as an off-white solid (1.69 g, 67%); mp 280-281° C.; 1H NMR δ 8.78 (d, J=1.5 Hz, 1H), 8.44 (dd, J=8.1 and 1.5 Hz, 1H), 8.20 (d, J=8.1 Hz, 1H), 8.15 (d, J=8.2 Hz, 2H), 8.07 (d, J=8.1 Hz, 2H), 7.88 (s, 1H); HPLC (Method B) tR 6.87 min (97.4 area % at 254 nm). Anal. (C17H8N4O3) C, H, N. 3-(4-cyanophenyl)-5-(2-chloro-4-cyanophenyl)isoxazole (53b) was prepared from phenylacetylene 51c and chlorooxime 52a as a white solid (2.10 g, 71%): mp 260-262° C.; 1H NMR δ 8.36 (d, J=1.6 Hz, 1H), 8.22 36 (d, J=8.6 Hz, 2H), 8.18 (d, J=8.2 Hz, 1H), 8.06 (d, J=8.6 Hz, 2H), 8.06 (d, J=8.2 Hz, 1H), 7.98 (s, 1H); HPLC (Method B) tR 7.84 min (96.1 area % at 265 nm). Anal. (C17H8ClN3O) C, H, N. 3-(4-cyano-2-nitrophenyl)-5-(4-cyanophenyl)isoxazole (53c) was prepared from phenylacetylene 51a and chlorooxime 52b to give, after column chromatography (CH2Cl2), a cream colored solid (2.26 g, 57%): mp 264-265° C. (CH3CN); 1H NMR δ 8.77 (d, J=1.5 Hz, 1H), 8.41 (dd, J=8.1 and 1.6 Hz, 1H), 8.11 (m, 5H), 7.74 (s, 1H); HPLC (Method B) tR 6.81 min (96.1 area % at 265 nm). Anal. (C17H8N4O3) C, H, N. 3-(2-Chloro-4-cyanophenyl)-5-(4-cyanophenyl)isoxazole (53d) was prepared from phenylacetylene 51a and chlorooxime 52c to give, after column chromatography (CH2Cl2) and recrystallization, a white solid (2.15 g, 56%): mp 247-248° C.; 1H NMR δ 8.35 (d, J=1.5 Hz, 1H), 8.17 (d, J=8.5 Hz, 2H), 8.07 (d, J=8.7 Hz, 2H), 8.03 (dd, J=8.1 and 1.5 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.81 (s, 1H); HPLC (Method B) tR 7.66 min (98.8 area % at 265 nm). Anal. (C17H8Cl N3O) C, H, N. 3-(4-Cyano-2-methoxyphenyl)-5-(4-cyanophenyl)isoxazole (53e) was prepared from phenylacetylene 51a and chlorooxime 52d to give, after column chromatography (CH2Cl2) white crystals (2.99 g, 80%): mp 243-244° C.; 1H NMR δ 8.17 (d, J=8.8 Hz, 2H), 8.05 (d, J=8.8 Hz, 2H), 7.99 (d, J=8.0 Hz, 1H), 7.76 (d, J=1.4 Hz, 1H), 7.73 (s, 1H), 7.57 (dd, J=8.0 and 1.5 Hz, 1H), 4.00 (s, 3H); HPLC (Method B) tR 7.48 min (100 area % at 265 nm). Anal. (C18H11N3O2) C, H, N. 3-5-Bis(4-cyano-2-methoxyphenyl)isoxazole (53f) was prepared from phenylacetylene 51d and chlorooxime 52d (5.28 g, 25.1 mmol). The precipitated product was recrystallized from CHCl3 using a Soxhlet extractor to give a white solid (6.27 g, 76%); mp 347-348° C.; 1H NMR δ 8.09 (d, J=8.1 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.79 (d, J=1.4 Hz, 1H), 7.76 (d, J=1.4 Hz, 1H), 7.62 (dd, J=8.1 and 1.4 Hz, 1H), 7.56 (dd, J=8.0 and 1.4 Hz, 1H), 7.43 (s, 1H), 4.05 (s, 3H), 3.98 (s, 3H). Anal. (C19H13N3O3) C, H, N. 3-(3-cyanophenyl)-5-(4-cyano-2-nitroxyphenyl)isoxazole (53g) was prepared from phenylacetylene 51b and chlorooxime 52e in benzene as a yellow solid (0.15 g, 83%): mp 198-199° C. (EtOH); 1H NMR δ 8.78 (d, J=1.5 Hz, 1H), 8.43 (m, 2H), 8.29 (dm, J=8.5 Hz, 1H), 8.19 (d, J=8.1 Hz, 1H), 8.06 (dm, J=7.9 Hz, 1H), 7.86 (s, 1H), 7.80 (t, J=7.8 Hz, 1H); HPLC (Method B) tR 6.95 min (100 area % at 230 nm). Anal. (C17H8N4O3.0.2H2O) C, H, N. 3-(3-cyanophenyl)-5-(2-chloro-4-cyanophenyl)isoxazole (53h). Triethylamine (1.25 g, 12.4 mmol) was added to a mixture of phenylacetylene 51c (1.00 g, 6.19 mmol) and chlorooxime 52e (2.00 g, 11.06 mmol) in CHCl3 under a N2 atmosphere. See Thomsen. I., et al., Acta Chem. Scand. (B), 319-313 (1988). The reaction mixture was stirred at reflux. Following aqueous work-up of the reaction mixture, the product was purified by column chromatography (CHCl3) to give a yellow solid (1.01 g, 54%): mp 146-148° C.; 1H NMR δ 8.52 (s, 1H), 8.34 (m, 2H), 8.17 (d, J=8.1 Hz, 1H), 8.04 (m, 2H), 8.00 (s, 1H), 7.76 (t, J=7.9 Hz, 1H); HPLC (Method B) tR 7.94 min (100 area % at 265 nm). Anal. (C17H8ClN3O) C, H, N. 3-(5-bromo-2-chlorophenyl)-5-(4-cyanophenyl)isoxazole (53i) was prepared analogously to 53h from phenylacetylene 51a and chlorooxime 52e as a yellow solid (1.78 g, 58%): mp 198-199° C. (EtOH); 1H NMR δ 8.16 (d, J=8.8 Hz, 2H), 8.07 (d, J=8.6 Hz, 2H), 7.97 (d, J=2.3 Hz, 1H), 7.80 (dd, J=8.6 and 2.4 Hz, 1H), 7.78 (s, 1H), 7.66 (d, J=8.5 Hz, 1H); HPLC (Method B) tR 9.05 min (100 area % at 265 nm). Anal. (C16H8BrClN2O) C, H, N, Br, Cl. 3-(4-Cyanophenyl)-5-(2-chloro-5-cyanophenyl)isoxazole (53k) was prepared from phenylacetylene 51f and chlorooxime 52a as a white solid (1.46 g, 32%); mp 207-209° C.; 1H NMR δ 8.46 (d, J=1.6 Hz, 1H), 8.19 (d, J=8.2 Hz, 2H), 8.07 (dd, J=8.8 and 1.6 Hz, 1H), 8.06 (d, J=8.2 Hz, 2H), 7.95 (d, J=8.8 Hz, 1H), 7.90 (s, 1H); HPLC (Method B) tR 7.69 min (98.0 area % at 254 nm). Anal. (C17H8ClN3O) C, H, N, Cl. 3-(4-Cyano-2-nitrophenyl)-5-(3-cyanophenyl)isoxazole (531) was prepared from phenylacetylene 51e and chlorooxime 52b as a white solid (3.10 g, 69%); mp 235-238° C.; 1H NMR δ 8.77 (d, J=1.1 Hz, 1H), 8.47 (dd, J=1.6 and 1.6 Hz, 1H), 8.41 (dd, J=7.7 and 1.1 Hz, 1H), 8.26 (ddd, J=8.2, 1.6 and 1.6 Hz, 1H), 8.09 (d, J=8.2 Hz, 1H), 8.04 (ddd, J=7.7, 1.6 and 1.6 Hz, 1H), 7.81 (dd, J=7.7 and 7.7 Hz, 1H), 7.68 (s, 1H); HPLC (Method B) tR 6.84 min (96.6 area % at 254 nm). Anal. (C17H8N4O3) C, H, N. 3-(2-Chloro-4-cyanophenyl)-5-(3-cyanophenyl)isoxazole (53m) was prepared from phenylacetylene 51e and chlorooxime 52c as a white solid (1.16 g, 27%); mp 221-223° C.; 1H NMR δ 8.51 (br s, 1H), 8.33 (br s, 1H), 8.29 (d, J=8.2 Hz, 1H), 8.03 (d, J=8.2 Hz, 1H), 8.01 (s, 1H), 7.97 (d, J=7.7 Hz, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.77 (s, 1H); HPLC (Method B) tR 7.65 min (98.0 area % at 254 nm). Anal. (C17H8ClN3O) C, H, N, Cl. 3-(4-Cyano-2-methoxyphenyl)-5-(3-cyanophenyl)isoxazole (53n) was prepared from phenylacetylene 51e and chlorooxime 52d as a white solid (2.66 g, 88%); mp 202-204° C.; 1H NMR δ 8.46 (br s, 1H), 8.25 (d, J=7.7 Hz, 1H), 7.97 (d, J=7.7 Hz, 2H), 7.76 (dd, J=7.7 and 7.7 Hz, 1H), 7.70 (br s, 1H), 7.66 (br s, 1H), 7.54 (d, J=7.7 Hz, 1H), 3.97 (s, 3H); HPLC (Method B) tR 7.48 min (100 area % at 254 nm). Anal. (C18H11N3O2) C, H, N. 3-(4-Cyano-2-nitrophenyl)-5-(5-cyano-2-methoxyphenyl)isoxazole (53o) was prepared from phenylacetylene 51 g and chlorooxime 52b as a white solid (1.44 g, 47%); mp 264-266° C.; 1H NMR δ 8.75 (d, J=1.1 Hz, 1H), 8.38 (dd, J=8.2 and 1.1 Hz, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.15 (d, J=8.2 Hz, 1H), 8.04 (dd, J=8.8 and 2.2 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.46 (br s, 1H), 4.07 (s, 3H); HPLC (Method B) tR 7.00 min (98.4 area % at 254 nm). Anal. (C18H10N4O4) C, H, N. 3-(4-Cyano-2-methoxyphenyl)-5-(5-cyano-2-methoxyphenyl)isoxazole (53p) was prepared from phenylacetylene 51g and chlorooxime 52d as a white solid (1.65 g, 76%); mp 271-273° C.; 1H NMR δ 8.29 (br s, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.71 (br s, 1H), 7.55 (d, J=7.7 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.34 (br s, 1H), 4.06 (s, 3H), 3.96 (s, 3H); HPLC (Method B) tR 7.58 min (100 area % at 254 nm). Anal. (C19H13N3O3) C, H, N. 3-(3-Cyanophenyl)-5-(2-chloro-5-cyanophenyl)isoxazole (53q) was prepared from phenylacetylene 51f and chlorooxime 52e in benzene. Column chromatography (CHCl3) afforded a yellow solid (1.22 g, 74%): mp 201-203° C.; 1H NMR δ 8.50 (s, 1H), 8.46 (d, J=1.6 Hz, 1H), 8.33 (d, J=7.7 Hz, 1H), 8.05 (m, 2H), 7.96 (d, J=8.2 Hz, 1H), 7.93 (s, 1H), 7.78 (t, J=7.7 Hz, 1H); HPLC (Method B) tR 7.76 min (100 area % at 254 nm). Anal. (C17H8ClN3O) C, H, N, Cl. 3-(2-Chloro-5-cyanophenyl)-5-(3-cyanophenyl)isoxazole (53r) was prepared from phenylacetylene 51a and chlorooxime 52g in benzene. Column chromatography (CHCl3) afforded a yellow solid (2.10 g, 49%): mp 124-125° C.; 1H NMR δ 8.50 (s, 1H), 8.28 (d, J=7.7 Hz, 1H), 8.27 (d, J=1.6 Hz, 1H), 8.07 (dd, J=8.2 and 1.6 Hz, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.80 (t, J=7.7 Hz, 1H), 7.75 (s, 1H); HPLC (Method B) tR 7.55 min (98.5 area % at 254 nm). Anal. (C17H8ClN3O) C, H, N, Cl. 3,5-Bis(5-cyano-2-methoxyphenyl)isoxazole (53s) was prepared from phenylacetylene 51g and chlorooxime 52h in benzene. Column chromatography (CHCl3) afforded a yellow solid (4.30 g, 79%): mp 268-270° C.; 1H NMR δ 8.31 (d, J=1.6 Hz, 1H), 8.18 (d, J=1.6 Hz, 1H), 8.02 (dd, J=8.8 and 1.6 Hz, 2H), 7.45 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.34 (s, 1H), 4.07 (s, 3H) 4.00 (s, 3H); HPLC (Method B) tR 7.27 min (100 area % at 254 nm). Anal. (C19H13N3O3) C, H, N. 3,5-Bis[4-(N-hydroxy)amidino-2-methoxyphenyl]isoxazole (54). Potassium tert-butoxide (11.2 g, 100 mmol) was added to a solution of hydroxylamine hydrochloride (7.01 g, 101 mmol) in dry DMSO 60 mL). Dinitrile 53f (3.32 g, 10.0 mmol) was added. The mixture was stirred under Ar for 12 d, with more DMSO (60 mL) added after 6 d. The reaction mixture was filtered, and the filtrate was poured into ice water to give a white precipitated solid (3.14 g, 79%): mp 203-204° C.; 1H NMR δ 9.87 (brs, 1H), 9.82 (brs, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.51 (d, J=1.3 Hz, 1H), 7.47 (m, 2H), 7.42 (dd, J=8.1 and 1.5 Hz, 1H), 7.27 (s, 1H), 6.00 (br s, 2H), 5.98 (br s, 2H), 4.02 (s, 3H), 3.95 (s, 3H); HPLC (Method A) tR 6.99 min (100 area % at 265 nm). Anal. (C19H19N5O6.0.6H2O) C, H, N. 3,5-Bis[4-(N-acetoxy)amidino-2-methoxyphenyl]isoxazole (55). Acetic anhydride (5 mL) was added to a suspension of diamidoxime (54 (1.00 g, 2.51 mmol) in glacial acetic acid (25 mL). The mixture was stirred overnight, then poured over ice to give a white solid (1.14 g, 94%): mp 238° C. (dec.); 1H NMR δ 7.97 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.51 (m, 3H), 7.46 (d, J=8.1 Hz, 1H), 7.33 (s, 1H), 6.98 (br s, 4H), 4.05 (s, 3H), 3.98 (s, 3H), 2.17 (s, 6H); HPLC (Method B) tR 4.08 min (96.0 area % at 265 nm). Anal. (C23H23N5O7) C, H, N. 4-Chloro-3-iodobenzaldoxime (59). A solution of aldehyde 58 (15.0 g, 56.3 mmol) and hydroxylamine hydrochloride (4.86 g, 69.9 mmol) in pyridine (30 mL) and dry EtOH (30 mL) was stirred overnight under Ar. The reaction mixture was concentrated to half-volume and poured into ice water to afford a white solid (12.1 g, 76%): mp 97-99° C.; 1H NMR δ 11.52 (s, 1H), 8.15 (d, J=1.6 Hz, 1H), 7.66 (dd, J=8.2 and 1.6 Hz, 1H), 7.59 (d, J=8.2, 1H). Anal. (C7H5ClINO) C, H, N, Cl, I. 4-Bromo-3-chlorobenzonitrile (60c). Aniline 56 (5.19 g, 26.4 mmol) was added to conc. HCl maintained below 0° C. A solution of sodium nitrite (3.67 g, 53.2 mmol) in water (10 mL) was added dropwise such that the temperature of the reaction mixture did not exceed 5° C. The mixture was maintained for 1 h, then was added to a solution of CuCl (6.55 g, 66.2 mmol) in conc. HCl (20 mL). Toluene (200 mL) was added, and the biphasic mixture was stirred at 60-80° C. for 1 h. Layers were separated, and the aqueous layer was extracted into toluene to afford a white solid (4.67 g, 82%); mp 80-81° C. (hexane); 1H NMR δ 9.55 (d, J=1.8 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 and 1.9 Hz, 1H); HPLC (Method B) tR 3.96 min (100 area % at 265 nm). Anal. (C7H3BrClN) C, H, N, Br, Cl. 3-methoxy-4-O-trifluoromethylsulfonylbenzonitrile (60d). Triethylamine (15.7 g, 155 mmol) was added to a stirred solution of 4-hydroxy-3-methoxybenzonitrile (20.0 g, 134 mmol) in dry CH2Cl2 maintained below 0° C. Triflic anhydride (47.4 g, 168 mmol) was added dropwise over 45 min such that the temperature of the reaction mixture did not exceed 5° C. The reaction mixture was maintained for 1 h, poured into ice water, and extracted into EtOAc. Column chromatography [hexane/EtOAc (9:1)], afforded colorless crystals (33.4 g, 89%): mp 51-53° C. (hexanes/EtOAC); 1H NMR δ 7.92 (d, J=1.9 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.56 (dd, J=8.4 and 1.9 Hz, 1H), 3.97 (s, 3H); HPLC (Method B) tR 6.89 min (100 area % at 230 nm). Anal. (C9H6F3NO4S) C, H, N, F, S. 4-Chloro-3-iodobenzonitrile (60f). A mixture of aldoxime 59 (5.65 g, 20.0 mmol) in acetic anhydride (10 mL) was refluxed for 4 h. The reaction mixture was poured into ice-water and stirred for 1 h. The product was filtered off as a light yellow solid (4.79 g, 91%): mp 91-93° C.; 1H NMR δ 8.49 (d, J=2.2 Hz, 1H), 7.90 (dd, J=8.2 and 2.2 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H); HPLC (Method B) tR 6.24 min (91.75 area % at 254 nm). Anal. (C7H3ClIN) C, H, N, Cl, I.