Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[NH:11]1CCC[CH2:12]1.COCCO[AlH2-]OCCOC.[Na+].CC(C)([O-])C.[K+].COC(=O)C1C=C(Br)C=CC=1Cl>CC(OC)(C)C.C1(C)C=CC=CC=1.C1COCC1>[Cl:10][C:5]1[CH:4]=[CH:3][C:2]([C:12]#[N:11])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: C1CCNC1
Reactant: O=Cc1cc(Br)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: COC(=O)c1cc(Br)ccc1Cl
Agent: COCCO[AlH2-]OCCOC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Cl)c(C=O)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
4-(3-hydroxy-3-methylbut-1-ynyl)-3-methoxy-benzonitrile (62c) was prepared from aryl triflate 60d to give off-white crystals (19.1 g, 86%): mp 68-70° C. (hexanes/EtOAc); 1H NMR δ 7.54 (d, J=1.4 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.40 (dd, J=7.8 and 1.5 Hz, 1H), 5.55 (s, 1H), 3.87 (s, 3H), 1.46 s, 6H); HPLC (Method B) tR 4.09 min (100 area % at 230 nm). Anal. (C13H13NO2 0.4H2O) C, H. 3-(3-Hydroxy-3-methylbut-1-ynyl)benzonitrile (62d) was prepared from 3-bromobenzonitrile to give a light-brown oil (20.0 g, 100%): 1H NMR δ 7.85 (dd, J=1.5 and 1.5 Hz, 1H), 7.84 (ddd, J=7.8, 1.5 and 1.5 Hz, 1H), 7.72 (ddd, J=7.8, 1.5 and 1.5 Hz, 1H), 7.61 (dd, J=7.8, and 7.8 Hz, 1H), 5.57 (s, 1H), 1.47 (s, 6H); HPLC (method B) tR 3.99 min (100 area % at 254 nm). Anal. (C12H11NO) C, H, N. 4-Chloro-3-(3-hydroxy-3-methylbut-1-ynyl)benzonitrile (62e) was prepared from aryl iodide 60f to give off-white crystals (3.40 g, 82%): mp 80-82° C. (hexanes/EtOAc); 1H NMR δ 8.03 (dd, J=2.0 and 0.7 Hz, 1H), 7.86 (ddd, J=8.4, 2.0 and 0.7 Hz, 1H), 7.78 (dd, J=8.4 and 0.7 Hz, 1H), 5.63 (s, 1H), 1.49 (s, 6H); HPLC (method B) tR 4.86 min (100 area % at 254 nm). Anal. (C12H10ClNO) C, H, N, Cl. 3-(3-Hydroxy-3-methylbut-1-ynyl)-4-methoxy-benzonitrile (62f) was from 3-bromo-4-methoxybenzonitrile to give off-white crystals (30.5 g, 99%): mp 63-65° C. (hexanes/EtOAc); 1H NMR δ 7.82 (dd, J=8.7 and 2.1 Hz, 1H), 7.77 (d, J=2.1 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H), 5.51 (s, 1H), 3.90 (s, 3H), 1.46 (s, 6H); HPLC (method B) tR 3.83 min (100 area % at 254 nm). Anal. (C13H13NO2) C, H, N. 3-Methoxy-4-dibromomethylbenzonitrile (65). A mixture of 4-methyl-3-methoxybenzonitrile 64 (11.4 g, 77.6 mmol), NBS (34.5 g, 194 mmol), benzoyl peroxide (1.01 g, 4.17 mmol) in CCl4 was refluxed for 3 h. The reaction mixture was diluted with water and extracted with CH2Cl2. Column chromatography [hexane/EtOAc (19:1)] of the extracts afforded white crystals (18.3 g, 77%): mp 78-79° C.; 1H NMR δ 7.88 (d, J=8.0 Hz, 1H), 7.60 (d, J=1.4 Hz, 1H), 7.52 (dd, J=8.0 and 1.5 Hz, 1H), 7.34 (s, 1H), 3.96 (s, 3H); HPLC (Method B) tR 7.03 min (100 area % at 254 nm). Anal. (C9H7Br2NO) C, H, N, Br. 3-nitro-4-[(2-N,N-dimethylamino)ethenyl]benzonitrile (66). N,N-Dimethyl-formamide dimethyl acetal (12.1 g, 101 mmol) was added to a solution of nitrotoluene 63 (16.3 g, 101 mmol) in dry DMF (60 mL). The mixture was refluxed overnight under N2. The reaction mixture was poured into ice water to give a red solid (21.5 g, 99%): mp 122-126° C.; 1H NMR δ 8.22 (d, J=1.6 Hz, 1H), 7.84 (d, J=13.2 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.65 (dd, J=8.8 and 1.6 Hz, 1H), 5.67 (d, J=13.2 Hz, 1H), 2.98 (s, 6H). Anal. (C11H11N3O2) C, H, N. 2-Chloro-5-bromobenzoic acid methyl ester (72). A solution of benzoic acid 69 (30.0 g, 127 mmol) and H2SO4 (2 mL) in MeOH (2 L) was stirred at reflux for 3 d. The reaction mixture was concentrated to give white crystals (31.2 g, 98%): mp 43-44° C.; 1H NMR δ 7.99 (d, J=2.4 Hz, 1H), 7.80 (dd, J=8.6 and 2.5 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 3.87 (s, 3H); HPLC (Method B) tR 6.34 min (100 area % at 230 nm). 2-Chloro-5-cyanobenzoic acid methyl ester (73). DCC (11.4 g, 55.0 mmol) was added to a solution of benzoic acid 71, (9.08 g, 50.0 mmol), DMAP (0.60 g, 5.00 mmol) and MeOH (5 mL) in CH2Cl2 (100 mL) at 0° C. After 1 h the solution was warmed to 25° C. The reaction mixture was filtered and evaporated. The residue was purified by column chromatography (CH2Cl2) to give a light solid (9.21 g, 94%): mp 100-103° C.; 1H NMR δ 8.30 (d, J=2.2 Hz, 1H), 8.07 (dd, J=8.2 and 2.2 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 3.89 (s, 3H); HPLC (Method B) tR 4.57 min (100 area % at 254 nm). 4-Cyano-2-nitrobenzaldehyde (74a). NalO4 (65.0 g, 304 mmol) was added to a solution of intermediate 66 (21.0 g, 96.7 mmol) in THF and water (350 mL each). The mixture was stirred for 2.5 h, filtered, and extracted into EtOAc, and evaporated. Filtration of a suspension of the residue in CHCl3 through a plug of silica gel followed by recrystallization from toluene with activated carbon gave yellow crystals (13.1 g, 77%): mp 109-111° C.; 1H NMR δ 10.27 (s, 1H), 8.75 (d, J=1.5 Hz, 1H), 8.40 (dd, J=8.0 and 1.5 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H. Anal. (C8H4N2O3) C, H, N. 2-Chloro 4-cyanobenzaldehyde (74b). A solution of NaOEt was prepared from sodium (2.01 g, 87.4 mmol) and dry EtOH (150 mL). 2-Nitropropane (8 mL, 89 mmol) was added, followed after a few min by 3-chloro-4-bromomethylbenzonitrile (68, 13.5 g, 58.6 mmol). The mixture was stirred overnight, filtered, and evaporated. The residue was partitioned between water and EtOAc to give white solid (8.63 g, 89%). An analytical sample was recrystallized from aq. EtOH to give white needles: mp 117-119° C. (lit. 122-1230), see Schultz, E. M., et al., J. Med. Chem., 19(6), 783-787 (1976); 1H NMR δ 10.34 (s, 1H), 8.29 (m, 1H), 8.00 (m, 2H). Anal. (C8H4ClNO) C, H, N, Cl. 5-Bromo-2-chlorobenzaldehyde (74c). A solution of pyrrolidine (4.00 g, 56.0 mmol) in MTBE (12 mL) was added dropwise over 20 min to a solution of Red-Al® (3.4 M solution in toluene, 16 ml, 54.4 mmol) in MTBE (33 mL) maintained at −20° C. The mixture was stirred for 1 h at 25° C. A solution of potassium tert-butoxide (0.60 g, 5.36 mmol) in THF (3 mL) was added. The resulting solution was added dropwise to a solution of 2-chloro-5-bromobenzoic acid methyl ester (72, 6.80 g, 27.3 mmol) in MTBE (15 mL) at 10° C. After 15 min the mixture was quenched with 2 N HCl (300 mL). Repeated recystallizations (hexanes) of the recovered material gave a crude solid (3.22 g, 54%, mp 43-46° C.), which was used without further purification in the next step. 2-Chloro-5-cyanobenzaldehyde (74e) was prepared from ester 73 as described above for 74c. See Dann, O., et al., Liebigs Ann. Chem., 3, 438-455 (1986). Column chromatography of crude material (7.60 g, 100%) [hexane/EtOAc (7:3)], followed by recrystallization from hexane/EtOAc (2:1) gave a solid (3.15 g, 41%): mp 191-193° C.; 1H NMR δ 10.28 (s, 1H), 8.28 (d, J=2.2 Hz, 1H), 8.17 (dd, J=8.2 and 2.2 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H); HPLC (Method B) tR 3.70 min (100 area % at 254 nm) Anal. (C8H4ClNO) C, H, N, Cl.