[C:1](Cl)(=[O:5])[C:2](Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:17][CH:16](C(O)=O)[CH2:15]2)=[CH:10][CH:9]=1.[Si](C=[N+]=[N-])(C)(C)C.Cl.[O:29]1CCCC1>CN(C=O)C.ClCCl.C(N(CC)CC)C.FC(F)(F)C([O-])=O.[Ag+].O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:17][CH:16]([CH2:2][C:1]([OH:5])=[O:29])[CH2:15]2)=[CH:12][CH:13]=1Oxalyl chloride (20.7 g, 164.29 mmol, 1.20 equiv) and two drops of DMF were added into a solution of 3-(4-bromophenyl)cyclobutane-1-carboxylic acid (38 g, 148.96 mmol, 1.00 equiv) (U.S. Pat. No. 5,541,343 A1) in dichloromethane (200 mL) at 0° C. After being stirred for 1 h at 25° C. the solvent was removed and the residue was dissolved in tetrahydrofuran (300 mL). To this was added triethylamine (16 g, 158.12 mmol, 1.07 equiv) dropwise with stirring at 0° C. The solution was stirred for 10 min at 0° C. and a solution of TMSCHN2 (2.0 M in hexane, 145 mL, 1.95 equiv) was added dropwise at 0° C. The resulting solution was stirred for 3 h at room temperature, quenched with sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 28.0 g (67%) of 2-[3-(4-bromophenyl)cyclobutyl]-2-oxoethane-1-diazonium as a yellow solid. LC-MS 279, 281 [M+H]+; A solution of silver trifluoroacetate (2.7 g, 12.27 mmol, 0.10 equiv) in triethylamine (48 mL) was added into a solution of the above diazonium (35 g, 125.39 mmol, 1.00 equiv) in tetrahydrofuran (350 mL)/water (35 mL) at −30° C. under a nitrogen atmosphere (1 atm) in darkness. The reaction solution was stirred for 4 h at room temperature and the pH value of the solution was adjusted to 2 with 2N hydrogen chloride. The resulting solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:3) to give 22 g (65%) of 2-[3-(4-bromophenyl)cyclobutyl]acetic acid as a yellow solid. LC-MS 267, 269 [M−H]+. A suspension of 2-[3-(4-bromophenyl)cyclobutyl]acetic acid (6 g, 22.29 mmol, 1.00 equiv) in polyphosphoric acid (100 mL) was stirred for 12 h at 100° C. The resulting solution was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 1.0 g (18%) 2-bromo-7,8-dihydro-5H-5,7-methanobenzo[7]annulen-9(6H)-one as yellow oil. Bromine (100 uL, 1.00 equiv) was added into a solution of this intermediate (500 mg, 1.99 mmol, 1.00 equiv) in dichloromethane (3 mL) with stirring at −10° C. After being stirred for 2 h at −10° C. the reaction was quenched by sodium bicarbonate, diluted with 50 mL of DCM, washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 600 mg (91%) of 2,8-dibromo-7,8-dihydro-5H-5,7-methanobenzo[7]annulen-9(6H)-one as yellow oil; LC-MS 329, 331 [M+H]+. A solution of this intermediate (650 mg, 1.97 mmol, 1.00 equiv) and thiourea (0.6 mg, 0.01 mmol, 4.00 equiv) in 1,4-dioxane (10 mL) was stirred for 12 h at 90° C. The resulting solution was diluted with 100 mL of DCM, washed with 50 mL of saturated sodium bicarbonate and 50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 350 mg (58%) of 9-bromo-5,6-dihydro-4H-4,6-methanobenzo[6,7]cyclohepta[1,2-d]thiazol-2-amine as light brown oil. LC-MS 307, 309 [M+H]+. A solution of this intermediate (350 g, 1.14 mol, 1.00 equiv), n-BuONO (0.65 g, 5.50 equiv), CH2I2 (0.5 mL) in dichloromethane (5 mL) was stirred for 6 h at room temperature. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column with petroleum ether. This resulted in 200 mg (42%) of 9-bromo-2-iodo-5,6-dihydro-4H-4,6-methanobenzo[6,7]cyclohepta[1,2-d]thiazole LC-MS 418, 420 [M+H]+. A suspension of this intermediate (200 mg, 0.48 mmol, 1.00 equiv) and cuprous cyanide (169 mg, 1.90 mmol, 4.00 equiv) in DMSO (2 mL) and water (0.2 mL) was stirred for 12 h at 90° C. The resulting solution was diluted with 100 mL of DCM and washed with water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:4) to give 30 mg (19%) of the titled compound.
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