2-Chloro-6-fluorobenzoxazole

Into a 500-mL round-bottom flask, was placed 6-fluoro-2, 3-dihydro-l, 3-benzoxazole-2- thione (9.2 g, 54.38 mmol, 1.00 equiv), thionyl chloride (200 mL) and DMF(0.5 mL). The resulting solution was stirred for 6 h at 80°C in an oil bath. After reaction, the excess of SOCh was removed under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0/100-7/93). The fractions were collected and concentrated under vacuum. This resulted in 3.5 g (38percent) of the title compound as brown oil. LC-MS (ES, m/z) 172 [M+H]Into a 500-mL round-bottom flask, was placed 6-fluoro-2, 3-dihydro-l, 3-benzoxazole-2- thione (9.2 g, 54.38 mmol, 1.00 equiv), thionyl chloride (200 mL) and DMF(0.5 mL). The resulting solution was stirred for 6 h at 80°C in an oil bath. After reaction, the excess of SOCh was removed under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0/100-7/93). The fractions were collected and concentrated under vacuum. This resulted in 3.5 g (38percent) of the title compound as brown oil. LC-MS (ES, m/z) 172 [M+H]To a solution of N-[(1S, 25)-2-arninocyclopentyl]-2-(difluoromethoxy)benzamide hydrochloride (Intermediate 11; 45 mg, 0.15 mmol) in DMSO (0.5 ml) was added DIPEA (57 mg, 0.44 mmol) and 2-chloro-6-fluoro-l, 3-benzoxazole (CAS number 153403-53-3; 30 mg, 0.17 mmol). The reaction mixture was heated to 140C for 4 hours then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 30 - 80% ethyl acetate / petrol) then purified further by reverse phase chromatography (C 8 silica, 5-95% water (with 0, 05% ammonia) / (0606) acetonitrile) to afford the title compound. (0607) 3H NMR (400 MHz, DMSO- ) delta ppm 1.53 - 1 .67 (m, 2 H), 1 .67 - 1 .81 (m, 2 H), 2.01 - 2.18 (m, 2 }. 4.06 - 4.19 (m, 1 H), 4.22 - 4.32 (m, 1 H), 6.88 - 7.38 (m, 4 H), 7.52 - 7.65 (m, 1 H), 7.67 - 7.79 (m, 1 H), 8.03 - 8.17 (m, 1 H), 8.44 - 8.53 (m, 1 H), 8.77 - 8.87 (m, 1 H) (0608) MS ES+: 407To a solution of N-[(/S, 2S)-2-aminocyclopentyl]-3-methoxypyridine-2-carboxarnide hydrochloride (Intermediate 2; 75 mg, 0.28 mmol) and DIPEA (0.15 ml, 0.83 mmol) in DMSO (1 ml) was added 2-chloro-6-fluoro-l, 3-benzoxazole (CAS number 153403-53-3; 57 mg, 0.33 mmol) and the reaction mixture was subjected to microwave irradiation at 140 C for 2 hours. The reaction mixture was partitioned between DCM and water. The organics were filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (eluted with acetonitrile / water containing 0.1 % ammonia) to afford the title compound. (0530) 1H NMR (DCM-ii2) delta ppm 1.66-1.82 (m, 2 H), 1.86-1.94 (m, 2 H), 2.21-2.32 (m, 1 H), 2.46-2.58 (m, 1 H), 3.91 (s, 3 H), 3.91 -3.99 (m, 1 H), 4.35-4.45 (m, 1 H), 6.55-6.66 (m, 1 H), 6.85-6.93 (m, 1 H), 6.98-7.02 (m, 1 H), 7.16-7.20 (m, 1 H), 7.45-7.56 (m, 2 H), 8.08- 8.19 (m, 1 H), 8.15-8.23 (m, 1 H) (0531) MS ES+: 371Example 66: N-[(/5, 25)-2-[(6-Fluoro-l<3-benzoxazol-2-vl)amino1cvclopentyl1-2<6- dimethoxybenzamide To a solution of N-((iS, 2S)-2-aminocyclopentyl)-2, 6-dimethoxybenzamide hydrochloride (Intermediate 11, 100 mg, 0.332 mmol) in dry DMSO (1 ml) was added 2-chloro-6- fluoro-l, 3-benzoxazole (57 mg, 0.332 mmol) and DIPEA (0.17 ml, 0.997 mmol). The reaction was irradiated under microwave conditions at 150 C for 8 hours and, upon cooling, was partitioned between ethyl acetate and water. The organic portion was washed with water and brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC (acetonitrile / water containing 0.1% ammonia) to afford the title compound.1H NMR (DMSO-i/6) delta ppm 1.47 - 1.75 (m, 4 H), 1.95 - 2.12 (m, 2 H), 3.57 (s, 6 H), 4.01 - 4.07 (m, 1 H), 4.23 - 4.30 ( m, 1 H), 6.57 - 6.66 (m, 2 H), 6.87 - 7.02 (m, 1 H), 7.13 - 7.26 (m, 2 H), 7.33 - 7.44 (m, 1 H), 7.92 - 8.20 (m, 2 H)MS ES+: 400Example 99: N-[(/5, 25)-2-[(6-Fluoro-l<3-benzoxazol-2-vl)amino1cvclopentyl1-2-(3- methyl-l, 2, 4-oxadiazol-5-yl)benzamide To a solution of N-[(lS, 2S)-2-aminocyclopentyl]-2-(3-methyl- l, 2, 4-oxadiazol-5- yl)benzamide hydrochloride (Intermediate 26; 100 mg, 0.310 mmol) in dry DMSO (1 ml) was added DIPEA (162 mu, 0.929 mmol) and 2-chloro-6-fluoro-l, 3-benzoxazole (CAS Number 153403-53-3; 64 mg, 0.372 mmol). The reaction was subjected to microwave irradiation at 140C for 1 hour. The reaction was then purified by reverse phase preparative HPLC (acetonitrile / water with 0.1% ammonia) to afford the title compound.1H NMR (400 MHz, DMSO-d6): delta ppm 1.55 - 1.78 (m, 4 H), 2.00 - 2.12 (m, 2 H), 2.35 (s, 3 H), 4.01 - 4.12 (m, 1 H), 4.19 - 4.29 (m, 1 H), 6.91 - 7.00 (m, 1 H), 7.15 - 7.21 (m, 1 H), 7.30 - 7.36 (m, 1 H), 7.50 - 7.56 (m, 1 H), 7.59 - 7.70 (m, 2 H), 7.89 - 7.95 (m, 1 H), 8.02 - 8.09 (m, 1 H), 8.58 - 8.65 (m, 1 H)MS ES+: 422Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 4-[[2-fluoro-4-(tetramethyl-l, 3, 2- dioxaborolan-2-yl)phenyl]carbonyl]piperazine-l-carboxylate (1.26 g, 2.90 mmol, 1.00 equiv) in toluene (24 mL), 2-chloro-6-fluoro-l, 3-benzoxazole (500 mg, 2.91 mmol, 1.00 equiv), Pd(PPh3)4 (336 mg, 0.29 mmol, 0.10 equiv), sodium carbonate (12 mL, 2M), ethanol (3.3 mL). The resulting mixture was stirred overnight at 95C. After cooling to room temperature, the resulting solution was diluted with 30 ml of water and extracted with 2x30 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with EA/DCM (3/10). This resulted in 1.1 g (86%) of the title compound as a gray solid. LC-MS (ES, m/z) 444 [M+H]+Into a 500-mL round-bottom flask, was placed 6-fluoro-2, 3-dihydro-l, 3-benzoxazole-2- thione (9.2 g, 54.38 mmol, 1.00 equiv), thionyl chloride (200 mL) and DMF(0.5 mL). The resulting solution was stirred for 6 h at 80C in an oil bath. After reaction, the excess of SOCh was removed under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0/100-7/93). The fractions were collected and concentrated under vacuum. This resulted in 3.5 g (38%) of the title compound as brown oil. LC-MS (ES, m/z) 172 [M+H]+

Molecular Weight:171.55
XLogP3:3.2
Hydrogen Bond Acceptor Count:3
Exact Mass:170.9887196
Monoisotopic Mass:170.9887196
Topological Polar Surface Area:26
Heavy Atom Count:11
Complexity:157
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes