(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hepta...

To a solution of acid 1 (50 mg, 0.1 1 mmol) in DMF (1 ml_) was added N- methylmorpholine (49 pl_, 0.45 mmol) followed by PyBOP (87 mg, 0.17 mmol). The reaction mixture was stirred for 30 min at rt before addition of (1 S, 4S)-2- oxa-5-azabicyclo[2.2.1]heptane hydrochloride (30 mg, 0.22 mmol). After 2 h 20 min the reaction mixture was diluted with EtOAc (30 ml_), washed with HCI solution (5%, 3 x 10 ml_), water (10 ml_), sodium bicarbonate solution (5%, 3 x 5 ml_), and brine (10 ml_), before being dried over MgS04, filtered and concentrated in vacuo. Purification by flash column chromatography with EtOAc/MeOH (1 :0 to 9:1 ) afforded FV as pale yellow solids (45 mg, 76%). (1398) LCMS (ES): Found 530.9 [M+Hf. (1399) 1H NMR (300 MHz, DMSO-cf6) d: Two rotamers in 3:2 ratio; 9.01 (d, J=1.7 Hz, 1 H minor), 8.99 (d, J=1.7 Hz, 1 H major), 8.87 (d, J=1.5 Hz, 1 H major), 8.81 (d, J=1.3 Hz, 1 H minor), 8.36-8.43 (m, 1 H major + 1 H minor), 8.31 (d, J=2.6 Hz, 1 H major + 1 H minor), 7.87 (d, J=1.7 Hz, 1 H minor), 7.82 (d, J=1.7 Hz, 1 H major), 7.72-7.78 (m, 1 H major + 1 H minor), 7.28-7.36 (m, 1 H major + 1 H minor), 5.69- 5.86 (m, 2H major + 2H minor), 4.87 (br s, 1 H minor), 4.67 (br s, 1 H major), 4.61 (br s, 1 H minor), 4.42 (br s, 1 H major), 3.89 (d, J=7.7 Hz, 1 H major), 3.81 (d, J=7.0 Hz, 1 H minor), 3.75 (dd, J=7.9, 1.9 Hz, 1 H minor), 3.64 (dd, J=7.6, 1.4 Hz, 1 H major), 3.45-3.52 (m, 1 H major + 1 H minor), 3.26-3.32 (m, 1 H major + 1 H minor), 1.76-1.94 (m, 2H major + 2H minor). (1400) 19F NMR (282 MHz, DMSO-cf6) d: -64.80 (s, 3F).To a solution of compound 1 (21.0 mg, 0.0467 mmol, 1.0 eq) in DMF (1 ml_) was added A/, A/-diisopropylethylamine (32.6 mI_, 0.187 mmol, 4.0 eq), HATU (26.7 mg, 0.0701 mmol, 1.5 eq) and (1 S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (2) (12.7 mg, 0.0935 mmol, 2.0 eq). The reaction was stirred at room temperature for 17.5 h then diluted with EtOAc (10 ml_), washed with 1 M HCI (2 x 10 ml_) and brine (10 ml_), dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel chromatography using hexane/EtOAc/MeOH (1 :0:0 - 0:1 :0 - 0:4: 1 ) yielded compound FE as an off-white solid (22.2 mg, 68%). (1248) LCMS (ES): Found 530.9 [M+Hf. (1249) 1H NMR (300MHz, DMSO-cf6), d: Two rotamers in 3:2 ratio; 8.82-8.91 (m, 1 H major rotamer + 1 H minor rotamer), 8.43-8.51 (m, 1 H major + 1 H minor), 8.32- 8.40 (m, 1 H major + 1 H minor), 7.79-7.97 (m, 2H major + 2H minor), 7.70-7.78 (m, 1 H major + 1 H minor), 7.27-7.37 (m, 1 H major + 1 H minor), 5.72-5.81 (m, 2H major + 2H minor), 5.14-5.20 (m, 1 H major), 4.94-5.01 (m, 1 H minor), 4.66-4.70 (m, 1 H major), 4.60-4.66 (m, 1 H minor), 3.85-3.93 (m, 1 H major + 1 H minor), 3.77-3.85 (m, 1 H major + 2H minor), 3.69-3.76 (m, 1 H minor), 3.52-3.58 (m, 1 H major), 3.38-3.43 (m, 1 H major), 1.88-1.97 (m, 1 H major + 1 H minor), 1.79-1.88 (m, 1 H major + 1 H minor). (1250) 19F NMR (282MHz, DMSO-cf6), d: -64.79 (s, 3F).2-bromo-5-chloropyridine (200 mg, 1.039 mmol) was dissolved in acetonitrile (2.5 mL), to this (1 S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (211 mg, 1.559 mmol) and triethylamine (0.362 mL, 2.60 mmol) were added and the suspension was irradiated in the microwave to 160C for 1 h20. The sample was then extracted between water (20 mL) and dichloromethane (20 mL). The aqueous layer was washed twice with dichloromethane. The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The crude was purified on a silica gel column using a Biotage Isolera One purification system with a dichloromethane/methanol gradient (100/0 -> 90/10) to get the product as a beige solid (57 mg, 26 %). (0876) MS: 21 1.03 (M+H)+. (0877) 1H-NMR (400 MHz, DMSO -d6) d = 8.06 (d, J = 2.6 Hz, 1 H), 7.56 (dd, J = 9.0, 2.7 Hz, 1 H), 6.57 (d, J = 9.0 Hz, 1 H), 4.80 (d, J = 2.3 Hz, 1 H), 4.65 (d, J = 2.4 Hz, 1 H), 3.76 (dd, J = 7.3, 1.5 Hz, 1 H), 3.61 (d, J = 7.3 Hz, 1 H), 3.43 (dd, J = 10.1 , 1.5 Hz, 1 H), 3.20 (d, J = 10.3 Hz, 1 H), 1.90 (dd, J = 9.7, 2.3 Hz, 1 H), 1.87 - 1.81 (m, 1 H).To a solution of D94 (200 mg, 0.51 mmol) and (1 S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (346 mg, 2.56 mmol) in MeOH (25 mL) was slowly added NaBH3CN (97 mg, 1 .55 mmol) and the reaction was stirred for 16 hrs. Sat. NaHCC>3 (50 mL) was added and the mixture was stirred for 30 min. MeOH was evaporated and the mixture was filtered and extracted with DCM (3x25 mL). The combined organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The crude was further chiral separated (chiral method A) to give the title compounds as yellow solids. E102: LC-MS: 474.2[M+H] +. 1H NMR (400 MHz, CDCI3): delta 7.84 (s, 1 H), 6.05 (br, 1 H), 5.1 1 (d, J= 6.8 Hz, 1 H), 4.56-4.25 (m, 3H), 4.05 (d, J= 7.6 Hz, 2H), 3.91 -3.53 (m, 3H), 3.1 1 (d, J= 9.6 Hz, 1 H), 2.47 (d, J= 10.2 Hz, 2H), 2.18 (s, 3H), 2.13-1 .72 (m, 1 1 H), 1.32 (d, J= 6.8 Hz, 3H). Chiral RT=2.841 min; ee=100percent. E103: LC-MS: 474.2[M+H] +. 1H NMR (400 MHz, CDC ): delta 7.81 (s, 1 H), 6.06 (br, 1 H), 5.1 1 (d, J= 6.8 Hz, 1 H), 4.58-4.22 (m, 3H), 4.13-3.81 (m, 3H), 3.72-3.52 (m, 2H), 3.05 (d, J= 9.6 Hz, 1 H), 2.72 (br, 1 H), 2.47-2.20 (m, 3H), 2.20 (s, 3H), 2.04-1.47 (m, 10H), 1.32 (d, J= 6.8 Hz, 3H) Chiral RT=3.031 min; ee=99.7percent. E104: LC-MS: 474.3[M+H] +. 1H NMR (400 MHz, CDCI3): delta 7.82 (s, 1 H), 6.05 (br, 1 H), 5.1 1 (d, J= 6.4 Hz, 1 H), 4.58-4.25 (m, 3H), 4.05 (d, J= 8.0 Hz, 2H), 3.90-3.53 (m, 3H), 3.10 (d, J= 9.6 Hz, 1 H), 2.47 (d, J= 9.6 Hz, 2H), 2.18 (s, 3H), 2.1 1 -1 .74 (m, 1 1 H), 1.31 (d, J= 6.8 Hz, 3H). Chiral RT=3.296 min; ee= 97.5percent E105: LC-MS: 474.2[M+H] +. 1H NMR (400 MHz, CDCI3): delta 7.81 (s, 1 H), 6.08 (br, 1 H), 5.1 1 (d, J= 6.8 Hz, 1 H), 4.61 -4.20 (m, 3H), 4.1 1 -3.80 (m, 3H), 3.70-3.56 (m, 2H), 3.09 (d, J= 9.6 Hz, 1 H), 2.73 (br, 1 H), 2.44-2.21 (m, 3H), 2.19 (s, 3H), 1.99-1.71 (m, 6H), 1.68-1.48 (m, 4H), 1 .31 (d, J= 6.8 Hz, 3H). Chiral RT= 3.539 min; ee= 99.3percent.To a solution of D85 (100 mg, 0.265 mmol), (1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (43 mg, 0.319 mmol), 4A molecular sieves (100 mg), AcOH (10 mg) in CH2CI2 (5 mL) under argon at 0 °C was added NaBHsCN (35 mg, 0.557 mmol). The reaction was stirred for 15 hrs at room temperature. The mixture was filtered and aq. NaHCC (20 mL) was added. The organic layer was concentrated and the crude was purified by prep-TLC (CH2CI2: MeOH = 8: 1) to give the mixture as a yellow solid (88 mg, yield 72percent). The title compounds E50 (10 mg) and E51 (21 mg) were obtained as white solids from chiral separation of the mixture (chiral method F). E50: LC-MS: 460.3 [M+H] +.1H NMR (400 MHz, CDCl3): delta 7.81 (s, 1 H), 6.07 (br, 1 H), 5.53 (br, 1H), 4.40 (br, 3H), 4.05 (d, J= 8.0 Hz, 1H), 3.85 (br, 1H), 3.74 (br, 1H), 3.68-3.46 (m, 3H), 3.11 (d, J= 9.6 Hz, 1H), 2.48 (d, J= 9.2 Hz, 2H), 2.19 (s, 3H), 2.13-1.82 (m, 9H), 1.83- 1.72 (m, 1H), 1.40-1.18 (m, 2H). Chiral RT =4.549 min. E51: LC-MS: 460.3 [M+H]+.1H NMR (400 MHz, CDCl3): delta 7.81 (br, 1H), 6.07 (br, 1H), 5.53 (br, 1H), 4.40 (br, 3H), 4.06 (d, J= 7.6 Hz, 1H), 3.91 (br, 1H), 3.70-3.58 (m, 2H), 3.52 (d, J= 4.8 Hz, 2H), 3.07 (d, J= 8.4 Hz, 1H), 2.72 (br, 1H), 2.44-2.23 (m, 3H), 2.23-2.14 (m, 4H), 1.93 (br, 5H), 1.68-1.43 (m, 4H). Chiral RT =5.341 min.Example 89A methyl 2-((1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidine-4-carboxylate Methyl 2-chloropyrimidine-4-carboxylate (2.4 g) and

Molecular Weight:135.59
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:2
Exact Mass:135.0450916
Monoisotopic Mass:135.0450916
Topological Polar Surface Area:21.3
Heavy Atom Count:8
Complexity:84.1
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes