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To a stirred solution of 3,4,5-trichloropyridazine (500 mg, 5.5 mmol) and DIPEA (1 mL) in propan-2-ol (5 mL) was added (R)-tert-butyl pyrrolidin-3-ylcarbamate (508 mg, 5.5 mmol) at ambient temperature. The solvent was removed and the residue was purified by column chromatography (petroleum ether/ethyl acetate=2/1, v/v) to afford the title desired product (500 mg, 55%). 1H NMR (300 MHz, CDCl3): 8.42 (s, 1H), 5.06 (br s, 1H), 4.36 (br s, 1H), 4.05-3.99 (m, 1H), 3.90-3.66 (m, 3H), 2.28-2.23 (m, 1H), 2.09-2.07 (m, 1H), 1.48 (s, 9H); LC-MS: m/z=333.1 [M+H]+ (R)-tert-butyl 1-(5-chloro-6-(2-methoxyethylamino)pyridazin-4-yl)pyrrolidin-3-ylcarbamate. A mixture of 100 mg of (R)-tert-butyl 1-(5,6-dichloropyridazin-4-yl)pyrrolidin-3-ylcarbamate and 2-methoxyethanamine (1 mL) was heated at 145° C. for 40 min in microwave. The mixture was concentrated and the crude was purified by silica gel chromatography (EA/PE=1/4, v/v) to give the title product (50 mg, 45%). LC-MS: m/z=372.2 [M+H]+. (R)-tert-butyl 1-(6-(2-methoxyethylamino)pyridazin-4-yl)pyrrolidin-3-ylcarbamate. To the mixture of (R)-tert-butyl 1-(5-chloro-6-(2-methoxyethylamino)pyridazin-4-yl)pyrrolidin-3-ylcarbamate (50 mg, 0.13 mmol) and ammonium formate (HCOONH4) (85 mg, 1.3 mmol) in MeOH (2 mL) was added 10% Pd/C (20 mg). The resulting mixture was refluxed for 2 hours. The reaction was allowed to cool to room temperature and filtered. The filtrate was concentrated, diluted with EA (20 mL) and washed with brine (10 mL*2). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by pre-TLC (PE/EA=1/5, v/v) to give the product as oil (20 mg, 44%). 1H NMR (300 MHz, CDCl3): 8.02 (s, 1H), 5.46 (s, 1H), 5.10-5.08 (m, 1H), 4.91 (br s, 1H), 4.33-4.26 (m, 1H), 3.59-3.51 (m, 4H), 3.40-3.35 (m, 4H), 3.19-3.15 (m, 1H), 2.28-2.19 (m, 1H), 1.99-1.97 (m, 1H), 1.44 (s, 9H); LC-MS: m/z=338.2 [M+H]+. (R)-5-(3-aminopyrrolidin-1-yl)-N-(2-methoxyethyl)pyridazin-3-amine dihydrochloride. To solution of (R)-tert-butyl 1-(6-(2-methoxyethylamino)pyridazin-4-yl)pyrrolidin-3-ylcarbamate (198 mg, 0.59 mmol) in MeOH (3 mL) was added 7N HCl in ether (10 mL). The reaction was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure to give the desired product as a light yellow solid (94.5 mg, 52%). 1H NMR (300 MHz, CD3OD): 8.14 (s, 1H), 6.12 (s, 1H), 4.15-3.54 (m, 9H), 3.40 (s, 3H), 2.57-2.52 (m, 1H), 2.32-2.30 (m, 1H); mass calcd. for C11H19N5O, 237.31, LC-MS: m/z=238.2 [M+H]+, tR=0.3 min; HPLC: 99% (214 nm), 95% (254 nm), tR=4.4 min. The compounds in Example 299 through Example 310 were prepared using methods analogous to those described in Example 298.
