Reaction SMILES: C(OC(=O)N([C@@H]1CCN(C2C([Cl:20])=C(NCCC3C=CC=CC=3)N=NC=2)C1)C)(C)(C)C.[Cl:31][C:32]1[C:33](N2CC[C@@H](N(C)C(=O)OC(C)(C)C)C2)=[CH:34][N:35]=[N:36][C:37]=1[Cl:38].C1(CCN)C=CC=CC=1>>[Cl:38][C:37]1[N:36]=[N:35][CH:34]=[C:33]([Cl:20])[C:32]=1[Cl:31]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2cnnc(Cl)c2Cl)C1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2cnnc(NCCc3ccccc3)c2Cl)C1
Agent: NCCc1ccccc1
Product: Clc1cnnc(Cl)c1Cl
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 59 %

Procedure:
A solution of 4,5-dichloropyridazin-3(2H)-one (2 g, 12 mmol) in 20 mL of phosphoryl trichloride was heated to reflux for 2 hrs. The solvent was removed under reduce pressure. The residue was poured into water with stirring and extracted with dichloromathene (50 mL*3). The organic layer was washed with brine, dried over Na2SO4, evaporated to give the crude product. The crude product was recrystallized with acetone/water to give the product (2 g, 89%). 1H NMR (300 MHz, CDCl3): 9.09 (s, 1H); LC-MS: m/z=182.9 [M+H]+. (R)-tert-butyl 1-(5,6-dichloropyridazin-4-yl)pyrrolidin-3-ylcarbamate. To a stirred solution of 3,4,5-trichloropyridazine (500 mg, 2.7 mmol) and DIPEA (1 mL) in propan-2-ol (5 mL) was added (R)-tert-butyl pyrrolidin-3-ylcarbamate (508 mg, 2.7 mmol) at ambient temperature (18 h). 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-(5,6-dichloropyridazin-4-yl)pyrrolidin-3-yl(methyl)-carbamate. NaH (60% in oil, 0.72 g, 18.0 mmol) was suspended in 40 mL of anhydrous DMF. A solution of (R)-tert-butyl 1-(5,6-dichloropyridazin-4-yl)pyrrolidin-3-ylcarbamate (5 g, 15 mmol) in anhydrous DMF (40 mL) was added at −5° C. After 40 min, CH3I (2.55 g, 18 mmol) was added. Then the resulting mixture was stirred at ambient temperature for 2 hours. The reaction was monitored by LC-MS. Water (100 mL) was added and the mixture was extracted with EtOAc (3×200 mL). The organic layer was washed with brine (3×200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel (Petroleum Ether/EtOAc=5/1, v/v) to afford the desired product (4.2 g, 80%). 1H NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 4.77-4.76 (m, 1H), 3.86-3.62 (m, 4H), 2.85 (s, 3H), 2.18-2.11 (m, 2H), 1.46 (s, 9H); LC-MS: m/z=347.1 [M+H]+. (R)-tert-butyl1-(5-chloro-6-(phenethylamino)pyridazin-4-yl)pyrrolidin-3-yl(methyl)-carbamate. A mixture of (R)-tert-butyl 1-(5,6-dichloropyridazin-4-yl)pyrrolidin-3-yl(methyl)carbamate (400 mg, 1.15 mmol) and 2-phenylethanamine (1 mL) was stirred at 150° C. for 40 min in microwave. The mixture was concentrated and the residue was purified by silica gel chromatography (MeOH/DCM=1/50, v/v) to afford the desired product (295 mg, 59%). LC-MS: m/z=432.1 [M+H]+. (R)-tert-butylmethyl(1-(6-(phenethylamino)pyridazin-4-yl)pyrrolidin-3-yl) carbamate. To a mixture of (R)-tert-butyl1-(5-chloro-6-(phenethylamino)pyridazin-4-yl)pyrrolidin-3-yl(methyl)-carbamate (295 mg, 0.68 mmol) and HCOONH4 (0.5 g, 7.9 mmol) in MeOH (15 mL) was added 10% Pd/C (0.3 g) and the resulting mixture was refluxed 30 min. The reaction was allowed to cool and filtered. The filtrate was concentrated, then diluted with EA (20 mL) and washed with brine (10 mL*2). The combined organic layer was dried over Na2SO4, filtered, concentrated and purified by prep-HPLC to give the product as oil (177 mg, 65%). 1H NMR (300 MHz, CDCl3): δ 8.80 (s, 1H), 7.70 (d, J=5.4 Hz 1H), 7.30-7.18 (m, 5H), 5.30 (5.30, J=9.6 Hz, 1H), 4.86 (d, J=6.3 Hz, 1H), 3.78-3.73 (m, 1H), 3.49-3.35 (m, 4H), 2.96 (t, J=7.2 Hz, 2H), 2.82 (s, 3H), 2.23 (s, 2H), 1.48 (s, 9H); LC-MS: m/z=398.1 [M+H]+. (R)-5-(3-(methylamino)pyrrolidin-1-yl)-N-phenethylpyridazin-3-amine dihydrochloride. To a solution of (R)-tert-butylmethyl(1-(6-(phenethylamino)pyridazin-4-yl)pyrrolidin-3-yl)carbamate (177 mg, 44 mmol) in MeOH (3 mL) was added ether solution of HCl gas (7N, 10 mL). The reaction was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure to give the desired product as a white solid (32.2 mg, 20%). 1H NMR (300 MHz, CD3OD): 8.13 (d, J=2.4 Hz, 1H), 7.33-7.25 (m, 5H), 5.98 (d, J=2.4 Hz, 1H), 4.01-3.62 (m, 7H), 3.00 (t, J=6.9 Hz, 2H), 2.84 (s, 3H), 2.60-2.30 (m, 2H); LC-MS: m/z=298.3 [M+H]+, tR=1.0 min; HPLC: 98% (214 nm), 99% (254 nm), tR=7.1 min. The compounds in Example 373 through Example 403 were prepared using methods analogous to those described in Example 372.