Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[N:25]3[CH2:30][CH2:29][C@H:28]([CH3:31])[C@H:27]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:26]3)=[N:16][CH:17]=2)[N:14]=1.FC1C=CC=C(F)C=1C1C=CC2N(C(NC3C=NC=CC=3N3CC[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C3)=NC=2)N=1.P(C)(C)C.N(CC1N=NC(C2C(F)=CC=CC=2F)=CC=1)=[N+]=[N-].N(C1C=NC=CC=1N1CCC(C)C(NC(=O)OC(C)(C)C)C1)=C=S>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[N:25]3[CH2:30][CH2:29][CH:28]([CH3:31])[CH:27]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:26]3)=[N:16][CH:17]=2)[N:14]=1
Reactant: C[C@H]1CCN(c2ccncc2Nc2ncc3ccc(-c4c(F)cccc4F)nn23)C[C@H]1NC(=O)OC(C)(C)C
Agent: CC1CCN(c2ccncc2N=C=S)CC1NC(=O)OC(C)(C)C
Agent: CP(C)C
Agent: C[C@@H]1CCN(c2ccncc2Nc2ncc3ccc(-c4c(F)cccc4F)nn23)C[C@H]1NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC1CCN(c2ccncc2Nc2ncc3ccc(-c4c(F)cccc4F)nn23)CC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 96 %

Procedure:
tert-butyl ((cis)-1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-4-methylpiperidin-3-yl)carbamate (enantiomer 1), tert-butyl ((cis)-1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-4-methylpiperidin-3-yl)carbamate (enantiomer 2), tert-butyl ((trans)-1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-4-methylpiperidin-3-yl)carbamate (enantiomer 1), tert-butyl ((trans)-1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-4-methylpiperidin-3-yl)carbamate (enantiomer 2). PMe3 (1.0 M solution in THF, 1.25 mL, 1.25 mmol) was added dropwise to a solution of 3-(azidomethyl)-6-(2,6-difluorophenyl)pyridazine (296 mg, 1.20 mmol, Preparation I) in THF (6.0 mL) at RT. The reaction mixture turned purple and an evolution of gas was observed. The reaction mixture was stirred at RT for 50 min. A solution of tert-butyl (1-(3-isothiocyanatopyridin-4-yl)-4-methylpiperidin-3-yl)carbamate (438 mg, 1.26 mmol, Preparation LVI) in THF (4 mL) was added, and the resulting bright orange solution was stirred at RT for 15 min. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (0-10% MeOH in DCM) to give tert-butyl (1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-4-methylpiperidin-3-yl)carbamate (613 mg, 1.15 mmol, 96% yield) as a mixture of isomers (ca. 4:1 ratio of cis:trans diastereomers) as an orange solid. MS (ESI, pos. ion) m/z: 536.2 (M+1). The isomers were purified by preparatory SFC (Chiralcel AS-H column (21×250 mm i.d., 5 μm) 80% liquid CO2/20% MeOH (40 mM NH3), 65 mL/min). The resulting material was then repurified using preparatory SFC (Chiralpak AD-H column (21×250 mm i.d., 5 μm) 70% liquid CO2/30% 2-propanol (20 mM NH3) 65 mL/min) to provide tert-butyl ((cis)-1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-4-methylpiperidin-3-yl)carbamate (enantiomer 1) (167 mg, 27% yield) which eluted first from an analytical SFC column (Chiralpak AD-H column (4.6×150 mm, 5 μm) 70% liquid CO2/30% 2-propanol (0.2% diethylamine), 4 mL/min). MS (ESI, pos. ion) m/z: 536.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 9.63 (s, 1 H), 8.22 (d, J=5.1 Hz, 1 H), 7.72-7.83 (m, 2H), 7.41-7.53 (m, 1 H), 7.38 (s, 1 H), 7.08 (t, J=8.1 Hz, 2 H), 6.90 (d, J=5.1 Hz, 1 H), 6.57 (d, J=9.6 Hz, 1 H), 5.24 (d, J=9.6 Hz, 1 H), 3.35 (d, J=12.3 Hz, 1 H), 3.09-3.19 (m, 2 H), 2.43 (td, J=11.5, 3.5 Hz, 1 H), 1.79 (br. s., 1 H), 1.59 (br. s., 3 H), 1.32 (s, 9 H), 0.89 (d, J=6.7 Hz, 3 H). 19F NMR (376 MHz, CDCl3) δ ppm −112.08 (s, 2 F); tert-butyl ((cis)-1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-4-methylpiperidin-3-yl)carbamate (enantiomer 2) (182 mg, 30% yield) which eluted second from an analytical SFC column (Chiralpak AD-H column (4.6×150 mm, 5 μm) 70% liquid CO2/30% 2-propanol (0.2% diethylamine), 4 mL/min). MS (ESI, pos. ion) m/z: 536.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 9.67 (s, 1 H), 8.27 (d, J=5.5 Hz, 1H), 7.80 (d, J=9.4 Hz, 1 H), 7.74 (s, 1 H), 7.43-7.52 (m, 1 H), 7.38 (s, 1 H), 7.08 (t, J=8.2 Hz, 2 H), 6.96 (d, J=5.5 Hz, 1 H), 6.60 (d, J=9.4 Hz, 1 H), 5.23 (d, J=10.0 Hz, 1H), 3.43 (d, J=11.7 Hz, 1 H), 3.14-3.25 (m, 2 H), 2.41-2.54 (m, 1 H), 1.75-1.88 (m, 2H), 1.49-1.55 (m, 2 H), 1.33 (s, 9 H), 0.90 (d, J=6.7 Hz, 3 H). 19F NMR (376 MHz, CDCl3) δ ppm −112.14 (s, 2 F); tert-butyl ((trans)-1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-4-methylpiperidin-3-yl)carbamate (enantiomer 1) (40 mg, 7% yield) which eluted first from an analytical SFC column (Chiralpak AS-H column (4.6×150 mm, 5 μm) 85% liquid CO2/15% MeOH (0.2% diethylamine) 4 mL/min). MS (ESI, pos. ion) m/z: 536.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 9.78 (s, 1 H), 8.28 (d, J=5.5 Hz, 1 H), 7.78 (d, J=9.4 Hz, 1 H), 7.71 (br. s., 1 H), 7.40-7.49 (m, 1 H), 7.36 (s, 1 H), 6.97-7.11 (m, 3 H), 6.55 (d, J=9.4 Hz, 1H), 4.40-4.48 (m, 1 H), 3.41-3.51 (m, 2 H), 3.32-3.40 (m, 1 H), 2.61-2.77 (m, 1 H), 2.43-2.56 (m, 1 H), 1.79-1.87 (m, 2 H), 1.58-1.70 (m, 3 H), 1.41 (br. s., 9 H), 1.00 (d, J=6.5 Hz, 3 H). 19F NMR (377 MHz, CDCl3) δ ppm −112.42 (s, 2 F); tert-butyl ((trans)-1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-4-methylpiperidin-3-yl)carbamate (enantiomer 2) (35 mg, 6% yield) which eluted as the second peak from an analytical SFC column (Chiralpak AS-H column (4.6×150 mm, 5 μm) 85% liquid CO2/15% MeOH (0.2% diethylamine) 4 mL/min). MS (ESI, pos. ion) m/z: 536.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 9.70 (s, 1 H), 8.20 (d, J=5.1 Hz, 1H), 7.76 (d, J=9.4 Hz, 2 H), 7.40-7.48 (m, 1 H), 7.35 (s, 1 H), 7.05 (t, J=8.2 Hz, 2 H), 6.92 (d, J=5.1 Hz, 1 H), 6.52 (d, J=9.4 Hz, 1 H), 4.36-4.49 (m, 1 H), 4.00-4.06 (m, 2H), 3.41-3.51 (m, 1 H), 3.33-3.41 (m, 1 H), 3.20-3.29 (m, 1 H), 2.58-2.70 (m, 1 H), 2.40-2.54 (m, 1 H), 1.76-1.85 (m, 1 H), 1.41 (br. s., 9 H), 0.99 (d, J=6.5 Hz, 3 H). 19F NMR (377 MHz, CDCl3) δ ppm −112.40 (s, 2 F).