Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][C@H:16]1[CH2:21][C@@H:20]([CH3:22])[CH2:19][N:18]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[NH:29][C:30]2[N:34]3[N:35]=[C:36]([C:39]4[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=4[F:46])[CH:37]=[CH:38][C:33]3=[N:32][N:31]=2)[CH2:17]1.ClC1C=CC2N(C(NC3C=NC=CC=3N3C[C@H](C)C[C@H](N[C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75])C3)=NN=2)N=1.[Br-].FC1C=CC=C(F)C=1[Zn+]>>[F:46][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]([F:45])[C:39]=1[C:36]1[CH:37]=[CH:38][C:33]2[N:34]([C:30]([NH:29][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][C:23]=3[N:18]3[CH2:19][C@H:20]([CH3:22])[CH2:21][C@H:16]([NH:15][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75])[CH2:17]3)=[N:31][N:32]=2)[N:35]=1
Reactant: C[C@@H]1C[C@H](N)CN(c2ccncc2Nc2nnc3ccc(-c4c(F)cccc4F)nn23)C1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2Nc2nnc3ccc(Cl)nn23)C1
Agent: Fc1cccc(F)c1[Zn+]
Agent: [Br-]
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2Nc2nnc3ccc(-c4c(F)cccc4F)nn23)C1
Temperature: 90 °C

Procedure:
N-(4-((cis)-3-amino-5-methylpiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine bis(2,2,2-trifluoroacetate). A 5 mL glass microwave reaction vessel was charged with tert-butyl ((cis)-1-(3-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)pyridin-4-yl)-5-methylpiperidin-3-yl)carbamate (94 mg, 0.21 mmol) and 2,6-difluorophenylzinc bromide (1.31 mL, 0.66 mmol, Rieke Metals, Inc.) followed by A-Phos (7.3 mg, 10.3 μmol, Sigma-Aldrich). The reaction mixture was stirred and heated at 90° C. for 2 h. The mixture was cooled to RT, quenched with 20 mL of EDTA solution (pH 8.0) and extracted with CHCl3/iPrOH (3/1) (4×20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude material was dissolved in DMSO and purified using preparative reverse-phase HPLC performed on a Gilson GX-1 equipped with a Phenomenex SiliaChrom XT C18 column with UV detection at 254 nm eluting with 20-95% CH3CN in water with 0.1% TFA for 11 min at 45 mL/min to give tert-butyl ((cis)-1-(3-((6-(2,6-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)pyridin-4-yl)-5-methylpiperidin-3-yl)carbamate as a yellow solid. MS (ESI, pos. ion) m/z: 537.2 (M+1). A solution of tert-butyl ((cis)-1-(3-((6-(2,6-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)pyridin-4-yl)-5-methylpiperidin-3-yl)carbamate in DCM (1 mL) was treated with 10 drops of TFA at RT. The solution was stirred at RT for 1 h. The volatiles were removed under reduced pressure. The material was dissolved in DMSO and purified using preparative reverse-phase HPLC performed on a Gilson GX-1 equipped with a Phenomenex SiliaChrom XT C18 column with UV detection at 254 nm eluting with 20-95% CH3CN in water with 0.1% TFA for 11 min at 45 mL/min to afford N-(4-((cis)-3-amino-5-methylpiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine bis(2,2,2-trifluoroacetate) (34 mg, 0.05 mmol, 24% yield for 2 steps) as a yellow oil. MS (ESI, pos. ion) m/z: 437.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.31 (br. s., 1 H), 8.73 (s, 1 H), 8.42 (d, J=9.6 Hz, 1 H), 8.36 (d, J=6.8 Hz, 1 H), 7.99 (br. s., 2 H), 7.64-7.76 (m, 1 H), 7.50 (d, J=9.8 Hz, 1 H), 7.30-7.40 (m, 3 H), 4.13 (d, J=11.0 Hz, 1 H), 3.95 (d, J=11.7 Hz, 1 H), 3.16 (br. s., 1 H), 2.83 (t, J=11.6 Hz, 1 H), 2.35-2.46 (m, 1 H), 1.97 (d, J=12.3 Hz, 1 H), 1.39 (br. s., 1 H), 1.11 (q, J=12.2 Hz, 1 H), 0.76 (d, J=6.5 Hz, 3 H). 19F NMR (376 MHz, DMSO-d6) δ ppm −73.98 (s, 6 F), −113.56 (s, 2 F).