Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.FC(F)(F)[C:10]([OH:12])=O.FC(F)(F)[C:17]([OH:19])=O.[NH2:22][C@H]1CCCN(C2C=CN=CC=2NC2N3N=C(C4C(F)=CC=CC=4F)C=CC3=CN=2)C1.[ClH:53].[OH-].[Na+].FC1C=CC=C(F)C=1C1C=CC2N(C(NC3C=NC=CC=3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)=NC=2)N=1.N#N>CCOC(C)=O>[CH2:10]([OH:12])[C:2]([NH2:22])([CH2:3][OH:5])[CH2:17][OH:19].[ClH:53]
Reactant: O=C(O)C(F)(F)F
Reactant: N[C@H]1CCCN(c2ccncc2Nc2ncc3ccc(-c4c(F)cccc4F)nn23)C1
Agent: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2Nc2ncc3ccc(-c4c(F)cccc4F)nn23)C1
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Product: NC(CO)(CO)CO
Reaction time: 8 h

Procedure:
N-(4-((3S)-3-amino-1-piperidinyl)-3-pyridinyl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine tris(2,2,2-trifluoroacetate). A 250 mL bottle with a 3-hole top was configured as follows: opening 1: ⅛th″ (OD) HDPE tubing connected to a HCl gas cylinder with a gas dispersion frit in the bottle; opening 2: positive pressure nitrogen source; opening three, ⅛th″ (OD) HDPE tubing connected to a 25×250 mm column packed with NaOH pellets. The bottle was charged with EtOAc (100 mL), and the volume above the EtOAc was gently purged with N2 from opening 2. HCl gas was introduced at a rate such that a majority of the HCl bubbles were dissolved prior to reaching the top of the EtOAc. The solution was sparged with HCl gas until the amount of HCl bubbles at the gas dispersion tube was approximately equal to the amount of gas that reached the reached the top of the solution. The HCl flow was discontinued, and the system was purged with N2 for 3 min. The bottle was sealed and used directly. The normality was assumed to be 7.5 M (Tetrahedron Letters, 1996, 37, 5131). A 250 mL, Schlenk type flask was charged with a stirbar and 7.5 M HCl in EtOAc (100 mL, 750 mmol). The flask was sealed with a septa/Ar inlet/PTFE addition needle. A syringe charged with tert-butyl ((3S)-1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)-4-pyridinyl)-3-piperidinyl)carbamate (2.61 g, 5.00 mmol) dissolved in EtOAc (40 mL) was fitted to the PTFE addition needle and added via syringe pump over 30 min. The slurry was stirred overnight. The slurry was N2 pressure filtered through a 47 mm, 0.2 μm Fluoropore® membrane (FGLP04700) fitted to a Millipore high pressure filter holder (XX4504700). The solids were washed with EtOAc (4×25 mL), and dried initially under a stream of N2 for 1 h. The solids were further dried in a vacuum oven (80° C., <0.2 mm Hg) for 5 d to afford ˜2.4 g of presumably a tris HCl salt. The sample was purified by prep HPLC method 2. The solvent was concentrated to remove the organic solvents, and the aqueous solution was lyophilized. The powder was dissolved in 1% TFA (aq., 40 mL), and N2-pressure filtered through a 28 mL Bohdan reaction vessel glass frit fitted with a 0.22 μm PTFE, 25 mm syringe filter unit (Millipore, SLFG025NK). The filtrate was lyophilized, and the resulting material was further dried in a vacuum oven (80° C., <1 mm Hg) for 30 min. The material was pulverized with a spatula to a consistent particle size. The material was again dried in a vacuum oven (80° C., <1 mm Hg) for 45 min to afford N-(4-((3S)-3-amino-1-piperidinyl)-3-pyridinyl)-2-(2,6-difluorophenyl)-imidazo[1,5-b]pyridazin-7-amine tris(2,2,2-trifluoroacetate) (3.2 g, 4.19 mmol, 84% yield). A ratio of 9:2 fluorines was observed by 19F NMR; consistent with 3:1 ratio of TFA to N-(4-((3S)-3-amino-1-piperidinyl)-3-pyridinyl)-2-(2,6-difluorophenyl)-imidazo[1,5-b]pyridazin-7-amine. MS (ESI, pos. ion) m/z: 422.0 [M+H]. 1l H NMR (400 MHz, D2O) δ ppm 1.28 (qq, J=10.80, 3.70 Hz, 1 H) 1.58 (dtd, J=13.30, 10.30, 10.30, 4.10 Hz, 1 H) 1.74 (dt, J=14.18, 3.86 Hz, 1 H) 2.03 (dq, J=12.60, 4.20 Hz, 1H) 3.08 (ddd, J=13.30, 10.95, 2.74 Hz, 1 H) 3.15 (dd, J=12.30, 9.98 Hz, 1 H) 3.23 (tt, J=9.80, 3.70 Hz, 1 H) 3.80 (br. dt, J=13.30, 3.60, 3.60 Hz, 1 H) 4.09 (br. d, J=10.40 Hz, 1H) 6.95 (d, J=9.59 Hz, 1 H) 7.13 (t, J=8.41 Hz, 2 H) 7.35 (d, J=7.04 Hz, 1 H) 7.43 (s, 1H) 7.54 (tt, J=8.40, 6.50 Hz, 1 H) 8.01 (d, J=9.78 Hz, 1 H) 8.23 (dd, J=7.04, 0.98 Hz, 1 H) 8.39 (d, J=0.98 Hz, 1 H). 19F NMR (377 MHz, D2O) δ ppm −117.35 (t, J=7.44 Hz, 2F) −78.50 (s, 9 F).