2-[(2-methylpropan-2-yl)oxy]ethanamine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using 4-pyridine carboxaldehyde and O-tert butyl ethanolamine, and the synthetic procedure described for Intermediate 16, a crude sample of the title compound was prepared, which was used directly in the next stage of the synthetic sequence.

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture comprising 2-tert-butoxyethanamine (1.2 g, 5.12 mmol, 50% w/w) and methyl 3-amino-4-fluorobenzoate (0.866 g, 5.12 mmol) in THF (10 ml) was treated with TBD (0.713 g, 5.12 mmol) and heated at 90° C. for 16 hrs. After cooling to RT, the solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic portion was separated and washed with 10% aq citric acid (×2), NaHCO3 (sat. aq), brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the title compound as a clear oil; After cooling to RT the solvent was removed in vacuo the residue was partitioned between water and EtOAc The organic portion was separated washed with 10% aq citric acid (×2), NaHCO3 (sat. aq), brine dried (MgSO4) concentrated in vacuo Purification of the crude product by chromatography on silica eluting with 0-100% EtOAc in iso-hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-bromo-6-fluoroimidazo[1,2-b]pyridazine (216 mg, 1.0 mmol), triethyl amine (0.35 mL, 2.5 mmol) and 2-(tert-butoxy)ethanamine (180 mg, 1.5 mmol) in isopropanol (2 mL) was heated at 65° C. for overnight. The mixture was cooled, diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO4 and concentrated to give brown solid as crude in quantitative yield for further synthesis. 20 mg was further purified by Prep HPLC to give pure 3-bromo-N-(2-(tert-butoxy)ethyl)imidazo[1,2-b]pyridazin-6-amine as white solid (8 mg). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.57 (d, J=9.85 Hz, 1H), 7.42 (s, 1H), 6.76 (d, J=9.60 Hz, 1H), 4.56 (s, 1H), 3.67 (t, J=5.94 Hz, 2H), 3.53 (t, J=5.94 Hz, 2H), 1.24 (s, 9H) LRMS (ESI) m/e 315.0 [(M+H)+, calcd for C12H18BrN4O 314.2]. The mixture was cooled washed with water The organic layer was dried over MgSO4 concentrated to give brown solid as crude in quantitative yield for further synthesis 20 mg was further purified by Prep HPLC

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using 4-pyridine carboxaldehyde and O-tert butyl ethanolamine, and the synthetic procedure described for Intermediate 16, a crude sample of the title compound was prepared, which was used directly in the next stage of the synthetic sequence.

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture comprising 2-tert-butoxyethanamine (1.2 g, 5.12 mmol, 50% w/w) and methyl 3-amino-4-fluorobenzoate (0.866 g, 5.12 mmol) in THF (10 ml) was treated with TBD (0.713 g, 5.12 mmol) and heated at 90° C. for 16 hrs. After cooling to RT, the solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic portion was separated and washed with 10% aq citric acid (×2), NaHCO3 (sat. aq), brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the title compound as a clear oil; After cooling to RT the solvent was removed in vacuo the residue was partitioned between water and EtOAc The organic portion was separated washed with 10% aq citric acid (×2), NaHCO3 (sat. aq), brine dried (MgSO4) concentrated in vacuo Purification of the crude product by chromatography on silica eluting with 0-100% EtOAc in iso-hexane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve the crude HI salt of (2-tert-butoxyethyl)methyl-(1-methylsulfanylethyl)amine (obtained using the crude HCl salt of 2-tert-butoxyethylamine, referenced in Example 9-1, using the methodology detailed in Example 6-1) (297.1 mg, 0.897 mmol) in 20 mL pyridine and add biphenyl-4-carboxylic acid (R)-(6-amino-2(R)-hydroxyindan-1-yl)amide (290.7 mg, 0.844 mmol). Allow the reaction to stir for 18 hours. Remove the solvent in vacuo and dissolve the residue in methylene chloride and wash with saturated aqueous sodium hydrogen carbonate. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to afford 248.7 mg of crude product. Purify the residue by Biotage chromatography (10% MeOH/EtOAc to 25% MeOH/EtOAc) to afford 91.7 mg of the titled product (22% yield). MS (ES): m/z 500.5 (M+H). obtained the reaction Remove the solvent in vacuo dissolve the residue in methylene chloride wash with saturated aqueous sodium hydrogen carbonate Dry the organic layer with magnesium sulfate Filter remove the solvent in vacuo to afford 248.7 mg of crude product Purify the residue by Biotage chromatography (10% MeOH/EtOAc to 25% MeOH/EtOAc)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve (2-tert-butoxyethyl)dicarbamic acid benzyl ester (387.8 mg, 1.01 mmol) and 5% Pd/C (0.212 g) in absolute ethanol and expose it to 60 psi of H2 for 18 hours. Filter the reaction mixture over a pad of celite. Acidify the filtrate with 5N HCl and concentrate in vacuo to obtain 139.4 mg of a crude residue containing the HCl salt of 2-tert-butoxyethylamine. Dissolve this crude material (139.4 mg, 0.852 mmol) in 10 mL pyridine at 25° C. To this add 2-thioacetylisoindole-1,3-dione (180.53 mg, 0.88 mmol) and allow to stir for 23 hours. Concentrate the reaction mixture in vacuo and dissolve the residue in methylene chloride and wash it with 1N HCl (1×). Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 266.9 mg of crude product. Triturate this crude material in diethyl ether and remove the solids by filtration. Concentrate the filtrate in vacuo to afford 176.2 mg of a crude solid. Purify via Biotage chromatography to afford 74.1 mg of N-(2-tert-butoxyethyl)thioacetamide. Dissolve this thioacetamide (74.1 mg, 0.423 mmol) in 20 mL methylene chloride and add methyl trifluoromethanesulfonate (76.3 mg, 0.465 mmol). Allow the reaction mixture to stir for an additional 21 hours. Decant the diethyl ether from the oil and triturate the oil with diethyl ether (3×). Remove any excess diethyl ether from the oily residue in vacuo to obtain 60.3 mg of crude triflic acid salt of N-(2-tert-butoxyethyl)thioacetimidic acid methyl ester as an oil. Dissolve this crude product (60.3 mg, 0.62.5 mmol) in 10 mL pyridine and add N-(R)-(6-amino-2(R)-hydroxyindan-1-yl)-4-bromobenzamide (62.5 mg, 0.180 mmol). Allow the reaction to stir at 25° C. for 22 hours. Remove the solvent in vacuo and partition the residue between methylene chloride and saturated aqueous sodium hydrogen carbonate. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 31.4 mg of crude product. Purify via Biotage chromatography (10% MeOH/EtOAc) to afford 6.6 mg of the titled product (8% yield). MS (ES): m/z 488.1 (M+H). for 18 hours Filter the reaction mixture over a pad of celite concentrate in vacuo to obtain 139.4 mg of a crude residue Concentrate the reaction mixture in vacuo dissolve the residue in methylene chloride wash it with 1N HCl (1×) Dry the organic layer with magnesium sulfate Filter remove the solvent in vacuo to give 266.9 mg of crude product Triturate this crude material in diethyl ether remove the solids by filtration Concentrate the filtrate in vacuo to afford 176.2 mg of a crude solid Purify via Biotage chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve the crude HI salt of (2-tert-butoxyethyl)methyl-(1-methylsulfanylethyl)amine (obtained using the crude HCl salt of 2-tert-butoxyethylamine, referenced in Example 9-1, using the methodology detailed in Example 6-1) (297.1 mg, 0.897 mmol) in 20 mL pyridine and add biphenyl-4-carboxylic acid (R)-(6-amino-2(R)-hydroxyindan-1-yl)amide (290.7 mg, 0.844 mmol). Allow the reaction to stir for 18 hours. Remove the solvent in vacuo and dissolve the residue in methylene chloride and wash with saturated aqueous sodium hydrogen carbonate. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to afford 248.7 mg of crude product. Purify the residue by Biotage chromatography (10% MeOH/EtOAc to 25% MeOH/EtOAc) to afford 91.7 mg of the titled product (22% yield). MS (ES): m/z 500.5 (M+H). obtained the reaction Remove the solvent in vacuo dissolve the residue in methylene chloride wash with saturated aqueous sodium hydrogen carbonate Dry the organic layer with magnesium sulfate Filter remove the solvent in vacuo to afford 248.7 mg of crude product Purify the residue by Biotage chromatography (10% MeOH/EtOAc to 25% MeOH/EtOAc)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve (2-tert-butoxyethyl)dicarbamic acid benzyl ester (387.8 mg, 1.01 mmol) and 5% Pd/C (0.212 g) in absolute ethanol and expose it to 60 psi of H2 for 18 hours. Filter the reaction mixture over a pad of celite. Acidify the filtrate with 5N HCl and concentrate in vacuo to obtain 139.4 mg of a crude residue containing the HCl salt of 2-tert-butoxyethylamine. Dissolve this crude material (139.4 mg, 0.852 mmol) in 10 mL pyridine at 25° C. To this add 2-thioacetylisoindole-1,3-dione (180.53 mg, 0.88 mmol) and allow to stir for 23 hours. Concentrate the reaction mixture in vacuo and dissolve the residue in methylene chloride and wash it with 1N HCl (1×). Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 266.9 mg of crude product. Triturate this crude material in diethyl ether and remove the solids by filtration. Concentrate the filtrate in vacuo to afford 176.2 mg of a crude solid. Purify via Biotage chromatography to afford 74.1 mg of N-(2-tert-butoxyethyl)thioacetamide. Dissolve this thioacetamide (74.1 mg, 0.423 mmol) in 20 mL methylene chloride and add methyl trifluoromethanesulfonate (76.3 mg, 0.465 mmol). Allow the reaction mixture to stir for an additional 21 hours. Decant the diethyl ether from the oil and triturate the oil with diethyl ether (3×). Remove any excess diethyl ether from the oily residue in vacuo to obtain 60.3 mg of crude triflic acid salt of N-(2-tert-butoxyethyl)thioacetimidic acid methyl ester as an oil. Dissolve this crude product (60.3 mg, 0.62.5 mmol) in 10 mL pyridine and add N-(R)-(6-amino-2(R)-hydroxyindan-1-yl)-4-bromobenzamide (62.5 mg, 0.180 mmol). Allow the reaction to stir at 25° C. for 22 hours. Remove the solvent in vacuo and partition the residue between methylene chloride and saturated aqueous sodium hydrogen carbonate. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 31.4 mg of crude product. Purify via Biotage chromatography (10% MeOH/EtOAc) to afford 6.6 mg of the titled product (8% yield). MS (ES): m/z 488.1 (M+H). for 18 hours Filter the reaction mixture over a pad of celite concentrate in vacuo to obtain 139.4 mg of a crude residue Concentrate the reaction mixture in vacuo dissolve the residue in methylene chloride wash it with 1N HCl (1×) Dry the organic layer with magnesium sulfate Filter remove the solvent in vacuo to give 266.9 mg of crude product Triturate this crude material in diethyl ether remove the solids by filtration Concentrate the filtrate in vacuo to afford 176.2 mg of a crude solid Purify via Biotage chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: From intermediate 21 and 2-(tert-butoxy)ethanamine, reacted in an analogous manner to the preparation of intermediate 102. (UPLC-MS 3) Rt=0.58 min; MS m/z [M+H]+ 235.