oxane-4-sulfonyl chloride

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

Procedure: Prepared according to procedures described above, by reacting tetrahydro-2H-pyran-4-sulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C30H42N4O11S2 m/z: 699 (M+H)+. Prepared

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

Procedure: Tetrahydropyran-4-sulfonyl chloride (16.28 mg, 0.08815 mmol) was added to a suspension of 2-amino-6-fluoro-N-(5-fluoro-4-piperazin-1-yl-3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 0.08014 mmol) (synthesized according to the procedure similar to Example 2) and Et3N (12.16 mg, 16.75 μL, 0.1202 mmol) in DMF (0.2 mL). The crude mixture was purified by Fractionlynx HPLC. The clean aqueous fractions were combined and lyophilised, yielding 2-amino-6-fluoro-N-(5-fluoro-4-(4-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. MS (ES+) 523.1. synthesized The crude mixture was purified by Fractionlynx HPLC

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

Procedure: Tetrahydropyran-4-sulfonyl chloride (16.28 mg, 0.08815 mmol) was added to a suspension of 2-amino-6-fluoro-N-(5-fluoro-4-piperazin-1-yl-3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 0.08014 mmol) (synthesized according to the procedure similar to Example 2) and Et3N (12.16 mg, 16.75 μL, 0.1202 mmol) in DMF (0.2 mL). The crude mixture was purified by Fractionlynx HPLC. The clean aqueous fractions were combined and lyophilised, yielding 2-amino-6-fluoro-N-(5-fluoro-4-(4-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. MS (ES+) 523.1. synthesized The crude mixture was purified by Fractionlynx HPLC

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

Procedure: Prepared according to procedures described above, by reacting tetrahydro-2H-pyran-4-sulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C30H42N4O11S2 m/z: 699 (M+H)+. Prepared

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-(3-Ethoxy-5-hydroxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (see example 32 stage a) (2,300 mg; 5.96 mmol) is dissolved in tetrahydrofuran (70 ml), potassium tert-butylate (1,000 mg; 8.9 mmol) is added and the mixture is cooled to −20° C. Tetrahydropyran-4-sulphonyl chloride (2.2 g; 11.9 mmol) is added at this temperature and the mixture is then stirred for one hour at −20° C. The reaction mixture is poured on to ice-water and extracted twice with ethyl acetate. The organic phase is dried over sodium sulphate, the salts are filtered off and the solvent is evaporated off. The residue is chromatographed over silica gel with methylene chloride 1 methanol (19/1) and 0.5% ammonia. The pure fractions are co mbidand the solvent is evaporated off. extracted twice with ethyl acetate The organic phase is dried over sodium sulphate the salts are filtered off the solvent is evaporated off The residue is chromatographed over silica gel with methylene chloride 1 methanol (19/1) and 0.5% ammonia is evaporated off

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

Procedure: Following the procedure as described in Example 38 step 4 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide and to replace methanesulfonyl chloride with tetrahydro-2H-pyran-4-sulfonyl chloride, the title compound was obtained as a colorless solid (0.15 g, 30%): 1H NMR (300 MHz, CDCl3) δ8.55-8.44 (m, 1H), 7.60-7.52 (m, 1H), 6.62-6.52 (m, 1H), 4.17-3.90 (m, 3H), 3.56 (s, 2H), 3.47-3.36 (m, 2H), 2.12-1.95 (m, 8H), 1.84-1.65 (m, 12H), 1.00-0.90 (m, 2H), 0.71-0.58 (m, 2H); MS (ES+) m/z 492.21 (M+1).

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

Procedure: Tetrahydropyran-4-sulfonyl chloride (16.28 mg, 0.08815 mmol) was added to a suspension of 2-amino-6-fluoro-N-(5-fluoro-4-piperazin-1-yl-3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 0.08014 mmol) (synthesized according to the procedure similar to Example 2) and Et3N (12.16 mg, 16.75 μL, 0.1202 mmol) in DMF (0.2 mL). The crude mixture was purified by Fractionlynx HPLC. The clean aqueous fractions were combined and lyophilised, yielding 2-amino-6-fluoro-N-(5-fluoro-4-(4-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. MS (ES+) 523.1. synthesized The crude mixture was purified by Fractionlynx HPLC