trimethylsilyl 2,2,2-trifluoroacetate

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2,3-Dihydroxybenzoyl)hydrazine, trifluoroacetate salt (2.82 g) was suspended in 50 ml of acetonitrile and 13.5 g of N-methyl-N-(trimethylsilyl)trifluoroacetamide were added. After stirring for one hour at 40° C., the solvent and trifluoroacetic acid, trimethylsilyl ester formed were distilled off in vacuo. The remaining oil was dissolved again in 50 ml of dried acetonitrile, cooled to 0° C. and added dropwise to a solution of 3.48 g of an adduct of chlorosulfonylisocyanate and (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester in 100 ml of acetonitrile at 0° C. with stirring. After continuous stirring overnight, the solvent was distilled off in vacuo and the residue stirred (1 hour) with 200 ml of isopropanol. (S)-3-[[(Phenylmethoxy)carbonyl]amino]-N-[[2-(2,3-dihydroxybenzoyl)hydrazino]sulfonyl]-2-oxo-1-azetidinecarboxamide precipitated from the solution. Isolation by filtration and washing with ether yielded 3.87 g of white powder.

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

Procedure: Trimethylsilyl trifluoroacetate (1.5 mL, 8.7 mmol) was added to a suspension of 2-amino-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylic acid (845 mg, 4.72 mmol) in ethyl acetate (10 mL). A solution was obtained but a precipitate formed within 5 minutes. The reaction mixture was stirred at RT for 5 minutes and triethyl orthoformate (1.4 mL, 8.4 mmol) was added. The mixture was stirred at RT for 5 minutes and azidotrimethylsilane (1.1 mL, 8.4 mmol) was added. The resulting suspension was stirred at RT overnight. The solvent was evaporated. The residue was purified by chromatography on silica gel (80 g cartridge) using CH2Cl2 (A) and CH2Cl2:MeOH:AcOH 90:10:1 (B) with gradient elution (100% A to 100% B over 16 column volumes) to afford crude product which was further purified by preparative HPLC to afford the title compound: NMR 500 MHz (CD3OD) 10.00 (s, 1H); 8.88 (s, 1H); 4.32 (t, 1H); 3.11-3.15 (m, 2H); 2.47-2.63 (m, 2H); LC/MS (M+Na)+ at 255, (M+1)+ at 233, (M+1-N2)+ at 205. A solution was obtained a precipitate formed within 5 minutes The mixture was stirred at RT for 5 minutes The resulting suspension was stirred at RT overnight The solvent was evaporated The residue was purified by chromatography on silica gel (80 g cartridge) with gradient elution (100% A to 100% B over 16 column volumes) to afford crude product which was further purified by preparative HPLC

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

Procedure: To a mixture of Methyl 2-amino-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxylate (65.2 mg, 0.364 mmol) in ethyl acetate (5 mL) was added trimethylsilyl trifluoroacetate (0.107 mL, 0.619 mmol) at room temperature. The mixture was stirred at room temperature then triethyl orthoformate (0.103 mL, 0.619 mmol) was added. The mixture was stirred for another 5 minutes then azidotrimethylsilane (0.081 mL, 0.619 mmol) was added. The reaction was stirred at room temperature overnight then concentrated in vacuo and the residue was triturated twice with dichloromethane. The resulting solid was collected by centrifugation and dried in vacuo to afford the title compound: LC/MS: [(M+1)]+=233. The mixture was stirred for another 5 minutes The reaction was stirred at room temperature overnight then concentrated in vacuo the residue was triturated twice with dichloromethane The resulting solid was collected by centrifugation dried in vacuo

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

Procedure: A 1 L 3-neck flask was purged with nitrogen and charged with a solution of ethyl (6-aminopyridin-3-yl)acetate (31.7 g, 176 mmol) in EtOAc (317 mL) at +22° C. Then 30 mL of TMS trifluoroacetate was added (1.0 equiv) while cooling in a water bath. A mild exotherm to +25° C. and partial crystallization was observed. After 5 min, triethylorthoformate was added (44.0 mL, 264 mmol) followed by TMS-azide (28.0 mL, 211 mmol). The resulting suspension was stirred at +23° C. After 15 min, an additional 10 mL of TMS trifluoroacetate was added (0.30 equiv). A clear soln formed after ˜10 min. The mixture was stirred for 3 days at +20° C. whereupon a thin, light yellow suspension had formed. The mixture was cooled in an ice bath, and 200 mL of 1M aq K3PO4 was added while maintaining the temperature below +20° C. Then 465 mL EtOAc was added to solubilize the product. The layers were separated (pH of aq˜8), then the organic phase was washed with 2×250 mL water, and concentrated to a thick slurry. Then 400 mL of n-heptane was added to the concentrated organic phase over 20 min. After 30 rnM, the suspension was filtered to afford the title tetrazole product. A 1 L 3-neck flask was purged with nitrogen while cooling in a water bath A mild exotherm to +25° C. and partial crystallization triethylorthoformate was added (44.0 mL, 264 mmol) After 15 min A clear soln formed after ˜10 min The mixture was stirred for 3 days at +20° C. whereupon a thin, light yellow suspension had formed The mixture was cooled in an ice bath while maintaining the temperature below +20° C The layers were separated (pH of aq˜8) the organic phase was washed with 2×250 mL water concentrated to a thick slurry Then 400 mL of n-heptane was added to the concentrated organic phase over 20 min After 30 rnM, the suspension was filtered

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

Procedure: Trimethylsilyl trifluoroacetate (23.8 μL, 0.137 mmol) was added to a suspension of 3-((3S,9aS)-8-(2-(2-aminopyrimidin-5-yl)-2,2-difluoroacetyl)octahydropyrazino[2,1-c][1,4]oxazin-3-yl)-6-fluoro-2-methylbenzonitrile (36.1 mg, 0.081 mmol) in ethyl acetate (735 μL). The mixture was stirred for 5 min at room temperature and triethyl orthoformate (23.67 μL, 0.142 mmol) was added. After stirring for 5 more min at room temperature, azidotrimethylsilane (16.91 μL, 0.129 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with methanol and purified on mass-directed preparative HPLC. Appropriate fractions were collected and solvent was removed under reduced pressure. The residue was converted to hydrochloric acid salt. LC/MS: [(M+1)]+=500.0; 1H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.35 (s, 2H), 7.85-7.94 (m, 1H), 7.43-7.54 (m, 1H), 5.14-5.27 (m, 1H), 4.01-4.60 (m, 5H), 3.13-3.95 (m, 6H), 2.53 (s, 3H). After stirring for 5 more min at room temperature The mixture was stirred at room temperature overnight purified on mass-directed preparative HPLC Appropriate fractions were collected solvent was removed under reduced pressure

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

Procedure: To 5-nitropyridin-2-amine (1.00 g, 7.19 mmol) in AcOH was added trimethylsilyl trifluoroacetate (2.111 mL, 12.22 mmol). After stirring for 5 min, triethyl orthoformate (2.155 ml, 12.94 mmol) was added. Azidotrimethylsilane (1.513 mL, 11.50 mmol) was added after stirring for another 5 min. The reaction mixture was stirred at RT overnight, and was concentrated to give the crude solid. The solid was washed with DCM, and dried under vacuum to give title compound. LC/MS: [(M+1)]+=193.19, [(M+1-28)]+=165.19 after stirring for another 5 min The reaction mixture was stirred at RT overnight was concentrated to give the crude solid The solid was washed with DCM dried under vacuum

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

Procedure: To tert-butyl 2-(6-amino-5-fluoropyridin-3-yl)acetate (120 mg, 0.53 mmol) in EtOAc (2.6 mL) was added trimethylsilyl trifluoroacetate (156 μL, 0.90 mmol), triethyl orthoformate (156 μl, 0.94 mmol), and azidotrimethylsilane (112 μL, 0.85 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was concentrated to give the crude product, which was purified by column chromatography to give title compound: LC/MS: [(M+1-56-28)]+=196.4; The reaction mixture was concentrated to give the crude product, which was purified by column chromatography

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

Procedure: To a solution of tert-butyl (6-amino-4-ethylpyridin-3-yl)acetate (198 mg, 0.838 mmol) in EtOAc (4 mL) was added trimethylsilyl trifluoroacetate (0.246 ml, 1.424 mmol) at room temperature. After stirred 5 min, triethyl orthoformate (0.251 ml, 1.508 mmol) was added. After stirred another 5 min, azidotrimethylsilane (0.176 ml, 1.34 mmol) was added. The reaction mixture was stirred at RT for two days, then concentrated. The residue was purified prep TLC (hex/EA=1/1) to give title compound. LC-MS: [(M+1)]+=290.23, [(M+1-28)]+=262.22, [(M+1-28-56)]+=206.21 After stirred another 5 min The reaction mixture was stirred at RT for two days concentrated The residue was purified prep TLC (hex/EA=1/1)

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

Procedure: Trimethylsilyl trifluoroacetate (0.14 mL, 0.81 mmol) was added to a suspension of tert-butyl (2-aminopyrimidin-5-yl)acetate (100 mg, 0.478 mmol) in Ethyl acetate (1.5 mL). The reaction mixture was stirred at RT for 5 minutes and triethyl orthoformate (0.14 mL, 0.84 mmol) was added. The reaction mixture was stirred at RT for 5 minutes and azidotrimethylsilane (0.1 mL, 0.760 mmol) was added. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc and washed with water and brine, dried (MgSO4), filtered and the solvent evaporated to afford the title compound: LC/MS (M+1)+ at 263 and (M+1-N2-tBu)+ at 179. The reaction mixture was stirred at RT for 5 minutes The reaction mixture was stirred at RT overnight washed with water and brine dried (MgSO4) filtered the solvent evaporated

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

Procedure: Trimethylsilyl trifluoroacetate (1.010 ml, 5.85 mmol) was added to a suspension of ethyl 2-(5-amino-6-methylpyridin-2-yl)acetate (710 mg, 3.66 mmol) in ethyl acetate (20 ml). The mixture was stirred for 5 mins then added triethyl orthoformate (1.096 ml, 6.58 mmol). Stirred for another 5 mins then added azidotrimethylsilane (0.817 ml, 6.21 mmol). The reaction was stirred overnight. The reaction was poured into brine and extracted with ethyl acetate. The ethyl acetate was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography through 120 g ISCO Redi-Sep column and eluted with 5% MeOH/DCM to yield ethyl 2-(6-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl)acetate. Stirred for another 5 mins The reaction was stirred overnight extracted with ethyl acetate The ethyl acetate was separated dried over Na2SO4 filtered concentrated The residue was purified by chromatography through 120 g ISCO Redi-Sep column eluted with 5% MeOH/DCM