(2,2,2-trichloroacetyl) 2,2,2-trichloroacetate

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

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

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

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

Procedure: Trichloroacetic anhydride (0.181 mL, 0.989 mmol) was added to 4-amino-N′-hydroxy-6-[(2 methoxyethyl)(phenyl)amino]-1,3,5-triazine-2-carboximidamide (Intermediate 160, 0.250 g, 0.824 mmol) in toluene (10 mL) and stirred at room temperature for 5 min. Pyridine (3 mL) was added and the mixture was heated to 85 C for 1 h. The mixture was concentrated under vacuum and the residue dissolved in EtOAc. This was washed with water, saturated aq. sodium bicarbonate and then brine. The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in DMF (2 mL) and 3-phenoxyazetidine hydrochloride (0.13 g, 0.685 mmol) and DIPEA (0.499 mL, 1.370 mmol) were added. The mixture was stirred at room temperature for 13 h and was then concentrated under vacuum. The mixture was extracted with EtOAc (30 mL), washed with water, saturated aq. sodium bicarbonate and then brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with 0-2% MeOH in DCM. The crude material was further purified by FCC, eluting with 50% EtOAc in heptane then 0-2% MeOH in DCM to afford the title compound (0.091 g, 29%). the mixture was heated to 85 C for 1 h The mixture was concentrated under vacuum the residue dissolved in EtOAc This was washed with water, saturated aq. sodium bicarbonate The organic layer was dried over sodium sulfate concentrated The residue was dissolved in DMF (2 mL) The mixture was stirred at room temperature for 13 h was then concentrated under vacuum The mixture was extracted with EtOAc (30 mL) washed with water, saturated aq. sodium bicarbonate The organic layer was dried over sodium sulfate concentrated under vacuum The residue was purified by FCC eluting with 0-2% MeOH in DCM The crude material was further purified by FCC eluting with 50% EtOAc in heptane

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

Procedure: Ethanol is reacted with trichloroacetic anhydride to yield ethyltrichloroacetate.

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

Procedure: Ethanol is reacted with trichloroacetic anhydride to yield ethyltrichloroacetate.

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

Procedure: Using (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (3.70 g), trichloroacetic anhydride (1.9 mL) as a dehydrating agent and trifluoroacetic acid (0.78 mL) as an acid, a white powder of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile was obtained (obtained amount: 2.86 g, yield: 81%) by the same method of Example 1.

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared from INT-57. To a stirring suspension of tert-butyl 2-(N-(4-(N-hydroxycarbamimidoyl)benzyl)-4-nitrobenzamido)acetate INT-57 (820 mg, 1.91 mmol) in dioxane (10 mL) was added 2,2,2-trichloroacetic anhydride (420 μL, 2.30 mmol) and heated to 120° C. for 2 h. To this mixture was added 7 M ammonia in MeOH (10 mL) and stirred at room temperature for 18 h. The reaction mixture was pre-absorbed onto silica gel and purified by chromatography (EA/hexanes) to afford 342 mg (39%) of tert-butyl 2-(N-(4-(5-amino-1,2,4-oxadiazol-3-yl)benzyl)-4-nitrobenzamido)acetate) INT-67 as a white solid. LCMS-ESI (m/z) calculated for C22H23N5O6: 453; found 454 [M+H]+, tR=2.30 min (Method 10). Prepared from INT-57 The reaction mixture was pre-absorbed onto silica gel purified by chromatography (EA/hexanes)

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

Procedure: To a mixture of trichloroacetic anhydride (1.5 eq.) and dimethylsulfoxide (2.0 eq.) in dichloromethane at −78° C. is added a solution of Compound 9 in dichloromethane. After 30 minutes, triethylamine (4.5 eq.) is added. Subsequently, the mixture is poured into ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The resulting material is carried into the next step without further purification. This procedure has been used to prepare the related 4′-C-α-formyl nucleosides (Nomura, M., et. al., J. Med. Chem. 1999, 42, 2901-2908). washed with water and brine dried over anhydrous sodium sulfate evaporated to dryness The resulting material is carried into the next step without further purification to prepare the related 4′-C-α-formyl nucleosides (Nomura, M., et. al., J. Med. Chem. 1999, 42, 2901-2908)

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 500 mL flask was charged (R)-2,3,4,5-tetrahydro-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile (20.0 g, 1 eq.), imidazole-4-carboxaldehyde (5.2 g, 1.1 eq.), and CH2Cl2 (80 mL) at room temperature. Cool to 0-5° C. Add trichloroacetic acid (32 g, 4 eq.) and trichloroacetic acid anhydride (12.2 mL, 1.36 eq.) while keeping the temperature below 20° C. Stir the mixture for 30 min at 0-5° C. Add Triethylsilane (11.6 mL, 1.5 eq.). Agitate the mixture at 20-25° C. for 26 h until the reaction is complete. Add CH2Cl2 (80 mL), then cool to 0° C. Adjust the pH to 8-9 with 10% NaOH. Separate the two phases. Wash the organic phase with H2O (50 mL). Remove most of the solvents, and add EtOH (150 mL); and heat up to reflux and stir at reflux for 10 min. Cool to room temperature in a period of 60 min. Crystals appeared at 65° C. Stir at room temperature for 2 h. Filter and wash the crystals with EtOH (150 mL). Dry at 40° C. in vacuum oven over night to give the product (20.4 g, 85% yield) as a white solid. the temperature below 20° C Agitate the mixture at 20-25° C. for 26 h until the reaction Separate the two phases Wash the organic phase with H2O (50 mL) Remove most of the solvents add EtOH (150 mL) and heat up to reflux stir at reflux for 10 min Cool to room temperature in a period of 60 min appeared at 65° C Stir at room temperature for 2 h Filter wash the crystals with EtOH (150 mL) Dry at 40° C. in vacuum oven over night

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 500 mL flask was charged (R)-2,3,4,5-tetrahydro-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile (25.0 g, 1 eq.), imidazole-4-carboxaldehyde (6.45 g, 1.1 eq.), and CH2Cl2 (150 mL) at room temperature. Cool to 0-5° C. Add trifluoroacetic acid (18.8 mL, 4 eq.) in a period of 10 min. A solution was obtained after addition. Stir the mixture for 10 min at 2° C. Add trichloroacetic acid anhydride (11.7 mL, 1.05 eq.) in a period of 20 min at 2° C. Stir the mixture for 30 min at 0-5° C. Add Na(OAc)3BH (15.51 g, 1.2 eq.) in two portions at 0-5° C. Agitate the mixture at 0° C. for 1.5 h, then room temperature for 1 hour. Add CH2Cl2 (100 mL), then cool to 0° C. Adjust the pH to 8-9 with 10% NaOH (about 125 mL used). Stir for 30 min. Separate the two phases. Wash the organic phase with H2O (2×100 mL), then separate the two phases. Remove most of the solvents, and add EtOH (200 mL); and heat up to 74° C. Stir for 10 min at 74° C. Cool to room temperature in a period of 60 min. Crystals appeared at 65° C. Filter and wash the crystals with EtOH (40 mL). Dry at 40° C. in vacuum oven over night to give the product (13.55 g, 90.7% yield) as a white solid. A solution was obtained after addition Stir the mixture for 30 min at 0-5° C at 0-5° C Agitate the mixture at 0° C. for 1.5 h room temperature for 1 hour Stir for 30 min Separate the two phases Wash the organic phase with H2O (2×100 mL) separate the two phases Remove most of the solvents add EtOH (200 mL) and heat up to 74° C Stir for 10 min at 74° C Cool to room temperature in a period of 60 min appeared at 65° C Filter wash the crystals with EtOH (40 mL) Dry at 40° C. in vacuum oven over night

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Trichloroacetic acid anhydride (120 mg, 0.39 mmol) was added slowly to a solution of (S)-tert-butyl 1-amino-3-(4-isopropoxyphenyl)-1-oxopropan-2-ylcarbamate (50 mg, 0.2 mmol) in methylene chloride (3 mL) and triethylamine (86 uL, 0.62 mmol) at 0° C. The reaction was stirred for 1 h. at 0° C. The reaction was quenched with saturated NaHCO3 and was extracted with ethyl acetate. The organic phase was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by Flash chromatography on a silica gel column (EtOAc:Hexane, 1:3 to 1:1) to obtain the (S)-tert-butyl 1-cyano-2-(4-isopropoxyphenyl)ethylcarbamate (40 mg, 80%) as clear oil. Analytical LCMS (M+Na)+: m/z=327.0. The reaction was quenched with saturated NaHCO3 was extracted with ethyl acetate The organic phase was washed with water, saturated brine dried over magnesium sulfate filtered concentrated under reduced pressure to give the crude product, which was purified by Flash chromatography on a silica gel column (EtOAc:Hexane, 1:3 to 1:1)