1-(bromomethyl)-2-(trifluoromethoxy)benzene

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: Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-(bromomethyl)-2-(trifluoromethoxy)benzene to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (77%) as a white solid: mp 130-135° C.; MS (ES+) m/z 456.3 (M+1).

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

Procedure: In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(trifluoromethoxy)benzene and isolated as light-yellow gum (7.3 mg, 39%). MS (m/e): 457.4 (MH+).

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

Procedure: The title compound was prepared using the protocol described in Example 30, Step A-C using 2-(trifluoromethoxy)benzyl bromide in Step B, and in Example 52, Step B-E substituting N-tert-butoxycarbonyl-4-(3-methylbenzyl)-4-hydroxymethylpiperidine with N-tert-butoxy-carbonyl-4-(2-trifluoromethoxybenzyl)-4-hydroxymethylpiperidine in Step B, and substituting 1-(4-cyanobenzyl)-5-chloromethyl-imidazole hydro-chloride salt with 1-(4-cyanobenzyl)-5-chloromethyl-2-methylimidazole hydrochloride salt in Step E.

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

Procedure: The title compound was prepared using the protocol described in Example 30, Step A-C using 2-(trifluoromethoxy)benzyl bromide in Step B, and in Example 52, Step B-E substituting N-tert-butoxycarbonyl-4-(3-methylbenzyl)-4-hydroxymethylpiperidine with N-tert-butoxy-carbonyl-4-(2-trifluoromethoxybenzyl)-4-hydroxymethylpiperidine in Step B, and substituting 1-(4-cyanobenzyl)-5-chloromethyl-imidazole hydro-chloride salt with 1-(4-cyanobenzyl)-5-chloromethyl-2-methylimidazole hydrochloride salt in Step E.

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

Procedure: Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-(trifluoromethoxy)benzyl bromide (94.4 mg; 0.37 mmol) to obtain 45.5 mg. (54% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.4 (br s, 1H), 10.0 (br s, 1H), 8.94 (br s, 1H), 7.69 (m, 3H), 7.42 (m, 3H), 7.27 (d, J=7.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 3.65 (s, 2H), 3.04 (d, J=10.4 Hz, 2H), 2.89 (m, 4H), 2.36 (t, J=11.2 Hz, 2H). ESIMS+419.5 m/z to obtain 45.5 mg

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

Procedure: Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-(trifluoromethoxy)benzyl bromide (94.4 mg; 0.37 mmol) to obtain 45.5 mg. (54% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.4 (br s, 1H), 10.0 (br s, 1H), 8.94 (br s, 1H), 7.69 (m, 3H), 7.42 (m, 3H), 7.27 (d, J=7.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 3.65 (s, 2H), 3.04 (d, J=10.4 Hz, 2H), 2.89 (m, 4H), 2.36 (t, J=11.2 Hz, 2H). ESIMS+419.5 m/z to obtain 45.5 mg

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

Procedure: 3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 50 mg, 0.24 mmol), K2CO3 (37 mg, 0.27 mmol) and tetrabutylammonium iodide (9 mg, 0.024 mmol) were taken up in DMF (2.4 mL). 2-(Trifluoromethoxy)benzyl bromide (38 mg, 0.27 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by high-throughput purification to give 3-[4-(2-trifluoromethoxy-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (1.2 mg, 1.3%). HRMS Calcd. for C18H14F3N2O4 (M+H)+, 379.0900. Found: 379.0987. The solvent was evaporated the residue was purified by high-throughput purification

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

Procedure: The procedure for the synthesis of example 1a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using 2-(trifluoromethoxy)benzyl bromide (available from Fluorochem) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+=458.

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

Procedure: The procedure for the synthesis of example 1a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using 2-(trifluoromethoxy)benzyl bromide (available from Fluorochem) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+=458.

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

Procedure: 7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (942 mg) was reacted with 2-(trifluoromethoxy)benzyl bromide as in General Procedure 1 to give the title compound as a light yellow solid (61% yield). m.p.=235° C., LCMS: m/z=449.92 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 4.29 (2H, s), 4.89 (1H, s), 5.16 (2H, s), 7.09 (2H, m), 7.24 (1H, m), 7.34 (2H, m), 7.92 (1H, s).