[2-(trifluoromethyl)phenyl]hydrazine

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

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

Procedure: (2-(trifluoromethyl)phenyl)hydrazine (CAS no. 365-34-4) (102 mg, 0.58 mmol) was added to 4,6-diphenoxypyrimidine-5-carbaldehyde (Intermediate Z2) (169 mg, 0.58 mmol) in THF (2 mL) the resulting solution was stirred at room temperature for 5 minutes. 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (526 mg, 1.16 mmol) was added and sealed into a microwave tube. The reaction was heated to 150° C. for 10 hours in a microwave reactor and cooled to RT. The reaction mixture was filtered and evaporated to dryness. The crude product was purified by flash silica chromatography, eluting with 10 to 80% ethyl acetate in isohexane to afford the product (88 mg, 42.7%). 1H NMR (400 MHz, CDCl3) δ 7.29-7.33 (2H, m), 7.34-7.39 (1H, m), 7.49-7.58 (3H, m), 7.67-7.71 (1H, m), 7.74-7.78 (1H, m), 7.90-7.92 (1H, m), 8.08 (1H, s), 8.56 (1H, s); m/z (ES+) (M+H)+=357; HPLC tR=2.66 min. sealed into a microwave tube The reaction was heated to 150° C. for 10 hours in a microwave reactor cooled to RT The reaction mixture was filtered evaporated to dryness The crude product was purified by flash silica chromatography eluting with 10 to 80% ethyl acetate in isohexane

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

Procedure: (2-(Trifluoromethyl)phenyl)hydrazine (CAS no. 365-34-4) (10.0 g, 56.77 mmol) was dissolved in MeOH (150 mL) under nitrogen at 0° C. 2-(ethoxymethylene)malononitrile (6.93 g, 56.77 mmol) added portionwise over 2 mins and the mixture stirred at ˜0° C. for 0.5 hours. The reaction was heated at reflux for 2 hours. Further methanol (15 mL) was added to aid mobility. The mixture was allowed to cool and was evaporated to give the product (14.3 g, 100%) which was used without further purification. 1H NMR (400 MHz, DMSO) δ 6.63 (2H, s), 7.53 (1H, d), 7.73 (1H, s), 7.74-7.77 (1H, m), 7.82-7.86 (1H, m), 7.91-7.94 (1H, m); m/z (ESI+) (M+H)+=253; HPLC tR=1.60 min. The reaction was heated at reflux for 2 hours to cool was evaporated

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

Procedure: 1,2-Diphenylethane-1,2-dione [2-(trifluoromethyl)phenyl]hydrazone was prepared from 2-trifluoromethylphenyl hydrazine and 1,2-diphenyl-ethane-1,2-dione according to the procedure of Step 1 Example 2. MS (ESI) m/z 369; MS (ESI) m/z 367;

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

Procedure: 1,2-Diphenylethane-1,2-dione [2-(trifluoromethyl)phenyl]hydrazone was prepared from 2-trifluoromethylphenyl hydrazine and 1,2-diphenyl-ethane-1,2-dione according to the procedure of Step 1 Example 2. MS (ESI) m/z 369; MS (ESI) m/z 367;

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

Procedure: The title compound was prepared from 2-(trifluoromethyl)-phenylhydrazine (1.41 g, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) using the procedure in Example 161A Step 3 to give 3-tert-butyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (1.45 g, 5.12 mmol, 64%). 1H NMR (300 MHz, DMSO-d6) δ 7.86 (d, 1H), 7.75 (t, 1H), 7.65 (t, 1H), 7.49 (d, 1H), 5.27 (s, 1H), 4.97 (s, 1H), 1.18 (s, 9H); LC-MS (ESI) m/z 284 (M+H)+.

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

Procedure: Ethyl-N-carbethoxyvalerimidate (from Example 4, Step B) was reacted with 2-(trifluoromethyl)phenylhydrazine according to the procedure of Example 4, Step C. Flash chromatography of the crude product on silica gel (gradient elution with 0.5-2% MeOH in CH2Cl2) gave a 66% yield of the title compound as white crystals, mp 124°-126° C.; homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 286 (M+1)+.

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

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

Procedure: Ethyl-N-carbethoxyvalerimidate (from Example 4, Step B) was reacted with 2-(trifluoromethyl)phenylhydrazine according to the procedure of Example 4, Step C. Flash chromatography of the crude product on silica gel (gradient elution with 0.5-2% MeOH in CH2Cl2) gave a 66% yield of the title compound as white crystals, mp 124°-126° C.; homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 286 (M+1)+.

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

Procedure: 71.7 g (0.37 mol) of 2-chloro-6-fluorobenzoyl chloride are slowly added dropwise to a solution, cooled to 5° C., of 65.4 g (0.37 mol) of o-trifluoromethylphenylhydrazine in 200 ml of pyridine in such a manner that the temperature of the reaction mixture does not exceed 5° C. The mixture is stirred at room temperature for a further 90 minutes and subsequently treated with 400 ml of water. The aqueous phase is extracted three times with 150 ml of diethyl ether each time and the combined organic phases are washed in sequence with 2N sodium hydroxide solution and concentrated sodium chloride solution. The organic phase is then dried over anhydrous sodium sulfate and evaporated under reduced pressure, the crude product being evaporated twice with a small amount of toluene in order to remove excess pyridine. After recrystallization from methylene chloride/n-hexane there is obtained N1 -(α,α,α-trifluoro-o-tolyl)-2-chloro-6-fluorobenzhydrazide, m.p. 147°-148° C.; mass spectrum: 332(19), 157(100). does not exceed 5° C The aqueous phase is extracted three times with 150 ml of diethyl ether each time the combined organic phases are washed in sequence with 2N sodium hydroxide solution and concentrated sodium chloride solution The organic phase is then dried over anhydrous sodium sulfate evaporated under reduced pressure the crude product being evaporated twice with a small amount of toluene in order to remove excess pyridine After recrystallization from methylene chloride/n-hexane there

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

Procedure: 71.7 g (0.37 mol) of 2-chloro-6-fluorobenzoyl chloride are slowly added dropwise to a solution, cooled to 5° C., of 65.4 g (0.37 mol) of o-trifluoromethylphenylhydrazine in 200 ml of pyridine in such a manner that the temperature of the reaction mixture does not exceed 5° C. The mixture is stirred at room temperature for a further 90 minutes and subsequently treated with 400 ml of water. The aqueous phase is extracted three times with 150 ml of diethyl ether each time and the combined organic phases are washed in sequence with 2N sodium hydroxide solution and concentrated sodium chloride solution. The organic phase is then dried over anhydrous sodium sulfate and evaporated under reduced pressure, the crude product being evaporated twice with a small amount of toluene in order to remove excess pyridine. After recrystallization from methylene chloride/n-hexane there is obtained N1 -(α,α,α-trifluoro-o-tolyl)-2-chloro-6-fluorobenzhydrazide, m.p. 147°-148° C.; mass spectrum: 332(19), 157(100). does not exceed 5° C The aqueous phase is extracted three times with 150 ml of diethyl ether each time the combined organic phases are washed in sequence with 2N sodium hydroxide solution and concentrated sodium chloride solution The organic phase is then dried over anhydrous sodium sulfate evaporated under reduced pressure the crude product being evaporated twice with a small amount of toluene in order to remove excess pyridine After recrystallization from methylene chloride/n-hexane there

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2-trifluoromethyl-phenyl)-hydrazine (12.0 g, 68.13 mmol) and 4-piperidone monohydrate (10.46 g, 68.09 mmol), in iso-propyl alcohol was bubbled HCl (g) for 15 minutes at rt. The reaction was sealed in a pressure vessel and heated to 95° C. for 5 h, then cooled to rt. The reaction mixture was filtered and washed with iso-propyl alcohol and dried in vacuo to yield 6-trifluoromethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole bis-hydrochloride as a white solid (13.3 g, 63% yield). 1H NMR (CD3OD, 300 MHz) δ 3.203 (t, 2H, 12.4 Hz), 3.642 (t, 2H, 12.0 Hz), 4.472 (t, 2H, 2.6 Hz), 7.189 (t, 1H, 15.7 Hz), 7.435 (d, 1H, 7.7 Hz), 7.709 (d, 1H, 8.0 Hz) ppm. The reaction was sealed in a pressure vessel cooled to rt The reaction mixture was filtered washed with iso-propyl alcohol dried in vacuo