[ CAS No. 123066-64-8 ] {[proInfo.proName]}

Name: 123066-64-8|CrAc intermediate 2|98%
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Quality Control of [ 123066-64-8 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 123066-64-8 ]

CAS No. :	123066-64-8	MDL No. :	MFCD00220969
Formula :	C₁₁H₇F₆N₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XOXBUERZFCPKDR-UHFFFAOYSA-N
M.W :	295.18	Pubchem ID :	2740668
Synonyms :		Chemical Name :	4-(3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl)aniline

Calculated chemistry of [ 123066-64-8 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	11
Fraction Csp3 :	0.18
Num. rotatable bonds :	3
Num. H-bond acceptors :	7.0
Num. H-bond donors :	1.0
Molar Refractivity :	57.97
TPSA :	43.84 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.94 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.15
Log Po/w (XLOGP3) :	3.05
Log Po/w (WLOGP) :	5.8
Log Po/w (MLOGP) :	3.07
Log Po/w (SILICOS-IT) :	2.8
Consensus Log Po/w :	3.37

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.8
Solubility :	0.0467 mg/ml ; 0.000158 mol/l
Class :	Soluble
Log S (Ali) :	-3.64
Solubility :	0.0681 mg/ml ; 0.000231 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.33
Solubility :	0.0137 mg/ml ; 0.0000466 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	1.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.12

Safety of [ 123066-64-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 123066-64-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 123066-64-8 ]
Downstream synthetic route of [ 123066-64-8 ]

[ 123066-64-8 ] Synthesis Path-Upstream 1~4

1
[ 123066-63-7 ]
[ 123066-64-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With palladium on activated charcoal; hydrogen In ethyl acetate at 20℃; for 2 h;	EtOAc (44 mL), Pd/C (1.3 g) and l-(4-nitrophenyl)-3,5- bis(trifluoromethyl)-lH-pyrazole (4.4 g, 13.5 mmol) are added under hydrogen atmosphere. After stirring at room temperature for 2 hours the resulting mixture is filtered under vacuo over a pad of celite, rinsed with EtOAc and evaporated to give compound 13 as a pale yellow solid (3.75 g, 12.7 mmol, 94percent). Analytical data:1H-NMR (300 MHz; CDC1₃): δ 7.22 (d, J 8.5 Hz, 2H), 7.00 (s, 1H), 6.72 (d, J 8.5 Hz, 2H). MS: M+l 296

Reference： [1] Journal of Organic Chemistry, 2011, vol. 76, # 16, p. 6657 - 6669
[2] Patent: WO2017/212414, 2017, A1, . Location in patent: Page/Page column 43
[3] Journal of Medicinal Chemistry, 2000, vol. 43, # 16, p. 2975 - 2981

2
[ 1522-22-1 ]
[ 123066-64-8 ]

Reference： [1] Journal of Medicinal Chemistry, 2000, vol. 43, # 16, p. 2975 - 2981
[2] Patent: WO2017/212414, 2017, A1,

3
[ 1694-30-0 ]
[ 123066-64-8 ]

Reference： [1] Journal of Organic Chemistry, 2011, vol. 76, # 16, p. 6657 - 6669

4
[ 636-99-7 ]
[ 123066-64-8 ]

Reference： [1] Journal of Organic Chemistry, 2011, vol. 76, # 16, p. 6657 - 6669

[ 123066-64-8 ] Synthesis Path-Downstream 1~87

1
[ 59944-65-9 ]
[ 123066-64-8 ]
YM-58483 [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

2
[ 55-22-1 ]
[ 123066-64-8 ]
[ 245745-65-7 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 6657 - 6669
[2]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466
[3]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

3
[ 14254-57-0 ]
[ 123066-64-8 ]
[ 245745-65-7 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

4
[ 2510-36-3 ]
[ 123066-64-8 ]
N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-3,5-dimethyl-4-isoxazolecarboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

5
[ 31301-45-8 ]
[ 123066-64-8 ]
N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-3,5-dimethyl-4-isoxazolecarboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

6
[ 35730-09-7 ]
[ 123066-64-8 ]
N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-2,5-difluorobenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

7
[ 4519-39-5 ]
[ 123066-64-8 ]
N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-2,3-difluorobenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

8
[ 18355-73-2 ]
[ 123066-64-8 ]
N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-2,3-difluorobenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

9
[ 654-87-5 ]
[ 123066-64-8 ]
N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-2,3,5-trifluorobenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

10
[ 393-53-3 ]
[ 123066-64-8 ]
N-(4-(3,5-bis(trifluoromethyl)-1H-pyrazole-1-yl)phenyl)-3-fluoroisonicotinamide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 6657 - 6669
[2]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

11
[ 609-65-4 ]
[ 123066-64-8 ]
N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-2-chlorobenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

12
[ 123066-63-7 ]
[ 123066-64-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With palladium on activated charcoal; hydrogen; In ethyl acetate; at 20℃; for 2h;	EtOAc (44 mL), Pd/C (1.3 g) and l-(4-nitrophenyl)-3,5- bis(trifluoromethyl)-lH-pyrazole (4.4 g, 13.5 mmol) are added under hydrogen atmosphere. After stirring at room temperature for 2 hours the resulting mixture is filtered under vacuo over a pad of celite, rinsed with EtOAc and evaporated to give compound 13 as a pale yellow solid (3.75 g, 12.7 mmol, 94%). Analytical data:1H-NMR (300 MHz; CDC13): delta 7.22 (d, J 8.5 Hz, 2H), 7.00 (s, 1H), 6.72 (d, J 8.5 Hz, 2H). MS: M+l 296

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 6657 - 6669
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 9756 - 9783
[3]Patent: WO2017/212414,2017,A1 .Location in patent: Page/Page column 43
[4]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

13
[ 122-01-0 ]
[ 123066-64-8 ]
N-(4-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-4-chlorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 4h;	4-chlorobenzoyl chloride (88 mg) and THF (2 ml) were added to a mixture of <strong>[123066-64-8]4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]aniline</strong> (150 mg), triethylamine (57 mg) and THF (2 ml) under ice-cooling, followed by stirring at room temperature for 4 hours. Water was added to the reaction solution, the thus formed product was extracted with ethyl acetate and then the extract was washed with 1 N hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution and saturated brine in that order. The organic lager was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. By recrystallizing the resulting residue from a mixed solvent of ethyl acetate and n-hexane, 4-chloro-4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]benzanilide (105 mg) was obtained as colorless powder crystals.

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 5370 - 5383
[2]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981
[3]Patent: US6348480,2002,B1 .Location in patent: Page column 18

14
[ 18212-21-0 ]
[ 123066-64-8 ]
YM-58483 [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 6657 - 6669
[2]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981
[3]Patent: US6348480,2002,B1 .Location in patent: Page column 27

15
[ 393-52-2 ]
[ 123066-64-8 ]
N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-2-fluorobenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

16
[ 903592-75-6 ]
[ 123066-64-8 ]
N-(4-(3,5-bis(trifluoromethyl)-1H-pyrazole-1-yl)phenyl)-3-fluoroisonicotinamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

17
[ 240800-48-0 ]
[ 123066-64-8 ]
N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-2,3,5-trifluorobenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

18
[ 123066-64-8 ]
[ 74-11-3 ]
N-(4-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-4-chlorobenzamide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 6657 - 6669
[2]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

19
[ 123066-64-8 ]
[ 118-91-2 ]
N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-2-chlorobenzamide [ No CAS ]

20
[ 123066-64-8 ]
[ 445-29-4 ]
N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-2-fluorobenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

21
[ 123066-64-8 ]
[ 2991-28-8 ]
N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-2,5-difluorobenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

22
[ 1522-22-1 ]
[ 123066-64-8 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981
[2]Patent: WO2017/212414,2017,A1
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 9756 - 9783

23
[ 100-16-3 ]
1-<2.3.4-trihydroxy-phenyl>-dodecanone-(1) [ No CAS ]
[ 123066-64-8 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981

24
[ 486-73-7 ]
[ 123066-64-8 ]
C₂₁H₁₂F₆N₄O [ No CAS ]

Reference： [1]Patent: US6348480,2002,B1 .Location in patent: Page column 31

25
[ 98-97-5 ]
[ 123066-64-8 ]
C₁₆H₉F₆N₅O [ No CAS ]

Reference： [1]Patent: US6348480,2002,B1 .Location in patent: Page column 31

26
[ 59-67-6 ]
[ 123066-64-8 ]
4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]nicotinanilide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466
[2]Patent: US6348480,2002,B1 .Location in patent: Page column 31

27
[ 84358-13-4 ]
[ 123066-64-8 ]
[ 223500-14-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃;	A mixture of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (198 mg), <strong>[123066-64-8]4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]aniline</strong> (206 mg), WSCD hydrochloride (172 mg) and THF (3 ml) was stirred overnight at room temperature. After adding ethyl acetate, the reaction solution was washed with water, saturated sodium bicarbonate aqueous solution, 1 N hydrochloric acid and saturated brine in that order. The organic layer was dried over anhydrous sodium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromtaography (eluent; n-hexane:ethyl acetate=7:1-5:1) to give tert-butyl 4-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenylaminocarbonyl]piperidine-1-carboxylate (279 mg) as a colorless amorphous solid. 4 N hydrochloric acid ethyl acetate solution (2.60 ml) was added to a mixture of this solid (263 mg) and ethyl acetate (2.6 ml), followed by stirring at room temperature for 2 hours and 45 minutes. The reaction solution was concentrated under a reduced pressure, diethyl ether was added to the thus obtained residue, and the mixture was concentrated under a reduced pressure. By recrystallizing the resulting residue from a mixed solvent of ethyl acetate and n-hexane, [4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]piperidine]-4-carboxyanilide hydrochloride (201 mg) was obtained as colorless powder crystals.

Reference： [1]Patent: US6348480,2002,B1 .Location in patent: Page column 20

28
[ 1918-78-1 ]
[ 123066-64-8 ]
C₁₇H₁₁F₆N₃OS [ No CAS ]

Reference： [1]Patent: US6348480,2002,B1 .Location in patent: Page column 29

29
[ 20485-41-0 ]
[ 123066-64-8 ]
4-methyl-4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]thiazole-5-carboxyanilide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride; In 1,2-dichloro-ethane; at 20℃;	A mixture of <strong>[20485-41-0]4-methylthiazole-5-carboxylic acid</strong> (108 mg), 4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]aniline (223 mg), WSCD hydrochloride 152 mg) and DCE (5 ml) was stirred overnight at room temperature. Water (10 ml) was added to the reaction mixture, and the thus formed product was extracted with a mixed solvent of diethyl ether (5 ml) and ethyl acetate (10 ml). The extract was washed with 1 N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated brine in that order. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The thus obtained residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=3:1-2:1) and then recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 4-methyl-4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]thiazole-5-carboxyanilide (143 mg) as colorless needles.

Reference： [1]Patent: US6348480,2002,B1 .Location in patent: Page column 17

30
[ 191103-80-7 ]
[ 123066-64-8 ]
4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1H-imidazole-4-carboxanilide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of 1-trityl-1H-imidazole-4-carboxylic acid (300 mg), <strong>[123066-64-8]4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]aniline</strong> (200 mg), WSCD hydrochloride (162 mg), DMF (0.5 ml) and THF (4 ml) was stirred overnight at room temperature. Water (10 ml) was added to the reaction solution, the thus formed product was extracted with ethyl acetate and then the extract was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=3:1). Then, concentrated hydrochloric acid (0.1 ml) and acetone (3 ml) were added, followed by stirring overnignt at room temperature. The reaction solution was concentrated under a reduced pressure, diethyl ether was added to the thus obtained residue, and when the mixture was concentrated under a reduced pressure. A mixed solvent of ethanol and diethyl ether was added to the thus obtained residue, time insoluble matter was removed by filtration and then the filtrate was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=1:1-2:3) and then recrystallized from a mixed solvent of ethyl acetate and n-hexane, thereby obtaining [4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1H-imidazole]-4-carboxyanilide (35 mg) as colorless powder crystals.

Reference： [1]Patent: US6348480,2002,B1 .Location in patent: Page column 22

31
[ 14190-59-1 ]
[ 123066-64-8 ]
4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]thiazole-2-carboxanilide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466
[2]Patent: US6348480,2002,B1 .Location in patent: Page column 27

32
[ 14527-41-4 ]
[ 123066-64-8 ]
4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]thiazole-5-carboxanilide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466
[2]Patent: US6348480,2002,B1 .Location in patent: Page column 29

33
[ 2510-32-9 ]
[ 123066-64-8 ]
C₁₆H₁₀F₆N₄O₂ [ No CAS ]

Reference： [1]Patent: US6348480,2002,B1 .Location in patent: Page column 29

34
[ 6973-60-0 ]
[ 123066-64-8 ]
N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-methyl-1H-pyrrole-2-carboxamide [ No CAS ]

Reference： [1]Patent: US6348480,2002,B1 .Location in patent: Page column 31

35
[ 15159-40-7 ]
[ 861359-74-2 ]
[ 123066-64-8 ]
[ 251655-39-7 ]

Yield	Reaction Conditions	Operation in experiment
19.6%	In dichloromethane;	Example 8 Synthesis of Morpholine-4-carboxylic Acid {4-[3.5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}amide (Method F) To a solution of 1-(4'-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.300 g, 1.02 mmol) in of methylene chloride (5 mL) was added diisopropylethyl amine (0.18 mL, 1.0 mmol) followed by 4-morpholine carbonylchloride (0.11 mL, 1.0 mmol). The mixture was stirred at rt for 6 days, and diluted with ethyl acetate. It was then washed twice with water, dried over sodium sulfate and evaporated. Chromatography of the residue over silica gel (50% EtOAc/hexanes) gave the above-named compound (0.080 g, 19.6%) as a white solid: mp 185-186 C. NMR (CDCl3) delta 7.56 (2H, d), 7.44 (2H, d), 7.07 (1H, s), 6.51 (1H, s), 3.79 (4H, m), 3.54 (4H, m).

Reference： [1]Patent: US6506747,2003,B1

36
[ 75-03-6 ]
[ 7087-68-5 ]
[ 123066-64-8 ]
[ 251655-41-1 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide;	Example 10 Synthesis of {4-[3,5-bis(Trifluoromethyl)pyrazol-1-yl]phenyl}ethylamine (Method H) A mixture of 1-(4'-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.15 g, 0.58 mmol), ethyl iodide (0.10 mL, 1.26 mmol), and Hunig's base (0.20 mL, 1.14 mmol) in N,N-dimethylformamide (10 mL) was heated to 50 C. under argon with stirring. After 24 hours the mixture was diluted with water, and extracted with ethyl acetate. The organic phase was washed with water (4*25 mL), brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography (ethyl acetate/hexanes) followed by recrystallization from ethanol/water to give the above-named compound (0.045 g) as yellow crystals. mp 54 C. NMR (CDCl3, 400 MHz): delta 7.26 (d, 2H), 7.02 (s, 1H), 6.64 (d, 2H), 3.93 (br s, 1H), 3.22 (q, 2H), 1.31 (t, 3H).

Reference： [1]Patent: US6506747,2003,B1

37
[ 872-85-5 ]
[ 123066-64-8 ]
[ 251655-42-2 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium cyanoborohydride; acetic acid; In methanol; dichloromethane; acetone;	Example 11 Synthesis of N-{4-[3,5-bis(Trifluoromethyl)pyrazol-1-yl]phenyl}pyridin-4-ylmethylamine (Method I) A mixture of 1-(4'-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.059 g, 0.2 mmol) and pyridine-4-carboxaldehyde (20 muL, 0.2 mmol) in methanol (0.8 mL) and acetic acid (0.2 mL) was stirred at room temperature for 15 minutes Sodium cyanoborohydride (0.032 g, 0.5 mmol) was added, and the reaction mixture stirred overnight. The reaction mixture was diluted with CH2Cl2 (50 mL), washed with brine (2*20 mL), dried over anhydrous Na2SO4 and evaporated. The residue was purified by flash column chromatography over silica gel (2% acetone in CH2Cl2) to give the above-named compound (0.060 g, 78%): mp 92-94 C. NMR (DMSO-d6) delta 4.40 (2H, d), 6.65 (2H, d), 6.97 (1H, t), 7.23 (2H, d), 7.35 (2H, d), 6.65 (2H, d), 7.7 (1H, s), 8.51 (2H, d).

Reference： [1]Patent: US6506747,2003,B1

38
[ 123066-64-8 ]
[ 98-89-5 ]
N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]cyclohexanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2-(Dimethylamino)pyridine; 1,2-dichloro-ethane; In dichloromethane;	Example 1 Synthesis of N-{4-[3,5-bis(Trifluoromethyl)pyrazol-1-yl]phenyl}cyclohexanecarboxamide (Method A). A mixture of cyclohexanecarboxylic acid (0.10 g, 0.8 mmol) and EDC (0.077 g, 0.4 mmol) in CH2Cl2 (1.5 mL) was stirred for 15 minutes. <strong>[123066-64-8]1(4'-Aminophenyl)-3,5-bis(trifluoromethyl)pyrazole</strong> (0.059 g, 0.2 mmol) was added followed by dimethylaminopyridine (0.01 g, 0.1 mmol). After 3 hours the mixture was diluted with CH2Cl2 (50 mL), washed with 10% NaHCO3 (250 mL), brine (325mL), and dried over anhydrous Na2SO4. Evaporation of the solvent gave the above-named compound as a solid that crystallized from benzene (0.075 g, 92%): mp 178-180 C.; 1H NMR (CDCl3) delta 1.35 (3H, m), 1.66 (2H, m), 1.75 (1H, m), 1.85 (2H, m), 2.0 (2H, m), 2.3 (1H, m), 7.08 (1H, s), 7.45 (1H, d, J=8.5 Hz), 7.75 (2H, d, J=8.5 Hz).

Reference： [1]Patent: US6506747,2003,B1

39
[ 75-44-5 ]
morpholinomethyl polystyrene [ No CAS ]
[ 123066-64-8 ]
[ 251658-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; toluene;	Example 6 Synthesis of N-{4-[(3,5-bis(Trifluoromethyl)pyrazol-1-yl]phenyl}-N'-cyclohexylurea (Method E) To morpholinomethyl polystyrene (Novabiochem, substitution=3.55 mmol/g, 1.02 g, 3.62 mmol) in methylene chloride (18.5 mL) under argon was added 1-(4'-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.555 g, 1.88 mmol). The mixture was cooled to 0 C. and phosgene (1.93M in toluene, Fluka, 1.95 mL, 3.76 mmol) was added. After thirty minutes the reaction mixture was filtered, washed with methylene chloride (2*30 mL) and concentrated to give 1-(4'-isocyanatophenyl)-3,5-bis(trifluoromethyl)pyrazole.

Reference： [1]Patent: US6506747,2003,B1

40
[ 1070-89-9 ]
[ 123066-64-8 ]
[ 16263-52-8 ]
[ 251655-36-4 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran;	Example 5 Synthesis of Benzo[d]isoxazol-3-yl-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}amine (Method D) To a stirred solution of 1-(4'-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.20 g, 0.68 mmol) and 3-chlorobenzisoxazole (0.10 g, 0.65 mmol) in tetrahydrofuran (2.5 mL) under argon was added sodium bis-trimethylsilyl amide (1.0 M in tetrahydrofuran, 0.68 mL, 0.68 mmol). After seven days, the mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography (elution with ethyl acetate/hexanes) to give the above-named compound (0.050 g). m.p. 209-210 C. NMR (CDCl3, 400 MHz): delta 7.77 (d, 1H), 7.64 (m, 3H), 7.53 (d, 2H), 7.37 (m, 1H), 7.09 (s, 1H), 6.68 (s, 1H).

Reference： [1]Patent: US6506747,2003,B1

41
[ 933-88-0 ]
[ 123066-64-8 ]
N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-2-methylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane;	Example 2 Synthesis of N-{4-[3,5-bis(Trifluoromethyl)pyrazol-1-yl]phenyl}-2-methylbenzamide (Method B). A mixture of 1-(4'-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.10 g, 0.34 mmol), o-toluoyl chloride (0.062 mL, 0.43 mmol), and triethylamine (0.06 mL, 0.43 mmol) in methylene chloride (7 mL) was stirred under argon for three days. The reaction mixture was diluted with methylene chloride, washed with 1N hydrochloric acid (250 mL), brine (240 mL), dried (magnesium sulfate) and concentrated to give an off-white solid. Recrystallization from methylene chloride/hexanes gave the above-named compound (0.065 g). m.p. 175 C. NMR (CDCl3, 400 MHz): delta 7.83 (d, 2H), 7.64 (br s, 1H), 7.53 (m, 3H), 7.43 (m, 1H), 7.31 (m, 2H), 7.10 (s, 1H), 2.56 (s, 3H).

Reference： [1]Patent: US6506747,2003,B1

42
[ 123066-64-8 ]
[ 251658-50-1 ]

Yield	Reaction Conditions	Operation in experiment
	With benzaldehyde; toluene-4-sulfonic acid; In toluene;	Example 12 Synthesis of {4-[3,5-bis(Trifluoromethyl)pyrazol-1-yl]phenyl}-(1-phenylethyl)amine (Method J) A mixture of 1-(4'-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (1.5 g), benzaldehyde (0.53 g) and tosic acid (0.03 g) in toluene (20 mL) was heated under a Dean Stark apparatus at 140 C. for 3 hours. The mixture was filtered and evaporated to dryness to give N-(benzylidene)-1-(4'-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole as a solid (1.4 g) which was used without further purification.

Reference： [1]Patent: US6506747,2003,B1

43
[ 33252-30-1 ]
[ 123066-64-8 ]
[ 251655-35-3 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; ethanol; dichloromethane;	Example 4 Synthesis of 1-{4-[N-(4-Cyanopyridin-2-yl)amino]phenyl}-3,5-bis(trifluoromethyl)pyrazole (Method D) A mixture of 1-(4'-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.36 g) and 2-chloro-4-cyanopyridine (0.14 g) in dioxane (1 mL) was heated at 125 C. in a sealed tube for 5 days. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried, filtered and evaporated. Chromatography of the residue over silica gel (methylene chloride to 2% ethanol/methylene chloride gradient gave the above-named compound (0.22 g) mp 152-153 C. NMR (CDCl3) 8.45 (1H, m), 7.86 (3H, m), 7.48 (2H, d), 7.20 (1H, br s), 7.07 (1H, s), 6.91 (1H, m).

Reference： [1]Patent: US6506747,2003,B1

44
[ 100791-00-2 ]
[ 123066-64-8 ]
[ 1076689-97-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466

45
[ 98-98-6 ]
[ 123066-64-8 ]
4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]pyridine-2-carboxanilide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466

46
[ 51598-76-6 ]
[ 123066-64-8 ]
[ 1076692-17-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466

47
[ 3222-49-9 ]
[ 123066-64-8 ]
[ 1076690-00-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466

48
[ 402-66-4 ]
[ 123066-64-8 ]
[ 1026350-55-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466

49
[ 22620-27-5 ]
[ 123066-64-8 ]
[ 1076690-01-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466

50
5-bromopyridine-3-carboxylic acid hydrochloride [ No CAS ]
[ 123066-64-8 ]
5-bromo-4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]nicotinanilide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466

51
[ 104326-73-0 ]
[ 123066-64-8 ]
[ 1076689-98-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466

52
4,6-dimethylnicotinoyl chloride [ No CAS ]
[ 123066-64-8 ]
4,6-dimethyl-4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]nicotinanilide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466

53
[ 56055-55-1 ]
[ 123066-64-8 ]
[ 245745-97-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466

54
[ 82776-24-7 ]
[ 123066-64-8 ]
[ 1076692-18-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466

55
[ 94015-05-1 ]
[ 123066-64-8 ]
[ 292610-93-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466

56
[ 53750-65-5 ]
[ 123066-64-8 ]
[ 1076689-99-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9457 - 9466

57
[ 22047-86-5 ]
[ 123066-64-8 ]
4,6-dimethyl-4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]nicotinanilide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 1 Oxalyl chloride (8.7 ml) was added to a mixture of <strong>[22047-86-5]4,6-dimethylnicotinic acid</strong> (15.1 g) and dichloromethane (150 ml) under ice cooling, followed by stirring at 15 to 20C for one hour. A mixture of 4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]aniline (23.59 g) and dichloromethane (300 ml) was added to the resulting reaction solution, followed by stirring at room temperature for 18 hours. An aqueous 20% potassium carbonate solution (about 200 ml) was added to the reaction solution, from which the organic layer was separated. Subsequently, the aqueous layer was extracted with dichloromethane (about 50 ml). The organic layer and the extract solution were combined together and subsequently concentrated under reduced pressure. The resulting residue was recrystallized from a mixed solvent (270 ml) of ethanol and water (2:1, respectively), to obtain 4,6-dimethyl-4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]nicotinanilide (26.70 g) as bluish white solid. FAB-MS(Pos.): m/z 429[(M+H)+]; NMR(DMSO-d6) delta: 2.41 (3H, s), 2.49(3H, s), 7.24(1H, s), 7.60(2h, d, J=8.8Hz), 7.79 (1H, s), 7.95 (2H, d, J=8.8Hz), 8.58 (1H, s), 10.72 (1H, s).

Reference： [1]Patent: EP1548015,2005,A1 .Location in patent: Page/Page column 7-8

58
[ 2257-35-4 ]
[ 123066-64-8 ]
[ 1101891-14-8 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 6657 - 6669

59
[ 1694-30-0 ]
[ 123066-64-8 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 6657 - 6669

60
[ 636-99-7 ]
[ 123066-64-8 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 6657 - 6669
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 9756 - 9783

61
[ 98-60-2 ]
[ 123066-64-8 ]
[ 1315322-99-6 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 6657 - 6669

62
[ 98-59-9 ]
[ 123066-64-8 ]
[ 1315323-00-2 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 6657 - 6669

63
[ 18063-02-0 ]
[ 123066-64-8 ]
(2,6-difiuorophenyl)-N-{4-[3,5-bis(trifluoromethyl)pyrazolyl]phenyl}carboxyamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.7%	With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	To a solution of <strong>[123066-64-8]4-[3,5-bis(trifluoromethyl)pyrazolyl]phenylamine</strong> (89 mg, 0.3 mmol) in 5 ml DCM was added 2,6-difluorobenzoyl chloride (75 ??, 0.6 mmol) followed by addition of DIE A (174 ??) and DMAP (2 mg). The resulting solution was stirred overnight at room temperature. The reaction mixture was worked up with aq. NaHCOs/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 3 mL THF/MeOH/H20 (5 :4: 1) and stirred with IN NaOH (600 ??) at room temperature for lh before worked up with EA/ aq. NaHCOs. Silica gel flash chromatography furnished (2,6-difiuorophenyl)-N-{4-[3,5- bis(trifluoromethyl)pyrazolyl]phenyl}carboxyamide 50 (78 mg, yield: 59.7%>, purity >95%>) as a white solid. MS (ESI) [M+H]+ 436.0.

Reference： [1]Patent: WO2013/59666,2013,A1 .Location in patent: Paragraph 00580

64
[ 18063-02-0 ]
[ 123066-64-8 ]
[ 1431385-27-1 ]

Reference： [1]Patent: WO2013/59666,2013,A1

65
3,5-bis(trifluoromethyl)-4,5-dihydro-5-hydroxy-1-(4-nitrophenyl)pyrazole [ No CAS ]
[ 123066-64-8 ]

Reference： [1]Patent: WO2017/212414,2017,A1
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 9756 - 9783

66
[ 123066-64-8 ]
1-(4-azidophenyl)-3,5-bis(trifluoromethyl)-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		To a solution of 4-(3,5-bis(trifluoromethyl)-lH-pyrazol-l-yl)aniline (4.16 g, 14.10 mmol) in water (62.7 mL) HC1 37% (5 mL) is added and the resulting mixture is cooled down at 0C. Then, a solution of NaN02 (0.97 g, 14.10 mmol) in water (6 mL) is added and after 10 minutes a solution of NaN3 (1.09 g, 16.9 mmol) in water (6 mL) is slowly added. The reaction is stirred at room temperature for additional 1 hour, diluted with EtOAc and washed with water (x 2). The organic layer is dried over sodium sulfate and the volatile is removed under vacuum. The crude material is purified by column chromatography using petroleum ether/ethyl acetate 95:5 as eluent, yielding compound 14 as a pale red oil (3.84 g, 11.96 mmol, 85%). Analytical data: 1H-NMR (300 MHz, CDC13): delta 7.47 (d, J 8.5 Hz, 2H), 7.14 (d, J 8.5 Hz, 2H), 7.0 (s, 1H). MS: M+l 322

Reference： [1]Patent: WO2017/212414,2017,A1 .Location in patent: Page/Page column 43; 44
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 9756 - 9783

67
[ 123066-64-8 ]
3-(1-(4-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)benzoic acid [ No CAS ]

Reference： [1]Patent: WO2017/212414,2017,A1
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 9756 - 9783

68
[ 123066-64-8 ]
1-(4-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-4-phenyl-1H-1,2,3-triazole [ No CAS ]