[ CAS No. 52222-73-8 ] {[proInfo.proName]}

Name: 52222-73-8|4-(Trifluoromethyl)-1H-pyrazole|97%
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Quality Control of [ 52222-73-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 52222-73-8 ]

Product Details of [ 52222-73-8 ]

CAS No. :	52222-73-8	MDL No. :	MFCD11226572
Formula :	C₄H₃F₃N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KDEJQUNODYXYBJ-UHFFFAOYSA-N
M.W :	136.08	Pubchem ID :	12777795
Synonyms :

Calculated chemistry of [ 52222-73-8 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.25
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	23.59
TPSA :	28.68 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.35 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.93
Log Po/w (XLOGP3) :	1.1
Log Po/w (WLOGP) :	2.58
Log Po/w (MLOGP) :	0.81
Log Po/w (SILICOS-IT) :	2.08
Consensus Log Po/w :	1.5

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.72
Solubility :	2.58 mg/ml ; 0.019 mol/l
Class :	Very soluble
Log S (Ali) :	-1.29
Solubility :	6.9 mg/ml ; 0.0507 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.09
Solubility :	1.11 mg/ml ; 0.00813 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.32

Safety of [ 52222-73-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H317-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 52222-73-8 ]

* 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 [ 52222-73-8 ]
Downstream synthetic route of [ 52222-73-8 ]

[ 52222-73-8 ] Synthesis Path-Upstream 1~2

1
[ 460-40-2 ]
[ 3724-43-4 ]
[ 52222-73-8 ]

Yield	Reaction Conditions	Operation in experiment
29%	Stage #1: at 75℃; for 5 h; Stage #2: With hydrazine In water; acetonitrile for 1 h; Stage #3: With trifluoroacetic acid In water; acetonitrile at 70℃; for 1.5 h;	3,3,3-Trifluoropropionic (5.64 g, 44.1 mmol) is combined with chlorornethylene dimethyl ammonium chloride (11.45 g, 96.6 mmol) in 42 mL 1,2-dichloroethane, is warmed to 75° C., and is stirred for 5 hrs under N2. The reaction mixture is cooled, and volatiles removed in vacuo overnight to afford 10.82 g of the intermediate, which is then combined with hydrazine monohydrate (2.72 mL, 1.2 eq) in 145 mL CH3CN, and allowed to stir for 1 hr. TFA (5.03 mL, 3 eq) is added to reaction mixture, which is then warmed to 70° C., and stirred for 1.5 hr under N2. The reaction mixture is cooled, and concentrated in vacuo, and partitioned between 30 mL H2O and 30 mL EtOAc. NaHCO3 (3.6 g) is added to the vigorously stirring mixture. The layers are then separated and the aqueous layer is washed (.x.3) using EtOAc. Organics are combined and concentrated. Product is chromatographed (Biotage 40+S) using 20percent EtOAc in hexanes. Appropriate fractions are concentrated in vacuo at R.T. (to discourage sublimation) to afford 1.75 g (29percent yield) of 4-(trifluoromethyl)-1H-pyrazol-1-amine a light yellow solid. Anal. Calcd for C4H3F3N2: C, 35.31; H, 2.22; N, 20.59. Found: C, 35.34; H, 2.40; N, 20.55. 4-(Trifluoromethyl)-1H-pyrazol-1-amine (0.68 g, 5 mmol) is added to a stirring solution of hydroxyamine-o-sulfonic acid (0.679 g, 6 mmol) in 20 mL 12N NaOH, and stirred overnight. The reaction mixture is extracted and washed (3.x.) with Et2O. The organic layers are combined, dried (MgSO4), and concentrated to afford 0.38 g of 4-(trifluoromethyl)-1H-pyrazol-1-amine as a yellow oil. 4-(Trifluoromethyl)-1H-pyrazol-1-amine (154 mg, 1 mmol) is combined with 5-chloro-2,4-dimethoxyphenylisocyanate (213 mg, 1 mmol) in 8 mL THF, to which 5 mg DMAP is added. The reaction mixture is allowed to stir at RT for 2 days, and then concentrated to a brown solid and chromatographed (Biotage 25+S) using 50percent EtOAc in hexanes to afford 66 mg (21percent yield) of Example 159 as a white solid. MS (EI) m/z: 364 (M)+.

Reference： [1] Patent: US2003/236287, 2003, A1, . Location in patent: Page 37

2
[ 176214-18-9 ]
[ 52222-73-8 ]

Reference： [1] Tetrahedron Letters, 1996, vol. 37, # 11, p. 1829 - 1832

[ 52222-73-8 ] Synthesis Path-Downstream 1~87

1
[ 176214-18-9 ]
[ 52222-73-8 ]

Reference： [1]Tetrahedron Letters,1996,vol. 37,p. 1829 - 1832

2
[ 460-40-2 ]
[ 3724-43-4 ]
[ 52222-73-8 ]

Yield	Reaction Conditions	Operation in experiment
29%		3,3,3-Trifluoropropionic (5.64 g, 44.1 mmol) is combined with chlorornethylene dimethyl ammonium chloride (11.45 g, 96.6 mmol) in 42 mL 1,2-dichloroethane, is warmed to 75 C., and is stirred for 5 hrs under N2. The reaction mixture is cooled, and volatiles removed in vacuo overnight to afford 10.82 g of the intermediate, which is then combined with hydrazine monohydrate (2.72 mL, 1.2 eq) in 145 mL CH3CN, and allowed to stir for 1 hr. TFA (5.03 mL, 3 eq) is added to reaction mixture, which is then warmed to 70 C., and stirred for 1.5 hr under N2. The reaction mixture is cooled, and concentrated in vacuo, and partitioned between 30 mL H2O and 30 mL EtOAc. NaHCO3 (3.6 g) is added to the vigorously stirring mixture. The layers are then separated and the aqueous layer is washed (×3) using EtOAc. Organics are combined and concentrated. Product is chromatographed (Biotage 40+S) using 20% EtOAc in hexanes. Appropriate fractions are concentrated in vacuo at R.T. (to discourage sublimation) to afford 1.75 g (29% yield) of 4-(trifluoromethyl)-1H-pyrazol-1-amine a light yellow solid. Anal. Calcd for C4H3F3N2: C, 35.31; H, 2.22; N, 20.59. Found: C, 35.34; H, 2.40; N, 20.55. 4-(Trifluoromethyl)-1H-pyrazol-1-amine (0.68 g, 5 mmol) is added to a stirring solution of hydroxyamine-o-sulfonic acid (0.679 g, 6 mmol) in 20 mL 12N NaOH, and stirred overnight. The reaction mixture is extracted and washed (3×) with Et2O. The organic layers are combined, dried (MgSO4), and concentrated to afford 0.38 g of 4-(trifluoromethyl)-1H-pyrazol-1-amine as a yellow oil. 4-(Trifluoromethyl)-1H-pyrazol-1-amine (154 mg, 1 mmol) is combined with 5-chloro-2,4-dimethoxyphenylisocyanate (213 mg, 1 mmol) in 8 mL THF, to which 5 mg DMAP is added. The reaction mixture is allowed to stir at RT for 2 days, and then concentrated to a brown solid and chromatographed (Biotage 25+S) using 50% EtOAc in hexanes to afford 66 mg (21% yield) of Example 159 as a white solid. MS (EI) m/z: 364 (M)+.

Reference： [1]Patent: US2003/236287,2003,A1 .Location in patent: Page 37

3
[ 52222-73-8 ]
4-(trifluoromethyl)-1H-pyrazol-1-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	With sodium hydroxide; hydroxylamine-O-sulfonic acid; In water;	3,3,3-Trifluoropropionic (5.64 g, 44.1 mmol) is combined with chlorornethylene dimethyl ammonium chloride (11.45 g, 96.6 mmol) in 42 mL 1,2-dichloroethane, is warmed to 75 C., and is stirred for 5 hrs under N2. The reaction mixture is cooled, and volatiles removed in vacuo overnight to afford 10.82 g of the intermediate, which is then combined with hydrazine monohydrate (2.72 mL, 1.2 eq) in 145 mL CH3CN, and allowed to stir for 1 hr. TFA (5.03 mL, 3 eq) is added to reaction mixture, which is then warmed to 70 C., and stirred for 1.5 hr under N2. The reaction mixture is cooled, and concentrated in vacuo, and partitioned between 30 mL H2O and 30 mL EtOAc. NaHCO3 (3.6 g) is added to the vigorously stirring mixture. The layers are then separated and the aqueous layer is washed (×3) using EtOAc. Organics are combined and concentrated. Product is chromatographed (Biotage 40+S) using 20% EtOAc in hexanes. Appropriate fractions are concentrated in vacuo at R.T. (to discourage sublimation) to afford 1.75 g (29% yield) of 4-(trifluoromethyl)-1H-pyrazol-1-amine a light yellow solid. Anal. Calcd for C4H3F3N2: C, 35.31; H, 2.22; N, 20.59. Found: C, 35.34; H, 2.40; N, 20.55. 4-(Trifluoromethyl)-1H-pyrazol-1-amine (0.68 g, 5 mmol) is added to a stirring solution of hydroxyamine-o-sulfonic acid (0.679 g, 6 mmol) in 20 mL 12N NaOH, and stirred overnight. The reaction mixture is extracted and washed (3×) with Et2O. The organic layers are combined, dried (MgSO4), and concentrated to afford 0.38 g of 4-(trifluoromethyl)-1H-pyrazol-1-amine as a yellow oil. 4-(Trifluoromethyl)-1H-pyrazol-1-amine (154 mg, 1 mmol) is combined with 5-chloro-2,4-dimethoxyphenylisocyanate (213 mg, 1 mmol) in 8 mL THF, to which 5 mg DMAP is added. The reaction mixture is allowed to stir at RT for 2 days, and then concentrated to a brown solid and chromatographed (Biotage 25+S) using 50% EtOAc in hexanes to afford 66 mg (21% yield) of Example 159 as a white solid. MS (EI) m/z: 364 (M)+.

Reference： [1]Patent: US2003/236287,2003,A1 .Location in patent: Page 37

4
[ 50-00-0 ]
[ 52222-73-8 ]
[ 860807-40-5 ]

Yield	Reaction Conditions	Operation in experiment
	at 130℃; for 4h;	Reference Production Example 17-2 <strong>[52222-73-8]4-(trifluoromethyl)pyrazole</strong>-1-yl-1H-methanol The mixture of 0. 59 g of 4- (trifluoromethyl) -1H-pyrazole and 0.26 g of paraformaldehyde was stirred at 130 C for 4 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The residue was concentration under reduced pressure to obtain 0.60 g of <strong>[52222-73-8]4-(trifluoromethyl)-1H-pyrazole</strong>-1-ylmethanol. 1H-NMR(CDCl3,TMS,delta(ppm)):5.58(2H,s),7.77(1H,s),7.90(1H,s)

Reference： [1]Patent: EP1710234,2006,A1 .Location in patent: Page/Page column 55

5
(Z)-N-(3-(dimethylamino)-2-(trifluoromethyl)allylidene)-N-methylmethanaminium chloride salt [ No CAS ]
[ 52222-73-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	With hydrazine; In water; acetonitrile; at 20 - 70℃; for 1h;	b) 4-Trifluoromethylpyrazole; The salt was dissolved in 120 ml of acetonitrile and hydrazine hydrate (11.7 g) was added dropwise at 20 C. The mixture was then heated to 70 C. for 1 h. The product was isolated by diluting the mixture with water and extracting with ethyl acetate. Yield: 5 g (86%) with a purity of 95%. For a further purification, the product can be distilled under reduced pressure. 4-Trifluoromethlypyrazole 1H NMR 7.9 s, ppm 19F NMR -57.2 (CF3) ppm

Reference： [1]Patent: US2007/149780,2007,A1 .Location in patent: Page/Page column 3

6
2-Fluoro-6-(1'-methyl-3'-trifluoromethylpyrazol-5'-yloxy)pyridine [ No CAS ]
[ 52222-73-8 ]
2-(1-methyl-3-trifluoromethyl-pyrazol-5-yloxy)-6-(4-trifluoromethylpyrazol-1-yl)pyridine [ No CAS ]

Reference： [1]Patent: WO2004/13129,2004,A1 .Location in patent: Page/Page column 21; 43

7
[ 202738-23-6 ]
[ 52222-73-8 ]
4-methoxy-2-(1-methyl-3-trifluoromethyl-pyrazol-5-yloxy)-6-(4-trifluoromethylpyrazol-1-yl)pyridine [ No CAS ]

Reference： [1]Patent: WO2004/13129,2004,A1 .Location in patent: Page/Page column 22; 48

8
[ 653593-16-9 ]
[ 52222-73-8 ]
2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-6-(4'-trifluoromethylpyrazol-1'-yl)-4-methylpyridine [ No CAS ]

Reference： [1]Patent: WO2004/13129,2004,A1 .Location in patent: Page/Page column 21-22; 45

9
[ 653601-80-0 ]
[ 52222-73-8 ]
2-(4-trifluoromethylpyrazol-1-yl)-6-(2-trifluoromethyl-4-thienyloxy)pyridine [ No CAS ]

Reference： [1]Patent: WO2004/13131,2004,A2 .Location in patent: Page/Page column 22; 23

10
[ 1207471-74-6 ]
[ 52222-73-8 ]
[ 1207470-04-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 70℃; for 1h;	Step 4. Synthesis of N-(2-ethyl-4- {1,1,1 ,3,3,3-hexafluoro-2-[4-(trifluoromethyl)- 1 H-pyrazol- 1 -yl]propan-2-yl} -6-methy lphenyl)-3-nitrobenzamide; 2-(3-ethyl-5-methyl-4-[(3-nitrophenyl)carbonyl]amino}phenyl)-l,l,l,3,3,3-hexafluoropropan-2-yl methanesulfonate (0.40 g) was dissolved in acetonitrile. To this solution, 4-(trifluoromethyl)-lH-pyrazole (0.11 g) and potassium carbonate (0.13 g) were added, and then stirred under heating at 700C for 1 hour. After cooling the reaction solution to room temperature, a saturated aqueous solution of ammonium chloride was added and the resulting solution was extracted twice with ethyl acetate. The organic layers were combined, washed with water, and dried over magnesium sulfate. After separating the drying agent by filtration, the solvent was evaporated off under reduced pressure to obtain a crude product. Thus obtained crude product was purified with silica gel chromatography to obtainN-(2-ethyl-4- {1,1,1 ,3,3,3-hexafluoro-2-[4-(trifluoromethyl)-lH-pyrazol-l -yl]prorhoan-2-yl} -6-methy lphenyl)-3-nitrobenzamide (0.35 g).1H-NMR (CDCl3) delta : 1.19 (3H, t), 2.34 (3H, s), 2.68 (2H, q), 7.16 (2H, s), 7.50 (IH, s), 7.77 (IH, dd), 7.87 (IH, s), 7.95 (IH, s), 8.30 (IH, d), 8.48 (IH, d), 8.75 (IH, s).

Reference： [1]Patent: WO2010/15355,2010,A2 .Location in patent: Page/Page column 71-72

11
[ 1192019-12-7 ]
[ 52222-73-8 ]
[ 1192019-50-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1.5h;	Production Example 63 A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of <strong>[52222-73-8]4-(trifluoromethyl)pyrazole</strong>, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50C for 1.5 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.36 g of 2-{3-[<strong>[52222-73-8]4-(trifluoromethyl)pyrazole</strong>-1-yl]pyridin-4-yl}-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as "active compound 62"). [Show Image] 1H-NMR (CDCl3) delta: 8.96 (d, J=5.1 Hz, 1H), 8.93 (d, J=0.5 Hz, 1H), 8.21 (dd, J=5.1, 0.5 Hz, 1H), 8.13-8.11 (m, 1H), 8.05-8.04 (m, 1H), 7.95 (s, 1H), 7.71-7.68 (m, 1H), 7.56 (d, J=8.8Hz, 1H)
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1.5h;	Production Example 63A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of <strong>[52222-73-8]4-(trifluoromethyl)pyrazole</strong>, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50 C. for 1.5 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.36 g of 2-{3-[<strong>[52222-73-8]4-(trifluoromethyl)pyrazole</strong>-1-yl]pyridin-4-yl}-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as ?active compound 62?).Active Compound 621H-NMR (CDCl3) delta: 8.96 (d, J=5.1 Hz, 1H), 8.93 (d, J=0.5 Hz, 1H), 8.21 (dd, J=5.1, 0.5 Hz, 1H), 8.13-8.11 (m, 1H), 8.05-8.04 (m, 1H), 7.95 (s, 1H), 7.71-7.68 (m, 1H), 7.56 (d, J=8.8 Hz, 1H)
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1.5h;	Production Example 63A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of <strong>[52222-73-8]4-(trifluoromethyl)pyrazole</strong>, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50C for 1.5 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.36 g of 2- { 3 - [<strong>[52222-73-8]4-(trifluoromethyl)pyrazole</strong>- 1 -yl]pyridin-4-yl } -5-(trifluoromethyl)benzoxazole (hereinafter, referred to as "active compound 62").Active compound 621 H-NMR (CDC13) delta: 8.96 (d, J=5.1 Hz, IH), 8.93 (d, J=0.5 Hz, IH), 8.21 (dd, J=5.1, 0.5 Hz, IH), 8.13-8.11 (m, IH), 8.05-8.04 (m, IH), 7.95 (s, IH), 7.71-7.68 (m, IH), 7.56 (d, J=8.8 Hz, IH)

	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1.5h;	A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of <strong>[52222-73-8]4-(trifluoromethyl)pyrazole</strong>, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50C for 1.5 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.36 g of 2- { 3 - [<strong>[52222-73-8]4-(trifluoromethyl)pyrazole</strong>- 1 -yl]pyridin-4-yl } -5 -(trifluoromethyl)benzoxazole (hereinafter, referred to as "active compound 62").Active compound 621 H-NMR (CDC13) delta: 8.96 (d, J=5.1 Hz, IH), 8.93 (d, J=0.5 Hz, IH), 8.21 (dd, J=5.1, 0.5 Hz, IH), 8.13-8.11 (m, IH), 8.05-8.04 (m, IH), 7.95 (s, IH), 7.71-7.68 (m, IH), 7.56 (d, J=8.8 Hz, IH)
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1.5h;	A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of <strong>[52222-73-8]4-(trifluoromethyl)pyrazole</strong>, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50C for 1.5 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.36 g of 2- { 3 - [<strong>[52222-73-8]4-(trifluoromethyl)pyrazole</strong>- 1 -yl]pyridin-4-yl } -5-(trifluoromethyl)benzoxazole (hereinafter, referred to as "active compound 62").Active compound 621 H-NMR (CDC13) delta: 8.96 (d, J=5.1 Hz, IH), 8.93 (d, J=0.5 Hz, IH), 8.21 (dd, J=5.1, 0.5 Hz, IH), 8.13-8.11 (m, IH), 8.05-8.04 (m, IH), 7.95 (s, IH), 7.71-7.68 (m, IH), 7.56 (d, J=8.8 Hz, IH)
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1.5h;	Production Example 63A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of <strong>[52222-73-8]4-(trifluoromethyl)pyrazole</strong>, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50C for 1.5 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.36 g of 2- { 3 - [<strong>[52222-73-8]4-(trifluoromethyl)pyrazole</strong>- 1 -yl]pyridin-4-yl } -5 -(trifluoromethyl)benzoxazole (hereinafter, referred to as "active compound 62").Active compound 621 H-NMR (CDC13) delta: 8.96 (d, J=5.1 Hz, IH), 8.93 (d, J=0.5 Hz, IH), 8.21 (dd, J=5.1, 0.5 Hz, IH), 8.13-8.11 (m, IH), 8.05-8.04 (m, IH), 7.95 (s, IH), 7.71-7.68 (m, IH), 7.56 (d, J=8.8 Hz, IH)
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1.5h;	Production Example 63A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of <strong>[52222-73-8]4-(trifluoromethyl)pyrazole</strong>, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50C for 1.5 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.36 g of 2-{3-[<strong>[52222-73-8]4-(trifluoromethyl)pyrazole</strong>-l-yl]pyridin-4-yl}-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as "active compound 62").Active compound 621 H-NMR (CDCI3) delta: 8.96 (d, J=5.1 Hz, IH), 8.93 (d, J=0.5 Hz, IH), 8.21 (dd, J=5.1, 0.5 Hz, IH), 8.13-8.11 (m, IH), 8.05-8.04 (m, IH), 7.95 (s, IH), 7.71-7.68 (m, IH), 7.56 (d, J=8.8 Hz, IH)

Reference： [1]Patent: EP2274983,2011,A1 .Location in patent: Page/Page column 84
[2]Patent: US2011/39843,2011,A1 .Location in patent: Page/Page column 53
[3]Patent: WO2011/40629,2011,A1 .Location in patent: Page/Page column 144
[4]Patent: WO2011/49220,2011,A1 .Location in patent: Page/Page column 143-144
[5]Patent: WO2011/49221,2011,A1 .Location in patent: Page/Page column 145
[6]Patent: WO2011/49223,2011,A1 .Location in patent: Page/Page column 143-144
[7]Patent: WO2011/49222,2011,A1 .Location in patent: Page/Page column 148

13
[ 105-36-2 ]
[ 52222-73-8 ]
ethyl 2-[4-(trifluoromethyl)pyrazol-1-yl]acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		[00564] Intermediate 57a: ethyl 2-[4-(trifluoromethyl)pyrazol-1 -yI]acetate [00565] 4-(Trifluoromethyl)-1 H-pyrazole (100mg, 0.73mmol) and potassium carbonate (305mg, 2.2Ommol) were left to stir in MeCN (2mL) for 30 minutes at room temperature before the addition of ethyl bromoacetate (0.l2mL, 1.lOmmol). The reaction mixture was then heated to 60C and left to stir at this temperature for 2 hours. The reaction was allowed to cool to room temperature andquenched by the addition of water (2OmL) and this solution was extracted with EtOAc (3 x 2OmL).The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to giveethyl 2-[4-(trifluoromethyl)pyrazol-1-yl]acetate (1 60mg, 0.72mmol, 100% yield) as a yellow oil.1H NMR (CDCI3,400MHZ) O/ppm: 7.82 (1H, 5), 7.77 (1H, 5), 4.95 (2H, 5), 4.29 (2H, q, J= 7.1Hz),1.32 (3H, t, J= 7.1Hz).MS Method 2: RT: 1.54 mi mlz 222.9 [M+H]
96%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 12h;	Example 3 Preparation of 5-(l,2,2,6,6-pentamethylpiperidin-4-yloxy)-N-(4-(2-(4-(trifluoromethyl)-lH-pyrazol-l-yl)acetamido)phenyl)picolinamide[00287] Step 1 : To a stirred mixture of 2-(4-(trifluoromethyl)-lH-pyrazole(1.68 g, 12.4 mmol) and K2C03 (2.45 g, 17.7 mmol) in DMF (30 mL) at rt was added ethyl 2-bromoacetate (2.69 g, 16.1 mmol). The resulting mixture was heated at 60 C for 12 h. The reaction mixture was cooled to rt, quenched with water, and extracted with DCM twice. The combined organic layers were dried over MgS04, and concentrated under reduced pressure. The residue was purified on a silica gel column, eluting with a mixture of EtOAc-hexanes, to afford ethyl 2-(4-(trifluoromethyl)-lH- pyrazol-l-yl)acetate (2.64 g, 96%) as an oil. LC-MS (ESI) m/z 223 (M+H)+; 1H NMR (300 MHz, CDC13) delta 7.80 (s, 1H), 7.05 (s, 1H), 4.93 (s, 2H), 4.25 (q, 2H), 1.30 (t, 3H).

Reference： [1]Patent: WO2016/51193,2016,A1 .Location in patent: Paragraph 00563; 00564; 00565
[2]Patent: WO2011/150201,2011,A2 .Location in patent: Page/Page column 109

14
[ 1194-02-1 ]
[ 52222-73-8 ]
[ 1393125-34-2 ]

Yield	Reaction Conditions	Operation in experiment
72%		Intermediate (13): 4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile To a 0 C. solution of <strong>[52222-73-8]4-(trifluoromethyl)-1H-pyrazole</strong> (1 g, 7 mmol) in N,N-dimethylformamide (10 mL) was added 60 wt % sodium hydride (132 mg, 3.31 mmol). The mixture was stirred at 0 C. for 30 minutes. 4-fluorobenzonitrile (979 mg, 8.08 mmol) was added and the reaction was heated to 80 C. overnight. Saturated ammonium chloride was added and the mixture extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (1.2 g, 72%). 1H NMR (400 MHz, CD3OD, delta): 8.84 (s, 1H), 7.96 (s, 1H), 7.95 (d, 2H), 7.78 (d, 2H).

Reference： [1]Patent: US2012/202834,2012,A1 .Location in patent: Page/Page column 19

15
[ 29241-60-9 ]
[ 52222-73-8 ]
[ 1393126-10-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 85 - 130℃; for 36h;	Step (A): 5-bromo-3-methyl-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine A flask was charged with 5-bromo-2-chloro-3-methylpyridine (250 mg, 1.21 mmol), <strong>[52222-73-8]4-(trifluoromethyl)-1H-pyrazole</strong> (165 mg, 1.21 mmol), potassium carbonate (512 mg, 3.63 mmol), and anhydrous dimethylformamide (1.21 mL). The reaction was heated at 85 to 130 C. for 36 h. The reaction was concentrated to give 690 mg of crude material. Purification by silica gel flash chromatography (0-5% ethyl acetate in heptane) afforded 5-bromo-3-methyl-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine (containing approximately 30% starting material) was carried forth to the next reaction. MS (M+1) 308.1.

Reference： [1]Patent: US2012/202834,2012,A1 .Location in patent: Page/Page column 41-42

16
[ 52222-73-8 ]
[ 147754-12-9 ]
[ 1393125-79-5 ]

Yield	Reaction Conditions	Operation in experiment
40%	With potassium carbonate; In acetonitrile; at 20 - 80℃;	Intermediate (67): 2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrileTo a solution of <strong>[52222-73-8]4-(trifluoromethyl)-1H-pyrazole</strong> (1.0 g, 7.0 mmol) and 4-fluoro-2-methylbenzonitrile (1.16 g, 8.50 mmol) in acetonitrile (8 mL) was slowly added potassium carbonate (1.96 g, 14.2 mmol) at room temperature.The reaction was heated to 80° C. and stirred overnight.The reaction was cooled to room temperature and poured into water.The layers were separated and the aqueous was extracted with ethyl acetate (3*15 mL).The combined organics were washed with water, dried over sodium sulfate, filtered, and concentrated.Purification by flash column chromatography gave 2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (710 mg, 40percent) as a yellow solid. 1H NMR (400 MHz, CDCl3, delta): 8.26 (s, 1H), 7.94 (s, 1H), 7.72-7.74 (m, 2H), 7.61-7.64 (m, 1H), 2.64 (s, 3H).

Reference： [1]Patent: US2012/202834,2012,A1 .Location in patent: Page/Page column 33-34

17
[ 10320-42-0 ]
[ 52222-73-8 ]
[ 1393125-74-0 ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium carbonate; In acetonitrile; at 80℃;Product distribution / selectivity;	Step A:5-nitro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidineTo a solution of 2-chloro-5-nitropyrimidine (1.5 g, 9.4 mmol) and <strong>[52222-73-8]4-(trifluoromethyl)-1H-pyrazole</strong> (1.41 g, 10.3 mmol) in acetonitrile (40 mL) was added potassium carbonate (2.60 g, 18.8 mmol).The reaction was heated to 80° C. and stirred overnight.The reaction was concentrated and the residue was diluted with water and extracted with ethyl acetate (2*40 mL).The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated.Purification by flash column chromatography gave 5-nitro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine (1.5 g, 62percent) as a yellow solid. 1H NMR (400 MHz, CDCl3, delta): 9.48 (s, 2H), 8.92 (s, 1H), 8.05 (s, 1H).

Reference： [1]Patent: US2012/202834,2012,A1 .Location in patent: Page/Page column 32

18
[ 52222-73-8 ]
[ 1026305-11-2 ]
[ 1393126-00-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 6h;	Step C: 3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butan-1-one To a solution of 1-(6-chloropyridin-3-yl)-3-methylbutan-1-one (1.0 g, 5.1 mmol) and <strong>[52222-73-8]4-(trifluoromethyl)-1H-pyrazole</strong> (766 mg, 5.62 mmol) in anhydrous DMF (20 mL) was added potassium carbonate (2.12 g, 15.3 mmol). The mixture was stirred at 50 C. for 6 h. The reaction mixture was poured into brine (30 mL) and extracted with ethyl acetate (30 mL*2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give 3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butan-1-one (1.4 g) as a colorless solid. 1H NMR (400 MHz, CDCl3) delta 8.92 (d, J=2.0 Hz, 1H), 8.85 (s, 1H), 8.33 (dd, J=2.0, 8.4 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.88 (s, 1H), 2.79 (d, J=6.8 Hz, 2H), 2.31-2.21 (m, 1H), 0.96 (d, J=6.8 Hz, 6H).

Reference： [1]Patent: US2012/202834,2012,A1 .Location in patent: Page/Page column 39-40

19
[ 918503-72-7 ]
[ 52222-73-8 ]
[ 1393126-52-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; at 20 - 50℃;	Step C: 1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butan-1-one A mixture of <strong>[52222-73-8]4-(trifluoromethyl)pyrazole</strong> (116 mg, 0.85 mmol), 1-(6-chloropyridin-3-yl)butan-1-one (130 mg, 0.71 mmol), and potassium carbonate (294 mg, 2.12 mmol) was stirred 4 h at 50 C. The mixture was cooled to room temperature and stirred overnight. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butan-1-one (200 mg) as a colorless solid. 1H NMR (400 MHz, CDCl3) delta 8.97-8.99 (m. 1H), 8.90-8.91 (m, 1H), 8.39 (dd, J=8.5, 2.4 Hz, 1H), 8.08 (dd, J=8.58, 0.78 Hz, 1H), 7.93 (s, 1H), 2.94 (t, J=7.4 Hz, 2H), 1.74-1.85 (m, 2H), 1.02 (t, J=7.4 Hz, 3H).

Reference： [1]Patent: US2012/202834,2012,A1 .Location in patent: Page/Page column 52-53

20
[ 27060-75-9 ]
[ 52222-73-8 ]
[ 1393125-68-2 ]

Yield	Reaction Conditions	Operation in experiment
29%	With caesium carbonate;copper(II) oxide; In N,N-dimethyl-formamide; at 120℃; for 1h;Microwave irradiation;	Step A: 1-(4-methoxy-2-methylphenyl)-<strong>[52222-73-8]4-(trifluoromethyl)-1H-pyrazole</strong> To a mixture of 1-bromo-4-methoxy-2-methylbenzene (1.5 g, 7.5 mmol) in N,N-dimethylformamide (15 mL) was added <strong>[52222-73-8]4-(trifluoromethyl)-1H-pyrazole</strong> (1.12 g, 8.21 mmol), copper(II) oxide (107 mg, 0.746 mmol), and cesium carbonate (4.86 g, 14.9 mmol). The mixture was heated in a microwave to 120 C. for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3*30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave 1-(4-methoxy-2-methylphenyl)-<strong>[52222-73-8]4-(trifluoromethyl)-1H-pyrazole</strong> (550 mg, 29%) as a white solid. 1H NMR (400 MHz, CDCl3, delta): 7.81 (s, 1H), 7.74 (s, 1H), 7.16 (m, 1H), 6.74 (m, 2H), 3.77 (s, 3H), 2.10 (s, 3H).

Reference： [1]Patent: US2012/202834,2012,A1 .Location in patent: Page/Page column 31

21
[ 18282-51-4 ]
[ 52222-73-8 ]
[ 1393125-26-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;copper(l) iodide; 4R-4-hydroxyproline; In dimethyl sulfoxide; at 85℃; for 20h;	Intermediate (1): (4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol A mixture of (4-iodophenyl)methanol (1030 mg, 4.41 mmol), <strong>[52222-73-8]4-(trifluoromethyl)-1H-pyrazole</strong> (600 mg, 4.41 mmol), copper (I) iodide (168 mg, 0.882 mmol), trans-4-hydroxy-L-proline (231 mg, 1.76 mmol) and cesium carbonate (2900 mg, 8.82 mmol) in dimethylsulfoxide (7.5 mL) was heated to 85 C. for 20 hours. The mixture was diluted with water and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-45% ethyl acetate in heptane), gave (4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol. 1H NMR (400 MHz, CDCl3, delta): 8.16 (s, 1H), 7.89 (s, 1H), 7.65 (d, J=8.39 Hz, 2H), 7.47 (d, J=8.39 Hz, 2H), 4.74 (d, J=5.66 Hz, 2H), 1.85 (t, J=5.86 Hz, 1H).

Reference： [1]Patent: US2012/202834,2012,A1 .Location in patent: Page/Page column 15

22
[ 1393125-47-7 ]
[ 52222-73-8 ]
[ 1393126-58-3 ]

Yield	Reaction Conditions	Operation in experiment
37%	With caesium carbonate;copper(l) iodide; 4R-4-hydroxyproline; In dimethyl sulfoxide; at 85℃; for 18h;	Step A: (+/-)-5-bromo-2-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)pyridine Intermediate (36) (216 mg, 0.50 mmol), <strong>[52222-73-8]4-trifluoromethylpyrazole</strong> (68 mg, 0.50 mmol), copper (I) iodide (19 mg, 0.10 mmol), trans-4-hydroxy-L-proline (26.2 mg, 0.20 mmol) and cesium carbonate (329 mg, 1.00 mmol) were suspended in dimethylsulfoxide and heated to 85 C. with stirring for 18 hours. The reaction was diluted with ethyl acetate (25 mL) and washed with water (2*25 mL) and brine (20 mL). The organics were dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography (0-50% ethyl acetate in heptanes) gave 5-bromo-2-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)pyridine (81 mg, 37%) as a clear oil. 1H NMR (400 MHz, CDCl3, delta): 8.63 (d, J=2.3 Hz, 1H), 8.00 (br. s, 1H), 7.82 (br. s, 1H), 7.75 (dd, J=8.4, 2.3 Hz, 1H), 7.49-7.43 (m, 2H), 7.26 (d, overlaps with CHCl3, 1 H), 6.94-6.88 (m, 2H), 5.22 (dd, J=8.0, 4.9 Hz, 1H), 2.03-1.86 (m, 2H), 1.62-1.38 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).

Reference： [1]Patent: US2012/202834,2012,A1 .Location in patent: Page/Page column 56

23
[ 1393126-60-7 ]
[ 52222-73-8 ]
[ 1393126-61-8 ]

Yield	Reaction Conditions	Operation in experiment
9.5%	With potassium carbonate;copper(l) iodide; 8-quinolinol; In dimethyl sulfoxide; at 90℃; for 18h;Inert atmosphere;	Step B: methyl 4-(4-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pent-1-en-2-yl)benzoate An oven-dried and nitrogen-cooled vial was charged with 4-trifluoromethyl pyrazole (77.0 mg, 0.56 mmol), quinolin-8-ol (10 mg, 0.07 mmol), copper (I) iodide (14 mg, 0.073 mmol), and potassium carbonate (140 mg, 1.0 mmol). A solution of methyl 4-(1-(4-bromophenyl)-4-methylpent-1-en-2-yl)benzoate (182.7 mg, 0.489 mmol) in dimethylsulfoxide (2.5 mL) was then added. The vial was capped and evacuated and back-filled with nitrogen four times. The reaction was then heated to 90 C. for 18 hours. The reaction was cooled to room temperature and partitioned between saturated ammonium chloride and ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the combined organics were dried over magnesium sulfate, filtered, and concentrated. Column chromatography (0-10% ethyl acetate in heptane) provided methyl 4-(4-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pent-1-en-2-yl)benzoate (19.8 mg, 9.5%) as an approximate 1:1 mixture of E/Z isomers. 1H NMR (400 MHz, CDCl3, delta): 8.20 (s, 1H), 8.06 (s, 1H), 8.05-8.01 (m, 2H), 7.98-7.93 (m, 2H), 7.91 (s, 1H), 7.83 (s, 1H), 7.71-7.66 (m, 2H), 7.53-7.49 (m, 2H), 7.46-7.42 (m, 2H), 7.41-7.36 (m, 2H), 7.24-7.20 (m, 2H), 7.01-6.96 (m, 2H), 6.78 (s, 1H), 6.49 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 2.62 (d, J=7.2 Hz, 2H), 2.41 (dd, J=7.2, 1.0 Hz, 2H), 1.70-1.48 (m, 2H), 0.90 (d, J=6.6 Hz, 6H), 0.80 (d, J=6.6 Hz, 6H). MS (M+1): 429.3.

Reference： [1]Patent: US2012/202834,2012,A1 .Location in patent: Page/Page column 57

24
[ 456-24-6 ]
[ 52222-73-8 ]
5-nitro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine [ No CAS ]