[ CAS No. 54396-44-0 ] {[proInfo.proName]}

Name: 54396-44-0|2-Methyl-3-(trifluoromethyl)aniline|97%
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Quality Control of [ 54396-44-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 54396-44-0 ]

Product Details of [ 54396-44-0 ]

CAS No. :	54396-44-0	MDL No. :	MFCD00153216
Formula :	C₈H₈F₃N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	TWLDBACVSHADLI-UHFFFAOYSA-N
M.W :	175.15	Pubchem ID :	2735932
Synonyms :

Calculated chemistry of [ 54396-44-0 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	40.81
TPSA :	26.02 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.6 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.74
Log Po/w (XLOGP3) :	2.49
Log Po/w (WLOGP) :	3.76
Log Po/w (MLOGP) :	2.88
Log Po/w (SILICOS-IT) :	2.57
Consensus Log Po/w :	2.69

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.8
Solubility :	0.278 mg/ml ; 0.00159 mol/l
Class :	Soluble
Log S (Ali) :	-2.68
Solubility :	0.365 mg/ml ; 0.00208 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.31
Solubility :	0.0862 mg/ml ; 0.000492 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.13

Safety of [ 54396-44-0 ]

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

Application In Synthesis of [ 54396-44-0 ]

* 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 [ 54396-44-0 ]
Downstream synthetic route of [ 54396-44-0 ]

[ 54396-44-0 ] Synthesis Path-Upstream 1~8

1
[ 150783-50-9 ]
[ 54396-44-0 ]

Yield	Reaction Conditions	Operation in experiment
98.5%	With hydrogenchloride In ethanol	Preparation of 2-Methyl-3-Trifluoromethyl-Aniline A solution of 2,2,2'-trimethyl-3'-trifluoromethyl-propionanilide (10 g.) in 75 ml. ethanol and 75 ml. concentrated HCl was refluxed for 24 hours. The reaction mixture was then concentrated in vacuo and diluted with water. It was then basified with 10percent NaOH solution and extracted with ether. The ether extract was washed with water and brine and dried with MgSO₄. Removal of ether gave a pale brown liquid (6.65 g., 98.5percent) which was purified by distillation under reduced pressure (b.p. 108°-110° C., 30 mm.) to give 5.73 g. of 2-methyl-3-trifluoromethyl-aniline which solidified on standing. The physical and spectroscopic properties of the product were found to be identical to those of an authentic sample of 2-methyl-3-trifluoromethyl-aniline prepared by the known method below. STR2

Reference： [1] Patent: US5248781, 1993, A,
[2] Heterocycles, 1994, vol. 38, # 10, p. 2243 - 2246

2
[ 6656-49-1 ]
[ 54396-44-0 ]

Yield	Reaction Conditions	Operation in experiment
92%	With hydrogen In methanol	C. 3-Amino-2-Methylbenzotrifluoride A solution of 2-methyl-3-nitrobenzotrifluoride (41.0 g, 0.2 m) in methanol (100 ml) was stirred under an atmosphere of dry nitrogen at room temperature and palladium on charcoal catalyst (10percent w/w, 1.0 g) was added. The stirred mixture was warmed to 40°-45° and then hydrogen was passed into the solution at atmospheric pressure until the reduction, as observed by thin-layer chromatography, was complete (4-5 hours). The solution was cooled to room temperature and the catalyst removed by filtration. Distillation of the solvent at atmospheric pressure followed by steam distillation of the crude product gave 3-amino-2-methylbenzotrifluoride (32.2 g, 92percent yield), as a pale-brown oil which slowly crystallized.

Reference： [1] Patent: US4831193, 1989, A,
[2] Patent: US4132737, 1979, A,

3
[ 62639-16-1 ]
[ 54396-44-0 ]

Reference： [1] Patent: US4209464, 1980, A,
[2] Patent: US4172095, 1979, A,

4
[ 72763-19-0 ]
[ 54396-44-0 ]

Reference： [1] Patent: US4209464, 1980, A,

5
[ 62639-16-1 ]
[ 7440-66-6 ]
[ 54396-44-0 ]

Reference： [1] Patent: US4209464, 1980, A,

6
[ 1939-19-1 ]
[ 54396-44-0 ]

Reference： [1] Heterocycles, 1994, vol. 38, # 10, p. 2243 - 2246

7
[ 98-16-8 ]
[ 54396-44-0 ]

Reference： [1] Heterocycles, 1994, vol. 38, # 10, p. 2243 - 2246

8
[ 56-23-5 ]
[ 95-53-4 ]
[ 25449-96-1 ]
[ 54396-44-0 ]

Reference： [1] Tetrahedron Letters, 2003, vol. 44, # 9, p. 1747 - 1750

[ 54396-44-0 ] Synthesis Path-Downstream 1~88

1
[ 54396-44-0 ]
[ 16497-87-3 ]
N-3-(trifluoromethyl)phenylanthranilic acid [ No CAS ]

Reference： [1]Arzneimittel-Forschung/Drug Research,1983,vol. 33,p. 621 - 627

2
[ 54396-44-0 ]
[ 1452-94-4 ]
[ 54396-42-8 ]

Reference： [1]Heterocycles,1994,vol. 38,p. 2243 - 2246

3
[ 150783-50-9 ]
[ 54396-44-0 ]

Yield	Reaction Conditions	Operation in experiment
98.5%	With hydrogenchloride; In ethanol;	Preparation of 2-Methyl-3-Trifluoromethyl-Aniline A solution of 2,2,2'-trimethyl-3'-trifluoromethyl-propionanilide (10 g.) in 75 ml. ethanol and 75 ml. concentrated HCl was refluxed for 24 hours. The reaction mixture was then concentrated in vacuo and diluted with water. It was then basified with 10percent NaOH solution and extracted with ether. The ether extract was washed with water and brine and dried with MgSO4. Removal of ether gave a pale brown liquid (6.65 g., 98.5percent) which was purified by distillation under reduced pressure (b.p. 108°-110° C., 30 mm.) to give 5.73 g. of 2-methyl-3-trifluoromethyl-aniline which solidified on standing. The physical and spectroscopic properties of the product were found to be identical to those of an authentic sample of 2-methyl-3-trifluoromethyl-aniline prepared by the known method below. STR2

Reference： [1]Patent: US5248781,1993,A
[2]Heterocycles,1994,vol. 38,p. 2243 - 2246

4
[ 1019327-29-7 ]
[ 54396-44-0 ]
[ 913067-77-3 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 5671 - 5686

5
3-(2-amino-quinazolin-6-yl)-4-methyl-benzoyl chloride [ No CAS ]
[ 54396-44-0 ]
3-(2-amino-6-quinazolinyl)-4-methyl-N-(2-methyl-3-(trifluoromethyl)phenyl)benzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 5671 - 5686

6
[ 54396-44-0 ]
[ 108-24-7 ]
[ 546434-38-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1860 - 1864

7
[ 54396-44-0 ]
[ 98-59-9 ]
[ 947407-68-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 4450 - 4455

8
[ 54396-44-0 ]
C₂₆H₂₄N₃SO₄F₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 4450 - 4455

9
[ 54396-44-0 ]
[ 947407-70-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 4450 - 4455

10
[ 54396-44-0 ]
[ 947407-75-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 4450 - 4455

11
[ 54396-44-0 ]
[ 573764-86-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1860 - 1864

12
[ 54396-44-0 ]
[ 627531-79-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1860 - 1864

13
[ 54396-44-0 ]
C₁₆H₁₆F₃N₃O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1860 - 1864

14
[ 54396-44-0 ]
C₁₅H₁₂F₃N₃O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1860 - 1864

15
[ 54396-44-0 ]
N-[4-bromo-2-methyl-3-(trifluoromethyl)phenyl]acetamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1860 - 1864

16
[ 54396-44-0 ]
C₁₁H₉F₃N₂O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1860 - 1864

17
[ 1939-19-1 ]
[ 54396-44-0 ]

Reference： [1]Heterocycles,1994,vol. 38,p. 2243 - 2246

18
[ 54396-44-0 ]
[ 38677-85-9 ]

Reference： [1]Heterocycles,1994,vol. 38,p. 2243 - 2246

19
[ 98-16-8 ]
[ 54396-44-0 ]

Reference： [1]Heterocycles,1994,vol. 38,p. 2243 - 2246

20
hydroxyammonium sulfate [ No CAS ]
[ 302-17-0 ]
[ 54396-44-0 ]
[ 851045-50-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium sulfate; In water; at 35 - 75℃; for 3.5h;	Example 135 Synthesis of (+/-)-Isopropyl 5- [acetyl- (3, 5-bistrifluoromethylbenzyl) amino]-9-methyl-8- trifluoromethyl-tetrahydrobenzo [b] azepine-1-carboxylate Step 1. Preparation of 7-methyl-6-trifluoromethyl-lH-indole, 2,3-dione To a solution of chloral hydrate (6.08 g, 36.74 mmol) and anhydrous sodium sulfate (28.5 g, 200.4 mmol) in water (102 mL) add a mixture of hydroxylamine sulfate (28.5 g, 173.68 mmol), 2-methyl-3-trifluoromethyl-phenylamine (5.85 g, 33.4 mmol), concentrated hydrochloric acid (3.5 mL) in water (34 mL). Heat the mixture at 35 °C for 1 h, then heat up to 52 °C for 90 min and at 75°C for 1 hr. Cool the mixture to room temperature and filter the solid. Wash the solid with water and hexane. Dry the solid under vacuum to afford 2-hydroxyimino-N- (2-methyl-3-trifluoromethyl-phenyl)- acetamide. MS (ES+): 245 (M-H). Add the former crude in small portions at 60°C to concentrated sulfuric acid (44 mL) and heat the mixture at 80°C for 1 h. Cool to room temperature, pour into ice water (100 mL) and filter the precipitate. Wash the solid with cool water twice. Dry the solid to afford the title compound (3.54 g, 46percent two steps). MS (ES-): 228 (M-H).

Reference： [1]Patent: WO2005/37796,2005,A1 .Location in patent: Page/Page column 133-134

21
[ 54396-44-0 ]
[ 75-87-6 ]
[ 851045-50-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; hydroxylamine sulfate; sodium sulfate; In water; at 35 - 75℃; for 3.5h;	Example 53; Synthesis of (+/-)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2fl-tetrazol-5-yl)-amino]-9-methyl-8-trifluormethyl-2,3,4,5-tetrahydrobenzo[]azepine-l-carboxylate; Step 1; Preparation of 7-methyl-6-trifluoromethyl-lH-indole,2,3-dione; To a solution of chloral hydrate (6.08 g, 36.74 mmol) and anhydrous sodium sulfate (28.5g, 200.4 mmol) in water (102 mL) add a mixture of hydroxylamine sulfate (28.5 g,173.68 mmol), 2-methyl-3-trifluoromethyl-phenylamine (5.85 g, 33.4 mmol),concentrated hydrochloric acid ( 3.5 mL) in water (34 mL). Heat the mixture at 35 °C for1 h, then heat up to 52 °C for 90 min and at 75 °C for 1 h. Cool the mixture to roomtemperature and filter the solid. Wash the solid with water and hexane. Dry the solidunder vacuum to afford 2-hydroxyimino-N-(2-methyl-3-trifluoromethyl-phenyl)-acetamide: MS (ES+): 245 (M-H). Add the former crude in small portions at 60 °C toconcentrated sulfuric acid (44 mL) and heat the mixture at 80 °C for 1 h. Cool to roomtemperature, pour into ice water (100 mL) and filter the precipitate. Wash the solid withcool water twice. Dry the solid to afford the title compound (3.54 g, 46percent two steps).

Reference： [1]Patent: WO2006/2342,2006,A1 .Location in patent: Page/Page column 115-116

22
[ 2942-59-8 ]
[ 54396-44-0 ]
[ 38677-85-9 ]

Yield	Reaction Conditions	Operation in experiment
97.1%	With perfluorosulfonic acid resin; In water; at 65 - 70℃; for 2.5h;Industrial scale;	300 L of water was added to a 1000 L reactor, 131.9 kg (837.5 mol) of 2-chloronicotinic acid and 140 kg of <strong>[54396-44-0]2-methyl-3-trifluoromethylaniline</strong> (800 mol) were added separately, stirred, 1.4kg perfluorosulfonated resin was added, the temperature was raised to 65 °C -70 °C, and reacted for 2.5h.Filtered, the filtrate was adjusted to pH 4.5 with a 60percent sulfuric acid solution, stirred for 15-20min, filtered , filter cake was washed with 30kg of water, filter cake was dried to obtain 230.1 kg of flunixin, the yield was 97.1percent, and the purity was 99.9percent, purity was tested according to the method of USP38, the same below.
83%	With potassium hydroxide; toluene-4-sulfonic acid; In water;	iv.) A mixture of <strong>[54396-44-0]2-methyl-3-trifluoromethylaniline</strong> (368 g, 2.1 moles) and 2-chloronicotinic acid (158.0 g, 1.0 mole) in 400 ml of water is heated at 100° C. for 24 hours together with p-toluenesulfonic acid (15.0 g) monohydrate as the acid catalyst. Potassium hydroxide (ca. 145 g) in water (255 ml) is added and the pH is maintained above 11. After diluting the reaction mixture to 1.2 liters with water, the mixture is cooled to 50° C., adjusted to pH 11, treated with 7 g of a decolorizing charcoal and 15 g of a filter aid, and clarified by filtration. The flitrate is diluted with 750 ml of water and the pH is adjusted to 5.0 with concentrated sulfuric acid. Agitation of the suspension for 10 minutes and filtration gives crude, precipitated 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid (flunixin) (83percent yield). The compound can be further purified by crystallization in methanol and washing with water.
	With toluene-4-sulfonic acid; copper(II) oxide; sodium hydroxide; In 1,2-dimethoxyethane; water; at 45℃; for 0.6h;	(1) 2-chloronicotinic acid and <strong>[54396-44-0]2-methyl-3-trifluoromethylaniline</strong> are stirred and added to an aqueous sodium hydroxide solution, 2-chloronicotinic acid and 2-methyl-3-trifluoromethyl The molar ratio of aniline is 3:1; the molar ratio of 2-chloronicotinic acid to sodium hydroxide used to prepare aqueous sodium hydroxide solution is 1:2; ethylene glycol and chain polyethylene glycol dialkyl are added. The ether and the catalyst A, the chain polyethylene glycol dialkyl ether is used in an amount of 3percent of the mass of 2-chloronicotinic acid; the catalyst A is p-toluenesulfonic acid and copper oxide, the pair The molar ratio of toluenesulfonic acid to copper oxide is 3:1; the temperature is controlled at 45 ° C, after 0.6 hours of reaction, the pH of the solution is adjusted, stirred and allowed to stand for stratification, stirred, filtered, and the filter cake is washed and dried to obtain flunixin.;

Reference： [1]Patent: CN108586327,2018,A .Location in patent: Paragraph 0025; 0026; 0027; 0028
[2]Patent: US5484931,1996,A
[3]Patent: CN109206365,2019,A .Location in patent: Paragraph 0022-0024; 0026-0037; 0042-0045; 0054-0057

23
[ 54396-44-0 ]
[ 863111-55-1 ]

Yield	Reaction Conditions	Operation in experiment
73%		3-Amino-2-methylbenzotrifluoride (Aldrich Co., 5.25 g) was added to a mixture of concentrated hydrochloric acid (20 ml) and water (20 ml) and, under ice-cooling, sodium nitrite (3.31 g) dissolved in water (10 ml) was added dropwise thereto. The mixture was stirred at 0°C for 1 hr. Potassium iodide (9.95 g) dissolved in water (20 ml) was added to the reaction mixture. The mixture was stirred at -4°C for 2 hr. The mixture was adjusted to pH 11 or above with a 6N aqueous sodium hydroxide solution, and an aqueous thiosodium sulfate solution was added thereto. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure to give a brown oil. The oil was purified by silica gel column chromatography (elution solvent: hexane) to give 3-iodo-2-methylbenzotrifluoride (6.28 g, yield 73percent). 1H-NMR(400MHz,DMSO-d6)delta(ppm): 2.52 (3H,s), 7.16(1H,t,J=7.8Hz), 7.73(1H,d,J=7.8Hz), 8.18(1H,d,J=7.8Hz). By a similar operation as in Starting Material Synthetic Example 59, 4-[2-methyl-3-(trifluoromethyl)phenyl]piperidin-4-ol (2.18 g, yield 32percent) was obtained from 3-iodo-2-methylbenzotrifluoride (6.28 g). 1H-NMR(400MHz,DMSO-d6)delta(ppm) : 1.76-1.91(4H,m), 2.69-2.78(2H,m), 2.71(3H,s), 2.94-3.04(2H,m), 4.91(1H,s), 7.34(1H,t,J=7.8Hz), 7.57(1H,d,J=7.8Hz), 7.70(1H,d,J=7.8Hz).

Reference： [1]Organic Letters,2008,vol. 10,p. 5095 - 5097
[2]Patent: EP1714961,2006,A1 .Location in patent: Page/Page column 31

24
copper(II) oxide powder [ No CAS ]
[ 54396-44-0 ]
[ 107-13-1 ]
2-chloro-3-(2-methyl-3-trifluoromethyl-phenyl)-propionitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium nitrite; In dichloromethane; water;	STR12 20 mol of concentrated hydrochloric acid is added at 0°-5° C. to a suspension of 16.7 g of <strong>[54396-44-0]2-methyl-3-trifluoromethylaniline</strong> (0.095 mol) in 50 ml of water and the mixture is then briefly warmed to 60°-80° C. until a clear solution has formed. The solution is cooled very rapidly to 0°-5° C. with vigorous stirring, 22.4 ml (0.286 mol) of acrylonitrile are added dropwise to the fine suspension at 0°-5° C. and a solution of 6.75 g of sodium nitrite in 10 ml of water is then rapidly added, and the mixture is kept at 5° C. for a further 5 minutes and stirred at 20° C. for 1 hour. After cooling, 0.8 g of copper(II) oxide powder is added to the reaction mixture at 0°-10° C. in portions, a vigorous evolution of nitrogen gas occurring. After completion of the evolution of gas, the mixture is stirred for a further 2 hours at 0°-10° C., then for 15 hours at room temperature, dichloromethane is added, and the mixture is washed with water, dried over sodium sulphate and concentrated in vacuo. 21.2 g (90percent of theory) of 2-chloro-3-(2-methyl-3-trifluoromethylphenyl)-propionitrile are obtained as a brown oil. M/e 247 (+), 228, 212, 173 (100percent)

Reference： [1]Patent: US5091408,1992,A

25
[ 2516-96-3 ]
[ 54396-44-0 ]
[ 12775-96-1 ]
[ 61708-31-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In pentan-1-ol;	EXAMPLE 5 5-Nitro-N-(2-methyl-3-trifluoromethylphenyl) anthranilic acid To a solution of 25 g. of 2-chloro-5-nitro-benzoic acid in 125 ml. of n-pentyl alcohol add 4.8 g. of sodium hydroxide pellets, 25 g. of <strong>[54396-44-0]2-methyl-3-trifluoromethylaniline</strong> and 2 g. of copper powder. With constant stirring, reflux the reaction mixture for 18 hours. Concentrate the mixture to one half volume and dilute with water and ether. Acidify the aqueous layer to obtain a crude product which is recrystallized to yield 5-nitro-N-(2-methyl-3-trifluoromethylphenyl) anthranilic acid, m.p. 244°-245° C.

Reference： [1]Patent: US4029815,1977,A

26
[ 54396-44-0 ]
[ 12775-96-1 ]
[ 50-79-3 ]
[ 61708-30-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In pentan-1-ol;	EXAMPLE 4 5-Chloro-N-(2-methyl-3-trifluoromethylphenyl) anthranilic acid To a solution of 25 g. of 2,5-dichlorobenzoic acid in 125 ml. of n-pentyl alcohol add 4.8 g. of sodium hydroxide pellets, 25 g. of <strong>[54396-44-0]2-methyl-3-trifluoromethylaniline</strong> and 2 g. of copper powder. With constant stirring, reflux the reaction mixture for 18 hours. Concentrate the mixture to one half volume and dilute with water and ether. Acidify the aqueous layer to yield the product which is recrystallized from methanol, m.p. 220°-222° C.

Reference： [1]Patent: US4029815,1977,A

27
[ 62639-16-1 ]
[ 54396-44-0 ]

Yield	Reaction Conditions	Operation in experiment
	aluminum nickel; In methanol;	C. 3-amino-2-methylbenzotrifluoride Wash 5 to 10 teaspoonfuls of W-2 Raney nickel catalyst with distilled water to neutrality, then three times with absolute alcohol. Dissolve 10 g. of 3-amino-2-methylthiomethylbenzotrifluoride in 100 ml. of methanol and add 4 teaspoonfuls of the washed W-2 Raney nickel. Reflux for 4 hours, filter to remove the catalyst and evaporate the solvent in vacuo to yield the title compound. Alternatively, the 3-amino-2-methylthiomethylbenzotrifluoride may be chemically reduced by the following technique.
	aluminum nickel; In methanol;	B. 3-Amino-2-methylbenzotrifluoride Wash 5 to 10 teaspoonsful of W-2 Raney nickel catalyst with distilled water to neutrality, then three times with absolute alcohol. Dissolve 10 g. of 3-amino-2-methylthiomethylbenzotrifluoride in 100 ml. of methanol and add 4 teaspoonsful of the W-2 Raney nickel. Reflux for 4 hours, filter to remove catalyst and evaporate solvent in vacuo to yield the title compound.

Reference： [1]Patent: US4209464,1980,A
[2]Patent: US4172095,1979,A

28
[ 62639-16-1 ]
[ 7440-66-6 ]
[ 54396-44-0 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In water; isopropyl alcohol;	C'. 3-amino-2-methylbenzotrifluoride Stir a mixture of 5 g. of 3-amino-2-methylthiomethylbenzotrifluoride, 12.5 ml of isopropanol, 15 g. of zinc powder and 2.5 ml of water in a 500 ml, 3-necked round bottom flask fitted with mechanical stirrer, dropping funnel with a nitrogen inlet, and reflux condenser with Clorox trap, and bubble-counter. Immerse the flask in an oil bath at 80° C. Slowly add a solution of 30 ml of water and 15 ml of acetic acid to the well-stirred mixture via the dropping funnel (about 2.5 ml per portion and 20 minutes for each portion). Stir the reaction mixture at 80° C. and cool the reaction mixture. Add 50 ml of water and extract three times with hexane. Dry the combined organic extracts and evaporate to yield the title compound which may be steam distilled for further purification.

Reference： [1]Patent: US4209464,1980,A

29
[ 54396-44-0 ]
[ 54396-42-8 ]
[ 1452-94-4 ]
[ 38677-85-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In methanol; water;	EXAMPLE 4 2-(2'-Methyl-3'-trifluoromethylanilino) nicotinic acid To 20 g. of <strong>[54396-44-0]2-methyl-3-trifluoromethyl aniline</strong> heated at 200°, add, in a dropwise fashion, 11 g. of ethyl 2-chloro-nicotinate. Heat the reaction mixture at 200° for one-half hour, cool, pour the mixture onto ice and extract with ether. Concentrate the ether extracts, dry and fractionate the residue in vacuo; b.p. 143°-146°/0.15 mm; m.p. 44°-46°. To a solution of 12 g. of ethyl 2-(2'-methyl-3'-trifluoromethylanilino) nicotinate in 100 ml. of methanol and 4.6 g. of potassium hydroxide in 10 ml. of water. Reflux the solution for three hours, concentrate in vacuo and dissolve the residue in water. Acidify the aqueous solution to yield the desired 2-(2'-methyl-3'-trifluoromethylanilino) nicotinic acid, m.p. 226°-228° C. after recrystallization from acetone-hexane. By following the teachings of the foregoing examples as well as by the teachings of the above cited reference, there may also be produced the following nicotinic acids:

Reference： [1]Patent: US4205073,1980,A

30
[ 54396-44-0 ]
[ 29241-65-4 ]
[ 108-95-2 ]
5-bromo-2-(2-methyl-3-trifluoromethylanilino)-nicotinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In methanol; sodium hydroxide;	EXAMPLE 2 5-Bromo-2-(2-methyl-3-trifluoromethylanilino) nicotinic acid Heat in an oil bath at 170° C. a mixture of 15 g. of 5-bromo-2-chloro-nicotinic acid, 12.2 g. of <strong>[54396-44-0]2-methyl-3-trifluoromethyl aniline</strong> and 60 g. of phenol for three hours. Treat the resulting reaction mixture with ether and 5percent sodium bicarbonate solution, concentrate and steam distil to obtain an oily residue. Dissolve the oily residue in dilute sodium hydroxide solution, acidify with dilute hydrochloric acid and filter. Recrystallize the product from methanol to yield 5-bromo-2-(2-methyl-3-trifluoromethylanilino) nicotinic acid, m.p. 222°-224° C.

Reference： [1]Patent: US4205073,1980,A

31
[ 321-14-2 ]
[ 54396-44-0 ]
5-chloro-2-hydroxy-N-[2-methyl-3-(trifluoromethyl)phenyl]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14.5%		Example 118 5-Chloro-2-hydroxy-N-[2-methyl-3-(trifluoromethyl)phenyl]benzamide (Comopund No. 118). Using 5-chlorosalicylic acid and <strong>[54396-44-0]2-methyl-3-(trifluoromethyl)aniline</strong> as the raw materials, the same operation as the example 16 gave the title compound. Yield: 14.5percent. 1H-NMR(DMSO-d6): delta 2.36(3H, d, J=1.2Hz), 7.05(1H, d, J=8.7Hz), 7.46(1H, t, J=8.1Hz), 7.50(1H, dd, J=8.7, 2.7Hz), 7.60(1H, d, J=7.2Hz), 7.99(1H, d, J=7.2Hz), 8.00(1H, d, J=2.4Hz), 10.43(1H, s), 12.08(1H, s).
	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6?7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Patent: EP1352650,2003,A1
[2]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

32
[ 72763-19-0 ]
[ 54396-44-0 ]

Yield	Reaction Conditions	Operation in experiment
	nickel; In water; acetic acid;	C. 3-amino-2-methylbenzotrifluoride Add 70 ml of water, 150 ml of glacial acetic acid and 100 g. of 3-amino-4-chloro-2-methylthiomethylbenzotrifluoride to a three-necked round bottom flask fitted with mechanical stirrer and condenser. Then add 535 g. of washed and neutralized Raney active nickel catalyst (Grace no. 28 in water). Heat to reflux (98° C.-100° C.) for 20 hours. Steam distill to obtain the title compound.

Reference： [1]Patent: US4209464,1980,A

33
[ 945667-88-9 ]
[ 945667-92-5 ]
[ 54396-44-0 ]
6-methyl-1-[2-methyl-3-(trifluoromethyl)phenyl]amino}-N-(tetrahydro-2H-pyran-4-ylmethyl)pyrrolo[1,2-a]pyrazine-4-carboxamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 25: 6-Methyl-1 -[2-methyl-3-(trifluoromethyl)phenyl]amino}-lambda/-(tetrahydro- 2/-/-pyran-4-ylmethyl)pyrrolo[1 ,2-a]pyrazine-4-carboxamide hydrochloride; <n="57"/>To Intermediate 8(a) (60mg) in 1 ,4-dioxane (1 ml) was added 2-methyl-3- (trifluoromethyl)aniline (68mg) and methanesulfonic acid (25ul) and the reaction mixture heated under microwave conditions at 18O0C for fifteen minutes. The reaction mixture was dissolved in methanol, transferred to a round bottomed flask and evaporated. The residue was partitioned between ethyl acetate, water and saturated aqueous sodium hydrogen carbonate and washed. The organic layer was dried (MgSO4) and evaporated to a brown oil. The oil was purified by MDAP and the white solid obtained was dissolved in methanol and treated with 1 M hydrochloric acid in diethyl ether. The solution was evaporated and co-evaporated from diethyl ether to give a white solid. The solid was transferred to a vial and dried to afford the title compound (42mg). LC/MS [MH+] 447 consistent with molecular formula C23H25F3N4O2

Reference： [1]Patent: WO2007/88168,2007,A1 .Location in patent: Page/Page column 55-56

34
[ 945667-94-7 ]
[ 945667-96-9 ]
[ 54396-44-0 ]
6-methyl-N-[2-(methyloxy)ethyl]-1-[2-methyl-3-(trifluoromethyl)phenyl]amino}pyrrolo[1,2-a]pyrazine-4-carboxamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 21 : 6-Methyl-lambda/-[2-(methyloxy)ethyl]-1 -[2-methyl-3- (trifluoromethyl)phenyl]amino}pyrrolo[1 ,2-a]pyrazine-4-carboxamide hydrochloride; To 1-chloro-6-methyl-lambda/-[2-(methyloxy)ethyl]pyrrolo[1 ,2-a]pyrazine-4-carboxamide (Intermediate 9 which contained 1-(1 H-1 ,2,3-benzotriazol-1-yloxy)-6-methyl-N-[2- (methyloxy)ethyl]pyrrolo[1 ,2-a]pyrazine-4-carboxamide (15percent by LCMS)) (53mg) in 1 ,4- dioxane (1 ml) was added <strong>[54396-44-0]3-amino-2-methylbenzotrifluoride</strong> (72mg) and methanesulfonic acid (26ul) and the reaction mixture heated under microwave conditions at 18O0C for fifteen minutes. The solid mass was dissolved in methanol, transferred to a round bottomed flask and evaporated. The residue was partitioned between ethyl acetate, water and saturated aqueous sodium hydrogen carbonate and washed. The organic layer was dried (MgSO4) and evaporated to a brown oil. The oil was dissolved in dichloromethane, applied to a Biotage Si 25+S column and eluted with 10percent ethyl acetate / hexane followed by 20percent, 40percent and 50percent ethyl acetate / hexane to afford a pale yellow solid. The solid was dissolved in ethyl acetate and treated with 1 M hydrochloric acid in diethyl ether to afford a precipitate. The mixture was evaporated and dried to afford the title compound (24mg). LC/MS [MH+] 407 consistent with molecular formula C20H2IF3N4O2

Reference： [1]Patent: WO2007/88168,2007,A1 .Location in patent: Page/Page column 53

35
[ 54396-44-0 ]
[ 10397-30-5 ]
C₁₆H₁₃F₃N₂O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1172 - 1176

36
[ 463-71-8 ]
[ 54396-44-0 ]
[ 1000577-12-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 8187 - 8195

37
4-chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3',4'-d]pyrrole bishydrochloride [ No CAS ]
[ 54396-44-0 ]
(2-methyl-3-trifluoromethyl-phenyl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3',4'-dipyrro]-4-yl)-amine bis-hydrochloride salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With potassium hydroxide; XPhos;palladium diacetate; In tert-butyl alcohol; at 100℃;	Example 48 (2-Methyl-3-trifluoromethyl-phenyl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3',4'-dipyrrol-4-yl)-amine* bis-hydrochloride Salt (48)4-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3',4'-d]pyrrole bishydrochloride (200 mg, 0.71 mmol), <strong>[54396-44-0]2-methyl-3-(trifluoromethyl)aniline</strong> (150 mg, 0.86 mmol), Pd(OAc)2 (8 mg, 0.04 mmol), X-Phos (34 mg, 0.07 mmol), and KOH (240 mg, 4.28 mmol) were suspended in tert-butanol (3 mL), and stirred overnight at 100 0C. The reaction was concentrated, and the reaction mixture was suspended in DMSO (ImL) and H2O (15mL). The resulting precipitate was filtered, and dissolved in MeOH (2mL) and 2M HCl in ether (3 equiv). Ether (10 mL) was added dropwise to the solution to induce precipitate formation. The resulting precipitate was filtered to provide 48 (109 mg, 36percent yield) as a yellow solid. LC-MS (M+H = 347, obsd. = 347).

Reference： [1]Patent: WO2010/80253,2010,A1 .Location in patent: Page/Page column 72

38
[ 54396-44-0 ]
[ 1169788-30-0 ]

Yield	Reaction Conditions	Operation in experiment
25%		Example 1503-Amino-2-methyl-5-nitrobenzotrifluoride70percent HNO3 (1.96 mL, 32.6 mmol, 1.1 equiv) was added dropwise to a mixture of <strong>[54396-44-0]3-amino-2-methylbenzotrifluoride</strong> (5.0 g, 28.55 mmol, 1 equiv) in 30 mL of fuming H2SO4 at 0° C. Then the mixture was left to reach room temperature and stirred for 1 hour. Poured into ice and the aqueous phase was extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO3 and concentrated. The residue was purified by column chromatography on silica gel using EtOAc/hexanes (3:7) as eluent to give 1.6 g of product (25percent) as a yellow solid.1H NMR (CDCl3, 300 MHz): delta 7.91 (s, 1H), 7.67 (s, 1H), 4.13 (br. s, 2H), 2.31 (s, 3H). m/z=221.1 (M+H)+.
	With sulfuric acid; nitric acid; at 15 - 20℃;Cooling with ice;	First Step [Show Image] To concentrated sulfuric acid (30 mL), <strong>[54396-44-0]2-methyl-3-trifluoromethylaniline</strong> (5.0 g, 28.5 mmol) was gradually added under ice cooling and fuming nitric acid (1.35 mL, 32.6 mmol) was added dropwise so that the inner temperature does not become higher than 15°C, followed by stirring for one hour while maintaining the liquid temperature at 15 to 20°C. The reaction mixture was gradually added to ice water and then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:10 to 1:1) to obtain 3.80 g of 2-methyl-5-nitro-3-trifluoromethylaniline. 1H-NMR (400 MHz, DMSO-d6) d: 2.21 (d, 3H, J = 1.2 Hz), 6.10 (br, 2H), 7.56 (d, 1H, J = 2.4 Hz), 7.74 (d, 1H, J = 2.4 Hz).

Reference： [1]Patent: US2011/130415,2011,A1 .Location in patent: Page/Page column 80
[2]Patent: EP2226315,2010,A1 .Location in patent: Page/Page column 46

39
[ 54396-44-0 ]
C₁₄H₁₈F₃NO [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1697 - 1700

40
[ 54396-44-0 ]
C₁₄H₁₇BrF₃NO [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1697 - 1700

41
[ 54396-44-0 ]
C₂₂H₂₃F₃N₂O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1697 - 1700

42
[ 54396-44-0 ]
C₁₄H₁₉BF₃N [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1697 - 1700

43
[ 54396-44-0 ]
[ 67-64-1 ]
[ 1292798-28-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1697 - 1700

44
[ 54396-44-0 ]
[ 1309832-36-7 ]

Reference： [1]Patent: US2011/130415,2011,A1

45
[ 54396-44-0 ]
[ 1309832-37-8 ]

Reference： [1]Patent: US2011/130415,2011,A1

46
[ 54396-44-0 ]
[ 1309832-38-9 ]

Reference： [1]Patent: US2011/130415,2011,A1

47
[ 54396-44-0 ]
[ 1309832-39-0 ]

Reference： [1]Patent: US2011/130415,2011,A1

48
[ 1446746-53-7 ]
[ 54396-44-0 ]
[ 1446746-10-6 ]

Yield	Reaction Conditions	Operation in experiment
37.5%		Step-8:8-Chloro-N,N-dimethyl-4-((2-methyl-3-(trifluoromethyl)phenyl)amino)-1-naphthamide In a 15 mL sealed tube, Pd(OAc)2 (3.0 mg, 0.013 mmol) and BINAP (16 mg, 0.026 mmol) were dissolved in dry and degassed toluene (5 mL). After stirring for 5 minutes, the above triflate derivative (step-7 intermediate) (100 mg, 0.262 mmol) was added and the mixture was stirred for another 10 minutes. Then, Cs2CO3 (300 mg, 0.917 mmol) and <strong>[54396-44-0]2-methyl-3-trifluoromethyl aniline</strong> (50 mg, 0.288 mmol) were added to the mixture. The reaction mixture was stirred for 15 min at RT and then heated to 110° C. overnight. It was cooled to RT and then filtered through celite and washed with EtOAc. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography to yield the desired compound as an offwhite solid (40 mg, 37.5percent). 1H NMR (400 MHz, CDCl3) delta: 2.23 (s, 3H), 2.73 (s, 3H), 3.0 (s, 3H), 6.66 (d, J=8.0 Hz, 1H), 7.20 (d, J=7.6 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.51-7.55 (m, 1H), 7.73-7.75 (m, 1H), 8.17 (s, 1H), 8.27-8.30 (m, 1H); MS m/z 407 (M+1).
37.5%		Step-8:8-Chloro-/V,/V-dimethyl-4-((2-methyl-3-(trifluoromethyl)phenyl)amino)-1 - naphthamide In a 15 mL sealed tube, Pd(OAc)2 (3.0 mg, 0.013 mmol) and BINAP (16 mg, 0.026 mmol) were dissolved in dry and degassed toluene (5 mL). After stirring for 5 minutes, the above triflate derivative (step-7 intermediate) (100 mg, 0.262 mmol) was added and the mixture was stirred for another 10 minutes. Then, Cs2C03 (300 mg, 0.917 mmol) and <strong>[54396-44-0]2-methyl-3-trifluoromethyl aniline</strong> (50 mg, 0.288 mmol) were added to the mixture. The reaction mixture was stirred for 15 min at RT and then heated to 1 10 °C overnight. It was cooled to RT and then filtered through celite and washed with EtOAc. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography to yield the desired compound as an offwhite solid (40 mg, 37.5percent). 1 H NMR (400 MHz, CDCI3) delta: 2.23 (s, 3H), 2.73 (s, 3H), 3.0 (s, 3H), 6.66 (d, J = 8.0 Hz, 1 H), 7.20 (d, J = 7.6 Hz, 1 H), 7.25 (d, J = 7.6 Hz, 1 H), 7.34 (t, J = 8.0 Hz, 1 H), 7.44 (d, J = 7.6 Hz, 1 H), 7.51 -7.55 (m, 1 H), 7.73-7.75 (m, 1 H), 8.17 (s, 1 H), 8.27-8.30 (m, 1 H); MS m/z 407 (M+1 ).

Reference： [1]Patent: US2013/178457,2013,A1 .Location in patent: Paragraph 0809; 0810
[2]Patent: WO2013/5168,2013,A2 .Location in patent: Page/Page column 229

49
[ 54396-44-0 ]
[ 36361-65-6 ]
[ 374889-67-5 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5744 - 5756

50
[ 1309581-38-1 ]
[ 54396-44-0 ]
[ 1309581-35-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	at 20℃; for 2h;Inert atmosphere;	[0322] (3) The Synthesis of RHg25: [0323] The intermediate 10 (0.38 g, 1 mmol) was added into a 100 ml single-necked flask, and then absolute 30 ml and <strong>[54396-44-0]2-methyl-3-(trifluoromethyl)aniline</strong> (0.47 g, 4 mmol) (excessive in amount) were added. The reaction mixture was stirred for 2 h at room temperature under nitrogen protection, and then the solvent was removed under reduced pressure. The product was purified through silica column chromatography with a mixture of petroleum ether (bp 60-90° C.) and ethyl acetate (v/v, 5/1) as elution solution to produce 0.43 g yellow solid RHg25 with a yield of 80percent. 1H NMR (400 MHz CDCl3) delta (ppm): 2.35 (s, 3H), 5.85 (s, 4H), 6.27 (d, J=8 Hz, 2H), 6.44 (s, 2H), 6.54 (d, J=8 Hz, 2H), 7.00 (m, 1H), 7.09 (m, 2H), 7.47 (m, 2H), 7.30 (d, J=8 Hz, 1H), 7.95 (d, J=8 Hz, 1H), 8.01 (d, J=8 Hz, 1H), 8.34 (d, J=8 Hz, 1H); 13C NMR (400 MHz, CDCl3), delta: 17.2, 68.0, 114.8, 121.7, 103.1, 109.9, 114.8, 123.5, 124.4, 125.5, 126.4, 127.4, 128.0, 128.4, 129.1, 131.3, 132.7, 139.5, 145.6, 147.5, 151.8, 163.0, 168.0; TOF MS (ES): m/z Calcd for C30H23F3N5O2+: 542.1798, Found: 542.1786.

Reference： [1]Patent: US2013/137879,2013,A1 .Location in patent: Paragraph 0322; 0323

51
[ 624-76-0 ]
[ 54396-44-0 ]
C₁₀H₁₂F₃NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	at 90℃; for 6h;Inert atmosphere;	a) Preparation of intermediate 52 A mixture of 2-iodoethanol (0.296 mL, 3.8 mmol) and 2-methyl-3-trifluoromethyl- aniline (1 g, 5.7 mmol) was heated at 90 °C under N2 atmosphere for 6 h.The resulting solid was dissolved in EtOAc and washed with 2M aq. NaOH solution. The organic layer was dried, filtered and concentrated to dryness. The crude product was purified by flash column chromatography (silica; EtOAc/hexane 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to yield intermediate 52 as an oil (0.711 g, 85percent).

Reference： [1]Patent: WO2013/171712,2013,A1 .Location in patent: Page/Page column 96

52
C₂₀H₂₇BF₃NO₄ [ No CAS ]
[ 54396-44-0 ]

Reference： [1]Journal of the American Chemical Society,2015,vol. 137,p. 3775 - 3778

53
[ 54396-44-0 ]
2-methyl-3-trifluoromethylaniline hydrochloride [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2015,vol. 137,p. 3775 - 3778

54
N-(2-methyl-3-trifluoromethylphenyl)-4-piperidone ethylene ketal [ No CAS ]
[ 54396-44-0 ]

Reference： [1]Journal of the American Chemical Society,2015,vol. 137,p. 3775 - 3778

55
[ 54396-44-0 ]
[ 149-73-5 ]
N,2-dimethyl-5-(trifluoromethyl)aniline [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 9722 - 9730

56
[ 54396-44-0 ]
[ 149-73-5 ]
[ 1263378-84-2 ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 9722 - 9730

57
[ 54396-44-0 ]
1-methyl-1-(2-methyl-3-(trifluoromethyl)phenyl)-3-(naphthalen-1-yl)guanidine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 9722 - 9730

58
[ 54396-44-0 ]
1-methyl-1-(2-methyl-5-(trifluoromethyl)phenyl)-3-(naphthalen-1-yl)guanidine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 9722 - 9730

59
[ 54396-44-0 ]
3-(2-chloro-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-methyl-5-(trifluoromethyl)phenyl)guanidine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 9722 - 9730

60
[ 54396-44-0 ]
3-(2-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-methyl-5-(trifluoromethyl)phenyl)guanidine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 9722 - 9730

61
[ 54396-44-0 ]
3-(2-bromo-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-methyl-5-(trifluoromethyl)phenyl)guanidine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 9722 - 9730

62
[ 54396-44-0 ]
[ 6160-65-2 ]
1-[2-methyl-3-(trifluoromethyl)phenyl]thiourea [ No CAS ]

Reference： [1]Chemical Science,2016,vol. 7,p. 2322 - 2330

63
[ 54396-44-0 ]
2,4-bis(trifluoromethyl)-1H-indole [ No CAS ]

Reference： [1]Organic Letters,2016,vol. 18,p. 1932 - 1935

64
[ 54396-44-0 ]
[ 76-05-1 ]
(Z)-2,2,2-trifluoro-N-(2-methyl-3-(trifluoromethyl)phenyl)acetimidoyl chloride [ No CAS ]

Reference： [1]Organic Letters,2016,vol. 18,p. 1932 - 1935

65
[ 33757-48-1 ]
[ 54396-44-0 ]
2-((2-methyl-3-(trifluoromethyl)phenyl)amino)-N-(quinolin-8-yl)-benzamide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 4295 - 4303

66
[ 54396-44-0 ]
C₂₇H₃₆F₃N₅O₄Si [ No CAS ]

Reference： [1]Patent: WO2016/97347,2016,A1

67
[ 54396-44-0 ]
C₂₆H₃₄F₃N₅O₄Si [ No CAS ]

Reference： [1]Patent: WO2016/97347,2016,A1

68
[ 54396-44-0 ]
C₂₅H₃₃F₃IN₅O₂Si [ No CAS ]

Reference： [1]Patent: WO2016/97347,2016,A1

69
[ 54396-44-0 ]
C₂₆H₃₅F₃N₆O₃Si [ No CAS ]

Reference： [1]Patent: WO2016/97347,2016,A1

70
[ 54396-44-0 ]
C₁₇H₂₇BrN₄O₂Si [ No CAS ]
C₂₅H₃₄F₃N₅O₂Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With tris-(dibenzylideneacetone)dipalladium(0); dicyclohexyl-(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; caesium carbonate; In toluene; at 85℃;Inert atmosphere;	Under nitrogen, to a mixture of intermediate 98 (15 g, 35.1 mmol), 2-methyl-3- (trifluoromethyl)aniline (7.4 g, 42.1 mmol), Pd2dba3 (3.21g; 3.51 mmol) and cesium carbonate (22.9 g, 70.2 mmol) in toluene (250 mL) was degassed with nitrogen for 10 minutes, then BrettPhos was added (3.8 g, 7.1 mmol). The reaction mixture was heated at 85 C overnight. The reaction was filtered and the filtrate was concentrated. The residue was purified by chromatography over silica gel mobile phase 50% petroleum ether 50% EtOAc). The fractions containing the product were collected and evaporated to dryness. The residue (10 g; 33%) by high performance liquid chromatography (C18 Si02, 25050iotaetaetaiota 10muetaiota, gradient from 40%o NH4HCO3 water 60% Acetonitrile to 15% NH4HC03 water to 85% Acetonitrile in 25 min).The fractions containing the product were collected and evaporated to dryness to afford 5.2 g (25%) of intermediate 99.

Reference： [1]Patent: WO2016/97347,2016,A1 .Location in patent: Page/Page column 147

71
[ 54396-44-0 ]
C₁₁H₁₃BrN₄O [ No CAS ]
C₁₉H₂₀F₃N₅O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With tris-(dibenzylideneacetone)dipalladium(0); johnphos; sodium t-butanolate; In toluene; at 100℃;Sealed tube; Inert atmosphere;	Under nitrogen, in a sealed tube, to a mixture of intermediate 90 (2.0 g, 6.7 mmol), 2- methyl-3-(trifluoromethyl)aniline (1.4 g, 8.1 mmol) and sodium tert-butoxide (1.3 g, 13 mmol) in toluene (28 mL) degassed with nitrogen, were added Pd2dba3 (0.62 g, 0.67 mmol) and 2-(di-t-butylphosphino)biphenyl (0.4 g, 1.3 mmol). The reaction mixture was heated at 100 °C overnight. EtOAc and a saturated aqueous solution of brine were added to the mixture. The organic layer was washed, separated, dried on MgS04, filtered and evaporated. The residue was purified by chromatography over silica gel (irregular SiOH, 120 g; mobile phase gradient from 98percent DCM 2percent CH3OH to 98percent DCM 2percent CH3OH 0.1percent NH4OH). The fractions containing the product were collected and evaporated to dryness to afford 1.7 g (65percent) of intermediate 91

Reference： [1]Patent: WO2016/97347,2016,A1 .Location in patent: Page/Page column 144

72
[ 54396-44-0 ]
[ 56-81-5 ]
[ 1609646-65-2 ]

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 11165 - 11169
[2]Organic Letters,2017,vol. 19,p. 2086 - 2089

73
[ 54396-44-0 ]
2-((7-(trifluoromethyl)quinolin-8-yl)methylamino)benzaldehyde [ No CAS ]

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 11165 - 11169

74
[ 54396-44-0 ]
C₂₆H₃₃F₃N₈O₂ [ No CAS ]

Reference： [1]Patent: WO2016/97359,2016,A1

75
[ 54396-44-0 ]
C₂₅H₃₁F₃IN₇O [ No CAS ]

Reference： [1]Patent: WO2016/97359,2016,A1

76
[ 54396-44-0 ]
C₂₇H₃₄F₃N₇O₃ [ No CAS ]

Reference： [1]Patent: WO2016/97359,2016,A1

77
[ 54396-44-0 ]
C₁₇H₂₅BrN₆O [ No CAS ]
C₂₅H₃₂F₃N₇O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With tris-(dibenzylideneacetone)dipalladium(0); johnphos; sodium t-butanolate; In toluene; at 100℃;Inert atmosphere; Sealed tube;	Under nitrogen, in a sealed tube, to a mixture of intermediate 54 (1.4 g, 3.4 mmol), 2- methyl-3-(trifluoromethyl)aniline (1.2 g, 6.8 mmol) and sodium tert-butoxide (0.66 g, 6.8 mmol) in toluene (14 mL) degassed with nitrogen, were added Pd2dba3 (0.31 g, 0.34 mmol) and 2-(di-t-butylphosphino)biphenyl (0.21 g, 0.68 mmol). The reaction mixture was heated at 100 °C overnight. EtOAc and a saturated aqueous solution of brine were added to the mixture. The organic layer was washed, separated, dried on MgSOzi, filtered and evaporated. The residue was purified by chromatography over silica gel (irregular SiOH, 40 g; mobile phase gradient from 96percent DCM 4percent CH3OH 0.1percent NuOmicronEta to 92percent DCM 8percent CH3OH 0.1percent NH4OH). The fractions containing the product were collected and evaporated to dryness to afford 0.96 g (56percent) of intermediate 55.

Reference： [1]Patent: WO2016/97359,2016,A1 .Location in patent: Page/Page column 119; 120

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[ 54396-44-0 ]
1-(2,4-dinitrophenyl)-3-{5-methyl-1-[2-methyl-3-(trifluoromethyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-pyrazole-4-carbaldehyde [ No CAS ]