[ CAS No. 1535-75-7 ]

Name: 1535-75-7|2-(Trifluoromethoxy)aniline|97%
Brand: Ambeed
SKU: A367971
Price: 5.0 USD
Availability: InStock
Rating: 95 (28 reviews)

{[proInfo.proName]} ,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

HazMat Fee +

There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

DV 2D 3D

3d Animation Molecule Structure of 1535-75-7

Structure of 1535-75-7 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Bulk Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 100K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 1535-75-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1535-75-7 ]

SDS Specification

Alternatived Products of [ 1535-75-7 ]

Product Details of [ 1535-75-7 ]

CAS No. :	1535-75-7	MDL No. :	MFCD00035959
Formula :	C₇H₆F₃NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZFCOUBUSGHLCDT-UHFFFAOYSA-N
M.W :	177.12 g/mol	Pubchem ID :	73754
Synonyms :

Calculated chemistry of [ 1535-75-7 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	37.53
TPSA :	35.25 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) :	-5.68 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.66
Log Po/w (XLOGP3) :	2.39
Log Po/w (WLOGP) :	3.44
Log Po/w (MLOGP) :	1.64
Log Po/w (SILICOS-IT) :	1.67
Consensus Log Po/w :	2.16

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.68
Solubility :	0.368 mg/ml ; 0.00208 mol/l
Class :	Soluble
Log S (Ali) :	-2.77
Solubility :	0.3 mg/ml ; 0.00169 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.66
Solubility :	0.385 mg/ml ; 0.00217 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.36

Safety of [ 1535-75-7 ]

Signal Word:	Danger	Class:	3
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	1993
Hazard Statements:	H225-H302-H312-H315-H319-H332-H335	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 1535-75-7 ]

* 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 [ 1535-75-7 ]
Downstream synthetic route of [ 1535-75-7 ]

[ 1535-75-7 ] Synthesis Path-Upstream 1~7

1
[ 1535-75-7 ]
[ 2252-44-0 ]

Yield	Reaction Conditions	Operation in experiment
34.0 %Chromat.	Stage #1: at 40℃; for 0.5 h; Stage #2: With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In sulfuric acid at 0 - 5℃; for 1.5 h;	EXAMPLE 3 (COMPARATIVE) Preparation of l-bromo-3-trifluoromethoxybenzene with DBI in concentrated sulphuric acid. 30.1 g of concentrated sulphuric acid (95-98percent) are placed in a 100 ml reactor and 10.1 g of 2-trifluoromethoxyaniline are added, dropwise. During said operation the temperature is maintained at approximately 40⁰C for approximately 30 minutes.Once a uniform solution has been obtained, it is cooled to 0-5⁰C using a cryostat and the portions of DBI are metered. During addition of the brominating agent, which takes approximately 1 hour, the mixture gradually turns brown. After completion of the reaction (30 minutes) a gas chromatograph analysis is performed: 13.6percent of 2-trifluoromethoxyaniline reagent, 34.0percent of mono-bromo-derivative as per the title, >40percent of di-bromo- and tri-bromo-derivatives.
66.6 %Chromat.	Stage #1: at 40 - 45℃; Stage #2: With N-Bromosuccinimide In sulfuric acid at 0 - 5℃; for 1.5 h;	EXAMPLE 4 (COMPARATIVE) Preparation of l-bromo-3-trifluoromethoxybenzene with NBS in concentrated sulphuric acid. 30.3 g of concentrated sulphuric acid (95-98percent) are placed in a 100 ml reactor and 10 g of 2-trifluoromethoxyaniline are added, dropwise, as in the previous example at approximately 40-45⁰C. Once a uniform solution has been obtained, it is cooled to 0- 5°C with cryostat. 10.1 g of NBS are metered in portions over a period of 1 hour, then left to complete for a further 30 minutes. The mixture gradually turns yellow and then brown. A gas chromatograph analysis is performed at the end of the reaction:15.3percent of 2-trifluoromethoxyaniline, 66.6percent of mono-bromo-derivative as per the title, 11.1 percent of di-bromo and tri-bromo-derivatives.

Reference： [1] Patent: WO2007/107820, 2007, A2, . Location in patent: Page/Page column 8-9
[2] Patent: WO2007/107820, 2007, A2, . Location in patent: Page/Page column 9

2
[ 1535-75-7 ]
[ 103008-51-1 ]
[ 37526-59-3 ]

Reference： [1] Patent: US6610853, 2003, B1,

3
[ 1535-75-7 ]
[ 103008-51-1 ]

Reference： [1] Patent: US6365780, 2002, B1, . Location in patent: Page column 5
[2] Patent: US6365780, 2002, B1, . Location in patent: Page column 6
[3] Patent: US6365780, 2002, B1, . Location in patent: Page column 5

4
[ 1535-75-7 ]
[ 63968-85-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 3, p. 886 - 896

5
[ 1535-75-7 ]
[ 149125-30-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 1, p. 21 - 39
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 1, p. 40 - 64
[3] Chinese Chemical Letters, 2017, vol. 28, # 6, p. 1248 - 1251

6
[ 1535-75-7 ]
[ 175278-09-8 ]

Reference： [1] Patent: WO2007/107820, 2007, A2, . Location in patent: Page/Page column 7

7
[ 1535-75-7 ]
[ 396075-91-5 ]

Reference： [1] Patent: WO2011/79102, 2011, A1,
[2] Patent: WO2011/79103, 2011, A1,

[ 1535-75-7 ] Synthesis Path-Downstream 1~59

1
[ 586-61-8 ]
[ 1535-75-7 ]
(2-trifluoromethoxyphenyl)-(4-isopropylphenyl)-amine [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 4306 - 4317

2
[ 302-17-0 ]
[ 1535-75-7 ]
2-hydroxyimino-<i>N</i>-(2-trifluoromethoxy-phenyl)-acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 40 - 64
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 21 - 39

3
[ 1535-75-7 ]
[2-(trifluoromethoxy)phenyl]hydrazine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%		Preparation 11(2 -Trifluoromethoxy-phenvD-hydrazine hydrochlorideTo a stirred solution of hydrochloric acid (37%, 1.6 L) at 0 0C is added 2- trifluoromethoxy-phenylamine (200 g, 113 mmol) followed by water (160 mL) and additional hydrochloric acid (160 mL). The mixture is warmed to room temperature, is stirred for 20 minutes, and is cooled to -5 0C. A solution of sodium nitrite (82 g, 1.19 mmol) in water (400 mL) is added dropwise keeping the internal temperature below 0 0C. The mixture is cooled to -5 0C and a solution of tin (II) chloride dihydrate (1020 g, 4520 mmol) in of HCl (37%, 3.2 L) is added dropwise keeping the internal temperature below O0C. The mixture is warmed to room temperature, is stirred for 3 h, filtered, and washed with 6 N HCl (3L) to obtain a yellow solid that is dried under vacuum overnight The title compound (115.8 g, 54%) is obtained pink-brown solid.Preparation 12 Trifluoromethoxy-phenyl-hydrazine hydrochlorideThe title compound (115.8 g, 54%) is prepared essentially according to the preparation of (2-trifluoromethoxy-phenyl)-hydrazine hydrochloride using 2- trifluoromethoxy-phenylamine.

Reference： [1]Patent: WO2007/140183,2007,A1 .Location in patent: Page/Page column 23

4
[ 1535-75-7 ]
[ 149125-30-4 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 21 - 39
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 40 - 64
[3]Chinese Chemical Letters,2017,vol. 28,p. 1248 - 1251

5
[ 1535-75-7 ]
[ 43091-72-1 ]
[ 220382-89-8 ]

Yield	Reaction Conditions	Operation in experiment
12%	In butan-1-ol; at 100℃; for 2h;	A solution of 2.09 g of <strong>[1535-75-7]2-trifluoromethoxyaniline</strong> and 3.15 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)-piperazine in 20 ml of n-butanol was stirred at 100C for 2 hours. The mixture was then cooled, diluted with water, alkalinised with 2N sodium hydroxide and extracted with chloroform. The organic phase was dried on anhydrous sodium sulphate, evaporated until dry and the crude purified via flash chromatography (ethyl acetate : petroleum ether 3:7) and subsequently crystallised from ethanol giving 0.55 g (12%) of 1-[N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(2-methoxyphenyl)-piperazine. Melting point: 69.5-71C.1H-NMR (CDCl3, delta): 8.02-7.85 (br, 1H, NH), 7.43-7.27 (m, 2H, aniline CHs), 7.03-6.80 (m, 4H, methoxyphenyl ring CHs), 6.72 (dd, 1H, aniline CH), 6.57 (t, 1H, aniline CH), 3.86 (s, 3H, OCH3), 3.43-3.23 (m, 2H, NHCH2CH2), 3.23-3.03 (m, 4H, piperazine protons), 2.85-2.60 (m, 6H, piperazine protons and NHCH2CH2). The title compound was prepared following the procedure described in Example I, second step, except that 1-[N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(2-methoxyphenyl)-piperazine, prepared as described above, was used in place of 1-[N-(2-nitrophenyl)-2-aminoethyl]4-(2-methoxyphenyl)-piperazine and that 4-dimethylaminopyridine was used in place of triethylamine, the mixture being heated for 1.5 h at reflux. The crude material was purified via flash chromatography (ethyl acetate : petroleum ether 4:6). Yield: 44%.1H-NMR (CDCl3, delta): 7.48-7.25 (m, 4H, trifluoromethoxyaniline ring CHs), 7.02-6.81 (m, 4H, methoxyphenyl ring CHs), 4.40-4.20 (m, 1H, C(O)NCH(H)CH2), 3.84 (s, 3H, OCH3), 3.36-3.18 (m, 1H, C(O)NCH(H)CH2), 3.10-2.90 (m, 4H, piperazine protons), 2.75-2.45 (m, 6H, piperazine protons and C(O)NCH2CH2), and 2.03-1.80 (m, 1H, CHC(O)), 1.75-0.80 (m, 10H, cyclohexyl protons).
	With sodium hydroxide; In butan-1-ol;	EXAMPLE 3 1-[N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(2-methoxyphenyl)piperazine A solution of 2.09 g of <strong>[1535-75-7]2-trifluoromethoxyaniline</strong> and 3.15 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine in 20 mL of n-butanol was stirred at 100 C. for 2 hrs. The mixture was then cooled, diluted with H2O alkalinized with 2 N NaOH and extracted with CHCl3. The organic phase was dried on anhydrous Na2SO4, evaporated until dry and the crude purified via flash chromatography (EtOAc-petrolium ether 3:7) and subsequently crystallized from EtOH giving 0.55 g (12%) of the title compound. Melting point: 69.5-71 C. 1H-NMR (CDCl3, delta): 8.02-7.85 (br, 1H, NH), 7.43-7.27 (m, 2H, aniline CHs), 7.03-6.80 (m, 4H, methoxyphenyl ring CHs), 6.72 (dd, 1H aniline CH), 6.57 (t, 1H, aniline CH), 3.86 (s, 3H, OCH3), 3.43-3.23 (m, 2H, NHCH2CH2), 3.23-3.03 (m, 4H, piperazine protons), 2.85-2.60 (m, 6H, piperazine protons and NHCH2CH2).
	With sodium hydroxide; In butan-1-ol;	EXAMPLE 3 1-[N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(2-methoxyphenyl)piperazine A solution of 2.09 g of <strong>[1535-75-7]2-trifluoromethoxyaniline</strong> and 3.15 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine in 20 mL of n-butanol was stirred at 100 C. for 2 hrs. The mixture was then cooled, diluted with H2 O, alkalinized with 2 N NaOH and extracted with CHCl3. The organic phase was dried on anhydrous Na2 SO4, evaporated until dry and the crude purified via flash chromatography (EtOAc-petrolium ether 3:7) and subsequently crystallized from EtOH giving 0.55 g (12%) of the title compound. Melting point: 69.5-71 C. 1 H-NMR (CDCl3, delta): 8.02-7.85 (br, 1H, NH), 7.43-7.27 (m, 2H, aniline CHs), 7.03-6.80 (m, 4H, methoxyphenyl ring CHs), 6.72 (dd, 1H, aniline CH), 6.57 (t, 1H, aniline CH), 3.86 (s, 3H, OCH3), 3.43-3.23 (m, 2H, NHCH2 CH2), 3.23-3.03 (m, 4H, piperazine protons), 2.85-2.60 (m, 6H, piperazine protons and NHCH2 CH2).

Reference： [1]Patent: EP1000047,2003,B1 .Location in patent: Page 9
[2]Patent: US6399614,2002,B1
[3]Patent: US6071920,2000,A

6
[ 1535-75-7 ]
[ 103008-51-1 ]

Reference： [1]Patent: US6365780,2002,B1 .Location in patent: Page column 5
[2]Patent: US6365780,2002,B1 .Location in patent: Page column 6
[3]Patent: US6365780,2002,B1 .Location in patent: Page column 5

7
[ 1535-75-7 ]
[ 541-41-3 ]
[ 259137-83-2 ]

Yield	Reaction Conditions	Operation in experiment
49%		. (2-Trifluoromethox -phenyl)-carbamic acid ethyl esterTo a solution of <strong>[1535-75-7]2-(trifluoromethoxy)aniline</strong> (15.9 g, 0.09 mol) in DME (300 ml_) at -5 C (ice/salt bath) is added sodium hydride (3.6 g, 60% by weight, 0.09 mol) in portions. The suspension is warmed to r.t. and ethyl chloroformate (7.5 ml_, 0.08 mol) is added dropwise. The reaction mixture is stirred for 2 h at r.t. then heated to reflux for 1 .5 h. The mixture is then cooled to r.t. and water (150 ml_) is slowly added to quench the reaction. The phases are separated and the water layer is extracted with EtOAc (2x100 ml_). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material is purified on silica gel with EtOAc/heptanes (1 -5%) as eluent to afford the title product (1 1 .0 g, 49%) as an amber oil. 1 H NMR (300 MHz, CDCI3) delta 8.20 (d, J = 8.1 Hz, 1 H), 7.30-7.22 (m, 2H), 7.07 (app t, 1 H), 6.90 (br s, 1 H), 4.25 (q, J = 7.2 Hz, 2H), 1 .34 (t, J = 7.2 Hz, 3H);19F NMR (300 MHz, CDCI3) delta -57.32 (s, 3F);LC Rt: 2.96 min; MS 250 (M+1 , 94%).
49%		To a solution of 2-(thfluoromethoxy)aniline (15.9 g, 0.09 mol) in DME (300 mL) at -5 C (ice/salt bath) was added sodium hydride (3.6 g, 60% by weight, 0.09 mol) in portions. The suspension was warmed to r.t. and ethyl chloroformate (7.5 mL, 0.08 mol) was added dropwise. The reaction mixture was stirred for 2 h at r.t. then heated to reflux for 1 .5 h. The mixture was then cooled to r.t. and water (150 mL) was slowly added to quench the reaction. The phases are separated and the water layer was extracted with EtOAc (2x100 mL). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified on silica gel with EtOAc/heptanes (1 -5%) as eluent to give 1 1 .0 g (49%) of the titled product as an amber oil.1 H NMR (300 MHz, CDCI3) delta 8.20 (d, J = 8.1 Hz, 1 H), 7.30-7.22 (m, 2H), 7.07 (app t, 1 H), 6.90 (br s, 1 H), 4.25 (q, J = 7.2 Hz, 2H), 1 .34 (t, J = 7.2 Hz, 3H);19F NMR (300 MHz, CDCI3) delta -57.32 (s, 3F);LC Rt: 2.96 min; LCMS m/z: [M+H]+=250.
	In 1,2-dimethoxyethane; ethyl acetate;	g (2-Trifluoromethoxy-phenyl)-carbamic acid ethyl ester 2-(Trifluoromethoxy)aniline (50 g, 0.282 mol) was dissolved in DME (1000 mL) and cooled to -5 C. Sodium hydride (12.3 g, 55%, 0.282 mol) was added in portions and the suspension was allowed to warm to room temperature. Ethyl chloroformate (23.5 mL, 0.245 mol) was added drop by drop and the mixture was stirred for 2 h at room temperature and for 1.5 h at reflux after addition was complete. Hydrolysis was with water (110 mL). The phases were separated and the water phase was extracted with ethyl acetate. The organic phases were washed with brine, pooled and dried with MgSO4. Evaporation of the solvent yielded 70.6 g of brown oil, which was purified by chromatography on silica gel with hexane/ethyl acetate (6:1). This yielded the title compound, (44.2 g, 62%) as a beige yellow oil. (EI-MS: m/e=249.1 (M+)).

In 1,2-dimethoxyethane; ethyl acetate;

g (2-Trifluoromethoxy-phenyl)-carbamic acid ethyl ester 2-(Trifluoromethoxy)aniline (50 g, 0.282 mol) was dissolved in DME (1000 mL) and cooled to -5 C. Sodium hydride (12.3 g, 55%, 0.282 mol) was added in portions and the suspension was allowed to warm to room temperature. Ethyl chloroformate (23.5 mL, 0.245 mol) was added drop by drop and the mixture was stirred for 2 h at room temperature and for 1.5 h at reflux after addition was complete. Hydrolysis was with water (110 mL). The phases were separated and the water phase was extracted with ethyl acetate. The organic phases were washed with brine, pooled and dried with MgSO4. Evaporation of the solvent yielded 70.6 g of a brown oil, which was purified by chromatography on silica gel with hexane/ethyl acetate (6:1). This yielded the title compound, (44.2 g, 62%) as a beige yellow oil. (EI-MS: m/e=249.1 (M+))

Reference： [1]Patent: WO2011/79102,2011,A1 .Location in patent: Page/Page column 17-18
[2]Patent: WO2011/79103,2011,A1 .Location in patent: Page/Page column 28
[3]Patent: US2002/169163,2002,A1
[4]Patent: US2002/35110,2002,A1

8
[ 1535-75-7 ]
[ 103008-51-1 ]
[ 37526-59-3 ]

Yield	Reaction Conditions	Operation in experiment
99.4%		Synthesis Example 32 Synthesis of 2-Trifluoromethoxybenzenesulfonamide [Compound (III-12)] Using 2-trifluoromethoxyaniline [Compound (XXV-12)] (5 g, 0.0282 mmol), 7.3 g (percent yield: 99.4%) of 2-trifluoromethoxybenzenesulfonyl chloride [Compound (XXII-12)] was synthesised according to the process of Synthesis Example 31 (3). Thereafter, the compound (III-12) was synthesised using 3.9 g (0.0149 mol) of the Compound (XXII-12) according to Synthesis Example 31 (3). White solid, m.p.: 183-184 C., yield: 2.09 g, percent yield: 46.2%. IR KBr cm-1: 3382, 3268, 1482, 1344, 1230, 1164, 768. 1H-NMR (60 MHz, d6-DMSO, delta): 7.2-7.65 (5H, m, aromatic ring H*3, NH2), 7.86 (1H, dd, J=2Hx, 8 Hz, aromatic ring H).

Reference： [1]Patent: US6610853,2003,B1

9
[ 91368-89-7 ]
[ 1535-75-7 ]
[ 220854-19-3 ]

Yield	Reaction Conditions	Operation in experiment
35%	In diphenylether;	(Step 2) Preparation of 4-oxo-6-trifluoromethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline 2-Trifluoromethoxy aniline(5.10 g, 30 mmol) was dissolved in diphenyl ether(50 ml), and diethyl 2-(ethoxyethyl)malonate(7.4 g, 32 mmol) was added. The reaction mixture was stirred at 220 C. for 7 hours, warmed up to 270 C. and refluxed in Dean-Stark apparatus for 24 hours. Reaction solvent, diphenyl ether, was removed from the above mixture by evaporating in vacuo, then the residue was crystallized in dichloromethane/hexane to obtain 2.4 g of desired compound as solid in 35% of yield. 1 H NMR(CDCl3, 200 MHz) delta 3.25(t, J=9.3 Hz, 2H), 4.86(t, J=9.3 Hz, 2H), 7.13-7.25(m, 1H), 7.39-7.45(m, 1H), 7.61(dd, J1 =8.0, J2 =1.3 Hz, 1H), 9.18(brs, 1H); m/e 271(M+).
35%	In diphenylether;	(Step 2) Preparation of 4-oxo-6-trifluoromethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline 2-Trifluoromethoxy aniline(5.10 g, 30 mmol) was dissolved in diphenyl ether(50 ml), and diethyl 2-(ethoxyethyl)malonate(7.4 g, 32 mmol) was added. The reaction mixture was stirred at 220 C for 7 hours, warmed up to 270 C and refluxed in Dean-Stark apparatus for 24 hours. Reaction solvent, diphenyl ether, was removed from the above mixture by evaporating in vacuo, then the residue was crystallized in dichloromethane/hexane to obtain 2.4 g of desired compound as solid in 35 % of yield. 1H NMR(CDCl3, 200 MHz) delta 3.25(t, J=9.3Hz, 2H), 4.86(t, J=9.3Hz, 2H), 7.13-7.25(m, 1H), 7.39-7.45(m, 1H), 7.61(dd, J1=8.0, J2=1.3Hz, 1H), 9.18(brs, 1H); m/e 271(M+).

Reference： [1]Patent: US6011044,2000,A
[2]Patent: EP966466,2002,B1

10
tin(II)chloride dihydrate [ No CAS ]
[ 1535-75-7 ]
[2-(trifluoromethoxy)phenyl]hydrazine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium nitrite; In hydrogenchloride; water;	Step (1) Preparation of 2-Trifluoromethoxyphenylhydrazine Hydrochloride A solution of <strong>[1535-75-7]o-trifluoromethoxyaniline</strong> (1.77 g, 10 mmol) in cold, concentrated HCl (11.6 mL) was diazotized at -5 C. (internal temperature) with a solution of NaNO2 (0.69 g, 10 mmol) in water (11 mL). After 15-20 minutes the mixture was treated portionwise with a cold (0 C.) solution of tin (II)chloride dihydrate (4.5 g, 20 mmol) in concentrated HCl (4 mL). Stirring was continued for another 3 hours with the ice bath warming to room temperature after one hour. The suspension was recooled, basified with 50% NaOH (to pH 14) and extracted with ether. The extracts were washed with 1N NaOH, water and brine, dried (MgSO4) and acidified with an excess of ethereal HCl. Removal of the solvent in vacuo yielded the title compound as an off-white solid (2 g, 88%). It was used without further purification. NMR (DMSO-d6, 400 MHz): delta7.03 (m, 1H, ArH), 7.18 (d, J=7.5 Hz, 1H, ArH), 7.34 (m, 2H, ArH), 8.40 (s, 1H, NH). MS (EI, m/z): 197 (M)+, 77 (b.p.).

Reference： [1]Patent: US4960902,1990,A

11
[ 1535-75-7 ]
[ 175278-09-8 ]

Yield	Reaction Conditions	Operation in experiment
		1a. Preparation of 4-bromo-2-trifluoromethoxyaniline (formula (IIIa). 3462 g of acetic acid and 1700 g of 2-trifluoromethoxyaniline are placed at room temperature in a 10 1 lined glass reactor with 4 necks, outlet on bottom, thermostat with brine cryostat, provided with mechanical agitation, bubble condenser and thermometer; the mixture is subsequently cooled to 0-5C and 1894.26 g of NBS are added, maintaining the temperature at 0-50C. At the end of the reaction the mixture is brought back to room temperature and the acetic acid is eliminated by distillation. The residue is washed with water, the phases are separated, the organic phase is neutralised with NaHCCbeta and the phases are separated again, the inorganic phase is washed with water and the product indicated in the title is isolated. B.p. 115C/30 mmHg.
	With N-Bromosuccinimide; acetic acid; at 0 - 20℃;	To a solution of 2-(trifluoromethoxy)aniline (318A) (2.655 mg, 15 mmol) in acetic acid (6 mL) was added NBS (2.94 g, 16.5 mmol) at 0 C and stirred at room temperature overnight. It was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 318B. LC-MS (ESI) m/z: 256 [M +H]+; 'H-NMR (CDCb, 400 MHz): d (ppm) 3.89 (s, 2H), 6.67 (d, J= 8.8 Hz, 1H), 7.18 (dd, J= 8.8, 2.4 Hz, 1H), 7.28 (d, J= 2.4 Hz, 1H).

Reference： [1]Patent: WO2007/107820,2007,A2 .Location in patent: Page/Page column 7
[2]Patent: WO2019/133770,2019,A2 .Location in patent: Paragraph 001669; 001670; 001671

12
[ 147470-60-8 ]
[ 1535-75-7 ]
[ 1092379-59-3 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 206 - 211

13
[ 1535-75-7 ]
[ 372-31-6 ]
[ 306935-26-2 ]

Yield	Reaction Conditions	Operation in experiment
51%	With phosphorous pentoxide p-toluenesulfonic acid; at 130℃;	General procedure: General Procedure A: To a pressure tube containing ethyl 4,4,4- trifluoroacetoacetate (1.2 eq) and Eaton"s reagent [7.5% wt. phosphorous pentoxide p- toluenesulfonic acid solution ( 1 mL/0.3 mmol)], was added the corresponding aniline (1 eq). Then the pressure vessel was sealed and heated to 130 , and the reaction mixture was stirred overnight. After cooling to 0 C, the reaction was poured into ice water (~5 mL/1 mmol) and the solution pH was adjusted to 5 by the addition of saturated aqueous potassium carbonate. In situations when a pale yellow precipitate was formed, the solution was filtered and the residue was washed with water and cold ethanol, then dried in vacuo to yield the crude 4-hydroxyquinoline. Alternatively, the solution could be extracted with CHCl3 (20 mL x 3) and dried over anhydrous Na2SO4. After filtration, the solvent was removed in vacuo to give the crude 4-hydroxyquinoline. Then the residue was purified by column chromatography using hexane"EtOAc as an eluent (30% of EtOAc) to give the desired products with yields ranging from 45% to 60%. (0217) Characterization data for compound 1 and 1a e have been reported by Kozikowski. [0140] 8-trifluoromethoxy-2-trifluoromethyl-4-quinolinol (compound 1): Yield 51%.1H NMR (DMSO-d6) 7.19 (1H, s), 7.74 (1H, apparent t, J = 8.4 Hz), 7.88 (1H, d, J = 7.2 Hz), 8.28 (1H, d, J = 8.4 Hz), 9.71 (1H, br s).13C NMR (DMSO-d6) 101.5 (q, J = 2.4 Hz), 119.9, 120.8 (q, J = 258 Hz), 122.4 (q, J = 273 Hz), 123.5, 123.7, 127.3, 128.8, 141.8 (q, 1.8 Hz), 144.5 (q, J = 36 Hz), 163.9. UVmax: 294 nm, 303 nm, 315 nm

Reference： [1]Patent: WO2017/136642,2017,A1 .Location in patent: Page/Page column 0139; 0140
[2]Journal of Medicinal Chemistry,2009,vol. 52,p. 2109 - 2118

14
[ 1535-75-7 ]
[ 75-87-6 ]
[ 848027-63-4 ]

Yield	Reaction Conditions	Operation in experiment
		According to Scheme 8, hydroxylamine sulfate (18 g, 3 equivalents) was dissolved in water (80 mL) and then chloral hydrate (7.3 g, 1.2 equivalents) was added. After 15 min, a solution of the starting aniline (5.0 mL, 37 mmol), dissolved in 1 N HCl (44 mL, 1.2 equivalents), was added dropwise (20 min) to the reaction mixture. The resulting cloudy mixture was heated at 80 C. for 1 h, cooled to rt, and diluted with CHCl3 (160 mL). The aqueous layer was extracted with CHCl3 (2×80 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated. Hexanes (40 mL) were added. Evaporation of the solvent provided crude product which was used in the next step without further purification: MS(ESI): 247 (M-H)-.

Reference： [1]Patent: US2005/59823,2005,A1 .Location in patent: Page 14

15
[ 16013-85-7 ]
[ 1535-75-7 ]
[ 1217350-05-4 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 100℃; for 48h;Sealed tube;	Example 1.48: Preparation of 3-(2-(Trifluoromethoxy)phenyl)-3//-imidazo[4,5-b]pyridin- 5-ol (Compound 107).; Step A: Preparation of 5-Nitro-6-(2-(trifluoromethoxy)phenylamino)pyridin-2-ol.; 2,6-Dichloro-3-nitropyridine (10.0 g, 51.8 mmol) and <strong>[1535-75-7]2-(trifluoromethoxy)aniline</strong> (18.4 g, 104 mmol) were taken up in ethanol (50 mL) and heated to 100 0C for 48 h in a sealed tube. The reaction mixture was cooled in an ice bath, and the resulting precipitate was collected by vacuum filtration to give an intermediate 6-chloro-3-nitro-N-(2- (trifluoromethoxy)phenyl)pyridin-2 -amine, which was dissolved in dioxane (65 mL) and H2O (35 mL). Potassium hydroxide (2.90 g, 51.7 mmol) was added and the reaction mixture was heated to 100 0C for 16 h. After cooling, the pH was adjusted to less than 7 with 1 Nu HCl. The resulting precipitate was collected by vacuum filtration to give the title compound as a bright yellow solid (5.10 g). LCMS m/z = 316.0 [M+H]+; 1H NuMR (400 MHz, CDCl3) delta ppm 5.91 (d, /=10.1 Hz , IH), 7.51 (m, 4H), 8.26 (d, 7=10.1 Hz, IH), 8.50 - 8.85 (broad s, IH), 10.78 (broad s, IH).

Reference： [1]Patent: WO2010/30360,2010,A1 .Location in patent: Page/Page column 75

16
[ 53939-30-3 ]
[ 1535-75-7 ]
[ 1227721-75-6 ]

Yield	Reaction Conditions	Operation in experiment
		2-Trifluoromethoxyaniline (0.8Og, 5.0mmol) and sodium hydride (60% dispersion in mineral oil, 1.7eq) were stirred in dry DMF at room temperature for 2 hours, and 5-bromo- 2-chloropyridine (1.0Og, 5.0mmol) was added and the mixture stirred at room temperature overnight. Iced water was added slowly to the mixture, and the mixture was extracted with DCM (3x). The DCM was washed with 2M HCl solution (2x), dried (MgSO4), and concentrated. The residue was purified by column chromatography eluting using a gradient (EtOAc/hexanes 1 :9 v/v).

Reference： [1]Patent: WO2010/57833,2010,A1 .Location in patent: Page/Page column 85

17
[ 1535-75-7 ]
[ 805237-13-2 ]
(-)-tert-butyl 2-((2-(trifluoromethoxy)phenyl)amino)propanoate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2010,vol. 49,p. 4763 - 4766

18
[ 1253380-72-1 ]
[ 1535-75-7 ]
[ 1253380-81-2 ]

Yield	Reaction Conditions	Operation in experiment
		The methyl [(2-chloro-4-fluorophenyl)methyl][2-({2-[(trifluoromethyl)oxy]phenyl} amino)ethyl]amino}(oxo)acetate used in the method described above was prepared as follows:Methyl [[(2-chloro-4-fluorophenyl)methyl](2-oxoethyl)amino](oxo)acetate (0.288 g, 1 mmol, prepared as described earlier) and <strong>[1535-75-7]2-[(trifluoromethyl)oxy]aniline</strong> (0.354 g, 2.00 mmol) were dissolved in 2% acetic acid/methanol (10 ml) at room temperature. The mixture was stirred for 15 minutes and polymer-supported cyanoborohydride (0.976 g, 4.00 mmol) was added. The mixture was stirred at room temperature for 48 hours and filtered through an SCX cartridge (Varian, 5g). The filtrate was concentrated in vacuo to afford methyl [(2-chloro-4-fluorophenyl)methyl][2-({2- [(trifluoromethyl)oxy]phenyl}amino)ethyl]amino}(oxo)acetate (0.293 g), which was used without purification.

Reference： [1]Patent: WO2010/125103,2010,A1 .Location in patent: Page/Page column 102

19
[ 20600-65-1 ]
[ 1535-75-7 ]
[ 1268468-75-2 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: Propylsulfanyl-acetic acid methyl ester (1.3 g, 8.78 mmol) in diethyl ether(10 ml.) was added dropwise to an ice-cold, stirred suspension of sodium methoxide (0.475 g, 8.78 mmol) in dry diethyl ether (10 ml_). The mixture was stirred at 0 0C for 1 h and then treated dropwise with a solution of methyl formate (0.6 ml_, 9.66 mmol). The mixture was stirred at 0 0C for 1 h and then at room temperature overnight. Water (30 ml.) was added, the mixture was equilibrated, and the two layers were separated. The aqueous layer was added to a cold solution (0 0C) of 2-trifluoromethoxy-phenylamine (1.55g, 8.78 mmol) in water (20 ml.) containing 10 N HCI (5 ml_). The mixture was stirred for 1 h at 0 0C and then allowed to reach room temperature and extracted with dichloromethane. The dichloromethane extracts were washed with water, dried on sodium sulfate, and evaporated to get 2-propylsulfanyl-3-(2-trifluoromethoxy- phenylamino)-acrylic acid methyl ester as oil. Thus obtained 2-propylsulfanyl-3-(2- trifluoromethoxy-phenylamino)-acrylic acid methyl ester was dissolved in diphenylether (6 ml.) and microwaved at 200 C for 80 min. Loaded the reaction mixture on to silica gel column and eluted with methanol in dichloromethane (0% to 10% methanol gradient) to provide S-propylsulfanyl-delta-trifluoromethoxy-quinolin^-ol. Yield: 400 mg.

Reference： [1]Patent: WO2011/22216,2011,A1 .Location in patent: Page/Page column 40

20
[ 1535-75-7 ]
[ 74479-50-8 ]
[ 1197356-84-5 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In toluene; at 20℃; for 5h;Cooling;	Example 18 (2-trifluoromethoxyphenyl)-(all-trans)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dim ethyl-2,4,6,8-nonatetraenoic acid amide (3b-00) In a reaction flask, etretin of 0.5 g, toluene of 10 ml and phosphorus trichloride of 0.19 ml are added and stirred at the room temperature for 2 h, and the resultant solution is added in a solution of o-trifluoromethylaniline of 0.25 g and pyridine of 6 ml in the cooling condition, and stirred to react with one another at the room temperature for 5 h; and the reaction liquid is poured in the crushed ice, followed by extraction by dichloromethane for three times, organic layer washing by saturated sodium bicarbonate, washing by water to neutrality, drying by anhydrous sodium sulphate, filtration, reduced pressure concentration to dryness, column chromatography (silica gel column: 100-200 meshes; mobile phase: petroleum ether: 60-90 C.:ethyl acetate=20:1), fraction collection, concentration, and recrystallization by methanol to obtain a yellow product of 0.18 g, mp 165.5-166.5 C. 1HNMR (CDCl3), delta(ppm): 8.26 (d, 1H), 7.54 (d, 1H); 7.48 (t, 1H); 7.36 (s, 1H); 7.13 (t, 1H); 6.98 (q, 1H); 6.65 (d, 1H); 6.53 (s, 1H); 6.29 (d, 1H); 6.15 (q, 2H); 5.22 (s, 1H); 3.75 (s, 3H); 2.37 (s, 3H); 2.23 (s, 3H); 2.21 (s, 3H); 2.08 (s, 3H); 2.05 (s, 3H) 13CNMR (CDCl3), delta(ppm): 165.08; 156.31; 151.85; 139.39; 138.22; 135.65; 134.01; 132.85; 130.90; 130.36; 129.95; 128.70; 126.10; 124.10; 122.86; 120.92; 110.09; 55.63; 21.50; 17.55; 13.90; 13.07; 11.93 High-resolution MS: m/z: 469.2236 (theoretical value: 469.2229) molecular formula: C28H30F3NO2

Reference： [1]Patent: US2011/77298,2011,A1 .Location in patent: Page/Page column 16

21
[ 1535-75-7 ]
[ 19182-81-1 ]
[ 1297344-95-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	In methanol; water; at 20℃;Darkness;	General procedure: 1-Aryl-4-nitro-1H-imidazoles were prepared following the general procedure we have developed in our laboratory [23] with some slight modifications. Equimolar amount of aniline derivative was treated with 1,4-dinitro-1H-imidazole in aqueous methanol at ambient temperature in the dark for several hours until complete disappearance of 1,4-dinitro-1H-imidazole monitored by TLC. In some cases, the mixture was heated under reflux to complete the reaction. On cooling, the desired crude 1-aryl-4-nitro-1H-imidazoles separated from the mixture by precipitation. After filtration and recrystallization the pure product was obtained. Yields, solvents used for recrystallization and specific data are given below in the respective sections. Further details are available on request.

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 1524 - 1535

22
[ 802535-77-9 ]
[ 1535-75-7 ]
[ 1034613-46-1 ]

Yield	Reaction Conditions	Operation in experiment
54%	With palladium diacetate; potassium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; at 80℃; for 4h;Inert atmosphere;	General procedure: Pd(OAc)2 (20 mg, 0.09 mmol), (+/-)-BINAP (55 mg, 0.09 mmol), and DMF (5 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. The mixture was stirred under argon for 30 min and added to a mixture of 27 (345 mg, 0.9 mmol), <strong>[1535-75-7]2-trifluoromethoxyaniline</strong> (0.184 mL, 1.35 mmol), and K2CO3 (1.24 g, 8.97 mmol) in DMF (10 mL). The resulting mixture was stirred at 80 C for 4 h under argon. After cooling to room temperature, the reaction mixture was filtered on a pad of celite. The solvent was evaporated, the crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 210 mg (54%) of 31 as white solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4507 - 4511

23
[ 552-16-9 ]
[ 1535-75-7 ]
[ 939920-68-0 ]

Reference： [1]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 465 - 469

24
[ 56667-12-0 ]
[ 1535-75-7 ]
[ 1414856-44-2 ]

Yield	Reaction Conditions	Operation in experiment
72%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; bis[2-(diphenylphosphino)phenyl] ether; In toluene; at 120℃; for 10h;Schlenk technique; Inert atmosphere;	General procedure: A Schlenk tube was charged with dibromides (0.3 mmol), Pd2dba3(0.0075 mmol), DPEPhos (0.03 mmol), and Cs2CO3 (0.75 mmol). The tube was evacuated and backfilled with argon before amine (0.36 mmol) and 2 mL toluene was added. The reaction mixture was stirred at 120 oC for 8-24h. After the reaction mixture was diluted with EtOAc and washed with water and brine, the solution was dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 50:1 petroleum ether/ethyl acetate) to provide the desired product.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 6406 - 6408,3

25
C₇H₁₀ClF₃N₂O [ No CAS ]
[ 1535-75-7 ]
C₁₄H₁₅F₆N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;	General procedure: The general procedure for the preparation of (R)-2-amino-3,3,3-trifluoro-2-methyl-N-phenylpropanamide derivatives was as follows. Reactions were carried out according to the literature procedure reported by Zhichkin et al2 with slight modifications. The Vilsmeier reagent was prepared by adding oxalyl chloride (2.52 g, 19.8 mmol) dropwise to a solution of anhyd. DMF (1.50 g, 20.5 mmol) in CH2Cl2 (20 mL) at 0-5 ºC (CAUTION: Foaming.) and stirring at rt for 30 min. Compound 5 (1.93 g, 10.0 mmol) was added at 0 ºC to Vilsmeier reagent (20.0 mmol) in CH2Cl2 (20 mL) prepared as described above, and the mixture was stirred at rt for 2 h. At 0 ºC, a solution of substituted aniline (10.0 mmol) in CH2Cl2 (10 mL) was added, followed by DIPEA (5.30 g, 41.0 mmol), and the mixture was stirred for 1 h at rt. It was then concentrated to dryness, and the residue was heated at reflux in ethanol (25 mL) with ethylenediamine (2.70 g, 45.0 mmol) for 3 h. The resulting mixture was evaporated to dryness, stirred with water (50 mL) and partitioned between CH2Cl2 and water. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate) to afford the desired compounds.

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 134 - 137

26
[ 355377-26-3 ]
[ 1535-75-7 ]
[ 459-57-4 ]
[ 1429227-58-6 ]

Yield	Reaction Conditions	Operation in experiment
67%	With p-toluene sulfinic acid; In methanol; at 20℃;	General procedure: To a solution of aldehyde 1 (1 mmol) in methanol, amine 2 (1 mmol), isocyanide 3 (1 mmol), and catalyst pTSIA (20 mol %) were added into a flask. Then the reaction mixture was stirred for 12-24 h at rt (monitored by TLC and LCMS until no further increase in the ratio of the desired product vs starting materials). After completion of reaction the solvent was removed under vacuum to get a crude residue. The crude residue was purified by silica gel column chromatography using (10-30%) ethylacetate-hexane to get the pure product 4.

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 2340 - 2343

27
[ 1535-75-7 ]
[ 1479-24-9 ]
[ 1436418-34-6 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a mixture of substituted phenyl amine (0.06 mol) and 20% HCl (50 mL), NaNO2 (0.123 mol) in H2O (200 mL) was added drop-wise at 0 C. After the completion of addition, the reaction mixture was stirred at this temperature for 30 min, and then it is dropped into the mixture of appropriate intermediate (10a or 10b) (0.047 mol), sodium acetate anhydrous (10.2 g, 0.124 mol), EtOH (200 mL) at 0 C. Upon completing the addition, the mixture was filtered and the cake was dried to give light yellow to white solid (11a-t, 12a and 12b) yielded 75-80%.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 2843 - 2855

28
[ 1315559-96-6 ]
[ 1535-75-7 ]
[ 1315555-52-2 ]

Yield	Reaction Conditions	Operation in experiment
41.7%	With potassium phosphate; palladium diacetate; XPhos; In toluene; at 20 - 105℃; for 12.5h;Inert atmosphere;	Added the 1 -methylethyl 2-{4-[(4-bromophenyl)methyl]-1 -pi perazinyl}-3-pyrid me carboxylate (25.0 mg, 0.060 mmol), Anilines (0.120 mmol), Xphos (5.7 mg, 0.012 mmol), potassium phosphate (38.1 mg, 0.179 mmol) and palladium(ll) acetate (1.34mg, 10 mol%) in 3.0 mL Toluene in a 5 mL reaction vial, and then stirred the mixture for 30mm at room temperature under nitrogen atmosphere. The stirring was kept for 12 hr at 105 C. Pretreated a StratoSpheres PL-Thiol MP SPE column with methanol, filtered reaction mixture through column, washed with Methanol. Concentrated to give the crude product, which was dissolved in DMSO, and purified on a Gilson HPLC (XBridge 19 x 100mm 5u preparatory column), eluting at 18 mLmin with a linear gradient running from 20% to 95% acetonitrile and 0.1% aqueous NH4OH over 18 mm. The desired fractions were concentrated under a stream of nitrogen at 45 C, giving the desired product (12.83 mg, 41.7%).LCMS: mz= 515.0 [M+H], Ret. Time: 1.16 mm.

Reference： [1]Patent: WO2013/6596,2013,A1 .Location in patent: Page/Page column 169; 170

29
[ 1535-75-7 ]
[ 1499-21-4 ]
P,P-diphenyl-N-[2-(trifluoromethoxy)phenyl]phosphinic amide [ No CAS ]

Reference： [1]Organic Letters,2013,vol. 15,p. 5722 - 5725

30
[ 1589488-07-2 ]
[ 1535-75-7 ]
[ 1589488-20-9 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a solution of respective anilines (1.0 eq.) in CH2Cl2 (15 mL) was added pyridine at 0 C and the mixture stirred for 5 min. Compound 4 (1.0 eq.) in CH2Cl2 (10 mL) wasadded and the mixture stirred at room temperature for 12-48 h. The mixture was diluted with CH2Cl2 (25 mL) and washed with diluted HCl and water. The organic layer wasdried over anhydrous Na2SO4 and concentrated to obtain crude was subjected to column chromatography on silica gel to yield title compounds 5.

Reference： [1]Journal of the Korean Chemical Society,2013,vol. 57,p. 731 - 737

31
[ 2548-29-0 ]
[ 1535-75-7 ]
[ 1031499-75-8 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile; at 20℃; for 16h;	General procedure: To a solution of anilines (1.2 eq.) in acetonitrile (15 mL) was added compound 5 (1.0 eq.) and the mixture stirred atroom temperature for 16 h. The solid formed was filtered and washed with acetonitrile (5 mL). The filtrate was concentrated to afford residue was subjected to column chromatography on silica gel to yield compound 7 (Yield: 47-78%).

Reference： [1]Journal of the Korean Chemical Society,2013,vol. 57,p. 731 - 737

32
[ 1352609-91-6 ]
[ 1535-75-7 ]
C₂₃H₁₆F₃N₇O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In 1,2-dichloro-ethane; for 2h;Inert atmosphere;	General procedure: To a stirred solution of 11 (13.14 mmol) in 1,2-dichloroethane (240 mL) were added appropriate substituted anilines (19.71 mmol) and AcOH (13.14 mmol), and the mixture was heated to reflux for 2 h under nitrogen atmosphere. The reaction mixture was cooled to 0 C, and MeOH (60 mL) and THF (20 mL) were added. To it, (AcO)3BHNa (26.20 mmol) or NaBH4 (52.56 mmol) was added portionwise, and then the reaction mixture was allowed to warm to room temperature and stirred for an additional 3 h. The pH of the reaction mixture was adjusted to 7-8 at 0 C with 1 NHCl, and then the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2× 300 mL). The combined organic layers was washed with brine (300 mL) and dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel to afford the titled compounds as a solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 2724 - 2732
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 4213 - 4238

33
[ 1535-75-7 ]
[ 141-97-9 ]
[ 1620683-57-9 ]

Yield	Reaction Conditions	Operation in experiment
92.3%		General procedure: To a mixture of substituted phenyl amine (0.06mol) and 15% HCl (60mL), NaNO2 (5g, 0.072mol) in H2O (200mL) was added drop-wise at 0C. After the completion of addition, the reaction mixture was stirred at this temperature for 30min, and then added into a mixture of ethyl acetylacetate (8.2g, 0.063mol), anhydrous sodium acetate (14.76g, 0.18mol), and EtOH (200mL) at 0C. Then, the mixture was filtered, and the residue was dried to afford light yellow solids (9a-i) in 90-95% yields.
		General procedure: Appropriate substituted anilines 6a-g or 12a-j (0.101mol) was added to the mixture solution of hydrogen chloride/water (1:1,10ml), sodium nitrite (0.1mol) and stirred for 5min at 0C, respectively. Then the mixture was added to the ethanol solution which ammonium acetate(1mol) and ethyl acetoacetate (0.1mol) were dissolved in. The reaction was monitored by TLC until completed. Finally the solution was filtered and washed with a plenty of water to give a yellow solid.
		General procedure: Appropriate substituted anilines 8a-h (0.101mol) was added to the mixture solution of hydrogen chloride/water (1:1, 10ml), sodium nitrite (0.1mol) and stirred for 5min at 0C, respectively. Then the mixture was added to the ethanol solution which ammonium acetate (1mol) and ethyl acetoacetate (0.1mol) were dissolved in. The reaction was monitored by TLC until completed. Finally the solution was filtered and washed with a plenty of water to give a yellow solid.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 83,p. 581 - 593
[2]European Journal of Medicinal Chemistry,2017,vol. 141,p. 538 - 551
[3]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 245 - 256

34
[ 2417-72-3 ]
[ 1535-75-7 ]
methyl 4-(((2-(trifluoromethoxy)phenyl)amino)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.6%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 16h;	(Formula 1-2: methyl 4-(((2-(trifluoromethoxy)phenyl)amino)methyl)benzoate)[1695][1696]Compound ofFormula 1-1(<strong>[1535-75-7]2-(trifluoromethoxy)aniline</strong>; 0.385 mL, 4.625 mmol), methyl 4-(bromomethyl)benzoate (1.271 g, 5.550 mmol) and DIPEA (1.228 mL, 6.937 mmol) were dissolved in acetonitrile (5 mL) at room temperature and stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=20%) to give the desired compound ofFormula 1-2(0.806 g, 53.6%) in the form of a colorless liquid.

Reference： [1]Patent: WO2014/178606,2014,A1 .Location in patent: Paragraph 1694; 1695; 1696

35
[ 1535-75-7 ]
[ 19646-07-2 ]
2-chloro-5-methoxy-N-(2-(trifluoromethoxy)phenyl)pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; at 160℃; for 48h;Inert atmosphere; Sealed tube;	To a stirred solution of 2, 4-dichloro-5-methoxypyrimidine (5 g, 28.08 mmol) in tertiary butyl alcohol (35 mL) under argon atmosphere were added <strong>[1535-75-7]2-(trifluoromethoxy) aniline</strong> (4 g, 22.47 mmol) and diisopropylethylamine (35 mL) at RT. The reaction mixture was stirred at 160 C for 48 h in a sealed tube. After completion of the reaction (monitored by TLC), the volatile components were removed in vacuo. The crude material was purified by silica gel column chromatography using 10% EtOAc:hexanes to afford 2-chloro-5-methoxy- N-(2-(trifluoromethoxy) phenyl) pyrimidin-4-amine (2 g, 22%) as a colorless syrup. ?H-NMR (CDC13, 400 MHz): oe 8.64 (d, 1H), 7.79 (s, 1H), 7.72 (br s, 1H), 7.38 (t, 1H), 7.30-7.27 (m, 1H), 7.10-7.07 (m, 1H), 4.00 (s, 3H); LC-MS: 320.3 (M+1); (column; X Select CSH C-18 (50 x 3.0 mm, 3.5 .im); RT 4.63 mm. 0.05% Aq TFA: ACN; 0.80 ml/min); TLC: 15% EtOAc:hexanes (Rf 0.3).
22%	With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; at 160℃; for 48h;Inert atmosphere; Sealed tube;	Synthesis of2-chloro-5-methoxy-N-(2-(trifluoromethoxy) phenyl) pyrimidin-4-amine [0342] To a stirred solution of 2, 4-dichloro-5-methoxypyrimidine (5 g, 28.08 mmol) in tertiary butyl alcohol (35 mL) under argon atmosphere were added <strong>[1535-75-7]2-(trifluoromethoxy) aniline</strong> (4 g, 22.47 mmol) and diisopropylethylamine (35 mL) at RT. The reaction mixture was stirred at 160 C for 48 h in a sealed tube. After completion of the reaction (monitored by TLC), the volatile components were removed in vacuo. The crude material was purified by silica gel column chromatography using 10% EtOAc:hexanes to afford 2-chloro-5-methoxy- N-(2-(trifluoromethoxy) phenyl) pyrimidin-4-amine (2 g, 22%) as a colorless syrup. 1H-NMR (CDCls, 400 MHz): delta 8.64 (d, 1H), 7.79 (s, 1H), 7.72 (br s, 1H), 7.38 (t, 1H), 7.30-7.27 (m, 1H), 7.10-7.07 (m, 1H), 4.00 (s, 3H); LC-MS: 320.3 (M+l); (column; X Select CSH C-18 (50 x 3.0 mm, 3.5 muiotaeta); RT 4.63 min. 0.05% Aq TFA: ACN; 0.80 ml/min); TLC: 15% EtOAc:hexanes {Rf. 0.3).

Reference： [1]Patent: WO2015/66696,2015,A1 .Location in patent: Paragraph 0290
[2]Patent: WO2015/66697,2015,A1 .Location in patent: Paragraph 0342

36
[ 1535-75-7 ]
[ 79-04-9 ]
2-chloro-N-(2-(trifluoromethoxy)phenyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In water; at 0℃; for 1h;	General procedure: Generalprocedure: To a solution of aniline or benzylamine (10 mmol) inwater (20 ml) and pyridine (1.6 ml) was added chloracetyl chloride(1.69 g, 15 mmol) slowly at 0 C. The reaction mixture was stirredat 0 C for 1.0 h and then diluted with water (50 ml). The precipitatewas collected by filtration, washed with water and dried undervacuum. N-substituted-2-chloroacetamides 3a-3r were obtainedas solid (yield 50-80%).
		General procedure: Under nitrogen atmosphere, dry CH2Cl2 (30 mL), amine (0.02 mol), and Et3N (0.05 mol) wereadded to a three-necked round bottom ask and stirred for 0.5 h, then chloroacetyl chloride droppedslowly and reacted for 3 h at room temperature. Then, the solution was washed with 2 mol L1hydrochloric acid (30 mL), saturated aq NaHCO3 solution (30 mL), and brine (40 mL), successively,then dried over anhydrous Na2SO4 and filtered. After evaporating CH2Cl2 in vacuum, the obtainedcrude product was rened by recrystallization using ethyl acetate/petroleum ether.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6173 - 6184
[2]Molecules,2018,vol. 23

37
[ 1300738-84-4 ]
[ 1535-75-7 ]
(E)-2-(4-methoxystyryl)-4,6-dimethoxy-N-(2-(trifluoromethoxy)phenyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31.15%		General procedure: A mixture of B (1 mmol) and dichloromethane (10 ml) was stirred for 10 min, then EDCI (1.2 mmol) and HOBt (1.2 mmol) were added. Added the appropriate amine (1.2 mmol) into the mixed solution after 30 min and refluxed for 12 h. The reaction mixture was filtrated with water and then the filtrate was dried and evaporated. Purification by silica gel afforded C1-C27

Reference： [1]Letters in drug design and discovery,2016,vol. 13,p. 495 - 504

38
[ 1535-75-7 ]
[ 609-15-4 ]
ethyl 2-chloro-2-(2-(2-(trifluoromethoxy)phenyl)hydrazono)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		General procedure: Commercially available substituted aniline (63.4mmol) was portionwise added to a solution of concentrated HCl (13mL), ethanol (20mL) and water (7mL). To the above mixture was added dropwise a solution of NaNO2 (4.69g, 69.7mmol) in water (15mL) at 0-5C. After the completion of addition, the reaction mixture was stirred at this temperature for 30min, and then added into a mixture of ethyl 2-chloroacetoacetate (10.88g, 63.4mmol), anhydrous sodium acetate (15.60g, 190.10mmol), and water (90mL) at 0C. The reaction mixture was stirred at 0C for 10min and then at room temperature for 4h. The solid which precipitated was collected by filtration and recrystallized from ethanol to afford light yellow solids (21a-21m) in 75.2-90% yields. 6.3.8 Ethyl 2-chloro-2-(2-(2-(trifluoromethoxy)phenyl)hydrazono)acetate (21h) Light yellow solid; Yield: 90%; M.p.: 93-94 C; MS (ESI) m/z(%): 333.1 [M+Na]+.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 123,p. 431 - 446

39
[ 1535-75-7 ]
C₁₂H₁₈ClN₃OS [ No CAS ]
5-isopropyl-2-(4"-methylpiperazin-1-yl)-N-(2'-(trifluoromethoxy)phenyl)thiazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
149 mg	With pyridine; In dichloromethane; at 20℃; for 12h;Inert atmosphere;	General procedure: 1 molar equivalent of the carboxylic acid obtained in the hydrolysis reaction (general procedure B) was introduced into a 25 mL round-bottom flask fitted with a condenser. The system was purged with an argon stream and 4 mL of SOCl2 (excess) were added. The reaction mixture was refluxed for 1 h, after which it was concentrated under reduced pressure and the crude acyl chloride was dissolved in dichloromethane. In parallel, 1.33 eq. of the corresponding aniline were dissolved in a 1:1 mixture of dichloromethane:pyridine (0.2 M). The resulting solution was added to the reaction mixture, which was then stirred for 12 h at rt. The solvents were removed under reduced pressure and the resulting crude mixture was purified by column chromatography on silica gel.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 3938 - 3944

40
[ 1535-75-7 ]
[ 1001054-16-5 ]

Yield	Reaction Conditions	Operation in experiment
		Stepl : 1-azido-2-(trifluoromethoxy)benzene (27a) Concentrated HCl (7.9 mL) was added to a solution of <strong>[1535-75-7]2-(trifluoromethoxy)aniline</strong> (1.1 mL, 7.9 mmol) in EtOAc (26 mL) at 0 C. After 10min, a solution of sodium nitrite (1.6 g, 23.7 mmol) dissolved in water (4.6 mL) was added slowly over 5 min. The mixture was stirred for 30min, and then treated with a solution of sodium azide (1.5 g, 23.7 mmol) in water (5.3 mL) slowly over 5min. The reaction was stirred for 1 h then treated with phosphate buffer saline (pH 7.4, 50 mL). The mixture was extracted with EtOAc, the organics were washed with brine, dried over Na2S04 and concentrated to give compound 27a.

Reference： [1]Patent: WO2016/96116,2016,A1 .Location in patent: Page/Page column 52
[2]Journal of Asian Natural Products Research,2019

41
[ 1535-75-7 ]
1-(2,4-dinitrophenyl)-1′-(2-isopropylphenyl)-4,4′-bipyridinium bis(tetrafluoroborate) [ No CAS ]
1-(2-trifluoromethoxyphenyl)-1′-(2-isopropylphenyl)-4,4′-bipyridinium bis(tetrafluoroborate) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	In methanol; for 48h;Reflux;	A solution of 1-(2,4-dinitrophenyl)-1?-(2-isopropylphenyl)-4,4?-bipyridinium bis(tetrafluoroborate) (1.44 g, 2.3 mmol) and <strong>[1535-75-7]2-trifluoromethoxyaniline</strong> (0.83 g, 4.7 mmol) in MeOH (30 mL) was heated at reflux for 2 days. The mixture was cooled, poured into water (200 mL) and washed with CHCl3 (3×100 ml) and the solvent removed under reduced pressure. The residue was triturated with EtOH to give Compound 3-2 (1.10 g, 77%) as a pale yellow powder. (0158) deltaH (300 MHz, CD3OD) 9.56 (2H, d, J=6.9 Hz), 9.42 (2H, d, J=6.9 Hz), 8.96 (2H, d, J=6.9 Hz), 8.91 (2H, d, J=6.9 Hz), 7.91-9.10 (2H, m), 7.73-7.89 (4H, m), 7.52-7.70 (2H, m), 2.64 (1H, m), 1.30 (6H, d, J=6.8 Hz). (0159) deltaF (282 MHz, CD3OD) -59.49 (s), -154.05-154.15 (br.s).

Reference： [1]Patent: US2016/231635,2016,A1 .Location in patent: Paragraph 0157-0159

42
methyl 2-methyl-4-phenylquinoline-3-carboxylate [ No CAS ]
[ 1535-75-7 ]
C₂₄H₁₇F₃N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 5h;	General procedure: Representative procedure for the 2-methyl-N,4-diphenylquinoline-3-carboxamide (Entry 22, Table 1): To the magnetically stirred solution of KOt-Bu (2 mmol) in THF (6 mL) at rt, was added methyl 2-methyl-4-phenylquinoline-3-carboxylate 3a (0.277 g, 1 mmol) followed by addition of aniline (0.093 mL, 1 mmol, 1 equiv) and the mixture was allow to stirred at rt until the completion of reaction (5 h, monitored by TLC) . After completion of reaction THF evaporated under rotary vacuum evaporation, crude reaction mixture was extracted with EtOAc (3 × 5 mL) and H2O (5 mL). The combined EtOAc extracts were dried (anh Na2SO4), filtered, and the filtrate was concentrated under rotary vacuum evaporation. The crude product was adsorbed on silica gel (230-400 mesh size, 500 mg), charged on to a flash chromatography column of silica-gel (230-400 mesh size, 2.5 g), and eluted with hexane-EtOAc (90:10) to obtain analytically pure 2-methyl-N,4-diphenylquinoline-3-carboxamide, 5a as white solid (0.219 g, 65%);

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 5960 - 5966

43
[ 300-57-2 ]
[ 1535-75-7 ]
2-phenyl-8-(trifluoromethoxy)quinoline [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 12189 - 12196

44
[ 1535-75-7 ]
[ 141-53-7 ]
N-(2-(trifluoromethoxy)phenyl)formamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.56%	With formic acid; for 12h;Reflux;	General procedure: A mixture of sodium formate (8.1 mmol), formic acid (12.5 mL)and various substituted N-phenylformamides (40.7 mmol) was stirred at reflux for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The solid was taken up inethyl acetate to form a solution which was successively washed with water (2 20 mL) and then evaporated under reduced pressure to obtain the corresponding amides 2a-e.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 886 - 896

45
[ 103-82-2 ]
[ 1535-75-7 ]
2-phenyl-N-[2-(trifluoromethoxy)phenyl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	General procedure: Acetamides (1a-1x, 1ab, 1ac and 1ba-1bc). To a solution of 2-phenylacetic acid (7.0mmol), <strong>[1535-75-7]2-(trifluoromethoxy)aniline</strong> (7.7mmol) in anhydrous CH2Cl2 (25mL) were added EDCI (1.745g, 9.1mmol) and DMAP (256.6mg, 2.1mmol). The reaction mixture was stirred at room temperature overnight, diluted with HCl (1M) aqueous solution, and extracted with CH2Cl2 (3×25mL). The combined organic phase was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Purification by flash chromatography (Silica gel, petroleum ether: ethyl acetate=50: 1 as eluent) gave the corresponding 2-phenyl-N-[2-(trifluoromethoxy)phenyl]acetamide compound. 2-Phenyl-N-[2-(trifluoromethoxy)phenyl]acetamide (1a): White solid; mp 85-86C; 1H NMR (400MHz, CDCl3) delta 8.41 (d, J=8.1Hz, 1H), 7.60-7.30 (m, 6H), 7.26 (t, J=7.8Hz, 1H), 7.16 (d, J=8.2Hz, 1H), 7.10-7.01 (m, 1H), 3.79 (s, 2H); 13C NMR (100MHz, CDCl3) delta 169.0, 137.9, 133.7, 130.5, 129.6, 129.4, 128.0, 127.5, 124.2, 120.2 (q, JC-F=257.8Hz), 121.4, 120.5 (d, J C-F=0.6Hz), 45.1; 19F NMR (376MHz, CDCl3) delta-58.11; HRMS (EI) Calculated for C15H12F3NO2 [M+]:295.0820, found 295.0819; IR (KBr) nu(cm-1): 3408, 3295, 1665, 1607, 1532, 1456,1264, 1168, 1104.