[ CAS No. 393-15-7 ] {[proInfo.proName]}

Name: 393-15-7|4-Methoxy-3-(trifluoromethyl)aniline|98%
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SKU: A546575
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Quality Control of [ 393-15-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 393-15-7 ]

CAS No. :	393-15-7	MDL No. :	MFCD00043460
Formula :	C₈H₈F₃NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CQJCPOVTPNWVBW-UHFFFAOYSA-N
M.W :	191.15	Pubchem ID :	600705
Synonyms :

Calculated chemistry of [ 393-15-7 ] Expand+

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	42.34
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) :	-5.98 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.75
Log Po/w (XLOGP3) :	2.1
Log Po/w (WLOGP) :	3.46
Log Po/w (MLOGP) :	2.22
Log Po/w (SILICOS-IT) :	2.13
Consensus Log Po/w :	2.33

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.56
Solubility :	0.529 mg/ml ; 0.00277 mol/l
Class :	Soluble
Log S (Ali) :	-2.47
Solubility :	0.647 mg/ml ; 0.00338 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.06
Solubility :	0.168 mg/ml ; 0.000881 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 393-15-7 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P261-P280-P305+P351+P338-P311	UN#:	2811
Hazard Statements:	H302+H312-H315-H319-H331-H335	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 393-15-7 ]

* 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 [ 393-15-7 ]
Downstream synthetic route of [ 393-15-7 ]

[ 393-15-7 ] Synthesis Path-Upstream 1~6

1
[ 654-76-2 ]
[ 393-15-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen In methanol; water at 20℃; for 3.5 h;	To a solution of 2-methoxy-5-nitrobenzotrifluoride (5.08 g, 23.0 mmol) in methanol (200 ml) was added 10percent Pd-C (containing 50percent water, 250 mg), and the resulting mixture was stirred for 3.5 hours under a hydrogen atmosphere at room temperature and atmospheric pressure while maintaining the temperature. The mixture was filtered by the use of Celite and the filtrate was concentrated to dryness under reduced pressure to obtain 4-methoxy-3-(trifluoromethyl)aniline (4.67 g, 100percent). MS : m/z = 192 (M + 1)
99%	for 4 h;	1-Methoxy-4-nitro-2-trifluoromethyl-benzene (10 g, 45 mmol) was hydrogenated in a Paar apparatus with shaking at 50 psi for 4 hours, with 1 g 10 wt percent Pd/C. The reaction mixture was filtered through celite, and the filtrate was evaporated in vacuo to give 8.6 g 4-Methoxy-3-trifluoromethyl-phenylamine, 99percent, as a solid.
99%	for 4 h;	1-Methoxy-4-nitro-2-trifluoromethyl-benzene (10 g, 45 mmol) was hydrogenated in a Paar apparatus with shaking at 50 psi for 4 hours, with 1 g 10 wt percent Pd/C. The reaction mixture was filtered through celite, and the filtrate was evaporated in vacuo to give 8.6 g 4-Methoxy-3-trifluoromethyl-phenylamine, 99percent, as a solid.

Reference： [1] Patent: EP1403255, 2004, A1, . Location in patent: Page 121
[2] Patent: US2005/209260, 2005, A1, . Location in patent: Page/Page column 143-144
[3] Patent: US2007/49609, 2007, A1, . Location in patent: Page/Page column 122
[4] Synthesis, 2006, # 19, p. 3316 - 3340
[5] Patent: FR745293, 1932, ,
[6] Journal of Organic Chemistry, 1961, vol. 26, p. 2707 - 2710
[7] Patent: WO2003/99771, 2003, A2, . Location in patent: Page 138
[8] Patent: US6335350, 2002, B1, . Location in patent: Example 1
[9] Patent: EP1137645, 2004, B1, . Location in patent: Page 15
[10] Patent: WO2005/80340, 2005, A1, . Location in patent: Page/Page column 51
[11] Patent: FR745293, 1932, ,

2
[ 654-76-2 ]
[ 7439-89-6 ]
[ 393-15-7 ]

Reference： [1] Patent: US6166028, 2000, A,

3
[ 1514-11-0 ]
[ 393-15-7 ]

Reference： [1] Nature Chemistry, 2017, vol. 9, # 7, p. 681 - 688

4
[ 1514-11-0 ]
[ 1445972-43-9 ]
[ 393-15-7 ]

Reference： [1] Organic Letters, 2013, vol. 15, # 14, p. 3734 - 3737

5
[ 777-37-7 ]
[ 393-15-7 ]

Reference： [1] Journal of Organic Chemistry, 1961, vol. 26, p. 2707 - 2710

6
[ 88-16-4 ]
[ 393-15-7 ]

Reference： [1] Journal of Organic Chemistry, 1961, vol. 26, p. 2707 - 2710

[ 393-15-7 ] Synthesis Path-Downstream 1~79

1
[ 654-76-2 ]
[ 393-15-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen;palladium 10% on activated carbon; In methanol; water; at 20℃; under 760.051 Torr; for 3.5h;	To a solution of 2-methoxy-5-nitrobenzotrifluoride (5.08 g, 23.0 mmol) in methanol (200 ml) was added 10% Pd-C (containing 50% water, 250 mg), and the resulting mixture was stirred for 3.5 hours under a hydrogen atmosphere at room temperature and atmospheric pressure while maintaining the temperature. The mixture was filtered by the use of Celite and the filtrate was concentrated to dryness under reduced pressure to obtain 4-methoxy-3-(trifluoromethyl)aniline (4.67 g, 100%). MS : m/z = 192 (M + 1)
99%	With hydrogen;palladium 10% on activated carbon; under 2585.81 Torr; for 4h;	<strong>[654-76-2]1-Methoxy-4-nitro-2-trifluoromethyl-benzene</strong> (10 g, 45 mmol) was hydrogenated in a Paar apparatus with shaking at 50 psi for 4 hours, with 1 g 10 wt % Pd/C. The reaction mixture was filtered through celite, and the filtrate was evaporated in vacuo to give 8.6 g 4-Methoxy-3-trifluoromethyl-phenylamine, 99%, as a solid.
99%	With hydrogen;palladium 10% on activated carbon; under 2585.81 Torr; for 4h;	<strong>[654-76-2]1-Methoxy-4-nitro-2-trifluoromethyl-benzene</strong> (10 g, 45 mmol) was hydrogenated in a Paar apparatus with shaking at 50 psi for 4 hours, with 1 g 10 wt % Pd/C. The reaction mixture was filtered through celite, and the filtrate was evaporated in vacuo to give 8.6 g 4-Methoxy-3-trifluoromethyl-phenylamine, 99%, as a solid.

	With hydrogen;nickel; In methanol; under 1050.11 - 3750.38 Torr; for 15h;	The title compound is prepared from <strong>[654-76-2]1-methoxy-4-nitro-2-trifluoromethyl-benzene</strong> (1 g, 4.43 [MMOL)] by hydrogenation [(5-] 1.4 bar) in the presence of Raney-Ni (0.3 g) in MeOH (20 mL) during 15 h. The product is isolated by filtration of the reaction suspension over Hyflo and evaporation of the solvent under reduced pressure to give compound of Stage 149.1 as a beige solid : M+H = 191.9 ; Rf [(ACOET/HEXANE] = 1 : 1): 0.33.
		A suspension of <strong>[654-76-2]4-methoxy-3-trifluoromethyl-nitrobenzene</strong> (2.2 g) and iron powder (1.68 g) in ethanol (35 mL) and water (15 mL) is treated with a solution of concentrated hydrochloric acid (0.42 mL) in ethanol (6 mL) and water (3 mL) and the mixture is heated to reflux for approximately 1 hour. The mixture is then cooled, filtered, and concentrated under reduced pressure. The resulting oil is dissolved in ethyl acetate and extracted three times with 5% aqueous hydrochloric acid. The pooled acidic extracts are then cooled in an ice bath and basified with solid potassium carbonate, then extracted with ethyl acetate. These organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, then passed through a short column of silica gel (ethyl acetate is used as the eluant) to provide the desired compound as an amber oil.
	With tin(ll) chloride; In ethyl acetate; at 20℃; for 5h;Heating / reflux;	[0185] 1-Methoxy-4-nitro-2-trifluoromethylbenzene 68 (0.1 mol) and SnCl2 (1 mol) was mixed in EtOAc. The mixture was stirred at rt for 2 hrs and then refluxed for 3 hrs until TLC indicated the completion of the reaction. The reaction mixture was cooled and quenched with aqueous NaHC03. The solid was filtered through a celite pad and washed with EtOAc. The organic layer of the filtrate was collected, dried and concentrated to afford the corresponding aniline. To the aniline (0.05 mol) in methylene chloride (200mL) was added Et3N and (CF3CO) 20 at 0C. The reaction was allowed to warm to 25C with stirring. The reaction was then worked up between EtOAc and water. The organic layer was dried and concentrated. The residue was purified on silica gel column to afford 70. This material is dissolved in methylene chloride (100 mL) and the solution was cooled to-78C. Boron tribromide (0.1 mol) was added. The mixture was warmed to room temperature. Water was added, and the organic phase was dried and concentrated. Chromatography afforded the title compound 71.

Reference： [1]Patent: EP1403255,2004,A1 .Location in patent: Page 121
[2]Patent: US2005/209260,2005,A1 .Location in patent: Page/Page column 143-144
[3]Patent: US2007/49609,2007,A1 .Location in patent: Page/Page column 122
[4]Synthesis,2006,p. 3316 - 3340
[5]Journal of Organic Chemistry,1961,vol. 26,p. 2707 - 2710
[6]Patent: WO2003/99771,2003,A2 .Location in patent: Page 138
[7]Patent: US6335350,2002,B1 .Location in patent: Example 1
[8]Patent: EP1137645,2004,B1 .Location in patent: Page 15
[9]Patent: WO2005/80340,2005,A1 .Location in patent: Page/Page column 51
[10]Patent: FR745293,1932,

2
[ 16480-05-0 ]
[ 393-15-7 ]
[ 70338-59-9 ]

Reference： [1]Patent: US4166735,1979,A

3
[ 2401-85-6 ]
[ 393-15-7 ]
[ 68105-67-9 ]

Reference： [1]Patent: DE2708440,1978,
Chem.Abstr.,1978,vol. 89

4
[ 393-15-7 ]
1-Isocyanato-4-trifluoromethanesulfonyl-benzene [ No CAS ]
[ 55225-78-0 ]

Reference： [1]Patent: DE2334355,1975,
Chem.Abstr.,1975,vol. 82

5
[ 393-15-7 ]
[ 1548-13-6 ]
[ 23742-57-6 ]

Reference： [1]Patent: DE1802739,1969,
Chem.Abstr.,1969,vol. 71

6
[ 393-15-7 ]
[ 88-65-3 ]
2-(4-Methoxy-3-trifluoromethyl-phenylamino)-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 1272 - 1277

7
[ 393-15-7 ]
[ 1514-11-0 ]

Reference： [1]Journal of Organic Chemistry,1961,vol. 26,p. 2707 - 2710

10
[ 777-37-7 ]
[ 393-15-7 ]

Reference： [1]Journal of Organic Chemistry,1961,vol. 26,p. 2707 - 2710

11
[ 88-16-4 ]
[ 393-15-7 ]

Reference： [1]Journal of Organic Chemistry,1961,vol. 26,p. 2707 - 2710

12
[ 393-15-7 ]
[ 814-68-6 ]
C₁₁H₁₀F₃NO₂ [ No CAS ]

Reference： [1]Patent: EP1186601,2002,A1 .Location in patent: Page 11

13
[ 393-15-7 ]
[ 3282-30-2 ]
[ 478837-02-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dichloromethane; at 20℃; for 1h;	Triethylamine (6.24 ml, 44.8 mmol) was added to a solution of <strong>[393-15-7]4-methoxy-3-(trifluoromethyl)aniline</strong> (4.29 g, 22.4 mmol) in dichloromethane (45.0 ml), and the resulting mixture was ice-cooled, followed by adding dropwise thereto pivaloyl chloride (2.84 g, 23.5 mmol) at 0 to 5C. The resulting mixture was warmed up to room temperature and stirred for 1 hour while maintaining the temperature. The mixture was partitioned by the use of a 5%-aqueous sodium hydrogencarbonate solution and ethyl acetate, and the organic layer was washed with a 5% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain N-[4-methoxy-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (6.16 g, 100%).1H-NMR (CDCl3) delta; 1.32 9H, s), 3.89 (3H, s), 6.96 (1H, d, J=8.9Hz), 7.31 (1H, br s), 7.63 (1H, d, J=2.8Hz), 7.76 (1H, dd, J=2.8, 8.9Hz).

Reference： [1]Patent: EP1403255,2004,A1 .Location in patent: Page 121

14
[ 393-15-7 ]
[ 407-25-0 ]
[ 1141713-96-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0℃;	[0185] 1-Methoxy-4-nitro-2-trifluoromethylbenzene 68 (0.1 mol) and SnCl2 (1 mol) was mixed in EtOAc. The mixture was stirred at rt for 2 hrs and then refluxed for 3 hrs until TLC indicated the completion of the reaction. The reaction mixture was cooled and quenched with aqueous NaHC03. The solid was filtered through a celite pad and washed with EtOAc. The organic layer of the filtrate was collected, dried and concentrated to afford the corresponding aniline. To the aniline (0.05 mol) in methylene chloride (200mL) was added Et3N and (CF3CO) 20 at 0C. The reaction was allowed to warm to 25C with stirring. The reaction was then worked up between EtOAc and water. The organic layer was dried and concentrated. The residue was purified on silica gel column to afford 70. This material is dissolved in methylene chloride (100 mL) and the solution was cooled to-78C. Boron tribromide (0.1 mol) was added. The mixture was warmed to room temperature. Water was added, and the organic phase was dried and concentrated. Chromatography afforded the title compound 71.

Reference： [1]Patent: WO2005/80340,2005,A1 .Location in patent: Page/Page column 50-51

Yield	Reaction Conditions	Operation in experiment
		STR57 4-Methoxy-1-pentafluorophenylsulfonamido-3-trifluoromethylbenzene. The compound was prepared in a manner similar to that described in example 46 by replacing 3-chloroanline with 4-methoxy-3-trifluoromethylaniline which was obtained by the hydrogenation of the corresponding nitro compound. White solid, mp 121-123 C. 1 H NMR (CDCl3): d 7.43-7.37 (m, 2H), 6.96 (d, J=8.8, 1H), 3.88 (s, 3H). MS (EI): m/z 421 (16, M+), 190 (100). Anal. Calcd. for C14 H7 F8 NO3 S: C, 39.92; H, 1.67; N, 3.32; S, 7.61. Found: C, 40.17; H, 1.68; N, 3.28; S, 7.67.

16
[ 654-76-2 ]
[ 7439-89-6 ]
[ 393-15-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In ethanol; water; ethyl acetate;	EXAMPLE 1 (METHOD 1A) 4-Methoxy-3-trifluoromethyl-phenylamine A suspension of <strong>[654-76-2]4-methoxy-3-trifluoromethyl-nitrobenzene</strong> (2.2 g) and iron powder (1.68 g) in ethanol (35 mL) and water (15 mL) is treated with a solution of concentrated hydrochloric acid (0.42 mL) in ethanol (6 mL) and water (3 mL) and the mixture is heated to reflux for approximately 1 hour. The mixture is then cooled, filtered, and concentrated under reduced pressure. The resulting oil is dissolved in ethyl acetate and extracted three times with 5% aqueous hydrochloric acid. The pooled acidic extracts are then cooled in an ice bath and basified with solid potassium carbonate, then extracted with ethyl acetate. These organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, then passed through a short column of silica gel (ethyl acetate is used as the eluant) to provide the desired compound as an amber oil.

Reference： [1]Patent: US6166028,2000,A

17
[ 98-01-1 ]
copper (II) chloride monohydrate [ No CAS ]
[ 393-15-7 ]
5-(4-methoxy-3-trifluoromethylphenyl)-2-furancarboxaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With hydrogenchloride; sodium nitrite; In water; ethyl acetate;	A. & B. 4-Methoxy-3-trifluoromethylaniline (46.54 g, 0.243 mole), concentrated HCl (87 ml) and water (122 ml) were stirred together and cooled to 0. A solution of sodium nitrite (17.07 g, 0.247 mole) in water (98 ml) was added dropwise, keeping the temperature at 0-5. After the addition was complete, the reaction was stirred at 0-5 for 0.5 hours. Then, all at once, 2-furaldehyde (23.42 g, 0.244 mole) and a solution of copper (II) chloride hydrate (5.60 g) in water (37 ml) were added. The ice bath was allowed to melt gradually as the reaction stirred for 2 days. An oil which had separated was extracted into ethyl acetate (400 ml). The ethyl acetate was washed with water (2*300 ml), dried over MgSO4, treated with Darco and filtered. The solvent was evaporated in vacuo leaving behind a dark oil (55.17 g). The sample required purification by liquid chromatography (solvent: hexane:ethyl acetate 3:1). The yield of purified sample was 16.56 g (25% yield) of 5-(4-methoxy-3-trifluoromethylphenyl)-2-furancarboxaldehyde (B). The IR and NMR confirmed the structure of B.

Reference： [1]Patent: US4882354,1989,A

18
[ 321-14-2 ]
[ 393-15-7 ]
5-chloro-2-hydroxy-N-[4-methoxy-3-(trifluoromethyl)phenyl]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79.1%		Example 121 5-Chloro-2-hydroxy-N- [4-methoxy-3-(trifluoromethyl)phenyl]benzamide (Comopund No. 121). Using 5-chlorosalicylic acid and <strong>[393-15-7]4-methoxy-3-(trifluoromethyl)aniline</strong> as the raw materials, the same operation as the example 16 gave the title compound. Yield: 79.1%. 1H-NMR(DMSO-d6): delta 7.02(1H, d, J=9.0Hz), 7.30(1H, d, J=9.0Hz) 7.48(1H, dd, J=9.0, 3.0Hz), 7.92(1H, dd, J=9.0, 2.4Hz), 7.96(1H, d, J=2.7Hz), 8.04(1H, d, J=2.4Hz), 10.47(1H, s), 11.78(1H, s).

Reference： [1]Patent: EP1352650,2003,A1

19
[ 89-56-5 ]
[ 393-15-7 ]
2-hydroxy-N-[4-methoxy-3-(trifluoromethyl)phenyl]-5-methylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65.1%		Example 137 2-Hydroxy-N-[4-methoxy-3-(trifluoromethyl)phenyl]-5-methylbenzamide (Comopund No. 137). Using 5-methylsalicylic acid and <strong>[393-15-7]4-methoxy-3-(trifluoromethyl)aniline</strong> as the raw materials, the same operation as the example 16 gave the title compound. Yield: 65.1%, slight yellow solid. 1H-NMR(DMSO-d6): delta 2.35(3H, s), 3.89(3H, s), 6.88(1H, d, J=8.4Hz), 7.26(1H, dd, J=8.1, 1.8Hz), 7.30(1H, d, J=8.4Hz), 7.77(1H, d, J=2.1Hz), 7.92(1H, dd, J=9.0, 2.1Hz), 8.04(1H, d, J=2.7Hz), 10.42(1H, s), 11.54(1H, s).

Reference： [1]Patent: EP1352650,2003,A1

20
[ 393-15-7 ]
C₈H₆F₃N₂O⁽¹⁺⁾*Cl^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		<strong>[393-15-7]4-Methoxy-3-trifluoromethyl-phenylamine</strong> (5 g, 26 mmol) in 12 mL water was cooled to -5 degrees C. (Ice/Methanol bath). Conc. HCl was added dropwise (7 ml), and the reaction mixture was stirred for five minutes. A solution of NaNO2 (2.0 g, 29 mmol) dissolved in 3 ml water was added dropwise over 10 minutes, and the reaction mixture was stirred for 30 min. Sodium acetate (1.8 g, 22 mmol) was then added, and stirring was continued at -5 degrees C. In a separate flask, ethyl alpha-acetoacetate (4.55 g, 29 mmol) in 20 ml absolute ethanol was stirred, and KOH (1.6 g, 29 mmol) dissolved in 3 ml water was added, followed by ice (30 g). The resulting diazonium salt was added quickly to the reaction mixture, rinsing in with 5 ml EtOH, and the reaction mixture was stirred at zero degrees C. for 3.5 hours, then stored at -10 C) for 16 hours. The reaction mixture was warmed to room temperature and extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. Solvent was removed under reduced pressure to leave a liquid residue. In a separate flask 100 ml EtOH and 21 ml acetyl chloride were mixed, with cooling in an ice bath, then heated to 70 degrees C. The liquid residue was added via pipette over 15 minutes to the acetyl chloride solution. This reaction mixture was heated to reflux for 2.5 hours, cooled, evaporated under reduced pressure. The residue was purified by column chromatography (10% ethyl acetate/hexane) to give 3.0 g 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester, 38% as a white solid and triturated with diethyl ether to give 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (1.0 g) as a white solid, and 5-Methoxy-3-methyl-4-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (14%) as a white solid.

Reference： [1]Patent: US2007/49609,2007,A1 .Location in patent: Page/Page column 122

21
[ 393-15-7 ]
[ 199620-14-9 ]
[ 118421-23-1 ]

Reference： [1]Synthesis and Reactivity in Inorganic and Metal-Organic Chemistry,1988,vol. 18,p. 243 - 250

22
[ 508211-35-6 ]
[ 74124-79-1 ]
[ 393-15-7 ]
[ 508213-25-0 ]

Yield	Reaction Conditions	Operation in experiment
53.5%		A solution of methyl 5-amino-2-[(4-trifluoromethylphenyl)(phenyl)methoxy]benzoate (300 mg, 0.748 mmol), diisopropylethyl amine (0.149 ML, 0.898 mmol), di(N-succinimidyl) carbonate (230 mg, 0.898 mmol) and acetonitrile (9 ML) was stirred for 1 hour under ice-cooling, diisopropylethyl amine (0.149 ML, 0.898 mmol) and 5-amino-2-methoxybenzotrifluoride (172 mg, 0.898 mmol) were added to the solution under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours.. The reaction solution was poured into water, extracted with ethyl acetate, was dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 1:1), to obtain the titled compound as a solid. 247 mg (53.5%) 1H-NMR (CDCl3) delta; 3.82 (3H, s), 3.88 (3H, s), 6.24 (1H, s), 6.73 to 7.66 (17H, m)

Reference： [1]Patent: EP1437344,2004,A1 .Location in patent: Page 53

23
[ 393-15-7 ]
[ 607-97-6 ]
[ 865305-95-9 ]
[ 865305-94-8 ]

Yield	Reaction Conditions	Operation in experiment
14%; 38%		<strong>[393-15-7]4-Methoxy-3-trifluoromethyl-phenylamine</strong> (5 g, 26 mmol) in 12 mL water was cooled to -5 degrees C (Ice/Methanol bath). Conc. HCl was added dropwise (7 ml), and the reaction mixture was stirred for five minutes. A solution of NaNO2 (2.0 g, 29 mmol) dissolved in 3 ml water was added dropwise over 10 minutes, and the reaction mixture was tirred for 30 min. Sodium acetate (1.8 g, 22 mmol) was then added, and stirring was continued at -5 degrees C. In a separate flask, ethyl alpha-acetoacetate (4.55 g, 29 mmol) in 20 ml absolute ethanol was stirred, and KOH (1.6 g, 29 mmol) dissolved in 3 ml water was added, followed by ice (30 g). The resulting diazonium salt was added quickly to the reaction mixture, rinsing in with 5 ml EtOH, and the reaction mixture was stirred at zero degrees C for 3.5 hours, then stored at -10 C) for 16 hours. The reaction mixture was warmed to room temperature and extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. Solvent was removed under reduced pressure to leave a liquid residue. In a separate flask 100 ml EtOH and 21 ml acetyl chloride were mixed, with cooling in an ice bath, then heated to 70 degrees C. The liquid residue was added via pipette over 15 minutes to the acetyl chloride solution. This reaction mixture was heated to reflux for 2.5 hours, cooled, evaporated under reduced pressure. The residue was purified by colunm chromatography (10% ethyl acetate/hexane) to give 3.0 g 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester, 38% as a white solid. and triturated with diethyl ether to give 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (1.0 g) as a white solid, and 5-Methoxy-3-methyl-4-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (14% ) as a white solid.

Reference： [1]Patent: US2005/209260,2005,A1 .Location in patent: Page/Page column 144

24
[ 393-15-7 ]
[ 10397-30-5 ]
[ 1213249-78-5 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane; at 20℃;Cooling with ice;	b) Method for synthesising A-1a;:4-methyl-3-nitrobenzoic acid E-1a (1.0 g, 5.47 mmol) is taken up in thionyl chloride (5 ml_, 68.5 mmol). The reaction mixture is refluxed for 4 h. Excess thionyl chloride is distilled off and the acid chloride obtained is further used directly. 4-methoxy-3-trifluoromethylaniline E-2a (1.12 g, 5.74 mmol) is taken up in DCM (30 ml_), combined with pyridine (1.5 ml_, 18.36 mmol) and cooled in the ice bath. Then the acid chloride (1.09 g, 5.46 mmol) dissolved in 20 ml. DCM is added dropwise. The reaction mixture is stirred for 10 min in the ice bath and for 1 h at RT, diluted with water and the phases are separated. The organic phase is extracted 2 x with semisaturated KHSO4 solution, 1 x with semisaturated NaHCC>;3 solution and 1 x with saturated NaCI solution and dried on magnesium sulphate, evaporated down and the intermediate compound Z-1a (HPLC-MS: tRet = 1.95 min; MS (M+H)+ = 355) is obtained.The aromatic nitro compound Z-1a (780 mg, 2.2 mmol) is taken up in MeOH (100 ml_), combined with Pd/C (100 mg, 10 %) and hydrogenated for 4 h at 4 bar. The reaction mixture is filtered off from the catalyst and the filtrate obtained is dried using the rotary evaporator. The crude product obtained A-1a is further used directly.

Reference： [1]Patent: WO2010/94695,2010,A1 .Location in patent: Page/Page column 35-36

25
[ 1240349-52-3 ]
[ 393-15-7 ]
[ 1240348-83-7 ]

Yield	Reaction Conditions	Operation in experiment
		i) Method for synthesising Example compound III- "I :; Z-20a (100 mg, 0.27 mmol) is placed in NMP (0.8 mL), combined with DIPEA (106 mg, 0.82 mmol) and HATU (115 mg, 0.30 mmol) and stirred for 30 min at RT. The resulting active ester Z-21a is combined with 4-methoxy-3-trifluoromethylaniline E-2a (63 mg, 0.33 mmol) and stirred overnight at RT. The reaction mixture is filtered and purified by preparative HPLC. The product-containing fractions of III-1 (HPLC-MS: tRet = 2.1 1 min; MS (M+H)+ = 539) are freeze-dried.

Reference： [1]Patent: WO2010/94695,2010,A1 .Location in patent: Page/Page column 44

26
[ 919278-09-4 ]
[ 393-15-7 ]
[ 1885-14-9 ]
1-{2-chloro-4-[(5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)oxy]phenyl}-3-[4-methoxy-3-(trifluoro-methyl)phenyl]urea [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 7150 - 7163

27
3-(1,1-dimethyl-2-methylthioethylimino)-4-iodo-3H-isobenzofuran-1-one [ No CAS ]
[ 393-15-7 ]
[ 1253787-11-9 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 10999 - 11006

28
3-(1,1-dimethyl-2-methylthioethylimino)-4-iodo-3H-isobenzofuran-1-one [ No CAS ]
[ 393-15-7 ]
[ 1253787-37-9 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 10999 - 11006

29
[ 393-15-7 ]
[ 1345857-30-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6739 - 6745

30
[ 393-15-7 ]
C₂₀H₂₀F₃N₃O₂S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6739 - 6745

31
[ 393-15-7 ]
[ 110-13-4 ]
C₁₄H₁₄F₃NO [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6739 - 6745

32
C₁₈H₁₇ClN₆O₂ [ No CAS ]
[ 393-15-7 ]
[ 1213242-83-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one;	Benzoic acid Z-17a (1.1 g, 3.0 mmol) is suspended in thionyl chloride and stirred for 1 h at 60 C. The reaction mixture is evaporated down and dried azeotropically with dry toluene. The acid chloride Z-18a (400 mg, 1.04 mmol) is then taken up in a little NMP (1.2 mL) and combined with 4-methoxy-3-trifluoromethyl-phenylamine E-2a (188 mg, 1.55 mmol) and DIPEA (300 muL, 1.75 mmol). For working up water is added, the precipitate obtained is filtered off, dried and Example compound III-2 (HPLC-MS: tRet.=2.20 min; MS (M+H)+=540) is obtained.

Reference： [1]Patent: US2012/94975,2012,A1 .Location in patent: Page/Page column 71-72

33
[ 393-15-7 ]
[ 28081-52-9 ]
[ 1245749-85-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1004 - 1007

34
[ 25084-14-4 ]
[ 393-15-7 ]
[ 1418733-83-1 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 796 - 806

35
[ 1514-11-0 ]
[ 1445972-43-9 ]
[ 393-15-7 ]

Reference： [1]Organic Letters,2013,vol. 15,p. 3734 - 3737

36
[ 876-08-4 ]
[ 393-15-7 ]
[ 1569880-05-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 20℃;Reflux;	General procedure: The compound 1(4-(chloromethyl)benzoyl chloride, 12 mmol) was added dropwise to a mixture of 2a-n (10 mmol) and triethylamine (12 mmol) in dichloromethane (20 mL) at room temperature with stirring. Then the reaction mixture was refluxed for 4-6 h. After cooling to room temperature, the mixture was slowly poured to ice water (50 mL). The solution was extracted with dichloromethane (3×60 mL) and the organic phase was dried over with sodium sulfate anhydrous. After removal of the dichloromethane, the solid residue was purified by recrystallization with petroleum ether-ethyl acetate to give compounds 3a-n.

Reference： [1]Chemical and Pharmaceutical Bulletin,2013,vol. 61,p. 1099 - 1104

37
[ 393-15-7 ]
[ 1569880-71-2 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2013,vol. 61,p. 1099 - 1104

38
[ 393-15-7 ]
[ 1569880-32-5 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2013,vol. 61,p. 1099 - 1104

39
[ 32315-10-9 ]
[ 393-15-7 ]
[ 72084-11-8 ]
[ 1608118-09-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 2118 - 2122

40
[ 882679-22-3 ]
[ 393-15-7 ]
3-iodo-N-(4-methoxy-3-(trifluoromethyl)phenyl)-4-methyl-2-nitrobenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 1426 - 1441

41
[ 393-15-7 ]
2-amino-3-iodo-N-(4-methoxy-3-(trifluoromethyl)phenyl)-4-methylbenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 1426 - 1441

42
[ 393-15-7 ]
2-amino-N-(4-methoxy-3-(trifluoromethyl)phenyl)-4-methyl-3-(2-(methylamino)quinazolin-6-yl)benzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 1426 - 1441

43
[ 393-15-7 ]
[ 149-73-5 ]
4-methoxy-N-methyl-3-(trifluoromethyl)aniline [ No CAS ]

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

44
[ 393-15-7 ]
1-(4-methoxy-3-(trifluoromethyl)phenyl)-1-methyl-3-(naphthalen-1-yl)guanidine [ No CAS ]

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

45
[ 393-15-7 ]
[ 6484-27-1 ]
N-(4-methoxy-3-(trifluoromethyl)phenyl)-2-(pyridin-4-yl)-quinazolin-4-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 4474 - 4495

46
4-chloro-2-(3,4-dimethoxyphenyl)quinazoline [ No CAS ]
[ 393-15-7 ]
2-(3,4-dimethoxyphenyl)-N-(4-methoxy-3-(trifluoromethyl)phenyl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	In isopropyl alcohol; at 110℃;Sealed tube; Microwave irradiation;	General procedure: The corresponding 4-chloroquinazoline derivative 8-14(1 mmol) was added to isopropanol (5 mL) with the correspondingsubstituted aniline derivative (1 mmol) and sealed in a microwavetube. The mixture was heated by 100 W microwave irradiation to110 C for a period of 15-30 min to completion of the reaction,indicated by TLC. The formed precipitate was filtered, washed with10 mL isopropanol and dried in vacuo. If no precipitate is formed,the solvent was removed under reduced pressure and theremaining solid recrystallized from ethanol.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 139,p. 587 - 611

47
[ 393-15-7 ]
[ 93256-31-6 ]
N-(4-methoxy-3-(trifluoromethyl)phenyl)-2-(3-nitrophenyl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	In isopropyl alcohol; at 110℃;Sealed tube; Microwave irradiation;	General procedure: The corresponding 4-chloroquinazoline derivative 8-14(1 mmol) was added to isopropanol (5 mL) with the correspondingsubstituted aniline derivative (1 mmol) and sealed in a microwavetube. The mixture was heated by 100 W microwave irradiation to110 C for a period of 15-30 min to completion of the reaction,indicated by TLC. The formed precipitate was filtered, washed with10 mL isopropanol and dried in vacuo. If no precipitate is formed,the solvent was removed under reduced pressure and theremaining solid recrystallized from ethanol.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 139,p. 587 - 611

48
[ 1171919-75-7 ]
[ 393-15-7 ]
tert-butyl (3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate [ No CAS ]
[ 530-62-1 ]
(R)-tert-butyl 3-(5-(4-methoxy-3-(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21.7%		To a microwave vial with a stir bar were added 2-chloro-4-iodonicotinonitrile (520 mg, 2.0 mmol), 4-methoxy-3- (trifluoromethyl)aniline (369 mg, 1.93 mmol), DPEPhos (31 mg, 0.058 mmol), Pd(OAc)2(9.9 mg, 0.044 mmol), and CS2CO3(924 mg, 2.84 mmol). The vial was treated with dioxane (4 mL) via syringe, and the entire mixture was degassed under vacuum for 1 minute, and then vented to nitrogen. The reaction mixture was heated in the microwave at 150 C for 30 minutes. The reaction was then cooled to room temperature, treated with fert-butyl (3R)-3-[(2- sulfanylacetyl)amino]piperidine-1-carboxylate (Intermediate 22) (0.49 M in dioxane, 522 mg, 1.90 mmol) via syringe, evacuated and flushed with nitrogen, and stirred at 150 C for 20 min. The reaction was then cooled to room temperature. The reaction mixture was then treated with solid CDI (1.195 g, 7.368 mmol) in one portion under air, resealed and evacuated and flushed with nitrogen, and stirred at 150 C for 20 min. The reaction was diluted with EtOAc (100 mL) and saturated aqueous sodium bicarbonate (100 mL), and the organic phase was collected. The aqueous layer was extracted again with EtOAc (100 mL), and the combined organics were dried over anhydrous MgSC>4, concentrated to dryness, and purified by flash column chromatography to give the title compound (252 mg, 21.7% yield).
21.7%		To a microwave vial with a stir bar were added 2-chloro-4-iodonicotinonitrile (520 mg, 2.0 mmol) , 4-methoxy-3- (trifluoromethyl) aniline (369 mg, 1.93 mmol) , DPEPhos (31 mg, 0.058 mmol) , Pd (OAc)2(9.9 mg, 0.044 mmol) , and Cs2CO3(924 mg, 2.84 mmol) . The vial was treated with dioxane (4 mL) via syringe, and the entire mixture was degassed under vacuum for 1 minute, and then vented to nitrogen. The reaction mixture was heated in the microwave at 150 for 30 minutes. The reaction was then cooled to room temperature, treated with tert-butyl (3R) -3- [ (2-sulfanylacetyl) amino] piperidine-1-carboxylate (Intermediate 22) (0.49 M in dioxane, 522 mg, 1.90 mmol) via syringe, evacuated and flushed with nitrogen, and stirred at 150 for 20 min. The reaction was then cooled to room temperature. The reaction mixture was then treated with solid CDI (1.195 g, 7.368 mmol) in one portion under air, resealed and evacuated and flushed with nitrogen, and stirred at 150 for 20 min. The reaction was diluted with EtOAc (100 mL) and saturated aqueous sodium bicarbonate (100 mL) , and the organic phase was collected. The aqueous layer was extracted again with EtOAc (100 mL) , and the combined organics were dried over anhydrous MgSO4, concentrated to dryness, and purified by flash column chromatography to give the title compound (252 mg, 21.7yield) .

Reference： [1]Patent: WO2017/100668,2017,A1 .Location in patent: Page/Page column 476
[2]Patent: WO2018/103058,2018,A1 .Location in patent: Page/Page column 496

49
[ 1514-11-0 ]
[ 393-15-7 ]

Reference： [1]Nature Chemistry,2017,vol. 9,p. 681 - 688

50
[ 393-15-7 ]
4-(trifluoromethyl)-1H-indazol-5-ol [ No CAS ]