[ CAS No. 368-53-6 ]

Name: 368-53-6|5-(Trifluoromethyl)benzene-1,3-diamine|98%
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Quality Control of [ 368-53-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 368-53-6 ]

Product Details of [ 368-53-6 ]

CAS No. :	368-53-6	MDL No. :	MFCD00014776
Formula :	C₇H₇F₃N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KZSXRDLXTFEHJM-UHFFFAOYSA-N
M.W :	176.14	Pubchem ID :	67781
Synonyms :

Calculated chemistry of [ 368-53-6 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	40.25
TPSA :	52.04 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.95 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.04
Log Po/w (XLOGP3) :	2.0
Log Po/w (WLOGP) :	3.04
Log Po/w (MLOGP) :	1.91
Log Po/w (SILICOS-IT) :	1.41
Consensus Log Po/w :	1.88

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.5
Solubility :	0.562 mg/ml ; 0.00319 mol/l
Class :	Soluble
Log S (Ali) :	-2.72
Solubility :	0.336 mg/ml ; 0.00191 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.56
Solubility :	0.482 mg/ml ; 0.00274 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.26

Safety of [ 368-53-6 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338	UN#:	3259
Hazard Statements:	H302-H318	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 368-53-6 ]

* 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 [ 368-53-6 ]
Downstream synthetic route of [ 368-53-6 ]

[ 368-53-6 ] Synthesis Path-Upstream 1~2

1
[ 368-53-6 ]
[ 535-87-5 ]

Reference： [1] Photochemistry and Photobiology, 2005, vol. 81, # 6, p. 1539 - 1543

2
[ 368-53-6 ]
[ 401-84-3 ]

Reference： [1] Chemical Communications, 2015, vol. 51, # 95, p. 16912 - 16915

[ 368-53-6 ] Synthesis Path-Downstream 1~68

1
[ 401-99-0 ]
[ 368-53-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen;palladium 10% on activated carbon; In methanol; ethyl acetate; at 20℃; under 760.051 Torr; for 20h;	Example 170 1-(3-Dimethylamino-5-(trifluoromethyl)phenyl)-3-[4-(6-(methylamino)purin-9-yl)phenyl]urea (Table 2, Compound No. 48) Step A Preparation of 5-(trifluoromethyl)benzene-1,3-diamine [Show Image] In a mixed solvent of 10 mL of ethyl acetate and 1 mL of methanol, 500 mg (2.12 mmol) of 3,5-dinitrobenzotrifluoride was dissolved, and 20 mg of 10% palladium carbon was added thereto, and the mixture solution was stirred at room temperature for 20 hours in a hydrogen atmosphere at normal pressures. The catalyst was removed by filtration, and the filtrate was concentrated and dried to obtain 380 mg (100%) of a brown oily target product. ESI (LC-MS positive mode) m/z 177 (M+H)

Reference： [1]Patent: EP1724258,2006,A1 .Location in patent: Page/Page column 158
[2]Photochemistry and Photobiology,2005,vol. 81,p. 1539 - 1543
[3]Journal of the Chemical Society,1949,p. 3016,3019
[4]Zhurnal Prikladnoi Khimii,1955,vol. 28,p. 969,972
Chem.Abstr.,1956,p. 4880

2
[ 368-53-6 ]
[ 349-61-1 ]

Reference： [1]Journal of the Chemical Society,1949,p. 3016,3019

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 1 A solution of 4-chloro-3,5-dinitrobenzotrifluoride (DTI) (5.41g, 0.02 mol) in ethyl acetate (40 mL) was charged in a Parr hydrogenator bottle and mixed with sodium acetate (1.64g, 0.02 mol), and 5% Pd/C (0.5g). After purging with nitrogen, hydrogen was charged periodically in the reaction bottle to maintain its pressure at 50 psig. The temperature inside the reactor was maintained at 40 C. for 4 hours. After this duration, analysis of the reaction mixture by gas chromatography showed formation of 62.4% 3,5-diaminobenzotrifluoride (DABTF) and 34.9% 4-chloro-3,5-diaminobenzotrifluoride (CDABTF).
		EXAMPLE 2 A solution of 4-chloro-3,5-dinitrobenzotrifluoride (DTI) (5.41g, 0.02 mol) in ethyl acetate (40 mL) was charged in a Parr hydrogenator bottle and mixed with sodium acetate (1.64g, 0.02 mol), and 5% Pd/C (0.5g). After purging with nitrogen, hydrogen was charged periodically in the reaction bottle to maintain its pressure at 50 psig. The temperature inside the reactor was maintained at 100 C. for 1.2 hours. After this duration, analysis of the reaction mixture by gas chromatography showed formation of 86.2% 3,5-diaminobenzotrifluoride (DABTF).
		EXAMPLE 3 A solution of 4-chloro-3,5-dinitrobenzotrifluoride (DTI) (5.41g, 0.02 mol) in ethyl acetate (40 mL) was charged in a Parr hydrogenator bottle and mixed with sodium acetate (2.46g, 0.03 mol), and 5% Pd/C (0.5g). After purging with nitrogen, hydrogen was charged periodically in the reaction bottle to maintain its pressure at 50 psig. The temperature inside the reactor was maintained at 100 C. for 1 hours. After this duration, analysis of the reaction mixture by gas chromatography showed formation of 94.9% 3,5-diaminobenzotrifluoride (DABTF) and 1.3% 4-chloro-3,5-diaminobenzotrifluoride (CDABTF).

EXAMPLE 4 The reaction of Example 3 was repeated except that anhydrous sodium carbonate (3.18g, 0.03 mol) was used instead of sodium acetate. After heating the reaction mixture for 1 hour at 100 C., analysis of the reaction mixture by gas chromatography showed formation of 89.8% 3,5-diaminobenzotrifluoride (DABTF) and 7.2% 4-chloro-3,5-diaminobenzotrifluoride (CDABTF).

4
[ 368-53-6 ]
[ 75-36-5 ]
[ 455279-96-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 28 - 33

5
[ 368-53-6 ]
C₁₄H₁₃F₃N₄O [ No CAS ]
C₁₄H₁₄N₄O₃ [ No CAS ]
C₂₁H₁₉F₃N₆O₂ [ No CAS ]
[ 535-87-5 ]

Reference： [1]Photochemistry and Photobiology,2005,vol. 81,p. 1539 - 1543

6
[ 368-53-6 ]
[ 108-24-7 ]
[ 349-61-1 ]

Reference： [1]Photochemistry and Photobiology,2005,vol. 81,p. 1539 - 1543

7
[ 67-56-1 ]
[ 368-53-6 ]
[ 1949-55-9 ]

Reference： [1]Photochemistry and Photobiology,2005,vol. 81,p. 1539 - 1543

8
[ 368-53-6 ]
[ 955938-65-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 28 - 33

9
[ 368-53-6 ]
[ 955957-00-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 28 - 33

10
[ 368-53-6 ]
[ 955958-93-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 28 - 33

11
[ 368-53-6 ]
[ 955955-98-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 28 - 33

12
[ 368-53-6 ]
[ 955959-18-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 28 - 33

13
[ 368-53-6 ]
N-adamantan-1-yl-3-(4-cyano-3-hydroxy-isothiazol-5-ylamino)-5-trifluoromethyl-benzenesulfonamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 28 - 33

14
[ 477592-86-2 ]
[ 368-53-6 ]
[ 702672-62-6 ]
[ 702674-91-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; water; In 1,4-dioxane; acetonitrile;Heating / reflux;	To a suspension of 5- (TRIFLUOROMETHYL)-1, 3-diaminobenzene (105 mg, 0.6 mmol, 1.2 equiv. ) in ACETONITRILE (10 mL), hydrogen chloride (4. 0M in dioxane, 0.15 mL. 0.6 MMOL) and water (0.15 mL) was added 5-bromo-2-chloro-N [2- (1H-imidazol-4- YL) ETHYL]-4-PYRIMIDINE (150 MG, 0.5 mmol, 1 equiv. ). The resulting mixture was REFLUXED overnight. The resulting white suspension was cooled to room temperature and concentrated. The crude residue was purified by HPLC chromatography using acetonitrile/water to afford the title compounds, N2-(3- AMINO-5-(TRIFLUOROMETHYL) PHENYL)-5-BROMO-N4-(2-(1H-IMIDAZOL4-YL) ETHYL)-2, 4- pyrimidinediamine (50 mg) and N-(3-((5-bromo-4-((2-(1H-imidazol-4- yl) ETHYL) AMINO)-2-PYRIMIDINYL) AMINO)-5- (TRIFLUOROMETHYL) PHENYL)-ETHANIMIDAMIDE (22 MG). <P>N2- (3-AMINO-5- (TRIFLUOROMETHYL) PHENYL)-5-BROMO-/V4- (2- (LH-IMIDAZOL-4- yl) ethyl)-2, 4-pyrimidinediamine :'H NMR (400 MHz, DMSO-D6) : O/PPM = 2.96 (t, 2H), 3.64 (t, 2H), 6.42 (s, 1H), 7.01 (s, 1H), 7.24 (BR T, 1 H), 7.44 (d, 2H), 8.06 (s, 1 H), 8.97 (s, 1 H), 9.39 (s, 1 H). N-(3-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl)amino)-2-pyrimidinyl)amino)-5- (trifluoromethyl) phenyl)-ethanimidamide :'H NMR (400 MHz, DMSO-d6) : O/PPM = 2.32 (s, 3H), 2.97 (m, 2H), 3.68 (m, 2H), 7.18 (s, 1H), 7.32 (m, 1H), 7.43 (s, 1H), 7.79 (s, 1 H), 8.13 (s, 1H), 8.36 (s, 1 H), 8.71 (s, 1H), 8.99 (s, 1H), 9.56 (s, 1 H), 9.92 (s, 1 H), 11.34 (s, 1 H).

Reference： [1]Patent: WO2004/48343,2004,A1 .Location in patent: Page 88; 89

15
[ 368-53-6 ]
[ 3173-56-6 ]
N-(3-amino-5-(trifluoromethyl)phenyl)-(benzylamino)carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In methanol; ethyl acetate; acetonitrile;	Step A N-(3-amino-5-(trifluoromethyl)phenyl) (benzylamino)carboxamide To a solution of <strong>[368-53-6]1-trifluoromethyl-3,5-diaminobenzene</strong> (5 g, 0.028 mol) in 25 mL of acetonitrile and acetic acid (0.5 mL) was added a solution of benzyl isocyanate (3.5 mL, 0.028 mol) in acetonitrile (25 mL). The reaction was allowed to stirred at room temperature for 10 hours. The reaction mixture was diluted with EtOAC and washed with saturated NaHCO3, then brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The product was purified by silica gel chromatograph (EtOAc to 10% MeOH/EtOAc). MS (ES+): 310.5 (M+H)+.

Reference： [1]Patent: US2002/19402,2002,A1

16
[ 393-75-9 ]
[ 368-53-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium formate; sodium acetate;palladium-carbon; In acetic acid;	EXAMPLE 1 Preparation of 3,5DABTF Under Anhydrous Conditions Sodium formate (12.24 g) was added to a mixture of 4-chloro-3,5-dinitrobenzotrifluoride (5.41 g), sodium acetate (1.64 g) and 5% Pd/C (0.5 g) in glacial acetic acid (60 mL). The mixture was stirred and the resultant exotherm, which lasted about an hour, was controlled by cooling to maintain a reaction temperature of about 40 C. As the exotherm subsided, external heating was applied to maintain the temperature at about 40 C. Gas chromatographic analysis of the reaction mixture, at the end of one hour, indicated diaminobenzotrifluoride as the major component (35%) with no 4-chloro-3,5-dinitrobenzotrifluoride remaining. The maximum amount (about 45%) of 3,5-diaminobenzotrifluoride formed after 2 hours after which it was converted to other undesirable products.
	With hydrogen;Pd on carbon; palladium; In methanol; water;	Example 1 A solution of 4-chloro-3,5-dinitrobenzotrifluoride (10 g) in methanol (100 mL) was charged in a Parr hydrogenator bottle and mixed with magnesium oxide (1.6 g--two equivalents based upon 4-chloro-3,5-dinitrobenzotrifluoride) and with a carbon supported palladium catalyst (5% Pd on carbon containing 50% water, 1.2 g wet weight). After purging with nitrogen, hydrogen was charged periodically in the reaction bottle to maintain its pressure at 40-50 psig. The reaction temperature began at approximately 20 C. and began to rise as soon as the agitation began. In eight minutes, the temperature rose to 87 C. and was held at 80 C. for 1.5 hours. The reaction mixture was then allowed to cool to room temperature over approximately 42 minutes. After the reaction, analysis of the reaction mixture by gas chromatography showed formation of 6.29 g of 3,5-diaminobenzotrifluoride and no 4-chloro-3,5-diaminobenzotrifluoride was detectable. The yield of 3,5-diaminobenzotrifluoride was 97% based upon starting material.
	With hydrogen;palladium; In pyrographite; isopropyl alcohol;	Comparative Example 5 A solution of 4-chloro-3,5-dinitrobenzotrifluoride (15.0g) in isopropanol (150 mL) was charged in a Parr hydrogenator bottle and mixed with 1.5g of carbon supported palladium catalyst (5% Pd/C). After purging with nitrogen, hydrogen was charged periodically in the reaction bottle to maintain its pressure at 50 psig. The reaction temperature in the hydrogenator was kept at 45-100 C for 1 hour and then at 100 C. for 2.5 hours. After this duration, the analysis of the reaction mixture by gas chromatography showed formation of 38.5% 3,5-diaminobenzotrifluoride (DABTF) and 59.5% 4-chloro-3,5-diaminobenzotrifluoride (CDABTF).

With hydrogen;palladium; In pyrographite; isopropyl alcohol;

Comparative Example 7 A solution of 4-chloro-3,5-dinitrobenzotrifluoride (5.Og) in isopropanol (50 mL) was charged in a Parr hydrogenator bottle and mixed with 0.5g of carbon supported palladium catalyst (5% Pd/C). After purging with nitrogen, hydrogen was charged periodically in the reaction bottle to maintain its pressure at 50 psig. The reaction temperature in the hydrogenator was kept at 50 C. for 4.5 hours and then at 75 C. for 2 hours. After this duration, the analysis of the reaction mixture by gas chromatography showed formation of 23.7% 3,5-diaminobenzotrifluoride (DABTF) and 73.3% 4-chloro-3,5-diaminobenzotrifluoride (CDABTF).

Reference： [1]Patent: US5336808,1994,A
[2]Patent: US5347052,1994,A
[3]Patent: US5144076,1992,A
[4]Patent: US5144076,1992,A

17
[ 393-75-9 ]
[ 34207-44-8 ]
[ 368-53-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;Pd on carbon; palladium; In methanol; water;	Example 2 A solution of 4-chloro-3,5-dinitrobenzotrifluoride (10 g) in methanol (100 mL) was charged in a Parr hydrogenator bottle and mixed with magnesium oxide (3.0 g--four equivalents based upon 4-chloro-3,5-dinitrobenzotrifluoride) and with a carbon supported palladium catalyst (5% Pd on carbon containing 50% water, 1.2 g wet weight). After purging with nitrogen, hydrogen was charged periodically in the reaction bottle to maintain its pressure at 40-50 psig. The reaction began at 20 C. and began to rise as soon as agitation began. The temperature rose to 72 C. in fourteen minutes. The reaction mixture was held at 75 C. for twenty-two minutes and then allowed to cool to room temperature over a period of 28 minutes. After the reaction, analysis of the reaction mixture by gas chromatography showed formation of 6.1 g of 3,5-diaminobenzotrifluoride and 0.28 g of 4-chloro-3,5-diaminobenzotrifluoride. The yield of 3,5-diaminobenzotrifluoride was 94% based upon starting material.
	With hydrogen;Pd on carbon; palladium; In methanol; water; pyrographite;	Comparative Example 9 The hydrogenation was run in methanol without any base. A solution of 4-chloro-3,5-dinitrobenzotrifluoride (10 g) in methanol (100 mL) was charged in a Parr hydrogenator bottle and mixed with a carbon supported palladium catalyst (5% Pd on carbon containing 50% water, 1.2 g wet weight). After purging with nitrogen, hydrogen was charged periodically in the reaction bottle to maintain its pressure at 40-50 psig. The reaction began at 20 C. and began to rise as soon as agitation began. The temperature rose to 76 C. in seven minutes. The reaction mixture was held at 80 C. for two hours and then allowed to cool to room temperature over a period of 30 minutes. After the reaction, analysis of the reaction mixture by gas chromatography showed formation of 2.85 g of 3,5-diaminobenzotrifluoride and 0.76 g of 4-chloro-3,5-diaminobenzotrifluoride. The yield of 3,5-diaminobenzotrifluoride based upon starting material was 44% which indicates that there is an appreciable amount of product not detected by gas chromatography.
	With hydrogen;Pd on carbon; palladium; In methanol; water;	Example 3 A solution of 4-chloro-3,5-dinitrobenzotrifluoride (20 g) in methanol (200 mL) was charged in a Parr hydrogenator bottle and mixed with magnesium oxide (3.2 g--two equivalents based upon 4-chloro-3,5-dinitrobenzotrifluoride) and with a carbon supported palladium catalyst (5% Pd on carbon containing 50% water, 1.2 g wet weight). After purging with nitrogen, hydrogen was charged periodically in the reaction bottle to maintain its pressure at 40-50 psig. The reaction temperature began at approximately 19 C. and began to rise as soon as the agitation began. In eighteen minutes, the temperature rose to 94 C. and was held at 80 C. for 2 hours. The reaction mixture was then allowed to cool to room temperature over approximately 85 minutes. After the reaction, analysis of the reaction mixture by gas chromatography showed formation of 12.9 g of 3,5-diaminobenzotrifluoride and 0.06 g of 4-chloro-3,5-diaminobenzotrifluoride. The yield of 3,5-diaminobenzotrifluoride was 99% based upon starting material.

	With hydrogen;Pd on carbon; palladium; In methanol; water;	Example 4 A solution of 4-chloro-3,5-dinitrobenzotrifluoride (10 g) in methanol (100 mL) was charged in a Parr hydrogenator bottle and mixed with magnesium oxide (0.8 g--one equivalent based upon 4-chloro-3,5-dinitrobenzotrifluoride) and with a carbon supported palladium catalyst (5% Pd on carbon containing 50% water, 1.2 g wet weight). After purging with nitrogen, hydrogen was charged periodically in the reaction bottle to maintain its pressure at 40-50 psig. The reaction temperature began at approximately 20 C. and began to rise as soon as the agitation began. In seven minutes, the temperature rose to 84 C. and was held at 80 C. for 73 minutes. The reaction mixture was then allowed to cool to room temperature over approximately 30 minutes. After the reaction, analysis of the reaction mixture by gas chromatography showed formation of 5.81 g of 3,5-diaminobenzotrifluoride and 0.04 g of 4-chloro-3,5-diaminobenzotrifluoride. The yield of 3,5-diaminobenzotrifluoride was 89% based upon starting material.
	With hydrogen;Pd on carbon; palladium; In methanol; water;	Example 5 A solution of 4-chloro-3,5-dinitrobenzotrifluoride (10 g) in methanol (60 mL) was charged in a Parr hydrogenator bottle and mixed with magnesium oxide (1.6 g--two equivalents based upon 4-chloro-3,5-dinitrobenzotrifluoride) and with a carbon supported palladium catalyst (5% Pd on carbon containing 50% water, 1.2 g wet weight). After purging with nitrogen, hydrogen was charged periodically in the reaction bottle to maintain its pressure at 40-50 psig. The reaction temperature began at approximately 22 C. and began to rise as soon as the agitation began. In thirteen minutes, the temperature rose to 80 C. and was held at 80 C. for 1.5 hours. The reaction mixture was then allowed to cool to room temperature and removed in approximately 108 minutes. After the reaction, analysis of the reaction mixture by gas chromatography showed formation of 5.65 g of 3,5-diaminobenzotrifluoride and 0.08 g of 4-chloro-3,5-diaminobenzotrifluoride. The yield of 3,5-diaminobenzotrifluoride was 87% based upon starting material.
	With hydrogen;Pd on carbon; palladium; In methanol; water;	Example 6 A solution of 4-chloro-3,5-dinitrobenzotrifluoride (10 g) in methanol (60 mL) was charged in a Parr hydrogenator bottle and mixed with magnesium oxide (1.6 g--two equivalents based upon 4-chloro-3,5-dinitrobenzotrifluoride) and with a carbon supported palladium catalyst (5% Pd on carbon containing 50% water, 0.8 g wet weight). After purging with nitrogen, hydrogen was charged periodically in the reaction bottle to maintain its pressure at 40-50 psig. The reaction temperature began at approximately 20 C. and began to rise as soon as the agitation began. In six minutes, the temperature rose to 80 C. and was held at 80 C. for 1 hours. The reaction mixture was then allowed to cool to room temperature over approximately 30 minutes. After the reaction, analysis of the reaction mixture by gas chromatography showed formation of 5.84 g of 3,5-diaminobenzotrifluoride and 0.48 g of 4-chloro-3,5-diaminobenzotrifluoride. The yield of 3,5-diaminobenzotrifluoride was 90% based upon starting material.
	With hydrogen;Pd on carbon; palladium; In methanol; water;	Example 7 A solution of 4-chloro-3,5-dinitrobenzotrifluoride (10 g) in methanol (100 mL) was charged in a Parr hydrogenator bottle and mixed with magnesium oxide (1.6 g--two equivalents based upon 4-chloro-3,5-dinitrobenzotrifluoride) and with a carbon supported palladium catalyst (5% Pd on carbon containing 50% water, 0.8 g wet weight). After purging with nitrogen, hydrogen was charged periodically in the reaction bottle to maintain its pressure at 40-50 psig. The reaction temperature began at approximately 20 C. and began to rise as soon as the agitation began. In ten minutes, the temperature rose to 83 C. and was held at 80 C. for 105 minutes. The reaction mixture was then allowed to cool to room temperature over approximately 32 minutes. After the reaction, analysis of the reaction mixture by gas chromatography showed formation of 6.23 g of 3,5-diaminobenzotrifluoride and 0.03 g of 4-chloro-3,5-diaminobenzotrifluoride. The yield of 3,5-diaminobenzotrifluoride was 96% based upon starting material.
	With sodium hydroxide; hydrogen;palladium; In methanol; pyrographite;	Comparative Example 1 A solution of 10 g of 4-chloro-3,5-dinitrobenzotrifluoride in methanol (100 mL) was charged in a Parr hydrogenator bottle and mixed with 1.2 g of carbon supported palladium catalyst (5% Pd on carbon--50% wet) and 1.5 g of sodium hydroxide. After purging with nitrogen, hydrogen was charged periodically in the reaction bottle to maintain its pressure at 40-50 psig. The reaction temperature began at approximately 24 C. and began to rise as soon as the agitation began. In twenty-nine minutes, the temperature rose to 79 C. and was held at 80 C. for 24 minutes. The reaction mixture was then allowed to cool to room temperature over approximately 20 minutes. After the reaction, the analysis of the mixture by gas chromatography showed the formation of 1.19 g of 3,5-diaminobenzotrifluoride, and 0.113 g of 4-chloro-3,5-diaminobenzotrifluoride. The yield of 3,5-diaminobenzotrifluoride was 31% based upon starting material.

Reference： [1]Patent: US5347052,1994,A
[2]Patent: US5347052,1994,A
[3]Patent: US5347052,1994,A
[4]Patent: US5347052,1994,A
[5]Patent: US5347052,1994,A
[6]Patent: US5347052,1994,A
[7]Patent: US5347052,1994,A
[8]Patent: US5347052,1994,A

18
[ 368-53-6 ]
[ 407-25-0 ]
[ 863675-98-3 ]

Yield	Reaction Conditions	Operation in experiment
25%	With pyridine; In dichloromethane; at 0℃; for 1h;	Step B Preparation of N-(3-amino-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroacetamide [Show Image] In dichloromethane, 370 mg (2.10 mmol) of <strong>[368-53-6]5-(trifluoromethyl)benzene-1,3-diamine</strong> and 0.25 ml (3.15 mmol) of pyridine were dissolved and the solution was cooled on an ice bath. To this solution, 0.293 ml (2.10 mmol) of trifluoroacetic anhydride was slowly added, and at that temperature the mixture solution was stirred for one hour. The reaction solution was poured into water and extracted with ethyl acetate and the extract was purified by silica gel column chromatography to obtain 138 mg (25%) of a pale yellow oily target product. ESI (LC-MS positive mode) m/z 273 (M+H)

Reference： [1]Patent: EP1724258,2006,A1 .Location in patent: Page/Page column 158-159

19
[ 368-53-6 ]
[ 199620-14-9 ]
[ 118073-80-6 ]

Reference： [1]Synthesis and Reactivity in Inorganic and Metal-Organic Chemistry,1987,vol. 17,p. 849 - 856

20
[ 24424-99-5 ]
[ 368-53-6 ]
[ 795307-83-4 ]

Yield	Reaction Conditions	Operation in experiment
68%		(24a) A solution of 5-trifluoromethyl-benzene-1,3-diamine (1.0 g, 5.8 mmol) in THF (25 mL) was cooled to -78 C. and treated with NaHMDS (12 mL of a 1.0 M THF solution, 12 mmol). The solution was stirred for 1 h at -78 C. and then charged with a solution of di-(tert-butyl)dicarbonate (1.3 g, 5.8 mmol) in THF (10 mL); the reaction was allowed to warm to RT in the melting cold bath while stirring for 12 h. The mixture was concentrated in vacuo and the residue was dissolved in EtOAc. This solution was washed with 1N HCl (3×), H2O (2×), and brine (1×) before being dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified via flash chromatography to afford (3-amino-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (1.1 g, 68% yield). 1H-NMR (CD3OD, 300 MHz): delta 1.51 (s, 9H), 6.57 (s, 1H), 6.96 (s, 1H), 6.99 (s, 1H); 19F-NMR (CD3OD, 300 MHz): delta-64.95 (s)
60%		(24a) A solution of 5-trifluoromethyl-benzene-1, 3-diamine (1.0 g, 5. 8 mmol) in THF (25 ML) was cooled TO-78 C and treated with NAHMDS (12 mL of a 1.0 M THF solution, 12 mmol). The solution was stirred for 1 h AT-78 C and then charged with a solution of DI- (TERT- butyl) DICARBONATE (1.3 g, 5. 8 mmol) in THF (10 ML) ; the reaction was allowed to warm to RT in the melting cold bath while stirring for 12 h. The mixture was concentrated in vacuo and the residue was dissolved in EtOAc. This solution was washed with 1N HCl (3x), H20 (2X), and brine (lx) before being dried (NA2SO4), filtered, and concentrated in vacuo. The residue was purified via flash chromatography to afford (3-amino-5- trifluoromethyl-phenyl) -carbamic acid TERT-BUTYL ester (1. 1 g, 68% YIELD). LH-NMR (CD30D, 300 MHz): 6 1. 51 (s, 9H), 6.57 (s, 1H), 6.96 (s, 1H), 6.99 (s, 1H) ; 19F-NMR (CD30D, 300 MHZ) : 8-64. 95 (s).

Reference： [1]Patent: US2005/43392,2005,A1 .Location in patent: Page/Page column 30
[2]Patent: WO2005/21499,2005,A1 .Location in patent: Page/Page column 145-146

21
aq. NH₄Cl [ No CAS ]
[ 368-53-6 ]
[ 124-63-0 ]
[ 873056-09-8 ]

Yield	Reaction Conditions	Operation in experiment
	In pyridine;	Example 7 D-19; N-(3-Amino-5-trifluoromethyl-phenyl)-methanesulfonamide A solution of 5-trifluoromethyl-benzene-1,3-diamine (250 mg, 1.42 mmol) in pyridine (0.52 mL) and CH2Cl2 (6.5 mL) was cooled to 0 C. Methanesulfonyl chloride (171 mg, 1.49 mmol) was slowly added at such a rate that the temperature of the solution remained below 10 C. The mixture was stirred at 8 C. and then allowed to warm to room temperature after 30 min. After stirring at room temperature for 4 h, reaction was almost complete as indicated by LCMS analysis. The reaction mixture was quenched with sat. aq. NH4Cl (10 mL) solution, extracted with CH2Cl2 (4*10 mL), dried over Na2SO4, filtered, and concentrated to yield N-(3-amino-5-trifluoromethyl-phenyl)-methanesulfonamide (D-19) as a reddish semisolid (0.35 g, 97%), which was used without further purification. 1H-NMR (CDCl3, 300 MHz) delta 6.76 (m, 1H), 6.70 (m, 1H), 6.66 (s, 1H), 3.02 (s, 3H); ESI-MS 255.3 m/z (MH+).

Reference： [1]Patent: US2011/98311,2011,A1

22
[ 160956-25-2 ]
[ 368-53-6 ]
[ 1392480-50-0 ]

Reference： [1]Journal of Porphyrins and Phthalocyanines,2012,vol. 16,p. 175 - 182

23
[ 160956-25-2 ]
[ 368-53-6 ]
[ 1392480-52-2 ]

Reference： [1]Journal of Porphyrins and Phthalocyanines,2012,vol. 16,p. 175 - 182

24
[ 1394321-86-8 ]
[ 368-53-6 ]
[ 1394320-92-3 ]

Yield	Reaction Conditions	Operation in experiment
	In butan-1-ol;Reflux;	A solution of (S)-3-(4-{3-[2-(benzyloxy)ethylamino]pyrrolidin-1-yl}-6-propylpyrimidin-2-ylamino)benzonitrile (60 mg, 0.13 mmol) prepared in Example 145, palladium/charcoal (12 mg, 10 wt%) and a catalytic amount of conc. HCl in methanol (6.0 ml) was stirred at room temperature under hydrogen atmosphere overnight and then filtered through a celite pad. The resulting filtrate was concentrated under reduced pressure.

Reference： [1]Patent: WO2012/115480,2012,A2 .Location in patent: Page/Page column 81

25
[ 1394808-05-9 ]
[ 368-53-6 ]
(R)-N¹-[4-(3-aminopiperidin-1-yl)-6-propylpyrimidin-2-yl]-5-(trifluoromethyl)benzene-1,3-diamine dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of (R)-tert-butyl [1-(2-chloro-6-propylpyrimidin-4-yl)piperidin-3-yl]carbamate (82 mg, 0.23 mmol) prepared in Preparation 26 and <strong>[368-53-6]5-(trifluoromethyl)benzene-1,3-diamine</strong> (44 mg, 0.25 mmol) in n-butanol (1 ml) was stirred at 130C for 3 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/methanol = 20/1) and then dissolved in ethyl acetate/methanol (1 ml/1 ml). The resulting solution was saturated with hydrogen chloride gas and then filtered to give 55.5 mg of the product as a white solid.
55.5 mg		A solution of (R)-tert-butyl [1-(2-chloro-6-propylpyrimidin-4-yl)piperidin-3-yl]carbamate (82 mg, 0.23 mmol) prepared in Preparation 26 and <strong>[368-53-6]5-(trifluoromethyl)benzene-1,3-diamine</strong> (44 mg, 0.25 mmol) in n-butanol (1 ml) was stirred at 130 C. for 3 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/methanol=20/1) and then dissolved in ethyl acetate/ methanol (1 ml/1 ml). The resulting solution was saturated with hydrogen chloride gas and then filtered to give 55.5 mg of the product as a white solid.

Reference： [1]Patent: WO2012/115478,2012,A2 .Location in patent: Page/Page column 74
[2]Patent: US2013/331377,2013,A1 .Location in patent: Paragraph 0667

26
[ 368-53-6 ]
[ 84358-13-4 ]
[ 1529769-80-9 ]

Yield	Reaction Conditions	Operation in experiment
600 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 17h;	Mix the compound obtained in Step 1 (1.1 g, crude), HOBt (1.6 g, 12 mmol), 5-(trifIuoromethyl)benzene-l,3-diamine (845 mg, 4.8 mmol) in DCM (16 mL), add diisopropylethylamine (1.55 g, 12 mmol), l-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (2.3 g, 12 mmol) and stir at room temperature for 17 hrs. TLC (PE:EtOAc-l :l) shows the reaction is complete. Remove the volatiles under reduced pressure, purify the residue by chromatography (silica gel, EOAc:PE=4:6) to give the title compound (600 mg, 40% two-step yield).
600 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 25℃; for 17h;	Mix the compound obtained in Step 1 (1.1 g, crude), HOBt (1.6 g, 12 mmol), <strong>[368-53-6]5-(trifluoromethyl)benzene-1,3-diamine</strong> (845 mg, 4.8 mmol) in DCM (16 mL), add diisopropylethylamine (1.55 g, 12 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (2.3 g, 12 mmol) and stir at room temperature for 17 hrs. TLC (PE:EtOAc=1:1) shows the reaction is complete. Remove the volatiles under reduced pressure, purify the residue by chromatography (silica gel, EOAc:PE=4:6) to give the title compound (600 mg, 40% two-step yield).

Reference： [1]Patent: WO2014/418,2014,A1 .Location in patent: Page/Page column 76
[2]Patent: US2015/197511,2015,A1 .Location in patent: Paragraph 0355; 0356

27
[ 627-00-9 ]
[ 368-53-6 ]
[ 1529769-45-6 ]

Yield	Reaction Conditions	Operation in experiment
52%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	Mix 5-(trifluoromethyl)benzene-l,3-diamine (300 mg, 1.70 mmol), <strong>[627-00-9]4-chlorobutanoic acid</strong> (230 mg, 1.87 mmol), l-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDCI-HCl, 650mg, 3.40mmol), 1 -hydroxybenzotriazole (HOBt, 230 mg, 1.70 mmol) and diisopropylethylamine (450 mg, 3.40 mmol) in dichloromethane (10 mL), stir overnight at room temperature. Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify by flash chromatography (silica gel, PE:EtOAc=l :10) to yield the product (250 mg, 52%). MS: (M+l): 281.2.
52%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 25℃;	Mix 5-(trifluoromethyl)benzene-1,3-diamine (300 mg, 1.70 mmol), <strong>[627-00-9]4-chlorobutanoic acid</strong> (230 mg, 1.87 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDCI.HCl, 650 mg, 3.40 mmol), 1-hydroxybenzotriazole (HOBt, 230 mg, 1.70 mmol) and diisopropylethylamine (450 mg, 3.40 mmol) in dichloromethane (10 mL), stir overnight at room temperature. Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify by flash chromatography (silica gel, PE:EtOAc=1:10) to yield the product (250 mg, 52%). MS: (M+1): 281.2.

Reference： [1]Patent: WO2014/418,2014,A1 .Location in patent: Page/Page column 54
[2]Patent: US2015/197511,2015,A1 .Location in patent: Paragraph 0264; 0265

28
[ 1394321-86-8 ]
[ 368-53-6 ]
(S)-N¹-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-5-(trifluoromethyl)benzene-1,3-diamine dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11.1 mg		A mixture of (S)-tert-butyl 1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-ylcarbamate (30 mg, 0.09 mmol) prepared in Preparation 21, <strong>[368-53-6]5-(trifluoromethyl)benzene-1,3-diamine</strong> (19.4 mg, 0.11 mmol), and n-butanol (1 ml) was refluxed under stirring overnight. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/methanol=20/1) and then dissolved in ethyl acetate (2 ml). Hydrogen chloride gas was added to the solution. The reaction mixture was stirred at room temperature for 1 hour and then filtered to give 11.1 mg of the product as a white solid.

Reference： [1]Patent: US2013/338179,2013,A1 .Location in patent: Paragraph 0757

29
[ 937807-95-9 ]
[ 368-53-6 ]
[ 1532526-02-5 ]

Reference： [1]Organometallics,2019,vol. 38,p. 3132 - 3138
[2]Organometallics,2014,vol. 33,p. 457 - 464

30
[ 85-44-9 ]
[ 368-53-6 ]
[ 1610038-13-5 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 1704 - 1707

31
[ 368-53-6 ]
[ 1579998-96-1 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 1704 - 1707

32
[ 368-53-6 ]
[ 1579999-01-1 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 1704 - 1707

33
[ 368-53-6 ]
[ 1579999-08-8 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 1704 - 1707

34
[ 368-53-6 ]
[ 1579999-13-5 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 1704 - 1707

35
[ 368-53-6 ]
[ 1613518-18-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3204 - 3206

36
[ 368-53-6 ]
[ 1613518-22-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3204 - 3206

37
[ 368-53-6 ]
[ 1613518-23-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3204 - 3206

38
[ 368-53-6 ]
[ 98-88-4 ]
[ 1613518-05-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3204 - 3206

39
[ 368-53-6 ]
[ 98-88-4 ]
[ 1613518-30-1 ]

Yield	Reaction Conditions	Operation in experiment
30.7%	With triethylamine; In dichloromethane; at 20℃;Inert atmosphere;	To a stirred solution of <strong>[368-53-6]5-(trifluoromethyl)benzene-1,3-diamine</strong> (500mg, 2.84 mmol) in DCM (4.7 mL) under a nitrogen atmosphere were added benzoylchloride (395 muL, 3.41 mmol) and triethylamine (514 muL, 3.69 mmol).The solution was stirred at room temperature overnight after which a saturatedsolution of sodium bicarbonate and DCM were added. The mixture was filtered ona phase separator column and concentrated under reduced pressure. The crudematerial was purified by flash chromatography to provideN-(3-amino-5-(trifluoromethyl)phenyl)benzamide (244 mg, 30.7 %) as a solid. MS m/z 281.3 [M+H]+ (ESI).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3204 - 3206

40
[ 368-53-6 ]
[ 385-00-2 ]
[ 1613518-32-3 ]

Yield	Reaction Conditions	Operation in experiment
89%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 17h;Inert atmosphere;	A mixture of<strong>[368-53-6]5-(trifluoromethyl)benzene-1,3-diamine</strong> (500 mg, 2.84 mmol) and2,6-difluorobenzoic acid (404 mg, 2.55 mmol) in DMF (8.7 mL) under a nitrogenatmosphere was stirred at ambient temperature for 5 minutes. triethylamine (766muL, 5.68 mmol) was added, and the resulting mixture was stirred for 5 minutes.2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V)(1295 mg, 3.41 mmol) was added, and the resulting mixture was stirred atambient temperature for 17 h. Water (10 mL) and ethyl acetate (30 mL) were added tothe reaction mixture, and the phases were separated. The aqueous phase wasextracted with ethyl acetate (3 X 30 mL). The combined organic extracts werewashed with brine, dried over Na2SO4, filtered andconcentrated under reduced pressure. The material was purified by preparativereverse phase HPLC to afford N-(3-amino-5-(trifluoromethyl)phenyl)-2,6-difluorobenzamide(800 mg, 89 %). 1H NMR (400 MHz, chloroform-d) delta 7.37 - 7.74 (m,3H), 7.01 (s, 3H), 6.58 - 6.76 (m, 1H), 3.84 - 4.08 (m, 3H). HRMS m/z calcd forC14H9F5N2O [M+H]+317.0708, found 317.0708.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3204 - 3206

41
[ 368-53-6 ]
[ 861881-15-4 ]

Reference： [1]Patent: US2015/197511,2015,A1

42
[ 368-53-6 ]
[ 124-63-0 ]
[ 873056-09-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	With pyridine; In dichloromethane; at 0 - 20℃; for 4.5h;	A solution of 5-trifluoromethyl-benzene-1,3-diamine (250 mg, 1.42 mmol) in pyridine (0.52 mL) and CH2Cl2 (6.5 mL) was cooled to 0 C. Methanesulfonyl chloride (171 mg, 1.49 mmol) was slowly added at such a rate that the temperature of the solution remained below 10 C. The mixture was stirred at ?8 C. and then allowed to warm to room temperature after 30 min. After stirring at room temperature for 4 h, reaction was almost complete as indicated by LCMS analysis. The reaction mixture was quenched with sat. aq. NH4Cl (10 mL) solution, extracted with CH2Cl2 (4*10 mL), dried over Na2SO4, filtered, and concentrated to yield N-(3-amino-5-trifluoromethyl-phenyl)-methanesulfonamide (D-19) as a reddish semisolid (0.35 g, 97%), which was used without further purification. 1H-NMR (CDCl3, 300 MHz) delta 6.76 (m, 1H), 6.70 (m, 1H), 6.66 (s, 1H), 3.02 (s, 3H); ESI-MS 255.3 m/z (MH+). Cyclic Amines

Reference： [1]Patent: US2015/231142,2015,A1 .Location in patent: Paragraph 0613

43
[ 368-53-6 ]
[ 401-84-3 ]

Reference： [1]Chemical Communications,2015,vol. 51,p. 16912 - 16915

44
[ 368-53-6 ]
2,2',6,6'-tetrabromo-4,4'-bis(trifluoromethyl)-1,1'-biphenyl [ No CAS ]

Reference： [1]Chemical Communications,2015,vol. 51,p. 16912 - 16915

45
[ 368-53-6 ]
(R)-6,6'-dibromo-4,4'-bis(trifluoromethyl)[1,1'-biphenyl]-2,2'-dicarbaldehyde [ No CAS ]
(S)-6,6'-dibromo-4,4'-bis(trifluoromethyl)[1,1'-biphenyl]-2,2'-dicarbaldehyde [ No CAS ]

Reference： [1]Chemical Communications,2015,vol. 51,p. 16912 - 16915

46
[ 368-53-6 ]
C₁₆H₁₀Br₂F₆O₂ [ No CAS ]

Reference： [1]Chemical Communications,2015,vol. 51,p. 16912 - 16915

47
(S)-N-{1-(2-chloroquinazolin-4-yl)pyrrolidin-3-yl}acetamide [ No CAS ]
[ 368-53-6 ]
(S)-N-{1-(2-[{3-amino-5-(trifluoromethyl)phenyl}amino]quinazolin-4-yl)pyrrolidin-3-yl}acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10 mg	for 0.666667h;Microwave irradiation;	Example 131 (S)-N-{1-(2-[{3-amino-5-(trifluoromethyl)phenyl}amino]quinazolin-4-yl)pyrrolidin-3-yl}acetamide A mixture of (S)-N-{1-(2-chloroquinazolin-4-yl)pyrrolidin-3-yl}acetamide (20 mg, 0.07 mmol) prepared in Reference Example 40 and <strong>[368-53-6]5-(trifluoromethyl)-1,3-phenylenediamine</strong> (15 mg, 0.08 mmol) was stirred for 40 minutes in a microwave (600 W). After cooling to room temperature, the resulting product was purified with silica gel column chromatography (dichloromethane/methanol=20/1) to prepare the titled compound (10 mg) as a pale brown solid. 1H NMR (400 MHz, CD3OD) delta 8.15 (d, 1H), 7.62 (t, 1H), 7.55-7.45 (m, 2H), 7.23 (t, 1H), 7.17 (s, 1H), 6.61 (s, 1H), 4.55-4.45 (m, 1H), 4.30-4.00 (m, 3H), 3.86 (dd, 1H), 2.35-2.20 (m, 1H), 2.15-2.05 (m, 1H), 1.95 (s, 3H)

Reference： [1]Patent: US2016/90374,2016,A1 .Location in patent: Paragraph 0475; 0476

48
(S)-1-(2-chloro-6,7-dimethoxy-quinazolin-4-yl)-N-methylpyrrolidin-3-amine [ No CAS ]
[ 368-53-6 ]
(S)-N-{6,7-dimethoxy-4-(3-methylaminopyrrolidin-1-yl)quinazolin-2-yl}-5-trifluoromethylbenzene-1,3-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9.2 mg	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 1h;Microwave irradiation;	Example 2 (S)-N-{6,7-dimethoxy-4-(3-methylaminopyrrolidin-1-yl)-quinazolin-2-yl}-5-trifluoromethyl-benzene-1,3-diamine A mixture of (S)-1-(2-chloro-6,7-dimethoxyquinazolin-4-yl)-N-methylpyrrolidin-3-amine (35 mg, 0.09 mmol) prepared in Reference Example 2, palladium acetate (1 mg, 5 mol %), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (5.2 mg, 10 mol %), cesium carbonate (59 mg, 0.18 mmol), <strong>[368-53-6]5-(trifluoromethyl)-1,3-phenylenediamine</strong> (19 mg, 0.11 mmol) and 1,4-dioxane (1 ml) was stirred for 1 hour in a microwave (600 W). After cooling the reaction mixture to room temperature, the same was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate=1/1?dichloromethane/methanol=20/1) to prepare the titled compound (9.2 mg) as a pale yellow solid. 1H-NMR (400 MHz, CD3OD) delta 7.55 (s, 1H), 7.47 (s, 1H), 7.20 (s, 1H), 6.87 (s, 1H), 6.55 (s, 1H), 4.14 (m, 1H), 3.99 (m, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.74 (m, 1H), 3.39 (m, 1H), 2.46 (s, 3H), 2.26 (m, 1H), 1.99 (m, 1H).

Reference： [1]Patent: US2016/90374,2016,A1 .Location in patent: Paragraph 0264; 0265

49
(S)-1-(2-chloroquinazolin-4-yl)-N-methylpyrrolidin-3-amine [ No CAS ]
[ 368-53-6 ]
(S)-N¹-[4-{3-(methylamino)pyrrolidin-1-yl}quinazolin-2-yl]-5-(trifluoromethyl)benzene-1,3-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5 mg	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 1h;Microwave irradiation;	j0485] A mixture of (S)-1-(2-chloroquinazolin-4-yl)-N- methylpyrrolidin-3-amine (25 mg, 0.1 mmol) prepared in Reference Example 41, 5-(trifluoromethyl)-1 ,3-phenylene- diamine (21.3 mg, 0.12 mmol), palladium acetate (0.22 mg, 0.001 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxan- thine (1.7mg, 0.003 mmol), cesium carbonate (81.5mg, 0.25 mmol) and anhydrous 1 ,4-dioxane (1 ml) was stirred for 1 hour in a microwave (600 W). Afier cooling the reaction solution to room temperature, the same was filtered by using celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified with silica gel colunm chromatography (dichloromethane/methanol=20/1) to prepare the titled compound (5 mg) as a pale yellow solid. 10486] ?H NMR (400 MHz, CD3OD) oe 8.14 (d, 1H), 7.65-7.55 (m, 2H), 7.45 (d, 1H), 7.20-7.10 (m, 2H), 6.57 (s, 1H),4.20-4.05 (m, 2H), 4.05-3.95 (m, 1H), 3.85-3.75 (m, 1H),3.45-3.40 (m, 1H), 2.47 (s, 3H), 2.35-2.25 (m, 1H), 2.05-1.95 (m, 1H)

Reference： [1]Patent: US2016/90374,2016,A1 .Location in patent: Paragraph 0485; 0486

50
C₁₄H₁₇ClN₄O [ No CAS ]
[ 368-53-6 ]
(S)-N¹-{4-(3-methylaminopyrrolidin-1-yl)-8-methoxyquinazolin-2-yl}-5-trifluoromethylbenzene-1,3-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16.7 mg	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 1h;Microwave irradiation;	<Step 2> (S)-N1-{4-(3-methylaminopyrrolidin-1-yl)-8-methoxyquinazolin-2-yl}-<strong>[368-53-6]5-trifluoromethylbenzene-1,3-diamine</strong> A mixture of (S)-{1-(2-chloro-8-methoxyquinazolin-4-yl)-pyrrolidin-3-yl}methylamine (20 mg, 0.07 mmol) prepared in Step 1, 3-(trifluoromethyl)-1,5-phenylenediamine (14 mg, 0.08 mmol), palladium acetate (0.77 mg, 0.003 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (4.0 mg, 0.01 mmol), cesium carbonate (44.5 mg, 0.14 mmol) and anhydrous 1,4-dioxane (1 ml) was stirred for 1 hour in a microwave (600 W). After cooling the reaction solution to room temperature, the same was filtered by celite. The filtrate was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/methanol=10/1) to prepare the titled compound (16.7 mg) as a pale yellow oil. 1H NMR (400 MHz, CD3OD) delta 7.63 (m, 2H), 7.04 (m, 3H), 6.56 (m, 1H), 4.03-3.86 (m, 6H), 3.69 (m, 1H), 2.43 (s, 3H), 2.21 (m, 1H), 1.89 (m, 1H)

Reference： [1]Patent: US2016/90374,2016,A1 .Location in patent: Paragraph 0354; 0355

51
(S)-1-{2-chloro-7-(trifluoromethyl)quinazolin-4-yl}-N-methylpyrrolidin-3-amine [ No CAS ]
[ 368-53-6 ]
(S)-N¹-[4-{3-(methylamino)pyrrolidin-1-yl}-7-(trifluoromethyl)quinazolin-2-yl]-5-(trifluoromethyl)benzene-1,3-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10.1 mg	for 1h;Microwave irradiation;	10295] A mixture of (S)-1 -{2-chloro-7-(trifluoromethyl)- quinazolin-4-yl}-N-methylpyrrolidin-3-amine (30 mg, 0.09 mmol) prepared in Reference Example 10 and 5-(trifluorom- ethyl)- 1 ,3-phenylenediamine (25 mg, 0.14 mmol) was stirred for 1 hour in a microwave (600W). Afier cooling the reaction mixture to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (n-hexane/ ethyl acetate=1/1 -dichloromethane/methanol=20/1). The resulting residue was dissolved in ethyl acetate, and hydrochloric acid gas was added thereto. The resulting solid was filtered, washed and dried to prepare the titled compound (10.1 mg) as a pale yellow solid. 10296] ?H-NMR (400 MHz, CD3OD) oe 8.31 (d, 1H), 7.74 (s, 1H), 7.48 (s, 1H), 7.35 (d, 1H), 7.30 (s, 1H), 6.59 (s, 1H), 4.20 (m, 2H), 4.04 (m, 1H), 3.91 (m, 1H), 3.59 (m, 1H), 2.53 (s, 3H), 2.36 (m, 1 H), 2.11 (m, 1 H).

Reference： [1]Patent: US2016/90374,2016,A1 .Location in patent: Paragraph 0295; 0296

52
(S)-tert-butyl {1-(2-chloroquinazolin-4-yl)pyrrolidin-3-yl}(propyl)carbamate [ No CAS ]
[ 368-53-6 ]
(S)-N¹-[4-{3-(propylamino)pyrrolidin-1-yl}quinazolin-2-yl]-5-(trifluoromethyl)benzene-1,3-diamine dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33.4 mg		10338] n-l3utanol (1.5 ml) solution of (S)-tert-butyl 1-(2- chioroquinazolin-4-yl)pyrrolidin-3-yl(propyl)carbamate(57.7 mg, 0.15 mmol) prepared in Reference Example 14 and 3-(trifluoromethyl)- 1 ,5-phenylenediamine (31.2 mg, 0.18 mmol) was stirred at 130 C. overnight. After cooling the reaction solution, the same was concentrated under reduced pressure. The resulting residue was crystallized with n-butanol/dichloromethane and dried under reduced pressure. The resulting solid was dissolved in methanol (2 ml), and then hydrochloric acid gas was added thereto. The resulting white solid was filtered to prepare the titled compound (33.4 mg). 10339] ?H NMR (400 MHz, DMSO-d5) oe 13.17 (brs, 1H),10.69 (s, 1H), 9.77-9.54 (m, 2H), 8.29 (s, 1H), 7.90 (t, 1H),7.61 (d, 1H), 7.53 (t, 1H), 7.40-7.18 (m, 2H), 6.78 (s, 1H),4.51-4.01 (m, 5H), 2.98 (m, 2H), 2.45 (m, 2H), 1.71 (m, 2H),1.04 (m, 3H)

Reference： [1]Patent: US2016/90374,2016,A1 .Location in patent: Paragraph 0338; 0339

53
[ 368-53-6 ]
[ 1073-70-7 ]
4-(4'-chlorophenyl)-5-trifluoromethyl-1,3-phenylenediamine [ No CAS ]
2-(4'-chlorophenyl)-5-trifluoromethyl-1,3-phenylenediamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%; 41%	With air; In dimethyl sulfoxide; at 25℃; for 24h;	General procedure: A mixture of arylhydrazine hydrochloride 1 (1.0 mmol), aromatic diamine 2 (20.0 mmol), and K2CO3 (276 mg, 2.0 mmol) in DMSO (10mL) was stirred at 25 C in air. The reaction was monitored by TLC and was completed in 24 h. Next, after quenching by the addition of H2O,the mixture was extracted with EtOAc. The organic layer was washedwith H2O and brine, and dried (anhyd MgSO4). The solvent was removedunder reduced pressure to give the crude product. Purification by column chromatography on silica gel (hexane/EtOAc) afforded the pure product (Table 2).

Reference： [1]Synthesis,2017,vol. 49,p. 1623 - 1631

54
[ 368-53-6 ]
[ 622-88-8 ]
2-(4'-bromophenyl)-5-trifluoromethyl-1,3-phenylenediamine [ No CAS ]
4-(4'-bromophenyl)-5-trifluoromethyl-1,3-phenylenediamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%; 49%	With air; In dimethyl sulfoxide; at 25℃; for 24h;	General procedure: A mixture of arylhydrazine hydrochloride 1 (1.0 mmol), aromatic diamine 2 (20.0 mmol), and K2CO3 (276 mg, 2.0 mmol) in DMSO (10mL) was stirred at 25 C in air. The reaction was monitored by TLC and was completed in 24 h. Next, after quenching by the addition of H2O,the mixture was extracted with EtOAc. The organic layer was washedwith H2O and brine, and dried (anhyd MgSO4). The solvent was removedunder reduced pressure to give the crude product. Purification by column chromatography on silica gel (hexane/EtOAc) afforded the pure product (Table 2).

Reference： [1]Synthesis,2017,vol. 49,p. 1623 - 1631

55
[ 368-53-6 ]
[ 5750-76-5 ]
N1-(2,5-dichloropyrimidin-4-yl)-5-(trifluoromethyl)benzene-1,3-diamine [ No CAS ]