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[ CAS No. 1535-76-8 ]

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CAS No. :	1535-76-8	MDL No. :	MFCD01862105
Formula :	C₇H₆F₃NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	177.12 g/mol	Pubchem ID :	-
Synonyms :

Safety of [ 1535-76-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1535-76-8 ]

Upstream synthesis route of [ 1535-76-8 ]
Downstream synthetic route of [ 1535-76-8 ]

[ 1535-76-8 ] Synthesis Path-Upstream 1~1

1
[ 1535-76-8 ]
[ 53903-51-8 ]

Yield	Reaction Conditions	Operation in experiment
700 mg	Stage #1: With hydrogenchloride; sodium nitrite In water; acetonitrile at 0℃; Stage #2: With hydrogenchloride; copper(l) chloride In water; acetonitrile at 100℃; for 6 h;	Sodium nitrite (0.47 g) in H₂O (3 ml) was added dropwise to a solution of 4-amino-2-(trifluoromethyl)phenol (1 g) in acetonitrile (20 ml) and hydrochloric acid (10 ml) at 0 °C. After stirring for 0.5 hour, copper(I) chloride (1.12 g) in 3 M HCl (5 ml) was added to the mixture. Then the reaction mixture was stirred at 100 °C for 6 h. After cooling to room temperature, the solution was diluted with EtOAc (200 ml). The organic phase was washed with water (100 ml) and brine (50 ml), dried, and concentrated. The residue was purified by flash chromatography (DCM/PE = 1:1) to afford 4-chloro-2-(trifluoromethyl)phenol (700 mg) as a brown oil. MS(ES⁺) m/z 195 (MH⁺).

Reference： [1] Patent: WO2012/100734, 2012, A1, . Location in patent: Page/Page column 28-29
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5293 - 5302

[ 1535-76-8 ] Synthesis Path-Downstream 1~26

1
[ 1548-61-4 ]
[ 1535-76-8 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium formate; zinc; In methanol; water; at 80℃; for 3h;	Step 2:; Zinc (4.42 g) was added to a solution of <strong>[1548-61-4]4-nitro-2-(trifluoromethyl)phenol</strong> (3.5 g) and ammonium formate (8.52 g) in methanol (5 mL) and water (5 mL) at room temperature. The reaction mixture was stirred at 80 C for 3 hours. After cooling to room temperature, the mixture was filtered and EtOAc (80 mL) was added to the filtrate. The organic layer was washed with water (30 mL) and brine (40 mL), dried, and concentrated to afford 4-amino-2-(trifluoromethyl)phenol (2.8 g) as a yellow solid.
2.8 g	With ammonium formate; zinc; In methanol; water; at 80℃; for 3h;	Zinc (4.42 g) was added to a solution of <strong>[1548-61-4]4-nitro-2-(trifluoromethyl)phenol</strong> (3.5 g) and ammonium formate (8.52 g) in methanol (5 ml) and water (5 ml) at room temperature. The reaction mixture was stirred at 80 C for 3 h. After cooling to room temperature, the mixture was filtered and EtOAc (80 ml) was added to the filtrate. The organic layer was washed with water (30 ml) and brine (40 ml), dried, and concentrated to afford 4-amino-2-(trifluoromethyl)phenol (2.8 g) as a yellow solid.

Reference： [1]Journal of Photochemistry and Photobiology A: Chemistry,2011,vol. 226,p. 57 - 63
[2]Journal of Organic Chemistry,1962,vol. 27,p. 4660 - 4662
[3]Patent: WO2012/100734,2012,A1 .Location in patent: Page/Page column 28
[4]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5293 - 5302

2
[ 1535-76-8 ]
<i>N</i>-[3-(3-carbamimidoyl-phenyl)-allyl]-<i>N</i>-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-3-trifluoromethyl-phenyl}-succinamic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: DEAD; PPh₃ 2.1: NaCNBH₃ 3.1: Et₃N 4.1: HCl (g); EtOH 4.2: NH₃ / ethanol 5.1: aq. LiOH / methanol

Reference： [1]Wu, Shung; Guilford, William J; Chou, Yuo-Ling; Griedel, Brian D; Liang, Amy; Sakata, Steve; Shaw, Kenneth J.; Trinh, Lan; Xu, Wei; Zhao, Zuchun; Morrissey, Michael M. [Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 9, p. 1307 - 1310]

3
[ 1535-76-8 ]
<i>N</i>-[3-(3-carbamimidoyl-phenyl)-allyl]-<i>N</i>-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-3-trifluoromethyl-phenyl}-succinamic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: DEAD; PPh₃ 2.1: NaCNBH₃ 3.1: Et₃N 4.1: HCl (g); EtOH 4.2: NH₃ / ethanol 5.1: Et₃N / methanol

Reference： [1]Wu, Shung; Guilford, William J; Chou, Yuo-Ling; Griedel, Brian D; Liang, Amy; Sakata, Steve; Shaw, Kenneth J.; Trinh, Lan; Xu, Wei; Zhao, Zuchun; Morrissey, Michael M. [Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 9, p. 1307 - 1310]

4
[ 1535-76-8 ]
<i>N</i>-[4-(1-acetyl-piperidin-4-yloxy)-3-trifluoromethyl-phenyl]-<i>N</i>-[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-succinamic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: DEAD; PPh₃ 2.1: NaCNBH₃ 3.1: Et₃N 4.1: HCl (g); EtOH 4.2: NH₃ / ethanol 5.1: aq. LiOH / methanol 5.2: Et₃N / CH₂Cl₂

Reference： [1]Wu, Shung; Guilford, William J; Chou, Yuo-Ling; Griedel, Brian D; Liang, Amy; Sakata, Steve; Shaw, Kenneth J.; Trinh, Lan; Xu, Wei; Zhao, Zuchun; Morrissey, Michael M. [Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 9, p. 1307 - 1310]

5
[ 1535-76-8 ]
<i>N</i>-[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-<i>N</i>-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-3-trifluoromethyl-phenyl}-succinamic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: DEAD; PPh₃ 2.1: NaCNBH₃ 3.1: Et₃N 4.1: HCl (g); EtOH 4.2: NH₃ / ethanol 5.1: aq. LiOH / methanol 6.1: aq. LiOH / methanol 6.2: Et₃N / methanol

Reference： [1]Wu, Shung; Guilford, William J; Chou, Yuo-Ling; Griedel, Brian D; Liang, Amy; Sakata, Steve; Shaw, Kenneth J.; Trinh, Lan; Xu, Wei; Zhao, Zuchun; Morrissey, Michael M. [Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 9, p. 1307 - 1310]

6
[ 1535-76-8 ]
<i>N</i>-[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-<i>N</i>-[4-(1-carboxymethyl-piperidin-4-yloxy)-3-trifluoromethyl-phenyl]-succinamic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: DEAD; PPh₃ 2.1: NaCNBH₃ 3.1: Et₃N 4.1: HCl (g); EtOH 4.2: NH₃ / ethanol 5.1: aq. LiOH / methanol 5.2: Et₃N / CH₂Cl₂

Reference： [1]Wu, Shung; Guilford, William J; Chou, Yuo-Ling; Griedel, Brian D; Liang, Amy; Sakata, Steve; Shaw, Kenneth J.; Trinh, Lan; Xu, Wei; Zhao, Zuchun; Morrissey, Michael M. [Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 9, p. 1307 - 1310]

7
[ 1535-76-8 ]
<i>N</i>-[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-<i>N</i>-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-3-trifluoromethyl-phenyl}-succinamic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: DEAD; PPh₃ 2.1: NaCNBH₃ 3.1: Et₃N 4.1: HCl (g); EtOH 4.2: NH₃ / ethanol 5.1: Et₃N / methanol

Reference： [1]Wu, Shung; Guilford, William J; Chou, Yuo-Ling; Griedel, Brian D; Liang, Amy; Sakata, Steve; Shaw, Kenneth J.; Trinh, Lan; Xu, Wei; Zhao, Zuchun; Morrissey, Michael M. [Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 9, p. 1307 - 1310]

8
[ 654-76-2 ]
[ 1535-76-8 ]

Reference： [1]Journal of Organic Chemistry,1962,vol. 27,p. 4660 - 4662
[2]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5293 - 5302
[3]Patent: WO2012/100734,2012,A1

9
[ 1535-76-8 ]
[ 6960-37-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: (i) aq. HCl, NaNO₂, (ii) /BRN= 635743/, CuCl 2: liq. NH₃

Reference： [1]Filler,R. et al. [Journal of Organic Chemistry, 1962, vol. 27, p. 4660 - 4662]

10
[ 1056623-90-5 ]
[ 1535-76-8 ]
3-methoxymethyl-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid (4-hydroxy-3-trifluoromethyl-phenyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20 - 55℃;	45 A mixture of compound 2 (0.058 mmols), HOBt (7.8 mg, 0.058 mmols), EDC (11 mg, 0.057 mmols) in DMF (1 ml) was stirred at r.t. overnight, then 550C overnight. The reaction mixture was directly purified by HPLC (Gilson) to provide titled compound. MS found 599.1 (M+H)

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2007/97937, 2007, A1 Location in patent: Page/Page column 207

11
[ 39062-69-6 ]
[ 1535-76-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogen In methanol for 4h;	1 To the suspension of 1-benzyloxy-4-nitro-2-trifluoromethylbenzene (575 mg, 1.96 mmol) in methanol was added catalytic amount of 5% palladium on carbon under a hydrogen atmosphere. The mixture was stirred for 4 hrs and filter through celite. The filtrate was concentrated to afford 4-amino-2-trifluoromethylphenol (311 mg, 90%).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2007/97937, 2007, A1 Location in patent: Page/Page column 175

12
[ 302-79-4 ]
[ 1535-76-8 ]
[ 1197356-48-1 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	7 At the room temperature, retinoic acid of 0.5g, 4-amino-2-trifluoromethylphenol of 0.32g, 4-dimethylaminopyridine (DMAP) of 0.23g and dichloromethane of 10ml are added and stirred; N,N-dicyclolhexylcarbodiimide (DCC) of 0.4g and dichloromethane solution are added to obtain a yellow, transparent liquid which is stirred overnight; and saturated ammonium chloride solution is added to stop the reaction, followed by extraction by dichloromethane, washing by water, drying by anhydrous sodium sulphate, suction filtration, concentration, column chromatography (mobile phase: petroleum ether: 60-90 °C: ethyl acetate = 2:1), concentration and recrystallization by petroleum ether (60-90 °C) to obtain a yellow solid of 0.21g. mp 89.7-91.3 °C 1H-NMR(CDCl3), δ(ppm): 1.04(s,6H); 1.72 (s,3H); 2.02 (s,3H); 2.39(s,3H); 1.46+1.63 (t,4H); 2.03 (m,2H); 5.99(s,1H); 6.14-6.39(m,4H); 7.08(m,H); 7.02 (m,); 6.91 (d,1H); 6.82 (t,1H) 13C-NMR(CDCl3), δ(ppm): 13.03; 14,16; 19.30; 21.83; 29.05; 33.21; 34.36; 39.71; 118.63; 129.21; 129.48; 130.29; 130.20; 134.81; 137.28; 137.76; 140.52; 156.02; 165.55; 112.54; 112.58; 116.69; 125.45; 139.81; 144.12; 123.34 High-resolution MS: m/z: 459.2378 (theoretical value: 459.2385) molecular formula: C27H32F3NO2
	With dmap; dicyclohexyl-carbodiimide In dichloromethane	7 Example 7 (4-amino-2-trifluoromethylphenyl)-(all-trans)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cycl ohexen-1-yl)-2,4,6,8-nonatetraenoate (4a-02) At the room temperature, retinoic acid of 0.5 g, 4-amino-2-trifluoromethylphenol of 0.32 g, 4-dimethylaminopyridine (DMAP) of 0.23 g and dichloromethane of 10 ml are added and stirred; N,N-dicyclohexylcarbodiimide (DCC) of 0.4 g and dichloromethane solution are added to obtain a yellow, transparent liquid which is stirred overnight; and saturated ammonium chloride solution is added to stop the reaction, followed by extraction by dichloromethane, washing by water, drying by anhydrous sodium sulphate, suction filtration, concentration, column chromatography (mobile phase: petroleum ether: 60-90° C.: ethyl acetate=2:1), concentration and recrystallization by petroleum ether (60-90° C.) to obtain a yellow solid of 0.21 g. mp 89.7-91.3° C. 1HNMR (CDCl3), δ(ppm): 1.04 (s, 6H); 1.72 (s, 3H); 2.02 (s, 3H); 2.39 (s, 3H); 1.46+1.63 (t, 4H); 2.03 (m, 2H); 5.99 (s, 1H); 6.14-6.39 (m, 4H); 7.08 (m, H); 7.02 (m,); 6.91 (d, 1H); 6.82 (t, 1H) 13CNMR (CDCl3), δ(ppm): 13.03; 14.16; 19.30; 21.83; 29.05; 33.21; 34.36; 39.71; 118.63; 129.21; 129.48; 130.29; 130.20; 134.81; 137.28; 137.76; 140.52; 156.02; 165.55; 112.54; 112.58; 116.69; 125.45; 139.81; 144.12; 123.34 High-resolution MS: m/z: 459.2378 (theoretical value: 459.2385) molecular formula: C27H32F3NO2

Reference： [1]Current Patent Assignee: ANHUI MEDICAL UNIVERSITY; ANHI NEW STAR PHARMACEUTICAL DEVELOPMENT - EP2279999, 2011, A1 Location in patent: Page/Page column 17-18
[2]Current Patent Assignee: ANHUI MEDICAL UNIVERSITY; ANHI NEW STAR PHARMACEUTICAL DEVELOPMENT - US2011/77298, 2011, A1 Location in patent: Page/Page column 14

13
[ 54757-46-9 ]
[ 1535-76-8 ]
[ 1197356-76-5 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide; In dichloromethane;Cooling with ice bath;	In a reaction flask, etretin of 0.53g, 4-amino-2-trifluoromethylphenol of 0.28g, 4-dimethylaminopyridine (DMAP) of 0.23g and dichloromethane of 5ml are added and stirred in the condition of ice bath with white insoluble substances generated; DDC of 0.4g and dichloromethane solution are added and stirred to react with one another for 4h; and saturated ammonium chloride solution is added to stop the reaction, followed by extraction by dichloromethane, washing by saturated sodium chloride aqueous solution, drying by anhydrous sodium sulphate, concentration, column chromatography (petroleum ether: 60-90 C:ethyl acetate = 20:1) and recrystallization by ethanol to obtain a yellow solid of 60mg, mp 118.7-123.8 C 1H-NMR(CDCl3), delta(ppm): 7.39 (d, 1H 7.26(m,1H); 7.12 (m,1H); 6.75 (d,1H); 6.61 (d,1H); 6.43 (d,1H); 6.30(s,1H); 6.26(d,1H); 6.01 (s,1H); 3.82 (s,3H); 2.42 (s,3H); 2.31 (s,3H); 2.25 (s,3H); 2.14(s,3H); 2.09(s,3H) 13C-NMR(CDCl3), delta(ppm): 165.62; 156.35; 155.93; 144.11; 140.15; 139.81; 138.14; 136.03; 135.33; 134.03; 132.02; 130.28; 129.88; 129.06; 125.43; 122.88; 121.07; 118.67; 116.98; 112.05; 110.10; 55.63; 21.49; 17.54; 14.19; 13.09; 11.92 High-resolution MS: m/z: 485.2177 (theoretical value: 485.2178) molecular formula: C28H30F3NO3
	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0℃; for 4h;	Example 20 (4-amino-2-trifluoromethylphenyl)-(all-trans)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate (4b-02) In a reaction flask, etretin of 0.53 g, 4-amino-2-trifluoromethylphenol of 0.28 g, 4-dimethylaminopyridine (DMAP) of 0.23 g and dichloromethane of 5 ml are added and stirred in the condition of ice bath with white insoluble substances generated; DDC of 0.4 g and dichloromethane solution are added and stirred to react with one another for 4 h; and saturated ammonium chloride solution is added to stop the reaction, followed by extraction by dichloromethane, washing by saturated sodium chloride aqueous solution, drying by anhydrous sodium sulphate, concentration, column chromatography (petroleum ether: 60-90 C.:ethyl acetate=20:1) and recrystallization by ethanol to obtain a yellow solid of 60 mg, mp 118.7-123.8 C. 1HNMR (CDCl3), delta(ppm): 7.39 (d, 1H); 7.26 (m, 1H); 7.12 (m, 1H); 6.75 (d, 1H); 6.61 (d, 1H); 6.43 (d, 1H); 6.30 (s, 1H); 6.26 (d, 1H); 6.01 (s, 1H); 3.82 (s, 3H); 2.42 (s, 3H); 2.31 (s, 3H); 2.25 (s, 3H); 2.14 (s, 3H); 2.09 (s, 3H) 13CNMR (CDCl3), delta(ppm): 165.62; 156.35; 155.93; 144.11; 140.15; 139.81; 138.14; 136.03; 135.33; 134.03; 132.02; 130.28; 129.88; 129.06; 125.43; 122.88; 121.07; 118.67; 116.98; 112.05; 110.10; 55.63; 21.49; 17.54; 14.19; 13.09; 11.92 High-resolution MS: m/z: 485.2177 (theoretical value: 485.2178) molecular formula: C28H30F3NO3

Reference： [1]Patent: EP2279999,2011,A1 .Location in patent: Page/Page column 21
[2]Patent: US2011/77298,2011,A1 .Location in patent: Page/Page column 16-17

14
[ 1535-76-8 ]
[ 53839-60-4 ]
[ 1197356-59-4 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine In toluene at 20℃; Cooling;	12 In a reaction flask, retinoic acid of 0.5g, toluene of 5ml and phosphorus trichloride of 0.11ml are added and stirred at the room temperature for 3h, and the resultant solution is added in a solution of 4-hydroxy-3-trifluoromethylaniline of 0.17g and pyridine of 5ml, stirred to react with one another for 5h in the cooling condition, and stirred at the room temperature overnight; and the reaction liquid is poured in the crushed ice, followed by pH regulation to 1 by concentrated hydrochloric acid, extraction by ethyl acetate for three times, organic layer washing by saturated sodium chloride, 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 = 10:1), fraction collection, and concentration to obtain a yellow product of 0.08g.
	With pyridine In toluene at 20℃; Cooling;	12 Example 12 (4-hydroxy-3-trifluoromethylphenyl)-(all-trans)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cy clohexen-1-yl)-2,4,6,8-nonatetraenoic acid amide (7a-01) In a reaction flask, retinoic acid of 0.5 g, toluene of 5 ml and phosphorus trichloride of 0.11 ml are added and stirred at the room temperature for 3 h, and the resultant solution is added in a solution of 4-hydroxy-3-trifluoromethylaniline of 0.17 g and pyridine of 5 ml, stirred to react with one another for 5 h in the cooling condition, and stirred at the room temperature overnight; and the reaction liquid is poured in the crushed ice, followed by pH regulation to 1 by concentrated hydrochloric acid, extraction by ethyl acetate for three times, organic layer washing by saturated sodium chloride, 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=10:1), fraction collection, and concentration to obtain a yellow product of 0.08 g.

Reference： [1]Current Patent Assignee: ANHUI MEDICAL UNIVERSITY; ANHI NEW STAR PHARMACEUTICAL DEVELOPMENT - EP2279999, 2011, A1 Location in patent: Page/Page column 19
[2]Current Patent Assignee: ANHUI MEDICAL UNIVERSITY; ANHI NEW STAR PHARMACEUTICAL DEVELOPMENT - US2011/77298, 2011, A1 Location in patent: Page/Page column 15

15
[ 1535-76-8 ]
[ 74479-50-8 ]
[ 1197356-88-9 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine In toluene at 20℃; for 5h; Cooling;	26 Example 26 (4-hydroxy-3-trifluoromethoxyphenyl)-(all-trans)-9-(4-methoxy-2,3,6-trimethylphen yl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid amide (7b-01) 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 4-hydroxy-3-trifluoromethylphenylamine of 0.27 g and pyridine of 6 ml in the cooling condition, and stirred to react with one another for 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=5:1), fraction collection, concentration, and recrystallization by methanol to obtain a yellow product of 0.20 g.

Reference： [1]Current Patent Assignee: ANHUI MEDICAL UNIVERSITY; ANHI NEW STAR PHARMACEUTICAL DEVELOPMENT - US2011/77298, 2011, A1 Location in patent: Page/Page column 17-18

16
[ 121-01-7 ]
[ 1535-76-8 ]

Reference： [1]Journal of Photochemistry and Photobiology A: Chemistry,2011,vol. 226,p. 57 - 63

17
[ 1535-76-8 ]
[ 79-30-1 ]
2-methyl-N-[4-hydroxy-3-(trifluoromethyl)phenyl]propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine at 20℃; for 19h;

Reference： [1]Location in patent: experimental part Udagawa, Chikako; Fukuyoshi, Shuichi; Morimoto, Shotaro; Tanimoto, Yoshifumi; Nakagaki, Ryoichi [Journal of Photochemistry and Photobiology A: Chemistry, 2011, vol. 226, # 1, p. 57 - 63]

18
[ 1535-76-8 ]
[ 53903-51-8 ]

Yield	Reaction Conditions	Operation in experiment
		Step 3:; Sodium nitrite (0.47 g) in ¾0 (3 mL) was added dropwise to a solution of 4-amino-2- (trifluoromethyl)phenol (1 g) in acetonitrile (20 mL) and hydrochloric acid (10 mL) at 0 C . After stirring for 0.5 hour, copper(I) chloride (1.12 g) in 3 M HC1 (5 mL) was added to the mixture. Then the reaction mixture was stirred at 100 C for 6 hours. After cooling to room temperature, the solution was diluted with EtOAc (200 mL). The organic phase was washed with water (100 mL) and brine (50 mL), dried, and concentrated. The residue was purified by flash chromatography (DCM : PE = 1: 1) to afford 4-chloro-2-(trifluoromethyl)phenoI (700 mg) as a brown oil. MS(ES+) m/z 195 (MH ).
700 mg		Sodium nitrite (0.47 g) in H2O (3 ml) was added dropwise to a solution of 4-amino-2-(trifluoromethyl)phenol (1 g) in acetonitrile (20 ml) and hydrochloric acid (10 ml) at 0 C. After stirring for 0.5 hour, copper(I) chloride (1.12 g) in 3 M HCl (5 ml) was added to the mixture. Then the reaction mixture was stirred at 100 C for 6 h. After cooling to room temperature, the solution was diluted with EtOAc (200 ml). The organic phase was washed with water (100 ml) and brine (50 ml), dried, and concentrated. The residue was purified by flash chromatography (DCM/PE = 1:1) to afford 4-chloro-2-(trifluoromethyl)phenol (700 mg) as a brown oil. MS(ES+) m/z 195 (MH+).

Reference： [1]Patent: WO2012/100734,2012,A1 .Location in patent: Page/Page column 28-29
[2]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5293 - 5302

19
[ 1535-76-8 ]
[ 1391980-14-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium nitrite; hydrogenchloride / acetonitrile; water / 0 °C 1.2: 6 h / 100 °C 2.1: caesium carbonate / acetone / 4 h / 45 °C
	Multi-step reaction with 2 steps 1.1: hydrogenchloride; sodium nitrite / water; acetonitrile / 0.5 h / 0 °C 1.2: 6 h / 100 °C 2.1: caesium carbonate / acetone / 4 h / 45 °C

Reference： [1]Wang, Yonghui; Yang, Ting; Liu, Qian; Ma, Yingli; Yang, Liuqing; Zhou, Ling; Xiang, Zhijun; Cheng, Ziqiang; Lu, Sijie; Orband-Miller, Lisa A.; Zhang, Wei; Wu, Qianqian; Zhang, Kathleen; Li, Yi; Xiang, Jia-Ning; Elliott, John D.; Leung, Stewart; Ren, Feng; Lin, Xichen [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5293 - 5302]
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/100734, 2012, A1

20
[ 1535-76-8 ]
[ 1391979-79-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium nitrite; hydrogenchloride / acetonitrile; water / 0 °C 1.2: 6 h / 100 °C 2.1: caesium carbonate / acetone / 4 h / 45 °C 3.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 12 h / 40 °C
	Multi-step reaction with 3 steps 1.1: hydrogenchloride; sodium nitrite / water; acetonitrile / 0.5 h / 0 °C 1.2: 6 h / 100 °C 2.1: caesium carbonate / acetone / 4 h / 45 °C 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 40 °C

Reference： [1]Wang, Yonghui; Yang, Ting; Liu, Qian; Ma, Yingli; Yang, Liuqing; Zhou, Ling; Xiang, Zhijun; Cheng, Ziqiang; Lu, Sijie; Orband-Miller, Lisa A.; Zhang, Wei; Wu, Qianqian; Zhang, Kathleen; Li, Yi; Xiang, Jia-Ning; Elliott, John D.; Leung, Stewart; Ren, Feng; Lin, Xichen [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5293 - 5302]
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/100734, 2012, A1

21
[ 892414-51-6 ]
[ 1535-76-8 ]
4-[6-chloro-3-(trifluoromethyl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-3-(trifluoromethyl)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 120℃; for 3h;	4-[6-chloro-3-(trifluoromethyl)-1-[2-(trimethylsi lyl)ethoxy]methyl}-1 H-pyrrolo[2,3-b]pyrid in-4- yl]oxy}-3-(trifluoromethyl)aniline A solution of 6-chloro-4-n itro-3-(trifluoromethyl)-1 -[2-(trimethylsilyl)ethoxy]methyl}-1 Hpyrrolo[2,3-b]pyridine (500 mg, 1.26 mmol, see Synthesis 2007, page 251-258, Org. ProcessRes. Dev. 2010, page 168-173), 4-amino-2-(trifluoromethyl)phenol (246 mg, 1.39 mmol) and potassium carbonate (524 mg, 3.79 mmol) in DMSO (5.0 mL) was stirred at 120°C for 3 hours. After cooling to room temperature the reaction mixture was diluted with ethyl actate (200 mL). This organic phase was washed two times with water (30 mL) and once with brine (20 mL), then dried over sodium sulfate and after filtration evaporated to dryness. The resulting residue was purified via a Biotage chromatography system (28g snap KP-NH column, hexane / 0 - 70% ethyl acetate) to obtain 550 mg (93 % purity, 77 % yield) of the desired title compound.14Jfl (400 MHz, DMSO-d6) δ [ppm]: -0.11 --0.07 (m, 9H), 0.79-0.88 (m, 2H), 3.54-3.61(m, 2H), 5.61 (s, 2H), 5.73 (s, 2H), 6.30 - 6.32 (m, 1H), 6.90 (dd, 1H), 6.99 (d, 1H), 7.17 (d, 1 H), 8.35 (s, 1 H).

Reference： [1]Current Patent Assignee: BAYER AG; Helmholtz Association - WO2018/228923, 2018, A1 Location in patent: Page/Page column 53; 54

22
[ 1535-76-8 ]
3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1-[2-(trimethylsi lyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / dimethyl sulfoxide / 3 h / 120 °C 2: triethylamine; palladium 10% on activated carbon; hydrogen / ethanol / 7 h / 20 °C

Reference： [1]Current Patent Assignee: BAYER AG; Helmholtz Association - WO2018/228923, 2018, A1

23
[ 1535-76-8 ]
phenyl [3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / dimethyl sulfoxide / 3 h / 120 °C 2: triethylamine; palladium 10% on activated carbon; hydrogen / ethanol / 7 h / 20 °C 3: pyridine / tetrahydrofuran / 0.58 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: BAYER AG; Helmholtz Association - WO2018/228923, 2018, A1

24
[ 1535-76-8 ]
1-[2-(morpholin-4-yl)ethyl]-3-[3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl]urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate / dimethyl sulfoxide / 3 h / 120 °C 2: triethylamine; palladium 10% on activated carbon; hydrogen / ethanol / 7 h / 20 °C 3: pyridine / tetrahydrofuran / 0.58 h / 0 - 20 °C 4: N,N-dimethyl-formamide / 2 h / 60 °C

Reference： [1]Current Patent Assignee: BAYER AG; Helmholtz Association - WO2018/228923, 2018, A1

25
[ 1535-76-8 ]
1-[2-(morpholin-4-yl)ethyl]-3-[3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin4-yl]oxy}phenyl]urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: potassium carbonate / dimethyl sulfoxide / 3 h / 120 °C 2: triethylamine; palladium 10% on activated carbon; hydrogen / ethanol / 7 h / 20 °C 3: pyridine / tetrahydrofuran / 0.58 h / 0 - 20 °C 4: N,N-dimethyl-formamide / 2 h / 60 °C 5: trifluoroacetic acid / dichloromethane / 3 h / 20 °C

Reference： [1]Current Patent Assignee: BAYER AG; Helmholtz Association - WO2018/228923, 2018, A1

26
[ 1535-76-8 ]
2,2,2-trichloroethyl (2-chloropyridin-4-yl)carbamate [ No CAS ]
1-(2-chloropyridin-4-yl)-3-[4-hydroxy-3-(trifluoromethyl)phenyl]urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15 mg	With triethylamine In 1-methyl-pyrrolidin-2-one at 80℃; for 17h;	4 1-(2-chloropyridin-4-yl)-3-[4-hydroxy-3-(trifluoromethyl)phenyl]urea 69.9 mg (395 pmol) 4-a ino-2-(trifluoromethyl)phenol in 1.2 ml N-methylpyrrolidone was treated with 120.0 mg (395 pmol) intermediate 2 and 110 pL (790 pmol) triethylamine and stirred at 80°C for 17 hours. The solvent was evaporated and the residue was purified by preparative HPLC (method A) to give 15.0 mg of the title compound. 1H NMR (400 MHz, DMSO-de) d ppm 6.98 (d, J= 8.87 Hz, 1 H), 7.32 (dd, J=5.58, 2.03 Hz, 2 H), 7.60 - 7.77 (m, 2 H), 8.17 (d, J=5.58 Hz, 1 H), 8.95 (s, 1 H), 9.37 (s, 1 H), 10.29 (s, 1 H). LC-MS (method 3): Rt = 0.93 min; MS (ESI+): m/z = 333 [M+H]+.

Reference： [1]Current Patent Assignee: BAYER AG - WO2020/126968, 2020, A2 Location in patent: Page/Page column 79-80

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
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P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
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P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
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P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere