[ CAS No. 886762-08-9 ]

Name: 886762-08-9|5-Bromo-2-(trifluoromethoxy)aniline|98%
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Quality Control of [ 886762-08-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 886762-08-9 ]

CAS No. :	886762-08-9	MDL No. :	MFCD04039242
Formula :	C₇H₅BrF₃NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FOJWHUFRHXEUBA-UHFFFAOYSA-N
M.W :	256.02	Pubchem ID :	2779367
Synonyms :

Calculated chemistry of [ 886762-08-9 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	45.23
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) :	-5.64 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.04
Log Po/w (XLOGP3) :	3.13
Log Po/w (WLOGP) :	4.2
Log Po/w (MLOGP) :	2.37
Log Po/w (SILICOS-IT) :	2.38
Consensus Log Po/w :	2.82

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.61
Solubility :	0.063 mg/ml ; 0.000246 mol/l
Class :	Soluble
Log S (Ali) :	-3.54
Solubility :	0.0739 mg/ml ; 0.000289 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.52
Solubility :	0.077 mg/ml ; 0.000301 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	1.81

Safety of [ 886762-08-9 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P280-P305+P351+P338-P304+P340-P405-P501	UN#:
Hazard Statements:	H302-H312-H332-H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 886762-08-9 ]

* 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 [ 886762-08-9 ]
Downstream synthetic route of [ 886762-08-9 ]

[ 886762-08-9 ] Synthesis Path-Upstream 1~1

1
[ 95668-20-5 ]
[ 886762-08-9 ]

Yield	Reaction Conditions	Operation in experiment
70%	at 0 - 20℃; for 2 h;	5-bromo-2-(trifluoromethoxy)aniline (1): To a solution of 4-bromo-2-nitro-l- (trifluoromethoxy)benzene (2.0 g, 7.0 mmol) in acetic acid (10.0 mL) was added Fe -powder (1.0 g, 17.9 mmol) at 0-10 °C. The reaction mixture was allowed to stir at room temperature for 2 h. After completion of the reaction, acetic acid was distilled and the residue was diluted with water, basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (2x50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 1 (1.2g, 70percent) as a brown gummy solid. 1H NMR (400 MHz, DMSO- d₆): δ 5.68 (s, 2H), 6.65-6.66 (dd, J = 2.4 Hz, 6.2 Hz, 1H), 6.95-6.96 (d, J = 2.5 Hz, 1H), 7.01- 7.01 (dd, J = 1.4 Hz, 8.6 Hz, 1H). MS m/z (M+H): 256.3.
2.5 g	With iron; ammonium chloride In water at 80℃; for 1 h; Inert atmosphere	Step 1: 5-bromo-2-(trifluoromethoxy) aniline 5-bromo-2-(trifluoromethoxy) nitrobenzene (2.86g, 10mmol), iron powder (2.86g) and saturated aqueous ammonium chloride solution (50mL) were added to a 250mL reaction flask. The reaction mixture was heated up to 80 °C under the protection of nitrogen and stirred for 1 hour. After completion of the reaction, the reaction mixture was filtered and concentrated to obtain the title compound (yellow solid, 2.5g, 98percent), which may be used directly for the subsequent reaction. (MS: [M+1] none)

Reference： [1] Patent: WO2014/149164, 2014, A1, . Location in patent: Paragraph 00758; 00892
[2] Patent: EP3150592, 2017, A1, . Location in patent: Paragraph 0126; 0127; 0128

[ 886762-08-9 ] Synthesis Path-Downstream 1~68

1
[ 886762-08-9 ]
[ 1048963-39-8 ]

Yield	Reaction Conditions	Operation in experiment
50%	With hydrogenchloride; sulfuric acid; sodium nitrite; In ethanol; water; at 0 - 100℃; for 13.5h;	Into a 250-mL 3-necked round-bottom flask, was placed 5-bromo-2- (trifluoromethoxy) aniline (2 g, 7.81 mmol, 1 equiv), ethanol (20 mL), HCl (2 mL). This was followed by the addition of NaN02 (595 mg, 8.62 mmol, 1.10 equiv) dropwise with stirring at 0 C. To this was added water (110 mL), sulfuric acid (5.5 mL). The resulting solution was stirred for 1.5 h at 0 C in a water/ice bath. The resulting solution was allowed to react, with stirring, for an additional 12 h while the temperature was maintained at 100 C in an oil bath. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x50 mL of sodium bicarbonate. The mixture was dried over anhydrous sodium sulfate. This resulted in 1 g (50%) of the title compound as an oil. Analytical Data: LC-MS: (ES, m/z): RT =1.715min, LCMS 53: m/z = 257 [M+l].
	With hydrogenchloride; conc. sulphuric acid; sodium nitrite; In ethanol; water;	b) 5-Bromo-2-trifluoromethoxyphenol A solution of 210 mmol of sodium nitrite in 120 ml of water is added dropwise to a suspension of 200 mmol of <strong>[886762-08-9]5-bromo-2-trifluoromethoxyaniline</strong> in 500 ml of ethanol and 50 ml of conc. HCl at 0C. The reaction mixture is stirred at 5C for 1.5 hours. The reaction mixture is slowly added dropwise to a solution of 135 ml of conc. sulphuric acid in 2.8 l of water and stirred under reflux overnight. The reaction mixture is extracted with diethyl ether (3x) - the combined organic phases are washed with water and 1 M sodium bicarbonate solution and then extracted with 2N NaOH (2x). The combined aqueous phases are acidified with conc. HCl and extracted with diethyl ether (3x). The combined organic phases are washed with water, dried with sodium sulphate and evaporated. The crude title compound is obtained from the residue.
		A solution of 210 mmol of sodium nitrite in 120 ml of water is added dropwise to a suspension of 200 mmol of <strong>[886762-08-9]5-bromo-2-trifluoromethoxyaniline</strong> in 500 ml of ethanol and 50 ml of cone. HCI at 00C. The reaction mixture is stirred at 5C for 1.5 hours. The reaction mixture is slowly added dropwise to a solution of 135 ml of cone, sulphuric acid in 2.8 I of water and stirred under reflux overnight. The reaction mixture is extracted with diethyl ether (3x) - the combined organic phases are washed with water and 1 M sodium bicarbonate solution and then extracted with 2N NaOH (2x). The combined aqueous phases are acidified with cone. HCI and extracted with diethyl ether (3x). The combined organic phases are washed with water, dried with sodium sulphate and evaporated. The crude title compound is obtained from the residue.

Reference： [1]Patent: WO2017/181177,2017,A1 .Location in patent: Paragraph 0875-0878
[2]Patent: EP1958666,2008,A1
[3]Patent: WO2006/95020,2006,A1 .Location in patent: Page/Page column 53

2
[ 886762-08-9 ]
[ 108-24-7 ]
[ 392726-69-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	In ethanol; at 0 - 20℃;	Example 29; 5-(4-Methyl-piperazin-l-yl)-2-trifluoromethoxy-phenylamine trihydrochloride salt; Step 1. N-(5-bromo-2-trifluoromethoxy-phenyl)-acetamide; To a solution of <strong>[886762-08-9]5-bromo-2-trifluoromethoxy-phenylamine</strong> (5.12 g, 20 mmol) inEtOH (50 mL) at 00C was added a solution of acetic anhydride (4.7 mL, 50 mmol) in EtOH (10 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated to drieness and the solid was tritured with diethyl ether and filtered to give 5.64 g (95% yield) of N-(5-bromo-2-trifluoromethoxy-phenyl)-acetamide .1H NMR (400 MHz, DMSO-J6) delta ppm: 2.11 (s, 3 H) 7.39 (m, 2 H) 8.21 (s, 1 H) 9.87(s, 1 H).
95%	In ethanol; at 0 - 20℃;	Example 6; 2-trifluoromethoxy-5-(4-methyl-piperazin-l-yl)-phenylamine trihydrochloride salt and l-(3-iodo-4-trifluoromethoxy-phenyl)-4-methyl-piperazine; Step 1: N-(5-bromo-2-trifluoromethoxy-phenyl)-acetamide; To a solution of <strong>[886762-08-9]2-trifluoromethoxy-5-bromo-phenylamine</strong> (5.12 g, 20 mmol) in EtOH (50 mL) at 00C was added a solution of acetic anhydride (4.7 mL, 50 mmol) in EtOH (10 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated to drieness and the solid was tritured with diethyl ether and filtered to give 5.64 g (95% yield) of N-(5-bromo-2-trifluoromethoxy-phenyl)-acetamide . <n="54"/>1H NMR (400 MHz, DMSO-d6) delta ppm: 2.11 (s, 3 H) 7.39 (m, 2 H) 8.21 (s, 1 H) 9.87 (s,1 H); MS (ESI): 257 [M+H]+.
95%	In ethanol; at 0 - 20℃;	To a solution of <strong>[886762-08-9]2-trifluoromethoxy-5-bromo-phenylamine</strong> (5.12 g, 20 mmol) in EtOH (50 niL) at 00C was added a solution of acetic anhydride (4.7 rnL, 50 mmol) in EtOH (10 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated to drieness and the solid was tritured with diethyl ether and filtered to give 5.64 g (95% yield) of N-(5-bromo-2-trifluoromethoxy-phenyl)-acetamide . 1H NMR (400 MHz, DMSO-d6) delta ppm: 2.11 (s, 3 H) 7.39 (m, 2 H) 8.21 (s, 1 H) 9.87 (s, 1 H); MS (ESI): 257 [M+H]+.

Reference： [1]Patent: WO2008/74788,2008,A1 .Location in patent: Page/Page column 87
[2]Patent: WO2009/40399,2009,A1 .Location in patent: Page/Page column 52-53
[3]Patent: WO2009/71480,2009,A2 .Location in patent: Page/Page column 21-22

3
[ 109-01-3 ]
[ 886762-08-9 ]
[ 1034618-02-4 ]

Yield	Reaction Conditions	Operation in experiment
64%	With lithium hexamethyldisilazane;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In tetrahydrofuran; for 1h;Heating / reflux;	Example 35; N-[5-(4-Methyl-piperazin-l-yl)-2-trifluoromethoxy-phenyl]-guanidine; Step 1. 5-(4-Methyl-piperazin-l-yl)-2-trifluoromethoxy-phenylamine; Tris(dibenzilideneacetone)dipalladium, Pd2(dba)3 (1.1 g, 1.2 mmol), 2- dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (0.94 g, 2.4 mmol), 5- bromo-2-trifluoromethoxy-phenylamine (30.7 g, 120 mmol) in THF (50 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. LiN(TMS)2 solution (IM in THF, 288 mL) and N- methylpiperazine (26.7 mL, 194 mmol) were added and the reaction refluxed for 1 h. The reaction mixture was then allowed to cool to room temperature and filtered through a pad of celite. The organic phase was concentrated, the residue dissolved inDCM (200 ml) and washed with water (1 x 100 ml). The organic phases were dried over anhydrous Na2SO4, the solvent evaporated in vacuo and the crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 21.1 g of 5-(4-methyl-piperazin- 1 -yl)-2-trifluoromethoxy-phenylamine (64% yield) as a light brown powder.1H NMR (400 MHz, DMSO-J6) delta ppm 2.23 (s, 3 H) 2.42 - 2.47 (m, 4 H) 3.02 - 3.08 (m, 4 H) 5.10 (s, 2 H) 6.16 (dd, J=8.90, 2.93 Hz, 1 H) 6.33 (d, J=2.93 Hz, 1 H) 6.90 (dd, J=8.90, 1.46 Hz, I H).

Reference： [1]Patent: WO2008/74788,2008,A1 .Location in patent: Page/Page column 93
[2]Bulletin of the Korean Chemical Society,2014,vol. 35,p. 1929 - 1930

4
[ 886762-08-9 ]
[ 420-04-2 ]
[ 1034617-98-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	With hydrogenchloride; In ethanol; water; for 72h;Heating / reflux;	Example 34; N-(5-Bromo-2-trifluoromethoxy-phenyl)-guanidine; <n="94"/>To a suspension of <strong>[886762-08-9]5-bromo-2-trifluoromethoxy-phenylamine</strong> (5.0 g, 19.5 mmol) in EtOH (15 mL), cyanamide (1.64 g, 39 mmol) dissolved in 5 mL of EtOH and 1 mL H2O, and HCl 37% (3.25 mL) diluted in 10 mL EtOH were added drop wise into the mixture under stirring. The mixture was refluxed for 72 h. The mixture was cooled down to room temperature, concentrated then diluted with water; NaOH IN was added to basic pH and extracted several times with ethyl acetate, dried over sodium sulfate and concentrated to afford 5.2 g of the title compound (89% yield). 1H NMR (400 MHz, DMSO-J6) delta ppm 5.40 (s, 4 H) 6.98 (dd, J=8.72, 2.38 Hz, 1 H) 7.05 (d, J=I.83 Hz, 1 H) 7.11 (m, 1 H).

Reference： [1]Patent: WO2008/74788,2008,A1 .Location in patent: Page/Page column 92-93

5
[ 454482-11-2 ]
[ 886762-08-9 ]
[ 1034618-10-4 ]

Yield	Reaction Conditions	Operation in experiment
65%	With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃; for 3h;	Example 43; 5-(l-Methyl-piperidin-4-yl)-2-trifluoromethoxy-phenylamine; Step 1. 5-(l-Methyl-l,2,3,6-tetrahydro-pyridin-4-yl)-2-trifluoromethoxy- phenylamine; 5-Bromo-2-trifluoromethoxy-phenylamine (0.43 g, 1.68 mmol), cesium carbonate (1.65 g, 5.06 mmol), 1 , r-bis(diphenylphosphino)ferrocenepalladium(ii) dichloride, complex with dichloromethane (1 :1) (0.08g, 0.1 mmol) in dry DMF (20 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. A solution of l-methyl-4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-l,2,3,6-tetrahydro-pyridine (0.45 g, 2.01 mmol) in dry DMF (10 mL) were added to the suspension and the reaction mixture warmed at 80 0C for 3 hours. The reaction mixture was then allowed to cool to room temperature, diluted with water (100 mL) and extracted with DCM (2 x 50 mL) and the combined <n="102"/>organic phases were extracted with IN HCl solution (50 rnL). The aqueous layer was basifed by addition of sodium bicarbonate and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, the solvent removed under reduced pressure and the crude solid purified by flash chromatography on silica gel (eluant: DCM/MeOH 90/10) to afford the intermediate as a light brown solid (0.3 g, 65 percent yield)1H NMR (400 MHz, DMSO-J6) delta ppm 2.29 (s, 3 H) 2.38 - 2.44 (m, 2 H) 2.58 (t, J=5.55 Hz, 2 H) 3.02 (d, J=2.32 Hz, 2 H) 5.29 (s, 2 H) 6.03 (t, J=3.48 Hz, 1 H) 6.64 (dd, J=8.54, 2.19 Hz, 1 H) 6.86 (d, J=2.32 Hz, 1 H) 7.03 (dd, J=8.54, 1.34 Hz, 1 H).

Reference： [1]Patent: WO2008/74788,2008,A1 .Location in patent: Page/Page column 100-101

6
[ 886762-08-9 ]
[ 1137468-13-3 ]
[ 1137467-60-7 ]

Yield	Reaction Conditions	Operation in experiment
52%	With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; at 80℃; for 3h;	Step (d'). 5-[2-(5-bromo-2-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-l- methyl-lH-pyrrole-3-carboxylic acid ethyl ester (AlBlClMl); Palladium acetate [Pd(OAc)2] (0.12 g, 0.55 mmol), (+)-BINAP (0.34 g, 0.55 mmol) and dimethylformamide (60 mL) were charged to a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. The mixture was stirred under argon for 30 minutes and added to a mixture of 5-bromo-2-trifluoromethoxy aniline (2.0 g, 5.60 mmol), 5 -(2-iodo-pyrimidin-4-yl)-l -methyl- lH-pyrrole-3-carboxylic acid ethyl ester (1.44 g, 5.60 mmol), and potassium carbonate (7.70 g, 55.80 mmol) in <n="40"/>dimethylformamide (90 niL). The resulting mixture was stirred at 800C for 3 hours under argon. After cooling to room temperature, the reaction mixture was filtered on a pad of celite. The solvent was concentrated, the crude solid was purified by flash chromatography on silica gel (eluant: hexane/ethyl acetate 70/30) to afford 1.41 g (52%) of the title compound as white solid.1H NMR (400 MHz, DMSO-J6) delta ppm 1.27 (t, J=7.07 Hz, 3 H) 3.92 (s, 3 H) 4.20 (q, J=7.07 Hz, 2 H) 7.29 (d, J=5.37 Hz, 1 H) 7.28 (d, J=I.83 Hz, 1 H) 7.35 - 7.38 (m, 1 H) 7.38 - 7.42 (m, 1 H) 7.66 (d, J=I.71 Hz, 1 H) 8.15 (d, J=2.20 Hz, 1 H) 8.40 (d, J=5.37 Hz, 1 H) 9.20 (s, 1 H); MS (ESI): 485 [M+H]+.

Reference： [1]Patent: WO2009/40399,2009,A1 .Location in patent: Page/Page column 38-39
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 96 - 101

7
[ 109-01-3 ]
[ 886762-08-9 ]
[ 1034732-96-1 ]

Yield	Reaction Conditions	Operation in experiment
70%	With lithium hexamethyldisilazane; DavePhos;tris-(dibenzylideneacetone)dipalladium(0); In tetrahydrofuran; for 1h;Inert atmosphere; Reflux;	Preparation F-(4-Methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine.Pd2(dba)3 (1.1 g, 1.2 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (0.94 g, 2.4 mmol), 5- bromo-2-trifluoromethoxy-phenylamine (30.7 g, 120 mmol) in THF (50 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. LiN(TMS)2 solution (1 M in THF, 288 mL) and N-methylpiperazine (26.7 mL, 194 mmol) were added and the reaction refluxed for 1 hours. The reaction mixture was then allowed to cool to room temperature and filtered through a pad of celite. The organic phase was concentrated, the residue dissolved in DCM (200 mL) and washed with H2O (1 x 100 mL). The organic phases were dried over anhydrous Na2S04, the solvent evaporated in vacuo and the crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 23 g of 4-(4-methyl-piperazin-1-yl)-2- trifluoromethoxy-phenylamine (70% yield) as a light brown powder.1H NMR (401 MHz, DMSO-d6) delta ppm 2.22 (s, 3H), 2.44 (t, J=4.88 Hz, 4H), 2.94 (t, J=4.88 Hz, 4 H) 4.77 (br.s., 2 H) 6.66-6.69 (m, 1 H) 6.73 - 6.80 (m, 2 H);MS calc: 276.1318; MS found: 276.1320
70%	With lithium hexamethyldisilazane;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In tetrahydrofuran; for 1h;Inert atmosphere; Reflux;	Preparation 7; 4-(4-Methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine; Tris(dibenzilideneacetone)dipalladium, Pd2(dba)3(1.1 g, 1.2 mmol), 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)-biphenyl (0.94 g, 2.4 mmol), <strong>[886762-08-9]5-bromo-2-trifluoromethoxy-phenylamine</strong> (30.7 g, 120 mmol) in THF (50 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. LiN(TMS)2 solution (1 M in THF, 288 mL) and N-methylpiperazine (26.7 mL, 194 mmol) were added and the reaction refluxed for 1 h. The reaction mixture was then allowed to cool to room temperature and filtered through a pad of celite. The organic phase was concentrated, the residue dissolved in DCM (200 mL) and washed with water (1 x 100 mL). The organic phases were dried over anhydrous Na2SU4, the solvent evaporated in vacuo and the crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 23 g of 4-(4- methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine (70% yield) as a light brown powder. MS calc: 276.1318; MS found: 276.1320

Reference： [1]Patent: WO2012/13557,2012,A1 .Location in patent: Page/Page column 33
[2]Patent: WO2009/156315,2009,A1 .Location in patent: Page/Page column 61

8
[ 802537-20-8 ]
[ 886762-08-9 ]
[ 1034614-87-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 6489 - 6494
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2969 - 2974

9
[ 886762-08-9 ]
[ 154065-33-5 ]

Yield	Reaction Conditions	Operation in experiment
52%	With copper(l) iodide; tert.-butylnitrite; In acetonitrile; at 60℃; for 1h;	10.74 g (93.75 mmol) of tert-butyl nitrite and 28.5 g (150 mmol) of copper iodide are suspended in 270 ml of acetonitrile and heated to 60 C. A solution of 15 g (62.5 mmol) of <strong>[886762-08-9]5-bromo-2-trifluoromethoxyaniline</strong> in 130 ml of acetonitrile is slowly added dropwise to this suspension and the mixture is left to stir at 60 C. for another hour. The reaction solution is then poured on to a mixture of 250 ml of 2 N aqueous HCl and 250 ml of ethyl acetate. The organic phase is washed twice more with aqueous NaCl solution, filtered through a little silica gel and concentrated. The residue is separated by chromatography on silica gel (ethyl acetate/n-heptane=1/18). This affords 12.2 g (52% yield) of product 96 as a colorless oil.

Reference： [1]Patent: US2011/59910,2011,A1 .Location in patent: Page/Page column 55

10
[ 886762-08-9 ]
[ 1181682-10-9 ]

Reference： [1]Patent: US2011/59910,2011,A1

11
[ 886762-08-9 ]
[ 1181682-12-1 ]

Reference： [1]Patent: US2011/59910,2011,A1

12
[ 886762-08-9 ]
[ 1304581-32-5 ]
C₁₉H₁₉BrF₃NO₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; for 16h;	General Procedure: Methyl 2-[4-(chlorosulfonyl)-2,3-dimethylphenyl]oxy}propanoate (7) (4 g, 13.0 mmol) was dissolved in pyridine (10 mL). After 5 min, 3-bromo-2-chloroaniline (3.22 g, 15.6 mmol) was added. The reaction was complete within a few hours. The reaction mixture was then extracted using diethyl ether. The combined organic phases were washed with 1N HCl and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound which was used without further purification.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2345 - 2350

13
[ 886762-08-9 ]
[ 1034616-36-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2969 - 2974

14
[ 886762-08-9 ]
[ 1310814-14-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2969 - 2974

15
[ 886762-08-9 ]
[ 1034616-30-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2969 - 2974

16
[ 886762-08-9 ]
[ 1034616-34-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2969 - 2974

17
[ 886762-08-9 ]
[ 1310814-15-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2969 - 2974

18
[ 886762-08-9 ]
[ 1034616-28-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2969 - 2974

19
[ 109-01-3 ]
[ 886762-08-9 ]
[ 1202057-07-5 ]

Reference： [1]Patent: WO2012/13557,2012,A1
[2]Patent: WO2009/156315,2009,A1

20
[ 66715-65-9 ]
[ 886762-08-9 ]
[ 1567837-64-2 ]

Reference： [1]Patent: WO2014/28968,2014,A1

21
[ 66715-65-9 ]
[ 886762-08-9 ]
[ 1567837-65-3 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 45℃; for 4h;	General procedure: To a stirred solution of <strong>[886762-08-9]5-bromo-2-(trifluoromethoxy)aniline</strong> (540 mg, 2.11 mmol) in pyridine was added pyridine-2-sulfonylchloride (410 mg, 2.31 mmol and the mixture was heated to 45C for 4 h. After quenchingwith water the mixture was extracted with CH2C12, dried over MgSO4 and evaporated togive a solid (769 mg) that was used without further purification. To a mixture of the aforementioned crude solid and (chloromethoxy)ethane (329 mg, 3.49 mmol) in DMF at room temperature was added a 60% w/w dispersion of Nail in mineral oil (140 mg, 3.49 mol) and the mixture was stirred for 1 h. After quenching with water the mixture was extracted with CH2CI2, dried with MgSO4 and evaporated to give a solid which waspurified by column chromatography eluting with hexanes/EtOAc 3:1. The title compound was isolated as a colourless oil (857 mg, 89%, 2 steps).?H NMR [400 MHz, CDCI3I 6 8.75 (ddd, J =4.8, 1.6, 1.0 Hz, 1H), 7.90-7.82 (m, 2 H), 7.54-7.46 (m, 3 H), 7.10 (dddd, J = 8.9, 1.9,1.8, 1.8 Hz, 1 H), 5.21 (br s, 2 H), 3.79 (q, J = 7.0 Hz, 2 Fl), 1.20 (t, J = 7.0 Hz, 3 H). LRMS (APCI?) calcd for C13H10BrF3N2O3S 409 (M-EtO), found 409.
	With pyridine; In dichloromethane; at 20 - 45℃;Inert atmosphere;	General procedure: To a solution of 76 (120 mg, 0.37 mmol) in dry pyridine (12 mL) under N2 at RT, was added 2,4-difluorobenzenesulphonyl chloride (159 mg, 0.74 mmol) in CH2Cl2 (1.5 mL) dropwise over 5 min. The mixture was stirred at 45 C under N2 for 16 , and the solvent then removed under reduced pressure. The reaction was quenched with a little water and the resulting solid collected by filtration and washed with water and Et2O. Purification was carried out by trituration with hot CH2Cl2/MeOH solution to give 4 as a pale brown solid (65%).

Reference： [1]Patent: WO2014/28968,2014,A1 .Location in patent: Page/Page column 136; 137
[2]European Journal of Medicinal Chemistry,2017,vol. 137,p. 139 - 155

22
[ 886762-08-9 ]
9-cyclopentyl-7-methyl-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-7H-purin-8(9H)-one [ No CAS ]

Reference： [1]Bulletin of the Korean Chemical Society,2014,vol. 35,p. 1929 - 1930

23
[ 886762-08-9 ]
7-methyl-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-9-phenyl-7H-purin-8(9H)-one [ No CAS ]

Reference： [1]Bulletin of the Korean Chemical Society,2014,vol. 35,p. 1929 - 1930

24
[ 886762-08-9 ]
[ 814-68-6 ]
N-(5-bromo-2-(trifluoromethoxy)phenyl)acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -78 - 0℃; for 2h;	N-(5-bromo-2-(trifiuoromethoxy)phenyl)acrylamide (2): To a solution of 5-bromo- 2-(trifiuoromethoxy)aniline (1.2 g, 4.7 mmol) in dichloromethane (5.0 niL), diisopropylethylamine (727 mg, 5.64 mmol) and acryloyl chloride (382 mg, 4.22 mmol) were added at -78 C. The reaction mixture was allowed to stir at 0 C for 2 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2 (1.4 g, 93%) as an off white solid. 1H NMR (400 MHz, DMSO-d6) : delta 5.79-5.80 (dd, J = 1.82 Hz, 10.2 Hz, 1H), 6.26-6.27 (dd, J = 1.8, 17.0 Hz, 1H), 6.61-6.63 (dd, J = 17.0 Hz, 1H), 7.38-7.40 (m, 2H), 8.28-8.29 (d, J = 2.3 Hz, 1H), 10.07 (brs, 1H). MS m/z (M+H): 310.45

Reference： [1]Patent: WO2014/149164,2014,A1 .Location in patent: Paragraph 00759; 00893

25
[ 95668-20-5 ]
[ 886762-08-9 ]

Yield	Reaction Conditions	Operation in experiment
70%	With iron; acetic acid; at 0 - 20℃; for 2h;	5-bromo-2-(trifluoromethoxy)aniline (1): To a solution of 4-bromo-2-nitro-l- (trifluoromethoxy)benzene (2.0 g, 7.0 mmol) in acetic acid (10.0 mL) was added Fe -powder (1.0 g, 17.9 mmol) at 0-10 C. The reaction mixture was allowed to stir at room temperature for 2 h. After completion of the reaction, acetic acid was distilled and the residue was diluted with water, basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (2x50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 1 (1.2g, 70%) as a brown gummy solid. 1H NMR (400 MHz, DMSO- d6): delta 5.68 (s, 2H), 6.65-6.66 (dd, J = 2.4 Hz, 6.2 Hz, 1H), 6.95-6.96 (d, J = 2.5 Hz, 1H), 7.01- 7.01 (dd, J = 1.4 Hz, 8.6 Hz, 1H). MS m/z (M+H): 256.3.
2.5 g	With iron; ammonium chloride; In water; at 80℃; for 1h;Inert atmosphere;	Step 1: 5-bromo-2-(trifluoromethoxy) aniline 5-bromo-2-(trifluoromethoxy) nitrobenzene (2.86g, 10mmol), iron powder (2.86g) and saturated aqueous ammonium chloride solution (50mL) were added to a 250mL reaction flask. The reaction mixture was heated up to 80 C under the protection of nitrogen and stirred for 1 hour. After completion of the reaction, the reaction mixture was filtered and concentrated to obtain the title compound (yellow solid, 2.5g, 98%), which may be used directly for the subsequent reaction. (MS: [M+1] none)

Reference： [1]Patent: WO2014/149164,2014,A1 .Location in patent: Paragraph 00758; 00892
[2]Patent: EP3150592,2017,A1 .Location in patent: Paragraph 0126; 0127; 0128

26
[ 886762-08-9 ]
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)phenyl)acrylamide [ No CAS ]

Reference： [1]Patent: WO2014/149164,2014,A1

27
[ 886762-08-9 ]
(R)-N-(5-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)-2-(trifluoromethoxy)phenyl)acrylamide [ No CAS ]

Reference： [1]Patent: WO2014/149164,2014,A1

28
[ 886762-08-9 ]
[ 32315-10-9 ]
5-(4-aminophenyl)-N-methylpyridine-2-carboxamide [ No CAS ]
5-{4-[([5-bromo-2-(trifluoromethoxy)phenyl]amino}carbonyl)amino]phenyl}-N-methylpyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Triphosgene (0.5 g, 1.72 mmol) was dissolved in anhydrous CH2Cl2 (15 mL) and the mixture was stirred on the ice-bath for 15 min. 4-Chloro-3-(trifluoromethyl)phenylamine (0.84 g, 3.7 mmol) in anhydrous CH2Cl2 (10 mL) was added dropwise to the above mixture and stirring continued for 20 min. Et3N (0.7 mL, 5.16 mmol) diluted with CH2Cl2 (5 mL) was then added into the mixture. Stirring was continued for 20 min and a solution of Et3N (0.7 mL, 5.16 mmol), compound (14) (0.84 g, 3.7 mmol) in anhydrous CH2Cl2 (20 mL) was added. After completion of the action, the reaction was quenched with dilute Na2CO3. The organic layer was washed with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residues was purified by silica gel flash chromatography (PE/AcOEt = 1:1) yielding (W13). yield (0.36 g, 37%)

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 3228 - 3236

29
[ 886762-08-9 ]
[ 32315-10-9 ]
N-[5-(4-aminophenyl)pyridin-2-yl]-2,2-dimethylpropanamide [ No CAS ]
N-(5-{4-[([5-bromo-2-(trifluoromethoxy)phenyl]amino}carbonyl)amino]phenyl}pyridin-2-yl)-2,2-dimethylpropanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Triphosgene (0.09 g, 0.3 mmol) was dissolved in anhydrous CH2Cl2 (15 mL) and the mixture was stirred on the ice-bath for 15 min. 3-Bromo-5-(trifluoromethyl)aniline (0.16 g, 0.7 mmol) in anhydrous CH2Cl2 (10 mL) was added dropwise to the above mixture and stirring continued for 20 min. Et3N (0.12 mL, 0.89 mmol) diluted with CH2Cl2 (5 mL) was then added into the mixture. Stirring was continued for 20 min and a solution of Et3N (0.12 mL, 0.89 mmol), compound (9) (0.2 g, 0.74 mmol) in anhydrous CH2Cl2 (20 mL) was added. After completion of the action, the reaction was quenched with dilute Na2CO3. The organic layer was washed with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residues was purified by silica gel flash chromatography (PE/AcOEt = 3:1) yielding (W1).

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 3228 - 3236

30
[ 82261-42-5 ]
[ 886762-08-9 ]
[ 32315-10-9 ]
N-[5-bromo-2-(trifluoromethoxy)phenyl]-N'-(4-pyridin-3-ylphenyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Triphosgene (0.14 g, 0.48 mmol) was dissolved in anhydrous CH2Cl2 (15 mL) and the mixture was stirred on the ice-bath for 15 min. 3-Bromo-5-(trifluoromethyl)aniline (0.3 g, 1.2 mmol) in anhydrous CH2Cl2 (10 mL) was added dropwise to the above mixture and stirring continued for 20 min. Et3N (0.2 mL, 1.44 mmol) diluted with CH2Cl2 (5 mL) was then added into the mixture. Stirring was continued for 20 min and a solution of Et3N (0.2 mL, 1.44 mmol), 4-pyridin-3-ylaniline (5) (0.2 g, 1.2 mmol) in anhydrous CH2Cl2 (20 mL) was added. After completion of the action, the reaction was quenched with dilute Na2CO3. The organic layer was washed with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residues was purified by silica gel flash chromatography (PE/AcOEt = 6:1) yielding (L1). yield 73%

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 3228 - 3236

31
[ 886762-08-9 ]
[ 32315-10-9 ]
C₈H₃BrF₃NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; for 0.75h;Cooling with ice;	General procedure: Triphosgene (0.74 g, 2.5 mmol) was dissolved in anhydrousCH2Cl2 (20 mL) and the mixture was stirred on the ice-bath for15 min. A solution of the [3-bromo-5-(trifluoromethyl)phenyl]amine (1.66 g, 6.9 mmol) in anhydrous CH2Cl2 (10 mL) was addeddropwise to the above mixture and stirring continued for 30 min.Then triethanolamine (0.75 mL, 5.5 mmol) diluted with CH2Cl2(10 mL) was then added into the mixture. Stirring was continuedfor 20 min, a solution of triethanolamine (0.75 mL, 5.5 mmol) andintermediate (4a) (1.50 g, 6.3 mmol) in anhydrous CH2Cl2 (10 mL)was added. After completion of the action, the reaction wasquenched with dilute NaHCO3. The organic layer was washed withwater and brine, and dried over Na2SO4. After filtration and concentrationin vacuo, the residues was purified by silica gel flash chromatography (PE/AcOEt 5:1) gave as white solid (5a) (1.36 g,43%).

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 103,p. 80 - 90

32
[ 886762-08-9 ]
[ 79-04-9 ]
N-[5-bromo-2-(trifluoromethoxy)phenyl]-2-chloroacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
324 g	In toluene; at 100℃; for 2h;	240 g (0.937 mol) of <strong>[886762-08-9]5-bromo-2-(trifluoromethoxy)aniline</strong> were dissolved in 2400 mL of anh toluene. 112 mL (1.406 mol) of chloroacetyl chloride were added. It was stirred for 2 h at 100 C. The reaction mixture was concentrated on the rotavap. The residue was treated with 600 mL of cyclopentyl methyl ether and concentrated again. This procedure was performed twice yielding 324 g of the title compound. 1H-NM (400MHz, DMSO-d6): delta [ppm]= 4.39 (s, 2H), 7.40 - 7.44 (m, 1H), 7.49 (dd, 1H), 8.20 (d, 1H), 10.23 (s, 1H). LC-MS (Method 4): Rt = 1.27 min; MS (ESIpos): m/z = 332 [M+H]+.
324 mg	In toluene; at 100℃; for 2h;	240 g (0.937 mol) of <strong>[886762-08-9]5-bromo-2-(trifluoromethoxy)aniline</strong> were dissolved in 2400 mL of anh toluene.112 mL (1.406 mol) of chloroacetyl chloride were added. It was stirred for 2 h at 100 C. The reactionmixture was concentrated under vacuum. The residue was treated with 600 mL of cyclopentyl methyl ether and concentrated again. This procedure was performed twice yielding 324 g of the title compound.?H-NMR (400MHz, DMSO-d6): 6 [ppm]= 4.39 (s, 2H), 7.40 - 7.44 (m, 1H), 7.49 (dd, 1H), 8.20 (d, 1H), 10.23 (s, 1H).LC-MS (Method 4): R = 1.27 mm; MS (ESIpos): m/z = 332 [M+H].
324 g	In toluene; at 100℃; for 2h;	240 g (0.937 mol) of <strong>[886762-08-9]5-bromo-2-(trifluoromethoxy)aniline</strong> were dissolved in 2400 mL of anh toluene.112 mL (1.406 mol) of chloroacetyl chloride were added. It was stirred for 2 h at 100 C. The reactionmixture was concentrated under vacuum. The residue was treated with 600 mL of cyclopentyl methylether and concentrated again. This procedure was performed twice yielding 324 g of the titlecompound.?H-NMR (400MHz, DMSO-d6): 6 [ppm]= 4.39 (s, 2H), 7.40 - 7.44 (m, 1H), 7.49 (dd, 1H), 8.20 (d, 1H), 10.23 (s, 1H).LC-MS (Method 4): R = 1.27 mm; MS (ESIpos): m/z = 332 [M+H].

Reference： [1]Patent: WO2015/140196,2015,A1 .Location in patent: Page/Page column 96-97
[2]Patent: WO2015/140195,2015,A1 .Location in patent: Page/Page column 111
[3]Patent: WO2016/131808,2016,A1 .Location in patent: Page/Page column 63

33
[ 886762-08-9 ]
3-[(4-methylpiperazin-1-yl)acetyl]amino}-N-[5-(pyridin-2-yl)pyrazin-2-yl]-4-(trifluoromethoxy)benzamide [ No CAS ]

Reference： [1]Patent: WO2015/140196,2015,A1

34
[ 886762-08-9 ]
3-[(4-methylpiperazin-1-yl)acetyl]amino}-4-(trifluoromethoxy)benzoyl chloride [ No CAS ]

Reference： [1]Patent: WO2015/140196,2015,A1

35
[ 886762-08-9 ]
N-[5-bromo-2-(trifluoromethoxy)phenyl]-2-(4-methylpiperazin-1-yl)acetamide [ No CAS ]

Reference： [1]Patent: WO2015/140196,2015,A1
[2]Patent: WO2016/131808,2016,A1

36
[ 886762-08-9 ]
ethyl 3-[(4-methylpiperazin-1-yl)acetyl]amino}-4-(trifluoromethoxy)benzoate [ No CAS ]

Reference： [1]Patent: WO2015/140196,2015,A1
[2]Patent: WO2016/131808,2016,A1

37
[ 886762-08-9 ]
lithium 3-[(4-methylpiperazin-1-yl)acetyl]amino}-4-(trifluoromethoxy)benzoate [ No CAS ]

Reference： [1]Patent: WO2015/140196,2015,A1

38
[ 504-29-0 ]
[ 886762-08-9 ]
[ 32315-10-9 ]
1-(5-bromo-2-(trifluoromethoxy)phenyl)-3-(pyridin-2-yl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%		General procedure: A solution of substituted anilines (12.4 mmol) dissolved in 30 mL anhydrous THF was added very slowly into a stirred solution of triphosgene (1.40 g, 4.80 mmol) in 20 mL of THF. After stirringfor 15 min, triethylamine (2.90 mL, 20.6 mmol) was then added slowly to the reaction mixture. Stirring was continued for 20 min, various aromatic heterocyclic amines (12.0 mmol) in anhydrous THF (20 mL) was added directly to the above residue. After completion of the action, the reaction was quenched with dilute NaHCO3 and the solvent was subsequently removed in vacuo and extracted with ethyl acetate (3 30 mL). The organic layer was washed with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residues was purified by silicagel flash chromatography (PE/AcOEt = 5:1) gave as white solid (3a-3h) (yield: 30-50%).