[ CAS No. 66417-30-9 ] {[proInfo.proName]}

Name: 66417-30-9|2-Bromo-1-methyl-4-(trifluoromethyl)benzene|98%
Brand: Ambeed
SKU: A207007
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Quality Control of [ 66417-30-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 66417-30-9 ]

CAS No. :	66417-30-9	MDL No. :	MFCD01631584
Formula :	C₈H₆BrF₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	TWWUWLMGYSLODU-UHFFFAOYSA-N
M.W :	239.03	Pubchem ID :	2779376
Synonyms :

Calculated chemistry of [ 66417-30-9 ] Expand+

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	44.11
TPSA :	0.0 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.02 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.46
Log Po/w (XLOGP3) :	3.86
Log Po/w (WLOGP) :	4.93
Log Po/w (MLOGP) :	4.39
Log Po/w (SILICOS-IT) :	3.96
Consensus Log Po/w :	3.92

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.06
Solubility :	0.0209 mg/ml ; 0.0000875 mol/l
Class :	Moderately soluble
Log S (Ali) :	-3.56
Solubility :	0.0663 mg/ml ; 0.000278 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.53
Solubility :	0.00705 mg/ml ; 0.0000295 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	1.62

Safety of [ 66417-30-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 66417-30-9 ]

* 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 [ 66417-30-9 ]
Downstream synthetic route of [ 66417-30-9 ]

[ 66417-30-9 ] Synthesis Path-Upstream 1~8

1
[ 6140-17-6 ]
[ 66417-30-9 ]

Yield	Reaction Conditions	Operation in experiment
59%	at 20℃; for 20 h;	4- (Trifluoromethyl) toluene (22b, 9.0g, 56 mmol) was placed in round-bottom flask. Then 20 ml TFA and 5.6 ml H₂SO₄ (28percent of the amount of TFA) were added. NBS (10. Og, 56 mmol, leq) was added to the reaction mixture in small portions. The reaction was allowed to run at ambient temperature overnight. After 2Oh the reaction was worked up. The reaction mixture was poured out to ice cold water (100ml) and the organic layer (oily residue) was separated from the <n="72"/>water layer by extraction with Et₂O. The ether layer was collected, dried over Na₂SO₄ and the solvent was removed. The pure product (7.86g, 59percent yield) as a slightly yellow oil was collected.Structure determination:RP-HPLC Conditions: HP 1100 HPLC chromatograph, Waters 3.9 x 150 mm NovaPak HR C18 column with guard column, 0.010 mL injection, 1.5 mL/min, 1.500 mL injection loop, 254 nm detection, A = water (0.1percent v/v TFA) and B = MeCN (0.1percent v/v TFA) , gradient 10percent B 1 min, 10-80percent B over 9 min, 80-100percent B over 1 min, 100 percentB 1 min, retention time 11.7 min. ¹H NMR (400 MHz, CDCl₃): δ 2.45 (s, 3H), 7.34 (d, IH), 7.50 (d, IH) , 7.80 (s, IH) .

Reference： [1] Patent: WO2008/66921, 2008, A2, . Location in patent: Page/Page column 69-70
[2] Journal of Organic Chemistry, 1978, vol. 43, p. 2941 - 2946

2
[ 1066-35-9 ]
[ 66417-30-9 ]

Reference： [1] Journal of the American Chemical Society, 1993, vol. 115, # 8, p. 3116 - 3124

3
[ 7697-26-9 ]
[ 66417-30-9 ]

Reference： [1] Journal of Fluorine Chemistry, 1989, vol. 43, p. 35 - 52

4
[ 349-95-1 ]
[ 66417-30-9 ]

Reference： [1] Journal of Organic Chemistry, 1978, vol. 43, p. 2941 - 2946

5
[ 455-24-3 ]
[ 66417-30-9 ]

Reference： [1] Journal of Organic Chemistry, 1978, vol. 43, p. 2941 - 2946

6
[ 3335-35-1 ]
[ 66417-30-9 ]

Reference： [1] Patent: US4155940, 1979, A,

7
[ 69902-80-3 ]
[ 7789-45-9 ]
[ 66417-30-9 ]

Reference： [1] Patent: US4132737, 1979, A,

8
[ 76710-78-6 ]
[ 66417-30-9 ]
[ 328-89-2 ]

Reference： [1] Patent: US2003/195201, 2003, A1,

[ 66417-30-9 ] Synthesis Path-Downstream 1~80

1
[ 6140-17-6 ]
[ 66417-30-9 ]

Yield	Reaction Conditions	Operation in experiment
59%	With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid; at 20℃; for 20h;	4- (Trifluoromethyl) toluene (22b, 9.0g, 56 mmol) was placed in round-bottom flask. Then 20 ml TFA and 5.6 ml H2SO4 (28percent of the amount of TFA) were added. NBS (10. Og, 56 mmol, leq) was added to the reaction mixture in small portions. The reaction was allowed to run at ambient temperature overnight. After 2Oh the reaction was worked up. The reaction mixture was poured out to ice cold water (100ml) and the organic layer (oily residue) was separated from the <n="72"/>water layer by extraction with Et2O. The ether layer was collected, dried over Na2SO4 and the solvent was removed. The pure product (7.86g, 59percent yield) as a slightly yellow oil was collected.Structure determination:RP-HPLC Conditions: HP 1100 HPLC chromatograph, Waters 3.9 x 150 mm NovaPak HR C18 column with guard column, 0.010 mL injection, 1.5 mL/min, 1.500 mL injection loop, 254 nm detection, A = water (0.1percent v/v TFA) and B = MeCN (0.1percent v/v TFA) , gradient 10percent B 1 min, 10-80percent B over 9 min, 80-100percent B over 1 min, 100 percentB 1 min, retention time 11.7 min. 1H NMR (400 MHz, CDCl3): delta 2.45 (s, 3H), 7.34 (d, IH), 7.50 (d, IH) , 7.80 (s, IH) .

Reference： [1]Patent: WO2008/66921,2008,A2 .Location in patent: Page/Page column 69-70
[2]Journal of Organic Chemistry,1978,vol. 43,p. 2941 - 2946

2
[ 66417-30-9 ]
[ 66417-45-6 ]

Reference： [1]Journal of Organic Chemistry,1978,vol. 43,p. 2941 - 2946

3
[ 1066-35-9 ]
[ 66417-30-9 ]

Reference： [1]Journal of the American Chemical Society,1993,vol. 115,p. 3116 - 3124

4
[ 1560-28-7 ]
[ 66417-30-9 ]
(5-(trifluoromethyl)-2-methylphenyl)pentametyldisilane [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1993,vol. 115,p. 3116 - 3124

5
[ 79-35-6 ]
[ 66417-30-9 ]
[ 121793-13-3 ]

Reference： [1]Journal of Fluorine Chemistry,1989,vol. 43,p. 35 - 52

6
[ 7697-26-9 ]
[ 66417-30-9 ]

Reference： [1]Journal of Fluorine Chemistry,1989,vol. 43,p. 35 - 52

Yield	Reaction Conditions	Operation in experiment
		The distillate was extracted with ether (3*100 ml) and the contained combined extracts were dried over sodium sulphate filtered and evaporated to give an oil which was distilled to give 2-bromo-4-trifluoromethyltoluene (9.5 g) b.p. 98-101 C./45 mm Hg.
		The diacid was decarboxylated by heating in an oil bath to about 180 C. for about 1.5 hours. The decarboxylation mixture containing beta-(2-bromo-4-trifluoromethylphenyl) propionic acid was cooled and the acid dissolved in ether. The ether solution was dried. Evaporation of the ether yielded 16.9 g. of a yellow solid which yielded 8.1 g. of crystalline material from hexane. beta-(2-Bromo-4-trifluoromethylphenyl) propionic acid thus purified melted at 80-82 C.; pKa = 7.11. Analysis Calc.: C, 49.43; H, 2.71; Br, 26.90; Found: C, 40.63; H, 2.66; Br, 27.14.

8
[ 66417-30-9 ]
<2-methyl-5-(trifluoromethyl)phenyl>acetylene [ No CAS ]

Reference： [1]Journal of Fluorine Chemistry,1989,vol. 43,p. 35 - 52

9
[ 349-95-1 ]
[ 66417-30-9 ]

Reference： [1]Journal of Organic Chemistry,1978,vol. 43,p. 2941 - 2946

10
[ 455-24-3 ]
[ 66417-30-9 ]

Reference： [1]Journal of Organic Chemistry,1978,vol. 43,p. 2941 - 2946

11
[ 111-34-2 ]
[ 66417-30-9 ]
[ 725743-50-0 ]

Yield	Reaction Conditions	Operation in experiment
		[00155] A mixture of <strong>[66417-30-9]2-bromo-4-trifluoromethyl toluene</strong> (1 equivalent), n- butyl vinyl ether (5 equivalents), palladium acetate (0.1 equivalents), DPPP (0.22 equivalents), K2CO3 (1.2 equivalents), and DMF-H20 (0.3 M to bromide) was stirred under N2 for 18 hours at 100C. The reaction mixture was then cooled to room temperature and hydrolyzed with 5% HCI for 30 min. Extraction with EtOAc, washing with H20, sat aq. NaCi, drying (MGS04), and concentration gave an oil. Purification of the crude material by silica gel flash chromatography using an 0% hexanes to 50% HEXANES-ETOAC gradient gave 2'-methyl-5'- trifluoromethylacetophenone : the compound prepared showed a molecular ion M-= 201. 1.

Reference： [1]Patent: WO2005/5382,2005,A2 .Location in patent: Page 55

12
[ 76710-78-6 ]
[ 66417-30-9 ]
[ 328-89-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydrogen sulfate; In pyridine;	(a) 2-Bromo-4-(trifluoromethyl)benzoic acid. To a solution of 2-bromo-1-methyl-4-trifluoromethylbenzene (7.6 g, 32 mmol, ABCR) in pyridine (75 mL) was added tetraethylammonium permanganate (24 g, 96 mmol, prepared according to the procedure of Sala, et al. J. Chem. Soc., Chem. Comm. 1978, 253). The reaction mixture was warmed to 70 C. and stirred at that temperature for 30 h. The reaction mixture was allowed to cool to 25 C. and poured into an ice bath containing cond HCl (150 mL) and NaHSO3 (150 g). The mixture turned to a clear aqueous solution and was extracted with EtOAc (4*200 mL). The combined extracts were washed with satd NaCl (200 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide the title product as a white solid. MS (ESI, neg. ion) m/z: 267 (M-1).

Reference： [1]Patent: US2003/195201,2003,A1

13
[ 66417-30-9 ]
[ 25449-96-1 ]
[ 657-64-7 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(I) bromide; sodium nitrite; In hydrogen bromide;	2-bromo-4-trifluoromethylbenzyl bromide as a mobile yellow oil from 2-bromo-4-trifluoromethyltoluene. 2-methyl-5-trifluoromethylaniline (10.1 g) was dissolved in hydrobromic acid (50%; 50 ml) and treated with sodium nitrite (2.8 g) at 0-5 C. The diazonium solution was treated with cuprous bromide (8.6 g) dissolved in hydrobromic acid (50 ml) and the solution was allowed to warm to ambient temperature and was steam distilled.

Reference： [1]Patent: US5206257,1993,A

14
iron sulfide [ No CAS ]
[ 3335-35-1 ]
[ 66417-30-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen fluoride; bromine;	EXAMPLE 6 0.5 g of iron sulphide is added to 240 g of 4-methylbenzotrichloride and 160 g of bromine are added dropwise at 30 C. The mixture is stirred for 6 hours at 30 C. and excess bromine is then separated off by passing nitrogen through. 200 g of anhydrous hydrofluoric acid are initially introduced, at -10 C., into a fluorinating apparatus and the crude bromination product is then added dropwise. Thereafter, the hydrogen chloride evolution is allowed to subside in the course of about 3 hours at 18 C., the pressure is increased to 5 bars of nitrogen and the mixture is warmed to 70 C., the hydrogen chloride being separated off at about 8.5 bars. After about 2 hours, the mixture is cooled, excess hydrofluoric acid is distilled off and the crude product is subjected to fractional distillation. After a fore-run of 4-methylbenzotrifluoride, 146 g (corresponding to 61% of theory) of 3-bromo-4-methyl-benzotrifluoride are obtained at boiling point14: 62 to 68 C.

Reference： [1]Patent: US4155940,1979,A

15
[ 69902-80-3 ]
[ 7789-45-9 ]
[ 66417-30-9 ]

Yield	Reaction Conditions	Operation in experiment
	In ice-water; dimethyl sulfoxide;	A solution was prepared from 23.4 g. of cupric bromide and 225 ml. of DMSO in a 1000 ml. round bottom flask. The mixture was stirred vigorously. Next, 14.4 g. of 2-methyl-5-trifluoromethylphenyldiazoniumfluoborate in 100 ml. of DMSO were added to the cupric bromide solution over a period of about 30 minutes while maintaining the temperature in the range 25-30 C. After the addition had been completed, the reaction mixture was poured over 1 liter of an ice-water mixture. The aqueous solution was extracted three times with ether. The ether extracts were combined and the combined extracts washed with water and with saturated aqueous sodium chloride. The ether solution was dried and the ether removed by evaporation to yield 9.0 g. of a yellow oil containing 2-bromo-4-trifluoromethyltoluene formed in the above reaction. Distillation of the residue through a Vigreaux column yielded 4.2 g. of purified 2-bromo-4-trifluoromethyltoluene boiling in the range 58-49 C. at 10 torr. Analysis Calc.: C, 40.20; H, 2.53; Br, 33.43; Found: C, 40.44; H, 2.57; Br, 33.18.

Reference： [1]Patent: US4132737,1979,A

16
[ 943606-90-4 ]
[ 66417-30-9 ]
6-methyl-N₁-(2-methyl-5-(trifluoromethyl)phenyl)-N₅-(3-(pyrimidin-4-yl)pyridin-2-yl)isoquinoline-1,5-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 140℃; for 1h;	Example 344; Preparation of 6-methyl-Nl-(2-methyl-5-(trifluoromethyI)phenyl)-N5-(3-(pyrimidin- 4-yl)pyridin-2-yl)isoquinoline-l,5-diamineTo 6-methyl-N5-(3-(pyrimidin-4-yl)pyridin-2-yl)isoquinoline-l,5-diamine (.040 g, 0.12 mmol), charged to a 5 mL mircowave reaction vessel, 2-bromo-l-methyl-4- (trifluoromethyl)benzene (0.044 g, 0.18 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethyl-9H-xanthene (0.016 g, 0.027 mmol), cesium carbonate (0.056 g, 0.17 mmol), and tris(dibenzylideneacetone)dipalladium (o) (0.011 g, 0.012 mmol) were added. The <n="121"/>reagents were then suspended in dioxane (2.0 mL). The reaction mixture was stirred at 140 0C for 1 hrs. The reaction mixture was cooled and diluted with excess EtOAc, and partioned with aqueous sodium carbonate. The aqueous layer was back extracted 2x EtOAc. The combined organics were washed with brine, dried with magnesium sulfate and concentrated under vacuum. The resulting residue was loaded on to silica and purified by column Chromatgraphy. (ISCO 40.0 g, 0.5-5% MeOH in DCM5 30 min.) to give 6-methyl-Nl-(2-methyl-5-(trifluoromethyl)phenyl)-N5-(3-(pyrimidin-4-yl)pyridin-2- yl)isoquinoline-l,5-diamine as a solid after treatment with diethyl ether. MS (M+H)+ 487.

Reference： [1]Patent: WO2007/76092,2007,A2 .Location in patent: Page/Page column 87; 109; 118-119

17
[ 66417-30-9 ]
[ 73183-34-3 ]
[ 1030832-71-3 ]

Yield	Reaction Conditions	Operation in experiment
67%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 150℃; for 0.166667h;Microwave irradiation;	A suspension of <strong>[66417-30-9]2-methyl-5-(trifluoromethyl)bromobenzene</strong> (20 g, 83.67 mmol), bis(pinacolato)diboron (42.49 g, 167.34 mmol), KOAc (24.63 g, 251.01 mmol) and PdCl2(dppf) (1.84 g, 2.51 mmol) in DMF (600 mL) was stirred at 150 C for 10 min. under microwave irradiation. The mixture was filtered through diatomaceous earth and washed with EtOAc. The separated o.l. was washed with brine, dried (MgS04), filtered and the solvent evaporated in vacuo. The residue was dissolved in Et20 and washed with brine followed by a sat. aq. NaHC03 sol. The separated o.l. was dried (MgS04), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; eluent: heptane/DCM from 100/0 to 0/100). The product fractions were collected and the solvent evaporated in vacuo. Yield: 16 g of intermediate 49 (67% yield).
58%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃; for 48h;	2-Bromo-4- (trifluoromethyl) toluene (23b, 5g, 21 mmol) was placed in round-bottom flask and dissolved in 150 ml DMF.Then KOAc (6.2g, 63 mmol, 3eq) was added to the reaction mixture in one portion followed by addition of PdCl2 (dppf)(0.46g, 0.63 mmol, 0.03eq) and Bis (pinacolato) diboron 5.9g,23.1 mmol, l.leq). The solution was stirred at 80C for 48h. Then the solvent was removed and the black residue was subjected to plug column chromatography (EtOAc) resulting in dark green oily residue. The compound was further purified by second column chromatography (2% MeOH/DCM) .Pure product (3.5g, 58%) as a slightly green oil was collected.Structure determination:RP-HPLC Conditions: HP 1100 HPLC chromatograph, Waters 3.9 x 150 mm NovaPak HR C18 column with guard column, 0.010 mL injection, 1.5 mL/min, 1.500 mL injection loop, 254 nm detection, A = water (0.1% v/v TFA) and B = MeCN (0.1% v/v <n="73"/>TFA), gradient 10% B 1 min, 10-80% B over 9 min, 80-100% B over 1 min, 100 %B 1 min, retention time 7.9 min (for boronic acid) and 12.6 min (for pinacol ester). 1H NMR (400 MHz, CDCl3): delta 1.35 (s, 12H), 2.58 (s, 3H), 7.26 (d, IH), 7.55 (d, IH), 8.00 (s, IH).

Reference： [1]Patent: WO2013/10904,2013,A1 .Location in patent: Page/Page column 75
[2]Patent: WO2008/66921,2008,A2 .Location in patent: Page/Page column 70-71

18
[ 1101205-22-4 ]
[ 66417-30-9 ]
[ 1101205-27-9 ]

Reference： [1]Organic Letters,2009,vol. 11,p. 345 - 347

19
[ 66417-30-9 ]
[ 15448-47-2 ]
[ 1188412-37-4 ]

Yield	Reaction Conditions	Operation in experiment
66%		A solution of <strong>[66417-30-9]2-bromo-1-methyl-4-(trifluoromethyl)benzene</strong> (4.78 g, 20 mmol) in 100 mL of anhydrous THF was cooled to -100 C (liquid nitrogen/ EtOH) under nitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was added dropwise at - 100 C to -90 C. The mixture was stirred at -100 C to -90 C for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at -100 C to -90 C, then the mixture was cooled to -105 C and a 46.5% solution Of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at -100 C to -90 C for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at -90 C. The mixture was stirred and warmed to 0 C overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2x60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silicagel, EtOAc/hexane 1 :9, Rf = 0.45 in EtOAc/hexane 3:7) to give (2R)-1-[2- methyl-5-(trifluoromethyl)phenyl]propan-2-ol (2.87 g, 66 %) as white solid. 1H NMR (300 MHz, CDCl3): delta 7.42 (s, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 4.06 (m, 1H), 2.81 (d, J = 6.39 Hz, 2H), 2.39 (s, 3H), 1.43 (d, J = 4.14 Hz, 1H), 1.29 (d, J = 6.21 Hz, 3H).

Reference： [1]Patent: WO2009/117097,2009,A1 .Location in patent: Page/Page column 75

20
[ 66417-30-9 ]
[ 657-64-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 70℃; for 5h;Inert atmosphere;	A mixture of <strong>[66417-30-9]2-bromo-1-methyl-4-(trifluoromethyl)benzene</strong> (5.5 g, 23.0 mmol, CAS RN 128-08-5), benzoyl peroxide (835 mg, 3.45 mmol) and NBS (4.07 g, 23.01 mmol) in CC4 (50.0 mL,23.0 mmol) was stirred at 70 C for 5 h. The mixture was poured into water (20 mL) andextracted twice with DCM (20 mL each). The combined organic layer was washed with brine(20 mL), dried over Na2SO4, filtered and concentrated in vacuum to give the desired compoundas light yellow oil which was used in the next step without further purification (7.1 g, 97%).
	With N-Bromosuccinimide; dibenzoyl peroxide; In benzene; for 16h;Reflux;	STEP B: 2-bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene Solid benzoyl peroxide (1.5 g, 6.3 mmol) was added to a benzene solution (200 mL) of <strong>[66417-30-9]2-bromo-1-methyl-4-(trifluoromethyl)benzene</strong> (10.0 g, 41.8 mmol) and NBS (8.2 g, 46.0 mmol) and the resulting mixture was refluxed. After 16 h the resulting mixture was cooled, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
	With N-Bromosuccinimide; dibenzoyl peroxide; In benzene; for 16h;Reflux;	Solid benzoyl peroxide (1.5 g, 6.3 mmol) was added to a benzene solution (200 mL) of <strong>[66417-30-9]2-bromo-1-methyl-4-(trifluoromethyl)benzene</strong> (10.0 g, 41.8 mmol) and NBS (8.2 g, 46.0 mmol) and the resulting mixture was refluxed. After 16 h the resulting mixture was cooled, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.

Reference： [1]Patent: WO2020/35425,2020,A1 .Location in patent: Page/Page column 64; 186-187; 194; 239-240
[2]Patent: WO2020/35424,2020,A1 .Location in patent: Page/Page column 195
[3]Patent: US2012/302641,2012,A1 .Location in patent: Page/Page column 20
[4]Patent: US2012/302610,2012,A1 .Location in patent: Page/Page column 39

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[ 66417-30-9 ]
[ 1415127-70-6 ]

Reference： [1]Patent: US2012/302610,2012,A1

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[ 66417-30-9 ]
[ 1414931-46-6 ]

Reference： [1]Patent: US2012/302610,2012,A1
[2]Patent: US2012/302610,2012,A1

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[ 66417-30-9 ]
[ 1415130-03-8 ]

Reference： [1]Patent: US2012/302610,2012,A1

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[ 66417-30-9 ]
[ 1414931-27-3 ]

Reference： [1]Patent: US2012/302641,2012,A1

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[ 66417-30-9 ]
[ 1414931-47-7 ]

Reference： [1]Patent: US2012/302641,2012,A1

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[ 66417-30-9 ]
[ 1414931-48-8 ]

Reference： [1]Patent: US2012/302641,2012,A1

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[ 1414931-49-9 ]

Reference： [1]Patent: US2012/302641,2012,A1

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[ 66417-30-9 ]
[ 1414931-59-1 ]

Reference： [1]Patent: US2012/302641,2012,A1
[2]Patent: US2012/302610,2012,A1

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[ 66417-30-9 ]
[ 1414931-31-9 ]

Reference： [1]Patent: US2012/302641,2012,A1

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[ 1414931-56-8 ]

Reference： [1]Patent: US2012/302641,2012,A1

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[ 1414931-57-9 ]

Reference： [1]Patent: US2012/302641,2012,A1

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[ 1414931-58-0 ]

Reference： [1]Patent: US2012/302641,2012,A1

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[ 66417-30-9 ]
[ 1415130-97-0 ]

Reference： [1]Patent: US2012/302610,2012,A1

34
[ 66417-30-9 ]
[ 1415135-98-6 ]

Reference： [1]Patent: US2012/302610,2012,A1

35
[ 66417-30-9 ]
[ 1420205-96-4 ]

Reference： [1]Patent: WO2013/10904,2013,A1

36
[ 66417-30-9 ]
[ 1420205-97-5 ]

Reference： [1]Patent: WO2013/10904,2013,A1

37
[ 66417-30-9 ]
[ 1262198-14-0 ]

Reference： [1]Patent: WO2013/10904,2013,A1

38
[ 66417-30-9 ]
[ 1420205-98-6 ]

Reference： [1]Patent: WO2013/10904,2013,A1

39
[ 66417-30-9 ]
[ 1420205-99-7 ]

Reference： [1]Patent: WO2013/10904,2013,A1

40
[ 66417-30-9 ]
[ 1420206-00-3 ]

Reference： [1]Patent: WO2013/10904,2013,A1

41
[ 66417-30-9 ]
[ 1420199-24-1 ]

Reference： [1]Patent: WO2013/10904,2013,A1

42
[ 66417-30-9 ]
[ 1429341-56-9 ]
[ 1429341-04-7 ]

Yield	Reaction Conditions	Operation in experiment
17%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 20 - 85℃; for 16h;Inert atmosphere;	3-(2,6-Difluoro-phenyl)-7-(2-methyl-5-trifluoromethyl-phenyl)-3,4-dihydro-2H-benzo[1,4]oxazine: To a stirred solution of 3-(2,6-difluoro-phenyl)-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[1,4]oxazine (0.1 g, 0.27 mmol) in 1,4-dioxane (5 mL) was added 1M K2CO3 (0.8 mL), Pd(PPh3)4, (0.031 g, 0.03 mmol), SPhos (0.006 g, 0.01 mmol) and 2-bromo-1-methyl-4-trifluoromethyl-benzene (0.065 g, 0.27 mmol) at rt. The mixture was then heated to 85 C. for 16 h (monitoring by TLC; ethyl acetate-hexane=1:9; Rf ?0.3), cooled, and filtered through celite. The filtrate was concentrated under reduced pressure and purified by HPLC to give 3-(2,6-difluoro-phenyl)-7-(2-methyl-5-trifluoromethyl-phenyl)-3,4-dihydro-2H-benzo[1,4]oxazine (0.018 g, 17%) as a light brown solid. LC-MS: 406 [M+H].

Reference： [1]Patent: US2013/90333,2013,A1 .Location in patent: Paragraph 0204

43
[ 66417-30-9 ]
[ 1620412-34-1 ]

Reference： [1]Patent: WO2014/111457,2014,A1
[2]Patent: US2018/319797,2018,A1

44
[ 66417-30-9 ]
[ 74685-00-0 ]
[ 1620412-32-9 ]

Yield	Reaction Conditions	Operation in experiment
71%		Butyl lithium (1.6 M in hexane, 2.6 mL, 4.18 mmol) was added dropwise to a solution of <strong>[66417-30-9]2-methyl-5-(trifluoromethyl)bromobenzene</strong> (1 g, 4.18 mmol) in Et20 (15 mL) at -78 C. The r.m. was stirred at -78 C for 20 min and then l-(tert-butyldimethylsilyloxy)-2- propanone (0.827 g, 4.39 mmol) in Et20 (5 mL) was added and the r.m. was further stirred for 2 h at -78 C. The r.m. was then quenched with water and the product was extracted with EtOAc. The organic layer was dried over MgS04, filtered and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (silica; heptanes/EtOAc 100/0 to 90/10). The fractions containing the product were collected and concentrated in vacuo to give intermediate 46 (1.036 g, 71%).
71%		Butyl lithium (1.6 M in hexane, 2.6 mL, 4.18 mmol) was added dropwise to a solution of <strong>[66417-30-9]2-methyl-5-(trifluoromethyl)bromobenzene</strong> (1 g, 4.18 mmol) in Et2O (15 mL) at -78 C. The r.m. was stirred at -78 C. for 20 min and then 1-(tert-butyldimethylsilyloxy)-2-propanone (0.827 g, 4.39 mmol) in Et2O (5 mL) was added and the r.m. was further stirred for 2 h at -78 C. The r.m. was then quenched with water and the product was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (silica; heptanes/EtOAc 100/0 to 90/10). The fractions containing the product were collected and concentrated in vacuo to give intermediate 46 (1.036 g, 71%).

Reference： [1]Patent: WO2014/111457,2014,A1 .Location in patent: Page/Page column 75; 76
[2]Patent: US2018/319797,2018,A1 .Location in patent: Paragraph 0654-0655

45
[ 66417-30-9 ]
[ 74685-00-0 ]
[ 1620412-33-0 ]

Reference： [1]Patent: WO2014/111457,2014,A1
[2]Patent: US2018/319797,2018,A1

46
[ 66417-30-9 ]
[ 1188412-49-8 ]

Reference： [1]Patent: WO2009/117097,2009,A1

47
[ 66417-30-9 ]
[ 1188412-42-1 ]

Reference： [1]Patent: WO2009/117097,2009,A1

48
[ 66417-30-9 ]
C₁₂H₁₅F₃O₃S [ No CAS ]

Reference： [1]Patent: WO2009/117097,2009,A1

49
[ 66417-30-9 ]
[ 271-58-9 ]
C₁₅H₁₀F₃NO [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 4831 - 4836

50
[ 66417-30-9 ]
5-fluoro-2,1-benzisoxazole [ No CAS ]
C₁₅H₉F₄NO [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 4831 - 4836

51
[ 66417-30-9 ]
(2-amino-5-fluorophenyl)(2-methyl-5-(trifluoromethyl)phenyl)methanone [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 4831 - 4836

52
[ 66417-30-9 ]
(S)-ethyl 2-methyl-4-(2-methyl-5-(trifluoromethyl)phenyl)quinoline-3-carboxylate [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 4831 - 4836

53
[ 66417-30-9 ]
(S)-ethyl 6-fluoro-2-methyl-4-(2-methyl-5-(trifluoromethyl)phenyl)quinoline-3-carboxylate [ No CAS ]
ethyl 6-fluoro-2-methyl-4-(2-methyl-5-(trifluoromethyl)phenyl)quinoline-3-carboxylate [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 4831 - 4836

54
[ 66417-30-9 ]
(S)-ethyl 2-methyl-4-(2-methyl-5-(trifluoromethyl)phenyl)-1-(λ¹-oxidanyl)-1λ⁴-quinoline-3-carboxylate [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 4831 - 4836

55
[ 66417-30-9 ]
(2-aminophenyl)(2-methyl-5-(trifluoromethyl)phenyl)methanone [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 4831 - 4836

56
[ 66417-30-9 ]
(4aR,8aS)-6-[4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ No CAS ]

Reference： [1]Patent: WO2020/35425,2020,A1

57
[ 66417-30-9 ]
4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methyl]piperidine formic acid [ No CAS ]