[ CAS No. 68322-84-9 ] {[proInfo.proName]}

Name: 68322-84-9|2-Bromo-1-fluoro-4-(trifluoromethyl)benzene|98%
Brand: Ambeed
SKU: A100698
Price: 6.0 USD
Availability: InStock
Rating: 94 (30 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

DV 2D 3D

3d Animation Molecule Structure of 68322-84-9

Structure of 68322-84-9 * Storage: {[proInfo.prStorage]}

Please Login or Create an Account to: See VIP prices and availability

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

* Shipping: {[proInfo.prShipping]}

For Research Only 120K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 68322-84-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 68322-84-9 ]

SDS Specification

Alternatived Products of [ 68322-84-9 ]

Product Details of [ 68322-84-9 ]

CAS No. :	68322-84-9	MDL No. :	MFCD00040938
Formula :	C₇H₃BrF₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RZJOIMPUMMQKFR-UHFFFAOYSA-N
M.W :	243.00	Pubchem ID :	144295
Synonyms :

Calculated chemistry of [ 68322-84-9 ] Expand+

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	39.1
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) :	-5.23 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.28
Log Po/w (XLOGP3) :	3.6
Log Po/w (WLOGP) :	5.18
Log Po/w (MLOGP) :	4.51
Log Po/w (SILICOS-IT) :	3.95
Consensus Log Po/w :	3.9

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.92
Solubility :	0.0293 mg/ml ; 0.000121 mol/l
Class :	Soluble
Log S (Ali) :	-3.29
Solubility :	0.126 mg/ml ; 0.000517 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.42
Solubility :	0.00922 mg/ml ; 0.0000379 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	1.68

Safety of [ 68322-84-9 ]

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

Application In Synthesis of [ 68322-84-9 ]

* 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 [ 68322-84-9 ]
Downstream synthetic route of [ 68322-84-9 ]

[ 68322-84-9 ] Synthesis Path-Upstream 1~2

1
[ 402-44-8 ]
[ 68322-84-9 ]

Yield	Reaction Conditions	Operation in experiment
95.94%	at 35 - 45℃; for 6 h;	In a 2000ml three-necked flask, 400g of concentrated sulfuric acid,p-fluorobenzotrifluoride 400g, lithium bromide 10g, ferric bromide 20g, tetrabutylammonium bromide 10g,Bromine 234.14g, temperature control 35-45 ° C, the reaction 6h, GC detection of raw materials 0.36percent. Cooled to below 30 , transferred to 2000ml separation funnel, stationary 1h, the acid was separated, the crude product was placed in 2000ml bottle,1000g of water was added under stirring, dropping 10percent sodium hydroxide solution to adjust PH = 7,548.6 g of 3-bromo-4-fluorobenzotrifluoride was isolated at a constant rate of 92.56percent with 97.9percentThe product was purified by vacuum distillation 526.33g, distillation yield 95.94percent.

Reference： [1] Patent: CN105152853, 2017, B, . Location in patent: Paragraph 0030

2
[ 68322-84-9 ]
[ 81107-97-3 ]

Reference： [1] Organic Letters, 2016, vol. 18, # 9, p. 2244 - 2247

[ 68322-84-9 ] Synthesis Path-Downstream 1~108

1
[ 68322-84-9 ]
[ 108-46-3 ]
C₁₃H₈BrF₃O₂ [ No CAS ]
C₂₀H₁₀Br₂F₆O₂ [ No CAS ]

Reference： [1]Synthetic Communications,2008,vol. 38,p. 21 - 32

2
[ 504-15-4 ]
[ 68322-84-9 ]
C₁₄H₁₀O₂F₃Br [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With sodium hydroxide; In dimethyl sulfoxide; at 90℃; for 1.66667h;	Step B To a solution of orcinol (25.54 g, 0.20 mol) in DMSO (250 mL) is added 5 N NaOH solution (64 mL). The mixture is stirred at 90 C for 15 min. , and then 3- bromo-4-fluoro-benzotrifluoride (25.0 g, 0.10 mol) is added dropwise over 10 minutes. The mixture is stirred at 90C for 1.5 h, cooled to rt, diluted with water (300 mL), and extracted with hexanes (3 x 200 mL). The aqueous layer is split into 2 portions with equal volume. One portion is extracted with EtOAc (3 x 200 mL). The combined EtOAc layers are washed with 5 N HCl (150 mL) and brine (150 mL), and then dried over Na2S04 and concentrated to provide 15. 3 g (67%) of the desired product. Under nitrogen purge, the compound obtained from the above procedure, CH3CN (8.6 vol. ), 325 mesh K2CO3 (3 equiv. ) are combined and stirred, and then benzyl bromide (1.02 equiv. ) in CH3CN (1.4 vol. ) is added slowly to the solution. Reaction is warmed to reflux (82C) and traced via TLC. Upon the reaction is completed, reaction contents are cooled and filtered. Filter cake is washed with 5 volumes of CH3CN, and filtrate is concentrated to provide an oil.

Reference： [1]Synthetic Communications,2008,vol. 38,p. 21 - 32
[2]Patent: WO2005/37763,2005,A1 .Location in patent: Page/Page column 151

3
[ 68322-84-9 ]
[ 73286-70-1 ]
[ 639072-48-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine;palladium diacetate; silver carbonate; In DMF (N,N-dimethyl-formamide); at 100℃; for 20h;	A deoxygenated solution of tert-butyl 2, 5-dihydro-lH-pyrrole-l- carboxylate (3.38 g, 20.0 mmol, 10.0 equiv), [2-BROMO-1-FLUORO-4-] (trifluoromethyl) benzene (486 mg, 2.00 mmol, 1 equiv), N, N diisopropylethylamine (1.39 mL, 8.00 mmol, 4.00 equiv), tri-o-tolylphosphine (67 mg, 0.22 mmol, 0.11 equiv), palladium [(II)] acetate (22 mg, 0.10 mmol, 0.050 equiv), and silver carbonate (386 mg, 1.40 mmol, 0.700 equiv) in DMF (8.0 mL) was heated under nitrogen at 100 [C] for 20 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (50 [ML).] The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by flash column chromatography (20% CH2C12 in hexanes, grading to 50% CH2C12 in hexanes) to give tert-butyl 3- [2-fluoro-5- (trifluoromethyl) phenyl] -2,3- [/DIHYDRO-LH-PYRROLE-L-CARBOXYLATE] (3-1) as a colorless [GUM. 1H] NMR (500 MHz, [CDC13)] major rotamer: [8] 7.51 (m, 2H), 7.15 (t, 1H, [J =] 9.1 Hz), 6.74 (br s, 1H), 5.03 (br s, 1H), 4.48 (m, 1H), 4.17 (m, 1H), 3.61 (m, 1H), 1.50 (s, 9H).

Reference： [1]Patent: WO2003/105855,2003,A1 .Location in patent: Page 145

4
[ 850793-29-2 ]
[ 68322-84-9 ]
3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-fluoro-phenoxy]-2-methyl-phenyl}propionic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 2.5h;Heating;	Step F 3- 4- [3- (2-Bromo-4-trifluoromethyl-phenoxy)-5-fluoro-phenoxy]-2-methyl-phenyl}- propionic acid ethyl ester A mixture of 3- [4- (3-fluoro-5-hydroxy-phenoxy)-2-methyl-phenyl]- propionic acid ethyl ester (0.557 g, 1.75 mmol), <strong>[68322-84-9]3-bromo-4-fluorobenzotrifluoride</strong> (0.425 g, 1.75 mmol) and 325 mesh potassium carbonate (0.29 g, 2.10 mmol) in dry DMSO (10 mL) is heated to 100 C and stirred 2.5 hours under N2. The reaction is cooled and acidified with 1 N HCI. The mixture is then diluted with Et20 and extracted with water. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 5/1 hexanes/ethyl acetate to afford 0.735 g (78%) of the title compound.'H NMR (400 MHz, CDCl3) ; MS (ES+) 7w/Z mass calculated for C25H2104F4Br 540, found 558 and 560 (M + NH4, 100%).

Reference： [1]Patent: WO2005/37763,2005,A1 .Location in patent: Page/Page column 97-98

5
[ 850793-70-3 ]
[ 68322-84-9 ]
3-{4-[5-(2-bromo-4-trifluoromethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-phenyl}propionic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 6h;Heating;	Example 75 3- {2-Methyl-4-[2-methyl-5-(2-phenoxy-4-trifluoromethyl-phenoxy)-phenoxy]-phenyl}- propionic acid Step A 3- {4- [5- (2-Bromo-4-trifluoromethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-phenyl}- propionic acid ethyl ester A mixture of 3- [4- (5-hydroxy-2-methyl-phenoxy)-2-methyl-phenyl]- propionic acid ethyl ester (Example 84, Step D) (0.46 g, 1.46 mmol), 3-bromo-4- fluorobenzotrifluoride (0.35 g, 1.45 mmol) and 325 mesh potassium carbonate (0.21 g, 1.52 mmol) in dry DMSO (10 mL) is heated to 100 C and stirred for 6 hours under N2. The reaction is cooled and acidified with 1 N HCI. The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 0. 633 g (81%) of the title compound. Rf = 0.38 (4/1 hexanes/EtOAc).'H NMR (400 MHz, CDC13) ; MS (ES+) mlz mass calculated for C26H2404F3Br 536, found 554 and 556 (M + NH4, 100%).

Reference： [1]Patent: WO2005/37763,2005,A1 .Location in patent: Page/Page column 116-117

6
[ 850793-73-6 ]
[ 68322-84-9 ]
3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-4-methyl-phenoxy]-2-methyl-phenyl}propionic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 6h;Heating;	Example 76 3- {2-Methyl-4- [4-methyl-3- (2-phenoxy-4-trifluoromethyl-phenoxy)-phenoxy]-phenyl}- propionic acid Step A 3-14- [3- (2-Bromo-4-trifluoromethyl-phenoxy)-4-methyl-phenoxy]-2-methyl-phenyll- propionic acid ethyl ester A mixture of 3- [4- (3-hydroxy-4-methyl-phenoxy)-2-methyl-phenyl]- propionic acid ethyl ester (Example 82, Step J) (1.05 g, 3.34 mmol), 3-bromo-4- fluorobenzotrifluoride (0.81 g, 3.34 mmol) and 325 mesh potassium carbonate (0.55 g, 3.97 mmol) in dry DMSO (1 5 mL) is heated to 100 C and stirred for 6 hours under N2. The reaction is cooled and acidified with 1 N HCI. The mixture is diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 1.57 g (88%) of the title compound. Rf = 0. 38 (4/1 hexanes/EtOAc). H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calculated for C26H2404F3Br 536, found 554 and 556 (M + NH4, 100%).

Reference： [1]Patent: WO2005/37763,2005,A1 .Location in patent: Page/Page column 118

7
[ 850793-81-6 ]
[ 68322-84-9 ]
3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)phenoxy]-2-methyl-phenyl}propionic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 6h;Heating;Product distribution / selectivity;	Step D 3- {4- [3- (2-Bromo-4-tnftuoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester A mixture of 3- [4- (3-hydroxy-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (8.18 g, 28.6 mmol), <strong>[68322-84-9]3-bromo-4-fluorobenzotrifluoride</strong> (6.80 g, 28.0 mmol) and 325 mesh potassium carbonate (4.64 g, 33. 68 mmol) in dry DMSO (80 mL) is heated to 100 C and stirred 6 hours under N2. The reaction is cooled and acidified with 1 N HCI. The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2S04, and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 15/1 hexanes/ethyl acetate to afford 11.74 g (81%) of the titled compound. Rf= 0.76 (9/1 hexanes/EtOAc). 'H NMR (400 MHz, CDCl3) ; MS (ES+) 7pilz mass calcd for C24H2004F3Br 509, found 526 and 528 (M + NH4, 100%).

Reference： [1]Patent: WO2005/37763,2005,A1 .Location in patent: Page/Page column 125; 139-140

8
[ 68322-84-9 ]
[ 36776-44-0 ]
[ 850793-46-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 8h;Heating;Product distribution / selectivity;	Example 63 3- {2-Ethyl-4- [3-methyl-5- (2-o-tolyloxy-4-trifluoromethyl-phenoxy)-phenoxy]-phenyl}- propionic acid Step A A mixture 3-benzyloxy-5-methyl-phenol (8.50 g, 39.7 mmol), 3-bromo-4- fluorobenzotrifluoride (9.64 g, 39.7 mmol) and 325 mesh potassium carbonate (6.58 g, 47.6 mmol) in dry DMSO (100 mL) is heated to 100 C and stirred for 8 hours under N2. The reaction is cooled and acidified with 1 N HCI. The mixture is then diluted with water and extracted with Et20. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 14.14 g (81%) product. Rf = 0.52 (4/1 hexanes/EtOAc).'H NMR (400 MHz, CDCl3).

Reference： [1]Patent: WO2005/37763,2005,A1 .Location in patent: Page/Page column 103

9
[ 850793-06-5 ]
[ 68322-84-9 ]
[ 850793-07-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 5h;Heating;	Step F 3- {4- [3- (2-Bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}- propionic acid ethyl ester A mixture of 3- [4- (3-hydroxy-5-methyl-phenoxy)-2-methyl-phenyl]- propionic acid ethyl ester (2.83 g, 9.01 mmol), <strong>[68322-84-9]3-bromo-4-fluorobenzotrifluoride</strong> (2.19 g, 9.01 mmol) and 325 mesh potassium carbonate (1.49 g, 10.8 mmol) in dry DMSO (36 mL) is heated to 100 C and stirred for 5 hours under N2. The reaction is cooled and acidified with 1 N HCI. The mixture is then diluted with Et20 and extracted with water. The organic layer is dried (Na2S04), and the solvent removed i7 vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 3.45 g (71%) of the title compound. Rf= 0.54 (2/1 hexanes/EtOAc).'H NMR (400 MHz, CDCl3) ; MS (ES+) inlet mass calculated for C26H2404F3Br 536, found 554 and 556 (M + NH4, 100%).

Reference： [1]Patent: WO2005/37763,2005,A1 .Location in patent: Page/Page column 84-85

10
[ 847943-39-9 ]
[ 68322-84-9 ]
[ 847943-57-1 ]

Yield	Reaction Conditions	Operation in experiment
40%	With sodium hydride; In DMF (N,N-dimethyl-formamide); at 20℃; for 1h;	Example 60 (2S)-1- ( (2S,5R)-5-[2-bromo-4-(trifluoromethyl)phenoxy]methyl}pyrrolidin-2- yl) CARBONYLLPYRROLIDINE-2-CARBONITRILE The compound of Example 14A (50 mg, 0.15 mmol) and 3-bromo-4- fluorobenzotrifluoride (30 uL, 0.2 mmol) were stirred in DMF (1ML) under N2. NaH (13 mg, 0.3 mmol) was added to the mixture. It was stirred at room temperature for LHOUR. After the reaction was over, the mixture was purified by reverse-phase HPLC to give the Boc-protected compound (40% yield). MS (ESI) M/Z 546,548 (M+H) +.
40%	With sodium hydride; In DMF (N,N-dimethyl-formamide); at 20℃; for 1h;	EXAMPLE 60 (2S)-1-[((2S,5R)-5-[2-bromo-4-(trifluoromethyl)phenoxy]methyl}pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carbonitrile The compound of Example 14A (50 mg, 0.15 mmol) and <strong>[68322-84-9]3-bromo-4-fluorobenzotrifluoride</strong> (30 muL, 0.2 mmol) were stirred in DMF (1 mL) under N2. NaH (13 mg, 0.3 mmol) was added to the mixture. It was stirred at room temperature for I hour. After the reaction was over, the mixture was purified by reverse-phase HPLC to give the Boc-protected compound (40% yield). MS (ESI) m/z 546, 548 (M+H)+. The Boc group was removed according to Example 1G to give the title compound. 1H NMR (500 MHz, MeOH-d4) delta ppm 2.05-2.44 (m, 7 H), 2.49-2.65 (m, 1 H), 3.50-3.59 (m, 1 H), 3.62-3.74 (m, 1 H), 4.20-4.32 (m, 1 H), 4.47-4.58 (m, 2 H), 4.68-4.76 (m, 1 H), 4.81-4.90 (m, 1 H), 7.27 (dd, J=8.42, 4.05 Hz, 1 H), 7.69 (d, J=8.73 Hz, 1 H), 7.85-7.94 (m, 1 H). MS (ESI) m/z 446, 448 (M+H)+.

Reference： [1]Patent: WO2005/23762,2005,A1 .Location in patent: Page/Page column 100
[2]Patent: US2005/131019,2005,A1 .Location in patent: Page/Page column 45

11
[ 905724-75-6 ]
[ 68322-84-9 ]
C₁₉H₁₃BrF₃NO₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl acetamide; at 120℃; for 0.5h;	INTERMEDIATE 1 (250 mg, l.Ommol) was combined with <strong>[68322-84-9]3-bromo-4-fluorobenzotrifluoride</strong> (255 mg, 1.05 mmol) and Cs2CO3 (1.0 g, 3 mmol) in 5 mL of NjN-dimethylacetamide. The reaction mixture was stirred at 120 0C for 30 min, then was dumped into water and acidified with 2N aq. HCl to pH <2. The resulting solid precipitate was extracted with ethyl acetate and washed with water followed by brine, dried over anhydrous Na2SO4, filtered, and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexane gradient) gave the product. LC-MS calc. for C19H13BrF3NO3S: 470; Found: 471 (M+H).

Reference： [1]Patent: WO2006/83781,2006,A1 .Location in patent: Page/Page column 61-62

12
[ 68322-84-9 ]
[ 230615-01-7 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 4 4-Trifluoromethyl-10-aza-tricyclo[6.3.1.02.7]dodeca-2(7),3,5-triene Hydrochloride (See Grunewald, G. L.; Paradkar, V. M.; Pazhenchevsky, B.; Pleiss, M. A.; Sall, D. J., Seibel, W. L.; Reitz, T. J. J. Org. Chem. 1983, 48, 2321-2327. Grunewald, G. L.; Markovich, K. M.; Sall, D. J. J. Med. Chem. 1987, 30, 2191-2208.) The title compound was prepared by the methods described in Example 1 and 2 starting with 2-fluoro-5-trifluoromethylbromobenzene 1H NMR (400 MHz, CD3OD) delta 7.71 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H) 3.46 (m, 4H), 3.21 (d, J=12.5 Hz, 2H), 2.41 (m, 1H), 2.16 (d, J=11.5 Hz. 1H). APCl MS m/e 228.2 [(M+1)+]. (HCl salt) mp 244-246 C. Anal Calcd for C12H12F3N HCl.1/3H2O C, 53.44, H, 5.11. N, 5.19, Found C, 53.77, H, 4.82: N, 5.18.
		EXAMPLE 4 4-Trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]-dodeca-2(7),3,5-triene Hydrochloride (See Grunewald, G. L.; Paradkar, V. M.; Pazhenchevsky, B.; Pleiss, M. A.; Sall, D. J.; Seibel, W. L.; Reitz, T. J. J. Org. Chem. 1983, 48, 2321-2327. Grunewald, G. L.; Markovich, K. M.; Sall, D. J. J. Med. Chem. 1987, 30, 2191-2208.) The title compound was prepared by the methods described in Examples 1 and 2 starting with 2-fluoro-5-trifluoromethylbromobenzene. 1H NMR (400 MHz, CD3OD) delta 7.71 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 3.46 (m, 4H), 3.21 (d, J=12.5 Hz, 2H), 2.41 (m, 1H), 2.16 (d, J=11.5 Hz, 1H). APCI MS m/e 228.2 [(M+1)+]. (HCl salt) M.p. 244-246 C. Anal. Calcd. for C12H12F3N.HCl.1/3H2O: C, 53.44; H, 5.11; N, 5.19. Found C, 53.77; H, 4.82; N, 5.18.

Reference： [1]Patent: US2002/72524,2002,A1
[2]Patent: US6605610,2003,B1

13
[ 176976-33-3 ]
[ 68322-84-9 ]
[ 497-19-8 ]
(+)-(4AR)-(10BR)-4-methyl-8-(2-fluoro-5-trifluoromethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
113 mg (44%)	tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; ethyl acetate;	EXAMPLE 211 (+)-(4aR)-(10bR)-4-methyl-8-(2-fluoro-5-trifluoromethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one STR229 A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), <strong>[68322-84-9]3-bromo-4-fluorobenzotrifluoride</strong> (158 mg, 0.65 mmol), 0.65 mL of 2M aqueous sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2*25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (70% ethyl acetate/hexanes eluent) to give 113 mg (44%) of the title compound as an oil. FDMS: m/e =391. alpha[D]589 =+55.84 (c=0.34, chloroform)
113 mg (44%)	tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; ethyl acetate;	EXAMPLE 211 (+)-(4aR)-(10bR)-4-methyl-8-(2-fluoro-5-trifluoromethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), <strong>[68322-84-9]3-bromo-4-fluorobenzotrifluoride</strong> (158 mg, 0.65 mmol), 0.65 mL of 2M aqueous sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2*25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (70% ethyl acetate/hexanes eluent) to give 113 mg (44%) of the title compound as an oil. FDMS: m/e=391. alpha[D]589 =+55.84 (c=0.34, chloroform).

Reference： [1]Patent: US5578724,1996,A
[2]Patent: US5629007,1997,A

14
bis(triphenylphosphine)palladium(II) dichloride [ No CAS ]
[ 68322-84-9 ]
[ 54060-30-9 ]
3-[(2-Fluoro-5-(trifluoromethyl)phenyl]ethynyl]aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(I) iodide; triphenylphosphine;	EXAMPLE 7 Preparation of 3-[(2-Fluoro-5-(trifluoromethyl)phenyl]ethynyl]aniline A multinecked flash as described in Example 1 was charged with 4.93 g (0.020 mol) of <strong>[68322-84-9]3-bromo-4-fluorobenzotrifluoride</strong>, 75 ml of dried, degassed triethylamine, 2.34 g (0.020 mol) of 3-aminophenylacetylene, 0.06 g (0.08 mmol) of bis(triphenylphosphine) palladium II chloride, 0.118 g (0.45 mmol) of triphenylphosphine, and 0.06 g (0.31 mmol) of cuprous iodide. The reaction mixture was heated at 70 C. for 40 hours at which point gas chromatography showed the reaction to be complete. The product mixture was cooled to room temperature and diluted with 75 ml of ether. Filtration of the insoluble hydrobromide salt followed by concentration of the filtrate gave the crude product (5.5 g, 89%) as an orange liquid. Short path distillation of the crude product under reduced pressure gave 4.05 g (0.014 mol, 70% yield) of the product as a yellow solid.

Reference： [1]Patent: US5107026,1992,A

15
[ 68322-84-9 ]
[ 27489-62-9 ]
4-trans(2-bromo-4-trifluoromethyl-phenoxy)-cyclohexylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With NaH; In N,N-dimethyl-formamide; mineral oil;	Example 43A 4-trans(2-bromo-4-trifluoromethyl-phenoxy)-cyclohexylamine To a stirred solution of trans-4-aminocyclohexanol (115 mg, 1 mmol) in DMF (3 mL) at 0 C. was added 60% NaH in mineral oil (120 mg, 3 mmol). The reaction mixture was stirred at 0 C. for 1/2 hour and then <strong>[68322-84-9]3-bromo-4-fluoro-1-trifluoromethyl benzene</strong> (0.17 ml, 1.2 mmol) was added. It was heated to 60 C. for 2 hours and stirred for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water (3 times) and brine. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the titled compound. MS (DCI) m/z 338 (M+H)+.
	With NaH; In N,N-dimethyl-formamide; mineral oil;	Example 58A 4-trans(2-bromo-4-trifluoromethyl-phenoxy)-cyclohexylamine To a stirred solution of trans-4-aminocyclohexanol (115 mg, 1 mmol) in DMF (3 mL) at 0 C. was added 60% NaH in mineral oil (120 mg, 3 mmol). The reaction mixture was stirred at 0 C. for 1/2 hour and then <strong>[68322-84-9]3-bromo-4-fluoro-1-trifluoromethyl benzene</strong> (0.17 ml, 1.2 mmol) was added. It was heated to 60 C. for 2 hours and stirred for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water (3 times) and brine. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the titled compound. MS (DCI) m/z 338 (M+H)+.
	With NaH; In N,N-dimethyl-formamide; mineral oil;	Example 43A 4-trans(2-bromo-4-trifluoromethyl-phenoxy)-cyclohexylamine To a stirred solution of trans-4-aminocyclohexanol (115 mg, 1 mmol) in DMF (3 mL) at 0 C. was added 60% NaH in mineral oil (120 mg, 3 mmol). The reaction mixture was stirred at 0 C. for 1/2 hour and then <strong>[68322-84-9]3-bromo-4-fluoro-1-trifluoromethyl benzene</strong> (0.17 mL, 1.2 mmol) was added. It was heated to 60 C. for 2 hours and stirred for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water (3 times) and brine. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the titled compound. MS (DCI) m/z 338 (M+H)+.

With NaH; In N,N-dimethyl-formamide; mineral oil;

Example 58A 4-trans(2-bromo-4-trifluoromethyl-phenoxy)-cyclohexylamine To a stirred solution of trans-4-aminocyclohexanol (115 mg, 1 mmol) in DMF (3 mL) at 0 C. was added 60% NaH in mineral oil (120 mg, 3 mmol). The reaction mixture was stirred at 0 C. for 1/2 hour and then 3-bromo-4fluoro-1-trifluoromethyl benzene (0.17 mL, 1.2 mmol) was added. It was heated to 60 C. for 2 hours and stirred for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water (3 times) and brine. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the titled compound. MS (DCI) m/z 338 (M+H)+.

Reference： [1]Patent: US2004/259843,2004,A1
[2]Patent: US2004/259843,2004,A1
[3]Patent: US2005/215784,2005,A1
[4]Patent: US2005/215784,2005,A1

16
[ 68322-84-9 ]
[ 109-73-9 ]
[ 1048344-63-3 ]

Reference： [1]Tetrahedron,2008,vol. 64,p. 7283 - 7288

17
[ 68322-84-9 ]
[ 27489-62-9 ]
4-trans(2-bromo-4-trifluoromethyl-phenoxy)-cyclohexylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of trans-4-aminocyclohexanol (115 mg, 1 mmol) in DMF (3 mL) at 0 [C] was added 60% NaH in mineral oil (120 mg, 3 mmol). The reaction mixture was stirred at 0 [C] for 1/2 hour and then [3-BROMO-4-FLUORO-1-TRIFLUOROMETHYL] benzene (0.17 ml, 1.2 mmol) was added. It was heated to 60 [C] for 2 hours and stirred for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water (3 times) and brine. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the titled compound. MS [(DCI) M/Z] 338 (M+H) [+.] To a stirred solution of trans-4-aminocyclohexanol (115 mg, [1] mmol) in DMF (3 mL) at 0 [C] was added 60% NaH in mineral oil (120 mg, 3 mmol). The reaction mixture was stirred at 0 [C] for [% 2 HOUR] and then <strong>[68322-84-9]3-bromo-4-fluoro-1-trifluoromethyl benzene</strong> (0.17 [ML,] 1.2 mmol) was added. It was heated to 60 [C] for 2 hours and stirred for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water (3 times) and brine. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the titled compound. MS (DCI) [M/Z] 338 (M+H) +.

Reference： [1]Patent: WO2004/26822,2004,A2 .Location in patent: Page 66; 80

18
[ 1160065-00-8 ]
[ 68322-84-9 ]
[ 1160065-73-5 ]

Yield	Reaction Conditions	Operation in experiment
18%	With potassium carbonate; In tetrahydrofuran; at 120℃; for 2h;	A mixture of [3,5-biotas(tnfluoromethyl)benzyl]-((3S,5R)-5-ethyl-pyrroliotadiotan-3-yl)-[5-(1-methyl- 1 H-pyrazol-4-yl)-py?miotadiotan-2-yl]-amiotane (45 mg, 0 27 mmol), 2-chloro-5-triotafluoromethyl- py?dine (196 mg, 0 81 mmol) and K2CO3 (11 1 mg, 0 81 mmol) in THF (2 0 ml_) in a sealed tube is stirred at 120 C for 2 hours The mixture is concentrated under reduced pressure The obtained residue is purified by silica gel column chromatography (eluent hexane / EtOAc) to give (3,5-biotas-t?fluoromethyl-benzyl)-[(3S,5R)-1-(2-bromo-4-triotafluoromethyl-phenyl)- 5-ethyl-pyrroliotadiotan-3-y.]-[5-(1 -methyl-1 H-pyrazol-4-yl)-py?miotadiotan-2-yl]-amiotane as a colorless oil (36 mg, 18%) 1 H NMR (400 MHz, chloroform-d) delta ppm 0 81 (t, 3H), 1 31 -1 35 (m, 1 H) 1 63-1 69 (m, 1 H),1 74 (q, 1 H), 2 40-2 43 (m, 1 H), 3 20 (dd, 1 H), 3 76-3 83 (m, 1 H) 3 88 (dd, 1 H), 3 95 (s, 3H), 5 02 (d, 1 H), 5 16 (d, 2H), 5 45-5 50 (m, 1 H), 6 98 (d, 1 H), 7 46 (dd, 1 H), 7 52 (s, 1 H), 7 66 (s, 1 H), 7 72 (s, 2H), 7 75 (d, 2H), 8 42 (s, 2H) ESI-MS m/z 722 [M+1]+, Retention time2 48 mm (condition A)

Reference： [1]Patent: WO2009/71509,2009,A1 .Location in patent: Page/Page column 104-105

19
[ 621-59-0 ]
[ 68322-84-9 ]
[ 1188267-41-5 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 140℃; for 5.25h;Inert atmosphere;	Intermediate 8: Preparation of 5-Cyano-5-(4-methoxy-8-trifluoromethyl- dibenzofuran-l-yl)-2-oxo-cyclohexanecarboxylic acid methyl esterStep-1: Preparation of 3-(2-Bromo-4-trifluoromethyl-phenoxy)-4-methoxy- benzaldehydeTo a stirred solution of Isovanillin (5 gm, 0.0328 moles) and Potassium carbonate (13.6 gm, 0.0985 moles) in dry DMF (20 ml) was added 3-Bromo-4- Fluorobenzotrifluoride (8.065 gm, 0.0331 moles) over a period of 15 min at room temperature under nitrogen atmosphere, and then above reaction mixture was stirred at 14O0C for 5 hrs. After completion of reaction, the reaction mixture was cooled to room temperature and the contents were poured in to water (100 ml) and extracted with ethyl acetate (3XlOOmI). The organic extracts were combined and washed with <n="41"/>IN sodium hydroxide, water and brine, dried with sodium sulfate, filtered and solvent evaporated under vacuum to obtain the title compound (11.58 gm, yield-94%) a pale yellow solid.1H NMR (300 MHz, CDCl3) delta 3.92 (s, 3H), 6.75 (d, J= 8.6 Hz, IH), 7.15 (d, J= 8.5 Hz, IH), 7.45 (d, J= 8.6 Hz, IH), 7.54 (d, J = 1.9 Hz, IH), 7.77 (dd, J=8.4 Hz, J=I.9Hz, IH,), 7.90 (s, IH), 9.87 (s, IH)MS (M++.): 376

Reference： [1]Patent: WO2009/115874,2009,A2 .Location in patent: Page/Page column 38-39

20
[ 68322-84-9 ]
[ 1066-54-2 ]
[ 1188446-61-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 20℃;Inert atmosphere;	A mixture of 2-bromo-l-fluoro-4-(trifluoromethyl)benzene (1.14 mL, 10 mmol), ethynyltrimethylsilane (2.1 mL, 15 mmol), CuI (0.38 g, 2 mmol), TEA (8.3 mL, 60 mmol), and Pd(Ph3P)4 (0.58 g, 0.5 mmol) in THF (30 mL) were stirred at rt under N2 overnight. The mixture was diluted with EtOAc (45 mL) and it was washed with H2O(2OmL), brine (20 mL), and saturated sodium bicarbonate solution (20 mL). The organics were filtered, dried, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% EtOAc/hexanes) to afford ((2- fluoro-5-(trifluoromethyl)phenyl)ethynyl) trimethylsilane.

Reference： [1]Patent: WO2009/117421,2009,A2 .Location in patent: Page/Page column 177

21
[ 852471-18-2 ]
[ 68322-84-9 ]
[ 1195951-81-5 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;copper(l) iodide; In N,N-dimethyl-formamide; at 90℃; for 3h;	The product from Scheme 14, Step 4 (136 mg, 0.407 mmol, 1 eq), 2-bromo-1- fluoro-4-(trifluoromethyl)benzene (148 mg, 0.61 mmol, 1.5 eq), CuI (16 mg, 0.084 mmol, 0.2 eq), and Cs2CO3 (265 mg, 0.82 mmol, 2 eq) were combined in DMF (1.5 ml_) and heated for 3h at 900C. The reaction was filtered and the filtrate was partitioned between EtOAc and water. The aqueous layer was discarded, and the organic layer was washed three times more with water, was dried over anhydrous sodium sulfate, was filtered, and was evaporated to afford a crude residue. Preparative thin layer silica gel chromatography (20cmX20cm, 1000 mum, developed with 3% EtOAc in hexanes) afforded the desired product (145 mg).

Reference： [1]Patent: WO2009/140342,2009,A1 .Location in patent: Page/Page column 129

22
[ 68322-84-9 ]
[ 68-12-2 ]
[ 1236538-66-1 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of n-BuLi (2.5 M in hexanes, 1.98 mL, 4.94 mmol) was added to a solution of diisopropylamine (0.700 mL, 4.94 mmol) in THF (10 mL) at -30 C. After 15 minutes, the mixture was cooled to -70 0C, then <strong>[68322-84-9]3-bromo-4-fluorobenzotrifluoride</strong> (1.00 g, 4.12 mmol) was added. After 30 minutes, anhydrous DMF (0.637 mL, 8.23 mmol) was added drop wise. After 15 minutes, acetic acid (0.50 mL, 8.2 mmol) was added, then the mixture was diluted with ethyl acetate and water. The resulting layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organics were washed with saturated NaCl (aq), dried over Na2SO4, filtered, then concentrated. The resulting light yellow oil was used directly for the following step. 1H NMR (500 MHz>; CDCl3) delta 10.38 (s, 1 H); 8.10-8.15 (m, 2 H). LCl: 3.44 min. Compound does not ionize.

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 623 - 628
[2]Patent: WO2010/88061,2010,A1 .Location in patent: Page/Page column 37-38

23
[ 68322-84-9 ]
calcium ({1-[2-fluoro-5-(trifluoromethyl)phenyl]pyrrolidin-3-yl}oxy)acetate [ No CAS ]

Reference： [1]Patent: EP2295406,2011,A1
[2]Patent: US2011/251187,2011,A1

24
[ 68322-84-9 ]
[ 1198181-71-3 ]

Reference： [1]Patent: EP2295406,2011,A1
[2]Patent: US2011/251187,2011,A1

25
[ 40499-83-0 ]
[ 68322-84-9 ]
[ 1198181-21-3 ]

Yield	Reaction Conditions	Operation in experiment
49%	With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 85℃; for 16h;Inert atmosphere;	Reference Example 55 1-[2-fluoro-5-(trifluoromethyl)phenyl]pyrrolidin-3-ol; A solution of <strong>[68322-84-9]2-bromo-1-fluoro-4-(trifluoromethyl)benzene</strong> (4.6 g), 3-hydroxypyrrolidine (1.5 g), palladium(II) acetate (193 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.07 g) and cesium carbonate (16.8 g) in toluene (90 mL) was stirred under an argon gas atmosphere at 85C for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 - 65:35) to give the title compound (2.12 g, yield 49%) as a brown oil. 1H-NMR (300 MHz, CDCl3)delta:1.67 (d, J = 4.3 Hz, 1 H), 1.96 - 2.23 (m, 2 H), 3.35 - 3.49 (m, 2 H), 3.56 - 3.76 (m, 2 H), 4.49 - 4.65 (m, 1 H), 6.79 - 6.88 (m, 1 H), 6.88 - 6.96 (m, 1 H), 6.97 - 7.10 (m, 1 H).
49%	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 85℃; for 16h;Inert atmosphere;	A solution of <strong>[68322-84-9]2-bromo-1-fluoro-4-(trifluoromethyl)benzene</strong> (4.6 g), 3-hydroxypyrrolidine (1.5 g), palladium(II) acetate (193 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.07 g) and cesium carbonate (16.8 g) in toluene (90 ml) was stirred under an argon gas atmosphere at 85 C. for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-65:35) to give the title compound (2.12 g, yield 49%) as a brown oil.1H-NMR (300 MHz, CDCl3) delta: 1.67 (d, J=4.3 Hz, 1H), 1.96-2.23 (m, 2H), 3.35-3.49 (m, 2H), 3.56-3.76 (m, 2H), 4.49-4.65 (m, 1H), 6.79-6.88 (m, 1H), 6.88-6.96 (m, 1H), 6.97-7.10 (m, 1H).

Reference： [1]Patent: EP2295406,2011,A1 .Location in patent: Page/Page column 67
[2]Patent: US2011/251187,2011,A1 .Location in patent: Page/Page column 48

26
[ 68322-84-9 ]
[ 121-33-5 ]
[ 1055361-54-0 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 788 - 808

27
[ 68322-84-9 ]
[ 121-33-5 ]
[ 1055361-85-7 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 788 - 808

28
[ 533-58-4 ]
[ 68322-84-9 ]
[ 1325219-84-8 ]

Reference： [1]Chemistry - A European Journal,2011,vol. 17,p. 8452 - 8461
[2]Organic Letters,2015,vol. 17,p. 70 - 73

29
[ 533-58-4 ]
[ 68322-84-9 ]
[ 1325219-85-9 ]

Reference： [1]Chemistry - A European Journal,2011,vol. 17,p. 8452 - 8461

30
[ 68322-84-9 ]
[ 1400692-09-2 ]
[ 1400691-91-9 ]

Yield	Reaction Conditions	Operation in experiment
20%	With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine; In N,N-dimethyl-formamide; at 170℃; for 6.33333h;	Cul (150 mg, 0.79 mmol) and N,/V-dimethylethylenediamine (0.17 mL, 1.58 mmol) were added to a mixture of <strong>[68322-84-9]3-bromo-4-fluorobenzotrifluoride</strong> (768 mg, 3.16 mmol), intermediate 21 (250 mg, 0.79 mmol), and Cs2C03 (644 mg, 1.98 mmol) in DMF (3 mL). The r.m. was heated at 170 C for 90 min twice, the r.m. was cooled, EtOAc was added and the mixure was washed with a IM aq. H4OH solution, water and brine. The organic layer was dried (MgS04), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (eluent: DCM/MeOH from 100/0 to 97/3). The product fractions were collected and concentrated in vacuo. Then the residue was repurified by RP preparative HPLC [RP Vydac Denali C18 - IotaOmicronmu?iota, 250 g, 5cm); mobile phase: a gradient of (0.25% H4HC03 sol. in water)/CH3CN)]. The product fractions were collected and concentrated in vacuo. Yield: 75 mg of compound 14 (20 %).

Reference： [1]Patent: WO2012/126984,2012,A1 .Location in patent: Page/Page column 54

31
[ 68322-84-9 ]
[ 1400692-12-7 ]
[ 1400692-11-6 ]
[ 1400691-82-8 ]
[ 1400691-81-7 ]

Yield	Reaction Conditions	Operation in experiment
14%; 9%	With caesium carbonate; XPhos;tris-(dibenzylideneacetone)dipalladium(0); In tert-butyl alcohol; at 100℃; for 16h;Inert atmosphere;	3-Bromo-4-fluorobenzotrifluoride (0.39 mL, 2.73 mmol), Cs2C03 (1.78 g, 5.47 mmol), X-Phos (211 mg, 0.36 mmol) and Pd2(dba)3 (167 mg, 0.18 mmol), were added to a mixture of intermediate 23 and intermediate 24 (500 mg, 1.82 mmol) in 2-methyl-2- propanol (41 mL) under a N2 atmosphere. The r.m. was heated at 100 C for 16 h. Then, the r.m. was cooled to r.t., water was added and the r.m. was extracted with DCM. The combined organic layers were dried (MgS04), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: DCM/MeOH from 100/0 to 95/5). The product fractions were collected and concentrated in vacuo. Yield: 69 mg of compound 7 (9 %) and 108 mg of compound 7a (14 %; regioisomer of compound 7).

Reference： [1]Patent: WO2012/126984,2012,A1 .Location in patent: Page/Page column 49

32
[ 68322-84-9 ]
[ 1400692-13-8 ]
[ 1400691-83-9 ]

Yield	Reaction Conditions	Operation in experiment
28%	With caesium carbonate; XPhos;tris-(dibenzylideneacetone)dipalladium(0); In tert-butyl alcohol; at 100℃; for 16h;Inert atmosphere;	3-Bromo-4-fluorobenzotrifluoride (0.086 mL, 0.63 mmol), Cs2C03 (618 mg, 1.9 mmol), X-Phos (73 mg, 0.13 mmol) and Pd2(dba)3 (58 mg, 0.063 mmol), were added to a sol. of intermediate 25 (200 mg, 0.63 mmol) in 2-methyl-2-propanol (14 mL) under a N2 atmosphere. The r.m. was heated at 100 C for 16 h. Then, the r.m. was cooled to r.t., water was added and the r.m. was extracted with DCM. The combined organic layers were dried (MgS04), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: DCM/MeOH from 100/0 to 95/5). The product fractions were collected and concentrated in vacuo. The residue was triturated with DIPE, filtered off and dried. Yield: 79 mg of compound 8 (28 %).

Reference： [1]Patent: WO2012/126984,2012,A1 .Location in patent: Page/Page column 50

33
[ 68322-84-9 ]
[ 1400692-15-0 ]
[ 1400691-84-0 ]

Yield	Reaction Conditions	Operation in experiment
25%	With caesium carbonate; XPhos;tris-(dibenzylideneacetone)dipalladium(0); In tert-butyl alcohol; at 100℃; for 16h;Inert atmosphere;	3-Bromo-4-fluorobenzotrifluoride (0.22 mL, 1.56 mmol), Cs2C03 (1.02 g, 3.12 mmol), X-Phos (120 mg, 0.21 mmol) and Pd2(dba)3 (95 mg, 0.1 mmol), were added to a sol. of intermediate 27 (300 mg, 1.04 mmol) in 2-methyl-2-propanol (23 mL) under a N2 atmosphere. The r.m. was heated at 100 C for 16 h. Then, the r.m. was cooled to r.t., water was added and the r.m. was extracted with DCM. The combined organic layers were dried (MgS04), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: DCM/MeOH from 100/0 to 95/5). The product fractions were collected and concentrated in vacuo. The residue was triturated with DIPE, filtered off and dried. Yield: 120 mg of compound 9 (25 %).

Reference： [1]Patent: WO2012/126984,2012,A1 .Location in patent: Page/Page column 50

34
[ 68322-84-9 ]
[ 1400692-17-2 ]
[ 1400692-18-3 ]
[ 1400691-86-2 ]
[ 1400691-85-1 ]

Yield	Reaction Conditions	Operation in experiment
20%; 28%	With caesium carbonate; XPhos;tris-(dibenzylideneacetone)dipalladium(0); In tert-butyl alcohol; at 100℃; for 16h;Inert atmosphere;	3-Bromo-4-fluorobenzotrifluoride (0.21 mL, 1.45 mmol), Cs2C03 (943 mg, 2.89 mmol), X-Phos (92 mg, 0.19 mmol) and Pd2(dba)3 (88 mg, 0.096 mmol), were added to a mixture of intermediate 29 and intermediate 30 (250 mg, 0.96 mmol) in 2-methyl-2- propanol (20 mL) under a N2 atmosphere. The r.m. was heated at 100 C for 16 h. Then, the r.m. was cooled to r.t., water was added and the r.m. was extracted with DCM. The combined organic layers were dried (MgS04), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: DCM/MeOH from 100/0 to 95/5). The product fractions were collected and concentrated in vacuo. The residue was repurified by RP preparative HPLC [RP Vydac Denali C18 - IotaOmicronmu?iota, 250 g, 5cm); mobile phase: a gradient of (0.25% H4HC03 sol. in water/CH3CN)]. The product fractions were collected and concentrated in vacuo. The residue was crystallized from DIPE, filtered off and dried. Yield: 112 mg of compound 10 (28 %) and 80 mg of compound 10a (20 %; regioisomer of compound 10).

Reference： [1]Patent: WO2012/126984,2012,A1 .Location in patent: Page/Page column 51

35
[ 68322-84-9 ]
[ 1400692-20-7 ]
[ 1400692-19-4 ]
[ 1400691-88-4 ]
N-[2-fluoro-5-(trifluoromethyl)phenyl]-1-methyl-3-{4-[(2-methyl-4-pyridinyl)methyl]-1-piperidinyl}-1H-1,2,4-triazol-5-amine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%; 13%		3-Bromo-4-fluorobenzotrifluoride (0.38 mL, 2.67 mmol), Cs2C03 (1.74 g, 5.34 mmol), X-Phos (207 mg, 0.036 mmol) and Pd2(dba)3 (164 mg, 0.18 mmol), were added to a mixture of intermediate 31 and intermediate 32 (510 mg, 1.78 mmol) in 2-methyl-2- propanol (40 mL) under a N2 atmosphere. The r.m. was heated at 100 C for 16 h. Then, the r.m. was cooled to r.t., water was added and the r.m. was extracted with DCM. The combined organic layers were dried (MgS04), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: DCM/MeOH from 100/0 to 95/5). The product fractions were collected and concentrated in vacuo. Both residue was suspended in DIPE and treated with a 6 N HC1 sol. in 2-propanol. Resulting precipitates were collected by filtration. The first compound impure was repurified by RP preparative HPLC [RP Vydac Denali CI 8 - IotaOmicronmu?iota, 250 g, 5cm); mobile phase: a gradient of (0.25% H4HC03 sol. in water/CH3CN)]. The product fractions were collected and concentrated in vacuo. Both residue was crystallized from DIPE, filtered off and dried. Yield: 118 mg of compound 11 (13 %) as HC1 salt (.HC1 .H20) and 97 mg of compound 11a (12 %; regioisomer of compound 11).

Reference： [1]Patent: WO2012/126984,2012,A1 .Location in patent: Page/Page column 52

36
[ 68322-84-9 ]
[ 1400692-21-8 ]
[ 1400691-89-5 ]

Yield	Reaction Conditions	Operation in experiment
53%	With caesium carbonate; XPhos;tris-(dibenzylideneacetone)dipalladium(0); In tert-butyl alcohol; at 100℃; for 16h;Inert atmosphere;	3-Bromo-4-fluorobenzotrifluoride (0.20 mL, 1.37 mmol), Cs2C03 (0.89 g, 2.74 mmol), X-Phos (87 mg, 0.18 mmol) and Pd2(dba)3 (94 mg, 0.091 mmol), were added to a sol. of intermediate 33 (250 mg, 0.91 mmol) in 2-methyl-2-propanol (20 mL) under a N2 atmosphere. The r.m. was heated at 100 C for 16 h. Then, the r.m. was cooled to r.t, water was added and the r.m. was extracted with DCM. The combined organic layers were dried (MgS04), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: DCM/MeOH from 100/0 to 95/5). The product fractions were collected and concentrated in vacuo. The residue was triturated with DIPE, filtered off and dried. Yield: 210 mg of compound 12 (53 %).

Reference： [1]Patent: WO2012/126984,2012,A1 .Location in patent: Page/Page column 53

37
[ 68322-84-9 ]
[ 1400692-22-9 ]
[ 1400691-92-0 ]

Yield	Reaction Conditions	Operation in experiment
21%	With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine; In N,N-dimethyl-formamide; at 170℃; for 1.5h;	Cul (186 mg, 0.98 mmol) and N,/V-dimethylethylenediamine (0.17 mL, 1.58 mmol) were added to a mixture of <strong>[68322-84-9]3-bromo-4-fluorobenzotrifluoride</strong> (580 mg, 3.91 mmol), intermediate 35 (282 mg, 0.98 mmol), and Cs2C03 (796 mg, 2.44 mmol) in DMF (3 mL). The r.m. was heated at 170 C for 90 min, the r.m. was cooled, EtOAc was added and the mixure was washed with a IM aq. H4OH solution, water and brine. The organic layer was dried (MgS04), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo. The residue was crystallized from CH3CN, filtered off and dried. Yield: 92 mg of compound 15 (21 %).

Reference： [1]Patent: WO2012/126984,2012,A1 .Location in patent: Page/Page column 54-55

38
[ 68322-84-9 ]
[ 5735-53-5 ]
[ 1450923-15-5 ]

Yield	Reaction Conditions	Operation in experiment
1.73 g		To a flask under nitrogen, 3,4-dihydro-2H-benzo[b][1,4]oxazine (Tyger Scientific Inc., Ewing, NJ, 0.457 mL, 3.70 mmol) was dissolved in DMF (18.50 mL) and at room temperature, NaH (60% dispersion in mineral oil) (0.326 g, 8.14 mmol) was added, and the reaction was stirred for 15 minutes. 2-Bromo-1-fluoro-4-(trifluoromethyl)benzene (Alfa Aesar, Ward Hill, MA, 0.790 mL, 5.55 mmol) was then added, and the reaction was stirred overnight at room temperature until complete conversion to the desired product. The reaction was then quenched with saturated aqueous ammonium chloride solution, and extracted with EtOAc (x2). The combined organics were washed with brine, dried over sodium sulfate, and concentrated to give material, which was purified via silica gel MPLC (Biotage Isolera One; PuriFlash HP, 15mu, 25 g (Biotage, Uppsala, Sweden)), eluting with 0 to 100% ethyl acetate in heptanes. Fractions containing clean product were collected and concentrated under a vacuum to yield 1.73 g of 4-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (INTERMEDIATE B) as an orange oil. 1H NMR (400 MHz, DMSO-d6) delta ppm 3.62 - 3.69 (m, 2 H) 4.28 (t, J=4.21 Hz, 2 H) 6.30 (dd, J=7.87, 1.71 Hz, 1 H) 6.71 (dtd, J=18.67, 7.42, 7.42, 1.71 Hz, 2 H) 6.85 (dd, J=7.78, 1.81 Hz, 1 H) 7.59 (d, J=8.41 Hz, 1 H) 7.81 (dd, J=8.41, 1.56 Hz, 1 H) 8.13 (d, J=1.66 Hz, 1 H). m/z (ESI) 357.0 (M+H)+
1.7 g		To a flask under nitrogen, 3,4-dihydro-2H-benzo[b][1,4]oxazine (Tyger Scientific Inc., Ewing, NJ, 0.46 mL, 3.7 mmol) was dissolved in DMF (19 mL) and at room temperature, NaH (60% dispersion in mineral oil) (0.33 g, 8.1 mmol) was added, and the reaction was stirred for 15 minutes. 2-Bromo-1-fluoro-4-(trifluoromethyl)benzene (Alfa Aesar, Ward Hill, MA, 0.790 mL, 5.6 mmol) was then added, and the reaction was stirred overnight at room temperature until complete conversion to the desired product. The reaction was then quenched with saturated aqueous ammonium chloride solution, and extracted with EtOAc (x2). The combined organics were washed with brine, dried over sodium sulfate, and concentrated to give material, which was purified via silica gel MPLC (Biotage Isolera One; PuriFlash HP, 15mu, 25 g (Biotage, Uppsala, Sweden)), eluting with 0 to 100% ethyl acetate in heptanes. Fractions containing clean product were collected and concentrated under a vacuum to yield 1.7 g of 4-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine as an orange oil. 1H NMR (400 MHz, DMSO-d6) d ppm 3.62 - 3.69 (m, 2 H) 4.28 (t, J=4.21 Hz, 2 H) 6.30 (dd, J=7.87, 1.71 Hz, 1 H) 6.71 (dtd, J=18.67, 7.42, 7.42, 1.71 Hz, 2 H) 6.85 (dd, J=7.78, 1.81 Hz, 1 H) 7.59 (d, J=8.41 Hz, 1 H) 7.81 (dd, J=8.41, 1.56 Hz, 1 H) 8.13 (d, J=1.66 Hz, 1 H). m/z (ESI) 357.0 (M+H)+.

Reference： [1]Patent: WO2013/122897,2013,A1 .Location in patent: Page/Page column 64; 65
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3477 - 3485

39
[ 68322-84-9 ]
[ 1450923-16-6 ]