Name: 194853-86-6|4-Fluoro-2-(trifluoromethyl)benzonitrile|98%
Brand: Ambeed
SKU: A189201
Price: 5.0 USD
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1
[ 77-71-4 ]
[ 194853-86-6 ]
[ 143782-20-1 ]

Yield	Reaction Conditions	Operation in experiment
79%		Weigh 508mg of 5,5-dimethylhein into eggplant-shaped bottles, add 5mL of DMF with stirring to completely dissolve it, then add 220mg of K2CO3 (1eq), stir at 45 C for half an hour to make them mix well. Finally, the DMF solution of 4-fluoro-2-trifluoromethylbenzonitrile (300 mg) was slowly added, and stirred under heating for 5 hours. After the reaction was fully completed, it was cooled to room temperature and diluted with 30 mL of ethyl acetate. It was extracted 3 times with 20 mL of saturated ammonium chloride aqueous solution and once with saturated brine. The organic layer was dried over anhydrous magnesium sulfate for 6 h, filtered with suction, and concentrated. Finally, 200-300 mesh column chromatography was performed to obtain 330 mg of a white solid. Yield 79%.
79%		Weigh 508mg of 5,5-dimethylhydantoin into eggplant-shaped bottles,Add 5mL DMF with stirring to completely dissolve it.Then add 220mg of K2CO3 (1eq) and stir at 45 C for half an hour.Make them fully mixed, and finally slowly add 4-fluoro-2-trifluoromethylbenzonitrile (300mg) in DMF and stir under heating for 5h. After the reaction is complete, cool to room temperature, add 30mL of ethyl acetate and dilute with 20 mL of saturated ammonium chloride aqueous solution was extracted three times, and saturated brine was extracted once. The organic layer was dried over anhydrous magnesium sulfate for 6 h, filtered with suction, and concentrated. Finally, 200-300 mesh column chromatography was performed to obtain 330 mg of a white solid. Yield 79%.
74%	With potassium carbonate; In N,N-dimethyl-formamide; at 45℃; for 48h;Inert atmosphere;	Procedure for synthesis of cyano-nilutamide (1) (Cogan, P. S.; Koch, T. H. Rational Design and Synthesis of Androgen Receptor-Targeted Nonsteroidal Anti-Androgen Ligands for the Tumor-Specific Delivery of a Doxorubicin-Formaldehyde Conjugate. J Med. Chem. 2003, 46, 5258-5270) 4-Fluoro-2-(trifluoromethyl)benzonitrile (4.02 g, 21.3 mmol) was added to Hydantoin (13.6 g, 106.3 mmol) and Potassium Carbonate (4.40 g, 31.9 mmol) in 60 mL DMF and stirred at 45C under argon for 48 hours. Reaction mixture was then diluted in ethyl acetate and washed three times with water. Organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (eluent 30: 1 DCM/Methanol) gave 1 as a white solid (4.62 g, 74%). 1H NMR (400 MHz, (CD3)2-CO) delta 1.54 (6H, s), 7.80 (1H, s), 8.13 (1H, dd, J = 1.8 Hz, J = 8.4 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.26 (1H, d, J = 1.8 Hz)

55%	With potassium carbonate; In N,N-dimethyl-formamide; at 45 - 55℃; for 64h;	To a stirring solution of 1.00 g (4. 78 mmol) of 4- fluoro-2- (trifluoromethyl)-benzonitrile in 15.0 mL of DMF was added 3.10 g (23.9 mmol) of 5,5-dimethylhydantoin and 0.990 g (7.17 mmol) of K2CO3. The resulting suspension was stirred under an argon atmosphere at 55 C for 16 h and then at 45 C for 48 h. The reaction mixture was diluted to 300 mL with ethyl acetate, vacuum filtered and rotary evaporated at 40 C followed by 50 C and 50 um Hg to yield a bright yellow paste. The paste was dissolved in 25% hexanes/75% ethyl acetate and eluted from a silica gel flash column (35 cm x 3 cm) with 50% hexanes/50% ethyl acetate. The collected product was rotary evaporated at 40 C to give a white solid which was recrystallized from ethyl acetate/hexanes to give 0.780 g (55%) of 2f as a white crystalline solid (mp 208-210 C)
46%	With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 0.333333h;Microwave irradiation;	Example 19; 4-(4,4-dimethyl-2,5-dioxo-3-{9-[(4,4,5,5,5-pentafluoropentylsulphanyl]nonyl}imidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile19.1) 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrileA mixture of 4-fluoro-2-(trifluoromethyl)benzonitrile (5.67 mg, 30 mmoles), 5,5-dimethyl-hydantoin (7.68 g, 60 mmoles), K2CO3 (8.28 g, 60 mmoles) in DMF (45 ml) is distributed in equal parts into three tubes to be placed in a microwave oven. Under magnetic stirring, each tube is irradiated at 140 C. for 20 minutes. The reaction masses are then combined, poured into water (200 ml) and extracted with AcOEt (2×75 ml). The organic phases are combined, washed with salt water, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue crystallized from Et20 (25 ml). After recrystallization from EtOH (75 ml), the powder is filtered and dried under vacuum. The expected compound is obtained in the form of a white solid with a yield of 46% (4.1 g). Melting point: 212-213 C.1H NMR 400 MHz (DMSO-d6) delta: 8.80 (s, 1H, NH); 8.29 (d, 1H, Ph); 8.18 (s, 1H, Ph); 8.02 (d, 1H, Ph); 1.42 (s, 6H, 2×CH3).
46%	With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 0.333333h;microwave irradiation;	5.1) 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile A mixture of 4-fluoro-2-(trifluoromethyl)benzonitrile (5.67 g, 30 mmoles), 5,5-dimethyl-hydantoin (7.68 g, 60 mmoles), K2CO3 (8.28 g, 60 mmoles) in DMF (45 ml) is distributed in equal parts into three tubes to be placed in a microwave oven. Under magnetic stirring, each tube is irradiated at 140 C. for 20 minutes. The reaction masses are then combined, poured into water (200 ml) and extracted with AcOEt (275 ml). The organic phases are combined, washed with salt water, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue crystallizeds from Et2O (25 ml). After recrystallization from EtOH (75 ml), the powder is filtered and dried under vacuum. The expected compound is obtained in the form of a white solid with a yield of 46% (4.1 g). Melting point: 212-213 C. 1H NMR 400 MHz (DMSO-d6) delta: 8.80 (s, 1H, NH); 8.29 (d, 1H, Ph); 8.18 (s, 1H, Ph); 8.02 (d, 1H, Ph); 1.42 (s, 6H, 2CH3).
32.2%	With potassium carbonate; In N,N-dimethyl-formamide; at 45℃; for 42h;Inert atmosphere;	4-fluoro-2-trifluorobenzonitrile (55) (994 mg),5,5-dimethylhydantoin (56) (3.37 g),Potassium carbonate (1.11 g) was added to N, N-dimethylformamide (15 mL) and stirred under nitrogen atmosphere at 45 C. for 42 hours.After returning the reaction solution to room temperature, the reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (developing solvent: chloroform: methanol = 50: 1) to give the title compound (57) (503 mg, yield 32.2%) as a white solid.

Reference： [1]Patent: CN110759897,2020,A .Location in patent: Paragraph 0027
[2]Patent: CN110790750,2020,A .Location in patent: Paragraph 0009; 0015; 0016
[3]Patent: WO2012/50868,2012,A1 .Location in patent: Page/Page column 26
[4]Inorganic Chemistry,2018,vol. 57,p. 5019 - 5029
[5]Journal of Medicinal Chemistry,2003,vol. 46,p. 5258 - 5270
[6]Synlett,2006,p. 2290 - 2292
[7]Patent: WO2005/34856,2005,A2 .Location in patent: Page/Page column 50
[8]Patent: US2012/83514,2012,A1 .Location in patent: Page/Page column 16
[9]Patent: US2012/95068,2012,A1 .Location in patent: Page/Page column 9-10
[10]Patent: JP2017/71567,2017,A .Location in patent: Paragraph 0233-0235

2
[ 79-39-0 ]
[ 194853-86-6 ]
[ 90357-53-2 ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogenchloride; In hexane; water; N,N-dimethyl-formamide;	EXAMPLE 1 Preparation of N-[4-Cyano-3-(trifluoromethyl)phenyl]methacrylamide To a solution of methacrylamide (153.00 g, 1797.88 mmol) in 800 mL of N,N-dimethylformamide was added <strong>[194853-86-6]4-cyano-3-(trifluoromethyl)phenyl fluoride</strong> (200 g, 1057.58 mmol) at room temperature. The solution was cooled in a methanol/dry ice bath to -20 C. To this cooled solution was added sodium hydride (102 g, 2696.84 mmol), portion-wise, while keeping the reaction mixture temperature below 70 C. The reaction mixture was allowed to cool to room temperature and stirred for 4 hours under nitrogen atmosphere. Water (915 mL) was added followed by 18% HCl (250 mL) and hexane (970 mL). The resultant slurry was allowed to stir overnight. The solid was filtered, washed sequentially with water (3*150 mL) and hexane (100 mL), and dried at 60 C. to give the title product as an off white solid (260 g, 97%). 1H NMR (CDCl3) delta 7.87 (d, J=1.9 Hz, 111), 7.80 (dd, J=1.9, 8.5 Hz, 1H), 7.69 (bs, 1H), 7.62 (d, J=8.5 Hz, 1H), 5.69 (s, 1H), 5.44 (t, J=1.5 Hz, 1H), 1.90 (s, 3H).

Reference： [1]Journal of Organic Chemistry,2003,vol. 68,p. 10181 - 10182
[2]Patent: US2002/86902,2002,A1
[3]Journal of Organometallic Chemistry,2011,vol. 696,p. 1049 - 1056

3
[ 84477-72-5 ]
[ 194853-86-6 ]
4-(3,3-dimethylpiperazin-1-yl)-2-(trifluoromethyl)benzonitrile [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2005,vol. 53,p. 402 - 409

4
[ 109-07-9 ]
[ 194853-86-6 ]
[ 262295-65-8 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2005,vol. 53,p. 402 - 409

5
[ 107-15-3 ]
[ 194853-86-6 ]
[ 904301-11-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In acetonitrile; at 50℃; for 4h;Inert atmosphere;	General procedure: 2-Aminoethyl amine (1 equiv.) and 2-trifluormethyl-4-fluoro benzonitrile(1 equiv.) were dissolved under argon in dry MeCN, followedby addition of Et3N (1.5 equiv). The resulting reaction mixture wasstirred at 50 C for 4 h. After cooling to room temperature water andCH2Cl2 were added, followed by thorough extraction. The combinedorganic layer was dried over Na2SO4, filtered and concentrated underreduced pressure to afford desired 4-[(2-aminoethyl)-amino]-2-(trifluormethyl)benzonitrile. 4-[(2-aminoethyl)-amino]-2-(trifluormethyl)benzonitrile (160 mg, 0.69 mmol) was dissolved in a flame-dried roundbottomedflask in CH2Cl2 (20 mL) under argon and diisopropylethylamine (0.37 mL, 2.09 mmol) was added. After stirring at room temperaturefor 5 min a solution of the corresponding aryl- or hetarylsulfonylchloride (0.69 mmol) in dry CH2Cl2 (5 mL) was added, andthe resulting reaction mixture was stirred at room temperature for20 h·H2O and CH2Cl2 were added, followed by thorough extraction. Thecombined organic layer was dried over Na2SO4, filtered, concentratedunder reduced pressure and purified via column chromatography(heptane/EtOAc, gradient 10:0 to 1:1) to afford desired N-(2-[4-cyano-3-(trifluormethyl)phenyl]amino}-ethyl)-aryl-/hetaryl sulfonamide 9i-z.

Reference： [1]Chemical and Pharmaceutical Bulletin,2005,vol. 53,p. 402 - 409
[2]Bioorganic and Medicinal Chemistry,2019,vol. 27

6
[ 120737-59-9 ]
[ 194853-86-6 ]
[ 262295-73-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	Reference Example 3 t-Butyl 4-(4-cyano-3-trifluoromethylphenyl)-3-methylpiperazine-1-carboxylate A 4.46 g portion of t-butyl 3-methylpiperazine-1-carboxylate synthesised in Reference Example 2, 6.74 g of 4-fluoro-2-trifluoromethylbenzonitrile and 7.76 ml of diisopropylethylamine were stirred in 50 ml of DMF at 100C for 2 days. The reaction solution was diluted with water and extracted with ethyl acetate, the organic layer was washed and dried and then the solvent was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (3:1, v/v) to obtain 5.6 g of the title compound as white crystals.
	With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 100℃; for 48h;	Reference Example 3 t-Butyl 4-(4-cyano-3-trifluoromethylphenyl)-3-methylpiperazine-1-carboxylate A 4.46 g portion of t-butyl 3-methylpiperazine-1-carboxylate synthesised in Reference Example 2, 6.74 g of 4-fluoro-2-trifluoromethylbenzonitrile and 7.76 ml of diisopropylethylamine were stirred in 50 ml of DMF at 100 C. for 2 days.. The reaction solution was diluted with water and extracted with ethyl acetate, the organic layer was washed and dried and then the solvent was evaporated under reduced pressure.. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (3:1, v/v) to obtain 5.6 g of the title compound as white crystals.

Reference： [1]Chemical and Pharmaceutical Bulletin,2005,vol. 53,p. 402 - 409
[2]Patent: EP1122242,2001,A1
[3]Patent: US6673799,2004,B1 .Location in patent: Page column 12

7
[ 194853-86-6 ]
2-[2-(4-Cyano-3-trifluoromethyl-phenoxy)-1-hydroxy-1-methyl-ethyl]-6-trifluoromethyl-1H-indole-5-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		2-[2-(4-Cyano-3-trifluoromethyl-phenoxy)-1-hydroxy-1-methyl-ethyl]-6-trifluoromethyl-1H-indole-5-carbonitrile, Compound No.429, was similarly prepared according to the procedure described in Example 91, to yield the product as an off-white solid. MS m/z (M-H) 452 1H NMR (300 Hz, DMSO d6). delta1.68 (s. 3H), 4.36 (s, 2H), 6.10 (s, 1H), 6.67 (s, 1H), 7.44 (m, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.87 (s, 1H), 8.05 (d, J=8.5 Hz, 1H), 8.32 (s, 1H).

Reference： [1]Patent: US2005/250740,2005,A1 .Location in patent: Page/Page column 60

8
[ 6760-99-2 ]
[ 194853-86-6 ]
C₁₅H₁₅F₃N₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660

9
[ 194853-86-6 ]
[ 90356-78-8 ]

Reference： [1]Journal of Organic Chemistry,2003,vol. 68,p. 10181 - 10182

10
[ 194853-86-6 ]
[ 90357-51-0 ]

Reference： [1]Journal of Organic Chemistry,2003,vol. 68,p. 10181 - 10182

11
[ 104-58-5 ]
[ 194853-86-6 ]
[ 685565-11-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hexamethylsilazane; In tetrahydrofuran; toluene; at 0 - 20℃;	4-Fluoro-2-trifluoromethyl-benzonitrile (1.20g) was dissolved in THF (20MOI) and 3- PIPERIDIN-1-YL-PROPAN-1-OL (0. 91MI) was added. The reaction was cooled to OOC and potassium HEXAMETHYLDISILAZIDE (0.5M solution in toluene; 12. 72ML) was added dropwise. The reaction was stirred at rt overnight, then diluted with ethyl acetate (50ML) and partitioned with aqueous 1 N HCI (50ML). The aqueous layer was washed with ethyl acetate (50ML), then basified to pH 8.0 with sodium hydrogen carbonate and extracted with ethyl acetate (3X75ML). The combined organic extracts were dried (MgSO4) and evaporated to give the title compound (D14) as a clear oil which crystallised on standing (0.80g).
	With potassium hexamethylsilazane; In tetrahydrofuran; toluene; at 0 - 20℃;	4-Fluoro-2-trifluoromethyl-benzonitrile (1.20g) was dissolved in THF (20 mi) and 3- PIPERIDIN-1-YL-PROPAN-1-OL (0.91 ML) was added. The reaction was cooled to 0C and potassium HEXAMETHYLDISILAZIDE (0.5M solution in toluene ; 12.72 mi) was added dropwise. The reaction was stirred at rt overnight, then diluted with ethyl acetate (50 ml) and partitioned with aqueous 1 N HCI (50 ML). The aqueous layer was washed with ethyl acetate (50 ML), then basified to pH 8.0 with sodium hydrogen carbonate and extracted with ethyl acetate (3x75 ML). The combined organic extracts were dried (MGS04) and evaporated to give the title compound (D4) as a clear oil which crystallised on standing (0.80g).

Reference： [1]Patent: WO2004/37800,2004,A1 .Location in patent: Page 23
[2]Patent: WO2004/37788,2004,A1 .Location in patent: Page 13

12
[ 84477-85-0 ]
[ 194853-86-6 ]
4-[4-benzyloxycarbonyl-2-methyl-1-piperazinyl]-2-trifluoromethylbenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In water; N,N-dimethyl-formamide;	Example 17 4-[4-Benzyloxycarbonyl-2-methyl-1-piperazinyl]-2-trifluoromethylbenzonitrile A 1.01 g portion of <strong>[84477-85-0]benzyl 3-methylpiperazine-1-carboxylate</strong> synthesised in Reference Example 10, 814 mg of 4-fluoro-2-trifluoromethylbenzonitrile and 2.38 g of potassium carbonate were added to 20 ml of DMF and stirred at 100C for 20 hours. This was mixed with water, extracted with ethyl acetate and dried, and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography to obtain 440 mg of the title compound from ethyl acetate-hexane (3:1, v/v) elude.
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 100℃; for 20h;	Example 17 4-[4-Benzyloxycarbonyl-2-methyl-1-piperazinyl]-2-trifluoromethylbenzonitrile A 1.01 g portion of <strong>[84477-85-0]benzyl 3-methylpiperazine-1-carboxylate</strong> synthesised in Reference Example 10, 814 mg of 4-fluoro-2-trifluoromethylbenzonitrile and 2.38 g of potassium carbonate were added to 20 ml of DMF and stirred at 100 C. for 20 hours.. This was mixed with water, extracted with ethyl acetate and dried, and then the solvent was evaporated.. The resulting residue was purified by a silica gel column chromatography to obtain 440 mg of the title compound from ethyl acetate-hexane (3:1, v/v) elude.

Reference： [1]Patent: EP1122242,2001,A1
[2]Patent: US6673799,2004,B1 .Location in patent: Page column 33

13
[ 124-68-5 ]
[ 194853-86-6 ]
4-(2-hydroxy-1,1-dimethyl-ethylamino)-2-trifluoromethyl-benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 140℃; for 0.305556h;Microwave irradiation;	Example 18 4-(2-Hydroxy-1,1-dimethyl-ethylamino)-2-trifluoromethyl-benzonirile 2-Amino-2-methyl-propan-1-ol (25 mg, 0.275 mmol) was dissolved in 0.7 mLDMSO and DIPEA (36 mg, 0.275 mmol) was added. 4-fluoro-2-hifluoromethyl-benzonitrile (40 mg, 0.212 mmol) was then added and the reaction was heated to 140 C for 1100 seconds in a microwave oven (Parameters : high absorbance, fixed holding time, pre-stiiring 25 seconds). The reaction was then diluted with 10 mL EtOAc, washed with an aqueous solution of NH4C1, dried with anhydrous MgSO4, filtered and then the organic phase was evaporated in vacuo. The crude product was purified on silica column with 3: 1 n- heptane: EtOAc as the mobile phase. Upon dissolving the crude product in the mobile phase, an insoluble precipitate was collected. On analysis this showed to be mainly pure product All insoluble precipitate was dissolved in acetone, celite TM was added, whereafter the acetone was evaporated. The celite was then applied to a silica column with 2 : 1 n-heptane: EtOAc as the mobile phase to give 34 mg (62%) of 4- (2-hydroxy-1, 1- dimethyl-ethylamino)-2-trifluoromethyl-benzonitrile as beige crystals.

Reference： [1]Patent: WO2005/42464,2005,A1 .Location in patent: Page/Page column 39-40

14
[ 80696-30-6 ]
[ 194853-86-6 ]
(R)-4-(1-hydroxymethyl-butylamino)-2-trifluoromethyl-benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 180℃; for 0.25h;Microwave irradiation;	Example 21 (R)-4-(1-Hydroxymethyl-butylamino)-2-trifluoromethyl-benzonitrile 4-Fluoro-2-trifluoromethyl-benzonitrile (40 mg, 0.21 mmol), (R)-2-Amino-pentan-l-ol (32 mg, 0.27 mmol) and DIPEA (47 muL, 0.27 mmol) was dissolved in DMSO (1 mL) and heated to 180 C for 900 seconds in a microwave oven (Parameters : Fixed Holding time, High absorbance, pre-stirring 25 sec. ). The crude product was diluted with CH2Ch and washed with an aqueous solution of NH4Cl, The organic phase was separated, dried and evaporated in vacuo. The crude product was purified on a silica column with 3: 1 n- heptane: EtOAc as the mobile phase. This gave 39 mg (68%) of (R)-4- (1-hydroxymethyl- butylamino)-2-hifluoromethyl-benzonitrile.

Reference： [1]Patent: WO2005/42464,2005,A1 .Location in patent: Page/Page column 41

15
[ 85803-43-6 ]
[ 194853-86-6 ]
4-((R)-1-benzylsulfanylmethyl-2-hydroxy-ethylamino)-2-trifluoromethyl-benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 180℃; for 0.25h;Microwave irradiation;	Example 103 4- ( (R)-1-Benzylsulfanylmethyl-2-hydroxy-ethylamino)-2-trifluoromethyl-benzonitrile 4-Fluoro-2-trifluoromethyl-benzonitrile (60 mg, 0.32 mmol) was solved in 1000 fiL DMSO. (R)-2-amino-3-benzylsulfanyl-propan-1-ol (81 mg, 0.41 mmol) was added and then diisopropyl-ethyl amine (DIPEA) (53 mg, 0.41 mmol). Reaction was heated to 180 C in microwave for 15 min (Parameters: Normal absorption, hold time on, pre-stirring 20 sec). Crude mixture was diluted in CH2Cl2 and washed several times with NH4CI (aq) and phases were separated on SPE Phase Separator. Organic phase was evaporated in vacuo and crude product mixture was then purified on silica column with 3: 1 n- heptane: EtOAc as mobile phase. This gave pure product 82 mg (71 %) of 4-((R)-1- benzylsulfanylmethyl-2-hydroxy-ethylamino)-2-trifluoromethyl-benzonitrile as transparent oil.

Reference： [1]Patent: WO2005/42464,2005,A1 .Location in patent: Page/Page column 61

16
[ 109-89-7 ]
[ 194853-86-6 ]
4-(diethylamino)-2-(trifluoromethyl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	In acetonitrile; at 120 - 150℃; for 0.5h;	A solution of 4-fluoro-2- (trifluoromethyl) benzonitrile (0.050 g, 0.264 MMOL) and diethylamine (0.096 g, 1.32 MMOL) in acetonitrile (3 mL) was heated in a microwave at 120C FOR 10 min. Upon cooling, additional diethylamine (0.096 g, 1.32 MMOL) was added and the reaction was heated in a microwave at 150C for 20 min. Upon cooling, the reaction mixture was partitioned between EtOAc and water. The organic phase was washed with water and brine, dried (NA2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (5-40% ETOAC-HEXANE gradient) to give the title compound (0.058 g, 90% yield) : MS (ES) M/Z 243 (M+1).

Reference： [1]Patent: WO2005/795,2005,A2 .Location in patent: Page 47

17
[ 26389-60-6 ]
[ 194853-86-6 ]
4-[(cyclopropylmethyl)(propyl)amino]-2-(trifluoromethyl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%		Solid supported N-methyl morpholine (PS-NMM) Resin (0.045 g, 180 mumol), 120 PL OF A 2 M N- (CYCLOPROPYLMETHYL)-N-PROPYLAMINE SOLUTION in DMSO, and 150 ; J. LOFA1 M 4-fluoro-2- (trifluoromethyl) benzonitrile solution were added to a well of a Robbins FLEXCHEM square well plate. The plate was rotated for 20 h at 99C and cooled. To the well was added 1.2 mL of DMSO, solid supported benzylisocyanate (PS- LSOCYANATE) (0.136 g, 150 mumol), and solid supported trisamine (PS-Trisamine) (0.061 g, 150 ; J. MOI). The plate was rotated at 90C for 12 h. The solvent in the well was collected via filtration. The resins were rinsed with 0.5 mL DMSO, and the organic solutions were combined and concentrated in vacuo at 60C to afford an analytically pure white solid (0.034 g, 81%): 1H NMR (CDCl3, 400 MHz) 8 7.51 (d, J = 9. 1 Hz, 1H), 7.00 (d, J = 2. 7 HZ, 1 H), 6.84 (dd, J = 9. 0,2. 6 Hz, 1H), 3.34 (t, J = 7. 7 Hz, 2H), 3.24 (d, J = 6.4 Hz, 2H), 1.63 (sex, J = 7.5 Hz, 2H), 1.02 (sept, J = 5.4 Hz, 1H), 0.95 (t, J = 7. 4 Hz, 3H), 0.59 (q, J = 5. 7 Hz, 2H), 0.27 (q, J = 5. 0 Hz, 2H).
81%	With caesium carbonate; In dimethyl sulfoxide; at 90℃; for 3h;	A DMSO (0.5 mL) solution of 4-fluoro-2- (trifluoromethyl) benzonitrile (0.050 g, 0.26 MMOL, 1 equiv) was treated with cesium carbonate (0.120 g, 0.37 MMOL, 1.4 equiv) and N- (cyclopropylmethyl)-N-propylamine (0.035 g, 0.31 mmol, 1.2 equiv). After 3 h at 90C, the cooled reaction was treated with H2O (1 mL), and extracted with EtOAc (3x 1 mL). Concentration was followed by radial chromatography (SIO2, 1 mm plate, 90: 10; Hex/EtOAc) to afford the title compound as a white solid (0.060 g, 81%) : 1H NMR (CDCI3, 400 MHz) 8 7.51 (d, J = 9.1 Hz, 1 H), 7.00 (d, J = 2.7 Hz, 1 H), 6.84 (dd, J = 9. 0,2. 6 Hz, 1 H), 3.34 (t, J = 7. 7 Hz, 2H), 3.24 (d, J = 6. 4 Hz, 2H), 1.63 (sex, J = 7. 5 HZ, 2H), 1.02 (sept, J = 5. 4 Hz, 1 H), 0.95 (t, J = 7. 4 Hz, 3H), 0.59 (q, J = 5. 7 Hz, 2H), 0.27 (q, J = 5. 0 Hz, 2H).

Reference： [1]Patent: WO2005/795,2005,A2 .Location in patent: Page 36
[2]Patent: WO2005/795,2005,A2 .Location in patent: Page 44

18
[ 2968-33-4 ]
[ 194853-86-6 ]
2-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 200℃; for 0.333333h;microwave;	2- (Trifluoromethyl)-4- [ (3,3, 3-trifluoropropyl) amino] benzonitrile A mixture of 4-fluoro-2- (trifluoromethyl) benzonitrile (0.158 g, 0.84 mmol), (3,3, 3- trifluoropropyl) amine hydrochloride (0.125 g, 0.84 mmol) and DIEA (0.326 g, 2.52 mmol) in 1.5 mL of DMSO was heated in a microwave at 200C for 20 min. Upon cooling, the mixture was partitioned between Et2O and 0. 1 N HCI. The organic phase was washed with 0. 1 N HCI (x2) and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (10-80% EtOAc- hexanes gradient) and the product crystallized from Et20-hexanes to give 0.144 g (61% yield) of the title compound : 1H NMR (400 MHz, CDCl3) No. 7.60 (d, J = 8.6 Hz, 1 H), 6.87 (d, J = 2.4 Hz, 1 H), 6.71 (dd, J = 8. 6,2. 4 Hz, 1H), 4.56 (bs, NH), 3.53 (q, J = 6.5 Hz, 2H), 2.51- 2.40 (m, 2H).
61%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 200℃; for 0.333333h;	A mixture of 4-fluoro-2- (trifluoromethyl) benzonitrile (0.158 g, 0.84 mmol), 3,3, 3- TRIFLUOROPROPYLAMINE. HCI (0.125 g, 0.84 mmol) and DIEA (0.326 g, 2.52 MMOL) in DMSO (1.5 mL) was heated under nitrogen in a microwave at 200C for 20 min. The mixture was partitioned between Et2O and 0. 1 N HCI. The organic phase was washed with 0. 1 N HCI (twice) and brine, dried (NA2SO4), and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% EtOAc-hexane gradient) and the product crystallized from ET2O-HEXANES to give the title compound as a white solid (0.144 g, 61% yield): 1H NMR (400 MHz, CDCI3) 8 7.60 (d, J = 8.6 Hz, 1 H), 6.87 (d, J = 2.4 Hz, 1 H), 6.71 (dd, J = 8.6, 2.4 Hz, 1 H), 4.56 (bs, NH), 3.53 (q, J = 6.5 Hz, 2H), 2.51-2. 40 (m, 2H); MS (ES) M/Z 283 (M+1).

Reference： [1]Patent: WO2005/85185,2005,A1 .Location in patent: Page/Page column 72
[2]Patent: WO2005/795,2005,A2 .Location in patent: Page 57-58

19
[ 2516-47-4 ]
[ 194853-86-6 ]
4-[(cyclopropylmethyl)amino]-2-(trifluoromethyl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; In acetonitrile; at 55℃; for 12h;	A mixture of 4-fluoro-2- (trifluoromethyl) benzonitrile (9.45 g, 50 mmol), 1- cyclopropylmethanamine (5.0 g, 70 mmol), and potassium carbonate (10 g) was stirred for 12 hours in acetonitrile (50 mL) at 55 C. The mixture was cooled to 20 C, filtered, and the filter-cake was washed with acetonitrile (3 x 25 mL). The filtrate was concentrated under vacuum to obtain 11.9 g (99%) of the title compound as a white solid :'H NMR (400 MHz, CDCI3) 6 7.53 (d, J = 8.6 Hz, 1 H), 6.83 (d, J = 2.4 Hz, 1 H), 6.65 (dd, J = 8.6, 2.4 Hz, 1 H), 4.62 (bs, 1 H), 3.02 (d, J = 7.1 Hz, 2H), 1.09 (m, 1 H), 0.61 (m, 2H), 0.27 (m, 2H).
99%	With potassium carbonate; In acetonitrile; at 55℃; for 12h;	EXAMPLES; Example 1; 4-[(Cyclopropylmethyl)(2-[4-(1 ,1 -dimethylethyl)phenyl]oxy} ethyl)amino]-2- (trifluoromethyl)benzonitrile; A. 4-[(Cyclopropylmethyl)amino]-2-(trifluoromethyl)benzonitrile; A mixture of <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (9.45 g, 50 mmol), 1- cyclopropylmethanamine (5.0 g, 70 mmol), and potassium carbonate (10 g) was stirred for 12 h in acetonitrile (50 mL) at 55 0C. The mixture was cooled to 20 0C, filtered, and the filter-cake was washed with acetonitrile (3 x 25 mL). The filtrate was concentrated under vacuum to obtain 11.9 g (99%) of the title compound as a white EPO <DP n="41"/>solid: 1H NMR (400 MHz, CDCI3) delta 7.53 (d, J = 8.6 Hz, 1 H), 6.83 (d, J = 2.4 Hz, 1 H), 6.65 (dd, J = 8.6, 2.4 Hz, 1H)1 4.62 (bs, 1 H), 3.02 (d, J = 7.1 Hz, 2H), 1.09 (m, 1 H), 0.61 (m, 2H), 0.27 (m, 2H).

Reference： [1]Patent: WO2005/85185,2005,A1 .Location in patent: Page/Page column 32-33
[2]Patent: WO2006/44707,2006,A1 .Location in patent: Page/Page column 39

20
[ 538-09-0 ]
[ 194853-86-6 ]
2-trifluoromethyl-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With pyridine; at 100℃; for 6h;	Example 5 2-(trifluoromethyl)-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)benzonitrile (196MBT4-B) Nortropine (269 mg, 2.12 mmol) and 4-fluoro-2-(trifluoromethyl)benzonitrile (100 mg, 0.529 mmol) were dissolved in pyridine (2 mL). The mixture was heated to 100 C. in a sealed flask for 6 hours and then concentrated. The residue was dissolved in 2 M HCl (20 mL) and extracted with dichloromethane (2×20 mL). The combined organic phases were dried over Na2SO4, filtered and evaporated, and the resulting oil was purified by preparative TLC (eluting with dichloromethane) to afford 133 mg (85%) of the title compound as a colorless solid. LC/MS m/z 297 [M+H]+. 1H-NMR (CDCl3) delta 7.65-6.75 (m, 3H), 4.35-4.28 (m, 2H), 4.12-4.05 (m, 1H), 2.48-2.39 (m, 2H), 2.17-2.04 (m, 4H), 1.82-1.73 (m, 2H), 1.60-1.52 (m, 1H).

Reference： [1]Patent: US2006/160845,2006,A1 .Location in patent: Page/Page column 18

21
[ 19444-84-9 ]
[ 194853-86-6 ]
4-(2-oxo-tetrahydro-furan-3-yloxy)-2-trifluoromethyl-benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	With sodium hydride; In tetrahydrofuran; at -10 - 25℃; for 0.666667h;	Sodium hydride (60% dispersion in mineral oil, 0.44 g, 18.34 mmol) was added in portions to a cold (-10 0C) stirring solution consisting of 2-hydroxy-gamma- butyrolactone (1.29 g, 12.6 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred for about 40 minutes before direct addition of the solid 4- fluoro-(2-trifluoromethyl)-benzonitrile (2.0 g, 11.0 mmol). The reaction mixture was allowed to gradually warm to room temperature overnight. Water was added and the product was extracted into ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, was dried over anhydrous magnesium sulfate, and was filtered and concentrated. The crude product was purified by flash chromatography. Elution with a gradient of 25-50% ethyl acetate in hexanes afforded a white solid. The product was recrystallized from ethyl acetate-hexanes to obtain 0.45 g (16 % yield) of a white crystalline solid; melting point 120 0C; 1H-NMR (400 MHz; CDCl3) delta 7.79 (d, IH, J=8.5 Hz), 7.43 (d, IH, J=2.4 Hz), 7.33 (dd, IH, J=8.5, 2.4 Hz), 5.08 (t, IH, J=7.8 Hz), 4.57 (m, IH), 4.43 (m, IH), 2.78 (m, IH), 2.56 (m, IH); 19F-NMR (376 MHz; CDCl3) 6 -62.72 (s, 3F); MS (APCI) 270.0 (M-I); microanalysis for C12H8F3O3N (Theoretical/Found): C, 53.15/53.01; H, 2.97/2.81; N, 5.16/4.97; F, 21.02/21.24.

Reference： [1]Patent: WO2006/24942,2006,A1 .Location in patent: Page/Page column 29-30

22
[ 79-50-5 ]
[ 194853-86-6 ]
[ 878209-30-4 ]

Yield	Reaction Conditions	Operation in experiment
79.45%	With sodium hydride; In tetrahydrofuran; at -15 - 20℃;	Sodium hydride/mineral oil (60% dispersion, Hg, 270 mmol) in dried tetrahydrofuran (50 mL)_was added to a cold (-15 C) stirring solution consisting of 3-hydroxy-4,4-dimethyl-dihydro-furan-2-one(37.1 g, 281 mmol) in anhydrous tetrahydrofuran (90ml). The reaction mixture was diluted with the addition of more anhydrous tetrahydrofuran (100 rnL). To this stirring mixture after cessation of hydrogen gas liberation was added via canula a solution consisting of 4-fluoro- 2-(trifluoromethyl) benzonitrile (55.4 g, 289 mmol) in anhydrous tetrahydrofuran (50 mL). The reaction mixture was allowed to stir overnight, whilst gradually warming to room temperature. Ethyl acetate (100 ml) was added and the solution was washed with saturated aqueous ammonium chloride, water, and twice with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The crude solid (86.72g) was recrystallised from ethanol to afford 65.47 g (79.45 % yield) of a white crystalline solid; 1H NMR (400MHz; CDC13) 87.76 (d, IH, J=8.5 Hz), 7.42 (d, IH, J=2.7 Hz), 7.30 (dd, IH, J=8.5, 2.4 Hz), 4.69 (s, IH), 4.15 (d, IH, J=9.0 Hz), 4.09 (d, IH, J=9.0 Hz), 1.27 (s, 3H)5 1.27 (s, 3H); 19F NMR (376MHz; CDC13) delta -62.70 (s, 3F); MS (APCI+) 341.1 (M+1+acetonitrile).
63%		DL-pantolactone 1 (7.81 g) was dissolved in anhydrous tetrahydrofuran (200 ml),Add 60% sodium hydride (3.00g) and stir the reaction. After the gas release is complete,4-Fluoro-2- (trifluoromethyl) benzonitrile (9.46 g) was added and reacted at room temperature overnight.The reaction solution was concentrated, and the residue was purified by a silica gel column.This gave 10.69 g of compound 2 as an off-white solid. Yield: 63%.
		Solid NaH (60 wt % dispersion in mineral oil, 13.80 g, 345 mmol) was added portionwise over 35 min to a cold (0-5 C.) sol'n of (+-)-pantolactone, (42.90 g, 330 mmol) in 600 mL dry tetrahydrofuran ("THF") under an N2 atmosphere. After stirring at 0-5 C. for 2 hours ("h") 4-fluoro-2-trifluoromethylbenzonitrile (56.73 g, 300 mmol) was added in one portion. The reaction mixture was allowed to slowly warm to 20-25 C. and then stirred at this temp for 16 h. The reaction mixture was then cooled to 5-10 C. and quenched with 500 mL sat'd aq. NH4Cl. The phases were separated and the aqueous was extracted with methyl tertbutyl ether "MTBE" (2*400 mL). The organic was conc'd under vac (40-45 C.) to a "wet" biege solid. Ethanol (300 mL) was added and the slurry was conc'd under vac again to a "drier" biege solid. The solid was combined with 500 mL EtOH and heated to 70-75 C. The slightly turbid hot sol'n was filtered and the filtrate was allowed to cool to 20-25 C. (ppt'n occurred quickly) and was stirred 16 h. The slurry was cooled in an ice/water bath 2 h. The cold slurry was filtered and the solid was washed with 200 mL cold EtOH, followed by 200 mL Hept. Suction dried the white granular solid 2 h.

Reference： [1]Patent: WO2006/24942,2006,A1 .Location in patent: Page/Page column 27
[2]Patent: CN110746399,2020,A .Location in patent: Paragraph 0309-0312
[3]Patent: US2006/252796,2006,A1 .Location in patent: Page/Page column 14
[4]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1230 - 1236

23
[ 6850-57-3 ]
[ 194853-86-6 ]
[ 913288-71-8 ]

Yield	Reaction Conditions	Operation in experiment
51%	With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 18h;	. 4-([2-(methyloxy)phenyI]methyl}amino)-2-(trifluoromethyl)benzonitriIeTo a solution of 4-flouro-2-(trifluouromethyl)benzonitrile (reagent A) (500 mg, 2.6 mmol) in anhydrous DMF (0.5 M) was added 2-methoxybenzylamine (reagent B) (0.35 mL, 2.6 mmol) and oven-dried potassium carbonate (365 mg, 2.6 mmol). The reaction mixture stirred at 85 0C for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water. The organics were extracted into ethyl ether and dried over sodium sulfate. The Filtrate was concentrated, and remaining DMF was removed under reduced pressure to yield a beige solid (415 mg, 51% crude yield): MS (ESI) 306.3 (MH)+.

Reference： [1]Patent: WO2006/113552,2006,A2 .Location in patent: Page/Page column 37

24
[ 27527-05-5 ]
[ 194853-86-6 ]
C₁₇H₁₉F₃N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 17. iV2-[(2-chlorophenyl)methyl]-N2-[4-cyano-3-(trifluoromethyl)phenyI]-3- cyclohexyl-Lambda^^-dimethyl-L-alaninamideA. Methyl N-[4-cyano-3-(trifluoromethyl)phenyl]-3-cyclohexyl-L-aIaninateTo a suspension of 3-cyclohexyl-L-alanine (1.36 g, 7.94 mmol) (reagent A) in 80 mL of DMF was added 4-fluoro-2-(trifluoromethyl)benzonitrile (reagent B) (1.0 g, 5.29 mmol) and potassium carbonate (2.19 g, 15.9 mmol). The reaction mixture was heated at 90 0C overnight and cooled to room temperature, diluted with an aqueous LiBr solution, and acidified to pH 3-4 with 6 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated. The crude residue was dissolved in MeOH (50 mL), and 1 mL of concentrated sulfuric acid was added. This mixture was heated at 65 0C for five hours. The reaction was cooled to room temperature and concentrated. The residue was slowly quenched with saturated NaHCO3 and diluted with diethyl ether. The layers were separated, and the organic layer was washed with an aqueous LiBr solution and water. The organic layer was dried over Na2SO4, EPO <DP n="33"/>concentrated, and purified by silica chromatography to afford the title compound. 1H NMR (400 MHz, CDCl3) delta 7.55 (d, IH, J = 8.8 Hz), 6.89 (d, IH, J = 2.4 Hz), 6.69 (dd, IH, J = 2.4, 8.4 Hz), 5.16 (d, IH, J= 8.4 Hz), 4.17 (q, IH, J = 5.6 Hz), 3.76 (s, 3H), 1.71 (m, 7H), 1.43 (m, IH), 1.22 (m, 3H), 0.97 (m, 2H). MS m/z 355 (M+ +1)

Reference： [1]Patent: WO2006/113552,2006,A2 .Location in patent: Page/Page column 31-32

25
[ 640-68-6 ]
[ 194853-86-6 ]
[ 913288-69-4 ]

Yield	Reaction Conditions	Operation in experiment
42%		A.7V-[4-cyano-3-(trifluoromethyl)phenyl]-D-valineA mixture of <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (reagent A) (500 mg, 2.64 mmol, 1 eq), D- valine (reagent B) (341 mg, 2.91 mmol, 1.1 eq), and K2CO3 (547 mg, 3.96 mmol, 1.5 eq) in DMF (6 mL) was sealed in a 10-20 mL microwave process vial and heated in a microwave reactor for 20 min at 100 0C. The reaction mixture was partitioned between ethyl acetate and water and acidified to pH 3 with IN HCl. The layers were separated, and the organic layer was washed with saturated aqueous sodium carbonate (2-50 mL portions) and dried over sodium sulfate. The residue was purified by ISCO silica gel chromatography (1Og silica cartridge, 100% CH2Cl2 grading to 10% CH3OH/CH2C12 over 10 min followed by 10% CH2Cl2 for 10 min) to provide the title compound (320 mg, 42%) as a pale yellow oil. 1H NMR (400 MHz, CD3OD) delta 7.63 (d, IH, J = 8.8 Hz), 7.13 (d, IH, J= 2.0 Hz), 6.88 (dd, IH, J = 8.4, 2.0 Hz), 3.91 (d, IH, 7= 6.4 Hz), 2.24 (m, IH), 1.09 (t, 6H, J = 6.8 Hz); LC/MS 287.2 (MH)+.

Reference： [1]Patent: WO2006/113552,2006,A2 .Location in patent: Page/Page column 33

26
[ 194853-86-6 ]
[ 862582-50-1 ]
[ 868597-38-0 ]

Yield	Reaction Conditions	Operation in experiment
65%		COMPARATIVE EXAMPLE B This example also illustrates the preparation of 4-[(1S, 4S)-4-Hydroxy-1 - methylpentyloxy]-2-trifluoromethylbenzonitrile, using a strong base in THF, as described in co-pending United States patent application United States patent application serial number 11/053,010 on a smaller scale than described in Example A.A 500 mL 3-necked flask was fitted with a mechanical stirrer, argon line and temperature probe. The flask was purged with argon and then charged with 4.237 g (177 mmol) of sodium hydride (60% in mineral oil) and 70 mL of tetrahydrofuran (THF). The grey suspension was stirred and to it was added a solution of 12.6 g (107 mmol) of (2S,5S)-2,5-hexanediol in 130 mL of THF over20 minutes. The thick mixture was stirred for 45 minutes and then a solution of 20.0 g (106 mmol) of 4-fluoro-2-trifluoromethylbenzonitrile in 130 mL of THF was added over 5 minutes. The mixture was stirred for 2.5 hours and then refluxed for 2 hours. The reaction solution was then allowed to cool to room temperature and stir over a weekend. HPLC analysis at this point showed a 69:25 mixture of the intended product (3) to bis-alkylated byproduct (4). The reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with water and brine and then dried over magnesium sulfate. The solvent was then removed at the Rotavap giving 35.93 g of clear oil. The product was purified by chromatography on silica gel using dichloromethane/methanol as the eluent. The product-containing fractions were pooled and evaporated at the Rotavap giving 19.63 g (65%) of (3) as a clear, colorless oil. The material assayed at 99.7% (a/a) purity by HPLC and had a proton NMR spectrum consistent with structure.
34%		COMPARATIVE EXAMPLE A This example illustrates the preparation of 4-[(1S, 4S)-4-Hydroxy-1- 0 methylpentyloxy]-2-trifluoromethylbenzonitrile, using a strong base under anhydrous conditions, as described in co-pending United States patent application serial number 11/053,010.A 10 L, jacketed ChemGlass reactor was fitted with a mechanical stirrer, nitrogen sweep line, and NesLab chiller. The vessel was purged with nitrogen for 5 15 minutes and then charged with 61 g (1.5 mol) of sodium hydride (60% in mineral oil) and 2.0 L of tetrahydrofuran (1THF"). The suspension was stirred and cooled to 6.5C and then a solution of 180.3 g (1.53 mol) of (2S,5S)-(+)-2,5- hexanediol in 1.0 L of THF was added, in 4 portions, over 35 minutes. The mixture became very thick and 1.0 L of THF was added about halfway through Q the addition in order to facilitate better stirring. The maximum internal temperature observed was 14.4C. The suspension was stirred for 30 minutes and then 288.1 g (1 .52 mol) of <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> was added. The mixture was further diluted with another 1.0 L of THF and then warmed to room temperature and allowed to stir overnight (a clear solution was obtained after 30 minutes). HPLC analysis at the 21 hour point showed a 48:45 mixture of the expected product (3) to the bis-alkylated byproduct (4). Water (3.0 L) and ethyl acetate (4.0 L) were added and the layers separated. The organic layer was washed with 2 x 2.0 L of water and 1 x 2.0 L of brine. The aqueous layers were back-extracted with 2.0 L of ethyl acetate and then the organic layers were combined and evaporated at the Rotavap. The residue was twice dissolved in 1.0 L of 2-propanol and evaporated at the Rotavap (to remove water). The crude product was twice purified by flash chromatography on silica gel using dichloromethane/methanol. A third chromatography column (Biotage system) was carried out using ethyl acetate/hexanes. The purified target was isolated as 149.8 g (34%) of an oil. The material assayed at >99% purity (a/a, HPLC) and had a proton NMR spectrum consistent with structure.

Reference： [1]Patent: WO2006/136910,2006,A1 .Location in patent: Page/Page column 12-13
[2]Patent: WO2006/136910,2006,A1 .Location in patent: Page/Page column 11-12

27
[ 34338-96-0 ]
[ 194853-86-6 ]
[ 862582-50-1 ]
[ 868597-38-0 ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium hydroxide;tetra(n-butyl)ammonium hydrogensulfate; In water; toluene;	EXAMPLE 1:This example illustrates the preparation of 4-[(1S, 4S)-4-hydroxy-1 - methylpentyloxy]-2-trifluoromethylbenzonitrile, using a base in a system containing an organic solvent and water. It also illustrates the use of a phase transfer catalyst.A 3 L, 4-necked flask was equipped with a mechanical stirrer and a J- KEM temperature probe. The flask was charged with 100.0 g (0.529 mol) of 4- fluoro-2-(trifluoromethyl)benzonitrile, 68.40 g (0.579 mol) of (2S,5S)-(+)-2,5- hexanediol, 9.03 g (0.027 mol) of tetrabutylammonium bisulfate and 1.0 L of toluene. The mixture was stirred and 0.230 L of 45 wt% potassium hydroxide was added. A slight exotherm from 140C to 200C was observed. The2-phase mixture was stirred overnight, at which time HPLC analysis indicated complete reaction and a 10:1 ratio of desired product to bis-ether adduct (i.e. Compound 3 to Compound 4). Water (1.0 L) was added and the layers were separated. The organic layer was washed with 3 xtheta.25 L of water and 1 x 0.25 L of brine, dried over magnesium sulfate, filtered through Celite, and then evaporated at the Rotavap. The crude product was isolated as 158.12 g (104%) of clear, almost colorless oil. Purification was achieved by flash chromatography on silica gel using a Biotage system (hexanes/ethyl acetate). This yielded 116.75 g (77%) of4-[(1S, 4S)-4-hydroxy-1-methylpentyloxy]-2-trifluoromethylbenzonitrile as a clear, colorless oil. The material assayed at >99% purity (a/a, HPLC) and had a proton NMR spectrum consistent with structure.
67 - 88%Chromat.; 0.85 - 9.2%Chromat.	With potassium hydroxide;cetyltrimethylammonim bromide; In water; toluene; at 20℃; for 1.25 - 240h;Product distribution / selectivity;	EXAMPLE 3A 50 mL reaction tube was charged with 262 mg ( 1.3 mmol) of 4-fluoro-2- (trif luoromethyl)benzonitrile, 181 mg( 1.4 mmol) of (2S,5S)-f+)-2,5-hexanediol, 25 mg of cetyltrimethylammonium bromide and 2.5 mL of toluene. Potassium hydroxide solution (45 wt%, 6.6 mmol) was added and the two-phase mixture was stirred vigorously and monitored by HPLC until the starting benzonitrile had been consumed (< 1 area%). The reaction was allowed to proceed at ambient temperature for approximately 75 minutes. HPLC analysis of organic phase showed 31 area % of unreacted benzonitrile, 67 area % of the desired final product and 0.85 area % of the bis-ether adduct. The reaction was allowed to proceed an additional 10 days over a vacation, HPLC analysis of the organic phase showed 88 area % of the desired final product and 9.2 area % of the bis- ether adduct. The final product was not isolated because the purpose of the 5 experiment was to determine the ratio of product (Compound 3) to bis-ether adduct (Compound 4).
89%Chromat.; 8.9%Chromat.	With potassium hydroxide;tetrabutylammomium bromide; In water; toluene; at 20℃; for 1.25h;Product distribution / selectivity;	EXAMPLE 2: This example illustrates the preparation of 4-[(1S, 4S)-4-hydroxy-1 - methylpentyloxy]-2-trifluoromethylbenzonitrile, using a base in a mixture of an organic solvent and water. A phase transfer catalyst was used.A 50 mL reaction tube was charged with 257 mg ( 1.3 mmol) of 4-fluoro-2- (trifluoromethyl)benzonitrile, 183 mg( 1.4 mmol) of (2S,5S)-(+)-2,5-hexanediol,22 mg of tetrabutylammonium bromide and 2.5 mL of toluene. Potassium hydroxide solution (45 wt%, 6.6 mmol) was added and the two-phase mixture was stirred vigorously and monitored by HPLC until the starting benzonitrile had been consumed (< 1 area%). The reaction was allowed to proceed at ambient temperature for approximately 75 minutes. HPLC analysis of organic phase showed 1 area% of unreacted benzonitrile, 89 area% of the desired final product and 8.9 area% of the bis-ether adduct. The final product was not isolated because the purpose of the experiment was to determine the ratio of product (Compound 3) to bis-ether adduct (Compound 4).

With sodium hydroxide;tetra(n-butyl)ammonium hydrogensulfate; In water; toluene; at 20℃; for 1.25h;Product distribution / selectivity;

EXAMPLE 4: A 25ml reaction tube was charged with 1022 mg (5.4 mmol) of 4-fluoro- jQ 2-(trifluoromethyl)benzonitrile, 699 mg {5.9 mmol) of (2S,5S)-(+)-2,5-hexanediol,96 mg ( 0.28 mmol) of tetrabutylammonium bisulfate and 10 mL of toluene. Stirred vigorously and then added 1.40 mL of 50 wt% NaOH. The reaction was stirred at ambient temperature for 75 minutes. HPLC analysis of the organic phase showed a 7.0:1 mix (mole:mole) of final product to bis-ether adduct. The j 5 final product was not recovered because the purpose the experiment was to determine the ratio of product (Compound 3) to bis-ether adduct (Compound 4).

Reference： [1]Patent: WO2006/136910,2006,A1 .Location in patent: Page/Page column 9-10
[2]Patent: WO2006/136910,2006,A1 .Location in patent: Page/Page column 10-11
[3]Patent: WO2006/136910,2006,A1 .Location in patent: Page/Page column 10
[4]Patent: WO2006/136910,2006,A1 .Location in patent: Page/Page column 11

28
[ 89855-48-1 ]
[ 194853-86-6 ]
4-[4-Hydroxy-4-(2-hydroxy-ethyl)-piperidin-1-yl]-2-trifluoromethyl-benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With triethylamine; In N,N-dimethyl-formamide; at 80℃; for 4h;	4-[4-Hydroxy-4-(2-hydroxy-ethyl)-piperidin-1-yl]-2-trifluoromethyl-benzonitrile (27a): To a solution of compound 26 (517 mg, 3.25 mmol) in anhydrous dimethylformamide (15 mL) under argon were added triethylamine (1.32 g, 13.0 mmol) and 4-fluoro-2-trifluoromethylbenzonitrile (1.80 g, 9.52 mmol). The solution was stirred at 80 C. for 4 hrs. The solution was cooled at room temperature and poured in water (100 mL), extracted with diethyl ether (3×25 mL), washed with brine and finally dried over magnesium sulphate. Purification of the resulting crude product by flash chromatography using ethyl acetate/hexane (7:3) as an eluant gave the desired compound 27a (687 mg, 68%). 1H NMR (400 MHz, Acetone-d6) delta: 1.74 (m, 6H), 3.45 (m, 2H), 3.85 (m, 4H), 7.24 (dd, 1H, J1=6.4 Hz, J2 =2.5 Hz), 7.32 (d, 1H, J=2.4 Hz), 7.72 (d, 1H, J=8.8 Hz).

Reference： [1]Patent: US2006/287327,2006,A1 .Location in patent: Page/Page column 56-57

29
[ 34338-96-0 ]
[ 194853-86-6 ]
[ 862582-50-1 ]

Yield	Reaction Conditions	Operation in experiment
		This Example further illustrates the preparation of (1S,4S)-4-(4-hydroxy-1-methylpentyoxy)-2-trifluoromethyl-benzonitrile, the product of Example 23. NaH (60% in mineral oil) was suspended in 100 ml of dry THF, it was stirred and cooled to 0 C. under N2 for 10 min before adding the (2S,5S)-(+)-2,5-hexanediol (12.g in 120 ml of dry THF). The diol was added drop wise through a dropping funnel over 30 min., this mixture was stirred at 0 C. for 60 min, then RT 30 min., it was re-cooled to 0 C. before adding the <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (20 g in 80 ml of dry THF) over 30 min. The reaction was then stirred at 0 C. to RT under N2 (11 am-9am the next day). The reaction was monitored by TLC (Hex:Ethyl acetate=1:1) and LC/MS. Purification: The crude product was dissolved in 80 ml of mixture solvent (hexane:ethyl acetate=3:1), column purification using hexane:ethyl acetate=5:1 to 1:1 as the elute to yield 22 g of the pure desired product.
		EXAMPLE 1(1S,4S) Acetic acid 4-(4-cvano-3-trifluoromethyI-phenoxy)-l-methvI-pentyl esterSTEP AIn Step A, (lS,4S)-4-(44iydroxy-l-memylpentyloxy)-2-trifluoromethyl- benzonitrile is prepared, which is then used in Step B to generate the final product. Step A describes an alternative method of producing the alcohol of structure 3, differing from that described above in Reaction Scheme I.NaH (60% in mineral oil) is suspended in 100 ml of dry THF, and is stirred and cooled to O0C under N2 for 10 min before adding (2S,5S)-(+)-2,5-hexanediol (12.g in 120 ml of dry THF("tetrahydrofuran")- The diol is added drop wise through a dropping funnel over 30 min., this mixture is stirred at O0C for 60 min("minutes"), then RT("room temperature") 30 min., it is re-cooled to 00C before adding the 4-fluoro-2- (trifluoromethyl)benzonitrile ( 2Og in 80 ml of dry THF) over 30 min. The reaction is then stirred at 00C to RT under N2 (1 lam-9am the next day). The reaction is monitored by TLC (Hex:Ethyl acetate=l:l) and LC/MS.Purification: The crude product is dissolved in 80 ml of mixture solvent (hexane:ethyl acetate=3:l), column purification using hexane :ethyl acetate=5:lto 1:1 as the elute to yield the pure desired product.

Reference： [1]Patent: US2005/182132,2005,A1 .Location in patent: Page/Page column 8; 11; 13
[2]Patent: WO2007/7149,2007,A1 .Location in patent: Page/Page column 24

30
[ 19132-06-0 ]
[ 194853-86-6 ]
[ 862582-28-3 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 1 (1S,2S)-4-(2-Hydroxy-1-methyl-propoxy)-2-trifluoromethyl-benzonitrile NaH (0.20g, 4.14 mmol) was suspended in 15 ml of dry THF, then (2S,3S)-(+)-2,3-butanediol was added (0.32g, 3.45 mmol, in 5 ml of dry THF). This mixture was stirred at 0 C. for 10 minutes, followed by the addition of 4-fluoro-2-trifluoromethyl-benzonitrile. The reaction mixture was stirred, 0 C. for 1 hour, under a nitrogen atmosphere. The mixture was then stirred for an additional 2 hours, at room temperature, in a hood. The reaction was quenched with 25 ml of distilled water, extracted with ethyl acetate (3*20 ml). The product was purified by column chromatography, using hexane: ethyl acetate=5:1 to 1:1 as elute to yield the pure product. MS: 260.0 (M+1 for C12H12F3NO2). LCMS: C-18 Column (50% H2O/50% CH3CN), Ret. Time: 1.81 min

Reference： [1]Patent: US2005/182132,2005,A1 .Location in patent: Page/Page column 8

31
[ 13524-04-4 ]
[ 194853-86-6 ]
[ 925416-28-0 ]

Yield	Reaction Conditions	Operation in experiment
59.8%		Example 22 4-[1-(2-Chloro-phenyl)-ethoxy]-2-trifluoromethyl-benzonitrile 1-(2-Chloro-phenyl)-ethanol (0.82 g, 5.29 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL) and purged with dry nitrogen. Sodium hydride (60% in mineral oil, 0.22 g, 5.55 mmol) was added. After 10 minutes at ambient temperature, 4-fluoro-2-trifluoromethyl-benzonitrile (1.0 g, 5.3 mmol) was added in one portion. The reaction was stirred for 2 hours at ambient temperature before partitioning between ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, evaporated to dryness, and chromatographed on a 40-g Isco Redisep silica gel column using a gradient of 5 to 50% ethyl acetate in hexanes to provide 1.03 g (59.8%) of the title compound. HPLC 100%. MS m/z 324 (M-H)-.

Reference： [1]Patent: US2009/170886,2009,A1 .Location in patent: Page/Page column 16

32
[ 84851-56-9 ]
[ 194853-86-6 ]
[ 925416-35-9 ]

Yield	Reaction Conditions	Operation in experiment
41.27%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;	Example 29 (+-)-4-[1-(4-Cyano-3-trifluoromethyl-phenoxy)-ethyl]-benzoic Acid Methyl Ester (+-)-4-[1-(4-cyano-3-trifluoromethyl-phenoxy)-ethyl]-benzoic acid methyl ester was prepared as follows: To a cooled solution (0 C.) of methyl-4-(1-hydroxyethyl)benzoate (1.00 g, 5.549 mmol) and 4-fluoro-2-(trifluoromethyl)benzonitrile (1.049 g, 5.549 mmol) in anhydrous dimethylformamide (8 mL) was added NaH (0.222 g as a 60% dispersion in mineral oil). The reaction mixture was allowed to warm to room temperature and was then stirred under nitrogen for 16 hr. The crude reaction mixture was added to ethyl acetate (150 ml) and was washed with saturated aqueous ammonium chloride (2150 mL), water (1150 mL), and saturated aqueous sodium chloride (1*150 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was chromatographed using hexanes and ethyl acetate (4:1) to afford 0.800 g (41.27% yield) of a viscous colorless oil; 1H NMR (400 MHz; CDCl3) delta 8.03 (d, 2H, J=8.3 Hz), 7.63 (d, 1H, J=8.3 Hz), 7.40 (d, 2H, J=8.3 Hz), 7.26 (apparent s occluded by solvent, 1H), 6.97 (dd, 1H, J=8.54, 2.44 Hz), 5.43 (q, 1H, J=6.34 Hz), 3.90 (s, 3H), 1.69 (d, 3H, 6.34 Hz); MS (APCI+) 373.1 ([M+1]+Na); CHN theoretical/actual: C, 61.89/61.90, H, 4.04/4.02, N, 4.01/3.94, F 16.32/16.20.

Reference： [1]Patent: US2009/170886,2009,A1 .Location in patent: Page/Page column 17

33
[ 1201-74-7 ]
[ 194853-86-6 ]
[ 916810-38-3 ]

Yield	Reaction Conditions	Operation in experiment
74%	With caesium carbonate; In dimethyl sulfoxide; at 90℃; for 2h;	A. 4-[(1R)-1-(2-Naphthyl)ethyl]amino}-2-(trifluoromethyl)benzonitrile A solution of 4-fluoro-2-trifluoromethylbenzonitrile (0.094 g, 0.497 mmol), (R)-(+)-1-(2-naphthyl)ethylamine (0.102 g, 0.596 mmol) and Cs2CO3 (0.243 g, 0.750 mmol) in DMSO (0.5 mL) under N2 was heated to 90 C. for 2 h and then cooled to ambient temperature. H2O was added and the mixture was extracted with EtOAc. The organic fraction was washed with brine, dried (Na2SO4), filtered, and concentrated to an oily residue, which was subjected to chromatography on silica gel using hexanes:EtOAc. The title compound was obtained as a white solid (0.125 g, 74% yield): MS (ES) m/z 339 (M-1).

Reference： [1]Patent: US2009/170907,2009,A1 .Location in patent: Page/Page column 22

34
[ 194853-86-6 ]
[ 27489-62-9 ]
4-(trans-4-hydroxy-cyclohexylamino)-2-trifluoromethyl-benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; In water; acetonitrile; at 80℃; for 72h;	Potassium carbonate (304 mg, 2 .2 mmol) was dissolved in a minimum amount of water. Next, 4-fluoro-2-trifluoromethylbenzonitrile (378 mg, 2.0 mmol) and trans-4- aminocyclohexanol (460 mg, 4.0 mmol) dissolved in acetonitrile (10 mL) were added. The resulting mixture was then heated at 80C for 3 days. After cooling at room temperature, the mixture was concentrated under vacuum, taken up in ethyl acetate (15 mL), washed with saturated aqueous ammonium chloride (2x10 mL), and washed with water (10 mL). The organic phase was collected and dried over sodium sulfate, filtered, and concentrated under vacuum. The desired product was isolated as a colorless solid (456 mg, 80% yield).

Reference： [1]Patent: WO2009/77527,2009,A1 .Location in patent: Page/Page column 61

35
[ 69395-13-7 ]
[ 194853-86-6 ]
[ 925416-74-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In acetonitrile; at 20℃; for 1h;	Example 75 4-[2-(4-Cyano-phenyl)-ethoxy]-2-trifluoromethyl-benzonitrile To a solution of 4-fluoro-2-trifluoromethyl-benzonitrile (3 g, 15.9 mmoles) and <strong>[69395-13-7]4-(2-hydroxy-ethyl)-benzonitrile</strong> (2.3 g, 15.9 moles) in 50 mL acetonitrile is added sodium hydride, 60% dispersion in mineral oil (0.890 g, 33.3 mmoles). The reaction mixture is stirred one hour at room temperature. After 1 hour 10 mL water is added to quench the excess sodium hydride. The reaction mixture is dissolved in 150 mL of ethyl acetate and washed with 2 50 mL portions of brine. The organic layer is dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is chromatographed over SiO2 (gradient 5% to 40% ethyl acetate hexanes) to yield. 4-[2-(4-Cyano-phenyl)-ethoxy]-2-trifluoromethyl-benzonitrile (2.11 g). (Analysis: C17H11F3N2O: theory C, 64.56; H, 3.51; N, 8.86. found C, 63.69; H, 3.34; N, 8.67).

Reference： [1]Patent: US2009/170886,2009,A1 .Location in patent: Page/Page column 29

36
[ 7287-81-2 ]
[ 194853-86-6 ]
[ 925416-34-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 72h;Product distribution / selectivity;	To 1 mL of a 0 C. 0.3M solution of the corresponding aryl fluoride in tetrahydrofuran ?THF? (0.3 mmol) was added 0.6 mL of a 1 M solution of potassium t-butoxide in THF (0.6 mmol) and 0.3 mL of a 1 M solution of the corresponding alcohol (0.3 mmol) in THF. The resultant mixtures were shaken and allowed to warm to room temperature over approximately 72 hours. The solvent was removed in vacuo using a Genevac HT-12 to obtain a sample that was then purified by reverse phase HPLC.

Reference： [1]Patent: US2009/170886,2009,A1 .Location in patent: Page/Page column 21; 23

37
[ 925416-98-4 ]
[ 194853-86-6 ]
[ 925416-99-5 ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium hydride; In 1,2-dimethoxyethane; at 0 - 60℃;	Step C demonstrates the formation of ether utilizing compound B prepared above as the structure 2 of Scheme 1. Compound B (5.00 g, 24 mmol), <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (4.54 g, 24 mmol), and DME (100 mL) were placed in a 300 mL three necked, round bottomed flask equipped with a nitrogen line, condenser, and thermometer. The reaction was cooled to 0 C. Sodium hydride (1.06 g, 26.41 mmol) was then added. The reaction was heated to 60 C. overnight. The reaction was allowed to cool and then water (100 mL) was added. The titled product was extracted into ethyl acetate (100 mL) three times. The organic layers were combined and washed with saturated aqueous sodium bicarbonate (250 mL), and brine (250 mL). The organic layer was then dried and condensed to yield crude product. The crude product was chromatographed using 10:1 Hex:EtOAc to yield compound C (8.55 g, 94% yield).

Reference： [1]Patent: US2009/170886,2009,A1 .Location in patent: Page/Page column 13

38
[ 925417-00-1 ]
[ 194853-86-6 ]
[ 1161015-35-5 ]

Yield	Reaction Conditions	Operation in experiment
64%	With sodium hydride; In 1,2-dimethoxyethane; at 0 - 60℃;	Compound B (0.30 g, 1.27 mmol), <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (0.264 g, 1.4 mmol), and DMF (20 mL) were placed in a 100 mL three neck round bottom flask equipped with a nitrogen line, condenser, and thermometer. The reaction was cooled to 0 C. Sodium hydride (0.056 g, 1.4 mmol) was then added. The reaction was heated to 60 C. overnight. The reaction was allowed to cool and then water (50 mL) was added. The product was extracted into ethyl acetate (50 mL, 3×). The organic layers were combined and washed with saturated aqueous sodium bicarbonate (100 mL), and brine (100 mL). The organic layer was then dried and condensed to yield crude product. The crude product was chromatographed using 10:1 Hex:EtOAc. This yielded the desired product C (0.33 g, 64% yield)

Reference： [1]Patent: US2009/170886,2009,A1 .Location in patent: Page/Page column 14-15

39
[ 68832-13-3 ]
[ 194853-86-6 ]
4-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 60℃;	A mixture of D-prolinol, 4-fluoro-2-trifluoromethylbenzonitrile, and triethylamine in THF was stirred over night at 60C. Standard work-up of the reaction mixture provided R-4-(2-hydroxylmethylpyrrolidinyl)-2-trifluoromethyl- benzonitrile in moderate yield. The intermediate alcohol was oxidized by sulfur trioxide pyridine complex to give /?-4-(2-formyl-pyrrolidinyl)-2-trifluoromethyl- benzonitrile. The aldehyde intermediate was treated with trimethyl(trifluoromethyl)- silane to provide a mixture of two diastereomers. HPLC separation generated pure forms of Compounds 101 and 102. Compound 101: 1H-NMR (500 MHz, CDCl3) 7.59 (d, J= 8.8, IH), 7.07 (d, J= 2.9, IH), 6.92 (dd, J= 8.8 and 2.9, IH), 4.24 (t, J= 7.5, IH), 3.91 (t, J= 6.3, IH), 3.63 (dd, J= 7.8 and 9.3, IH), 3.29 (td, J= 6.9 and 9.7, IH), 2.55 (s, IH), and 2.05- 2.23 (m, 4H).Compound 102: 1H-NMR (500 MHz, acetone-d6) 7.78 (d, J= 8.8, IH), 7.01 (d, J= 2.9, IH), 6.94 (dd, J= 8.8 and 2.9, IH), 5.68 (bd, J= 3.3, IH), 4.44-4.50 (m, IH), 4.36 (d, J= 8.3, IH), 3.64-3.77 (m, IH), 3.44 (td, J= 9.8 and 7.8, IH), 2.30-2.47 (m, 2H), and 2.07-2.17 (m, 2H).

Reference： [1]ACS Medicinal Chemistry Letters,2020
[2]Patent: WO2009/82437,2009,A2 .Location in patent: Page/Page column 145

40
[ 24830-94-2 ]
[ 194853-86-6 ]
[ 1182368-21-3 ]

Yield	Reaction Conditions	Operation in experiment
100%		Example 44; 4-((1R,2R)-1-(5-(4-Cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-2-(trifluoro-methyl)benzonitrile; Intermediate 44a; (2R,3R)-2-(4-Cyano-3-(trifluoromethyl)phenylamino)-3-hydroxybutanoic acid; To a suspension of D-allo-threonine (4.30 g, 36.1 mmol) and K2CO3 (8.73 g, 63.2 mmol) in DMSO (50 mL) was added <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (5.69 g, 30.1 mmol) at room temperature. The reaction mixture was heated to 75 C. and stirred for 39 h. The reaction mixture was allowed to cool to room temperature and quenched with H2O (400 mL) and extracted with EtOAc (3×200 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×100 mL). The later organic extracts were combined, washed with H2O (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a brown oil (8.67 g, 100%): 1H NMR (400 MHz, acetone-d6, delta in ppm) 7.69 (d, J=8.6 Hz, 1H), 7.30 (d, J=2.5 Hz, 1H), 7.07 (dd, J=2.5, 8.4 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 4.35 (dd, J=4.9, 8.4 Hz, 1H), 4.29 (dq, J=4.9, 6.5 Hz, 1H), 1.32 (d, J=6.4 Hz, 3H).

Reference： [1]Patent: US2009/253758,2009,A1 .Location in patent: Page/Page column 86

41
[ 1195-09-1 ]
[ 194853-86-6 ]
[ 876760-11-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 50℃;

Reference： [1]Location in patent: experimental part Mitchell, Lorna H.; Hu, Lain-Yen; Nguyen, Maria; Fakhoury, Stephen; Smith, Yvonne; Iula, Donna; Kostlan, Catherine; Carroll, Matthew; Dettling, Danielle; Du, Daniel; Pocalyko, David; Wade, Kimberly; Lefker, Bruce [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 8, p. 2176 - 2178]

42
[ 1073-29-6 ]
[ 194853-86-6 ]
[ 876759-87-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 50℃;

Reference： [1]Location in patent: experimental part Mitchell, Lorna H.; Hu, Lain-Yen; Nguyen, Maria; Fakhoury, Stephen; Smith, Yvonne; Iula, Donna; Kostlan, Catherine; Carroll, Matthew; Dettling, Danielle; Du, Daniel; Pocalyko, David; Wade, Kimberly; Lefker, Bruce [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 8, p. 2176 - 2178]

43
[ 4383-06-6 ]
[ 194853-86-6 ]
[ 876759-99-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2176 - 2178

44
[ 73943-41-6 ]
[ 194853-86-6 ]
[ 876760-31-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2176 - 2178

45
[ 71-23-8 ]
[ 194853-86-6 ]
[ 1094760-47-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium hydride; at 85℃; for 2h;	Step 1. 4-(Propyloxy)-2-(trifluoromethyl)benzonitrile Solid <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (80 g, 423 mmol) was dissolved in a mixture of n-Propanol (500 mL) and sodium hydride (22.4 g, 560 mmol)-washed with hexanes (3*50 mL) and then heated to 85 C for 2 hrs. The mixture was cooled by addition of ice (100 g) and then citric acid (10% w/v aq., 200 mL) was added. The phases were seperated, the aqueous layer washed with EtOAc (150 mL), the organics washed with NaHCO3 (aq. Sat) then brine and finally dried with Na2SO4. The solvents were removed and the product crystallized. This was riturated with hexanes (50 mL), filtered and put on the hi-vac for 30 minutes yielding the product as a white solid (85 g, 88% yield).

Reference： [1]Patent: US2010/29655,2010,A1 .Location in patent: Page/Page column 92

46
[ 27489-62-9 ]
[ 194853-86-6 ]
[ 1163268-86-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; In water; acetonitrile; at 80℃; for 72h;	Potassium carbonate (304 mg, 2 .2 mmol) is dissolved in a minimum amount of water and 4-fluoro-2-trifluoromethylbenzonitrile (378 mg, 2.0 mmol) and trans-4- aminocyclohexanol (460 mg, 4.0 mmol) dissolved in acetonitrile (10 mL) are added. The reaction is then heated at 800C for 3 days. After cooling to room temperature, the mixture is concentrated under reduced pressure, is taken up in ethyl acetate (15 mL) and washed with saturated aqueous ammonium chloride (2 x 10 mL) followed by water (10 mL). The organic phase is collected and dried over sodium sulphate, filtered and concentrated under reduced pressure. The desired product is isolated as a colourless solid (80% yield).
33%	With potassium carbonate; In acetonitrile; at 90℃;	The aryl fluoride (2 g, 10.6 mmol) was placed in a 100 ml round-bottomed flask and stirred in 20 ml acetonitrile at room temperature. Potassium carbonate (3.3 g, 23.9 mmol, 2.2 eq) and 1,4-trans- amino-cyclohexanol (1.34 g, 11.6 mmol, 1.1 eq) were added and the mixture was then heated at 90 C overnight. The mixture was cooled to room temperature and then concentrated under vacuum. The crude material was purified by silica gel chromatography using 20 - 40 % ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to provide 1 g (33 %) of the desired aniline as a yellow oil. (ES, m/z): [M+H]+ 285.0; NMR (300 MHz, DMSO): delta 8.04 (d, J = 9.3 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 1.8 Hz, 1H), 6.82 - 6.86 (m, 1H), 4.59 (d, J = 4.2 Hz, 1H), 3.39 - 3.49 (m, 2H), 1.78 - 1.94 (m, 4H), 1.18 - 1.32 (m, 4H).

Reference： [1]Patent: WO2010/146083,2010,A1 .Location in patent: Page/Page column 36-37
[2]Patent: WO2016/118638,2016,A1 .Location in patent: Page/Page column 123

47
[ 6995-79-5 ]
[ 194853-86-6 ]
[ 1258838-30-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium hydride; In dimethyl sulfoxide; mineral oil; at 20℃; for 1h;	Trans-cyclohexane-l,4-diol (4.30 mmol) and sodium hydride (60percent suspension in oil, 2.15 mmol) are suspended in dry dimethylsulfoxide (4 mL) and a solution of 4-fluoro-2-trifluoromethyl-benzonitrile (2.15 mmol) in dry dimethylsulfoxide (4 mL) is added dropwise. The resulting mixture is stirred at room temperature. After 1 hour reaction time, the reaction is treated with water (10 mL), the precipitate formed is separated by filtration and the filtrate is extracted with dichloromethane (25 mL). The organic phase is washed with aqueous saturated ammonium chloride (5 mL), dried over magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The precipitate is triturated with diethylether (15 mL), filtered and the filtrate concentrated under reduced pressure. Both fractions of crude product are combined, dissolved in dichloromethane and purified by chromatography through a short pad of silica gel (dichloromethane and then diethylether as eluents) to afford the desired product (60percent yield).

Reference： [1]Patent: WO2010/146083,2010,A1 .Location in patent: Page/Page column 35-36

48
[ 15174-69-3 ]
[ 194853-86-6 ]
[ 1262328-62-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate In N,N-dimethyl-formamide at 95℃; for 5h;

Reference： [1]Location in patent: experimental part Patch, Raymond J.; Searle, Lily L.; Kim, Alexander J.; De, Debyendu; Zhu, Xizhen; Askari, Hossein B.; O'Neill, John C.; Abad, Marta C.; Rentzeperis, Dionisios; Liu, Jianying; Kemmerer, Michael; Lin, Ling; Kasturi, Jyotsna; Geisler, John G.; Lenhard, James M.; Player, Mark R.; Gaul, Micheal D. [Journal of Medicinal Chemistry, 2011, vol. 54, # 3, p. 788 - 808]

49
[ 7770-45-8 ]
[ 194853-86-6 ]
[ 1262328-66-4 ]

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

50
[ 121-33-5 ]
[ 194853-86-6 ]
[ 1262328-60-8 ]

Yield	Reaction Conditions	Operation in experiment
92%	With lithium carbonate; In dimethyl sulfoxide; at 100℃; for 48h;	Reference Example 44 4-(4-formyl-2-methoxyphenoxy)-2-(trifluoromethyl)benzonitrile; [Show Image] To a solution (15 mL) of 4-hydroxy-3-methoxybenzaldehyde (1.00 g) in dimethyl sulfoxide were added lithium carbonate (721 mg) and <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (1.49 g), and the mixture was stirred at 100C for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-heptane to give the title compound as a colorless solid (yield: 1.91 g, 92%). 1H-NMR (DMSO-d6, 300 MHz):delta3.84 (3H, s), 7.26 (1H, dd, J = 8.7, 2.5 Hz), 7.48 (1H, d, J = 7.9 Hz), 7.57 (1H, d, J = 2.5 Hz), 7.67 (1H, dd, J = 7.9, 1.7 Hz), 7.72 (1H, d, J = 1.7 Hz), 8.12 (1H, d, J = 8.7 Hz), 10.02 (1H, s).

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 788 - 808
[2]Patent: EP2450352,2012,A1 .Location in patent: Page/Page column 75-76

51
[ 2280-48-0 ]
[ 194853-86-6 ]
[ 1354339-84-6 ]

Yield	Reaction Conditions	Operation in experiment
98%		4-fluoro-2-(trifluoromethyl)benzonitrile (7.10 g, 37.55 mmol) was mixed together with (R)-2-amino-3-hydroxy-3-methylbutanoic acid (5 g, 37.55 mmol) in DMSO (220 mL). K2CO3 (15.57 g, 112.65 mmol) was added to the reaction mixture and the reaction mixture stirred at 85 C. for 96 h. The reaction mixture was allowed to cool to room temperature and quenched with H2O (40 mL) and extracted with EtOAc (2×80 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×80 mL). The later organic extracts were combined, washed with H2O (2×30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a pale yellow solid (11.1 g, 98%): 1H NMR (400 MHz, d6-acetone, delta in ppm) 7.57 (d, J=9 Hz, 1H), 6.98 (d, J=2 Hz, 1H), 6.80 (dd, J=9 and 2 Hz, 1H), 5.52 (br s, 1H), 3.96 (d, J=7 Hz, 1H), 1.42 (s, 3H), and 1.36 (s, 3H).

Reference： [1]Patent: US2012/4270,2012,A1 .Location in patent: Page/Page column 9

52
[ 312-84-5 ]
[ 194853-86-6 ]
[ 1371608-84-2 ]

Yield	Reaction Conditions	Operation in experiment
48%		Examples 7 and 8Example 77a to 7b( )-2-(4-Cyano-3-(trifluoromethyl) phenyl amino)-3-hydroxypropanoic acidTo a solution of D-Serine (1) (3.65 gm, 34.8 mmol) in DMSO (30 mL),K2C03 (4.36 gm, 31.6 mmol) followed by 4-Fluoro-2-(trifluoromethyl) benzonitrile (7a) (3.0 gm, 15.8 mmol) was added and the reaction was heated to 80C for 4 h. After completion of reaction (by TLC), the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL). The aqueous layer was acidified with citric acid and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over Na2S04 and concentrated under reduced pressure to afford the crude compound which was triturated with Hexane/EtOAc to afford the acid 7b (2.1 gm, 48%) as a crystalline solid.TLC: 30% MeOH/DCM (Rf: 0.3)1H NMR (500MHz, DMSO-c¾, delta in ppm): 7.72 (d, J= 9.0 Hz, 1H), 7.32 (d, J= 8.0 Hz, 1H), 7.20 (s, 1H), 6.90 (d, J= 8.0 Hz, 1H), 4.28-4.25 (m, 1H), 3.81-3.74 (m, 2H).

Reference： [1]Patent: WO2012/47617,2012,A1 .Location in patent: Page/Page column 49-50

53
[ 194853-86-6 ]
[ 74-88-4 ]
[ 1182367-75-4 ]

Yield	Reaction Conditions	Operation in experiment
25%		Example 13 and 14Example 13 Example 1413a to 13b4-Fluoro-3-methyl-2-(trifluoromethyl) benzo nitrileTo a solution of 2,2,6,6-tetramethylpiperidine (1.4 mL, 8.2 mmol) in dry THF (4 mL), cooled to -78 C, n-BuLi (2.9 mL, 2.5M solution in hexane, 8.2 mmol) was added drop wise under nitrogen atmosphere. After being stirred for 30 min at - 78 C, the resulting solution was brought to -20 C and stirred for additional 30min. 4-fluoro-2-(trifluoromethyl) benzonitrile (13a) (1.0 g, 5.2 mmol) was dissolved in dry THF (8 mL), cooled to -78C, and the above prepared lithiated piperidine solution was added under nitrogen atmosphere. After 5 h, Mel (0.6 mL, 9.3 mmol) was added to the reaction mixture maintaining the temperature at -78 C. The resulting reaction mixture was slowly brought to room temperature and stirred for 16 h. After completion of reaction (by TLC), aqueous NH4C1 (20 mL) was added to the reaction mixture and extracted with EtOAc (2x 20 mL). The combined organic extracts were dried over Na2S04 and concentrated under reduced pressure to give the crude compound. The crude material was purified by column chromatography to afford the nitrile 13b (0.25 g, 25%) as a yellow oil.TLC: 7% EtOAc/Hexane (Rf: 0.5)1H NMR (500MHz, CDC13, 6 in ppm): 7.69 (dd, J= 8.5 Hz, 1H), 2.45 (s, 3H).

Reference： [1]Patent: WO2012/47617,2012,A1 .Location in patent: Page/Page column 64-65

54
[ 615-16-7 ]
[ 194853-86-6 ]
[ 1363401-37-9 ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate; In dimethyl sulfoxide; for 144h;	<strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (4) (946 mg, 5 mmol) was added to a mixture of 1H-benzo[d]imidazol-2(3H)-one (5) (1340 mg, 10 mmol) and K2CO3 (2760 mg, 20 mmol) in DMSO (25.0 mL). After 6 days, 50 mL of water was added dropwise. The resulting suspension was filtered and the filter cake was dried in a vacuum oven. The solid was purified by flash chromatography (50% ethyl acetate in heptane) to afford 4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-2-(trifluoromethyl)benzonitrile (6) (1.07 g, 71%). LCMS RT = 1.56 min, M-1 = 302.1 AMU. 1H NMR (400 MHz, MeOD) d ppm 6.89 - 7.00 (m, 3 H) 7.03 (d, J=7.83 Hz, 1 H) 7.85 - 7.89 (m, 1 H) 7.94 - 7.99 (m, 1 H) 8.01 (d, J=1.77 Hz, 1H)

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2572 - 2578

55
[ 120902-45-6 ]
[ 194853-86-6 ]
[ 1363401-52-8 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium tert-butylate; In dimethyl sulfoxide; for 25h;	<strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (3) (37.8 mg, 0.2 mmol) was added to a mixture of 5-bromo-3,3-dimethylindolin-2-one (27) (48.0 mg, 0.2 mmol) and POTASSIUM T- BUTOXIDE (26.0 mg, 0.22 mmol) in DMSO (1.00 mL). After stirring for 25 h, 3 mL of water was added. The resulting suspension was filtered and the solid was dried to yield 68 mg of 4-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-2-(trifluoromethyl)benzonitrile (28) (83%). LCMS RT = 1.94 min, M+1 = 409.0 AMU. 1H NMR (400 MHz, DMSO-d6) d ppm 1.45 (s, 6 H) 6.98 (d, J=8.34 Hz, 1 H) 7.46 (dd, J=8.34, 2.02 Hz, 1 H) 7.78 (d, J=2.02 Hz, 1 H) 8.06 (dd, J=8.34, 2.02 Hz, 1 H) 8.19 (d, J=1.52 Hz, 1 H) 8.38 (d, J=8.34 Hz, 1 H)

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2572 - 2578

56
[ 540-38-5 ]
[ 194853-86-6 ]
[ 1097084-96-2 ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium carbonate; In N,N-dimethyl-formamide; at 100℃; for 20h;	4-Fluoro-2-(trifluoromethyl)benzonitrile (53 g, 280.4 mmol, AK Scientific) was treated with 4-iodophenol (61.7 g, 280.4 mmol, Aldrich) and sodium carbonate (44.6 g, 420.6 mmol) in 90 mL anhydrous DMF at 100C for 20 hours. The reaction mixture was diluted with 250 mL water and extracted with 2 X 200 mL EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 4-(4-iodophenoxy)-2-(trifluoromethyl)benzonitrile as a white solid (75 g, 69%). ? NMR (400 MHz, CDC13): 7.80-7.72 (3 H, m), 7.36-7.32 (1 H, m), 7.17-7.10 (1 H, m), 6.89-6.82 (2 H, m).
	With sodium carbonate; In N,N-dimethyl-formamide; at 100℃;	Compound 5e: A suspension of compound 9 (53 g, 0.28 mol,Aldrich), compound 8 (64 g, 0.29 mol, Aldrich) and sodium carbonate (45 g, 0.42 mol) in DMF was heated at 100C for 12 hours. After cooling to room temperature the mixture was diluted with H20 (600 mL) and extracted withEtOAc (2X 300 mL). The organic layer was dried over sodium sulfate and concentrated to dryness. The product was collected by vacuum filtration and washed with DCM to give a first batch of crystalline compound 10a (~75 g).

Reference： [1]Patent: WO2013/72758,2013,A1 .Location in patent: Page/Page column 88
[2]Patent: WO2012/35421,2012,A2 .Location in patent: Page/Page column 247

57
[ 1189140-61-1 ]
[ 194853-86-6 ]
[ 1189135-45-2 ]

Yield	Reaction Conditions	Operation in experiment
87%		General procedure: To an ice-cooled solution of 12 (0.200 g, 0.979 mmol) in DMF (2.0 mL) was added NaH (60% in mineral oil, 0.047 g, 1.18 mmol), and the mixture was stirred at 0 C for 30 min. To the mixture was added 4-fluorobenzonitrile (0.237 g, 1.96 mmol), and the mixture was stirred at 0 C for 2 h and room temperature for 18 h. The mixture was acidified with saturated aqueous solution of NH4Cl and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc). The product was recrystallized from hexane-EtOAc to give 3 (0.131 g, 44%) as white crystals.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 2338 - 2352

58
[ 194853-86-6 ]
[ 202522-22-3 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;Raney Ni; In ethanol; under 2585.81 Torr;	(4-Fluoro-2-(trifluoromethyl)phenyl)methanamine To a solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (2.0 g) in ethanol (10.0 mL) was added Raney Ni (catalytic amount). The reaction mixture was subjected for hydrogenation in Parr apparatus under 50 psi for 2-3 h. The reaction mass filtered through celite and concentrated the filtrate to afford 0.400 g of the desired product. 1HNMR (CDCl3): delta 3.98 (s, 2H), 7.24 (t, J=9.0 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H); MS [M+H]+: 194.03.
0.4 g	With hydrogen; In ethanol; under 2585.81 Torr;	To a solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (2.0 g) in ethanol (10.0 mL) was added Raney Ni (catalytic amount). The reaction mixture was subjected for hydrogenation in Parr apparatus under 50 psi for 2-3 h. The reaction mass was filtered through celite and the filtrate was concentrated to afford 0.400 g of desired product. 1HNMR (CDCl3): delta 3.98 (s, 2H), 7.24 (t, J - 9.0 Hz, 1H), 7.34 (d, - 8.7 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H); MS [M+H]+ : 194.03.

Reference： [1]Patent: US2012/108583,2012,A1 .Location in patent: Page/Page column 36
[2]Patent: WO2013/186692,2013,A1 .Location in patent: Page/Page column 72

59
[ 194853-86-6 ]
4-mercapto-2-(trifluoromethyl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		General procedure: Into an oven-dried flask equipped with a magnetic stir bar was added aryl fluoride (1.00 g, 1.0 eq.), Na2S (1.1 eq.) and DMF (5 mL) under argon. The reaction mixture was stirred at room temperature for 1 h. Then 1 M NaOH (50 mL) was added and was washed with CH2Cl2 (2 x 25 mL). The aqueous layer was acidified to pH ~ 1-2 with 6 N HCl and extracted with CH2Cl2 (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide a crude residue. To the residue was added 10% HCl (40 mL) and cooled with an ice-water bath. Then zinc dust (4 g) was added and the mixture was stirred for 1 h. Then EtOAc (100 mL) was added and the mixture was stirred for an additional 30 minutes. The organic layer was separated and washed with water (40 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated to provide the desired product with satisfactory purity.
		General procedure: The starting material 1 (7.0 mmol) was dissolved in 40 mL DMSO, and the mixture was heated and kept at 75 C for 20 min under stirring. After that sodium sulfide nonahydrate (10.5 mmol) was added to the solution in batch and the reaction continued under 75 C for 2 h. The reaction was then monitored by TLC and cooled to room temperature. The crude product was further extracted three times by using water and ethyl acetate. The aqueous layer was then adjusted by hydrochloric acid to a pH value of 3-4. Enough water was added and intermediate 2 precipitated out subsequently. The resulting solid 2 was filtered out in 75%-90% yields (Some of them were hard to purify and were used directly for the next reaction). Characterizations for 2 were listed in Table S2.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 2548 - 2551
[2]European Journal of Medicinal Chemistry,2019,vol. 167,p. 472 - 484

60
(±)-trans-1,2-diaminocycloheptane dihydrochloride [ No CAS ]
[ 194853-86-6 ]
(±)-trans-4-[(2-aminocycloheptyl)amino]-2-(trifluoromethyl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dimethyl sulfoxide; at 20 - 45℃; for 16h;	To a solution of frans-1 ,2-diaminocycloheptane dihydrochloride [racemic (±)] (1.0 g, 4.97 mmol) in DMSO (25 ml_) under argon atmosphere was added triethylamine (1 .37 ml_, 9.94 mmol) followed by <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (0.845 g, 4.47 mmol) at RT and the resulting reaction mixture was heated to 45 C. After stirring for 16 h, the reaction mixture was cooled to RT, poured onto ice-water (50 ml_), basified with 1 N NaOH solution, and extracted with ethyl acetate (100 ml_ x 2). The combined organic layer was washed with water (50 ml_) followed by brine (50 ml_), dried over Na2SC>4, and concentrated under reduced pressure to give the title compound (1.1 g) as a brown residue. The crude residue was directly used for next step without further purification.
	With triethylamine; In dimethyl sulfoxide; at 45℃; for 16h;Inert atmosphere;	[0474] To a solution of trans-1,2-diaminocycloheptane dihydrochloride [racemic (±)] (1.0 g, 4.97 mmol) in DMSO (25 mL) under argon atmosphere was added triethylamine (1.37 mL, 9.94 mmol) followed by <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (0.845 g, 4.47 mmol) at RT and the resulting reaction mixture was heated to 45 C. After stirring for 16 h, the reaction mixture was cooled to RT, poured onto ice-water (50 mL), basified with 1N NaOH solution, and extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with water (50 mL) followed by brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give the title compound (1.1 g) as a brown residue. The crude residue was directly used for next step without further purification.

Reference： [1]Patent: WO2013/84138,2013,A1 .Location in patent: Page/Page column 82
[2]Patent: US2014/329858,2014,A1 .Location in patent: Paragraph 0473; 0474

61
[ 194853-86-6 ]
[ 1539314-78-7 ]

Yield	Reaction Conditions	Operation in experiment
44.1%		To a freshly prepared solution of LDA (119 mmcl) in anhyd THF (250 mL) at -45C was added a solution of commercially available <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (21.5g, 114 mmol) in THF (30 mL), dropwise at a rate such that the internal temperature remained < -40C (became dark brown during addition). The mixture was stirred 30 mm at -45C, cooled to -70C and iodine (31.7 g, 125 mmol) was added in one portion (- 70C -> -52C). The mixture was stirred for 1 h, removed from the cooling bath and quenched by addition of 10% Na2S2O3 (ca. 250 mL) and IN HCl (ca. 125 mL). Themixture was extracted with EtOAc (x3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc hexanes, gradient elution) followed by recrystallization from heptane (30 mL), twice, affording 4-fluoro-3-iodo-2-(trifluoromethyl)benzonitrile (.15.79 g, 50.1 mmol, 44.1 % yield) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) delta 7.85 (ddd, J = 8.6, 5.1, 0.5 Hz, 1H), 7.36 (ddd, J = 8.6, 6.6,0.5 Hz, 1H); MS (GCMS EI) m/z 315 ([M]+, 100%).
44.1%		D. 4-Fluoro-3-iodo-2-(trifluoromethyl)benzonitrile To a freshly prepared solution of LDA (1 19 mmol) in anhyd THF (250 mL) at -45C is added a solution of commercially available <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (21 .5 g, 1 14 mmol) in THF (30 mL), dropwise at a rate such that the internal temperature remained < -40C (became dark brown during addition). The mixture is stirred 30 min at -45C, cooled to -70C and iodine (31 .7 g, 125 mmol) is added in one portion (-70C? - 52C). The mixture is stirred for 1 h, removed from the cooling bath and quenched by addition of 10% Na2S203 (ca. 250 mL) and 1 N HCI (ca. 125 mL). The mixture is extracted with EtOAc (x3). Combined organics are washed (water, brine), dried over Na2S04 and concentrated in vacuo. The residue is purified by low pressure liquid chromatography (silica gel, EtOAc / hexanes, gradient elution) followed by recrystallization from heptane (30 mL), twice, affording 4-fluoro-3-iodo-2- (trifluoromethyl)benzonitrile (15.79 g, 50.1 mmol, 44.1 % yield) as a pale yellow solid.
44.1%		To a freshly prepared solution of LDA (119 mmol) in anhyd THF (250 mL) at -45 C. is added a solution of commercially available <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (21.5 g, 114 mmol) in THF (30 mL), dropwise at a rate such that the internal temperature remained <-40 C. (became dark brown during addition). The mixture is stirred 30 min at -45 C., cooled to -70 C. and iodine (31.7 g, 125 mmol) is added in one portion (-70 C.?-52 C.). The mixture is stirred for 1 h, removed from the cooling bath and quenched by addition of 10% Na2S2O3 (ca. 250 mL) and 1N HCl (ca. 125 mL). The mixture is extracted with EtOAc (×3). Combined organics are washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue is purified by low pressure liquid chromatography (silica gel, EtOAc hexanes, gradient elution) followed by recrystallization from heptane (30 mL), twice, affording 4-fluoro-3-iodo-2-(trifluoromethyl)benzonitrile (15.79 g, 50.1 mmol, 44.1% yield) as a pale yellow solid.

Reference： [1]Organometallics,2019,vol. 38,p. 129 - 137
[2]Patent: WO2014/13309,2014,A1 .Location in patent: Page/Page column 42; 43
[3]Patent: WO2015/110958,2015,A1 .Location in patent: Page/Page column 29
[4]Patent: US2016/332967,2016,A1 .Location in patent: Paragraph 0126

62
[ 194853-86-6 ]
[ 1539314-06-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -45 °C 1.2: 1 h / -70 - -52 °C 2.1: diisopropylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / toluene / 0.17 h / Sealed tube; Sonication 2.2: 60 °C / Sonication 3.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 0.83 h / 100 °C / Sealed tube 4.1: potassium <i>tert</i>-butylate / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 0.67 h / 50 °C 5.1: ozone / methanol; water / 0.83 h
	Multi-step reaction with 5 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -45 - -40 °C 1.2: 1 h / -70 - -52 °C 2.1: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; diisopropylamine / toluene / 60 °C / Sealed tube; Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 0.83 h / 100 °C / Sealed tube 4.1: potassium <i>tert</i>-butylate / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 0.67 h / 50 °C 5.1: Oxone / water; methanol / 0.83 h / Cooling with ice

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2014/13309, 2014, A1
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2015/110958, 2015, A1

63
[ 87120-72-7 ]
[ 194853-86-6 ]
[ 1247030-47-2 ]

Yield	Reaction Conditions	Operation in experiment
51%	With potassium carbonate; In dimethyl sulfoxide; at 100℃;	To a solution of <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (5 g, 26 mmol,) in DMSO (50 ml) was added tert-butyl 4-aminopiperidine-1-carboxylate (5.3 g, 26.5 mmol, 1 eq.) and potassium carbonate (7.3 g, 52.8 mmol, 2 eq.). The resulting solution was stirred with heating overnight at 100 C. (oil bath). The resulting solution was diluted with of ethyl acetate (300 ml) and washed with sodium chloride (sat., 300 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was applied onto a silica gel column and eluted with ethyl acetate to afford tert-butyl 4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]piperidine-1-carboxylate as a white powder (5 g, 51%). (ES, m/z):[M+H]+ 370.1.
51%	With potassium carbonate; In dimethyl sulfoxide; at 100℃;	To a solution of <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (5 g, 26 mmol,) in DMSO (50 ml) was added /er/-butyl 4-aminopiperidine-l-carboxylate (5.3 g, 26.5 mmol, 1 eq.) and potassium carbonate (7.3 g, 52.8 mmol, 2 eq.). The resulting solution was stirred with heating overnight at 100 C (oil bath). The resulting solution was diluted with of ethyl acetate (300 ml) and washed with sodium chloride (sat., 300 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was applied onto a silica gel column and eluted with ethyl acetate to afford /er/-butyl 4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]piperidine- 1-carboxylate as a white powder (5 g, 51 %). (ES, m/z): [M+R]+ 370.1.

Reference： [1]Patent: US2014/142114,2014,A1 .Location in patent: Paragraph 0423; 0424
[2]Patent: WO2016/118638,2016,A1 .Location in patent: Page/Page column 127

64
[ 194853-86-6 ]
[ 27489-62-9 ]
[ 1355697-18-5 ]

Yield	Reaction Conditions	Operation in experiment
33%	With potassium carbonate; In acetonitrile; at 20 - 90℃;	0406] The aryl fluoride (2 g, 10.6 mmol) was placed in a 100 ml round-bottomed flask and stirred in 20 ml acetonitrile at room temperature. Potassium carbonate (3.3 g, 23.9 mmol, 2.2 eq) and 1,4-trans-amino-cyclohexanol (1.34 g, 11.6 mmol, 1.1 eq) were added and the mixture was then heated at 90 C. overnight. The mixture was cooled to room temperature and then concentrated under vacuum. The crude material was purified by silica gel chromatography using 20-40% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to provide 1 g (33%) of the desired aniline as a yellow oil. (ES, m/z): [M+H]+ 285.0; 1H NMR (300 MHz, DMSO): delta 8.04 (d, J=9.3 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 6.82-6.86 (m, 1H), 4.59 (d, J=4.2 Hz, 1H), 3.39-3.49 (m, 2H), 1.78-1.94 (m, 4H), 1.18-1.32 (m, 4H).

Reference： [1]Patent: US2014/142114,2014,A1 .Location in patent: Paragraph 0405; 0406

65
[ 811-93-8 ]
[ 194853-86-6 ]
4-((2-amino-2-methylpropyl)amino)-2-(trifluoromethyl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h;	Step A. 4-((2-amino-2-methylpropyl)amino)-2-(trifluoromethyl)benzonitrile A mixture of <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (3.0 g, 15.87 mmol), 2- methylpropane-l ,2-diamine (2.1 g, 23.85 mmol), and K2C03(4.5 g, 29.61 mmol) in DMF (30 mL) was stirred at 80 C for 3 hours. The reaction mixture was poured into water (90 mL) and extracted with ethyl acetate (60 mL x 4). The extracts were combined, washed with brine (50 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 4-((2-amino-2-methylpropyl)amino)-2-(trifluoromethyl)benzonitrile as a white solid (2.94 g, 72%). LCMS (ESI) m/z: 258.0 [M+H]+.

Reference： [1]Patent: WO2015/100617,2015,A1 .Location in patent: Page/Page column 45

66
[ 1194-02-1 ]
[ 76-05-1 ]
[ 67515-59-7 ]
[ 194853-86-6 ]

Reference： [1]Organic Letters,2015,vol. 17,p. 38 - 41

67
[ 105-53-3 ]
[ 194853-86-6 ]
diethyl 2-[4-cyano-3-(trifluoromethyl)phenyl]propanedioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		[00442] Intermediate 36a: diethyl 2-[4-cyano-3-(trifluoromethyl)phenyl]propanedioate[00443] A solution of diethyl malonate (4.O3mL, 26.44mmol) and caesium carbonate (18.95g, 58.l7mmol) in DMF (5OmL) was heated to 70 C under nitrogen for 30 minutes. 2-cyano-5- fluorobenzotrifluoride (5.OOg, 26.44mmol) was then added. The reaction mixture was then stirred at 70 C for 2 hours. The mixture was cooled to room temperature, diluted with Et0Ac and poured intowater. The aqueous layer was brought to a neutral pH with concentrated HCI and the crude product extracted into Et0Ac (3xlOOmL). The combined organic layers were then dried over Na2504 and concentrated to give diethyl 2-[4-cyano-3-(trifluoromethyl)phenyl]propanedioate (7.39g, 22.44mmol, 85% yield) as a yellow oil.MS Method 2: RT: 2.56 mi m/z 330.1 [M+H]

Reference： [1]Patent: WO2016/51193,2016,A1 .Location in patent: Paragraph 00441; 00442; 00443

68
[ 1984-49-2 ]
[ 194853-86-6 ]
4,4'-(9H,9'H-[3,3'-bicarbazole]-9,9'-diyl)bis(2-(trifluoromethyl)benzonitrile) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate; In dimethyl sulfoxide; at 140℃; for 12h;	3,3?-bicarbazole (0.50 g, 1.5 mmol), potassium carbonate (0.99 g, 7.2 mmol), 2-trifluoromethyl-4-fluorobenzonitrile (0.60 g, 3.3 mmol), DMSO 6 ml, 140 Heated at for 12h.Cool to room temperature and pour into 200ml of water to precipitate a large amount of solid and stir for 0.5h.A white solid was obtained by suction filtration and purified by column chromatography to obtain a white solid with a yield of 92%.
90%	With potassium carbonate; In dimethyl sulfoxide; at 140℃; for 12h;Inert atmosphere;	General procedure: A mixture of <strong>[1984-49-2]9H,9'H-3,3'-bicarbazole</strong> (500 mg, 1.50 mmol), 4-fluoro-2-methylbenzonitrile (450 mg, 3.33 mmol) and K2CO3(0.99 g, 7.2 mmol) in dimethyl sulfoxide (DMSO) (6 mL) was stirredat 140 C for 12 h under nitrogen atmosphere. After cooling to roomtemperature, the mixture was poured into water, filtered and thenpurified by column chromatography over silica gel with CH2Cl2/petroleum ether (1: 1) as eluent to afford a white solid (760 mg,89%).

Reference： [1]Patent: CN105037247,2019,B .Location in patent: Paragraph 0013; 0029-0031
[2]Dyes and Pigments,2017,vol. 136,p. 543 - 552

69
[ 194853-86-6 ]
4-fluoro-N-hydroxy-2-(trifluoromethyl)benzenecarboximidamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine; In methanol; water; at 60℃; for 21h;	To a solution of <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (15.0 g, 79.3 mmol) in methanol (190 mL) was added an aqueous solution of hydroxylamine (50% w/w, 48 mL, 783 mmol) and the reaction mixture was warmed to 60 C and allowed to stir for 21 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes: ethyl acetate - 100:0 to 70:30 to afford the title compound. MS: m/z = 223.3 [M+H]

Reference： [1]ACS Combinatorial Science,2016,vol. 18,p. 616 - 624
[2]Patent: WO2019/212927,2019,A1 .Location in patent: Page/Page column 64

70
[ 349447-28-5 ]
[ 194853-86-6 ]
(R)-4-((3-(4-cyanophenoxy)-2-hydroxypropyl)amino)-2-(trifluoromethyl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With dimethyl sulfoxide; triethylamine; at 60℃; for 16h;	Step 3. Preparation of (R)-4-((3-(4-cyanophenoxy)-2-hydroxypropyl)amino)-2-(trifluoromethyl)benzonitrile To a 250-ml flask, 2.02 g (10.5 mmol, 1.1 eq) of the compound (R)-4-(3-amino-2-hydroxypropoxy)benzonitrile obtained in Step 2 of Example 5 was added and 100 ml of dimethyl sulfoxide was added, followed by stirring. 1.81 g (9.55 mmol, 1 eq) of <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> and 1.6 ml (11.5 mmol, 1.2 eq) of triethylamine were added thereto, followed by stirring at 60C for 16 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate (100 ml) and washed with water (200 ml) three times. After separation of layers, an aqueous layer was removed and an organic layer was washed with a saturated NaCl aqueous solution, dehydrated and dried over MgSO4 and then concentrated under reduced pressure to obtain 2.6 g (70%) of a title compound. 1H NMR (CDCl3, 400MHz) delta 7.60(d, 2H), 7.56(d, 1H), 7.72(s, 1H), 6.96(d, 2H), 6.91(d, 1H), 6.74(dd, 1H), 4.91(t, 1H), 4.31(br, 1H), 4.12~4.04(m, 2H), 3.50~3.47(m, 1H), 3.40~3.37(m, 1H) Mass[M+H] : 362.10

Reference： [1]Patent: EP3135669,2017,A1 .Location in patent: Paragraph 0167; 0168

71
[ 565-71-9 ]
[ 194853-86-6 ]
(S)-3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxypropanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; In water; dimethyl sulfoxide; at 120℃; for 16h;	To a 250-ml flask, 20 g (105.7 mmol) of 4-fluoro-2-(trifluoromethyl)benzonitrile was added and 106 ml of dimethylsulfoxideand 46 ml of water were added thereto, followed by stirring. To this reaction solution, 13.34 g (126.9 mmol,1.2 eq) of (S)-isoserine and 44.6 ml (317.1 mmol, 3.0 eq) of triethylamine were added, followed by stirring at 120 °C for16 hours. After completion of the reaction, the reaction product was diluted with 150 ml of ethyl acetate and washedwith 200 ml of water three times. After separation of layers, the layer was washed with a NaCl aqueous solution,dehydrated and dried over MgSO4, and concentrated under reduced pressure to obtain 28 g (95percent) of a title compound.1H NMR (Acetone-d6, 400MHz) delta 7.66(d, 1H), 7.22(d, 1H), 7.04(dd, 1H), 6.49(s, 1H), 4.43(q, 1H), 3.72~3.575(m, 2H)Mass[M+H] : 275.06

Reference： [1]Patent: EP3135669,2017,A1 .Location in patent: Paragraph 0078; 0079

72
[ 61278-21-5 ]
[ 194853-86-6 ]
(S)-4-((2,3-dihydroxypropyl)amino)-2-(trifluoromethyl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; In dimethyl sulfoxide; at 120℃; for 16h;	To a 2-L flask, 180 g (952 mmol) of 4-fluoro-2-(trifluoromethyl)benzonitrile was added, and 1 L of dimethyl sulfoxide was added thereto, followed by stirring. 86.72 g (952 mmol, 1 eq) of (S)-3-aminopropane-1,2-diol was added and 267.6 ml (1.90 mol, 2 eq) of triethylamine was added, and followed by stirring at 120C about 16 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate (1 L), and then washed with water (1 L) three times. After separation of layers, an aqueous layer was removed and an organic layer was washed with a saturated NaCl aqueous solution, and dehydrated and dried over MgSO4, and concentrated under reduced pressure to obtain 223 g (90%) of a title compound. 1H NMR (Acetone-d6, 400MHz) delta 7.66(d, 1H), 7.17(d, 1H), 6.99(dd, 1H), 6.44(s, 1H), 3.87(t, 1H), 3.59(t, 2H), 3.51~3.45(m, 1H), 3.30~3.23(m, 1H) Mass[M+H] : 261.22

Reference： [1]Patent: EP3135669,2017,A1 .Location in patent: Paragraph 0054; 0055

73
[ 22190-33-6 ]
[ 194853-86-6 ]
C₁₆H₁₀BrF₃N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.1%		NaH (25 mg, 0.625 mmol) dissolved in dry DMF (3 ml) and cooled to 0CCompound b (50 mg, 0.25 mmol) was added slowly,After stirring for 30 min, compound a (95 mg, 0.5 mmol) was added, and the mixture was transferred to room temperature and stirred for 2 h.Diluted with water, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate and concentrated.Purification by silica gel column (PE:EA=10:1) gave a yellow-green solid c (80 mg), yield: 87.1%.
		General procedure: The mixture of 60% dispersion of NaH (80.0 mg, 2.0 mmol) inmineral oil and 5-bromo-tetrahydroquinoline (3) (212.0 mg,1.0 mmol) in dry DMF (4.0 ml) was stirred at 0 C for 30 min. 4-Fluoro-2-(trifluoromethyl) benzonitrile (378.2 mg, 2.0 mmol) wasadded and the mixture was warmed to room temperature. After2 h, the reaction mixture was quenched with cold water andextracted with ethyl acetate. The organic phase was washed withwater twice and then dried over anhydrous Na2SO4, filtered, andconcentrated under vacuum. Pure 4-(5-bromo-3,4-dihydroquinolin 1(2H)-yl)-2-(trifluoromethyl)benzonitrile (6)was obtained as a yellow solid (100.0 mg, yield 26.2%) after flashcolumn chromatography using a solvent of 10% ethyl acetate inhexanes. For the synthesis of intermediate 5 and 7, commerciallyavailable 2 and 4 were used respectively by the proceduredescribed for intermediate 6.

Reference： [1]Patent: CN107814785,2018,A .Location in patent: Paragraph 0062; 0073-0075
[2]European Journal of Medicinal Chemistry,2019,vol. 171,p. 265 - 281

74
[ 114744-50-2 ]
[ 194853-86-6 ]
4-(5-bromo-3,4-dihydroquinolin 1(2H)-yl)-2-(trifluoromethyl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26.2%		NaH (189.1 mg, 1 mmol) was dissolved in dry DMF (2 ml) and cooled to 0C.Compound b (106 mg, 0.5 mmol) was added slowly, and after stirring for 30 min 4-fluoro-2-(trifluoromethyl)benzonitrile (189.1 mg, 1 mmol) was added and the mixture was transferred to room temperature and stirred for 2 h.Diluted with water, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate and concentrated.Purification by silica gel column (PE:EA=10:1) gave a pale yellow solid g (50 mg), yield: 26.2%.
26.2%		The mixture of 60% dispersion of NaH (80.0 mg, 2.0 mmol) inmineral oil and <strong>[114744-50-2]5-bromo-tetrahydroquinoline</strong> (3) (212.0 mg,1.0 mmol) in dry DMF (4.0 ml) was stirred at 0 C for 30 min. 4-Fluoro-2-(trifluoromethyl) benzonitrile (378.2 mg, 2.0 mmol) wasadded and the mixture was warmed to room temperature. After2 h, the reaction mixture was quenched with cold water andextracted with ethyl acetate. The organic phase was washed withwater twice and then dried over anhydrous Na2SO4, filtered, andconcentrated under vacuum. Pure 4-(5-bromo-3,4-dihydroquinolin 1(2H)-yl)-2-(trifluoromethyl)benzonitrile (6)was obtained as a yellow solid (100.0 mg, yield 26.2%) after flashcolumn chromatography using a solvent of 10% ethyl acetate inhexanes. For the synthesis of intermediate 5 and 7, commerciallyavailable 2 and 4 were used respectively by the proceduredescribed for intermediate 6.

Reference： [1]Patent: CN107814785,2018,A .Location in patent: Paragraph 0062; 0081; 0082; 0084
[2]European Journal of Medicinal Chemistry,2019,vol. 171,p. 265 - 281

75
[ 51644-96-3 ]
[ 194853-86-6 ]
tert-butyl 5-(4-cyano-3-(trifluoromethyl)phenylamino)pentylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	A solution of <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (7.00 g, 37.1 mmol), tert- butyl N-(5-aminopentyl)carbamate (10 g, 49.43 mmol), and Nu,Nu-diisopropylethyl amine (11 g, 85.11 mmol) in DMF (100 mL) stirred for 6 h at room temperature. The resulting solution was diluted with 400 mL of ethyl acetate, washed with 2x200mL brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography with silica gel (eluting with ethyl acetate/petroleum ether (1 : 1)) to give tert- butyl 5-(4-cyano-3-(trifluoromethyl)phenylamino)pentylcarbamate (11 g, 60%) as colorless oil. MS: (ESI, m/z): 372[M+H]+.

Reference： [1]Patent: WO2018/75959,2018,A1 .Location in patent: Paragraph 0589-0590

76
[ 226942-29-6 ]
[ 194853-86-6 ]
C₁₇H₁₂BrF₃N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The mixture of 60% dispersion of NaH (80.0 mg, 2.0 mmol) inmineral oil and 5-bromo-tetrahydroquinoline (3) (212.0 mg,1.0 mmol) in dry DMF (4.0 ml) was stirred at 0 C for 30 min. 4-Fluoro-2-(trifluoromethyl) benzonitrile (378.2 mg, 2.0 mmol) wasadded and the mixture was warmed to room temperature. After2 h, the reaction mixture was quenched with cold water andextracted with ethyl acetate. The organic phase was washed withwater twice and then dried over anhydrous Na2SO4, filtered, andconcentrated under vacuum. Pure 4-(5-bromo-3,4-dihydroquinolin 1(2H)-yl)-2-(trifluoromethyl)benzonitrile (6)was obtained as a yellow solid (100.0 mg, yield 26.2%) after flashcolumn chromatography using a solvent of 10% ethyl acetate inhexanes. For the synthesis of intermediate 5 and 7, commerciallyavailable 2 and 4 were used respectively by the proceduredescribed for intermediate 6.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 171,p. 265 - 281

77
[ 626-02-8 ]
[ 194853-86-6 ]
C₁₄H₇F₃INO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.1%	With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 2h;	A mixture of <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (8) (378.0 mg, 2.0 mmol), 3-iodophenol(440.0 mg, 2.0 mmol) and K2CO3 (414.6 mg, 3.0 mmol) in DMSO(4.0 ml) was heated to 110 C and stirred for 2 h. The reactionmixture was cooled to room temperature, diluted with ethyl acetateand washed with water. The organic layer was dried overanhydrous Na2SO4, filtered and concentrated under vacuum. Purificationon silica using a solvent of 10% ethyl acetate in hexanesyielded the product 9 (670.0 mg, yield 86.1%) as a white solid.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 171,p. 265 - 281

78
[ 92-84-2 ]
[ 194853-86-6 ]
4-phenothiazin-10-yl-2-trifluoromethylbenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%		General procedure: Sixty per cent NaH in oil was washed with hexane and then added to a stirred solution of phenothiazine 5 or phenoxazine 6 derivative (10.0mmol) in dry THF (15mL) under a nitrogen atmosphere at room temperature. After stirring for 30min, 4-fluoro-2-(fluoromethyl)-benzonitrile 7 was added. (0007) The reaction mixture was quenched with water (30mL). The organic phase was separated, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography using a mixture of hexane/ethyl acetate (3:1) as eluent.

Reference： [1]Dyes and Pigments,2020,vol. 175

79
[ 135-67-1 ]
[ 194853-86-6 ]
4-phenoxazin-10-yl-2-trifluoromethylbenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%		General procedure: Sixty per cent NaH in oil was washed with hexane and then added to a stirred solution of phenothiazine 5 or phenoxazine 6 derivative (10.0mmol) in dry THF (15mL) under a nitrogen atmosphere at room temperature. After stirring for 30min, 4-fluoro-2-(fluoromethyl)-benzonitrile 7 was added. (0007) The reaction mixture was quenched with water (30mL). The organic phase was separated, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography using a mixture of hexane/ethyl acetate (3:1) as eluent.

Reference： [1]Dyes and Pigments,2020,vol. 175

80
[ 1338812-41-1 ]
[ 194853-86-6 ]
[ 2505499-31-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-fluoro-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.333333h; Stage #2: tert-butyl N-[(1,3-trans)-3-hydroxy-2,2,4,4-tetramethylcyclobutyl]carbamate In N,N-dimethyl-formamide at 20℃; for 4h;

Reference： [1]Han, Xin; Zhao, Lijie; Xiang, Weiguo; Qin, Chong; Miao, Bukeyan; McEachern, Donna; Wang, Yu; Metwally, Hoda; Wang, Lu; Matvekas, Aleksas; Wen, Bo; Sun, Duxin; Wang, Shaomeng [Journal of Medicinal Chemistry, 2021, vol. 64, # 17, p. 12831 - 12854]

81
[ 1338812-41-1 ]
[ 194853-86-6 ]
[ 2055343-99-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl N-[(1r,3r)-3-hydroxy-2,2,4,4-tetramethylcyclobutyl]carbamate With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-cyano-3-(trifluoromethyl)phenyl fluoride In N,N-dimethyl-formamide at 40℃; for 3h; Inert atmosphere;	16 Reference Example 16: Preparation of Intermediate I-16 Reagent 2 (777 mg, 4.11 mmol) was dissolved in N,N-dimethylformamide (15 mL) at room temperature, and sodium hydride (296 mg, 60% content, 7.40 mmol) was added at 0°C under nitrogen protection, After stirring for 30 minutes, 4-fluoro-2-(trifluoromethyl)benzonitrile (1.00 g, 4.11 mmol) was added, the mixture was stirred and reacted at 40° C. for 3 hours, water (50 mL) was added to the reaction solution, and ethyl acetate (50 mL) was added to the reaction solution. × 3) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. After the crude product was purified by forward column chromatography, a dioxane solution of hydrogen chloride (15 mL, 3 M) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was directly spin-dried and concentrated to obtain intermediate I-16.The intermediate was used directly in the next reaction without purification.

Reference： [1]Current Patent Assignee: SHANGHAI JIYU PHARMACEUTICAL TECH; SHANGHAI JEMINCARE PHARMACEUTICALS; JIANGXI JEMINCARE GROUP CO LTD - WO2021/249534, 2021, A1 Location in patent: Page/Page column 25

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	194853-86-6	MDL No. :	MFCD00061283
Formula :	C₈H₃F₄N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LCCPQUYXMFXCAC-UHFFFAOYSA-N
M.W :	189.11	Pubchem ID :	605085
Synonyms :

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	1
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	36.12
TPSA :	23.79 Å²

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) :	-5.59 cm/s

Log Po/w (iLOGP) :	1.83
Log Po/w (XLOGP3) :	2.63
Log Po/w (WLOGP) :	4.29
Log Po/w (MLOGP) :	2.94
Log Po/w (SILICOS-IT) :	3.25
Consensus Log Po/w :	2.99

[ CAS No. 194853-86-6 ] {[proInfo.proName]}

Quality Control of [ 194853-86-6 ]

Related Doc. of [ 194853-86-6 ]

Product Details of [ 194853-86-6 ]

Calculated chemistry of [ 194853-86-6 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 194853-86-6 ]

Application In Synthesis of [ 194853-86-6 ]

[ 194853-86-6 ] Synthesis Path-Downstream 1~81

Related Functional Groups of
[ 194853-86-6 ]

Fluorinated Building Blocks

Aryls

Nitriles

Trifluoromethyls

Precautionary Statements-General

Prevention

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Disposal

Physical hazards

Health hazards

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Inquiry

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Log S (ESOL) :	-2.94
Solubility :	0.215 mg/ml ; 0.00114 mol/l
Class :	Soluble
Log S (Ali) :	-2.78
Solubility :	0.314 mg/ml ; 0.00166 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.65
Solubility :	0.0422 mg/ml ; 0.000223 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.93

Signal Word:	Warning	Class:
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P378
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