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[ CAS No. 373-88-6 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}

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

2D 3D

Chemical Structure| 373-88-6

Chemical Structure| 373-88-6

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Quality Control of [ 373-88-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 373-88-6 ]

SDS Specification

Alternatived Products of [ 373-88-6 ]

Product Details of [ 373-88-6 ]

CAS No. :	373-88-6	MDL No. :	MFCD00012875
Formula :	C₂H₅ClF₃N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZTUJDPKOHPKRMO-UHFFFAOYSA-N
M.W :	135.52	Pubchem ID :	9772
Synonyms :

Calculated chemistry of [ 373-88-6 ]

Physicochemical Properties

Num. heavy atoms :	7
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	21.59
TPSA :	26.02 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.39 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.04
Log Po/w (WLOGP) :	2.57
Log Po/w (MLOGP) :	0.96
Log Po/w (SILICOS-IT) :	0.86
Consensus Log Po/w :	1.08

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	3.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.27
Solubility :	7.29 mg/ml ; 0.0538 mol/l
Class :	Very soluble
Log S (Ali) :	-1.18
Solubility :	9.02 mg/ml ; 0.0666 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.73
Solubility :	25.2 mg/ml ; 0.186 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 373-88-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P264-P280-P337+P313-P302+P352+P312-P304+P340+P312	UN#:	N/A
Hazard Statements:	H302+H312+H332-H315-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 373-88-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 373-88-6 ]
Downstream synthetic route of [ 373-88-6 ]

[ 373-88-6 ] Synthesis Path-Upstream 1~7

1
[ 753-90-2 ]
[ 373-88-6 ]

Yield	Reaction Conditions	Operation in experiment
96.3%	With hydrogenchloride In ethanol; water at 25 - 50℃; for 1 h;	Add 100 g to a three-necked flaskEthanol and 33 gTrifluoroethylamine,At temperatures below 25 ° C, 35 g of saturated hydrochloric acid solution was slowly added dropwise,After the drop was completed, the temperature was raised to 50 ° C for one hour.The reaction solution in the system after the vacuum of 0.98MPa,The control temperature is 45 ± 5 ° C,After 5 hours of distillation under reduced pressure, the water and ethanol were removed,To give trifluoroethylamine hydrochloride 43. 5 g,The product yield was 96. 30percent. The obtained trifluoroethylamine hydrochloride was a white powdery crystalline solid,The water content was 0.13percent.

Reference： [1] Patent: CN105801428, 2016, A, . Location in patent: Paragraph 0016; 0017

2
[ 100-46-9 ]
[ 76-05-1 ]
[ 373-88-6 ]

Reference： [1] Tetrahedron Letters, 2002, vol. 43, # 31, p. 5449 - 5452

3
[ 348-08-3 ]
[ 373-88-6 ]

Reference： [1] Tetrahedron Letters, 2002, vol. 43, # 31, p. 5449 - 5452

4
[ 373-88-6 ]
[ 182438-97-7 ]
[ 182438-98-8 ]

Yield	Reaction Conditions	Operation in experiment
76.1%	Stage #1: With oxalyl dichloride In dichloromethane at 25℃; for 2 h; Inert atmosphere Stage #2: With triethylamine In dichloromethane at 25℃; for 2 h;	In a thermometer,In a three-necked flask of a dropping funnel,(25.0 g, 73 mmol), methylene chloride (250 ml), oxalyl chloride (11.0 g, 87 mol) and DMF (5 drops) under nitrogen atmosphere at room temperature for 2 h and the solvent was evaporated under reduced pressure , The residue was dissolved in dichloromethane (50 ml)A solution of trifluoroethylamine hydrochloride (10.9 g, 80 mmol)And triethylamine (31 ml, 220 mmol) in dichloromethane (100 ml). The organic phase was washed with water, 1N HCl solution, saturated aqueous NaHCO3 solution and saturated brine (200 ml x 3 times each), dried over anhydrous Na2SO4, and evaporated to remove the solvent. The residue was purified by silica gel column chromatography (eluent: To give a light yellow oil which was recrystallized from anhydrous ethanol (200 ml) at -5 ° C and the solid was collected to give the title compound as an intermediate (4) (23.7 g, 76.1percent) as a white solid,
73%	Stage #1: With 4-methyl-morpholine; isobutyl chloroformate In dichloromethane at 0 - 5℃; for 0.25 h; Inert atmosphere Stage #2: With 4-methyl-morpholine In dichloromethane at 20℃;	To a solution of 9-(4-bromobutyl)-9H-fluorene-9-carboxylic acid (200 gm, 0.579 moles) in dichloromethane (4 L) was charged N-methyl morpholine (87.88 gm, 0.87 moles). The reaction mass was cooled to about 0-5°C under nitrogen atmosphere and isobutylchloroformate (102.68 gm, 0.75 moles) was added slowly at about 0-5°C. The reaction mass was stirred for about 15 min at same temperature and a suspension of 2,2,2-trifluoroethylamine hydrochloride (94.2 gm, 0.70 moles) and N-methyl morpholine (87.88 gm, 0.868 moles) in dichloromethane (1 L) was slowly added. The reaction mass was stirred for about 8-12 hrs at room temperature. After completion of the reaction, water was added to the reaction mass at about 25-30°C and the layers were separated. The organic layer was washed with dilute hydrochloric acid followed by water. The organic layer was distilled off under vacuum at about 35-40°C to afford a residue. Water was added to the solution of residue in methanol and the obtained mass was stirred. The precipitated solid was filtered and dried under vacuum at about 50-55°C for about 12 hrs to afford 180 gm of 9-(4-bromobutyl)-N-(2,2,2-trifluroethyl)-9H-fluorene-9-carboxamide as pale yellow solid (Yield 73 percent, HPLC purity 95.40 percent).
71%	Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 1.66667 h; Stage #2: With triethylamine In dichloromethane at 0℃; for 1 h;	To a solution of Part A(1) acid (60 g, 173 mmol) and DMF (100 μL) in CH2Cl2 (600 mL) under argon at 0°C was added oxalyl chloride (104 mL, 2.0M in CH2Cl2, 208 mmol) dropwise. The reaction was stirred at 0°C for 10 min, then warmed to room temperature and stirred for 1.5 h. The reaction was concentrated in vacuo to give the crude acid chloride as a yellow oil. To a suspension of 2,2,2-trifluoroethylamine hydrochloride (25.9 g, 191 mmol) in CH2Cl2 (500 mL) at 0°C under argon was added triethylamine (73 mL, 521 mmol) followed by dropwise addition of a solution of the crude acid chloride in CH2Cl2 (15 mL). The reaction was stirred at 0°C for 1 h, diluted with CH2Cl2 (500 mL), and washed with water (2 x 300 mL), 1N HCl (2 x 300 mL), saturated NaHCO3 (2 x 300 mL), and brine (2 x 300 mL), then dried over MgSO4. Evaporation gave 80 g of a oil which was purified by flash chromatography on silica gel (2.5 kg). The crude product was loaded in a mixture of CH2Cl2 and hexane, and eluted with a step gradient of 10percent EtOAc/hexane (4L) to 15percent EtOAc/hexane (2L) to 20percent EtOAc/hexane (4L). Pure fractions were combined and evaporated to give title compound (52.5 g, 71percent) as a white solid (mp 88-92°C).

Reference： [1] Patent: CN106146385, 2016, A, . Location in patent: Paragraph 0037; 0038
[2] Patent: WO2016/55934, 2016, A1, . Location in patent: Paragraph 0124; 0133
[3] Patent: EP904262, 2004, B1, . Location in patent: Page 145

5
[ 373-88-6 ]
[ 331767-53-4 ]
[ 182438-98-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 20, p. 5067 - 5070
[2] Journal of Medicinal Chemistry, 2001, vol. 44, # 6, p. 851 - 856
[3] Patent: US2003/166637, 2003, A1,
[4] Patent: US2003/114442, 2003, A1,
[5] Patent: US6818644, 2004, B1,
[6] Patent: WO2016/71849, 2016, A1, . Location in patent: Page/Page column 15; 16

6
[ 110-52-1 ]
[ 1989-33-9 ]
[ 373-88-6 ]
[ 182438-98-8 ]

Yield	Reaction Conditions	Operation in experiment
155 g	Stage #1: With sodium t-butanolate In toluene at 5 - 30℃; for 3 h; Inert atmosphere Stage #2: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 25 - 30℃; for 2 h; Stage #3: With sodium carbonate In dichloromethane; water at 5 - 10℃; for 0.75 h;	A mixture of 9H-fluorene-9-carboxylic acid compound of formula-2a (100 gm), 1,4-dibromobutane (308 gm) and toluene (1000 ml) was stirred for 15 mm at 25-30°C undernitrogen atmosphere. Cooled the reaction mixture to 5-10°C, sodium tert.butoxide (100.5 gm) was slowly added to it and stirred the reaction mixture for 3 hrs at the same temperature. Water was added to the reaction mixture at 25-30°C and stirred for 15 mm at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with water. Both the organic and aqueous layers were separated and washed the aqueouslayer with toluene. Acidified the aqueous layer using aqueous hydrochloric acid solution at25-30°C aiid stirred the reaction mixture for 20 mm at the same temperature. Dichioromethane was added to the reaction mixture at 25-30°C and stirred for 15 mm at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous citric acid solution. Distilled off the solvent completely from theorganic layer. Dichioromethane (500 ml) was added to the reaction mixture at 25-30°C and stirred for 15 mm at the same temperature. N,N-dimethylformamide (6.9 gm) followed by oxalyl chloride (66.4 gm) were slowly added to the reaction mixture at 25-30°C and stirred for 2 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under nitrogen atmosphere and co-distilled with dichloromethane under reducedpressure. Dichloromethane (500 ml) was added to the obtained compound at 25-30°C and stirred for .15 mm at the same temperature. The obtained compound was slowly added to a pre-cooled mixture of water (500 ml), 2,2,2-trifluoroethylamine hydrochloride (64.4 gm) and sodium carbonate (75.6 gm) at 5-10°C and stirred the reaction mixture for 45 mm at the same temperature. Both the organic and aqueous layers were separated and washed the organiclayer with aqueous hydrochloric acid solution followed by with aqueous sodium bicarbonate solution and then finally washed with water. Distilled off the solvent completely from the organic layer and then co-distilled with n-heptane under reduced pressure. n-Heptane (100 ml) and isopropanol (5 ml) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 1 hr at the same temperature. Cooled the reaction ttiture to 25-30°C and stirred for 1 hr at the same temperature. Filtered the precipitatedsolid, washed with n-heptäne and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-5.Yield: 155.0 gm; M.R: 95-102°C.

Reference： [1] Patent: WO2017/98522, 2017, A1, . Location in patent: Page/Page column 18; 19; 24; 25

7
[ 373-88-6 ]
[ 79-04-9 ]
[ 170655-44-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: With tert-butyl methyl ether; sodium hydroxide In water at 20℃; for 0.5 h; Stage #2: at 5 - 10℃; for 1 h;	To a 500 ml four-necked flask, 30.4 g (759.3 mmol) of sodium hydroxide and 50 g of water were added, dissolved at room temperature, and then cooled to 5 ° C. A solution prepared by dissolving 50 g (370.4 mmol) of 2,2,2-trifluoroethylamine hydrochloride in 60 g of water was added dropwise thereto at 5 ° C. After 85 g of tert-butyl methyl ether was added and stirred for 30 minutes, a solution of 43.9 g (388.9 mmol) of chloroacetyl chloride dissolved in 15 g of tert-butyl methyl ether was added dropwise while keeping at 5 ° C. The reaction solution was heated to 10 ° C. and stirred for 1 hour. After disappearance of 2,2,2-trifluoroethylamine was confirmed by gas chromatography, the temperature was raised to room temperature and liquid separation was carried out. The aqueous layer was extracted with 100 g of tert-butyl methyl ether, the organic layers were combined, the solvent was distilled off under reduced pressure to adjust the liquid volume, and 2-chloro-N- (2,2,2-trifluoroethyl) acetamide Of a tert-butyl methyl ether solution was obtained. As a result of the internal standardization by high performance liquid chromatography, the yield was 65 g, the yield was 100percent, and the concentration was 25.1 wtpercent. The melting point of 2-chloro-N- (2,2,2-trifluoroethyl) acetamide taken out by dropping the obtained solution in heptane and crystallizing it was 53.8 ° C. (DSC).

Reference： [1] Patent: JP5652628, 2015, B2, . Location in patent: Paragraph 0057
[2] Inorganic Chemistry, 2018, vol. 57, # 17, p. 11252 - 11263
[3] Chemical Communications, 2016, vol. 52, # 96, p. 13885 - 13888

[ 373-88-6 ] Synthesis Path-Downstream 1~88

1
[ 354-38-1 ]
[ 373-88-6 ]
[ 407-37-4 ]

Reference： [1]Journal of Organic Chemistry,1954,vol. 19,p. 391,399

2
[ 590-28-3 ]
[ 373-88-6 ]
[ 819-60-3 ]

Reference： [1]Journal of medicinal chemistry,1963,vol. 6,p. 669 - 681
[2]Journal of the American Chemical Society,2019,vol. 141,p. 12657 - 12662

3
[ 373-88-6 ]
N-aminoiminomethyl-N'-ethyl-thiourea-carbonate [ No CAS ]
C₆H₁₂F₃N₅ [ No CAS ]

Reference： [1]Patent: US3960949,1976,A

4
[ 373-88-6 ]
[ 707-71-1 ]

Reference： [1]Tetrahedron, Supplement,1963,vol. 4,p. 131 - 135

5
[ 373-88-6 ]
[ 461-38-1 ]

Reference： [1]Tetrahedron, Supplement,1963,vol. 4,p. 131 - 135

6
[ 373-88-6 ]
[ 2108-48-7 ]

Reference： [1]Monatshefte fur Chemie,1965,vol. 96,p. 388 - 395
[2]Journal of general chemistry of the USSR,1964,vol. 34,p. 1404 - 1405
Zhurnal Obshchei Khimii,1964,vol. 34,p. 1401 - 1403

7
[ 373-88-6 ]
[ 624-83-9 ]
[ 692-10-4 ]

Reference： [1]Journal of medicinal chemistry,1963,vol. 6,p. 669 - 681

8
[ 1121-76-2 ]
[ 373-88-6 ]
[ 74415-03-5 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions II,1980,p. 741 - 748

9
[ 463-71-8 ]
[ 373-88-6 ]
[ 79652-02-1 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 3942 - 3948

10
[ 141-53-7 ]
[ 373-88-6 ]
[ 34005-37-3 ]

Reference： [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 1046 - 1052

11
[ 85230-69-9 ]
[ 373-88-6 ]
[ 129662-25-5 ]

Reference： [1]Carbohydrate Research,1990,vol. 200,p. 111 - 126

12
[ 373-88-6 ]
3,7-Dichloro-2,4,6,8-tetrakis-(2,2,2-trifluoro-ethyl)-9-oxa-2,4,6,8-tetraaza-1,3,5,7-tetraphospha-bicyclo[3.3.1]nonane 1,3,5,7-tetraoxide [ No CAS ]

Reference： [1]Phosphorus, Sulfur and Silicon and the Related Elements,1990,vol. 51/52,p. 946

13
[ 373-88-6 ]
2,4,6-Trichloro-1,3,5-tris-(2,2,2-trifluoro-ethyl)-[1,3,5,2,4,6]triazatriphosphinane 2,4,6-trioxide [ No CAS ]

Reference： [1]Phosphorus, Sulfur and Silicon and the Related Elements,1989,vol. 41,p. 399 - 404

14
[ 373-88-6 ]
[ 103-72-0 ]
1-Phenyl-3-(2,2,2-trifluoro-ethyl)-thiourea [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 957 - 961

15
(2,2'-bis-methoxymethoxy-[1,1']binaphthalenyl-3-yl)-acetaldehyde [ No CAS ]
[ 373-88-6 ]
[ 863555-90-2 ]

Reference： [1]Tetrahedron Letters,2005,vol. 46,p. 5377 - 5381

16
(5S,8S,11S,14S,17S)-14-(2-Carbamoyl-1,2-dihydroxy-ethyl)-21-hydroxy-17-((R)-1-hydroxy-ethyl)-8-hydroxymethyl-11-isopropyl-3,6,9,12,15,18,22-heptaoxo-5-[(2-oxo-propionylamino)-methyl]-1,4,7,10,13,16,19-heptaaza-cyclodocosane-2-carboxylic acid [ No CAS ]
[ 373-88-6 ]
14-(2-carbamoyl-1,2-dihydroxy-ethyl)-21-hydroxy-17-(1-hydroxy-ethyl)-8-hydroxymethyl-11-isopropyl-3,6,9,12,15,18,22-heptaoxo-5-[2-(2,2,2-trifluoro-ethylamino)-propionylamino]-methyl}-1,4,7,10,13,16,19heptaaza-cyclodocosane-2-carboxylic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 3748 - 3752

17
[ 2208-07-3 ]
[ 373-88-6 ]
[ 790644-59-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate; In dichloromethane; water; for 0.5h;	Ethyl acetimidate hydrochloride (1.23 g, 9.95 mtnol) and 2,2,2- trifluoroethylamine hydrochloride (1.35 g, 9.95 mmol) were dissolved in CH2CI2 (32 mL) / H2O (3.2 mL). K2CO3 (0.69 g, 4.98 mmol) was added and stirred for 30 minutes. The two layers were separated. The aqueous layer was extracted with CH2Cl2 (2 x 10 mL). The combined organic layer was dried with Na2SO4 and concentrated to give 1.48 g of N-(2,2,2-Trifluoro-ethyl)-acetimidic acid ethyl ester as a light yellow liquid in 87% yield.

Reference： [1]Patent: WO2008/5565,2008,A2 .Location in patent: Page/Page column 211-212; 254

18
[ 1003043-76-2 ]
[ 373-88-6 ]
[ 1003042-16-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 50℃; for 16h;	(6-bromo-2-methylthio)-quinazolin-4-yl)-(2,2,2-t?Yluoro-ethyl)-amine: ; Diisopropylethylamine (1.6 ml, 9.25 mmol) was added to a solution of 6-bromo-4- chloro-2-(methylthio)-quinazoline and <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (752 mg, 5.55 mmol) in THF. The reaction was heated at 50 0C for 16 hours. After cooling to room temperature, the reaction was diluted with EtOAc and washed with brine twice. The organic layer was dried with sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column on silica gel (Rf: 0.3, 5% of EtOAc / Hexane). The yield was 62.5% for the two steps. The product was characterized as follows: MS (m/z) 352 [M+H]+; HPLC Rf = 2.97 minutes (Method B)

Reference： [1]Patent: WO2008/9078,2008,A2 .Location in patent: Page/Page column 77-78

19
[ 301665-15-6 ]
[ 373-88-6 ]
3-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-N-(2,2,2-trifluoroethyl)benzamide [ No CAS ]

Reference： [1]Patent: EP1180514,2002,A1 .Location in patent: Example 33

20
9-[2-[4-(2-cyclohexyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)-piperazin-1-yl]-ethyl]-9H-fluorene-9-carboxylic acid [ No CAS ]
[ 373-88-6 ]
2-cyclohexyl-6-[4-[2-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]ethyl]-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one [ No CAS ]

Reference： [1]Patent: EP1180514,2002,A1 .Location in patent: Example 127

21
9-allyloxy-9H-fluorene-9-carboxylic acid [ No CAS ]
[ 373-88-6 ]
9-allyloxy-9H-fluorene-9-carboxylic acid (2,2,2-trifluoroethyl)amide [ No CAS ]

Reference： [1]Patent: EP1180514,2002,A1 .Location in patent: Example 132

22
[ 218952-61-5 ]
[ 373-88-6 ]
[ 218952-62-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine; 1,1'-carbonyldiimidazole; In dichloromethane; at 40℃; for 48h;	To a suspension of N,N'-carbonyldiimidazole (69 g, 426 mmol) and <strong>[373-88-6]2,2,2-trifluoro-ethylamine hydrochloride</strong> (71 g, 527 mmol) in dichloromethane (500 mL) was added triethylamine (76 mL, 544 mmol) at about 0 C. dropwise. The reaction was then warmed to room temperature and stirred at room temperature for about 30 minutes. A solution of the title compound of Example Five, Step B (57 g, 170 mmol) in dichloromethane (100 mL) was then added, and the reaction was heated to about 40 C. and then stirred for approximately 2 days. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was then extracted twice with dichloromethane. The combined organic layers were extracted twice with water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give crude product. Purification by silica gel chromatography using 1:9 to 1:2 to 1:1 ethyl acetate/hexanes as eluent afforded the title compound of Example Five, Step C (68.3 g, 94%) as an amorphous solid: +APCI MS (M+H)+ 429; 1H NMR=400 MHz (CDCl3) delta: 8.4 (arom, d, 1H), 7.54 (arom, t, 1H), 7.12 (arom, t, 1H), 7.04 (arom, d, 1H), 4.16-4.00 (CF3CH2, m, 2H), 3.41 (PyrCH2, Abq, 2H), 1.50 (Boc, s, 9H).

Reference： [1]Patent: US6657063,2003,B1 .Location in patent: Page column 89

23
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-5-methoxyindoline-2(R/S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-5-methoxyindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 23

24
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-5-trifluoromethoxyindoline-2(R/S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-5-trifluoromethoxyindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 25

25
1-(N-t-Butoxycarbonyl-2-(S)-aminobutyril)-4,5-dichloroindoline-2-(R/S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2-(S)-aminobutyril)-4,5-dichloroindoline-2-(R/S)-carboxylic acid 2,2,2-trifluoroethyl amide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 30

26
1-(N-t-Butoxycarbonyl-2-(S)-aminobutyryl)-4,5-dichloroindoline-2-(S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2-(S)-aminobutyril)-4,5-dichloroindoline-2-(S)-carboxylic acid trifluoroethyl amide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 28

27
1-(N-t-Butoxycarbonyl-2-(S)-aminobutyril)-5,6-dichloroindoline-2-(S)-carboxylic [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2-(S)-aminobutyril)-5,6-dichloroindoline-2-(S)-carboxylic acid trifluoroethyl amide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 28

28
[ 230291-63-1 ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2-(S)-aminobutyril)-benz-[e]-indoline-2-(S)-carboxylic acid trifluoroethylamide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 29

29
1-(N-t-Butoxycarbonyl-2-(S)-aminobutyril)-benz-[f]-indoline-2-(S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2-(S)-aminobutyril)-benz-[f]-indoline-2-(S)-carboxylic acid 2,2,2-trifluoroethylamide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 32

30
1(N-t-Butoxycarbonyl-2(S)-phenylalanyl)-5-cloroindoline-2-(R/S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1(N-t-Butoxycarbonyl-2(S)-phenylalanyl)-5-chloroindoline-2-(R/S)-carboxylic acid 2,2,2-trifluoroethylamide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 32

31
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-4-methoxyindoline-2(S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-4-methoxyindoline-2(S)-carboxylic acid 2,2,2-trifluoroethylamide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 33

32
1-(N-t-Butoxycarbonyl-2(S)-alanyl)-5-chloroindoline-2(R/S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2(S)-alanyl)-5-chloroindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 34

33
1-(N-t-Butoxycarbonyl-2(S)-norvalyl)-5-chloroindoline-2(R/S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2(S)-norvalyl)-5-chloroindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 35

34
1-(N-t-Butoxycarbonyl-2(S)-methionyl)-5-chloroindoline-2(R/S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2(S)-methionyl)-5-chloroindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 11

35
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-4-methylindoline-2(R/S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-4-methylindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 36

36
1-(N-t-Butoxycarbonyl-2-(S)-aminobutyril)-4,5-dimethoxyindoline-2-(R/S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2-(S)-aminobutyril)-4,5-dimethoxyindoline-2-(R/S)-carboxylic acid (2,2,2-trifluoroethyl) amide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 37

37
1-(N-t-Butoxycarbonyl-2-(S)-aminobutyril)-4,5-methylenedioxyindoline-2-(R/S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2-(S)-aminobutyril)-4,5-methylenedioxyindoline-2-(R/S)-carboxylic acid (2,2,2-trifluoroethyl) amide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 38

38
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-4-chloroindoline-2(S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl )-4-chloroindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 19

39
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-4-fluoroindoline-2(S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-4-fluoroindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 21

40
1-(N-t-Butoxycarbonyl-2-glycyl)-5-chloroindoline-2(R/S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2-glycyl)-5-chloroindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 34

41
[ 230291-30-2 ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-5-chloroindoline-2(S)-carboxylic acid (2,2,2-trifluoroethyl)amide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 11

42
1-(N-Benzyloxycarbonyl-2(S)-aminobutyryl)-indoline-2(S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-Benzyloxycarbonyl-2(S)-aminobutyryl)-indoline-2(S)-carboxylic acid (2,2,2-trifluoroethyl)amide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 15

43
[ 230291-40-4 ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-5-benzyloxyindoline-2(R/S)-carboxylic acid (2,2,2-trifluoro)ethylamide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 29

44
1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)-5-benzyloxyindoline-2(S)-carboxylic acid [ No CAS ]
[ 373-88-6 ]
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-5-benzyloxyindoline-2(R/S)-carboxylic acid (2,2,2-trifluoro)ethylamide [ No CAS ]

Reference： [1]Patent: US6335360,2002,B1 .Location in patent: Page column 17

45
[ 221043-16-9 ]
[ 373-88-6 ]
[ 221042-31-5 ]

Reference： [1]Patent: US6339089,2002,B2 .Location in patent: Example 56

46
[ 209737-88-2 ]
[ 373-88-6 ]
[1S-[1α,2β,3β,4α(1S*,2R*)]]-2,3-dihydroxy-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)-cyclopentanecarboxamide [ No CAS ]

Reference： [1]Patent: US6369064,2002,B1 .Location in patent: Example 33

47
dimethyl-2-[(2-formyl-4-hydroxyphenyl)methyl]butanedioate [ No CAS ]
[ 373-88-6 ]
[ 779349-65-4 ]

Reference： [1]Patent: WO2004/89890,2004,A2 .Location in patent: Page 26

48
dimethyl (2S)-2-[(2-formyl-4-hydroxyphenyl)methyl]butanedioate [ No CAS ]
[ 373-88-6 ]
[ 1027930-43-3 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of (S)-2- (2-formyl-4-hydroxy-benzyl)-succinic acid dimethyl ester in CH3CN (259 g of solution, 15.4 % w/w assay, 40.0 g (S)-2- (2-formyl-4-hydroxy-benzyl)- succinic acid dimethyl ester, 0.14 mol), TRIFLUOROETHYLAMINE-HCL (23.0 g, 1.2 eq, 0.17 mol) and ZnCl2 (9.5 g, 0.5 eq, 0.07 mol) was heated to reflux for 2 hours in a 1L round bottom flask, equipped with a Dean-Stark trap and condenser. A total of 80 ml of solvent was collected in the Dean-Stark trap. After cooling to room temperature, a solution of 65.7 g NaBH (OAC) 3 (2.2 eq, 0.31 mol) in 200 ML DMF was slowly added, with stirring. Stirring was continued for 15 minutes at RT. The pH of the solution was adjusted to 6-6.5 by adding 400 mL saturated NAHCO3 solution. The resulting solution was extracted with 200 mL EtOAc (2X), the combined EtOAc extracts were filtered and concentrated. Toluene (200 ML) was added and the resulting mixture was concentrated by rotary evaporation. Repeat. The resulting residue was dissolved in 300 ML toluene and 8 mL TFA, and resulting solution was heated to reflux for 24 hours, then cooled to RT. The reaction solution was concentrated by rotary evaporation, then diluted with 200 mL EtOAc, washed with 200 ML saturated NAHC03 (2X), then concentrated to minimum volume by rotary evaporation. Toluene (200 mL) was added to the residue, then 200 mL was removed from solution by rotary evaporation. Tolune (100 ML) was added, followed by removal of 50 ML solvent by rotary evaporation. The resulting mixture was cooled to 0 C for 0.5 hour and the solid material was filtered through a Buchner funnel and dried. The product may be dried to constant weight in a vacuum oven at 60 C. YIELD = 34. 0g (72%).

Reference： [1]Patent: WO2004/89890,2004,A2 .Location in patent: Page 27; 34-35

49
[ 373-88-6 ]
[ 871553-67-2 ]

Yield	Reaction Conditions	Operation in experiment
74%		To a solution of thionyl chloride (15 mL) was added Intermediate K (495 mg, 1.73 mmol) which was heated at 50 C for 3 h. Upon cooling to rt the reaction mixture was concentrated to dryness chasing with THF. The reaction mixture was then diluted with <strong>[373-88-6]2,2,2-trifluoro-ethylamine hydrochloride</strong> salt (587 mg, 4.33 mmol) and triethylamine (1.15 ml, 8.66 mmol) in THF (8 mL) and stirred at rt overnight. The solution was rotavapped to dryness, diluted with EtOAc (50 mL), transferred to a separatory funnel, and washed with water (50 mL). The water layer was back extracted with EtOAc (4 x 20 mL), dried (Na2S04), filtered, and concentrated to dryness. Then it was triturated with EtOAc/MeOH. The product was collected to afford 490 mg of the above. compound as a yellow solid (yield 74%). (at)H-NMR (DMSO-d6) No. 8.77 (t, J = 6.2 Hz, 1H), 8.29 (s, 1H), 8.23 (d, J = 8.9 Hz, 2H), 7.97 (s, 1H), 7.59 (d, J = 8.9 Hz, 2H), 3.97 to 3.91 (m, 2H) ; MS [M+H](at) = 381.1; LCMS RT = 2.33 min).

Reference： [1]Patent: WO2005/121147,2005,A1 .Location in patent: Page/Page column 84; 85

50
[ 866923-60-6 ]
[ 373-88-6 ]
[ 866923-59-3 ]

Yield	Reaction Conditions	Operation in experiment
	With tetraethylammonium iodide; tetraethylammonium bromide; N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; for 96h;	Step 1. Preparation of 1-(2-(2,2,2-trifluoroethoxy) ethyl)-3- ((2,2,2-trifluoroethylamino)methyl)-5-chloro- N-(pyrimidin-4-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine; 5-Chloro-3-(chloromethyl)-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d] pyrimidin-7-amine (610 mg, 1.5 mmol), trifluoroethylamine hydrochloride (390 mg, 2.9 mmol) and N, N-diisopropylethylamine (410 mg, 3.2 mmol) along with tetraethylammonium bromide ( 1 mg) and tetraethylammonium iodide were mixed in dimethyl sulfoxide (10 ml) in a reaction vial. The reaction mixture was stirred for two days at room temperature and a second quantity of trifluoroethylamine hydrochloride ( 390 mg, 2.9 mmol) and N, N-diisopropyl- ethylamine (410 mg, 3.2 mmol) were added and the reaction allowed to proceed for another two days. The reaction mixture was partitioned between ethyl acetate ( 70 mLs) and water ( 2 x 25 mLs) and the organic layer dried (Na2S04) and concentrated to an oil that solidified on standing. This intermediate was used without further purification. MS ES+ [MH] + m/z (relative intensity): 485.1(100), 486.1(10), 487.1(20).

Reference： [1]Patent: WO2005/97799,2005,A1 .Location in patent: Page/Page column 145

51
[ 373-88-6 ]
[ 1018988-77-6 ]

Yield	Reaction Conditions	Operation in experiment
		E. Preparation of 3-oxo-1-(2,2,2-trifluoroethylcarbamoyl)cyclopentanecarboxylic acid ethyl ester.; [Show Image] Isobutyl chloroformate (0.49 mL, 0.00378 mole) is added to a solution of 3-oxo-cyclopentane-1,1-dicarboxylic acid ethyl ester (0.75 g, 0.00375 mole) and N-methyl-morpholine (0.62 mL., 0.0056 mole) in tetrahydrofuran (10 mL) at -10 to -15C temperature. Stir the reaction mixture at -10 to -15C for 1 h, triethyl amine (0.78 mL, 0.0056 mole) and <strong>[373-88-6]2,2,2-trifluroethylamine hydrochloride</strong> (0.51 g, 0.00377 mole) are added. The reaction mixture is slowly brought to room temperature and stirred at room temperature for 1.5 h. It is then quenched with water (5 mL) and extracted with ethyl acetate (2x15 mL). Combined organic extracts are washed with saturated sodium bicarbonate solution and dried over anhydrous sodium sulphate. Removal of solvent under reduced pressure yields a viscous liquid which is purified by column chromatography (silica gel 230-400 mesh, hexane:ethyl acetate 1:1) to get 3-oxo-1-(2,2,2-trifluoroethylcarbamoyl)cyclopentanecarboxylic acid ethyl ester.

Reference： [1]Patent: EP1650186,2006,A1 .Location in patent: Page/Page column 19

52
1-(4-chloro-phenyl)-2-pyridin-4-yl-ethane-1,2-dione [ No CAS ]
[ 373-88-6 ]
[ 83-38-5 ]
4-[5-(4-Chloro-phenyl)-2-(2,6-dichloro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-imidazol-4-yl]-pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium acetate; acetic acid; at 100℃; for 4h;	Example 25 4-[5-(4-Chloro-phenyl)-2-(2,6-dichloro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-imidazol-4-yl]-pyridine A mixture of 1-(4-chloro-phenyl)-2-pyridin-4-yl-ethane-1,2-dione (122 mg, 0.5 mmol), 2,6-dichloro-benzaldehyde (88 mg, 0.5 mmol), <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (339 mg, 2.5 mmol), ammonium acetate (192 mg, 2.5 mmol), and acetic acid (2.5 mL), was heated to 100 C. for 4 h. The cooled reaction mixture was diluted with water and then extracted with ethyl acetate (40 mL). The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using dichloromethane/methanol/acetic acid (95:4:1, v/v/v) as eluent. The more polar product was collected and crystallized from ethyl acetate/hexane to give the title compound (57 mg) as white solid. MS (ISP) 482.2 [(M+H)+]; mp 213-214 C.

Reference： [1]Patent: US2006/173048,2006,A1 .Location in patent: Page/Page column 11

53
[ 208660-70-2 ]
[ 373-88-6 ]
[ 182439-20-9 ]

Yield	Reaction Conditions	Operation in experiment
		c. 9-allyl-9H-fluorene-9-carboxylic Acid-(2,2,2-trifluoro-ethyl)-amide Prepared analogously to Example 1 from 9-allyl-9H-fluorene-9-carboxylic acid chloride and 2,2,2-trifluoroethylamine-hydrochloride. Yield: 1.65 g (66.9% of theory), Melting point: 81 C.

Reference： [1]Patent: US2003/166637,2003,A1

54
[ 2905-24-0 ]
[ 373-88-6 ]
[ 214210-12-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	a (N-2,2,2-Trifluoroethyl)-3-bromobenzenesulfonic acid amide 3-Bromobenzenesulfonyl chloride (1.27 g) was added to a stirred solution of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (0.8 g) and triethylamine (1.7 ml) in tetrahydrofuran (30 ml) and the resulting mixture was stirred for 20 hours at room temperature. The reaction mixture was concentrated and the residue partitioned between ether (20 ml) and 2M hydrochloric acid (30 ml). The mixture was separated and the aqueous layer extracted with ether and the combined extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hexane to afford the sub-title compound as a solid (0.60 g). m.p. 98-99 C. MS (GC) 317, 319 (M)+ 1H NMR (CDCl3) 8.02 (1H, t); 7.81 (1H, ddd); 7.74 (1H, ddd); 7.42 (1H, t); 4.95 (1H, t); 3.71 (2H, m).

Reference： [1]Patent: US6300352,2001,B1

55
[ 373-88-6 ]
[ 122-01-0 ]
[ 26930-21-2 ]

Yield	Reaction Conditions	Operation in experiment
81.7%	With triethylamine; In toluene;	EXAMPLE 1 Preparation of N-(2,2,2-Trifluoroethyl)-4-Chlorobenzamide Using Triethylamine as the Base STR24 A mixture of 4-chlorobenzoyl chloride (64.6 g, 0.37 mol) and <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (50.0 g, 0.37 mol) in toluene is treated with triethylamine (80.9 g, 0.8 mol) at such a rate that the temperature is kept below 40 C. The reaction mixture is stirred overnight at room temperature and diluted with water and ethyl acetate. The organic layer is separated, washed with water and concentrated in vacuo to obtain a residue. The residue is crystallized from heptane to give the title product as a white solid (71.9 g, 81.7% yield, mp 108-111 C.) which is identified by 1 H and 19 F NMR.
81.7%	With triethylamine; In toluene;	EXAMPLE 1 Preparation of N-(2,2,2-Trifluoroethyl)-4-chlorobenzamide Using Triethylamine as the Base STR24 A mixture of 4-chlorobenzoyl chloride (64.6 g, 0.37 mol) and <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (50.0 g, 0.37 mol) in toluene is treated with triethylamine (80.9 g, 0.8 mol) at such a rate that the temperature is kept below 40 C. The reaction mixture is stirred overnight at room temperature and diluted with water and ethyl acetate. The organic layer is separated, washed with water and concentrated in vacuo to obtain a residue. The residue is crystallized from heptane to give the title product as a white solid (71.9 g, 81.7% yield, mp 108-111 C.) which is identified by 1 H and 19 F NMR.
81.7%	With triethylamine; In toluene;	EXAMPLE 1 Preparation of N-(2,2,2-Trifluoroethyl)-4-chlorobenzamide Using Triethylamine as the Base STR24 A mixture of 4-chlorobenzoyl chloride (64.6 g, 0.37 mol) and <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (50.0 g, 0.37 mol) in toluene is treated with triethylamine (80.9 g, 0.8 mol) at such a rate that the temperature is kept below 40 C. The reaction mixture is stirred overnight at room temperature and diluted with water and ethyl acetate. The organic layer is separated, washed with water and concentrated in vacuo to obtain a residue. The residue is crystallized from heptane to give the title product as a white solid (71.9 g, 81.7% yield, mp 108-111 C.) which is identified by 1 H and 19 F NMR.

Reference： [1]Patent: US5965773,1999,A
[2]Patent: US6011161,2000,A
[3]Patent: US5817834,1998,A

56
[ 2905-62-6 ]
[ 373-88-6 ]
[ 122-01-0 ]
N-(2,2,2-trifluoroethyl)-3,5-dichlorobenzamide [ No CAS ]
[ 26930-21-2 ]

Yield	Reaction Conditions	Operation in experiment
95.5%	With sodium carbonate; In n-heptane; water; toluene;	EXAMPLE 2 Preparation of N-(2,2,2-Trifluoroethyl)-4-Chlorobenzamide Using Sodium Carbonate as the Base STR26 A mixture of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (100.0 g, 0.74 mol) and sodium carbonate (169.4 g, 1.6 mol) in a 1:1 toluene and water mixture is treated with 4-chlorobenzoyl chloride (129.2 g, 0.74 mol) over 30 minutes as the temperature rises to 38 C., stirred for one hour, and diluted with ethyl acetate and water. The aqueous phase is separated and extracted with ethyl acetate. The organic phases are combined, washed with water, concentrated in vacuo and treated with heptane. The crystalline solids are filtered and dried to give the title product as a white solid (175.8 g, 100% yield, mp 108.5-112 C.). Using essentially the same procedure, but substituting 3,5-dichlorobenzoyl chloride for 4-chlorobenzoyl chloride, N-(2,2,2-trifluoroethyl)-3,5-dichlorobenzamide is obtained as a white solid, mp 145-147 C., 95.5% yield.
95.5%	With sodium carbonate; In n-heptane; water; toluene;	EXAMPLE 2 Preparation of N-(2,2,2-Trifluoroethyl)-4-chlorobenzamide Using Sodium Carbonate as the Base STR26 A mixture of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (100.0 g, 0.74 mol) and sodium carbonate (169.4 g, 1.6 mol) in a 1:1 toluene and water mixture is treated with 4-chlorobenzoyl chloride (129.2 g, 0.74 mol) over 30 minutes as the temperature rises to 38 C., stirred for one hour, and diluted with ethyl acetate and water. The aqueous phase is separated and extracted with ethyl acetate. The organic phases are combined, washed with water, concentrated in vacuo and treated with heptane. The crystalline solids are filtered and dried to give the title product as a white solid (175.8 g, 100% yield, mp 108.5-112 C.). Using essentially the same procedure, but substituting 3,5-dichlorobenzoyl chloride for 4-chlorobenzoyl chloride, N-(2,2,2-trifluoroethyl)-3,5-dichlorobenzamide is obtained as a white solid, mp 145-147 C., 95.5% yield.
95.5%	With sodium carbonate; In n-heptane; water; toluene;	EXAMPLE 2 Preparation of N-(2,2,2-Trifluoroethyl)-4-chlorobenzamide Using Sodium Carbonate as the Base STR26 A mixture of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (100.0 g, 0.74 mol) and sodium carbonate (169.4 g, 1.6 mol) in a 1:1 toluene and water mixture is treated with 4-chlorobenzoyl chloride (129.2 g, 0.74 mol) over 30 minutes as the temperature rises to 38 C., stirred for one hour, and diluted with ethyl acetate and water. The aqueous phase is separated and extracted with ethyl acetate. The organic phases are combined, washed with water, concentrated in vacuo and treated with heptane. The crystalline solids are filtered and dried to give the title product as a white solid (175.8 g, 100% yield, mp 108.5-112 C.). Using essentially the same procedure, but substituting 3,5-dichlorobenzoyl chloride for 4-chlorobenzoyl chloride, N-(2,2,2-trifluoroethyl)-3,5-dichlorobenzamide is obtained as a white solid, mp 145-147 C., 95.5% yield.

Reference： [1]Patent: US5965773,1999,A
[2]Patent: US6011161,2000,A
[3]Patent: US5817834,1998,A

57
[ 109-02-4 ]
[ 104062-70-6 ]
[ 373-88-6 ]
[ 198084-18-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; In 1,1-dichloroethane;	Step C N-(2,2,2,-Trifluoroethyl)-2(S)-(tert-butoxycarbonylamino)-hexanamine 2,2,2-Trifluoroethylamine hydrochloride (0.407 g, 3.0 mmol) was dissolved in dichloroethane under nitrogen. N-Methyl morpholine (0.330 mL, 3.0 mmol) was added to obtain pH 5-6, and sodium triacetoxyborohydride (0.795 g, 3.75 mmol) was added. A solution of the product from Step B (0.573 g, 2.5 mmol) in dichloroethane (80 mL) was added slowly dropwise at 20 C. The reaction was stirred overnight, then quenched with saturated sodium bicarbonate solution. The aqueous layer was removed, the organic phase washed with saturated brine and dried over magnesium sulfate. The title compound was obtained as an oil.

Reference： [1]Patent: US5972942,1999,A

58
[ 127957-66-8 ]
[ 373-88-6 ]
7-(2,2,2-Trifluoroethylamino)-4-oxo-2-(2-propoxyphenyl)-3.4-dihydropyrimido[4,5-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; chloroform;	EXAMPLE 63 7-(2,2,2-Trifluoroethylamino)-4-oxo-2-(2-propoxyphenyl)-3.4-dihydropyrimido[4,5-d]pyrimidine A solution of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.72 g), <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (0.97 g) and triethylamine (0.73 g) in dichloromethane (15 ml) was stirred at ambient temperature for 48 hours and allowed to stand for 4 days. A yellow solid had formed which was collected by filtration and washed with dichloromethane. The filtrate was washed with dilute hydrochloric acid (15 ml) then water (10 ml) and the aqueous layers extracted with dichloromethane (2*7.5 ml). The combined organic layers were dried (magnesium sulphate) and evaporated under reduced pressure to yield a crude product. This was eluted from a silica column with diethyl ether:chloroform (4:1) and the combined fractions containing product were evaporated under reduced pressure to yield a residue which was recrystallized from isopropanol to yield the title compound, 0.13 g, m.p. 214-215.5 C.

Reference： [1]Patent: US6060477,2000,A

59
[ 373-88-6 ]
[ 104214-40-6 ]
N-(2,2,2-trifluoroethyl)-4-methyl-3-oxo-4-aza-5α-androstane-17β-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	EXAMPLE 2 N-(2,2,2-trifluoroethyl)-4-methyl-3-oxo-4-aza-5alpha-androstane-17beta-carboxamide [(I): X=single bond; Y=single bond; B=bond; R=CH3; R1 =H; R2 =H; R3 =H; R4 =F; R5 =F; A=F] To a suspension of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (948.5 mg) in anhydrous tetrahydrofuran (10 ml), triethylamine (0.973 ml) was added. After stirring for 15 min at room temperature, solid 2-pyridyl 4-methyl-3-oxo-4-aza-5alpha-androstane-17beta-carbothioate (426 mg) was added and the mixture was heated to reflux for 4 hours. The volatiles were removed under vacuum and the crude was purified by flash chromatography on silica gel (eluent: ethylacetate/methylene chloride 20:1) to yield 330 mg of the title compound (m.p. 242-244 C.). NMR (CDCl3) delta: 6:5.65 (m, 1H, NH), 4.5-3.5 (m, 2H, CH2 CF3), 3.1 (dd, 1H, H(5alpha)), 2.9 (s, 3H, N--CH3), 0.87 (S, 3H, CH3 (19)) 0.67 (s, 3H, CH3 (18)). Elemental analysis Calculated for C22 H33 F3 N2 O2: C 63.75%, H 8.02%, N 6.76%. Found: C 63.44%, H 7.78%, N 6.67%.

Reference： [1]Patent: US5407939,1995,A

60
[ 373-88-6 ]
[ 136598-92-0 ]
[ 145942-35-4 ]

Yield	Reaction Conditions	Operation in experiment
	With chlorine; triethylamine;	Working Example 27 Using bis[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]disulfide (3.0 g), chlorine (0.47 g), <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (2.15 g) and triethylamine (4.04 ml), substantially the same reaction as in Working Example 15 was allowed to proceed to give N-(2,2,2-trifluoroethyl)-[ (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butane]sulfenamide (Compound 38) as a crude product.

Reference： [1]Patent: US5389663,1995,A

61
[ 110-52-1 ]
[ 79-37-8 ]
[ 1989-33-9 ]
[ 373-88-6 ]
[ 182428-72-4 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; triethylamine; In tetrahydrofuran; hexane; dichloromethane; ethyl acetate; N,N-dimethyl-formamide;	9-[4-[4-(Benzoylamino)-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride STR546 To a solution of 9-fluorenecarboxylic acid (50 g, 240 mmol) in THF (1200 mL) at 0 C. was added dropwise a solution of n-butyllithium (2.5M, 211 mL, 530 mmol) in THF. The yellow reaction was stirred at 0 C. for 1 h, then 1,4-dibromobutane (31.3 mL, 260 mmol) was added dropwise over 30 min. The reaction was stirred at 0 C. for 30 min, then the reaction was warmed to RT for 30 h. The reaction was extracted with water (3750 mL). The combined aqueous layers were extracted with ethyl ether (800 mL). The aqueous layer was made acidic with HCl solution (1N, 500 mL), then extracted with dichloromethane (3750 mL). The combined organic layers were dried over MgSO4. Evaporation gave title compound (71 g, 85%) as a white solid. STR547 To a solution of Part A acid (60 g, 173 mmol) and DMF (100 muL) in CH2 Cl2 (600 mL) under argon at 0 C. was added oxalyl chloride (104 mL, 2.0M in CH2 Cl2, 208 mmol) dropwise. The reaction was stirred at 0 C. for 10 min, then warmed to RT and stirred for 1.5 h. The reaction was concentrated in vacuo to give the crude acid chloride as a yellow oil. To a suspension of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (25.9 g, 191 mmol) in CH2 Cl2 (500 mL) at 0 C. under argon was added triethylamine (73 mL, 521 mmol) followed by dropwise addition of a solution of the crude acid chloride in CH2 Cl2 (15 mL). The reaction was stirred at 0 C. for 1 h, diluted with CH2 Cl2 (500 mL), and washed with water (2300 mL), 1N HCl (2300 mL), saturated NaHCO3 (2300 mL), and brine (2300 mL), then dried over MgSO4. Evaporation gave 80 g of a oil which was purified by flash chromatography on silica gel (2.5 kg). The crude product was loaded in a mixture of CH2 Cl2 and hexane, and eluted with a step gradient of 10% EtOAc/hexane (4 L) to 15% EtOAc/hexane (2 L) to 20% EtOAc/hexane (4 L). Pure fractions were combined and evaporated to give title compound (52.5 g, 71%) as a white solid (mp 88-92 C.).

Reference： [1]Patent: US5739135,1998,A

62
[ 79-37-8 ]
[ 1989-33-9 ]
[ 23418-85-1 ]
[ 373-88-6 ]
9-[4-[5-(benzoylamino)-2-pyridinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; triethylamine;N,N-dimethyl-formamide; In tetrahydrofuran; dichloromethane; ethyl acetate;	EXAMPLE 274 9-[4-[5-(Benzoylamino)-2-pyridinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide STR281 Butyllithium (12.6 mL, 31.5 mmmol) was added dropwise over 5 min to a solution of 9-fluorenecarboxylic acid (3.0 g, 14.3 mmol) in THF (150 mL) at 0 C. under argon. The reaction went cloudy during addition, then cleared upon completion. The reaction was stirred at 0 C. for 30 min, then 3-butynyl p-toluenesulfonate (9.6 g, 42.9 mmol) was added dropwise. The amber reaction was warmed to RT, then stirred for 24 h. The reaction solution was extracted with water (275 mL). The combined aqueous layers were washed with Et2 O (50 mL), then acidified with 1N HCl (30 mL). The cloudy mixture was extracted with CH2 Cl2 (250 mL), and the combined organic layers were dried over MgSO4. Evaporation gave 1.85 g of a crude orange gummy solid. A portion (1.75 g) of crude acid product was dissolved in CH2 Cl2 (20 mL) under argon. A catalytic amount of DMF (26 muL, 0.33 mmol) was added, followed by oxalyl chloride (5.0 mL, 2.0M in CH2 Cl2, 10 mmol) slowly. After bubbling for a few minutes, the reaction was stirred at RT for 1.5 h, then concentrated in vacuo. The crude acid chloride was dissolved in CH2 Cl2 (20 mL) and added dropwise to a suspension of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (1.08 g, 8.02 mmol) and triethylamine (2.8 mL, 20 mmol) in CH2 Cl2 (30 mL) at 0 C. under argon. The reaction was stirred at 0 C. for 10 min, diluted with CH2 Cl2 (50 mL), washed with 1N HCl (2*20 mL) and saturated NaHCO3 (20 mL), then dried over Na2 SO4. Evaporation gave 2.24 g of a dark orange semi-solid, which was dissolved in 2:1 CH2 Cl2:10% EtOAc/hexane and purified by flash chromatography on silica gel (175 g) eluding with 10% EtOAc/hexane to provide title compound (1.16 g, 22%) as a yellow solid (mp 109-113 C.).

Reference： [1]Patent: US5760246,1998,A

63
[ 79-37-8 ]
[ 1989-33-9 ]
[ 373-88-6 ]
[ 626-87-9 ]
9-[4-[4-[[(1,1-Dimethylethoxy)carbonyl]amino]-1-piperidinyl]pentyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; sodium iodide; potassium carbonate; triethylamine; citric acid; In tetrahydrofuran; methanol; dichloromethane; ethyl acetate; N,N-dimethyl-formamide; butanone;	9-[4-[4-[[(1,1-Dimethylethoxy)carbonyl]amino]-1-piperidinyl]pentyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide STR686 To a solution of 2.50 g (11.9 mmol) of 9-fluorenecarboxylic acid in 25 mL of THF under argon (evacuated and purged with argon three times) at -10 C., was added 10.0 mL of n-butyllithium (25.0 mmol, 2.5M in hexanes) over 10 min. A thick slurry formed initially followed by a yellow solution. After 40 min, 2.05 mL (15.0 mmol) of 1,4-dibromopentane was added. The reaction was allowed to warm to room temperature. After 60 h, the reaction was quenched with 10% citric acid solution and extracted twice with ethyl acetate. The organic extract was dried (MgSO4) and evaporated. Trituration of the residue in ethyl acetate/hexanes gave title compound as a white solid, 3.72 g, 87%. STR687 To a stirred solution of 1.80 g (ca. 5.0 mmol) of Part A compound in 10 mL of dichloromethane at room temperature under argon was added 0.65 mL of oxalyl chloride (7.5 mmol) followed by DMF (100 muL). After 1 h, the resulting solution was evaporated at less than 30 C. and the residue was then redissolved in 15 mL of dichloromethane. This solution was added to a solution of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (820 mg, 6.0 mmol) and 2.1 mL of triethylamine (15 mmol in 20 mL of dichloromethane under argon at 0 C. After 1 h, the reaction was quenched with 10% citric acid solution and extracted twice with ethyl acetate. The extracts were combined, dried (MgSO4) and evaporated. The crude product was dissolved in 25 mL of 2-butanone, 7.7 g (52 mmol) of sodium iodide was added and the reaction mixture was set to reflux for 48 h under argon. The solution was cooled, evaporated and the residue partitioned between ethyl acetate and 10% sodium bisulfite solution. The organic extract was dried (MgSO4) and evaporated. Purfication by flash chromatography on silica gel (515 cm column, 3:7 hexanes/dichloromethane as elutant) provided title compound as a white solid, 1.42 g, 58% yield, mp 102-106 C. STR688 A solution of Part B compound (1.27 g, 2.60 mmol), Example 1 Part B amine (680 mg, 3.38 mmol) and potassium carbonate (420 mg, 3.0 mmol) in 5 mL of DMF at room temperature under argon was heated to 50 C. After 15 h, the reaction was quenched with water, decanted and the oily residue extracted twice with ethyl acetate. The extracts were combined, washed once with water, once with saturated sodium bicarbonate solution, dried (Na2 SO4) and evaporated. Purification by flash chromatography on silica gel (515 cm column, 1:99 methanol/ethyl acetate as elutant) provided title compound as a white solid, 1.20 g, 82% yield, mp 58-60 C. Anal. Calcd for C31 H40 F3 N3 O3 +0.25 H2 O: C, 66.00; H, 7.24; F, 10.18; N, 7.45. Found: C, 66.00; H, 7.14; F, 10.39; N, 7.60. MS (electrospray, +ions) m/e 560.3 (M+H).

Reference： [1]Patent: US5739135,1998,A

64
[ 887003-23-8 ]
[ 373-88-6 ]
4-chloro-6-methyl-10,10-dioxo-2-[2-(2,2,2-trifluoro-ethylamino)-acetylamino]-10,11-dihydro-5-oxa-10λ6-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;	Example 135k:4-Chloro-6-methyl- 10, 10-dioxo-2-[2-(2,2,2-trifluoro-ethylamino)-acetylamino]-l 0, 11 - dihydro-5-oxa-l 01ambda6-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester; Anhydrous pottasium carbonate was added with stirring to a solution of 2,2,2- trifluoroethyl amine hydrochloride (0.256g, 1.88mmol) and Example 133 (0.7g, 1.57mmol) in dry DMF (1OmL). The reaction mixture was stirred at 5O0C overnight, concentrated, treated with water and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, methanol /chloroform) to obtain the title compound as a white solid. Yield: 0.28Og, (35%); 1H NMR (DMSO-d6):delta 2.67 (s, 3H, CH3), 3.83-3.87 (m, 2H, CH2), 3.88 (s, 3H, OCH3), 4.66 (s, 2H, CH2), 5.38 EPO <DP n="194"/>(s, 2H, CH2), 7.70 (s, IH, Ar), 7.88 (s, IH, Ar), 8.15 (s, IH, Ar), 8.18 (s, IH, Ar), 8.28 (t, IH, NH), 10.26 (s, IH, NH); MS: m/e (ES+) 506(M+l).

Reference： [1]Patent: WO2006/51476,2006,A1 .Location in patent: Page/Page column 191-192

65
[ 373-88-6 ]
[ 10191-60-3 ]
N-cyano-N'-(2,2,2-trifluoroethyl)-S-methylisothiourea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethanol;	(a) N-Cyano-N'-(2,2,2-trifluoroethyl)-S-methylisothiourea A mixture of 8.0 g (0.055 moles) of dimethyl N-cyanodithioiminocarbonate, of 8.1 g (0.060 moles) of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> and of 6.0 g (0.059 moles) of triethylamine in 75 ml of ethanol is heated to 40 C. for 7 hours. A release of methyl mercaptan is produced. 3.7 g (0.027 moles) of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> and 2.7 g (0.027 moles) of triethylamine are then added to the reaction mixture and heating to 40 C. is continued for 4 hours. The same quantities of reactants are added again and heating to 40 C. is continued for 3 more hours. After cooling, a very slight precipitate is removed by filtration. The filtrate is concentrated to dryness under reduced pressure. The residue is washed with water and recrystallized from ethanol. Yld: 4.9 g (45%), mp=151-153 C. Percentage analysis: C5 H6 F3 N3 S (FW=197.18)

Reference： [1]Patent: US5001134,1991,A

66
[ 115466-95-0 ]
[ 373-88-6 ]
1,1,1-trifluoro-2-[4-(2,2,2-trifluoroethoxy)phenyl]-5-(3-phenoxyphenyl)pentane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrafluoroboric acid; sodium nitrite; In chloroform; water;	EXAMPLE 34 This Example illustrates the preparation of 1,1,1-trifluoro-2-[4-(2,2,2-trifluoroethoxy)phenyl]-5-(3-phenoxyphenyl)pentane. A solution of 1,1,1-trifluoro-2-(4-hydroxyphenyl)-5-(3-phenoxyphenyl)pentane (0.5 g) and tetrafluoroboric acid (0.1 cm3) in chloroform was contained in a conical flask fitted with a side arm leading to a trap containing acetic acid. In a second reaction vessel, diazo-2,2,2-trifluoroethane was generated by the dropwise addition of a solution of sodium nitrite (0.99 g) in water (8 cm3) to a cooled solution (0 C.) of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (1.76 g) in water (8 cm3). The generated diazo compound (a pale yellow gas) was passed into the chloroform solution of the phenol by means of a slow stream of nitrogen passed from the diazo compound generated into the chloroform solution by way of an inlet tube fitted in a rubber bung in the neck of the conical flask. In view of the explosive nature of the diazo compound, no ground glass joints were used in the connected apparatus. This method of diazo compound generation is similar to that described in Anal. Chem. (1982), 54, 529- 533. Following the addition of the diazo compound, both the aqueous and chloroform solutions from the two reaction vessels were cautiously quenched with excess acetic acid. The chloroform solution was washed with water, then with saturated sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure gave an oil containing only 3% of the required product (gas liquid chromatographic analysis). Purification by chromatography on silica gel eluding with hexane containing 1% ethyl acetate gave the pure title compound in low overall yield (0.009 g). 1 H NMR (CDCl3) delta (ppm): 1.45 (2H, m); ca 1.8, 2.0 (each 1H, broad m); 2.56 (2H, m); 3.16 (1H, broad m); 4.33 (2H, q); 6.7-7.4 (13H, m).

Reference： [1]Patent: US4791139,1988,A

67
[ 108-97-4 ]
[ 373-88-6 ]
[ 101234-96-2 ]

Yield	Reaction Conditions	Operation in experiment
	In pyridine;	REFERENCE EXAMPLE 25 1-(2,2,2-Trifluoroethyl)-4-pyridone 1 g (10.4 mmol) of 4H-pyran-4-on was dissolved in 10 ml of pyridine, 3.38 g (25 mmol) of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> was added, and reacted at 70° C. for an hour. The solvent was removed, and the residue was purified by chloroform-methanol (10:1) silica gel chromatograph to obtain 1.7 g of the title compound. NMR (DMSO-d6) delta: 5.50-5.70 (2H ABq J=9 Hz), 7.45 (2H d J=8 Hz), 8.73 (2H d J=8 Hz).
	In pyridine;	Reference Example 25 1-(2,2,2-Trifluoroethyl)-4-pyridone 1 g (10.4 mmol) of 4H-pyran-4-on was dissolved in 10 ml of pyridine, 3.38 g (25 mmol) of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> was added, and reacted at 70oC for an hour. The solvent was removed, and the residue was purified by chloroform - methanol (10:1) silica gel chromatograph to obtain 1.7 g of the title compound. NMR (DMSO-d6) delta: 5.50-5.70 (2H ABq J=9Hz), 7.45 (2H d J=8Hz), 8.73 (2H d J=8Hz).

Reference： [1]Patent: US4785090,1988,A
[2]Patent: EP153709,1991,B1

68
[ 84544-45-6 ]
[ 373-88-6 ]
[ 541-41-3 ]
[ 497-19-8 ]
[ 110-16-7 ]
N-(2,2,2-trifluoroethyl)-5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]valeronitrile maleate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; ethyl acetate;	EXAMPLE 37 To a suspension of 5-[4-(2-[2,2,2-trifluoroethyl)guanidino)pyrimid-2-yl]valeric acid (0.25 g.) in freshly distilled THF (10 ml.) was added triethylamine (0.093 g.) with ice cooling. After stirring 15 minutes, ethyl chloroformate (0.095 g.) was added dropwise and stirred 30 minutes at 0. Further triethylamine (0.093 g.) was added, followed by <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (0.124 g.), and the mixture was stirred at 0 for 30 minutes, then allowed to come to room temperature. After evaporation in vacuo, aqueous sodium carbonate solution was added and the mixture extracted with EtOAc. The extract was dried (MgSO4) filtered and evaporated in vacuo to give an oil which was dissolved in a small volume of EtOAc and excess of a solution of maleic acid in EtOAc added. Addition of ether, with scratching, caused a colourless solid to precipitate. This was collected and recrystallized from EtOAc to give N-(2,2,2-trifluoroethyl)-5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]valeronitrile maleate. 0.25H2 O, m.p. 135-140.

Reference： [1]Patent: US4447441,1984,A

69
ammonium thiocyanate [ No CAS ]
[ 373-88-6 ]
[ 62-56-6 ]
2,2,2-trifluoroethylthiourea hydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water;	The isothiourea used as starting material may be prepared as follows: A solution of ammonium thiocyanate (9.12 g.), and <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (13.6 g.) in water (50 ml.) was heated at 100 for 20 hours. Water (50 ml.) was added and the mixture reheated to redissolve the solid. On cooling crystals of 2,2,2-trifluoroethylthiourea hydrate, m.p. 154-156 (52.4%), were precipitated.

Reference： [1]Patent: US4447441,1984,A

70
2-guanidino-4-(3-aminocyclohexyl)thiazole [ No CAS ]
[ 373-88-6 ]
[ 88681-68-9 ]
2-guanidino-4-{3-[3-(2,2,2-trifluoroethyl)thioureido]cyclohexyl}thiazole hydrogen maleate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide; triethylamine; In tetrahydrofuran; methanol; chloroform; acetone;	EXAMPLE 34 To a solution of 2-guanidino-4-(3-aminocyclohexyl)thiazole (0.5 g.) in tetrahydrofuran (20 ml.) was added thiocarbonyldiimidazole (0.4 g.) in tetrahydrofuran (15 ml.) in portions over 15 minutes. After 30 minutes at room temperature the solvent was evaporated and the residue partitioned between ethyl acetate (100 ml.) and water (20 ml.). The organic layer was separated, washed with water (20 ml.) and dried (magnesium sulphate) concentrated to small volume and petroleum ether (b.p. 40-60) added whereupon crystals of the 2-guanidino-4-(3-isothiocyantocyclohexyl)thiazole were deposited (0.35 g.). To this material in methanol (5 ml.) was added <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (0.4 g.) and triethylamine (0.4 g.) and the mixture allowed to stand at room temperature in a stoppered vessel for 2 days. The residue obtained on evaporation of the solvent was partitioned between ethyl acetate (100 ml.) and 2 N hydrochloric acid (20 ml.) and the ethyl acetate layer separated, washed with water (2*20 ml.), dried (magnesium sulphate) and evaporated. The residue was subjected to preparative thin layer chromatography on Merck 60 F-254 plates using chloroform/methanol/aqueous ammonia (s.g. 0.88) 80:20:01 v/v/v for development. The appropriate zone of the chromatogram was isolated and extracted with hot ethanol/chloroform 50:50 v/v (200 ml.) and the extract evaporated to give a gummy residue. This residue was dissolved in acetone (1 ml.) and to the solution was added an excess of maleic acid in ether. The white amorphous solid which precipitated collected, and washed with ether to give 0.12 g. of 2-guanidino-4-{3-[3-(2,2,2-trifluoroethyl)thioureido]cyclohexyl}thiazole hydrogen maleate, m.p. 148-150.

Reference： [1]Patent: US4342765,1982,A

71
[ 51535-00-3 ]
[ 373-88-6 ]
[ 6674-22-2 ]
5-Oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidine carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; dichloromethane;	5-Oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidine carboxamide A mixture of 21.9 g (0.10 mole) methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate in 150 ml tetrahydrofuran, was cooled to 0 C. in an ice bath under nitrogen and 24.3 g (0.15 mole) carbonyl diimidazole was added. The reaction was stirred at 0 C. for 30 minutes, then at room temperature for 30 minutes. A solution of 13.6 g (0.10 mole) of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong>, 15.2 g (0.10 mole) 1,8-diazabicyclo[5.4.0]undec-7-ene and 100 ml tetrahydrofuran was added. The reaction was stirred at room temperature overnight. The solvent was removed at reduced pressure. The residue was taken up in dichloromethane and washed 3*150 ml saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure. The product was purified by column chromatography on silica with ethyl acetate to give 8.50 g of 5-oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinecarboxamide, mp 110-112

Reference： [1]Patent: US4822801,1989,A

72
ethyl-m-[N,N-di(N-hexadecyl)aminomethyl]-thiobenzimidate dihydrochloride [ No CAS ]
[ 373-88-6 ]
[ 63290-52-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	With hydrogenchloride; sodium acetate; In 1,4-dioxane; chloroform; acetic acid;	EXAMPLE 28 m-[N,N-Di(n-hexadecyl)aminomethyl]-N-(2,2,2-trifluoroethyl)-benzamidine Ethyl-m-[N,N-di(n-hexadecyl)aminomethyl]-thiobenzimidate dihydrochloride (1.074 g., 1.5 mmoles) was added to a slurry of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (406 mg., 3.0 mmoles) and anhydrous sodium acetate (246 mmoles) in chloroform (10 ml.) and glacial acetic acid (0.3 ml., 5.3 mmoles). The mixture was held for 12 hours at room temperature. It was then diluted to 300 ml. with chloroform, washed with saturated aqueous sodium bicarbonate solution (2 * 50 ml.), washed with saturated aqueous sodium chloride solution (2 * 50 ml.), dried (Na2 SO4) and filtered. The filtrate was acidified with a 10% solution of anhydrous hydrogen chloride in dioxane (5 ml.) and then evaporated in vacuo to a foam. The foam was crystallized from 1,2-dimethoxyethane [974 mg., 86% yield, Rf 0.39 (4:1, benzene:ethanol on silicic acid), m.p.-forms a gel at 125-127 C.].

Reference： [1]Patent: US4025555,1977,A

73
[ 16694-46-5 ]
[ 7732-18-5 ]
[ 373-88-6 ]
ethyl N-(2,2,2-trifluoroethyl)formimidate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dichloromethane;	EXAMPLE 45 Ethyl N-(2,2,2-trifluoroethyl)formimidate Ethyl formimidate hydrochloride (0.555 g, 5 mmole), <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (0.677 g, 5 mmole) and potassium carbonate (0.345 g, 2.5 mmole) are suspended in 20 ml CH2 Cl2 and treated with 1 ml H2 O. The mixture is shaken vigorously for 3 minutes. The organic phase is separated and the aqueous extracted twice with 10 ml portions of CH2 Cl2. The combined organic phase is dried and the CH2 Cl2 distilled through a Vigreauxe column to give the Ethyl N-(2,2,2-trifluoroethyl)formimidate. n.m.r. delta1.333 t (CH3 CH2); 3.8 q (j=10 c.p.s., CF3 CH2) 4.23 q (j=7.5, CH3 CH2 O); 7.6 S (H--C=N).
	With potassium carbonate; In dichloromethane;	EXAMPLE 45 Ethyl N-(2,2,2-trifluoroethyl)formimidate Ethyl formimidate hydrochloride (0.555 g, 5 mmole), <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (0.677 g, 5 mmole) and potassium carbonate (0.345 g, 2.5 mmole) are suspended in 20 ml CH2 Cl2 and treated with 2 ml H2 O. The mixture is shaken vigorously for 3 minutes. The organic phase is separated and the aqueous extracted twice with 10 ml portions of CH2 Cl2 The combined organic phase is dried and the CH2 Cl2 distilled through a Vigreauxe column to give the Ethyl N-(2,2,2-trifluoroethyl)formimidate. n.m.r. delta1.33 t (CH3 CH2); 3.8 q (j=10 c.p.s., CF3 CH2) 4.23 q (j=7.5, CH3 CH2 O); 7.6 S (H-C=N).

Reference： [1]Patent: US4232030,1980,A
[2]Patent: US4194047,1980,A

74
[ 177759-47-6 ]
[ 373-88-6 ]
N-(2,2,2-trifluoroethyl)-2-benzyloxy-5-bromobenzylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In diethyl ether; dichloromethane;	The starting material was prepared as follows: A mixture of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (68 g), diethyl ether (500 ml) and 40% aqueous sodium hydroxide solution (55 ml) was shaken together. The organic layer was dried (MgSO4), added to 2-benzyloxy-5-bromobenzylbromide (17.0 g) in dichloromethane (100 ml) and left to stand in a closed flask for 72 hours. The solvent was evaporated, the residue partitioned between diethyl ether and 2N aqueous sodium hydroxide. The organic layer was removed, dried (MgSO4) and evaporated to give N-(2,2,2-trifluoroethyl)-2-benzyloxy-5-bromobenzylamine (17.5 g) as a yellow oil.

Reference： [1]Patent: US5843942,1998,A

75
[ 15761-38-3 ]
[ 373-88-6 ]
[ 916176-69-7 ]

Yield	Reaction Conditions	Operation in experiment
78%		Boc-Ala-OH (14.24 g, 75.3 mmol), HOBT (1.35 g, 10 mmol), EDC (17.3 g, 90.4 mmol) and <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (10.2 g, 75.3 mmol) were dissolved in DMF (100 mL) using a water bath to maintain temperature. After the solids dissolved, triethylamine (20 mL, 150 mmol) was added and the resulting heterogeneous mixture stirred at room temperature overnight. The mixture was poured into ethylacetate (350 mL), washed with IN HCl and brine then dried over Na2SO4. The solvent was removed under reduced pressure and the resulting oil dissolved in methanol (50 mL) and 2M HCl in ether (95 mL) then heated at 5O0C for 0.5 hours. The solvent was removed and the residue dried at 450C under vacuum to afford 12.2 g (78% yield) of the title compound (FF) as a white solid. FIA for C5H9F3N2O: 170.9 ES+.

Reference： [1]Patent: WO2006/127587,2006,A1 .Location in patent: Page/Page column 103-104

76
[ 15761-38-3 ]
[ 373-88-6 ]
[ 934178-98-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 16h;	As shown in Figure 2-step i), to a stirred solution of the compound of formula IV, where R is a methyl group with the ^-configuration (Boc-L-alanine, compound 1006, 3.8 g, 0.02 mol), EDC (4.63 g, 0.024 mol), etaOBt (4.0 g, 0.026 mol), DIEA (10.5 mL, 0.06 mol) in 100 mL of DCM was added trifluoroethylamine HCl (2.92 g, 0.022 mol). The reaction mixture was stirred for 16 hours. The volatiles were removed in vacuo and the resulting residue dissolved in EtOAc, washed successively with 0.5N HCl, saturated aqueous solution of NaHCO3, and brine. The organics were dried (Na2SO4) and concentrated in vacuo to give a compound of formula V, where R1 is CH3 (tert-butyl (S)- 1 -(2,2,2- EPO <DP n="43"/>trifluoroethylcarbamoyl) ethylcarbamate, compound 1007) as a white solid (5.4 g, 98% yield), 1H-NMR (CDCl3): delta 6.9 (bs, IH); 4.9 (bs, IH); 4.1 (bs, IH); 3.8 (bs, 2H); 1.4 (s, 9H); 1.3 (d, 3H).
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane;	Example 1; Preparation of Compounds of the Invention; General Synthetic Schemes Compounds of formula F may be prepared as outlined in Scheme I using methods previously described in WO2005/095400.Specifically, compounds of formulae A and C as well as R7R8NH-HCl may be obtained commercially or prepared by one having ordinary skill in the art. Compounds of formula E and/or R3-B(OR27)2 may be obtained commercially or prepared by one having ordinary skill in the art, such as described in the cited references in Table 2. Further derivatives of R3 or other substituents may be made using known methods.; Compounds 1-32 and 59-168 were prepared according to Scheme I.

Reference： [1]Patent: WO2007/41130,2007,A2 .Location in patent: Page/Page column 41-42
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 7195 - 7216
[3]Patent: US2010/160287,2010,A1 .Location in patent: Page/Page column 42; 44

77
[ 934179-13-2 ]
[ 373-88-6 ]
[ 934179-14-3 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 20h;	As shown in Figure 9-step iv, compound 1043 (143 mg, 0.56 mmol),<strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (83 mg, 0.62 mmol), HOBT (83 mg, 0.62 mmol), EDC (119 mg, 0.62 mmol), and DIEA (0.22 mL, 1.2 mmol) were dissolved in about 5 mL of DMF. After stirring at rt for 20 hours, the reaction mixture was diluted with EtOAc (about 25 mL) and washed with water (3x), 0.5 M HCl (aq) (Ix) and brine (Ix). The organics were dried over sodium sulfate and the volatiles removed in vacuo to give crude product, which was treated with ethyl ether/hexanes (approximately 1:1), filtered, and concentrated in vacuo to give compound 1044 (187 mg) as a viscous oil.

Reference： [1]Patent: WO2007/41130,2007,A2 .Location in patent: Page/Page column 54-55; Sheet 9/9

78
C₁₃H₈ClN₅O₃ [ No CAS ]
[ 373-88-6 ]
[ 871553-67-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; for 16h;	A solution 4-amino-5-(4-nitrophenyl)pyrrolo[2,1-f][1 ,2,4]triazine-6-carboxylic acid (495 mg, <n="51"/>1.73 mmol) in thionyl chloride (15 ml_) was heated (50 C) for 3 h. Upon cooling to rt the reaction mixture was concentrated to dryness. The resulting acid chloride intermediate was combined with <strong>[373-88-6]2,2,2-trifluoro-ethylamine hydrochloride</strong> salt (587 mg, 4.33 mmol), triethylamine (1.15 ml, 8.66 mmol), and THF (8 mL). The reaction was stirred for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL) and then washed with water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was tritureated with ethyl acetate and methanol to afford the desired product (490 mg, 74%). 1H-NMR (300 MHz, DMSOd6) delta 8.77 (t, J = 6.2 Hz, 1 H), 8.29 (s, 1 H), 8.23 (d, J = 8.9 Hz, 2 H), 7.97 (s, 1 H), 7.59 (d, J = 8.9 Hz, 2 H), 3.91-3.99 (m, 2 H); ES-MS m/z 381.1 (MH)+; HPLC RT (Method B) 2.33 min.

Reference： [1]Patent: WO2007/64932,2007,A2 .Location in patent: Page/Page column 49-50

79
[ 3744-87-4 ]
[ 373-88-6 ]
[ 934179-15-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 16h;	To a stirred solution of Boc-valine (1; Ri is Me; 3.8 g, 0.02 mol), EDC (4.63 g, 0.024 mol), HOBt (4.0 g, 0.026 mol), DEEA (10.5 mL, 0.06 mol) in 100 mL of DCM is added trifluoroethylamine HCl (2.92 g, 0.022 mol). The reaction mixture is stirred for 16 h. It is concentrated to dryness and redissolved in EtOAc, washed successively with 0.5N HCl, saturated aqueous solution of NaHCO3 and brine. The organic layer is dried (Na2SO_j) and concentrated in vacuo to give 5.4g (98%) of 2 as a white solid.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 16h;	Step 1. N2-ftert-butoxycarbonylVN-(2,2,2-trifluoroethyl)-D-alaninan ideTo a stirred solution of N-(tert-butoxycarbonyl)-D-alanine (5 g, 26.4 mmol), EDC (6.08 g, 31.7 mmol), HOBT (5.26 g, 34.4 mmol), Hunig's base (13.85 ml, 79 mmol) inDichloromethane (132 ml) was added <strong>[373-88-6]2,2,2-trifluoroethanamine hydrochloride</strong> (3.94 g, 29.1 mmol) and the reaction was stirred for 16 h. The mixture was then diluted with dichloromethane and washed with water and brine. The organic layer was dried over magnesium sulfate. The solvent was evaporated and the resulting colorless oil was diluted with benzene and lyophilized under high vacuum to afford title compound as a colorless solid. The material was used directly in the subsequent step without purification.

Reference： [1]Patent: WO2007/84557,2007,A2 .Location in patent: Page/Page column 66-67
[2]Patent: WO2011/137022,2011,A1 .Location in patent: Page/Page column 35-36
[3]Journal of Medicinal Chemistry,2015,vol. 58,p. 7195 - 7216

80
4'-trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(α-(carboxy)-benzyl)-piperazin-1-yl)-phenyl]-amide [ No CAS ]
[ 373-88-6 ]
[ 378230-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	With NaCl; NaHCO3; benzotriazol-1-ol; triethylamine; In dichloromethane;	EXAMPLE 13 4'-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-(alpha-((2,2,2-trifluoroethyl)-aminocarbonyl)-benzyl)-piperazin-1-yl)-phenyl]-amide To a stirred solution of 4'-trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-(alpha-(carboxy)-benzyl)-piperazin-1-yl)-phenyl]-amide (330 mg), <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (86 mg), HOBT (94 mg) and triethylamine (139 mg) in CH2Cl2 (8 mL) was added EDCl (132 mg) and the mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2, and the organic solution was washed with water, then with a saturated solution of NaHCO3, then with a saturated solution of NaCl and dried over Na2SO4. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography eluding with CH2Cl2/MeOH (97/3). After crystallization from diisopropyle oxyde, the title compound was obtained as white crystals (210 mg). m.p.: 206-208 C.

Reference： [1]Patent: US2004/24215,2004,A1

81
[ 30924-93-7 ]
[ 373-88-6 ]
[ 916057-94-8 ]

Reference： [1]Organic and Biomolecular Chemistry,2006,vol. 4,p. 3790 - 3801

82
[ 118-48-9 ]
[ 373-88-6 ]
[ 869629-11-8 ]

Yield	Reaction Conditions	Operation in experiment
51%	With triethylamine; for 16h;	Intermediate 8; 2-Amino-N-(2,2,2-trifluoroethyl)benzamide A round-bottomed flask was charged with isatoic anhydride (5.0 g, 0.030 mol), 15 mL water, and triethylamine (4.69 mL, 0.033 mol). (2,2,2-trifluoroethyl)amine hydrochloride (4.98 g, 0.036 mol) was added slowly to the reaction mixture. After 16 h, the reaction mixture was concentrated to dryness. The crude product was purified silica gel column (EtOAc/Hexanes) to afford the title compound as a white solid (3.42 g, 51%): Mass (M+H)+=120, 219.

Reference： [1]Patent: US2008/182852,2008,A1 .Location in patent: Page/Page column 11

83
[ 1042918-45-5 ]
[ 373-88-6 ]
[ 1042918-49-9 ]

Yield	Reaction Conditions	Operation in experiment
26%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	b) 2-Chloro-9-(tetrahydropyran-2-yl)-6-[3-(2,2,2- trifluoroethyl)aminocarbonylphenyl]-9H-purine <n="120"/>A mixture of the compound obtained in the previous section (420 mg, 1.17 mmol), DIEA (0.92 ml_, 5.26 mmol), <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (476 mg, 3.51 mmol) and HBTU (533 mg, 1.40 mmol) were stirred at room temperature in 30 mL DMF overnight. The mixture was evaporated to dryness and chromatographed over silica gel using Hexane/Ethyl Acetate mixtures of increasing polarity as eluent, to afford the desired compound (26%). LC-MS (method 5): tR = 2.46 min; m/z = 440 (MH+).

Reference： [1]Patent: WO2008/90181,2008,A1 .Location in patent: Page/Page column 118-119

84
[ 373-88-6 ]
[ 75-07-0 ]
[ 1080474-98-1 ]

Yield	Reaction Conditions	Operation in experiment
75%	With hydrogenchloride; sodium hydroxide; sodium borohydrid; triethylamine; In methanol; diethyl ether;	B. Synthesis of N-ethyl-<strong>[373-88-6]2,2,2-trifluoroethanamine hydrochloride</strong> To a solution of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (0.5 g, 3.7 mmol) in MeOH (5 mL) was added triethylamine (0.51 mL, 0.37 mmol) followed by acetaldehyde (1.0 mL, excess). The reaction mixture was then stirred at 0 C. for 3 h. Sodium borohydride (1 g, 5.9 mmol) was then added and the reaction mixture was stirred at 0 C. for 20 min. The reaction was quenched with 1M NaOH (10 mL) and the aqueous layer was extracted with DCM (25 mL). The organic layer was separated and to it was added 2M HCl in Et2O (10 mL). The resultant precipitate was filtered to give 0.45 g of N-ethyl-<strong>[373-88-6]2,2,2-trifluoroethanamine hydrochloride</strong>, (yield: 75%).

Reference： [1]Patent: US2008/280900,2008,A1

85
[ 75-44-5 ]
[ 373-88-6 ]
[ 371-92-6 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane; toluene; at 0 - 35℃;	This reagent was prepared by dissolving 2 , 2 , 2-trifluoroethylamine hydrochloride (1.92 g, 14.1 mmol, 1.0 equiv.) in DCM (28 ml, 0.5 M) in a flame- dried round-bottom flask under a nitrogen atmosphere at 00C. Pyridine (4.5 ml, 4.0 equiv.) was added followed by phosgene (20% solution in toluene, 7.3 ml, 1.0 equiv.). The resulting mixture was stirred for 10 minutes at 00C them warmed to ambient temperature . Stirring was continued for an additional 1 hour at ambient temperature, then an additional 2 hours at 350C, followed by fractional <n="24"/>distillation (isocyanate product boiling point was 6O0C) . The colorless isocyante solution was stored at -200C for one week with no decrease in concentration.

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 7247 - 7249
[2]Patent: WO2009/137691,2009,A2 .Location in patent: Page/Page column 22-23

86
[ 1072433-63-6 ]
[ 373-88-6 ]
[ 1072433-52-3 ]

Yield	Reaction Conditions	Operation in experiment
45%	With N-ethyl-N,N-diisopropylamine; at 160℃; for 0.833333h;Microwave irradiation;	Method E: l-tosyl-4- (2 ,2 , 2-trifluoroethyl) piperazine; <n="40"/>[00123] A mixture of 1- (1, 5-dichloropentan-3-ylsulfonyl) - 4 ) methylbenzene (1.5 g, 5 mmol), trifluoromethylmethylamine HCl salt (1.35 g, 10 mmol) in diisopropylethylamine (15 ml) was stirred at 160 0C in a CEM microwave for 50 minutes. The residue was diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated in diethyl ether. A white solid was collected by filtration (730 mg, 45% yield). 1H NMR (CDCl3, 400 MHz) 2.45(3H, s), 2.82-2.86 (4H, m) , 2.90-3.00 (2H, qd) , 3.01-3.05 (4H, m) , 7.30-7.35 (2H, d) , 7.60-7.65 (2H, d) ; MS (ES+) 323.

Reference： [1]Patent: WO2008/128009,2008,A2 .Location in patent: Page/Page column 38-39

87
C₃₁H₄₀ClNO₃ [ No CAS ]
[ 373-88-6 ]
CDDO-TFEA [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In water; phenol;Heating / reflux;	The various amide derivatives were synthesized by the condensation of CDDO acid chloride with the respective amine hydrochlorides (or free amines) using previously published methods Honda et al. (2002).

Reference： [1]Patent: WO2008/136838,2008,A1 .Location in patent: Page/Page column 27; 35

88
[ 74173-77-6 ]
[ 373-88-6 ]
[ 107-11-9 ]
[ 221042-30-4 ]

Reference： [1]Patent: US6339089,2002,B2 .Location in patent: Example 55

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
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Prevention
Code	Phrase
P201	Obtain special instructions before use.
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P234	Keep only in original container.
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P242	Use only non-sparking tools.
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Code	Phrase
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P321
P322
P330	Rinse mouth.
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P378
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P401
P402	Store in a dry place.
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Ghs Hazard Statements

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