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[ CAS No. 2740-83-2 ] {[proInfo.proName]}

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Chemical Structure| 2740-83-2

Chemical Structure| 2740-83-2

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Quality Control of [ 2740-83-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 2740-83-2 ]

Product Details of [ 2740-83-2 ]

CAS No. :	2740-83-2	MDL No. :	MFCD00008117
Formula :	C₈H₈F₃N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YKNZTUQUXUXTLE-UHFFFAOYSA-N
M.W :	175.15	Pubchem ID :	75962
Synonyms :

Calculated chemistry of [ 2740-83-2 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	39.12
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) :	-5.96 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.74
Log Po/w (XLOGP3) :	1.98
Log Po/w (WLOGP) :	3.16
Log Po/w (MLOGP) :	2.61
Log Po/w (SILICOS-IT) :	2.44
Consensus Log Po/w :	2.39

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.41
Solubility :	0.679 mg/ml ; 0.00388 mol/l
Class :	Soluble
Log S (Ali) :	-2.15
Solubility :	1.23 mg/ml ; 0.00704 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.33
Solubility :	0.0827 mg/ml ; 0.000472 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.2

Safety of [ 2740-83-2 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P301+P330+P331-P302+P352-P304+P340-P305+P351+P338-P310	UN#:	2735
Hazard Statements:	H314	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 2740-83-2 ]

* 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 [ 2740-83-2 ]
Downstream synthetic route of [ 2740-83-2 ]

[ 2740-83-2 ] Synthesis Path-Upstream 1~9

1
[ 368-77-4 ]
[ 2740-83-2 ]

Reference： [1] Applied Organometallic Chemistry, 2018, vol. 32, # 1,
[2] Synlett, 2001, # 10, p. 1623 - 1625
[3] Journal of medicinal chemistry, 1973, vol. 16, # 2, p. 101 - 106
[4] Journal of the American Chemical Society, 1988, vol. 110, # 12, p. 4019 - 4022
[5] Journal of Medicinal Chemistry, 1986, vol. 29, # 7, p. 1302 - 1305

2
[ 402-23-3 ]
[ 227616-77-5 ]
[ 2740-83-2 ]
[ 437761-03-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	With NaH; tetra-(n-butyl)ammonium iodide In tetrahydrofuran; water	(6S)-3-[(Benzyloxy)carbonyl][3-(trifluoromethyl)benzyl]amino}-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (12a) To a mixture of acid 1i (4.50 g, 13.7 mmol) in 70 mL THF at 0° C., was added 3-(trifluoromethyl)benzyl bromide (8.35 mL, 54.7 mmol), NaH (60percent dispersion in oil, 1.64 g, 41.4 mmol), and TBAI (100 mg, catalytic). The reaction was stirred at rt for 15 h, then quenched with the addition of 50 mL H₂O. The volatile solvents were removed by rotary evaporation and the aqueous solution obtained was partitioned with Et₂O. The organic phase was extracted with 20percent sat. NaHCO₃ (3). The combined organic extract was acidified with 1N HCl and extracted with EtOAc (5). The combined organic extract was washed (brine), dried (Na₂SO₄), and concentrated to afford 6.18g (93percent) of the 3-(trifluoromethyl)benzyl amine (12a), which was used in the following step without additional purification.

Reference： [1] Patent: US2003/64962, 2003, A1,

3
[ 368-77-4 ]
[ 2740-83-2 ]
[ 946495-09-6 ]

Reference： [1] ACS Catalysis, 2014, vol. 4, # 7, p. 2191 - 2194

4
[ 454-89-7 ]
[ 2740-83-2 ]

Reference： [1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 39, p. 9306 - 9311

5
[ 368-83-2 ]
[ 2740-83-2 ]

Reference： [1] Journal of Medicinal Chemistry, 1984, vol. 27, # 9, p. 1111 - 1118

6
[ 100-46-9 ]
[ 2740-83-2 ]

Reference： [1] Chemistry - A European Journal, 2017, vol. 23, # 16, p. 3804 - 3809

7
[ 109-73-9 ]
[ 2740-83-2 ]

Reference： [1] Chemistry - A European Journal, 2017, vol. 23, # 16, p. 3804 - 3809

8
[ 2740-83-2 ]
[ 1801-10-1 ]

Reference： [1] Chemistry - A European Journal, 2018, vol. 24, # 5, p. 1067 - 1071

9
[ 2740-83-2 ]
[ 64-19-7 ]
[ 1134915-25-5 ]

Reference： [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 14, p. 3036 - 3039

[ 2740-83-2 ] Synthesis Path-Downstream 1~85

1
[ 368-77-4 ]
[ 2740-83-2 ]

Reference： [1]Applied Organometallic Chemistry,2018,vol. 32
[2]Catalysis science and technology,2019,vol. 9,p. 1779 - 1783
[3]Synlett,2001,p. 1623 - 1625
[4]Journal of medicinal chemistry,1973,vol. 16,p. 101 - 106
[5]Journal of the American Chemical Society,1988,vol. 110,p. 4019 - 4022
[6]Journal of Medicinal Chemistry,1986,vol. 29,p. 1302 - 1305

2
[ 2740-83-2 ]
[ 463-71-8 ]
[ 2740-85-4 ]

Yield	Reaction Conditions	Operation in experiment
84.2%	With sodium hydrogencarbonate; In chloroform; water;	Compound 1 (3.23 g, 20 mmol) was dissolved in 40 mL of chloroform.A mixed solution of 8 g of NaHCO3 and 80 mL of water was added.Slowly add thiophosgene (1.84mL, 24mmol) at 0 Ca solution obtained by dissolving in 40 mL of chloroform,Then continue to react for 1-2 h.The mixture was allowed to stand, and the aqueous layer was extracted with chloroform. The combined organic phases were washed with brine and dried over anhydrous Na? OverFilter, concentrate,Flash column chromatography (CH2Cl2) gave compound 2 (3.43 g, 84.2%) light yellow oily liquid.
45%		General procedure: The amine (e.g. tyramine.HCl 200mg, 1.15mmol, 1 equiv.) in dichloromethane (6mL) with saturated sodium hydrogen carbonate (3mL) or triethylamine (4 equiv.) was stirred at 0C for 5min. Thiophosgene (95muL, 1.2mmol, 1.05 equiv.) was added and the mixture stirred at 0C for 20min then brought to RT and stirred for 2h. Dichloromethane was separated, the aqueous phase was then acidified and extracted with chloroform. The combined organic phases were dried (magnesium sulfate), filtered and concentrated to give the crude product as an orange gum. The crude material was purified using silica gel chromatography 0-5% ethyl acetate in dichloromethane which gave the pure product.
	With triethylamine; In dichloromethane; at 0 - 20℃; for 12h;	General procedure: To a solution of alkylamine (2.96 mmol) and triethylamine (4 eq.) in dichloromethane (15 mL)was added a solution of thiophosgene (1.1 eq.) in dichloromethane (5 mL) slowly at 0 C. Afterthe addition, the reaction mixture was allowed to warm up to room temperature and stirredovernight. After the completion of the reaction, solvent was removed and the crude was filteredthrough a short silica plug using ethyl acetate/hexane (1:4) as eluent to get the desiredalkylisothiocyanate 1-1 which was immediately taken to the next step. To the solution ofalkylthiocyanate 1-1 (2.72 mmol) in diethyl ether (2 mL) was added hydrazine monohydrate (2eq.). The reaction mixture was stirred overnight at room temperature. The product precipitated outof the solution which was filtered, washed with diethyl ether and vacuum dried to afford the desiredthiosemicarbazide 1-2 as white solid.

With sodium hydrogencarbonate; In dichloromethane; water; at 0 - 20℃;

General procedure: a) To a stirred mixture of 3-(trifluoromethyl)aniline (22a, 10.5 g, 60 mmol) and NaHCO3 (25.2 g, 300 mmol) in mixed-solvent of dichloromethane (100 mL) and H2O (200 mL) was dropwise added the solution of thiophosgene (9.660 g, 84 mmol) in dichloromethane (100 mL) at 0 C. Then the mixture was stirred overnight at room temperature (RT). The reaction mixture was stirred overnight at room temperature. After the reaction was complete as monitored by thin layer chromatography (TLC), the reaction mixture was diluted with dichloromethane (300 mL). The resulting solution was washed with H2O (80 mL) and brine (80 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil 23a (8.62 g). The crude product was used in next step without further purification.

Reference： [1]Patent: CN109111408,2019,A .Location in patent: Paragraph 0182-0187
[2]European Journal of Medicinal Chemistry,2015,vol. 93,p. 501 - 510
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 4087 - 4102
[4]Bioscience, Biotechnology and Biochemistry,1992,vol. 56,p. 1062 - 1065
[5]Journal of Heterocyclic Chemistry,2017,vol. 54,p. 2440 - 2446
[6]European Journal of Medicinal Chemistry,2018,vol. 157,p. 1005 - 1016
[7]Bioorganic and medicinal chemistry letters,2020,vol. 30

3
[ 2740-83-2 ]
[ 1004-38-2 ]
[ 50-00-0 ]
[ 79988-63-9 ]

Reference： [1]Journal of Heterocyclic Chemistry,1981,vol. 18,p. 929 - 931

4
[ 2740-83-2 ]
[ 65372-54-5 ]
[ 556-61-6 ]
[ 109-85-3 ]
2,2-Dimethyl-4-[3-methyl-1-(3-trifluoromethyl-benzyl)-thioureido]-chroman-6-carboxylic acid (2-methoxy-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	solid phase synthesis; Yield given. Multistep reaction;

Reference： [1]Breitenbucher, J. Guy; Hui, Hon C. [Tetrahedron Letters, 1998, vol. 39, # 45, p. 8207 - 8210]

5
[ 2740-83-2 ]
[ 151838-62-9 ]
3-(3-trifluoromethyl-benzylcarbamoyl)-3,4-dihydro-1<i>H</i>-isoquinoline-2-carboxylic acid <i>tert</i>-butyl ester [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2001,vol. 36,p. 265 - 286

6
[ 2740-83-2 ]
[ 30418-59-8 ]
[ 90914-41-3 ]
[3-(3-amino-phenyl)-1<i>H</i>-pyrazolo[3,4-<i>d</i>]pyrimidin-4-yl]-(3-trifluoromethyl-benzyl)-amine [ No CAS ]

Reference： [1]Organic Letters,2003,vol. 5,p. 3587 - 3590

7
[ 2740-83-2 ]
[ 132684-59-4 ]
[ 345347-68-4 ]
5-(4-formyl-3,5-dimethoxyphenoxy)valeric aldehyde linker on a polyethylene glycol resin [ No CAS ]
2-butyl-<i>N</i>⁴-hydroxy-<i>N</i>¹-[3-phenyl-1-(3-trifluoromethyl-benzylcarbamoyl)-propyl]-succinamide [ No CAS ]

Reference： [1]Antimicrobial Agents and Chemotherapy,2004,vol. 48,p. 250 - 261

8
[ 2740-83-2 ]
[ 368-77-4 ]

Reference： [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 5992 - 5997
[2]Angewandte Chemie - International Edition,2016,vol. 55,p. 15802 - 15806
Angew. Chem.,2016,vol. 128,p. 16034 - 16038,5

9
[ 2740-83-2 ]
[ 5936-58-3 ]
2-amino-4,5,6,7-tetrahydro-benzo[<i>b</i>]thiophene-3-carboxylic acid 3-trifluoromethyl-benzylamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 2358 - 2365

10
[ 2740-83-2 ]
[ 3338-32-7 ]
[ 512783-76-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	In tetrahydrofuran;	Example 5. General procedure for amide formation from an activated ester derivative. N-Benzyloxycarbonyl-L-aspartic acid (3-t-butyl ester a- (3- trifluoromethyl) benzylamide. A solution of N-benzyloxycarbonyl-L-aspartic acid (3-t-butyl ester a-N-hydroxysuccinimide ester (1.95 g, 4.64 mmol, Advanced ChemTech) in 20 mL of dry tetrahydrofuran was treated with 0. 68 mL (4.74 mmol) of 3- (trifluoromethyl) benzyl amine. Upon completion (TLC, 60: 40 hexanes/ethyl acetate), the mixture was evaporated, and the resulting oil was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The organic laer was evaporated to give 2.23 g (quantitative yield) of the title compound as a white solid; 1H NMR (CDC13) 8 1.39 (s, 9H), 2.61 (dd, J = 6.5 Hz, J = 17.2 Hz, 1H), 2.98 (dd, J = 3.7 Hz, J = 17.0 Hz, 1H), 4.41 (dd, J = 5.9 Hz, J = 15.3 Hz, 1H), 4.50-4. 57 (m, 2H), 5.15 (s, 2H), 5.96-5. 99 (m, 1H), 6.95 (s, 1H), 7.29-7. 34 (m, 5H), 7.39-7. 43 (m, 2H), 7.48-7. 52 (m, 2H).
100%	In tetrahydrofuran;	A solution of N-benzyloxycarbonyl-L-aspartic acid beta-^-butyl ester alpha-N-hydroxysuccinimide ester (1.95 g, 4.64 mmol, Advanced ChemTech) in 20 mL of dry tetrahydrofuran was treated with 0.68 mL (4.74 mmol) of 3-(trifluoromethyl)benzyl amine. Upon completion (TLC, 60:40 hexanes/ethyl acetate), the mixture was evaporated, and the resulting oil was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The organic laer was evaporated to give 2.23 g (quantitative yield) of the title compound as a white solid; 1H NMR (CDCl3) delta 1.39 (s, 9H), 2.61 (dd, J=6.5 Hz, J=17.2 Hz, IH), 2.98 (dd, J=3.7 Hz, J=17.0 Hz, IH), 4.41 (dd, J=5.9 Hz, J=15.3 Hz, IH), 4.50-4.57 (m, 2H), 5.15 (s, 2H), 5.96-5.99 (m, IH), 6.95 (s, IH), 7.29-7.34 (m, 5H), 7.39- 7.43 (m, 2H), 7.48-7.52 (m, 2H).
100%	In tetrahydrofuran;	Example 2. General procedure for amide formation from an activated ester derivative. N-Benzyloxycarbonyl-L-aspartic acid beta--butyl ester oc-(3- trifluoromethyl)benzylamide. A solution of N-benzyloxycarbonyl-L-aspartic acid beta--butyl ester -N-hydroxysuccinimide ester (1.95 g, 4.64 mmol, Advanced ChemTech) in 20 mL of dry tetrahydrofuran was treated with 0.68 mL (4.74 mmol) of 3-(trifluoromethyl)benzyl amine. Upon completion (TLC, 60:40 hexanes/ethyl acetate), the mixture was evaporated, and the resulting oil was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The organic laer was evaporated to give 2.23 g (quantitative yield) of the title compound as a white solid; 1H NMR (CDC13) delta 1.39 (s, 9H), 2.61 (dd, J=6.5 Hz, J=17.2 Hz, IH), 2.98 (dd, J=3.7 Hz, J=17.0 Hz, IH), 4.41 (dd, J=5.9 Hz, J=15.3 Hz, IH), 4.50-4.57 (m, 2H), 5.15 (s, 2H), 5.96-5.99 (m, IH), 6.95 (s, IH), 7.29-7.34 (m, 5H), 7.39- 7.43 (m, 2H), 7.48-7.52 (m, 2H).

100%	In tetrahydrofuran;	Example 2. General procedure for amide formation from an activated ester derivative. N-Benzyloxycarbonyl-L-aspartic acid beta--butyl ester cc-(3- trifluoromethyl)benzylamide. A solution of N-benzyloxycarbonyl-L-aspartic acid beta--butyl ester -N-hydroxysuccinimide ester (1.95 g, 4.64 mmol, Advanced ChemTech) in 20 mL of dry tetrahydrofuran was treated with 0.68 mL (4.74 mmol) of 3-(trifluoromethyl)benzyl amine. Upon completion (TLC, 60:40 hexanes/ethyl acetate), the mixture was evaporated, and the resulting oil was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The organic laer was evaporated to give 2.23 g (quantitative yield) of the title compound as a white solid; 1H NMR (CDC13) delta 1.39 (s, 9H), 2.61 (dd, J=6.5 Hz, J=17.2 Hz, IH), 2.98 (dd, J=3.7 Hz, J=17.0 Hz, IH), 4.41 (dd, J=5.9 Hz, J=15.3 Hz, IH), 4.50-4.57 (m, 2H), 5.15 (s, 2H), 5.96-5.99 (m, IH), 6.95 (s, IH), 7.29-7.34 (m, 5H), 7.39-7.43 (m, 2H), 7.48- 7.52 (m, 2H).
100%	In tetrahydrofuran;	A solution of N-benzyloxycarbonyl-L-aspartic acid beta-t-butyl ester alpha-N-hydroxysuccinimide ester (1.95 g, 4.64 mmol, Advanced ChemTech) in 20 mL of dry tetrahydrofuran was treated with 0.68 mL (4.74 mmol) of 3-(triftuoromethyl)benzyl amine. Upon completion (TLC, 60:40 hexanes/ethyl acetate), the mixture was evaporated, and the resulting oil was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The organic laer was evaporated to give 2.23 g (quantitative yield) of the title compound as a white solid; 1H NMR (CDCl3) delta 1.39 (s, 9H), 2.61 (dd, J = 6.5 Hz, J = 17.2 Hz, 1H), 2.98 (dd, J = 3.7 Hz, J = 17.0 Hz, 1H), 4.41 (dd, J = 5.9 Hz, J = 15.3 Hz, 1H), 4.50-4.57 (m, 2H), 5.15 (s, 2H), 5.96-5.99 (m, 1H), 6.95 (s, 1H), 7.29-7.34 (m, 5H), 7.39-7.43 (m, 2H), 7.48-7.52 (m, 2H).
100%	In tetrahydrofuran;	A solution of N-benzyloxycarbonyl-L-aspartic acid beta-/-butyl ester alpha-N-hydroxysuccmimide ester (1.95 g, 4.64 mmol, Advanced ChemTech) in 20 mL of dry tetrahydrofuran was treated with 0.68 mL (4.74 mmol) of 3 -(t?fluoromethyl)benzyl amine. Upon completion (TLC, 60:40 hexanes/ethyl acetate), the mixture was evaporated, and the resulting oil was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The organic laer was evaporated to give 2.23 g (quantitative yield) of the title compound as a white solid; 1H NMR (CDCl3) delta 1.39 (s, 9H), 2.61 (dd, J=6.5 Hz, J=17.2 Hz, IH), 2.98 (dd, J=3.7 Hz, J=17.0 Hz, IH), 4.41 (dd, J=5.9 Hz, J=15.3 Hz, IH), 4.50-4.57 (m, 2H), 5.15 (s, 2H), 5.96-5.99 (m, IH), 6.95 (s, IH), 7.29-7.34 (m, 5H), 7.39- 7.43 (m, 2H), 7.48-7.52 (m, 2H).
100%	In tetrahydrofuran;	N-Benzyloxycarbonyl-L-aspartic acid f3-t-butyl ester x-(3 - trifluoromethyl)benzylamide. A solution of N-benzyloxycarbonyl-L-aspartic acid 13-t-butyl ester cL-N-hydroxysuccinimide ester (1.95 g, 4.64 mmol, Advanced ChemTech) in 20 mL of drytetrahydrofuran was treated with 0.68 niL (4.74 mmol) of 3-(trifluoromethyl)benzyl amine. Upon completion (TLC, 60:40 hexanes/ethyl acetate), the mixture was evaporated, and the resulting oil was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The organic laer was evaporated to give 2.23 g (quantitative yield) of the title compound as a white solid; ?HNMR (CDC13) oe 1,39 (s, 9H), 2.61 (dd, J6.5 Hz, J17.2Hz, 111), 2.98 (dd, J=3.7 Hz, J=17.0 Hz, 111), 4.41 (dd, J=5.9 Hz, J15.3 Hz, 111), 4.50-4.57 (m,211), 5.15 (s, 2H), 5.96-5.99 (m, 1H), 6.95 (s, 1H), 7.29-7.34 (m, 5H), 7.39-7.43 (m, 2H), 7.48-7.52 (m, 2H).

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 2054 - 2080
[2]Patent: WO2005/35492,2005,A1 .Location in patent: Page/Page column 42
[3]Patent: WO2006/102283,2006,A2 .Location in patent: Page/Page column 23
[4]Patent: WO2012/3436,2012,A1 .Location in patent: Page/Page column 47
[5]Patent: WO2015/148962,2015,A1 .Location in patent: Page/Page column 55
[6]Patent: EP1434763,2018,B1 .Location in patent: Paragraph 0107
[7]Patent: WO2007/109615,2007,A2 .Location in patent: Page/Page column 64
[8]Patent: WO2019/55913,2019,A1 .Location in patent: Page/Page column 55

11
[ 2740-83-2 ]
[ 27869-04-1 ]
[ 951399-49-8 ]

Yield	Reaction Conditions	Operation in experiment
32%	In diethyl ether at 20℃; for 2h;

Reference： [1]Winterwerber, Martin; Geiger, Rouzita; Predoiu, Ursula; Otto, Hans-Hartwig [Monatshefte fur Chemie, 2006, vol. 137, # 11, p. 1441 - 1451]

12
[ 2740-83-2 ]
[ 51644-83-8 ]
[ 512783-86-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 2054 - 2080

13
[ 2740-83-2 ]
[ 71449-08-6 ]
[ 512783-84-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;	Example 11. General procedure for amide formation from a carboxylic acid. N-Benzyloxycarbonyl-D-aspartic acid (3-t-butyl ester a- (3- trifluoromethyl) benzylamide. A solution of 1 g (2.93 mmol) of N-benzyloxycarbonyl-D-aspartic acid P-t-butyl ester monohydrate (Novabiochem) in 3-4 mL of dichloromethane was treated by sequential addition of 0.46 mL (3.21 mmol) of3- (trifluoromethyl) benzylamine, 0.44 g (3.23 mmol) of 1-hydroxy-7-benzotriazole, and 0.62 g (3.23 mmol) of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride. After at least 12 hours at ambient temperature or until complete as determined by thin layer chromatography (95: 5 dichloromethane/methanol eluent), the reaction mixture was washed sequentially with a saturated aqueous sodium bicarbonate solution and with distilled water. The organic layer was evaporated to give 1.41 g (quantitative yield) of the title compound as an off- white solid ;'H NMR (CDC13) 8 1.39 (s, 9H); 2.61 (dd, J = 6.5 Hz, J = 17.2 Hz, 1H); 2.98 (dd, J = 4.2 Hz, J = 17.2 Hz, 1H); 4.41 (dd, J = 5.9 Hz, J = 15.3 Hz, 1H); 4.50-4. 57 (m, 2H); 5.10 (s, 2H); 5.96-6. 01 (m, 1H); 6.91-7. 00 (m, 1H) ; 7.30-7. 36 (m, 5H) ; 7.39-7. 43 (m, 2H); 7.48-7. 52 (m, 2H).
100%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;	A solution of 1 g (2.93 mmol) of N-benzyloxycarbonyl-D-aspartic acid beta-^-butyl ester monohydrate (Novabiochem) in 3-4 mL of dichloromethane was treated by sequential addition of 0.46 mL (3.21 mmol) of 3-(trifluoromethyl)benzylamine, 0.44 g (3.23 mmol) of l-hydroxy-7-benzotriazole, and 0.62 g (3.23 mmol) of l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride. After at least 12 hours at ambient temperature or until complete as determined by thin layer chromatography (95:5 dichloromethane/methanol eluent), the reaction mixture was washed sequentially with a saturated aqueous sodium bicarbonate solution and with distilled water. The organic layer was evaporated to give 1.41 g (quantitative yield) of the title compound as an off-white solid; 1H NMR (CDCl3) delta 1.39 (s, 9H); 2.61 (dd, J=6.5 Hz, J=17.2 Hz, IH); 2.98 (dd, J=4.2 Hz, J=17.2 Hz, IH); 4.41 (dd, J=5.9 Hz, J=15.3 Hz, IH); 4.50-4.57 (m, 2H); 5.10 (s, 2H); 5.96-6.01 (m, IH); 6.91-7.00 (m, IH); 7.30-7.36 (m, 5H); 7.39-7.43 (m, 2H); 7.48-7.52 (m, 2H).
100%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;	A solution of 1 g (2.93 mmol) of N- benzyloxycarbonyl-D-aspartic acid beta-t-butyl ester monohydrate (Novabiochem) in 3- 4 mL of dichloromethane was treated by sequential addition of 0.46 mL (3.21 mmol) of 3-(trifluoromethyl)benzylamine, 0.44 g (3.23 mmol) of l-hydroxy-7-benzotriazole, and 0.62 g (3.23 mmol) of l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. After at least 12 hours at ambient temperature or until complete as determined by thin layer chromatography (95:5 dichloromethane/methanol eluent), the reaction mixture was washed sequentially with a saturated aqueous sodium <n="89"/>bicarbonate solution and with distilled water. The organic layer was evaporated to give 1.41 g (quantitative yield) as an off-white solid; 1H NMR (CDCl3) delta 1.39 (s, 9H); 2.61 (dd, J=6.5 Hz, J=17.2 Hz, IH); 2.98 (dd, J=4.2 Hz, J=17.2 Hz, IH); 4.41 (dd, J=5.9 Hz, J=15.3 Hz, IH); 4.50-4.57 (m, 2H); 5.10 (s, 2H); 5.96-6.01 (m, IH); 6.91- 7.00 (m, IH); 7.30-7.36 (m, 5H); 7.39-7.43 (m, 2H); 7.48-7.52 (m, 2H).

100%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;	Example 6. General procedure for amide formation from a carboxylic acid. N-Benzyloxycarbonyl-D-aspartic acid beta--butyl ester -(3-trifluoromethyl)benzylamide. A solution of 1 g (2.93 mmol) of N-benzyloxycarbonyl-D-aspartic acid beta--butyl ester monohydrate (Novabiochem) in 3-4 mL of dichloromethane was treated by sequential addition of 0.46 mL (3.21 mmol) of 3-(trifluoromethyl)benzylamine, 0.44 g (3.23 mmol) of l-hydroxy-7-benzotriazole, and 0.62 g (3.23 mmol) of l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride. After at least 12 hours at ambient temperature or until complete as determined by thin layer chromatography (95:5 dichloromethane/methanol eluent), the reaction mixture was washed sequentially with a saturated aqueous sodium bicarbonate solution and with distilled water. The organic layer was evaporated to give 1.41 g (quantitative yield) of the title compound as an off-white solid; 1H NMR (CDC13) delta 1.39 (s, 9H); 2.61 (dd, J=6.5 Hz, J=17.2 Hz, IH); 2.98 (dd, J=4.2 Hz, J=17.2 Hz, IH); 4.41 (dd, J=5.9 Hz, J=15.3 Hz, IH); 4.50-4.57 (m, 2H); 5.10 (s, 2H); 5.96-6.01 (m, IH); 6.91-7.00 (m, IH); 7.30-7.36 (m, 5H); 7.39-7.43 (m, 2H); 7.48-7.52 (m, 2H).
100%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;	Example 6. General procedure for amide formation from a carboxylic acid. N- Benzyloxycarbonyl-D-aspartic acid beta--butyl ester -(3-trifluoromethyl)benzylamide. A solution of 1 g (2.93 mmol) of N-benzyloxycarbonyl-D-aspartic acid beta--butyl ester monohydrate (Novabiochem) in 3-4 mL of dichloromethane was treated by sequential addition of 0.46 mL (3.21 mmol) of 3-(trifluoromethyl)benzylamine, 0.44 g (3.23 mmol) of 1-hydroxy- 7-benzotriazole, and 0.62 g (3.23 mmol) of l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. After at least 12 hours at ambient temperature or until complete as determined by thin layer chromatography (95:5 dichloromethane/methanol eluent), the reaction mixture was washed sequentially with a saturated aqueous sodium bicarbonate solution and with distilled water. The organic layer was evaporated to give 1.41 g (quantitative yield) of the title compound as an off-white solid; 1H NMR (CDCI3) delta 1.39 (s, 9H); 2.61 (dd, J=6.5 Hz, J=17.2 Hz, IH); 2.98 (dd, J=4.2 Hz, J=17.2 Hz, IH); 4.41 (dd, J=5.9 Hz, J=15.3 Hz, IH); 4.50-4.57 (m, 2H); 5.10 (s, 2H); 5.96-6.01 (m, IH); 6.91-7.00 (m, IH); 7.30-7.36 (m, 5H); 7.39-7.43 (m, 2H); 7.48-7.52 (m, 2H).
100%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;	A solution of 1 g (2.93 mmol) of N-benzyloxycarbonyl-D-aspartic acid beta-t-butyl ester monohydrate (Novabiochem) in 3-4 mL of dichloromethane was treated by sequential addition of 0.46 mL (3.21 mmol) of 3-(trifluoromethyl)benzylamine, 0.44 g (3.23 mmol) of 1-hydroxy-7-benzotriazole, and 0.62 g (3.23 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. After at least 12 hours at ambient temperature or until complete as determined by thin layer chromatography (95:5 dichloromethane/methanol eluent), the reaction mixture was washed sequentially with a saturated aqueous sodium bicarbonate solution and with distilled water. The organic layer was evaporated to give 1.41 g (quantitative yield) of the title compound as an off-white solid; 1H NMR (CDCl3) delta 1.39 (s, 9H); 2.61 (dd, J = 6.5 Hz, J = 17.2 Hz, 1H); 2.98 (dd, J = 4.2 Hz, J = 17.2 Hz, 1H); 4.41 (dd, J = 5.9 Hz, J = 15.3 Hz, 1H); 4.50-4.57 (m, 2H); 5.10 (s, 2H); 5.96-6.01 (m, 1H); 6.91-7.00 (m, 1H); 7.30-7.36 (m, 5H); 7.39-7.43 (m, 2H); 7.48-7.52 (m, 2H).
100%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;	A solution of 1 g (2.93 mmol) of N-benzyloxycarbonyl-D-aspartic acid beta-/-butyl ester monohydrate (Novabiochem) in 3-4 mL of dichloromethane was treated by sequential addition of 0.46 mL (3.21 mmol) of 3-(trifluoromethyl)benzylamine, 0.44 g (3.23 mmol) of 1 -hydroxy-7-benzotriazole, and 0.62 g (3.23 mmol) of l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. After at least 12 hours at ambient temperature or until complete as determined by thin layer chromatography (95:5 dichloromethane/methanol eluent), the reaction mixture was washed sequentially with a saturated aqueous sodium bicarbonate solution and with distilled water. The organic layer was evaporated to give 1.41 g (quantitative yield) of the title compound as an off-white solid; 1H NMR (CDCl3) delta 1.39 (s, 9H); 2.61 (dd, J=6.5 Hz, J=17.2 Hz, IH); 2.98 (dd, J=4.2 Hz, J=17.2 Hz, IH); 4.41 (dd, J=5.9 Hz, J=15.3 Hz, IH); 4.50-4.57 (m, 2H); 5.10 (s, 2H); 5.96-6.01 (m, IH); 6.91-7.00 (m, IH); 7.30-7.36 (m, 5H); 7.39-7.43 (m, 2H); 7.48-7.52 (m, 2H).
100%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;	Example 11. General procedure for amide formation from a carboxylic acid.N-Benzyloxycarbonyl-D-aspartic acid beta-/-butyl ester alpha-(3- trifluoromethyl)benzylamide. A solution of 1 g (2.93 mmol) of N-benzyloxycarbonyl-D- aspartic acid beta-t-butyl ester monohydrate (Novabiochem) in 3-4 mL of dichloromethane was treated by sequential addition of 0.46 mL (3.21 mmol) of 3-(trifluoromethyl)benzylamine, 0.44 g (3.23 mmol) of l-hydroxy-7-benzotriazole, and 0.62 g (3.23 mmol) of l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. After at least 12 hours at ambient temperature or until complete as determined by thin layer chromatography (95:5 dichloromethane/methanol eluent), the reaction mixture was washed sequentially with a saturated aqueous sodium bicarbonate solution and with distilled water. The organic layer was evaporated to give 1.41 g (quantitative yield) of the title compound as an off-white solid; 1H NMR (CDCl3) delta 1.39 (s, 9H); 2.61 (dd, J = 6.5 Hz, J = 17.2 Hz, IH); 2.98 (dd, J = 4.2 Hz, J = 17.2 Hz, IH); 4.41 (dd, J == 5.9 Hz, J = 15.3 Hz, IH); 4.50-4.57 (m, 2H); 5.10 (s, 2H); 5.96- 6.01 (m, IH); 6.91-7.00 (m, IH); 7.30-7.36 (m, 5H); 7.39-7.43 (m, 2H); 7.48-7.52 (m, 2H).
100%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	N-Benzyloxycarbonyl-D-aspartic acid f3-t-butyl ester u-(3-trifluoromethyl)benzylamide. A solution of 1 g (2.93 mmol) of N-benzyloxycarbonyl-D-aspartic acid f3-t-butyl ester monohydrate (Novabiochem) in 3-4 mL of dichloromethane was treated by sequential additionof 0.46 mL (3.21 mmol) of 3-(trifluoromethyl)benzylamine, 0.44 g (3.23 mmol) of 1 -hydroxy7-benzotriazole, and 0.62 g (3.23 mmol) of 1- [3-(dimethylamino)propylj -3 -ethylcarbodiimide hydrochloride. After at least 12 hours at ambient temperature or until complete as determined by thin layer chromatography (95:5 dichloromethane/methanol eluent), the reaction mixture was washed sequentially with a saturated aqueous sodium bicarbonate solution and with distilled water. The organic layer was evaporated to give 1.41 g (quantitative yield) ot the title compound as an off-white solid; ?H NMR (CDC13) oe 1.39 (s, 9H); 2.61 (dd, J=6.5 Hz, J17.2 Hz, 1H); 2,98 (dd, J4.2 Hz, J17.2 Hz, 1H); 4,41 (dd, J5.9 Hz, J15.3 Hz, 1H); 4,50-4,57 (m, 2H); 5.10 (s, 2H); 5.96-6.01 (m, 1H): 6.91-7.00 (m, ill); 7.30-7.36 (m, 5H); 7.39-7.43 (m, 2H);7.48-7.52 (m, 2H).

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 2054 - 2080
[2]Patent: WO2005/35492,2005,A1 .Location in patent: Page/Page column 44
[3]Patent: WO2006/102283,2006,A2 .Location in patent: Page/Page column 25
[4]Patent: WO2008/34032,2008,A2 .Location in patent: Page/Page column 87-88
[5]Patent: WO2012/3436,2012,A1 .Location in patent: Page/Page column 49
[6]Patent: WO2015/148962,2015,A1 .Location in patent: Page/Page column 57
[7]Patent: EP1434763,2018,B1 .Location in patent: Paragraph 0114
[8]Patent: WO2007/109615,2007,A2 .Location in patent: Page/Page column 66
[9]Patent: WO2007/109098,2007,A2 .Location in patent: Page/Page column 51
[10]Patent: WO2019/55913,2019,A1 .Location in patent: Page/Page column 57; 58

14
[ 2740-83-2 ]
2,2,2-trichloroethyl 2(RS)-(tert-butoxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetate [ No CAS ]
2(R,S)-(tert-butoxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	In tetrahydrofuran;Heating / reflux;	A solution of 0.20 g (0.32 mmol) of Example 17 and 52 muL (0.36 mmol) of (3-trifluoromethylbenzyl)amine in THF was heated at reflux. Upon complete conversion (TLC), the solvent was evaporated and the residue was recrystallized (chloroform/hexane) to give 0.17 g (82%) as a white solid; mp 182- 184 0C.
82%	In tetrahydrofuran;Reflux;	Example 18. 2(RS)-(iert-Butoxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2- on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl] acetic acid N-(3-trifluoromethylbenzyl)amide.; A solution of 0.20 g (0.32 mmol) of Example 17 and 52 muL· (0.36 mmol) of (3- trifluoromethylbenzyl) amine in THF was heated at reflux. Upon complete conversion (TLC), the solvent was evaporated and the residue was recrystallized (chloroform/hexane) to give 0.17 g (82%) of Example 18 as a white solid; mp 182-184 C.
82%	In tetrahydrofuran;Reflux;	Example 18. 2(RS)-(iert-Butoxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on- 3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. A solution of 0.20 g (0.32 mmol) of Example 17 and 52 muL· (0.36 mmol) of (3- trifluoromethylbenzyl) amine in THF was heated at reflux. Upon complete conversion (TLC), the solvent was evaporated and the residue was recrystallized (chloroform/hexane) to give 0.17 g (82%) of Example 18 as a white solid; mp 182-184 C.

Reference： [1]Patent: WO2008/34032,2008,A2 .Location in patent: Page/Page column 96
[2]Patent: WO2012/3436,2012,A1 .Location in patent: Page/Page column 57
[3]Patent: WO2015/148962,2015,A1 .Location in patent: Page/Page column 64
[4]Patent: EP1434763,2018,B1 .Location in patent: Paragraph 0139
[5]Patent: WO2019/55913,2019,A1 .Location in patent: Page/Page column 64

15
[ 2740-83-2 ]
[ 24851-69-2 ]
2-methyl-N-[3-trifluoromethylbenzyl]-1,3-benzothiazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 18h;	2-Methyl-l,3-benzothiazole-5-carboxylic acid (150 mg, 0.660 mmol) was mixed with 3- trifluoromethylbenzylamine (228 mg, 1.30 mmol), EDC (249 mg, 1.30 mmol) and DMAP (158 mg, 1.30 mmol) in DCM (5.00 mL) and DMF (2.00 mL) for 18 hours. The mixture was concentrated, and the product was purified by flash chromatography on silica gel, eluting with mixtures of heptanes and EtOAc (95/5 to 50/50), to yield the product (131 mg, o 0.370 mmol, 57.0%). 1H NMR (600 MHz, MeOD) delta ppm 2.84 (s, 3 H) 4.56 (s, 2 H) 7.43 EPO <DP n="24"/>(s, 2 H) 7.53 (d, J=7.42 Hz, 1 H) 7.56 (s, 1 H) 7.87 (dd, J=8.45, 1.54 Hz, 1 H) 8.01 (d, J=8.45 Hz, 1 H) 8.29 (s, 1 H); MS [M+H] calcd. 351.0, found 351.0.

Reference： [1]Patent: WO2006/68592,2006,A1 .Location in patent: Page/Page column 22-23

16
[ 2740-83-2 ]
[ 1020656-72-7 ]
[ 1020656-15-8 ]

Yield	Reaction Conditions	Operation in experiment
69%		Acylation; CDI (286 mg, 1.76 mmol) was added to a solution of (1.68 mmol) of acid S6 in DCM (27 ml), and the mixture was stirred for 1 h at RT. The corresponding amine (1.68 mmol) was then added, and stirring was continued for a further 16 h at RT. A 4N aq. ammonium chloride solution was then added and the phases were separated. The aqueous phase was extracted twice with DCM. The organic phases were combined and washed with a 1M sodium bicarbonate solution, dried over MgSO4 and concentrated in vacuo. The crude product was purified by CC (ethyl acetate).

Reference： [1]Patent: US2008/167315,2008,A1 .Location in patent: Page/Page column 32

17
[ 2740-83-2 ]
[ 98760-08-8 ]
[ 388071-74-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	In isopropyl alcohol; at 75℃; for 9h;	To a solution of tert-butyl {(S)-1-[(S)-oxiran-2-yl]-2-phenylethyl}carbamate (7) (0.13 mmol, 34.2 mg) in iPrOH (2 mL), 3-(trifluoromethyl)benzylamine (8) (0.36 mmol, 0.05 ml) was added at 23 C. The resulting mixture was heated at 75 C. for 9 h. [0105] Isopropanol was removed under reduced pressure and the residue was purified by silica gel column chromatography (1-3% MeOH/CH2Cl2) to furnish tert-butyl {(2S,3R)-3-hydroxy-1-phenyl-4-[(3-(trifluoromethyl)-benzylamino]butan-2-yl}carbamate in 70% yields (39.9 mg).
	In isopropyl alcohol; at 20 - 65℃;Inert atmosphere;	EXAMPLE 9; 9.1: Base; N-[(1S,2R)-1-Benzyl-2-hydroxy-3-[3-(trifluoromethyl)benzyl]amino}propyl]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide9.1.1: tert-Butyl[(1S,2R)-1-benzyl-2-hydroxy-3-[3-(trifluoromethyl)benzyl]-amino}propyl]carbamate Poured, over 20 min, into a suspension, under argon, of 10 g of tert-butyl [S-(R,R)]-(-)-(1-oxiranyl-2-phenylethyl)carbamate in 100 cm3 of 2-propanol is a solution of 6.5 cm3 of 3-(trifluoromethyl)benzylamine in 20 cm3 of 2-propanol at a temperature close to 20 C. The reaction mixture is heated at a temperature of 65 C. for 20 h. It is then cooled in order to be concentrated using a rotary evaporator under reduced pressure (5 kPa). The 20 g of colorless oil obtained are purified by flash chromatography over silica (column: 400 g; particle size: 15-40 mum; flow rate: 20 cm3/min; eluant: 100% dichloromethane to 95% dichloromethane/5% methanol gradient over 140 min). After concentrating the fractions under reduced pressure, 11 g of tert-butyl[(1S,2R)-1-benzyl-2-hydroxy-3-[3-(trifluoromethyl)benzyl]amino}propyl]carbamate are obtained in the form of a white solid. LC-MS-DAD-ELSD: 439(+)=(M+H)(+); 483(-)=(M+formic acid-H)(-) NMR: For this batch, all the signals are broad with: 1.22 (s, 9H) 2.25 (m, 1H) 2.38-2.65 (partially masked m, 3H) 2.99 (m, 1H) 3.51-3.65 (m, 2H) 3.80 (m, 2H) 4.83 (d, J=6.3 Hz, 1H) 6.61 (d, J=9.1 Hz, 1H) 6.99-7.30 (m, 5H) 7.48-7.80 (m, 4H).
	In isopropyl alcohol; for 16h;Reflux;	c) [(1S,2R)-1-Benzyl-2-hydroxy-3-(3-trifluoromethyl-benzylamino)-propyl]-carbamic acid tert-butyl ester A mixture of tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (183 mg, 0.695 mmol) and (3-(trifluoromethyl)phenyl)methanamine (305 mg, 1.74 mmol) in 2-propanol (4 mL) was refluxed for 16 hr. The reaction mixture was cooled to room temperature and all volatiles were removed under reduced pressure. The residue was poured into 20 mL 1 M KHSO4 and extracted with DCM (2*15 mL). The organic layers were concentrated and the residue was used without further purification in the subsequent step. MH+: 439.3

In isopropyl alcohol; for 16h;Reflux;

c) [(IS ,2R)- 1 -B enzyl-2-hydroxy-3 -(3 -trifluoromethyl-benzylamino)-propyl] -carbamic acid tert-butyl ester; A mixture of tert-butyl (S)-l-((S)-oxiran-2-yl)-2-phenylethylcarbamate (183 mg, 0.695 mmol) and (3-(trifluoromethyl)phenyl)methanamine (305mg, 1.74 mmol) in 2-propanol (4 mL) was refluxed for 16 hr. The reaction mixture was cooled to room temperature and all volatiles were removed under reduced pressure. The residue was poured into 20 mL 1 M KHS04 and extracted with DCM (2 x 15 mL). The organic layers were concentrated and the residue was used without further purification in the subsequent step. MH+: 439.3

Reference： [1]Patent: US2013/261052,2013,A1 .Location in patent: Paragraph 0103; 0104; 0105
[2]Journal of Medicinal Chemistry,2008,vol. 51,p. 3313 - 3317
[3]Patent: US2010/197668,2010,A1 .Location in patent: Page/Page column 14-15
[4]Patent: US2012/53200,2012,A1 .Location in patent: Page/Page column 12-13
[5]Patent: WO2012/28563,2012,A1 .Location in patent: Page/Page column 36

18
[ 2740-83-2 ]
[ 677306-38-6 ]
[ 1194019-70-9 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred room temperature solution of <strong>[677306-38-6]indazole-4-carboxylic acid</strong> (1.0 g, 6.1 mmol) in DMF (15 niL) was added PyBOP (3.5 g, 6.5 mmol) and triethylamine (0.90 g, 7.5 mmol). After 15 minutes, 3-trifluoromethyl-benzylamine (1.2 g, 7.0 mmol) was added. After 4 hours, the mixture was quenched with water (30 niL) and diluted with ethyl acetate (20 mL). The organic layer was separated, washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 20-60% ethyl acetate in hexanes to afford lH-indazole-4- carboxylic acid 3-trifluoromethyl-benzylamide.

Reference： [1]Patent: WO2009/134666,2009,A1 .Location in patent: Page/Page column 47
[2]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 441 - 448

19
[ 2740-83-2 ]
[ 959138-50-2 ]
[ 959130-68-8 ]

Yield	Reaction Conditions	Operation in experiment
99%		Example 12-[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[3-(trifluoro-methyl)phenylmethyl]-acetamide 50.0 mg (0.170 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 88A and 32.8 mg (0.187 mmol) of 3-trifluoromethylbenzylamine are placed in 2 ml dimethylformamide and treated with 27.6 mg (0.204 mmol) of HOBt. After 10 mins' stirring, 42.4 mg (0.221 mmol) of EDC hydrochloride are added and the mixture stirred overnight at room temperature. For the workup, the reaction mixture is partitioned between dichloromethane and water, and the organic phase is separated, dried over sodium sulphate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200:1, then 100:1) and thus yields 76 mg (99% of theory) of the target compound.MS [ESIpos]: m/z=451 (M+H)+. HPLC [Method 1]: Rt=4.74 min. 1H-NMR (400 MHz, DMSO-d6): delta=0.59 (m, 2H), 0.90 (m, 2H), 3.18 (tt, 1H), 4.40 (d, 2H), 4.44 (s, 2H), 7.53-7.66 (m, 6H), 7.80 (d, 2H), 8.67 (t, 1H).

Reference： [1]Patent: US2009/312381,2009,A1 .Location in patent: Page/Page column 82

20
[ 2740-83-2 ]
[ 959138-54-6 ]
[ 959131-50-1 ]

Yield	Reaction Conditions	Operation in experiment
89%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	Example 832-[3-(4-chlorophenyl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[3-(trifluoromethyl)phenylmethyl]acetamide 50.0 mg (0.160 mmol) of 2-[3-(4-chlorophenyl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 90A, 30.9 mg (0.176 mmol) of 3-trifluoromethylbenzyl-amine and 40.0 mg (0.209 mmol) of HOBt are placed in 2 ml of dimethylformamide and treated with 26.0 mg (0.192 mmol) of EDC hydrochloride. This is stirred overnight at room temperature, then stirred with 15 ml of water and the resulting precipitate recovered by filtration. The crude product is washed with water and dried in vacuo. 66.9 mg (89% of theory) of the target compound are thus obtained.LC/MS [Method 7]: Rt=2.24 min. 1H-NMR (400 MHz, DMSO-d6): delta=3.13 (s, 3H), 3.50 (t, 2H), 3.88 (t, 2H), 4.41 (d, 2H), 4.50 (s, 2H), 7.54-7.65 (m, 6H), 7.70-7.75 (m, 2H), 8.71 (t, 1H).

Reference： [1]Patent: US2009/312381,2009,A1 .Location in patent: Page/Page column 110

21
[ 2740-83-2 ]
[ 959139-21-0 ]
[ 959132-63-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	Example 1942-[4-(4-chlorophenyl)-3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-N-[3-(trifluoromethyl)-phenylmethyl]acetamide 50.0 mg (0.171 mmol) of 4-(4-chlorophenyl)-3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-acetic acid from Example 130A, 32.9 mg (0.188 mmol) of 3-trifluoromethylbenzylamine and 27.7 mg (0.205 mmol) of HOBt are placed in 1.5 ml of dimethylformamide and treated with 42.6 mg (0.222 mmol) of EDC hydrochloride. This is stirred overnight at room temperature, then stirred with 19 ml of water and the resulting precipitate recovered by filtration. The crude product is washed with water and dried in vacuo. 65 mg (85% of theory) of the target compound are thus obtained.LC/MS [Method 4]: Rt=2.59 min. 1H-NMR (400 MHz, DMSO-d6): delta=0.42-0.55 (m, 2H), 0.73-0.88 (m, 2H), 3.02 (dddd, 1H), 4.27 (s, 2H), 4.39 (d, 2H), 6.76 (s, 1H), 7.43-7.66 (m, 8H), 8.66 (t, 1H).

Reference： [1]Patent: US2009/312381,2009,A1 .Location in patent: Page/Page column 149

22
[ 2740-83-2 ]
[ 1186367-48-5 ]
9-(3-trifluoromethyl-benzylamino)-5H-benzo[c][1,8]naphthyridin-6-one hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%		Example 69: <n="82"/> 9-(3-Trifluoromethyl-benzylamino)-5H-benzo[c1[1 ,81naphthyridin-6-one (69; ) 9-Chloro-5H-benzo[c][1 ,8]naphthyridin-6-one (50 mg, 0.22 mmol), 3- trifluoromethylbenzylamine (76 mg, 0.43 mmol), palladium(ll) acetate (2 mg, 0.01 mmol), 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (10 mg, 0.02 mmol), and sodium ferf-butoxide (63 mg, 0.65 mmol) were suspended in dioxane (2 ml_), and stirred overnight at 100 C. The reaction mixture was diluted with MeOH, filtered, and purified via prep-LC-MS. The purified product was converted to the HCI salt via dissolving in MeOH, addition of 1 M HCI / ether, and concentration. The HCI salt was triturated in CH2CI2, filtered, washed with CH2CI2, and dried under vacuum to provide 68 (20 mg, 23 % yield) as a yellow solid. LC-MS (M+H = 370, obsd. = 370). 1H NMR (400 MHz, d6-DMSO) : delta 11.49 (s, 1 H), 8.58 (dd, 1 H), 8.41 (dd, 1 H), 8.01 (d, 1 H), 7.83 (s, 1 H), 7.74 (d, 1 H), 7.60 (m, 3H), 7.42 (d, 1 H), 7.25 (dd, 1 H), 6.97 (dd, 1 H), 4.62 (s, 2H).

Reference： [1]Patent: WO2009/108670,2009,A1 .Location in patent: Page/Page column 80-81

23
[ 2740-83-2 ]
[ 1073561-04-2 ]
[ 1193643-61-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-(tetrahydropyran-2-yloxymethyl)isophthalic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: 3-(TRIFLUOROMETHYL)BENZYLAMINE In dichloromethane at 20 - 40℃; for 2.66667h; Inert atmosphere;

Reference： [1]Af Gennäs, Gustav Boije; Talman, Virpi; Aitio, Olli; Ekokoski, Elina; Finel, Moshe; Tuominen, Raimo K.; Yli-Kauhaluoma, Jari [Journal of Medicinal Chemistry, 2009, vol. 52, # 13, p. 3969 - 3981]

24
[ 2740-83-2 ]
[ 2344-80-1 ]
[ 1219624-34-6 ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine; at 90℃; for 16h;Inert atmosphere; Neat (no solvent);	(3-(Trifluoromethyl)phenyl)methanamine (25 g, 143 mmol), (chloromethyl)trimethylsilane (19.92 mL, 143 mmol), and triethylamine (23.87 mL, 171 mmol) were combined neat and the resultant mixture was refluxed overnight. The reaction was cooled to room temperature and 150 mL of heptane was added. The HCl salts were removed by filtration and washed with heptane. The solvent was removed by placing under house vacuum and then high vacuum. N-(3-(Trifluoromethyl)benzyl)-1-(trimethylsilyl)methanamine (29.89 g, 80%) was isolated by vacuum distillation (bp 70-90 C/3.2 torr): 1H NMR (300 MHz, CDCl3) delta ppm 7.59 (s, 1H), 7.53-7.38 (m, 3H), 3.86 (s, 2H), 2.04 (s, 2H), 1.34 (s, 1H), 0.06 (s, 9H).
	With triethylamine;Reflux;	Example 56; 2-(2-oxo-3,3-diphenylpyrrolidin-l-yl)-7V-{(3aS,4S,6aR*)-2-[3- (trifluoromethyl)benzyl] octahydrocyclopenta [c] pyr rol-4-yl} acetamide; Example 56A; 7V-(3-(trifluoromethyl)benzyl)-l-(trimethylsilyl)methanamine; (3-(Trifluoromethyl)phenyl)methanamine (25 g, 143 mmol), (chloromethyl)trimethylsilane (19.92 mL, 143 mmol), and triethylamine (23.87 mL, 171 mmol) were combined neat. The resultant reaction mixture was refluxed overnight. The reaction was cooled to room temperature, and heptane (150 mL) was added. The HCl salts were removed by filtration, washing with heptane. The solvent was removed under reduced pressure, and the product was isolated by vacuum distillation (bp 70-90 C/3.2 torr) to give the title compound. 1H NMR (300 MHz, CDCl3) delta ppm 7.59 (s, 1 H), 7.53 - 7.38 (m, 3 H), 3.86 (s, 2 H), 2.04 (s, 2 H), 1.34 (s, 1 H), 0.06 (s, 9H).
	With triethylamine;Reflux;	Step A: (3-(Trifluoromethyl)phenyl)methanamine (25 g, 143 mmol), (chloromethyl)trimethylsilane (19.92 mL, 143 mmol), and triethylamine (23.87 mL, 171 mmol) were combined neat and the resultant mixture was refluxed overnight. The reaction was cooled to room temperature and 150 mL of heptane was added. The HCl salts were removed by filtration and washed with heptane. The solvent was removed by placing under house vacuum and then high vacuum. N-(3-(Trifluoromethyl)benzyl)-1-(trimethylsilyl)methanamine was isolated by vacuum distillation (bp 70-90 C./3.2 torr): 1H NMR (300 MHz, CDCl3) delta ppm 7.59 (s, 1H), 7.53-7.38 (m, 3H), 3.86 (s, 2H), 2.04 (s, 2H), 1.34 (s, 1H), 0.06 (s, 9H).

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 4128 - 4139
[2]Patent: WO2010/39947,2010,A1 .Location in patent: Page/Page column 91
[3]Patent: US2010/130558,2010,A1 .Location in patent: Page/Page column 61

25
[ 2740-83-2 ]
[ 23268-03-3 ]
[ 1224397-35-6 ]

Yield	Reaction Conditions	Operation in experiment
63%	With triethylamine; HATU; In tetrahydrofuran; at 20℃; for 16h;	1.32 g (7.5 mmol) of 3-(trifluoromethyl)phenyl)methylamine, 2.60 g (6.8 mmol) of HATU and 1.8 ml (13.0 mmol) of NEt3were added in succession to a solution of 1.0 g (6.8 mmol) of (R)-4-methoxy-2-methyl-4-oxobutyric acid in THF (50 ml). After 16 h stirring at RT, the reaction solution was diluted with EA (30 ml), and washing was carried out twice with a sat. aq. NH4Cl sol. and twice with a 1N aq. NaHCO3 sol. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. After CC (EA) of the residue, 1.30 g (4.3 mmol, 63%) of (R)-3-methyl-4-oxo-4-(3-(trifluoro-methyl)benzylamino)butyric acid methyl ester were obtained.

Reference： [1]Patent: US2010/105722,2010,A1 .Location in patent: Page/Page column 29

26
[ 2740-83-2 ]
[ 1224397-15-2 ]
(R)-3-methyl-4-oxo-4-(4-phenyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-N-(3-(trifluoromethyl)benzyl)butanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With triethylamine; HATU; In tetrahydrofuran; at 20℃; for 72h;	To a solution of 515 mg (1.56 mmol) of intermediate SAAS02 in THF (12 ml) there were added in succession 274 mg (1.56 mmol) of (3-trifluoromethyl)phenyl)methyl-amine, 594 mg (1.56 mmol) of HATU and 433 mul (3.13 mmol) of NEt3. After 72 h stirring at RT, the reaction solution was diluted with EA and washed three times with a sat. aq. NH4Cl sol. and three times with a sat. aq. NaHCO3 sol. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. After CC (EA) of the residue, 550 mg (1.13 mmol, 72%) of illustrative compound 34 were obtained. MS: m/z 487.2 [M+H]+.

Reference： [1]Patent: US2010/105722,2010,A1 .Location in patent: Page/Page column 31

27
[ 2740-83-2 ]
[ 1228598-59-1 ]
[ 1228598-47-7 ]

Yield	Reaction Conditions	Operation in experiment
66%	With triethylamine; In N,N-dimethyl-formamide; at 120℃; for 0.5h;	1,8-Bis[2-(3-(trifluoromethyl)benzylamino)acetamido]anthraquinone (3q); Add 0.4 g, 1.0 mmol 1,8-bis(chloroacetamido)anthraquinone (compound 3) with 0.5 ml TEA, and 0.8 ml, 6 mmole 3-(trifluoromethyl)benzylamine, dissolved in 20 ml dehydrated dimethylformamide (DMF). The mixture is reacted in a mini-reactor. The reaction temperature is 120 C. in the oil bath and the reaction time is 30 minutes. The reacted mixture is poured into 50 ml ice water and is filtered to collect precipitate. The precipitate is recrystallized from ethanol to get yellow compound 3q.Mol. Wt.: 668.1858 (C34H26F6N4O4)Yield: 66%Mp: 190-191 C. (EtOH)IR (KBr) cm-1: 3202 (NH), 2836 (NH), 1693 (CO), 1632 (CO)HRMS (EI) m/z calcd for C34H26F6N4O4 +[M+H]+: 668.1858. Found: 668.1859.1H-NMR (300 MHz, CDCl3) delta (ppm):3.40 (s, 4H, -CH2-), 3.77 (s, 4H, -CH2-), 7.74-7.54 (m, 6H, Ar'-H4,5,6), 7.65 (s, 2H, Ar'-H2) 7.75 (t, J=8.1 Hz, 2H, Ar-H3,6), 8.08 (d, J=7.2 Hz, 2H, Ar-H4,5), 9.23 (d, J=8.4 Hz, 2H, Ar-H2,7), 12.91 (s, 2H, Ar-NH-)13C-NMR (300 MHz, CDCl3) delta (ppm):52.80, 52.87, 114.95, 118.67 (C8a,9a), 122.17 (C2,7), 123.87, 124.52, 126.29 (C4,5), 128.50, 131.17, 133.04 (C3,6), 135.21 (C4a,5a), 139.85, 140.81 (C1,8), 171.05 (NCO), 182.14 (C10O), 190.28 (C9O)
66%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 130 - 150℃;Autoclave;	General procedure: 1,8-Bis(chloroacetamido)anthraquinone (0.3 g, 0.75 mmol) was dissolved in anhydrous DMF (10 ml) and glycine methyl ester hydrochloride (0.75 g, 6 mmol), DIPEA (12 mmol) were added dropwise under nitrogen. The reaction mixture was heated and refluxed at 130 C in miniclave for 1 h. Upon completion, the mixture was cooled to room temperature. The solution put into the ice water, the precipitated and was collected by filtration, washed with ice-cold water and ethanol and dried in vacuo. The crude compound was purified by column chromatography (CH2Cl2) and recrystallization from ethanol provided 3a as dark yellow powder (42%).

Reference： [1]Patent: US2010/145070,2010,A1 .Location in patent: Page/Page column 13-14; 23
[2]European Journal of Medicinal Chemistry,2012,vol. 50,p. 102 - 112

28
[ 2740-83-2 ]
[ 201230-82-2 ]
[ 1220165-54-7 ]
[ 1220025-85-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; bis(benzonitrile)palladium(II) dichloride; In toluene; at 140℃; under 11251.1 Torr; for 3h;Sealed;	A mixture of 4-bromo-l-(4-fluorophenyl)-lH-pyrazolo[3,4-c]pyridine (340 mg, 1.2 mmol), Et3N (320 muL, 2.3 mmol), 3-trifluoromethylbenzylamine (250 muL, 1.7 mmol), Pd[PhCN]2Cl2 (10 mg, 0.03 mmol), and l,l-bis(diphenylphosphino)ferrocene (dppf) (0.04 g, 0.07 mmol) in toluene (15 mL) was sealed in a bomb with stirring, placed under 15 bars of carbon monoxide and warmed at 14O0C. After 3 hours, the mixture was cooled to room temperature, returned to atmospheric pressure and opened. The reaction was monitored by EtaPLC-MS indicating the desired mass M+ = 415.43. The reaction was diluted with saturated aqueous ammonium chloride (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (3 x 20 mL), brine (20 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was dissolved in dichloromethane and purified by silica gel chromatography using a gradient of 0-30% EtOAc in dichloromethane to afford partially purified material. The material from the column was triturated with ether- hexanes to afford an off-white solid. This material was dissolved in dichloromethane and passed through a pad of silica gel (15 mL funnel) eluting with a gradient of 0-40% dichloromethane in EtOAc. The material from the pad was triturated with ether to afford the title compound, mp 172-1730C.

Reference： [1]Patent: WO2010/36632,2010,A1 .Location in patent: Page/Page column 109; 110

29
[ 2740-83-2 ]
[ 1229515-34-7 ]
[ 1229513-95-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 23℃;	A solution of 200 mg (0.61 mmol) of 4-(7-fluoro-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyric acid (intermediate VVV04) and 88.0 mul (0.61 mmol) of 3-trifluoromethyl benzylamine in DCM (15 ml) was cooled to 0 C. and then 8.3 mg (0.06 mmol) of HOAt and 129 mg (0.67 mmol) of EDC were added in succession. The mixture was then stirred for 16 h at room temperature. The reaction solution was poured into water (75 ml) and extracted with DCM (2×75 ml). The combined organic phases were washed with a 1M aqueous NaOH solution (100 ml) and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (heptane/EE 1:1+2% 7N NH3 in MeOH) of the residue produced 240 mg (0.50 mmol, 81%) of 4-(7-fluoro-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxo-N-(3-(trifluoromethyl)benzyl)butyric acid amide. MS: m/z 485.2 [M+H]+.

Reference： [1]Patent: US2010/152234,2010,A1 .Location in patent: Page/Page column 18

30
[ 2740-83-2 ]
[ 1000578-10-8 ]
[ 1240480-18-5 ]

Yield	Reaction Conditions	Operation in experiment
66%		To a suspension of methyl 4-oxo-3,4-dihydroquinazoline-8-carboxylate (150 mg, 0.73 mmol) in 4 ml_ of anhydrous DCE1 POCI3 (80 mul_, 0. 87 mmol, 1.2 equiv.) was added followed by DIPEA (630 muL, 3.6 mmol, 5.0 equiv.). The resulting mixture was stirred at 90 C for 1-2h. After cooling down to rt , 3-(trifluoromethyl)benzylamine (97 muL, 0. 81 mmol, 1.1 equiv.) was added. The reaction mixture was stirred at 80 C for 2-4h. After work-up, the crude was purified by chromatography to yield the title compound in 66% yield. 1HNMR (in CDCI3): 3.19 (s, 3H), 4.90 (s, 2H), 7.41-7.45 (m, 2H), 7.53 (t, J=8.9 Hz, 2H), 7.58 (s, 1 H), 7.97 (dd, J=1.5 and 8.4 Hz, 1 H), 8.04 (dd, J=1.5 and 7.3 Hz, 1 H). Mass: M+H+: 362.

Reference： [1]Patent: WO2010/93419,2010,A1 .Location in patent: Page/Page column 195

31
[ 2740-83-2 ]
[ 1020743-28-5 ]
4-[3-(trifluoromethyl)benzyl]amino}quinoline-8-carbonitrile trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With potassium carbonate In isopropyl alcohol at 110℃; for 48h;	53 To a suspension of 4-bromoquinoline-8-carbonitrile (100 mg, 0.43 mmol) in 4 ml_ of iso- propanol, 3-(trifluoromethyl)benzylamine (150 mg, 0. 85 mmol, 2.0 equiv.) and K2CO3 (119 mg, 0.85 mmol, 2.0 equiv.) were added. The resulting mixture was stirred at 110 °C 2 days. After work-up, the crude was purified by preparative HPLC to yield the title compound as TFA salt in 20% yield. 1HNMR (in MeOD): 4.96 (s, 2H), 6.96 (d, J=7.0 Hz, 1 H), 7.58-7.71 (m, 3H), 7.76 (s, 1 H), 7.86 (dd, J=7.7 and 8.8 Hz, 1 H), 8.39 (d, J=7.3Hz, 1H), 8.44 (dd, J=1.1 and 7.3 Hz, 1H), 8.75 (dd, J=1.1 and 8.8 Hz, 1H). Mass: M+H+: 328.

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2010/93419, 2010, A1 Location in patent: Page/Page column 208

32
[ 2740-83-2 ]
[ 372-09-8 ]
[ 566926-07-6 ]

Yield	Reaction Conditions	Operation in experiment
51%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 60℃; for 18h;	Cyanoacetic acid (297.0 mg, 3.5 mmol), Lambda/-(3-dimethylaminopropyl)-LambdaT-ethyl- carbodiimide hydrochloride (1.34 g, 7.0 mmol), 1-hydroxybenzotriazole hydrate (641.0 mg, 4.2 mmol) and DIPEA (1.8 g, 14.0 mmol) and 3-(trifluoromethyl)benzylamine (61 l.Omg, 3.5 mmol) were suspended in THF. The mixture was heated to 60 for 18h. Water was added to the mixture and the product extracted with EtOAc, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography, CH2Cl2MeOH 98:2, yielding 430.0 mg (51%) of the title compound.1H NMR (CDCl3) delta 7.60 (m, 4H), 6.52 (bs, IH), 4.55 (d, 3H), 3.46 (s, 3H).
51%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 60℃; for 18h;	2-Cyano-N-(3-(trifluoromethyl)benzyl)acetamide Cyanoacetic acid (297.0 mg, 3.5 mmol), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (1.34 g, 7.0 mmol), 1-hydroxybenzotriazole hydrate (641.0 mg, 4.2 mmol) and DIPEA (1.8 g, 14.0 mmol) and 3-(trifluoromethyl)benzylamine (611.0 mg, 3.5 mmol) were suspended in THF. The mixture was heated to 60 for 18 h. Water was added to the mixture and the product extracted with EtOAc, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography, CH2Cl2/MeOH 98:2, yielding 430.0 mg (51%) of the title compound. 1H NMR (CDCl3) delta 7.60 (m, 4H), 6.52 (bs, 1H), 4.55 (d, 3H), 3.46 (s, 3H).

Reference： [1]Patent: WO2010/97410,2010,A1 .Location in patent: Page/Page column 124
[2]Patent: US2012/40942,2012,A1 .Location in patent: Page/Page column 57

33
[ 2740-83-2 ]
[ 2488-15-5 ]
[ 1257526-79-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 0 - 5℃; for 17.25h;	To a mixture of Boc-L-methionine (1.47 g, 5.9 mmol) in methylene chloride (10 mL) was added HATU (2.6 g, 6.8 mmol) and DIPEA (1.1 mL) and the solution was cooled to 0-50C with an ice bath. Meta-trifluorobenzylamine (1.0 g, 5.7 mmol) in 1 mL methylene chloride was added dropwise over 15 minutes and the reaction was stirred at 0-50C for 1 hour and then allowed to stir at room temperature for 16 hours. The reaction was neutralized with IM citric acid (30 mL) and the layers were separated. The aqueous layer was extracted two times with methylene chloride (25 mL). The organic layers were combined and washed once with brine (50 mL), dried over Mg2SO4, filtered, and concentrated to an oil. The material was purified by flash chromatography (40% ethyl acetate/ hexane) to provide 1.94 g (84%) amide 6 as a white solid.TLC: Rf 0.30 (40% ethyl acetate/ hexane visualized by UV and Iodine); 1H NMR (CDCl3): 7.51 (m, 2H), 7.45 (m, 2H), 6.84 (brs, IH), 5.20 (d, J=7.8 Hz, IH), 4.49 (brs, 2H), 4.30 (m, IH), 2.55 (m, 2H), 2.12 (m, IH), 2.08 (s, 3H), 1.96 (m, IH), 1.41 (s, 9H); LC/MS: amide 6, R, 8.4 min, (M+ +1) 407.

Reference： [1]Patent: WO2010/141932,2010,A1 .Location in patent: Page/Page column 144; 145

34
[ 2740-83-2 ]
[ 201230-82-2 ]
[ 1300022-22-3 ]
[ 1300022-76-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; bis(benzonitrile)palladium(II) dichloride; In toluene; at 140℃; under 11251.1 Torr; for 3h;	Example 8: Synthesis of 3-(4-Fluorophenyl)-imidazo[l,5-a]pyridine-8-carboxylic acid 3-trifluoromethyl-benzylamide (8); A mixture of 8-bromo-3-(4-fluorophenyl)-imidazo[l,5-a]pyridine (0.100 g, 0.344 mmol), Et3N (95.0 mu,, 0.683 mmol), 3-(trifluoromethyl)benzylamine (89.0 mu,, 0.621 mmol), Pd[PhCN]2Cl2 (5.0 mg, 0.013 mmol), and dppf (21 mg, 0.038 mmol) in degassed toluene (10 mL) is placed in a pressure reactor. The stirred mixture is placed under 15 bars of carbon monoxide and warmed at 140C. After 3 hours, the pressure reactor is cooled to room temperature, returned to atmospheric pressure and opened. The reaction mixture is diluted with saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers are washed with saturated aqueous ammonium chloride (3 x 10 mL), brine (10 mL), dried over magnesium sulfate, filtered and concentrated. The residue is purified by silica gel chromatography eluting with a gradient of 0-50% EtOAc in dichloromethane. The resulting solid is triturated with ether-hexanes to afford the title compound.

Reference： [1]Patent: WO2011/56440,2011,A1 .Location in patent: Page/Page column 45

35
[ 2740-83-2 ]
[ 203436-45-7 ]
[ 1240046-58-5 ]

Yield	Reaction Conditions	Operation in experiment
60%	With triethylamine; In butan-1-ol; at 120℃; for 0.5h;Microwave irradiation; Inert atmosphere;	2-Chloro-9-isopropyl-A^-(3-(trifluoromethyl)benzyl)-9H-purin-6-amine (16v). To a solution of 15c (65.8 mg, 0.273 mmol) in n-BuOH (1.0 mL) were added 3-(trifluoromethyl)benzylamine (52.4 mg, 0.300 mmol) and Et3N (46.1 mg, 0.456 mmol) under a nitrogen atmosphere. The reaction mixture was heated with microwave irradiation at 120 C for 30 min. The n-BuOH was evaporated, and the residue was dissolved in EtOAc (20.0 mL) and washed with water (10.0 mL). The aqueous phase was further extracted with EtOAc (2 x 10.0 mL), and the combined organic extracts were dried (MgS04), filtered, and concentrated to yield a colorless solid. The solid was resuspended (hexanes/Et20, 3: 1), filtered, washed (hexanes/Et20, 3: 1), and dried under high- vacuum to yield 16v (63.0 mg, 0.170 mmol, 60%) as a colorless amorphous solid: IR (ATR, neat) 3250, 3150, 2990, 2925, 1625, 1446, 1313, 1230, 1159, 1140, 1099, 980, 930, 700 cm"1; NMR (300 MHz, CDC13) delta 7.77 (s, 1 H), 7.63 (s, 1 H), 7.59 (d, 1 H, / = 7.5 Hz), 7.56 (d, 1 H, / = 7.8 Hz), 7.47 (t, 1 H, / = 7.5 Hz), 6.33 (bs, 1 H), 4.90 (bs, 2 H), 4.83 (sept, 1 H, / = 6.8 Hz), 1.58 (d, 6 H, / = 6.9 Hz); 13C NMR (75 MHz, CDCb) delta 155.1, 154.2, 150.0, 139.4, 137.8, 131.2, 130.9 (q, J = 32.2 Hz), 129.3, 124.4, 124.3, 124.0 (q, J = 270.1 Hz), 118.8, 47.0, 43.9, 22.7; HRMS [EI] m/z calcd for [C16H15CIF3N5] 369.0968, found 369.9640.

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 1989 - 1998
[2]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 985 - 990
[3]Patent: WO2014/189830,2014,A1 .Location in patent: Page/Page column 57

36
[ 2740-83-2 ]
[ 34678-35-8 ]
[ 1422286-16-5 ]

Yield	Reaction Conditions	Operation in experiment
70%		Concentrated hydrochloric acid (0.14 ml, 1.58 mmol) was added to a solution obtained by dissolving (3-trifluoromethyl)benzyl amine (0.28 mg, 1.58 mmol) in n-butanol (10 ml) and stirred at room temperature for 30 minutes. The compound (0.3 mg, 1.97 mmol) prepared in above step (1-1) was added to the reaction mixture and stirred for 12 hours under reflux. The reaction mixture was concentrated under reduced pressure, the concentrate was then dissolved while adding a 6N hydrochloric acid/methanol solution (3 ml), and a white solid target compound (596 mg, 70%) was obtained using ethyl acetate. 1H NMR (400 MHz, DMSO-d6)d 7.64 (br s, 1H), 7.62-7.55 (m, 4H), 7.40 (br s, 1H), 6.74 (br s, 2H), 4.39 (s, 2H), 3.32 (m, 4H), 1.54 (m, 2H), 1.43 (m, 4H); LCMS m/z 328.3 [M+1]+; mp 259-260 C.

Reference： [1]Patent: WO2013/22279,2013,A2 .Location in patent: Paragraph 110
[2]Patent: US2014/179661,2014,A1 .Location in patent: Paragraph 0091; 0092; 0093

37
[ 2740-83-2 ]
[ 2065-37-4 ]
[ 1421609-34-8 ]

Yield	Reaction Conditions	Operation in experiment
48%	In ethanol; for 0.166667h;	(trifluoromethyl)benzyl)amino)naphthalene-l,4-dione (2v). To a solution of 2-bromo-l,4- napthoquinone (283 mg, 1.2 mmol) in abs EtOH (40 mL) was added an excess of 3- (trifluoromethyl)benzylamine (420 mg, 2.4 mmol). The reaction was stirred for 10 minutes and then concentrated in vacuo. Compound was purified using chromatography on silica gel eluting with ethyl acetate and hexane to yield 397 mg yellowish powder (48% yield). MS m/z calcd (M+) 332.09, found 332.1. 1H NMR (400 MHz, DMSO-d6) Shift 8.28 (t, J = 6.53 Hz, 1H), 8.01 (d, J = 6.78 Hz, 1H), 7.87 - 7.94 (m, 1H), 7.83 (dt, J = 1.13, 7.47 Hz, 1H), 7.72 - 7.79 (m, 2H), 7.69 (d, J = 7.53 Hz, 1H), 7.54 - 7.67 (m, 2H), 5.64 (s, 1H), 4.56 (d, J = 6.53 Hz, 2H). C13-HSQC (400 MHz, DMSO-d6) Shift (ppm) 40.22, 45.02, 100.83, 124.20, 124.21, 126.33, 126.33, 130.13, 131.76, 135.16.

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 1007 - 1022
[2]Patent: WO2014/74976,2014,A1 .Location in patent: Paragraph 00230

38
[ 2740-83-2 ]
[ 598-45-8 ]
[ 40359-34-0 ]
C₂₂H₂₄F₃N₅O₃ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2013,vol. 11,p. 6036 - 6046

39
[ 2740-83-2 ]
C₁₆H₁₄O₂S [ No CAS ]
C₂₄H₂₀F₃NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With sulfuric acid; In ethanol; at 20℃;	General procedure: To a solution of1,3-bis(het)arylmonothiodiketones 1 (5mmol) and (het)aryl methyl amine (5 mmol) in EtOH (25 mL), catalytic amountof conc. H2SO4 (0.5 mmol) was added at room temperatureand stirred for 1-1.5 h (monitored by TLC). The solvent was removed under reducedpressure and the residue was diluted with EtOAc (100 mL) and water (100 mL). TheEtOAc layer was separated and washed with brine (50 mL), then dried overanhydrous Na2SO4 and concentrated to give crude productswhich were purified by column chromatography over silica gel using hexane-EtOAc(8:2) mixture as eluent.

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 5288 - 5292

40
[ 2740-83-2 ]
[ 615-43-0 ]
[ 133389-19-2 ]

Yield	Reaction Conditions	Operation in experiment
45%	With 1,4-diaza-bicyclo[2.2.2]octane; 1,10-Phenanthroline; copper(II) acetate monohydrate; sulfur; In dimethyl sulfoxide; at 100℃;	General procedure: A mixture of 2-iodoaniline 1 (1 mmol), benzylamine 2 (1.2 mmol), sulfur powder (6 mmol), DABCO (2 mmol), Cu(OAc)2·H2O (0.02 mmol), and 1,10-phenanthroline (0.02 mmol) was stirred in DMSO (5mL) at 100 C. After completion of the reaction as indicated by TLC, the mixture was cooled to room temperature, water (20 mL) was added, and then the aqueous solution was extracted with ethyl acetate (3×15 mL). The organic layers were combined, dried over anhydrous MgSO4, the filtrate was concentrated under vacuum and then the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate (10:1 to 14:1) on silica gel to provide the desired product.
45%	With 1,4-diaza-bicyclo[2.2.2]octane; 1,10-Phenanthroline; copper(II) acetate monohydrate; sulfur; In dimethyl sulfoxide; at 100℃;	General procedure: A mixture of 2-iodoaniline 1 (1 mmol), benzylamine 2 (1.2 mmol), sulfur powder (6 mmol), DABCO (2 mmol), Cu(OAc)2.H2O (0.02 mmol), and 1,10-phenanthroline (0.02 mmol) was stirredin DMSO (5 mL) at 100 C. After completion of the reaction as indicated by TLC, the mixture was cooled to room temperature, water (20 mL) was added, and then the aqueous solution was extracted with ethyl acetate (3 15 mL). The organic layers were combined, dried over anhydrous MgSO4, the filtrate was concentrated under vacuum and then the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate (10:1 to 14:1) on silicagel to provide the desired product.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 945 - 949
[2]Tetrahedron Letters,2015,vol. 55,p. 945 - 949

41
[ 2740-83-2 ]
[ 1568938-38-4 ]
[ 1568942-75-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃;	General procedure: A mixture of compound 10 (1.5 mmol), corresponding amine (2.25 mmol), EDC·HCl (1.8 mmol) DMAP (0.15 mmol) and pyridine (10 ml) was stirred at room temperature for 10 minutes. Acetonitrile (20 ml) was added and the mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with dichloromethane/acetone (v/v 10:1) to afford target products 12a-y.

Reference： [1]Synthetic Communications,2014,vol. 44,p. 858 - 867

42
[ 2740-83-2 ]
[ 1449221-76-4 ]
[ 1449221-55-9 ]

Yield	Reaction Conditions	Operation in experiment
72.36%		General procedure: A mixture of 7 (100mg, 0.24mmol), HBTU (92mg, 0.24mmol) and DIPEA (63mg, 0.48mmol) was dissolved in CH2Cl2 (30mL) under N2 atmosphere. The solution was stirred at room temperature for 15min before 4-fluorobenzylamine (30mg, 0.24mmol) was added. Then the mixture was stirred for additional 12h. The solution was concentrated under reduced pressure and the residue was extracted with ethyl acetate (30mL×3) and washed with water (20mL×3). The combined organic layers were concentrated and purified by chromatography on silica gel (CH2Cl2/MeOH=100:1) to afford 8a as a white solid (35mg, 28.2% yield). m.p. 243-244C; 1H NMR (400MHz, DMSO-d6): delta 13.05 (s, 1H), 10.93 (s, 1H), 10.14 (t, 1H, J=6.0Hz), 8.82 (s, 1H), 8.63 (d, 1H, J=2.0Hz), 8.05 (dd, 1H, J1=8.8Hz, J2=2.0Hz), 7.86 (d, 1H, J=8.8Hz), 7.46-7.52 (m, 1H), 7.35-7.42 (m, 5H), 7.16 (t, 2H, J=8.8Hz), 4.54 (d, 2H, J=5.6Hz); 13C NMR (100MHz, DMSO-d6): delta 176.02, 164.29, 162.86, 160.47, 145.58, 142.03, 138.84, 136.01, 135.49, 131.19, 130.10, 129.80, 125.98, 125.73, 123.80, 121.43, 121.13, 116.30, 115.68, 115.47, 112.55, 41.89; HRMS (ESI) for C24H17F4N3O4S: calcd. 520.09487 (M+H)+, found: 520.09421 (M+H)+.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 79,p. 413 - 421

43
[ 2740-83-2 ]
[ 1877-72-1 ]
[ 1181107-44-7 ]

Yield	Reaction Conditions	Operation in experiment
76%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	Step 1 : General protocol for the preparation of 3-cyano-benzamide compounds 3-Cyano-benzoic acid (1.2 eq), the amine derivative (1 eq), HOBt (1.2eq), DIEA (1.2eq) and EDCl.HCl (1.2eq) were dissolved in dry DMF (0.15 M), under argon. The mixture was stirred at room temperature overnight. DMF is evaporated and saturated NaHC03 solution was added. Product was extracted with EtOAc, dried over Na2S04, filtered and evaporated. The crude was purified on reverse phase (H20 l%TFA/MeCN 1 %TFA 100/0, 0/100). MeCN was evaporated. The product was suspended in H20 and basified with saturated NaHC03 solution until pH = 8-9. The aqueous layer was extracted three times with AcOEt. The organic layer was evaporated to give the final compound

Reference： [1]Patent: WO2014/102378,2014,A1 .Location in patent: Page/Page column 81

44
[ 2740-83-2 ]
[ 606-18-8 ]
[ 1622400-39-8 ]

Yield	Reaction Conditions	Operation in experiment
75%		General procedure: A mixture of 2-amino-3-nitrobenzoic acid (5.0 mmol), EDCI (6.0 mmol),and HOBt (0.6 mmol) in DCM (30 mL) was stirred at room temperature for 5 mins. Then, amines (6.0 mmol) were added and the reaction was stirred at room temperature overnight. After completion, the mixture was diluted with DCM, washed with water twice, dried over anhydrous Na2SO4, evaporated, and chromatographed (EtOAc - petroleum ether) to afford the compounds 2a-k.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3948 - 3951

45
[ 2740-83-2 ]
[ 64-19-7 ]
[ 1134915-25-5 ]

Reference： [1]European Journal of Organic Chemistry,2015,vol. 2015,p. 3036 - 3039

46
[ 2740-83-2 ]
[ 18995-35-2 ]
4-(tert-butoxy)-N-(3-(trifluoromethyl)benzyl)aniline [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2015,vol. 54,p. 9507 - 9511
Angew. Chem.,2015,vol. 127,p. 9643 - 9647,5

47
[ 2740-83-2 ]
[ 500-05-0 ]
2-oxo-N-(3-(trifluoromethyl)benzyl)-2H-pyran-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 72h;	General procedure: To a solution of carboxylic acids (2 mmol) in methylene chloride (10 mL), solid 1-hydroxybenzotriazole monohydrate (0.27 g, 2 mmol) and N-ethyl-N?-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.38 g, 2 mmol) were added. The mixture solutions were reacted with various anilines (4 mmol) and then stirred at room temperature for 3 days in parallel synthesis reactor. The reaction mixture was evaporated to dryness under reduced pressure and the residue was extraction with ethyl acetate, washed with 10% NaHCO3, and H2O. The organic phasewas separated and dried with anhydrous MgSO4, and dried in vacuo. The crude product was washed and purified by crystallization from hot ethanol and methylene chloride to obtain title compounds. 2-Oxo-N-(3-(trifluoromethyl)benzyl)-2H-pyran-5-carboxamide (Aa). 1H NMR (400MHz, DMSO-d6): delta ppm 4.69 (d, J = 6.4 Hz, 2H), 7.47 (d, J = 9.2 Hz, 1H), 7.60-7.70 (m, 4H),7.75 (s, 1H), 8.17 (d, J = 14.4 Hz, 1H), 10.10 (t, J = 6.8 Hz, 1H); 13C NMR (100 MHz, DMSOd6):delta ppm 93.30, 101.28, 101.46, 103.29, 104.35, 110.95, 111.21, 122.80, 128.47, 129.37, 130.80,133.25, 139.74, 148.52, 149.02, 149.16, 152.83, 160.42, 160.70, 161.52, 163.67; HRMS (ESI) m/z:calcd [M]+, 297.0613 (C14H10F3NO3+), found [M-H]+, 296.0550 (C14H9F3NO3+).

Reference： [1]PLoS ONE,2016,vol. 11

48
[ 2740-83-2 ]
[ 621-82-9 ]
N-(3-(trifluoromethyl)benzyl)cinnamamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 72h;	General procedure: To a solution of carboxylic acids (2 mmol) in methylene chloride (10 mL), solid 1-hydroxybenzotriazole monohydrate (0.27 g, 2 mmol) and N-ethyl-N?-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.38 g, 2 mmol) were added. The mixture solutions were reacted with various anilines (4 mmol) and then stirred at room temperature for 3 days in parallel synthesis reactor. The reaction mixture was evaporated to dryness under reduced pressure and the residue was extraction with ethyl acetate, washed with 10% NaHCO3, and H2O. The organic phasewas separated and dried with anhydrous MgSO4, and dried in vacuo. The crude product was washed and purified by crystallization from hot ethanol and methylene chloride to obtain title compounds.

Reference： [1]PLoS ONE,2016,vol. 11

49
[ 2740-83-2 ]
[ 66572-56-3 ]
N-(3-(trifluoromethyl)benzyl)-2-bromoisonicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃;	Into a 250-mL round bottom flask, was placed a solution of <strong>[66572-56-3]2-bromoisonicotinic acid</strong> (1.4 g, 6.93 mmol, 1.20 equiv) in dichloromethane (50 mL), EDC.HCl (1.64 g, 8.56 mmol, 1.50 equiv), 4-dimethylaminopyridine (1.04 g, 8.51 mmol, 1.50 equiv), and 3-(trifluoromethyl)benzylamine (1.0 g, 5.71 mmol, 1.00 equiv). The resulting solution was stirred overnight at 25 C. in an oil bath. The resulting solution was diluted with 100 mL of dichloromethane. The resulting mixture was washed with 250 mL of sat. NH4Cl, 250 mL of sat. Na2CO3, and 2*50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10-1:5). The product was obtained as 1.2 g (59%) of a white solid.

Reference： [1]Patent: US9301951,2016,B2 .Location in patent: Page/Page column 137

50
[ 2740-83-2 ]
4-fluoro-2-(2-nitro-5-(piperidin-1-yl)phenyl)pyridine [ No CAS ]
2-(2-nitro-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)pyridin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃;	Into a 30-mL round bottom flask, was placed a solution of 4-fluoro-2-(2-nitro-5-(piperidin-1-yl)phenyl)pyridine (500 mg, 1.66 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), (3-(trifluoromethyl)benzylamine (581 mg, 3.32 mmol, 2.00 equiv), and potassium carbonate (985 mg, 7.14 mmol, 4.00 equiv). The resulting solution was stirred overnight at 100 C. in an oil bath. The resulting solution was diluted with 30 mL of water. The resulting solution was extracted with 330 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 220 mL of brine and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/hexane (1:1). The product was obtained as 500 mg (66%) of a yellow oil.

Reference： [1]Patent: US9301951,2016,B2 .Location in patent: Page/Page column 212

51
[ 2740-83-2 ]
[ 6313-54-8 ]
N-(3-(trifluoromethyl)benzyl)-2-chloroisonicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 3h;	Into a 500-mL round bottom flask, was placed a solution of 2-chloroisonicotinic acid (18 g, 113.92 mmol, 2.00 equiv) in dichloromethane (200 mL), 3-(trifluoromethyl)benzylamine (10 g, 57.14 mmol, 1.00 equiv), EDC.HCl (22 g, 115.18 mmol, 2.00 equiv), and 4-dimethylaminopyridine (14 g, 114.75 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 25 C. The resulting solution was diluted with 500 mL of dichloromethane. The resulting mixture was washed with 250 mL of aqueous NH4Cl, 150 mL of 10% sodium bicarbonate, and 1*50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (5:1). The product was obtained as 11.8 g (63%) of a white solid.

Reference： [1]Patent: US9301951,2016,B2 .Location in patent: Page/Page column 119

52
[ 2740-83-2 ]
2-(2-(3-((3-tert-butoxy-3-oxopropylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid [ No CAS ]
tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	Into a 50 mL round bottom flask, was placed 2-(2-(3-((3-tert-butoxy-3-oxopropylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid (220 mg, 0.38 mmol, 1.00 equiv), 3-(trifluoromethyl)benzylamine (134 mg, 0.77 mmol, 2.00 equiv), EDC.HCl (124 mg, 0.63 mmol, 1.65 equiv), 4-dimethylaminopyridine (76 mg, 0.62 mmol, 1.63 equiv), and dichloromethane (10 mL). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was washed with 5*30 mL of aqueous NH4Cl. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 360 mg (90%) of tert-butyl 3-(3-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)propanoate as yellow oil.

Reference： [1]Patent: US9301951,2016,B2 .Location in patent: Page/Page column 35

53
[ 2740-83-2 ]
[ 102393-82-8 ]
6-bromo-2-chloro-N-(3-(trifluoromethyl)benzyl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 3h;	Into a 500-mL round-bottom flask, was placed a solution of <strong>[102393-82-8]6-bromo-2,4-dichloroquinazoline</strong> (10 g, 35.98 mmol, 1.00 equiv) in tetrahydrofuran (300 mL). This was followed by the addition of DIPEA (31.27 mL, 5.00 equiv) dropwise with stirring at 0 C. To the resulting mixture was added [3-(trifluoromethyl)phenyl]methanamine (7.55 g, 43.11 mmol, 1.20 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with water (100 mL). The resulting solution was extracted with ethyl acetate (2*200 mL) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (15:85), to yield 6-bromo-2-chloro-N-[[3-(trifluoromethyl)phenyl]methyl]quinazolin-4-amine as a yellow solid. (ES (m/z) 416 [M+H]+

Reference： [1]Patent: US2016/68512,2016,A1 .Location in patent: Paragraph 0505-0506

54
[ 2740-83-2 ]
[ 211693-73-1 ]
2-fluoro-4-nitro-N<SUP>1</SUP>-(3-(trifluoromethyl)benzyl)benzene-1,3-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With iodine; triethylamine; In dimethyl sulfoxide; at 120℃; for 24h;	2-fluoro-4-nitro-A^l-(3-(trifluoromethyl)benzyl)benzene-l,3-diamine. To a stirred solution of <strong>[211693-73-1]2,3-difluoro-6-nitroaniline</strong> (0.200 g, 1.11 mmol, 1.00 equiv) in dry DMSO (4.6 mL) were added 3- (trifluoromethyl)benzylamine (0.195 mL, 1.34 mmol, 1.2 equiv) followed by Et3N (0.135 g, 1.34 mmol, 1.2 equiv) and I2 (cat. 2 mg). The reaction mixture was heated to 120 C for 24h. The reaction mixture was cooled to room temperature, diluted with water (25 mL) and extracted with EtOAc (3 x 15 mL). The separated organic layer was washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexanes = 1:10 to 1:4 to 1:3) to afford the product as a yellow solid (0.280 g, 76%). 1H NMR (400 MHz, CDCb) delta 7.86 (dd, J = 9.6, 1.6 Hz, 1 H), 7.59- 7.57 (m, 2 H), 7.54-7.47 (m, 2 H), 6.15-6.00 (m, 3 H), 4.93 (br, 1 H), 4.54 (d, / = 6.0 Hz, 2 H); 13C NMR (100 MHz, CDCI3) delta 140.86 (d, / = 9.5 Hz), 138.89, 138.03 (d, / = 228.6 Hz), 135.21 (d, / = 12.9 Hz), 131.51 (q, / = 32.5 Hz), 130.48, 129.63, 125.62 (d, / = 3.5 Hz), 124.89 (q, / = 3.7 Hz), 124.05 (q, J = 272.4 Hz), 123.99 (q, J =3.7 Hz), 123.66 (d, / = 2.9 Hz), 100.71 (d, J = 2.9 Hz), 46.75; 19F NMR (471 MHz , CDCb) delta -62.65, -160.62; IR (neat) 3495.2, 3383.4, 1627.4, 1480.1, 1411.1, 1275.1, 1250.8, 1120.3, 1070.0, 797.8 cm-1; HRMS (ESI) m/z calcd for C14H12N3O2F4 [M+H]+ 330.0860, found 330.0858.
76%	With iodine; triethylamine; In dimethyl sulfoxide; at 120℃; for 24h;Inert atmosphere;	To a stirred solution of <strong>[211693-73-1]2,3-difluoro-6-nitroaniline</strong> (0.200 g, 1.11 mmol, 1.00 equiv) in dry DMSO (4.6 mL) were added 3-(trifluoromethyl)benzylamine (0.195 mL, 1.34 mmol, 1.2 equiv) followed by Et3N (0.135 g,1.34 mmol, 1.2 equiv) and I2 (cat. 2 mg). The reaction mixture was heated to 120 C for 24 h, cooled to room temperature, diluted with water (25 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 (EtOAc/hexanes,1:10 to 1:4 to 1:3) to afford 2-fluoro-4-nitro-N1-(3-(trifluoromethyl)benzyl)benzene-1,3-diamineas a yellow solid (0.280 g, 76%).
76%	With iodine; triethylamine; In dimethyl sulfoxide; at 120℃; for 24h;Inert atmosphere;	To a stirred solution of <strong>[211693-73-1]2,3-difluoro-6-nitroaniline</strong> 4a (0.200 g, 1.11 mmol) in dry DMSO (4.6 mL) were added 3- (trifluoromethyl)benzylamine 3b (0.195 mL, 1.34 mmol) followed by Et3N (0.135 g, 1.34 mmol) and L (cat. 2 mg). The reaction mixture was heated to 120 C for 24 h, cooled to room temperature, diluted with water (25 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine, dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified by chromatography on S1O2 (EtO Ac/hexanes, 1:10 to 1:4 to 1:3) to afford 5b as a yellow solid (0.280 g, 76%): Mp 156.0-157.2 C; IR (ATR) 3495, 3383, 1627, 1480, 1411, 1275, 1251, 1120, 1070, 798 cm 1; NMR (400 MHz, CDCL) d 7.86 (dd, 1 H, 7 = 9.6, 1.6 Hz), 7.59-7.57 (m, 2 H), 7.54-7.47 (m, 2 H), 6.15-6.00 (m, 3 H), 4.93 (brs, 1 H), 4.54 (d, 2 H, 7 = 6.0 Hz); 13C NMR (100 MHz, CDCL) d 140.9 (d, 7 = 9.5 Hz), 138.9, 138.0 (d, 7 = 228.6 Hz), 135.2 (d, 7 = 12.9 Hz), 131.5 (q, 7 = 32.5 Hz), 130.5, 129.6, 125.6 (d, 7 = 3.5 Hz), 124.9 (q, 7 = 3.7 Hz), (0195) 124.1 (q, 7 = 272.4 Hz), 124.0 (q, 7 = 3.7 Hz), 123.7 (d, 7 = 2.9 Hz), 100.7 (d, 7 = 2.9 Hz), 46.8; 19F NMR (471 MHz , CDCL) d -62.7 (s, 3 F), -160.6 (s, 1 F); HRMS (HESI) m/z calcd for (0196) C14H12N3O2F4 [M+H]+ 330.0860, found 330.0858.

Reference： [1]Patent: WO2016/77724,2016,A1 .Location in patent: Page/Page column 65
[2]Molecular Pharmacology,2016,vol. 89,p. 667 - 677
[3]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 929 - 935
[4]Patent: WO2019/203951,2019,A1 .Location in patent: Page/Page column 34

55
[ 2740-83-2 ]
[ 57-13-6 ]
[ 296277-59-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrogenchloride In water for 3h; Reflux;	24A Example 24A 1-[3-(Trifluoromethyl)benzyl]urea Example 24A 1-[3-(Trifluoromethyl)benzyl]urea 3.9 g (39.5 mmol) of conc. hydrochloric acid were added dropwise to 54 g (308 mmol) of 3-(trifluoromethyl)benzylamine and 74 g (1.23 mol) of urea in 124 ml of water, and the mixture was heated at reflux for three hours. The mixture was then allowed to cool to 20° C. and the solid formed was filtered off with suction. The solid was washed with water and then dried under reduced pressure. This gave 66.6 g (95% of theory) of the target compound. LC-MS (Method 3): Rt=0.73 min; m/z=219 (M+H)+.

Reference： [1]Current Patent Assignee: BAYER AG - US2016/297771, 2016, A1 Location in patent: Paragraph 0480; 0481; 0482

56
[ 2740-83-2 ]
[ 598-21-0 ]
2-bromo-N-(3-(trifluoromethyl)benzyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With triethylamine; In dichloromethane; at 0 - 25℃; for 2h;Inert atmosphere;	General procedure: Substituted Benzyl amine IV (a-p) (10 mmol) in dichloromethane(50 mL) charged with triethylamine (12 mmol), and cooled to 0 C. 2-bromoacetylbromide (11 mmol) was added drop wise, continued stirring for 2 h at room temperature (monitored by TLC). The resulting mixture was concentrated under reduced pressure and the residue waspurified by column chromatography using EtOAc/Hexanes as eluent to afford the desired product Va - Vp.

Reference： [1]Bioorganic Chemistry,2020,vol. 100
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 11148 - 11160

57
[ 2740-83-2 ]
[ 21279-62-9 ]
3-[(3-trifluoromethylbenzyl)amino]pyrazine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	With triethylamine; In tetrahydrofuran; at 70℃; for 15.0h;	General procedure: Compounds 1-6 were prepared according to conventional organic synthesis methods. 3-Chloropyrazine-2-carboxamide (1.27 mmol) was dissolved in THF (20 mL) in a round bottom flask and after that treated with two equivalents of the corresponding benzylamine and an equimolar amount of triethylamine. The reaction was conducted with continuous stirring and heating (70 C) under reflux in an oil bath for 15 h. Compounds 7-15 were synthesised using a microwave reactor with a focused field. 3-Chloropyrazine-2-carboxamide (1.27 mmol) was put into a thick-walled tube together with the corresponding benzylamine (2.54 mmol), pyridine (1.27 mmol), methanol (approx. 5 mL) and a magnetic stir bar and then sealed with a special cap. The reaction parameters were set according to the previously published paper as follows-140 C, 30 min, 200 W [29]. Reaction progress was checked by TLC (hexane:ethyl acetate-1:1). Regardless of the synthesis method used,all reaction mixtures were adsorbed on silica and subjected to preparative flash chromatography (hexane and ethyl acetate, gradient elution, detection wavelengths 260 nm and 280 nm). Products were recrystallized from ethanol or ethanol and water if necessary. All final substances were chemically characterized (1H-NMR, 13C-NMR, IR, melting point and elemental analysis).

Reference： [1]Molecules,2017,vol. 22

58
[ 2740-83-2 ]
[ 331-39-5 ]
(E)-3-(3,4-dihydroxyphenyl)-N-(3-(trifluoromethyl)benzyl)acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80.2%		Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 3- (trifluoromethyl) benzylamine (0.16 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1N-HCl and brine. The organic layer was dried over anhydrous Mg2SO4, concentrated under reduced pressure and purified by column chromatography. Yield 80.2%
		General procedure: To a solution of caffeic acid (1.0 equiv.), HOBt (1.0 equiv.) and EDCI (1.0 equiv.) in DMF were stirred at room temperature for 15 min. To this solution was added amine derivative (1.0 equiv.) and the reaction mixture was stirred at room temperature. After 15 min the reaction mixture was treated with DIPEA (2.0 equiv.) stirred at room temperature for 16 h. The reaction progress is monitored by TLC and then it was quenched with 1N HCl and extracted with EtOAc (3 x 15 mL), the organic layer was dried over MgSO4, filtered, concentrated in vacuo. The residue was purified by silica gel column chromatography (10-25% EtOAc/hexanes) to afford desired products in good yields (5-90%).

Reference： [1]Patent: KR101693033,2017,B1 .Location in patent: Paragraph 0282; 0283; 0284; 0285
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3374 - 3377

59
[ 2740-83-2 ]
[ 886-66-8 ]
3,6-diphenyl-2-[3-(trifluoromethyl)phenyl]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 10h;	General procedure: 1,4-Disubstituted-1,3-diacetylene (0.25 mmol) and K2CO3 (0.5 mmol) were added, under air, toa solution of appropriate benzylamine (2.0 mmol) in DMSO (0.5 mL) previously heated at 140 C.The resulting solution was stirred for 10 h at this temperature and washed with saturated aqNaCl,extracted with ethyl acetate (3 15 mL). The combined organic phase was dried with anhydrousNa2SO4, filtrated and concentrated under vacuum to yield the crude product. The crude product waspurified by thin layer chromatography on silica gel with petroleum ether as eluent.

Reference： [1]Molecules,2017,vol. 22

60
[ 2740-83-2 ]
[ 2369-11-1 ]
4-nitro-N¹-(3-(trifluoromethyl)benzyl)benzene-1,3-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With iodine; triethylamine In dimethyl sulfoxide for 4h; Reflux; Inert atmosphere;	6.1 Step 1: Synthesis of 4-Nitro-N¹-(3-(trifluoromethyl)benzyl)benzene-1,3-diamine 5-Fluoro-2-nitroaniline (10.24 g, 58.46 mmole) was dissolved in anhydrous dimethylsulfoxide (90 mL). 3-fluorobenzylamine (6.1 g, 39.0 mmole) was added triethylamine (13.0 mL) and solid iodine (90 mg) were added and the mixture was heated at reflux for 4 h. under argon. The reaction was dissolved in ethyl acetate (200 mL) and extracted with water (3*200 mL). The combined aqueous layers were washed with (300 mL) ethyl acetate, combined and then evaporated to dryness. The crude material was triturated with hexane/ethyl acetate (7:3, 100 mL) and dried under high vacuum to give 4-nitro-N1-(3-(trifluoromethyl)benzyl)benzene-1,3-diamine (8.29 g, 77% yield).

Reference： [1]Current Patent Assignee: OCUTERRA THERAPEUTICS INC - US2017/355679, 2017, A1 Location in patent: Paragraph 0348; 0349

61
[ 2740-83-2 ]
[ 30982-08-2 ]
C₁₈H₁₈F₃NO₄ [ No CAS ]

Reference： [1]ACS Catalysis,2018,vol. 8,p. 742 - 746

62
[ 2740-83-2 ]
[ 1801-10-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With tert.-butylhydroperoxide; caesium carbonate; In water; acetonitrile; for 4h;Reflux;	General procedure: To a solution of 4-methoxybenzyl amine (1.0 mmol) and cesium carbonate (1.0 mmol) in 3 mL of CH3CN was added a solution of 70% aqueous TBHP (3.0 mmol) and the mixture was refluxed for 4 h. The mixture was then dried to vacuum and extracted three times with ethyl acetate followed by washing with brine,and dried over anhydrous Na2SO4. Evaporation of the solvent under vacuum afforded the crude product, which was furthur purified by column chromatography using hexane/ethyl acetate mixture and then analyzed by spectroscopy.

Reference： [1]Chemistry - A European Journal,2018,vol. 24,p. 1067 - 1071
[2]Tetrahedron Letters,2019,vol. 60

63
[ 2740-83-2 ]
[ 75541-62-7 ]
2-(cyclohexanecarboxamido)-N-(3-(trifluoromethyl)benzyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With trimethylaluminum; In toluene; at 20 - 100℃; for 16h;	General procedure: A solution of methyl or ethyl benzoate(0.191 mmol) and amine (0.383 mmol) in toluene (2.00 mL) wastreated at room temperature with AlMe3 (0.192 mL, 2.0M intoluene, 0.384 mmol). The reaction mixture was stirred overnightat 100 C and then quenched with 100 mL of water. The mixturewasconcentrated, redissolved in 2.00mL of DMSO, filtered and purifiedvia C18 reverse phase HPLC to give the final product.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 156,p. 79 - 92

64
[ 2740-83-2 ]
C₂₃H₃₂O₄ [ No CAS ]
C₃₁H₃₈F₃NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%		General procedure: Taking 100.0 mg of carnosic acid derivative of formula (I) R1 as -OH structure,Soluble in 5ml DCM,0.14 ml of N,N-diisopropylethylamine (DIPEA) (0.81 mmol) was added.Stir in the ice bath for 15 min,112.4 mg of O-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) was added.After stirring at room temperature for 1 h, add different primary amines.Thin layer chromatography to detect the progress of the reaction,DCM/H2O extraction,The organic phase is washed with a saturated NaCl solution.Dry anhydrous Na2SO4,filter,Concentrated under reduced pressure,Purified by column chromatography,Obtaining the formula (I) R1 is a methylamino group,Ethylamine,Allylamine group,Cyclohexylamine,Benzylamine,4-methylbenzylamino,3-aminobenzylamino,4-methoxybenzylamino,O-chlorobenzylamine,2-phenethylamine,3-pyridinemethylamino group,2-furanylamino group,4-hydroxybenzylamino group,4-bromobenzylamine,3-chlorobenzylamino,3-(trifluoromethyl)benzylamino,An amide series of compounds A1 to A19 having a 2,4-dichlorobenzylamino group or a p-chlorobenzylamino structure.The primary amine used and the corresponding reaction time,
87%		General procedure: 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.1 equivalents) was added to a solution of compound 1 (1 equivalent) and N-ethyldiisopropylamine (3 equivalents) in CH2Cl2 (5 ml) at 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. Then, in a typical experiment, primary amine (1.1 equivalents) was added and stirred for 1-6 h, diluted with CH2Cl2 (50 ml), washed with brine (3×50 ml), dried over Na2SO4, filtered and evaporated in vacuo. Chromatography on silica gel using petroleum ether : ethyl acetate as the eluent gave 5a-5m.

Reference： [1]Patent: CN108191812,2018,A .Location in patent: Paragraph 0060-0064
[2]Phytochemistry Letters,2018,vol. 27,p. 82 - 86

65
[ 2740-83-2 ]
(4-chloro)phenethyl benzyl carbamate [ No CAS ]
1-(4-chlorophenethyl)-3-(3-trifluoromethylbenzyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%		General procedure: To a solution of morpholine (0.115 g, 1.321 mmol) in toluene (5 mL) DABAL-Me3 (0.406 g. 1.321 mmol) was added. The mixture was stirred for 20 min at 40 C. 4a (0.250 g, 1.100 mmol) were added and allowed to stir for 2 h at 90 C. The reaction mixture was quenched by the addition of 1M HCl (4 mL) and extracted with CH2Cl2 (2 × 20 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by flash column chromatography on silica gel with hexane-EtOAc as eluent to afford the desired product 6a (0.213 g, 94 %).

Reference： [1]Tetrahedron,2018,vol. 74,p. 4036 - 4046

66
[ 2740-83-2 ]
[ 91-02-1 ]
1-phenyl-3-(3-(trifluoromethyl) phenyl) imidazo[1,5-a]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With iodine; sodium acetate In 1,2-dichloro-ethane for 5.5h; Reflux;
80%	Stage #1: phenyl(pyridin-2-yl)methanone With manganese(IV) oxide; toluene-4-sulfonic acid at 20℃; for 0.25h; Inert atmosphere; Stage #2: 3-(TRIFLUOROMETHYL)BENZYLAMINE at 170℃; for 5.5h; Inert atmosphere; Microwave irradiation;	General procedures for the preparation of imidazo[1,5-a]pyridine and-quinoline derivates General procedure: Ketone (1.1 mmol), activated MnO2 (1.8 mmol), and pTsOH (0.3 mmol) were stirred briefly in a 15 mL round bottom flask at room temperature for 5 min. Afterward, the mixture was heated in an open microwave reactor (equipped with a condenser) for 5.5 h at 170 °C (max. 300 W). During this time, the amine (1.6 mmol) was added with a syringe pump (PTFE tube). The crude product was purified via flash chromatography or recrystallization.

Reference： [1]Hu, Zhiyuan; Hou, Jiao; Liu, Jie; Yu, Wenquan; Chang, Junbiao [Organic and Biomolecular Chemistry, 2018, vol. 16, # 31, p. 5653 - 5660]
[2]Herr, Jasmin Martha; Rössiger, Carina; Albrecht, Georg; Yanagi, Hisao; Göttlich, Richard [Synthetic Communications, 2019, vol. 49, # 21, p. 2931 - 2940]

67
[ 2740-83-2 ]
[ 96989-50-3 ]
[ 2740-85-4 ]

Yield	Reaction Conditions	Operation in experiment
53%	In dichloromethane for 16h; Inert atmosphere;

Reference： [1]Anderson, Ruthellen H.; Lensing, Cody J.; Forred, Benjamin J.; Amolins, Michael W.; Aegerter, Cassandra L.; Vitiello, Peter F.; Mays, Jared R. [ChemMedChem, 2018, vol. 13, # 16, p. 1695 - 1710]

68
[ 2740-83-2 ]
[ 677306-38-6 ]
[ 1194017-42-9 ]

Reference： [1]Patent: WO2009/134666,2009,A1

69
[ 2740-83-2 ]
[ 1020743-28-5 ]
[ 1240473-96-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / isopropyl alcohol / 48 h / 110 °C 2: lithium hydroxide / 1,4-dioxane / 0.33 h / 90 °C / microwave irradiation

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2010/93419, 2010, A1

70
[ 2740-83-2 ]
[ 150841-01-3 ]
N-[3-oxolup-20⁽²⁹⁾-en-28-oyl]-3-(trifluoromethyl)benzylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With pyridine; In benzene; at 20℃; for 20h;	General procedure: To a stirred solution of a fluorine-containing aromatic amine(1 mmol) in dry benzene (15 ml), pyridine (0.15 ml) and then dropwisea solution of betulonic acid chloride 20 (1 mmol) in dry benzene(10 ml) were added. The reaction mixture was stirred for 20 h at roomtemperature, washed with 3% aqueous HCl (3×10 ml) and dried overanhydrous MgSO4. After a filtration, the solvent was removed underreduced pressure. A column chromatography (an EtOAc/hexane eluation)of the residue afforded pure compounds 1-4 as colorless solids.

Reference： [1]Steroids,2019,vol. 147,p. 62 - 69

71
[ 75-15-0 ]
[ 2740-83-2 ]
[ 762-42-5 ]
methyl 2-[4-oxo-3-(m-trifluoromethylphenylmethyl)-2-thioxo-1,3-thiazolidine-5-yliden]ethanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		General procedure: Amine (0.386 mL) was added to Triton-B and stirred for 10 min followed by the addition of CS2 (0.321 mL) dropwise. Then dimethyl acetate carboxylate was added again dropwise. The mixture was stirred for 2.5 h. TLC plate showed the formation of some new compound. The reaction was seen continuously and formation of product was monitored with TLC. After the completion, the reaction mixture was drained into distilled water and extraction was done three times using ethyl acetate (Scheme-I). 2-[4-Oxo-3-(m-trifluoromethylphenylmethyl)-2-thioxo-1,3-thiazolidine-5-yliden]ethanoate (1): Yield 75 %, m.p.:76 C, yellow powder. IR (KBr, numax, cm-1): 1720 (C=O), 1680(C=C), 1342, 1187 (C=S). 1H NMR: (400 MHz, CDCl3): delta 7.5 (multiplet arom. H), 6.8-7.0 (singlet delta vinylic H), delta 5.4 (singlet2H adj. to N), 3.9 (singlet 3H of CH3O). Elemental analysis calcd. (found) % for C14H10NO3S2F3: C 47.9 (46.8), H 2.84 (2.64), O13.6 (14.4), S 18.2 (17.2), F 16.2 (15.9).

Reference： [1]Asian Journal of Chemistry,2019,vol. 31,p. 176 - 180

72
[ 2740-83-2 ]
[ 98534-80-6 ]
C₁₉H₁₂ClF₆N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine

Reference： [1]Harcken, Christian; Sarko, Christopher; Mao, Can; Lord, John; Raudenbush, Brian; Razavi, Hossein; Liu, Pingrong; Swinamer, Alan; Disalvo, Darren; Lee, Thomas; Lin, Siqi; Kukulka, Alison; Grbic, Heather; Patel, Mita; Patel, Monica; Fletcher, Kim; Joseph, David; White, Della; Amodeo, Laura; Berg, Karen; Brown, Maryanne; Thomson, David S. [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 3, p. 435 - 440]

73
[ 515131-35-8 ]
[ 2740-83-2 ]
C₂₂H₂₅BF₃NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 8h;	General procedure: <strong>[515131-35-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</strong> (8.95g, 31mmol) was stirred in a solvent of 58 dimethyl formamide (25mL).The reaction solution was added with 59 HATU (12.98g, 34.1mmol), 72 DIPEA (10.26mL, 62.0mmol) and 104 3-(trifluoromethyl)aniline (5g, 31mmol), followed by stirring for about 8h at room temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was concentrated to give the crude 132 product, which was purified by silica gel column chromatography.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 163,p. 671 - 689

74
[ 2740-83-2 ]
[ 5424-01-1 ]
3-amino-N-(3-(trifluoromethyl)benzyl)pyrazine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With 1,1'-carbonyldiimidazole; In dimethyl sulfoxide; at 120℃; for 0.5h;Microwave irradiation;	General procedure: The starting 3-aminopyrazine-2-carboxylic acid (200 mg; 1.44 mmol) was treated with1,10-carbonyldiimidazole (CDI; 303 mg; 1.88 mmol; 1.3 equiv) in DMSO (2 mL) in a special tubeused for microwave reactions. The reaction mixture was left to react for 5-10 min until the bubblingdue to emerging CO2 ceased. Subsequently the corresponding alkylamine/aniline/benzylamine(2.15 mmol, 1.5 equiv) was added. The microwave reactor was used to form the amide bond underfollowed conditions: 120 C, 30 min, 100 W. The progress of the reaction was checked using TLCon silica desk developed by hexane/ethyl-acetate 2:1 system. Water (6 mL) was poured into thereaction mixture, the precipitate was filtered off, dissolved again in acetone and adsorbed to silica.The prepared sample was subjected to flash chromatography as described in previous section.

Reference： [1]Molecules,2019,vol. 24

75
[ 2740-83-2 ]
[ 138528-62-8 ]
C₁₈H₁₆F₃NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	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 12h;	General procedure: To a solution of (E)-2-(2-methoxyvinyl)benzoic acid (1.0 eq.), various amines (1.2 equiv), EDCI HCl (1.1 equiv), HOBt H2O (1.1equiv) in DMF (1 mL), DIPEA (2.5 equiv) was added at rt and the reaction mixture was stirred for 12 h. The reaction workup is proceed by diluting the reaction mixture with water, then extracted with EtOAc. The combined organic layers were dried over MgSO4 and the solvent was removed under vacuum to give a crude oil. The crude mixture was purified by column chromatography using MeOH/DCM as an eluent to afford various coupled products with yield ranging from 30 to 80%.

Reference： [1]Tetrahedron Letters,2019,vol. 60,p. 1259 - 1261

76
[ 2740-83-2 ]
[ 100-09-4 ]
4-methoxy-N-[3-(trifluoromethyl)phenyl]methyl}benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%		General procedure: A solution of 24 (1.0 equiv.), HOBt (1.1 equiv.) and EDC (1.5 equiv.) in DMF (1.3 mmol/mL) was stirred at rt for 15 minutes. The appropriate amine (2.0 equiv.) was added and the resulting solution was stirred at rt for 5 hours. Reaction media was diluted with water and aqueous phase was extracted 3 times with EtOAc. Combined organic layers were washed successively with a solution of HCl 1N, a saturated solution of NaHCO3 and brine, dried over Na2SO4 and concentrated. The resulting solid was then purified by column chromatography on silica gel using the appropriate heptanes:EtOAc mixture.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 177,p. 269 - 290

77
[ 2740-83-2 ]
[ 1312012-36-4 ]
9-(3-(trifluoromethyl)benzyl)-9H-pyrido[3,4-b]indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; In toluene; at 110℃; for 8h;Inert atmosphere;	General procedure: Aniline (89 mg, 0.958 mmol, 3 equiv.) was added to a pressure tube that was charged with 3-bromo-4-(2-bromophenyl)pyridine 3 (100 mg, 0.319 mumol, 1 equiv.), Pd2(dba)3 (15 mg, 16 mumol, 0.05 equiv.), dppf (18 mg, 32 mumol, 0.1 equiv.) and sodium tert-butoxide (184 mg, 1.917 mmol, 6 equiv.) under argon. The tube was backfilled with argon several times. The degassed anhydrous toluene (5 mL) was added under argon. The reaction mixture then heated at 110 C for 12 h. After cooling, the reaction mixture was diluted with dichloromethane (10 mL), and the resulting mixture was filtered through a pad of Celite, which was washed three times with dichloromethane (30 mL). The filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel; hexane/ethyl acetate, 5:1) to yield 5a (72 mg, 92%)

Reference： [1]Tetrahedron,2019,vol. 75

78
[ 2740-83-2 ]
[ 933-20-0 ]
C₁₁H₉ClF₃N₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 7557 - 7574

79
[ 2740-83-2 ]
[ 53413-67-5 ]
N-(4,5-dimethoxy-2-nitrobenzyl)-1-(3-(trifluoromethyl)phenyl)methanamine [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2019,vol. 141,p. 15784 - 15791

80
[ 2740-83-2 ]
[ 5451-40-1 ]
2-chloro-N-(3-(trifluoromethyl)benzyl)-9H-purine-6-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With triethylamine; In butan-1-ol; at 110℃; for 3h;	Add n-butanol (50mL) and 2,4-dichloropyrimidine (5g, 26.7mmol) to the eggplant-shaped bottle (250mL), stir to dissolve,Then, 3- (trifluoromethyl) benzylamine (4.7 g, 27 mmol) and triethylamine (3.4 g, 33.6 mmol) were slowly added dropwise, and the temperature was raised to 110 C for 3 hours.The reaction was detected by TLC. After cooling to 20 C, solids precipitated.It was washed with n-butanol (5 mL) and dried to give a white solid product (5.9 g, yield 67%).

Reference： [1]Patent: CN110256436,2019,A .Location in patent: Paragraph 0096; 0115-0117

81
[ 2740-83-2 ]
[ 2379-60-4 ]
N<SUP>2</SUP>-(3-(trifluoromethyl)benzyl)-N<SUP>3</SUP>-(3-(dimethylamino)propyl)-6-nitroquinoxaline-2,3-diamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 7840 - 7856

82
[ 2740-83-2 ]
[ 2379-60-4 ]
C₁₆H₁₀ClF₃N₄O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 7840 - 7856

83
[ 2740-83-2 ]
[ 331-39-5 ]
(E)-3-(3,4-dihydroxyphenyl)-N-(3-(trifluoromethyl)benzyl)acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80.2%		Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and stirred at room temperature for 20 minutes. After 20 minutes, 3- (trifluoromethyl) benzylamine (0.16 mL, 1.11 mmol) was added thereto and stirred at room temperature for 20 minutes.After 20 minutes DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h and then extracted with EtOAc, water, 1N-HCl and brine.The organic layer was dried over anhydrous Mg 2 SO 4, concentrated under reduced pressure, and purified by column chromatography.Yield 80.2%;

Reference： [1]Patent: KR101693034,2017,B1 .Location in patent: Paragraph 0093; 0173-0176

84
[ 2740-83-2 ]
[ 2935-44-6 ]
2,5-dimethyl-1-(3-(trifluoromethyl)benzyl)pyrrolidine [ No CAS ]
2,5-dimethyl-1-(3-(trifluoromethyl)benzyl)pyrrolidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52 % de	With trimethylamine-N-oxide; [bis(hexamethylene)cyclopentadienone]iron tricarbonyl In toluene at 150℃; for 24h; Inert atmosphere; Schlenk technique; Molecular sieve; Sealed tube; Overall yield = 72 percent; Overall yield = 92.6 mg;	HB Amination of Alcohols; General Procedure Toluene (0.25 mL) was added to a mixture of pre-catalyst 1i (9.6 mg,0.025 mmol, 0.05 equiv) and Me3NO (3.8 mg, 0.050 mmol, 0.010equiv) under argon in a Schlenk vessel fitted with a Teflon screw cap.The resulting solution, which gradually turned from yellow to darkred, was stirred for 20 minutes at r.t. The amine substrate 3 (0.5mmol, 1 equiv) was added, followed by 3Å MS (beads, 400 mg), the respective alcohol (2.0 mmol, 4.0 equiv), and additional toluene (1.75mL). The reaction vessel was sealed and stirred in a pre-heated oil bath at 150 °C for 24 h or 72 h. After cooling down, the mixture was filtered through Celite (rinsing several times with EtOAc), and then the solvent was removed with a rotavapor. The product was purifiedby flash chromatography

Reference： [1]Aiolfi, Francesco; Bai, Xishan; Cettolin, Mattia; Dal Corso, Alberto; Gennari, Cesare; Piarulli, Umberto; Pignataro, Luca [Synthesis, 2019, vol. 51, # 18, p. 3545 - 3555]

85
[ 2740-83-2 ]
[ 791061-00-2 ]
[ 530-62-1 ]
1-(3,3-difluorocyclobutyl)-3-(3-trifluoromethylbenzyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-(TRIFLUOROMETHYL)BENZYLAMINE; 1,1'-carbonyldiimidazole With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; for 3h; Inert atmosphere; Stage #2: 3,3-difluorocyclobutan-1-amine In water monomer; acetonitrile at 60℃; Inert atmosphere;	1 Example 1: 1-(3,3-Difluoro-cyclobutyl)-3-(3-trifluoromethyl-benzyl)-urea To a solution of 3-(trifluoromethyl)benzylamine (18 mg, 0.1 mmol, 1.0 eq) in MeCN (0.5 mL), DIPEA (19 μL, 0.11 mmol, 1.1 eq) and a solution of CDI (32 mg, 0.2 mmol, 2.0 eq) in MeCN (0.2 mL) were added in sequence. The mixture was stirred at 60 °C for 3 hours. A solution of 3,3-difluorocyclobutan-1-amine (21 mg, 0.2 mmol, 2.0 eq) in MeCN (0.5 mL) and H2O (0.1 mL) was added. The mixture was further stirred at 60 °C overnight. The mixture was allowed to cool to rt and purified by prep. HPLC (column: Waters XBridge, 30x75 mm, 10 um, UV/MS, basic conditions). LC-MS (1): tR = 0.99min; [M+H]+: 309.2.

Reference： [1]Current Patent Assignee: IDORSIA PHARMACEUTICALS LTD - WO2021/260090, 2021, A1 Location in patent: Page/Page column 40

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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.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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