[ CAS No. 402-49-3 ] {[proInfo.proName]}

Name: 402-49-3|1-(Bromomethyl)-4-(trifluoromethyl)benzene|98%
Brand: Ambeed
SKU: A439908
Price: 5.0 USD
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Quality Control of [ 402-49-3 ]

COA NMR CNMR HPLC LC-MS

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Product Citations Expand+

N-substituted-4-(pyridin-4-ylalkyl) piperazine-1-carboxamides and related compounds as Leishmania CYP51 and CYP5122A1 inhibitors

La Rosa, Chris ; Sharma, Pankaj ; Dar, M Junaid , et al. Bioorgan. Med. Chem.,2024,117907. DOI: 10.1016/j.bmc.2024.117907

Abstract: CYP5122A1, an enzyme involved in sterol biosynthesis in Leishmania, was recently characterized as a sterol C4-methyl oxidase. Screening of a library of compounds against CYP5122A1 and CYP51 from Leishmania resulted in the identification of two structurally related classes of inhibitors of these enzymes. Analogs of screening hit N-(3,5-dimethylphenyl)-4-(pyridin-4-ylmethyl)piperazine-1-carboxamide (4a) were generally strong inhibitors of CYP51 but were less potent against CYP5122A1 and typically displayed weak inhibition of L. donovani promastigote growth. Analogs of screening hit N-(4-(benzyloxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18a) were stronger inhibitors of both CYP5122A1 and L. donovani promastigote proliferation but also remained selective for inhibition of CYP51. Two compounds in this series, N-(4-((3,5-bis(trifluoromethyl)benzyl)oxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18e) and N-(4-((3,5-di-tert-butylbenzyl)oxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18i) showed modest selectivity for inhibiting L. donovani promastigote proliferation compared to J774 macrophages and were effective against intracellular L. donovani with EC₅₀ values in the low micromolar range. Replacement of the 4-pyridyl ring present in 18e with imidazole resulted in a compound (4-(2-(1H-imidazol-1-yl)ethyl)-N-(4-((3,5-bis(trifluoromethyl)benzyl)oxy)phenyl)piperazine-1-carboxamide, 18p) with approximately fourfold selectivity for CYP5122A1 over CYP51 that inhibited both enzymes with IC₅₀ values ≤ 1 µM, although selective potency against L. donovani promastigotes was lost. Compound 18p also inhibited the proliferation of L. major promastigotes and caused the accumulation of 4-methylated sterols in L. major membranes, indicating that this compound blocks sterol demethylation at the 4-position in Leishmania parasites. The molecules described here may therefore be useful for the future identification of dual inhibitors of CYP51 and CYP5122A1 as potential antileishmanial drug candidates and as probes to shed further light on sterol biosynthesis in Leishmania and related parasites.

Keywords: Leishmaniasis ; drug discovery ; CYP51 ; CYP5122A1

Purchased from AmBeed: 62089-74-1 ; 6293-56-7 ; 402-49-3 ; 32247-96-4

Quinolone-3-amidoalkanol: A New Class of Potent and Broad-Spectrum Antimicrobial Agent

Dube, Phelelisiwe S. ; Angula, Klaudia T. ; Legoabe, Lesetja J. , et al. ACS Omega,2023,8(19):17086-17102. DOI: 10.1021/acsomega.3c01406 PubMed ID: 37214682

Abstract: Herein, we describe 39 novel quinolone compounds bearing a hydrophilic amine chain and varied substituted benzyloxy units. These compounds demonstrate broad-spectrum activities against acid-fast bacterium, Gram-pos. and -neg. bacteria, fungi, and leishmania parasite. Compound 30 maintained antitubercular activity against moxifloxacin-, isoniazid-, and rifampicin-resistant Mycobacterium tuberculosis, while 37 exhibited low micromolar activities (<1 μg/mL) against World Health Organization (WHO) critical pathogens: Cryptococcus neoformans, Acinetobacter baumannii, and Pseudomonas aeruginosa. Compounds in this study are metabolically robust, demonstrating % remnant of >98% after 30 min in the presence of human, rat, and mouse liver microsomes. Several compounds thus reported here are promising leads for the treatment of diseases caused by infectious agents.

Purchased from AmBeed: 403-19-0 ; 636-93-1 ; 5847-59-6 ; 87-13-8 ; 1548-61-4 ; 99-53-6 ; 402-49-3 ; 619-08-9 ; 18880-00-7 ; 111-41-1 ; 619-10-3 ; 766-80-3 ; 140-75-0 ; 823-78-9 ; 622-95-7 ; 402-23-3 ; 141776-91-2 ...More

Product Details of [ 402-49-3 ]

CAS No. :	402-49-3	MDL No. :	MFCD00000403
Formula :	C₈H₆BrF₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IKSNDOVDVVPSMA-UHFFFAOYSA-N
M.W :	239.03	Pubchem ID :	123062
Synonyms :

Calculated chemistry of [ 402-49-3 ] Expand+

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	44.28
TPSA :	0.0 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.24 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.32
Log Po/w (XLOGP3) :	3.55
Log Po/w (WLOGP) :	4.6
Log Po/w (MLOGP) :	4.12
Log Po/w (SILICOS-IT) :	3.83
Consensus Log Po/w :	3.69

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.8
Solubility :	0.0382 mg/ml ; 0.00016 mol/l
Class :	Soluble
Log S (Ali) :	-3.24
Solubility :	0.139 mg/ml ; 0.000582 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.55
Solubility :	0.00678 mg/ml ; 0.0000284 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	1.74

Safety of [ 402-49-3 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	3261
Hazard Statements:	H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 402-49-3 ]

* 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 [ 402-49-3 ]
Downstream synthetic route of [ 402-49-3 ]

[ 402-49-3 ] Synthesis Path-Upstream 1~13

1
[ 349-95-1 ]
[ 402-49-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2010, vol. 53, # 8, p. 3389 - 3395
[2] Organic Letters, 2018, vol. 20, # 10, p. 3061 - 3064
[3] Journal of the American Chemical Society, 1983, vol. 105, # 5, p. 1221 - 1227
[4] Journal of the American Chemical Society, 1949, vol. 71, p. 1767,1768, 3482, 3485
[5] Canadian Journal of Chemistry, 1970, vol. 48, p. 125 - 132
[6] Journal of Organic Chemistry USSR (English Translation), 1970, vol. 6, p. 2091 - 2095[7] Zhurnal Organicheskoi Khimii, 1970, vol. 6, p. 2085 - 2090
[8] Journal of Medicinal Chemistry, 1971, vol. 14, p. 862 - 866
[9] Arzneimittel Forschung, 1965, vol. 15, p. 1251 - 1253
[10] Tetrahedron, 1984, vol. 40, # 10, p. 1863 - 1868
[11] Journal of Organic Chemistry, 1981, vol. 46, # 21, p. 4247 - 4252
[12] Tetrahedron, 1997, vol. 53, # 24, p. 8211 - 8224
[13] Journal of Medicinal Chemistry, 2005, vol. 48, # 2, p. 556 - 568
[14] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6842 - 6846
[15] Patent: US5554620, 1996, A,
[16] Organic and Biomolecular Chemistry, 2015, vol. 13, # 40, p. 10136 - 10149
[17] Chemical Biology and Drug Design, 2016, p. 97 - 109
[18] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 100 - 114

2
[ 455-24-3 ]
[ 402-49-3 ]

Reference： [1] Organic Letters, 2012, vol. 14, # 18, p. 4842 - 4845,4
[2] Journal of the American Chemical Society, 1983, vol. 105, # 5, p. 1221 - 1227
[3] Canadian Journal of Chemistry, 1970, vol. 48, p. 125 - 132
[4] Synthesis (Germany), 2013, vol. 45, # 23, p. 3233 - 3238

3
[ 583-02-8 ]
[ 402-49-3 ]

Reference： [1] Journal of the American Chemical Society, 1983, vol. 105, # 5, p. 1221 - 1227
[2] Journal of the American Chemical Society, 1949, vol. 71, p. 1767,1768, 3482, 3485
[3] Canadian Journal of Chemistry, 1970, vol. 48, p. 125 - 132

4
[ 6140-17-6 ]
[ 402-49-3 ]

Reference： [1] Chemical Communications, 2014, vol. 50, # 49, p. 6530 - 6533
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 15, p. 6622 - 6637
[3] Journal of Organic Chemistry USSR (English Translation), 1987, vol. 23, # 4, p. 711 - 719[4] Zhurnal Organicheskoi Khimii, 1987, vol. 23, # 4, p. 788 - 797
[5] European Journal of Organic Chemistry, 2009, # 36, p. 6328 - 6335

5
[ 329-15-7 ]
[ 402-49-3 ]

Reference： [1] Journal of the American Chemical Society, 1949, vol. 71, p. 1767,1768, 3482, 3485
[2] Canadian Journal of Chemistry, 1970, vol. 48, p. 125 - 132
[3] Patent: US5554620, 1996, A,

6
[ 455-19-6 ]
[ 402-49-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6842 - 6846
[2] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 100 - 114

7
[ 774197-61-4 ]
[ 6140-17-6 ]
[ 402-49-3 ]

Reference： [1] Organic Letters, 2004, vol. 6, # 19, p. 3353 - 3356

8
[ 402-51-7 ]
[ 402-49-3 ]

Reference： [1] Arzneimittel Forschung, 1965, vol. 15, p. 1251 - 1253

9
[ 402-49-3 ]
[ 2338-75-2 ]

Reference： [1] Patent: US5502054, 1996, A,
[2] Patent: US5622954, 1997, A,

10
[ 143-33-9 ]
[ 402-49-3 ]
[ 2338-75-2 ]

Reference： [1] Canadian Journal of Chemistry, 1970, vol. 48, p. 125 - 132
[2] Journal of Organic Chemistry, 1981, vol. 46, # 21, p. 4247 - 4252

11
[ 151-50-8 ]
[ 402-49-3 ]
[ 2338-75-2 ]

Reference： [1] Arzneimittel Forschung, 1965, vol. 15, p. 1251 - 1253

12
[ 402-49-3 ]
[ 775-00-8 ]

Reference： [1] Journal of Organic Chemistry, 1981, vol. 46, # 21, p. 4247 - 4252
[2] Canadian Journal of Chemistry, 1970, vol. 48, p. 125 - 132

13
[ 402-49-3 ]
[ 74-89-5 ]
[ 90390-11-7 ]

Reference： [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 15, p. 2882 - 2891

[ 402-49-3 ] Synthesis Path-Downstream 1~109

1
[ 34846-64-5 ]
[ 402-49-3 ]
[ 87861-96-9 ]

Reference： [1]Journal of the American Chemical Society,1983,vol. 105,p. 7629 - 7631

2
[ 6140-17-6 ]
[ 402-49-3 ]

Reference： [1]Chemical Communications,2014,vol. 50,p. 6530 - 6533
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 6622 - 6637
[3]Journal of Organic Chemistry USSR (English Translation),1987,vol. 23,p. 711 - 719
Zhurnal Organicheskoi Khimii,1987,vol. 23,p. 788 - 797
[4]European Journal of Organic Chemistry,2009,p. 6328 - 6335

4
[ 402-49-3 ]
[ 657-64-7 ]

Yield	Reaction Conditions	Operation in experiment
37%	With bromine; iron In dichloromethane for 24h; Heating;

Reference： [1]Kira, Mitsuo; Miyazawa, Takashi; Sugiyama, Hisashi; Yamaguchi, Munehiro; Sakurai, Hideki [Journal of the American Chemical Society, 1993, vol. 115, # 8, p. 3116 - 3124]

5
[ 402-49-3 ]
[ 60886-80-8 ]
[ 132549-56-5 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 173 - 182

6
[ 13438-65-8 ]
[ 402-49-3 ]
2-Imino-1-(4-trifluoromethyl-benzyl)-1,2-dihydro-pyridine-3-carboxylic acid amide; hydrobromide [ No CAS ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1995,vol. 60,p. 1009 - 1015

7
[ 7418-66-8 ]
[ 402-49-3 ]
4-Imino-1-(4-trifluoromethyl-benzyl)-1,4-dihydro-pyridine-3-carboxylic acid amide; hydrobromide [ No CAS ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1995,vol. 60,p. 1009 - 1015

8
[ 1873-77-4 ]
[ 622-95-7 ]
[ 402-49-3 ]
[ 6140-17-6 ]
[ 106-43-4 ]
[ 5089-31-6 ]

Reference： [1]Tetrahedron,1997,vol. 53,p. 8479 - 8490

9
[ 402-49-3 ]
[ 18672-03-2 ]
5,6-Dichloro-1-(4-trifluoromethyl-benzyl)-1H-benzoimidazol-2-ylamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 1252 - 1262

10
[ 402-49-3 ]
[ 16865-11-5 ]
2,5,6-Trichloro-1-(4-trifluoromethyl-benzyl)-1H-benzoimidazole [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 1252 - 1262

11
[ 402-49-3 ]
[ 74-89-5 ]
[ 90390-11-7 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 2882 - 2891

12
[ 31374-18-2 ]
[ 402-49-3 ]
7-chloro-3-(4-trifluoromethyl-benzyl)-3<i>H</i>-quinazolin-4-one [ No CAS ]

Reference： [1]Revue Roumaine de Chimie,1999,vol. 44,p. 341 - 350

13
[ 144978-12-1 ]
[ 402-49-3 ]
(2R,4S)-5-Oxo-4-(4-trifluoromethyl-benzyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 4559 - 4570

14
[ 1483-27-8 ]
[ 402-49-3 ]
[ 648956-85-8 ]

Reference： [1]Helvetica Chimica Acta,2003,vol. 86,p. 2610 - 2619

15
[ 774197-61-4 ]
[ 6140-17-6 ]
[ 402-49-3 ]

Reference： [1]Organic Letters,2004,vol. 6,p. 3353 - 3356

16
[ 64318-28-1 ]
[ 402-49-3 ]
[ 788824-77-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In acetone; for 4h;Reflux;	General procedure: To a N-Boc-tyramine dissolved in acetone was added benzyl bromide derivative and potassium carbonate. The reaction mixture was refluxed at 50-60 C for 4 h. After the reaction, the reaction mixture was filtered, and filtered solution was evaporated in vacuo. The product residue was purified by column chromatography. Using Method C, N-Boc-tyramine (0.50 g, 2.1 mmol), 4-(trifluoromethyl)benzyl bromide (0.60 g, 2.5 mmol), and potassium carbonate (1.17 g, 8.4 mmol) gave 11c as a white solid (0.85 g, 100%): Rf = 0.38 (EtOAc 1: n-Hexane 3): 1H NMR (DMSO-d6, 400 MHz) d 1.35 (s, C(CH3)3), 2.61 (t, J = 7.5 Hz, NHCH2CH2), 3.08 (q, J = 7.9 Hz, NHCH2CH2), 5.19 (s, OCH2), 6.85 (t, J = 5.4 Hz, 1 ArH), 6.91-6.96 (m, 2 ArH), 7.08-7.14 (m, 2 ArH), 7.63-7.78 (m, 4 ArH); 13C NMR (DMSO-d6, 100 MHz) d 28.2 (C(CH3)3), 34.2 (NHCH2CH2), 41.7 (NHCH2CH2), 68.2 (OCH2), 77.4 (C(CH3)3), 114.7, 124.2 (q, JC-F = 270.2 Hz), 125.3, 127.9, 128.2 (q, JC-F = 31.4 Hz), 129.6, 131.9, 142.2, 155.5 (13 ArC), 156.4 (C(O)C(CH3)3).

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 232 - 244
[2]Journal of Medicinal Chemistry,2006,vol. 49,p. 1101 - 1112

17
[ 402-49-3 ]
[ 84057-84-1 ]
5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(4-trifluoromethylphenyl)methyl-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; In acetone; for 5h;Heating / reflux;	4-Trifiuoromethylbenzyl chloride (1.0 g, 4.0 mmol) was added to a stirred suspension of 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine (0.56 g, 2.2 mmol), NaI (0.1 g) and acetone (25 ml). The mixture was stirred and heated at reflux for 5 h. After cooling, the solid was collected by filtration and then stirred with 0.88 aqueous ammonia-water (40 ml, 1:1) for 0.5 h. The resulting solid (ca.0.7 g) was removed by filtration and dried in vacuo. Recrystallisation from methanol gave the product (0.42 g) as a pale yellow solid, mp 198-200 0C. deltaH (500 MHz, dmso-de) 3.32 (3H, s, MeOH), 5.20 (2H, brs, NCH2), 5.3-5.8 (IH, vbrpeak, NH, exchang.), 6.4-6.8 (IH, brs, NH, exchang.), 7- 8 (IH, vbrpeak, NH, exchang.), 7.43 (2H, m, aromatic H), 7.53 (2H, brd, J= 8 Hz, aromatic H), 7.73 (3H, brd, J= 8 Hz, aromatic H). m/z 414, 416 (M+ + 1)

Reference： [1]Patent: WO2008/7149,2008,A2 .Location in patent: Page/Page column 22

18
[ 7770-45-8 ]
[ 402-49-3 ]
[ 925441-98-1 ]

Yield	Reaction Conditions	Operation in experiment
92%		Sodium hydride (104 mg, 2.38 mmol) was suspended in N,N-dimethylformamide (10 mL) in a nitrogen atmosphere, and the suspension was cooled to 0C. <strong>[7770-45-8]4-Hydroxy-1-naphthaldehyde</strong> (257 mg, 1.49 mmol) was slowly added, and the mixture was stirred at 0C for 30 minutes. 1-(Bromomethyl)-4-(trifluoromethyl)benzene (533 mg, 2.23 mmol) was further added, and the mixture was stirred at room temperature for three hours. A dilute hydrochloric acid solution (30 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 ml). The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate = 20/l to 5/1) to give the target compound (451 mg, yield: 92%) as a colorless solid. 1H-NMR (CDCl3, 500MHz):delta ppm: 5.42 (2H, s), 6.98 (1H, d, J=7.8Hz), 7.59-7.75 (6H, m), 7.93 (1H, d, J=7.8Hz), 8.41 (1H, d, J=8.8Hz), 9.33 (1H, d, J=8.8Hz), 10.23 (1H, s). MS (EI) m/z: 330 (M+)

Reference： [1]Patent: EP1914229,2008,A1 .Location in patent: Page/Page column 125

19
[ 3034-62-6 ]
[ 402-49-3 ]
1-[4-(trifluoromethyl)benzyl]-2-iodo-1H-imidazole [ No CAS ]

Reference： [1]Synthesis,2007,p. 529 - 540

20
[ 40928-13-0 ]
[ 402-49-3 ]
C₆H₃C₂O₃NClCH₂C₆H₄CF₃ [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 7058 - 7061

21
[ 402-49-3 ]
[ 67531-86-6 ]
[ 946134-83-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3624 - 3629

22
[ 6374-91-0 ]
[ 402-49-3 ]
5,7-dibromo-N-(p-trifluoromethylbenzyl)isatin [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 5109 - 5117

23
[ 402-49-3 ]
[ 153181-07-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: 1.) EtONa / 1.) EtOH, RT, 10 min, 2.) EtOH, reflux, 15 h 2: 85 percent / 3.9 M aq. NaOH / ethanol / 0.67 h / Ambient temperature 3: 80 percent / dioxane / 1 h / Heating 4: 47 percent / aq. KCl, NaHCO₃, aq. NaOH / acetonitrile / 5 h / Ambient temperature; subtilisin, pH 7.8 5: 90 percent / 6 M aq. HCl / 4 h / Heating 6: 94 percent / SOCl₂ / 2 h / Heating 7: 75 percent / NaBH₄ / ethanol; H₂O / 4.5 h / Heating

Reference： [1]Combret, Yves; Duflos, Jack; Dupas, Georges; Bourguignon, Jean; Queguiner, Guy [Tetrahedron Asymmetry, 1993, vol. 4, # 7, p. 1635 - 1644]

24
[ 583-02-8 ]
[ 402-49-3 ]

Reference： [1]Journal of the American Chemical Society,1983,vol. 105,p. 1221 - 1227
[2]Journal of the American Chemical Society,1949,vol. 71,p. 1767,1768, 3482, 3485
[3]Canadian Journal of Chemistry,1970,vol. 48,p. 125 - 132

25
[ 402-49-3 ]
[ 775-00-8 ]

Reference： [1]Journal of Organic Chemistry,1981,vol. 46,p. 4247 - 4252
[2]Canadian Journal of Chemistry,1970,vol. 48,p. 125 - 132

26
[ 4383-06-6 ]
[ 402-49-3 ]
[ 613240-66-7 ]

Yield	Reaction Conditions	Operation in experiment
		The title compound was prepared in the manner analogous to Example 14A using 1-bromomethyl-4-trifluoromethyl-benzene and 5-hydroxymethyl-2-methoxy-phenol. MS m/z 295 (M-OH).

Reference： [1]Patent: US2003/225158,2003,A1 .Location in patent: Page 67

27
[ 5900-58-3 ]
[ 124-09-4 ]
[ 5162-44-7 ]
[ 446-48-0 ]
[ 7209-38-3 ]
[ 74-96-4 ]
[ 4784-77-4 ]
[ 22288-78-4 ]
[ 542-69-8 ]
bromomethyl resin [ No CAS ]
9-fluorenyl-methoxycarbonyl-cyclohexyl alanine [ No CAS ]
[ 462-94-2 ]
[ 1458-98-6 ]
[ 78-77-3 ]
[ 1809-10-5 ]
[ 110-53-2 ]
[ 592-55-2 ]
[ 7328-91-8 ]
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[ 105-83-9 ]
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[ 35661-40-6 ]
[ 100-39-0 ]
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[ 23915-07-3 ]
[ 71989-23-6 ]
[ 35737-15-6 ]
[ 2592-95-2 ]
[ 18880-00-7 ]
[ 88681-68-9 ]
[ 100063-22-7 ]
[ 75-03-6 ]
[ 106-94-5 ]
[ 104-81-4 ]
[ 589-10-6 ]
[ 107-15-3 ]
[ 109-76-2 ]
[ 110-60-1 ]
[ 7051-34-5 ]
[ 106-95-6 ]
[ 622-95-7 ]
[ 589-15-1 ]
[ 134-20-3 ]
[ 2550-36-9 ]
[ 89-92-9 ]
[ 456-41-7 ]
[ 766-80-3 ]
[ 459-46-1 ]
[ 874-98-6 ]
[ 402-49-3 ]
[ 870-63-3 ]
[ 85118-01-0 ]
[ 22115-41-9 ]
[ 3958-57-4 ]
[ 100-11-8 ]
[ 107-82-4 ]
[ 6482-24-2 ]
[ 3132-64-7 ]
[ 112883-41-7 ]
[ 3433-80-5 ]
[ 52727-57-8 ]
C₁₈H₁₅N₂O₃PolS [ No CAS ]
C₂₀H₂₀N₃OPolS [ No CAS ]
C₂₃H₁₉N₂O₂PolS [ No CAS ]
C₁₈H₂₃ClN₃OPolS [ No CAS ]
C₂₂H₂₆N₃OPolS [ No CAS ]
C₂₂H₂₃N₂O₅PolS [ No CAS ]
C₂₀H₂₆ClN₂O₃PolS [ No CAS ]
C₂₃H₂₂ClN₂O₃PolS [ No CAS ]
C₂₀H₂₁FN₃O₃PolS [ No CAS ]
C₂₂H₂₉N₂O₃PolS [ No CAS ]
C₂₁H₂₈N₃O₃PolS [ No CAS ]
C₁₉H₂₆N₃O₄PolS₂ [ No CAS ]
C₂₂H₃₀N₃OPolS [ No CAS ]
C₂₁H₂₈N₃O₄PolS [ No CAS ]
C₂₆H₂₆N₃OPolS [ No CAS ]
C₂₃H₁₅ClF₃N₂O₂PolS [ No CAS ]
C₂₄H₂₂N₃O₃PolS [ No CAS ]
C₂₃H₁₆ClF₂N₂O₂PolS [ No CAS ]
C₂₂H₂₂Br₂N₃OPolS [ No CAS ]
C₂₄H₂₆FN₂O₅PolS [ No CAS ]
C₂₅H₂₂FN₂O₄PolS [ No CAS ]
C₂₆H₂₂N₃O₄PolS [ No CAS ]
C₂₅H₂₅ClN₃O₃PolS [ No CAS ]
C₂₅H₁₈ClF₂N₂O₃PolS [ No CAS ]
C₂₉H₂₆N₃O₃PolS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With piperidine; Carbonyldiimidazole; tin-2-ethylhexanoate dihydrate; potassium tert-butylate; water; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; diisopropyl-carbodiimide; dibromotriphenylphosphorane; In DMF (N,N-dimethyl-formamide); dichloromethane; N,N-dimethyl acetamide; 1,2-dichloro-ethane;Combinatorial reaction / High throughput screening (HTS);	EXAMPLE 1 [0213] This example shows the synthesis of a combinatorial library of thioquinazolinone derivatives. [0214] Step 1a: Preparation of Wang Bromide Resin [0215] 40 tea bags containing 2 g each of Wang resin (80 g, 120 mmol) was taken in a 5 L PP container. A solution of triphenylphosphine dibromide (152 g, 0.15 M, 3 eq., 360 mmol) in 2000 ml DCM was added and the solution was shaken at room temperature overnight. The resin was sequentially washed with DCM (4×, 1.5 L each) and diethylether (6×, 1.5 L each) and dried under vacuum, to give the bromo wang resin. [0216] Step 1b: Loading of the Nitrophenol on Bromo Wang [0217] 20 g of the Bromo wang resin (1.5 meq/g) was taken in a 2 L wide-mouthed glass container and 1000 mL DMA was addded to it followed by the addition of the nitro phenol (10 eq., 0.3M, 300 mmol). Potasium t-butoxide (33.46 g, 10 eq., 300 mmol) was then added to it and the bottles were heated at 50 C. overnight. The bags were washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The tea bags were then dried overnight in air. The following nitrophenols were used: [0218] 2-METHYL-5-NITROPHENOL [0219] 5-HYDROXY-2-NITROBENZOTRIFLUORIDE [0220] 3-METHYL-4-NITROPHENOL [0221] 2-METHOXY-5-NITROPHENOL [0222] M-NITROPHENOL [0223] Step 1c: Reduction of the Nitro Group to Amine [0224] A 2.0 M solution of tin-2-ethylhexanoate dihydrate was prepared in DMF containing 0.5% H2O. The tea bags were added and the solution is heated at 50 C. for 40 hours. After cooling the bags are washed with DMF/10% HOAc (3×), DMF (3×), 5% DIEA/DCM (2×), DCM (2×) and MeOH (2×) and dried in air overnight. [0225] Step 1d: Coupling N-FMOC Protected Amino Acid to Wang Resin. [0226] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL plastic bottle. DMF (300 mL), DCM (300 mL), FMOC-Cyclohexyl alanine (70.82 g, 6 eq., 0.3M, 180 mmol), DIC (22.71 g, 6 eq., 180 mmol), HOBt (24.32 g, 6 eq., 180 mmol) were added sequentially. After shaking for 12 hours, the packet was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried overnight in air. The tea bags containing the amino acids were then treated with 20% piperidine/DMF for 2 h at room temperature to deblock the FMOC group. The following amino acids were used: [0227] FMOC-GLY-OH [0228] FMOC-ALA-OH [0229] FMOC-L-ISOLEUCINE [0230] FMOC-L-PHENYLALANINE [0231] FMOC-D-NLE-OH [0232] FMOC-CHA-OH [0233] FMOC-L-TRYPTOPHAN [0234] Step 1e: Coupling of the Diamines to Wang Resin [0235] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL Nalgene bottle. 600 mL of DCM was added followed by the addition of the carbonyl diimidazole (29.9 g, 6 eq., 0.3M, 180 mmol) and the flasks were shaken at room temperature for 3 hours after which they were decanted and washed with DCM (2×, 600 mL). To these Nalgene bottles were added the diamines (6 eq., 0.4M, 180 mmol) in 450 mL of DCM (0.4M) and they were shaken at room temperature overnight. The diamines used were as follows: [0236] 2,2-DIMETHYL-1,3-PROPANEDIAMINE [0237] 1,3-CYCLOHEXANEDIAMINE [0238] (1R,2R)-(-)-1,2-DIAMINOCYCLOHEXANE [0239] TRANS-1,4-DIAMINOCYCLOHEXANE [0240] P-XYLYLENEDIAMINE [0241] 1,4-BIS(3-AMINOPROPYL)PIPERAZINE [0242] ETHYLENEDIAMINE [0243] 1,3-DIAMINOPROPANE [0244] 1,8-DIAMINO-3,6-DIOXAOCTANE [0245] 1,4-DIAMINOBUTANE [0246] 1,5-DIAMINOPENTANE [0247] 1,6-HEXANEDIAMINE [0248] N,N-BIS(3-AMINOPROPYL)METHYLAMINE [0249] 2,2'-THIOBIS(ETHYLAMINE) [0250] 2,5-DIMETHYL-1,4-PHENYLENEDIAMINE [0251] After shaking overnight, the packets was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried in air. [0252] Step 2: Formation of the Isothiocyanate [0253] The o-amino benzoate ester (136 g, 10 eq., 900 mmol) was taken in a 5 L wide-mouthed glass bottle and 2.7 L of dichloroethane was added to it (0.3M). The following esters were used: [0254] METHYL ANTHRANILATE [0255] METHYL 2-AMINO-4-CHLOROBENZOATE [0256] 2-AMINO-4,5-DIMETHOXYBENZOIC ACID [0257] METHYL ESTER [0258] METHYL 3,4,5-TRIMETHOXYANTHRANILATE [0259] DIMETHYL AMINOTEREPHTHALATE [0260] METHYL 2-AMINO-5-BROMOBENZOATE [0261] METHYL 3-AMINOTHIOPHENE-2-CARBOXYLATE [0262] METHYL 3-AMINO-5-PHENYLTHIOPHENE-2-CARBOXYLATE [0263] Thiocarbonyl diimidazole (160 g, 10 eq., 900 mmol) was added to it and the solution was heated at 55 C. overnight to form the isothiocyanate. [0264] Step 3: Formation of the Thioquinazolinone [0265] The next day the tea bags containing the amino acids, diamines and the amino phenols on wang resin (90 mmol) was added to the isothiocyanate solution from reaction 2 and the glass bottles were heated at 55 C. overnight. After cooling the bags was washed alternatively with DMF (2000 mL) and DCM (2000 mL) 3 cycles followed by 6 cycles of MeOH...

Reference： [1]Patent: US2004/102629,2004,A1 .Location in patent: Page 16-18

28
[ 402-49-3 ]
[ 2338-75-2 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water	6.A Step A Step A Synthesis of 4-trifluoromethylphenylacetonitrile as an intermediate A stirred solution of 250.0 grams (1.05 moles) of 4-trifluoromethylphenylmethyl bromide in 1000 mL of ethanol was heated to about 80° C., and a solution of 109.0 grams (1.67 moles) of potassium cyanide in about 275 mL of water was added. Upon completion of addition, the reaction mixture was stirred at 80° C. for about 1.75 hours. After this time the reaction mixture was cooled to ambient temperature and extracted with three portions of diethyl ether. The combined extracts were washed with two portions of water and one portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding about 197 grams of 4-trifluoromethylphenylacetonitrile.
	With magnesium sulfate In ethanol; water	17.A Step A Step A Synthesis of 4-trifluoromethylphenylacetonitrile as an intermediate A stirred solution of 250.0 grams (1.05 moles) of 4-trifluoromethylphenylmethyl bromide in 1000 mL of ethanol was heated to about 80° C., and a solution of 109.0 grams (1.67 moles) of potassium cyanide in about 275 mL of water was added. Upon completion of addition, the reaction mixture was stirred at 80° C. for about 1.75 hours. After this time the reaction mixture was cooled to ambient temperature and extracted with three portions of diethyl ether. The combined extracts were washed with two portions of water and one portion of an aqueous solution saturated with sodium chloride. The organic layer was added with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding about 197 grams of 4-trifluoromethylphenylacetonitrile.

Reference： [1]Current Patent Assignee: FMC CORP - US5502054, 1996, A
[2]Current Patent Assignee: FMC CORP - US5622954, 1997, A

29
[ 618-49-5 ]
[ 402-49-3 ]
NU 1036 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In water; acetonitrile;	EXAMPLE 8 3-(4-Trifluoromethylbenzyloxy)benzamide (Compound NU1036) <strong>[618-49-5]3-hydroxybenzamide</strong> (0.137 g; 1 mmol) was dissolved in anhydrous acetonitrile (20 ml) under a nitrogen atmosphere. To this was added potassium carbonate (0.138 g; 1 mmol) and 4-(trifluoromethyl)benzyl bromide (0.155 ml; 1 mmol). This mixture was left to reflux for 17 hours. The reaction was followed by TLC. Upon completion the acetonitrile was removed under reduced pressure to leave a white solid which was dissolved in water. The organics were extracted into dichloromethane (3*30 ml), dried over magnesium sulphate, filtered and the solvent removed under reduced pressure to leave a white crystalline solid which was recrystallized from boiling ethyl acetate and petrol (60-80). M/Z (EI): 295 (35%; M+) 159 (100%)

Reference： [1]Patent: US5756510,1998,A

30
[ 80866-82-6 ]
[ 402-49-3 ]
4-bromo-1-methoxy-2-([4-(trifluoromethyl)benzyl]oxy}methyl)benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; water;	Production Example 26b) 0.8 g of 5-bromo-2-methoxyphenyl methanol was dissolved in 30 ml tetrahydrofuran. 2.6 g of 4- (trifluoromethyl)benzyl bromide and 0.22 g of sodium hydride (60 % oily) were added thereto, followed by stirring at room temperature for 16 hours. Water was added to the reaction solution, followed by extracting with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, to give 1.4 g of 4-bromo-1-methoxy-2-([4-(trifluoromethyl)benzyl]oxy}methyl)benzene from fractions eluted with hexane-ethyl acetate (9:1). 1H-NMR(CDCl3) delta: 3.80 (s, 3H) 4.57 (s, 2H) 4.64 (s, 2H) 6.77 (d, J=8.0Hz, 1H) 7.37 (dd, J=2.0, 8.0Hz, 1H) 7.50 (d, J=8.0Hz, 2H) 7.52 (d, J=2.0Hz, 1H) 7.61 (d, J=8.0Hz, 2H)

Reference： [1]Patent: EP1216980,2002,A1

31
[ 402-49-3 ]
[ 82317-83-7 ]

Yield	Reaction Conditions	Operation in experiment
60%		Example II-6 N-t-butoxycarbonyl-DL-4-trifluoromethylphenylalanine In the same manner as in Example II-5 except for using 9 4-trifluoromethylbenzyl bromide in place of 4-cyanobenzyl bromide, the reaction was carried out to obtain the title compound (overall yield 60%) as white solid. 1H-NMR (CDCl3) delta; 8.04 (brs, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 5.08-4.98 (m, 1H), 4.71-4.62 (m, 1H), 3.25-3.07 (m, 2H), 1.41 (s, 9H). CI-MS (m/z); 278

Reference： [1]Patent: US6265418,2001,B1

32
[ 350-29-8 ]
[ 402-49-3 ]
[ 636795-20-5 ]

Yield	Reaction Conditions	Operation in experiment
69%		a 3-Fluoro-4-(4-trifluoromethyl-benzyloxy)-benzoic Acid 4-Trifluoromethyl-benzyl Ester As described for example 18a, <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (2.5 g, 16 mmol) [using 4-(trifluoromethyl)-benzyl bromide instead of 4-fluorobenzyl bromide] was converted to the title compound (5.3 g, 69percent) which was obtained as a white solid. MS: m/e=472.1 (M+).

Reference： [1]Patent: US2003/236304,2003,A1

33
[ 93247-78-0 ]
[ 402-49-3 ]
[ 1050656-28-4 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of lH-Indole-7-carboxylic acid methyl ester 1 (209.8 g, 1.20 mole) in DMF (1.4 L) at 9 0C was added KOtBu (161.6 g, 1.44 mole) portion wise (temperature rose to 15 0C). The cold bath was removed and the reaction mixture was stirred at r.t. for 2 hours. The reaction mixture was cooled to 10 0C and a solution of l-bromomethyl-4-trifluoromethyl-benzene 2 (343.7g, 1.44 mole) in DMF (400 mL) was added over 2.5 hours and the flask was rinsed with DMF (100 mL). H2O (1.9 L) was added at 15 0C in order to precipitate the product. The slurry was filtered and rinsed with H2O (4 X IL) and the product dried under a flow of N2 under vacuum. 411.1 g of material was obtained at 82 A%. A sample was purified by chromatography : 1H NMR (500 MHz, Acetone-/) delta 7.88 (dd, J = 7.8, 1.1 Hz, IH), 7.60 (d, J = 8.2 Hz, IH), 7.58 (d, J = 3.2 Hz, IH), 7.53 (dd, J= 7.5, 1.1 Hz, IH), 7.13 (X, J = 7.6 Hz, IH), 7.07 (d, J = 8.0 Hz, IH), 6.74 (d, J = 3.2 Hz, IH), 5.83 (s, 2H), 3.72 (s, 3H); 19F NMR (377 MHz, Acetone-afe) delta - 62.4; 13C NMR (100 MHz, Acetone-tf6) delta 167.7, 143.8, 132.8, 132.7, 132.2, 128.9 (q, J= 32 Hz), 127.3, 126.0, 125.5 (m), 124.9, 123.3, 119.0, 117.4, 102.8, 52.2, 51.8; IR (CDCl3) 3112, 3076, 3038, 2987, 2949, 2844, 1925, 1716, 1619, 1524, 1448, 1421, 1321, 1275, 1161, 1134, 1113, 1067, 1017, 844, 749, 731cm"1; HRMS-ESI (m / z): [M+H]+ calcd for Ci8H14F3NO2, 334.10494; found 334.10548
	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃;	EXAMPLE 34- { 1 -[( { 1 - [4-(trifluoromethyl)benzyl] - 1 H-indol-7-yl } carbonyl)amino]cyclopropyl } benzoic acidStep 1 : Methyl l-[4-(trifluoromethyl)benzyl]-lH-indole-7-carboxylateMethyl lH-indole-7-carboxylate (47.8 g, 273 mmol) and l-(bromomethyl)-4- (trifluoromethyl)benzene (81 g, 341 mmol) were dissolved in DMF (1.3 L) at O0C. 60% w/w NaH (12 g, 300 mmol) was added portion wise. The ice bath was removed and the mixture stirred at O0C for 3 hours, then overnight at RT. The reaction mixture was quenched with 3 L of NH4Cl(sat.) and the aqueous layer was extracted 3 times with 1 L of ether. The organic layers were combined, washed with water and brine. The compound was purified by flash chromatography on silica gel. 1H NMR (500 MHz, DMSO-d): delta 8.90 (d, IH), 7.70 (s, IH), 7.60 (d, 2H), 7.40 (d, IH), 7.10 (t, IH), 7.00 (d, 2H), 6.70 (d, IH), 5.70 (s, 2H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 3760 - 3763
[2]Patent: WO2010/121382,2010,A1 .Location in patent: Page/Page column 9; 10
[3]Patent: WO2008/104055,2008,A1 .Location in patent: Page/Page column 28

34
[ 402-49-3 ]
[ 408355-23-7 ]
[ 1050656-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at -10℃; for 1.08333h;	Step 2: 7-bromo-5-fluoro-l-[4-(trifluoromethyl)benzyl]-l//-indole7-bromo-5-fiuoro-lH-indole (900mg, 4.20mmol) and l-(bromomethyl)-4- (trifluoromethyl)benzene (1.6g, 6.7mmol) were dissolved in DMF (20 ml). The mixture was cooled to -100C and NaH (185 mg, 4.6 mmol) was added portion wise over 5 min. The mixture was stirred for 1 hour at this temperature. Quenched with NH4Cl (1/2 sat.) and IN HCl. The mixture was diluted with water and the aqueous phase was extracted 3x with ether. The combined organic layers were washed with 3x water, Ix brine and dried over MgSO4. The product was purified by flash chromatography on silica gel. 1H NMR (500 MHz, DMSO-d6): delta 7.70 (m, 3H), 7.45 (dd, IH), 7.25 (dd, IH), 7.10 (d, 2H), 6.65 (d, IH), 5.90 (s, 2H).

Reference： [1]Patent: WO2008/104055,2008,A1 .Location in patent: Page/Page column 32

35
[ 402-49-3 ]
[ 485-71-2 ]
[ 101311-12-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	In tetrahydrofuran;Reflux;	General procedure: The phase-transfer catalysts (C1-C11) were synthesized according to the proceduresbelow. To a solution of cinchonidine (1.00 g, 3.4 mmol) in THF (50 mL) was addedthe aryl benzyl bromides (3.4 mmol). The mixture was heated for 6-8 h at reflux.After cooling to room temperature, the mixture was poured into MTBE (150 mL)under stirring. The precipitated solid was filtrated and recrystallized fromCH3OH/MTBE to afford C1-C11

Reference： [1]Beilstein Journal of Organic Chemistry,2018,vol. 14,p. 1421 - 1427
[2]Angewandte Chemie - International Edition,2008,vol. 47,p. 3238 - 3241

36
[ 39824-26-5 ]
[ 402-49-3 ]
6-chloro-9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-(((4-(trifluoromethyl)benzyl)oxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 1510 - 1513
[2]Chemical Communications,2017,vol. 53,p. 5167 - 5170

37
[ 1640-39-7 ]
[ 17028-61-4 ]
[ 402-49-3 ]
[ 1039745-00-0 ]

Yield	Reaction Conditions	Operation in experiment
	In hexane-CH2Cl2; ethanol; dichloromethane; toluene;	1-(4'-trifluoromethyl-benzyl)-3,3-dimethyl-2-methylene-indoline A solution of 2,3,3-trimethylindolenine (3 g, 12.3 mmol) and 4-(trifluoromethyl)benzyl bromide (2.35 g, 14.8 mmol) was stirred under nitrogen in 20 ml toluene for 24 h at 90 C. The mixture was cooled to room temperature, evaporated under reduced pressure, a residue was dissolved in CH2Cl2 and treated with NaOH(aq) 5% for 45 min. The organic phase was separated, dried over Na2SO4, chromatographed through a short alumina column in hexane-CH2Cl2 (1:1). The solvent was evaporated (cooling under nitrogen), giving rise to 151(2.9 g, 9.1 mmol), as a free base which was immediately dissolved in 45 ml ethanol containing a few drops of Et3N. 3-methoxy-5-nitrosalicylaldehyde (1.8 g, 9.1 mmol) was added to the solution and the reaction mixture was refluxed for 50 min. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, a residue was chromatographed on a short alumina column, eluent: hexane-CH2Cl2 (10-40%). The product was crystallized from ether-hexane, dried in vacuo. Yield 1.35 g, 19.7%

Reference： [1]Patent: US2010/34961,2010,A1

38
[ 402-49-3 ]
[ 3060-50-2 ]
[ 1204177-05-8 ]

Reference： [1]Organic Letters,2010,vol. 12,p. 316 - 319

39
[ 402-49-3 ]
[ 939-69-5 ]
[ 676460-22-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetone; for 15h;Reflux;	6-(4-Trifluoromethylbenzyloxy)-2-cyanobenzothiazole: A suspension of <strong>[939-69-5]2-cyano-6-hydroxybenzothiazole</strong> (1.0 g, 5.68 mmol) in acetone (5 mL) was prepared in a 100-mL 2-necked round-bottomed flask fitted with a reflux condenser. Anhydrous potassium carbonate (0.94 g, 6.82 mmol) was added to the reaction mixture and the suspension turned to a yellow solution. Then 4-(trifluoromethyl)benzyl bromide (1.49 g, 6.25 mmol) was added and the reaction mixture was heated at reflux for 15 h using a heated stir plate and oil bath. The reaction mixture was allowed to cool to ambient temperature and then filtered to remove inorganic salts. The filtrate was concentrated by rotoevaporation to provide 1.7 g (89percent yield) of an off-white solid that was used without purification. The structure was confirmed by 1H NMR analysis in DMSO-d6

Reference： [1]Patent: US7692022,2010,B2 .Location in patent: Page/Page column 36

40
[ 352359-22-9 ]
[ 402-49-3 ]
[ 1227625-76-4 ]

Reference： [1]Tetrahedron Letters,2010,vol. 51,p. 2281 - 2283

41
[ 20283-92-5 ]
[ 402-49-3 ]
[ 18107-18-1 ]
[ 1115211-08-9 ]

Yield	Reaction Conditions	Operation in experiment
84%		TMS-diazomethane (2.0 M in Et2O, 7.9 mL, 15.8 mmol, 0.95 equiv) was added in small portions over 1 h to a solution of rosmarinic acid (5, 6.00 g, 16.7 mmol, 1.0 equiv) in THF:MeOH (10:1, 110 mL) at -78 0C. Upon completion, the reaction contents were allowed to warm to 25 0C over 1 h, concentrated directly, and filtered through a short plug of silica gel (CH2Cl2:Me0H, 19:1) . The resultant thick brown oil was dried thoroughly under high vacuum to provide the desired ester intermediate that was carried forward without any additional purification. Next, p-trifluoromethylbenzyl bromide (7.40 mL, 48.0 mmol, 6.0 equiv), K2CO3 (6.60 g, 48.0 mmol, 6.0 equiv), and KI (catalytic) were added sequentially and in single portions to a solution of half of the crude ester just prepared (8.0 mmol, 1.0 equiv) in DMF (30 mL) at 25 0C. The resultant reaction mixture was then stirred at 60 0C for 8 h, and at 25 0C for 16 h. Upon completion, the reaction contents were carefully quenched by the addition of 1 M aqueous HCl (until gas evolution ceased), poured into water (50 mL) , and extracted with EtOAc (2 x 100 itiL) . The combined organic layers were then washed with 1 M aqueous HCl (50 mL) , saturated aqueous NaHCO3 (50 mL) and brine (50 mL) , dried (MgSO4), and concentrated. The resultant crude material was purified by flash column chromatography (silica gel, hexanes: EtOAc: CH2Cl2, 17 : 1 :2?5 :4 : 1) to afford dienophile 27 (6.00 g, 84% yield over 2 steps) as a white amorphous solid. 27: Rf = 0.45 (silica gel, hexanes : EtOAc : CH2Cl2, 3:1:1); IR (film) {max 1751, 1715, 1625, 1598, 1511, 1324, 1265, 1160, 1120, 1065, 1016, 824, 736 cm-1; 1H NMR (400 MHz, CDCl3) delta 7.66-7.49 (m, 17 H), 7.11-7.08 (m, 2 H), 6.92- 6.81 (m, 4 H), 6.29 (d, J = 16.0 Hz, 1 H), 5.36 (dd, J = 8.0, 4.8 Hz, 1 H), 5.23 (s, 2 H), 5.19 (s, 2 H), 5.17 (s, 2 H), 5.16 (s, 2 H), 3.71 (s, 3 H), 3.18 (dd, J" = 14.4, 5.0 Hz, 1 H), 3.11 (dd, J = 14.4, 8.4 Hz, 1 H); 13C NMR (75 MHz, CDCl3) delta 170.1, 166.0, 150.8, 148.6, 148.5, 147.7, 145.5, 141.2, 141.1, 140.7, 140.5, 127.9, 127.2, 127.2, 127.1, 125.8, 125.4, 125.3, 125.3, 123.3, 122.7, 122.2, 116.2, 115.2, 114.9, 114.0, 113.5, 72.8, 70.5, 70.3, 69.9, 52.2, 36.9; HRMS (FAB) calcd for C5IH38Fi2O8+ [M+] 1006.2375, found 1006.2424.

Reference： [1]Patent: WO2010/74764,2010,A1 .Location in patent: Page/Page column 214-215

42
[ 22300-52-3 ]
[ 402-49-3 ]
[ 1248676-30-3 ]
[ 1248676-65-4 ]

Reference： [1]Organic Letters,2010,vol. 12,p. 4632 - 4635

43
[ 79660-46-1 ]
[ 402-49-3 ]
[ 214602-42-3 ]

Yield	Reaction Conditions	Operation in experiment
72%		To a suspension of sodium hydride (1.5 equiv.) in dry DMF, compound 3 (1 equiv.) was added and allow to stir at room temperature. After 1 h, 4-(triflouromethylbenzyl) bromide (1.5 equiv.) was added to the reaction mixture and refluxed for 4 h. The solvent was evaporated to dryness and water was added to solid residue. The compound was extracted with DCM, dried over anhyd Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography using (CHCl3/MeOH = 10:1) to afford compound 5.

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 1232 - 1244

44
[ 15015-57-3 ]
[ 402-49-3 ]
[ 1309876-42-3 ]

Reference： [1]Synthetic Communications,2011,vol. 41,p. 1805 - 1808

45
[ 1004-40-6 ]
[ 402-49-3 ]
[ 1094534-57-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In ethanol; water; at 20 - 50℃; for 17h;	General procedure: In 2-dram vials (round bottom, 15x75 mm) containing substituted alkyl or benzyl bromides (0.800 mmol) was added 0.5 mL of EtOH via a syringe. The stock solution containing 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.500 mmol) and 3.45 M aqueous solution of NaOH (0.800 mmol) in EtOH was prepared as followed. In a 250 mL round-bottom flask was added 4.82 g of 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one, 69.6 mL of EtOH, 20 mL of water, and 10.4 mL of 3.25 M aqueous solution of NaOH. This mixture was stirred at rt until a homogenous solution was formed. 2.50 mL of this stock solution was dispensed into each 2-dram vial.The vials were capped and heated to 50 C in a shaker. After 17 h, LCMSs were randomly taken from different reactions and all showed product formation cleanly. All vials were placed in a Genevac to remove the solvents and the product was purified by mass-directed high throughput purification.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1055 - 1060

46
[ 402-49-3 ]
[ 68-41-7 ]
C₁₁H₁₁F₃N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Constant current electrolyses (I = 25 mA cm-2) were performed under a nitrogen atmosphere, at 20C, using an Amel Model 552 potentiostat equipped with an AmelModel 731 integrator. All the experiments were carried out in a divided glass cell separated through a porous glass plug filled up with a layer of gel (i.e., methylcellulose 0.5% vol dissolved in DMF-Et4NPF6 1.0 mol dm-3); Pt spirals (apparent areas 0.8 cm2) were used both as cathode and anode. MeCN-Et4NPF6 0.1 mol dm-3 was used as solvent-supporting electrolyte system (catholite: 20 cm3; anolite: 5 cm3).1 mmol of substrate was present in the catholyte (except for D-<strong>[68-41-7]cycloserine</strong>, which was added to the catholyte after the end of the electrolysis). After 145 C (if not otherwise stated) were passed, the current was switched off and 1 mmol of alkylating agent was added to the catholyte. The solution was kept under stirring at room temperature for 2 hours, than the solvent was evaporated under reduced pressure and the residue was extracted three times with diethyl ether. The products were purified by flash column chromatography, using a mixture of ethyl acetate/light petroleum ether 2/8 in volume. The reactions on D-<strong>[68-41-7]cycloserine</strong> were carried out following the general method, but the substrate was added to the catholyte after the end of the electrolysis. After 15 minutes at room temperature, the alkylating agent was added and the solution was kept under stirring at rt for 2 hours. The solvent was evaporated under reduced pressure and the residue was treated with 1 cm3 of saturated acqueous NaHCO3 and 1 mmol of ethyl chloroformate, at 0C, for 2 h. The solution was then acidified with diluted HCl (pH 4) and extracted with diethyl ether. The products were purified by flash column chromatography.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 2564 - 2567

47
[ 402-49-3 ]
[ 82337-58-4 ]
[ 3832-75-5 ]

Reference： [1]Patent: WO2012/109164,2012,A1

48
[ 402-49-3 ]
[ 142643-29-6 ]
[ 1093396-77-0 ]

Reference： [1]Patent: WO2008/156715,2008,A1

49
[ 402-49-3 ]
[ 142643-29-6 ]
[ 1093396-78-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In methanol; at 70℃; for 0.5h;	To a mixture of 830 mg of potassium carbonate in 50 ml of methanol was added ter t-butyl (piperidin-3 -ylmethyl)carbamate (643 mg), followed by l-(bromomethyl)-4- (trifluoromethyl)benzene (717 mg). The mixture was heated to 7O0C and stirred for 0.5 h. The sample was filtered through a small plug of silica gel and concentrated in vacuo to provide tert- butyl({ l-[4-(trifluoromethyl)benzyl]piperidin-3-yl}methyl)carbamate (640 mg). To a solution of this protected amine in 10 ml of dichloromethane was added trifluoroacetic acid (5 ml). The mixture was stirred at 7O0C for 1.5 h, and then concentrated in vacuo. The residue was diluted with 30 ml of ethyl acetate and basified by slow and cautious addition of 30 ml of a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated and extracted once with 30 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound (418 mg, 89%). Mass spectrum (ESI) 273.2 (M+l).

Reference： [1]Patent: WO2008/156715,2008,A1 .Location in patent: Page/Page column 57

50
[ 96293-19-5 ]
[ 402-49-3 ]
C₃₅H₃₀F₃N₃NiO₃ [ No CAS ]
{N-{phenyl{2-{[(1R,2S)-1-(phenylmethyl)pyrrolidin-2-yl-kN]carbonyl}amino-kN}phenyl}methylene}-4-(trifluoromethyl)-L-phenylalaninato(2 )-kN,kO}nickel [ No CAS ]

Reference： [1]Helvetica Chimica Acta,2012,vol. 95,p. 2672 - 2679

51
[ 402-49-3 ]
[ 25163-98-8 ]
4-isobutyl-2-phenyl-4-[4-(trifluoromethyl)benzyl]oxazol-5(4H)-one [ No CAS ]

Reference： [1]Synlett,2013,vol. 24,p. 701 - 704

52
[ 4294-57-9 ]
[ 402-49-3 ]
[ 613-33-2 ]
[ 538-39-6 ]
[ 170789-13-6 ]

Yield	Reaction Conditions	Operation in experiment
76%Chromat.	With FeCl(THF)L1; In diethyl ether; at 20℃; for 0.5h;Schlenk technique; Inert atmosphere;Catalytic behavior;	General procedure: [00283] Catalyst 20 (0.10 mmol) in CH2C12 (3 mL) was added to a 30 mL Schlenk flask and the solvent removed in vacuo. Et20 (5 mL) and the alkyl halide (2.0 mmol) were added to the catalyst under dry nitrogen. A solution of Grignard reagent (4.0 mmol) was added dropwise under vigorous stirring. The resulting mixture was stirred at roomtemperature for 30 min and the reaction was quenched with HC1 (2.0 M, 5 mL). The organic phase was extracted with Et20 (5 mL) and dried over MgSC>4. The organic phase was then passed through a plug of silica and the diethyl ether was removed in vacuo. The resulting products were then analyzed by GC-MS (using dodecane as internal standard) and NMR spectroscopy (using acetophenone as internal standard).

Reference： [1]Patent: WO2013/53046,2013,A1 .Location in patent: Paragraph 00282; 00283; 00285

53
[ 38427-94-0 ]
[ 402-49-3 ]
[ 1445435-59-5 ]

Reference： [1]Organic Letters,2013,vol. 15,p. 3476 - 3479

54
[ 15297-33-3 ]
[ 402-49-3 ]
(R)-N-methyl-1-(naphthalen-1-yl)-N-(4-(trifluoromethyl)benzyl)ethanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 2h;Reflux; Inert atmosphere;	General procedure: N-Methyl-1-(naphthalen-1-yl)ethanamine (8) (0.37g, 2.00mmol), N,N-diisopropylethylamine (0.39g, 3.02mmol), 1-(bromomethyl)-4-tert-butylbenzene (0.50g, 2.20mmol) and acetonitrile (5mL) were mixed and stirred at reflux under an N2-atmosphere for 2h. The solvent was then removed at reduced pressure and CH2Cl2 (5mL) was added. The dichloromethane phase was washed with water (5mL) and the water phase was back extracted with CH2Cl2 (3×5mL). The combined organic fractions were dried over Na2SO4, and concentrated in vacuum. The crude product was purified by silica-gel column chromatography. Alternatively, the purification was done by filtration through a short silica-gel column (pentane:EtOAc, 9:1), followed by precipitation as it hydrochloride salt by addition of HCl saturated ether. The solid material was washed with cold pentane. Alternatively, using 8·HCl the reaction was run similarly, but employing a 3-fold excess of N,N-diisopropylethylamine.

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 68,p. 482 - 496

55
[ 3470-50-6 ]
[ 402-49-3 ]
[ 1610447-05-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate; In acetone; for 6h;Reflux;	General procedure: <strong>[3470-50-6]6-Hydroxy-1-tetralone</strong> (0.3 g, 1.85 mmol) was suspended in acetone (15 mL) containing K2CO3 (3.70 mmol). The reaction was treated with an appropriately substituted arylalkyl bromide (2.035 mmol) and heated under reflux for 6 h. The reaction progress was monitored using silica gel TLC with ethyl acetate:petroleum ether (1:2) as mobile phase. Upon completion, the reaction was filtered through a pad of celite and concentrated in vacuo. The crude thus obtained was purified by recrystallization from cyclohexane.
88%	With potassium carbonate; In acetone; for 6h;Reflux;	General procedure: <strong>[3470-50-6]6-Hydroxy-1-tetralone</strong> (0.3 g, 1.85 mmol) was suspended in acetone (15 mL) containing K2CO3 (3.70mmol). The reaction was treated with an appropriately substituted arylalkyl bromide (2.035 mmol) and heated under reflux for 6 h. The reaction progress was monitored using silica gel TLC with ethyl acetate:petroleum ether (1:2) as mobile phase. Upon completion, the reaction was filtered through a pad of celite and concentrated in vacuo. The crude thus obtained was purified by recrystallization from cyclohexane.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 2758 - 2763
[2]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 2758 - 2763

56
[ 60481-36-9 ]
[ 402-49-3 ]
1-(3,5-dimethylphenyl)-1-(4-(trifluoromethyl)benzyl)hydrazine [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 5202 - 5205
Angew. Chem.,2014,vol. 126,p. 5303 - 5306,4

57
[ 590418-08-9 ]
[ 402-49-3 ]
[ 1627143-97-8 ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 4404 - 4407
Angew. Chem.,2014,vol. 126,p. 4493 - 4496,4

58
[ 402-49-3 ]
[ 321574-29-2 ]

Reference： [1]Patent: WO2014/192023,2014,A1
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 3064 - 3066

59
[ 4663-99-4 ]
[ 402-49-3 ]
3,5-dicarbamoyl-1-[4-(trifluoromethyl)benzyl]pyridinium bromide [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,2015,vol. 52,p. 221 - 226

60
[ 3920-50-1 ]
[ 402-49-3 ]
1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-3-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With potassium carbonate; In acetonitrile; at 20℃;	General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent).

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 86,p. 639 - 652

61
[ 1303587-99-6 ]
[ 402-49-3 ]
2-chloro-8-(4-(trifluoromethyl)benzyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0℃; for 0.5h;Inert atmosphere;	Synthesis of2-chloro-8-(4-(trifluoromethyl) benzyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] [0459] To a stirred solution of 2-chloro-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (150 mg, 0.87 mmol) in DMF (3 mL) under argon atmosphere were added sodium hydride (42 mg, 1.75 mmol) and l-(bromomethyl)-4-(trifluoromethyl) benzene (251 mg, 1.05 mmol) at 0 C. The reaction mixture was stirred for 30 min at 0 C. After consumption of the starting materials (monitored by TLC), the reaction was quenched with cold water (20 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was washed with n-pentane (2 x 5 mL) to afford 2-chloro-8-(4-(trifluoromethyl) benzyl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (220 mg, 76%) as an off-white solid. 1H-NMR (OMSO-d6, 500 MHz): delta 7.76 (s, 1H), 7.74 (d, 2H), 7.52 (d, 2H), 4.89 (s, 2H), 4.23-4.20 (m, 2H), 3.57-3.54 (m, 2H); LCMS: 329.8 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 mupiiota); RT 3.88 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 90.0%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 mupiiota); RT 2.58 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 30% EtOAc/hexane (R 0.4).

Reference： [1]Patent: WO2015/66697,2015,A1 .Location in patent: Paragraph 0459

62
[ 402-49-3 ]
[ 6140-17-6 ]

Reference： [1]Chemical Science,2015,vol. 6,p. 3434 - 3439
[2]Chemical Communications,2019,vol. 55,p. 7247 - 7250

63
[ 442-51-3 ]
[ 402-49-3 ]
7-methoxy-1-methyl-9-[[4-(triuoromethyl)phenyl]methyl]-pyrido[3,4-b]indole [ No CAS ]

Reference： [1]RSC Advances,2015,vol. 5,p. 53809 - 53818

64
[ 402-49-3 ]
[ 288-36-8 ]
[ 63778-04-1 ]

Reference： [1]Organic and Biomolecular Chemistry,2015,vol. 13,p. 7146 - 7148

65
[ 40598-94-5 ]
[ 402-49-3 ]
3-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%		[0164] A mixture of KOH (1.12 g, 20 mmol) in DMSO (50 mL) was stirred at room temperature for 5 min. 3-bromo-lH-indazole (1.97 g, 10 mmol) was then added in one portion. The resulting mixture was stirred at room temperature for 5 min. A solution of 1- (bromomethyl)-4-(trifluoromethyl)benzene (3.6 g, 15 mmol) in DMSO (5 mL) was then added dropwise over 10 min. When the addition was complete, the resulting mixture was stirred at room temperature for an additional 1 h. The mixture was quenched by the addition of water (200 mL). The mixture was then extracted with CH2C12 (3 X 100 mL). The combined extracts were washed with () (2 X 100 mL), brine (1 X 100 mL), then dried over MgS0 , filtered and concentrated in vacuo. Purification by flash chromatography (0553) (Silica, 200g, 10 - 100% EtOAc/Hexanes) gave 3-Bromo-l-(4-(trifluoromethyl)benzyl)-lH- indazole (3.1 g, 8.7 mmol, 87 % yield) as an off-white crystalline solid. MS (ESI) m/z: (0554) 355and 357 (Mu+Eta)+·

Reference： [1]Patent: WO2015/127125,2015,A1 .Location in patent: Paragraph 0164

66
[ 40598-94-5 ]
[ 402-49-3 ]
3-phenyl-1-(4-(trifluoromethyl)benzyl)-1H-indazole [ No CAS ]

Reference： [1]Patent: WO2015/127125,2015,A1

67
[ 874-05-5 ]
[ 402-49-3 ]
1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91.3%		Preparation of Intermediate 1: l-(4-(trifluoromethyl)benzyl)-lH-indazol-3-amine (0515) [0152] A mixture of KOH (6.95 g, 124 mmol) in DMSO (165 mL) was stirred at room temperature for 5 min. lH-indazol-3 -amine (8.25 g, 62.0 mmol) was then added in one portion. The resulting mixture was stirred at room temperature for 5 min. A solution of 4- trifluoromethylbenzyl bromide (15.6 g, 65.1 mmol) in DMSO (83 ml) was then added dropwise over 30 min. When the addition was complete, the resulting mixture was stirred at room temperature for an additional 1 h. The mixture was quenched by the addition of water (200 mL). The mixture was then extracted with CH2CI2 (3 X 100 mL). The combined extracts were washed with H20 (2 X 100 mL), brine (1 X 100 mL), then dried over MgS04, filtered and concentrated in vacuo. Purification by flash chromatography (Silica, 200 g, 10 - 100% EtOAc/Hexanes) gave l-(trifluoromethylbenzyl)-lH-indazol-3 -amine (21.79 g, 56.6 mmol, 91.3 % yield) as an off-white crystalline solid. MS (ESI) m/z: 292 (M+H)+

Reference： [1]Patent: WO2015/127125,2015,A1 .Location in patent: Paragraph 0152

68
[ 22818-40-2 ]
[ 402-49-3 ]
[4-(4-trifluoromethyl)benzyloxy]-D-phenylglycine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 9354 - 9370

69
[ 1105187-36-7 ]
[ 402-49-3 ]
3-bromo-4-(4-trifluoromethylbenzyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4 g	With caesium carbonate; at 20℃; for 14.0h;	A solution of 3-Bromo-4-(4-trifluoromethyl-benzyl)-4H-thieno[3,2-b]pyrrole-S-carboxylic acid methyl ester (2.3 g), 4-trifluoromethybenzyl bromide (2.4 g) and Cs2CO3 (4 g) was stirred for 14 h at room temperature. The reaction mixture was then diluted with 100 ml of 1:1 hexane/EtOAc and filtered through a pad of silica gel. The filtrate was concentrated to give 4.0 g of the crude title compound which was used for the next step without further purification.

Reference： [1]Patent: EP2320906,2016,B1 .Location in patent: Paragraph 0142; 0143

70
[ 42726-73-8 ]
[ 402-49-3 ]
1-tert-butyl 3-methyl 2-benzoyloxy-2-(4-trifluoromethylbenzyl)malonate [ No CAS ]

Reference： [1]Organic Letters,2016,vol. 18,p. 5484 - 5487

71
[ 42726-73-8 ]
[ 402-49-3 ]
1-tert-butyl 3-methyl 2-(4-trifluoromethylbenzyl)malonate [ No CAS ]

Reference： [1]Organic Letters,2016,vol. 18,p. 5484 - 5487

72
[ 185613-91-6 ]
[ 402-49-3 ]
4-(benzo[d][1,3]dioxol-5-yl)-N-(4-(trifluoromethyl)benzyl)thiazole-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%		General procedure: A solution of <strong>[185613-91-6]4-(benzo[d][1,3]dioxol-5-yl)thiazol-2-amine</strong> (1.0 equiv) and NaH (1.5 equiv) in THF was stirred at room temperature. After 1 h, benzyl bromide (1.5 equiv) was added and stirring was continued for 10 more min. The reaction progress was monitored by TLC. After completion of the reaction, quenched with saturated NH4Cl solution and extracted with EtOAc, the organic layer was dried over MgSO4, filtered, concentrated invacuo. The residue was purified by silica gel column chromatography (16% EtOAc/hexanes) to afford desired product.
16.7%		4-(Benzo[d] [1,3]dioxol-5-yl)thiazol-2-amine(2) (1.00 g, 4.54 mmol) and NaH (0.164 g, 6.82 mmol) to THF (15 ml) todissolved and then allowed to react at room temperature for 1 hour under a nitrogen stream. Then slowly added dropwise atroom temperature to 4-(trifluoromethyl) benzyl bromide (1.63g, 6.82mmol) and the reaction was carried out for 10 minutes.After the reaction was finished, it was concentrated under reduced pressure and extracted three times into a saturatedsolution of NaHCO3 is dissolved in ethyl acetate. The ethyl acetate layer was separated and dried with anhydrous Na2SO4,then purified by column chromatography (Ethyl acetate: Hexane = 1: 5) to give the compound 1d to give. Yield 16.7%

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4854 - 4857
[2]Patent: KR101651208,2016,B1 .Location in patent: Paragraph 0139-0141

73
[ 1221239-08-2 ]
[ 402-49-3 ]
4-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In tetrahydrofuran; water at 80℃; for 0.75h; Microwave irradiation;	4.1.6. General procedure 5 for Suzuki coupling 30a-30d General procedure: The mixture of boronic ester 29 (0.5 g, 1.9 mmol, 1.0 equiv.),ArCH2Br (5.8 mmol, 3.0 equiv.), Na2CO3 (3.8 mmol, 2.0 equiv.), THF/H2O (9:1, 10.0 mL) and Pd[P(Ph)3]4 (30 mg) were microwaved at80 °C for 45 min. The reaction was monitored by TLC. The solventwas evaporated and the residue was diluted with EtOAc andwashed with brine, organic layer was dried over Na2SO4, filteredand concentrated. The crude product was purified by flash column chromatography (EtOAc/hexane; 1:9) to afford desired compound(30a-d).

Reference： [1]Tang, Jing; Vernekar, Sanjeev Kumar V.; Chen, Yue-Lei; Miller, Lena; Huber, Andrew D.; Myshakina, Nataliya; Sarafianos, Stefan G.; Parniak, Michael A.; Wang, Zhengqiang [European Journal of Medicinal Chemistry, 2017, vol. 133, p. 85 - 96]

74
[ 82380-18-5 ]
[ 402-49-3 ]
2-fluoro-4-[(4-trifluoromethylphenylmethoxy)]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In acetonitrile; at 100℃; for 1.5h;Sealed tube; Inert atmosphere;	[00191]To a stirred solution of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (200 mg, 1.46 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (349 mg, 1.46 mmol) in anhydrous acetonitrile (3.8ml) at room temperature in a sealable pressure tube under nitrogen was added Cs2CO3 (523 mg,1.6 mmol). The tube was then sealed and the mixture heated to 100 oC for 1.5 hr.[00192]The reaction was cooled to rt and diluted with DCM (10 ml) and washed with water(3x 5 ml). The organic layer was dried over MgSO4, filtered and evaporated to dryness to give369mg of the title compound TH NIvIR (500 M}Iz, DMSO-d6) 7.91-7.85 (m, 1H), 7.80 (d, J8.1 Hz, 2H), 7.69 (d, J = 8.0 Hz, 211), 7.30 (dd, J = 11.8, 2.4 Hz, lH), 7.08 (dd, J = 8.8, 2.4 Hz,1 H), 5.36 (s, 2H).

Reference： [1]Patent: WO2017/45751,2017,A1 .Location in patent: Paragraph 00191; 00192

75
[ 402-49-3 ]
[ 196603-96-0 ]
4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(4-trifluoromethylbenzyloxy)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With potassium carbonate; In N,N-dimethyl-formamide; for 4h;Reflux;	Example 4 Synthesis of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(4-trifluoromethyl-benzyloxy)quinazoline (Compound 5) <strong>[196603-96-0]4-(4-bromo-2-fluoroanilino)-6-methoxy-7-hydroxyquinazoline</strong> (500mg, 1.37mmol), 1-(trifluoromethyl)-4-bromomethylbenzene (393mg, 1.64mmol) and potassium carbonate (568mg, 4.11mmol) were dispersed in N,N-dimethylformamide (DMF, 15mL). The resulting mixture was heated to reflux for 4 hours to conduct the reaction. The reaction mixture was cooled to room temperature and poured into water (80mL). The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated to obtain a crude product (800mg). The crude product was purified by a preparative thin-layer chromatography (methylene chloride:methanol=10:1) to produce a white solid (287mg, yield: 40%). 1H-NMR(400 MHz, DMSO-d6) delta: 9.57(s, 1H), 8.36(s, 1H), 7.85-7.80(m, 3H), 7.74-7.72(m, 2H), 7.66(dd, 1H, J = 10.0, 2.0 Hz), 7.53-7.45(m, 2H), 7.30(s, 1H), 5.43(s, 2H), 3.97(s, 3H). MS 522, 524(M+1).

Reference： [1]Patent: EP3181554,2017,A1 .Location in patent: Paragraph 0110-0113

76
[ 402-49-3 ]
[ 163295-75-8 ]

Reference： [1]ACS Catalysis,2017,vol. 7,p. 5357 - 5362

77
[ 402-49-3 ]
[ 385-00-2 ]
4-(trifluoromethyl)benzyl 2,6-difluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In benzene at 100℃; for 3h;	General Procedure 1 (GP1): General procedure: To a solution of 2,6-difluorobenzoic acid (3.16 g, 20 mmol) and DBU(9.12 g, 60 mmol) in benzene (40 mL) was added benzyl bromide (10.3 g, 60 mmol) at ambienttemperature. The reaction mixture was then stirred at 100 °C for 3 h. After cooling to ambienttemperature, the resulting mixture was diluted with water, and then extracted with EtOAc. The organiclayer was washed with brine, dried over MgSO4, and evaporated under reduced pressure. The crudematerial was purified by flash column chromatography on silica gel (EtOAc/hexane = 1/20) to give 1a(4.51 g, 91%) as colorless oil.

Reference： [1]Makida, Yusuke; Matsumoto, Yasutaka; Kuwano, Ryoichi [Synlett, 2017, vol. 28, # 19, p. 2573 - 2576]

78
[ 32996-16-0 ]
[ 402-49-3 ]
C₁₉H₁₆F₃NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%		As shown in Figure 1A, (i) NaH (60% dispersion in mineral oil, 11.0 mmol) was added in portionsat 0 C to a stirred solution of m<strong>[32996-16-0]ethyl 1H-indole-5-carboxylate</strong> 1 (1.89 g, 10.0 mmol) in dry DMF (10 mL).After stirring for 30 min at 0 C, 1-(bromomethyl)-4-(trifluoromethyl) benzene 2 (2.88 g, 12.0 mmol)was added and the mixture was then stirred at room temperature for 24 h. Then, the reaction mixturewas cooled to ambient temperature, poured into H2O (100 mL), and extracted with EtOAc (100 mL).The organic phase was dried over anhydrous Na2SO4. After evaporation of the solvents underreduced pressure, the crude product was purified on a silica gel column using EtOAc/petroleumether (1:9) to obtain the pure 3 (2.94 g, 80%) as a white solid. 1H NMR (400 MHz, CDCl3)delta 8.29(d, J = 1.6 Hz, 1H), 7.76-7.65 (m, 4H), 7.55 (d, J = 8.7 Hz, 1H), 7.36 (d, J = 7.9 Hz, 2H), 6.74-6.66 (m, 1H),5.60 (s, 2H), 3.83 (s, 3H); (ii) A suspension of 3 (1.67 g, 5.0 mmol) and 5 M NaOH solution (5 mL) inTHF (20 mL) was stirred at 50 C until consumption of the starting material. It was allowed to reachroom temperature, 2 M HCl was added, diluted with EtOAc (50 mL) and washed brine. The combinedorganic phase was dried (Na2SO4). After evaporation of the solvents under reduced pressure, the crudeproduct was purified on Flash chromatography to afford the product 4 (1.41 g, 88%) as a white solid.1H NMR (400 MHz, CDCl3) delta 12.47 (s, 1H), 8.26 (s, 1H), 7.76-7.66 (m, 3H), 7.65 (d, J = 3.2 Hz, 1H),7.51 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 6.68 (d, J = 3.1 Hz, 1H), 5.60 (s, 2H), 1.39 (s, 2H);(iii) To a solution of 4 (1.60 g, 5.0 mmol) in dry DMF (20 mL) were added 2.0 equiv. of DMAP (1.22 g,10 mmol) and 2.0 equiv. of BOP (4.42 g, 10 mmol) at 0 C in an ice bath. After stirring for 0.5 h, 1.2 equiv.of pyridin-4-ylmethanamine 5 (0.65 g, 6.0 mmol) were added, and the reaction was allowed to stiruntil all starting material had disappeared. Then, the mixture was poured into a 10% aqueous solutionof HCl. The aqueous phase was extracted with EtOAc (2 times), and the combined organic layers weredried (anhydrous Na2SO4) and concentrated in vacuo. Flash chromatography (Silica gel, hexane/ethylacetate = 2/1) yielded the desired product VSP-17 (1.64 g, 80%) as a colorless solid. 1H NMR (400 MHz,CDCl3)delta 8.59-8.51 (m, 2H), 7.83-7.77 (m, 2H), 7.65 (d, J = 8.1 Hz, 2H), 7.58-7.52 (m, 2H), 7.25-7.22(m, 2H), 7.04-6.96 (m, 2H), 6.63 (t, J = 6.0 Hz, 1H), 5.17 (s, 2H), 4.64 (d, J = 6.0 Hz, 2H). HRMS (ESI) m/zcalcd. for [M + H]+: 410.1480, found: 410.1478 [M + H]+.

Reference： [1]Molecules,2018,vol. 23

79
[ 64318-28-1 ]
[ 402-49-3 ]
2-(4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethan-1-aminium chloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 232 - 244

80
[ 402-49-3 ]
[ 520-33-2 ]
(S)-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-7-[4-(trifluoromethyl)benzyl]oxy}chroman-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;Alkaline conditions;	General procedure: K2CO3 (172.76 mg, 1.25 mmol) and the appropriate substitutedbromine (4-10 mmol) were added, under stirring, to a solution of <strong>[520-33-2]hesperetin</strong>(604 mg, 2 mmol) in anhydrous DMF (15 mL). Another 1 mmolof K2CO3 was intermittently added to the solution to keep the pH as aweak alkaline. The mixture was reacted at room temperature for 4-6 hunder atmospheric conditions. The progress of the reaction was monitoredby TLC. The reaction mixture poured into ice cold water thenacidified by dilute hydrochloric acid and extracted with ethyl acetate,then washed three times with saturated aqueous NaCl solution. After drying with anhydrous sodium sulfate, the solution was filtered throughabsorbent cotton. The precipitate obtained by removing the solventunder reduced pressure was purified by column chromatography (SiO2)using trichloromethane/petroleum ether (1:1-5) as eluent. The purifiedprecipitate was recrystallized from dichloromethane/petroleum ether.

Reference： [1]International Immunopharmacology,2018,vol. 61,p. 82 - 91

81
[ 617-05-0 ]
[ 402-49-3 ]
ethyl 3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%		In a round bottomed flask equipped with a nitrogen inlet and a magnetic stir bar, potassium carbonate (1.86 g, 13.46 mmol), <strong>[617-05-0]ethyl 4-hydroxy-3-methoxybenzoate</strong> (1.2 g, 6.12 mmol) and CH3CN (26 mL) were added. The mixture was stirred for 30 minutes before 1- (bromomethyl)-3-(trifluoromethyl)benzene (1.59 g, 6.65 mmol) was added. The mixture was then stirred at reflux temperature for overnight hours. The reaction mixture was rotary evaporated. Water (100 mL) was then added to the residue and the aqueous was then extracted with EtOAc (50 mL x 3). The combined organic layers were evaporated and then dried in vacuo yielding 2.08 g (96 %) of ethyl 3-methoxy-4-((3-(trifluoromethyl)benzyl)oxy)benzoate as beige solid. (0311) lH NMR (400 MHz, Chloroform-d) delta 7.80 - 7.39 (m, 6H), 6.83 (d, J= 8.4 Hz, 1H), 5.24 (0312) (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H).

Reference： [1]Patent: WO2018/144900,2018,A1 .Location in patent: Page/Page column 50

82
[ 14140-15-9 ]
[ 402-49-3 ]
1-(2-bromoethyl)-4-[4-(trifluoromethyl)benzyloxy]benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With potassium carbonate; In acetone; at 20℃; for 24h;	General procedure: The commercially available 4-hydroxyphenethyl bromide(4.9 mmol) was dissolved in 20 mL of acetone; K2CO3 (10 mmol) andthe appropriate benzyl bromide (9.9 mmol) were added, and the reactionmixture was stirred at room temperature for 24 h. After this timethe solvent was removed in vacuum, water was added, and the resultingsuspension was extracted with EtOAc (3×50 mL). The combined organiclayers were washed with water, dried on anhydrous sodium sulfate,and evaporated to obtain a residue that was recrystallized by theopportune solvent. By use of this procedure, the subsequent compoundswere obtained.

Reference： [1]Bioorganic Chemistry,2018,vol. 81,p. 334 - 339

83
[ 2403-88-5 ]
[ 402-49-3 ]
N-p-trifluoromethylbenzyl-2,2,6,6-tetramethylpiperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	In toluene; at 130℃; for 40h;Autoclave;	General procedure: In a 30 mL PARR autoclave were introduced 2,2,6,6-tetramethylpiperidin-4-ol 1 ( 2.0 g, 1 equiv.) and the allyl or benzyl bromide 2 (0.5 equiv.) dissolved in dry toluene (13 mL). The autoclave was sealed and the mixture was heated to 130 C. After 40 hours stirring, the mixture was cooled down to room temperature then diluted in AcOEt and water. The aqueous layer was extracted 3 times with AcOEt (3x25 mL) and the combined organic phases were washed with water (20 mL), brine (20 mL) and dryed over Na2SO4. After filtration and concentration under vacuum, the residue was purified by flash chromatography on silicagel using a combination of petroleum ether and ethyl acetate for benzylic products and dichloromethane and methanol for allylic products to yield the pure desired products 3.

Reference： [1]European Journal of Organic Chemistry,2018,vol. 2018,p. 5427 - 5434
[2]Tetrahedron Letters,2019,vol. 60,p. 240 - 243

84
[ 15965-30-7 ]
[ 402-49-3 ]
C₁₉H₁₃Cl₂F₆N₂⁽¹⁺⁾*Br^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: 4,5-dichloroimidazole With potassium carbonate In acetonitrile at 20℃; for 1h; Stage #2: 4-bromomethyltrifluoromethylbenzene In acetonitrile at 160℃; for 3h;

Reference： [1]Genç, Sertaç; Günnaz, Salih; Çetinkaya, Bekir; Gülcemal, Süleyman; Gülcemal, Derya [Journal of Organic Chemistry, 2018, vol. 83, # 5, p. 2875 - 2881]

85
[ 93247-78-0 ]
[ 402-49-3 ]
1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/195123,2018,A1

86
[ 93247-78-0 ]
[ 402-49-3 ]
C₁₇H₁₃F₃N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;	A suspension of methyl 1H-indazole-7-carboxylate (1 eq.) and cesium carbonate (3 eq.) in DMF (0.74 M) was cooled to 0°C and 1-(bromomethyl)-4-(trifluoromethyl)benzene (1.2 eq., 0.89M in DMF) was added dropwise. The reaction mixture was allowed to warm slowly to rt over 16 h and then quenched with ice-water and extracted with TBME. The combined organic extracts were washed further with water and brine, dried over MgSO4, and filtered. Concentration of the filtrate in vacuo furnished the crude reaction product as a golden yellow oil, which was purified with column chromatography (Si02, 9:1 (v/v) Hex:EtOAc to EtOAc) to afford the product as a colorless oil (76percent yield).

Reference： [1]Patent: WO2018/195123,2018,A1 .Location in patent: Paragraph 00242

87
[ 3304-70-9 ]
[ 402-49-3 ]
dimethyl 1-(4-(trifluromethyl)benzyl)-1H-imidazole-4,5-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 30 - 120℃;	Free <strong>[3304-70-9]dimethyl 1H-imidazole-4,5-dicarboxylate</strong> (7 g, 38 mmol, 1 eq), 4-(trifluromethyl)benzyl bromide (1 to 5 eq) and potassium carbonate (0.2 to 5 eq) were dissolved in about 60 ml of DMF, and then the mixture was stirred at 30 to 120 C. for 3 to 24 hours. TLC (PE:EA=1:2) showed that the <strong>[3304-70-9]dimethyl 1H-imidazole-4,5-dicarboxylate</strong> was reacted almost completely, and a new spot appeared. The mixture was added with 150 ml of water and further added with 200 ml of ethyl acetate, and thereby the layers were separated. The organic layer was washed with 200 ml of water and dried by a rotary evaporator to obtain a transparent liquid which was used in the next step.

Reference： [1]Patent: US2018/370921,2018,A1 .Location in patent: Paragraph 0101-0103

88
[ 41489-76-3 ]
[ 402-49-3 ]
methyl 5-formyl-2-((4-(trifluoromethyl)benzyl)oxy)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.9%	With potassium carbonate; at 25 - 70℃; for 5h;	Taking Compound 1b obtained in Step A, 0.9 g (5 mmol),4-(trifluoromethyl)bromobenzyl 1.3 g (5.5 mmol),1.38 g (10 mmol) of potassium carbonate was added to 35 mL of dimethylformamide.Heat to 70 C reaction,Thin layer chromatography (TLC) is used to track the progress of the reaction.After 5.0 hours of reaction,Reduce the system temperature to 25 C,Then wash with water,The organic phase is decompressed to a solvent-free fraction.Yielding 1.3 g of compound 2b,The yield was 76.90%.

Reference： [1]Patent: CN109180521,2019,A .Location in patent: Paragraph 0062; 0066; 0067; 0068
[2]ChemMedChem,2020

89
[ 99-53-6 ]
[ 402-49-3 ]
2-methyl-4-nitro-1-((4-(trifluoromethyl)benzyl)oxy)benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%		The <strong>[99-53-6]2-methyl-4-nitrophenol</strong> (7.66 g, 50 mom), potassium carbonate (13.8 g, 100 mom), dry N, N - dimethylformamide (70 ml) is added to the 250 ml single-port in the bottle, stir at room temperature 30 minutes later, dropping 4-trifluoromethylbenzyl bromide (14.34 g, 60 mom) of N, N - dimethyl formamide solution (30 ml), after dropping the temperature to 60 C reaction 10 hours. After the reaction the reaction mixture is cooled to room temperature and poured into ice water (300 ml) in violent stirring 30 minutes, solids are separated out, filtering, the filter cake is washed with water (100 ml x3), drying, to obtain 14.94 g yellow solid, yield: 96%.

Reference： [1]Patent: CN109320452,2019,A .Location in patent: Paragraph 0354; 0356; 0357

90
[ 402-49-3 ]
[ 518-34-3 ]
C₅₄H₅₄F₆N₂O₆⁽²⁺⁾*2Br^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.14%	With triethylhexadecylammonium chloride; In water; at 200℃; for 0.1h;Microwave irradiation;	Microwave method: Weigh 6.23 g of tetrandrine and 5.00 g of p-trifluoromethylbenzyl bromide.Triethylhexadecyl ammonium chloride 0.05g, deionized water 80mL, mixed uniformly into the microwave reactor, set the microwave radiation conditions:The temperature is 200 C, the microwave power is 1000 W and the frequency is 2450 MHz, and the reaction is 0.1 h.The temperature was lowered to room temperature, extracted with acetone three times at room temperature (200 mL × 3), and the extracted liquid phase was evaporated until the liquid volume was reduced to 50 mL.Cool to 5 C overnight, filter, TLC tracking reaction and product separation and purification process,The solid was dried at 60 C for 4 h to give 9.53 g of product as pale yellow powder, yield 94.14%.

Reference： [1]Patent: CN109678871,2019,A .Location in patent: Paragraph 0062-0067

91
[ 71759-89-2 ]
[ 402-49-3 ]
4-iodo-1-(4-(trifluoromethyl)benzyl)-1H-imidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	4-Iodo-1H-imidazole (1 g, 5.2 mmol) and N,N-diisopropylethylamine (1.34 g, 10.4 mmol) wereadded to dry dimethylformamide (20 mL), and 1-(bromomethyl)-4-(trifluoromethyl)benzene (1.48 g,6.2 mmol) was added to reaction mixture at 20 C. After the reaction mixture was stirred at 20 Cuntil the starting material disappeared in thin layer chromatography (TLC), the reaction mixture was distilled in vacuo, dichloromethane (50 mL) was added to the mixture. The organic extract was washed twice with saturated aqueous NaHCO3 and NaCl (20 mL) respectively, and the organic extract was dried over Na2SO4. After solvent was removed under vacuum, the unpurified product was added to the next step directly.

Reference： [1]Molecules,2019,vol. 24

92
[ 22479-95-4 ]
[ 402-49-3 ]
C₁₈H₁₅F₃O₅ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2020,vol. 141,p. 8171 - 8184

93
[ 1076-22-8 ]
[ 402-49-3 ]
C₁₄H₁₁F₃N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;Sealed tube;	General procedure: Synthesis of VU0071063 analogs was carriedabout by alkylation of commercially available theophylline (1)with various benzyl bromides (2)(see Supplemental Table S1). Benzylbromides not commercially available were synthesized by reduction ofthe benzaldehyde to the alcohol then conversion to the bromide viaAppel reaction or by radical bromination of the methylbenzene.Generally, one equivalent of theophylline and benzyl bromide weredissolved in 1 ml of dimethylformamide (DMF) in a 2-dram screw capvial at room temperature. Two equivalents of potassium carbonatewere then added and the reactions were stirred overnight. The productwas precipitated by addition of 2 ml of water and an additional hour ofstirring, then isolated via vacuum filtration. Impure products werepurified by normal-phase column chromatography. Products wereisolated in 5%-85% yield. Guanine-based compounds were synthesizedfrom guanosine using the method above, except dimethylsulfoxide (DMSO) was used in place of DMF. After overnight stirring,the sugar was cleaved by addition of concentrated HCl and an hour ofstirring, then isolated via vacuum filtration. For VU0071063, theophylline(50 mg, 0.278 mmol) and 4-tert-butylbenzyl bromide (63.038 mg,0.278 mmol) were mixed in a 2-g vial. To this mixture was added DMF(1 ml, 0.278 M) and then potassium carbonate (77.831 mg, 0.555mmol). The reaction was stirred overnight, forming a white precipitate,to which 1 ml water was added to induce further precipitation.The white solid was collected via vacuum filtration, washed withwater, and dried under vacuum to yield VU0071063 (60 mg, 66%) asa white solid. Heteronuclear multiple bond coherence analysisconfirmed N7 alkylation. 1H NMR (400 MHz, CDCl3) d (ppm): 7.55(s, 1H), 7.38 (d, J 5 8.4 Hz, 2H), 7.26 (d, J 5 8.4 Hz, 2H), 5.47 (s, 2H),3.58 (s, 3H), 3.41 (s, 3H), 1.29 (s, 9H); 13C NMR (100.6 MHz, CDCl3)d (ppm): 155.4, 151.8, 151.7, 148.9, 140.9, 132.5, 127.9, 126.1, 107.1, 50.1,34.7, 31.3, 29.8, 28.1; high-resolution mass spectrometry (TOF, ES1):calculated for C18H22N4O2, 326.1743; found, 326.1746.

Reference： [1]Journal of Pharmacology and Experimental Therapeutics,2019,vol. 370,p. 350 - 359

94
[ 402-49-3 ]
[ 374538-01-9 ]
(E)-3-(2-fluoro-5-(4-(trifluoromethyl)benzyl)phenyl)-2-(methylsulfonyl)acrylonitrile [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1148 - 1153

95
[ 402-49-3 ]
[ 374538-01-9 ]
C₁₅H₁₀F₄O [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1148 - 1153

96
[ 402-49-3 ]
[ 21725-69-9 ]
2-(4-(trifluoromethyl)benzyl)benzo[d]isoxazol-3(2H)-one [ No CAS ]
3-((4-(trifluoromethyl)-benzyl)oxy)benzo[d]isoxazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With sodium hydride; In N,N-dimethyl-formamide; at 20℃;	A mixture of <strong>[21725-69-9]3-hydroxybenzisoxazole</strong> 4a (0.30g, 2.2mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.64g, 2.66mmol) in the presence of NaH (0.06g, 2.66mmol) and DMF (10mL) was stirred at room temperature for overnight. Then, the resulting solution was diluted with DCM, washed with brine, dried over anhydrous MgSO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel to afford the desired compound 5a (0.21g, 0.72mmol, 33%) and a side product compound 5g. For 5a: 1H NMR (400MHz, CDCl3) delta 7.80 (d, J=7.82Hz, 1H), 7.54 (t, J=7.83Hz, 3H), 7.45 (d, J=7.83Hz, 2H), 7.20 (t, J=7.34Hz, 1H), 7.11 (d, J=8.80Hz, 1H), 5.20 (s, 2H); 13C NMR (101MHz, CDCl3) delta 162.8, 160.3, 138.9, 138.9, 133.6, 130.36 (q, J=32Hz), 125.5 (q, J=3Hz), 124.3, 124.0 (q, J=271Hz), 123.6, 116.1, 109.9, 49.1; HRMS m/z calcd for [C15H10F3NO2+H]+ 294.0736, found 294.0741. For 5g: 1H NMR (400MHz, CDCl3) delta 7.57-7.68 (m, 5H), 7.36-7.51 (m, 2H), 7.17-7.28 (m, 1H), 5.52 (s, 2H); 13C NMR (101MHz, CDCl3) delta 166.2, 164.1, 139.7, 131.0, 130.5 (q, J=32Hz), 128.2, 125.5 (q, J=3Hz), 124.1 (q, J=270Hz) , 123.1, 120.7, 114.0, 110.1, 70.8; HRMS m/z calcd for [C15H10F3NO2+H]+ 294.0736, found 294.0743.

Reference： [1]Patent: WO2019/174279,2019,A1 .Location in patent: Paragraph 0333; 0334
[2]Bioorganic Chemistry,2020,vol. 100

97
[ 83-67-0 ]
[ 402-49-3 ]
3,7-dimethyl-1-(4-trifluoromethylbenzyl)xanthine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%		A suspension of theobromine (360 mg, 2.0mmol) in DMF (15 mL) was heated to 50C for 10 min before adding 3 equiv. of potassium carbonate (830mg, 6mmol). After 30 min, an equimolar amount of 4-(trifluoromethyl)benzyl bromide (309 muL, 2.0mmol) was added and the reaction mixture stirred overnight at 50C. Thus, the suspension was filtered off and the resulting clear solution was dried to achieve a white solid. Further recrystallization in isopropanol allowed the isolation of the final product as an off-white solid (423mg, 63%). 1H NMR (300MHz, CDCl3) delta 7.65-7.49 (m, 4H, Ar), 5.25 (s, 2H, CH2), 4.01 (s, 3H, CH3), 3.60 (s, 3H, CH3). 13C NMR (101MHz, CDCl3) delta 154.12 (Ar), 150.54 (Ar), 148.03 (Ar), 140.75 (Ar), 140.19 (Ar), 128.74 (q, J=32.32Hz, Ar, Calpha-CF3), 128.02 (Ar), 126.03 (q, J=272.7Hz, CF3), 124.37 (q, J=3.8Hz, Ar, Cbeta-CF3), 106.59 (Ar), 43.02 (CH2), 32.62 (CH3), 28.82 (CH3).

Reference： [1]Journal of Inorganic Biochemistry,2020,vol. 202

98
[ 1416819-91-4 ]
[ 402-49-3 ]
cobalt(II) bromide [ No CAS ]
C₂₁H₂₁Br₂CoF₆N₂O [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2019,vol. 141,p. 18877 - 18889

99
[ 67-20-9 ]
[ 402-49-3 ]
(E)-1-([(5′-nitrofuran-2′-yl)methylene]amino)-3-(p-(trifluoromethyl)benzyl) imidazolidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: <strong>[67-20-9]Nitrofurantoin</strong>, 1, (2.94mmol, 0.7g) was dissolved in 10mL of anhydrous dimethyl formamide (DMF), and trimethylamine (TEA, 4.41mmol, 1.5eq.) was added. The solution was stirred at room temperature for 15min. To resulting yellow solution, the appropriate n-alkyl or benzyl bromide (4.41mmol, 1.5eq) was added. The reaction was stirred at room temperature and monitored by TLC eluting with DCM:MeOH (19:1, v/v). Upon completion, the reaction was quenched with 20mL water and extracted with ethyl acetate (3X20mL). The organic layer was washed once with saturated NH4Cl and once with water. The solution was concentrated in vacuo. The resulting paste was purified by recrystallization in ethanol/water) to afford the desired analogue (Scheme 1 ).

Reference： [1]Bioorganic Chemistry,2020,vol. 96

100
[ 15965-30-7 ]
[ 402-49-3 ]
4,5-dichloro-1-(4-(trifluoromethyl)benzyl)-1H-imidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: 4,5-dichloroimidazole With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4-bromomethyltrifluoromethylbenzene In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
	Stage #1: 4,5-dichloroimidazole With potassium carbonate In acetonitrile at 25℃; for 1h; Stage #2: 4-bromomethyltrifluoromethylbenzene In acetonitrile for 12h; Reflux;

Reference： [1]Lessi, Marco; Lucci, Antonio; Cuzzola, Angela; Bellina, Fabio [European Journal of Organic Chemistry, 2020, vol. 2020, # 7, p. 796 - 802]
[2]Genç, Sertaç; Gülcemal, Süleyman; Günnaz, Salih; Çetinkaya, Bekir; Gülcemal, Derya [Journal of Organic Chemistry, 2020, vol. 85, # 14, p. 9139 - 9152]

101
[ 405-04-9 ]
[ 402-49-3 ]
3-fluoro-4-((4-(trifluoromethyl)benzyl)oxy)benzonitrile [ No CAS ]