22902-86-9|4-Chloro-3-(trifluoromethyl)phenylacetic acid| Ambeed

Structure of 22902-86-9

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Quality Control of [ 22902-86-9 ] Purity: 98% SDS Specification

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Product Details of [ 22902-86-9 ]

CAS No. :	22902-86-9
Formula :	C₉H₆ClF₃O₂
M.W :	238.59
SMILES Code :	OC(=O)CC1=CC(=C(Cl)C=C1)C(F)(F)F
MDL No. :	MFCD04116012
InChI Key :	AZBFOENSKLAYKT-UHFFFAOYSA-N
Pubchem ID :	3519882

Safety of [ 22902-86-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 22902-86-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	6
Fraction Csp3	0.22
Num. rotatable bonds	3
Num. H-bond acceptors	5.0
Num. H-bond donors	1.0
Molar Refractivity	48.0
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	37.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.76
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.9
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.14
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	3.25
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	3.26
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.06

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.24
Solubility	0.136 mg/ml ; 0.00057 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.34
Solubility	0.108 mg/ml ; 0.000453 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.69
Solubility	0.0493 mg/ml ; 0.000207 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.7 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.8

Application In Synthesis of [ 22902-86-9 ]

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

Downstream synthetic route of [ 22902-86-9 ]

[ 22902-86-9 ] Synthesis Path-Downstream 1~29

1
[ 22902-82-5 ]
[ 22902-86-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; acetic acid; at 100℃; for 2h;	Carbon tetrabromide (3.48 g, 10.5 mmol) and triphenylphosphine (2.75 g, 10.5 mmol) were added to a solution of [4-chloro-3-(trifluoromethyl)phenyl]methanol (2.00 g, 9.59 mmol) in tetrahydrofuran (12 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Hexane was added to the reaction mixture, and the insolubles were removed by filtration. The obtained filtrate was poured into water and, after the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=4/1-2/1) to obtain 4-(bromomethyl)-1-chloro-2-(trifluoromethyl)benzene. Potassium cyanide (687 mg, 10.5 mmol) was added to a mixed solution of the obtained 4-(bromomethyl)-1-chloro-2-(trifluoromethyl)benzene in ethanol-water (3:1, 20 ml), and the mixture was stirred at 60C for 2 hours. The reaction mixture was poured into water and, after the mixture was extracted with ethyl acetate, the organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=4/1-2/1) to obtain crude [4-chloro-3-(trifluoromethyl)phenyl]acetonitrile. Acetic acid (6 ml) and concentrated hydrochloric acid (6 ml) were added to the obtained crude product, and the mixture was stirred at 100C for 2 hours. After the temperature of the reaction mixture was returned to room temperature, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain crude [4-chloro-3-(trifluoromethyl)phenyl]acetic acid. Methanol (12 ml) and concentrated sulfuric acid (1.0 ml) were added to the obtained crude product, and the mixture was stirred at 50C for 1 hour. The temperature of the reaction mixture was returned to room temperature, and the solvent was evaporated under reduced pressure. After ethyl acetate was added thereto, the organic layer was successively washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=10/1) to obtain methyl [4-chloro-3-(trifluoromethyl)phenyl]acetate (1.08 g, two steps total yield: 45%). 1H-NMR (400MHz, CDCl3) : delta 7.58 (1H, d, J = 2.0 Hz), 7.45 (1H, d, J = 8.0 Hz), 7.37 (1H, dd, J = 8.0, 2.0 Hz), 3.70 (3H, s), 3.64 (2H, s).

References: [1]Patent: WO2006/46593,2006,A1 .Location in patent: Page/Page column 209-210.
[2]Patent: EP1764075,2007,A1 .Location in patent: Page/Page column 108-109.

2
[ 67-56-1 ]
[ 22902-86-9 ]
[ 66504-62-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; at 50℃; for 1h;	Carbon tetrabromide (3.48 g, 10.5 mmol) and triphenylphosphine (2.75 g, 10.5 mmol) were added to a solution of [4-chloro-3-(trifluoromethyl)phenyl]methanol (2.00 g, 9.59 mmol) in tetrahydrofuran (12 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Hexane was added to the reaction mixture, and the insolubles were removed by filtration. The obtained filtrate was poured into water and, after the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=4/1-2/1) to obtain 4-(bromomethyl)-1-chloro-2-(trifluoromethyl)benzene. Potassium cyanide (687 mg, 10.5 mmol) was added to a mixed solution of the obtained 4-(bromomethyl)-1-chloro-2-(trifluoromethyl)benzene in ethanol-water (3:1, 20 ml), and the mixture was stirred at 60C for 2 hours. The reaction mixture was poured into water and, after the mixture was extracted with ethyl acetate, the organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=4/1-2/1) to obtain crude [4-chloro-3-(trifluoromethyl)phenyl]acetonitrile. Acetic acid (6 ml) and concentrated hydrochloric acid (6 ml) were added to the obtained crude product, and the mixture was stirred at 100C for 2 hours. After the temperature of the reaction mixture was returned to room temperature, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain crude <strong>[22902-86-9][4-chloro-3-(trifluoromethyl)phenyl]acetic acid</strong>. Methanol (12 ml) and concentrated sulfuric acid (1.0 ml) were added to the obtained crude product, and the mixture was stirred at 50C for 1 hour. The temperature of the reaction mixture was returned to room temperature, and the solvent was evaporated under reduced pressure. After ethyl acetate was added thereto, the organic layer was successively washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=10/1) to obtain methyl [4-chloro-3-(trifluoromethyl)phenyl]acetate (1.08 g, two steps total yield: 45%). 1H-NMR (400MHz, CDCl3) : delta 7.58 (1H, d, J = 2.0 Hz), 7.45 (1H, d, J = 8.0 Hz), 7.37 (1H, dd, J = 8.0, 2.0 Hz), 3.70 (3H, s), 3.64 (2H, s).

References: [1]Patent: WO2006/46593,2006,A1 .Location in patent: Page/Page column 209-210.
[2]Patent: EP1764075,2007,A1 .Location in patent: Page/Page column 108-109.

Yield	Reaction Conditions	Operation in experiment
		Acetic acid (6 ml) and concentrated hydrochloric acid (6 ml) were added to the obtained [4-chloro-3-(trifluoromethyl)phenyl]acetonitrile and the mixture was stirred at 100C for 2 hours. After the temperature of the reaction mixture was returned to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous NaCI solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give crude [4-chloro-3-(trifluoromethyl)phenyl]acetic acid.

4
[ 22902-86-9 ]
4-chloro-3-trifluromethylphenylacetyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; at 60℃; for 1h;	e. Acetic acid 2-5-[2-(4-chloro-3-trifluoromethyl-phenyl)-acetylamino]-1-oxo-1H-isoquinolin-2-yl-ethyl ester The solution of <strong>[22902-86-9]2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid</strong> (131 mg, 0.000548 mol) in thionyl chloride (5 mL) was stirred at 60 C. for 1 hour. Thionyl chloride was removed, and residue was dissolved in tetrahydrofuran (5 mL). 2-(5-Amino-1-oxoisoquinolin-2(1H)-yl)ethyl acetate (100.0 mg, 0.0003655 mol) and N,N-diisopropylethylamine (95.5 muL, 0.000548 mol) were added and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were removed, the residue was dissolved in ethylacetate, washed with water, dilute HCl and brine, and purified by column. The product was obtained as a beige solid (65 mg). MS m/z=467.4 (M+1). 1H NMR (DMSO-d6) delta 10.11(s, 1 H), 8.08(d, J=8.0 Hz, 1 H), 7.90(s, 1 H), 7.84(d, J=7.0 Hz, 1 H), 7.75-7.65 (m, 2 H), 7.55-7.42(m, 2 H), 6.69(d, J=7.6 Hz, 1 H), 4.33(t, J=5.1 Hz, 2 H), 4.20(t, J=5.1 Hz, 2 H), 3.92(s, 2 H), 1.96(s, 3 H).
	In dichloromethane; at 0℃; for 1h;Inert atmosphere;	Oxalyl chloride (133 mg; 1.05 mmol) was added to a solution of 4-chloro-3- (trifluoromethyl)phenylacetic acid (50 mg; 0.21 mmol) and DMF (0.005 mL) in DCM (6 mL) at 0C under inert atmosphere and the resulting mixture was stirred at 0C for 1 hour. It was concentrated in vacuo and the residue was taken up in DCM (6 mL). N,N-diisopropylethylamine (72.23 mu; 0.42 mmol)

References: [1]Patent: US2007/225324,2007,A1 .Location in patent: Page/Page column 25.
[2]Patent: WO2013/182274,2013,A1 .Location in patent: Page/Page column 68; 69.

5
[ 951015-85-3 ]
[ 22902-86-9 ]
2-(4-Chloro-3-trifluoromethyl-phenyl)-N-[2-(2-hydroxy-1-hydroxymethyl-ethyl)-1-oxo-1,2-dihydro-isoquinolin-5-yl]-acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		c. 2-(4-Chloro-3-(trifluoromethyl)phenyl)-N-(2-(1,3-dihydroxypropan-2-yl)-1-oxo-1, 2-dihydroisoquinolin-5-yl)acetamide To a solution of 5-amino-2-(1,3-dihydroxypropan-2-yl)isoquinolin-1(2H)-one (100.0 mg, 0.0004055 mol) in N,N-dimethylformamide (8 mL, 0.1 mol) was added <strong>[22902-86-9]2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid</strong> (378.0 mg, 0.001584 mol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (448.0 mg, 0.001178 mol) and N,N-diisopropylethylamine (600.0 muL, 0.003445 mol). The reaction mixture was stirred for 16 hours at 50 C. After most of the DMF was rotovaped, MeOH (20 mL) and 2N NaOH (5 mL) were added to the residue. The solution was stirred for 1 hour at room temperature. MeOH was rotovaped and EtOAc (100 mL) was added, and the resultant solution was then washed with water (2*100 mL), Sat. NaHCO3, H2O, and brine. The EtOAc layer was dried by MgSO4 and was rotovaped. The resultant solution was washed with DCM and then purified with silica-gel. The final productproduct was obtained as a solid. MS m/z=455.1 (M+1). 1H NMR (400 MHz; DMSO-d6) delta 10.09(s, 1 H), 8.09(d, J=8.0 Hz, 1 H), 7.89(s, 1 H), 7.80(d, J=7.6 Hz, 1 H), 7.75-7.65(m, 2 H), 7.55-7.40(m, 2 H), 6.63(d, J=7.6 Hz, 1 H), 4.98-4.85(m, 3 H), 3.92(s, 2 H), 3.85-3.65 (m, 4 H).

References: [1]Patent: US2007/225324,2007,A1 .Location in patent: Page/Page column 26.

6
[ 950908-80-2 ]
[ 22902-86-9 ]
(R)-2-{5-[2-(4-Chloro-3-trifluoromethyl-phenyl)-acetylamino]-1-oxo-1H-isoquinolin-2-yl}-propionamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h;	c. (R)-2-(5-(2-(4-Chloro-3-(trifluoromethyl)phenyl)acetamido)-1-oxoisoquinolin-2(1H) -yl)propanamide A round bottom flask was charged with <strong>[22902-86-9]2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid</strong> (0.13 g, 0.00056 mol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.3 g, 0.0009 mol), N,N-diisopropylethylamine (0.2 mL, 0.0009 mol), N,N-dimethylformamide (3 mL, 0.04 mol) and (R)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)propanamide (0.1 g, 0.0004 mol). The reaction was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue purified by flash chromatography (12 g, 0-10% MeOH/DCM) to get the product as white solid. MS m/z=451.8(M+H). 1H NMR (400 MHz; DMSO-d6) delta 10.10 (s, 1H), 8.07(d, J=8.42 Hz, 1H), 7.89 (s, 1H), 7.82 (d, J=8.47 Hz, 1H) 7.73-7.68 (m, 2H), 7.63 (s, 1H), 7.46 (d, J=7.57 Hz, 2H), 7.23 (bs, 1H), 6.68 (d, J=8.02 Hz, 1H), 5.50-5.45 (q, J=7.24 Hz, 1H), 3.92 (s, 2H), 1.54 (d, J=7.66 Hz, 3H).

References: [1]Patent: US2007/225324,2007,A1 .Location in patent: Page/Page column 31.

7
[ 950914-84-8 ]
[ 22902-86-9 ]
2-{5-[2-(4-Chloro-3-trifluoromethyl-phenyl)-acetylamino]-1-oxo-1H-isoquinolin-2-yl}-acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h;	c. N-(2-(2-Amino-2-oxoethyl)-1-oxo-1,2-dihydroisoquinolin-5-yl)-2-(4-chloro-3-(trifluoromethyl)phenyl)acetamide A round bottom flask was charged with <strong>[22902-86-9]2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid</strong> (170 mg, 0.00072 mol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (400 mg, 0.001 mol), N,N-diisopropylethylamine (0.2 mL, 0.001 mol), N,N-dimethylformamide (2 mL, 0.03 mol) and 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)acetamide (120 mg, 0.00055 mol). The reaction was stirred for 16 h at room temperature and the solvent was removed and the residue purified by preparative HPLC (reverse phase) to yield the product as a white powder. MS m/z=437.8 (M+1). 1H NMR (400 MHz; DMSO-d6) delta 10.09 (s, 1H), 8.04 (d, J=8.07 Hz, 1H), 7.89 (bs, 1H), 7.83 (d, J=8.07 Hz, 1H), 7.73-7.70 (m, 2H), 7.63 (bs, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.42 (d, J=7.76 Hz, 1H) 7.19 (bs, 1H), 6.64 (d, J=7.70 Hz, 1H), 4.56 (s, 2H), 3.92 (s, 2H).

References: [1]Patent: US2007/225324,2007,A1 .Location in patent: Page/Page column 32.

8
[ 950914-93-9 ]
[ 22902-86-9 ]
(S)-2-{5-[2-(4-Chloro-3-trifluoromethyl-phenyl)-acetylamino]-1-oxo-1H-isoquinolin-2-yl}-3-hydroxy-propionamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; at 20℃; for 16h;	c. (S)-2-5-[2-(4-Chloro-3-trifluoromethyl-phenyl)-acetylamino]-1-oxo-1 H-isoquinolin-2-yl-3-hydroxy-propionamide A round bottom flask was charged with <strong>[22902-86-9]2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid</strong> (0.12 g, 0.00052 mol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.3 g, 0.0008 mol), N,N-diisopropylethylamine (0.1 mL, 0.0008 mol) and(S)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-3-hydroxypropanamide (0.1 g, 0.0004 mol). The reaction was stirred for 16 h at room temperature and the solvent was removed and the residue purified by preparative HPLC (reverse phase) to yield the product as a white powder. MS m/z=468.3(M+H). 1H NMR (400 MHz; DMSO-d6) delta10.09 (s, 1H), 8.07 (d, J=8.34 Hz, 1H), 7.89 (bs, 1H), 7.81 (d, J=7.78 Hz, 1H), 7.73-7.66 (m, 3H), 7.53 (d, J=8.21 Hz, 1H), 7.44 (t, J=7.88 Hz, 1H), 7.30 (bs, 1H), 6.64 (d, J=7.88 Hz, 1H), 5.50 (t, J=6.69 Hz, 1H), 5.16 (t, J=5.48 Hz, 1H), 3.98-3.96 (m, 2H), 3.92 (s, 2H).

References: [1]Patent: US2007/225324,2007,A1 .Location in patent: Page/Page column 33.

9
[ 951015-94-4 ]
[ 22902-86-9 ]
C₂₉H₃₁ClF₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 50℃; for 16h;	c. 2-(4-Chloro-3-(trifluoromethyl)phenyl)-N-(1-oxo-2-(piperidin-4-ylmethyl)-1, 2-dihydroisoquinolin-5-yl)acetamide hydrochloride To a solution of tert-butyl 4-((5-amino-1-oxoisoquinolin-2(1H)-yl)methyl)piperidine-1-carboxylate (100.0 mg, 0.0002658 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) were added <strong>[22902-86-9]2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid</strong> (143.0 mg, 0.0005994 mol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (360.0 mg, 0.0009468 mol) and N,N-diisopropylethylamine (305.0 muL, 0.001751 mol). The reaction mixture was stirred for 16 hours at 50 C. LC/MS was checked and the reaction was complete. EtOAc (100 mL) was added and the mixture was washed with water (2*100 mL), Sat. NaHCO3, H2O, and brine. The EtOAc layer was dried by MgSO4 and was rotovaped. The yellow residue was purified by silica-gel column, and a pure Boc protected product was obtained. To a solution of the Boc-protected product in 2 mL of dioxane was added 2M HCl in EtOEt (15 mL). The mixture was then stirred for 2 hours at room temperature to yield the final compound as a light colored solid (65.3 mg). MS m/z=478.2 (M+1). 1H NMR (400 MHz; DMSO-d6) delta 10.25(s, 1 H), 8.83(s, 1 H), 8.08(d, J=7.5 Hz, 1 H), 7.91(s, 1 H), 7.82(d, J=6.9 Hz, 1 H), 7.72(bs, 2 H), 7.55-7.40(m, 2 H), 6.71(d, J=6.8 Hz, 1 H), 4.20-3.80(m, 4 H), 3.28-3.15(m, 2 H), 2.90-2.70(m, 2 H), 2.10(bs 1 H), 1.80-1.60(m, 2 H), 1.52-1.35(m, 2 H).

References: [1]Patent: US2007/225324,2007,A1 .Location in patent: Page/Page column 35-36.

10
[ 951015-96-6 ]
[ 22902-86-9 ]
[ 1243210-47-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 50℃; for 16h;	c. N-(2-(3-Amino-2-(chloromethyl)propyl)-1-oxo-1,2-dihydroisoquinolin-5-yl)-2-(4-chloro-3-(trifluoromethyl)phenyl)acetamide To a solution of 3-(5-amino-1-oxo-1H-isoquinolin-2-ylmethyl)-azetidine-1-carboxylic acid-tert-butyl ester (96.0 mg, 0.000277 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) is added <strong>[22902-86-9]2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid</strong> (150.0 mg, 0.0006287 mol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (230.0 mg, 0.0006049 mol) and N,N-diisopropylethylamine (215 muL, 0.00123 mol). The reaction mixture was stirred for 16 hours at 50 C. LC/MS was checked, and the reaction was found to be complete. EtOAc (100 mL) was added, and the mixture was washed with water (2*100 mL), Sat. NaHCO3, H2O, and brine. The EtOAc layer was dried with MgSO4 and was rotovaped. The yellow residue was purified by silica-gel column to yield the pure Boc protected product. To a solution of the Boc-protected product in 2 mL dioxane was added 2M HCl in EtOEt (15 mL) and stirred for 2 hours at room temperature to obtain the title product which was purified by HPLC. MS m/z=487.2 (M+l). 1H NMR (400 MHz; DMSO-d6) delta 10.15(s, 1 H), 8.08(d, J=8.0 Hz, 1 H), 7.90(s, 1 H), 7.84(d, J=7.5 Hz, 1 H), 7.75-7.65(m, 2 H), 7.55-7.42(m, 2 H), 6.73(d, J=7.6 Hz, 1 H), 5.30-4.30(bs, 2H), 4.08(dd, J=13.4, 7.3 Hz, 1 H), 3.97(dd, J=13.5, 6.6 Hz, 1 H), 3.93(s, 2 H), 3.80(dd, J=11.2, 4.8 Hz, 1H), 3.73(dd, J=11.2, 5.1 Hz, 1 H), 2.67(d, J=6.0 Hz, 2 H), 2.45-2.30 (m, 1 H).

References: [1]Patent: US2007/225324,2007,A1 .Location in patent: Page/Page column 36-37.

11
[ 1243210-29-8 ]
[ 22902-86-9 ]
[ 951153-39-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 50℃; for 16h;	c. (S)-tert-Butyl 2-((5-(2-(4-chloro-3-(trifluoromethyl)phenyl)acetamido)-1-oxoisoquinolin-2(1H)-yl)methyl)pyrrolidine-1-carboxylate To a solution of (S)-tert-butyl 2-((5-amino-1-oxoisoquinolin-2(1H)-yl)methyl)pyrrolidine-1-carboxylate (248.0 mg, 0.0006860 mol) in N,N-dimethylformamide (10 mL, 0.1 mol) was added 2-(4-chloro-2-(trifluoromethyl)phenyl)acetic acid (350.0 mg, 0.001467 mol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (530.0 mg, 0.001394 mol) and N,N-diisopropylethylamine (488.0 muL, 0.002802 mol). The reaction mixture was stirred for 16 hours at 50 C. LC/MS was checked, and revealed that the reaction was completed. EtOAc (100 ML) was added and the resulting solution was washed by water (2*100 mL), Sat. NaHCO3, H2O and brine. The EtOAc layer was dried with MgSO4 and was rotovaped. The yellow residue was purified by silica-gel column.

References: [1]Patent: US2007/225324,2007,A1 .Location in patent: Page/Page column 27.

12
[ 22902-86-9 ]
2-(4-chloro-3-(trifluoromethyl)phenyl)-N-[4-(5-methylimidazo[5,1-b][1,2,4]oxadiazol-2-yl)phenyl]acetamide [ No CAS ]

References: [1]Patent: WO2013/182274,2013,A1 .

13
[ 22902-86-9 ]
[ 1402558-21-7 ]
N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)phenyl]-2-[4-chloro-3-(trifluoromethyl)phenyl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; at 66℃; for 12h;	[00781] Example I[00782] N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]pyrim idin-5-yl)phenyl]-2- [4-chloro-3-(trifluoromethyl)phenyl]acetamide [00783] N,N-Diisopropylethylamine (131 pL, 0.7Smmol) was added to a stirred solution of 5-(4- aminophenyl)-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-4-amine (100mg, 0.38mmol), propylphosphonic anhydride (50%, wt in EtOAc, 336jL, 0.S7mmol) and 2-[4-chloro-3- (trifluoromethyl)phenyl]acetic acid (89mg, 0.38mmol) in THF (3mL) and the solution was stirred at reflux for 12 hours. The solvent was removed in vacuo and the resulting residue was separated viaSCX eluting with 2M NH3 in methanol. The solvent was removed in vacuo and the resulting solid was purified via column chromatography using an eluent of 0-15% MeOH in DCM and then purified via preparative LCMS. The collected fractions were separated via SCX eluting with 2M NH3 in MeOH. The solvents were removed in vacuo, yielding an oil to which DCM (1 mL) and heptane (5mL) were added causing a solid to crash out which was filtered and dried to give N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]pyrimid in-5-yl)phenyl]-2-[4-chloro-3-(trifluoromethyl)phenyl]acetamide (58mg, 0.l2mmol, 32% yield) as a white powder.1H NMR (DMSO-d6, 400MHz) Olppm: 10.49 (1H, 5), 8.13 (1H, 5), 7.87-7.85 (1H, m), 7.65 (2H, d, J= 8.8Hz), 7.73-7.64 (2H, m), 7.39 (2H, d, J = 8.8Hz), 5.54 (2H, 5), 3.84 (2H, 5), 2.79 (2H, t, J =7.2Hz), 2.73 (2H, t, J = 7.2Hz), 2.47-2.40 (2H, m).MS Method 1: RT: 3.52mm, mlz 486.3 [M+H]

References: [1]Patent: WO2016/51193,2016,A1 .Location in patent: Paragraph 00781; 00782; 00783.

14
[ 22902-86-9 ]
3-(indolin-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ No CAS ]
1-(5-{4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2,3-dihydro-1H-indol-1-yl)-2-[4-chloro-3-(trifluoromethyl)phenyl]ethan-1-one [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 11398 - 11414.

15
[ 886230-76-8 ]
[ 22902-86-9 ]
(E)-2-(4-chloro-3-(trifluoromethyl)phenyl)-N-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)acetamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 5006 - 5024.

16
[ 886230-76-8 ]
[ 22902-86-9 ]
C₂₈H₂₄ClF₃N₄O₂ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 5006 - 5024.

17
[ 190728-25-7 ]
[ 22902-86-9 ]
2-(4-chloro-3-(trifluoromethyl)phenyl)-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)acetamide [ No CAS ]