[ CAS No. 6342-60-5 ] {[proInfo.proName]}

Name: 6342-60-5|2-Chloro-5-methylbenzoic acid|97%
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SKU: A374649
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Quality Control of [ 6342-60-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 6342-60-5 ]

Product Details of [ 6342-60-5 ]

CAS No. :	6342-60-5	MDL No. :	MFCD00045798
Formula :	C₈H₇ClO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LEBWXJZAWTVKFL-UHFFFAOYSA-N
M.W :	170.59	Pubchem ID :	240430
Synonyms :

Calculated chemistry of [ 6342-60-5 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	43.38
TPSA :	37.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.5
Log Po/w (XLOGP3) :	3.21
Log Po/w (WLOGP) :	2.35
Log Po/w (MLOGP) :	2.52
Log Po/w (SILICOS-IT) :	2.31
Consensus Log Po/w :	2.38

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-3.26
Solubility :	0.0943 mg/ml ; 0.000553 mol/l
Class :	Soluble
Log S (Ali) :	-3.67
Solubility :	0.0369 mg/ml ; 0.000216 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.77
Solubility :	0.29 mg/ml ; 0.0017 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.29

Safety of [ 6342-60-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 6342-60-5 ]

* 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 [ 6342-60-5 ]
Downstream synthetic route of [ 6342-60-5 ]

[ 6342-60-5 ] Synthesis Path-Upstream 1~5

1
[ 73129-52-9 ]
[ 6342-60-5 ]

Reference： [1] Journal fuer Praktische Chemie (Leipzig), 1892, vol. <2> 46, p. 26
[2] Journal fuer Praktische Chemie (Leipzig), 1892, vol. <2> 46, p. 26
[3] Journal of Medicinal Chemistry, 1967, vol. 10, p. 478 - 481

2
[ 106-43-4 ]
[ 6342-60-5 ]

Reference： [1] Journal fuer Praktische Chemie (Leipzig), 1892, vol. <2> 46, p. 26

3
[ 106-43-4 ]
[ 6342-60-5 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1934, vol. 513, p. 295,301

4
[ 2941-78-8 ]
[ 6342-60-5 ]

Reference： [1] Journal of Organic Chemistry, 1960, vol. 25, p. 1016 - 1020

5
[ 63549-34-8 ]
[ 7697-37-2 ]
[ 6342-60-5 ]

Reference： [1] Chemische Berichte, 1927, vol. 60, p. 2281

[ 6342-60-5 ] Synthesis Path-Downstream 1~84

1
[ 106-43-4 ]
[ 6342-60-5 ]
2,2'-dichloro-5,5'-dimethyl-benzophenone [ No CAS ]

Reference： [1]Justus Liebigs Annalen der Chemie,1934,vol. 513,p. 295,301

2
[ 73129-52-9 ]
[ 6342-60-5 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1892,vol. <2> 46,p. 26
[2]Journal fur praktische Chemie (Leipzig 1954),1892,vol. <2> 46,p. 26
[3]Journal of Medicinal Chemistry,1967,vol. 10,p. 478 - 481

3
[ 6342-60-5 ]
[ 21900-50-5 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃;	To a ice-cold solution of 94a (4.0 g; 23.44 mmol) and CH2Cl2 (60 mL) was added oxalyl chloride (10.26 mL; 0.117 mol) and one drop of DMF. The reaction mixture was allowed to warm to rt and stirred overnight. The volatile solvents were removed in vacuo and oxalyl chloride removed by thrice adding CH2Cl2 (30 mL) and re-evaporating the solvent to yield 94b (4.4 g) as a yellow oil which was used directly in step 2.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃;	At 0C, oxalyl chloride (2.6 mL, 30.5 mmol, 5.2 eq) was added slowly in a dropwise manner into a solution of <strong>[6342-60-5]2-chloro-5-methyl-benzoic acid</strong> (1 g, 5.9 mmol, 1.0 eq) in CH2Cl2 (15 mL), a drop of DMF was added, and stirred overnight at room temperature, subjecting same to rotary drying.
	With thionyl chloride; for 2h;Heating / reflux;	<strong>[6342-60-5]2-Chloro-5-methyl-benzoic acid</strong> [(1G,] 5.8 mmol) was treated with thionyl chloride (5 [ML)] at reflux for two hours. Excess thionyl chloride was removed under reduced pressure. The residue was added to a suspension of 2-chloro-N-hydroxy-acetamidine (638 mg, 5.8 mmol) in dichloromethane (10 [ML)] at room temperature. After stirring for 30 minutes, triethylamine (2.04 [ML,] 14.6 mmol) was added and stirred for an additional hour. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Flash column chromatography using 10-20% ethyl acetate in hexanes afforded 460 mg of the acyclic ester intermediate. DMF was added to this intermediate and then heated at [135C] for 4 h to effect cyclization to oxadiazole. After cooling the reaction mixture was washed with water (3 times) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography on silica gel using 5% ethyl acetate in hexanes afforded the title compound [160] mg (12 % over 2 steps) as a white solid. m/z 244 (GCMS)

Reference： [1]Justus Liebigs Annalen der Chemie,1934,vol. 513,p. 295,301
[2]Bulletin des Societes Chimiques Belges,1968,vol. 77,p. 287 - 293
[3]Patent: US2004/198736,2004,A1 .Location in patent: Page/Page column 74
[4]Journal of Medicinal Chemistry,2016,vol. 59,p. 2478 - 2496
[5]Journal of Medicinal Chemistry,2016,vol. 59,p. 6807 - 6825
[6]Patent: EP3339294,2018,A1 .Location in patent: Paragraph 0224; 0225
[7]Patent: WO2004/14370,2004,A2 .Location in patent: Page/Page column 65

4
[ 2941-78-8 ]
[ 6342-60-5 ]

Reference： [1]Journal of Organic Chemistry,1960,vol. 25,p. 1016 - 1020

5
[ 6342-60-5 ]
[ 16220-95-4 ]

Reference： [1]Journal of Medicinal Chemistry,1967,vol. 10,p. 478 - 481

8
diazotized 2-amino-5-methyl-benzoic acid [ No CAS ]
[ 6342-60-5 ]

Reference： [1]Journal of the American Chemical Society,1952,vol. 74,p. 4296,4301

9
[ 63549-34-8 ]
[ 7697-37-2 ]
[ 6342-60-5 ]

Reference： [1]Chemische Berichte,1927,vol. 60,p. 2281

10
[ 6342-60-5 ]
[ 89-56-5 ]

Yield	Reaction Conditions	Operation in experiment
		Under nitrogen, 2 mmol of the halogen-substituted benzoic acid indicated in Table 6 was stirred with a solution of 3 mmol Na2CO3 at 50-75 C. until all of the halogen-substituted benzoic acid was dissolved. Subsequently, 0.02 mmol CuSO4 and 0.04 mmol rac-trans-N,N'-dimethylcyclohexane-1,2-diamine (Ligand F) dissolved in 1 mL deionized water were added and the reaction mixture was heated at 80-100 C. for 4 h. After cooling to ambient temperature the reaction mixtures were carefully acidified with 35% aqueous HCl.In isolation method A, the products were extracted from the aqueous layer twice with ethyl acetate, the ethyl acetate fractions were combined and the crude reaction product was isolated by evaporation of ethyl acetate under vacuum. In isolation method B, the products were isolated by filtration, washed with water and dried under vacuum. The crude reaction product was analyzed by 1H NMR (d6-dmso). The results are summarized in Table 6. TABLE 6 Examples 8~23 Starting material Halogenated Benzoic Acid Isolation CONV SEL Example Benzoic Acid Product T ( C.) Method (%) (%) 8 2,5-dibromo- 2-hydroxy-5- 80 B >99 >99 bromo- 9 2-bromo-5-nitro- 2-hydroxy-5- 80 B >99 >99 nitro- 10 2-bromo-5-nitro- 2-hydroxy-5- 100 A >99 >99 nitro- 11 2-bromo-5-methyl- 2-hydroxy-5- 80 B >99 >99 methyl- 12 2-bromo-5-methyl- 2-hydroxy-5- 100 A >99 >99 methyl- 13 4-bromo- 4-hydroxy- 100 A >99 >99 14 4-chloro- 4-hydroxy- 80 B >99 >99 15 2,4-dichloro- 2-hydroxy-4- 100 A 70 >99 chloro- 16 2,5-dichloro- 2,5-dihydroxy- 80 B 93 >99 17 2-chloro-5-nitro- 2-hydroxy-5- 100 A 74 >99 nitro- 18 2-chloro-3,5-dinitro- 2-hydroxy-3,5- 100 A >99 >99 dinitro- 19 2-chloro-3,5-dinitro- 2-hydroxy-3,5- 80 B >99 >99 dinitro- 20 2-chloro-5-methyl- 2-hydroxy-5- 100 A >99 >99 methyl- 21 2-bromo-5- 2-hydroxy-5- 100 A >99 >99 methoxy- methoxy- 22 2-bromo-5- 2-hydroxy-5- 80 B >99 >99 methoxy- methoxy- 23 2-chloro-5-bromo- 2-hydroxy-5- 80 B 73 >99 bromo-

Reference： [1]Synthetic Communications,2002,vol. 32,p. 2055 - 2059
[2]Patent: US7335791,2008,B1 .Location in patent: Page/Page column 20-21

11
[ 6342-60-5 ]
[ 62-53-3 ]
[ 95216-56-1 ]

Reference： [1]Molecular Pharmacology,2005,vol. 67,p. 60 - 68

12
[ 6342-60-5 ]
[ 66658-57-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chlorobenzene; at 20℃; for 23h;Inert atmosphere; Reflux;	Example 142 2-Chloro-N-(1 -hydroxy-cyclohexylmethyl)-5-(2-oxo-2H-pyridin-1 - ylmethyl)-benzamide142.1 5-Bromomethyl-2-chloro-benzoic acidA suspension of <strong>[6342-60-5]2-chloro-5-methylbenzoic acid</strong> (10 g) in chlorobenzene (200 mL) was heated to 50C and N-bromosuccinimide (10.95 g) was added. The reaction mixture was flushed with argon and 2,2'-azobis(2-methylpropionitrile) (98 mg) was added. The reaction mixture was refluxed for 4h and 2,2'-azobis(2-methylpropionitrile) (98 mg) was added. The reaction mixture was refluxed for 1 h and stirred for 18h at RT. The solvent was evaporated off and the residue taken up in Et20 and filtered. The filtrate was washed with a 2M solution of hydrochloric acid and brine, dried over MgS04 and concentrated in vacuo. The crude was recrystallised from Et20/Hept to give 8 g of the titled compound as a beige solid.1H NMR ((CD3)2SO) delta: 13.51 (bs, 1 H), 7.88 (d, J = 2.2 Hz, 1 H), 7.61 (dd, Ji = 8.3 Hz, J2 = 2.2 Hz, 1 H), 7.55 (d, J = 8.3 Hz ,1 H), 4.76 (s, 2 H)
	With N-Bromosuccinimide; azobisisobutyronitrile; In chlorobenzene; at 50℃; for 5h;Inert atmosphere; Reflux;	142.1 5-Bromomethyl-2-chloro-benzoic acid A suspension of <strong>[6342-60-5]2-chloro-5-methylbenzoic acid</strong> (10 g) in chlorobenzene (200 mL) was heated to 50 C. and N-bromosuccinimide (10.95 g) was added. The reaction mixture was flushed with argon and 2,2'-azobis(2-methylpropionitrile) (98 mg) was added. The reaction mixture was refluxed for 4 h and 2,2'-azobis(2-methylpropionitrile) (98 mg) was added. The reaction mixture was refluxed for 1 h and stirred for 18 h at RT. The solvent was evaporated off and the residue taken up in Et2O and filtered. The filtrate was washed with a 2M solution of hydrochloric acid and brine, dried over MgSO4 and concentrated in vacuo. The crude was recrystallised from Et2O/Hept to give 8 g of the titled compound as a beige solid. 1H NMR ((CD3)2SO) delta: 13.51 (bs, 1H), 7.88 (d, J=2.2 Hz, 1H), 7.61 (dd, J1=8.3 Hz, J2=2.2 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 4.76 (s, 2H)
	With hydrogenchloride; N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In diethyl ether; chloroform;	a) 5-Bromomethyl-2-chloro-benzoic acid To a stirred solution of <strong>[6342-60-5]2-chloro-5-methyl-benzoic acid</strong> (25 g) in chloroform (500 ml) at 50 C. was added N-bromosuccinimide (27.40 g). The flask was purged with nitrogen and azobisisobutyronitrile (0.10 g) added in one portion. The solution was heated at reflux for 1 h. Further azobisisobutyronitrile (0.10 g) was added and the mixture heated a further 3 h. The solution was concentrated in vacuo, redissolved in diethyl ether and filtered to remove insoluble succinimide. The ether solution was washed with 2N aqueos hydrochloric acid solution followed by brine then dried over magnesium sulphate. The solution was concentrated to a volume of 150 ml then diluted with isohexane. After further partial concentration crystallization started. The mixture was allowed to stand in an ice-bath for 1 h. The resulting crystals were filtered, washed with isohexane and dried in vacuo to give the subtitle compound (17 g).

With hydrogenchloride; N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In diethyl ether; chloroform;

a 5-Bromomethyl-2-chloro-benzoic acid To a stirred solution of <strong>[6342-60-5]2-chloro-5-methyl-benzoic acid</strong> (25 g) in chloroform (500 ml) at 50 C. was added N-bromosuccinimide (27.40 g). The flask was purged with nitrogen and azobisisobutyronitrile (0.10 g) added in one portion. The solution was heated at reflux for 1 h. Further azobisisobutyronitrile (0.10 g) was added and the mixture heated a further 3 h. The solution was concentrated in vacuo, redissolved in diethyl ether and filtered to remove insoluble succinimide. The ether solution was washed with 2N aqueos hydrochloric acid solution followed by brine then dried over magnesium sulphate. The solution was concentrated to a volume of 150 ml then diluted with isohexane. After further partial concentration crystallization started. The mixture was allowed to stand in an ice-bath for 1 h. The resulting crystals were filtered, washed with isohexane and dried in vacuo to give the subtitled compound (17 g).

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 5882 - 5885
[2]Patent: WO2012/114268,2012,A1 .Location in patent: Page/Page column 124-125
[3]Patent: US2014/73651,2014,A1 .Location in patent: Paragraph 0918; 0919
[4]Patent: US6492355,2002,B1
[5]Patent: US2003/13704,2003,A1

13
[ 106-43-4 ]
[ 6342-60-5 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1892,vol. <2> 46,p. 26

14
[ 6342-60-5 ]
[ 16220-99-8 ]

Reference： [1]Journal of Medicinal Chemistry,1967,vol. 10,p. 478 - 481
[2]Organic and Biomolecular Chemistry,2018,vol. 16,p. 3189 - 3202
[3]Chinese Chemical Letters,2019,p. 255 - 258

15
[ 6342-60-5 ]
[ 13406-46-7 ]

Reference： [1]Journal of Medicinal Chemistry,1967,vol. 10,p. 478 - 481

16
[ 6342-60-5 ]
[ 16277-18-2 ]

Reference： [1]Journal of Medicinal Chemistry,1967,vol. 10,p. 478 - 481

17
[ 79-37-8 ]
[ 6342-60-5 ]
[ 16220-95-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	In methanol; dichloromethane; N,N-dimethyl-formamide;	Example 83 6-(2-CHLORO-5-METHYL-PHENYL)-N-(4-CHLORO-PHENYL)-[1,3,5]TRIAZINE-2,4-DIAMINE To a suspension of <strong>[6342-60-5]2-chloro-5-methyl-benzoic acid</strong> (3.0 g, 17.6 mmol) in dichloromethane (50 ml) was added a solution of oxalyl chloride in dichloromethane (2 M, 10 ml, 20 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 1 hour, methanol (20 ml) was added. After stirring for 3 hours, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (200 ml) and saturated aqueous potassium carbonate solution (100 ml). The organic layer was concentrated under reduced pressure to provide methyl 2-chloro-5-methyl-benzoate (3.2 g, 100% yield).

Reference： [1]Patent: US2003/153570,2003,A1

18
[ 6342-60-5 ]
[ 164341-37-1 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 19 2-Chloro-5-methylbenzoylguanidine hydrochloride: colorless crystals, m.p. 134 C. from <strong>[6342-60-5]2-chloro-5-methylbenzoic acid</strong> in accordance with variant A.

Reference： [1]Patent: US5965744,1999,A

19
[ 6342-60-5 ]
[ 3272-96-6 ]
[ 660417-31-2 ]

Yield	Reaction Conditions	Operation in experiment
		<strong>[6342-60-5]2-Chloro-5-methyl-benzoic acid</strong> [(LG,] 5.8 mmol) was treated with 5 ml thionyl chloride at reflux for two h. Excess thionyl chloride was removed under reduced pressure. The residue was added to a suspension of 2-chloro-N-hydroxy-acetamidine (638 mg, 5.8 mmol) in dichloromethane (10 ml) at room temperature. After stirring for 30 min, triethylamine (2.04 ml, 14.6 mmol) was added and stirred for an additional h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Flash column chromatography using 10-20% ethyl acetate in hexanes afforded 460 mg of the acyclic ester intermediate. DMF was added to this intermediate and then heated at [135C] for 4 h to effect cyclization to oxadiazole. After cooling the reaction mixture was washed with water (3 times) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography on silica gel using 5% ethyl acetate in hexanes afforded the title compound 160 mg (12 % over 2 steps) as a white solid. m/z 244 (GCMS).

Reference： [1]Patent: WO2004/14881,2004,A2 .Location in patent: Page 151-152

20
[ 64-17-5 ]
[ 6342-60-5 ]
[ 945262-03-3 ]

Yield	Reaction Conditions	Operation in experiment
96%		Intermediate 10; Ethyl 2-chloro-5-methylbenzoateTo a solution of <strong>[6342-60-5]2-chloro-5-methylbenzoic acid</strong> (7.62 mmol, 1.30 g) in ethanol (16 ml), H2SO4 (35 mmol, 1.82 ml) was added and the mixture was refluxed for 20 hours. The solvent was evaporated and the crude residue was dissolved in water. The solution neutralised with 6N NaOH aqueous solution and extracted with CHCI3. The organic phase was evaporated affording 1.46 g (yield 96%) of the expected product.1H NMR (300 MHz, CDCI3) delta ppm: 1.41 (t, 3H), 2.35 (s, 3H)1 4.40 (q, 2H), 7.21 (d, 1 H), 7.32 (d, 1 H), 7.61 (s, 1 H). ESI/MS (m/e, %): 199 [(M+1)+, 100].

Reference： [1]Patent: WO2009/21696,2009,A1 .Location in patent: Page/Page column 47

21
[ 67-56-1 ]
[ 6342-60-5 ]
[ 16220-95-4 ]

Yield	Reaction Conditions	Operation in experiment
	sulfuric acid; for 5h;Reflux;	A mixture of <strong>[6342-60-5]2-chloro-5-methylbenzoic acid</strong> (4.0 g, 23.4 mmol) in methanol (50 niL) and a few drops of concentrated sulfuric acid were stirred at reflux for 5 hours. After cooling to room temperature, methanol was evaporated. The residue was dissolved in ethyl acetate (50 mL). The solution was extracted with saturated NaHCO3 (3 x 50 mL). The organic layer was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording methyl 2-chloro-5-methylbenzoate (3.07g, 71% yield). The product was used without further purification.
	With sulfuric acid; for 20h;Reflux;	A solution of 2- chloro-5-methylbenzoic acid (5g, 29.3 immol, 1 equiv.) in MeOH (60 mL) was added with concentrated H2S04 (1 mL), the mixture was refluxed for 20 h. Then cooled toroom temperature and concentrated to remove most of MeOH, the residue was diluted with water and extracted with CH2C12, dried over Na2SO4, concentrated and purified via FCC (Hexanes: EtOAc, 10:1) to give product methyl 2-chloro-5-methylbenzoate as grey solid. A solution of above obtained methyl 2-chloro-5-methylbenzoate in CC14 (60 mL) was added with NBS (13g, 2.5 equiv.) and benzoyl peroxide (5 mol%,0.4g), the mixture was stirred at reflux condition for 48 h, then cooled to room temperature and filtered, the filtrated was collected and concentrated. The cmde product was diluted with Et20 and filtered again, the filtrate was collect and concentrated, which was used for next step without purification.

Reference： [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 3189 - 3202
[2]Organic Letters,2013,vol. 15,p. 3698 - 3701
[3]Patent: WO2010/132999,2010,A1 .Location in patent: Page/Page column 115
[4]Chinese Chemical Letters,2019,p. 255 - 258
[5]Patent: WO2019/18718,2019,A1 .Location in patent: Page/Page column 44

22
[ 6342-60-5 ]
[ 89981-57-7 ]

Yield	Reaction Conditions	Operation in experiment
95%		The required (2-chloro-5- methylphenyl) methanol was prepared as follows: To a solution of 2-chloro-5- methylbenzoic acid (2.05 g; 12.2 mmol) in THF (20 mL) was added borane-THF complex (1M, 24.03 mL; 24.3 mmol) dropwise and subsequently stirred for 2 hours at 60C. To the reaction mixture was added 1 M HC1 (30 mL), at 0C, and the resulting mixture was stirred at RT for 10 minutes. The resulting mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 5% aqueous NaHC03-solution. The organic layer was dried(Na2S04), filtered, and concentrated in vacuo to afford the product (1.8 g, 95%), which was used as such in the next step.
390 mg	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 0.333333h;	(1) Synthesis of 2-chloro-5-methylbenzyl alcohol [31-1] (hereinafter referred to as a compound [31-1]) To a solution of <strong>[6342-60-5]2-chloro-5-methylbenzoic acid</strong> (1.0 g) in tetrahydrofuran (59 mL) was added lithium aluminum hydride (445 mg) at 0C, and the mixture was stirred at 0C for 20 minutes. The reaction mixture was quenched with saturated aqueous solution of sodium sulfate, and the mixture was stirred at room temperature for 2 hours. The obtained white gel was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (390 mg) as a yellow solid. 1H-NMR (400 MHz, CDCl3) delta: 7.29 (1H, s), 7.24 (1H, d, J = 8.4 Hz), 7.05 (1H, d, J = 7.6 Hz), 4.75 (2H, d, J = 6.3 Hz), 2.34 (3H, s), 1.91 (1H, t, J = 6.3 Hz).

Reference： [1]Patent: WO2012/4378,2012,A1 .Location in patent: Page/Page column 60
[2]Patent: EP2878594,2015,A1 .Location in patent: Paragraph 0499-0501
[3]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1278 - 1283

23
[ 6342-60-5 ]
[ 100-63-0 ]
[ 1358761-64-4 ]

Reference： [1]Organic and Biomolecular Chemistry,2012,vol. 10,p. 1381 - 1387

24
[ 6342-60-5 ]
[ 100-63-0 ]
[ 1358761-76-8 ]

Reference： [1]Organic and Biomolecular Chemistry,2012,vol. 10,p. 1381 - 1387

25
[ 6342-60-5 ]
[ 933735-22-9 ]
[ 1601469-56-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	Example 1a 2-Chloro-5-methyl-N-(2-morpholin-4-yl-2-pyridin-2-yl-ethyl)-benzamide A mixture of (2-morpholin-4-yl-2-pyridin-2-ylethyl)amine (62.2 mg, 0.3 mmol), <strong>[6342-60-5]2-chloro-5-methylbenzoic acid</strong> (54 mg, 0.315 mmol), PyBOP (187 mg, 0.36 mmol) and DIPEA (78 mg, 0.60 mmol) in DCM (1.5 mL) was stirred at room temperature overnight. The mixture was purified by preparative HPLC to yield the title compound (100 mg, yield: 90

Reference： [1]Patent: US2014/107335,2014,A1 .Location in patent: Paragraph 0188; 0189; 0190

26
[ 6342-60-5 ]
[ 927993-56-4 ]
[ 1600494-36-7 ]

Yield	Reaction Conditions	Operation in experiment
31%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;	A mixture of [4-(4-Chloro-phenyl)-tetrahydro-pyran-4-yl]methylamine (67.7 mg, 0.3 mmol), 2-choloro-5-methylbenzoic acid (54 mg, 0.315 mmol), PyBOP (187 mg, 0.36 mmol) and DIPEA (78 mg, 0.60 mmol) in DCM (1.5 mL) was stirred at room temperature for 16 h. The mixture was purified by preparative HPLC to yield the title compound (35.5 mg, yield: 31%). LCMS (MH+): m/z=378.0, tR (minutes, Method A)=1.38

Reference： [1]Patent: US2014/107340,2014,A1 .Location in patent: Paragraph 0409

27
[ 6342-60-5 ]
4-(2-amino-3-methylbutanoyl)benzonitrile hydrochloride [ No CAS ]
2-chloro-N-(1-(4-cyanophenyl)-3-methyl-1-oxobutan-2-yl)-5-methylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		2-Chloro-5-methylbenzoic acid (CAS 6342-60-5, 30.0 mg, 0.18 mmol) was dissolved in DMF(200 jiL). HBTU (83 mg, 0.22 mmol) and TEA (61.1 iL, 0.44 mmol) were added and thesolution was stirred for 6 mm. 4-(2-ammno-3-methylbutanoyl)benzonitrile hydrochloride(Example 49b, 35 mg, 0.15 mmol) in DMF (400 iL) and TEA (61.1 iL, 0.44 mmol) was added.The reaction mixture was stirred for 1 h and then purified by preparative HPLC to give 2-chloro-N-(1-(4-cyanophenyl)-3-methyl-1-oxobutan-2-yl)-5-methylbenzamide (35 mg, 67%).?H NMR (500 MHz, CDCI3) 6 ppm 0.89 (d, 3 H) 1.14 (d, 3 H) 2.22 - 2.33 (m, 1 H) 2.36 (s, 3 H) 5.77 (dd, 1 H) 6.99 (d, 1 H) 7.21 (dd, 1 H) 7.32 (d, 1 H) 7.49 (dd, 1 H) 7.84 (d, 2 H) 8.15 (d, 2 H).MS (ESI) m/z 354.8 [M+H]

Reference： [1]Patent: WO2014/184235,2014,A1 .Location in patent: Page/Page column 83; 84

28
[ 6342-60-5 ]
[ 637-44-5 ]
C₁₆H₁₃NO [ No CAS ]

Reference： [1]Bulletin of the Korean Chemical Society,2015,vol. 36,p. 1745 - 1746

29
[ 6342-60-5 ]
2-chloro-5-methyl-N-(2-(4-methylpiperazin-1-yl)-5-nitrophenyl)benzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 2478 - 2496

30
[ 6342-60-5 ]
C₁₄H₁₀ClFN₂O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 2478 - 2496

31
[ 6342-60-5 ]
C₃₇H₂₈FN₅O₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 6807 - 6825

32
[ 6342-60-5 ]
C₄₂H₄₀FN₅O₄Si [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 6807 - 6825

33
[ 6342-60-5 ]
2,6-dimethyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 6807 - 6825
[2]Patent: EP3339294,2018,A1

34
[ 6342-60-5 ]
2,6-dimethyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-3-carboxylicacid methyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 6807 - 6825
[2]Patent: EP3339294,2018,A1

35
[ 6342-60-5 ]
N-(3-fluoro-4-((5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-2,6-dimethyl-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 6807 - 6825

36
[ 6342-60-5 ]
[ 189999-35-7 ]
[ 1705-84-6 ]

Reference： [1]Organic Letters,2018,vol. 20,p. 1491 - 1495

37
[ 6342-60-5 ]
3,7-difluorodibenzo[b,d]iodol-5-ium trifluoromethanesulfonate [ No CAS ]
6,11-difluoro-2-methyltriphenylene [ No CAS ]

Reference： [1]Organic Letters,2018,vol. 20,p. 1491 - 1495

38
[ 6342-60-5 ]
2-chloro-N-(1-(cyclopropylmethyl)pyrrolidin-3-yl)-5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)benzamide [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 3189 - 3202

39
[ 6342-60-5 ]
3-(2-chloro-5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)benzoylamino)pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 3189 - 3202

40
[ 6342-60-5 ]
2-chloro-5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-N-(pyrrolidin-3-yl)benzamide [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 3189 - 3202

41
[ 6342-60-5 ]
2-chloro-5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)benzoic acid methyl ester [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 3189 - 3202

42
[ 6342-60-5 ]
2-chloro-N-(1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)benzamide [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 3189 - 3202

43
[ 6342-60-5 ]
N-(1-benzylpyrrolidin-3-yl)-2-chloro-5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)benzamide [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 3189 - 3202

44
[ 6342-60-5 ]
[ 1401683-82-6 ]

Reference： [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 3189 - 3202

45
[ 6342-60-5 ]
ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate [ No CAS ]
N-(2-chloro-5-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide [ No CAS ]

Reference： [1]Patent: US2018/186818,2018,A1

46
[ 6342-60-5 ]
ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate [ No CAS ]
ethyl 5-[(2-chloro-5-methylphenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a suspension of 270 mg (1.58 mmol) of<strong>[6342-60-5]2-chloro-5-methylbenzoic acid</strong> in 4 ml of dehydrated toluene, 0.368 ml (2.11 mmol) of DIPEA and 0.341 ml (1.58 mmol) of DPPA were added at room temperature in an argon atmosphere and reacted at room temperature for 0.5 hours and subsequently at 1000 C. for 1 hour with stirring. The reaction solution was cooled, and then, a solution of 400 mg (1.06 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cy- clobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole- 2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 4 ml of dehydrated dichioromethane was added dropwise thereto at 0 C. and reacted at room temperature for 3 hours with stirring.j0915] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction three times with ethyl acetate. The whole organic layer thus obtained was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent:n-hexane:ethyl acetate=91 :9-70:30 (V/V)), and a fraction containing ethyl 5-[(2-chloro-5-methylphenyl)carbamoyl] - 6,6-dimethyl-3-[1 -(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxy- late was concentrated under reduced pressure.

Reference： [1]Patent: US2018/186818,2018,A1 .Location in patent: Paragraph 0914; 0915

47
[ 6342-60-5 ]
[ 1119085-69-6 ]

Reference： [1]Patent: WO2009/21696,2009,A1

48
[ 6342-60-5 ]
[ 1119090-69-5 ]

Reference： [1]Patent: WO2009/21696,2009,A1

49
[ 6342-60-5 ]
[ 301672-76-4 ]

Reference： [1]Patent: US6492355,2002,B1

50
[ 6342-60-5 ]
[ 301672-94-6 ]

Reference： [1]Patent: US6492355,2002,B1

51
[ 6342-60-5 ]
2-chloro-5-(4-[{1,1-dimethylethyl}oxycarbonyl]piperazin-1-yl)methyl-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide [ No CAS ]

Reference： [1]Patent: US6492355,2002,B1

52
[ 6342-60-5 ]
[ 301672-78-6 ]

Reference： [1]Patent: US6492355,2002,B1

53
[ 6342-60-5 ]
[ 301672-56-0 ]

Reference： [1]Patent: US6492355,2002,B1

54
[ 6342-60-5 ]
[[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]-methyl]phosphonic acid, dimethyl ester [ No CAS ]

Reference： [1]Patent: US6492355,2002,B1

55
[ 6342-60-5 ]
2-chloro-5-[(4-oxo-1-piperidinyl)methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide [ No CAS ]

Reference： [1]Patent: US6492355,2002,B1

56
[ 6342-60-5 ]
[ 301672-79-7 ]

Reference： [1]Patent: US6492355,2002,B1

57
[ 6342-60-5 ]
[ 345304-74-7 ]

Reference： [1]Patent: US2003/13704,2003,A1

58
[ 6342-60-5 ]
[ 345304-75-8 ]

Reference： [1]Patent: US2003/13704,2003,A1

59
[ 6342-60-5 ]
3-chloromethyl-5-(2-chloro-5-methyl-phenyl)-[1,2,4]oxadiazole [ No CAS ]

Reference： [1]Patent: WO2004/14370,2004,A2

60
[ 6342-60-5 ]
4-[5-(2-chloro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-piperazine-1-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Patent: WO2004/14370,2004,A2

61
[ 6342-60-5 ]
[ 660417-31-2 ]

Reference： [1]Patent: WO2004/14370,2004,A2

62
[ 36052-24-1 ]
[ 6342-60-5 ]
6-(2-chloro-5-methylbenzamido)pyridine-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.03 g		To a solution of <strong>[6342-60-5]2-chloro-5-methylbenzoic acid</strong> (0.83 g) in DCM (3 mL) were added (COC1)2 (0.51 mL) and DMF (19 1iL) under nitrogen atmosphere, and the mixture was stilTed at room temperature for 1 hour. The mixture was concentrated and the resulted residue was added dropwise to a solution of methyl 6-aminonicotinate (0.74 g) in Pyr (4.0 mL) under ice cooling, and the mixture was stirred at room temperature for 1 day. Water was added to the reaction solution, and the precipitate was filtered and washed with water. To the resulted solid were added MeOH (12 mL) and 5N aqueous NaOH solution (4.9 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction soluion was neutralized by addition of SN HC1 (4.9 mL) and water under ice cooling, and the precipitate was filtered and washed with water to give 6-(2-chloro-S-methylbenzamido)pyridine-3-carboxylic acid (1.03 g).

Reference： [1]Patent: WO2019/4421,2019,A1 .Location in patent: Paragraph 0081; 0108

63
[ 6342-60-5 ]
[ 2486-69-3 ]
3-methoxy-4-(2-chloro-5-methylbenzamido)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.4 g		To a solution of <strong>[6342-60-5]2-chloro-5-methylbenzoic acid</strong> (0.83 g) in DMA (6.0 mL) was added dropwise SOC12 (0.36 mL) at room temperature under nitrogen atmosphere, and the mixture was stirred for 2 hours. To the reaction solution was added 4-amino-3-methoxybenzoic acid (1.0 g), and the mixture was stirred at room temperature for 1 day. Water was added thereto, and the precipitate was filtered and washed with water to give 3-methoxy-4-(2-chloro-5-methylbenzamido)benzoic acid (1.4g).

Reference： [1]Patent: WO2019/4421,2019,A1 .Location in patent: Paragraph 0081; 0107

64
[ 6342-60-5 ]
(E)-N-(1-(4-chloro-3-(hydrazinecarbonyl)benzyl)imidazolidin-2-ylidene)nitramide [ No CAS ]

Reference： [1]Chinese Chemical Letters,2019,p. 255 - 258

65
[ 6342-60-5 ]
N-(4-chloro-3-(hydrazinecarbonyl)benzyl)-N'-cyano-N-methylacetimidamide [ No CAS ]

Reference： [1]Chinese Chemical Letters,2019,p. 255 - 258

66
[ 6342-60-5 ]
(E)-2-chloro-N-methyl-5-((2-(nitroimino)imidazolidin-1-yl)methyl)benzamide [ No CAS ]

Reference： [1]Chinese Chemical Letters,2019,p. 255 - 258

67
[ 6342-60-5 ]
2-chloro-5-((N'-cyano-N-methylacetimidamido)methyl)-N-methylbenzamide [ No CAS ]

Reference： [1]Chinese Chemical Letters,2019,p. 255 - 258

68
[ 6342-60-5 ]
methyl (E)-2-chloro-5-((2-(nitroimino)imidazolidin-1-yl)methyl)benzoate [ No CAS ]

Reference： [1]Chinese Chemical Letters,2019,p. 255 - 258

69
[ 6342-60-5 ]
methyl (E)-2-chloro-5-((N'-cyano-N-methylacetimidamido)methyl)benzoate [ No CAS ]

Reference： [1]Chinese Chemical Letters,2019,p. 255 - 258

70
[ 6342-60-5 ]
methyl 2-chloro-5-(5-((4-methoxybenzo[d]thiazol-2-yl)amino)-1,3,4-oxadiazol-2-yl)benzoate [ No CAS ]