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Quality Control of [ 35598-05-1 ] Purity: 97% SDS Specification

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Product Details of [ 35598-05-1 ]

CAS No. :	35598-05-1
Formula :	C₁₀H₁₂O₃
M.W :	180.20
SMILES Code :	O=C(OC)C1=CC=C(OC)C=C1C
MDL No. :	MFCD06203918
InChI Key :	OGYAVWKYDVBIMW-UHFFFAOYSA-N
Pubchem ID :	13257269

Safety of [ 35598-05-1 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 35598-05-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.3
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	49.18
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	35.53 ?2

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.44
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	2.11
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.79
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.	1.94
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	2.19
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.09

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.43
Solubility	0.669 mg/ml ; 0.00371 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.	-2.49
Solubility	0.587 mg/ml ; 0.00326 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	-2.99
Solubility	0.186 mg/ml ; 0.00103 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.	-5.9 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	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

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)	1.42

Application In Synthesis of [ 35598-05-1 ]

* 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 [ 35598-05-1 ]

[ 35598-05-1 ] Synthesis Path-Downstream 1~33

1
[ 35598-05-1 ]
[ 6245-57-4 ]

References: [1]Chemische Berichte,1879,vol. 12,p. 818,821.

2
[ 578-39-2 ]
[ 77-78-1 ]
[ 35598-05-1 ]

References: [1]Bulletin de la Societe Scientifique de Bretagne,1956,vol. 31,p. Sonderheft S.9,41.

3
[ 67-56-1 ]
[ 6245-57-4 ]
[ 35598-05-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride; at 20℃;Reflux;	To a stirred mixture of 4-methoxy-2-methyl benzoic acid (1.0 g, 6 mmol) and methanol (50 mL) was added thionyl chloride (1.3 mL, 17.8 mmol), dropwise, at room temperature under a nitrogen atmosphere. The reaction mixture was heated at reflux for 3 h. The reaction mixture was allowed to cool at room temperature and concentrated to give a pale yellow liquid. The crude product was purified by flash chromatography over silica with hexanes:ethyl acetate (9:1) to give 1.11 g (100%) of methyl 2-methyl-4-(methyloxy)benzoate as a colorless liquid. 1H NMR (400 MHz, DMSO-J6): delta 7.81 (d, J = 9 Hz, IH), 6.86 (d, J = 3 Hz, IH), 6.83 (dd, J = 9, 3 Hz, IH), 3.78 (s, 3H), 3.75 (s, 3H), 2.49 (s, 3H). ES-LCMS m/z 181(M + H)+.
98%	sulfuric acid; In water; for 48h;Heating / reflux;	According to J. Org. Chem. 33: 494 (1968), a mixture of 4-methoxy-2-methylbenzoic acid (20 g, 120 mmol) and [MEOH] (97 mL) containing sulfuric acid [(CONC.,] 0.6 mL) was heated under reflux 48 h. After cooling the mixture was evaporated and the residue diluted with diethyl ether and washed with a saturated sodium hydrogen carbonate solution and brine. The organic phase was then separated and dried over sodium sulphate. After evaporation the residue was distilled through a 8 cm Vigreux column to afford the title compound (21.2 g, 98%) as a colourless liquid. Bp 60 [C/1] mbar. MS: m/e = 180.3 (M+).
94%	With sulfuric acid; In water; at 65℃; for 18h;	4-Methoxy-2-methyl-benzoic acid methyl esterA solution of 4-Methoxy-2-methyl-benzoic acid (15 g, 90 mmol) in methanol {200 mL) was heated to 65 0C. Sulfuric acid (8.9 g, 90 mmol) was added and the mixture was stirred for 18 h at 65 C. The reaction was cooled and concentrated and the residual oil was dissolved in ethyl acetate and washed with water, brine, and absorbed onto silica to perform chromatography (10 % ethyl acetate/hexanes) to yield 4-Methoxy-2-methyl-benzoic acid methyl ester as an oil, (15.3 g, 94 %). MS: ES M+1: 181.0 (180.1).

84%	With sulfuric acid; for 24h;Reflux;	Benzoic acid (1 equiv) was dissolved in MeOH (1.66 mL per mmol) and H2SO4 (0.07 mL per mmol). The solution was refluxed for 7-24 h before being cooled to rt and concentrated in vacuo. The resulting mixture was dissolved in EtOAc. The organics were washed with an aqueous solution of NaOH (10 %), combined, dried over MgSO4 and concentrated in vacuo to afford the desired ester.
81%	With thionyl chloride; for 3h;Heating / reflux;	Preparation 67 4-Methoxy-2-methyl-benzoic acid methyl esterTo an ambient temperature suspension of 4-Methoxy-2-methyl-benzoic acid (1.0 g, 6.02 mmol) in MeOH (10 mL) is added thionyl chloride (1.10 mL, 15.04 mmol) dropwise. The reaction mixture is heated to reflux. After 3h, the reaction is concentrated and the residue is partitioned between EtOAc and NaHCO3. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried (MgSO4), filtered, and concentrated to yield the title compound (877 mg, 81%) 1H NMR (400 MHz, CDCl3) delta 7.95-7.91 (m, IH), 6.77-6.72 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H).

References: [1]Patent: WO2009/5998,2009,A1 .Location in patent: Page/Page column 214.
[2]Patent: WO2004/14856,2004,A1 .Location in patent: Page 9; 14.
[3]Patent: WO2008/20306,2008,A2 .Location in patent: Page/Page column 35.
[4]Journal of Medicinal Chemistry,2013,vol. 56,p. 8561 - 8578.
[5]Tetrahedron,2018,vol. 74,p. 224 - 239.
[6]Patent: WO2007/140183,2007,A1 .Location in patent: Page/Page column 50.
[7]Journal of Medicinal Chemistry,1987,vol. 30,p. 1798 - 1806.
[8]Journal of Organic Chemistry,1968,vol. 33,p. 494 - 503.
[9]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1628 - 1631.
[10]Inorganic Chemistry,2014,vol. 53,p. 2932 - 2942.

4
[ 108-31-6 ]
[ 91416-36-3 ]
[ 22246-27-1 ]
[ 35598-05-1 ]
7-Methoxy-9,9a-dihydro-3aH-naphtho[2,3-c]furan-1,3,4-trione [ No CAS ]

References: [1]Tetrahedron Letters,1984,vol. 25,p. 2201 - 2204.

5
[ 67-56-1 ]
[ 52289-54-0 ]
[ 35598-05-1 ]

References: [1]Synthesis,1984,p. 504 - 506.

6
[ 67-56-1 ]
[ 91416-36-3 ]
[ 22246-27-1 ]
[ 35598-05-1 ]
7-Methoxy-9,9a-dihydro-3aH-naphtho[2,3-c]furan-1,3,4-trione [ No CAS ]

References: [1]Tetrahedron Letters,1984,vol. 25,p. 2201 - 2204.

7
[ 67-56-1 ]
[ 91416-36-3 ]
[ 35598-05-1 ]

References: [1]Tetrahedron Letters,1984,vol. 25,p. 2201 - 2204.

8
[ 67-56-1 ]
[ 103562-90-9 ]
[ 35598-05-1 ]

References: [1]Journal of Organic Chemistry,1986,vol. 51,p. 3566 - 3572.

9
[ 672-89-9 ]
[ 922-67-8 ]
[ 35598-05-1 ]
[ 108593-44-8 ]

References: [1]Chemische Berichte,1987,vol. 120,p. 1339 - 1346.

10
[ 35598-05-1 ]
[ 52289-55-1 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[35598-05-1]methyl 4-methoxy-2-methylbenzoate</strong> (11.4 g, 63.3 mmol) in THF (65 mL) at 0 C, LiAlH4 (1M in ether, 76.0 mL, 75.9 mmol) was added via addition funnel over 50 min. The ice water bath was removed, and the reaction was allowed to stir at room temperature for 30 min. Upon completion, the reaction was cooled to 0 C and sodium sulfate decahydrate was added portionwise until the bubbling ceased. The reaction was then diluted with ether and filtered. The filtrate was concentrated under reduced pressure to give (4-methoxy-2- methylphenyl)methanol (8.2 g) as a clear oil. ? NMR (300MHz, CDC13): delta 7.23 (d, 1H), 6.72 (m, 2H), 4.63 (d, 2H), 3.79 (s, 3H), 2.36 (s, 3H), 1.42 (t, 1H).

References: [1]Tetrahedron,1989,vol. 45,p. 5791 - 5804.
[2]Tetrahedron Letters,1989,vol. 30,p. 111 - 112.
[3]Patent: WO2011/156518,2011,A2 .Location in patent: Page/Page column 115; 116.

11
[ 35598-05-1 ]
[ 15365-25-0 ]

Yield	Reaction Conditions	Operation in experiment
~ 100%	With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane; for 2h;Reflux;	To a solution of <strong>[35598-05-1]methyl 4-methoxy-2-methylbenzoate</strong> (1 g, 5.6 mmol) in CC14 (25 mL) was added dropwise N-bromosuccinimide (1.1 g, 6.2 mmol) previously dissolved in CCI4 (5 mL) and a catalytic amount of benzoylperoxide. The mixture was refluxed for 2 hours, cooled to room temperature and poured onto ice water. The aqueous mixture was extracted with DCM (3x), and the combined organics were dried over MgS04, filtered, and concentrated in vacuo to provide 2.1 g of the titled product as light yellow solid (~ 100% yield): [M+H+] m/z 260.
~ 100%	With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane; for 2h;Reflux;	[00121] Step 1 : Methyl 2-(bromomethyl)-4-methoxybenzoate[00122] To a solution of <strong>[35598-05-1]methyl 4-methoxy-2-methylbenzoate</strong> (1 g, 5.6 mmol) inCC14 (25 mL) was added dropwise N-bromosuccinimide (1.1 g, 6.2 mmol) previously dissolved in CC14 (5 mL) and a catalytic amount of benzoyl peroxide. The mixture was refluxed for 2 hours, cooled to room temperature and poured onto iced water. The aqueous mixture was extracted with DCM (3x), and the combined organics were dried over MgS04, filtered, and concentrated in vacuo to provide 2.1 g of the titled product as light yellow solid (~ 100% yield): [M+H+] m/z 260.
94%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 6h;Reflux;	[0247] To a solution of <strong>[35598-05-1]methyl 4-methoxy-2-methylbenzoate</strong> (10 g, 55.56 mmol) in carbon tetrachloride (150 mL) at RT was added NBS (10 g, 55.57 mmol) and 2,2?- azobis(2-methylpropionitrile) (4.0 mg, 9.43 mmol). The mixture was stirred at reflux 6 hrs. The solvent was evaporated to give the crude product which was purified by silica gel chromatography (EtOAc/petroleum ether, 1:20 to 1:5) to give methyl 2-(bromomethyl)-4- methoxybenzoate (13.6 g, 94% yield) as a white solid.

68%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 2.5h;Heating / reflux;	To a solution of <strong>[35598-05-1]4-methoxy-2-methyl-benzoic acid methyl ester</strong> (1.47 g, 8.16 mmol, 1.0 equiv; commercially available) in CCl4 (15 mL) was added N-bromosuccinimide (1.60 g, 8.97 mmol, 1.1 equiv) and dibenzoyl peroxide (0.198 g, 0.45 mmol, 0.05 equiv). The mixture was heated to reflux for 1.5 h, when TLC indicated that still some starling material was left. Therefore, additional N-bromosuccinimide (0.16 g, 0.90 mmol, 0.11 equiv) and dibenzoyl peroxide (0.080 g, 0.41 mmol, 0.18 equiv) was added and heating continued for 1 h. The reaction mixture was cooled down, poured on crashed ice, extracted with ethyl acetate, the combined organic phases washed with a sat. solution of NaCl, dried over Na2SO4 and concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with hexane/ethyl acetate (95:5) affording 1.43 g (68%) of the title compound as yellow crystals. 1H NMR (300 MHz, CDCl3): delta 3.87 (s, 3H), 3.91 (s, 3H), 4.97 (s, 2H), 6.86 (dd, J=8.7 Hz, J=2.7 Hz, 1H), 6.97 (d, J=2.7 Hz, 1H), 7.99 (d, J=8.7 Hz, 1H).
62%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 18h;Heating / reflux;	2-Bromomethyl-4-methoxy-benzoic acid methyl esterTo a solution of 4-Methoxy-2-methyl-benzoic acid methyl ester (6.92g, 38.4 mmol) in CCI4 (100 mL) was added N-bromosuccinimide (7.99 g, 1.17 mmol). Benzoyl peroxide (1.82 g, 7.54 mmol) was added to the slurry and the mixture was heated at reflux for 18 h. The reaction was cooled and the solid was filtered off. The filtrate was absorbed onto silica to perform chromatography (0-10 % ethyl acetate/hexanes) to yield 2-Bromomethyl-4-methoxy- benzoic acid methyl ester, (6.12 g, 62 %, CASNo. 15365-25-0). MS: ES M+1 : 258.9, M+2 260.9 (258.0, 260.0).
60%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 24h;Reflux;	Methyl 2-methyl-4-(methyloxy)benzoate (1.1 g, 6.1 mmol), N-bromosuccinimide (1.2 g, 6.74 mmol), benzoyl peroxide (0.073 g, 0.30 mmol), and carbon tetrachloride (40 mL) were combined and the stirred reaction mixture was heated at reflux for 24 h under a nitrogen atmosphere. The reaction mixture was allowed to cool at room temperature and filtered through a pad of Celite. The pad was washed with ethyl acetate. The filtrate was concentrated to give the crude product which was purified by flash chromatography over silica with a hexanes:dichloromethane gradient (100:0 to 50:50) to give 0.95 g (60%) of methyl 2-(bromomethyl)-4-(methyloxy)benzoate as an oil which solidified to a white solid. 1U NMR (400 MHz, CDCl3): delta 7.98 (d, J = 9 Hz, IH), 6.96 (d, J = 3 Hz, IH), 6.85 (dd, J = 9, 3 Hz, IH), 4.96 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H).
58%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 4.5h;UV-irradiation; Heating / reflux;	A mixture of <strong>[35598-05-1]4-methoxy-2-methyl-benzoic acid methyl ester</strong> (20 g, 111 mmol), N-bromo- succinimide (20.7 g, 117 mmol) and dibenzoylperoxide (0.54 g, 2 mmol) in [CC14] (150 mL) was irradiated with a 300 W lamp. The reaction maintains a steady reflux and after 4.5 h, the lamp was removed and the mixture cooled to [5 C.] The mixture was then filtered, the filtrate evaporated and the residue purified twice by chromatography [(SI02,] Heptane: Di- ethyl ether: 95: 5 to 85: 15) to afford the title product (16.6 g, 58%) as a white solid. MS m/e = 258.1 (M-H+).
	With N-Bromosuccinimide; dibenzoyl peroxide; In benzene; at 75℃; for 2h;	Compound 9C (prepared according to the procedure described by Wyrick, S. D. et al. Journal of Medicinal Chemistry, 1987, 30(10), 1798-806) (3.33 g, 18.5 mmol) was dissolved in dry benzene (40 ml). NBS (3.45 g, 19.4 mmol) and benzoyl peroxide (134 mg, 0.55 mmol) were added. The solution was stirred in a 75 C oil bath for about 2 hours. After cooling down, the solid was filtered and washed with Et2O (150 mL). The organic solution was then washed with water (50 ml) twice, dried over Na2SO4 or MgSC>4, filtered, and concentrated by rotary evaporator. The crude product was dried under vacuum to give compound 9D which was used without further purification. 1H-NMR appeared to indicate that approximately 75% of this material was compound 9D.
	With N-Bromosuccinimide; acetic acid; In tetrachloromethane; at 90℃; for 3h;	[0180] 4-Fluoro-2-methyl-benzoic acid methyl ester (600 mg, 3.6 mmol), N-bromosuccinimide (635 mg, 3.6 mmol) and benzoyl peroxide (43 mg, 1.79 mmol) in CCU (15 mL) was stirred at 90 C for 3 hours. The reaction was cooled to room temperature, filtered, washed with CCI4 and the solvent was removed under reduced pressure to provide a white solid. .H NMR (300 MHz, CDCI3): 5 8.01 (d, 1H), 6.99 (d, 1H), 6.88 (dd, 1H), 4.98 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H). [0181] The following compounds were made in a similar fashion:
	With N-Bromosuccinimide; dibenzoyl peroxide; In chloroform; at 65℃; for 5h;Inert atmosphere; Schlenk technique; Reflux;	General procedure: To a solution of 6.0 g (0.04 mol) of methyl 2-methylbenzoate derivatives in 38 mL of chloroform, 7.5 g (0.042 mol) of N-bromosuccinimide and 0.078 g of benzoyl peroxide were added and carefully warmed up to 65 C until reaction started. Then the mixture was refluxed for 5 h. After cooling down to room temperature, the deposit of succinimide was filtered. The solvent was removed under reduced pressure and the crude product was used in the next step without further purification. To a solution of functionalized methyl 2-(bromomethyl)benzoate (6.55 mmol), substituted phenol (8.5 mmol), K3PO4 (16.4 mmol) and toluene 20 mL were added to Schlenk under argon. The resulting solution was stirred to 110 C for 5 h. The progress of the reaction was monitored by TLC. The mixture was extracted with EtOAc, washed with water, brine and the combined organic layers were dried over anhydrous Na2SO4and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification. To the solution of the ester (0.015 mol) in MeOH (73 mL), was added 13 mL aqueous KOH (20%) and refluxed at 80C for 5 h. MeOH was removed and the aqueous phase was washed with DCM. After acidifying with HCl (10%) the deposit was collected and washed with water.
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; for 2.5h;Reflux;	To a solution of methyl o-methylbenzoate (1.00 equiv) in CHCl3 (2-5 mL per mmol of methyl o-methylbenzoate) or CCl4 (5 mL per mmol of methyl o-methylbenzoate) was added NBS(1.10-2.20 equiv) and AIBN (0.02-0.04 equiv). The reaction was refluxed for 2-22 h before being cooled to rt. The solvent was then removed in vacuo (CHCl3 solvent) or via distillation (CCl4 solvent) within a fumehood to afford the desired brominated compound. CAUTION: CHCl3 and especially CCl4 are extremely toxic and carcinogenic and thus must be handled cautiously with gloves and within a fumehood appropriately ventilated.
	With N-Bromosuccinimide; dibenzoyl peroxide; In 1,2-dichloro-ethane; at 80℃; for 12h;	General procedure: A mixture of methyl 5-fluoro-2-methylbenzoate (0.5 g, 3.0 mmol),NBS (0.18 g, 3.0 mmol), and di-benzoyl peroxide (BPO) (36 mg, 0.15 mmol) in 1,2-dichloroethane (5 mL) was heated at 80 C for 12 huntil all starting material was consumed. The reaction was cooled to room temperature, and the precipitated solid was removed by filtration and washed with ethers (10 mL). The filtrate was concentrated in vacuo and the residue was partitioned between 2 N NaHCO3 (15 mL) and ethers (15 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to give a crude product (0.65 g, 89%), which was used in the next step reaction without further purification.
	With N-Bromosuccinimide; dibenzoyl peroxide; In 1,2-dichloro-ethane; at 80℃; for 12h;	General procedure: A mixture of methyl 3-bromo-2-methylbenzoate (500 mg, 3.3 mmol), NBS (770.4 mg, 4.3 mmol), and di-benzoyl peroxide (BPO, 80.7 mg, 0.3 mmol) in 1,2-dichloroethane (10 mL) was heated at 80 C for 12 h. The reaction mixture was cooled to room temperature, and the precipitated solid was removed by filtration and washed with ethers (10 mL). The filtrate was concentrated in vacuo and the residue was partitioned between 2 N NaHCO3 (15 mL) and ethers (15 mL). The organic layer was separated, dried over NaSO4, filtered and concentrated to give a crude product (683.2 mg, 89.6%), which was used in the next step reaction without further purification.

References: [1]Patent: WO2011/85261,2011,A1 .Location in patent: Page/Page column 36.
[2]Patent: WO2011/85128,2011,A1 .Location in patent: Page/Page column 56.
[3]Patent: WO2019/40274,2019,A1 .Location in patent: Paragraph 0247.
[4]Journal of Medicinal Chemistry,1987,vol. 30,p. 1798 - 1806.
[5]Patent: US2008/249101,2008,A1 .Location in patent: Page/Page column 40.
[6]Patent: WO2008/20306,2008,A2 .Location in patent: Page/Page column 35.
[7]Patent: WO2009/5998,2009,A1 .Location in patent: Page/Page column 214.
[8]Patent: WO2004/14856,2004,A1 .Location in patent: Page 9; 14.
[9]Journal of Organic Chemistry,1988,vol. 53,p. 1912 - 1918.
[10]Patent: WO2006/19768,2006,A1 .Location in patent: Page column 90.
[11]Patent: WO2006/20879,2006,A1 .Location in patent: Page/Page column 62-63.
[12]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1628 - 1631.
[13]Journal of Medicinal Chemistry,2012,vol. 55,p. 3975 - 3991.
[14]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 360 - 365.
[15]Journal of Medicinal Chemistry,2013,vol. 56,p. 8561 - 8578.
[16]Inorganic Chemistry,2014,vol. 53,p. 2932 - 2942.
[17]Tetrahedron,2017,vol. 73,p. 2913 - 2922.
[18]Tetrahedron,2018,vol. 74,p. 224 - 239.
[19]ChemMedChem,2018,vol. 13,p. 1530 - 1540.
[20]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 644 - 654.
[21]European Journal of Medicinal Chemistry,2019,vol. 180,p. 509 - 523.

12
[ 57556-31-7 ]
[ 74-88-4 ]
[ 35598-05-1 ]

References: [1]Tetrahedron,1989,vol. 45,p. 5791 - 5804.
[2]Tetrahedron Letters,1989,vol. 30,p. 111 - 112.

13
[ 22246-27-1 ]
[ 124-41-4 ]
[ 18927-05-4 ]
[ 35598-05-1 ]

References: [1]Helvetica Chimica Acta,1998,vol. 81,p. 251 - 267.

Yield	Reaction Conditions	Operation in experiment
		Reference Example 19 Methyl 4-methoxy-o-toluate 12.6 g of a 28% sodium methylate methanol solution and 4.2 g of copper iodide were added to 5 g of methyl 4-bromo-toluate dissolved in 20 ml of dimethylformamide and the mixture was refluxed under heating for 2 hours. The reaction mixture was adjusted to about pH 2 by adding 1N-hydrochloric acid thereto and extracted with ethyl acetate. and the organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The residue obtained by removing the solvent was applied to silica gel column chromatography to obtain 2.47 g of the title compound.

16
[ 74-88-4 ]
disodium salt of/the/ 4-oxy-2-methyl-benzoic acid [ No CAS ]
[ 35598-05-1 ]

References: [1]Chemische Berichte,1879,vol. 12,p. 818,821.

17
[ 35598-05-1 ]
potassium; 4-methoxy-2-methyl-benzoate [ No CAS ]

References: [1]Tetrahedron Letters,2006,vol. 47,p. 565 - 567.

18
[ 35598-05-1 ]
4-methoxy-2-methyl-benzoic acid allyl ester [ No CAS ]

References: [1]Tetrahedron Letters,2006,vol. 47,p. 565 - 567.

19
[ 35598-05-1 ]
4-methoxy-2-methyl-benzoic acid benzyl ester [ No CAS ]

References: [1]Tetrahedron Letters,2006,vol. 47,p. 565 - 567.

20
[ 24826-74-2 ]
[ 35598-05-1 ]

References: [1]Journal of Medicinal Chemistry,1987,vol. 30,p. 1798 - 1806.
[2]Journal of Organic Chemistry,1968,vol. 33,p. 494 - 503.

21
[ 35598-05-1 ]
[ 109803-65-8 ]