[ CAS No. 155380-11-3 ] {[proInfo.proName]}

Name: 155380-11-3|Methyl 2-(4-(hydroxymethyl)phenyl)acetate|98%
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Quality Control of [ 155380-11-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 155380-11-3 ]

Product Details of [ 155380-11-3 ]

CAS No. :	155380-11-3	MDL No. :	MFCD08061910
Formula :	C₁₀H₁₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LLDQUDYCTIKKFV-UHFFFAOYSA-N
M.W :	180.20	Pubchem ID :	12575321
Synonyms :

Calculated chemistry of [ 155380-11-3 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.3
Num. rotatable bonds :	4
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	48.43
TPSA :	46.53 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) :	-6.73 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.74
Log Po/w (XLOGP3) :	0.94
Log Po/w (WLOGP) :	0.74
Log Po/w (MLOGP) :	1.41
Log Po/w (SILICOS-IT) :	1.91
Consensus Log Po/w :	1.35

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.63
Solubility :	4.25 mg/ml ; 0.0236 mol/l
Class :	Very soluble
Log S (Ali) :	-1.5
Solubility :	5.65 mg/ml ; 0.0313 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.71
Solubility :	0.354 mg/ml ; 0.00196 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.41

Safety of [ 155380-11-3 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P313-P337+P313-P362-P403+P233-P405-P501	UN#:
Hazard Statements:	H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 155380-11-3 ]

* 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 [ 155380-11-3 ]
Downstream synthetic route of [ 155380-11-3 ]

[ 155380-11-3 ] Synthesis Path-Upstream 1~1

1
[ 155380-11-3 ]
[ 96524-70-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With Dess-Martin periodane In dichloromethane at 20℃; for 4 h;	To a stirring solution of Dess-Martin Periodinane (1.5 eq) in dichloromethane (0.3 M) at room temperature under nitrogen was added a solution of 29 in dichloromethane (0.2 M). After 4 hours the reaction was diluted with ether (0.1 M). The reaction mixture was then poured into a solution of sodium thiosulfate (10.5 eq) in saturated sodium bicarbonate (0.5 M) and stirred for 30 minutes. The phases were separated and the organic phase was washed with saturated sodium bicarbonate (1?), H2O (1?) and brine (1?) then dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. (94percent) 1H NMR (400 MHz, CDCl3) ? 10.00 (s, 1H), 7.86 (d, 2H), 7.46 (d, 2H), 3.72 (m, 5H).
70%	With manganese(IV) oxide In dichloromethane at 20 - 55℃; for 22 h;	A solution of 2-(4-(hydroxymethyl)phenyl)acetate (intermediate compound 14) (1 .2 mmol, 216 mg) was dissolved in DCM (4 ml_) and treated with manganese (IV) oxide (10.8 mmol, 938 mg) stirred 16h at room temperature. Total conversion was not achieved, then the reaction mixture was heated at 55⁵C for 6 h. The crude product was filtered and concentrated in vacuum to give the compound methyl 2-(4-formylphenyl)acetate (150mg. Yield: 70percent). ¹ H NMR (400 MHz, DMSO-d₆) δ 9.99 (1 H, s), 7.87 (2H, d, J=6Hz), 7.50 (2H, d, J=5.6Hz), 3.83 (2H, s), 3.63 (3H, s). LC-MS: t_R = 2.47 [M+H]⁺ = 179 (method 3).
1.72 g	With manganese(IV) oxide In dichloromethane at 20℃; for 18 h;	Acetyl chloride (5 mL) was added to an ice-cooled solution of 4- (hydroxymethyl)phenylacetic acid (5.78 g, 34.8 mmol) in methanol (200 mL). The reaction mixture allowed to warm to RT at stirred at this temperature for 42 hours. The solvent was evaporated under reduced pressure and the residue dissolved in DCM (100 mL). Manganese dioxide (29.47 g, 339 mmol) was added and the resultant suspension stirred at RT for 18 hours. The suspension was filtered through celite and the filter cake washed with further DCM. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography eluting with 0-25percent ethyl acetate in iso-hexane to afford the title compound (1.72 g, 28percent). NMR (400 MHz, CDC1₃): δ 10.0 (s, 1 H); 7.87-7.83 (m, 2 H); 7.46 (d, J = 8 Hz, 2 H); 3.69-3.65 (m, 5 H).

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 10, p. 2647 - 2652
[2] Patent: US2004/254156, 2004, A1, . Location in patent: Page 22
[3] Patent: WO2013/149997, 2013, A1, . Location in patent: Page/Page column 47
[4] Patent: WO2014/86924, 2014, A1, . Location in patent: Page/Page column 74; 75
[5] Patent: WO2007/106016, 2007, A1, . Location in patent: Page/Page column 68

[ 155380-11-3 ] Synthesis Path-Downstream 1~88

1
[ 7398-42-7 ]
[ 155380-11-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With water; calcium carbonate; In 1,4-dioxane; at 20℃;Heating / reflux;	To a stirring solution of 15 in dioxane (0.4 M) at room temperature under nitrogen was added calcium carbonate (5.5 eq) and H2O (0.8 M). The reaction was refluxed overnight then vacuum filtered. The dioxane was removed under reduced pressure. The reaction mixture was diluted with H2O then extracted with dichloromethane (3?). The organic phases were combined, dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. (77percent) 1H NMR (400 MHz, CDCl3) ? 7.33 (d, 2H), 7.27 (d, 2H), 4.67 (s, 2H), 3.69 (s, 3H), 3.63 (s, 2H), 1.78 (br s, 1H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2647 - 2652
[2]Patent: US2004/254156,2004,A1 .Location in patent: Page 22

2
[ 155380-11-3 ]
[ 96524-70-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With Dess-Martin periodane; In dichloromethane; at 20℃; for 4h;	To a stirring solution of Dess-Martin Periodinane (1.5 eq) in dichloromethane (0.3 M) at room temperature under nitrogen was added a solution of 29 in dichloromethane (0.2 M). After 4 hours the reaction was diluted with ether (0.1 M). The reaction mixture was then poured into a solution of sodium thiosulfate (10.5 eq) in saturated sodium bicarbonate (0.5 M) and stirred for 30 minutes. The phases were separated and the organic phase was washed with saturated sodium bicarbonate (1?), H2O (1?) and brine (1?) then dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. (94%) 1H NMR (400 MHz, CDCl3) ? 10.00 (s, 1H), 7.86 (d, 2H), 7.46 (d, 2H), 3.72 (m, 5H).
70%	With manganese(IV) oxide; In dichloromethane; at 20 - 55℃; for 22h;	A solution of 2-(4-(hydroxymethyl)phenyl)acetate (intermediate compound 14) (1 .2 mmol, 216 mg) was dissolved in DCM (4 ml_) and treated with manganese (IV) oxide (10.8 mmol, 938 mg) stirred 16h at room temperature. Total conversion was not achieved, then the reaction mixture was heated at 555C for 6 h. The crude product was filtered and concentrated in vacuum to give the compound methyl 2-(4-formylphenyl)acetate (150mg. Yield: 70%). 1 H NMR (400 MHz, DMSO-d6) delta 9.99 (1 H, s), 7.87 (2H, d, J=6Hz), 7.50 (2H, d, J=5.6Hz), 3.83 (2H, s), 3.63 (3H, s). LC-MS: tR = 2.47 [M+H]+ = 179 (method 3).
1.72 g	With manganese(IV) oxide; In dichloromethane; at 20℃; for 18h;	Acetyl chloride (5 mL) was added to an ice-cooled solution of 4- (hydroxymethyl)phenylacetic acid (5.78 g, 34.8 mmol) in methanol (200 mL). The reaction mixture allowed to warm to RT at stirred at this temperature for 42 hours. The solvent was evaporated under reduced pressure and the residue dissolved in DCM (100 mL). Manganese dioxide (29.47 g, 339 mmol) was added and the resultant suspension stirred at RT for 18 hours. The suspension was filtered through celite and the filter cake washed with further DCM. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography eluting with 0-25% ethyl acetate in iso-hexane to afford the title compound (1.72 g, 28%). NMR (400 MHz, CDC13): delta 10.0 (s, 1 H); 7.87-7.83 (m, 2 H); 7.46 (d, J = 8 Hz, 2 H); 3.69-3.65 (m, 5 H).

	With manganese(IV) oxide; In dichloromethane; for 18h;	a) (4-Formylphenyl)acetic acid methyl ester; Acetyl chloride (5mL) was added cautiously to solution of (4-hydroxymethylphenyl)acetic acid (5.78g) in methanol (20OmL), stirred for 18 hours and evaporated. The residue was dissolved in dichloromethane (10OmL) and treated with manganese (IV) oxide (29.47g), stirred for 18 hours and filtered through Celite. The filter pad was washed with dichloromethane and the combined filtrates evaporated. Purification on silica, eluting with 20% diethyl ether in iso-hexane, afforded the subtitle compound as a white solid (3.60g). 1H NMR (300MHz, CDCl3) delta 10.01 (s, IH), 7.86 (d, 2H), 7.46 (d, 2H), 3.72 (s, 5H).
	With Dess-Martin periodane; In dichloromethane; at 0 - 20℃;	To a stirred solution of methyl 2-(4-(hydroxymethyl)phenyl)acetate 43 in 4 ml DCM at 0 C was added Dess Martin Periodinate (636 mg, 1.5 mmol, 1.5 equivalent). Then the reaction mixture was brought to room temperature and a mixture of 2 ml DCM and 0.02 ml of water were added slowly over 2 hours. The reaction mixture was stirred for an additional 1 hour followed by the addition of sodium bicarbonate. The resulting mixture was extracted 3 times with ethyl acetate and washed with brine. The combined organic layer was dried over sodium sulfate, filtrated and concentrated under vacuum. The crude mixture was purified by flash chromatography using ethyl acetate/ hexanes (0 %-> 50% ethyl acetate) to yield product 44. NMR (600 MHz, CDCI3) delta 9.94 (s, 1H), 7.79 (d, / = 8.1 Hz, 2H), 7.40 (d, / = 8.1 Hz, 2H), 3.66 (s, 2H), 3.65 (s, 3H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2647 - 2652
[2]Patent: US2004/254156,2004,A1 .Location in patent: Page 22
[3]Patent: WO2013/149997,2013,A1 .Location in patent: Page/Page column 47
[4]Patent: WO2014/86924,2014,A1 .Location in patent: Page/Page column 74; 75
[5]Patent: WO2007/106016,2007,A1 .Location in patent: Page/Page column 68
[6]Patent: WO2019/36607,2019,A1 .Location in patent: Paragraph 00154-00155

3
[ 13737-36-5 ]
[ 155380-11-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2647 - 2652
[2]Patent: WO2017/86941,2017,A1

4
[ 155380-11-3 ]
[ 789457-36-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2647 - 2652

5
[ 155380-11-3 ]
[ 808753-11-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2647 - 2652

6
[ 155380-11-3 ]
[ 808753-12-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2647 - 2652

7
[ 155380-11-3 ]
<i>N</i>-[2-(3-hydroxy-pyrrolidin-1-yl)-1-phenyl-ethyl]-2-[4-(3-methanesulfonylamino-propyl)-phenyl]-<i>N</i>-methyl-acetamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2647 - 2652

8
[ 155380-11-3 ]
[ 808753-10-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2647 - 2652

9
[ 288-32-4 ]
[ 155380-11-3 ]
methyl 4-t-butyldimethylsilyloxymethylphenylacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	In N,N-dimethyl-formamide;	Step 1, methyl 4-t-butyldimethylsilyloxymethylphenylacetate To a solution of methyl p-hydroxymethylphenylacetate (3.30 g, 18.3 mmol, prepared according to the method of G. Biagi et al., E. Ed. Farmaco., 43, 597 (1988)) in 6.6 ml DMF was added TBDMS-Cl (3.31 g, 22.0 mmol) and imidazole (3.12 g, 45.8 mmol), and the resulting solution was stirred at ambient temperature for 18 hours. The mixture was poured into 100 ml H2 O and extracted (EtOAc, 4*50 ml). The combined extracts were dried (MgSO4), filtered and concentrated. The crude material was chromatographed (EtOAc:hexane, 5:95) to afford the title compound (5.0 g, 92% yield) as an oil. 1 H NMR (CDCl3) δ 0.09 (s, 6H), 1.94 (s, 9H), 3.60 (s, 2H), 3.67 (s, 3H), 4.70 (s, 2H), 7.23 (m, 4H).

Reference： [1]Patent: US5300668,1994,A

10
[ 67-56-1 ]
[ 73401-74-8 ]
[ 155380-11-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With acetyl chloride; at 20℃;	To a solution of <strong>[73401-74-8]2-(4-(hydroxymethyl)phenyl)acetic acid</strong> (1 .2 mmol, 200mg) in dry MeOH (7 mL) was added acetyl chloride (2.4 mmol, 0.171 mL). The reaction mixture was stirred overnight at room temperature. The crude product was concentrated in vacuum to give the compound methyl 2-(4- (hydroxymethyl)phenyl)acetate. (216 mg. Yield: 100%) LC-MS: tR = 2.28 [M+H]+ = 181 (method 3).
98%	With sulfuric acid; at 55℃; for 1h;	INTERMEDIATE 127 2-(4-Formylphenyl)-7V-methylacetamide To a solution of <strong>[73401-74-8]4-(hydroxymethyl)phenylacetic acid</strong> in MeOH (75 mL) was added cone. H2SO4 (ca 10 drops). The mixture was stirred at 55 C for 1 h and was then allowed to cool to room temperature and solid NaHC03 was added until neutral pH. The mixture was filtered and the solvent evaporated to furnish 6.2 g of crude material. Further drying in vacuum furnished 5.32 g (98%) of pure methyl [4-(hydroxymethyl)phenyl]acetate. MS (ESI+) m/z 181 [M+H]+.
98%	With sulfuric acid; at 0℃; for 1h;Inert atmosphere;	To <strong>[73401-74-8]2-<strong>[73401-74-8][4-(hydroxymethyl)phenyl]acetic acid</strong></strong> (1) (5 g, 30.1 mmol) in MeOH (30 mL) cooled to 0 C was added H2SO4 (3 mL) and the solution was stirred for 1 h at 0 C. The solution was then poured into H2O and EtOAc and washed with H2O (2). The aqueous layer was backextracted with EtOAc (2). The combined EtOAc layers were washed with NaHCO3 (sat.) (3). The organics were dried (Na2SO4), filtered and evaporated to give methyl 2-[4-(hydroxymethyl)phenyl]acetate (2) (5.3 g, 98%) as an oil. 1H NMR (600 MHz, CDCl3): delta = 7.35 (d, J = 6.0 Hz, 2 H), 7.29 (d, J = 6.0 Hz, 2 H), 4.69 (s, 2 H), 3.71 (s, 3 H), 3.65 (s, 3 H). 13C NMR (150 MHz, CDCl3): delta = 172.1, 139.8, 133.4, 129.5, 127.3, 65.1, 52.1, 40.1.

83%	With diazomethyl-trimethyl-silane; In toluene; at 0 - 20℃; for 16h;	To a solution of <strong>[73401-74-8]2-(4-(hydroxymethyl) phenyl) acetic acid</strong> (20 g, 120.48 mmol) in MeOH: toluene (1: 1) (200 mL) at 0C was added (trimethylsilyl)diazomethane(TMSCHN2, 27.51 g, 240 mmol), and the mixture was stirred at room temperature for16 hours. After completion, the solvent was evaporated and the crude compound was purified by flash CC (eluent: EtOAc/Pet ether, on silica gel) to afford methyl 2-(4- (hydroxymethyl) phenyl) acetate (18 g, 83 %) as an off white solid.
	With acetyl chloride; at 20℃; for 42h;Cooling with ice;	Acetyl chloride (5 mL) was added to an ice-cooled solution of 4- (hydroxymethyl)phenylacetic acid (5.78 g, 34.8 mmol) in methanol (200 mL). The reaction mixture allowed to warm to RT at stirred at this temperature for 42 hours. The solvent was evaporated under reduced pressure and the residue dissolved in DCM (100 mL). Manganese dioxide (29.47 g, 339 mmol) was added and the resultant suspension stirred at RT for 18 hours. The suspension was filtered through celite and the filter cake washed with further DCM. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography eluting with 0-25% ethyl acetate in iso-hexane to afford the title compound (1.72 g, 28%). NMR (400 MHz, CDC13): delta 10.0 (s, 1 H); 7.87-7.83 (m, 2 H); 7.46 (d, J = 8 Hz, 2 H); 3.69-3.65 (m, 5 H).
	With sulfuric acid; at 0 - 20℃;Large scale;	To a solution of C (2.5 kg, 15.06 mol, 1 eq) in MeOH (15 L) was slowly added concentrated H2S04 (1.5 L) at 0C. The resulting mixture was allowed to stir at RT overnight. After C was consumed as indicated by TLC, the reaction mixture was poured into water (20 L) and extracted with EtOAc (20 L x 3). The combined organic layers were washed with saturated NaHC03 solution (aq.) (20 L x 3) and then brine (20 L). The organic phase was dried over Na2S04, filtered and concentrated to give the title compound (2.2 kg) as a viscous oil. HPLC purity: 90% (220 nm); 1H NMR (300 MHz, CDC13) delta 7.35-7.28 (m, 4H), 4.68 (s, 2H), 3.70 (s, 3H), 3.64 (s, 2H).
2.2 kg	With sulfuric acid; at 0 - 25℃;Large scale;	Methyl 2-(4-(hydroxymethyl)phenyl)acetate (D) To a solution of C (2.5 kg, 15.06 mol, 1 eq) in MeOH (15 L) was slowly added concentrated H2SO4 (1.5 L) at 0 C. The resulting mixture was allowed to stir at RT overnight. After C was consumed as indicated by TLC, the reaction mixture was poured into water (20 L) and extracted with EtOAc (20 L3). The combined organic layers were washed with saturated NaHCO3 solution (aq.) (20 L3) and then brine (20 L). The organic phase was dried over Na2SO4, filtered and concentrated to give the title compound (2.2 kg) as a viscous oil. HPLC purity: 90% (220 nm); 1H NMR (300 MHz, CDCl3) delta 7.35-7.28 (m, 4H), 4.68 (s, 2H), 3.70 (s, 3H), 3.64 (s, 2H).
	With acetyl chloride; for 18h;	a) (4-Formylphenyl)acetic acid methyl ester; Acetyl chloride (5mL) was added cautiously to solution of (4-hydroxymethylphenyl)acetic acid (5.78g) in methanol (20OmL), stirred for 18 hours and evaporated. The residue was dissolved in dichloromethane (10OmL) and treated with manganese (IV) oxide (29.47g), stirred for 18 hours and filtered through Celite. The filter pad was washed with dichloromethane and the combined filtrates evaporated. Purification on silica, eluting with 20% diethyl ether in iso-hexane, afforded the subtitle compound as a white solid (3.60g). 1H NMR (300MHz, CDCl3) delta 10.01 (s, IH), 7.86 (d, 2H), 7.46 (d, 2H), 3.72 (s, 5H).

Reference： [1]Patent: WO2013/149997,2013,A1 .Location in patent: Page/Page column 46; 47
[2]Patent: WO2016/124553,2016,A1 .Location in patent: Page/Page column 112
[3]Synthesis,2019,vol. 51,p. 953 - 959
[4]ChemMedChem,2013,vol. 8,p. 709 - 718
[5]Patent: WO2016/20288,2016,A1 .Location in patent: Page/Page column 180
[6]Journal of Medicinal Chemistry,2017,vol. 60,p. 1768 - 1792
[7]Patent: WO2014/86924,2014,A1 .Location in patent: Page/Page column 74; 75
[8]Patent: WO2017/86941,2017,A1 .Location in patent: Paragraph 00106
[9]Patent: US9643927,2017,B1 .Location in patent: Page/Page column 35
[10]Patent: WO2007/106016,2007,A1 .Location in patent: Page/Page column 68

11
[ 18162-48-6 ]
[ 155380-11-3 ]
[ 155380-03-3 ]

Yield	Reaction Conditions	Operation in experiment
98%	With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃;	Methyl 2-(4-(hydroxymethyl)phenyl)acetate (5.0g, 27.8mmol)And imidazole (2.8g, 41.7mmol) dissolved in 50mL of N,N-dimethylformamide,Then tert-butyldimethylchlorosilane (5.0 g, 33.4 mmol) was added, and the reaction was carried out at room temperature overnight.TLC monitors that the reaction is complete.The reaction was quenched by adding water, extracted with ethyl acetate (20 mL×3), and the organic phases were combined,Wash with saturated brine (50 mL), and dry the organic phase with anhydrous sodium sulfate. Filter and spin dry.Purified by column chromatography, the product 2.1 (8.1 g, yield: 98%) was obtained.

Reference： [1]Patent: CN111217834,2020,A .Location in patent: Paragraph 0095-0101
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5186 - 5190

12
[ 80522-42-5 ]
[ 155380-11-3 ]
[ 1253955-08-6 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,6-dimethylpyridine; In dichloromethane; at 0 - 20℃;	Methyl 2-(4-((triisopropylsilyloxy)methyl) phenyl)acetate (E133) was prepared from E132 according to the below: E132E133To <strong>[155380-11-3]methyl 2-(4-(hydroxymethyl)phenyl)acetate</strong> (E132) in CH2CI2 at O0C was added 2,6- lutidine and TIPS-OTf. The ice bath was removed and the solution was allowed to warm to room temperature and stir. After 4 h the solution was poured into NH4CI(sat) and CH2CI2 and the organic layer was further extracted with NH4CI(sat). The organics were dried (MgSO4) filtered and evaporated. Column chromatography (SiO2, 0-15% EtOAc/Hexanes) gave pure methyl 2-(4-((triisopropylsilyloxy)methyl)phenyl)acetate (E133).
	With 2,6-dimethylpyridine; In dichloromethane; at 0 - 20℃; for 2.0h;	To a zero degree solution of <strong>[155380-11-3]methyl 2-(4-(hydroxymethyl)phenyl)acetate</strong> (11b) (5674 mg, 31.49 mmol) in CH2Cl2 (50 mL), 2,6-lutidine (5.47 mL, 47.23 mmol) and TIPS-OTf (14.48 g, 47.23 mmol) were added. The ice bath was removed and the solution was allowed to warm to room temperature and stirred. After 2 hours, the reaction was quenched by the addition of NH4Cl(aq) (50 mL). The reaction was diluted with CH2Cl2 (100 mL) and washed with H2O (2 x 50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 5 percent EtOAc/hexanes) to afforded methyl 2-(4-(((triisopropylsilyl)oxy)methyl)phenyl)acetate (11c). 1H-NMR (500 MHz, CDCl3): δ 7.31 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H), 4.82 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H), 1.21-1.15 (m, 3H), 1.10-1.06 (m, 18H)

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 2475 - 2480
[2]Patent: WO2010/127329,2010,A1 .Location in patent: Page/Page column 54
[3]Patent: EP3845276,2021,A1 .Location in patent: Paragraph 0061; 0096; 0098

13
[ 73401-74-8 ]
[ 18107-18-1 ]
[ 155380-11-3 ]

Yield	Reaction Conditions	Operation in experiment
		Methyl 2-(4-(hydroxymethyl)phenyl)acetate (E132) was prepared according to the below:O TMS-CHN2 HO'^0H MeOH OMeE132To <strong>[73401-74-8]2-(4-(hydroxymethyl)phenyl)acetic acid</strong> in MeOH at O0C was added TMS-CHN2. The solution was stirred for 3 h then quenched with a few drops of AcOH. The solvents were evaporated. Column chromatography (SiO2, 3-15% EtOAc/Hex) gave pure methyl 2-(4- (hydroxymethyl)phenyl)acetate (E132).

Reference： [1]Patent: WO2010/127329,2010,A1 .Location in patent: Page/Page column 54

14
[ 71939-50-9 ]
[ 155380-11-3 ]
[ 1456814-33-7 ]

Reference： [1]ChemMedChem,2013,vol. 8,p. 709 - 718

15
[ 155380-11-3 ]
[ 1456814-28-0 ]

Reference： [1]ChemMedChem,2013,vol. 8,p. 709 - 718

16
[ 155380-11-3 ]
[ 1456814-36-0 ]

Reference： [1]ChemMedChem,2013,vol. 8,p. 709 - 718

17
[ 155380-11-3 ]
[ 1456814-29-1 ]

Reference： [1]ChemMedChem,2013,vol. 8,p. 709 - 718

18
2-(2-fluoro-4-(2-(methylsulfinyl)pyrimidin-5-yl)phenyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole [ No CAS ]
[ 155380-11-3 ]
C₂₇H₁₈F₄N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In 1-methyl-pyrrolidin-2-one; at 110℃; for 20.0h;	To a solution of <strong>[155380-11-3]methyl 2-(4-(hydroxymethyl)phenyl)acetate</strong> (21 mg, 0.119 mmol, 2 eq) in anhydrous NMP (lmL) was added NaH (60%, 12 mg, 0.297 mmol, 5 eq) slowly. The resulting suspension was stirred at ambient temperature for 20 mm and then 2-(2-fluoro-4-(2- (methylsulfinyl)pyrimidin-5-yl)phenyl)-5 -(trifluoromethyl)- 1 H-benzo [d] imidazole (25 mg, 0.059 mmol, 1 eq) was added. The resulting reaction mixture was stirred at 110C for 20 hr andthen cooled to ambient temperature. The reaction was quenched with MeOH (0.5 mL) and stirred at ambient temperature for 2 hr. LC-MS showed that the hydrolysis was completed. The solution was concentrated in vacuum and DMSO (1 mL) was added. The resulting solution was neutralized with HOAc to pH = 5 and filtered. The crude product was purified by using preparative reversed-phase HPLC (acetonitrile with 0.1% formic acid: water with 0.1% formicacid from 10% to 90%) to give the product as a white solid. LC-MS Found: 523 [M+H]+

Reference： [1]Patent: WO2013/130370,2013,A2 .Location in patent: Page/Page column 61; 62

19
[ 155380-11-3 ]
[ 1000505-73-6 ]

Reference： [1]Patent: WO2014/86924,2014,A1

20
[ 155380-11-3 ]
[ 1613414-62-2 ]

Reference： [1]Patent: WO2014/86924,2014,A1

Yield	Reaction Conditions	Operation in experiment
82%	With thionyl chloride; at 0 - 25℃; for 2.0h;Inert atmosphere;	General procedure: Under a nitrogen atmosphere, SOCl2 (0.55 mL, 7.55 mmol, 0.2 eq). was added dropwise to a stirred suspension of 2-(4-(bromomethyl)phenyl)acetic acid (8.65 g, 37.74 mmol, 1 eq) in MeOH (85.0 mL) at 0 C. The mixture was stirred at room temperature for 2 h, then was diluted with water. The solvent was partially removed in vacuo and the resulting aqueous phase was extracted with EtOAc (x3) The combined organic layers were washed with brine (xl), dried over sodium sulfate and concentrated in vacuo, to give 8,23 g of product as an amorphous off-white solid; yield 90%, which was used in the next step without further purification. IR (KBr) 2998, 2951, 1736, 1435, 1160, 1012, 602; 1H- MR (300 MHz, CDC13) δ 7.35 (d, J = 8.0 Hz, 2-H), 7.25 (d, J = 8.0 Hz, 2-H), 4.48 (s, 2-H), 3.69 (s, 3-H), 3.62 (s, 2-H) ppm; 1 C- MR (75 MHz, CDC13) δ 171.7, 136.7, 134.3, 129.8, 129.3, 52.1, 40.9, 33.2 ppm.

22
[ 155380-11-3 ]
C₃₀H₄₄NO₆P [ No CAS ]