[ CAS No. 52085-14-0 ] {[proInfo.proName]}

Name: 52085-14-0|4-(Benzyloxy)-2-hydroxybenzaldehyde|97%
Brand: Ambeed
SKU: A105026
Price: 9.0 USD
Availability: InStock
Rating: 94 (35 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

2D 3D

Structure of 52085-14-0 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 52085-14-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 52085-14-0 ]

SDS Specification

Alternatived Products of [ 52085-14-0 ]

Product Details of [ 52085-14-0 ]

CAS No. :	52085-14-0	MDL No. :	MFCD01075698
Formula :	C₁₄H₁₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AMLKEDBYDOCGEG-UHFFFAOYSA-N
M.W :	228.24	Pubchem ID :	561235
Synonyms :

Calculated chemistry of [ 52085-14-0 ]

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.07
Num. rotatable bonds :	4
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	64.83
TPSA :	46.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.53 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.1
Log Po/w (XLOGP3) :	3.05
Log Po/w (WLOGP) :	2.63
Log Po/w (MLOGP) :	1.99
Log Po/w (SILICOS-IT) :	3.08
Consensus Log Po/w :	2.57

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.43
Solubility :	0.0838 mg/ml ; 0.000367 mol/l
Class :	Soluble
Log S (Ali) :	-3.69
Solubility :	0.0462 mg/ml ; 0.000203 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.44
Solubility :	0.00827 mg/ml ; 0.0000362 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.85

Safety of [ 52085-14-0 ]

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 [ 52085-14-0 ]

* 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 [ 52085-14-0 ]
Downstream synthetic route of [ 52085-14-0 ]

[ 52085-14-0 ] Synthesis Path-Upstream 1~17

1
[ 52085-14-0 ]
[ 23681-89-2 ]

Reference： [1] Journal of the Chemical Society, 1948, p. 2254,2258

2
[ 100-39-0 ]
[ 95-01-2 ]
[ 52085-14-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: With sodium hydrogencarbonate In acetonitrile at 20℃; for 0.75 h; Inert atmosphere Stage #2: Inert atmosphere; Reflux	2,4-Dihydroxybenzaldehyde (3.0g, 1.0equiv) was dissolved in acetonitrile (220ml) and treated with NaHCO₃ (2.2equiv) for 45min at rt followed by the addition of benzylbromide (1.1equiv). The reaction mixture was stirred under reflux O.N. and then quenched with H₂O (100ml) and extracted with ethyl acetate (3×25ml). The combined organic layers were washed with brine (2×15ml), dried over Na₂SO₄, filtered and the solvent was eliminated under vacuo to give the title compound 12 as a white solid that was used as it is.
82%	With sodium hydrogencarbonate In acetonitrile for 48 h; Reflux; Inert atmosphere	Anhydrous NaHCO₃ (10.1 g, 120 mmol) was added to a stirred solution of 2,4-dihydroxybenzaldehyde (16.6 g, 120 mmol) in CH₃CN (80 mL). BnBr (14.1 mL, 120 mmol) was then added and the reaction mixture refluxed for 48 h. Upon completion (TLC), the reaction mixture was brought to rt followed by addition of H₂O (40 mL) and EtOAc (40 mL). The layers were separated and the organic layer was washed with sat. NaHCO₃ and brine, dried over anhydrous Na₂SO₄ and evaporated to give a brown solid which was subjected to crystallization (MeOH) to afford the title compound as an off-white solid (22.5 g, 82percent); mp 82-83 °C (Lit. 80-82 °C¹); TLC R_f 0.88 [EtOAc/Hex (1:1)]; ¹H NMR (CDCl₃) δ 11.47 (s, 1H), 9.72 (s, 1H), 7.35-7.45 (m, 6H), 6.60 (dd, 1H, J = 2.2, 8.8 Hz), 6.51 (d, 1H, J = 2.2 Hz), 5.11 (s, 2H); ¹³C NMR (CDCl₃): δ 194.4, 165.9, 164.4, 135.6, 135.3, 128.7, 128.4, 127.5, 115.3, 108.9, 101.6, 70.4.
80%	Stage #1: With sodium hydrogencarbonate In acetonitrile at 20℃; for 1 h; Stage #2: for 6 h; Reflux	Anhydrous sodium bicarbonate (0.1 g, 1.2 mmol) was added to a solution of 2,4-dihydroxy-benzaldehyde (0.138 g, 1 mmol) in 10 mL of acetonitrile and the mixture was stirred for 1 hour at RT. Benzylbromide (0.13 mL, 1.1 mmol) was added and the mixture was refluxed for 6 hours. After disappearance of the reactant (TLC), the reaction was poured into ice water with vigorous stirring. A white solid precipitated and it was recrystallized from methanol (ca. 4 mL) to obtain 0.182 g (80percent) of white powder: mp 78-80° C.; TLC R_f0.88 in toluene:methanol (10:1); ¹H NMR (600 MHz, acetone-d₆) δ 11.41 (s, 1H, OH), 9.81 (s, 1H, CHO), 7.68-7.67 (d, 1H, J=8.4 Hz, Ar-H6), 7.45-7.35 (m, 5H, C₆H₅), 6.71-6.69 (dd, 1H, ²J=8.4 Hz, ³J=2.4 Hz, Ar-H5), 6.56 (d, 1H, J=1.8 Hz, Ar-H3), 5.24 (s, 2H, PhCH₂); ¹³C NMR (100 MHz, acetone-d₆) 194.61, 166.1, 164.4, 135.9, 128.9, 128.6, 127.8, 115.5, 109.1, 101.8, 70.6; analysis calcd. for C₁₄H₁₂O₃: C 73.67, H 5.30, found: C 73.62, H 5.35.

80%	Stage #1: With sodium hydrogencarbonate In acetonitrile at 20℃; for 1 h; Stage #2: for 24 h; Reflux	Anhydrous sodium bicarbonate (1.2 mmol) was added to a solution of 2,4-dihydroxy-benzaldehyde (1 mmol) in acetonitrile and the mixture was stirred for 1 hour at room temperature. Benzylbromide (1.1 mmol) was added and the mixture was refluxed for 24 h. After disappearance of the reactant (TLC), the reaction was poured into ice water with vigorous stirring. A white solid precipitated was filter and purified by column chromatography (using ethyl acetate/n-hexane (1:9) as the eluent) to obtain 80 percent yield as a white solid. Mp.² 80–81 °C; ¹H NMR (600 MHz, CDCl₃) δ 11.48 (s, 1H), 9.72 (s, 1H), 7.46 - 7.32 (m, 6H), 6.62 (dd, J = 8.8, 2.2 Hz, 1H), 6.52 (d, J = 2.2 Hz, 1H), 5.11 (s, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 194.6, 166.0, 164.6, 135.8, 135.4, 128.9, 128.6, 127.7, 115.5, 109.1, 101.8, 70.6. Experimental data in agreement with reported data.
80%	Stage #1: With sodium hydrogencarbonate In acetonitrile at 20℃; for 1 h; Stage #2: for 24 h; Reflux	Anhydrous sodium bicarbonate (1.2 mmol) was added to a solution of 2,4-dihydroxy-benzaldehyde (1 mmol) in acetonitrile and the mixture was stirred for 1 hour at room temperature. Benzylbromide (1.1 mmol) was added and the mixture was refluxed for 24 hours. After disappearance of the reactant (TLC), the reaction was poured into ice water with vigorous stirring. A white solid precipitated was filter and purified by column chromatography (using ethyl acetate/n-hexane (1:9) as the eluent) to obtain 80 percent yield as a white solid. Mp.² 80–81 °C; ¹H NMR (600 MHz, CDCl₃) δ 11.48 (s, 1H), 9.72 (s, 1H), 7.46 - 7.32 (m, 6H), 6.62 (dd, J = 8.8, 2.2 Hz, 1H), 6.52 (d, J = 2.2 Hz, 1H), 5.11 (s, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 194.6, 166.0, 164.6, 135.8, 135.4, 128.9, 128.6, 127.7, 115.5, 109.1, 101.8, 70.6. Experimental data in agreement with reported data.³
65%	With sodium hydrogencarbonate In acetonitrile for 16 h; Inert atmosphere; Reflux	2,4-dihydroxybenzaldehyde (10 g, 0.072 mol) was dissolved in acetonitrile (83 mL). To this solution was added NaHCO₃ (9.1 g, 0.10 mol) and stirred for 5 min. Benzyl bromide (12.9 mL, 0.10 mol) was added in under an argon atmosphere. The reaction was heated to reflux for 16 h. After cooling to room temperature, the reaction was quenched by addition of distilled water, and the organic layer extracted into dichloromethane (3 x 50 mL), and organic layers combined, washed with water and brine, dried (Na₂SO₄) and concentrated. The crude mixture was purified by column chromatography (Silica gel, 10percent -20 percent EtOAc in hexane) to give 25 in 65percent yield.
59.9%	With sodium hydrogencarbonate In acetonitrile at 85℃; for 20 h;	A mixture of sodium bicarbonate (1.216 g, 14.48 mmol), benzyl bromide (2.477 g, 14.48 mmol) and 2,4-dihydroxybenzaldehyde (2 g, 14.48 mmol)) in acetonitrile (50 mL) was stirred at 85 °C for 20 hours. The solvent was removed to give a brown oil The residue was diluted with 80 mL of water, extracted with ethyl acetate (3 x 75 mL). The combined organic layers were dried over Na2S04, filtered through glass funnel and concentrated to give an orange oil. The crude material was purified by silica gel column chromatography and eluted with 5percent ethyl acetate/heptane. The following fractions were collected and concentrated to give the title compound 4- (benzyloxy)-2-hydroxybenzaldehyde (2.2 g, 8.67 mmol, 59.9 percent yield) as a white solid.LCMS(ESI-MS): m/z: 312.1 [M + H]⁺; Rt = 2.09 min. (Method A)
49%	With sodium hydrogencarbonate; sodium iodide In acetonitrile at 80℃; for 18 h; Inert atmosphere	To 2,4-dihydroxybenzaldehyde (2.0 g, 14 mmol), Nal (1.0 g, 7.2 mmoi), and NaHC0₃ (1.5g, 17 mmol) in acetonitrile (30 mL, 0.50 M) was added benzyl bromide (1.7 mL, 14 mmol). The reaction mixture was stirred at 80 °C for 18 h under argon, cooled to RT, diluted with EtOAc (100 mL), washed with H₂0 and brine, and dried over MgS04, and filtered. The filterate was concentrated and purified by flash chromatography (silica, EtOAcihexanes = 1:8) to provided compound 3 as a white solid (49percent). NMR (CDC1₃, 300 MHz): δ 11.48 (1H, s), 9.72 (1H, s), 7.51 - 7.32 (6H, m), 6.62 (1H, dd, J = 8.7, 2.3 Hz), 6.54 (1H, d, / = 2.3 Hz), 5.11 (2H, s). ^I3C NMR (CDCI3, 100 MHz): δ 194.5, 166.0, 164.6, 135.8, 135.4, 128.9, 128.5, 127.6, 115.5, 109.0, 101.8, 70.5. LRMS (APCI+): Calc'd for C_l4H_l20₃ 228.1 m/z, measured 229.2 (AfH+).
49%	With sodium hydrogencarbonate; sodium iodide In acetonitrile at 80℃; for 18 h; Inert atmosphere	To 2,4-dihydroxybenzaldehyde (2.0 g, 14 mmol), Nal (1.0 g,7.2 mmol), and NaHCO3 (1.5 g, 17 mmol) in acetonitrile (30mE, 0.50 M)was added benzyl bromide (1.7 mE, 14 mmol).The reaction mixture was stirred at 80° C. for 18 h under argon, cooled to RT, diluted with EtOAc (100 mE), washed with H20 and brine, and dried over MgSO4, and filtered. The filterate was concentrated and purified by flash chromatography (silica, EtOAc:hexanes=1 :8) to provided compound 3 aswhite solid (49percent). ‘H NMR (CDC13, 300 MHz): ö 11.48 (1H, s), 9.72 (1H, s), 7.51-7.32 (6H, m), 6.62 (1H, dd, J=8.7, 2.3 Hz), 6.54 (1H, d, J=2.3 Hz), 5.11 (2H, s). ‘3C NMR (CDC13, 100 MHz): ö 194.5, 166.0, 164.6, 135.8, 135.4, 128.9, 128.5, 127.6, 115.5, 109.0, 101.8, 70.5. ERMS (APCI+): Calc’d for C,4H,203 228.1 mlz, measured 229.2 (MH+).
30.77%	With potassium carbonate In acetonitrile at 20℃; for 3 h;	Intermediate 98: 4-(Benzyloxy)-2-hydroxybenzaldehydeTo a 250 mL RB flask fitted with magnetic stirrer was charged with 30 mL of acetonitrile. To the stirred solvent were added 2, 4-dihydroxybenzaldehyde (8.0 g, 57.0 mmol), potassium carbonate (15.77 g, 114.0 mmol). The reaction mixture was brought to 0 °C, was added benzyl bromide (9.905 g, 57.0 mmol) in acetonitrile (100 mL) drop wise and stirred at room temperature for 3 h. The reaction mixture was concentrated to distill off the solvent. The residue was extracted with ethyl acetate (80 mL). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na₂S0₄ and the solvent was removed under reduced pressure. The product obtained as a white solid (4.0 g, yield: 30.77percent).
40%	With potassium carbonate In acetone	EXAMPLE I 4-Benzyloxy-2-hydroxybenzaldehyde 13.8 g (0.1 mol) 2,4-dihydroxybenzaldehyde are dissolved in 150 ml acetone, 17.1 g (0.1 mol) benzylbromide and 13.8 g (0.1 mol) potassium carbonate are added, and the mixture is stirred at room temperature for 3 d. After filtration, the solvent is removed in vacuo and the residual crude product further purified by column chromatography on silica gel using dichloromethane as eluent. Yield: 9.2 g (40percent); m.p.: 81-82° C. ¹H-NMR (CDCl₃, 400 MHz): δ=5.11 (s, 2H; CH₂): 6.51 (d, 1H, Ar-H); 6.61 (dd, 1H, Ar-H); 7.32-7.45 (m, 6H, Ar-H); 9.82 (s, 1H, CHO); 11.60 (s, 1H, OH) ppm.

Reference： [1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 15, p. 4502 - 4510
[2] Synlett, 2011, # 11, p. 1605 - 1607
[3] Organic Process Research and Development, 2011, vol. 15, # 5, p. 1149 - 1162
[4] Tetrahedron Letters, 2013, vol. 54, # 31, p. 4121 - 4124
[5] Organic Letters, 2008, vol. 10, # 21, p. 5007 - 5010
[6] Patent: US2011/144195, 2011, A1, . Location in patent: Page/Page column 2; 4; 11
[7] Phosphorus, Sulfur and Silicon and the Related Elements, 2018, vol. 193, # 5, p. 306 - 316
[8] Phosphorus, Sulfur and Silicon and the Related Elements, 2018, vol. 193, # 9, p. 574 - 581
[9] Journal of Medicinal Chemistry, 2012, vol. 55, # 12, p. 5797 - 5812
[10] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 15, p. 3633 - 3637
[11] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1428 - 1435
[12] Patent: WO2015/200514, 2015, A2, . Location in patent: Page/Page column 69
[13] Journal of Heterocyclic Chemistry, 1987, vol. 24, # 1, p. 75 - 77
[14] Patent: WO2013/119985, 2013, A1, . Location in patent: Paragraph 00335; 00336
[15] Patent: WO2018/83171, 2018, A1, . Location in patent: Page/Page column 48; 49
[16] Journal of the American Chemical Society, 2010, vol. 132, # 26, p. 8828 - 8830
[17] Patent: WO2011/94560, 2011, A1, . Location in patent: Page/Page column 54
[18] Patent: US9075014, 2015, B2, . Location in patent: Page/Page column 39
[19] Patent: WO2012/11125, 2012, A1, . Location in patent: Page/Page column 145-146
[20] Rikagaku Kenkyusho Iho, 1940, vol. 19, p. 802,803[21] Chem.Abstr., 1940, p. 5842
[22] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 11, p. 1421 - 1426
[23] Patent: US6610687, 2003, B1,
[24] Tetrahedron Asymmetry, 2008, vol. 19, # 3, p. 343 - 347
[25] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 19, p. 5252 - 5254
[26] Journal of Natural Products, 2009, vol. 72, # 11, p. 2072 - 2075
[27] Organic Letters, 2012, vol. 14, # 17, p. 4544 - 4547
[28] Tetrahedron Letters, 2015, vol. 56, # 11, p. 1338 - 1343

3
[ 100-44-7 ]
[ 95-01-2 ]
[ 52085-14-0 ]

Yield	Reaction Conditions	Operation in experiment
77.8%	With sodium hydrogencarbonate; potassium iodide In acetonitrile at 60 - 65℃;	General procedure: A mixture of 2,4-dihydroxybenzaldehyde (1.38 g, 0.01 mol), substituted benzyl chloride (0.011 mol), NaHCO₃ (1.26 g, 0.015 mol) and catalytic amount of potassium iodide in 20 mL acetonitrile was heated to 60 °C for 36 h and hot filtered, the filtrate was cooled to 10 °C and filtered, the filtrated cake was collected and recrystallized with EtOH to obtain compounds 10a–g.
67%	With sodium hydrogencarbonate; potassium iodide In acetonitrileReflux	2,4-dihydroxybenzaldehyde (100 mg, 0.72 mmol), potassium iodide (179.3 mg, 1.08 mmol) and sodium bicarbonate (90.7 mg, 1.08 mmol) were dissolved in acetonitrile (15 mL), then benzyl chloride (100 uL, 0.87 mmol) were added slowly to the resulted solution. The mixture was stirred at refluxing overnight, and then the reaction was quenched with water and extracted with ethyl acetate (20 mL .x. 3). The combined organic layer was washed with brine (15 mL .x. 3), dried with sodium sulphate anhydrous, concentrated under vacuum, and purified by flash chromatography with eluent (petroleum ether: ethyl acetate = 10:1), to get a colorless solid. Yield 67percent; m.p. 70-72 °C; ¹H NMR (300 MHz, CDCl₃), δ 5.12 (s, 2H, OCH₂Ph), 6.40-6.64 (m, 2H, ArH), 7.41-7.43 (m, 6H, ArH), 9.73 (s, 1H, CHO), 11.44 (brs, 1H, OH); EI-MS m/z: 229.1.
66%	With sodium hydrogencarbonate; potassium iodide In acetonitrile for 30 h; Reflux	The reaction of 2,4-dihydroxybenzaldehyde with benzyl chloride,To give 2-hydroxy-4-benzyloxybenzaldehyde,As shown in Scheme 5,The specific preparation method is as follows: A mixture of 2,4-dihydroxybenzaldehyde (50 g, 0.362 mol)Benzyl chloride (59.3 g, 0.471 mol)Sodium bicarbonate (34.7 g, 0.413 mol)Potassium iodide (12 g, 0.0724 mol) was added to 200 mL of acetonitrile,The reaction was refluxed for 30 h.Reaction finished,The reaction solution was poured into water,Precipitation of solids,Filter,Washed cake,dry.Recrystallization from methanol,A white solid of 54 g,Yield 66percent

64%	With sodium hydrogencarbonate; potassium iodide In acetonitrileReflux	To a solution of2,4-dihydroxybenzaldehyde (5.00 g, 36 mmol) and benzylchloride (5.50 g, 43.5 mmol) in CH3CN (50 mL), KI (5.50g, 54 mmol) and NaHCO3 (4.50 g, 54 mmol) were added.The mixture was refluxed overnight and cooled to roomtemperature. The reaction was quenched with water andextracted by ethyl acetate. The combined organic extractswere washed with brine, dried over anhydrous Na2SO4,concentrated and purified over silica gel column (elution:10/1 petroleum ether/ethyl acetate) to give compound 1(5.25 g, 64 percent) as white solid. 1H NMR (CDCl3, 300 MHz):δ = 5.11 (s, 2H, OCH2Ph), 6.51–6.52 (d, 1H, J = 3.0 Hz,ArH), 6.60–6.63 (dd, 1H, J = 1.5 Hz, 7.5 Hz ArH), 7.36–7.46 (m, 6H, ArH), 9.72 (s, 1H, OH), 11.48 (s, 1H, OH).
64%	With sodium hydrogencarbonate; potassium iodide In acetonitrile for 12 h; Reflux	2,4-dihydroxybenzaldehyde (5.00 g, 36 mmol) was dissolved in acetonitrile (500 mL)Then potassium iodide (9.00 g, 54 mmol) and sodium bicarbonate (4.50 g, 54 mmol) were added,Benzyl chloride (5.50 g, 43.5 mmol) was slowly added dropwise and refluxed for 12 h.After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: : 1)4- (benzyloxy) -2-hydroxybenzaldehyde5.25 g (white solid, yield 64percent).
56%	With sodium hydrogencarbonate; potassium iodide In acetonitrile for 24 h; Heating / reflux	(Example 197)2-Methyl-(1R)-[2-(4-methylthiophenoxy)-ethyl] -2,3 -dihydro-1H-benzo[c]azepin-7-yl dimethylcarbamate hydrochloride (Exemplification compound number 4-136)(a) 4-Benzyloxy-2-hydoxy-benzaldehydeTo a solution of 2,4-dihydroxybenzaldehyde (50.0 g, 362 mmol) in acetonitrile (350 ml) were added sodium hydrogen carbonate (34.6 g, 412 mmol), potassium iodide (6.0 g, 36 mmol), and benzyl chloride (54.0 ml, 470 mmol), and the resulting mixture was refluxed for 24 hours under a nitrogen atmosphere. At the end of the reaction, 1N hydrochloric acid (400 ml) was added, and the resulting mixture was extracted with ethyl acetate (400 ml ? 2). The organic layer was washed successively with 3percent aqueous potassium carbonate solution (300 ml ? 2), water (300 ml ? 1), 1N hydrochloric acid (300 ml ? 1) and saturated aqueous sodium chloride solution (300 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was recrystallized from a mixture of t-butyl methyl ether and hexane to afford the title compound (45.9 g, yield: 56percent) as pale orange crystals. Mp 71-72C.1H NMR (CDCl3, 500MHz) ? ppm : 5.11 (2H,s), 6.51 (1H,d,J=2.0Hz), 6.62 (1H,dd,J=2.0,8.5Hz), 7.35-7.45 (6H,m), 9.72 (1H,s), 11.46 (1H,s).(b) 4-Benzyloxy-2-methoxymethoxy-benzaldehyde o a solution of -benzyloxy-2-hydoxy-benzaldehyd (44.9 g, 197 mmol) synthesized in step (a) of Example 197 in dichloromethane (200 ml) were added diisopropylethylamine (52.0 ml, 300 mmol) and methoxymethyl chloride (20.5 ml, 270 mmol) at 0C with stirring, and the resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. After stirring, water (200 ml) was added, and the resulting mixture was extracted with dichloromethane (200 ml ? 2). The organic layer was washed successively with water (300 ml ? 1) and saturated aqueous sodium chloride solution (300 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1 - 1:1) as the eluent to afford the title compound (42.2 g, yield: 79percent) as a colorless oil.1H NMR (CDCl3, 500MHz) ? ppm : 3.51 (3H,s), 5.11(2H,s), 5.26 (2H,s), 6.68 (1H,dd,J=2.0,9.0 Hz), 6.80 (1H,d,J=9.0Hz), 7.34-7.43 (5H,m), 7.81 (1H,d,J=9.0Hz), 9.72 (1H,s), 11.46 (1H,s).(c) Ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-acrylate To a suspension of 55percent sodium hydride dispersion in mineral oil (1.57 g, 36.0 mmol) in tetrahydrofuran (100 ml) was added ethyl diethylphosphonoacetate (7.17 g, 32.0 mmol) at 0C with stirring, and the resulting mixture was stirred for 30 minutes at 0C under a nitrogen atmosphere. Subsequently, a solution of 4-benzyloxy-2-methoxymethoxy-benzaldehyde (7.46 g, 27.4 mmol) obtained in step (b) of Example 197 in tetrahydrofuran was added at 0C with stirring, and the resulting mixture was stirred for 2 hours at 0C under a nitrogen atmosphere. After stirring, water (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (200 ml ? 2). The organic layer was washed successively with water (100 ml ? 1) and saturated aqueous sodium chloride solution (100 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1 - 1:1) as the eluent to afford the title compound (9.32 g, yield: 99percent) as a colorless oil.1H NMR (CDCl3, 400MHz) ? ppm : 1.32 (3H,t,J=7.2 Hz), 3.47 (3H,s), 4.24 (2H,q,J=7.2Hz), 5.05 (2H,s), 5.21 (2H,s), 6.39 (1H,d,J=16.0Hz), 6.62 (1H,dd,J=2.0,8.8Hz), 6.81 (1H,d,J=2.0Hz), 7.30-7.43 (5H,m), 7.45 (1H,d,J=8.8Hz), 7.95 (1H,d,J=16.0Hz). (d) Ethyl (3R)-amino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate acetate To a solution of (S)-N-benzyl-1-phenylethylamine (4.24 g, 20.1 mmol) in tetrahydrofuran (40 ml) was added 1.6 M solution of n-butyllithium in hexane (12.4 ml, 18.9 mmol) at -78C with stirring, and the resulting mixture was stirred for 20 minutes at -78C under a nitrogen atmosphere. Subsequently, a solution of ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-acrylate (4.32 g, 12.6 mmol) synthesized in Example 3 in tetrahydrofuran was added dropwise at -78C with stirring, and the resulting mixture was stirred for 30 minutes at -78C under a nitrogen atmosphere. After stirring, a saturated aqueous ammonium chloride solution (40 ml) was added at -78C with stirring, and the resulting mixture was extracted with ethyl acetate (50 ml ? 2). The organic layer was washed with saturated aqueous sodium chloride solution (50 ml ? 1), dried over anhydrous e product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 0:1) as the eluent to afford the title compound (3.48 g, yield: 82percent) as a colorless oil. [?]D23 +48.0 (c 1.09, CHCl3) .1H NMR (CDCl3, 400MHz) ? ppm : 1.43 (9H,s), 1.94 (2H,dt,J=4.8,6.0Hz), 3.00 (3H,s), 3.08 (3H,s), 3.30 (1H,br s), 3.49 (3H,s), 3.61-3.74 (2H,m), 5.06 (1H,q,J=5.6Hz), 5.23 (2H,dd,J=6.4,10.8Hz), 5.47 (1H,d,J=9.6Hz), 6.74 (1H,dd,J=2.4,8.8Hz), 6.90 (1H,d,J=2.4Hz), 7.19 (1H,d,J=8.8Hz). (h) -[(1R)-Amino-3-(4-methylthiophenoxy)-propyl]-3-hydroxyphenyl dimethylcarbamate To a solution of t-butyl (1R)-(4-dimethylcarbamoyloxy-2-methoxymethoxy-phenyl)-3-hydroxypropyl]-carbamate (1.63 g, 4.08 mmol) synthesized in step (g) of Example 197, 4-methylthiophenol (660 mg, 4.50 mmol) and triphenylphosphine (1.60 g, 6.12 mmol) in tetrahydrofuran (15 ml), was added dropwise 40 wt percent solution of diethyl azodicarboxylate in toluene (2.66 g, 6.12 mmol) at 0C with stirring, and the resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 1:2) as the eluent to afford the crude product (2.74 g) containing hydrazine dicarboxylate. Subsequently, to a solution of the crude product (2.74 g) in methanol (18 ml) was added concentrated hydrochloric acid (6 ml), and the resulting mixture was stirred overnight at room temperature. After stirring, the reaction mixture was neutralized with 15percent aqueous sodium hydroxide solution and adjusted to pH 10 with saturated aqueous sodium hydrogen carbonate solution and then extracted with ethyl acetate (50 ml ? 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and methanol (1:0-5:1) as the eluent to afford the title compound (1.05 g, yield: 69percent) as a colorless oil. [?]D23 -66.5 (c 0.77, CHCl3).1H NMR (CDCl3, 500MHz) ? ppm : 2.12-2.18 (1H,m), 2.21-2.28 (1H,m), 2.44 (3H,s), 2.99 (3H,s), 3.07 (3H,s), 3.89 (1H,dt,J=4.0,10.0Hz), 4.00 (1H,dt,=5.0,10.0Hz), 4.43 (1H,t,J=7.5Hz), 6.51 (1H,dd,J=2.5,8.0Hz), 6.60 (1H,d,J=2.5Hz), 6.82 (2H,d,J=8.5 Hz), 6.86 (1H,d,J=8.0Hz), 7.25 (2H,d,J=8.5Hz). (i) t-Butyl [(1R) - 4-dimethylcarbamoyloxy-2-hydroxy-phenyl) -3-(4-methylthiophenoxy)-propyl]-carbamate To a solution of -[(1R)-amino-3-(4-methylthiophenoxy)-propyl] -3-hydroxy-phenyl dimethylcarbamate (1.05 g, 2.80 mmol) synthesized in step (h) of Example 197 in methanol (10 ml) were added triethylamine (0.83 ml, 6.0 mmol) and di-t-butyl dicarbonate (650 mg, 3.00 mmol), and the resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 0:1) as the eluent to afford the title compound (1.34 g, yield: 100percent) as a colorless solid. [?]D23 +14.3 (c 0.52, CHCl3).1H NMR (CDCl3, 400MHz) ? ppm : 1.40 (9H,s), 2.26-2.37 (2H,m), 2.44 (3H,s), 3.00 (3H,s), 3.07 (3H,s), 3.89-3.95 (1H,m), 3.98-4.03 (1H,m), 5.00 (1H,dd,J=8.0,15.2Hz), 5.25 (1H,br s), 6.63 (1H,dd,J=3.2,8.0Hz), 6.66 (1H,d,J=3.2Hz), 6.81 (2H,d,J=8.8Hz), 7.10 (1H,d,J=8.0Hz), 7.24 (2H,d,J=8.8Hz).(j) t-Butyl [(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-(4-methylthiophenoxy)-propyl] -carbamate To a solution of t-butyl [(1R)-(4-dimethylcarbamoyloxy-2-hydroxy-phenyl)-3-(4-methylthiophenoxy)-propyl] -carbamate (1.34 g, 2.80 mmol) synthesized in step (i) of Example 197 in dichloromethane (10 ml) were added pyridine (0.48 ml, 6.0 mmol) and trifluoromethanesulfonic anhydride (0.50 ml, 3.0 mmol) at 0C with stirring, and the resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. After stirring, water (20 ml) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (20 ml ? 2). The organic layer was washed successively with 0.5N hydrochloric acid (20 ml ? 1) and saturated aqueous sodium chloride solution (20 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude triflate derivative (1.48 g).1H NMR (CDCl3, 500MHz) ? ppm : 1.38 (9H,br s), 2.17-2.34 (2H,m), 2.44 (3H,s), 3.01 (3H,s), 3.09 (3H,s), 3.97 (2H,t,J=6.0Hz), 5.13 (1H,dd,J=8.0,12.5Hz, 5.44 (1H,br s), 6.82 (2H,d,J=8.5Hz), 7.14 (1H,d,J=8.5Hz), 7.15 (1H,s), 7.25 (2H,d,J=8.5Hz), 7.43 (1H d,J=8.5Hz). Subsequently, to a solution of the crude triflate derivative (1.48 g) obtained above in 1,4-dioxane (20 ml) were added tetrakis(triphenylphosphine)palladium (647 mg, 0.560 mmol), 2,6-di-t-butylphenol (5 mg), lithium chloride (356 mg, 8.40 mmol) and tributyl(vinyl)tin (0.88 ml, 3.0 mmol), and the resulting mixture was stirred for 3 hours at 100C under a nitrogen atmosphere. Subsequently, saturated aqueous potassium fluoride solution (10 ml) was added, and the resulting mixture was stirred for 2 hours at room temperature and then filtered and evaporated in vacuo. To the residue obtained was added water (40 ml), and the resulting mixture was extracted with ethyl acetate (50 ml ? 2). The organic layer was washed successively with 1N hydrochloric acid (40 ml ? 1) and saturated aqueous sodium chloride solution (40 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1 - 1:1) as the eluent to afford the title compound (1.08 g, yield: 79percent) as a colorless oil. [?]D23 -7.7 (c 0.58, CHCl3).1H NMR (CDCl3, 400MHz) ? ppm : 1.40 (9H,s), 2.18 (2H,br m), 2.44 (3H,s), 3.01 (3H,s), 3.09 (3H,s), 3.84-3.96 (2H,m), 5.23 (1H,br s), 5.31 (1H,d,J=10.8Hz), 5.58 (1H,dd,J=1.2,16.8Hz), 6.80 (2H,d,J=8.0Hz), 7.00-7.16 (1H,br m), 7.02 (1H,dd,J=2.8,8.8Hz), 7.19-7.28 (4H,m).(k) t-Butylallyl-[(1R)-(4-dimethylcarbamoyloxy-2-vinylphenyl)-3-(4-methylthiophenoxy)-propyl]-carbamate To a solution of t-butyl [(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl) -3-(4-methylthiophenoxy)-propyl) -carbamate (1.08 g, 2.22 mmol) synthesized in step (j) of Example 197 in dimethylformamide (10 ml) was added sodium hydride (160 mg, 6.66 mmol), being prepared free from mineral oil by washing with hexane, at 0C, and the resulting mixture was stirred for 30 minutes at 0C under a nitrogen atmosphere. Subsequently, allyl bromide (0.57 ml, 6.7 mmol) was added at 0C, and the resulting mixture was stirred for 2 hours at room temperature under a nitrogen atmosphere. After stirring, water (30 ml) was added, and the resulting mixture was extracted with ethyl acetate (30 ml ? 2). The organic layer was washed successively with water (30 ml ? 1) and saturated aqueous sodium chloride solution (30 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 1:1) as the eluent to afford the title compound (932 mg, yield: 80percent) as a colorless oil. [?]D23 +76.1 (c 0.63, CHCl3).1H NMR (CDCl3, 500MHz) ? ppm : 1.43 (9H,s), 2.29-2.42 (1H,br m), 2.40-2.52 (1H,br m), 2.43 (3H,s), 3.02 (3H,s), 3.11 (3H,s), 3.47 (2H, brs), 3.97 (1H,dt,J=6.0,8.0Hz), 4.06 (1H,br q,J=8.0Hz), 4.82 (1H,d,J=17.0Hz), 4.84 (1H,d,J=9.5Hz), 5.28 (1H,d,J=10.5Hz), 5.48 (1H,br s), 5.58 (1H,d,J=16.5Hz), 5.67 (1H,br s), 6.82 (2H,d,J=8.5Hz), 7.02 (1H,dd,J=10.5,16.5Hz), 7.04-7.06 (1H,m),7.24-7.26 (3H,m), 7.34 (1H,d,J=7.5Hz).(1) t-Butyl 7-dimethylcarbamoyloxy-(1R)-[2(4-methylthiophenoxy)-ethyl] -1, 3-dihydro-benzo[c]azepine-2-carboxylate To a solution of t-butyl allyl-[(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-(4-methylthiophenoxy)-propyl]-carbamate (907 mg, 1.72 mmol) synthesized in step (k) of Example 197 in dichlorometane (100 ml) was added tricyclohexylphosphine [1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene] [benzylidene] ruthenium(IV) dichloride (146 mg, 0.172 mmol), and the resulting mixture was stirred for 3 hours at 45C under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 1:1) as the eluent to afford the title compound (796 mg, yield: 93percent) as a colorless oil. [?]D23 -43.8 (c 0.71, CHCl3).1H NMR (CDCl3, 500MHz) ? ppm : 1.29 (6H,s), 1.38 (3H,s), 2.27 (1H,br s), 2.36 (1H,br s), 2.44 (3H,s), 3.00 (3H,s), 3.09 (3H,s), 3.77-4.18 (3H,br m), 4.74 (0.34H,d,J=16.0Hz), 4.99 (0.66H,br s), 5.23 (0.66H,br s), 5.35 (0.34H,br s), 5.78 (0.34H,d,J=11.5 Hz), 5.84 (0.66H,d,J=11.5Hz), 6.35 (1H,d,J=11.5Hz), 6.80 (0.68H,d,J=7.5Hz), 6.82 (1.32H,d,J=7.5 Hz), 6.88 (1H,br s), 6.96 (1H,s), 7.08 (1H,br s), 7.20-7.26 (2H,m). (m) -Methyl-(1R)-[2-(4-methylthiophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yl dimethylcarbamate hydrochloride The title compound was obtained as an amorphous solid using t-butyl 7-dimethylcarbamoyloxy-(1R)-[2-(4-methylthiophenoxy)-ethyl]-1,3-dihydro-benzo [c] azepine-2-carboxylate obtained in step (1) of Example 197 by conducting successively reactions similar to those mentioned in step (d) of Example 6 and Example 3. [?]D23 -24.2 (c 0.73, CHCl3).1H NMR (CDCl3, 400MHz) ? ppm : 2.03-2.15 (1H,m), 2.43 (3H,s), 2.53 (3H,s), 2.64-2.76 (1H,m), 3.02 (3H,s), 3.10 (3H,s), 3.76-3.79 (2H,m), 3.92 (1H, quintet,J=5.2Hz), 4.19 (1H,br s), 4.63 (1H,d,J=7.6Hz), 5.84 (1H,d,J=12.4Hz), 6.60 (1H,d,J=12.4Hz), 6.76 (2H,d,J=8.8Hz), 7.00 (1H,dd,J=2.0,8.0Hz), 7.14 (1H,d,J=2.0Hz), 7.15 (1H,d,J=8.0Hz), 7.21 (2H,d,J=8.8Hz).sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (10:1 - 5:1) as the eluent to afford ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-(3R)-[benzyl-((1S)-phenyl-ethyl)-amino]-propionate (7.21 g) containing a small amount of (S)-N-benzyl-1-phenylethylamine.1H NMR (CDCl3, 500MHz) ? ppm : 0.98 (3H,t,J=7.0Hz), 1.23 (3H,d,J=7.0Hz), 2.60 (1H,dd,J=9.0,13.5Hz), 2.73 (1H,dd,J=7.0,15.0Hz), 3.47 (3H,s), 3.73 (2H,dd,J=14.5,22.5Hz), 3.79-3.92 (2H,m), 4.08 (1H,q,J=7.0Hz), 4.80 (1H,dd,J=6.0,8.0 Hz), 5.03 (2H,s), 5.15 (2H,dd,J=7.0,17.0Hz), 6.61 (1H,dd,J=2.5,8.5 Hz), 6.83 (1H,d,J=2.5Hz), 7.13-7.44 (16H,m).Subsequently, to a solution of ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-(3R)-(benzyl-((1S)-phenyl-ethyl)-amino]-propionate (7.21 g) obtained above as a yellow oil in a mixture of methanol/water/acetic acid (80 ml/8 ml/4 ml) was added 20percent palladium hydroxide (1.8 g), and the resulting mixture was stirred for 4 hours at room temperature. After stirring, the reaction mixture was filtered through celite and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and methanol (1 : 0-3 : 1) as the eluent to afford the title compound (2.77 g, yield: 67percent) as an amorphous solid. [?]D23 -8.0 (c 0.82, MeOH) .1H NMR (CD3OD, 400MHz) ? ppm : 1.20 (3H,t,J=7.6Hz), 1.90 (3H,s), 2.93 (1H,dd,J=6.0,16.4Hz), 2.98 (1H,dd,J=8.8,16.4Hz), 3.49 (3H,s), 4.13 (2H,q,J=7.6Hz), 4.71 (1H,t,J=7.4Hz), 5.24 (2H,s), 6.45 (1H,dd,J=2.4,8.8Hz), 6.69 (1H,d,J=2.8Hz), 7.12 (1H,d,J=8.8Hz). (e) Ethyl (3R)-t-butoxycarbonylamino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate To a solution of ethyl (3R)-amino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate acetate (4.26 g, 12.9 mmol) obtained in step (d) of Example 197 in methanol (20 ml) were added triethylamine (3.62 ml, 26.0 mmol) and di-t-butyl dicarbonate (3.27 g, 15.0 mmol) with stirring, and the resulting mixture was stirred for 30 minutes at room temperature under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 1:2) as the eluent to afford the title compound (4.64 g, yield: 97percent) as a colorless solid. The optical purity of the title compound obtained was determined to be 98.8percent ee by chiral liquid chromatography (Dicel Chiral cel OJ, hexane : isopropanol = 95:5, 1 ml/min, R-isomer: 20.48 min and S-isomer: 23.68 min). Mp 82-86C. [?]D23 +42.3 (c 0.86, CHCl3).1H NMR (CDCl3, 500MHz) ? ppm : 1.16 (3H,t,J=7.0Hz), 1.43 (9H,s), 2.79 (1H,dd,J=7.0,14.5Hz), 2.86 (1H,dd,J=6.0,14.5Hz), 3.45 (3H,s), 4.05 (2H,q,J=7. Hz),4.85-5.20 (3H,m), 5.43 (0.2H,br s), 5.81 (0.8H,d,J=8.0Hz), 6.28 (1H,d,J=8.0Hz), 6.50 (1H,br s), 6.57 (1H,br s), 6.98 (1H,d,J=8.0Hz). (f) Ethyl 3R)-t-butoxycarbonylamino-(3R)-(4-dimethylcaramoyloxy-2-methoxymethoxy-phenyl)-propionate To a solution of ethyl 3R)-t-butoxycarbonylamino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate (2.35 g, 6.36 mmol) synthesized in step (e) of Example 197 in dimethylformamide (10 ml) were added potassium carbonate (1.80 g, 13.0 mmol) and N,N-dimethylcarbamoyl chloride (0.65 ml, 7.0 mmol) with stirring, and the resulting mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere. After stirring, water (30 ml) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (40 ml ? 2). The organic layer was washed with saturated aqueous sodium chloride solution (40 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 1:2) as the eluent to afford the title compound (2.73 g, yield: 97percent) as a colorless oil. [?]D23 +25.3 (c 1.09, CHCl3) .1H NMR (CDCl3, 500MHz) ? ppm : 1.17 (3H,t,J=7.0Hz), 1.41 (9H,s), 2.77-2.89 (2H,m), 2.99 (3H,s), 3.07 (3H,s), 3.49 (3H,s), 4.01-4.10 (2H,m), 5.24 (2H,dd,J=7.0,10.0Hz), 5.30 (1H,br s), 5.74 (1H,br d,J=9.0Hz), 6.73 (1H,dd,J=2.0,9.0Hz), 6.89 (1H,d,J=2.0Hz), 7.23 (1H,d,J=9.0Hz).(g) t-Butyl [(1R) (4-dimethylcarbamoyloxy-2-methoxymethoxyphenyl)-3-hydroxypropyl]-carbamate To a solution of ethyl 3R)-t-butoxycarbonylamino-(3R)-(4-dimethylcarbamoyloxy-2-methoxymethoxy-phenyl)-propionate (4.68 g, 10.6 mmol) synthesized in step (f) of Example 197 in tetrahydrofuran (30 ml) was added lithium aluminum hydride (524 mg, 13.8 mmol) at -50C with stirring, and the resulting mixture was stirred successively for 10 minutes at -50C and for 15 minutes at 0C under a nitrogen atmosphere. After stirring, to the reaction mixture were added water (0.5 ml), 15percent aqueous sodium hydroxide solution (0.5 ml) and water (1.5 ml) at 0C in this order, and the resulting mixture was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crud

Reference： [1] Heterocycles, 2010, vol. 81, # 7, p. 1697 - 1702
[2] Journal of the American Chemical Society, 2006, vol. 128, # 17, p. 5887 - 5894
[3] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 22, p. 6758 - 6763
[4] Organic and Biomolecular Chemistry, 2017, vol. 15, # 44, p. 9415 - 9423
[5] European Journal of Medicinal Chemistry, 2014, vol. 86, p. 257 - 269
[6] Archiv der Pharmazie, 2014, vol. 347, # 12, p. 936 - 949
[7] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 18, p. 6567 - 6582
[8] European Journal of Medicinal Chemistry, 2012, vol. 54, p. 879 - 886
[9] Patent: CN104230845, 2017, B, . Location in patent: Paragraph 0437; 0438; 0439; 0440
[10] Journal of Organic Chemistry, 2007, vol. 72, # 26, p. 10283 - 10286
[11] Medicinal Chemistry Research, 2016, vol. 25, # 11, p. 2485 - 2497
[12] Patent: CN104478836, 2017, B, . Location in patent: Paragraph 0054-0055
[13] Patent: EP1362844, 2003, A1, . Location in patent: Page/Page column 131-135
[14] Journal of Medicinal Chemistry, 2012, vol. 55, # 4, p. 1538 - 1552
[15] Synthetic Communications, 1981, vol. 11, # 10, p. 853 - 858
[16] Helvetica Chimica Acta, 1935, vol. 18, p. 816,826
[17] Journal of the American Chemical Society, 1961, vol. 83, p. 4787 - 4792
[18] Patent: US2003/153599, 2003, A1,

4
[ 13246-46-3 ]
[ 52085-14-0 ]

Yield	Reaction Conditions	Operation in experiment
72%	With zinc(II) chloride In 1,2-dichloro-ethane at 80℃;	General procedure: A clean, oven dried 2 dram screw cap vial was charged with ZnCl2 (1.05 equiv) and DCE (1 mL). A solution of ortho-protected phenol (0.15 mmol, 1 equiv) in DCE (0.5 mL) was added via syringe and the reaction stirred at the indicated temperature until starting material was consumed as determined by TLC analysis. The reaction was then diluted with saturated aqueous NH4Cl (20 mL), the layers were separated,and the aqueous phase extracted with CH2Cl2 (3 x 10 mL). The combined organic fractions were washed with saturated aqueous NaCl (20 mL), dried (MgSO4), and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography eluting with hexanes/EtOAc to give the ortho-deprotected phenol 33 mg (72percent) as white solid

Reference： [1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1986, vol. 40, # 5, p. 400 - 401
[2] Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 2, p. 222 - 230
[3] Tetrahedron Letters, 2012, vol. 53, # 40, p. 5376 - 5379

5
[ 100-44-7 ]
[ 52085-14-0 ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: With sodium hydrogencarbonate; potassium iodide In acetonitrile at 60℃; Stage #2: at 82℃; for 16 h;	Step 1 4-Ben7ry1oxy-2-hydτoxy-ben7:aldehvdeA solution of 2,4-dihydroxy-benzaldehyde (101 g, 0.731 mol) in acetonitrile (700 mL) is treated with KI (12.1 g, 73.1 mmol) and NaHCO₃ (70.0 g, 0.834 mol). The mixture is stirred while heating to 60 ^UC. Benzyl chloride (120 g, 0.950 mol) is added and the mixture is refluxed at 82 ⁰C for 16 hours and cooled to room temperature. The solvent is evaporated and the reaction is quenched with water (250 mL) and HCl (5.0 N, 30 mL). The mixture is extracted with EtOAc (300 mL x2), and the organic layers is dried over Na₂SO^ filtered, and concentrated to an approximate volume of 200 mL. To 400 mL hexanes is added and the resulting solution is heated to 60 ⁰C to dissolve. The solution is cooled to room temperature and crystallized for 16 hours The solid is filtered and dried to obtain the title compound (130 g, 78percent). LC- ES/MS m/e 227.0 (M-I).

Reference： [1] Patent: WO2007/92751, 2007, A2, . Location in patent: Page/Page column 33

6
[ 412339-25-4 ]
[ 52085-14-0 ]

Reference： [1] Patent: WO2007/67615, 2007, A2, . Location in patent: Page/Page column 112-113

7
[ 24677-78-9 ]
[ 100-39-0 ]
[ 52085-14-0 ]

Reference： [1] Patent: CN105777632, 2016, A, . Location in patent: Paragraph 0318; 0319; 0320

8
[ 1634-04-4 ]
[ 100-44-7 ]
[ 95-01-2 ]
[ 52085-14-0 ]

Reference： [1] Patent: US5599988, 1997, A,

9
[ 50-00-0 ]
[ 3769-41-3 ]
[ 52085-14-0 ]

Reference： [1] Tetrahedron Letters, 2009, vol. 50, # 46, p. 6339 - 6341

10
[ 100-39-0 ]
[ 95-01-2 ]
[ 52085-14-0 ]

Reference： [1] Patent: US5232948, 1993, A,

11
[ 100-44-7 ]
[ 95-01-2 ]
[ 13246-46-3 ]
[ 52085-14-0 ]

Reference： [1] Synthetic Communications, 1996, vol. 26, # 3, p. 593 - 601

12
[ 1194-98-5 ]
[ 100-44-7 ]
[ 52085-14-0 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 2012, vol. 60, # 8, p. 1046 - 1054

13
[ 1024-41-5 ]
[ 95-01-2 ]
[ 52085-14-0 ]

Reference： [1] Synthetic Communications, 1981, vol. 11, # 10, p. 853 - 858

14
[ 108-46-3 ]
[ 52085-14-0 ]

Reference： [1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 44, p. 9415 - 9423

15
[ 74-88-4 ]
[ 52085-14-0 ]
[ 58026-14-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In acetonitrile at 0 - 20℃; for 16 h;	Intermediate 99: 4-(Benzyloxy)-2-methoxybenzaldehydeTo a 100 mL RB flask fitted with magnetic stirrer was charged with 10 mL of acetonitrile. To the stirred solvent were added 4-(benzyloxy)-2-hydroxybenzaldehyde (1.0 g, 4.38 mmol), potassium carbonate (1.21 g, 8.76 mmol). The reaction mixture was brought to 0 °C, was added methyl iodide (1.135 g, 8.76 mmol) in acetonitrile (5 mL) drop wise and stirred at room temperature for 16 h. The reaction mixture was concentrated to distill off the solvent. The residue was extracted with ethyl acetate (50 mL). The organic layer was washed with water (40 mL) and saturated brine solution (40 mL). The organic layer was dried over anhydrous Na₂S0₄ and the solvent was removed under reduced pressure. The product obtained as a white solid (1.06 g, yield: 100.0percent).

Reference： [1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 20, p. 3029 - 3038
[2] Patent: WO2012/11125, 2012, A1, . Location in patent: Page/Page column 145-146
[3] Journal of the American Chemical Society, 2006, vol. 128, # 17, p. 5887 - 5894

16
[ 77-78-1 ]
[ 52085-14-0 ]
[ 58026-14-5 ]

Reference： [1] Tetrahedron Asymmetry, 2008, vol. 19, # 3, p. 343 - 347

17
[ 52085-14-0 ]
[ 189439-24-5 ]

Reference： [1] Tetrahedron Letters, 2011, vol. 52, # 25, p. 3226 - 3227
[2] Patent: US6610687, 2003, B1,
[3] Patent: US5969146, 1999, A,
[4] Soft Matter, 2010, vol. 6, # 8, p. 1704 - 1721
[5] Journal of Materials Chemistry C, 2017, vol. 5, # 33, p. 8454 - 8468

[ 52085-14-0 ] Synthesis Path-Downstream 1~36

1
[ 100-39-0 ]
[ 95-01-2 ]
[ 52085-14-0 ]

Yield	Reaction Conditions	Operation in experiment
100%		2,4-Dihydroxybenzaldehyde (3.0g, 1.0equiv) was dissolved in acetonitrile (220ml) and treated with NaHCO3 (2.2equiv) for 45min at rt followed by the addition of benzylbromide (1.1equiv). The reaction mixture was stirred under reflux O.N. and then quenched with H2O (100ml) and extracted with ethyl acetate (3×25ml). The combined organic layers were washed with brine (2×15ml), dried over Na2SO4, filtered and the solvent was eliminated under vacuo to give the title compound 12 as a white solid that was used as it is.
82%	With sodium hydrogencarbonate; In acetonitrile; for 48h;Reflux; Inert atmosphere;	Anhydrous NaHCO3 (10.1 g, 120 mmol) was added to a stirred solution of 2,4-dihydroxybenzaldehyde (16.6 g, 120 mmol) in CH3CN (80 mL). BnBr (14.1 mL, 120 mmol) was then added and the reaction mixture refluxed for 48 h. Upon completion (TLC), the reaction mixture was brought to rt followed by addition of H2O (40 mL) and EtOAc (40 mL). The layers were separated and the organic layer was washed with sat. NaHCO3 and brine, dried over anhydrous Na2SO4 and evaporated to give a brown solid which was subjected to crystallization (MeOH) to afford the title compound as an off-white solid (22.5 g, 82%); mp 82-83 C (Lit. 80-82 C1); TLC Rf 0.88 [EtOAc/Hex (1:1)]; 1H NMR (CDCl3) delta 11.47 (s, 1H), 9.72 (s, 1H), 7.35-7.45 (m, 6H), 6.60 (dd, 1H, J = 2.2, 8.8 Hz), 6.51 (d, 1H, J = 2.2 Hz), 5.11 (s, 2H); 13C NMR (CDCl3): delta 194.4, 165.9, 164.4, 135.6, 135.3, 128.7, 128.4, 127.5, 115.3, 108.9, 101.6, 70.4.
80%		Anhydrous sodium bicarbonate (0.1 g, 1.2 mmol) was added to a solution of 2,4-dihydroxy-benzaldehyde (0.138 g, 1 mmol) in 10 mL of acetonitrile and the mixture was stirred for 1 hour at RT. Benzylbromide (0.13 mL, 1.1 mmol) was added and the mixture was refluxed for 6 hours. After disappearance of the reactant (TLC), the reaction was poured into ice water with vigorous stirring. A white solid precipitated and it was recrystallized from methanol (ca. 4 mL) to obtain 0.182 g (80%) of white powder: mp 78-80 C.; TLC Rf0.88 in toluene:methanol (10:1); 1H NMR (600 MHz, acetone-d6) delta 11.41 (s, 1H, OH), 9.81 (s, 1H, CHO), 7.68-7.67 (d, 1H, J=8.4 Hz, Ar-H6), 7.45-7.35 (m, 5H, C6H5), 6.71-6.69 (dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar-H5), 6.56 (d, 1H, J=1.8 Hz, Ar-H3), 5.24 (s, 2H, PhCH2); 13C NMR (100 MHz, acetone-d6) 194.61, 166.1, 164.4, 135.9, 128.9, 128.6, 127.8, 115.5, 109.1, 101.8, 70.6; analysis calcd. for C14H12O3: C 73.67, H 5.30, found: C 73.62, H 5.35.

80%		Anhydrous sodium bicarbonate (1.2 mmol) was added to a solution of 2,4-dihydroxy-benzaldehyde (1 mmol) in acetonitrile and the mixture was stirred for 1 hour at room temperature. Benzylbromide (1.1 mmol) was added and the mixture was refluxed for 24 h. After disappearance of the reactant (TLC), the reaction was poured into ice water with vigorous stirring. A white solid precipitated was filter and purified by column chromatography (using ethyl acetate/n-hexane (1:9) as the eluent) to obtain 80 % yield as a white solid. Mp.2 80-81 C; 1H NMR (600 MHz, CDCl3) delta 11.48 (s, 1H), 9.72 (s, 1H), 7.46 - 7.32 (m, 6H), 6.62 (dd, J = 8.8, 2.2 Hz, 1H), 6.52 (d, J = 2.2 Hz, 1H), 5.11 (s, 2H); 13C NMR (151 MHz, CDCl3) delta 194.6, 166.0, 164.6, 135.8, 135.4, 128.9, 128.6, 127.7, 115.5, 109.1, 101.8, 70.6. Experimental data in agreement with reported data.
80%		Anhydrous sodium bicarbonate (1.2 mmol) was added to a solution of 2,4-dihydroxy-benzaldehyde (1 mmol) in acetonitrile and the mixture was stirred for 1 hour at room temperature. Benzylbromide (1.1 mmol) was added and the mixture was refluxed for 24 hours. After disappearance of the reactant (TLC), the reaction was poured into ice water with vigorous stirring. A white solid precipitated was filter and purified by column chromatography (using ethyl acetate/n-hexane (1:9) as the eluent) to obtain 80 % yield as a white solid. Mp.2 80-81 C; 1H NMR (600 MHz, CDCl3) delta 11.48 (s, 1H), 9.72 (s, 1H), 7.46 - 7.32 (m, 6H), 6.62 (dd, J = 8.8, 2.2 Hz, 1H), 6.52 (d, J = 2.2 Hz, 1H), 5.11 (s, 2H); 13C NMR (151 MHz, CDCl3) delta 194.6, 166.0, 164.6, 135.8, 135.4, 128.9, 128.6, 127.7, 115.5, 109.1, 101.8, 70.6. Experimental data in agreement with reported data.3
65%	With sodium hydrogencarbonate; In acetonitrile; for 16h;Inert atmosphere; Reflux;	2,4-dihydroxybenzaldehyde (10 g, 0.072 mol) was dissolved in acetonitrile (83 mL). To this solution was added NaHCO3 (9.1 g, 0.10 mol) and stirred for 5 min. Benzyl bromide (12.9 mL, 0.10 mol) was added in under an argon atmosphere. The reaction was heated to reflux for 16 h. After cooling to room temperature, the reaction was quenched by addition of distilled water, and the organic layer extracted into dichloromethane (3 x 50 mL), and organic layers combined, washed with water and brine, dried (Na2SO4) and concentrated. The crude mixture was purified by column chromatography (Silica gel, 10% -20 % EtOAc in hexane) to give 25 in 65% yield.
59.9%	With sodium hydrogencarbonate; In acetonitrile; at 85℃; for 20h;	A mixture of sodium bicarbonate (1.216 g, 14.48 mmol), benzyl bromide (2.477 g, 14.48 mmol) and 2,4-dihydroxybenzaldehyde (2 g, 14.48 mmol)) in acetonitrile (50 mL) was stirred at 85 C for 20 hours. The solvent was removed to give a brown oil The residue was diluted with 80 mL of water, extracted with ethyl acetate (3 x 75 mL). The combined organic layers were dried over Na2S04, filtered through glass funnel and concentrated to give an orange oil. The crude material was purified by silica gel column chromatography and eluted with 5% ethyl acetate/heptane. The following fractions were collected and concentrated to give the title compound 4- (benzyloxy)-2-hydroxybenzaldehyde (2.2 g, 8.67 mmol, 59.9 % yield) as a white solid.LCMS(ESI-MS): m/z: 312.1 [M + H]+; Rt = 2.09 min. (Method A)
49%	With sodium hydrogencarbonate; sodium iodide; In acetonitrile; at 80℃; for 18h;Inert atmosphere;	To 2,4-dihydroxybenzaldehyde (2.0 g, 14 mmol), Nal (1.0 g, 7.2 mmoi), and NaHC03 (1.5g, 17 mmol) in acetonitrile (30 mL, 0.50 M) was added benzyl bromide (1.7 mL, 14 mmol). The reaction mixture was stirred at 80 C for 18 h under argon, cooled to RT, diluted with EtOAc (100 mL), washed with H20 and brine, and dried over MgS04, and filtered. The filterate was concentrated and purified by flash chromatography (silica, EtOAcihexanes = 1:8) to provided compound 3 as a white solid (49%). NMR (CDC13, 300 MHz): delta 11.48 (1H, s), 9.72 (1H, s), 7.51 - 7.32 (6H, m), 6.62 (1H, dd, J = 8.7, 2.3 Hz), 6.54 (1H, d, / = 2.3 Hz), 5.11 (2H, s). I3C NMR (CDCI3, 100 MHz): delta 194.5, 166.0, 164.6, 135.8, 135.4, 128.9, 128.5, 127.6, 115.5, 109.0, 101.8, 70.5. LRMS (APCI+): Calc'd for Cl4Hl203 228.1 m/z, measured 229.2 (AfH+).
49%	With sodium hydrogencarbonate; sodium iodide; In acetonitrile; at 80℃; for 18h;Inert atmosphere;	To 2,4-dihydroxybenzaldehyde (2.0 g, 14 mmol), Nal (1.0 g,7.2 mmol), and NaHCO3 (1.5 g, 17 mmol) in acetonitrile (30mE, 0.50 M)was added benzyl bromide (1.7 mE, 14 mmol).The reaction mixture was stirred at 80 C. for 18 h under argon, cooled to RT, diluted with EtOAc (100 mE), washed with H20 and brine, and dried over MgSO4, and filtered. The filterate was concentrated and purified by flash chromatography (silica, EtOAc:hexanes=1 :8) to provided compound 3 aswhite solid (49%). ?H NMR (CDC13, 300 MHz): oe 11.48 (1H, s), 9.72 (1H, s), 7.51-7.32 (6H, m), 6.62 (1H, dd, J=8.7, 2.3 Hz), 6.54 (1H, d, J=2.3 Hz), 5.11 (2H, s). ?3C NMR (CDC13, 100 MHz): oe 194.5, 166.0, 164.6, 135.8, 135.4, 128.9, 128.5, 127.6, 115.5, 109.0, 101.8, 70.5. ERMS (APCI+): Calc?d for C,4H,203 228.1 mlz, measured 229.2 (MH+).
30.77%	With potassium carbonate; In acetonitrile; at 20℃; for 3h;	Intermediate 98: 4-(Benzyloxy)-2-hydroxybenzaldehydeTo a 250 mL RB flask fitted with magnetic stirrer was charged with 30 mL of acetonitrile. To the stirred solvent were added 2, 4-dihydroxybenzaldehyde (8.0 g, 57.0 mmol), potassium carbonate (15.77 g, 114.0 mmol). The reaction mixture was brought to 0 C, was added benzyl bromide (9.905 g, 57.0 mmol) in acetonitrile (100 mL) drop wise and stirred at room temperature for 3 h. The reaction mixture was concentrated to distill off the solvent. The residue was extracted with ethyl acetate (80 mL). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2S04 and the solvent was removed under reduced pressure. The product obtained as a white solid (4.0 g, yield: 30.77%).
9.2 g (40%)	With potassium carbonate; In acetone;	EXAMPLE I 4-Benzyloxy-2-hydroxybenzaldehyde 13.8 g (0.1 mol) 2,4-dihydroxybenzaldehyde are dissolved in 150 ml acetone, 17.1 g (0.1 mol) benzylbromide and 13.8 g (0.1 mol) potassium carbonate are added, and the mixture is stirred at room temperature for 3 d. After filtration, the solvent is removed in vacuo and the residual crude product further purified by column chromatography on silica gel using dichloromethane as eluent. Yield: 9.2 g (40%); m.p.: 81-82 C. 1H-NMR (CDCl3, 400 MHz): delta=5.11 (s, 2H; CH2): 6.51 (d, 1H, Ar-H); 6.61 (dd, 1H, Ar-H); 7.32-7.45 (m, 6H, Ar-H); 9.82 (s, 1H, CHO); 11.60 (s, 1H, OH) ppm.
		General procedure: NaHCO3 (0.69 g, 0.008moles), KI (0.120 g, 0.0007 moles) were added to the stirred solution of 2,4-dihydroxybenzaldehyde (1 g, 0.007 moles) in acetonitrile (10 ml). These contents were stirred at 50 0C for 30 min. Then methyl iodide (1.02 g, 0.007moles) in acetonitrile (5 ml) solution was added to that reaction mixture slowly for 5 min. These contents were stirred at 70 0C for 12 h. After completion of the reaction(TLC), the solvent removed under reduced pressure, the crude reaction mixture was quenched with water and extracted with diethyl ether (3 x 20 ml), the layers were separated and the organic layer was dried over Na2SO4. Solvent was removed under reduced pressure; the crude product was purified by column chromatography (hexane/ethyl acetate 9:1) to afford the desired product 1k as colourless solid in 25% yield. Similarly, the compounds 1l and 1m were prepared from corresponding alkyl halides. All the compounds were well characterised by spectral data.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 4502 - 4510
[2]Synlett,2011,p. 1605 - 1607
[3]Synthetic Communications,2020
[4]Organic process research and development,2011,vol. 15,p. 1149 - 1162
[5]Tetrahedron Letters,2013,vol. 54,p. 4121 - 4124
[6]Organic Letters,2008,vol. 10,p. 5007 - 5010
[7]Patent: US2011/144195,2011,A1 .Location in patent: Page/Page column 2; 4; 11
[8]Phosphorus, Sulfur and Silicon and the Related Elements,2018,vol. 193,p. 306 - 316
[9]Phosphorus, Sulfur and Silicon and the Related Elements,2018,vol. 193,p. 574 - 581
[10]Journal of Medicinal Chemistry,2012,vol. 55,p. 5797 - 5812
[11]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3633 - 3637
[12]Patent: WO2015/200514,2015,A2 .Location in patent: Page/Page column 69
[13]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 75 - 77
[14]Patent: WO2013/119985,2013,A1 .Location in patent: Paragraph 00335; 00336
[15]Patent: WO2018/83171,2018,A1 .Location in patent: Page/Page column 48; 49
[16]Journal of the American Chemical Society,2010,vol. 132,p. 8828 - 8830
[17]Patent: WO2011/94560,2011,A1 .Location in patent: Page/Page column 54
[18]Patent: US9075014,2015,B2 .Location in patent: Page/Page column 39
[19]Patent: WO2012/11125,2012,A1 .Location in patent: Page/Page column 145-146
[20]Rikagaku Kenkyusho Iho,1940,vol. 19,p. 802,803
Chem.Abstr.,1940,p. 5842
[21]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1421 - 1426
[22]Patent: US6610687,2003,B1
[23]Tetrahedron Asymmetry,2008,vol. 19,p. 343 - 347
[24]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 5252 - 5254
[25]Journal of Natural Products,2009,vol. 72,p. 2072 - 2075
[26]Organic Letters,2012,vol. 14,p. 4544 - 4547
[27]Tetrahedron Letters,2015,vol. 56,p. 1338 - 1343

2
[ 100-44-7 ]
[ 95-01-2 ]
[ 52085-14-0 ]

Yield	Reaction Conditions	Operation in experiment
77.8%	With sodium hydrogencarbonate; potassium iodide; In acetonitrile; at 60 - 65℃;	General procedure: A mixture of 2,4-dihydroxybenzaldehyde (1.38 g, 0.01 mol), substituted benzyl chloride (0.011 mol), NaHCO3 (1.26 g, 0.015 mol) and catalytic amount of potassium iodide in 20 mL acetonitrile was heated to 60 C for 36 h and hot filtered, the filtrate was cooled to 10 C and filtered, the filtrated cake was collected and recrystallized with EtOH to obtain compounds 10a-g.
67%	With sodium hydrogencarbonate; potassium iodide; In acetonitrile;Reflux;	2,4-dihydroxybenzaldehyde (100 mg, 0.72 mmol), potassium iodide (179.3 mg, 1.08 mmol) and sodium bicarbonate (90.7 mg, 1.08 mmol) were dissolved in acetonitrile (15 mL), then benzyl chloride (100 uL, 0.87 mmol) were added slowly to the resulted solution. The mixture was stirred at refluxing overnight, and then the reaction was quenched with water and extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with brine (15 mL × 3), dried with sodium sulphate anhydrous, concentrated under vacuum, and purified by flash chromatography with eluent (petroleum ether: ethyl acetate = 10:1), to get a colorless solid. Yield 67%; m.p. 70-72 C; 1H NMR (300 MHz, CDCl3), delta 5.12 (s, 2H, OCH2Ph), 6.40-6.64 (m, 2H, ArH), 7.41-7.43 (m, 6H, ArH), 9.73 (s, 1H, CHO), 11.44 (brs, 1H, OH); EI-MS m/z: 229.1.
66%	With sodium hydrogencarbonate; potassium iodide; In acetonitrile; for 30h;Reflux;	The reaction of 2,4-dihydroxybenzaldehyde with benzyl chloride,To give 2-hydroxy-4-benzyloxybenzaldehyde,As shown in Scheme 5,The specific preparation method is as follows: A mixture of 2,4-dihydroxybenzaldehyde (50 g, 0.362 mol)Benzyl chloride (59.3 g, 0.471 mol)Sodium bicarbonate (34.7 g, 0.413 mol)Potassium iodide (12 g, 0.0724 mol) was added to 200 mL of acetonitrile,The reaction was refluxed for 30 h.Reaction finished,The reaction solution was poured into water,Precipitation of solids,Filter,Washed cake,dry.Recrystallization from methanol,A white solid of 54 g,Yield 66%

64%	With sodium hydrogencarbonate; potassium iodide; In acetonitrile;Reflux;	To a solution of2,4-dihydroxybenzaldehyde (5.00 g, 36 mmol) and benzylchloride (5.50 g, 43.5 mmol) in CH3CN (50 mL), KI (5.50g, 54 mmol) and NaHCO3 (4.50 g, 54 mmol) were added.The mixture was refluxed overnight and cooled to roomtemperature. The reaction was quenched with water andextracted by ethyl acetate. The combined organic extractswere washed with brine, dried over anhydrous Na2SO4,concentrated and purified over silica gel column (elution:10/1 petroleum ether/ethyl acetate) to give compound 1(5.25 g, 64 %) as white solid. 1H NMR (CDCl3, 300 MHz):delta = 5.11 (s, 2H, OCH2Ph), 6.51-6.52 (d, 1H, J = 3.0 Hz,ArH), 6.60-6.63 (dd, 1H, J = 1.5 Hz, 7.5 Hz ArH), 7.36-7.46 (m, 6H, ArH), 9.72 (s, 1H, OH), 11.48 (s, 1H, OH).
64%	With sodium hydrogencarbonate; potassium iodide; In acetonitrile; for 12h;Reflux;	2,4-dihydroxybenzaldehyde (5.00 g, 36 mmol) was dissolved in acetonitrile (500 mL)Then potassium iodide (9.00 g, 54 mmol) and sodium bicarbonate (4.50 g, 54 mmol) were added,Benzyl chloride (5.50 g, 43.5 mmol) was slowly added dropwise and refluxed for 12 h.After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: : 1)4- (benzyloxy) -2-hydroxybenzaldehyde5.25 g (white solid, yield 64%).
56%	With sodium hydrogencarbonate; potassium iodide; In acetonitrile; for 24h;Heating / reflux;	(Example 197)2-Methyl-(1R)-[2-(4-methylthiophenoxy)-ethyl] -2,3 -dihydro-1H-benzo[c]azepin-7-yl dimethylcarbamate hydrochloride (Exemplification compound number 4-136)(a) 4-Benzyloxy-2-hydoxy-benzaldehydeTo a solution of 2,4-dihydroxybenzaldehyde (50.0 g, 362 mmol) in acetonitrile (350 ml) were added sodium hydrogen carbonate (34.6 g, 412 mmol), potassium iodide (6.0 g, 36 mmol), and benzyl chloride (54.0 ml, 470 mmol), and the resulting mixture was refluxed for 24 hours under a nitrogen atmosphere. At the end of the reaction, 1N hydrochloric acid (400 ml) was added, and the resulting mixture was extracted with ethyl acetate (400 ml ? 2). The organic layer was washed successively with 3% aqueous potassium carbonate solution (300 ml ? 2), water (300 ml ? 1), 1N hydrochloric acid (300 ml ? 1) and saturated aqueous sodium chloride solution (300 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was recrystallized from a mixture of t-butyl methyl ether and hexane to afford the title compound (45.9 g, yield: 56%) as pale orange crystals. Mp 71-72C.1H NMR (CDCl3, 500MHz) ? ppm : 5.11 (2H,s), 6.51 (1H,d,J=2.0Hz), 6.62 (1H,dd,J=2.0,8.5Hz), 7.35-7.45 (6H,m), 9.72 (1H,s), 11.46 (1H,s).(b) 4-Benzyloxy-2-methoxymethoxy-benzaldehyde o a solution of -benzyloxy-2-hydoxy-benzaldehyd (44.9 g, 197 mmol) synthesized in step (a) of Example 197 in dichloromethane (200 ml) were added diisopropylethylamine (52.0 ml, 300 mmol) and methoxymethyl chloride (20.5 ml, 270 mmol) at 0C with stirring, and the resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. After stirring, water (200 ml) was added, and the resulting mixture was extracted with dichloromethane (200 ml ? 2). The organic layer was washed successively with water (300 ml ? 1) and saturated aqueous sodium chloride solution (300 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1 - 1:1) as the eluent to afford the title compound (42.2 g, yield: 79%) as a colorless oil.1H NMR (CDCl3, 500MHz) ? ppm : 3.51 (3H,s), 5.11(2H,s), 5.26 (2H,s), 6.68 (1H,dd,J=2.0,9.0 Hz), 6.80 (1H,d,J=9.0Hz), 7.34-7.43 (5H,m), 7.81 (1H,d,J=9.0Hz), 9.72 (1H,s), 11.46 (1H,s).(c) Ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-acrylate To a suspension of 55% sodium hydride dispersion in mineral oil (1.57 g, 36.0 mmol) in tetrahydrofuran (100 ml) was added ethyl diethylphosphonoacetate (7.17 g, 32.0 mmol) at 0C with stirring, and the resulting mixture was stirred for 30 minutes at 0C under a nitrogen atmosphere. Subsequently, a solution of 4-benzyloxy-2-methoxymethoxy-benzaldehyde (7.46 g, 27.4 mmol) obtained in step (b) of Example 197 in tetrahydrofuran was added at 0C with stirring, and the resulting mixture was stirred for 2 hours at 0C under a nitrogen atmosphere. After stirring, water (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (200 ml ? 2). The organic layer was washed successively with water (100 ml ? 1) and saturated aqueous sodium chloride solution (100 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1 - 1:1) as the eluent to afford the title compound (9.32 g, yield: 99%) as a colorless oil.1H NMR (CDCl3, 400MHz) ? ppm : 1.32 (3H,t,J=7.2 Hz), 3.47 (3H,s), 4.24 (2H,q,J=7.2Hz), 5.05 (2H,s), 5.21 (2H,s), 6.39 (1H,d,J=16.0Hz), 6.62 (1H,dd,J=2.0,8.8Hz), 6.81 (1H,d,J=2.0Hz), 7.30-7.43 (5H,m), 7.45 (1H,d,J=8.8Hz), 7.95 (1H,d,J=16.0Hz). (d) Ethyl (3R)-amino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate acetate To a solution of (S)-N-benzyl-1-phenylethylamine (4.24 g, 20.1 mmol) in tetrahydrofuran (40 ml) was added 1.6 M solution of n-butyllithium in hexane (12.4 ml, 18.9 mmol) at -78C with stirring, and the resulting mixture was stirred for 20 minutes at -78C under a nitrogen atmosphere. Subsequently, a solution of ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-acrylate (4.32 g, 12.6 mmol) synthesized in Example 3 in tetrahydrofuran was added dropwise at -78C with stirring, and the resulting mixture was stirred for 30 minutes at -78C under a nitrogen atmosphere. After stirring, a saturated aqueous ammonium chloride solution (40 ml) was added at -78C with stirring, and the resulting mixture was extracted with ethyl acetate (50 ml ? 2). The organic layer was washed with saturated aqueous sodium chloride solution (50 ml ? 1), dried over anhydrous e product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 0:1) as the eluent to afford the title compound (3.48 g, yield: 82%) as a colorless oil. [?]D23 +48.0 (c 1.09, CHCl3...
	With potassium; In ethyl acetate; acetonitrile;	EXAMPLE 47 Preparation of 4-(Benzyloxy)-2-hydroxybenzaldehyde A solution of 2,4-dihydroxybenzaldehyde (20 g, 0.144 mol), potassium flouride (16.7 g, 2 equivalents) and benzyl chloride (29 mL, 1.75 equivalents) in acetonitrile (150 mL) is heated at reflux temperature for 16 hr, cooled to room temperature, concentrated, diluted with water and extracted with EtOAc. The combined extracts are dried over MgSO4 and concentrated in vacuo to give an oil residue. The residue is chromatographed (silica gel/10% EtOAc in hexanes to 50% EtOAc in hexanes as gradient eluents) to give the title product as a white solid, 25.9 g, identified by NMR and mass spectral analyses.
	With sodium hydrogencarbonate; potassium iodide; In acetonitrile; for 16h;Inert atmosphere; Reflux;	Synthesis Example 3: Compound No.2 (2S,3R,4R,5S,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-hydroxy-4-methoxyphenyl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol Into a 500-mL round-bottom flask, was placed a solution of 2,4-dihydroxybenzaldehyde (25 g, 181.00 mmol, 1.00 equiv) in dry CH3CN (200 mL), sodium bicarbonate (20 g, 238.08 mmol, 1.30 equiv) and Kl (3 g, 18.10 mmol, 0.10 equiv) at room temperature under an nitrogen atmosphere. The mixture was slowly warmed to 60 C., followed by addition of (chloromethyl)benzene (27.5 g, 217.25 mmol, 1.20 equiv). The resulting solution was heated to reflux for 16 h, cooled and the solids were filtered out. The resulting mixture was concentrated under vacuum. The mixture was washed by 2*100 ml PE:EA(1:20) to yield 4-(benzyloxy)-2-hydroxybenzaldehyde as a yellow solid.

Reference： [1]Heterocycles,2010,vol. 81,p. 1697 - 1702
[2]Journal of the American Chemical Society,2006,vol. 128,p. 5887 - 5894
[3]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 6758 - 6763
[4]Organic and Biomolecular Chemistry,2017,vol. 15,p. 9415 - 9423
[5]European Journal of Medicinal Chemistry,2014,vol. 86,p. 257 - 269
[6]Archiv der Pharmazie,2014,vol. 347,p. 936 - 949
[7]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 6567 - 6582
[8]European Journal of Medicinal Chemistry,2012,vol. 54,p. 879 - 886
[9]Patent: CN104230845,2017,B .Location in patent: Paragraph 0437; 0438; 0439; 0440
[10]Journal of Organic Chemistry,2007,vol. 72,p. 10283 - 10286
[11]Medicinal Chemistry Research,2016,vol. 25,p. 2485 - 2497
[12]Patent: CN104478836,2017,B .Location in patent: Paragraph 0054-0055
[13]Patent: EP1362844,2003,A1 .Location in patent: Page/Page column 131-135
[14]Journal of Medicinal Chemistry,2012,vol. 55,p. 1538 - 1552
[15]Synthetic Communications,1981,vol. 11,p. 853 - 858
[16]Helvetica Chimica Acta,1935,vol. 18,p. 816,826
[17]Journal of the American Chemical Society,1961,vol. 83,p. 4787 - 4792
[18]Patent: US2003/153599,2003,A1
[19]Chemical and Pharmaceutical Bulletin,2019,vol. 67,p. 351 - 360
[20]Patent: US2019/55226,2019,A1 .Location in patent: Paragraph 0405

3
[ 105-36-2 ]
[ 52085-14-0 ]
[ 412300-65-3 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate; In acetone; at 20℃; for 48h;	A solution of 4-benzyloxy-2-hydroxybenzaldehyde (7.90 g, 25.1 mmol) in acetone is treated with ethyl bromoacetate (5.79 g, 34.7 mmol) and potassium carbonate (7.98 g, 57.8 mmol). The mixture is stirred for 48 h at RT and filtered and concentrated, purified on column with 20% EtOAc/Hex to afford the intermediate ether (7.90 g, 87%). The intermediate is dissolved in DMF (40 mL) and treated with DBU (3.83 g, 25.1 mmol). The mixture is stirred at 140 C for 2 h, cooled down, poured into water (500 mL) and extracted with EtOAc (2 x 100 mL). The organic layer is dried over Na2SO4, concentrated, purified on column chromatography (10-15% EtOAc/Hex) to afford the title compound (5.80 g, 78%). H-NMR (ppm, CDC13) USD : 7.53 (1 H, d, J=8. 8 Hz), 7.46 (1 H, s), 7.46 (1 H, s), 7. 44-7. 32 (4 H, m), 7.12 (1 H, d, J=2. 2 Hz), 7.02 (1 H, dd, J=2. 2,8. 4 Hz), 5.12 (2 H, s), 4.43 (2 H, q, J=7. 0 Hz), 1.42 (3 H, t, J=7. 0 Hz).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 6758 - 6763
[2]Patent: WO2005/51938,2005,A1 .Location in patent: Page/Page column 131-132
[3]Journal of the Chemical Society,1948,p. 2254,2258

4
[ 685-87-0 ]
[ 52085-14-0 ]
[ 122443-91-8 ]

Yield	Reaction Conditions	Operation in experiment
70.3%	With potassium carbonate; In acetone; at 20℃;	To a solution of <strong>[52085-14-0]4-(benzyloxy)-2-hydroxybenzaldehyde</strong> (1.0 g, 4.38 mmol) in acetone (15 mL) was added K2CO3 (1.817 g, 13.14 mmol) and followed by addition of diethyl2-bromomalonate (1.047 g, 4.38 mmol). The mixture was stirred at RT for 10 hours.The mixture was filtered. The filtrate was concentrated under reduced pressure.The crude material was purified by silica gel column chromatography and eluted with 50% ethyl acetate/hexane to give the title compound 3 (1.4 g, 3.08 mmol, 70.3 % yield) as a yellow solid.LCMS(ESI-MS): m/z: 309 [M + Na]+; Rt = 2.04 min. (Method A)

Reference： [1]Patent: WO2018/83171,2018,A1 .Location in patent: Page/Page column 49
[2]Bulletin of the Chemical Society of Japan,1957,vol. 30,p. 3,6

5
[ 78-95-5 ]
[ 52085-14-0 ]
[ 412300-33-5 ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium carbonate; In acetone; for 1h;Reflux;	Example 40A 1-[6-(Benzyloxy)-1-benzofur-2-yl]ethanone To a solution of 97.0 g (0.43 mol) of 4-benzyloxy-2-hydroxybenzaldehyde and 117.5 g (0.85 mol) of potassium carbonate in 200 ml of acetone were added dropwise at RT 42.6 ml (0.53 mol) of chloroacetone. The reaction mixture was stirred under reflux for 1 h. After cooling to RT, solid constituents were filtered off and the filtrate was concentrated. The residue was taken up in dichloromethane and purified by column chromatography (4.5 kg of silica gel, mobile phase: petroleum ether/ethyl acetate 9:1, 130 litres). 87.0 g (77% of theory, purity 100%) of the title compound were obtained. 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=7.85 (s, 1H), 7.72 (d, 1H), 7.51-7.31 (m, 6H), 7.07 (dd, 1H), 5.20 (s, 2H), ca. 2.54 (s, 3H, hidden). LC/MS (Method 1, ESIpos): Rt=1.16 min, m/z=267 [M+H]+.

Reference： [1]Patent: US2017/121315,2017,A1 .Location in patent: Paragraph 0474-0477
[2]Journal of the Chemical Society,1949,p. 2058
[3]Journal of Medicinal Chemistry,2019,vol. 62,p. 7400 - 7416

7
[ 13621-50-6 ]
[ 52085-14-0 ]
[ 154076-58-1 ]

Reference： [1]Heterocycles,1993,vol. 36,p. 1979 - 1988

8
[ 74-88-4 ]
[ 52085-14-0 ]
[ 58026-14-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In acetonitrile; at 0 - 20℃; for 16h;	Intermediate 99: 4-(Benzyloxy)-2-methoxybenzaldehydeTo a 100 mL RB flask fitted with magnetic stirrer was charged with 10 mL of acetonitrile. To the stirred solvent were added 4-(benzyloxy)-2-hydroxybenzaldehyde (1.0 g, 4.38 mmol), potassium carbonate (1.21 g, 8.76 mmol). The reaction mixture was brought to 0 C, was added methyl iodide (1.135 g, 8.76 mmol) in acetonitrile (5 mL) drop wise and stirred at room temperature for 16 h. The reaction mixture was concentrated to distill off the solvent. The residue was extracted with ethyl acetate (50 mL). The organic layer was washed with water (40 mL) and saturated brine solution (40 mL). The organic layer was dried over anhydrous Na2S04 and the solvent was removed under reduced pressure. The product obtained as a white solid (1.06 g, yield: 100.0%).

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1999,p. 3029 - 3038
[2]Patent: WO2012/11125,2012,A1 .Location in patent: Page/Page column 145-146
[3]Journal of the American Chemical Society,2006,vol. 128,p. 5887 - 5894

9
[ 107-30-2 ]
[ 52085-14-0 ]
[ 474295-91-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 5252 - 5254
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 5797 - 5812
[3]Patent: WO2013/119985,2013,A1 .Location in patent: Paragraph 00122; 00123
[4]Organic letters,2002,vol. 4,p. 3359 - 3362
[5]Patent: EP1362844,2003,A1 .Location in patent: Page/Page column 131-135

10
[ 137848-29-4 ]
[ 52085-14-0 ]
2'-[1-(4-Benzyloxy-2-hydroxy-phenyl)-meth-(E)-ylidene]-amino}-[1,1']binaphthalenyl-2-ol [ No CAS ]

Reference： [1]Chemistry - A European Journal,2003,vol. 9,p. 5989 - 5996

11
[ 62779-70-8 ]
[ 52085-14-0 ]
[ 860464-76-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	In ethanol at 45℃; for 24h;

Reference： [1]Dey, Sangeeta; Karukurichi, Kannan R.; Shen, Weijun; Berkowitz, David B. [Journal of the American Chemical Society, 2005, vol. 127, # 24, p. 8610 - 8611]

12
[ 5437-45-6 ]
[ 52085-14-0 ]
[ 910225-67-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	4-Benzyloxy-2-hydroxybenzaldehyde (1 g, 4.39 mmol) was dissolved in distilled dimethylformamide (DMF, 8 mL), the solution was added with benzyl bromoacetate (1.1 g, 4.82 mmol) and cesium carbonate (1.57 g, 4.83 mmol), and the mixture was stirred overnight at room temperature under an argon atmosphere. The reaction solution was added with water (150 mL), and the mixture was extracted three times with ethyl acetate (100 mL). The extracted organic layer was washed five times with water (50 mL) and once with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained solid was purified by column chromatography (carrier: silica gel 60 N, solvent: dichloromethane), and recrystallized from hexane to obtain the objective compound, Compound 1, as white solid at a yield of 93%.1H NMR (300 MHz, CDCl3): delta 4.73 (s, 2H), 5.03 (s, 2H), 5.23 (s, 2H), 6.35 (d, J=2.0 Hz, 1H), 6.66 (dd, J=2.0, 8.8 Hz, 1H), 7.33-7.40 (m, 10H), 7.94 (d, J=8.8 Hz, 1H), 10.38 (s, 1H). 13C NMR (75 MHz, CDCl3): delta 65.4, 67.1, 70.3, 99.6, 107.6, 119.4, 127.5, 128.3, 128.4, 128.6, 128.7, 130.7, 134.8, 135.6, 161.6, 164.9, 167.8, 188.0. MS (ESI+): 399 [M+Na]+.Anal. Calcd for C23H20O5: N, 0; C, 73.39; H, 5.36. Found: N, 0; C, 73.18; H, 5.62. Mp: 84.4-85.7 C.

Reference： [1]Journal of the American Chemical Society,2006,vol. 128,p. 10640 - 10641
[2]Patent: US8178669,2012,B2 .Location in patent: Page/Page column 11-12

13
[ 105-36-2 ]
[ 52085-14-0 ]
[ 110060-70-3 ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 125℃; for 3h;	To a N,N-dimethylformamide (200 mL) solution of 4-benzyloxy-2-hydroxybenzaldehyde (18.6 g, 81.4 mmol) were added ethyl bromoacetate (9.94 mL, 89.6 mmol) and potassium carbonate (22.6 g, 163 mmol) at room temperature, which was stirred at 125C for 3 hours. To the reaction mixture was added water at room temperature followed by extraction with ethyl acetate. After washing the organic layer with water and sat. NaCl, the organic layer was dried over anhydrous magnesium sulfate and filtered followed by concentrating the filtrate under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate = 7:3) to obtain the title compound (18.4 g, 76%) as a white solid. 1H-NMR spectrum (DMSO-d6) delta (ppm): 1.33 (3H, t, J=7.1 Hz), 4.34 (2H, q, J=7.1 Hz), 5.19 (2H, s), 7.07 (1 H, dd, J=2.2 Hz, J=8.6 Hz), 7.35 (1 H, t, J=7.1 Hz), 7.37-7.43 (3H, m), 7.49 (2H, d, J=7.0 Hz), 7.67-7.69 (2H, m).

Reference： [1]Patent: EP1864980,2007,A1 .Location in patent: Page/Page column 35-36

14
[ 52085-14-0 ]
[ 13196-11-7 ]

Reference： [1]Helvetica Chimica Acta,1935,vol. 18,p. 816,826
[2]Journal of the Chemical Society,1948,p. 2254,2258

15
[ 52085-14-0 ]
[ 334022-87-6 ]

Reference： [1]Helvetica Chimica Acta,1935,vol. 18,p. 816,826
[2]Journal of the Chemical Society,1948,p. 2254,2258

16
[ 52085-14-0 ]
[ 23681-89-2 ]

Reference： [1]Journal of the Chemical Society,1948,p. 2254,2258

17
[ 52085-14-0 ]
[ 66-97-7 ]

Reference： [1]Journal of the Chemical Society,1948,p. 2254,2258

18
[ 52085-14-0 ]
[ 628332-28-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium hydroxide; hydrazine; In ethylene glycol; at 20 - 199℃;	Reference Example 329 To a solution of4- (benzyloxy)-2-hydroxybenzaldehyde (16.5 g) in ethylene glycol (90 ml) were added potassium hydroxide (12.2 g) and hydrazine monohydrate (10.6 ml) at room temperature and the mixture was stirred at120 C for 3 hours and at199 C overnight. The reaction solution was cooled to room temperature and 2N hydrochloric acid (110 ml) was added. The mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried(MgS04) and concentrated to give5- (benzyloxy)-2-methylphenol (14.8 g, yield 95%) as a brown oily substance. 1H-NMR(CDC13)5 : 2.17 (3H, s), 5.01 (2H, s), 6.43-6. 51 (2H, m), 6.99(1H, d, J=8.4 Hz), 7.27-7. 43 (5H, m).
30%	With hydrogenchloride; water; sodium cyanoborohydride; In tetrahydrofuran; at 20℃;	EXAMPLE 111; 4-Amino-3-(5-benzyloxy-2-methyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester; To a solution of 4-benzyloxy-2-hydroxybenzaldehyde (2.28 g, 10.0 mmol) (prepared by the method of Example 105 supra) and sodium cyanoborohydride (2.0 g, 15.9 mmol) in tetrahydrofuran (60 mL) was added methyl orange as an indicator, giving the solution a yellow color; 1N aqueous HCl solution (15 mL) was added slowly, keeping the solution orange. The mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate three times. The combined organic phase was washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 0-40% ethyl acetate in hexanes to 5-benzyloxy-2-methyl-phenol. (Yield 0.64 g, 30%).
	With hydrogenchloride; sodium cyanoborohydride; In tetrahydrofuran; at 20℃;	To a solution of 4-benzyloxy-2-hydroxybenzaldehyde (2.28 g, 10.0 mmol, prepared by the method of Example 18 below) and sodium cyanoborohydride (2.0 g, 15.9 mmol) in tetrahydrofuran (60 mL) was added methyl orange as an indicator, giving the solution a yellow color; 1N aqueous HCl solution (15 mL) was added slowly, keeping the solution orange. The mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate three times. The combined organic phase was washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 0-40% ethyl acetate in hexanes to give 5-benzyloxy-2-methyl-phenol. (Yield 0.64 g).

Reference： [1]Patent: WO2003/99793,2003,A1 .Location in patent: Page 279
[2]Patent: US2007/60607,2007,A1 .Location in patent: Page/Page column 53
[3]Patent: US2009/48274,2009,A1 .Location in patent: Page/Page column 11

19
[ 1663-39-4 ]
[ 52085-14-0 ]
tert-butyl 7-(benzyloxy)-2H-chromene-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 155℃; for 8h;	Step A: Preparation of tert-butyl 7- (BENZYLOXY)-2H-CHROMENE-3-CARBOXYLATE having following formular : To a stirred solution of 4-benzyloxy-2-hydroxy benzaldehyde (11.41g, 50MMOL) in NMP (30ML) was added K2CO3 (13. 0G, 100MMOL) and heated to 155 C under N2 atmosphere. t-Butyl acrylate (36.5 ML, 250MMOL) was divided into 4 portions (10, 10,10 & 6.5 ml). First 10ML was added to the reaction mixture and heated at 155C. The rest were added after 2 HR INTERVALS and the reaction mixture was heated for total of 8 hrs. The reaction mixture was cooled to room temperature and water (150ML) was added. The product was extracted with 150ML of ether. The ether layer was washed with water twice and dried. Ether layer was diluted with 50% hexanes and passed through a pad of silica (3 inch length and 4 inch diameter). The silica was washed with 50% ether/hexane mixture and the solvent was evaporated to give the product as pale yellow solid (13G, 77%). 1H NMR: (300MHZ, CDC13) : 6 7.43-7. 38 (m, 5H), 7.06 (d, 1H), 6.57 (d, 1H), 6.50 (s, 1H), 5.07 (s, 2H), 4.95 (s, 2H), 1.48 (s, 9H).

Reference： [1]Patent: WO2005/21540,2005,A1 .Location in patent: Page/Page column 13-14

20
[ 134419-59-3 ]
[ 52085-14-0 ]
[ 661481-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at 80℃; for 12h;	To a solution of tetrahydro-4H-pyran-4-ol (3.62 g) and triethylamine (5.6 mL) in tetrahydrofuran (35 mL) was added methanesulfonyl chloride (2.93 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration. To the filtrate were addedN,N-dimethylformamide (70 mL), 4-benzyloxy-2-hydroxybenzaldehyde (5.39 g) and cesium carbonate (23 g), and the mixture was stirred at 80C for 12 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 4/1 - 2/1) to give 4-benzyloxy-2-(tetrahydro-4H-pyran-4-yl-oxy)benzaldehyde (4.58 g). This material was dissolved in ethanol (70 mL). To the solution was added sodium borohydride (0.28 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added methanol, and the resulting mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with diethyl ether. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 3/1 - 1/1) to give the title compound (4.45 g).1H-NMR (CDCl3) delta ppm: 1.75-1.85 (2H, m), 1.95-2.05 (2H, m), 2.11 (1H, t, J=6.3Hz), 3.5-3.65 (2H, m), 3.9-4.0 (2H, m), 4.45-4.55 (1H, m), 4.63 (2H, d, J=6.3Hz), 5.05 (2H, s), 6.5-6.6 (2H, m), 7.19 (1H, d, J=7.7Hz), 7.3-7.45 (5H, m)

Reference： [1]Patent: EP1544208,2005,A1 .Location in patent: Page/Page column 76

21
[ 100-44-7 ]
[ 52085-14-0 ]

Yield	Reaction Conditions	Operation in experiment
78%		Step 1 4-Ben7ry1oxy-2-hydtauoxy-ben7:aldehvdeA solution of 2,4-dihydroxy-benzaldehyde (101 g, 0.731 mol) in acetonitrile (700 mL) is treated with KI (12.1 g, 73.1 mmol) and NaHCO3 (70.0 g, 0.834 mol). The mixture is stirred while heating to 60 UC. Benzyl chloride (120 g, 0.950 mol) is added and the mixture is refluxed at 82 0C for 16 hours and cooled to room temperature. The solvent is evaporated and the reaction is quenched with water (250 mL) and HCl (5.0 N, 30 mL). The mixture is extracted with EtOAc (300 mL x2), and the organic layers is dried over Na2SO^ filtered, and concentrated to an approximate volume of 200 mL. To 400 mL hexanes is added and the resulting solution is heated to 60 0C to dissolve. The solution is cooled to room temperature and crystallized for 16 hours The solid is filtered and dried to obtain the title compound (130 g, 78%). LC- ES/MS m/e 227.0 (M-I).

Reference： [1]Patent: WO2007/92751,2007,A2 .Location in patent: Page/Page column 33

22
[ 77-78-1 ]
[ 52085-14-0 ]
[ 58026-14-5 ]

Reference： [1]Tetrahedron Asymmetry,2008,vol. 19,p. 343 - 347

23
[ 52085-14-0 ]
[ 412339-25-4 ]

Yield	Reaction Conditions	Operation in experiment
76%		To an ice cooled suspension of <strong>[52085-14-0]4-benzyloxy-2-hydroxy-benzaldehyde</strong> (0.228 g, 1 mmol) in 10 mL of methanol was slowly added sodium borohydride (0.038 g, 1 mmol). After addition of sodium borohydride, a clear solution was obtained. The reaction was stirred at 0 C. for 20 minutes followed by stirring at RT for 10 minutes. The solvent was evaporated under vacuum. To this solid residue was carefully added 0.1 N H2SO4 until the pH dropped to 6.5 with vigorous stirring. Additional water (ca. 40 mL) was added with continuous stirring which then caused the product to precipitate. The solid was filtered and copiously washed with water to remove all traces of acid (last wash pH>7). The solid was immediately vacuum dried to obtain 0.175 g (76%) white solid: mp 88-90 C.; TLC, Rf0.29, in hexanes:EtOAc (2:1); 1H NMR (600 MHz, DMSO-d6) delta, 9.36 (s, 1H, Ph-OH), 7.43-7.32 (m, 5H, C6H5), 7.14-7.12 (d, 1H, J=8.4 Hz, Ar-H6), 6.44-6.41 (m, 2H, Ar-H5/Ar-H3), 5.01 (s, 2H, PhCH2), 4.8 (t, 1H, CH2OH), 4.39 (s, 2H, CH2OH); 13C NMR (100 MHz, DMSO-d6) delta 158.0, 155.2, 137.3, 128.5, 128.4, 128.3, 127.6, 127.5, 127.3, 121.2, 104.8, 101.8, 68.9, 57.9; analysis calcd. for C14H14O3. C 73.03, H 6.13 found: C 73.16, H 5.94.

Reference： [1]Tetrahedron Letters,2008,vol. 49,p. 2974 - 2978
[2]Organic Letters,2008,vol. 10,p. 5007 - 5010
[3]Patent: US2011/144195,2011,A1 .Location in patent: Page/Page column 2; 4; 11
[4]Organic process research and development,2011,vol. 15,p. 1149 - 1162
[5]Synlett,2011,p. 1605 - 1607
[6]Journal of Natural Products,2009,vol. 72,p. 2072 - 2075

24
[ 61832-41-5 ]
[ 52085-14-0 ]
[ 1173429-61-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With cholin hydroxide; In water; at 20℃; for 5h;Green chemistry;	General procedure: The ChOH 10 mol% in water (3 mL) was added to a mixture of 2-hydroxybenzaldehyde (1a, 1.0 mmol) and (E)-N-methyl-1-(methylthio)-2-nitroethenamine (2, 1.0 mmol) (1 mmol) in a 10mL reaction flask equipped with a magnetic stirrer. The resulting mixture was stirred for the appropriate time at room temperature. After completion of the reaction (confirmed by TLC, hexanes: EtOAc 1:1), the solid product was filtered and washed with water. The obtained crude product was recrystallized from ethanol to yield the pure product. The same method was adopted for the synthesis of all the targeted products 3a-x.

Reference： [1]Phosphorus, Sulfur and Silicon and the Related Elements,2018,vol. 193,p. 574 - 581
[2]Tetrahedron Letters,2009,vol. 50,p. 3836 - 3839

25
[ 1485-07-0 ]
[ 52085-14-0 ]
[ 1192491-32-9 ]

Yield	Reaction Conditions	Operation in experiment
73%	With triphenylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 20℃; for 12h; Inert atmosphere;

Reference： [1]Location in patent: experimental part Asada, Masaki; Obitsu, Tetsuo; Nagase, Toshihiko; Sugimoto, Isamu; Yamaura, Yoshiyuki; Sato, Kazutoyo; Narita, Masami; Ohuchida, Shuichi; Nakai, Hisao; Toda, Masaaki [Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 18, p. 6567 - 6582]

26
[ 52085-14-0 ]
4-(benzyloxy)-5-bromo-2-hydroxybenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With pyridinium hydrobromide perbromide; In methanol; at 0 - 20℃; for 12h;	To a mixture of A-2 (228 mg, 0.98 mmol, 1.00 equiv, 98%) in methanol (20 mL) was added pyridinium hydrobromide perbromide (90% purity, 345.2 mg, 0.98 mmol, 1.00 equiv) in several batches at 0 C. The reaction was stirred for 12 h at room temperature. Concentration and chromatograph on silica gel (10:1 PE/EA) gave 240 mg (78%) of B-2 as yellow solid.
	With pyridinium hydrobromide perbromide; In methanol; at 0 - 25℃;	Into a 250-mL round-bottom flask, was placed a solution of <strong>[52085-14-0]4-(benzyloxy)-2-hydroxybenzaldehyde</strong> (12.7 g, 55.64 mmol, 1.00 equiv) in MeOH (150 mL). This was followed by the addition of pyridine perbromide hydrobromide (18.6 g, 58.49 mmol, 1.05 equiv) in several batches at 0 C. The resulting solution was stirred overnight at 25 C., monitored by TLC (EA:PE=1:5), and the reaction terminated by addition of water (50 mL). The MeOH was removed under vacuum. The resulting solution was diluted with water (200 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers were combined. The resulting mixture was washed with 1N HCl (1×100 mL) and water (1×100 mL). The resulting mixture was washed with brine (1×100 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was washed by 2×50 ml PE:EA=1:20 to yield 4-(benzyloxy)-5-bromo-2-hydroxybenzaldehyde as a yellow solid.

Reference： [1]Patent: US2014/256657,2014,A1 .Location in patent: Paragraph 0306
[2]Patent: US2019/55226,2019,A1 .Location in patent: Paragraph 406

27
[ 57294-38-9 ]
[ 52085-14-0 ]
[ 1234064-51-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With diisopropyl-carbodiimide;dmap; In dichloromethane; at 20℃; for 9h;	To Boc GABA-OH (0.85 g, 4.2 mmol, 1.2 equiv.) in dichloromethane (35 mL, 0.1 M) were added N,N '-diisopropylcarbodiimide (DIC, 0.70 niL. 4.6 mmol, 1.3 equiv.), 4-(dimethylamino)pyridine (DMAP, 0.1 1 g, 0.90 mmol, 0.25 equiv.), and compound 3 (0.80 g, 3.5 mmol, 1.0 equiv.) successively. The reaction mixture was stirred at RT for 9 h, after which time the reaction mixture was washed with ¾0 and brine, dried over M0SO4, filtered, and concentrated. The crude product was purified by flash chromatography (silica, EtOAcihexanes - 1:5 - » 1:3) to give compound 4 as a white solid (90%). NMR (CDCI3, 400 MHz): delta 9.91 ( 1H, s), 7.79 (1H, d, ./ = 8.7 Hz), 7.54 - 7.30 (5H, m), 6.96 ( 1H, dd, J = 8.6, 2.4 Hz), 6.79 (1H, d. J = 2.3 Hz), 5.13 (2H, s), 4.79 (1H, s), 3.36 - 3.15 (2H, m), 2.71 (2H, t, J = 7.2 Hz), 2.02 - 1.89 (2H, m), 1.45 (9H, s). I 3C NMR (CDCI3, 100 MHz): delta 187.8, 171.5, 164.4, 156.2, 153.1, 135.6, 133.8, 122.0, 113.0, 109.9, 79.4, 70.7, 39.7, 31.2, 28.5, 25.1.
90%	With dmap; diisopropyl-carbodiimide; In dichloromethane; at 20℃; for 9h;	To Boc-GABA-OH (0.85 g, 4.2 mmol, 1.2 equiv.) in dichloromethane (35 mE, 0.1 M) were added N,N?-diisopropylcarbodiimide(DIC, 0.70 mE, 4.6mmol, 1.3 equiv.), 4-(dimethy- lamino)pyridine (DMAP, 0.11 g, 0.90 mmol, 0.25 equiv.), and compound 3 (0.80 g, 3.5 mmol, 1.0 equiv.) successively. The reaction mixture was stirred at RT for 9 h, afier which time the reaction mixture was washed with H20 and brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (silica, EtOAc:hexanes=1:5- 1:3) to give compound 4 as a white solid (90%). ?H NMR(CDC13, 400 MHz): oe 9.91 (1H, s), 7.79 (1H, d, J=8.7 Hz),7.54-7.30 (5H, m), 6.96 (1H, dd, J=8.6, 2.4 Hz), 6.79 (1H, d, J=2.3 Hz), 5.13 (2H, s), 4.79 (1H, s), 3.36-3.15 (2H, m), 2.71 (2H, t, J=7.2 Hz), 2.02-1.89 (2H, m), 1.45 (9H, s). ?3CNMR(CDC13, 100 MHz): oe 187.8, 171.5, 164.4, 156.2, 153.1,135.6, 133.8, 122.0,113.0,109.9,79.4,70.7,39.7,31.2,28.5,

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 8828 - 8830
[2]Patent: WO2011/94560,2011,A1 .Location in patent: Page/Page column 54; 55
[3]Patent: US9075014,2015,B2 .Location in patent: Page/Page column 39

28
[ 2632-13-5 ]
[ 52085-14-0 ]
2-(5-benzyloxy-2-vinylphenoxy)-1-(4-methoxyphenyl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%		Ex. 1 Synthesis of 4-benzyloxy-2-[2-(4-methoxyphenyl)allyloxy]-1-vinylbenzene (compound 2)A. Synthesis of 2-(5-benzyloxy-2-vinylphenoxy)-1-(4-methoxyphenyl)ethanone (compound 2a)A suspension of methyl triphenyl phosphonium bromide (MTPPB, 16.90 g, 47.31 mmol) in anhydrous THF (50 mL) was cooled in an ice bath and added with potassium tert-butoxide (t-BuOK, 5.31 g, 47.32 mmol) in portions under nitrogen. After stirring at 0 C. for 15 min, a mixture of 4-benzyloxy-2-hydroxybenzaldehyde (1)(9.0 g, 39.43 mmol), t-BuOK (4.87 g, 43.40 mmol) and THF (50 mL) was added, and the resultant mixture was stirred at 0 C. for 2 hrs. Thereafter, the mixture was heated under reflux, and a solution of 2-bromo-4'-methoxyacetophenone (10.85 g, 47.36 mmol) in THF (30 mL) was added dropwise. After stirring under reflux for 1 hr (TLC monitoring), the mixture was quenched with a saturated NH4Cl solution. After removal of most of the THF in vacuo, the resultant residue was extracted six times with EtOAc (50 mL). The organic layers were combined, washed with a saturated NaCl solution, and dried with anhydrous MgSO4. After filtration, the filtrate was concentrated in vacua, followed by purification via silica gel column chromatography (ethyl acetate/n-hexane=1:15), thus giving the title compound 2a as a colorless crystal (11.81 g, 80% yield).Defected Properties of the Title Compound:M.p.: 93-94 C., Rf: 0.21 (ethyl acetate/n-hexane=1:9); IR (neat) vmax: 3063, 2930, 1691, 1601, 1574, 1501, 1453, 1419, 1311, 1261, 1236, 1169, 1122, 1026, 832 cm-1; 1H-NMR (200 MHz, CDCl3); delta 3.87 (s. 3H, OCH3), 5.02 (s, 2H, OCH2Ph), 5.17 (dd, J=11.2, 1.4 Hz, 1H, ArCHCHaHb), 5.17 (s, 2H, OCH2CO), 5.68 (dd, J=17.8, 1.4 Hz, 1H, ArCHCHaHb), 6.45 (d, J=2.6 Hz, 1H, ArH), 6.58 (dd, J=8.4, 2.6 Hz, 1H, ArH), 6.95 (d, J=9.0 Hz, 2H, ArH), 7.03 (dd, J=17.8, 11.2, 1H, ArCHCH2), 7.33-7.43 (m, 6H, ArH), 7.97 (d, J=9.0, 2H, ArH); 13C-NMR (50 MHz, CDCl3): delta 55.5, 70.2, 71.3, 100.7, 107.0, 112.8, 114.0, 120.6, 127.5, 127.7, 128.0, 128.6, 130.5, 131.0, 136.7, 156.3, 159.5, 164.0, 192.6; EIMS (70 eV) m/z (relative intensity, %): 374 (M+, 40), 345 (11), 225 (27), 224 (17), 150 (20), 135 (99), 121 (17), 92 (11), 91 (100), 77 (14), 65 (14). Anal. calcd for C24H22O4: C, 76.99; H, 5.92; found: C, 76.96; H, 5.90.

Reference： [1]Patent: US2010/298582,2010,A1 .Location in patent: Page/Page column 3

29
[ 52085-14-0 ]
[ 56701-24-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: sodium tetrahydroborate / ethanol / 11 h / 0 - 20 °C 2: potassium carbonate / acetone / Inert atmosphere; Reflux 3: acetonitrile / Inert atmosphere 4: potassium <i>tert</i>-butylate / methanol / Inert atmosphere; Reflux 5: palladium 10% on activated carbon; hydrogen / ethyl acetate / 1800.18 Torr

Reference： [1]Luniwal, Amarjit; Erhardt, Paul W. [Synlett, 2011, # 11, p. 1605 - 1607]

30
[ 358-23-6 ]
[ 52085-14-0 ]
[ 1049093-75-5 ]

Yield	Reaction Conditions	Operation in experiment
75.4%	With pyridine; dmap; In dichloromethane; at 25℃; for 2h;	A solution of <strong>[52085-14-0]4-(benzyloxy)-2-hydroxybenzaldehyde</strong> (42.0 g, 184.0 mmol, 1.0 eq.), pyridine (36.4 g, 460.0 mmol, 2.5 eq.) and DMAP (449.6 mg, 3.7 mmol, 0.02 eq.) in DCM (1.0 L) was added Tf20 (77.9 g, 276.0 mmol, 1.5 eq.). The mixture was stirred at 25C for 2 hours. TLC indicated <strong>[52085-14-0]4-(benzyloxy)-2-hydroxybenzaldehyde</strong> was consumed completely. The reaction mixture was quenched by addition H20 500 mL at 25C, and then the organic layer were washed with 0.5 M HC1 (aq, 500 mL) and brine 500 mL, dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=50/l to 10: 1). 5-(benzyloxy)- 2-formylphenyl trifluoromethanesulfonate (50.0 g, 138.8 mmol, 75.4% yield) was obtained as a colorless oil.
48%	With triethylamine; In dichloromethane; at 0℃;	A solution of phenol 2 (11.2 g, mmol) in anhydrous DCM (245mL) was stirred at 0 C and triethylamine (10.2 mL, 73.5mmol) was added followed by triflic anhydride (13.8 mL, 63.5 mmol) over 5 minutes. Upon completion the reaction was quenched by addition of water (50 mL), washed with saturated aqueous NaCl solution, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, 4:1, Hex:EtOAc) to afford triflate 3 as a yellow oil (8.4g, 23.6 mmol, 48%).

Reference： [1]Patent: WO2017/151489,2017,A1 .Location in patent: Paragraph 0350
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 5797 - 5812
[3]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3633 - 3637
[4]Patent: WO2015/200514,2015,A2 .Location in patent: Page/Page column 69
[5]Patent: WO2013/119985,2013,A1 .Location in patent: Paragraph 00226; 00337; 00338

31
[ 37595-74-7 ]
[ 52085-14-0 ]
[ 1049093-75-5 ]

Yield	Reaction Conditions	Operation in experiment
93%	With dmap; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere;	To a solution of <strong>[52085-14-0]4-(benzyloxy)-2-hydroxybenzaldehyde</strong> (1 g, 4.38 mmol) in anhydrous A/,A/-dimethylformamide (20 mL) at 0C under nitrogen atmosphere were added N- phenyl-bis(trifluoromethanesulfonimide) (2.35 g, 8.76 mmol), 4- (dimethylamino)pyridine (53 mg, 0.44 mmol) and triethylamine (1 .25 mL, 8.76 mmol). The mixture was stirred at room temperature overnight and poured in water (100 mL). The aqueous layer was extracted with dichloromethane (2x30 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 40/60) to provide 5-(benzyloxy)-2-formylphenyl trifluoromethane sulfonate (23a) (1 .47 g, 4.08 mmol, 93%) as a colorless oil.1 H NMR (400 MHz, CDCI3) £5.16 (s, 2H), 6.95 (d, J = 1 .0 Hz, 1 H), 7.09 (dd, J = 1 .0 Hz, J= 8.0 Hz, 1 H), 7.33-7.43 (m, 5H), 7.95 (d, J = 8.0 Hz, 1 H), 10.13 (s, 1 H).

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 123

32
[ 124-63-0 ]
[ 52085-14-0 ]
[ 1447351-35-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dichloromethane; at 20℃;Inert atmosphere;	4-Benzyloxy-2-hydroxy-benzaldehyde 1 (5.61g, 1.0equiv) was dissolved in dry DCM (250ml) followed by addition of triethylamine (1.2equiv) and methanesulfonylchloride (1.6equiv). The reaction was stirred at rt until starting material was consumed (TLC monitoring) and then quenched with a 1.0M hydrochloric acid aqueous solution (100ml) and extracted with ethyl acetate (3×25ml). The combined organic layers were washed with brine (2×15ml), dried over Na2SO4, filtered and the solvent was eliminated under vacuo to give the title compound 2 as a white solid that was used as it is.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 4502 - 4510

33
N-(6-((diethylamino)methyl)benzo[d]thiazol-2-yl)hydrazinecarboxamide [ No CAS ]
[ 52085-14-0 ]
(E)-[2-hydroxy-4-benzyloxybenzaldehyde]-N⁴-[6-(diethylamino)methylbenzo[d]thiazol-2-yl]semicarbazone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With acetic acid; In ethanol; at 78℃; for 6h;	General procedure: A mixture of the compounds 9a-e (0.001 mol), appropriate 2-hydroxy aromatic aldehydes (0.0011 mol) and a drop of glacial acetic acid in 10 mL ethanol was heated at reflux for 6 h and cooled to room temperature, separated by filtration, and the cake was washed with diethyl ether to get a white to light yellow solid. The crude product was purified by chromatography on silica gel using MeOH/CH2Cl2 to afford the compounds 14a-h, 15a-x, 16a-d.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 86,p. 257 - 269

34
[ 1100-88-5 ]
[ 52085-14-0 ]
[ 1359977-04-0 ]

Yield	Reaction Conditions	Operation in experiment
79%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile;Reflux;	To asolution of compound 1 (1.70 g, 7.45 mmol) and benzyl(triphenyl)phosphonium chloride (2.89 g, 7.45 mmol) inCH3CN (30 mL), 1,8-Diazabicyclo[5.4.0]undec-7-ene(1.17 mL, 7.7 mmol) was added dropwise. The mixture wasrefluxed overnight and was then concentrated. The residuewas dissolved in CH2Cl2, washed with water and acidifiedwith 1M HCl to pH 7.0. The organic layer was dried overanhydrous Na2SO4, concentrated and purified by chromatographer(elution: 10/1 petroleum ether/ethyl acetate) togive compound 2a (1.78 g, 79 %) as a white solid. 1H NMR(DMSO-d6, 300 MHz): delta = 5.07(s, 2H, OCH2Ph), 6.51-6.53 (m, 2H, ArH), 7.04-7.09 (d, 1H, J = 15 Hz, CH=CH), 7.181-7.245 (q, 1H, J = 7.5 Hz, J = 4.5 Hz, ArH), 7.299-7.51 (m, 11H, ArH), 9.829 (s, 1H, OH).
79%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile;Reflux;	In the atmosphere of nitrogen,A solution of 4- (benzyloxy) -2-hydroxybenzaldehyde (1.70 g, 7.45 mmol)And triphenylbenzylphosphonium chloride (2.89 g, 7.45 mmol) were dissolved in 12 mL of acetonitrile,DBU (1.17 g, 7.70 mmol) was added dropwise and heated under reflux overnight.After completion of the reaction, the solvent was dried and the residue was dissolved in methylene chloride. The residue was washed with water, 1N HCl solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether Ethyl ester = 5: 1) to give (E)-5-(benzyloxy)-2- (styryl) phenol1.78 g (white solid, yield 79%).

Reference： [1]Medicinal Chemistry Research,2016,vol. 25,p. 2485 - 2497
[2]Patent: CN104478836,2017,B .Location in patent: Paragraph 0069-0070

35
[ 18162-48-6 ]
[ 52085-14-0 ]
4-benzyloxy-2-(tert-butyldimethylsilyloxy)benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 3h;	Step (a). 4-Benzyloxy-2-(tert-butyldimethylsilyloxy)-benzaldehyde 4-Benzyloxy-2-hydroxybenzaldehyde (11.40 g, 50 mmol), imidazole (3.74 g, 55 mmol), and TBSCl (8.39 g, 54 mmol) were mixed in DMF (100 ml) and stirred at room temperature for 3 hours. MeOH was then added and the mixture was stirred for another 30 minutes. Water was poured in and the resultant mixture was extracted with ether. The organic layers were combined and washed with H2O and brine, dried over MgSO4, and purified by flash chromatography to give compound 1 in quantitative yield as a colorless oil. 1H NMR (400 MHz, CDCl3): delta 10.28 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.40-7.33 (m, 5H), 6.68 (dd, J=8.8 Hz, 2.4 Hz, 1H), 6.37 (d, J=2.4 Hz, 1H), 5.10 (s, 2H), 0.99 (s, 9H), 0.22 (s, 6H); 13C NMR (100 MHz, CDCl3) delta 188.5, 164.7, 160.6, 135.9, 130.0, 128.7, 128.2, 127.2, 121.4, 108.8, 105.9, 70.2, 60.3, 25.6, 18.2, -4.4; ESI MS m/z calcd for C21H29O3Si 357.1886 [M+CH3+H]+, found 357.1886.

Reference： [1]Journal of Natural Products,2017,vol. 80,p. 3284 - 3288
[2]Patent: US2018/86772,2018,A1 .Location in patent: Page/Page column 6

36
[ 52085-14-0 ]
[ 874668-62-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine hydro-chloride; In ethanol; for 3.0h;Reflux;	General procedure: To a solution of 2-hydroxy-3-methylbenzaldehyde (5 g, 36.7 mmol) inEtOH (30 mL) was added hydrazine hydrochloride (in excess) in a 250 mL flask. The solution was refluxed for 3 h and the solvent was distilled under reduced pressure. Purification of the residue by column chromatography (EtOAc:PE=10:1) on silica gel was performed to give 3.5 g of 7-methyl-1H-indazole, yellow crystals (73% yield).

Reference： [1]Heterocycles,2018,vol. 96,p. 74 - 85

Same Skeleton Products

Related Products

Historical Records

Pharmaceutical Intermediates of
[ 52085-14-0 ]

Phenoxodiol Intermediates

[ 486-66-8 ]

7-Hydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one

Related Functional Groups of
[ 52085-14-0 ]

Aryls

[ 5896-17-3 ]

2-(Benzyloxy)benzaldehyde

Similarity: 0.98

[ 22924-16-9 ]

2,4-Diethoxybenzaldehyde

Similarity: 0.98

[ 613-69-4 ]

2-Ethoxybenzaldehyde

Similarity: 0.95

[ 613-45-6 ]

2,4-Dimethoxybenzaldehyde

Similarity: 0.93

[ 4397-53-9 ]

4-(Benzyloxy)benzaldehyde

Similarity: 0.93

Aldehydes

[ 5896-17-3 ]

2-(Benzyloxy)benzaldehyde

Similarity: 0.98

[ 22924-16-9 ]

2,4-Diethoxybenzaldehyde

Similarity: 0.98

[ 613-69-4 ]

2-Ethoxybenzaldehyde

Similarity: 0.95

[ 613-45-6 ]

2,4-Dimethoxybenzaldehyde

Similarity: 0.93

[ 4397-53-9 ]

4-(Benzyloxy)benzaldehyde

Similarity: 0.93

Ethers

[ 5896-17-3 ]

2-(Benzyloxy)benzaldehyde

Similarity: 0.98

[ 22924-16-9 ]

2,4-Diethoxybenzaldehyde

Similarity: 0.98

[ 613-69-4 ]

2-Ethoxybenzaldehyde

Similarity: 0.95

[ 613-45-6 ]

2,4-Dimethoxybenzaldehyde

Similarity: 0.93

[ 4397-53-9 ]

4-(Benzyloxy)benzaldehyde

Similarity: 0.93

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 52085-14-0 ] {[proInfo.proName]}

Quality Control of [ 52085-14-0 ]

Related Doc. of [ 52085-14-0 ]

Product Details of [ 52085-14-0 ]

Calculated chemistry of [ 52085-14-0 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 52085-14-0 ]

Application In Synthesis of [ 52085-14-0 ]

[ 52085-14-0 ] Synthesis Path-Upstream 1~17

[ 52085-14-0 ] Synthesis Path-Downstream 1~36

Pharmaceutical Intermediates of [ 52085-14-0 ]

Phenoxodiol Intermediates

Related Functional Groups of [ 52085-14-0 ]

Aryls

Aldehydes

Ethers

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Pharmaceutical Intermediates of
[ 52085-14-0 ]

Related Functional Groups of
[ 52085-14-0 ]