[ CAS No. 1486-53-9 ] {[proInfo.proName]}

Name: 1486-53-9|4-Benzyloxy-3-methoxybenzoicacid|98%
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Quality Control of [ 1486-53-9 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 1486-53-9 ]

CAS No. :	1486-53-9	MDL No. :	MFCD00183281
Formula :	C₁₅H₁₄O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JGMBQAGNZLBZCE-UHFFFAOYSA-N
M.W :	258.27	Pubchem ID :	226335
Synonyms :

Calculated chemistry of [ 1486-53-9 ]

Physicochemical Properties

Num. heavy atoms :	19
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.13
Num. rotatable bonds :	5
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	70.87
TPSA :	55.76 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) :	-5.67 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.33
Log Po/w (XLOGP3) :	3.1
Log Po/w (WLOGP) :	2.82
Log Po/w (MLOGP) :	2.47
Log Po/w (SILICOS-IT) :	2.82
Consensus Log Po/w :	2.71

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.53
Solubility :	0.0759 mg/ml ; 0.000294 mol/l
Class :	Soluble
Log S (Ali) :	-3.94
Solubility :	0.0297 mg/ml ; 0.000115 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.57
Solubility :	0.00703 mg/ml ; 0.0000272 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.12

Safety of [ 1486-53-9 ]

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 [ 1486-53-9 ]

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

Upstream synthesis route of [ 1486-53-9 ]
Downstream synthetic route of [ 1486-53-9 ]

[ 1486-53-9 ] Synthesis Path-Upstream 1~8

1
[ 1486-53-9 ]
[ 60547-92-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With nitric acid; acetic acid In dichloromethane for 6 h;	4-(Benzyloxy)-3-methoxybenzoic acid (63.5 g, 246.0 mmol) in the mixture of CH2CI2 (400 ml) and I lOAc (100 ml) was added HNO₃ (fuming, 25.0 ml, 528.5 mmol). The mixture was stirred for 6 h, concentrated, crystallized with EtOH, dried over the oven at 40 °C with vacuum to afford the title compound (63.3 g, 85percent yield). ESI MS m/z+ 326.1 (M + Na).
85%	With nitric acid; acetic acid In dichloromethane for 6 h;	Example 9. 4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid 4-(Benzyloxy)-3-methoxybenzoic acid (63.5 g, 246.0 mmol) in the mixture of CH2C12(400 ml) and FIOAc (100 ml) was added HNO3 (fuming, 25.0 ml, 528.5 mmoi). The mixture was stirred for 6 h, concentrated, crystallized with EtOH, dried over the oven at 40 °Cwith vacuum to afford the title compound (63.3 g, 85percent yield). ESI MS mlz+ 326.1 (M +Na).
85%	With nitric acid; acetic acid In dichloromethane for 6 h;	To a solution of compound 238 (63.5 g, 246.0 mmol) in CH₂Cl₂ (400 ml) and HOAc (100 ml) was added HNO₃ (fuming, 25.0 ml, 528.5 mmol). The mixture was stirred for 6 h, concentrated, crystallized with EtOH, dried at 40 °C under vacuum to afford the title compound (63.3 g, 85percent yield). ESI MS m/z 326.1 ([M+Na]⁺).

59%

With nitric acid In dichloromethane; acetic acid at 0 - 20℃; for 3 h;

Compound 33a (20 g, 77 mmol) was added as a thick suspension in anhydrous dichloromethane (100 mL) and was cooled to 0° C. Acetic acid (191 mL) was added, resulting in a clear solution which stirred at 0° C. until cool. Nitric acid (26 mL, 581 mmol) was added slowly dropwise through an addition funnel. The ice bath was removed and the solution continued to stir at room temperature. After 3 hours, the reaction was diluted with deionized water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the filtrate concentrated in vacuo. The crude residue was recrystallized using ethyl acetate and hexanes. The solid was filtered and washed with hexanes to give compound 33b as a yellow fluffy solid (13.8 g, y=59percent). ¹H NMR (400 Hz, CDCl₃): δ 7.48-7.43 (m, 6H), 7.25 (s, 1H), 5.25 (s, 2H), 4.02 (s, 3H), MS (m/z): 326.1 (M+Na)⁺. See FIG. 45.

Reference： [1] Patent: WO2015/28850, 2015, A1, . Location in patent: Page/Page column 84
[2] Patent: WO2015/155753, 2015, A2, . Location in patent: Page/Page column 87
[3] Patent: WO2016/59622, 2016, A2, . Location in patent: Page/Page column 126
[4] Patent: WO2018/86139, 2018, A1, . Location in patent: Page/Page column 182; 183
[5] Synthesis, 1990, # 1, p. 81 - 84
[6] Patent: US9169272, 2015, B2, . Location in patent: Page/Page column 247
[7] Heterocycles, 1984, vol. 22, # 2, p. 253 - 256
[8] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 15, p. 1933 - 1935
[9] Patent: US6562806, 2003, B1,

2
[ 1486-53-9 ]
[ 61032-42-6 ]

Reference： [1] Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837
[2] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
[3] Patent: CN105884699, 2016, A,

3
[ 1486-53-9 ]
[ 74-88-4 ]
[ 56441-97-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate In acetone for 16 h; Heating / reflux	Preparation of 4-benzyloxy-3-methoxy-methylbenzoate 2.84 g of 4-benzyloxy-3-methoxy-benzoic acid was combined with 3.04 g of potassium carbonate and 1.03 mL of iodomethane in 100 mL of acetone. The mixture was refluxed for 16 hours, cooled to room temperature and diluted with dichloromethane. The slurry was filtered and washed with dichloromethane and the filtrate concentrated to dryness. The solids were redissolved in dichloromethane, washed twice with water, dried over sodium sulfate and filtered. The filtrate was concentrated to a clear, colorless oil which was triturated with methanol to give a white solid in 90percent yield (2.7 grams). Proton

Reference： [1] Patent: US2007/208164, 2007, A1, . Location in patent: Page/Page column 14
[2] Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837

4
[ 1486-53-9 ]
[ 56441-97-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sulfuric acid In methanol for 10 h; Reflux	A catalytic amount of concentrated H₂SO₄ was added to a solution of compound 3 (5.4g, 20.9mmol) in 50mL of methanol and the mixture was refluxed for 10h. It was allowed to cool. The product crystallization from solution gave pure 4 (4.5g) as a white solid with a yield of 80percent. Mp: 70–72°C; ¹H NMR (CDCl₃, 300MHz): δ (ppm) 3.90 (s, 3H), 3.95 (s, 1H), 5.23 (s, 2H), 7.32–7.57 (m, 5H), 7.58 (s, 1H), 7.60–7.61 (d, J=2.0Hz, 1H), 7.63–7.64 (d, J=1.8Hz, 1H).

Reference： [1] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254

5
[ 67-56-1 ]
[ 1486-53-9 ]
[ 56441-97-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sulfuric acid In methanol for 10 h; Reflux	A solution of 3-methoxy-4-benzyloxybenzoic acid (20.9 mmol, 5.4 g) in 50 ml of methanol was added to a 250 ml reaction flask, and 1 ml of concentrated sulfuric acid was slowly added dropwise with stirring. The mixture was heated under reflux for 10 hours.Concentrated and crystallized from methanol, filtration, the filter cake washed with a small amount of methanol, and dried to give a white solid 4.5g, 3-methoxy-4-benzyloxy-benzoic acid methyl ester Yieldpercent 80,

Reference： [1] Patent: CN105884699, 2016, A, . Location in patent: Paragraph 0054; 0055

6
[ 1486-53-9 ]
[ 27883-60-9 ]

Reference： [1] Patent: CN105884699, 2016, A,

7
[ 1486-53-9 ]
[ 155666-33-4 ]

Reference： [1] Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837

8
[ 1486-53-9 ]
[ 162364-72-9 ]

Reference： [1] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
[2] Patent: CN105884699, 2016, A,

[ 1486-53-9 ] Synthesis Path-Downstream 1~88

1
[ 2426-87-1 ]
[ 1486-53-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium chlorite; sodium dihydrogenphosphate; dihydrogen peroxide In water; acetonitrile at 20℃; for 1.5h;
99%	With sodium chlorite; sodium dihydrogenphosphate dihydrate; dihydrogen peroxide In water; acetonitrile at 10 - 20℃; Inert atmosphere;	4-(Benzyloxy)-3-methoxybenzoic acid (16) To a stirred solution of aldehyde 15 (2.5 g, 10.33 mmol, 1.0 equiv), NaH2PO4·2H2O (0.483 g, 3.10 mmol, 0.3 equiv) and H2O2 (60 %, 0.31 mL, 10.84 mmol, 1.04 equiv) in MeCN/H2O (60 mL, 5:1, v/v) was added a solution of NaClO2 (1.64 g, 14.46 mmol, 1.4 eq) in H2O (15 mL) dropwise while keeping the temperature of the mixture below 10 °C with a water bath. The mixture was stirred at room temperature for 90 min, before solid Na2S2O3 (0.254 g, 1.6 mmol) was added followed by stirring of the mixture at room temperature for 5 min to decompose excess H2O2. The mixture was diluted with saturated NaCl solution (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated NaCl solution (2 × 20 mL) and with saturated NaHCO3 solution (3 × 20 mL). The organic layers were discarded. The combined aqueous layers were acidified with concentrated HCl until pH 4 followed by extraction with EtOAc (3 × 20 mL). These organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the crude acid (2.55 g, 99 %) as white solid, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): d = 3.94 (s,3H, OMe), 5.23 (s, 2H, CH2Ph), 6.92 (d, J = 8.6 Hz, 1H, 5-H), 7.28-7.34 (m, 1H, Ar), 7.35-7.40 (m, 2H, Ar),7.41-7.46 (m, 2H, Ar), 7.61(d, J =2.0 Hz, 2-H), 7.70 (dd, J = 2.0, 8.3Hz, 1H, 6-H); 13C NMR (100 MHz, CDCl3): d = 56.0 (OMe), 70.7 (CH2Ph),112.3 (C-5), 112.7 (C-2), 121.9 (C-6), 124.4 (Ar), 127.2 (Ar), 128.1 (Ar),128.7 (Ar), 136.2 (Ar), 149.1 (Ar), 152.8 (Ar), 172.0 (CO2H).
96%	With sodium chlorite; sulfur trioxide * ammonia In water at 20℃; for 12h;

89%	With potassium permanganate In water; acetone for 1h; Reflux;	4.1.3 3-methoxy-4-benzyloxybenzoic acid (3) The above benzaldehyde (6.05g, 25mmol) was dissolved in a mixture of acetone: H2O (75: 62.5mL) and to it KMnO4 (4.74g, 30mmol) was added and the mixture was stirred for 1hat reflux. The reaction mixture was filtered while hot. The filtrate was made alkaline (40% NaOH solution) to PH 10-11 and filtered. Then the filtrate was acidified with HCl until no further precipitate formed (PH 2-3). The resulting white precipitate was filtered, washed with water and dried to afford 5.7g of the product as a white solid with a yield of 89%. Mp: 173-175°C; 1H NMR (CDCl3, 300MHz): δ (ppm) 3.94 (s, 3H), 5.22 (s, 2H), 6.90-6.92 (d, J=8.4Hz, 1H), 7.31-7.44 (m, 5H), 7.60 (s, 1H), 7.65-7.68 (m, 1H).
89%	With potassium permanganate In water; acetone for 1h; Reflux;	11 Example 11 3-Methoxy-4-benzyloxybenzoic acid Methoxy-4-benzyloxybenzaldehyde (25 mmol, 6.05 g) was added to a 250-ml round-bottomed flask, and then a mixed solvent of acetone: water (V: V = 75: 62.5 ml) was added, Will KMnO4(30 mmol, 4.74 g) was slowly added to the reaction flask and heated under reflux for 1 hour.After the reaction was complete, the residue was filtered off and the filtrate was adjusted to pH = 10-11 with 40% sodium hydroxide solution. The solution was clarified and a small amount of insoluble residue was filtered off and the residue was filtered off. The filtrate was then adjusted to pH 6N HCl = 2-3, a lot of white solid was precipitated, with stirring, suction filtered, the filter cake was washed with water, and drying give 5.7 g of a white solid, 3-methoxy-4-benzyloxy benzoic acid yield% 89,
85%	With chromium(VI) oxide; acetic acid for 1h; Ambient temperature;
79%	Stage #1: 3-methoxy-4-(phenylmethoxy)benzaldehyde With potassium permanganate In acetone at 0 - 20℃; for 1 - 2h; Stage #2: With hydrogenchloride; ethanol; water In acetone	8.A Example 8A4-(benzyloxy)-3-methoxybenzoic acid; 8.83 g (36.4 mmol) 4-benzyloxy-3-methoxybenzaldehyde are dissolved in 150 ml acetone and cooled to 00C. 5.76 g (36.4 mmol) potassium permanganate are added at 00C in portions. The rapidly stirred mixture is allowed to warm slowly to rt. After 1 to 2 h the reaction is terminated by addition of ethanol (50 ml). After excess of potassium permanganate is destroyed the mixture is treated with IN hydrochloric acid and filtered over celite. The residual solid is washed with ethanol. All filtrates are combined and concentrated, the residual solution is poured onto water. The precipitate is collected by filtration and washed three times with water. Additional crops of product can be obtained: the filter cake is washed with dichloromethane / methanol mixtures or ethanol, concentration to remove the bulk of the solvent and precipitation by addition of water. In total 7.48 g (79% of th.) of the title compound can be obtained.LC-MS (method 5): R, = 2.09 min; m/z = 259 (M+H)+1H-NMR (400 MHz, DMSO-(I6): δ = 12.68 (bs, IH) 7.54 (dd, IH), 7.51-7.31 (m, 6H), 7.14 (d, IH), 5.18 (s, 2H), 3.81 (s, 3H).
	With potassium permanganate; acetone
	With sodium hydroxide; silver(l) oxide
	With silver(l) oxide
	With sodium chlorite; sodium dihydrogenphosphate; dihydrogen peroxide In water; acetonitrile at 0 - 10℃;
	With sodium hypochlorite; disodium hydrogenphosphate; dihydrogen peroxide In tetrahydrofuran; water	4.2 Prepared compound 3-methoxy-4-benzyloxybenzoic acid (11) 7.27g (30mmol) of 3-Methoxy-4-benzyloxybenzaldehyde (10) dissolved in 100mL of Anhydrous tetrahydrofen, then added the 40mL of distilled water and 2.16g (18mmol) of disodium hydrogen phosphate, under the ice condition added the drops of 8.96g (99mmol) sodium hypochlorite and 6.80mL (66mmol) of a 30% aqueous solution of hydrogen peroxide, after dripping at room temperature for 3 h; after completion of the reaction, tetrahydrofuran was recovered under reduced pressure, then extracted with 160 mL of ethyl acetate, washed with 2 mol / L NaOH solution to the organic phase without absorption. The combined aqueous phases were collected and acidified to pH 3~4 with concentrated hydrochloric acid to precipitate a white solid, after filtered and dried obtained white 7.05g of3-Methoxy-4-benzyloxybenzoic acid (11) , yield 91%.
	With potassium hydroxide; oxygen In 1,2-dimethoxyethane	3.ii (ii) Synthesis of 4-benzyloxy)-3-methoxybenzoicacid (3) A mixture of 1,2-dimethoxyethane and potassium hydroxide (5 to 20 eq.) is purged with oxygen and the calculated amount of isolated product 2 (1.0 eq.) is added. After the absorption of oxygen ceases, the mixture is diluted with distilled water and neutral organic products are extracted with an appropriate solvent. The aqueous layer is acidified and the acidic organic products are extracted with an appropriate solvent. Product 3 is isolated from the organic layer.
	With oxygen; potassium hydroxide In 1,2-dimethoxyethane	3.ii (ii) Synthesis of 4-(benzyloxy)-3-methoxybenzoic acid (3): A mixture of 1 ,2-dimethoxyethane and potassium hydroxide (5 to 20 eq.) is purged with oxygen and the calculated amount of isolated product 2 (1 .0 eq.) is added. After the absorption of oxygen ceases, the mixture is diluted with distilled water and neutral organic products are extracted with an appropriate solvent. The aqueous layer is acidified and the acidic organic products are extracted with an appropriate solvent. Product 3 is isolated from the organic layer.
	With potassium permanganate In water; acetone

Reference： [1]Correa, Arkaitz; Tellitu, Imanol; Dominguez, Esther; Moreno, Isabel; SanMartin, Raul [Journal of Organic Chemistry, 2005, vol. 70, # 6, p. 2256 - 2264]
[2]Mishra, Vivek Kumar; Ravikumar, Ponneri C.; Maier, Martin E. [Tetrahedron, 2016, vol. 72, # 41, p. 6499 - 6509]
[3]Rao, Maddali L.N.; Awasthi, Dheeraj K.; Banerjee, Debasis [Tetrahedron Letters, 2010, vol. 51, # 15, p. 1979 - 1981]
[4]Zhang, Hai-Qi; Gong, Fei-Hu; Ye, Ji-Qing; Zhang, Chi; Yue, Xiao-Hong; Li, Chuan-Gui; Xu, Yun-Gen; Sun, Li-Ping [European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254]
[5]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN105884699, 2016, A Location in patent: Paragraph 0052; 0053
[6]Kuo; Lin [Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 9, p. 1507 - 1512]
[7]Current Patent Assignee: BAYER AG - WO2007/17092, 2007, A1 Location in patent: Page/Page column 25
[8]Lovecy; Robinson; Sugasawa [Journal of the Chemical Society, 1930, p. 817,818]
[9]Baggaley; Fears; Hindley; Morgan; Murrell; Thorne [Journal of Medicinal Chemistry, 1977, vol. 20, # 11, p. 1388 - 1393]
[10]Hey; Lobo [Journal of the Chemical Society, 1954, p. 2246,2255] Mori, Miwako; Ishikura, Minoru; Ikeda, Toshihito; Ban, Yoshio [Heterocycles, 1984, vol. 22, # 2, p. 253 - 256]
[11]Zhang, Mei; Yang, Xiao-Ying; Tang, Wei; Groeneveld, Tom W. L.; He, Pei-Lan; Zhu, Feng-Hua; Li, Jia; Lu, Wei; Blom, Anna M.; Zuo, Jian-Ping; Nan, Fa-Jun [ACS Medicinal Chemistry Letters, 2012, vol. 3, # 4, p. 317 - 321]
[12]Current Patent Assignee: XI AN JIAOTONG UNIVERSITY - CN103980152, 2016, B Location in patent: Paragraph 0076-0077
[13]Current Patent Assignee: CMBLU PROJEKT AG - US2019/85006, 2019, A1 Location in patent: Paragraph 0311-0312
[14]Current Patent Assignee: CMBLU PROJEKT AG - WO2019/158615, 2019, A1 Location in patent: Page/Page column 140
[15]Pugachev, Mikhail V.; Agafonova, Maria N.; Bastrikova, Oksana A.; Gnezdilov, Oleg I.; Nikishova, Tatyana V.; Balakin, Konstantin V.; Shtyrlin, Yurii G. [Medicinal Chemistry Research, 2021, vol. 30, # 5, p. 1139 - 1150]

2
[ 1486-53-9 ]
[ 1486-52-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With 1,2,3-Benzotriazole; thionyl chloride In dichloromethane at 20℃; for 1.16667h;
82%	With thionyl chloride at 0 - 60℃;	2.B 2.B. Synthesis of 3-methoxy-4-benzyloxy-benzoyl chloride; 3-Methoxy-4-benzyloxy-benzoic acid (cf. A.2. 5g, 22 mmoles) was dissolved under vigorous stirring in thionyl chloride (15 ml) cooled with a ice-bath at 0°C. The reaction mixture was let to warm to room temperature and then refluxed for 30 minutes at 60°C. After this period, the reagent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (15 ml.) and the solvent was evaporated under reduced pressure. This operation was done two times. Yield 82% of white solid
	With phosphorus pentachloride

	With thionyl chloride
	With thionyl chloride
	With thionyl chloride for 4.5h; Heating;
	With thionyl chloride Heating;
	With thionyl chloride for 0.5h; Heating;
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 20 - 40℃; for 1h;	18.A Example 18A4-(benzyloxy)-3-methoxybenzoyl chloride; 1.0 g (3.87 mmol) 4-(benzyloxy)-3-methoxybenzoic acid are suspended in 20 ml dichloromethane. After a drop of DMF is added 1.84 g (15.5 mmol) thionylchloride is added carefully in portions. The suspension dissolves and the mixture is stirred at it for 1 h, then at 4O0C till evolution of gas has ceased. The solvents and excess of reagents are removed in vacuo and the resulting acid chloride can be used without further purification
	With thionyl chloride In dichloromethane at 50℃; for 2h;	76.1 Example 76; Preparation of 2-(4-benzyloxy-3-methoxyphenyl)benzimidazole(Step 1); In 20 ml of methylene chloride was suspended 2.0 g (7.7 mmol) of 4-benzyloxy-3-methoxy benzoic acid. DMF (0.05 g) and thionyl chloride (0.68 ml) were added to this suspension. The mixture was stirred at 50° C. for 2 hours. At a temperature of 0° C., 20 ml of pyridine wherein 1.1 g (8.0 mmol) of 2-nitroaniline had been dissolved at room temperature was added dripwise to the mixture. The mixture was stirred for 2 hours at room temperature, and water was added thereto to extract the methylene chloride phase. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The crystals thus obtained were recrystallized using methylene chloride-hexane, thereby yielding 1.5 g of N-(2-nitrophenyl)-4-benzyloxy-3-methoxybenzamide crystals.1H-NMR (DMSO-d6, δ): 11.32 (1H, br s), 8.99 (1H, d, J=8.0 Hz), 8.27 (1H, d, J=7.6 Hz), 7.70 (1H, dd, J=7.6, 7.6 Hz), 7.59 (1H, d, J=2.0 Hz), 7.51 (1H, dd, J=2.0, 8.4 Hz), 7.30-7.47 (5H, m), 7.20 (1H, dd, J=7.6, 8.0 Hz), 6.99 (1H, d, J=8.4 Hz)
	With thionyl chloride In dichloromethane at 50℃; for 2h;	78 Example 78 Preparation of 2-(4-benzyloxy-3-methoxyphenyl)benzothiazole In methylene chloride (10 ml) was suspended 2.0 g (7.7 mmol) of 4-benzyloxy-3-methoxy benzoic acid. To this suspension was added 0.05 g of DMF and 0.68 ml of thionyl chloride, followed by stirring at 50° C. for 2 hours. This reaction solution was introduced dropwise at 0° C. into a solution wherein 1.2 g (9.3 mmol) of 2-aminothiophenol had been dissolved in 10 ml of pyridine at room temperature. The mixture was further stirred overnight at room temperature, diluted with water, and subjected to ethyl acetate extraction (50 ml*2 times). The extracts were dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue thus obtained was dissolved in 30 ml of toluene. This toluene solution was heated to reflux overnight while water was distilled off. Toluene was removed from this solution by distillation under reduced pressure, and the residue was purified using a silica gel column (eluant: ethyl acetate/hexane=1/5). The solvent was distilled off under reduced pressure. Using the crystals thus obtained, the desired compound was recrystallized in an amount of 0.18 g from methylene chloride-hexane.
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane for 8h; Reflux;	4 4.2.2. Procedure 2 General procedure: To a solution of benzoic acid (1.0 equiv) in dry CH2Cl2 (3 mL per mmol of acid) was added SOCl2 (5.0 equiv) at room temperature followed by the addition of a catalytic amount of DMF (4 drops per 10 mmol of acid). The mixture was refluxed for 8 h. After cooling, solvent and excess reagent were removed in vacuo to afford the crude acid chloride, which was used in the next step without further purification. O-Pivaloylhydroxylamine triflate19 (1.2 equiv) was added to a biphasic mixture of Na2CO3 (2.0 equiv) in EtOAc/H2O (9 mL permmol of acid chloride, 2:1). To the cooled mixture containing the pivaloylhydroxylamine at 0 °C was added crude acid chloride (1.0 equiv) in EtOAc (1 mL per mmol of acid chloride) dropwise. The reaction mixture was allowed to reach room temperature within 5 h. The layers were separated and the aqueous layer was extracted with EtOAc (210 mL (per mmol of acid chloride)). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to provide the crude product which was purified by flash chromatography to afford pure O-pivaloyl hydroxamic acid.
	With thionyl chloride In toluene for 4h; Reflux;	General procedure for preparation of 5-bromo-7-methoxy-2-arylbenzofurans (7-12) General procedure: A solution of substituted benzoic acids (1 mmol) in thionyl chloride (1.5 mmol) in toluene was heated under reflux for 4 h. Excess of toluene and thionyl chloride was removed under reduced pressure to furnish benzoyl chlorides which were used further without purication. A mixture of phosphonium salt 4 (1mmol), benzoyl chlorides (1.1 mmol) and triethylamine (2.3 mmol) in toluene was heated under reflux for 3-6 h. Once the reaction completed, usual work up was done as mentioned above. Solid products obtained were puried through silicagel column using hexane:ethyl acetate (9.5:0.5) as an eluent to give the desired derivatives (7-12) in 60-70% yield range.
	With thionyl chloride at 60 - 120℃;	3.iii (iii) Synthesis of 4-(benzyloxy)-3-methoxybenzoyl chloride (4) Isolated product 3 (1.0 eq.) is dissolved in thionyl chloride (5-20 eq.) and the mixture is stirred at 60 to 120° C. for 1 to 8 h. After completion of the reaction excess thionyl chloride is evaporated to yield desired acyl chloride 4.
	With thionyl chloride at 60 - 120℃;	3.iii (iii) Synthesis of 4-(benzyloxy)-3-methoxybenzoyl chloride (4): Isolated product 3 (1 .0 eq.) is dissolved in thionyl chloride (5-20 eq.) and the mixture is stirred at 60 to 120 °C for 1 to 8 h. After completion of the reaction excess thionyl chloride is evaporated to yield desired acyl chloride 4.
	With thionyl chloride for 2h; Reflux;	General method of synthesis of benzoyl chlorides (5a-5c) General procedure: The aromatic carboxylic acid 4a-4c (3.00 g) was dissolvedin 12 mL of SOCl2 and refluxed for 2 h. Excess ofSOCl2 was removed under vacuum, and the obtainedresidue was used at the next step without furtherpurification.

Reference： [1]Rao, Maddali L.N.; Awasthi, Dheeraj K.; Banerjee, Debasis [Tetrahedron Letters, 2010, vol. 51, # 15, p. 1979 - 1981]
[2]Current Patent Assignee: UNIVERSITE LIBRE DE BRUXELLES - WO2010/43631, 2010, A1 Location in patent: Page/Page column 43-44
[3]Hey; Lobo [Journal of the Chemical Society, 1954, p. 2246,2255]
[4]Kametani et al. [Chemical and pharmaceutical bulletin, 1959, vol. 7, p. 641,644] Subramanya Raj Urs; Surendranath [Molecular Crystals and Liquid Crystals (1969-1991), 1982, vol. 99, # 1-4, p. 279 - 284]
[5]Barton, Derek H.R.; Lacher, Brigitte; Zard, Samir Z. [Tetrahedron, 1987, vol. 43, # 19, p. 4321 - 4328]
[6]Herbert, Richard B.; Jackson, Frederick B.; Nicolson, Ian T. [Journal of the Chemical Society. Perkin transactions I, 1984, # 4, p. 825 - 831]
[7]Pelter, Andrew; Ward, Robert S.; Watson, Derrick J.; Jack, Ibiba R. [Journal of the Chemical Society. Perkin transactions I, 1982, p. 183 - 190]
[8]Black, David St. C.; Keller, Paul A.; Kumar, Naresh [Tetrahedron, 1993, vol. 49, # 1, p. 151 - 164]
[9]Current Patent Assignee: BAYER AG - WO2007/17092, 2007, A1 Location in patent: Page/Page column 30
[10]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - US2011/65728, 2011, A1 Location in patent: Page/Page column 10
[11]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - US2011/65728, 2011, A1 Location in patent: Page/Page column 10-11
[12]Mishra, Vivek Kumar; Ravikumar, Ponneri C.; Maier, Martin E. [Tetrahedron, 2016, vol. 72, # 41, p. 6499 - 6509]
[13]More, Kishor R.; Mali [Tetrahedron, 2016, vol. 72, # 47, p. 7496 - 7504]
[14]Current Patent Assignee: CMBLU PROJEKT AG - US2019/85006, 2019, A1 Location in patent: Paragraph 0313-0314
[15]Current Patent Assignee: CMBLU PROJEKT AG - WO2019/158615, 2019, A1 Location in patent: Page/Page column 140; 141
[16]Pugachev, Mikhail V.; Agafonova, Maria N.; Bastrikova, Oksana A.; Gnezdilov, Oleg I.; Nikishova, Tatyana V.; Balakin, Konstantin V.; Shtyrlin, Yurii G. [Medicinal Chemistry Research, 2021, vol. 30, # 5, p. 1139 - 1150]

3
[ 1486-53-9 ]
[ 60547-92-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With nitric acid; acetic acid; In dichloromethane; for 6h;	4-(Benzyloxy)-3-methoxybenzoic acid (63.5 g, 246.0 mmol) in the mixture of CH2CI2 (400 ml) and I lOAc (100 ml) was added HNO3 (fuming, 25.0 ml, 528.5 mmol). The mixture was stirred for 6 h, concentrated, crystallized with EtOH, dried over the oven at 40 C with vacuum to afford the title compound (63.3 g, 85% yield). ESI MS m/z+ 326.1 (M + Na).
85%	With nitric acid; acetic acid; In dichloromethane; for 6h;	Example 9. 4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid 4-(Benzyloxy)-3-methoxybenzoic acid (63.5 g, 246.0 mmol) in the mixture of CH2C12(400 ml) and FIOAc (100 ml) was added HNO3 (fuming, 25.0 ml, 528.5 mmoi). The mixture was stirred for 6 h, concentrated, crystallized with EtOH, dried over the oven at 40 Cwith vacuum to afford the title compound (63.3 g, 85% yield). ESI MS mlz+ 326.1 (M +Na).
85%	With nitric acid; acetic acid; In dichloromethane; for 6h;	To a solution of compound 238 (63.5 g, 246.0 mmol) in CH2Cl2 (400 ml) and HOAc (100 ml) was added HNO3 (fuming, 25.0 ml, 528.5 mmol). The mixture was stirred for 6 h, concentrated, crystallized with EtOH, dried at 40 C under vacuum to afford the title compound (63.3 g, 85% yield). ESI MS m/z 326.1 ([M+Na]+).

85%	With nitric acid; In dichloromethane; acetic acid; for 6h;	To a solution of 4- (benzyloxy) -3-methoxybenzoic acid (63.5 g, 246.0 mmol) in CH 2Cl 2 (400 ml) and HOAc (100 ml) was added HNO 3 (fuming, 25.0 ml, 528.5 mmol) . The mixture was stirred for 6 h, concentrated, crystallized with EtOH, dried at 40 under vacuum to afford the title compound (63.3 g, 85%yield) . ESI MS m/z 326.1 ( [M+Na] +) .
85%	With nitric acid; acetic acid; In dichloromethane; for 6h;	To a solution of 4- (benzyloxy) -3-methoxybenzoic acid (63.5 g, 246.0 mmol) in dichloromethane (400 mL) and acetic acid (100 mL) was added fuming nitric acid (25.0 mL, 528.5 mmol). The mixture was stirred for 6 hours, concentrated, crystallized from ethanol,Drying under vacuum at 40 C gave the title compound (63.3 g, 85% yield).
59%	With nitric acid; In dichloromethane; acetic acid; at 0 - 20℃; for 3h;	Compound 33a (20 g, 77 mmol) was added as a thick suspension in anhydrous dichloromethane (100 mL) and was cooled to 0 C. Acetic acid (191 mL) was added, resulting in a clear solution which stirred at 0 C. until cool. Nitric acid (26 mL, 581 mmol) was added slowly dropwise through an addition funnel. The ice bath was removed and the solution continued to stir at room temperature. After 3 hours, the reaction was diluted with deionized water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the filtrate concentrated in vacuo. The crude residue was recrystallized using ethyl acetate and hexanes. The solid was filtered and washed with hexanes to give compound 33b as a yellow fluffy solid (13.8 g, y=59%). 1H NMR (400 Hz, CDCl3): delta 7.48-7.43 (m, 6H), 7.25 (s, 1H), 5.25 (s, 2H), 4.02 (s, 3H), MS (m/z): 326.1 (M+Na)+. See FIG. 45.
	With nitric acid; tin(IV) chloride; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;	Synthesis of 4-Benzyloxy-5-methoxy-2-nitrobenzoic acid (3) Method A: A freshly prepared mixture of SnCl4 (5 g, 19.5 mmol) and fuming nitric acid (1.67 g, 26.5 mmol) was added dropwise over 5 minutes to a mechanically stirred solution of 2 (4.35 g, 17 rmmol) in DCM at -25 C. (dry ice/carbon tetrachloride). The mixture was maintained at the same temperature for a further 15 min, quenched with water (150 ml), and allowed to warm to room temperature After the organic layer was separated, the aqueous layer was extracted with EtOAc (2*75 ml). The combined organic phase was dried (MgSO4) and evaporated in vacuo to afford a light brown gum which was recrystallized to form 3 as pale yellow needles. Yield=4.16 g (82%) Method B: 4-benzyloxy-3-methoxybenzoic acid (8.5 g, 32.9 mmol) was added in small portions over 30 minutes to stirred solution of 70% nitric acid (100 ml). When addition was complete the reaction mixture was allowed to warm to 15 C. and maintained at that temperature for a further 30 min. The reaction mixture was then poured onto ice and the resultant precipitate was collected by filtration, washed with ice-cold water and dried to afford the nitrated product 3 as a yellow powder. Yield (after recrystallisation from EtOAc/hexane) 7.8 g (78%); mp 182>=185 C.; IR (cm-1) 3400-3200, 2820-2930, 1670, 1600, 1580, 1550, 1510, 1450, 1410, 1400, 1370, 1350, 1330, 1265, 1210, 1160, 1160, 1055, 1005; 1H-NMR (CDCl3+DMSO-d6) delta 7.36-7.45 (m, 6H), 7.16 (s, 1H), 5.19 (s, 2H), 3.95 (s, 3H); 13C-NMR (CDCl3+DMSO-d6) delta 167.3, 152.7, 149.0, 140.9, 135.2, 128.4, 127.6, 127.3, 111.1, 71.2, 56.5; MS (EI) (m/z, relative intensity) 303 (M+, 64), 286 (36), 273 (5), 259 (5), 181 (7), 123 (8), 105 (13), 91 (100), 77 (8), 65 (63), 51 (23); EI-HRMS m/z 303.0824 (calc'd for C15H13NO6 m/z 303.0743).

Reference： [1]Patent: WO2015/28850,2015,A1 .Location in patent: Page/Page column 84
[2]Patent: WO2015/155753,2015,A2 .Location in patent: Page/Page column 87
[3]Patent: WO2016/59622,2016,A2 .Location in patent: Page/Page column 126
[4]Patent: WO2018/86139,2018,A1 .Location in patent: Page/Page column 182; 183
[5]Patent: WO2020/6722,2020,A1 .Location in patent: Page/Page column 145-146
[6]Patent: CN110621673,2019,A .Location in patent: Paragraph 1092-1094
[7]Patent: WO2020/73345,2020,A1 .Location in patent: Page/Page column 291-292
[8]Synthesis,1990,p. 81 - 84
[9]Patent: US9169272,2015,B2 .Location in patent: Page/Page column 247
[10]Heterocycles,1984,vol. 22,p. 253 - 256
[11]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 1933 - 1935
[12]Patent: US6562806,2003,B1

4
[ 121-34-6 ]
[ 100-44-7 ]
[ 1486-53-9 ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium hydroxide In tetrahydrofuran; water for 48h; Heating;
74%	With sodium hydroxide In tetrahydrofuran; water at 0 - 90℃; for 22h;	2 The 4-(benzyloxy)-3-methoxybenzoic acid used as starting material was prepared as follows:- To a stirred solution of 4-hydroxy-3-methoxybenzoic acid (5 g, 30 mmol) in THF (15 mL) was added a solution of sodium hydroxide (3 g) in water (37.5 mL). The resulting mixture was cooled to 0°C and a solution of benzyl chloride (4.1 mL, 34. 8 mmol) in THF (15 mL) was added. The resulting mixture was allowed to wann to room temperature then heated to 70°C for 18 hours then to 90°C for 4 hours. The mixture was cooled and evaporated. The residual aqueous mixture was washed with isohexane then acidified with 2M hydrochloric acid solution. The resulting precipitate was collected by filtration, washed with isohexane and dried giving the title compound (5.76 g, 74%); NMR Spectrum: (DMSOd6) 3.83 (s, 3H), 5.19 (s, 2H), 7.14 (m, 1H), 7.40 (m, 6H), 7.55 (dd, 1H), 12.69 (m, 1 H) ; Mass Spectrum : M-H-257.
63%	With sodium hydroxide In tetrahydrofuran; water at 0 - 90℃;	2.A 2.A. Synthesis of 3-Methoxy-4-benzyloxy-benzoic acid; To a stirred solution of vanillic acid (5g, 30 mmol) in THF(15 ml_), a solution of NaOH (3g) in water (37 ml.) is added. The medium is cooled at 0°C and a solution of benzyl chloride (4.1 ml_, 34.8 mmol) is added. The medium is allowed to warm to room temperature and is then heated at 70°C for 18 hours and then at 90°C for 4 hours. After cooling to room temperature, the organic solvent is evaporated and the residual aqueous phase is acidified with 2M HCI. The precipitate is filtered and washed with cyclohexane to afford 4.8g of white solid. Yield : 63%.

63%	Stage #1: 3-methoxy-4-hydroxybenzoic acid; benzyl chloride With sodium hydroxide In tetrahydrofuran; water at 0 - 90℃; Stage #2: With hydrogenchloride In water
	With sodium hydroxide
	With aq. NaOH In tetrahydrofuran	1 Synthesis of 4-Benzyloxy-3-methoxybenzoic acid (2) Synthesis of 4-Benzyloxy-3-methoxybenzoic acid (2) A solution of benzyl chloride (24.6 ml, 209 mmol, 1.1 eq.) in THF (100 ml) was added dropwise at 0° C. over 15 min, to a mechanically stirred solution of 4-hydroxy-3-methoxybenzoic acid (vanillic acid, 1) (30 g, 179 mmol) in THF (90 ml) and 2.0 M aq. NaOH (225 ml). The mixture was allowed to warm to room temperature and then heated under reflux for 48 hours. After cooling, the mixture was washed with hexane (2*100 ml) and the THF was removed in vacuo. The remaining aqueous phase was acidified to pH 1 with conc. HCl. The resulting precipitate was collected by filtration, washed with water and dried to afford 4-benzyloxy-3-methoxybenzoic acid (2) as a pale amorphous solid. Yield (after recrystallisation from EtOAc) 31 g (67%); mp 171-172° C; IR (cm-1) 3700-3200, 2820-3000, 2210, 2140, 1670, 1600, 1580, 1510, 1450, 1430, 1410, 1380, 1340, 1300, 1265, 1220, 1180, 1130-1110, 1030, 1010; 1H NMR (CDCl3+DMSO-d6) δ 7.60 (d, J=2 Hz, 1H), 7.55 (d, J=2 Hz 1H), 7.30-7.44 (m, 5H), 6.90 (d, J=8.4 Hz, 1H), 5.19 (s, 2H), 3.91 (s, 3H); 13C NMR (CDCl3+DMSO-d6) δ 168.3, 151.7, 148.8, 136.3, 128.5, 128.0, 127.2, 123.7, 123.5, 112.5, 112.2, 70.6, 55.9; MS (EI) (m/z, relative intensity) 258 (M+, 20), 91 (100), 79 (3), 65 (10), 51 (3); EI-HRMS m/z 258.0949 (calc'd for C15H14O4 m/z 258.0892).
	With sodium hydroxide In ethanol; water	S.5.1 Synthesis Example 5 (1) To a suspension of 4-hydroxy-3-methoxybenzoic acid (25 g, 0.15 mole) in ethanol (150 ml), 2N NaOH aq. (74.3 g, 0.15 mole) and benzyl chloride (56.5 g, 0.45 mole) were added, continued to stir for 1 hour under reflux. Then, 5N NaOH aq. (150 ml) was added dropwise with stirring under reflux, and continued to stir for 1 hour under reflux. After reaction, the solvent was removed, and H2O was added to the residue and acidified with conc. hydrochloric acid to make pH 1. The precipitate was filtered, washed with H2O and dried to give 22.1 g of 4-benzyloxy-3-methoxybenzoic acid as pale yellow crystals having a m.p. of 171-172.5°C.
	Stage #1: 3-methoxy-4-hydroxybenzoic acid; benzyl chloride With sodium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 30.5h; Heating / reflux; Stage #2: With hydrogenchloride; water	Preparation of 4-benzyloxy-3-methoxy-benzoic acid 5.0 grams of 4-hydroxy-3-methoxy-benzoic acid and 15 mL of THF were combined at room temperature. 37.5 mL of 2 N NaOH was added and the mixture cooled on ice. 4.0 mL of benzyl chloride was diluted with THF and added to the reaction mixture in a dropwise manner over 30 minutes. After the addition was complete, the mixture was warmed to room temperature and then refluxed. After a total of 30 hours of reflux, the reaction mixture was cooled to room temperature and washed twice with hexane. The aqueous THF phase was concentrated in vacuo such that most of the THF was removed and a solid remained. 50 mL of 1 N NaOH was added to give a slurry. Concentrated HCl was added slowly until all the material dissolved and the product then precipitated out of the acidic solution. After the pH was adjusted to 1, a white precipitate was filtered off and washed with 10% HCl. The precipitate was dissolved in hot ethyl acetate, separately, dried over sodium sulfate, filtered and the filtrate evaporated. The resulting solid was recrystallized from hot ethyl acetate. The yield of the first crop was 3.34 grams. Additional material could be isolated from the filtrate. Proton NMR was in agreement with the proposed structure. (lit. ref. Synthesis 1990 pp. 81-84 by Thurston et. al.)

Reference： [1]Thurston; Murty; Langley; Jones [Synthesis, 1990, # 1, p. 81 - 84]
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2005/61465, 2005, A1 Location in patent: Page/Page column 41-42
[3]Current Patent Assignee: UNIVERSITE LIBRE DE BRUXELLES - WO2010/43631, 2010, A1 Location in patent: Page/Page column 43
[4]Location in patent: experimental part Lamoral-Theys, Delphine; Pottier, Laurent; Kerff, Frédéric; Dufrasne, François; Proutière, Fabien; Wauthoz, Nathalie; Neven, Philippe; Ingrassia, Laurent; Antwerpen, Pierre Van; Lefranc, Florence; Gelbcke, Michel; Pirotte, Bernard; Kraus, Jean-Louis; Nève, Jean; Kornienko, Alexander; Kiss, Robert; Dubois, Jacques [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 11, p. 3823 - 3833]
[5]Kamal, Ahmed; Reddy; Reddy, G.Suresh Kumar; Ramesh [Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 15, p. 1933 - 1935]
[6]Current Patent Assignee: ASTRAZENECA PLC - US6562806, 2003, B1
[7]Current Patent Assignee: FUJIFILM HOLDINGS CORP.; PANASONIC CORPORATION - EP636941, 1995, A1
[8]Current Patent Assignee: PFIZER INC - US2007/208164, 2007, A1 Location in patent: Page/Page column 14

5
[ 91203-74-6 ]
[ 1486-53-9 ]

Yield	Reaction Conditions	Operation in experiment
96%	With water; sodium hydroxide In ethanol for 2h; Reflux;	5 4-Benzyloxy-3-methoxybenzoic acid (18) To a suspension of (17) (41.3 g, 119 mmol) in a mixture water-ethanol (1:1, 200 mL), was added sodium hydroxide (9.4 g, 238 mmol). The reaction mixture was refluxed for 2 hours and concentrated under reduced pressure to the water volume. The aqueous residue was successively diluted in cooled H2O (100 mL), washed with Et20 (2 x 20 mL), acidified with concentrated aqueous HC1 and then extracted with EtOAc (3 x 30 mL). The organic layers were combined, washed with water (20 mL) and dried over Na2S04- The solvent was removed under reduced pressure to afford 4-benzyloxy-3- methoxybenzoic acid (18) (29.4 g, 96%). NMR (250 MHz, CDCL) d 7.70 (dd, J = 8.4 and 1.9 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.46-7.32 (m, 5H), 6.93 (d, J = 8.4 Hz, 1H), 5.24 (s, 2H) and 3.95 (s, 3H); LCMS C15H14O4 Rt = 6.252 min, ESI+ m/z = 258.9 (M+H).
94%	With sodium hydroxide In ethanol for 6h; Heating;
88%	With hydrogenchloride; sodium hydroxide In ethanol	S.53.2 Synthetic Example 53 (2) Benzyl 4-benzyloxy-3-methoxybenzoate (112.36 g) was dissolved into ethanol (350 ml). After the addition of a 5% sodium hydroxide aqueous solution (400 ml), the mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and ethanol was removed. After adjusting the mixture to about pH 1 with 3 N hydrochloric acid, deposited crude crystals were collected by filtration, dried under reduced pressure, and recrystallized from a mixed solvent of ethyl acetate an hexane to obtain colorless needle-like crystals of 4-benzyloxy-3-methoxybenzoic acid (73.67 g, 88%).

87%	Stage #1: 4-benzyloxy-3-methoxybenzoic acid benzyl ester With potassium hydroxide Reflux; Stage #2: With sulfuric acid In water
58%	With lithium hydroxide monohydrate; water In tetrahydrofuran; methanol at 60℃;	1.6 Next, the purified product was hydrolyzed in the presence of lithium hydroxide (Wako Pure Chemical Industries, Ltd.) in a solvent (THF (Kanto Chemical Co., Inc.) : H2O : MeOH (Wako Pure Chemical Industries, Ltd.) = 3:2:1) so as to remove a benzyl group protecting a hydroxyl group of carboxylic acid. Then, the resultant was purified using an open column (at different concentration ratios of hexane : ethyl acetate = 10:1, 4:1, and 0:1) so as to remove the unreacted product and benzyl alcohol. The yield was found to be 58%: 1H NMR (300 MHz, CDCl3): δ7.68 (1H, dd, H-6), 7.60 (1H, d, H-2), 7.45-7.25 (5H, m, H-benzylic CH2), 6.90 (1H, d, H-5), 5.25 (2H, s, H-benzylic CH2), and 3.92 (3H, s, CH3).
	With sodium hydroxide In tetrahydrofuran at 50℃;	General procedure: Compound 2a (1.85 g mmol, 5.81 mmol) was dissolved intetrahydrofuran (10 mL), and 6 mol/L NaOH solution(30 mL) was added. The mixture was stirred at 50 °C.After the reaction was complete, the solvent was removedunder reduced pressure, and the residue was adjusted to acidto precipitate white solid 3a (1.05 g). The yield was 78.95%.

Reference： [1]Current Patent Assignee: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; AIX-MARSEILLE UNIVERSITY; NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH; PAOLI CALMETTES INSTITUTE - WO2021/74392, 2021, A1 Location in patent: Page/Page column 41
[2]Herbert, Richard B.; Jackson, Frederick B.; Nicolson, Ian T. [Journal of the Chemical Society. Perkin transactions I, 1984, # 4, p. 825 - 831]
[3]Current Patent Assignee: TSUMURA & CO. - EP613879, 1994, A1
[4]Location in patent: experimental part Catel, Yohann; Aladedunye, Felix; Przybylski, Roman [Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 20, p. 11081 - 11089]
[5]Current Patent Assignee: TOKYO UNIVERSITY OF AGRICULTURE AND TECHNOLOGY - EP2463366, 2015, B1 Location in patent: Paragraph 0102
[6]Xie, Yundong; Liu, Jiping; Shi, Yongheng; Bin Wang; Wang, Xiaoping; Wang, Wei; Sun, Meng; Xu, Xinya; He, Shipeng [Medicinal Chemistry Research, 2021, vol. 30, # 9, p. 1688 - 1702]

6
[ 1486-53-9 ]
[ 70-11-1 ]
4-Benzyloxy-3-methoxy-benzoic acid 2-oxo-2-phenyl-ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.7%	With sodium carbonate In ethanol; water for 1.5h; Heating;

Reference： [1]Huang, Wei; Pei, Jian; Chen, Bingzi; Pei, Weiwei; Ye, Xiulin [Tetrahedron, 1996, vol. 52, # 30, p. 10131 - 10136]

7
[ 1486-53-9 ]
veracevine [ No CAS ]
3-O-(4-benzyloxy-3-methoxybenzoyl)veracevine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With dmap; dicyclohexyl-carbodiimide In pyridine; dichloromethane for 4h; Ambient temperature;

Reference： [1]Ujvary, Istvan; Casida, John E. [Phytochemistry, 1997, vol. 44, # 7, p. 1257 - 1260]

8
4-benzyloxy-3-methoxy-benzoic acid 3-methyl-but-2-enyl ester [ No CAS ]
[ 1486-53-9 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hydrogen sulfate; silica gel In dichloromethane at 20℃; for 5h;

Reference： [1]Ramesh; Mahender; Ravindranath; Das, Biswanath [Tetrahedron Letters, 2003, vol. 44, # 7, p. 1465 - 1467]

9
[ 1486-53-9 ]
[ 143-08-8 ]
4-benzyloxy-3-methoxy-benzoic acid nonyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃;
	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 2h;

Reference： [1]Nihei, Ken-Ichi; Nihei, Atsuko; Kubo, Isao [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 22, p. 3993 - 3996]
[2]Nihei, Ken-Ichi; Nihei, Atsuko; Kubo, Isao [Journal of Agricultural and Food Chemistry, 2004, vol. 52, # 16, p. 5011 - 5020]

10
4-benzyloxy-3-methoxy-benzoic acid methoxymethyl ester [ No CAS ]
[ 1486-53-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	In tetrahydrofuran; water at 20℃; for 0.25h;

Reference： [1]Venkat Reddy; Jagadeeshwar Rao; Sampath Kumar; Madhusudana Rao [Chemistry Letters, 2003, vol. 32, # 11, p. 1038 - 1039]

11
[ 1486-53-9 ]
[ 2133-40-6 ]
[ 849795-68-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃;

Reference： [1]Correa, Arkaitz; Tellitu, Imanol; Dominguez, Esther; Moreno, Isabel; SanMartin, Raul [Journal of Organic Chemistry, 2005, vol. 70, # 6, p. 2256 - 2264]

12
4-benzyloxy-3-methoxy-benzoic acid <i>tert</i>-butyl ester [ No CAS ]
[ 1486-53-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	With water In acetonitrile for 3h; Heating;

Reference： [1]Yadav; Balanarsaiah; Raghavendra; Satyanarayana [Tetrahedron Letters, 2006, vol. 47, # 28, p. 4921 - 4924]

13
[ 1486-53-9 ]
[ 74-88-4 ]
[ 56441-97-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In acetone; for 16.0h;Heating / reflux;	Preparation of 4-benzyloxy-3-methoxy-methylbenzoate 2.84 g of 4-benzyloxy-3-methoxy-benzoic acid was combined with 3.04 g of potassium carbonate and 1.03 mL of iodomethane in 100 mL of acetone. The mixture was refluxed for 16 hours, cooled to room temperature and diluted with dichloromethane. The slurry was filtered and washed with dichloromethane and the filtrate concentrated to dryness. The solids were redissolved in dichloromethane, washed twice with water, dried over sodium sulfate and filtered. The filtrate was concentrated to a clear, colorless oil which was triturated with methanol to give a white solid in 90% yield (2.7 grams). Proton

Reference： [1]Patent: US2007/208164,2007,A1 .Location in patent: Page/Page column 14
[2]Organic Letters,1999,vol. 1,p. 1835 - 1837

14
[ 2426-87-1 ]
[ 33693-48-0 ]
[ 1486-53-9 ]

Yield	Reaction Conditions	Operation in experiment
1: 45% 2: 44%	With potassium hydroxide In methanol at 90℃; for 3h;

Reference： [1]Singh, Rekha; Singh, Gobind C.; Ghosh, Sunil K. [European Journal of Organic Chemistry, 2007, # 32, p. 5376 - 5385]

15
[ 1486-53-9 ]
[ 75-65-0 ]
4-benzyloxy-1-tert-butyloxycarbonylamino-3-methoxybenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: 4-(benzyloxy)-3-methoxybenzoic acid With diphenylphosphoranyl azide; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Stage #2: <i>tert</i>-butyl alcohol In N,N-dimethyl-formamide at 20 - 90℃; Further stages.;

Reference： [1]Singh, Rekha; Singh, Gobind C.; Ghosh, Sunil K. [European Journal of Organic Chemistry, 2007, # 32, p. 5376 - 5385]

16
[ 1486-53-9 ]
C₂₁H₂₅BrN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: 58.6 percent / potassium carbonate / acetone / 3 h / Heating 2: 82.6 percent / nitric acid / tin(IV) chloride / CH₂Cl₂ / 0.17 h / -20 °C 3: 95.8 percent / sodium borohydride / nickel(II) chloride hexahydrate / methanol; CH₂Cl₂ / 0.5 h / 0 - 5 °C 4: 98 percent / aq. sodium hydroxide / methanol / 1 h / Heating 5: 81.1 percent / toluene / aq. NaOH / 2 h / 20 °C 6: 87.3 percent / sodium hydride / N,N-dimethyl-acetamide / 12 h / 20 °C 7: triethylamine / CH₂Cl₂ / 2 h / 20 °C

Reference： [1]Wang, Tiansheng; Lui, Alfred S.; Cloudsdale, Ian S. [Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837]

17
[ 1486-53-9 ]
[ 253777-48-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: 58.6 percent / potassium carbonate / acetone / 3 h / Heating 2: 82.6 percent / nitric acid / tin(IV) chloride / CH₂Cl₂ / 0.17 h / -20 °C 3: 95.8 percent / sodium borohydride / nickel(II) chloride hexahydrate / methanol; CH₂Cl₂ / 0.5 h / 0 - 5 °C 4: 98 percent / aq. sodium hydroxide / methanol / 1 h / Heating 5: 81.1 percent / toluene / aq. NaOH / 2 h / 20 °C 6: 87.3 percent / sodium hydride / N,N-dimethyl-acetamide / 12 h / 20 °C 7: triethylamine / CH₂Cl₂ / 2 h / 20 °C 8: 0.31 g / triethylamine / CH₂Cl₂ / 0.17 h / 0 °C

Reference： [1]Wang, Tiansheng; Lui, Alfred S.; Cloudsdale, Ian S. [Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837]

18
[ 1486-53-9 ]
C₂₂H₂₂BrF₃N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1.1: 58.6 percent / potassium carbonate / acetone / 3 h / Heating 2.1: 82.6 percent / nitric acid / tin(IV) chloride / CH₂Cl₂ / 0.17 h / -20 °C 3.1: 95.8 percent / sodium borohydride / nickel(II) chloride hexahydrate / methanol; CH₂Cl₂ / 0.5 h / 0 - 5 °C 4.1: 98 percent / aq. sodium hydroxide / methanol / 1 h / Heating 5.1: 81.1 percent / toluene / aq. NaOH / 2 h / 20 °C 6.1: 87.3 percent / sodium hydride / N,N-dimethyl-acetamide / 12 h / 20 °C 7.1: triethylamine / CH₂Cl₂ / 2 h / 20 °C 8.1: 0.31 g / triethylamine / CH₂Cl₂ / 0.17 h / 0 °C 9.1: ozone / CH₂Cl₂; methanol / 0.08 h 9.2: dimethyl sulfide / CH₂Cl₂; methanol / 2 h / -78 - 20 °C

Reference： [1]Wang, Tiansheng; Lui, Alfred S.; Cloudsdale, Ian S. [Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837]

19
[ 1486-53-9 ]
[ 253777-50-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1.1: 58.6 percent / potassium carbonate / acetone / 3 h / Heating 2.1: 82.6 percent / nitric acid / tin(IV) chloride / CH₂Cl₂ / 0.17 h / -20 °C 3.1: 95.8 percent / sodium borohydride / nickel(II) chloride hexahydrate / methanol; CH₂Cl₂ / 0.5 h / 0 - 5 °C 4.1: 98 percent / aq. sodium hydroxide / methanol / 1 h / Heating 5.1: 81.1 percent / toluene / aq. NaOH / 2 h / 20 °C 6.1: 87.3 percent / sodium hydride / N,N-dimethyl-acetamide / 12 h / 20 °C 7.1: triethylamine / CH₂Cl₂ / 2 h / 20 °C 8.1: 0.31 g / triethylamine / CH₂Cl₂ / 0.17 h / 0 °C 9.1: ozone / CH₂Cl₂; methanol / 0.08 h 9.2: dimethyl sulfide / CH₂Cl₂; methanol / 2 h / -78 - 20 °C 10.1: 0.064 g / camphorsulfonic acid / benzene / Heating

Reference： [1]Wang, Tiansheng; Lui, Alfred S.; Cloudsdale, Ian S. [Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837]

20
[ 1486-53-9 ]
8-benzyloxy-7-methoxy-10-trifluoroacetyl-1,2,3,10,11,11a-hexahydro-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 11 steps 1.1: 58.6 percent / potassium carbonate / acetone / 3 h / Heating 2.1: 82.6 percent / nitric acid / tin(IV) chloride / CH₂Cl₂ / 0.17 h / -20 °C 3.1: 95.8 percent / sodium borohydride / nickel(II) chloride hexahydrate / methanol; CH₂Cl₂ / 0.5 h / 0 - 5 °C 4.1: 98 percent / aq. sodium hydroxide / methanol / 1 h / Heating 5.1: 81.1 percent / toluene / aq. NaOH / 2 h / 20 °C 6.1: 87.3 percent / sodium hydride / N,N-dimethyl-acetamide / 12 h / 20 °C 7.1: triethylamine / CH₂Cl₂ / 2 h / 20 °C 8.1: 0.31 g / triethylamine / CH₂Cl₂ / 0.17 h / 0 °C 9.1: ozone / CH₂Cl₂; methanol / 0.08 h 9.2: dimethyl sulfide / CH₂Cl₂; methanol / 2 h / -78 - 20 °C 10.1: 0.064 g / camphorsulfonic acid / benzene / Heating 11.1: 91 percent / tributyltin hydride; AIBN / benzene / 2 h / Heating

Reference： [1]Wang, Tiansheng; Lui, Alfred S.; Cloudsdale, Ian S. [Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837]

21
[ 1486-53-9 ]
[ 253777-44-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: 58.6 percent / potassium carbonate / acetone / 3 h / Heating 2: 82.6 percent / nitric acid / tin(IV) chloride / CH₂Cl₂ / 0.17 h / -20 °C 3: 95.8 percent / sodium borohydride / nickel(II) chloride hexahydrate / methanol; CH₂Cl₂ / 0.5 h / 0 - 5 °C 4: 98 percent / aq. sodium hydroxide / methanol / 1 h / Heating 5: 81.1 percent / toluene / aq. NaOH / 2 h / 20 °C 6: 87.3 percent / sodium hydride / N,N-dimethyl-acetamide / 12 h / 20 °C

Reference： [1]Wang, Tiansheng; Lui, Alfred S.; Cloudsdale, Ian S. [Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837]

22
[ 1486-53-9 ]
[ 61032-42-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 58.6 percent / potassium carbonate / acetone / 3 h / Heating 2: 82.6 percent / nitric acid / tin(IV) chloride / CH₂Cl₂ / 0.17 h / -20 °C 3: 95.8 percent / sodium borohydride / nickel(II) chloride hexahydrate / methanol; CH₂Cl₂ / 0.5 h / 0 - 5 °C
	Multi-step reaction with 3 steps 1: sulfuric acid / methanol / 10 h / Reflux 2: acetic acid; nitric acid / 6.5 h / 0 - 20 °C 3: acetic acid; zinc / water; methanol / 3 h / Reflux
	Multi-step reaction with 3 steps 1: sulfuric acid / methanol / 10 h / Reflux 2: nitric acid; acetic acid / 6.5 h / 0 - 20 °C / Cooling with ice 3: methanol; water / 3 h / 20 °C / Reflux

Reference： [1]Wang, Tiansheng; Lui, Alfred S.; Cloudsdale, Ian S. [Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837]
[2]Zhang, Hai-Qi; Gong, Fei-Hu; Ye, Ji-Qing; Zhang, Chi; Yue, Xiao-Hong; Li, Chuan-Gui; Xu, Yun-Gen; Sun, Li-Ping [European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254]
[3]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN105884699, 2016, A

23
[ 1486-53-9 ]
[ 61032-41-5 ]

Reference： [1]Organic Letters,1999,vol. 1,p. 1835 - 1837
[2]European Journal of Medicinal Chemistry,2017,vol. 125,p. 245 - 254
[3]Patent: CN105884699,2016,A

24
[ 1486-53-9 ]
[ 155666-33-4 ]

Reference： [1]Organic Letters,1999,vol. 1,p. 1835 - 1837

25
[ 1486-53-9 ]
[ 175409-52-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 13 steps 1.1: 58.6 percent / potassium carbonate / acetone / 3 h / Heating 2.1: 82.6 percent / nitric acid / tin(IV) chloride / CH₂Cl₂ / 0.17 h / -20 °C 3.1: 95.8 percent / sodium borohydride / nickel(II) chloride hexahydrate / methanol; CH₂Cl₂ / 0.5 h / 0 - 5 °C 4.1: 98 percent / aq. sodium hydroxide / methanol / 1 h / Heating 5.1: 81.1 percent / toluene / aq. NaOH / 2 h / 20 °C 6.1: 87.3 percent / sodium hydride / N,N-dimethyl-acetamide / 12 h / 20 °C 7.1: triethylamine / CH₂Cl₂ / 2 h / 20 °C 8.1: 0.31 g / triethylamine / CH₂Cl₂ / 0.17 h / 0 °C 9.1: ozone / CH₂Cl₂; methanol / 0.08 h 9.2: dimethyl sulfide / CH₂Cl₂; methanol / 2 h / -78 - 20 °C 10.1: 0.064 g / camphorsulfonic acid / benzene / Heating 11.1: 91 percent / tributyltin hydride; AIBN / benzene / 2 h / Heating 12.1: potassium carbonate / acetonitrile; H₂O / 20 °C 13.1: 0.0523 g / ammonium formate / palladium on carbon / methanol / 1 h / Heating
	Multi-step reaction with 4 steps 1: acetic acid; nitric acid / dichloromethane / 6 h 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 20 °C 3: Dess-Martin periodane / dichloromethane / 20 °C / Inert atmosphere 4: palladium 10% on activated carbon; hydrogen / methanol / 258.58 Torr

Reference： [1]Wang, Tiansheng; Lui, Alfred S.; Cloudsdale, Ian S. [Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837]
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/73345, 2020, A1

26
[ 1486-53-9 ]
[ 849795-72-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 12 steps 1.1: 58.6 percent / potassium carbonate / acetone / 3 h / Heating 2.1: 82.6 percent / nitric acid / tin(IV) chloride / CH₂Cl₂ / 0.17 h / -20 °C 3.1: 95.8 percent / sodium borohydride / nickel(II) chloride hexahydrate / methanol; CH₂Cl₂ / 0.5 h / 0 - 5 °C 4.1: 98 percent / aq. sodium hydroxide / methanol / 1 h / Heating 5.1: 81.1 percent / toluene / aq. NaOH / 2 h / 20 °C 6.1: 87.3 percent / sodium hydride / N,N-dimethyl-acetamide / 12 h / 20 °C 7.1: triethylamine / CH₂Cl₂ / 2 h / 20 °C 8.1: 0.31 g / triethylamine / CH₂Cl₂ / 0.17 h / 0 °C 9.1: ozone / CH₂Cl₂; methanol / 0.08 h 9.2: dimethyl sulfide / CH₂Cl₂; methanol / 2 h / -78 - 20 °C 10.1: 0.064 g / camphorsulfonic acid / benzene / Heating 11.1: 91 percent / tributyltin hydride; AIBN / benzene / 2 h / Heating 12.1: potassium carbonate / acetonitrile; H₂O / 20 °C
	Multi-step reaction with 6 steps 1: 100 percent / EDCHCl; HOBt; Et₃N / CH₂Cl₂ / 0 - 20 °C 2: 96 percent / LiOHH₂O / tetrahydrofuran; H₂O / 20 °C 3: 91 percent / EDC*HCl; HOBt; Et₃N / CH₂Cl₂ / 0 - 20 °C 4: 67 percent / phenyliodine(III) bis(trifluoroacetate) / CH₂Cl₂ / 20 °C 5: 82 percent / Mo(CO)6 / acetonitrile; H₂O / Heating 6: 70 percent / NaBH₄; TFA / various solvent(s) / Heating

Reference： [1]Wang, Tiansheng; Lui, Alfred S.; Cloudsdale, Ian S. [Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837]
[2]Correa, Arkaitz; Tellitu, Imanol; Dominguez, Esther; Moreno, Isabel; SanMartin, Raul [Journal of Organic Chemistry, 2005, vol. 70, # 6, p. 2256 - 2264]

27
[ 1486-53-9 ]
[ 253777-45-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 58.6 percent / potassium carbonate / acetone / 3 h / Heating 2: 82.6 percent / nitric acid / tin(IV) chloride / CH₂Cl₂ / 0.17 h / -20 °C 3: 95.8 percent / sodium borohydride / nickel(II) chloride hexahydrate / methanol; CH₂Cl₂ / 0.5 h / 0 - 5 °C 4: 98 percent / aq. sodium hydroxide / methanol / 1 h / Heating 5: 81.1 percent / toluene / aq. NaOH / 2 h / 20 °C

Reference： [1]Wang, Tiansheng; Lui, Alfred S.; Cloudsdale, Ian S. [Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837]

28
[ 1486-53-9 ]
(11aS)-8-hydroxy-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: 100 percent / EDCHCl; HOBt; Et₃N / CH₂Cl₂ / 0 - 20 °C 2: 96 percent / LiOHH₂O / tetrahydrofuran; H₂O / 20 °C 3: 91 percent / EDC*HCl; HOBt; Et₃N / CH₂Cl₂ / 0 - 20 °C 4: 67 percent / phenyliodine(III) bis(trifluoroacetate) / CH₂Cl₂ / 20 °C 5: 82 percent / Mo(CO)6 / acetonitrile; H₂O / Heating 6: 70 percent / NaBH₄; TFA / various solvent(s) / Heating 7: 60 percent / NMO; TPAP / acetonitrile / 1.5 h / 20 °C 8: 90 percent / 1,4-cyclohexadiene / Pd/C / ethanol / 2.5 h / 20 °C
	Multi-step reaction with 5 steps 1: 83 percent / SnCl₄, HNO₃ / CH₂Cl₂ / 0.08 h / -25 °C 2: 1.) oxalyl chloride, DMF 2.) Et₃N / 1. THF, r. t., 3h 2. THF, H₂O, r. t., 1.5h 3: 75 percent / SnCl₂*H₂O / methanol / 0.67 h / Heating 4: 68 percent / HgCl₂, CaCO₃ / acetonitrile; H₂O / 24 h / Ambient temperature 5: 89 percent / 1,4-cyclohexadiene / Pd-C / ethanol / 3 h / 20 °C
	Multi-step reaction with 5 steps 1.1: acetic acid; nitric acid / dichloromethane / 6 h 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide 3.1: diisobutylaluminium hydride / dichloromethane; toluene / 3.5 h / -78 °C / Inert atmosphere 4.1: sodium dithionite / tetrahydrofuran; water / 8 h 4.2: 1 h / pH 2 5.1: methanesulfonic acid / dichloromethane / 0 - 20 °C

Reference： [1]Correa, Arkaitz; Tellitu, Imanol; Dominguez, Esther; Moreno, Isabel; SanMartin, Raul [Journal of Organic Chemistry, 2005, vol. 70, # 6, p. 2256 - 2264]
[2]Thurston; Murty; Langley; Jones [Synthesis, 1990, # 1, p. 81 - 84]
[3]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2015/28850, 2015, A1

29
[ 1486-53-9 ]
[ 127810-79-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: 100 percent / EDCHCl; HOBt; Et₃N / CH₂Cl₂ / 0 - 20 °C 2: 96 percent / LiOHH₂O / tetrahydrofuran; H₂O / 20 °C 3: 91 percent / EDC*HCl; HOBt; Et₃N / CH₂Cl₂ / 0 - 20 °C 4: 67 percent / phenyliodine(III) bis(trifluoroacetate) / CH₂Cl₂ / 20 °C 5: 82 percent / Mo(CO)6 / acetonitrile; H₂O / Heating 6: 70 percent / NaBH₄; TFA / various solvent(s) / Heating 7: 60 percent / NMO; TPAP / acetonitrile / 1.5 h / 20 °C
	Multi-step reaction with 4 steps 1: 83 percent / SnCl₄, HNO₃ / CH₂Cl₂ / 0.08 h / -25 °C 2: 1.) oxalyl chloride, DMF 2.) Et₃N / 1. THF, r. t., 3h 2. THF, H₂O, r. t., 1.5h 3: 75 percent / SnCl₂*H₂O / methanol / 0.67 h / Heating 4: 68 percent / HgCl₂, CaCO₃ / acetonitrile; H₂O / 24 h / Ambient temperature
	Multi-step reaction with 4 steps 1.1: acetic acid; nitric acid / dichloromethane / 6 h 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide 3.1: diisobutylaluminium hydride / dichloromethane; toluene / 3.5 h / -78 °C / Inert atmosphere 4.1: sodium dithionite / tetrahydrofuran; water / 8 h 4.2: 1 h / pH 2

30
[ 1486-53-9 ]
[ 132622-12-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 100 percent / EDCHCl; HOBt; Et₃N / CH₂Cl₂ / 0 - 20 °C 2: 96 percent / LiOHH₂O / tetrahydrofuran; H₂O / 20 °C 3: 91 percent / EDC*HCl; HOBt; Et₃N / CH₂Cl₂ / 0 - 20 °C 4: 67 percent / phenyliodine(III) bis(trifluoroacetate) / CH₂Cl₂ / 20 °C 5: 82 percent / Mo(CO)6 / acetonitrile; H₂O / Heating

Reference： [1]Correa, Arkaitz; Tellitu, Imanol; Dominguez, Esther; Moreno, Isabel; SanMartin, Raul [Journal of Organic Chemistry, 2005, vol. 70, # 6, p. 2256 - 2264]

31
[ 1486-53-9 ]
nonyl 4-hydroxy-3-methoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Ph₃P; diisopropyl azodicarboxylate / tetrahydrofuran / 2 h / 20 °C 2: H₂; AcOH / Pd(OH)2/C / ethyl acetate / 12 h
	Multi-step reaction with 2 steps 1: PPh₃; diisopropyl azodicarboxylate / tetrahydrofuran / 20 °C 2: H₂; AcOH / Pd(OH)2/C / ethyl acetate

Reference： [1]Nihei, Ken-Ichi; Nihei, Atsuko; Kubo, Isao [Journal of Agricultural and Food Chemistry, 2004, vol. 52, # 16, p. 5011 - 5020]
[2]Nihei, Ken-Ichi; Nihei, Atsuko; Kubo, Isao [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 22, p. 3993 - 3996]

32
[ 1486-53-9 ]
[ 64154-78-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: HNO₃; H₂SO₄ / CH₂Cl₂ / -25 °C 2: SOCl₂ / benzene
	Multi-step reaction with 2 steps 1: acetic acid; nitric acid / dichloromethane / 6 h 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C
	Multi-step reaction with 2 steps 1: nitric acid; acetic acid / dichloromethane / 6 h 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C

	Multi-step reaction with 2 steps 1: nitric acid; acetic acid / dichloromethane / 6 h 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C
	Multi-step reaction with 2 steps 1: nitric acid / dichloromethane; acetic acid / 6 h 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C
	Multi-step reaction with 2 steps 1: acetic acid; nitric acid / dichloromethane / 72 h / 20 °C / Inert atmosphere 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C / Inert atmosphere

Reference： [1]Kamal, Ahmed; Reddy; Reddy, G.Suresh Kumar; Ramesh [Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 15, p. 1933 - 1935]
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2015/28850, 2015, A1
[3]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD; SUZHOU M CONJ BIOTECH CO LTD - WO2016/59622, 2016, A2
[4]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2018/86139, 2018, A1
[5]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/6722, 2020, A1
[6]Current Patent Assignee: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; AIX-MARSEILLE UNIVERSITY; NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH; PAOLI CALMETTES INSTITUTE - WO2021/74392, 2021, A1

33
[ 1486-53-9 ]
[ 140693-22-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: HNO₃; H₂SO₄ / CH₂Cl₂ / -25 °C 2: SOCl₂ / benzene 3: TFA / tetrahydrofuran 4: H₂SO₄ / Heating 5: DIBAL-H / CH₂Cl₂ / -78 °C
	Multi-step reaction with 3 steps 1: acetic acid; nitric acid / dichloromethane / 6 h 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide 3: diisobutylaluminium hydride / dichloromethane; toluene / 3.5 h / -78 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: nitric acid / dichloromethane; acetic acid / 6 h 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 20 °C 3: Dess-Martin periodane / dichloromethane / 20 °C / Inert atmosphere

Multi-step reaction with 3 steps 1: acetic acid; nitric acid / dichloromethane / 6 h 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 20 °C 3: Dess-Martin periodane / dichloromethane / 20 °C / Inert atmosphere

34
[ 1486-53-9 ]
3-O-vanilloylveracevine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 77 percent / 4-dimethylaminopyridine, dicyclohexylcarbodiimide / CH₂Cl₂; pyridine / 4 h / Ambient temperature 2: 90 percent / H₂ / Pd-C / ethyl acetate; ethanol / Ambient temperature

Reference： [1]Ujvary, Istvan; Casida, John E. [Phytochemistry, 1997, vol. 44, # 7, p. 1257 - 1260]

35
[ 617-05-0 ]
[ 1486-53-9 ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1982,vol. 99,p. 279 - 284

36
[ 121-34-6 ]
[ 1486-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: H+ / ethanol 2: NaOEt 3: NaOH
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide 2: lithium hydroxide monohydrate; water / tetrahydrofuran; methanol / 60 °C
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: sodium hydroxide; water / ethanol / 2 h / Reflux

	Multi-step reaction with 3 steps 1: sulfuric acid / 24 h / Reflux; Inert atmosphere 2: potassium iodide; potassium carbonate / acetone / Inert atmosphere; Reflux 3: sodium hydroxide / ethanol / 2 h / Inert atmosphere; Reflux
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 75 °C / Inert atmosphere 2: sodium hydroxide / tetrahydrofuran / 50 °C

Reference： [1]Subramanya Raj Urs; Surendranath [Molecular Crystals and Liquid Crystals (1969-1991), 1982, vol. 99, # 1-4, p. 279 - 284]
[2]Current Patent Assignee: TOKYO UNIVERSITY OF AGRICULTURE AND TECHNOLOGY - EP2463366, 2015, B1
[3]Current Patent Assignee: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; AIX-MARSEILLE UNIVERSITY; NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH; PAOLI CALMETTES INSTITUTE - WO2021/74392, 2021, A1
[4]Ruyet, Louise; Poisson, Thomas; Besset, Tatiana [European Journal of Organic Chemistry, 2021, vol. 2021, # 23, p. 3407 - 3410]
[5]Xie, Yundong; Liu, Jiping; Shi, Yongheng; Bin Wang; Wang, Xiaoping; Wang, Wei; Sun, Meng; Xu, Xinya; He, Shipeng [Medicinal Chemistry Research, 2021, vol. 30, # 9, p. 1688 - 1702]

37
[ 1486-53-9 ]
sen-215 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 13 steps 1: HNO₂ 2: 62 percent / H₂ / 10percent Pd/C 3: 83 percent 4: 65 percent 5: 83 percent / oxalyl chloride 6: benzene / 12 h / Heating 7: p-TsOH 9: 23 percent / KH / tetrahydrofuran 10: 92 percent / K₂CO₃ 11: 77 percent / PCC 12: 70 percent / t-BuOK / tetrahydrofuran 13: 1.) HCl conc., 2.) 10percent NaOH / 1.) EtOH, 2.) MeOH

Reference： [1]Mori, Miwako; Ishikura, Minoru; Ikeda, Toshihito; Ban, Yoshio [Heterocycles, 1984, vol. 22, # 2, p. 253 - 256]

38
[ 1486-53-9 ]
[ 89625-59-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 12 steps 1: HNO₂ 2: 62 percent / H₂ / 10percent Pd/C 3: 83 percent 4: 65 percent 5: 83 percent / oxalyl chloride 6: benzene / 12 h / Heating 7: p-TsOH 9: 23 percent / KH / tetrahydrofuran 10: 92 percent / K₂CO₃ 11: 77 percent / PCC 12: 70 percent / t-BuOK / tetrahydrofuran

Reference： [1]Mori, Miwako; Ishikura, Minoru; Ikeda, Toshihito; Ban, Yoshio [Heterocycles, 1984, vol. 22, # 2, p. 253 - 256]

39
[ 1486-53-9 ]
[ 89625-58-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 11 steps 1: HNO₂ 2: 62 percent / H₂ / 10percent Pd/C 3: 83 percent 4: 65 percent 5: 83 percent / oxalyl chloride 6: benzene / 12 h / Heating 7: p-TsOH 9: 23 percent / KH / tetrahydrofuran 10: 92 percent / K₂CO₃ 11: 77 percent / PCC

Reference： [1]Mori, Miwako; Ishikura, Minoru; Ikeda, Toshihito; Ban, Yoshio [Heterocycles, 1984, vol. 22, # 2, p. 253 - 256]

40
[ 1486-53-9 ]
[ 89625-57-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1: HNO₂ 2: 62 percent / H₂ / 10percent Pd/C 3: 83 percent 4: 65 percent 5: 83 percent / oxalyl chloride 6: benzene / 12 h / Heating 7: p-TsOH 9: 23 percent / KH / tetrahydrofuran 10: 92 percent / K₂CO₃

Reference： [1]Mori, Miwako; Ishikura, Minoru; Ikeda, Toshihito; Ban, Yoshio [Heterocycles, 1984, vol. 22, # 2, p. 253 - 256]

41
[ 1486-53-9 ]
[ 89625-56-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1: HNO₂ 2: 62 percent / H₂ / 10percent Pd/C 3: 83 percent 4: 65 percent 5: 83 percent / oxalyl chloride 6: benzene / 12 h / Heating 7: p-TsOH 9: KBr / dimethylsulfoxide 10: NaH / tetrahydrofuran

Reference： [1]Mori, Miwako; Ishikura, Minoru; Ikeda, Toshihito; Ban, Yoshio [Heterocycles, 1984, vol. 22, # 2, p. 253 - 256]

42
[ 1486-53-9 ]
[ 89625-45-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1: HNO₂ 2: 62 percent / H₂ / 10percent Pd/C 3: 83 percent 4: 65 percent 5: 83 percent / oxalyl chloride 6: benzene / 12 h / Heating 7: p-TsOH 9: 23 percent / KH / tetrahydrofuran

Reference： [1]Mori, Miwako; Ishikura, Minoru; Ikeda, Toshihito; Ban, Yoshio [Heterocycles, 1984, vol. 22, # 2, p. 253 - 256]

43
[ 1486-53-9 ]
[ 89625-53-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: HNO₂ 2: 62 percent / H₂ / 10percent Pd/C 3: 83 percent 4: 65 percent 5: 83 percent / oxalyl chloride 6: benzene / 12 h / Heating 7: p-TsOH

Reference： [1]Mori, Miwako; Ishikura, Minoru; Ikeda, Toshihito; Ban, Yoshio [Heterocycles, 1984, vol. 22, # 2, p. 253 - 256]

44
[ 1486-53-9 ]
[ 491-71-4 ]

Reference： [1]Journal of the Chemical Society,1930,p. 817,818

45
[ 100-44-7 ]
[ 1486-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: aqueous KOH / 110 - 120 °C 2: potassium permanganate; acetone
	Multi-step reaction with 2 steps 1: potassium carbonate / ethanol / 6 h / Reflux 2: potassium permanganate / acetone; water / 1 h / Reflux
	Multi-step reaction with 2 steps 1: potassium carbonate / ethanol / 6 h / Reflux 2: potassium permanganate / water; acetone / 1 h / Reflux

	Multi-step reaction with 2 steps 1.1: potassium carbonate / ethanol / 0.17 h / 20 °C 1.2: 5 h / Reflux 2.1: dihydrogen peroxide; sodium hypochlorite; disodium hydrogenphosphate / tetrahydrofuran; water
	Multi-step reaction with 2 steps 1: potassium iodide; potassium carbonate / N,N-dimethyl-formamide / 60 - 120 °C 2: potassium hydroxide; oxygen / 1,2-dimethoxyethane
	Multi-step reaction with 2 steps 1: potassium iodide; potassium carbonate / N,N-dimethyl-formamide / 60 - 120 °C 2: potassium hydroxide; oxygen / 1,2-dimethoxyethane
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone 2: potassium permanganate / acetone; water

Reference： [1]Lovecy; Robinson; Sugasawa [Journal of the Chemical Society, 1930, p. 817,818]
[2]Zhang, Hai-Qi; Gong, Fei-Hu; Ye, Ji-Qing; Zhang, Chi; Yue, Xiao-Hong; Li, Chuan-Gui; Xu, Yun-Gen; Sun, Li-Ping [European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254]
[3]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN105884699, 2016, A
[4]Current Patent Assignee: XI AN JIAOTONG UNIVERSITY - CN103980152, 2016, B
[5]Current Patent Assignee: CMBLU PROJEKT AG - US2019/85006, 2019, A1
[6]Current Patent Assignee: CMBLU PROJEKT AG - WO2019/158615, 2019, A1
[7]Pugachev, Mikhail V.; Agafonova, Maria N.; Bastrikova, Oksana A.; Gnezdilov, Oleg I.; Nikishova, Tatyana V.; Balakin, Konstantin V.; Shtyrlin, Yurii G. [Medicinal Chemistry Research, 2021, vol. 30, # 5, p. 1139 - 1150]

46
[ 121-33-5 ]
[ 1486-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: aqueous KOH / 110 - 120 °C 2: potassium permanganate; acetone
	Multi-step reaction with 2 steps 1: NaOEt 2: Ag₂O, aq. NaOH
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 12 h / Inert atmosphere; Reflux 2: sodium dihydrogenphosphate; sodium chlorite; dihydrogen peroxide / water; acetonitrile / 0 - 10 °C

	Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 10 h / Inert atmosphere; Reflux 2: sodium dihydrogenphosphate dihydrate; sodium chlorite; dihydrogen peroxide / water; acetonitrile / 10 - 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: potassium carbonate / ethanol / 6 h / Reflux 2: potassium permanganate / acetone; water / 1 h / Reflux
	Multi-step reaction with 2 steps 1: potassium carbonate / ethanol / 6 h / Reflux 2: potassium permanganate / water; acetone / 1 h / Reflux
	Multi-step reaction with 2 steps 1.1: potassium carbonate / ethanol / 0.17 h / 20 °C 1.2: 5 h / Reflux 2.1: dihydrogen peroxide; sodium hypochlorite; disodium hydrogenphosphate / tetrahydrofuran; water
	Multi-step reaction with 2 steps 1: potassium iodide; potassium carbonate / N,N-dimethyl-formamide / 60 - 120 °C 2: potassium hydroxide; oxygen / 1,2-dimethoxyethane
	Multi-step reaction with 2 steps 1: potassium iodide; potassium carbonate / N,N-dimethyl-formamide / 60 - 120 °C 2: potassium hydroxide; oxygen / 1,2-dimethoxyethane
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone 2: potassium permanganate / acetone; water

Reference： [1]Lovecy; Robinson; Sugasawa [Journal of the Chemical Society, 1930, p. 817,818]
[2]Baggaley; Fears; Hindley; Morgan; Murrell; Thorne [Journal of Medicinal Chemistry, 1977, vol. 20, # 11, p. 1388 - 1393]
[3]Zhang, Mei; Yang, Xiao-Ying; Tang, Wei; Groeneveld, Tom W. L.; He, Pei-Lan; Zhu, Feng-Hua; Li, Jia; Lu, Wei; Blom, Anna M.; Zuo, Jian-Ping; Nan, Fa-Jun [ACS Medicinal Chemistry Letters, 2012, vol. 3, # 4, p. 317 - 321]
[4]Mishra, Vivek Kumar; Ravikumar, Ponneri C.; Maier, Martin E. [Tetrahedron, 2016, vol. 72, # 41, p. 6499 - 6509]
[5]Zhang, Hai-Qi; Gong, Fei-Hu; Ye, Ji-Qing; Zhang, Chi; Yue, Xiao-Hong; Li, Chuan-Gui; Xu, Yun-Gen; Sun, Li-Ping [European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254]
[6]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN105884699, 2016, A
[7]Current Patent Assignee: XI AN JIAOTONG UNIVERSITY - CN103980152, 2016, B
[8]Current Patent Assignee: CMBLU PROJEKT AG - US2019/85006, 2019, A1
[9]Current Patent Assignee: CMBLU PROJEKT AG - WO2019/158615, 2019, A1
[10]Pugachev, Mikhail V.; Agafonova, Maria N.; Bastrikova, Oksana A.; Gnezdilov, Oleg I.; Nikishova, Tatyana V.; Balakin, Konstantin V.; Shtyrlin, Yurii G. [Medicinal Chemistry Research, 2021, vol. 30, # 5, p. 1139 - 1150]

47
[ 56441-97-5 ]
[ 1486-53-9 ]

Yield	Reaction Conditions	Operation in experiment
74%	With sodium hydroxide; In methanol; for 4.0h;Heating / reflux;	E) 4-Benzyloxy-3-methoxy benzoic acid; A solution of sodium hydroxide (2.0 g) in methanol (50 ml) was added to a solution of 4-benzyloxy-3-methoxy benzoic acid methyl ester (4.64 g) in methanol (50 ml) and refluxed for 4 hrs. After removal of methanol under reduced pressure the residue was dissolved in water (150 ml) and washed with ethyl acetate (2 x 50 ml). The aqueous layer was acidified with 2N hydrochloric acid to pH 2. The precipitated product was collected by filtration which on drying under vacuum provided 4.17 g of 4-benzyloxy- 3-methoxy benzoic acid. (Yield = 74%) 'H NMR CDCl3 7.7 (1H, d, J = 8Hz) 7.63 (1H, s) 7.3-7.5 (5H, m) 6.92 (1H, d, J 8Hz) 5.25 (2H, s) 3.98 (3H, s)
		(1) Benzyl bromide (3.59 ml) and potassium carbonate (5.69 g) were added to an acetone (50 ml) solution of methyl 4-hydroxy-3-methoxybenzoate (5.00 g), and heated at reflux for 4 hours. After removing solid matter by filtration and concentrating the filtrate under reduced pressure, the residue was dissolved in ethyl acetate, and washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure, thereby giving 7.47 g of <strong>[56441-97-5]methyl 4-benzyloxy-3-methoxybenzoate</strong>.(2) An aqueous 2 M sodium hydroxide solution (13.72 ml) was added to an ethanol (15 ml) solution of the above-obtained 4-benzyloxy compound (7.47 g), and heated at reflux for 2 hours. After evaporating the solvent under reduced pressure, 2M hydrochloric acid was added, and the thus-precipitated crystals were filtered, thereby giving 7.00 g of the desired compound.

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 1690 - 1695
[2]Patent: WO2005/113489,2005,A1 .Location in patent: Page/Page column 93
[3]Synlett,2010,p. 753 - 756
[4]Patent: EP1489077,2004,A1 .Location in patent: Page 40
[5]RSC Advances,2016,vol. 6,p. 40238 - 40249

48
[ 1486-53-9 ]
[ 61324-40-1 ]
[ 870090-77-0 ]

Yield	Reaction Conditions	Operation in experiment
69%	With benzotriazol-1-ol; diisopropyl-carbodiimide In DMF (N,N-dimethyl-formamide) for 12h;	12.F F) 4-Benzyloxy-3-methoxy-N-(3-benzyloxy-4-methoxyphenyl) benzamide; N, N-1,3-Diisopropyl carbodiimide (0.40 g, 3.36 mmol) was added to a solution of 1-benzyloxy-2-methoxy-5-aminobenzene (0.771 g, 3.36 mmol), 4- benzyloxy-3-methoxy benzoic acid (0.87 g, 3.36 mmol) and 1-hydroxybenzotriazole (0.454 g, 3.36 mmol) in N, N- dimethylformamide (15 ml) and stirred for 12 hrs. The product was precipitated by diluting with a mixture of ethyl acetate/hexane (1:1) (120ml). Filtration of the reaction mixture provided 1.12 g of 4-Benzyloxy-3- methoxy-N- (3-benzyloxy-4-methoxyphenyl) benzamide. Yield = 69 %. ¹H NMR (CD3)2SO 9.93 (1H, s) 7.29-7.59 (14H, m) 7.16 (1H, d, J 8Hz) 6.96 (lH, d, J 8Hz) 5.18 (2H, s) 5.06 (2H, s) 3.85 (3H, s) 3.76 (3H, s)

Reference： [1]Current Patent Assignee: PROTAMED, INC. - WO2005/113489, 2005, A1 Location in patent: Page/Page column 93-94

49
[ 121-34-6 ]
[ 7732-18-5 ]
[ 100-44-7 ]
[ 1486-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide In ethanol	5.1 Synthesis of 2,6,9-tris(4-hydroxy-3-methoxybenzoyloxy)anthracene (1) To a suspension of 4-hydroxy-3-methoxybenzoic acid (25 g, 0.15 mole) in ethanol (150 ml), 2N NaOH aq. (74.3 g, 0.15 mole) and benzyl chloride (56.5 g, 0.45 mole) were added, continued to stir for 1 hour under reflux, then 5N NaOH aq. (150 ml) was added dropwise with stirring under reflux, and continued to stir for 1 hour under reflux. After reaction, the solvent was removed, and H2 O was added to the residue and acidified with conc. hydrochloric acid to make pH 1. The resulting precipitate was filtered, washed with H2 O and dried to give 22.1 g of 4-benzyloxy-3-methoxybenzoic acid as pale yellow crystals having a m.p. of 171°-172.5°. 1 H-NMR δ ppm (DMSO-d6): 3.81 (3H, s, CH3 O-), 5.16 (2H, s, ARCH2 O-), 7.13 (1H, d, J=8Hz, Ar 5-H), 7.33-7.44 (5H, m, ArH), 7.47 (1H, d, J=2Hz, Ar 2-H), 7.54 (1H, dd, J=2Hz and 8Hz, Ar 6-H). IR (KBr-disk) ν cm-1: 1676 (COOH).

Reference： [1]Current Patent Assignee: FUJIFILM HOLDINGS CORP. - US5498748, 1996, A

50
C₉H₁₂ClN₂Pol [ No CAS ]
[ 1486-53-9 ]
C₂₄H₂₄ClN₂O₃Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With diisopropyl-carbodiimide In N,N-dimethyl-formamide at 20℃;	65.3 Step 3: benzoic acid; The resin is suspended in 2.5 ml DMF and treated with 61.9 mg 4-benzyloxy-3-methoxybenzoic acid (5.00 mmol, 5 eq) and 121 mg (10.00 mmol, 10 eq.) DIC over night at rt. The resin is washed three times with DMF, and alternately three times with methanol and dichloromethane.

Reference： [1]Current Patent Assignee: BAYER AG - WO2007/17092, 2007, A1 Location in patent: Page/Page column 15; 64

51
[ 926025-92-5 ]
[ 1486-53-9 ]
tert-butyl {3-[[4-(benzyl-oxy)-3-methoxy-benzoyl](4-fluorobenzyl)-amino]propyl}-carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl (3-((4-fluorobenzyl)-amino)propyl)carbamate; 4-(benzyloxy)-3-methoxybenzoic acid With dmap; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃;	11 General procedure A; Amide bond formation; The carboxylic acid (1.0 eq.) is dissolved in anhydrous DMF (0.1 to 0.2 mol/1), amine derivative (1.0 to 1.3 eq.), HOBT (0 to 1.2 eq.), 4-DMAP (0.1 to 1.2 eq.), diisoppropylethylamine (1.5 to 2.0 eq.) are added. The mixture is stirred at rt for 10 min, cooled to O0C, before l-(3-dimethyl- aminopropyl)-3-ethylcarbodiimid hydrochloride (1.1 eq.) is added in one portion. The cooling bath is removed and stirring is continued at rt (typically over night). The reaction mixture is poured onto water and extracted three times with ethyl acetate. The combined organic layers are washed (IN hydrochloric acid, saturated sodium bicarbonate solution, pH 7 buffer solution and / or brine), dried with magnesium sulfate or sodium sulfate and concentrated in vacuo. The residue is purified by chromatography on silica gel (mixtures of cyclohexane and ethyl acetate or dichloromethane and methanol) or reverse phase HPLC (gradients of water and acetonitrile) to afford the title compound.

Reference： [1]Current Patent Assignee: BAYER AG - WO2007/17092, 2007, A1 Location in patent: Page/Page column 39-40

52
[ 1486-53-9 ]
[ 88-74-4 ]
[ 1298086-95-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-(benzyloxy)-3-methoxybenzoic acid With thionyl chloride In dichloromethane at 50℃; for 2h; Stage #2: 2-nitro-aniline With pyridine In dichloromethane at 20℃;	76.1 Example 76; Preparation of 2- (4-benzyloxy-3- iuethoxyphenyl) benzimidazole (Step 1)In 20 ml of methylene chloride was suspended 2.0 g (7.7 mmol) of 4-benzyloxy-3-methoxy benzoic acid. DMF (0.05 g) and thionyl chloride (0.68 ml) were added to this suspension. The mixture was stirred at 500C for 2 hours. At a temperature of O0C, 20 ml of pyridine wherein 1.1 g (8.0 mmol) of 2-nitroaniline had been dissolved at room temperature was added dripwise to the mixture. The mixture was stirred for 2 hours at room temperature, and water was added thereto to extract the methylene chloride phase. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The crystals thus obtained were recrystallized using methylene chloride-hexane, thereby yielding 1.5 g of N- (2- nitrophenyl) -4-benzyloxy-3-methoxybenzamide crystals . 1H-NMR (DMSO-de, δ) : 11.32 (IH, br s) , 8.99 (IH, d, J = 8.0 Hz), 8.27(1H, d, J = 7.6 Hz), 7.7O(1H, dd, J= 7.6, 7.6 Hz), 7.59(1H, d, J = 2.0 Hz), 7.51(1H, dd, J = 2.0, 8.4 Hz), 7.30-7.47 (5H, m) , 7.2O(1H, dd, J = 7.6, 8.0 Hz), 6.99(1H, d, J = 8.4 Hz)

Reference： [1]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2009/139076, 2009, A1 Location in patent: Page/Page column 48-49

53
[ 1486-53-9 ]
[ 137-07-5 ]
[ 902096-57-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-(benzyloxy)-3-methoxybenzoic acid With thionyl chloride In dichloromethane at 50℃; for 2h; Stage #2: 2-amino-benzenethiol With pyridine In dichloromethane at 0 - 20℃; Stage #3: In toluene Reflux;	78 Example 78; Preparation of 2- (4-benzyloxy-3- methoxypheny1) benzothiazoleIn methylene chloride (10 ml) was suspended 2.0 g (7.7 mmol) of 4-benzyloxy-3-methoxy benzoic acid. To this suspension was added 0.05 g of DMF and 0.68 ml of thionyl chloride, followed by stirring at 500C for 2 hours.This reaction solution was introduced dropwise at 0°C into a solution wherein 1.2 g (9.3 mmol) of 2-aminothiophenol had been dissolved in 10 ml of pyridine at room temperature . The mixture was further stirred overnight at room temperature, diluted with water, and subjected to ethyl acetate extraction (50 ml x 2 times) . The extracts were dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue thus obtained was dissolved in 30 ml of toluene. This toluene solution was heated to reflux overnight while water was distilled off. Toluene was removed from this solution by distillation under reduced pressure, and the residue was purified using a silica gel column (eluant: ethyl acetate/hexane = 1/5). The solvent was distilled off under reduced pressure. Using the crystals thus obtained, the desired compound was recrystallized in an amount of 0.18 g from methylene chloride-hexane .

Reference： [1]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2009/139076, 2009, A1 Location in patent: Page/Page column 50-51

54
(1R,2R)-trans-1,2-cyclohexanediol [ No CAS ]
[ 1486-53-9 ]
[ 1222382-19-5 ]

Yield	Reaction Conditions	Operation in experiment
48%	With dmap; dicyclohexyl-carbodiimide In toluene at 20℃;	5.A 5. An other general procedure for the three step synthesis using benzyl ether as phenol protecting group.The diol (100 to 200 mg), the DMAP (2.1 eq.) and the protected vanillic acid (3-Methoxy-4- benzyloxy-benzoic acid (cf. A.2.) 2.5 eq.) are wheight in the reactor. Toluene is added (100 ml. for 100 mg of diol) and then the DCC (2.3 eq.). The medium is stirred at RT for 3 to 4 days. The solvent is evaporated to dryness and the medium is directly purified by silica gel chromatography using the eluent given for the Rf.The dibenzylated compound (200 to 500 mg) is wheight in the reactor. MeOH is added (20 ml. for 100 mg) and the medium is cooled by a water-ice bath before addition of the 10%Palladium on carbon catalyst (same wheight as the dibenzylated product). The medium is then placed under hydrogen atmosphere and stirred at RT overnight. The medium is filtered throught silica gel and then chromatographed if necessary.Yield = 63%1H NMR (DMSO) : 12.68 (bs ; 1 H ; COOH) ; 7.54 (dd ; 2H ; 7 ; 3J6,7 = 8.4 ; 4J37 = 2.1 ) ; 7.42(m ; 12H ; 3.11.12&13) ; 7.14 (d ; 2H ; 6 ; 3J6,7 = 8.4) ; 5.16 (s ; 2H ; 9) ; 3.80 (s ; 6H ; 8). 5. A. Synthesis of compound DLT8:Yield = 48% ; Rf = 0.25 (Petroleum ether / AcOEt 8/2)1H NMR (DMSO) : 7.50 (dd ; 2H ; 7 ; 3J6,7 = 8.5 ; 4J3,7 = 1.8) ; 7.40 (m ; 12H ; 3, 14, 15&16) ; 7.08 (d ; 2H ; 6 ; 3J6,7 = 8.5 ) ; 5.10 (bs ; 6H ; 8&12) ; 3.75 (s ; 6H ; 1 1 ) ; 2.10 (m ; 2H ; 9a) ; 1.72 to 1.42 (m ; 6H ; 2b, 3a&3b). 13C NMR (DMSO) : 164.9 (1) ; 151.9 (5) ; 148.5 (4) ; 136.3 (10) ; 128.4/127.8 (11&12) ; 127.9 (13) ; 122.8 (7) ; 121.9 (2) ; 112.4 (6) ; 111.7 (3) ; 74.1 (9) ; 69.8 (14) ; 55.54 (8) ; 29.7 (15) ; 23.0 (16).Yield = 81 % ; Rf = 0.25 (Petroleum ether / AcOEt 8/2)1H NMR (DMSO) : 7.36 (m ; 4H ; 7&3) ; 6.81 (d ; 2H ; 6 ; 3J6,7 = 8.1) ; 5.08 (bs ; 2H ; 9) ; 2.13 to 2.10 (m ; 2H ; 10a) ; 1.78 to 1.48 (m ; 6H ; 10b&11).13C NMR (DMSO) : 164.9 (1) ; 151.9 (5) ; 148.5 (4) ; 136.3 (10) ; 128.4/127.8 (11&12) ;127.9 (13) ; 122.8 (7) ; 121.9 (2) ; 112.4 (6) ; 111.7 (3) ; 74.1 (9) ; 69.8 (14) ; 55.54 (8) ; 29.7(15) ; 23.0 (16).
48%	With dmap; dicyclohexyl-carbodiimide In toluene

Reference： [1]Current Patent Assignee: UNIVERSITE LIBRE DE BRUXELLES - WO2010/43631, 2010, A1 Location in patent: Page/Page column 52-53
[2]Lamoral-Theys, Delphine; Pottier, Laurent; Kerff, Frédéric; Dufrasne, François; Proutière, Fabien; Wauthoz, Nathalie; Neven, Philippe; Ingrassia, Laurent; Antwerpen, Pierre Van; Lefranc, Florence; Gelbcke, Michel; Pirotte, Bernard; Kraus, Jean-Louis; Nève, Jean; Kornienko, Alexander; Kiss, Robert; Dubois, Jacques [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 11, p. 3823 - 3833]

55
[ 1486-53-9 ]
[ 121-34-6 ]

Yield	Reaction Conditions	Operation in experiment
80%	With magnesium iodide for 10h; neat (no solvent);

Reference： [1]Location in patent: scheme or table Bao, Kai; Fan, Aixue; Dai, Yi; Zhang, Liang; Zhang, Weige; Cheng, Maosheng; Yao, Xinsheng [Organic and Biomolecular Chemistry, 2009, vol. 7, # 24, p. 5084 - 5090]

56
[ 1486-53-9 ]
[ 37073-15-7 ]
[ 1228255-36-4 ]

Reference： [1]Synlett,2010,p. 753 - 756

57
[ 504-01-8 ]
[ 1486-53-9 ]
[ 1222382-14-0 ]
trans-[3-(4-benzyloxy-3-methoxybenzoyl)oxycyclohexyl]-4-benzyloxy-3-methoxybenzoate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 3823 - 3833

58
[ 1486-53-9 ]
[ 107-21-1 ]
[ 1234569-92-6 ]

Yield	Reaction Conditions	Operation in experiment
68%	With dmap; dicyclohexyl-carbodiimide In toluene

Reference： [1]Location in patent: experimental part Lamoral-Theys, Delphine; Pottier, Laurent; Kerff, Frédéric; Dufrasne, François; Proutière, Fabien; Wauthoz, Nathalie; Neven, Philippe; Ingrassia, Laurent; Antwerpen, Pierre Van; Lefranc, Florence; Gelbcke, Michel; Pirotte, Bernard; Kraus, Jean-Louis; Nève, Jean; Kornienko, Alexander; Kiss, Robert; Dubois, Jacques [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 11, p. 3823 - 3833]

59
[ 1486-53-9 ]
[ 504-63-2 ]
[ 1234569-93-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	With dmap; dicyclohexyl-carbodiimide In toluene

60
[ 1486-53-9 ]
[ 171270-07-8 ]
[ 1253587-35-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 15h; Inert atmosphere;

Reference： [1]Location in patent: experimental part Catel, Yohann; Aladedunye, Felix; Przybylski, Roman [Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 20, p. 11081 - 11089]

61
[ 1486-53-9 ]
1-Benzyloxy-4,5-diiodo-2-methoxy-benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With [bis(acetoxy)iodo]benzene; lithium iodide In 1,1,1,3,3,3-hexafluoroisopropanol at 20℃;

Reference： [1]Location in patent: scheme or table Hamamoto, Hiromi; Hattori, Sho; Takemaru, Kaori; Miki, Yasuyoshi [Synlett, 2011, # 11, p. 1563 - 1566]

62
[ 1486-53-9 ]
C₁₅H₁₃NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With diphenyl phosphoryl azide; triethylamine In benzene at 20℃; for 5h; Inert atmosphere; Reflux;

63
[ 100-39-0 ]
[ 1486-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 12 h / Inert atmosphere; Reflux 2: sodium dihydrogenphosphate; sodium chlorite; dihydrogen peroxide / water; acetonitrile / 0 - 10 °C
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone 2: methanol; potassium hydroxide
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 10 h / Inert atmosphere; Reflux 2: sodium dihydrogenphosphate dihydrate; sodium chlorite; dihydrogen peroxide / water; acetonitrile / 10 - 20 °C / Inert atmosphere

Reference： [1]Zhang, Mei; Yang, Xiao-Ying; Tang, Wei; Groeneveld, Tom W. L.; He, Pei-Lan; Zhu, Feng-Hua; Li, Jia; Lu, Wei; Blom, Anna M.; Zuo, Jian-Ping; Nan, Fa-Jun [ACS Medicinal Chemistry Letters, 2012, vol. 3, # 4, p. 317 - 321]
[2]Orlowska, Ewelina; Roller, Alexander; Wiesinger, Hubert; Pignitter, Marc; Jirsa, Franz; Krachler, Regina; Kandioller, Wolfgang; Keppler, Bernhard K. [RSC Advances, 2016, vol. 6, # 46, p. 40238 - 40249]
[3]Mishra, Vivek Kumar; Ravikumar, Ponneri C.; Maier, Martin E. [Tetrahedron, 2016, vol. 72, # 41, p. 6499 - 6509]

64
[ 1486-53-9 ]
[ 445388-24-9 ]
[ 1448792-48-0 ]

Yield	Reaction Conditions	Operation in experiment
81%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 6h; Inert atmosphere;

Reference： [1]Khandelwal, Anuj; Hall, Jessica A.; Blagg, Brian S.J. [Journal of Organic Chemistry, 2013, vol. 78, # 16, p. 7859 - 7884]

65
[ 17625-83-1 ]
[ 1486-53-9 ]
N-(4-benzoylamino)phenyl-4-benzyloxy-3-methoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 72h;

Reference： [1]Doig, Peter; Boriack-Sjodin, P. Ann; Dumas, Jacques; Hu, Jun; Itoh, Kenji; Johnson, Kenneth; Kazmirski, Steven; Kinoshita, Tomohiko; Kuroda, Satoru; Sato, Tomo-O; Sugimoto, Kaori; Tohyama, Katsumi; Aoi, Hiroshi; Wakamatsu, Kazusa; Wang, Hongming [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 21, p. 6256 - 6269]

66
[ 1486-53-9 ]
[ 491839-49-7 ]
N-{4-[(4-benzyloxy-3-methoxybenzene)amido]phenyl}pyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 24h;

67
[ 121-34-6 ]
[ 100-39-0 ]
[ 1486-53-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium hydroxide In ethanol at 65℃; for 8h;	212 Example 212.4: Synthesis of 4-(benzyloxy) -3-methoxybenzoic acid To a mixture of 4-hydroxy-3-methoxybenzoic acid (50.0 g, 297.5 mmol) in ethanol (350 mL) and a sodium hydroxide solution (2.0 M, 350 mL) was added benzyl bromide (140.0 g, 823.5 mmol). The mixture was stirred at 65 ° C. for 8 hours, concentrated, co-concentrated with water (2 × 400 mL) to about 400 mL, and acidified to pH 3.0 with 6N hydrochloric acid. The solid was collected by filtration, recrystallized from ethanol, and dried under vacuum at 45 ° C to obtain the title compound (63.6 g, 83% yield). ESI MS m / z: 281.2 ([M + Na] +).
83%	With sodium hydroxide In ethanol at 65℃; for 8h;	19 Example 19. 4-(benzyloxy)-3-methoxybenzoic acid 4-Hydroxy-3-methoxybenzoic acid (50.0 g, 297.5 mmol) in the mixture of ethanol (350 ml) and NaOH solution (2.0 M, 350 ml) was added BnBr (140.0 g, 823.5 mmol). The mixture was stirred at 65 °C for 8 h, concentrated, co-evaporated with water (2 x 400 ml) to -400 ml. acidified with 6 M HQ to pi I 3.0, filtered the solid, crystallized with EtOH, dried over the oven at 45 °C with vacuum to afford the title compound (63.6 g, 83% yield).
83%	With sodium hydroxide In ethanol at 65℃; for 8h;	8 Example 8. 4-(benzyloxy)-3-methoxybenzoic acid Example 8. 4-(benzyloxy)-3-methoxybenzoic acid 4-Hydroxy-3-methoxybenzoic acid (50.0 g, 297.5 mmoi) in the mixture of ethanol (350 ml) and NaOH solution (2.0 M, 350 ml) was added BnBr (140.0 g, 823.5 mmol). The mixture was stirred at 65 °C for 8 h, concentrated, co-evaporated with water (2 x 400 ml) to 400 ml, acidified with 6 M HC1 to pH 3.0, filtered the solid, crystallized with EtOH,dried over the oven at 45 °C with vacuum to afford the title compound (63.6 g, 83% yield). ESI MS mlz+ 281.2 (M + Na). ESI MS mlz+ 281.2 (M + Na).

83%	With sodium hydroxide In ethanol; water at 65℃; for 8h;	91 Example 91. Synthesis of 4-(benzyloxy)-3-methoxybenzoic acid (238). To a mixture of 4-hydroxy-3-methoxybenzoic acid (50.0 g, 297.5 mmol) in ethanol (350 ml) and aq. NaOH solution (2.0 M, 350 ml) was added BnBr (140.0 g, 823.5 mmol). The mixture was stirred at 65 °C for 8 h, concentrated, co-evaporated with water (2 × 400 ml) and concentrated to ~400 ml, acidified to pH 3.0 with 6 N HCl. The solid was collected by filtration, crystallized with EtOH, dried at 45 °C under vacuum to afford the title compound (63.6 g, 83% yield). ESI MS m/z 281.2 ([M+Na]+).
83%	With sodium hydroxide In ethanol; water at 65℃; for 8h;
83%	With sodium hydroxide In ethanol; water at 65℃; for 8h;	80 Example 80. Synthesis of 4- (benzyloxy) -3-methoxybenzoic acid. To a mixture of 4-hydroxy-3-methoxybenzoic acid (50.0 g, 297.5 mmol) in ethanol (350 ml) and aq. NaOH solution (2.0 M, 350 ml) was added BnBr (140.0 g, 823.5 mmol) . The mixture was stirred at 65 for 8 h, concentrated, co-evaporated with water (2 × 400 ml) and concentrated to 400 ml, acidified to pH 3.0 with 6 N HCl. The solid was collected by filtration, crystallized with EtOH, dried at 45 under vacuum to afford the title compound (63.6 g, 83%yield) . ESI MS m/z 281.2 ( [M+Na] +) .
83%	With sodium hydroxide In ethanol; water at 65℃; for 8h;

Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - CN110621673, 2019, A Location in patent: Paragraph 1089-1091
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2015/28850, 2015, A1 Location in patent: Page/Page column 84
[3]Current Patent Assignee: SUZHOU M CONJ BIOTECH CO LTD - WO2015/155753, 2015, A2 Location in patent: Page/Page column 86; 87
[4]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD; SUZHOU M CONJ BIOTECH CO LTD - WO2016/59622, 2016, A2 Location in patent: Page/Page column 125-126
[5]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2018/86139, 2018, A1 Location in patent: Page/Page column 182
[6]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/6722, 2020, A1 Location in patent: Page/Page column 145
[7]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/73345, 2020, A1 Location in patent: Page/Page column 291

68
[ 1486-53-9 ]
[ 945490-07-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: acetic acid; nitric acid / dichloromethane / 6 h 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3: triethylamine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: nitric acid; acetic acid / dichloromethane / 6 h 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3: triethylamine / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: nitric acid; acetic acid / dichloromethane / 6 h 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3: triethylamine / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere

	Multi-step reaction with 3 steps 1: nitric acid / dichloromethane; acetic acid / 6 h 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3: triethylamine / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1.1: acetic acid; nitric acid / dichloromethane / 6 h 2.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C 2.2: 8 h / 0 - 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: acetic acid; nitric acid / dichloromethane / 72 h / 20 °C / Inert atmosphere 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C / Inert atmosphere 3: triethylamine / dichloromethane / 8.25 h / 0 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2015/28850, 2015, A1
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD; SUZHOU M CONJ BIOTECH CO LTD - WO2016/59622, 2016, A2
[3]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2018/86139, 2018, A1
[4]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/6722, 2020, A1
[5]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/73345, 2020, A1
[6]Current Patent Assignee: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; AIX-MARSEILLE UNIVERSITY; NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH; PAOLI CALMETTES INSTITUTE - WO2021/74392, 2021, A1

69
[ 1486-53-9 ]
[ 945490-08-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: acetic acid; nitric acid / dichloromethane / 6 h 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3: triethylamine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 4: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: acetic acid; nitric acid / dichloromethane / 6 h 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 2.2: 8 h / 0 - 20 °C / Inert atmosphere 3.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: nitric acid; acetic acid / dichloromethane / 6 h 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3: triethylamine / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere 4: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere

	Multi-step reaction with 4 steps 1: nitric acid; acetic acid / dichloromethane / 6 h 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3: triethylamine / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere 4: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: nitric acid / dichloromethane; acetic acid / 6 h 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3: triethylamine / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere 4: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: acetic acid; nitric acid / dichloromethane / 6 h 2.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C 2.2: 8 h / 0 - 20 °C / Inert atmosphere 3.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: nitric acid; acetic acid / dichloromethane / 6 h 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C / Inert atmosphere 2.2: 8 h / 0 - 20 °C 3.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: acetic acid; nitric acid / dichloromethane / 72 h / 20 °C / Inert atmosphere 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C / Inert atmosphere 3: triethylamine / dichloromethane / 8.25 h / 0 - 20 °C / Inert atmosphere 4: diisobutylaluminium hydride / dichloromethane; hexane / 1.5 h / -78 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2015/28850, 2015, A1
[2]Current Patent Assignee: SUZHOU M CONJ BIOTECH CO LTD - WO2015/155753, 2015, A2
[3]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD; SUZHOU M CONJ BIOTECH CO LTD - WO2016/59622, 2016, A2
[4]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2018/86139, 2018, A1
[5]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/6722, 2020, A1
[6]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/73345, 2020, A1
[7]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - JP2021/73185, 2021, A
[8]Current Patent Assignee: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; AIX-MARSEILLE UNIVERSITY; NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH; PAOLI CALMETTES INSTITUTE - WO2021/74392, 2021, A1

70
[ 1486-53-9 ]
[ 945490-09-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: acetic acid; nitric acid / dichloromethane / 6 h 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3.1: triethylamine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 4.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 5.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 5.2: 1 h / 20 °C / pH 2 6.1: methanesulfonic acid / dichloromethane / 0 - 20 °C
	Multi-step reaction with 5 steps 1.1: acetic acid; nitric acid / dichloromethane / 6 h 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 2.2: 8 h / 0 - 20 °C / Inert atmosphere 3.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 4.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 4.2: 1 h / 20 °C / pH Ca_. 2 5.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C
	Multi-step reaction with 6 steps 1.1: nitric acid; acetic acid / dichloromethane / 6 h 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3.1: triethylamine / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere 4.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 5.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 5.2: 1 h / 20 °C / pH Ca_. 2 6.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C

	Multi-step reaction with 5 steps 1.1: acetic acid; nitric acid / dichloromethane / 6 h 2.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C 2.2: 8 h / 0 - 20 °C / Inert atmosphere 3.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 4.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 5.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C
	Multi-step reaction with 6 steps 1.1: acetic acid; nitric acid / dichloromethane / 72 h / 20 °C / Inert atmosphere 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 8.25 h / 0 - 20 °C / Inert atmosphere 4.1: diisobutylaluminium hydride / dichloromethane; hexane / 1.5 h / -78 °C / Inert atmosphere 5.1: sodium dithionite / water; tetrahydrofuran / 20 °C 5.2: 1 h / pH 2 6.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2015/28850, 2015, A1
[2]Current Patent Assignee: SUZHOU M CONJ BIOTECH CO LTD - WO2015/155753, 2015, A2
[3]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD; SUZHOU M CONJ BIOTECH CO LTD - WO2016/59622, 2016, A2
[4]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/73345, 2020, A1
[5]Current Patent Assignee: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; AIX-MARSEILLE UNIVERSITY; NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH; PAOLI CALMETTES INSTITUTE - WO2021/74392, 2021, A1

71
2,3,4,6-Tetra-O-benzyl-D-glucopyranose [ No CAS ]
[ 1486-53-9 ]
C₄₉H₄₈O₉ [ No CAS ]
C₄₉H₄₈O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33.333 % de	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 60℃; Overall yield = 84 %;	1.6 Vanillic acid having a benzyl-protected hydroxyl group at the 4 position and 2,3,4,6-tetrabenzyl glucose having benzyl-protected hydroxyl groups at positions other than the 1 position (Sigma-Aldrich) were condensed in a DMF solvent (at a reaction temperature of 60°C) using the following condensing agents: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, Kokusaikagaku Co., Ltd.), 4-dimethylaminopyridine (DMAP, Tokyo Kasei Kogyo), and triethylamine (Et3N, Wako Pure Chemical Industries, Ltd.). The obtained condensate was a mixture comprising α anomer and β anomer at a ratio of 1:2. The condensate was purified using an open column (at different concentration ratios of hexane : ethyl acetate = 6:1 and 5:1). A unreacted starting material was removed. The yield was found to be 84%: Molecular MS [M+Na]+ m/z 803.14, 1H NMR (300 MHz, CDCl3): δ7.60 (1H, dd, H-6), 7.59 (1H, d, H-2), 7.45-7.26 (60H, m, H-benzylic CH2), 6.90 (1H, d, H-5), 6.55 (1H, d, H-Glc1α, J=3.21), 5.84 (1H, d, H-Glc1β, J = 7.65), 5.25 (10H, s, H-benzylic CH2), 4.96-3.56 (94H, m, CH3, H-Glc).

Reference： [1]Current Patent Assignee: TOKYO UNIVERSITY OF AGRICULTURE AND TECHNOLOGY - EP2463366, 2015, B1 Location in patent: Paragraph 0103

72
[ 1486-53-9 ]
(11aS,11a’S)-8,8’-(pentane-1,5-diylbis(oxy))bis(7-methoxy-2-methylene-2,3 -dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(11aH)-one) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: acetic acid; nitric acid / dichloromethane / 6 h 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 2.2: 8 h / 0 - 20 °C / Inert atmosphere 3.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 4.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 4.2: 1 h / 20 °C / pH Ca_. 2 5.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C 6.1: caesium carbonate / butanone / 20 °C
	Multi-step reaction with 7 steps 1.1: nitric acid; acetic acid / dichloromethane / 6 h 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3.1: triethylamine / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere 4.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 5.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 5.2: 1 h / 20 °C / pH Ca_. 2 6.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C 7.1: caesium carbonate / butanone / 20 °C
	Multi-step reaction with 7 steps 1: nitric acid; acetic acid / dichloromethane / 6 h 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3: triethylamine / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere 4: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 5: sodium dithionite / water; tetrahydrofuran / 20 h / 20 °C 6: methanesulfonic acid / dichloromethane / 2 h / 0 - 20 °C 7: caesium carbonate / butanone / 20 °C

	Multi-step reaction with 7 steps 1: nitric acid / dichloromethane; acetic acid / 6 h 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3: triethylamine / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere 4: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 5: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 6: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C 7: caesium carbonate / butanone / 20 °C
	Multi-step reaction with 6 steps 1.1: acetic acid; nitric acid / dichloromethane / 6 h 2.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C 2.2: 8 h / 0 - 20 °C / Inert atmosphere 3.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 4.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 5.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C 6.1: caesium carbonate / butanone / 20 °C
	Multi-step reaction with 6 steps 1.1: nitric acid; acetic acid / dichloromethane / 6 h 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C / Inert atmosphere 2.2: 8 h / 0 - 20 °C 3.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 4.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 4.2: 1 h / 20 °C / pH 2 5.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C 6.1: caesium carbonate / butanone / 20 °C

Reference： [1]Current Patent Assignee: SUZHOU M CONJ BIOTECH CO LTD - WO2015/155753, 2015, A2
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD; SUZHOU M CONJ BIOTECH CO LTD - WO2016/59622, 2016, A2
[3]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2018/86139, 2018, A1
[4]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/6722, 2020, A1
[5]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/73345, 2020, A1
[6]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - JP2021/73185, 2021, A

73
[ 1486-53-9 ]
(S)-8-((5-(((S)-10-(3-(2-(2-azidoethoxy)ethoxy)propanoyl)-7-methoxy-2-methylene-5-oxo-2,3,5,10,11,11a-hexahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)pentyl)oxy)-7-methoxy-2-methylene-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(11aH)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: acetic acid; nitric acid / dichloromethane / 6 h 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 2.2: 8 h / 0 - 20 °C / Inert atmosphere 3.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 4.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 4.2: 1 h / 20 °C / pH Ca_. 2 5.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C 6.1: caesium carbonate / butanone / 20 °C 7.1: ethanol; sodium tetrahydroborate / dichloromethane; diethylene glycol dimethyl ether / 3.08 h / 0 - 20 °C 8.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C
	Multi-step reaction with 9 steps 1.1: nitric acid; acetic acid / dichloromethane / 6 h 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3.1: triethylamine / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere 4.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 5.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 5.2: 1 h / 20 °C / pH Ca_. 2 6.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C 7.1: caesium carbonate / butanone / 20 °C 8.1: ethanol; sodium tetrahydroborate / dichloromethane; ethyl methyl ether / 3.08 h / 0 - 20 °C 9.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C
	Multi-step reaction with 9 steps 1: nitric acid; acetic acid / dichloromethane / 6 h 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3: triethylamine / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere 4: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 5: sodium dithionite / water; tetrahydrofuran / 20 h / 20 °C 6: methanesulfonic acid / dichloromethane / 2 h / 0 - 20 °C 7: caesium carbonate / butanone / 20 °C 8: ethanol; sodium tetrahydroborate / dichloromethane; diethylene glycol dimethyl ether / 3 h / 0 - 20 °C 9: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C

	Multi-step reaction with 8 steps 1.1: nitric acid / dichloromethane; acetic acid / 6 h 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3.1: triethylamine / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere 4.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 5.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 6.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C 7.1: caesium carbonate / butanone / 20 °C 8.1: sodium tetrahydroborate; ethanol / dichloromethane; diethylene glycol dimethyl ether / 3.08 h / 0 - 20 °C 8.2: 20 °C
	Multi-step reaction with 8 steps 1.1: acetic acid; nitric acid / dichloromethane / 6 h 2.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C 2.2: 8 h / 0 - 20 °C / Inert atmosphere 3.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 4.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 5.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C 6.1: caesium carbonate / butanone / 20 °C 7.1: sodium tetrahydroborate / dichloromethane; ethanol / 3.08 h / 0 - 20 °C 8.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C
	Multi-step reaction with 8 steps 1.1: nitric acid; acetic acid / dichloromethane / 6 h 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C / Inert atmosphere 2.2: 8 h / 0 - 20 °C 3.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 4.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 4.2: 1 h / 20 °C / pH 2 5.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C 6.1: caesium carbonate / butanone / 20 °C 7.1: sodium tetrahydroborate / dichloromethane; ethanol; diethylene glycol dimethyl ether / 3.08 h / 0 - 20 °C 8.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C

74
[ 1486-53-9 ]
(S)-8-((5-(((S)-10-(3-(2-(2-aminoethoxy)ethoxy)propanoyl)-7-methoxy-2-methylene-5-oxo-2,3,5,10,11,11a-hexahydro-1H-benzo[e]pyrrolo[ 1,2-a][1,4]diazepin-8-yl)oxy)pentyl)oxy)-7-methoxy-2-methylene-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(11aH)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1.1: acetic acid; nitric acid / dichloromethane / 6 h 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 2.2: 8 h / 0 - 20 °C / Inert atmosphere 3.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 4.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 4.2: 1 h / 20 °C / pH Ca_. 2 5.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C 6.1: caesium carbonate / butanone / 20 °C 7.1: ethanol; sodium tetrahydroborate / dichloromethane; diethylene glycol dimethyl ether / 3.08 h / 0 - 20 °C 8.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 9.1: triphenylphosphine / tetrahydrofuran; aq. phosphate buffer / 20 °C / pH 5.0
	Multi-step reaction with 10 steps 1.1: nitric acid; acetic acid / dichloromethane / 6 h 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3.1: triethylamine / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere 4.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 5.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 5.2: 1 h / 20 °C / pH Ca_. 2 6.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C 7.1: caesium carbonate / butanone / 20 °C 8.1: ethanol; sodium tetrahydroborate / dichloromethane; ethyl methyl ether / 3.08 h / 0 - 20 °C 9.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 10.1: triphenylphosphine; sodium dihydrogenphosphate / tetrahydrofuran; water / 20 °C / pH 7.5
	Multi-step reaction with 10 steps 1: nitric acid; acetic acid / dichloromethane / 6 h 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3: triethylamine / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere 4: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 5: sodium dithionite / water; tetrahydrofuran / 20 h / 20 °C 6: methanesulfonic acid / dichloromethane / 2 h / 0 - 20 °C 7: caesium carbonate / butanone / 20 °C 8: ethanol; sodium tetrahydroborate / dichloromethane; diethylene glycol dimethyl ether / 3 h / 0 - 20 °C 9: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 10: triphenylphosphine / tetrahydrofuran; aq. phosphate buffer / 20 °C

	Multi-step reaction with 9 steps 1.1: nitric acid / dichloromethane; acetic acid / 6 h 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 3.1: triethylamine / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere 4.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 5.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 6.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C 7.1: caesium carbonate / butanone / 20 °C 8.1: sodium tetrahydroborate; ethanol / dichloromethane; diethylene glycol dimethyl ether / 3.08 h / 0 - 20 °C 8.2: 20 °C 9.1: triphenylphosphine; sodium dihydrogenphosphate / tetrahydrofuran / 20 °C / pH 7.5
	Multi-step reaction with 9 steps 1.1: acetic acid; nitric acid / dichloromethane / 6 h 2.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C 2.2: 8 h / 0 - 20 °C / Inert atmosphere 3.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 4.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 5.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C 6.1: caesium carbonate / butanone / 20 °C 7.1: sodium tetrahydroborate / dichloromethane; ethanol / 3.08 h / 0 - 20 °C 8.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 9.1: triphenylphosphine; sodium dihydrogenphosphate / tetrahydrofuran / 20 °C / pH 7.5
	Multi-step reaction with 9 steps 1.1: nitric acid; acetic acid / dichloromethane / 6 h 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C / Inert atmosphere 2.2: 8 h / 0 - 20 °C 3.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Inert atmosphere 4.1: sodium dithionite / tetrahydrofuran; water / 20 h / 20 °C 4.2: 1 h / 20 °C / pH 2 5.1: methanesulfonic acid / dichloromethane / 2.17 h / 0 - 20 °C 6.1: caesium carbonate / butanone / 20 °C 7.1: sodium tetrahydroborate / dichloromethane; ethanol; diethylene glycol dimethyl ether / 3.08 h / 0 - 20 °C 8.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 9.1: triphenylphosphine / tetrahydrofuran / 20 °C / pH 5

75
[ 2280-44-6 ]
[ 1486-53-9 ]
1,2,3,4,6-pentakis[O-(4-benzyloxy,3-methoxybenzoyl)]-D-glucopyranoside [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52.1%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 40℃;	5 4.2.1.1. General procedure. A suspension of D-glucose (0.03 g,0.16 mmol), 4-(benzyloxy)-3-methoxybenzoic acid (0.34 g,1.30 mmol), dicyclohexylcarbodiimide (DCC) (0.28 g, 1.32 mmol) andN,N-(di-methylamino) pyridine (DMAP) (0.16 g, 1.36 mmol) in freshlydistilled dichloromethane (DCM) was refluxed for 16-18 hrs (monitoredby TLC). After cooling reaction mixture at room temperature,urea by-product was removed by gravity filtration and the filtratewas evaporated. Compound 11 was purified by column chromatographyeluting with a mixture of dichloromethane, hexane, andethyl acetate. The product was collected, evaporated and precipitatedusing toluene and cyclohexane

Reference： [1]Shaikh, Qurat-Ul-Ain; Yang, Meiting; Memon, Khadim Hussain; Lateef, Mehreen; Na, Du; Wan, Shengbiao; Eric, Deslandes; Zhang, Lijuan; Jiang, Tao [Carbohydrate Research, 2016, vol. 430, p. 72 - 81]

76
[ 74-96-4 ]
[ 1486-53-9 ]
[ 185033-64-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	Ethyl 4-(benzyloxy)-3-methoxybenzoate (17) To the stirred solution of acid 16 (0.5 g, 1.94 mmol, 1.0 equiv) and K2CO3 (0.655 g, 4.75 mmol, 2.5 equiv) in DMF (10 mL) was added bromoethane (350 µL, 4.75 mmol, 2.5 equiv). The reaction mixture was stirred at room temperature overnight under N2 atmosphere. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with water (2 × 10 mL) and saturated NaCl solution (20 mL).They were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude ester was purified by flash chromatography (ethyl acetate/petroleum ether, 5:1) to afford pure ester 17 (0.508 g, 93 %) as white solid. 1H NMR (400 MHz, CDCl3): d = 1.36 (t, J = 7.1 Hz, 3H, OCH2CH3), 3.92 (s, 3H, OMe), 4.33 (q, J = 7.3,14.4 Hz, 2H, OCH2CH3),5.20 (s, 2H, CH2Ph), 6.88 (d, J= 8.3 Hz, 1H, 5-H), 7.26-7.32 (m, 1H, Ar), 7.33-7.38 (m, 2H, Ar), 7.39-7.45 (m,2H, Ar), 7.56 (d, J = 2.0 Hz, 1H,2-H), 7.60 (dd, J = 2.0, 8.3 Hz, 1H,6-H); 13C NMR (100 MHz, CDCl3): d = 14.3 (OCH2CH3), 56.0 (OMe), 60.7 (OCH2CH3), 70.7 (CH2Ph),112.3 (C-5), 123.2 (C-2), 123.2 (Ar), 127.1 (Ar), 128.0 (Ar), 128.6 (Ar), 136.3(Ar), 149.0 (Ar), 151.9 (Ar), 166.3 (CO2Et).

Reference： [1]Mishra, Vivek Kumar; Ravikumar, Ponneri C.; Maier, Martin E. [Tetrahedron, 2016, vol. 72, # 41, p. 6499 - 6509]

77
[ 1486-53-9 ]
[ 56441-97-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sulfuric acid; In methanol; for 10.0h;Reflux;	A catalytic amount of concentrated H2SO4 was added to a solution of compound 3 (5.4g, 20.9mmol) in 50mL of methanol and the mixture was refluxed for 10h. It was allowed to cool. The product crystallization from solution gave pure 4 (4.5g) as a white solid with a yield of 80%. Mp: 70-72C; 1H NMR (CDCl3, 300MHz): delta (ppm) 3.90 (s, 3H), 3.95 (s, 1H), 5.23 (s, 2H), 7.32-7.57 (m, 5H), 7.58 (s, 1H), 7.60-7.61 (d, J=2.0Hz, 1H), 7.63-7.64 (d, J=1.8Hz, 1H).

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 125,p. 245 - 254

78
[ 95-14-7 ]
[ 1486-53-9 ]
[ 1228255-36-4 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: 4-(benzyloxy)-3-methoxybenzoic acid With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 1.5h; Inert atmosphere; Stage #2: 1,2,3-Benzotriazole With triethylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Inert atmosphere;	(1H-Benzo[d][1,2,3]triazol-1-yl)(4-(benzyloxy)-3-methoxyphenyl)methanone (22c) To a solution of 4-(benzyloxy)-3-methoxybenzoic acid (1.0 g, 3.87 mmol) in CH2Cl2 (13.0 mL) wereadded SOCl2 (0.84 mL, 11.6 mmol, 3.0 equiv) and DMF (0.12 mL, 1.55 mmol, 0.4 equiv) at 0 °C underan Ar atmosphere. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixturewas concentrated under reduced pressure. The crude mixture was applied to following reaction withoutfurther purification.To a solution of crude material in CH2Cl2 (13.0 mL) were added Et3N (0.81 mL, 5.81 mmol, 1.5 equiv)and benzotriazole (0.51 g, 5.81 mmol, 1.1 equiv) at 0 °C under an Ar atmosphere. The reaction mixturewas stirred at room temperature for 30 min. After stirring, the reaction mixture was quenched with sat.NH4Cl solution at 0 °C, and extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4,and concentrated under reduced pressure to give a residue including 22c. The crude residue was purifiedby recrystallization from n-hexane/CH2Cl2 to afford 22c (1.10 g, 3.06 mmol, 79%) as a white solid.IR (film): 3111, 3030, 2958, 2875, 1701, 1597, 1512, 1359, 1215, 1145 cm-1; 1H NMR (500 MHz,CDCl3): " 8.37 (d, J = 8.3 Hz, 1H, Ar), 8.15 (d, J = 8.3 Hz, 1H, Ar), 7.95 (dd, J1 =8.3 Hz, J2 = 2.6 Hz 1H,Ar), 7.82 (s, 1H, Ar), 7.65 (d, J = 8.3 Hz, 1H, Ar), 7.56-7.26 (m, 6H, Ar), 7.04 (d, J = 8.3 Hz, 1H, Ar),5.28 (s, 2H, CH2), 4.00 (s, 3H, OCH3); 13C NMR (125 MHz, CDCl3): " 165.6, 153.2, 149.3, 147.8, 136.1,130.2, 128.8, 128.3, 127.3, 127.0, 126.2, 123.6, 120.1, 114.9, 112.3, 77.4, 77.2, 76.9, 70.9, 56.2; MS(ESI): m/z 382 (M+Na)+; HRMS (ESI): calcd for C21H17N3NaO3, (M+Na)+ 382.1162, found 382.1100.

Reference： [1]Hiza, Aiki; Tsukaguchi, Yuta; Ogawa, Takahiro; Inai, Makoto; Asakawa, Tomohiro; Hamashima, Yoshitaka; Kan, Toshiyuki [Heterocycles, 2014, vol. 8, # 2, p. 1371 - 1396]

79
[ 1486-53-9 ]
[ 27883-60-9 ]

Reference： [1]Patent: CN105884699,2016,A

80
[ 67-56-1 ]
[ 1486-53-9 ]
[ 56441-97-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sulfuric acid; In methanol; for 10.0h;Reflux;	A solution of 3-methoxy-4-benzyloxybenzoic acid (20.9 mmol, 5.4 g) in 50 ml of methanol was added to a 250 ml reaction flask, and 1 ml of concentrated sulfuric acid was slowly added dropwise with stirring. The mixture was heated under reflux for 10 hours.Concentrated and crystallized from methanol, filtration, the filter cake washed with a small amount of methanol, and dried to give a white solid 4.5g, 3-methoxy-4-benzyloxy-benzoic acid methyl ester Yield% 80,

Reference： [1]Patent: CN105884699,2016,A .Location in patent: Paragraph 0054; 0055

81
[ 50609-01-3 ]
[ 1486-53-9 ]
4-benzyloxy-3-methoxy-N-[4-(2-pyrrolidin-1-ylethoxy)phenyl]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		0.98g (3.8mmol) 3-Methoxy-4-benzyloxybenzoic acid (11) dissolved in 100ml of anhydrous tetrahydrofuran, then added the 1.46g (7.6mmol) of EDCI, 0.77g (5.7mmol) HOBTO, 0.24g of DMAP, 5mL of Triethylamine, after the addition stirring continued for 15 min, then, 30 mL of an anhydrous tetrahydrofuran solution of 1.16 g (4.6 mmol) of 1-[2-(4-Aminophenoxy) ethyl] pyrrolidine (6), was added drop-wise to the reaction solution, and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the filtrate was recovered under reduced pressure, and then extracted with 140 mL of ethyl acetate. The organic phase was washed successively with water, saturated sodium bicarbonate and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure then obtained white crude, and after separation by chromatography column obtained 1.16g of 4-Benzyloxy-3-methoxy-N- [4- (2-pyrrolidin-1-ylethoxy) phenyl] benzamide (12), yield 57%.

Reference： [1]Patent: CN103980152,2016,B .Location in patent: Paragraph 0087-0089

82
[ 38519-63-0 ]
[ 1486-53-9 ]
N-{4-[2-(diethylamino)ethoxy]phenyl}-4-benzyloxy-3-methoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	Stage #1: 4-(benzyloxy)-3-methoxybenzoic acid With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran for 0.25h; Stage #2: 4-[2-(diethylamino)ethoxy]aniline In tetrahydrofuran at 20℃; for 8h;	4.3 Prepared compound N-{4-[2-(diethylamino) ethoxy] phenyl}-4-Benzyloxy-3-methoxybenzamide 0.98g (3.8mmol) 3-Methoxy-4-benzyloxybenzoic acid (11) dissolved in 100ml of anhydrous tetrahydrofuran, then added the 1.46g (7.6mmol) of EDCI, 0.77g (5.7mmol) HOBT, 0.24g of DMAP, 5mL of Triethylamine, after the addition stirring continued for 15 min, then, 30 mL of an anhydrous tetrahydrofuran solution of 1.16 g (4.6 mmol) of N, N-Diethyl-2- (4-aminophenoxy) -1-ethanamin (6), was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the filtrate was recovered under reduced pressure, and then extracted with 140 mL of ethyl acetate. The organic phase was washed successively with water, saturated sodium bicarbonate and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure then obtained white crude, and after separation by chromatography column obtained 1.05g of N-{4-[2-(diethylamino) ethoxy] phenyl}-4-Benzyloxy-3-methoxybenzamide (12), yield 51%.

Reference： [1]Current Patent Assignee: XI AN JIAOTONG UNIVERSITY - CN103980152, 2016, B Location in patent: Paragraph 0078-0079

83
[ 1486-53-9 ]
[ 572-09-8 ]
1-O-(4-benzyloxy-3-methoxybenzoyl)-2,3,4,6-tetra-O-acetyl-β-D-glucopyranose [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With tetraethylammonium bromide; potassium carbonate In dichloromethane at 20℃; Molecular sieve;	3.2. General Procedure for the Synthesis of 1-O-Acyl-b-D-Glucopyranose Tetraacetates General procedure: A mixture of glucosyl bromide 1 (1.03 g, 2.5 mmol), acid (5.0 mmol), K2CO3 (0.69 g, 5.0 mmol),TEAB (0.05 g, 0.25 mmol) and 4 Å MS (0.25 g) in 35 mL DCM was stirred 24-48 h at room temperature.Next, the insoluble substances, made up of the slightly soluble potassium carboxylate, 4 Å MS andother salts, were filtered off. The filtrate was washed with water, and the separated organic layer wasthen washed with 25% aqueous K2CO3 to removed any remaining potassium carboxylate. After dryingover MgSO4 and concentration in vacuo, the residue was purified via silica gel column chromatographyusing EtOAc/hexane or EtOAc/petroleum ether (1:10 to 1:1) as eluents to yield the desired product.

Reference： [1]Chen, Yu; Lu, Huan; Chen, Yanyu; Yu, Wansheng; Dai, Hui; Pan, Xianhua [Molecules, 2017, vol. 22, # 4]

84
[ 1344995-05-6 ]
[ 1486-53-9 ]
((2R,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-((5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-4-oxo-4H-chromen-3-yl)oxy)tetrahydro-2H-pyran-2-yl)methyl 4-(benzyloxy)-3-methoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With dmap; dicyclohexyl-carbodiimide In dichloromethane

Reference： [1]Heřmánková-Vavříková, Eva; Křenková, Alena; Petrásková, Lucie; Chambers, Christopher Steven; Zápal, Jakub; Kuzma, Marek; Valentová, Kateřina; Křen, Vladimír [International Journal of Molecular Sciences, 2017, vol. 18, # 5]

85
[ 1486-53-9 ]
[ 6638-79-5 ]
4-(benzyloxy)-N, 3-dimethoxy-N-methylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine In dichloromethane at 20℃;

Reference： [1]Tay, Nicholas E. S.; Nicewicz, David A. [Journal of the American Chemical Society, 2017, vol. 139, # 45, p. 16100 - 16104]

86
[ 1486-53-9 ]
2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)aniline [ No CAS ]
N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(benzyloxy)-3-methoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With chloro-N,N,N',N'-bis(tetramethylene)formamidinium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 100℃; for 0.5h; Microwave irradiation; Sealed tube;

Reference： [1]Reed, Carson W.; Yohn, Samantha E.; Washecheck, Jordan P.; Roenfanz, Hanna F.; Quitalig, Marc C.; Luscombe, Vincent B.; Jenkins, Matthew T.; Rodriguez, Alice L.; Engers, Darren W.; Blobaum, Anna L.; Conn, P. Jeffrey; Niswender, Colleen M.; Lindsley, Craig W. [Journal of Medicinal Chemistry, 2019, vol. 62, # 3, p. 1690 - 1695]

87
[ 578-66-5 ]
[ 1486-53-9 ]
4-(benzyloxy)-3-methoxy-N-(quinolin-8-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: 4-(benzyloxy)-3-methoxybenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 25℃; for 3h; Schlenk technique; Inert atmosphere; Stage #2: 8-amino quinoline With triethylamine In dichloromethane at 0 - 25℃; for 16h; Schlenk technique; Inert atmosphere;

Reference： [1]Ruyet, Louise; Poisson, Thomas; Besset, Tatiana [European Journal of Organic Chemistry, 2021, vol. 2021, # 23, p. 3407 - 3410]

88
[ 533-31-3 ]
[ 1486-53-9 ]
C₂₂H₁₈O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	General procedure: 3,4-methylenedioxyphenol 5 (0.50 g, 3.62 mmol), compound3a (0.91 g, 3.98 mmol), EDCI (0.76 g, 3.98 mmol),and DMAP (0.04 g, 0.36 mmol) were dissolved in DMF(30 mL). The reaction was reacted overnight at roomtemperature under the condition of nitrogen, and thereaction process was monitored by TLC. At the end ofthe reaction, 60 mL ethyl acetate was added to the reactionsystem, and then washed with 1 mol/L hydrochloric acidsolution (20 mL × 3), saturated sodium carbonate solution(20 mL × 3) and saturated sodium chloride solution(20 mL × 3), dried with anhydrous sodium sulfate, filtered,and the solvent ethyl acetate was removed by decompression.The white solid 4a (1.01 g) was obtained by columnchromatography (petroleum ether-ethyl acetate, 10:1). Theyield was 80.16%.

Reference： [1]Xie, Yundong; Liu, Jiping; Shi, Yongheng; Bin Wang; Wang, Xiaoping; Wang, Wei; Sun, Meng; Xu, Xinya; He, Shipeng [Medicinal Chemistry Research, 2021, vol. 30, # 9, p. 1688 - 1702]

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Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
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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

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[ 1486-53-9 ] Synthesis Path-Upstream 1~8

[ 1486-53-9 ] Synthesis Path-Downstream 1~88

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Aryls

Ethers

Carboxylic Acids

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