[ CAS No. 95-01-2 ]

Name: 95-01-2|2,4-Dihydroxybenzaldehyde|98%
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{[proInfo.proName]} (Synonyms:2,4-Dihydroxybenzaldehyde) ,{[proInfo.pro_purity]}

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Quality Control of [ 95-01-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 95-01-2 ]

Product Details of [ 95-01-2 ]

CAS No. :	95-01-2	MDL No. :	MFCD00011686
Formula :	C₇H₆O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IUNJCFABHJZSKB-UHFFFAOYSA-N
M.W :	138.12	Pubchem ID :	7213
Synonyms :	2,4-Dihydroxybenzaldehyde

Calculated chemistry of [ 95-01-2 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	35.88
TPSA :	57.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.76 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.72
Log Po/w (XLOGP3) :	0.54
Log Po/w (WLOGP) :	0.91
Log Po/w (MLOGP) :	0.18
Log Po/w (SILICOS-IT) :	1.02
Consensus Log Po/w :	0.67

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.41
Solubility :	5.32 mg/ml ; 0.0385 mol/l
Class :	Very soluble
Log S (Ali) :	-1.32
Solubility :	6.62 mg/ml ; 0.0479 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.17
Solubility :	9.4 mg/ml ; 0.0681 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 95-01-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P273-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335-H412	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 95-01-2 ]

* 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 [ 95-01-2 ]
Downstream synthetic route of [ 95-01-2 ]

[ 95-01-2 ] Synthesis Path-Upstream 1~34

1
[ 95-01-2 ]
[ 531-95-3 ]

Reference： [1] Patent: US2015/57456, 2015, A1,

2
[ 543-24-8 ]
[ 95-01-2 ]
[ 79418-41-0 ]

Reference： [1] Angewandte Chemie, International Edition, 2009, vol. 48, p. 4034 - 4037[2] Angewandte Chemie, 2009, vol. 121, p. 4094 - 4097
[3] Tetrahedron Letters, 2012, vol. 53, # 39, p. 5280 - 5283
[4] Chemical Communications, 2015, vol. 51, # 11, p. 2029 - 2032
[5] Tetrahedron Letters, 2015, vol. 56, # 42, p. 5761 - 5766
[6] Patent: CN105693674, 2016, A, . Location in patent: Paragraph 0024
[7] Chemical Communications, 2017, vol. 53, # 25, p. 3583 - 3586

3
[ 95-01-2 ]
[ 79418-41-0 ]

Reference： [1] Tetrahedron Letters, 2007, vol. 48, # 29, p. 5077 - 5080
[2] Journal of Organic Chemistry, 2011, vol. 76, # 12, p. 4964 - 4972
[3] Chemistry of Heterocyclic Compounds, 2011, vol. 46, # 12, p. 1514 - 1519
[4] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2012, vol. 90, p. 40 - 44
[5] Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 2779 - 2790
[6] Journal of the American Chemical Society, 2014, vol. 136, # 20, p. 7205 - 7208
[7] Medicinal Chemistry Research, 2014, vol. 23, # 8, p. 3632 - 3643
[8] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 8, p. 2400 - 2402
[9] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 24, p. 5737 - 5742
[10] Tetrahedron, 2016, vol. 72, # 32, p. 4925 - 4930
[11] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 22, p. 5557 - 5561

4
[ 105-56-6 ]
[ 95-01-2 ]
[ 19088-73-4 ]

Yield	Reaction Conditions	Operation in experiment
80%	With [bis(acetoxy)iodo]benzene In ethanol at 35 - 40℃;	General procedure: α-substituted ethyl acetate (1.0 mmol)and Phenyliododiacetate (1.0 mmol) was dissolved in ethanol (5 ml) with constant stirring. After 10 minutes benzaldehyde/salicylaldehyde (1.0 mmol), was added and the mixture was allowed to stir for appropriate time. Then the progress of the reaction was monitored by thin layer chromatography. After completion of reaction as indicated by TLC, ethanol was evaporated under reduce pressure. The product was extracted with ethyl acetate, dried over Na₂SO₄and solvent was evaporated under reduce pressure. The residue obtained was recrystallized by ethyl acetate and hexane to product 3a-3h and 4a-4r.

Reference： [1] Synthetic Communications, 2005, vol. 35, # 6, p. 785 - 790
[2] Phosphorus, Sulfur and Silicon and the Related Elements, 2002, vol. 177, # 11, p. 2555 - 2559
[3] Tetrahedron Letters, 2017, vol. 58, # 32, p. 3183 - 3187
[4] Journal of Heterocyclic Chemistry, 2007, vol. 44, # 4, p. 867 - 870
[5] Journal of the Iranian Chemical Society, 2016, vol. 13, # 1, p. 149 - 153
[6] Proceedings - Indian Academy of Sciences, Section A, 1942, # 16, p. 68,77
[7] Journal of Molecular Liquids, 2017, vol. 242, p. 293 - 307
[8] Chemical Papers, 2018, vol. 72, # 6, p. 1461 - 1466

5
[ 109-77-3 ]
[ 95-01-2 ]
[ 19088-73-4 ]

Reference： [1] Journal of Heterocyclic Chemistry, 2011, vol. 48, # 4, p. 799 - 802
[2] Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 12, p. 3571 - 3577
[3] Molecular crystals and liquid crystals, 1983, vol. 100, # 3-4, p. 299 - 305
[4] Heterocycles, 1996, vol. 43, # 6, p. 1257 - 1266

6
[ 105-53-3 ]
[ 95-01-2 ]
[ 6093-71-6 ]

Yield	Reaction Conditions	Operation in experiment
97%	at 20℃; for 2 h;	To a solution of 2,4-dihydroxybenzaldehyde (3.70 mmol) in diethyl malonate (7.90 mmol) piperidine (10 drops) was added, and the resulting solution was stirred for 2 hours at r.t. The resulting solution was then acidified with an aqueous solution of HCl10percent (5 mL). The precipitate was filtrated and washed with cold water (10 mL). The desired product was purified by flash chromatography using dichloromethane : ethyl acetate (70: 30) as eluent furnishing 3 (0.735g) in 97percent yield. ¹H NMR (400 MHz, DMSO-d6) : 1.28 (t, J=7.1 Hz, 3H), 4.24 (q, J=7.1 Hz, 2H), 6.71 (d, J= 1.8Hz, 1H), 6.83 (dd, J= 1.8, 8.3Hz, 1H), 7.74 (d, J= 8.3Hz, 1H), 8.66 (s, 1H), 11.07 (s, OH). ¹³C NMR (100 MHz, DMSO-d6): 14.1, 60.8, 101.7, 110.4, 112.0, 113.9, 132.1, 149.4, 156.3, 157.0, 162.9, 164.0.
92%	at 20℃; for 1 h;	Diethyl malonate (6.6 mL, 43.3 mmol) and 2,4-dihydroxybenzaldehyde (6.0 g, 43.3 mmol) were added to the flask and piperidine (4.4 mL, 44.3 mmol) was slowly added at room temperature.When the reaction mixture turns pale yellow, it is further stirred for 1 hour,HCl 10percent (50 mL) was added. After grinding the green suspension,Filtration and washing with water gave the desired compound as a pink solid (9.32 g, 92percent).
90%	With piperidine In ethanol at 90℃; for 6 h;	A solution of 2,4-dihydroxybenzaldehyde (0.500 g, 3.60 mmol) and diethyl malonate (0.70 ml, 4.00 mmol) were placed in 100 ml of a vial and dissolved in 95percent Ethanol (20ml), the solution color is reddish brown transparent liquid; then add piperidine (0.40ml, 4.00mmol), the solution surface pan-green light, began to reflux, the reaction after about 6h, the solution becomes dark brown.Cooled to room temperature, concentrated under reduced pressure to a red viscous, ethanol recrystallized, and filtered to give compound 3 (0.758 g, 3.24 mmol) as a pale yellow solid in 90percent yield.ESI-MS m / z 233 (M-1).

88%	With amino acid fuctionalized Fe₃O₄ nanoparticles(Fe₃O₄-DA-Phe) In neat (no solvent) at 130℃; for 0.116667 h; Microwave irradiation; Green chemistry	General procedure: A mixture of o-hydroxy benzaldehyde (2 mmol), 1,3-dicarbonyl compound (2 mmol) and Fe3O4-DA-Phe (30mg)was mixed in a 50 mL flask and irradiated under microwavefor the time indicated in (Table 6.1). The reaction progresswas monitored by TLC. After completion of the reaction, thereaction mixture was cooled to room temperature which thensolidified within an hour. The resulting solidified mixturewas diluted with ethyl acetate (5 mL) and the catalyst wasseparated by using external magnet and dried for reuse. Thereaction mixture was washed twice with water and solventwas evaporated under reduced pressure which yielded thecrude product, which was further purified by recrystallization.The same procedure was used for synthesis of derivatives.All synthesized coumarin derivatives were characterizedusing analytical techniques such as IR and 1H NMR.The identity of these compounds was established by comparisonof IR, 1H NMR spectral data and their melting pointswith those of reported samples (Table 4) [23-33]. Spectraldata for all compounds are listed.
84%	With [bis(acetoxy)iodo]benzene In ethanol at 35 - 40℃;	General procedure: α-substituted ethyl acetate (1.0 mmol)and Phenyliododiacetate (1.0 mmol) was dissolved in ethanol (5 ml) with constant stirring. After 10 minutes benzaldehyde/salicylaldehyde (1.0 mmol), was added and the mixture was allowed to stir for appropriate time. Then the progress of the reaction was monitored by thin layer chromatography. After completion of reaction as indicated by TLC, ethanol was evaporated under reduce pressure. The product was extracted with ethyl acetate, dried over Na₂SO₄and solvent was evaporated under reduce pressure. The residue obtained was recrystallized by ethyl acetate and hexane to product 3a-3h and 4a-4r.
81%	With piperidine In ethanolReflux	2, 4-dihydroxybenzaldehyde (6.9 g, 0.05 mol), diethyl malonate (9.6 g, 0.06 mol) and piperidine(0.2 g, 2.5 mmol) were refluxing in 150 mL ethanol for 10 h. After cooled to room temperature, thecrude products were filtrated and recrystallized from methanol [19].Ethyl 7-hydroxy-2-oxo-2H-chromene-3-carboxylate (1e): Light yellow solid; yield 81percent. ESI-HRMS [M +Na]+: (m/z) Calcd. for C12H10O5Na: 257.0420. Found: 257.0434.
70%	With piperidine; acetic acid In ethanol for 4.5 h; Heating	General procedure: Diethyl malonate (7.5 mL, 49 mmol), 2, 4-dihydroxybenzaldehyde (5.1 g, 37 mmol) or 2, 4-dihydroxy-5-halogenbenzaldehyde, piperidine (0.5 mL, 6 mmol) and 3 drops of acetic acid were dissolved in a 50 mL flask of ethanol (10 mL) to form a mixture. The reaction mixture was heated with stirring for 4.5 h. After cooling, the solid was collected using a vacuum filer. The solid product was filtered and washed with cold ethanol, then dried. The crude product was recrystallized with ethanol to obtain the purified product 1a (6.06g, 25.9 mmol) or 1b-1d. The complex was characterized by¹H NMR (Fig. S4).
64.5%	With piperidine In ethanol for 12 h; Reflux	Compound 1 was synthesized according to the reported papers.^37–39 2,4-dihydroxybenzaldehyde 2.76g (20mmol) and diethylmalonate 6.4mL (40mmol) were mixed together in 30mL anhydrous ethanol. 1.5mL piperidine was added to the above solution dropwise after that. The whole mixture was refluxed for 12h after which the solvent was evaporated. The product was extracted with CH₂Cl₂, washed with brine and purified by column chromatography to give compound 1 as a white yellow solids (4.1g 12.89mmol). ¹HNMR (400MHz, DMSO) δ 8.677 (s,1H), 7.768 (d, J=8, 1H) 6.84 (dd, J=4, 1H), 6.73 (d, J=1.2,1H), 4.26 (q, 2 H), 1.29 (t, J=8, 3H) (Fig. S1). ¹³C NMR δ 164.03, 162.91, 157.07, 156.37, 149.41, 132.08, 113.97, 112.04, 110.39, 101.75, 60.77, 39.47, 14.10 (Fig. S2). HRMS: 257.0422, calcd for: 257.0426 (Fig. S5). Yield: 64.5percent.
64%	With piperidine; acetic acid In ethanol at 90℃; for 15 h;	To a 250 mL round bottom flask was added 2,4-dihydroxybenzaldehyde(10 g, 72.5 mmol) and 30 mL of absolute ethanol,Stir to make it fully dissolved. diethyl malonate (17.2 mL, 101.9 mmol), hexahydropyridine (0.57 mL, 5.76 mmol)Glacial acetic acid (0.16 mL, 2.88 mmol), heated at 90 °C with stirring, TLC tracks the progress of the reaction. After about 15 h, TLC (EA: PE = 1: 2) was significantThe reaction is basically complete. The reaction solution was allowed to cool to room temperature, 200 mL of ice water was added and allowed to stand overnight at -20 ° C. The filtrate was filtered to give 12.4 g of a yellow solid in 73percent yield. The crude product was recrystallized from 95percent ethanol to give 10.8 g of a pale yellow needle-like solid in a yield of 64percent
63%	Stage #1: With piperidine In tetrahydrofuran at 20℃; for 2 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water	Example 12; Synthesis of a compound of Formula (I) where R¹, R³, R(at), and R8 are OMe, R², R(at), and R10 are Me, R4 and R5 are OH, R9 is H, R¹¹ is CN, Y is CH2, and R¹² is 7-(2- methoxyethyloxy)coumarin-3-ylcarbonylamino (compound 42); Step 1; To a solution of 2,4-dihydroxy-benzaldehyde (5.52 g, 40.0 mmol) in THF (50 mL) were added diethyl malonate (6.7 mL, 44 mmol) and piperidine (11.9 mL, 120 mmol). After 2 hr of stirring at room temperature, the reaction mixture was acidified to pH -1-2 with IN HCl (aq), and extracted with large amount of EtOAc. The organic layer was dried over Na2S04, filtered, and concentrated in vacuo. Purification of the crude material by column chromatography provided 7-hydroxy-2-oxo-2H-chromene-3-carboxylic acid ethyl ester as an off-white solid (5.9 g, 63percent).
51.04%	With piperidine In ethanol at 20℃;	General procedure: The substituted coumarin-3-carboxylic acid ethyl esters (Scheme 2) were prepared by Knoevenagel reaction. To a mixture of diethyl malonate (1 mmol) and the appropriate salicylaldehyde (1 mmol) in ethanol (10 ml) was added piperidine (5 mol percent) and the reaction mixture was stirred at the room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed under vacuum and the residue was purified by chromatography. The obtained substituted coumarin-3-carboxylic acid ethyl ester (2 mmol) was dissolved in 10percent NaOH (50 ml), then 3 N HCl (50 ml) was added the mixture. The suspension was filtered and dried under vacuum to provide substituted coumarin-3-carboxylic acid. The coumarin-3-carboxylic acid (2 mmol) was added to thionyl chloride (30 ml), the reaction mixture was refluxed for about 2 h, the thionyl chloride was removed under vacuum. The desired substituted coumarin-3-carbonyl chloride was obtained. To a mixture of substituted coumarin-3-carbonyl chloride (2 mmol) and toluene (20 ml) or ethyl ether (20 ml) was added dropwise appropriate alcohol (2 mmol) and then the reaction mixture was refluxed for about 12 h. The solvent was removed under vacuum and the residue was purified by chromatography.

Reference： [1] Tetrahedron Letters, 2012, vol. 53, # 22, p. 2715 - 2718
[2] Patent: KR101744655, 2017, B1, . Location in patent: Paragraph 0058-0060
[3] Patent: CN106279125, 2017, A, . Location in patent: Paragraph 0039; 0040
[4] Letters in Organic Chemistry, 2013, vol. 10, # 7, p. 468 - 477
[5] Chemical Communications, 2017, vol. 53, # 11, p. 1813 - 1816
[6] Chinese Chemical Letters, 2014, vol. 25, # 7, p. 1082 - 1086
[7] Journal of Chemical Sciences, 2011, vol. 123, # 5, p. 615 - 621
[8] Tetrahedron Letters, 2017, vol. 58, # 32, p. 3183 - 3187
[9] Synthetic Communications, 2005, vol. 35, # 6, p. 785 - 790
[10] Molecules, 2016, vol. 21, # 6,
[11] Tetrahedron Letters, 2002, vol. 43, # 6, p. 1127 - 1130
[12] Chinese Chemical Letters, 2016, vol. 27, # 2, p. 295 - 301
[13] Journal of Heterocyclic Chemistry, 2007, vol. 44, # 4, p. 867 - 870
[14] Synthetic Communications, 2009, vol. 39, # 9, p. 1666 - 1678
[15] Organic and Biomolecular Chemistry, 2013, vol. 11, # 47, p. 8214 - 8220
[16] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 7, p. 1738 - 1745
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[59] Cell Chemical Biology, 2018,

7
[ 3702-98-5 ]
[ 95-01-2 ]
[ 6093-71-6 ]

Yield	Reaction Conditions	Operation in experiment
41%	With piperidine In toluene for 6 h; Reflux	General procedure: Piperidine (21 mg, 30 molpercent) was added slowly to a stirred solution of salicylaldehyde (1a, 100 mg, 1 equiv) and ethyl 4,4,4-trichloro-3-oxobutanoate(2, 192 mg, 1 equiv) in toluene (2mL) at room temperature. The reaction mixture was refluxed for 4 h. After completion of the reaction (TLC), the crude product was subjected to column chromatography purification using silica gel(60:120) provided coumarin 3a as colorless solid.

Reference： [1] Tetrahedron Letters, 2015, vol. 56, # 11, p. 1338 - 1343

8
[ 105-53-3 ]
[ 95-01-2 ]
[ 1313212-09-7 ]
[ 1401998-72-8 ]
[ 6093-71-6 ]

Reference： [1] Patent: WO2012/134724, 2012, A1, . Location in patent: Page/Page column 36-38

9
[ 105-56-6 ]
[ 95-01-2 ]
[ 6093-71-6 ]

Reference： [1] Advanced Synthesis and Catalysis, 2006, vol. 348, # 3, p. 297 - 300

10
[ 2033-24-1 ]
[ 95-01-2 ]
[ 779-27-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With tomato juice In water at 20℃; for 0.0833333 h; Sonication; Green chemistry	General procedure: 2-Hydroxybenzaldehyde (acetophenone, or benzaldehydes) (1.0 mmol) and Meldrum’s acid (1.01 mmol) were suspended in the aqueous medium (juice or waste water) (2 mL). The resulting mixture was subjected to ultrasound irradiation at room temperature for 5 min (15 min). The precipitate so formed was filtrated under vacuum. Structural assignments (NMR) was made by comparison of the recorded analytical data with those of commercially available sample or those already reported for the same compounds.^2-6 The aqueous medium (juice or waste water) was recovered by filtration and re-used as such to perform further processes.
92%	at 60℃; for 4 h; Schlenk technique; Green chemistry	General procedure: A mixture of Meldrum’s acid (0.5 mmol) and salicylaldehydes (0.55 mmol) was placed in a 10-mL Schlenk tube, then Et₃N (0.015 mmol) and 50 μL water were added. The reaction mixture was stirred at the indicated temperature for 4 h. After completion of the reaction, 3 mL aqueous ethanol was added to the mixture and vigorously stirred for a moment. The pH was adjusted to 2–3 with dilute hydrochloric acid. Finally, the precipitate was separated by filtration and washed with aqueous ethanol without further purification to afford the corresponding pure adducts.
90%	for 10 h; Reflux	General procedure: In a round-bottomed flask the selected salicylaldehyde (1 mmol) and Meldrum's acid (1.2 mmol) in water (2 mL) were heated at reflux under stirring for 10 h; then, the reaction mixture was cooled and filtered on Büchner funnel. The products were purified by recrystallization from methanol.

77%

With ammonium acetate In water at 20℃; for 0.1 h;

A suspension of 2,4-dihydroxybenzaldehyde (1.30 g, 9.5 mmol) in 21 mL of water was added Meldrum's acid (1.55 g, 10.8 mmol) and ammonium acetate (150 mg, 1.9 mmol). The suspension was stirred at room temperature for about 1 h. The precipitate formed was filtered and washed with cold water (2 x 10 mL) and vacuum drying (1.5 g, yellow-orange solid, 77percent). m.p. 260-264 °C; ¹H NMR (DMSO-d₆): δ 11.93 (bs, 2H, OH), 8.66 (s, 1H, =CH), 7.73 (d, 1H, Ar-H, J = 8.6 Hz ), 6.83 (dd, 1H, Ar-H, J = 8.6, 2.1 Hz), 6.72 (d, 1H, Ar-H, J = 2.1 Hz)

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[12] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2013, vol. 52, # 8, p. 1157 - 1160

11
[ 141-82-2 ]
[ 95-01-2 ]
[ 779-27-1 ]

Reference： [1] Oriental Journal of Chemistry, 2012, vol. 28, # 4, p. 1725 - 1728
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[3] Journal of the American Chemical Society, 1952, vol. 74, p. 5346

12
[ 95-01-2 ]
[ 779-27-1 ]

Reference： [1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 9, p. 3530 - 3540
[2] Food Chemistry, 2012, vol. 135, # 4, p. 2872 - 2878
[3] European Journal of Medicinal Chemistry, 2013, vol. 70, p. 623 - 630
[4] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 5, p. 502 - 506
[5] European Journal of Medicinal Chemistry, 2016, vol. 121, p. 40 - 46
[6] Chemical Communications, 2017, vol. 53, # 11, p. 1813 - 1816
[7] Patent: CN106279125, 2017, A,
[8] European Journal of Medicinal Chemistry, 2018, vol. 152, p. 600 - 614
[9] Cell Chemical Biology, 2018,

13
[ 100-39-0 ]
[ 95-01-2 ]
[ 52085-14-0 ]

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

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

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

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

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

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

15
[ 1634-04-4 ]
[ 100-44-7 ]
[ 95-01-2 ]
[ 52085-14-0 ]

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

16
[ 100-39-0 ]
[ 95-01-2 ]
[ 52085-14-0 ]

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

17
[ 100-44-7 ]
[ 95-01-2 ]
[ 13246-46-3 ]
[ 52085-14-0 ]

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

18
[ 1024-41-5 ]
[ 95-01-2 ]
[ 52085-14-0 ]

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

19
[ 107-86-8 ]
[ 95-01-2 ]
[ 54287-99-9 ]

Yield	Reaction Conditions	Operation in experiment
50%	With calcium hydroxide In methanol at 20℃; for 48 h;	2,4-Dihydroxybenzaldehyde (15) (3 g/20.17 mmol), calcium hydroxide (1.543 g/20.8 mmol) and 150 mL of methanol were place in a two-necked round-bottom flask. Then, prenal (9.135 g/108.6 mmol) was added dropwise. The mixture was allowed to stir at room temperature for 48 h. The reaction was quenched with HCl 1 M until pH 1–2. The methanol was evaporated and the aqueous phase was extracted with 3 × 150 mL of ethyl acetate. The organic phase was washed with 2 × 100 mL of brine, dried over sodium sulfate anhydrous, filtered and the organic solvent evaporated. The crude product was purified by silica gel flash chromatography (n-hexane/ethyl acetate 9:1). Compound 16 was crystallized from n-hexane/ethyl acetate 3:1 as a yellow solid (2.06 g/50percent).
50%	With calcium hydroxide In methanol at 20℃; for 48 h;	2,4-Dihydroxybenzaldehyde (42) (3g/20.17mmol), calcium hydroxide (1.543g/20.8mmol) and 150mL of methanol were placed in a round-bottom flask. Then, prenal (9.135g/108.6mmol) was added dropwise. The mixture was stirred at room temperature for 48h. The reaction was quenched with HCl 1M until pH 1–2. The methanol was evaporated and the aqueous phase was extracted with 3×150mL of ethyl acetate. The organic phase was washed with 2×100mL of brine, dried over sodium sulfate anhydrous, filtered and the organic solvent evaporated. The crude product was purified by silica gel flash chromatography (n-hexane/ethyl acetate 9:1). Compound 43 was crystallized from n-hexane/ethyl acetate 3:1 as a yellow solid (2.06g/50percent).6-Formyl-5-hydroxy-2,2-dimethyl-2H-benzopyran (43). Mp: 68–69°C. IR ν_max (cm⁻¹) (KBr): 3464, 2967, 2922, 2857, 1628, 1484, 1330, 1294, 1247, 1176, 1107, 1081, 748. ¹H NMR (300.13MHz, CDCl₃) δ (ppm): 11.65 (OH), 9.66 (s, CHO), 7.29 (d, J=8.6), 6.88 (d, J=10.0), 6.44 (d, J=8.6), 5.61 (d, J=10.0), 1.46 (s, 6H). ¹³C NMR (100.63MHz, CDCl₃) δ (ppm): 194.5, 160.6, 158.7, 134.7, 128.6, 115.2, 115.1, 109.4, 108.8, 78.2, 28.4. EIMS m/z (percent): 205 (5, [M+1]^+.), 204 (10 [M]^+.), 190 (15), 189 (100), 187 (60), 159 (12), 131 (12), 103 (10), 77 (12), 51 (6). HRMS (ESI) m/z calcd for C₁₂H₁₃O₃ [M+H]⁺: 205.08570, found: 205.08592.
0.68 g	With calcium hydroxide In methanol at 20℃; for 12 h;	A 1 g portion of 2,4-2 hydroxybenzaldehyde (Compound 2 shown in Figure 1)0.514 g Ca (OH) 2, methanol150mL.3.045 g of prenyl aldehyde (compound 1 shown in FIG. 1) was then added dropwise.Stir at room temperature for 12h.Quench with HCl (1 M) until the pH is 1-2.Methanol was evaporated and the aqueous phase was extracted with 3 * 150 mL of ethyl acetate.The organic phase was washed with 2 * 100 mL saturated brine, dried over anhydrous Na2SO4,Vacuum filtration, and spin dry. The crude product was passed through a column of silica gel (petroleum ether: ethyl acetate = 9: 1)Crystallization gave product 3 (0.68 g) as shown in FIG.

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[9] Patent: CN106187974, 2016, A, . Location in patent: Paragraph 0044

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[ 513-35-9 ]
[ 95-01-2 ]
[ 54287-99-9 ]

Yield	Reaction Conditions	Operation in experiment
32%	With pyridine In acetone at 120℃; for 23.5 h; Heating	[0174] Pyridine (0.01 M) solution containing 3-methyl-but-2-enyl (2.0 equivalent) was added to anhydrous acetone solution (0.01 M) containing 2,4-dihydroxyaldehyde (1 equivalent) drop by droop at 120 °C for 5.5 hours, followed by heating for 18 hours. After cooling down at room temperature, the solvent was eliminated under reduced pressure using a rotary evaporator. Pyridine was eliminated by azeotropic distillation along with toluene. The obtained non-purified product was purified by flash column chromatography (EtOAc:n-hexane=1:8) to give the compound 119 as a colorless solid (yield: 32percent, 1.12 g). [0175] ¹H-NMR (CDCl₃, 300 MHz) δ11.61 (s, 1H), 9.62 (s, 1H), 7.25 (d, 1H, J = 8.6 Hz), 6.39 (d, 1H, J = 8.6 Hz), 5.58 (d, 1H, J = 10.0 Hz), 1.42 (s, 6H).

Reference： [1] Patent: EP2871187, 2015, A1, . Location in patent: Paragraph 0173-0175

21
[ 115-19-5 ]
[ 95-01-2 ]
[ 54287-99-9 ]

Yield	Reaction Conditions	Operation in experiment
32%	at 120℃; for 23.5 h;	Pyridine (0.01 M) solution containing 3-methyl-but-2-enyl (2.0 equivalent) was added to anhydrous acetone solution (0.01 M) containing 2,4-dihydroxyaldehyde (1 equivalent) drop by droop at 120° C. for 5.5 hours, followed by heating for 18 hours. After cooling down at room temperature, the solvent was eliminated under reduced pressure using a rotary evaporator. Pyridine was eliminated by azeotropic distillation along with toluene. The obtained non-purified product was purified by flash column chromatography (EtOAc:n-hexane=1:8) to give the compound 119 as a colorless solid (yield: 32percent, 1.12 g). [0272] ¹H-NMR (CDCl₃, 300 MHz) δ11.61 (s, 1H), 9.62 (s, 1H), 7.25 (d, 1H, J=8.6 Hz), 6.39 (d, 1H, J=8.6 Hz), 5.58 (d, 1H, J=10.0 Hz), 1.42 (s, 6H).

Reference： [1] Patent: US2015/183797, 2015, A1, . Location in patent: Paragraph 0270-0272

22
[ 31525-67-4 ]
[ 95-01-2 ]
[ 54287-99-9 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1987, p. 431 - 438
[2] Organic Letters, 1999, vol. 1, # 13, p. 2113 - 2115
[3] Tetrahedron Letters, 1984, vol. 25, # 10, p. 1099 - 1102

23
[ 107-86-8 ]
[ 95-01-2 ]
[ 54287-99-9 ]
[ 33279-69-5 ]

Reference： [1] Bulletin of the Chemical Society of Japan, 1999, vol. 72, # 2, p. 259 - 263

24
[ 95-01-2 ]
[ 58026-14-5 ]

Reference： [1] Journal of the American Chemical Society, 2006, vol. 128, # 17, p. 5887 - 5894
[2] Patent: WO2012/11125, 2012, A1,

25
[ 100-44-7 ]
[ 95-01-2 ]
[ 74-88-4 ]
[ 58026-14-5 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 1227 - 1236

26
[ 90-02-8 ]
[ 24677-78-9 ]
[ 95-01-2 ]

Reference： [1] Patent: DE155731, , ,

27
[ 67-66-3 ]
[ 108-46-3 ]
[ 387-46-2 ]
[ 95-01-2 ]

Reference： [1] Journal of the American Chemical Society, 1983, vol. 105, # 7, p. 2018 - 2021

28
[ 75-03-6 ]
[ 95-01-2 ]
[ 22924-16-9 ]

Reference： [1] Chemische Berichte, 1877, vol. 10, p. 2212

29
[ 75-03-6 ]
[ 95-01-2 ]
[ 22924-16-9 ]

Reference： [1] Journal of the Chemical Society, 1934, p. 1491,1497
[2] Journal of the Chemical Society, 1934, p. 1491,1497

30
[ 95-01-2 ]
[ 64419-24-5 ]

Yield	Reaction Conditions	Operation in experiment
70.5%	at 20 - 100℃; for 2.25 h;	In a double walled reactor 50.0 g (0.362 mol, 1.0 meq) 2,4-dihydroxybenzaldehyde were added to 180 mL formic acid, which resulted in a brown suspension at room temperature. Then 45.8 g (0.673 mol, 1.8 meq) sodium formate were added over 2 min, and the temperature increased to 33° C. After the temperature decreased to 30° C., 35.6 g (0.217 mol, 1.2 meq) hydroxyl ammonium sulfate were added during 3 min to give a thick brown suspension which became a brown solution after stirring 10 min at 30-32° C. While heating the mixture to 100° C., crystallization occurred at 38° C. and stirring was interrupted. At 70° C. the reaction mixture became a thin suspension, which was easy to stir. This reaction mixture was stirred for 2 hours at 100° C. The color turned dark brown. TLC (silica gel 60 F254, acetone:n-hexane:water 20:20:1) showed an almost complete reaction. Formic acid (170 mL) was evaporated under reduced pressure (60° C., 10 mbar). The solid dark brown residue was stirred with 400 mL MTBE at 40° C. for 1 hour (incomplete dissolution). The insoluble residue (62.5 g) was filtered and washed two times each with 50 mL MTBE. To the mother liquor 10 g activated carbon (Norit CA 5) were added and this mixture was refluxed for 1 hour and filtered at 40° C. by Celite Super Hyflow (washing with 2*50 mL portions of MTBE). The MTBE-mother liquor was washed three times each with 100 mL water. After removing the water from this MTBE solution with azeotropic distillation (water separator) it was concentrated under reduced pressure to 20percent of the starting volume and 500 mL toluene were added. Then the MTBE was distilled off under reduced pressure. During this process a brown residue began to precipitate, which was filtered. The toluene mother liquor was concentrated to 150 mL and 2,4-dihydroxybenzonitrile precipitated, which was filtered and washed two times each with 30 mL toluene. The pale tan product was dried under reduced pressure (45° C., 20 mbar). The reaction yielded 34.5 g of 2,4-dihydroxybenzonitrile (70.5percent, purity 97percent (HPLC)).

Reference： [1] Tetrahedron, 1999, vol. 55, # 46, p. 13265 - 13268
[2] Patent: US2003/220504, 2003, A1, . Location in patent: Page/Page column 4
[3] Journal of Medicinal Chemistry, 1999, vol. 42, # 1, p. 95 - 108
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2001, vol. 40, # 10, p. 1000 - 1006
[5] Soft Matter, 2010, vol. 6, # 8, p. 1704 - 1721
[6] Advanced Functional Materials, 2014, vol. 24, # 12, p. 1703 - 1717
[7] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 4, p. 657 - 667
[8] Chemistry - A European Journal, 2017, vol. 23, # 23, p. 5541 - 5556

31
[ 95-01-2 ]
[ 131088-02-3 ]

Yield	Reaction Conditions	Operation in experiment
47%	With sulfuryl dichloride In diethyl ether at 0 - 20℃; for 0.5 h; Inert atmosphere	To a solution of 2,4-dihydroxybenzaldehyde (3.0 g, 22 mmol) in Et20 (100 mL, 0.22 M) was added dropwise sulfurylchloride (2.1 mL, 26 mmol) at 0 °C under argon. After being stirred at RT for 30 min, the reaction solution was poured into ice-chilled brine, washed with H2O and brine, dried over MgS04, filtered, and concentrated. Purification by flash chromatography (Et20:hexanes = 1:2) provided compound 6 as an ivory solid (47percent). NMR (DMSO-d6, 300 MHz): δ 11.38 (1H, s), 10.87 (1H, s), 9.97 (1H, s), 7.59 (1H, s), 6.58 (1H, s). LRMS (APCI+): Calc'd for C7H5C103 172.0 m/z, measured 173.1 (MH+).
47%	With sulfuryl dichloride In diethyl ether at 0 - 20℃; for 0.5 h; Inert atmosphere	To a solution of2,4-dihydroxybenzaldehyde (3.0 g, 22 mmol) in Et20 (100 mE, 0.22 M) was added dropwise sulfurylchloride (2.1 mE, 26 mmol) at 00 C. under argon. Afier being stirred at RT for 30 mm, the reaction solution was poured into ice-chilled brine, washed with H20 and brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (Et20:hexanes=1 :2) provided compound 6 as an ivory solid (47percent). ‘H NMR (DMSO-d6, 300 MHz): ö 11.38 (1H, s), 10.87 (1H, s), 9.97 (1H, s), 7.59 (1H, s), 6.58 (1H, s). ERMS (APCI+): Calc’d for C7H5C10C3 172.0 ink, measured 173.1 (MH+).
26%	With sulfuryl dichloride In diethyl ether at 0 - 20℃; for 0.5 h; Inert atmosphere	To a solution of 2,4-dihydroxybenzaldehyde (20 g, 144.92 mmol) in diethyl ether (500 mL) was added drop wise sulfuryl chloride (14 mL, 171.2 mmol) at 0° C. under argon and stirred at room temperature for 30 min. The reaction mixture was poured into ice-water, the organic layer was separated and washed with water, brine, dried over Na₂SO₄, filtered, and concentrated to give the crude product, which was purified on a silica gel column (pet. ether:ethyl acetate=90:10) to get 5-chloro-2,4-dihydroxybenzaldehyde as an off white solid. (6.7 g, 26percent, LC/MS; 97percent). ES−, m/z 170.9 [M−H]; [C₇H₅ClO₃]; NMR (DMSO-d₆, 400 MHz): δ 11.39 (1H, s), 10.87 (1H, s), 9.98 (1H, s), 7.0 (1H, s), 6.58 (1H, s).

Reference： [1] Chemical Biology and Drug Design, 2015, vol. 86, # 5, p. 1030 - 1035
[2] Angewandte Chemie - International Edition, 2007, vol. 46, # 19, p. 3505 - 3508
[3] Chemical Communications, 2008, # 10, p. 1217 - 1219
[4] Heterocycles, 1997, vol. 45, # 7, p. 1345 - 1361
[5] Journal of the American Chemical Society, 2010, vol. 132, # 26, p. 8828 - 8830
[6] Patent: WO2011/94560, 2011, A1, . Location in patent: Page/Page column 54; 56
[7] Patent: US9075014, 2015, B2, . Location in patent: Page/Page column 40; 41
[8] Patent: US2018/65917, 2018, A1, . Location in patent: Paragraph 0379
[9] Canadian Journal of Research, Section B: Chemical Sciences, 1946, vol. 24, p. 208
[10] Patent: EP2857010, 2015, A1, . Location in patent: Paragraph 0102; 0104

32
[ 95-01-2 ]
[ 131088-02-3 ]
[ 131088-00-1 ]

Yield	Reaction Conditions	Operation in experiment
65%	With piperidine; sodium hypochlorite; sulfuric acid In water at 0 - 20℃; for 5 h;	Sodium hypochlorite (75 mL, 0.055 mol) and piperidine (4.68 g, 0.055 mol) were cooled to 0° C., combined cautiously and added dropwise over 2 h to a solution of 2,4,-dihydroxybenzaldehyde (6.91 g, 0.05 mol) in 50percent aqueous sulfuric acid (150 mL) while cooling to 0° C. After three additional hours, the precipitate was collected via filtration in quantitative yield. ¹H NMR indicates that it is about 65percent 5-chloro-2,4-dihdroxybenzaldehyde, with the balance being 3-chloro-2,4-dihdroxybenzaldehyde. The product can be purified via column chromatography and/or repeated recrystallizations from toluene. However, the 3-chloro-2,4-dihdroxybenzaldehyde does not react in the next reaction, so the product was used without further purification.
32%	With sulfuryl dichloride In diethyl ether at 0℃; for 0.5 h; Inert atmosphere	In a scintillation vial, 2,4-dihydroxybenzaldehyde (1.38 g, 10 mmol) was dissolved in ethyl ether (18 ml). The mixture was placed under N2 atmosphere and cooled to 0° C. To the mixture was added sulfuryl chloride (0.91 ml, 11 mmol). The mixture was kept under N2 atmosphere at 0° C. for 30 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate (20 ml). Organic layer was washed with brine, concentrated and chromatographed to yield 5-chloro-2,4-dihydroxybenzaldehyde (0.55 g, 3.2 mmol, 32percent) and 3-chloro-2,4-dihydroxybenzaldehyde (0.233 g, 1.34 mmol, 13.4percent)

Reference： [1] Patent: US8343710, 2013, B1, . Location in patent: Page/Page column 17
[2] Macromolecules, 2010, vol. 43, # 6, p. 2824 - 2831
[3] Patent: US2017/182051, 2017, A1, . Location in patent: Paragraph 0137

33
[ 2969-81-5 ]
[ 95-01-2 ]
[ 152942-06-8 ]

Reference： [1] Journal of the American Chemical Society, 2018, vol. 140, # 44, p. 15114 - 15123
[2] Organic letters, 2000, vol. 2, # 13, p. 1787 - 1790
[3] Patent: US5994378, 1999, A,

34
[ 95-01-2 ]
[ 189439-24-5 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 4, p. 657 - 667

[ 95-01-2 ] Synthesis Path-Downstream 1~68

1
[ 15832-09-4 ]
[ 95-01-2 ]
[ 32396-77-3 ]

Yield	Reaction Conditions	Operation in experiment
12%	With potassium hydroxide; In methanol; water; at 60℃;	General procedure: To a solution of compound 3a or 3b (2.0 mmol) in methanol (20 mL) was added successively anaqueous 50% potassium hydroxide (3 mL) and benzaldehyde derivatives 4 (3.0 mmol). The mixture was heated at 60 C and then solvent was evaporated. The residue was diluted in water and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography to give aurones.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4520 - 4523
[2]Journal of the Indian Chemical Society,1958,vol. 35,p. 83,86

2
[ 105-56-6 ]
[ 95-01-2 ]
[ 19088-73-4 ]

Yield	Reaction Conditions	Operation in experiment
80%	With [bis(acetoxy)iodo]benzene; In ethanol; at 35 - 40℃;	General procedure: alpha-substituted ethyl acetate (1.0 mmol)and Phenyliododiacetate (1.0 mmol) was dissolved in ethanol (5 ml) with constant stirring. After 10 minutes benzaldehyde/salicylaldehyde (1.0 mmol), was added and the mixture was allowed to stir for appropriate time. Then the progress of the reaction was monitored by thin layer chromatography. After completion of reaction as indicated by TLC, ethanol was evaporated under reduce pressure. The product was extracted with ethyl acetate, dried over Na2SO4 and solvent was evaporated under reduce pressure. The residue obtained was recrystallized by ethyl acetate and hexane to product 3a-3h and 4a-4r.
	With piperidine; at 20℃;	The ligand (HL) was prepared by two steps: Step 1, 3-Cyano-7-hydroxy coumarine (0.01mol)was prepared [12] via the condensation of 2,4-dihydroxy benzaldehyde with ethylcyanoacetate in presence of piperdine. The medium temperature should be maintained at 5 C by using ice salt bath during addition, and then the reaction mixture was kept at room temperature overnight, and then poured with vigorous stirring into a mixture crushed ice and water. The solid 3-Cyano-7-hydroxycoumarine was filtered off and washed several times with cold water and recrystallized from ethanol. Elemental analysis: C10H5NO3 (M = 187.16); C 64.66 (calc. 64.17); H 2.74 (calc.2.70); N 7.58 (calc. 7.49); O 25.72(calc. 25.65). %. IR (KBr):3432 upsilon(OH), 1622 upsilon(C_O), 2330 upsilon(CXiN) cm-1. 1H NMR in DMSO, internal TMS, d (ppm): 6.72, 6.70 (m, 3H, ArH),9.1(s,1H, OH).

Reference： [1]Synthetic Communications,2005,vol. 35,p. 785 - 790
[2]Phosphorus, Sulfur and Silicon and the Related Elements,2002,vol. 177,p. 2555 - 2559
[3]Tetrahedron Letters,2017,vol. 58,p. 3183 - 3187
[4]Journal of Heterocyclic Chemistry,2007,vol. 44,p. 867 - 870
[5]Journal of the Iranian Chemical Society,2016,vol. 13,p. 149 - 153
[6]Proceedings - Indian Academy of Sciences, Section A,1942,p. 68,77
[7]Journal of Molecular Liquids,2017,vol. 242,p. 293 - 307
[8]Chemical Papers,2018,vol. 72,p. 1461 - 1466

3
[ 95-01-2 ]
[ 19112-35-7 ]
[ 130907-50-5 ]

Reference： [1]Journal of the Chemical Society,1957,p. 2593,2596

4
[ 109-77-3 ]
[ 95-01-2 ]
[ 19088-73-4 ]

Reference： [1]Journal of Heterocyclic Chemistry,2011,vol. 48,p. 799 - 802
[2]Bulletin of the Chemical Society of Japan,1983,vol. 56,p. 3571 - 3577
[3]Molecular Crystals and Liquid Crystals (1969-1991),1983,vol. 100,p. 299 - 305
[4]Heterocycles,1996,vol. 43,p. 1257 - 1266

5
[ 926-39-6 ]
[ 95-01-2 ]
[ 110925-67-2 ]

Reference： [1]Pharmaceutical Chemistry Journal,1987,vol. 21,p. 323 - 326
Khimiko-Farmatsevticheskii Zhurnal,1987,vol. 21,p. 551 - 554

6
[ 31525-67-4 ]
[ 95-01-2 ]
[ 54287-99-9 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1987,p. 431 - 438
[2]Organic Letters,1999,vol. 1,p. 2113 - 2115
[3]Tetrahedron Letters,1984,vol. 25,p. 1099 - 1102

7
[ 32136-81-5 ]
[ 95-01-2 ]
4',7-dihydroxy-3-methoxyflavylium chloride [ No CAS ]

Reference： [1]Helvetica Chimica Acta,1994,vol. 77,p. 1595 - 1610

8
[ 95-01-2 ]
[ 64419-24-5 ]

Yield	Reaction Conditions	Operation in experiment
70.5%	With formic acid; hydroxyammonium sulfate; sodium formate; at 20 - 100℃; for 2.25h;	In a double walled reactor 50.0 g (0.362 mol, 1.0 meq) 2,4-dihydroxybenzaldehyde were added to 180 mL formic acid, which resulted in a brown suspension at room temperature. Then 45.8 g (0.673 mol, 1.8 meq) sodium formate were added over 2 min, and the temperature increased to 33 C. After the temperature decreased to 30 C., 35.6 g (0.217 mol, 1.2 meq) hydroxyl ammonium sulfate were added during 3 min to give a thick brown suspension which became a brown solution after stirring 10 min at 30-32 C. While heating the mixture to 100 C., crystallization occurred at 38 C. and stirring was interrupted. At 70 C. the reaction mixture became a thin suspension, which was easy to stir. This reaction mixture was stirred for 2 hours at 100 C. The color turned dark brown. TLC (silica gel 60 F254, acetone:n-hexane:water 20:20:1) showed an almost complete reaction. Formic acid (170 mL) was evaporated under reduced pressure (60 C., 10 mbar). The solid dark brown residue was stirred with 400 mL MTBE at 40 C. for 1 hour (incomplete dissolution). The insoluble residue (62.5 g) was filtered and washed two times each with 50 mL MTBE. To the mother liquor 10 g activated carbon (Norit CA 5) were added and this mixture was refluxed for 1 hour and filtered at 40 C. by Celite Super Hyflow (washing with 2*50 mL portions of MTBE). The MTBE-mother liquor was washed three times each with 100 mL water. After removing the water from this MTBE solution with azeotropic distillation (water separator) it was concentrated under reduced pressure to 20% of the starting volume and 500 mL toluene were added. Then the MTBE was distilled off under reduced pressure. During this process a brown residue began to precipitate, which was filtered. The toluene mother liquor was concentrated to 150 mL and 2,4-dihydroxybenzonitrile precipitated, which was filtered and washed two times each with 30 mL toluene. The pale tan product was dried under reduced pressure (45 C., 20 mbar). The reaction yielded 34.5 g of 2,4-dihydroxybenzonitrile (70.5%, purity 97% (HPLC)).

Reference： [1]Tetrahedron,1999,vol. 55,p. 13265 - 13268
[2]Patent: US2003/220504,2003,A1 .Location in patent: Page/Page column 4
[3]Journal of Medicinal Chemistry,1999,vol. 42,p. 95 - 108
[4]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2001,vol. 40,p. 1000 - 1006
[5]Soft Matter,2010,vol. 6,p. 1704 - 1721
[6]Advanced Functional Materials,2014,vol. 24,p. 1703 - 1717
[7]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 657 - 667
[8]Chemistry - A European Journal,2017,vol. 23,p. 5541 - 5556

9
[ 107-86-8 ]
[ 95-01-2 ]
[ 54287-99-9 ]
[ 33279-69-5 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1999,vol. 72,p. 259 - 263

10
[ 1483-73-4 ]
[ 95-01-2 ]
[ 131-56-6 ]

Reference： [1]Synthetic Communications,2000,vol. 30,p. 531 - 536

12
[ 107-86-8 ]
[ 95-01-2 ]
[ 54287-99-9 ]

Yield	Reaction Conditions	Operation in experiment
50%	With calcium hydroxide; In methanol; at 20℃; for 48h;	2,4-Dihydroxybenzaldehyde (15) (3 g/20.17 mmol), calcium hydroxide (1.543 g/20.8 mmol) and 150 mL of methanol were place in a two-necked round-bottom flask. Then, prenal (9.135 g/108.6 mmol) was added dropwise. The mixture was allowed to stir at room temperature for 48 h. The reaction was quenched with HCl 1 M until pH 1-2. The methanol was evaporated and the aqueous phase was extracted with 3 × 150 mL of ethyl acetate. The organic phase was washed with 2 × 100 mL of brine, dried over sodium sulfate anhydrous, filtered and the organic solvent evaporated. The crude product was purified by silica gel flash chromatography (n-hexane/ethyl acetate 9:1). Compound 16 was crystallized from n-hexane/ethyl acetate 3:1 as a yellow solid (2.06 g/50%).
50%	With calcium hydroxide; In methanol; at 20℃; for 48h;	2,4-Dihydroxybenzaldehyde (42) (3g/20.17mmol), calcium hydroxide (1.543g/20.8mmol) and 150mL of methanol were placed in a round-bottom flask. Then, prenal (9.135g/108.6mmol) was added dropwise. The mixture was stirred at room temperature for 48h. The reaction was quenched with HCl 1M until pH 1-2. The methanol was evaporated and the aqueous phase was extracted with 3×150mL of ethyl acetate. The organic phase was washed with 2×100mL of brine, dried over sodium sulfate anhydrous, filtered and the organic solvent evaporated. The crude product was purified by silica gel flash chromatography (n-hexane/ethyl acetate 9:1). Compound 43 was crystallized from n-hexane/ethyl acetate 3:1 as a yellow solid (2.06g/50%).6-Formyl-5-hydroxy-2,2-dimethyl-2H-benzopyran (43). Mp: 68-69C. IR numax (cm-1) (KBr): 3464, 2967, 2922, 2857, 1628, 1484, 1330, 1294, 1247, 1176, 1107, 1081, 748. 1H NMR (300.13MHz, CDCl3) delta (ppm): 11.65 (OH), 9.66 (s, CHO), 7.29 (d, J=8.6), 6.88 (d, J=10.0), 6.44 (d, J=8.6), 5.61 (d, J=10.0), 1.46 (s, 6H). 13C NMR (100.63MHz, CDCl3) delta (ppm): 194.5, 160.6, 158.7, 134.7, 128.6, 115.2, 115.1, 109.4, 108.8, 78.2, 28.4. EIMS m/z (%): 205 (5, [M+1]+.), 204 (10 [M]+.), 190 (15), 189 (100), 187 (60), 159 (12), 131 (12), 103 (10), 77 (12), 51 (6). HRMS (ESI) m/z calcd for C12H13O3 [M+H]+: 205.08570, found: 205.08592.
21%	With pyridine; at 140℃; for 10h;	Weigh compound 18-1 (2g, 14.5mmol) in pyridine (2.5mL), Add 3-methyl-2-butenal (2.78 mL, 28.8 mmol), The system was reacted at 140 C for 10 hours. After the reaction was completed, The solvent was distilled off under reduced pressure, The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 300: 5-300: 10), Compound 18-2 (brown oil, 31 mg) was obtained.

0.68 g

With calcium hydroxide; In methanol; at 20℃; for 12h;

A 1 g portion of 2,4-2 hydroxybenzaldehyde (Compound 2 shown in Figure 1)0.514 g Ca (OH) 2, methanol150mL.3.045 g of prenyl aldehyde (compound 1 shown in FIG. 1) was then added dropwise.Stir at room temperature for 12h.Quench with HCl (1 M) until the pH is 1-2.Methanol was evaporated and the aqueous phase was extracted with 3 * 150 mL of ethyl acetate.The organic phase was washed with 2 * 100 mL saturated brine, dried over anhydrous Na2SO4,Vacuum filtration, and spin dry. The crude product was passed through a column of silica gel (petroleum ether: ethyl acetate = 9: 1)Crystallization gave product 3 (0.68 g) as shown in FIG.

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 9266 - 9286
[2]Journal of Organic Chemistry,2015,vol. 80,p. 11460 - 11467
[3]Angewandte Chemie - International Edition,2012,vol. 51,p. 8092 - 8096
[4]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 2941 - 2959
[5]European Journal of Medicinal Chemistry,2013,vol. 69,p. 798 - 816
[6]Tetrahedron,2001,vol. 57,p. 5335 - 5338
[7]Patent: CN110627817,2019,A .Location in patent: Paragraph 0328-0331
[8]Tetrahedron Letters,2009,vol. 50,p. 5075 - 5079
[9]Advanced Synthesis and Catalysis,2005,vol. 347,p. 555 - 562
[10]Patent: CN106187974,2016,A .Location in patent: Paragraph 0044

13
[ 122-88-3 ]
[ 108-24-7 ]
[ 95-01-2 ]
3-(4-chlorophenoxy)-7-acetoxycoumarin [ No CAS ]

Reference： [1]Il Farmaco,2003,vol. 58,p. 1201 - 1207

14
[ 1190-39-2 ]
[ 95-01-2 ]
7-Hydroxy-2-oxo-2H-chromene-3-carboxylic acid butyl ester [ No CAS ]

Reference： [1]Journal of Materials Chemistry,2003,vol. 13,p. 1253 - 1258

15
[ 16188-55-9 ]
[ 108-24-7 ]
[ 95-01-2 ]
acetic acid 3-(4-methylsulfanyl-phenyl)-2-oxo-2<i>H</i>-chromen-7-yl ester [ No CAS ]

Reference： [1]Annales Pharmaceutiques Francaises,2003,vol. 61,p. 51 - 56

16
[ 95-01-2 ]
[ 79418-41-0 ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 5077 - 5080
[2]Journal of Organic Chemistry,2011,vol. 76,p. 4964 - 4972
[3]Chemistry of Heterocyclic Compounds,2011,vol. 46,p. 1514 - 1519
[4]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,2012,vol. 90,p. 40 - 44
[5]Journal of Medicinal Chemistry,2013,vol. 56,p. 2779 - 2790
[6]Journal of the American Chemical Society,2014,vol. 136,p. 7205 - 7208
[7]Medicinal Chemistry Research,2014,vol. 23,p. 3632 - 3643
[8]Bulletin of the Korean Chemical Society,2014,vol. 35,p. 2400 - 2402
[9]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 5737 - 5742
[10]Tetrahedron,2016,vol. 72,p. 4925 - 4930
[11]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 5557 - 5561
[12]Journal of Molecular Liquids,2020,vol. 297

17
[ 95-01-2 ]
[ 13196-11-7 ]

Reference： [1]Synlett,2006,p. 567 - 570
[2]Helvetica Chimica Acta,1935,vol. 18,p. 816,826

18
[ 95-01-2 ]
[ 66-97-7 ]

Reference： [1]Synlett,2006,p. 567 - 570

19
[ 95-01-2 ]
Me-X (X=Br or Cl) [ No CAS ]
[ 19088-73-4 ]

Reference： [1]Synthesis,2003,p. 2331 - 2334

20
[ 95-01-2 ]
Me-X (X=Br or Cl) [ No CAS ]
[ 6147-11-1 ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 291 - 293

21
[ 95-01-2 ]
resorcinoldialdehyde [ No CAS ]
[ 87080-27-1 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1993,vol. 32,p. 713 - 715

22
[ 95-01-2 ]
resorcinoldialdehyde [ No CAS ]
[ 54287-99-9 ]

Reference： [1]Heterocycles,1983,vol. 20,p. 661 - 666

23
[ 95-01-2 ]
[ 87080-27-1 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1983,vol. 22,p. 276 - 277

24
[ 2150-45-0 ]
[ 95-01-2 ]

Reference： [1]Journal of the Indian Chemical Society,1942,vol. 19,p. 393

25
[ 95-01-2 ]
[ 57543-36-9 ]

Reference： [1]Journal Of Scientific and Industrial Research,1952,vol. 11 B,p. 39,43

26
[ 95-01-2 ]
air [ No CAS ]
[ 4721-07-7 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1971,vol. 750,p. 109 - 127

27
[ 95-01-2 ]
air [ No CAS ]
[ 1885-13-8 ]

Reference： [1]Monatshefte fur Chemie,1964,vol. 95,p. 649 - 670

28
[ 95-01-2 ]
air [ No CAS ]
[ 20734-74-1 ]

Reference： [1]Monatshefte fur Chemie,1964,vol. 95,p. 649 - 670

29
[ 110-87-2 ]
[ 24057-28-1 ]
[ 95-01-2 ]
[ 72041-59-9 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane;	10) Preparation of 2-hydroxy-4-(2-tetrahydropyranyl)oxybenzaldehyde (procedure A) A solution of 2,4-dihydroxybenzaldehyde (2.76 g, 20 mmol), pyridinium-toluenesulfonate (100 mg, 0.4 mmol) and 3,4-dihydro-2H-pyran (2.7 ml, 30 mmol) in methylene chloride (30 ml) was stirred for 4 h at room temperature. The solution was washed with 1M sodium carbonate (20 ml) and concentrated in vacuo to give 4.3 g of an brown oil, which according to the 1H NMR spectrum consisted of almost pure 2-hydroxy-4-(2-tetrahydropyranyl)oxybenzaldehyde. 1H NMR (CDCl3) delta 11.4 (s, OH), 9.72 (s, CHO), 7.43 (d, J 8.4 Hz, H6), 6.66 (dd, J 8.4, 2.5 Hz, H5), 6.62 (d, J 2.5 Hz, H3), 5.50 (t, J 3 Hz, H2'), 3.83 (bt, J 9.2 Hz, H6a'), 3.65 (bt, J 5.4 Hz, H6e'), 2.0-1.5 (m, H340-540).

Reference： [1]Patent: US2003/65039,2003,A1

30
[ 13134-31-1 ]
2-methoxy-4-(prop-2-yn-1-yloxy)benzaldehyde [ No CAS ]
[ 95-01-2 ]
2-(2-methoxy-4-propargyloxyphenyl)-1,3,4,7-tetraazaindene hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ethereal hydrochloric acid; hydrogen sulfide; In 1,3,5-trimethyl-benzene;	EXAMPLE 10 11 g of IIa, 19 g of 2-methoxy-4-propargyloxybenzaldehyde (obtainable from 2,4-dihydroxybenzaldehyde via 2-hydroxy-4-propargyloxybenzaldehyde) and 10 g of sulfur are stirred at 180 for 10 hours in 200 ml of mesitylene, the mixture is evaporated to dryness, the residue is extracted with methanol, the solution is filtered and the filtrate is concentrated to 350 ml. The addition of ethereal hydrochloric acid precipitates 2-(2-methoxy-4-propargyloxyphenyl)-1,3,4,7-tetraazaindene hydrochloride; free base, m.p. 189-190.

Reference： [1]Patent: US4477454,1984,A

31
[ 543-24-8 ]
[ 95-01-2 ]
[ 79418-41-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium acetate; acetic anhydride; at 140℃; for 8h;	1.38g of 2,4-dihydroxybenzaldehyde, 1.17g of acetylglycine, 2.48g of sodium acetate dissolved in 25ml of acetic anhydride, heated to 140 condensed reflux reaction 8 hours, adding a small amount of distilled water, filtered and filtered to obtain solid . The solid was dissolved in a mixed solution of concentrated hydrochloric acid and ethanol at a volume ratio of 2: 1. The reaction was condensed at 80 C for 3 hours. After cooling, the solution was adjusted to pH 6.5 with 30% sodium hydroxide solution and the solid was collected by suction filtration. The solid was dried in a vacuum desiccator and recrystallized from ethanol to give the product 3-amino-7-hydroxycoumarin.

Reference： [1]Angewandte Chemie - International Edition,2009,vol. 48,p. 4034 - 4037
Angew. Chem., Int. Ed.,2009,vol. 121,p. 4094 - 4097
[2]Tetrahedron Letters,2012,vol. 53,p. 5280 - 5283
[3]Chemical Communications,2015,vol. 51,p. 2029 - 2032
[4]Tetrahedron Letters,2015,vol. 56,p. 5761 - 5766
[5]Patent: CN105693674,2016,A .Location in patent: Paragraph 0024
[6]Chemical Communications,2017,vol. 53,p. 3583 - 3586
[7]Bioorganic Chemistry,2020,vol. 96

32
[ 72-80-0 ]
[ 95-01-2 ]
[ 1251918-07-6 ]

Reference： [1]Molecules,2010,vol. 15,p. 288 - 304

33
[ 19840-99-4 ]
[ 95-01-2 ]
[ 1258219-92-9 ]

Reference： [1]Inorganica Chimica Acta,2010,vol. 363,p. 4048 - 4058

34
[ 932-52-5 ]
[ 95-01-2 ]
[ 273745-68-9 ]

Reference： [1]Russian Journal of General Chemistry,2009,vol. 79,p. 985 - 990

35
[ 14741-71-0 ]
[ 95-01-2 ]
[ 68482-66-6 ]

Reference： [1]Research on Chemical Intermediates,2012,vol. 38,p. 1403 - 1409

36
[ 94-99-5 ]
[ 95-01-2 ]
[ 1387637-34-4 ]

Yield	Reaction Conditions	Operation in experiment
82.6%	With sodium hydrogencarbonate; potassium iodide; In acetonitrile; at 60 - 65℃;	General procedure: A mixture of 2,4-dihydroxybenzaldehyde (1.38 g, 0.01 mol), substituted benzyl chloride (0.011 mol), NaHCO3 (1.26 g, 0.015 mol) and catalytic amount of potassium iodide in 20 mL acetonitrile was heated to 60 C for 36 h and hot filtered, the filtrate was cooled to 10 C and filtered, the filtrated cake was collected and recrystallized with EtOH to obtain compounds 10a-g.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 86,p. 257 - 269
[2]Archiv der Pharmazie,2014,vol. 347,p. 936 - 949
[3]Molecules,2013,vol. 18,p. 2904 - 2923
[4]Chemical and Pharmaceutical Bulletin,2019,vol. 67,p. 351 - 360

37
[ 456-42-8 ]
[ 95-01-2 ]
[ 1387637-35-5 ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h;	3-Fluorobenzyl chloride (0.10 mol, 14.5 g) and 2,5-dihydroxybenzaldehyde (0.10 mol, 13.8 g) were dissolved in 30 mL of DMF, and K2CO3 (0.10 mol, 13.8 g) was added.[22] The mixture was stirred at 80 C for 8 h and the reaction was controlled by TLC in petroleum: acetic ether (3:1, v/v).At the end of the reaction, the mixture was diluted with waterand extracted 3 times with acetic ether, and the combinedorganic layers were dried (MgSO4). After removal of thesolvent, the residue was recrystallized from acetic ether to get compound 1.

Reference： [1]Archiv der Pharmazie,2014,vol. 347,p. 936 - 949
[2]Letters in drug design and discovery,2014,vol. 11,p. 736 - 741
[3]Molecules,2013,vol. 18,p. 2904 - 2923

38
[ 2491-38-5 ]
[ 95-01-2 ]
[ 486-66-8 ]

Yield	Reaction Conditions	Operation in experiment
82%		General procedure: To prepare catalyst, 0.21 g of thiamine hydrochloride (0.6 mmol) was dissolved in 0.64 mL of water and added 2.4 mLof 95% ethanol (water : 95% ethanol = ~1:4). The solution was cooled in an ice bath, then added 0.40 mL of 3 M NaOH(1.2 mmol) dropwise with stirring in a manner such that thetemperature remained below 20 C. Intense yellow coloured solution changed to pale yellow solution of thiamine (thiazolium ion)/N-heterocyclic carbene (Scheme 1).47 In a 25-mL round bottom flask, a mixture of phenacylbromide 1 (2.5 mmol, 0.5 g in case of 1a) and thiamine (0.6 mmol, 25 mol %) in ethanol (4 mL) was stirred at room temperature for 15 min. Then, salicylaldehyde 2 (2.5 mmol, 0.26 mL in case of 2a) was added slowly and the mixture was stirred at room temperature until the reaction was completed (as monitored by TLC) (Table 3) . The reaction mixture was then poured into 20 mL of distilled water and extracted with ethyl acetate (3 × 10 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The resulting product isoflavone 3 was further purified either by recrystallizationor by column chromatography (Ethyl acetate:Hexane, 1:4v/v). All compounds were characterized by their mp and 1HNMR, 13CNMR and mass spectral data.

Reference： [1]Bulletin of the Korean Chemical Society,2013,vol. 34,p. 1070 - 1076

39
[ 2650-14-8 ]
[ 1193-24-4 ]
[ 95-01-2 ]
[ 1575814-93-5 ]

Reference： [1]Journal of the Iranian Chemical Society,2014,vol. 11,p. 155 - 162

40
[ 7474-78-4 ]
[ 95-01-2 ]
[ 1611449-83-2 ]

Reference： [1]RSC Advances,2014,vol. 4,p. 3355 - 3363

41
[ 81-16-3 ]
[ 95-01-2 ]
[ 1623816-37-4 ]

Reference： [1]Applied Organometallic Chemistry,2014,vol. 28,p. 383 - 388

42
[ 153-78-6 ]
[ 95-01-2 ]
N-(2,4-dihydroxyphenyl)methylidene-9H-fluoren-2-amine [ No CAS ]

Reference： [1]Journal of the Chemical Society of Pakistan,2013,vol. 35,p. 426 - 430

43
[ 95-23-8 ]
[ 95-01-2 ]
(E)-5-((2,4-dihydroxybenzylidene)amino)-1H-benzo[d]imidazol-2(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.4%	With acetic acid; In i-Amyl alcohol;Reflux; Inert atmosphere;	2,4-Dihydroxybenzaldehyde (0.1 g, 0.72 mmol), 5-Amino-2-benzimidazolinone (0.07 g, 0.47 mmol), and isoamyl alcohol (3 mL) were stirred at room temperature under N2. Acetic acid (0.11 mL) was added drop-wise, and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH2Cl2, MeOH, and dried to give 15 (0.12 g, 0.44 mmol, 94.4%) as a yellow powder.1H NMR (DMSO, 300 MHz) delta 13.76 (s, 1H), 10.75 (s, 1H), 10.69 (s, 1H), 10.19 (bs, 1H), 8.77 (s, 1H), 7.40 (d, 1H, J=8.4 Hz), 7.21-6.88 (m, 3H), 6.37 (dd, 1H, J=8.6 Hz, 2.0 Hz), 6.27(s, 1H); 13C NMR (DMSO, 500 MHz) delta 163.52, 162.66, 161.02, 156.28, 142.16, 134.76, 131.25, 129.21, 115.12, 112.89, 109.51, 108.33, 103.07, 101.47. Rf=0.31 (CH2Cl2/MeOH 9:1)
94.4%	With acetic acid; In i-Amyl alcohol;Inert atmosphere; Reflux;	2,4-dihydroxy-benzaldehyde (0.1g, 0.72 mmol), 5-amino-2 - benzimidazolyl BBIT (0.07g, 0.47 mmol) and isoamyl alcohol (3 mL)was stirred at room temperature andthe N2.It was added dropwise acetic acid (0.11 mL) and the mixture was refluxed overnight.Filtering the reaction mixture, CH2Cl2and dried and then washed with MeOH, the compound as a yellow powder15was obtained (0.12g, 0.44mmol, 94.4%).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4659 - 4663
[2]Patent: KR101639289,2016,B1 .Location in patent: Paragraph 0203-0206

44
[ 513-35-9 ]
[ 95-01-2 ]
[ 54287-99-9 ]

Yield	Reaction Conditions	Operation in experiment
32%	With pyridine; In acetone; at 120℃; for 23.5h;Heating;	[0174] Pyridine (0.01 M) solution containing 3-methyl-but-2-enyl (2.0 equivalent) was added to anhydrous acetone solution (0.01 M) containing 2,4-dihydroxyaldehyde (1 equivalent) drop by droop at 120 C for 5.5 hours, followed by heating for 18 hours. After cooling down at room temperature, the solvent was eliminated under reduced pressure using a rotary evaporator. Pyridine was eliminated by azeotropic distillation along with toluene. The obtained non-purified product was purified by flash column chromatography (EtOAc:n-hexane=1:8) to give the compound 119 as a colorless solid (yield: 32%, 1.12 g). [0175] 1H-NMR (CDCl3, 300 MHz) delta11.61 (s, 1H), 9.62 (s, 1H), 7.25 (d, 1H, J = 8.6 Hz), 6.39 (d, 1H, J = 8.6 Hz), 5.58 (d, 1H, J = 10.0 Hz), 1.42 (s, 6H).

Reference： [1]Patent: EP2871187,2015,A1 .Location in patent: Paragraph 0173-0175

45
[ 32136-81-5 ]
[ 95-01-2 ]
4’,7-dihydroxy-3-methoxyflavylium perchlorate [ No CAS ]

Reference： [1]Chemical Communications,2015,vol. 51,p. 7349 - 7351

46
[ 115-19-5 ]
[ 95-01-2 ]
[ 54287-99-9 ]

Yield	Reaction Conditions	Operation in experiment
32%	With pyridine; at 120℃; for 23.5h;	Pyridine (0.01 M) solution containing 3-methyl-but-2-enyl (2.0 equivalent) was added to anhydrous acetone solution (0.01 M) containing 2,4-dihydroxyaldehyde (1 equivalent) drop by droop at 120 C. for 5.5 hours, followed by heating for 18 hours. After cooling down at room temperature, the solvent was eliminated under reduced pressure using a rotary evaporator. Pyridine was eliminated by azeotropic distillation along with toluene. The obtained non-purified product was purified by flash column chromatography (EtOAc:n-hexane=1:8) to give the compound 119 as a colorless solid (yield: 32%, 1.12 g). [0272] 1H-NMR (CDCl3, 300 MHz) delta11.61 (s, 1H), 9.62 (s, 1H), 7.25 (d, 1H, J=8.6 Hz), 6.39 (d, 1H, J=8.6 Hz), 5.58 (d, 1H, J=10.0 Hz), 1.42 (s, 6H).

Reference： [1]Patent: US2015/183797,2015,A1 .Location in patent: Paragraph 0270-0272

47
[ 76350-90-8 ]
[ 95-01-2 ]
2-hydroxy-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Cooling with ice;	Combined 2,4-dihydroxybenzaldehyde (3.14 g, 22.75 mmol),triphenylphosphine (5.97 g, 22.75 mmol) and (2-methyl-[1,1?-biphenyl]-3-yl)methanol (4.1 g, 20.68 mmol) in dry tetrahydrofuran (50 mL) and cooled on an ice/water bath. Added diisopropyl azodicarboxylate (4.33 mL, 22.25 mmol) in tetrahydrofuran (50 mL) dropwise. The resulting yellow solution was allowed to slowly warm to room temperature with stirring overnight. Excess solvent was removed by rotary evaporator. The reaction mixture was chromatoghraphed with 0-20% ethyl acetate in hexanes on silica gel to give the desired product (4.2 g, 64%). 1H NMR (400 MHz, CHLOROFORM-d) delta 11.53 (s, 1H), 9.76 (s, 1H), 7.51-7.29 (m, 11H), 6.67 (dd, J=8.6, 2.2 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 5.17 (s, 2H), 2.26 (s, 3H).

Reference： [1]Patent: US2015/291549,2015,A1 .Location in patent: Paragraph 0256; 0257

48
[ 15317-58-5 ]
[ 95-01-2 ]
N'-(2,4-dihydroxybenzylidene)-1H-indole-3-carbohydrazide [ No CAS ]

Reference： [1]Medicinal Chemistry Research,2016,vol. 25,p. 1 - 18

49
[ 1760-24-3 ]
[ 95-01-2 ]
C₁₅H₂₆N₂O₅Si [ No CAS ]

Reference： [1]Applied Catalysis A: General,2014,vol. 488,p. 148 - 159

50
[ 1115-70-4 ]
[ 95-01-2 ]
C₁₁H₁₅N₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol;Alkaline conditions; Reflux;	General procedure: The Schiff-bases have been prepared by addition of methanolic MF solution to a methanolic solution of the aldehyde in 1:1 ratio in basic medium [24]. The mixture was refluxed with continuous stirring over water bath for two hours. The solution turned to yellow color indicating the formation of the Schiff-base.
	In methanol; for 2h;Reflux; Alkaline conditions;	General procedure: The Schiff-bases have been prepared by addition of methanolicMF solution to a methanolic solution of the aldehyde in1:1 mol ratio in basic medium [11]. The mixture was refluxedwith continuous stirring over water bath for 2 h. The solutionturned to yellow color indicating the formation of the Schiffbase.Only, HL1 Schiff-base was isolated in the solid state,dried under vacuum and recrystallized from methanol (m.p.195 C). We followed the same method in preparation of theother Schiff-bases with different aldehydes but trials to obtainthe solid compounds were unsuccessful. Accordingly, theSchiff-bases were obtained dissolved in methanol solutionand used further for template synthesis of the complexes.

Reference： [1]Journal of Thermal Analysis and Calorimetry,2017,vol. 128,p. 957 - 969
[2]Journal of Fluorescence,2019,vol. 29,p. 319 - 333

51
[ 21667-62-9 ]
[ 56062-81-8 ]
[ 95-01-2 ]
(5-amino-4-(3-chlorobenzoyl)-3-(2,4-dihydroxyphenyl)-1H-pyrrol-2-yl)(phenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With potassium carbonate; In ethanol;Reflux;	General procedure: The synthesis of 2-aminopyrrole analogues was based on a multicomponent reaction by refluxing a solution of three reactants including a methylsulfonamidoacetophenone, an aldehydes and acyanoacetic acid with 0.6 equiv of K2CO3 in ethanol. This reaction results in three substituted 2-aminopyrroles [35]. Compounds1-30 in Tables 1 and 2, and Fig. 3 were synthesized as shown in Scheme 1.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 139,p. 633 - 643

52
[ 168646-54-6 ]
[ 95-01-2 ]
4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)benzene-1,3-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	In ethanol; at 70 - 80℃; for 24h;	General procedure: A mixture of 44 <strong>[168646-54-6]1,10-phenanthroline-5,6-diamine</strong> (1mmol), 45 2,3-dihydroxybenzaldehyde (1mmol) and 46 EtOH (10mL) was heated at 70?80°C for 24h. The reaction mixture was cooled to room temperature, dried and concentrated in vacuo. Yield: 89percent 4.2.2 2-(1H-Imidazo[4,5-f][1,10]phenanthrolin-2-yl)benzene-2,4-diol (ODHPIP) This ligand was synthesized in a manner identical to that described for MDHPIP, with 2,4-dihydroxybenzaldehyde instead of 2,3-dihydroxybenzaldehyde. Yield: 85percent. Anal. Calcd for C19H12N4O2: C, 69.51; H, 3.68; N, 17.06. Found: C, 69.49; H, 3.71; N, 17.02. ESI-MS: 328 ([Mr+H]+). 1H NMR (300 MHz, CD3OD-d6): delta 9.03 (d, J = 8.7 Hz, 2H), 8.74 (d, J = 9.0 Hz, 2H), 7.95 (t, J = 7.8 Hz, 2H), 7.25 (d, J = 7.5 Hz, 2H,), 7.23 (s, 1H,),5.67 (s, 1H). 13C NMR (300 MHz, CD3OD-d6): delta 166.45, 163.42, 159.78, 156.32, 150.81, 154.6, 145.80, 142.93, 140.59, 132.44, 130.65, 130.26, 128.54, 126.84, 124.65, 122.25, 121.85, 119.32.

Reference： [1]Inorganica Chimica Acta,2018,vol. 469,p. 593 - 599

53
[ 79418-41-0 ]
[ 95-01-2 ]
(E)-3-((2,4-dihydroxybenzylidene)amino)-7-hydroxy-2H-chromen-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	In ethanol; for 2h;Reflux;	General procedure: 3-Amino-7-hydroxy-2H-chromen-2-one (0.56 g, 31 mmol) and the appropriate benzaldehyde (31 mmol) were dissolved in absolute EtOH (10 mL) and refluxed for 2 h. The precipitate formed was collected and washed with hot EtOH. In this way, the following (E)-7-hydroxy-3-(benzylidenimino)- 2H-chromen-2-ones 1-6 were prepared.

Reference： [1]Medicinal Chemistry Research,2017,vol. 26,p. 2707 - 2717

54
[ 7474-78-4 ]
[ 95-01-2 ]
2-(2,4-dihydroxyphenyl)-1H-benzimidazole-5-sulfonic acid [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2017,vol. 32,p. 527 - 537

55
[ 95-01-2 ]
[ 4721-07-7 ]

Reference： [1]Patent: CN106554254,2017,A

56
[ 127-79-7 ]
[ 95-01-2 ]
4-(2,4-dihydroxy-5-formylphen-1-ylazo)-N-(4-methylpyrimidin-2-yl)benzenesulfonamide [ No CAS ]

Reference： [1]Applied Organometallic Chemistry,2017,vol. 31

57
[ 188347-49-1 ]
[ 95-01-2 ]
7-hydroxy-3-(3’,5’-dibromophenyl)coumarin [ No CAS ]

Reference： [1]Green Chemistry,2018,vol. 20,p. 804 - 808

58
[ 188347-49-1 ]
[ 95-01-2 ]
E-3’,5’-dibromo-2,4-dihydroxystilbene [ No CAS ]

Reference： [1]Green Chemistry,2018,vol. 20,p. 804 - 808

59
[ 4670-09-1 ]
[ 95-01-2 ]
[ 4721-07-7 ]

Reference： [1]Green Chemistry,2018,vol. 20,p. 804 - 808

60
[ 4457-67-4 ]
[ 95-01-2 ]
2-hydroxy-4-(4-methoxybutoxy)benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48.5%	With 18-crown-6 ether; potassium carbonate; In acetone; for 15h;Reflux;	A 250 mL capacity 3-neck round bottom flash (reactor) was equipped with a magnetic stirrer, a reflux condenser and a thermometer. 18- crown-6 (2.64 g, 10 mmol), K2C03 (20.01 g, 145 mmol), 2,4-dihydroxybenzaldehide (17.96 g, 130 mmol), acetone (130 mL) and 1-bromo- 4-methoxybutane (24.96 g, 149.5 mmol) were successively added into the reactor in that order. The reactor was heated with oil bath to reflux for 15 hours. The reaction mixture was cooled down to room temperature. Acetone was evaporated from the reaction mixture by Rotovap. 150 mL of Hexanes was added to resuspend the residue obtain after acetone removal. Hexanes phase that contains dialkylated and monoalkylated products but not starting material, was separated by filtration. Solid obtained after filtration was dissolved with NaOH aq. 1M (150 mL). The mixture was extracted with hexanes (100 mL). Hexanes phase from filtration and from extracting were combined. The combined hexanes phase was washed with NaOH, aq. 1 M (20 mL) to migrate monoalkylated desired product and starting material to aqueous layer and keep dialkylated product in organic layer. Combined aqueous layer was acidified with HCI, 50percent to pH = 8 and extracted with ethyl acetate. Ethyl acetate phase was dried over Mg504, concentrated and chrom atographed to yield 2-hydroxy-4-(4-m ethoxybutoxy)benzaldehyde (14.14 g, 63.1 mmol, 48.5percent).

Reference： [1]Patent: WO2018/125867,2018,A1 .Location in patent: Paragraph 0076

61
[ 13612-34-5 ]
[ 95-01-2 ]
7-hydroxy-3-(2,5-dimethylphenyl)-coumarin [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2019,vol. 34,p. 15 - 30

62
[ 53348-04-2 ]
[ 6018-89-9 ]
[ 95-01-2 ]
N,N′-bis(4-(hydroxysalicylidine))-9,10-diaminophenanthrenenickel(II)*3H2O [ No CAS ]

Reference： [1]Dalton Transactions,2018,vol. 47,p. 13573 - 13591

63
[ 932-52-5 ]
[ 95-01-2 ]
(E)-5-{(2,4-dihydroxybenzylidene)amino}pyrimidine-2,4(1H,3H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With acetic acid; In methanol; at 20℃;	General procedure: To a mixture of 5-aminouracil (127 mg, 1 mmol) with an appropriate aldehyde (241 mg, 1.2 mmol) in methanol (15 mL) were added few drops of glacial acetic acid. The reaction mixture was stirred at room temperature until 5-aminouracil was completely consumed (TLC). The precipitate was filtered off, washed with methanol and air dried to give the corresponding product 1-10 as a yellow solid.

Reference： [1]Russian Journal of General Chemistry,2019,vol. 89,p. 122 - 127
Zh. Obshch. Khim.,2019,vol. 89,p. 122 - 127,6

64
[ 2518-24-3 ]
[ 95-01-2 ]
C₁₅H₁₀N₂O₄ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2019

65
[ 2518-24-3 ]
[ 95-01-2 ]
4-((2,4-dihydroxybenzyl)amino)isoindoline-1,3-dione [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2019

66
[ 16188-55-9 ]
[ 95-01-2 ]
3-(4-methylthiophenyl)-7-hydroxycoumarin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74.2%		A mixture of 2,4-dihydroxybenzaldehyde (1.51g, 10.9mmol), p-(thiomethylphenyl) acetic acid (2g, 10.9mmol), anhydrous NaOAc (1.36g, 16.35mmol) and 15mL acetic anhydride was heated at 160C while stirring under nitrogen atmosphere for 10h. After removal of acetic acid by distillation, the resulting solid was dissolved in 100mL THF:methanol (3:1) mixture and then LiOH (1g, 42mmol) in 5mL water was added to the suspension. About 3h later, the reaction mixture was poured into 100mL ice-water and treated with 10% HCl, the precipitate was collected by filtration. The dried product was purified by recrystallization from methanol. Yield 2.3g (74.2%). Mp 230-232C. Anal. Calcd for C16H12O3S: C, 67.59; H, 4.25%; Found: C, 67.57; H, 4.22%. 1H-NMR (500MHz, CDCl3): deltaH, ppm 8.13 (s, 1H, lactone-H), 7.66 (d, 2H, J=8.09Hz, Ar-H), 7.57 (d, 1H, J=8.33Hz, Ar-H), 7.31 (d, 2H, J=8.11Hz, Ar-H), 6.79 (d, 1H, J=8.33Hz, Ar-H), 6.72 (s, 1H, Ar-H), 3.41 (bs, 1H, ArOH), 2.50 (s, 3H, -SCH3). FT-IR (ATR): upsilonmax, cm-1: 3209 (-OH), 3055-3034 (Ar-CH), 2926 (Aliphatic-CH), 1685 (lactone-C=O), 1605-1566 (Ar-C=C) and 809 (Ar-SCH3). UV-vis (THF): lambdamax=352nm. Florescence (THF): lambdaem=444nm. MS (MALDI-TOF) m/z: calcd. 284.33, found 285.31 [M+H]+, 307.58 [M+Na]+.

Reference： [1]Inorganica Chimica Acta,2019,vol. 498

67
[ 4542-77-2 ]
[ 95-01-2 ]
4,4'-[[naphthalene-2,6-diylbis(methylene)]bis(oxy)]bis(2-hydroxybenzaldehyde) [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 7250 - 7263

68
[ 6018-89-9 ]
[ 19777-66-3 ]
[ 95-01-2 ]
C₁₇H₁₆N₂NiO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Triethylamine(1.10 g, 11 mmol) and (S)-1,2-propanediamine2HCl (0.73 g, 5 mmol) were added to ethanol 30 mL. This mixture was stirred for 15 min at room temperature. Then, 2,4-dihydroxybenzaldehyde(1.51 g, 11 mmol) was added. The yellow solution was refluxed for 15 min. Ni(CH3COO)24H2O (1.30 g, 5 mmol) in 20mL of ethanol was added. The mixture was refluxed 10 h, and cooled to room temperature. 30mL of 20% acetic acid and some pieces of ice were added, and the mixture was stirred. Red precipitates (S-OH-salpn, 1.81 g) were formed and filtered under suction. The alkylation was performed by the same procedure as Rac-OC12-salpn using 0.37 g of S-OH-salpn, 1.0 gof K2CO3, and 0.61 g of N-bromododecane. S-OC12-salpn was obtained as orange powder (0.31 g, Yield: 44%).

Reference： [1]Bulletin of the Chemical Society of Japan,2019,vol. 92,p. 1853 - 1858

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

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

[ CAS No. 95-01-2 ]

Quality Control of [ 95-01-2 ]

Related Doc. of [ 95-01-2 ]

Product Details of [ 95-01-2 ]

Calculated chemistry of [ 95-01-2 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 95-01-2 ]

Application In Synthesis of [ 95-01-2 ]

[ 95-01-2 ] Synthesis Path-Upstream 1~34

[ 95-01-2 ] Synthesis Path-Downstream 1~68

Related Functional Groups of [ 95-01-2 ]

Aryls

Aldehydes

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 95-01-2 ]