[ CAS No. 90-24-4 ] {[proInfo.proName]}

Name: 90-24-4|2'-Hydroxy-4',6'-dimethoxyacetophenone|95%
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Quality Control of [ 90-24-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 90-24-4 ]

Product Details of [ 90-24-4 ]

CAS No. :	90-24-4	MDL No. :	MFCD00017243
Formula :	C₁₀H₁₂O₄	Boiling Point :	-
Linear Structure Formula :	CH₃C(O)C₆H₂(OH)(OCH₃)₂	InChI Key :	FBUBVLUPUDBFME-UHFFFAOYSA-N
M.W :	196.20	Pubchem ID :	66654
Synonyms :	Xanthoxyline;Brevifolin	Chemical Name :	2'-Hydroxy-4',6'-dimethoxyacetophenone

Calculated chemistry of [ 90-24-4 ] Expand+

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.3
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	51.64
TPSA :	55.76 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.26 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.61
Log Po/w (XLOGP3) :	1.74
Log Po/w (WLOGP) :	1.61
Log Po/w (MLOGP) :	0.55
Log Po/w (SILICOS-IT) :	1.72
Consensus Log Po/w :	1.45

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.27
Solubility :	1.05 mg/ml ; 0.00535 mol/l
Class :	Soluble
Log S (Ali) :	-2.53
Solubility :	0.582 mg/ml ; 0.00297 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.42
Solubility :	0.749 mg/ml ; 0.00382 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.49

Safety of [ 90-24-4 ]

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

Application In Synthesis of [ 90-24-4 ]

* 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 [ 90-24-4 ]
Downstream synthetic route of [ 90-24-4 ]

[ 90-24-4 ] Synthesis Path-Upstream 1~40

1
[ 90-24-4 ]
[ 54107-66-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 11, p. 2098 - 2102
[2] Patent: KR2018/64130, 2018, A,

2
[ 90-24-4 ]
[ 855-97-0 ]

Reference： [1] Synthesis, 1980, # 11, p. 874 - 875
[2] Australian Journal of Chemistry, 2012, vol. 65, # 10, p. 1377 - 1383,7
[3] Journal of Chemical Research, 2014, vol. 38, # 1, p. 60 - 61
[4] Molecules, 2014, vol. 19, # 7, p. 8933 - 8948
[5] European Journal of Medicinal Chemistry, 2014, vol. 86, p. 153 - 164
[6] European Journal of Medicinal Chemistry, 2015, vol. 97, p. 259 - 274
[7] Journal of Chemical Research, 2015, vol. 39, # 9, p. 550 - 552
[8] Asian Journal of Chemistry, 2016, vol. 28, # 5, p. 1139 - 1143
[9] RSC Advances, 2016, vol. 6, # 69, p. 64544 - 64556
[10] Synthesis (Germany), 2018, vol. 50, # 8, p. 1610 - 1620

3
[ 90-24-4 ]
[ 3535-37-3 ]
[ 855-97-0 ]

Reference： [1] Synthesis, 1982, # 3, p. 221 - 222

4
[ 90-24-4 ]
[ 93-07-2 ]
[ 855-97-0 ]

Reference： [1] Tetrahedron Letters, 2016, vol. 57, # 34, p. 3841 - 3843

5
[ 90-24-4 ]
[ 4521-61-3 ]
[ 53350-26-8 ]

Reference： [1] Journal of Heterocyclic Chemistry, 2002, vol. 39, # 6, p. 1251 - 1258

6
[ 90-24-4 ]
[ 53350-26-8 ]

Reference： [1] Molecules, 2014, vol. 19, # 7, p. 8933 - 8948
[2] Synthesis (Germany), 2018, vol. 50, # 8, p. 1610 - 1620

7
[ 480-66-0 ]
[ 77-78-1 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In acetone for 3 h; Reflux	To a refluxing solution of 2,4,6-trihydroacetophenone-monohydrate (10 g, 53.7 mmol) and K₂CO₃ (15 g, 108.7 mmol) in acetone (150 mL), (CH₃)₂SO₄ was added at three hour intervals (3 x 3.5 mL, 40.0 mmol). The solution was filtered and the solvent was evaporated to afford 2,4-dimethoxy-6-hydroxyacetophenone as a yellow solid (98percent).
99%	With potassium carbonate In acetone at 0 - 20℃; Inert atmosphere	Example 14 synthesis of 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (11) To a solution of commercial 2',4',6'-trihydroxyacetophenone dihydrate (15.0 g, 80.57 mmol, 1eq) in acetone (170 mL), potassium carbonate (23.4 g, 169.20 mmol, 2.1 eq) and dimethylsulfate (15.6 mL, 165.17 mmol, 2.05 eq) were added under argon at 0°C. After vigorous stirring at room temperature for 17h, the resulting mixture was filtered and the filtrate concentrated in vacuo. The resulting product 5 was recristallized from ethyl acetate / heptanes (3/97) to give 15.80 g (99percent) of a pale yellow solid. Molecular Weight: 196.20 (C₁₀H₁₂O₄). ¹H-NMR δ (CDCl₃, 300 MHz) ppm (J in Hz): 2.61 (s, 3H, CH₃CO), 3.82 (s, 3H, MeO), 3.85 (s, 3H, MeO), 5.91 (d, 1H, J=2.4, H- 3'), 6.05 (d, 1H, J=2.4, H-5'), 14.03 (s, 1H, OH).
99%	With potassium carbonate In acetone	2,4,6-trihydroxy-acetophenone (2) and the reaction wasdissolved in a dimethyl sulfate to potassium carbonate in acetone to synthesize4,6-dimethoxy-2-hydroxy acetophenone (3)

95.8%	With potassium carbonate In acetone at 10 - 15℃;	A mixtureof phloroacetophenone (1) (300 g, 1.78 mol), acetone (1.5 L)and potassium carbonate (739.2 g, 5.35 mol) was chargedunder stirring at room temperature. Dimethyl sulphate (494.9g, 3.92 mol) was charged drop wise with the help of the additionfunnel at 10-15 °C for 3 h. TLC (20 percent EtOAc in hexane)showed no traces of starting material but observed traces oftrimethoxyacetophenone. After completion of the reaction, thereaction mixture was poured into ice cold water and stirredfor 3 h. A crude solid material was obtained on filtration andwashed with cold water and drained thoroughly. The yieldwas 84 percent with a purity of 95.8 percent obtained.
94%	With potassium carbonate In acetone for 2 h; Reflux	A mixture of 2,4,6-trihydroxyacetophenone (1) (1.0 g, 5.95 mmol) anhydrous K₂CO₃ (1.64 g, 11.88 mmol) and (CH₃)₂SO₄ (1.08 mL, 11.22 mmol) was stirred and refluxed in acetone (60 mL) for 2 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated and the residue subjected to silica gel column chromatography with PE/AcOEt 2:1 as an eluent to afford white solids 1.1 g, yield: 94percent. m.p. 77-79 °C (Lit.1: 79~80°C ).
93.5%	Stage #1: With potassium carbonate In acetone at 25℃; for 0.5 h; Stage #2: at 25℃;	To a solution of 1-(2,4,6-trihydroxyphenyl)ethanone (11.16 g, 0.06 mol) in dry acetone (150 mL), potassium carbonate (24.84 g, 0.18 mol) was added and stirred for 30 min at room temperature. Then dimethyl sulphate (12 mL, 0.12 mol) was added drop-wise, the reaction solution was stirred for 4-5 h at room temperature and monitored by thin-layer chromatograph (TLC). Poured the reaction solution to ice-water (1000 mL) and the precipitate was filtered, washed with water, dried to afford 1 (11.0 g) as white solid in 93.5percent yield. ¹H NMR (400 MHz, DMSO‑d₆) δ: 13.79 (s, 1H, OH), 6.11 (d, 1H, J = 2.3 Hz), 6.08 (d, 1H, J = 2.3 Hz), 3.86 (s, 1H), 3.81 (s, 1H), 2.55 (s, 1H). ¹³C NMR (100 MHz, DMSO‑d₆) δ: 203.2, 166.7, 166.4, 163.2, 105.9, 94.1, 91.2, 56.5, 56.1, 33.1.
87%	With potassium carbonate In acetoneReflux	(1 g, 5.95 mmol) was dissolved in 30 ml of acetone followed by the addition of potassium carbonate (4.11 g, 5 eq.), And dimethylsulfate (4 eq) was added dropwise. The suspension was refluxed for 5 to 8 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered and washed with acetone. The filtrate was evaporated under reduced pressure to give intermediate 5a (2-hydroxy-4,6-dimethoxyacetophenone) , 6a (2-hydroxy-4,6-diethoxyacetophenone) (5a, 1.01 g, yield 87percent; 6a, 1.15 g, 79percent yield); intermediate 5a, 6a, (4-hydroxy-5,7-dimethoxycoumarin), 6b (4-hydroxy-5,7-diethoxy coumarin) obtained by Method B of Method 9, (44 mg), 6b (50 mg) were each obtained by the method A of Example 9 to obtain the compound of the formula (5b, 1.00 g, yield 93percent; 6b, 1.07 g, yield 91percent 6,6 (Derivative 5, 60 mg, yield 74percent; derivative 6,63 mg, 64percent); nitration was carried out using Intermediate 6b (500 mg, 2 mmol) (see reaction of compound 2 (68 mg, yield 85percent) was obtained from Intermediate 6c (59 mg, 0.2 mmol) followed by Method A of Example 9 to give the intermediate 6c (484 mg, yield 82percent
84.2%	With potassium carbonate In acetone for 5 h; Reflux	4.1.5 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethanone (16) To a mixture of 1-(2,4,6-trihydroxyphenyl)ethanone 15 (4.5 g, 24.2 mmol) and anhydrous K₂CO₃ (8.29 g, 55.6 mmol) in acetone (90 mL), Me₂SO₄ (6.84 mL, 72.5 mmol) was added dropwise with stirring. The resulting mixture was refluxed for 5 h and then filtered and concentrated under reduced pressure. The residue was purified on a silica gel chromatography using CH₂Cl₂ as eluent, obtaining compound 16; 84.2percent yield; white solid; mp 78-79 °C (lit. ³⁸ 79-80 °C).
84%	With potassium carbonate In acetone at 0 - 20℃; for 3 h; Inert atmosphere	To a stirred solution of ketone 1 (1.18 g, 10 mmol) and K₂CO₃ (3.45 g 25 mmol) in acetone (20 mL), (CH₃)₂SO₄ (2.37 mL, 25 mmol) was added dropwise at 0 °C. After stirring at room temperature for 3 h, the solvent was then removed under reduced pressure. The residue was dissolved in water (30 mL) and the solution was extracted three times with EtOAc. The combined organics were washed with water and brine, then dried over anhydrous MgSO₄ and concentrated in vacuo to give compound 11 (1.65 g, 84percent). ¹H NMR (500 MHz, CDCl₃) δ 14.03 (s, 1H), 6.08 (d, J = 2.4 Hz, 1H), 5.94 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.63 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 203.19, 167.58, 166.09, 162.91, 105.97, 93.45, 90.71, 55.55, 32.96; ESIMS: m/z = 197.2 [M+H]⁺.
82%	With potassium carbonate In acetone at 20℃;	1 -(2,4,6- trihydroxyphenyl)ethanone, 4, (16.8 g, 0.10 mol), anhydrous potassium carbonate (41.50 g, 0.30 mol) and anhydrous acetone (168 mL) were combined and stirred at room temperature after which dimethyl sulfate (26.9 g, 0.21 mol) was slowly added. Once the addition was complete, the reaction was stirred for 1 hour. The pH of the solution was adjusted to neutral using 2N HCl. The resulting yellow solid was collected by filtration and washed with water then dried to afford 16 g (82percent yield) of the desired product as a white solid. M.p. 76-78 ⁰C.
82%	With potassium carbonate In acetone for 0.333333 h; Reflux; Inert atmosphere	K2CO3 (7.23 g, 52.32 mmol) and Me2SO4 (2.48 mL, 26.16 mmol) were added to a solution of 2′,4′,6′-trihydroxyacetophenone (1, 2.00 g, 11.89 mmol) in acetone (50 mL). The reaction mixture was refluxed for 20 min under nitrogen atmosphere. After that, K2CO3 was filtered off, the acetone evaporated, and the residue recrystallized in EtOH affording the 2′-hydroxy-4′,6′-dimethoxyacetophenonein good yield (82percent, 1.91 g).
82.5%	With potassium carbonate In acetone at 20℃;	This compound was prepared from a mixture of 1 (17.85 mmol, 3 g), K₂CO₃ (43.47 mmol, 6 g), Me₂SO₄ (19.67 mmol, 3.85 g), and 50 ml acetone, which was stirred at RT for 5–6 h, and then, the mixture was poured into water (300 ml). The precipitated solid was filtered, washed with water, and crystallized from 95 percent ethanol to give 2 as white powder, yield: 82.5 percent; IR (KBr) ν_max 2,960 (OH),1,620 (C=O) cm^-1; ¹H NMR (DMSO-d₆, 400 MHz): δ = 14.15 (1H, s, OH), 6.36 (1H, d, J = 2.5 Hz, H-3), 5.97(1H, d, J = 2.7 Hz, H-5), 3.89 (3H, s, OCH3-4), 3.83 (3H,s, OCH3-6), 2.7 (3H, s, COCH3). ¹³C NMR (DMSO-d₆,100 MHz): δ = 203.1 (C, C=O), 167.6 (C, C-4), 166.1(C,C-6), 162.9 (C, C-2), 106.0 (C, C-1), 92.9 (CH, C-3), 90.1(CH, C-5), 55.4 (2CH3, OCH3), 32.1(CH3, COCH3); ESI–MS: m/z 197.09 [M+H]⁺. Anal. Calcd. for C₁₀H₁₂O₄₁ 96.07: C, 61.22; H, 6.16. Found: C, 61.27; H, 6.19.
81.36%	With potassium carbonate In acetone at 50℃; for 6 h;	Anhydrous operation, 5 g of Intermediate 6 (26.85 mmol) was put in 80 ml of acetone, and 7.5 g of potassium carbonate was added(54.35 mmol) and 5.25 ml of dimethyl sulfate (20 mmol) were added, and the reaction solution was heated to 50 ° C, After the reaction was completed for 6 hours, the excess acetone was removed by distillation under reduced pressure, Purification by column chromatography gave a white solid in a yield of 81.36percent.
78%	With potassium carbonate In acetone for 20 h; Reflux	The 9g compound (1) is dissolved in 30 ml of acetone, is added under stirring 14g potassium carbonate, then using the constant voltage dropping funnel slowly add sulfuric acid dimethyl ester 15g, reflux stirring 20h, cooling to room temperature, adding ice water precipitating a large amount of white solid, filtered, methanol recrystallization to obtain 7.5g white solid (2), yield 78percent. Compound mp: 74.4-75.1 °C.
78%	With potassium carbonate In acetone for 20 h; Reflux	The compound 1 (9g ) dissolved in 30ml of acetone, 14g of potassium carbonate was added under stirring, then added slowly with constant pressure dropping funnel dimethyl sulfate 15g, was stirred at reflux for 20h, cooled to at room temperature, ice water was added to precipitate large amount of white solid was suction filtered, and recrystallized from methanol to give a white solid 7. 5g (2), a yield of 78percent. Compound mp 74. 4-75. 1 ° C. The product structure was confirmed by IR, NMR and MS analysis
75%	With potassium carbonate In acetone at 20℃; for 4 h;	The 2,4,6-trihydroxyacetophenone monohydrate (3.72g, 20mmol) added to acetone (60 ml), then adding potassium carbonate (6.06g, 40mmol)with stirring, undissolved, then slowly dropping dimethyl sulfate (4 ml, 42mmol), after completion of dropwise addition the reaction was stirred at the room temperature 4 hours and degree of reaction was monitored by TLC monitoring. The end of the to be reacted, filtering off the solid insoluble materials, ten slowly adding water (100 ml), repeated oscillation, allowed to stand for half an for white solid precipitation. Filtering, drying to obtain the white solid (3.0g), yield 75percent.
74%	With potassium carbonate In acetone for 5 h; Reflux	To a solution of 2’,4’,6’-trihydroxyacetophenone (3) (10.0 g, 59.5 mmol) in acetone (350 mL)was added K₂CO₃ (16.45 g, 119 mmol, 2.0 equiv) while stirring with a KPG stirrer at room temperature. Dimethyl sulfate (14.15 g, 112.2 mmol, 10.6 mL) was added dropwise to the suspension under vigorous stirring and then the reaction mixture was refluxed for 5 h. Then the reaction mixture was allowed to cool down and was stirred overnight. Afterwards, the reaction mixture was filtered, the solvent was evaporated under vacuum and the residue was recrystallized from methanol (15 mL). The crystals were filtered, washed with water to yield 8.65 g (44.1 mmol, 74percent) off-white solid; mp 74-75 °C [Lit. 73-76 °C]. Spectroscopic data is in accordance with the literature.
54%	With potassium carbonate In acetone for 10 h; Reflux	A mixture of 1-(2,4,6-trihydroxyphenyl)ethan-1-one (2.50 g, 15 mmol), (CH₃)₂SO₄ (2.85 mL, 30 mmol) and anhydrous K₂CO₃ (4.56 g, 33 mmol) in dry acetone (60 mL) was refluxed for 10 h. The reaction mixture was concentrated and poured on to ice-water (100 mL). The resulting precipitate was filtered off and washed with cold water. The obtained residue was purified by silica gel column chromatography with hexane: ethyl acetate (95: 5) as eluent. White solid, Yield: 54percent, M.P: 78-80 °C; ¹H NMR (CDCl₃, 400 MHz, ppm) δ: 14.03 (s, 1H,-OH), 6.06-6.05 (d, J = 2.20 Hz, 1H, Ar-H), 5.93-5.92 (d, J = 2.20 Hz, 1H, Ar-H), 3.86, 3.82 (s, each 3H, 2 * -OCH₃), 2.61 (s, 3H, -COCH₃); ¹³C NMR (CDCl₃, 100 MHz, ppm) δ: 203.17 (-C=O); 167.56; 166.06; 162.88; 105.97; 93.43; 90.72; 55.53 (-OCH₃); 50.86 (-OCH₃); 32.91 (-CH₃).

Reference： [1] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 12, p. 3782 - 3786
[2] Patent: WO2010/19861, 2010, A1, . Location in patent: Page/Page column 38; 50
[3] Patent: EP2112145, 2009, A1, . Location in patent: Page/Page column 14-15
[4] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 4, p. 1154 - 1158
[5] Patent: KR2015/49695, 2015, A, . Location in patent: Paragraph 0063-0072
[6] Journal of Medicinal Chemistry, 2008, vol. 51, # 19, p. 6230 - 6234
[7] Asian Journal of Chemistry, 2016, vol. 28, # 5, p. 1139 - 1143
[8] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 19, p. 4749 - 4753
[9] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 16, p. 4602 - 4614
[10] Journal of Organic Chemistry, 1997, vol. 62, # 21, p. 7222 - 7227
[11] British Journal of Pharmacology, 2004, vol. 142, # 5, p. 811 - 820
[12] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 1, p. 278 - 281
[13] Journal of Natural Products, 2003, vol. 66, # 8, p. 1144 - 1146
[14] Medicinal Chemistry Research, 2011, vol. 20, # 7, p. 838 - 846
[15] Synthesis (Germany), 2012, vol. 44, # 14, p. 2217 - 2224
[16] Green Chemistry, 2013, vol. 15, # 11, p. 3165 - 3169
[17] European Journal of Organic Chemistry, 2017, vol. 2017, # 37, p. 5617 - 5626
[18] Chemical and Pharmaceutical Bulletin, 2013, vol. 61, # 4, p. 486 - 488
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[23] Patent: WO2010/129858, 2010, A1, . Location in patent: Page/Page column 48
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8
[ 500-99-2 ]
[ 75-36-5 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: With boron trichloride In dichloromethane at -10℃; for 0.0833333 h; Inert atmosphere Stage #2: for 3 h; Reflux; Inert atmosphere	3,5-Dimethoxyphenol (15.0 g, 97.3 mmol) was dissolved in100 mL of anhydrous dichloromethane. Boron trichloride (1 M solution in dichloromethane, 102.2 mL, 102.2 mmol) was slowly added under nitrogen at 10 °C. After 5 min, acetyl chloride (7.3 mL, 102.2 mmol) was added dropwise. The mixture was heated and kept under reflux for 3 h and was stirred overnight at room temperature. The reaction mixture was cooled at 0 °C and was slowly hydrolyzed with 1 M HCl. The organic phase was separated and the aqueous layer was extracted twice with dichloromethane.The organic layers were dried over sodium sulfate and evaporated under reduced pressure. Recrystallization from methanol afforded 1 (18.5 g, 97percent) as a white powder.
87%	With boron trichloride In dichloromethane for 3 h; Inert atmosphere	In a 200-mL two-necked round-bottomed flask equipped with a magnetic stirring bar, a rubber septum,and an argon balloon was placed 3,5-dimethoxyphenol 13 (5.00 g, 32.4 mmol) in CH2Cl2 (66 mL) at -10oC, and to it was added BCl3 in CH2Cl2 (32 mL, 32.4 mmol, 1.0 M, 1.0 equiv) and acetyl chloride (3.0 mL,42.2 mmol) slowly. After the mixture was stirred for 20 min, the whole mixture was heated at reflux for 3h. The reaction was quenched with 2N HCl (80 mL), and the mixture was extracted with CH2Cl2 (20 mL x3) and dried over anhydrous Na2SO4, and concentrated in vacuo to give a crude product, which waspurified by silica gel column chromatography (CH2Cl2/MeOH = 100 / 1) to give the title compound 12(5.49 g, 87percent).

Reference： [1] European Journal of Medicinal Chemistry, 2013, vol. 69, p. 823 - 832
[2] Heterocycles, 2016, vol. 93, # 1, p. 310 - 322
[3] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1275 - 1284
[4] Synlett, 2005, # 6, p. 927 - 930

9
[ 500-99-2 ]
[ 64-19-7 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
79%	at 145℃; for 2 h;	A mixture of fused ZnCl2 (13.6 g, 0.1 mol) and acetic acid (6 mL, 0.1 mol) was heated slowly with stirring until the solution became homogeneous. Compound 2 (15.4 g,0.1 mol) was added and the reaction mixture was kept for about 2 h at 145 °C. The reaction mixture was cooled and poured over crushed ice containing hydrochloric acid (1:1). The solid that separated was filteredand washed separately with water and sodium bicarbonate solution. The crude product was purified by column chromatography over silicagel. Elution was with a gradient solvent system of petroleum ether/ethylacetate gave compound 3 as a white powder (15.5 g, yield 79percent); m.p.80–82 °C (lit.²⁵ 82–83 °C); IR νmax (KBr/cm⁻¹): 3448 (OH), 1613 (C=O);1H NMR (400 MHz, CDCl3): δ 2.60 (s, 3H, COCH3), 3.76 (s, 3H, OCH3-6), 3.82 (s, 3H, OCH3-4), 5.97 (s, 1H, H-3), 6.12 (s, 1H, H-5), 13.88(s, 1H,OH-2); MS (m/z): 197 [M+H]+.
79%	at 145℃; for 2 h;	A mixture of fusedZnCl2 (13.6 g, 0.1 mol) and acetic acid (6 mL, 0.1 mol) was heatedslowly with stirring until the solution became homogeneous.Compound 2 (15.4 g, 0.1 mol) was added and the reaction mixturewas kept for about 2 h at 145 °C. The reaction mixture was cooledand poured over crushed ice containing hydrochloric acid (1 : 1). The solid that separated out was filtered and washed separately with waterand sodium bicarbonate solution. The crude product was purified bycolumn chromatography over silica gel; elution was effected witha gradient solvent system of petroleum ether/ethyl acetate to givecompound 4 as white powder (15.5 g, yield 79percent)
79%	at 145℃; for 2 h;	A mixture of fused ZnCl2 (13.6 g, 0.1 mol) and acetic acid (6 ml, 0.1 mol) was heated slowly with stirring till the solution became homogeneous. Compound 2 (15.4 g, 0.1 mol) was added and the reaction mixture was kept fo rabout 2 h at 145 °C. The reaction mixture was cooled, poured over crushed ice containing hydrochloric acid (1:1). The solid that separated out was filtered and washed separately with water and sodium bicarbonate solution. The crude product was purified using column chromatography over silica gel. Elution with a gradient solvent system of petroleum ether/ethyl acetate gave compound 4 as white powdery (15.5 g, yield 79percent); m.p. 80–82 °C (lit. 26 82–83 °C); IR νmax (KBr/cm−1): 3448 (OH), 1613 (C=O); 1H NMR (400 MHz, CDCl3): δ 13.88 (s, 1H, OH), 6.12 (s, 1H), 5.97 (s, 1H), 3.82 (s, 3H, OCH3), 3.76 (s, 3H,OCH3), 2.60 (s, 3H, COCH3); MS (m/z): 197 [M+H]+.

Reference： [1] Archiv der Pharmazie, 2012, vol. 345, # 5, p. 368 - 377
[2] Journal of Chemical Research, 2015, vol. 39, # 5, p. 300 - 302
[3] Journal of Chemical Research, 2015, vol. 39, # 2, p. 67 - 69
[4] Journal of Chemical Research, 2015, vol. 39, # 8, p. 455 - 457
[5] Journal of Chemical Research, 2015, vol. 39, # 9, p. 550 - 552

10
[ 832-58-6 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With boron tribromide In dichloromethane at 20℃; for 2 h; Inert atmosphere	A flame-dried flask was charged with 2,4,6-trimethoxyacetophenone (23.8 mmol, 5 g)(SIGMA-ALDRICH 630594) and dry CH2C12 (75 ml) under argon. BBr3 (87.3 mmol, 15 ml)was added drop-wise. The resulting solution was stirred at room temperature for 2 h beforeadding NaOH 4M (90 ml) and allowed to stand for 30 mm. The solution was extracted withCH2C12 and combined organic layers were washed with brine, dried over Na2504 and finallyconcentrated under reduced pressure. The resulting solid was recrystallized from EtOH andwhite crystals of 2-hydroxy-4,6-dimethoxyacetophenone 2 (4.43 g, 98percent yield) were obtained.2-hydroxy-4,6-dimethoxyacetophenone (2)White solid, (4.43 g) 98 percent yield. Mp: 8 1-82 °C. ‘H NMR (400 MHz, Acetone-d6): (ppm)13.8 (s, 1H, OH), 5.94 (d, 1H, J = 2.4 Hz, ArH), 5.91 (d, 1H, J = 2.4 Hz, ArH), 3.80 (s, 3H,OCH3), 3.72 (s, 3H, OCH3), 2.43 (s, 3H, CH3); ‘3C NMR (400 MHz, Acetone-d6): (ppm)202.5 (s, C=O), 167.36 (s, C-4), 166.34 (s, C-6), 163.15 (s, C-2), 105.5 (s, C-i), 93.42 (d, C-3),90.43 (d, C-5), 55.20, 55.00 (q, 2 x OCH3), 31.94 (q, CH3). ESI-MS (positive): m/z calcd forC,0H,2O4+H: 197.080800 [M+Hj (monoisotopic mass); found: 197.080848.
90%	With boron trichloride In dichloromethane at 0 - 20℃; for 4.5 h;	A solutionof compound 2 (4.2 g, 0.02 mol) in dichloromethane (20 mL) was treated dropwise at approximately 0 °C, with 1 mol L–1 BCl3 in dichloromethane (24 mL, 0.024 mol) for about 0.5 h. Once the addition was completed, the reaction mixture was stirred at room temperature for another 4 h. After completion of the reaction, H2O (100 mL) was added and the mixture was stirred for another 1 h and extracted with dichloromethane (50 mL × 2). The organic layers were combined and washed sequentially with H2O (100 mL × 2), saturated sodium bicarbonate (100 mL × 2) and H2O (100 mL × 1). Then the extracts were dried over anhydrous magnesium sulfate and evaporated in vacuo to give a solid. The residue was recrystallised from ethanol to give compound 3 (3.5 g), yield 90percent, white crystals, m.p. 81–82 °C (lit.22 80–81 °C) 1H NMR (500 MHz, DMSO-d6) (δ, ppm): 2.60 (s, 3H, COCH3), 3.81 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 5.92 (s, 1H, ArH), 6.05 (s, 1H, ArH), 14.02 (s, 1H, OH). IR νmax (KBr/cm−1): 3461 (OH), 1619 (C=O).
89%	Stage #1: With boron trichloride In dichloromethane at 0℃; for 2 h; Stage #2: With water In dichloromethane for 1 h;	A solution of compound 3 (3.2 g, 0.015 mol) in dichloromethane (15 mL), was treated with1 mol L^–1BCl₃ in dichloromethane (18 mL, 0.018 mol) for 1 h atapproximately 0 °C. After the reaction mixture had been stirred at 0 °C for another 2 h, H₂O (50 mL) was added and the mixture stirred for another 1 hour and extracted with dichloromethane twice (50 mL × 2).The combined organic layers were washed with H₂O (50 mL), saturated NaHCO₃ solution (50 mL), brine (50 mL), dried with anhydrous magnesium sulfate overnight. The solvent was removed under reduced pressure and the residue was recrystallised from ethanol to give compound 4 as white crystal (2.6 g, yield 89percent); m.p. 79–80 °C (lit.¹³82–83 °C); IR, ν/cm^–1: 2952 (OH), 1619 (C=O); 1H NMR (400 MHz,CDCl₃), δ 2.61 (s, 3H, COCH₃), 3.82 (s, 3H, OCH₃-6), 3.85 (s, 3H,OCH₃-4), 5.93 (s, 1H, H‑3), 6.06 (s, 1H, H‑5), 14.03 (s, 1H, OH‑2). MS(m/z): 197 [M + 1]⁺.

87%

With boron trichloride In dichloromethane at 0 - 20℃; for 2 h;

A solution of the compound 2 (4.2 g, 0.02 mol) in dichloromethane (20 mL) at approximately 0 °C was treated with 1 mol L–1 BCl3 in dichloromethane (24 mL, 0.024 mol) dropwise for about 1 h, and then the reaction mixture was stirred at room temperature for another 1 h. H2O (100 mL) was added, the mixture was stirred for another hour and extracted with dichloromethane twice (50 mL × 2). The organic layers were combined and washed sequentially with H2O (100 mL × 2), saturated sodium bicarbonate (100 mL × 2) and H2O (100 mL × 1) and then dried with anhydrous sodium sulfate overnight. The solvent was removed under reduced pressure, and the residue was recrystallised from ethanol to give compound 3 (3.24 g); yield 87percent, white crystals, m.p. 79–80 °C (lit.17 80–81 °C) 1H NMR (400 MHz, CDCl3) (δ, ppm): 2.61 (s, 3H, COCH3), 3.82 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 5.93 (s, 1H, ArH), 6.06 (s, 1H, ArH), 14.03 (s, 1H, OH). IR νmax (KBr/cm−1): 3461 (OH), 1619(C= O).

Reference： [1] Patent: WO2014/207069, 2014, A1, . Location in patent: Page/Page column 31; 32
[2] Tetrahedron, 2004, vol. 60, # 11, p. 2647 - 2655
[3] Journal of Chemical Research, 2014, vol. 38, # 11, p. 686 - 689
[4] Journal of Chemical Research, 2014, vol. 38, # 3, p. 134 - 136
[5] Journal of Chemical Research, 2014, vol. 38, # 1, p. 60 - 61
[6] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 11, p. 2098 - 2102
[7] Synthesis, 2010, # 16, p. 2776 - 2786
[8] Collection of Czechoslovak Chemical Communications, 2000, vol. 65, # 2, p. 280 - 296
[9] Bulletin of the Chemical Society of Japan, 1994, vol. 67, # 2, p. 511 - 515
[10] Journal of the Chemical Society, 1939, p. 91,93
[11] Scientific Proceedings of the Royal Dublin Society, 1949, vol. 25, p. 19,28
[12] Journal of the American Chemical Society, 1955, vol. 77, p. 2894
[13] Chemische Berichte, 1897, vol. 30, p. 2153
[14] Journal of the Chemical Society, 1910, vol. 97, p. 2064
[15] Chemische Berichte, 1899, vol. 32, p. 2262
[16] Justus Liebigs Annalen der Chemie, 1964, vol. 677, p. 21 - 33
[17] Tetrahedron Letters, 1985, vol. 26, # 39, p. 4807 - 4810

11
[ 480-66-0 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
94.4%	With potassium carbonate; dimethyl sulfate In acetone	Production Example 7 To 50.1 g of 2',4',6'-trihydroxyacetophenone and 123.5 g of anhydrous potassium carbonate was added 500 ml of anhydrous acetone, and the mixture was stirred at room temperature for 30 minutes. Then, 78.9 g of dimethyl sulfate was added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours to effect a reaction. After the reaction, the reaction mixture was neutralized with dilute hydrochloric acid, extracted with diethyl ether and filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was recrystallized from n-hexane to obtain 55.2 g (yield=94.4percent) of 2'-hydroxy-4',6'-dimethoxyacetophenone in the form of a colorless prism. Melting point: 77° to 78° C. Infrared absorption spectrum ν_max^KBr cm^-1: 1622, 1596, 1574, 1460, 1440, 1424, 1368, 1272, 1222, 1206, 1156, 1110, 1080, 894, 834, 596. Proton nuclear magnetic resonance (δ ppm in CDCl₃): 2.61 (3H, s), 3.82 (3H, s), 3.85 (3H, s), 5.92 (1H, d, J=2.4 Hz), 6.05 (1H, d, J=2.4 Hz), 14.03 (1H, s, disappeared by addition of D₂ O).

Reference： [1] Patent: US5106871, 1992, A,
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 19, p. 4672 - 4677

12
[ 480-66-0 ]
[ 616-38-6 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium carbonate In dimethyl sulfoxide at 120℃;	Compound 4 (2.5 g, 0.015 mol), K2CO3 (1.7 g, 0.01 mol), and DMC (7.5 mL, 0.09 mol) in DMSO (20 mL) were heated at 120 °C until TLC showed that compound 4 had disappeared. Then the mixture was cooled to room temperature and H2O (30 mL) was added. The reaction mixture was neutralised to pH 3–4 with 10percent aqueous HCl and the precipitate was filtered and recrystallised from methanol to give compound 3 (2.0 g), yield 69percent, white crystals, m.p. 81–82 °C (lit.22 80–81 °C) 1H NMR (500 MHz, DMSO-d6) (δ, ppm): 2.60 (s, 3H,COCH3), 3.81 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 5.92 (s, 1H, ArH), 6.05 (s, 1H, ArH), 14.02 (s, 1H, OH). IR νmax (KBr/cm−1): 3461 (OH), 1619 (C=O).

Reference： [1] Journal of Chemical Research, 2014, vol. 38, # 11, p. 686 - 689

13
[ 23133-74-6 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
33%	With aluminum (III) chloride In chlorobenzene at 70℃; for 4 h;	To a mixture of 3,5-dimethoxyphenol (2.0 g, 12.9 mmol) and triethylamine (2.0 g, 19.4 mmol) in 1,2-dichloroethane (10 mL) was added acetyl chloride (1.2 g, 15.6 mmol) at 0 °C. The resulting mixture was then stirred for 0.5 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography (hexanes/ethyl acetate: 15/1) to afford the title compound 3,5-Dimethoxyphenyl acetate as a yellow solid (2.2 g, 85 percent yield). LCMS: 197.1 [M+1]. ‘HNIVIR (400 1VIHz, CDC13): 2.27 (s, 3H), 3.76 (s, 6H), 6.26 (d, J=2.4 Hz, 2H), 6.3 1-6.38 (m, 1H). To a suspension of aluminum trichloride (120 mg, 1.53 mmol) in chlorobenzene (4 mL) was added the above obtained compound (200 mg, 1.02 mmol) in chlorobenzene (4 mL). The resulting mixture was stirred at 70 °C for 4 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography (hexanes/ethyl acetate: 20/1) to afford the title compound 303-7 as a yellow solid (65 mg, 33 percent yield). ‘H NIVIR (400 IV[Hz, DMSO-d6): 2.55 (s, 3H), 3.81 (s, 3H), 3.86 (s, 3H), 6.08 (d,J=2.4Hz, 1H),6.11(d,J2.4Hz, 1H), 13.76(s, 1H).

Reference： [1] Patent: WO2017/132928, 2017, A1, . Location in patent: Paragraph 000147
[2] Natural Product Research, 2010, vol. 24, # 11, p. 995 - 1003

14
[ 480-66-0 ]
[ 74-88-4 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
36%	With potassium carbonate In acetone for 24 h; Reflux; Darkness	4.1.1 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethan-1-one 21 2,4,6-Trihydroxyacetophenone (2 g, 10.7 mmol), methyl iodide (2.70 mL, 42.9 mmol) and K₂CO₃ (2.96 g, 21.4 mmol) were dissolved in 50 mL of acetone. The mixture was heated to reflux for 24 h in the dark. The reaction mixture was filtered under vacuum, and the filtrate was evaporated under reduced pressure. The crude product was purified by flash chromatography using cyclohexane/ethyl acetate 95:5 as eluting system; 1.13 g of title compound 21 were obtained. Yield: 36percent. ¹H NMR (CDCl₃) δ: 6.05 (d, J = 2.4 Hz, 1H, CH arom.); 5.92 (d, J = 2.4 Hz, 1H, CH arom.); 3.85 (s, 3H, OCH₃); 3.81 (s, 3H, OCH₃); 2.60 (s, 3H, CH₃) ppm.
1.2 g	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 48 h;	Heating 2, 4, 6-tri-hydroxy acetophenone 2g (12mmol), added to the 15mlDMF in, then adding CH ₃ I1.72g (12.1mmol), K ₂ CO ₃ 5 g. Stir at room temperature reaction 48h, is poured into the reaction liquid to the ice water, stirring 1h, then filter. Drying the obtained solid, recrystallized with ethanol, to obtain 2-hydroxy -4,6-di-methoxy acetophenone 1.2 g.

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 18, p. 2271 - 2284
[2] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 1346 - 1351
[3] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 1, p. 50 - 64
[4] Patent: CN105669625, 2016, A, . Location in patent: Paragraph 0172

15
[ 77-78-1 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate In acetoneReflux	To a refluxing solution of 2,4,6-trihydroxyacetophenone-monohydrate (6,10 g, 59.5 mmol) and K₂CO₃ (16.5 g, 119 mmol) in acetone (150 mL), (CH₃)₂SO₄ was added at 3-h intervals (3 * 3.76 mL, 119 mmol). The solution was filtered and the solvent was evaporated to afford 7 (11.3 g, 97percent) as a yellow solid. mp 74-75 °C (Lit;¹⁷ : 73-76 °C). ¹H NMR (400 MHz, CDCl₃): δ 6.06 (d, J = 2.0 Hz, 1H, Ar-H), 5.92 (d, J = 2.0 Hz, 1H, Ar-H), 3.86 (s, 3H, OCH₃), 3.82 (s, 3H, OCH₃), 2.61 (s, 3H, COCH₃). IR (neat): ν 2970, 2833, 1617, 1440, 1157, 895, 597 cm^-1.

Reference： [1] Tetrahedron, 2017, vol. 73, # 25, p. 3485 - 3491

16
[ 621-23-8 ]
[ 75-36-5 ]
[ 90-24-4 ]

Reference： [1] Phytochemistry (Elsevier), 1989, vol. 28, # 11, p. 3193 - 3196
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 2, p. 730 - 733
[3] European Journal of Medicinal Chemistry, 2010, vol. 45, # 6, p. 2629 - 2633
[4] Letters in Drug Design and Discovery, 2011, vol. 8, # 8, p. 725 - 732
[5] Letters in Drug Design and Discovery, 2011, vol. 8, # 8, p. 725 - 732
[6] Medicinal Chemistry Research, 2012, vol. 21, # 9, p. 2292 - 2299
[7] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 912 - 916
[8] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1315 - 1321
[9] Journal of Enzyme Inhibition and Medicinal Chemistry, 2015, vol. 30, # 1, p. 22 - 31

17
[ 2142-68-9 ]
[ 77-78-1 ]
[ 90-24-4 ]

Reference： [1] Patent: US2006/63801, 2006, A1, . Location in patent: Page/Page column 5

18
[ 480-66-0 ]
[ 7087-68-5 ]
[ 90-24-4 ]

Reference： [1] Patent: US4024272, 1977, A,

19
[ 480-66-0 ]
[ 80-48-8 ]
[ 90-24-4 ]

Reference： [1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 23, p. 5025 - 5032
[2] Journal of Chemical Research, 2012, vol. 36, # 3, p. 121 - 122

20
[ 18107-18-1 ]
[ 90-24-4 ]
[ 7507-89-3 ]
[ 3602-54-8 ]

Reference： [1] Organic Letters, 2016, vol. 18, # 4, p. 708 - 711

21
[ 75-18-3 ]
[ 480-66-0 ]
[ 90-24-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 15, p. 3464 - 3467

22
[ 480-66-0 ]
[ 333-27-7 ]
[ 90-24-4 ]

Reference： [1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 11, p. 3061 - 3068

23
[ 77-78-1 ]
[ 90-24-4 ]

Reference： [1] Journal of Organic Chemistry, 1998, vol. 63, # 25, p. 9300 - 9305

24
[ 108-73-6 ]
[ 90-24-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 1, p. 278 - 281
[2] Journal of Heterocyclic Chemistry, 2002, vol. 39, # 6, p. 1251 - 1258
[3] Molecules, 2013, vol. 18, # 11, p. 14070 - 14084
[4] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 19, p. 4749 - 4753
[5] Journal of Chemical Research, 2014, vol. 38, # 11, p. 686 - 689
[6] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 5, p. 911 - 923
[7] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2016, vol. 152, p. 304 - 310
[8] Asian Journal of Chemistry, 2016, vol. 28, # 5, p. 1139 - 1143
[9] Patent: CN105801543, 2016, A,

25
[ 480-66-0 ]
[ 77-78-1 ]
[ 90-24-4 ]
[ 23121-32-6 ]

Reference： [1] Journal of Natural Products, 2008, vol. 71, # 7, p. 1237 - 1241

26
[ 480-66-0 ]
[ 77-78-1 ]
[ 90-24-4 ]
[ 7507-89-3 ]

Reference： [1] Journal of Natural Products, 2003, vol. 66, # 8, p. 1144 - 1146

27
[ 621-23-8 ]
[ 90-24-4 ]

Reference： [1] Journal of Chemical Research, 2014, vol. 38, # 1, p. 60 - 61
[2] Journal of Chemical Research, 2014, vol. 38, # 3, p. 134 - 136
[3] Journal of Chemical Research, 2014, vol. 38, # 11, p. 686 - 689
[4] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 11, p. 2098 - 2102

28
[ 500-99-2 ]
[ 108-24-7 ]
[ 75-36-5 ]
[ 90-24-4 ]

Reference： [1] Journal of the American Chemical Society, 1957, vol. 79, p. 3582,3585

29
[ 500-99-2 ]
[ 90-24-4 ]

Reference： [1] Patent: WO2017/132928, 2017, A1,

30
[ 832-58-6 ]
[ 90-24-4 ]
[ 480-66-0 ]
[ 7507-89-3 ]
[ 3602-54-8 ]

Reference： [1] Tetrahedron Letters, 1985, vol. 26, # 39, p. 4807 - 4810

31
[ 480-66-0 ]
[ 77-78-1 ]
[ 90-24-4 ]
[ 7507-89-3 ]
[ 3602-54-8 ]

Reference： [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1987, vol. 26, p. 57 - 58
[2] Journal of the Indian Chemical Society, 1987, vol. 64, # 4, p. 253 - 254

32
[ 480-66-0 ]
[ 18107-18-1 ]
[ 90-24-4 ]
[ 7507-89-3 ]
[ 3602-54-8 ]

Reference： [1] European Journal of Medicinal Chemistry, 2010, vol. 45, # 9, p. 4258 - 4269

33
[ 186581-53-3 ]
[ 480-66-0 ]
[ 90-24-4 ]

Reference： [1] Chemische Berichte, 1925, vol. 58, p. 1697
[2] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 4, p. 525 - 528

34
[ 500-99-2 ]
[ 108-24-7 ]
[ 90-24-4 ]
[ 13246-14-5 ]

Reference： [1] Journal of the Chemical Society, 1950, p. 2965,2969
[2] Journal of the Chemical Society, 1953, p. 1241,1245
[3] Journal of the Chemical Society, 1950, p. 2965,2969
[4] Journal of the Chemical Society, 1953, p. 1241,1245

35
[ 186581-53-3 ]
[ 480-66-0 ]
[ 90-24-4 ]
[ 7507-89-3 ]

Reference： [1] Chemische Berichte, 1925, vol. 58, p. 1697

36
[ 72221-04-6 ]
[ 64-19-7 ]
[ 90-24-4 ]
[ 13246-14-5 ]

Reference： [1] Journal of the Chemical Society, 1953, p. 1241,1245

37
[ 500-99-2 ]
[ 75-05-8 ]
[ 90-24-4 ]
[ 13246-14-5 ]

Reference： [1] Journal of the Chemical Society, 1931, p. 1255,1264

38
[ 81325-94-2 ]
[ 90-24-4 ]

Reference： [1] Monatshefte fuer Chemie, 1982, vol. 113, p. 73 - 80

39
[ 7446-70-0 ]
[ 60-29-7 ]
[ 832-58-6 ]
[ 90-24-4 ]

Reference： [1] Scientific Proceedings of the Royal Dublin Society, 1949, vol. 25, p. 19,28

40
[ 10034-85-2 ]
[ 108-24-7 ]
[ 832-58-6 ]
[ 90-24-4 ]

Reference： [1] Journal of the Chemical Society, 1939, p. 91,93

[ 90-24-4 ] Synthesis Path-Downstream 1~67

1
[ 621-59-0 ]
[ 90-24-4 ]
[ 121245-87-2 ]

Yield	Reaction Conditions	Operation in experiment
66%	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone With sodium hydroxide In methanol at 0℃; for 0.5h; Inert atmosphere; Stage #2: isovanillin In methanol Inert atmosphere;	The general method for the preparation of chalconesseries 1 and series 2 General procedure: Under N2 atmosphereand 0 OC, 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (1mmol, 1 eq) or1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-one (1mmol, 1 eq) was dissolved into10 ml MeOH, followed by the addition of 10 ml aq. 40% NaOH solution, themixture was stirred for about 30 min, then benzaldehydes (1.2 mmol, 1.2eq.)were added respectively. The mixture was stirred for overnight and monitored byTLC. After the starting material 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone or 1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-onewas consumed completely, the pH value was adjusted to 3 with aq. 3 N HClsolution, a large amount of yellowish solid formed. The crude product was filtrated,recrystallized from MeOH or purified by si-gel column chromatography to affordfine desired products.
	With potassium hydroxide

2
[ 4397-53-9 ]
[ 90-24-4 ]
[ 19158-99-7 ]

Yield	Reaction Conditions	Operation in experiment
79%	With potassium hydroxide In ethanol at 20℃; for 30h;
61.7%	With potassium hydroxide In methanol for 20h; Reflux;	(E)-3-(4-(Benzyloxy)phenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one (25) A solution of compound 23 (10.00g, 50.90mmol), compound 24 (12.98g, 61.08mmol) and KOH (20.00g, 356.3mmol) in methanol (300.0mL) were stirred and reflux for 20h. The reaction mixture was neutralized with 1N HCl to pH∼7 and extracted with DCM (600.0mL). Solvent was removed. Recrystallization from EtOAc gave compound 25 (6.760g, 61.7%). mp 151.7-153.6°C; IR (KBr): 3013, 1630, 1553, 1346, 1153, 1115, 825cm -1.1H NMR (400MHz, CDCl3) δ 14.41 (s, 1H), 7.79 (d, J=2.1Hz, 2H), 7.59-7.49 (m, 2H), 7.47-7.30 (m, 5H), 7.03-6.94 (m, 2H), 6.10 (d, J=2.3Hz, 1H), 5.96 (d, J=2.4Hz, 1H), 5.11 (s, 2H), 3.91 (s, 3H), 3.83 (s, 3H). 13C NMR (100MHz, CDCl3) δ 187.8, 163.6, 161.3, 137.6, 131.8, 125.4, 123.9, 123.8, 123.4, 122.7, 120.5, 110.5, 89.1, 86.5, 65.4, 51.1, 50.8. HRMS (ESI) calculated for C24H22NaO5+[M+Na]+ 413.1359, found 413.1358.
	With potassium hydroxide

3.0 g
	With potassium hydroxide In ethanol at 35 - 40℃; for 12h;

Reference： [1]Lin, An-Shen; Nakagawa-Goto, Kyoko; Chang, Fang-Rong; Yu, Donglei; Morris-Natschke, Susan L.; Wu, Chin-Chung; Chen, Shu-Li; Wu, Yang-Chang; Lee, Kuo-Hsiung [Journal of Medicinal Chemistry, 2007, vol. 50, # 16, p. 3921 - 3927]
[2]Wei, Mingming; Xie, Maodun; Zhang, Zhen; Wei, Yujiao; Zhang, Juan; Pan, Hongli; Li, Benlong; Wang, Jingjing; Song, Yang; Chong, Chuangke; Zhao, Rui; Wang, Jiefu; Yu, Li; Yang, Guang; Yang, Cheng [European Journal of Medicinal Chemistry, 2020, vol. 206]
[3]Mahal; Venkataraman [Journal of the Chemical Society, 1936, p. 569]
[4]Mizuno, Mizuo; Kojima, Hiroyuki; Tanaka, Toshijuki; Iinuma, Munekazu; Kimura, Rie; et al. [Phytochemistry, 1987, vol. 26, # 7, p. 2071 - 2074]
[5]Sekizaki, Haruo [Bulletin of the Chemical Society of Japan, 1988, vol. 61, p. 1407 - 1409]

3
[ 90-24-4 ]
[ 2150-41-6 ]
[ 65612-84-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone With lithium hexamethyldisilazane In tetrahydrofuran at -78 - -10℃; for 2h; Inert atmosphere; Stage #2: methyl 2, 4-dimethoxybenzoate With N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran for 24h; Inert atmosphere; Reflux;	1-(2-Hydroxy-4,6-dimethoxyphenyl)-3-(2,4-dimethoxyphenyl)propane-1,3-dione (10) In a 200-mL two-necked round-bottomed flask equipped with a magnetic stirring bar, a rubber septum,and an argon balloon was placed LHMDS in THF (39 mL, 51.0 mmol, 1.3 M) at -78 oC, and to it wasadded 12 (2.00 g, 10.2 mmol) in THF (51 mL). After the mixture was stirred for 1 h at -78 oC and warmedto -10 oC for 1 h, to it were added methyl 2,4-dimethoxybenzoate 11 (2.00 g, 10.2 mmol) in THF (51 mL)and TMEDA (7.6 mL, 51.0 mmol), and the whole mixture was heated at reflux for 24 h. The reaction wasquenched reversely by pouring the solution into ice water and 2N HCl (50 mL), and the mixture wasextracted with CHCl3 (20 mL x 3). The combined extracts were washed with sat. NaCl aq. (30 mL) anddried over anhydrous Na2SO4, and concentrated in vacuo to give a crude product, which was purified bysilica gel column chromatography (n-hexane/EtOAc = 4 / 1) to give the title compound 10 (3.15 g, 86%).Yield 86%, keto : enol = 48:52; Yellow solid; mp 108-109 ; 1H NMR (500 MHz, CDCl3) δ3.59 (s,1.44H), 3.77 (s, 1.44H), 3.80 (s, 1.44H), 3.81 (s, 1.56H), 3.86 (s, 1.44H), 3.86 (s, 1.56H), 3.89 (s, 1.56H),3.94 (s, 1.56H), 4.51 (s, 0.96H), 5.86 (d, J = 2.5 Hz, 0.48H), 5.97 (d, J = 2.5 Hz, 0.52H), 6.07 (d, J = 2.5Hz, 0.48H), 6.09 (d, J = 2.5 Hz, 0.52H), 6.44 (d, J = 2.5 Hz, 0.48H), 6.50 (d, J = 2.5 Hz, 0.52H), 6.56 (dd, J = 2.5, 8.6 Hz, 0.48H), 6.58 (dd, J = 2.5, 8.6 Hz, 0.52H), 7.65 (s, 0.52H), 7.93 (d, J = 8.6 Hz, 0.48H),7.95 (d, J = 8.6 Hz, 0.52H), 13.5 (s, 0.52H), 13.7 (s, 0.48H); 13C NMR (125 MHz, CDCl3) δ55.3, 55.4,55.5, 55.5, 55.6, 55.6, 59.7, 90.8, 91.3, 93.7, 94.1, 98.2, 98.9, 101.8, 104.8, 105.1, 105.5, 105.7, 116.1,120.1, 131.5, 132.9, 160.2, 160.9, 161.7, 162.2, 163.5, 164.8, 165.0, 166.2, 166.6, 167.6, 174.3, 193.3,193.4, 200.0; IR (neat)2942, 2844, 1658, 1597, 1290, 1215, 1159, 1114, 1027, 822 cm-1; HRMS(EI)Calcd for C19H20O7(M)+ 360.1209, found 360.1200.
	With sodium

Reference： [1]Mizota, Isao; Taniguchi, Kana; Shimizu, Makoto [Heterocycles, 2016, vol. 93, # 1, p. 310 - 322]
[2]Doporto et al. [Journal of the Chemical Society, 1955, p. 4249,4253]

4
[ 90-24-4 ]
[ 120-14-9 ]
2'-hydroxy-3,4,4',6'-tetramethoxychalcone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium hydroxide In ethanol; water at 0 - 20℃;	Synthesis of Chalcones 6; General Procedure General procedure: To a suspension of 2’-hydroxy-4’,6’-dimethoxyacetophenone (4) in ethanol (approx. 2.7-3.0 mL per 1.0 mmol 4) was added 60% KOH solution (2.5 mL per 1.0 mmol 4) at 0 °C in an ice bath. The mixture was stirred for a few minutes and then the appropriate aldehyde (5a-d) (1.5 equiv) was added. After a few hours the colour of the reaction mixture changed to orange or red; the reaction mixture was stirred overnight at room temperature. The solution was acidified to pH 1 by adding 10% aqueous HCl, the yellow precipitate was filtered, washed with cold ethanol and water and recrystallized from methanol if necessary.
82%	With potassium hydroxide In methanol at 20℃; for 24h;
82%	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone With sodium hydroxide In methanol at 0℃; for 0.5h; Inert atmosphere; Stage #2: 3,4-dimethoxy-benzaldehyde In methanol Inert atmosphere;	The general method for the preparation of chalconesseries 1 and series 2 General procedure: Under N2 atmosphereand 0 OC, 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (1mmol, 1 eq) or1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-one (1mmol, 1 eq) was dissolved into10 ml MeOH, followed by the addition of 10 ml aq. 40% NaOH solution, themixture was stirred for about 30 min, then benzaldehydes (1.2 mmol, 1.2eq.)were added respectively. The mixture was stirred for overnight and monitored byTLC. After the starting material 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone or 1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-onewas consumed completely, the pH value was adjusted to 3 with aq. 3 N HClsolution, a large amount of yellowish solid formed. The crude product was filtrated,recrystallized from MeOH or purified by si-gel column chromatography to affordfine desired products.

72.7%	With potassium hydroxide In methanol; water at 20℃; for 36h;	preparation of (E)-3-(3,4-dimethoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one 4,6-dimethoxy-2-hydroxy - acetophenone (0.5 g, 2.5mmol) was dissolved in 9ml of methanol, was added 3,4-dimethoxybenzaldehyde (0.42g, 2.5mmol), after 3,4-methoxybenzaldehyde were dissolved, was added a 50% aqueous potassium hydroxide solution (4.5ml), stirred at room temperature for 36 hours. After completion of the reaction, adjusting the PH The reaction solution was filtered with a Buchner funnel, was collected as a yellow solid. The filtrate was extracted with ethyl acetate (30ml × 2). The combined organic phases were dried over anhydrous MgSO4, evaporated under reduced pressure.The combined yellow solid, to which was added methanol (50ml), stirred for 5 minutes, filtered, the filter cake was collected to give a yellow solid 0.64g ,, a yield of 72.7%.
71%	With sodium hydroxide In ethanol at 20℃;	4.2. General procedures for synthesis of chalcones General procedure: For synthesis of chalcones we have used 2 different methods. Chalcones 1-30 were synthesized by method A and chalcones 31-44 were synthesized by method B. For Method B we used LiOHinstead of usual base NaOH for Claisen-Schmidt synthesis and the reaction was carried out in an ultrasonic bath. The general reaction scheme is depicted in Scheme 1.Method A: 20% NaOH (5 ml) was added dropwise to a previously cooled mixture of 5 mmol of selected acetophenone and 5 mmol of selected benzaldehyde in 25 ml ethanol under vigorous stirring. The mixture was stirred at room temperature for 24-72 h. After completion of the reaction as indicated by TLC, the mixture was poured onto crushed ice and acidified with dilute HCl. Precipitated product was filtered by suction and washed to neutral. The solid was recrystallised from dilute ethanol to get crystalline chalcone.Method B: To a mixture of 5 mmol of selected acetophenone and 5 mmol of selected benzaldehyde in 50 ml round bottom flask, 20 ml methanol and 35 mmol of LiOH was added. The reaction mixture was kept in an ultrasonic bath for 1-5 h, until reaction completion was indicated by TLC. The reaction was worked up as described for method A.
61%	With sodium hydroxide In methanol; dimethyl sulfoxide at 20℃; for 4h;	General Optimized Experimental Procedure for the Synthesisof (E)-2′-Hydroxychalcones 3a,b NaOH (aq, 60%, 37 mL) was added to a solution of 2′-hydroxy-4′,6′-dimethoxyacetophenone (1.50 g, 7.645 mmol) in MeOH (37 mL; in the case of derivative a), or in MeOH-DMSO (v/v,37:4.5 mL; in the case of derivative b). After that, the appropriate benzaldehyde 2a,b (15.04 mmol) was added, and the reaction mixture was stirred for 3 h (derivative a) and 4 h (derivativeb) at r.t. Then, the mixture was poured into ice (50 g) andH2O (100 mL) and the pH adjusted to 4 with a solution of HCl (20%). After filtration, the precipitate was taken in CH2Cl2,washed repeatedly with a sat. solution of KHCO3 (1 × 300 mL) and H2O (3 × 300 mL), and the organic layer was dried over anhydrous Na2SO4. Subsequently, after solvent evaporation, the residue was recrystallized in EtOH giving the correspondent (E)-2′-hydroxychalcones 3a,b in good yields [3a (77%, 1.78 g); 3b (61%, 1.61 g)].
50%	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone; 3,4-dimethoxy-benzaldehyde With potassium hydroxide In ethanol; water at 20℃; Stage #2: With hydrogenchloride In ethanol; water at 0℃;
	With sodium ethanolate
	With sodium hydroxide
	base-catalyzed Claisen-Schmidt reaction;
0.32 g	With potassium hydroxide In ethanol
	With sodium hydroxide In ethanol at 20℃;
	In ethanol; water at 20℃; Alkaline conditions;	3.3. Synthesis of Flavokawain B derivatives General procedure: KOH (20% w/v aqueous solution) was added to a stirred solution of the appropriate acetophenone(1.0 eq) and a substituted benzaldehyde (1.25 eq.) in ethanol, and the mixture was stirred at roomtemperature for 48-72 h. The reaction mixture was cooled to 0 °C (ice-water bath) and acidified withHCl (10% v/v aqueous solution). In most cases, yellow precipitate was formed, filtered and washedwith 10% aqueous HCl solution. In the cases where an orange-yellow layer was formed, the mixturewas extracted with CH2Cl2 or ethyl acetate, the extracts was dried over Na2SO4 anhydrous and thesolvent was evaporated and crystalized with methanol or ethanol.
	With sodium hydroxide In ethanol; water at 20℃;

Reference： [1]Sipos, Zoltán; Kónya, Krisztina [Synthesis, 2018, vol. 50, # 8, p. 1610 - 1620]
[2]Singh, Om V.; Muthukrishnan; Sunderavadivelu [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2005, vol. 44, # 12, p. 2575 - 2581]
[3]Chen, Lijuan; Fan, Tiantian; Lei, Xiangui; Teichmann, Alexander Tobias; Wang, Amu; Wang, Chao; Wei, Zhe; Wieland, Frank Heinrich; Yang, Youzhe; Yin, Jinxiang; Zhou, Li; Zhu, Yue [European Journal of Medicinal Chemistry, 2020, vol. 193]
[4]Current Patent Assignee: SECOND MILITARY MEDICAL UNIVERSITY - CN104230869, 2016, B Location in patent: Paragraph 0083; 0084
[5]Location in patent: experimental part Juvale, Kapil; Pape, Veronika F.S.; Wiese, Michael [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 1, p. 346 - 355]
[6]De Azevedo, Orlando D. C. C.; Seixas, Raquel S. G. R.; Silva, Artur M. S. [Synlett, 2015, vol. 26, # 10, p. 1379 - 1384]
[7]Location in patent: experimental part Detsi, Anastasia; Majdalani, Maya; Kontogiorgis, Christos A.; Hadjipavlou-Litina, Dimitra; Kefalas, Panagiotis [Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 23, p. 8073 - 8085]
[8]King; Robertson [Journal of the Chemical Society, 1931, p. 1704,1708]
[9]Reichel et al. [Justus Liebigs Annalen der Chemie, 1942, vol. 550, p. 146,151]
[10]Parmar, V. S.; Sharma, Sunil; Rathore, J. S.; Garg, Meenu; Gupta, Sandhya; et al. [Magnetic Resonance in Chemistry, 1990, vol. 28, # 5, p. 470 - 474]
[11]Tanaka, Toshiyuki; Iinuma, Munekazu; Yuki, Kaoru; Fujii, Yuko; Mizuno, Mizuo [Phytochemistry, 1992, vol. 31, # 3, p. 993 - 998]
[12]Cabrera, Mauricio; Simoens, Macarena; Falchi, Gabriela; Lavaggi, M. Laura; Piro, Oscar E.; Castellano, Eduardo E.; Vidal, Anabel; Azqueta, Amaia; Monge, Antonio; de Cerain, Adela Lopez; Sagrera, Gabriel; Seoane, Gustavo; Cerecetto, Hugo; Gonzalez, Mercedes [Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 10, p. 3356 - 3367]
[13]Bakar, Addila Abu; Akhtar, Muhammad Nadeem; Ali, Norlaily Mohd; Yeap, Swee Keong; Quah, Ching Kheng; Loh, Wan-Sin; Alitheen, Noorjahan Banu; Zareen, Seema; Ul-Haq, Zaheer; Shah, Syed Adnan Ali [Molecules, 2018, vol. 23, # 3]
[14]Li, Cui; Wang, Gangqiang; Li, Xueli; Wang, Qiuan [Medicinal Chemistry Research, 2018, vol. 27, # 3, p. 972 - 979]

5
[ 90-24-4 ]
[ 587-04-2 ]
[ 108979-34-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium hydroxide In ethanol; water at 20℃;	General procedure: To a stirred solution of 4 (0.364 g, 2 mmol) and K2CO3 (0.552 g, 4 mmol) in DMSO (15 mL), and BnBr (0.44 mL, 4.4 mmol) was dropwise added at the room temperature. The reaction was then quenched by ice water, extracted with EtOAc (3 * 20 mL), then dried over Na2SO4, finally concentrated under reduced pressure to afford 5 (6.25 g). In the presence of 40% KOH, 5 reacted with corresponding benzaldehydes in a mixture of water and ethanol to obtain the chalcones 6a-g, which purified through a silica gel column. BCl3 (10 mL, 1 M in DCM) was dropwise added in anhydrous DCM (50 mL) of 6a-g (1.96 g, 10 mmol) under ice bath and stirring. After 0.5 h, the ice bath was removed, and the reaction was carried out for 2 h at room temperature. After being monitored by TLC, 15 mL ice water was added. The reaction was extracted with EtOAc (3 * 30 mL). The combined extract was dried over anhydrous Na2SO4 and was concentrated. The concentrated solution was purified by column chromatography to gain A1-7.
83.1%	In ethanol; water at 20℃; Alkaline conditions;	3.3. Synthesis of Flavokawain B derivatives General procedure: KOH (20% w/v aqueous solution) was added to a stirred solution of the appropriate acetophenone(1.0 eq) and a substituted benzaldehyde (1.25 eq.) in ethanol, and the mixture was stirred at roomtemperature for 48-72 h. The reaction mixture was cooled to 0 °C (ice-water bath) and acidified withHCl (10% v/v aqueous solution). In most cases, yellow precipitate was formed, filtered and washedwith 10% aqueous HCl solution. In the cases where an orange-yellow layer was formed, the mixturewas extracted with CH2Cl2 or ethyl acetate, the extracts was dried over Na2SO4 anhydrous and thesolvent was evaporated and crystalized with methanol or ethanol.
36%	With potassium hydroxide In methanol at 20℃; for 24h;

36%	With potassium hydroxide In methanol; water at 20℃; for 24h;
	With potassium hydroxide
	With sodium hydroxide In ethanol; water at 20℃;
	With potassium hydroxide In methanol at 20℃; for 24h;	General procedure: All chalcones were prepared by aldol condensation between aromatic acetophenones and corresponding aldehydes, in methanol, KOH (50% w/v), at room temperature and magnetic agitation for 24 h.16 Distilled water and 10% hydrochloric acid were added to the reaction for total precipitation of the compounds, which were then obtained by vacuum filtration and later recrystallized in dichloromethane and hexane. All solvents used were of analytical grade. The purified chalcones were obtained in yields between 36% and 97%, and are soluble in dimethylsulfoxide, ethyl acetate, acetone, chloroform and dichloromethane.

Reference： [1]Liu, Jianwen; Ma, Lei; Shi, Ximeng; Yin, Huanhuan; Zhao, Yuyu; Zhou, Licheng [Letters in drug design and discovery, 2020, vol. 17, # 10, p. 1270 - 1282]
[2]Bakar, Addila Abu; Akhtar, Muhammad Nadeem; Ali, Norlaily Mohd; Yeap, Swee Keong; Quah, Ching Kheng; Loh, Wan-Sin; Alitheen, Noorjahan Banu; Zareen, Seema; Ul-Haq, Zaheer; Shah, Syed Adnan Ali [Molecules, 2018, vol. 23, # 3]
[3]Location in patent: experimental part Navarini, Andreia Lilian Formento; Chiaradia, Louise Domeneghini; Mascarello, Alessandra; Fritzen, Marcio; Nunes, Ricardo Jose; Yunes, Rosendo Augusto; Creczynski-Pasa, Tania Beatriz [European Journal of Medicinal Chemistry, 2009, vol. 44, # 4, p. 1630 - 1637]
[4]Chiaradia, Louise Domeneghini; Mascarello, Alessandra; Purificacao, Marcela; Vernal, Javier; Cordeiro, Marlon Norberto Sechini; Zenteno, Maria Emilia; Villarino, Andrea; Nunes, Ricardo Jose; Yunes, Rosendo Augusto; Terenzi, Hernan [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 23, p. 6227 - 6230]
[5]Hsue et al. [Taiwan Kexue, 1959, vol. 13, p. 91,92][Chem.Abstr., 1960, p. 4553]
[6]Location in patent: scheme or table Bandgar, Babasaheb P.; Patil, Sachin A.; Gacche, Rajesh N.; Korbad, Balaji L.; Hote, Balwant S.; Kinkar, Santosh N.; Jalde, Shivkumar S. [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 2, p. 730 - 733]
[7]Location in patent: experimental part Bello, Murilo Lamim; Chiaradia, Louise Domeneghini; Dias, Luiza Rosaria Sousa; Pacheco, Leticia Kramer; Stumpf, Taisa Regina; Mascarello, Alessandra; Steindel, Mario; Yunes, Rosendo Augusto; Castro, Helena Carla; Nunes, Ricardo Jose; Rodrigues, Carlos Rangel [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 16, p. 5046 - 5052]

6
[ 832-58-6 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With boron tribromide; In dichloromethane; at 20℃; for 2h;Inert atmosphere;	A flame-dried flask was charged with 2,4,6-trimethoxyacetophenone (23.8 mmol, 5 g)(SIGMA-ALDRICH 630594) and dry CH2C12 (75 ml) under argon. BBr3 (87.3 mmol, 15 ml)was added drop-wise. The resulting solution was stirred at room temperature for 2 h beforeadding NaOH 4M (90 ml) and allowed to stand for 30 mm. The solution was extracted withCH2C12 and combined organic layers were washed with brine, dried over Na2504 and finallyconcentrated under reduced pressure. The resulting solid was recrystallized from EtOH andwhite crystals of 2-hydroxy-4,6-dimethoxyacetophenone 2 (4.43 g, 98% yield) were obtained.2-hydroxy-4,6-dimethoxyacetophenone (2)White solid, (4.43 g) 98 % yield. Mp: 8 1-82 C. ?H NMR (400 MHz, Acetone-d6): (ppm)13.8 (s, 1H, OH), 5.94 (d, 1H, J = 2.4 Hz, ArH), 5.91 (d, 1H, J = 2.4 Hz, ArH), 3.80 (s, 3H,OCH3), 3.72 (s, 3H, OCH3), 2.43 (s, 3H, CH3); ?3C NMR (400 MHz, Acetone-d6): (ppm)202.5 (s, C=O), 167.36 (s, C-4), 166.34 (s, C-6), 163.15 (s, C-2), 105.5 (s, C-i), 93.42 (d, C-3),90.43 (d, C-5), 55.20, 55.00 (q, 2 x OCH3), 31.94 (q, CH3). ESI-MS (positive): m/z calcd forC,0H,2O4+H: 197.080800 [M+Hj (monoisotopic mass); found: 197.080848.
90%	With boron trichloride; In dichloromethane; at 0 - 20℃; for 4.5h;	A solutionof compound 2 (4.2 g, 0.02 mol) in dichloromethane (20 mL) was treated dropwise at approximately 0 C, with 1 mol L-1 BCl3 in dichloromethane (24 mL, 0.024 mol) for about 0.5 h. Once the addition was completed, the reaction mixture was stirred at room temperature for another 4 h. After completion of the reaction, H2O (100 mL) was added and the mixture was stirred for another 1 h and extracted with dichloromethane (50 mL × 2). The organic layers were combined and washed sequentially with H2O (100 mL × 2), saturated sodium bicarbonate (100 mL × 2) and H2O (100 mL × 1). Then the extracts were dried over anhydrous magnesium sulfate and evaporated in vacuo to give a solid. The residue was recrystallised from ethanol to give compound 3 (3.5 g), yield 90%, white crystals, m.p. 81-82 C (lit.22 80-81 C) 1H NMR (500 MHz, DMSO-d6) (delta, ppm): 2.60 (s, 3H, COCH3), 3.81 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 5.92 (s, 1H, ArH), 6.05 (s, 1H, ArH), 14.02 (s, 1H, OH). IR numax (KBr/cm-1): 3461 (OH), 1619 (C=O).
89%		A solution of compound 3 (3.2 g, 0.015 mol) in dichloromethane (15 mL), was treated with1 mol L-1 BCl3 in dichloromethane (18 mL, 0.018 mol) for 1 h atapproximately 0 C. After the reaction mixture had been stirred at 0 C for another 2 h, H2O (50 mL) was added and the mixture stirred for another 1 hour and extracted with dichloromethane twice (50 mL × 2).The combined organic layers were washed with H2O (50 mL), saturated NaHCO3 solution (50 mL), brine (50 mL), dried with anhydrous magnesium sulfate overnight. The solvent was removed under reduced pressure and the residue was recrystallised from ethanol to give compound 4 as white crystal (2.6 g, yield 89%); m.p. 79-80 C (lit.1382-83 C); IR, nu/cm-1: 2952 (OH), 1619 (C=O); 1H NMR (400 MHz,CDCl3), delta 2.61 (s, 3H, COCH3), 3.82 (s, 3H, OCH3-6), 3.85 (s, 3H,OCH3-4), 5.93 (s, 1H, H-3), 6.06 (s, 1H, H-5), 14.03 (s, 1H, OH-2). MS(m/z): 197 [M + 1]+.

87%	With boron trichloride; In dichloromethane; at 0 - 20℃; for 2h;	A solution of the compound 2 (4.2 g, 0.02 mol) in dichloromethane (20 mL) at approximately 0 C was treated with 1 mol L-1 BCl3 in dichloromethane (24 mL, 0.024 mol) dropwise for about 1 h, and then the reaction mixture was stirred at room temperature for another 1 h. H2O (100 mL) was added, the mixture was stirred for another hour and extracted with dichloromethane twice (50 mL × 2). The organic layers were combined and washed sequentially with H2O (100 mL × 2), saturated sodium bicarbonate (100 mL × 2) and H2O (100 mL × 1) and then dried with anhydrous sodium sulfate overnight. The solvent was removed under reduced pressure, and the residue was recrystallised from ethanol to give compound 3 (3.24 g); yield 87%, white crystals, m.p. 79-80 C (lit.17 80-81 C) 1H NMR (400 MHz, CDCl3) (delta, ppm): 2.61 (s, 3H, COCH3), 3.82 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 5.93 (s, 1H, ArH), 6.06 (s, 1H, ArH), 14.03 (s, 1H, OH). IR numax (KBr/cm-1): 3461 (OH), 1619(C= O).
87%	With aluminum (III) chloride; In dichloromethane; for 22h;Inert atmosphere; Reflux;	Compound 11 (0.9 g, 4.28 mmol) was dissolved in anhydrous CH 2 Cl 2 (10 mL).To the stirred solution was added AlCl 3 (0.71 g, 5.35 mmol) under a nitrogen atmosphere, and the mixture was refluxed for 22 hours.After the reaction was completed, the reaction mixture was cooled to 0 C., 1N HCl (6 mL) was added, and the mixture was stirred at room temperature for 15 minutes.The mixture was extracted with CH 2 Cl 2 (2 × 50 mL).The mixed organic solvent layer was washed with H 2 O (2 × 25 mL) and brine (20 mL),It was dried over anhydrous Na 2 SO 4 and concentrated in vacuo.The crude compound was purified by column chromatography (EtOAc / Hexane = 1/4) to give a pure white solid compound (0.72 g, 87%).
87%	With aluminum (III) chloride; In dichloromethane; for 22h;Inert atmosphere; Reflux;	Compound 11 (0.9 g, 4.28 mmol) was added to anhydrous CH2Cl2 (10 mL), and AlCl3 (0.71 g, 5.35 mmol) was added to the stirred solution under a nitrogen atmosphere, and the mixture was refluxed for 22 hours. After the reaction was completed, the reaction mixture was cooled to 0 C., 1N HCl (6 mL) was added, and the mixture was stirred at room temperature for 15 minutes.The mixture was extracted with CH2Cl2 (2 × 50 mL).The mixed organic solvent layer was washed with H2O (2 × 25 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo.The crude compound was purified by column chromatography (EtOAc /Hexane = 1/4) to give a pure white solid compound (0.72 g, 87%).

Reference： [1]Patent: WO2014/207069,2014,A1 .Location in patent: Page/Page column 31; 32
[2]Tetrahedron,2004,vol. 60,p. 2647 - 2655
[3]Journal of Chemical Research,2014,vol. 38,p. 686 - 689
[4]Journal of Chemical Research,2014,vol. 38,p. 134 - 136
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[7]Patent: KR2019/94819,2019,A .Location in patent: Paragraph 0088; 0097; 0098
[8]Patent: KR101997515,2019,B1 .Location in patent: Paragraph 0063; 0064
[9]Synthesis,2010,p. 2776 - 2786
[10]Collection of Czechoslovak Chemical Communications,2000,vol. 65,p. 280 - 296
[11]Bulletin of the Chemical Society of Japan,1994,vol. 67,p. 511 - 515
[12]Journal of the Chemical Society,1939,p. 91,93
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[14]Journal of the American Chemical Society,1955,vol. 77,p. 2894
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[17]Tetrahedron Letters,1985,vol. 26,p. 4807 - 4810

7
[ 480-66-0 ]
[ 77-78-1 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In acetone Inert atmosphere;
100%	With potassium carbonate In acetone for 3h; Reflux;	To a refluxing solution of 2,4,6-trihydroacetophenone-monohydrate (10 g, 53.7 mmol) and K2CO3 (15 g, 108.7 mmol) in acetone (150 mL), (CH3)2SO4 was added at three hour intervals (3 x 3.5 mL, 40.0 mmol). The solution was filtered and the solvent was evaporated to afford 2,4-dimethoxy-6-hydroxyacetophenone as a yellow solid (98%).
100%	With potassium carbonate In acetone at 66℃; for 2h; Inert atmosphere;	4.1.2. 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethanone (2) A mixture of 2',4',6'-trihydroacetophenone hydrate (2.0 g, 11.89 mmol), potassium carbonate(3.62 g, 26.17 mmol) and dimethylsulfate (2.32 mL, 24.38 mmol) in acetone (30 mL) was stirred underargon at 66 °C for 2 h. The resulting mixture was cooled to room temperature, filtered, and washedwith acetone. The filtrate was extracted with ethyl acetate. The organic layer was washed three timeswith saturated NaHCO3 solution, dried over Na2SO4, and concentrated under reduced pressure toproduce compound 2 with 100% yield (Rf = 0.34 (1:9 ethyl acetate: hexane); 1H NMR (400 MHz, CDCl3) δ 14.06 (s, 1H), 6.05 (d, J = 2.0 Hz, 1H), 5.81 (d, J = 2.4 Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 2.61 (s, 3H)).

99%	With potassium carbonate In acetone at 0 - 20℃; Inert atmosphere;	14 Example 14 synthesis of 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (11) To a solution of commercial 2',4',6'-trihydroxyacetophenone dihydrate (15.0 g, 80.57 mmol, 1eq) in acetone (170 mL), potassium carbonate (23.4 g, 169.20 mmol, 2.1 eq) and dimethylsulfate (15.6 mL, 165.17 mmol, 2.05 eq) were added under argon at 0°C. After vigorous stirring at room temperature for 17h, the resulting mixture was filtered and the filtrate concentrated in vacuo. The resulting product 5 was recristallized from ethyl acetate / heptanes (3/97) to give 15.80 g (99%) of a pale yellow solid. Molecular Weight: 196.20 (C10H12O4). 1H-NMR δ (CDCl3, 300 MHz) ppm (J in Hz): 2.61 (s, 3H, CH3CO), 3.82 (s, 3H, MeO), 3.85 (s, 3H, MeO), 5.91 (d, 1H, J=2.4, H- 3'), 6.05 (d, 1H, J=2.4, H-5'), 14.03 (s, 1H, OH).
99%	With potassium carbonate In acetone
99%	With potassium carbonate In acetone	1 Example1 2,4,6-trihydroxy-acetophenone (2) and the reaction wasdissolved in a dimethyl sulfate to potassium carbonate in acetone to synthesize4,6-dimethoxy-2-hydroxy acetophenone (3)
98%	With potassium carbonate In acetone at 65℃; for 6h;
98%	Stage #1: 2,4,6-trihydroxyacetophenone With potassium carbonate In acetone Inert atmosphere; Stage #2: dimethyl sulfate In acetone for 0.4h; Inert atmosphere;	3.2.1. Synthesis of 2,4-Dimethoxy-3-hydroxyacetophenone 1a After K2CO3 (10.0 mmol, 2.0 eq) was added to a solution of 2,4,6-trihydroxyacetophenone 1(5.0 mmol, 1.0 eq), the resulting solution was stirred in acetone at room temperature under argon.Then, Me2SO4 (10.0 mmol, 2.0 eq) was added dropwise and the temperature was slowly increased to 40 °C. The reaction was monitored by thin layer chromatography (TLC) after about 4 h. The mixturewas then filtered and washed with acetone three times. The organic phase was evaporated to provide1a (white powder; yield 98%). Other data can be found in Reference [11].
98%	With potassium carbonate In acetone at 40℃; for 4h; Inert atmosphere;	1.1 (1) Synthesis of compound 1a: At room temperature, 2,4,6-trihydroxyacetophenone 1 (1.0 equivalent) and K2CO3 (2.0 equivalent) were dissolved in acetone and dropped into Me2SO4 (2.0eq) under the protection of nitrogen. The reaction was monitored by TLC for about 4 hours.The reaction was filtered and washed 3 times with acetone. Evaporation of the organic phase gave 1a in 98% yield.
95.8%	With potassium carbonate In acetone at 10 - 15℃;	2-Hydroxy-4,6-dimethoxyacetophenone (2) A mixtureof phloroacetophenone (1) (300 g, 1.78 mol), acetone (1.5 L)and potassium carbonate (739.2 g, 5.35 mol) was chargedunder stirring at room temperature. Dimethyl sulphate (494.9g, 3.92 mol) was charged drop wise with the help of the additionfunnel at 10-15 °C for 3 h. TLC (20 % EtOAc in hexane)showed no traces of starting material but observed traces oftrimethoxyacetophenone. After completion of the reaction, thereaction mixture was poured into ice cold water and stirredfor 3 h. A crude solid material was obtained on filtration andwashed with cold water and drained thoroughly. The yieldwas 84 % with a purity of 95.8 % obtained.
95%	With potassium carbonate In acetone for 4h; Inert atmosphere; Reflux;	1-(2-Hydroxy-4,6-dimethoxyphenyl)ethan-1-one (Int. IX) 1-(2,4,6-Trihydroxyphenyl)ethan-1-one (0.50 g, 3.00 mmol), potassium carbonate (0.86 g, 6.25mmol) were suspended in dry acetone (7 mL) and dimethyl sulfate (0.60 mL, 6.00 mmol) wasadded. The reaction mixture was refluxed for 4 h under inert atmosphere. The reaction mixturewas quenched by addition of 5% HCl aqueous solution (40 mL) and extracted with diethyl ether(3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4and evaporated to dryness under reduced pressure. The residue was purified by columnchromatography (DCM) to furnished the alcohol derivative IX (0.56 g, 95%).
95%	With potassium carbonate In acetone for 2.5h; Reflux;	1 Synthesis of intermediate f Combine 2,4,6-trihydroxyacetophenone (55.8g, 0.3mol), anhydrous potassium carbonate (104.0g, 0.75mol), acetone(500mL) was added to the three-necked flask in turn, under reflux and stirring,Slowly add dimethyl sulfate (75.6 g, 0.6 mol) dropwise. Dripping,carry on React for 2.5 hours. TLC monitoring, the reaction is over. Cool to room temperature,Filter, concentrate the filtrate, and homogenize the residue with 5% hydrochloric acid solution The slurry is filtered and the filter cake is washed with water to neutrality.The filter cake was collected and recrystallized with methanol to obtain a white solid, the product, with a yield of 95%.
95%	With potassium carbonate In acetone at 56℃; for 8h;
94%	With potassium carbonate In acetone for 2h; Reflux; regioselective reaction;	1.1. General Method for synthesis of 2-hydroxy-4,6-dimethoxyacetophenone (2) A mixture of 2,4,6-trihydroxyacetophenone (1) (1.0 g, 5.95 mmol) anhydrous K2CO3 (1.64 g, 11.88 mmol) and (CH3)2SO4 (1.08 mL, 11.22 mmol) was stirred and refluxed in acetone (60 mL) for 2 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated and the residue subjected to silica gel column chromatography with PE/AcOEt 2:1 as an eluent to afford white solids 1.1 g, yield: 94%. m.p. 77-79 °C (Lit.1: 79~80°C ).
94.3%	With potassium carbonate In acetone at 20℃; for 16h;	1.1 (1) Synthesis of Compound 3 2,4,6-Trihydroxyacetophenone (2) (10 g, 59.47 mmol) was added to a 250 mL round bottom flask, which was then dissolved in acetone 20 mL, followed by K2CO3 (16.5 g, 119.38 mmol), Me2SO4 (15 g) , 118.92), after the addition, the reaction at room temperature, after 16h, by TLC detection, the basic reaction of the starting material is complete. 100 mL of water was added, and K2CO3 was dissolved by stirring, and a white solid was gradually precipitated, filtered, washed with water (100 mL × 3), and dried under vacuum.A white solid of 3 11 g was obtained in a yield of 94.3%.
93.5%	Stage #1: 2,4,6-trihydroxyacetophenone With potassium carbonate In acetone at 25℃; for 0.5h; Stage #2: dimethyl sulfate In acetone at 25℃;	1 4.1.1.1 Preparation of 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone To a solution of 1-(2,4,6-trihydroxyphenyl)ethanone (11.16 g, 0.06 mol) in dry acetone (150 mL), potassium carbonate (24.84 g, 0.18 mol) was added and stirred for 30 min at room temperature. Then dimethyl sulphate (12 mL, 0.12 mol) was added drop-wise, the reaction solution was stirred for 4-5 h at room temperature and monitored by thin-layer chromatograph (TLC). Poured the reaction solution to ice-water (1000 mL) and the precipitate was filtered, washed with water, dried to afford 1 (11.0 g) as white solid in 93.5% yield. 1H NMR (400 MHz, DMSO-d6) δ: 13.79 (s, 1H, OH), 6.11 (d, 1H, J = 2.3 Hz), 6.08 (d, 1H, J = 2.3 Hz), 3.86 (s, 1H), 3.81 (s, 1H), 2.55 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 203.2, 166.7, 166.4, 163.2, 105.9, 94.1, 91.2, 56.5, 56.1, 33.1.
93%	With potassium carbonate In acetone at 50℃; for 24h;	1-(2-Hydroxy-4,6-dimethoxyphenyl)ethanone (17) A solution of 2,4,6-trihydroxyacetophenone (16; 100 mg, 0.54 mmol) and K2CO3 (238 mg, 1.7 mmol) in anhydrous acetone (1.5 mL) was warmed at 50 °C and treated with a solution of Me2SO4 (156 mg, 1.24 mmol) in acetone (1 mL), delivered dropwise (1.0 mL/h) with a syringe pump. The system was further heated at 50 °C for 24 h, when completion of the reaction was checked by TLC. Then the solvent was evaporated, brine (10 mL) added, and the product was extracted with EtOAc (3 × 20 mL). The combined extracts were concentrated under reduced pressure and the residue was chromatographed to afford 17 as a light brown solid; yield: 109 mg (93 %); mp 74-75 °C (Lit.22e mp 73-76 °C). IR (KBr): 2943, 1614, 1593, 1568, 1456, 1440, 1423, 1367, 1271, 1220, 1205, 1157, 1113, 895 and 835 cm-1. 1H NMR (300 MHz, CDCl3/TMS): δ = 14.02 (s, 1 H, OH), 6.04 (d, J = 2.4 Hz, 1 H, H-3′), 5.90 (d, J = 2.4 Hz, 1 H, H-5′), 3.84* (s, 3 H, OCH3-6′), 3.80* (s, 3 H, OCH3-4′), 2.59 (s, 3 H, CH3-2). 13C NMR (75 MHz, CDCl3): δ = 203.1 (C-1), 167.6 (C-4′), 166.1 (C-2′), 162.9 (C-6′), 106.0 (C-1′), 93.5 (C-3′), 90.7 (C-5′), 55.5 (2 C, OCH3-3′ and OCH3-5′), 32.9 (CH3-2). EI-MS: m/z (%) = 196 (M+, 33), 181 [(M - 15)+, 100], 178 181 [(M -18)+, 7], 166 (11), 138 (9), 95 (11).
92%	With potassium carbonate In acetone
92%	With potassium carbonate In acetone at 65℃; for 3h;
90%	With potassium carbonate In acetone at 20℃;
90%	With potassium carbonate In acetone for 5h; Heating;
90%	With potassium carbonate In acetone at 20℃; for 4h;
90%	With potassium carbonate In acetone for 5h; Reflux;
90%	With potassium carbonate In acetone at 65℃; for 6h; Schlenk technique; Sealed tube;
90%	With potassium carbonate In acetone for 7h; Inert atmosphere; Reflux;
90%	Stage #1: 2,4,6-trihydroxyacetophenone With potassium carbonate In acetone at 20℃; for 0.25h; Stage #2: dimethyl sulfate In acetone for 8h; Reflux;	Synthesis of 4, 6-Dimethoxy 2-hydroxyacetophenone (3) To the solution of 1-(2,4,6-trihydroxyphenyl)-ethanone (40 mmol) (2) in anhydrous acetone (100 mL), K2CO3 (119 mmol) was added. The mixture was allowed to stir at roomtemperature for 15 min, then dimethyl sulfate (119 mmol) was added dropwise and refluxed for 8h. The progress of the reaction was noticed by TLC. After completion of the reaction, the solution was cooled at room temperature, filtered, and concentrated under vacuum to get the residue, which was purified by silica gel chromatography (hexane: ethyl acetate 5:1) to afford (3) in 90% yield. [Mp 75°C (lit. 73-76°C)] 1H-NMR [DMSO-d6, 400 MHz] δ: 13.79 (s, 1H, -OH), 6.09 (d, 1H, Ar-H), 6.07 (d, 1H, Ar-H), 3.85 (s, 3H, OCH3), 3.085 (s, 3H, OCH3), 2.537 (s, 3H, CH3).
90%	With potassium carbonate In acetone for 12h; Reflux;
88%	With potassium carbonate In acetone
87%	With potassium carbonate In acetone Reflux;	14 Preparation of derivatives of Hirtellanine B 5,6,7 (1 g, 5.95 mmol) was dissolved in 30 ml of acetone followed by the addition of potassium carbonate (4.11 g, 5 eq.), And dimethylsulfate (4 eq) was added dropwise. The suspension was refluxed for 5 to 8 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered and washed with acetone. The filtrate was evaporated under reduced pressure to give intermediate 5a (2-hydroxy-4,6-dimethoxyacetophenone) , 6a (2-hydroxy-4,6-diethoxyacetophenone) (5a, 1.01 g, yield 87%; 6a, 1.15 g, 79% yield); intermediate 5a, 6a, (4-hydroxy-5,7-dimethoxycoumarin), 6b (4-hydroxy-5,7-diethoxy coumarin) obtained by Method B of Method 9, (44 mg), 6b (50 mg) were each obtained by the method A of Example 9 to obtain the compound of the formula (5b, 1.00 g, yield 93%; 6b, 1.07 g, yield 91% 6,6 (Derivative 5, 60 mg, yield 74%; derivative 6,63 mg, 64%); nitration was carried out using Intermediate 6b (500 mg, 2 mmol) (see reaction of compound 2 (68 mg, yield 85%) was obtained from Intermediate 6c (59 mg, 0.2 mmol) followed by Method A of Example 9 to give the intermediate 6c (484 mg, yield 82%
86%	With potassium carbonate In acetone at 25℃; for 15h; Inert atmosphere;
85.7%	With potassium carbonate In acetone for 1.5h; Reflux;	2 Synthesis of 2,4-Dimethoxy-6-hydroxy-acetophenone (a kind of compound represented by structural formula 3, denoted as 3a) Compound 2 (10.0g, 0.059mol) was dissolved in 100ml of acetone, anhydrous potassium carbonate (24.58g, 0.178mol) was added, and while stirring, dimethyl sulfate (13ml, 0.137mol) was added dropwise and heated to reflux for 1.5h. Cooled to room temperature, filtered to remove solid potassium carbonate to obtain orange-yellow acetone solution. Rotary evaporation to obtain 11.24g yellow crude product. The crude product was recrystallized with 50ml ethanol-water to obtain white solid. Then vacuum dried at 45 for 12h to obtain orange-red solid 9.25g (85.7% yield).
84.2%	With potassium carbonate In acetone for 5h; Reflux;	5 4.1.5. 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethanone (16) 4.1.5 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethanone (16) To a mixture of 1-(2,4,6-trihydroxyphenyl)ethanone 15 (4.5 g, 24.2 mmol) and anhydrous K2CO3 (8.29 g, 55.6 mmol) in acetone (90 mL), Me2SO4 (6.84 mL, 72.5 mmol) was added dropwise with stirring. The resulting mixture was refluxed for 5 h and then filtered and concentrated under reduced pressure. The residue was purified on a silica gel chromatography using CH2Cl2 as eluent, obtaining compound 16; 84.2% yield; white solid; mp 78-79 °C (lit. 38 79-80 °C).
84%	With potassium carbonate In acetone at 0 - 20℃; for 3h; Inert atmosphere;	Procedure for synthesis of compound 11 To a stirred solution of ketone 1 (1.18 g, 10 mmol) and K2CO3 (3.45 g 25 mmol) in acetone (20 mL), (CH3)2SO4 (2.37 mL, 25 mmol) was added dropwise at 0 °C. After stirring at room temperature for 3 h, the solvent was then removed under reduced pressure. The residue was dissolved in water (30 mL) and the solution was extracted three times with EtOAc. The combined organics were washed with water and brine, then dried over anhydrous MgSO4 and concentrated in vacuo to give compound 11 (1.65 g, 84%). 1H NMR (500 MHz, CDCl3) δ 14.03 (s, 1H), 6.08 (d, J = 2.4 Hz, 1H), 5.94 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.63 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 203.19, 167.58, 166.09, 162.91, 105.97, 93.45, 90.71, 55.55, 32.96; ESIMS: m/z = 197.2 [M+H]+.
83%	With potassium carbonate In acetone at 20℃; for 18h;
83%	With potassium carbonate In acetone for 12h;	1.1-3.1 1. Hydroxyl protection Trihydroxyacetophenone (16.8 g, 0.1 mol) was dissolved in 500 ml of acetone, anhydrous potassium carbonate (27.6 g, 0.2 mol) was added, and the mixture was heated to reflux at 56 ° C; Take dimethyl sulfate (25.2 g, 0.2 mol), add one-third to the reaction solution every 3 h, and reflux the reaction at 56 ° C for 9 h, then filter the reaction solution, and evaporate the filtrate to give a yellow solid. After washing three times with water, it was dried under low temperature to give a white solid product I (16.3 g). The yield was 83%.
83%	With potassium carbonate In acetone at 45℃; for 4h;	5.1.3. 4, 6-Dimethoxy-2-hydroxyacetophenone (12) Compound 11 (33.6 g, 0.2 mol) was dissolved in anhydrousacetone (350 mL) and K2CO3 (63.48 g, 0.46 mol) was added. Thendimethyl sulphate was added dropwise at room temperature andthe mixture was heated to 45 °C for 4 h. The reaction was monitoredby TLC. After the end of the reaction, the mixture was cooledto room temperature, filtered and the filtrate was poured into 5 volof water and adjusted to pH = 3-4 with 1M HCl to precipitate alarge amount of solid. The mixture was filtered and dried to give awhite solid (32.5 g, 83% yield). mp 80-82 °C.
83%	With potassium carbonate In acetone at 20 - 45℃; for 5h;	1.2 The second step: preparation of intermediate I-3 Add intermediate I-2 (33.6 g, 0.2 mol)To 350 mL of anhydrous acetone,Stir at room temperature,Add 63.48g K2CO3 (0.46mol),Dimethyl sulfate (39.78 mL, 0.42 mol) was added dropwise at room temperature.After 1 hour, the drop is completed.The reaction was continued at 45 ° C for 4 h.TLC detection (V petroleum ether: V ethyl acetate = 3:1) reaction is complete,Cool down to room temperature,Filter by suction and pour the filtrate into 5 volumes of water.Adjust pH to 3-4 with 1M HCl,A large amount of solid is precipitated.Filtered and dried to a white solid 32.5g.The yield was 83%.
82%	With potassium carbonate In acetone at 20℃;	2 1 -(2,4,6- trihydroxyphenyl)ethanone, 4, (16.8 g, 0.10 mol), anhydrous potassium carbonate (41.50 g, 0.30 mol) and anhydrous acetone (168 mL) were combined and stirred at room temperature after which dimethyl sulfate (26.9 g, 0.21 mol) was slowly added. Once the addition was complete, the reaction was stirred for 1 hour. The pH of the solution was adjusted to neutral using 2N HCl. The resulting yellow solid was collected by filtration and washed with water then dried to afford 16 g (82% yield) of the desired product as a white solid. M.p. 76-78 0C.
82%	With potassium carbonate In acetone for 0.333333h; Reflux; Inert atmosphere;	Optimized Experimental Procedure for the Synthesis of 2′-Hydroxy-4′,6′-dimethoxyacetophenone K2CO3 (7.23 g, 52.32 mmol) and Me2SO4 (2.48 mL, 26.16 mmol) were added to a solution of 2′,4′,6′-trihydroxyacetophenone (1, 2.00 g, 11.89 mmol) in acetone (50 mL). The reaction mixture was refluxed for 20 min under nitrogen atmosphere. After that, K2CO3 was filtered off, the acetone evaporated, and the residue recrystallized in EtOH affording the 2′-hydroxy-4′,6′-dimethoxyacetophenonein good yield (82%, 1.91 g).
82.5%	With potassium carbonate In acetone at 20℃;	Preparation of 2-hydroxy-4,6-dimethoxyacetophenone (2): white powder (EtOH) This compound was prepared from a mixture of 1 (17.85 mmol, 3 g), K2CO3 (43.47 mmol, 6 g), Me2SO4 (19.67 mmol, 3.85 g), and 50 ml acetone, which was stirred at RT for 5-6 h, and then, the mixture was poured into water (300 ml). The precipitated solid was filtered, washed with water, and crystallized from 95 % ethanol to give 2 as white powder, yield: 82.5 %; IR (KBr) νmax 2,960 (OH),1,620 (C=O) cm-1; 1H NMR (DMSO-d6, 400 MHz): δ = 14.15 (1H, s, OH), 6.36 (1H, d, J = 2.5 Hz, H-3), 5.97(1H, d, J = 2.7 Hz, H-5), 3.89 (3H, s, OCH3-4), 3.83 (3H,s, OCH3-6), 2.7 (3H, s, COCH3). 13C NMR (DMSO-d6,100 MHz): δ = 203.1 (C, C=O), 167.6 (C, C-4), 166.1(C,C-6), 162.9 (C, C-2), 106.0 (C, C-1), 92.9 (CH, C-3), 90.1(CH, C-5), 55.4 (2CH3, OCH3), 32.1(CH3, COCH3); ESI-MS: m/z 197.09 [M+H]+. Anal. Calcd. for C10H12O41 96.07: C, 61.22; H, 6.16. Found: C, 61.27; H, 6.19.
81.36%	With potassium carbonate In acetone at 50℃; for 6h;	20 Example 20 Preparation of 2-hydroxy-4,6-dimethoxyacetophenone (10) Anhydrous operation, 5 g of Intermediate 6 (26.85 mmol) was put in 80 ml of acetone, and 7.5 g of potassium carbonate was added(54.35 mmol) and 5.25 ml of dimethyl sulfate (20 mmol) were added, and the reaction solution was heated to 50 ° C, After the reaction was completed for 6 hours, the excess acetone was removed by distillation under reduced pressure, Purification by column chromatography gave a white solid in a yield of 81.36%.
80%	With potassium carbonate In acetone at 25℃; for 4h;	4.1.2.20 4,6-Dimethoxy-2-hydroxyacetophenone (13) To a solution of 12 (16.8g, 0.1mol) in dry acetone (180mL) was added K2CO3 (31.74g, 0.23mol) and dimethyl sulfate (20mL, 0.2mol). After stirring at 25°C for 4h the mixture was filtered. Then the filtrate was put into 100mL water and 0.5M HCl was conducted to adjust PH to 3-4. After filtration, the cake was washed with ice water for three times. The residue was dried to obtain 13 (16g, 80%). m.p. 81-83 ○C.
78%	With potassium carbonate In acetone at 0℃;
78%	With potassium carbonate In acetone for 48h; Inert atmosphere; Reflux;
78%	With potassium carbonate In acetone for 20h; Reflux;	1 preparation of Intermediate product (2) The 9g compound (1) is dissolved in 30 ml of acetone, is added under stirring 14g potassium carbonate, then using the constant voltage dropping funnel slowly add sulfuric acid dimethyl ester 15g, reflux stirring 20h, cooling to room temperature, adding ice water precipitating a large amount of white solid, filtered, methanol recrystallization to obtain 7.5g white solid (2), yield 78%. Compound mp: 74.4-75.1 °C.
78%	With potassium carbonate In acetone for 20h; Reflux;	1 Preparation of intermediate 2 The compound 1 (9g ) dissolved in 30ml of acetone, 14g of potassium carbonate was added under stirring, then added slowly with constant pressure dropping funnel dimethyl sulfate 15g, was stirred at reflux for 20h, cooled to at room temperature, ice water was added to precipitate large amount of white solid was suction filtered, and recrystallized from methanol to give a white solid 7. 5g (2), a yield of 78%. Compound mp 74. 4-75. 1 ° C. The product structure was confirmed by IR, NMR and MS analysis
77%	With potassium carbonate In acetone at 20℃; for 3h;
76%	With potassium carbonate In acetone for 20h; Reflux;	3.1 step one,Dissolve 9.300g of 2,4,6-trihydroxyacetophenone inIn 100 mL of anhydrous acetone,Slowly add with stirring14g anhydrous potassium carbonate,Then use a constant pressure dropping funnel15g of dimethyl sulfate was added dropwise within 10 minutes.Reflux 20h,Cool to room temperature,Add ethyl acetate,Pour in dilute hydrochloric acid,Water extraction,Dry with anhydrous sodium sulfate,Subsequent column chromatography V (petroleum ether):V (ethyl acetate) = 10:1,The first intermediate product in the form of white crystal(7.401g yield 76%),Structure by IR,NMR and MS analysis confirmed thatThe structure is as follows:
76.6%	Stage #1: 2,4,6-trihydroxyacetophenone; dimethyl sulfate With potassium carbonate In acetone at 60℃; Stage #2: With sodium hydroxide In acetone at 60℃; for 1h;	1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone : compound 1-(2,4,6-trihydroxyphenyl)ethanone12.0 g (71.5 mmol, 1.0 eq) was dissolved into 50.0 ml acetone, then anhydrousK2CO3 29.6 g (214.5mmol, 3 eq) was added. The mixture was stirred for a whilefollowed by the addition of dimethylsulfate 22.5 g (178.8 mmol, 2.5 eq). Themixture was heated under 60 oC until the starting material wascompletely consumed. 10.0 % aq. NaOH solution was added carefully, and stirredunder 60 oC for about 1 hour, a large amount of the solvent wasremoved under reduced pressure, and 200.0 ml water was added, and extracted by ethylacetate for 3 times. The organic phase was combined and dried by anhydrousNa2SO4. The solvent was removed and the crude product was purified by si-gelchromatography (PE/EA=4/1) to afford 11.0 g 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanoneas white solid powder, yield 76.6%. 1H NMR (600 MHz, CDCl3):δ (ppm) = 2.60 (s, 3H), 3.81 (s, 3H), 3.84 (s, 3H), 5.92 (d, J = 2.2 Hz, 1H),6.05 (d, J = 2.2 Hz, 1H), 14.00 (s, 1H).
75%	With potassium carbonate In acetone at 20℃; for 4h;	preparation of 2-hydroxy-4,6-dimethoxyacetophenone The 2,4,6-trihydroxyacetophenone monohydrate (3.72g, 20mmol) added to acetone (60 ml), then adding potassium carbonate (6.06g, 40mmol)with stirring, undissolved, then slowly dropping dimethyl sulfate (4 ml, 42mmol), after completion of dropwise addition the reaction was stirred at the room temperature 4 hours and degree of reaction was monitored by TLC monitoring. The end of the to be reacted, filtering off the solid insoluble materials, ten slowly adding water (100 ml), repeated oscillation, allowed to stand for half an for white solid precipitation. Filtering, drying to obtain the white solid (3.0g), yield 75%.
74%	With potassium carbonate In acetone for 5h; Reflux;	Synthesis of 2’-hydroxy-4’,6’-dimethoxyacetophenone (4) To a solution of 2’,4’,6’-trihydroxyacetophenone (3) (10.0 g, 59.5 mmol) in acetone (350 mL)was added K2CO3 (16.45 g, 119 mmol, 2.0 equiv) while stirring with a KPG stirrer at room temperature. Dimethyl sulfate (14.15 g, 112.2 mmol, 10.6 mL) was added dropwise to the suspension under vigorous stirring and then the reaction mixture was refluxed for 5 h. Then the reaction mixture was allowed to cool down and was stirred overnight. Afterwards, the reaction mixture was filtered, the solvent was evaporated under vacuum and the residue was recrystallized from methanol (15 mL). The crystals were filtered, washed with water to yield 8.65 g (44.1 mmol, 74%) off-white solid; mp 74-75 °C [Lit. 73-76 °C]. Spectroscopic data is in accordance with the literature.
72%	With potassium carbonate In acetone for 5h; Reflux;
70%	With potassium carbonate In acetone
54%	With potassium carbonate In acetone for 10h; Reflux;	1 4.1 Synthesis of 1-(2-hydroxy-4,6-dimethoxyphenyl)ethan-1-one (1) A mixture of 1-(2,4,6-trihydroxyphenyl)ethan-1-one (2.50 g, 15 mmol), (CH3)2SO4 (2.85 mL, 30 mmol) and anhydrous K2CO3 (4.56 g, 33 mmol) in dry acetone (60 mL) was refluxed for 10 h. The reaction mixture was concentrated and poured on to ice-water (100 mL). The resulting precipitate was filtered off and washed with cold water. The obtained residue was purified by silica gel column chromatography with hexane: ethyl acetate (95: 5) as eluent. White solid, Yield: 54%, M.P: 78-80 °C; 1H NMR (CDCl3, 400 MHz, ppm) δ: 14.03 (s, 1H,-OH), 6.06-6.05 (d, J = 2.20 Hz, 1H, Ar-H), 5.93-5.92 (d, J = 2.20 Hz, 1H, Ar-H), 3.86, 3.82 (s, each 3H, 2 * -OCH3), 2.61 (s, 3H, -COCH3); 13C NMR (CDCl3, 100 MHz, ppm) δ: 203.17 (-C=O); 167.56; 166.06; 162.88; 105.97; 93.43; 90.72; 55.53 (-OCH3); 50.86 (-OCH3); 32.91 (-CH3).
54.9%	With potassium carbonate In acetone for 2h; Reflux;	14.A Step A: containing 2,4,6-trihydroxyacetophenone (25.0 g, 149 mmol), potassium carbonate (20.6 g, 149 mmol),A mixture of dimethyl sulfate (28.1 g, 223 mmol) and acetone (250 mL) was stirred under reflux for 2 hr.Cool to room temperature, remove insolubles by filtration, distill off the solvent under reduced pressure, and purify the product by column chromatography (200-300 mesh silica gel,Ethyl acetate:dichloromethane: petroleum ether = 1:1:40 to 1:1:6) eluted to give 1-(4-hydroxy-2,6-methoxy-phenyl)ethanone (86) (16.0 g), the yield was 54.9%.
	With potassium carbonate; acetone; benzene
	With potassium carbonate In acetone
50 mg	With potassium carbonate In acetone for 0.5h; Heating;
	With potassium carbonate In acetone at 50 - 60℃; for 0.5h;
	With sodium hydroxide In dichloromethane; water monomer at 20℃; for 24h;
	With potassium carbonate In acetone for 5h; Reflux;
	With potassium carbonate In acetone at 65℃; for 6h;
	With potassium carbonate In acetone Reflux;
	With potassium carbonate In acetone at 20℃;
	With potassium carbonate
	With potassium carbonate In acetone for 2h; Reflux;
	In acetone at 65℃;
	With potassium carbonate In acetone Reflux;
	With potassium carbonate In acetone at 20℃; for 3h;
	With potassium carbonate In acetone at 15 - 60℃; for 2h;	1.1 To a mixture of 1- (2,· 4, 6-trihydro xyphenyl)ethanone (50 g, 297.36 mmol, 1 eq) and K2CO3 (102.74 g, 743.40 mmol, 2.5 eq) in acetone (500 mL) was added Me2S04 (78.76 g, 624.46 mmol, 59.22 mL, 2.1 eq) at 15 °C. The mixture was stirred at 60 °C for 2 h. The reaction mixture was filtered and the filter cake was washed with EtOAc (40 rnL*3). The filtrate was concentrated under reduced pressure to give l-(2-hydroxy-4,6-dimethoxy-phenyl)ethanone (53 g, crude) as gray solid. The product will be used directly in next step without further purification. H NMR: (CDCI3, 400 MHz) d - 14.01 (s, 1 H), 6.06 (d, I - 2.2 Hz, 1H), 5.92 (d, I = 2.4 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 2.61 (s, 3H).

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8
[ 90-24-4 ]
[ 494-08-6 ]
[ 112572-59-5 ]

Reference： [1]Pharmaceutica Acta Helvetiae,1946,vol. 21,p. 341,344

9
[ 90-24-4 ]
[ 2426-87-1 ]
[ 114021-61-3 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium hydroxide In ethanol at 20℃; for 72h;
70%	With potassium hydroxide In methanol at 20℃; for 36h;	preparation of (E)-3-(4-(benzyloxy)-3-methoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)propan-2-en-1-one The intermediate 4,6-dimethoxy-2-hydroxy - acetophenone (2g, 10.2mmol) and Intermediate 4-benzyloxy-3-methoxybenzaldehyde (2.5g, 10.2mmol) was dissolved in methanol (50ml), the stirring was slowly added dropwise a 50% aqueous potassium hydroxide solution (6 ml of), yellow color of the solution gradually, dropwise, stirred for 36 hours at room temperature, the extent of reaction is monitored by TLC.After completion of the reaction, stirring was added dropwise 1mol / L hydrochloric acid solution, adjusted to PH = 5, standing for a while, to give a yellow oily solid was filtered, washed with methanol (30ml), filtered, and dried to give a yellow solid (3.0 g), yield about 70%.
	With potassium hydroxide In ethanol at 35 - 40℃; for 12h;

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[2]Current Patent Assignee: SECOND MILITARY MEDICAL UNIVERSITY - CN104230869, 2016, B Location in patent: Paragraph 0067; 0068
[3]Sekizaki, Haruo [Bulletin of the Chemical Society of Japan, 1988, vol. 61, p. 1407 - 1409]

10
[ 90-24-4 ]
[ 490-63-1 ]
[ 77394-23-1 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1981,p. 514 - 521

11
[ 90-24-4 ]
[ 123-11-5 ]
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium hydroxide In ethanol; water monomer at 0 - 20℃;	Synthesis of Chalcones 6; General Procedure General procedure: To a suspension of 2’-hydroxy-4’,6’-dimethoxyacetophenone (4) in ethanol (approx. 2.7-3.0 mL per 1.0 mmol 4) was added 60% KOH solution (2.5 mL per 1.0 mmol 4) at 0 °C in an ice bath. The mixture was stirred for a few minutes and then the appropriate aldehyde (5a-d) (1.5 equiv) was added. After a few hours the colour of the reaction mixture changed to orange or red; the reaction mixture was stirred overnight at room temperature. The solution was acidified to pH 1 by adding 10% aqueous HCl, the yellow precipitate was filtered, washed with cold ethanol and water and recrystallized from methanol if necessary.
92%	With sodium hydroxide In methanol at 20℃;	General Procedure for the synthesis of chalcones (3A-L). General procedure: A solution of MeOH (25 mL), the corresponding acetophenones 1A-C (1 eq), theappropriate benzaldehyde 2A-G (1 eq), and excess of NaOH were stirred at room temperature, and the progress of the reaction was monitored by TLC. Upon completion, the excess of NaOH was neutralized by addition of HCl (1 M) with pH control. The solvent was evaporated, the residue was taken up in EtOAc, and the resulting solution was washed with distilled water. The organic layer was dried with MgSO4 and filtered, and the solventwas evaporated under reduced pressure. The crude product was purified by crystallization from methanol (MeOH) or by column chromatography.
88%	With potassium hydroxide In ethanol; water monomer at 20℃;	General procedure: To a stirred solution of 4 (0.364 g, 2 mmol) and K2CO3 (0.552 g, 4 mmol) in DMSO (15 mL), and BnBr (0.44 mL, 4.4 mmol) was dropwise added at the room temperature. The reaction was then quenched by ice water, extracted with EtOAc (3 * 20 mL), then dried over Na2SO4, finally concentrated under reduced pressure to afford 5 (6.25 g). In the presence of 40% KOH, 5 reacted with corresponding benzaldehydes in a mixture of water and ethanol to obtain the chalcones 6a-g, which purified through a silica gel column. BCl3 (10 mL, 1 M in DCM) was dropwise added in anhydrous DCM (50 mL) of 6a-g (1.96 g, 10 mmol) under ice bath and stirring. After 0.5 h, the ice bath was removed, and the reaction was carried out for 2 h at room temperature. After being monitored by TLC, 15 mL ice water was added. The reaction was extracted with EtOAc (3 * 30 mL). The combined extract was dried over anhydrous Na2SO4 and was concentrated. The concentrated solution was purified by column chromatography to gain A1-7.

85%	With potassium hydroxide In methanol at 20℃; for 24h;
82.4%	With potassium hydroxide In ethanol; water monomer at 20℃;	(E)-1-(2'-Hydroxy-4',6'-dimethoxyphenyl)-3-(4-methoxyphenylprop-2-en-1-one (2) General procedure: To a stirred solution of appropriate acetophenone (1 equiv),substituted benzaldehyde (1 equiv) in ethanol, KOH (20% w/vaqueous solution) were added. The mixture was stirred at roomtemperature for 48-72 h. The reaction mixture was cooled to0 C (ice-water bath) and acidified with HCl (10% v/v aqueous solution).In most cases, yellow precipitate were formed, filtered andwashed with 10% aqueous HCl solution. The mixture was extracted with ethyl acetate, the extracts were dried over Na2SO4 anhydrousand the solvent was evaporated to obtain final product as in solidor crystalline form hot MeOH. The crude products were purifiedwith column chromatography by elution with ethyl acetate andhexane. (E)-1-(2'-Hydroxy-4',6'-dimethoxyphenyl)-3-(4-methoxyphenylprop-2-en-1-one (2) Yield 82.4%. Yellow needles crystals. mp 110-112 °C. IR (KBr): 1654 (C=O), 3200 (Ar C-H str.), 1590, 1589, 1476, (C=C), 1202 (C-O str.), 850 cm-1. 1H NMR (CDCl3, 500 MHz): δ 13.6 (s, 1H, OH), 8.02 (d,1H, J = 15.5 Hz, Hβ), 7.81 (d,1H, J = 15.5 Hz, Hα), 7.73 (brd, 2H, H-2, 6), 7.49 (m, 2H, H-3, 5), 6.87 (br,s, 1H, H-5'), 6.02 (br,s, 1H, H-3'), 3.93 (s, 3H, OMe, C-6'), 3.85 (s, 3H, OMe, C-4'), 3.82 (s, 3H, OMe, C-4). 13C NMR (CDCl3, 125 MHz): δ 192.6 (C=O), 168.7 (C2'), 166.2 (C4'), 163.1 (C6'), 160.9 (C4), 141.6 (Cβ), 130.1(C2, C6), 127.5 (C1), 125.4 (Cα), 114.3 (C3, C5), 93.56 (C3'), 91.4 (C5'), 55.79 (OCH3), 55.53 (OCH3), 55.35 (OCH3). EI-MS m/z 298.33, (Molcular formula C18H18O5).
81%	With potassium hydroxide In ethanol; water monomer at 60℃; for 6h;
78.4%	With potassium hydroxide In ethanol; dimethyl sulfoxide	S.11 Specific Example 11 Specific Example 11 To a mixture of 34.7 g of the 2'-hydroxy-4',6'-dimethoxyacetophenone obtained in Production Example 7, 25.3 g of p-anisaldehyde, 150 ml of ethanol and 150 ml of dimethylsulfoxide was added 150 ml of a saturated solution of potassium hydroxide in ethanol at 0° C., and the mixture was stirred at room temperature for 4 hours to effect reaction. After the reaction, the reaction mixture was made acidic by dilute hydrochloric acid to obtain a precipitate. The precipitate was washed with water and recrystallized from a mixed solvent of methanol and ethyl acetate to obtain 43.4 g (yield=78.4%) of 2'-hydroxy-4,4',6'-trimethoxychalcone in the form of a yellow needle.
77%	With sodium hydroxide In methanol at 20℃; for 3h;	General Optimized Experimental Procedure for the Synthesisof (E)-2′-hydroxychalcones 3a,b NaOH (aq, 60%, 37 mL) was added to a solution of 2′-hydroxy-4′,6′-dimethoxyacetophenone (1.50 g, 7.645 mmol) in MeOH (37 mL; in the case of derivative a), or in MeOH-DMSO (v/v,37:4.5 mL; in the case of derivative b). After that, the appropriate benzaldehyde 2a,b (15.04 mmol) was added, and the reaction mixture was stirred for 3 h (derivative a) and 4 h (derivativeb) at r.t. Then, the mixture was poured into ice (50 g) andH2O (100 mL) and the pH adjusted to 4 with a solution of HCl (20%). After filtration, the precipitate was taken in CH2Cl2,washed repeatedly with a sat. solution of KHCO3 (1 × 300 mL) and H2O (3 × 300 mL), and the organic layer was dried over anhydrous Na2SO4. Subsequently, after solvent evaporation, the residue was recrystallized in EtOH giving the correspondent (E)-2′-hydroxychalcones 3a,b in good yields [3a (77%, 1.78 g); 3b (61%, 1.61 g)].
70.1%	With potassium hydroxide In methanol; water monomer at 20℃;
70.1%	With potassium hydroxide In methanol; water monomer at 25℃;	Example syntheses of some Formula (I) compounds, such as chalcone- and dihydrochalcone-related compounds. To prepare chalcone-related compounds, the corresponding acetophenone (1.2 mmol), aromatic aldehyde (1.4 mmol), KOH (1.5 g, 26.7 mmol), H2O (1.5 mL) and CH3OH (3.0 mL) were stirred at room temperature (e.g., 25 0C) for 1 to 48 hours. Deionized water (50 mL) was added and the solution was extracted with EtOAc (2 x 30 mL), the organic layer was dried over MgSO4 and evaporated. The crude extract was subjected to column chromatography using hexanes-EtOAc gradient (10:1 to 1:1). (2£r)-l-(2-Hvdroxy-4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)-2-propen-l-one (I- 01). Yellow solid (mp: 112 0C); 70.1%; 1U NMR: δ 7.78 (d, / = 16.5 Hz, IH); 7.77 (d, /= 16 Hz, IH); 7.58 (d, / = 8.5 Hz, 2H); 6.94 (d, /= 8.5 Hz, 2H); 6.12 (d, / = 2 Hz, IH); 5.97 (d, / = 2.5 Hz, IH); 3.93 (s, 3H); 3.86 (s, 3H); 3.84 (s, 3H). 13C NMR: δ 192.8, 168.6, 166.3, 162.7, 161.6, 142.7, 130.4, 130.4, 128.6, 125.4, 114.6, 114.6, 106.6, 94.1, 91.5, 56.1, 55.8, 55.6 Anal. (Ci8Hi8O5) C: calcd, 68.78 found, 68.99; H: calcd, 5.77 found, 5.82.
65%	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone With sodium hydroxide In methanol at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-methoxy-benzaldehyde In methanol Inert atmosphere;	The general method for the preparation of chalconesseries 1 and series 2 General procedure: Under N2 atmosphereand 0 OC, 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (1mmol, 1 eq) or1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-one (1mmol, 1 eq) was dissolved into10 ml MeOH, followed by the addition of 10 ml aq. 40% NaOH solution, themixture was stirred for about 30 min, then benzaldehydes (1.2 mmol, 1.2eq.)were added respectively. The mixture was stirred for overnight and monitored byTLC. After the starting material 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone or 1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-onewas consumed completely, the pH value was adjusted to 3 with aq. 3 N HClsolution, a large amount of yellowish solid formed. The crude product was filtrated,recrystallized from MeOH or purified by si-gel column chromatography to affordfine desired products.
55%	With sodium hydroxide In ethanol at 20℃;	4.2. General procedures for synthesis of chalcones General procedure: For synthesis of chalcones we have used 2 different methods. Chalcones 1-30 were synthesized by method A and chalcones 31-44 were synthesized by method B. For Method B we used LiOHinstead of usual base NaOH for Claisen-Schmidt synthesis and the reaction was carried out in an ultrasonic bath. The general reaction scheme is depicted in Scheme 1.Method A: 20% NaOH (5 ml) was added dropwise to a previously cooled mixture of 5 mmol of selected acetophenone and 5 mmol of selected benzaldehyde in 25 ml ethanol under vigorous stirring. The mixture was stirred at room temperature for 24-72 h. After completion of the reaction as indicated by TLC, the mixture was poured onto crushed ice and acidified with dilute HCl. Precipitated product was filtered by suction and washed to neutral. The solid was recrystallised from dilute ethanol to get crystalline chalcone.Method B: To a mixture of 5 mmol of selected acetophenone and 5 mmol of selected benzaldehyde in 50 ml round bottom flask, 20 ml methanol and 35 mmol of LiOH was added. The reaction mixture was kept in an ultrasonic bath for 1-5 h, until reaction completion was indicated by TLC. The reaction was worked up as described for method A.
41%	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone; 4-methoxy-benzaldehyde With potassium hydroxide In ethanol; water monomer at 20℃; Stage #2: With hydrogenchloride In ethanol; water monomer at 0℃;
	base-catalyzed Claisen-Schmidt reaction;
400 mg	With sodium hydroxide In ethanol for 80h; Ambient temperature;
	With sodium hydroxide In ethanol at 20℃;
	In ethanol at 20℃; Alkaline conditions;
	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone With sodium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 4-methoxy-benzaldehyde In ethanol at 20℃; Inert atmosphere;	General procedure for the synthesis of chalcones 1 - 46 General procedure: A total of 46 chalcones with different electron-donating and electron-withdrawing substituents (chalcones1-46, Table 1) were synthesisedby following a Claisen-Schmidt condensation reaction. All solvents and reagents were purchased from Merck and Sigma-Aldrich, MO, USA and used without further purification. Briefly, sodium hydroxide (3 eq) was added to a solution of substituted acetophenone (1.0eq) in ethanol followed by the addition of the substituted benzaldehydes (1.2 eq) after 10 minutes and stirred at room temperature overnight under nitrogen. The reaction mixture was then cooled in an ice bath and neutralisedwith 1M hydrochloric acid. The neutralised mixture was then extracted using ethyl acetate. The organic layer was washed with distilled water, dried with anhydrous sodium sulphate, concentrated and the resultant mixture was purified through a column of silica gel to obtain the pure compounds.Column chromatography was performed on silica gel (Merck, Kieselgel 60, 230-400mesh) with hexane:ethyl acetate as the mobile phase. The thin layer chromatography was performed on silica gel plates (Merck, Kieselgel 60, 0.25mm thickness) with F254 as the indicator. The plate was observed under UV light (254nm and 366nm). Melting points of the chalcones were determined using Mel-Temp II melting point instrument. NMR spectra were recorded using a Jeol ECA 400 (400MHz) and/or Lambda 400 (400MHz) spectrometers with trimethylsilane (TMS) esters as the internal standard. All chemical shifts are reported in ppm.
	With potassium hydroxide at 20℃; for 18h;
	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone With sodium hydroxide In ethanol at 35℃; for 0.5h; Stage #2: 4-methoxy-benzaldehyde In ethanol	4.1 4.4.1. 2'-Hydroxy-4,6'-dimethoxychalcone (Ch-2) General procedure: The 2-Hydroxy-6-methoxyacetophenone (500 mg, 3.012 mmol) was dissolved in ethanol (30 mL), and sodium hydroxide (482 mg, 12.048 mmol) was added to the stirred solution at 35 °C. After stirring for 30 min, p-methoxybezaldehyde (428 μL, 3.150 mmol) was added to the solution. Overnight, the resulting mixture was acidified with dilute hydrochloric acid and water to pH = 7. Then the resulting precipitate was collected and on recrystallization from ethanol gave yellow needles (698 mg, 82%).
	In ethanol; water monomer at 20℃; Alkaline conditions;	3.3. Synthesis of Flavokawain B derivatives General procedure: KOH (20% w/v aqueous solution) was added to a stirred solution of the appropriate acetophenone(1.0 eq) and a substituted benzaldehyde (1.25 eq.) in ethanol, and the mixture was stirred at roomtemperature for 48-72 h. The reaction mixture was cooled to 0 °C (ice-water bath) and acidified withHCl (10% v/v aqueous solution). In most cases, yellow precipitate was formed, filtered and washedwith 10% aqueous HCl solution. In the cases where an orange-yellow layer was formed, the mixturewas extracted with CH2Cl2 or ethyl acetate, the extracts was dried over Na2SO4 anhydrous and thesolvent was evaporated and crystalized with methanol or ethanol.

Reference： [1]Sipos, Zoltán; Kónya, Krisztina [Synthesis, 2018, vol. 50, # 8, p. 1610 - 1620]
[2]Bregier, Frédérique; Chaleix, Vincent; Lebouvier, Nicolas; Matsui, Mariko; Oelgemöller, Michael; Sinyeue, Cynthia; Sol, Vincent [Molecules, 2022, vol. 27, # 6]
[3]Liu, Jianwen; Ma, Lei; Shi, Ximeng; Yin, Huanhuan; Zhao, Yuyu; Zhou, Licheng [Letters in drug design and discovery, 2020, vol. 17, # 10, p. 1270 - 1282]
[4]Singh, Om V.; Muthukrishnan; Sunderavadivelu [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2005, vol. 44, # 12, p. 2575 - 2581]
[5]Akhtar, Muhammad Nadeem; Sakeh, Nurshafika M.; Zareen, Seema; Gul, Sana; Lo, Kong Mun; Ul-Haq, Zaheer; Shah, Syed Adnan Ali; Ahmad, Syahida [Journal of Molecular Structure, 2015, vol. 1085, p. 97 - 103]
[6]Lu, Kui; Li, Ming; Huang, Yuna; Sun, Yuanyuan; Gong, Zhi; Wei, Qijun; Zhao, Xia; Zhang, Yongmin; Yu, Peng [Organic and Biomolecular Chemistry, 2019, vol. 17, # 35, p. 8206 - 8213]
[7]Current Patent Assignee: TSUMURA & CO. - US5106871, 1992, A
[8]De Azevedo, Orlando D. C. C.; Seixas, Raquel S. G. R.; Silva, Artur M. S. [Synlett, 2015, vol. 26, # 10, p. 1379 - 1384]
[9]Location in patent: experimental part Aponte, José C.; Verástegui, Manuela; Málaga, Edith; Zimic, Mirko; Quiliano, Miguel; Vaisberg, Abraham J.; Gilman, Robert H.; Hammond, Gerald B. [Journal of Medicinal Chemistry, 2008, vol. 51, # 19, p. 6230 - 6234]
[10]Current Patent Assignee: THE JOHNS HOPKINS UNIVERSITY - WO2010/19861, 2010, A1 Location in patent: Page/Page column 38-39
[11]Chen, Lijuan; Fan, Tiantian; Lei, Xiangui; Teichmann, Alexander Tobias; Wang, Amu; Wang, Chao; Wei, Zhe; Wieland, Frank Heinrich; Yang, Youzhe; Yin, Jinxiang; Zhou, Li; Zhu, Yue [European Journal of Medicinal Chemistry, 2020, vol. 193]
[12]Location in patent: experimental part Juvale, Kapil; Pape, Veronika F.S.; Wiese, Michael [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 1, p. 346 - 355]
[13]Location in patent: experimental part Detsi, Anastasia; Majdalani, Maya; Kontogiorgis, Christos A.; Hadjipavlou-Litina, Dimitra; Kefalas, Panagiotis [Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 23, p. 8073 - 8085]
[14]Parmar, V. S.; Sharma, Sunil; Rathore, J. S.; Garg, Meenu; Gupta, Sandhya; et al. [Magnetic Resonance in Chemistry, 1990, vol. 28, # 5, p. 470 - 474]
[15]Srivastava, Savitri D.; Srivastava, Santosh K. [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1987, vol. 26, p. 57 - 58]
[16]Cabrera, Mauricio; Simoens, Macarena; Falchi, Gabriela; Lavaggi, M. Laura; Piro, Oscar E.; Castellano, Eduardo E.; Vidal, Anabel; Azqueta, Amaia; Monge, Antonio; de Cerain, Adela Lopez; Sagrera, Gabriel; Seoane, Gustavo; Cerecetto, Hugo; Gonzalez, Mercedes [Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 10, p. 3356 - 3367]
[17]Juvale, Kapil; Stefan, Katja; Wiese, Michael [European Journal of Medicinal Chemistry, 2013, vol. 67, p. 115 - 126]
[18]Mai, Chun Wai; Yaeghoobi, Marzieh; Abd-Rahman, Noorsaadah; Kang, Yew Beng; Pichika, Mallikarjuna Rao [European Journal of Medicinal Chemistry, 2014, vol. 77, p. 378 - 387]
[19]Abu, Nadiah; Akhtar, M. Nadeem; Yeap, Swee Keong; Lim, Kian Lam; Ho, Wan Yong; Zulfadli, Aimi Jamil; Omar, Abdul Rahman; Sulaiman, Mohd Roslan; Abdullah, Mohd Puad; Alitheen, Noorjahan Banu [PLoS ONE, 2014, vol. 9, # 10]
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[21]Bakar, Addila Abu; Akhtar, Muhammad Nadeem; Ali, Norlaily Mohd; Yeap, Swee Keong; Quah, Ching Kheng; Loh, Wan-Sin; Alitheen, Noorjahan Banu; Zareen, Seema; Ul-Haq, Zaheer; Shah, Syed Adnan Ali [Molecules, 2018, vol. 23, # 3]

12
[ 90-24-4 ]
[ 120-14-9 ]
[ 10496-67-0 ]

Yield	Reaction Conditions	Operation in experiment
91.1%	With potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 4h;	3',4',5,7-tetramethoxychalcone (4) To a mixture ofpotassium hydroxide (57.1 g, 1.02 mol) and N,N-dimethylforamide (300 mL) was added 2-hydroxy-4,6-dimethoxyacetophenone(2) (100 g, 0.51 mol) under stirring. To the above3,4-dimethoxy benzaldehyde (veratraldehyde, 101.6 g, 0.61mol) was added slowly at room temperature and reaction wasstirred vigorously for 4 h. TLC (20 % EtOAc in hexane) showedcomplete absence of starting material. After completion of thereaction the reaction mixture was quenched with 25 % dil.HCl (400 mL) up to pH = 6 and stirred for 1 h. Then the reactionmixture was filtered and washed with water. The crude productwas dried under vacuum to get corresponding pure 3',4',5,7-tetramethoxychalcone (4). The yield was 91.1 % obtained.
87%	With sodium hydroxide In methanol; water at 20℃; for 3h;
87%	With sodium hydroxide In ethanol at 50℃; for 0.5h;

86%	With sodium hydride In N,N-dimethyl-formamide at 0℃; for 2h;
81%	With potassium hydroxide In methanol at 20℃; for 78h;	2′-Hydroxy-3,4,4′,6′-tetramethoxychalcone (4) Potassium hydroxide (11.2 g, 0.2 mol) was added to methanol (90 mL). After cooling to room temperature, compound 3 (2.0 g, 0.01 mol) and 3,4-dimethoxybenzaldehyde (1.8 g, 0.011 mol) were added to the solution. It was stirred for 78 h at room temperature. Then the mixture was acidified to pH 5 with 10% aqueous HCl. The precipitate was filtered off, washed with water and recrystallised from methanol to give yellow crystals of compound 4 (2.8 g, yield 81%).
31%	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone; 3,4-dimethoxy-benzaldehyde In ethanol at 20℃; for 0.333333h; Stage #2: With potassium hydroxide In ethanol at 20℃; for 3h;	5.8. Syntheses of 1 and 3 Compound 1 was synthesized according to the methods described by Chu et al. (2004). A mixture of 2,4,6-trimethoxyacetophenone (210 mg,1.0 mmol) and 3,4-dimethoxybenzaldehyde (191 mg, 1.15 mmol) in 20mL of anhydrous EtOH was stirred at room temperature for 20 min. A solution of 50% KOH (40 mL) was added to the mixture and the mixture was stirred at room temperature for 3 h. The resulting solution was neutralized by the addition of 4 M HCl and extracted with CH2Cl2. Theorganic layer was dried over Na2SO4, filtered, and the solvent wasremoved under reduced pressure. The residue was subjected to silica gel column chromatography (Daisogel IR-60-63-210). The compounds were eluted with EtOAc/n-hexane (3:7, v/v), and the fraction volume was set to 5 mL. The fractions containing 1 were combined and concentrated to give the product (353 mg, 99% yield). 1H NMR (600 MHz, CDCl3) δH:3.77 (6H, s, OMe × 2), 3.86, 3.90, and 3.91 (3H each, s, OMe × 3), 6.17(2H, s, H-3,5), 6.84 (1H, d, J = 16.0 Hz, H-7), 6.86 (1H, d, J = 8.0 Hz,H-5′ ), 7.07 (1H, s, H-2′ ), 7.09 (1H, d, J = 8.0 Hz, H-6′ ), and 7.29 (1H, d,J = 16.0 Hz, H-8). Compound 3 was synthesized from 2-hydroxy-4,6-dimethoxyacetophenone (98 mg, 0.5 mmol) and 3,4-dimethoxybenzaldehyde (96 mg,0.58 mmol) using the same method utilized for the synthesis of 1. After extraction with CH2Cl2, the residue of 3 was recrystallized from EtOH and purified 3 was obtained (54.0 mg, 31% yield). 1H NMR (600 MHz,CDCl3) δH: 3.83, 3.90, 3.92, 3.93 (3H each, s, OMe × 4), 5.95 (1H, d, J =1.8 Hz, H-5), 6.10 (1H, d, J = 1.8 Hz, H-3), 6.89 (1H, d, J = 8.0 Hz, H-5′ ),7.21 (1H, d, J = 8.0 Hz, H-6′ ), 7.25 (1H, s, H-2′ ), 7.75 (1H, d, J = 15.5Hz, H-8), 7.79 (1H, d, J = 15.5 Hz, H-7), and 14.40 (1H, bs, -OH).
21%	With potassium hydroxide In methanol at 50℃; for 12h; Inert atmosphere;	General Procedure for Preparing Compounds (1a-k), as Exemplified for Compound 1k. General procedure: A mixture of compound 3 (0.2 g, 1.02 mmol), 4-methoxy-1-naphthaldehyde (0.19 g,1.02 mmol), and potassium hydroxide (1.0 g) in 10 mL ofmethanol was stirred at 50 °C for 12 h. The mixture wasneutralized with 6 N HCl to pH 6 and then extracted with ethyl aceatate. The organic layer was washed with saturated NaHCO3 solution three times, dried over Na2SO4, and concentrated under reduced pressure, and purified by MPLC to afford compound 1k in 18% yield as yellow solid.
2.0 g	With alkali In ethanol Ambient temperature;
	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone; 3,4-dimethoxy-benzaldehyde In ethanol at 20℃; for 0.0833333h; Stage #2: With sodium hydroxide In ethanol at 20℃;
	With sodium hydroxide In ethanol; water at 20 - 50℃; for 8h;
	With sodium hydroxide In methanol
	With sodium hydroxide In methanol at 20℃;

Reference： [1]Rambabu; Kumari; Baby Ramana; Ramani; Subbaraju; Hari Babu [Asian Journal of Chemistry, 2016, vol. 28, # 5, p. 1139 - 1143]
[2]Freitas, Marisa; Ribeiro, Daniela; Tomé, Sara M.; Silva, Artur M.S.; Fernandes, Eduarda [European Journal of Medicinal Chemistry, 2014, vol. 86, p. 153 - 164]
[3]Deodhar, Mandar; Wood, Kasey; Black, David Stclair; Kumar, Naresh [Australian Journal of Chemistry, 2012, vol. 65, # 10, p. 1377 - 1383,7]
[4]Choe, Jung-Won; Heo, Hee-Young; Jung, Se-Hui; Kim, Jaehyun; Lee, Kooyeon [Molecules, 2021, vol. 26, # 10]
[5]Wang, Qian; Zhang, Ji; Liu, Man; Yang, Jian; Zhang, Xiang-Ming; Zhou, Lei; Cao, Lang; Liao, Xia-Li [Journal of Chemical Research, 2015, vol. 39, # 9, p. 550 - 552]
[6]Ube, Naoki; Katsuyama, Yuhka; Kariya, Keisuke; Tebayashi, Shin-ichi; Sue, Masayuki; Tohnooka, Takuji; Ueno, Kotomi; Taketa, Shin; Ishihara, Atsushi [Phytochemistry, 2021, vol. 184]
[7]Seo, Young Ho; Park, Sun You [Bulletin of the Korean Chemical Society, 2014, vol. 35, # 4, p. 1154 - 1158]
[8]Babber, Sunanda; Chandra, S.; Aggarwal, Anil K. [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1987, vol. 26, p. 797 - 798]
[9]Location in patent: experimental part Srinivasan, Balasubramanian; Johnson, Thomas E.; Lad, Rahul; Xing, Chengguo [Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7228 - 7235]
[10]Location in patent: experimental part Hasan, Aurangzeb; Sadiq; Abbas; Mughal; Khan, Khalid M.; Ali, Muhammad [Natural Product Research, 2010, vol. 24, # 11, p. 995 - 1003]
[11]Hu, Chunling; Zhou, Zongbao; Xiang, Yuanhang; Song, Xiaoying; Wang, Hong; Tao, Kaiqi; Ye, Xiaochuan [Medicinal Chemistry Research, 2018, vol. 27, # 1, p. 194 - 205]
[12]Kasashima, Yoshio; Mino, Takashi; Sakamoto, Masami; Shimizu, Waku; Uemura, Naohiro; Yoshida, Yasushi [Crystal Growth and Design, 2020, vol. 20, # 9, p. 5676 - 5681]

13
[ 621-23-8 ]
[ 75-36-5 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: acetyl chloride With aluminum (III) chloride In diethyl ether at 0 - 5℃; for 1h; Stage #2: 1,2,3-trimethoxybenzene In diethyl ether for 24h;	2.4. Synthesis of intermediate 2 (4,6-dimethoxy-2-hydroxyacetophenone) A solution of anhydrous aluminium chloride (AlCl3, 2.4 mmol) and substituted acetyl chloride (1.7 mmol) in dry ether (15 ml) was stirred at 0-5 C. After 1 h of stirring, a solution of trimethoxybenzene (1 mmol) in dry ether (5 ml) was added to the reaction vessel, and the stirring was continued for 24 h under anhydrous condition. The solution was left at room temperature for another 24 h. The separated aluminium chloride complex was decomposed with ice (approx. 20 g). The precipitates were filtered and recrystallized from aq. Methanol as colourless white powder.Yield 80%, m.p. 101-102 C. IR (KBr, cm1): 3011, 2830, 1588.1H NMR(400 MHz, DMSO, δ, ppm): 13.62 (s, 1H, OH); 6.07 (d, 1H, H-5,J 2.32 Hz); 6.05 (d, 1H, H-3, J 2.32 Hz); 3.66 (s, 3H, 4-OCH3); 3.61(s, 3H, 6-OCH3); 2.55 (s, 1H, CH3).
	With hydrogenchloride; aluminium trichloride; water 1.) Et₂O, reflux, 1 h then r.t., overnight; Yield given. Multistep reaction;
	With aluminum (III) chloride In diethyl ether at 0 - 20℃;

	With aluminum (III) chloride In diethyl ether
	With aluminum (III) chloride In diethyl ether
	With aluminum (III) chloride In diethyl ether
	With aluminum (III) chloride In diethyl ether at 0 - 20℃; Inert atmosphere;
	With aluminum (III) chloride In diethyl ether at 0 - 20℃; Inert atmosphere;

Reference： [1]Bansal, Yogita; Kaur, Sukhvir [Journal of the Indian Chemical Society, 2021, vol. 98, # 10]
[2]Ghosal, Shibnath; Mittal, Peeyush; Kumar, Yatendra; Singh, Sushil, K. [Phytochemistry, 1989, vol. 28, # 11, p. 3193 - 3196]
[3]Location in patent: scheme or table Bandgar, Babasaheb P.; Patil, Sachin A.; Gacche, Rajesh N.; Korbad, Balaji L.; Hote, Balwant S.; Kinkar, Santosh N.; Jalde, Shivkumar S. [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 2, p. 730 - 733] Location in patent: scheme or table Bandgar, Babasaheb P.; Patil, Sachin A.; Korbad, Balaji L.; Nile, Shivraj H.; Khobragade, Chandrahase N. [European Journal of Medicinal Chemistry, 2010, vol. 45, # 6, p. 2629 - 2633]
[4]Location in patent: body text Bandgar, Babasaheb P.; Hote, Baliram S.; Nile, Shivraj H. [Letters in drug design and discovery, 2011, vol. 8, # 8, p. 725 - 732]
[5]Location in patent: scheme or table Bandgar, Babasaheb P.; Hote, Baliram S.; Nile, Shivraj H. [Letters in drug design and discovery, 2011, vol. 8, # 8, p. 725 - 732]
[6]Bandgar, Babasaheb P.; Hote, Baliram S.; Dhole, Nagesh A.; Gacche, Rajesh N. [Medicinal Chemistry Research, 2012, vol. 21, # 9, p. 2292 - 2299]
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[8]Chavan, Hemant V.; Adsul, Laxman K.; Kotmale, Amol S.; Dhakane, Valmik D.; Thakare, Vishnu N.; Bandgar, Babasaheb P. [Journal of Enzyme Inhibition and Medicinal Chemistry, 2015, vol. 30, # 1, p. 22 - 31]

14
[ 90-24-4 ]
[ 613-45-6 ]
(E)-1-(2′-hydroxy-4′,6′-dimethoxyphenyl)-3-(2,4-dimethoxyphenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone With sodium hydroxide In methanol at 0℃; for 0.5h; Inert atmosphere; Stage #2: 2,4-Dimethoxybenzaldehyde In methanol Inert atmosphere;	The general method for the preparation of chalconesseries 1 and series 2 General procedure: Under N2 atmosphereand 0 OC, 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (1mmol, 1 eq) or1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-one (1mmol, 1 eq) was dissolved into10 ml MeOH, followed by the addition of 10 ml aq. 40% NaOH solution, themixture was stirred for about 30 min, then benzaldehydes (1.2 mmol, 1.2eq.)were added respectively. The mixture was stirred for overnight and monitored byTLC. After the starting material 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone or 1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-onewas consumed completely, the pH value was adjusted to 3 with aq. 3 N HClsolution, a large amount of yellowish solid formed. The crude product was filtrated,recrystallized from MeOH or purified by si-gel column chromatography to affordfine desired products.
	base-catalyzed Claisen-Schmidt reaction;
2.1 g	With sodium hydroxide In ethanol Ambient temperature; overnight;

	With potassium hydroxide In ethanol at 35 - 40℃; for 12h;
	In ethanol; water at 20℃; Alkaline conditions;	3.3. Synthesis of Flavokawain B derivatives General procedure: KOH (20% w/v aqueous solution) was added to a stirred solution of the appropriate acetophenone(1.0 eq) and a substituted benzaldehyde (1.25 eq.) in ethanol, and the mixture was stirred at roomtemperature for 48-72 h. The reaction mixture was cooled to 0 °C (ice-water bath) and acidified withHCl (10% v/v aqueous solution). In most cases, yellow precipitate was formed, filtered and washedwith 10% aqueous HCl solution. In the cases where an orange-yellow layer was formed, the mixturewas extracted with CH2Cl2 or ethyl acetate, the extracts was dried over Na2SO4 anhydrous and thesolvent was evaporated and crystalized with methanol or ethanol.

Reference： [1]Chen, Lijuan; Fan, Tiantian; Lei, Xiangui; Teichmann, Alexander Tobias; Wang, Amu; Wang, Chao; Wei, Zhe; Wieland, Frank Heinrich; Yang, Youzhe; Yin, Jinxiang; Zhou, Li; Zhu, Yue [European Journal of Medicinal Chemistry, 2020, vol. 193]
[2]Parmar, V. S.; Sharma, Sunil; Rathore, J. S.; Garg, Meenu; Gupta, Sandhya; et al. [Magnetic Resonance in Chemistry, 1990, vol. 28, # 5, p. 470 - 474]
[3]Pathak, V. P.; Khanna, R. N. [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1982, vol. 21, # 9, p. 891 - 892]
[4]Sekizaki, Haruo [Bulletin of the Chemical Society of Japan, 1988, vol. 61, p. 1407 - 1409]
[5]Bakar, Addila Abu; Akhtar, Muhammad Nadeem; Ali, Norlaily Mohd; Yeap, Swee Keong; Quah, Ching Kheng; Loh, Wan-Sin; Alitheen, Noorjahan Banu; Zareen, Seema; Ul-Haq, Zaheer; Shah, Syed Adnan Ali [Molecules, 2018, vol. 23, # 3]

15
[ 480-66-0 ]
[ 74-88-4 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium carbonate In acetone for 5h; Heating;
50%	With potassium carbonate In acetone for 5h; Reflux;
45%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 25℃;

36%	With potassium carbonate In acetone for 24h; Reflux; Darkness;	1 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethan-1-one 21 4.1.1 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethan-1-one 21 2,4,6-Trihydroxyacetophenone (2 g, 10.7 mmol), methyl iodide (2.70 mL, 42.9 mmol) and K2CO3 (2.96 g, 21.4 mmol) were dissolved in 50 mL of acetone. The mixture was heated to reflux for 24 h in the dark. The reaction mixture was filtered under vacuum, and the filtrate was evaporated under reduced pressure. The crude product was purified by flash chromatography using cyclohexane/ethyl acetate 95:5 as eluting system; 1.13 g of title compound 21 were obtained. Yield: 36%. 1H NMR (CDCl3) δ: 6.05 (d, J = 2.4 Hz, 1H, CH arom.); 5.92 (d, J = 2.4 Hz, 1H, CH arom.); 3.85 (s, 3H, OCH3); 3.81 (s, 3H, OCH3); 2.60 (s, 3H, CH3) ppm.
1.2 g	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 48h;	9 Heating 2, 4, 6-tri-hydroxy acetophenone 2g (12mmol), added to the 15mlDMF in, then adding CH 3 I1.72g (12.1mmol), K 2 CO 3 5 g. Stir at room temperature reaction 48h, is poured into the reaction liquid to the ice water, stirring 1h, then filter. Drying the obtained solid, recrystallized with ethanol, to obtain 2-hydroxy -4,6-di-methoxy acetophenone 1.2 g.
	With potassium carbonate	1 General procedure: First, with 2,4-dihydroxyacetophenone (a) or 2,4,6-trihydroxyacetophenone as raw material, The intermediate 2,4-dimethoxyacetophenone is obtained by methylation (b) or 2-hydroxy-4,6-dimethoxyacetophenone, Secondly, Use 2,4-dimethoxyacetophenone or 2-Hydroxy-4,6-dimethoxyacetophenone and different substituted benzaldehydes undergo condensation reactions to obtain target molecules and their analogs.

Reference： [1]Chandler, I. Michael; McIntyre, C. Rupert; Simpson, Thomas J. [Journal of the Chemical Society. Perkin transactions I, 1992, # 18, p. 2271 - 2284]
[2]Ndoile, Monica M.; Van Heerden, Fanie R. [Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 1346 - 1351]
[3]Zhang, Ni; Yang, Jin; Li, Ke; Luo, Jun; Yang, Su; Song, Jun-Rong; Chen, Chao; Pan, Wei-Dong [Molecules, 2019, vol. 24, # 15]
[4]Dei, Silvia; Romanelli, Maria Novella; Manetti, Dina; Chiaramonte, Niccolò; Coronnello, Marcella; Salerno, Milena; Teodori, Elisabetta [Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 1, p. 50 - 64]
[5]Current Patent Assignee: SECOND MILITARY MEDICAL UNIVERSITY - CN105669625, 2016, A Location in patent: Paragraph 0172
[6]Current Patent Assignee: FIRST HOSPITAL LANZHOU UNIV - CN112870363, 2021, A Location in patent: Paragraph 0094-0096

16
[ 90-24-4 ]
[ 1202-25-1 ]
1-(4-Dimethylamino-phenyl)-3-(2-hydroxy-4,6-dimethoxy-phenyl)-propane-1,3-dione [ No CAS ]

Reference： [1]Journal of Chemical Research, Miniprint,1982,p. 2461 - 2487

17
[ 90-24-4 ]
[ 7507-89-3 ]
[ 3602-54-8 ]

Yield	Reaction Conditions	Operation in experiment
1: 58% 2: 24%	With boron tribromide In dichloromethane at 20℃; for 3h;

Reference： [1]Bringmann, Gerhard; Menche, Dirk; Brun, Reto; Msuta, Thomas; Abegaz, Berhanu [European Journal of Organic Chemistry, 2002, # 6, p. 1107 - 1111]

18
[ 90-24-4 ]
[ 3602-54-8 ]

Yield	Reaction Conditions	Operation in experiment
70%	With aluminum (III) chloride In chlorobenzene for 1h; Reflux; Sealed tube; Schlenk technique;
60%	With aluminium trichloride In chlorobenzene for 1h; Heating;
44.1%	With aluminum (III) chloride In chlorobenzene for 1h; Reflux;

44.1%	With aluminum (III) chloride In chlorobenzene for 1h; Reflux;	To obtain 2,4-dihydroxy-6-methoxyacetophenone, anhydrous AlCl3 (11.0 g, 82.5 mmol) and 2,4- dimethoxy-6-hydroxyacetophenone (11.0 g, 56.1 mmol) were suspended in chlorobenzene (133 mL) and refluxed for 1 h. After cooling and evaporating of the solvent, an ice-cold H2O-HCl (1:1, 290 mL) solution was added to the residue and sonicated until the white precipitate seemed homogeneous. The solution was filtered and the solid was dissolved in EtOAc (200 mL) and extracted with an aqueous solution of NaOH (10%, 3 x 200 mL). The aqueous portions were mixed and neutralized with HCl (cone, 40 mL) to finally be extracted with EtOAc (2 x 250 mL) and recrystallized from the same solvent (44.1%).
	With aluminum (III) chloride In benzene for 1h; Reflux;
	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone With aluminum (III) chloride In chlorobenzene at 130℃; Stage #2: With hydrogenchloride In water; chlorobenzene at 20℃;	2.2.2. General Preparation for Chalcones A1-A7 Phloroglucinol 1 (18.9 g, 0.15 mol) and Ac2O (19 mL) were dissolved in ethyl acetate (100 mL), and BF3Et2O (15 mL) was added dropwise. The reaction mixture was heated at 40 °C for 10 h. Then, H2O (150 mL) was added and the mixture was extracted with EtOAc. After evaporation of the solvent, the solid was recrystallized from H2O to give 2 (Yellow solid, yield 90%). To a mixture of 2 (16.8 g, 0.1 mol) and K2CO3 (28 g, 0.2 mol) in ethanol (250 mL) was added TsOCH3 (38 mL, 0.25 mol) dropwise at room temperature, then refluxed at 80°C for 3 h. After 500 mL of water was added, standing overnight. The crude product was obtained by suction filtration and purified by column chromatography to obtain white crystals 3 of 13.3 g, yield 68%. To a stirred solution of 3 (1.96 g, 10 mmol) in chlorobenzene (50 mL) was added anhydrous AlCl3 (2 equ.). The reaction mixture was heated at 130 °C for 1 h. Then, the reaction was added 40 mL 10% hydrochloric acid solution, a large amount of white solid was produced at room temperature. After filtration, the solid was dissolved in EtOAc, and then extracted three times with 10% NaOH solution. The aqueous phase was combined and modulated PH = 6 with glacial acetic acid, which extracted with EtOAc (3 30 mL) and purified through a silica gel column to give intermediate 4.

Reference： [1]Wei, Yu; Tang, Jinghua; Cong, Xuefeng; Zeng, Xiaoming [Green Chemistry, 2013, vol. 15, # 11, p. 3165 - 3169]
[2]Kavvadias, Dominique; Sand, Philipp; Youdim, Kuresh A.; Qaiser, M. Zeeshan; Rice-Evans, Catherine; Baur, Roland; Sigel, Erwin; Rausch, Wolf-Dieter; Riederer, Peter; Schreier, Peter [British Journal of Pharmacology, 2004, vol. 142, # 5, p. 811 - 820]
[3]Location in patent: experimental part Aponte, José C.; Verástegui, Manuela; Málaga, Edith; Zimic, Mirko; Quiliano, Miguel; Vaisberg, Abraham J.; Gilman, Robert H.; Hammond, Gerald B. [Journal of Medicinal Chemistry, 2008, vol. 51, # 19, p. 6230 - 6234]
[4]Current Patent Assignee: THE JOHNS HOPKINS UNIVERSITY - WO2010/19861, 2010, A1 Location in patent: Page/Page column 38; 50
[5]Location in patent: scheme or table Aponte, Jose C.; Castillo, Denis; Estevez, Yannick; Gonzalez, German; Arevalo, Jorge; Hammond, Gerald B.; Sauvain, Michel [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 1, p. 100 - 103]
[6]Liu, Jianwen; Ma, Lei; Shi, Ximeng; Yin, Huanhuan; Zhao, Yuyu; Zhou, Licheng [Letters in drug design and discovery, 2020, vol. 17, # 10, p. 1270 - 1282]

19
[ 90-24-4 ]
[ 119-67-5 ]
(E)-2-(3-(2'-hydroxy-4',6'-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With sodium hydroxide In ethanol at 20℃;
44%	With sodium hydroxide In ethanol; water monomer at 20℃;
36%	With sodium hydroxide In methanol at 20℃;	General Procedure for the synthesis of chalcones (3A-L). General procedure: A solution of MeOH (25 mL), the corresponding acetophenones 1A-C (1 eq), theappropriate benzaldehyde 2A-G (1 eq), and excess of NaOH were stirred at room temperature, and the progress of the reaction was monitored by TLC. Upon completion, the excess of NaOH was neutralized by addition of HCl (1 M) with pH control. The solvent was evaporated, the residue was taken up in EtOAc, and the resulting solution was washed with distilled water. The organic layer was dried with MgSO4 and filtered, and the solventwas evaporated under reduced pressure. The crude product was purified by crystallization from methanol (MeOH) or by column chromatography.

Reference： [1]Boeck, Paula; Leal, Paulo C.; Yunes, Rosendo A.; Cechinel Filho, Valdir; Lopez, Silvia; Sortino, Maximiliano; Escalante, Andrea; Furlan, Ricardo L. E.; Zacchino, Susana [Archiv der Pharmazie, 2005, vol. 338, # 2-3, p. 87 - 95]
[2]Boeck, Paula; Bandeira Falcao, Camila Alves; Leal, Paulo Cesar; Yunes, Rosendo Augusto; Filho, Valdir Cechinel; Torres-Santos, Eduardo Caio; Rossi-Bergmann, Bartira [Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 5, p. 1538 - 1545]
[3]Bregier, Frédérique; Chaleix, Vincent; Lebouvier, Nicolas; Matsui, Mariko; Oelgemöller, Michael; Sinyeue, Cynthia; Sol, Vincent [Molecules, 2022, vol. 27, # 6]

20
[ 90-24-4 ]
[ 104-87-0 ]
[ 861107-94-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone; 4-methyl-benzaldehyde With potassium hydroxide In ethanol; water at 20℃; Stage #2: With hydrogenchloride In ethanol; water at 0℃;
71%	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone With sodium hydroxide In methanol at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-methyl-benzaldehyde In methanol Inert atmosphere;	The general method for the preparation of chalconesseries 1 and series 2 General procedure: Under N2 atmosphereand 0 OC, 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (1mmol, 1 eq) or1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-one (1mmol, 1 eq) was dissolved into10 ml MeOH, followed by the addition of 10 ml aq. 40% NaOH solution, themixture was stirred for about 30 min, then benzaldehydes (1.2 mmol, 1.2eq.)were added respectively. The mixture was stirred for overnight and monitored byTLC. After the starting material 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone or 1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-onewas consumed completely, the pH value was adjusted to 3 with aq. 3 N HClsolution, a large amount of yellowish solid formed. The crude product was filtrated,recrystallized from MeOH or purified by si-gel column chromatography to affordfine desired products.
70%	With sodium hydroxide In ethanol; water at 20℃;

56%	With potassium hydroxide In ethanol at 20℃; for 84h;
	With potassium hydroxide In ethanol; water at 20℃; for 3h;	2 KOH (10.0 g, 0.18 mol) was dissolved in the mixture of ethanol (80 mL) and water (20 mL) followed by the addition of l-(2-hydroxy-4,6-dimethoxyphenyl)ethanone, 5, (4.0 g, 0.02 mol) and 4-methylphenyl aldehyde (3.6 mL, 0.03 mol). The solution was stirred at room temperature for 3 hours. The pH was then adjusted to 8-9 with 2N HCl and the resulting solid was collected by filtration and washed with water until the pH of the washings tested neutral. The solid was dried to afford 5.5 g (92% yield) of the desired product as a yellow powder that was used for the next step without further characterization.
	In ethanol; water at 20℃; Alkaline conditions;	3.3. Synthesis of Flavokawain B derivatives General procedure: KOH (20% w/v aqueous solution) was added to a stirred solution of the appropriate acetophenone(1.0 eq) and a substituted benzaldehyde (1.25 eq.) in ethanol, and the mixture was stirred at roomtemperature for 48-72 h. The reaction mixture was cooled to 0 °C (ice-water bath) and acidified withHCl (10% v/v aqueous solution). In most cases, yellow precipitate was formed, filtered and washedwith 10% aqueous HCl solution. In the cases where an orange-yellow layer was formed, the mixturewas extracted with CH2Cl2 or ethyl acetate, the extracts was dried over Na2SO4 anhydrous and thesolvent was evaporated and crystalized with methanol or ethanol.

Reference： [1]Location in patent: experimental part Detsi, Anastasia; Majdalani, Maya; Kontogiorgis, Christos A.; Hadjipavlou-Litina, Dimitra; Kefalas, Panagiotis [Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 23, p. 8073 - 8085]
[2]Chen, Lijuan; Fan, Tiantian; Lei, Xiangui; Teichmann, Alexander Tobias; Wang, Amu; Wang, Chao; Wei, Zhe; Wieland, Frank Heinrich; Yang, Youzhe; Yin, Jinxiang; Zhou, Li; Zhu, Yue [European Journal of Medicinal Chemistry, 2020, vol. 193]
[3]Boeck, Paula; Bandeira Falcao, Camila Alves; Leal, Paulo Cesar; Yunes, Rosendo Augusto; Filho, Valdir Cechinel; Torres-Santos, Eduardo Caio; Rossi-Bergmann, Bartira [Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 5, p. 1538 - 1545]
[4]Mostahar, Sohel; Alam, Sayed; Islam, Azizul [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2006, vol. 45, # 6, p. 1478 - 1486]
[5]Current Patent Assignee: UNIVERSITY SYSTEM OF GEORGIA; SHANDONG UNIVERSITY - WO2010/129858, 2010, A1 Location in patent: Page/Page column 48-49
[6]Bakar, Addila Abu; Akhtar, Muhammad Nadeem; Ali, Norlaily Mohd; Yeap, Swee Keong; Quah, Ching Kheng; Loh, Wan-Sin; Alitheen, Noorjahan Banu; Zareen, Seema; Ul-Haq, Zaheer; Shah, Syed Adnan Ali [Molecules, 2018, vol. 23, # 3]

21
[ 90-24-4 ]
[ 20029-76-9 ]
[ 1621-83-6 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone; methyl 2,4,5-trimethoxybenzoate With lithium hexamethyldisilazane In tetrahydrofuran Stage #2: With sulfuric acid In acetic acid Heating; Further stages.;

Reference： [1]Laroche, Marie-France; Marchand, Arnaud; Duflos, Alain; Massiot, Georges [Tetrahedron Letters, 2007, vol. 48, # 51, p. 9056 - 9058]

22
[ 90-24-4 ]
[ 5128-44-9 ]

Reference： [1]Journal of Organic Chemistry,1998,vol. 63,p. 9300 - 9305
[2]Organic and Biomolecular Chemistry,2017,vol. 15,p. 5025 - 5032
[3]Synthesis,2018,vol. 50,p. 1610 - 1620
[4]Patent: WO2008/19292,2008,A2

23
[ 90-24-4 ]
[ 4049-38-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 2.0 g / alkali / ethanol / Ambient temperature 2: 2.5 g / ethanolic H₂SO₄ 3: 2 g / AlCl₃ / benzene

Reference： [1]Babber, Sunanda; Chandra, S.; Aggarwal, Anil K. [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1987, vol. 26, p. 797 - 798]

24
[ 480-66-0 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
94.4%	With potassium carbonate; dimethyl sulfate In acetone	P.7 Production Example 7 Production Example 7 To 50.1 g of 2',4',6'-trihydroxyacetophenone and 123.5 g of anhydrous potassium carbonate was added 500 ml of anhydrous acetone, and the mixture was stirred at room temperature for 30 minutes. Then, 78.9 g of dimethyl sulfate was added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours to effect a reaction. After the reaction, the reaction mixture was neutralized with dilute hydrochloric acid, extracted with diethyl ether and filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was recrystallized from n-hexane to obtain 55.2 g (yield=94.4%) of 2'-hydroxy-4',6'-dimethoxyacetophenone in the form of a colorless prism. Melting point: 77° to 78° C. Infrared absorption spectrum νmaxKBr cm-1: 1622, 1596, 1574, 1460, 1440, 1424, 1368, 1272, 1222, 1206, 1156, 1110, 1080, 894, 834, 596. Proton nuclear magnetic resonance (δ ppm in CDCl3): 2.61 (3H, s), 3.82 (3H, s), 3.85 (3H, s), 5.92 (1H, d, J=2.4 Hz), 6.05 (1H, d, J=2.4 Hz), 14.03 (1H, s, disappeared by addition of D2 O).
	With dimethylsulfide; potassium carbonate In acetone at 20℃;

Reference： [1]Current Patent Assignee: TSUMURA & CO. - US5106871, 1992, A
[2]Zheng, Can-Hui; Zhang, Meng; Chen, Hui; Wang, Chong-Qing; Zhang, Min-Min; Jiang, Jun-Hang; Tian, Wei; Lv, Jia-Guo; Li, Tie-Jun; Zhu, Ju; Zhou, You-Jun [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 19, p. 4672 - 4677]

25
[ 90-24-4 ]
[ 3535-37-3 ]
[ 71847-56-8 ]

Yield	Reaction Conditions	Operation in experiment
73%	With pyridine at 100℃; for 0.166667h;	15 Example 15 synthesis of 2-acetyl-3,5-dimethoxyphenyl 3,4-dimethoxybenzoate (12) 3,4-dimethoxybenzoyl chloride (10.55 g, 52.72 mmol, 1.2 eq) was added to a suspension of 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (8.62 g, 43.93 mmol, 1eq) in pyridine (120 mL). The reaction mixture was then stirred at 100°C for 10 mins. After cooling, to this suspension was added ethanol (100 mL) then water (100 mL). This solution was placed at 0°C and following scratching with a glass rod to afford white tiny crystals. The precipitate was filtered, washed with ethanol/water (1/1) (30 mL), dried to give 11.57 g (73%) of a white solid. Molecular Weight: 360.36 (C19H20O7). 1H-NMR δ (CDCl3, 300 MHz) ppm (J in Hz): 2.47 (s, 3H, CH3CO), 3.82 (s, 3H, MeO), 3.85 (s, 3H, MeO), 3.94 (s, 3H, MeO), 3.95 (s, 3H, MeO), 6.37 (d, 1H, J=2.2, H-3'), 6.39 (d, 1H, J=2.2, H-5'), 6.92 (d, 1H, J=8.5, H-5'), 7.61 (d, 1H, J=2.0, H-2'), 7.79 (dd, 1H, J=2.0, J=8.5, H-6').
60%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In pyridine at 50 - 75℃; for 1.25h;	4.1.2.1. 2-Acetyl-3, 5-dimethoxyphenyl 3, 4-dimethoxy benzoate (7) 4.1.2.1. 2-Acetyl-3, 5-dimethoxyphenyl 3, 4-dimethoxy benzoate (7). 1-(2-Hydroxy-4, 6-dimethoxyphenyl)ethanone (5) (1 g,5.09 mmol) was dissolved in pyridine (20 mL) and heated to 50°C. DBU (1% v/v of pyridine) was added and the mixture was stirred at 50°C for 30 min. 3,4-Dimethoxy benzoyl chloride (6) (1.53 g,7.63 mmol, 1.5 eq.) was added slowly over 15 min, the mixture was heated to 75°C and stirred for 1 h. The reaction was cooled to room temperature, acidified to pH 5 with 2 M HCl and extracted with EtOAc (2 x 20 mL). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the desired product. The pure compound was obtained as a white solid after purification by column chromatography [Hexane: CHCl3:EtOAc (3:6:1 v/v/v)]. Yield: 60%
	With pyridine at 110℃;	3.1.1. General Procedure for the Synthesis of Flavones General procedure: A mixture of the corresponding 2'-hydroxyacetophenone (1 equiv) and benzoyl chloride (1.1 equiv) in pyridine (10 mL/mmol of acetophenone) was heated at 110 °C for 2-3 h. The mixture was then poured into ice and HCl and extracted with ethyl acetate. The extract was washed with water and aqueous sodium carbonate and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to yield the crude phenolic ester. Powdered KOH (4-5 g) was added to a solution ofthe ester in pyridine (10-15 mL) and the mixture was stirred vigorously at 60 °C for 4 h. The mixture was then poured into ice and HCl, extracted with ethyl acetate and dried over sodium sulphate to give the 1,3-diketone in 60%-80% yield. To a yellow suspension of the 1,3-diketone (2 mmol) in glacial acetic acid (7 mL), concentrated sulfuric acid (a few drops) was added and refluxed overnight. The resulting mixture was cooled and water added until no further white precipitate was formed. The crude solid was filtered, purified using column chromatography and crystallised from methanol to give the flavone in 35%-55% yield.

With pyridine at 75℃; for 1h;

Reference： [1]Current Patent Assignee: AXOGLIA THERAPEUTICS - EP2112145, 2009, A1 Location in patent: Page/Page column 15
[2]Ravishankar, Divyashree; Watson, Kimberly A.; Boateng, Samuel Y.; Green, Rebecca J.; Greco, Francesca; Osborn, Helen M.I. [European Journal of Medicinal Chemistry, 2015, vol. 97, p. 259 - 274]
[3]Swaminathan, Meyyammai; Chee, Chin Fei; Chin, Sek Peng; Buckle, Michael J. C.; Rahman, Noorsaadah Abd.; Doughty, Stephen W.; Chung, Lip Yong [Molecules, 2014, vol. 19, # 7, p. 8933 - 8948]
[4]Ravishankar, Divyashree; Watson, Kimberly A.; Greco, Francesca; Osborn, Helen M. I. [RSC Advances, 2016, vol. 6, # 69, p. 64544 - 64556]

26
[ 621-59-0 ]
[ 90-24-4 ]
[ 38186-71-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium hydroxide In methanol at 20℃;	General Procedure for the Synthesis of Chalcones 1a-1d. General procedure: To a mixture of 2-hydroxy-4,6-dimethoxyacetophenone (1.0 equiv) and KOH (4 equiv) in MeOH was added the appropriate aryl aldehyde (1.0 equiv). The resulting mixture was stirred overnight at room temperature then an excess volume of HCl (3%) was added to form a yellow solid that was filtered, washed with water and methanol to give the corresponding product (1a-1d).
	Stage #1: isovanillin; 2-hydroxy-4,6-dimethoxyacetophenone In ethanol at 20℃; for 0.0833333h; Stage #2: With sodium hydroxide In ethanol at 20℃;
	With potassium hydroxide In ethanol at 0℃; for 24h;

Reference： [1]Kim, Sung Soo; Van Vo, Anh; Park, Haeil [Bulletin of the Korean Chemical Society, 2014, vol. 35, # 11, p. 3219 - 3223]
[2]Location in patent: experimental part Srinivasan, Balasubramanian; Johnson, Thomas E.; Lad, Rahul; Xing, Chengguo [Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7228 - 7235]
[3]Anand, Preet; Singh, Baldev [Medicinal Chemistry Research, 2013, vol. 22, # 4, p. 1648 - 1659]

27
[ 90-24-4 ]
[ 32723-67-4 ]
[ 1197288-77-9 ]

Yield	Reaction Conditions	Operation in experiment
20%	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone; 3-methyl-4-anisaldehyde In ethanol at 20℃; for 0.0833333h; Stage #2: With sodium hydroxide In ethanol at 20℃;

Reference： [1]Location in patent: experimental part Srinivasan, Balasubramanian; Johnson, Thomas E.; Lad, Rahul; Xing, Chengguo [Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7228 - 7235]

28
[ 90-24-4 ]
[ 613-45-6 ]
[ 76583-07-8 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium hydroxide In ethanol; water at 20℃; for 17h; Inert atmosphere;	3 Producing 3-(2,4-Dimethoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one (8) Under an argon atmosphere, the acetophenone derivative (6) (4.80 g, 24.5 mmol, 1.0 eq.) and 2,4-Dimethoxybenzaldehyde (7) (6.01 g, 36.7 mmol, 1.5 eq.) were solubilised in ethanol (150 ml). A solution of NaOH (8.80 g, 220 mmol, 9.0 eq.) in distilled water (38 ml) was added dropwise. The reaction mixture was stirred for 17 hrs at room temperature. Subsequently, 1 M aqueous HCl solution (350 ml) was added and stirred for another 15 min. The solution was extracted three times with ethyl acetate (250 ml, respectively). The combined organic phases were driedsodium sulphate, and the solvent removed in high vacuum. After column-chromatographic cleaning on silica gel [Petrol ether/Ethyl acetate (3:1-1:1)] the chalcone (8) (5.87 g, 17.0 mmol, 70%) was obtained as yellow solid. DC [Petrol ether/Ethyl acetate (4:1)]1: Rf=0.32. Melting point.: 126-129° C. 1H-NMR (400 MHz, CDCl3): d=14.54 (s, 1H, 2'-OH), 8.10 (d, J=15.7 Hz, 1H, ß-H), 7.90 (d, J=15.7 Hz, 1H, a-H), 7.54 (d, J=8.6 Hz, 1H, 6-H), 6.53 (dd, J=8.6, 2.4 Hz, 1H, 5-H), 6.47 (d, J=2.4 Hz, 1H, 3-H), 6.10 (d, J=2.4 Hz, 1H, 3'-H), 5.95 (d, J=2.4 Hz, 1H, 5'-H), 3.90 (s, 3H, 6'-OCH3), 3.89 (s, 3H, 2-OCH), 3.85 (s, 3H, 4-OCH3), 3.83 (s, 3H, 4'-OCH3). 13C-NMR (100 MHz, CDCl3): d=193.0 (C-0), 168.3 (C-6'), 165.8 (C-4'), 162.8 (C-4), 162.4 (C-2'), 160.2 (C-2), 138.3 (C-ß), 130.4 (C-6), 125.3 (C-a), 117.8 (C-1), 106.5 (C-1'), 105.5 (C-5), 98.4 (C-3), 93.8 (C-5'), 91.1 (C-3'), 55.7 (2-OCH3), 55.5 (2-OCH3), 55.5 (4'-OCH3), 55.4 (4-OCH). IR (Diamant-ATR): V=3120 (w, br.), 3082 (w, br.), 3000 (w), 2942 (m, br.), 2840 (w, br.), 1604 (s), 1547 (s), 1502 (s), 1451 (m), 1437 (m), 1414 (m), 1343 (m), 1315 (m), 1293 (m), 1268 (s), 1206 (s), 1158 (s), 1108 (s), 1057 (m), 1028 (s), 980 (m), 940 (m), 867 (m), 849 (m), 814 (s), 795 (s), 767 (m), 720 (m), 697 (m), 674 (m), 648 (m), 621 (m), 604 (m), 582 (m), 563 (m). UV (MeOH): λmax (Ig ε)=379 (4.52), 251 (3.95), 207 (4.60). MS (EI): m/z (%)=345 [M+H]+ (47), 367 [M+Na]+ (67), 71 1 [2M+Na]+ (100). HRMS (ESI+): m/z=71 1.24176 (0.1 ppm, ber.: 71 1.24120 [2M+Na]+).
	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone; 2,4-Dimethoxybenzaldehyde With potassium hydroxide In methanol; water at 75℃; for 3h; Stage #2: With hydrogenchloride In methanol; water Stage #3: In N,N-dimethyl-formamide at 20℃; for 2h;
	With potassium hydroxide In methanol; water at 0 - 20℃; for 51h; Inert atmosphere;	General procedure: A solution of acetophenone (1.2 mmol) and aldehyde (1.4 mmol) in methanol (3 ml) was added dropwise under nitrogen to a stirred solution of KOH (26.7 mmol) in water (1.5 ml) that had been cooled to 0° C in an ice bath. The reaction mixture was held at 0 °C for 3 h and then at room temperature for 2 days. The mixture was poured into ice-water, adjusted to pH 3-4 with 1 M HCl, and then extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous Na2SO4. After concentration under reduced pressure,the resultant solid was recrystallized from a solution hexane and ethyl acetate.

Reference： [1]Current Patent Assignee: ORSATEC - US2020/308131, 2020, A1 Location in patent: Paragraph 0035
[2]Location in patent: experimental part Alvim, Joel; Severino, Richele P.; Marques, Emerson F.; Martinelli, Ariane M.; Vieira, Paulo C.; Fernandes, Joao B.; Da Silva, M. Fatima Das G. F.; Correa, Arlene G. [Journal of Combinatorial Chemistry, 2010, vol. 12, # 5, p. 687 - 695]
[3]Jeong, Hye-Jin; Lee, Chang Seok; Choi, Janggyoo; Hong, Yong Deog; Shin, Song Seok; Park, Jun Seong; Lee, John Hwan; Lee, Seokyong; Yoon, Kee Dong; Ko, Jaeyoung [Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 4, p. 799 - 802]

29
[ 90-24-4 ]
[ 66-99-9 ]
[ 912547-82-1 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium hydroxide In methanol at 50℃; for 12h; Inert atmosphere;	General Procedure for Preparing Compounds (1a-k), as Exemplified for Compound 1k. General procedure: A mixture of compound 3 (0.2 g, 1.02 mmol), 4-methoxy-1-naphthaldehyde (0.19 g,1.02 mmol), and potassium hydroxide (1.0 g) in 10 mL ofmethanol was stirred at 50 °C for 12 h. The mixture wasneutralized with 6 N HCl to pH 6 and then extracted with ethyl aceatate. The organic layer was washed with saturated NaHCO3 solution three times, dried over Na2SO4, and concentrated under reduced pressure, and purified by MPLC to afford compound 1k in 18% yield as yellow solid.
	With potassium hydroxide In methanol at 20℃; for 24h;
	With potassium hydroxide In ethanol; water at 20℃; for 24h;

	With potassium hydroxide In ethanol
	With sodium hydroxide In methanol at 20℃;

Reference： [1]Seo, Young Ho; Park, Sun You [Bulletin of the Korean Chemical Society, 2014, vol. 35, # 4, p. 1154 - 1158]
[2]Location in patent: scheme or table Pedrini, Fernanda Spezia; Chiaradia, Louise Domeneghini; Licinio, Marley Aparecida; De Moraes, Ana Carolina Rabello; Curta, Juliana Costa; Costa, Aline; Mascarello, Alessandra; Creczinsky-Pasa, Tania Beatriz; Nunes, Ricardo Jose; Yunes, Rosendo Augusto; Santos-Silva, Maria Claudia [Journal of Pharmacy and Pharmacology, 2010, vol. 62, # 9, p. 1128 - 1136]
[3]Ahn, Seunghyun; Shin, Soon Young; Jung, Yearam; Jung, Hyeryoung; Kim, Beom Soo; Koh, Dongsoo; Lim, Yoongho [Magnetic Resonance in Chemistry, 2016, vol. 54, # 5, p. 382 - 390]
[4]Koh, Dongsoo; Shin, Soon Young; Sung, Jiha; Ahn, Seunghyun; Lim, Yoongho [Magnetic Resonance in Chemistry, 2017, vol. 55, # 9, p. 856 - 863]
[5]Kasashima, Yoshio; Mino, Takashi; Sakamoto, Masami; Shimizu, Waku; Uemura, Naohiro; Yoshida, Yasushi [Crystal Growth and Design, 2020, vol. 20, # 9, p. 5676 - 5681]

30
[ 90-24-4 ]
[ 2215-76-1 ]
[ 1266348-22-4 ]

Yield	Reaction Conditions	Operation in experiment
41%	With potassium hydroxide In tetrahydrofuran; methanol at 20℃; for 48h;

Reference： [1]Location in patent: experimental part Gurung, Santosh K.; Kim, Soo Bae; Park, Haeil [Archives of Pharmacal Research, 2010, vol. 33, # 12, p. 1919 - 1926]

31
[ 480-66-0 ]
[ 80-48-8 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium carbonate; In ethanol; at 80℃;	16.8 g (0.1 mol) in a dry 150 mL three-necked flask2,4,6-trihydroxyacetophenone (intermediate S5),Add 250mL of ethanol solution,Further, 28 g (0.2 mol) of potassium carbonate and 38 mL (0.25 mol) of methyl p-toluenesulfonate were added.Heat to 80 C,Reflux for 3h,Stop the reaction,The reaction solution was diluted with 500 mL of water and allowed to stand overnight.Pumping to get a crude product,Recrystallization from methanol gave the compound recrystallized to give white crystals, 13.3 g.The yield was 68%.

Reference： [1]Organic and Biomolecular Chemistry,2017,vol. 15,p. 5025 - 5032
[2]Journal of Chemical Research,2012,vol. 36,p. 121 - 122
[3]Patent: CN109251189,2019,A .Location in patent: Paragraph 0070-0074; 0084-0086; 0093; 0094
[4]European Journal of Medicinal Chemistry,2019,vol. 180,p. 350 - 366

32
[ 90-24-4 ]
[ 1253584-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: potassium carbonate / dimethyl sulfoxide / 2 h / 110 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.5 h / -50 °C 2.2: 2 h / 20 °C 3.1: hydroxylamine hydrochloride / ethanol / 2 h / Reflux 4.1: boron tribromide / dichloromethane / 120 h / 0 - 20 °C 5.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl acetamide / 0.25 h / 20 °C 5.2: 20 °C

Reference： [1]Brasca, Maria Gabriella; Mantegani, Sergio; Amboldi, Nadia; Bindi, Simona; Caronni, Dannica; Casale, Elena; Ceccarelli, Walter; Colombo, Nicoletta; De Ponti, Anna; Donati, Daniele; Ermoli, Antonella; Fachin, Gabriele; Felder, Eduard R.; Ferguson, Ronald D.; Fiorelli, Claudio; Guanci, Marco; Isacchi, Antonella; Pesenti, Enrico; Polucci, Paolo; Riceputi, Laura; Sola, Francesco; Visco, Carlo; Zuccotto, Fabio; Fogliatto, Gianpaolo [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 22, p. 7047 - 7063]

33
[ 90-24-4 ]
[ 123-08-0 ]
[ 37308-75-1 ]

Yield	Reaction Conditions	Operation in experiment
51%	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone With sodium hydroxide In methanol at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-hydroxy-benzaldehyde In methanol Inert atmosphere;	The general method for the preparation of chalconesseries 1 and series 2 General procedure: Under N2 atmosphereand 0 OC, 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (1mmol, 1 eq) or1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-one (1mmol, 1 eq) was dissolved into10 ml MeOH, followed by the addition of 10 ml aq. 40% NaOH solution, themixture was stirred for about 30 min, then benzaldehydes (1.2 mmol, 1.2eq.)were added respectively. The mixture was stirred for overnight and monitored byTLC. After the starting material 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone or 1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-onewas consumed completely, the pH value was adjusted to 3 with aq. 3 N HClsolution, a large amount of yellowish solid formed. The crude product was filtrated,recrystallized from MeOH or purified by si-gel column chromatography to affordfine desired products.
35%	With potassium hydroxide In methanol at 50℃; for 12h; Inert atmosphere;	General Procedure for Preparing Compounds (1a-k), as Exemplified for Compound 1k. General procedure: A mixture of compound 3 (0.2 g, 1.02 mmol), 4-methoxy-1-naphthaldehyde (0.19 g,1.02 mmol), and potassium hydroxide (1.0 g) in 10 mL ofmethanol was stirred at 50 °C for 12 h. The mixture wasneutralized with 6 N HCl to pH 6 and then extracted with ethyl aceatate. The organic layer was washed with saturated NaHCO3 solution three times, dried over Na2SO4, and concentrated under reduced pressure, and purified by MPLC to afford compound 1k in 18% yield as yellow solid.
	With potassium hydroxide In methanol; water at 0 - 20℃; for 51h; Inert atmosphere;	General procedure: A solution of acetophenone (1.2 mmol) and aldehyde (1.4 mmol) in methanol (3 ml) was added dropwise under nitrogen to a stirred solution of KOH (26.7 mmol) in water (1.5 ml) that had been cooled to 0° C in an ice bath. The reaction mixture was held at 0 °C for 3 h and then at room temperature for 2 days. The mixture was poured into ice-water, adjusted to pH 3-4 with 1 M HCl, and then extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous Na2SO4. After concentration under reduced pressure,the resultant solid was recrystallized from a solution hexane and ethyl acetate.

34
[ 480-66-0 ]
[ 616-38-6 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium carbonate In dimethyl sulfoxide at 120℃;	2-Hydroxy-4,6-dimethoxyacetophenone (3): Method (b2) Compound 4 (2.5 g, 0.015 mol), K2CO3 (1.7 g, 0.01 mol), and DMC (7.5 mL, 0.09 mol) in DMSO (20 mL) were heated at 120 °C until TLC showed that compound 4 had disappeared. Then the mixture was cooled to room temperature and H2O (30 mL) was added. The reaction mixture was neutralised to pH 3-4 with 10% aqueous HCl and the precipitate was filtered and recrystallised from methanol to give compound 3 (2.0 g), yield 69%, white crystals, m.p. 81-82 °C (lit.22 80-81 °C) 1H NMR (500 MHz, DMSO-d6) (δ, ppm): 2.60 (s, 3H,COCH3), 3.81 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 5.92 (s, 1H, ArH), 6.05 (s, 1H, ArH), 14.02 (s, 1H, OH). IR νmax (KBr/cm-1): 3461 (OH), 1619 (C=O).

Reference： [1]Cui, Wei; Zhang, Ji; Wang, Qian; Gao, Kai; Zhang, Wei; Yang, Jian [Journal of Chemical Research, 2014, vol. 38, # 11, p. 686 - 689]

35
[ 90-24-4 ]
[ 22927-13-5 ]
C₁₉H₂₀O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In methanol; water; at 0 - 20℃; for 51h;Inert atmosphere;	General procedure: A solution of acetophenone (1.2 mmol) and aldehyde (1.4 mmol) in methanol (3 ml) was added dropwise under nitrogen to a stirred solution of KOH (26.7 mmol) in water (1.5 ml) that had been cooled to 0 C in an ice bath. The reaction mixture was held at 0 C for 3 h and then at room temperature for 2 days. The mixture was poured into ice-water, adjusted to pH 3-4 with 1 M HCl, and then extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous Na2SO4. After concentration under reduced pressure,the resultant solid was recrystallized from a solution hexane and ethyl acetate.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 799 - 802

36
[ 90-24-4 ]
[ 50276-96-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium hydroxide / methanol / 20 °C 2.1: iodine / dimethyl sulfoxide / 100 °C 3.1: potassium carbonate / N,N-dimethyl acetamide; toluene / 4 h / 140 °C / Inert atmosphere 3.2: 12 h / 160 °C / Inert atmosphere 4.1: boron tribromide / dichloromethane / 24 h / 0 - 60 °C / Reflux
	Multi-step reaction with 4 steps 1.1: potassium hydroxide / methanol / 20 °C 2.1: iodine / dimethyl sulfoxide / 100 °C 3.1: potassium carbonate / N,N-dimethyl acetamide; toluene / 4 h / 140 °C / Inert atmosphere 3.2: 12 h / 160 °C / Inert atmosphere 4.1: boron tribromide / dichloromethane / 24 h / 0 - 60 °C / Reflux
	Multi-step reaction with 4 steps 1: potassium hydroxide / methanol / 20 °C 2: iodine / dimethyl sulfoxide / 100 °C 3: copper(l) iodide; caesium carbonate / 1,4-dioxane / 24 h / Reflux 4: boron tribromide / dichloromethane / 24 h / 0 - 60 °C / Reflux

	Multi-step reaction with 4 steps 1: potassium hydroxide / methanol / 20 °C 2: iodine / dimethyl sulfoxide / 100 °C 3: copper(l) iodide; caesium carbonate / 1,4-dioxane / 24 h / Reflux 4: boron tribromide / dichloromethane / 24 h / 0 - 60 °C / Reflux
	Multi-step reaction with 4 steps 1: potassium hydroxide / methanol / 20 °C 2: iodine / dimethyl sulfoxide / 100 °C 3: copper(l) iodide; caesium carbonate / 1,4-dioxane / 24 h / Reflux 4: boron tribromide / dichloromethane / 24 h / 0 - 60 °C / Reflux
	Multi-step reaction with 4 steps 1: potassium hydroxide / methanol / 20 °C 2: iodine / dimethyl sulfoxide / 100 °C 3: copper(l) iodide; caesium carbonate / 1,4-dioxane / 24 h / Reflux 4: boron tribromide / dichloromethane / 24 h / 0 - 60 °C / Reflux

Reference： [1]Kim, Sung Soo; Van Vo, Anh; Park, Haeil [Bulletin of the Korean Chemical Society, 2014, vol. 35, # 11, p. 3219 - 3223]
[2]Kim, Sung Soo; Van Vo, Anh; Park, Haeil [Bulletin of the Korean Chemical Society, 2014, vol. 35, # 11, p. 3219 - 3223]
[3]Kim, Sung Soo; Van Vo, Anh; Park, Haeil [Bulletin of the Korean Chemical Society, 2014, vol. 35, # 11, p. 3219 - 3223]
[4]Kim, Sung Soo; Van Vo, Anh; Park, Haeil [Bulletin of the Korean Chemical Society, 2014, vol. 35, # 11, p. 3219 - 3223]
[5]Kim, Sung Soo; Van Vo, Anh; Park, Haeil [Bulletin of the Korean Chemical Society, 2014, vol. 35, # 11, p. 3219 - 3223]
[6]Kim, Sung Soo; Van Vo, Anh; Park, Haeil [Bulletin of the Korean Chemical Society, 2014, vol. 35, # 11, p. 3219 - 3223]

37
[ 90-24-4 ]
terbium(III) nitrate pentahydrate [ No CAS ]
[ 119-91-5 ]
C₄₈H₄₅N₂O₁₂Tb [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium hydroxide In ethanol; water at 35℃; for 3h;	2 Synthesis of complex Tb(HDAP)₃biq (1) The complex Tb(HDAP)3biq was prepared by mixing ethanolic solutions of HDAP (0.58 g, 3 mmol) and biq (1 mmol) with an aqueous solution of Tb(NO3)35H2O (1 mmol) with constant stirring on magnetic stirrer. The pH of mixture was adjusted to 7-8 with 0.05 M NaOH solution. This resulted into formation of white precipitates. These precipitates were stirred for 3 h at 35 °C and then allowed to stand for 1 h. The precipitates were filtered, washed with water, ethanol, dried in air and then in vacuum desiccators to obtain complex Tb(HDAP)3biq (1). White powder with 86% yield was obtained. The elemental analysis data of Tb(HDAP)3biq (C48H45O12N2Tb) is found (calculated)% C, 57.56 (57.60); H, 4.54 (4.50); N, 2.78 (2.80). IR (KBr):cm-1 3008 (m), 2947 (m), 1616 (s), 1593 (s), 1534 (s), 1516 (s), 1496 (s), 1418 (m), 1384 (s), 1328 (m),1263 (m), 1220 (s), 1212 (m), 1159 (m), 1128 (s), 1057 (m), 1013 (w), 936 (m), 869 (m), 839 (m), 829 (s), 787 (m), 738 (s), 625 (m), 538 (w), 471 (w). 1H NMR (400 MHz, DMSO): δ 2.67 (bs, 9H, CH3), 3.52 (bs, 18H, OCH3), 6.31 (bs, 6H, Ar-H), 7.63 (d, 2H, biq), 7.84 (d, 2H, biq), 8.02 (d, 2H, biq), 8.21 (d, 2H, biq), 8.49 (d, 2H, biq), 8.83 (d, 2H, biq).

Reference： [1]Poonam; Kumar, Rajesh; Boora, Priti; Khatkar, Anurag; Khatkar; Taxak [Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2016, vol. 152, p. 304 - 310]

38
[ 90-24-4 ]
[ 3002-81-1 ]
terbium(III) nitrate pentahydrate [ No CAS ]
C₄₄H₄₅N₂O₁₂Tb [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium hydroxide In ethanol; water at 35℃; for 3h;	3 Synthesis of complex Tb(HDAP)₃biq (1) General procedure: The complex Tb(HDAP)3biq was prepared by mixing ethanolic solutions of HDAP (0.58 g, 3 mmol) and biq (1 mmol) with an aqueous solution of Tb(NO3)35H2O (1 mmol) with constant stirring on magnetic stirrer. The pH of mixture was adjusted to 7-8 with 0.05 M NaOH solution. This resulted into formation of white precipitates. These precipitates were stirred for 3 h at 35 °C and then allowed to stand for 1 h. The precipitates were filtered, washed with water, ethanol, dried in air and then in vacuum desiccators to obtain complex Tb(HDAP)3biq (1). White powder with 86% yield was obtained. The elemental analysis data of Tb(HDAP)3biq (C48H45O12N2Tb) is found (calculated)% C, 57.56 (57.60); H, 4.54 (4.50); N, 2.78 (2.80).

Reference： [1]Poonam; Kumar, Rajesh; Boora, Priti; Khatkar, Anurag; Khatkar; Taxak [Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2016, vol. 152, p. 304 - 310]

39
2,4,6-trihydroxyacetophenone monohydrate [ No CAS ]
[ 18107-18-1 ]
[ 90-24-4 ]
[ 7507-89-3 ]
[ 3602-54-8 ]

Yield	Reaction Conditions	Operation in experiment
1: 43% 2: 6% 3: 5%	Stage #1: 2,4,6-trihydroxyacetophenone monohydrate; diazomethyl-trimethyl-silane In methanol; chloroform at 0 - 20℃; for 24h; Stage #2: With acetic acid In methanol; chloroform at 0℃; for 0.5h;

Reference： [1]Grayfer, Tatyana D.; Grellier, Philippe; Mouray, Elisabeth; Dodd, Robert H.; Dubois, Joëlle; Cariou, Kevin [Organic Letters, 2016, vol. 18, # 4, p. 708 - 711]

40
[ 90-24-4 ]
[ 5651-83-2 ]
(2E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium hydroxide In ethanol; water at 20℃;	4.4 General procedure for the synthesis of chalcones (4, 6 and 7) General procedure: A mixture of the 1-(2-hydroxy-4,6-dimethoxyphenyl)ethan-1-one (1, 1 eq) and the corresponding substituted benzaldehyde (3a, 3b and 2c, 1 eq) in ethanol (4.0 mL/mmol of acetophenone 1) was stirred at room temperature during 10 min. Then, the aqueous solution of KOH (3 eq, 20% w/v) was added to reaction mixture. The reaction mixture was stirred at room temperature until benzaldehyde consumption as monitored by TLC. After completion of the reaction, HCl (10% v/v aqueous solution) was added until neutral. In all cases a yellow precipitate of chalcone was formed, which was filtered and dried. The products were purified using column chromatography with an eluent of chloroform: hexane (1: 1). 4.4.1 (2E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]prop-2-en-1-one (4) Yellow solid, Yield: 66%, M.P: 145-147 °C; IR (KBr) cm-1: 3238, 2918, 2854, 2122, 1618, 1579, 1546, 1505, 1438, 1361, 1256, 1205, 1136, 1112, 1012, 980, 812, 757; 1H NMR (DMSO-d6, 400 MHz, ppm) δ: 13.35 (s, 1H, -OH), 7.67-7.63 (d, J = 15.36 Hz, 1H, -COC=CH), 7.61-7.57 (d, J = 15.40 Hz, 1H, -COCH=C), 7.32 (s, 1H, Ar-H), 7.30-7.28 (d, J = 8.08 Hz, 1H, Ar-H), 7.08-7.06 (d, J = 8.80 Hz, 1H, Ar-H), 6.14 (s, 1H, Ar-H), 6.11 (s, 1H, Ar-H), 4.85-4.84 (d, J = 2.20 Hz, 2H, -OCH2), 3.87, 383, 3.80 (s, each 3H, 3 * -OCH3), 3.61-3.59 (t, J = 2.20 Hz, 1H, -C≡CH); 13C NMR (DMSO-d6, 100 MHz, ppm) δ: 192.24 (-CO); 165.23; 165.13; 161.69; 149.28; 148.63; 142.67; 128.51; 125.69; 122.14; 113.73; 111.30; 106.44; 93.85; 91.00; 78.93 (-C≡CH); 78.52 (-C≡CH); 56.10 (-OCH2); 55.97 (-OCH3); 55.58 (-OCH3); 55.54 (-OCH3).

Reference： [1]Kant, Rama; Kumar, Dharmendra; Agarwal, Drishti; Gupta, Rinkoo Devi; Tilak, Ragini; Awasthi, Satish Kumar; Agarwal, Alka [European Journal of Medicinal Chemistry, 2016, vol. 113, p. 34 - 49]

41
[ 480-66-0 ]
[ 333-27-7 ]
[ 90-24-4 ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate In acetone at 0 - 70℃; for 10h;
88%	With potassium carbonate In acetone for 3h; Reflux;

Reference： [1]Lu, Kui; Li, Ming; Huang, Yuna; Sun, Yuanyuan; Gong, Zhi; Wei, Qijun; Zhao, Xia; Zhang, Yongmin; Yu, Peng [Organic and Biomolecular Chemistry, 2019, vol. 17, # 35, p. 8206 - 8213]
[2]Arai, Midori A.; Kofuji, Yuuki; Tanaka, Yuuki; Yanase, Natsuki; Yamaku, Kazuki; Fuentes, Rolly G.; Karmakar, Utpal Kumar; Ishibashi, Masami [Organic and Biomolecular Chemistry, 2016, vol. 14, # 11, p. 3061 - 3068]

42
[ 90-24-4 ]
[ 586-89-0 ]
(E)-4-(3-(2-hydroxy-4,6-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With sodium hydroxide In methanol at 20℃;	2.1. general procedures for synthesis of FKd General procedure: In 20 mL of MeOH, corresponding acetophenones (1.5 mmol, 2-hydroxy-4,6-dimethoxyacetophenone for compounds 1-10, and 2,4,6-trimethoxy-2-hydroxyacetophenone for compounds 11-22),benzaldehyde derivatives (1.5 mmol) and NaOH (2.5 equivalentof acetophenone) were dissolved. The reaction mixture was stirred at room temperature until the completion of the reaction which was monitored by TLC. The excess of NaOH was neutralized by addition of HCl 0.1 M. Compounds 6, 7 and 19 were directly purified by Sephadex column chromatography. For the others, MeOH was evaporated and the solid residue was dissolved in CH2Cl2(50 mL) and washed with distilled water (3 50 mL). The organic phase was dried with MgSO4, filtered and CH2Cl2 was removed under vacuum. Finally, FKd were purified by column chromatography or by crystallization in MeOH or EtOAc. Purity of FKd reached at least 95%, as confirmed by HPLC. All chemicals were purchased from Sigma-Aldrich (Saint-Louis, MO, USA) and HPLC quality solvents from Fischer Chemicals (Leicestershire, UK). Mass spectral(MS) analysis was carried on a Bruecker Esquire HCT Ultra MSinstrument equipped with an electrospray ion source. High resolution mass spectral (HRMS) analysis was carried on a Waters SYNAPT G2 HDMS instrument equipped with an atmospheric pressure ionization source. NMR analyses were performed on a Bruecker Avance III spectrometer. Melting points were determinedon an Electrothermal 9100 apparatus.

Reference： [1]Thieury, Charlotte; Lebouvier, Nicolas; Le Guével, Rémy; Barguil, Yann; Herbette, Gaëtan; Antheaume, Cyril; Hnawia, Edouard; Asakawa, Yoshinori; Nour, Mohammed; Guillaudeux, Thierry [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 6, p. 1817 - 1829]

43
[ 90-24-4 ]
[ 2124-31-4 ]
(E)-3-(4-(dimethylamino)phenyl)-1-(2'-hydroxy-4',6'-dimethoxyphenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium hydroxide In methanol at 20℃;	2.1. general procedures for synthesis of FKd General procedure: In 20 mL of MeOH, corresponding acetophenones (1.5 mmol, 2-hydroxy-4,6-dimethoxyacetophenone for compounds 1-10, and 2,4,6-trimethoxy-2-hydroxyacetophenone for compounds 11-22),benzaldehyde derivatives (1.5 mmol) and NaOH (2.5 equivalentof acetophenone) were dissolved. The reaction mixture was stirred at room temperature until the completion of the reaction which was monitored by TLC. The excess of NaOH was neutralized by addition of HCl 0.1 M. Compounds 6, 7 and 19 were directly purified by Sephadex column chromatography. For the others, MeOH was evaporated and the solid residue was dissolved in CH2Cl2(50 mL) and washed with distilled water (3 50 mL). The organic phase was dried with MgSO4, filtered and CH2Cl2 was removed under vacuum. Finally, FKd were purified by column chromatography or by crystallization in MeOH or EtOAc. Purity of FKd reached at least 95%, as confirmed by HPLC. All chemicals were purchased from Sigma-Aldrich (Saint-Louis, MO, USA) and HPLC quality solvents from Fischer Chemicals (Leicestershire, UK). Mass spectral(MS) analysis was carried on a Bruecker Esquire HCT Ultra MSinstrument equipped with an electrospray ion source. High resolution mass spectral (HRMS) analysis was carried on a Waters SYNAPT G2 HDMS instrument equipped with an atmospheric pressure ionization source. NMR analyses were performed on a Bruecker Avance III spectrometer. Melting points were determinedon an Electrothermal 9100 apparatus.

44
[ 90-24-4 ]
[ 39828-35-8 ]
2-acetyl-3,5-dimethoxyphenyl 2,4-dimethoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.0833333h; Stage #2: 2,4-dimethoxybenzoyl chloride In tetrahydrofuran; mineral oil at 0 - 20℃; for 3h;	3 4.3. 2-Acetyl-3,5-dimethoxyphenyl 2,4-dimethoxybenzoate (5) To a solution of 7 (11.3 g, 57.63 mmol) in THF (30 mL), NaH (60 %, 3.46 g, 86.45 mmol) was added at 0 °C. After stirring the mixture for 5 min, 2,4-dimethoxybenzoyl chloride (13.9 g, 69.16 mmol) was added dropwise. The resulting solution was slowly warmed to room temperature over a period of 3 h and then poured into ice water (30 mL), followed by extraction with EtOAc (3 * 30 mL). The organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was then purified by silica gel column chromatography (PE/EA 10:1) to afford 5 (20.33 g, 98%) as a white solid, mp 105-106 °C. 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.8 Hz, 1H, Ar-H), 6.55 (dd, J = 8.8, 2.0 Hz, 1H, Ar-H), 6.50 (d, J = 2.0 Hz, 1H, Ar-H), 6.38 (s, 2H, Ar-H), 3.90 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 2.47 (s, 3H, COCH3). 13C NMR (150 MHz, CDCl3): δ 199.8, 164.9, 163.1, 162.1, 161.9, 158.7, 149.7, 134.7, 117.5, 110.8, 104.7, 100.1, 98.9, 96.4, 56.0, 55.8, 55.6, 55.5, 31.9. IR (neat): ν 2943, 1737, 1610, 1157, 1096, 830, 761 cm-1. MS (ESI): [M+H]+: 361.1. HRMS (ESI) calcd mass for C19H20NaO7 [M+Na]+ 383.1106, found 383.1101.

Reference： [1]Sheng, Xiao; Jia, Xin-Yu; Tang, Fei; Wang, Yang; Hou, Ai-Jun [Tetrahedron, 2017, vol. 73, # 25, p. 3485 - 3491]

45
[ 90-24-4 ]
[ 94-30-4 ]
[ 76288-41-0 ]

Yield	Reaction Conditions	Operation in experiment
74%	With sodium hydride In tetrahydrofuran at 70℃; for 2h;

Reference： [1]Han, Jie; Wang, Tao; Liang, Yong; Li, Ying; Li, Chenchen; Wang, Rui; Feng, Siqi; Zhang, Zunting [Organic Letters, 2017, vol. 19, # 13, p. 3552 - 3555]

46
[ 90-24-4 ]
[ 5392-12-1 ]
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(2-methoxynaphthalen-1-yl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With potassium hydroxide; In ethanol; water; at 0 - 20℃; for 24h;	A solution of 4,6-dimethoxy-2-hydroxyacetophenone (compound 101, 10 mmol, 1.96 g) dissolved in ethanol (50 mL) was treated with the same molar amount of <strong>[5392-12-1]2-methoxy-1-naphthaldehyde</strong> , 10 mmol, 1.86 g) and the reaction temperature was maintained at about 0-4 & lt; 0 & gt; C in an ice bath. 50% (v / v) KOH aqueous solution (10 mL) was added to the reaction mixture and stirred at room temperature for 24 hours. The reaction was monitored by TLC (Thin Layer Chromatography). At the end of the reaction, ice water was added to the reaction mixture and acidified with 6 N HCl (pH = 3-4). The precipitate was filtered off and washed with water and ethanol. The crude solid was purified by recrystallization from ethanol to give the desired compound 11 (m.p. 121-123, yield: 51%). Compounds 1-10 and 12-24 were prepared using the preparation method of Example 1 above.

Reference： [1]Magnetic Resonance in Chemistry,2016,vol. 54,p. 842 - 851
[2]Patent: KR2017/130932,2017,A .Location in patent: Paragraph 0147-0149

47
[ 90-24-4 ]
[ 93-02-7 ]
(E)-1-(2′-hydroxy-4′,6′-dimethoxyphenyl)-3-(2,5-dimethoxyphenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone With sodium hydroxide In methanol at 0℃; for 0.5h; Inert atmosphere; Stage #2: 2,5-dimethoxybenzaldehyde In methanol Inert atmosphere;	The general method for the preparation of chalconesseries 1 and series 2 General procedure: Under N2 atmosphereand 0 OC, 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (1mmol, 1 eq) or1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-one (1mmol, 1 eq) was dissolved into10 ml MeOH, followed by the addition of 10 ml aq. 40% NaOH solution, themixture was stirred for about 30 min, then benzaldehydes (1.2 mmol, 1.2eq.)were added respectively. The mixture was stirred for overnight and monitored byTLC. After the starting material 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone or 1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-onewas consumed completely, the pH value was adjusted to 3 with aq. 3 N HClsolution, a large amount of yellowish solid formed. The crude product was filtrated,recrystallized from MeOH or purified by si-gel column chromatography to affordfine desired products.
	In ethanol; water at 20℃; Alkaline conditions;	3.3. Synthesis of Flavokawain B derivatives General procedure: KOH (20% w/v aqueous solution) was added to a stirred solution of the appropriate acetophenone(1.0 eq) and a substituted benzaldehyde (1.25 eq.) in ethanol, and the mixture was stirred at roomtemperature for 48-72 h. The reaction mixture was cooled to 0 °C (ice-water bath) and acidified withHCl (10% v/v aqueous solution). In most cases, yellow precipitate was formed, filtered and washedwith 10% aqueous HCl solution. In the cases where an orange-yellow layer was formed, the mixturewas extracted with CH2Cl2 or ethyl acetate, the extracts was dried over Na2SO4 anhydrous and thesolvent was evaporated and crystalized with methanol or ethanol.

48
[ 90-24-4 ]
[ 2973-58-2 ]
(E)-3-(2-bromo-3-hydroxy-4-methoxyphenyl)-1-(2'-hydroxy-4',6'-dimethoxyphenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85.6%	In ethanol; water; at 20℃;Alkaline conditions;	General procedure: KOH (20% w/v aqueous solution) was added to a stirred solution of the appropriate acetophenone(1.0 eq) and a substituted benzaldehyde (1.25 eq.) in ethanol, and the mixture was stirred at roomtemperature for 48-72 h. The reaction mixture was cooled to 0 C (ice-water bath) and acidified withHCl (10% v/v aqueous solution). In most cases, yellow precipitate was formed, filtered and washedwith 10% aqueous HCl solution. In the cases where an orange-yellow layer was formed, the mixturewas extracted with CH2Cl2 or ethyl acetate, the extracts was dried over Na2SO4 anhydrous and thesolvent was evaporated and crystalized with methanol or ethanol.

Reference： [1]Molecules,2018,vol. 23

49
[ 90-24-4 ]
[ 520-28-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium hydroxide / ethanol; water / 0 - 20 °C 2: iodine / dimethyl sulfoxide / Reflux 3: aluminum (III) chloride / acetonitrile / 0 °C / Inert atmosphere; Reflux

Reference： [1]Sipos, Zoltán; Kónya, Krisztina [Synthesis, 2018, vol. 50, # 8, p. 1610 - 1620]

50
[ 90-24-4 ]
[ 54107-66-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2098 - 2102
[2]Patent: KR2018/64130,2018,A

51
[ 90-24-4 ]
[ 5392-10-9 ]
(E)-3-(2-bromo-4,5-dimethoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57.6%	With sodium hydroxide In ethanol; water at 20℃; for 24h;	Synthesis of (E)-3-(2-bromo-4,5-dimethoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one (5) 2-hydroxy-4,6-dimethoxyacetophenone (38.8 mg, 0.2 mmol) in ethanol (4 mL) was treated with 2-bromo-4,5-dimethoxybenzaldehyde (48.8 mg, 0.2 mmol) and followed by 0.5 mL of 8N NaOH solution. The reaction was stirred at room temperature for 24 hours. The reaction mixture was extracted with ethyl acetate (30 mL 3) and H2O after adjusted pH=7. Solvent was dried with NaSO4 and evaporated under reduced pressure. The crude was purified by column chromatography with EA:Hex=1:5 to afford compound 5 (48.6 mg, 57.6%). 1H-NMR (CDCl3): 14.28 ppm (s, 1H, phenolic OH), 8.07 ppm (d, J=15.6 Hz, 1H, CH=CH), 7.75 ppm (d, J=15.6 Hz, 1H, CH=CH), 7.17 ppm (s, 1H), 7.09 ppm (s, 1H), 6.12 ppm (d, J=2.4, 1H), 5.96 ppm (d, J=2.4Hz, 1H), 3.93 ppm (s, 3H), 3.92 ppm (s, 3H), 3.90 (s, 3H), 3.84 ppm (s, 3H). ESI-MS: m/z calcd for C19H20BrO6 [M+H]=423.04 found 423.0.
57.6%	With sodium hydroxide In ethanol at 20℃; for 24h;	5 [Example 5] Synthesis of ((E)-3-(2-bromo-4,5-dimethoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl) prop-2-en-1-one) (5) 2-hydroxy-4,6-dimethoxyacetophenone (38.8 mg, 0.2 mmol) was dissolved in ethyl alcohol (4 ml) and then 2-bromo-4,5-dimethoxyphenylaldehyde (48.8 mg, 0.2 mmol) After addition of 8N sodium hydroxide (0.5 ml) solution was treated and stirred at room temperature for 24 hours. The pH was adjusted to 7.0, extracted with ethyl acetate, and then the silica gel column and ethyl acetate: hexane = 1: 5 purified using to obtain compound 5 (48.6 mg, 57.6%) represented by the following formula (5).

Reference： [1]Lee, Dahae; Lee, Heesu; Kang, Ki Sung; Lee, Jae Wook [Bulletin of the Korean Chemical Society, 2018, vol. 39, # 5, p. 699 - 702]
[2]Current Patent Assignee: KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - KR2019/50074, 2019, A Location in patent: Paragraph 0092-0097

52
[ 5381-20-4 ]
[ 90-24-4 ]
C₁₉H₁₄O₄S [ No CAS ]

Reference： [1]Patent: JP2016/141638,2016,A .Location in patent: Paragraph 0012

53
[ 90-24-4 ]
[ 3934-87-0 ]
3,4,2′-trihydroxy-5,4′,6′-trimethoxychalcone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	In ethanol; water; at 20℃; for 48h;Alkaline conditions;	General procedure: To a stirred solution of substituted benzaldehyde(2.0 g, 15.62 mmol) and 2-hydroxy-3,4,5,6-tetramethoxyacetophenone or 2-hydroxy-4,6-dimethoxyacetophenone (2.5 g,15.62 mmol) in ethanol (30 mL) was added 20 mL of 20% aqueous KOH, and the reaction mixture was stirred at roomtemperature for 48 h. The reaction mixture was cooled to 0C (ice-water bath) and acidified with 10% aqueous HCl. A yellowprecipitate was formed, which was filtered and washed with 10% aqueous HCl. The yellow solid was recrystallized frompetroleum ether-EtOAc to give chalcone 4a-e and 8a-c.

Reference： [1]Chemistry of Natural Compounds,2019,vol. 55,p. 11 - 17
Khim. Prir. Soedin.,2019,p. 12 - 17,6

54
[ 90-24-4 ]
[ 38226-86-7 ]

Reference： [1]Patent: CN109776559,2019,A

55
[ 90-24-4 ]
[ 35826-59-6 ]
1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-isopropoxyphenyl)propane-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55.6%	With sodium hydride In tetrahydrofuran; mineral oil Reflux;	5.2.4. Synthesis of 1,3-diketone derivatives (D) General procedure: To a suspension of sodium hydride (60% in mineral oil, 5 eq) in dryTHF was added solution of substituted methyl benzoate (2 eq) in dryTHF. After mixture refluxed, substituted acetophenone (1 eq) in dryTHF was added dropwise. The mixture was refluxed overnight, then quenched with 1 N HCl. The mixture was extracted with ethyl acetatetwice, and the combined organic phase was washed with brine solution,dried with anhydrous Na2SO4, filtrated, and concentrated under reduced pressure. The residue was purified on a silica gel column.

Reference： [1]Jeong, Jieun; Kim, Kun-Hee; Kim, Dong-Young; Chandrasekaran, Gopalakrishnan; Kim, Minhee; Pagire, Suvarna H.; Dighe, Mahesh; Choi, Eun Young; Bak, Su-Min; Kim, Eun-Young; Shin, Myung-Geun; Choi, Seok-Yong; Ahn, Jin Hee [Bioorganic and Medicinal Chemistry, 2019, vol. 27, # 19]

56
[ 90-24-4 ]
[ 446866-87-1 ]
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(3-morpholinylphenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With potassium hydroxide In ethanol; water at 20℃;

Reference： [1]Yin, Huanhuan; Dong, Jingjing; Cai, Yingchun; Shi, Ximeng; Wang, Hao; Liu, Guixia; Tang, Yun; Liu, Jianwen; Ma, Lei [European Journal of Medicinal Chemistry, 2019, vol. 180, p. 350 - 366]

57
[ 90-24-4 ]
[ 197638-83-8 ]
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-(4-boc-piperazinyl)phenyl)prop-2-en-1-one [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 180,p. 350 - 366

58
[ 90-24-4 ]
[ 197638-83-8 ]
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-piperazinylphenyl)prop-2-en-1-one [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 180,p. 350 - 366

59
[ 50-00-0 ]
[ 90-24-4 ]
[ 344-25-2 ]
(R)‐1‐(3‐acetyl‐2‐hydroxy‐4,6‐dimethoxy‐benzyl)‐pyrrolidine‐2‐carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	In ethanol at 80℃; for 15h; Sealed tube; regiospecific reaction;	(+)-Monophyllidin (3b) A mixture of 2-hydroxy-4,6-dimethoxyacetophenone (1) (0.344 g, 1.752 mmol), formaldehyde(37%, 0.156 mL, 2.102 mmol) and (R)-proline (2b) (0.242 g, 2.102 mmol) in ethanol (4 mL) wasprepared in a screw cap tube. The tube was sealed and kept in an oil bath at 80 °C for 15 h. The solventwas removed under reduced-pressure and the residue was taken up with water. Upon setting pH to10 by addition of aqueous ammonia unreacted starting material precipitated in a rapid manner andwas filtered off. The aqueous solution was acidified with NH4Cl to pH 9 and four times extractedwith 25 mL of EtOH/CHCl3 = 1/4. The solvents of the combined organic phases were removed underreduced pressure.The resulting residue was purified by column chromatography (silica gel, eluent: ethyl acetate:MeOH = 3:1). (R)-1-(3-acetyl-2-hydroxy-4,6-dimethoxy-benzyl)-pyrrolidine-2-carboxylic acid (3b,0.142 g, 0.44 mmol, 25% yield, mp: 148 °C (dec); optical rotation: [α]D20 = +11.2°, (c = 1.00, CHCl3);enantiomeric purity: ee = 93%, tR = 3.3 min (for ee-determination see Supplementary Materials).

Reference： [1]Dank, Christian; Wurzer, Richard; Felsinger, Susanne; Bugl, Ricarda; Kählig, Hanspeter; Hela, Wolfgang; Roller, Alexander; Gstach, Hubert [Molecules, 2020, vol. 25, # 3]

60
[ 90-24-4 ]
[ 4460-86-0 ]
[ 73694-15-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone With sodium hydroxide In methanol at 0℃; for 0.5h; Inert atmosphere; Stage #2: asaraldehyde In methanol Inert atmosphere;	The general method for the preparation of chalconesseries 1 and series 2 General procedure: Under N2 atmosphereand 0 OC, 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (1mmol, 1 eq) or1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-one (1mmol, 1 eq) was dissolved into10 ml MeOH, followed by the addition of 10 ml aq. 40% NaOH solution, themixture was stirred for about 30 min, then benzaldehydes (1.2 mmol, 1.2eq.)were added respectively. The mixture was stirred for overnight and monitored byTLC. After the starting material 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone or 1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-onewas consumed completely, the pH value was adjusted to 3 with aq. 3 N HClsolution, a large amount of yellowish solid formed. The crude product was filtrated,recrystallized from MeOH or purified by si-gel column chromatography to affordfine desired products.

61
[ 90-24-4 ]
[ 65055-17-6 ]
C₁₇H₁₄ClFO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; triethylamine In dichloromethane for 24h; Inert atmosphere;	4.2.1. General procedure for the synthesis of 1, 9, 10, 11, 20, 43 and 52 General procedure: 2′-Hydroxy-4′,6′-dimethoxyacetophenone (1 eq.) was added to therequired benzoyl chloride (1.1 eq.) dissolved in dichloromethane(0.1 M). 4-Dimethylaminopyridine (0.1 eq.) and triethylamine (1.5 eq.)were added and the reaction was allowed to stir for 24 h under a nitrogenatmosphere. Upon completion (TLC - EtOAc, petroleum ethermixtures) the product was acidified with HCl and the organic layer waswashed with distilled water, brine and dried (MgSO4). The solution wasevaporated in vacuo leaving a crude solid. The crude solid was dissolvedin dry THF (0.1 M) and NaH (60% in mineral oil, 1.0 eq.) was addedand the reaction was heated at reflux for 20 h. Upon completion (TLC -EtOAc, petroleum ether mixtures) the solution was washed with HCland extracted with EtOAc. The organic layer was washed with distilledwater, brine and dried (MgSO4). The solution was evaporated in vacuoleaving a crude solid. The crude solid was suspended in conc. H2SO4and acetic acid and this mixture was allowed to stir at reflux for 15 h.After allowing to cool, the solution was poured onto an ice/water slurryand the resulting crystalline solid was collected using vacuum filtration.The crude solid was suspended in HBr (47-49%) and glacial acetic acidand this mixture heated at reflux for 40 h. After allowing to cool, thesolution was poured onto an ice/water slurry, and following isolationand purification by flash column chromatography, yielded the titlecompound as a pure solid.

Reference： [1]Chetter, Ben A.; Kyriakis, Efthimios; Barr, Daniel; Karra, Aikaterini G.; Katsidou, Elisabeth; Koulas, Symeon M.; Skamnaki, Vassiliki T.; Snape, Timothy J.; Psarra, Anna-Maria G.; Leonidas, Demetres D.; Hayes, Joseph M. [Bioorganic Chemistry, 2020, vol. 102]

62
[ 4397-53-9 ]
[ 90-24-4 ]
[ 37308-75-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium hydroxide / ethanol; water / 20 °C 2: boron trichloride / dichloromethane / 0 - 20 °C

Reference： [1]Liu, Jianwen; Ma, Lei; Shi, Ximeng; Yin, Huanhuan; Zhao, Yuyu; Zhou, Licheng [Letters in drug design and discovery, 2020, vol. 17, # 10, p. 1270 - 1282]

63
[ 4397-53-9 ]
[ 90-24-4 ]
[ 19158-99-7 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium hydride In N,N-dimethyl-formamide at 0℃; for 2h;
77.8%	With potassium hydroxide In methanol at 20℃; for 96h;	9 2’,4’-Dimethoxy-6’-hydroxy-4-O-benzylchalcone (a compound represented by structural formula 6, denoted as 6a) 2,4-Dimethoxy-6-hydroxy-acetophenone (compound 3a) (1.00g 5.13mmol), 4-benzyloxybenzaldehyde (compound 5a) (1.21g, 5.70mmol) and KOH (1.14g) , 20.4mmol) was added to 11ml of methanol solution and reacted at room temperature for 4d. Add ice water, adjust PH≈3, extract with dichloromethane, wash the oil phase with water, saturated NaCl, and rotary steam to obtain a crude product. The crude product was recrystallized with ethyl acetate to obtain a yellow solid I. The mother liquor was separated by a silica gel column (petroleum ether: ethyl acetate (V:V) = 15:1), and the solvent was removed to obtain a yellow solid II. The two products were combined and vacuum After drying, 1.56 g of the product was obtained with a yield of 77.8%.
	With potassium hydroxide In ethanol; water at 20℃;	General procedure: To a stirred solution of 4 (0.364 g, 2 mmol) and K2CO3 (0.552 g, 4 mmol) in DMSO (15 mL), and BnBr (0.44 mL, 4.4 mmol) was dropwise added at the room temperature. The reaction was then quenched by ice water, extracted with EtOAc (3 * 20 mL), then dried over Na2SO4, finally concentrated under reduced pressure to afford 5 (6.25 g). In the presence of 40% KOH, 5 reacted with corresponding benzaldehydes in a mixture of water and ethanol to obtain the chalcones 6a-g, which purified through a silica gel column. BCl3 (10 mL, 1 M in DCM) was dropwise added in anhydrous DCM (50 mL) of 6a-g (1.96 g, 10 mmol) under ice bath and stirring. After 0.5 h, the ice bath was removed, and the reaction was carried out for 2 h at room temperature. After being monitored by TLC, 15 mL ice water was added. The reaction was extracted with EtOAc (3 * 30 mL). The combined extract was dried over anhydrous Na2SO4 and was concentrated. The concentrated solution was purified by column chromatography to gain A1-7.

Reference： [1]Choe, Jung-Won; Heo, Hee-Young; Jung, Se-Hui; Kim, Jaehyun; Lee, Kooyeon [Molecules, 2021, vol. 26, # 10]
[2]Current Patent Assignee: SUZHOU HIGHFINE BIOTECH - CN112047916, 2020, A Location in patent: Paragraph 0111; 0194-0201
[3]Liu, Jianwen; Ma, Lei; Shi, Ximeng; Yin, Huanhuan; Zhao, Yuyu; Zhou, Licheng [Letters in drug design and discovery, 2020, vol. 17, # 10, p. 1270 - 1282]

64
[ 90-24-4 ]
[ 28090-12-2 ]
2’,4’-dimethoxy-6’-hydroxy-4-O-isopentenylchalcone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.6%	With potassium hydroxide; In methanol; for 72h;	2,4-Dimethoxy-6-hydroxy-acetophenone (compound 3a) (0.65g, 3.30mmol), 4-O-isopentenylbenzaldehyde (compound 5d) (0.62g, 3.28mmol), KOH (0.76g, 13.6mmol) in 7.6ml methanol was added, and the color of the reaction liquid became clear and slightly yellowish. React for 3d, pour into 100ml ice water, add 1M HCl to adjust the pH to 1, add ethyl acetate for extraction, wash twice with water and once with saturated brine. Dry overnight with anhydrous sodium sulfate. Separation by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) = 10:1) yielded a yellow solid, which was dried under vacuum at 35C for 15 hours to obtain 0.81 g of product with a yield of 66.6%.

Reference： [1]Patent: CN112047916,2020,A .Location in patent: Paragraph 0111; 0209-0216

65
[ 832-58-6 ]
[ 90-24-4 ]
[ 3602-54-8 ]

Yield	Reaction Conditions	Operation in experiment
1: 27% 2: 31%	With aluminum (III) chloride In chlorobenzene at 20 - 70℃;

Reference： [1]Perera, Shashika; Fernando, Asantha; Dallman, Johnathan; Weeramange, Chamitha; Lansakara, Ashabha; Nguyen, Thi; Rafferty, Ryan J. [ChemMedChem, 2021, vol. 16, # 10, p. 1631 - 1639]

66
[ 90-24-4 ]
[ 581102-27-4 ]
C₁₈H₁₅NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
350 mg	With sodium hydroxide In ethanol at 25℃;

Reference： [1]Current Patent Assignee: SALK INSTITUTE FOR BIOLOGICAL STUDIES - WO2021/236578, 2021, A1 Location in patent: Sheet 39

67
[ 90-24-4 ]
[ 3002-81-1 ]
samarium(III) nitrate hexahydrate [ No CAS ]
C₄₄H₄₅N₂O₁₂Sm [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hydroxide In ethanol; lithium hydroxide monohydrate at 35℃; for 3h;	General procedure: The synthesis of complex Sm(HDMA)3·neo (C1) was accomplished via solution precipitation method. The ethanolic solution of 3 mmol HDMA ligand and 1 mmol neo was mixed with ethanolic solution of 1 mmol Sm(NO3)3·6H2O. Subsequently, the pH of mixture was fixed to 7, using M/20 NaOH solution with constant stirring till the white precipitates were formed. The precipitates were further stirred for 3 h at about 35 °C and then left to digest for 1 h. Subsequently, the precipitate was separated with the help of suction filter, cleansed with distilled water and finally with ethanol. Further these precipitates were dried in vacuum oven at 50 °C (Yield: 79%)

Reference： [1]Poonam; Khatri, Savita; Kumar, Manoj; Bhayana, Seema; Khatkar; Taxak; Kumar, Rajesh [Asian Journal of Chemistry, 2022, vol. 34, # 7, p. 1749 - 1754]

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{[ item.p_purity ]}	{[ item.pr_size ]}	Inquiry	{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price) ]}	{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate,item.pr_is_large_size_no_price) ]}	{[ item.pr_usastock ]}		{[ item.pr_chinastock ]}	{[ item.pr_remark ]}

[ CAS No. 90-24-4 ] {[proInfo.proName]}

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[ 90-24-4 ] Synthesis Path-Upstream 1~40

[ 90-24-4 ] Synthesis Path-Downstream 1~67

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