[ CAS No. 2040-04-2 ]

Name: 2040-04-2|2',6'-Dimethoxyacetophenone|98%
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Product Details of [ 2040-04-2 ]

CAS No. :	2040-04-2	MDL No. :	MFCD00008729
Formula :	C₁₀H₁₂O₃	Boiling Point :	313.7°C at 760 mmHg
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	180.20 g/mol	Pubchem ID :	-
Synonyms :

Calculated chemistry of of [ 2040-04-2 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.3
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	49.62
TPSA :	35.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.55 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.02
Log Po/w (XLOGP3) :	1.19
Log Po/w (WLOGP) :	1.91
Log Po/w (MLOGP) :	1.13
Log Po/w (SILICOS-IT) :	2.19
Consensus Log Po/w :	1.69

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.85
Solubility :	2.54 mg/ml ; 0.0141 mol/l
Class :	Very soluble
Log S (Ali) :	-1.53
Solubility :	5.29 mg/ml ; 0.0294 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.99
Solubility :	0.186 mg/ml ; 0.00103 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.34

Safety of [ 2040-04-2 ]

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

Application In Synthesis of [ 2040-04-2 ]

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

Upstream synthesis route of [ 2040-04-2 ]
Downstream synthetic route of [ 2040-04-2 ]

[ 2040-04-2 ] Synthesis Path-Upstream 1~7

1
[ 2040-04-2 ]
[ 699-83-2 ]

Reference： [1] Journal fuer Praktische Chemie (Leipzig), 1934, vol. <2>139, p. 290,292
[2] Journal of the Chemical Society, 1934, p. 1483[3] Yakugaku Zasshi, 1935, vol. 55, p. 176,179

2
[ 7446-70-0 ]
[ 2040-04-2 ]
[ 108-90-7 ]
[ 699-83-2 ]

Reference： [1] Journal fuer Praktische Chemie (Leipzig), 1934, vol. <2>139, p. 290,292
[2] Journal of the Chemical Society, 1934, p. 1483[3] Yakugaku Zasshi, 1935, vol. 55, p. 176,179

3
[ 7446-70-0 ]
[ 2040-04-2 ]
[ 108-88-3 ]
[ 699-83-2 ]

Reference： [1] Journal fuer Praktische Chemie (Leipzig), 1934, vol. <2>139, p. 290,292
[2] Journal of the Chemical Society, 1934, p. 1483[3] Yakugaku Zasshi, 1935, vol. 55, p. 176,179

4
[ 2040-04-2 ]
[ 703-23-1 ]

Reference： [1] Synthetic Communications, 1988, vol. 18, # 2, p. 191 - 196
[2] Journal of the University of Poona, Science and Technology, 1959, # 16, p. 51,54
[3] Bulletin of the Chemical Society of Japan, 1994, vol. 67, # 2, p. 511 - 515

5
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[ 77-78-1 ]
[ 703-23-1 ]
[ 2040-04-2 ]

Reference： [1] Rasayanam, 1936, vol. 1, p. 64,66
[2] Zhurnal Obshchei Khimii, 1946, vol. 16, p. 99,102[3] Chem.Abstr., 1947, p. 104
[4] Chemische Berichte, 1942, vol. 75, p. 785,792

6
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[ 126829-31-0 ]

Reference： [1] Tetrahedron Letters, 1990, vol. 31, # 47, p. 6753 - 6756

7
[ 2040-04-2 ]
[ 103068-41-3 ]

Reference： [1] Canadian Journal of Chemistry, 1988, vol. 66, p. 1479 - 1482

[ 2040-04-2 ] Synthesis Path-Downstream 1~31

1
[ 917-64-6 ]
[ 16932-49-3 ]
[ 2040-04-2 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1934,vol. <2>139,p. 290,292

2
[ 2040-04-2 ]
1-(2,6-dimethoxy-phenyl)-ethanone oxime [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydroxylamine hydrochloride; sodium acetate In methanol; water Reflux;	19. All of the oxime substrates used in this investigation were synthesized in quantitative yields by refluxing a mixture of 1 equiv of the corresponding ketones or aldehydes, 1.6 equiv of hydroxylamine hydrochloride, and 2.0 equiv of sodium acetate in aqueous methanol.

Reference： [1]Location in patent: experimental part Augustine, John Kallikat; Kumar, Rajesha; Bombrun, Agnes; Mandal, Ashis Baran [Tetrahedron Letters, 2011, vol. 52, # 10, p. 1074 - 1077]
[2]Schamschurin [Zhurnal Obshchei Khimii, 1945, vol. 15, p. 978,979][Chem.Abstr., 1946, p. 6451]

3
[ 2040-04-2 ]
[ 99501-03-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	With RuBr₂[(S,S)-2,4-bis-(di-3,5-xylylphosphino)pentane]-2-picolylamine; potassium <i>tert</i>-butylate; hydrogen In isopropyl alcohol at 40℃; for 21h; Autoclave; Inert atmosphere;	19 In an autoclave, 3.12 mg (3.38 × 10 -3 mmol, S / C = 1000) of RuBr 2 [(S, S) - xylskewphos] (pica)And 7.64 mg (6.81 × 10 -2 mmol) of potassium tert-butoxide were charged and purged with argon gas. Under argon gas flow, 0.5 mL (3.39 mmol) of 2 ', 6'-dichloro-3'-fluoroacetophenone and 2.9 mL of 2-propanol were weighed with a syringe and pressurized to 10 atm with hydrogen, After stirring at 40 ° C. for 21 hours, reduction in hydrogen pressure was confirmed, and (S) -1- (2,6-dichloro-3-fluorophenyl) ethanol was obtained in 100% yield. In addition, HPLC (DAICEL CHRALPAK AD-RH, acetonitrile / water = 25/75, 0.5 mL / min, 25 ° C., 220 nm, retention time of each enantiomer is 56.1 min in the (S) 64.5 min), the optical purity was found to be 94.0% ee. The same conditions as in Example 1 were carried out except that S / C, substrate concentration, potassium tert-butoxide (KOtBu) concentration was changed for the purpose of improving the efficiency of the reaction. As a result, it was confirmed that the substrate was hydrogenated almost quantitatively under the condition of S / C = 20000. In addition, all the alcohol bodies formed were the (S) isomer as the main component. hydrogenation reaction ofketones with ortho di-substituted phenyl group other than 2 ',6'-dichloro-3'-fluoroacetophenone was carried out. An ortho-disubstituted phenyl group other than 2 ', 6'-dichloro-3'-fluoroacetophenoneTo carry out the hydrogenation reaction of the ketone.The reaction was carried out in the same manner as in Example 15, except that S / C = 2000.However, in Examples 19 and 22,In consideration of the solubility of the substrate, the substrate concentration was 1.0 mol / L.
95%	Stage #1: 2,6-dimethoxyacetophenone With zinc diacetate In tetrahydrofuran at 65℃; for 0.166667h; Stage #2: With methyl-di(n-propoxy)silane In tetrahydrofuran at 65℃; for 12h; Stage #3: With potassium fluoride; tetrabutyl ammonium fluoride In tetrahydrofuran at 0℃; for 2h;
91%	With C₃₆H₁₀₃AlO₄Si₁₄; isopropyl alcohol In neat (no solvent) at 80℃; for 24h; Glovebox; Schlenk technique;

67%	With C₁₅H₁₈BF₃; hydrogen; tert-butylimino-tri(pyrrolidino)phosphorane In tetrahydrofuran at 75℃; for 40h;
60%	With zirconium dioxide hydrate; isopropyl alcohol at 130℃; for 0.75h;
	With sodium tetrahydroborate In methanol for 0.75h;
	With (-)-diisopinocamphenylborane chloride In diethyl ether at 20℃; for 48h;
	With lithium aluminium tetrahydride In tetrahydrofuran at -78 - 20℃; Inert atmosphere; Schlenk technique; Glovebox;

Reference： [1]Current Patent Assignee: HOKKAIDO UNIVERSITY; KANTO KAGAKU HOLDINGS K.K. - JP2015/24975, 2015, A Location in patent: Paragraph 0132; 0140; 0141; 0144; 0151
[2]Location in patent: experimental part Inagaki, Tomohiko; Yamada, Yoko; Le, Thanh Phong; Furuta, Akihiro; Ito, Jun-Ichi; Nishiyama, Hisao [Synlett, 2009, # 2, p. 253 - 256]
[3]McNerney, Brian; Whittlesey, Bruce; Cordes, David B.; Krempner, Clemens [Chemistry - A European Journal, 2014, vol. 20, # 46, p. 14959 - 14964]
[4]Mummadi, Suresh; Brar, Amandeep; Wang, Guoqiang; Kenefake, Dustin; Diaz, Rony; Unruh, Daniel K.; Li, Shuhua; Krempner, Clemens [Chemistry - A European Journal, 2018, vol. 24, # 62, p. 16526 - 16531]
[5]Battilocchio, Claudio; Hawkins, Joel M.; Ley, Steven V. [Organic Letters, 2013, vol. 15, # 9, p. 2278 - 2281]
[6]Knauer, Birgit; Krohn, Karsten [Liebigs Annalen, 1995, # 4, p. 677 - 684]
[7]Ramachandran, P. Veeraraghavan; Gong, Baoqing; Brown, Herbert C.; Francisco, Joseph S. [Tetrahedron Letters, 2004, vol. 45, # 12, p. 2603 - 2605]
[8]Lau, Samantha; Ward, Bryan; Zhou, Xueer; White, Andrew J.P.; Casely, Ian J.; MacGregor, Stuart A.; Crimmin, Mark R. [Organometallics, 2017, vol. 36, # 18, p. 3654 - 3663]

4
[ 2040-04-2 ]
[ 123184-19-0 ]

Yield	Reaction Conditions	Operation in experiment
70%	With phenyltrimethylammonium tribromide In tetrahydrofuran at 20℃; for 1.16667h;	C.14 (C-14) To a solution of the above-mentioned compound C-13 (4.0g, 22.2mmol) in tetrahydrofuran (40ml), was added phenyltrimethylammoniumtribromide (8.34g, 22.2mmol) over 10 minutes at room temperature and the mixture was stirred at the same temperature for 1 hour.. water was added thereto, and the mixture was extracted with ethyl acetate, washed, and dried, then the solvent was evaporated under reduced pressure.. The residue was purified with silica gel column chromatography (ethyl acetate:n-hexane=1:4).. After allowing to stand at room temperature, the obtained solid residue was washed with diisopropylether to give 2-bromo-1-(2,6-dimethoxyphenyl)etanone (4.22g yield: 70%). Melting point: 78-82°C NMR(CDCl3)δ: 3.82(6H, s), 4.38(2H, s), 6.57(2H, d, J=8.4Hz), 7.32(1H, t, J=8.4Hz).
57%	With copper(I) bromide In chloroform; ethyl acetate at 12℃; Reflux;
40%	With N-Bromosuccinimide; toluene-4-sulfonic acid In dichloromethane at 40℃; for 0.25h; Microwave irradiation; Green chemistry;

	With 4-dimethylaminopyridine tribromide; acetic acid
	With bromine In chloroform Heating;

Reference： [1]Current Patent Assignee: SHIONOGI & CO., LTD. - EP1422218, 2004, A1 Location in patent: Page 188
[2]Hampannavar, Girish A.; Karpoormath, Rajshekhar; Palkar, Mahesh B.; Shaikh, Mahamadhanif S.; Chandrasekaran, Balakumar [ACS Medicinal Chemistry Letters, 2016, vol. 7, # 7, p. 686 - 691]
[3]Rodríguez, Juan C.; Maldonado, Rony A.; Ramírez-García, Gonzalo; Díaz Cervantes, Erik; de la Cruz, Fabiola N. [Journal of Heterocyclic Chemistry, 2020, vol. 57, # 5, p. 2279 - 2287]
[4]Jaramillo, Carlos; De Diego, J. Eugenio; Hamdouchi, Chafiq [Synlett, 2002, # 9, p. 1544 - 1546]
[5]Skoumbourdis, Amanda P.; Huang, Ruili; Southall, Noel; Leister, William; Guo, Vicky; Cho, Ming-Hsuang; Inglese, James; Nirenberg, Marshall; Austin, Christopher P.; Xia, Menghang; Thomas, Craig J. [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 4, p. 1297 - 1303]

5
[ 2040-04-2 ]
[ 103068-41-3 ]

Reference： [1]Canadian Journal of Chemistry,1988,vol. 66,p. 1479 - 1482

6
[ 2040-04-2 ]
[ 126829-31-0 ]

Reference： [1]Tetrahedron Letters,1990,vol. 31,p. 6753 - 6756

7
[ 2040-04-2 ]
[ 121083-00-9 ]

Yield	Reaction Conditions	Operation in experiment
67%	With ammonium hydroxide; ammonium acetate; sodium cyanoborohydride; zinc In ethanol; water at 80℃; for 36h;	4.2.1. General procedure for the synthesis of amines via reductive amination of acetophenones General procedure: To a saturated solution of NH4OAc in EtOH (40 mL) were added activated Zn (5 equiv), acetophenone (1 equiv), NaBCNH3(3 equiv) and 30% aq NH3 (10 mL) respectively. The mixture wasstirred at 80 C for 36 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and made basic using 1 M NaOH (50 mL). Theorganic phase was separated and aqua phase was extracted with (2x25 mL) CH2Cl2. The organic phases were combined and acidified with HCl (pH: 2.0). The organic layer was separated andH2O layer was extracted with CH2Cl2 (2 25 mL). The H2O layer was made basic with NaOH (pH: 10.0), The organic layer was extracted with CH2Cl2 (3 25 mL). Combined organic layers weredried over Na2SO4 and evaporation of the solvent afforded thedesired amines.
	Multi-step reaction with 2 steps 2: sodium-amalgam; acetic acid; water

Reference： [1]Akincioʇlu, Akin; Akincioʇlu, Hülya; Gülçin, Ilhami; Durdagi, Serdar; Supuran, Claudiu T.; Göksu, Süleyman [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 13, p. 3592 - 3602]
[2]Schamschurin [Zhurnal Obshchei Khimii, 1945, vol. 15, p. 978,979][Chem.Abstr., 1946, p. 6451]

8
[ 699-83-2 ]
[ 74-88-4 ]
[ 2040-04-2 ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	Example 6 (S)-N-(2-cymo- 1 -( 1 -hydroxy-7-isopropyl- 1 ,3 -dihydrobenzo [c] [ 1 ,2"\|oxaborol-6-yloxy")pro pan-2-yl')-4-('trifluoromethoxy')benzamide To a solution of l-(2,6-dihydroxyphenyl)ethanone (50.0g, 329.0mmol) and potassium carbonate (136.2g, 986.8mmol) in DMF (200mL) is added CH3I (48.6mL, 822.5mmol) slowly at rt. The mixture is stirred for 16h at rt, poured into ice water (lOOOmL) and stirred for 30 min. The precipitate is filtered, washed with water and dried to give the desired product as a light yellow solid (50g, yield 84%).
84%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of compound l-(2,6-dihydroxyphenyl)ethanone (25.0 g, 164.5 mmol) and potassium carbonate (68.1 g, 493.4 mmol) in DMF (100 mL) was added iodomethane (24.3 mL, 41 1.2 mmol) slowly at room temperature. The mixture was stirred for 16 h at room temperature. The mixture was poured into ice water (500 mL) and stirred for 30 min. The precipitate was filtered, washed with water and dried to give l-(2,6-dimethoxyphenyl)ethanone as a light yellow solid (25 g, yield 84%). MS: m/z =181.0 (M+H, ESI+).
71%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	(C-13) To a suspension of 2', 6'-dihydroxyacetophenone (5.0g, 32.9mmol) and powder potassium carbonate (10.0g, 72.4mmol) in dimethylformamide (30ml), was added iodomethane (7.1ml, 114mmol) at room temperature and the mixture was stirred at the same temperature overnight.. To the solution was added 2N hydrochloric acid (45ml) and water (45ml) and the precipitated crystals were filtered off.. The crude crystals were washed with water and dried, then crystallized from ethyl acetate / n-hexane to give 1-(2,6-dimethoxyphenyl)etanone (4.2g, yield: 71%). Melting point: 69C NMR(CDCl3)delta:2.48(3H, s), 3.81(6H, s), 6.55(2H, d, J=8.1Hz), 7.26(1H, t, J=8.1Hz).

Reference： [1]Patent: WO2014/149793,2014,A1 .Location in patent: Page/Page column 51
[2]Patent: WO2015/13318,2015,A1 .Location in patent: Paragraph 0244
[3]Patent: EP1422218,2004,A1 .Location in patent: Page 188

9
[ 4460-86-0 ]
[ 2040-04-2 ]
[ 944447-13-6 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium hydroxide In methanol at 70℃;
62%	With lithium hydroxide monohydrate In ethanol at 40℃; for 5.5h;	B.B.1 Preparation of Chalcones Via Claisen-Schmidt Condensation. General procedure: A solution of the acetophenone (10 mmol) and LiOH.H2O (10 mol %) in 10 mL of absolute ethanol is stirred at the appropriate temperature for 10 min (for reactions at 40° C., the bulb is equipped with a reflux condenser). Then, the benzaldehyde (10 mmol, 1 equiv.) is added and the system is protected from the atmosphere with a cork stopper. Reaction progress is monitored by TLC or LCMS-analysis; during the course of the reaction, the chalcone may precipitate. Upon attaining maximum conversion grade, the reaction mixture is quenched with 15 mL of 1% hydrochloric acid. [0362] If the chalcone has precipitated, it is isolated by means of filtration. In order to remove residual amounts of benzaldehyde, the residue is washed thoroughly with water until the filtrate turns clear. The obtained solid is the chalcone, which can be dried in a dessicator. Subsequently, the chalcone can be recrystallized in absolute ethanol so as to obtain high purity crystals. [0363] If the chalcone has formed a separate oily liquor at the bottom of the bulb, it can be extracted from the mixture with diethyl ether. The organic phase is subsequently washed with brine (2×) and dried over MgSO4, upon which the solution is concentrated in vacuo. Again, purification of the thus obtained residue can be performed through recrystallization in absolute ethanol. [0369] The synthesis of compounds 37-51 was conducted via a Claisen-Schmidt condensation of suitably functionalized acetophenones and benzaldehydes. Whilst other syntheses have been proposed to prepare chalcones (e.g. via 1,3-diaryl-1-siloxy allenes or by Suzuki or Heck coupling reactions), this crossed aldol condensation remains the method of choice, given its simplicity and the ready availability of the required acetophenones 35 and benzaldehydes 36. Wherein R and R′ are as represented in table 3 Scheme: [0370] Chalcone synthesis. a) 1 equiv. benzaldehyde 36, 5 mol % LiOH.H2O, abs. EtOH., conditions see table 3. [0371] Over the years, numerous basic (e.g. NaOH, Ba(OH)2 and Al2O3) and acid (e.g. dry HCl and BF3) catalysts have been proposed for this transformation. We considered the LiOH.H2O catalyzed protocol as proposed by Bhagat and co-workers to be the most elegant, because of its high catalyst turnover and yields, short reaction times and easy work-up. Nevertheless, as we could only obtain the high yields reported by these researchers after prolonged reaction times, we evaluated the influence of the reaction temperature on its outcome. As such, by rising the temperature to 40 or 70° C., and by optimizing the work-up procedure, we were able to obtain the pure chalcones 37-51 in reasonable to excellent yield after crystallization in ethanol (see table 3). [TABLE-US-00003] TABLE 3 Synthesis conditions and yield for the synthetic chalcones 37-51 in the training set. Reaction conditions Temperaturea Time Yieldb R R′ (° C.) (h) (%) 37 H H 20 .83 74 38 4′-MeO H 20 2 80 39 H 4-MeO 20 3 77 40 4′-MeO 4-MeO 40 2 82 41 4′-MeO 3-MeO 20 1 62 42 2′,4′,6′-triMeO 2,4,5-triMeO 20 168 78 43 2′,4′,6′-triMeO 4-MeO 20 86 69 44 4′-MeO 2,4,5-triMeO 20 15 92 45 4′-MeO 2,4,6-triMeO 70 2 89 46 2′,6′-diMeO 2,4,5-triMeO 40 5.5 62 47 2′,6′-diMeO 2,4,6-triMeO 40 48 64 48 4′-MeO 4-F 20 4 91 49 3′,4′,5′-triMeO 4-F 20 24 69 50 4′-F 4-F 20 1 42 51 H 4-F 40 2 51 [0372] The synthesis of compounds 52-55 was conducted in a similar way as described above for compounds 37-51, and the synthesis conditions are as depicted in table 4. [TABLE-US-00004] TABLE 4 Synthesis conditions and yield for the synthetic chalcones 52-55. R R′ Conditions Yielda (%) 52 4′-MeO 4-Cl r.t., 2 h 85 53 4′-F 3-F r.t., 1 h 15 min 70 54 4′-MeO 3-F r.t., 30 min 76 55 4′-MeO 2-F r.t., 4 h 88
62%	With lithium hydroxide monohydrate In ethanol at 40℃; for 5.5h;	Preparation of chalcones via Claisen-Schmidt condensation General procedure: A solution of the acetophenone(10 mmol) and LiOH.H2O (10 mol%) in 10 mL of absoluteethanol is stirred at the appropriate temperature for 10 min (for reactions at40 °C, the bulb is equipped with a reflux condenser). Then, the benzaldehyde(10 mmol, 1 equiv.) is added and the system is protected from theatmosphere with a cork stopper. Reaction progress is monitored by TLC orLCMS-analysis; during the course of the reaction, the chalcone may precipitate.Upon attaining maximum conversion grade, the reaction mixture is quenched with15 mL of 1% hydrochloric acid.If the chalcone has precipitated, it isisolated by means of filtration. In order to remove residual amounts ofbenzaldehyde, the residue is washed thoroughly with water until the filtrateturns clear. The obtained solid is the chalcone, which can be dried in adessicator. Subsequently, the chalcone can be recrystallized in absoluteethanol so as to obtain high purity crystals.If the chalcone has formed a separate oilyliquor at the bottom of the bulb, it can be extracted from the mixture withdiethyl ether. The organic phase is subsequently washed with brine (2x) anddried over MgSO4, upon which the solution is concentrated in vacuo. Again, purification of the thusobtained residue can be performed through recrystallization in absoluteethanol.Detailed reaction conditions and yields for chalcones 35-50are provided in Table S13

Reference： [1]Boumendjel, Ahcène; Boccard, Julien; Carrupt, Pierre-Alain; Nicolle, Edwige; Blanc, Madeleine; Geze, Annabelle; Choisnard, Luc; Wouessidjewe, Denis; Matera, Eva-Laure; Dumontet, Charles [Journal of Medicinal Chemistry, 2008, vol. 51, # 7, p. 2307 - 2310]
[2]Current Patent Assignee: GHENT UNIVERSITY - US2015/11620, 2015, A1 Location in patent: Paragraph 0361-0363; 0369-0372
[3]Roman, Bart I.; De Ryck, Tine; Patronov, Atanas; Slavov, Svetoslav H.; Vanhoecke, Barbara W.A.; Katritzky, Alan R.; Bracke, Marc E.; Stevens, Christian V. [European Journal of Medicinal Chemistry, 2015, vol. 101, p. 627 - 639]

10
[ 830-79-5 ]
[ 2040-04-2 ]
[ 944447-03-4 ]

Yield	Reaction Conditions	Operation in experiment
64%	With lithium hydroxide monohydrate; In ethanol; at 40℃; for 48h;	General procedure: A solution of the acetophenone (10 mmol) and LiOH.H2O (10 mol %) in 10 mL of absolute ethanol is stirred at the appropriate temperature for 10 min (for reactions at 40 C., the bulb is equipped with a reflux condenser). Then, the benzaldehyde (10 mmol, 1 equiv.) is added and the system is protected from the atmosphere with a cork stopper. Reaction progress is monitored by TLC or LCMS-analysis; during the course of the reaction, the chalcone may precipitate. Upon attaining maximum conversion grade, the reaction mixture is quenched with 15 mL of 1% hydrochloric acid. [0362] If the chalcone has precipitated, it is isolated by means of filtration. In order to remove residual amounts of benzaldehyde, the residue is washed thoroughly with water until the filtrate turns clear. The obtained solid is the chalcone, which can be dried in a dessicator. Subsequently, the chalcone can be recrystallized in absolute ethanol so as to obtain high purity crystals. [0363] If the chalcone has formed a separate oily liquor at the bottom of the bulb, it can be extracted from the mixture with diethyl ether. The organic phase is subsequently washed with brine (2×) and dried over MgSO4, upon which the solution is concentrated in vacuo. Again, purification of the thus obtained residue can be performed through recrystallization in absolute ethanol. [0369] The synthesis of compounds 37-51 was conducted via a Claisen-Schmidt condensation of suitably functionalized acetophenones and benzaldehydes. Whilst other syntheses have been proposed to prepare chalcones (e.g. via 1,3-diaryl-1-siloxy allenes or by Suzuki or Heck coupling reactions), this crossed aldol condensation remains the method of choice, given its simplicity and the ready availability of the required acetophenones 35 and benzaldehydes 36. Wherein R and R? are as represented in table 3 Scheme: [0370] Chalcone synthesis. a) 1 equiv. benzaldehyde 36, 5 mol % LiOH.H2O, abs. EtOH., conditions see table 3. [0371] Over the years, numerous basic (e.g. NaOH, Ba(OH)2 and Al2O3) and acid (e.g. dry HCl and BF3) catalysts have been proposed for this transformation. We considered the LiOH.H2O catalyzed protocol as proposed by Bhagat and co-workers to be the most elegant, because of its high catalyst turnover and yields, short reaction times and easy work-up. Nevertheless, as we could only obtain the high yields reported by these researchers after prolonged reaction times, we evaluated the influence of the reaction temperature on its outcome. As such, by rising the temperature to 40 or 70 C., and by optimizing the work-up procedure, we were able to obtain the pure chalcones 37-51 in reasonable to excellent yield after crystallization in ethanol (see table 3). [TABLE-US-00003] TABLE 3 Synthesis conditions and yield for the synthetic chalcones 37-51 in the training set. Reaction conditions Temperaturea Time Yieldb R R? ( C.) (h) (%) 37 H H 20 .83 74 38 4?-MeO H 20 2 80 39 H 4-MeO 20 3 77 40 4?-MeO 4-MeO 40 2 82 41 4?-MeO 3-MeO 20 1 62 42 2?,4?,6?-triMeO 2,4,5-triMeO 20 168 78 43 2?,4?,6?-triMeO 4-MeO 20 86 69 44 4?-MeO 2,4,5-triMeO 20 15 92 45 4?-MeO 2,4,6-triMeO 70 2 89 46 2?,6?-diMeO 2,4,5-triMeO 40 5.5 62 47 2?,6?-diMeO 2,4,6-triMeO 40 48 64 48 4?-MeO 4-F 20 4 91 49 3?,4?,5?-triMeO 4-F 20 24 69 50 4?-F 4-F 20 1 42 51 H 4-F 40 2 51 [0372] The synthesis of compounds 52-55 was conducted in a similar way as described above for compounds 37-51, and the synthesis conditions are as depicted in table 4. [TABLE-US-00004] TABLE 4 Synthesis conditions and yield for the synthetic chalcones 52-55. R R? Conditions Yielda (%) 52 4?-MeO 4-Cl r.t., 2 h 85 53 4?-F 3-F r.t., 1 h 15 min 70 54 4?-MeO 3-F r.t., 30 min 76 55 4?-MeO 2-F r.t., 4 h 88
64%	With lithium hydroxide monohydrate; In ethanol; at 40℃; for 48h;	General procedure: A solution of the acetophenone(10 mmol) and LiOH.H2O (10 mol%) in 10 mL of absoluteethanol is stirred at the appropriate temperature for 10 min (for reactions at40 C, the bulb is equipped with a reflux condenser). Then, the benzaldehyde(10 mmol, 1 equiv.) is added and the system is protected from theatmosphere with a cork stopper. Reaction progress is monitored by TLC orLCMS-analysis; during the course of the reaction, the chalcone may precipitate.Upon attaining maximum conversion grade, the reaction mixture is quenched with15 mL of 1% hydrochloric acid.If the chalcone has precipitated, it isisolated by means of filtration. In order to remove residual amounts ofbenzaldehyde, the residue is washed thoroughly with water until the filtrateturns clear. The obtained solid is the chalcone, which can be dried in adessicator. Subsequently, the chalcone can be recrystallized in absoluteethanol so as to obtain high purity crystals.If the chalcone has formed a separate oilyliquor at the bottom of the bulb, it can be extracted from the mixture withdiethyl ether. The organic phase is subsequently washed with brine (2x) anddried over MgSO4, upon which the solution is concentrated in vacuo. Again, purification of the thusobtained residue can be performed through recrystallization in absoluteethanol.Detailed reaction conditions and yields for chalcones 35-50are provided in Table S13
24%	With potassium hydroxide; In methanol; water; at 70℃; for 3h;	1 mM of 2,6-methoxyacetophenone and 1 mM of <strong>[830-79-5]2,4,6-trimethoxybenzaldehyde</strong> in 10 ml of methanol, in the presence of 1 ml of 25% KOH, were heated to 70 C. for 3 hours. The solvent is then evaporated under reduced pressure, water is added and the mixture is extracted with CH2Cl2. The organic phase is dried, evaporated. The obtained products are solids. Purification is carried out with chromatography by eluting with a (1:5) mixture of ethyl acetate and cyclohexane The chalcone is obtained with a yield of 24%. m.p.=170 C.

Reference： [1]Patent: US2015/11620,2015,A1 .Location in patent: Paragraph 0361-0363; 0369-0372
[2]European Journal of Medicinal Chemistry,2015,vol. 101,p. 627 - 639
[3]Journal of Medicinal Chemistry,2008,vol. 51,p. 2307 - 2310
[4]Patent: US2009/182058,2009,A1 .Location in patent: Page/Page column 5

11
[ 2040-04-2 ]
[ 99-61-6 ]
[ 1365643-99-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 2,6-dimethoxyacetophenone With lithium hydroxide monohydrate In ethanol at 20℃; for 0.166667h; Stage #2: 3-nitro-benzaldehyde In ethanol at 20℃; for 2h;	General procedure for synthesis of chalcones General procedure: In a 14-ml vial, the substituted acetophenone (1.25 mmol) and lithium hydroxide monohydrate (0.251 mmol) were dissolved in ethanol (5 mL) and the mixture was stirred at RT for 10 min followed by addition of substituted benzaldehyde (1.272 mmol). The reaction mixture was then stirred at RT and monitored by TLC using 25% ethyl acetate/hexanes as the solvent system. The reaction was quenched after 2 hr by pouring into 50 ml of stirring ice cold water. If the product precipitated out after quenching with cold water, it was filtered off and crystallized with hot ethanol. In some examples, a sticky mass was observed in the aqueous solution after quenching. In those cases, the product was extracted by ethyl acetate (3 x 50 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography using ethyl acetate/hexanes as the solvent system in increasing order of polarity. Chalcones 1a- 1j, 2a- 2j, 3a- 3j, 4a- 4j, 5a- 5j, 6a-e, 6g-h, 6i, 7a-h, 7j, 8a, 9a, 9d-e, 9i, 10a-b, 10d-e, 10h-j have been reported earlier in the literature.1-32 To the best of our knowledge, there is no literature available for rest of the chalcones. The characterization data of these chalcone derivatives i.e. 1H, 13C NMR, LC-MS-TOF and purity analysis are given in subsequent sections.

Reference： [1]Kim, Yeong Sang; Kumar, Vineet; Lee, Sunmin; Iwai, Aki; Neckers, Len; Malhotra, Sanjay V.; Trepel, Jane B. [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 5, p. 2105 - 2109]

12
[ 2040-04-2 ]
[ 105-07-7 ]
[ 1365644-39-8 ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: 2,6-dimethoxyacetophenone With lithium hydroxide monohydrate In ethanol at 20℃; for 0.166667h; Stage #2: 4-cyanobenzaldehyde In ethanol at 20℃; for 2h;	General procedure for synthesis of chalcones General procedure: In a 14-ml vial, the substituted acetophenone (1.25 mmol) and lithium hydroxide monohydrate (0.251 mmol) were dissolved in ethanol (5 mL) and the mixture was stirred at RT for 10 min followed by addition of substituted benzaldehyde (1.272 mmol). The reaction mixture was then stirred at RT and monitored by TLC using 25% ethyl acetate/hexanes as the solvent system. The reaction was quenched after 2 hr by pouring into 50 ml of stirring ice cold water. If the product precipitated out after quenching with cold water, it was filtered off and crystallized with hot ethanol. In some examples, a sticky mass was observed in the aqueous solution after quenching. In those cases, the product was extracted by ethyl acetate (3 x 50 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography using ethyl acetate/hexanes as the solvent system in increasing order of polarity. Chalcones 1a- 1j, 2a- 2j, 3a- 3j, 4a- 4j, 5a- 5j, 6a-e, 6g-h, 6i, 7a-h, 7j, 8a, 9a, 9d-e, 9i, 10a-b, 10d-e, 10h-j have been reported earlier in the literature.1-32 To the best of our knowledge, there is no literature available for rest of the chalcones. The characterization data of these chalcone derivatives i.e. 1H, 13C NMR, LC-MS-TOF and purity analysis are given in subsequent sections.

13
[ 2040-04-2 ]
[ 105-07-7 ]
[ 1365644-40-1 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: 2,6-dimethoxyacetophenone With lithium hydroxide monohydrate In ethanol at 20℃; for 0.166667h; Stage #2: 4-cyanobenzaldehyde In ethanol at 20℃; for 2h;	General procedure for synthesis of chalcones General procedure: In a 14-ml vial, the substituted acetophenone (1.25 mmol) and lithium hydroxide monohydrate (0.251 mmol) were dissolved in ethanol (5 mL) and the mixture was stirred at RT for 10 min followed by addition of substituted benzaldehyde (1.272 mmol). The reaction mixture was then stirred at RT and monitored by TLC using 25% ethyl acetate/hexanes as the solvent system. The reaction was quenched after 2 hr by pouring into 50 ml of stirring ice cold water. If the product precipitated out after quenching with cold water, it was filtered off and crystallized with hot ethanol. In some examples, a sticky mass was observed in the aqueous solution after quenching. In those cases, the product was extracted by ethyl acetate (3 x 50 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography using ethyl acetate/hexanes as the solvent system in increasing order of polarity. Chalcones 1a- 1j, 2a- 2j, 3a- 3j, 4a- 4j, 5a- 5j, 6a-e, 6g-h, 6i, 7a-h, 7j, 8a, 9a, 9d-e, 9i, 10a-b, 10d-e, 10h-j have been reported earlier in the literature.1-32 To the best of our knowledge, there is no literature available for rest of the chalcones. The characterization data of these chalcone derivatives i.e. 1H, 13C NMR, LC-MS-TOF and purity analysis are given in subsequent sections.

14
[ 93-58-3 ]
[ 2040-04-2 ]
[ 1402815-87-5 ]

Yield	Reaction Conditions	Operation in experiment
69%	Stage #1: 2,6-dimethoxyacetophenone With sodium hydride In tetrahydrofuran at 5 - 10℃; Stage #2: benzoic acid methyl ester In tetrahydrofuran for 6h; Reflux;	General procedure for synthesis of compounds 2, 9, 11, 18 General procedure: Mixture of sodium hydride (0.20 mole for 2, 9, 11, 0.30 mole for 18) and THF (72g, 82ml) was cooled to 5°C, and the substituted acetophenone (0.10 mole) was added dropwise keeping the temperature below 10°C and rapid stirring. Next, methyl benzoate (0.20 mole) was added, and the mixture was warmed up to the boiling point and refluxed for 6 hours. After cooling down to 5°C,the mixture was poured on crushed ice (200g), and 10% solution of hydrochloric acid was added until neutral pH. Separated aqueous layer was extracted with methylene chloride, and combined organic layers were rinsed with 5% solution of sodium bicarbonate, next with water and dried with anhydrous magnesium sulfate. After filtering the drying agent, solution was concentrated on vacuum rotary evaporator, filtered and crystalized from ethanol.

Reference： [1]Zawadiak, Jan; Mrzyczek, Marek [Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2012, vol. 96, p. 815 - 819]

15
[ 2040-04-2 ]
[ 95-92-1 ]
[ 1443991-21-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium In ethanol at 20℃; for 6h;	3.7. Ethyl 4-(2,6-dimethoxyphenyl)-4-hydroxy-2-oxobut-3-enoate (19) Sodium (11.4g, 496mmol) was dissolved in EtOH (450mL) using an ice bath to control the exotherm. To this solution, diethyl oxalate (45mL, 332mmol) was added in one portion, followed by a slurry of 2′,6′-dimethoxyacetophenone (30.0g, 166mmol) in EtOH (250mL). The resulting suspension was allowed to stir at ambient temperature for 6h then the solvent removed in vacuo. The mixture was extracted with EtOAc (8×350mL) ensuring the pH remained below 6 between each extraction (addition of concd hydrochloric acid). The organic phases were combined, dried (MgSO4), and the solvent removed in vacuo. Following recrystallisation from EtOH, the title compound was as a glassy crystalline solid (41.2g, 147mmol, 88% yield).Mp: 102-104°C;1H NMR (400MHz, CDCl3): 14.33 (1H, br s, OH), 7.34 (1H, t,J=8.4Hz, H-1), 6.60 (1H, s, H-6), 6.59 (1H, d,J=8.4Hz, H-2), 4.35 (2H, q,J=7.1Hz, H-1′), 3.82 (6H, s, H-3′), 1.37 (3H, t,J=7.1Hz);13C NMR (100MHz, CDCl3): 195.8 (C-5), 164.0 (C-7), 162.6 (C-8), 158.0 (C-3), 132.4 (C-1), 117.2 (C-4), 106.4 (C-6), 104.3 (C-2), 62.5 (C-1′), 56.2 (C-3′), 14.2 (C-2′); LC-MS:Rt=4.19, [MNa]+=302.83; IR (neat) cm-1: 1735.7 (m), 1625.1 (m), 1586.8 (s), 1475.3 (m), 1257.5 (s); HRMS: calcd for [C14H16O6Na]+=303.0845, found 303.0847,Δ=0.7ppm; Microanalysis: calcd (found) for C14H16O6; C=59.99% (59.99%), H=5.75% (5.72%), N=0.00% (0.00%); The structure was unambiguously confirmed by X-ray crystallography and the structure deposited at the CCDC with the unique reference 913971.

Reference： [1]Baxendale; Cheung; Kitching; Ley; Shearman [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 14, p. 4378 - 4387]

16
[ 99501-03-8 ]
[ 2040-04-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With acetone In toluene at 80℃; for 0.25h; Flow reactor;
72%	With C₃₅H₂₈Cl₂N₅PRu; potassium <i>tert</i>-butylate In toluene at 50℃; for 6h; chemoselective reaction;	2.5. Procedure for catalytic alcohol oxidation reaction General procedure: using the complex 1 as catalyst in presence of a base following a general procedure. In a round-bottom flask, 1 mmol of substrate, 0.005mmol of catalyst (3.6mg) and 0.010 mmol of tBuOK (1.1mg) were mixed in 10mL toluene. The reaction mixture was heated at 50°C in aerobic condition with continuous stirring for 6h and then the solvent was evaporated with a rotary evaporator under reduced pressure. The crude product, thus obtained, was purified on preparative silica gel GF-254 TLC plate using ethyl acetate: hexane (1:10) solvent mixture as eluent. The oxidized products were characterized by NMR spectroscopy (See Figs. S4-S32).
	With chromium(VI) oxide 2,6-Dimethoxy-benzoylchlorid, Dimethylcadmium;

Reference： [1]Chorghade, Rajeev; Battilocchio, Claudio; Hawkins, Joel M.; Ley, Steven V. [Organic Letters, 2013, vol. 15, # 22, p. 5698 - 5701]
[2]Saha, Tanushri; Pramanick, Rajib; Sengupta, Debabrata; Goswami, Sreebrata [Inorganica Chimica Acta, 2019, vol. 484, p. 160 - 166]
[3]Dhami,K.S.; Stothers,J.B. [Canadian Journal of Chemistry, 1965, vol. 43, p. 479]

17
[ 126829-31-0 ]
[ 2040-04-2 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 948 - 951

18
[ 16932-44-8 ]
[ 2040-04-2 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 948 - 951

19
[ 2040-04-2 ]
[ 95-92-1 ]
ethyl 4-(2,6-dimethoxyphenyl)-2,4-dioxobutanoate sodium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium ethanolate In ethanol at 20℃; for 4.5h; Reflux;	157.1 Step 1: Preparation of ethyl 4-(2,6-dimethoxyphenyl)-2,4-dioxobutanoate Step 1: Preparation of ethyl 4-(2,6-dimethoxyphenyl)-2,4-dioxobutanoate: To a solution of sodium ethoxide (21 % in EtOH) (5.4 mL, 14.37 mmol) was added dropwise a mixture of diethyl oxalate (1.85 mL, 13.690 mmol) and 2,6-dimethoxy acetophenone (2.45 g, 13.690 mmol) in anhydrous ethanol (15 mL). The resultant mixture was stirred at room temperature for 30 minutes, upon which yellow suspension formed. The reaction mixture was heated to reflux for 4 h. The reaction was cooled to room temperature. Ethanol was evaporated in vacuo. The resultant residue was triturated with diethyl ether (30 mL) and filtered to obtain sodium salt of ethyl 4-(2,6-dimethoxyphenyl)-2,4-dioxobutanoate as yellow solid (4.0 g, 97 %). MS m/z: Calcd. for CwHieOe 280.09 [M]+, found 279.3 [M-H]+. H
	With sodium ethanolate In ethanol at 20℃; for 4.5h; Inert atmosphere; Reflux;	5.1.1. Ethyl 4-(2,6-dimethoxyphenyl)-2,4-dioxobutanoate (40) To a solution of sodium ethoxide (21% in EtOH) (5.4 mL,14.37 mmol) was added dropwise a mixture of diethyl oxalate(1.85 mL, 13.690 mmol) and 2,6-dimethoxy acetophenone (2.45 g,13.69 mmol) in anhydrous ethanol (15 mL). The resultant mixture wasstirred at room temperature for 30 min, upon which yellow suspensionformed. The reaction mixture was heated to reflux for 4 h. The reactionwas cooled to room temperature. Ethanol was evaporated in vacuo. Theresultant residue was triturated with diethyl ether (30 mL) and filteredto obtain sodium salt of ethyl 4-(2,6-dimethoxyphenyl)-2,4-dioxobutanoateas yellow solid (4.0 g, 97%). MS (ESI) m/z: Calcd. for C14H16O6280.09 [M]+, found 279.3 [M-H]-.

Reference： [1]Current Patent Assignee: RESEARCH TRIANGLE INSTITUTE - WO2015/188073, 2015, A1 Location in patent: Paragraph 00122
[2]Maitra, Rangan; Narayanan, Sanju; Rajagopal, Sudarshan; Runyon, Scott P.; Vasukuttan, Vineetha [Bioorganic and medicinal chemistry, 2020]

20
[ 2040-04-2 ]
[ 380481-66-3 ]
1-(3-methoxy-4′-methyl[1,1′-biphenyl]-2-yl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With styrene; carbonylchlorohydridobis(triisopropylphosphine)ruthenium(II); cesium fluoride In toluene at 80℃; for 0.25h; Glovebox; Inert atmosphere; Sealed tube;

Reference： [1]Kondo, Hikaru; Kochi, Takuya; Kakiuchi, Fumitoshi [Organic Letters, 2017, vol. 19, # 4, p. 794 - 797]

21
[ 2040-04-2 ]
[ 501374-30-7 ]
1-(3-methoxy-4′-[trifluoromethyl][1,1′-biphenyl]-2-yl)ethan-1-one [ No CAS ]