Name: 70-70-2|4'-Hydroxypropiophenone|98%
Brand: Ambeed
SKU: A103825
Price: 5.0 USD
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1
[ 637-27-4 ]
[ 70-70-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	With trifluorormethanesulfonic acid at 0 - 20℃; for 4.5h; Inert atmosphere;	12.b (b) 4-Hydroxypropiophenone A mixture of phenyl propionate (1.0 g, 6.66 mmol) and trifluoromethanesulfonic acid (35 mL) was stirred at 0 °C for 30 minutes and at rt for 4 h and poured into cold water and ethyl acetate. CH2CI2 was added and the layers were separated. The aq layer was extractedwith CH2CI2 and the combined organic phases were washed with 1M HCI (aq, 1M), sat NaHCO3 (aq, sat), brine, dried over Na2504 and concentrated to give the sub-title compound (800 mg, 5.3 mmol, 80 %).
80%	With trifluorormethanesulfonic acid at 0 - 20℃; for 4.5h;	12.b 4-Hydroxypropiophenone A mixture of phenyl propionate (1.0 g, 6.66 mmol) and trifluoromethanesulfonic acid (35mL) was stirred at 0 °C for 30 minutes and at rt for 4 h and poured into cold water and ethylacetate. CH2CI2 was added and the layers were separated. The aq layer was extracted with CH2CI2 and the combined organic phases were washed with 1M HCI (aq, 1M), sat NaHCO3 (aq, sat), brine, dried over Na2504 and concentrated to give the sub-title compound (800 mg, 5.3 mmol, 80 %).
60%	With aluminium trichloride In nitrobenzene at 30℃; for 24h;

52%	With aluminum (III) chloride at 25 - 165℃; for 2h;	4.3.2. 4'-Hydroxy-3'-methylacetophenone (7a) General procedure: Anhydrous AlCl3 (22.2 g, 0.166 mol) was added in small portions to O-acetyl-2-methylphenol 6a (25 gm, 0.166 mol) at 25 °C and reaction temperature was slowly raised to 160 °C and stirred at the same temperature for 2 h. The reaction mixture was poured in ice cold 6 N HCl (500 ml) and extracted with ethyl acetate (200 ml × 3). The organic extract was washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure to yield 20 g crude product as thick oil. The crude product was purified by column chromatography (10% ethyl acetate in hexane) to give title compound 7a as yellow solid (7.0 g); yield: 28%
	With aluminium trichloride zuletzt bei 120grad;
	With aluminium trichloride; nitrobenzene
	With aluminium trichloride; chlorobenzene at 115℃;
	With aluminium trichloride
	With aluminium trichloride In nitrobenzene at 30℃; for 24h;

Reference： [1]Current Patent Assignee: ATROGI AB - WO2017/153737, 2017, A1 Location in patent: Page/Page column 54
[2]Current Patent Assignee: ATROGI AB - WO2019/53428, 2019, A1 Location in patent: Page/Page column 51
[3]Viswanathan; Kodgule; Chaudhari [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 15, p. 3532 - 3535]
[4]Location in patent: experimental part Makadia, Pankaj; Shah, Shailesh R.; Pingali, Harikishore; Zaware, Pandurang; Patel, Darshit; Pola, Suresh; Thube, Baban; Priyadarshini, Priyanka; Suthar, Dinesh; Shah, Maanan; Giri, Suresh; Trivedi, Chitrang; Jain, Mukul; Patel, Pankaj; Bahekar, Rajesh [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 2, p. 771 - 782]
[5]Farinholt; Harden; Twiss [Journal of the American Chemical Society, 1933, vol. 55, p. 3383,3386] Edkins; Linnell [Quarterly Journal of Pharmacy and Pharmacology, 1936, vol. 9, p. 203,215]
[6]Cullinane; Edwards [Journal of the Chemical Society, 1958, p. 2926,2929]
[7]Dongorozi [1957, vol. 8, p. 357,361]
[8]Krausz,F.; Martin,R. [Bulletin de la Societe Chimique de France, 1965, p. 2192 - 2197]
[9]Viswanathan; Chaudhari [Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 19, p. 6581 - 6585]

2
[ 637-27-4 ]
[ 610-99-1 ]
[ 70-70-2 ]

Reference： [1]Synthetic Communications,1999,vol. 29,p. 1195 - 1200
[2]Journal of the American Chemical Society,1952,vol. 74,p. 1249,1251
[3]Journal of the American Chemical Society,1932,vol. 53,p. 4153
[4]Journal of the American Chemical Society,1952,vol. 74,p. 1249,1251

3
[ 79-03-8 ]
[ 108-95-2 ]
[ 70-70-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With trifluorormethanesulfonic acid at 0 - 20℃; for 1h; regiospecific reaction;	4.3. General procedure of Friedel-Crafts acylation of phenols in TfOH General procedure: Phenol (0.28 mmol) and acyl chloride (0.28 mmol) were dissolved in TfOH (3 ml) at 0 °C. The reaction mixture was warmed to room temperature for appropriate time in Table 2, then poured into cold water and ethyl acetate. The organic layer was washed with 1 M HCl, saturated NaHCO3, and saturated NaCl, and dried over MgSO4, then filtrated. The filtrate was concentrated and the residue was subjected silica column chromatography to afford acylated products. All spectral data were identical with the literatures.27
53%	With aluminium trichloride In dichloromethane
	man verseift das Propionat mit alkoh. Kalilauge;

	With aluminium trichloride at 100℃; anschliessenden Erhitzen auf 130grad;
	With aluminium trichloride In dichloromethane 1.) 0 deg C, 30 min; 0 deg C, 30 min; 2.) room temperature, overnight;
	With aluminum (III) chloride In carbon disulfide
	With carbon disulfide; aluminum (III) chloride at 0℃;
	With aluminum (III) chloride In dichloromethane
	With aluminum (III) chloride In carbon disulfide	2.1. General procedure for the preparation of ethacrynic acidand its analogues General procedure: The synthesis of ethacrynic acid (IV-1) and its sevenanalogues (IV-2-8, Fig. 1) was accomplished by a threestepreaction shown in Scheme 1. The Friedel-Craftsacylation reaction of the phenol or the substituted phenolsI-1-4 (Scheme 1), respectively, with propanoyl chloride (n = 1) or butanoyl chloride (n = 2), respectively, wasperformed in the presence of powdered aluminiumchloride (AlCl3) in carbon disulfide, as recently describedby us [22]. Compounds II-1-8 were purified by flashcolumn chromatography on silica gel and consecutivelyrefluxed in acetone for 48 hours in the presence of 1.2equivalents of ethyl bromoacetate and two equivalentspotassium carbonate (K2CO3) to yield compounds III-1-8.In the third step, an aldol condensation reaction, compoundsIII-1-8 were refluxed in an ethanol/water (50/50)mixture for 24 hours in the presence of two equivalents offormaldehyde and 2.5 equivalents of K2CO3. CompoundsIV-1-8 were obtained by flash chromatography using ahexanes/ethyl acetate/methanol mixture as the eluent.
	Stage #1: phenol With aluminum (III) chloride In dichloromethane Stage #2: propionyl chloride In dichloromethane	General procedure: Aluminium chloride (4.5g, 33.8mmol) was added to a solutionof phenol (1.5g, 16.0mmol) in anhydrous dichloromethane(DCM) (15mL). The slurry was left to stir for 1hbefore acetyl chloride (1.3mL, 17.6mmol) was added in adropwise manner. The solution was left to stir for a further14h. The reaction was quenched using an ice-cold solution ofaqueous hydrochloric acid (HCl, 1M) (30mL) and extractedinto diethyl ether (DEE) (2x50mL). The combined organiclayer was extracted into sodium hydroxide (NaOH, 2M)(2x50mL) and then acidified to pH 2 using aqueous HCl(1M, 40mL). The product was extracted into DEE(2x50mL), the organic layer was washed with water(2x50mL) and dried over anhydrous magnesium sulfate(MgSO4). The solvent was removed under vacuum to give abrown solid. Column chromatography of the crude solidgave 5a as a white solid (1.6g, 73.5% yield); m.p.=109.4-110.3oC (lit. m.p.=110.2-110.4oC [12]); Rf: 0.35[DEE/petroleum spirit (40-60oC) (50:50)]. (max) (Film) cm-1:3315.6 (OH), 1661.6 (C=O), 1605.3 (Ar C=C); H(d6-Acetone): 9.20 (1H, s, OH), 7.89 (2H, dd, J=8.9Hz, Ph-H),6.91 (2H, dd, J=8.9Hz, Ph-H), 2.48 (3H, s, CH3); c(d6-Acetone): 196.36 (C=O), 162.63 (C-O), 131.57, 130.51,115.97 (Ar-C), 26.34 (CH3); GC: tR=5.6min; LRMS (m/z):136 (M+, 41%), 121 (M+-CH3, 100%), 93 (M+-C2H3O, 28%);HRMS (ES): found 137.05971 C8H9O2 requires 137.15586;Elemental analysis: found C 70.42%, H 5.88% C8H8O2 requiresC 70.58%, H 5.92%.Fig. (2). To show the theoretically derived TS for the oxidation ofthe C(17)-OH to the C(17)=O catalysed by 17-HSD3 [6].RR1OFig. (3). Proposed pharmacophore for the inhibition of type 1 and 3of the 17-HSD family of enzymes (R=hydrogen bonding group,e.g. OH; R1=alkyl or cycloalkyl moiety).

Reference： [1]Location in patent: experimental part Murashige, Ryo; Hayashi, Yuka; Ohmori, Syo; Torii, Ayuko; Aizu, Yoko; Muto, Yasuyuki; Murai, Yuta; Oda, Yuji; Hashimoto, Makoto [Tetrahedron, 2011, vol. 67, # 3, p. 641 - 649]
[2]Lota, Rupinder K.; Dhanani, Sachin; Owen, Caroline P.; Ahmed, Sabbir [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4519 - 4522]
[3]Perkin [Journal of the Chemical Society, 1889, vol. 55, p. 551][Journal of the Chemical Society, 1896, vol. 69, p. 1176]
[4]Torres; Amargos [Anales de la Real Sociedad Espanola de Fisica y Quimica, 1933, vol. 31, p. 37,42]
[5]Malthete, Jacques; Canceill, Josette; Gabard, Jacqueline; Jacques, Jean [Tetrahedron, 1981, vol. 37, # 16, p. 2815 - 2821]
[6]Location in patent: experimental part Janser, Romy F.J.; Meka, Ranjith K.; Bryant, Zack E.; Adogla, Enoch A.; Vogel, Elizabeth K.; Wharton, Jaimie L.; Tilley, Cynthia M.; Kaminski, Catherine N.; Ferrey, Seth L.; Van slambrouck, Severine; Steelant, Wim F.A.; Janser, Ingo [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 6, p. 1848 - 1850]
[7]Location in patent: scheme or table Bryant, Zack E.; Janser, Romy F.J.; Jabarkhail, Medina; Candelaria-Lyons, Melissa S.; Romero, Brittni B.; Slambrouck, Severine Van; Steelant, Wim F.A.; Janser, Ingo [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 3, p. 912 - 915]
[8]Location in patent: scheme or table Olusanjo, Moniola S.; Mashru, Shreena N.; Cartledge, Timothy; Ahmed, Sabbir [Letters in drug design and discovery, 2012, vol. 9, # 6, p. 604 - 610]
[9]Janser, Ingo; Vortolomei, Caitlyn M.; Meka, Ranjith K.; Walsh, Courtney A.; Janser, Romy F.J. [Comptes Rendus Chimie, 2013, vol. 16, # 7, p. 660 - 664]
[10]Olusanjo, Moniola S.; Cartledge, Timothy; Shah, Kruti; Ahmed, Sabbir [Letters in drug design and discovery, 2011, vol. 8, # 3, p. 253 - 259]

4
[ 80-46-6 ]
[ 802294-64-0 ]
[ 859059-71-5 ]
[ 70-70-2 ]

Reference： [1]Bulletin de la Societe Chimique de France,1956,p. 629,631

5
[ 106-93-4 ]
[ 70-70-2 ]
[ 103509-19-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In pentane at 110℃; Inert atmosphere;	1.1 Preparation of the Bridging Anchor Molecule Under a protective gas atmosphere 3.05 g (22.02 mmol) of potassium carbonate and 1.10 g (7.34 mmol) of hydroxypropiophenone in 25 mE of n-pentane were charged into a 3-neck flask. 0.65 ml (7.5 mmol) of dibromoethane was added dropwise thereto and the mixture was heated to 1100 C. with stirring. The reaction mixture was stirred overnight at this temperature. Next, the mixture was filtered through a glass frit (filled with Celite) and washed twice with acetone, and the solvent was removed at reduced pressure. GC/MS: (25-320 M), mlz: 326, 297, 177, 163, 147, 134, 121, 104, 92, 77, 66, 57. tR (25-320M)=24.224. ‘H NMR: (400 MHz, CDC13) ö (ppm)=7.88 (d, 4H); 6.91 (d, 4H); 4.35 (s, 4H); 2.90 (m, 4H); 1.17 (m, 6H).
	With sodium hydroxide

Reference： [1]Current Patent Assignee: HENKEL AG & CO. KGAA - US2016/362356, 2016, A1 Location in patent: Paragraph 0100; 0101; 0102; 103
[2]Current Patent Assignee: ELI LILLY & CO - US2798094, 1956, A

6
[ 106-95-6 ]
[ 70-70-2 ]
[ 2089-23-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 12h;	229A EXAMPLE 229A, 1-(4-Allyloxy-phenyl)-propan-1-one To 1-(4-hydroxy-phenyl)-propan-1-one (4.6 g, 30 mmol) and K2CO3 (5 g, 36 mmol) in DMF (10 mL) was added allylbromide (7.26 g, 60 mmol) dropwise with violent stirring. The reaction mixture was stirred at room temperature for 12 h and filtered to remove salt. The filtrate was concentrated to yield the titled compound (5.5 g, 97%) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 7.94 (d, 2H, J=9.0 Hz), 7.05 (d, 2H, J=9.0 Hz), 6.05 (m, 1H), 5.44, 5.38, 5.30, 5.26 (4d, 2H, J=3.0 Hz), 4.66 (d, 2H, J=6.0 Hz), 2.98 (q, 2H, J=7.5 Hz), 1.07 (t, 3H, J=7.5 Hz). MS (ESI) m/e 191 (M+H)+; 189 (M-H)-.
89.4%	at 75 - 90℃; for 6h;
	With sodium hydroxide

	With potassium carbonate; acetone
	With potassium carbonate; butanone
17.3 g	With potassium carbonate In N,N-dimethyl-formamide at 60 - 90℃;	1.1-1; 1.1-1.1 Preparation: 1) Weigh 15g 4-hydroxypropiophenone and 13g 3-bromopropene, dissolve it in 100ml DMF, add 15g potassium carbonate, and react at 60-90°C until the reaction is complete. Cooled to room temperature, added water, extracted with ethyl acetate, the organic phase was rotary evaporated under reduced pressure, and the solvent was removed to obtain 17.3 g of Intermediate 1-1;

Reference： [1]Current Patent Assignee: ABBVIE INC - US2005/38068, 2005, A1 Location in patent: Page/Page column 67-68
[2]Bauld, Nathan L.; Yang, Jingkui [Journal of Physical Organic Chemistry, 2000, vol. 13, # 9, p. 518 - 522]
[3]Buu-Hoi; Hoan; Jacquignon [Recueil des Travaux Chimiques des Pays-Bas, 1949, vol. 68, p. 781,785]
[4]Takahashi; Oshika [Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan, 1954, vol. 74, p. 48,50][Chem.Abstr., 1955, p. 1623]
[5]Nitz et al. [Arzneimittel-Forschung/Drug Research, 1955, vol. 5, p. 357,358]
[6]Current Patent Assignee: CHONGQING ACADEMY OF AGRICULTURAL SCIENCES; CHONGQING INST FOR FOOD AND DRUG CONTROL; SHENZHEN BIOEASY BIOTECHNOLOGY CO LTD - CN111978271, 2020, A Location in patent: Paragraph 0101; 0135-0137

7
[ 77-78-1 ]
[ 70-70-2 ]
[ 121-97-1 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate In acetonitrile for 20.5h; Heating / reflux;	12; 16 4'-Methoxypropiophenone; Scheme 12 To a solution of 4 -HYDROXYPROPIOPHENONE (1.0 g, 6.67 mmol) in ACETONITRILE (50.0 mL) was added potassium carbonate (7. 17 g, 66.7 mmol) and the mixture heated to reflux for 90 min. After this time the reaction mixture was allowed to cool to room temperature and dimethyl sulphate (1. 05 mL, 11.1 mmol) was added and the reaction mixture was heated to reflux for a further 19 h. After cooling the ACETONITRILE was evaporated under reduced pressure and the residue taken up in water and extracted with dichloromethane. The dichloromethane extract was dried (MGSO4) and evaporated under reduced pressure to give 4 -METHOXYPROPIOPHENONE as a yellow oil, (970 mg, 89 %) LH NMR (D6-DMSO, 300 MHz) 1.06, t (7.2 Hz), CH3 ; 2.95, q (7.2 Hz), CH2 ; 3. 83, s, OMe; 7.02, d (6.9 Hz), H3', 5 ; 7.93, d (6.9 Hz), H2 , 6'. ESI (+ve) MS M/ZL65 (M+H, 100%).
	With sodium hydroxide
	With hydroxide

Reference： [1]Current Patent Assignee: CORTICAL - WO2004/89927, 2004, A1 Location in patent: Page 34; 67
[2]Bernstein; Wallis [Journal of the American Chemical Society, 1940, vol. 62, p. 2871]
[3]Orth,W.A.; Riedl,W. [Justus Liebigs Annalen der Chemie, 1963, vol. 663, p. 74 - 82]

8
[ 70-70-2 ]
[ 53946-87-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With pyridinium hydrobromide perbromide; acetic acid; at 20℃; for 3.08333h;Product distribution / selectivity;	Step 5 2-bromo- 1 -("4-hydroxyphenv?propan- 1 -one; Acetic acid (25 ml) was added to l-(4-hydroxyphenyl)propan-l-one (10.000 g, 66.587 mmol) and pyridine hydroperbromide (24.767 g, 69.916 mmol) at rt. The reaction mixture was stirred at rt for 3 h and 5 min. Water (1 10 ml) was added dropwise during 20 min and after 30 min of stirring more water (40 ml) was added during 5 min. The mixture was cooled to 0 0C and left at rt overnight. Solid material had formed in the reaction mixture which was collected by filtration, washed with water and dried under vacuum to yield the product as a solid (13.76 g, 90%). 1H-NMR (400 MHz, CDCl3) delta 7.96 (d, 2H), 6.91 (d, 2H), 5.25 (q, IH), 1.87 (d, 3H). MS m/z 229 (M+H)+.Alternatively the reaction was performed by adding a mixture of l-(4-hydroxyphenyl)- propan-1-one (1 equivalent) in ethyl acetate (5 volumes) to a mixture of ground CuBr2 (2 equivs) in ethyl acetate (7.5 volumes) which was being boiled under reflux with vigorous stirring. After boiling for 4 hours the mixture was filtered at 600C through a filtration aid. The residue was washed with ethyl acetate and the filtrate and washings were treated with activated charcoal, filtered and evaporated to give the product.
66%	With pyridinium hydrobromide perbromide; acetic acid; at 20℃; for 3.0h;	Step-1: Preparation of 2-bromo-l-(4-hydroxyphenyl)propan-l-one [0136] To stirred solution of 2-bromo-l-(4-hydroxyphenyl)propan-l-one (1.0 g, 6.67 mmol) in acetic acid (2.5 mL) was added pyridinium tribromide (2.3 g, 7.33 mmol) at room temperature and stirred for 3 h. After completion of reaction (monitored by TLC), the reaction mixture was diluted with cold water (100 mL) and stirred for 30 min, product get precipitated. The solid was filtered, washed thoroughly with water, dried to afford the title compound 2-bromo-l-(4-hydroxyphenyl)propan-l-one (1.0 g, 66 % yield) as a white solid and taken for next step without purification. Calculated (M+H): 228.98; Found (M+2H): 231.0.
61.3%	With bromine; In chloroform; ethyl acetate;	General procedure: (substituted) acetophenone or propiophenone(ACM) (1.0 eq) was dissolved in the mixture solvent of chloroform andethyl acetate (1:1) and then heated to 2re(1f.6u-x2,.0Ceuq)Brwasadded in portions. The reaction was monitored by HPLC (mobile phase:acetonitrile/H2O=40:60, 1 mL/min, 20 min, 254 nm). After reaction,the mixture was filtered and washed with solvent, the filtrate wasevaporated, and the residue was purified by flash column chromatographyon silica gel to give intermediates ACM-Br.

	With bromine; In 1,4-dioxane; diethyl ether; water; toluene;	EXAMPLE 2 2-Bromo-4'-hydroxypropiophenone 15 g (0.12 mol) of p-hydroxypropiophenone are added to a mixture of 16 ml of dioxane and 60 ml of diethyl ether. The suspension is heated to 30 C. and 22.4 g (0.14 mol) of bromine are added dropwise. Stirring is continued for 1 hour at ambient temperature. 40 ml of water and 40 ml of diethyl ether are then added, the organic phase is decanted, washed with water and dried over magnesium sulphate and the solvent is driven off to give a crude product. Recrystallization of the crude product from toluene gives 18 g of fine lilac crystals which melt at 95-97 C.
	With copper(ll) bromide; In ethyl acetate; for 2.0h;Reflux;Product distribution / selectivity;	40 mL of ethyl acetate was added to 6.26 g (corresponding to 27.9 mmol) of cupric bromide to obtain a suspension, to which 2.00 g (corresponding to 13.3 mmol) of 4'-hydroxypropiophenone was added. Then, the resulting mixture was heated under reflux. After 2 hours, the reaction mixture was cooled down to room temperature and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: a hexane/ethyl acetate = 3/1), to obtain 3.49 g (corresponding to 15.2 mmol) of 2-bromo-4'-, hydroxypropiophenone (Fig. 1, Step 1).
	With copper(ll) bromide; In ethyl acetate; for 4.0h;Heating / reflux;Product distribution / selectivity;	Step 5 2-bromo- 1 -("4-hydroxyphenv?propan- 1 -one; Acetic acid (25 ml) was added to l-(4-hydroxyphenyl)propan-l-one (10.000 g, 66.587 mmol) and pyridine hydroperbromide (24.767 g, 69.916 mmol) at rt. The reaction mixture was stirred at rt for 3 h and 5 min. Water (1 10 ml) was added dropwise during 20 min and after 30 min of stirring more water (40 ml) was added during 5 min. The mixture was cooled to 0 0C and left at rt overnight. Solid material had formed in the reaction mixture which was collected by filtration, washed with water and dried under vacuum to yield the product as a solid (13.76 g, 90%). 1H-NMR (400 MHz, CDCl3) delta 7.96 (d, 2H), 6.91 (d, 2H), 5.25 (q, IH), 1.87 (d, 3H). MS m/z 229 (M+H)+.Alternatively the reaction was performed by adding a mixture of l-(4-hydroxyphenyl)- propan-1-one (1 equivalent) in ethyl acetate (5 volumes) to a mixture of ground CuBr2 (2 equivs) in ethyl acetate (7.5 volumes) which was being boiled under reflux with vigorous stirring. After boiling for 4 hours the mixture was filtered at 600C through a filtration aid. The residue was washed with ethyl acetate and the filtrate and washings were treated with activated charcoal, filtered and evaporated to give the product.

Reference： [1]Patent: WO2008/120000,2008,A1 .Location in patent: Page/Page column 34
[2]Patent: WO2015/48507,2015,A1 .Location in patent: Paragraph 0136
[3]Journal of Photochemistry and Photobiology A: Chemistry,2020,vol. 388
[4]Journal of the Chemical Society,1954,p. 1034,1037
[5]Patent: US4690931,1987,A
[6]Patent: WO2007/918,2007,A1 .Location in patent: Page/Page column 14-15
[7]Patent: EP2213672,2010,A1 .Location in patent: Page/Page column 9; 25
[8]Patent: WO2008/120000,2008,A1 .Location in patent: Page/Page column 34
[9]Tetrahedron,2018,vol. 74,p. 6922 - 6928
[10]RSC Advances,2019,vol. 9,p. 2092 - 2101
[11]Tetrahedron,2019,vol. 75

9
[ 70-70-2 ]
[ 645-56-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	In ethanol at 34℃; for 0.833333h;
	With palladium on activated charcoal; ethanol Hydrogenation;
	With methanol; copper oxide-chromium oxide at 115 - 125℃; Hydrogenation;

	With sodium hydroxide; aluminum nickel at 90℃; Hydrogenation;
	In methanol	1.A Example 1A Example 1A : Synthesis of 4-propyl phenol A 500 ml autoclave was fed with 4-hydroxypropiophenone (30 g; 0.2 mols) in methanol (100 ml) and 5% Pd/C (1 g; 50% wet). Once the mixture had been washed with nitrogen, it was hydrogenated at room temperature and atmospheric pressure. The catalyst was filtered and the product was evaporated in vacuo (40°C / 24 mbar). 4-Propyl phenol was obtained in a quantitative yield.
	In methanol	1.A Synthesis of 4-propyl Phenol EXAMPLE 1A Synthesis of 4-propyl Phenol A 500 ml autoclave was fed with 4-hydroxypropiophenone (30 g; 0.2 mols) in methanol (100 ml) and 5% Pd/C (1 g; 50% wet). Once the mixture had been washed with nitrogen, it was hydrogenated at room temperature and atmospheric pressure. The catalyst was filtered and the product was evaporated in vacuo (40° C./24 mbar). 4-Propyl phenol was obtained in a quantitative yield.
93 %Chromat.	With ethanol at 20℃; for 12h; Inert atmosphere; Irradiation; Sealed tube; Green chemistry;

Reference： [1]NEUBERT; STAHL; CLINE [Molecular Crystals and Liquid Crystals (1969-1991), 1982, vol. V 89, # N 1-4, p. 93 - 117]
[2]Hartung; Crossley [Journal of the American Chemical Society, 1934, vol. 56, p. 158]
[3]Nightingale; Radford [Journal of Organic Chemistry, 1949, vol. 14, p. 1089,1091]
[4]Papa; Schwenk; Whitman [Journal of Organic Chemistry, 1942, vol. 7, p. 587,589]
[5]Current Patent Assignee: ENDURA SPA - EP1048664, 2000, A2
[6]Current Patent Assignee: ENDURA SPA - US6252092, 2001, B1
[7]Gao, Zhuyan; Han, Jianyu; Hong, Feng; Lei, Lijun; Li, Hongji; Liu, Huifang; Luo, Nengchao; Wang, Feng [Green Chemistry, 2020, vol. 22, # 12, p. 3802 - 3808]

10
[ 70-70-2 ]
[ 50916-44-4 ]

Yield	Reaction Conditions	Operation in experiment
69.3%	With sulfuric acid; potassium nitrate at 3℃; for 0.0666667h;	1.G 1G. 1-(4-hydroxy-3-nitrophenyl)propan-1-one 1G. 1-(4-hydroxy-3-nitrophenyl)propan-1-one To a stirred conc. H2SO4 (100 ml, 1876 mmol) at 3° C. was added 1-(4-hydroxyphenyl)propan-1-one (10.0 g, 66.6 mmol) followed by potassium nitrate (8.08 g, 80 mmol) in two approximately equal portions about 4 minutes apart. The reaction was slowly poured into crushed ice/water mixture and was extracted with ethyl acetate (200 mL). Organic layer was concentrated in vacuo to give 1G (yellow solid, 9.0 g, 46.1 mmol, 69.3% yield). 1H NMR (400 MHz, CDCl3) δ 10.89 (s, 1H), 8.73 (d, J=2.40 Hz, 1H), 8.22 (dd, J=2.00, 8.80 Hz, 1H), 7.24 (d, J=8.80 Hz, 1H), 2.50 (q, J=7.20 Hz, 2H), 1.24 (t, J=7.20 Hz, 3H).
25%	With Iron(III) nitrate nonahydrate In industrial methylated spirit at 80℃;
	With nitric acid at -8℃;

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2020/69646, 2020, A1 Location in patent: Paragraph 0326
[2]Location in patent: scheme or table Chancellor, Daniel R.; Davies, Kay E.; De Moor, Olivier; Dorgan, Colin R.; Johnson, Peter D.; Lambert, Adam G.; Lawrence, Daniel; Lecci, Cristina; Maillol, Carole; Middleton, Penny J.; Nugent, Gary; Poignant, Séverine D.; Potter, Allyson C.; Price, Paul D.; Pye, Richard J.; Storer, Richard; Tinsley, Jonathon M.; Van Well, Renate; Vickers, Richard; Vile, Julia; Wilkes, Fraser J.; Wilson, Francis X.; Wren, Stephen P.; Wynne, Graham M. [Journal of Medicinal Chemistry, 2011, vol. 54, # 9, p. 3241 - 3250]
[3]Edkins; Linnell [Quarterly Journal of Pharmacy and Pharmacology, 1936, vol. 9, p. 203,215]

11
[ 18180-30-8 ]
[ 70-70-2 ]
[ 16221-32-2 ]

Reference： [1]Bulletin de la Societe Chimique de France,1967,p. 3190 - 3195

12
[ 100-44-7 ]
[ 70-70-2 ]
[ 4495-66-3 ]

Yield	Reaction Conditions	Operation in experiment
91.5%	With potassium carbonate In propan-2-one for 24h; Reflux;	1.C Preparation of 1- (4-benzyloxyphenyl) -1-propanone 1- (4-hydroxyphenyl) -1-propanone (20.0g, 0.146mol), anhydrous potassium carbonate (100.7g, 0.730mol) placed 1000mL round-bottomed flask, acetone as solvent, was added dropwise benzyl chloride (22.3g, 0.176mol), reflux for 24h, the solvent was evaporated under reduced pressure, the residue was stirred with water, suction filtered and dried to give a white solid 30.4g, a yield of 91.5%. m.p.101-102 . ESI-MS: m / z241 ([M + H] +).
91.1%	With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 65℃; Large scale;	Step 1, the synthesis of BAZ-A-1 S11: in a 20L reaction kettle, drop into 1800g of p-hydroxypropiophenone and 5040g of DMF, and stir to dissolve completely; S12: drop into 1822g potassium carbonate, 1669g benzyl chloride, 72g sodium iodide, be warming up to 65 of conditions and start the reaction;S13: The reaction is completed, 242 g of triethylamine are put in, and the temperature is kept at 65° C. and stirred for 1 h; S14: The temperature is controlled at 65°C, and 12.2L warm water is added dropwise; S15: After the dropwise addition is completed, the temperature is lowered to 20°C, and the crystallization is performed for more than 1 hour;S16: centrifugation, the filter cake was washed with 3.6L warm water and 1422g methanol successively to obtain a white wet product; S17: Dry the white wet product under reduced pressure at a drying temperature of 63 °C and a vacuum degree of -0.08 MPa to a moisture content of less than 0.5% to obtain 2623 g of white dry product, which is BAZ-A-1, and the yield is 91.1%, the BAZ-A-1 is 4-benzyloxypropiophenone;
	With potassium carbonate In propan-2-one Heating;

	With sodium hydroxide
	With sodium hydroxide In water monomer for 4h; Heating;
	With potassium carbonate In propan-2-one for 24h; Reflux;	1.1 1) Preparation of intermediate 1 Take 20 g of 4-hydroxypropanone and 100 g of anhydrous potassium carbonate and dissolve in 20 times the amount of acetone.Then, 22 g of lower benzyl chloride was reacted therein for 24 h under reflux,The solvent acetone was distilled off under reduced pressure. The residue was stirred with water, filtered, and dried. The obtained white solid was intermediate 1.
	Stage #1: p-hydroxypropiophenone With tetrabutylammonium bromide In water monomer; toluene at 90℃; Reflux; Large scale; Stage #2: benzyl chloride In water monomer; toluene Reflux; Large scale;	1.I Step I: Preparation of 4-benzyloxypropiophenone Distilled water (15 Kg), sodium hydrate (4.50 Kg; 0.1125 moles), toluene (57.0 Kg), 4-hydroxypropiophenone (15.0 Kg; 0.10 moles) and tetrabutylammonium bromide (0.75 Kg) are loaded into a reactor. The mass is reflux heated (about 90° C.), and benzyl chloride (14.25 Kg; 0.1125 moles) is then added. The mass is maintained at reflux until complete conversion, and the aqueous phase is then separated and eliminated. The resulting toluene solution is cooled to 15-25° C. and sent to the next step without further processing.

Reference： [1]Current Patent Assignee: SHENYANG PHARMACEUTICAL UNIVERSITY - CN105801564, 2016, A Location in patent: Paragraph 0026; 0030; 0035; 0036
[2]Current Patent Assignee: ANHUI TINGWORLD PHARMACEUTICAL - CN113816892, 2021, A Location in patent: Paragraph 0017; 0129-0135
[3]Rao, K. V. B.; Iyer, R. N. [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1980, vol. 19, # 1, p. 54 - 58]
[4]Viswanathan; Kodgule; Chaudhari [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 15, p. 3532 - 3535]
[5]Viswanathan; Chaudhari [Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 19, p. 6581 - 6585]
[6]Current Patent Assignee: JIAXING JUETUO TECH - CN110256410, 2019, A Location in patent: Paragraph 0065; 0070; 0072
[7]Current Patent Assignee: ERREGIERRE SPA. - US2019/389842, 2019, A1 Location in patent: Paragraph 0058

13
[ 1009-11-6 ]
[ 109-70-6 ]
[ 70-70-2 ]

Reference： [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 1778 - 1785
[2]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2031 - 2034

14
[ 109-70-6 ]
[ 70-70-2 ]
[ 65976-48-9 ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate In acetone for 24h; Heating;
65%	With potassium carbonate In acetone at 80℃;
	With potassium hydroxide In methanol for 24h; Heating;

	With potassium carbonate In butanone for 24h; Heating;
	With potassium hydroxide; potassium carbonate In acetone; benzene	76 1-[4-(3-Chloropropoxy)phenyl]-1-propanone PREPARATION 76 1-[4-(3-Chloropropoxy)phenyl]-1-propanone A mixture of 37.6 g (0.25 mole) of 4'-hydroxypropiophenone (97%)*, 78.7 g (0.5 mole) of 1-bromo-3-chloropropane and 103.5 g (0.75 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 18 hr. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure. The oily residue was dissolved in 500 ml of benzene and the solution stirred with potassium hydroxide pellets for 1.5 hr to remove unreacted phenol. The mixture was filtered and the filtrate was concentrated to give 56.1 g (99% yield) of title compound as an oil. The oil gradually crystallized and a portion of the solid was recrystallized from petroleum ether (60°-110° C.) to yield title compound as a fluffy, white solid, mp 41°-43° C. Available commercially, e.g., Aldrich Chemical Co., Inc., 940 West Saint Paul Avenue, Milwaukee, Wis. 53233 USA. Analysis: Calculated for C12 H15 ClO2: C, 63.58; H, 6.67. Found: C, 63.46; H, 6.82.
	With potassium carbonate In acetone at 80℃; for 15h;

Reference： [1]Walsh, David A.; Franzyshen, Stephen K.; Yanni, John M. [Journal of Medicinal Chemistry, 1989, vol. 32, # 1, p. 105 - 118]
[2]Location in patent: scheme or table Hudkins, Robert L.; Aimone, Lisa D.; Bailey, Thomas R.; Bendesky, Robert J.; Dandu, Reddeppa Reddy; Dunn, Derek; Gruner, John A.; Josef, Kurt A.; Lin, Yin-Guo; Lyons, Jacquelyn; Marcy, Val R.; Mathiasen, Joanne R.; Sundar, Babu G.; Tao, Ming; Zulli, Allison L.; Raddatz, Rita; Bacon, Edward R. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5493 - 5497]
[3]Sanfilippo; Urbanski; Press; Hajos; Shriver; Scott [Journal of Medicinal Chemistry, 1988, vol. 31, # 9, p. 1778 - 1785]
[4]Faghih, Ramin; Dwight, Wesley; Gentles, Robert; Phelan, Kathleen; Esbenshade, Timothy A; Ireland, Lynne; Miller, Thomas R; Kang, Chae-Hee; Fox, Gerard B; Gopalakrishnan, Sujatha M; Hancock, Arthur A; Bennani, Youssef L [Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 15, p. 2031 - 2034]
[5]Current Patent Assignee: PFIZER INC - US4950674, 1990, A
[6]Location in patent: scheme or table Sundar, Babu G.; Bailey, Thomas R.; Dunn, Derek; Hostetler, Greg A.; Chatterjee, Sankar; Bacon, Edward R.; Yue, Christoph; Schweizer, Dominique; Aimone, Lisa D.; Gruner, John A.; Lyons, Jacquelyn; Raddatz, Rita; Lesur, Brigitte [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1546 - 1549]

15
[ 100-63-0 ]
[ 70-70-2 ]
[ 69181-53-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With acetic acid; zinc(II) chloride at 20 - 90℃; for 6h; Inert atmosphere;	1 Example 1. Synthesis of 4-(3-methyl-1H-indol-2-yl)phenol A three-neck 1 L flask was charged with 4′-hydroxypropiophenone (100 g, 0.67 mol) in acetic acid (500 mL). The content of this flask was purged with argon for 10 min. To this solution was added phenyl hydrazine (86.4 g, 0.8 mol) at room temperature while stirring. A slight exotherm (to 38° C.) was noticed. Then, zinc(II) chloride (91 g, 0.67 mol) was added as a single portion. Again, slight exotherm to around 40° C. was observed. The temperature control was increased to 70° C. while stirring was kept constant at 400-500 rpm. Special care must be taken because the reaction is exothermic (cooling of the flask in a water bath can be needed). When the exotherm was over, the temperature was then stabilized and kept at 90° C. (0956) After six hours at 90° C., the set-up was cooled down to room temperature with an ice bath. The resulting mixture was filtrated (on a glass filter) to remove as much salt as possible and then, some water ( 1/10 of the total volume: 50 mL here) was added and the bulk acetic acid was removed in vacuo. The resulting residue was redissolved in diethylether (750 mL)+75 mL of water to help the dissolution, and transferred to a big beaker (3 L). Then, solid K2CO3 was slowly added until no CO2 formation was detected (efficient stirring). The content of the beaker was then decanted to remove the formed potassium acetate (in the water phase) and the organic phase was collected in a separation funnel. It was washed with sodium bicarbonate (2 times around 50 mL of saturated solution), water (2 times around 50 mL) and then brine (saturated NaCl solution, 50 mL). The washed organic phase was then dried over magnesium sulphate, filtered over a glass filter and the solvent was removed under reduced pressure affording a dark yellow oil (approximately 130 g, around 85-90% yield). (0957) 1H-NMR (DMSO-d6, 300 MHz) δ=10.99 (s (br.), 1H, -OH), 9.63 (s (br.), 1H, -NH), 7.51 (d, 1H, J=8.7 Hz, -CHAr), 7.53-7.49 (band, 2H, -CHAr), 7.34 (dt, 1H, J=7.5 and 0.9 Hz, -CHAr), 7.05 (m, 2H, J=7.5 Hz, -CHAr), 6.94 (d, 1H, J=8.7 Hz, -CHAr), 6.94 (m, 1H, -CHAr) and 2.39 (s, 3H, -CH3) ppm. (0958) 1H-NMR (CDCl3, 300 MHz) δ=7.93 (s (br.), 1H, -NH), 7.57 (d(br.), 1H, J=7.6 Hz, -HAr), 7.45 (m, 2H, J=8.7 Hz, 2×-HAr), 7.34 (d(br.), 1H, J=7.9 Hz, -HAr), 7.15 (app. dtd, 2H, J=14.5, 7.0 and 1.3 Hz, -HAr), 6.93 (m, 2H, -HAr), 4.98 (s(br.), 1H, -OH), 2.42 (s, 3H, -CH3) ppm.
25%	With hydrogenchloride In ethanol; water for 5h; Heating;

Reference： [1]Current Patent Assignee: GHENT UNIVERSITY; RECTICEL SA - US2021/371576, 2021, A1 Location in patent: Paragraph 0954-0958
[2]Kumar, Surat; Rastogi, Shri Nivas [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1983, vol. 22, # 7, p. 659 - 663]

16
[ 358-23-6 ]
[ 70-70-2 ]
[ 87241-55-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With 2,6-dimethylpyridine; dmap In dichloromethane for 2h; Ambient temperature;
90%	With dmap In dichloromethane at -20 - 20℃; Inert atmosphere;
88%	With pyridine In dichloromethane at 0 - 20℃;

88%	With pyridine In dichloromethane at 0 - 20℃; Inert atmosphere;
14 g	With 2,6-dimethylpyridine; dmap In dichloromethane at 20℃; for 2h;

Reference： [1]Gerlach, Uwe; Wollmann, Theo [Tetrahedron Letters, 1992, vol. 33, # 38, p. 5499 - 5502]
[2]Swart, Marthinus R.; Twigge, Linette; Erasmus, Elizabeth; Marais, Charlene; Bezuidenhoudt, Barend C. B. [European Journal of Inorganic Chemistry, 2021, vol. 2021, # 18, p. 1752 - 1762]
[3]Goossen, Lukas J.; Rodriguez, Nuria; Linder, Christophe [Journal of the American Chemical Society, 2008, vol. 130, # 46, p. 15248 - 15249]
[4]Goossen, Lukas J.; Linder, Christophe; Rodriguez, Nuria; Lange, Paul P. [Chemistry - A European Journal, 2009, vol. 15, # 37, p. 9336 - 9349]
[5]Gangjee, Aleem; Zeng, Yibin; McGuire, John J.; Kisliuk, Roy L. [Journal of Medicinal Chemistry, 2002, vol. 45, # 9, p. 1942 - 1948]

17
[ 646-06-0 ]
[ 6091-44-7 ]
[ 70-70-2 ]
1-(4-Hydroxy-phenyl)-2-methyl-3-piperidin-1-yl-propan-1-one; hydrochloride [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1994,vol. 42,p. 1676 - 1678

18
[ 4495-66-3 ]
[ 70-70-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	With hydrogen; nickel In isopropyl alcohol at 60℃; 20-24 h;
	With trifluoroacetic acid

Reference： [1]Regla, Ignacio; Reyes, Adelfo; Koerber, Claudia; Demare, Patricia; Estrada, Osvaldo; Juaristi, Eusebio [Synthetic Communications, 1997, vol. 27, # 5, p. 817 - 823]
[2]Marsh,J.P.; Goodman,L. [Journal of Organic Chemistry, 1965, vol. 30, p. 2491 - 2492]

19
[ 70-70-2 ]
[ 133595-72-9 ]

Yield	Reaction Conditions	Operation in experiment
44%	With hydroxylamine hydrochloride; potassium acetate In ethanol; water for 6h; Heating;
	With hydroxylamine hydrochloride; sodium acetate In ethanol at 60℃; for 6h;	73 First step, hydroxyamine hydrochloride (4.60 g) and NaOAc (10.9 g) were added to a solution of 1-(4-hydroxy)-propiophenone (5 g) in EtOH (80 ml). The reaction mixture was stirred at 60°C for 6 h. EtOH was removed under reduced pressure. H2O (40 ml) was added to the residue, and the resulting solution was extracted with EtOAc (3 × 40 ml). The EtOAc of the combined organic layer was removed by rotary evaporation under reduced pressure to yield 1-(4-hydroxy)-propiophenone oxime (2.72 g) as a pale yellowish solid. Second step, a solution of 1-(4-hydroxy)-propiophenone oxime (2.72 g) and concentrated HCl (7.25 ml) in EtOH (50 ml) was subjected to hydrogenation at atmospheric pressure in the presence of 10% Pd/C (350 mg). The reaction solution was filtered and the filtrate was concentrated to yield 1-(4-hydroxyphenyl)-propylamine hydrochloride (3.1 g) as a white solid. Third step, a mixture of 1-(4-hydroxyphenyl)-propylamine (392 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60 ml) was heated to 70°C and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20 : 1) to yield N6-[(+/-)-1-(4-hydroxyphenyl)-propyl]-adenosine(225 mg) as a white solid: positive ESIMS m/z 402 [M + H]+ and 424 [M + Na]+; negative ESIMS m/z 400 [M - H]- [Show Image] 436 [M + Cl]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety δ 8.34 (1H, s, H-2), 8.14 (2H, s, H-8, -NH), 5.85 (1H, d, J= 5.7 Hz, H-1'), 5.40 (1H, m, -OH), 5.15 (2H, m, 2×-OH), 4.58 (1H, m, H-2'), 4.12 (1H, m, H-3'), 3.93 (1H, m, H-4'), 3.67 (1H, m, H-5'a), 3.56 (1H, m, H-5'b); the (+/-)-1-(4-hydroxyphenyl)-propyl moiety δ 9.19 (1H, s, -OH), 7.23 (1H, d, J = 8.1 Hz, H-2", H-6"), 6.65 (1H, d, J = 8.1 Hz, H-3", H-5"), 5.40 (1H, m, H-7"), 1.90 (1H, m, H-8"a), 1.78 (1H, m, H-8"b), 0.85 (3H, t, J = 6.6 Hz, H-9"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety δ 154.3 (s, C-6), 152.4 (d, C-2), 148.5 (s, C-4), 139.8 (d, C-8), 119.8 (s, C-5), 88.2 (d, C-1'), 86.0 (d, C-4'), 73.6 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-5'); the (+/-)-1-(4-hydroxyphenyl)-propyl moiety δ 156.1 (s, C-4"), 134.4 (s, C-1"), 127.9 (d, C-2", C-6"), 115.0 (d, C-3", C-5"), 54.7 (d, C-7"), 29.1 (t, C-8"), 11.5 (q, C-9").
2.72 g	With hydroxylamine hydrochloride; sodium acetate In ethanol at 60℃; for 6h;	73 First step, hydroxyamine hydrochloride (4.60 g) and NaOAc (10.9 g) were added to a solution of 1-(4-hydroxy)-propiophenone (5 g) in EtOH (80 ml). The reaction mixture was stirred at 60° C. for 6 h. EtOH was removed under reduced pressure. H2O (40 ml) was added to the residue, and the resulting solution was extracted with EtOAc (3*40 ml). The EtOAc of the combined organic layer was removed by rotary evaporation under reduced pressure to yield 1-(4-hydroxy)-propiophenone oxime (2.72 g) as a pale yellowish solid.

2.72 g

With hydroxylamine hydrochloride; sodium acetate In ethanol at 60℃; for 6h;

73.1 First step 1-(4-hydroxy)propiophenone (5 g), hydroxylamine hydrochloride (4.60 g) and anhydrous sodium acetate (10.9 g) were weighed and dissolved together in ethanol (80 ml) Mixer reaction at 60 ° C for 6 h. The solvent was recovered with the reaction solution, suspended and dissolved with water (40 ml), and extracted from ethyl acetate (40 ml '3), and the solution was removed by steaming with ethyl acetate layer, a pale yellow solid To obtain 1-(4-hydroxycyclohexylphenyl ketone)acetone oxime (2.72 g).

Reference： [1]Yamanaka; Moritomo; Fujii; Tanaka; Fukuda; Nishimura [Pesticide Science, 1998, vol. 54, # 3, p. 223 - 229]
[2]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - EP2511283, 2012, A1 Location in patent: Page/Page column 77
[3]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - US2013/45942, 2013, A1 Location in patent: Paragraph 0308
[4]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - JP2015/172077, 2015, A Location in patent: Paragraph 0165

20
[ 53946-87-5 ]
[ 64-19-7 ]
zinc-powder [ No CAS ]
[ 70-70-2 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1938,vol. 535,p. 219,248

21
[ 2008-75-5 ]
[ 70-70-2 ]
[ 101255-84-9 ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate In acetone at 60℃; for 6h;
64%	With potassium carbonate In acetone for 6h; Heating;
43%	With potassium carbonate; sodium iodide In acetone at 60℃; for 7h;	53 Take 1.5g of p-hydroxyacetophenone and Α51 in a 100 ml round bottom flask,Adding 1.4 g of potassium carbonate, 500 mg of sodium iodide and 50 ml of acetone,60 ° C for 7 hours, and the filtrate was removed by filtration to remove the solid.And then gradually increased to petroleum methyl ether: ethyl acetate = 1: 1 to dichloromethane: methanol: triethylamine = 1: 0: 5: 1,The silica gel column gave 1.1 g of intermediate A52 in a yield of 43%.

Reference： [1]Leung, Suet C.; Gibbons, Peter; Amewu, Richard; Nixon, Gemma L.; Pidathala, Chandrakala; Hong, W. David; Pacorel, Bénédicte; Berry, Neil G.; Sharma, Raman; Stocks, Paul A.; Srivastava, Abhishek; Shone, Alison E.; Charoensutthivarakul, Sitthivut; Taylor, Lee; Berger, Olivier; Mbekeani, Alison; Hill, Alasdair; Fisher, Nicholas E.; Warman, Ashley J.; Biagini, Giancarlo A.; Ward, Stephen A.; O'Neill, Paul M. [Journal of Medicinal Chemistry, 2012, vol. 55, # 5, p. 1844 - 1857]
[2]Meegan; Hughes; Lloyd; Williams; Zisterer [Journal of Medicinal Chemistry, 2001, vol. 44, # 7, p. 1072 - 1084]
[3]Current Patent Assignee: TSINGHUA UNIVERSITY (CHINA) - CN106946775, 2017, A Location in patent: Paragraph 0398; 0399; 0400

22
[ 84348-38-9 ]
[ 70-70-2 ]
(4-propionyl)phenyl N-Boc-4-methylene-L-prolinate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2002,vol. 67,p. 5673 - 5677

23
[ 121-97-1 ]
[ 70-70-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 4-Methoxypropiophenone With 1-n-butyl-3-methylimidazolim bromide at 220℃; for 0.666667h; Inert atmosphere; Sealed tube; Microwave irradiation; Stage #2: With hydrogenchloride; water	1.1 Step 1 A microwave vial was initially charged with 0.35 ml (2 mmol) of methoxypropiophenone and 1.32 g (6 mmol) of [bmim][Br], flooded with protective gas and sealed with a septum. The sample was allowed to react in the microwave and under the following conditions: maximum temperature=220° C. maximum pressure=12 bar maximum output=20 watts (varied) time=40 min [0096] After cooling the sample, 0.1M HCl (pH=1) was added to the reaction mixture and extraction was performed 3 times with EtOAc. The combined organic phases were washed with saturated NaCl solution, dried over MgSO4, filtered and the solvent was removed under vacuum. The desired product could be detected by GC/MS and 1H-NMR spectroscopy. The yield was 0.27 g (90%). [0097] GC/MS: m/z: 150, 121, 93, 65, 53. [0098] tR=12.044 min [0099] 1H-NMR: (400 MHz, CDCl3, TMS) [0100] δ (ppm)=7.91 (d, 2H); 6.90 (d, 2H); 5.29 (s, 1H); 2.95 (q, 2H), 1.22 (t, 3H).
70%	With hydrogen bromide; acetic acid In water at 100℃; for 18h; Heating / reflux;	1-3 1-3 : 1-(4-hydroxyphenyl)propan-l-one (8) While 2Og (0.121rranol) of 1- (4-methoxyphenyl) -1- propanone (7) prepared in Example 1-2 were added to 139 ml(2.4mol) of acetic acid and stirred, 270ml (2.4mmol) of 48% bromic acid were added. Subsequently, the temperature was gradually increased to 100°C and stirring under reflux was continued for 18 hr. The temperature was decreased to room temperature, and ethyl acetate was added, and organic layer was washed with water. Thereafter, the organic layer was washed with a saturated aqueous solution of potassium carbonate, then concentrated under reduced pressure, after which the precipitated solid was recrystallized with ethyl acetate/n-hexane system, and filtered, thus obtaining 12.7g (yield: 70%) of a title compound (8) as a solid. m. p . : 143 ~ 150°C 1H-NMR (DMSOd6) (ppm) 1 . 03 (t, 3H) , 2. 91 (q, 2H) , 6. 83 (d, 2H) , 7 . 82 (d, 2H) , 10 .28 (s , IH) .
60%	With Pyridine hydrobromide at 240℃; for 0.25h;

Reference： [1]Current Patent Assignee: HENKEL AG & CO. KGAA - US2015/99810, 2015, A1 Location in patent: Paragraph 0094-0100
[2]Current Patent Assignee: DONGWHA PHARM CO.,LTD. - WO2006/14087, 2006, A1 Location in patent: Page/Page column 67
[3]Panda, Atulya Kumar [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2002, vol. 41, # 1, p. 181 - 183]

24
[ 3332-29-4 ]
[ 70-70-2 ]
(E)-1-(4-hydroxyphenyl)propan-1-one-O-ethylketoxime [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium acetate In ethanol at 80℃; for 4h;	54.54A Embodiment 54A (E)-1-(4-hydroxyphenyl)-propan-1-one-O-ethyl ketoxime Agitate the mixture solution of 4-hydroxyphenyl acetone (1 g, 6.7 mmol), sodium acetate (1.1 g, 3.3 mmol), ethoxyamine hydrochloride (814 mg, 13.3 mmol) in ethanol (10 ml) 2 hours at 80° C. Then add water (10 ml) and ethyl acetate (20 ml) into the reaction system. Then extract the aqueous layer with ethyl acetate (20 ml×3) before filter and evaporate to obtain the title compound (brown solid, 1.28 g, yield of 99%). 1H NMR(400 MHz,CDCl3)7.48(d,J=8.5 Hz,2H),6.74-6.79(m,2H),4.20(q,J=7.0 Hz,2H),2.72(q,J=7.7 Hz,2H),1.30(t,J=7.0 Hz,3H),1.11(t,J=7.5 Hz,3H).
	With sodium acetate at 80℃; for 2h;

Reference： [1]Current Patent Assignee: JIANGSU KANION PHARMACEUTICAL CO., LTD. - US2017/66732, 2017, A1 Location in patent: Paragraph 0457-0458
[2]Chern, Jyh-Haur; Lee, Chung-Chi; Chang, Chih-Shiang; Lee, Yen-Chun; Tai, Chia-Liang; Lin, Ying-Ting; Shia, Kak-Shan; Lee, Ching-Yin; Shih, Shin-Ru [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 20, p. 5051 - 5056]

25
[ 7462-74-0 ]
[ 70-70-2 ]
2-methyl-2-(4-propionyl-phenoxy)-propionamide [ No CAS ]

Reference： [1]Organic Letters,2005,vol. 7,p. 3629 - 3631

26
[ 109384-19-2 ]
[ 70-70-2 ]
[ 1005402-97-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran
	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 0 - 20℃;	189.1 To a solution of triphenylphosphine (5.79 g, 22.1 mmol) in THF (35 mL) was added 40% w/w DEAD in toluene (10 mL, 15 mmol). The mixture was cooled to 0° C. and a mixture of 4-(3,5-difluoro-4-hydroxy-phenyl)-4-oxo-butyric acid ethyl ester (example 186 step 2) (3.8 g, 14.7 mmol) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (3.6 g, 18 mmol) in THF (35 mL) was added dropwise under argon. After the addition, the cooling bath was removed and stirred at rt overnight. The reaction mixture was concentrated at reduced pressure and purified by ISCO (120 g) chromatography using 15 to 30% EtOAc in hexane to provide 4-[4-(3-ethoxycarbonyl-propionyl)-2,6-difluoro-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (3.21 g, 49% yield).

Reference： [1]Location in patent: scheme or table Hudkins, Robert L.; Zulli, Allison L.; Dandu, Reddeppa Reddy; Tao, Ming; Josef, Kurt A.; Aimone, Lisa D.; Haltiwanger, R. Curtis; Huang, Zeqi; Lyons, Jacquelyn A.; Mathiasen, Joanne R.; Raddatz, Rita; Gruner, John A. [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1504 - 1509]
[2]Current Patent Assignee: ALTO NEUROSCIENCE - US2008/27041, 2008, A1 Location in patent: Page/Page column 105

27
[ 3282-30-2 ]
[ 70-70-2 ]
[ 120703-45-9 ]

Reference： [1]Journal of Organometallic Chemistry,2007,vol. 692,p. 1219 - 1225
[2]Chemistry - A European Journal,2009,vol. 15,p. 684 - 696

28
[ 72824-04-5 ]
[ 70-70-2 ]
4-(3-hydroxyhex-5-en-3-yl)phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With indium iodide In tetrahydrofuran at 40℃; for 24h;

Reference： [1]Schneider, Uwe; Kobayashi, Shu [Angewandte Chemie - International Edition, 2007, vol. 46, # 31, p. 5909 - 5912]

29
[ 70-70-2 ]
[ 84-16-2 ]

Reference： [1]Chemische Berichte,1941,vol. 74,p. 571,576
[2]Chemische Berichte,1941,vol. 74,p. 571,576

30
[ 100-39-0 ]
[ 70-70-2 ]
[ 4495-66-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In acetone Heating / reflux;	1.A Examples of the Invention; Example 1; Step A 1- (4-BenzyloxyphenyDpropan-1-one; 4-Hydroxypropiophenone (15.0 g, 0.10 mol) was dissolved in acetone (200 ml) together with potassium carbonate (13.8 g, 0.10 mol). Benzyl bromide (17.1 g, 0.10 mol) was added and the reaction mixture heated at reflux overnight. After cooling to room temperature the mixture was filtered and concentrated on the rotary evaporator to afford 24.0 g (100%) of the title compound as a white solid
100%	With potassium carbonate In acetone Heating / reflux;	4.A 4-Hydroxypropiophenone (15.0 g, 0.10 mol) was dissolved in acetone (200 ml) together with potassium carbonate (13.8 g, 0.10 mol). Benzyl bromide (17.1 g, 0.10 mol) was added and the reaction mixture heated at reflux overnight. After cooling to room temperature the mixture was filtered and concentrated on the rotary evaporator to afford 24.0 g (100%) of the title compound as a white solid
100%	With potassium carbonate In acetone Heating / reflux;	1.A 4-Hydroxypropiophenone (15.0 g, 0.10 mol) was dissolved in acetone (200 ml) together with potassium carbonate (13.8 g, 0.10 mol). Benzyl bromide (17.1 g, 0.10 mol) was added and the reaction mixture heated at reflux overnight. After cooling to room temperature the mixture was filtered and concentrated on the rotary evaporator to afford 24.0 g (100%) of the title compound as a white solid

100%	With potassium carbonate In acetone at 60℃;
93%	With potassium carbonate In acetone for 18h; Heating / reflux;	1.A To a solution of 4-hydroxypropiophenone (50 g, 0.3329 mol) in dry acetone (500 ml) was added benzyl bromide (56.94 g, 0.333 mol) followed by anhydrous K2CO3 (91.8 g, 0.665 mol). Reaction mixture was boiled under reflux for 18h, cooled to RT, filtered and filtrate was concentrated to yield 4-benzyloxy propiophenone (75 g, 93%) as a white solid.
93%	With potassium carbonate In acetone for 18h; Heating / reflux;	3.A; 9.A Step A 1 -(4-B enzyloxy-phenvD-propane- 1 -one4-Ηydroxypropiophenone (15.0 g, 0.10 mol) was dissolved in acetone (200 ml) together with potassium carbonate (13.8 g, 0.10 mol). Benzyl bromide (17.1 g, 0.10 mol) was added and the reaction mixture boiled under reflux overnight. After cooling to room temperature the mixture was filtered and concentrated on the rotary evaporator to afford 24.0 g (100%) of the title compound as a white solid; Step A: 4-benzyloxy propiophenoneTo a solution of 4-hydroxy propiophenone (50 g, 0.3329 mol) in dry acetone (500 ml) was added benzyl bromide (56.94 g, 0.333 mol) followed by anh. K2CO3 (91.8 g, 0.665 mol).Reaction mixture was refluxed for 18h, cooled to RT, filtered and filtrate was concentrated to yield 4-benzyloxy propiophenone (75 g, 93%) as a white solid.
93%	Stage #1: 4-hydroxypropiophenone With potassium carbonate In acetone at 20℃; for 0.5h; Stage #2: benzyl bromide In acetone Reflux;
93%	With potassium carbonate In acetonitrile at 20℃; for 16h; Inert atmosphere;	1 8.1.1. 1-(4-(Benzyloxy)phenyl)propan-1-one (2) 4-Hydroxypropiophenone (1) (5.0 g, 33 mmol) was dissolved inacetonitrile (50 mL) under N2, to the solution was added K2CO3(3.0 g, 21.6 mmol) and benzyl bromide (5.7 g, 4.0 mL, 33 mmol).The mixture was stirred at RT for 16 h. The mixture was filteredand the solvent was evaporated under reduced pressure. Theresulting oil was dissolved in DCM (100 mL) and the mixture wasextracted with 1 M HCL (50 mL), water (2 50 mL), brine(50 mL) and dried over Na2SO4. The solvent was evaporated underreduced pressure to obtain a pale yellow resin. The material waspurified via flash chromatography on silica gel (DCM) to affordthe product as a white solid. (7.5 g, 93%), Mp 100-102 C.49 IR: mmax(KBr) cm1: 2938, 1680 (CO), 1599, 1224, 1012. 1H NMR (CDCl3,400 MHz) d 7.97 (d, J = 9.35 Hz, 2H, Ar-H), 7.34-7.51 (m, 5H, Ar-H),7.04 (d, J = 9.35 Hz, 2H, Ar-H), 5.15 (s, 2H, CH2), 2.98 (q, J = 7.02 Hz,2H, CH2), 1.24 (t, J = 7.31 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) d199.0 (CO), 162.0 (ArC), 135.8 (ArC), 129.8 (ArC), 129.8 (ArC),128.3 (ArC), 127.8 (ArC), 127.1 (ArC), 114.1 (ArC), 69.7(CH2), 31.0 (CH2), 8.0 (CH3). HRMS (EI): Found 263.1052 (M+Na)+,C16H16O2Na requires 263.1048.
81%	With potassium carbonate In acetonitrile at 80℃; for 12h;
78%	With potassium carbonate In acetone at 60℃;	4.1 Step 1: Preparation of 1-[4-(benzyloxy)phenyl]propan-1-one In a 250 mL round bottom flask, 1-(4-hydroxyphenyl)propan-1-one (20.0 g, 133.18 mmol, 1.00 equiv), (bromomethyl)benzene (23.0 g, 134.48 mmol, 1.00 equiv) and potassium carbonate (30.0 g, 2.00 equiv) were mixed in acetone (100 mL) at room temperature. The resulting solution was stirred overnight at 60° C. The reaction was then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate (20 mL*3) and the organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure. This resulted in 25.0 g (78%) of 1-[4-(benzyloxy)phenyl]propan-1-one as white solid.
59%	Stage #1: 4-hydroxypropiophenone With potassium carbonate In acetone at 20℃; for 0.5h; Inert atmosphere; Stage #2: benzyl bromide In acetone at 20℃; Reflux; Inert atmosphere;	12.c (c) 4-Benzyloxypropiophenone K2003 (1.47 g, 10.7 mmol) was added to a solution of 4-hydroxypropiophenone (0.80 g,5.33 mmol) in acetone (40 mL) and the mixture was stirred for 30 minutes at rt.Benzylbromide (0.63 mL, 5.33 mmol) was added and the mixture was heated at reflux for4 h and stirred at rt overnight. Filtration, concentration and crystallization from Et201petroleum ether gave the sub-title compound (0.76 g, 3.16 mmol, 59 %).
59%	Stage #1: 4-hydroxypropiophenone With potassium carbonate In acetone at 20℃; for 0.5h; Stage #2: benzyl bromide In acetone for 4h; Reflux;	12.c 4-Benzyloxypropiophenone KCO3 (1.47 g, 10.7 mmol) was added to a solution of 4-hydroxypropiophenone (0.80 g,5.33 mmol) in acetone (40 mL) and the mixture was stirred for 30 minutes at rt.Benzylbromide (0.63 mL, 5.33 mmol) was added and the mixture was heated at reflux for4 h and stirred at rt overnight. Filtration, concentration and crystallization from Et201petroleum ether gave the sub-title compound (0.76 g, 3.16 mmol, 59 %).
	With sodium hydroxide In water
	With potassium carbonate In acetone for 18h; Reflux;

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2005/80343, 2005, A2 Location in patent: Page/Page column 20; 36
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2006/67443, 2006, A1 Location in patent: Page/Page column 38
[3]Current Patent Assignee: ASTRAZENECA PLC - WO2007/20388, 2007, A1 Location in patent: Page/Page column 35; 54
[4]Location in patent: experimental part Lušin, Tina Trdan; Tomašić, Tihomir; Trontelj, Jurij; Mrhar, Aleš; Peterlin-Mašič, Lucija [Chemico-Biological Interactions, 2012, vol. 197, # 1, p. 8 - 15]
[5]Current Patent Assignee: ASTRAZENECA PLC - WO2007/10222, 2007, A2 Location in patent: Page/Page column 28
[6]Current Patent Assignee: ASTRAZENECA PLC; SCHELI PETER - WO2007/10217, 2007, A1 Location in patent: Page/Page column 32; 40
[7]Hodnik, Žiga; Peterlin Mašič, Lucija; Tomašić, Tihomir; Smodiš, Domen; D'Amore, Claudio; Fiorucci, Stefano; Kikelj, Danijel [Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4819 - 4833]
[8]Kelly, Patrick M.; Bright, Sandra A.; Fayne, Darren; Pollock, Jade K.; Zisterer, Daniela M.; Williams, D. Clive; Meegan, Mary J. [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4075 - 4099]
[9]Siddaraju, Yogesh; Prabhu, Kandikere Ramaiah [Organic and Biomolecular Chemistry, 2015, vol. 13, # 24, p. 6749 - 6753]
[10]Current Patent Assignee: ARVINAS - US2018/72711, 2018, A1 Location in patent: Paragraph 0432; 0433
[11]Current Patent Assignee: ATROGI AB - WO2017/153737, 2017, A1 Location in patent: Page/Page column 55
[12]Current Patent Assignee: ATROGI AB - WO2019/53428, 2019, A1 Location in patent: Page/Page column 51; 52
[13]Feio-Azevedo; Costa; Ferreira; Branco; Pereira; Bastos; Carvalho; Capela [Toxicology Letters, 2017, vol. 269, p. 65 - 76]
[14]Argaez, Aida Nelly Garcia; Dalla Via, Lisa; Hyeraci, Mariafrancesca; Kikelj, Danijel; Mašič, Lucija Peterlin; Passarella, Daniele; Secci, Daniela; Tomašič, Tihomir; Zidar, Nace [ACS Medicinal Chemistry Letters, 2020, vol. 11, # 5, p. 691 - 697]

31
[ 124-63-0 ]
[ 70-70-2 ]
[ 929431-57-2 ]

Yield	Reaction Conditions	Operation in experiment
93%	With triethylamine In tetrahydrofuran at 5℃; for 1.5h;	4 REFERENCE EXAMPLE 4 Synthesis of 1-[4-(methanesulfonyloxy)phenyl]-2-bromo-1-propanone A tetrahydrofuran solution (50 mL) of 15.0 g (100 mmol) of p-hydroxypropiophenone and 12.143 g (1.2 equivalents) of triethylamine was cooled to 5°C. To this solution, 12.60 g (1.1 equivalents) of methanesulfonyl chloride was added dropwise over 30 minutes, followed by 1 hour of stirring. To the resulting solution, 40 mL of water and 70 mL of ethyl acetate were added to conduct extraction. The organic layer was washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvents. A white solid was obtained as a result. This white solid was crystallized from 40 mL of ethyl acetate and 120 mL of hexane to thereby obtain white crystals of p-(methanesulfonyloxy)propiophenone (21.17 g, isolation yield: 93%). To a tetrahydrofuran solution (20 mL) of 4.560 g (20 mmol) of p-(methanesulfonyloxy)propiophenone, a hexane solution (5 mL) of 3.516 g (1.1 equivalent) of bromine was added at 15°C, followed by 1 hour of stirring. To the resulting solution, 30 mL of saturated sodium hydrogen carbonate and 30 mL of ethyl acetate were added to conduct extraction. The organic layer was washed with 20 mL of a saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvent. 1-[4-(Methanesulfonyloxy)phenyl]-2-bromo-1-propanone was obtained as an yellow, oily substance (10.12 g, crude yield: 97%).1H-NMR (CDCl3, 400 MHz/ppm): δ 1.91 (3H, d), 3.21 (3H, s), 5.23 (1H, q), 7.40 (2H, d), 8.10 (2H, d)

Reference： [1]Current Patent Assignee: KANEKA CORPORATION - EP1512677, 2005, A1 Location in patent: Page/Page column 27

32
[ 98-88-4 ]
[ 70-70-2 ]
[ 96187-97-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	With triethylamine In tetrahydrofuran at 20℃; for 1h;
87%	With triethylamine In tetrahydrofuran at 5℃; for 1.5h;	5 REFERENCE EXAMPLE 5 Synthesis of 1-[4-(benzoyloxy)phenyl]-2-bromo-1-propanone A tetrahydrofuran solution (40 mL) of 5.00 g (33.3 mmol) of p-hydroxypropiophenone and 3.71 g (1.1 equivalents) of triethylamine was cooled to 5°C. To the resulting solution, 4.92 g (1.05 equivalents) of benzoyl chloride was added dropwise for 30 minutes, followed by 1 hour of stirring. Extraction was conducted by adding 70 mL of water, 5 mL of 3 N hydrochloric acid, and 100 mL of ethyl acetate. The organic layer was washed with 50 mL of a saturated sodium hydrogen carbonate solution and then with 50 mL of water, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvents. As a result, 8.58 g of a white solid was obtained. The white solid (5.53 g) was crystallized from 30 mL of ethyl acetate and 20 mL of hexane. White crystals of p-(benzoyloxy)propiophenone were obtained as a result (4.77 g, isolation yield: 87%). To a tetrahydrofuran solution (30 mL) of 3.00 g (11.9 mmol) of the p-(benzoyloxy)propiophenone, a hexane solution (5 mL) of 2.07 g (1.1 equivalents) of bromine was added at 5°C. The temperature of the mixture was elevated to room temperature, followed by 1 hour of stirring. To the resulting mixture, 30 mL of a saturated sodium hydrogen carbonate solution and 40 mL of ethyl acetate were added to conduct extraction. The organic layer was washed with 30 mL of a saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvents. An yellow oily substance (5.54 g) was obtained as a result. This substance was crystallized from 5 mL of ethyl acetate and 30 mL of hexane. White crystals of 1-[4-(benzoyloxy)phenyl]-2-bromo-1-propanone were obtained as a result (3.147 g, isolation yield: 80%).1H-NMR (CDCl3, 400 MHz/ppm): δ 1.92 (3H, d), 5.28 (1H, q), 7.37 (2H, d), 7.54 (2H, dd), 7.67 (1H, dd), 8.13 (2H, d), 8.20 (2H, d)

Reference： [1]Siddaraju, Yogesh; Prabhu, Kandikere Ramaiah [Organic and Biomolecular Chemistry, 2015, vol. 13, # 24, p. 6749 - 6753]
[2]Current Patent Assignee: KANEKA CORPORATION - EP1512677, 2005, A1 Location in patent: Page/Page column 29

33
tetrabutylammonium [ No CAS ]
[ 70-70-2 ]
[ 53946-87-5 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran;	(a) Ketone bromination A mixture of 4'-hydroxypropiophenone (175 g; 1.16 mole), tetrabutylammonium prebromide (641.65 g; 1.33 mole) in tetrahydrofuran (2.3 l) is heated at 40 C., while being stirred under a nitrogen atmosphere for 8 hours. The mixture is then poured into water (5 l) and extracted with toluene. The toluenic extract is washed with water, dried on sodium sulphate, and the solvent is evaporated. The oily residue is crystallized from a 1/1 methylene chloride/hexane mixture, to give 2-bromo-(4'-hydroxyphenyl)-propan-1-one (203 g; 0.88 mole; yield of 76%). Melting point 95-97 C. 1 H-NMR (CDCl3 TMS) ppm: 1.9 (d, 3H, J=7 Hz); 5.4 (q, 1H, J=7 Hz); 5.9 (s, 1H broad); 6.9-8.3 (AB q, 4H); 60 MHz equipment.

Reference： [1]Patent: US4642376,1987,A

34
[ 2116-65-6 ]
ammonium hydroxide [ No CAS ]
[ 70-70-2 ]
[ 23210-56-2 ]

Yield	Reaction Conditions	Operation in experiment
	With bromine In 1,4-dioxane; methanol; diethyl ether; nitrogen; Petroleum ether	1 EXAMPLE 1 EXAMPLE 1 To 4 ml of dioxane were added 6.0 g of 4'-hydroxypropiophenone. 6.4 Grams of bromine were added dropwise to the mixture with stirring at room temperature. The reaction liquid was stirred for an additional 10 minutes and then air was introduced thereinto at a flow rate of 400 ml/minute for 15 minutes at 60° C. To the reaction liquid were then added 7.5 g of 4-benzylpyridine and 50 ml of methanol, and the mixture was refluxed under heating for 5 hours. After replacing the air in the reaction container with nitrogen, 2.0 g of 10% palladium-carbon were added and hydrogen gas was then introduced and the mixture was stirred for 8 hours at 90°-95° C. under pressure of 50 kg/cm2. After completion of the reaction, solid matters including the catalyst were filtered off and 30 ml of 10% ammonia water were added to the filtrate and the reaction liquid was concentrated under reduced pressure until its volume became 20 ml. The residual oily substance was crystallized from a mixture of 15 ml of diethyl ether and 15 ml of petroleum ether under ice-cooling and the resultant crude product was recrystallized from isopropanol whereby 10.6 g (68.8%) of ifenprodil were obtained as white crystals. M.P. 109°-111° C.
	With bromine In 1,4-dioxane; methanol; diethyl ether; nitrogen; Petroleum ether	17 EXAMPLE 17 EXAMPLE 17 To 4 ml of dioxane were added 6.0 g of 4'-hydroxypropiophenone. 6.4 Grams of bromine were added dropwise to the mixture with stirring at room temperature. The reaction liquid was stirred for an additional 10 minutes and then air was introduced thereinto at a flow rate of 400 ml/minute for 15 minutes at 60° C. To the reaction liquid were then added 7.5 g of 4-benzylpyridine and 50 ml of methanol, and the mixture was refluxed under heating for 5 hours. After replacing the air in the reaction container with nitrogen gas, 2.0 g of 10% palladium-carbon were added and hydrogen was then introduced and the mixture was stirred for 8 hours at 90°-95° C. under pressure of 50 kg/cm2. After completion of the reaction, the catalyst and the like were filtered off and 30 ml of 10% ammonia water were added to the filtrate and the reaction liquid was concentrated under reduced pressure until its volume became 20 ml. The residual oily substance was crystallized from a mixture of 15 ml of diethyl ether and 15 ml of petroleum ether under ice cooling and the resultant crude product was recrystallized from isopropanol whereby 10.9 g (70.7%) of ifenprodil were obtained as white crystals. The physical characteristics of these crystals were identical with those of the crystals obtained in Example 1. To the mother liquor obtained in the crystallization and recrystallization treatments were added 50 ml of methanol and 40 g of silica gel (Wakogel C-200, Wako Pure Chemicals, Japan). The mixture was concentrated under reduced pressure until dryness. This was layered on 80 g of silica gel (Wakogel C-200) packed into a column (diameter: 2 cm) and eluated with a mixture of 800 ml of chloroform and 200 ml of ethyl acetate. The eluated liquid was discarded. The pack in the column was then eluated with 800 ml of ethyl acetate and the elude was concentrated under reduced pressure until dryness. The residue was crystallized from isopropanol to obtain 3.9 g (25.3%) of ifenprodil as white crystals. The physical characteristics of these crystals were identical with those of the crystals obtained in Example 1. 14.8 Grams (96.0%) in toto of ifenprodil were thus obtained.
	With bromine In 1,4-dioxane; methanol; nitrogen	20 EXAMPLE 20 EXAMPLE 20 To 4 ml of dioxane were added 6.0 g of 4'-hydroxypropiophenone. 6.4 Grams of bromine were added dropwise to the mixture with stirring at room temperature, and the reaction liquid was stirred for an additional 5 minutes. To the reaction liquid were then added 14.8 g of 4-benzylpyridine and 100 ml of methanol, and the mixture was refluxed under heating for 3 hours. After replacing the air in the reaction container with nitrogen gas, 3.0 g of 5% palladium-carbon were added and hydrogen was then introduced and the mixture was stirred for 8 hours at 90°-95° C. under pressure of 50 kg/cm2. After completion of the reaction, solid matters including the catalyst were filtered off and 30 ml of 10% ammonia water were added to the filtrate and the reaction liquid was concentrated under reduced pressure until its whole volume became about 30 ml. The residue was crystallized from diethyl ether and recrystallized from isopropanol whereby 11.4 g (74.0%) of ifenprodil were obtained as white crystals. The physical characteristics of these crystals were identical with those of the crystals obtained in Example 18.

	With nitrogen; bromine In 1,4-dioxane; methanol; chloroform; ethyl acetate	35 EXAMPLE 35 EXAMPLE 35 To 4 ml of dioxane were added 6.0 g of 4'-hydroxypropiophenone. 6.8 Grams of bromine were added dropwise to the mixture with stirring at room temperature. The reaction liquid was stirred for an additional 10 minutes and then nitrogen was introduced thereinto at a flow rate of 400 ml/minute for 10 minutes at 60° C. To the reaction liquid were then added 8.1 g of 4-benzylpyridine and 100 ml of methanol, and the mixture was refluxed under heating for 5 hours. After stopping the heating, 0.3 g of platinum oxide were added and hydrogen was then introduced, and the mixture was stirred for 8 hours under pressure of about 1 atm. After completion of the reaction, solid matters including the catalyst were filtered off and 30 ml of 10% ammonia water were added to the filtrate and the reaction liquid was concentrated under reduced pressure until dryness. The residue was taken up in 100 ml of methanol and 100 g of silica gel (Wakogel C-200) were added thereto. The mixture was heated under reduced pressure until dryness and layered on 150 g of silica gel (Wakogel C-200) charged into a column (diameter: 4 cm). The pack in the column was eluated with a mixture of 2 l of chloroform and 500 ml of ethyl acetate and the elude was discarded. The pack was then eluated with 1.5 l of ethyl acetate and the elude was concentrated under reduced pressure until dryness. The residue was crystallized from isopropanol whereby 12.5 g (81.2%) of ifenprodil were obtained as white crystals. M.P. 109°-111° C. TLC: Rf 0.35
	With bromine In 1,4-dioxane; methanol; diethyl ether; Petroleum ether	37 EXAMPLE 37 EXAMPLE 37 To 4 ml of dioxane were added 6.0 g of 4'-hydroxypropiophenone. 6.8 Grams of bromine were added dropwise to the mixture with stirring at room temperature. The reaction liquid was stirred for an additional 5 minutes and then air was introduced thereinto at a flow rate of 200 ml/minute for one hour at room temperature. To the reaction liquid were then added 7.5 g of 4-benzylpyridine and 50 ml of methanol, and the mixture was refluxed under heating for 4 hours. After stopping the heating, 0.5 g of platinum oxide and 50 ml of methanol were added and hydrogen was then introduced and the mixture was stirred for 7 hours under pressure of about 1 atm. After completion of the reaction, the catalyst was filtered off and 30 ml of 10% ammonia water were added to the filtrate and the reaction liquid was concentrated under reduced pressure until dryness. The residue was crystallized from a mixture of 15 ml of diethyl ether and 15 ml of petroleum ether under ice cooling and the resultant crude product was recrystallized from isopropanol whereby 10.2 g (66.2%) of ifenprodil were obtained as white crystals. The physical characteristics of these crystals were identical with those of the crystals obtained in Example 35.

Reference： [1]Current Patent Assignee: SANOFI - US4377691, 1983, A
[2]Current Patent Assignee: SANOFI - US4377691, 1983, A
[3]Current Patent Assignee: SANOFI - US4377691, 1983, A
[4]Current Patent Assignee: SANOFI - US4377691, 1983, A
[5]Current Patent Assignee: SANOFI - US4377691, 1983, A

35
[ 2116-65-6 ]
[ 70-70-2 ]
1-(4-hydroxyphenyl)-2-(4-benzylpiperidino)-1-propanol hydrobromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bromine In 1,4-dioxane; methanol; nitrogen	2 EXAMPLE 2 EXAMPLE 2 To 4 ml of dioxane were added 6.0 g of 4'-hydroxypropiophenone. 6.4 Grams of bromine were added dropwise to the mixture with stirring at room temperature. The reaction liquid was stirred for an additional 5 minutes and then air was introduced thereinto at a flow rate of 200 ml/minute for 30 minutes at room temperature. To the reaction liquid were then added 7.5 g of 4-benzylpyridine and 50 ml of methanol, and the mixture was refluxed under heating for 5 hours. After replacing the air in the reaction container with nitrogen, 2.0 g of 10% palladium-carbon were added and hydrogen gas was then introduced and the mixture was stirred for 8 hours at 60°-70° C. under pressure of 50 kg/cm2. After completion of the reaction, the catalyst and the like were filtered off and the filtrate was concentrated under reduced pressure until dryness. The residue was crystallized from acetone and the resultant crude product was recrystallized from ethanol whereby 14.9 g (92.0%) of ifenprodil hydrobromide were obtained as white crystals. M.P. 188°-191° C.
	With bromine In 1,4-dioxane; methanol; diethyl ether; nitrogen	19 EXAMPLE 19 EXAMPLE 19 To 5 ml of dioxane were added 3.0 g of 4'-hydroxypropiophenone. 3.6 Grams of bromine were added dropwise to the mixture with stirring at room temperature, and the reaction liquid was stirred for an additional 10 minutes. To the reaction liquid were then added 7.4 g of 4-benzylpyridine and 40 ml of methanol, and the mixture was refluxed under heating for 5 hours. After replacing the air in the reaction container with nitrogen gas, 60 ml of methanol and 2.0 g of 10% palladium-carbon were added and hydrogen was then introduced and the mixture was stirred for 8 hours at 90°-95° C. under pressure of 50 kg/cm2. After completion of the reaction, solid matters including the catalyst were filtered off and the filtrate was concentrated under reduced pressure and the residual oily substance was washed with water. 10 Milliliters of diethyl ether were added to the oily substance under ice cooling and the precipitated crystals were collected and recrystallized from ethanol whereby 7.6 g (93.5%) of ifenprodil hydrobromide were obtained as white crystals. M.P. 188°-191° C.
	With nitrogen; bromine In 1,4-dioxane; methanol; diethyl ether	34 EXAMPLE 34 EXAMPLE 34 To 4 ml of dioxane were added 6.0 g of 4'-hydroxypropiophenone. 6.8 Grams of bromine were added dropwise to the mixture with stirring at room temperature. The reaction liquid was stirred for an additional 10 minutes and then nitrogen was introduced thereinto at a flow rate of 200 ml/minute for 1 hour at 60° C. To the reaction liquid were then added 7.5 g of 4-benzylpyridine and 100 ml of methanol, and the mixture was refluxed under heating for 5 hours. After stopping the heating, 0.3 g of platinum oxide were added and hydrogen was then introduced and the mixture was stirred for 9 hours under pressure of about 1 atm. After completion of the reaction, solid matters including the catalyst were filtered off and the filtrate was concentrated under reduced pressure until dryness. The residue was washed with 15 ml of diethyl ether and recrystallized from ethanol whereby 11.5 g (71.0%) of ifenprodil hydrobromide were obtained as white crystals. M.P. 188°-191° C.

Reference： [1]Current Patent Assignee: SANOFI - US4377691, 1983, A
[2]Current Patent Assignee: SANOFI - US4377691, 1983, A
[3]Current Patent Assignee: SANOFI - US4377691, 1983, A

36
[ 106-93-4 ]
[ 70-70-2 ]
[ 34645-63-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate In acetone Reflux;	Synthesis of compounds of type (2) General procedure: The appropriate 4-hydroxyalkylophenoiie (40 nimol ), dibromoethane (200 mmol), potassium carbonate ( 15 g) and acetone ( 1 0 mL) were mixed together and the resulting reaction mixture was refluxed until the reaction was judged to be complete by TLC. The reaction mixture was then cooled, the inorganic salts removed by filtered, and the solvent evaporated to dryness. The crude product was purified by LC using a toluene/ethyl acetate gradient. Fractions containing product were pooled together and evaporated to dryness. The following compounds were prepared according to this procedure. 1-(4-(2-bromoethoxy)pheiiyl)propan- l-one (2a, R ~1 R ~1 Et): Yield 85%,1H NMR (CDCl3, 300 MHz, δ) ppm, 7.98-7.93 (m, 2H), 6.97-6.92 (m, 2H), 4.35 (dd, 2H, J = 6.1 Hz, J = 6.3 Hz), 3.66 (dd, 1H, J = 6.3 Hz, J 6.2 Hz), 2.95 (q, 2H, J = 7.2 Hz), 1.22 (t, 3H, J - 7.2 Hz)
69%	Stage #1: 4-hydroxypropiophenone With sodium n-propoxide In propan-1-ol at 20℃; for 0.0833333h; Stage #2: ethylene dibromide In propan-1-ol at 60℃; for 7h; Reflux;	General synthetic procedure for compounds 1a-1u General procedure: A solution of freshly prepared sodium 1-propanolate, proper substituted phenols were added and stirred in room temperature for 5 min. α,ω-dibromoalkanes were then added drop wisely in the time of 1 h. The reaction mixture was stirred in 60 °C for 3 h, and then refluxed for another 3 h. After cooling down to RT mixture was filtrated and evaporated. To a rough product, 100 ml of 10% NaOH was added and left overnight in cold. To a resulting white oil CH2Cl2 was added, mixed and layers were then separated. Organic layer was dried over sodium sulphate filtered and evaporated. Rough product was used for further reactions after purification.
46%	With sodium hydroxide; mercury In ethanol	1.a 4-[2-(1-methyl-phenethylamino)-ethoxy]-propiophenone a. 4-(2-bromo-ethoxy)-propiophenone is first prepared: to a 60% ethanol solution (200cc) containing para-hydroxy-propiophenone (0.1 mole) and ethylene bromide (0.13 mole) is added, under refluxing conditions, 5% sodium hydroxide (0.1 mole). After 6 hours, the solution is evaporated in vacuo and is then extracted with diethyl ether. It is then washed with dilute sodium hydroxide and with water. The ether phase is dried, concentrated, and the residue is then distilled: b.p./18 mm of mercury = 202°-207°C, m.p. = 88°C. Yield: 46%.

With potassium carbonate In pentan-3-one for 16h; Reflux;

1.2 Step 2 A round-bottomed flask was initially charged with 2 eq K2CO3 and 1 eq hydroxypropiophenone in 3-pentanone. To this was added 1 eq 1,2-dibromoethane and the mixture was stirred under reflux for 16 h. After cooling, the mixture was filtered, the solid was washed 2× with 3-pentanone and the combined phases were concentrated under reduced pressure. [0103] Column chromatography was performed (1:3 EtOAc/pet. ether).

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF TEXAS SYSTEM - WO2019/94689, 2019, A1 Location in patent: Page/Page column 34
[2]Szczepańska, Katarzyna; Karcz, Tadeusz; Siwek; Kuder, Kamil J.; Latacz, Gniewomir; Bednarski; Szafarz, Małgorzata; Hagenow, Stefanie; Lubelska, Annamaria; Olejarz-Maciej, Agnieszka; Sobolewski, Michał; Mika; Kotańska, Magdalena; Stark, Holger; Kieć-Kononowicz, Katarzyna [Bioorganic Chemistry, 2019, vol. 91]
[3]Current Patent Assignee: LAROCHE NAVARRON LAB - US3959359, 1976, A
[4]Current Patent Assignee: HENKEL AG & CO. KGAA - US2015/99810, 2015, A1 Location in patent: Paragraph 0101-0103

37
[ 105-36-2 ]
[ 70-70-2 ]
[ 51828-70-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate In acetone for 4h; Heating / reflux;	11.1 A round-bottom flask was charged with 1-(4-hydroxyphenyl)-1-propanone (10.0 g, 0.067 mol), K2CO3 (11.11 g, 0.080 mol), acetone (15OmL), and ethylbromoacetate (22 mL, 0.201 mol) under N2 and the reaction mixture refluxed for 4 h. After cooling to room temperature the reaction was filtered and the filtrate concentrated under reduced pressure. The crude product was purified by SiO2 column chromatography with hexanes:EtOAc (19:1 to 4:1 ) to yield 15.35 g (97%) of the title compound 2J. as an oil. 1H NMR (300 MHz, CDCI3): δ 1.21 (t, J = 7.2 Hz, 3 H), 1.30 (t, J = 7.2 Hz, 3 H), 2.95 (q, J= 7.2 Hz, 2 H), 4.28 (q, J= 7.2 Hz, 2 H), 4.68 (s, 2 H), 6.94 (d, J= 9.0 Hz, 2 H), 7.95 (d, J= 9.0 Hz1 2 H). LCMS (ESI): m/z 237 (M + H) +.
94%	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 3h;	1.1 Step 1: Ethyl 2-(4-propionylphenoxy)acetate Step 1: Ethyl 2-(4-propionylphenoxy)acetate To a solution of 1-(4-hydroxyphenyl)propan-1-one (33 g, 0.2200 moles) in DMF (165 mL), potassium carbonate (60.7 gm, 0.4400 moles) and ethyl bromo acetate (40.6 gm, 0.2420 moles) were added and the reaction mixture was srirred at 50° C. for 3 hours. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure to yield 49 gm (94%) of product as thick liquid. 1H NMR: DMSO-d6 δ 1.06 (t, J=7.2 Hz, 3H), 1.20 (t, J=4.8 Hz, 3H), 2.96 (q, J=7.4 Hz, 2H), 4.14 (q, J=3.6 Hz, 2H), 4.88 (s, 2H), 7.02 (dd, J=2.0 & 6.8 Hz, 2H), 7.92 (dd, J=2.0 & 6.8 Hz, 2H).
94%	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 3h;	1.1 Step 1: Ethyl 2-(4-propionylphenoxy)acetate To a solution of 1-(4-hydroxyphenyl)propan-1-one (33 g, 0.2200 moles) in DMF (165 mL), potassium carbonate (60.7 gm, 0.4400 moles) and ethyl bromo acetate (40.6 gm, 0.2420 moles) were added and the reaction mixture was srirred at 50 °C for 3 hours. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure to yield 49 gm (94%) of product as thick liquid. 1H NMR: DMSO-d6 δ 1.06 (t, J = 7.2 Hz, 3H), 1.20 (t, J= 4.8 Hz, 3H), 2.96 (q, J= 7.4 Hz, 2H), 4.14 (q, J= 3.6 Hz, 2H), 4.88 (s, 2H), 7.02 (dd, J = 2.0 & 6.8 Hz, 2H), 7.92 (dd, J= 2.0 & 6.8 Hz, 2H).

With potassium carbonate In toluene for 48h; Reflux;

2.1. General procedure for the preparation of ethacrynic acidand its analogues General procedure: The synthesis of ethacrynic acid (IV-1) and its sevenanalogues (IV-2-8, Fig. 1) was accomplished by a threestepreaction shown in Scheme 1. The Friedel-Craftsacylation reaction of the phenol or the substituted phenolsI-1-4 (Scheme 1), respectively, with propanoyl chloride (n = 1) or butanoyl chloride (n = 2), respectively, wasperformed in the presence of powdered aluminiumchloride (AlCl3) in carbon disulfide, as recently describedby us [22]. Compounds II-1-8 were purified by flashcolumn chromatography on silica gel and consecutivelyrefluxed in acetone for 48 hours in the presence of 1.2equivalents of ethyl bromoacetate and two equivalentspotassium carbonate (K2CO3) to yield compounds III-1-8.In the third step, an aldol condensation reaction, compoundsIII-1-8 were refluxed in an ethanol/water (50/50)mixture for 24 hours in the presence of two equivalents offormaldehyde and 2.5 equivalents of K2CO3. CompoundsIV-1-8 were obtained by flash chromatography using ahexanes/ethyl acetate/methanol mixture as the eluent.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/62148, 2007, A2 Location in patent: Page/Page column 40-41
[2]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2013/281366, 2013, A1 Location in patent: Paragraph 0185; 0186
[3]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - EP2658851, 2013, A1 Location in patent: Paragraph 0055
[4]Janser, Ingo; Vortolomei, Caitlyn M.; Meka, Ranjith K.; Walsh, Courtney A.; Janser, Romy F.J. [Comptes Rendus Chimie, 2013, vol. 16, # 7, p. 660 - 664]

38
[ 824-94-2 ]
[ 70-70-2 ]
[ 935859-44-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium carbonate; sodium iodide In butanone at 20 - 60℃; for 12h;	16-1.1 (1) Synthesis of 1- {4-[(4-methoxybenzyl)oxy]phenyl}propan-1-one: 4'-Hydroxypropiophenone (50.0 g, 0.33 mol), potassium carbonate (69.0 g, 0.50 mol), and sodium iodide (25.0 g, 0.17 mol) were suspended in 2-butanone (500 mL), and with stirring at room temperature, 4-methoxybenzyl chloride (57.4 g, 0.37 mol) was added at room temperature. The reaction solution was stirred at 60°C for 12 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated saline, and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting pale yellow solid was washed with hexane to obtain the entitled compound (86.3 g, 96 %) as a milky white solid. 1H-NMR (400 MHz, CDCl3, δ): 1.21 (3H, t, J=7.3 Hz), 2.95 (2H, q, J=7.3 Hz), 3.82 (3H, s), 5.05 (2H, s), 6.93 (2H, d, J=8.8 Hz), 7.00 (2H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8 Hz), 7.95 (2H, d, J=8.8 Hz)
	With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 12h; Inert atmosphere;	6.1 Step 1: Synthesis of Compound BB-6-2 PMB-Cl (5.48 g) was added to a DMF (10 mL) mixture of a compound BB-6-1 (5 g) and potassium carbonate (9.2 g) and a reaction was carried out at 40 °C under the protection of nitrogen for 12 hours. The reaction liquid was poured into water (200 mL) and the solid was collected to obtain the compound BB-6-2. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.99-7.92 (m, 2H), 7.37 (d, J=8.7 Hz, 2H), 7.03-6.91 (m, 4H), 5.06 (s, 2H), 3.83 (s, 3H), 2.96 (d, J=7.3 Hz, 1H), 2.99-2.92 (m, 1H), 1.22 (t, J=7.2 Hz, 3H)

Reference： [1]Current Patent Assignee: MERCK & CO INC - EP1944301, 2008, A1 Location in patent: Page/Page column 81
[2]Current Patent Assignee: WUXI APPTEC CO., LTD.; SHANDONG BUCHANG PHARMACEUTICAL CO LTD - EP3626699, 2020, A1 Location in patent: Paragraph 0146-0148

39
[ 147983-18-4 ]
[ 70-70-2 ]
[ 875488-06-5 ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: 4-hydroxypropiophenone With sodium hydroxide In N,N-dimethyl-formamide at 70℃; for 1h; Stage #2: 5-(4-cyanophenoxy)pentyl chloride In N,N-dimethyl-formamide at 70 - 95℃; for 5h;	2.2-1 30.O g (200 mmol) of 4-hydroxypropiophenone was added to and dissolved in 0.1 L of N, N-dimethylformamide, and 9.59 g (240 mmol) of sodium hydroxide was slowly added thereto. The temperature was increased to 700C, and then themixture was stirred for 1 hour. 45.6 g (204 itnnol) of 4- (5-chloropentoxy) -benzonitrile (4) obtained in Preparative Example 1-1 was added thereto at the same temperature, and the temperature was increased to 95°C, followed by stirring for 5 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and then the organic layer was washed with water and a sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, recrystallized from methanol, and then dried under reduced pressure to obtain 56.9 g (yield: 84%) of a title compound (14) .1H-NMR (DMSO-d6) (ppm) 1.06(t, 3H) , 1.57 (m, 2H) , 1.79 (m, 4H) , 2.95(m, 2H), 4.08 (m, 4H), 7.02(d, 2H), 7.09(d, 2H), 7.74(d, 2H), 7.91(d, 2H).
80%	Stage #1: 4-hydroxypropiophenone With sodium hydride In N,N-dimethyl-formamide for 0.333333h; Stage #2: 5-(4-cyanophenoxy)pentyl chloride In N,N-dimethyl-formamide at 40℃; for 4h;	1-4 1-4 : 4-[5-(4-propionylphenoxγ)pentoxyl]-benzonitrile (9) While 12g (80mmol) of 1-(4-hydroxyphenyl)propan-l-one (8) prepared in Example 1-3 were added to 100 ml of dimethylformamide and stirred, 3.5g(84mmol) of sodium hydride were added, and stirring was continued for 20 rain. Thereafter, 17.9g(80mmol) of 4- (5-chloro-ρentoxy)- benzonitrile (4) prepared in Example 1-1 were dissolved in 20ml of dimethylformamide. The reaction temperature was gradually increased and stirring was continued at 4O0C for 4 hr. After the reaction was completed, the temperature was decreased to room temperature, and the resultant reaction mixture was added with ethylacetate, and then washed with distilled water. Subsequently, the organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified with column- chromatography in which the mixture of ethylacetate and n- hexane(l:5) were used as a eluent, thus obtaining 21.6g (yield: 80%) of a title compound (9) . m.p. : 107 ~ Hl0C 1H-NMR(DMSO-d6) (ppm) 1.04 (t, 3H), 1.56(m, 2H), 1.78 (brm, 4H), 2.95(q, 2H), 4.07(4H), 7.00(d, 2H), 7.08(d, 2H), 7.74(d, 2H) , 7.90 (d, 2H) .

Reference： [1]Current Patent Assignee: DONGWHA PHARM CO.,LTD. - WO2009/17346, 2009, A1 Location in patent: Page/Page column 69-70
[2]Current Patent Assignee: DONGWHA PHARM CO.,LTD. - WO2006/14087, 2006, A1 Location in patent: Page/Page column 68

40
[ 105-39-5 ]
[ 70-70-2 ]
[ 51828-70-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 18h;	4.3.8. Ethyl 2-(4-acetyl-2-methylphenoxy)acetate (8a) General procedure: To an ice cold solution of 7a (20 g, 0.133 mol) in DMF (100 ml), K2CO3 (36.8 g, 0.266 mol) and ethyl chloroacetate (15.9 g, 0.150 mol) was added and reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was poured in ice cold water (700 ml) and extracted with ethyl acetate (200 ml × 3). The organic extract was washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure to yield 23.8 g product as thick oil. Yield: 98%

Reference： [1]Location in patent: experimental part Makadia, Pankaj; Shah, Shailesh R.; Pingali, Harikishore; Zaware, Pandurang; Patel, Darshit; Pola, Suresh; Thube, Baban; Priyadarshini, Priyanka; Suthar, Dinesh; Shah, Maanan; Giri, Suresh; Trivedi, Chitrang; Jain, Mukul; Patel, Pankaj; Bahekar, Rajesh [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 2, p. 771 - 782]

41
[ 3439-73-4 ]
[ 70-70-2 ]
[ 1276031-01-6 ]

Yield	Reaction Conditions	Operation in experiment
44%	With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; Inert atmosphere; Reflux;	(Z)-2-(4-Hydroxylphenyl)-1-[4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-1-phenylbut-1-ene [(Z)-11a]: Titanium tetrachloride (1.97 mL, 18 mmol) was added drop wise to a stirred suspension of Zn powder (2.35 g, 36 mmol) in dry THF (30 mL) under an argon atmosphere at -10 °C, and this mixture was heated at reflux for 1.5 h to produce the titanium reagent. A cooled suspension of this titanium reagent was added to a solution of 4-(2-chloroethoxy)benzophenone (5a, 1.56 g, 6.0 mmol) and 4-hydroxypropiophenone (9, 0.9 g, 6.0 mmol) in THF (40 mL) at 0 °C, and the reaction was allowed to proceed at reflux for 2 h. After cooling to 25 °C, the reaction mixture was poured into a 10% aqueous K2CO3 solution (90 mL), this mixture was stirred vigorously for 5 min, and the dispersed insoluble material was removed by vacuum filtration. The organic fraction was separated, the aqueous layer was extracted with EtOAc (3 x 50 mL), and the combined organic fractions were dried (Na2SO4). Removal of the solvent in vacuo gave a residue which was purified by silica gel column chromatography using EtOAc-hexane (1:4, v/v) as eluent to furnish a mixture of the (Z)-10a and (E)-10b stereoisomers in a ratio of 1:1 (1H NMR integrals) in 44% yield (1.0 g); mp 136-138 °C. All attempts to separate these (Z)-10a and (E)-10b stereoisomers by fractional crystallization from solvents of different polarity (diethyl ether, ethyl acetate, isopropanol and ethanol) were unsuccessful. Therefore, this mixture of (Z)-10a and (E)-10b, without separation, was added to a solution of N-methylpiperazine (26.4 g, 264 mmol) in ethanol (50 mL). The mixture was heated under reflux for 24 h, the solvent was evaporated in vacuo, and the residue obtained was purified by silica gel column chromatography using methanol-chloroform (1:9, v/v) as eluent to give a 1:1 (1H NMR integrals) of the (Z)-11a and (E)-11b stereoisomers in 90% yield (1.05 g). Repeated fractional crystallization of this mixture from methanol furnished 170 mg of (Z)-11a as a white solid;

Reference： [1]Location in patent: experimental part Abdellatif, Khaled R.A.; Velázquez, Carlos A.; Huang, Zhangjian; Chowdhury, Morshed A.; Knaus, Edward E. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 4, p. 1195 - 1198]

42
[ 139301-27-2 ]
[ 70-70-2 ]
[ 1361005-77-7 ]

Yield	Reaction Conditions	Operation in experiment
63%	With copper diacetate; triethylamine In dichloromethane at 20℃; for 24h; Inert atmosphere; Molecular sieve;
63%	With copper diacetate; triethylamine In dichloromethane at 17 - 25℃; for 24h; Inert atmosphere; Molecular sieve;	1 Preparation of 1 -(4-(4-(trifluoromethoxy)phenoxy)phenyl)propan-l -one 4r[00222] 4-Tri-fluoromethoxy-phenyl boronic acid (1.34 g, 6.5 mmol) was added to a solution of 4' -hydroxypropiophenone (0.75 g, 5 mmol) and copper (II) acetate (0.91 g, 5 mmol) in DCM (40 mL). Freshly prepared 4 Amolecular sieves were added and the flask was placed under an inert atmosphere of nitrogen. Triethylamine (3.5 mL, 25 mmol) was added and the resultant green solution was stirred at room temperature for 24 hours. The solution was filtered through a pad of silica gel and washed with excess EtOAc. The filtrate was concentrated under vacuum to afford a yellow oil. The product was purified by column chromatography (eluting with 15% EtOAc in n- hexane) to yield ketone 4r. [00223] Clear oil. (Yield 63 %); 1H NMR (400 MHz,CDCl3) δΗ7.97 (d, 2H, J = 8.8, Ar), 7.24 (d, 2H, J = 8.5, Ar), 7.08 (d, 2H, J = 8.8, Ar), 7.02 (d, 2H, J = 8.8, Ar), 2.98 (q, 2H, J = 7.2, CH2), 1.23 (t, 3H, J = 7.2, CH3); 13C NMR (100MHz, CDC13), 5C 199.8, 161.5, 154.5, 132.6, 130.7, 123.2, 121.4, 118.0, 32.0, 8.7; HRMS calcd for Ci6Hi303F3Na [M+Na]+ 333.0715 found333.0713.

Reference： [1]Pidathala, Chandrakala; Amewu, Richard; Pacorel, Bénédicte; Nixon, Gemma L.; Gibbons, Peter; Hong, W. David; Leung, Suet C.; Berry, Neil G.; Sharma, Raman; Stocks, Paul A.; Srivastava, Abhishek; Shone, Alison E.; Charoensutthivarakul, Sitthivut; Taylor, Lee; Berger, Olivier; Mbekeani, Alison; Hill, Alasdair; Fisher, Nicholas E.; Warman, Ashley J.; Biagini, Giancarlo A.; Ward, Stephen A.; O'Neill, Paul M. [Journal of Medicinal Chemistry, 2012, vol. 55, # 5, p. 1831 - 1843]
[2]Current Patent Assignee: LIVERPOOL SCHOOL TROPICAL MEDICINE - WO2012/69856, 2012, A1 Location in patent: Page/Page column 67

43
[ 22419-35-8 ]
[ 70-70-2 ]
[ 1361967-57-8 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1844 - 1857

44
[ 22419-35-8 ]
[ 70-70-2 ]
[ 1361968-60-6 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1844 - 1857

45
[ 70-70-2 ]
[ 198479-63-9 ]

Reference： [1]Chemico-Biological Interactions,2012,vol. 197,p. 8 - 15
[2]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 4075 - 4099
[3]Patent: CN105801564,2016,A
[4]Patent: US2018/72711,2018,A1
[5]Patent: US2019/389842,2019,A1

46
[ 70-70-2 ]
[ 198480-21-6 ]

Reference： [1]Chemico-Biological Interactions,2012,vol. 197,p. 8 - 15
[2]Patent: US2019/389842,2019,A1
[3]Patent: CN113816892,2021,A

47
1-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)propan-1-one [ No CAS ]
[ 70-70-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With cerium (IV) sulfate tetrahydrate In methanol at 130℃; for 0.333333h; Microwave irradiation;	Microwave Irradiation Procedure General procedure: A 10-mL reaction vessel was charged with a magnetic stir bar, 0.4 mmol of THP ether and 20 mol % Ce(SO4)24H2O in 2mL of MeOH. A septum cap was affixed; the vessel was placed in the microwave cavity of an Anton-Paar microwave equipment. The stirring reaction mixture was irradiated at 130 C for 20 min. After cooling to room temperature, TLC indicated the disappearance of starting material. The solid cerium sulfate was filtered off and the solvent was removed under reduced pressure. Column chromatography afforded pure alcohol. All products were spectrally identical with authentic alcohols.

Reference： [1]González-Calderón, Davir; González-González, Carlos A.; Fuentes-Benítez, Aydeé; Cuevas-Yáñez, Erick; Corona-Becerril, David; González-Romero, Carlos [Tetrahedron Letters, 2013, vol. 54, # 52, p. 7164 - 7166]

48
[ 68-12-2 ]
[ 70-70-2 ]
[ 34917-91-4 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 66 - 69

49
[ 51862-24-9 ]
[ 70-70-2 ]
2-ferrocenyl-2-(4-hydroxyphenyl)pentan-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	With titanium tetrachloride; zinc In tetrahydrofuran for 2h; Schlenk technique; Inert atmosphere; Reflux;	General Procedure for McMurry Coupling Reactions General procedure: Zinc powder was suspended in dry THF at room temperature in a Schlenk tube under argon, andtitanium tetrachloride was added slowly via a syringe while stirring. The reaction mixture was heatedat reflux for 2 h, after which time a THF solution containing the two ketones was added, and themixture was heated at reflux for a further two hours. The reaction mixture was cooled, poured into water, acidified with HCl until the dark color disappeared and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude mixture was chromatographed on silica gel column using a mixture of dichloromethane/acetone 90/10 as an eluent and/or purified by semi-preparative HPLC using a mixture of acetonitrile/water as an eluent.

Reference： [1]Pigeon, Pascal; Goermen, Meral; Kowalski, Konrad; Mueller-Bunz, Helge; Mcglinchey, Michael J.; Top, Siden; Jaouen, Gerard [Molecules, 2014, vol. 19, # 7, p. 10350 - 10369]

50
1-(bromomethyl)-4-((3,7-dimethyloctyl)oxy)benzene [ No CAS ]
[ 70-70-2 ]
1-(4-((4-((3,7-dimethyloctyl)oxy)benzyl)oxy)phenyl)propan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	Synthetic procedure 1: Williamson ether synthesis General procedure: Substituted benzyl alcohol (1.0 mmol) and K2CO3 (3.0 mmol) were dissolved in DMF (10 mL). Then, 1-bromo alkane (1.1mmol) was added and the suspension was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with water (3×20 mL) and brine (2×20 mL). The organic layers were dried over MgSO4, filtered and the solvent was evaporated under reduce pressure.

Reference： [1]Eleftheriadis, Nikolaos; Thee, Stephanie; Te Biesebeek, Johan; Van Der Wouden, Petra; Baas, Bert-Jan; Dekker, Frank J. [European Journal of Medicinal Chemistry, 2015, vol. 94, p. 265 - 275]

51
1-(bromomethyl)-4-(nonyloxy)benzene [ No CAS ]
[ 70-70-2 ]
1-(4-((4-(nonyloxy)benzyl)oxy)phenyl)propan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	Synthetic procedure 1: Williamson ether synthesis General procedure: Substituted benzyl alcohol (1.0 mmol) and K2CO3 (3.0 mmol) were dissolved in DMF (10 mL). Then, 1-bromo alkane (1.1mmol) was added and the suspension was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with water (3×20 mL) and brine (2×20 mL). The organic layers were dried over MgSO4, filtered and the solvent was evaporated under reduce pressure.

Reference： [1]Eleftheriadis, Nikolaos; Thee, Stephanie; Te Biesebeek, Johan; Van Der Wouden, Petra; Baas, Bert-Jan; Dekker, Frank J. [European Journal of Medicinal Chemistry, 2015, vol. 94, p. 265 - 275]

52
[ 2606-58-8 ]
[ 70-70-2 ]
1-(4-((4-propoxybenzyl)oxy)phenyl)propan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	Synthetic procedure 1: Williamson ether synthesis General procedure: Substituted benzyl alcohol (1.0 mmol) and K2CO3 (3.0 mmol) were dissolved in DMF (10 mL). Then, 1-bromo alkane (1.1mmol) was added and the suspension was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with water (3×20 mL) and brine (2×20 mL). The organic layers were dried over MgSO4, filtered and the solvent was evaporated under reduce pressure.

Reference： [1]Eleftheriadis, Nikolaos; Thee, Stephanie; Te Biesebeek, Johan; Van Der Wouden, Petra; Baas, Bert-Jan; Dekker, Frank J. [European Journal of Medicinal Chemistry, 2015, vol. 94, p. 265 - 275]

53
C₁₉H₂₀BrNO₃ [ No CAS ]
[ 70-70-2 ]
(E)-5-bromo-3-(4-(2-(dimethylamino)ethoxy)phenyl)-1-(1-(4-hydroxyphenyl)propylidene)-2,3-dihydro-1H-inden-2-ol [ No CAS ]
(Z)-5-bromo-3-(4-(2-(dimethylamino)ethoxy)phenyl)-1-(1-(4-hydroxyphenyl)propylidene)-2,3-dihydro-1H-inden-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 55% 2: 8%	With tin(IV) chloride; zinc In tetrahydrofuran at 64 - 66℃; for 5h; Inert atmosphere;	General procedure for the synthesis compounds 2ab-2ad/8a-8g/11ab-11ad/3ab-3ao/4ab-4ac & 5ab-5ac: General procedure: Under N2 atmosphere, a three neck flask equipped with magnetic stirrer was charged with Zn-powder (1.5gm, 12 mmol) and 50 mLTHF solvent. The mixture was cooled at 0 0C and SnCl4 (2.3mL, 6 mmol) was added drop wise at 0 0C. The suspension was warmed to room temperature and stirred for 15 min and then heated at 64-66 0C for 1.5 h. The solution of aromatic aldehyde or ketone 6a-6c /chalcone epoxide 4a-4j/ indanone and propiophenone derivatives (1:1.5 molar ratio, 2 mmol) dissolved in THF (30 mL) was added slowly at same temperature. TLC monitoring, the reaction mixture was stirred at same temperature until the carbonyl compound was consumed in the reaction. Then, the reaction mixture was cooled and quenched with 10% aqueous NaHCO3 solution and extracted in EtOAc. The organic layer was washed with brine solution, dried with anhydrous Na2SO4 and concentrated in vacuo.The crude material was purified by column chromatography to give the desired products 2ab-2ad/8a-8g/11ab-11ad/3ab-3ao/4ab-4ac & 5ab-5ac in 55-86 % yields.
1: 55% 2: 8%	With tin(IV) chloride; zinc In tetrahydrofuran at 64 - 66℃; for 5h; Inert atmosphere;

Reference： [1]Pathe, Gulab Khushalrao; Ahmed, Naseem [Tetrahedron Letters, 2015, vol. 56, # 12, p. 1555 - 1561]
[2]Pathe, Gulab Khushalrao; Konduru, Naveen K.; Parveen, Iram; Ahmed, Naseem [RSC Advances, 2015, vol. 5, # 101, p. 83512 - 83521]

54
C₂₂H₂₄BrNO₃ [ No CAS ]
[ 70-70-2 ]
(E)-5-bromo-1-(1-(4-hydroxyphenyl)propylidene)-3-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-2,3-dihydro-1H-inden-2-ol [ No CAS ]
(Z)-5-bromo-1-(1-(4-hydroxyphenyl)propylidene)-3-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-2,3-dihydro-1H-inden-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 52% 2: 10%	With tin(IV) chloride; zinc In tetrahydrofuran at 64 - 66℃; for 5h; Inert atmosphere;	General procedure for the synthesis compounds 2ab-2ad/8a-8g/11ab-11ad/3ab-3ao/4ab-4ac & 5ab-5ac: General procedure: Under N2 atmosphere, a three neck flask equipped with magnetic stirrer was charged with Zn-powder (1.5gm, 12 mmol) and 50 mLTHF solvent. The mixture was cooled at 0 0C and SnCl4 (2.3mL, 6 mmol) was added drop wise at 0 0C. The suspension was warmed to room temperature and stirred for 15 min and then heated at 64-66 0C for 1.5 h. The solution of aromatic aldehyde or ketone 6a-6c /chalcone epoxide 4a-4j/ indanone and propiophenone derivatives (1:1.5 molar ratio, 2 mmol) dissolved in THF (30 mL) was added slowly at same temperature. TLC monitoring, the reaction mixture was stirred at same temperature until the carbonyl compound was consumed in the reaction. Then, the reaction mixture was cooled and quenched with 10% aqueous NaHCO3 solution and extracted in EtOAc. The organic layer was washed with brine solution, dried with anhydrous Na2SO4 and concentrated in vacuo.The crude material was purified by column chromatography to give the desired products 2ab-2ad/8a-8g/11ab-11ad/3ab-3ao/4ab-4ac & 5ab-5ac in 55-86 % yields.
1: 52% 2: 10%	With tin(IV) chloride; zinc In tetrahydrofuran at 64 - 66℃; for 5h; Inert atmosphere;

Reference： [1]Pathe, Gulab Khushalrao; Ahmed, Naseem [Tetrahedron Letters, 2015, vol. 56, # 12, p. 1555 - 1561]
[2]Pathe, Gulab Khushalrao; Konduru, Naveen K.; Parveen, Iram; Ahmed, Naseem [RSC Advances, 2015, vol. 5, # 101, p. 83512 - 83521]

55
[ 931-53-3 ]
[ 762-42-5 ]
[ 70-70-2 ]
C₂₂H₂₇NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: 4-hydroxypropiophenone With zirconium(IV) oxide In dichloromethane at -10℃; for 2h; Inert atmosphere; Stage #2: Cyclohexyl isocyanide; dimethyl acetylenedicarboxylate In dichloromethane at 20℃; for 2h; Stage #3: In dichloromethane; water at 45℃; for 5h;	Experimental section General procedure: 8-Acetyl-2-cyclohexylamino-4H-chromene-3,4-dicarboxylic Acid Dimethyl Ester (5a).Typical ProcedureTo a stirred (stir bar, magnetic stirrer) mixture of 2-hydroxyacetophenone 4a (0.272 g,2.0 mmol) and nano-sized ZrO2(0.025 g, 10 mol%) in dry CH2Cl2 (10 mL) in a threeneckflask at 10C were added dropwise under nitrogen gas over 2 hours, a solution ofdimethyl acetylenedicarboxylate (0.28 g, 2.0 mmol) in dry CH2Cl2 (10 mL) and a solutionof cyclohexyl isocyanide 3 (0.22 g, 2 mmol) in dry CH2Cl2 (10 mL) simultaneouslyby two addition funnels. The mixture was stirred at room temperature for 2 h thenrefluxed at about 45C for 5 h. The progress of the reaction was monitored by IR; afterthe absorption band at 2065 cm1 had disappeared, water (20 mL) was added to thecooled reaction mixture which was stirred for 2 h. The organic phase was then separatedand the solvent (CH2Cl2) was removed under reduced pressure. The residue was re-dissolvedin diethyl ether or n-hexane (n-hexane was preferable if recrystallization was to beperformed) and washed with water and recrystallized from ethyl acetate. Compound 5awas obtained as light yellow crystals (0.67 g, 87% yield), mp. 109-110C.

Reference： [1]Zonouzi; Afjei; Rahmani; Ng [Organic Preparations and Procedures International, 2016, vol. 48, # 1, p. 45 - 54]

56
[ 128-13-2 ]
[ 70-70-2 ]
C₃₃H₄₈O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97.3%	With dicyclohexyl-carbodiimide; In dichloromethane; at 10 - 20℃; for 2h;	A mixture of <strong>[128-13-2]ursodeoxycholic acid</strong> 50.0g (127.4mmol) and 4-hydroxyphenyl acetone 21.04g (140.1mmol) was added 200mL of methylene chloride and stirred cooling to 15 .At 10-20 , added dropwise N, N'- dicyclohexyl carbodiimide 26.24g (140.1mmol) methylene chloride solution addition was complete, the reaction after 10-20 2 hours, filtered to remove insolubles the filtrate was concentrated to give a pale yellow oil 65.63g. The above oil was recrystallized from acetonitrile to give tauro<strong>[128-13-2]ursodeoxycholic acid</strong> 4-propionyl-white solid mofetil 65.03g, 97.3% yield, 99.6% purity.At room temperature, taurine potassium crown-6 complex of 79.48g (185.9mmol) and the white solid was added methylene chloride and stirred. After reaction for 5 hours at room temperature, TLC (ethyl acetate: petroleum ether = 1: 1) monitoring the reaction was complete. 7.45g glacial acetic acid was added, followed by stirring large amount of solid precipitated was filtered to give a white solid, the white solid was added 200mL of water, stirred for crystallization. Filtered and dried to obtain a solid 70.55g, total yield of 86.8% (purity 99.8%, HPLC), taurocholic chenodeoxycholic acid was not detected, the largest single unknown Miscellaneous 0.03%.

Reference： [1]Patent: CN105330715,2016,A .Location in patent: Paragraph 0043; 0044; 0045; 0046

57
[ 110-52-1 ]
[ 70-70-2 ]
1-(4-(4-Bbromobutoxy)phenyl)propan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: 4-hydroxypropiophenone With sodium n-propoxide at 20℃; for 0.0833333h; Stage #2: 1,4-dibromo-butane at 60℃; for 7h; Reflux;	General synthetic procedure for compounds 1a-1d General procedure: General synthetic procedure for compounds 1a-1d To a solution of freshly prepared sodium propanolate, proper substituted phenols were added and stirred at room temperature for 5 min. α,ω-dibromoalkanes were then added dropwise in the time of 1 h. The reaction mixture was stirred at 60 °C for 3 h, and then refluxed for another 3 h. After cooling down to RT, mixture was filtrated and evaporated. To a rough product, 100 ml of 10% NaOH was added and left overnight in cold. To a resulting white oil CH2Cl2 was added, mixed and layers were then separated. Organic layer was dried over sodium sulphate, filtered and evaporated. Resulting product was used for further reactions after CC purification.
	With potassium hydroxide In methanol; dimethyl sulfoxide

Reference： [1]Szczepańska, Katarzyna; Karcz, Tadeusz; Kotańska, Magdalena; Siwek, Agata; Kuder, Kamil J.; Latacz, Gniewomir; Mogilski, Szczepan; Hagenow, Stefanie; Lubelska, Annamaria; Sobolewski, Michał; Stark, Holger; Kieć-Kononowicz, Katarzyna [Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 23-24, p. 6056 - 6066]
[2]Chambers, Janice E.; Chambers, Howard W.; Funck, Kristen E.; Meek, Edward C.; Pringle, Ronald B.; Ross, Matthew K. [Chemico-Biological Interactions, 2016, vol. 259, p. 154 - 159]

58
[ 111-24-0 ]
[ 70-70-2 ]
1-(4-((5-bromopentyl)oxy)phenyl)propan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	Stage #1: 4-hydroxypropiophenone With sodium n-propoxide In propan-1-ol at 20℃; for 0.0833333h; Stage #2: 1,5-dibromo-pentane In propan-1-ol at 60℃; for 7h; Reflux;	General synthetic procedure for compounds 1a-1u General procedure: A solution of freshly prepared sodium 1-propanolate, proper substituted phenols were added and stirred in room temperature for 5 min. α,ω-dibromoalkanes were then added drop wisely in the time of 1 h. The reaction mixture was stirred in 60 °C for 3 h, and then refluxed for another 3 h. After cooling down to RT mixture was filtrated and evaporated. To a rough product, 100 ml of 10% NaOH was added and left overnight in cold. To a resulting white oil CH2Cl2 was added, mixed and layers were then separated. Organic layer was dried over sodium sulphate filtered and evaporated. Rough product was used for further reactions after purification.
	With potassium hydroxide In methanol; dimethyl sulfoxide

Reference： [1]Szczepańska, Katarzyna; Karcz, Tadeusz; Siwek; Kuder, Kamil J.; Latacz, Gniewomir; Bednarski; Szafarz, Małgorzata; Hagenow, Stefanie; Lubelska, Annamaria; Olejarz-Maciej, Agnieszka; Sobolewski, Michał; Mika; Kotańska, Magdalena; Stark, Holger; Kieć-Kononowicz, Katarzyna [Bioorganic Chemistry, 2019, vol. 91]
[2]Chambers, Janice E.; Chambers, Howard W.; Funck, Kristen E.; Meek, Edward C.; Pringle, Ronald B.; Ross, Matthew K. [Chemico-Biological Interactions, 2016, vol. 259, p. 154 - 159]

59
[ 645-56-7 ]
[ 70-70-2 ]

Yield	Reaction Conditions	Operation in experiment
21.2 %Chromat.	Stage #1: 4-n-Propylphenol With ferredoxin reductase; ferredoxin; 4-methylphenyl phosphate synthase; P₄₅₀ monooxygenase; nicotinamide adenine dinucleotide phosphate; nicotinamide adenine dinucleotide; ATP; magnesium chloride; manganese(ll) chloride; alcohol dehydrogenase; aldehyde dehydrogenase In aq. buffer at 30℃; for 2h; Enzymatic reaction; Stage #2: With phosphohydrolase In aq. buffer at 30℃; for 2h; Enzymatic reaction;	Enzymatic Assays General procedure: Unless specified otherwise, all enzymatic assays were carriedout in 100 μL of 50 mM Tris·HCl buffer (pH 8.0) at 30 °C for 2 h, and thefinal concentration of each enzyme was 10 μM. Methanol (3× volume) wasadded to quench reactions. Precipitated proteins were removed by centrifugationat 20,000 × g for 10 min and the supernatants were used as LC-MSsamples. For reactions catalyzed by CreHI, the reaction mixture contained1 mM substrate, 20 mM MgCl2, 2 mM MnCl2, 2 mM ATP, and purified CreHand CreI. For CreJEF activity toward phosphorylated compounds (2′-9′), theCreHI reactions were used to generate the phosphorylated substrates. Next,CreJ, CreE, and CreF together with 3 mM NADPH were added into the individualpost-CreHI reaction mixture.For one-pot chemomimetic alkylphenol oxidation reactions, the reactionmixtures contained CreHI, CreJEF, and the two optional enzymes CreG (with2 mM NAD+) and CreC (with 2 mM NADP+), 1 mM substrate 2-7, and necessarycofactors, including 20 mM MgCl2, 2 mM MnCl2, 2 mM ATP, and 3 mMNADPH. After incubation at 30 °C for 2 h, CreD was added into each of theone-pot mixtures, followed by another 2-h incubation at 30 °C.

Reference： [1]Du, Lei; Dong, Sheng; Zhang, Xingwang; Jiang, Chengying; Chen, Jingfei; Yao, Lishan; Wang, Xiao; Wan, Xiaobo; Liu, Xi; Wangi, Xinquan; Huang, Shaohua; Cui, Qiu; Feng, Yingang; Liu, Shuang-Jiang; Li, Shengying [Proceedings of the National Academy of Sciences of the United States of America, 2017, vol. 114, # 26, p. E5129 - E5137]

60
[ 7356-60-7 ]
[ 70-70-2 ]
4-(2-(pyridin-3-yl)pyrimidin-4-yl)phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With ferrous(II) sulfate heptahydrate; 1,10-Phenanthroline; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In N,N-dimethyl-formamide; at 120℃; for 12h;Sealed tube;	Weigh 0.3 mmol3-pyrimidine formamidine hydrochloride (0.0473 g), 0.75 mmol 4-hydroxyphenylacetone (0.1126(0.0083 g), 0.03 mmol of 1,1,10-phenanthroline (0.0054 g), tetramethylpiperidineNitrogen oxide (TEMPO) (0.0563 g) was added to a 10 mL tube of test tubes and 2 mL of N, N-dimethylformamide (DMF) was addedAnd the mixture was sealed and sealed at 120 C for 12 hours. After the reaction, the reaction solution was successively passed through water, ethyl acetate, anhydrous sulfurSodium sulfate and column chromatography (column chromatography separation conditions: the stationary phase of 300 ~ 400 mesh silica gel, the mobile phase ethyl acetate(A) and petroleum ether (B), the mobile phase change program (A: B) is 1: 50 ? 1: 20, 0.0582 g of the reaction product (white solidbody). According to the characterization data, the reaction was carried out to produce 4- (2- (3-pyridyl) pyrimidin-4-yl) phenol (purity>95%), the structure is as follows:The product yield was calculated and the result was 78%.

Reference： [1]Patent: CN106496127,2017,A .Location in patent: Paragraph 0225; 0026; 0227; 0028; 0229; 0230; 0231
[2]Journal of Organic Chemistry,2017,vol. 82,p. 1145 - 1154

61
[ 121-33-5 ]
[ 70-70-2 ]
(E)-1,3-bis(4-hydroxyphenyl)-2-methylprop-2-en-1-one [ No CAS ]