Name: 15174-69-3|4-Hydroxy-3-methylbenzaldehyde|95%
Brand: Ambeed
SKU: A213243
Price: 7.0 USD
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1
[ 15174-69-3 ]
[ 499-76-3 ]

Reference： [1]Chemische Berichte,1878,vol. 11,p. 769

2
[ 67-66-3 ]
[ 95-48-7 ]
[ 824-42-0 ]
[ 15174-69-3 ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium hydroxide for 1.5h; Heating;
1: 28% 2: 18%	With sodium hydroxide In water at 60℃; for 8h;
	With alkali

Reference： [1]Malhotra, S.; Misra, K. [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1982, vol. 21, # 2, p. 107 - 108]
[2]Komiyama, Makoto; Hirai, Hidefumi [Journal of the American Chemical Society, 1983, vol. 105, # 7, p. 2018 - 2021]
[3]Hodgson; Jenkinson [Journal of the Chemical Society, 1929, p. 469,470]

3
[ 110-89-4 ]
[ 15174-69-3 ]
[ 68097-75-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	With formic acid at 110 - 115℃; for 2h;
48%	Stage #1: piperidine; 4-hydroxy-3-methyl-benzaldehyde In methanol at 20℃; for 2h; Stage #2: With sodium cyanoborohydride In methanol at 20℃; for 24h;	6 2-Methyl-4-((piperidin-1-yl)methyl)phenol Example 6: 4-(5-(2-methyl-4-((piperidin-1-yl)methyl)phenoxy)pentylthio)-7-(trifluoromethyl)quinoline dihydrochloride 6. 2-Methyl-4-((piperidin-1-yl)methyl)phenol To a solution of 4-hydroxy-3-methylbenzaldehyde (1.08 g, 7.90 mmol) in MeOH (20 mL) was added piperidine (0.8 mL, 7.9 mmol) in a 100 mL round-bottomed flask equipped with a magnetic stirrer. The reaction mixture was stirred for 2 h at RT. NaCNBH3 (0.6 g, 9.5 mmol) was added and the reaction mixture was stirred at RT for 24 h. MeOH was evaporated and EtOAc (100 mL) was added. The precipitate was filtered off and EtOAc was evaporated at 40 °C to dryness. The crude compound was purified by column chromatography (SiO2; eluent CH2Cl2:MeOH = 98:2 to 95:5) to give after evaporation 2-methyl-4-((piperidin-1-yl)methyl)phenol (800 mg, 48 % yield) as a beige solid. [Show Image] MW: 205.30; Yield: 48 %; Beige Solid; Mp (°C) = 117.2 Rf. 0.47 (CH2Cl2:MeOH = 9:1). 1H-NMR (CDCl3, δ): 1.35-1.45 (m, 2H, CH2), 1.55-1.62 (m, 4H, CH2), 2.16 (s, 3H, CH3), 2.44 (s broad, 4H, N-CH2), 3.38 (s, 2H, N-CH2), 6.41 (d, 1H, J = 8.1 Hz, Ar-H), 6.87 (d, 1H, J = 8.1 Hz, Ar-H), 7.00 (s, 1H, Ar-H), 7.94 (s broad, 1H, OH). 13C-NMR (CDCl3, δ): 16.1, 24.2, 25.3, 54.2, 63.4, 114.9, 124.4, 127.8, 128.4, 132.7, 154.0. MS-ESI m/z (rel. int.): 206.1 ([MH]+, 15), 121.0 (100). HPLC: Method A, detection UV 254 nm, RT = 3.5 min, peak area 95.0 %
	With sodium tris(acetoxy)borohydride at 0 - 20℃; for 24h;

Reference： [1]Bonjean; Schunack [Arzneimittel-Forschung/Drug Research, 1988, vol. 38, # 4, p. 501 - 507]
[2]Current Patent Assignee: DIAXONHIT GROUP - EP1746092, 2007, A1 Location in patent: Page/Page column 20
[3]Gao, Lanchang; Hao, Chao; Ma, Ru; Chen, Jiali; Zhang, Guisen; Chen, Yin [RSC Advances, 2021, vol. 11, # 28, p. 16931 - 16941]

4
[ 67-66-3 ]
[ 95-48-7 ]
[ 15174-69-3 ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: chloroform; ortho-cresol With sodium hydroxide In water at 60℃; for 6.5h; Stage #2: With hydrogenchloride In water	4.2.1. 4-Hydroxy-3-methylbenzaldehyde (7) To a solution of o-cresol (54.0 g, 0.5 mol) in 10% aqueous sodium hydroxide (800 ml, 2.0 mol) was added trichloromethane (148.0 g, 1.25 mol) dropwise at 60 °C over 5 h, and then the reaction mixture was stirred for 1.5 h at 60 °C. After cooling, the mixture was neutralized by 2 N hydrochloric acid and extracted with dichloromethane (300 ml×3). The combined organic layer was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by crystallization from ethyl acetate and petroleum ether to afford aldehyde 7 (44.3 g, 65%) as brown solid; mp: 115-117 °C; 1H NMR (400 MHz, CDCl3) δ 2.34 (s, 3H, ArCH3), 6.95 (d, J=8.0 Hz, 1H, ArH), 7.67 (dd, J=1.6, 8.0 Hz, 1H, ArH), 7.72 (s, 1H, ArH), 9.85 (s, 1H, CHO); 13C NMR (CDCl3, 100 MHz) δ 15.8, 115.3, 125.2, 129.6, 130.5, 133.1, 160.4, 191.8; MS (+C, ESI): M=136, found 137 [M+H]+.
65%	With sodium hydroxide In water at 60℃; for 7h;
11%	With sodium hydroxide; β‐cyclodextrin In water at 60℃; for 8h;

Reference： [1]Location in patent: experimental part Wang, Ping; Zheng, Guo-Jun; Wang, Ya-Ping; Wang, Xiang-Jing; Wei, He-Geng; Xiang, Wen-Sheng [Tetrahedron, 2012, vol. 68, # 11, p. 2509 - 2512]
[2]Sarkar, Debayan; Rout, Nilendri [Organic Letters, 2019, vol. 21, # 11, p. 4132 - 4136]
[3]Komiyama, Makoto; Hirai, Hidefumi [Journal of the American Chemical Society, 1983, vol. 105, # 7, p. 2018 - 2021]

5
[ 32723-67-4 ]
[ 15174-69-3 ]

Yield	Reaction Conditions	Operation in experiment
87%	With boron tribromide In dichloromethane for 21h; Ambient temperature;
70%	Stage #1: 3-methyl-4-anisaldehyde With boron tribromide In dichloromethane at 0 - 20℃; for 50h; Stage #2: In methanol at 15℃; for 0.5h; Heating / reflux; Stage #3: In methanol; water for 0.5h;	7 Intermediate 74-hydroxv-3-methvlbenzaldehvde To a solution of3-methyl-4-(methyloxy) benzaldehyde (150g, 1mol) inCH2CI2at 0-5 C under N2 atmosphere was added dropwiseBBr3 (1.5L, 1.5eq) in 2h. The reaction mixture was stirred at room temperature for 48h. The solvent was evaporated to give 200 mL of solution. This residue was cooled to15 C,MeOH (500 mL) was added to give a black suspension. The mixture was refluxed for 30min and concentrated. Water (600 mL) was added and stirred for 30 min. The mixture was extracted with diethyl ether (3 x 600mL). The organic layers were dried onMgS04 and treated with charcoal, concentrated and purified by chromatography (Dichloromethane andDichloromethane/Methanol 98/2) to give the title compound as a yellow solid (94.87g). Yield=70% 'H NMR (DMSO): 8 10.55 (s, 1H) ; 9.75 (s, 1H) ; 7.63 (s, 1H) ; 7.60 (dd, 1H) ; 6.94 (d, 1H) ; 2.17 (s, 3H).

Reference： [1]Villagomez-Ibarra, Roberto; Alvarez-Cisneros, Celina; Joseph-Nathan, Pedro [Tetrahedron, 1995, vol. 51, # 34, p. 9285 - 9300]
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2005/49578, 2005, A1 Location in patent: Page/Page column 16; 25-26

6
[ 201230-82-2 ]
[ 60577-30-2 ]
[ 15174-69-3 ]

Reference： [1]European Journal of Organic Chemistry,1999,p. 1471 - 1473

7
[ 15174-69-3 ]
KOH [ No CAS ]
[ 499-76-3 ]

Reference： [1]Chemische Berichte,1930,vol. 63,p. 551,557

8
[ 15174-69-3 ]
[ 3747-74-8 ]
3-methyl-4-(quinolin-2-ylmethoxy)-benzaldehyde [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 690 - 705

9
[ 15174-69-3 ]
[ 100-39-0 ]
[ 158771-31-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate
100%	With potassium carbonate In N,N-dimethyl-formamide at 55℃; for 3h;	3-Methyl-4-[benzyloxy]benzaldehyde 4-Hydroxy-3-methylbenzaldehyde (4.2 g, 30.8 mmol) was dissolved in DMF (40 mL) and potassium carbonate (8.53 g, 61.7 mmol) and benzyl bromide (3.85 mL, 32.4 mmol) were added. The solution was heated to 55 °C for 3 h and cooled. The reaction was diluted with water and extracted with EtOAc. The extracts were washed with water and brine, dried (MgSO4), and concentrated to provide 7.4 g (100%) of 3-methyl-4-[(phenylmethyl)oxy]benzaldehyde as a brown oil which solidified upon standing. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.21 (s, 3 H), 5.22 (s, 2 H), 7.19 (d, J=8.40 Hz, 1 H), 7.26 - 7.32 (m, 1 H), 7.34 - 7.40 (m, 2 H), 7.42 - 7.46 (m, 2 H), 7.68 (br. s., 1 H), 7.72 (dd, J=8.40, 2.15 Hz, 1 H), 9.79 (s, 1 H).
95%	With caesium carbonate In acetone at 20℃; Inert atmosphere;

88%	With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 14h;
56%	With potassium carbonate In ethanol at 20℃; for 40h;
	With potassium carbonate In N,N-dimethyl-formamide at 20℃;
	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;	27 To a mixture of 4-hydroxy-3-methylbenzaldehyde (500 mg, 3.67 mmol) in DMF (5 ml) with K2C03 (1014 mg, 7.34 mmol) was added BnBr (692 mg, 4.05 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with EA thrice. The combined extracts were washed with water, saturated brine and dried over anhydrous Na2S04, then concentrated and purified by chromatography on silica gel (1 :30 EA/PE) to yield 4-(benzyloxy)-3- methylbenzaldehyde as a yellow oil.

Reference： [1]Jessen; Tonn; Meier [Nucleosides, nucleotides and nucleic acids, 2007, vol. 26, # 6-7, p. 827 - 830]
[2]Sparks, Steven M.; Aquino, Christopher; Banker, Pierette; Collins, Jon L.; Cowan, David; Diaz, Caroline; Dock, Steven T.; Hertzog, Donald L.; Liang, Xi; Swiger, Erin D.; Yuen, Josephine; Chen, Grace; Jayawickreme, Channa; Moncol, David; Nystrom, Christopher; Rash, Vincent; Rimele, Thomas; Roller, Shane; Ross, Sean [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 5, p. 1278 - 1283]
[3]Rajput, Sunnia; McLean, Kirsty J.; Poddar, Harshwardhan; Selvam, Irwin R.; Nagalingam, Gayathri; Triccas, James A.; Levy, Colin W.; Munro, Andrew W.; Hutton, Craig A. [Journal of Medicinal Chemistry, 2019, vol. 62, # 21, p. 9792 - 9805]
[4]Fukuhara, Kiyoshi; Nakanishi, Ikuo; Matsuoka, Atsuko; Matsumura, Tomohiro; Honda, Sachiko; Hayashi, Mikiko; Ozawa, Toshihiko; Miyata, Naoki; Saito, Shinichi; Ikota, Nobuo; Okuda, Haruhiro [Chemical Research in Toxicology, 2008, vol. 21, # 2, p. 282 - 287]
[5]Cheng, Xue Qin; Chen, Xingqiang; Hughes, Richard A.; Williams, Spencer J.; Woodman, Owen L. [Journal of Medicinal Chemistry, 2008, vol. 51, # 6, p. 1874 - 1884]
[6]Das, Saibal Kumar; Reddy, K. Anantha; Abbineni, Chandrasekhar; Iqbal, Javed; Suresh; Premkumar; Chakrabarti, Ranjan [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 3, p. 399 - 403]
[7]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2018/89449, 2018, A1 Location in patent: Page/Page column 103-106

10
[ 358-23-6 ]
[ 15174-69-3 ]
[ 716344-13-7 ]

Yield	Reaction Conditions	Operation in experiment
91%	With triethylamine In dichloromethane at -78 - 20℃; for 16h;	7; 16 Compound 16a; 4-formyl-2-methylphenyl trifluoromethanesulfonate; General procedure 7 Following General Procedure 7,4-hydroxy-3-methylbenzaldehyde (0.500 g, 3.67 mmol), DMAP (0.045 g, 0.37 mmol), NEt3 (1.126 mL, 8.08 mmol), and triflic anhydride (1.139 g, 4.04 mmol) were combined. Silica gel column chromatography (8: 2 Hexanes: EtOAc) provided the title compound (0.896 g, 91%) as a white solid. 1H-NMR (CDCl3): 8 10.01 (s, 1H), 7.86 (s, 1H), 7.81 (d, J=8. 0 Hz, 1H), 7.44 (d, J=7. 6 Hz, 1H), 2.48 (s, 3H).; General Procedure 7:; Triethylamine (2. 2 equiv. ), followed by triflic anhydride (1.1 equiv. ), was added dropwise to a solution of the phenol (XVI, 1 equiv. ) and DMAP (0.1 equiv. ) in dry CH2C12 (10 ML/MMOL phenol) maintained AT-78°C. The reaction was allowed to slowly warm to room temperature and stirred until the starting phenol was completely consumed (typically 16 h). Once the reaction was complete, water was added (10 mL/mmol phenol), the layers were separated, and the aqueous phase was extracted with CH2C12 (2 X 10 ML/MMOL phenol). The combined organic phases were then dried over NA2S04, filtered, and concentrated in vacuo. Silica gel column chromatography on the organic phase residue provided the compound (XVIII).
81%	With triethylamine In dichloromethane at -78 - 20℃; for 14h; Inert atmosphere;
	With pyridine In dichloromethane at 0 - 20℃;

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2004/60882, 2004, A1 Location in patent: Page 21; 52
[2]Si, Tengda; Li, Bowen; Xiong, Wenrui; Xu, Bin; Tang, Wenjun [Organic and Biomolecular Chemistry, 2017, vol. 15, # 46, p. 9903 - 9909]
[3]Yang, Cuijian; Edsall Jr., Richard; Harris, Heather A.; Zhang, Xiaochun; Manas, Eric S.; Mewshaw, Richard E. [Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 10, p. 2553 - 2570]

11
[ 75-52-5 ]
[ 15174-69-3 ]
[ 415704-24-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With sodium acetate for 1h; Heating;
53.19%	With ammonium acetate In nitromethane at 110℃; for 2h;	1.1 Step 1 To a solution of 4-hydroxy-3-methyl-benzaldehyde (1 g, 7.34 mmol, 1 eq) in CH3NO2 (10 ml_) was added NhUOAc (113.23 mg, 1.47 mmol, 0.2 eq). The mixture was stirred at 110 °C for 2 hr. LC-MS showed 4-hydroxy-3-methyl- benzaldehyde was consumed completely and one main peak with desired m/z was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=80/1 to 0/1 ). Compound 2-methyl-4-[(E)-2-nitrovinyl]phenol (700 mg, 3.91 mmol, 53.19% yield) was obtained as yellow solid.
53.19%	With ammonium acetate at 110℃; for 2h;	1.1 Step 1 : To a solution of 4-hydroxy-3-methyl-benzaldehyde (1 g, 7.34 mmol, 1 eq) in CH3NO2 (10 ml_) was added NH4OAC (113.23 mg, 1.47 mmol, 0.2 eq). The mixture was stirred at 110 °C for 2 h. LC-MS showed 4-hydroxy-3-methyl-benzaldehyde was consumed completely and one main peak with desired m/z was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=80/1 to 0/1). Compound 2-methyl-4-[(E)-2- nitrovinyl]phenol (700 mg, 3.91 mmol, 53.19% yield) was obtained as yellow solid.

53.19%	With ammonium acetate at 110℃; for 2h;	1.1 Compound P: 4-(2-aminoethyl)-2-methylphenol To a solution of 4-hydroxy-3-methyl-benzaldehyde (1 g, 7.34 mmol, 1 eq) in CH3NO2 (10 ml_) was added NhUOAc (113.23 mg, 1.47 mmol, 0.2 eq). The mixture was stirred at 110 °C for 2 hr. LC-MS showed 4-hydroxy-3-methyl- benzaldehyde was consumed completely and one main peak with desired m/z was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=80/1 to 0/1). Compound 2-methyl-4-[(E)-2-nitrovinyl]phenol (700 mg, 3.91 mmol, 53.19% yield) was obtained as yellow solid.
	With sodium acetate at 110℃; for 48h;	100.1 Step 1 : 2-Methyl-4-[(E)-2-nitrovinyl] phenol A mixture of 4-hydroxy-3-methyl-benzaldehyde (1 g, 7.34 mmol, 1 eq) and NaOAc (602.53 mg, 7.34 mmol, 1 eq) in CH3NO2 (10 mL) was stirred at 110 °C for 48 h. TLC (PE/EtOAc = 5/1, Rf = 0.23) indicated starting material was consumed completely and one new spot formed. The mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 5/1, Rf= 0.23) to yield 2-methyl- 4-[()-2-nitrovinyl]phenol (400 mg, 1.12 mmol, 15.2% yield, 50% purity) as a yellow solid. NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J= 13.6 Hz, 1H), 7.75 (d, J = 13.6 Hz, 1H), 7.65-7.59 (m, 1H), 7.46-7.37 (m, 1H), 6.88 (d, J= 8.4 Hz, 1H), 2.24 (s, 3H); ES-LCMS m/z 180.1 [M+H]+

Reference： [1]Hart, Matthew E.; Suchland, Katherine L.; Miyakawa, Motonori; Bunzow, James R.; Grandy, David K.; Scanlan, Thomas S. [Journal of Medicinal Chemistry, 2006, vol. 49, # 3, p. 1101 - 1112]
[2]Current Patent Assignee: SENDA BIOSCIENCES; SENDA BIOSCIENCES INC; KINTAI THERAPEUTICS - WO2020/118163, 2020, A1 Location in patent: Paragraph 0168
[3]Current Patent Assignee: SENDA BIOSCIENCES - WO2021/207634, 2021, A1 Location in patent: Paragraph 0265; 0293
[4]Current Patent Assignee: SENDA BIOSCIENCES - WO2021/247963, 2021, A1 Location in patent: Paragraph 0159; 0187
[5]Current Patent Assignee: IKENA ONCOLOGY INC - WO2018/195397, 2018, A2 Location in patent: Paragraph 00683-00684

12
[ 15174-69-3 ]
[ 106-94-5 ]
3-methyl-4-propoxybenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 75℃; for 12h;	1 4-Hydroxy-3-methylbenzaldehyde [(l); 16.65g; leq], 1-bromopropane [12.2ml; l.leq], sodium iodide [4.58g; 0.25eq], potassium carbonate [33.8g; 2eq], and DMF (300 mL) were added to a dry round bottom flask. The flask was capped with a condenser and rubber septum men flushed with argon. The reaction was heated to 750C for 12 hours under an argon atmosphere. The reaction was then poured into a seperatory funnel containing water (900 mL) and ethyl acetate (900 mL). The organic layer was washed twice more with water and twice with brine, and dried over sodium sulfate. The organic filtrate was concentrated in vacuo to yield 3-methyl-4-ρroρoxybenzaldeyhde as a crude oil. The product was used in the next step without further purification.

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2007/120160, 2007, A2 Location in patent: Page/Page column 28

13
[ 89-87-2 ]
[ 15174-69-3 ]

Reference： [1]Patent: DE87255,
Fortschr. Teerfarbenfabr. Verw. Industriezweige,vol. 4,p. 138

14
[ 600-00-0 ]
[ 15174-69-3 ]
[ 637352-45-5 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate In acetone for 124.5h;	8 Intermediate 8 ethyl2-r (4-formvl-2-methviphenvl) oxvl-2-methvlpropanoate To a solution of intermediate 7 (94.9g, 0.70mol) in acetone (1L) was addedK2CO3 (145g, 1.5eq). The mixture was stirred at reflux for16h30. Then, ethyl 2-bromoisobutyrate(155mL, 1.5eq) was added. The mixture was stirred for 24h. 0.5eq ofK2CO3 and 0.5 eq of ethyl 2- bromoisobutyrate were added. After 20h of reaction, 0.5eq ofK2CO3 and 0.5 eq of ethyl 2- bromoisobutyrate were added. After 60h, 0.5eq of K2CO3 and 0.5 eq of ethyl 2- bromoisobutyrate were added. After 4h, the mixture was filtered, cleared with acetone and concentrated. The residue was diluted in CH2CI2 (800mL) and washed with NaOH (1N), water. The organic layer was dried withMgS04 and concentrated to give 143.1g brown oil used without purification in the next step). Yield=82% 1H NMR(CDC13) :5 9.86 (s, 1H) ; 7.71 (s, 1H) ; 7.60 (dd, 1H) ; 6.68 (d, 1H) ; 4.24 (quad, 2H); 2.30 (s, 3H); 1.69 (s, 6H); 1.23 (t, 3H).
	With Cs₂CO₃ In N,N-dimethyl-formamide at 80℃;
	With Cs₂CO₃ In DMF (N,N-dimethyl-formamide) at 40℃; for 42h;	To a solution of 4-hydroxy-3-methyl [BENZALDEHYDE] (3 g, 22 [MMOL)] and ethyl [2-BROM-2-] methylpropionate (6.5 mL, 44 [MMOL)] in DMF (100 mL) was added caesium carbonate (15.8 g, 48 [MMOL).] The resulting mixture was heated at [40°C] for 42 h, then allowed to cool to room temperature. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2 x 150 mL). The organic solution was dried [(MGSO4),] filtered and evaporated. Purification by [BIOTAGETM] chromatography (Silica, 90 g) eluting 9: 1 cyclohexane : EtOAc afforded the title compound as a pale yellow oil (3.5 g). ['H] NMR (400 MHz; CDCi3) 8 : 1.21 (3H, t, J 7 Hz), 1.68 (6H, s) 2.29 (3H, s), 4.23 (2H, q, J 7 Hz), 6.68 [(1 H,] d, J 8 Hz), 7.59 [(1 H,] dd, J 8,2 Hz), 7.70 [(1 H,] d, J 2 Hz), 9.85 [(1 H,] s).

	With Cs₂CO₃ In 1,4-dioxane at 90℃; for 1h;	77.1 Step 1: Compound 77-b Cesium carbonate (179.48 g, 550.86 mmol, 3.00 eq) and ethyl 2-bromo-isobutyrate (71.63 g, 367.24 mmol, 53.86 mL, 2.00 eq) was added into a solution of Compound 77-a (25.00 g, 183.62 mmol, 1.00 eq) in 1,4-dioxane (500.00 mL), and stirred at 90°C. for 1 h. The reaction system was diluted with ethyl acetate (500 mL) and water (500 mL). The organic phase was washed with saturated brine (3500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Compound 77-b . 1H NMR (400 MHz, CDCl3) δ ppm 9.83 (s, 1H), 7.68 (d, J=1.5 Hz, 1H), 7.58 (dd, J=2.0, 8.5 Hz, 1H), 6.66 (d, J=8.3 Hz, 1H), 4.23-4.17 (m, 2H), 2.27 (s, 3H), 1.66 (s, 6H), 1.20 (t, J=7.2 Hz, 3H).
	With potassium carbonate In acetonitrile for 6h; Reflux;	2. The procedure for preparation of compounds 14a-14m General procedure: 5 mmol formyl substituted phenol and 10 mmolK2CO3 were mixed fully in 25 mL acetonitrile, then 10mmol ethyl 2-bromo-2-methylpropanoate was added. The mixture was refluxed forabout 6 h. When it cooled to room temperature, the mixture was suctionfiltered, and filter cake was washed by acetonitrile. Combined filtrate wasevaporated with vacuum distillation. Crude product was added 20 mL water, andextracted with ethyl acetate (20 mL × 3). The extracts were washed withsaturated NaCl solution, dried over by anhydrous Na2SO4,filtered and evaporated under reduced pressure. The residue purified by columnchromatography on silica gel (ethyl acetate / petroleum ether) to intermediate products.
	With Cs₂CO₃ In acetonitrile at 80℃;

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2005/49578, 2005, A1 Location in patent: Page/Page column 16; 26
[2]Shibata, Yoshihiro; Usui, Hiroyuki; Kagechika, Katsuji; Yamaguchi, Mitsuhiro; Kubo, Hideo [Bioorganic and medicinal chemistry letters, 2012, vol. 22, # 23, p. 7075 - 7079,5]
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2004/762, 2003, A2 Location in patent: Page 20
[4]Current Patent Assignee: GUANGDONG ZHONGSHENG PHARMACEUTICAL CO., LTD. - US2019/225597, 2019, A1 Location in patent: Paragraph 0887-0889
[5]Huang, Yunyuan; Wei, Lin; Han, Xinya; Chen, Haifeng; Ren, Yanliang; Xu, Yanhong; Song, Rongrong; Rao, Li; Su, Chen; Peng, Chao; Feng, Lingling; Wan, Jian [European Journal of Medicinal Chemistry, 2019, vol. 184]
[6]Dai, Liang; Feng, Zhiqi; Li, Jiaxin; Liu, Hui; Liu, Junlong; Sun, Gang; Sun, Hongbin; Wen, Xiaoan; Xiang, Jiehao; Xu, Qinglong; Xu, Xiangrui; Yang, Shanlin; Yuan, Haoliang; Zhang, Shangran; Zheng, Runan [Journal of Medicinal Chemistry, 2022, vol. 65, # 3, p. 2571 - 2592]

15
[ 15174-69-3 ]
[ 105-36-2 ]
[ 637352-46-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 16h;	To a solution [OF 4-HYDROXY-3-METHYLBENZALDEHYDE (8 G,] 58.8 [MMOL)] in anhydrous acetonitrile (300 mL), under nitrogen at [0°C,] was added caesium carbonate (21 g, 64.6 [MMOL)] and ethyl bromoacetate (6.52 [ML,] 58.8 [MMOL).] The resulting mixture was allowed to come to room temperature and stirred for 16 h. The reaction mixture was diluted with water (400 mL) and extracted with EtOAc (2 x 500 mL). The combined organic extracts were dried (MgSO4) and the solvents removed in vacuo, to afford the title compound as brown solid (11.5 [G).] LC/MS: [M/Z] 223.2 [M+H] [+, RT2.] 8 min.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2004/762, 2003, A2 Location in patent: Page 20

16
[ 15174-69-3 ]
[ 18299-15-5 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution [OF 4-HYDROXY-3-METHYLBENZALDEHYDE (10G,] 73.5 [MMOL)] in dry [CH2CI2] (550 mL) under nitrogen at [5C] was added tetra-N-butylammonium borohydride (20.58 g, 80 [MMOL)] and the resultant mixture stirred for 1.25 h at [5C.] Saturated ammonium chloride solution (30 mL) was added to the reaction mixture and the resultant mixture stirred for 1 h at [5C.] Saturated ammonium chloride solution (60 mL) was added and the reaction mixture extracted with [CH2CI2,] dried [(NA2SO4)] and the solvents removed in vacuo. Purification by flushing through silica (2 x 150 g) eluting with EtOAc afforded the title compound as an oily yellow solid (8.01 g). [1H] NMR (400 MHz; [MEOH-D4)] 8 : 2.19 (3H, s), 4.46 (2H, s), 6.71 [(1H, D,] J 8Hz), 6.99 [(1H,] dd, J 8Hz, 2Hz), 7.06 (1 H, d, J 2Hz), OH not observed.

Reference： [1]Patent: WO2004/762,2003,A2 .Location in patent: Page 23

17
[ 15174-69-3 ]
[ 18162-48-6 ]
[ 381226-61-5 ]

Yield	Reaction Conditions	Operation in experiment
	With 1H-imidazole In DMF (N,N-dimethyl-formamide) for 0.5h;	6.1 EXAMPLE 6; 2-[3-Methyl-4-[3-(2-pyridinylamino)propoxy]phenyl]Cyclopropaneacetic Acid; Step 1 4-hydroxy-3-methylbenzaldehyde (3.0 g, 22 mmol) was dissolved in DMF (25 ml). Imidazole (2.72 g, 40 ml) and dimethyl-t-butylsilyl chloride (3.76 g, 25 mmol) were added. After 30 min, the product was extracted with ethyl acetate, and washed with H2O. The aqueous layer was extracted with additional ethyl acetate. The combined organic layer was washed with H2O, brine, and dried. The crude product was purified by vacuum distillation to afford a clean oil in 4.1 g. NMR spectra of the product were consistent for the proposed structure.
	With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃;
263.8 mg	With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 4h;

Reference： [1]Current Patent Assignee: PFIZER INC - US2004/92538, 2004, A1 Location in patent: Page 34-35
[2]Nemoto, Tetsuhiro; Ishige, Yuta; Yoshida, Mariko; Kohno, Yuta; Kanematsu, Mutsumi; Hamada, Yasumasa [Organic Letters, 2010, vol. 12, # 21, p. 5020 - 5023]
[3]Nakayama, Hiroki; Harada, Shingo; Kono, Masato; Nemoto, Tetsuhiro [Journal of the American Chemical Society, 2017, vol. 139, # 30, p. 10188 - 10191]

18
[ 15174-69-3 ]
[ 637352-45-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	With ethyl 2-bromoisobutyrate for 36h;	Intermediate 25 Intermediate 25 [2- (4-FORMYL-2-METHYL-PHENOXY)-2-METHYL-PROPIONIC] acid ethyl ester The same method was employed as in the preparation of intermediate 1 but starting from 3-Methyl-4-hydroxybenzaldehyde and gave the title compound in a 86% yield after purification by flash chromatography using DCM as eluent. GC/MS: m/z 250

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2004/785, 2003, A2 Location in patent: Page 27

19
[ 50-00-0 ]
[ 15174-69-3 ]
[ 3328-73-2 ]

Yield	Reaction Conditions	Operation in experiment
26%	With triethylamine; magnesium chloride In acetonitrile at 0 - 90℃; for 19h;	617.1 Example 617; 6-(hydroxymethyl)-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid; Step 1. Preparation of 4-HYDROXY-5-METHYLISOPHTHALALDELMDE. [1069] The 4-hydroxy-3-methylbenzaldehyde (7.0 g, 51.41 mmole) and magnesium chloride (7.3 g, 77.12 mmole) were mixed in acetonitrile (100 mL) and cooled to 0 °C (ice bath). Triethylamine (19.51 g, 192.79 mmole) followed by para-formaldehyde (10.41 g, 347 mmole) were added to above mixture, which was stirred for 1 hour. The mixture was warmed to room temperature and then heated to 90 °C for 18 hours. The contents were poured into water (100 mL) and extracted with EtOAc (2 X 100 mL). The combined extracts were washed with brine (50 mL), dried over MgS04, filtered and concentrated in vacuo to give an off-white solid which was subject to flash chromatography (silica gel) and eluted with 100% CH2C12 to give an off-white solid (2. 2 g, 26%). GCMS M/Z 164.0 (M+). 1H NMR (CDC13/400 MHz) 11.82 (s, 1H), 9.96 (s, 1H), 9.89 (s, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 2.32 (s, 3H).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2004/87686, 2004, A2 Location in patent: Page 515-516 Current Patent Assignee: PFIZER INC - WO2004/87687, 2004, A1 Location in patent: Page 515-516

20
[ 15174-69-3 ]
[ 107-21-1 ]
2-(2-hydroxyethoxy)-2-(4-hydroxy-3-methylphenyl)-1,3-dioxolane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	In toluene for 24h; Heating / reflux;	1 Example 1: Preparation of 2-(2-hydroxyethoxy)-2-(4-hydroxy-3-methylphenyl)-1,3-dioxolane (Compound 1) A mixture of 3-METHYL-P-HYDROXYBENZALDEHYDE (0.5 g, 3.6 mmol), ethylene glycol (0.34 g, 5. 5 MMOL) and P-TOLUENESULFONIC acid (0.07 g, 0.36 mmol) in toluene was heated under reflux. After 24 h, the reaction mixture was cooled to room temperature, TLC showed no starting material. The toluene was removed in vacuo and saturated solution of sodium hydrogen carbonate (20 ml) was added to the residue, which was then extracted with ethyl acetate (3 x 20 ml). The organic layer was washed with water (20 ml), dried over anhydrous sodium sulfate and the solvent was removed in vacuo. The residue was then recrystallised from an ethyl acetate and hexane mixture to give the product as a brown solid in 24% yield. 1H NMR (CDCL3) : 2.21 (s, 3H), 3.62 (t, 2H, J = 4. 5 HZ), 3.70 (t, 2H, J = 4.2 Hz), 3.81 (t, 2H, J = 4.7 Hz), 4.42 (t, 2H, J = 4.7 Hz), 6.74 (d, 1H, J = 8.4 Hz), 7.21 (d, 1H, J = 8.4 Hz) and 7.78 (s, 1H). MS: m/e 263 (M+ + Na), 179 (M+-OCH2CH2OH), 147,135, 118 and 107. 3C NMR (CDC13) : 15.7, 61.1, 63.5, 69.1, 72.4, 114.0, 120.5, 124.5, 128.4, 135.6, 159.8 and 167.1.

Reference： [1]Current Patent Assignee: CORTICAL - WO2004/89927, 2004, A1 Location in patent: Page 52

21
[ 6271-78-9 ]
[ 15174-69-3 ]
[ 676494-24-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 100℃; for 4h;	Combine 4-hydroxy-3-methyl-benzaldehyde (401 mg, 2.94 mmol), K2CO3 (570 mg, 4.12 mmol) and 6-CHLORONICOTINONITRILE (408 mg, 2. 94 MMOL) in DMF (6 ml), heat at 100C. After 4 h cool to ambient temperature and pour into water. Extract the aqueous layer with EtOAc. Dry the organic layer over NA2SO4 and eliminate the solvent. Dry under vacuum at 45 C overnight to get the title compound (680 mg, 97%). 1H-NMR (CDC13, 400 MHz): 9.99 (s, 1H), 8.43 (d, 1H, J=2. 5 Hz), 7.97 (dd, 1H, J=2. 5 and 8.8 Hz), 7.84 (bs, 1H), 7.80 (dd, 1H, J= 2.5 and 8.8 Hz), 7.22 (d, 1H. J= 8.4 Hz), 7. 11 (d, 1H, J= 8.4 Hz), 2.24 (s, 3H).

Reference： [1]Patent: WO2004/26305,2004,A1 .Location in patent: Page/Page column 129

22
[ 6271-78-9 ]
[ 15174-69-3 ]
[ 676494-29-4 ]

Yield	Reaction Conditions	Operation in experiment
40%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); for 0.0833333h;Microwave irradiation;Product distribution / selectivity;	A solution of 4-hydroxy-3-methylbenzaldehyde (1. 0 equiv) in DMF (0.2 M solution) was treated with K2CO3 (1.5 equiv) and 6-CHLORONICOTINAMIDE (1.0 equiv). The reaction mixture was placed inside the microwave oven and then irradiated for 5 min. Upon completion of the reaction, the mixture was cooled, poured into H20 and extracted with ethyl acetate, and the combined organic layers were washed twice with water and brine. After drying the extracts over magnesium sulfate and evaporation under vacuum the crude product was purified by silica gel chromatography using CHCl3 : EtOH 7%: NH40H 0.7% to afford the title compound as a solid. 40% yield 'H NMR (CD30D, 200 MHz) 8 : 9.94 (s, I H), 8.59 (d, J = 2.2 Hz, 1H), 8.29 (dd, J=8.8, 2.6 Hz, 1H), 7.86 (s, 1H), 7.80 (dd, J = 8.4, 1.8 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8. 8 Hz, 1H), 2.22 (s, 3H). 13C NMR (CD30D, 200 MHz) 5 : 191.6, 167.3, 165.3, 157.2, 147.6, 140.0, 134.1, 133.4, 132.2, 129.5, 125.0, 122.7, 111.6, 16. 8.
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); for 0.0833333h;microwave irradiation;Product distribution / selectivity;	A solution OF 4-HYDROXY-3-METHYLBENZALDEHYDE (1.0 equiv) in DMF (0.2 M solution) was treated with K2CO3 (1.5 equiv) and 6-CHLORONICOTINAMIDE (1.0 equiv). The reaction mixture was placed inside the microwave oven and then irradiated for 5 min. Upon completion of the reaction, the mixture was cooled, poured into H20 and extracted with ethyl acetate, and the combined organic layers were washed twice with water and brine. After drying the extracts over magnesium sulfate and evaporation under vacuum the crude product was purified by silica gel chromatography using CHCl3 : EtOH 7%: NH40H 0.7% to afford the title compound as a solid.

Reference： [1]Patent: WO2004/26305,2004,A1 .Location in patent: Page/Page column 131-132
[2]Patent: WO2004/26305,2004,A1 .Location in patent: Page/Page column 169

23
[ 15174-69-3 ]
[ 107-30-2 ]
[ 199166-97-7 ]

Yield	Reaction Conditions	Operation in experiment
53%	With triethylamine In dichloromethane at 25℃; for 16h;	3.a Example 3 (Entry 1041); 3-{4-[2-(11-Ethyl-6,11-dihydro-5-methyl-6-oxo-5H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-8-yl)ethoxy]-3-methylphenyl}-5-isoxazolecarboxylic Acid; a) 4-(Methoxymethoxy)-3-methylbenzaldehyde To a solution of 4-hydroxy-3-methylbenzaldehyde (900 mg, 6.61 mmol) in CH2Cl2 (19 mL) was added Et3N (5.90 mL, 42.3 mmol) and chloromethyl methyl ether (2.00 mL, 26.3 mmol). The reaction was stirred at 25° C. for 16 h. The reaction mixture was diluted with EtOAc and was successively washed with aqueous 1 N HCl solution, aqueous saturated NaHCO3 solution, water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane:EtOAc, 4:1) to give the title compound (630 mg, 53% yield) as a clear oil.
	With sodium hydride In tetrahydrofuran at 0℃; for 0.5h;	72.1 Step 1: Preparation of 4-(methoxymethoxy)-3-methyl-benzaldehyde To a solution of 4-hydroxy-3-methyl-benzaldehyde (3000.0 mg, 22.03 mmol) and chloro methyl methyl ether (2.01 mL, 26.44 mmol) in THF (40 mL) cooled at 0 °C was added and sodium hydride (634.59 mg, 26.44 mmol), the mixture was stirred at 0 °C for 30 minutes. After the reaction was completed, the mixture was quenched by water (30 mL) and the resulting mixture was extracted with EtOAc (20 mL) twice. The combined organic layer was dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution with PE: EtOAc 10:1- 5:1) to give 4-(methoxymethoxy)-3-methyl- benzaldehyde as a yellow liquid. MS obsd. (ESL) [(M+H)+]: 181.1.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2004/6071, 2004, A1 Location in patent: Page/Page column 14
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2020/53249, 2020, A1 Location in patent: Page/Page column 131

24
[ 15174-69-3 ]
[ 211750-50-4 ]
[ 627906-73-4 ]

Yield	Reaction Conditions	Operation in experiment
64%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 25℃; for 16h;	13.a Example 13 (Entry 1096); 11-Ethyl-5,11-dihydro-8-{2-[4-(1H-imidazol-2-yl)-2-methylphenoxy]ethyl}-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one; a) 11-Ethyl-8-[2-(4-formyl-2-methylphenoxy)ethyl]-5,11-dihydro-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one A solution of DIAD (395 μL, 2.15 mmol) in THF (0.8 mL) was added dropwise to a solution of 11-ethyl-5,11-dihydro-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (430 mg, 1.44 mmol), 4-hydroxy-3-methylbenzaldehyde (200 mg, 1.47 mmol) and PPh3 (564 mg, 2.15 mmol) in THF (15 mL) at 25° C. The mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (EtOAc:toluene, 1:3) to yield the title compound (385 mg, 64% yield).

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2004/6071, 2004, A1 Location in patent: Page/Page column 18

25
[ 15174-69-3 ]
[ 76513-69-4 ]
[ 905911-48-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20 - 25℃; for 5h;	35.B B] 3-Methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-benzaldehyde 5.12 g (37.6 mmol) of 3-methyl-4-hydroxy-benzaldehyde was dissolved in 250 ml of MeCl2; 19.7 ml=14.9 g (112.8 mmol) of N-ethyl-diisopropylamine was added at RT, then, 8.85 ml=8.36 g (45.1 mmol) of 2-(trimethylsilyl)ethoxymethyl chloride was added drop by drop below 25° C. After 5 hours, the reaction mixture was poured into crashed ice and the product was extracted twice with MeCl2; the organic phases were washed with water, dried with MgSO4, filtered and evaporated to give 11.59 g of crude product which was purified by chromatography over silica gel with a gradient of n-heptane and AcOEt to yield 10.61 g of the title compound as light yellow oil. MS: 208.1 (M-C3H6O)+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2006/183754, 2006, A1 Location in patent: Page/Page column 32

26
[ 15174-69-3 ]
[ 15777-70-5 ]

Yield	Reaction Conditions	Operation in experiment
66%	With hydroxylamine hydrochloride; acetic acid; for 1.5h;Heating / reflux;	Preparation 70: 4-Hydroxy-3-methylbenzonitrile A mixture of 4-hydroxy-3-methylbenzaldehyde (530 mg, 3.91 mmol) and hydroxyl ammonium chloride (406 mg, 5.81 mmol) in acetic acid (5 mL) was heated under reflux for 90 minutes. The cooled reaction mixture was then diluted with diethyl ether (30 mL) and washed with water (30 mL). The combined organic solution was washed with brine, dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 97.5:2.5, to afford the title compound as a pale yellow oil in 66% yield, 345 mg. 1H NMR(400 MHz, CDCl3) δ: 2.25(s, 3H), 6.84(d, 1H), 7.37(d, 1H), 7.40(s, 1H)

Reference： [1]Patent: US2006/160786,2006,A1 .Location in patent: Page/Page column 36

27
[ 565165-44-8 ]
[ 15174-69-3 ]
[ 841259-10-7 ]

Yield	Reaction Conditions	Operation in experiment
34%	With potassium carbonate In tetrahydrofuran at 50℃; for 72h;	49.1 Example 49: (E)-4-acetyl-1-{4-[2-(1H-indazol-3-yl)vinyl]-2-methylphenoxy}acetylpiperazine (Compound 49); Step 1; A THF (8.0 mL) solution of 4-hydroxy-3-methylbenzaldehyde (400 mg, 2.94 mmol) was added with potassium carbonate (813 mg, 5.88 mmol) and 1-acetyl-4-chloroacetylpiperazine (1.69 g, 8.26 mmol), followed by stirring at 50°C for 3 days. The reaction mixture was added with ethyl acetate and a saturated aqueous ammonium chloride solution, and was extracted. The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to obtain 4-(4-acetylpiperazin-1-ylcarbonyl)methoxy-3-methylbenzaldehyde (304 mg, 34%). 1H-NMR (270 MHz, CDCl3) δ 2.12 (s, 3H), 2.30 (s, 3H), 3.43-3.50 (br, 2H), 3.60-3.70 (br, 6H), 4.84 (s, 2H), 6.97 (d, J = 8.44 Hz, 1H), 7.69-7.71 (m, 2H), 9.87 (s, 1H). ESI-MS (m/z); 305 [M+H]+

Reference： [1]Current Patent Assignee: Kyowa Kirin (in: Kirin Holdings); KIRIN HOLDINGS CO., LTD. - EP1650194, 2006, A1 Location in patent: Page/Page column 39

28
[ 15174-69-3 ]
[ 3647-69-6 ]
[ 841259-09-4 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 4h;	48.1 Example 48: (E)-3-{2-[3-methyl-4-(2-morpholinoethoxy)phenyl]vinyl}-1H-indazole (Compound 48); Step 1; A DMF (12 mL) solution of 4-hydroxy-3-methylbenzaldehyde (1.00 g, 7.34 mmol) was added with potassium carbonate (2.03 g, 14.7 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (1.50 g, 8.07 mmol), followed by stirring at 70°C for 4 hours. The reation mixture was concentrated, and the residue was added with ethyl acetate and water, and then was extracted. The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to obtain 3-methyl-4-(2-morpholinoethoxy)benzaldehyde (1.37 g, 75%). 1H-NMR (300 MHz, CDCl3) δ 2.26 (s, 3H) , 2.62 (t, J = 4.77 Hz, 4H), 2.87 (t, J = 5.69 Hz, 2H), 3.73 (t, J = 4.77 Hz, 4H), 4.21 (t, J = 5.69 Hz, 2H), 6.91 (d, J = 8.99 Hz, 1H), 7.69-7.72 (m, 2H), 9.85 (s, 1H). EI-MS (m/z); 250 [M+H]+

Reference： [1]Current Patent Assignee: Kyowa Kirin (in: Kirin Holdings); KIRIN HOLDINGS CO., LTD. - EP1650194, 2006, A1 Location in patent: Page/Page column 39

29
[ 15174-69-3 ]
[ 540778-51-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	With pyridine; acetic anhydride In dichloromethane	3.1 Step 1 Step 1 4-Acetoxy-3-methylbenzaldehyde A mixture of 5.20 g (38.2 mmol) of 4-hydroxy-3-methylbenzaldehyde, 5.0 ml (61.8 mmol) of pyridine in 40 ml of CH2Cl2 was stirred in a 0° C. ice bath, then 4.0 ml (42.3 mmol) of acetic anhydride was added over a period of 20 min. The reaction mixture was stirred for 1.5 hours more, then warmed to room temperature. The mixture was extracted with EtOAc, washed with 10% HCl, brine, and water, dried (MgSO4), filtered, and concentrated to afford a yellowish oil (6.51 g, 95% yield): Rf0.28 (20% EtOAc/hexane); 1H NMR (400 MHz, CDCl3) δ2.27 (s, 3, CH3), 2.36 (s, 3, CH3), 7.20 (d, J=7.6 Hz, 1, ArH), 7.75 (dd, J=7.8,1.6 Hz, 1, ArH), 7.78 (s, 1, ArH), 9.96 ppm (s, 1, CHO).

Reference： [1]Current Patent Assignee: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE - US2003/176506, 2003, A1

30
[ 95-48-7 ]
[ 15174-69-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With boron trifluoride In hydrogen fluoride	2 Preparation of 4-hydroxy-3-methylbenzaldehyde EXAMPLE 2 Preparation of 4-hydroxy-3-methylbenzaldehyde 10.8 g (100 mmol) of o-cresol are admixed in a 250 ml stainless-steel autoclave with 100 g (5 mol) of anhydrous hydrogen fluoride and 13.8 g (203 mmol) of boron trifluoride. Subsequently the reaction mixture is heated to 40° C. and carbon monoxide is passed in until the pressure has reached 100 bar. This pressure must be readjusted a number of times during the reaction time. After 14 hours the reaction solution is poured onto 1 kg of ice and is neutralized with concentrated KOH solution. Further workup as in Example 1 gave 13.5 g of an oil. The 1 H-NMR spectrum and the gas chromatogram gave the purity of the 4-hydroxy-3-methylbenzaldehyde obtained as 95% (94% of theoretical).
	With boron trifluoride In hydrogen fluoride	3 Preparation of 4-hydroxy-3-methylbenzaldehyde EXAMPLE 3 (Comparative) Preparation of 4-hydroxy-3-methylbenzaldehyde 10.8 g (100 mmol) of o-cresol are admixed in a 250 ml stainless-steel autoclave with 100 g (5 mol) of anhydrous hydrogen fluoride and 14 g (206 mmol) of boron trifluoride. Subsequently carbon monoxide is passed into the reaction mixture first at room temperature until the pressure has reached 100 bar. The mixture is then heated to 40° C. and stirred for 22 hours. The reaction solution is then poured onto 1 kg of ice and is neutralized with concentrated KOH solution. Further workup as in Example 1 gave 13.5 g of a product. The molar ratio of 4-hydroxy-3-methylbenzaldehyde to the isomeric 2-hydroxy-3-methylbenzaldehyde is 83:17 (82% and 17% respectively of theoretical).

Reference： [1]Current Patent Assignee: SANOFI - US5395978, 1995, A
[2]Current Patent Assignee: SANOFI - US5395978, 1995, A

31
[ 111-25-1 ]
[ 15174-69-3 ]
4-hexyloxy-3-methylbenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 5h;	19 [Example 19]; [Production of D-166]; D-166 was produced according to the following scheme:; 5.5 g of 3-methyl-4-hydroxybenzaldehyde was dissolved in 50 ml of dimethylformamide, to which were added 8.4 g of potassium carbonate and 6.8 g of 1-bromohexane. Then, this was stirred under nitrogen atmosphere at 110°C for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated saline. The organic layer was concentrated under reduced pressure, and 100 ml of ethanol was added to the resulting oily product. With cooling with ice, an aqueous solution of 9.0 g of hydroxylamine-O-sulfonic acidwas dropwise added to it. This was reacted at 55°C for 6 hours, and water was added to the reaction solution, extracted withRO/JF 22.9.200ethyl acetate and washed with saturated saline. The organic layer was concentrated under reduced pressure and purified through column chromatography to obtain 5.6 g of D-166A.Next, D-166A was converted into D-166 in the same manner as in Example 1. The yield of D-166 was 3. 0 g. The NMR spectrum of the thus-obtained D-166 was as follows:RO/J P 22.9.200.1H-NMR (solvent: CDC13, standard: tetramethylsilane) 8 (ppm)0.90 (9H, t)1.30-1.40 (12H, m)1.50-1.60 (6H, m)1.80-1.90 (6H, m)2.32 (9H, s)4.05 (6H, t)6.92 (3H, d)8.00 (3H, d)8.02 (3H, dd)9.20 (3H, s)The phase transition temperature of the thus-obtained D-166 was determined through texture observation with a polarization microscope. The temperature was elevated, and the crystal phase of the compound changed to a discotic nematic liquid-crystal phase at around 135°C. At over 160°C, the phase changed to an isotropic liquid phase. Specifically, it was found that D-166 exhibits a discotic nematic liquid-crystal phase within a temperature range of from 135°C to 160°C.

Reference： [1]Current Patent Assignee: FUJIFILM HOLDINGS CORP. - WO2006/16724, 2006, A2 Location in patent: Page/Page column 62-63

32
[ 2832-10-2 ]
[ 15174-69-3 ]
C₂₆H₂₈O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: ethyl 4-acetyl-5-oxohexanoate With boron trioxide In ethyl acetate at 40℃; for 0.5h; Stage #2: 4-hydroxy-3-methyl-benzaldehyde With boric acid tributyl ester In ethyl acetate at 40 - 42℃; for 0.5h; Stage #3: With hydrogenchloride; N-butylamine more than 3 stages;	1; 4 This compound was synthesized starting from a commercially available substituted benzaldehyde with 4-acetyl-5-oxohexanoate as shown in Scheme 4.More specifically, 4-acetyl-5-oxohexanoate was reacted with boron oxide (0.7 eq) in ethyl acetate at 40 0C for 30 min. To the resulting mixture tributyl borate and 3-methyl-4-hydroxy benzaldehyde (both 1.6-1.8 eq) were added and the mixture was stirred at 40-42 0C for 30 min. A solution of butyl amine (1.5 eq) in ethyl acetate was added slowly and the mixture was further allowed to stir at 40-42 0C overnight. 10% hydrochloride acid (2.5 eq) was added and the reaction mixture was stirred at 60 0C for Ih. The reaction mixture was cooled to r.t. and partitioned. The aqueous portion was extracted with ethyl acetate twice. The combined ethyl acetate extract was washed with water to pH~4 and dried over MgSO4. After filtration and concentration, the crude was purified by silica gel column chromatography (HPFC) with hexanes:ethyl acetate as eluent and crystallized from ethyl acetate.

Reference： [1]Current Patent Assignee: ANNJI PHARMACEUTICAL - WO2008/85984, 2008, A1 Location in patent: Page/Page column 34

33
[ 15174-69-3 ]
[ 86864-60-0 ]
[ 820238-18-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride In N,N-dimethyl-formamide at 20 - 80℃; for 1.5h; Microwave reactor;	97 A mixture of 3-methyl-4-hydroxybenzaldehyde (0.200 g, 1.5 mmol), (2-bromoethoxy)-tert-butyidimethylsilane (0.538 g, 2.25 mmol) and sodium hydride (0.061 g, 2.55 mmol) in DMF (5.00 mL) was stirred open at room temperature for 30 min in a microwave vial. The vial was then capped and heated in the microwave reactor for 1 h at 80° C. Water (55.0 mL) was added to quench. The solution was diluted with 1 N HCl (25.0 mL) and extracted with EtOAc (2×25.0 mL), dried and evaporated. The crude material was purified via CombiFlash to yield the alkylated aldehyde. A mixture of 2-amino-4,6-dimethoxybenzamide (0.167 g, 0.85 mmol), 4-(2-(tert-butyidimethylsilyloxy)ethoxy)-3-methylbenzaldehyde (0.250 g, 0.85 mmol), p-TsOH.H2O (0.016 g, 0.085 mmol) and NaHSO3 (0.088 g, 0.85 mmol) in DMA (5.00 mL) was stirred at 155° C. for 90 min. The solution was diluted with EtOAc (150 mL), washed with saturated NaHCO3 (2×50 mL), 1 N HCl (2×75 mL), brine (50 mL), dried and the solvent was removed under reduced pressure to yield the TBS protected material (0.068 g, 17%) as a tan solid. The crude material was used directly in the next step. The TBS-protected material (0.068 g, 0.144 mmol) and 1 M TBAF in THF (1.00 mL, 7 mmol) was stirred at room temperature for 1 h. The volatiles were removed under vacuum, and the residue diluted with EtOAc (100 mL). The solution was washed with water (2×50.0 mL), brine (50.0 mL), dried and the solvent was removed. The residue was purified via CombiFlash to yield 2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.024 g, 47%) as an orange solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.05 (m, 2H), 7.05 (d, 1H, J=8.3 Hz), 6.72 (d, 1H, J=2.2 Hz), 6.50 (d, 1H, J=2.2 Hz), 4.87 (t, 1H, J=5.5 Hz), 4.09 (t, 2H, J=4.9 Hz), 3.89 (s, 3H), 3.84 (s, 3H), 3.76 (dd, 2H, J=5.1 Hz, J=10.0 Hz), 2.24 (s, 3H); MS (APCl) m/z 357 [M+H]+.
	With sodium hydride In N,N-dimethyl-formamide at 20 - 80℃; for 1.5h; Microwave irradiation; Sealed tube;	91 Example 91 2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one A mixture of 3-methyl-4-hydroxybenzaldehyde (0.200 g, 1.5 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (0.538 g, 2.25 mmol) and sodium hydride (0.061 g, 2.55 mmol) in DMF (5.00 mL) was stirred open at room temperature for 30 min in a microwave vial. The vial was then capped and heated in the microwave reactor for 1 h at 80° C. Water (55.0 mL) was added to quench. The solution was diluted with 1 N HCl (25.0 mL) and extracted with EtOAc (225.0 mL), dried and evaporated. The crude material was purified via CombiFlash to yield the alkylated aldehyde. A mixture of 2-amino-4,6-dimethoxybenzamide (0.167 g, 0.85 mmol), 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3-methylbenzaldehyde (0.250 g, 0.85 mmol), p-TsOH.H2O (0.016 g, 0.085 mmol) and NaHSO3 (0.088 g, 0.85 mmol) in DMA (5.00 mL) was stirred at 155° C. for 90 min. The solution was diluted with EtOAc (150 mL), washed with saturated NaHCO3 (250 mL), 1 N HCl (275 mL), brine (50 mL), dried and the solvent was removed under reduced pressure to yield the TBS protected material (0.068 g, 17%) as a tan solid. The crude material was used directly in the next step. The TBS-protected material (0.068 g, 0.144 mmol) and 1 M TBAF in THF (1.00 mL, 7 mmol) was stirred at room temperature for 1 h. The volatiles were removed under vacuum, and the residue diluted with EtOAc (100 mL). The solution was washed with water (250.0 mL), brine (50.0 mL), dried and the solvent was removed. The residue was purified via CombiFlash to yield 2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.024 g, 47%) as an orange solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.05 (m, 2H), 7.05 (d, 1H, J=8.3 Hz), 6.72 (d, 1H, J=2.2 Hz), 6.50 (d, 1H, J=2.2 Hz), 4.87 (t, 1H, J=5.5 Hz), 4.09 (t, 2H, J=4.9 Hz), 3.89 (s, 3H), 3.84 (s, 3H), 3.76 (dd, 2H, J=5.1 Hz, J=10.0 Hz), 2.24 (s, 3H); MS (APCI) m/z 357 [M+H]+.

Reference： [1]Current Patent Assignee: RESVERLOGIX CORP - US2008/188467, 2008, A1 Location in patent: Page/Page column 59
[2]Current Patent Assignee: ZENITH CAPITAL CORP - US2013/281397, 2013, A1 Location in patent: Paragraph 0651; 0652

34
[ 15174-69-3 ]
[ 63920-73-0 ]
[ 1044871-44-4 ]

Yield	Reaction Conditions	Operation in experiment
35%	With toluene-4-sulfonic acid; sodium hydrogensulfite In N,N-dimethyl acetamide for 1h; Heating / reflux;	98 A mixture of 4-hydroxy-3-methylbenzaldehyde (0.200 g, 1.47 mmol), 2-amino-4,6-dimethoxybenzamide (0.288 g, 1.47 mmol), NaHSO3 (94%, 0.163 g, 1.47 mmol), and p-TsOH.H2O (0.028 g, 0.147 mmol) in DMA (18.4 mL) was heated at reflux for 1 h. The mixture was diluted with EtOAc (300 mL), washed with saturated aqueous NH4Cl (2×150 mL) and brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was triturated with MeOH and filtered off a yellow solid, which was freeze-dried from MeCN/H2O to provide 2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.161 g, 35%). Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.71 (s, 1H), 10.02 (s, 1H), 7.99 (d, J=1.88 Hz, 1H), 7.89 (dd, J=8.47, 2.29 Hz, 1H), 6.86 (d, J=8.50 Hz, 1H), 6.69 (d, J=2.31 Hz, 1H), 6.48 (d, J=2.31 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.18 (s, 3H); MS (APCl) m/z 313 [M+H]+.
35%	With toluene-4-sulfonic acid; sodium hydrogensulfite In N,N-dimethyl acetamide for 1h; Reflux;	92 Example 92 2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one Example 92 2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one A mixture of 4-hydroxy-3-methylbenzaldehyde (0.200 g, 1.47 mmol), 2-amino-4,6-dimethoxybenzamide (0.288 g, 1.47 mmol), NaHSO3 (94%, 0.163 g, 1.47 mmol), and p-TsOH.H2O (0.028 g, 0.147 mmol) in DMA (18.4 mL) was heated at reflux for 1 h. The mixture was diluted with EtOAc (300 mL), washed with saturated aqueous NH4Cl (2*150 mL) and brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was triturated with MeOH and filtered off a yellow solid, which was freeze-dried from MeCN/H2O to provide 2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.161 g, 35%). Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.71 (s, 1H), 10.02 (s, 1H), 7.99 (d, J=1.88 Hz, 1H), 7.89 (dd, J=8.47, 2.29 Hz, 1H), 6.86 (d, J=8.50 Hz, 1H), 6.69 (d, J=2.31 Hz, 1H), 6.48 (d, J=2.31 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.18 (s, 3H); MS (APCI) m/z 313 [M+H]+.

Reference： [1]Current Patent Assignee: RESVERLOGIX CORP - US2008/188467, 2008, A1 Location in patent: Page/Page column 59
[2]Current Patent Assignee: ZENITH CAPITAL CORP - US2013/281397, 2013, A1 Location in patent: Paragraph 0653; 0654

35
[ 15174-69-3 ]
[ 34956-31-5 ]
[ 1076188-42-5 ]

Yield	Reaction Conditions	Operation in experiment
		[00607] To a mixture of <strong>[34956-31-5]N-(4-acetyl-3-methylphenyl)acetamide</strong> (1.3g, 7.0 mmol) and NaOH (1.4 g, 36 mmol) in 25 mL of absolute EtOH was added 4-hydroxy-3-methylbenzaldehyde (1.0 g, 7.3 mmol). The reaction mixture was stirred at room temperature for 18 hr. 5 mL of water was added and the reaction mixture was acidified with concentrated HCl to pH 5-6. The aqueous layer was extracted with two 25 mL portions of EOAc, and the layers were separated. The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The resulting product was submitted to the next step without further purification. MS (EI) for Ci9Hi9NO3: 310 (MH+).

Reference： [1]Patent: WO2008/133955,2008,A1 .Location in patent: Page/Page column 185

36
[ 15174-69-3 ]
[ 34956-31-5 ]
[ 1076188-17-4 ]

Yield	Reaction Conditions	Operation in experiment
55%		[00248] To a round bottomed flask was added EtOH (30 mL) and potassium hydroxide (6.0 g, 109.5 mmol). The mixture was stirred until homogeneous before adding commercially available 4-hydroxy-3-methyl benzaldehyde (3.Og, 21.9 mmol) and commercially available 4- acetamido-2-methyl acetophenone (4.2 g, 21.9 mmol). The reaction was heated to 80 0C overnight, cooled to rt, and concentrated via rotary evaporation. The solid was dissolved in H2O and neutralized with IN HCl until pH =7. The aqueous mixture was extracted 5 X with EtOAc. The combined EtOAc layers were concentrated and column purified on silica gel (1 : 1 EtOAc: Hexanes) to afford (E)-I -(4-amino-2-methylphenyl)-3-(4-hydroxy-3-methylphenyl) prop-2-en-l -one (2) (3.1 g, 55% yield).1H NMR (400 MHz, d6-DMSO) δ 7.64 (dd, 2H), 7.37 (s, 2H), 6.81 (d, IH), 6.42 (m, 2H), 5.87 (d, 2H), 2.38 (d, 4H), 2.15 (s, 2H); MS (EI) for Ci7H17NO2: 268.2 (MH+).

Reference： [1]Patent: WO2008/133955,2008,A1 .Location in patent: Page/Page column 106

37
[ 62254-74-4 ]
[ 15174-69-3 ]
[ 1076188-34-5 ]

Yield	Reaction Conditions	Operation in experiment
		00267) To a mixture of commercially available 4'-hydroxy-3'-methylacetophenone (700 mg, 4.66 mmol) and NaOH (365 mg, 9.1 mmol) in 10 mL of absolute EtOH was added commercially available 5-methylisoxazole-3-carbaldehyde (518 mg, 4.66 mmol). The reaction mixture was stirred at room temperature for 18 hr. 5 mL of water was added and the reaction mixture was acidified with concentrated HCI to pH 5-6. The precipitate was filtered, washed15 <n="117"/>with water and dried to give (E)-l-(4-hydroxy-3-methylphenyl)-3-(5-methylisoxazol-3- yl)prop-2-en-l-one. MS (EI) for Ci4H13NO3: 244 (MH+).

Reference： [1]Patent: WO2008/133955,2008,A1 .Location in patent: Page/Page column 115-116

38
[ 1076188-32-3 ]
[ 15174-69-3 ]
[ 1076188-33-4 ]

Yield	Reaction Conditions	Operation in experiment
47%	With potassium hydroxide In ethanol at 80℃; for 5h;	12.2 [00265] To a round bottomed flask was added EtOH (10 mL) and potassium hydroxide (507 mg, 9.05 mmol). The mixture was stirred until homogeneous before adding commercially available 4-hydroxy-3-methyl benzaldehyde (247 mg, 1.81 mmol) and tert-butyl 4-((4-acetyl-3-methylphenoxy)methyl)piperidine-l -carboxylate ( 630 mg, 1.81 mmol). The reaction was heated to 80 0C for 5 h, cooled to it, and concentrated via rotary evaporation. The product was dry-loaded onto a silica gel column and purified through flash chromatography (1 : 1EtOAc: Hexanes) to afford (E)-tert-butyl 4-((4-(3-(4-hydroxy-3-methylphenyl)acryloyl)-3- methylphenoxy)methyl)piperidine-l -carboxylate (400 mg, 47% yield). 1H NMR (400 MHz, d6-DMSO) δ 7.82 (d, IH), 6.82 (m, 2H), 3.98 (m, IH), 3.90 (d, IH), 2.70 (br s, 2H), 2.42 (s, 3H), 1.95 (m, IH), 1.77 (br d, 2H), 1.40 (s, 9H); MS (EI) for C28H35NO5: 464.3 (M-H).

Reference： [1]Current Patent Assignee: EXELIXIS INC - WO2008/133955, 2008, A1 Location in patent: Page/Page column 114-115

39
[ 875012-78-5 ]
[ 15174-69-3 ]
[ 910814-12-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In ethanol; isopropyl alcohol at 20℃; for 2h;	A solution of 4-hydroxy-3-methyl-benzaldehyde (772 mg, 5.67 mmol) and (1aS,5aR)-1-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-ethanone (1.0 g, 4.54 mmol) in ethanol (20 mL) and approx. 6 N HCl in isopropanol (5 mL) is stirred at rt for 2 h. The dark brown solution is diluted with diethyl ether and washed with sat. aq. NaHCO3 solution and water. The aq. phases are extracted with diethyl ether. The combined organic extracts are dried over MgSO4 and evaporated. The crude product is suspended in methanol, filtered, washed with additional methanol and dried to give 3-(4-hydroxy-3-methyl-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propenone (1.27 g) as an olive-green powder; LC-MS: tR=1.09 min, [M+1]+=339.23; 1H NMR (D6-DMSO): δ 9.98 (s, 1H), 7.54-7.47 (m, 2H), 7.44-7.39 (m, 1H), 7.10 (d, J=15.8 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 3.15 (dd, J=6.4, 18.8 Hz, 1H), 2.93 (d, J=18.8 Hz, 1H), 2.36 (s, 3H), 2.14 (s, 3H), 2.02-1.92 (m, 2H), 1.09 (s, 3H), 0.70 (s, 3H).
	With hydrogenchloride In ethanol; isopropyl alcohol at 20℃; for 20h;

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2008/194670, 2008, A1 Location in patent: Page/Page column 13
[2]Bolli, Martin H.; Müller, Claus; Mathys, Boris; Abele, Stefan; Birker, Magdalena; Bravo, Roberto; Bur, Daniel; Hess, Patrick; Kohl, Christopher; Lehmann, David; Nayler, Oliver; Rey, Markus; Meyer, Solange; Scherz, Michael; Schmidt, Gunther; Steiner, Beat; Treiber, Alexander; Velker, Jörg; Weller, Thomas [Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9737 - 9755]

40
[ 96-49-1 ]
[ 15174-69-3 ]
4-(2-hydroxy-ethoxy)-3-methylbenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 6h; Inert atmosphere;	75 Example 75 Preparation of 5,7-Dimethoxy-2-(3-methyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one To a solution of 4-hydroxy-3-methylbenzaldehyde (1.10 g, 8.08 mmol) in anhydrous DMF (12 mL) was added K2CO3 (2.23 g, 16.16 mmol) and ethylene carbonate (1.42 g, 16.16 mmol) at room temperature. The resulting reddish-orange suspension was stirred at 110° C. for 6 hours under nitrogen. DMF was removed and the residue was diluted with water (50 mL) and dichloromethane (50 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (2*20 mL). The combined organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 4-(2-hydroxy-ethoxy)-3-methylbenzaldehyde as a brown oil. Yield: 1.46 g (100%).
94%	Stage #1: 4-hydroxy-3-methyl-benzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: [1,3]-dioxolan-2-one In N,N-dimethyl-formamide at 80℃; for 90h;	1.9 4-(2-Hydroxyethoxy)-3-methylbenzaldehyde A stirred solution of 4-hydroxy-3-methyl-benzaldehyde (0.545 g, 4.00 mmol) in DMF (10 mL) was added with potassium carbonate (1.10 g, 7.97 mmol). The reaction mixture was stirred at RT for 5 minutes and then a solution of ethylene carbonate (0.705 g, 8.00 mmol) in DMF (2 mL) was added. The resultant mixture was heated at 80 °C for 90 hours. The reaction mixture was allowed to cool and diluted with ethyl acetate and water. The organic phase was removed, washed with brine (x2), dried (magnesium sulfate), filtered and the solvent evaporated under reduced pressure to afford the title compound (0.677 g, 94%). NMR (400 MHz, CDC13): δ 9.87 (s, 1 H); 7.72-7.70 (m, 2 H); 6.95-6.93 (m, 1 H); 4.20-4.18 (m, 2 H); 4.04-4.03 (m, 2 H); 2.29 (s, 3 H); 1.98 (s, 1 H).
91%	With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 60h; Inert atmosphere;	19 Example 19. Preparation of 3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3- methylphenyl)quinazolin-4(3H)-one; [0192] To a solution of 4-hydroxy-3-methylbenzaldehyde (0.50 g, 3.67 mmol) in anhydrous DMF (8 ml_) was added K2CO3 (1.01 g, 7.34 mmol) and 1 ,3-dioxolan-2- one (0.65 g, 7.34 mmol), and the mixture was stirred at 1100C for 60 hours under nitrogen. DMF was removed under vacuum, the residue was diluted with water (50 ml_) and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrate under vacuum to give 3-methyl-4-hydroxylethoxybenzaldehyde as a yellow oil. Yield: 0.60 g (91%).[0193] A mixture of isatoic anhydride (4.00 g, 24.5 mmol) and 4-bromoaniline (4.20 g, 24.5 mmol) in anhydrous DMF (30 mL) was stirred at 1150C for 60 hours under nitrogen. DMF was removed under vacuum and the residue was partitioned between ethyl acetate (75 mL) and water (75 mL). The organic phase was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum to give crude 2-amino-Λ/-(4-bromophenyl)benzamide. Yield: 1.00 g (14%).[0194] To a solution of 3-methyl-4-hydroxyethoxy-benzaldehyde (0.38 g, 2.10 mmol) and 2-amino-Λ/-(4-bromophenyl)benzamide (0.60 g, 2.10 mmol) in anhydrous ethanol (15 mL) was added anhydrous CuCI2 (0.85 g, 6.30 mmol). The reaction mixture was heated at reflux for 18 hours and then cooled to room temperature. Organic solvents were removed under reduced pressure, and the resulting residue was diluted with dichloromethane, washed with water, then brine, and dried over anhydrous magnesium sulfate. The solvent was removed under vacuum and the residual solid was purified by column chromatography (silica gel 230-400 mesh; 25-50% ethyl acetate in hexanes as eluent) to afford the title compound as a white solid. Yield: 0.21 g (22%). MP 92.0-93.00C. 1H-NMR (400 MHz, CDCI3): δ 8.32 (d, J = 8.4 Hz, 1 H), 7.81 (dd, J = 4.8 and 1.2 Hz, 2H), 7.45-7.54 (m, 3H), 7.23 (m, 1 H), 7.00 (m, 3H), 6.63 (d, J = 8.4 Hz and 1 H), 4.05 (t, J = 4.4 Hz, 2H), 3.97 (t, J = 4.4 Hz, 2H), 2.15 (s, 3H). MS (ES+) m/z: 453.39, 451.37.

10%

With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 6h; Inert atmosphere;

73 To a solution of 4-hydroxy-3-methylbenzaldehyde (1.10 g, 8.08 mmol) in anhydrous DMF (12 mL) was added K2CO3 (2.23 g, 16.16 mmol) and ethylene carbonate (1.42 g, 16.16 mmol) at room temperature. The resulting reddish-orange suspension was stirred at 110° C. for 6 hours under nitrogen. DMF was removed and the residue was diluted with water (50 mL) and dichloromethane (50 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (2*20 mL). The combined organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 4-(2-hydroxy-ethoxy)-3-methylbenzaldehyde as a brown oil. Yield: 1.46 g (100%)

Reference： [1]Current Patent Assignee: RESVERLOGIX CORP - US9238640, 2016, B2 Location in patent: Page/Page column 109
[2]Current Patent Assignee: Valline SRL - WO2014/86924, 2014, A1 Location in patent: Page/Page column 45; 51
[3]Current Patent Assignee: RESVERLOGIX CORP - WO2010/79431, 2010, A2 Location in patent: Page/Page column 70-71
[4]Current Patent Assignee: ZENITH CAPITAL CORP - US2013/281399, 2013, A1 Location in patent: Paragraph 0638

41
[ 15174-69-3 ]
[ 4943-86-6 ]
[ 1235480-90-6 ]

Yield	Reaction Conditions	Operation in experiment
57%	With copper dichloride; In ethanol; for 4h;Reflux;	Example 34. Preparation of 3-(4-chlorophenyl)-2-(4-(2-hydroxyethoxy)-3- methylphenyl)quinazolin-4(3H)-one; [0219] Anhydrous CuCI2 (0.306 g, 2.20 mmol) and 4-hydroxy-3- methylbenzaldehyde (0.155 g, 1.10 mmol) were added to a solution of 2-amino-Lambda/-(4- chlorophenyl)benzamide (0.280 g, 1.10 mmol) in anhydrous EtOH (10 ml_). The mixture was heated at reflux temperature for 4 hours and concentrated in vacuo. The residue was dissolved in EtOAc, washed with H2O and brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% to 50% EtOAc in heptane, afforded 3-(4-chlorophenyl)-2-(4- hydroxy-3-methylphenyl)quinazolin-4(3H)-one (0.230 g, 57%).[0220] K2CO3 (0.131 g, 0.95 mmol) was added to a solution of 3-(4- chlorophenyl)-2-(4-hydroxy-3-methylphenyl)quinazolin-4(3H)-one (0.230 g, 0.63 mmol) in DMF (15 ml_) and stirred for 30 min. (2-Bromoethoxy)(tert- butyl)dimethylsilane (0.16 ml_, 0.76 mmol) was added and the reaction was heated to reflux temperature for 3 hours, and concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3, and then brine, dried (Na2SO4), filtered, and concentrated in vacuo, to afford 2-(4-(2-(feAt-Butyldimethylsilyloxy)ethoxy)-3-methylphenyl)-3-(4-chlorophenyl)quinazolin-4(3/-/)- one (0.340 g, quantitative).[0221] A 1 M THF solution of TBAF (1.90 ml_, 1.90 mmol) was added to a solution of 2-(4-(2-(te/t-butyldimethylsilyloxy)ethoxy)-3-methylphenyl)-3-(4- chlorophenyl)quinazolin-4(3H)-one (0.340 g, 0.65 mmol) in THF (5 ml_). The mixture was stirred at room temperature for 1 hour and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 10% to 100% EtOAc in heptane, afforded the title compound as a white solid (0.190 g, 72%). 1H-NMR (300 MHz, DMSO-de): delta 8.17 (dd, J = 6.8, 1.0 Hz, 1 H), 7.89 (d, J = 6.8 Hz, 1 H), 7.75 (d, J = 8.8 Hz, 1 H), 7.55-7.59 (m, 1 H), 7.28-7.48 (m, 4H), 7.21 (d, J = 1.5 Hz, 1 H), 7.04-7.16 (m, 1 H), 6.77 (d, J = 8.7 Hz, 1 H), 4.81 (t, J = 5.7 Hz, 1 H), 3.86-4.01 (m, 2H), 3.60-3.77 (m, 2H), 2.06 (s, 3H). MS (APCI) m/z: 407 (M+H)+.

Reference： [1]Patent: WO2010/79431,2010,A2 .Location in patent: Page/Page column 85-86

42
[ 5927-18-4 ]
[ 15174-69-3 ]
[ 1264273-54-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium In methanol at 70℃; for 24h;	Wittig-Horner reaction of benzaldehydes. General Procedure. Na (5.0 mmol) was dissolved in dry MeOH (7 ml) and to the resulting solution methyl trimethylphosphonacetate (3.0 mmol) and a solution of the aldehyde (1.0 mmol) in dry MeOH (1 ml) were added in sequence. The resulting mixture was allowed to react for 24 h at 70 °C. The solution was then acidified with HCl (aq) 10%, and extracted with Et2O (3 x 10 ml). The combined organic phases were dried over Na2SO4 and evaporated to dryness yielding the desired product that was used for the next reaction without further purification.
	With sodium In methanol at 70℃; for 24h;	Wittig-Horner reaction of benzaldehydes General procedure: Na (5.0 mmol) was dissolved in dry MeOH (7 ml) and to the resulting solution methyl trimethylphosphonacetate (3.0 mmol) and a solution of the aldehyde (1.0 mmol) in dry MeOH (1 ml) were added in sequence. The resulting mixture was allowed to react for 24 h at 70 °C. The solution was then acidified with HCl (aq) 10%, and extracted with Et2O (3 x 10 ml). The combined organic phases were dried over Na2SO4 and evaporated to dryness yielding the desired product that was used for the next reaction without further purification.

Reference： [1]Epifano, Francesco; Sosa, Silvio; Tubaro, Aurelia; Marcotullio, M. Carla; Curini, Massimo; Genovese, Salvatore [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 2, p. 769 - 772]
[2]Genovese, Salvatore; Curini, Massimo; Gresele, Paolo; Corazzi, Teresa; Epifano, Francesco [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5995 - 5998]

43
[ 15174-69-3 ]
[ 1805-32-9 ]
4-[(3,4-dichlorobenzyl)oxy]-3-methylbenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere;	(37A) 4-(3,4-Dichlorobenzyloxy)-3-methylbenzaldehyde 4-Hydroxy-3-methylbenzaldehyde (365 mg, 2.68 mmol), <strong>[1805-32-9]3,4-dichlorobenzyl alcohol</strong> (665 mg, 3.76 mmol), and triphenylphosphine (980 mg, 3.74 mmol) were dissolved in tetrahydrofuran (8 mL), and a diethyl azodicarboxylate toluene solution (2.2 M, 1.71 mL, 3.76 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a white solid (542 mg, yield: 69%). 1H NMR (CDCl3, 400 MHz): delta2.31 (3H, s), 5.10 (2H, s), 6.92 (1H, d, J=8.2 Hz), 7.26 (1H, m), 7.46 (1H, d, J=8.2 Hz), 7.52 (1H, m), 7.68 (1H, m), 7.71 (1H, s), 9.85 (1H, s)
69%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 60℃; for 4h;Inert atmosphere;	General procedure: To a solution of 18 (100 mg,0.420 mmol) and [4-(trifluoromethyl)phenyl]methanol (111 mg,0.630 mmol) in THF (10.0 mL), PPh3 (178 mg, 0.68 mmol), a 40%diethyl azodicarbonate toluene solution (309 lL, 0.680 mmol)were added at room temperature, and stirred under N2 atmosphereat 60 C for 4 h. After cooling to room temperature, the solvent wasdistilled off under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/AcOEt = 100:0 to 95:5(v/v)) to obtain 19k as colorless oil (125 mg, 75%).

Reference： [1]Patent: US2011/53974,2011,A1 .Location in patent: Page/Page column 47
[2]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5546 - 5565

44
[ 15174-69-3 ]
[ 100-49-2 ]
[ 1095989-35-7 ]

Yield	Reaction Conditions	Operation in experiment
83%	With diethylazodicarboxylate;triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;	Step 1: To the solution in which cyclohexanemethanol (1 g, 8.8 mmol), 4-hydroxy-3-methylbenzaldehyde (1.20 g, 8.8 mmol) and triphenylphosphine in THF (20 ml) (2.54 g, 9.7 mmol) were mixed, diethyl azodicarboxylate (40% in toluene, 9.7 mmol) was added at 0 C. over 10 minutes while stirring. Then, the mixture was stirred at room temperature until the initial reaction product of cyclohexanemethanol and 4-hydroxy-3-methylbenzaldehyde disappeared. The resulting solution was concentrated under reduced pressure and purified by silica gel chromatography (hexane:ethyl acetate=10:1) to afford 4-(2-cyclomethoxy)-3-methylbenzaldehyde as yellow oil (1.69 g, yield: 83%)

Reference： [1]Patent: US2011/269954,2011,A1 .Location in patent: Page/Page column 20-21

45
[ 109-01-3 ]
[ 15174-69-3 ]
[ 1354792-33-8 ]

Yield	Reaction Conditions	Operation in experiment
66%	Stage #1: 1-methyl-piperazine; 4-hydroxy-3-methyl-benzaldehyde In 1,1-dichloroethane at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In 1,1-dichloroethane at 20℃; Stage #3: With water; sodium hydrogencarbonate In 1,1-dichloroethane	9.A 9A. 2-Methyl-4((4-methylpiperazin-1-yl)methyl)phenol A mixture of 4-hydroxy-3-methylbenzaldehyde (3.27 g, 24 mmol) and 1-methylpiperazine (2.7 g, 27.0 mmol) in dichloroethane (100 mL) was stirred at rt for 30 min. Sodium triacetoxyborohydride (6.2 g, 29 mmol) was added in portions and the reaction mixture was stirred at rt over night. A further portion of 1-methylpiperazine was added and stirring was continued for 24 h. Aqueous NaHCO3 (sat.) was added, the phases were separated and the aqueous phase was saturated with sodium chloride and extracted with DCM twice. The combined organic solutions were dried (MgSO4) and evaporated and the residue was purified by column chromatography on SiO2 using 0-20% MeOH in EtOAc:MeOH 95:5 as eluent. There was obtained 3.50 g (66%) of 9A as a solid. 1H NMR (500 MHz, CDCl3): δ 2.21 (2, 3H), 2.29 (s, 3H), 2.32-2.72 (bm, 8H), 3.42 (s, 2H), 6.55 (d, 1H), 6.90 (d, 1H), 7.02 (s, 1H).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED; ASTRAZENECA PLC; PFIZER INC - US2012/10189, 2012, A1 Location in patent: Page/Page column 21-22

46
[ 141-82-2 ]
[ 15174-69-3 ]
[ 377091-82-2 ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: malonic acid; 4-hydroxy-3-methyl-benzaldehyde With pyridine at 60℃; for 22h; Inert atmosphere; Stage #2: With hydrogenchloride In water	17 Example 17 3-Methyl-4-hydroxybenzaldehyde (794 mg, 5.83 mmol), malonic acid (911 mg, 8.75 mmol) and piperidine (144 μl) were added to pyridine (5 ml), and the mixture was stirred at 60°C for 22 hr under an argon atmosphere. The reaction mixture was allowed to cool to room temperature, and water (20 ml) was added. 6N Hydrochloric acid was added to allow precipitation of a solid. The precipitated solid was collected by filtration, and the filtrate was washed with water and dried under reduced pressure. The obtained solid was recrystallized from diethylether - n-hexane to give 3-methyl-4-hydroxycinnamic acid (872 mg, yield 84.0%) as crystals. 1H NMR (DMSO, 400MHz) δ 9.95 (OH), 7.45 (d, J=15.9Hz, 1H), 7.42 (s, 1H), 7.32 (d, J=8.3Hz, 1H), 6.79 (d, J=8.3Hz, 1H), 6.26 (d, J=15.9Hz, 1H), 2.13 (s, 3H).
72%	With piperidine; pyridine at 120℃;

Reference： [1]Current Patent Assignee: AJINOMOTO COMPANY INC - EP2412701, 2012, A1 Location in patent: Page/Page column 11
[2]Busto, Eduardo; Simon, Robert C.; Kroutil, Wolfgang [Angewandte Chemie - International Edition, 2015, vol. 54, # 37, p. 10899 - 10902][Angew. Chem., 2015, vol. 127, p. 11049 - 11052,4]

47
[ 15174-69-3 ]
[ 54674-91-8 ]

Yield	Reaction Conditions	Operation in experiment
83%	With nitric acid at -15℃; for 1.66667h;	4.2.2. 4-Hydroxy-3-methyl-5-nitrobenzaldehyde (8) To a stirring fuming nitric acid (210 ml) was added slowly aldehyde 7 (30 g, 0.22 mol) portion-wise over the course of 40 min at -15 °C and stirred for 1 h at this temperature. Then the reaction mixture was poured slowly into a mixture of ice-water (630 ml) with stirring. The resultant suspension was filtered and the collected solid washed with water and dried under vacuum to give compound 8 (33.2 g, 83%) as brown solid; mp: 150-152 °C; 1H NMR ( 400 MHz, CDCl3) δ 2.43 ( s, 3H, CH3), 8.02 (s, 1H, ArH), 8.50 (s, 1H, ArH), 9.92 (s, 1H, CHO), 11.39 (s, 1H, ArOH); 13C NMR ( 100 MHz, CDCl3) δ 16.0, 126.5, 128.2, 131.2, 133.3, 136.2, 158.1, 188.9; MS (+C, ESI): M=181, found 182 [M+H]+.
	With sulfuric acid; nitric acid at 0 - 20℃;

Reference： [1]Location in patent: experimental part Wang, Ping; Zheng, Guo-Jun; Wang, Ya-Ping; Wang, Xiang-Jing; Wei, He-Geng; Xiang, Wen-Sheng [Tetrahedron, 2012, vol. 68, # 11, p. 2509 - 2512]
[2]Mizuhara, Tsukasa; Kato, Takayuki; Hirai, Atsushi; Kurihara, Hideki; Shimada, Yasuhiro; Taniguchi, Masahiko; Maeta, Hideki; Togami, Hiroaki; Shimura, Kazuya; Matsuoka, Masao; Okazaki, Shiho; Takeuchi, Tomoki; Ohno, Hiroaki; Oishi, Shinya; Fujii, Nobutaka [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 16, p. 4557 - 4561]

48
[ 15174-69-3 ]
[ 152628-02-9 ]

Reference： [1]Tetrahedron,2012,vol. 68,p. 2509 - 2512

49
[ 15174-69-3 ]
[ 144701-48-4 ]

Reference： [1]Tetrahedron,2012,vol. 68,p. 2509 - 2512

50
[ 15174-69-3 ]
[ 140690-56-8 ]
[ 1264753-61-8 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1h;	Reference Example 7 4-[2,4-bis(trifluoromethyl)benzyl]oxy}-3-methylbenzaldehyde; [Show Image] To a solution (7.3 mL) of 4-hydroxy-3-methylbenzaldehyde (1.00 g) and potassium carbonate (1.22 g) in DMF was added <strong>[140690-56-8]1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene</strong> (1.52 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as a colorless powder (yield: 2.30 g, 85%). 1H-NMR (CDCl3, 300 MHz):delta2.41 (3H, s), 5.44 (2H, s), 6.95 (1H, d, J= 8.5 Hz), 7.73 (1H, dd, J = 8.5, 1.7 Hz), 7.76-7.80 (1H, m), 7.86-7.97 (2H, m), 8.00 (1H, s), 9.91 (1H, s).

Reference： [1]Patent: EP2450352,2012,A1 .Location in patent: Page/Page column 60

51
[ 15174-69-3 ]
[ 1426663-40-2 ]
[ 1426665-76-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With acetic acid for 4h; Reflux;	22 4-(3,4-dihydro-4,9,11,11a-tetraazadibenzo[cd,f]azulen-3-yl)-2-methylphenol (29ac) To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 4-hydroxy-3-methylbenzaldehyde 29ab (0.14 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 4-(3,4-dihydro- 4,9,11,1 la-tetraazadibenzo[cd,f azulen-3-yl)-2-methylphenol 29ac (0.234 g, 75 %) as a brown solid. 1H NMR (300 MHz, DMSO-d6) ? 9.23 (s, 1H), 8.52 - 8.46 (m, 2H), 8.01 (d, J = 2.5 Hz, 1H), 7.28 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.07 (d, J= 7.3 Hz, 1H), 6.96 - 6.88 (m, 2H), 6.74 (dd, J= 9.8, 2.8 Hz, 2H), 6.62 (d, J= 8.2 Hz, 1H), 6.54 (d, J= 2.5 Hz, 1H), 5.58 (d, J= 3.3 Hz, 1H), 2.02 (s, 3H).; MS (ES+) 329.1 (M+l), (ES-) 327.0 (M-l).

Reference： [1]Current Patent Assignee: BIOCRYST PHARMACEUTICALS INC - WO2013/33093, 2013, A1 Location in patent: Page/Page column 148; 149

52
[ 15174-69-3 ]
[ 220000-87-3 ]
[ 1573056-26-4 ]

Yield	Reaction Conditions	Operation in experiment
598 mg	Stage #1: 4-hydroxy-3-methyl-benzaldehyde With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: 4-chloro-N-methylpicolinamide With potassium carbonate In N,N-dimethyl-formamide at 130℃; for 120h;	2.3.1 Example 2.3.: Synthesis of (4-trifluoromethyl-pyridin-2-yl)-carbamic acid 3-methyl-4-(2-methyicarbamoyl-pyridin-4-yloxy)-benzyl ester 1) Synthesis of 4-(4-formyl-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide Example 2.3.: Synthesis of (4-trifluoromethyl-pyridin-2-yl)-carbamic acid 3-methyl-4-(2-methyicarbamoyl-pyridin-4-yloxy)-benzyl ester 1) Synthesis of 4-(4-formyl-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide A solution of 4-hydroxy-3-methylbenzaldehyd (503.7 mg; 3.7 mmol) in dry DMF (7 mL) was treated with potassium-ie/t-butoxide (456.7 mg; 4.1 mmol).The reaction mixture was stirred at RT for 2 h and then 4-chloro- pyridine-2-carboxylic acid methylamide (672.6 mg; 3.7 mmol) and potassium carbonate (255.7 mg; 1.9 mmol) were added. The resulting suspension was heated to 130°C for 5 days. For purification the reaction mixture was allowed to cool down to RT and water (50 mL) and DCM (50 mL) were added. The phases were separated and the organic layer was washed with 1 M NaOH- solution (50 mL) brine (20 mL), dried over Na2S04 and the solvent was evaporated. The crude product was purified with flash column chromatography (Combi Flash RF, Si-60, 120 g-column, gradient CH/EE 100:0 to 45:55 in 28 min, flow 85 ml/min, UV 254 nM and 280 nM) obtaining 4-(4-formyl-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide (598 mg; 2.21 mmol) as white solid. 2) Synthesis of 4-(4-hvdroxymethyl-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide 4-(4-formyl-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide (400 mg; 1.5 mmol) was dissolved in dry THF (6 ml_). The mixture was treated with sodium borohydride (61 mg; 1.6 mmol) and stirred for 3 h at 50°C. For purification methanol (15 ml_) was added and the mixture was stirred for further 30 min. Then the mixture was evaporated to dryness and water (10 ml_) and ethylacetate (30 mL) were added. The phases were separated, the organic layer was washed with brine (10 mL) and dried over Na2SO4. Finally the solvent was evaporated yielding in 4-(4-hydroxymethyl-2-methyl- phenoxy)-pyridine-2-carboxylic acid methylamide (370 mg; 1.4 mmol) as white solid. 3) Synthesis of (4-trifluoromethyl-pyridin-2-yl)-carbamic acid 3-methyl-4-(2- methylcarbamoyl-Pyridin-4-yloxy)-benzyl ester 4-Trifluoromethyl-pyridin-2-ylamine (53.6 mg; 0.33 mmol) was dissolved in DCM (1.1 ml). Additionally, 4-nitrophenylchlorformiate (73.6 mg; 0,37 mmol) and pyridine (0,029 ml; 0,37 mmol) were added and the reaction mixture was stirred for 2 h. Then 4-(4-hydroxymethyl-2-methyl-phenoxy)-pyridine-2- carboxylic acid methylamide (90 mg; 0.33 mmol) dissolved in DMF (1 mL) and N-ethyldiisopropylamina (0.112 mL; 0.66 mmol) were added and the reaction mixture was stirred for further 2 d at RT. For purification the solvent was evaporated and the crude product was directly purified with prep. HPLC (Agilent 1100 Series, SunFire Prep C18 OBM 5 pm (150-30 mm) column, gradient ACN/H20 99:1 to 30:70 in 3 min, then 30:70 to 60:40 in 18 min, flow 50 ml/min, UV 220 nM) yielding in (4-trifluoromethyl-pyridin-2-yl)- carbamic acid 3-methyl-4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl ester (22.8 mg; 0.05 mmol) as white TFA-salt. HPLC/MS: (T: 30 °C \| Flow: 2 ml/min \| Column: Chromolith, RP-18e 50-4,6 mm, 4% -> 100% B: 0 -> 2,8 min \| 100% B: 2,8 -> 3,3 min, A: H2O + 0,05% HCOOH, B: MeCN + 0,04% HCOOH): Rt = 2.470 min, [M+H] 461.2 1H NMR (500 MHz, DMSO-d6) ppm = 10.80 (s, 1H), 8.75 (q, J=4.8, 1H), 8.55 (d, J=5.2, 1H), 8.51 (d, J=5.6, 1 H), 8.16 (s, 1 H), 7.52 - 7.49 (m, 1H), 7.44 - 7.39 (m, 2H), 7.28 (d, J=2.6, 1 H), 7.21 - 7.15 (m, 1 H), 7.12 (dd, J=5.6, 2.6, 1H), 5.23 (s, 2H), 2.78 (d, J=4.9, 3H), 2.12 (s, 3H).

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2014/32755, 2014, A2 Location in patent: Page/Page column 145; 146

53
[ 96-49-1 ]
[ 15174-69-3 ]
[ 127154-21-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate In N,N-dimethyl-formamide	1.9 Step 9 Step 9 -(2-Hydroxyethoxy)-3-methylbenzaldehyde To a stirred solution of 4-hydroxy-3-methyl-benzaldehyde (0.545 g, 4.00 mmol) in DMF (10 mL) was added potassium carbonate (1.10 g, 7.97 mmol). The reaction mixture was stirred at RT for 5 minutes and then a solution of ethylene carbonate (0.705 g, 8.00 mmol) in DMF (2 mL) was added. The resultant mixture was heated at 80° C. for 90 hours. The reaction mixture was allowed to cool and diluted with ethyl acetate and water. The organic phase was removed, washed with brine (*2), dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure to afford the title compound (0.677 g, 94%). 1H NMR (400 MHz, CDCl3): δ 9.87 (s, 1H); 7.72-7.70 (m, 2H); 6.95-6.93 (m, 1H); 4.20-4.18 (m, 2H); 4.04-4.03 (m, 2H); 2.29 (s, 3H); 1.98 (s, 1H).

Reference： [1]Current Patent Assignee: Valline SRL - US2014/161736, 2014, A1 Location in patent: Page/Page column

54
[ 15174-69-3 ]
[ 1621522-73-3 ]
[ 1621522-74-4 ]

Yield	Reaction Conditions	Operation in experiment
34%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	5 Example 5 Intermediate 5 _{RRN 31}3-Methyl-4-((5-phenyl-1-propyl-4,5-dihydro-1H-pyrazol-3-yl)methoxy)benzaldehyde Example 5 Intermediate 5 RRN 313-Methyl-4-((5-phenyl-1-propyl-4,5-dihydro-1H-pyrazol-3-yl)methoxy)benzaldehyde [0143] 4-hydroxy-3-methylbenzaldehyde (1.8 g, 0.013 mol), and triphenylphosphine (3.1 g, 0.012 mol) in tetrahydrofuran (25 mL) at 0° C. was added diisopropyldiazocarboxylate (2.4 g, 0.012 mol) over 30 min under argon. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (75 mL), washed with 50 mL water:brine (4:1), brine (50 mL), filtered and concentrated to give to give crude material as an oil. The oil was flash chromatographed over silica gel (75 g) with anhydrous sodium sulfate (7 g) on top packed with hexanes. The compound was eluted with 10% ethyl acetate in hexane to give intermediate 5 1.14 g (34%) as a light orange oil. [0145] 1H NMR (300 MHz, CDCl3): δ 9.9 (s, 1H), 7.7 (d, 2H), 7.4 (m, 5H), 7.1 (d, 1H), 4.8 (dd, 2H), 4.4 (dd, 1H), 3.2 (dd, 1H), 2.8 (m, 3H), 2.3 (s, 3H), 1.7 (m, 2H), 0.85 (t, 3H) ppm.

Reference： [1]Current Patent Assignee: ABBVIE INC - US2014/228324, 2014, A1 Location in patent: Paragraph 0143-0145

55
[ 15174-69-3 ]
[ 1895-39-2 ]
4-(difluoromethoxy)-3-methylbenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 95℃; for 3.25h;	3.2.2 Step 2: Synthesis of 4-(difluoromethoxy)-3-methylbenzaldehyde [0459j A solution of sodium chlorodifluoroacetate (2.60 g, 17.04 mmol) and 4- hydroxy-3 -methylbenzaldehyde (1 .16 g, 8.52 mmol) in DMF (15 ml) was added over 3 hours to a solution of DMF (15 ml) containing potassium carbonate (1.77 g, 12.78 mmol) at 95 °C. The reaction was allowed to age for an additional 15 minutes and then cooled. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3 x 50 ml). The organic extract was washed with 10% (mlv) aqueous LiC1 solution (3 x 25 ml), driedover sodium sulfate, filtered and evaporated to give a residue that was flash chromatographed (15% EtOAc/hexane) to give 4-(difluoromethoxy)-3 -methylbenzaldehyde (O21GLM-0531(2), 1.00 g, 5.37 mmol, 63%) as a yellow oil. This oil was combined with that of the previous experiment and passed through a Pasteur pipette column eluting with 10% EtOAC/hexane to give an oil that solidified on standing (1.3 15 g, 7.06 mmol, 67%over the two reactions). The proton NMR was consistent with the proposed structure.

Reference： [1]Current Patent Assignee: BUCK INSTITUTE FOR RESEARCH ON AGING - WO2014/127042, 2014, A1 Location in patent: Paragraph 0459; 477; 0485; 0491; 0497; 0503

56
[ 15174-69-3 ]
[ 78364-55-3 ]
6-fluoro-2-(2-(4-hydroxy-3-methylbenzylidene)hydrazino)benzothiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With acetic acid; In ethanol; at 80℃; for 0.166667h;Microwave irradiation;	General procedure: A mixture of compound 2 (0.0549 g, 0.0003 mol), the appropriate aromatic aldehyde (0.00033 mol) and glacial acetic acid (0.1 mL) in ethanol (5 mL) was heated under microwave (20 W) at 80 °C for 10 min. On cooling, the precipitated solid was collected by filtration, washed with water, dried and crystallized to give compounds 3-29.

Reference： [1]Chinese Chemical Letters,2016,vol. 27,p. 380 - 386

57
[ 15174-69-3 ]
[ 106-95-6 ]
4-(allyloxy)-3-methylbenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate In acetone at 23℃; for 4h; Reflux; Inert atmosphere;
90%	With potassium carbonate In acetone for 4h; Reflux;
90%	Stage #1: 4-hydroxy-3-methyl-benzaldehyde With potassium carbonate; potassium iodide In ethanol at 20℃; for 0.333333h; Inert atmosphere; Stage #2: allyl bromide In ethanol at 80℃; Inert atmosphere;

89.7%	Stage #1: 4-hydroxy-3-methyl-benzaldehyde With potassium carbonate In ethanol at 20℃; for 0.5h; Stage #2: allyl bromide In ethanol at 80℃; for 48h; Inert atmosphere;	3 Experimental steps: Add 3-methyl-4-hydroxybenzaldehyde (10 mmol) to 30 ml of absolute ethanol, add anhydrous potassium carbonate (15 mmol), stir at room temperature for 30 min, under nitrogen atmosphere Bromopropene (12 mmol) was added dropwise, and the molar ratio of syringaldehyde to bromopropene to anhydrous potassium carbonate was 1:1.2:1.5. After the addition was completed, the temperature was gradually raised to 80 ° C, condensed and refluxed, reacted for 48 hours, and filtered. The solvent was removed by distillation under reduced pressure, diluted with water and ethyl acetate and brine. The organic phase was combined, anhydrous sodium sulfate was added, and the mixture was allowed to stand overnight, and the silica gel was collected in a dry manner. Separation was carried out by using a mixed solvent of petroleum ether/ethyl acetate (volume ratio: 10:1) as an eluent, and the vacuum was separated at 50 ° C. After drying, 1.88 g of the ethylenic monomer 3-methyl-4-(allyloxy)benzaldehyde was obtained in a yield of 89.7% as a pale yellow liquid.
	With potassium carbonate In acetone at 60℃; for 12h; Reflux;

Reference： [1]Sarkar, Debayan; Ghosh, Manoj Kumar; Rout, Nilendri [Organic and Biomolecular Chemistry, 2016, vol. 14, # 33, p. 7883 - 7898]
[2]Sarkar, Debayan; Rout, Nilendri [Organic Letters, 2019, vol. 21, # 11, p. 4132 - 4136]
[3]Ren, Tianhua; Chen, Qin; Zhao, Changbo; Zheng, Qiang; Xie, Haibo; North, Michael [Green Chemistry, 2020, vol. 22, # 5, p. 1542 - 1547]
[4]Current Patent Assignee: GUIZHOU UNIVERSITY - CN110183328, 2019, A Location in patent: Paragraph 0089-0093
[5]Liao, Jianhua; Fan, Lianfeng; Guo, Wei; Zhang, Zhenming; Li, Jiawei; Zhu, Chuanle; Ren, Yanwei; Wu, Wanqing; Jiang, Huanfeng [Organic Letters, 2017, vol. 19, # 5, p. 1008 - 1011]

58
[ 15174-69-3 ]
[ 123-54-6 ]
[ 107-91-5 ]
5-acetyl-2-amino-6-methyl-4-(4-hydroxy-5-methylphenyl)-4H-pyran-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With ytterbium(III) trifluoromethanesulfonate hydrate In neat (no solvent) at 50℃; for 9h;	General procedure for 2-amino-4H-pyrane derivatives synthesis using Yb(OTf)3. General procedure: Acetylacetone (1.02 mmol), cyanoacetamide (1.02 mmol), the aldehyde (1.0 mmol), and Yb(OTf)3 hydrate (0.1 mmol) were intimately mixed in around bottom flask and the resulting mixture was heated at 50 °C under magnetic stirring for 9 h. The reaction medium was first diluted with Et2O, the precipitate formed filtered under vacuum and the filtrate then poured into water (50 mL) and extracted three times with Et2O (10 mL). The collected organic phases were dried over MgSO4 and evaporated to dryness. The resulting raw solid was crystallized from n-hexane yielding pure desired adduct.

Reference： [1]Fiorito, Serena; Genovese, Salvatore; Curini, Massimo; Preziuso, Francesca; Taddeo, Vito Alessandro; Epifano, Francesco [Tetrahedron Letters, 2017, vol. 58, # 16, p. 1659 - 1661]

59
[ 15777-70-5 ]
[ 15174-69-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1278 - 1283

60
[ 15174-69-3 ]
3,3'-bis(bromomethyl)-2,2'-dimethyl-1,1'-biphenyl [ No CAS ]
4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))bis(3-methylbenzaldehyde) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate In acetonitrile at 20℃;	1.6 Step-6: 4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))bis(3-methylbenzaldehyde), IV-4 A mixture of 3,3'-bis(bromomethyl)-2,2'-dimethyl-1,1'-biphenyl, IV-3 (337 mg, 0.92 mmol), 4-hydroxy-3-methylbenzaldehyde (272 mg, 2.0 mmol) and K2C03 (386 mg, 2.8 mmol) in 20 mL of acetonitrile was stirred at room temperature overnight. The mixture was concentrated and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered and concentrated. The product IV-4 was obtained a yellow solid (415 mg, 95%). 1H NMR (400 MHz, CDC13) _ 9.88 (s, 2H), 7.74-7.73 (m, 4H), 7.48 (d, J = 7.2 Hz, 2H), 7.30 (t, J = 7.6 Hz, 7.6 Hz, 2H), 7.18 (d, J = 7.6 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 5.21 (s, 4H), 2.33 (s, 6H), 2.07 (s, 6H).
67%	With potassium carbonate In acetonitrile at 80℃; for 3h;	11.2 4,4′-(((2,2′-dimethyl-[1,1′-biphenyl]-3,3′-diyl)bis(methylene))bis(oxy))bis(3-methylbenzaldehyde) (22) To a stirred solution of 3,3′-bis(bromomethyl)-2,2′-dimethylbiphenyl (1 g, 2.732 mmol) in ACN (20 mL) at room temperature were added K2CO3 (1.5 g, 10.928 mmol) and 4-hydroxy-3-methylbenzaldehyde (1.2 g, 8.196 mmol) and stirred at 80° C. for 3 h. The reaction mixture was concentrated to remove most of the solvent. The residue was poured into ice-water and the resulting precipitate was filtered and dried in vacuum to get 4,4′-(((2,2′-dimethyl-[1,1′-biphenyl]-3,3′-diyl)bis(methylene))bis(oxy))bis(3-methylbenzaldehyde) (1.1 g, yield: 67%, LC/MS 95%); 1H NMR (500 MHz, CDCl3) δ 9.88 (s, 2H), 7.74-7.73 (m, 4H), 7.48 (d, J=7.5 Hz, 2H), 7.30 (d, J=7.5 Hz, 2H), 7.18 (d, J=6.5 Hz, 2H), 7.06 (d, J=8.5 Hz, 2H), 5.20 (s, 4H), 2.32 (s, 6H), 2.07 (s, 6H).

Reference： [1]Current Patent Assignee: ARISING INTERNATIONAL INC; QILU PHARMACEUTICAL GROUP CO LTD - WO2018/26971, 2018, A1 Location in patent: Page/Page column 24-25
[2]Current Patent Assignee: POLARIS GROUP - US2018/65917, 2018, A1 Location in patent: Paragraph 0250

61
[ 15174-69-3 ]
[ 74-88-4 ]
[ 32723-67-4 ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: 4-hydroxy-3-methyl-benzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃;	Preparation of methoxy-methylbenzaldehydes General procedure: To a solution of the hydroxy-methylbenzaldehyde (34 mg,0.25 mmol) in anhydrous DMF (6.0 mL), K2CO3 (35 mg,0.25 mmol) was added and the mixture was stirred at room temperaturefor 30 minutes. Then, methyl iodide (30 μL, 68 mg,0.5 mmol) was added and the reaction was stirred at room temperatureovernight. The reaction was quenched by the additionof distilled water, and the aqueous phase was extracted threetimes with ethyl acetate. The combined organic phases weredried with MgSO4 and concentrated in vacuo. The residue waspurified by column chromatography on silica gel.

Reference： [1]Dickschat, Jeroen S.; Wang, Tao; Stadler, Marc [Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 734 - 746]

62
[ 25006-87-5 ]
[ 15174-69-3 ]
4,4'-(2-chloro-1,3-phenylene)bis(methylene)bis(oxy)bis(3-methylbenzaldehyde) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium carbonate In acetonitrile at 20℃; for 16h;	2.2 Step-2: synthesis of 4,4'-(2-chloro-1,3-phenylene)bis(methylene)bis(oxy)bis(3-methylbenzaldehyde) (IV-5) To the solution of 1,3-bis(bromomethyl)-2-chlorobenzene (200 mg, 0.67 mmol) and 4-hydroxy-3-methylbenzaldehyde (192 mg, 1.4 mmol) in acetonitrile (10 mL) was added K2CO3 (195 mg, 138 mmol). The suspended solution was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with brine. Then the organic layer was concentrated and purified by silica gel column (Petroleum ether : ethyl acetate = 2 : 1) to give the title compound as white solid (200 mg, 73%).

Reference： [1]Current Patent Assignee: ARISING INTERNATIONAL INC; QILU PHARMACEUTICAL GROUP CO LTD - WO2018/26971, 2018, A1 Location in patent: Page/Page column 26

63
[ 15174-69-3 ]
[ 1400755-05-6 ]
3-methyl-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; Cooling with ice;	6 The preparation of Intermediate (_-3): 3-methyl-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)benzaldehyde A solution of 4-hydroxy-3-methylbenzaldehyde (1.1 mmol), triphenyl phosphine (1.1 mmol) and (2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (1.0 mmol) in dry THF (6 mL) is cooled in an ice bath. Diisopropyl azodicarboxylate (1.1 mmol) in THF (6 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature while stirring overnight. The solvent is removed and the residue is purified on a silica column with a mixture of hexanes:ethyl acetate. Collected fractions to afford the desired product (_-3).

Reference： [1]Current Patent Assignee: ARISING INTERNATIONAL INC; QILU PHARMACEUTICAL GROUP CO LTD - WO2018/26971, 2018, A1 Location in patent: Page/Page column 31

64
[ 15174-69-3 ]
methyl 2-cyano-3-(hydroxymethyl)benzoate [ No CAS ]
methyl 2-cyano-3-((4-formyl-2-methylphenoxy)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; Cooling with ice;	9.1 Step-l: methyl 2-cyano-3-((4-formyl-2-methylphenoxy)methyl)benzoate A solution of 4-hydroxy-3-methylbenzaldehyde (1.1 mmol), triphenyl phosphine (1.1 mmol) and methyl 2-cyano-3-(hydroxymethyl)benzoate (1.0 mmol) in dry THF (5 mL) is cooled in an ice bath. Diisopropyl azodicarboxylate (1.1 mmol) in THF (5 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature while stirring overnight. The solvent is removed and the residue is purified on a silica column with a mixture of hexanes:ethyl acetate. Collected fractions to afford the desired product.

Reference： [1]Current Patent Assignee: ARISING INTERNATIONAL INC; QILU PHARMACEUTICAL GROUP CO LTD - WO2018/26971, 2018, A1 Location in patent: Page/Page column 37

65
[ 15174-69-3 ]
5-((4-chloro-5-((2-cyano-3'-(hydroxymethyl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile [ No CAS ]
5-((4-chloro-5-((2-cyano-3'-((4-formyl-2-methylphenoxy)methyl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃;	23.5 Step-5: 5-((4-chloro-5-((2-cyano-3'-((4-formyl-2-methylphenoxy)methyl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile, IV-25. A mixture of 4-hydroxy-3-methylbenzaldehyde (1.1 mmol), triphenylphosphine (1.1 mmol) and 5-((4-chloro-5-((2-cyano-3'-(hydroxymethyl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile, IV-24 (1.0 mmol) is dissolved in dry tetrahydrofuran (7 mL) and cooled to 0 C. Diisopropyl azodicarboxylate (1.1 mmol) in tetrahydrofuran (7 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature overnight. Solvent is removed by rotary evaporator. The crude is purified with an eluent (hexanes: ethyl acetate) on a silica gel column to afford the desired product, IV-25.

Reference： [1]Current Patent Assignee: ARISING INTERNATIONAL INC; QILU PHARMACEUTICAL GROUP CO LTD - WO2018/26971, 2018, A1 Location in patent: Page/Page column 56

66
[ 2365-44-8 ]
[ 15174-69-3 ]
[ 122-52-1 ]
(Z)-diethyl (4-hydroxy-3-methylphenyl)(2-(2-oxoindolin-3-ylidene)hydrazinyl)methylphosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With ammonium cerium (IV) nitrate In ethanol at 20℃; for 1.36667h; Green chemistry;	3.3.2. General Procedure for the Synthesis of Diethyl(substitutedphenyl/heteroaryl)(2-(2-oxoindolin-3-ylidene)hydrazinyl)methylphosphonates General procedure: Equimolar quantities of 3-hydrazonoindolin-2-one (1, 1 mmol), a substituted aromatic aldehyde/heteroaldehyde 2(a-n) (1 mmol) and triethylphosphite (3, 1 mmol) were stirred at room temperature in absolute ethanol, in the presence of ceric ammonium nitrate (CAN, 0.003 mmol) as a catalyst. The TLC method was used to verify the completion of the reaction. After completion of the reaction, the reaction mixture was cooled and poured into water, filtered and the solid obtained was dried and recrystallized using ethanol. The time required for completion of reaction varies from 70 min to 89 min. The details are shown in Table 1. Our work represents a one pot Kabachnik-Fields synthesis of diethyl (substitutedphenyl/heteroaryl)(2-(2-oxoindolin-3-ylidene)hydrazinyl)-methylphosphonate derivatives from 3-hydrazonoindolin-2-one and substituted aromatic aldehyde/heteroaldehydes using CAN as a green catalyst at room temperature with better yield 84-95%.

Reference： [1]Tiwari, Shailee V.; Sharif, Nawaz S.; Gajare, Rekha I.; Seijas Vazquez, Julio A.; Sangshetti, Jaiprakash N.; Damale, Manoj D.; Nikalje, Anna Pratima G. [Molecules, 2018, vol. 23, # 8]

67
[ 15174-69-3 ]
[ 18650-39-0 ]
methyl (S)-1-(4-hydroxy-3-methylbenzyl)piperidine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20℃;	To a solution of 4-hydroxy-3-methylbenzaldehyde (Aldrich cat316911: 400.0 mg, 2.938 mmol) and N,N-diisopropylethylamine (8.8 mmol) in 1,2-dichloroethane (200 mmol) was added <strong>[18650-39-0](S)-methyl piperidine-2-carboxylate hydrochloride</strong> (Combi-Blocks catSS-2950: 690 mg, 3.8 mmol) followed by sodium triacetoxyborohydride (1.9 g, 8.8 mmol). The mixture was stirred at room temperature overnight. The crude reaction mixture was diluted with DCM, then sequentially washed with an aqueous NaHCO3 solution, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 40percent ethyl acetate in hexanes to give the desired product. LC-MS calculated for C15H22NO3 (M+H)+: m/z=264.2; found: 264.2.

Reference： [1]Patent: US2018/177784,2018,A1 .Location in patent: Paragraph 0544-0545

68
[ 15174-69-3 ]
[ 105-53-3 ]
[ 45803-83-6 ]

Yield	Reaction Conditions	Operation in experiment
80.2%	With 1,6-Hexanediamine; 4-tert-Butylcatechol In octane; dimethyl sulfoxide at 60℃; for 24h;	7 Example 7 200 g of 3-methyl-4-hydroxybenzaldehyde and 400 g of diethyl malonate were added to a 2 L four-necked flask. 58g hexamethylenediamine, 2g 4-tert-butylcatechol, 900g DMSO and 100g n-octane, stirred, heated to 60 ° C, After refluxing for 24 hours under reduced pressure, a sample was analyzed (Central Control 1, starting material <0.1%). The depressurization was stopped and the temperature was raised to 130 °C. N-octane (150 g) was recovered during the heating. After 18 h of reaction, sample analysis (central control 2, starting material <1.0%). After passing the middle control, DMSO (750 g) was distilled off under reduced pressure. After the end of the recovery, 500 g of ethyl acetate was added, and the organic layer was washed three times with 100 g of water. Ethyl acetate (450 g) was recovered under reduced pressure. After the end of the recovery, 200 g of tert-butyl ether and 20 g of activated carbon were added, and the mixture was heated to reflux, and then beaten for 0.5 h, and cooled and filtered. The filter cake was rinsed with 100 g of tert-butyl ether, and the filtrate was sampled and analyzed (central control 4, main content >95%). The filtrate was concentrated and the solvent was removed to give a yellow solid, 3-methyl-4-hydroxystyrene. The yield of 3-methyl-4-hydroxystyrene according to this example was 80.2%, 158 g.

Reference： [1]Current Patent Assignee: XUZHOU B&C CHEMICAL CO LTD - CN108640819, 2018, A Location in patent: Paragraph 0068-0070

69
[ 141-82-2 ]
[ 15174-69-3 ]
[ 19780-88-2 ]

Yield	Reaction Conditions	Operation in experiment
84%	With piperidine; pyridine at 100℃;	2.1 Step 1: Synthesis of Compound 4a-2 Compound 3a-2 (15.25 g, 112.1 mmol) was added to pyridine (30 mL).Additional malonic acid (11.67 g, 112.1 mmol) and piperidine (5.5 g, 64 mmol) were added.Stir the reaction overnight by heating to 100 ° C.Concentrated under reduced pressure to remove a portion of pyridine.Add 0.5N dilute hydrochloric acid (50 ml), precipitate a white solid, filter, wash,Wash and dry with ethanol,The white solid compound 4a-2 (16.76 g, yield 84%) was obtained.

Reference： [1]Current Patent Assignee: HUNAN HUATENG PHARMACEUTICAL CO LTD - CN108658944, 2018, A Location in patent: Paragraph 0060-0061; 0063-0064

70
[ 15174-69-3 ]
[ 885518-50-3 ]
4-(((6-bromo-1H-indazol-4-yl)amino)methyl)-2-methylphenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69.2%	With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; trifluoroacetic acid In methanol; dichloromethane at 45℃; for 4h;	5.1.2. General procedure 1: Hantzschester-involved reductive amination General procedure: TFA (0.1 equiv.) were added to the solution of substituted anilins (1.0 equiv.), different aromatic aldehydes (1.2 equiv.), and Hantzschester (1.2 equiv.) in DCM/MeOH (3:1) at room temperature, and thereaction was warmed to 45 °C and reacted for about 4 h. After completion (monitored by TLC), the solution was adjusted to pH 7-8 byaddition of NaHCO3, and the crude residue was obtained by concentrating in vacuo. Finally, the crude residue was purified by columnchromatography to give the intermediate or target compounds in high yield.

Reference： [1]Yang, Lingling; Chen, Yang; He, Junlin; Njoya, Emmanuel Mfotie; Chen, Jianjun; Liu, Siyan; Xie, Congqiang; Huang, Wenze; Wang, Fei; Wang, Zhouyu; Li, Yuzhi; Qian, Shan [Bioorganic and Medicinal Chemistry, 2019, vol. 27, # 6, p. 1087 - 1098]

71
[ 15174-69-3 ]
[ 39684-80-5 ]
[2-(4-formyl-2-methyl-phenoxy)-ethyl]-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 24h;	General procedure for preparation of substituted aldehydes General procedure: In a dried flask the aldehyde (10 mmol) was dissolved in DMF (20 mL) under nitrogen atmosphere. The alkylation agent (15 mmol, 1.5 eq) in DMF (10 mL) was added, followed by potassium carbonate (2.76 g, 20 mmol) and potassium iodide (1.66 g, 10 mmol). The well stirring mixture was heated to 80°C for 24h. After cooling to room temperature ethyl acetate (100 mL) was added and the organic solution was washed with brine (3x 40 mL) and water (50 mL). The organic layer was separated, dried with MgSO4 and the solvent was evaporated. The crude material was purified by column chromatography with silica gel and ethyl acetate / petroleum ether 1:2 as the eluent.

Reference： [1]Spaeth, Andreas; Graeler, Andre; Maisch, Tim; Plaetzer, Kristjan [European Journal of Medicinal Chemistry, 2018, vol. 159, p. 423 - 440]

72
[ 23426-63-3 ]
[ 15174-69-3 ]
methyl 2-(4-formyl-2-methylphenoxy)-2-methylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetonitrile at 50℃; for 12h;	1.1 methyl 2-(4-formyl-2-methylphenoxy)-2-methylpropanoate (2a) 3-Methyl-4-hydroxybenzaldehyde 1a (1.0 g, 7.35 mmol) and methyl 2-bromoisobutyrate (4.0 g, 22.1 mmol)Dissolved in acetonitrile (20mL), added potassium carbonate (3.0g, 22.1mmol), reacted at 50 ° C for 12h, after TLC detection reaction is complete, addThe solid mixture in the water-dissolved reaction was extracted with ethyl acetate (30 mL×4), and the organic phases were combined with water (20 mL×1), 1N.HCl (20 mL×1), washed with a saturated NaCI solution (20 mL×2), dried and concentrated

Reference： [1]Current Patent Assignee: GUANGDONG PHARMACEUTICAL UNIVERSITY - CN109456274, 2019, A Location in patent: Paragraph 0066; 0068

73
[ 103-82-2 ]
[ 15174-69-3 ]
[ 108-24-7 ]
(E)-3-(4-acetoxy-3-methylphenyl)-2-phenylacrylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With triethylamine at 90℃; for 3h;	4.1.1. General procedure for the syntheses of 2a-2n, and 2l′, 1m and 1n General procedure: Substituted benzaldehydes (70 mg) and phenylacetic acid (1.0 equiv.) were added to a 25 mL round bottom flask and then 1.5 mL of acetic anhydride and 0.7 mL of triethylamine were added sequentially. This reaction mixture was then stirred at 90 °C for 3 h. On completion of the reaction, conc. HCl was added at 0 °C and the pH was adjusted to 2. The reaction mixture was then partitioned between ethylacetate and water, and the organic layer was dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The residue was then purified either by recrystallization from ethanol or column chromatography using hexane/ethyl acetate gradient elution at 2-5:1to give 2,3-DPA derivatives 2a-2l, 2l′, 1m, and 1n as solids in yields of 20-73%.

Reference： [1]Ullah, Sultan; Park, Yujin; Park, Chaeun; Lee, Sanggwon; Kang, Dongwan; Yang, Jungho; Akter, Jinia; Chun, Pusoon; Moon, Hyung Ryong [Bioorganic and Medicinal Chemistry, 2019, vol. 27, # 11, p. 2192 - 2200]

74
[ 15174-69-3 ]
[ 105-34-0 ]
methyl alpha-cyano-3-methyl-4-hydroxycinnamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium acetate In toluene at 100℃; for 12h;	4.1.1.1.1. General procedures for synthesizing compounds b1-7, e1-2. General procedure: NH4OAc (0.5 eq, 4.0 mmol, 308.0 mg) and hydroxy aryl aldehyde a1-7 or d1-2 (0.9 eq, 7.2 mmol) were dissolved in a solution of methyl cyanoacetate (1.0 eq, 8.0 mmol, 706 ml) in tolune (45 ml). The mixture was refluxed at 100 °C for 12 h by stirring. The reaction mixture was filtered and then the crude product was purified by column chromatography using petroleum ether: ethyl acetate (EtOAc) = 2:1 (v/v).

Reference： [1]Xu, Manyi; Li, Na; Zhao, Zihao; Shi, Zhixian; Sun, Jianbo; Chen, Li [European Journal of Medicinal Chemistry, 2019, vol. 174, p. 265 - 276]

75
[ 15174-69-3 ]
[ 57260-71-6 ]
C₁₇H₂₆N₂O₃*ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	Stage #1: 4-hydroxy-3-methyl-benzaldehyde; 1-t-Butoxycarbonylpiperazine With acetic acid In tetrahydrofuran at 20℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 40℃;	1 Synthesis of Compound 33B Tert-butyl piperazine- l-carboxylate (1.00 g, 5.37 mmol) and 4-hydroxy-3- methyl-benzaldehyde (1.46 g, 10.74 mmol) were charged in a round bottom flask and suspended in THF (30 mL) and acetic acid (6.45 g, 107.40 mmol, 6.14 mL). The imine formation proceeded at room temperature for 1 hour before the addition of Sodium Triacetonxyborohydride (5.69 g, 26.85 mmol). The reaction was heated to 40 °C and stirred overnight. The reaction was neutralized with saturated sodium bicarbonate (50 mL) and extracted with MTBE (50 mL). The organic phase was washed with brine and dried over anhydrous sodium sulfate before evaporation. The remaining residue was dissolved in methanol and precipitated with 2M HC1 in diethyl ether (5 mL). The product was filtered and placed under vacuum to dry. The solid was resuspended in DCM with a few drops of methanol and loaded to a silica gel column (0-9% MeOH in DCM). Pure fractions were pooled and evaporated to yield 536 mg of Compound 33B (29%) as an off-white solid (2.82m, M+H = 307).

Reference： [1]Current Patent Assignee: ROCK CREEK ADVISORS LLC - WO2019/118830, 2019, A1 Location in patent: Paragraph 0343; 0385

76
[ 15174-69-3 ]
[ 65094-22-6 ]
4-(difluoromethoxy)-3-methylbenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33.4%	With potassium hydroxide In water; acetonitrile at -20 - 20℃; for 1.25h;	2 Preparation of 4-(difluoromethoxy)-3-methylbenzaldehyde (9) Potassium hydroxide (8.176 g, 146.0 mmol, 20.0 eq) was suspended in a mixture of acetonitrile (15 mL) and water (15 mL) and cooled to -20 °C.4-Hydroxy-3-methyl- benzaldehyde (9A) (1.000g, 7.3mmol, 1.0 eq) was dissolved in acetonitrile (10 mL) and was added dropwise, followed by bromodifluoromethyl diethylphosphonate (3.811 g, 14.6 mmol, 2.0 eq) over 15 minutes. Then the mixture was allowed to warm to room temperature over 1h. The mixture was extracted with ethyl acetate (3 × 30 mL). Then it was washed with brine (2 × 30 mL) and finally dried over sodium sulfate. The combined organics were removed under reduced pressure. Resulting residue was dissolved in DCM and loaded to silica gel column (12 g, 0-20% EA/ Hex, TLC 10% EA/Hex). The title compound was obtained as clear oil (9) (0.454 g, 33.4%).1H NMR (300 MHz, CDCl3), d 9.95 (s, 1H), 7.77 - 7.71 (m, 2H), 7.26- 7.19 (m, 1H), 6.62 (t, J = 72.9 Hz, 1H), 2.36 (s, 3H).

Reference： [1]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2019/169183, 2019, A1 Location in patent: Page/Page column 38; 40

77
[ 15174-69-3 ]
C₁₉H₂₃F₃O₈ [ No CAS ]
C₂₇H₂₉F₃O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.1 g	With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; for 8h; Inert atmosphere; Cooling with ice;	8 Under a nitrogen atmosphere, 5.0 g of a compound represented by the formula (I-8-4), 1.6 g of a compound represented by the formula (I-8-5), 0.1 g of 4-dimethylaminopyridine, 50 mL of dichloromethane was added. While cooling with ice, 1.7 g of diisopropylcarbodiimide was added dropwise, and the mixture was stirred at room temperature for 8 hours. The precipitate was removed by filtration, and washed sequentially with 5% hydrochloric acid, water and brine. Purification by column chromatography (silica gel, dichloromethane / ethyl acetate) gave 5.1 g of the compound represented by the formula (I-8-6).

Reference： [1]Current Patent Assignee: DIC CORP. - JP2019/210263, 2019, A Location in patent: Paragraph 0177; 0178; 0181

78
[ 667-27-6 ]
[ 15174-69-3 ]
ethyl 2,2-difluoro-2-(4-formyl-2-methylphenoxy)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56.2%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 60℃; for 8h;	1.3.2 3. General synthesis method of compounds 5a to 5e General procedure: Substituted benzaldehyde (compound 4a-4e, 2.0 g) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 1.2 eq.)Ethyl bromodifluoroacetate (1.0 eq.) Was added into the containing anhydrous THF (tetrahydrofuran, 30 mL) solution and stirred at 60 °C for 3-48 hours. The reaction mixture was extracted with water and diethyl ether, and the organic layer was dried over anhydrous MgSO4 and filtered.The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain compound 5a-5e as a colorless liquid

Reference： [1]Current Patent Assignee: PUSAN NATIONAL UNIVERSITY - KR2020/11270, 2020, A Location in patent: Paragraph 0086; 0088; 0120; 0121; 0124; 0125

79
[ 22421-97-2 ]
[ 15174-69-3 ]
methyl 2-(4-formyl-2-methylphenoxy)-2-methylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetonitrile at 45℃; for 12h;	4.1.1. General synthetic procedure for target compounds 1-12 General procedure: To a stirred solution of A (1 equiv) in acetonitrile was added potassiumcarbonate (3 equiv) and B (2 equiv). The mixture was stirred at45 °C for 12 h, and filtered. The filtrate was concentrated and the residuewas dissolved in ethyl acetate. The organic layers were washedwith brine (2 × 20 mL), dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated to give intermediate C, which wasused for the next reaction without further purification. The intermediateC (1.0 equiv) and D (1.0 equiv) were dissolved in DMF (90 vol% in H2O). The resulting reaction mixture was stirred at 80 °C in an open flask, and the reaction progress was monitored by TLC. Then thereaction mixture was poured into water (60 mL) and extracted withethyl acetate (3 × 25 mL). The combined organic phases were washedwith water (25 mL), dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated and the residue was purified by silica gelcolumn chromatography (petroleum ether/ethyl acetate, 10:1, v/v). Toa solution of the obtained solid (1 equiv) in 2:3:1 THF/MeOH/H2O(18 mL) was added LiOH·H2O (3 equiv). After stirring at room temperaturefor 4 h, the volatiles were removed under reduced pressure.The residue was acidified with 1 N hydrochloric acid solution and thenfiltered and the filter cake was washed with 5 mL of water, dried invacuum to afford a white powder. The white powder was purified bycolumn chromatography using a mixture of petroleum ether/ethylacetate (2:1-1:2, v/v) as eluent to afford the target compounds as solid.

Reference： [1]Li, Zheng; Xu, Yawen; Cai, Zongyu; Wang, Xuekun; Ren, Qiang; Zhou, Zongtao; Xie, Rongrong [Bioorganic Chemistry, 2020, vol. 99]

80
[ 17639-93-9 ]
[ 15174-69-3 ]
C₁₂H₁₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetonitrile at 45℃; for 12h;	4.1.1. General synthetic procedure for target compounds 1-12 General procedure: To a stirred solution of A (1 equiv) in acetonitrile was added potassiumcarbonate (3 equiv) and B (2 equiv). The mixture was stirred at45 °C for 12 h, and filtered. The filtrate was concentrated and the residuewas dissolved in ethyl acetate. The organic layers were washedwith brine (2 × 20 mL), dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated to give intermediate C, which wasused for the next reaction without further purification. The intermediateC (1.0 equiv) and D (1.0 equiv) were dissolved in DMF (90 vol% in H2O). The resulting reaction mixture was stirred at 80 °C in an open flask, and the reaction progress was monitored by TLC. Then thereaction mixture was poured into water (60 mL) and extracted withethyl acetate (3 × 25 mL). The combined organic phases were washedwith water (25 mL), dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated and the residue was purified by silica gelcolumn chromatography (petroleum ether/ethyl acetate, 10:1, v/v). Toa solution of the obtained solid (1 equiv) in 2:3:1 THF/MeOH/H2O(18 mL) was added LiOH·H2O (3 equiv). After stirring at room temperaturefor 4 h, the volatiles were removed under reduced pressure.The residue was acidified with 1 N hydrochloric acid solution and thenfiltered and the filter cake was washed with 5 mL of water, dried invacuum to afford a white powder. The white powder was purified bycolumn chromatography using a mixture of petroleum ether/ethylacetate (2:1-1:2, v/v) as eluent to afford the target compounds as solid.

Reference： [1]Li, Zheng; Xu, Yawen; Cai, Zongyu; Wang, Xuekun; Ren, Qiang; Zhou, Zongtao; Xie, Rongrong [Bioorganic Chemistry, 2020, vol. 99]

81
[ 15174-69-3 ]
[ 96-34-4 ]
[ 476156-34-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetonitrile at 45℃; for 12h;	4.1.1. General synthetic procedure for target compounds 1-12 General procedure: To a stirred solution of A (1 equiv) in acetonitrile was added potassiumcarbonate (3 equiv) and B (2 equiv). The mixture was stirred at45 °C for 12 h, and filtered. The filtrate was concentrated and the residuewas dissolved in ethyl acetate. The organic layers were washedwith brine (2 × 20 mL), dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated to give intermediate C, which wasused for the next reaction without further purification. The intermediateC (1.0 equiv) and D (1.0 equiv) were dissolved in DMF (90 vol% in H2O). The resulting reaction mixture was stirred at 80 °C in an open flask, and the reaction progress was monitored by TLC. Then thereaction mixture was poured into water (60 mL) and extracted withethyl acetate (3 × 25 mL). The combined organic phases were washedwith water (25 mL), dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated and the residue was purified by silica gelcolumn chromatography (petroleum ether/ethyl acetate, 10:1, v/v). Toa solution of the obtained solid (1 equiv) in 2:3:1 THF/MeOH/H2O(18 mL) was added LiOH·H2O (3 equiv). After stirring at room temperaturefor 4 h, the volatiles were removed under reduced pressure.The residue was acidified with 1 N hydrochloric acid solution and thenfiltered and the filter cake was washed with 5 mL of water, dried invacuum to afford a white powder. The white powder was purified bycolumn chromatography using a mixture of petroleum ether/ethylacetate (2:1-1:2, v/v) as eluent to afford the target compounds as solid.

Reference： [1]Li, Zheng; Xu, Yawen; Cai, Zongyu; Wang, Xuekun; Ren, Qiang; Zhou, Zongtao; Xie, Rongrong [Bioorganic Chemistry, 2020, vol. 99]

82
[ 15174-69-3 ]
[ 638-45-9 ]
4-hexyloxy-3-methylbenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate In N,N-dimethyl-formamide Inert atmosphere; Reflux;	1-42.4 Scheme 4 Into a 100-ml four-necked flask equipped with a cooling tube, a nitrogen inlet tube, and a thermometer, 4-hydroxy-3-methylbenzaldehyde (3.0 g, 22.0 mmol), 1-iodohexane (14.0 g, 66.1 mmol), potassium carbonate (7.6 g, 55.1 mmol), and 30 ml of dimethylformamide were introduced, and the mixture was heated to reflux. The reaction liquid was washed with water and then concentrated, and the resultant was purified by column chromatography (ethyl acetate:heptane=1:9 (volume ratio)). Thus, 4.1 g (yield 84%) of 4-hexyloxy-3-methylbenzaldehyde was obtained.

Reference： [1]Current Patent Assignee: KONICA MINOLTA, INC. - US2020/264530, 2020, A1 Location in patent: Paragraph 0441-0442

83
[ 15174-69-3 ]
[ 57561-39-4 ]
tert-butyl (2-(4-formyl-2-methylphenoxy)ethyl)(methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃;	A Step A: tert-butyl (2- (4-formyl-2-methylphenoxy) ethyl) (methyl) carbamate To a solution of 4-hydroxy-3-methylbenzaldehyde (1.36 g, 10 mmol) in THF (20 mL) was added tert-butyl (2-hydroxyethyl) (methyl) carbamate (1.75 g, 10 mmol) and PPh3(3.4 g, 13 mmol) , The mixture was protected by nitrogen and cooled down to 0 degrees. A solution of DIAD (2.6 g, 13 mmol) in THF (5 ml) was added to the mixture. The reaction mixture was stirred at room temperature for overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (1.7 g, 58%) . MS: m/e: 294 (M+1)+.

Reference： [1]Current Patent Assignee: BEIGENE LTD. - WO2020/160711, 2020, A1 Location in patent: Paragraph 0867-0868

84
[ 15174-69-3 ]
C₁₆H₁₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium persulfate; iron(II) sulfate In water at 50℃; for 1.5h;	12.1 Example 12 (1) Dissolve 1 part of 3-methyl-4-hydroxybenzaldehyde, 0.02 part of ferrous sulfate and 0.8 part of sodium persulfate in 1000 parts of water at 50°C,And react at this temperature for 1.5 hours to obtain a bisphenol monomer, the structural formula of which is as follows:

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF SCIENCES; Ningbo Institute of Material Technology and Engineering (in: CAS) - CN111793091, 2020, A Location in patent: Paragraph 0076

85
[ 15174-69-3 ]
2-Bromo-6-(chlorodiisopropylsilyl)phenyl tosylate [ No CAS ]
C₂₇H₃₁BrO₅SSi [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 3h;

Reference： [1]Hirano, Keiichi; Nishii, Arata; Ohmori, Ken; Suzuki, Keisuke; Takiguchi, Hiromu; Takikawa, Hiroshi; Tanaka, Masato; Uchiyama, Masanobu; Yagishita, Hirotoshi [Angewandte Chemie - International Edition, 2020, vol. 59, # 30, p. 12440 - 12444][Angew. Chem., 2020, vol. 132, # 30, p. 12540 - 12544,5]

86
[ 1778-09-2 ]
[ 15174-69-3 ]
(E)-3-(4-hydroxy-3-methylphenyl)-1-(4-(methylthio)phenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With hydrogenchloride In methanol at 20℃; for 24h; Inert atmosphere;	4.1.4 General produce C for the preparation of 17, 19-32, 35-40 General procedure: To a solution of 4 M HCl in methanol were added 1a or 1d-l (1.0 equiv.) and 2b or 2e-o (1.0 equiv.). The solution was stirred at room temperature for 24 h. The forming precipitate was filtered and dried to obtain target compounds.

Reference： [1]Zhang, Cheng; Yue, Hu; Sun, Ping; Hua, Lei; Liang, Shuli; Ou, Yitao; Wu, Dan; Wu, Xinyi; Chen, Hao; Hao, Ying; Hu, Wenhui; Yang, Zhongjin [European Journal of Medicinal Chemistry, 2021, vol. 219]

87
[ 15174-69-3 ]
2-fluoro-1-(4-(methylthio)phenyl)ethanone [ No CAS ]
C₁₇H₁₅FO₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With piperidine In methanol at 20℃; for 96h; Inert atmosphere;	73.1 Step 1: Compound P073-a At room temperature, compound P001-c (2.50g, 13.57mmol, 1.00eq.) and 3-methyl-4-hydroxybenzaldehyde (1.85g, 13.57mmol, 1.00eq.) in anhydrous methanol (55.00mL, 25.11 eqv.) piperidine (3.30mL, 3.00eqv.), heated to room temperature under nitrogen protection, and reacted for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=3:1) to obtain compound P073-a. Yield: 42%.

Reference： [1]Current Patent Assignee: ALPHA FLUORO CHALCONE TYPE COMPOUND AND APPLICATION THEREOF; HANGHZOU BIO SINCERITY PHARMA TECH COP - CN112824380, 2021, A Location in patent: Paragraph 0699-0703

88
[ 15174-69-3 ]
N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)hydrazinecarboxamide [ No CAS ]
(E)-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(4-hydroxy-3-methylbenzylidene)hydrazine-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24.27%	With acetic acid In methanol at 80℃; for 0.5h; Microwave irradiation;	1.1. Synthesis of compounds 5-39 General procedure: The compound 4 (0.50 mmol, 1 eq) was reacted with different aromatic aldehydes (0.60 mmol, 1.2 eq) in the mixture of acetic acid (2 mL) and methanol (2 mL) under microwave condition (100 W, 80°C ) for 0.5 h. After completion of reaction, the reaction mixture was distilled under vacuum to remove methanol, and the crude product was extracted with ethyl acetate/water. The organic phase was dried with anhydrous sodium sulfate and evaporated to afford a crude residue. The crude product was purified by silica gel column (dichloromethane/ methanol = 20:1) to produce corresponding pure products 5-39 in good to excellent yields.

Reference： [1]Zhang, Jin-He; Xie, Hong-Xu; Li, Yue; Wang, Kai-Ming; Song, Zhiling; Zhu, Kong-Kai; Fang, Lei; Zhang, Juan; Jiang, Cheng-Shi [Bioorganic and Medicinal Chemistry Letters, 2021, vol. 52]

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CAS No. :	15174-69-3	MDL No. :	MFCD00012360
Formula :	C₈H₈O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BAKYASSDAXQKKY-UHFFFAOYSA-N
M.W :	136.15	Pubchem ID :	139901
Synonyms :

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	38.82
TPSA :	37.3 Å²

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.61 cm/s

Log Po/w (iLOGP) :	1.36
Log Po/w (XLOGP3) :	0.73
Log Po/w (WLOGP) :	1.51
Log Po/w (MLOGP) :	1.12
Log Po/w (SILICOS-IT) :	1.96
Consensus Log Po/w :	1.34

[ CAS No. 15174-69-3 ] {[proInfo.proName]}

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[ 15174-69-3 ] Synthesis Path-Upstream 1~5

[ 15174-69-3 ] Synthesis Path-Downstream 1~88

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[ 15174-69-3 ]

Aryls

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

Log S (ESOL) :	-1.52
Solubility :	4.09 mg/ml ; 0.0301 mol/l
Class :	Very soluble
Log S (Ali) :	-1.09
Solubility :	11.0 mg/ml ; 0.0809 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.13
Solubility :	1.02 mg/ml ; 0.00746 mol/l
Class :	Soluble

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

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

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

[ CAS No. 15174-69-3 ] {[proInfo.proName]}

Quality Control of [ 15174-69-3 ]

Related Doc. of [ 15174-69-3 ]

Product Details of [ 15174-69-3 ]

Calculated chemistry of [ 15174-69-3 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 15174-69-3 ]

Application In Synthesis of [ 15174-69-3 ]

[ 15174-69-3 ] Synthesis Path-Upstream 1~5

[ 15174-69-3 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 15174-69-3 ]

Aryls

Aldehydes

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 15174-69-3 ]