[ CAS No. 41438-18-0 ] {[proInfo.proName]}

Name: 41438-18-0|4-Hydroxy-2-methylbenzaldehyde|97%
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Quality Control of [ 41438-18-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 41438-18-0 ]

Product Details of [ 41438-18-0 ]

CAS No. :	41438-18-0	MDL No. :	MFCD04037443
Formula :	C₈H₈O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JDWWIEFMFPWBST-UHFFFAOYSA-N
M.W :	136.15	Pubchem ID :	458185
Synonyms :

Calculated chemistry of [ 41438-18-0 ]

Physicochemical Properties

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

Pharmacokinetics

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

Lipophilicity

Log Po/w (iLOGP) :	1.26
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 :	1.32

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.52
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

Medicinal Chemistry

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

Safety of [ 41438-18-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 41438-18-0 ]

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

Upstream synthesis route of [ 41438-18-0 ]
Downstream synthetic route of [ 41438-18-0 ]

[ 41438-18-0 ] Synthesis Path-Upstream 1~3

1
[ 41438-18-0 ]
[ 14143-26-1 ]

Reference： [1] Journal of the Chemical Society, 1949, p. 885,889

2
[ 41438-18-0 ]
[ 100-39-0 ]
[ 101093-56-5 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate In acetonitrile at 20℃; for 3 h;	To a mixture of A-1 (2.72 g, 19.98 mmol, 1.00 equiv) in CH3CN (30 mL) with K₂CO₃(4.14 g, 29.95 mmol, 1.50 equiv) was added BnBr (3.8 g, 22.22 mmol, 1.11 equiv). The reaction was stirred for 3 h at room temperature. Water was added and the mixture was extracted with EtOAc thrice. Concentration and chromatograph on silica gel (10:1 PE/EA) gave 3.4 g (75percent) of B-1 as white solid.

Reference： [1] Patent: US2014/256657, 2014, A1, . Location in patent: Paragraph 0297

3
[ 41438-18-0 ]
[ 100-44-7 ]
[ 101093-56-5 ]

Reference： [1] Journal of Organic Chemistry, 1956, vol. 21, p. 415,417, 418

[ 41438-18-0 ] Synthesis Path-Downstream 1~88

1
[ 141-82-2 ]
[ 41438-18-0 ]
[ 103203-88-9 ]

Reference： [1]Journal of the American Chemical Society,1959,vol. 81,p. 4728

2
[ 104-03-0 ]
[ 41438-18-0 ]
4'-nitro-2-methyl-trans-stilbenol-⁽⁴⁾ [ No CAS ]

Reference： [1]Philosophical transactions of the Royal Society of London. Series A, Mathematical and physical sciences,1948,vol. 241,p. 147,184,186

3
[ 52289-54-0 ]
[ 628-13-7 ]
[ 41438-18-0 ]

Reference： [1]Journal of Organic Chemistry,1956,vol. 21,p. 415,417, 418

4
[ 2835-99-6 ]
[ 41438-18-0 ]
4-hydroxy-2-methyl-benzaldehyde-(4-hydroxy-2-methyl-phenylimine) [ No CAS ]

Reference： [1]Nippon Kagaku Zasshi,1956,vol. 77,p. 1072,1074
Chem.Abstr.,1959,p. 5175

5
[ 41438-18-0 ]
[ 13066-95-0 ]
[ 100866-95-3 ]

Reference： [1]Nippon Kagaku Zasshi,1956,vol. 77,p. 1072,1074
Chem.Abstr.,1959,p. 5175

6
[ 41438-18-0 ]
[ 124-41-4 ]
[ 52289-54-0 ]

Reference： [1]Journal of the Chemical Society,1946,p. 85

7
[ 41438-18-0 ]
[ 22574-58-9 ]

Reference： [1]Chemistry and industry,1954,p. 932

8
[ 41438-18-0 ]
[ 155912-29-1 ]

Reference： [1]Journal of the Chemical Society,1949,p. 885,889

9
[ 52289-54-0 ]
[ 41438-18-0 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 5595 - 5598

10
[ 41438-18-0 ]
[ 115352-70-0 ]
4-({(E)-4'-[(1H-Benzoimidazol-2-ylmethyl)-amino]-biphenyl-4-ylimino}-methyl)-3-methyl-phenol [ No CAS ]

Reference： [1]Journal of the Indian Chemical Society,1987,vol. 64,p. 446-448

11
[ 41438-18-0 ]
[ 108-24-7 ]
[ 120802-53-1 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 5595 - 5598
[2]European Journal of Organic Chemistry,2016,vol. 2016,p. 2115 - 2119

12
[ 41438-18-0 ]
[ 124-63-0 ]
[ 14143-30-7 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 5595 - 5598

13
[ 4832-52-4 ]
[ 108-39-4 ]
[ 41438-18-0 ]

Reference： [1]Synthesis,1984,p. 166 - 168

14
[ 80193-36-8 ]
[ 41438-18-0 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1981,vol. 54,p. 2120 - 2123

15
[ 41438-18-0 ]
[ 98-59-9 ]
[ 120802-54-2 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 5595 - 5598

16
[ 108-39-4 ]
o-cresol and p-cresol [ No CAS ]
[ 41438-18-0 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1981,vol. 54,p. 2120 - 2123

17
[ 27060-75-9 ]
[ 41438-18-0 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 5595 - 5598

18
[ 41438-18-0 ]
[ 120802-44-0 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 5595 - 5598

19
[ 41438-18-0 ]
[ 120802-50-8 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 5595 - 5598

20
[ 41438-18-0 ]
[ 120802-45-1 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 5595 - 5598

21
[ 41438-18-0 ]
[ 120802-48-4 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 5595 - 5598

22
[ 41438-18-0 ]
[ 120802-57-5 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 5595 - 5598

23
[ 100-84-5 ]
[ 41438-18-0 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 5595 - 5598

24
[ 41438-18-0 ]
[ 14143-26-1 ]

Reference： [1]Journal of the Chemical Society,1949,p. 885,889

25
[ 41438-18-0 ]
[ 855612-74-7 ]

Reference： [1]Journal of the Chemical Society,1949,p. 885,889

26
[ 41438-18-0 ]
[ 28353-92-6 ]

Reference： [1]Journal of the American Chemical Society,1959,vol. 81,p. 4728

27
[ 41438-18-0 ]
4-((Z?)-4-methoxy-2-methyl-benzylidene)-2-phenyl-4H-oxazol-5-one [ No CAS ]

Reference： [1]Journal of the Chemical Society,1946,p. 85
[2]Journal of the Chemical Society,1946,p. 85

28
[ 41438-18-0 ]
4,4'-dimethoxy-2,2'-dimethyl-trans(?)-chalcone [ No CAS ]

Reference： [1]Journal of the Chemical Society,1946,p. 85
[2]Journal of the Chemical Society,1946,p. 85

29
[ 41438-18-0 ]
3-(4-methoxy-2-methylphenyl)-1-(4-methoxyphenyl)propenone [ No CAS ]

Reference： [1]Journal of the Chemical Society,1946,p. 85
[2]Journal of the Chemical Society,1946,p. 85

30
[ 41438-18-0 ]
4,4'-Dimethoxy-2,2'-dimethyl-benzil [ No CAS ]

Reference： [1]Journal of the Chemical Society,1946,p. 85
[2]Journal of the Chemical Society,1946,p. 85

31
[ 41438-18-0 ]
α,β-dihydroxy-4,4'-dimethoxy-2,2'-dimethyl-chalcone [ No CAS ]

Reference： [1]Journal of the Chemical Society,1946,p. 85
[2]Journal of the Chemical Society,1946,p. 85

32
[ 41438-18-0 ]
[ 102479-64-1 ]

Reference： [1]Journal of Organic Chemistry,1956,vol. 21,p. 415,417, 418

33
[ 41438-18-0 ]
[ 102479-63-0 ]

Reference： [1]Journal of Organic Chemistry,1956,vol. 21,p. 415,417, 418

34
[ 41438-18-0 ]
β-4-Methoxy-2-methyl-thiobenzaldehyd [ No CAS ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1961,vol. 80,p. 775 - 791

35
[ 110-87-2 ]
[ 41438-18-0 ]
2-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 5A molecular sieve; pyridinium p-toluenesulfonate; In dichloromethane; at 20℃;	To a solution of [4-HYDROXY-3-METHYLBENZALDEHYDE] (3.0 g, 22.03 mmol) in 45 mL methylene chloride was added 3, [4-DIHYDRO-2H-PYRAN] (5.0 mL, 54.8 mmol) and pyridinium p-toluenesulfonate (0.55 g, 2.19 [MMOL).] The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with three portions of methylene chloride. The combined organic layers were washed with saturated aqueous sodium chloride, dried (sodium sulfate), filtered, and concentrated. Silica gel flash chromatography of the residue (10% ether/hexanes to 20% ether/hexanes) afforded 4.35 g of the title compound of Step A. MS 221. 1 [(M+1) +]

Reference： [1]Patent: WO2004/26823,2004,A1 .Location in patent: Page 40

36
[ 41438-18-0 ]
[ 109-70-6 ]
[ 848848-22-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate; In acetonitrile; at 65℃; for 16h;	1-Bromo-3-chloropropane (5.03 g, 32.0 mmol, 1.0 equiv) was added to a solution of <strong>[41438-18-0]2-methyl-4-hydroxybenzaldehyde</strong> (4.35 g, 32.0 mmol, 1.0 equiv) and K2CO3 (8.8 g, 64.0 mmol, 2.0 equiv) in acetonitrile (75 mL). The mixture was heated at 65 C. for 16 h, then cooled to rt and filtered through diatomaceous earth. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, 10% ethyl acetate in hexanes) to afford 5.58 g (82%) of 4-(3-chloro-propoxy)-2-methyl-benzaldehyde. To a refluxing solution of 4-(3-chloro-propoxy)-2-methyl-benzaldehyde in acetone (100 mL), KI (58 g) was added portion wise over 3 d. The mixture was cooled to rt and water was added. The aqueous mixture was extracted three times with ethyl acetate and the combined extracts were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, 5% ethyl acetate in hexanes) to afford 6.13 g (77%) of the title compound. 1H NMR (400 MHz, CD3OD): 10.1 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 6.84 (dd, J=8.6, 2.5 Hz, 1H), 6.74 (d, J=2.2 Hz, 1H), 4.11 (t, J=5.8 Hz, 2H), 3.36 (t, J=6.7 Hz, 2H), 2.65 (s, 3H), 2.29 (m, 2H).

Reference： [1]Patent: US2005/70550,2005,A1 .Location in patent: Page/Page column 35

37
[ 203859-94-3 ]
[ 41438-18-0 ]
[ 848848-28-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In acetonitrile; at 20℃; for 96h;	To a solution of (3-hydroxy-propyl)-piperidine-1-carboxylic acid tert-butyl ester (4.00 g, 16.4 mmol, 1.0 equiv) and triethylamine (3.40 mL, 24.6 mmol, 1.5 equiv) in dichloromethane at 0 C. was added methanesulfonyl chloride (1.53 mL, 19.7 mmol, 1.2 equiv). The solution was warmed to rt and stirred for 1.0 h then poured into satd. aq. NaHCO3. The aqueous mixture was extracted three times with chloroform and the combined extracts were dried (Na2SO4), filtered, and concentrated. The residue was subjected to column chromatography (silica gel, 10% methanol in dichloromethane). The partially purified 4-(3-methanesulfonyloxy-propyl)-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.56 mmol, 1.0 equiv) was stirred with <strong>[41438-18-0]4-hydroxy-2-methyl-benzaldehyde</strong> (212 mg, 1.56 mmol, 1.0 equiv) and cesium carbonate (1.01 g, 3.12 mmol, 2.0 equiv) in acetonitrile at rt for 4 d. The mixture was filtered through diatomaceous earth and the filtrate was concentrated. The crude material was partially purified by column chromatography (silica gel, 25% ethyl acetate in hexanes). 4-[3-(4-Formyl-3-methyl-phenoxy)-propyl]-piperidine-1-carboxylic acid tert-butyl ester (146 mg, 0.41 mmol, 1.0 equiv), 5-chloro-3-methyl-benzene-1,2-diamine (63 mg, 0.41 mmol, 1.0 equiv), and Na2S2O5 (100 mg, 0.53 mmol, 1.3 equiv) were stirred at 90 C. in DMF for 2.5 h. The mixture was cooled to rt and water (75 mL) was added causing a light brown precipitate to form. The solid 4-{3-[4-(6-chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propyl}-piperidine-1-carboxylic acid tert-butyl ester was collected by filtration, dissolved in a solution of dichloromethane (2.0 mL) and trifluroacetic acid (1.0 mL), and stirred at rt for 1.5 h. The reaction mixture was loaded directly on silica gel and purified according to Method 2, which afforded 52.1 mg of the title compound. MS (electrospray): mass calculated for C23H28ClN3O, 397.19; m/z found, 398.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.55 (d, J=8.4 Hz, 1H), 7.42 (br s, 1H), 7.10-7.07 (m, 1H), 6.96-6.95 (m, 1H), 6.91 (dd, J=8.5, 2.4 Hz, 1H), 4.09 (t, J=6.2 Hz, 2H), 3.45-3.39 (m, 2H), 3.06-2.96 (m, 2H), 2.59 (s, 3H), 2.50 (s, 3H), 2.07-1.99 (m, 2H), 1.93-1.84 (m, 2H), 1.76-1.64 (m, 1H), 1.59-1.50 (m, 2H), 1.48-1.36 (m, 2H).

Reference： [1]Patent: US2005/70550,2005,A1 .Location in patent: Page/Page column 36

38
toluene-4-sulfonic acid 2-(1-methyl-piperidin-4-yloxy)-ethyl ester [ No CAS ]
[ 41438-18-0 ]
[ 848848-37-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 100℃; for 16h;	To a solution of 1,4-dioxa-8-aza-spiro[4.5]decane (1.0 g, 7.0 mmol, 1.0 equiv) in toluene (20 mL) at 0 C. was added 1.0 M diisobutylaluminum hydride in hexane (20 mL, 20 mmol, 2.9 equiv). The solution was warmed to 80 C. and stirred for 12 h. Methanol (20 mL), satd. aq. sodium potassiuim tartrate (20 mL), and 10% 2-propanol in chloroform (100 mL) were added and the mixture was stirred for 30 min. The chloroform layer was separated and the aqueous mixture was extracted five times with 10% 2-propanol in chloroform (25 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to provide crude 2-(piperidin-4-yloxy)-ethanol as a white solid. The solid was dissolved in dichloroethane (20 mL) and 37% aq. formaldehyde (0.60 mL, 6.9 mmol) was added. After stirring for 30 min, sodium triacetoxyborohydride (2.04 g, 9.6 mmol) was added and the mixture was stirred for 1.5 h. The reaction mixture was diluted with satd. aq. NaHCO3 (20 mL) and extracted six times with 10% 2-propanol in chloroform (80 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to give 2-(1-methyl-piperidin-4-yloxy)-ethanol. The residue was dissolved in dichloromethane, cooled to 0 C., and pyridine (463 muL, 5.7 mmol) and p-toluenesulfonyl chloride (1.1 g, 5.7 mmol) were added. The solution was warmed to rt and stirred for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partially purified by Method 2. The resulting material, toluene-4-sulfonic acid 2-(1-methyl-piperidin-4-yloxy)-ethyl ester, was added to a mixture of <strong>[41438-18-0]4-hydroxy-2-methyl-benzaldehyde</strong> (275 mg, 2.0 mmol) and K2CO3 (699 mg, 5.1 mmol) in DMF. The mixture was heated to 100 C. and stirred for 16 h. After cooling to rt, the mixture was poured into water and extracted three times with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude product was purified by Method 2 to afford 409 mg of the title compound. 1H NMR (400 MHz, CD3OD): 10.10 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.2 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 6.96 (dd, J=8.6, 2.4 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 4.27-4.22 (m, 2H), 3.90-3.85 (m, 2H), 3.75-3.65 (m, 1H), 3.19-3.07 (m, 2H), 3.03-2.86 (m, 2H), 2.67 (s, 3H), 2.65 (s, 3H), 2.39 (s, 3H), 2.07-1.83 (m, 4H).

Reference： [1]Patent: US2005/70550,2005,A1 .Location in patent: Page/Page column 37-38

39
C₁₆H₂₃NO₃S [ No CAS ]
[ 41438-18-0 ]
[ 848848-40-8 ]

Yield	Reaction Conditions	Operation in experiment
9%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 100℃; for 16h;	B. 2-Methyl-4-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-benzaldehyde. To a solution of 3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propan-1-ol (2.24 g, 14.5 mmol, 1.0 equiv) and pyridine (1.64 mL, 20.2 mmol, 1.4 equiv) in dichloromethane (50 mL) at 0 C. was added p-toluenesulfonyl chloride (3.85 g, 20.2 mmol, 1.4 equiv). The reaction mixture, which was allowed to warm to rt, was stirred for 12 h and then poured into water. The aqueous mixture was extracted with dichloromethane and the extract was dried (Na2SO4), filtered, and concentrated. The residue was subjected to column chromatography on silica gel (10% methanol in dichloromethane) and the resulting oil was added to a mixture of <strong>[41438-18-0]4-hydroxy-2-methyl-benzaldehyde</strong> (639 mg, 4.69 mmol) and K2CO3 (1.62 g, 11.7 mmol) in DMF and warmed to 100 C. After stirring for 16 h, the mixture was allowed to cool to rt and filtered through a pad of diatomaceous earth. The diatomaceous earth was rinsed with ethyl acetate, and the filtrate was concentrated. The residue was purified by Method 2 to afford 356 mg (9%) of the title compound. 1H NMR (400 MHz, CD3OD): 10.1 (s, 1H), 7.78 (d, J=8.6 Hz, 1H), 6.92 (dd, J=8.6, 2.4 Hz, 1H), 6.84 (d, J=2.1 Hz, 1H), 5.49-5.43 (m, 1H), 4.09 (t, J=6.3 Hz, 2H), 2.97-2.91 (m, 2H), 2.65-2.57 (m, 5H), 2.35 (s, 3H), 2.25-2.16 (m, 4H), 1.99-1.88 (m, 2H).

Reference： [1]Patent: US2005/70550,2005,A1 .Location in patent: Page/Page column 38

40
[ 57-57-8 ]
[ 41438-18-0 ]
[ 661481-13-6 ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of <strong>[41438-18-0]4-hydroxy-2-methylbenzaldehyde</strong> (5 g) and potassium tert-butoxide (4.12 g) in tetrahydrofuran (60 mL) was added beta-propiolactone (4.6 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was suspended in ethyl acetate (20 mL) - n-hexane (100 mL). The insoluble material was collected by filtration, and washed with n-hexane and dried under reduced pressure to give the title compound (7.2 g).1H-NMR (CDCl3) delta ppm: 2.65 (3H, s), 2.89 (2H, t, J=6.4Hz), 4.32 (2H, t, J=6.4Hz), 6.76 (1H, d, J=2.5Hz), 6.85 (1H, dd, J=8.7Hz, 2.5Hz), 7.76 (1H, d, J=8.7Hz), 10.12 (1H, s)

Reference： [1]Patent: EP1544208,2005,A1 .Location in patent: Page/Page column 60

41
[ 661481-12-5 ]
[ 41438-18-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In tetrahydrofuran; methanol; water; at 50℃; for 1.5h;	To a solution of 4-bromo-3-methylphenol (14 g) andN,N-diisopropylamine (39.1 mL) in dichloromethane (150 mL) was added chloromethyl methyl ether (11.4 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 days. The reaction mixture was poured into a saturated aqueous citric acid solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water, 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-bromo-3-methyl-1-(methoxymethoxy)benzene (16.7 g). This material was dissolved in tetrahydrofuran (250 mL). To the solution was added n-butyl lithium (2.64 mol/Ln-hexane solution, 32.7 mL) at -78C under an argon atmosphere, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added N,N-dimethylformamide (16.6 mL), and the mixture was stirred under ice-cooling for 1 hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2-methyl-4-(methoxymethoxy)benzaldehyde (12.9 g). This material was dissolved in tetrahydrofuran (70 mL)methanol (10 mL). To the solution was added concentrated hydrochloric acid (6 mL), and the mixture was stirred at 50C for 1. 5 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) with heating at 60C. n-Hexane (100 mL) was added to the solution gently, and the mixture was stirred at the same temperature for 10 minutes. The mixture was cooled to room temperature. n-Hexane (170 mL) was added to the mixture, and the resulting mixture was stirred overnight. The precipitated crystals were collected by filtration, and washed with n-hexane and dried under reduced pressure to give the title compound (5.6 g).1H-NMR (CDCl3) delta ppm: 2.63 (3H, s), 5.47 (1H, s), 6.7 (1H, d, J=2.3Hz), 6.79 (1H, dd, J=8.4Hz, 2.3Hz)., 7.73 (1H, d, J=8.4Hz), 10.11 (1H, s)

Reference： [1]Patent: EP1544208,2005,A1 .Location in patent: Page/Page column 59-60

42
[ 41438-18-0 ]
[ 106-95-6 ]
[ 206122-92-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate; potassium iodide; In butanone; at 65℃; for 16h;	a) 4-Allyloxy-2-methyl-benzaldehyde; EPO <DP n="26"/>31.7 g (229 mmol) potassium carbonate and 9.51 g (57.3 mmol) potassium iodide were given to a solution of 15.6 g ( 115 mmol) <strong>[41438-18-0]4-hydroxy-2-methyl-benzaldehyde</strong> and 55.4 g (458 mmol) allyl bromide in 500 ml 2-butanone and stirred for 16 h at 65C. Solvents were distilled off and the residue distributed between ethyl acetate and 1 N sodium hydroxide. The organic layer was separated and the aqueous solution extracted once with ethyl acetate. The combined organic phases were dried and evaporated to give 19.8 g (98%) of 4-allyloxy-2-methyl-benzaldehyde. Eta-NMR(400 MHZ, D-DMSO): delta= 2.59 (s, 3H), 4.67 (d, 2H), 5.29 (d, IH), 5.41 (d, IH), 6.05 (m, IH), 6.96 (d, IH), 6.74 (s, IH), 7.77 (d, IH), 10.07 (s, IH).
98%	With potassium carbonate; potassium iodide; In butanone; at 65℃; for 16h;	31.7 g (229 mmol) potassium carbonate and 9.51 g (57.3 mmol) potassium iodide were given to a solution of 15.6 g (115 mmol) <strong>[41438-18-0]4-hydroxy-2-methyl-benzaldehyde</strong> and 55.4 g (458 mmol) allyl bromide in 500 ml 2-butanone and stirred for 16 h at 65 C. Solvents were distilled off and the residue distributed between ethyl acetate and 1 N sodium hydroxide. The organic layer was separated and the aqueous solution extracted once with ethyl acetate. The combined organic phases were dried and evaporated to give 19.8 g (98%) of 4-allyloxy-2-methyl-benzaldehyde. 1H-NMR(400 MHz, D6-DMSO): delta=2.59 (s, 3H, CH3), 4.67 (d, 2H, OC2-vinyl), 5.29 (d, 1H, =CH2), 5.41 (d, 1H, =CH2), 6.05 (m, 1H, C=CH2), 6.96 (d, 1H, 5-H), 6.74 (s, 1H, 3-H), 7.77 (d, 1H, 6-H), 10.07 (s, 1H, CHO).
98%	With potassium carbonate; potassium iodide; In butanone; at 65℃; for 16h;	31.7 g (229 mmol) potassium carbonate and 9.51 g (57.3 mmol) potassium iodide were given to a solution of 15.6 g (115 mmol) <strong>[41438-18-0]4-hydroxy-2-methyl-benzaldehyde</strong> and 55.4 g (458 mmol) allyl bromide in 500 ml 2-butanone and stirred for 16 h at 65 C. Solvents were distilled off and the residue distributed between ethyl acetate and 1 N sodium hydroxide. The organic layer was separated and the aqueous solution extracted once with ethyl acetate. The combined organic phases were dried and evaporated to give 19.8 g (98%) of 4-allyloxy-2-methyl-benzaldehyde. 1H-NMR(400 MHz, D6-DMSO): delta=2.59(s, 3H, CH3), 4.67(d, 2H, OCH2-vinyl), 5.29(d, 1H, CH2), 5.41(d, 1H, CH2), 6.05(m, 1H, CHCH2), 6.96(d, 1H, 5-H), 6.74(s, 1H, 3-H), 7.77(d, 1H, 6-H), 10.07(s, 1H, CHO).

Reference： [1]Patent: WO2007/17222,2007,A1 .Location in patent: Page/Page column 24-25
[2]Patent: US2005/209290,2005,A1 .Location in patent: Page/Page column 13
[3]Patent: US2005/267179,2005,A1 .Location in patent: Page/Page column 17; 18

43
[ 7037-30-1 ]
[ 41438-18-0 ]
4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With di-tert-butyl-diazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; for 16h;	To an ice-cooled solution of <strong>[41438-18-0]2-methyl-4-hydroxybenzaldehyde</strong> (722 mg, 5.3 mmol), PPh3 polymer resin (3 mmol/g, 2.2 g, 6.4 mmol), and 3-(1-methyl-piperidin-4-yl)-propan-1-ol (833 mg, 5.3 mmol, 1.0 equiv) in THF (25 mL) was added di-tert-butyl-azodicarboxylate (1.47 g, 6.4 mmol). The reaction mixture was allowed to warm to rt and was stirred for 16 h. The mixture was filtered through diatomaceous earth, diluted with water, and extracted three times with EtOAc. The combined extracts were dried (Na2SO4) and concentrated. Purification by Method 1 afforded 578 mg (40%) of the desired aldehyde. MS (ESI): mass calcd for C16H23NO2, 261.17; m/z found, 262.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.85 (s,1H), 7.80 (d, J=8.6, 2H), 6.97 (d, J=8.6, 2H), 4.01 (t, J=6.4, 2H), 2.84-2.82 (m, 2H), 2.25 (s, 3H), 1.92-1.78 (m, 4H), 1.71-1.69 (m, 2H), 1.41-1.37 (m, 2H), 1.29-1.26 (m, 3H).

Reference： [1]Patent: US2005/261309,2005,A1 .Location in patent: Page/Page column 17

44
[ 206122-92-1 ]
[ 41438-18-0 ]

Yield	Reaction Conditions	Operation in experiment
3.61 g (35%)	With formic acid; triphenylphosphine;palladium diacetate; In ethyl acetate;	C. Preparation of 2-methyl-4-hydroxybenzaldehyde The compound of Step B, 13.54 g (76.9 mmole), 1.72 g (7.69 mmole) palladium acetate, and 12.09 g (46.2 mmole) triphenylphosphine were mixed in a 250 ml flask. Formic acid, 3.2 ml (84.6 mmole), was added and the reaction was swirled. Within 15 seconds, the reaction foamed, exothermed and formed a gum which was dissolved in ethyl acetate, washed once with sodium bicarbonate and once with brine. The organic layer was chromatographed on 350 ml silica, eluding with 20%, then 40% ethyl acetate/hexane. The fractions were combined and the product crystallized from methylene chloride/hexane to give 3.61 g (35%) of product which was used without further purification. NMR (CDCl3), delta 2.50 (s, 3H), 6.70 (d, 1H, J=2 Hz), 6.78 (dd, 1H, J=2 Hz,9 Hz), 7.75 (d, 1H, J=9 Hz), 10.36 (s, 1H)
3.61 g (35%)	With formic acid; triphenylphosphine;palladium diacetate; In ethyl acetate;	C. Preparation of 2-methyl-4-hydroxybenzaldehyde The compound of Step B, 13.54 g (76.9 mmole), 1.72 g (7.69 mmole) palladium acetate, and 12.09 g (46.2 mmole) triphenylphosphine were mixed in a 250 ml flask. Formic acid, 3.2 ml (84.6 mmole), was added and the reaction was swirled. Within 15 seconds, the reaction foamed, exothermed and formed a gum which was dissolved in ethyl acetate, washed once with sodium bicarbonate and once with brine. The organic layer was chromatographed on 350 ml silica, eluding with 20%, then 40% ethyl acetate/hexane. The fractions were combined and the product crystallized from methylene chloride/hexane to give 3.61 g (35%)of product which was used without further purification. NMR (CDCl3), delta 2.50 (s, 3H), 6.70 (d, 1H, J=2 Hz), 6.78 (dd, 1H, J=2 Hz, 9 Hz), 7.75 (d, 1H, J=9 Hz), 10.36 (s, 1H)
3.61 g (35%)	With formic acid; triphenylphosphine;palladium diacetate; In ethyl acetate;	C. Preparation of 2-methyl-4-hydroxybenzaldehyde The compound of Step B, 13.54 g (76.9 mmole), 1.72 g (7.69 mmole) palladium acetate, and 12.09 g (46.2 mmole) triphenylphosphine were mixed in a 250 ml flask. Formic acid, 3.2 ml (84.6 mmole), was added and the reaction was swirled. Within 15 seconds, the reaction foamed, exothermed and formed a gum which was dissolved in ethyl acetate, washed once with sodium bicarbonate and once with brine. The organic layer was chromatographed on 350 ml silica, eluding with 20%, then 40% ethyl acetate/hexane. The fractions were combined and the product crystallized from methylene chloride/hexane to give 3.61 g (35%)of product which was used without further purification. NMR (CDCl3), delta2.50 (s, 3H), 6.70 (d, 1H, J=2 Hz), 6.78 (dd, 1H, J=2 Hz,9 Hz), 7.75 (d, 1H, J=9 Hz), 10.36 (s, 1H)

3.61g (35%)	With formic acid; triphenylphosphine;palladium diacetate; In ethyl acetate;	C. Preparation of 2-methyl-4-hydroxybenzaldehyde The compound of Step B, 13.54g (76.9 mmole), 1.72g (7.69 mmole) palladium acetate, and 12.09g (46.2 mmole) triphenylphosphine were mixed in a 250ml flask. Formic acid, 3.2 ml (84.6 mmole), was added and the reaction was swirled. Within 15 seconds, the reaction foamed, exothermed and formed a gum which was dissolved in ethyl acetate, washed once with sodium bicarbonate and once with brine. The organic layer was chromatographed on 350 ml silica, eluding with 20%, then 40% ethyl acetate/hexane. The fractions were combined and the product crystallized from methylene chloride/hexane to give 3.61g (35%)of product which was used without further purification. NMR (CDCl3), delta 2.50 (s, 3H), 6.70 (d, 1H, J=2Hz), 6.78 (dd, 1H, J=2Hz,9Hz), 7.75 (d, 1H, J=9Hz), 10.36 (s, 1H)
3.61g (35%)	With formic acid; triphenylphosphine;palladium diacetate; In ethyl acetate;	C. Preparation of 2-methyl-4-hydroxybenzaldehyde The compound of Step B, 13.54g (76.9 mmole), 1.72g (7.69 mmole) palladium acetate, and 12.09g (46.2 mmole) triphenylphosphine were mixed in a 250ml flask. Formic acid, 3.2 ml (84.6 mmole), was added and the reaction was swirled. Within 15 seconds, the reaction foamed, exothermed and formed a gum which was dissolved in ethyl acetate, washed once with sodium bicarbonate and once with brine. The organic layer was chromatographed on 350 ml silica, eluding with 20%, then 40% ethyl acetate/hexane. The fractions were combined and the product crystallized from methylene chloride/hexane to give 3.61g (35%)of product which was used without further purification. NMR (CDCl3), delta 2.50 (s, 3H), 6.70 (d, 1H, J=2Hz), 6.78 (dd, 1H, J=2Hz,9Hz), 7.75 (d, 1H, J=9Hz), 10.36 (s, 1H)

Reference： [1]Patent: US5942530,1999,A
[2]Patent: US5952360,1999,A
[3]Patent: US6156748,2000,A
[4]Patent: EP906755,1999,A2
[5]Patent: EP908180,1999,A2

45
[ 41438-18-0 ]
[ 106-89-8 ]
2-methyl-4-(2,3-epoxypropoxy)-benzaldehyde [ No CAS ]
2-methyl-4-(2,3-epoxypropyl)benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In sodium hydroxide;	Step A Preparation of 2-methyl-4-(2,3-epoxypropoxy)-benzaldehyde To epichlorohydrin (20 g., 0.216 mole) heated at 55 C. is added dropwise a solution of <strong>[41438-18-0]2-methyl-4-hydroxybenzaldehyde</strong> (9.0 g., 0.066 mole) in 2.5N sodium hydroxide solution (40 ml.). After the addition, the solution is allowed to stir an additional 3 hours at 55 C. and then at room temperature overnight. The oil is distilled to give 8.3 g of 2-methyl-4-(2,3-epoxypropyl)benzaldehyde, m.p. 160-170 C. at 1 mm. Hg.
	In sodium hydroxide;	Step A: Preparation of 2-methyl-4-(2,3-epoxypropoxy)-benzaldehyde To epichlorohydrin (20 g., 0.216 mole) heated at 55 C. is added dropwise a solution of <strong>[41438-18-0]2-methyl-4-hydroxybenzaldehyde</strong> (9.0 g., 0.006 mole) in 2.5 N sodium hydroxide solution (40 ml.). After the addition, the solution is allowed to stir an additional 3 hours at 55 C. and then at room temperature overnight. the oil is distilled to give 8.3 g. of 2-methyl-4-(2,3-epoxypropyl)benzaldehyde, m.p. 160-170 C. at 1 mm. Hg.
	In sodium hydroxide;	A. Preparation of 2-methyl-4-(2,3-epoxypropoxy)benzaldehyde To epichlorohydrin (20 g., 0.216 mole) heated at 55 C. is added dropwise a solution of <strong>[41438-18-0]2-methyl-4-hydroxybenzaldehyde</strong> (9.0 g., 0.066 mole) in 2.5 N sodium hydroxide solution (40 ml.). After the addition, the solution is allowed to stir an additional 3 hours at 55 C. and then at room temperature overnight. The oil is distilled to give 8.3 g. of 2-methyl-4-(2,3-epoxypropyl)benzaldehyde, m.p. 160-170 C. at 1 mm. Hg.

Reference： [1]Patent: US4642311,1987,A
[2]Patent: US4853383,1989,A
[3]Patent: US4134983,1979,A

46
[ 41438-18-0 ]
[ 18162-48-6 ]
[ 1160178-00-6 ]

Yield	Reaction Conditions	Operation in experiment
57%	With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; for 6h;Inert atmosphere;	To a stirred solution of <strong>[41438-18-0]4-hydroxy-2-methylbenzaldehyde</strong> 1 (2 g, 14.7 mmol) in DMF (14 mL) were added imidazole (2.5 g, 36.76 mmol) and tert-butyldimethylchlorosilane (3.32 g, 22.06 mmol) at 0 C under inert atmosphere. The reaction mixture was gradually warmed to RT and stirred for 6 h. The progress of the reaction was monitored by TLC; after the completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAcri? -hexanes) to afford compound 2 (2.1 g, 8.39 mmol, 57%) as colorless liquid. NMR (400 MHz, CDCb): d 10.12 (s, 1H), 7.70 (d, J= 8.4 Hz, 1H), 6.78 (dd, J= 8.4, 2.4 Hz, 1H), 6.69 (d, J= 2.3 Hz, 1H), 2.62 (s, 3H), 0.99 (s, 9H), 0.24 (s, 6H). LC-MS: m/z 251.2 [M+H]+ at 3.31 RT98.30% purity).

Reference： [1]Journal of the American Chemical Society,2020,vol. 141,p. 8171 - 8184
[2]Patent: WO2019/213148,2019,A1 .Location in patent: Page/Page column 71
[3]Organic Letters,2010,vol. 12,p. 5020 - 5023

47
C₁₇H₃₄O₂Si [ No CAS ]
C₈H₁₂O₂ [ No CAS ]
[ 41438-18-0 ]
[ 95218-47-6 ]
[ 58403-93-3 ]

Yield	Reaction Conditions	Operation in experiment
17%; 25%	With palladium diacetate; In acetonitrile; at 20℃; for 23h;	General procedure: A solution of 6c (94 mg, 0.3 mmol) in MeCN (750 muL) was added Pd(OAc)2 (72 mg, 0.33 mmol) and stirred for 18 h at rt. The mixture was diluted with CH2Cl2 (3 mL) and filtered through a Celite pad. After volatile material was removed under reduced pressure, the resulting residue was purified by column chromatography (SiO2, hexane/AcOEt = 1/1) to give 7a (4.5 mg, yield 10%) as a colorless solid and 8b (22.5 mg, yield 48%) as a colorless solid.

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 3079 - 3082

48
[ 41438-18-0 ]
[ 506-59-2 ]
[ 1354792-43-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium tris(acetoxy)borohydride; triethylamine; In dichloromethane; at 20℃;	20A. 4-((4(Dimethylamino)methyl)-3-methylphenol To a mixture of <strong>[41438-18-0]4-hydroxy-2-methylbenzaldehyde</strong> (5.0 g, 37 mmol) and dimethylamine hydrochloride (12 g, 147 mmol) in DCM (200 mL), triethylamine (10 mL, 73 mmol) was added. Sodium triacetoxyborohydride (9.3 g, 44 mmol) was added in portions and the reaction mixture was stirred at rt over night. Water (20 mL) was added and the solution was concentrated by evaporation. THF (100 mL) and aqueous NaHCO3 (sat., 30 mL) was added and the two phases were separated. NaCl (3-4 g) was added to the aqueous phase and it was extracted twice with THF (50 mL). The combined solutions were evaporated. EtOAc (150 mL) was added to the residue and the two phases were separated. The organic phase was dried (Na2SO4) and evaporated to dryness. There was obtained 5.8 g (96%) of 20A as an oil. 1H NMR (600 MHz, DMSO-d6): delta 2.08 (s, 6H), 2.21 (s, 3H), 3.19 (s, 2H), 6.49 (d, 1H), 6.54 (s, 1H), 6.92 (d, 1H).

Reference： [1]Patent: US2012/10189,2012,A1 .Location in patent: Page/Page column 26-27
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 2497 - 2511

49
[ 41438-18-0 ]
[ 1354791-41-5 ]

Reference： [1]Patent: US2012/10189,2012,A1

50
[ 41438-18-0 ]
[ 1354791-89-1 ]

Reference： [1]Patent: US2012/10189,2012,A1

51
[ 41438-18-0 ]
[ 1354792-44-1 ]

Reference： [1]Patent: US2012/10189,2012,A1
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 2497 - 2511

52
[ 41438-18-0 ]
[ 1354792-45-2 ]

Reference： [1]Patent: US2012/10189,2012,A1
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 2497 - 2511

53
[ 41438-18-0 ]
[ 1354792-79-2 ]

Reference： [1]Patent: US2012/10189,2012,A1

54
[ 41438-18-0 ]
[ 141699-58-3 ]
[ 1354792-77-0 ]

Yield	Reaction Conditions	Operation in experiment
20%		69A. tert-Butyl 3-(4-formyl-3-methylphenoxy)azetidine-1-carboxylate A slurry of sodium hydride (60%, 0.12 g, 3.10 mmol) in DMF (4 ml) was cooled by an ice-bath. Under nitrogen, <strong>[41438-18-0]4-hydroxy-2-methylbenzaldehyde</strong> in DMF (2 ml) was added. The mixture was stirred for 30 min and then tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate in DMF (4 ml) was added. The mixture was heated to 100 C. using an oil bath for 3 days and then cooled to RT. Water (100 ml) was added while stirring. The mixture was extracted trice with EtOAc. The combined organic solutions were dried (MgSO4) and then evaporated. The residue was purified by silica gel chromatography eluting with EtOAc/heptane (10:90). There was obtained 120 mg (20%) of partly purified 69A as an oil. 1H NMR (500 MHz, CDCl3): delta 1.46 (s, 9H), 2.64 (s, 3H), 4.01 (m, 2H), 4.33 (m, 2H), 4.94 (m, 1H), 6.60 (d, 1H), 6.66 (dd, 1H), 7.76 (d, 1H), 10.13 (s, 1H).

Reference： [1]Patent: US2012/10189,2012,A1 .Location in patent: Page/Page column 47

55
[ 41438-18-0 ]
[ 141699-58-3 ]
[ 1354792-78-1 ]

Reference： [1]Patent: US2012/10189,2012,A1

56
[ 1254035-93-2 ]
[ 41438-18-0 ]
[ 1354792-67-8 ]

Yield	Reaction Conditions	Operation in experiment
72%	With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 20h;Inert atmosphere;	53C. 2-Methyl-4-(1-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde To a solution of <strong>[41438-18-0]4-hydroxy-2-methylbenzaldehyde</strong> (0.11 g, 0.79 mmol) and 53B (0.20 g, 0.62 mmol) in DMF (10 mL) under nitrogen was added Cs2CO3 (0.24 g, 0.74 mmol). The mixture was stirred at 90 C. for 20 h, cooled to RT and then diluted with DCM. The solids were filtered off and the filtrate was evaporated. The product was purified on two occasions by preparative HPLC (Kromasil, C8) eluting with a gradient of acetonitrile and a mixture of acetic acid and water (0.2%). The pure fractions were iii combined and concentrated. The aqueous residues were extracted with DCM and the organic solutions were evaporated. There was obtained 162 mg (72%) of 53C as a solid. 1H NMR (500 MHz, CDCl3): delta 2.66 (s, 3H), 4.34 (d, 1H), 4.69 (dd, 1H), 4.76 (d, 1H), 5.17 (m, 2H), 6.64 (d, 1H), 6.72 (dd, 1H), 7.53 (t, 2H), 7.59 (t, 1H), 7.78 (d, 1H), 8.15 (d, 1H), 10.14 (s, 1H), MS (APCI+) m/z 364 [M+H]+.
72%	With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 20h;Inert atmosphere;	To a solution of of <strong>[41438-18-0]4-hydroxy-2-methylbenzaldehyde</strong> (0.11 g, 0.79 mmol) and 1-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yl methanesulfonate (0.20 g, 0.62 mmol, Intermediate IB above) in DMF (10 mL) under nitrogen was added Cs2C03 (0.24 g, 0.74 mmol). The mixture was stirred at 90 C for 20 h, cooled to RT and then diluted with DCM. The solids were filtered off and the filtrate was evaporated. The product was purified on two occasions by preparative HPLC (Kromasil, C8) eluting with a gradient of acetonitrile and a mixture of acetic acid and water (0.2%). The pure fractions were combined and concentrated. The aqueous residues were extracted with DCM and the organic solutions were evaporated. There was obtained 162 mg (72%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3): delta 2.66 (s, 3H), 4.34 (d, 1H), 4.69 (dd, 1H), 4.76 (d, 1H), 5.17 (m, 2H), 6.64 (d, 1H), 6.72 (dd, 1H), 7.53 (t, 2H), 7.59 (t, 1H), 7.78 (d, 1H), 8.15 (d, 1H), 10.14 (s, 1H), MS (APCI+) m/z 364 [M+H]+.

Reference： [1]Patent: US2012/10189,2012,A1 .Location in patent: Page/Page column 40
[2]Patent: WO2013/11285,2013,A1 .Location in patent: Page/Page column 54

57
[ 41438-18-0 ]
[ 140690-56-8 ]
[ 1264753-62-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3.5h;	Reference Example 8 4-[2,4-bis(trifluoromethyl)benzyl]oxy}-2-methylbenzaldehyde; [Show Image] To a solution (7.3 mL) of <strong>[41438-18-0]4-hydroxy-2-methylbenzaldehyde</strong> (1.00 g) and potassium carbonate (1.22 g) in DMF was added 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (1.52 mL), and the mixture was stirred at room temperature for 3.5 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 pale-yellow powder (yield: 2.50 g, 94%). 1H-NMR (CDCl3, 300 MHz):delta2.69 (3H, s), 5.40 (2H, s), 6.85 (1H, d, J= 2.4 Hz), 6.92 (1H, dd, J = 8.7, 2.4 Hz), 7.80 (1H, d, J = 8.7 Hz), 7.84-7.94 (2H, m), 7.99 (1H, s), 10.16 (1H, s).

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

58
[ 41438-18-0 ]
[ 1264753-77-6 ]

Reference： [1]Patent: EP2450352,2012,A1

59
[ 41438-18-0 ]
[ 1264754-18-8 ]

Reference： [1]Patent: EP2450352,2012,A1

60
[ 41438-18-0 ]
[ 1264751-16-7 ]

Reference： [1]Patent: EP2450352,2012,A1

61
[ 41438-18-0 ]
[ 1426663-88-8 ]
[ 1426666-59-2 ]

Yield	Reaction Conditions	Operation in experiment
50%	With acetic acid; for 4h;Reflux;	To a solution of methyl (4-(2-aminophenyl)pyrrolo[2,l-fJ[l,2,4]triazin-2- yl)carbamate 17e (0.3 g, 1.06 mmol) in acetic acid (5 mL) was added 4-hydroxy-2- methylbenzaldehyde 29z (0.15 g, 1.1 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 methyl (3-(4-hydroxy-2-methylphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate 35c (0.215 g, 50 %) as a orange brown solid. 1H NMR (300 MHz, DMSO- 6) ? 10.16 (s, 1H), 9.28 (s, 1H), 8.52 (dd, J= 8.1, 1.6 Hz, 1H), 7.84 (d, J= 2.5 Hz, 1H), 7.29 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.13 (dd, J= 8.1, 0.7 Hz, 1H), 6.94 (dd, J= 8.1, 6.9 Hz, 1H), 6.80 (d, J= 8.4 Hz, 1H), 6.63 (d, J= 2.4 Hz, 1H), 6.47 (dd, J= 8.3, 2.4 Hz, 1H), 6.33 (d, J= 2.1 Hz, 1H), 6.18 (d, J= 2.3 Hz, 1H), 5.71 (s, 1H), 3.69 (s, 3H), 2.35 (s, 3H); MS (ES+) 402.107 (M+l), (ES-) 399.484 (M-l).

Reference： [1]Patent: WO2013/33093,2013,A1 .Location in patent: Page/Page column 161; 162

62
[ 41438-18-0 ]
[ 1426663-40-2 ]
[ 1426665-71-5 ]

Yield	Reaction Conditions	Operation in experiment
60%	With acetic acid; for 4h;Reflux;	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 <strong>[41438-18-0]4-hydroxy-2-methylbenzaldehyde</strong> 29z (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,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)-3-methylphenol 29aa (0.185 g, 60 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) ? 9.34 (s, 1H), 8.56 - 8.49 (m, 2H), 7.97 (d, J= 2.5 Hz, 1H), 7.35 - 7.24 (m, 1H), 7.15 (d, J= 7.4 Hz, 1H), 7.00 - 6.91 (m, 1H), 6.80 (d, J= 8.4 Hz, 1H), 6.64 (d, J= 2.4 Hz, 1H), 6.47 (dd, J= 8.4, 2.5 Hz, 1H), 6.33 (d, J= 1.9 Hz, 1H), 6.29 (d, J= 2.5 Hz, 1H), 5.73 (d, J= 1.7 Hz, 1H), 2.35 (s, 3H); MS (ES+) 329.117 (M+l), (ES-) 327.107 (M-l).

Reference： [1]Patent: WO2013/33093,2013,A1 .Location in patent: Page/Page column 148

63
[ 41438-18-0 ]
[ 898538-71-1 ]

Reference： [1]Patent: US2014/256657,2014,A1
[2]Patent: WO2019/215633,2019,A1

64
[ 41438-18-0 ]
benzo[b]thiophen-2-yl(4-(benzyloxy)-5-bromo-2-methylphenyl)methanol [ No CAS ]

Reference： [1]Patent: US2014/256657,2014,A1
[2]Patent: WO2019/215633,2019,A1

65
[ 41438-18-0 ]
2-[[4-(benzyloxy)-5-bromo-2-methylphenyl]methyl]-1-benzothiophene [ No CAS ]

Reference： [1]Patent: US2014/256657,2014,A1
[2]Patent: WO2019/215633,2019,A1

66
[ 41438-18-0 ]
C₅₀H₄₈O₆S [ No CAS ]