[ CAS No. 40137-29-9 ] {[proInfo.proName]}

Name: 40137-29-9|4-Chloro-2-methylbenzaldehyde|97%
Brand: Ambeed
SKU: A120968
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2D 3D

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Quality Control of [ 40137-29-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 40137-29-9 ]

SDS Specification

Alternatived Products of [ 40137-29-9 ]

Product Details of [ 40137-29-9 ]

CAS No. :	40137-29-9	MDL No. :	MFCD02261735
Formula :	C₈H₇ClO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YLXSEAVHGJWSTK-UHFFFAOYSA-N
M.W :	154.59	Pubchem ID :	2757658
Synonyms :

Calculated chemistry of [ 40137-29-9 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	41.81
TPSA :	17.07 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.26 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.86
Log Po/w (XLOGP3) :	2.8
Log Po/w (WLOGP) :	2.46
Log Po/w (MLOGP) :	2.37
Log Po/w (SILICOS-IT) :	3.08
Consensus Log Po/w :	2.51

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.94
Solubility :	0.177 mg/ml ; 0.00115 mol/l
Class :	Soluble
Log S (Ali) :	-2.82
Solubility :	0.237 mg/ml ; 0.00153 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.33
Solubility :	0.0718 mg/ml ; 0.000465 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 40137-29-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H302+H312+H332	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 40137-29-9 ]

* 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 [ 40137-29-9 ]
Downstream synthetic route of [ 40137-29-9 ]

[ 40137-29-9 ] Synthesis Path-Upstream 1~11

1
[ 201230-82-2 ]
[ 108-41-8 ]
[ 40137-29-9 ]
[ 50817-80-6 ]

Reference： [1] Patent: EP1544189, 2005, A1, . Location in patent: Page/Page column 6

2
[ 104-88-1 ]
[ 142-25-6 ]
[ 74-88-4 ]
[ 40137-29-9 ]

Reference： [1] Patent: US5547972, 1996, A,

3
[ 615-60-1 ]
[ 40137-29-9 ]

Reference： [1] Synthesis, 1989, # 4, p. 293 - 295

4
[ 104-88-1 ]
[ 40137-29-9 ]

Reference： [1] Tetrahedron Letters, 1982, vol. 23, # 39, p. 3979 - 3982

5
[ 74-88-4 ]
[ 40137-29-9 ]

Reference： [1] Tetrahedron Letters, 1982, vol. 23, # 39, p. 3979 - 3982

6
[ 6611-78-5 ]
[ 40137-29-9 ]

Reference： [1] Chemische Berichte, 1905, vol. 38, p. 1693

7
[ 104-88-1 ]
[ 74-88-4 ]
[ 40137-29-9 ]

Reference： [1] Journal of Organic Chemistry, 1984, vol. 49, # 6, p. 1078 - 1083

8
[ 75-17-2 ]
[ 95-69-2 ]
[ 40137-29-9 ]

Reference： [1] Bulletin de la Societe Chimique de France, 1964, p. 3103 - 3112

9
[ 6611-78-5 ]
[ 10026-13-8 ]
[ 40137-29-9 ]

Reference： [1] Chemische Berichte, 1905, vol. 38, p. 1693

10
[ 201230-82-2 ]
[ 108-41-8 ]
[ 40137-29-9 ]
[ 50817-80-6 ]

Reference： [1] Patent: EP1544189, 2005, A1, . Location in patent: Page/Page column 6

11
[ 40137-29-9 ]
[ 938-35-2 ]

Reference： [1] Bulletin de la Societe Chimique de France, 1964, p. 3103 - 3112

[ 40137-29-9 ] Synthesis Path-Downstream 1~88

1
[ 6611-78-5 ]
[ 40137-29-9 ]

Reference： [1]Chemische Berichte,1905,vol. 38,p. 1693

2
[ 40137-29-9 ]
[ 7499-07-2 ]

Reference： [1]Chemische Berichte,1905,vol. 38,p. 1693

3
[ 141-82-2 ]
[ 40137-29-9 ]
[ 879-76-5 ]

Reference： [1]Bulletin de la Societe Chimique de France,1964,p. 3103 - 3112

4
[ 75-17-2 ]
[ 95-69-2 ]
[ 40137-29-9 ]

Reference： [1]Bulletin de la Societe Chimique de France,1964,p. 3103 - 3112

5
[ 615-60-1 ]
[ 40137-29-9 ]

Reference： [1]Synthesis,1989,p. 293 - 295

6
[ 104-88-1 ]
[ 74-88-4 ]
[ 40137-29-9 ]

Reference： [1]Journal of Organic Chemistry,1984,vol. 49,p. 1078 - 1083

7
[ 40137-29-9 ]
[ 62-53-3 ]
[ 80617-35-2 ]

Reference： [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 170 - 181

8
[ 40137-29-9 ]
[ 129716-11-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3463 - 3468

9
[ 947403-80-7 ]
[ 40137-29-9 ]
C₃₁H₃₁F₂N₅O₂ClCH₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 5590 - 5603

10
[ 1067-74-9 ]
[ 40137-29-9 ]
methyl (E)-3-(4-chloro-2-methylphenyl)acrylate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6463 - 6466

11
[ 40137-29-9 ]
[ 900505-06-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3463 - 3468

12
[ 40137-29-9 ]
[ 900505-19-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3463 - 3468

13
[ 40137-29-9 ]
4-(4-Chloro-2-methyl-benzyl)-3-(4-chloro-phenyl)-7-iodo-1-(2-morpholin-4-yl-ethyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3463 - 3468

14
[ 40137-29-9 ]
(2-{(4-chloro-2-methyl-benzyl)-[(4-chloro-phenyl)-(cyclohex-1-enylcarbamoyl)-methyl]-carbamoyl}-4-iodo-phenyl)-carbamic acid <i>tert</i>-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3463 - 3468

15
[ 40137-29-9 ]
[ 27917-11-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3463 - 3468
[2]Patent: WO2015/103317,2015,A1

16
[ 40137-29-9 ]
[ 944913-41-1 ]

Reference： [1]Heterocycles,2001,vol. 55,p. 1591 - 1597

17
[ 40137-29-9 ]
[ 371785-39-6 ]

Reference： [1]Heterocycles,2001,vol. 55,p. 1591 - 1597

18
[ 40137-29-9 ]
[ 371785-37-4 ]

Reference： [1]Heterocycles,2001,vol. 55,p. 1591 - 1597

19
[ 40137-29-9 ]
N-(2-methyl-4-trimethylsilylbenzylidene)benzylamine [ No CAS ]

Reference： [1]Heterocycles,2001,vol. 55,p. 1591 - 1597

20
[ 40137-29-9 ]
trans-2-(2-methylphenyl)-6-phenyl-4-piperidone [ No CAS ]

Reference： [1]Heterocycles,2001,vol. 55,p. 1591 - 1597
[2]Heterocycles,2001,vol. 55,p. 1591 - 1597

21
[ 40137-29-9 ]
cis-2-(2-methylphenyl)-6-phenyl-4-piperidone [ No CAS ]

Reference： [1]Heterocycles,2001,vol. 55,p. 1591 - 1597

22
[ 40137-29-9 ]
[ 80617-36-3 ]

Reference： [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 170 - 181

23
[ 104-88-1 ]
[ 40137-29-9 ]

Reference： [1]Tetrahedron Letters,1982,vol. 23,p. 3979 - 3982

24
[ 40137-29-9 ]
[ 104095-31-0 ]

Reference： [1]Journal of the Karnatak University,1956,vol. 1,p. 56,58
[2]Patent: US2012/46307,2012,A1

25
[ 40137-29-9 ]
[ 100122-00-7 ]

Reference： [1]Journal of the Karnatak University,1956,vol. 1,p. 56,58

26
[ 40137-29-9 ]
[ 936-19-6 ]

Reference： [1]Bulletin de la Societe Chimique de France,1964,p. 3103 - 3112

27
[ 40137-29-9 ]
[ 938-92-1 ]

Reference： [1]Bulletin de la Societe Chimique de France,1964,p. 3103 - 3112

28
[ 40137-29-9 ]
[ 942-53-0 ]

Reference： [1]Bulletin de la Societe Chimique de France,1964,p. 3103 - 3112

29
[ 40137-29-9 ]
[ 879-75-4 ]

Reference： [1]Bulletin de la Societe Chimique de France,1964,p. 3103 - 3112

30
[ 40137-29-9 ]
6-Isopropenyl-4-methyl-indan [ No CAS ]

Reference： [1]Bulletin de la Societe Chimique de France,1964,p. 3103 - 3112

31
[ 40137-29-9 ]
2-(7-Methyl-indan-5-yl)-propan-2-ol [ No CAS ]

Reference： [1]Bulletin de la Societe Chimique de France,1964,p. 3103 - 3112

32
[ 40137-29-9 ]
7-Methyl-indan-5-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Bulletin de la Societe Chimique de France,1964,p. 3103 - 3112

33
[ 201230-82-2 ]
[ 108-41-8 ]
[ 40137-29-9 ]
[ 50817-80-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen fluoride; boron trifluoride; at -30 - -20℃; under 15001.5 Torr; for 1h;	The reaction and the treatment of the reaction liquid mixture were carried out in the same manner as in Example 11 except for changing the starting compound to 3-chlorotoluene. The results of gas chromatography on the oil layer showed that the conversion of 3-chlorotoluene was 57.1 mol %, the selectivity to 4-chloro-2-methylbenzaldehyde was 75.8 mol %, the selectivity to 2-chloro-4-methylbenzaldehyde was 23.9 mol %, and the total selectivity to two isomers was 99.7 mol %.

Reference： [1]Patent: EP1544189,2005,A1 .Location in patent: Page/Page column 6

34
[ 104-88-1 ]
[ 142-25-6 ]
[ 74-88-4 ]
[ 40137-29-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; n-butyllithium; In tetrahydrofuran; hexane;	EXAMPLE E A solution of n-butyllithium in hexane (30.4 ml, 2.5M) was added dropwise with stirring under nitrogen to a solution of N,N,N'-trimethylethylenediamine (7.9 g) in dry THF (150 ml) at -15 to -20 C. After the addition the mixture was stirred at -23 C. for 15 minutes and then 4-chlorobenzaldehyde (10.0 g) was added dropwise at -15 to -20 C. After the addition the mixture was stirred at -23 C. for 15 minutes and then more n-butyllithium in hexane (85.4 ml, 2.5M) was added dropwise at -15 C. The mixture was stirred at -23 C. for 3 hours, cooled to -40 C. and iodomethane (60.6 g) added at -40 to -20 C. After the addition, the mixture was stirred at -40 C. for 5 minutes and then allowed to warm up to ambient temperature and then stirred at that temperature for 30 minutes. The mixture was carefully poured into ice cold 10% hydrochloric acid (2 1) and left standing for 64 hours. The mixture was extracted with diethyl ether to give an oil which was distilled twice under vacuum to give 4-chloro-2-methylbenzaldehyde, b.p. 105-110 (15 mmHg) which was sufficiently pure for synthetic use in Example 40.

Reference： [1]Patent: US5547972,1996,A

35
[ 40137-29-9 ]
[ 80617-35-2 ]

Yield	Reaction Conditions	Operation in experiment
	With aniline; In toluene;	Step A: Preparation of N-[4-chloro-2-methyl(phenyl)methylene]-benzeneamine A mixture of <strong>[40137-29-9]4-chloro-2-methylbenzaldehyde</strong> (3.5 g, 22.6 mmol) and aniline (2.11 g, 22.6 mmol) in toluene (40 ml) was heated at reflux in a Dean-Stark apparatus for 1 hour. The mixture was cooled and evaporated in vacuo to leave an oily residue. The residue was redissolved in ether, washed with 5% sodium bicarbonate solution. The organic phase was separated, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford an oily residue which was purified by distillation via a Kugelrohr apparatus (oven temperature 160 C., 0.5 mm) to provide the title compound (4.0 g, 7.4 mmol, 77%) as a viscous oil; pmr(CDCl3)delta2.5 (3H, s), 6.3~7.5(7H, m), 7.95(H, d), 8.6(H, s).
	With aniline; In toluene;	Step A: Preparation of N- [4-chloro-2-methyl (phenyl) methylene]-benzeneamine A mixture of <strong>[40137-29-9]4-chloro-2-methylbenzaldehyde</strong> (3.5 g, 22.6 mmol) and aniline (2.11 g, 22.6 mmol) in toluene (40 ml) was heated at reflux in a Dean-Stark apparatus for 1 hour. The mixture was cooled and evaporated in vacuo to leave an oily residue. The residue was redissolved in ether, washed with 5% sodium bicarbonate solution. The organic phase was separated, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford an oily residue which was purified by distillation via a Kugelrohr apparatus (oven temperature 160 C., 0.5 mm) to provide the title compound (4.0 g, 7.4 mmol, 77%) as a viscous oil; pmr (CDCl3)delta2.5(3H, s), 6.3-7.5(7H,m), 7.95(H, d), 8.6(H,s).

Reference： [1]Patent: US4567289,1986,A
[2]Patent: US4375475,1983,A

36
[ 40137-29-9 ]
N-[(4-chloro-2-methylphenyl)-methylene]benzeneamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With aniline; In toluene;	Step A: Preparation of N-[(4-chloro-2-methylphenyl)-methylene]benzeneamine A mixture of <strong>[40137-29-9]4-chloro-2-methylbenzaldehyde</strong> (3.5 g, 22.6 mmol) and aniline (2.11 g, 22.6 mmol) in toluene (40 ml) was heated at reflux in a Dean-Stark apparatus for 1 hour. The mixture was cooled and evaporated in vacuo to leave an oily residue. The residue was redissolved in ether and washed with 5% sodium bicarbonate solution. The organic phase was separated, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford an oily residue which was purified by distillation via a Kugelrohr apparatus (oven temperature 160 C., 0.5 mm) to provide the title compound (4.0 g, 17.4 mmol, 77%) as a viscous oil; pmr (CDCl3) delta 2.5(3H,s), 6.3-7.5(7H,m), 7.95(H,d), 8.6(H,s).

Reference： [1]Patent: US4322563,1982,A

37
[ 110-91-8 ]
[ 40137-29-9 ]
[ 933785-20-7 ]

Yield	Reaction Conditions	Operation in experiment
35%		Example 64(a) 4-(4-Chloro-2-methylberiotazyl)morpholineTo a stirred, cooled (0 C) solution of <strong>[40137-29-9]4-chloro-2-methylbenzaldehyde</strong> (0.23 g, 1.5 mmol) in MeOH (5 mL) was added morpholine (0.15 g, 1.7 mmol), NaCNBH3 (0.49 g, 7.8 mmol) and HOAc (0.063 g, 1.0 mmol) and the reaction was stirred at r.t. over night. The solvent was removed in vacuo and the crude product was partitioned between EtOAc / IM NaHCO3 (aq.). The organic phase was dried (Na2SO4), filtered, concentrated and purified twice by flash chromatography (gradient from 100% pentane to 10% EtOAc in pentane) to give the title compound as a clear liquid (0.120 g, 35%).1H NMR (400 MHz, DMSO-^6) delta ppm 7.27 - 7.21 (m, 2 H) 7.20 - 7.14 (m, 1 H) 3.57 - 3.49 (m, 4 H) 3.38 (s, 2 H) 2.36 - 2.31 (m, 4 H) 2.31 (s, 3 H); MS (ESI) m/z 226 (M+l).

Reference： [1]Patent: WO2007/40440,2007,A1 .Location in patent: Page/Page column 117

38
[ 40137-29-9 ]
[ 74-89-5 ]
C₉H₁₀ClN [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 1295 - 1301

39
[ 40137-29-9 ]
[ 557-20-0 ]
[ 1190216-49-9 ]
C₁₀H₁₃ClO [ No CAS ]

Reference： [1]Letters in Organic Chemistry,2009,vol. 6,p. 264 - 268

40
[ 75-52-5 ]
[ 40137-29-9 ]
[ 1201189-90-3 ]

Yield	Reaction Conditions	Operation in experiment
65%	With ammonium acetate; acetic acid; at 140℃; for 2h;Inert atmosphere;	a) 4-Chloro-2-methyl-1-((E)-2-nitro-vinyl)-benzene Under an atmosphere of nitrogen was added to a solution of <strong>[40137-29-9]4-chloro-2-methylbenzaldehyde</strong> (10.0 g, 64.9 g) in acetic acid (70 mL) ammonium acetate (11.5 g, 149 mmol) and nitromethane (10.0 ml, 185 mmol). The solution was stirred at reflux (oil bath 140 C.) for 2 h. After cooling to ambient temperature water (70 mL) was added and extracted twice with ethyl acetate (70 mL). The organic layers were washed with water (70 mL) and brine (70 mL) and were dried over sodium sulfate. The filtrated was concentrated and the resulting solid was suspended in methanol (30 mL), at 0 C. filtered off and was washed with cold methanol (10 mL) affording the title compound (8.30 g, 65%) as a yellow solid. MS m/e: 197.0 [M]<SUP>+</SUP>.

Reference： [1]Patent: US2009/312327,2009,A1 .Location in patent: Page/Page column 51

41
[ 75-52-5 ]
[ 40137-29-9 ]
[ 1202889-97-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	With methylamine hydrochloride; sodium acetate; at 20℃; for 24h;	A mixture of <strong>[40137-29-9]4-chloro-2-methylbenzaldehyde</strong> (1.56 g, 10.1 mmol), methylamine hydrochloride (0.44 g, 6.5 mmol), and sodium acetate (0.53 g, 6.5 mmol) in nitromethane (4 mL) was vigorously stirred at ambient temperature for 24 hours. The reaction mixture was diluted with water (20 mL) and dichloromethane (40 mL). The organic layer was dried over sodium sulfate and evaporated to afford 4-chloro-2-methyl-l-(2-nitrovinyl)benzene as a light brown solid (1.87 g, 94% yield).

Reference： [1]Patent: WO2009/158426,2009,A1 .Location in patent: Page/Page column 92

42
[ 930-60-9 ]
[ 40137-29-9 ]
[ 1208222-33-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 206 - 208

43
[ 40137-29-9 ]
[ 141-97-9 ]
C₂₀H₂₅ClO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With piperidine; In ethanol; at 20℃; for 96h;	To a solution of commercial 4- chloro-2-methylbenzaldehyde (5.16 g) and ethyl acetoacetate (8.69 g) in ethanol (10 ml) piperidine (1 ml) was added with stirring at rt. The mixture was kept at rt for 4d. The precipitate was collected by suction filtration, washed with ethanol, and dried in vacuo to give 4.5 g of a light yellow solid (the bis-adduct of acetoacetate to the benzaldehyde). The powdered solid was added in portions to 40 % NaOH (50 g) with stirring. The resulting yellow slurry was stirred at reflux for 2 h. After cooling in an ice bath the mixture was acidified by portionwise addition of cone. HCI (30 ml) to give a yellow resinous precipitate. The aqueous layer was extracted with ethyl acetate, the organic layer dried (sodium sulphate), and filtered. After evaporation of the solvent a crude was obtained which was recrystallised from benzene to afford 3-(4-chloro-2-methylphenyl)glutaric acid (1.43 g). The suspension of finely divided 3-(4-chloro-2-methylphenyl)glutaric acid in acetyl chloride (4 ml) was heated to reflux with stirring for 1 h. Further acetyl chloride (15 ml) was added and reflux continued for another hour. Then the excess of acetyl chloride is removed by distillation, petrol ether (55 ml) is added to the residue, and the solution is kept in the refrigerator. The precipitate is isolated by suction filtration, washed with petrol ether, and dried in vacuo to give 3-(4-chloro-2-methylphenyl)glutaric anhydride (0.9 g) as colourless solid.

Reference： [1]Patent: WO2010/43711,2010,A1 .Location in patent: Page/Page column 78

44
[ 40137-29-9 ]
[ 1221962-39-5 ]

Reference： [1]Patent: US2012/46307,2012,A1

45
[ 67-56-1 ]
[ 40137-29-9 ]
[ 99585-12-3 ]

Reference： [1]RSC Advances,2013,vol. 3,p. 1695 - 1698

46
[ 40137-29-9 ]
[ 2393-23-9 ]
[ 64195-85-3 ]
[ 1441739-40-7 ]

Yield	Reaction Conditions	Operation in experiment
11 g	With acetic acid; at 120℃;	5-Methyl-2,4-dioxo-hexanoic acid ethyl ester (5.6 g, 36.4 mmol) was added to a solution of 4-methoxybenzyl amine (5 g, 36.4 mmol) in acetic acid (40 mL). The mixture was stirred for 10 min at rt. 4-Chloro-2-methylbenzaldehyde (6.77 g, 36.4 mmol) was added. The reaction mixture was heated to 120C, stirred at this temperature overnight, allowed to cool to rt and diluted with acetonitrile. The resulting precipitate was collected by vacuum filtration and dried to provide 1 1 g of the title compound. tR: 1.80 min (LC-MS 2); ESI-MS: 414 [M+H]+(LC-MS 2).

Reference： [1]Patent: WO2013/80141,2013,A1 .Location in patent: Page/Page column 111

47
5-methyl-2,4-dioxo-hexanoic acid ethyl ester sodium salt [ No CAS ]
[ 40137-29-9 ]
[ 2106-04-9 ]
[ 1441734-83-3 ]

Yield	Reaction Conditions	Operation in experiment
426 mg	With acetic acid; for 3h;Reflux;	A mixture of 3-chloro-2-fluoro-aniline (0.70 g, 4.8 mmol), <strong>[40137-29-9]4-chloro-2-methyl-benzaldehyde</strong> (0.74 g, 4.8 mmol) and the sodium salt of 5-methyl-2,4-dioxo-hexanoic acid ethyl ester (1.0 g, 4.8 mmol) in acetic acid (6 mL) was refluxed for 3 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2S04), filtered, and concentrated. The residue was purified by silica gel column chromatography (CH2CI2/MeOH, 1 :0? 9:1 ), followed by crystallization fromEtOAc/hexane, to provide 426 mg of the title compound. tR: 5.47 min (HPLC 1 ); ESI-MS: 422 [M+H]+(LC-MS 1 ).

Reference： [1]Patent: WO2013/80141,2013,A1 .Location in patent: Page/Page column 85; 86

48
[ 40137-29-9 ]
[ 1441741-52-1 ]

Reference： [1]Patent: WO2013/80141,2013,A1

49
[ 40137-29-9 ]
[ 1441745-28-3 ]

Reference： [1]Patent: WO2013/80141,2013,A1

50
[ 40137-29-9 ]
[ 1441747-84-7 ]

Reference： [1]Patent: WO2013/80141,2013,A1
[2]Patent: WO2014/115080,2014,A1

51
[ 40137-29-9 ]
[ 1441749-66-1 ]

Reference： [1]Patent: WO2013/80141,2013,A1

52
[ 40137-29-9 ]
[ 1441738-77-7 ]

Reference： [1]Patent: WO2013/80141,2013,A1

53
[ 40137-29-9 ]
[ 104-86-9 ]
[ 1438071-12-5 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 4729 - 4737

54
[ 40137-29-9 ]
[ 104-86-9 ]
C₁₅H₁₅Cl₂N [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃;	GSK2945 was synthesized as described previously (Trump et al., 2013). The reductiveamination of <strong>[40137-29-9]4-chloro-2-methylbenzaldehyde</strong> (1) with 4-chlorobenzylamine (2) andsodium triacetoxyborohydride gave secondary amine 2 (3).

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 4729 - 4737
[2]Drug Metabolism and Disposition,2018,vol. 46,p. 248 - 258

55
[ 40137-29-9 ]
[ 92406-50-3 ]
[ 24653-75-6 ]
[ 1616363-78-0 ]

Yield	Reaction Conditions	Operation in experiment
76%	With toluene-4-sulfonic acid; In acetonitrile; at 150℃; for 0.5h;Sealed tube; Microwave irradiation;	A mixture of 1-methyl-3-(2-pyridyl)pyrazol-5-amine (0.215 g, 1.23 mmol), <strong>[40137-29-9]4-chloro-2-methyl-benzaldehyde</strong> (0.1906 g, 1.23 mmol, Fluorochem), 1-sulfanylpropan-2-one (0.45 g, 4.93 mmol, Enamine), and p-toluenesulfonic acid (0.070 g, 0.37 mmol) in acetonitrile (3 mL) was heated, in a sealed microwave vessel, for about 30 min, at about 150 C., in a microwave. After cooling to rt the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (70 mL) and methanol (10 mL), and washed with 5% aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with water (40 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:4) to afford 4-(4-chloro-2-methyl-phenyl)-1,7-dimethyl-3-(2-pyridyl)-4,6-dihydropyrazolo[3,4-e][1,4]thiazepine (0.36 g, 0.94 mmol, 76%), as a yellow oil: LC-MS (Table 1, Method a) Rt=5.41 min, m/z 383 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) delta 2.36 (3H, s) 2.60 (3H, s) 3.16 (1H, d, J=16.3 Hz) 3.29 (1H, dd, J=16.3, 1.5 Hz) 4.03 (3H, s) 6.50 (1H, d, J=8.2 Hz) 6.60 (1H, d, J=1.5 Hz) 6.88 (1H, dd, J=8.2, 2.1 Hz) 7.01 (1H, ddd, J=7.4, 4.9, 1.1 Hz) 7.16 (1H, d, J=2.1 Hz) 7.56 (1H, td, J=7.8, 1.7 Hz) 7.86 (1H, dt, J=8.1, 1.0 Hz) 8.35 (1H, ddd, J=4.8, 1.8, 0.8 Hz).

Reference： [1]Patent: US2014/179676,2014,A1 .Location in patent: Paragraph 0943

56
[ 40137-29-9 ]
[ 68-11-1 ]
[ 92406-50-3 ]
[ 1616360-36-1 ]

Yield	Reaction Conditions	Operation in experiment
48%	In acetonitrile; at 150℃; for 0.333333h;Sealed tube; Microwave irradiation;	A mixture of 2-methyl-5-(2-pyridyl)pyrazol-3-amine (1.1 g, 6.3 mmol, Example No.2, step B), <strong>[40137-29-9]4-chloro-2-methylbenzaldehyde</strong> (1.0 g, 6.5 mmol, Fluorochem), and thioglycolic acid (2.4 g, 26 mmol) in acetonitrile (20 mL) was heated, in a sealed microwave vessel, for about 20 min, at about 150 C., in a microwave. After cooling to rt the precipitated solid was collected by filtration and washed with acetonitrile (2 mL) to afford 4-(4-chloro-2-methyl-phenyl)-1-methyl-3-(2-pyridyl)-4,8-dihydropyrazolo[3,4-e][1,4]thiazepin-7-one (1.16 g, 3.0 mmol, 48%), which was used as such: 1H-NMR (CDCl3, Bruker 400 MHz) delta 2.50 (3H, s); 3.07 (1H, d, J=12 Hz); 3.50 (1H, d, J=12 Hz); 3.84 (3H, s); 6.59 (1H, s); 6.86 (1H, d, J=8 Hz); 6.98 (1H, m); 7.1-7.2 (2H, m); 7.68 (1H, m), 7.76 (1H, d, J=6 Hz); 8.4 (1H, s); 10.2 (1H, s).

Reference： [1]Patent: US2014/179676,2014,A1 .Location in patent: Paragraph 0809; 0902

57
[ 40137-29-9 ]
[ 118430-74-3 ]
[ 4695-31-2 ]
[ 1616360-80-5 ]

Yield	Reaction Conditions	Operation in experiment
15%	at 80 - 150℃; for 25h;Sealed tube; Microwave irradiation;	A mixture of 3-cyclopropyl-1-methyl-1H-pyrazol-5-amine (3 g, 22 mmol, Fluorochem), <strong>[40137-29-9]4-chloro-2-methylbenzaldehyde</strong> (3.1 g, 22 mmol, Fluorochem), and 2-mercapto-2-methylpropanoic acid (3.5 g, 33 mmol, Chemwish) was heated, in a sealed microwave vessel, for about 60 min, at about 80 C. Subsequently, the reaction mixture was heated, for about 24 h, at about 150 C. After cooling to rt, acetonitrile (20 mL) was added and the reaction mixture was stirred for about 2 h, at about 40 C. After cooling to about 0 C., the precipitated solid was collected by filtration and washed with acetonitrile (2 mL) to afford 4-(4-chloro-2-methyl-phenyl)-3-cyclopropyl-1,6,6-trimethyl-4,8-dihydropyrazolo[3,4-e][1,4]thiazepin-7-one as white solid (1.25 g, 3.3 mmol, 15%). 1H-NMR (CDCl3, Bruker 400 MHz) delta 0.30-0.39 (1H, s); 0.46-0.67 (3H, m); 0.83-0.93 (1H, m); 1.50 (3H, s); 1.66 (3H, s); 2.48 (3H, s); 3.75 (3H, s); 5.58 (1H, s); 7.09 (1H, dd, J=8.5, 2.5 Hz); 7.14 (1H, d, J=2.5 Hz); 7.21 (1H, d, J=8.5 Hz); H, m); 8.65 (1H, s).

Reference： [1]Patent: US2014/179676,2014,A1 .Location in patent: Paragraph 0891

58
[ 40137-29-9 ]
[ 1616360-37-2 ]

Reference： [1]Patent: US2014/179676,2014,A1

59
[ 40137-29-9 ]
[ 1616363-61-1 ]

Reference： [1]Patent: US2014/179676,2014,A1

60
[ 40137-29-9 ]
[ 1616363-62-2 ]
[ 1616363-63-3 ]

Reference： [1]Patent: US2014/179676,2014,A1

61
[ 40137-29-9 ]
[ 1616363-64-4 ]
[ 1616363-65-5 ]

Reference： [1]Patent: US2014/179676,2014,A1

62
[ 3524-32-1 ]
[ 40137-29-9 ]
[ 1616363-91-7 ]
[ 1616363-92-8 ]

Yield	Reaction Conditions	Operation in experiment
37%	With toluene-4-sulfonic acid; In acetonitrile; at 90℃; for 18h;	To a solution of 1,3-dimethyl-1H-pyrazol-5-amine (0.58 g, 5.22 mmol, Oakwood Chemicals), <strong>[40137-29-9]4-chloro-2-methylbenzaldehyde</strong> (0.81 g, 5.22 mmol, Ark Pharm) and p-TSA (0.10 g, 0.52 mmol) in acetonitrile (10.5 mL) was added ethyl 3-mercapto-4-oxopentanoate (1.74 g, 9.87 mmol) and stirred at about 90 C. for about 18 h. The reaction mixture was cooled to ambient temperature and saturated NaHCO3 (15 mL) and DCM (20 mL) were added. The organic layer was separated and the aqueous layer was back extracted using DCM (20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, EtOAc/heptane 100:0 to 0:50) to afford ethyl 2-(4-(4-chloro-2-methylphenyl)-1,3,7-trimethyl-4,6-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-6-yl)acetate (0.85 g, 1.97 mmol, 37%). LC-MS (Table 1, Method g) Rt=2.66, 2.63 min, m/z 406 (M+H)+.

Reference： [1]Patent: US2014/179676,2014,A1 .Location in patent: Paragraph 0965

63
[ 40137-29-9 ]
[ 1620583-20-1 ]
5-[(4-chloro-2-methyl-phenyl)hydroxy-methyl]-1-isopropyl-2-(2-methoxy-phenyl)-1H-imidazole-4-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		Step 2.4: 5-r(4-Chloro-2-methyl-phenyl)-hvdroxy-methyll-1 -isopropyl-2-(2-methoxy- phenyl)-1 H-imidazole-4-carboxylic acid methyl ester A solution of the product of step 2.5 (450 mg, 1.640 mmol) in 15 ml THF was cooled down to -78C under argon. LDA (2.73 ml, 4.92 mmol) was slowly added to the reaction mixture and stirred at -78C for 1.5 h. A solution of <strong>[40137-29-9]4-chloro-2-methylbenzaldehyde</strong> (761 mg, 4.92 mmol) in 3 ml THF was slowly added and stirred for 1 hour at -78C. Then reaction mixture was slowly warmed up and quenched with AcOH at -30C. Then the mixture was diluted with EtOAc and washed with saturated aqueous NaHC03 and brine. The water phase was back extracted with EtOAc. The combined organic phases were evaporated and purified by chromatography (silicagel, heptane, heptane-EtOAc 7:3) to afford 580 mg (1.285 mmol, 78% yield) of the title compound. LCMS: (M+H) = 429; tR = 1 .17 min (LC-MS 1 ). HPLC: tR = 4.28 min (HPLC 2).

Reference： [1]Patent: WO2014/115077,2014,A1 .Location in patent: Page/Page column 58; 59

64
[ 40137-29-9 ]
[ 1620582-86-6 ]