[ CAS No. 1123-56-4 ] {[proInfo.proName]}

Name: 1123-56-4|2,6-Dimethylbenzaldehyde|95%
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Product Citations

Selective and Cell-Active PBRM1 Bromodomain Inhibitors Discovered through NMR Fragment Screening

Shifali Shishodia ; Raymundo Nuñez ; Brayden P. Strohmier , et al. J. Med. Chem.,2022,65(20):13714-13735. DOI: 10.1021/acs.jmedchem.2c00864 PubMed ID: 36227159

Abstract: PBRM1 is a subunit of the PBAF chromatin remodeling complex that uniquely contains six bromodomains. PBRM1 can operate as a tumor suppressor or tumor promoter. PBRM1 is a tumor promoter in prostate cancer, contributing to migratory and immunosuppressive phenotypes. Selective chemical probes targeting PBRM1 bromodomains are desired to elucidate the association between aberrant PBRM1 chromatin binding and cancer pathogenesis and the contributions of PBRM1 to immunotherapy. Previous PBRM1 inhibitors unselectively bind SMARCA2 and SMARCA4 bromodomains with nanomolar potency. We used our protein-detected NMR screening pipeline to screen 1968 fragments against the second PBRM1 bromodomain, identifying 17 hits with Kd values from 45 μM to >2 mM. Structure–activity relationship studies on the tightest-binding hit resulted in nanomolar inhibitors with selectivity for PBRM1 over SMARCA2 and SMARCA4. These chemical probes inhibit the association of full-length PBRM1 to acetylated histone peptides and selectively inhibit growth of a PBRM1-dependent prostate cancer cell line.

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Product Details of [ 1123-56-4 ]

CAS No. :	1123-56-4	MDL No. :	MFCD00128003
Formula :	C₉H₁₀O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QOJQBWSZHCKOLL-UHFFFAOYSA-N
M.W :	134.18	Pubchem ID :	583841
Synonyms :

Calculated chemistry of [ 1123-56-4 ] Expand+

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	41.76
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) :	-5.62 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.84
Log Po/w (XLOGP3) :	2.11
Log Po/w (WLOGP) :	2.12
Log Po/w (MLOGP) :	2.1
Log Po/w (SILICOS-IT) :	2.92
Consensus Log Po/w :	2.22

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.38
Solubility :	0.56 mg/ml ; 0.00418 mol/l
Class :	Soluble
Log S (Ali) :	-2.1
Solubility :	1.07 mg/ml ; 0.00796 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.09
Solubility :	0.11 mg/ml ; 0.000818 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 1123-56-4 ]

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

Application In Synthesis of [ 1123-56-4 ]

* 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 [ 1123-56-4 ]
Downstream synthetic route of [ 1123-56-4 ]

[ 1123-56-4 ] Synthesis Path-Upstream 1~4

1
[ 1123-56-4 ]
[ 2142-76-9 ]

Reference： [1] Chemistry - A European Journal, 2006, vol. 12, # 3, p. 949 - 955

2
[ 1123-56-4 ]
[ 5402-60-8 ]

Reference： [1] Journal of Medicinal Chemistry, 1981, vol. 24, # 4, p. 382 - 389

3
[ 1123-56-4 ]
[ 62285-58-9 ]

Reference： [1] Advanced Synthesis and Catalysis, 2011, vol. 353, # 8, p. 1279 - 1284
[2] Catalysis Communications, 2016, vol. 78, p. 52 - 54
[3] Journal of Medicinal Chemistry, 1981, vol. 24, # 4, p. 382 - 389
[4] Organometallics, 2016, vol. 35, # 17, p. 2840 - 2849
[5] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 12, p. 3145 - 3157

4
[ 608-28-6 ]
[ 201230-82-2 ]
[ 62285-58-9 ]
[ 108-38-3 ]
[ 1123-56-4 ]

Reference： [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 32, p. 10362 - 10367[2] Angew. Chem., 2018, vol. 130, # 32, p. 10519 - 10524,6

[ 1123-56-4 ] Synthesis Path-Downstream 1~93

1
[ 2039-90-9 ]
[ 78924-72-8 ]
[ 1123-56-4 ]

Yield	Reaction Conditions	Operation in experiment
1: 64% 2: 6%	With 4-methylpyridine-1-oxide; oxochromium(V) complex of dichloro tetramethylsalen IIf In acetonitrile at 25℃;
	With pyridine N-oxide; oxochromium(V) complex of dichloro tetramethylsalen IIf In acetonitrile at 23℃; effect of donor ligands on the rate of further olefins; ligand-induced cleavage of olefins by oxochromium(V); ⁽¹⁸⁾O-labeling studies of oxochromium(V);

Reference： [1]Samsel, E. G.; Srinivasan, K.; Kochi, J. K. [Journal of the American Chemical Society, 1985, vol. 107, # 25, p. 7606 - 7617]
[2]Samsel, E. G.; Srinivasan, K.; Kochi, J. K. [Journal of the American Chemical Society, 1985, vol. 107, # 25, p. 7606 - 7617]

2
[ 2039-90-9 ]
2-Chloro-1-(2,6-dimethyl-phenyl)-ethanone [ No CAS ]
2-((Z)-2-Chloro-vinyl)-1,3-dimethyl-benzene [ No CAS ]
2-((E)-2-Chloro-vinyl)-1,3-dimethyl-benzene [ No CAS ]
[ 1123-56-4 ]

Yield	Reaction Conditions	Operation in experiment
1: 46.3 % Chromat. 2: 1.5 % Chromat. 3: 11.5 % Chromat. 4: 1.5 % Chromat.	With chlorine dioxide In tetrachloromethane at 52 - 54℃; for 2h; Further byproducts given. Title compound not separated from byproducts;
1: 46.3 % Chromat. 2: 1.5 % Chromat. 3: 1.5 % Chromat. 4: 11.5 % Chromat.	With chlorine dioxide In tetrachloromethane at 52 - 54℃; for 2h; Further byproducts given;

Reference： [1]Kwiecien, Halina; Jalowiczor, Jozef [Polish Journal of Chemistry, 1986, vol. 60, # 7-12, p. 811 - 824]
[2]Kwiecien, Halina; Jalowiczor, Jozef [Polish Journal of Chemistry, 1986, vol. 60, # 7-12, p. 811 - 824]

3
[ 1123-56-4 ]
[ 62285-58-9 ]

Yield	Reaction Conditions	Operation in experiment
	With methanol; sodium tetrahydroborate; for 1h;Cooling with ice;	General procedure: To a solution of compound 7a (1.06 g, 10 mmol) in methanol(10 mL) was added NaBH4 (0.57 g, 15 mmol). After stirring for 1 hwhile cooled with an ice-water bath, methanol was evaporatedand the residue was dissolved in EtOAc (100 mL). The organic layerwas washed with water (3 100 mL) and brine (3 100 mL), anddried over MgSO4 overnight. EtOAc was evaporated to give 8a ascolorless oil (2.01 g, yield: 94%). ESI-MS m/z 109.4 [M+H]+. The crude product was used directly in the next reaction without furtherpurification. Compounds 8b-8u, 8aa-8ff, 10v-10w, 17a-17b and 22a-22hwere prepared using the same procedure described above

Reference： [1]Advanced Synthesis and Catalysis,2011,vol. 353,p. 1279 - 1284
[2]Catalysis Communications,2016,vol. 78,p. 52 - 54
[3]Journal of Medicinal Chemistry,1981,vol. 24,p. 382 - 389
[4]Organometallics,2016,vol. 35,p. 2840 - 2849
[5]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3145 - 3157

4
[ 1123-56-4 ]
[ 15855-34-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	With hydroxylamine hydrochloride; sodium hydroxide; In ethanol; at 90℃;	To a 500 mL round-bottom fla;;;k was added NI-bOH hydrochloride (13.388 g, 192.6610 mmol, 1.3 equiv.), water (70 mL), sodium hydroxide (7 761 g, 194.03 mmol, 1.30 equiv.), asolution of <strong>[1123-56-4]2,6-dimethylbenzaldehyde</strong> ll6a (20 g, 149.06 mmol, 1.0 equiv.) in ethanol (60mL), and ethanol (100 mL). The resulting mixture was stirred at 90C overnight. EtOH wasremoved under vacuum Tiw solids precipitated were collected by filtration, dried lmdervacuum to give N-[(2,6-dimethylphenyl)methylidene]hydroxylamine ll6b(18.89 g, 85%) as15 a white solid.

Reference： [1]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 245
[2]Chemical and pharmaceutical bulletin,1984,vol. 32,p. 3830 - 3839
[3]Journal of Medicinal Chemistry,2011,vol. 54,p. 765 - 781
[4]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 2940 - 2949
[5]ChemMedChem,2015,vol. 10,p. 1184 - 1199
[6]Journal of Organic Chemistry,2019,vol. 84,p. 5803 - 5812

5
[ 87-41-2 ]
[ 1123-56-4 ]
[ 13935-97-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium methylate; In methanol; for 2h;Reflux;	General procedure: A solution of sodium methoxide in methanol (28%, 2.196 g, 11.4 mmol) was added to a suspension of benzaldehyde (307 mg, 2.89 mmol) and phthalide (387 mg, 2.89 mmol) in ethyl propionate (1.2 mL) at 30 C, and the mixture was heated under reflux for 1 h. The reaction mixture was diluted with methanol and, was further heated for 1 h. After concentration in vacuo, water was added to the residue, and was washed with diethyl ether. After acidified with acetic acid, the suspension was stirred for 15 min. The product was collected by filtration, washed with water, and dried in vacuo to afford 12 (331 mg, 52%) as colorless powder.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 102,p. 310 - 319
[2]Journal of the Chemical Society. Perkin transactions II,1994,p. 1247 - 1252
[3]Recueil des Travaux Chimiques des Pays-Bas,1966,vol. 85,p. 1259 - 1262

6
[ 576-22-7 ]
[ 68-12-2 ]
[ 1123-56-4 ]

Yield	Reaction Conditions	Operation in experiment
99%		Add 2-bromo-m-xylene (18.06 mL, 135.1 mmol) and 350 mL of THF to a two neck flask with complete removal of moisture through flame dry and stir. Make a dry ice bath at -78 C and slowly drop 54.04 mL of n-BuLi (2.5M in Hx). Continue maintain at 78 degree C. After 30 minutes, slowly add DMF. Remove the ice bath and let it react for about 1 hour. Upon completion of the reaction, the reaction mixture was extracted with CH2Cl2 and the following reaction was carried out without further purification (yield: 99%)

Reference： [1]Patent: KR2018/50795,2018,A .Location in patent: Paragraph 0036; 0043-0047; 0086-0090; 0134-0138; 0182-0185
[2]Tetrahedron Letters,2008,vol. 49,p. 5024 - 5027
[3]Chemical Communications,2019,vol. 55,p. 4917 - 4920
[4]Tetrahedron Asymmetry,1995,vol. 6,p. 83 - 86

7
[ 867-13-0 ]
[ 1123-56-4 ]
[ 527759-23-5 ]

Reference： [1]Synthetic Communications,2007,vol. 37,p. 965 - 976
[2]Organic Letters,2018,vol. 20,p. 3819 - 3823
[3]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 1185 - 1187
[4]Tetrahedron Asymmetry,1995,vol. 6,p. 83 - 86

8
[ 75-52-5 ]
[ 1123-56-4 ]
2-nitro-1-(2,6-dimethylphenyl)ethanol [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 4298 - 4303
[2]Organic Letters,2008,vol. 10,p. 1831 - 1834

9
[ 62285-58-9 ]
[ 1123-56-4 ]

Yield	Reaction Conditions	Operation in experiment
		A. 2,6-Dimethyl benzaldehyde Oxidation of 2,6-dimethyl benzyl alcohol by standard Swern oxidation procedure (oxalyl chloride/DMSO) provided the desired compound. 300 MHz 1 H NMR (CDCl3) delta2.62 (s, 6H), 7.10 (m, 2H), 7.33 (t, J=7 Hz, 1H), 10.63 (s, 1H), Mass spectrum: (M+H)+ =135.

Reference： [1]ChemCatChem,2015,vol. 7,p. 2585 - 2589
[2]Journal of Medicinal Chemistry,2000,vol. 43,p. 1094 - 1108
[3]Patent: US5914332,1999,A
[4]Patent: EP1170289,2002,A2 .Location in patent: Page 51

10
[ 65854-91-3 ]
[ 1123-56-4 ]
N-{4-chloro-2-[(2,6-dimethylphenyl)hydroxymethyl]phenyl}-2,2-dimethylpropionamide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2003,vol. 68,p. 92 - 103

11
[ 1666-17-7 ]
[ 1123-56-4 ]
[ 67456-93-3 ]
1,3-dimethyl-2-[(Z)-2-phenyl-1-ethenyl]benzene [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 6034 - 6035

12
[ 80-65-9 ]
[ 1123-56-4 ]
3-[1-(2,6-Dimethyl-phenyl)-meth-(E)-ylidene]-amino}-oxazolidin-2-one [ No CAS ]

Reference： [1]Organic Letters,2005,vol. 7,p. 2767 - 2770

13
[ 42201-71-8 ]
[ 1123-56-4 ]
methyl 4-(2,6-dimethylphenyl)-4-trimethylsilyloxy-2-butynoate [ No CAS ]

Reference： [1]Chemistry - A European Journal,2005,vol. 11,p. 5408 - 5418

14
[ 1779-49-3 ]
[ 1123-56-4 ]
[ 2039-90-9 ]

Yield	Reaction Conditions	Operation in experiment
40%	Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In diethyl ether; hexane for 1.5h; Stage #2: 2,6-dimethylbenzaldehyde In diethyl ether; hexane Heating;

Reference： [1]Wright, Joseph A.; Gaunt, Matthew J.; Spencer, Jonathan B. [Chemistry - A European Journal, 2006, vol. 12, # 3, p. 949 - 955]

15
[ 625-82-1 ]
[ 1123-56-4 ]
4,4-difluoro-8-(2,6-dimethylphenyl)-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2007,vol. 129,p. 5597 - 5604

16
[ 107-11-9 ]
[ 1123-56-4 ]
N-allyl-(2,6-dimethyl-benzyl)-amine [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2007,vol. 129,p. 11336 - 11337

17
[ 1123-56-4 ]
[ 2142-76-9 ]

Reference： [1]Chemistry - A European Journal,2006,vol. 12,p. 949 - 955

18
[ 1123-56-4 ]
[ 6575-13-9 ]

Reference： [1]Chemical and pharmaceutical bulletin,1984,vol. 32,p. 3830 - 3839
[2]Journal of Organic Chemistry,1980,vol. 45,p. 4653 - 4659
[3]Journal of Organic Chemistry,2019,vol. 84,p. 5803 - 5812

19
4-amino-6-bromo-2-(N,N-dimethylamino)-1-methyl-1H-benzimidazole [ No CAS ]
[ 1123-56-4 ]
6-bromo-2-(N,N-dimethylamino)-4-(2,6-dimethyl-benzylamino)-1-methyl-1H-benzimidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		To a solution of 0.46 G (1.7 MMOL) 4-AMINO-6-BROMO-2-(N, N-DIMETHYLAMINO)-1-METHYL-1H-BENZIMIDAZOLE and 0.3 G (2.2 MMOL) 2, 6-dimethyl-benzaldehyde in 10 ml dichloromethane and 2.5 ml acetic acid were added 0.6 G (2.8 MMOL) sodium triacetoxyborohydride. After 1 h at ambient temperature, saturated aqueous sodium hydrogen carbonate was added and stirring was continued for 30 min. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate and crystallization from ethyl ace- tate/n-heptane yielded 0.46 G (70 %) of the title compound as a colourless solid (m. p. 157-158 C).

Reference： [1]Patent: WO2004/54984,2004,A1 .Location in patent: Page 36

20
[ 245748-61-2 ]
[ 1123-56-4 ]
[ 251655-66-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium cyanoborohydride; In methanol; dichloromethane; acetic acid; ethyl acetate;	To a stirred solution of 1-(4-aminophenyl)-3-(3-pyridyl)-5-cyanopyrazole (130 mg, 0.5 mmol) and <strong>[1123-56-4]2,6-dimethylbenzaldehyde</strong> (0.9 g) in acetic acid (2 mL) and MeOH (5 mL) at room temperature was added sodium cyanoborohydride (79 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 18 hr and then concentrated under a stream of nitrogen, diluted with water, extracted into ethyl acetate, washed with sodium bicarbonate solution, water and dried (MgSO4). The residue obtained on concentration was flash chromatographed on silica gel (elution with a gradient of 15-25% EtOAc in CH2Cl2) providing the title compound (142 mg, 75%). NMR (CDCl3, 400 MHz): 9.1 (s, 1H); 8.7 (br, 1H); 8.3 (d, 1H); 7.6 (d, 2H), 7.5 (m, 1H), 7.35 (s, 1H); 7.2 (m, 1H), 7.1 (overlapping m, 2H), 6.8 (d, 2H), 4.3 (s, 2H), 2.4 (s, 6H).

Reference： [1]Patent: US6506747,2003,B1

21
[ 6575-13-9 ]
[ 1123-56-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; diisobutylaluminium hydride; In tetrahydrofuran;	Example 35 Synthesis of [4-(5-Cyano-3-pyridin-3-yl-pyrazol-1-yl)phenyl]-(2,6-dimethylbenzyl)-amine To a stirred solution of <strong>[6575-13-9]<strong>[6575-13-9]2,6-dimethylbenzonitril</strong>e</strong> (1 g, 7.6 mmol) in THF (15 mL) under argon at 0 C. a solution of DIBAL (1 M in THF, 8 mL, 8 mmol) was added dropwise over 5 minutes. After 3 hr at 0 C., the reaction mixture was brought to room temperature and stirred overnight. The reaction was quenched with 5% sulfuric acid at 0 C., extracted with ether, washed with brine and dried (MgSO4). Concentration provided 2,6-dimethylbenzaldehyde (0.9 g) which was used without further purification.

Reference： [1]Patent: US6506747,2003,B1

22
[ 927887-41-0 ]
[ 1123-56-4 ]
7-(2,6-dimethylbenzyl-amino)-2-methyl-3H-benzimidazole-5-carboxylic acid hexadeuteriodimethylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%		To a solution of 4.5 g (20 mmol) 7-amino-2-methyl-3H-benzimidazole-5-carboxylic acid hexadeuterio- dimethylamide and 3.5 g (26.1 mmol) <strong>[1123-56-4]2,6-dimethylbenzaldehyde</strong> in 60 ml dichloromethane and 11 ml acetic acid were added 10.5 g (50 mmol) sodium triacetoxyborohydride in small portions. After 30 min, the reaction mixture is carefully poured into saturated aqueous sodium hydrogencarbonate and extracted with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethyl acetate yielded 6.7 g (97 %) of the title compound as a colourless solid (m.p. 224-225 C).

Reference： [1]Patent: WO2007/23135,2007,A1 .Location in patent: Page/Page column 48

23
[ 10602-01-4 ]
[ 1123-56-4 ]
[ 691905-13-2 ]

Yield	Reaction Conditions	Operation in experiment
73%		Reference Example 176 (2,6-dimethylphenyl)[4-(1,3-dioxolan-2-yl)phenyl]methanol Iodine (10 mg) was added to a mixture of magnesium (1.20 g) and tetrahydrofuran (50 mL) with vigorous stirring and 2-(4-bromophenyl)-1,3-dioxolane (10.0 g) was added dropwise at room temperature. After the completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hr and a solution of <strong>[1123-56-4]2,6-dimethylbenzaldehyde</strong> (5.0 g) in tetrahydrofuran (20 mL) was added dropwise at 0C. After the completion of the dropwise addition, the temperature of the reaction mixture was allowed to return to room temperature and the mixture was further stirred for 1 hr. The reaction mixture was poured into saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated and the residue was purified by silica gel column chromatography. The residue was developed with ethyl acetate-hexane (gradient of 1:9 to 7:3 by volume ratio) to give the title compound (9.10 g, yield 73%) as a yellow oil. 1H NMR (300 MHz, Chloroform-D) delta: 2.14 - 2.23 (1 H, m), 2.26 (6 H, s), 3.97 - 4.19 (4 H, m), 5.79 (1 H, s), 6.35 (1 H, d, J=4.1 Hz), 7.03 (2 H, d, J=7.5 Hz), 7.05 - 7.2 (1 H, m), 7.29 (2 H, d, J=7.7 Hz), 7.35 - 7.45 (2 H, m).

Reference： [1]Patent: EP1559422,2005,A1 .Location in patent: Page/Page column 131

24
[ 1123-56-4 ]
[ 98-80-6 ]
[ 21945-72-2 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 4076 - 4086

25
[ 33577-16-1 ]
[ 1123-56-4 ]
[ 1160608-86-5 ]

Yield	Reaction Conditions	Operation in experiment
68%	With N-benzyl-trimethylammonium hydroxide; In 1,4-dioxane; at 80℃; for 16h;	Intermediate 36: 2-(2-Methanesulfinyl-2-methylsulfanyl-vinyl)-1,3-dimethyl-benzene To a solution of 2,6-dimethyl-benzaldehyde (14.6 g, 109 mmol) in 1,4-dioxane (24.7 mL) was added methyl methylsulfinylmethyl sulfide (13.5 g, 109 mmol) followed by benzyltrimethylammonium hydroxide (9.10 g, 54.4 mmol). The resulting mixture was heated at 80 C. After 16 h, the mixture was cooled to rt and concentrated. The resulting residue was purified by FCC to afford a yellow oil (17.9 g, 68%). MS (ESI): mass calcd. for C12H16OS2, 240.1; m/z found, 241.1 [M+H]+. 1H NMR (CDCl3): 7.71 (s, 1H), 7.19-7.13 (m, 1H), 7.07 (d, J=7.5 Hz, 2H), 2.82 (s, 3H), 2.24 (s, 6H), 2.06 (s, 3H).

Reference： [1]Patent: US2009/156599,2009,A1 .Location in patent: Page/Page column 17

26
[ 70-55-3 ]
[ 1123-56-4 ]
[ 1010721-72-8 ]

Yield	Reaction Conditions	Operation in experiment
68%	With boron trifluoride diethyl etherate; In toluene; for 12h;Reflux; Inert atmosphere;	General procedure: To a mixture of p-toluenesulfonamide (10.0 mmol) and aldehyde (10.0 mmol) in toluene (20 mL) was slowly added boron trifluoride diethyl ether complex (0.80 mmol, 0.098 mL) at reflux under argon and the mixture was stirred for 12 h. After cooling to room temperature, the mixture was quenched with 1 N NaOH aq and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was then recrystallized (EtOAc/hexane) to give N-tosylarylimines 1.

Reference： [1]Tetrahedron Asymmetry,2011,vol. 22,p. 1225 - 1230
[2]Journal of the American Chemical Society,2009,vol. 131,p. 12904 - 12905

27
[ 1123-56-4 ]
[ 581078-85-5 ]
[ 1241906-83-1 ]

Yield	Reaction Conditions	Operation in experiment
25%	With potassium hydroxide; In methanol; water; at 65℃;	General procedure: Azaaurones were obtained by the condensation of indolinone A (Scheme 1) and substitutedbenzaldehydes [23]. Indolinone A was dissolved in MeOH (10 mL/mmol) and treated with KOH(50% in H2O, 1 mL/mmol). The solution was stirred at room temperature and allowed to reach 65 C progressively. The reaction was quenched when TLC indicated no reaction progression (3 to 24h). The solution was acidified by adding HCl (30 mL, 2 N), evaporated, and the crude was dissolvedin H2O and extracted with ethyl acetate. The organic solution was separated, dried over Na2SO4, and concentrated. The crude mixture was purified by flash chromatography over silica gel, eluted witha mixture of ethyl acetate:cyclohexane (1:2) to aord pure azaaurones. The synthesized compoundswere isolated in 96-98% pure form as evidenced by elemental analysis. For each azaaurone, carbon,hydrogen, and nitrogen atoms were analyzed and were found in nearly full (96-98%) agreementwith the expected values. The compounds were fully characterized by 1H NMR, 13C NMR, andhigh-resolution mass spectrometry (HRMS) (data shown in Supplementary Materials, Table S5).

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 5724 - 5731
[2]Molecules,2020,vol. 25

28
[ 109-77-3 ]
[ 1123-56-4 ]
[ 771575-93-0 ]

Yield	Reaction Conditions	Operation in experiment
43%	With piperidine; In ethanol; for 0.166667h;	General procedure: 1 equivalent of 2-methylbenzaldehyde (3.573 g, 29.7 mmol) and anexcess of malononitrile (2.13 g, 32.2 mmol) were added to ~80 ml ofethanol (100%) in a 100 ml beaker along with a stir bar. The reagentsand solvent were stirred until they became uniform, at which time 1drop of piperidine was added. After stirring for 10 min, the stir bar wasremoved, and the beaker was covered with parafilm and set aside for the night. White crystals began to form within two hours of the completionof the reaction. The white crystals were collected the followingday, washed with ethanol (95%), and weighed.

Reference： [1]Heterocycles,2011,vol. 83,p. 371 - 383
[2]Journal of Magnetism and Magnetic Materials,2020,vol. 497
[3]Russian Journal of General Chemistry,2016,vol. 86,p. 1330 - 1338
Zh. Obshch. Khim.,2016,vol. 86,p. 1000 - 1009,10

29
[ 825-55-8 ]
[ 1123-56-4 ]
[ 1313735-36-2 ]

Yield	Reaction Conditions	Operation in experiment
40%		(Example 6) 25 ml of a tetrahydrofuran solution of 1.0 g of phenylthiophene was cooled to -78 C, and 2.6 ml (2.6 M) of n-butyllithium was slowly dropped thereto, and stirred at the same temperature for 2 hours. Thereafter, 0.65 g of <strong>[1123-56-4]2,6-dimethylbenzaldehyde</strong> was added thereto, and stirred for 12 hours while the temperature was being slowly raised to 25 C. After the confirmation of the degree of reaction progress by TLC, the reaction was terminated with anammonium chloride aqueous solution, and an organic phase was extracted with ethyl acetate.[0087] After the obtained organic phase was dried with anhydrous magnesium sulfate, the organic phase was concentrated and purified by column chromatography. 5 g of manganese dioxide was added to 30 ml of a chloroform solution of the obtained intermediate compound, and the mixture was stirred at 25 C for 12 hours. After the confirmation of the degree of reaction progress by TLC, the manganese dioxide was filtered, and 0.57 g (yield: 40%) of Product 6 shown below was obtained as a white crystal by recrystallization. The structure of Product 6 was confirmed by 1HNMR. 1H-NMR (CDC13; TMS) : delta 2.24 (s, 6H) , 7.08 (d, 2H) , 7.22- 7.29 (m, 3H) , 7.37-7.42 (m, 3H) , 7.66 (d, 2H)

Reference： [1]Patent: WO2011/81078,2011,A1 .Location in patent: Page/Page column 26-27

30
[ 10485-09-3 ]
[ 1123-56-4 ]
[ 1335329-00-4 ]

Yield	Reaction Conditions	Operation in experiment
40%		(Comparative Example 3) 1.2 ml of a tetrahydrofuran solution of 0.25 g of magnesium was cooled to 0C, and 5.0 ml of a tetrahydrofuran solution of 1.0 g of 2-bromoindene was slowly dropped thereto.After the dropping, the mixture was stirred at the same temperature for 1 hour, and 0.57 g of 2,6- dimethylbenzaldehyde was added thereto, and stirred for 12 hours while the temperature was being raised to 25C.After the confirmation of the degree of reaction progress by TLC, the reaction was terminated with an ammonium chloride aqueous solution, and an organic phase was extracted with ethyl acetate.[0132] After the obtained organic phase was dried with anhydrous magnesium sulfate, the organic phase was concentrated and purified by column chromatography. Then, 5 g of manganese dioxide was added to 30 ml of a chloroform solution of the obtained intermediate compound, and the mixture was stirred at 25 C for 12 hours. After the confirmation of the degree of reaction progress by TLC, the manganese dioxide was filtered, and 0.42 g (yield: 40%) of Comparative Product 3 shown below was obtained by recrystallization. Thestructure of Comparative Product 3 was confirmed by 1HNMR. 1H-NMR (CDC13; TMS) : delta 2.21 (s, 6H) , 3.85 (s, 2H) , 7.07 (d, 2H) , 7.20-7.26 (m, 2H) , 7.33-7.41 (m, 2H) , 7.47 (d, 1H) , 7.58 (d, 1H)

Reference： [1]Patent: WO2011/81078,2011,A1 .Location in patent: Page/Page column 36

31
[ 1352211-40-5 ]
[ 1123-56-4 ]
[ 1352210-69-5 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 414 - 417
[2]Helvetica Chimica Acta,2012,vol. 95,p. 1773 - 1789,17

32
[ 1066-54-2 ]
[ 1123-56-4 ]
[ 1370519-92-8 ]

Yield	Reaction Conditions	Operation in experiment
93.3%		n-BuLi (2.5 M in hexane) (1.5 eq., 16.2 mmol, 6.5 ml) was added to a solution of trimethylsilyl acetylene (1.5 eq., 16.2 mmol, 2.3 ml) in 45 ml of dry THF at -90 C. After addition, the reaction mixture was warmed up till room temperature and stirred for 30 mi. <strong>[1123-56-4]2,6-dimethylbenzaldehyde</strong> (1 eq., 1.46 g, 10.8 mmol) in dry THF (10 ml) was added and the resulting mixture was stirred for 1 h at -90 C and allowed to warm up to room temperature for 20 h. The crude mixture was quenched using 20 ml 1 N HCI and diluted with diethyl ether. The organic phase was washed with water and the aqueous phase was extracted twice with diethyl ether, thereafter the ether fractions were combined and dried with anhydrous Mg504. Removal of Mg504 by filtration followed by purification, using flash column chromatography (silica gel, n-Hexane/EtOAc = 15/1) a yellow oil was obtained; 2.34g (yield: 93.3%).1H NMR (300 MHz, CDCI3, TMS): 67.11 (t, 1H), 7.03 (d, 2H), 5.90 (s, 1H), 2.53 (s, 6H), 0.17 (tetra, 9H);13C NMR (75 MHz, CDCI3): 6137.01, 136.35, 129.42, 128.36, 104.94, 91.09, 61.10,20.61 0.00.

Reference： [1]Patent: WO2014/108071,2014,A1 .Location in patent: Page/Page column 30
[2]Dalton Transactions,2012,vol. 41,p. 3695 - 3700
[3]Advanced Synthesis and Catalysis,2012,vol. 354,p. 828 - 834

33
[ 109-97-7 ]
[ 1123-56-4 ]
[ 1420764-63-1 ]

Yield	Reaction Conditions	Operation in experiment
91%		2,6-Dimethylbenzaldehyde (3.8 g, 29.0 mmol, 1 equiv) was added to a two-necked flask under nitrogen. The flask was heated to 40 C, following which pyrrole (80 mL, 1.16mol, 40 equiv) was added to the solution with stirring. After being stirred for 10 min, trifluoroacetic acid (230 muL, 2.90 mmol, 0.1 equiv) was added to the solution and the reaction mixture was stirred at 40 C for 30 min. The solution was then cooled to room temperature, after which dichloromethane was added and the mixture was washed with water, followed by washing with saturated aqueous sodium bicarbonate. The organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated and the crude product was purified by column chromatography on silica gel (hexane/ethyl acetate = 5/1) to yield compound 6 (6.5 g, 91%) as a black solid. 1H NMR (400 MHz, CDCl3): 7.94 (br, 2H), 7.137.09 (m, 1H), 7.04 (d, 2H, J = 7.5 Hz), 6.686.67 (m, 2H), 6.18 (q, 2H, J = 2.9 Hz), 6.015.99 (m, 2H), 5.97 (s, 1H), 2.10 (s, 6H); 13C NMR (100 MHz, CDCl3): 137.6, 130.8, 129.4, 127.0, 116.1, 108.5, 106.5, 38.6, 20.6; HRMS (ESI): m/z calcd for C17H18N2H: 251.1543 [M + H]+; found: 251.1542.
91%	With trifluoroacetic acid; at 40℃; for 0.166667h;Inert atmosphere;	<strong>[1123-56-4]2,6-dimethylbenzaldehyde</strong> (ALDRICH) (3.8 g, 28.96 mmol)Was added to the recovery flask, degassing and N 2 substitution were carried out three times, and the temperature was brought to 40 C.Thereafter, pyrrole (Wako) (80 mL, 1158.25 mmol) and trifluoroacetic acid (230 muL, 2.9 mmol) were added and stirred for 10 minutes.After standing to cool, it was extracted three times with dichloromethane, washed with saturated sodium hydrogen carbonate, and then dried with Na 2 SO 4.The solvent was removed under reduced pressure and separated and purified by silica gel chromatography (eluent; hexane: ethyl acetate = 1: 1) to obtain a black solid (compound 1) (6.45 g, 91%).

Reference： [1]Bulletin of the Chemical Society of Japan,2015,vol. 88,p. 447 - 454
[2]Patent: JP6108341,2017,B2 .Location in patent: Paragraph 0034; 0035
[3]ChemSusChem,2012,vol. 5,p. 2361 - 2375

34
[ 18648-66-3 ]
[ 1123-56-4 ]
[ 1335328-82-9 ]

Reference： [1]Patent: US2012/330052,2012,A1

35
[ 10485-09-3 ]
[ 1123-56-4 ]
C₁₈H₁₈O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Comparative Example 3A tetrahydrofuran solution (1.2 mL) containing 0.25 g of magnesium was cooled to 0 C., and a tetrahydrofuran solution (5.0 mL) of <strong>[10485-09-3]2-bromoindene</strong> (1.0 g) was slowly dropped into the tetrahydrofuran solution. After completion of the dropping, the mixture was stirred at the same temperature for 1 hour, and then 2,6-dimethylbenzaldehyde (0.57 g) was added thereto. The mixture was stirred for 12 hours while warming to 25 C. After confirmation of the degree of reaction progress by TLC, the reaction was quenched with an aqueous solution of ammonium chloride, and the organic phase was extracted with ethyl acetate. The resulting organic phase was dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography.

Reference： [1]Patent: US2012/330052,2012,A1 .Location in patent: Page/Page column 10

36
[ 18648-66-3 ]
[ 1123-56-4 ]
C₂₉H₂₆O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 6A tetrahydrofuran solution (25 mL) of 2-(4-bromophenyl)-1,1-diphenyl ethylene (2.0 g) was cooled to -78 C., and n-butyllithium (2.6 M, 2.6 mL) was gradually dropped therein. The resulting mixture was stirred at the same temperature for 2 hours. After addition of 2,6-dimethylbenzaldehyde (0.65 g), the mixture was stirred for 12 hours while slowly warming to 25 C. After confirmation of the degree of reaction progress by TLC, the reaction was quenched with an aqueous solution of ammonium chloride, and the organic phase was extracted with ethyl acetate. The resulting organic phase was dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography.

Reference： [1]Patent: US2012/330052,2012,A1 .Location in patent: Page/Page column 8

37
[ 5927-18-4 ]
[ 1123-56-4 ]
[ 86761-31-1 ]

Yield	Reaction Conditions	Operation in experiment
43%	With sodium hydride; In tetrahydrofuran; at 20℃; for 12h;	To a solution of 60% NaH (37g, 0.93mo1) in 500mL dry THF was added methyl 2-(dimethoxyphosphoryl)acetate (102g, 0.56mo1). Then a solution of Compound 3-1 (50g, 0.37mo1) in 100mL dry THF was added to the solution. The reaction mixture was stirred for 12 hours at room temperature. To the reaction mixture was added saturated aqueous NH4Cl. The reaction mixture was concentrated and extracted with ethyl acetate (3x50mL). The organic phase was washed with water (3x25mL), brine (3x25mL), dried with anhydrous Na2SO4, and concentrated in vacuo to give a crude product. The residue was purified with column chromatography (ethyl acetate in petroleum ether 10% v/v) to give Compound 3-2 (30 g, Yield 43%) as a yellow liquid. m/z: 191 [M+H]+.
43%	With sodium hydride; In tetrahydrofuran; at 20℃; for 12h;	A. Preparation of Compound 3-2 33] To a solution of 60% NaH (37g, 0.93mol) in 500mL dry THF was added methyl 2- (dimethoxyphosphoryl)acetate (102g, 0.56mol). Then a solution of Compound 3-1 (50g, 0.37mol) in lOOmL dry THF was added to the solution. The reaction mixture was stirred for 12 hours at room temperature. To the reaction mixture was added saturated aqueous NH4CI. The reaction mixture was concentrated and extracted with ethyl acetate (3x50mL). The organic phase was washed with water (3x25mL), brine (3x25mL), dried with anhydrous Na2S04, and concentrated in vacuo to give a crude product. The residue was purified with column chromatography (ethyl acetate in petroleum ether 10% v/v) to give Compound 3-2 (30 g, Yield 43%) as a yellow liquid, m/z: 191 [M+H]+

Reference： [1]Patent: WO2013/13190,2013,A1 .Location in patent: Paragraph 00222
[2]Patent: WO2014/116651,2014,A1 .Location in patent: Paragraph 00233

38
[ 50-00-0 ]
[ 30095-98-8 ]
[ 1123-56-4 ]
[ 1430088-10-0 ]