56008-20-9|3,6,6-Trimethyl-6,7-dihydro-1H-indol-4(5H)-one| Ambeed

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Quality Control of [ 56008-20-9 ] Purity: 95% SDS Specification

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Product Details of [ 56008-20-9 ]

CAS No. :	56008-20-9
Formula :	C₁₁H₁₅NO
M.W :	177.24
SMILES Code :	CC1=CNC2=C1C(=O)CC(C)(C)C2
MDL No. :	MFCD08060464
InChI Key :	REGIWYJKSKEPMU-UHFFFAOYSA-N
Pubchem ID :	24820798

Safety of [ 56008-20-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 56008-20-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	5
Fraction Csp3	0.55
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	52.97
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	32.86 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.96
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.04
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.48
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.42
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	3.5
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.28

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.51
Solubility	0.549 mg/ml ; 0.0031 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.36
Solubility	0.777 mg/ml ; 0.00438 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.75
Solubility	0.0313 mg/ml ; 0.000177 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.93 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.2

Application In Synthesis of [ 56008-20-9 ]

* 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.

Downstream synthetic route of [ 56008-20-9 ]

[ 56008-20-9 ] Synthesis Path-Downstream 1~35

1
[ 50-00-0 ]
[ 56008-20-9 ]
3,6,6,3',6',6'-hexamethyl-1,5,6,7,1',5',6',7'-octahydro-2,2'-methanediyl-bis-indol-4-one [ No CAS ]

References: [1]Buletinul Societatii de Chimie din Romania,vol. 10,p. 141.
Chemisches Zentralblatt,1929,vol. 100,p. 2186.

2
[ 56008-20-9 ]
[ 100-34-5 ]
3,6,6-trimethyl-6,7-dihydro-5<i>H</i>-indole-2,4-dione-2-phenylhydrazone [ No CAS ]

References: [1]Buletinul Societatii de Chimie din Romania,vol. 10,p. 141.
Chemisches Zentralblatt,1929,vol. 100,p. 2186.

3
[ 56008-20-9 ]
[ 122-51-0 ]
3,6,6,3',6',6',3'',6'',6''-nonamethyl-1,5,6,7,1',5',6',7',1'',5'',6'',7''-dodecahydro-2,2',2''-methanetriyl-tris-indol-4-one [ No CAS ]

References: [1]Buletinul Societatii de Chimie din Romania,vol. 10,p. 141.
Chemisches Zentralblatt,1929,vol. 100,p. 2186.

4
[ 56008-20-9 ]
3,6,6-trimethyl-4,5,6,7-tetrahydro-indole [ No CAS ]

References: [1]Buletinul Societatii de Chimie din Romania,vol. 10,p. 141.
Chemisches Zentralblatt,1929,vol. 100,p. 2186.

5
[ 56008-20-9 ]
3,6,6-trimethyl-4,5,6,7-tetrahydro-indole [ No CAS ]
bis-(3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-ylidene)-hydrazine [ No CAS ]

References: [1]Buletinul Societatii de Chimie din Romania,vol. 10,p. 141.
Chemisches Zentralblatt,1929,vol. 100,p. 2186.

6
[ 129689-88-9 ]
[ 56008-20-9 ]

References: [1]Australian Journal of Chemistry,1990,vol. 43,p. 825 - 837.
[2]Buletinul Societatii de Chimie din Romania,vol. 10,p. 134.
Chemisches Zentralblatt,1929,vol. 100,p. 2185.

7
[ 31915-82-9 ]
[ 126-81-8 ]
[ 56008-20-9 ]

References: [1]Journal and Proceedings - Royal Society of New South Wales,1932,vol. 66,p. 477,481.

8
[ 56008-20-9 ]
[ 61810-29-5 ]
[ 129689-90-3 ]

References: [1]Australian Journal of Chemistry,1990,vol. 43,p. 825 - 837.

11
4-oxo-3.6.6-trimethyl-4.5.6.7-tetrahydro-indole-carboxylic acid-⁽²⁾ [ No CAS ]
[ 56008-20-9 ]

References: [1]Buletinul Societatii de Chimie din Romania,vol. 10,p. 134.
Chemisches Zentralblatt,1929,vol. 100,p. 2185.

12
[ 56008-20-9 ]
[ 64-17-5 ]
[ 7803-57-8 ]
3,6,6-trimethyl-4,5,6,7-tetrahydro-indole [ No CAS ]
bis-(3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-ylidene)-hydrazine [ No CAS ]

References: [1]Buletinul Societatii de Chimie din Romania,vol. 10,p. 141.
Chemisches Zentralblatt,1929,vol. 100,p. 2186.

13
[ 1009036-29-6 ]
[ 56008-20-9 ]
1-(4-Amino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	With sodium hydride; In ISOPROPYLAMIDE; at 160℃; for 0.333333h;Microwave irradiation;	A solution of 7-Fluoro-quinazolin-4-ylamine (0.2203 g, 1.35 mmol), 6,6,6,-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.286 g, 1.62 mmol) and NaH (60% suspension in mineral oil, 0.081 g, 2.025 mmol) in dimethylacetamide (5 mL) is microwaved at 160 C. for 20 min. The reaction mixture is poured onto a saturated solution of NH4Cl (5 mL), and the aqueous phase is extracted with EtOAc (3×). The combined organic layers are washed with brine, dried over MgSO4, and evaporated to dryness. Purification of the crude material by column chromatography (5% MeOH in CH2Cl2) affords 1-(4-Amino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.1131 g, 26%). LC/MS m/z=321 [M+H]+.

References: [1]Patent: US2008/70935,2008,A1 .Location in patent: Page/Page column 45.
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554.

14
[ 214045-86-0 ]
[ 56008-20-9 ]
1-(3-chloro-isoquinolin-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9%	With sodium hydride; In N,N-dimethyl-formamide; at 160℃; for 0.333333h;Microwave irradiation;	Example 14 1-(3-chloro-isoquinolin-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one; To a solution of <strong>[214045-86-0]1-chloro-6-fluoro-isoquinoline</strong> (0.0847 g, 0.47 mmol) in DMF (2 mL) are added pyrrole (0.1 g, 0.56 mmol) and NaH (0.028 g, 0.71 mmol). The reaction mixture is microwaved at 160 C. for 20 min. The reaction mixture is cooled to RT, and treated with NH4Cl (satd. aq., 2 mL). The aqueous phase is extracted with EtOAc (2×). The combined organic layers are washed with brine, and dried over MgSO4. The solvent is evaporated and the residue is dried under vacuum. Purification of the crude material using a Biotage column (0-50% EtOAc/hexanes) affords 0.014 g (9%) of 1-(3-chloro-isoquinolin-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one. LC/MS m/z=339 [M+H]+, RT=4.01 min.

References: [1]Patent: US2008/70935,2008,A1 .Location in patent: Page/Page column 49.

15
[ 1009034-73-4 ]
[ 56008-20-9 ]
1-(1-Amino-4-bromo-isoquinolin-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With sodium hydride; In N,N-dimethyl-formamide; at 120℃; for 0.666667h;Microwave irradiation;	Example 18 1-(1-Amino-4-bromo-isoquinolin-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (Compound 9); To a solution of 1-amino-4-bromo-6-fluoro-isoquinoline (0.029 g, 0.12 mmol) in DMF (1 mL) are added 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.042 g, 0.24 mmol) and NaH (0.01 g, 0.24 mmol). The reaction mixture is microwaved at 120 C. for 40 min, cooled to RT, and treated with NH4Cl (satd. aq, 2 mL). The aqueous phase is extracted with EtOAc (2×). The combined organic layers are washed with brine, and dried over MgSO4. The solvent is evaporated and the residue is dried under vacuum. Purification of the crude material using a Biotage column (0-10% MeOH/CH2Cl2) affords 0.0118 g (25%) of 1-(1-Amino-4-bromo-isoquinolin-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one. LC/MS m/z=399 [M+H]+.

References: [1]Patent: US2008/70935,2008,A1 .Location in patent: Page/Page column 50.

16
[ 1009034-82-5 ]
[ 56008-20-9 ]
[ 1009034-84-7 ]

Yield	Reaction Conditions	Operation in experiment
40%	With sodium hydride; In N,N-dimethyl-formamide; at 120℃; for 0.666667h;Microwave irradiation;	Example 22 1-amino-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-isoquinoline-4-carbonitrile; To a solution of 1-amino-6-fluoro-isoquinoline-4-carbonitrile (0.109 g, 0.58 mmol) in DMF (5 mL) are added pyrrole (0.15 g, 0.87 mmol) and NaH (0.035 g, 0.87 mmol). The reaction mixture is microwaved at 120 C. for 40 min. The reaction mixture is cooled to RT, and treated with H2O (10 mL). The aqueous phase is extracted with EtOAc (2×). The combined organic layers are washed with brine, and dried over MgSO4. The solvent is evaporated and the residue is dried under vacuum. Purification of the crude material using a Biotage column (0-20% MeOH/CH2Cl2) affords 0.08 g (40%) of 1-amino-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-isoquinoline-4-carbonitrile. LC/MS m/z=345 [M+H]+, RT=2.98 min.

References: [1]Patent: US2008/70935,2008,A1 .Location in patent: Page/Page column 51.

17
Cyclopropyl-(7-fluoro-quinazolin-4-yl)-amine [ No CAS ]
[ 56008-20-9 ]
1-(4-Cyclopropylamino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at 100℃; for 0.416667h;Microwave irradiation;	Example 34 1-(4-Cyclopropylamino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one; 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.177 g, 1 mmol), sodium hydride (60% in oil, 40 mg, 1 mmol), Cyclopropyl-(7-fluoro-quinazolin-4-yl)-amine (0.20 g, 1 mmol), and N,N-dimethylformamide are sealed in a microwave vessel and irradiated at 100 degrees Celsius for 1500 seconds. The mixture is extracted with ethyl acetate and washed with water. The organic phase is dried over magnesium sulfate, filtered concentrated, and chromatographed to afford 0.2 g of 1-(4-Cyclopropylamino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one as a solid (55%). LC/MS m/z=361 [M+H]+.

References: [1]Patent: US2008/70935,2008,A1 .Location in patent: Page/Page column 54.

18
[ 56008-20-9 ]
7-fluoroquinazolin-2-amine [ No CAS ]
1-(2-Amino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium hydride; In N,N-dimethyl-formamide; at 150℃; for 0.416667h;Microwave irradiation;	3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.65 g, 3.68 mmol), sodium hydride (60% in oil, 0.177 g, 4.4 mmol), 7-fluoroquinazolin-2-amine (0.60 g, 3.68 mmol), and N,N-dimethylformamide are sealed in a microwave vessel and irradiated at 150 degrees Celsius for 1500 seconds. The mixture is purified by column chromatography and recrystallized from dichloromethane/hexane, affording 0.96 g of 1-(2-Amino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (81%). LC/MS m/z=321 [M+H]+.

References: [1]Patent: US2008/70935,2008,A1 .Location in patent: Page/Page column 55.
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554.

19
[ 56008-20-9 ]
2-amino-7-fluoro-4-methylquinazoline [ No CAS ]
1-(2-amino-4-methylquinazolin-7-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With sodium hydride; In N,N-dimethyl-formamide; at 150℃; for 0.416667h;Microwave irradiation;	3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.7 g, 4 mmol), sodium hydride (60% in oil, 0.20 g, 4.8 mmol), 7-Fluoro-4-methyl-quinazolin-2-ylamine (0.7 g, 4 mmol), and N,N-dimethylformamide are heated at 150 degrees Celsius for 2 h. The mixture is extracted with ethyl acetate/water. The organic layer is dried and concentrated. The residue is purified by column chromatography, affording 0.9 g of a solid 1-(2-Amino-4-methyl-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (68%). LC/MS m/z=335 [M+H]+.

References: [1]Patent: US2008/70935,2008,A1 .Location in patent: Page/Page column 55.
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554.

20
[ 56008-20-9 ]
[ 129689-93-6 ]

References: [1]Australian Journal of Chemistry,1990,vol. 43,p. 825 - 837.

21
[ 56008-20-9 ]
[ 129715-51-1 ]

References: [1]Australian Journal of Chemistry,1990,vol. 43,p. 825 - 837.

22
[ 37711-24-3 ]
[ 56008-20-9 ]

References: [1]Australian Journal of Chemistry,1990,vol. 43,p. 825 - 837.
[2]Buletinul Societatii de Chimie din Romania,vol. 10,p. 134.
Chemisches Zentralblatt,1929,vol. 100,p. 2185.

23
[ 126-81-8 ]
[ 56008-20-9 ]

References: [1]Buletinul Societatii de Chimie din Romania,vol. 10,p. 134.
Chemisches Zentralblatt,1929,vol. 100,p. 2185.

24
[ 17280-41-0 ]
[ 126-81-8 ]
[ 56008-20-9 ]

Yield	Reaction Conditions	Operation in experiment
52%	With acetic acid; zinc; In water;Reflux;	Step 1. Synthesis of 3,6,6-trimethyl-6,7-dihydro-lH-indole-4(5H)-on [formula 6-2]Anti-pyruvic aldehyde- 1-oxime [formula 6-1] (0.50 g, 5.74 mmol) and 5,5-dimethyl- 1,3-cyclohexandion [formula 6-7] (0.80 g, 5.74 mmol) were dissolved in acetic acid (35 mL) and H20 (15 mL) . Thereto, zinc powder (0.75 g, 11.5 mmol) was added slowly maintaining room temperature. The reaction mixture was refluxed with stirring, concentrated under reduced pressure and extracted with CH2C12 and brine, of which pH was adjusted to 6 using saturated NaHC03. The reaction mixture was extracted with CH2C12; organic layer was dried over anhydrous MgS04 and filtered. Residue was concentrated under reduced pressure and purified by column chromatography (Si02; hexane/ethylacetate, 1/3) to yield the title compound as yellow solid (4.9 g, 52 %).
45%	With zinc; In water; acetic acid; at 20℃;Heating / reflux;	To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5, 5-dimethyl-l, 3-cyclohexanedione (16.1 g, 1 eq) in HOAc- H2O (7:3, 200 mL) was added zinc powder (14.95 g, 2 eq) slowly with cooling by a water bath at room temperature. The mixture then was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL) . The pH was adjusted to ca. 6 with saturated aqueous NaHCO3, then the mixture was extracted with dichloromethane (3x200 mL) . The organic layers were combined, dried overNa2SO4, filtered, concentrated. The crude product was purified by flash chromatography eluting with 5% ethyl acetate in dichloromethane. The combined organic fractions were concentrated, triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give the pure title compound (9 g, 45% yield) as a solid. LCMS m/z: (M+H) = 178.1.
45%		To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc-H2O (7:3, 200 mL), was added zinc powder (14.95 g, 2 eq) slowly cooling with a water bath at room temperature. The mixture was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL). The pH was adjusted to ca. 6 with saturated aqueous NaHCO3, then extracted with dichloromethane (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, concentrated to give crude product. This was purified by flash chromatography, eluting with 5% ethyl acetate in dichloromethane to give expected product, which was triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give pure title compound (9 g, 45% yield) as a solid.

45%

With acetic acid; zinc; In water; at 20℃;Heating / reflux;

Example 1; 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one; To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc-H2O (7:3, 200 mL), was added zinc powder (14.95 g, 2 eq) slowly cooling with a water bath at room temperature. The mixture was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL). The pH was adjusted to ca. 6 with saturated aqueous NaHCO3, then extracted with dichloromethane (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, concentrated to give crude product. This was purified by flash chromatography, eluting with 5% ethyl acetate in dichloromethane to give expected product, which was triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give pure title compound (9 g, 45% yield) as a solid.

References: [1]Patent: WO2013/62344,2013,A1 .Location in patent: Page/Page column 87.
[2]Patent: WO2006/91963,2006,A1 .Location in patent: Page/Page column 84; 89.
[3]Patent: US2008/269193,2008,A1 .Location in patent: Page/Page column 39.
[4]Journal of Medicinal Chemistry,2009,vol. 52,p. 4288 - 4305.
[5]Patent: US2007/207984,2007,A1 .Location in patent: Page/Page column 23.

25
[ 56008-20-9 ]
[ 36282-26-5 ]
[ 908111-21-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium hydride; In N,N-dimethyl-formamide; at 55℃; for 1h;	The title compound of Example 1 (9.8 g, 55.3 itimol) and 2- bromo-4-fluorobenzonitrile (13.27 g, 66.4 mmol) were dissolved in anhydrous dimethylformamide (DMF, 300 mL) . To this was added sodium hydride (95%, 2.79 g, 111 mmol) and the reaction was stirred at 55 0C for 1 hour. The reaction mixture was cooled to room temperature and water was added. A tan solid precipitated which was filtered, washed with water and ether and then dried in vacuo (16.5 g, 84%). LCMS m/z: (M+H) = 358.1
84%	With sodium hydride; In N,N-dimethyl-formamide; at 55℃; for 1h;	Example 2; 2-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile; The title compound of Example 1 (9.8 g, 55.3 mmol) and 2-bromo-4-fluorobenzonitrile (13.27 g, 66.4 mmol) were dissolved in anhydrous dimethylformamide (DMF, 300 mL). To this was added sodium hydride (NaH, 95%, 2.79 g, 111 mmol) and the reaction was stirred at 55 C. for 1 hour. The reaction mixture was cooled to room temperature and water was added. A tan solid precipitated which was filtered, washed with water and ether and then dried in vacuo (16.5 g, 84%). MS m/z: (M+H)=358.1.
	With sodium hydride; In N,N-dimethyl-formamide; at 55℃; for 1h;	10235] Thetitle compound of Example 1 (9.8g, 55.3 mmol) and 2-bromo-4-fluorobenzonitrile (13.27 g, 66.4 mmol) are dissolved in anhydrous dimethylformamide (DMF, 300 mL). To this is added sodium hydride (95%, 2.79 g, 111 mmol) and the reaction is stirred at 550 C. for 1 hour. The reaction mixture is cooled to room temperature and water is added. A tan solid precipitated which is filtered, washed with water and ether and then dried in vacuo.

References: [1]Patent: WO2006/91963,2006,A1 .Location in patent: Page/Page column 84; 90.
[2]Journal of Medicinal Chemistry,2009,vol. 52,p. 4288 - 4305.
[3]Patent: US2007/207984,2007,A1 .Location in patent: Page/Page column 23.
[4]Patent: US2015/329493,2015,A1 .Location in patent: Paragraph 0228; 0234; 0235.

26
[ 56008-20-9 ]
[ 1073973-23-5 ]
[ 1073973-24-6 ]

Yield	Reaction Conditions	Operation in experiment
39%	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 0 - 100℃; for 96h;microwave cap;	Potassium carbonate (1.21 g, 8.75 mmol) was added to a solution of 4-bromo-2-fluoro-6-(S-tetrahydro-furan-3-ylamino)-benzonitrile (0.5 g, 1.75 mmol) and 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.31 g, 1.75 mmol) in 1,4-dioxane (6 mL). The solution was degassed under N2. The flask was then cooled at 0 C. and connected to a vacuum line. The vacuum was pulled until the solvent started bubbling. The degassing/vacuum cycle was repeated 2 times. Then N,N'-dimethylethylenediamine (0.27 mL, 2.54 mmol) and CuI (0.5 g, 2.63 mmol) were added. The degassing/vacuum cycle was performed 3 times. The rubber septum was replaced by a microwave cap. The solution was degassed one more time, and placed in an oil bath at 100 C. The reaction mixture was stirred at 100 C. for 4 days. The reaction mixture was filtered through a pad of Celite, and the filter pad was rinsed with EtOAc. The solvent was removed under reduced pressure. Purification of the residue using a Biotage column eluted with 0-50% MeOH/CH2Cl2 afforded 0.263 g (39%) of 2-fluoro-6-(S-tetrahydro-furan-3-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile. LC/MS: m/z=382 [M+H]+. 1H NMR (DMSO, 20 C., 400 MHz) δ (ppm) 7.73-7.69 (m, 2H), 7.44 (d, 1H), 6.55 (d, 1H), 6.46 (s, 1H), 4.46 (b, 1H), 3.87-3.70 (m, 7H), 2.97 (s, 3H), 2.74 (s, 2H), 2.49 (s, 2H), 0.98 (s, 6H)

References: [1]Patent: US2008/269193,2008,A1 .Location in patent: Page/Page column 40.

27
[ 56008-20-9 ]
[ 1073973-35-9 ]
[ 1073973-63-3 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 0 - 100℃;Sealed;	To a stirred solution of 2-((1S,2S)-2-benzyloxy-cyclopentylamino)-4-bromo-6-fluoro-bezonitrile (1.48 g) and 3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.56 g) in dioxane (15 mL) were added K2CO3 (2.64 g). The suspension was freezed in ice-bath and degassed by pump/backfill of N2 3 times. Then CuI (1.1 g) and N,N'-dimethylethylenediamine (0.6 mL) were added. The reaction mixture was degassed again for 3 times with backfill of N2. Then the sealed reaction mixture was stirred at 100 C. overnight. The reaction mixture was filtered through a celite pad, washed by EtOAc, concentrated to give a gum (LCMS m/z M+H=486.3). That was dissolved in EtOH-DMSO (4:1, 50 mL), then 1N NaOH aq (10 mL), and H2O2 (3 mL) were added and the mixture stirred at RT for 4 h. The reaction mixture was concentrated and poured into Sat'd NH4Cl aq. (250 mL), extracted by EtOAc (3×150 mL), dried over Na2SO4, filtered, concentrated to give a gum, which was purified by Biotage chromatography, eluted by 30% EtOAc in hexane to give 2-fluoro-6-((1S,2S)-2-benzyloxy-cyclopentylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide (1.2 g, 63% for 2 steps). LCMS (M+H) m/z=504.3.

References: [1]Patent: US2008/269193,2008,A1 .Location in patent: Page/Page column 45; 55.

28
[ 56008-20-9 ]
4-bromo-2-fluoro-6-(trans-4-hydroxy-cyclohexylamino)-benzonitrile [ No CAS ]
4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-2-fluoro-6-(4-hydroxy-cyclohexylamino)-benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 0 - 100℃; for 17h;	4-Bromo-2-fluoro-6-(4-hydroxy-cyclohexylamino)-benzonitrile (1.74 g, 5.56 mmol), 3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (1 g, 5.56 mmol), and K2CO3 (3.84 g, 27.8 mmol) are dissolved in 1,4-dioxane (16 mL). The reaction mixture is degassed by 3 freeze (0 C.)/pump/thaw cycles under N2. Then, N,N'-dimethylethylenediamine (0.87 mL, 8.1 mmol) and CuI (1.6 g, 8.34 mmol) are added and the reaction is again degassed by three more freeze/pump/thaw cycles. The reaction mixture is then heated to 100 C. for 17 hours. After cooling, the reaction is filtered through Celite, washed with EtOAc (3×20 mL), concentrated and purified via Biotage column (0-50% EtOAc in Hex) to give 4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-2-fluoro-6-(4-hydroxy-cyclohexylamino)-benzonitrile (1.78 g; 78% yield). LC/MS: m/z=409 [M+H]+.

References: [1]Patent: US2008/269193,2008,A1 .Location in patent: Page/Page column 49-50.

29
[ 56008-20-9 ]
[ 1194-02-1 ]
C₁₈H₁₈N₂O [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4288 - 4305.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 3382 - 3400.
[3]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 1338 - 1342.

30
7-Fluoro-2-methyl-quinazolin-4-ylamine [ No CAS ]
[ 56008-20-9 ]
1-(4-Amino-2-methyl-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one [ No CAS ]