52537-00-5|6-Chloro-2,3-dihydro-1H-indole| Ambeed

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Quality Control of [ 52537-00-5 ] Purity: 95% SDS Specification

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Product Details of [ 52537-00-5 ]

CAS No. :	52537-00-5
Formula :	C₈H₈ClN
M.W :	153.61
SMILES Code :	ClC1=CC2=C(C=C1)CCN2
MDL No. :	MFCD07371639
InChI Key :	HSLNYVREDLDESE-UHFFFAOYSA-N
Pubchem ID :	258567

Safety of [ 52537-00-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H317
Precautionary Statements:	P280

Computational Chemistry of [ 52537-00-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	0
Num. H-bond acceptors	0.0
Num. H-bond donors	1.0
Molar Refractivity	46.54
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	12.03 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.88
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	2.72
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.74
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.	2.33
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	2.86
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.3

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.95
Solubility	0.172 mg/ml ; 0.00112 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.	-2.63
Solubility	0.363 mg/ml ; 0.00236 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	-3.6
Solubility	0.0387 mg/ml ; 0.000252 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.	-5.31 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	2.0
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)	1.33

Application In Synthesis of [ 52537-00-5 ]

* 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 [ 52537-00-5 ]

[ 52537-00-5 ] Synthesis Path-Downstream 1~35

1
[ 52537-00-5 ]
[ 17422-33-2 ]

References: [1]Journal of Organic Chemistry,1990,vol. 55,p. 580 - 584.
[2]Advanced Synthesis and Catalysis,2017,vol. 359,p. 2358 - 2363.
[3]Chemical Science,2019,vol. 10,p. 4883 - 4889.
[4]ACS Catalysis,2018,vol. 8,p. 1192 - 1196.
[5]Organometallics,2018,vol. 37,p. 584 - 591.
[6]Journal of Organic Chemistry,1990,vol. 55,p. 580 - 584.

2
[ 54664-52-7 ]
[ 1073-67-2 ]
[ 17422-33-2 ]
[ 52537-00-5 ]
[ 54664-55-0 ]

References: [1]Journal of the American Chemical Society,1981,vol. 103,p. 1525 - 1533.

3
[ 76653-03-7 ]
[ 17422-33-2 ]
[ 52537-00-5 ]

References: [1]Journal of the American Chemical Society,1981,vol. 103,p. 1525 - 1533.

4
[ 52537-00-5 ]
[ 333-20-0 ]
6-Chloro-5-thiocyanato-2,3-dihydro-1H-indole [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 3494 - 3496.

5
[ 52537-00-5 ]
[ 15268-31-2 ]
6-Chloro-1-(pyridin-3-ylcarbamoyl)indoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%		Example 19 6-Chloro-1-(3-pyridylcarbamoyl)indoline (E19) The title compound was prepared as in the method of (Example 2) from 3-pyridylisocyanate and <strong>[52537-00-5]6-chloroindoline</strong> (D36) to give (E19) (1.54 g, 73%) m.p. 204-5 C. NMR (DMSO-d6) delta: 3.19 (2H, t, J=8), 4.19 (2H, t, J=8), 6.93-6.99 (1H, m), 7.23 (1H, d, J=8), 7.31-7.38 (1H, m), 7.88 (1H, s), 7.94-8.02 (1H, m), 8.24 (1H, d, J=6), 8.72 (1H, s), 8.82 (1H, s). Found: C, 61.34; H, 4.60; N, 15.38 C14 H12 N3 OCl requires: C, 61.43; H, 4.42; N, 15.35

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 1598 - 1612.
[2]Patent: US5834494,1998,A .
[3]Bioorganic and Medicinal Chemistry,1999,vol. 7,p. 2767 - 2773.

6
[ 52537-00-5 ]
[ 200940-27-8 ]
6-chloro-2,3-dihydro-indole-1-carboxylic acid [6-(2-methyl-pyridin-3-yloxy)-pyridin-3-yl]-amide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1863 - 1866.

7
[ 17422-33-2 ]
[ 52537-00-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium cyanoborohydride; acetic acid; at 20℃; for 0.333333h;	Reduction of Indoles to Indolines:; PREPARATION 142; 6-Chloro-2, 3-dihydro-lH-indole; Dissolve 6-chloro-lH-indole (2 g, 0.013 mol) in acetic acid (10 mL) under nitrogen. Add sodium cyanoborohydride (1.24 g, 1.5 eq) and stir 20 minutes at room temperature. Dilute with ethyl acetate and extract with sodium hydroxide (5 N aqueous). Dry over magnesium sulfate, filter and concentrate to give 2.35 g (116%) crude product. MS (ES, m/z) : 154.0 (M+1).
87%		6-chloro-2,3-dihydro-1H-indole Under a nitrogen atmosphere 0.50 g (7.9 mmol) sodium cyanoborohydride were added batchwise to 1.0 g (6.6 mmol) 5-hydroxyindole in 5.0 mL glacial acetic acid and the mixture was stirred for 60 min at RT. Then the reaction mixture was poured onto a 4N aqueous sodium hydroxide solution and extracted with EtOAc. The combined organic phases were washed several times with saturated sodium hydrogen carbonate solution, dried on sodium sulphate and evaporated down. Yield: 1.1 g (87% of theoretical) Rt (HPLC-MS): 1.24 min (method C)
87%	With sodium cyanoborohydride; acetic acid; at 20℃; for 3h;	Synthesis of In acetic acid (2.0 mL) solution of 6-chloro -1H- indole (200 mg, 1.3 mmol), sodium cyanoborohydride (170 mg, 2.6 mmol) was added at room temperature,and was stirred at 3 hours. It added 1 N aqueous sodium hydroxide to the reaction mixture (30 mL) at room temperature, followed by extraction with ethyl acetate (30 mL). The organic layer was dried over sodium sulfate, and concentratedIt was. The resulting concentrate was purified by silica gel column chromatography is purified by (eluent ethyl acetate / n-hexane = 25/75), 6-chloro-indoline as a colorless oilObtained (180mg, 87% yield).

86%		Preparation 30: 6-Chloro-2,3-dihydro-1 H-indole6-Chloroindole (1.0 g, 6.6 mmol) was dissolved in a solution of borane in THF (1 M, 9.83 mmol) at 0 C and stirred for 30 min. TFA (9.83 mL) was added dropwise and the solution stirred at 0 C for 30 min. 6 M aqueous NaOH was added until the solution was basic (pH 1 1 ). The aqueous solution was extracted with DCM (3 x 25 mL), dried over sodium sulfate, filtered and concentrated to give the title compound (864 mg, 86%) as a yellow oil. 1H NMR (Me-d3-OD): 6.99 (1 H, d), 6.64-6.55 (2H, m), 3.50 (2H, t), 2.95 (2H, t).
72%	With sodium cyanoborohydride; for 22h;	In a 250 mL round bottom flask, 12.4 grams of sodium cyanoborohydride (198 mmol, 2 eq. ) were added potion-wise over 5 minutes to a solution of 15 grams (98.9 mmol) of 6-chloroindole. After stirring for 22 hours, the mixture had become a brown solution and analysis by [HPLC] (MRH 1 method) revealed no starting material remaining and a mixture of two product peaks. The mixture was diluted with 100 [ML] of water, then made basic [WITH-200] mL of 6N sodium hydroxide. The desired product was extracted into 3 X 400 mL of methylene chloride. The extracts were then dried over anhydrous magnesium sulfate and evaporated in vacuo leaving a cloudy oil. The crude product was chromatographed over a plug of silica in 100 % methylene chloride giving a mixed fraction [(RF=] 0.9 and 0.7), a pure product fraction [(RF= 0. 7),] and a baseline fraction (Rf = 0.0-0. 2). The pure fraction was evaporated to dryness in vacuo to yield a clear, colorless oil weighing 10.90 grams (72 %). It was stored at [4C] and saved for future [USE. 1H] NMR (300 MHz, DMSO-d6) 8 6.95 (d, J= 5 Hz, 1 H), 6.46 (d, [J=] 5 Hz, 2 H), 3.43 (t, [J=] 6,2 H), 2.86 (t, [J=] 6,2 H).
	With sodium cyanoborohydride; In acetic acid; at 20℃; for 1h;	[0278] 6-Chloroindole (1 g, 6.6 mmol) in glacial acetic acid (10 mL) was treated with sodium cyanoborohydride (829 mg, 13.2 mmol) portionwise at room temperature with stirring. After 1 hour, the reaction was diluted with water (25 mL) and basified with 40% sodium hydroxide with cooling. The mixture was then extracted with dichloromethane (3×50 mL), dried and concentrated to give 1 g of 6-chloroindoline. It was used in the next step without further purification. 1HNMR (300 MHz, dimethylsulfoxide-d6) delta 6.95 (d, 1H), 6.46 (dd, 1H), 6.43 (d, 1H), 5.74 (br s, 1H, NH), 3.42 (t, 2H, CH2), 2.85 (t, 2H, CH2). MS m/z 349 [M+1].
		EXAMPLE 208a Preparation of intermediate 6-chloro-2,3-dihydro-1H-indole Sodium borohydride (2.0 g, 53 mmol) (Aldrich) was added in small portions to a mixture of 6-chloro-1H-indole (1.0 g, 6.6 mmol) (Aldrich) in TFA (10 mL), which was cooled in ice-water bath, at such a rate that gas evolution was not too vigorous. When the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was concentrated in vacuo and the residue was dissolved in DCM. The organic layer was washed with Na2CO3 solution, dried with Na2SO4, and concentrated to give 0.6 g crude 6-chloro-2,3-dihydro-1H-indole. MS: [M+H]+=154
16%Chromat.	With 6C53H32O8(4-)13Zr(4+)18O(2-)8Co(2+)8Cl(1-); hydrogen; sodium triethylborohydride; In toluene; at 80℃; under 30003.0 Torr; for 72h;	General procedure: At a 0.5 mol % Co loading, Zr-MTBC-CoH catalyzed hydrogenation of indole in toluene at 80 C. to afford a mixture of indoline and 4,5,6,7-tetrahydroindole. Indoline was obtained in 84% isolated yield after preparative TLC. See first entry, Table 19, below. Hydrogenation of 3-methyl-indole gave 3-methyl-indoline and 3-methyl-4,5,6,7-tetrahydroindole in 46:54 ratio, which indicates that reduction of the phenyl ring is also possible. Hydrogenation of quinolines in toluene at 80 C. gave a mixture of two products, 1,2,3,4-tetrahydroquinoline and 5,6,7,8-tetrahydro-quinoline in a 1:1 ratio. Under identical reaction conditions, the selectivity appears dependent on the substitution of the phenyl ring. Electron-donating substituents at the 6-position of the quinolines favor the hydrogenation of the phenyl ring. For example, the 6-methylquinoline, 6-methoxyquinoline and 2,6-dimethylquinoline were hydrogenated to give 6-methyl-5,6,7,8-tetrahydro-quinoline, 6-methoxy-5,6,7,8-tetrahydro-quinoline and 2,6-dimethyl-5,6,7,8-tetrahydro-quinoline, respectively, as the major products. See Table 19. In contrast, strong electron-withdrawing substituents seem to disfavor the reduction of the phenyl ring. The hydrogenation of 2-methyl-6-fluoro-quinoline afforded 2-methyl-6-fluoro-1,2,3,4,-tetrahydro-quinoline exclusively in 72% yield. See second to last entry, Table 19. Zr-MTBC-CoH was also an active catalyst for hydrogenation of benzofuran. At a 0.2 mol % Co loading, benzofuran was completely hydrogenated to 2,3-dihydrobenzofuran in qualitative yield. See next to last entry, Table 19.

References: [1]Patent: WO2003/76398,2003,A2 .Location in patent: Page/Page column 41.
[2]Patent: US2011/21500,2011,A1 .Location in patent: Page/Page column 49.
[3]Patent: JP2015/193573,2015,A .Location in patent: Paragraph 0043.
[4]Patent: WO2012/143726,2012,A1 .Location in patent: Page/Page column 129.
[5]Journal of Medicinal Chemistry,2015,vol. 58,p. 6574 - 6588.
[6]Patent: WO2004/18414,2004,A2 .Location in patent: Page 92.
[7]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3105 - 3109.
[8]Patent: US2004/266843,2004,A1 .Location in patent: Page 22.
[9]Journal of Medicinal Chemistry,2011,vol. 54,p. 166 - 178.
[10]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 373 - 377.
[11]Chemistry - A European Journal,2014,vol. 20,p. 58 - 63.
[12]Journal of Organic Chemistry,2016,vol. 81,p. 396 - 403.
[13]Journal of the American Chemical Society,2016,vol. 138,p. 12234 - 12242.
[14]Journal of Organic Chemistry,2018,vol. 83,p. 2425 - 2437.
[15]Organic and Biomolecular Chemistry,2018,vol. 16,p. 3889 - 3892.
[16]Patent: US2008/81810,2008,A1 .Location in patent: Page/Page column 67.
[17]Patent: US2018/361370,2018,A1 .Location in patent: Paragraph 0349.

8
[ 52537-00-5 ]
[ 79-04-9 ]
[ 85892-76-8 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3105 - 3109.

9
[ 52537-00-5 ]
[ 7516-60-1 ]
4-Br-2-[C(O)O-Wang resin]-aniline [ No CAS ]
5-bromo-2-({4-[(6-chloro-2,3-dihydro-1H-indol-1-yl)sulfonyl]benzoyl}amino)benzoic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 6173 - 6177.

10
[ 52537-00-5 ]
[ 959118-73-1 ]
6-chloro-2,3-dihydroindole-1-carboxylic acid [4-(2-aminoethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenyl]amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20.1%		A mixture of tert-butyl 2-(4-amino-2-(4-bromo-l-methyl-lH-pyrazol-5-yl)rhohenoxy) ethylcarbamate (30 mg, 54 mumol) and <strong>[52537-00-5]6-chloroindoline</strong> (8.3 mg, 54 mumol) in ImL of DMF was <n="179"/>stirred at room temperature overnight. Then to the mixture was added 1 mL of 2M HCl. The mixture was stirred at room temperature overnight. The mixture was concentrated and the crude product was subjected to purification on HPLC. The proper fractions were collected and lyophilized to afford yellow oil in 20.1 % yield. LCMS m/z (%) = 492 (M+H 35Cl 79Br, 100). 1H NMR (400 MHz, MeOD) delta ppm 3.1 (m, 4 H), 3.7 (s, 3 H)3 4.1 (m, 3 H), 4.2 (m, 1 H), 6.8 (dd, J=7.6, 2.0 Hz, 1 H), 7.1 (d, 3=7.6 Hz, 1 H), 7.1 (d, J=9.1 Hz, 1 H), 7.3 (d, J=3.0 Hz, 1 H), 7.5 (s, 1 H), 7.6 (dd, J=9.1, 2.5 Hz, 1 H)5 7.8 (d, J=2.0 Hz, 1 H).

References: [1]Patent: WO2007/136703,2007,A1 .Location in patent: Page/Page column 176-177.

11
[ 52537-00-5 ]
[ 917918-15-1 ]
rac-6,6'-Dichloro-3'-(3-chloro-benzyl)-2,3,1',3'-tetrahydro-[1,3']biindolyl-2'-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	EXAMPLE 208b Preparation of rac-6,6'-Dichloro-3'-(3-chloro-benzyl)-2,3,1',3'-tetrahydro-[1,3']biindolyl-2'-one The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) (from example 1c supra), <strong>[52537-00-5]6-chloro-2,3-dihydro-1H-indole</strong> (62 mg, 0.45 mmol) and K2CO3 (110 mg, 0.80 mmol) in DMF (1 mL) was stirred at room temperature overnight. Then water (10 mL) was added and the desired product was precipitated out. The crude product was purified by prep-HPLC to give 55 mg rac-6,6'-Dichloro-3'-(3-chloro-benzyl)-2,3,1',3'-tetrahydro-[1,3']biindolyl-2'-one. MS: [M+H]+=443

References: [1]Patent: US2008/81810,2008,A1 .Location in patent: Page/Page column 68.

12
[ 52537-00-5 ]
1-(6-chloroindolinyl)-2-(4-(4-chlorobenzyl)piperazinyl)ethan-1-one [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3105 - 3109.

13
[ 52537-00-5 ]
6-Chloro-2,3-dihydro-1H-indole-5-thiol [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 3494 - 3496.

14
[ 52537-00-5 ]
[ 162100-60-9 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 3494 - 3496.

15
[ 52537-00-5 ]
6-Chloro-5-methylthio-1-(pyridin-3-ylcarbamoyl)indoline [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 3494 - 3496.

16
[ 52537-00-5 ]
[ 496-15-1 ]

Yield	Reaction Conditions	Operation in experiment
39%	With sodium cyanoborohydride; In acetic acid; for 10h;	Sodium cyanoborohydride (4. [88] g, 77.8 mmol) was added to a solution of 6- chloroindoline (5.9 g, [38.] 9 mmol) in acetic acid (100 mL). Gas evolution was evident at the beginning of the reaction. After stirring for 10 h, the solution was diluted with water (100 mL) and 6 N [NAOH] was added until the pH of the reaction mixture was 12-13. The resulting mixture was extracted with [CH2CLZ] (3 x 200 mL), and the combined organic layers dried over [MGS04.] Flash column chromatography on silica gel (35% [ETOAC/HEXANES)] yielded 2.3 g (39%) of a clear liquid : 1H NMR (DMSO-d6) 8 2.87 (t, J= 8.4 Hz, 2H), 3.44 (t, [J =] 8.4 Hz, 2H), 6.45 (d, J= 1.8 Hz, 1H), 6.47 (dd, J = 1.8, 7.6 Hz, 1H), 6.96 (d, J = 7.3 Hz, 1H).

References: [1]Patent: WO2004/18414,2004,A2 .Location in patent: Page 135-136.

17
[ 52537-00-5 ]
1-chloro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole maleic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In 4,5,8,9,10,1-Hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole Hydrochloride;	EXAMPLE 40 Preparation of 1-Chloro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole Maleic Acid Following the general procedure outlined in EXAMPLE 14, and making non-critical variations but starting with <strong>[52537-00-5]6-chloro-indoline</strong>, the title compound was obtained (amorphous solid). 1H NMR (CD3OD) 6.91, 6.81, 6.77, 4.90, 3.69, 3.34, 3.21; MS (ESI+) for C14H15ClN2 m/z 247.2 (M+H)+.

References: [1]Patent: US6407092,2002,B1 .

18
[ 52537-00-5 ]
[ 51752-67-1 ]
4-(6-chloro-2,3-dihydro-indol-1-yl)-pyrido[3,4-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane; N,N-dimethyl-formamide;	EXAMPLE 37 4-(6-Chloro-2,3-dihydro-indol-1-yl)-pyrido[3,4-d ]pyrimidine 4-Chloropyrido[3,4-d]pyrimidine (0.10 g, 0.60 mmol), <strong>[52537-00-5]6-chloroindoline</strong> (0.10 g, 0.66 mmol) and pyridine (0.14 g, 1.81 mmol) were combined in DMF (1 mL) and heated at 70 C. for 3 hours. The reaction was cooled to room temperature and then added to methylene chloride (150 mL). The organic layer was washed with saturated sodium carbonate and water and then dried over sodium sulfate. The solvent was removed by rotary evaporation and the residue purified by column chromatography (silica gel, 9/2/1-CH2Cl2/hexanes/methanol) to give the title product as a pale yellow residue (0.048 g, 28%). MP 194-6 C.; LCMS: 283 (MH+).

References: [1]Patent: US6395733,2002,B1 .

19
4-Chloropyrido[3,4]pyrimidine [ No CAS ]
[ 52537-00-5 ]
[ 51752-67-1 ]
4-(6-chloro-2,3-dihydro-indol-1-yl)-pyrido[3,4-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane; N,N-dimethyl-formamide;	EXAMPLE 28 4-(6-Chloro-2,3-dihydro-indol-1-yl)-pyrido[3,4-d]pyrimidine 4-Chloropyrido[3,4]pyrimidine (0.10 g, 0.60 mmol), <strong>[52537-00-5]6-chloroindoline</strong> (0.10 g, 0.66 mmol) and pyridine (0.14 g, 1.81 mmol) were combined in DMF (1 mL) and heated at 70 C. for 3 hr. The reaction was cooled to room temperature and then added to methylene chloride (150 mL). The organic layer was washed with saturated sodium carbonate and water and then dried over sodium sulfate. The solvent was removed by rotary evaporation and the residue purified by column chromatography (silica gel, 9/2/1-CH2Cl2/hexanes/methanol) to give a pale yellow residue (0.048 g, 28%). MP 194-6 C.; LCMS: 283 (MH+). The products of examples 29-31 were prepared according to the method of Example 1 from 4-chloropyrido[3,4-d]pyrimidine (1 eq.) and the indicated amine.

References: [1]Patent: US6395733,2002,B1 .

20
[ 186520-04-7 ]
[ 52537-00-5 ]
4-(6-chloro-2,3-dihydro-indol-1-yl)-6-methyl-pyrido[3,4-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With ammonium acetate; In acetonitrile;	EXAMPLE 76 4-(6-Chloro-2,3-dihydro-indol-1-yl)-6-methyl-pyrido[3,4-d]pyrimidine This material was produced from 4-chloro-6-methyl-pyrido[3,4-d]pyrimidine (1.0 eq.) and <strong>[52537-00-5]6-chloroindoline</strong> (1.1 eq.) as described for Example 74. Preparative reversed-phase (C18) chromatography utilizing a gradient of 15% to 70% acetonitrile/pH4.5, 50 mM ammonium acetate followed by lyophilization of the appropriate fractions afforded the title product (30%) (M.P. 232-234 C.; LC-MS: 297 (MH+); anal.RP-HPLC:4.33 min.).

References: [1]Patent: US6395733,2002,B1 .

21
[ 187724-90-9 ]
[ 52537-00-5 ]
4-(6-chloro-2,3-dihydroindol-1-yl)-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]-pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 8 4-(6-Chloro-2,3-dihydroindol-1-yl)-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]-pyrimidine This product is prepared in a manner analogous to that described in Example 6 from 4-chloro-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and <strong>[52537-00-5]6-chloro-2,3-dihydroindole</strong> (1.1 equivalents).

References: [1]Patent: US6140317,2000,A .

22
[ 52537-00-5 ]
[ 82703-38-6 ]
4-(6-Chloro-2.3-dihydroindol-1-yl)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 2 4-(6-Chloro-2.3-dihydroindol-1-yl)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine This product is prepared in a manner analogous to that described in Example 1 from 4-chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine and <strong>[52537-00-5]6-chloro-2,3-dihydroindole</strong> (1.1 equi-valents, see J. Org. Chem. 55(2), 580-584 (1990); CAS Reg. No. 52 537-00-5).

References: [1]Patent: US6140317,2000,A .

Yield	Reaction Conditions	Operation in experiment
74.9%	With sodium cyanoborohydride; acetic acid; at 25℃; for 1h;	General procedure: At 25 , 5-methoxy-indole (1.5g, 10.2mmol) was added to acetic acid (20 mL), and then added portionwise sodium cyanoborohydride (0.77g, 12.2mmol), 1 hour reaction, was added sodium hydroxide solution (20%) neutralized to pH = 9 ~ 10, then ethyl acetate (50 mL) and extracted, the organic phase after separation was dried over anhydrous sodium sulfate. Filtered, the filtrate was spin dry, purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 10/1) to give the title compound as a brown solid (1.46g, 95.9%).
		Preparation 39 6-Chloro-indoline This material was conveniently prepared on multigram scale from the cyclization of 2,4-dichlorophenethylamine in the presence of Na2 CO3 (s)(s) (1.2 mol eq), Cu2 Cl2 (0.01 mol eq) and 8-hydroxyquinoline (0.012 mol eq) in isoamyl alcohol (1 vol) at 130 C. for 5 hours. After addition of hydrazine (0.0055 vol) and 1 hour reflux, the mixture was filtered, solvent was removed in vacuo (45 C. a ~10 mm Hg) and 6-chloro-indoline was obtained pure by vacuum distillation (95-100 C. a 2 mm Hg)(65-95%).
		4.21 g (31.57 mmol*1.05 equivalents) of chloropropionyl chloride in 40 ml of acetone were added at room temperature to a solution of 4.85 g (31.57 mmol) of 6-chloroindoline ?prepared as described in step (5) above! in acetone, and the mixture was heated under reflux for 2 hours. At the end of this time, the reaction mixture was poured into 10% w/v aqueous hydrochloric acid, and the solids which precipitated were collected by filtration. The filtrate was extracted with ethyl acetate and washed with water, after which it was dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent was removed by distillation under reduced pressure, and the residue was dissolved in a small amount of ethyl acetate.

24
[ 55496-52-1 ]
[ 52537-00-5 ]
[ 172079-14-0 ]