[ CAS No. 86626-38-2 ] {[proInfo.proName]}

Name: 86626-38-2|4-Bromoindoline|97%
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SKU: A393566
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Quality Control of [ 86626-38-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 86626-38-2 ]

Product Details of [ 86626-38-2 ]

CAS No. :	86626-38-2	MDL No. :	MFCD07371633
Formula :	C₈H₈BrN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YCJCSDSXVHEBRU-UHFFFAOYSA-N
M.W :	198.06	Pubchem ID :	13098386
Synonyms :

Calculated chemistry of [ 86626-38-2 ]

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 :	49.23
TPSA :	12.03 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) :	-5.64 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.95
Log Po/w (XLOGP3) :	2.63
Log Po/w (WLOGP) :	1.85
Log Po/w (MLOGP) :	2.49
Log Po/w (SILICOS-IT) :	2.89
Consensus Log Po/w :	2.36

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.17
Solubility :	0.134 mg/ml ; 0.000678 mol/l
Class :	Soluble
Log S (Ali) :	-2.53
Solubility :	0.581 mg/ml ; 0.00293 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.86
Solubility :	0.0276 mg/ml ; 0.000139 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.64

Safety of [ 86626-38-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 86626-38-2 ]

* 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 [ 86626-38-2 ]
Downstream synthetic route of [ 86626-38-2 ]

[ 86626-38-2 ] Synthesis Path-Upstream 1~6

1
[ 86626-38-2 ]
[ 20780-72-7 ]

Yield	Reaction Conditions	Operation in experiment
87%	With iodine pentoxide In dimethyl sulfoxide at 80℃;	General procedure: Indoles 1 (0.5 mmol), DMSO (3mL) and I₂O₅(1 mmol) were added into a flask and vigorously stirred at 80^oC under air. The reaction was stopped until indoles were completely consumed as monitored by TLC analysis. After the completion of reaction, saturated Na₂S₂O₃ solution (20 mL) was added to the mixture. The mixture was extracted with EtOAc (3×20 mL) and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator. Then, the crude product was purified by column chromatography on silica gel using ethyl acetate and petroleum ether as the eluent to give the products 2.

Reference： [1] Tetrahedron Letters, 2017, vol. 58, # 18, p. 1747 - 1750

2
[ 52488-36-5 ]
[ 86626-38-2 ]

Yield	Reaction Conditions	Operation in experiment
52%	Stage #1: With sodium cyanoborohydride; acetic acid In methanol at 0 - 20℃; for 1 h; Stage #2: With sodium hydrogencarbonate In water	Step 1. 4-Bromoindole (5.00 mL, 39.9 mmol) was dissolved in a mixture of acetic acid (5.00 mL, 87.9 mmol) and methanol (25.0 mL, 617 mmol) and cooled to 0° C. Sodium cyanoborohydride (7.52 g, 0.120 mol) was added and the mixture was slowly warmed to room temperature over a period of 1 h. The reaction mixture was then concentrated and neutralized using a saturated aqueous solution of sodium bicarbonate. The organics were extracted with ether and ethyl acetate (and the combined organics were washed with brine, dried, filtered, and concentrated to afford 4.11 g (52percent yield) of 4-bromoindoline.

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2462 - 2471
[2] Patent: US2007/265258, 2007, A1, . Location in patent: Page/Page column 24
[3] Patent: WO2007/100880, 2007, A1, . Location in patent: Page/Page column 81
[4] Journal of Medicinal Chemistry, 2011, vol. 54, # 1, p. 166 - 178
[5] Organic Letters, 2013, vol. 15, # 22, p. 5662 - 5665
[6] Journal of Organic Chemistry, 2018, vol. 83, # 4, p. 2425 - 2437
[7] Organic and Biomolecular Chemistry, 2018, vol. 16, # 32, p. 5889 - 5898
[8] Chemical Communications, 2018, vol. 54, # 20, p. 2494 - 2497

3
[ 99365-48-7 ]
[ 86626-38-2 ]

Yield	Reaction Conditions	Operation in experiment
45%	Stage #1: With borane-THF In tetrahydrofuran at 20℃; Stage #2: With hydrogenchloride; methanol; water In tetrahydrofuran at 0 - 20℃; for 1 h; Stage #3: With sodium hydroxide In tetrahydrofuran; methanol; water	Step 85a: 73/4rt-butyl 4-bromoindoline-l-carboxylate (Compound 0601-177)A mixture of 4-bromooxindole (2.77 g, 0.01 mol) and a solution of BH₃ in THF (2M, 40 mL) was stirred at room temperature overnight. The mixture was cooled to 0°C and diluted with 30 mL of methanol, followed by addition of 12 N HC1 (7.5 mL). The resulting mixture was stirred at room temperature for 1 hour, adjusted to pH 8-9 with 10percent> aqueous NaOH. Water was added to the mixture and extracted with ethyl acetate (3 x 100 mL). The organic layer was dried and concentrated to get the crude product which was washed through a silica gel column (ethyl acetate in petroleum ether (10percent). The crude product was dissolved in 10percent HC1 (3 x 10 mL). The aqueous layer was adjusted to pH7 with NaHC0₃, extracted with ethyl acetate (3 x 20 mL). The organic layer was dried and concentrated to get 4-bromoindoline (1.16 g, 45percent) as an oil. LCMS: 200 [M+l]⁺. 1H-NMR (400 MHz. OMSO-d₆) δ 2.90 (t, J= 8.8 Hz, 2H), 3.46 (t, J= 8.8 Hz, 2H), 5.86 (s, 1H), 6.43 (m, 1H), 6.64 (m, 1H), 6.83 (t, J= 8.0 Hz, 1H).
45%	With borane-THF In tetrahydrofuran at 20℃;	Step 85a: Tert-butyl 4-bromoindoline-1-carboxylate (Compound 0601-177)[0565]A mixture of 4-bromooxindole (2.77 g, 0.01 mol) and a solution of BH₃in THF (2 M, 40 mL) was stirred at room temperature overnight. The mixture was cooled to 0° C. and diluted with 30 mL of methanol, followed by addition of 12 N HCl (7.5 mL). The resulting mixture was stirred at room temperature for 1 hour, adjusted to pH 8-9 with 10percent aqueous NaOH. Water was added to the mixture and extracted with ethyl acetate (3×100 mL). The organic layer was dried and concentrated to get the crude product which was washed through a silica gel column (ethyl acetate in petroleum ether (10percent). The crude product was dissolved in 10percent HCl (3×10 mL). The aqueous layer was adjusted to pH7 with NaHCO₃, extracted with ethyl acetate (3×20 mL). The organic layer was dried and concentrated to get 4-bromoindoline (1.16 g, 45percent) as an oil. LCMS: 200 [M+1]⁺. ¹H-NMR (400 MHz. DMSO-d₆) δ 2.90 (t, J=8.8 Hz, 2H), 3.46 (t, J=8.8 Hz, 2H), 5.86 (s, 1H), 6.43 (m, 1H), 6.64 (m, 1H), 6.83 (t, J=8.0 Hz, 1H).
45%	Stage #1: With diborane In tetrahydrofuran at 20℃; Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water at 0 - 20℃; for 1 h;	THF (2M, 40mL) solution of 4-bromo-oxindole (2.77g, 0.01mol) A mixture of and BH3 solution was stirred at room temperature overnight. The mixture was cooled to 0 diluted with methanol 30 mL, followed by addition of 12N HCl (7.5mL). The resulting mixture was stirred for 1 hour at room temperature and adjusted to pH 8 ~. 9 with 10percent aqueous NaOH. With the addition of water to the mixture, and the mixture was extracted with ethyl acetate (3x100mL). The organic layer was dried and concentrated to give the crude product, which was dissolved in a silica gel column (washing through petroleum ether in ethyl acetate (10percent). The crude product was 10percent HCl (3 × 10 mL). Water adjust to the layer with NaHCO3 pH 7, and extracted with ethyl acetate (3 × 20 mL). the organic layer was dried and concentrated to give 4-bromo-indoline (1.16g, 45percent) as an oil.

Reference： [1] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 224-225
[2] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0564; 0565
[3] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0480

4
[ 496-15-1 ]
[ 86626-38-2 ]
[ 63839-24-7 ]

Reference： [1] Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 349 - 352
[2] Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 349 - 352
[3] Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 349 - 352

5
[ 496-15-1 ]
[ 86626-38-2 ]
[ 63839-24-7 ]

6
[ 24424-99-5 ]
[ 86626-38-2 ]
[ 885272-46-8 ]

Yield	Reaction Conditions	Operation in experiment
74%	at 20℃;	A mixture of above obtained 4-bromoindoline (759 mg, 3.81 mmol), and (Boc)₂0 (976 mg, 4.48 mmol) in MeCN (8 mL) was stirred at room temperature overnight. After evaporated, the residue was dissolved in ethyl acetate (40 mL), washed with water (3 x 20 mL) and brine (1 x 20 mL). The organic layer was concentrated and purified by column chromatography on silica gel (petroleum ether) to give 0601-177(840 mg, 74percent>) as a white solid. 1H-NMR (400 MHz. DMSO-<3/4) δ 1.50 (s, 9H), 3.02 (t, J= 8.8 Hz, 2H), 3.94 (t, J = 8.8 Hz, 2H), 7.12 (m, 2H), 7.56 (m, 1H).
74%	at 20℃;	A mixture of above obtained 4-bromoindoline (759 mg, 3.81 mmol), and (Boc)₂O (976 mg, 4.48 mmol) in MeCN (8 mL) was stirred at room temperature overnight. After evaporated, the residue was dissolved in ethyl acetate (40 mL), washed with water (3×20 mL) and brine (1×20 mL). The organic layer was concentrated and purified by column chromatography on silica gel (petroleum ether) to give 0601-177 (840 mg, 74percent) as a white solid. ¹H-NMR (400 MHz. DMSO-d₆) δ 1.50 (s, 9H), 3.02 (t, J=8.8 Hz, 2H), 3.94 (t, J=8.8 Hz, 2H), 7.12 (m, 2H), 7.56 (m, 1H).
74%	at 20℃;	Obtained above in MeCN (8mL) 4- bromo-indoline (759mg, 3.81mmol) and the mixture of (Boc) 2O (976mg, 4.48mmol) was stirred at room temperature overnight. After evaporation, the residue was dissolved in ethyl acetate (40 mL), washed with water (3 × 20 mL) and brine (1x20mL). The organic layer was concentrated and purified by column chromatography on silica gel (petroleum ether) to give 0601-177 as a white solid (840 mg, 74percent).

62.5%

With dmap In dichloromethane at 20℃; for 48 h;

To a solution of 4-bromoindoline (12.2 g, 61.6 mmol) in dichloromethane (200 mL) was added Boc₂0 (14.8 g, 67.8 mmol) and DMAP (0.75 g, 6.16 mmol). The mixture was stirred at room temperature for 48 h and then evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0 to 10percent gradient) to provide the title compound (11.5 g, 62.5percent). 1H NMR (CDC1₃) δ: 7.80 (br. s, 1H), 6.98-7.12 (m, 2H), 4.00 (t, J=8.7 Hz, 2H), 3.08 (t, J=8.7 Hz, 2H), 1.50-1.66 (s, 9H).

Reference： [1] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 225
[2] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0566
[3] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0481
[4] Patent: WO2016/25933, 2016, A2, . Location in patent: Page/Page column 185

[ 86626-38-2 ] Synthesis Path-Downstream 1~88

1
[ 496-15-1 ]
[ 86626-38-2 ]
[ 63839-24-7 ]

Reference： [1]Journal of Heterocyclic Chemistry,1983,vol. 20,p. 349 - 352
[2]Journal of Heterocyclic Chemistry,1983,vol. 20,p. 349 - 352
[3]Journal of Heterocyclic Chemistry,1983,vol. 20,p. 349 - 352

2
[ 86626-38-2 ]
[ 13790-39-1 ]
[ 949158-20-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; sodium iodide; In N,N-dimethyl acetamide; at 160℃; for 2.75h;	Step 2. 4-Chloro-6,7-dimethoxyquinazoline (2.20 g, 9.9 mmol) was added to a solution of <strong>[86626-38-2]4-bromoindoline</strong> (1.97 g, 9.95 mmol, prepared as described in Step 1) in N,N-dimethylacetamide (50 mL). Sodium iodide (0.7 g, 4 mmol) and potassium carbonate (0.55 g, 39.8 mmol) were then added, and the resulting mixture was heated at 160 C. for 2.75 h. The reaction mixture was diluted with water and extracted with ethyl acetate (100 mL). The organic layer was washed with water and brine, dried, filtered, and concentrated to afford 1.89 g of 4-(4-bromo-2,3-dihydro-1H-indol-1-yl)-6,7-dimethoxyquinazoline.

Reference： [1]Patent: US2007/265258,2007,A1 .Location in patent: Page/Page column 24

3
[ 52488-36-5 ]
[ 86626-38-2 ]

Yield	Reaction Conditions	Operation in experiment
57.5%		At room temperature,4-Bromo-1H-indole (17 g, 87.19 mmol) was dissolved in glacial acetic acid (15 mL) and stirred for 10 min.Sodium cyanoborohydride (16.32 g, 258.92 mmol) was slowly added to the reaction mixture.After the addition was completed, the reaction was further stirred at room temperature for 1 hour.Add sodium hydroxide solution to the system to pH 8-9, extract with dichloromethane, wash the organic layer with saturated brine, and distill off the organic layer.Column chromatography gave 9.88 g of a yellow oil.The yield was 57.5%.
52%		Step 1. 4-Bromoindole (5.00 mL, 39.9 mmol) was dissolved in a mixture of acetic acid (5.00 mL, 87.9 mmol) and methanol (25.0 mL, 617 mmol) and cooled to 0 C. Sodium cyanoborohydride (7.52 g, 0.120 mol) was added and the mixture was slowly warmed to room temperature over a period of 1 h. The reaction mixture was then concentrated and neutralized using a saturated aqueous solution of sodium bicarbonate. The organics were extracted with ether and ethyl acetate (and the combined organics were washed with brine, dried, filtered, and concentrated to afford 4.11 g (52% yield) of 4-bromoindoline.
		Example 40; Synthesis of 7-methoxy-6-(2-methoxyethoxy)-4-(4-morpholin-4-yl-2,3-dihydro-lH-indol-l- yl)quinazoline; [00305] Step 1; 4-Bromoindole (5.00 mL, 0.0399 mol) is dissolved in a mixture of acetic acid (5.00 mL, 0.0879 mol) and methanol (25.0 mL, 0.617 mol) and cooled to 0 0C. Sodium cyanoborohydride (7.52 g, 0.120 mol) is added and the mixture is slowly warmed to room temperature over a period of 1 h. The reaction mixture is then concentrated and neutralized using a saturated aqueous solution of sodium bicarbonate. The organics are extracted with ether and ethyl acetate and the combined organics are washed with brine, dried, filtered, and concentrated to afford 4-bromoindoline.

Reference： [1]Organic Letters,2020
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471
[3]Patent: CN110128415,2019,A .Location in patent: Paragraph 0341; 0343-0345
[4]Patent: US2007/265258,2007,A1 .Location in patent: Page/Page column 24
[5]Patent: WO2007/100880,2007,A1 .Location in patent: Page/Page column 81
[6]Journal of Medicinal Chemistry,2011,vol. 54,p. 166 - 178
[7]Organic Letters,2013,vol. 15,p. 5662 - 5665
[8]Journal of Organic Chemistry,2018,vol. 83,p. 2425 - 2437
[9]Chemical Communications,2018,vol. 54,p. 2494 - 2497

4
[ 947691-52-3 ]
[ 86626-38-2 ]
4-(4-bromo-2,3-dihydro-1H-indol-1-yl)-7-methoxy-6-(2-methoxyethoxy)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; sodium iodide; In N,N-dimethyl acetamide; at 160℃; for 2.75h;	Step 2; 4-Bromo-7-methoxy-6-(2-methoxyethoxy)cinnoline (0.0099 mol) is added to a solution of <strong>[86626-38-2]4-bromoindoline</strong> (1970 mg, 0.00995 mol) in N,N-dimethylacetamide (50 <n="83"/>raL). Sodium iodide (700 mg, 0.004 mol) and potassium carbonate (550 mg, 0.0398 mol) are then added, and the resulting mixture is heated at 160 0C for 2.75 h. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with water and brine, dried, filtered, and concentrated to afford 4-(4-bromo-2>3-dihydro-lH-indol-l-yl)- 7- methoxy-6-(2-methoxyethoxy)quinazoline.

Reference： [1]Patent: WO2007/100880,2007,A1 .Location in patent: Page/Page column 81-82

5
[ 86626-38-2 ]
[ 459-46-1 ]
[ 1160359-95-4 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium hydride; In N,N-dimethyl-formamide; at 20℃;	To <strong>[86626-38-2]4-bromoindoline</strong> (200 mg, 1.00 mmol) in 5 ml DMF was added 4- Fluorobenzylbromide (0.14 ml, 1.1 mmol) then add NaH (40 mg, 1.0 mmol) and stir at room temperature overnight. Work up by adding water and EtOAc and extract three times with EtOAc. Pool all organics and wash one time with brine then dry over sodium sulfate, filter and concentrate to dryness. The residue was purified by chromatography over silica gel (eluted with Hexanes/EtOAc 99:1 to 50:50) to provide 280 mg (92%) of product

Reference： [1]Patent: WO2009/73777,2009,A1 .Location in patent: Page/Page column 189

6
[ 86626-38-2 ]
[ 124-63-0 ]
[ 1100508-87-9 ]

Yield	Reaction Conditions	Operation in experiment
83%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃;	4-Bromo- 1 -(methylsulfonvDindoline4-Bromo-2,3-dihydro-lH-indole (1.0 g, 5.0 mmol) and DIPEA (0.95 mL, 5.5 mmol) were mixed in dry DMF (5 mL) and cooled to 0 0C. Methanesulphonylchloride (0.60 mL, 5.0 mmol) was added dropwise at 0 0C. The reaction mixture was allowed to reach RT and stirred overnight. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with 0.1N HCl, dried (Na2SO4) and concentrated. The residue was purified by column chromatography eluting with heptane/EtOAc 3:1, concentrated, washed with heptane/EtOAc 3:1 and filtered to give a solid product (0.73 g, 83%). <n="33"/>1H-NMR (CDCl3): delta 7.37 - 7.32 (m, IH), 7.21 - 7.16 (m, IH), 7.12 - 7.05 (m, IH), 4.03 (t, J= 8.7 Hz, 2H), 3.17 (t, J= 8.5 Hz, 2H), 2.90 (s, 3H); GC-MS m/z: 275/277 1 : 1 [M+].

Reference： [1]Patent: WO2009/7747,2009,A2 .Location in patent: Page/Page column 31-32

7
[ 86626-38-2 ]
[ 109-94-4 ]
[ 1100509-03-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	at 80℃; for 24h;	4-Bromoindoline- 1 -carbaldehyde4-Bromo-2,3-dihydro-lH-indole (0.9 g, 4.5 mmol) was mixed with ethyl formate (5 mL) and stirred at 80 0C for 24h. When cooling to RT, white needles precipitated that were collected by filtration to give the product (1.0 g, 92%). 1H-NMR (300 MHz, CDCl3): delta 8.91 and 8.51 rotamers 4:1 (s, IH), 8.05 - 8.00 and 7.24 - 7.02 (m, 3H), 4.21 - 4.05 (m, 2H), 3.24 - 3.08 (m, 2H); APCI-MS m/z: 226/228 1:1 [MH+].

Reference： [1]Patent: WO2009/7747,2009,A2 .Location in patent: Page/Page column 41

8
[ 87-72-9 ]
[ 86626-38-2 ]
C₁₃H₁₆BrNO₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 166 - 178

9
[ 24424-99-5 ]
[ 86626-38-2 ]
[ 885272-46-8 ]

Yield	Reaction Conditions	Operation in experiment
74%	In acetonitrile; at 20℃;	A mixture of above obtained 4-bromoindoline (759 mg, 3.81 mmol), and (Boc)20 (976 mg, 4.48 mmol) in MeCN (8 mL) was stirred at room temperature overnight. After evaporated, the residue was dissolved in ethyl acetate (40 mL), washed with water (3 x 20 mL) and brine (1 x 20 mL). The organic layer was concentrated and purified by column chromatography on silica gel (petroleum ether) to give 0601-177(840 mg, 74%>) as a white solid. 1H-NMR (400 MHz. DMSO-<¾) delta 1.50 (s, 9H), 3.02 (t, J= 8.8 Hz, 2H), 3.94 (t, J = 8.8 Hz, 2H), 7.12 (m, 2H), 7.56 (m, 1H).
74%	In acetonitrile; at 20℃;	A mixture of above obtained 4-bromoindoline (759 mg, 3.81 mmol), and (Boc)2O (976 mg, 4.48 mmol) in MeCN (8 mL) was stirred at room temperature overnight. After evaporated, the residue was dissolved in ethyl acetate (40 mL), washed with water (3×20 mL) and brine (1×20 mL). The organic layer was concentrated and purified by column chromatography on silica gel (petroleum ether) to give 0601-177 (840 mg, 74%) as a white solid. 1H-NMR (400 MHz. DMSO-d6) delta 1.50 (s, 9H), 3.02 (t, J=8.8 Hz, 2H), 3.94 (t, J=8.8 Hz, 2H), 7.12 (m, 2H), 7.56 (m, 1H).
74%	In acetonitrile; at 20℃;	Obtained above in MeCN (8mL) 4- bromo-indoline (759mg, 3.81mmol) and the mixture of (Boc) 2O (976mg, 4.48mmol) was stirred at room temperature overnight. After evaporation, the residue was dissolved in ethyl acetate (40 mL), washed with water (3 × 20 mL) and brine (1x20mL). The organic layer was concentrated and purified by column chromatography on silica gel (petroleum ether) to give 0601-177 as a white solid (840 mg, 74%).

62.5%

With dmap; In dichloromethane; at 20℃; for 48.0h;

To a solution of 4-bromoindoline (12.2 g, 61.6 mmol) in dichloromethane (200 mL) was added Boc20 (14.8 g, 67.8 mmol) and DMAP (0.75 g, 6.16 mmol). The mixture was stirred at room temperature for 48 h and then evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0 to 10% gradient) to provide the title compound (11.5 g, 62.5%). 1H NMR (CDC13) delta: 7.80 (br. s, 1H), 6.98-7.12 (m, 2H), 4.00 (t, J=8.7 Hz, 2H), 3.08 (t, J=8.7 Hz, 2H), 1.50-1.66 (s, 9H).

Reference： [1]Patent: WO2011/130628,2011,A1 .Location in patent: Page/Page column 225
[2]Patent: US2013/102595,2013,A1 .Location in patent: Paragraph 0566
[3]Patent: JP2015/187145,2015,A .Location in patent: Paragraph 0481
[4]Patent: WO2016/25933,2016,A2 .Location in patent: Page/Page column 185

10
[ 99365-48-7 ]
[ 86626-38-2 ]

Yield	Reaction Conditions	Operation in experiment
45%		Step 85a: 7¾rt-butyl 4-bromoindoline-l-carboxylate (Compound 0601-177)A mixture of <strong>[99365-48-7]4-bromooxindole</strong> (2.77 g, 0.01 mol) and a solution of BH3 in THF (2M, 40 mL) was stirred at room temperature overnight. The mixture was cooled to 0C and diluted with 30 mL of methanol, followed by addition of 12 N HC1 (7.5 mL). The resulting mixture was stirred at room temperature for 1 hour, adjusted to pH 8-9 with 10%> aqueous NaOH. Water was added to the mixture and extracted with ethyl acetate (3 x 100 mL). The organic layer was dried and concentrated to get the crude product which was washed through a silica gel column (ethyl acetate in petroleum ether (10%). The crude product was dissolved in 10% HC1 (3 x 10 mL). The aqueous layer was adjusted to pH7 with NaHC03, extracted with ethyl acetate (3 x 20 mL). The organic layer was dried and concentrated to get 4-bromoindoline (1.16 g, 45%) as an oil. LCMS: 200 [M+l]+. 1H-NMR (400 MHz. OMSO-d6) delta 2.90 (t, J= 8.8 Hz, 2H), 3.46 (t, J= 8.8 Hz, 2H), 5.86 (s, 1H), 6.43 (m, 1H), 6.64 (m, 1H), 6.83 (t, J= 8.0 Hz, 1H).
45%	With borane-THF; In tetrahydrofuran; at 20℃;	Step 85a: Tert-butyl 4-bromoindoline-1-carboxylate (Compound 0601-177)[0565]A mixture of <strong>[99365-48-7]4-bromooxindole</strong> (2.77 g, 0.01 mol) and a solution of BH3 in THF (2 M, 40 mL) was stirred at room temperature overnight. The mixture was cooled to 0 C. and diluted with 30 mL of methanol, followed by addition of 12 N HCl (7.5 mL). The resulting mixture was stirred at room temperature for 1 hour, adjusted to pH 8-9 with 10% aqueous NaOH. Water was added to the mixture and extracted with ethyl acetate (3×100 mL). The organic layer was dried and concentrated to get the crude product which was washed through a silica gel column (ethyl acetate in petroleum ether (10%). The crude product was dissolved in 10% HCl (3×10 mL). The aqueous layer was adjusted to pH7 with NaHCO3, extracted with ethyl acetate (3×20 mL). The organic layer was dried and concentrated to get 4-bromoindoline (1.16 g, 45%) as an oil. LCMS: 200 [M+1]+. 1H-NMR (400 MHz. DMSO-d6) delta 2.90 (t, J=8.8 Hz, 2H), 3.46 (t, J=8.8 Hz, 2H), 5.86 (s, 1H), 6.43 (m, 1H), 6.64 (m, 1H), 6.83 (t, J=8.0 Hz, 1H).
45%		THF (2M, 40mL) solution of <strong>[99365-48-7]4-bromo-oxindole</strong> (2.77g, 0.01mol) A mixture of and BH3 solution was stirred at room temperature overnight. The mixture was cooled to 0 diluted with methanol 30 mL, followed by addition of 12N HCl (7.5mL). The resulting mixture was stirred for 1 hour at room temperature and adjusted to pH 8 ~. 9 with 10% aqueous NaOH. With the addition of water to the mixture, and the mixture was extracted with ethyl acetate (3x100mL). The organic layer was dried and concentrated to give the crude product, which was dissolved in a silica gel column (washing through petroleum ether in ethyl acetate (10%). The crude product was 10% HCl (3 × 10 mL). Water adjust to the layer with NaHCO3 pH 7, and extracted with ethyl acetate (3 × 20 mL). the organic layer was dried and concentrated to give 4-bromo-indoline (1.16g, 45%) as an oil.

Reference： [1]Patent: WO2011/130628,2011,A1 .Location in patent: Page/Page column 224-225
[2]Patent: US2013/102595,2013,A1 .Location in patent: Paragraph 0564; 0565
[3]Patent: JP2015/187145,2015,A .Location in patent: Paragraph 0480

11
[ 557-21-1 ]
[ 86626-38-2 ]
[ 885278-80-8 ]

Yield	Reaction Conditions	Operation in experiment
	tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl acetamide; at 100℃; for 4h;Inert atmosphere; Sealed tube;	Example 21: Synthesis of 3-[(R)-l-(4-Cyano-2,3-dihydro-indole-l-carbonyl)- pyrrolidin-2-yl]-N-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)- benzamide trifluoroacetic acid (Compound 42). Degas a solution of 4-bromo-2,3-dihydro-lH-indole (250 mg, 1.224 mmol) in DMAC (2 mL) under Ar. To this add zinc cyanide (147 mg, 1.224 mmol) followed by tetrakis- (triphenylphosphine) palladium(O) (143 mg, 0.123 mmol) and heat the reaction under argon in a sealed tube at 100 C for 4 h. Quench the cooled reaction with sat. NH4C1 (50 mL) and extract with EtOAc (3 x 50 mL). Wash the organics with water (50 mL), dry (Na2S04), then concentrate in vacuo to give a gum. Purify by silica gel chromatography eluting with 5% to 30% EtOAc/hexane. Pool and concentrate fractions containing product then dissolve the residue in Et20 (5 mL) and hexane (50 mL). Reconcentrate this to a solid. Suspend in hexane and filter washing with hexane to afford 2,3-dihydro-lH- indole-4-carbonitrile as a powder (131 mg). MS, electrospray 145.2 (M+H), rt 1.02 min.
	tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl acetamide; at 100℃; for 4h;Inert atmosphere; Sealed tube;	Example 6: Synthesis of 4-cyano-2,3-dihydro-indole-l-carboxylic acid 3-(2-methyl- l,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzylamide (Cpd 201, Table 1); Degas a solution of 4-bromo-2,3-dihydro-lH-indole (250 mg, 1.224 mmol) indimethylacetamide (2 mL) under Ar. To this add zinc cyanide (147 mg, 1.224 mmol) followed by tetrakis-(triphenylphosphine) palladium(O) (143 mg, 0.123 mmol) and heat the reaction under argon in a sealed tube at 100C for 4 h. Quench the cooled reaction with sat. NH4CI (50 mL) and extract with EtOAc (3 x 50 mL). Wash the organics with water (50 mL), dry (Na2SC>4), then concentrate in vacuo to give a gum. Purify by silica gel chromatography eluting with 5% to 30% EtOAc/hexane. Pool and concentrate fractions containing product then dissolve the residue in Et20 (5 mL) and hexane (50 mL).Reconcentrate this to a solid. Suspend in hexane and filter washing with hexane to afford the product 2,3-dihydro-lH-indole-4-carbonitrile as a powder (131 mg, 0.863 mmol). MS, electrospray 145.2 (M+H), rt 1.02 min.

Reference： [1]Patent: WO2012/6202,2012,A1 .Location in patent: Page/Page column 85-86
[2]Patent: WO2012/6203,2012,A1 .Location in patent: Page/Page column 114-115

12
[ 86626-38-2 ]
[ 1354719-06-4 ]

Reference： [1]Patent: WO2012/6202,2012,A1

13
[ 86626-38-2 ]
C₁₃H₁₀N₄O [ No CAS ]

Reference： [1]Patent: WO2012/6202,2012,A1

14
[ 86626-38-2 ]
[ 1354555-09-1 ]

Reference： [1]Patent: WO2012/6203,2012,A1

15
[ 86626-38-2 ]
(E)-4-bromo-N,N-diethyl-7-styryl-1H-indole-1-carboxamide [ No CAS ]

Reference： [1]Organic Letters,2013,vol. 15,p. 5662 - 5665

16
[ 86626-38-2 ]
C₂₁H₂₃BrN₂O [ No CAS ]

Reference： [1]Organic Letters,2013,vol. 15,p. 5662 - 5665

17
[ 86626-38-2 ]
[ 88-10-8 ]
4-bromo-N,N-diethylindoline-1-carboxamide [ No CAS ]

Reference： [1]Organic Letters,2013,vol. 15,p. 5662 - 5665

18
[ 1260543-99-4 ]
[ 86626-38-2 ]
[ 1260584-84-6 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 903 - 920

19
[ 1384053-31-9 ]
[ 86626-38-2 ]
[ 1384053-83-1 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile; at 40℃; for 16h;	General procedure: to a suspension of iv (1mmol) in acetonitrile (10ml) was added 5-fluoroindoline (1.2mmol). The reaction mixture was stirred at 40C for 16h and then evaporated to dryness under reduced pressure. Water (10mL) and diethylether (15mL) were added and the resulting mixture was stirred for 5min. The precipitate formed was filtered off and dried to give 7 (86%) as a white solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1506 - 1510

20
[ 86626-38-2 ]
[ 407-25-0 ]
[ 1578263-84-9 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

21
[ 86626-38-2 ]
[ 1578263-46-3 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

22
[ 86626-38-2 ]
[ 1578263-48-5 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

23
[ 86626-38-2 ]
[ 1578263-49-6 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

24
[ 86626-38-2 ]
[ 1578263-50-9 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

25
[ 86626-38-2 ]
[ 1578263-51-0 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

26
[ 86626-38-2 ]
[ 1578263-52-1 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

27
[ 86626-38-2 ]
[ 1578263-53-2 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

28
[ 86626-38-2 ]
[ 1578263-54-3 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

29
[ 86626-38-2 ]
[ 1578263-55-4 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

30
[ 86626-38-2 ]
[ 1578263-56-5 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

31
[ 86626-38-2 ]
[ 1578263-57-6 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

32
[ 86626-38-2 ]
[ 1578263-58-7 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

33
[ 86626-38-2 ]
[ 1578263-59-8 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

34
[ 86626-38-2 ]
[ 1578263-60-1 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

35
[ 86626-38-2 ]
[ 1578263-61-2 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

36
[ 86626-38-2 ]
[ 1578263-62-3 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

37
[ 86626-38-2 ]
[ 1578263-63-4 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

38
[ 86626-38-2 ]
[ 1578263-64-5 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

39
[ 86626-38-2 ]
[ 1578263-65-6 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

40
[ 86626-38-2 ]
[ 1578263-66-7 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

41
[ 86626-38-2 ]
[ 1578263-67-8 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

42
[ 86626-38-2 ]
[ 1578263-68-9 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

43
[ 86626-38-2 ]
[ 1578263-69-0 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

44
[ 86626-38-2 ]
[ 1578263-70-3 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

45
[ 86626-38-2 ]
[ 1578263-71-4 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

46
[ 86626-38-2 ]
[ 1578263-72-5 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

47
[ 86626-38-2 ]
[ 1578263-73-6 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

48
[ 86626-38-2 ]
[ 1578263-74-7 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

49
[ 86626-38-2 ]
[ 1578263-47-4 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

50
[ 86626-38-2 ]
[ 1578263-85-0 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

51
[ 86626-38-2 ]
[ 885278-80-8 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2462 - 2471

52
[ 86626-38-2 ]
[ 1622173-44-7 ]

Reference： [1]Patent: WO2014/125410,2014,A1

53
[ 86626-38-2 ]
[ 73183-34-3 ]
[ 937591-97-4 ]

Reference： [1]Patent: WO2014/125410,2014,A1

54
[ 86626-38-2 ]
[ 73183-34-3 ]
[ 1622173-47-0 ]

Yield	Reaction Conditions	Operation in experiment
63%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 2h;Inert atmosphere; Sealed tube;	A solution of <strong>[86626-38-2]4-bromoindoline</strong> (694 mg, 3.50 mmol, 1.0 eq) in 1,4-dioxane (10 mL) was degassed with argon for 30 mm before the addition of bis(pinacolato)diboron (1 .07 g, 4.20 mmol, 1 .2 eq). Whilst degassing, potassiumacetate (1.03 g, 10.5 mmol, 3.0 eq) and PdCI2(dppf)CH2CI2 (143 mg, 0.175mmol, 5 mol%) were added. The vessel was then sealed and stirred at 100C for2 h. Upon cooling, the reaction mixture was diluted with H20 (5 mL), poured into50% brine (15 mL) and extracted with EtOAc (3 x 20 mL). The combined organicextracts were dried over MgSO4, filtered and concentrated in vacuo. Purificationby silica gel column chromatography with hexane/EtOAc (1:0-9:1) yieldedIntermediate 37 as a cream solid (539 mg, 63%).1H NMR (300MHz, CDCI3) oH. 7.17 (d, J=7.5 Hz, 1H), 7.04 (t, J7.5 Hz, 1H),6.77 (d, J=7.5 Hz, 1H), 3.48-3.61 (m, 2H), 3.18-3.31 (m, 2H), 1.84 (br. 5., 1H),1.33 (5, 12H).MS (ESj 246.2 (100%, [M+H]j.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 2h;Inert atmosphere;	Step-(i): Synthesis of 4-(4,4, 5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)indoline:To a stirred solution of <strong>[86626-38-2]4-bromoindoline</strong> (1.0 g, 5.07 mmol), bis(pinacolato)diborane (1.54 g, 6.09 mmol) and CH3COOK (1.50 g, 15.21 mmol) in 1,4-dioxane (20 mL) was added Pd(dppf)C12.DCM complex (0.4 10 g, 0.50 mmol). The reaction mixture was purged with argonfor 5 minutes and stirred at 100C for 2h. After the reaction was completed it was cooled to room temperature and the solvent was evaporated under reduced pressure. The obtained residue was extracted with ethyl acetate (2 x 250 mL). The combined organic layer was washed with brine, dried over sodium sulphate and concentrated to get the crude product. 1H NMR (400 MHz,CDC13): 7.07 (d, 1H, J=7.6 Hz), 6.94 (t, 1H, J=7.6 Hz), 6.69 (d, 1H, J=7.6 Hz), 3.45 (t, 2H,J=8.6 Hz), 3.15 (t, 2H, J=8.6 Hz), 1.24 (s, 12H); MS (ES) 246 (M+1).
1.4 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; dimethyl sulfoxide; for 2h;Reflux; Inert atmosphere;	A mixture of <strong>[86626-38-2]4-bromoindoline</strong> (1.000g, ) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (2.550g) and potassium acetate (2.220g) in 1, 4-dioxane (14.8mL) and DMSO (1.0mL) was purged with nitrogen for 10min. [1, 1'-Bis (diphenylphosphino) ferrocene] -dichloropalladium DCM adduct (0.127g) was added, the mixture was purged for another 5min then was heated at reflux for 2h. The mixture was cooled and filtered through Celite. The solids were washed with EtOAc, and the combined filtrates were washed with water and brine, and dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc using a gradient from 20: 1 to 85: 15) . 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline (compound 2-1) as a light yellow waxy solid (1.400g) .

Reference： [1]Patent: WO2017/29521,2017,A1 .Location in patent: Page/Page column 48; 49
[2]Patent: WO2014/125410,2014,A1 .Location in patent: Page/Page column 24
[3]Patent: WO2019/192506,2019,A1 .Location in patent: Page/Page column 45

55
[ 86626-38-2 ]
2-(4-bromoindolin-1-yl)ethanamine trifluoroacetate [ No CAS ]