[ CAS No. 99365-40-9 ] {[proInfo.proName]}

Name: 99365-40-9|6-Bromoindolin-2-one|98%
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SKU: A146590
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2D 3D

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Quality Control of [ 99365-40-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 99365-40-9 ]

Product Details of [ 99365-40-9 ]

CAS No. :	99365-40-9	MDL No. :	MFCD02179605
Formula :	C₈H₆BrNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JARRYVQFBQVOBE-UHFFFAOYSA-N
M.W :	212.04	Pubchem ID :	2773289
Synonyms :	6-Bromo-2-oxindole	Chemical Name :	6-Bromoindolin-2-one

Calculated chemistry of [ 99365-40-9 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	49.43
TPSA :	29.1 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) :	-6.28 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.78
Log Po/w (XLOGP3) :	1.85
Log Po/w (WLOGP) :	1.37
Log Po/w (MLOGP) :	1.87
Log Po/w (SILICOS-IT) :	2.53
Consensus Log Po/w :	1.88

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.72
Solubility :	0.401 mg/ml ; 0.00189 mol/l
Class :	Soluble
Log S (Ali) :	-2.08
Solubility :	1.76 mg/ml ; 0.00828 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.75
Solubility :	0.0379 mg/ml ; 0.000179 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.63

Safety of [ 99365-40-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 99365-40-9 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 99365-40-9 ]
Downstream synthetic route of [ 99365-40-9 ]

[ 99365-40-9 ] Synthesis Path-Upstream 1~9

1
[ 99365-40-9 ]
[ 6326-79-0 ]
[ 1147124-21-7 ]

Reference： [1] Chemical Communications, 2018, vol. 54, # 59, p. 8265 - 8268

2
[ 99365-40-9 ]
[ 63839-24-7 ]

Reference： [1] Patent: WO2010/128152, 2010, A1, . Location in patent: Page/Page column 106-107

3
[ 557-21-1 ]
[ 99365-40-9 ]
[ 199327-63-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	at 80℃; for 15 h;	Commercially available 6-bromoxindole (656 mg), zinc cyanide (288 mg) and tetrakis triphenylphosphine palladium(0) (175 mg) were suspended in dry N,N-dimethylformamide (6 mL). The resulting mixture was degassed by three pump/vent cycles with argon and then placed in a preheated oil bath (80° C.). After stirring at this temperature for 15 h the mixture was cooled to room temperature, diluted with water (60 mL) and extracted with ethyl acetate (3.x.60 mL). The combined organic layers were washed with water (2.x.60 mL), dried (MgSO₄), filtered and concentrated. The remaining residue was purified by flash chromatography (silica, dichloromethane/methanol) to afford the title compound (385 mg; 81percent). [MH]⁺=159.

Reference： [1] Patent: US2006/173183, 2006, A1, . Location in patent: Page/Page column 105

4
[ 557-21-1 ]
[ 99365-40-9 ]
[ 199327-63-4 ]

Yield	Reaction Conditions	Operation in experiment
80%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In N,N-dimethyl-formamide at 80℃; for 16 h;	bl .l) 2-Oxoindoline-6-carbonitrile A mixture of palladium-tetrakis(triphenylphosphine) (10.90 g, 9.43 mmol), 6- bromoindolin-2-one (10 g, 47.2 mmol) and dicyanozinc (7.75 g, 66.0 mmol) in DMF (80 mL) was heated to 80 °C for 16 h. The reaction mixture was cooled to rt and water was added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel column and elution with 5percent MeOH/CfLC^) to give 2-oxoindoline-6-carbonitrile (5.97 g, 37.7 mmol, 80 percent yield) as a brown solid. RT=1.15 min (3 min).

Reference： [1] Patent: WO2015/173393, 2015, A1, . Location in patent: Page/Page column 69

5
[ 99365-40-9 ]
[ 73183-34-3 ]
[ 893441-85-5 ]

Yield	Reaction Conditions	Operation in experiment
75%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In 1,2-dimethoxyethane at 80℃;	Four microwave vials were loaded as follows: 6-bromoindolin-2-one(500 mg, 2.36 mmol), bis(pinacolato)diboron (898 mg, 3.54 mmol),potassium acetate (694 mg, 7.07 mmol) and Pd(dppf)C12CH2C12 (96.0mg, 0.118 mmol) were dissolved in DME (17 mL). The reaction was heated at 80 °C overnight. The content of the four vials was then combined, concentrated and purified bycolumn chromatography (CyHex/EtOAc) to afford the title compound as a white solid (2.27 g, 75percent, purity 80percent). IH NMR (500 MHz, CDCI3) ppm = 8.57 (bs, IH), 7.48 (d, J7.3, IH), 7.31 (5, 1H), 7.23 (d, J=7.3, IH), 3.55 (s, 2H), 1.33 (s, 12H); LC — MS (ESI, mlz) Rt = 2.75 mm — 260 (M+H) (H PLC method E).
55%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In dimethyl sulfoxide at 90℃; for 18 h;	6-Brornoindohn-2-one 27) (2 00 u, 9 40 mmol) bispmacolatodiboron (6 00 g 23 60 mniol), potassium acetate (2.76g. 28.2 mmol) and diehloro[i,i’bis(dipheuylphosphino)feuocenrJj palladrum (11) dichloromethane addutt (0 40 g 0 55 rnniol) in DM80 (30 niL) were stirred at 90 °C tbr 18 hours, The reaction mixture was cooled to ambient temperature., then partitioned between water and ethyl acetate. Thelayers were separated and the aqueous layer extracted again with ethyl acetate (2x). The combined organic layers were washed with water and brine and concentrated to give a purple solid. The crude material was pre-absorbed onto Celite and chroniatographed (‘DCVC) eluting with a gradient of ethyl acetate in heptane (0 50percent ethyl. acetate.) Like fractions were combined and recrystallised from DCM and PE to give 6-(4,5,5-tetrainethyi—l,3,2—dioxahorolan—2yi)indoiin—2—one (24) as a colourless solid in 2 crops (1.33 g, 55percent); nip 178.5 181.4 °C. ‘H NMR (200 MHz, CDCI3) 8 8.61 (br s, 1H), 7.46 (d, 111. J7,4 Hz), 7.30 (s, lH), 7.21 (d. lH,J7.4 Hz), 3.53 (s, 2H). 1.32 (s. 1211).
40%	With potassium acetate In N,N-dimethyl-formamide at 95℃; for 18 h; Inert atmosphere; Sealed flask	6-bromoindolin-2-one (0.424 g; 2 mmol), potassium acetate (0.687 g; 7.0 mmol) and bis[pinacolato]diborane (0.762 g; 3.0 mmol) were placed in a 20 mL microwave vial, dissolved in dry DMF (13 mL) and the flask was purged with nitrogen. The catalyst [1 ,1 '- Bis(diphenylphosphino)ferrocene]palladium(ll) chloride, complex with dichloromethane (0.169 g; 0.20 mmol) was added, the flask was again purged with argon, sealed and the reaction was heated at 95⁰C for 18 h. The reaction mixture was diluted with water and the suspension was extracted twice with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (10 - 80 percent) in heptane furnished 0.390 g (40 percent) of the title compound.ESI/APCI(+): 260 (M₊H);1H NMR (DMSO-d6) δ 10.40 (s, 1 H), 7.27 (dd, J= 7,3, 0,8 Hz, 1 H), 7.21 (m, 1 H), 7.07 (s, 1 H), 3.50 (s, 2 H), 1.28 (s, 12 H).

39%	With potassium acetate In N,N-dimethyl-formamide at 90℃; for 16 h; Inert atmosphere	a) 6-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2- l)-1 ,3-dihydro-indol-2-one6-Bromo-1 ,3-dihydro-2H-indol-2-one (150 mg, 0.71 mmol), bis(pinacolato)diboron (233 mg, 0.92 mmol), KOAc (104 mg, 1.07 mmol) and Pd(dppf)CI₂ (29 mg) in anhydrous DMF (3 mL) were heated under N₂ at 90°C for 16 h. The mixture was diluted with EtOAc (40 mL) and washed with water (30 mL) then brine (30 mL). The organic layer was dried (Na₂S0₄) and concentrated in vacuo. Purification by column chromatography (MeOH-DCM gradient) gave a yellow solid (72 mg, 39percent); ¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1 H), 7.27 (dd, J=7.3, 0.9 Hz, 1 H), 7.23 (d, J=7.3 Hz, 1 H), 7.07 (s, 1 H), 3.49 (s, 2H), 1.29 (s, 12H); m/z (ES+APCI)⁺: 260 [M+H]⁺.
22%	With potassium acetate In 1-methyl-pyrrolidin-2-one at 130℃; for 3 h;	To a solution of 6-bromo-2-oxindole (1 equiv) in NMP (0.05 M) were added bispinacolato diboron (2.4 equiv), potassium acetate (1.5 equiv), dppf (0.05 equiv) and PdCl₂(dppf) (0.05 equiv). The reaction mixture was stirred at 130°C for 3 hours and then concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel eluting with EtOAc/hexane (9 / 1), yielding the desired product as a red solid. 6-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-l,3-dihydro-indol-2-one: (22 percent yield, 51 percent purity main impurity being the boronic acid 28 percent) m/z (LC-MS, ESP): 260 [M+H]⁺ R/T = 3.51 min

Reference： [1] Patent: WO2015/144290, 2015, A1, . Location in patent: Page/Page column 85
[2] Patent: WO2015/39172, 2015, A1, . Location in patent: Page/Page column 60
[3] Patent: WO2011/15641, 2011, A1, . Location in patent: Page/Page column 128
[4] Patent: WO2011/101640, 2011, A1, . Location in patent: Page/Page column 106
[5] Patent: WO2008/23161, 2008, A1, . Location in patent: Page/Page column 120
[6] Patent: WO2006/66172, 2006, A1, . Location in patent: Page/Page column 77
[7] Patent: WO2014/63778, 2014, A1, . Location in patent: Page/Page column 46

6
[ 5414-19-7 ]
[ 99365-40-9 ]
[ 1190861-43-8 ]

Yield	Reaction Conditions	Operation in experiment
31%	Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -40℃; for 0.75 h; Stage #2: at 20℃; for 16 h;	n-BuLi (2M in hexane, 22.6 mL, 45.27 mmol) was added drop wise at -40°C to a solution of 6-bromo-indolin-2-one (3 g, 14.14 mmol) and diisopropylamine (6.3 mL, 45.27 mmol) in THF (60 mL). The mixture was stirred for 45 min at -40°C, 1-bromo-2-(2-bromoethoxy)ethane was added drop wise at this temperature and stirring was continued at RT for 16 h. The reaction mixture was quenched with 4N hydrogen chloride solution (40 mL) and the aqueous phase was separated and extracted with EtOAc (3x 60 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04 and concentrated. The raw product was triturated with hexane (20 mL) and filtered. The filter was washed with hexane/EtOAc = 4:1 (100 mL) affording the target compound as light brown solid. Yield: 1.2 g (31 percent). HPLC (method 1 ): Rt = 2.94 min, m/z [M+H]+ = 282.1 (MW calc. 282.13).

Reference： [1] Patent: WO2017/108204, 2017, A1, . Location in patent: Page/Page column 133

7
[ 34270-90-1 ]
[ 99365-40-9 ]
[ 1190861-43-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5270 - 5273

8
[ 99365-40-9 ]
[ 1147124-23-9 ]

Reference： [1] Chemistry Letters, 2014, vol. 43, # 12, p. 1870 - 1872
[2] Patent: CN107739374, 2018, A,

9
[ 99365-40-9 ]
[ 77-78-1 ]
[ 897957-06-1 ]

Reference： [1] Patent: WO2010/142985, 2010, A1, . Location in patent: Page/Page column 22

[ 99365-40-9 ] Synthesis Path-Downstream 1~60

1
[ 6127-11-3 ]
[ 99365-40-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sulfuric acid; zinc; In ethanol; at 100℃;	4-Bromo-2-nitrophenylacetic acid (0.26 g), 0.26 g zinc powder and 3 mL 50% sulfuric acid in 5 mL of ethanol were heated at 100 C. overnight. The reaction mixture was filtered, diluted with a little acetic acid, concentrated to remove ethanol, diluted with water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 0.19 g (90% yield) of 6-bromo-2-oxindole as a yellow solid.
90%	With sulfuric acid; zinc; In ethanol; at 100℃;Heating / reflux;	4-Bromo-2-nitrophenylacetic acid (0.26 g), 0.26 g zinc powder and 3 ML 50% sulfuric acid in 5 ML of ethanol were heated at 100 C. overnight.. The reaction mixture was filtered, diluted with a little acetic acid, concentrated to remove ethanol, diluted with water and extracted twice with ethyl acetate.. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 0.19 g (90% yield) of 6-bromo-2-oxindole as a yellow solid.
90%	With sulfuric acid; zinc; In ethanol; at 100℃;	A mixture of <strong>[6127-11-3]4-bromo-2-nitrophenylacetic acid</strong> (0.26 g, 1 mmol), 0.26 g of zinc powder (4 mmol) and 3 mL of 50% sulfuric acid in ethanol (5 mL) was heated at 100 C. overnight. The reaction mixture was filtered, diluted with a little acetic acid, concentrated to remove ethanol, diluted with water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 0.19 g (90% yield) of the title compound as a yellow solid. 1HNMR (360 MHz, DMSO-d6) delta10.45 (br s, 1H), 7.14 (d, 1H,), 7.09 (dd, 1H), 6.93 (d, 1H), 3.43 (s, 2H). MS (m/z) 212 [M]+ and 210 [M-2]+.

63%	With sulfuric acid; zinc; In ethanol; water; at 90℃;	Preparation of 6-Bromo-1,3-dihydro-indol-2-one. To a stirred solution of <strong>[6127-11-3]4-bromo-2-nitrophenylacetic acid</strong> (1.00 g, 3.85 mmol) dissolved in 50% H2SO4 (8.2 ML)/EtOH (10.9 ML) was added Zn dust (1.01 g, 15.38 mmol) at 90 C. under nitrogen.The reaction was then treated in a manner analogous to the cyclization described above in example 6 to provide the intermediate title compound, 6-bromo-1,3-dihydro-indol-2-one, (0.512 g, 63%); mp 167-169 C.
58%	With iron; acetic acid; at 100℃; for 1.0h;	Iron (40.0 g, 700 mmol) was added slowly to a stirred solution of 2-<strong>[6127-11-3](4-bromo-2-nitrophenyl)acetic acid</strong> (preparation 1b, 46.6 g, 200 mmol) in acetic acid (390 mL) at 75 C, and then mixture was stirred for 1 hour at 100 C. The mixture was cooled and ethyl acetate was added. The mixture was filtered through Celite and the solvent evaporated. The crude product was washed with 0.1 M aqueous hydrochloric acid, water, diethyl ether and dried to give the title compound (22.0 g, 58%) as a solid. LRMS (m/z): 212/214 (M+1)+. 1H-NMR delta (DMSO-d6): 3.45 (s, 2H), 6.94 (s, 1H), 7.09-7.17 (m, 2H), 10.50 (s, 1H).
58%	With iron; acetic acid; at 75 - 100℃;	Iron (40.0 g, 700 mmol) was added slowly to a stirred solution of 2-<strong>[6127-11-3](4-bromo-2-nitrophenyl)acetic acid</strong> (preparation 1b, 46.6 g, 200 mmol) in acetic acid (390 mL) at 75 C, and then mixture was stirred for 1 hour at 100 C. Then the mixture was cooled and ethyl acetate was added. The mixture was filtered through Celite and the solvent evaporated. The crude product was washed with 0.1 M aqueous hydrochloric acid, water, diethyl ether and dried to give the title compound (22.0 g, 58%) as a solid. LRMS (m/z): 212/214 (M+1)+. 1H-NMR delta (DMSO-d6): 3.45 (s, 2H), 6.94 (s, 1H), 7.09-7.17 (m, 2H), 10.50 (s, 1H).
3.8 g (56%)	With zinc; In ethanol; sulfuric acid;	Example 133c 6-Bromooxindole Zinc dust (8.5 g, 0.13 mol) was added slowly to a solution of <strong>[6127-11-3]4-bromo-2-nitrophenylacetic acid</strong> (8.4 g, 0.03 mol) in 50% sulfuric acid (200 mL) and absolute ethanol (300 mL) at 90 C. over 0.75 h. The mixture was heated at this temperature for 2 h with stirring. The excess ethanol was removed by evaporation in vacuo and the mixture was filtered. The filtrate was extracted with diethyl ether. The combined organic portions were washed with saturated sodium bicarbonate, saturated sodium chloride, filtered with Whatman 1 PS Phase Separator paper and evaporated in vacuo to give 3.8 g (56%) a pale peach solid. 1H-NMR (DMSO-d6): delta10.57 (brs, 1H), 7.14 (m, 2H), 6.98 (s, 1H), 3.47 (s, 2H).

Reference： [1]Chemical and Pharmaceutical Bulletin,1985,vol. 33,p. 1414 - 1418
[2]Patent: US6878733,2005,B1 .Location in patent: Page/Page column 177; 228
[3]Patent: US6350754,2002,B2 .Location in patent: Page column 29
[4]Patent: US2004/186160,2004,A1 .Location in patent: Page/Page column 23
[5]Journal of Chemical Research,2008,p. 287 - 288
[6]Patent: US2003/225127,2003,A1 .Location in patent: Page 13
[7]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4130 - 4133
[8]Patent: EP2108641,2009,A1 .Location in patent: Page/Page column 29
[9]Patent: EP2113503,2009,A1 .Location in patent: Page/Page column 21
[10]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 421 - 426
[11]Patent: US6268391,2001,B1

2
[ 100487-82-9 ]
[ 99365-40-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With iron; acetic acid; at 20 - 100℃;	To a stirred solution of methyl (4-bromo-2-nitrophenyl)acetate A.97 (6.5 g, 23.7 mmol) in glacial acetic acid (80 mL) was added iron powder (6.6 g, 5 eq.) at room temperature. The resulting mixture was stirred in an oil bath preheated at 100 0C for 2 h at which time LC-MS showed completion. The mixture was filtered, while still warm, through a layer of celite and more glacial acetic acid was used to wash off the residual product. The filtrate was concentrated under high vacuum. The residue was mixed with ice and saturated NaHCO3 aqueous solution and extracted with ethyl acetate (2 x). The combined organics were washed with saturated NaHCO3 aqueous solution (1 x), brine (2 x) and dried over Na2SO4. The residue after concentration in vacuo was triturated with ethyl acetate/hexanes to give 6-bromoindolin-2-one A.35(4.8 g, 95 %) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 6 10.48 (br s, IH), 7.16 (d, J= 6.4 Hz, IH), 7.1 1 (dd, J= 6.4, 1.2 Hz, IH), 6.95 (d, J= 1.2 Hz, IH), 3.45 (s, 2H). LCMS-ESI (POS), M/Z, M+l : Found 212.0 and 214.0.
31%	With sulfuric acid;zinc; In ethanol; water; for 3h;Heating / reflux;	Sodium hydride (60% oil dispersion, 4.00 g, 100 mmol) was added to a dry 500 ml flask under nitrogen and washed with three 25 ml portions of hexanes. Anhydrous DMSO (100 ml) was added, followed by dimethyl malonate (11.4 ml, 100 mmol). The reaction was heated briefly to 100 C. with stirring, then cooled to room temperature. 2,5-Dibromonitrobenzene (12.9 g, 46.0 mmol) was added and the reaction was heated at 110 C. for 2 hrs. After cooling to room temperature, the solution was added in portions to 300 ml of saturated aqueous ammonium chloride with 150 ml of 1:1 hexanes/ethyl acetate. The organic layer was washed with 300 ml of saturated aqueous ammonium chloride, four 200 ml portions of water, and 200 ml of saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and the solvent was evaporated to give 13.6 g of crude dimethyl 2-(4-bromo-2-nitrophenyl)malonate as a brown oil. This material (30-40 mmol) was heated to 110 C. in 250 ml DMSO with 3.6 g (84 mmol) of lithium chloride and 750 mg (42 mmol) of water for 4.5 hrs. The reaction was cooled to room temperature and added to 300 ml of ethyl acetate with 300 ml of saturated aqueous sodium chloride. The organic layer was washed with a second portion of 300 ml saturated aqueous sodium chloride, dried over magnesium sulfate, and the solvent was removed to give 11.1 g brown oil. This material was adsorbed on 40 g of silica gel and applied to a column containing another 80 g of silica gel. Elution with 0-10% ethyl acetate in hexanes gave 3.53 g (28% from 2,5-dibromonitrobenzene) of methyl (4-bromo-2-nitrophenyl) acetate as a yellow solid. This material (3.53 g, 12.8 mmol) was dissolved in ethanol (80 ml) with 50 ml of 50% sulfuric acid and heated to reflux with stirring. Zinc powder (3.40 g, 52 mmol) was added in portions over 1 hr. Heating was continued for another 2 hrs and the reflux condenser was removed to allow ethanol to evaporate from the hot reaction under a stream of nitrogen. The reaction mixture was filtered through celite, washing with 100 ml of ethyl acetate. The water layer was separated from the filtrate and extracted with 100 ml of ethyl acetate. Combined ethyl acetate layers were washed with 30 ml of saturated aqueous sodium bicarbonate and 30 ml of saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporation of solvent gave 1.6 g of crude product which was purified by chromatography on 25 g of silica gel with 10-40% ethyl acetate/hexanes to give 0.85 g (31%) of 6-bromooxindole as an off-white solid.

Reference： [1]Patent: WO2009/158011,2009,A1 .Location in patent: Page/Page column 39-40
[2]Synthesis,1993,p. 51 - 53
[3]Patent: US6350747,2002,B1 .Location in patent: Page column 48
[4]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4130 - 4133

3
[ 99365-40-9 ]
[ 109-94-4 ]
[ 99365-41-0 ]

Yield	Reaction Conditions	Operation in experiment
92.1%	With sodium ethanolate 1.) room temp., 1 h; 2.) 90 deg C, 0.5 h;

Reference： [1]Kosuge; Ishida; Inaba; Nukaya [Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 4, p. 1414 - 1418]

4
[ 1003-29-8 ]
[ 99365-40-9 ]
[ 550373-95-0 ]

Yield	Reaction Conditions	Operation in experiment
82%	With piperidine; acetic acid In toluene at 80℃; for 2h;	Step a: To a solution of 6-bromoindolin-2-one (2) (2.12g, 10.0mmol, 1.00 equiv) and 1H-pyrrole-2-carboxaldehyde (3) (0.95g, 10.0mmol, 1.00 equiv) in toluene (40ml) was added catalytic amount of piperdine (200µl) and glacial acetic acid (200µl) and the reaction mixture was heated at 80°C for 2h. Upon completion of the reaction as indicated by TLC, the mixture was cooled, evaporated, and the resulting residue was stirred with hexane, filtered, dried, and purified by flash chromatography (DCM/Hexane 9:1) to yield the desired (Z)-3-((1H-pyrrol-2-yl)methylene)-6-bromoindolin-2-one (4) in 82% yield.
	With piperidine In methanol

Reference： [1]Dokla, Eman M.E.; Abdel-Aziz, Amal Kamal; Milik, Sandra N.; Mahmoud, Amr H.; Saadeldin, Mona Kamal; McPhillie, Martin J.; Minucci, Saverio; Abouzid, Khaled A.M. [Bioorganic Chemistry, 2021, vol. 117]
[2]Lin, Nan-Horng; Xia, Ping; Kovar, Peter; Park, Chang; Chen, Zehan; Zhang, Haiying; Rosenberg, Saul H.; Sham, Hing L. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 2, p. 421 - 426]

5
[ 4771-50-0 ]
[ 99365-40-9 ]
[ 1055407-18-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 421 - 426

6
[ 99365-40-9 ]
[ 10111-08-7 ]
6-Bromo-3-[1-(1H-imidazol-2-yl)-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 421 - 426

7
[ 7486-35-3 ]
[ 99365-40-9 ]
[ 297756-30-0 ]

Yield	Reaction Conditions	Operation in experiment
31%	With 2,6-di-tert-butyl-4-methyl-phenol; lithium chloride;bis-triphenylphosphine-palladium(II) chloride; In acetonitrile; at 80℃; for 16h;Heating / reflux;	To a mixture of 6-bromooxindole (Procedure D, 0.50 g, 2.4 mmol), vinyltributylstannane (0.95 g, 3.0 mmol), lithium chloride (0.03 g, 7.1 mmol), 2,6-di-tert-butyl-4-methylphenol (0.01 g, 0.05 mmol) in acetonitrile (25 ml) stirring at 80 C. was added dichlorobis(triphenylphosphine)palladium (II). The resulting reaction was stirred with heating for 16 h. The reaction was poured into a vigorously stirring mixture of 5M potassium fluoride solution: ethyl acetate/ 1:1 (250 mL) and stirred for 0.75 h. The resulting biphashic mixture was filtered through a Celite 521 pad and the pad flushed with ethyl acetate (5×2 mL). The combined organic phases were washed with water (200 mL), saturated sodium chloride (200 mL) and filtered through Whatman PS 1 paper and evaporated in vacuo to a golden yellow syrup. The syrup was titurated with diethyl ether to yield several crops of tan solid. Pure samples were combined, slurried with diethyl ether, filtered, and air dried to yield 0.12 g (31%) of 6-vinyloxindole: 1H NMR (DMSO-d6): delta 10.36 (s, 1H), 7.13 (d, 1H, J=7.7 Hz), 6.98 (d, 1H, J=7.5 Hz), 6.66 (dd, 1H, J=10.9, 17.7 Hz), 5.70 (d, 1H, J=17.6 Hz), 5.18 (d, 1H, J=10.9 Hz), 3.42 (s, 2H).

Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 197
[2]Patent: US6350747,2002,B1 .Location in patent: Page column 50

8
[ 118486-94-5 ]
[ 99365-40-9 ]
[ 297756-69-5 ]

Yield	Reaction Conditions	Operation in experiment
34%	With tetraethylammonium chloride;bis-triphenylphosphine-palladium(II) chloride; In acetonitrile; at 85℃; for 20h;	6-(Furan-2-yl)-oxindole 6-Bromo-oxindole (0.40 g, 1.88 mmol), 2-tributyltinfuran (0.71 ML, 2.26 mmol), and tetraethylammonium chloride hydrate (0.31 g, 1.88 mmol) were combined and dissolved in acetonitrile (15 ML).. The palladium catalyst, bistriphenylphosphinedichloropalladium (II) (0.66 g, 0.09 mmol) was added and the reaction was warmed to 85 C. under nitrogen for 20 h.. The reaction was cooled to room temperature and diluted with water (15 ML) before passing the mixture through celite.. The pad of celite was washed with EtOAc and the filtrates were combined and separated.. The aqueous layer was washed with EtOAc (2*20 ML each).. The combined organic phases were washed with brine and dried over sodium sulfate.. The volatiles ere removed in vacuo.. The resulting residue was triturated with diethyl ether and the solid was collected by filtration (0.13 g, 34%). 1H NMR 300 MHz (DMSO-d6) delta 10.5 (s, 1H); 7.75 (s, 1H); 7.30 (m, 2H); 7.11 (s, 1H); 6.91 (m, 1H); 6.60 (m, 1H); 3.52 (s, 2H).

Reference： [1]Patent: US6350747,2002,B1 .Location in patent: Page column 72

9
[ 99365-40-9 ]
[ 98-80-6 ]
[ 90751-00-1 ]

Yield	Reaction Conditions	Operation in experiment
65%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 20 - 85℃; for 6h;	2.4 g of <strong>[99365-40-9]6-bromo-2-indolinone</strong> are placed in 60 ml of dimethoxyethane, 1.9 g of phenylboric acid in 8 ml of ethanol and 0.3 g of tetrakistriphenylphosphine palladium are added and to this mixture 12 ml of 2N sodium carbonate solution are added dropwise at ambient temperature.. The mixture is stirred for 6 hours at 85 C. After cooling the catalyst is filtered off, the solvent is eliminated and the residue is washed with 100 ml of water and 20 ml of 1N sodium hydroxide solution.. The residue is purified through a silica gel column with petroleum ether/ethyl acetate (8:2) as eluant. Yield: 1.5 g (65% of theory), Rf value: 0.45 (silica gel, petroleum ether/ethyl acetate=1:1) Melting point: 167-170 C.

Reference： [1]Patent: US6794395,2004,B1 .Location in patent: Page/Page column 18 - 19

10
[ 6165-68-0 ]
[ 99365-40-9 ]
[ 295800-02-1 ]

Yield	Reaction Conditions	Operation in experiment
42%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃; for 13.5h;	To a warm, stirred solution of 6-bromo-2-oxindole (4 g, 26.3 mmol) dissolved in 60 mL toluene and 60 mL ethanol was added tetrakis(triphenylphosphine)palladium(0) (2.3 g, 1.9 mmol) followed by 2M aqueous sodium carbonate (50 mL, 100 mmol) and thiophene-2-boronic acid (4.38 g, 34.2 mmol) in three portions over 1.5 hours. The mixture was stirred at 100 C. in an oil bath for 12 hours. The mixture was then diluted with ethyl acetate (400 mL) and washed with saturated sodium bicarbonate (200 mL), water (200 mL) and brine (200 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated to give 2.53 g (42%) of 6-thiophen-2-yl-1,3-dihydro-indol-2-one a tan solid. 1H NMR (360 MHz, DMSO-d6) delta 10.42 (s, 1H, NH), 7.50 (dd, J=0.83 and 4.97 Hz, 1H, Ar-H), 7.43 (dd, J=0.89 and 3.52 Hz, 1H, Ar-H), 7.21 (s, 2H, Ar-H), 7.10 (dd, J=3.31 and 4.82 Hz, 1H, Ar-H), 7.01 (s, 1H, Ar-H), 3.47 (s, 2H, CH2CO). MS EI: 215 [M]+.

Reference： [1]Patent: US6689806,2004,B1 .Location in patent: Page/Page column 66

11
[ 6165-69-1 ]
[ 99365-40-9 ]
[ 295800-03-2 ]

Yield	Reaction Conditions	Operation in experiment
36%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃; for 12h;	To a warm, stirred solution of 6-bromo-2-oxindole (4 g, 26.3 mmol) dissolved in 60 mL toluene and 60 mL ethanol was added tetrakis(triphenylphosphine)palladium(0) (2.3 g, 1.9 mmol) followed by 2M aqueous sodium carbonate (50 mL, 100 mmol) and thiophene-3-boronic acid (4.3 g, 33.6 mmol). The mixture was stirred at 100 C. in an oil bath for 12 hours. The reaction mixture was cooled, diluted with ethyl acetate (500 mL), washed with IN hydrochloric acid (200 mL), water (200 mL), saturated sodium bicarbonate (200 mL) and brine (200 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated to give a black solid. The solid was triturated with methylene chloride to give 2.02 g (36%) of 6-thiophen-3-yl-1,3-dihydroindol-2-one as a purple-gray solid. 1H NMR (360 MHz, DMSO-d6) delta 10.49 (s, 1H, NH), 7.77 (s, 1H, Ar-H), 7.59 (m, 1H, Ar-H), 7.45 (m, 1H, Ar-H), 7.24 (m, 2H, Ar-H), 7.07 (m, 1H, Ar-H), 3.46 (s, 2H, CH2CO). MS m/z: 215 [M]+.

Reference： [1]Patent: US6689806,2004,B1 .Location in patent: Page/Page column 67

12
[ 99365-40-9 ]
3-amino-6-(4-{2-hydroxy-2-[5-(2-oxo-2,3-dihydro-1H-indol-6-yl)-pyridin-2-yl]-ethylamino}-piperidin-1-yl)-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylic acid amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11.9%		Example 20: 3-Amino-6- (4-12-hydroxy-2- [5- (2-oxo-2, 3-dihydro-lH-indol-6-yl)- pyridin-2-yl]-ethylamino}-piperidin-1-yl)-4-trifluoromethyl-thieno [2, 3-b] pyridine-2- carboxylic acid amide An N2-purged suspension of 3-Amino-6-{4-[2-(5-bromo-pyridin-2-yl)-2-hydroxy- ethylamino]-piperidin-1-yl}-4-trifluoromethyl-thieno [2, 3-b] pyridine-2-carboxylic acid amide (150 mg, 0.268 mmol), bis (pinacolato) diboron (153 mg, 0.590 mmol), [1,1'- bis (diphenylphosphino) ferrocene] dichloropalladium (II)-CH2Cl2 complex (33 mg, 0.040 mmol), and potassium acetate (133 mg, 1.34 mmol) in dry DMF (4 ml) was heated at 80 C for 2.5 h. The crude reaction mixture was then added directly via syringe to a stirring, N2- purged suspension of 6-bromo-2-oxindole (65 mg, 0.295 mmol), tetrakis (triphenylphosphine) palladium (0) (47 mg, 0.040 mmol), and potassium carbonate (74 mg, 0.536 mmol) in dry DMF (6 ml) and water (2 ml) at rt. The sealed mixture was heated to 85 C for 4 h. The crude reaction was applied direcly to a Si02 column and purified (0-25% MeOH/CH2Cl2 with NH4OH). Fractions containing desired product were pooled and concentrated. The yellow residue was dissolved in 2 ml DMF and applied to a 2 mm prep plate (Merck) eluting with 10% MeOH/CH2Cl2 with 1% NH40H. The yellow product crystallized at the origin and the impurities were removed by being carried up the plate. The recovered yellow residue was dissolved in 1 ml DMF, 2 ml MeOH, 5 ml EtOAc, and 5 ml CH2C12 and crystallized by the addition of 30 ml hexanes to give 20.5 mg, 11.9% of 3-Amino-6- (4-f2-hydroxy-2- [5- (2-oxo-2, 3-dihydro-lH-indol-6-yl)-pyridin-2-yl]- ethylamino}-piperidin-l-yl)-4-trifluoromethyl-thieno [2, 3-b] pyridine-2-carboxylic acid amide product. ES+ 612. 4 m/z (MH+).

Reference： [1]Patent: WO2005/56562,2005,A1 .Location in patent: Page/Page column 90-91

13
[ 99365-40-9 ]
pyridine-3-boronic acid 1,3-propanediol cyclic ester [ No CAS ]
[ 295800-01-0 ]

Yield	Reaction Conditions	Operation in experiment
42%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃; for 12h;	To a warm, stirred solution of 6-bromo-2-oxindole (4 g, 26.3 mmol) in 60 mL toluene and 60 mL ethanol was added tetrakis(triphenylphosphine)palladium(0) (2.3 g, 1.9 mmol) followed by 2M aqueous sodium carbonate (50 mL, 100 mmol) and pyridine-3-boronic acid, propanediol ester (5 g, 30.7 mmol). The mixture was stirred at 100 C. in an oil bath for 12 hours. The reaction mixture was cooled, diluted with ethyl acetate (500 mL) and washed with saturated sodium bicarbonate (200 mL), water (200 mL) and brine (200 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated to afford a brown solid. The solid was triturated with methylene chloride/diethyl ether to give 2.32 g (42%) of 6-pyridin-3-yl-1,3-dihydro-indol-2-one as a brown solid. 1H NMR (360 MHz, DMSO-d6) delta 10.51 (s, 1H, NH), 8.81 (d, J=2.5 Hz, 1H, Ar-H), 8.55 (dd, J=1.8 and 5.7 Hz, 1H, Ar-H), 8 (m, 1H, Ar-H), 7.45 (dd, J=5.7 and 9.3 Hz, 1H, Ar-H), 7.3 (m, 2H, Ar-H), 7.05 (s, 1H, Ar-H), 3.51 (s, 2H, CH2CO). MS: 210 [M]+.

Reference： [1]Patent: US6689806,2004,B1 .Location in patent: Page/Page column 65

14
[ 99365-40-9 ]
[ 73183-34-3 ]
[ 893441-85-5 ]

Yield	Reaction Conditions	Operation in experiment
75%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,2-dimethoxyethane; at 80℃;	Four microwave vials were loaded as follows: <strong>[99365-40-9]6-bromoindolin-2-one</strong>(500 mg, 2.36 mmol), bis(pinacolato)diboron (898 mg, 3.54 mmol),potassium acetate (694 mg, 7.07 mmol) and Pd(dppf)C12CH2C12 (96.0mg, 0.118 mmol) were dissolved in DME (17 mL). The reaction was heated at 80 C overnight. The content of the four vials was then combined, concentrated and purified bycolumn chromatography (CyHex/EtOAc) to afford the title compound as a white solid (2.27 g, 75%, purity 80%). IH NMR (500 MHz, CDCI3) ppm = 8.57 (bs, IH), 7.48 (d, J7.3, IH), 7.31 (5, 1H), 7.23 (d, J=7.3, IH), 3.55 (s, 2H), 1.33 (s, 12H); LC - MS (ESI, mlz) Rt = 2.75 mm - 260 (M+H) (H PLC method E).
55%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In dimethyl sulfoxide; at 90℃; for 18h;	6-Brornoindohn-2-one 27) (2 00 u, 9 40 mmol) bispmacolatodiboron (6 00 g 23 60 mniol), potassium acetate (2.76g. 28.2 mmol) and diehloro[i,i?bis(dipheuylphosphino)feuocenrJj palladrum (11) dichloromethane addutt (0 40 g 0 55 rnniol) in DM80 (30 niL) were stirred at 90 C tbr 18 hours, The reaction mixture was cooled to ambient temperature., then partitioned between water and ethyl acetate. Thelayers were separated and the aqueous layer extracted again with ethyl acetate (2x). The combined organic layers were washed with water and brine and concentrated to give a purple solid. The crude material was pre-absorbed onto Celite and chroniatographed (?DCVC) eluting with a gradient of ethyl acetate in heptane (0 50% ethyl. acetate.) Like fractions were combined and recrystallised from DCM and PE to give 6-(4,5,5-tetrainethyi-l,3,2-dioxahorolan-2yi)indoiin-2-one (24) as a colourless solid in 2 crops (1.33 g, 55%); nip 178.5 181.4 C. ?H NMR (200 MHz, CDCI3) 8 8.61 (br s, 1H), 7.46 (d, 111. J7,4 Hz), 7.30 (s, lH), 7.21 (d. lH,J7.4 Hz), 3.53 (s, 2H). 1.32 (s. 1211).
40%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 95℃; for 18h;Inert atmosphere; Sealed flask;	<strong>[99365-40-9]6-bromoindolin-2-one</strong> (0.424 g; 2 mmol), potassium acetate (0.687 g; 7.0 mmol) and bis[pinacolato]diborane (0.762 g; 3.0 mmol) were placed in a 20 mL microwave vial, dissolved in dry DMF (13 mL) and the flask was purged with nitrogen. The catalyst [1 ,1 '- Bis(diphenylphosphino)ferrocene]palladium(ll) chloride, complex with dichloromethane (0.169 g; 0.20 mmol) was added, the flask was again purged with argon, sealed and the reaction was heated at 950C for 18 h. The reaction mixture was diluted with water and the suspension was extracted twice with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (10 - 80 %) in heptane furnished 0.390 g (40 %) of the title compound.ESI/APCI(+): 260 (M+H);1H NMR (DMSO-d6) delta 10.40 (s, 1 H), 7.27 (dd, J= 7,3, 0,8 Hz, 1 H), 7.21 (m, 1 H), 7.07 (s, 1 H), 3.50 (s, 2 H), 1.28 (s, 12 H).

39%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 90℃; for 16h;Inert atmosphere;	a) 6-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2- l)-1 ,3-dihydro-indol-2-one6-Bromo-1 ,3-dihydro-2H-indol-2-one (150 mg, 0.71 mmol), bis(pinacolato)diboron (233 mg, 0.92 mmol), KOAc (104 mg, 1.07 mmol) and Pd(dppf)CI2 (29 mg) in anhydrous DMF (3 mL) were heated under N2 at 90C for 16 h. The mixture was diluted with EtOAc (40 mL) and washed with water (30 mL) then brine (30 mL). The organic layer was dried (Na2S04) and concentrated in vacuo. Purification by column chromatography (MeOH-DCM gradient) gave a yellow solid (72 mg, 39%); 1H NMR (400 MHz, DMSO-d6) delta 10.38 (s, 1 H), 7.27 (dd, J=7.3, 0.9 Hz, 1 H), 7.23 (d, J=7.3 Hz, 1 H), 7.07 (s, 1 H), 3.49 (s, 2H), 1.29 (s, 12H); m/z (ES+APCI)+: 260 [M+H]+.
22%	With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1-methyl-pyrrolidin-2-one; at 130℃; for 3h;	To a solution of 6-bromo-2-oxindole (1 equiv) in NMP (0.05 M) were added bispinacolato diboron (2.4 equiv), potassium acetate (1.5 equiv), dppf (0.05 equiv) and PdCl2(dppf) (0.05 equiv). The reaction mixture was stirred at 130C for 3 hours and then concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel eluting with EtOAc/hexane (9 / 1), yielding the desired product as a red solid. 6-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-l,3-dihydro-indol-2-one: (22 % yield, 51 % purity main impurity being the boronic acid 28 %) m/z (LC-MS, ESP): 260 [M+H]+ R/T = 3.51 min
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 85℃; for 18h;	A solution of 0.17 g (0.82 mmol)of <strong>[99365-40-9]6-bromoindolin-2-one</strong>, 0.25 g of bis(pinacolato)diboron and 0.20 g (0.98 mmol) of KOAc in 5 mL of DMSO was degassed with Ar sparging for 5 min, then 33 mg (0.041 mmol) of 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride was added and the reaction solution was stirred at 85 0C for 18 h. The reaction solution was poured into 250 mL ofEtOAc, washed twice with a 1 M aqueous solution Of MgSO4, once with brine, then concentrated in vacuo, and purified by flash chromatography eluting with a linear gradient of 20% EtOAc in hexane to neat EtOAc to yield the title compound. MS (M+H)+ 260.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,2-dimethoxyethane; at 80℃;	Four microwave vials were loaded as follows: 6-Bromoindolin-2-one (500 mg, 2.36 mmol), bis(pinacolato)diboron (898 mg, 3.54 mmol), potassium acetate (694 mg, 7.07 mmol) and Pd(dppf)Cl2*CH2Cl2 (96.0 mg, 0.118 mmol) were dissolved in DME (17 mL). The reaction was heated at 80 C overnight. The content of the four vials was then combined, concentrated and purified by column chromatography (cyclohexane/EtOAc) to afford the title compound as a white solid (2.27 g, 75%, purity 80%). 1 H NMR (500 MHz, CDCl3) ppm = 8.57 (bs, 1 H), 7.48 (d, J=7.3, 1 H), 7.31 (s, 1 H), 7.23 (d, J=7.3, 1 H), 3.55 (s, 2H), 1.33 (s, 12H). LC - MS (ESI, m/z) Rt = 2.75 min - 260 (M+H)+ (HPLC method B).

Reference： [1]Patent: WO2015/144290,2015,A1 .Location in patent: Page/Page column 85
[2]Patent: WO2015/39172,2015,A1 .Location in patent: Page/Page column 60
[3]Patent: WO2011/15641,2011,A1 .Location in patent: Page/Page column 128
[4]Patent: WO2011/101640,2011,A1 .Location in patent: Page/Page column 106
[5]Patent: WO2008/23161,2008,A1 .Location in patent: Page/Page column 120
[6]Patent: WO2006/66172,2006,A1 .Location in patent: Page/Page column 77
[7]Patent: WO2014/63778,2014,A1 .Location in patent: Page/Page column 46

15
[ 557-21-1 ]
[ 99365-40-9 ]
[ 199327-63-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 80℃; for 15h;	Commercially available 6-bromoxindole (656 mg), zinc cyanide (288 mg) and tetrakis triphenylphosphine palladium(0) (175 mg) were suspended in dry N,N-dimethylformamide (6 mL). The resulting mixture was degassed by three pump/vent cycles with argon and then placed in a preheated oil bath (80 C.). After stirring at this temperature for 15 h the mixture was cooled to room temperature, diluted with water (60 mL) and extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with water (2×60 mL), dried (MgSO4), filtered and concentrated. The remaining residue was purified by flash chromatography (silica, dichloromethane/methanol) to afford the title compound (385 mg; 81%). [MH]+=159.

Reference： [1]Patent: US2006/173183,2006,A1 .Location in patent: Page/Page column 105

16
[ 6127-11-3 ]
[ 7440-66-6 ]
[ 99365-40-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sulfuric acid; In ethanol;	4-Bromo-2-nitrophenylacetic acid (0.26 g), 0.26 g zinc powder and 3 mL 50% sulfuric acid in 5 mL of ethanol were heated at 100 C. overnight. The reaction mixture was filtered, diluted with a little acetic acid, concentrated to remove ethanol, diluted with water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 0.19 g (90% yield) of 6-bromo-2 oxindole as a yellow solid.
90%	With sulfuric acid; In ethanol;	4-Bromo-2-nitrophenylacetic acid (0.26 g), 0.26 g zinc powder and 3 mL 50% sulfuric acid in 5 mL of ethanol were heated at 100 C. overnight. The reaction mixture was filtered, diluted with a little acetic acid, concentrated to remove ethanol, diluted with water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 0.19 g (90% yield) of 6-bromo-2-oxindole as a yellow solid.
90%	With sulfuric acid; In ethanol;	4-Bromo-2-nitrophenylacetic acid (0.26 g), 0.26 g zinc powder and 3 mL 50% sulfuric acid in 5 mL of ethanol were heated at 100 C. overnight. The reaction mixture was filtered, diluted with a little acetic acid, concentrated to remove ethanol, diluted with water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 0.19 g (90% yield) of 6-bromo-2-oxindole as a yellow solid.

Reference： [1]Patent: US2003/69421,2003,A1
[2]Patent: US6051593,2000,A
[3]Patent: US6486185,2002,B1

17
[ 99365-40-9 ]
[ 74-88-4 ]
[ 158326-84-2 ]

Yield	Reaction Conditions	Operation in experiment
93.0%	With ammonium chloride; lithium diisopropyl amide; In tetrahydrofuran;	(293-1) 3,3-Dimethyl-<strong>[99365-40-9]6-bromoindolin-2-one</strong> A solution (50 ml) of <strong>[99365-40-9]6-bromoindolin-2-one</strong> (3.18 g) in THF was cooled to -78 C. and 1.5 M lithium diisopropylamide (20 ml) was added dropwise thereinto followed by stirring for 15 min. After adding methyl iodide (0.92 ml), the reaction mixture was brought to room temperature and stirred for 1 hr. Then the reaction solution was cooled to -78 C. again and 1.5 M lithium diisopropylamide (10 ml) was added dropwise thereinto followed by stirring for 15 min. After adding methyl iodide (0.92 ml), the reaction solution was brought to room temperature with stirring. Then a saturated aqueous solution of ammonium chloride was added thereto and the resultant mixture was extracted with ethyl acetate. The residue was washed with hexane to give the title compound (3.35 g) as a white amorphous solid (yield: 93.0%). 1H-NMR (400 MHz, CDCl3): delta(ppm) 1.38(6H, s), 7.05(1H, d, J=8.0Hz), 7.096(1H, d, J=1.6Hz), 7.169(1H, d, J=1.6Hz), 8.41(1H, m).
91%	With copper(I) bromide dimethylsulfide complex; potassium tert-butylate; In tetrahydrofuran; at 0 - 22℃; for 16.75h;	To a suspension of potassium tert-butylate (12.8 g) in dry THF (80 ml) was added portion wise at 0 C <strong>[99365-40-9]6-bromoindolin-2-one</strong> (5.0 g,) followed by copper (I) bromide-dimethylsulfide complex (470 mg). Mel (6.82 g) was added drop wise within 45 min keeping the internal temperature below 8 C, the mixture was warmed to 22 C and stirring was continued for 16 h. hours. The mixture was quenched at 0 C with saturated aqueous ammonium chloride solution and diluted with TBME and water. The organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, EtOAc/ n-heptane, 1: 1) to give the title compound (5.17 g) as a brown solid (5.17 g, 91%). MS ESI (m/z): 240.4/ 242.4 [(M+H)+].
91%	With copper(I) bromide dimethylsulfide complex; potassium tert-butylate; In tetrahydrofuran; at 0 - 22℃; for 16.75h;	To a suspension of potassium tert-butylate (12.8 g) in dry THF (80 ml) was added portion wise at 0 C <strong>[99365-40-9]6-bromoindolin-2-one</strong> (5.0 g,) followed by copper (I) bromide-dimethylsulfide complex(470 mg). Mel (6.82 g) was added drop wise within 45 mm keeping the internal temperature below 8 C, the mixture was warmed to 22 C and stirring was continued for 16 hours. The mixture was quenched at 0 C with saturated aqueous ammonium chloride solution and diluted with TBME and water. The organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, EtOAc/ n-heptane, 1:1) to give the title compound (5.17 g) as abrown solid (5.17 g, 9 1%). MS (mlz): 240.4/ 242.4 [(M+H)?i.

1.4 g	With copper(I) bromide dimethylsulfide complex; potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 0.583333h;	Potassium tert-butoxide (6.2 g) was suspended in tetrahydrofuran (55 mL), and a suspension of <strong>[99365-40-9]6-bromo-1,3-dihydroindole-2-one</strong> (2.3 g) in tetrahydrofuran (39 mL) and copper (I) bromide dimethyl sulfide complex (252 mg) were added. To the reaction mixture, methyl iodide (1.9 mL) was added at 0C, and then the reaction mixture was stirred at 0C for 5 minutes, and subsequently stirred at room temperature for 30 minutes. To the reaction mixture, an aqueous solution of ammonium chloride was added, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (1.4 g) as a white solid. 1H-NMR (400 MHz, CDCl3) delta: 7.65 (1H, brs), 7.18 (1H, dd, J = 7.8, 2.0 Hz), 7.06 (1H, d, J = 2.0 Hz), 7.05 (1H, d, J = 7.8 Hz), 1.38 (6H, s). ESI-MS found: 240 [M+H]+
5.17 g		a) 6-Bromo-3,3-dimethyl-l,3-dihydro-indol-2-one To a suspension of potassium tert-butylate (12.8 g, 114 mmol) in dry THF (80 ml) at 0C under an argon atmosphere was added portionwise <strong>[99365-40-9]6-bromoindolin-2-one</strong> (5.0 g, 22.9 mmol) followed by copper(I) bromide-dimethylsulfide complex (470 mg, 2.29 mmol). Mel (6.82 g, 3.00 ml, 48.0 mmol) was added dropwise within 45 minutes, keeping temperature of the reaction mixture below 8C. The reaction mixture was warmed to room temperature and kept at this temperature for 16 hours. The reaction mixture was cooled to 0C again and saturated aqueous ammonium chloride solution was cautiously added. The mixture was diluted with tert-butyl methyl ether and water. The aqueous phase was extracted with tert-butyl methyl ether, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/ heptane as eluent. The title compound was obtained as light yellow solid (5.17 g). MS ESI (m/z): 240.0/ 242.1 [(M+H)+]. 1H NMR (CDC13, 400 MHz): (ppm) = 8.12 (m, 1H), 7.20-7.16 (m, 1H), 7.09-7.08 (m, 1H), 7.06-7.04 (m, 1H), 1.39 (s, 6H).
5.17 g	With copper(I) bromide dimethylsulfide complex; potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 16.75h;Inert atmosphere;	a) 6-Bromo-3,3-dimethyl-indolin-2-one To a suspension of potassium tert-butylate (12.8 g, 114 mmol) in dry THF (80 ml) at 0C under an argon atmosphere was added portionwise <strong>[99365-40-9]6-bromoindolin-2-one</strong> (5.0 g, 22.9 mmol) followed by copper(I) bromide-dimethylsulfide complex (470 mg, 2.29 mmol). Mel (6.82 g, 3.00 ml, 48.0 mmol) was added dropwise within 45 minutes, keeping internal temperature below 8 C. Thereaction mixture was warmed to room temperature and kept at this temperature for 16 hours. The reaction mixture was cooled to 0 C again and saturated aqueous ammonium chloride solution was cautiously added. The mixture was diluted with tert-butyl methyl ether and water. The aqueous phase was extracted with tert-butyl methyl ether, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by silica gelchromatography using ethyl acetate heptane as eluent. The title compound was obtained as light yellow solid (5.17 g).MS ESI (mz): 240.0 242.1 [(M+H)i.1H NMR (CDC13, 400 MHz): (ppm) = 8.12 (m, 1H), 7.20-7.16 (m, 1H), 7.09-7.08 (m, 1H),7.06-7.04 (m, 1H), 1.39 (s, 6H).

Reference： [1]Patent: US2002/19531,2002,A1
[2]Patent: WO2015/177110,2015,A1 .Location in patent: Page/Page column 42
[3]Patent: WO2015/197567,2015,A1 .Location in patent: Page/Page column 23; 52; 53
[4]Patent: EP2669270,2013,A1 .Location in patent: Paragraph 0581-0582
[5]Patent: WO2014/40969,2014,A1 .Location in patent: Page/Page column 25
[6]Patent: WO2014/202493,2014,A1 .Location in patent: Page/Page column 45

18
[ 199328-35-3 ]
[ 199328-34-2 ]
ethyl(4-bromo-2-nitrophenyl)acetate [ No CAS ]
[ 99365-40-9 ]

Yield	Reaction Conditions	Operation in experiment
42%	With iron; In acetic acid;	Using a procedure analogous to that described for the starting material in Example 57, diethyl(4-bromo-2-nitrophenyl)malonate (35 g, 97 mmol) was converted into <strong>[199328-35-3]ethyl (4-bromo-2-nitrophenyl)acetate</strong> (26 g, 93%). Using a procedure analogous to that described for the starting material in Example 57, ethyl(4-bromo-2-nitrophenyl)acetate (26 g, 90 mmol) was treated with iron in acetic acid. The product thus obtained was recystallised from ether/isohexanes to give 6-bromooxindole (8.2 g, 42%). 1H NMR Spectrum: (DMSOd6) 3.45(s, 2H); 6.9(s, 1H); 7.1(m, 2H); 10.45(br s, 1H). MS-ESI: 210 and 212 [M-H]+

Reference： [1]Patent: US6265411,2001,B1

19
[ 99365-40-9 ]
[ 919103-45-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium iodide;copper(l) iodide; trans-N,N'-dimethylcyclohexane-1,2-diamine; In 1,4-dioxane; at 110℃; for 24h;	Preparation 1: 6-Iodooxindole A schlenk tube and stir bar were dried in an oven overnight and then were evacuated, filled with Ar(g) and cooled. The schlenk tube was charged with CuI (45 mg, 0.236 mmol, 5 mol %), 6-bromoxindole (1.0 g, 4.72 mmol), and NaI (1.42 g, 9.44 mmol). The schlenk tube was evacuated and backfilled with Ar(g) (3 times). Racemic trans-N,N'-dimethyl-1,2-cyclohexanediamine (74 muL, 0.472 mmol, 10 mol %) and anhydrous dioxane (4.72 mL) were added via syringe under Ar(g). The schlenk tube was sealed with a teflon valve and the suspension was stirred at 110 C. for 24 h. The reaction was then cooled to room temperature and 15% NH4OH(aq) (50 mL) was added to the reaction mixture while stirring. The suspension was allowed to stir for about 30 min after which the tan solid was vacuum filtered and dried affording 6-Iodooxindole in 84% yield (1.027 g, 3.96 mmol).

Reference： [1]Patent: US2007/15748,2007,A1 .Location in patent: Page/Page column 5

20
[ 919363-08-9 ]
[ 99365-40-9 ]
N-(6-(2-oxoindolin-6-yl)naphthalen-2-yl)thiophene-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	With potassium carbonate;Fibercat palladium catalyst; In 1,4-dioxane; water; at 80℃; for 0.5h;Microwave irradiation;	<strong>[99365-40-9]6-bromoindolin-2-one</strong> (25.2 mg, 0.119 mmol), N-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)naphthalen-2-yl)thiophene-3-carboxamide (72.1 mg, 0.190 mmol), Fibercat palladium catalyst (Johnson-Matthey, 35.4 mg), and K2CO3 (2 M in water, 0.25 ml, 0.5 mmol) were combined in a microwave reaction vessel and 1 ,4-dioxane (1.1 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C, first for 10 minutes, and then for 20 minutes. The reaction was cooled to room temperature, diluted with water (5 ml), and extracted with dichloromethane (3 x 10 ml) and EtOAc (6 x 10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on HPLC (10% -> 95% MeCN / water with 0.1% EPO <DP n="39"/>L <.) to arroralpha tiue compounalpha (7.1 mg, 16%). MS (ESI pos. ion) m/z: 385 (M+H). Calc'd Exact Mass for C23H16N2O2S: 384.

Reference： [1]Patent: WO2007/5668,2007,A2 .Location in patent: Page/Page column 32; 37

21
[ 890315-85-2 ]
di(acetato)dicyclohexylphenylphosphine palladium [ No CAS ]
trans-di(μ-acetato)bis-o-(di-o-tolylphosphino)benzyl dipalladium [ No CAS ]
[ 7560-83-0 ]
[ 99365-40-9 ]
tert-butyl 2-(benzamido)-4-((E)-2-(2-oxoindolin-6-yl)vinyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium bicarbonate; In N,N-dimethyl acetamide; ethyl acetate;	Example 126 0.20 g of 6-bromo-2-oxoindoline, 0.40 mL of N,N-dicyclohexylmethylamine and 18 mg of trans-di(mu-acetato)bis-o-(di-o-tolylphosphino)benzyl dipalladium(II) were added to 2.0 mL of N,N-dimethylacetamide solution containing 0.46 g of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred under nitrogen atmosphere at 110C for 7 hours. After the reaction mixture was cooled to room temperature, a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane: ethyl acetate = 1:1] to obtain 0.15 g of tert-butyl 2-(benzamido)-4-((E)-2-(2-oxoindolin-6-yl)vinyl)benzoate as green solid. 1H-NMR (DMSO-d6) delta: 1.56 (9H, s), 3.50 (2H, s), 7. 11 (1H, s), 7.21-7.39 (4H, m), 7.50 (1H, dd, J = 8.3, 1.5 Hz), 7.59-7.70 (3H, m), 7.95 (1H, d, J = 8.3 Hz), 7.97-8.02 (2H, m), 8.69-8.74 (1H, m), 10.50 (1H, s), 11.65 (1H, s).

Reference： [1]Patent: EP1820795,2007,A1

22
[ 99365-40-9 ]
[ 79-04-9 ]
[ 557093-35-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With aluminum (III) chloride; In 1,2-dichloro-ethane; at 0 - 50℃; for 17.3333h;	Chloroacetyl chloride (0.65 mL, 8.2 mmol) was added to a cooled (0 C) suspension of 6- bromooxindol (0.825 g, 3.9 mmol) and aluminium chloride (1.82 g, 13.6 mmol) in 1,2- dichloroethane (8 ML). The resulting mixture was stirred at 0 C for 20 min and at 50 C for 17 h. The mixture was cooled to room temperature and was then poured on ice. The formed solid was filtered off, washed with water, and dried in vacuo to give 1.10 g (99% yield) of the title compound : 1H NMR (DMSO-D6, 400 MHz) 8 7.69 (s, 1 H), 7.09 (s, 1 H), 4.97 (s, 2H), 3.52 (s, 2H).

Reference： [1]Patent: WO2005/27823,2005,A2 .Location in patent: Page/Page column 45
[2]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3500 - 3511

23
[ 1431-20-5 ]
[ 99365-40-9 ]
3-[5-(6-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With piperidine; In ethanol; at 90℃; for 4h;	4-Bromo-2-nitrophenylacetic acid 0.26 g), 0.26 g zinc powder and 3 mL 50% sulfuric acid in 5 mL ethanol was heated at 100 C. overnight. The reaction mixture was filtered, diluted with a little acetic acid, concentrated to remove ethanol, diluted with water and extracted twice and ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 0.19 g (90% yield) of 6-bromo-2-oxindole as a yellow solid. 1H-NMR (360 MHz, DMSO-d6): delta 10.45 (s, br, 1H, NH-1), 7.14 (d, J=7.89 Hz, 1H, H-4), 7.09 (dd, J=1.53, 7.89 Hz, 1H, H-5), 6.93 (d, J=1.53 Hz, 1H, H-7), and 3.43 (s, 2H, CH2-3); MS m/z (relative intensity, %) 210 ([M-2]+, 100) and 212 (M+, 100).

Reference： [1]Patent: US6878733,2005,B1 .Location in patent: Page/Page column 228

24
[ 24424-99-5 ]
[ 99365-40-9 ]
[ 1190861-45-0 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium hydrogencarbonate; In tetrahydrofuran; for 3h;Reflux;	Di-tert-butyl dicarbonate (4.63 g, 21.2 mmol) and sodium hydrogen carbonate (10.7 g, 127 mmol) were added to a stirred solution of <strong>[99365-40-9]6-bromoindolin-2-one</strong> (preparation 1, 3.0 g, 14.2 mmol) in tetrahydrofuran (150 mL) and the mixture was heated to reflux. After 3 hours the mixture was cooled and filtered and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (10:1 hexanes/ethyl acetate) gave the title compound (3.58 g, 81%) as a white solid. LRMS (m/z): 312/314 (M+1)+. 1H-NMR delta (CDCl3): 1.65 (s, 9H), 3.66 (s, 2H), 7.10(d, 1H), 7.27 (d, 1H), 8.03 (s, 1H).
81%	With sodium hydrogencarbonate; In tetrahydrofuran; for 3h;Reflux;	Di-tert-butyl dicarbonate (4.63 g, 21.2 mmol) and sodium hydrogen carbonate (10.7 g, 127 mmol) were added to a stirred solution of <strong>[99365-40-9]6-bromoindolin-2-one</strong> (preparation 1, 3.0 g, 14.2 mmol) in tetrahydrofuran (150 mL) and the mixture was heated to reflux. After 3 hours the mixture was cooled and filtered and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (10:1 hexanes/ethyl acetate) gave the title compound (3.58 g, 81%) as a white solid. LRMS (m/z): 312/314 (M+1)+. 1H-NMR delta (CDCl3): 1.65 (s, 9H), 3.66 (s, 2H), 7.10(d, 1H), 7.27 (d, 1H), 8.03 (s, 1H).
81%	With sodium hydrogencarbonate; In tetrahydrofuran; at 20℃;Inert atmosphere; Reflux;	To a stirred mixture of <strong>[99365-40-9]6-bromoindolin-2-one</strong> A.35 (5.0 g, 23.6 mmol) and NaHCO3 (10 eq., 21.0 g) in THF (130 mL) was added (Boc)2O (2.5 eq., 14.0 g) at room temperature under N2. The resulting mixture was heated at reflux for 3 h. After cooling, the mixture was vacuum filtered through a layer of celite and the filter cake was thoroughly washed with THF. The filtrate was concentrated in vacuo and the residue was subjected to combi-flash column chromatography (ethyl acetate/hexanes) to give tert-butyl 6-bromo-2-oxo-2,3-dihydro-lH- indole-1-carboxylate A.36 (6.0 g, 81% yield) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 8.04 (1 H, d, J=I.6 Hz), 7.29 (1 H, dd, J=8.0, 1.8 Hz), 7.1 1 (1 H, d, J=7.8 Hz), 3.60 (2 H, s), 1.65 (9 H, s). LCMS-ESI (POS), M/Z, M+Na+: Found 334.0 and 336.0.

79%	With sodium hydrogencarbonate; In tetrahydrofuran; for 3h;Reflux;	NaHC03 (23 g, 283 mmol, 2.0 eq) and di-tert-butyl dicarbonate (46 mL, 212 mmol, 1.5 eq) were added to a stirred solution of <strong>[99365-40-9]6-bromoindolin-2-one</strong> (30 g, 141.5 mmol, 1.0 eq) in THF (300 mL) at rt. The mixture was refluxed for 3 h, then cooled to rt, diluted with water (100 mL) and extracted with EtOAc (2x 100 mL). The combined organic layers were washed with brine (50 mL), dried and evaporated under reduced pressure. The raw product was purified by column chromatography [silica gel 100-200 mesh, PE/EtOAc = 9:1]. White solid. Yield: 35 g, (79%). 1H NMR (400 MHz, CDCI3, delta ppm): 8.03 (d, J = 1.2 Hz, 1H), 7.27 (dd, J = 8.0, 1.6 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 3.58 (s, 2H), 1.64 (s, 9H).
54%	With sodium hydrogencarbonate; In tetrahydrofuran; at 66℃;	4 mmol of 6-bromo-2-indolone (XI) was dissolved in 20 ml of tetrahydrofuran solution, 4.8 m mol of sodium hydrogencarbonate was added, and then 8 mmol of di-tert-butyl dicarbonate was added, and the reaction system was stirred at 66 C. The reaction was quenched with TLC until the title material was evaporated. The mixture was evaporated to ethyl ether. Separation and purification with n-hexane:ethyl acetate = 5:1 as eluent gave 668 mg of white solid.The yield was 54%.

Reference： [1]Patent: EP2108641,2009,A1 .Location in patent: Page/Page column 32-33
[2]Patent: EP2113503,2009,A1 .Location in patent: Page/Page column 23
[3]Patent: WO2009/158011,2009,A1 .Location in patent: Page/Page column 40
[4]Patent: WO2017/108204,2017,A1 .Location in patent: Page/Page column 43-44
[5]Angewandte Chemie - International Edition,2015,vol. 54,p. 691 - 695
Angew. Chem.,2015,vol. 127,p. 701 - 705,5
[6]Patent: CN108299491,2018,A .Location in patent: Paragraph 0130; 0131; 0132; 0133
[7]Chemical Communications,2015,vol. 51,p. 10186 - 10189
[8]Organic Letters,2019,vol. 21,p. 618 - 622
[9]Patent: EP3632910,2020,A1 .Location in patent: Paragraph 0221

25
[ 99365-40-9 ]
[ 118753-70-1 ]
[ 1160247-29-9 ]

Yield	Reaction Conditions	Operation in experiment
22%	Stage #1: 6-bromo-2,3-dihydro-1H-indole-2-one With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.25h; Stage #2: N-(tert-butyloxycarbonyl)bis(2-chloroethyl)amine In tetrahydrofuran at 0 - 20℃; Stage #3: With hydrogenchloride In tetrahydrofuran; water	11 Lithium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran, 2.80 mL, 2.80 mmol) was added dropwise to a stirred suspension of 6-bromoindolin-2-one (preparation 1, 0.20 g, 0.94 mmol) in tetrahydrofuran (1.5 mL) at 0°C. The mixture was stirred for 15 minutes, then tert-butyl bis(2-chloroethyl)carbamate (0.25 g, 1.04 mmol) in THF (1 mL) was added dropwise and the mixture was warmed to room temperature. After stirring overnight, 2M aqueous hydrochloric acid was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (5:1 hexanes/ethyl acetate) gave the title compound (0.08 g, 22%) as a yellow solid. LRMS (m/z): 381/383 (M+1)+. 1H-NMR δ (CDCl3): 1.50 (s, 9H), 1.71-1.89 (m, 4H), 3.77-3.83 (m, 4H), 7.07 (d, 1H), 7.14 (s, 1 H), 7.18 (d, 1H), 7.72 (brs, 1H).

Reference： [1]Current Patent Assignee: ALMIRALL SA - EP2108641, 2009, A1 Location in patent: Page/Page column 34

26
[ 55-86-7 ]
[ 99365-40-9 ]
[ 1160248-46-3 ]

Yield	Reaction Conditions	Operation in experiment
82%		General procedure: To a solution of 5-bromo-1,3-dihydro-2H-indole-2-one (1.272 g, 6 mmol) in THF(15 ml) was added a solution of NaN(SiMe3)2 in THF (30 ml, 30 mmol). The reaction mixture was cooled to -78 C and stirring was continued at the same temperature for 0.5 h. The 2-chloro-N-(2-chloroethyl)-N-methyl ethylamine hydrochloride (1.155 g, 6 mmol) was added to the mixture, continued to stir at -78 C for 0.5 h, then stirred for 2 d at room temperature (TLC control). 4 M HCl (10 ml) was added, the mixture was adjusted pH to 10 with concentrated ammonia and extracted with CH2Cl2 (3 × 20 ml). The combined organic layer was dried (3 g of Na2SO4) and concentrated to afford the crude product, which was purified by FC with MeOH/CH2Cl2.
31%		Sodium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran, 9.40 mL, 9.40 mmol) was added dropwise to a stirred suspension of <strong>[99365-40-9]6-bromoindolin-2-one</strong> (preparation 1, 0.40 g, 1.89 mmol) in tetrahydrofuran (4 mL) at -78C. The mixture was stirred for 30 minutes, then 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (0.36 g, 1.89 mmol) was added and the mixture was warmed to room temperature. After stirring overnight, water was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated. Purification of the residue by reverse phase chromatography (0% CH3CN in H2O to 100% CH3CN in H2O) gave the title compound as a yellow oil (0.17 g, 31%). LRMS (m/z): 295/297 (M+1)+. 1H-NMR delta (DMSO-d6): 1.68-1.86 (m, 4H), 2.51-2.62 (m, 4H), 2.80-2.87 (s, 3H), 7.00 (s, 1H), 7.14 (d, J=6.0 Hz, 1H), 7.41 (d, J=6.0 Hz, 1H), 8.28 (brs, 1H).

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 50,p. 370 - 375
[2]Patent: EP2108641,2009,A1 .Location in patent: Page/Page column 34

27
[ 99365-40-9 ]
[ 74-88-4 ]
[ 1190861-69-8 ]
[ 158326-84-2 ]

Yield	Reaction Conditions	Operation in experiment
1: 29% 2: 19%	Stage #1: 6-bromo-2,3-dihydro-1H-indole-2-one With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexane at -78℃; for 1h; Stage #2: methyl iodide In tetrahydrofuran; hexane at -78 - 20℃; Stage #3: With sodium hydrogencarbonate In tetrahydrofuran; hexane; water	15 n-Butyl lithium (2.5 M in hexanes, 11.3 mL, 28.25 mmol) was added dropwise over 30 minutes to a stirred suspension of 6-bromoindolin-2-one (preparation 1, 3.00 g, 14.15 mmol) and N,N,N',N'-tetramethylethylenediamine (4.30 mL, 28.30 mmol) in tetrahydrofuran (40 mL) at -78°C. The mixture was stirred for 1 hour and then iodomethane (4.40 mL, 70.73 mmol) was added dropwise over 5 minutes. The mixture was warmed to -20°C over a 1 hour period, was stirred for a further hour at this temperature and then was warmed to ambient temperature. After 1 hour, saturated aqueous sodium hydrogen carbonate solution was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (5:1 hexanes/ethyl acetate) gave 6-bromo-3,3-dimethylindolin-2-one (0.97 g, 29%) and 6-bromo-1,3,3-trimethylindolin-2-one (0.68 g, 19%). 6-Bromo-3,3-dimethylindolin-2-one: LRMS (m/z): 240/242 (M+1)+. 1H-NMR δ (CDCl3): 1.39 (s, 6H), 7.06 (d, J=9.0 Hz, 1H), 7.09 (s, 1H), 7.19 (d, J=9.0 Hz, 1H), 8.26 (brs, 1H).6-Bromo-1,3,3-trimethylindolin-2-one: LRMS (m/z): 254/256 (M+1)+. 1H-NMR δ (CDCl3): 1.36 (s, 6H), 3.20 (s, 3H), 7.00 (s, 1H), 7.07 (d, J=9.0 Hz, 1H), 7.20 (d, J=9.0 Hz, 1H).

Reference： [1]Current Patent Assignee: ALMIRALL SA - EP2108641, 2009, A1 Location in patent: Page/Page column 37-38

28
[ 99365-40-9 ]
[ 292638-85-8 ]
[ 1190861-87-0 ]

Yield	Reaction Conditions	Operation in experiment
42%		Pottasium tert-butoxide (0.085 g, 0.8 mmol) was added to a suspension of <strong>[99365-40-9]6-bromoindolin-2-one</strong> (preparation 1, 3.00 g, 14.2 mmol) in dimethylsulphoxide (7 mL) and, after stirring for 10 minutes at room temperature, the mixture was heated to 40-45 C and methyl acrylate (4.00 mL, 44.4 mmol) was added dropwise over 70 minutes. After the addition, the mixture was stirred for 1 hour and then further potassium tert-butoxide (3.82 g, 34.0 mmol) was added portionwise over 30 minutes keeping the temperature below 50 C. The mixture was then heated to 100 C and stirred for 1.5 hours. Water (45 mL) was added and heating was continued at 85 C for 4 hours and then the mixture was left to cool overnight. The resultant precipitate was filtered and the solid washed with water and hexanes to give the crude product. Recrystallization from ethyl alcohol gave the title compound (1.95 g, 42%) as a white solid. LRMS (m/z): 292/294 (M-1)-. 1H-NMR delta (DMSO-d6): 1.99-2.08 (m, 2H), 2.13-2.22 (m, 2H), 2.41-2.50 (m, 2H), 2.82-2.92 (m, 2H), 7.07 (d, J=3.0 Hz, 1 H), 7.21 (dd, J=9.0 and 3.0 Hz, 1 H), 7.50 (d, J=9.0 Hz, 1 H), 10.70 (brs, 1H).
42%		Pottasium tert-butoxide (0.085 g, 0.80 mmol) was added to a suspension of <strong>[99365-40-9]6-bromoindolin-2-one</strong> (preparation 1, 3.00 g, 14.2 mmol) in dimethylsulphoxide (7 mL) and, after stirring for 10 minutes at ambient temperature, the mixture was heated to 40-45 C and methyl acrylate (4.00 mL, 44.40 mmol) was added dropwise over 70 minutes. After the addition, the mixture was stirred for 1 hour and then further potassium tert-butoxide (3.82 g, 34.00 mmol) was added portionwise over 30 minutes keeping the temperature below 50 C. The mixture was then heated to 100 C and stirred for 1.5 hours. Water (45 mL) was added and heating was continued at 85 C for 4 hours and then the mixture was left to cool overnight. The resultant precipitate was filtered and the solid washed with water and hexanes to give the crude product. Recrystallization from ethyl alcohol gave the title compound (1.95 g, 42%) as a white solid. LRMS (m/z): 292/294 (M-1)-. 1H-NMR delta (DMSO-d6): 1.99-2.08 (m, 2H), 2.13-2.22 (m, 2H), 2.41-2.50 (m, 2H), 2.82-2.92 (m, 2H), 7.07 (d, J=3.0 Hz, 1H), 7.21 (dd, J=9.0/3.0 Hz, 1H), 7.50 (d, J=9.0 Hz, 1H), 10.70 (br s, 1H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5270 - 5273
[2]Patent: EP2108641,2009,A1 .Location in patent: Page/Page column 41
[3]Patent: EP2113503,2009,A1 .Location in patent: Page/Page column 25-26

29
[ 628-21-7 ]
[ 99365-40-9 ]
[ 79208-84-7 ]

Yield	Reaction Conditions	Operation in experiment
45%		n-Butyl lithium (2.5 M in hexanes, 3.8 mL, 9.5 mmol) was added dropwise over 30 minutes to a stirred suspension of 6-bromoindolin-2-one (preparation 1, 1.00 g, 4.7 mmol) and N,N,N',N'-tetramethylethylenediamine (1.42 mL, 9.4 mmol) in tetrahydrofuran (20 mL) at - 78 C. The mixture was stirred for 1 hour, then 1,4-diiodobutane (3.11 mL, 23.6 mmol) was added dropwise over 5 minutes. The mixture was warmed to -20 C over a 1 hour period, was stirred for a further hour at this temperature and was then warmed to room temperature. After 3 hours stirring at room temperature, saturated aqueous ammonium chloride solution was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (10:1 hexanes/ethyl acetate) gave the title compound (0.57 g, 45%) as a pale pink solid. LRMS (m/z): 266/268 (M+1)+. 1H-NMR delta (CDCl3): 1.81-2.20 (m, 8H), 7.02-7.06 (m, 2H), 7.14-7.18 (m, 1H), 7.83 (brs, 1H).
45%		n-Butyl lithium (2.5 M in hexanes, 3.8 mL, 9.5 mmol) was added dropwise over 30 minutes to a stirred suspension of 6-bromoindolin-2-one (preparation 1, 1.00 g, 4.7 mmol) and N,N,N',N'-tetramethylethylenediamine (1.42 mL, 9.4 mmol) in tetrahydrofuran (20 mL) at - 78 C. The mixture was stirred for 1 hour, then 1,4-diiodobutane (3.11 mL, 23.6 mmol) was added dropwise over 5 minutes. The mixture was warmed to -20 C over a 1 hour period, was stirred for a further hour at this temperature and was then warmed to room temperature. After 3 hours stirring at room temperature, saturated aqueous ammonium chloride solution was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (10:1 hexanes/ethyl acetate) gave the title compound (0.57 g, 45%) as a pale pink solid. LRMS (m/z): 266/268 (M+1)+. 1H-NMR delta (CDCl3): 1.81-2.20 (m, 8H), 7.02-7.06 (m, 2H), 7.14-7.18 (m, 1H), 7.83 (br s, 1H).

Reference： [1]Patent: EP2108641,2009,A1 .Location in patent: Page/Page column 30
[2]Patent: EP2113503,2009,A1 .Location in patent: Page/Page column 21-22
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4130 - 4133

30
[ 6326-79-0 ]
[ 99365-40-9 ]
[ 1147124-21-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrogenchloride; acetic acid; In water; at 100℃; for 24h;	A 50 ml single-mouth flask was charged with 6-bromohydroxyindole (compound 1,500 mg, 2.36 mmol), 6-bromoisatin (compound 2,533 mg, 2.36 mmol) and AcOH (15 mL), and concentrated HCl was added to the suspension. The solution (0.1 ml) was heated to 100[deg.] C. and refluxed for 24 hours. After the mixture was cooled and filtered, the solid matter was separately washed with water, EtOH, and AcOEt, followed by vacuum drying to obtain 951 mg of brown 6,6-dibromoisoindole (compound 3) in a yield of 95%.

Reference： [1]Organic Letters,2010,vol. 12,p. 660 - 663
[2]Macromolecules,2010,vol. 43,p. 8348 - 8352
[3]Journal of the American Chemical Society,2014,vol. 136,p. 9477 - 9483
[4]Patent: CN107739374,2018,A .Location in patent: Paragraph 0032; 0033; 0034
[5]Journal of Polymer Science, Part A: Polymer Chemistry,2013,vol. 51,p. 3477 - 3485
[6]RSC Advances,2015,vol. 5,p. 269 - 273
[7]Chemistry of Materials,2012,vol. 24,p. 1762 - 1770
[8]Journal of the American Chemical Society,2017,vol. 139,p. 12035 - 12042
[9]Angewandte Chemie - International Edition,2018,vol. 57,p. 531 - 535
Angew. Chem.,2018,vol. 130,p. 540 - 544,5
[10]Macromolecules,2012,vol. 45,p. 8211 - 8220
[11]Chemical Communications,2014,vol. 50,p. 2180 - 2183
[12]Chemistry Letters,2014,vol. 43,p. 1870 - 1872
[13]RSC Advances,2015,vol. 5,p. 85460 - 85469
[14]Patent: CN102993190,2016,B .Location in patent: Sheet 7
[15]Chemical Communications,2017,vol. 53,p. 5882 - 5885
[16]Chemistry - A European Journal,2019,vol. 25,p. 7463 - 7468
[17]Journal of Materials Chemistry C,2019,vol. 7,p. 13192 - 13202

31
[ 115269-99-3 ]
[ 99365-40-9 ]
C₂₁H₂₈N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 2h;	A.2a Method for svnthesising A.2 a; Bromoindolinone A.4p (3.433 g, 16.19 mmol), A.3a (5.0 g, 19.43 mmol), palladium(II)- acetate (363 mg, 1.619 mmol), tri-o-tolylphosphine (986 mg, 3.24 mmol) and Hnig base (5.771 mL, 34.0 mmol) are suspended in 15 mL acetonitrile and stirred for 2 h at 900C. The reaction mixture is stirred into 0.1 N hydrochloric acid, extracted with DCM, the organic phase is dried and the solvent is eliminated in vacuo. The residue is taken up in 100 niL DCM, combined with 100 niL trifluoroacetic acid, stirred for 45 min at 200C and the solvent is eliminated in vacuo. The residue is purified by RP chromatography (method prep. HPLCl; 5 % acetonitrile to 50 % in 12 min) and the amine A.2*a (HPLC-MS: tRet. = 1.25 min; MS(M+H)+ = 189; method FECB3) is obtained.
	With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 2h;	c c) Synthesis of components HR4N-L-Q11* A.2* or HR4N-L-Q11 A.2; Method for svnthesising A.2aA.3a A.2a; Bromoindolinone A.4 p (3.433 g, 16.19 mmol), A.3a (5.0 g, 19.43 mmol), palladium(II)- acetate (363 mg, 1.619 mmol), tri-o-tolylphosphine (986 mg, 3.24 mmol) and Hnig base (5.771 mL, 34.0 mmol) are suspended in 15 mL acetonitrile and stirred for 2 h at 900C. The reaction mixture is stirred into 0.1 N hydrochloric acid, extracted with DCM, the organic phase is dried and the solvent is eliminated in vacuo. The residue is taken up in 100 mL DCM, combined with 100 mL trifluoroacetic acid, stirred for 45 min at 200C and the solvent is eliminated in vacuo. The residue is purified by RP chromatography (method prep. HPLCl; 5 % acetonitrile to 50 % in 12 min) and the amine A.2*a (HPLC-MS: tRet. = 1.25 min; MS(M+H)+ = 189; method FECB3) is obtained.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2010/7116, 2010, A2 Location in patent: Page/Page column 85-86
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2010/7114, 2010, A2 Location in patent: Page/Page column 119-120

32
[ 6326-79-0 ]
[ 99365-40-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With titanium tetrachloride; zinc; In tetrahydrofuran; at 20℃; for 0.0833333h;Inert atmosphere;	General procedure: TiCl4 (0.7 mL, 6 mmol)was added to a stirred suspension of Zn powder (0.78 g, 12 mmol) in freshlydistilled anhydrous THF (15 mL) at room temperature (rt) under a dry N2atmosphere. After completion of the addition, the mixture was refluxed for 2 h.The suspension of the low-valent titanium reagent thus-formed was cooled tort. A solution of isatin or its derivatives 1 or 3 (2 mmol) in THF (10 mL) wasadded dropwise. The mixture was stirred at room temperature for about 5 minunder N2. After this period, the thin layer chromatography (TLC) analysis of themixture showed the reaction completed. The reaction mixture was quenchedwith 3% HCl (15 mL) and extracted with CHCl3 (3 50 mL). The combinedextracts were washed with water (3 50 mL) and dried over anhydrousNa2SO4. After evaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography (petroleum ether/ethylacetate = 5:1) to give the pure products 2 or 4.
71%		General procedure: Isatins (1a-j, 3.0 g), hydrazine hydrate (80%, 13 mL) and water (13 mL) were added to a flask equipped with a thermometer with vigorous stirring. The reaction mixture was kept at 140 C in an oil bath for 6 h before being cooled to r.t., when hydrochloric acid (2.0 mol L-1) was added to bring the pH to pH 2. The reaction mixture was stirred at r.t. for 12 h. Compounds 2a-j were obtained by filtering under vacuum and recrystallisation from absolute ethanol.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 2238 - 2242
[2]Journal of Chemical Research,2017,vol. 41,p. 537 - 540
[3]Organic and Biomolecular Chemistry,2015,vol. 13,p. 6371 - 6379
[4]Journal of Materials Chemistry C,2019,vol. 7,p. 13192 - 13202

33
[ 99365-40-9 ]
[ 63839-24-7 ]

Yield	Reaction Conditions	Operation in experiment
	With borane-THF; In tetrahydrofuran; at 20℃; for 18h;Reflux;	Step I: To a stirred solution of 6-bromoxindole (5.0 g, 23.6 mmol) in THF (25 ml) was added 1.0 M borapie-tetrahydrofuran complex in THF (82.5 ml, 82.5 mmol) at room temperature After complete addition, the reaction mixture was refluxed for 18 h. Reaction mixture was cooled to room temperature, quenched by the addition of methanol and solvents were evaporated under reduced pressure. The resulting residue was taken \\n ethyl acetate (70 mi) and washed with aqueous sodium bicarbonate solution (50 mi) followed by water (50 ml) brine (50 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 6-bromo- indoline. (3.72 g). 1H NMR (400 MHz, CDCI3): delta 2.96 (t, J * 8.4 Hz1 2H): 3.57 (t J * 8.4 Hz, 2H), 3.80 (bs, 1H). 6.74 (s, 1H). 6.78-6.95 (m, 2H). MS (El) m/z 200.1 (M+2).

Reference： [1]Patent: WO2010/128152,2010,A1 .Location in patent: Page/Page column 106-107

34
[ 99365-40-9 ]
[ 77-78-1 ]
[ 897957-06-1 ]

Yield	Reaction Conditions	Operation in experiment
		v) 6-Bromo-l-methylindolin-2-oneSodium hydride (113 mg) in xylenes (5 rnL) was heated to near reflux under nitrogen. 6- Bromoindolin-2-one (500 mg) was then slowly added and the mixture was refluxed for 90 mins. Dimethyl sulfate (0.225 mL) was added and the mixture heated for a further 2 h. The reaction was cooled, diluted with ethyl acetate and washed with water (x3) the organic layer was dried using sodium sulphate and concentrated in vacuo. The orange residue was purified by flash chromatography eluting with 15-25% ethyl acetate in ohexane to give the sub-titled compound (90 mg) as a solid.m/e (APCI+) 227 [M+H]+

Reference： [1]Patent: WO2010/142985,2010,A1 .Location in patent: Page/Page column 22

35
[ 99365-40-9 ]
[ 85070-48-0 ]
[ 1309685-37-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With piperidine; In methanol; at 80℃; for 2h;	To the mixture of 6-bromo-2-oxindole (5 g, 24 mmol) (Combi-blocks) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (3.7 g, 24 mmol) (Oakwood) in methanol (200 mL) was added piperidine (2 g, 24 mmol) (Aldrich) dropwise. The mixture was then heated at 80 C. for 2 h. After cooled to 4 C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-bromo-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 7.8 g, 94%).

Reference： [1]Patent: US2011/130398,2011,A1 .Location in patent: Page/Page column 45

36
[ 34270-90-1 ]
[ 99365-40-9 ]
[ 1190861-43-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5270 - 5273

37
[ 99365-40-9 ]
[ 74-88-4 ]
[ 1190862-33-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 6-bromo-2,3-dihydro-1H-indole-2-one With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran Stage #2: methyl iodide In tetrahydrofuran at -78 - 20℃;

Reference： [1]Location in patent: scheme or table Eastwood, Paul; González, Jacob; Gómez, Elena; Caturla, Francisco; Balagué, Cristina; Orellana, Adelina; Domínguez, María [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5270 - 5273]

38
[ 19725-82-7 ]
[ 1355049-21-6 ]
[ 99365-40-9 ]

Reference： [1]Synthesis,2011,p. 3697 - 3705

39
[ 99365-40-9 ]
[ 106-93-4 ]
[ 1378865-57-6 ]

Yield	Reaction Conditions	Operation in experiment
92%		n-Butyllithium (2.25 M in hexane, 130 mL, 259.4 mmol) was added drop wise at -40C to a solution of <strong>[99365-40-9]6-bromoindolin-2-one</strong> (25.0 g, 117.9 mmol) and diisopropylamine (36.54 mL, 259.4 mmol) in THF (500 mL).The mixture was stirred for 45 mm at that temperature, 1,2-dibromoethane (31.0 mL, 353.7 mmol) wasadded drop wise and stirring was continued for 16 h while the temperature was slowly raised to RT. Thereaction mixture was quenched with 4 N HCI (400 mL) and the aqueous part was separated andextracted with EtOAc (3x 100 mL). The combined organic layers were washed with brine and dried overNa2504. The solvents were evaporated and the residue was triturated with EtOAchexane (1:4, 200 mL),filtered and washed with EtOAc/hexane (1:4, 100 mL). Brown solid. Yield: 26.0 g (92%). HPLC (method 1): R = 2.92 mi mlz [M+H] = 240.0 (MW calc. 238.08)
1.11 g		a) 6'-Bromospirorcyclopropane-l,3'-indolinl-2'-one A solution of <strong>[99365-40-9]6-bromoindolin-2-one</strong> (2 g, 9.43 mmol) and diisopropylamine (2.00 g, 2.82 ml, 19.8 mmol) in tetrahydrofuran (16 ml) was cooled to -25C and a solution of nBuLi (1.6 M in hexane, 23.6 ml, 37.7 mmol) was added dropwise. The reaction mixture was warmed to 0C and a solution of 1,2-dibromoethane (5.32 g, 2.44 ml, 28.3 mmol) in tetrahydrofuran (2 ml) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 20 hours and carefully quenched with brine (2 ml) and cone. HC1 (2 ml, ice bath). The reaction mixture was diluted with tert-butyl methyl ether and water. The aqueous phase was extracted with tert-butyl methyl ether, the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/ heptane as eluent. The title compound was obtained as red crystals (1.11 g). MS ESI (m/z): 238.3/ 240.3 [(M+H)+]. 1H NMR (DMSO-D6, 400 MHz): (ppm) = 10.67 (bs, IH), 7.12-7.09 (m, IH), 7.03 (m, IH), 6.95-6.92 (m, IH), 1.61-1.57 (m, 2H), 1.49-1.45 (m, 2H).
20.03 g	With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; at -40 - 23℃; for 18h;Inert atmosphere;	n-BuLi (2.5M in hexane, 158 mL, 396 mmol) was added dropwise to a stirred and cooled (-40C) suspension of <strong>[99365-40-9]6-bromoindolin-2-one</strong> (21.0 g, 99 mmol) and i-Pr2NH (29.4 mL, 208 mmol) in dry THE (225mL) under Ar. During addition the temperature is maintained below -20C. After complete addition, the temperature was allowed to warm to 0C, then a solution of 1 ,2-dibromoethane (25.6 mL, 297 mmol) in dry THF (25 mL) was added dropwise maintaining a temperature of below 10C. After complete addition, the reaction mixture was stirred at room temperature for 1 8h. The reaction mixture was concentrated to a smaller volume (-75 mL) under reduced pressure.The residue was diluted with EtOAc (200 mL) and brine (100 mL). The biphasic mixture was then stirred vigorously. The pH of the solution was brought to a value of 5 by slowly adding 4M aqueous HCI (-50 mL). The biphasic system was filtered through a glass filter in order to remove the solids which appeard in the bisphasic system. The solids were rinsed with EtOAc (-10 mL), collected and dried on the air to give a first batch of INT-1 as a pale solid (13.99 g, 58.8 mmol, 59.3%).The filtrate layers were separated. The aqueous phase was extracted with EtOAc (2x 100 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4 and the solvent was distilled off. The viscous dark-brown residue was stirred with EtOAc (25 mL) for 5 mm at rt. The suspension was then slowly diluted with heptane (75 mL) while stirring which again resulted in solids which were filtered off, rinsed with heptane (10 mL), collected and air-dried to give a second batch of INT-1 (1)as a brown solid (6.04 g, 25.4 mmol, 25.6%).LCMS: calculated for [M+H]: 238/240, found: 238/240, mono-Br isotope pattern observed.

Reference： [1]Patent: WO2017/108203,2017,A1 .Location in patent: Page/Page column 30; 35; 36
[2]Patent: WO2014/40969,2014,A1 .Location in patent: Page/Page column 49
[3]Patent: WO2016/8593,2016,A1 .Location in patent: Page/Page column 97

40
[ 32364-72-0 ]
[ 99365-40-9 ]
[ 1589549-19-8 ]

Reference： [1]Journal of Materials Chemistry A,2014,vol. 2,p. 5427 - 5433

41
[ 6326-79-0 ]
[ 99365-40-9 ]
[ 1263379-85-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: acetic acid; hydrogenchloride / water / Reflux 2: potassium carbonate / N,N-dimethyl-formamide / Reflux

Reference： [1]Kim, Gyoungsik; Kang, Seok-Ju; Dutta, Gitish K.; Han, Young-Kyu; Shin, Tae Joo; Noh, Yong-Young; Yang, Changduk [Journal of the American Chemical Society, 2014, vol. 136, # 26, p. 9477 - 9483]

42
[ 99365-40-9 ]
[ 74-88-4 ]
[ 1190861-69-8 ]

Yield	Reaction Conditions	Operation in experiment
84%		Under an argon atmosphere NaH (60 % on mineral oil, 7.32 g) was suspended in dry THF (45 ml). A suspension of <strong>[99365-40-9]6-bromoindolin-2-one</strong> (10.0 g) in dry THF (108 ml) was added in portions during 10 min keeping the temperature below 27 C. The reaction mixture was warmed to 25 C, Mel (11.4 ml) was added drop wise during 1 h while the internal temperature was carefully kept between 24 and 27 C and stirring was continued for 18 h. Saturated aqueous NH4C1 solution (20 ml) was carefully added at 10-15 C, the mixture was diluted with EtOAc and saturated aqueous NaHC03 solution, the organic layer was washed with saturated aqueous NaHC03 solution, dried and evaporated. The residue was purified by flash chromatography (siliga gel, gradient 0% to 30% EtOAc in n-heptane) to give the title compound (10.1 g, 84%) as a light red solid. MS (ESI, m/z): 254.1/256.2 [(M+H)+].
69%		Sodium hydride (4.53 g, 94.3 mmol, Eq: 4) and dry tetrahydrofuran (20 ml) were mixed under argon. A suspension of <strong>[99365-40-9]6-bromoindolin-2-one</strong> (5 g, 23.6 mmol, Eq: 1.00) in dry tetrahydrofuran (50 ml) was added in portions. The mixture was stirred at room temperature for 20 min. Then iodomethane (13.4 g, 5.87 ml, 94.3 mmol, Eq: 4) was added dropwise at 23-26 C. The light brown suspension was stirred at room temperature overnight. The reaction mixture was carefully quenched with 10 ml of saturated ammonium chloride. The mixture was diluted with 200 ml of ethyl acetate, 100 ml of water and 50 ml of saturated sodium bicarbonate. The mixture was extracted with 100 ml of ethyl acetate (2x) and the organic layers were washed with 50 ml of saturated sodium bicarbonate. The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford the desired product a white solid (4.16g, 69 %). MS (m/z) = 254.4/256.4 [M + H]+.
10.1 g		a) 6-Bromo-1,3,3-trimethylindolin-2-oneUnder an argon atmosphere NaH (60 % on mineral oil, 7.32 g, 183 mmol) was suspended in dry THF (45 ml). A suspension of <strong>[99365-40-9]6-bromoindolin-2-one</strong> (10 g, 45.7 mmol) in dry THF (108 ml) was added in portions during 10 minutes while temperature was kept below 27 C. The reaction mixture was warmed to 25 C and Mel (11.4 ml, 183 mmol) was added dropwise during 1 hour while the internal temperature was carefully kept between 24 and 27 C. The reaction mixturewas stirred at room temperature for 18 hours. Saturated aqueous NT-L1C1 solution (20 ml) was carefully added at 10-15 C. The mixture was diluted with EtOAc, H20 and saturated aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc, the organic layers were washed with saturated aqueous NaHCO3 solution, combined and dried with Na2504. The solvent was evaporated and the residue was purified by silica gel chromatography using heptane / ethylacetate as eluent. The title compound was obtained as light red solid (7.0 g). Mixed fractions were purified again by preparative HPLC yielding further 3.1 g of the title compound.MS ESI (m/z): 254.1, 256.2 [(M+H)i.1H NMR (CDC13, 300 MHz): oe = 7.19 (dd, J=1.5, 7.8 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.99 (d, J=1.6 Hz, 1H), 3.19 (s, 3H), 1.35 (s, 6H).

Reference： [1]Patent: WO2015/177110,2015,A1 .Location in patent: Page/Page column 44
[2]Patent: WO2017/76842,2017,A1 .Location in patent: Page/Page column 43
[3]Patent: WO2014/202493,2014,A1 .Location in patent: Page/Page column 33

43
[ 99365-40-9 ]
[ 1147124-23-9 ]

Reference： [1]Chemistry Letters,2014,vol. 43,p. 1870 - 1872
[2]Patent: CN107739374,2018,A

44
[ 59278-65-8 ]
[ 99365-40-9 ]

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 6370 - 6372

45
[ 557-21-1 ]
[ 99365-40-9 ]
[ 199327-63-4 ]

Yield	Reaction Conditions	Operation in experiment
80%	With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 80℃; for 16h;	bl .l) 2-Oxoindoline-6-carbonitrile A mixture of palladium-tetrakis(triphenylphosphine) (10.90 g, 9.43 mmol), 6- bromoindolin-2-one (10 g, 47.2 mmol) and dicyanozinc (7.75 g, 66.0 mmol) in DMF (80 mL) was heated to 80 C for 16 h. The reaction mixture was cooled to rt and water was added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel column and elution with 5% MeOH/CfLC^) to give 2-oxoindoline-6-carbonitrile (5.97 g, 37.7 mmol, 80 % yield) as a brown solid. RT=1.15 min (3 min).

Reference： [1]Patent: WO2015/173393,2015,A1 .Location in patent: Page/Page column 69

46
[ 10429-82-0 ]
[ 99365-40-9 ]
1‘-benzyl-6-bromospiro[indoline-3,4‘-piperidine]-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%		A solution of 28 (3.74 g, 17.64 mmol) in dry THF (150mL) was degassed with N2 for 15 min. The solution was then cooled to-78 C and a solution of NaHMDS (1 M in THF, 88.2 mL) was added dropwise over a10 min period. The reaction was stirred at -78 C for 1 h before adding solid N-benzyl-2-chloro-N-(2-chloroethyl)ethan-1-amine HCl salt (5.20 g, 19.40 mmol) in oneportion. The reaction was stirred at -78 C for 1 h before removing the coldbath and allowing the reaction to warm to rt. Upon reaching rt, the reactionwas heated to 70 C (reflux) for 15 hours. The mixture was cooled to 0 C and asaturated aq. NH4Cl solution (150 mL) was added followed by EtOAc(300 mL) for the workup. The organic layer was separated and the aqueous layerwas extracted twice with EtOAc (50 mL x 2).The organic layers were combined, washed with brine, dried using Na2SO4and evaporated to afford the crude product. This crude product wastriturated using hot petroleum ether to give 29 (6.10 g, 93%) as a pink colored solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 1384 - 1391

47
2-methoxy-5-(3,4,5-trimethoxybenzoyl)benzaldehyde [ No CAS ]
[ 99365-40-9 ]
(E)-6-bromo-3-(2-methoxy-5-(3,4,5-trimethoxybenzoyl)benzylidene)indolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With piperidine; In ethanol; at 85℃; for 4h;	General procedure: To the phenstatin-3-aldehyde/isocombretastatin-3-aldehyde(16a-b) (0.303 mmol/0.304 mmol) prepared in the above stepwas added corresponding substituted oxindoles (17a-h)(0.303 mmol) and catalytic amount of piperidine (1.0 ml) in ethanol.Heated the reaction mixture to reflux for 4 h at 85 C. The solidcompounds obtained in the reaction vessel were filtered and washed with ethanol for 4-5 times. After complete air drying thefinal compounds phenstatin/isocombretastatin-oxindole analogs(5a-h and 6a-h) were obtained as pure solids (yield 71-90%).

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 1729 - 1740

48
2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)vinyl)benzaldehyde [ No CAS ]
[ 99365-40-9 ]
(E)-6-bromo-3-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)vinyl)benzylidene)indolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With piperidine; In ethanol; at 85℃; for 4h;	General procedure: To the phenstatin-3-aldehyde/isocombretastatin-3-aldehyde(16a-b) (0.303 mmol/0.304 mmol) prepared in the above stepwas added corresponding substituted oxindoles (17a-h)(0.303 mmol) and catalytic amount of piperidine (1.0 ml) in ethanol.Heated the reaction mixture to reflux for 4 h at 85 C. The solidcompounds obtained in the reaction vessel were filtered and washed with ethanol for 4-5 times. After complete air drying thefinal compounds phenstatin/isocombretastatin-oxindole analogs(5a-h and 6a-h) were obtained as pure solids (yield 71-90%).

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 1729 - 1740

49
C₂₇H₄₂BrNO₂ [ No CAS ]
[ 99365-40-9 ]
C₃₅H₄₆Br₂N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With hydrogenchloride; acetic acid; In water; at 130℃; for 24h;Inert atmosphere;	Compound 2 (2.1g, 10mmol), 6- bromo-indole (5.6g, 11mmol), glacial acetic acid (60ml) was addedThe two bottles, 3 drops of hydrochloric acid was added dropwise, under a nitrogen atmosphere, 130 refluxed for 24h, cooled to room temperature, adding a lot of water,Extracted with methylene chloride three times, the combined organic phase was washed with saturated sodium chloride, dried over anhydrous MgSO4, spin dry solvent,Petroleum ether: methylene chloride 1:1 (by volume) as eluent, column separation, spin dry to give a brown flaky solid(6.46g, 92%).

Reference： [1]Patent: CN105367480,2016,A .Location in patent: Paragraph 0053; 0054; 0055; 0056

50
[ 99365-40-9 ]
diphenyl(vinyl)sulfonium trifluoromethanesulfonate [ No CAS ]
[ 1378865-57-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	With zinc trifluoromethanesulfonate; 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 21℃; for 4h;

Reference： [1]Zhou, Mingwei; En, Ke; Hu, Yimin; Xu, Yufang; Shen, Hong C.; Qian, Xuhong [RSC Advances, 2017, vol. 7, # 7, p. 3741 - 3745]

51
[ 5414-19-7 ]
[ 99365-40-9 ]
[ 1190861-43-8 ]

Yield	Reaction Conditions	Operation in experiment
31%		n-BuLi (2M in hexane, 22.6 mL, 45.27 mmol) was added drop wise at -40C to a solution of 6-bromo-indolin-2-one (3 g, 14.14 mmol) and diisopropylamine (6.3 mL, 45.27 mmol) in THF (60 mL). The mixture was stirred for 45 min at -40C, 1-bromo-2-(2-bromoethoxy)ethane was added drop wise at this temperature and stirring was continued at RT for 16 h. The reaction mixture was quenched with 4N hydrogen chloride solution (40 mL) and the aqueous phase was separated and extracted with EtOAc (3x 60 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04 and concentrated. The raw product was triturated with hexane (20 mL) and filtered. The filter was washed with hexane/EtOAc = 4:1 (100 mL) affording the target compound as light brown solid. Yield: 1.2 g (31 %). HPLC (method 1 ): Rt = 2.94 min, m/z [M+H]+ = 282.1 (MW calc. 282.13).

Reference： [1]Patent: WO2017/108204,2017,A1 .Location in patent: Page/Page column 133

52
[ 6639-57-2 ]
[ 99365-40-9 ]
(E)-3-(benzothiazol-2-ylmethylene)-6-bromoindolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With piperidine In ethanol for 6h; Reflux;	Synthesis of (E)-3-(benzothiazol-2-ylmethylene)indolin-2-ones (6a-j); general procedure General procedure: A mixture of 2a-j (1.50 mmol) and 5 (1.50 mmol) in ethanol (10 mL) was treated with a catalytic amount of piperidine. The reaction mixture was stirred under reflux until complete consumption of the substituted indolin-2-ones was observed by TLC. After cooling, the precipitate was filtered, recrystallised from absolute ethanol and dried in air to furnish pure (E)-3-(benzothiazol-2-ylmethylene)indolin-2-ones 6a-j.

Reference： [1]Zhang, Chao; Xu, Juan; Zhao, Xinyu; Kang, Congmin [Journal of Chemical Research, 2017, vol. 41, # 9, p. 537 - 540]

53
[ 3460-18-2 ]
[ 105-53-3 ]
[ 99365-40-9 ]

Yield	Reaction Conditions	Operation in experiment
65%		To a suspension of 2,5-dibromonitrobenzene (1 g, 3.55 mmol) inDMSO (2.6 mL) was added anhydrous K2CO3 (4.92 g, 35.6 mmol) inone portion under an argon atmosphere. The mixture was heated to50 C, and then diethylmalonate (4.92 g, 30.7 mmol) in DMSO (5 mL)was added in small portions. The reaction mixture was left to react for18 h after which it was extracted with diethyl ether and the combinedorganic phases were washed with water. After removal of the solventsunder reduced pressure, this core productwas usedwithout further purificationin the next step and was dissolved in a mixture of 22 mL ofethanol, 7.3 mL of water and 7.3 mL of conc. Sulfuric acid, and heatedto reflux. Zinc powder (2.3 g, 35.2mmol)was added to the reaction vesselslowly. After 1 h later, the second portion of zinc powder (2.3 g,35.2 mmol) was added. The reaction was refluxed for 2 h. Then, the solutionwaspoured into 100 mL ofwater. The productwas left to crystallizeovernight after which it was filtered. The precipitate was washedwith water, yielding 65%. FT-IR (KBr pellet, cm-1): 3108, 3064, 3023(aromatic nuCH), 1727 (nuC_O), 1664, 1618 (aromatic nuC_C), 1483,1459, 1333, 1307, 1254, 1232, 1202, 1053, 924, 801, 696, 552 cm-1.1H NMR (400 MHz, DMSO d6 delta 2.49 ppm): delta = 10.48 (1H, s), 7.14(1H, d, J = 7.8 Hz), 7.09 (1H, dd, J = 7.8 Hz, 1.7 Hz), 6.93 (1H, d, J =1.7 Hz), 3.42 (2H, s) ppm. 13C NMR [100 MHz, DMSO-d6 delta 39.9 (7peaks)]: delta = 177.7, 146.5, 127.3, 126.0, 124.6, 120.6, 112.7, 35.7 ppm.

Reference： [1]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,2018,vol. 202,p. 196 - 206

54
[ 99365-40-9 ]
[ 6326-79-0 ]
[ 1147124-21-7 ]

Yield	Reaction Conditions	Operation in experiment
1: 85% 2: 9%	With oxygen; sodium iodide In tetrahydrofuran at 60℃; for 12h; Schlenk technique; chemoselective reaction;

Reference： [1]Zhang, Hong-Hua; Wang, Yong-Qiang; Huang, Long-Tao; Zhu, Long-Qing; Feng, Yi-Yue; Lu, Ying-Mei; Zhao, Quan-Yi; Wang, Xue-Qiang; Wang, Zhen [Chemical Communications, 2018, vol. 54, # 59, p. 8265 - 8268]

55
[ 99365-40-9 ]
(2-bromoethyl)(diphenyl)sulfonium trifluoromethanesulfonate [ No CAS ]
[ 1378865-57-6 ]

Yield	Reaction Conditions	Operation in experiment
72%		General procedure: To a 25 mL round bottomed flask was added different substituted oxindoles 8 (0.2 mmol, 1.0 equiv.) and bromoethylsulfonium salt 9 (132.99 mg, 0.3 mmol, 1.5 equiv.), DMF (2 mL). The mixture was stirred at room temperature for 5min and Et3N (61.88 mg, 0.6 mmol, 3.0 equiv.) was added into reaction system. The mixture was stirred for 6h at room temperature until the reaction completed, quenched with saturated ammonium chloride solution (5 mL), and was extracted with EtOAc (3×30 mL). The combined organic layer washed with H2O (2×10 mL), dried with anhydrous sodium sulfate. After concentration, product was purified using column chromatography on silica gel with suitable eluent.

Reference： [1]Tetrahedron,2018,vol. 74,p. 6809 - 6814

56
[ 111-25-1 ]
[ 99365-40-9 ]
[ 1445719-54-9 ]

Yield	Reaction Conditions	Operation in experiment
58.1%		Reaction condition three: Under the protection of nitrogen,6-bromopyridin-2-one (212.0 mg, 1.0 mmol),Potassium carbonate (276 mg, 2 mmol),Tetrabutylammonium bromide (33 mg, 0.1 mmol) was placed in a two-neck reaction flask.Sealing the reaction unit,The nitrogen gas was exchanged three times and a nitrogen balloon was inserted.Inject 22 mL of tetrahydrofuran,Stir at 85 C for 30 min,Then slowly inject 3 mL of bromohexane,Stir at 85 C for 8 h.After the reaction was slowly cooled to room temperature, it was poured into ice water and quenched. The organic phase was extracted with dichloromethane and washed three times with water.After suction filtration, the organic phase was concentrated under reduced pressure in vacuo to give a crude material, which was purified by column chromatography chromatography (DCM/PE = 1:1).To give a white waxy solid compound 1-hexyl-6-bromo - indol-one (172mg),The yield was 58.1%.
58.1%		The reaction condition is three: under the protection of nitrogen, the 6 - bromo indole -2 - ketone (212.0 mg, 1.0 mmol), potassium carbonate (276 mg, 2 mmol), tetrabutyl ammonium bromide (33 mg, 0.1 mmol) is placed in the dual-port reaction bottle. The good sealing of the reaction device, replacing the nitrogen three times, nitrogen balloon is inserted. Injection 22 ml tetrahydrofuran, in 85 C under stirring conditions for 30 min, then slowly injected into the 3 ml bromo hexane, maintain 85 C under stirring 8 h. To be reaction slowly cooling to the room temperature after quenching in the into ice water, dichloromethane is used for extracting the organic phase, deionized water after washing three times, the organic phase for water-free magnesium sulfate drying. After filtering the organic phase by the vacuum concentrated under reduced pressure to get the crude product, using column chromatography (eluate to DCM/PE=1:1) purification, to obtain white waxy solid compound 1 - hexyl -6 - bromo - indolone (172 mg), yield 58.1%.

Reference： [1]Patent: CN108948026,2018,A .Location in patent: Paragraph 0042; 0043; 0044; 0045; 0046
[2]Patent: CN108794494,2018,A .Location in patent: Paragraph 0047; 0048; 0049; 0050; 0051

57
[ 99365-40-9 ]
[ 189323-09-9 ]
benzyl 6-bromo-2-oxospiro[dihydroindole-3,4′-piperidine]-1′-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12.3%	Stage #1: 6-bromo-2,3-dihydro-1H-indole-2-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: benzyl bis(2-bromoethyl)carbamate In tetrahydrofuran at 80℃; for 1h;	68.I Step I Benzyl 6-bromo-2-oxospiro[dihydroindole-3,4′-piperidine]-1′-carboxylate 68b The compound 66b (6-bromo-1,3-dihydro-2H-indol-2-one) (2.9 g, 1.38 mmol) was dissolved in tetrahydrofuran (100 mL), and lithium bis(trimethylsilyl)amide (28 mL, 5.51 mmol) was slowly added dropwise at -78° C. The mixture was stirred at this temperature for 30 minutes, followed by adding benzyl bis(2-bromoethyl)carbamate (5.0 g, 1.38 mmol), slowly heating to 80° C. and stirring for 1 hour. After the reaction was completed, it was quenched with water under ice water bath, and the reaction solution was extracted by water and ethyl acetate. The organic phase was washed with saturated NaCl solution, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain a title compound 68b (700 mg, 1.69 mmol) with a yield of 12.3%.
12.3%	Stage #1: 6-bromo-2,3-dihydro-1H-indole-2-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: benzyl bis(2-bromoethyl)carbamate In tetrahydrofuran at 80℃; for 1h;	68.I Step I Benzyl 6-bromo-2-oxospiro[dihydroindole-3,4′-piperidine]-1′-carboxylate 68b The compound 66b (6-bromo-1,3-dihydro-2H-indol-2-one) (2.9 g, 1.38 mmol) was dissolved in tetrahydrofuran (100 mL), and lithium bis(trimethylsilyl)amide (28 mL, 5.51 mmol) was slowly added dropwise at -78° C. The mixture was stirred at this temperature for 30 minutes, followed by adding benzyl bis(2-bromoethyl)carbamate (5.0 g, 1.38 mmol), slowly heating to 80° C. and stirring for 1 hour. After the reaction was completed, it was quenched with water under ice water bath, and the reaction solution was extracted by water and ethyl acetate. The organic phase was washed with saturated NaCl solution, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain a title compound 68b (700 mg, 1.69 mmol) with a yield of 12.3%.

Reference： [1]Current Patent Assignee: SHANGHAI SYNERGY PHARMACEUTICAL SCIENCES; ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD. - US2022/24941, 2022, A1 Location in patent: Paragraph 0627-0628
[2]Current Patent Assignee: SHANGHAI SYNERGY PHARMACEUTICAL SCIENCES; ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD. - US2022/24941, 2022, A1 Location in patent: Paragraph 0627-0628

58
[ 99365-40-9 ]
[ 189323-09-9 ]
Benzyl 6-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(methoxycarbonyl)-4-methylphenyl)-2-oxospiro[dihydroindole-3,4'-piperidine]-1'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.5 h / -78 °C 1.2: 1 h / 80 °C 2.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane / 2 h / 110 °C

Reference： [1]Current Patent Assignee: SHANGHAI SYNERGY PHARMACEUTICAL SCIENCES; ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD. - US2022/24941, 2022, A1

59
[ 2343-89-7 ]
[ 99365-40-9 ]
methyl 2-fluoro-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; triethylamine In N,N-dimethyl-formamide at 110℃; for 2h; Sealed tube; Inert atmosphere;	47.1 Example 47: (Z)-2-fluoro-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide Step 1: Into a 40-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed DMF (20.0 mL), 6-bromo-1,3-dihydroindol-2-one (1.0 g, 4.72 mmol, 1.0 eq), methyl 2-fluoroacrylate (0.59 g, 5.66 mmol, 1.20 eq), Pd(dppf)Cl2.CH2Cl2 (77.0 mg, 0.094 mmol, 0.02 eq), Et3N (1.3 mL, 9.43 mmol, 2.0 eq). The resulting solution was stirred for 2 h at 110 °C. The resulting mixture was concentrated. The residue was applied onto a silica gel column with (25/75). This resulted in 420 mg (37%) of methyl 2-fluoro-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2- enoate as
37%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; triethylamine In N,N-dimethyl-formamide at 110℃; for 2h; Sealed tube; Inert atmosphere;	47.1 Example 47: (Z)-2-fluoro-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide Step 1: Into a 40-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed DMF (20.0 mL), 6-bromo-1,3-dihydroindol-2-one (1.0 g, 4.72 mmol, 1.0 eq), methyl 2-fluoroacrylate (0.59 g, 5.66 mmol, 1.20 eq), Pd(dppf)Cl2.CH2Cl2 (77.0 mg, 0.094 mmol, 0.02 eq), Et3N (1.3 mL, 9.43 mmol, 2.0 eq). The resulting solution was stirred for 2 h at 110 °C. The resulting mixture was concentrated. The residue was applied onto a silica gel column with (25/75). This resulted in 420 mg (37%) of methyl 2-fluoro-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2- enoate as

Reference： [1]Current Patent Assignee: NRG THERAPEUTICS - WO2022/49376, 2022, A1 Location in patent: Page/Page column 93
[2]Current Patent Assignee: NRG THERAPEUTICS - WO2022/49376, 2022, A1 Location in patent: Page/Page column 93

60
[ 99365-40-9 ]
[ 1428666-17-4 ]

Reference： [1]Patent: WO2022/42591,2022,A1

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P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 99365-40-9 ] {[proInfo.proName]}

Quality Control of [ 99365-40-9 ]

Related Doc. of [ 99365-40-9 ]

Product Details of [ 99365-40-9 ]

Calculated chemistry of [ 99365-40-9 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 99365-40-9 ]

Application In Synthesis of [ 99365-40-9 ]

[ 99365-40-9 ] Synthesis Path-Upstream 1~9

[ 99365-40-9 ] Synthesis Path-Downstream 1~60

Related Functional Groups of [ 99365-40-9 ]

Bromides

Amides

Related Parent Nucleus of [ 99365-40-9 ]

Indolines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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[ 99365-40-9 ]

Related Parent Nucleus of
[ 99365-40-9 ]