[ CAS No. 7699-18-5 ] {[proInfo.proName]}

Name: 7699-18-5|5-Methoxyindolin-2-one|95%
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Quality Control of [ 7699-18-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 7699-18-5 ]

Product Details of [ 7699-18-5 ]

CAS No. :	7699-18-5	MDL No. :	MFCD01860251
Formula :	C₉H₉NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DFGZEOUBIHLXFD-UHFFFAOYSA-N
M.W :	163.17	Pubchem ID :	1514286
Synonyms :

Calculated chemistry of [ 7699-18-5 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	48.23
TPSA :	38.33 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.49 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.69
Log Po/w (XLOGP3) :	1.13
Log Po/w (WLOGP) :	0.62
Log Po/w (MLOGP) :	0.84
Log Po/w (SILICOS-IT) :	1.82
Consensus Log Po/w :	1.22

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.87
Solubility :	2.21 mg/ml ; 0.0136 mol/l
Class :	Very soluble
Log S (Ali) :	-1.53
Solubility :	4.83 mg/ml ; 0.0296 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.01
Solubility :	0.161 mg/ml ; 0.000984 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.47

Safety of [ 7699-18-5 ]

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

Application In Synthesis of [ 7699-18-5 ]

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

Upstream synthesis route of [ 7699-18-5 ]
Downstream synthetic route of [ 7699-18-5 ]

[ 7699-18-5 ] Synthesis Path-Upstream 1~2

1
[ 7699-18-5 ]
[ 3416-18-0 ]

Yield	Reaction Conditions	Operation in experiment
53%	With boron tribromide-dimethyl sulfide complex In 1,2-dichloro-ethane for 18 h; Reflux	An oven-dried flask was charged with BBr₃.SMe₂ (2.80 g, 9.20 mmol) and 1,2-dichloroethane (15 mL). 5-Methoxyindolin-2-one (0.3Og, 1.84 mmol) was then added and the mixture was heated to reflux for 18 hours. The reaction was then cooled to room temperature and quenched with MeOH (1.0 mL). The mixture was then extracted into EtOAc washing with brine (3X). The organic layer was dried over MgSO₄, filtered and the solvent removed in vacuo; the resulting residue was then purified by column chromatography (silica gel, 94:6 to 92:8, CH₂Cl₂/Me0H) to give 144 mg, 53 percent of a beige powder. MS ESI 149.9 [M + H]⁺, calcd for [C₈H₇NO₂+ H]⁺ 150.06

Reference： [1] Patent: WO2009/79767, 2009, A1, . Location in patent: Page/Page column 185
[2] Patent: WO2012/25726, 2012, A1, . Location in patent: Page/Page column 17

2
[ 7699-18-5 ]
[ 109-94-4 ]
[ 52508-88-0 ]

Reference： [1] Tetrahedron Asymmetry, 1996, vol. 7, # 1, p. 1 - 4

[ 7699-18-5 ] Synthesis Path-Downstream 1~67

1
[ 7699-18-5 ]
[ 73424-96-1 ]

Reference： [1]Journal of Organic Chemistry,2005,vol. 70,p. 1828 - 1834
[2]Chemical and Pharmaceutical Bulletin,1984,vol. 32,p. 877 - 886

2
[ 39755-95-8 ]
[ 7699-18-5 ]

Yield	Reaction Conditions	Operation in experiment
81%	With hydrazine hydrate; potassium hydroxide; In ethylene glycol; at 140℃; for 0.0833333h;Microwave irradiation;	To a suspension of 5-methoxyindoline-2,3-dione (250 mg, 1.41 mmol) in ethylene glycol (1mL) were added hydrazine monohydrate (140 mL) and KOH (79 mg, 1.41 mmol). The mixture was heated under microwave irradiation at 140 C for 5 minutes. Water was added and the mixture was neutralized with 1N HCl. The obtained suspension was extracted 3 times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum to give 186 mg (81%) as a yellow solid and was used for the next step without further structure determination.
77%		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.
35%		A stirred solution of 5-methoxyisatin (0.1 mol) in hydrazine hydrate (60 ml) was heated to 140C for 4 h. The reaction mixture was cooled to room temperature, poured into 300 ml of ice water, and acidified to pH 2 with 10% hydrochloric acid. After standing at room temperature for one night the precipitate was collected by vacuum filtration, washed with water, and dried under vacuum (35% yield).

27%	With hydrazine hydrate; for 0.25h;Reflux;	Preparation of 5-methoxy-2-(1 -methyl-1 H-pyrazol-4-yl)-indole-3-carbaldehyde; 5-Methoxy isatin (0.2 g, 1.1 mmol, 1 eq.) was dissolved in hydrazine hydrate (1.2 ml_, 38 mmol, 34 eq.) and refluxed for 15 minutes. The reaction mixture was poured into cold water and extracted with EtOAc. The combined organic extracts were dried on Na2SO4. The solvent was evaporated to afford crude 5-methoxy-1 ,3-dihydro-indol-2-one that was purified by silica gel column chromatography (eluent: hexane/EtOAc from 10:0 to 6:4). Yield: 27%. MS (m/z): 164.2 (MH+).Phosphorous oxybromide (0.35 ml_, 3.1 mmol, 2.5 eq.) was added drop wise to a solution of DMF (0.3 ml_, 3.7 mmol, 3 eq.) in dry methylene chloride at 00C. The mixture was stirred at 00C for 30 minutes, then a solution of 5-methoxy-1 ,3-dihydro-indol-2-one (0.2 g, 1.2 mmol, 1 eq.) in dry methylene chloride (2 ml_) was added and the mixture was refluxed for 3 hours. The solution was neutralized with solid NaHCO3 and extracted with methylene chloride. The organic layer was dried on Na2SO4 and evaporated under reduced pressure. The crude mixture was purified by silica gel column chromatography (eluent: hexane/AcOEt 6:4 to 4:6) to give pure 2-bromo-5-methoxy-indole-3-carbaldehyde. Yield: 45%. MS (m/z): 254.1 (MH+). A stirred solution of 2-bromo-5-methoxy-indole-3-carbaldehyde (2.0 g, 7.9 mmol, 1 eq.) in DME (2 ml_) was deoxygenated by bubbling argon for 10 minutes at rt. Pd(PPh3)4 (0.9 g, 0.8 mmol, 0.1 eq.) was added followed by a solution of 1-methyl-4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (2.4 g, 1 1.63 mmol, 1.48 eq.) in ethanol (2.5 ml_). 2M Na2CO3 (33 ml_, 8.5 eq.) was also deoxygenated with argon and added. The resulting mixture was heated at 78C for 18 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with methylene chloride. Organic layer was dried on anhydrous Na2SO4 and evaporated under reduced pressure to give the crude product 1f. Yield: 89%. MS (m/z): 256.1 (MH+).
20%		Intermediate 20: 5-Methoxyindolin-2-one[0507] A solution of 5-methoxyisatin (1.0 g, 5.6 mmol) in hydrazine hydrate (85%, 6.0 mL) was refluxed for 3 h. After the mixture was concentrated, the residue was treated with 50%> aqueous NaOH solution (40.0 mL) and the resulting mixture was stirred at room temperature for 48 h. The mixture was poured into water and extracted with diethyl ether. The combined extracts were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography (PE/EA = 10: 1 to 2:1) to afford 184 mg of the title compound as a white solid (20% yield).
	With hydrazine hydrate; In water; ethyl acetate;	The mixture was poured into 500 g of ice and extracted 3 times with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated to give 5.1 g (65% yield) of 5-methoxyisatin as a dark red solid. 5-methoxyisatin (5.0 g) and 30 mL of hydrazine hydrate were heated to reflux for 15 minutes. The reaction mixture was cooled to room temperature and 50 mL of water was added. The mixture was extracted 3 times with 25 mL of ethyl acetate each time, the organic layers combined, dried over anhydrous sodium sulfate and concentrated to give a yellow solid. The solid was stirred in ethyl acetate and 1.1 g of insoluble material was removed by vacuum filtration and saved. This material proved to be 2-hydrazinocarbonylmethyl-4-anisidine. The filtrate was concentrated and chromatographed on silica gel eluding with ethyl acetate:hexane (1:1) to give 0.7 g of 5-methoxy-2-oxindole as a yellow solid.
	With hydrazine hydrate; In water; ethyl acetate;	The mixture was poured into 500 g of ice and extracted 3 times with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated to give 5.1 g (65% yield) of 5-methoxyisatin as a dark red solid. 5-Methoxyisatin (5.0 g) and 30 mL of hydrazine hydrate were heated to reflux for 15 minutes. The reaction mixture was cooled to room temperature and 50 mL of water was added. The mixture was extracted 3 times with 25 mL of ethyl acetate each time, the organic layers combined, dried over anhydrous sodium sulfate and concentrated to give a yellow solid. The solid was stirred in ethyl acetate and 1.1 g of insoluble material was removed by vacuum filtration and saved. This material proved to be 2-hydrazinocarbonylmethyl-4-anisidine. The filtrate was concentrated and chromatographed on silica gel eluding with ethyl acetate:hexane (1:1) to give 0.7 g of 5-methoxy-2-oxindole as a yellow solid.
	With hydrazine hydrate; In water; ethyl acetate;	The mixture was poured into 500 g of ice and extracted 3 times with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated to give 5.1 g (65% yield) of 5-methoxyisatin as a dark red solid. 5-Methoxyisatin (5.0 g) and 30 mL of hydrazine hydrate were heated to reflux for 15 minutes. The reaction mixture was cooled to room temperature and 50 mL of water was added. The mixture was extracted 3 times with 25 mL of ethyl acetate each time, the organic layers combined, dried over anhydrous sodium sulfate and concentrated to give a yellow solid. The solid was stirred in ethyl acetate and 1.1 g of insoluble material was removed by vacuum filtration and saved. This material proved to be 2-hydrazinocarbonylmethyl-4-anisidine. The filtrate was concentrated and chromatographed on silica gel eluding with ethyl acetate:hexane (1:1) to give 0.7 g of 5-methoxy-2-oxindole as a yellow solid.
	With hydrazine hydrate; ethylene glycol; potassium hydroxide; In ethanol; at 150℃; for 0.0833333h;Microwave irradiation; Sealed vessel;	Description 11:5-Methoxyindolin-2-oneTo 5-methoxyisatin (0.25 g, 1.41 mmol) in ethylene glycol (1 ml) was added hydrazine hydrate (~50%, 1.5 equiv., 0.14 ml) and potassium hydroxide (1 equiv., 79 mg). The reaction mixture was heated in microwave (150C, 5 min). Tic (EtOAc : hexane, 1:1) indicated the completion of the reaction. The reaction mixture was diluted with water, acidified to pH~1 with 2M HCI and extracted into ethyl acetate. The organic layer was dried (MgS04), filtered and volatiles were removed in vacuo. The residue was purified by ISCO Combiflash (100% DCM - 5% MeOH/DCM) to give the product as an off-white solid. The results set out below indicate the final product was the title compound D1 .1H NMR (CDCI3): 8.08 (1H, br s), 6.83 (1H, s), 6.77-6.71 (2H, m), 3.75 (3H, s), 3.50 (2H, s). 13C NMR (CDCI3): 176.3, 159.5, 135.7, 126.6, 112.5, 111.8, 109.8, 55.8, 36.5.MS: (MH+41) 205.0
		General procedure: The preparation was divided into two steps. Firstly, substituent indoline-2,3-dione (1 equiv) was dissolved in ethanol (10 mL), hydrazine hydrate (2 mL) was added. The reaction mixture was refluxed with magnetic stirring for 3 h and cooled to 0 C, then sodium hydroxide (3 equiv) was added, refluxed for 0.5 h and cooled to room temperature, then 150 mL water was added. The mixture was acidified by adding 2 N hydrochloric acid to pH 2, and extracted twice with dichloromethane. The organic filtrate was washed twice with brine, dried (Na2SO4), and then concentrated to give corresponding indolin-2-one by high-vacuum drying. Secondly, a mixture of the corresponding indolin-2-one (1 equiv) and furan-2-carbaldehyde (1 equiv) in ethanol was added two drops of piperidine and refluxed with magnetic stirring for 5 h. After the mixture cooled, the precipitate was filtered, washed with cold ethanol, dried, and recrystallized from methanol to afford the terminal product.
	With hydrazine; for 0.25h;Heating / reflux;Reactivity;	The combined extracts were dried over anhydrous sodium sulfate and concentrated to give 5.1 g (65% yield) of 5-methoxyisatin as a dark red solid. 5-Methoxyisatin (5.0 g) and 30 mL of hydrazine hydrate were heated to reflex for 15 minutes. The reaction mixture was cooled to room temperature and 50 mL of water was added. The mixture was extracted 3 times with 25 mL of ethyl acetate each time, the organic layers combined, dried over anhydrous sodium sulfate and concentrated to give a yellow solid. The solid was stirred in ethyl acetate and 11 g of insoluble material was removed by vacuum filtration and saved. This material proved to be 2-hydrszinocmbonylmethyl-4-anisidine. The filtrate was concentrated and chromatographed on silica gel eluding with ethyl acetate:hexane (1:1) to give 0.7 g of 5-methoxy-2-oxindole as a yellow solid. The 11 g of 2-hydrazinocarbonylmethyl-4-anisidine was refluxed for 1 hour in 20 mL of 1N sodium hydroxide. The mixture was cooled, acidified to pH 2 with concentrated hydrochloric acid and extracted 3 times with 25 mL of ethyl acetate each time. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated to give 0.8 g of 5-methoxy-2-oxindole as a yellow solid. The combined yield was 1.5 g or 33%.

Reference： [1]Synthetic Communications,1994,vol. 24,p. 2835 - 2841
[2]Tetrahedron Asymmetry,1996,vol. 7,p. 1 - 4
[3]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4630 - 4637
[4]Journal of Chemical Research,2017,vol. 41,p. 537 - 540
[5]Tetrahedron,2012,vol. 68,p. 1483 - 1491
[6]Patent: WO2010/30727,2010,A1 .Location in patent: Page/Page column 101-102
[7]Patent: WO2012/178015,2012,A2 .Location in patent: Page/Page column 129
[8]Journal of Organic Chemistry,2005,vol. 70,p. 1828 - 1834
[9]Patent: US6486185,2002,B1
[10]Patent: US2003/69421,2003,A1
[11]Patent: US6114371,2000,A
[12]Patent: WO2012/25726,2012,A1 .Location in patent: Page/Page column 16
[13]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 1724 - 1734
[14]Organic and Biomolecular Chemistry,2015,vol. 13,p. 6371 - 6379
[15]Patent: US6878733,2005,B1 .Location in patent: Page/Page column 174; 223

3
[ 7699-18-5 ]
[ 109-94-4 ]
[ 52508-88-0 ]

Reference： [1]Tetrahedron Asymmetry,1996,vol. 7,p. 1 - 4

4
[ 3416-18-0 ]
[ 77-78-1 ]
[ 7699-18-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; at 0℃; for 2h;	The compoundwas prepared as described at Laksmaiah et al. [23]: 179mg (1.2mmol) of 1was dissolved in 1.3mL of 1.0MKOH solution and cooled to 0 C. Dimethyl sulfate (124 mL,1.3mmol)was added and stirring was continued for 2 h, after dilution with 15 mL water the mixturewas extracted with ethyl acetate (3 15 mL). The combined organic layer was dried with Na2SO4, filtered and evaporated under reduced pressure. After column chromatographic purification (silica gel, dichloromethane/methanol = 95:5 v/v) 69 mg (35%) 2 was obtained as crystals.Mp: 144e148 C(lit:148e151 C), ESI-MS (ES+):m/z = 164 [M th H].

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 1699 - 1704
[2]Organic Letters,2012,vol. 14,p. 2544 - 2547
[3]Organic Letters,2018,vol. 20,p. 7066 - 7070
[4]European Journal of Medicinal Chemistry,2012,vol. 58,p. 272 - 280

5
[ 7699-18-5 ]
[ 24424-99-5 ]
[ 374898-41-6 ]

Reference： [1]Tetrahedron Letters,2001,vol. 42,p. 7315 - 7317
[2]Journal of Organic Chemistry,2004,vol. 69,p. 2478 - 2486
[3]Organic Letters,2012,vol. 14,p. 2544 - 2547
[4]Chemical Communications,2015,vol. 51,p. 10186 - 10189
[5]Organic Letters,2018,vol. 20,p. 892 - 895
[6]Angewandte Chemie - International Edition,2019,vol. 58,p. 6732 - 6736
Angew. Chem.,2019,vol. 131,p. 6804 - 6808,5

6
[ 129822-42-0 ]
[ 7699-18-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1) s-BuLi / 1) THF, cyclohexane, -40 to -20 deg C, 2) -40 deg C, 1 min 2: 1) 10percent HCl, 2) 10percent HCl / 1) EtOH, reflux, 15 min, 2) toluene, EtOH, reflux, 3 h

Reference： [1]Clark; Muchowski; Fisher; Flippin; Repke; Souchet [Synthesis, 1991, # 10, p. 871 - 878]

7
[ 7699-18-5 ]
[ 55-51-6 ]
[ 752234-63-2 ]

Yield	Reaction Conditions	Operation in experiment
39%	With sodium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃; for 15h;	To a solution OF NAHMDS (1 M THF solution) (800 ml, 0.8 mol), the solution OF 5-METHOXY-1, 3- dihydro-indol-2-one (26.1 g, 0.16 mol) in THF (160 ml) and benzyl-bis- (2-chloro-ethyl)-amine (47.3 g, 0.18 mol) in THF (176 ml) are added AT-78?C. The reaction mixture is stirred for 15 h at room temperature, quenched with saturated ammonium chloride and ice-water and extracted with ethyl acetate. The combined extracts are washed with brine, dried over sodium sulphate and evaporated down. Ethyl ether is added to the residue to give the powder, which is filtrated. Yield: 39 % Rf=0.25 (N-hexane: AcOEt = 1:1). 1H-NMR (400MHz, CDCl3) delta: 1.81-1.99 (m, 2H), 2.00-2.04 (m, 2H), 2.66-2.72 (m, 2H), 2.90-2.96 (m, 2H), 3.67 (s, 2H), 3.77 (s, 3H), 6.71-6.81 (m, 2H), 7.00 (s, 1H), 7.25-7.40 (m, 5H), 8.32 (brs, 1H)

Reference： [1]Patent: WO2004/76455,2004,A1 .Location in patent: Page 25; 26

8
[ 742067-26-1 ]
[ 7699-18-5 ]

Yield	Reaction Conditions	Operation in experiment
59%		To a solution of crude 5-methoxy-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester in MeOH (320 ml), 6N HCl (255 ml, 1.92 mol) is added at ambient temperature. The reaction mixture is stirred at 70 C for 3 h. After cooling down to room temperature, 8 N KOH (269 ml, 1.82 mol) is added to reaction mixture. The reaction mixture is stirred at 40 C for 30 min. 12 N HCl (41 ml) is added to reaction mixture. MeOH is evaporated down and the white powder is filtrated. Yield: 59 % (three steps). Rf=0. 25 (n-hexane:AcOEt = 1:1). 1H-NMR (400MHz, CDCl3) delta: 3.51 (s, 2H), 3.78 (s, 3H), 6.72-6.85 (m, 3H), 7.60 (brs, 1H)
		To a solution of crude 5-methoxy-2-oxo-2,3-dihydro-1 H-indole-3-carboxylic acid methyl ester in MeOH (320 ML), 6N HCI (255 ml, 1. 92 mol) is added at ambient temperature. The reaction mixture is stirred at 70 C for 3 h. After cooling down to room temperature, 8 N KOH (269 ml, 1.82 mol) is added to reaction mixture. The reaction mixture is stirred at 40 C FOR 30 min. 12 N HCI (41 ML) is added to reaction mixture. MeOH is evaporated down and the white powder is FILTRATEDTO provide the title compound ; RF=0. 25 (n-hexane: AcOEt = 1 : 1) ; 1H-NMR (400MHZ, CDCI3) J : 3.51 (s, 2H), 3.78 (s, 3H), 6.72-6. 85 (m, 3H), 7.60 (brs, 1 H).

Reference： [1]Patent: WO2004/76455,2004,A1 .Location in patent: Page 25
[2]Patent: WO2004/69256,2004,A1 .Location in patent: Page/Page column 45

9
[ 7699-18-5 ]
[ 74-88-4 ]
[ 7699-22-1 ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium carbonate; In acetone;	PREPARATION A N-methyl-5-methoxyoxindole 5-methoxy oxindole (450 mg, 2.76 mmol) and potassium carbonate (585 mg, 4.23 mmol) were combined in 45 ml of acetone under an inert atmosphere. To this white, heterogenous mixture was added 0.33 ml of methyl iodide (5.30 mmol) via syringe. The reaction mixture was stirred at room temperature for 10 hours and then at 75 C. for 3 hours. Additional potassium carbonate and methyl iodide were added (290 mg and 0.11 ml, respectively), and the reaction mixture was stirred at 75 C. for 6 more hours. The reaction mixture was then poured into 300 ml of saturated brine solution and extracted with 3*200 ml ether. The combined organic layers were dried over MgSO4, filtered, and stripped to a yellow oil. This was purified via flash chromatography (3:1 ethyl ether/hexane) to provide the title compound (307 mg, 63% yield) as white crystals: m.p. 93-94 C. M/z calculated for C10 H11 NO2: 177.0790, Found: 177.08066.

Reference： [1]Patent: US5502072,1996,A

10
[ 104-94-9 ]
[ 7699-18-5 ]

Yield	Reaction Conditions	Operation in experiment
	With chlorine; In dichloromethane;	PREPARATION 6 5-Methoxy-2-oxindole 5-Methoxy-2-oxindole was prepared from 4-methoxyaniline in a manner similar to the procedure of Preparation 5, except that the initial chlorination step was carried out using a solution of chlorine gas in dichloromethane in place of t-butyl hypochlorite. The title product melted at 150.5-151.5 C.
	With chlorine; In dichloromethane;	PREPARATION 9 5-Methoxy-2-oxindole 5-Methoxy-2-oxindole was prepared from 4-methoxyaniline in a manner similar to the procedure of Preparation 8, except that the initial chlorination step was carried out using a solution of chlorine gas in dichloromethane in place of t-butyl hypochlorite. Th title product melted at 150.5-151.5 C.
	With chlorine; In dichloromethane;	PREPARATION D 5-Methoxyoxindole 5-Methoxyoxindole was prepared from 4-methoxy aniline in a manner similar to the procedure of Preparation C, except that the initial chlorination step was carried out using a solution of chlorine gas in dichloromethane in place of t-butyl hypochlorite. The title product melted at 150.5-151.5 C.

	With chlorine; In dichloromethane;	PREPARATION F 5-Methoxyoxindole 5-Methoxyoxindole was prepared from 4-methoxy aniline in a manner similar to the procedure of Preparation E, except that the initial chlorination step was carried out using a solution of chlorine gas in dichloromethane in place of t-butyl hypochlorite. The title product melted at 150.5-151.5 C.
	With chlorine; In dichloromethane;	PREPARATION 12 5-Methoxy-2-oxindole 5-Methoxy-2-oxindole was prepared from 4-methoxyaniline in a manner similar to the procedure of Preparation 11, except that the initial chlorination step was carried out using a solution of chlorine gas in dichloromethane in place of t-butyl hypochlorite. The title product melted at 150.5-151.5 C.
	With chlorine; In dichloromethane;	PREPARATION D 5-Methoxyoxindole 5-Methoxyoxindole was prepared from 4-methoxy aniline in a manner similar to the procedure of Preparation C, except that the initial chlorination step was carried out using a solution of chlorine gas in dichloromethane in place of t -butyl hypochlorite. The title product melted at 150.5-151.5C.

Reference： [1]Patent: US4658037,1987,A
[2]Patent: US4721712,1988,A
[3]Patent: US4725616,1988,A
[4]Patent: US4678802,1987,A
[5]Patent: US4556672,1985,A
[6]Patent: EP208510,1991,B1
[7]Organic and Biomolecular Chemistry,2015,vol. 13,p. 6371 - 6379
[8]Synthesis,2016,vol. 48,p. 1872 - 1879
[9]Patent: US6878733,2005,B1

11
[ 7699-18-5 ]
[ 1431-20-5 ]
3-[5-(5-Methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With piperidine; In ethanol; at 95℃;	5-Methoxyisatin (5.0 g) and 30 mL hydrazine hydrate were heated to reflux for 15 minutes. The reaction mixture was cooled to room temperature and 50 mL water was added. The mixture was extracted 3 times with 25 mL of ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give a yellow solid. The solid was stirred in ethyl acetate and 1.1 g of insoluble material removed by vacuum filtration and saved. This material proved to be 2-hydrazino-carbonylmethyl-4-anisidine. The filtrate was concentrated and chromatographed on silica gel eluding with ethyl acetate:hexane 1:1 to give 0.7 g of 5-methoxy-2-oxindole as a dirty yellow solid.

Reference： [1]Patent: US6878733,2005,B1 .Location in patent: Page/Page column 223

12
[ 7699-18-5 ]
[ 3416-18-0 ]

Yield	Reaction Conditions	Operation in experiment
53%	With boron tribromide-dimethyl sulfide complex; In 1,2-dichloro-ethane; for 18h;Reflux;	An oven-dried flask was charged with BBr3.SMe2 (2.80 g, 9.20 mmol) and 1,2-dichloroethane (15 mL). 5-Methoxyindolin-2-one (0.3Og, 1.84 mmol) was then added and the mixture was heated to reflux for 18 hours. The reaction was then cooled to room temperature and quenched with MeOH (1.0 mL). The mixture was then extracted into EtOAc washing with brine (3X). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo; the resulting residue was then purified by column chromatography (silica gel, 94:6 to 92:8, CH2Cl2/Me0H) to give 144 mg, 53 % of a beige powder. MS ESI 149.9 [M + H]+, calcd for [C8H7NO2+ H]+ 150.06
	With boron tribromide; In dichloromethane; at 20℃; for 1h;	Description 13:5-Hydroxyindolin-2-oneTo <strong>[7699-18-5]5-methoxyindolin-2-one</strong> (200 mg, 1.23 mmol) in dry DCM (5 ml), cooled down to 0C, was added a solution of boron tribromide in DCM (1M, 3.5 equiv., 4.3 ml). The reaction mixture was slowly warmed up to room temperature and stirred overnight, then carefully poured into stirring ice-water and stirred for 1 hour. The precipitate was collected by filtration, washed with water, air-dried to give the title compound as a grey solid. The results of NMR spectroscopy set out below indicate the final product was the title compound D13.'H NMR (dmso-d6): 10.06 (1 H, NH, br s), 8.93 (1H, OH. br s), 6.65 (1 H. s), 6.60-6.52 (2H, m), 3.37 (2H, s).13C NMR (dmso-d6): 176.1 , 152.2, 135.5, 126.9, 113.3, 112.3, 109.3, 33.1. MS: (MH+ 41) 191.0.

Reference： [1]Patent: WO2009/79767,2009,A1 .Location in patent: Page/Page column 185
[2]Patent: WO2012/25726,2012,A1 .Location in patent: Page/Page column 17

13
[ 7699-18-5 ]
[ 1168723-08-7 ]
[ 1168723-07-6 ]

Yield	Reaction Conditions	Operation in experiment
26%	With piperidine; In methanol; at 60℃; for 4h;	A round bottom flask was charged with 3-(2-(4-methylpiperazin-l-yl)pyrimidin-5- yl)-lH-indazole-6-carbaldehyde (26 mg, 0.80 mmol), 5-methoxyoxindole (13 mg, 0.80 mmol), piperidine (0.8 uL, 0.008 mmol) and MeOH (2 mL). The reaction was then heated to 6O0C for 4 hrs. An orange precipitate formed which was further precipitated by cooling to room temperature. The orange solid was then filtered and washed with MeOH (5 mL) giving 9.8 mg, 26 % of the title compound. 1H NMR (400 MHz, de-DMSO) delta 13.46 (s, IH), 10.44 (s, IH), 8.97 (s, 2H), 8.18 (d, J = 8.5 Hz, IH), 7.94 (s, IH), 7.78 (s, IH), 7.48 (d, J = 8.8 Hz, IH), 7.20 (s, IH), 6.85 (d, J = 10.6 Hz, IH), 6.80 (d, J = 9.0 Hz, IH), 3.82 (br t, 4H), 3.59 (s, 3H), 2.39 (br t, 4H), 2.23 (s, 3H); MS ESI 468.3 [M + H]+, calcd for [C26H25N7O2 + H]+ 468.2.

Reference： [1]Patent: WO2009/79767,2009,A1 .Location in patent: Page/Page column 207

14
[ 7699-18-5 ]
[ 55-86-7 ]
[ 742067-27-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-methoxyindolin-2-one With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: mechlorethamine hydrochloride In tetrahydrofuran at -78 - 20℃; for 13.5h;	ZL To a solution of the product of Example ZK (1.06 g, 6.49 MMOL) in THF (13 ML), a solution of NAHMDS (1 M THF solution) (32.5 ML, 32.5 MMOL) is added AT-78C. After stirring for 30 min AT-78C, METHYL-BIS- (2-CHLORO-ETHYL)-AMINE HYDROCHLORIDE (1.37g, 7.14 mol) is added and the reaction mixture is stirred for 13.5 h at room temperature, quenched with saturated ammonium chloride and ice-water and extracted with ethyl acetate. The combined extracts are washed with brine, dried over sodium sulphate and evaporated down. Ethyl ether is added to the residue to give the powder, which is filtrated ; RF=0. 10 (CH2CI2 : MEOH = 30: 1) H-NMR (400MHz, DMSO-D6) D : 1.66-1. 78 (m, 4H), 2.28 (s, 3H), 2.44-2. 47 (m, 2H), 2.71- 2.77 (m, 2H), 3.70 (s, 3H), 6.74 (s, 2H), 7.01 (s, 1H), 10. 15 (brs, 1H).

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2004/69256, 2004, A1 Location in patent: Page/Page column 46

15
[ 7699-18-5 ]
[ 68-12-2 ]
[ 1200525-65-0 ]

Yield	Reaction Conditions	Operation in experiment
45%		Preparation of 5-methoxy-2-(1 -methyl-1 H-pyrazol-4-yl)-indole-3-carbaldehyde; 5-Methoxy isatin (0.2 g, 1.1 mmol, 1 eq.) was dissolved in hydrazine hydrate (1.2 ml_, 38 mmol, 34 eq.) and refluxed for 15 minutes. The reaction mixture was poured into cold water and extracted with EtOAc. The combined organic extracts were dried on Na2SO4. The solvent was evaporated to afford crude 5-methoxy-1 ,3-dihydro-indol-2-one that was purified by silica gel column chromatography (eluent: hexane/EtOAc from 10:0 to 6:4). Yield: 27%. MS (m/z): 164.2 (MH+).Phosphorous oxybromide (0.35 ml_, 3.1 mmol, 2.5 eq.) was added drop wise to a solution of DMF (0.3 ml_, 3.7 mmol, 3 eq.) in dry methylene chloride at 00C. The mixture was stirred at 00C for 30 minutes, then a solution of 5-methoxy-1 ,3-dihydro-indol-2-one (0.2 g, 1.2 mmol, 1 eq.) in dry methylene chloride (2 ml_) was added and the mixture was refluxed for 3 hours. The solution was neutralized with solid NaHCO3 and extracted with methylene chloride. The organic layer was dried on Na2SO4 and evaporated under reduced pressure. The crude mixture was purified by silica gel column chromatography (eluent: hexane/AcOEt 6:4 to 4:6) to give pure 2-bromo-5-methoxy-indole-3-carbaldehyde. Yield: 45%. MS (m/z): 254.1 (MH+). A stirred solution of 2-bromo-5-methoxy-indole-3-carbaldehyde (2.0 g, 7.9 mmol, 1 eq.) in DME (2 ml_) was deoxygenated by bubbling argon for 10 minutes at rt. Pd(PPh3)4 (0.9 g, 0.8 mmol, 0.1 eq.) was added followed by a solution of 1-methyl-4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (2.4 g, 1 1.63 mmol, 1.48 eq.) in ethanol (2.5 ml_). 2M Na2CO3 (33 ml_, 8.5 eq.) was also deoxygenated with argon and added. The resulting mixture was heated at 78C for 18 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with methylene chloride. Organic layer was dried on anhydrous Na2SO4 and evaporated under reduced pressure to give the crude product 1f. Yield: 89%. MS (m/z): 256.1 (MH+).

Reference： [1]Patent: WO2010/30727,2010,A1 .Location in patent: Page/Page column 101-102

16
[ 2199-58-8 ]
[ 7699-18-5 ]
(Z)-3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-5-methoxy-1,3-dihydro-indol-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	piperidine; In ethanol; at 150℃; for 0.5h;Microwave irradiation;	Description 12:(Z)-3-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-<strong>[7699-18-5]5-methoxyindolin-2-one</strong>5-Methoxyindolin-2-one (50 mg, 0.31 mmol) and 3,5-dimethyl-W-pyrrole-2- carboxaldehyde (1.2 equiv., 45 mg) were heated together in ethanol (1 ml) and piperidine (2 drops) in a microwave (150C, 30 min). The reaction mixture was cooled to room temperature and diluted with ethanol. The precipitate was filtered, washed with ethanol, and then with ethyl ether, air-dried to give the product as an orange crystalline solid. The results set out below indicate the final product was the title compound 012.1H NMR (dmso-d6): 13.45 (1H, NH, br s), 10.58 (1H, NH, br s), 7.57 (1H, s), 7.40 (1H, s), 6.75 (1H, d), 6.65 (2H, d), 6.00 (1H, s), 3.77 (3H, s), 2.31 (6H, s).13C NMR (CDC ): 169.9, 155.5, 137.0, 32.7, 131.0, 127.6, 127.0, 123.6, 112.7, 112.0, 111.2, 109.5, 103.7, 56.0, 13.9, 11.7.MS: MH+ 269.0

Reference： [1]ChemMedChem,2016,vol. 11,p. 72 - 80
[2]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 1482 - 1496
[3]Patent: WO2012/25726,2012,A1 .Location in patent: Page/Page column 16-17

17
[ 20876-29-3 ]
[ 7699-18-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 1482 - 1496

18
[ 56139-74-3 ]
[ 7699-18-5 ]
[ 1227783-58-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 3004 - 3011

19
[ 7699-18-5 ]
[ 2092-49-1 ]
[ 1227783-61-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 3004 - 3011

20
[ 7699-18-5 ]
[ 77-78-1 ]
[ 7699-22-1 ]

Yield	Reaction Conditions	Operation in experiment
53%		Example A lOO. (l R.2SV5'-methoxy-l'-methyl-2-(3-(4-(4-methylpiperazin-l- vDphenv?-l H-indazol--v?spirofcvclopropane-U'-indolini^'-one Sigma^^-trifluoroacetateA . 5-methoxy- 1 -methylindolin-2-oneA dry round-bottom flask was charged with NaH (60% wt) (64 mg, 1.61 mmol) and toluene (2.0 mL). The suspension was heated to 100 0C and then 5-methoxyindolin-2- one (250 mg, 1.53 mmol) was added. After 30 min at 100 0C, Me2SO4 (0.16 mL, 1.68 mmol) was added and the temperature maintained at 1000C for 2.5 h. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, hexanes/EtOAc, 3: 1 to 2:1) to give the product as a beige solid (144mg, 53%); MS ESI 164.1 [M + H]+, calcd for [C9H9NO2 +H]+ 164.07.

Reference： [1]Patent: WO2010/115279,2010,A1 .Location in patent: Page/Page column 214

21
[ 7699-18-5 ]
[ 1247002-01-2 ]
[ 1247002-02-3 ]

Yield	Reaction Conditions	Operation in experiment
63%	With piperidine; In methanol; at 60℃; for 4h;	B. (E)-5-Methoxy-3-((3-(6-morpholinopyridin-3-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-indazol-6-yl)methylene)indolin-2-oneA round bottom flask was charged with 5-methoxyoxindole (100 mg, 0.61 mmol), 3-(6-Morpholinopyridin-3-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole- 6-carbaldehyde (266 mg, 0.61 mmol), piperidine (6 uL, 0.06 mmol) and MeOH (4 mL). The reaction was then heated to 6O0C for 4h. An orange precipitate formed which was further precipitated by cooling to room temperature. The orange powder was then filtered and washed with MeOH to give the title compound (224 mg, 63 %). 1H NMR (400 MHz, DMSO-d6) 10.46 (s, I H), 8.79 (d, J = 1.5 Hz, I H), 8.20 (d, J = 8.5, I H), 8.17- 8.13 (m, 2H), 7.77 (s, I H), 7.57 (d, J = 8.3 Hz, IH), 7.13 (s, IH), 7.01 (d, J = 8.5 Hz, I H), 6.85 (d, J = 8.5 Hz, I H), 6.80 (d, J = 8.5 Hz, I H), 5.82 (s, 2H), 3.73 (t, J = 4.3 Hz, 4H), 3.62-3.53 (m, 9H), 0.82 (t, J = 8.2 Hz, 2H), -0.12 (s, 9H); MS ESI 584.3 [M + H]+, calcd for [C32H37N5O4Si + H]+ 584.26.

Reference： [1]Patent: WO2010/115279,2010,A1 .Location in patent: Page/Page column 144

22
[ 99275-47-5 ]
[ 7699-18-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: lithium diisopropyl amide / tetrahydrofuran / 1.17 h / 0 °C 2: Oxone; sodium hydrogencarbonate; sodium hydroxide / tetrahydrofuran; water; acetone / 0.5 h / 0 °C 3: trifluoroacetic acid / dichloromethane / 1 h / 0 °C

Reference： [1]Current Patent Assignee: ATKINSON Benjamin; BEATTIE David; CULSHAW Andrew James; DEVEREUX Nicholas James; MCKENNA Jeffrey; DALE James - WO2011/92293, 2011, A1

23
[ 374898-41-6 ]
[ 7699-18-5 ]

Yield	Reaction Conditions	Operation in experiment
		Step 4: 5-Methoxy-1,3-dihydro-indol-2-one ester To a solution of 5-methoxy-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.800 g, 3.04 mmol) in dichloromethane (6 ml) at 0C was added trifluoroacetic acid (0.234 ml, 3.04 mmol). The reaction mixture was stirred at 0C for 1 hour and quenched by pouring into sat NaHC03 (50 ml). The aqueous layer was back- extracted with EtOAc (3 x 35 ml). The combined organic extracts were washed with brine (1 x 50 ml) dried (MgS04) and concentrated in vacuo to yield a solid residue. The residue was crystallized from hot EtOAc (4 ml) and iso-hexane (2 mi) was added on cooling to yield the title compound as a pink solid: LC-MS Rt =0.54 mins; MS m/z 164.0 [M+H]+; Method 2minl_C_30_v002; H NMR (400 MHz, DMSO-d6) delta 10.20 (1H, br s), 6.86 (1H, s), 6.72 (2H, m), 3.69 (3H, s), 3.43 (2H, s).

Reference： [1]Patent: WO2011/92293,A1 .Location in patent: Page/Page column 86-87
Patent: ,2011, .Location in patent: Page/Page column 86-87

24
[ 7699-18-5 ]
[ 1168722-33-5 ]
3-((3-(4-((dimethylamino)methyl)styryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)-5-methoxyindolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With piperidine; In ethanol; at 75℃; for 25h;	B. (E)-3-((3-(4-((dimethylamino)methyl)styryl)-l-((2-(trimethylsilyl)indazol-6-yl)methylene)-<strong>[7699-18-5]5-methoxyindolin-2-one</strong>[00108] Piperidine (0.01 mL, 0.1 mmol) was added to a solution of 5-methoxyoxindole (52 mg, 0.32 mmol) and (E)-3-(4-((dimethylamino)methyl)styryl)-l-((2- (trimethylsilyl)ethoxy)-methyl)-lH-indazole-6-carbaldehyde (contaminated with TBAF from previous deprotection attempt, 95.5 mg, 0.22 mmol) in EtOH (5 mL). The reaction was then heated to 75C for 25 hrs. The solvent was evaporated in vacuo. Chromatography (5g silica SPE tube, Silicycle, 5-10% MeOH in CH2C12) gave a brown oil (105 mg, contained product and TBAF by NMR). The residue was dissolved in EtOAc (100 mL) and washed with brine (3 x 15 mL), dried over Na2S04 and the solvent was evaporated in vacuo to give the title compound as a brown oil (1 lOmg, used without further purification).

Reference： [1]Patent: WO2011/123946,2011,A1 .Location in patent: Page/Page column 34
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 6069 - 6087

25
[ 39755-95-8 ]
[ 7699-18-5 ]
[ 109103-45-9 ]

Yield	Reaction Conditions	Operation in experiment
~ 10%		Synthesis of 5-methoxyoxindole; [0095] To a solution of 5-methoxyisatin ( 10.62 g, 60 mmol) in DMSO (30 mL) was added N2H4 xH20 (hydrazine hydrate, 6 mL, 120 mmol) dropwise over 5 min (exothermic). After addition, the resulting mixture was heated at 140 C (oil temp.) for 2h and then cooled to rt. After diluting with H20 (30 mL), 6 M HC1 (12 mL, 72 mmol) was added and the resulting mixture was stirred for lh at rt. Ice (30 mL) was added and the reaction mixture was stirred O/N at rt. The precipitate formed was collected by suction filtration, rinsed with H20, then dried to give the 5-methoxyoxindole (6.523 g) as a brown solid, (about 10% impurity being the oxime from starting material 5-methoxyisatin) NMR (400 MHz, d6- DMSO) 6.78 (s, 1H), 6.85 (s, 1 H), 6.72-6.79 (m, 2H), 3.39 (s, 3H); ESI 164.0 [M + H]+, calcd for [C9H9N02 + H]+ 164.1.

Reference： [1]Patent: WO2011/123946,2011,A1 .Location in patent: Page/Page column 27

26
[ 7699-18-5 ]
[ 1885-14-9 ]
[ 1355679-73-0 ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine; In tetrahydrofuran; at 25 - 30℃;	General procedure: To a solution of the corresponding substituted oxindole (5, 40 mmol) and triethylamine (88 mmol) in THF (140 mL) was added phenyl chloroformate (13.76 g, 11.0 mL, 88 mmol) dropwise. The temperature was kept below 30 C during the addition. After stirring for 30 min at room temperature, the solvent was evaporated. Water (40 mL) was added to the residue and the mixture was stirred for 2 h at 0-5 C. The crystalline product was filtered and recrystallized from ethyl acetate to give compounds 6.

Reference： [1]Tetrahedron,2012,vol. 68,p. 1427 - 1435

27
[ 7699-18-5 ]
[ 67-64-1 ]
5-methoxy-3-(propan-2-ylidene)indolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With morpholine; for 16h;Reflux;	General procedure: 3-(Propan-2-yliden)indolin-2-one (7a): A solution of indolin-2-one (500 mg, 3.76 mmol, 1.0 equiv.) in acetone (15 mL, 0.25 M) was heated in the presence of catalytic amounts of morpholine (164 mL, 164 mg, 1.88 mmol, 0.5 equiv.) for 16 h at reflux temperature. After complete consumption of the indolin-2-one (determined by thin layer chromatography (TLC)) all volatiles were removed under vacuum. Column chromatography(column diameter 5 cm, 30 g silica, v/v (P/EA)6 : 4-1 : 1) afforded the title compound (650 mg, 3.75 mmol, 99 %) as a yellow solid. Apparent multiplets which occur as a result of accidental equality of coupling constants to those of magnetically non-equivalent protons are marked as virtual (virt.). RF 0.70 (P/EA3 : 7; UV). deltaH (CDCl3, 250 MHz,300 K) 7.96 (1H, br s, NH), 7.52 (1H, br d, 3J 7.7, H-4), 7.19(1H, virt. td, 3JE3J 7.7, 4J 1.2, H-6), 7.01 (1H, virt. td, 3JE3J7.7, 4J 1.2, H-5), 6.85 (1H, ddd, 3J 7.7, 4J 1.2, 5J 0.6, H-7), 2.62(3H, s, H-30), 2.39 (3H, s, H-1'). deltaC (CDCl3, 63 MHz, 300 K)169.5 (s, C-2), 155.7 (s, C-2'), 139.3 (s, C-7a), 127.7 (d, C-6),124.6 (s, C-3), 123.9 (d, C-5), 123.0 (s, C-3a), 121.8 (d, C-4),109.3 (d, C-7), 25.4 (q, C-1'), 23.3 (q, C-3'). The NMR data match the values reported in the literature.[9] 5-Methoxy-3-(propan-2-ylidene)indolin-2-one (7g): Prepared from 5-methoxy-2-oxindole according to RP 1 on a938 mmol scale. The title compound (176 mg, 866 mmol, 92 %) was obtained as a yellow solid. RF 0.45 (P/EA1 : 1; UV). numax(ATR)/cm1 3150w, 3030w, 2938w, 2836w, 1694vs (CO),1619s, 1594w, 1479s, 1305m, 1203w. deltaH (CDCl3, 250 MHz,300 K) 8.07 (1H, s, NH), 7.14 (1H, d, 4J 1.6, H-4), 6.78-6.72(2H, m, H-6/H-7), 3.81 (3H, s, OCH3), 2.62 (3H, s, H-3'), 2.36(3H, s, H-1'). deltaC (CDCl3, 63 MHz, 300 K) 169.8 (s, C-2), 156.0(s, C-3'), 155.2 (s, C-5), 133.4 (s, C-7a), 125.6 (s, C-3a), 123.4 (s,C-3), 111.9 (d, C-4), 111.8 (d, C-6), 109.3 (d, C-7), 56.1 (q,OCH3), 25.3 (q, C-1'), 23.3 (q, C-30). m/z (HRMS ESI)204.1019; [M H)](C12H13NO2) requires 204.1019.
	With acetic acid; benzylamine; In ethanol; for 2h;Reflux;	General procedure: A 50 mL round-bottom flask equipped with a reflux condenser and a magnetic stir bar was charged with indolin-2-one (10.0 mmol), ethanol(10 mL), acetone (7.3 mL, 0.1 mmol, 10.0 equiv), benzylamine(0.33 mL, 3.0 mmol, 0.3 equiv), and acetic acid (0.17 mL, 3.0 mmol,0.3 equiv). Then, the reaction mixture was heated under reflux for 2 h. The precipitation was filtered off and washed with cold PE (10 mL). The obtained product was dried for 30 min and used without further purification.

Reference： [1]Australian Journal of Chemistry,2015,vol. 68,p. 1682 - 1692
[2]Letters in Organic Chemistry,2012,vol. 9,p. 225 - 232
[3]Synlett,2015,vol. 26,p. 67 - 72
[4]Journal of Fluorine Chemistry,2018,vol. 208,p. 73 - 79

28
[ 7699-18-5 ]
[ 356068-86-5 ]
[ 1126899-03-3 ]

Yield	Reaction Conditions	Operation in experiment
45%	With piperidine; In ethanol; for 4h;Reflux;	In a 10 mL flask 94 mg (0.58 mmol) 2 and 171 mg (0.64 mmol) 3 [24] were dissolved in 3.0 mL of ethyl alcohol, four drops of piperidine were added and the mixture was refluxed for 4 h. The solution was allowed to cool and stored in a refrigerator overnight. The orange crystals that have precipitated were filtered andwashed with small amounts of ethyl alcohol and petrol ether and yielded after drying under vacuum 107 mg (45%) of 5. Mp: 220e222 C, 1H NMR (d, ppm, DMSO-d6): 0.99 (t, 6H, 2 CH3), 2.45 (s, 3H, CH3/ pyrrole), 2.46 (s, 3H, CH3/pyrrole), 2.52 (m, 6H, 3 CH2), 3.29 (q, 2H, CH2), 3.79 (s, 3H, CH3O), 6.71 (m, 1H, CH), 6.78 (d, 1H, CH), 7.42 (t, 1H, CONH), 7.50 (d, 1H, CH), 7.68 (s, 1H, CHvinyl), 10.72 (s, 1H, NHoxindole), 13.76 (s, 1H, NHpyrrole), 13C NMR (d, ppm, DMSO-d6): 10.63 (CH3), 11.84 (CH3), 13.23 (CH3), 36.90 (CH2), 46.43 (CH2), 51.56 (CH2), 55.56 (OCH3), 104.44, 109.80, 112.54, 115.60, 120.27, 13.64, 125.62, 126.40, 129.00, 132.19, 135.65, 154.81 (12 C]C), 164.52 (C]O), 169.42 (C]O), ESI-MS (ESth): m/z ¼ 411.42 (M th H).

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 58,p. 272 - 280

29
[ 27387-22-0 ]
[ 7699-18-5 ]

Yield	Reaction Conditions	Operation in experiment
70%	With copper(I) oxide; 1,2-diamino-benzene; sodium t-butanolate; In tert-butyl alcohol; at 100℃; for 24h;Sealed tube;	General procedure: To a screw-capped vial (20-mL) were added CuI (0.005 mmol, 0.7 mg, 1.0 mol %), Benzene-1,2-diamine (0.01 mmol, 1.1 mg, 2.0 mol %), NaOtBu (1.5 mmol, 144.2 mg, 3.0 equiv) and amide 1 (0.5 mmol, 1.0 equiv) in t-BuOH (tert-butanol, 5.0 mL). The vial was sealed with cap and allowed to stir at 100 C for the specific reaction time. The crude reaction mixture was diluted with CH2Cl2, filtered through a thin Celite pad, and concentrated in vacuo. The residue was isolated through a column chromatography by using hexane and ethyl acetate as eluent to give the pure product. Products 2 were obtained according to this procedure. The known structures were characterized by the HRMS, 1H NMR and 13C NMR spectra of reported literatures. Spectral data, melting point, HRMS data and the copies of 1H NMR and 13C NMR spectra for all compounds are listed below.

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 1155 - 1159

30
[ 27387-23-1 ]
[ 7699-18-5 ]

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 1155 - 1159

31
[ 7699-18-5 ]
[ 142016-38-4 ]
(E)-5-methoxy-3-((2-para-tolylimidazo[1,2-a]pyridin-3-yl)methylene)indolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With piperidine In ethanol Reflux;

Reference： [1]Kamal, Ahmed; Reddy, Vangala Santhosh; Karnewar, Santosh; Chourasiya, Sumit S.; Shaik, Anver Basha; Kumar, G. Bharath; Kishor, Chandan; Reddy, M. Kashi; Narasimha Rao; Nagabhushana, Ananthamurthy; Ramakrishna, Kallaganti V. S.; Addlagatta, Anthony; Kotamraju, Srigiridhar [ChemMedChem, 2013, vol. 8, # 12, p. 2015 - 2025]

32
[ 7699-18-5 ]
[ 98-86-2 ]
[ 1554668-40-4 ]
[ 1554668-66-4 ]

Yield	Reaction Conditions	Operation in experiment
72%; 23%	With pyridine; titanium(IV) isopropylate; In tetrahydrofuran; at 20℃; for 5h;	General procedure: To a stirred solution of oxindole (1a, 67 mg, 0.5 mmol), acetophenone (72 mg, 0.6 mmol), and pyridine (59 mg, 0.75 mmol) in dry THF (0.5 mL) was added dropwise a solution of Ti(OiPr)4 (284 mg, 1.0 mmol) in THF (0.3 mmL), and the reaction mixture was stirred at room temperature for 4 h. After the usual aqueous extractive workup and column chromatographic purification process (hexanes/ether, 2:1) 2e-Z (92 mg, 78%) and 2e-E (18 mg, 15%) were obtained. Other compounds were synthesized similarly, and the structures of known compounds 2a-e and 2k-p were characterized by comparing their melting points and 1H NMR spectrum with the reported.3,4 The selected spectroscopic data of unknown compounds 2f-j and 2q are as follows.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 1183 - 1187

33
[ 7699-18-5 ]
[ 134903-49-4 ]
C₂₇H₂₃ClN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With piperidine; In methanol;Reflux;	General procedure: The appropriate compound 1 (10 mmol) was dissolved in methanol (100 mL) and treated with the equivalent of the appropriate aldehyde 2 and piperidine (1 mL). The reaction mixture was refluxed for 3-5 h (progress of the reaction followed by TLC), and the precipitate that formed on cooling was collected byfiltration.Compounds 16, 25 and 27 were purified by column chromatography,compounds 16 and 25 with petroleum ether/acetone, and compound 27 with methylene chloride/acetone as the eluent. All the crude products were crystallized from ethanol except compound 4 (CHCl3/MeOH) and compound 5 (acetone/petroleumether).For compounds 25-28 the yield was much lower, and an improvement was obtained by replacing piperidine with NH4OH conc.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 79,p. 382 - 390

34
[ 7699-18-5 ]
2-chloro-1-[(2E)-3-phenylprop-2-en-1-yl]-1H-indole-3-carbaldehyde [ No CAS ]
C₂₇H₁₉ClN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With hydrogenchloride; In water; acetic acid; at 20℃;Reflux;	General procedure: The appropriate oxindole 1 (5 mmol) was dissolved in acetic acid (25 mL) and treated with an equivalent of appropriate indole-3-carbaldehyde 2 and 37% hydrochloric acid (1 mL). The reaction mixture was refluxed for 20 h, the solid separated on cooling was collected by filtration. The crude products were purified by crystallization with ethanol to give the desired products, with the exception of compound 6 purified by column chromatography, with petroleum ether/acetone as the eluent.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 79,p. 382 - 390

35
[ 7699-18-5 ]
[ 2973-77-5 ]
C₁₆H₁₁Br₂NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With pyridine; In methanol; at 100℃; for 0.5h;Microwave irradiation;	General procedure: A suspension of indolinone (0.3mmol), aldehyde (0.3mmol) and pyridine (30muL) in methanol (1mL) were heated under microwave irradiation at 100 C for 30 minutes. The reaction mixture was cooled to room temperature and the resulting precipitate was removed by filtration, carefully washed with methanol and dried in vacuo. When no precipitate was observed methanol was removed under vacuum and the residue was purified by silica gel chromatography to give the desired product.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4630 - 4637

36
[ 7699-18-5 ]
[ 1192020-91-9 ]
(Z)-5-methoxy-3-((3-(4-methoxyphenyl)-1H-pyrazol-5-yl)methylene)indolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With piperidine; In ethanol; at 85℃; for 4h;	General procedure: To the 3-subtitutedphenyl-1H-pyrazole-5-carbaldehydes 11(a-d) prepared in the above step was added corresponding substituted oxindoles and catalytic amount of piperdine (1.0ml) in ethanol. Heated the reaction mixture to reflux for 4h at 85C. The solid compounds obtained in the reaction vessel were filtered and washed with ethanol for 4-5 times. After complete air drying the final compounds (Z)-3-((3-phenyl-1H-pyrazol-5-yl)methylene)indolin-2-one analogs 12(a-u) were obtained as pure solids (yield 75-80%).

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 92,p. 501 - 513

37
[ 7699-18-5 ]
3-(3,4-dimethoxyphenyl)-1H-pyrazole-5-carbaldehyde [ No CAS ]
(Z)-3-((3-(3,4-dimethoxyphenyl)-1H-pyrazol-5-yl)methylene)-5-methoxyindolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With piperidine; In ethanol; at 85℃; for 4h;	General procedure: To the 3-subtitutedphenyl-1H-pyrazole-5-carbaldehydes 11(a-d) prepared in the above step was added corresponding substituted oxindoles and catalytic amount of piperdine (1.0ml) in ethanol. Heated the reaction mixture to reflux for 4h at 85C. The solid compounds obtained in the reaction vessel were filtered and washed with ethanol for 4-5 times. After complete air drying the final compounds (Z)-3-((3-phenyl-1H-pyrazol-5-yl)methylene)indolin-2-one analogs 12(a-u) were obtained as pure solids (yield 75-80%).

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 92,p. 501 - 513

38
[ 7699-18-5 ]
3-(3,4,5-trimethoxyphenyl)-1H-pyrazole-5-carbaldehyde [ No CAS ]
(Z)-5-methoxy-3-((3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-5-yl)methylene)indolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With piperidine; In ethanol; at 85℃; for 4h;	General procedure: To the 3-subtitutedphenyl-1H-pyrazole-5-carbaldehydes 11(a-d) prepared in the above step was added corresponding substituted oxindoles and catalytic amount of piperdine (1.0ml) in ethanol. Heated the reaction mixture to reflux for 4h at 85C. The solid compounds obtained in the reaction vessel were filtered and washed with ethanol for 4-5 times. After complete air drying the final compounds (Z)-3-((3-phenyl-1H-pyrazol-5-yl)methylene)indolin-2-one analogs 12(a-u) were obtained as pure solids (yield 75-80%).

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 92,p. 501 - 513

39
[ 7699-18-5 ]
3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazole-5-carbaldehyde [ No CAS ]
(Z)-3-((3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)methylene)-5-methoxyindolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With piperidine; In ethanol; at 85℃; for 4h;	General procedure: To the 3-subtitutedphenyl-1H-pyrazole-5-carbaldehydes 11(a-d) prepared in the above step was added corresponding substituted oxindoles and catalytic amount of piperdine (1.0ml) in ethanol. Heated the reaction mixture to reflux for 4h at 85C. The solid compounds obtained in the reaction vessel were filtered and washed with ethanol for 4-5 times. After complete air drying the final compounds (Z)-3-((3-phenyl-1H-pyrazol-5-yl)methylene)indolin-2-one analogs 12(a-u) were obtained as pure solids (yield 75-80%).

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 92,p. 501 - 513

40
[ 7699-18-5 ]
[ 126824-22-4 ]
(Z)-5-methoxy-3-((2-(4-methoxyphenyl)-1H-benzo[d]imidazol-6-yl)methylene)indolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With piperidine; In ethanol;Reflux;	General procedure: 4.4.2 (Z)-5-methoxy-3-((2-(4-methoxyphenyl)-1H-benzo[d]imidazol-6-yl)methylene)indolin-2-one (5b) Compound 5b was prepared according to the method described for compound 5a, employing aldehyde 11a (126 mg, 0.5 mmol) and <strong>[7699-18-5]5-methoxyindolin-2-one</strong> (12b, 81 mg, 0.5 mmol) to obtain the pure product 5c as a yellow solid (114 mg, 58%); mp: 177-179 C; IR (KBr): 3422, 3153, 2931, 2352, 1681, 1642, 1576, 1474, 1435, 1254, 1179, 1029, 961, 864 cm-1; 1H NMR (300 MHz, DMSO-d6): delta 10.41 (bs, 1H), 8.25-8.16 (m, 3H), 7.82 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.40 (s, 1H), 7.12 (d, J = 8.6 Hz, 2H), 6.82-6.70 (m, 2H), 3.90 (s, 3H), 3.68 (s, 3H); 13C NMR (75 MHz, DMSO-d6): delta 168.9, 160.6, 154.3, 153.7, 153.1, 137.4, 136.2, 128.0, 127.9, 127.6, 126.1, 124.5, 123.7, 122.0, 121.9, 113.9, 109.9, 108.5, 55.0; MS (ESI): m/z 398 [M + H]+; HRMS (ESI): calcd for C24H20O3N3 m/z 398.14923 [M + H]+; found 398.14992.