[ CAS No. 356068-86-5 ] {[proInfo.proName]}

Name: 356068-86-5|N-(2-(Diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide|98%
Brand: Ambeed
SKU: A193863
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Quality Control of [ 356068-86-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 356068-86-5 ]

CAS No. :	356068-86-5	MDL No. :	MFCD12913910
Formula :	C₁₄H₂₃N₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BRZYBFNUINXZMJ-UHFFFAOYSA-N
M.W :	265.35	Pubchem ID :	20761785
Synonyms :

Calculated chemistry of [ 356068-86-5 ]

Physicochemical Properties

Num. heavy atoms :	19
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.57
Num. rotatable bonds :	8
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	76.04
TPSA :	65.2 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) :	-6.98 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.57
Log Po/w (XLOGP3) :	1.32
Log Po/w (WLOGP) :	1.52
Log Po/w (MLOGP) :	0.26
Log Po/w (SILICOS-IT) :	2.78
Consensus Log Po/w :	1.69

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.98
Solubility :	2.76 mg/ml ; 0.0104 mol/l
Class :	Very soluble
Log S (Ali) :	-2.29
Solubility :	1.36 mg/ml ; 0.00513 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.06
Solubility :	0.023 mg/ml ; 0.0000865 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.41

Safety of [ 356068-86-5 ]

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 [ 356068-86-5 ]

* 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 [ 356068-86-5 ]
Downstream synthetic route of [ 356068-86-5 ]

[ 356068-86-5 ] Synthesis Path-Upstream 1~15

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Yield	Reaction Conditions	Operation in experiment
86.3%	With dmap; dicyclohexyl-carbodiimide In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 59 h;	To a three-necked flask equipped with a thermometer, 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3, 5.50 g, 32.7 mmol) and anhydrous DMF (13.1 mL) were added while being cooled down to 0 °C with an ice-salt bath. To the above mixture was added dropwise a solution of dicyclohexylcarbodiimide (DCC, 10.13 g, 49.0 mmol) in dichloromethane (78.4 mL) under stirring while keeping the reaction temperature between 0 and 2 °C, to which were then added at r.t. 4-dimethylaminopyridine (DMAP, 1.65 g) and N¹,N¹-diethylethane-1,2-diamine (4, 5.03 mL, 35.9 mmol). The reaction mixture was then allowed to react at r.t. for 59 h with TLC monitoring (eluent: chloroform/methanol, v/v = 5:1). The filtrate obtained from filtration was added with water, which was extracted with dichloromethane (15 mL x 3). The organic layers were combined, washed withsaturated brine (65.7 mL), then dried over anhydrous sodium sulfate. The filtrate was concentrated to give some solids, which were dissolved in a small amount of dichloromethane (5.0 mL). The obtained organic phase was washed with aqueous citric acid solution (5.0 percent, 330 mL x 3) until there was no product in the organic layer (as monitored by TLC). The reason was that the weak basic product 10 could form a water-soluble salt with citric acid. The aqueous phase was then basified with saturated aqueous sodium hydroxide solution and a large amount of aqueous sodium bicarbonate solution to pH 8, which was then extracted with dichloromethane (330 mL 9 3). The combined organic layers were combined and concentrated to provide brownish-red oily liquid. Further purification could be achieved with stepwise column chromatography with petroleum ether/ethyl acetate eluent (v/v = 3:1 to 1:1) to provide 10 as yellowish solid (8.11 g, 86.3 percent), m.p. 153-154 °C (lit. 177-181 °C [13]), yield 42.5 percent (lit. [13]). R_f = 0.60 (eluent: chloroform/methanol, v/v = 5:1). ¹H NMR (400 MHz, DMSO-d₆) δ: 11.85 (s, 1H, NH), 9.54 (s, 1H, CHO), 7.36-7.38 (t, 1H, CONH), 3.24-3.29 (m, 2H, NHCH₂), 2.50-2.56 (m,6H, 3 x (N-CH₂)), 2.32 (s, 3H, 4-CH₃), 2.37 (s, 3H, 2-CH₃), 0.95-0.99 (t, 6H, 2 x (CH3)).

Reference： [1] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8941 - 8954

2
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Yield	Reaction Conditions	Operation in experiment
43%	With sodium hydroxide; triethylamine In <i>N</i>-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene	5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10percent methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34° C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43percent yield) as a light brown solid. ¹H-NMR (dimethylsulfoxide-d₆) δ 0.96 (t, 6H, 2CH₃), 2.31, 2.38 (2s, 2CH₃), 2.51 (m, 6H 3CH₂), 3.28 (m, 2H, CH₂), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%	With sodium hydroxide; triethylamine In <i>N</i>-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene	5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10percent methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34° C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (819 g, 43 percent yield) as a light brown solid. ¹H-NMR (dimethylsulfoxide-d₆) δ0.96 (t, 6H, 2CH₃), 2.31, 2.38 (2s, 2CH₃), 2.51 (m, 6H 3CH₂), 3.28 (m, 2H, CH₂), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%	With sodium hydroxide; triethylamine In <i>N</i>-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene	5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10percent methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34° C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43percent yield) as a light brown solid. ¹H-NMR (dimethylsulfoxide-d₆) δ 0.96 (t, 6H, 2CH₃), 2.31, 2.38 (2s, 2CH₃), 2.51 (m, 6H 3CH₂), 3.28 (m, 2H, CH₂), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].

43%	With sodium hydroxide; triethylamine In <i>N</i>-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene	5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10percent methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34° C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43percent yield) as a light brown solid. ¹H-NMR (dimethylsulfoxide-d₆) δ0.96 (t, 6H, 2CH₃), 2.31, 2.38 (2s, 2CH₃), 2.51 (m, 6H 3CH₂), 3.28 (m, 2H, CH₂), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%	With sodium hydroxide; triethylamine In <i>N</i>-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene	5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10percent methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34° C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43percent yield) as a light brown solid. ¹H-NMR (dimethylsulfoxide-d₆) δ 0.96 (t, 6H, 2CH₃), 2.31, 2.38 (2s, 2CH₃), 2.51 (m, 6H 3CH₂), 3.28 (m, 2H, CH₂), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%	With sodium hydroxide; triethylamine In <i>N</i>-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene	5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10percent methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34° C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43percent yield) as a light brown solid. ¹H-NMR (dimethylsulfoxide-d₆) δ 0.96 (t, 6H, 2CH₃), 2.31, 2.38 (2s, 2CH₃), 2.51 (m, 6H 3CH₂), 3.28 (m, 2H, CH₂), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].

Reference： [1] Patent: US2003/216410, 2003, A1,
[2] Patent: US2003/130280, 2003, A1,
[3] Patent: US2003/100555, 2003, A1,
[4] Patent: US2002/32204, 2002, A1,
[5] Patent: US2002/156292, 2002, A1,
[6] Patent: US2004/209937, 2004, A1,

3
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[ 100-36-7 ]
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Yield	Reaction Conditions	Operation in experiment
66%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 5 - 20℃;	General procedure: The substituted acid (5a or 6a, 1.0 mmol), EDC (229 mg, 1.2 mmol) and HOBt (160 mg, 1.2 mmol) were dissolved in DMF (25 mL). After cooling to 5 °C, the substituted amine was added to the mixture and was stirred at room temperature overnight followed by evaporation under reduced pressure to remove DMF. The residue was purified by column chromatography (pet. ether/EtOAc 7:1 to 2:1) to afford 5 and 6 with the yields of 66percent and 84percent respectively.
53%	Stage #1: With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran for 0.5 h; Stage #2: With triethylamine In tetrahydrofuran at 25 - 30℃; for 16 h;	Step (v): Preparation of 5-formyI-2,4-dimethyl-lH-pyrrole-3-carboxyIic acid(2-diethylaminoethyl)-amide (VII):Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel and an air condenser were charged 5-formyl-2,4- dimethyl- lH-pyrrole-3-carboxylic acid (0.25 Kg; 1.5 mole), tetrahydrofuran(3.5 L), dicyclohexyl carbodimide (0.432 Kg), 1 -hydroxy benzotriazole (0.306 Kg)and stirred well for 30 minutes. To this solution, a premixed solution of TEA (0.42 L) in tetrahydrofuran (1.25 L) and 2-diethylaminoethyl amine (0.286 L; 2.04 mole) in tetrahydrofuran (1.25 L) were added successively at 25-30° C. After addition, the reaction mixture was stirred for 16 hours at 25-30° C and the byproduct generated was removed by filtration through filtration funnel. The solvent was removed by distillation under diminished pressure. The resulting product was suspended in DM water and the pH of the slurry adjusted to 12-13 with aqueous NaOH solution. After pH adjustment, the product was extracted with ethyl acetate and washed successively organic layer with aqueous NaHCψ₃, saturated solution of NaCl and DM water. Organic layer was separated and 3/4^th of the solvent distilled under diminished pressure. The product was cooled to 0- <n="31"/>5⁰ C and stirred for 2 hours, filtered and washed with chilled ethyl acetate (70 mL). The product was dried at 60° C.Dry Weight: 210.2 g Yield: 53.0percent HPLC purity: 99.95percent
53%	Stage #1: With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran for 0.5 h; Stage #2: With triethylamine In tetrahydrofuran at 25 - 30℃; for 16 h;	Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel and an air condenser were charged 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (0.25 Kg; 1.5 mole), tetrahydrofuran (3.5 L), dicyclohexyl carbodimide (0.432 Kg), 1-hydroxy benzotriazole (0.306 Kg) and stirred well for 30 minutes. To this solution, a premixed solution of TEA (0.42 L) in tetrahydrofuran (1.25 L) and 2-diethylaminoethyl amine (0.286 L; 2.04 mole) in tetrahydrofuran (1.25 L) were added successively at 25-30^oC. After addition, the reaction mixture was stirred for 16 hours at 25-30^oC. and the byproduct generated was removed by filtration through filtration funnel. The solvent was removed by distillation under diminished pressure. The resulting product was suspended in DM water and the pH of the slurry adjusted to 12-13 with aqueous NaOH solution. After pH adjustment, the product was extracted with ethyl acetate and washed successively organic layer with aqueous NaHCO₃, saturated solution of NaCl and DM water. Dry Weight: 210.2 g Yield: 53.0percent HPLC purity: 99.95percent

Reference： [1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 21, p. 4829 - 4841
[2] European Journal of Medicinal Chemistry, 2011, vol. 46, # 12, p. 5970 - 5977
[3] Patent: WO2009/157011, 2009, A1, . Location in patent: Page/Page column 29-30
[4] Patent: US2011/92717, 2011, A1, . Location in patent: Page/Page column 15
[5] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 16, p. 2153 - 2157
[6] Patent: US2003/125370, 2003, A1,
[7] Patent: WO2011/33472, 2011, A1, . Location in patent: Page/Page column 7
[8] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 3062 - 3065
[9] Patent: WO2011/110199, 2011, A1, . Location in patent: Page/Page column 14
[10] Patent: WO2012/59941, 2012, A1, . Location in patent: Page/Page column 16-17
[11] European Journal of Medicinal Chemistry, 2014, vol. 85, p. 268 - 288
[12] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 14, p. 2782 - 2787
[13] Nature Chemistry, 2017, vol. 9, # 6, p. 571 - 577

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Reference： [1] Patent: CN106588888, 2017, A, . Location in patent: Paragraph 0034; 0043; 0044

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[ 356068-86-5 ]

Reference： [1] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 16, p. 2153 - 2157
[2] Patent: US2011/92717, 2011, A1,
[3] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 3062 - 3065
[4] Patent: WO2012/59941, 2012, A1,
[5] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 14, p. 2782 - 2787
[6] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8941 - 8954
[7] Organic and Biomolecular Chemistry, 2016, vol. 14, # 21, p. 4829 - 4841

6
[ 253870-02-9 ]
[ 356068-86-5 ]

Reference： [1] Journal of Organic Chemistry, 2004, vol. 69, # 7, p. 2565 - 2568

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[ 356068-86-5 ]

Reference： [1] Journal of Organic Chemistry, 2004, vol. 69, # 7, p. 2565 - 2568

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[ 356068-86-5 ]

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[ 356068-86-5 ]

Reference： [1] Patent: US2011/92717, 2011, A1,
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 3062 - 3065
[3] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8941 - 8954
[4] Organic and Biomolecular Chemistry, 2016, vol. 14, # 21, p. 4829 - 4841

10
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[ 100-36-7 ]
[ 356068-86-5 ]

Reference： [1] Patent: US2003/69297, 2003, A1,

11
[ 2436-79-5 ]
[ 356068-86-5 ]

Reference： [1] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8941 - 8954

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[ 5442-91-1 ]
[ 356068-86-5 ]

Reference： [1] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8941 - 8954

13
[ 590424-04-7 ]
[ 356068-86-5 ]

Reference： [1] Patent: CN106588888, 2017, A,

14
[ 100-36-7 ]
[ 356068-86-5 ]

Reference： [1] Patent: CN106588888, 2017, A,

15
[ 590424-03-6 ]
[ 356068-86-5 ]

Reference： [1] Patent: CN106588888, 2017, A,

[ 356068-86-5 ] Synthesis Path-Downstream 1~80

1
[ 253870-02-9 ]
[ 100-36-7 ]
[ 356068-86-5 ]

Yield	Reaction Conditions	Operation in experiment
86.3%	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 59h;	To a 250 mL three-neck flask equipped with a thermometer and a magnet, 32.7 mmol of <strong>[253870-02-9]2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid</strong> and 13.1 mL of anhydrous DMF were added, and then cooled to 0 with an ice-salt bath. , followed by the dropwise addition of 49.0mmol of dichloromethane solution of cyclohexylcarbodiimide under stirring and controlling the reaction temperature at 0 C. After the addition was completed, 1.65g of 4-dimethylaminopyridine and 35.9mmol of N, N-di Ethylethylenediamine was reacted at room temperature, and the reaction process was detected to be complete by TLC. The developing solvent used for TLC monitoring was a mixed solvent of chloroform and methanol with a volume ratio of 5: 1. After 59 hours of reaction, TLC monitoring found that the reaction was complete. After the reaction was completed, the obtained reaction solution was suction-filtered, and water and dichloromethane were added to the filtrate for the first extraction (3 times). The organic phase of the first extraction was collected and washed with 65.7 mL of saturated brine, and anhydrous sodium sulfate Dried and then filtered with suction, the resulting filtrate was concentrated to remove the solvent to form a solid, the solid was dissolved with a small amount of dichloromethane, and then subjected to a second extraction (3 times) with 1000 mL of a 5% citric acid aqueous solution, as shown by TLC The organic phase contains no product and the reason for analysis is N- (2-diethyl Ethyl) -2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxamide is weakly basic, reacts with citric acid to form a salt and enters the aqueous phase, so the water for the second extraction is collected Phase, and then neutralize it with a large amount of a saturated solution of sodium bicarbonate and a saturated solution of sodium hydroxide, and adjust the pH to pH = 8, and then extract the above aqueous solution for a third time with a large amount of dichloromethane and collect The third extracted organic phase, the third extracted organic phase was concentrated to a reddish brown oily liquid, and finally the column Chromatography gave N- (2-diethylaminoethyl) -2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxamide (8.11 g) as a yellow solid. The eluent system used is in the order of elution: a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3: 1, and a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1: 1. Yield 86.3%,
79%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h;	5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (11, 0.500 g, 2.99 mmol) was dissolved in dry DMF (10 mL), to which 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (635 mL, 3.59 mmol), 1-hydroxybenzotriazole (HOBt) (0.485 g, 3.59 mmol) and N,N-diethylethylenediamine (505 mL, 3.59 mmol) were added. The reaction mixture was stirred at RT for 16 h, before the solvent was removed in vacuo and the residuewas partitioned between sat. NaHCO3 solution (50 mL) and EtOAc (50 mL), and the aqueous phase was extracted with further EtOAc (50 mL). The combined organic extracts were washed with brine (50 mL) before being concentrated in vacuo and the residue triturated with 3:1 hexanes:Et2O (30 mL) and the suspension stirred for 30 min. The mixture was filtered and the filtrand was dried under air to give the desired product as a beige solid (0.627 g, 2.36 mmol, 79%). M.p.135-138 C; IR (cm-1) 1533, 1621, 2138, 2187, 2807, 2925, 2965,3251; 1H NMR (400 MHz, DMSO-d6) 0.97 (6H, t, J 7.0 Hz,N(CH2CH3)2), 2.32 (3H, s, pyrrole-CH3), 2.37 (3H, s, pyrrole-CH3),2.47-2.54 (6H, m, N(CH2CH3)2 and NHCH2CH2NEt2), 3.26 (2H, dt,J 6.6, 6.2 Hz, NHCH2CH2NEt2), 7.33 (1H, t, J 6.2 Hz,NHCH2CH2NEt2), 9.54 (1H, s, CHO), 11.83 (1H, s, pyrrole-NH); 13CNMR (100 MHz, DMSO-d6) 10.1 (pyrrole-CH3), 12.3 (N(CH2CH3)2),12.9 (pyrrole-CH3), 37.4 (NHCH2CH2NEt2), 47.0 (N(CH2CH3)2), 52.1(NHCH2CH2NEt2), 119.9 (Ar-C), 128.2 (Ar-C), 138.3 (Ar-C), 164.8(CO), 177.7 (CO); HRMS calcd. for C14H24N3O2 (ES+) m/z266.186852 [M+H]+, found 266.183829.
66%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 5 - 20℃;	General procedure: The substituted acid (5a or 6a, 1.0 mmol), EDC (229 mg, 1.2 mmol) and HOBt (160 mg, 1.2 mmol) were dissolved in DMF (25 mL). After cooling to 5 C, the substituted amine was added to the mixture and was stirred at room temperature overnight followed by evaporation under reduced pressure to remove DMF. The residue was purified by column chromatography (pet. ether/EtOAc 7:1 to 2:1) to afford 5 and 6 with the yields of 66% and 84% respectively.

53%		Step (v): Preparation of 5-formyI-2,4-dimethyl-lH-pyrrole-3-carboxyIic acid(2-diethylaminoethyl)-amide (VII):Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel and an air condenser were charged 5-formyl-2,4- dimethyl- lH-pyrrole-3-carboxylic acid (0.25 Kg; 1.5 mole), tetrahydrofuran(3.5 L), dicyclohexyl carbodimide (0.432 Kg), 1 -hydroxy benzotriazole (0.306 Kg)and stirred well for 30 minutes. To this solution, a premixed solution of TEA (0.42 L) in tetrahydrofuran (1.25 L) and 2-diethylaminoethyl amine (0.286 L; 2.04 mole) in tetrahydrofuran (1.25 L) were added successively at 25-30 C. After addition, the reaction mixture was stirred for 16 hours at 25-30 C and the byproduct generated was removed by filtration through filtration funnel. The solvent was removed by distillation under diminished pressure. The resulting product was suspended in DM water and the pH of the slurry adjusted to 12-13 with aqueous NaOH solution. After pH adjustment, the product was extracted with ethyl acetate and washed successively organic layer with aqueous NaHCtheta3, saturated solution of NaCl and DM water. Organic layer was separated and 3/4th of the solvent distilled under diminished pressure. The product was cooled to 0- <n="31"/>50 C and stirred for 2 hours, filtered and washed with chilled ethyl acetate (70 mL). The product was dried at 60 C.Dry Weight: 210.2 g Yield: 53.0% HPLC purity: 99.95%
53%		Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel and an air condenser were charged <strong>[253870-02-9]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid</strong> (0.25 Kg; 1.5 mole), tetrahydrofuran (3.5 L), dicyclohexyl carbodimide (0.432 Kg), 1-hydroxy benzotriazole (0.306 Kg) and stirred well for 30 minutes. To this solution, a premixed solution of TEA (0.42 L) in tetrahydrofuran (1.25 L) and 2-diethylaminoethyl amine (0.286 L; 2.04 mole) in tetrahydrofuran (1.25 L) were added successively at 25-30oC. After addition, the reaction mixture was stirred for 16 hours at 25-30oC. and the byproduct generated was removed by filtration through filtration funnel. The solvent was removed by distillation under diminished pressure. The resulting product was suspended in DM water and the pH of the slurry adjusted to 12-13 with aqueous NaOH solution. After pH adjustment, the product was extracted with ethyl acetate and washed successively organic layer with aqueous NaHCO3, saturated solution of NaCl and DM water. Dry Weight: 210.2 g Yield: 53.0% HPLC purity: 99.95%
6.19 g (78%)		(b) 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (Pyrrole Aldehyde 3) 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (5 g, 2.99 mmol) reacted with N,N-diethylethylenediamine (4.62 mL) to give 6.19 g (78%) of <strong>[253870-02-9]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid</strong> (2-diethylamino-ethyl)-amide. 1H NMR (360 MHz, DMSO-d6) delta 11.7 (br s, 1H, NH), 9.52 (s, 1H, CO), 7.27 (m, 1H, CON), 3.2 (m, 2H, NC2), 2.5 (m, 6H, 3NC2), 2.35 (s, 3H, C3), 2.30 (s, 3H, C3), 0.95 (t, J=6.7 Hz, 6H, 2NCH2C3). MS m/z 266 (M++1).
		Step-1: Preparation of N- [2- (diethyl amino) ethyl-5-formyl-2, 4 dimethyl-lH pyrrole- 3-carboxamideA mixture of 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (100 g) in dimethylformamide (900 ml) was stirred for 15 minutes. l-(3-Dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (171.8 g), 1-hydroxybenzotriazole (121.2 g) and triethylamine (169.4 g) were added to the reaction mixture and stirred at 20C to 25C for 10 minutes. N,N-Diethylethylenediamine (104.2 g) was slowly added to the reaction mixture and stirred at 20C to 25C for 20 hours. The reaction mixture was diluted with water (350 ml), brine (250 ml) and saturated sodium bicarbonate solution (350 ml) followed by the addition of 10% v/v methanol in dichloromethane (1500 ml). The reaction mixture was stirred for 30 minutes and allowed to settle for 30 minutes. The organic layer was separated and washed with a saturated sodium bicarbonate solution (1500 ml). The organic layer was separated, dried over sodium sulfate and concentrated to obtain a residue. Toluene (300 ml) was added to the residue and evaporated to dryness. Ethyl acetate (600 ml) was added to the residue and washed with brine (400 ml). The organic layer was separated, dried over sodium sulfate and concentrated under vacuum to obtain a sticky solid. The solid so obtained was triturated with hexane: diethyl ether (3:1; 500 ml), stirred for 15 minutes, filtered under vacuum and dried under vacuum at 55C for 16 hours to obtain the title compound.Yield: 44 g
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In ethyl acetate; at 20℃;Product distribution / selectivity;	Example 1 - Conversion of (2a) to (la)To a solution of acid derivative (2a) (835 mg, ~5mmol) in N-diethylethylene-diamine (10 ml), with stirring at room temperature, propane phosphoric acid anhydride (T3P) (10 ml, 50% EtOAc solution) was added dropwise and completed in 1.5 hours. The resulting reaction mixture was stirred further over night. Water (25 ml) and dichloromethane (25 ml) were added, and the mixture was stirred for 25 minutes. The dichloromethane layer was separated and concentrated in vacuo to give an oily material. The oil was mixed with ethyl acetate (50 ml) and sodium carbonate solution (4%, 25 ml), and stirred at 70C for 30 minutes. After cooling, the ethyl acetate layer was separated and washed with water (10 ml), dried ( a2S04) and concentrated to give a yellow solid (la) (1.35 g).
		To a stirred slurry of 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (1.0 kg, 5.98 mol), hydroxybenzotriazole (0.969 kg,), l -ethyl-3-(3-dimethylaminopropyl) carbodiimide (1.6 kg, 8.34 mol) in tetrahydrofuran (15L) at 25-30 C, triethylamine (1.162 kg, 1 1.48 mol) was added and mixture was stirred for 30 minutes. Nu,Nu-diethyl ethylenediamine (1.902 kg, 16.37 mol) was added to resulting mixture at 25-30 C and stirred for 5-6 hours at 25-30 C. After completion of reaction, reaction mixture was cooled to ambient followed by addition of saturated 15 % sodium bicarbonate solution (10 L ) till pH = 9-10. Resulting product was extracted with a mixture of dichloromethane- methanol (5% methanol, 3 x 10 L). The organic layers were combined, washed with demineralized water (2 x 5L). Solvent was distilled off from resulting organic layer. Methyl tert-butyl ether (5 L) was added to resulting product and stirred at 45-50 C for 30 minutes. Mixture was cooled to ambient temperature and resulting product was filtered. Filtered solid was washed with methyl tert- butyl ether (5L) and dried. Water (10 L) was added to thus obtained solid followed by addition of sodium bicarbonate (568 g), and a mixture of dichloromethane-methanol (10% methanol, 10 L). Resulting mixture was stirred at ambient temperature for 1 hour. The organic layer was separated, washed with demineralised water (2 x 5 L) and distilled off. Cyclohexane ( 5 L) was added to the crude mass, stirred for 30 minutes, filtered and dried in vacuum oven at 75-80 C for 24 hours to give 0.524 kg of title compound having purity 99.83 % by HPLC.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In water; N,N-dimethyl-formamide; at 20℃; for 12h;	General procedure: N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1.92mmol), hydroxybenzotriazole hydrate (1.92mmol), triethylamine (1.85mL, 13.26mmol) and the appropriate amine (1.60mmol) were added into a stirred solution of <strong>[253870-02-9]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid</strong> (5) or (5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)propanoic acid (6) (1.28mmol) in DMF (5mL). The mixtures were stirred at room temperature for 12h and then diluted with water (5mL). The resultant mixture was adjusted to pH 10 with 10N NaOH and extracted with 10% (v/v) methanol in CH2Cl2. The organic extracts were dried over MgSO4, filtered through Celite, and evaporated to give the 5-formylpyrrole-carboxamides 9-15, which were used for the aldol condensations without purification.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;Inert atmosphere;	General procedure: A solution of compound 2 (167 mg, 1 mmol), EDC·HCl (230mg, 1.2mmol) and HOBt (162mg, 1.2mmol) in DMF (15mL) was stirred at 0-4C under the atmosphere of nitrogen for 20min. The substituted amine a-f (2 mmol) was added to the mixture and stirred at the same temperature for 30 min and then overnight at room temperature. The mixture was diluted with water and adjusted to pH 9 with saturated Na2CO3 solution and then extracted with dichloromethane and methanol (9:1, v/v). The combined extracts were dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide crude product 3a-f (50-60%) as red oils.
		In a 20 L reactor, 4 L of acetonitrile and 1.8 kg of Compound II (10.8 mol) were added in that order.1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride 2.5 kg (12.9 mol),1.75 kg (12.9 mol) of 1-hydroxybenzotriazole, stirred well, and reacted at 35 C for 2 hours.At the end of the reaction, 1.9 kg (16.2 mol) of N,N diethylethylenediamine was added, and the reaction was carried out at 35 C for 2 hours. The reaction was completed, and 1.6-kg (10.8 mol) of 5-fluoroindol-2-one and 3 kg of triethylamine were added. ,The temperature was raised to 60 C for 2 hours, the reaction was completed, and the temperature was lowered to below 40 C.4L of methanol and 5kg (37.7mol) of L-malic acid were added, and the mixture was heated to 60 C for 1 hour.The reaction was completed, and it was cooled to room temperature, and filtered to give an orange-yellow solid, 5.1 kg.That is, compound I sunitinib malate, the yield was 88%, and the HPLC purity was 99.8%.

Reference： [1]Patent: CN103992308,2016,B .Location in patent: Paragraph 0091-0098
[2]Organic and Biomolecular Chemistry,2016,vol. 14,p. 4829 - 4841
[3]Journal of Medicinal Chemistry,2019,vol. 62,p. 2428 - 2446
[4]European Journal of Medicinal Chemistry,2020,vol. 197
[5]European Journal of Medicinal Chemistry,2011,vol. 46,p. 5970 - 5977
[6]Patent: WO2009/157011,2009,A1 .Location in patent: Page/Page column 29-30
[7]Patent: US2011/92717,2011,A1 .Location in patent: Page/Page column 15
[8]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 2153 - 2157
[9]Patent: US2003/125370,2003,A1
[10]Patent: WO2011/33472,2011,A1 .Location in patent: Page/Page column 7
[11]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3062 - 3065
[12]Patent: WO2011/110199,2011,A1 .Location in patent: Page/Page column 14
[13]Patent: WO2012/59941,2012,A1 .Location in patent: Page/Page column 16-17
[14]European Journal of Medicinal Chemistry,2014,vol. 85,p. 268 - 288
[15]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 2782 - 2787
[16]Nature Chemistry,2017,vol. 9,p. 571 - 577
[17]Patent: CN109503555,2019,A .Location in patent: Paragraph 0042; 0043

2
[ 253870-02-9 ]
[ 356068-86-5 ]

Reference： [1]Journal of Organic Chemistry,2004,vol. 69,p. 2565 - 2568

3
[ 452105-37-2 ]
[ 356068-86-5 ]

Reference： [1]Journal of Organic Chemistry,2004,vol. 69,p. 2565 - 2568

4
[ 2199-59-9 ]
[ 356068-86-5 ]

Reference： [1]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 2153 - 2157
[2]Patent: US2011/92717,2011,A1
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3062 - 3065
[4]Patent: WO2012/59941,2012,A1
[5]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 2782 - 2787
[6]Research on Chemical Intermediates,2015,vol. 41,p. 8941 - 8954
[7]Organic and Biomolecular Chemistry,2016,vol. 14,p. 4829 - 4841
[8]Journal of Medicinal Chemistry,2019,vol. 62,p. 2428 - 2446
[9]Patent: CN103992308,2016,B

5
[ 86770-31-2 ]
[ 356068-86-5 ]

7
[ 110-89-4 ]
[ 59-48-3 ]
[ 356068-86-5 ]
2,4-Dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
422 mg (55%)	In ethanol;	Example 126 2,4-Dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-diethylamino-ethyl)-amide A mixture of 1,3-dihydro-indol-2-one (266 mg, 2 mmol), <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide</strong> (530 mg, 2 mmol) and piperidine (I drop) in ethanol was heated at 90 C. for 2 hours. The reaction was cooled to room temperature, the resulting precipitate was collected by vacuum filtration, washed with ethanol and dried to give 422 mg (55%) of the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 13.7 (s, 1H, NH), 10.9 (s, 1H, NH), 7.88 (d, J=7.6 Hz, 1H), 7.64 (s, 1H, H-vinyl), 7.41 (t, J=5.4 Hz, 1H, NH), 7.13 (dt, J=1.2 & 7.6 Hz, 1H), 6.99 (dt, J=1.2 & 7.6 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 3.28 (m, 2H), 2.48-2.55 (m, 6H), 2.44 (s, 3H, CH3), 2.41 (s, 3H, CH3), 0.97 (t, J=7.2 Hz, 6H, N(CH2CH3)2). MS+ve APCI 381 [M++1].
422 mg (55%)	In ethanol;	Example 126 2,4-Dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide A mixture of 1,3-dihydro-indol-2-one (266 mg, 2 mmol), <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide</strong> (530 mg, 2 mmol) and piperidine (1 drop) in ethanol was heated at 90 C. for 2 hours. The reaction was cooled to room temperature, the resulting precipitate was collected by vacuum filtration, washed with ethanol and dried to give 422 mg (55%) of the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 13.7 (s, 1H, NH), 10.9 (s, 1H, NH), 7.88 (d, J=7.6 Hz, 1H), 7.64 (s, 1H, H-vinyl), 7.41 (t, J=5.4 Hz, 1H, NH), 7.13 (dt, J=1.2 & 7.6 Hz, 1H), 6.99 (dt, J=1.2 & 7.6 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 3.28 (m, 2H), 2.48-2.55 (m, 6H), 2.44 (s, 3H, CH3), 2.41 (s, 3H, CH3), 0.97 (t, J=7.2 Hz, 6H, N(CH2CH3)2). MS+ve APCI 381 [M++1].

Reference： [1]Patent: US2003/216410,2003,A1
[2]Patent: US2002/156292,2002,A1

8
[ 110-89-4 ]
[ 59-48-3 ]
[ 356068-86-5 ]
(Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
422 mg (55%)	In ethanol;	Example 67 Synthesis of 2,4-Dimethyl-5-(2-oxo-1,2-Dihydro-Indol-3-Ylidenemethyl)-1H-Pyrrole-3-Carboxylic Acid (2-Diethylamino-Ethyl)Amide A mixture of 1,3-dihydro-indol-2-one (266 mg, 2 mmol), <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide</strong> (530 mg, 2 mmol) and piperidine (1 drop) in ethanol was heated at 90 C. for 2 hours. The reaction was cooled to room temperature, the resulting precipitate was collected by vacuum filtration, washed with ethanol and dried to give 422 mg (55%) of the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 13.7 (s, 1H, NH), 10.9 (s, 1H, NH), 7.88 (d, J=7.6 Hz, 1H), 7.64 (s, 1H, H-vinyl), 7.41 (t, J=5.4 Hz, 1H, NH), 7.13 (dt, J=1.2 & 7.6 Hz, 1H), 6.99 (dt, J=1.2 & 7.6 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 3.28 (m, 2H), 2.48-2.55 (m, 6H), 2.44 (s, 3H, CH3), 2.41 (s, 3H, CH3), 0.97 (t, J=7.2 Hz, 6H, N(CH2CH3)2). MS+ve APCI 381 [M++1].

Reference： [1]Patent: US2003/100555,2003,A1

9
[ 110-89-4 ]
[ 442562-87-0 ]
[ 356068-86-5 ]
5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	In ethanol;	Example 5 5- [4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (82.9 mg, 70%) 1 H-NMR (400 MHz, DMSO-d6) delta 13.47 (br s, 1 H, pyrrole NH), 11.04 (br s, 1 H, CONH), 7.46 (m, 2 H, aromatic), 7.38 (m, 2 H, aromatic), 7.32 (t, 1 H, CONH), 7.18 (t, 1 H, aromatic), 6.93 (m, 1 H, aromatic), 6.79 (m, 1 H, aromatic), 6.71 (s, 1 H, aromatic), 3.20 (m, 2 H, CH2), 2.49 (m, 6 H, 3CH2), 2.39 (s, 3 H, CH3), 1.74 (s, 3 H, CH3), 0.95 (t, 6 H, 2CH3). MS m/z 473 [M--1].

Reference： [1]Patent: US2003/69297,2003,A1

10
[ 110-89-4 ]
[ 442562-88-1 ]
[ 356068-86-5 ]
5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	In ethanol;	Example 13 5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole3-carboxylic acid (2-diethylamino-ethyl)-amide To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (70 mg, 59%) 1 H-NMR (400 MHz, DMSO-d6) delta 13.48 (br s, 1 H, pyrrole NH), 11.07 (br s, 1 H, CONH), 7.59 (m, 1 H, aromatic), 7.32 (m, 4 H, aromatic), 7.20 (t, 1 H, CONH), 6.95 (d, 1 H, aromatic), 6.80 (m, 2 H, aromatic), 3.22 (m, 2 H, CH2), 2.49 (m, 6 H, 3CH2), 2.39 (s, 3 H, CH3), 1.73 (s, 3 H, CH3), 0.95 (t, 6 H, 2CH3). MS m/z 475 [M++1].

Reference： [1]Patent: US2003/69297,2003,A1

11
[ 110-89-4 ]
[ 442562-89-2 ]
[ 356068-86-5 ]
5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	In ethanol;	Example 21 5-[4-(4-Chloro-phenyl)-2-oxo1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (59.4 mg, 48%). 1 H-NMR (400 MHz, DMSO-d6) delta 13.44 (br s, 1 H, pyrrole NH), 11.05 (br s, 1 H, CONH), 7.61 (m, 2 H, aromatic), 7.44 (m, 2 H, aromatic), 7.33 (t, 1 H, CONH), 7.19 (t, 1 H, aromatic), 6.95 (m, 1 H, aromatic), 6.80 (m, 1 H, aromatic), 6.71 (s, 1 H, aromatic), 3.20 (m, 2 H, CH2), 2.49 (m, 6 H, 3CH2), 2.39 (s, 3 H, CH3), 1.74 (s, 3 H, CH3), 0.95 (t, 6 H, 2CH3). MS m/z 491 [M++1].

Reference： [1]Patent: US2003/69297,2003,A1

12
[ 110-89-4 ]
[ 442562-91-6 ]
[ 356068-86-5 ]
5-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihvdro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole3-carboxylic acid (2-diethylamino-ethyl)-amide [ No CAS ]
5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	In ethanol;	Example 54 5-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihvdro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole3-carboxylic acid (2-diethylamino-ethyl)-amide To a solution of 4- (4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg,0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(4-bromo-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (59 mg, 44%) 1 H-NMR (400 MHz, DMSO-d6) delta 13.44 (br s, 1 H, pyrrole NH), 11.04 (br s, 1 H, CONH), 7.74 (d, 2 H, aromatic), 7.37 (d, 2 H, aromatic), 7.33 (t, 1 H, CONH), 7.19 (t, 1 H, aromatic), 6.93 (d, 1 H, aromatic), 6.80 (m, 1 H, aromatic), 6.66 (s, 1 H, aromatic), 3.24 (m, 2 H, CH2), 2.49 (m, 6 H, 3CH2), 2.39 (s, 3 H, CH3), 1.75 (s, 3 H, CH3), 0.96 (t, 6 H, 2CH3). MS m/z 535 [M++1].

Reference： [1]Patent: US2003/69297,2003,A1

13
[ 110-89-4 ]
[ 442562-92-7 ]
[ 356068-86-5 ]
5-l4-(3-Bromophenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide [ No CAS ]
5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	In ethanol;	Example 63 5-l4-(3-Bromophenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (89.7 mg, 67%) 1 H-NMR (400 MHz, DMSO-d6) delta 13.48 (br s, 1 H, pyrrole NH), 11.06 (br s, 1 H, CONH), 7.71 (d, 1 H, aromatic), 7.65 (s, 1 H, aromatic), 7.53 (t, 1 H, aromatic), 7.44 (d, 1 H, aromatic), 7.37 (t, 1 H, CONH), 7.20 (t, 1 H, aromatic), 6.94 (d, 1 H, aromatic), 6.80 (d, 1 H, aromatic), 6.78 (s, 1 H, aromatic), 3.23 (m, 2 H, CH2), 2.49 (m, 6 H, 3CH2), 2.39 (s, 3 H, CH3), 1.76 (s, 3 H, CH3), 0.95 (t, 6 H, 2CH3). MS m/z 535 [M++1].

Reference： [1]Patent: US2003/69297,2003,A1

14
[ 110-89-4 ]
[ 442562-93-8 ]
[ 356068-86-5 ]
5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	In ethanol;	Example 37 5-[4-(4-Methoxy-phenyl) 2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (87 mg, 72%). 1 H-NMR (400 MHz, DMSO-d6) delta 13.44 (br s, 1 H, pyrrole NH), 10.98 (br s, 1 H, CONH), 7.31 (m, 3 H; aromatic), 7.16 (t, 1 H, aromatic), 7.11 (m, 2 H, aromatic), 6.90 (m, 1 H, aromatic), 6.78 (m, 2 H, aromatic), 3.82 (s, 3 H, OCH3), 3.22 (m, 2 H, CH2), 2.49 (m, 6 H, 3CH2), 2.39 (s, 3 H, CH3), 1.73 (s, 3 H, CH3), 0.95 (t, 6 H, 2CH3). 106221 MS m/z 487 [M++1].

Reference： [1]Patent: US2003/69297,2003,A1

15
[ 110-89-4 ]
[ 442562-94-9 ]
[ 356068-86-5 ]
5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	In ethanol;	Example 46 5-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluding with MeOH-CH2Cl2 5:95 to provide 5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (94 mg, 78%). 1 H-NMR (400 MHz, DMSO-d6) delta 13.48 (br s, 1 H, pyrrole NH), 11.02 (br s, 1 H, CONE), 7.47 (t, 1 H, aromatic), 7.35 (t, 1 H, CONH), 7.19 (t, 1 H, aromatic), 7.06 (m, 1 H, aromatic), 6.98 (m, 2 H, aromatic), 6.92 (d, 1 H, aromatic), 6.88 (s, 1 H, aromatic), 6.80 (d, 1 H, aromatic), 3.77 (s, 1 H, CH3), 3.25 (m, 2 H, CH2), 2.38 (s, 3 H, CH3), 2.50 (m, 6 H, 3CH2), 1.73 (s, 3 H, CH3), 0.95 (t, 6 H, 2CH3). MS m/z 487 [M++1].

Reference： [1]Patent: US2003/69297,2003,A1

16
[ 110-89-4 ]
[ 442562-98-3 ]
[ 356068-86-5 ]
2,4-Dimethyl-5-[2-oxo4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	In ethanol;	Example 140 2,4-Dimethyl-5-[2-oxo4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide</strong> (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 2,4-dimethyl-5-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (75.6 mg, 56%). 1H-NMR (400 MHz, DMSO-d6) delta 13.49 (br s, 1H, pyrrole NH), 11.07 (br s, 1H, CONH), 7.57 (m, 3H, aromatic), 7.29 (t, 1H, aromatic), 7.20 (t, 1H, aromatic), 6.94 (d, 1H, aromatic), 6.80 (d, 1H, aromatic), 6.74 (s, 1H, aromatic), 3.23 (q, 2H, CH2), 2.49 (m, 6H, 3CH2), 2.39 (s, 3H, CH3), 1.70 (s, 3H, CH3), 0.95 (t, 6H, 2CH3). MS m/z 539 [M--1].

Reference： [1]Patent: US2003/69297,2003,A1

17
[ 110-89-4 ]
4-(3-Chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-2-one [ No CAS ]
[ 356068-86-5 ]
5-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	In ethanol;	Example 117 5-[4-(3-Chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide To a solution a solution of 4-(3-Chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-2-one (65.4 mg, 0.25 mmol) and 5-formyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 ml) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(3-Chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (72 mg, 57%). 1H-NMR (400 MHz), DMSO-d6) delta13.47 (br s, 1H, pyrrole NH), 11.07 (br s, 1H, CONH), 7.70 (d, 1H aromatic), 7.61 (t, 1H, CONH), 7.46 (m, 1H aromatic), 7.35 (m, 1H, aromatic), 7.20 (t, 1H, aromatic), 6.95 (d, 1H, aromatic), 6.82 (d, 1H, aromatic), 6.73 (d, 1H, aromatic), 3,24 (m, 2H, CH2), 2.50 (m, 6H, 3CH2), 2.38 (s, 3H, CH3), 1.78 (s, 3H, CH3), 0.95 (t, 6H, 2CH3). MS m/z 507 [M--1].

Reference： [1]Patent: US2003/69297,2003,A1

18
[ 110-89-4 ]
[ 35523-93-4 ]
[ 356068-86-5 ]
2,4-dimethyl-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1 H-pyrrole-3-carboxylic acid (2-diethylarnino-ethyl)-amide [ No CAS ]
2,4-dimethyl-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	In ethanol;	Example 3 2,4-Dimethyl-5-(2-oxo4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide To a solution of 4-phenyl-1,3-dihydro-indol-2-one (41.9 mg, 0.20 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (53.1 mg, 0.20 mmol) in ethanol (1 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 2,4-dimethyl-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1 H-pyrrole-3-carboxylic acid (2-diethylarnino-ethyl)-amide (51 mg, 56%) 1 H-NMR (400 MHz, DMSO-d6) delta 13.48 (br s, 1 H, pyrrole NH), 11.03 (br s, 1 H, CONH), 7.43 (m, 6 H, aromatic), 7.18 (t, 1 H, CONH), 7.18 (t, 1 H, aromatic), 6.93 (m, 1 H, aromatic), 6.77 (m, 2 H, aromatic), 3.21 (m, 2 H, CH2), 2.48 (m, 6 H, 3CH2), 2.38 (s, 3 H, CH3), 1.66 (s, 3 H, CH3), 0.87 (t, 6 H, 2CH3). MS m/z 455 [M--1].

Reference： [1]Patent: US2003/69297,2003,A1

19
[ 110-89-4 ]
[ 442562-90-5 ]
[ 356068-86-5 ]
5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol;	Example 29 5-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluding with MeOH-CH2Cl2 5:95 to provide pure product 5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (73 mg, 59%)

Reference： [1]Patent: US2003/69297,2003,A1

20
[ 110-89-4 ]
[ 17630-75-0 ]
[ 356068-86-5 ]
5-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
565 mg (68%)	In ethanol;	Example 127 5-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylamino-ethyl)-amide A mixture of 5-Chloro-1,3-dihydro-indol-2-one (335 mg, 2 mmol), <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide</strong> (530 mg, 2 mmol) and piperidine (1 drop) in ethanol was heated at 90 C. for 2 hours. The reaction was cooled to room temperature, the resulting precipitate was collected by vacuum filtration, washed with ethanol and dried to give 565 mg (68%) of the title compound as an orange solid. 1H NMR (400 MHz, DMSO-d6) delta 13.65 (s, 1H, NH), 11.0 (s, 1H, NH), 7.98 (d, J=2.1 Hz, 1H) 7.77 (s, 1H H-vinyl), 7.44 (t, NH), 7.13 (dd, J=2,1 & 8.4 Hz, 1H) 6.87 (d, J=8.4 Hz, 1H), 3.28 (g, 2H), 2.48-2.53 (m, 6H), 2.44 (s, 3H, CH3), 2.43 (s, 3H, CH3), 0.97 (t, J=7.0 Hz, 6H, N(CH2CH3)2) MS+ve APCI 415 [M++1].,
565 mg (68%)	In ethanol;	Example 68 Synthesis of 5-(5-Chloro-2-oxo-1,2-Dihydro-Indol-3-Ylidenemethyl)-2,4-Dimethyl-1H-Pyrrole-3-Carboxylic Acid (2-Diethylamino-Ethyl)-Amide A mixture of 5-Chloro-1,3-dihydro-indol-2-one (335 mg, 2 mmol), <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide</strong> (530 mg, 2 mmol) and piperidine (1 drop) in ethanol was heated at 90 C. for 2 hours. The reaction was cooled to room temperature, the resulting precipitate was collected by vacuum filtration, washed with ethanol and dried to give 565 mg (68%) of the title compound as an orange solid. 1H NMR (400 MHz, DMSO-d6) delta 13.65 (s, 1H, NH), 11.0 (s, 1H, NH), 7.98 (d, J=2.1 Hz, 1H) 7.77 (s, 1H H-vinyl), 7.44 (t, NH), 7.13 (dd, J=2,1 & 8.4 Hz, 1H) 6.87 (d, J=8.4 Hz, 1H), 3.28 (g, 2H), 2.48-2.53 (m, 6H), 2.44 (s, 3H, CH3), 2.43 (s, 3H, CH3), 0.97 (t, J=7.0 Hz, 6H, N(CH2CH3)2). MS+ve APCI 415 [M++1].
565 mg (68%)	In ethanol;	Example 127 5-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide A mixture of 5-Chloro-1,3-dihydro-indol-2-one (335 mg, 2 mmol), <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide</strong> (530 mg, 2 mmol) and piperidine (1 drop) in ethanol was heated at 90 C. for 2 hours. The reaction was cooled to room temperature, the resulting precipitate was collected by vacuum filtration, washed with ethanol and dried to give 565 mg (68%) of the title compound as an orange solid. 1H NMR (400 MHz, DMSO-d6) delta 13.65 (s, 1H, NH), 11.0 (s, 1H, NH), 7.98 (d, J=2.1 Hz, 1H) 7.77 (s, 1H H-vinyl), 7.44 (t, NH), 7.13 (dd, J=2,1 & 8.4 Hz, 1H) 6.87 (d, J=8.4 Hz, 1H), 3.28 (g, 2H), 2.48-2.53 (m, 6H), 2.44 (s, 3H, CH3), 2.43 (s, 3H, CH3), 0.97 (t, J=7.0 Hz, 6H, N(CH2CH3)2) MS+ve APCI 415 [M++1].

Reference： [1]Patent: US2003/216410,2003,A1
[2]Patent: US2003/100555,2003,A1
[3]Patent: US2002/156292,2002,A1

21
[ 90751-00-1 ]
[ 356068-86-5 ]
2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65 mg (38%)		Example 59 2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 6-Phenyl-1,3-dihydroindol-2-one (0.08 g, 0.4 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (0.1 g) to give 65 mg (38%) of the title compound as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) delta 13.61 (s, br, 1H, NH), 10.99 (, br, 1H, NH), 7.86 (d, J=7.8 Hz, 1H), 7.62-7.66 (m, 3H), 7.40-7.47 (m, 3H), 7.28-7.36 (m, 2H), 7.10 (d, J=1.2 Hz, 1H), 3.26 (m, 2H, NCH2), 2.46-2.55 (m, 6H, 3NCH2), 2.44 (s, 3H, CH3), 2.41 (s, 3H, CH3), 0.97 (t, J=7.2 Hz, 6H, 2NCH2CH3). MS-EI m/z 456 [M+].
65 mg (38%)		Example 59 2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 6-Phenyl-1,3-dihydroindol-2-one (0.08 g, 0.4 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (0.1 g) to give 65 mg (38%) of the title compound as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) delta 13.61 (s, br, 1H, NH), 10.99 (, br, 1H, NH), 7.86 (d, J=7.8 Hz, 1H), 7.62-7.66 (m, 3H), 7.40-7.47 (m, 3H), 7.28-7.36 (m, 2H), 7.10 (d, J=1.2 Hz, 1H), 3.26 (m, 2H, NCH2), 2.46-2.55 (m, 6H, 3NCH2), 2.44 (s, 3H, CH3), 2.41 (s, 3H, CH3), 0.97 (t, J=7.2 Hz, 6H, 2NCH2CH3). MS-EI m/z 456 [M+].

Reference： [1]Patent: US2003/216410,2003,A1
[2]Patent: US2002/156292,2002,A1

22
[ 90751-00-1 ]
[ 356068-86-5 ]
2,4-Dimethyl-5-(2-oxo-6-Phenyl-1,2-Dihydroindol-3-Ylidenemethyl)-1H-Pyrrole-3-Carboxylic Acid (2-Diethylaminoethyl)-Amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65 mg (38%)		Example 27 Synthesis of 2,4-Dimethyl-5-(2-oxo-6-Phenyl-1,2-Dihydroindol-3-Ylidenemethyl)-1H-Pyrrole-3-Carboxylic Acid (2-Diethylaminoethyl) Amide 6-Phenyl-1,3-dihydroindol-2-one (0.08 g, 0.4 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (0.1 g) to give 65 mg (38%) of the title compound as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) delta 13.61 (s, br, 1H, NH), 10.99 (, br, 1H, NH), 7.86 (d, J=7.8 Hz, 1H), 7.62-7.66 (m, 3H), 7.40-7.47 (m, 3H), 7.28-7.36 (m, 2H), 7.10 (d, J=1.2 Hz, 1H), 3.26 (m, 2H, NCH2), 2.46-2.55 (m, 6H, 3NCH2), 2.44 (s, 3H, CH3), 2.41 (s, 3H, CH3), 0.97 (t, J=7.2 Hz, 6H, 2NCH2CH3). MS-EI m/z 456 [M+].

Reference： [1]Patent: US2003/100555,2003,A1

23
[ 56341-41-4 ]
[ 356068-86-5 ]
5-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.83 g (55%)		EXAMPLE 13 5-(5-Fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)amide (Compound 1) 5-Fluoro-1,3-dihydroindol-2-one (0.54 g, 3.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylaminoethyl)amide to give 0.83 g (55%) of the title compound as a yellow green solid. 1H-NMR (360 MHz, DMSO-d6) delta13.66 (s, 1H, NH), 10.83 (s, br, 1H, NH), 7.73 (dd, J=2.5 & 9.4 Hz, 1H), 7.69 (s, 1H, H-vinyl), 7.37 (t, 1H, CONHCH2CH2), 6.91 (m, 1H), 6.81-6.85 (m, 1H), 3.27 (m, 2H, CH2), 2.51 (m, 6H, 3*CH2), 2.43 (s, 3H, CH3), 0.96 (t, J=6.9 Hz, 6H, N(CH2CH3)2). MS-EI m/z 398 [M+].
0.83 g (55%)		Example 80 5-(5-Fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide 5-Fluoro-1,3-dihydroindol-2-one (0.54 g, 3.8 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> to give 0.83 g (55%) of the title compound as a yellow green solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.66 (s, 1H, NH), 10.83 (s, br, 1H, NH), 7.73 (dd, J=2.5 & 9.4 Hz, 1H), 7.69 (s, 1H, H-vinyl), 7.37 (t, 1H, CONHCH2CH2), 6.91 (m, 1H), 6.81-6.85 (m, 1H), 3.27 (m, 2H, CH2), 2.51 (m, 6H, 3*CH2), 2.43 (s, 3H, CH3), 2.41 (s, 3H, CH3), 0.96 (t, J=6.9 Hz, 6H, N(CH2CH3)2). MS-EI m/z 398 [M+].

Reference： [1]Patent: US2003/130280,2003,A1
[2]Patent: US2002/156292,2002,A1

24
[ 56341-41-4 ]
[ 356068-86-5 ]
[ 557795-19-4 ]

Yield	Reaction Conditions	Operation in experiment
97.3%	With piperidine; In toluene; for 3h;Reflux;	To a flask equipped with a condenser were added 10 (0.50 g, 1.89 mmol), 2 (0.32 g, 2.08 mmol), and toluene (8.0 mL). The mixture was stirred to be fully dissolved before addition of a drop of piperidine with stirring. The mixture was heated to reflux for 3 h before cooling down with an ice-bath. The precipitates were collected by filtration. The filter cake was washed with petroleum ether and dried under vacuum to give the free base of the desired target molecule 1 as orange-yellow solid (0.73 g, 97.3 %), m.p. 222-223 C (lit. 195-197 C [13]), yield 90.0 % (lit. [13]). Rf = 0.24 (eluent:chloroform/methanol, v/v = 10:1). 1H NMR (400 MHz, DMSO-d6) delta: 13.69 (s, 1H,NH-pyrrole), 10.90 (s, 1H, NH-indole), 7.75-7.78 (m, 1H, CONH), 7.72 (s, 1H, alkenyl-H), 7.43-7.46 (m, 1H, aryl-7-H), 6.90-6.95 (m, 1H, aryl-4-H), 6.83-6.86(m, 1H, aryl-6-H), 3.26-3.31 (m, 2H, NHCH2), 2.51-2.57 (m, 6H, 3 x (N-CH2)), 2.43 (s, 3H, pyrrole-2-CH3), 2.44 (s, 3H, pyrrole-4-CH3), 0.96-1.00 (t, 6H,2 x (CH3)); EI MS m/z (%): 398.1 ([M]+, 5), 326.1 (2), 283.0 (4), 149.1 (8), 86.1 (100); the purity of sunitinib was 99.5 %.
97.3%	With piperidine; In toluene; for 3h;Reflux;	To the reflux condenser, a 50 mL round-bottomed flask of magnetics was charged with 1.89 mmol of N-(2-diethylaminoethyl)-2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxamide,2.08 mmol of 5-fluoro-1,3-dihydroindole-2-one and 8 mL of toluene to completely dissolve,Add 15 drops of piperidine as the catalyst (20 drops is 1 mL) and stir well.Then heated under reflux for 3h, finally cooled in an ice bath, suction filtered, and the resulting filter cake was washed with petroleum ether and dried to obtain 0.73 g of orange-yellow solid sunitinib, yield 97.3%, m.p. 222-223 C (document: yield 90%, m.p. 195-197 C).
94%	With potassium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 3.5h;Darkness; Inert atmosphere;	a) under dark conditions: 120g, 0.452mol beating purified B5 (MW: 265.35), 72g,0.476 mol of 5-fluoroindol-2-one (MW: 151.14) and 76 g of 1.355 mol of KOH (MW: 56.1) were added to 2 L of DMF and the mixture was stirred under argon at room temperature.After 3.5h, TLC showed that the reaction of starting material B5 was completed, water was added dropwise to the reaction solution,Stirring, there is a yellow-orange solid precipitation; filtered and dried to give an orange-yellow solid B6 (168g,Molar yield: 94%, HPLCPurity 99.79%, single-content less than 0.1%, as shown in Figure 1 shows the HPLC chromatogram)The resulting B6 was used directly in the next reaction without purification.

90.5%		Example 14 A 25 mL single neck flask was charged with 8 (1.14 g, 1.0 eq), (NH4)2SO4 (0.10 g, 0.1 eq) and of HMDS (14.1 mL, 9 eq). The mixture was heated to reflux for 7 h to give a clear solution, which was then distilled at 60 C. under vacuum to remove HMDS. The distillation residue and MeCN (44 mL, 22 P) were added in to a 100 mL three-neck flask. After TMSOTf (2.74 mL, 2.0 eq) diluted with MeCN (10 mL, 5 P) was added dropwise over approximately 30 seconds, a solution of 13 (2.0 g, 1 eq.) in DMF (6 mL, 3 P) was added dropwise over a 3 h period. The reaction mixture was allowed to keep stirring at r.t. over night. The reaction mixture was poured into saturated NaHCO3 solution (100 mL) and was stirred at r.t. for 0.5 h and then was cooled in an bath for 2 h. The slurry was filtered and the filter cake was washed with water (100 mL) and then dried at 40 C. under vacuum for 8 h to give the Sunitinib as a yellow solid (2.80 g, 97.1% purity by HPLC) in 90.5% yield.
78.1%	With pyrrolidine; In methanol; for 5 - 7h;Reflux;Product distribution / selectivity;	Step (vii): Preparation of N-[2- (diethylamino)ethyl]-5-[(Z)-(5-fluoro-l,2- dihydro-2-oxo-3fT-indol-3-y.idine) methyl]-2,4-dimethyl-l/-f-pyrroIe- 3-carboxamide -Sunitinib-I: Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, and a reflux condenser were charged 5-formyl-2,4-dimethyl-lH- pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (VII) (0.35 Kg; 1.32 mole) and 5- Fluoro-2-oxindole (IX) (0.191 Kg; 1.26 mole) and methanol (7.0 L). To this stirred solution pyrrolidine (5.6 mL) was added and heated to reflux for 5-7 hours. The progress of the reaction was monitored by TLC. After completion of reaction, the product solution was filtered and washed with methanol. The wet cake was again triturated in methanol at 60-65 C for 1 hour, cooled and filtered. The product was dried at 80 C. Dry Weight: 410 g Yield: 78.1% HPLC purity:>99.7%
78.1%	pyrrolidine; In methanol; for 5 - 7h;Reflux;Product distribution / selectivity;	Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, and a reflux condenser were charged 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (VII) (0.35 Kg; 1.32 mole) and 5-Fluoro-2-oxindole (IX) (0.191 Kg; 1.26 mole) and methanol (7.0 L). To this stirred solution pyrrolidine (5.6 mL) was added and heated to reflux for 5-7 hours. The progress of the reaction was monitored by TLC. After completion of reaction, the product solution was filtered and washed with methanol. The wet cake was again triturated in methanol at 60-65oC. for 1 hour, cooled and filtered. The product was dried at 80oC. Dry Weight: 410 g Yield: 78.1% HPLC purity: >99.7%
77%	With pyrrolidine; In ethanol; for 3h;Reflux;	Example 3 - Conversion of (la) to (lb)(l a) (lb)To a mixture of 150 mg of 5-fluoro-l,3-dihydroindol-2-one of formula (5) and 450 mg of the aldehyde derivative (la) in 10 ml of ethanol, -0.5 ml of pyrrolidine (10 drops) was added. The mixture was heated to reflux for 3 hours. After cooling to room temperature, the formed solid sunitinib (lb) was filtered off. The filtrate was concentrated and the residue was dissolved in 2 ml of ethanol. The clear solution was stored at room temperature over night to generate 2 crop of solid sunitinib.In total, 310 mg desired solid sunitinib was obtained after drying at 40 C over night in vacuo, (yield: 77%)
72%	With triethylamine; In ethanol; at 20 - 78℃;	Example 1: Preparation of Sunitinib base Sunitinib base form I <n="32"/>5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid, N-(2- diethylaminoethyl)amide (1.3 g), 5-fluoro-l,3-dihydro-indol-2-one (0.7 g), ethanol (1Og) and 2 drops of triethylamine were mixed and heated at reflux (78) for 3 hours. The suspension was left overnight at room temperature, filtered and the crystalline cake was washed with small amount of ethanol. The product was dried at 70C under vacuum for 4 hours to give 1.4 g (72%) of Sunitinib base Form I.
0.83 g (55%)		Example 80 5-(5-Fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylamino-ethyl)amide 5-Fluoro-1,3-dihydroindol-2-one (0.54 g, 3.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide to give 0.83 g (55%) of the title compound as a yellow green solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.66 (s, 1H, NH), 10.83 (s, br, 1H, NH), 7.73 (dd, J=2.5 & 9.4 Hz, 1H), 7.69 (s, 1H, H-vinyl), 7.37 (t, 1H, CONHCH2CH2), 6.91 (m, 1H), 6.81-6.85 (m, 1H), 3.27 (m, 2H, CH2), 2.51 (m, 6H, 3*CH2), 2.43 (s, 3H, CH3), 2.41 (s, 3H, CH3), 0.96 (t, J=6.9 Hz, 6H, N(CH2CH3)2). MS-EI m/z 398 [M+].
0.83 g (55%)		Example 48 Synthesis of 5-(5-Fluoro-2-oxo-1,2-Dihydroindol-3-Ylidenemethyl)-2,4-Dimethyl-1H-Pyrrole-3-Carboxylic Acid (2-Diethylamino-Ethyl)Amide 5-Fluoro-1,3-dihydroindol-2-one (0.54 g, 3.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide to give 0.83 g (55%) of the title compound as a yellow green solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.66 (s, 1H, NH), 10.83 (s, br, 1H, NH), 7.73 (dd, J=2.5 & 9.4 Hz, 1H), 7.69 (s, 1H, H-vinyl), 7.37 (t, 1H, CONHCH2CH2), 6.91 (m, 1H), 6.81-6.85 (m, 1H), 3.27 (m, 2H, CH2), 2.51 (m, 6H, 3*CH2), 2.43 (s, 3H, CH3), 2.41 (s, 3H, CH3), 0.96 (t, J=6.9 Hz, 6H, N(CH2CH3)2). MS-EI m/z 398 [M+].
0.83 g (55%)		Example 13 Synthesis of 5-(5-Fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 1) 5-Fluoro-1,3-dihydroindol-2-one (0.54 g, 3.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide to give 0.83 g (55%) of the title compound as a yellow green solid.
	pyrrolidine; In cyclohexane;Reflux;Product distribution / selectivity;	5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0.018 moles) and 5-Fluoro-l,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in cyclohexane were reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at reflux temperature for 2-8 hours. The resultant Sunitinib base was triturated in cyclohexane at reflux temperature for 1-2 hours and isolated at 25-30 C and dried at 60 C for 5-20 hours to get Sunitinib base (I) as Orange crystalline solid. Yield: 6.8 g HPLC Purity: 97.7%Powdered XRD: Fig. 7 FTIR: Fig. 8 DSC: Principal Peak Max: 223.4 C.(Fig. 9)
	With pyrrolidine; In ethanol; at 20℃; for 3h;Heating / reflux;Product distribution / selectivity;	This example was carried out following the teachings of Example 80 (AlternativeSynthesis) of U.S. Patent No. 6,573,293.[0068] N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide(5.00 g), 5-fluoro-2-oxindole (2.85 g) and ethanol (80 mL) were stirred at room temperature.Pyrrolidine (80 muL) was then added and the suspension was heated to reflux. Complete dissolution of the materials was observed at 47 0C and after 30 minutes at reflux an orange solid started to crystallize. The reaction was monitored by TLC and was shown to be complete after 3 h at reflux. The mixture was cooled to room temperature and stirred for30 minutes. The mixture was filtered, and the collected solid was washed with 25 mL of ethanol. The solid was dried at 54 0C for 4h under vacuum to give 6.65 g (88.6 % yield) of light orange solid.[0069] Analytical data: XRD: Form III, substantially identical to Figure 13.[0070] 4.50 g of the solid was stirred in 40 mL of ethanol and heated to reflux. The suspension was stirred for 30 minutes, cooled to room temperature, and stirred for an additional 30 minutes. The thick suspension was filtered, and the collected solid was washed with ethanol (15 mL) and dried at 54 0C for 4 hours under vacuum to give 4.24 g (94.2 % yield) of light orange solid.[0071] Analytical data: XRD: Analytical data: XRD: Form III, See Figure 13. IR:Form III, See Figure 14; DSC (open pan): Form III, See Figure 15.[0072] These results demonstrate that sunitinib base polymorphic Form III is the polymorphic form obtained in the prior art.
	With pyrrolidine; In butan-1-ol; at 20 - 94℃; for 2h;Product distribution / selectivity;	This example illustrates a process for preparing sunitinib base polymorphic Form III in accordance with an embodiment of the invention. <n="16"/>[0108] N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (10.02 g), 5-fluoro-2-oxindole (5.70 g) and «-butanol (100 mL) were stirred at room temperature. Pyrrolidine (160 muL) was then added and the suspension was heated to 94 0C. Complete dissolution of the materials was observed at 47 C, and once at 94 C an orange solid started to crystallize. After 30 minutes at 94 0C the suspension was very thick. The reaction was monitored by TLC and after 2 h at 94 C it was complete. The mixture was cooled to room temperature and stirred for 30 minutes. The thick light orange suspension was then filtered and the collected solid was washed with 40 mL of H-butanol to give 26.77 g of light orange solid (LOD = 44.31%, yield = 89.1 %).[0109] Analytical data: XRD: Form III, substantially identical to Figure 13. [0110] 21.94 g of wet solid were stirred in 88 mL of w-butanol and heated to 95 0C. The suspension was stirred for 30 minutes, cooled to room temperature and stirred for further 30 minutes. The thick suspension was filtered, the collected solid was washed with 37 mL of n- butanol and the solid was dried at 60 0C for 4 hours under vacuum to give 11.05 g ( 101.0 % yield) of light orange solid.[0111] Analytical data: XRD: Form III, substantially identical to Figure 13; IR: Form III, substantially identical to Figure 14; DSC (open pan): Form III, substantially identical to Figure 15.
	With pyrrolidine; In isopropyl alcohol; at 20℃; for 3h;Heating / reflux;Product distribution / selectivity;	This example illustrates a process for preparing sunitinib base polymorphic Form III in accordance with an embodiment of the invention.[0100] N-[2-(diethylamino)ethyl] -5 -formyl-2,4-dimethyl- 1 H-pyrrole-3 -carboxamide (10.03 g), 5-fluoro-2-oxindole (5.70 g) and 2-propanol (100 mL) were stirred at room temperature. Pyrrolidine (160 muL) was then added and the suspension was heated to reflux. <n="15"/>Complete dissolution of the materials was observed at 44 0C and after 20 minutes at reflux an orange solid started to crystallize. The suspension became very thick quickly. The reaction was monitored by TLC and after 3 h at reflux it was complete. The mixture was cooled down to room temperature and stirred for 30 minutes. The thick light orange suspension was then filtered and the collected solid was washed with 33 mL of 2-propanol to give 15.90 g of light orange solid (LOD = 13.51%, yield = 91.2 %).[0101] Analytical data: XRD: Form III, substantially identical to Figure 13.[0102] 14.62 g of solid were stirred in 102 mL of 2-propanol and heated to 72 0C. The suspension was stirred for 30 minutes, cooled to room temperature and stirred for further 30 minutes. The thick suspension was filtered, the collected solid was washed with 20 mL of 2- propanol and the solid was dried at 54 0C for 4 hours under vacuum to give 12.36 g (97.8 % yield) of light orange solid.[0103] Analytical data: XRD: Form III, substantially identical to Figure 13; IR: FormIII, substantially identical to Figure 14; DSC (open pan): Form III, substantially identical toFigure 15.
	With pyrrolidine; In ethanol; at 78℃; for 3h;	Step-2: Preparation of SunitinibA mixture of N-[2-(Diethylamino)ethyl-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxamide (8.0 g) in ethanol (80 mL) was stirred. 5-Fluoro-l,3-dihydroindol-2-one (4.5 g) and pyrrolidine (0.123 ml) were added to the reaction mixture and stirred at 78C (internal temperature) for 1 hour. After 1 hour at 78C, additional ethanol (20 ml) was added and the stirring was continued for an additional 2 hours. The reaction mixture was cooled to 20C to 25C and filtered under vacuum. The solid was stirred at 72C (internal temperature) in ethanol (80 ml) for 30 minutes. The reaction mixture was cooled to 20C to 25C, filtered under vacuum, washed with ethanol (2 X 50 ml) and dried under vacuum at 55C to 60C for 42 hours to obtain the title compound.Yield: 8.2 g
		A mixture of 5-fluoro-l,3-dihydro-indol-2-one (1 g), 5-formyl-2,4-dimethyl-lH- pyrrole-3-carboxylic acid-(2-diethylaminoethyl) amide (1.8 g), methanol (20 ml) and methanolic hydrochloride (10 %, 0.3 ml) was refluxed for 2 hours, followed by cooling to room temperature. The reaction mixture was diluted with methanol (20 ml). Reaction mixture was filtered and washed with methanol (10 ml). Resulting product was neutralized with aqueous ammonia (25 %, 3 ml) and stirred for 30 minutes. The product thus obtained was filtered, washed with water (10 ml) and dried to give the 2.1 g of the title compound having purity 99 % by HPLC.
		A 25 mL single neck flask was charged with 0.57 g ( l .Oeq) of 8, 0.05g (0.1 eq) of (NH4)2S04 and 7. lmL (9 eq.) of HMDS. The mixture was heated to reflux for 5 h to give a clear solution, then MeCN (21 mL) and 13 (0.93g, 1.0 eq) were added followed by TMSOTf (127mu1, 0.2eq) added dropwise over 0.5 min. The reaction mixture was heated to reflux for 29.3 h and was then cooled to room temperature and poured in to 50mL saturated NaHC03 solution. The slurry was stirred in an ice bath for 2 h and then filtered. The filter cake was washed with 50mL water and then dried at 40 C under vacuum for 8hrs to give a yellow solid (1 .24 g, 92.2% purity by HPLC) in 82% yield.
	With pyrrolidine; In ethanol; for 3.4h;Reflux;	N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide (2) (50 g, 0.188 mol) of 99.86 % purity, containing 0.06 % (HPLC) of (4), and 5-fluoro-l ,3- dihydroindol-2-one (3) (28.46 g, 0,188 mol) were dissolved in ethanol (650 mL). After addition of pyrrolidine (807 mu), the mixture was stirred and refluxed, in 1.40 h precipitation of the product was observed. After 3 h the mixture was cooled down to room temperature, than the solid was filtered off and washed with ethanol (2 x 150 mL). The wet paste was transferred into the flask, suspended in ethanol (500 mL) and refluxed for 15 min. After cooling down the solution to room temperature, the solid was filtered off, washed with ethanol (2 x 100 mL) and air dried. After transfer of the wet solid into the flask, methanol (625 mL) and L-malic acid (27.12 g, 0.202 mol) were added, the resulting mixture was stirred for 10 min. The solvents were removed under reduced pressure, to the residue acetonitrile (625 mL) was added. The solution was stirred for 10 min., than the product was filtered off, washed with methylene dichloride (3 x 200 mL) and air dried to furnish 87.7 g of sunitynib L- malate (1) with 87% yield. Purity according to HPLC: 99.61%, contents of desethyl sunitynib L-malate (6) - 013% and other single impurities < 0.02%. NMR (600 MHz, DMSOd6): delta 1.14 (6H,2 x CH3, Nu-6 iotaLambda J= 7.1 Hz), 2.45(s,3H,C4- CH3,pyrro,e), 2.47 (s,3H,C2-CH3,pyrroie), 2.96(4H, 2 x CH2, N-ethyi, q, J = 7.2 Hz), 2.98(2H,CH2-NEt2, t, J = 6.4 Hz), 3.48(2H, CH2-NHamide, dt, J = 6.1, 6.0 Hz), 6.85(lH,C7-Hindoi,dd, J = 8.4, 4.5 Hz), 6.93(1H, C6-Hindoi, ddd, J = 9.3, 8.5, 2.3 Hz), 7.69 (1H, NHamide,t, J =5.4 Hz), 7.73(s,lH,CHvinyl), 7.77(1H, C4-Hindol, dd, J = 9.9, 2.2 Hz), 10.92 (s,lH,NHindoi), 13.73(s,lH,pyrroie), and L-malic acid: 2.36(lH,dd, J = 15.6, 5.3Hz i 2.55(lH,dd, J = 15.6, 8.2 Hz), 4.01(1H,CH-OH, dd, J = 8.1, 5.4 Hz), ~10.2(lH,OH,bs), ~10.2(lH,COOH,bs), -10.2 (lH,COOH,bs); ,3C NMR: delta 169.56(Cl=Oindoi), 165.18(C=Oamide), 158.22(C5-Findoi,d, J - 232.8 Hz), 136.82(C2pyrroie), 134.56(C8i?doi), 130.58(C4), 130.19(C4pyrro,e), 127.09(C3indol,d, J = 9.9 Hz), 125.83(C5 indol), 124.81(Cvinyl), 119.95(C3pyrrole), 114.92(C2indol,d, J = 2.8 Hz), 112.46(C6indoi,d, J = 24.2 Hz), 110.04(C7indoi, d, J = 8.1 Hz), 105.97(C4indol,d, J = 2.9 Hz), 50.59(CH2-NEt2), 46.71(CH2,Nethyi), 35.19(CH2-NHamide), 13.41(C2-CH3), 10.63(C4-CH3), 9.78(CH3,Nethyi) and L-malic acid: 176.04, 172.10 (2 x COOH), 66.41(C-OH), 40.89(CH2).
115 g	With pyrrolidine; In ethanol; for 3h;Reflux;	Example 1:Preparation of sunitinib5-Formyl-2,4-dimethyl- 1 H-pyrrole-3-carboxylicacid-(2-diethylamino-ethyl)amide (100 gm) was dissolved in ethanol (1500 ml) and then added 5-fluoro-1,3-dihydro-indol- 2-one (54 gm) and pyrrolidine (1.57 ml). The contents were then heated to reflux and stirred for 3 hours. The reaction mass was then cooled to room temperature, stirred for I hour and filtered. To the wet solid thus obtained was added ethanol (1200 ml) and thenheated to 50C. The solution was stirred for 1 hour at 50C and then cooled to room temperature. The contents were stirred for 1 hour at room temperature and filtered. The solid obtained was dried at 55 to 60C for 9 hours to obtain 1 15 gm of sunitinib.
	With triethylamine; at 60℃; for 2h;Large scale;	In a 20 L reactor, 4 L of acetonitrile and 1.8 kg of Compound II (10.8 mol) were added in that order.1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride 2.5 kg (12.9 mol),1.75 kg (12.9 mol) of 1-hydroxybenzotriazole, stirred well, and reacted at 35 C for 2 hours.At the end of the reaction, 1.9 kg (16.2 mol) of N,N diethylethylenediamine was added, and the reaction was carried out at 35 C for 2 hours. The reaction was completed, and 1.6-kg (10.8 mol) of 5-fluoroindol-2-one and 3 kg of triethylamine were added. ,The temperature was raised to 60 C for 2 hours, the reaction was completed, and the temperature was lowered to below 40 C.4L of methanol and 5kg (37.7mol) of L-malic acid were added, and the mixture was heated to 60 C for 1 hour.The reaction was completed, and it was cooled to room temperature, and filtered to give an orange-yellow solid, 5.1 kg.That is, compound I sunitinib malate, the yield was 88%, and the HPLC purity was 99.8%.

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[18]Patent: WO2012/59941,2012,A1 .Location in patent: Page/Page column 17
[19]Patent: WO2012/58780,2012,A1 .Location in patent: Page/Page column 26
[20]Patent: WO2013/162390,2013,A1 .Location in patent: Page/Page column 12-13
[21]Patent: WO2013/160916,2013,A1 .Location in patent: Page/Page column 6
[22]Patent: CN109503555,2019,A .Location in patent: Paragraph 0042; 0043

25
[ 253870-02-9 ]
1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride [ No CAS ]
[ 2592-95-2 ]
[ 100-36-7 ]
[ 356068-86-5 ]

Yield	Reaction Conditions	Operation in experiment
43%	With sodium hydroxide; triethylamine; In N-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene;	5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10% methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34 C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43% yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) delta 0.96 (t, 6H, 2CH3), 2.31, 2.38 (2s, 2CH3), 2.51 (m, 6H 3CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%	With sodium hydroxide; triethylamine; In N-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene;	5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10% methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34 C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (819 g, 43 % yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) delta0.96 (t, 6H, 2CH3), 2.31, 2.38 (2s, 2CH3), 2.51 (m, 6H 3CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%	With sodium hydroxide; triethylamine; In N-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene;	5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10% methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34 C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43% yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) delta 0.96 (t, 6H, 2CH3), 2.31, 2.38 (2s, 2CH3), 2.51 (m, 6H 3CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].

43%	With sodium hydroxide; triethylamine; In N-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene;	5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10% methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34 C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43% yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) delta0.96 (t, 6H, 2CH3), 2.31, 2.38 (2s, 2CH3), 2.51 (m, 6H 3CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%	With sodium hydroxide; triethylamine; In N-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene;	5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10% methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34 C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43% yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) delta 0.96 (t, 6H, 2CH3), 2.31, 2.38 (2s, 2CH3), 2.51 (m, 6H 3CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%	With sodium hydroxide; triethylamine; In N-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene;	5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10% methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34 C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43% yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) delta 0.96 (t, 6H, 2CH3), 2.31, 2.38 (2s, 2CH3), 2.51 (m, 6H 3CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].

Reference： [1]Patent: US2003/216410,2003,A1
[2]Patent: US2003/130280,2003,A1
[3]Patent: US2003/100555,2003,A1
[4]Patent: US2002/32204,2002,A1
[5]Patent: US2002/156292,2002,A1
[6]Patent: US2004/209937,2004,A1

26
[ 253870-02-9 ]
[ 100-36-7 ]
5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylarnino-ethyl)-amide [ No CAS ]
[ 356068-86-5 ]

Yield	Reaction Conditions	Operation in experiment
6.19g (78%)		Example B-2 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (5 g, 2.99 mmol) reacted with N,N-diethylethylenediamine (4.62 mL) to give 6.19g (78%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylarnino-ethyl)-amide. 1H NMR (360 MHz, DMSO-d6)delta 11.7 (br s, H, NH), 9.52 (s,1H, CHO), 7.27 (m,1H, CONH), 3.2 (m, 2H, NCH2), 2.5 (m, 6H, 3NCH2), 2.35 (s, 3H, CH3), 2.30 (s, 3H, CH3), 0.95 (t, J=6.7 Hz, 6H, 2NCH2CH3). MS m/z 266 (M++1)

Reference： [1]Patent: US2003/69297,2003,A1

27
6-(3,5-Dichlorophenyl)-1,3-dihydroindol-2-one [ No CAS ]
[ 356068-86-5 ]
5-[6-(3,5-Dichlorophenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53 mg (44%)		Example 62 5-[6-(3,5-Dichlorophenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 6-(3,5-Dichlorophenyl)-1,3-dihydroindol-2-one (64 mg, 0.23 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (60 mg) to give 53 mg (44%) of the title compound as a light brown solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.62 (s, br, 1H, NH), 10.99 (s, 1H, NH), 7.89 (d, J=7.9 Hz, 1H, H-4), 7.69-7.71 (m, 3H), 7.55 (m, 1H, CONHCH2), 7.37 (m, 2H), 7.14 (d, J=1.4 Hz, 1H, H-7), 3.27 (m, 2H, NCH2), 2.48-2.58 (m, 6H, 3NCH2), 2.45 (s, 3H, CH3), 2.42 (s, 3H, CH3), 0.97 (t, J=6.8 Hz, 6H, 3NCH2CH3). MS m/z 526.9 [M++1].
53 mg (44%)		Example 30 Synthesis of 5-[6-(3,5-Dichlorophenyl)-2-oxo-1,2-Dihydroindol-3-Ylidenemethyl]-2,4-Dimethyl-1H-Pyrrole-3-Carboxylic Acid (2-Diethylaminoethyl)Amide 6-(3,5-Dichlorophenyl)-1,3-dihydroindol-2-one (64 mg, 0.23 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (60 mg) to give 53 mg (44%) of the title compound as a light brown solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.62 (s, br, 1H, NH), 10.99 (s, 1H, NH), 7.89 (d, J=7.9 Hz, 1H, H-4), 7.69-7.71 (m, 3H), 7.55 (m, 1H, CONHCH2), 7.37 (m, 2H), 7.14 (d, J=1.4 Hz, 1H, H-7), 3.27 (m, 2H, NCH2), 2.48-2.58 (m, 6H, 3NCH2), 2.45 (s, 3H, CH3), 2.42 (s, 3H, CH3), 0.97 (t, J=6.8 Hz, 6H, 3NCH2CH3). MS m/z 526.9 [M++1].
53 mg (44%)		Example 62 5-[6-(3,5-Dichlorophenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 6-(3,5-Dichlorophenyl)-1,3-dihydroindol-2-one (64 mg, 0.23 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (60 mg) to give 53 mg (44%) of the title compound as a light brown solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.62 (s, br, 1H, NH), 10.99 (s, 1H, NH), 7.89 (d, J=7.9 Hz, 1H, H-4), 7.69-7.71 (m, 3H), 7.55 (m, 1H, CONHCH2), 7.37 (m, 2H), 7.14 (d, J=1.4 Hz, 1H, H-7), 3.27 (m, 2H, NCH2), 2.48-2.58 (m, 6H, 3NCH2), 2.45 (s, 3H, CH3), 2.42 (s, 3H, CH3), 0.97 (t, J=6.8 Hz, 6H, 3NCH2CH3). MS m/z 526.9 [M++1].

Reference： [1]Patent: US2003/216410,2003,A1
[2]Patent: US2003/100555,2003,A1
[3]Patent: US2002/156292,2002,A1

28
[ 356068-86-5 ]
[ 170565-89-6 ]
5-(5-Dimethylsulfamoyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80 mg (43%)		Example 87 5-(5-Dimethylsulfamoyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (90 mg, 0.38 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (100 mg) to give 80 mg (43%) of the title compound as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) delta 11.30 (s, 1H, NH), 8.27 (d, J=1.7 Hz, 1H), 7.94 (s, 1H, H-vinyl), 7.49 (dd, J=1.7 & 8.0 Hz, 1H), 7.44 (m, 1H, CONHCH2CH2), 7.07 (d, J=8.0 Hz, 1H), 3.26 (m, 2H, CH2), 2.60 (s, 6H, N(CH3)2), 2.53 (m, 2H, CH2), 2.45-2.50 (m, 10H, 2*CH3 & N(CH2CH3)2, 0.96 (t, J=7.2 Hz, 6H, N(CH2CH3)2). MS-EI m/z 487 [M+].
80 mg (43%)		Example 56 Synthesis of 5-(5-Dimethylsulfamoyl-2-oxo-1,2-Dihydroindol-3-Ylidenemethyl)-2,4-Dimethyl-1H-Pyrrole-3-Carboxylic Acid (2-Diethylaminoethyl)Amide 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (90 mg, 0.38 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide (100 mg) to give 80 mg (43%) of the title compound as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) delta 11.30 (s, 1H, NH), 8.27 (d, J=1.7 Hz, 1H), 7.94 (s, 1H, H-vinyl), 7.49 (dd, J=1.7 & 8.0 Hz, 1H), 7.44 (m, 1H, CONHCH2CH2), 7.07 (d, J=8.0 Hz, 1H), 3.26 (m, 2H, CH2), 2.60 (s, 6H, N(CH3)2), 2.53 (m, 2H, CH2), 2.45-2.50 (m, 10H, 2*CH3 & N(CH2CH3)2, 0.96 (t, J=7.2 Hz, 6H, N (CH2CH3)2). MS-EI m/z 487 [M+].
80 mg (43%)		Example 87 5-(5-Dimethylsulfamoyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (90 mg, 0.38 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide (100 mg) to give 80 mg (43%) of the title compound as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) delta 11.30 (s, 1H, NH), 8.27 (d, J=1.7 Hz, 1H), 7.94 (s, 1H, H-vinyl), 7.49 (dd, J=1.7 & 8.0 Hz, 1H), 7.44 (m, 1H, CONHCH2CH2), 7.07 (d, J=8.0 Hz, 1H), 3.26 (m, 2H, CH2), 2.60 (s, 6H, N(CH3)2), 2.53 (m, 2H, CH2), 2.45-2.50 (m, 10H, 2*CH3 & N(CH2CH3)2, 0.96 (t, J=7.2 Hz, 6H, N(CH2CH3)2). MS-EI m/z 487 [M+].

Reference： [1]Patent: US2003/216410,2003,A1
[2]Patent: US2003/100555,2003,A1
[3]Patent: US2002/156292,2002,A1

29
[ 334952-09-9 ]
[ 356068-86-5 ]
3-[4-(2-Diethylaminoethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
210 mg (92%)		Example 81 3-[4-(2-Diethylaminoethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic Acid <strong>[334952-09-9]2-Oxo-2,3-dihydro-1H-indole-6-carboxylic acid</strong> (80 mg, 0.45 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide to give 210 mg (92%) of the title compound as a yellow orange solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.6 (s, 1H, NH), 7.76 (d, J=8.0 Hz, 1H), 7.66 (s, 1H, H-vinyl), 7.57 (dd, J=1.5 & 8.0 Hz, 1H), 7.40-7.42 (m, 2H), 3.28 (m, 2H, CH2), 2.88 (m, H-piperidine), 2.54 (m, 6H, 3*CH2), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3), 1.56 (m, H-piperidine), 0.97 (t, J=6.98 Hz, 6H, N(CH2CH3)2). MS m/z 424 [M+].
210 mg (92%)		Example 50 Synthesis of 3-[4-(2-Diethylaminoethylcarbamoyl)-3,5-Dimethyl-1H-Pyrrol-2-Ylmethylene]-2-oxo-2,3-Dihydro-1H-Indole-6-Carboxylic Acid <strong>[334952-09-9]2-Oxo-2,3-dihydro-1H-indole-6-carboxylic acid</strong> (80 mg, 0.45 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide to give 210 mg (92%) of the title compound as a yellow orange solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.6 (s, 1H, NH), 7.76 (d, J=8.0 Hz, 1H), 7.66 (s, 1H, H-vinyl), 7.57 (dd, J=1.5 & 8.0 Hz, 1H), 7.40-7.42 (m, 2H), 3.28 (m, 2H, CH2), 2.88 (m, H-piperidine), 2.54 (m, 6H, 3*CH2), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3), 1.56 (m, H-piperidine), 0.97 (t, J=6.98 Hz, 6H, N(CH2CH3)2). MS m/z 424 [M+]
210 mg (92%)		Example 81 3-[4-(2-Diethylaminoethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-<strong>[334952-09-9]2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid</strong> <strong>[334952-09-9]2-Oxo-2,3-dihydro-1H-indole-6-carboxylic acid</strong> (80 mg, 0.45 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide to give 210 mg (92%) of the title compound as a yellow orange solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.6 (s, 1H, NH), 7.76 (d, J=8.0 Hz, 1H), 7.66 (s, 1H, H-vinyl), 7.57 (dd, J=1.5 & 8.0 Hz, 1H), 7.40-7.42 (m, 2H), 3.28 (m, 2H, CH2), 2.88 (m, H-piperidine), 2.54 (m, 6H, 3*CH2), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3), 1.56 (m, H-piperidine), 0.97 (t, J=6.98 Hz, 6H, N(CH2CH3)2). MS m/z 424 [M+].

Reference： [1]Patent: US2003/216410,2003,A1
[2]Patent: US2003/100555,2003,A1
[3]Patent: US2002/156292,2002,A1

30
[ 295800-01-0 ]
[ 356068-86-5 ]
2,4-Dimethyl-5-(2-oxo-6-pyridin-3-yl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29 mg (33%)		Example 63 2,4-Dimethyl-5-(2-oxo-6-pyridin-3-yl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 6-Pyridin-3-yl-1,3-dihydroindol-2-one (40 mg, 0.19 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (50 mg) give, 29 mg (33%) of the title compound as a light orange solid. 1H-NMR (300 MHz, DMSO-d6) delta 13.62 (s, br, 1H, NH), 11.05 (s, br, 1H, NH), 8.86 (s, br, 1H), 8.53 (d, J=5.8 Hz, 1H), 8.04 (m, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.70 (s, 1H, H-vinyl), 7.40-7.48 (m, 2H), 7.35 (d, J=7.5 Hz, 1H), 7.14 (s, 1H), 3.26 (m, 2H, NCH2), 2.48-2.55 (m, 3NCH2), 2.42 (s, 3H, CH3), 2.38 (s, 3H, CH3), 0.96 (t, J=6.9 Hz, 6H, 2NCH2CH3). MS-EI m/z 457 [M+].
29 mg (33%)		Example 31 Synthesis of 2,4-Dimethyl-5-(2-oxo-6-Pyridin-3-yl-1,2-Dihydroindol-3-Ylidenemethyl)-1H-Pyrrole-3-Carboxylic Acid (2-Diethylaminoethyl)Amide 6-Pyridin-3-yl-1,3-dihydroindol-2-one (40 mg, 0.19 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (50 mg) give 29 mg (33%) of the title compound as a light orange solid. 1H-NMR (300 MHz, DMSO-d6) delta 13.62 (s, br, 1H, NH), 11.05 (s, br, 1H, NH), 8.86 (s, br, 1H), 8.53 (d, J=5.8 Hz, 1H), 8.04 (m, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.70 (s, 1H, H-vinyl), 7.40-7.48 (m, 2H), 7.35 (d, J=7.5 Hz, 1H), 7.14 (s, 1H), 3.26 (m, 2H, NCH2), 2.48-2.55 (m, 3NCH2), 2.42 (s, 3H, CH3), 2.38 (s, 3H, CH3), 0.96 (t, J=6.9 Hz, 6H, 2NCH2CH3). MS-EI m/z 457 [M+].
29 mg (33%)		Example 63 2,4-Dimethyl-5-(2-oxo-6-pyridin-3-yl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 6-Pyridin-3-yl-1,3-dihydroindol-2-one (40 mg, 0.19 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (50 mg) give 29 mg (33%) of the title compound as a light orange solid. 1H-NMR (300 MHz, DMSO-d6) delta 13.62 (s, br, 1H, NH), 11.05 (s, br, 1H, NH), 8.86 (s, br, 1H), 8.53 (d, J=5.8 Hz, 1H), 8.04 (m, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.70 (s, 1H, H-vinyl), 7.40-7.48 (m, 2H), 7.35 (d, J=7.5 Hz, 1H), 7.14 (s, 1H), 3.26 (m, 2H, NCH2), 2.48-2.55 (m, 3NCH2), 2.42 (s, 3H, CH3), 2.38 (s, 3H, CH3), 0.96 (t, J=6.9 Hz, 6H, 2NCH2CH3). MS-EI m/z 457 [M+].

Reference： [1]Patent: US2003/216410,2003,A1
[2]Patent: US2003/100555,2003,A1
[3]Patent: US2002/156292,2002,A1

31
[ 342642-67-5 ]
[ 356068-86-5 ]
5-[5-(3-Chlorophenylsulfamoyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80 mg (37%)		Example 88 5-[5-(3-Chlorophenylsulfamoyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)amide (120 mg, 3.8 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (100 mg) to give 80 mg (37%) of the title compound as a yellow solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.55 (s, 1H, NH), 11.24 (s, 1H, NH), 10.29 (s, 1H, NH), 8.25 (d, J=1.87 Hz, 1H), 7.79 (s, 1H, H-vinyl), 7.52 (dd, J=1.87 & 8.3 Hz, 1H), 7.42 (m, 1H, CONHCH2CH2), 7.22 (t, J=8.02 Hz, 1H), 7.15 (t, J=2 Hz, 1H), 7.08 (m, 1H), 7.0 (m, 2H), 3.27 (m, 2H, CH2), 2.48-2.57 (m, 6H, 3*CH2), 2.45 (s, 3H, CH3), 2.44 (s, 3H, CH3), 0.97 (t, J=7.0 Hz, 6H, N(CH2CH3)2). MS m/z 570.1 [M+].
80 mg (37%)		Example 57 Synthesis of 5-[5-(3-Chlorophenylsulfamoyl)-2-oxo-1,2-Dihydroindol-3-Ylidenemethyl]-2,4-Dimethyl-1H-Pyrrole-3-Carboxylic Acid (2-Diethylaminoethyl)Amide 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)amide (120 mg, 3.8 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (100 mg) to give 80 mg (37%) of the title compound as a yellow solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.55 (s, 1H, NH), 11.24 (s, 1H, NH), 10.29 (s, 1H, NH), 8.25 (d, J=1.87 Hz, 1H), 7.79 (s, 1H, H-vinyl), 7.52 (dd, J=1.87 & 8.3 Hz, 1H), 7.42 (m, 1H, CONHCH2CH2), 7.22 (t, J=8.02 Hz, 1H), 7.15 (t, J=2 Hz, 1H), 7.08 (m, 1H), 7.0 (m, 2H), 3.27 (m, 2H, CH2), 2.48-2.57 (m, 6H, 3*CH2), 2.45 (s, 3H, CH3), 2.44 (s, 3H, CH3), 0.97 (t, J=7.0 Hz, 6H, N(CH2CH3)2). MS m/z 570.1 [M+].
80 mg (37%)		Example 88 5-[5-(3-Chlorophenylsulfamoyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chlorophenyl)amide (120 mg, 3.8 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (100 mg) to give 80 mg (37%) of the title compound as a yellow solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.55 (s, 1H, NH), 11.24 (s, 1H, NH), 10.29 (s, 1H, NH), 8.25 (d, J=1.87 Hz, 1H), 7.79 (s, 1H, H-vinyl), 7.52 (dd, J=1.87 & 8.3 Hz, 1H), 7.42 (m, 1H, CONHCH2CH2), 7.22 (t, J=8.02 Hz, 1H), 7.15 (t, J=2 Hz, 1H), 7.08 (m, 1H), 7.0 (m, 2H), 3.27 (m, 2H, CH2), 2.48-2.57 (m, 6H, 3*CH2), 2.45 (s, 3H, CH3), 2.44 (s, 3H, CH3), 0.97 (t, J=7.0 Hz, 6H, N(CH2CH3)2). MS m/z 570.1 [M+].

Reference： [1]Patent: US2003/216410,2003,A1
[2]Patent: US2003/100555,2003,A1
[3]Patent: US2002/156292,2002,A1

32
[ 20870-78-4 ]
[ 356068-86-5 ]
5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With piperidine; In ethanol; at 90℃; for 6h;	To a solution of commercial available 5-bromoindoline-2-one 2b (425 mg, 2 mmol) and pyrrole 3 (636 mg, 2.4 mmol) in ethanol (4.0 mL) six drops of piperidine were added and the mixture was heated for six hours under reflux. After cooling on ice the precipitate was filtered off, washed with ethanol and dried under vacuum to give 5 (886 mg) as an orange solid in 96% yield, mp: 245-247C, HNMR (d, ppm, DMSO-d): 0.97 (t, 6H, N(CH2CH3)2); 2.43 (s, 3H, CH3); 2.44 (s, 3H, CH3); 2.50 (m, 6H, 3xCH2); 3.29 (m, 2H, NH-CH2); 6.82 (d, 1H, 7-H); 7.25 (d, 1H, 6-H); 7.42 (s, 1H, 4-H); 7.77 (s, 1H, NH-CH2); 8.10 (s, 1H, Hvinyl); 10.99 (s, 1H, NHindole); 13.62 (s, 1H, NHpyrrole); ESI-MS (ES+): m/z=461 (M+H)+
0.09 g (26%)		Example 51 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylamino-ethyl)amide 5-Bromo-1,3-dihydroindol-2-one (0.17 g, 0.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (0.2 g) to give 0.09 g (26%) of the title compound as a yellow solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.61 (s, br, 1H, NH), 10.98 (, br, 1H, NH), 8.09 (d, J=1.7 Hz, 1H, H-4), 7.76 (s, 1H, H-vinyl), 7.42 (t, J=5.5 Hz, 1H, CONHCH2), 7.24 (dd, J=1.7 & 8.0 Hz, 1H, H-6), 6.82 (d, J=8.0 Hz, 1H, H-7), 3.23-3.32 (m, 2H, NCH2), 2.46-2.55 (m, 6H, 3NCH2), 2.43 (s, 3H, CH3), 2.42 (s, 3H, CH3), 0.96 (t, J=7.2 Hz, 6H, 2NCH2CH3). MS-EI m/z 458 and 460 [M+-1 and M++1].
0.09 g (26%)		Example 51 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide 5-Bromo-1,3-dihydroindol-2-one (0.17 g, 0.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (0.2 g) to give 0.09 g (26%) of the title compound as a yellow solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.61 (s, br, 1H, NH), 10.98 (, br, 1H, NH), 8.09 (d, J=1.7 Hz, 1H, H-4), 7.76 (s, 1H, H-vinyl), 7.42 (t, J=5.5 Hz, 1H, CONHCH2), 7.24 (dd, J=1.7 & 8.0 Hz, 1H, H-6), 6.82 (d, J=8.0 Hz, 1H, H-7), 3.23-3.32 (m, 2H, NCH2), 2.46-2.55 (m, 6H, 3NCH2), 2.43 (s, 3H, CH3), 2.42 (s, 3H, CH3), 0.96 (t, J=7.2 Hz, 6H, 2NCH2CH3). MS-EI m/z 458 and 460 [M+-1 and M++1].

368 mg

With piperidine; In ethanol; at 80℃; for 1h;

Reference Example 27 Production of (Z)-5-((5-bromo-2-oxoindolin-3-ylidene)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide To the solution of 5-bromoindolin-2-one (262 mg, 1.24 mmol) in EtOH (5 ml) was added N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (298 mg, 1.12 mmol) and piperidine (112 muL, 1.13 mmol). The mixture was stirred at 80 C. for 1 hour. After cooled down to room temperature, the reaction mixture was concentrated, filtrated, and washed with EtOH to give (Z)-5-((5-bromo-2-oxoindolin-3-ylidene)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (368 mg) as orange solid. MS m/z 459.4/461.4 (M+H)

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2850 - 2855
[2]Patent: US2003/216410,2003,A1
[3]Patent: US2002/156292,2002,A1
[4]Patent: US2014/275076,2014,A1 .Location in patent: Paragraph 0387; 0388; 0389

33
[ 20870-78-4 ]
[ 356068-86-5 ]
5-(5-Bromo-2-oxo-1,2-Dihydroindol-3-Ylidenemethyl)-2,4-Dimethyl-1H-Pyrrole-3-Carboxylic Acid (2-Diethylamino-Ethyl)-Amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.09 g (26%)		Example 19 Synthesis of 5-(5-Bromo-2-oxo-1,2-Dihydroindol-3-Ylidenemethyl)-2,4-Dimethyl-1H-Pyrrole-3-Carboxylic Acid (2-Diethylamino-Ethyl) Amide 5-Bromo-1,3-dihydroindol-2-one (0.17 g, 0.8 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (0.2 g) to give 0.09 g (26%) of the title compound as a yellow solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.61 (s, br, 1H, NH), 10.98 (, br, 1H, NH), 8.09 (d, J=1.7 Hz, 1H, H-4), 7.76 (s, 1H, H-vinyl), 7.42 (t, J=5.5 Hz, 1H, CONHCH2), 7.24 (dd, J=1.7 & 8.0 Hz, 1H, H-6), 6.82 (d, J=8.0 Hz, 1H, H-7), 3.23-3.32 (m, 2H, NCH2), 2.46-2.55 (m, 6H, 3NCH2), 2.43 (s, 3H, CH3), 2.42 (s, 3H, CH3), 0.96 (t, J=7.2 Hz, 6H, 2NCH2CH3). MS-EI m/z 458 and 460 [M+-1 and M++1].

Reference： [1]Patent: US2003/100555,2003,A1

34
[ 90750-91-7 ]
[ 356068-86-5 ]
2,4-Dimethyl-5-(2-oxo-5-Phenyl-1,2-Dihydroindol-3-Ylidenemethyl)-1H-Pyrrole-3-Carboxylic Acid (2-Diethylamino-Ethyl)Amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79 mg (46%)		Example 56 2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 5-Phenyl-1,3-dihydroindol-2-one (80 mg, 0.4 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (0.1 g) using method B to give 79 mg (46%) of the title compound. 1H-NMR (300 MHz, DMSO-d6) delta 13.66 (s, br, 1H, NH), 10.95 (, br, 1H, NH), 8.15 (d, J=1.2 Hz, 1H), 7.81 (s, 1H, H-vinyl), 7.71 (d, J=7.5 Hz, 1H), 7.40-7.47 (m, 4H), 7.31 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 3.2-3.31 (m, 2H, NCH2), 2.46-2.55 (m, 6H, 3NCH2), 2.44 (s, 6H, 2CH3), 0.96 (t, J=7.4 Hz, 6H, 2*NCH2CH3). MS-EI m/z 456 [M+].
79 mg (46%)		Example 24 Synthesis of 2,4-Dimethyl-5-(2-oxo-5-Phenyl-1,2-Dihydroindol-3-Ylidenemethyl)-1H-Pyrrole-3-Carboxylic Acid (2-Diethylamino-Ethyl)Amide 5-Phenyl-1,3-dihydroindol-2-one (80 mg, 0.4 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (0.1 g) using method B to give 79 mg (46%) of the title compound. 1H-NMR (300 MHz, DMSO-d6) delta 13.66 (s, br, 1H, NH), 10.95 (, br, 1H, NH), 8.15 (d, J=1.2 Hz, 1H), 7.81 (s, 1H, H-vinyl), 7.71 (d, J=7.5 Hz, 1H), 7.40-7.47 (m, 4H), 7.31 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 3.2-3.31 (m, 2H, NCH2), 2.46-2.55 (m, 6H, 3NCH2), 2.44 (s, 6H, 2CH3), 0.96 (t, J=7.4 Hz, 6H, 2*NCH2CH3). MS-EI m/z 456 [M+].
79 mg (46%)		Example 56 2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 5-Phenyl-1,3-dihydroindol-2-one (80 mg, 0.4 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (0.1 g) using method B to give 79 mg (46%) of the title compound. 1H-NMR (300 MHz, DMSO-d6) delta 13.66 (s, br, 1H, NH), 10.95 (, br, 1H, NH), 8.15 (d, J=1.2 Hz, 1H), 7.81 (s, 1H, H-vinyl), 7.71 (d, J=7.5 Hz, 1H), 7.40-7.47 (m, 4H), 7.31 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 3.2-3.31 (m, 2H, NCH2), 2.46-2.55 (m, 6H, 3NCH2), 2.44 (s, 6H, 2CH3), 0.96 (t, J=7.4 Hz, 6H, 2*NCH2CH3). MS-EI m/z 456 [M+].

Reference： [1]Patent: US2003/216410,2003,A1
[2]Patent: US2003/100555,2003,A1
[3]Patent: US2002/156292,2002,A1

35
[ 110-89-4 ]
[ 356068-86-5 ]
[ 346600-16-6 ]
[ 346599-89-1 ]

Yield	Reaction Conditions	Operation in experiment
78.5 mg (62%)	In ethanol;	EXAMPLE 25 SYNTHESIS OF 5-[4-(3-CHLORO-4-FLUORO-PHENYLAMINO)-6-OXO-6,7-DIHYDRO-PYRROLO [2,3-D]PYRIMIDIN-5-YLIDENEMETHYL]-2,4-DIMETHYL-1H-PYRROLE-3-CARBOXYLIC ACID (2-DIETHYLAMINO-ETHYL)-AMIDE (FORMULA 28) A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (66 mg, 0.24 mmol), <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide</strong> (63.7 mg, 0.24 mmol) and piperidine (1 drop) in ethanol (2 mL) was stirred at room temperature for 3 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 78.5 mg (62%) of the title compound. 1H NMR (360 MHz, DMSO-d6)delta13.33 (br s, 1 H, NH), 11.61 (br s, 1H, NH), 9.17 (br s, 1H), 8.29 (s, 1H), 7.69 (dd, J=2.5 & 6.5 Hz, 1H), 7.35 (m, 4H), 3.29 (m, 2H, CH2), 2.5 (m, 6H, N(CH2CH3)2 & CH2), 2.45 (s, 3H, CH3), 2.25 (s, 3H, CH3), 0.96 (t, J=7 Hz, 6H, N(CH2CH3)2). MS 526 [M+1].

Reference： [1]Patent: US2002/183319,2002,A1

36
[ 110-89-4 ]
[ 388116-39-0 ]
[ 356068-86-5 ]
2,4-Dimethyl-5-(2-oxo-4-pyridin-3-yl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water;	Example 75 2,4-Dimethyl-5-(2-oxo-4-pyridin-3-yl-1,2-dihydroindol-3-ylidenemethyl) -1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl) amide A mixture of 4-pyridin-3-yl-1,3-dihydroindol-2-one (42 mg, 0.2 mmol), <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (53 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol(1 mL) was heated in a sealed tube at 80 C. for 2 hours, heating was stopped and the tube was shaken at room temperature for 2 days. A small amount of water was added to the reaction and the solid which formed was collected by vacuum filtration, washed with water and dried to give the title compound. 1H NMR (400 MHz, DMSO-d6) delta 13.47 (s, 1H, NH), 11.10 (s, 1H, NH), 8.71 (dd, J=1.5 & 4.7 Hz, 1H), 8.64 (d, J=1.5 Hz, 1H), 7.89 (m, 1H), 7.58 (m, 1H), 7.36 (t, J=5.5 Hz, 1H, NH), 7.23 (t, J=7.6 Hz, 1H, NH),6.98 (d, J=7.6 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.68 (s, 1H, H-vinyl), 3.21 (m, 2H), 2.5 (m, 6H), 2.39 (s, 3H, CH3), 1.68 (s, 3H, CH3), 0.95 (t, J=7.2 Hz, 6H, N(CH2CH3)2). MS -ve APCI m/z 456 [M+-1].

Reference： [1]Patent: US2002/187978,2002,A1

37
[ 110-89-4 ]
[ 388116-40-3 ]
[ 356068-86-5 ]
5-{3-[4-(2-Diethylaminoethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-nicotinic Acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; ethanol; water;	Example 72 5-{3-[4-(2-Diethylaminoethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-nicotinic Acid A mixture of 5-(2-oxo-2,3-dihydro-1H-indol-4-yl)-nicotinic acid (381 mg, 1.5 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (398 mg, 1.5 mmol) and piperidine (1 mL) in ethanol (5 mL) was heated in a sealed tube at 60 C. for 10 hours. The reaction was concentrated, the residue was dissolved in a mixture of water and methanol and then acidified with 1N HCl. The resulted precipitate was collected by vacuum filtration, washed with methanol and dried to give the title compound. 1H NMR (360 MHz, DMSO-d6) delta 13.54 (s, 1H, NH), 11.15 (s, 1H, NH), 9.19 (d, J=2 Hz, 1H), 8.88 (d, J=2 Hz, 1H), 8.3 (m, 1H), 7.72 (br t, J=5.8 Hz, 1H), 7.26 (t, J=7.7 Hz, 1H), 7.01 (d, J=7.7 Hz, 1H), 6.89 (d, J=7.7 Hz, 1H), 6.66 (s, 1H, H-vinyl), 3.52 (m, 2H), 3.18 (m, 6H), 2.43 (s, 3H, CH3), 1.69 (s, 3H, CH3), 1.21 (t, J=7.4 Hz, 6H, N(CH2CH3)2). MS +ve APCI m/z 502 [M++1].

Reference： [1]Patent: US2002/187978,2002,A1

38
[ 388116-26-5 ]
[ 356068-86-5 ]
2,4-Dimethyl-5-(2-oxo-4-pyridin-4-yl-1,2-dihydroindol-3-ylidene-methyl)-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 18 2,4-Dimethyl-5-(2-oxo-4-pyridin-4-yl-1,2-dihydroindol-3-ylidene-methyl)-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide to give the title compound. 1H NMR (400 MHz, DMSO-d6) delta 13.46 (s, 1H, NH), 11.10 (br s, 1H, NH), 8.74 (d, J=5.9 Hz, 2H), 7.50 (d, J=5.9 Hz, 2H), 7.35 (t, 1H, CONH), 7.22 (t, J=7.7 Hz, 1H), 6.98 (d, J=7.7 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 6.75 (s, 1H, H-vinyl), 3.23 (q, J=6.8 Hz, 2H, NCH2CH3), 2.45-2.5 (m, 6H), 2.39 (s, 3H, CH3), 1.69 (s, 3H, CH3), 0.95 (t, J=6.8 Hz, 6H, N(CH2CH3)2). MS -ve APCI m/z 456 [M+-1].

Reference： [1]Patent: US2002/187978,2002,A1

39
[ 356068-86-5 ]
[ 388116-29-8 ]
2,4-Dimethyl-5-(2-oxo-4-piperidin-4-yl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-diethylamino-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 48 2,4-Dimethyl-5-(2-oxo-4-piperidin-4-yl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-diethylamino-ethyl)-amide 4-Piperidin-4-yl-1,3-dihydroindol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide to give the title compound. 1H NMR (360 MHz, DMSO-d6) delta 13.79 (s, 1H, NH), 11.0 (br s, 1H, NH), 7.51 (s, 1H, H-vinyl), 7.44 (t, J=5.6 Hz, 1H, CONHCH2), 7.11 (t, J=7.7 Hz, 1H), 6.93 (d, J=7.7 Hz, 1H), 6.77 (d, J=7.7 Hz, 1H), 3.3 (m, 4H), 2.72 (m, 2H), 2.52 (q, J=7.2 Hz, 4H, N(CH2CH3)2), 2.43 (s, 3H, CH3), 2.37 (s, 3H, CH3), 1.85 (m, 2H), 1.64 (m, 2H), 0.97 (t, J=7.2 Hz, 6H, N(CH2CH3)2. MS +ve APCI m/z 464 [M++1].

Reference： [1]Patent: US2002/187978,2002,A1

40
[ 388116-42-5 ]
[ 356068-86-5 ]
5-[4-(2-Aminopyrimidin-5-yl)-2-oxo-1,2-dihydroindol-3-ylidene-methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 73 5-[4-(2-Aminopyrimidin-5-yl)-2-oxo-1,2-dihydroindol-3-ylidene-methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 4-(2-Aminopyrimidin-5-yl)-1,3-dihydroindol-2-one (55 mg) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (65 mg) to give the title compound. 1H NMR (360 MHz, DMSO-d6) delta 13.46 (s, 1H, NH), 11.02 (br s, 1H, NH), 8.27 (s, 2H), 7.38 (t, 1H, NH), 7.17 (t, J=7.8 Hz, 1H), 7.02 (s, 1H, H-vinyl), 6.91 (d, J=7.8 Hz, 1H), 6.86 (s, 2H, NH2), 6.79 (d, J=7.8 Hz, 1H), 3.22 (m, 2H), 2.45-2.52 (m, 6H), 2.39 (s, 3H, CH3), 1.90 (s, 3H, CH3), 0.95 (t, J=7.0 Hz, 6H, N(CH2CH3)2). MS -ve APCI m/z 472 [M+-1].

Reference： [1]Patent: US2002/187978,2002,A1

41
[ 56341-41-4 ]
[ 97-67-6 ]
[ 356068-86-5 ]
[ 341031-54-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With pyrrolidine; In ethanol; at 78℃; for 3h;	N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (1.0 g), 5-Fluoro-l,3-dihydro-2H-indol-2-one (0.57 g), pyrrolidine (0.013 g) and L-malic acid (0.37 g) were added to absolute ethanol (15 ml) and the reaction mixture was stirred at 78C (internal temperature) for 3 hours. The reaction mixture was cooled to 20C to 25C, filtered under vacuum, washed with absolute ethanol (10 ml) and dried under vacuum at 50C for 10 hours to 12 hours to obtain the title compound. Percentage yield: 80%Purity: 99.37%.
80%	With pyrrolidine; In ethanol; at 78℃; for 3h;	Preparation of L-Malic Acid Salt of Sunitinib N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (1.0 g), 5-Fluoro-1,3-dihydro-2H-indol-2-one (0.57 g), pyrrolidine (0.013 g) and L-malic acid (0.37 g) were added to absolute ethanol (15 ml) and the reaction mixture was stirred at 78 C. (internal temperature) for 3 hours. The reaction mixture was cooled to 20 C. to 25 C., filtered under vacuum, washed with absolute ethanol (10 ml) and dried under vacuum at 50 C. for 10 hours to 12 hours to obtain the title compound. Percentage yield: 80% Purity: 99.37%.
71.2%		Example 3; Preparation of the Malic Acid Salt of SunitinibMalic Acid Salt of Compound of Formula (I)In accordance with an embodiment of the invention, this example describes the preparation of the malic acid salt of sunitinib via (i) preparation of the malic acid salt of compound II without isolation, and (ii) reaction of the non-isolated malic acid salt of compound II with compound III.2.50 g of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide and 25 mL of n-butanol were heated to 48 C. to completely dissolve the solid. A previously prepared solution of 1.50 g L-(-)-malic acid and 7.5 mL of n-butanol was then added dropwise to the reaction mixture while maintaining the reaction temperature. Once addition was complete stirring was continued for 15 minutes. A previously prepared solution of 1.43 g of 5-fluoro-1,3-dihydroindol-2-one and 20 mL n-butanol was then added dropwise while maintaining the temperature of the reaction mixture. After the addition was complete 40 muL of pyrrolidine were added and the mixture was heated to 94 C. After 20 minutes at 94 C. an orange solid started to crystallize. The reaction was monitored by TLC and after 2.5 h at 94 C. the mixture was cooled to 0-5 C. and stirred for 1 h. The orange suspension was then filtered, the collected solid was washed with 2×8 mL of n-butanol and then dried at 60 C. for 4 h under vacuum to give 3.92 g (78.1% yield) of a light orange solid.3.16 g of the dry solid obtained previously and 15.8 mL of distilled water were heated to dissolution. At 77 C. a clear red solution was obtained. The solution was filtered to remove insolubles, and the filter was washed with 4.25 mL of water. The filtrate was heated to 75 C. and 23.7 mL of 2-propanol were added dropwise, while maintaining the temperature of the mixture. Once the addition was complete, the mixture was cooled to room temperature and stirred for 1 h. Crystallization was observed at 26 C. The light orange suspension was then cooled to 0-5 C., stirred for 1 h and filtered. The collected solid was washed with 2×6.4 mL of 2-propanol, and then dried at 60 C. for 4 h under vacuum to give 2.88 g (91.1% yield) of a light orange solid, which was the malic acid salt of sunitinib. Overall yield: 71.2%.Analytical data: IR (KBr): Essentially identical to the IR spectrum shown in FIG. 2; Potentiometric assay: 100.07%; HPLC: 99.56% (% area); Melting point: 188.3-189.1 C. Crystalline Form I.

71%		Into a 500 mL four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, and a reflux condenser were charged 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (VII) (10.0 g; 0.03 mole), 5-fluoro-2-oxindole (5.46 g; 0.03 mole) and ethanol (70 mL). The reaction mixture was then heated to refluxed for 8-10 hours. The progress of the reaction was monitored by TLC. After completion of reaction, L(-)-malic acid (3.9 g; 0.029 mole) was charged and further maintained at reflux temperature for 4-6 hours. After maintenance, the reaction mixture was cooled to room temperature and filtered the solids. The wet solids were then triturated in acetone (60 mL) at reflux temperature for 1 hour and cooled to room temperature. The product was isolated by filtration and dried at 80-85oC. Dry Weight: 14.3 g Yield: 71.0% HPLC Purity: >99.5%
		Example 25: Preparation of (2S)-2-hydroxy butanedioic acid compound with N-[2- (diethylamino)ethyl]-5-[(Z)-(5-fluoro-l,2-dihydro-2-oxo-3fT-indol-3-yIidine) methyl]- 2,4-dimethyl-l/-pyrrole-3-carboxamide (1:1) - Sunitinib Malate-I(a):Into a 500 mL four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, a nitrogen bubbler, and a reflux condenser were charged 5- formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (V) (10.0 g; 0.06 mole), 1 -Hydroxy benzotriazole (12.0 g), dicyclohexylcarbodimide (17.2 g) and tetrahydrofuran (150 mL). To this stirred solution, a solution of triethyl amine (16.8 mL) in 65 mL tetrahydrofuran followed by N,N-diethylaminoethyl amine (10 mL; 0.07 mole) in 65 mL tetrahydrofuran were added through addition funnel and stirred for 20 hours. The progress of the reaction was monitored by TLC. After completion of reaction, the urea derivative was filtered off and the filtrate was re-charged into a fresh 500 mL round-bottomed flask equipped with a mechanical stirrer, thermometer pocket, a nitrogen bubbler, and a reflux condenser. To this stirred solution L(-)-malic acid (8.9 g; 0.06 mole) was charged and further maintained for 4-6 hours. To the resulting solution, 5-fluoro-2-oxindole (8.99 g; 0.06 mole) was charged and continued at reflux temperature for 4-6 hours. The yellow crystalline precipitate was filtered off and wet cake was washed with tetrahydrofuran (50 mL). The product was again triturated in tetrahydrofuran (70 mL) at reflux temperature for 1 hour and filtered. The product was dried at 80-85 C. Dry Weight: 21.5 g Yield: 67.0% HPLC Purity: > 99.5%

Reference： [1]Patent: WO2011/107919,2011,A1 .Location in patent: Page/Page column 4
[2]Patent: US2013/123511,2013,A1 .Location in patent: Paragraph 0014; 0015; 0016
[3]Patent: US2009/318525,2009,A1 .Location in patent: Page/Page column 4
[4]Patent: US2011/92717,2011,A1 .Location in patent: Page/Page column 19-20
[5]Patent: WO2009/157011,2009,A1 .Location in patent: Page/Page column 44

42
[ 97-67-6 ]
[ 356068-86-5 ]
[ 1200435-83-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	In dichloromethane; at 25 - 30℃;	Dichloromethane (30 ml), N-[2-(diethylamino)ethyl]-5-forrnyl-2,4-dirnethyl-lH-pyrrole-3- carboxamide (1O g, 1 equivalent, purity 90-97%) and (L) malic acid (5.04 g, 1 equivalent) were added together and stirred at 25-300C for 15 minutes. A sticky mass was progressively formed. The dichloromethane was decanted and fresh dichloromethane (30 ml) added to the sticky mass, followed by stirring and decantation of the dichloromethane. Methanol (20 ml) was added until the sticky mass completely dissolved. The DCM and methanol solvents were removed by rotary evaporation to obtain a brown coloured sticky mass, which was characterized as the malate salt by NMR.Yield (w/w) = 13 g (86%)Purity (HPLC) > 99.0%
	In butan-1-ol; at 57℃;	Example 1; Preparation of the malic acid salt of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylaminoethyl)amideMalic Acid Salt of Compound of Formula IIThis example describes the preparation and isolation of the malic acid salt of compound II in accordance with an embodiment of the invention.7.05 g of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide and 21 mL of n-butanol were heated to dissolution. At 57 C. a brown, slightly opaque solution was obtained and a previously prepared solution of 3.89 g L-(-)-malic acid and 20 mL of n-butanol was added dropwise, maintaining the temperature of the reaction mixture. The resulting solution was stirred for 30 minutes and then cooled to room temperature. A gummy solid was formed at 25 C. Heating the mixture to dissolution (33 C.) and cooling again produced the same gummy solid. Finally, heating the mixture to 35 C. a brownish solid started to crystallize to give a very thick suspension. An additional 35 mL of n-butanol were then added, the reaction mixture was heated to 42 C. and cooled to 0-5 C. After stirring for 1 h at 0-5 C., the suspension was filtered, the collected solid was washed with 2×14 mL of n-butanol and then dried at 60 C. for 4 h under vacuum, to give 10.00 g (94.9% yield) of a brownish solid, which was the malic acid salt of compound of formula II.Analytical data: IR (KBr): characteristic peaks at (cm-1): 3414, 3057, 2982, 2951, 2773, 2667, 2494, 1717, 1624, 1562, 1529, 1433, 1390, 1371, 1342, 1283, 1165, 1113, 1053, 1037, 1013, 957, 881, 779, 706, 650. See FIG. 1; potentiometric assay: 99.77%; HPLC: 99.82% (% area); melting point: 110.6-111.8 C.

Reference： [1]Patent: WO2011/4200,2011,A1 .Location in patent: Page/Page column 21-22
[2]Patent: US2009/318525,2009,A1 .Location in patent: Page/Page column 3

43
[ 56341-41-4 ]
[ 64-19-7 ]
[ 356068-86-5 ]
[ 1221149-36-5 ]

Yield	Reaction Conditions	Operation in experiment
75.3%		12.02 g of iV-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxamide (compound of Formula II), 6.84 g of 5-fluoro-l,3-dihydro-2H-indol-2-one (compound of Formula III) and 230 mL of «-butanol were stirred at room temperature. Pyrrolidine (187 muL) was added and the suspension was heated to reflux. Complete dissolution of the materials was observed at 45 C. Once at reflux the reaction was monitored by TLC and after 1.5 h the formation of sunitinib base was complete. To the clear red reaction mixture a solution of 3.10 mL glacial acetic acid and 10 mL ?-butanol was added dropwise, while maintaining the mixture at reflux. The red clear solution was stirred for 30 minutes at reflux and cooled. At 41 C crystallization was observed and the mixture was cooled to 0-5 0C and stirred for Ih. The mixture was heated again to dissolution, which took place at 93 C, and then cooled. Crystallization was observed at 72C. The mixture was cooled to room temperature and stirred for 15 minutes. The thick orange suspension was filtered and the collected solid was washed with 2 x 24 mL of n-butanol. The solid was dried at 60 0C for 4 h under vacuum to give 15.64 g (75.3 % yield) of a light orange solid. [0030] Analytical data: IR (KBr): Characteristic peaks at (cm"1): 3452, 3169, 3045, 2991, 2978, 2874, 2810, 2768, 2706, 2100, 1672, 1651, 1620, 1614, 1589, 1576, 1539, 1495, 1477, 1446, 1402, 1396, 1377, 1340, 1325, 1300, 1290, 1279, 1257, 1230, 1196, 1165, 1144, 1115, 1099, 1059, 1040, 1024, 1007, 987, 972, 924, 914, 903, 883, 845, 837, 797, 750, 723, 698, 669, 658, 617, 588, 579, 534, 486, 440, 411. See Figure 1; HPLC: 99.44 % (% area); DSC (openpan) onset: 132.4 C.

Reference： [1]Patent: WO2010/41134,2010,A1 .Location in patent: Page/Page column 6-7

44
[ 56341-41-4 ]
[ 356068-86-5 ]
[ 342641-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	pyrrolidine; In ethanol; for 5h;Reflux;	To a solution of 6.63g (25 mmol) Lambda/-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1 H-pyrrole- 3-carboxamide (I) and 3.78g (25 mmol) 5-fluoroindolin-2-one (II) in ethanol (400 ml), 0.25 ml of pyrrolidine was added and mixture was refluxed for 5h.

Reference： [1]Patent: WO2010/49449,2010,A2 .Location in patent: Page/Page column 16; 17

45
[ 56341-41-4 ]
[ 97-67-6 ]
[ 356068-86-5 ]
sunitinib L-malate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%		To a solution of 1 .40 g (5.28 mmol) N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl- 1 H-pyrrole-3-carboxamide (I) and 0.76g (5.03 mmol) 5-fluoroindolin-2-one (II) in ethanol (140 ml), 0.023 ml of pyrrolidine was added and mixture was refluxed for 1 .5h. After that, 0.71 g of L-malic acid was added and mixture left to cool to room temperature and stirred for few hours until all precipitate was formed. Crystals were collected by filtration to give 2.07g (84 %) of the novel form, defined above as sunitinib malate form III. Melting point: 217-219C.An XRD of the resulting sunitinib L-malate Form III is shown in Figure 1 , and a DSC curve thereof is shown in Figure 2.

Reference： [1]Patent: WO2010/55082,2010,A2 .Location in patent: Page/Page column 17-18

46
2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one [ No CAS ]
[ 356068-86-5 ]
[ 1196883-66-5 ]

Yield	Reaction Conditions	Operation in experiment
48%	piperidine; In ethanol; at 20℃;	A mixture of N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxamide (250 mg, 0.94 mmol, 1.05 equiv), 2-amino-4-chloro-7-((4-methoxy-3,5- dimethylpyridin-2-yl)methyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (300 mg, 0.90 mmol), and piperidine (a drop) in EtOH (20 ml) was stirred for overnight at room temperature. The solids were collected by filtration and washed with 2x30 mL of EtOH, resulted in 250 mg (48%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 1.03 (6H, t), 2.19 (3H, s), 2.35 (3H, s), 2.46 (3H, s), 2.54 (3H, s), 2.57 (4H, m), 2.66 (2H, m), 3.49 (2H, d), 3.76 (3H, s), 5.06 (2H, s), 5.08 (2H, s), 6.50 (IH, s), 7.96 (IH, s), 8.06 (IH, s), 12.94 (IH, s). MS m/z: 581 [M+l] + .

Reference： [1]Patent: WO2009/139834,2009,A1 .Location in patent: Page/Page column 173

47
[ 356068-86-5 ]
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide citrate [ No CAS ]

Reference： [1]Patent: WO2011/33472,2011,A1

48
[ 356068-86-5 ]
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide p-toluenesulfonate [ No CAS ]

Reference： [1]Patent: WO2011/33472,2011,A1

49
[ 356068-86-5 ]
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide sulfate [ No CAS ]

Reference： [1]Patent: WO2011/33472,2011,A1

50
[ 356068-86-5 ]
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, acetate [ No CAS ]

Reference： [1]Patent: WO2011/33472,2011,A1
[2]Patent: WO2012/58780,2012,A1

51
[ 2199-51-1 ]
[ 356068-86-5 ]

Reference： [1]Patent: US2011/92717,2011,A1
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3062 - 3065
[3]Research on Chemical Intermediates,2015,vol. 41,p. 8941 - 8954
[4]Organic and Biomolecular Chemistry,2016,vol. 14,p. 4829 - 4841
[5]Patent: CN103992308,2016,B

52
[ 56341-41-4 ]
[ 356068-86-5 ]
[ 341031-54-7 ]

Reference： [1]Patent: US2011/92717,2011,A1
[2]Patent: US2013/190512,2013,A1

53
[ 1243148-18-6 ]
[ 356068-86-5 ]
[ 1310011-59-6 ]

Yield	Reaction Conditions	Operation in experiment
	With pyrrolidine; In methanol; for 2h;Reflux;	General Procedure: To a stirring solution of 9a (4.95 g, 30 mmol) in methanol (80 mL) was added dropwise 85% hydrazine hydrate (3.53 mL, 60 mmol) over a period of 30 min at room temperature. The reaction mixture was heated to refluxing and stirred for 1 h, and then cooled to room temperature and filtrated. The solid obtained was washed with methanol and dried in vacuo to give 10a (4.85 g, 90.2%) as a yellow solid, mp: 183-185 C (183-185 C20). A mixture of 10a (3.58 g, 20 mmol) and sodium ethoxide (6.80 g, 100 mmol) in absolute ethanol (100 mL) was heated to refluxing and stirred for 5 h, and then cooled to room temperature. To the mixture was added slowly ice-water (100 mL), adjusted to pH 1 with 4 N HCl and filtrated. The solid obtained was recrystallized from water to afford 11a (2.43 g, 80.4%) as an off-white solid, mp: 135-137 C (135-137 C20). A suspension of KF (23.24 g, 400 mmol) and Al2O3 (40.80 g, 400 mmol) in water was stirred for 0.5 h at room temperature, and then concentrated under reduced pressure, dried in vacuo to prepare KF-Al2O3(64.04 g, 100%). A mixture of 11a (6.04 g, 40 mmol), 1-chloro-3-dimethylaminopropane hydrochloride (5.53 g, 35 mmol) and KF-Al2O3 (19.21 g, 120 mmol) in anhydrous acetonitrile (150 mL) was heated to refluxing and stirred for 10 h, and then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel) eluted with petroleum ether and ethyl acetate (v:v = 1:1) to afford 12a (4.73 g, 50.1%) as a brown oil. A mixture of 12a (0.73 g, 3.1 mmol), 8a (0.58 g, 3 mmol) and pyrrolidine (0.3 mL) in methanol (15 mL) was heated to refluxing and stirred for 2 h, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel) eluted with methanol and dichloromethane (v:v = 1:40) to yield the free base of 1a, which was dissolved in absolute diethyl ether, and then pumped dried hydrochloride gas at 0-5 C for 30 min. The reaction mixture was allowed to stir for another 30 min at room temperature, the resulting solid was collected by suction, and dried in vacuo to give the title compound 1a (0.62 g, 46.3%, for two steps) as a yellow solid, mp: 120-122 C.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3062 - 3065

54
[ 1243148-18-6 ]
[ 356068-86-5 ]
C₂₇H₃₈FN₅O₂*2ClH [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3062 - 3065

55
[ 1309935-13-4 ]
[ 356068-86-5 ]
[ 1310011-60-9 ]

Yield	Reaction Conditions	Operation in experiment
	With pyrrolidine; In methanol; for 2h;Reflux;	General Procedure: To a stirring solution of 9a (4.95 g, 30 mmol) in methanol (80 mL) was added dropwise 85% hydrazine hydrate (3.53 mL, 60 mmol) over a period of 30 min at room temperature. The reaction mixture was heated to refluxing and stirred for 1 h, and then cooled to room temperature and filtrated. The solid obtained was washed with methanol and dried in vacuo to give 10a (4.85 g, 90.2%) as a yellow solid, mp: 183-185 C (183-185 C20). A mixture of 10a (3.58 g, 20 mmol) and sodium ethoxide (6.80 g, 100 mmol) in absolute ethanol (100 mL) was heated to refluxing and stirred for 5 h, and then cooled to room temperature. To the mixture was added slowly ice-water (100 mL), adjusted to pH 1 with 4 N HCl and filtrated. The solid obtained was recrystallized from water to afford 11a (2.43 g, 80.4%) as an off-white solid, mp: 135-137 C (135-137 C20). A suspension of KF (23.24 g, 400 mmol) and Al2O3 (40.80 g, 400 mmol) in water was stirred for 0.5 h at room temperature, and then concentrated under reduced pressure, dried in vacuo to prepare KF-Al2O3(64.04 g, 100%). A mixture of 11a (6.04 g, 40 mmol), 1-chloro-3-dimethylaminopropane hydrochloride (5.53 g, 35 mmol) and KF-Al2O3 (19.21 g, 120 mmol) in anhydrous acetonitrile (150 mL) was heated to refluxing and stirred for 10 h, and then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel) eluted with petroleum ether and ethyl acetate (v:v = 1:1) to afford 12a (4.73 g, 50.1%) as a brown oil. A mixture of 12a (0.73 g, 3.1 mmol), 8a (0.58 g, 3 mmol) and pyrrolidine (0.3 mL) in methanol (15 mL) was heated to refluxing and stirred for 2 h, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel) eluted with methanol and dichloromethane (v:v = 1:40) to yield the free base of 1a, which was dissolved in absolute diethyl ether, and then pumped dried hydrochloride gas at 0-5 C for 30 min. The reaction mixture was allowed to stir for another 30 min at room temperature, the resulting solid was collected by suction, and dried in vacuo to give the title compound 1a (0.62 g, 46.3%, for two steps) as a yellow solid, mp: 120-122 C.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3062 - 3065

56
[ 1309935-13-4 ]
[ 356068-86-5 ]
C₂₇H₃₈ClN₅O₂*2ClH [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3062 - 3065

57
[ 56341-41-4 ]
[ 2689-91-0 ]
[ 356068-86-5 ]
[ 341031-54-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	In methanol; acetonitrile; at 25 - 30℃; for 3h;	Into 20ml of acetonitrile : methanol (3:2), diammonium malate (1.9g, 1.5 mol equivalent), N-[2-(diemylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxam^ (2g, 1 mol equivalent) and 5-fluoro-2-oxindole (1.13g, 1 mol equivalent) were added at 25-30C to obtain a clear solution. After 3 hours stirring at 25-30C, an orange solid progressively precipitated out of the solution. The orange solid was isolated by filtration, washed with methanol (10ml) and dried under vacuum at 60-65C for 3-4 hours.Yield = 3g (75%)Chemical Purity (HPLC) > 98.51%This solid was further purified by dissolving in butanol : water (4:1, 20 volumes) at 60- 65C, cooling to 25-30C, and filtering and drying the precipitated sunitinib malate.Yield = 50%Chemical Purity (HPLC) > 99.49%Polymorphic Purity (XRPD) > 99% (other polymorphic forms below detection limit)The structure of sunitinib malate was confirmed by NMR and HPLC retention time with standard sample. XRPD analysis indicated polymorphic form I as shown in Figure 1. Sumtinib malate polymorphic form I was obtained before and after recrystallisation.

Reference： [1]Patent: WO2011/104555,2011,A2 .Location in patent: Page/Page column 25

58
[ 56341-41-4 ]
di-(diisopropyl ammonium) L-malate [ No CAS ]
[ 356068-86-5 ]
[ 341031-54-7 ]

Yield	Reaction Conditions	Operation in experiment
72.5%	In methanol; acetonitrile; at 25 - 30℃; for 3h;	Into 20ml of acetonitrile : methanol (3:2), di-diisopropyl ammonium malate (1.9g, 1.5 mol equivalent), N-[2-(<diethylamino)emyl]-5-formyl-2,4-dimemyl-lH-pyrrole-3-carboxami (2g, 1 mol equivalent) and 5-fluoro-2-oxindole (1.13g, 1 mol equivalent) were added at 25- 30C to obtain a clear solution. After stirring for 3 hours at 25-30C, a yellow solid progressively precipitated out of the solution. The yellow solid was isolated by filtration, washed with methanol (10ml) and dried in a vacuum oven at 60-65C for 3-4 hours.Yield = 2.9g (72.5%)Chemical Purity (HPLC) > 97.84%This solid was further purified by dissolving in butanol : water (4:1, 20 volumes) at 60- 65C, cooling to 25-30C, and filtering and drying the precipitated sunitinib malate.Yield = 70%Chemical Purity (HPLC) > 98.77%Polymorphic Purity (XRPD) > 99% (other polymorphic forms below detection limit)The structure of sunitinib malate was confirmed by NMR and HPLC retention time with standard sample. XRPD analysis indicated polymorphic form I as shown in Figure 1. Sunitinib malate polymorphic form I was obtained before and after recrystallisation.

Reference： [1]Patent: WO2011/104555,2011,A2 .Location in patent: Page/Page column 26

59
[ 56341-41-4 ]
dipyrrolidine L-malate [ No CAS ]
[ 356068-86-5 ]
[ 341031-54-7 ]

Yield	Reaction Conditions	Operation in experiment
32%	In methanol; acetonitrile; at 25 - 30℃; for 3h;	Into 20ml of acetonitrile : methanol (3:2), dipyrrolidine malate (3.1g, 1.5 mol equivalent), N-[2-(diethylamino)ediyl]-5-foimyl-2,4-dimemyl-lH-pyrrole-3-carboxamide (2g, 1 mol equivalent) and 5-fiuoro-2-oxindole (l-13g, 1 mol equivalent) were added at 25-30C to obtain a clear solution. After 3 hours stirring at 25-30C, a yellow solid progressively precipitated out of the solution. The yellow solid was isolated by filtration, washed with methanol (10ml) and dried under vacuum at 60-65C for 3-4 hours.Yield = 1.3g (32%)Chemical Purity (HPLC) > 97.87%Polymorphic Purity (XRPD) > 95%The structure of sunitinib malate was confirmed by NMR and HPLC retention time with standard sample. XRPD analysis indicated polymorphic form I as shown in Figure 1.

Reference： [1]Patent: WO2011/104555,2011,A2 .Location in patent: Page/Page column 26-27

60
[ 56341-41-4 ]
di-(n-propyl ammonium) L-malate [ No CAS ]
[ 356068-86-5 ]
[ 341031-54-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	In methanol; acetonitrile; at 25 - 30℃; for 3h;	Into 20ml of acetonitrile : methanol (3:2), di-n-propyl ammonium malate (2.85g, 1.5 mol equivalent), N-[2-(diemylammo)emyl]-5-formyl-2,4-dimemyl-lH-pyrrole-3-carboxami (2g, 1 mol equivalent) and 5-fluoro-2-oxindole (1.13g, 1 mol equivalent) were added at 25- 30C to obtain a clear solution. After 3 hours stirring at 25-30C, a yellow solid progressively precipitated out of the solution. The yellow solid was isolated by filtration, washed with methanol (10ml) and dried under vacuum at 60-65C for 3-4 hours.Yield = 3g (75%)Chemical Purity (HPLC) > 98.39%Polymorphic Purity (XRPD) > 95%The structure of sunitinib malate was confirmed by NMR and HPLC retention time with standard sample. XRPD analysis indicated polymorphic form I as shown in Figure 1.

Reference： [1]Patent: WO2011/104555,2011,A2 .Location in patent: Page/Page column 27

61
[ 56341-41-4 ]
2-(N,N-diethylamino)ethyl ammonium di(L-malate) [ No CAS ]
[ 356068-86-5 ]
[ 341031-54-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	In methanol; acetonitrile; at 25 - 30℃; for 3h;	2-( ,N-Diemylamino)ethyl ammonium dimalate (4.3g, 1.5 mol equivalent), N-[2- (diemylammo)emyl]-5-formyl-2,4-dimemyl-lH-pyrrole-3-carboxamide (2g, 1 mol equivalent) and 5-fiuoro-2-oxindole (1.13g, 1 mol equivalent) were added to 20ml of acetonitrile : methanol (3:2) at 25-30C to obtain a clear solution. After 3 hours stirring at 25-30C, a yellow solid progressively precipitated out of the solution. The yellow solid was isolated by filtration, washed with methanol (10ml) and dried under vacuum at 55-60C for 3-4 hours.Yield = 3.2g (80%)Chemical Purity (HPLC) > 98%This solid was further purified by dissolving in butanol : water (4:1, 20 volumes) at 60- 65C, cooling to 25-30C, and filtering and drying the precipitated sunitinib malate.Yield = 80%Chemical Purity (HPLC) > 99.7%Polymorphic Purity (XRPD) > 99% (other polymorphic forms below detection limit) The structure of sunitinib malate was confirmed by NMR and HPLC retention time with standard sample. XRPD analysis indicated polymorphic form I as shown in Figure 1. Sunitinib malate polymorphic form I was obtained before and after recrystallisation.

Reference： [1]Patent: WO2011/104555,2011,A2 .Location in patent: Page/Page column 23

62
[ 56341-41-4 ]
[ 1332307-07-9 ]
[ 356068-86-5 ]
[ 341031-54-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	In methanol; acetonitrile; at 25 - 30℃; for 3h;	Into 20ml of acetonitrile : methanol (3:2), 2-(N,N-cHethylamino)ethyl ammonium malate (2.83g, 1.5 mol equivalent), N-[2-(diemylamino)emyl]-5-formyl-2,4-dimemyl-lH-pyrrole-3- carboxamide (2g, 1 mol equivalent) and 5-fiuoro-2-oxindole (1.13g, 1 mol equivalent) were added at 25-30C to obtain a clear solution within 15 minutes. After 3 hours stirring at 25- 30C, a yellow solid progressively precipitated out of the solution. The yellow solid was isolated by filtration, washed with methanol (10ml) and dried under vacuum at 55-60C for 3-4 hours.Yield = 2.9g (72%)Chemical Purity (HPLC) > 98.77%This solid was further purified by dissolving in butanol : water (4:1, 20 volumes) at 60- 65C, cooling to 25-30C, and filtering and drying the precipitated sunitinib malate.Yield = 80%Chemical Purity (HPLC) > 99.76%Polymorphic Purity (XRPD) > 99% (other polymorphic forms below detection limit)The structure of sumtinib malate was confirmed by NMR and HPLC retention time with standard sample. XRPD analysis indicated polymorphic form I as shown in Figure 1. Sunitinib malate polymorphic form I was obtained before and after recrystallisation.

Reference： [1]Patent: WO2011/104555,2011,A2 .Location in patent: Page/Page column 24

63
[ 56341-41-4 ]
[ 97-67-6 ]
[ 356068-86-5 ]
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide L-malate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%		A mixture of N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxamide (1.0 g) and ethanol (12 ml) were stirred. 5-Fluoro-l,3-dihydro-2H-indol-2- one (0.57 g) and pyrrolidine (0.013 g) were added and the reaction mixture was stirred at 78C (internal temperature) for 1.5 hours. L-Malic acid (0.37 g) was added to the reaction mixture and the reaction mixture was stirred at 78C (internal temperature) for 1 hour. The reaction mixture was cooled to 20C to 25 C, filtered under vacuum, washed with ethanol (10 ml) and dried under vacuum at 50C for 10 hours to 12 hours to obtain the title compound.Yield: 80%

Reference： [1]Patent: WO2011/114246,2011,A1 .Location in patent: Page/Page column 4

64
[ 356068-86-5 ]
[ 341031-54-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium hydrogensulfite / ethanol; water / 10 - 20 °C 2: acetonitrile; methanol / 3 h / 25 - 30 °C
	Multi-step reaction with 2 steps 1.1: 1,1,1,3,3,3-hexamethyl-disilazane / ammonium sulfate / 5 h / Reflux 1.2: 29.3 h / Reflux 2.1: methanol / 8 h / 25 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: VIATRIS INC - WO2011/128699, 2011, A2
[2]Current Patent Assignee: SCINOPHARM TAIWAN, LTD. - WO2012/58780, 2012, A1

65
[ 356068-86-5 ]
[ 1338703-87-9 ]

Yield	Reaction Conditions	Operation in experiment
79%	With sodium hydrogensulfite; In ethanol; water; at 10 - 20℃;	Example 2: Preparation of the sodium salt of pyrrole derivative (I)N-[2-(Oiethylarrrbo)ethyl]-5-formyl-2,4-(iimethyl-lH-pyrrole-3-carboxai^ (2g, 0.0075 mol) was added to ethanol (30ml, 15vol) under stirring and cooled to 10-15C. A solution of sodium bisulphite (2.1g, 0.0202mol) in water (4ml, 2vol) was added dropwise to the above solution over a time period of 15 to 20 minutes, whilst mamtaining the temperature below 20C. The temperature of the reaction mixture was reduced and maintained at about 10C and the reaction mixture was stirred for a further 1 to 2 hours. The resulting precipitate was filtered and washed with ethanol (10ml, 5vol) followed by water (4ml, 2vol). The solid obtained was then dried in a vacuum oven at 40C to obtain the title compound. Yield = 2.1g (79%)IR (KBr, cm"1): 3376 ( -H str.), 3298 (O-H str.) 2976 & 2943 (ali C-H str.), 1609 (C-O str.), 1533, 1511, 1438, 1381, 1341, 1254, 1171, 1061, 1025, 980, etc.'H-NMR (DMSO-d6): 2.04 (s, 3H, -CH3), 2.28 (s, 3H, -CH3), 2.50 (m, 6H, 2 x -CH2-CH3), 3.34 (m, 8H, 4 x -CH2-), 4.87 (d, 1H, >CH-OH), 5.52 (d, 1H, -OH, D20 exchangeable), 6.92 (s, 1H, >NH, D20 exchangeable), 10.07 (bs, 1H, >NH, D20 exchangeable).

Reference： [1]Patent: WO2011/128699,2011,A2 .Location in patent: Page/Page column 31

66
[ 134682-54-5 ]
[ 356068-86-5 ]
[ 1350702-94-1 ]

Yield	Reaction Conditions	Operation in experiment
62%	With piperidine; In methanol; for 5h;Reflux;	General procedure: Piperidine (0.08 mL) was added to methanol (25 mL) dissolved in substituted aldehydes 5-7 (0.18 mmol) and starting 2-indolinone derivatives 8-11 (0.18 mmol) which were prepared as described previously refPreviewPlaceHolder[6], refPreviewPlaceHolder[21], refPreviewPlaceHolder[22], refPreviewPlaceHolder[23], refPreviewPlaceHolder[24] and refPreviewPlaceHolder[25]. The mixture was refluxed for 5 h. For the targeted compounds 12-21 and 28-36, the mixture was evaporated to remove the solvent and the residue was purified by column chromatography (CH2Cl2/MeOH 100:1-10:1). For the targeted compounds 22-27, ethyl ether (15 mL) was added to the residue and the yellow precipitate was collected by filtration. The obtained precipitate was subjected to the hydrogen chloride saturated methanol to afford it as hydrochloride derivative. All the targeted compounds 12-36 show moderate to good yields under this reaction condition with the yields of 60-92%.

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 5970 - 5977

67
[ 193354-13-1 ]
[ 356068-86-5 ]
[ 1372783-13-5 ]

Yield	Reaction Conditions	Operation in experiment
76%	With piperidine; In ethanol; at 90.0℃; for 5.0h;	5-Iodoindoline-2-one 2 (130 mg, 0.5 mmol) and pyrrole 3 (160 mg, 0.6mmol) were dissolved at 1.0 mL of ethanol and two drops of piperidine were added. The mixture was heated under reflux for 5 hours and then cooled on ice overnight. The precipitate was separated by filtration, washed with a small amount of ethanol and dried under vacuum to give 4 (193 mg) as a brown solid in 76% yield. mp: 258-261C, HNMR (d, ppm, DMSO-d): 0.97 (t, 6H, N(CH2CH3)2); 2.43 (s, 3H, CH3); 2.44 (s, 3H, CH3); 2.49 (m, 6H, 3xCH2); 3.29 (m, 2H, NH-CH2); 6.72 (d, 1H, 7-H); 7.41 (s, 1H, 4-H); 7.42 (d, 1H, 6-H); 7.75 (s, 1H, NH-CH2); 8.22 (s, 1H, Hvinyl); 10.97 (s, 1H, NHindole); 13.62 (s, 1H, NHpyrrole); ESI-MS (ES+): m/z=507 (M+H)+

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2850 - 2855

68
[ 356068-86-5 ]
[ 557795-19-4 ]

Reference： [1]Patent: WO2012/59941,2012,A1
[2]Patent: WO2012/59941,2012,A1

69
[ 97-67-6 ]
[ 1374685-40-1 ]
[ 356068-86-5 ]
[ 341031-54-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: 5-fluoro-1-(trimethylsilyl)-2-(trimethylsilyloxy)-1H-indole; N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide In acetonitrile for 13h; Reflux; Stage #2: (S)-Malic acid In methanol; acetonitrile at 20℃; for 22h;	11 13 (3.0 g), MeCN (35 mL) and TMSOTf (0.38 mL, 0.2 eq.) were charged into a flask with a mechanical stirrer and a thermometer at ambient temperature. The heterogeneous mixture was heated to reflux, 20 (prepared as in example 5; 1.0 eq.) in MeCN (35 mL) was dropped at reflux over 1 h, and the reaction mixture was further stirred at reflux over period of 12 h. The mixture was cooled down to r.t., malic acid (3.03 g, 2.0 eq.) in MeOH (23 mL) was added into above reaction mixture. The reaction mixture turned clear. After 2 h, some solid appeared; after 22 h, filtered, washed with MeOH (10 ml). Filter cake was dried in vacuo to give 4.2 g of crude sunitinib malate with 97.3% purity by HPLC analysis in 70.0% yield
	Stage #1: 5-fluoro-1-(trimethylsilyl)-2-(trimethylsilyloxy)-1H-indole; N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide With trimethylsilyl trifluoromethanesulfonate In acetonitrile for 13h; Reflux; Stage #2: (S)-Malic acid In methanol for 24h;	11 Example 11 Direct Isolation of Sunitinib Malate From Coupling Reaction 13 (3.0 g), MeCN (35 mL) and TMSOTf (0.38 mL, 0.2 eq.) were charged into a flask with a mechanical stirrer and a thermometer at ambient temperature. The heterogeneous mixture was heated to reflux, 20 (prepared as in example 5; 1.0 eq.) in MeCN (35 mL) was dropped at reflux over 1 h, and the reaction mixture was further stirred at reflux over period of 12 h. The mixture was cooled down to r.t., malic acid (3.03 g, 2.0 eq.) in MeOH (23 mL) was added into above reaction mixture. The reaction mixture turned clear. After 2 h, some solid appeared; after 22 h, filtered, washed with MeOH (10 ml). Filter cake was dried in vacuo to give 4.2 g of crude sunitinib malate with 97.3% purity by HPLC analysis in 70.0% yield.
	Stage #1: 5-fluoro-1-(trimethylsilyl)-2-(trimethylsilyloxy)-1H-indole; N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide With trimethylsilyl trifluoromethanesulfonate In acetonitrile for 9.5h; Reflux; Stage #2: (S)-Malic acid In methanol for 24h;	12 Example 12 Direct Isolation of Sunitinib as a MsOH, Tartaric Acid, Frifluoroacetic Acid, CSA, AcOH, BzOH, HCl, or HBr Salt From the Coupling Reaction 13 (5.3 g), MeCN (60 mL) and TMSOTf (1.01 mL, 0.3 eq.) were charged into a flask with a mechanical stirrer and a thermometer at ambient temperature. The heterogeneous mixture was heated to reflux, 20 (prepared as in example 5; 1.0 eq.) in MeCN (60 mL) was dropped at reflux over 1.5 h, and the reaction mixture was further stirred at reflux over period of 8 h. The mixture was divided up and treated as follows: A 40 mL sample from a similar reaction as above was concentrated under vacuum and MeOH (70 mL) and malic acid (1.59 g, 2 eq.) were added at r.t. The reaction mixture turned clear soon. After 24 h the mixture was concentrated, and n-BuOH (30 mL) was added, and after 16 h the mixture was filtered. The filter cake was washed with MeOH and dried in vacuo to give 2.29 g of crude sunitinib malate with 98.9% purity by HPLC analysis in 71.8% yield.

Reference： [1]Current Patent Assignee: SCINOPHARM TAIWAN, LTD. - WO2012/58780, 2012, A1 Location in patent: Page/Page column 30
[2]Current Patent Assignee: SCINOPHARM TAIWAN, LTD. - US2013/190512, 2013, A1 Location in patent: Paragraph 0072
[3]Current Patent Assignee: SCINOPHARM TAIWAN, LTD. - US2013/190512, 2013, A1 Location in patent: Paragraph 0073; 0081

70
[ 1374685-40-1 ]
[ 356068-86-5 ]
[ 557795-19-4 ]

Yield	Reaction Conditions	Operation in experiment
	trimethylsilyl trifluoromethanesulfonate; In N,N-dimethyl-formamide; acetonitrile;Reflux;Product distribution / selectivity;	Under N2, 5-fluoroindolin-2-one (8; 45.6 g, 0.301 mol, 1.0 eq.), (NH )2S04 (3.96 g, 0.030 mol, 0.1 eq.) and HMDS (437.2 g, 567.8 mL, 2.709 mol, 9.0 eq.) were charged into a flask with a magnetic stirrer and a thermometer at ambient temperature. The mixture was heated with stirring at reflux until the in-process control criterion was passed (7 to 8 h). The mixture was concentrated in vacuo (relative vacuum NLT 0.095 MPa) at about 60C until no further distillate was collected. The thus obtained crude 5-fluoro-l -(trimethylsilyl)-2-(trimethylsilyloxy)- l H-indole (20) was obtained and MeCN (1685 g, 2160 mL, 27 P w.r.t. N-(2- (diethylamino)ethyl)-5-formyl-2,4-dimethyl-l H-pyrrole-3-carboxamide (13)) were charged into a 5 L flask with a mechanical stirrer and a thermometer at ambient temperature, the mixture was stirred, and TMSOTf (13.38 g, 10.8 mL, 0.060 mol, 0.2 eq.) was added dropwise into the above mixture. The heterogeneous mixture was heated to reflux, and then a solution of 13 (80.0 g, 0.301 mol, 1.0 eq) in DMF (240 mL, 3 P w.r.t. 13) that was prepared at about 60 C in advance was added dropwise to the refluxing mixture over a 3 to 4 h period. The reaction mixture was further stirred at reflux until the in-process control criterion was passed (1 to 2 h). The mixture was cooled down to about 25C, and poured into aqueous saturated NaHC03 (4 L, 50 P w.r.t. 13) at ambient temperature. The mixture was stirred at ambient temperature for 30 min and at about 0C for 2 h, and vacuum filtered at ambient temperature. The filter cake was slurried with water (4 L, 50 P w.r.t. 13) for 10-15 min at ambient temperature, vacuum filtered at ambient temperature, and the filter cake was slurried with EtOH (315g, 400 mL, 5 P w.r.t. 13) for about 5 min at ambient temperature, vacuum filtered at ambient temperature, and dried in vacuo (relative vacuum NLT 0.095 MPa) at about 40C for 30 to 40 h to give 99.8 g of crude sunitinib with 99.2 % purity by HPLC analysis and 0.37 % by LOD in about 82.4 % yield, m.p. 214 ~ 216.0 C, NMR (DMSO-d6) delta: 0.96-1.01 (t, 6H, J=7.2 Hz, 2CH3), 2.43 (s. 3H, CH3), 2.45 (s. 3Eta, CH3), 2.48-2.58 (m, 6Eta, J=7.2 Hz, 6.9 Hz, 3CH2), 3.28-3.33 (t, 2H, J= 6.9 Hz, CH2), 6.85 (dd, 1 H, J=2.1 Hz, 9.4 Hz, 2.7 Hz CH), 6.98 (dd, 1 H, J=2.1 Hz, 9.4 Hz, 2.7 Hz CH), 7.50-7.54 (1 H, N/ ), 7.68 (s, 1 H, CH), 7.69-7.73 (m, 1 Eta, J=2.1 Hz, 9.4 Hz, CH), 13.62 (s, 1 Eta, NH), 13C NMR (300 MHz, DMSO-d6) delta: 1 1 .25, 12.53, 13.93, 37.51 , 47.15, 52.28, 106.58, 1 10.63, 1 1 5.33, 121 .25, 125.40, 126.36, 127.79, 130.80, 135.1 1 , 137.15, 157.34, 160.44, 165.16, 170.13
	With trimethylsilyl trifluoromethanesulfonate; In N,N-dimethyl-formamide; acetonitrile;Reflux;	Under N2, 5-fluoroindolin-2-one (8; 45.6 g, 0.301 mol, 1.0 eq.), (NH4)2SO4 (3.96 g, 0.030 mol, 0.1 eq.) and HMDS (437.2 g, 567.8 mL, 2.709 mol, 9.0 eq.) were charged into a flask with a magnetic stirrer and a thermometer at ambient temperature. The mixture was heated with stirring at reflux until the in-process control criterion was passed (7 to 8 h). The mixture was concentrated in vacuo (relative vacuum NLT 0.095 MPa) at about 60 C. until no further distillate was collected. The thus obtained crude 5-fluoro-1-(trimethylsilyl)-2-(trimethylsilyloxy)-1H-indole (20) was obtained and MeCN (1685 g, 2160 mL, 27 P w.r.t. N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (13)) were charged into a 5 L flask with a mechanical stirrer and a thermometer at ambient temperature, the mixture was stirred, and TMSOTf (13.38 g, 10.8 mL, 0.060 mol, 0.2 eq.) was added dropwise into the above mixture. The heterogeneous mixture was heated to reflux, and then a solution of 13 (80.0 g, 0.301 mol, 1.0 eq) in DMF (240 mL, 3 P w.r.t. 13) that was prepared at about 60 C. in advance was added dropwise to the refluxing mixture over a 3 to 4 h period. The reaction mixture was further stirred at reflux until the in-process control criterion was passed (1 to 2 h). The mixture was cooled down to about 25 C., and poured into aqueous saturated NaHCO3 (4 L, 50 P w.r.t. 13) at ambient temperature.

Reference： [1]Patent: WO2012/58780,2012,A1 .Location in patent: Page/Page column 15; 22; 24-25
[2]Patent: US2013/190512,2013,A1 .Location in patent: Paragraph 0058; 0059; 0066; 0067; 0068; 0069; 0070

71
[ 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

72
[ 837392-64-0 ]
[ 356068-86-5 ]
(Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-3-ylidene)methyl)-1H-pyrrole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
218 mg	With piperidine; In ethanol; at 80℃; for 1h;	Reference Example 26 Production of (Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-3-ylidene)methyl)-1H-pyrrole-3-carboxamide To a solution of <strong>[837392-64-0]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one</strong> (195 mg, 0.75 mmol) in EtOH (3 ml) was added N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (200 mg, 0.76 mmol) and piperidine (82 muL, 0.83 mmol). The mixture was stirred at 80 C. for 1 hour. After cooled down to room temperature, the reaction mixture was concentrated, filtrated, and washed with EtOH to give (Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-3-ylidene)methyl)-1H-pyrrole-3-carboxamide (218 mg) as yellow solid. MS m/z 507.6 (M+H)

Reference： [1]Patent: US2014/275076,2014,A1 .Location in patent: Paragraph 0384; 0385; 0386

73
[ 1190314-85-2 ]
[ 356068-86-5 ]
C₂₁H₂₆FN₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With piperidine; In ethanol; at 20.0℃; for 3.0h;Inert atmosphere;	General procedure: A solution of 1-3, 7a,b, 11 (1mmol) and 12a-c (0.7mmol) in anhydrous ethanol (10mL) and piperidine (6 drops) was stirred at room temperature under atmosphere of nitrogen for 2-3 h. The yellow precipitate was collected by suction and washed with ethanol and then dried under vacuum to afford the targeted compounds 13a1-11, 13b1-8, 13c1-8 (50-70%) as yellow solids.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 2782 - 2787

74
[ 183208-34-6 ]
[ 356068-86-5 ]
(Z)-N-{2-[diethylamino]ethyl}-5-((5-bromo-2-oxo-1H-pyrrolo[2,3-b]pyridin-3(2H)-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With piperidine; In ethanol; at 20℃; for 3h;Inert atmosphere;	General procedure: A solution of 1-3, 7a,b, 11 (1mmol) and 12a-c (0.7mmol) in anhydrous ethanol (10mL) and piperidine (6 drops) was stirred at room temperature under atmosphere of nitrogen for 2-3 h. The yellow precipitate was collected by suction and washed with ethanol and then dried under vacuum to afford the targeted compounds 13a1-11, 13b1-8, 13c1-8 (50-70%) as yellow solids.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 2782 - 2787

75
[ 2436-79-5 ]
[ 356068-86-5 ]

Reference： [1]Research on Chemical Intermediates,2015,vol. 41,p. 8941 - 8954
[2]Patent: CN103992308,2016,B

76
[ 5442-91-1 ]
[ 356068-86-5 ]

Reference： [1]Research on Chemical Intermediates,2015,vol. 41,p. 8941 - 8954
[2]Patent: CN103992308,2016,B

77
[ 590424-04-7 ]
[ 356068-86-5 ]

Reference： [1]Patent: CN106588888,2017,A

78
[ 5346-38-3 ]
[ 65435-04-3 ]
[ 356068-86-5 ]
(Z)-N-[2-(diethylamino)ethyl]-2,4-dimethyl-5-({2-oxo-5-[2-(pyridin-2-yl)thiazol-4-yl]indolin-3-ylidene}methyl)-1H-pyrrole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The titled compound can be produced by using the same procedure as Production example 1. Dimethylformamide is added to 5-(2-chloroacetyl)indolin-2-one and <strong>[5346-38-3]pyridine-2-carbothioamide</strong>, and then the mixture is heat-stirred at 80 C. After 4 hours, the mixture is cooled to 60 C., and then N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide dissolved in dimethylformamide, followed by pyrrolidine are added. After 2 hours, acetonitrile is added dropwise over 30 minutes. After stirring at the same temperature for 30 minutes, the mixture is cooled to 20 C. over 3 hours. The precipitated crystal is filtered, and then the crude crystal can be washed with acetonitrile and dried under reduced pressure at 45 C. to yield a crudely purified product of the titled compound.

Reference： [1]Patent: US2018/230141,2018,A1 .Location in patent: Paragraph 0180

79
[ 61394-50-1 ]
[ 356068-86-5 ]
[ 1126899-86-2 ]

Yield	Reaction Conditions	Operation in experiment
55%	With pyrrolidine In ethanol for 3h; Reflux;	4.3.42. General procedure for the coupling of oxindoles to formyl pyrrole 53 General procedure: The relevant oxindole (1.0 equiv.), formyl pyrrole 53 (1.05 equiv.) and pyrrolidine (2.0 equiv.) were combined in EtOH (10 mL/mmol) and heated to reflux for 3 h. The reaction was cooled to RT and the resultant precipitate collected by filtration and washed with cold EtOH. Additional purification was performed on the filtrand if necessary. If no precipitate formed the solvent was removed in vacuo and further purification performed.

Reference： [1]Backos, Donald S.; Casalvieri, Kimberly A.; Jordan, Craig T.; Matheson, Christopher J.; Minhajuddin, Mohammed; Reigan, Philip [European Journal of Medicinal Chemistry, 2020, vol. 197]

80
[ 56341-39-0 ]
[ 356068-86-5 ]
(Z)-N-(2-(diethylamino)ethyl)-5-((6-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With pyrrolidine; In ethanol; for 3h;Reflux;	General procedure: The relevant oxindole (1.0 equiv.), formyl pyrrole 53 (1.05 equiv.) and pyrrolidine (2.0 equiv.) were combined in EtOH (10 mL/mmol) and heated to reflux for 3 h. The reaction was cooled to RT and the resultant precipitate collected by filtration and washed with cold EtOH. Additional purification was performed on the filtrand if necessary. If no precipitate formed the solvent was removed in vacuo and further purification performed.

Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 197

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Precautionary Statements-General
Code	Phrase
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Prevention
Code	Phrase
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P222	Do not allow contact with air.
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P233	Keep container tightly closed.
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P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
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P270	Do not eat, drink or smoke when using this product.
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P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
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P285	In case of inadequate ventilation wear respiratory protection.
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Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
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P320
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P321
P322
P330	Rinse mouth.
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P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
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P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
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P372	Explosion risk in case of fire.
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P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
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P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
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.
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Storage
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P401
P402	Store in a dry place.
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P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
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P501	Dispose of contents/container to ...
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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
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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
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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. 356068-86-5 ] {[proInfo.proName]}

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[ 356068-86-5 ] Synthesis Path-Upstream 1~15

[ 356068-86-5 ] Synthesis Path-Downstream 1~80

Related Functional Groups of [ 356068-86-5 ]

Aldehydes

Amides

Amines

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Pyrroles

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[ 356068-86-5 ]

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[ 356068-86-5 ]