[ CAS No. 669050-69-5 ] {[proInfo.proName]}

Name: 669050-69-5|1H-Indazole-6-carbaldehyde|95%
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SKU: A578415
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Quality Control of [ 669050-69-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 669050-69-5 ]

CAS No. :	669050-69-5	MDL No. :	MFCD06738282
Formula :	C₈H₆N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JTWYTTXTJFDYAG-UHFFFAOYSA-N
M.W :	146.15	Pubchem ID :	18538368
Synonyms :

Calculated chemistry of [ 669050-69-5 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	41.48
TPSA :	45.75 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.99 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.58
Log Po/w (XLOGP3) :	1.69
Log Po/w (WLOGP) :	1.38
Log Po/w (MLOGP) :	0.49
Log Po/w (SILICOS-IT) :	2.17
Consensus Log Po/w :	1.26

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.35
Solubility :	0.652 mg/ml ; 0.00446 mol/l
Class :	Soluble
Log S (Ali) :	-2.27
Solubility :	0.793 mg/ml ; 0.00542 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.84
Solubility :	0.213 mg/ml ; 0.00146 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.16

Safety of [ 669050-69-5 ]

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

Application In Synthesis of [ 669050-69-5 ]

* 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 [ 669050-69-5 ]
Downstream synthetic route of [ 669050-69-5 ]

[ 669050-69-5 ] Synthesis Path-Upstream 1~3

1
[ 916902-55-1 ]
[ 669050-69-5 ]

Yield	Reaction Conditions	Operation in experiment
98%	With manganese(IV) oxide In dichloromethane at 20℃;	To a solution of the (lH-indazole-6-yl)methanol {Eur. J. Inorg. Chem. 2006, 5, 980 - 987) (278.0 mg, 1.876 mmol) in 10.0 ml of CH₂Cl₂ was added MnO₂ (816.0 mg, 9.38 mmol) and the mixture was stirred at room temperature overnight. Filtered, washed with CH2C12 (2x25 ml). The filtrate was washed with water and brine, dried (MgSO4), filtered and the solvent <n="39"/>was evaporated under reduced pressure to give 270 mg of the crude title compound as a white solid (0.27 g, 98percent). MS (Electrospray): m/z 147.1 (M+H).
1.3 g	With Dess-Martin periodane In tetrahydrofuran; dichloromethane at 20 - 25℃; for 16 h;	To the stirred solution of 1H-indazol-6-ylmethanol (1.5g) in DCM (15 ml) and THF (15 ml) was added Dess Martin Periodinane (4.29 g) and stirred at room temperature for 16 h. DCM was added and filtered through celite. Filtrate was epaporated under vacuum to afford the title com- pound (1.3 g). HPLC/MS (method 1): R_t:1.290 min; m / z = 146 (M+1).

Reference： [1] Patent: WO2009/54983, 2009, A1, . Location in patent: Page/Page column 37-38
[2] Patent: US2008/200535, 2008, A1, . Location in patent: Page/Page column 133
[3] Patent: WO2005/44817, 2005, A1, . Location in patent: Page/Page column 101-102
[4] Patent: WO2018/177781, 2018, A1, . Location in patent: Page/Page column 82; 99-100

2
[ 79762-54-2 ]
[ 68-12-2 ]
[ 669050-69-5 ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: With sodium hydride In tetrahydrofuran at 20℃; for 1 h; Stage #2: With sec.-butyllithium In tetrahydrofuran; hexane at -78℃; for 2.25 h; Stage #3: at 20℃;	To a suspension of 60 percent NaH (10.0 g, 0.24 mol) in THF (240 mL) was added a suspension of 6-bromo-lH-indazole (39.4 g, 0.2 mol) in THF (280 mL) dropwise over 45 min. After addition, the resulting mixture was stirred for 1 h at rt to give a dark red clear solution which was cooled to -78 ⁰C.5-BuLi (1.4 M in <n="86"/>hexane, 300 mL, 0.42 mol) was added dropwsie over 1 h. During this addition, additional THF (130 mL) was added to keep the mixture stirring. After the addition, the resulting mixture was stirred for 75 min at -78 ⁰C; DMF (90 mL) was added dropwise (note: reaction solidified upon addition of DMF, occasional warming was needed to keep the mixture stirring). The resulting mixture was stirred at it overnight and cooled to 0 ⁰C. Solid NH₄Cl and saturated NH₄Cl were added to quench the reaction and bring the pH to about 7. The product was extracted with EtOAc (800 mL + 200 mL +300 mL, 1.3 L in total) and the combined extracts were washed with H₂O (300 mL x 3) and dried (Na₂SO₄). Evaporation of the solvent gave a dark red solid which was triturated by EtOAc (4 times, the last filtrate was purified by flash chromatography) to give the title compound (16.96 g in total, 58percent) as yellow brown solid. ¹H NMR (400 MHz, DMSO-d6) δ 13.62 (s, IH, NH), 10.12 (s, IH, CHO), 8.23 (s, IH), 8.17 (s, IH), 7.93 (d, J = 8.4 Hz, IH), 7.59 (d, J = 8.4 Hz, IH); MS ESI 147.0 [M + H]⁺, calcd for [C₈H₆N₂O+ H]⁺ 147.0.

Reference： [1] Patent: WO2009/79767, 2009, A1, . Location in patent: Page/Page column 84-85

3
[ 170487-40-8 ]
[ 669050-69-5 ]

Reference： [1] Patent: WO2018/177781, 2018, A1,

[ 669050-69-5 ] Synthesis Path-Downstream 1~74

1
[ 669050-69-5 ]
[ 4301-14-8 ]
C₁₀H₈N₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 0 - 20℃; for 2.5h;	c) 2.1 equivalents of ethyl magnesium bromide (0. 5M in THF) were added to a pre-cooled solution containing 18.2 in THF at 0C. After 30 minutes, the reaction was warmed to room temperature and stirred for an additional 2 hours. The resulting reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was then dried with MgS04, filtered, and concentrated in vacuo. The residue was then purified on silica gel column chromatography (gradient elution using ethyl acetate and hexanes) to provide pure compound 18.3.

Reference： [1]Patent: WO2005/44817,2005,A1 .Location in patent: Page/Page column 101-102

2
[ 669050-69-5 ]
C₈H₇N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine; In ethanol; for 10h;	a) A solution of compound 18.2 in ethanol is treated with hydroxylamine (1.05 eq). After 10 hours, the reaction is concentrated and the residue is dried under vacuum to give compound 43.1.

Reference： [1]Patent: WO2005/44817,2005,A1 .Location in patent: Page/Page column 143

3
[ 916902-55-1 ]
[ 669050-69-5 ]

Yield	Reaction Conditions	Operation in experiment
98%	With manganese(IV) oxide; In dichloromethane; at 20℃;	To a solution of the (lH-indazole-6-yl)methanol {Eur. J. Inorg. Chem. 2006, 5, 980 - 987) (278.0 mg, 1.876 mmol) in 10.0 ml of CH2Cl2 was added MnO2 (816.0 mg, 9.38 mmol) and the mixture was stirred at room temperature overnight. Filtered, washed with CH2C12 (2x25 ml). The filtrate was washed with water and brine, dried (MgSO4), filtered and the solvent <n="39"/>was evaporated under reduced pressure to give 270 mg of the crude title compound as a white solid (0.27 g, 98%). MS (Electrospray): m/z 147.1 (M+H).
	With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione; In ethyl acetate; at 90℃; for 17h;	Reference Example 6 1H-indazole-6-carboaldehyde To an ethyl acetate solution (861 mL) of (1H-indazol-6-yl)methanol (8.61 g) obtained in Reference Example 5, IBX (17.1 g, Synthetic Product 2) was added. The resultant mixture was stirred for 17 hours at 90 C. After the stirring was ended, filtering was performed, and the filtered solution was distilled away under a reduced pressure. Subsequently, a column chromatography (as an elution solution, 100:0 to 96:4 (v/v) of chloroform/methanol was used) using silica gel 60 N was performed, so that 7.69 g of the titled compound was obtained. ESI-MS: 147 (M+H), RTime 3.34 min.
	With Dess-Martin periodane; In dichloromethane; at 20℃; for 3h;	b) 1.1 equivalent of Dess-Martin periodinane was added to 1 equivalent of 18. 1 in dichloromethane. After stirring the reaction for 3 hours at room temperature, the resulting precipitate was removed by filtering thru a plug of celite. The celite plug was washed with dichloromethane. The combined organics were concentrated to provide the aldehyde 18.2 in high enough purity to be used without further purification.

1.3 g

With Dess-Martin periodane; In tetrahydrofuran; dichloromethane; at 20 - 25℃; for 16h;

To the stirred solution of 1H-indazol-6-ylmethanol (1.5g) in DCM (15 ml) and THF (15 ml) was added Dess Martin Periodinane (4.29 g) and stirred at room temperature for 16 h. DCM was added and filtered through celite. Filtrate was epaporated under vacuum to afford the title com- pound (1.3 g). HPLC/MS (method 1): Rt:1.290 min; m / z = 146 (M+1).

Reference： [1]Patent: WO2009/54983,2009,A1 .Location in patent: Page/Page column 37-38
[2]Patent: US2008/200535,2008,A1 .Location in patent: Page/Page column 133
[3]Patent: WO2005/44817,2005,A1 .Location in patent: Page/Page column 101-102
[4]Patent: WO2018/177781,2018,A1 .Location in patent: Page/Page column 82; 99-100

5
[ 669050-69-5 ]
[ 2567-29-5 ]
[ 1008769-27-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 22h;	Reference Example 7 1-(4-phenylbenzyl)-1H-indazole-6-carboaldehyde To an N,N-dimethyl formamide solution (3.3 mL) of 1H-indazole-6-carboaldehyde (48.4 mg) obtained in Reference Example 6, potassium carbonate (91.2 mg) and <strong>[2567-29-5]4-bromomethylbiphenyl</strong> (106 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) were added. The resultant mixture was stirred for 22 hours at 50 C. After the stirring was ended, a saturated ammonium chloride aqueous solution (10 mL) was poured into the reaction mixture solution, and extraction was performed by using ethyl acetate (20 mL*2). An organic layer was washed with a saturated saline solution and dried, and a solvent was distilled away under a reduced pressure. Subsequently, a chromatography (as an elution solution, 3:1 (v/v) of hexane/ethyl acetate was used) using Biotage 12M cartridge was performed, so that 49.2 mg of the titled compound was obtained. 1H-NMR (CDCl3) 5.71 (2H, s), 7.28-7.45 (5H, in), 7.49-7.56 (4H, m), 7.68 (1H, d, J=8.4), 7.87 (1H, d, J=8.4), 7.93 (1H, s), 8, 15 (1H, s), 10.13 (1H, s).

Reference： [1]Patent: US2008/200535,2008,A1 .Location in patent: Page/Page column 133

6
[ 669050-69-5 ]
C₁₅H₁₁ClN₂O [ No CAS ]
C₂₃H₁₅ClN₄O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4344 - 4347

7
[ 821767-60-6 ]
[ 669050-69-5 ]
C₂₃H₁₇N₅O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4344 - 4347

8
(2-amino-phenyl)-(1H-indol-3-yl)-methanone [ No CAS ]
[ 669050-69-5 ]
C₂₃H₁₆N₄O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4344 - 4347

9
(2-amino-phenyl)-(5-methyl-1H-indol-3-yl)-methanone [ No CAS ]
[ 669050-69-5 ]
C₂₄H₁₈N₄O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4344 - 4347

10
[ 669050-69-5 ]
C₁₆H₁₄N₂O [ No CAS ]
C₂₄H₁₈N₄O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4344 - 4347

11
[ 669050-69-5 ]
C₁₆H₁₄N₂O [ No CAS ]
C₂₄H₁₈N₄O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4344 - 4347

12
[ 669050-69-5 ]
C₁₆H₁₄N₂O [ No CAS ]
C₂₄H₁₈N₄O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4344 - 4347

13
[ 669050-69-5 ]
C₁₅H₁₁FN₂O [ No CAS ]
C₂₃H₁₅FN₄O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4344 - 4347

14
[ 669050-69-5 ]
C₁₅H₁₁FN₂O [ No CAS ]
C₂₃H₁₅FN₄O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4344 - 4347

15
[ 669050-69-5 ]
[ 1056249-32-1 ]
C₂₂H₁₅N₅O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4344 - 4347

16
[ 669050-69-5 ]
[ 151-50-8 ]
[ 541-41-3 ]
[ 1146323-44-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	In ethanol; at 0℃; for 3h;	To a 0 C solution of the lH-indazole-6-carbaldehyde (260.0 mg, 1.779 mmol) in 4.0 ml of dry ethanol was added KCN (174.0 mg, 2.67 mmol), followed by the drop- wise addition of ethyl chloroformate (0.256 ml, 2.67 mmol). The mixture was stirred at 0 C for 3 h. Water was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic fractions were washed with brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to give 350 mg of light yellow solid as the crude title compound as a white solid (0.35 g, 80%). MS (Electrospray): m/z 246.1 (M+H).

Reference： [1]Patent: WO2009/54983,2009,A1 .Location in patent: Page/Page column 38

17
[ 79762-54-2 ]
[ 68-12-2 ]
[ 669050-69-5 ]

Yield	Reaction Conditions	Operation in experiment
58%		To a suspension of 60 % NaH (10.0 g, 0.24 mol) in THF (240 mL) was added a suspension of 6-bromo-lH-indazole (39.4 g, 0.2 mol) in THF (280 mL) dropwise over 45 min. After addition, the resulting mixture was stirred for 1 h at rt to give a dark red clear solution which was cooled to -78 0C.5-BuLi (1.4 M in <n="86"/>hexane, 300 mL, 0.42 mol) was added dropwsie over 1 h. During this addition, additional THF (130 mL) was added to keep the mixture stirring. After the addition, the resulting mixture was stirred for 75 min at -78 0C; DMF (90 mL) was added dropwise (note: reaction solidified upon addition of DMF, occasional warming was needed to keep the mixture stirring). The resulting mixture was stirred at it overnight and cooled to 0 0C. Solid NH4Cl and saturated NH4Cl were added to quench the reaction and bring the pH to about 7. The product was extracted with EtOAc (800 mL + 200 mL +300 mL, 1.3 L in total) and the combined extracts were washed with H2O (300 mL x 3) and dried (Na2SO4). Evaporation of the solvent gave a dark red solid which was triturated by EtOAc (4 times, the last filtrate was purified by flash chromatography) to give the title compound (16.96 g in total, 58%) as yellow brown solid. 1H NMR (400 MHz, DMSO-d6) delta 13.62 (s, IH, NH), 10.12 (s, IH, CHO), 8.23 (s, IH), 8.17 (s, IH), 7.93 (d, J = 8.4 Hz, IH), 7.59 (d, J = 8.4 Hz, IH); MS ESI 147.0 [M + H]+, calcd for [C8H6N2O+ H]+ 147.0.

Reference： [1]Patent: WO2009/79767,2009,A1 .Location in patent: Page/Page column 84-85

18
[ 669050-69-5 ]
[ 56341-41-4 ]
[ 1168720-87-3 ]
[ 1168721-04-7 ]

Yield	Reaction Conditions	Operation in experiment
15%	With piperidine; In methanol; at 60℃; for 2h;	A scintillation vial was charged with 5-fluoroindolin-2-one (40 mg, 0.265 mmol), lH-indazole-6-carbaldehyde (43 mg, 0.292 mmol), piperidine (3 uL, 0.027 mmol) and MeOH (2 mL). The reaction was then heated to 6O0C for 2 hrs. LC-MS analysis of the filtered yellow solid indicated a 9: 1 mixture of geometric isomers. The mixture was resolved through prep-HPLC purification to give 11 mg, 15 % of the major isomer (E) as the title compound. The minor fraction was also isolated; see Example A32. 1H NMR (400 MHz, de-DMSO) delta 13.31 (s, IH), 10.66 (s, IH), 8.18 (s, IH), 7.92 (d, J = 8.7 Hz, IH), 7.91 (s, IH), 7.86 (s, IH), 7.42 (d, J = 8.5 Hz, IH), 7.29 (d, J = 9.5 Hz, IH), 7.10 (t, J = 6.8 Hz, IH), 6.88 (dd, Jl = 8.8 Hz, J2 = 4.7, IH); MS ESI 280.0 [M + H]+, calcd for [Ci6H10FN3O + H]+ 280.09.

Reference： [1]Patent: WO2009/79767,2009,A1 .Location in patent: Page/Page column 106
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 6069 - 6087

19
[ 669050-69-5 ]
[ 75-16-1 ]
[ 181820-44-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	In tetrahydrofuran; at -78 - 20℃;	To a solution of lH-indazole-6-carbaldehyde (200 mg, 1.37 mmol) in THF (7 mL) at -780C was added methyl magnesium bromide (1.4 mL, 4.11 mmol) dropwise under argon. The solution was warmed to rt and quenched with saturated ammonium chloride (2 mL). The mixture was extracted into ethyl acetate (3 x 10 mL), dried over MgSO4 and concentrated. The yellow oil was purified by silica gel chromatography (EtO Ac/Hex 4:1) to yield the title compound as a clear oil (135 mg, 60%). 1H NMR (400 MHz, CDCl3) delta 8.07 (s, IH), 7.76 (s, IH), 7.50-7.47 (m, 2H), 5.05 (q, 1 H, J = 7.4 Hz), 1.57 (d, 3H, J = 7.2 Hz); MS ESI [M + H]+, calcd for [C9H10N2O +H]+ 163.1; found m/z 163.0.

Reference： [1]Patent: WO2009/79767,2009,A1 .Location in patent: Page/Page column 127

20
[ 6165-68-0 ]
[ 669050-69-5 ]
[ 1168722-01-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 16h;Reflux;	A mixture of lH-indazole-6-carbaldehyde (50 mg, 0.18 mmol), thiophen-2- ylboronic acid (47 mg, 0.37 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol) and 2M Na2CO3 (0.28 mL, 0.55 mmol) in DME/H2O (2 mL/1 mL) was heated under reflux for 16 hours. The crude reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel using EtOAc (10 to 20 %) in DCM as the eluent to provide the title compound as a pale yellow solid (29 mg, 70 %). 1U NMR (400 MHz, CD3OD) delta ppm 10.09 (s, 1 H), 8.15 (d, J = 8.5 Hz, 1 H), 8.09 (s, 1 H), 7.72 (d, J= 8.5 Hz, 1 H), 7.69 (d, J= 3.8 Hz, 1 H), 7.48 (d, J= 5.0 Hz, 1 H), 7.19 (dd, J = 4.8, 3.8 Hz, 1 H); MS ESI 229.0 (100) [M + H]+, calcd for [Ci2H8N2OS + H]+ 229.04.

Reference： [1]Patent: WO2009/79767,2009,A1 .Location in patent: Page/Page column 156

21
[ 669050-69-5 ]
[ 114741-27-4 ]
[ 1168720-93-1 ]

Yield	Reaction Conditions	Operation in experiment
34%	With piperidine; In methanol; at 85℃; for 0.5h;	To a solution of N-(2-oxoindolin-5-yl)acetamide (19 mg, 0.1 mmol) was added lH-indazole-6-carbaldehyde (16 mg, 0.12 mmol), piperidine (2 uL, 0.011 mmol) and MeOH (2 mL). The reaction was then heated to 850C for 30 min. The MeOH was removed in vacuo and the solid triturated with ether to give 11 mg, 34 % of the title compound as an orange solid. 1H NMR (400 MHz, CD3OD) delta 8.13 (s, IH), 8.06 (s, IH), 7.92-7.88 (m, 2H), 7.84 (s, IH), 7.49 (d, J = 8.6 Hz, IH), 7.35 (d, IH), 6.88 (d, J = 8.3 Hz, IH), 2.04 (s, 3H); MS ESI 319.1 [M + H]+, calcd for [C18H17N5O3S + H]+ 319.11.

Reference： [1]Patent: WO2009/79767,2009,A1 .Location in patent: Page/Page column 109

22
[ 295800-01-0 ]
[ 669050-69-5 ]
[ 1168721-00-3 ]
(Z)-3-(3-((1H-indazol-6-yl)methylene)-2-oxoindolin-6-yl)pyridinium 2,2,2-trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 90℃; for 0.25h;Microwave irradiation;	6-(Pyridin-3-yl)indolin-2-one (25 mg, 0.12 mmol) and lH-indazole-6- carbaldehyde (17.4 mg, 0.12 mmol) were heated with stirring in a sealed tube under microwave irradiation at 90 0C for 15 min. The crude mixture was concentrated and purified by prepTLC (SiO2 20 % MeOH/DCM) followed by HPLC. Subsequent recrystalization from MeCN provided the title compound as a dark orange solid (6.2 mg, 12 %) in a (2:1) mixture of E and Z isomers. E-isomer: 1H NMR (400 MHz, CD3OD) 8.97 (br. s., 1 H), 8.67 (br. s., 1 H), 8.45 (d, J=7.83 Hz, 1 H), 8.15 (s, 1 H), 7.76 - 8.01 (m, 5 H), 7.50 (d, J=8.34 Hz, 1 H), 7.22 - 7.29 (m, 2 H); Z-isomer: 1H NMR (400 MHz, CD3OD) delta ppm 9.01 (br. s., 1 H), 8.67 (br. s., 1 H), 8.54 (d, J=7.33 Hz, 1 H), 8.09 (s, 1 H), 7.76 - 8.01 (m, 6 H), 7.43 (d, J=7.58 Hz, 1 H), 7.22 - 7.29 (m, 1 H); MS ESI 339.1 (100) [M + H]+, calcd for [C21H14N4O+ H]+ 339.4.

Reference： [1]Patent: WO2009/79767,2009,A1 .Location in patent: Page/Page column 112

23
[ 5654-97-7 ]
[ 669050-69-5 ]
[ 1168721-71-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With piperidine; In methanol; for 2h;Reflux;	To a mixture of lH-pyrrolo[2,3-b]pyridin-2(3H)-one (26.8 mg, 0.2 mmol) and lH-indazole-6-carbaldehyde (29.2 mg, 0.2 mmol) in MeOH (2 mL) was added 1 drop of piperidine via syringe needle. The resulting mixture was refluxed for 2 h (oil temp. 70 0C) and then cooled to rt. The resulting precipitate was collected by suction filtration to give the title compound as a yellow solid (37 mg, 71%). 1H NMR (400 MHz, DMSO-d6) delta 13.31 (s, IH, NH), 11.25 (s, IH, NH), 8.16 (s, IH), 8.10 (d, J = 5.2 Hz, IH), 7.93-7.87 (m, 4H), 7.44 (d, J = 8.8 Hz, IH), 6.90 (dd, J = 7.6 Hz, 5.6 Hz, IH); MS ESI 263.0 [M + H]+, calcd for [C15H10N4O + H]+ 263.1.

Reference： [1]Patent: WO2009/79767,2009,A1 .Location in patent: Page/Page column 142

24
[ 669050-69-5 ]
[ 944904-42-1 ]

Yield	Reaction Conditions	Operation in experiment
81%	With iodine; potassium carbonate; In N,N-dimethyl-formamide; for 2h;	To a solution of lH-Indazole-6-carbaldehyde (2.00 g, 13.7 mmol), K2CO3 (3.79 g, 27.4 mmol) in DMF (15 mL) was added dropwise a solution of I2 (5.91 g, 23.3 mmol) in DMF (15 mL) and the reaction allowed to stir for two hours. An aqueous solution consisting Of Na2S2O4 (3.30 g) / K2CO3 (0.20 g) / H2O (30 mL) was then added and the solution stirred for one hour. The product was then precipitated by pouring the solution over ice-water (300 mL) and collected by vacuum filtration to give after drying 3.02 g, 81 % of a beige powder. 1H NMR (400 MHz, CD3OD) delta 10.11 (s, IH), 8.11 (s, IH), 7.74 (d, J= 8.34 Hz, IH), 7.62 (d, J= 8.34 Hz, IH); MS ESI 272.9 [M + H]+, calcd for [C8H5IN2O + H]+ 272.95.
81%	With iodine; potassium carbonate; In N,N-dimethyl-formamide; for 2h;	Synthesis of 3-iodo-l H-indazole-6-carbaldehyde; [00103] To a solution of lH-indazole-6-carbaldehyde (2.00 g, 13.7 mmol), K2C03 (3.79 g, 27.4 mmol) in DMF (15 mL) was added dropwise a solution of I2 (5.91 g, 23.3 mmol) in DMF (15 mL) and the reaction allowed to stir for two h. An aqueous solution consisting of Na2S204 (3.30 g) / K2C03 (0.20 g) / H20 (30 mL) was then added and the solution stirred for one h. The product was then precipitated by pouring the solution over ice-water (300 mL) and collected by vacuum filtration to give after drying 3.02 g, 81 % of a beige powder. NMR (400 MHz, CD3OD) delta 10.1 1 (s, 1 H), 8.1 1 (s, 1H), 7.74 (d, J= 8.34 Hz, 1H), 7.62 (d, J= 8.34 Hz, 1H); MS ESI 272.9 [M + H] calcd for [C8H5IN20 + H]+ 272.95.
3.8 g	With iodine; potassium carbonate; In N,N-dimethyl-formamide; at 20 - 25℃; for 2h;	To a stirred solution of <strong>[669050-69-5]1H-indazole-6-carbaldehyde</strong> (2.4 g) in DMF (20 ml), K2CO3 (5.6 g) and I2 (7.5 g) were added. Reaction mixture was stirred at room temperature for 2 h. After comple- tion, reaction mixture was diluted with Sodium thiosulphate solution and stirred for 10 min, solid was precipitated. Solid was filtered and dried under vacuum to afford the title compound (3.8 g). HPLC/MS (method 1): Rt:1.624 min; m / z = 271 (M-1).

Reference： [1]Patent: WO2009/79767,2009,A1 .Location in patent: Page/Page column 85
[2]Patent: WO2011/123946,2011,A1 .Location in patent: Page/Page column 31
[3]Patent: WO2018/177781,2018,A1 .Location in patent: Page/Page column 82; 100

25
[ 669050-69-5 ]
[ 25369-32-8 ]
[ 1168721-50-3 ]

Yield	Reaction Conditions	Operation in experiment
28%	With piperidine; In methanol; at 60℃; for 4h;	A 13 mg (0.0877 mmol) solution of 7-aminooxindole (T. Nakashima & I. Suzuki, Chem. Pharm. Bull. (1969) 11, 2293) and lH-indazole-6-carbaldehyde (14 mg, 0.0965 mmol) in MeOH (1.0 mL) was treated with piperidine (~1 uL, 0.00877 mmol) and the reaction was heated to 60 0C for 4 hours. The MeOH was then removed in vacuo and the residue treated with 95:5 CH2Cl2/Me0H. The resulting precipitate was filtered and washed with 95:5 CH2Cl2MeOH to obtain the title compound as a orange powder (6.7 mg, 28 %). 1H NMR (400 MHz, CD3OD) delta 8.14 (s, IH), 7.94-7.87 (m, 3H), 7.46 (d, J = 8.19 Hz, IH), 7.31 (d, J = 7.63 Hz, IH), 6.90 <n="134"/>(d, J = 7.89 Hz, IH), 6.81 (t, J = 7.79 Hz, IH); MS ESI 277.0 [M + H]+, calcd for [C16H12N4O + H]+ 277.11.

Reference： [1]Patent: WO2009/79767,2009,A1 .Location in patent: Page/Page column 132

26
[ 669050-69-5 ]
[ 942922-07-8 ]
[ 1168723-08-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 125℃; for 2h;Microwave irradiation;	A mixture of lH-indazole-6-carbaldehyde (50 mg, 0.18 mmol), 2-(4- Methylpiperazin-l-yl)pyrimidine-5-boronic acid pinacol ester (70 mg, 0.22 mmol), Pd(PPh3)4 (13 mg, 0.018 mmol) and 2M Na2CO3 (0.10 mL, 0.22 mmol) in DME/H2O/EtOH (1.4 mL/0.4 mL/0.2 mL) was sealed and heated with stirring under microwave irradiation at 125 0C for 120 min. The crude reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel using MeOH (5% to 10 %) in DCM as the eluent to provide the title compound as a pale yellow solid (47 mg, 80 %). 1H NMR (400 MHz, CD3OD) delta ppm 10.12 (s, 1 H), 8.91 (s, 2 H), 8.14 (s, 1 H), 8.09 (d, J= 8.6 Hz, 1 H), 7.74 (d, J= 8.4 Hz, 1 H), 3.94 (t, J= 4.5 Hz, 4 H), 2.56 (t, J= 4.9 Hz, 4 H), 2.37 (s, 3 H); MS ESI 323.1 (100) [M + H]+, calcd for [Ci7H18N6O + H]+ 323.2.

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

27
[ 669050-69-5 ]
[ 1168720-81-7 ]
[ 1168720-80-6 ]

Yield	Reaction Conditions	Operation in experiment
24%	With piperidine; In methanol; at 60℃; for 2h;	A scintillation vial was charged with 2-oxo-N-phenylindoline-5-carboxamide (22 mg, 0.087 mmol), lH-indazole-6-carbaldehyde (14 mg, 0.096 mmol), piperidine (1 uL, 0.008 mmol) and MeOH (2 mL). The reaction was then heated to 6O0C for 2 hrs. A yellow precipitate formed which was further precipitated by cooling to room temperature and adding more MeOH (2 mL). The yellow solid was then filtered and washed with MeOH (10 mL) to give 8.0 mg, 24 % of the title compound. 1H NMR (400 MHz, de-DMSO) delta 13.42 (s, IH), 11.02 (s, IH), 10.16 (s, IH), 9.01 (s, IH), 8.39 (s, IH), 8.14 (s, 2H), 8.03 (d, J = 7.3 Hz, IH), 7.89-7.82 (m, 2H), 7.79 (d, J = 6.5 Hz, 2H), 7.36 (t, J = 6.6 Hz, 2H), 7.11-7.09 (m, IH), 6.96 (d, J = 6.9 Hz, IH); MS ESI 381.1 [M + H]+, calcd for [C23Hi6N4O2 + H]+ 381.14.

Reference： [1]Patent: WO2009/79767,2009,A1 .Location in patent: Page/Page column 103

28
[ 669050-69-5 ]
[ 1168720-55-5 ]
N'-[(3E)-3-(1H-indazol-6-ylmethylidene)-2-oxo-2,3-dihydro-1H-indol-5-yl]-N,N-dimethylsulfamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With piperidine; In methanol; at 85℃; for 0.5h;	To a solution of lambdayV-dimethyl-iV-(2-oxo-2,3-dihydro-lH-indol-5- yl)sulfamide (28 mg, 0.11 mmol) was added leta-indazole-6-carbaldehyde (18 mg,0.12 mmol), piperidine (2 uL, 0.012 mmol) and MeOH (2 mL). The reaction was then heated to 850C for 30 min. The MeOH was removed in vacuo and the residue purified by column chromatography (silica gel, 95:5, CH2Cl2MeOH) to give 14 mg,33 % of the title compound as an orange solid. 1H NMR (400 MHz, CDCl3) delta 8.13 (s, IH), 7.91 (s, IH), 7.84 (s, IH), 7.64 (s, IH), 7.45 (d, J = 8.3 Hz, IH), 7.07 (d, J =8.1 Hz, IH), 6.86 (d, J = 8.3 Hz, IH), 2.59 (s, 6H); MS ESI 384.1 [M + H]+, calcd for [C18H17N5O3S + H]+ 384.1.

Reference： [1]Patent: WO2009/79767,2009,A1 .Location in patent: Page/Page column 108

29
[ 669050-69-5 ]
C₁₀H₈Cl₂O₃ [ No CAS ]
C₁₈H₁₄Cl₂N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		b) A solution of compound 42.1 in THF at-78 C is treated with LDA (2. 0 eq). After 1 hour, a solution of compound 18.2 (1.0 eq) in THF is added to the dry ice cooled reaction. After another 3 hours, saturated aqueous NH4C1 is added to the reaction and the mixture is allowed to warm to room temperature. The reaction mixture is partitioned between ethyl acetate and water, and the organic layer is washed with water and brine, dried with anhydrous magnesium sulfate and filtered. The residue after concentration of the filtrate is purified by silica gel column to give compound 42.2

Reference： [1]Patent: WO2005/44817,2005,A1 .Location in patent: Page/Page column 141-142

30
[ 669050-69-5 ]
[ 1168721-12-7 ]
(Z)-3-((3-iodo-1H-indazol-6-yl)methylene)indolin-2-one [ No CAS ]