[ CAS No. 94444-96-9 ] {[proInfo.proName]}

Name: 94444-96-9|5-Methoxy-1H-indazole|95%
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Quality Control of [ 94444-96-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 94444-96-9 ]

CAS No. :	94444-96-9	MDL No. :	MFCD07781657
Formula :	C₈H₈N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GZWWDKIVVTXLFL-UHFFFAOYSA-N
M.W :	148.16	Pubchem ID :	13346860
Synonyms :

Calculated chemistry of [ 94444-96-9 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.12
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	42.59
TPSA :	37.91 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.03 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.2
Log Po/w (XLOGP3) :	1.66
Log Po/w (WLOGP) :	1.57
Log Po/w (MLOGP) :	0.84
Log Po/w (SILICOS-IT) :	2.02
Consensus Log Po/w :	1.46

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.34
Solubility :	0.671 mg/ml ; 0.00453 mol/l
Class :	Soluble
Log S (Ali) :	-2.07
Solubility :	1.26 mg/ml ; 0.00851 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.02
Solubility :	0.142 mg/ml ; 0.000959 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.44

Safety of [ 94444-96-9 ]

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 [ 94444-96-9 ]

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

Upstream synthesis route of [ 94444-96-9 ]
Downstream synthetic route of [ 94444-96-9 ]

[ 94444-96-9 ] Synthesis Path-Upstream 1~11

1
[ 94444-96-9 ]
[ 15579-15-4 ]

Yield	Reaction Conditions	Operation in experiment
71%	With boron tribromide In dichloromethane at 20℃; for 10 h;	A methylene chloride solution of boron tribromide (18.5 ml, 18.5 mmol) was added to a solution of 5-methoxy-1H-indazole (1.24 g, 8.40 mmol) in methylene chloride (84 ml) at 0°C and stirred at room temperature for 10 hours. Then, water was poured into the reaction solution in an ice-water bath, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol = 96/4) to obtain 1H-indazol-5-ol (877 mg, 71percent).1H-NMR (DMSO-d6) δ; 6.88 (1H, dd, J=8.8, 2.2Hz), 6.96 (1H, d, J=2.2Hz), 7.34 (1H, d, J=8.8Hz), 7.84 (1H, s).

Reference： [1] Patent: EP1403255, 2004, A1, . Location in patent: Page 44

2
[ 102-50-1 ]
[ 94444-96-9 ]

Yield	Reaction Conditions	Operation in experiment
18%	With acetic acid; sodium nitrite In water at 20℃;	A solution of sodium nitrite (3.38 g, 49.0 mmol) in water (8.1 ml) was added to a solution of 4-methoxy-2-methylaniline (6.69 g, 48.8 mmol) in acetic acid (350 ml) in an ice-water bath while maintaining the temperature at 25°C or lower, and stirred overnight at room temperature. Then, the reaction solution was poured into water and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol = 9/1) to obtain 5-methoxy-1H-indazole (1.30 g, 18percent).1H-NMR (DMSO-d6) δ; 3.76 (3H, s), 6.98 (1H, dd, J=8.8, 1.8Hz), 7.15 (1H, d, J=1.8Hz), 7.42 (1H, d, J=8.8Hz), 7.93 (1H, s), 12.89 (1H, brs).

Reference： [1] Patent: EP1403255, 2004, A1, . Location in patent: Page 44
[2] Bulletin of the Chemical Society of Japan, 1985, vol. 58, # 1, p. 309 - 315
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 23, p. 5293 - 5297
[4] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 9, p. 1153 - 1156
[5] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 8, p. 2410 - 2414

3
[ 31601-41-9 ]
[ 94444-96-9 ]

Reference： [1] Yakugaku Zasshi, 1959, vol. 79, p. 997,1001[2] Chem.Abstr., 1960, p. 5719
[3] Patent: WO2006/52555, 2006, A2, . Location in patent: Page/Page column 33; 74

4
[ 672-13-9 ]
[ 94444-96-9 ]

Reference： [1] Heterocycles, 2018, vol. 96, # 1, p. 74 - 85

5
[ 105728-90-3 ]
[ 94444-96-9 ]

Reference： [1] Journal of Organic Chemistry, 2006, vol. 71, # 21, p. 8166 - 8172

6
[ 459-60-9 ]
[ 94444-96-9 ]

Reference： [1] Tetrahedron Letters, 2004, vol. 45, # 8, p. 1769 - 1771

7
[ 420-37-1 ]
[ 94444-96-9 ]
[ 541539-88-2 ]

Yield	Reaction Conditions	Operation in experiment
59%	at 20℃; for 3 h;	To a solution of 5-methoxy-indazole (1.0 g, 6.7 mmol) in ethyl acetate (10 ml) was added BF₄0(CH₃)₃(1.3 g, 8.9 mmol). The solution was stirred at rt for 3 h. Sat. NaHC0₃aq. (10 ml) was added and extracted with ethyl acetate (20 ml). Organics were dried over Na₂S0₄, concentrated, and purified by flash chromatography on silica gel (PE /EA = 2/1) to afford 0.64 g (59percent) of the title compound as a yellow solid. [M+H] Calc'd for C₉H₁₀N₂O, 163; Found, 163.

Reference： [1] Journal of Organic Chemistry, 2003, vol. 68, # 10, p. 4093 - 4095
[2] Patent: WO2016/44138, 2016, A1, . Location in patent: Paragraph 00116
[3] Patent: WO2007/3419, 2007, A1, . Location in patent: Page/Page column 69-72

8
[ 94444-96-9 ]
[ 2533-69-9 ]
[ 541539-88-2 ]

Reference： [1] Tetrahedron Letters, 2013, vol. 54, # 13, p. 1661 - 1663

9
[ 94444-96-9 ]
[ 885519-30-2 ]

Reference： [1] Synthesis, 2011, # 16, p. 2651 - 2663
[2] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 23, p. 5293 - 5297

10
[ 94444-96-9 ]
[ 478834-25-2 ]

Reference： [1] Patent: EP1403255, 2004, A1,

11
[ 94444-96-9 ]
[ 78299-75-9 ]

Reference： [1] Patent: EP1403255, 2004, A1,

[ 94444-96-9 ] Synthesis Path-Downstream 1~88

1
[ 31601-41-9 ]
[ 94444-96-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate; acetic anhydride; acetic acid; isopentyl nitrite;18-crown-6 ether; In chloroform; at 18 - 25℃;Heating / reflux;	As shown in Scheme 15, acetylchloride (2.78 mL, 38.1 mmol, 1.05 eq) was added to a THF (200 mL) solution of 2-methyl-4-methoxylaniline (5 g, 36.3 mmol, 1 eq) and Et3N ( 6.31 mL, 45.4 mmol, 1.25 eq.) at 0 0C in 5 min. The solution was warmed up to room temperature for 4 h and filtered through a silica gel pad. The crude product was obtained after removing the solvent in vacuo. Isoamymitrite (4.54 g, 55.85 mmol, 2.9 eq) was added to a chloroform (100 mL) solution of this crude intermediate acetamide (3.45 g, 19.27 mmol, 1 eq), KOAc (3,78 g, 38.54 mmol , 2 eq), HOAc (2.31 g, 38.54 mmol, 2 eq), Ac2O (3.94 g, 38.54 mmol, 2 eq) and 18-crown-6 (1.01 g, 3.65 mmol, 0.2 eq) at RT. The solution was heated to reflux overnight, followed by washing with H2O, NaHCO3 and brine, and then chromatographed on SiO2 with EtOAc/Hexanes (1 :4) to obtain the desired product. Solid t-BuOK (0.725 g g, 3.72 mmol, 1.1 eq) was added to a DMF (10 mL) solution of the indazole intermediate (0.5 g, 3.38 mmol, 1 eq), and the mixture stirred for 30 min at 0 0C. Ethyl-3-bromo-butanoate was added and the solution was warmed to RT for 3 h. To this solution, 1N NaOH (7 mL) was added and stirred for another 2 h. The reaction solution was washed with Et2O (2 x 10 mL), then acidified with 3N HCl to pH = 7 and extracted with EtOAc (2 x 20 mL). The organic extracts were purified on RPHPLC to obtain two N-alkyl indazole regioisomeric fractions. The desired EXAMPLE 74 was then obtained using similar procedures as described above. 1H NMR (CD3OD, 500 MHz) delta 8.44 (d, 1H), 8.16 (s, 1H), 8.01 (dd, 1H), 7.51 (m, 2H), 7.13 (t, 1H), 6.98 (m, 2H), 5.22 (m, 1H), 3.80 (s, 3H), 3.23 (m, 1H), 3.07 (m, 1H), 1.73 (d, 3H); LCMS m/z 354 (M++1).

Reference： [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1959,vol. 79,p. 997,1001
Chem.Abstr.,1960,p. 5719
[2]Patent: WO2006/52555,2006,A2 .Location in patent: Page/Page column 33; 74

2
[ 53-84-9 ]
[ 94444-96-9 ]
5-Methoxy-2H-indazole adenine dinucleotide [ No CAS ]

Reference： [1]Bulletin of the Chemical Society of Japan,1985,vol. 58,p. 309 - 315

3
(2-methyl-4-methoxyphenyl)diazonium tetrafluoroborate [ No CAS ]
[ 94444-96-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 18-crown-6 ether; potassium acetate; In chloroform; at 20℃; for 2h;	2-methyl-4-methoxyphenylamine (27.4 g, 200 mmol) was added to a solution of tetrafluoroboric acid (HBF4, 50% aqueous solution, 100 mL). The solution was stirred at room temperature for about 10 min, then cooled to 0~5C. A solution of sodium nitrite (13.9 g, 200 mmol) in water (20 mL) was dropped in. The mixture was warmed to room temperature and stirred 1 h. The reaction mixture was filtrated and the crude product was washed with diethyl ether (3 x 100 mL) and dried in air to provided 49.7 g of 2-methyl-4-methoxyphenyldiazonium tetrafluoroborate. 2-methyl-4-methoxyphenyldiazonium tetrafluoroborate (49.7 g, 21 1 mmol), 18-crown-6 (2.79 g, 10.6 mmol), potassium acetate (43.4 g, 422 mmol) were added to chloroform (300 mL). The reaction mixture was stirred at room temperature for 2 h. The solution was washed with brine (3 x 30 mL), dried over sodium sulphate, and the solvents evaporated under vacuum. The residue was purified by flash chromatography (ethyl acetate/petroleum ether 2:8 to 4:6) to provide 5-methoxy- lH-indazole (10.2 g). LC-MS (ESI) M+lfound= 149 (MWcalc= 148.1) To a stirred mixture of 5-methoxy-lH-indazole (9.5 g, 64.6 mmol) in ethyl acetate (200 mL), was added trimethyloxonium tetrafluoroborate (19.1 g, 129 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was washed with saturated NaHCO3 solution (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and the solvents evaporated. Purification of the residue by flash chromatography (ethyl acetate/petroleum ether 2:3) gave 5-methoxy-2-methyl-2H-indazole (8.6 g). LC-MS (ESI) M+lfound= 163 (MWca,c= 162.1).To a mixture of 5-methoxy-2-methyl-2H-indazole (8.2 g, 50.6 mmol) in acetic acid (100 mL) was added N-bromosuccinimide (9.01 g, 50.6 mmol). The mixture was stirred at room temperature for 4 h. The reaction was quenched with ethyl acetate (200 mL) and washed with saturated NaHCO3 aqueous solution until stopped bubbling. The organic layer was separated and washed with brine, then dried over anhydrous sodium sulphate, filtered and concentrated under vacuum. Purification of the residue by flash chromatography (ethyl acetate/petroleum ether 1 :9) gave 3-bromo-5-methoxy- 2-methyl-2H-indazole (8.23 g). LC-MS (ESI) Mfound= 241 (MWcalc= 241.1) 3-Bromo-5-methoxy-2-methyl-2H-indazole (7.9 g, 32.7 mmol) was dissolved in dimethylacetamide (200 mL), and the following reagents were added: Pd2(dba)3 (1.2 g, 1.3 mmol, 4 mol%), Dppf (1.4 g, 2.6 mmol, 8 mol%), Zn powder (513 mg, 7.8 mmol, 24 mol%) and Zn(CN)2 (4.6 g, 39.2 mmol). The mixture was stirred at 170C for 6 h. The reaction mixture was quenched with water (400 mL) and extracted with ethyl acetate (3 x 200 mL). The organic extracts were dried over sodium sulphate and concentrated in vacuum. The crude product was purified by flash chromatography (ethyl acetate/petroleum ether 2:8) to give 5-methoxy-2-methyl-2H-indazole-3-carbonitrile as a white solid (5.9 g).5-Methoxy-2-methyl-2H-indazole-3-carbonitrile (4.67 g, 25 mmol) was dissolved in methanol (60 mL) and an aqueous solution of sodium hydroxide (10%, 60 mL) was added. The reaction mixture was refluxed for 4 h. Methanol was evaporated in vacuum. The residue was acidified to pH=4~5 EPO <DP n="72"/>and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried and evaporated to provide 5-methoxy-2-methyl-2H-indazole-3-carboxylic acid (4.3 g) as a white powder.To a dichloromethane (400 mL) solution of 5-methoxy-2-methyl-2H-indazole-3-carboxylic acid (4.3 g, 20.6 mmol) were added methy lam ine (hydrochloride salt, 2.8 g, 41.3 mmol), 1- hydroxybenzotriazole hydrate (HOBt) (5.6 g, 41.3 mmol), 3-ethyl-l-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI) (11.9 g, 62 mmol) and triethylamine (17 mL, 124 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with water (200 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with diluted hydrochloric acid and brine, dried and evaporated to provide 5-methoxy-2-methyl-2H- indazole-3-carboxylic acid methylamide (3.03 g). LC-MS (ESI) Mfound= 219 (MWcalc= 219.2) To a solution of 5-methoxy-2-methyl-2H-indazole-3-carboxylic acid methylamide (2.9 g, 13.1 mmol) in dry dichloromethane (150 mL), Boron trifluoride-methyl sulfide complex (IM, 35 mL) was dropped in at O0C and the reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water, the water phase was extracted with dichloromethane (3 x 50 mL), and the combined organic phases were washed with brine, dried over sodium sulphate, and concentrated under vacuum to provide 5-hydroxy-2-methyl-2H-indazole-3- carboxylic acid methylamide (2.7 g). Yield from 2-methyl-4-methoxyphenylamine: 10%To a soluti...

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 2324 - 2328
[2]Synthesis,2006,p. 3506 - 3514
[3]Journal of Heterocyclic Chemistry,1984,vol. 21,p. 1063 - 1064
[4]Tetrahedron Letters,2002,vol. 43,p. 2695 - 2697
[5]Patent: WO2007/3419,2007,A1 .Location in patent: Page/Page column 69-72

4
tert-butyl (4-methoxy-2-methylphenyl)azo sulfide [ No CAS ]
[ 94444-96-9 ]

Reference： [1]Tetrahedron,1994,vol. 50,p. 3529 - 3536

5
[ 102-50-1 ]
[ 94444-96-9 ]

Yield	Reaction Conditions	Operation in experiment
18%	With acetic acid; sodium nitrite; In water; at 20℃;	A solution of sodium nitrite (3.38 g, 49.0 mmol) in water (8.1 ml) was added to a solution of 4-methoxy-2-methylaniline (6.69 g, 48.8 mmol) in acetic acid (350 ml) in an ice-water bath while maintaining the temperature at 25C or lower, and stirred overnight at room temperature. Then, the reaction solution was poured into water and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol = 9/1) to obtain 5-methoxy-1H-indazole (1.30 g, 18%).1H-NMR (DMSO-d6) delta; 3.76 (3H, s), 6.98 (1H, dd, J=8.8, 1.8Hz), 7.15 (1H, d, J=1.8Hz), 7.42 (1H, d, J=8.8Hz), 7.93 (1H, s), 12.89 (1H, brs).

Reference： [1]Patent: EP1403255,2004,A1 .Location in patent: Page 44
[2]Bulletin of the Chemical Society of Japan,1985,vol. 58,p. 309 - 315
[3]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5293 - 5297
[4]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1153 - 1156
[5]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2410 - 2414

6
[ 124-38-9 ]
[ 94444-96-9 ]
[ 90417-53-1 ]

Reference： [1]Journal of medicinal chemistry,1995,vol. 38,p. 2331 - 2338

7
[ 420-37-1 ]
[ 94444-96-9 ]
[ 541539-88-2 ]

Yield	Reaction Conditions	Operation in experiment
59%	In ethyl acetate; at 20℃; for 3h;	To a solution of 5-methoxy-indazole (1.0 g, 6.7 mmol) in ethyl acetate (10 ml) was added BF40(CH3)3(1.3 g, 8.9 mmol). The solution was stirred at rt for 3 h. Sat. NaHC03aq. (10 ml) was added and extracted with ethyl acetate (20 ml). Organics were dried over Na2S04, concentrated, and purified by flash chromatography on silica gel (PE /EA = 2/1) to afford 0.64 g (59%) of the title compound as a yellow solid. [M+H] Calc'd for C9H10N2O, 163; Found, 163.
	In ethyl acetate; at 20℃; for 2h;	2-methyl-4-methoxyphenylamine (27.4 g, 200 mmol) was added to a solution of tetrafluoroboric acid (HBF4, 50% aqueous solution, 100 mL). The solution was stirred at room temperature for about 10 min, then cooled to 0~5C. A solution of sodium nitrite (13.9 g, 200 mmol) in water (20 mL) was dropped in. The mixture was warmed to room temperature and stirred 1 h. The reaction mixture was filtrated and the crude product was washed with diethyl ether (3 x 100 mL) and dried in air to provided 49.7 g of 2-methyl-4-methoxyphenyldiazonium tetrafluoroborate. 2-methyl-4-methoxyphenyldiazonium tetrafluoroborate (49.7 g, 21 1 mmol), 18-crown-6 (2.79 g, 10.6 mmol), potassium acetate (43.4 g, 422 mmol) were added to chloroform (300 mL). The reaction mixture was stirred at room temperature for 2 h. The solution was washed with brine (3 x 30 mL), dried over sodium sulphate, and the solvents evaporated under vacuum. The residue was purified by flash chromatography (ethyl acetate/petroleum ether 2:8 to 4:6) to provide 5-methoxy- lH-indazole (10.2 g). LC-MS (ESI) M+lfound= 149 (MWcalc= 148.1) To a stirred mixture of 5-methoxy-lH-indazole (9.5 g, 64.6 mmol) in ethyl acetate (200 mL), was added trimethyloxonium tetrafluoroborate (19.1 g, 129 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was washed with saturated NaHCO3 solution (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and the solvents evaporated. Purification of the residue by flash chromatography (ethyl acetate/petroleum ether 2:3) gave 5-methoxy-2-methyl-2H-indazole (8.6 g). LC-MS (ESI) M+lfound= 163 (MWca,c= 162.1).To a mixture of 5-methoxy-2-methyl-2H-indazole (8.2 g, 50.6 mmol) in acetic acid (100 mL) was added N-bromosuccinimide (9.01 g, 50.6 mmol). The mixture was stirred at room temperature for 4 h. The reaction was quenched with ethyl acetate (200 mL) and washed with saturated NaHCO3 aqueous solution until stopped bubbling. The organic layer was separated and washed with brine, then dried over anhydrous sodium sulphate, filtered and concentrated under vacuum. Purification of the residue by flash chromatography (ethyl acetate/petroleum ether 1 :9) gave 3-bromo-5-methoxy- 2-methyl-2H-indazole (8.23 g). LC-MS (ESI) Mfound= 241 (MWcalc= 241.1) 3-Bromo-5-methoxy-2-methyl-2H-indazole (7.9 g, 32.7 mmol) was dissolved in dimethylacetamide (200 mL), and the following reagents were added: Pd2(dba)3 (1.2 g, 1.3 mmol, 4 mol%), Dppf (1.4 g, 2.6 mmol, 8 mol%), Zn powder (513 mg, 7.8 mmol, 24 mol%) and Zn(CN)2 (4.6 g, 39.2 mmol). The mixture was stirred at 170C for 6 h. The reaction mixture was quenched with water (400 mL) and extracted with ethyl acetate (3 x 200 mL). The organic extracts were dried over sodium sulphate and concentrated in vacuum. The crude product was purified by flash chromatography (ethyl acetate/petroleum ether 2:8) to give 5-methoxy-2-methyl-2H-indazole-3-carbonitrile as a white solid (5.9 g).5-Methoxy-2-methyl-2H-indazole-3-carbonitrile (4.67 g, 25 mmol) was dissolved in methanol (60 mL) and an aqueous solution of sodium hydroxide (10%, 60 mL) was added. The reaction mixture was refluxed for 4 h. Methanol was evaporated in vacuum. The residue was acidified to pH=4~5 EPO <DP n="72"/>and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried and evaporated to provide 5-methoxy-2-methyl-2H-indazole-3-carboxylic acid (4.3 g) as a white powder.To a dichloromethane (400 mL) solution of 5-methoxy-2-methyl-2H-indazole-3-carboxylic acid (4.3 g, 20.6 mmol) were added methy lam ine (hydrochloride salt, 2.8 g, 41.3 mmol), 1- hydroxybenzotriazole hydrate (HOBt) (5.6 g, 41.3 mmol), 3-ethyl-l-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI) (11.9 g, 62 mmol) and triethylamine (17 mL, 124 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with water (200 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with diluted hydrochloric acid and brine, dried and evaporated to provide 5-methoxy-2-methyl-2H- indazole-3-carboxylic acid methylamide (3.03 g). LC-MS (ESI) Mfound= 219 (MWcalc= 219.2) To a solution of 5-methoxy-2-methyl-2H-indazole-3-carboxylic acid methylamide (2.9 g, 13.1 mmol) in dry dichloromethane (150 mL), Boron trifluoride-methyl sulfide complex (IM, 35 mL) was dropped in at O0C and the reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water, the water phase was extracted with dichloromethane (3 x 50 mL), and the combined organic phases were washed with brine, dried over sodium sulphate, and concentrated under vacuum to provide 5-hydroxy-2-methyl-2H-indazole-3- carboxylic acid methylamide (2.7 g). Yield from 2-methyl-4-methoxyphenylamine: 10%To a soluti...

Reference： [1]Journal of Organic Chemistry,2003,vol. 68,p. 4093 - 4095
[2]Patent: WO2016/44138,2016,A1 .Location in patent: Paragraph 00116
[3]Patent: WO2007/3419,2007,A1 .Location in patent: Page/Page column 69-72

8
[ 94444-96-9 ]
[ 885519-30-2 ]

Reference： [1]Synthesis,2011,p. 2651 - 2663
[2]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5293 - 5297

9
2-fluoro-5-methoxy-benzaldehyde O-methyl-oxime [ No CAS ]
[ 94444-96-9 ]

Reference： [1]Journal of Organic Chemistry,2006,vol. 71,p. 8166 - 8172

10
[ 4885-02-3 ]
[ 94444-96-9 ]
[ 850363-99-4 ]

Yield	Reaction Conditions	Operation in experiment
24%		45.0 g (337 mmol) of aluminum chloride was added to a solution of 25.0 g (169 mmol) of <strong>[94444-96-9]5-methoxy-1H-indazole</strong> in 500 ml of methylene chloride in an argon stream and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was cooled down to -10 C., 17.5 ml (193 mmol) of dichloromethyl methyl ether was added dropwise thereto over 20 minutes and the mixture was stirred at 0 C. for 2 hours. After the reaction was completed, 300 ml of a mixed solution of methanol:water=1:1 (v/v) was gradually poured into the reaction solution at 0 C. and the resulting solid was collected by filtration and washed with chloroform. Then, 300 ml of chloroform, 150 ml of methanol and 150 ml of a saturated aqueous solution of sodium hydrogen carbonate were added to the resulting solid and the mixture was stirred at room temperature for 1 hour. The resulting mixed solution was extracted with 150 ml of a mixed solvent of chloroform:methanol=2:1 (v/v) and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chloroform was added to the resulting solid, the mixture was subjected to an ultrasonic treatment. The solid was collected by filtration and washed with chloroform, whereby 7.20 g of the title compound was obtained as green powder (yield: 24%). Rf value: 0.50 (ethyl acetate) Mass spectrum (CI, m/z): 177 (M++1) 1H-NMR spectrum (DMSO-d6, deltappm): 4.00 (s, 3H), 7.40 (d, J=9.0 Hz, 1H), 7.93 (dd, J1=9.0 Hz, J2=1.0 Hz, 1H), 8.43 (d, J=1.0 Hz, 1H), 10.57 (s, 1H), 13.32 (brs, 1H)
24%		(Reference Example 22) Synthesis of 4-formyl-<strong>[94444-96-9]5-methoxy-1H-indazole</strong> (Reference compound 22) 45.0 g (337 mmol) of aluminum chloride was added to a solution of 25.0 g (169 mmol) of <strong>[94444-96-9]5-methoxy-1H-indazole</strong> in 500 ml of methylene chloride in an argon stream and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was cooled down to -10C, 17.5 ml (193 mmol) of dichloromethyl methyl ether was added dropwise thereto over 20 minutes and the mixture was stirred at 0C for 2 hours. After the reaction was completed, 300 ml of a mixed solution of methanol: water = 1: 1 (v/v) was gradually poured into the reaction solution at 0C and the resulting solid was collected by filtration and washed with chloroform. Then, 300 ml of chloroform, 150 ml of methanol and 150 ml of a saturated aqueous solution of sodium hydrogen carbonate were added to the resulting solid and the mixture was stirred at room temperature for 1 hour. The resulting mixed solution was extracted with 150 ml of a mixed solvent of chloroform: methanol = 2: 1 (v/v) and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chloroform was added to the resulting solid, the mixture was subjected to an ultrasonic treatment. The solid was collected by filtration and washed with chloroform, whereby 7.20 g of the title compound was obtained as green powder (yield: 24%). Rf value: 0.50 (ethyl acetate) Mass spectrum (CI, m/z): 177 (M++1) 1H-NMR spectrum (DMSO-d6, deltappm): 4.00 (s, 3H), 7.40 (d, J=9.0 Hz, 1H), 7.93 (dd, J1=9.0Hz, J2=1.0Hz, 1H), 8.43 (d, J=1.0Hz, 1H), 10.57 (s, 1H), 13.32 (brs, 1H)

Reference： [1]Patent: US2009/12123,2009,A1 .Location in patent: Page/Page column 13
[2]Patent: EP1870099,2007,A1 .Location in patent: Page/Page column 19

11
[ 94444-96-9 ]
[ 918440-12-7 ]

Reference： [1]Synthesis,2006,p. 3506 - 3514

12
[ 94444-96-9 ]
[ 918440-16-1 ]

Reference： [1]Synthesis,2006,p. 3506 - 3514

13
[ 94444-96-9 ]
5,5'-dimethoxy-1,1'-bis[2-(trimethylsilanyl)ethoxymethyl]-[3,3']biindazolyl [ No CAS ]

Reference： [1]Synthesis,2006,p. 3506 - 3514
[2]Synthesis,2006,p. 3506 - 3514

14
[ 94444-96-9 ]
2-acetylamino-3-{5-methoxy-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazol-3-yl}propanoic acid methyl ester [ No CAS ]

Reference： [1]Synthesis,2006,p. 3506 - 3514

15
[ 105728-90-3 ]
[ 94444-96-9 ]

Reference： [1]Journal of Organic Chemistry,2006,vol. 71,p. 8166 - 8172

16
[ 94444-96-9 ]
[ 870766-00-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5293 - 5297

17
[ 94444-96-9 ]
(1-benzo[1,3]dioxol-5-ylmethyl-piperidin-4-yl)-(5-methoxy-1-methyl-1H-indazol-3-yl)-amine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5293 - 5297

18
[ 94444-96-9 ]
[1-(1H-indazol-6-ylmethyl)-piperidin-4-yl]-(5-methoxy-1H-indazol-3-yl)-amine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5293 - 5297

19
[ 94444-96-9 ]
[ 870766-17-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5293 - 5297

20
[ 94444-96-9 ]
3-(1-benzo[1,3]dioxol-5-ylmethyl-piperidin-4-ylamino)-5-methoxy-indazole-1-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5293 - 5297

21
[ 94444-96-9 ]
3-[1-(1H-indazol-6-ylmethyl)-piperidin-4-ylamino]-5-methoxy-indazole-1-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5293 - 5297

22
[ 459-60-9 ]
[ 94444-96-9 ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 1769 - 1771

23
[ 94444-96-9 ]
[ 290368-12-6 ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 4363 - 4366

24
[ 94444-96-9 ]
[ 290368-10-4 ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 4363 - 4366

25
[ 94444-96-9 ]
[ 290368-03-5 ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 4363 - 4366
[2]Molecules,2018,vol. 23

26
[ 94444-96-9 ]
3-(5-methoxy-1H-indazol-3-yl)-propionic acid [ No CAS ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 4363 - 4366

27
[ 94444-96-9 ]
[ 290368-02-4 ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 4363 - 4366

28
[ 94444-96-9 ]
3-(3-iodo-5-methoxy-indazol-1-yl)-propionic acid methyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 4363 - 4366

29
[ 94444-96-9 ]
[ 290368-01-3 ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 4363 - 4366

30
[ 94444-96-9 ]
[ 290368-08-0 ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 4363 - 4366

31
[ 94444-96-9 ]
3-(1-benzyl-5-methoxy-1H-indazol-3-yl)-acrylic acid methyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 4363 - 4366

32
[ 94444-96-9 ]
3-[5-methoxy-1-(toluene-4-sulfonyl)-1H-indazol-3-yl]-acrylic acid methyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 4363 - 4366

33
[ 94444-96-9 ]
[ 882803-11-4 ]

Reference： [1]Journal of medicinal chemistry,1995,vol. 38,p. 2331 - 2338

34
[ 94444-96-9 ]
[ 169789-37-1 ]

Reference： [1]Journal of medicinal chemistry,1995,vol. 38,p. 2331 - 2338

35
[ 94444-96-9 ]
[ 169789-36-0 ]

Reference： [1]Journal of medicinal chemistry,1995,vol. 38,p. 2331 - 2338

36
[ 94444-96-9 ]
3-[(5-hydroxy-1H-indazol-3-yl)methylene]-N-pentylcarbazimidamide [ No CAS ]

Reference： [1]Journal of medicinal chemistry,1995,vol. 38,p. 2331 - 2338

37
[ 94444-96-9 ]
C₁₅H₂₂N₆O [ No CAS ]

Reference： [1]Journal of medicinal chemistry,1995,vol. 38,p. 2331 - 2338

38
[ 94444-96-9 ]
[ 15579-15-4 ]

Yield	Reaction Conditions	Operation in experiment
71%	With boron tribromide; In dichloromethane; at 20℃; for 10h;	A methylene chloride solution of boron tribromide (18.5 ml, 18.5 mmol) was added to a solution of <strong>[94444-96-9]5-methoxy-1H-indazole</strong> (1.24 g, 8.40 mmol) in methylene chloride (84 ml) at 0C and stirred at room temperature for 10 hours. Then, water was poured into the reaction solution in an ice-water bath, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol = 96/4) to obtain 1H-indazol-5-ol (877 mg, 71%).1H-NMR (DMSO-d6) delta; 6.88 (1H, dd, J=8.8, 2.2Hz), 6.96 (1H, d, J=2.2Hz), 7.34 (1H, d, J=8.8Hz), 7.84 (1H, s).

Reference： [1]Patent: EP1403255,2004,A1 .Location in patent: Page 44

39
[ 78-77-3 ]
[ 94444-96-9 ]
[ 765914-93-0 ]

Yield	Reaction Conditions	Operation in experiment
36%	With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide;	Step A: 1-Isobutyl-<strong>[94444-96-9]5-methoxy-1H-indazole</strong> A solution of <strong>[94444-96-9]5-methoxy-1H-indazole</strong> (5.00 g, 33.7 mmol) in DMF (100 mL) was treated with K2CO3 (5.83 g, 42.2 mmol) and stirred at room temperature for 15 minutes. To this solution was added 1-bromo-2-methylpropane (5.09 g, 37.1 mmol) and the resulting mixture was heated to 110 C. for 18 hours. Another equivalent of 1-bromo-2-methyl-propane was added and the mixture continued to heat for 48 hours more. The mixture was concentrated under reduced pressure and dissolved in dichloromethane. The solution was washed with 1N HCl, filtered, and concentrated under reduced pressure. The residue was chromatographed on Biotage eluding with hexanes/ether (5:1) to afford 2.51 g of orange oil (36% yield).

Reference： [1]Patent: US2004/192653,2004,A1

40
[ 94444-96-9 ]
[ 75-36-5 ]
[ 850363-98-3 ]

Yield	Reaction Conditions	Operation in experiment
30%		30 g (220 mmol) of aluminum chloride was added to a solution of 10 g (67 mmol) of <strong>[94444-96-9]5-methoxy-1H-indazole</strong> (see R. A. Bartsch, et al., J. Heterocyclic Chem., vol. 21, p. 1063 (1984)) in 200 ml of 1,2-dichloroethane at room temperature in an argon stream and the mixture was stirred for 30 minutes. Then, 12 ml (170 mmol) of acetyl chloride was added thereto at room temperature and the mixture was stirred at 60 C. for 2.5 hours. After the reaction was completed, the reaction solution was allowed to cool, water was added thereto and the mixture was extracted with chloroform. The organic layer was successively washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was washed with chloroform, whereby 3.6 g of the title compound was obtained as yellow powder (yield: 30%). Melting point: 188 to 191 C. Rf value: 0.14 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI, m/z): 177 (M++1) 1H-NMR spectrum (DMSO-d6, deltappm): 2.79 (s, 3H), 7.05 (d, J=8.9 Hz, 1H), 7.81 (dd, J1=8.9 Hz, J2=0.9 Hz, 1H), 8.25 (d, J=0.9 Hz, 1H), 12.61 (brs, 1H), 13.38 (brs, 1H)
30%		(Reference Example 21) Synthesis of 5-hydroxy-4-methylcarbonyl-1H-indazole (Reference compound 21) 30 g (220 mmol) of aluminum chloride was added to a solution of 10 g (67 mmol) of <strong>[94444-96-9]5-methoxy-1H-indazole</strong> (see)) in 200 ml of 1,2-dichloroethane at room temperature in an argon stream and the mixture was stirred for 30 minutes. Then, 12 ml (170 mmol) of acetyl chloride was added thereto at room temperature and the mixture was stirred at 60C for 2.5 hours. After the reaction was completed, the reaction solution was allowed to cool, water was added thereto and the mixture was extracted with chloroform. The organic layer was successively washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was washed with chloroform, whereby 3.6 g of the title compound was obtained as yellow powder (yield: 30%). Melting point: 188 to 191C Rf value: 0.14 (n-hexane: ethyl acetate = 2: 1 (v/v)) Mass spectrum (CI, m/z): 177 (M++1) 1H-NMR spectrum (DMSO-d6, deltappm): 2.79 (s, 3H), 7.05 (d, J=8.9Hz, 1H), 7.81 (dd, J1=8.9Hz, J2=0.9Hz, 1H), 8.25 (d, J=0.9Hz, 1H), 12.61 (brs, 1H), 13.38 (brs, 1H)

Reference： [1]Patent: US2009/12123,2009,A1 .Location in patent: Page/Page column 12-13
[2]Patent: EP1870099,2007,A1 .Location in patent: Page/Page column 18-19
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2410 - 2414

41
[ 536-57-2 ]
[ 10486-19-8 ]
[ 94444-96-9 ]
5-methoxy-3-{1-[(4-methylphenyl)sulfonyl]tridecyl}-1H-indazole [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2009,p. 3184 - 3188

42
[ 94444-96-9 ]
[ 96-32-2 ]
[ 92567-20-9 ]

Reference： [1]Organic Letters,2009,vol. 11,p. 5054 - 5057

43
[ 76513-69-4 ]
[ 94444-96-9 ]
[ 1210745-26-8 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 2324 - 2328

44
[ 7425-49-2 ]
[ 94444-96-9 ]
C₁₂H₁₄N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		As shown in Scheme 15, acetylchloride (2.78 mL, 38.1 mmol, 1.05 eq) was added to a THF (200 mL) solution of 2-methyl-4-methoxylaniline (5 g, 36.3 mmol, 1 eq) and Et3N ( 6.31 mL, 45.4 mmol, 1.25 eq.) at 0 0C in 5 min. The solution was warmed up to room temperature for 4 h and filtered through a silica gel pad. The crude product was obtained after removing the solvent in vacuo. Isoamymitrite (4.54 g, 55.85 mmol, 2.9 eq) was added to a chloroform (100 mL) solution of this crude intermediate acetamide (3.45 g, 19.27 mmol, 1 eq), KOAc (3,78 g, 38.54 mmol , 2 eq), HOAc (2.31 g, 38.54 mmol, 2 eq), Ac2O (3.94 g, 38.54 mmol, 2 eq) and 18-crown-6 (1.01 g, 3.65 mmol, 0.2 eq) at RT. The solution was heated to reflux overnight, followed by washing with H2O, NaHCO3 and brine, and then chromatographed on SiO2 with EtOAc/Hexanes (1 :4) to obtain the desired product. Solid t-BuOK (0.725 g g, 3.72 mmol, 1.1 eq) was added to a DMF (10 mL) solution of the indazole intermediate (0.5 g, 3.38 mmol, 1 eq), and the mixture stirred for 30 min at 0 0C. Ethyl-3-bromo-butanoate was added and the solution was warmed to RT for 3 h. To this solution, 1N NaOH (7 mL) was added and stirred for another 2 h. The reaction solution was washed with Et2O (2 x 10 mL), then acidified with 3N HCl to pH = 7 and extracted with EtOAc (2 x 20 mL). The organic extracts were purified on RPHPLC to obtain two N-alkyl indazole regioisomeric fractions. The desired EXAMPLE 74 was then obtained using similar procedures as described above. 1H NMR (CD3OD, 500 MHz) delta 8.44 (d, 1H), 8.16 (s, 1H), 8.01 (dd, 1H), 7.51 (m, 2H), 7.13 (t, 1H), 6.98 (m, 2H), 5.22 (m, 1H), 3.80 (s, 3H), 3.23 (m, 1H), 3.07 (m, 1H), 1.73 (d, 3H); LCMS m/z 354 (M++1).

Reference： [1]Patent: WO2006/52555,2006,A2 .Location in patent: Page/Page column 33; 74

45
[ 94444-96-9 ]
C₁₉H₂₃N₃O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2410 - 2414

46
[ 94444-96-9 ]
C₁₉H₂₅N₃O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2410 - 2414

47
[ 94444-96-9 ]
[ 1307262-59-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2410 - 2414

48
[ 94444-96-9 ]
C₁₄H₁₇N₃O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2410 - 2414

49
[ 94444-96-9 ]
[ 1307262-60-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2410 - 2414

50
[ 94444-96-9 ]
[ 1339955-80-4 ]

Reference： [1]Synthesis,2011,p. 2651 - 2663

51
[ 94444-96-9 ]
[ 1339955-96-2 ]

Reference： [1]Synthesis,2011,p. 2651 - 2663

52
[ 76513-69-4 ]
[ 94444-96-9 ]
[ 1361332-16-2 ]

Reference： [1]Chemical Communications,2012,vol. 48,p. 2680 - 2682

53
[ 76513-69-4 ]
[ 94444-96-9 ]
[ 1361331-67-0 ]

Reference： [1]Chemical Communications,2012,vol. 48,p. 2680 - 2682

54
[ 94444-96-9 ]
[ 2533-69-9 ]
[ 541539-88-2 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Preparation of 2-methyl-6-nitro-2H-indazole (5d). To a stirred mixture of 6-nitro-1H-indazole (1.0 g, 0.0061 mmol) in dichloromethane (25.0 mL) was added trifluoromethanesulfonic acid (0.54 mL, 0.0061 mmol), stirred for 5-10 min at 25-35 C. To this mixture was added methyl 2,2,2,-trichlroacetimidate (2.69 g, 0.015 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16-18 h under N2. After reaction completion, chilled saturated NaHCO3 solution was added. The aqueous and organic phases were separated. Aqueous phase was extracted with dichloromethane 10 mL. Combined organic layers were washed with DM water (2 × 10 mL). Organic layer was dried over anhydrous Na2SO4, filtered, and evaporated completely under vacuum to obtain 2-methyl-6-nitro-2H-indazole (1.03 g, 95.0%) as a yellow solid.

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 1661 - 1663

55
C₃₄H₂₈N₄O [ No CAS ]
[ 94444-96-9 ]

Yield	Reaction Conditions	Operation in experiment
264 mg	With toluene-4-sulfonic acid; In tetrahydrofuran; water; at 100℃; for 1h;Microwave irradiation; Sealed tube;	General procedure: In a Schlenk tube under nitrogen atmosphere at room temperature were added BINAP (5.5 mol %), Pd(OAc)2 (5 mol %) and Cs2CO3 (1.4 equiv) and toluene (10 mL per mmol of 1bem). The suspension was heated at 80 C for 10 min and benzophenonehydrazone (2.1 equiv) and the chosen substituted starting material 1b-m (1 equiv) were added. The resulting mixture was heated at100 C for the time depicted in Tables 1 and 2. The mixture was poured in water (20 mL per mmol of 1bem) and CH2Cl2 (20 mL per mmol of 1b-m), filtrated on a short pad of Celite, andextracted with CH2Cl2 (320 mL per mmol of 1bem). The combined organic layers were washed with water (320 mL per mmolof 1bem), dried over MgSO4, filtrated and evaporated. The crude product was eluted on a short pad of silica gel using CH2Cl2 aseluent and evaporated. The crude was introduced in a microwavevial with p-toluenesulfonic acid (2 or 3 equiv see Tables 1 and 2) and solvents (see Tables 1 and 2, 10 mL per mmol of 1b-m). The vial was sealed and the suspension was heated at 100 C for the time depicted in Tables 1 and 2. The resulting mixture was poured in water (20 mL per mmol of 1b-m) and extracted with EtOAc (320 mL per mmol of 1bem). The combined layers were driedon MgSO4, filtrated, evaporated purified by silica gel chromatography.

Reference： [1]Tetrahedron,2014,vol. 70,p. 8413 - 8418

56
5-methoxy-1-tosyl-1H-indazole [ No CAS ]
[ 94444-96-9 ]

Reference： [1]Advanced Synthesis and Catalysis,2016,vol. 358,p. 926 - 939

57
C₁₅H₁₅BrN₂O₃S [ No CAS ]
[ 94444-96-9 ]

Reference： [1]Advanced Synthesis and Catalysis,2016,vol. 358,p. 926 - 939

58
[ 637-87-6 ]
[ 94444-96-9 ]
1-(4-chlorophenyl)-5-methoxy-1H-indazole [ No CAS ]
C₁₄H₁₃ClN₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate; In aq. buffer; at 60℃; for 2h;	General procedure: To a mixture of indazoles, indoles, or indolin-2-ones (1 equiv), aryl halides (1.2 equiv), cesium carbonate (2.5 equiv), copper (I) iodide (0.2 equiv) in Tween 20/water (2%, w/w, 0.2M) was added trans-N1,N2-dimethylcyclohexane-1,2-diamine (0.8 equiv). The reaction mixture was stirred at 60C for 2h. The reaction mixture was extracted with ethyl acetate (20mL×3). The organic layers were combined, washed with brine (50mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel and eluted with PE/EA to afford the desired product 3, 5, 8 and 10.

Reference： [1]Tetrahedron,2017,vol. 73,p. 172 - 178

59
[ 94444-96-9 ]
(E)-methyl 3-(1-(diisopropylcarbamoyl)-5-methoxy-1H-indazol-7-yl)acrylate [ No CAS ]

Reference： [1]Chemistry - An Asian Journal,2017,vol. 12,p. 289 - 292

60
[ 94444-96-9 ]
C₁₅H₂₁N₃O₂ [ No CAS ]

Reference： [1]Chemistry - An Asian Journal,2017,vol. 12,p. 289 - 292
[2]Synlett,2020,vol. 31,p. 77 - 82

61
[ 32315-10-9 ]
[ 94444-96-9 ]
C₉H₇ClN₂O₂ [ No CAS ]

Reference： [1]Chemistry - An Asian Journal,2017,vol. 12,p. 289 - 292
[2]Synlett,2020,vol. 31,p. 77 - 82

Yield	Reaction Conditions	Operation in experiment
	With magnesium; In methanol; at 20℃; for 3h;Inert atmosphere;	General procedure: Route 1: Argon under the protection,Compound 2 (0.2 mmol) was dissolved in 2 mL of methanol,Add magnesium powder,Room temperature reaction for 3 hours,The organic phase was washed with saturated ammonium chloride solution and brine, dried over anhydrous MgSO4, the solvent was evaporated under reduced pressure, and the column was evaporated on the column.The compound 3 was isolated by chromatography.

63
[ 94444-96-9 ]
N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(5-methoxy-1H-indazol-1-yl)pyrimidin-2-amine [ No CAS ]

Reference： [1]Patent: EP3205650,2017,A1

64
[ 49844-90-8 ]
[ 94444-96-9 ]
5-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium hydride; In N,N-dimethyl-formamide; at 0℃; for 2h;Inert atmosphere;	5-methoxy-1H-indazole (500 mg, 3.38 mmol) was dissolved in DMF (10 mL). NaH (148 mg, 3.72 mmol) was added at 0 °C, and then 4-chloro-2-(methylthio)pyrimidine (542 mg, 3.38 mmol) was added. After stirring at this temperature for 2 hours, 30 mL of water was added. The reaction solution was filtered, extracted and dried to obtain 5-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-indazole (850 mg, 92percent) as a white solid.

Reference： [1]Patent: EP3205650,2017,A1 .Location in patent: Paragraph 0106; 0313; 0314

65
[ 49844-90-8 ]
[ 94444-96-9 ]
5-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-indazole [ No CAS ]

Reference： [1]Patent: EP3205650,2017,A1

66
[ 94444-96-9 ]
N₁-(2-(dimethylamino)ethyl)-5-methoxy-N₄-(4-(5-methoxy-1H-indazol-1-yl)pyrimidin-2-yl)-N₁-methyl-2-nitrobenzene-1,4-diamine [ No CAS ]

Reference： [1]Patent: EP3205650,2017,A1

67
[ 94444-96-9 ]
4-bromo-1H-indazol-5-ol [ No CAS ]