[ CAS No. 404827-77-6 ] {[proInfo.proName]}

Name: 404827-77-6|6-Bromo-1H-indazol-3-amine|98%
Brand: Ambeed
SKU: A219894
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Quality Control of [ 404827-77-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 404827-77-6 ]

CAS No. :	404827-77-6	MDL No. :	MFCD05665872
Formula :	C₇H₆BrN₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WLDHNAMVDBASAW-UHFFFAOYSA-N
M.W :	212.05	Pubchem ID :	2786631
Synonyms :

Calculated chemistry of [ 404827-77-6 ] Expand+

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	2.0
Molar Refractivity :	48.2
TPSA :	54.7 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) :	-6.24 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.31
Log Po/w (XLOGP3) :	1.9
Log Po/w (WLOGP) :	1.92
Log Po/w (MLOGP) :	1.95
Log Po/w (SILICOS-IT) :	1.99
Consensus Log Po/w :	1.81

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.96
Solubility :	0.234 mg/ml ; 0.0011 mol/l
Class :	Soluble
Log S (Ali) :	-2.67
Solubility :	0.452 mg/ml ; 0.00213 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.41
Solubility :	0.0823 mg/ml ; 0.000388 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.75

Safety of [ 404827-77-6 ]

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 [ 404827-77-6 ]

* 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 [ 404827-77-6 ]
Downstream synthetic route of [ 404827-77-6 ]

[ 404827-77-6 ] Synthesis Path-Upstream 1~2

1
[ 105942-08-3 ]
[ 404827-77-6 ]

Yield	Reaction Conditions	Operation in experiment
85.7%	With hydrazine hydrate In butan-1-ol for 4 h; Inert atmosphere; Reflux	Under nitrogen protection, 4-bromo-2-fluorobenzonitrile (5 g, 25.13 mmol) was dissolved in 20 mL of n-butanol,Hydrazine hydrate (1.04 mL, 50.26 mmol) was added,Heated to reflux for 4 h. After cooling to room temperature, a large amount of solid was precipitated.The filter cake was washed with suction and petroleum ether, dried to give 4.759 g of a white solid,Yield 85.7percent.
85.7%	With hydrazine In ethanol for 4 h; Reflux	4-Bromo-2-fluorobenzonitrile (5.0 g, 25.1 mmol) was dissolvedin absolute ethyl alcohol (20 mL), then followed by the addition ofNH2NH2 (1.0 mL, 50.3 mmol). The reaction mixture was heated toreflux for 4 h, then cooled to rt, filtered, washed with petroleumether and dried to give 3 as white solid (4.8 g, 85.7percent). 1H NMR(400 MHz, DMSO d6) d: 11.52 (brs, 1H), 7.64 (d, J = 8.5 Hz, 1H),7.37–7.52 (m, 1H), 7.02 (dd, J = 8.5, 1.6 Hz, 1H), 5.47 (brs, 2H).ESI-MS (m/z): [M+H]+ = 213.0 (Calcd: 213.05).
79.2%	With hydrazine hydrate In butan-1-ol at 100℃; for 14 h;	400 mg of 4-bromo-2-fluorobenzonitrile was dissolved in 6 ml of n-butanol and 0.46 ml of hydrazine hydrate (85percent, w / w)The mixture was heated to 100 ° C and stirred for 14 hours. After heating, the reaction solution was concentrated to 2 ml, filtered, washed with water and a small amount of ethyl acetateThe cake and filter cake were dried in vacuo to give 336 mg of a pale orange solid in a yield of 79.2percent.

76%	With hydrazine hydrate In ethanol at 70℃; for 5 h;	2-Fluoro-4-bromo-benzonitrile (26.9 mmol, 5.38 g) and hydrazine hydrate 50percent (107.6 mmol, 6.7 ml) were dissolved in ethanol (90 ml) and heated at 70°C for 5 hours. After cooling to room temperature the title compound was filtered and isolated as a white solid (4.36 g, 76percent).1HNMR(400 MHz, DMSO-d6)ö 11.51 (s, 1H), 7.63 (dd,J= 8.5, 0.5 Hz, 1H), 7.42 (dd, J= 1.6, 0.5 Hz, 1H), 7.02 (dd, J= 8.5, 1.6 Hz, 1H), 5.47 (s, 2H).13C NMR (101 MHz, DMSO-d6)ö 149.4, 142.1, 122.1, 120.3, 119.8, 113.1, 111.8. (ESI+) MS: mlz 233.1 (MNa+).
653.7 mg	With hydrazine hydrate In butan-1-ol at 120℃; for 4 h;	4-Bromo-2-fluorobenzonitrile (5 g, 25.13 mmol) was dissolved in n-butanol (20mL), followed by the addition of NH₂NH₂(1.04 mL, 50.26 mmol). The reaction mixture was heated to reflux for 4 h, then cooled to rt, filtered, washed with n-hexane and dried to give 9 as a white solid (4.76g, 85.7percent).¹H NMR (400 MHz, DMSO-d₆) δ 11.52 (brs, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.37–7.52 (m, 1H), 7.02 (dd, J = 8.5, 1.6 Hz,1H), 5.47 (brs, 2H). ESI-MS (m/z): [M + H]⁺ = 213.0.

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4579 - 4584
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 6, p. 1985 - 1989
[3] Patent: CN106032359, 2016, A, . Location in patent: Paragraph 0044; 0045; 0046
[4] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 3, p. 747 - 757
[5] Patent: CN106146493, 2016, A, . Location in patent: Paragraph 0452; 0453; 0454; 0455
[6] Patent: WO2016/96709, 2016, A1, . Location in patent: Page/Page column 51; 52
[7] Organic Process Research and Development, 2011, vol. 15, # 3, p. 565 - 569
[8] Patent: US2006/106083, 2006, A1, . Location in patent: Page/Page column 23
[9] Patent: US2007/161626, 2007, A1, . Location in patent: Page/Page column 8
[10] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 1, p. 279 - 282
[11] Patent: US2004/14802, 2004, A1, . Location in patent: Page/Page column 17
[12] Patent: WO2011/115725, 2011, A2, . Location in patent: Page/Page column 51
[13] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 16, p. 3782 - 3786
[14] Advanced Synthesis and Catalysis, 2018, vol. 360, # 10, p. 1943 - 1948

2
[ 404827-77-6 ]
[ 74-88-4 ]
[ 1214899-85-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5 h; Stage #2: at 0 - 20℃; for 2 h;	Intermediate 3. 6-bromo-1 -methyl-1 H-indazol-3-amine A solution of 6-bromo-1 /-/-indazol-3-amine (788mg, 3.71 mmol) in dimethylformamide (3ml_) was cooled to 0°C and sodium hydride (60percent of an oil dispersion; 163mg, 6.79mmol) was added in portions. The mixture was stirred for 30 minutes at 0°C. Methyl iodide (225μΙ_, 4.09mmol) was added into the mixture and stirred for 2 hours at room temperature. Water was added into the crude mixture and a red solid precipitates. The crude mixture was filtered and dried. A red solid was obtained as the title compound (80percent of yield). LRMS (m/z): 226 (M)⁺, 228 (M+2)⁺ ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.75 (s, 3H); 5.7 (s, 2H); 7.01 (d, 1 H); 7.59 (d, 1 H); 7.6 (s, 1 H).

Reference： [1] Patent: WO2016/150971, 2016, A1, . Location in patent: Page/Page column 23

[ 404827-77-6 ] Synthesis Path-Downstream 1~56

1
[ 404827-77-6 ]
[ 625-35-4 ]
[ 599191-41-0 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 3 - 19℃; for 12h;	1.07 cm3 of crotonyl chloride are added to 2 g of <strong>[404827-77-6]6-bromo-1H-indazole-3-amine</strong>, prepared previously, in 30 cm3 of pyridine, cooled to about 3 C. The medium is allowed to return to about 19 C. over 12 hours. The reaction medium is evaporated under reduced pressure (2 kPa; 50 C.) and the residue is taken up in 20 cm3 of ethyl acetate and 20 cm3 of distilled water. The aqueous phase is re-extracted with 20 cm3 of ethyl acetate. The aqueous phases are combined and then evaporated under the conditions described previously. The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 mum; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 by volume) and collecting 15 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50 C.). After drying (90 Pa; 45 C.), 130 mg of N-(6-bromo-1H-indazol-3-yl)-2-butenamide (E form) are obtained in the form of a beige-coloured solid melting at 232 C. [0441] 1H NMR spectrum (300 MHz, (CD3)2SO-d6, delta in ppm): 1.91 (dd, J=7 and 1.5 Hz: 3H); 6.27 (dd, J=15 and 1.5 Hz: 1H); 6.89 (dq, J=15 and 7 Hz: 1H); 7.20 (dd, J=9 and 2 Hz: 1H); 7.68 (d, J=2 Hz: 1H); 7.87 (d, J=9 Hz: 1H); 10.54 (unresolved peak: 1H); 12.80 (broad unresolved peak: 1H).

Reference： [1]Patent: US2004/14802,2004,A1 .Location in patent: Page/Page column 17

2
[ 404827-77-6 ]
[ 141-75-3 ]
[ 599191-53-4 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 5 - 19℃; for 50h;	0.24 cm3 of butyryl chloride is added to 500 mg of <strong>[404827-77-6]6-bromo-1H-indazole-3-amine</strong> described previously in Example 12, in 15 cm3 of pyridine, and cooled to about 50C. The reaction medium is allowed to return to about 19 C. over 50 hours. The reaction medium is evaporated under reduced pressure (2 kPa; 50 C.). The residue is taken up in 15 cm3 of ethyl acetate and 15 cm3 of distilled water. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 50 C.). The residue is taken up in 15 cm3 of dichloromethane and filtered to give after drying (90 Pa; 50 C.), 356 mg of N-[6-bromo-1H-indazol-3-yl]butanamide in the form of an off-white solid melting at 202 C. [0483] 1H NMR spectrum (300 MHz, (CD3)2SO-d6, delta in ppm): 0.98 (broad t, J=7.5 Hz: 3H); 1.67 (mt: 2H); 2.39 (broad t, J=7 Hz: 2H); 7.20 (broad d, J=9 Hz: 1H); 7.68 (broad s: 1H); 7.78 (broad d, J=9 Hz: 1H); 10.40 (unresolved peak: 1H); 12.75 (unresolved peak: 1H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1985 - 1989
[2]Patent: US2004/14802,2004,A1 .Location in patent: Page/Page column 20

3
[ 105942-08-3 ]
[ 404827-77-6 ]

Yield	Reaction Conditions	Operation in experiment
85.7%	With hydrazine hydrate; In butan-1-ol; for 4h;Inert atmosphere; Reflux;	Under nitrogen protection, 4-bromo-2-fluorobenzonitrile (5 g, 25.13 mmol) was dissolved in 20 mL of n-butanol,Hydrazine hydrate (1.04 mL, 50.26 mmol) was added,Heated to reflux for 4 h. After cooling to room temperature, a large amount of solid was precipitated.The filter cake was washed with suction and petroleum ether, dried to give 4.759 g of a white solid,Yield 85.7%.
85.7%	With hydrazine; In ethanol; for 4h;Reflux;	4-Bromo-2-fluorobenzonitrile (5.0 g, 25.1 mmol) was dissolvedin absolute ethyl alcohol (20 mL), then followed by the addition ofNH2NH2 (1.0 mL, 50.3 mmol). The reaction mixture was heated toreflux for 4 h, then cooled to rt, filtered, washed with petroleumether and dried to give 3 as white solid (4.8 g, 85.7%). 1H NMR(400 MHz, DMSO d6) d: 11.52 (brs, 1H), 7.64 (d, J = 8.5 Hz, 1H),7.37-7.52 (m, 1H), 7.02 (dd, J = 8.5, 1.6 Hz, 1H), 5.47 (brs, 2H).ESI-MS (m/z): [M+H]+ = 213.0 (Calcd: 213.05).
85%	With hydrazine hydrate; In butan-1-ol; for 4h;Reflux;	4-bromo-2-fluorobenzonitrile (5.0 g, 25.1 mmol) was dissolvedin 1-butanol (20 mL), then followed by the addition of hydrazinemonohydrate (1.0 mL, 50.3 mmol). The reaction mixture washeated to reflux for 4 h. Then cooled to room temperture, filtered,washed with n-hexane and dried to give 4 as white solid (4.77 g,85%).

79.2%	With hydrazine hydrate; In butan-1-ol; at 100℃; for 14h;	400 mg of 4-bromo-2-fluorobenzonitrile was dissolved in 6 ml of n-butanol and 0.46 ml of hydrazine hydrate (85%, w / w)The mixture was heated to 100 C and stirred for 14 hours. After heating, the reaction solution was concentrated to 2 ml, filtered, washed with water and a small amount of ethyl acetateThe cake and filter cake were dried in vacuo to give 336 mg of a pale orange solid in a yield of 79.2%.
76%	With hydrazine hydrate; In ethanol; at 70℃; for 5h;	2-Fluoro-4-bromo-benzonitrile (26.9 mmol, 5.38 g) and hydrazine hydrate 50% (107.6 mmol, 6.7 ml) were dissolved in ethanol (90 ml) and heated at 70C for 5 hours. After cooling to room temperature the title compound was filtered and isolated as a white solid (4.36 g, 76%).1HNMR(400 MHz, DMSO-d6)oe 11.51 (s, 1H), 7.63 (dd,J= 8.5, 0.5 Hz, 1H), 7.42 (dd, J= 1.6, 0.5 Hz, 1H), 7.02 (dd, J= 8.5, 1.6 Hz, 1H), 5.47 (s, 2H).13C NMR (101 MHz, DMSO-d6)oe 149.4, 142.1, 122.1, 120.3, 119.8, 113.1, 111.8. (ESI+) MS: mlz 233.1 (MNa+).
	With hydrazine; In butan-1-ol; at 112℃; for 5h;	EXAMPLE 1 6-bromo-1H-indazol-3-amine 4-bromo-2-fluorobenzonitrile (67.8 g), hydrazine hydrate (32.8 ml) in n-butanol (410 ml) were heated to 112 C. for five hours. The reaction mixture was allowed to cool down to r.t. The precipitated crystalline solid was filtered off and washed three times with ethylacetate (100 ml each). The product was dried in vacuo at 40 C. mp. 222-225 C. [M+H]+=213; 1H-NMR (300 MHz DMSO-d6): 11.43 (s, 1H); 7.61 (d, 1H); 7.4 (d, 1H); 7.0 (d of d, 1H); 5.4 (s, 2H)
	With hydrazine; In ethanol; for 22h;Heating / reflux;	6-Bromo-3-amino-1H-indazole; A solution of 10 g of 4-bromo-2-fluorobenzonitrile in 300 mL of ethanol is admixed with 7.29 mL of hydrazine hydrate. The reaction mixture is stirred for 22 hours at reflux and then concentrated under reduced pressure. The residue obtained is stirred for 30 minutes in 200 mL of distilled water. The suspended solid is isolated by filtration, washed with water and treated with suction. After drying under vacuum, 10 g of 6-bromo-3-amino-1H-indazole are obtained, whose characteristics are as follows: MS spectrum (ES+): m/z=213 [MH+]Melting point: 249 C.
	With hydrazine; In ethanol; water; at 78℃; for 12h;Heating / reflux;	7.3 cm3 of hydrazine monohydrate are added to 10 g of 4-bromo-2-fluorobenzonitrile in 100 cm3 of ethanol. The medium is refluxed at about 78 C. for 12 hours. The precipitate formed is then filtered off on a sinter funnel. After drying (90 Pa; 45 C.), 9.7 g of 6-bromo-1H-indazole-3-amine are obtained in the form of a white solid. [0438] 1H NMR spectrum (300 MHz, (CD3)2SO-d6, delta in ppm): 5.45 (broad s: 2H); 7.03 (dd, J=9 and 2 Hz: 1H); 7.43 (d, J=2 Hz: 1H); 7.65 (d, J=9 Hz: 1H); 11.50 (unresolved peak: 1H).
	With hydrazine hydrate; In butan-1-ol; at 130℃;	The reaction mixture of 4-bromo-2-fluorobenzonitrile ( 10 g, 50 mmol), hydrazine hydrate (7.85 ml, 250 mmol) in n-butanol (60 mL) was heated at 130 C for overnight. After cooling down to room temperature, the precipitated crystalline solid was filtered off and washed three times with ethyl acetate ( 15 mL each). The product was dried in vacuo ( 10.3 g). NMR 600 MHz (DMSO-d6) delta 1 1 .48 (s, I H); 7.62 (d, 8.4 Hz, I H), 7.40 (d, 1 .2 Hz, I H), 6.99 (dd, 8.4, 1 .2 Hz, I H), 5.43 (s, 2H). MS m/z : 21 1 .97(M + 1 )
653.7 mg	With hydrazine hydrate; In butan-1-ol; at 120℃; for 4h;	4-Bromo-2-fluorobenzonitrile (5 g, 25.13 mmol) was dissolved in n-butanol (20mL), followed by the addition of NH2NH2 (1.04 mL, 50.26 mmol). The reaction mixture was heated to reflux for 4 h, then cooled to rt, filtered, washed with n-hexane and dried to give 9 as a white solid (4.76g, 85.7%).1H NMR (400 MHz, DMSO-d6) delta 11.52 (brs, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.37-7.52 (m, 1H), 7.02 (dd, J = 8.5, 1.6 Hz,1H), 5.47 (brs, 2H). ESI-MS (m/z): [M + H]+ = 213.0.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4579 - 4584
[2]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1985 - 1989
[3]Journal of Enzyme Inhibition and Medicinal Chemistry,2020,vol. 35,p. 72 - 84
[4]Patent: CN106032359,2016,A .Location in patent: Paragraph 0044; 0045; 0046
[5]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 747 - 757
[6]European Journal of Medicinal Chemistry,2019,vol. 178,p. 232 - 242
[7]Patent: CN106146493,2016,A .Location in patent: Paragraph 0452; 0453; 0454; 0455
[8]Patent: WO2016/96709,2016,A1 .Location in patent: Page/Page column 51; 52
[9]Organic process research and development,2011,vol. 15,p. 565 - 569
[10]Patent: US2006/106083,2006,A1 .Location in patent: Page/Page column 23
[11]Patent: US2007/161626,2007,A1 .Location in patent: Page/Page column 8
[12]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 279 - 282
[13]Patent: US2004/14802,2004,A1 .Location in patent: Page/Page column 17
[14]Patent: WO2011/115725,2011,A2 .Location in patent: Page/Page column 51
[15]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3782 - 3786
[16]Advanced Synthesis and Catalysis,2018,vol. 360,p. 1943 - 1948

4
trityl chloride polystyrene resin [ No CAS ]
[ 404827-77-6 ]
C₂₉H₂₄BrN₄Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 20℃; for 48h;	EXAMPLE 3; N'-(6-bromo-1-trityl resin-1H-indazol-3-yl)-N,N-dimethylimidoformamide; To commercial polystyrene resin bearing TritylChloride (loading 0.75-1.35 mmol/g, 125 g) and <strong>[404827-77-6]6-bromo-1H-indazol-3-amine</strong> (62.5 g), 62.5 ml of dry 1,8-diazabiciclo[5.4.0]undec-7-ene (DBU) and dry dimethylformamide (900 ml) were added. The slurry was stirred for 48 hours at room temperature under exclusion of moisture with a mechanical overhead stirrer. An aliquot of the slurry containing 10-50 mg of resin was removed from the reaction mixture, transferred into a sinter glass frit with a valve on its bottom and washed the following way: 3× a) 1 ml DMF; b) 1 ml H2O 2× a) 1 ml MeOH; b) 1 ml DMF 1×1 ml MeOH 2× a) 1 ml toluene; 1 ml diethylether 3×1 ml diethylether. The resin was dried in vacuo, then weighed. From the known amount of resin the bound indazole was determined upon cleavage using TFA whereby collecting the cleavage solutions. The cleavage was performed the following way: 1×0.5 ml 20% TFA/DCM 5 min. 4×0.2 ml 20% TFA/DCM 2 min. The combined cleavage solutions combined and then dried in vacuo. The dried TFA-salt of the N'-(6-bromo-1H-indazol-3-yl)-N,N-dimethylimidoformamide was weighed, and analyzed. The weight of the recovered material revealed the loading of the resin. When the loading exceeded 0.7 mmol/g the immobilization reaction was quenched upon addition of MeOH (100 ml). The slurry was transferred into a commercial ?resin wash station? (Rink) an washed as follows: 3×700 ml DMF: the effluent from the washing vessel was collected to recover unused indazole. 3× a) 700 ml DMF; b) 700 ml H2O 2× a) 700 ml MeOH; b) 700 ml DMF 1×700 ml MeOH 2× a) 700 ml toluene; 700 ml diisopropylether 3×700 ml diisopropylether. The resin was dried in vacuo until constancy of weight. The weight of the resin revealed the loading of the indazole. The loading determined by weight increase corresponded to that determined by cleavage.

Reference： [1]Patent: US2006/106083,2006,A1 .Location in patent: Page/Page column 23-24

5
[ 41507-35-1 ]
[ 404827-77-6 ]
[ 1279846-99-9 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 25℃; for 16h;	6-Bromo-1-[(thiophen-2-yl)carbonyl]-3-[(thiophen-2-yl)carbonylamino]indazole; A solution of 10 g of 6-bromo-3-amino-1H-indazole in 250 mL of pyridine is admixed with 13.8 g of 3-thiophenecarboxylic chloride. The reaction mixture is stirred under an argon atmosphere for 16 hours at a temperature close to 25 C. and then poured into 400 mL of water. The suspension is then filtered and the product is washed with 2×80 mL of water, treated with suction and dried, to give 19.27 g of 6-bromo-1-[(thiophen-2-yl)carbonyl]-3-[(thiophen-2-yl)carbonylamino]indazole, whose characteristics are as follows: MS spectrum (ES+): m/z=433 [MH+]

Reference： [1]Patent: US2007/161626,2007,A1 .Location in patent: Page/Page column 7-8

6
[ 404827-77-6 ]
[ 74-88-4 ]
[ 1214899-85-0 ]

Yield	Reaction Conditions	Operation in experiment
80%		Intermediate 3. 6-bromo-1 -methyl-1 H-indazol-3-amine A solution of 6-bromo-1 /-/-indazol-3-amine (788mg, 3.71 mmol) in dimethylformamide (3ml_) was cooled to 0C and sodium hydride (60% of an oil dispersion; 163mg, 6.79mmol) was added in portions. The mixture was stirred for 30 minutes at 0C. Methyl iodide (225muIota_, 4.09mmol) was added into the mixture and stirred for 2 hours at room temperature. Water was added into the crude mixture and a red solid precipitates. The crude mixture was filtered and dried. A red solid was obtained as the title compound (80% of yield). LRMS (m/z): 226 (M)+, 228 (M+2)+ 1H NMR (300 MHz, DMSO-d6) delta ppm 3.75 (s, 3H); 5.7 (s, 2H); 7.01 (d, 1 H); 7.59 (d, 1 H); 7.6 (s, 1 H).

Reference： [1]Patent: WO2016/150971,2016,A1 .Location in patent: Page/Page column 23

7
[ 404827-77-6 ]
[ 108-24-7 ]
[ 1227909-36-5 ]

Yield	Reaction Conditions	Operation in experiment
68%	With dmap; at 120℃; for 5h;Inert atmosphere;	Intermediate 6; Lambda/-Acetyl-Lambda/-(1-acetyl-6-bromo-1/-/-indazol-3-yl)acetamide; In a 100 mL flask under argon were combined 6-bromo-1 /-/-indazol-3-amine (2.47 g, 1 1.7 mmol), acetic anhydride (22.0 mL, 233 mmol), and DMAP (0.07 g, 0.58 mmol). The reaction mixture was heated at 120 0C for 5 hours after which time it was cooled to room temperature and stirred overnight. LCMS shows a mixture of 2 products, bis- and tris- acetylated. The reaction mixture was concentrated to dryness. The resulting residue was dry-loaded in acetone onto Sitheta2 and chromatographed on 90 g Sitheta2 (Analogix) using a EtOAc/Hexanes gradient. The first compound to elute is the desired tris-acetylated product. The fractions were combined and concentrated to afford the title compound (2.84 g, 68%) as a white solid. 1H NMR (400 MHz, DMSOd6): delta 2.31 (s, 6H), 2.70 (s, 3H), 7.67 (dd, J = 8.6, 1.8 Hz, 1 H), 7.83 (d, J = 8.6 Hz, 1 H), 8.53 (d, J = 1.5 Hz, 1 H).

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 90
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 1871 - 1895

8
[ 404827-77-6 ]
[ 24424-99-5 ]
[ 1227911-38-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-ethyl-N,N-diisopropylamine;dmap; In tetrahydrofuran; at 0 - 20℃; for 3h;	tert-Butyl 3-(bis(tert-butoxycarbonyl)amino)-6-bromo-lH- indazole-1-carboxylate [0096] To a cooled (0 0C) solution of 6-bromo-lH-indazol-3 -amine (0.30 g, 1.4 mmol), DIPEA (2.5 mL, 14 mmol) and di tert-butyl dicarbonate (1.5 g, 7.0 mmol) in THF (15 mL) was added DMAP (0.09 g, 0.70 mmol). The reaction mixture was then stirred at ambient temperature for three hours. The resulting solution was diluted with ethyl acetate (75 mL) and washed with saturated aqueous ammonium chloride (2 x 50 mL). The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography provided tert-butyl 3-(bis(tert- butoxycarbonyl)amino)-6-bromo-lH-indazole-l-carboxylate (0.57 g, 80%) as a waxy solid. MS (ES) for C22H30BrN3O6: 512 (MH+).
	With dmap; In acetonitrile; at 20 - 80℃; for 1.08333h;	Intermediate 117; 1 ,1-Dimethylethyl 3-(bis{r(1 ,1-dimethylethyl)oxylcarbonyl}amino)-6-bromo-1 /-/-indazole-1- carboxylate; To a stirred suspension of 6-bromo-1/-/-indazol-3-amine (25 g, 118 mmol) and DMAP (0.72 g, 5 mole%) in CH3CN (400 mL) was added (Boc)2O (129 g, 589 mmol, 5 equiv) in one portion, followed by heating to 80 0C for 1 hour, and then cooling to 45 0C. To the mixture was added another 30 g of (Boc)2O. The mixture was stirred at ambient temperature for 20 minutes and concentrated in vacuo. The resulting residue was partitioned between CH2CI2 (500 mL) and water (250 mL). The organic was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give an oil (95 g), which upon aging at rt for 48 hours became a suspension. To this mixture was added some hexane, and chilled in the refrigerator. The solids formed were collected by filtration, and washed with cold hexane (100 ml_). Drying under vacuum at room temperature gave 37.58 g of the title compound as a beige solid. LC-MS (ES) m/z = 512, 514 [M+H]+.
	With triethylamine; In tetrahydrofuran; at 20℃; for 72h;	6-Bromo-1H-indazol-3-amine (500 mg, 2.36 mmol) was dissolved in THF (10 mL). Di-tert-butyl dicarbonate (2.52 mL, 11.8 mmol) and triethylamine (3.27 mL, 23.6 mmol) were added and the reaction as stirred 3 days at RT. The reaction mixture was poured into 100 ml of water. The mixture was extracted twice with ethyl acetate. The organic layer was washed with water, dried, filtered and evaporated to dryness to yield in 1 .42 g (73% purity, 2.02 mmol, 86%) of a brown oil.

With dmap; triethylamine; In tetrahydrofuran; at 20℃; for 72h;

21 a. tert-Butyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-indazole-1 -carboxylate In a screw-capped vessel 6-bromo-1 H-indazol-3-amine (95 % purity,500 mg, 2.36 mmol) and 4-(dimethylamino)-pyridine (57.6 mg, 0.47mmol) were dissolved in THF SeccoSolv (10 mL). Di-tertBrbutyldicarbonate (2.52 mL, 11.8 mmol) and triethylammne (3.27 mL,23.6 mmol) were added and the reaction solution was stirred 3 days at RT. The reaction mixture was treated with 100 mL of water. The oily residue did not crystallize. The mixture was taken up in EtOAc and washed with water, dried, filtered and evaporated to dryness to give the title compound (1.01 g , 73 % purity, 86 %) as a colorless oil, which was used without further purification. LC/MS (Method B): Rt 3.87 mm, (M÷Na) 534/536.

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 73 - 78
[2]Patent: WO2010/135568,2010,A1 .Location in patent: Page/Page column 33
[3]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 191-192
[4]Patent: WO2014/63778,2014,A1 .Location in patent: Page/Page column 49; 50
[5]Patent: WO2015/144290,2015,A1 .Location in patent: Page/Page column 100
[6]Journal of Medicinal Chemistry,2016,vol. 59,p. 1078 - 1101

9
[ 876322-58-6 ]
[ 404827-77-6 ]
[ 1238376-14-1 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 120℃; for 0.25h;Inert atmosphere; Microwave irradiation;	Example 121; N-[3-(3-amino-1H-indazol-6-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide (Scheme 3); A solution of N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)benzamide (intermediate 3.2.1, 40 mg, 0.1 mmol) and <strong>[404827-77-6]6-bromo-1H-indazol-3-amine</strong> (23 mg, 0.11 mmol) in DMF (0.5 mL) and 1M cesium carbonate (0.25 mL) is degassed with nitrogen for 2 min. 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride, DCM complex (4 mg, 0.005 mmol) was added and the reaction mixture was irradiated at 120 C. in a microwave for 15 min. The reaction mixture was filtered and purified by reverse phase preparative HPLC to provide N-[3-(3-amino-1H-indazol-6-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide as a TFA salt. MS M+1=411.

Reference： [1]Patent: US2010/197688,2010,A1 .Location in patent: Page/Page column 50

10
[ 404827-77-6 ]
[ 24424-99-5 ]
[ 1257211-58-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With dmap; In tetrahydrofuran; for 30h;	To a solution of 6-bromo-lH-indazol-3 -amine (0.5 g, 2.4 mmol) in THF (10 mL) at room temperature was added di-te/t-butyl dicarbonate (0.5 g, 2.4 mmol) followed by 4-di m e t h y I a m i n o p y ridinc (0.01 g, 0.08 mmol ). The resulting mixture was allowed to stir for 30 h. Then the reaction mixture was concentrated under reduced pressure to provide a yellowish semisolid. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (dichloromethane/methanol 98:2) to give tert-butyl 3-amino-6- bromo-lH-indazole-l-carboxylate (0.7 g, 95%) as a solid. The obtained product (0.1 g, 0.3 mmol) was dissolved in acetic anhydride (2 mL) and 4-dimethylaminopyridine was added. The reaction mixture was stirred at room temperature overnight and then at 100C for 3h. After cooled to ambient temperature the solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (silica gel; dichloromethane 100%). The tert-butyl 6-bromo-3- acetamido-lH-indazole-l-carboxylate was obtained as a solid (0.054 g); yield 61%. LC-MS (m/z) 355.9 (M+l).
88.8%	With dmap; In tetrahydrofuran; at 20℃; for 3h;Inert atmosphere; Cooling with ice;	Under nitrogen protection, <strong>[404827-77-6]6-bromo-1H-indazol-3-amine</strong> (4.759 g, 22.43 mmol) was dissolved in 20 mL of tetrahydrofuran, di-tert-butyl dicarbonate (5.385 g, 24.67 mmol) was added under ice-cooling,4-dimethylaminopyridine (1.0 g, 8.19 mmol).After reaction at room temperature for 3 h,TLC (petroleum ether / ethyl acetate = 1/1) showed disappearance of the starting material,The reaction mixture was concentrated under reduced pressure,The residue was acidified by addition of 1 mol / L hydrochloric acid,Ethyl acetate extraction.The extract was washed with saturated brine, dried over anhydrous sodium sulfate,Concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 2/1) to obtain 6.964 g of a yellow solid, yield 88.8%.
88.8%	With dmap; In tetrahydrofuran; for 2h;	DMAP (100.0 mg) and Boc2O (566.1 mg, 2.6 mmol) were addedto the solution of building block 2 (500.0 mg, 2.4 mmol) in THF (10mL). The reaction mixture was stirred for 2 h and monitored byTLC. After concentrated, the residue was dissolved in EtOAc (100mL) and washed with 1 M HCl (20 mL 2), NaHCO3 (20 mL 2)and brine (20 mL 2), dried over Mg2SO4, and concentrated invacuo. The residue was purified by chromatography on silica gelusing petroleum ether-EtOAc (1:1) to give 3 as white solid(653.7 mg, 88.8%). 1H NMR (400 MHz, DMSO d6) d: 8.12 (s, 1H),7.80 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 8.4, 1.7 Hz, 1H), 6.44 (s, 2H),1.57 (s, 9H). ESI-MS (m/z): [M+H]+ = 313.0 (Calcd: 313.16).

72%	With dmap; In tetrahydrofuran; at 20℃; for 74h;	Step A - Synthesis of Compound Int-42bTo a solution of 6-bromo-lH-indazol-3-amine Int-42a (5 g, 24 mmol) in THF (100 mL) at rt was added Boc20 (5.2 g, 23.7 mmol) followed by DMAP (0.10 g, 0.82 mmol). The resulting mixture was allowed to stir for 72 h. A small portion of Boc20 (0.60 g, 2.8 mmol) was added and the mixture was allowed to stir for 2h. The reaction mixture was concentrated in vacuo to provide a yellowish semisolid. The material was taken up in CH2CI2 (-20 mL) and was filtered to removed a light yellow solid which was set aside. The filtrate was loaded directly onto a 220 g silica gel column and a gradient of 100% hexanes to 100% EtOAc was run over ~ 50 minutes to provide 5.3 g (72%) of Int-42b as a yellow solid.
50%	With dmap; triethylamine; In acetonitrile; at 20℃; for 7h;	To a solution of <strong>[404827-77-6]6-bromo-1H-indazole-3-amine</strong> (20.3 g, 95.7 mmol) in acetonitrile (200 mL) in a round-bottom flask were added di-tert-butyl dicarbonate (31.3 g, 144 mmol), triethylamine (19.9 mL, 144 mmol) and 4-dimethylaminopyridine (1.17 g, 9.57 mmol). The resulting mixture was stirred at room temperature for 7 hours, then concentrated under reduced pressure. Purification by flash chromatography on silica gel (0% to 50% AcOEt/n-hexane linear gradient) provided the title compound (14.9 g, 47.8 mmol, 50% yield): 1H NMR (500 MHz, CDCl3) delta 8.31 (brs,1 H), 7.38 (s, 2H), 4.44 (brs, 2H), 1.67 (s, 9H).
50%	With dmap; triethylamine; In tetrahydrofuran; at 20℃; for 7h;	Toa solution of <strong>[404827-77-6]6-bromo-1H-indazole-3-amine</strong> (20.3 g, 95.7mmol) inacetonitrile (200 mL) in a round-bottom flask were added di-tert-butyl dicarbonate (31.3 g,144 mmol), triethylamine (19.9 mL, 144 mmol) and 4-dimethylaminopyridine (1.17 g, 9.57mmol). The resulting mixture was stirred at roomtemperature for 7 hours, then concentrated under reduced pressure. Purification by flash chromatography on silica gel(0% to 50% AcOEt/n-hexanelinear gradient) provided the title compound (14.9 g,47.8 mmol, 50% yield): 1H NMR (500 MHz, CDCl3) d 8.31 (brs,1H), 7.38 (s,2H), 4.44 (brs, 2H), 1.67(s, 9H);LCMS m/z 212[M - Boc + H]+.
		To a solution of 6-bromo-lH-indazol-3-amine (3.05 g, 14.4 mmol) in THF (60 niL) rt was added BOC2O (3.15 g, 14.4 mmol) and the mixture was allowed to stir at rt. After 2h the reaction showed only starting material by LCMS. A crystal of DMAP (ca. 40 mg) was added and stirring continued for 48 h. A further 400 mg (1.83 mmol) of BOC2O was added and stirring allowed to continue for 2h. The solvent was removed in vacuo and the residue was purified by BIOTAGE using a gradient of 20 to 100% EtOAc in hexanes (TLC 4: 1 hex:EtOAc) to afford the title compound as a light yellow foam (3.21 g, 72%). 1H NMR (400 MHz, DMSOd6) delta 8.11 (s, IH), 7.79 (d, J = 8.1 Hz, IH), 7.45 (dd, J - 2.0, 8.1 Hz, IH), 6.42 (s, 2H), 1.57 (s, 9H). LCMS: Anal. Calcd. for C12H14BrN3O2: 311, 313; found: 212, 214 (M+H-boc)+.
653.7 mg	With dmap; In tetrahydrofuran; for 1h;	DMAP (100.0 mg) and Boc2O (566.1 mg, 2.6 mmol) were added to the solution of the building block 9 (500.0 mg, 2.4 mmol) in THF (10 mL). The reaction mixture was stirred for 1 h and monitored by TLC. After concentration, the residue was dissolved in EtOAc (100 mL) and washed with 1 M HCl (20 mL × 2), NaHCO3 (20 mL × 2) and brine (20 mL × 2), dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel using petroleum ether-EtOAc (1 : 1) to give 10 as a white solid (653.7 mg, 88.8%). 1H NMR (400 MHz, DMSO-d6) delta 8.12 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.45 (dd, J =8.4, 1.7 Hz, 1H), 6.44 (s, 2H), 1.57 (s, 9H). ESI-MS (m/z): [M + H]+ = 313.0.

Reference： [1]Patent: WO2017/68064,2017,A1 .Location in patent: Page/Page column 195; 196
[2]Journal of Enzyme Inhibition and Medicinal Chemistry,2020,vol. 35,p. 72 - 84
[3]Patent: CN106032359,2016,A .Location in patent: Paragraph 0047; 0048; 0049
[4]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 747 - 757
[5]Patent: WO2013/39876,2013,A1 .Location in patent: Page/Page column 107-108
[6]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3716 - 3722
[7]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 5252 - 5257
[8]Patent: WO2010/138488,2010,A1 .Location in patent: Page/Page column 64
[9]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3782 - 3786

11
[ 404827-77-6 ]
[ 4023-34-1 ]
[ 1334419-88-3 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 0℃; for 4h;	To a solution of 6-bromo- 1 H-indazol-3-amine (4.24 g, 20 mmol) in pyridine ( 100 mL) was added cyclopropanecarbonyl chloride ( 1.83 mL, 20 mmol) dropwise at 0 C. The reaction mixture was stirred at this temperature for 4 hours. Once the reaction was completed, the solvent was removed in vacuo. The residue was dissolved in DMF, and water was added dropwise. The precipitated solid was filtered off and washed three times with hexanes ( 15 ml each). The product was dried in vacuo and used without further purification (4.3 g). NMR 600 MHz (DMSO-d6) delta 12.7 1 (s, I H), 10.72 (s, I H), 7.74 (d, 8.4 Hz, I H), 7.62 (d, 1 .2 Hz, I H), 7. 14 (dd, 8.4, 1 .2 Hz, I H), 1.90 (m, I H), 0.82 (m, 4H). MS m/z : 280.0 (M + 1 )

Reference： [1]Patent: WO2011/115725,2011,A2 .Location in patent: Page/Page column 51; 52
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4579 - 4584
[3]ACS Medicinal Chemistry Letters,2020,vol. 11,p. 340 - 345

12
[ 404827-77-6 ]
[ 1885-14-9 ]
[ 1334419-90-7 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 0℃; for 4h;	To a solution of 6-bromo- l H-indazol-3-amine ( 1.27 g, 6.0 mmol) in pyridine (24 mL) was added phenyl chloroformate (0.83 mL, 6.6 mmol) dropwise at 0 C. After stirring at this temperature for 4 hours, the reaction was quenched by water. After the solvent was removed, the residue was dissolved in ethyl acetate and washed by 1 N HC1 and brine. The organic layer was dried with sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography with 30:70 (v/v) ethyl acetate - hexanes to afford the title product (0.80 g). NMR 600 MHz (DMSO-d6) delta 12.82 (s, I H), 10.53 (br, I H), 7.77 (d, 8.4 Hz, I H), 7.68 (d, 1 .2 Hz, I H), 7.40 (m, 2H), 7.23 (m, 3H), 7.20 (dd, 8.4, 1.2 Hz, I H). MS m/z : 332.0(M + 1 )

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4579 - 4584
[2]Patent: WO2011/115725,2011,A2 .Location in patent: Page/Page column 54

13
[ 404827-77-6 ]
[ 4334-87-6 ]
[ 1334419-92-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 4h;	To a solution of 6-bromo- l H-indazol-3-amine (2. 1 g, 10.0 mmol) in dioxane ( 100 mL) and sodium carbonate ( I , 40 mL) were added 3-(ethoxycarbonyl)phenylboronic acid ( 1.94 g, 10.0 mmol) and Pd(dppf)Cl2 (816 mg, 1.0 mmol). After the reaction was stirred at 1 00 C for 4 hours and cooled to room temperature, the mixture was filtered through Celite and washed by ethyl acetate. The combined organic solution was washed by brine, dried with sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography with 50: 1 (v/v) methylene chloride - methanol to afford the title product ( 1 .46 g), MS m/z : 282. 1 1 (M + 1 )

Reference： [1]Patent: WO2011/115725,2011,A2 .Location in patent: Page/Page column 57

14
[ 404827-77-6 ]
C₁₈H₁₅N₃O₃ [ No CAS ]

Reference： [1]Patent: WO2011/115725,2011,A2
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4579 - 4584
[3]ACS Medicinal Chemistry Letters,2020,vol. 11,p. 340 - 345

15
[ 404827-77-6 ]
[ 479630-08-5 ]
tert-butyl 4-(8-bromo-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9%	With potassium phosphate; at 180℃; for 0.25h;Microwave irradiation;	Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 6-bromo- lH-indazol-3-ylamine (472 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (11 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50C in vacuo to yield the title compound (94 mg, 9% of theory) as yellowish solid. LC-MS (Method IB): Rt = 1.12 min, MS (ESIPos): m z = 447 [M+H]+
94 mg	With potassium phosphate; at 180℃; for 0.25h;Microwave irradiation;	Example 37A Tert-butyl 4-(8-bromo-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), <strong>[404827-77-6]6-bromo-1H-indazol-3-ylamine</strong> (472 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (11 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180 C. for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4:1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4:1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50 C. in vacuo to yield the title compound (94 mg, 9% of theory) as yellowish solid. LC-MS (Method 1B): Rt=1.12 min, MS (ESIPos): m/z=447 [M+H]+

Reference： [1]Patent: WO2015/67549,2015,A1 .Location in patent: Page/Page column 80; 81
[2]Patent: US2015/126449,2015,A1 .Location in patent: Paragraph 0452 - 0454

16
[ 843663-18-3 ]
[ 404827-77-6 ]
4-(3-amino-1H-indazol-6-yl)-2-fluorobenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,2-dimethoxyethane; ethanol; at 160℃; for 0.333333h;Inert atmosphere; Microwave irradiation;	Step 14-(3-amino-1H-indazol-6-yl)-2-fluorobenzonitrileTo a suspension of <strong>[404827-77-6]6-bromo-1H-indazol-3-amine</strong> (0.86 g, 4.1 mmol) and 4-cyano-3- fluorophenylboronic acid, (0.85 g, 5.15 mmol) in dimethoxyethane: ethanol (15 mL, 2:1) was added 1 M potassium carbonate (5.0 mL). The mixture was purged with nitrogen and bis(triphenylphosphine)palladium(II) dichloride (0.090 g, 0.128 mmol) was added. The reaction mixture was heated in a microwave reactor (CEM Discover, 300 W)) at 160 C for 20 minutes and then concentrated. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2x100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was triturated with ether to yield the titled compound. ?H NMR (300 MHz, DMSO-d6) 5 ppm 5.43 (s, 2H), 7.30 (dd, J=8.5, 1.4 Hz, 1H), 7.59-7.60 (m, 1H), 7.76-7.82 (m, 2H), 7.91 (dd, J=11.2, 1.7 Hz, 1H), 7.96-8.01 (m, 1H),11.62 (s, 1H); MS (ESI) m/z 253 (M+H).
	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,2-dimethoxyethane; ethanol; at 160℃; for 0.333333h;Inert atmosphere; Microwave irradiation;	Step 1 4-(3-amino-1H-indazol-6-yl)-2-fluorobenzonitrile To a suspension of <strong>[404827-77-6]6-bromo-1H-indazol-3-amine</strong> (0.86 g, 4.1 mmol) and 4-cyano-3-fluorophenylboronic acid, (0.85 g, 5.15 mmol) in dimethoxyethane:ethanol (15 mL, 2:1) was added 1 M potassium carbonate (5.0 mL). The mixture was purged with nitrogen and bis(triphenylphosphine)palladium(II) dichloride (0.090 g, 0.128 mmol) was added. The reaction mixture was heated in a microwave reactor (CEM Discover, ?300 W)) at 160 C. for 20 minutes and then concentrated. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2*100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was triturated with ether to yield the titled compound. 1H NMR (300 MHz, DMSO-d6) delta ppm 5.43 (s, 2H), 7.30 (dd, J=8.5, 1.4 Hz, 1H), 7.59-7.60 (m, 1H), 7.76-7.82 (m, 2H), 7.91 (dd, J=11.2, 1.7 Hz, 1H), 7.96-8.01 (m, 1H), 11.62 (s, 1H); MS (ESI) m/z 253 (M+H)+.

Reference： [1]Patent: WO2015/112445,2015,A1 .Location in patent: Page/Page column 96; 97
[2]Patent: US2016/376240,2016,A1 .Location in patent: Paragraph 0513

17
[ 404827-77-6 ]
[ 97674-02-7 ]
1-(3-amino-1H-indazol-6-yl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); N,N-dimethyl-formamide; at 120℃; for 4h;Sealed tube; Inert atmosphere;	Step A: 1 -(3 -Amino- 1 H-indazol-6-yl)ethan- 1-oneA mixture of <strong>[404827-77-6]3-amino-6-bromo-1H-indazole</strong> (2.13 g, 10.0 mmol), 1-ethoxy-1-(tributylstannyl)ethylene (5.10 mL, 15.1 mmol), tetrakis(triphenylphosphine)palladium(0) (1 .16g, 1.00 mmol), and degassed N,N-dimethylformamide (20.0 mL) in a sealed tube was stirred at120C for 4 hours under a nitrogen gas atmosphere and cooled to ambient temperature. To thecooled mixture was added hydrochloric acid (1.0 M in water; 170 mL, 170 mmol). The resulting mixture was stirred at ambient temperature for 4 hours and concentrated under reduced pressure. To the resulting residue was added saturated aqueous sodium bicarbonate and the pH was adjusted to 9. The precipitated solids were filtered and washed with water and hexane. The solids were purified by column chromatography (silica gel 50 g, step gradient eluting with 1:0 and 10:1ethyl acetate/methanol) to give 1-(3-amino-1H-indazol-6-yl)ethan-1-one. LCMS [M+1] = 176

Reference： [1]Patent: WO2015/164308,2015,A1 .Location in patent: Page/Page column 123; 124

18
[ 404827-77-6 ]
[ 1885-14-9 ]
[ 1334419-90-7 ]
3-amino-6-bromo-indazole-1-carboxylic acid phenyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3%; 17%	In pyridine; dichloromethane; water; at 0℃; for 4h;	17a. (6-Bromo-1H-indazol-3-yl)-carbamic acid phenyl ester In a screw-capped vessel, 6-bromo-IH-indazol-3-amine (95 %,1.00 g,4.48 mmol) was dissolved in pyridine SeccoSolv (20). At 0C phenylchloroformate, 99 % (0.62 mL, 4.93 mmol) was added dropwise. Themixture was stirred at 0C for 4hr before the mixture was diluted with DCM (50 mL) and water (50 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated to dryness. The residue was purified by flash chromatography (heptane/DCM) to yield in of the title compound (54 mg, 3 %) as a white solid. LCIMS (Method B): Rt = 2.62 mm, (Mi-H)332/334.In addition 346 mg (17 %) of 3-amino-6-bromo-indazole-1-carboxylic acid phenyl ester was isolated as a white solid.

Reference： [1]Patent: WO2015/144290,2015,A1 .Location in patent: Page/Page column 97
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 1078 - 1101

19
[ 404827-77-6 ]
2-(2,6-dichloro-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ No CAS ]
6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-indazol-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.7%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;	848 mg of 6-bromo-lH-indazol-3-amine and 2.664(2- (2,6-dichloro-3,5-dimethoxyphenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane was dissolved in 40 ml of dioxane, followed by the addition of 16 ml of an aqueous solution of sodium carbonate (1 mole per liter) and300 mg of [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride, which was heated to 100 C under argon and stirred for 18 hoursAfter heating, the reaction solution was filtered, the ethyl acetate was washed and the filtrate was separated, extracted with ethyl acetate, and the organic phase was combinedWashed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was subjected to column chromatography (dichloromethane: methanol= 99: 1-98: 2, V / V) to give 1.308 g of a yellow solid, yield96.7%.

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 629 - 634
[2]Patent: CN106146493,2016,A .Location in patent: Paragraph 0470; 0471; 0472; 0473

20
[ 404827-77-6 ]
[ 76-05-1 ]
N-(6-bromo-1H-indazol-3-yl)-2,2,2-trifluoroacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	In tetrahydrofuran; dichloromethane;Inert atmosphere;	Under nitrogen atmosphere to a cooled suspension of 6-bromo- 1 H-indazo 1-3 -amine (2.24 mmol, 475 mg) in a mixture of DCM (15 ml) and THF (2 ml), was slowly added TFA (6.7 mmol, 0.9 ml). When reaction is completed, solvent was removed and the crudedissolved in ethyl acetate, washed with a saturated solution of aqueous NaHCO3, dried over sodium sulfate, filtered and evaporated to dryness.The title compound was isolated as a white solid (789 mg, 99%).1H NMR (400 MHz, CDC13) oe 8.73 (s, 1H), 8.68- 8.61 (m, 1H), 8.16 (d, J 8.7 Hz, 1H), 7.66 (dd, J 8.8, 1.7 Hz, 1H).13C NMR (101 MHz, CDC13) oe 145.6, 142.1, 130.4, 127.0, 125.6, 118.7, 118.2,116.8, 113.9.(ESI+) MS: m/z 306.1 (MH+).

Reference： [1]Patent: WO2016/96709,2016,A1 .Location in patent: Page/Page column 52

21
[ 404827-77-6 ]
1-methyl-4-[[4-prop-2-ynoxy-2-(trifluoromethyl)phenyl]methyl]piperazine [ No CAS ]
6-[3-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenoxy]prop-1-ynyl]-1H-indazol-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In 1,4-dioxane; at 100℃;Inert atmosphere;	Under nitrogen atmosphere, a solution of 1 -methyl-4- [ [4-prop-2-ynoxy-2- (trifluoromethyl)phenyl]methyl]piperazine (1.6 mmol, 500 mg) in 1 ,4-dioxane (15 ml) wasadded with <strong>[404827-77-6]6-bromo-1H-indazol-3-amine</strong> (2.4 mmol, 500 mg), Cul (0.32 mmol, 60 mg), Pd(PPh3)2C12 (0.16 mmol, 112 mg) and TEA (4.8 mmol, 480 mg). The mixture was stirred at 100C overnight under nitrogen atmosphere. The mixture was partitioned between water and DCM. The organic phase was washed with water and brine. The resulting solution was dried over sodium sulfate and evaporated to dryness. The residue was purified by flashcolumn chromatography with eluent AcOEt/MeOH 50:1 to afford the title compound as yellow oil (20 mg, 3%).1H NMR (400 MHz, CD3OD) oe 7.61 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H),7.24 (m, 2H), 7.19 (m, 1H), 6.89 (d, J = 8.4 Hz, 1H), 4.94 (s, 2H), 3.52 (s, 2H), 2.43 (bs, 8H), 2.23 (s, 3H).(ESI+) MS: m/z 444.2 (MH+).

Reference： [1]Patent: WO2016/96709,2016,A1 .Location in patent: Page/Page column 59; 60

22
[ 404827-77-6 ]
[ 86864-60-0 ]
6-bromo-1-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-indazol-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With caesium carbonate; In N,N-dimethyl-formamide; at 65℃; for 3h;	Intermediate 8. 6-bromo-1 -(2-(ieri-butyldimethylsilyloxy)ethyl)-1 H-indazol-3-amine To a solution of 6-bromo-1 /-/-indazol-3-amine (200mg, 0.94mmol) in dimethylformamide (2ml_) was added cesium carbonate (614mg, 1 .88mmol) and (2-bromoethoxy)(ie f- butyl)dimethylsilane (215mu, 1 .03mmol). The reaction mixture was stirred for 3 hours at 65C. Water was added into the crude mixture. A solid precipitates and it was dried to obtain the title compound as an orange solid (83% of yield), which was used in the next step without further purification. LRMS (m/z): 371 (M+1 )+

Reference： [1]Patent: WO2016/150971,2016,A1 .Location in patent: Page/Page column 24-25

23
[ 404827-77-6 ]
[ 683-57-8 ]
2-(3-amino-6-bromo-1H-indazol-1-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		Intermediate 1. 2-(3-amino-6-bromo-1 H-indazol-1 -yl)acetamide To a solution of 6-bromo-1 /-/-indazol-3-amine (544mg, 2.5mmol) in anhydrous dimethylformamide (3ml_) was added in portions at 0C sodium hydride (60% of an oil dispersion; 1 10mg, 4.5mmol). The mixture was stirred for 30 minutes at 0C. A solution of 2- bromoacetamide (371 mg, 2.68mmol) in dimethylformamide (1 ml_) was added into the solution and the crude was stirred for 1 hour at room temperature. Water was added into the crude mixture and an orange precipitate was obtained. It was filtered and dried to give the title compound as an orange solid (75% of yield), which was used in the next step without further purification. LRMS (m/z): 269 (M)+; 271 (M+2)+ 1H NMR (300 MHz, DMSO-de) delta ppm 4.71 (s, 2H); 5.6 (s, 2H); 7.02 (d, 1 H); 7.61 (m, 2H)

Reference： [1]Patent: WO2016/150971,2016,A1 .Location in patent: Page/Page column 23

24
[ 404827-77-6 ]
C₁₈H₂₁BFNO₃ [ No CAS ]
5-(3-amino-1H-indazol-6-yl)-1-(2-fluorobenzyl)pyridin-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 125℃;Inert atmosphere; Microwave irradiation;	A 1 -[(2-fluorophenyl)methyl]-5-(tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 ,2- dihydropyridin-2-one (Method 2AD) (0.4 g, 1.2 mmol), 6-bromo-lH-indazol-3- amine (0.25 g, 1.2 mmol), caesium carbonate (0.9 g, 3 mmol) in mixture dioxane/water (2: 1) were flushed with argon for 10 minutes and [ 1 , Gamma- bis(diphenyiphosphino)ferrocene]paliadium(II) chloride, comple with dichloromethane (0.06 g) was added. The reaction mixture was heated at 125C under microwave irradiation until the reaction was completed. After cooled to ambient temperature reaction mixture was filtered through Celite, washed with ethyl acetate and solvents were evaporated under reduced pressure. Crude product was purified by flash chromatography (dichloromethane/methanol 95 :5) to give 5-(3- amino-lH-indazol-6-yl)-l-(2-fluorobenzyl)pyridin-2(lH)-one (0.19 g); yield 48%. LC-MS (m/z) 335.1 (M+l). NMR (400 MHz, DMSO) delta 1 1.46 (s, 1H), 8.23 (d, J = 2.5 Hz, 1H), 7.92 (dd, J = 9.5, 2.7 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.25 (d, J = 10.7 Hz, 1H), 7.20 - 7.16 (m, 2H), 7.1 1 (dd, J = 8.4, 1.3 Hz, 1H), 6.54 (d, J = 9.5 Hz, 1H), 5.38 (s, 2H), 5.26 (s, 2H).

Reference： [1]Patent: WO2017/68064,2017,A1 .Location in patent: Page/Page column 104

25
[ 404827-77-6 ]
[ 365564-07-4 ]
6-(3,5-dimethoxyphenyl)-1H-indazol-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.6%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; at 100℃; for 11h;Inert atmosphere;	A mixture of 212 mg of <strong>[404827-77-6]6-bromo-1H-indazol-3-amine</strong> and 265 mg of 2- (3,5-dimethoxyphenyl) -4,4,5,5-tetramethyl- - dioxaborolane was dissolved in 10 ml of dioxane followed by the addition of 4 ml of an aqueous solution of sodium carbonate (1 mole per liter) and 74 mg of [1,1'-bis (diphenylphosphino) ferrocene] Palladium dichloride, heated to 100 C under argon, stirred for 11 hours. After heating, the reaction solution was filtered and the ethyl acetate was washed. The filtrate was concentrated and evaporated to dryness. The residue was dissolved in ethyl acetate and washed with saturated chlorine The residue was purified by column chromatography (dichloromethane: methanol = 99: 1-98: 2, v / v) to give 209 mg of a white solid, the yield was 77.6%

Reference： [1]Patent: CN106146493,2016,A .Location in patent: Paragraph 0456; 0457; 0458; 0459

26
[ 404827-77-6 ]
methyl 4-((3S, 5R)-3,5-dimethylpiperazin-1-yl)benzoate [ No CAS ]
C₂₀H₂₂BrN₅O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trimethylaluminum; In toluene; for 8h;Heating;	General procedure: The building block 10 (500.0 mg, 1.6 mmol) was dissolved in dry toluene (10 mL), followed by the addition of building block 4a (317.6 mg, 1.3 mmol) and Al(CH3)3 (2.0 mL, 3.2 mmol, 1.6 M in toluene). The reaction mixture was heated to 125 C and stirred for 8 h. Then it was allowed to cool to rt and the residue was dissolved in EtOAc (100 mL), and washed with brine (20 mL × 2), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography using CH2Cl2-MeOH (10:1) to aord 16a (267.8 mg, 39.2%) as a yellow solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3782 - 3786

27
[ 404827-77-6 ]
[ 1035271-52-3 ]
C₂₀H₂₂BrN₅O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trimethylaluminum; In toluene; for 8h;Heating;	General procedure: The building block 10 (500.0 mg, 1.6 mmol) was dissolved in dry toluene (10 mL), followed by the addition of building block 4a (317.6 mg, 1.3 mmol) and Al(CH3)3 (2.0 mL, 3.2 mmol, 1.6 M in toluene). The reaction mixture was heated to 125 C and stirred for 8 h. Then it was allowed to cool to rt and the residue was dissolved in EtOAc (100 mL), and washed with brine (20 mL × 2), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography using CH2Cl2-MeOH (10:1) to aord 16a (267.8 mg, 39.2%) as a yellow solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3782 - 3786

28
[ 404827-77-6 ]
[ 1035271-10-3 ]
C₂₀H₂₀BrN₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trimethylaluminum; In toluene; for 8h;Heating;	General procedure: The building block 10 (500.0 mg, 1.6 mmol) was dissolved in dry toluene (10 mL), followed by the addition of building block 4a (317.6 mg, 1.3 mmol) and Al(CH3)3 (2.0 mL, 3.2 mmol, 1.6 M in toluene). The reaction mixture was heated to 125 C and stirred for 8 h. Then it was allowed to cool to rt and the residue was dissolved in EtOAc (100 mL), and washed with brine (20 mL × 2), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography using CH2Cl2-MeOH (10:1) to aord 16a (267.8 mg, 39.2%) as a yellow solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3782 - 3786

29
[ 404827-77-6 ]
methyl 4-(4-(2-methoxyethyl)piperazin-1-yl)benzoate [ No CAS ]
C₂₁H₂₄BrN₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trimethylaluminum; In toluene; for 8h;Heating;	General procedure: The building block 10 (500.0 mg, 1.6 mmol) was dissolved in dry toluene (10 mL), followed by the addition of building block 4a (317.6 mg, 1.3 mmol) and Al(CH3)3 (2.0 mL, 3.2 mmol, 1.6 M in toluene). The reaction mixture was heated to 125 C and stirred for 8 h. Then it was allowed to cool to rt and the residue was dissolved in EtOAc (100 mL), and washed with brine (20 mL × 2), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography using CH2Cl2-MeOH (10:1) to aord 16a (267.8 mg, 39.2%) as a yellow solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3782 - 3786

30
[ 404827-77-6 ]
C₁₃H₂₀N₂O₂ [ No CAS ]
C₁₉H₂₂BrN₅O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trimethylaluminum; In toluene; for 8h;Heating;	General procedure: The building block 10 (500.0 mg, 1.6 mmol) was dissolved in dry toluene (10 mL), followed by the addition of building block 4a (317.6 mg, 1.3 mmol) and Al(CH3)3 (2.0 mL, 3.2 mmol, 1.6 M in toluene). The reaction mixture was heated to 125 C and stirred for 8 h. Then it was allowed to cool to rt and the residue was dissolved in EtOAc (100 mL), and washed with brine (20 mL × 2), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography using CH2Cl2-MeOH (10:1) to aord 16a (267.8 mg, 39.2%) as a yellow solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3782 - 3786

31
[ 354813-17-5 ]
[ 404827-77-6 ]
N-(6-bromo-1H-indazol-3-yl)-4-(4-ethylpiperazin-1-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39.2%	With trimethylaluminum; In toluene; for 8h;Heating;	The building block 10 (500.0 mg, 1.6 mmol) was dissolved in dry toluene (10 mL), followed by the addition of building block 4a (317.6 mg, 1.3 mmol) and Al(CH3)3 (2.0 mL, 3.2 mmol, 1.6 M in toluene). The reaction mixture was heated to 125 C and stirred for 8 h. Then it was allowed to cool to rt and the residue was dissolved in EtOAc (100 mL), and washed with brine (20 mL × 2), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography using CH2Cl2-MeOH (10:1) to aord 16a (267.8 mg, 39.2%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 12.86 (brs, 1H), 10.56 (brs, 1H), 7.94 (d, J = 8.7 Hz, 2H), 7.61-7.70 (m, 1H), 7.17 (d, J = 7.9 Hz, 1H), 6.99 (d, J = 8.6 Hz, 2H), 3.29-3.40 (m, 4H), 2.51-2.56 (m, 4H), 2.36 (q, J = 7.1 Hz, 2H), 1.02 (t, J = 7.1 Hz, 3H). ESI-MS (m/z): [M + H]+ = 428.2.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3782 - 3786

32
[ 404827-77-6 ]
[ 20054-45-9 ]
2-(3-amino-1H-indazol-6-ylthio)-N-methylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%		To a nitrogen-purged reactor vessel at ambientconditions was charged 1, 4-dioxane (12 mL) followed by <strong>[404827-77-6]6-bromo-1H-indazol-3-amine</strong> (106 mg,0.5 mmol, 1.0 equiv), Xantphos (28.9 mg, 0.05 mmol, 0.1 equiv), tris(dibenzylideneacetone)dipalladium[Pd2(dba)3] (22.9 mg, 0.025 mmol, 0.05 equiv), and Cesium carbonate (325.8 mg, 1.0 mmol, 2.0 equiv).The reactor was purged, and the mixture was held at a target of 25 C and stirred for about 30 min.A solution of 2-mercapto-N-methylbenzamide (87.8 mg, 0.525 mmol, 1.05 equiv) in 1,4-dioxane (8 mL)was added over about 30 min. The batch mixture was heated to a target of 80 C. The reaction was heldfor 12 h. Once TLC indicated the reaction was complete, the reaction mixture was evaporated at 40 C,dissolved in chloroform and purified on a silica column with CH2Cl2/MeOH (50:1). Obtained as alight-yellow powder 80 mg (yield: 57%). 1H-NMR (400 MHz, DMSO-d6) delta 11.47 (s, 1H), 8.35-8.32 (m,1H), 7.68-7.66 (m, 1H), 7.43-7.40 (m, 1H), 7.26-7.25 (m, 1H), 7.24-7.21 (m, 1H), 7.20-7.16 (m, 1H),6.91-6.88 (m, 1H), 6.86-6.84 (m, 1H), 5.41 (s, 2H), 2.73 (d, J = 4.64 Hz, 3H). 13C-NMR (100 MHz,DMSO-d6) delta 168.4, 149.8, 142.3, 137.1, 136.8, 131.9, 130.7, 129.8, 128.2, 126.2, 122.8, 122.0, 114.8, 114.6,26.6. HR-MS (ESI) m/z calculated for C15H14N4OS [M + H]+ 299.0967, found 299.0963.

Reference： [1]Molecules,2018,vol. 23

33
[ 404827-77-6 ]
[ 2292-84-4 ]
8-bromo-4-isopropylpyrimido[1,2-b]indazole [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2018,vol. 360,p. 1943 - 1948

34
[ 404827-77-6 ]
2-fluoro-5-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide [ No CAS ]
N-(4-(3-amino-1H-indazol-6-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 18h;Inert atmosphere;	A mixture of <strong>[404827-77-6]6-bromo-1H-indazol-3-amine</strong> (50 mg, 0.236 mmol), 2-fluoro-5-methoxy-N- (4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (106 mg, 0.259 mmol), Pd(dppf)C12DCM (10 mg, 0.012 mmol) and Cs2CO3 (154 mg, 0.472 mmol) in dioxane (3 mL) and H20 (0.3 mL) was heated under N2 at 90 C for 18 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with DCM: MeOH (100:1 to 50:1) to afford the title compound (77 mg, yield: 79%). ESI-MS: 413.2 (M+1), ?H NMR (400 MHz, DMSO) oe 11.41 (s, 1H), 10.75 (s, 1H), 7.69 (d, J= 8.4 Hz, 1H), 7.58 (d, J= 8.5 Hz, 2H), 7.39-7.26 (m, 3H), 7.25-7.17 (m, 3H), 7.11 (d, J= 8.5 Hz, 1H), 5.35 (s, 2H), 3.76 (s, 3H).

Reference： [1]Patent: WO2018/106459,2018,A1 .Location in patent: Paragraph 00127

35
[ 404827-77-6 ]
[ 119072-55-8 ]
[ 87-48-9 ]
2,10-dibromo-14-(tert-butylamino)indazolo[3',2':2,3]imidazo[1,5-c]quinazolin-6(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With mono-6A-succinyl-beta-cyclodextrin; In water; at 100℃; for 1h;	General procedure: A mixture of isatin (1, 1mmol), 1H-indazol-3-amine (2, 1mmol) and isocyanide (3, 1mmol) and 1 mol% Suc-beta-CD in 5 mL pure water was stirred at 100 C for the appropriate time, as given in Table 2. The completion of the reaction was confirmed by thin layer chromatography (TLC) using DCM/Methanol as the eluent (95 : 05); the formed precipitate was filtered and washed with water (15 mL) to afford the desired product 4. The Suc-beta-CD catalyst was recovered from the aqueous fraction, and simply precipitated by the addition of acetone (25 mL). The recovered catalyst was filtered, washed with acetone (3 × 10 mL), dried under vacuum at 60 C for 7 hours and reused.

Reference： [1]Tetrahedron,2019,vol. 75,p. 778 - 783

36
[ 404827-77-6 ]
[ 119072-55-8 ]
[ 17630-76-1 ]
10-bromo-14-(tert-butylamino)-2-chloroindazolo[3',2':2,3]imidazo[1,5-c]quinazolin-6(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With mono-6A-succinyl-beta-cyclodextrin; In water; at 100℃; for 0.916667h;	General procedure: A mixture of isatin (1, 1mmol), 1H-indazol-3-amine (2, 1mmol) and isocyanide (3, 1mmol) and 1 mol% Suc-beta-CD in 5 mL pure water was stirred at 100 C for the appropriate time, as given in Table 2. The completion of the reaction was confirmed by thin layer chromatography (TLC) using DCM/Methanol as the eluent (95 : 05); the formed precipitate was filtered and washed with water (15 mL) to afford the desired product 4. The Suc-beta-CD catalyst was recovered from the aqueous fraction, and simply precipitated by the addition of acetone (25 mL). The recovered catalyst was filtered, washed with acetone (3 × 10 mL), dried under vacuum at 60 C for 7 hours and reused.

Reference： [1]Tetrahedron,2019,vol. 75,p. 778 - 783

37
[ 443-69-6 ]
[ 404827-77-6 ]
[ 119072-55-8 ]
10-bromo-14-(tert-butylamino)-2-fluoroindazolo[3',2':2,3]imidazo[1,5-c]quinazolin-6(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With mono-6A-succinyl-beta-cyclodextrin; In water; at 100℃; for 1.08333h;	General procedure: A mixture of isatin (1, 1mmol), 1H-indazol-3-amine (2, 1mmol) and isocyanide (3, 1mmol) and 1 mol% Suc-beta-CD in 5 mL pure water was stirred at 100 C for the appropriate time, as given in Table 2. The completion of the reaction was confirmed by thin layer chromatography (TLC) using DCM/Methanol as the eluent (95 : 05); the formed precipitate was filtered and washed with water (15 mL) to afford the desired product 4. The Suc-beta-CD catalyst was recovered from the aqueous fraction, and simply precipitated by the addition of acetone (25 mL). The recovered catalyst was filtered, washed with acetone (3 × 10 mL), dried under vacuum at 60 C for 7 hours and reused.

Reference： [1]Tetrahedron,2019,vol. 75,p. 778 - 783

38
[ 404827-77-6 ]
(4-((2-(4-fluorobenzamido)ethyl)carbamoyl)phenyl)boronic acid [ No CAS ]
4-(3-amino-1H-indazol-6-yl)-N-(2-(4-fluorobenzamido)ethyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; acetonitrile; at 90℃; for 24h;Inert atmosphere;	General procedure: In a 100 mL round bottom flask with an a condenser tube, 4-iodo-1H-indazol-3-amine (1) (0.39 g, 1.5 mmol), (4-((2-(4-fluorobenzamido)ethyl)carbamoyl)phenyl)boronic acid (3a)(1.8 mmol), Cs2CO3 (1.46 g, 4.5 mmol), Pd(PPh3)4 (0.09 g,0.075 mmol)was dissolved in 50 mL ACN/H2O (v/v 3: 2). Then thereaction mixture was degassed for 3 times, heated at 90 C in an oilbath and stirred under nitrogen for 24 h. The mixturewas cooled toroom temperature, filtered, and evaporated to remove ACN. Theresidue was diluted with 30 mL H2O and then extracted with ethylacetate (30 mL 3). The combined organic layer was washed withbrine, dried over Na2SO4 for overnight, filtered, and concentrated invacuo to give the crude product, which was isolated by flashchromatography on silica gel (EtOAc) to obtain the title compound(0.12 g, 19%).