129488-10-4|tert-Butyl 5-amino-1H-indazole-1-carboxylate| Ambeed

Structure of 129488-10-4

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Quality Control of [ 129488-10-4 ] Purity: 97% SDS Specification

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Product Details of [ 129488-10-4 ]

CAS No. :	129488-10-4
Formula :	C₁₂H₁₅N₃O₂
M.W :	233.27
SMILES Code :	O=C(N1N=CC2=C1C=CC(N)=C2)OC(C)(C)C
MDL No. :	MFCD04114656
InChI Key :	LRSDPIIWOZRHNJ-UHFFFAOYSA-N
Pubchem ID :	19800556

Safety of [ 129488-10-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 129488-10-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	17
Num. arom. heavy atoms	9
Fraction Csp3	0.33
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	66.34
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	70.14 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.28
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.16
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.41
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.76
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.8
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.88

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.84
Solubility	0.337 mg/ml ; 0.00144 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.27
Solubility	0.127 mg/ml ; 0.000543 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.63
Solubility	0.542 mg/ml ; 0.00232 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.19 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.36

Application In Synthesis of [ 129488-10-4 ]

* 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.

Downstream synthetic route of [ 129488-10-4 ]

[ 129488-10-4 ] Synthesis Path-Downstream 1~35

1
[ 129488-09-1 ]
[ 129488-10-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	In methanol; palladium; ethyl acetate;	Part B Preparation of 5-amino-indazole-1-carboxylic acid t-butyl ester In a Paar flask charged with palladium (10 wt percent on carbon, 0.44 g) was added ethyl acetate (30 mL) and 5-nitro-indazole-1-carboxylic acid t-butyl ester (1.61 g, 6.2 mmol). The reaction mixture was hydrogenated at 50 psi for 30 minutes with vigorous shaking. The reaction mixture was filtered through a plug of celite. The plug was washed with 20 mL of methanol and the combined filtrates were concentrated in vacuo to give a white solid (1.4 g, 100percent). 1H NMR (300 MHz, CDCl3), delta: 7.99 (s, 1H), 7.97 (d, J=10, 1H), 6.94 (dd, J=10, J'=2, 1H), 6.92 (d, J=2, 1H), 1.71 (s, 9H).
98.6%	With palladium 10% on activated carbon; hydrogen; In methanol;	Compound Reg-1-1-b (38 g, 144.35 mmol) was dissolved in methanol (700 mL), Pd/C (3.8 g, 10percent water) wasadded, purge with hydrogen was performed for three times, and the reaction was performed under a hydrogen atmosphereovernight. Thin layer chromatography (petroleum ether : ethyl acetate=3:1) indicated the reaction was complete. Thereaction solution was filtered through Celite to afford compound Reg-1-1-c (33.2 g, brown solid, yield: 98.6percent).1H NMR (400 MHz, CDCl3) delta 7.97 (d, J = 10.8 Hz, 2H), 7.00 - 6.87 (m, 2H), 3.74 (s, 2H), 1.71 (s, 9H).
98.6%	With palladium on activated charcoal; hydrogen; In methanol; water;	Compound Reg-1-1-b (38 g, 144.35 mmol) was dissolved in methanol (700 mL), Pd/C (3.8 g, 10percent water) was added, purge with hydrogen was performed for three times, and the reaction was performed under a hydrogen atmosphere overnight. Thin layer chromatography (petroleum ether : ethyl acetate=3:1) indicated the reaction was complete. The reaction solution was filtered through Celite to afford compound Reg-1-1-c (33.2 g, brown solid, yield: 98.6percent). 1H NMR (400 MHz, CDCl3) delta 7.97 (d, J = 10.8 Hz, 2H), 7.00 - 6.87 (m, 2H), 3.74 (s, 2H), 1.71 (s, 9H).

	With hydrogen;palladium on activated charcoal; In tetrahydrofuran; at 40℃; under 2585.81 Torr; for 16h;	To a solution of 5-nitro-indazole-1 -carboxylic acid tert-butyl ester (300 g, 1 .1 mol, 1 .0 eq) in THF (3 L), and the mixture was hydrogenated at 40 °C with Pd/C (30 g) as catalyst in the presence of H2 (50 psi). The reaction mixture was stirred at 40 °C fori 6 hrs. TLC (PE: EA=4:1 ) showed the reaction was complete. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated to afford the crude 5-amino-indazole-1 -carboxylic acid tert-butyl ester (252 g, 95percent) which was used directly for next step without purification.
	With palladium on activated charcoal; hydrogen; In tetrahydrofuran; at 40℃; under 2585.81 Torr; for 16h;	To a solution of 5-nitro-indazole-1-carboxylic acid tert-butyl ester (300 g, 1.1 mol, 1.0 eq) in THF (3 L), and the mixture was hydrogenated at 40° C. with Pd/C (30 g) as catalyst in the presence of H2 (50 psi). The reaction mixture was stirred at 40° C. for 16 hrs. TLC (PE:EA=4:1) showed the reaction was complete. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated to afford the crude 5-amino-indazole-1-carboxylic acid tert-butyl ester (252 g, 95percent) which was used directly for next step without purification.
	With palladium on activated charcoal; hydrogen; In tetrahydrofuran; at 40℃; under 2585.81 Torr; for 16h;	To a solution of 5-nitro-indazole-1-carboxylic acid tert-butyl ester (300 g, 1.1 mol, 1.0 eq) in THF (3 L) was added Pd/C (30 g). The reaction mixture was stirred at 40°C for 16 hours under pressure of H2 (50 psi). TLC (PE: EtOAc = 4:1) showed complete conversion. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated to afford the crude 5-amino-indazole-1-carboxylic acid tert-butyl ester (252 g, 95percent) which was used directly for next step without purification.
	With palladium 10% on activated carbon; hydrogen; In ethyl acetate; at 20℃; for 3h;	[0003711 To a stirred solution of compound 2 (1 g, 1 eq) in ethyl acetate (30 mL), 10percentPd-C (0.28 g) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h under hydrogen atmosphere (balloon pressure). The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure to afford the title compound 3.

References: [1]Patent: US2003/32654,2003,A1 .
[2]Patent: EP3421465,2019,A1 .Location in patent: Paragraph 0104; 0106.
[3]Patent: EP3421464,2019,A1 .Location in patent: Paragraph 0102; 0104.
[4]Patent: WO2012/146724,2012,A2 .Location in patent: Page/Page column 47.
[5]Patent: US2014/57942,2014,A1 .Location in patent: Paragraph 0329.
[6]Patent: WO2014/68035,2014,A1 .Location in patent: Page/Page column 36.
[7]Asian Journal of Chemistry,2014,vol. 26,p. 7539 - 7543.
[8]Patent: WO2016/57834,2016,A1 .Location in patent: Paragraph 000371.

2
[ 129488-10-4 ]
[ 911418-02-5 ]
[ 911418-03-6 ]

Yield	Reaction Conditions	Operation in experiment
59%	In isopropyl alcohol; at 95℃; for 5h;	A mixture of 4-chloro-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-6- yl acetate (3.14g, 7.42 mmol) and tert-butyl 5-amino-lH-indazole-l-carboxylate (1.85g, 7.93 mmol) in IPA (180 mL) was heated at 95 0C for 5 h. The mixture was allowed to cool to RT and the solid was collected via filtration. The solid was subjected to flash chromatography (SiO2, CH2Cl2/Me0H) to give the desired compound tert-butyl 5-(6- acetoxy-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)- 1 H-indazole- 1 - carboxylate (2.7Og, 4.36 mmol, 59percent). MS 620.4 (M+l). HPLC retention time 8.10 mins (5-95-13 method).
59%	In isopropyl alcohol; at 95℃; for 5h;	A mixture of 4-chloro-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-6- yl acetate (3.14g, 7.42 mmol) and /<;?/v-butyl 5-amino- I H-indazole- l -carboxylate (1.85g, 7.93 mmol) in IPA (180 mL) was heated at 95 °C for 5 h. The mixture was allowed to cool to RT and the solid was collected via filtration. The solid was subjected to flash chromatography (SiOi, C^Ch/MeOH) to give the desired compound /ctau/-butyl 5-(6- acetoxy-2-(3-fluoro-4-(phenyl)phenyI)-7-methoxyquinazolin-4-ylamino)- lH-indazole- l - carboxylate (2.7Og, 4.36 mmol, 59percent). MS 620.4 (M+ 1 ). HPLC retention time 8. 10 mi ns (5-95- 13 method).
59%	In isopropyl alcohol; at 95℃; for 5h;	[0275] A mixture of 4-chloro-2~(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolm-6-yl acetate (3.14g, 7.42 mmol) and tert-huty\\ 5-amino-lH-indazole-l-carboxylate (1.85g, 7.93 mmol) in IPA (180 mL) was heated at 95 °C for 5 h. The mixture was allowed to cool to RT and the solid was collected via filtration. The solid was subjected to flash chromatography (SiO2, CH2Cl2MeOH) to give the desired compound tert-butyl 5-(6- acetoxy-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-lH-indazole-l- carboxylate (2.7Og, 4.36 mmol, 59percent). MS 620.4 (M+l). HPLC retention time 8.10 mins (5-95-13 method).

References: [1]Patent: WO2008/54599,2008,A2 .Location in patent: Page/Page column 157.
[2]Patent: WO2010/104851,2010,A1 .Location in patent: Page/Page column 152.
[3]Patent: WO2006/105081,2006,A2 .Location in patent: Page/Page column 141.

3
[ 129488-10-4 ]
[ 911417-24-8 ]
[ 911417-25-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	In isopropyl alcohol; at 95℃; for 0.25h;	3-(4-Chloroquinazolin-2-yl)phenyl acetate (9.77 g, 29.97mmole) was dissolved in isopropanol (290 mL) and tert-butyl 5-amino-lH-indazole-l-carboxylate (6.99 g, 29.97 mmole) was added. The solution was heated to 95 0C and stirred for 0.25 h. A gelatinous formation developed which was manually broken up and dissolution gradually occurred followed by formation of a yellow precipitate. The reaction was stirred for an additional EPO <DP n="108"/>0.25 h, cooled to ambient temperature and filtered. The filtered solid was washed with ether and then dried under high vacuum overnight to give tert-butyl 5-(2-(3- acetoxyphenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate. (14.58 g, mmol, 98 percent)
98%	In isopropyl alcohol; at 95℃; for 0.5h;	3-(4-ChIoroquinazolin-2-yl)phenyl acetate (9.77 g, 29.97mmole) was dissolved in isopropanol (290 mL) and /m-butyl 5-amino- I H-indazole-l -carboxylate (6.99 g, 29.97 mmole) was added. The solution was heated to 95 °C and stirred for 0.25 h. A gelatinous formation developed which was manually broken up and dissolution gradually occurred followed by formation of a yellow precipitate. The reaction was stirred for an additional 0.25 h, cupsilonupsilonled lupsilon ambient temperature and Tillered. The filtered solid was washed wilh ether and then dried under high vacuum overnight to give ten-butyl 5-(2-(3- acetoxyphenyl)quinazolin-4-ylamino)- I H-indazole- l -carboxylate. ( 14.58 g, mmol, 98 percent)
98%	In isopropyl alcohol; at 95℃; for 0.5h;	[0181] 3-(4-Chloroquinazolin-2-yl)phenyl acetate (9.77 g, 29.97mmole) was dissolved in isopropanol (290 mL) and tert-butyl 5-amino-lH-indazole-l-carboxylate (6.99 g, 29.97 mmole) was added. The solution was heated to 95 0C and stirred for 0.25 h. A gelatinous formation developed which was manually broken up and dissolution gradually occurred followed by formation of a yellow precipitate. The reaction was stirred for an additional 0.25 h, cooled to ambient temperature and filtered. The filtered solid was washed with ether and then dried under high vacuum overnight to give tert-butyl 5-(2-(3- acetoxyphenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate. (14.58 g, mmol, 98 percent)

References: [1]Patent: WO2008/54599,2008,A2 .Location in patent: Page/Page column 106-107.
[2]Patent: WO2010/104851,2010,A1 .Location in patent: Page/Page column 101; 102.
[3]Patent: WO2006/105081,2006,A2 .Location in patent: Page/Page column 90.

4
[ 129488-10-4 ]
[ 911418-13-8 ]
[ 911418-14-9 ]

Yield	Reaction Conditions	Operation in experiment
77%	In isopropyl alcohol; at 95℃; for 2h;	A mixture of 4-chloro-2-[(3-phenyl)phenyl]-7-methoxyquinazolin-6-yl acetate (4.0Og, 9.88 mmole), tert-butyl 5-amino-lH-indazole-l-carboxylate (2.42g, 10.37 mmole) in wo-propanol (130 mL) was stirred at 95 0C for 2 h. The reaction was cooled to RT and the crude product was filtered and then washed with ether, wo-propanol, and hexane and dried under vacuum to give tert-butyl 5-(6-acetoxy-2-[(3-phenyl)phenyl)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate ( 4.33g, 7.20 mmole, 77percent over two steps). MS 602 (M+ 1). HPLC retention time 6.47 mins.
	In isopropyl alcohol; at 95℃; for 2h;	A mixture of 4-chloro-2-[(3-phenyl)phenyl]-7-methoxyquinazolin-6-yl acetate (4.0Og, 9.88 mmole), te/7-butyl 5-amino- I H-indazole-l -carboxylate (2.42g, 10.37 mmole) in /.vo-propanol ( 130 mL) was stirred at 95 °C for 2 h The reaction was cooled to RT and the crude product was filtered and then washed with ether, lambdavo-propanol, and hexane and dried under vacuum to give /c/7-butyl 5-(6-acetoxy-2-[(3-phenyl)phenyl)-7- methoxyquinazolin-4-yIamino)- l H-indazole- l-carboxylate ( 4.33g, 7.20 mmole, 77percent over two steps). MS 602 (M+ 1 ). HPLC retention time 6.47 mins.
	In isopropyl alcohol; at 95℃; for 2h;	[0286] A mixture of 4-chloro-2-[(3-phenyl)phenyl]-7-methoxyquinazolin-6-yl acetate (4.0Og, 9.88 mmole), tert-butyl 5-amino-lH-mdazole-l-carboxylate (2.42g, 10.37 mmole) in zso-propanol (130 mL) was stirred at 95 0C for 2 h. The reaction was cooled to RT and the crude product was filtered and then washed with ether, wo-propanol, and hexane and dried under vacuum to give tert-hvXyl 5-(6-acetoxy-2-[(3-phenyl)phenyl)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate ( 4.33g, 7.20 mmole, 77percent over two steps). MS 602 (M+ 1). HPLC retention time 6.47 mins.

References: [1]Patent: WO2008/54599,2008,A2 .Location in patent: Page/Page column 163.
[2]Patent: WO2010/104851,2010,A1 .Location in patent: Page/Page column 158.
[3]Patent: WO2006/105081,2006,A2 .Location in patent: Page/Page column 147.

5
[ 129488-10-4 ]
[ 911418-32-1 ]
[ 911418-33-2 ]

Yield	Reaction Conditions	Operation in experiment
84%	In isopropyl alcohol; at 95℃; for 5h;	A mixture of 4-chloro-2-(3-nitrophenyl)quinazolin-6-yl acetate (1.63g, 4.74 mmol) and tert-butyl 5-amino-lH-indazole-l-carboxylate (1.16g, 4.28 mmol) in IPA (80 mL) were heated at 95 0C for 5h. The mixture was allowed to cool to RT, the yellow solid was collected via filtration and washed with Et2O to give the product tert-butyl 5-(6- EPO <DP n="177"/>acetoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)- 1 H-indazole- 1 -carboxylate (2.14g, 3.96mmol, 84percent). HPLC retention time 9.649 min.
84%	In isopropyl alcohol; at 95℃; for 5h;	[0309] A mixture of 4-chloro-2-(3-nitrophenyl)quinazolin-6-yl acetate (1.63g, 4.74 mmol) and fert-butyl 5-amino-lH-indazole-l-carboxylate (1.16g, 4.28 mmol) in IPA (80 niL) were heated at 95 °C for 5h. The mixture was allowed to cool to RT, the yellow solid was collected via filtration and washed with Et2O to give the product tert-butyl 5-(6- acetoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (2.14g, 3.96mmol, 84percent). HPLC retention time 9.649 min.
	In isopropyl alcohol; at 95℃; for 5h;	A mixture of 4-chloro-2-(3-nitrophenyl)quinazolin-6-yl acetate ( 1 63g, 4 74 mmol) and /tw -butyl 5-amino-l H-indazole- l -carboxylate ( I 16g, 4 28 mmol) in IPA (80 mL) were heated at 95 °C for 5h. The mixture was allowed to cool to RT, the yellow solid was collected via filtration and washed with Et2O to give the product tert-buty] 5-(6- acetoxy-2-(3-nitrophenyl)quina2psilin-4-ylamino)- 1H-indazole-1-carboxylate (2.14g, 3.96mmol, 84percent). KPLC retention time 9.649 min.

References: [1]Patent: WO2008/54599,2008,A2 .Location in patent: Page/Page column 175-176.
[2]Patent: WO2006/105081,2006,A2 .Location in patent: Page/Page column 160.
[3]Patent: WO2010/104851,2010,A1 .Location in patent: Page/Page column 170; 171.

6
[ 129488-10-4 ]
[ 911418-47-8 ]
[ 911418-48-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	In isopropyl alcohol; for 5h;Heating / reflux;	A mixture of 4-chloro-7-methoxy-2-(3-nitrophenyl)quinazolin-6-yl acetate (1.6Og, 4.23 mmol) and tert-butyl 5-amino-lH-indazole-l-carboxylate (1.Og, 4.28 mmol) were refluxed in anhydrous wo-propanol (6OmL) for 5 h. The mixture was allowed to cool to RT, upon which the solid was collected via filtration and was washed with Et2O to give EPO <DP n="188"/>tert-butyl 5-(6-acetoxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)- 1 H-indazole- 1-carboxylate. (2.2g, 4.23mmol, 100percent). HPLC retention time = 7.75 mins.
100%	In isopropyl alcohol; for 5h;Reflux;	A mixture of 4-chloro-7-methoxy-2-(3-nitrophenyl)quinazolin-6-yl acetate (1 6Og, 4.23 mmol) and lerl-buty\\ 5-amino-1H-indazole- l -carboxylate ( 1 Og, 4 28 mmol) were refluxed in anhydrous /.so-propanol (6OmL) for 5 h The mixture was allowed to cool to RT, upon which the solid was collected via filtration and was washed with EtaO to give /etau/-butyl 5-(6-acetoxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-l H-indazole- 1 -carboxylate (2 2g, 4 23mmol, 100percent) HPLC retention time = 7 75 mins
100%	In isopropyl alcohol; for 5h;Heating / reflux;	[0336] A mixture of 4-chloro-7-methoxy-2-(3-nitrophenyl)quinazolin-6-yl acetate(1.6Og, 4.23 mmol) and tert-buty\\ 5-amino-lH-indazole-l-carboxylate (l.Og, 4.28 mmol) were refluxed in anhydrous wo-propanol (6OmL) for 5 h. The mixture was allowed to cool to RT, upon which the solid was collected via filtration and was washed with Et2O to give tert-butyl 5-(6-acetoxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-lH-mdazole- 1-carboxylate. (2.2g, 4.23mmol, 100percent). HPLC retention time = 7.75 mins.

References: [1]Patent: WO2008/54599,2008,A2 .Location in patent: Page/Page column 186-187.
[2]Patent: WO2010/104851,2010,A1 .Location in patent: Page/Page column 181; 182.
[3]Patent: WO2006/105081,2006,A2 .Location in patent: Page/Page column 171.

7
[ 129488-10-4 ]
[ 93256-31-6 ]
[ 911417-27-1 ]

Yield	Reaction Conditions	Operation in experiment
79%	In isopropyl alcohol; at 95℃; for 1.5h;	A suspension of 4-chloro-2-(3-nitrophenyl)quinazoline (6.3 g, 21.9 mmole), 5-amino-lH-indazole-l-carboxylate (5.10 g, 21.9 mmole) in isopropanol (300 mL) was heated at 95 0C for 1.5 h. The suspension was filtered and the filtered solid was washed with isopropanol. The product was dried under high vacuum for several hours to give the desired product tert-butyl 5-(2-(3-nitrophenyl)quinazolin-4-ylamino)-lH- indazole-1-carboxylate. ( 8.3 g, mmol, 79percent).
79%	In isopropyl alcohol; at 95℃; for 1.5h;	A suspension of 4-chIoro-2-(3-nitrophenyl)quinazoline (6.3 g, 21.9 mmole), /e/7-butyl 5-amino-l H-indazole-1-carboxylate (5.10 g, 21.9 mmole) in isopropanol (300 mL) was heated at 95 °C for 1.5 h. The suspension was filtered and the filtered solid was washed with isopropanol. The product was dried under high vacuum for several hours to give the desired product teriota-buty\\ 5-(2-(3-nitrophenyl)quinazolin-4-ylamino)- 1H- indazole-1 -carboxylate. ( 8.3 g, mmol, 79percent).
79%	In isopropyl alcohol; at 95℃; for 1.5h;	[0186] A suspension of 4-chloro-2-(3-nitrophenyl)quinazoline (6.3 g, 21.9 mmole), tert-butyl 5-amino-lH-indazole-l-carboxylate (5.10 g, 21.9 mmole) in isopropanol (300 mL) was heated at 95 0C for 1.5 h. The suspension was filtered and the filtered solid was washed with isopropanol. The product was dried under high vacuum for several hours to give the desired product tert-butyl 5-(2-(3-nitrophenyl)quinazolin-4- ylamino)-lH-indazole-l-carboxylate. ( 8.3 g, mmol, 79percent).

References: [1]Patent: WO2008/54599,2008,A2 .Location in patent: Page/Page column 109.
[2]Patent: WO2010/104851,2010,A1 .Location in patent: Page/Page column 104.
[3]Patent: WO2006/105081,2006,A2 .Location in patent: Page/Page column 92.

8
[ 129488-10-4 ]
[ 911418-78-5 ]
[ 911418-79-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	In isopropyl alcohol; at 95℃; for 8.5h;	A mixture of 4-chloro-7-methoxy-6-(2-methoxyethoxy)-2-(3 - nitrophenyl)quinazoline (0.500g,1.28 mmol) and 5-amino-lH-indazole-l-carboxylate (0.314g, 1.34mmol) in iso-propanol (30 mL) was heated at 95°C for 30 minutes and at 95 0C for 8 h. The mixture was allowed to cool to RT and the solid was collected via filtration. The cake was washed with iso-propanol and Et2O, triturated with CH2Cl2 and EtOAc and dried in vacuo to give tert-Butyl 5-(7-methoxy-6-(2-methoxyethoxy)-2-(3- nitrophenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.56Og, 0.955 mmol, 71percent). MS 587 (M+l). HPLC retention time 7.21 mins.
71%	In isopropyl alcohol; at 95℃; for 8.5h;	A mixture of 4-chloro-7-methoxy-6-(2-methoxyethoxy)-2-(3- nitrophenyl)quinazoline (0 500g,1.28 mmol) and 5-amino-l H-indazole-l -carboxylate (0.3 14g, 1.34mmol) in iso-propanol (30 mL) was heated at 95°C for 30 minutes and at 95 °C for 8 h The mixture was allowed to cool to RT and the solid was collected via filtration. The cake was washed with iso-propanol and Et2O, triturated with CH2Ch and EtOAc and dried in vacuo to give (erl-Buty\\ 5-(7-methoxy-6-(2-methoxyethoxy)-2-(3- nitrophenyl)quinazolin-4-ylamino)- l H-indazole-l -carboxylate (0.56Og, 0.955 mmol, 71percent). MS 587 (M+ 1 ). HPLC retention time 7.21 mins.
71%	In isopropyl alcohol; at 95℃; for 8.5h;	[0375] A mixture of 4-chloro-7-methoxy-6-(2-methoxyethoxy)-2-(3 - nitrophenyl)quinazoline (0.500g,1.28 mmol) and 5-amino-lH-indazole-l-carboxylate (0.314g, 1.34mmol) in iso-propanol (30 mL) was heated at 95°C for 30 minutes and at 95 0C for 8 h. The mixture was allowed to cool to RT and the solid was collected via filtration. The cake was washed with iso-propanol and Et2O, triturated with CH2Cl2 and EtOAc and dried in vacuo to give fe/t-Butyl 5-(7-methoxy-6-(2-methoxyethoxy)-2-(3- nitrophenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.560g, 0.955 mmol, 71percent). MS 587 (M+l). HPLC retention time 7.21 mins.

References: [1]Patent: WO2008/54599,2008,A2 .Location in patent: Page/Page column 204.
[2]Patent: WO2010/104851,2010,A1 .Location in patent: Page/Page column 199.
[3]Patent: WO2006/105081,2006,A2 .Location in patent: Page/Page column 189.

9
[ 129488-10-4 ]
[ 911418-85-4 ]
[ 911418-86-5 ]

Yield	Reaction Conditions	Operation in experiment
100%		A mixture of 2-(3-(benzyloxy)phenyl)-4-chloro-7-methoxy-6-(2- methoxyethoxy)quinazoline (1.55g, 3.44 mmol) and tert-butyl 5-amino-lH-indazole-l- carboxylate (0.842g, 3.61 mmol) in iso-propanol (100 mL) was heated at 95 0C for 2h, upon which the an additional aliquot of tert-buty\\ 5-amino-lH-indazole-l-carboxylate (0.10Og, 0.43 mmol) was added. Stirring was continued at 95 0C for a further 3 h upon which a third aliquot of tert-butyl 5-amino-lH-indazole-l-carboxylate (0.050g, 0.22 mmol) was added. Stirring was continued at 95 °C for a further 1 h upon which the mixture was allowed to cool to RT and the precipitate was collected via filtration. The solid was washed with iso-propanol and dried under vacuum to give tert-buty\\ 5-(2-(3- (benzyloxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-lH-indazole- 1-carboxylate (2.35g, 3.44 mmol, 100percent). MS 648 (M+l). HPLC retention time 7.79 mins.
100%	In isopropyl alcohol; at 95℃; for 6h;	A mixture of 2-(3-(benzyloxy)phenyl)-4-chloro-7-methoxy-6-(2- methoxyethoxy)quinazoline ( 1.55g, 3.44 mmol) and /e/7-butyl 5-amino- l H-indazole-1- carboxylate (0.842g, 3.61 mmol) in iso-propanol (100 mL) was heated at 95 °C for 2h, upon which the an additional aliquot of /<;?/7-butyl 5-amino-l H-indazole-l -carboxylate (0.10Og, 0.43 mmol) was added. Stirring was continued at 95 °C for a further 3 h upon which a third aliquot of /e/7-butyl 5-amino-l H-indazole- l -carboxylate (0.05Og, 0.22 mmol) was added. Stirring was continued at 95 °C for a further 1 h upon which the mixture was allowed to cool to RT and the precipitate was collected via filtration. The solid was washed with iso-propanol and dried under vacuum to give to/V-butyl 5-(2-(3- (benzyloxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)- l H-indazole- 1-carboxylate (2.35g, 3.44 mmol, 100percent). MS 648 (M+l ). HPLC retention time 7.79 mins.
100%	In isopropyl alcohol; at 95℃; for 6h;	[0382] A mixture of 2-(3-(benzyloxy)phenyl)-4-chloro-7-methoxy-6-(2- methoxyethoxy)quinazoline (1.55g, 3.44 mmol) and tert-butyl 5-amino-lH-indazole-l- carboxylate (0.842g, 3.61 mmol) in iso-propanol (100 mL) was heated at 95 °C for 2h, upon which the an additional aliquot of fert-butyl 5-amino-lH-indazole-l-carboxylate EPO <DP n="194"/>(0.10Og, 0.43 mmol) was added. Stirring was continued at 95 °C for a further 3 h upon which a third aliquot of tert-butyl 5-amino-lH-indazole-l-carboxylate (0.050g, 0.22 mmol) was added. Stirring was continued at 95 0C for a further 1 h upon which the mixture was allowed to cool to RT and the precipitate was collected via filtration. The solid was washed with iso-propanol and dried under vacuum to give tert-butyl 5-(2-(3- (benzyloxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-lH-indazole- 1-carboxylate (2.35g, 3.44 mmol, 100percent). MS 648 (M+l). HPLC retention time 7.79 mins.

References: [1]Patent: WO2008/54599,2008,A2 .Location in patent: Page/Page column 208.
[2]Patent: WO2010/104851,2010,A1 .Location in patent: Page/Page column 202; 203.
[3]Patent: WO2006/105081,2006,A2 .Location in patent: Page/Page column 192; 193.

10
[ 24424-99-5 ]
[ 5401-94-5 ]
[ 129488-10-4 ]

Yield	Reaction Conditions	Operation in experiment
96%		A soln of di-tert-butyl dicarbonate (6.719 g, 30.8 mmol) in DCM (20 mL) was added over 5 min to a suspension of 5-nitro-lH-indazole (5.009 g, 30.7 mmol), Et3N (4.30 mL, 30.9 mmol) and DMAP (0.751 g, 6.15 mmol) in DCM (60 mL). After 17 h the solution was washed with water (1 x 50 mL), 1 M citric acid (3 x 10 mL) and satd NaCl (1 x 20 mL), then dried (MgSO4), filtered through silica, washed with DCM and concentrated to give 7.75 g (96percent) an off-white solid. LC-MS (ESI) m/z 162 [M- Boc-H]-.

References: [1]Patent: WO2006/135383,2006,A2 .Location in patent: Page/Page column 123.
[2]Patent: WO2016/57834,2016,A1 .

11
[ 40114-49-6 ]
[ 129488-10-4 ]
[ 916991-31-6 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium tris(acetoxy)borohydride; acetic acid; In 1,1-dichloroethane; at 20℃; for 43h;	To a solution of 5-amino-indazole-l-carboxylic acid tert-butyl ester (2.333 g, 10.0 mmol) and l-benzyl-piperidin-3-one (1.900 g, 10.0 mmol) in DCE (35 mL) was added NaBH(OAc)3 (95percent; 2.970 g, 13.3 mmol) followed by AcOH (0.58 mL, 10.1 mmol) at room temperature and stirring continued for 43 h. The reaction was washed with 1 M NaOH (50 mL) then the organic phase dried (MgSO4), filtered, adsorbed onto silica and purified by MPLC using gradient of 0 - 10percent /-PrOH in DCM yielding 3.24 g (80percent) of 5-(l-benzyl-piperidin-3-ylamino)-indazole-l-carboxylic acid tert-butyl ester as a brown foam. LC-MS (ESI) m/z 407 [M+H]+.

References: [1]Patent: WO2006/135383,2006,A2 .Location in patent: Page/Page column 124.

12
[ 5401-94-5 ]
[ 129488-10-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen;palladium 10% on activated carbon; In ethanol; for 23h;	A suspension of 10percent Pd-C (0.054 g, 0.051 mmol in Pd) and the above carbamate Example 105 (2.647 g, 10.1 mmol) in 95percent EtOH was degassed under reduced pressure then reacted under hydrogen. After 23 h the solvent was evaporated on a rotary evaporator. EtOAc (20 mL) was added and the reaction filtered then slowly EPO <DP n="125"/>concentrated on a rotary evaporator yielding 2.335 g (100percent) of a tan solid.LC- MS (ESI) m/z 134 [M-Boc+H]+.

References: [1]Patent: WO2006/135383,2006,A2 .Location in patent: Page/Page column 123-124.
[2]Patent: WO2012/146724,2012,A2 .
[3]Patent: US2014/57942,2014,A1 .
[4]Patent: WO2014/68035,2014,A1 .
[5]Asian Journal of Chemistry,2014,vol. 26,p. 7539 - 7543.
[6]Patent: EP3421465,2019,A1 .
[7]Patent: EP3421464,2019,A1 .

14
[ 129488-10-4 ]
[ 74124-79-1 ]
[ 1094503-56-6 ]
[ 1094506-60-1 ]
[ 1094506-63-4 ]

Yield	Reaction Conditions	Operation in experiment
		Into a three-necked flask equipped with a magnetic stirrer and placed under N2 is introduced tert-butyl (2S)-2-[(3,4-dichlorophenyl)(hydroxy)methyl]piperidine-1-carboxylate (1.9 g, 5.2 mmol) dissolved in acetonitrile (30 mL). N,N'-Disuccinimyl carbamate (2.05 g, 8 mmol) and triethylamine (2.19 mL, 15.6 mmol) are then added and the reaction medium is stirred for 4 hours at RT. After concentrating the reaction medium by evaporation under RP, the residue thus obtained is taken up in saturated aqueous sodium hydrogen carbonate solution and the aqueous phase is extracted with EtOAc (3.x.30 mL). The organic phase is washed with aqueous NaCl solution, dried over MgSO4 and concentrated by evaporation under RP. The residue obtained is diluted in DCM (15 mL). This solution is then added dropwise to solution, prepared beforehand and placed in a one-necked flask, of <strong>[129488-10-4]5-amino-N-tert-butoxycarbonyl-1H-indazole</strong> (1.45 g, 6.2 mmol), DCM (40 mL) and triethylamine (1.1 mL, 7.8 mmol). The reaction medium is stirred at RT overnight. 40 mL of DCM and 30 mL of saturated aqueous sodium hydrogen carbonate solution are then added. After separation of the phases by settling, the organic phase is washed with aqueous NaCl solution, dried over MgSO4, filtered and concentrated by evaporation under RP. The residue is purified by chromatography on silica gel eluted with a 3/1 cyclohexane/EtOAc mixture. tert-Butyl (2S)-2-[(S)-(3,4-dichlorophenyl)[(1-(tert-butoxycarbonyl)-1H-indazol-5-yl)carbamoyl]oxy}methyl]piperidine-1-carboxylate (0.215 g) is thus obtained the form of a colourless lacquer and tert-butyl (2S)-2-[(R)-(3,4-dichlorophenyl)[(1-(tert-butoxycarbonyl)-1H-indazol-5-yl)carbamoyl]oxy}methyl]piperidine-1-carboxylate (0.434 g) is obtained in the form of a white foam. (M-H)-=617.

References: [1]Patent: US2010/298377,2010,A1 .Location in patent: Page/Page column 29; 30.

15
[ 129488-10-4 ]
[ 74124-79-1 ]
[ 1094503-74-8 ]
[ 1094506-77-0 ]

Yield	Reaction Conditions	Operation in experiment
		Into a one-necked flask equipped with a magnetic stirrer is introduced tert-butyl (2S)-2-[3-(ethoxycarbonyl)phenyl](hydroxy)methyl}piperidine-1-carboxylate (4.7 g, 12.8 mmol) dissolved in acetonitrile (85 mL) with N,N'-disuccinimidyl carbonate (13.1 g, 51 mmol). Triethylamine (8.95 mL, 64 mmol) is then added and the reaction medium is stirred for 4 hours at a temperature in the region of 20° C. The reaction medium is concentrated to dryness and the evaporation residue is taken up in saturated aqueous sodium hydrogen carbonate solution (50 mL) and extracted with twice 40 mL of EtOAc. A persistent insoluble material is removed by filtration of the organic phases through a sinter funnel. The filtrate is dried over MgSO4, filtered and concentrated to dryness under RP to give the activated intermediate. Into a second one-necked flask equipped with a magnetic stirrer is introduced tert-butyl 5-amino-indazole-1-carboxylate (3 g, 12.8 mmol) with DCM (125 mL) and triethylamine (2.7 mL, 19.1 mmol). Into this solution is poured the activated intermediate dissolved in DCM (40 mL) over about 10 minutes. The reaction medium is stirred in the region of 20° C. for 16 hours. The medium is hydrolysed with saturated aqueous sodium hydrogen carbonate solution (80 mL), the phases are separated by settling and the aqueous phase is re-extracted with DCM (30 mL). The combined organic extracts are dried over MgSO4, filtered and concentrated to dryness under RP. The garnet-coloured oil isolated is chromatographed on 420 g of silica gel 60, particle size 15-40 mum, contained in a column 5 cm in diameter, eluting with a 7/3v/v cyclohexane/EtOAc mixture, under an excess pressure of 0.6 bar of argon. The evaporation of the fractions gives 1.53 g of tert-butyl 5-[([(2S)-1-(tert-butoxycarbonyl)piperid-2-yl][3-(ethoxycarbonyl)phenyl]methoxy}carbonyl)amino]-1H-indazole-1-carboxylate in the form of a white-coloured foam. (M-H)-=621. 1H NMR (DMSO, 400 MHz): 70percent-30percent mixture of isomers, delta (ppm) from 0.98 to 2.00 (m, 27H); 2.98 (m, 1H); 3.90 (broad m, 1H); 4.33 (q, J=7.5 Hz, 2H); 4.50 (broad m, 1H); 6.09 (d, J=10.0 Hz, 0.7H); 6.23 (broad d, J=9.0 Hz, 0.3H); 7.50 (t, J=7.5 Hz, 0.7H); 7.58 (m, 1.3H); 7.68 (broad d, J=7.5 Hz, 0.7H); 7.75 (broad d, J=7.5 Hz, 0.3H); from 7.85 to 8.00 (m, 3H); 8.04 (broad s, 0.7H); 8.08 (broad s, 0.3H); 8.32 (s, 0.7H); 8.34 (s, 0.3H); 9.82 (broad m, 0.3H); 10.1 (s, 0.7H).

References: [1]Patent: US2010/298377,2010,A1 .Location in patent: Page/Page column 31.

16
[ 24424-99-5 ]
[ 129488-10-4 ]

References: [1]Patent: WO2012/146724,2012,A2 .
[2]Patent: US2014/57942,2014,A1 .
[3]Patent: WO2014/68035,2014,A1 .
[4]Asian Journal of Chemistry,2014,vol. 26,p. 7539 - 7543.
[5]Patent: EP3421465,2019,A1 .
[6]Patent: EP3421464,2019,A1 .

17
[ 129488-10-4 ]
[ 916989-48-5 ]

References: [1]Patent: WO2012/146724,2012,A2 .
[2]Patent: US2014/57942,2014,A1 .
[3]Patent: WO2006/135383,2006,A2 .
[4]Patent: EP3421465,2019,A1 .

18
[ 129488-10-4 ]
[ 1404375-40-1 ]