444731-75-3|N-(2-Chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine| Ambeed

Structure of 444731-75-3

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Quality Control of [ 444731-75-3 ] Purity: 97% SDS Specification

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Product Details of [ 444731-75-3 ]

CAS No. :	444731-75-3
Formula :	C₁₄H₁₄ClN₅
M.W :	287.75
SMILES Code :	CC1=C2C=CC(N(C3=NC(Cl)=NC=C3)C)=CC2=NN1C
MDL No. :	MFCD12923006
InChI Key :	DVGMRZQSSNNTFY-UHFFFAOYSA-N
Pubchem ID :	11608962

Safety of [ 444731-75-3 ]

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

Computational Chemistry of [ 444731-75-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	20
Num. arom. heavy atoms	15
Fraction Csp3	0.21
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	81.01
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	46.84 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.61
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	3.23
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.09
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.	2.26
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	2.12
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.66

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.08
Solubility	0.0238 mg/ml ; 0.0000828 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.89
Solubility	0.0374 mg/ml ; 0.00013 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	-4.97
Solubility	0.0031 mg/ml ; 0.0000108 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	Yes
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	Yes
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.	-5.76 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	0.0 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<0.0
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)	2.4

Application In Synthesis of [ 444731-75-3 ]

* 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 [ 444731-75-3 ]

[ 444731-75-3 ] Synthesis Path-Downstream 1~41

1
[ 74-88-4 ]
[ 444731-75-3 ]

Yield	Reaction Conditions	Operation in experiment
90.4%		A 3L 3-necked flask equipped with air-driven mechanical stirrer, thermometer, addition funnel and nitrogen inlet/outlet was charged with DMF (272 mL, 5 volumes) and the product of Intermediate Example 3 (54.4 g, 0.20 mol, 1.0 equiv) with stirring. The reaction mixture was further charged with cesium carbonate (194.5 g, 0.60 mol, 3.0 equiv) while maintaining the reaction temperature between 20 ~ 25C. The reaction mixture was stirred at 20 ~ 25C for 10 minutes, lodomethane (45.1 g, 0.32 mol, 1.6 equiv) was charged over - 10 minutes while maintaining the temperature 20 ~ 3O0C. The reaction mixture was stirred at 20 ~ 30C (Typically, the reaction is complete in 1 ~ 2 hours). Deionized H2O (925 mL, 17 volumes) was added over ~ 30 minutes while maintaining the temperature at 25 ~ 40C. The reaction mixture was stirred at 20 ~ 25C for 40 minutes. The product was isolated by filtration and then the filter cake washed with H2O / DMF (6 : 1 , 252 mL, 4.6 volumes). The wet cake was dried under vacuum at 40 ~ 45C and /V-(2-chloropyrimidin-4-yl)-Lambda/,2,3-trimethyl-2H- indazol-6-amine (51.7 g, 90.4%) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-de) delta 7.94 (d, J = 6.0 Hz, 1 H), 7.80 (d, J = 7.0 Hz, 1 H), 7.50 (d, J = 1.0 Hz, 1 H), 6.88 (m, 1 H), 6.24 (d, J = 6.2 Hz, 1 H), 4.06 (s, 3H), 3.42 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 288 (M+H).

References: [1]Patent: WO2007/64753,2007,A2 .Location in patent: Page/Page column 30.

2
[ 444731-74-2 ]
[ 74-88-4 ]
[ 444731-75-3 ]

Yield	Reaction Conditions	Operation in experiment
90.4%		A 3L 3-necked flask equipped with air-driven mechanical stirrer, thermometer, addition funnel and nitrogen inlet/outlet was charged with DMF (272 mL, 5 volumes) and the product of Intermediate Example 3 (54.4 g, 0.20 mol, 1.0 equiv) with stirring. The reaction mixture was further charged with cesium carbonate (194.5 g, 0.60 mol, 3.0 equiv) while maintaining the reaction temperature between [20 N 25 C.] The reaction mixture was stirred at [20 # 25 C ] for 10 minutes. lodomethane (45.1 g, 0.32 mol, 1.6 equiv) was charged [OVER ~ 10] minutes while maintaining the temperature 20 [~] 30C. The reaction mixture was stirred at [20- 30 C (TYPICALLY,] the reaction is complete in [1 N 2] hours). Deionized [H20] (925 mL, 17 volumes) was added [OVER # 30] minutes while maintaining the temperature at [25-40 OC.] The reaction mixture was stirred at [20 # 25 C ] for 40 minutes. The product was isolated by filtration and then the filter cake washed with H20/DMF (6: 1,252 mL, 4.6 volumes). The wet cake was dried under vacuum at [40 45 C] and [N- (2-CHLOROPYRIMIDIN-4-YL)-N,] 2, 3-trimethyl- 2H-indazol-6-amine (51.7 g, 90.4%) was isolated as a yellow [SOLID.'H] NMR (400 MHz, [DMSO-DS)] 8 7.94 (d, J = 6.0 Hz, [1 H),] 7.80 (d, J = 7.0 Hz, 1 H), 7.50 (d, J = 1.0 Hz, 1 H), 6.88 (m, 1H), 6.24 (d, J = 6.2 Hz, 1H), 4.06 (s, [3H),] 3.42 (s, [3H),] 2.62 (s, [3H).] MS [(ES+,] m/z) 288 (M+H).
90.4%	With caesium carbonate; In N,N-dimethyl-formamide; at 25 - 30℃; for 6h;	Example 4a Synthesis of N-(2-Chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine Cesium carbonate (238 g, 0.73 mol) and iodomethane (57 g, 0.40 mol) were added to a stirred suspension of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (100g, 0.37 mol) in N,N-dimethylformamide (300 mL) at 25 C. to 30 C. The reaction mixture was further stirred at 25 C. to 30 C. for 6 hours followed by cooling of the reaction mixture to 0 C. to 5 C. De-ionized water (300 mL) was added drop-wise to the reaction mixture, then the reaction mixture was stirred at 5 C. to 10 C. for 30 minutes. The solid was collected by filtration, and washed with de-ionized water (100 mL*2). The wet material so obtained was dried in an air oven at 50 C. for 12 hours to obtain the title compound.
90.4%		A 3 L 3-necked flask equipped with air-driven mechanical stirrer, thermometer, addition funnel and nitrogen inlet/outlet was charged with DMF (272 mL, 5 volumes) and the product of Intermediate Example 3 (54.4 g, 0.20 mol, 1.0 equiv) with stirring. The reaction mixture was further charged with cesium carbonate (194.5 g, 0.60 mol, 3.0 equiv) while maintaining the reaction temperature between 2025 C. The reaction mixture was stirred at 2025 C. for 10 minutes. Iodomethane (45.1 g, 0.32 mol, 1.6 equiv) was charged over 10 minutes while maintaining the temperature 2030 C. The reaction mixture was stirred at 2030 C. (Typically, the reaction is complete in 12 hours). Deionized H2O (925 mL, 17 volumes) was added over 30 minutes while maintaining the temperature at 2540 C. The reaction mixture was stirred at 2025 C. for 40 minutes. The product was isolated by filtration and then the filter cake washed with H2O/DMF (6:1, 252 mL, 4.6 volumes). The wet cake was dried under vacuum at 4045 C. and N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (51.7 g, 90.4%) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 7.94 (d, J=6.0 Hz, 1H), 7.80 (d, J=7.0 Hz, 1H), 7.50 (d, J=1.0 Hz, 1H), 6.88 (m, 1H), 6.24 (d, J=6.2 Hz, 1H), 4.06 (s, 3H), 3.42 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 288 (M+H).

90.4%		A 3L 3-necked flask equipped with air-driven mechanical stirrer, thermometer, addition funnel and nitrogen inlet/outlet was charged with DMF (272 ml_, 5 volumes) and the product of Intermediate Example 3 (54.4 g, 0.20 mol, 1.0 equiv) with stirring. The reaction mixture was further charged with cesium carbonate (194.5 g, 0.60 mol, 3.0 equiv) while maintaining the reaction temperature between 20 ~ 25C. The reaction mixture was stirred at 20 ~ 25C for 10 minutes, lodomethane (45.1 g, 0.32 mol, 1.6 equiv) was charged over ~ 10 minutes while maintaining the temperature 20 ~ 3O0C. The reaction mixture was stirred at 20 ~ 300C (Typically, the reaction is complete in 1 ~2 hours). Deionized H2O (925 ml_, 17 volumes) was added over ~ 30 minutes while maintaining the temperature at 25 ~ 400C. The reaction mixture was stirred at 20 ~ 25C for 40 minutes. The product was isolated by filtration and then the filter cake washed with H2O / DMF (6 : 1 , 252 ml_, 4.6 volumes). The wet cake was dried under vacuum at 40 ~ 45C and lambda/-(2-chloropyhmidin-4-yl)-lambda/,2,3-trimethyl-2/-/-indazol-6-amine (51.7 g, 90.4%) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 7.94 (d, J = 6.0 Hz, 1 H), 7.80 (d, J = 7.0 Hz, 1 H), 7.50 (d, J = 1.0 Hz, 1 H), 6.88 (m, 1 H), 6.24 (d, J = 6.2 Hz, 1 H), 4.06 (s, 3H), 3.42 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 288 (M+H).
89.1%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h;	To a stirred solution of the intermediate 4a (6.50 g, 24 mmol) in DMF (30 mL) was added Cs2CO3 (10.00 g, 31 mmol) and CH3I (5.70 g, 40 mmol) at room temperature. The mixture was stirred at rt for 5 h. The reaction mixture was then poured into an ice-water bath, and the precipitate was collected via fitration and washed with water. The precipitate was dried to afford 5a as an off-white solid (5.90 g, 89.1% yield). Mp: 172~173 C. 1HNMR (400MHz, DMSO-d6) delta: 2.62 (s, 3H), 3.41 (s, 3H), 4.05 (s, 3H), 6.23 (d, J=6.0 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 7.49 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.93 (d, J=6.4 Hz, 1H).
85.7%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	The suspension of ISO-IM1 (1g, 3.6 mmol), CH3I (0.76g, 5.4 mmol) and Cs2CO3 (2.34g, 7.2 mmol) in DMF (15 mL) was stirred for 2 h at room temperature.Then to the reaction mixture was added 100 mL H2O, filtered and dried to afford ISO-IM2 (0.9 g, 85.7%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) (delta, ppm):8.28 (d, J = 5.1 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.39 (s, 1H), 6.87 (d, J = 8.8 Hz,1H), 6.80 (d, J = 5.1Hz, 1H), 4.03 (s, 3H), 3.47 (s, 3H), 2.59 (s, 3H).
83%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;Product distribution / selectivity;	To a stirred solution of the product of Intermediate Example 3 (7.37 g) in DMF (50 ml) was added Cs2CO3 (7.44 g, 2 eqv.) and iodomethane (1.84 ml, 1.1 eqv.) at room temperature. The mixture was stirred at rt overnight. The reaction mixture was then poured into an ice-water bath, and the precipitate was collected via filtration and washed with water. The precipitate was air-dried to afford /V-(2-chloropyrimidin-4-yl)- Lambda/,2,3-trimethyl-2H-indazol-6-amine as an off-white solid (6.43 g, 83%). 1H NMR (400 MHz, DMSO-de) delta 7.94 (d, J = 6.0 Hz, 1 H), 7.80 (d, J = 7.0 Hz, 1 H), 7.50 (d, J = 1.0 <n="31"/>Hz, 1 H), 6.88 (m, 1 H), 6.24 (d, J= 6.2 Hz, 1 H), 4.06 (s, 3H), 3.42 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 288 (M+H).
83%	With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20 - 30℃; for 1 - 2h;	To a stirred solution of the product of Intermediate Example 3 (7.37 g) in DMF (50 mi) was added Cs2CO3 (7.44 g, 2 eqv. ) and iodomethane (1.84 [ML,] 1.1 eqv. ) at room temperature. The mixture was stirred at rt overnight. The reaction mixture was then poured into an ice-water bath, and the precipitate was collected via filtration and washed with water. The precipitate was air-dried to afford [N- (2-CHLOROPYRIMIDIN-4-] [YL)-N,] 2, 3-trimethyl-2H-indazol-6-amine as an off-white solid (6.43 [G,] 83%).'H NMR (400 MHz, [DMSO-D6)] [8] 7.94 (d, J = 6.0 Hz, 1 H), 7.80 (d, [J =] 7.0 Hz, 1 H), 7.50 [(D, J =] 1.0 Hz, 1 H), 6.88 (m, 1 H), 6.24 (d, J = 6.2 Hz, 1 H), 4.06 (s, [3H),] 3.42 (s, [3H),] 2.62 (s, [3H).] MS (ES+, m/z) 288 (M+H)
83 - 90.4%	With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 30℃;Product distribution / selectivity;	To a stirred solution of the product of Intermediate Example 3 (7.37 g) in DMF (50 ml) was added Cs2CO3 (7.44 g, 2 eqv.) and iodomethane (1.84 ml, 1.1 eqv.) at room temperature. The mixture was stirred at rt overnight. The reaction mixture was then poured into an ice-water bath, and the precipitate was collected via filtration and washed with water. The precipitate was air-dried to afford Lambda/-(2-chloropyrimidin-4-yl)- /V,2,3-trimethyl-2H-indazol-6-amine as an off-white solid (6.43 g, 83%). 1H NMR (400 MHz, DMSO-d6) delta 7.94 (d, J = 6.0 Hz, 1 H), 7.80 (d, J = 7.0 Hz, 1 H), 7.50 (d, J = 1.0 Hz, 1 H), 6.88 (m, 1 H), 6.24 (d, J = 6.2 Hz, 1 H), 4.06 (s, 3H), 3.42 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 288 (M+H).; A 3L 3-necked flask equipped with air-driven mechanical stirrer, thermometer, addition funnel and nitrogen inlet/outlet was charged with DMF (272 ml_, 5 volumes) and the product of Intermediate Example 3 (54.4 g, 0.20 mol, 1.0 equiv) with stirring. The reaction mixture was further charged with cesium carbonate (194.5 g, 0.60 mol, 3.0 equiv) while maintaining the reaction temperature between 20 ~ 25 0C. The reaction mixture was stirred at 20 ~ 25 0C for 10 minutes, lodomethane (45.1 g, 0.32 mol, 1.6 equiv) was charged over ~ 10 minutes while maintaining the temperature 20 ~ 3O0C. The reaction mixture was stirred at 20 ~ 30 0C (Typically, the reaction is complete in 1 ~ 2 hours). Deionized H2O (925 ml_, 17 volumes) was added over ~ 30 minutes while maintaining the temperature at 25 ~ 40 0C. The reaction mixture was stirred at 20 ~ 25 0C for 40 minutes. The product was isolated by filtration and then the filter cake washed with H2O / DMF (6 : 1 , 252 ml_, 4.6 volumes). The wet cake was dried under vacuum at 40 ~ 45 0C and Lambda/-(2-chloropyrimidin-4-yl)-Lambda/,2,3-trimethyl-2H- indazol-6-amine (51.7 g, 90.4%) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 7.94 (d, J = 6.0 Hz, 1 H), 7.80 (d, J = 7.0 Hz, 1 H), 7.50 (d, J = 1.0 Hz, 1 H), 6.88 (m, 1 H), 6.24 (d, J = 6.2 Hz, 1 H), 4.06 (s, 3H), 3.42 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 288 (M+H).
83%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	Intermediate Example 13 Preparation of N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine To a stirred solution of the Intermediate 12 (7.37 g) in DMF (50 ml) was added C2CO3 (7.44 g, 2 eqv.) and MeI (1.84 ml, 1.1 eqv.) at room temperature. Mixture was stirred at rt for overnight. The reaction mixture was poured into ice-water bath, and the precipitate was collected via filtration and washed with water. The precipitate was air-dried to afford N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine as an off-white solid (6.43 g, 83%). 1H NMR (400 MHz, d6DMSO) delta 7.94 (d, J = 6.0 Hz, 1H), 7.80 (d, J = 7.0 Hz, 1H), 7.50 (d, J = 1.0 Hz, 1H), 6.88 (m, 1H), 6.24 (d, J = 6.2 Hz, 1H), 4.06 (s, 3H), 3.42 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 288 (M+H).
83%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;Product distribution / selectivity;	To a stirred solution of the product of Intermediate Example 3 (7.37 g) in DMF (50 ml) was added Cs2CO3 (7.44 g, 2 eqv.) and iodomethane (1.84 ml, 1.1 eqv.) at room temperature. The mixture was stirred at rt overnight. The reaction mixture was then poured into an ice-water bath, and the precipitate was collected via filtration and washed with water. The precipitate was air-dried to afford N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine as an off-white solid (6.43 g, 83%). 1H NMR (400 MHz, DMSO-d6) delta 7.94 (d, J=6.0 Hz, 1H), 7.80 (d, J=7.0 Hz, 1H), 7.50 (d, J=1.0 Hz, 1H), 6.88 (m, 1H), 6.24 (d, J=6.2 Hz, 1H), 4.06 (s, 3H), 3.42 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 288 (M+H).
83 - 90.4%	With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 30℃;Product distribution / selectivity;	Intermediate Example 4 Preparation of N-(2-chloropyrimidin-4-yi )-N,2,3-trimethyl-2H-indazol-6-amine Procedure 1 To a stirred solution of the product of Intermediate Example 3 (7.37 g) in DMF (50 ml) was added Cs2C03 (7.44 g, 2 eqv. ) and iodomethane (1.84 ml, 1.1 eqv. ) at room temperature. The mixture was stirred at rt overnight. The reaction mixture was then poured into an ice-water bath, and the precipitate was collected via filtration and washed with water. The precipitate was air-dried to afford N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6- amine as an off-white solid (6.43 g, 83%).; Procedure 2 A 3L 3-necked flask equipped with air-driven mechanical stirrer, thermometer, addition funnel and nitrogen inlet/outlet was charged with DMF (272 mL, 5 volumes) and the product of Intermediate Example 3 (54.4 g, 0.20 mol, 1.0 equiv) with stirring. The reaction mixture was further charged with cesium carbonate (194.5 g, 0.60 mol, 3.0 equiv) while maintaining the reaction temperature between 20 - 25 C. The reaction mixture was stirred at 20 - 25 C for 10 minutes. lodomethane (45.1 g, 0.32 mol, 1.6 equiv) was charged over - 10 minutes while maintaining the temperature 20 - 30C. The reaction mixture was stirred at 20 - 30 C (Typically, the reaction is complete in 1 - 2 hours). Deionized H20 (925 mL, 17 volumes) was added over - 30 minutes while maintaining the temperature at 25 - 40 C. The reaction mixture was stirred at 20 - 25 C for 40 minutes. The product was isolated by filtration and then the filter cake washed with H2O / DMF (6 : 1, 252 mL, 4.6 volumes). The wet cake was dried under vacuum at 40 - 45 C and N-(2- chloropyrimidin-4-yl) -N,2,3-trimethyl-2H-indazol-6-amine (51.7 g, 90.4%) was isolated as a yellow solid.
83%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;Product distribution / selectivity;	To a stirred solution of the product of Intermediate Example 3 (7.37 g) in DMF (50 ml) was added Cs2CO3 (7.44 g, 2 eqv.) and iodomethane (1.84 ml, 1.1 eqv.) at room temperature. The mixture was stirred at rt overnight. The reaction mixture was then poured into an ice-water bath, and the precipitate was collected via filtration and washed with water. The precipitate was air-dried to afford lambda/-(2-chloropyrimidin-4-yl)- lambda/,2,3-thmethyl-2H-indazol-6-amine as an off-white solid (6.43 g, 83%). 1H NMR (400 MHz, DMSO-d6) delta 7.94 (d, J = 6.0 Hz, 1 H), 7.80 (d, J = 7.0 Hz, 1 H), 7.50 (d, J = 1.0 Hz, <n="34"/>1 H), 6.88 (m, 1 H), 6.24 (d, J = 6.2 Hz, 1 H), 4.06 (s, 3H), 3.42 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 288 (M+H).
80%		The previous product, 2 1.00 g, and cesium carbonate, 2.40 g, were added to 50 mL of N,N-dimethylformamide.After reacting for 20 minutes at room temperature, then slowly adding 0.78 g of methyl iodide,After the addition, the reaction was carried out at room temperature for 2 hours. The reaction solution was poured into ice water and a large amount of light yellow solids precipitated immediately.After filtration, drying and recrystallization from ethyl acetate, 1.06 g of product 3 was obtained as pale yellow crystals. Yield: 80.0%
37%		N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (2.21g; 8mmol, 1 equiv) was dissolved in DMF (11 ml) and cesium carbonate (7.9g; 24.2mmol, 3 equiv) was added.The reaction mixture was stirred for 30 min under nitrogen. Iodomethane (0.8ml, 13mmol,1.6 equiv) was added and the reaction mixture was stirred at room temperature for 2 hrs.The reaction mixture was poured in ice cold water and stirred for 30 minutes. The resulting precipitate was collected by filtration to yield the desired compound (0.84g, 37%). 1H NMR (MeOD, 400MHz) delta= 7.75 (d, J = 7Hz, IH), 7.71 (d, J = 7Hz, IH), 7.35 (d, J =2Hz, IH), 6.8 (dd, J = 2Hz, J = 9Hz, IH), 6.14 (d, J = 6Hz, IH), 4.01 (s, 3H), 3.4 (s, 3H),2.56 (s, 3H).

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3
[ 444731-75-3 ]
[ 6973-09-7 ]
pazopanib hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogenchloride; In isopropyl alcohol;Reflux;	Example 4b: Synthesis of Pazopanib Hydrochloride (0040) To a suspension of <strong>[444731-75-3]N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine</strong> (90 g, 0.312 mol) and 5-amino-2-methyl benzene sulfonamide (64.07 g, 0.344 mol) in isopropyl alcohol (900 mL) was added 4M hydrochloric acid solution in isopropyl alcohol (1.56 mL, 6.25 mol). The reaction mixture was heated to reflux temperature for 10 hours to 12 hours. The reaction mixture was cooled to 25 C. The reaction mixture was further stirred at 25 C. to 30 C. for 30 minutes, then the solid was filtered. The wet solid was washed with isopropyl alcohol (180 mL×2), and then dried under vacuum at 45 C. to 50 C. for 12 hours to afford the hydrochloride salt of 5-({4-[(2,3-dimethyl-21-I-indazol-6-yl)(methyl) amino] pyrimidin-2-yl} amino-Z-methylbenzene sulfonamide as a light brown solid. Yield: 97% w/w.
96.4%		A 250-mL 3-necked flask equipped with a magnetic stir bar, thermometer, reflux condenser, and nitrogen inlet/outlet was charged with ethanol (60 ml_, 10 volumes), the product of Intermediate Example 4 (6.00 g, 20.85 mmol, 1.0 equiv) and 5-amino-2-rnethylbenzenesulfonamide (4.00 g, 21.48 mmol, 1.03 equiv) with stirring. The reaction mixture was heated to 70 0C. After stirring the reaction mixture at 68 - 72 0C for 3 hrs, 4M HCI in dioxane (0.11 mL, 0.44 mmol, 0.02 equiv) was charged over ca. 2 min. The reaction mixture was stirred at 68 - 72 0C until < 1.5% by area of the starting product of Intermediate Example 4 was remaining by HPLC analysis (Typically, this reaction is complete in > 8 hrs). The reaction mixture was cooled to 20 <n="33"/>0C over ca. 30 min and stirred at 20 - 22 0C for 40 min. The product was then isolated by filtration and the filter cake washed with ethanol (20 mL, 3.3 volumes). The wet cake was dried under vacuum at 45 - 50 0C. The monohydrochloride salt of 5-({4- [(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-pyrimidin-2-yl}amino)-2- methylbenzenesulfonamide (9.52 g, 96.4%) was isolated as a white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1 H), 8.55 (br s, 1 H), 7.81 (d, J = 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1 H), 7.69 (m, 1 H), 7.43 (s, 1 H), 7.23 (s, 2H), 7.15 (d, J = 8.4 Hz, 1 H), 6.86 (m, 1 H), 5.74 (d, J = 6.1 Hz, 1 H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).
96.4%		A 250-mL 3-necked flask equipped with a magnetic stir bar, thermometer, reflux condenser, and nitrogen inlet/outlet was charged with ethanol (60 mL, 10 volumes), the product of Intermediate Example 4 (6.00 g, 20.85 mmol, 1.0 equiv) and 5-amino-2-methylbenzenesulfonamide (4.00 g, 21.48 mmol, 1.03 equiv) with stirring. The reaction mixture was heated to [70 C.] After stirring the reaction mixture at 68- [72 C] for 3 hrs, 4M HCI in dioxane (0.11 mL, 0.44 mmol, 0.02 equiv) was charged over ca. 2 min. The reaction mixture was stirred at [68-72 C UNTIL] < 1. [5%] by area of the starting product of Intermediate Example 4 was remaining by HPLC analysis (Typically, this reaction is complete in > 8 hrs). The reaction mixture was cooled to [20 C] over ca. 30 min and stirred at [20-22 C] for 40 min. The product was then isolated by filtration and the filter cake washed with ethanol (20 mL, 3.3 volumes). The wet cake was dried under vacuum at [45-50 C.] The [MONOHYDROCHLORIDE] salt of [5- ( {4- [ (2,] 3- [DIMETHYL-2H-INDAZOL-6-YL) (METHYL) AMINO]-PYRIMIDIN-2-YL} AMINO)-2-] [METHYLBENZENESULFONAMIDE] (9.52 g, 96. [40/0)] was isolated as a white [SOLID.'H] NMR (400 MHz, [D6DMSO+NAHCO3)] 8 9.50 (br s, [1] [H),] 8.55 (br s, 1 H), 7.81 (d, J = 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1H), 7.69 (m, 1H), 7.43 (s, [1 H),] 7. [23 (S, 2H),] 7.15 [(D, J =] 8.4 Hz, 1H), 6. [86] (m, [1 H),] 5.74 (d, J = 6.1 Hz, 1H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).

96.4%	With hydrogenchloride; In 1,4-dioxane; ethanol; at 68 - 72℃; for 11.0333h;Product distribution / selectivity;	A 250-mL 3-necked flask equipped with a magnetic stir bar, thermometer, reflux condenser, and nitrogen inlet/outlet was charged with ethanol (60 mL, 10 volumes), the product of Intermediate Example 4 (6.00 g, 20.85 mmol, 1.0 equiv) and 5-amino-2- methylbenzenesulfonamide (4.00 g, 21.48 mmol, 1.03 equiv) with stirring. The reaction mixture was heated to 70 0C. After stirring the reaction mixture at 68 - 72 0C for 3 hrs, 4M HCI in dioxane (0.11 mL, 0.44 mmol, 0.02 equiv) was charged over ca. 2 min. The reaction mixture was stirred at 68 - 72 0C until < 1.5% by area of the starting product of Intermediate Example 4 was remaining by HPLC analysis (Typically, this reaction is complete in > 8 hrs). The reaction mixture was cooled to 20 0C over ca. 30 min and stirred at 20 - 22 0C for 40 min. The product was then isolated by filtration and the filter cake washed with ethanol (20 mL, 3.3 volumes). The wet cake was dried under vacuum at 45 - 50 0C. The monohydrochloride salt of 5-({4-[(2,3-dimethyl-2/-/-indazol- 6-yl)(methyl)amino]-pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide (9.52 g, 96.4%) was isolated as a white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1 H), 8.55 (br s, 1 H), 7.81 (d, J = 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1 H), 7.69 (m, 1 H), 7.43 (s, 1 H), 7.23 (s, 2H), 7.15 (d, J = 8.4 Hz1 1 H), 6.86 (m, 1 H)1 5.74 (d, J = 6.1 Hz, 1 H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H)1 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).
96.4%		A 250-mL 3-necked flask equipped with a magnetic stir bar, thermometer, reflux condenser, and nitrogen inlet/outlet was charged with ethanol (60 mL, 10 volumes), the product of Intermediate Example 4 (6.00 g, 20.85 mmol, 1.0 equiv) and 5-amino-2-methylbenzenesulfonamide (4.00 g, 21.48 mmol, 1.03 equiv) with stirring. The reaction mixture was heated to 70 C. After stirring the reaction mixture at 68-72 C. for 3 hrs, 4M HCl in dioxane (0.11 mL, 0.44 mmol, 0.02 equiv) was charged over ca. 2 min. The reaction mixture was stirred at 68-72 C. until <1.5% by area of the starting product of Intermediate Example 4 was remaining by HPLC analysis (Typically, this reaction is complete in >8 hrs). The reaction mixture was cooled to 20 C. over ca. 30 min and stirred at 20-22 C. for 40 min. The product was then isolated by filtration and the filter cake washed with ethanol (20 mL, 3.3 volumes). The wet cake was dried under vacuum at 45-50 C. The monohydrochloride salt of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide (9.52 g, 96.4%) was isolated as a white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1H), 8.55 (br s, 1H), 7.81 (d, J=6.2 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.69 (m, 1H), 7.43 (s, 1H), 7.23 (s, 2H), 7.15 (d, J=8.4 Hz, 1H), 6.86 (m, 1H), 5.74 (d, J=6.1 Hz, 1H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).
96.4%		Procedure 2 A 250-mL 3-necked flask equipped with a magnetic stir bar, thermometer, reflux condenser, and nitrogen inlet/outlet was charged with ethanol (60 mL, 10 volumes), the product of Intermediate Example 4 (6.00 g, 20.85 mmol, 1.0 equiv) and 5-amino-2-methylbenzenesulfonamide (4.00 g, 21.48 mmol, 1.03 equiv) with stirring. The reaction mixture was heated to 70 C. After stirring the reaction mixture at 68 - 72 C for 3 hrs, 4M HCI in dioxane (0.11 mL, 0.44 mmol, 0.02 equiv) was charged over ca. 2 min. The reaction mixture was stirred at 68 - 72 C until < 1.5% by area of the starting product of Intermediate Example 4 was remaining by HPLC analysis (Typically, this reaction is complete in > 8 hrs). The reaction mixture was cooled to 20 C over ca. 30 min and stirred at 20 - 22 C for 40 min. The product was then isolated by filtration and the filter cake washed with ethanol (20 mL, 3.3 volumes). The wet cake was dried under vacuum at 45 - 50 C. The monohydrochloride salt of 5-({4-[(2,3-dimethyl-2H-indazol-6- yl)(methyl)amino]-pyrimidin-2-yl)amino)-2-methylbenzenesulfonamide (9.52 g, 96.4%) was isolated as a white solid.
96.4%		A 250-mL 3-necked flask equipped with a magnetic stir bar, thermometer, reflux condenser, and nitrogen inlet/outlet was charged with ethanol (60 ml_, 10 volumes), Intermediate Example 4 (6.00 g, 20.85 mmol, 1.0 equiv) and 5-amino-2- methylbenzenesulfonamide (4.00 g, 21.48 mmol, 1.03 equiv) with stirring. The reaction mixture was heated to 70 0C. After stirring the reaction mixture at 68 - 72 0C for 3 hrs, 4M HCI in dioxane (0.1 1 ml_, 0.44 mmol, 0.02 equiv) was charged over ca. 2 min. The reaction mixture was stirred at 68 - 72 0C until < 1.5% by area of the starting product of Intermediate Example 4 was remaining by HPLC analysis (Typically, this reaction is <n="36"/>complete in > 8 hrs). The reaction mixture was cooled to 20 0C over ca. 30 min and stirred at 20 - 22 0C for 40 min. The product was then isolated by filtration and the filter cake washed with ethanol (20 ml_, 3.3 volumes). The wet cake was dried under vacuum at 45 - 50 0C. The monohydrochloride salt of 5-({4-[(2,3-dimethyl-2H-indazol-6- yl)(methyl)amino]-pyhmidin-2-yl}amino)-2-methylbenzenesulfonamide (9.52 g, 96.4%) was isolated as a white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1 H), 8.55 (br s, 1 H), 7.81 (d, J = 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1 H), 7.69 (m, 1 H), 7.43 (s, 1 H), 7.23 (s, 2H), 7.15 (d, J = 8.4 Hz, 1 H), 6.86 (m, 1 H), 5.74 (d, J = 6.1 Hz, 1 H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).
92%		To a stirred suspension of the product of Intermediate Example 4 (1.1 g, 3.7 mmol) in 10 mL of THF, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1.0 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (18 muL, 0.072 mmol) was added in one portion. After 5 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 16 mL of THF and dried in the air to yield 1.6 g (92%) of 5-({4- [(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methylbenzene sulfonamide monohydrochloride as a light yellow solid.
92%		To a stirred suspension of the product of Intermediate Example 4 (1.1 g, 3.7 [MMOL)] in 10 mL of THF, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1.0 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1,4-dioxane (18 l, 0.072 [MMOL)] was added in one portion. After 5 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 16 [ML OF THF AND] dried in the air to yield 1. [6 G (92%) OF 5-({4-[(2,] 3- dimethyl-2H-indazol-6-yl) [METHYLAMINO]-2-PYRIMIDINYL} AMINO)-2-METHYLBENZENE] sulfonamide monohydrochloride as a light yellow solid.
92%	With hydrogenchloride; In tetrahydrofuran; 1,4-dioxane; at 20℃; for 8h;Heating / reflux;Product distribution / selectivity;	To a stirred suspension of the product of Intermediate Example 4 (1 .1 g, 3.7 mmol) in 10 mL of THF, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1 .0 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (18 muL, 0.072 mmol) was added in one portion. After 5 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 16 mL of THF and dried in the air to yield 1 .6 g (92%) of 5-({4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methylbenzene sulfonamide monohydrochloride as a light yellow solid.
92%		To a stirred suspension of the product of Intermediate Example 4 (1.1 g, 3.7 mmol) in 10 mL of THF, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1.0 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCl in 1,4-dioxane (18 muL, 0.072 mmol) was added in one portion. After 5 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 16 mL of THF and dried in the air to yield 1.6 g (92%) of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methylbenzene sulfonamide monohydrochloride as a light yellow solid.
92%		Procedure 4 To a stirred suspension of the product of Intermediate Example 4 (1.1 g, 3.7 mmol) in 10 mL of THF, was added 5-amino-2- methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1.0 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1,4-dioxane (18 muL, 0.072 mmol) was added in one portion. After 5 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 16 mL of THF and dried in the air to yield 1.6 g (92%) of 5- ({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl)amino)-2- methylbenzene sulfonamide monohydrochloride as a light yellow solid.
92%		To a stirred suspension of Intermediate Example 4 (1.1 g, 3.7 mmol) in 10 mL of THF, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1.0 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (18 mul_, 0.072 mmol) was added in one portion. After 5 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 16 mL of THF and dried in the air to yield 1.6 g (92%) of 5-({4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl}amino)-2-methylbenzene sulfonamide monohydrochloride as a light yellow solid
88.5%	In acetic acid; at 55 - 100℃; for 28.5h;Product distribution / selectivity;	Example 60: Process for the preparation of PZP.HCI[000177] A 250 mL reactor equipped with a mechanical stirrer was charged with CPM I (4.84 g, 16.82 mmol), AMBS (3.29 g, 17.66 mmol, 1 .05 eq) and 90% acetic acid (29 mL, 6V) and the reaction mixture was heated to 55 C with stirring, leading to dissolution. After 3.5 h precipitation commenced and the reaction was continue for 22 h in total. The resulting mixture was then heated to 65 C over 0.5 h and stirring was continued at the same temperature for an additional 5 h. The reaction mixture was then heated to 100 C over 1 h leading to complete dissolution. Stirring was continued at the same temperature for 0.5 h and then EtOH abs. (48 mL, 10V) was added drop-wise with concomitant cooling to 80 C over a period of 0.5 h. The mixture was then cooled to 0 C over a period of 4 h and stirring was continued at the same temperature for 16 h. The solids were filtered and the filter cake was washed with EtOH abs. (4x 14.5 mL, 4x3 V) at Patent ApplicationAtty Docket No. 14669.0172 WOU 1 room temperature and dried in a vacuum oven (35 mbar) at 60 C for 22 h to give pure PZP.HC1 (7.05 g, 88.5% yield, 99.4% assay, 99.9% purity, 7.32% CI, CPMI < 20 ppm) as a beige powder.
81%	With hydrogenchloride; In 1,4-dioxane; methanol; at 50 - 85℃; for 10h;Heating / reflux;Product distribution / selectivity;	To a 2 L jacketed reactor was charged with MeOH (1005 ml_), the product of Intermediate Example 4 (84 g, 0.292 mol, 1 equiv) and 5-amino-2- methylbenzenesulfonamide (60 g, 0.320 mol, 1.1 equiv). The solution was stirred and heated to 50 0C and 4M HCI in Dioxane (1.46 ml_, 2 mol%) was added. The solution was then stirred and heated to reflux with a jacket temperature of 85 0C for 10 hours. The resulting slurry was then cooled to 20-25 0C and filtered. The filtered solid was washed with acetonitrile (293 ml_ X 2) at room temperature. After drying at overnight, under vacuum at 60 0C afforded 116 g (81%) of 5-({4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride.
81%	With hydrogenchloride; In 1,4-dioxane; methanol; at 50 - 85℃; for 10h;Heating / reflux;Product distribution / selectivity;	To a 2 L jacketed reactor was charged with MeOH (1005 mL), Intermediate Example 4 (84 g, 0.292 mol, 1 equiv) and 5-amino-2-methylbenzenesulfonamide (60 g, 0.320 mol, 1.1 equiv). The solution was stirred and heated to 50 0C and 4M HCI in Dioxane (1.46 mL, 2 mol%) was added. The solution was then stirred and heated to reflux with a jacket temperature of 85 0C for 10 hours. The resulting slurry was then cooled to 20-25 0C and filtered. The filtered solid was washed with acetonitrile (293 mL X 2) at room temperature. After drying at overnight, under vacuum at 60 0C afforded 1 16 g (81 %) of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)- 2-methyl benzenesulfonamide monohydrochlohde.
73%		To a stirred suspension of the product of Intermediate Example 4 (1.0 g, 3.6 mmol) in 10 ml_ of CH3CN, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1.Oequiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (18 mul_, 0.076 mmol) was added in one portion. After 20 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 ml_ of CH3CN and dried in the air to yield 1.3 g(73%) of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2- methyl benzenesulfonamide monohydrochloride as an off-white solid.
73%		To a stirred suspension of the product of Intermediate Example 4 (1.0 g, 3.6 [MMOL)] in 10 mL of CH3CN, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1. [OEQUIV)] at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1,4-dioxane [(18] uL, 0.076 [MMOL)] was added in one portion. After 20 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of CH3CN and dried in the air to yield 1.3 g [(73%)] of 5- [( {4- [ (2, 3-DIMETHYL-2H-INDAZOL-6-YL) METHYLAMINO]-2-PYRIMIDINYL} AMINO)-2-METHYL] [BENZENESULFONAMIDE] [MONOHYDROCHLORIDE] as an off-white solid.
73%	With hydrogenchloride; In 1,4-dioxane; acetonitrile; at 20℃; for 23h;Heating / reflux;Product distribution / selectivity;	To a stirred suspension of the product of Intermediate Example 4 (1 .0 g, 3.6 mmol) in 10 mL of CH3CN, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1 .Oequiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (18 muL, 0.076 mmol) was added in one portion. After 20 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of CH3CINI and dried in the air to yield 1.3 g (73%) of 5-({4- [(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride as an off-white solid.
73%		To a stirred suspension of the product of Intermediate Example 4 (1.0 g, 3.6 mmol) in 10 mL of CH3CN, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1.0 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCl in 1,4-dioxane (18 muL, 0.076 mmol) was added in one portion. After 20 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of CH3CN and dried in the air to yield 1.3 g (73%) of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride as an off-white solid.
73%		Procedure 5 To a stirred suspension of the product of Intermediate Example 4 (1.0 g, 3.6 mmol) in 10 mL of CH3CN, was added 5-amino-2- methylbenzenesulfonamide (0.70 g, 3.8 mmol, I.Oequiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1,4-dioxane (18 (at)L, 0.076 mmol) was added in one portion. After 20 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of CH3CN and dried in the air to yield 1.3 g (73%) of 5-((at)4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2- methyl benzenesulfonamide monohydrochloride as an off-white solid.
73%		To a stirred suspension of Intermediate Example 4 (1.0 g, 3.6 mmol) in 10 mL of CH3CN, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, <n="37"/>1.Oequiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (18 mul_, 0.076 mmol) was added in one portion. After 20 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of CH3CN and dried in the air to yield 1.3 g (73%) of 5-({4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochlohde as an off-white solid.
72%		To a stirred suspension of the product of Intermediate Example 4 (1.1 g, 3.8 mmol) in 14 mL of MeOH, was added 5-amino-2-methylbenzenesulfonamide (0.78 g, 4.2 mmol, 1.1 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (19 mul_, 0.076 mmol) was added in one portion. After 4 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of MeOH and dried in vacuo to yield 1.3 g (72%) of 5- ({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride as a white solid. 1 H NMR (DMSO-d6, 400 MHz) delta 10.95 (s, 1 H), 8.36 (s, 1 H), 7.86 (d, J= 8.8 Hz, 2H), 7.64-7.59 (m, 2H), 7.40 (m, 3H), 6.93 (dd, J = 8.8, 2.0 Hz, 1 H), 5.92 (s, 1 H), 4.08 (s, 3H), 3.57 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H).
72%		To a stirred suspension of the product of Intermediate Example 4 (1.1 g, 3.8 [MMOL)] in 14 mL of MeOH, was added [5-AMINO-2-METHYLBENZENESULFONAMIDE] (0.78 g, 4.2 mmol, 1.1 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1,4-dioxane (19 L, 0.076 [MMOL)] was added in one portion. After 4 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of MeOH and dried in vacuo to yield 1.3 g [(72%)] of 5- ({4-[(2,3-=dimethyl-2H-indazol-6-yl)metylamino]-2-pyrimidinyl}amino)-2-mnethyl [BENZENESULFONAMIDE] [MONOHYDROCHLORIDE] as a white [SOLID. 1H] NMR [(DMSO-D6,] 400 MHz) [5] 10.95 (s, 1H), 8.36 (s, [1 H),] 7.86 (d, J = 8.8 Hz, 2H), 7.64-7. 59 (m, 2H), 7.40 (m, [3H),] 6.93 [(DD,] [J =] 8. 8, 2.0 Hz, 1H), 5.92 (s, 1H), 4.08 (s, [3H),] 3.57 (s, [3H),] 2.65 (s, 3H), 2. [56 (S, 3H).]
72%	With hydrogenchloride; In 1,4-dioxane; methanol; at 20℃; for 7h;Heating / reflux;Product distribution / selectivity;	To a stirred suspension of the product of Intermediate Example 4 (1 .1 g, 3.8 mmol) in 14 mL of MeOH, was added 5-amino-2-methylbenzenesulfonamide (0.78 g, 4.2 mmol, 1.1 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (19 mul_, 0.076 mmol) was added in one portion. After 4 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of MeOH and dried in vacuo to yield 1 .3 g (72%) of 5-({4- [(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride as a white solid. 1 H NMR (DMSO-d6, 400 MHz) delta 10.95 (s, 1 H), 8.36 (s, 1 H), 7.86 (d, J = 8.8 Hz, 2H), 7.64-7.59 (m, 2H), 7.40 (m, 3H), 6.93 (dd, J = 8.8, 2.0 Hz, 1 H), 5.92 (s, 1 H), 4.08 (s, 3H), 3.57 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H).
72 - 81%		To a stirred suspension of the product of Intermediate Example 4 (1.1 g, 3.8 mmol) in 14 mL of MeOH, was added 5-amino-2-methylbenzenesulfonamide (0.78 g, 4.2 mmol, 1.1 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCl in 1,4-dioxane (19 muL, 0.076 mmol) was added in one portion. After 4 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of MeOH and dried in vacuo to yield 1.3 g (72%) of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride as a white solid. 1H NMR (DMSO-d6, 400 MHz) delta 10.95 (s, 1H), 8.36 (s, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.64-7.59 (m, 2H), 7.40 (m, 3H), 6.93 (dd, J=8.8, 2.0 Hz, 1H), 5.92 (s, 1H), 4.08 (s, 3H), 3.57 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H).; Procedure 6To a 2 L jacketed reactor was charged with MeOH (1005 mL), the product of Intermediate Example 4 (84 g, 0.292 mol, 1 equiv) and 5-amino-2-methylbenzenesulfonamide (60 g, 0.320 mol, 1.1 equiv). The solution was stirred and heated to 50 C. and 4M HCl in Dioxane (1.46 mL, 2 mol %) was added. The solution was then stirred and heated to reflux with a jacket temperature of 85 C. for 10 hours. The resulting slurry was then cooled to 20-25 C. and filtered. The filtered solid was washed with acetonitrile (293 mL×2) at room temperature. After drying at overnight, under vacuum at 60 C. afforded 116 g (81%) of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride.
72%		Procedure 3: To a stirred suspension of the product of Intermediate Example 4 (1.1 g, 3.8 mmol) in 14 mL of MeOH, was added 5-amino-2- methylbenzenesulfonamide (0.78 g, 4.2 mmol, 1.1 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1,4-dioxane (19 muL, 0.076 mmol) was added in one portion. After 4 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of MeOH and dried in vacuo to yield 1.3 g (72%) of 5- ((at)4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride as a white solid.
72%		To a stirred suspension of Intermediate Example 4 (1.1 g, 3.8 mmol) in 14 ml. of MeOH, was added 5-amino-2-methylbenzenesulfonamide (0.78 g, 4.2 mmol, 1.1 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (19 mul_, 0.076 mmol) was added in one portion. After 4 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 ml. of MeOH and dried in vacuo to yield 1.3 g (72%) of 5-({4-[(2,3-dimethyl-2H-indazol- 6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride as a white solid. 1 H NMR (DMSO-d6, 400 MHz) delta 10.95 (s, 1 H), 8.36 (s, 1 H), 7.86 (d, J = 8.8 Hz, 2H), 7.64-7.59 (m, 2H), 7.40 (m, 3H), 6.93 (dd, J = 8.8, 2.0 Hz, 1 H), 5.92 (s, 1 H), 4.08 (s, 3H), 3.57 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H).
45.2%	With hydrogenchloride; In isopropyl alcohol; for 2h;Reflux;	A mixture of ISO-IM2 (0.7g, 2.4 mmol) and SM3 (0.44 g, 2.4 mmol), conc HCl 0.5ml in isopropanol (50 mL) was stirred at reflux for 2 h. The mixture was cooled to room temperature and the resultant precipitate was collected by filtration and washed with isopropanol. The solid was dried to give impurity I (0.52 g, 45.2 %) as a off-white solid. 1H NMR (300 MHz, DMSO-d6) (delta, ppm): 11.84 (s, 1H), 7.84 (d, J= 7.2 Hz, 1H), 7.73 - 7.75 (m, 2H), 7.67 (s, 1H), 7.40 - 7.42 (m, 2H), 6.98 (d, J = 8.7Hz, 1H), 6.71 (d, J = 6.8 Hz, 1H), 4.10 (s, 3H), 3.58 (s, 3H), 2.67 (s, 3H), 2.53 (s, 3H). 13C NMR (600 MHz, DMSO-d6) (delta, ppm): 160.8, 153.7, 147.2, 143.1, 142.6, 136.4, 133.0, 131.9, 124.2, 123.3, 120.8, 119.9, 119.1, 115.7, 99.6, 38.0, 19.7, 9.88; HRMSm/z calcd for C21H24N7O2S [M+H]+ 438.1707, found 438.1705.
	With hydrogenchloride; In water; isopropyl alcohol;Heating / reflux;Product distribution / selectivity;	To a solution of Intermediate Example 4 (200 mg, 0.695 mmol) and 5-amino-2- methylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol (6 ml) was added 4 drops of cone. HCI. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 ml). Precipitate was collected via filtration and washed with ether. The hydrochloride salt of 5-({4-[(2,3-dimethyl-2H-indazol~6- yl)(methyl)amino]-pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide was isolated as an off-white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1 H), 8.55 (br s, 1 H), 7.81 (d, J= 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz1 1 H), 7.69 (m, 1 H), 7.43 (s, 1 H), 7.23 (S1 2H), 7.15 (d, J= 8.4 Hz1 1H), 6.86 (m, 1 H), 5.74 (d, J= 6.1 Hz, 1 H), 4.04 (s, 3H), 3.48 (S1 3H)1 2.61 (s, 3H)1 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).
	With hydrogenchloride; In water; isopropyl alcohol;Heating / reflux;	To a solution of Intermediate Example 4 (200 mg, 0.695 [MMOL)] and 5-amino- 2-methylbenzenesulfonamide (129.4 mg, 0.695 [MMOL)] in isopropanol (6 ml) was added 4 drops of conc. HCI. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 [ML).] Precipitate was collected via filtration and washed with ether. The hydrochloride salt of [5- ( {4- [ (2, 3-DIMETHYL-2H-INDAZOL-6-] yl) (methyl) [AMINO]-PYRIMIDIN-2-YL} AMINO)-2-METHYIBENZENESULFONAMIDE] was isolated as an off-white [SOLID.'H NMR (400 MHZ, D6DMSO+NAHC03)] 8 9.50 (br s, 1 H), 8.55 (br s, 1H), 7.81 (d, [J= 6.] 2 Hz, [1 H),] 7.75 (d, J = 8.7 Hz, 1H), 7.69 (m, 1H), 7.43 (s, [1 H),] 7.23 (s, 2H), 7.15 (d, [J= 8.] 4 Hz, [1 H),] 6.86 (m, 1H), 5.74 (d, J = 6.1 Hz, [1 H),] 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS [(ES+,] [M/Z)] 438 (M+H).
	With hydrogenchloride; In water; isopropyl alcohol;Heating / reflux;Product distribution / selectivity;	To a solution of Intermediate Example 4 (200 mg, 0.695 mmol) and 5-amino-2- methylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol (6 ml) was added 4 drops of cone. HCI. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 ml). Precipitate was collected via filtration and washed with ether. The hydrochloride salt of 5-({4-[(2,3-dimethyl-2H-indazol-6- yl)(methyl)amino]-pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide was isolated as an off-white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1 H), 8.55 (br s, 1 H), 7.81 (d, J = 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1 H), 7.69 (m, 1 H), 7.43 (s, 1 H), 7.23 (s, 2H), 7.15 (d, J = 8.4 Hz, 1 H), 6.86 (m, 1 H), 5.74 (d, J = 6.1 Hz, 1 H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).
		Intermediate 3; Synthesis of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-2- pyrimidinyl}amino)-2-methylbenzenesulfonamide Hydrochloride (Intermediate 3); Intermediate 3; <strong>[444731-75-3]N-(2-chloro-4-pyrimidinyl)-N,2,3-trimethyl-2H-indazol-6-amine</strong> (Intermediate 2) (1.66 kg, 5.8 mol, 1.0 equiv) and 5-amino-2-methyl benzenesulfonamide (Starting Material 3 (SM3)) (commercially available from Asymchem Laboratories (Fuxin) Co., Ltd, PR China and from Sumitomo Seika Chemicals Co. Ltd, Japan) (1.19 kg, 6.4 mol, 1.1 equiv) is suspended in 19.9 L of methanol. The mixture is heated to reflux and stirred until complete dissolution is observed. At this stage, the mixture is charged with 4M HCl in 1, 4-dioxane (30.0 mL, 0.116 mol, 0.02 equiv) between 60-65 C. The mixture is stirred at reflux for 12 hours. The reaction is deemed complete when the amount IM2 is less than or equal to 0.05% w/w by HPLC. The mixture is cooled to 20-25 C and stirred for 1 hour. The product is isolated by filtration and the filter cake is washed with acetonitrile (2 X 5.8 L). The wet cake is dried under vacuum at 50-60 C to afford Intermediate 3.
	With hydrogenchloride; In water; isopropyl alcohol;Reflux; Inert atmosphere;	Example 69 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide To a solution of Intermediate Example 13 (200 mg, 0.695 mmol) and 5-amino-2-methylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol (6 ml) was added 4 drops of conc. HCl. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 ml). Precipitate was collected via filtration and washed with ether. HCl salt of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide was isolated as an off-white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1H), 8.55 (br s, 1H), 7.81 (d, J = 6.2 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.69 (m, 1H), 7.43 (s, 1H), 7.23 (s, 2H), 7.15 (d, J = 8.4 Hz, 1H), 6.86 (m, 1H), 5.74 (d, J = 6.1 Hz, 1H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).
	With hydrogenchloride; In isopropyl alcohol;Heating / reflux;Product distribution / selectivity;	To a solution of Intermediate Example 4 (200 mg, 0.695 mmol) and 5-amino-2-methylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol (6 ml) was added 4 drops of conc. HCl. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 ml). Precipitate was collected via filtration and washed with ether. The hydrochloride salt of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide was isolated as an off-white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1H), 8.55 (br s, 1H), 7.81 (d, J=6.2 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.69 (m, 1H), 7.43 (s, 1H), 7.23 (s, 2H), 7.15 (d, J=8.4 Hz, 1H), 6.86 (m, 1H), 5.74 (d, J=6.1 Hz, 1H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).
	With hydrogenchloride; In water; isopropyl alcohol;Heating / reflux;Product distribution / selectivity;	Example 1 5-((at)4-[(2, 3-dimeth yl-2H-indazol-6-yl) (meth yl) amino]p yrimidin-2-yl}a min o)-2- methylbenzenesulfonamide Procedure 1 To a solution of Intermediate Example 4 (200 mg, 0.695 mmol) and 5- amino-2-methylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol (6 ml) was added 4 drops of conc. HCI. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 ml). Precipitate was collected via filtration and washed with ether. The hydrochloride salt of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]- pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide was isolated as an off- white solid.
	With hydrogenchloride; In water; isopropyl alcohol;Heating / reflux;Product distribution / selectivity;	To a solution of Intermediate Example 4 (200 mg, 0.695 mmol) and 5-amino-2- methylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol (6 ml) was added 4 drops of cone. HCI. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 ml). Precipitate was collected via filtration and washed with ether. The hydrochloride salt of 5-({4-[(2,3-dimethyl-2/-/-indazol-6- yl)(methyl)amino]-pyhmidin-2-yl}amino)-2-methylbenzenesulfonamide was isolated as an off-white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1 H), 8.55 (br s, 1 H), 7.81 (d, J = 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1 H), 7.69 (m, 1 H), 7.43 (s, 1 H), 7.23 (s, 2H), 7.15 (d, J = 8.4 Hz, 1 H), 6.86 (m, 1 H), 5.74 (d, J = 6.1 Hz, 1 H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).

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4
[ 444731-74-2 ]
[ 616-38-6 ]
[ 444731-75-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium carbonate; In N,N-dimethyl-formamide; at 135℃; for 6h;Heating / reflux;Product distribution / selectivity;	To a 2 L jacketed reactor was charged with DMF (383 mL), dimethyl carbonate (192 mL), the product of Intermediate Example 3 (115 g, 0.420 mol, 1 equiv) and Potassium Carbonate (174 g, 1.26 mol, 3 equiv). The suspension was stirred and heated to reflux with a jacket temperature of 135C for 6 hours. The resulting slurry was then cooled to 60C, and water (1150 mL) was added slowly maintaining the reaction temperature between 50 and 65 C. The reaction was then cooled down to 20C and stirred at an internal temperature of 200C for two hours, and then cooled to 100C and held overnight after which it was filtered. The solid was washed with water (230 mL X 2) at room temperature, and rinsed with the mixture IMS:Water (1 :1) (230 mL X 1). After drying at overnight, under vacuum at 600C afforded 101 g (83%) of N- (2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine.
83%	With potassium carbonate; In N,N-dimethyl-formamide; at 135℃; for 6h;Heating / reflux;Product distribution / selectivity;	Procedure 3 To a 2 L jacketed reactor was charged with DMF (383 mL), dimethyl carbonate (192 mL), the product of Intermediate Example 3 (115 g, 0.420 mol, 1 equiv) and Potassium Carbonate (174 g, 1.26 mol, 3 equiv). The suspension was stirred and heated to reflux with a jacket temperature of 135 C. for 6 hours. The resulting slurry was then cooled to 60 C., and water (1150 mL) was added slowly maintaining the reaction temperature between 50 and 65 C. The reaction was then cooled down to 20 C. and stirred at an internal temperature of 20 C. for two hours, and then cooled to 10 C. and held overnight after which it was filtered. The solid was washed with water (230 mL2) at room temperature, and rinsed with the mixture IMS:Water (1:1) (230 mL1). After drying at overnight, under vacuum at 60 C. afforded 101 g (83%) of N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine.
83%	With potassium carbonate; In N,N-dimethyl-formamide; at 135℃; for 6h;Heating / reflux;Product distribution / selectivity;	To a 2 L jacketed reactor was charged with DMF (383 ml_), dimethyl carbonate (192 ml_), the product of Intermediate Example 3 (1 15 g, 0.420 mol, 1 equiv) and Potassium Carbonate (174 g, 1.26 mol, 3 equiv). The suspension was stirred and heated to reflux with a jacket temperature of 135C for 6 hours. The resulting slurry was then cooled to 600C, and water (1 150 mL) was added slowly maintaining the reaction temperature between 50 and 65 0C. The reaction was then cooled down to 200C and stirred at an internal temperature of 200C for two hours, and then cooled to 100C and held overnight after which it was filtered. The solid was washed with water (230 mL X 2) at room temperature, and rinsed with the mixture IMS:Water (1 :1 ) (230 mL X 1 ). After drying at overnight, under vacuum at 600C afforded 101 g (83%) of N-(2-chloropyrimidin-4-yl)- N,2,3-thmethyl-2H-indazol-6-amine.

With potassium carbonate; In N,N-dimethyl-formamide;Reflux; Inert atmosphere; Industry scale;Product distribution / selectivity;

Intermediate 2; Synthesis of N-(2-chloro-4-pyrimidinyl)-N,2,3-trimethyl-2H-indazol-6-amine (Intermediate 2) and pseudodimer (Impurity 2); Intermediate 2; Procedure 2a; N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine (IMl) (1.31 kg, 4.78 mol, 1 equiv) and potassium carbonate having a D99 as described below of > 300 muiotaeta (1.96 kg, 14.3 mol, 3 equiv) (commercially available from Armand ProductsCompany, Princeton, New Jersey) is suspended in a solution of dimethylformamide (4.3 L) and dimethyl carbonate (2.2 L) under a nitrogen atmosphere. The reaction mixture is heated to reflux (> 110 C) and stirred for 10-12 hours. The reaction mixture is cooled to 55-70 C and waster is charged (2.6 L) slowly to the mixture. The biphasic mixture is stirred for lh and then layers are settled for extraction. The bottom aqueous layer is removed to waste. Water is charged (13.1 L) over ~1 hr to the organic layer maintaining the reaction temperature between 55-70 C. After addition the mixture is slowly cooled to 5-10 C and the suspension is stirred for 2 hours at 5-10 C. The product is isolated by filtration and then the filter cake is washed with water (2 X 5.9 L), followed by cold 1: 1 industrial methylated spirits: water (1 X 2.6 L). The wet cake is dried under vacuum at 55-60 C to afford a product that is > 98 % Intermediate 2 (IM2), and < 2% combined impurities 2-4 as determined by HPLC and/or LC/MS.

References: [1]Patent: WO2007/64753,2007,A2 .Location in patent: Page/Page column 30.
[2]Patent: US2008/293691,2008,A1 .Location in patent: Page/Page column 10.
[3]Patent: WO2007/143483,2007,A2 .Location in patent: Page/Page column 33.
[4]Patent: WO2011/50159,2011,A1 .Location in patent: Page/Page column 22.
[5]Organic Process Research and Development,2019,vol. 23,p. 2057 - 2068.

5
[ 444731-66-2 ]
[ 74-88-4 ]
[ 444731-75-3 ]
[ 1042366-93-7 ]

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 4632 - 4640.

6
[ 444731-75-3 ]
[ 98-18-0 ]
3-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide dihydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 4632 - 4640.

7
[ 72299-68-4 ]
[ 444731-75-3 ]
[ 72299-67-3 ]
N₄-(2,3-dimethyl-2H-indazol-6-yl)-N₄-methyl-N₂-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine hydrochloride [ No CAS ]
N₄-(2,3-dimethyl-2H-indazol-6-yl)-N₄-methyl-N₂-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidine-2,4-diamine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In water; isopropyl alcohol;Heating / reflux;	To a solution of <strong>[444731-75-3]N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine</strong> (0.58g, 2 mmol, 1 equiv) and a mixture of l,2,3,4-tetrahydroisoquinolin-7-amine and 1,2,3,4- tetrahydroisoquinolin-6-amine (0.3g; 2 mmol, 1 equiv) in isopropanol (17ml) was added 12 drops of concentrated HCl. The reaction mixture was re fluxed overnight, then cooled down to room temperature and diluted with diethyl ether (18ml). The precipitate was filtered and washed with diethyl ether. The resulting solid was purified by column chromatography using DCM/MeOH:95/5 as eluent to give a white solid. After tritutation with petrol then DCM, the title mixture of isomers was filtered as an hydrochloride salt (0.06Og, 7.5% yield). 1H NMR (d6-DMSO, 400 MHz) delta= 9.04 (m, I H), 7.79 (m, IH), 7.69 (d, IH, J = 9 Hz, IH), 7.51 (m, IH), 7.36 (m, 2H), 6.90 (d, J = 10.0 Hz, IH), 6.82 (d, J = 9.0 Hz, IH), 5.91 (m, I H), 4.0 (s, 3H), 3.66 (s, IH), 3.4 (s, 3H), 3.11 (m. 2H), 3.0 (m, 2H), 2.66 (m, 2H), 2.57 (m, 3H).

References: [1]Patent: WO2009/62658,2009,A1 .Location in patent: Page/Page column 37; 2/10.

8
[ 444731-75-3 ]
[ 609-55-2 ]
pazopanib hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With hydrogenchloride; In water; isopropyl alcohol;Heating / reflux;	To a solution of <strong>[444731-75-3]N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine</strong> (55mg; 0.2 mmol, 1 equiv) and 5-amino-2-methylbenzenesulfonimide (37 mg; 0.2mmol, 1 equiv) in isopropanol (2ml) was added 1 drop of concentrated HCl. The reaction mixture was refluxed overnight. The reaction mixture was cooled down to room temperature and diluted with diethyl ether (2ml). The precipitate was filtered and washed with diethyl ether. The solid was then boiled in ethanol and filtered to yield the desired product as a white solid hydrochloride salt (0.07Og, 77%).1H NMR (400MHz, d6-DMSO; 11.5 (br s, IH), 8.42 (br s, IH), 7.95 (d, J = 8.0 Hz, IH), 7.85 (br s, IH), 7.62 (s, IH), 7.45 (s, 2H), 6.95 (d, J = 8.0Hz, IH), 5.87 (br s, IH, 4.03 (s, 3H), 3.75 (s, 3H), 2.65 (s, 3H), 2.57 (s, 3H).

References: [1]Patent: WO2009/62658,2009,A1 .Location in patent: Page/Page column 36; 1/10.

9
[ 444731-75-3 ]
pazopanib [ No CAS ]

References: [1]Patent: WO2011/69053,2011,A1 .
[2]Letters in Organic Chemistry,2012,vol. 9,p. 276 - 279.
[3]Patent: EP2311825,2015,B1 .

10
[ 444731-75-3 ]
pazopanib dihydrochloride [ No CAS ]

References: [1]Patent: WO2011/69053,2011,A1 .
[2]Patent: WO2011/69053,2011,A1 .

11
[ 3934-20-1 ]
[ 1376676-65-1 ]
[ 444731-75-3 ]

Yield	Reaction Conditions	Operation in experiment
81.6%	With sodium hydrogencarbonate; In tetrahydrofuran; ethanol; for 20h;Reflux;	Formula III (5 g, 0.029 mol)And sodium bicarbonate (7.2 g, 0.086 mol)Was added to THF (20 ml)And absolute ethanol (80 ml).2,4-dichloropyrimidine (12.8 g, 0.086 mol) was added at room temperature,Heated to reflux for 20 h.The reaction was cooled to room temperature,filter,The filter cake was washed with absolute ethanol (20 ml x 2).The filtrates were combined,After concentration under reduced pressure to dryness, isopropyl ether (60 ml)And toluene (30 ml) were mixed,Stirred at room temperature for 1 h,filter,The filter cake was dried to give pale yellow solid 7 (6.7 g, 81.6%),

References: [1]Letters in Organic Chemistry,2012,vol. 9,p. 276 - 279.
[2]Patent: CN103373989,2016,B .Location in patent: Paragraph 0063; 0064.

12
[ 6494-19-5 ]
[ 444731-75-3 ]

References: [1]Letters in Organic Chemistry,2012,vol. 9,p. 276 - 279.
[2]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1108 - 1110.
[3]Patent: US2015/329526,2015,A1 .
[4]Patent: US2008/293691,2008,A1 .
[5]Patent: US2008/293691,2008,A1 .
[6]Patent: WO2005/105094,2005,A2 .
[7]Patent: WO2005/105094,2005,A2 .
[8]Patent: WO2005/105094,2005,A2 .
[9]Patent: WO2007/143483,2007,A2 .
[10]Patent: WO2007/143483,2007,A2 .
[11]Patent: WO2007/143483,2007,A2 .
[12]Patent: WO2007/143483,2007,A2 .
[13]Patent: WO2007/143483,2007,A2 .
[14]Patent: WO2007/143483,2007,A2 .

13
[ 444731-73-1 ]
[ 444731-75-3 ]

14
[ 444731-72-0 ]
[ 444731-75-3 ]

References: [1]Letters in Organic Chemistry,2012,vol. 9,p. 276 - 279.
[2]Patent: WO2011/50159,2011,A1 .
[3]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1108 - 1110.
[4]Chemical Biology and Drug Design,2014,vol. 83,p. 306 - 316.
[5]Patent: US2015/329526,2015,A1 .
[6]Patent: CN103373989,2016,B .
[7]Patent: CN107619407,2018,A .
[8]Journal of Medicinal Chemistry,2018,vol. 61,p. 5304 - 5322.
[9]Pharmazie,2018,vol. 73,p. 494 - 497.
[10]Patent: US2008/293691,2008,A1 .
[11]Patent: US2008/293691,2008,A1 .
[12]Patent: WO2005/105094,2005,A2 .
[13]Patent: WO2007/143483,2007,A2 .
[14]Patent: WO2007/143483,2007,A2 .

15
C₁₀H₁₁N₃ [ No CAS ]
[ 444731-75-3 ]

References: [1]Letters in Organic Chemistry,2012,vol. 9,p. 276 - 279.

16
[ 20191-74-6 ]
[ 444731-75-3 ]

References: [1]Letters in Organic Chemistry,2012,vol. 9,p. 276 - 279.
[2]Patent: CN103373989,2016,B .

17
[ 444731-75-3 ]
[ 108-44-1 ]
[ 1307297-53-5 ]

Yield	Reaction Conditions	Operation in experiment
69%	With hydrogenchloride; In ethanol; water; for 3h;Reflux;	General procedure: To a solution of intermediate 5a (5.00 g, 17 mmol) and 3-fluorobenzenamine (6a, 1.89 g, 17 mmol) in ethanol (80 mL) was added concentrated HCl (2.0 mL). The mixture was heated to reflux for 3 h. After cooling to rt, the reaction mixture was filtered to give 7a as an off-white solid (4.86 g, 79.1%).

References: [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1108 - 1110.

18
[ 444731-75-3 ]
[ 108-69-0 ]
[ 1307297-66-0 ]

Yield	Reaction Conditions	Operation in experiment
75.9%	With hydrogenchloride; In ethanol; water; for 3h;Reflux;	General procedure: To a solution of intermediate 5a (5.00 g, 17 mmol) and 3-fluorobenzenamine (6a, 1.89 g, 17 mmol) in ethanol (80 mL) was added concentrated HCl (2.0 mL). The mixture was heated to reflux for 3 h. After cooling to rt, the reaction mixture was filtered to give 7a as an off-white solid (4.86 g, 79.1%).

References: [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1108 - 1110.

19
[ 444731-75-3 ]
[ 104-96-1 ]
[ 1307297-69-3 ]

Yield	Reaction Conditions	Operation in experiment
89.8%	With hydrogenchloride; In ethanol; water; for 3h;Reflux;	General procedure: To a solution of intermediate 5a (5.00 g, 17 mmol) and 3-fluorobenzenamine (6a, 1.89 g, 17 mmol) in ethanol (80 mL) was added concentrated HCl (2.0 mL). The mixture was heated to reflux for 3 h. After cooling to rt, the reaction mixture was filtered to give 7a as an off-white solid (4.86 g, 79.1%).

References: [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1108 - 1110.

20
[ 444731-75-3 ]
[ 461-82-5 ]
[ 1307297-68-2 ]

Yield	Reaction Conditions	Operation in experiment
90.6%	With hydrogenchloride; In ethanol; water; for 3h;Reflux;	General procedure: To a solution of intermediate 5a (5.00 g, 17 mmol) and 3-fluorobenzenamine (6a, 1.89 g, 17 mmol) in ethanol (80 mL) was added concentrated HCl (2.0 mL). The mixture was heated to reflux for 3 h. After cooling to rt, the reaction mixture was filtered to give 7a as an off-white solid (4.86 g, 79.1%).

References: [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1108 - 1110.

21
[ 372-19-0 ]
[ 444731-75-3 ]
[ 1307297-62-6 ]

Yield	Reaction Conditions	Operation in experiment
79.1%	With hydrogenchloride; In ethanol; water; for 3h;Reflux;	To a solution of intermediate 5a (5.00 g, 17 mmol) and 3-fluorobenzenamine (6a, 1.89 g, 17 mmol) in ethanol (80 mL) was added concentrated HCl (2.0 mL). The mixture was heated to reflux for 3 h. After cooling to rt, the reaction mixture was filtered to give 7a as an off-white solid (4.86 g, 79.1%). HPLC: 99.1%. Mp > 220 C. 1HNMR(400MHz, DMSO-d6) delta: 2.62 (s, 3H), 3.47 (s, 3H), 4.08 (s, 3H), 5.82 (d, J=6.0 Hz, 1H), 6.61-6.66 (m, 1H), 6.87 (q, J=8.8 Hz, 1H), 7.15-7.21 (m, 1H), 7.43-7.45 (m, 2H), 7.77-7.80 (m, 2H), 7.86 (d, J=6.0 Hz, 1H), 9.37 (s, 1H). EI-MS (m/z): 361.2 [M]+.

References: [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1108 - 1110.

22
[ 444731-75-3 ]
[ 591-19-5 ]
[ 1307297-61-5 ]

Yield	Reaction Conditions	Operation in experiment
82.0%	With hydrogenchloride; In ethanol; water; for 3h;Reflux;	General procedure: To a solution of intermediate 5a (5.00 g, 17 mmol) and 3-fluorobenzenamine (6a, 1.89 g, 17 mmol) in ethanol (80 mL) was added concentrated HCl (2.0 mL). The mixture was heated to reflux for 3 h. After cooling to rt, the reaction mixture was filtered to give 7a as an off-white solid (4.86 g, 79.1%).

References: [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1108 - 1110.

23
[ 444731-75-3 ]
[ 108-42-9 ]
[ 1307297-65-9 ]

Yield	Reaction Conditions	Operation in experiment
78.5%	With hydrogenchloride; In ethanol; water; for 3h;Reflux;	General procedure: To a solution of intermediate 5a (5.00 g, 17 mmol) and 3-fluorobenzenamine (6a, 1.89 g, 17 mmol) in ethanol (80 mL) was added concentrated HCl (2.0 mL). The mixture was heated to reflux for 3 h. After cooling to rt, the reaction mixture was filtered to give 7a as an off-white solid (4.86 g, 79.1%).

References: [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1108 - 1110.

24
[ 444731-75-3 ]
[ 536-90-3 ]
[ 1307297-63-7 ]

Yield	Reaction Conditions	Operation in experiment
72.3%	With hydrogenchloride; In ethanol; water; for 3h;Reflux;	General procedure: To a solution of intermediate 5a (5.00 g, 17 mmol) and 3-fluorobenzenamine (6a, 1.89 g, 17 mmol) in ethanol (80 mL) was added concentrated HCl (2.0 mL). The mixture was heated to reflux for 3 h. After cooling to rt, the reaction mixture was filtered to give 7a as an off-white solid (4.86 g, 79.1%).

References: [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1108 - 1110.

25
[ 444731-75-3 ]
[ 6973-09-7 ]
pazopanib [ No CAS ]