1083326-75-3|N-(2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide| Ambeed

Structure of 1083326-75-3

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Quality Control of [ 1083326-75-3 ] Purity: 95% SDS Specification

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Product Details of [ 1083326-75-3 ]

CAS No. :	1083326-75-3
Formula :	C₁₃H₂₁BN₂O₅S
M.W :	328.19
SMILES Code :	CS(=O)(NC1=CC(B2OC(C)(C)C(C)(C)O2)=CN=C1OC)=O
MDL No. :	MFCD12964555
InChI Key :	NLKPUGUGRJNIMU-UHFFFAOYSA-N
Pubchem ID :	59564698

Safety of [ 1083326-75-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 1083326-75-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	22
Num. arom. heavy atoms	6
Fraction Csp3	0.62
Num. rotatable bonds	4
Num. H-bond acceptors	6.0
Num. H-bond donors	1.0
Molar Refractivity	85.47
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	95.13 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
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	1.11
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.65
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.	-0.58
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	-0.08
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.42

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.51
Solubility	1.01 mg/ml ; 0.00308 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.	-2.7
Solubility	0.654 mg/ml ; 0.00199 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	-4.09
Solubility	0.0266 mg/ml ; 0.0000811 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	No
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	Yes
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	No
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.	-7.51 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<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)	3.39

Application In Synthesis of [ 1083326-75-3 ]

* 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 [ 1083326-75-3 ]

[ 1083326-75-3 ] Synthesis Path-Downstream 1~35

1
[ 893440-50-1 ]
[ 124-63-0 ]
[ 1083326-75-3 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 20℃; for 18h;	To a solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinamine (0.5 g, 1.999 mmol) in pyridine (5 ml) was added methanesulphonyl chloride (0.309 ml, 4.00 mmol) and the mixture stirred at 20 0C for 18 hr when the solvent was removed in vacuo. The residue was partitioned between saturated sodium bicarbonate solution (10ml) and dichloromethane (20ml), separated by hydrophobic frit and purified by silica (7Og) cartridge on Flashmaster Il using a gradient of dichloromethane and methanol to give the title compound as a brown solid (0.46g). LCMS (Method A) Rt 0.98mins, MH+ 329.
	With pyridine; at 20℃; for 18h;	To a solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinamine (0.5 g) in pyridine (5 ml) was added methanesulphonyl chloride (0.309 ml) and the mixture stirred at RT for 18 h when the solvent was removed in vacuo. The residue was partitioned between saturated sodium bicarbonate solution (10 ml) and DCM (20 ml), separated by hydrophobic frit and purified by silica (70g) cartridge on Flashmaster II using a gradient of DCM and methanol to give the title compound as a brown solid, 0.46 9-LCMS (method B); Rt = 0.98 min, MH+ = 329.
	With pyridine; at 20℃; for 18h;	Intermediate 8N-[2-(Methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- ridinyl]methanesulfonamideTo a solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinamine (0.5 g, 1.999 mmol) in pyridine (5 ml) was added methanesulphonyl chloride (0.309 ml, 4.00 mmol) and the mixture stirred at 20 C for 18 hr then the solvent was removed in vacuo. The residue was partitioned between saturated sodium bicarbonate solution (10 ml) and dichloromethane (20 ml), separated by hydrophobic frit and purified by silica gel chromatography, eluting with a gradient of dichloromethane and methanol to give the title compound as a brown solid (0.46g).LCMS (Method A): Rt 0.98mins, MH+ 329.

	With pyridine; at 0℃;Inert atmosphere;	2-Methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-amine (940 mg, 3.76 mol) was dissolved in 20 mL pyridine. The mixture was submitted to three vacuum-argon cycles and was cooled at 0C with an ice bath. Methanesulfonyl chloride (600 muIota, 7.75 mol) was added dropwise and the reaction mixture was stirred overnight. The solvent was concentrated and the residue was partitioned between dichloromethane and a saturated sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated under reduced pressure. The semi-solid was crystallized with diethyl ether and isopropyl ether to obtain a solid that was filtered and dried in the oven to give 720 mg (58% yield) of the final compound as a mixture of boronic acid and boronate. Purity 100%.LRMS (m/z): 329 (M+1 )+.
0.46 g	With pyridine; at 20℃; for 18h;	N-[2-(Methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide To a solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine (0.5 g, 1.999 mmol) in pyridine (5 ml) was added methanesulphonyl chloride (0.309 ml, 4.00 mmol) and the mixture stirred at 20 C. for 18 hr when the solvent was removed in vacuo. The residue was partitioned between saturated sodium bicarbonate solution (10 ml) and dichloromethane (20 ml), separated by hydrophobic frit and purified by silica (70 g) cartridge on Flashmaster II using a gradient of dichloromethane and methanol to give the title compound as a brown solid (0.46 g). LCMS (Method A) Rt 0.98 mins, MH+ 329.
	With pyridine; at 20℃; for 18h;	Intermediate 30N-[2-(Methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- pyridinyljmethanesulfonamide To a solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinamine (0.5 g, 1.999 mmol) in pyridine (5 ml) was added methanesulphonyl chloride (0.309 ml, 4.00 mmol) and the mixture stirred at 20 0C for 18 hr when the solvent was removed in vacuo. The residue was partitioned between saturated sodium bicarbonate solution (10 ml) and DCM (20 ml), separated by hydrophobic frit and purified by silica (7Og) cartridge on Flashmaster Il using a gradient of DCM and methanol to give the title compound as a brown solid (0.46 g). LCMS (Method B) Rt 0.98mins, MH+ 329.
	With pyridine; at 20℃; for 18h;	Intermediate 8N-[2-(Methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- pyridinyljmethanesulfonamideTo a solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinamine (0.5 g, 1.999 mmol) in pyridine (5 ml) was added methanesulphonyl chloride (0.309 ml, 4.00 mmol) and the mixture stirred at 20 0C for 18 hr then the solvent was removed in vacuo. The residue was partitioned between saturated sodium bicarbonate solution (10 ml) and dichloromethane (20 ml), separated by hydrophobic frit and purified by silica gel chromatography, eluting with a gradient of dichloromethane and methanol to give the title compound as a brown solid (0.46g). LCMS (Method A): Rt 0.98mins, MH+ 329.

References: [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 7381 - 7399.
[2]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 98; 99.
[3]Patent: WO2011/67365,2011,A1 .Location in patent: Page/Page column 69.
[4]Patent: WO2012/32067,2012,A1 .Location in patent: Page/Page column 55.
[5]Patent: WO2014/60432,2014,A1 .Location in patent: Page/Page column 130.
[6]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 95; 133.
[7]Patent: WO2009/147187,2009,A1 .Location in patent: Page/Page column 114.
[8]Patent: WO2010/125082,2010,A1 .Location in patent: Page/Page column 75.

2
[ 1083326-75-3 ]
[ 1245465-34-2 ]
[ 1245466-41-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 0.333333h;Microwaves;	To a solution of 9-({5-[6-bromo-1-(phenylsulfonyl)-1 H-indazol-4-yl]-1 ,3,4-oxadiazol-2- yl}methyl)-6-oxa-9-azaspiro[4.5]decane (74 mg, 0.133 mmol) in 1 ,4 dioxane (2.5 ml) and water (1 ml) was added N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]methanesulfonamide (47.8 mg, 0.146 mmol), 1 ,1'- bis(diphenylphosphino)ferrocene palladium dichloride (19.39 mg, 0.027 mmol) and potassium phosphate tribasic (84 mg, 0.398 mmol). The mixture was heated under microwave irradiation at 100 0C for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The protected compound was dissolved in 1 ,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 4 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen and the crude residue was dissolved in DMSO (1 ml) and purified by Mass Directed Automated Preparative HPLC. The appropriate fraction was blown down under a stream of nitrogen to give the title compound as a white solid (71.5 mg). LCMS (Method A): Rt 0.82 mins, MH+ 540.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 100℃; for 0.333333h;Microwave irradiation;	Example 42 N-(2-(Methyloxy)-5-{4-[5-(6-oxa-9-azaspiro[4.5]dec-9-ylmethyl)-1,3,4-oxadiazol-2-yl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide To a solution of 9-({5-[6-bromo-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3,4-oxadiazol-2-yl}methyl)-6-oxa-9-azaspiro[4.5]decane (74 mg, 0.133 mmol) in 1,4 dioxane (2.5 ml) and water (1 ml) was added <strong>[1083326-75-3]N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide</strong> (47.8 mg, 0.146 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (19.39 mg, 0.027 mmol) and potassium phosphate tribasic (84 mg, 0.398 mmol). The mixture was heated under microwave irradiation at 100 C. for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The protected compound was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 4 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen and the crude residue was dissolved in DMSO (1 ml) and purified by Mass Directed Automated Preparative HPLC. The appropriate fraction was blown down under a stream of nitrogen to give the title compound as a white solid (71.5 mg).LCMS (Method A): Rt 0.82 mins, MH+ 540.

References: [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 148; 149.
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 192; 193.

3
[ 1083326-75-3 ]
[ 1245465-37-5 ]
[ 1245466-45-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 1.33333h;Microwaves;	6-Bromo-4-{5-[(2-methyl-4-morpholinyl)methyl]-1 ,3,4-oxadiazol-2-yl}-1-(phenylsulfonyl)- 1 H-indazole (269 mg, 0.519 mmol) was dissolved in 1 ,4-dioxane (5 ml) and half of this stock solution was charged to a reaction vessel. N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (1 10 mg, 0.335 mmol) , 1 ,1'- bis(diphenylphosphino)ferrocene palladium dichloride (38 mg, 0.052 mmol), potassium phosphate tribasic (165 mg, 0.779 mmol) and water (0.25 ml) were added. The reaction mixture was heated under microwave irradiation at 1000C for 20 mins, then 1000C for 40 mins and lastly 100C for 20 mins. More N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (34.1 mg, 0.104 mmol), 1 ,1'- bis(diphenylphosphino)ferrocene palladium dichloride (7.59 mg, 10.38 mumol) and potassium phosphate tribasic (33.0 mg, 0.156 mmol) were added and the mixture was heated under microwave irradiation at 1000C for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The crude was purified using preparative HPLC as follows:Column Packing Waters Sunfire c18 Column Particle Size 5.0 mum Column Dimensions 100x19mmlD Solvent A 0.1 % v/v formic acid in water Solvent B MeCN + 0.1 % v/v of formic acid Temperature ambient Flow Rate 20 ml/ min Injection Volume 500 muL Injection Vehicle 1 :1 DMSO/ MeCN UV detection Diode-array 210-400 nm (averaged) MS detection Electrospray, +ve/ -ve switching, 100-1000amu, centroid modeMS scan function Electrospray, +ve/ -ve switching, centroid modeThe appropriate fraction were blown to dryness. 1 ,4-Dioxane (1 ml) was added and 2M sodium hydroxide (1 ml, 2.000 mmol) and the mixture stirred at 20 0C for 2 h. The mixture was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride solution (2 ml), separated with a hydrophilic frit. The organic layer was evaporated to dryness under a stream of nitrogen to give the title compound as a cream solid (27 mg). LCMS (Method A): Rt 0.63 mins, MH+ 500.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 100℃; for 1.66667h;Microwave irradiation;	6-l3romo-4-{5-[(2-methyl-4-morpholinyl)methyl]-1 ,3,4- oxadiazol-2-yl}- 1 -(phenylsulfonyl)- 1H-indazole (269 mg, 0.519 mmol) was dissolved in 1 ,4-dioxane (5 ml) and half of this stock solution was charged to a reaction vessel. N-[2- (methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-3-pyridinyl]methanesulfonamide (110mg, 0.33 5 mmol), 1,1 ?-bis(diphenylphosphino)ferrocene palladium dichloride (38 mg, 0.052 mmol), potassium phosphate tribasic (165 mg, 0.779 mmol) and water (0.25 ml) were added. The reaction mixture was heated under microwave irradiation at 1000 C. for 20 mins, then 100C. for 40 mins and lastly 100C. for 20 mins. More N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (34.1 mg, 0.104 mmol), 1,1 ?-bis(diphenylphosphino)ferrocene palladium dichloride (7.59 mg, 10.38 tmol) and potassium phosphate tribasic (33.0 mg, 0.156 mmol) were added and the mixture was heated under microwave irradiation at 100 C. for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOR. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The crude was purified using preparative HPLC as follows:The appropriate fraction were blown to dryness. 1,4-Dioxane (1 ml) was added and 2M sodium hydroxide (1 ml, 2.000 mmol) and the mixture stirred at 20 C. for 2 h. The mixture was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride solution (2 ml), separated with a hydrophilic frit. The organic layer was evaporated to dryness under a stream of nitrogen to give the title compound as a cream solid (27 mg).LCMS (Method A): Rt 0.63 mins, MH+ 500.

References: [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 156; 157; 158.
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 199; 200.

4
[ 1083326-75-3 ]
[ 1245465-38-6 ]
[ 1245465-47-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 0.333333h;	-Bromo-1-(phenylsulfonyl)-4-[5-(tetrahydro-1 ,4-oxazepin-4(5H)-ylmethyl)-1 ,3,4- oxadiazol-2-yl]-1 H-indazole (279 mg, 0.538 mmol) was dissolved in 1 ,4-dioxane (5 ml) and half of the resulting solution was charged to a reaction vessel. N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]methanesulfonamide (114 mg, 0.347 mmol), 1 , 1'- bis(diphenylphosphino)ferrocene palladium dichloride (39.5 mg, 0.054 mmol), potassium phosphate tribasic (171.5 mg, 0.808 mmol) and water (0.25 ml) were added. The reaction mixture was heated at 100 0C for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The residue was purified by preparative HPLC using the following method:Column Packing Waters Sunfire c18Column Particle Size 5.0 mumColumn Dimensions 100x19mmlDSolvent A 0.1 % v/v formic acid in water Solvent B MeCN + 0.1 % v/v of formic acid Temperature ambient Flow Rate 20 ml/ min Injection Volume 500 muL Injection Vehicle 1 :1 DMSO/ MeCN UV detection Diode-array 210-400 nm (averaged) MS detection Electrospray, +ve/ -ve switching, 100-1000amu, centroid modeMS scan function Electrospray, +ve/ -ve switching, centroid modeThe appropriate fractions were dried down to give the title compound as a cream solid (50 mg). LCMS (Method A): Rt 0.78, MH+ 640
50 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 100℃; for 0.333333h;	N-(2-(Methyloxy)-5-{1-(phenylsulfonyl)-4-[5-(tetrahydro-1,4-oxazepin-4(5H)-ylmethyl)-1,3,4-oxadiazol-2-yl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide 6-Bromo-1-(phenylsulfonyl)-4-[5-(tetrahydro-1,4-oxazepin-4(5H)-ylmethyl)-1,3,4-oxadiazol-2-yl]-1H-indazole (279 mg, 0.538 mmol) was dissolved in 1,4-dioxane (5 ml) and half of the resulting solution was charged to a reaction vessel. <strong>[1083326-75-3]N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide</strong> (114 mg, 0.347 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (39.5 mg, 0.054 mmol), potassium phosphate tribasic (171.5 mg, 0.808 mmol) and water (0.25 ml) were added. The reaction mixture was heated at 100 C. for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The residue was purified by preparative HPLC using the following method: The appropriate fractions were dried down to give the title compound as a cream solid (50 mg).LCMS (Method A): Rt 0.78, MH+ 640

References: [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 115; 116.
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 112; 113.

5
[ 1083326-75-3 ]
[ 1245465-40-0 ]
[ 1245465-88-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 0.333333h;Microwaves;	N-[5-[4-(5-[(3R,5S)-3,5-Dimethyl-4-(1-methylethyl)-1-piperazinyl]methyl}-1 ,3,4- oxadiazol-2-yl)-1 H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide6-Bromo-4-(5-[(3R,5S)-3,5-dimethyl-4-(1-methylethyl)-1-piperazinyl]methyl}-1 ,3,4- oxadiazol-2-yl)-1-(phenylsulfonyl)-1 H-indazole (172 mg, 0.300 mmol), N-[2-(methyloxy)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (108 mg, 0.330 mmol), 1 ,1'-bis(diphenylphosphino)ferrocene palladium dichloride (43.9 mg, 0.060 mmol) and potassium phosphate tribasic (191 mg, 0.900 mmol) were added to a microwave vial and dissolved in 1 ,4-dioxane (2.5 ml) and water (0.25 ml). The mixture was heated under microwave irradiation at 100 0C for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The protected compound was dissolved in 1 ,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 4 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen and the crude residue was dissolved in DMSO (1 ml) and purified by high pH MDAP (Method E). The appropriate fraction was blown to dryness to give the title compound as a white solid (40 mg).LCMS (Method A): Rt 0.76 mins, MH+ 555.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 100℃; for 0.333333h;Microwave irradiation;	Example 45 N-[5-[4-(5-[(3R,5S)-3,5-Dimethyl-4-(1-methylethyl)-1-piperazinyl]methyl}-1,3,4-oxadiazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide 6-Bromo-4-(5-[(3R,5S)-3,5-dimethyl-4-(1-methylethyl)-1-piperazinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (172 mg, 0.300 mmol), <strong>[1083326-75-3]N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide</strong> (108 mg, 0.330 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (43.9 mg, 0.060 mmol) and potassium phosphate tribasic (191 mg, 0.900 mmol) were added to a microwave vial and dissolved in 1,4-dioxane (2.5 ml) and water (0.25 ml). The mixture was heated under microwave irradiation at 100 C. for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The protected compound was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 4 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen and the crude residue was dissolved in DMSO (1 ml) and purified by high pH MDAP (Method E). The appropriate fraction was blown to dryness to give the title compound as a white solid (40 mg).LCMS (Method A): Rt 0.76 mins, MH+ 555.

References: [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 151; 152.
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 194; 195.

6
[ 1083326-75-3 ]
[ 1245465-43-3 ]
[ 1245465-91-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 0.333333h;Microwaves;	6-Bromo-4-{5-[(2-ethyl-4-morpholinyl)methyl]-1 ,3,4-oxadiazol-2-yl}-1-(phenylsulfonyl)-1 H- indazole (170 mg, 0.319 mmol), N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (115 mg, 0.351 mmol), 1 ,1'- bis(diphenylphosphino)ferrocene palladium dichloride (46.7 mg, 0.064 mmol) and potassium phosphate tribasic (203 mg, 0.958 mmol) were added to a microwave vial and dissolved in 1 ,4-dioxane (5 ml) and water (0.5 ml). The mixture was heated under microwave irradiation at 1000C for 20 mins. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The protected compound was dissolved in 1 ,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 4 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen and the crude residue was dissolved in DMSO (2 ml) and purified by Mass Directed Automated Preparative HPLC. The appropriate fraction was blown down under a stream of nitrogen to give a yellow solid. The solid was purified further by high pH MDAP (Method E) and the appropriate fraction was blown down under a stream of nitrogen to give the title compound as a white solid (12 mg).LCMS (Method A): Rt 0.90 mins, MH+ 514.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 100℃; for 0.333333h;Microwave irradiation;	Example 47 N-[5-(4-{5-[(2-Ethyl-4-morpholinyl)methyl]-1,3,4-oxadiazol-2-yl}-1H-indazol-6-yl)-2-(methyloxy)-3-pyridinyl]methanesulfonamide 6-Bromo-4-{5-[(2-ethyl-4-morpholinyl)methyl]-1,3,4-oxadiazol-2-yl}-1-(phenylsulfonyl)-1H-indazole (170 mg, 0.319 mmol), <strong>[1083326-75-3]N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide</strong> (115 mg, 0.351 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (46.7 mg, 0.064 mmol) and potassium phosphate tribasic (203 mg, 0.958 mmol) were added to a microwave vial and dissolved in 1,4-dioxane (5 ml) and water (0.5 ml). The mixture was heated under microwave irradiation at 100 C. for 20 mins. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The protected compound was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 4 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen and the crude residue was dissolved in DMSO (2 ml) and purified by Mass Directed Automated Preparative HPLC. The appropriate fraction was blown down under a stream of nitrogen to give a yellow solid. The solid was purified further by high pH MDAP (Method E) and the appropriate fraction was blown down under a stream of nitrogen to give the title compound as a white solid (12 mg).LCMS (Method A): Rt 0.90 mins, MH+ 514.

References: [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 152; 153.
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 195; 196.

7
[ 1083326-75-3 ]
[ 1245465-51-3 ]
[ 1245466-00-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 80 - 100℃; for 0.666667h;Microwaves;	1-[({5-[6-Bromo-1-(phenylsulfonyl)-1 H-indazol-4-yl]-1 ,3,4-oxadiazol-2-yl}methyl)amino]-3- (4-morpholinyl)-2-propanol (100 mg, 0.346 mmol), N-[2-(methyloxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (81 mg, 0.247 mmol), 1 ,1'-bis(diphenylphosphino)ferrocene palladium dichloride (25.35 mg, 0.0345 mmol) and potassium phosphate tribasic (1 10.5 mg, 0.5195 mmol) were added to a mixture of 1 ,4-dioxane (2.5 ml) and water (0.25 ml). The reaction mixture was heated under microwave irradiation at 800C for 30 mins and then 1000C for 10 mins. The mixture was then passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated by a hydrophobic frit and the solvent again removed under a stream of nitrogen. The protected compound was dissolved in 1 ,4-dioxane (1 ml) and sodium hydroxide (1 ml) and stirred at room temperature for 1 h. The mixture was neutralised with addition of 2M HCI, dissolved in DMSO, filtered through a filter tube and purified by high pH MDAP (Method E). The appropriate fractions and waste were evaporated to dryness in vacuo. The residue was dissolved in 1 :1 DMSO/ water and purified by preparative HPLC using the following method:Column Packing Waters Atlantis Column Particle Size 5.0 mum Column Dimensions 100x19mmlD Solvent A 0.1 % v/v TFA in water Solvent B MeOH + 0.1 % v/v TFA Temperature ambient Flow Rate 20 ml/ min Injection Volume 500 muL UV detection Diode-array 210-400 nm (averaged) MS detection Electrospray, +ve/ -ve switching, 100-1000amu, centroid mode MS scan function Electrospray, +ve/ -ve switching, centroid modeThe crude residue was collected and re-purified using a similar method but using 10-30 % MeCN/ TFA and the following gradient.The appropriate fractions were dried down give the title compound as a pale yellow solid(12 mg).LCMS (Method A): 0.40 mins, MH+ 559.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 80 - 100℃; for 0.666667h;Microwave irradiation;	1 -[({5-[6-l3romo- 1 -(phenylsulfonyl)- 1H-indazol-4-yl]- 1,3,4-oxadiazol-2-yl}methyl)amino] -3-(4-morpholinyl)-2- propanol (100 mg, 0.346 mmol), N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (81 mg, 0.247 mmol), 1,1?-bis (diphenylphosphino)ferrocene palladium dichioride (25.35mg, 0.0345 mmol) and potassium phosphate tribasic (110.5 mg, 0.5 195 mmol) were added to a mixture of 1,4-dioxane(2.5 ml) andwater (0.25 ml). The reaction mixture was heatedunder microwave irradiation at 80 C. for 30 mins and then100 C. for 10 mins. The mixture was then passed through a1 g silica SPE cartridge, washing with MeOR. The solvent was removed under a stream of nitrogen and the residue waspartitioned between DCM (10 ml) and water (10 ml), sepa15 rated by a hydrophobic frit and the solvent again removedunder a stream of nitrogen. The protected compound was dissolved in 1 ,4-dioxane (1 ml) and sodium hydroxide (1 ml) and stirred at room temperature for 1 h. The mixture wasneutralised with addition of 2M HC1, dissolved in DM50,filtered through a filter tube and purified by high pH MDAP(Method E). The appropriate fractions and waste were evaporated to dryness in vacuo. The residue was dissolved in 1:1 DM50/water and purified by preparative HPLC using the following method: The crude residue WB5 collected and re-purified using a similar method but using 10-30% MeCN/TFA and the fol10lowing gradient.The appropriate fractions were dried down give the title compound as a pale yellow solid (12 mg).LCMS (Method A): 0.40 mins, MH+ 559.

References: [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 161; 162; 163.
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 203; 204; 205; 206.

8
[ 1083326-75-3 ]
[ 1245465-57-9 ]
[ 1245465-53-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; at 100℃; for 0.333333h;Microwaves;	To a solution of 6-bromo-4-{5-[(8aS)-hexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-ylmethyl]- 1 ,3,4-oxadiazol-2-yl}-1-(phenylsulfonyl)-1 H-indazole (100 mg, 0.184 mmol) was added N- [2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]methanesulfonamide (72.5 mg, 0.221 mmol), 1 ,1'- bis(diphenylphosphino)ferrocene palladium dichloride (36 mg, 0.049 mmol) and potassium phosphate tribasic (126 mg, 0.594 mmol). The mixture was heated under microwave irradiation at 100 0C for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The residue was dissolved in DCM and added to the top of a 10 g silica SPE cartridge that was subsequently eluted with 0-15% MeOH/DCM over 20 mins. The product-containing fractions were combined and the solvent removed in vacuo to give the title compound as an orange oil (95 mg). LCMS (Method A). Product Rt 0.69, MH+ 665.
95 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; at 100℃; for 0.333333h;Microwave irradiation;	N-[5-[4-{5-[(8aS)-Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylmethyl]-1,3,4-oxadiazol-2-yl}-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide To a solution of 6-bromo-4-{5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylmethyl]-1,3,4-oxadiazol-2-yl}-1-(phenylsulfonyl)-1H-indazole (100 mg, 0.184 mmol) was added <strong>[1083326-75-3]N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide</strong> (72.5 mg, 0.221 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (36 mg, 0.049 mmol) and potassium phosphate tribasic (126 mg, 0.594 mmol). The mixture was heated under microwave irradiation at 100 C. for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The residue was dissolved in DCM and added to the top of a 10 g silica SPE cartridge that was subsequently eluted with 0-15% MeOH/DCM over 20 mins. The product-containing fractions were combined and the solvent removed in vacuo to give the title compound as an orange oil (95 mg). LCMS (Method A). Product Rt 0.69, MH+ 665.

References: [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 117; 118.
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 115; 116.

9
[ 1083326-75-3 ]
[ 1245465-01-3 ]
[ 1245465-06-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 60℃; for 0.166667h;Microwaves;	To a solution of 6-bromo-4-(5-[4-(1-methylethyl)-1-piperazinyl]methyl}-1 ,3,4-oxadiazol-2- yl)-1-(phenylsulfonyl)-1 H-indazole (100 mg, 0.183 mmol) in 1 ,4-dioxane (2.5 ml) and water (0.250 ml) was added N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-3-pyridinyl]methanesulfonamide (78 mg, 0.238 mmol), 1 ,1'- bis(diphenylphosphino)ferrocene palladium dichloride (26.8 mg, 0.037 mmol) and potassium phosphate tribasic (1 17 mg, 0.550 mmol). The mixture was heated under microwave irradiation at 60 0C for 10 min, then the solvent was removed in vacuo and the residue partitioned between dichloromethane (5ml) and water (5ml), separated by hydrophobic frit and purified by silica (5g) cartridge using a gradient of dichloromethane and methanol to give the title compound as a brown solid (122mg). LCMS (Method A) Rt 0.87mins, MH+ 667.
122 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 60℃; for 0.166667h;Microwave irradiation;	Intermediate 27 N-[5-[4-(5-[4-(1-Methylethyl)-1-piperazinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide To a solution of 6-bromo-4-(5-[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (100 mg, 0.183 mmol) in 1,4-dioxane (2.5 ml) and water (0.250 ml) was added <strong>[1083326-75-3]N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide</strong> (78 mg, 0.238 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (26.8 mg, 0.037 mmol) and potassium phosphate tribasic (117 mg, 0.550 mmol). The mixture was heated under microwave irradiation at 60 C. for 10 min, then the solvent was removed in vacuo and the residue partitioned between dichloromethane (5 ml) and water (5 ml), separated by hydrophobic frit and purified by silica (5 g) cartridge using a gradient of dichloromethane and methanol to give the title compound as a brown solid (122 mg). LCMS (Method A) Rt 0.87 mins, MH+ 667.

References: [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 101.
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 97; 98.

10
[ 1083326-75-3 ]
[ 1245465-15-9 ]
[ 1245463-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 110℃; for 0.25h;	6-Bromo-4-(5-[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1 ,3,4-oxadiazol-2-yl)-1- methyl-1 H-indazole (45 mg, 0.1 11 mmol), N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (36.4 mg, 0.11 1 mmol), sodium carbonate (35.2 mg, 0.332 mmol) and 1 ,1-bis(diphenylphosphino)ferrocene palladium dichloride (8.10 mg, 0.01 1 mmol) were added to a microwave vial and dissolved in 1 ,4- dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 11 O0C for 15 mins. The reaction mixture was passed through a 2 g silica cartridge that was then washed with methanol. The solvent was evaporated under a stream of nitrogen and the residual solid was purified by Mass Directed Automated Preparative HPLC (Method B) and the solvent was evaporated under a stream of nitrogen to give the title compound as a white solid (10 mg). LCMS (Method A): Rt 0.77 min, MH+ 528.
10 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 0.25h;Microwave irradiation;	Example 26 N-[5-[4-(5-[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-methyl-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide 6-Bromo-4-(5-[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-methyl-1H-indazole (45 mg, 0.111 mmol), <strong>[1083326-75-3]N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide</strong> (36.4 mg, 0.111 mmol), sodium carbonate (35.2 mg, 0.332 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (8.10 mg, 0.011 mmol) were added to a microwave vial and dissolved in 1,4-dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 110 C. for 15 mins. The reaction mixture was passed through a 2 g silica cartridge that was then washed with methanol. The solvent was evaporated under a stream of nitrogen and the residual solid was purified by Mass Directed Automated Preparative HPLC (Method B) and the solvent was evaporated under a stream of nitrogen to give the title compound as a white solid (10 mg).LCMS (Method A): Rt 0.77 mi MH+ 528.

References: [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 138; 139.
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 183.

11
[ 1083326-75-3 ]
[ 1245465-19-3 ]
[ 1245463-50-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 110℃; for 0.25h;Microwaves;	6-Bromo-1-methyl-4-(5-[4-(1-methylethyl)-1-piperazinyl]methyl}-1 ,3,4-oxadiazol-2-yl)-1 H- indazole (40 mg, 0.095 mmol), N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (31.3 mg, 0.095 mmol), sodium carbonate (30.3 mg, 0.286 mmol) and 1 ,1-bis(diphenylphosphino)ferrocene palladium dichloride (6.98 mg, 9.54 mumol) were added to a microwave vial and dissolved in 1 ,4- dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 1 1O0C for 15 mins. The reaction mixture was evaporated under a stream of nitrogen and the residual solid was dissolved in DMSO (1 ml), filtered through a frit and purified by Mass Directed Automated Preparative HPLC (Method B). The solvent was evaporated under a stream of nitrogen and the residue was dissolved in 1 ,4-dioxane (1 ml) and water (1 ml), frozen in a cardice bath and placed on the freeze-drier for 18 h to afford the title compound as a white solid (20 mg). LCMS (Method A): Rt 0.56 min, MH+ 541.
20 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 0.25h;Microwave irradiation;	Example 25 N-[5-[1-Methyl-4-(5-[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3,4-oxadiazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide 6-Bromo-1-methyl-4-(5-[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3,4-oxadiazol-2-yl)-1H-indazole (40 mg, 0.095 mmol), <strong>[1083326-75-3]N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide</strong> (31.3 mg, 0.095 mmol), sodium carbonate (30.3 mg, 0.286 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (6.98 mg, 9.54 mumol) were added to a microwave vial and dissolved in 1,4-dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 110 C. for 15 mins. The reaction mixture was evaporated under a stream of nitrogen and the residual solid was dissolved in DMSO (1 ml), filtered through a frit and purified by Mass Directed Automated Preparative HPLC (Method B). The solvent was evaporated under a stream of nitrogen and the residue was dissolved in 1,4-dioxane (1 ml) and water (1 ml), frozen in a cardice bath and placed on the freeze-drier for 18 h to afford the title compound as a white solid (20 mg).LCMS (Method A): Rt 0.56 mi MH+ 541.

References: [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 137; 138.
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 182.

12
[ 1083326-75-3 ]
[ 1245465-20-6 ]
[ 1283761-17-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; at 100℃; for 0.333333h;Microwaves;	To a solution of 6-bromo-4-{5-[(2,2-dimethyl-4-morpholinyl)methyl]-1 ,3,4-oxadiazol-2-yl}-1- (phenylsulfonyl)-I H-indazole (112 mg, 0.210 mmol) was added N-[2-(methyloxy)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (69.0 mg, 0.210 mmol), 1 ,1'-bis(diphenylphosphino)ferrocene palladium dichloride (30.8 mg, 0.042 mmol) and potassium phosphate tribasic (134 mg, 0.631 mmol). The mixture was heated under microwave irradiation at 100 0C for 20 min, then concentrated in vacuo and the residue partitioned between DCM (10 ml) and water (5 ml). The layers were separated by hydrophobic frit and the organics were concentrated, then re-dissolved in DCM and loaded on the top of a 20 g silica SPE cartridge, which was then eluted with 0-100% EtOAc/cyclohexane followed by 0-20% MeOH/EtOAc on the FlashMaster II. The desired fractions were combined and the solvent removed in vacuo to give a pale orange solid (80 mg), which was dissolved in 1 ,4-dioxane (0.5 ml), treated with 2M sodium hydroxide (0.5 ml, 1.000 mmol) and stirred at 20 0C for 18 h. The mixture was evaporated to dryness under a stream of nitrogen and the residue partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated by hydrophilic frit. The solvent was removed under a stream of nitrogen and the residue was dissolved in DMSO (1 ml) and purified by MDAP (Method B). The product-containing fractions were evaporated to dryness under a stream of nitrogen to afford the title compound as a white solid (24 mg). LCMS (Method A) Rt = 0.75 min, MH+ 514.
80 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; at 100℃; for 0.333333h;Microwave irradiation;	Example 28 N-[5-(4-{5-[(2,2-Dimethyl-4-morpholinyl)methyl]-1,3,4-oxadiazol-2-yl}-1H-indazol-6-yl)-2-(methyloxy)-3-pyridinyl]methanesulfonamide To a solution of 6-bromo-4-{5-[(2,2-dimethyl-4-morpholinyl)methyl]-1,3,4-oxadiazol-2-yl}-1-(phenylsulfonyl)-1H-indazole (112 mg, 0.210 mmol) was added <strong>[1083326-75-3]N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide</strong> (69.0 mg, 0.210 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (30.8 mg, 0.042 mmol) and potassium phosphate tribasic (134 mg, 0.631 mmol). The mixture was heated under microwave irradiation at 100 C. for 20 min, then concentrated in vacuo and the residue partitioned between DCM (10 ml) and water (5 ml). The layers were separated by hydrophobic frit and the organics were concentrated, then re-dissolved in DCM and loaded on the top of a 20 g silica SPE cartridge, which was then eluted with 0-100% EtOAc/cyclohexane followed by 0-20% MeOH/EtOAc on the FlashMaster II. The desired fractions were combined and the solvent removed in vacuo to give a pale orange solid (80 mg), which was dissolved in 1,4-dioxane (0.5 ml), treated with 2M sodium hydroxide (0.5 ml, 1.000 mmol) and stirred at 20 C. for 18 h. The mixture was evaporated to dryness under a stream of nitrogen and the residue partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated by hydrophilic frit. The solvent was removed under a stream of nitrogen and the residue was dissolved in DMSO (1 ml) and purified by MDAP (Method B). The product-containing fractions were evaporated to dryness under a stream of nitrogen to afford the title compound as a white solid (24 mg). LCMS (Method A) R=0.75 mi MH+ 5i4.

References: [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 139; 140.
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 184.

13
[ 1083326-75-3 ]
[ 1254036-85-5 ]
[ 1254036-66-2 ]

Yield	Reaction Conditions	Operation in experiment
26 mg	With potassium phosphate; chloro(di-norbonylphosphino)(2?-dimethylamino-1,1?-biphenyl-2-yl)palladium(II); In 1,4-dioxane; water; at 120℃; for 3h;Microwave irradiation;	Method ATo a solution of 6-chloro-4-(5-{ [(2R,6S)-2,6-dimethyl-4- morpholinyl]methyl}-1 ,3-oxazol-2-yl)- 1 -(phenylsulfonyl)1H-indazole (0.20 g, 0.411 mmol) and N-[2-(methoxy)-5-(4, 4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridyl] methanesulfonamide (0.175 g, 0.534 mmol) in 1 ,4-dioxane (2 ml) was added chloro[2?-(dimethylamino)-2-biphenylyl]pal- ladium-1 (1R,4S)-bicyclo[2.2. 1 ]hept-2-yl[(1 S,4R)-bicyclo [2.2. 1]hept-2-yl]phosphane (11.5 mg, 0.021 mmol), potassium phosphate tribasic (0.262 g, 1.23 mmol) and water (0.2 ml). The reaction mixture was heated and stirred at 120 C. under microwave irradiation for 1 h. Additional chloro[2?- (dimethylamino)-2-biphenylyl]palladium-1 (1 R,4S)-bicyclo [2.2. 1]hept-2-yl[(1 S,4R)-bicyclo[2.2. 1]hept-2-yl]phos- phane (11.5 mg, 0.021 mmol) and potassium phosphate tribasic (80 mg) were added and the reaction heated to 120C. under microwave irradiation for 1 h. Additional potassium phosphate tribasic (80 mg) was added and the reaction heated under the same conditions for a further 1 h. The reaction mixture was filtered through a silica SPE and eluted with methanol. The solvent was removed in vacuo and the residue partitioned between dichloromethane (5 ml) and water (5 ml). The layers were separated and the aqueous extracted with further dichloromethane (2x2 ml). The combined organics were concentrated under a stream of nitrogen and the residue dissolved in MeOH:DMSO (3 ml, 1:1, v/v) and purified by MDAP (method H) in 3 injections. The appropriate fractions were combined and concentrated to give a white solid which was dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and further purified by MDAP (method 1). The appropriate fractions were basified to pH 6 with saturated sodium bicarbonate solution and extracted with ethyl acetate (2x25 ml). The combined organics were dried and evaporated in vacuo to give a white solid which was further dried under nitrogen at 40 C. for 3 h to give the title compound as a white solid (26 mg).LCMS (Method A): Rt 0.53 mins, MH 513.
	With potassium phosphate; water;(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane-chloro[2'-(dimethylamino)biphenyl-2-yl]palladium(1:1); In 1,4-dioxane; at 120℃; for 3h;Microwave irradiation;Product distribution / selectivity;	Method ATo a solution of 6-chloro-4-(5-[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1 ,3-oxazol-2- yl)-1-(phenylsulfonyl)-1 H-indazole (0.20 g, 0.411 mmol) and N-[2-(methoxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridyl]methanesulfonamide (0.175 g, 0.534 mmol) in 1 ,4-dioxane (2 ml) was added chloro[2'-(dimethylamino)-2-biphenylyl]palladium- 1 (1 /?,4S)-bicyclo[2.2.1]hept-2-yl[(1 S,4/?)-bicyclo[2.2.1]hept-2-yl]phosphane (11.5 mg, 0.021 mmol), potassium phosphate tribasic (0.262 g, 1.23 mmol) and water (0.2 ml). The reaction mixture was heated and stirred at 12O0C under microwave irradiation for 1 h. Additional chloroP'^dimethylamino^-biphenylyOpalladium-^I R^S^bicycloP^.ilhept^- yl[(1 S,4/?)-bicyclo[2.2.1]hept-2-yl]phosphane (11.5 mg, 0.021 mmol) and potassium phosphate tribasic (80 mg) were added and the reaction heated to 12O0C under microwave irradiation for 1 h. Additional potassium phospate tribasic (80 mg) was added and the reaction heated under the same conditions for a further 1 h. The reaction mixture was filtered through a silica SPE and eluted with methanol. The solvent was removed in vacuo and the residue partitioned between dichloromethane (5 ml) and water (5 ml). The layers were separated and the aqueous extracted with further dichloromethane (2x 2 ml). The combined organics were concentrated under a stream of nitrogen and the residue dissolved in MeOH:DMSO (3ml, 1 :1 , v/v) and purified by MDAP (method A) in 3 injections. The appropriate fractions were combined and concentrated to give a white solid which was dissolved in MeOH:DMSO (1 ml, 1 :1 , v/v) and further purified by MDAP (method B). The appropriate fractions were basified to pH 6 with saturated sodium bicarbonate solution and extracted with ethyl acetate (2x 25 ml). The combined organics were dried and evaporated in vacuo to give a white solid which was further dried under nitrogen at 4O0C for 3 h to give the title compound as a white solid (26 mg). LCMS (Method A): Rt 0.53 mins, MH+ 513.

References: [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 7381 - 7399.
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 209.
[3]Organic Process Research and Development,2018,vol. 22,p. 368 - 376.
[4]Patent: WO2010/125082,2010,A1 .Location in patent: Page/Page column 80-81.

14
[ 1083326-75-3 ]
[ 1254036-86-6 ]
[ 1254036-67-3 ]

Yield	Reaction Conditions	Operation in experiment
22 mg	With potassium phosphate; chloro(di-norbonylphosphino)(2?-dimethylamino-1,1?-biphenyl-2-yl)palladium(II); In 1,4-dioxane; water; at 120℃; for 3h;Microwave irradiation;	212To a solution of 6-chloro-4-(5-{ [4-(1 -methylethyl)- 1-pip- erazinyl]methyl}- 1 ,3-oxazol-2-yl)-1 -(phenylsulfonyl)-1 Hindazole (200 mg, 0.400 mmol) and N-[2-(methoxy)-5-(4,4, 5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3-pyridyl]methanesulfonamide (171 mg, 0.520 mmol) in 1,4-dioxane (2 ml) was added chloro[2?-(dimethylamino)-2-biphenylyl] palladium-i (1 R,45)-bicyclo[2.2. 1 ]hept-2-yl[(i S,4R)-bicy- clo[2.2. 1 ]hept-2-yl]phosphane (11.2 mg, 0.020 mmol), potassium phosphate tribasic (255 mg, 1.20 mmol) and water(0.2 ml). The reaction mixture was heated and stirred at 120 C. under microwave irradiation for 3 h. The reaction mixture was filtered through a silica SPE and eluted with methanol. The solvent was removed in vacuo and the residue partitioned between dichloromethane (5 ml) and water (5 ml). The layerswere separated and the aqueous extracted with further dichloromethane (2x2 ml). The combined organics were concentrated under a stream of nitrogen and the residue dissolved in MeOH:DMSO (2 ml, 1:1, v/v) and purified by MDAP (method H) in 2 injections. The appropriate fractions werecombined and concentrated and the residue dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and further purified by MDAP (method 1). The appropriate fractions were basified to pH 7 with saturated sodium bicarbonate solution and extracted with dichioromethane (2x20 ml). The combined organicswere dried (hydrophobic frit) and concentrated to give the title compound as a white solid (22 mg).ECMS (Method A): Rt 0.51 mins, MH 526.
	With potassium phosphate; water;(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane-chloro[2'-(dimethylamino)biphenyl-2-yl]palladium(1:1); In 1,4-dioxane; at 120℃; for 3h;Microwave irradiation;Product distribution / selectivity;	Example 2 Lambda/-[5-[4-(5-[4-(1 -Methyl ethyl )-1 -piperazinyl]methyl}-1 ,3-oxazol-2-yl)-1 H-indazol-6-yl]- 2-(methyloxy)-3-pyridinyl]methanesulfonamideTo a solution of 6-chloro-4-(5-[4-(1-methylethyl)-1-piperazinyl]methyl}-1 ,3-oxazol-2-yl)-1- (phenylsulfonyl)-IH-indazole (200 mg, 0.400 mmol) and N-[2-(methoxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridyl]methanesulfonamide (171 mg, 0.520 mmol) in 1 ,4-dioxane (2 ml) was added chloro[2'-(dimethylamino)-2-biphenylyl]palladium- 1 (1 R,4S)-bicyclo[2.2.1]hept-2-yl[(1 S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (11.2 mg, 0.020 mmol), potassium phosphate tribasic (255 mg, 1.20 mmol) and water (0.2 ml). The reaction mixture was heated and stirred at 12O0C under microwave irradiation for 3 h. The reaction mixture was filtered through a silica SPE and eluted with methanol. The solvent was removed in vacuo and the residue partitioned between dichloromethane (5 ml) and water (5 ml). The layers were separated and the aqueous extracted with further dichloromethane (2x 2 ml). The combined organics were concentrated under a stream of nitrogen and the residue dissolved in MeOH:DMSO (2ml, 1 :1 , v/v) and purified by MDAP (method A) in 2 injections. The appropriate fractions were combined and concentrated and the residue dissolved in MeOH:DMSO (1 ml, 1 :1 , v/v) and further purified by MDAP (method B). The appropriate fractions were basified to pH 7 with saturated sodium bicarbonate solution and extracted with dichloromethane (2x 20 ml). The combined organics were dried (hydrophobic frit) and concentrated to give the title compound as a white solid (22 mg). LCMS (Method A): Rt 0.51 mins, MH+ 526.

References: [1]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 211; 212.
[2]Patent: WO2010/125082,2010,A1 .Location in patent: Page/Page column 83-84.

15
[ 1083326-75-3 ]
[ 1254036-91-3 ]
[ 1254036-75-3 ]

Yield	Reaction Conditions	Operation in experiment
43 mg		Example 70 N-[5-[4-(5-[(2R,6R)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide To a solution of 6-chloro-4-(5-[(2R,6R)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (109.5 mg, 0.225 mmol), <strong>[1083326-75-3]N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide</strong> (148 mg, 0.450 mmol) and sodium bicarbonate (56.7 mg, 0.675 mmol) in 1,4-Dioxane (5 mL) and Water (1.5 mL) stirred in air at room temp was added solid Solvias Catalyst (12.60 mg, 0.022 mmol). The reaction mixture was stirred at 120 C. for 2 hr. After this time, sodium hydroxide solution (2N, 0.5 mL) was added and the reaction mixture left to stir at room temperature for two hours. On cooling, the reaction mixture was passed through a celite cartridge (10 g) and washed with ethyl acetate. The resulting solution was evaporated and the crude residue purified by MDAP (Method J). Appropriate fractions were combined and concentrated in vacuo to afford the title compound (43 mg). ECMS (Method A) Rt 0.63 mins, MH 513.
		Example 8Lambda/-[5-[4-(5-[(2/?,6/?)-2,6-Dimethyl-4-morpholinyl]methyl}-1 ,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideTo a solution of 6-chloro-4-(5-[(2R,6R)-2,6-dimethyl-4-morpholinyl]methyl}-1 ,3-oxazol-2- yl)-1-(phenylsulfonyl)-1 H-indazole (109.5 mg, 0.225 mmol), N-[2-(methyloxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (148 mg, 0.450 mmol) and sodium bicarbonate (56.7 mg, 0.675 mmol) in 1 ,4-Dioxane (5 ml.) and Water (1.5ml_) stirred in air at room temp was added solid Solvias Catalyst (12.60 mg, 0.022 mmol). The reaction mixture was stirred at 120 0C for 2 hr. After this time, sodium hydroxide solution (2N, 0.5 ml.) was added and the reaction mixture left to stir at room temperature for two hours. On cooling, the reaction mixture was passed through a celite cartridge (10g) and washed with ethyl acetate. The resulting solution was evaporated and the crude residue purified by MDAP (Method C). Appropriate fractions were combined and concentrated in vacuo to afford the title compound (43 mg). LCMS (Method A) Rt 0.63 mins, MH+ 513.

References: [1]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 216; 217.
[2]Patent: WO2010/125082,2010,A1 .Location in patent: Page/Page column 89.

16
[ 73183-34-3 ]
[ 1083326-75-3 ]

References: [1]Patent: WO2011/67365,2011,A1 .
[2]Patent: WO2014/60431,2014,A1 .
[3]Patent: US9326987,2016,B2 .
[4]Patent: WO2009/147187,2009,A1 .

17
[ 884495-39-0 ]
[ 1083326-75-3 ]

References: [1]Patent: WO2011/67365,2011,A1 .
[2]Patent: WO2012/32067,2012,A1 .
[3]Patent: WO2014/28968,2014,A1 .
[4]Patent: US2014/134133,2014,A1 .
[5]Patent: US9326987,2016,B2 .
[6]Patent: US9326987,2016,B2 .
[7]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 637 - 646.
[8]European Journal of Medicinal Chemistry,2018,vol. 146,p. 460 - 470.
[9]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 1675 - 1685.
[10]Journal of Medicinal Chemistry,2018,vol. 61,p. 6087 - 6109.
[11]Patent: WO2009/147187,2009,A1 .
[12]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 2729 - 2740.
[13]Bioorganic Chemistry,2019,vol. 93.

18
[ 1083326-75-3 ]
[ 1309785-36-1 ]
[ 1309784-78-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 120℃; for 0.333333h;microwave vial;	N-[2-(Methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]methanesulfonamide (53 mg), sodium carbonate (46 mg) and Pd(dppf)CI2 (1 1 mg) were weighed to a microwave vial. /V-[6-bromo-2-(tetrahydro-2/-/-pyran-2-yl)-2/-/- indazol-4-yl]-1 -(tetrahydro-2/-/-pyran-4-ylmethyl)-1 /-/-pyrazole-3-carboxamide (71 mg) was dissolved in 1 ,4-dioxane (1 ml) and added followed by water (1 ml). The reaction was heated in the microwave at 120 C for 20 min. The reaction was passed through a 1 g silica cartridge, washing with methanol, then evaporated to dryness in the blow down. The residue was dissolved in DMSO:methanol (1 ml, 1 :1 . v/v) and purified by MDAP (method A). Pure fractions were combined, evaporated to dryness and the residue dissolved in dioxane:water (3 ml, 1 :1 , v/v) and freeze dried to give the title compound, 1 1 mg.LCMS (method B); Rt = 0.77 min, MH+ = 526.

References: [1]Patent: WO2011/67365,2011,A1 .Location in patent: Page/Page column 86-87.

19
[ 1083327-58-5 ]
[ 73183-34-3 ]
[ 1083326-75-3 ]

Yield	Reaction Conditions	Operation in experiment
74%		A suspension of N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide (3.35 g, 11.9 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.24 g, 16.7 mmol, Beijing datianfengtuo) in toluene (100 mL) was degassed and charged with N2 for 3 times, then Pd(dba)3 (616 mg, 0.595 mmol, Matthey) and PPh3 (243 mg, 0.892 mmol) were added. The mixture was heated to 45 C. and stirred for 45 minutes, then KOAc (3.74 g, 23.8 mmol) was added. The resulted mixture was heated to reflux and stirred further for 3 hours, then cooled to rt, diluted with EtOAc (100 mL), and filtered through a CELITE. The filtrate was washed with water (70 mL*3) and brine (100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a white solid (2.90 g, 74%). MS (ESI, pos. ion) m/z: 328.9 [M+H]+; 1H NMR (600 MHz, CDCl3): delta 8.32 (d, J=1.4 Hz, 1H), 8.06 (d, J=1.3 Hz, 1H), 6.66 (brs, 1H), 4.05 (s, 3H), 3.02 (s, 3H), 1.33 (s, 12H).
72%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;	General procedure: A mixture of 16a (11.38 g, 30 mmol), bis(pinacolato)diboron (9.14 g, 36 mmol) and potassium acetate (5.89 g, 60 mmol) in 1,4-dioxane (200 mL) was degassed, and then PdCl2(dppf) (1.1 g, 1.5 mmol) was added. The reaction mixture was degassed and back-filled with argon (three cycles), stirred at 100 C under argon atmosphere for 4 h, and then cooled to room temperature. The resulting mixture was filtered and the filtrate was concentrated and purified with column chromatography (silica gel, PE/EtOAc = 7:1) to afford 17a as a pale yellow solid (12.69 g, 99% yield).
60.4%	With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); potassium acetate; In N,N-dimethyl-formamide; at 100℃; for 8h;Inert atmosphere;	A solution of the 2a (2.80 g, 10 mmol), bis(pinacolato)diborane(1.27 g, 5 mmol), Pd(dppf)2Cl2 (0.18 g, 0.25 mmol) and KOAc (1.47 g,15 mmol) in anhydrous DMF (30 ml) under N2 was stirred at 100 Cfor 8 h. DMF was removed under reduced pressure and add water(100 ml), extracted with ethyl acetate (3 100 ml), the organiclayer was washed with water (20 ml), dried with Na2SO4 andevaporated to give compound 3a as a white solid (1.98 g, 60.4%yield). mp 90e92 C. 1H NMR (400 MHz, DMSO) d 9.25 (s, 1H, NH),8.21 (d, J 1.6 Hz, 1H, Ar-H), 7.78 (d, J 1.6 Hz, 1H, Ar-H), 3.94 (s, 3H,OCH3), 3.01 (s, 3H, CH3), 1.30 (s, 12H, CH3). ESI-MS: m/z 329.1[MH].

60.4%	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate; In N,N-dimethyl-formamide; at 100℃; for 8h;Inert atmosphere;	A solution of the 2a(2.80 g, 10 mmol), bis(pinacolato)diborane (1.27 g, 5 mmol), Pd(dppf)2Cl2 (0.18 g, 0.25 mmol) and KOAc (1.47 g, 15 mmol) inanhydrous DMF (30 ml) under N2 was stirred at 100 C for 8 h.DMF was removed under reduced pressure and adding water(100 ml), extracted with ethyl acetate (3 100 ml), the organiclayer was washed with water (20 ml), dried with Na2SO4 and evaporatedto give compound 3a as a white solid (1.98 g, 60.4% yield).Mp 90-92 C. 1H NMR (400 MHz, DMSO) d 9.25 (s, 1H, NH), 8.21(d, J = 1.6 Hz, 1H, Ar-H), 7.78 (d, J = 1.6 Hz, 1H, Ar-H), 3.94 (s, 3H,OCH3), 3.01 (s, 3H, CH3), 1.30 (s, 12H, CH3). ESI-MS: m/z 329.1 [M+H]+.
60.4%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 100℃; for 8h;Inert atmosphere;	General procedure: A solution of the 5a (2.80 g, 10 mmol), bis(pinacolato)diborane(1.27 g, 5 mmol), Pd(dppf)2Cl2 (0.18 g, 0.25 mmol) and KOAc (1.47 g,15 mmol) in anhydrous DMF (30 ml) under N2 was stirred at 100 C for8 h. Then DMF was removed under reduced pressure and add water(100 ml), extracted with ethyl acetate (200 ml) for two times, dried with anhydrous Na2SO4 and evaporated to get the residue which was purified through a column chromatography on silica with petroleum ether / ethyl acetate (V:V 5:1) to give compound 6a as a white solid(1.98 g, 60.4% yield). mp 90-92 C. 1H NMR (400 MHz, DMSO-d6) delta9.25 (s, 1H, NH), 8.21 (d, J=1.6 Hz, 1H, Ar-H), 7.78 (d, J=1.6 Hz,1H, Ar-H), 3.94 (s, 3H, OCH3), 3.01 (s, 3H, CH3), 1.30 (s, 12H, CH3).ESI-MS: m/z 329.1 [M+H]+.
	With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In toluene; at 90℃; for 1.16667h;Inert atmosphere;	Intermediate 16W-(2-Methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3- ideAll weights, volumes and equivalents are relative to A/-(5-bromo-2-methoxypyridin-3- yl)methanesulfonamide.Tricyclohexylphosphine (0.1 191 g, 0.425 mmol, 0.008eq, 0.008wt) and Pd2(dba)3 (0.1438 g, 0.157 mmol, 0.003 eq, 0.01 wt) are mixed together and then toluene (15.00 mL, 1 vol, 0.86wt, sparged with nitrogen for 1 hr) is added. The mixture is stirred and heated to 40- 45C for 45 mins before being allowed to cool back to room temp and sit under nitrogen to give an orange-gold solution with suspended black particulates. In a separate vessel, N- (5-bromo-2-methoxypyridin-3-yl)methanesulfonamide (15.0323 g, 53.5 mmol, 1 wt, 1 eq), bis(pinacolato)diboron (16.2962 g, 64.2 mmol, 1 .2 eq, 1.08 wt) and potassium acetate (10.4879 g, 107 mmol, 2 eq, 0.70 wt) are mixed together with toluene (150 mL, 10 vols, 8.6 wt). The resultant slurry is stirred and heated to 90 C under a flow of nitrogen. Having reached the desired temperature, the catalyst mixture is added over 10 minutes followed by a wash of toluene (7.50 mL, 0.5 vol, 0.43 wt). The mixture is stirred at 90 C for at least one hour and then sampled for HPLC analysis. Once complete, the reaction mixture is cooled to 50 C and filtered to remove inorganic material. The filtered solid is washed with toluene (2 x 15 mL, 2 x 1 vol, 2 x 0.86 wt) and the liquors and washes combined and distilled down to 5 vols. The product solution is allowed to cool to room temperature by which stage it has become a slurry. Heptane (75 mL, 5 vols, 3.4 wt) is slowly added to the slurry. The slurry is aged and the supernatant analysed by HPLC to ensure sufficient crystallisation has occurred. The slurry is filtered and the solid product is washed with 1 : 1 toluene: heptane (2 x 15mL, 2 x 1vol) and dried under vacuum at 40-50 C to afford N-(2- methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide as an off-white solid.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; N,N-dimethyl-formamide; at 110℃; for 2h;Sealed tube; Inert atmosphere;	General procedure: The following is based on a modified literature procedure (Knight S. D. et al., ACS Med. Chern. Let., 2010, 1, 39-43 and W02008 150827). To N-(5-bromo-2-methoxypyridin-3 -yI)methanesulphonamide(350 mg, 1.24 mmol) in dry 1,4-dioxane (9 mL)/dry DMF (1 mL) in a sealed tube was added, bis(pinacolato)diboron (347 mg, 1.37 mmol), KOAc (366 mg, 3.73 mmol), and the whole mixture was degassed and purged with N2. Pd(dppf)C12.CH2C12 (52 mg, 0.06mmol) was then added with vigorous stirring and the mixture heated to 110C for 2 h. The disappearance of the starting bromide was monitored by LRMS. This mixture was then allowed to cool to room temperature and used in situ without further purification. LRMS (APCI) calcd for C13H21BN205S 330 (M1-I), found 330 (boronate ester).
		All weights, volumes and equivalents are relative to N-(S30 bromo-2-methoxypyridin-3-yl)methanesulfonamide.Tricyclohexylphosphine (0.1191 g, 0.425 mmol, 0.008 eq,0.008 wt) and Pd2(dba)3 (0.1438 g, 0.157 mmol, 0.003 eq,0.01 wt) are mixed together and then toluene (15.00 mE,vol, 0.86 wt, sparged with nitrogen for 1 hr) is added. Themixture is stirred and heated to 40-45 C. for 45 mins beforebeing allowed to cool back to room temp and sit under nitrogen to give an orange-gold solution with suspended blackparticulates. In a separate vessel, N-(S -bromo-2-methoxypy-ridin-3-yl)methanesulfonamide (15.0323 g, 53.5 mmol, 1 wt,eq), bis(pinacolato)diboron(16.2962 g, 64.2 mmol, 1.2 eq,1.08 wt) and potassium acetate (10.4879 g, 107 mmol, 2 eq,0.70 wt) are mixed together with toluene (150 mE, 10 vols,8.6 wt). The resultant slurry is stirred and heated to 90 C.under a flow ofnitrogen. Having reached the desired temperature, the catalyst mixture is added over 10 minutes followedby a wash oftoluene (7.50 mE, 0.5 vol, 0.43 wt). The mixtureis stirred at 90 C. for at least one hour and then sampled forHPEC analysis. Once complete, the reaction mixture iscooled to 50 C. and filtered to remove inorganic material.The filtered solid is washed with toluene (2x1 S mE, 2x 1 vol,2x0.86 wt) and the liquors and washes combined and distilleddown to S vols. The product solution is allowed to cool toroom temperature by which stage it has become a slurry.Heptane (75 mE, S vols, 3.4 wt) is slowly added to the slurry.The slurry is aged and the supernatant analysed by HPEC toensure sufficient crystallisation has occurred. The slurry isfiltered and the solid product is washed with 1:1 toluene:heptane (2x1 S mE, 2x1 vol) and dried under vacuum at40-S0 C. to afford N-(2-methoxy-S-(4,4,S,S-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide asan off-white solid.Recrystallisation-All weights, volumes and equivalentsare relative to N-(2-methoxy-S-(4,4,S,S-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide.A stirred suspension of N-(2-methoxy-S-(4,4,S,S-tetram-ethyl-i ,3,2-dioxaborolan-2-yl)pyridin-3-yl)methane-sulfonamide (1 wt, 1.01 kg) in propan-2-ol (4 vol, 4.OS E) isheated to 70-75C. under a nitrogen atmosphere, then aged atthis temperature for at least 2 hr. The batch is allowed to cool to 20-25 C. over at least 1 hr, then the suspension is aged at this temperature for a further 1 hr. The liquors are sampled by HPLC to ensure complete crystallisation, then the resulting solids are filtered, washed with propan-2-ol (2x1 vol, 2x1.01 L) before being sucked dry for 0.5 hr, then the batch is dried in vacuo at 50 C. to constant probe temperature to afford N-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridin-3-yl)methanesulfonamide as a white solid.5
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 120℃; for 3h;Inert atmosphere;	A solution of 0.32 g (1.15 mmol) of 3-methanesulfonamido-2-methoxy-5-bromopyridine0.34 g (1.38 mmol) of diphenylolate borate,0.04 g (3.48 mmol) of potassium acetate and 0.06 g (0.08 mmol) of Pd (dppf) Cl2 in 100 mL eggplant vials,Adding dioxane 12mL, nitrogen protection, heating at 120 reflux 3h,To give the product containing 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5-methanesulfonamido-6-methoxypyridine Of the reaction system, cooled to room temperature,To this system was added (S) -N1- (6-bromo-2-benzothiazolyl) -1,2-tetrahydropyrrole dicarboxamide, 35 g (0.96 mmol) of potassium carbonate, 0.48 g (3.45 mmol) of potassium carbonate,Pd (dppf) Cl2 0.11 g (0.14 mmol) and water (3 mL), protected under nitrogen, heated at 120 C for 7 h,(V / V): chloroform / methanol = 25/1 to give 0.05 g of a white solid, yield: 10.83%, mp: 190-194, and the residue was purified by flash chromatography on silica gel. .

References: [1]Organic Process Research and Development,2018,vol. 22,p. 368 - 376.
[2]Patent: US2014/134133,2014,A1 .Location in patent: Paragraph 0441.
[3]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 637 - 646.
[4]Journal of Medicinal Chemistry,2018,vol. 61,p. 6087 - 6109.
[5]European Journal of Medicinal Chemistry,2018,vol. 146,p. 460 - 470.
[6]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 1675 - 1685.
[7]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 2729 - 2740.
[8]Patent: WO2012/32067,2012,A1 .Location in patent: Page/Page column 61.
[9]Patent: WO2014/28968,2014,A1 .Location in patent: Page/Page column 87; 88.
[10]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 166; 167.
[11]Patent: CN106674200,2017,A .Location in patent: Paragraph 0096; 0097.
[12]Bioorganic Chemistry,2019,vol. 93.

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[ 152684-30-5 ]
[ 1083326-75-3 ]

References: [1]Patent: WO2012/32067,2012,A1 .
[2]Patent: WO2012/32067,2012,A1 .
[3]Patent: WO2012/32067,2012,A1 .
[4]Patent: US2014/134133,2014,A1 .
[5]Patent: US9326987,2016,B2 .
[6]Patent: US9326987,2016,B2 .

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol; at 20 - 75℃; for 4h;Inert atmosphere; Industry scale;Purification / work up;	Recrystallisation - All weights, volumes and equivalents are relative to A/-(2-methoxy-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide. A stirred suspension of A/-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3- yl)methanesulfonamide (1 wt, 1.01 kg) in propan-2-ol (4 vol, 4.05 L) is heated to 70-75 C under a nitrogen atmosphere, then aged at this temperature for at least 2 hr. The batch is allowed to cool to 20-25 C over at least 1 hr, then the suspension is aged at this temperature for a further 1 hr. The liquors are sampled by HPLC to ensure complete crystallisation, then the resulting solids are filtered, washed with propan-2-ol (2 x 1 vol, 2 x 1.01 L) before being sucked dry for 0.5 hr, then the batch is dried in vacuo at 50 C to constant probe temperature to afford A/-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide as a white solid.

22
[ 1083326-75-3 ]
[ 1254036-66-2 ]

References: [1]Patent: WO2012/32067,2012,A1 .
[2]Patent: US9326987,2016,B2 .

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[ 1083326-75-3 ]
N-[5-[4-(5-[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide sodium salt [ No CAS ]