454482-11-2|1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine| Ambeed

Structure of 454482-11-2

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Quality Control of [ 454482-11-2 ] Purity: 98% SDS Specification

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Product Details of [ 454482-11-2 ]

CAS No. :	454482-11-2
Formula :	C₁₂H₂₂BNO₂
M.W :	223.12
SMILES Code :	CN1CCC(=CC1)B1OC(C)(C)C(C)(C)O1
MDL No. :	MFCD11506069
InChI Key :	SQMVRFXDBRYXFQ-UHFFFAOYSA-N
Pubchem ID :	20773371

Safety of [ 454482-11-2 ]

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

Computational Chemistry of [ 454482-11-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	0
Fraction Csp3	0.83
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	70.96
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	21.7 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	1.49
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.5
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.07
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	0.91
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.99

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.1
Solubility	1.79 mg/ml ; 0.00802 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.	-1.55
Solubility	6.24 mg/ml ; 0.028 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.35
Solubility	0.999 mg/ml ; 0.00448 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	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.	-6.6 cm/s

Druglikeness

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

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.65

Application In Synthesis of [ 454482-11-2 ]

* 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 [ 454482-11-2 ]

[ 454482-11-2 ] Synthesis Path-Downstream 1~35

1
[ 73183-34-3 ]
[ 180692-27-7 ]
[ 454482-11-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 15h;	A mixture of 1-methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (1.1 g, 4.47 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.24 g, 4.9 mmol), potassium acetate (1.7 mL, 17 mmol), PdCl2(dppf) (0.13 g, 0.15 mmol) and dppf (83 mg, 0.15 mmol) in 50 mL dioxane was degassed by consecutively flushing and evacuating with nitrogen 3 times. The mixture was stirred at 80° C. under nitrogen for 15 h. The reaction mixture was cooled to room temperature, diluted with 100 mL ethyl acetate and washed with H2O (2.x.25 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated and purified via flash chromatography (silica gel) eluting with a gradient of 5/1 hexanes/EtOAc to 4/1 hexanes/EtOAc to give 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine as a pale yellow solid (1.1 g). Found MS (ES+): 224 (M+H)+.
	With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 4h;	A mixture of above triflate (5.0 g, 20 mmol), bis(pinacolato)diboron (5.6 g, 22 mmol), potassium acetate (6.5 g, 66 mmol), PdCl2dppf (0.44 g, 0.6 mmol), and (dppf)2 (0.33 g, 0.6 mmol) in 60 mL of dioxane was heated at 80° C. for 4 h. The resulting mixture was cooled to RT, diluted with Et2O (150 mL). The ethereal solution was washed with H2O followed by brine. The organic layer dried over Na2SO4, concentrated, and recrystallized in hexane-Et2O to give the title intermediate.

References: [1]Patent: US2006/199817,2006,A1 .Location in patent: Page/Page column 37.
[2]Patent: US2003/225106,2003,A1 .Location in patent: Page 60; 83.

2
[ 454482-11-2 ]
[ 54962-75-3 ]
[ 453560-88-8 ]

Yield	Reaction Conditions	Operation in experiment
	With monopotassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In DMF (N,N-dimethyl-formamide); at 80℃; for 16h;	To a mixture of 4,4,5,5-tetramethyl-2-(1-methyl(4-1,2,5,6-tetrahydropyridyl))-1,3,2-dioxaborolane (1.0 g, 4.4 mmol), PdCl2pddf (0.16 g, 0.2 mmol) and K2CO3 (1.8 g, 13.2 mmol) and 3-amino-5-bromobenzotrifluoride (0.8 g, 3.3 mmol) in DMF (25 mL) was heated at 80° C. for 16 h. The resulting mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, and concentrated. The residue was purified by SiO2 chromatography to give the title intermediate. MS (ES+): 257 (M+H)+. Calc'd C13H15F3N2 - 256.3.

References: [1]Patent: US2003/225106,2003,A1 .Location in patent: Page 83.

3
[ 454482-11-2 ]
[ 909186-04-5 ]
N-cyclopropyl-4-methyl-3-(1-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phthalazin-6-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 90℃; for 2h;	A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.1 g, 0.3 mmol), <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (70 mg, 0.3 mmol) and tetrakis(triphenylphosphine)palladium (0.03 g, 0.03 mmol) in 10 mL DME/EtOH (4:1) was treated with 2 M potassium carbonate (0.6 mL, 1.2 mmol). The mixture was stirred at 90° C. for 2 h. The mixture was cooled to room temperature, diluted with 100 mL DCM, washed with sat. NaHCO3, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified via flash chromatography (silica gel) eluting with a gradient of 2percent 2 M ammonia in MeOH/DCM to 6percent 2 M ammonia in MeOH/DCM to give N-cyclopropyl-4-methyl-3-(1-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phthalazin-6-yl)benzamide (0.10 g) as a pale yellow solid. Found MS (ES+): 399(M+H)+.

References: [1]Patent: US2006/199817,2006,A1 .Location in patent: Page/Page column 37.

4
[ 454482-11-2 ]
[ 886762-08-9 ]
[ 1034618-10-4 ]

Yield	Reaction Conditions	Operation in experiment
65%	With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃; for 3h;	Example 43; 5-(l-Methyl-piperidin-4-yl)-2-trifluoromethoxy-phenylamine; Step 1. 5-(l-Methyl-l,2,3,6-tetrahydro-pyridin-4-yl)-2-trifluoromethoxy- phenylamine; 5-Bromo-2-trifluoromethoxy-phenylamine (0.43 g, 1.68 mmol), cesium carbonate (1.65 g, 5.06 mmol), 1 , r-bis(diphenylphosphino)ferrocenepalladium(ii) dichloride, complex with dichloromethane (1 :1) (0.08g, 0.1 mmol) in dry DMF (20 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. A solution of l-methyl-4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-l,2,3,6-tetrahydro-pyridine (0.45 g, 2.01 mmol) in dry DMF (10 mL) were added to the suspension and the reaction mixture warmed at 80 0C for 3 hours. The reaction mixture was then allowed to cool to room temperature, diluted with water (100 mL) and extracted with DCM (2 x 50 mL) and the combined <n="102"/>organic phases were extracted with IN HCl solution (50 rnL). The aqueous layer was basifed by addition of sodium bicarbonate and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, the solvent removed under reduced pressure and the crude solid purified by flash chromatography on silica gel (eluant: DCM/MeOH 90/10) to afford the intermediate as a light brown solid (0.3 g, 65 percent yield)1H NMR (400 MHz, DMSO-J6) delta ppm 2.29 (s, 3 H) 2.38 - 2.44 (m, 2 H) 2.58 (t, J=5.55 Hz, 2 H) 3.02 (d, J=2.32 Hz, 2 H) 5.29 (s, 2 H) 6.03 (t, J=3.48 Hz, 1 H) 6.64 (dd, J=8.54, 2.19 Hz, 1 H) 6.86 (d, J=2.32 Hz, 1 H) 7.03 (dd, J=8.54, 1.34 Hz, 1 H).

References: [1]Patent: WO2008/74788,2008,A1 .Location in patent: Page/Page column 100-101.

5
[ 39856-50-3 ]
[ 454482-11-2 ]
[ 1346673-24-2 ]

Yield	Reaction Conditions	Operation in experiment
26%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 85℃; for 12h;	Add to the reaction flask5-bromo-2-nitropyridine (20.3 g, 0.1 mol)1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaboride-2-yl) -1,2,3,6-tetrahydropyridine (22.3 g , 0.1 mol), cesium carbonate (65 g, 0.2 mol), Pd (dppf) Cl2 (7.33 g,0.01 mol) and dioxane / water (250 mL / 30 mL).The mixture was heated and stirred at 85 ° C for 12 hours, cooled to room temperature, concentrated under reduced pressure,The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 1: 1)To give the title compound (5.7 g, white solid) in 26percent yield.
26%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 85℃; for 12h;Inert atmosphere;	Cesium carbonate ([Cs2CO3] 66.00g, 0.2mol) and Pd(dppf)Cl2 (7.33g, 0.01mol) were added to a solution of 82 5-bromo-2-nitropyridine (20.30g, 0.1mol) and 110 <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (22.30g, 0.1mol) in 111 dioxane/112 H2O (250 mL/30mL). The mixture was allowed to stir at 85°C for 12h under nitrogen (N2). Then the solution was cooled to RT, concentrated under a vacuum, and purified by silica gel column chromatography (from 102 PE/86 EA=1:1 to 103 DCM/87 MeOH=20:1) to obtain 113 1?-methyl-6-nitro-1?,2?,3?,6?-tetrahydro-3,4?-bipyridine (5.70g; yield, 26percent) as a white solid. Next, Pd/C (0.10g) was added to the solution of 1?-methyl-6-nitro-1?,2?,3?,6?-tetrahydro-3,4?-bipyridine (657.0mg, 3.0mmol) in EA/MeOH (10 mL/10mL). The mixture was degassed by flushing with H2, stirred at RT under a H2 atmosphere for 2h, and then filtered and concentrated under a vacuum to obtain INT-4 (550.0mg; yield, 96percent) as a white solid. ESI-MS: m/z 192.2 [M+H]+.
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 10h;	To a round-bottomed flask equipped with a stirring bar, l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine (1.50 g, 6.72 mmol), 5- bromo-2-nitropyridine (1.64 g, 8.07 mmol), Pd(PPh3)4 (388 mg, 0.336 mmol), Na2C03 aqueous solution (1.0 N, 20.2 mL, 20.2 mmol), dioxane (60.6 mL) were added. The reaction mixture was heated at 100 °C for 10 hrs. CH2CI2 (200 mL) was added to the resulting mixture was washed with water (30 mL X 3). CH2CI2 (200 mL) was added and the resulting mixture was washed with water (30 mL X 3), brine (30 mL X 1), dried over MgS04, filtered, and removed solvent in vacuo. Silica gel column chromatography (MeOH: DCM = 5: 95) gave 5- (l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-2-nitropyridine (130a) as a yellow solid.

5.7 g

With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 85℃; for 12h;Inert atmosphere;

A reaction flask was charged with 5-bromo-2-nitropyridine (20.3 g, 0.1 mol), <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (22.3 g, 0.1 mol), dioxane/water (250 mL/30 mL), cesium carbonate (66 g, 0.2 mol) and Pd(dppf)Cl2 (7.33 g, 0.01 mol). The mixture was stirred to react at 85°C under the protection of nitrogen gas for 12 h. The reaction product was cooled to room temperature, concentrated and separated by column chromatography (PE/EA = 1:1 to DCM/MeOH = 20:1) to give the titled product (5.7 g, white solid). MS (ESI): mass calcd. for C11H13N3O2 219.1, m/z found 220.1 [M+H]+.

References: [1]Patent: CN106608879,2017,A .Location in patent: Paragraph 0470-0473.
[2]European Journal of Medicinal Chemistry,2018,vol. 144,p. 1 - 28.
[3]Patent: WO2011/140488,2011,A1 .Location in patent: Page/Page column 183.
[4]Patent: EP3385262,2018,A1 .Location in patent: Paragraph 0200; 0201; 0202.

6
[ 454482-11-2 ]
5-(1-methylpiperidin-4-yl)pyridin-2-amine [ No CAS ]

References: [1]Patent: WO2011/140488,2011,A1 .

7
[ 454482-11-2 ]
[ 1346673-26-4 ]

References: [1]Patent: WO2011/140488,2011,A1 .

8
[ 454482-11-2 ]
[ 1346673-27-5 ]

References: [1]Patent: WO2011/140488,2011,A1 .

9
[ 454482-11-2 ]
[ 1346669-79-1 ]

References: [1]Patent: WO2011/140488,2011,A1 .

10
[ 454482-11-2 ]
[ 1383703-43-2 ]
[ 1383703-25-0 ]

Yield	Reaction Conditions	Operation in experiment
	With cesium fluoride;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 150℃; for 0.166667h;Inert atmosphere; Microwave irradiation;	Example 104: 5-(1 -methyl-1 ,2,3,6-tetrahvdropyridin-4-yl)-3-{1 -r4-(morpholin-4- ylcarbonyl)phenvn-1 H-1 ,2,3-triazol-4-yl)-1 H-indazoleA suspension of {4-[4-(5-Bromo-1 H-indazol-3-yl)-[1 ,2,3]triazol-1-yl]-phenyl}-morpholin-4- yl-methanone (150 mg; 0.33 mmol; 1.0 eq.), 1-Methyl-1 ,2,3,6-tetrahydropyridine-4-boronic acid, pinacol ester (Boron Molecular, 221 mg; 0.99 mmol; 3.0 eq.), PdCI2(PPh3)2 (23 mg; 0.03 mmol; 0.10eq.), cesium fluoride (151 mg; 0.99 mmol; 3.0 eq.) in dioxane (3 mL) and water (1.5 mL) was degassed with nitrogen flow and heat in MW at 150°C for 10 min. The reaction mixture was filtered through a celite pad, water was added to the filtrate. Aqueous phase was extracted three time with DCM using separators tubes. Combined organic phases were concentrated under reduced pressure and the crude was purified by flash chromatography on silica (DCM/MeOH , gradient from 100:0 to 90: 10) to give the title compound as a yellow powder. 1 H NMR (300 MHz, DMSO) delta 13.36 (brs, 1 H), 9.39 (s, 1 H), 8.31 (s, 1 H), 8.15 (d, J = 8.0 Hz, 2H), 7.78-7.47 (m, 4H), 6.32-6.11 (m, 1 H), 3.84-3.49 (m, 6H), 3.46-3.25 (m, 2H), 3.1 1-2.98 (m, 2H), 2.71-2.58 (m, 4H), 2.30 (s, 3H). HPLC (Condition A): Rt 2.22 min (purity 94.5percent). MS (ESI+): 470.3, MS(ESI-): 468.3

References: [1]Patent: WO2012/84704,2012,A1 .Location in patent: Page/Page column 186-187.

11
[ 454482-11-2 ]
[ 1383703-43-2 ]
[ 1383703-45-4 ]

References: [1]Patent: WO2012/84704,2012,A1 .

12
[ 454482-11-2 ]
[ 1421371-97-2 ]
[ 1421371-96-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; for 2h;Inert atmosphere; Reflux;	A mixture of 4-bromo-2-methoxy-5-nitroaniline (Intermediate 4, 1.112 g, 4.5 mmol), <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine</strong> (1.004 g, 4.50 mmol) and K2CO3 (2.488 g, 18.00 mmol) was stirred in 1,4-dioxane (20 mL) and water (5 mL). The mixture was purged with N2 for 0.25h. Tetrakis(triphenylphosphine)palladium(0) (0.052 g, 0.05 mmol) was then added and the mixture was heated at reflux for 2h. The mixture was then cooled, filtered and the filtrate was concentrated in vacuo to give an aqueous mixture. This mixture was dissolved in EtOAc and water and the phases were separated. The aqueous solution was extracted with EtOAc. The combined organic solutions were then extracted twice with 2M HCl (40 mL). The aqueous solutions were basified with 2M Na2CO3 (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in a mixture of CH2Cl2 and 2N methanolic ammonia (10:1, 10 mL) and the solution was filtered through a silica plug. The filtrate was concentrated in vacuo to give an oil which subsequently crystallised. Trituration with isohexane and diethyl ether (1:1, 5 mL) and collection of the resulting solid by filtration gave the title compound (1.093 g, 92percent) as a yellow crystalline solid; 1H NMR: 2.23 (2H, dd), 2.27 (3H, s), 2.53 (2H, t), 2.93 (2H, d), 3.87 (3H, s), 5.27 (2H, s), 5.42-5.53 (1H, m), 6.65 (1H, s), 7.23 (1H, s); m/z: ES+ MH+ 264.

References: [1]Patent: WO2013/14448,2013,A1 .Location in patent: Page/Page column 85.

13
[ 454482-11-2 ]
[ 1421373-00-3 ]
[ 1421372-99-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere;	1,1?-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (16.7 mg, 0.03 mmol) was added to a solution of 1-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (139 mg, 0.62 mmol), 4-bromo-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 137, 215 mg, 0.52 mmol), and K3PO4 (220 mg, 1.04 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL, degassed for 20 minutes prior to use). The mixture was then heated at 100°C for1h and then concentrated in vacuo. The resulting residue was dissolved in EtOAc and this solution was washed three times with water, then with brine. The solution was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10percent methanolic ammonia in CH2Cl2 gave the title compound (160 mg, 72percent) as a tan solid after trituration with diethyl ether; 1H NMR: 1.79-1.87 (2H, m), 1.96-2.03 (2H, m), 2.29 (3H, s), 2.34-2.40 (2H, m), 2.58 (2H, t), 2.98-3.02 (2H, m), 3.15 (2H, t), 3.75 (3H, s), 4.12 (2H, t), 4.32 (2H, br s), 5.67-5.71 (1H, m), 6.60 (1H, s), 7.01 (1H, d), 7.58 (1H, s), 7.69 (1H, s), 8.09 (1H, s), 8.32 (1H, d); m/z: ES+ MH+ 432.72.

References: [1]Patent: WO2013/14448,2013,A1 .Location in patent: Page/Page column 141.

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[ 1421373-07-0 ]
[ 1421373-06-9 ]

Yield	Reaction Conditions	Operation in experiment
84%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere;	1,1 Bis(di-tert-butylphosphino)ferrocene palladium dichloride (16.74 mg, 0.03 mmol) was added to a solution containing 1-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (139 mg, 0.62 mmol), 4-bromo-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 144, 220 mg, 0.52 mmol), and K3PO4 (220 mg, 1.04 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL, degassed for 20 minutes prior to use). The mixture was heated at 100°C for1h and then concentrated in vacuo. The resulting residue was dissolved in EtOAc. This solution was washed with water (x3), brine, and was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10percent methanolic ammonia in CH2Cl2 gave the title compound (191 mg, 84percent) as a tan solid after trituration with diethyl ether; 1H NMR: 2.31 (3H, s), 2.37-2.43 (2H, m), 2.61 (2H, t), 3.01-3.04 (2H, m), 3.76 (3H, s), 3.89 (3H, s), 4.37 (2H, br s), 5.70-5.73 (1H, m), 6.63 (1H, s), 7.18-7.22 (2H, m), 7.25-7.29 (1H, m), 7.54 (1H, d), 7.63 (1H, s), 7.81 (1H, s), 8.31 (1H, d), 8.34 (1H, s), 8.46 (1H, d); m/z: ES+ MH+ 441.57.

References: [1]Patent: WO2013/14448,2013,A1 .Location in patent: Page/Page column 144; 145.

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[ 454482-11-2 ]
[ 1421373-89-8 ]