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Chemical Structure| 1403257-80-6

Chemical Structure| 1403257-80-6

Chemical Structure| 1403257-80-6

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5-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide

CAS No.: 1403257-80-6

4.5 *For Research Use Only !

Cat. No.: A773420 Purity: 98% (contains 2-3%DCM)

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Quality Control of [ 1403257-80-6 ] Purity: 98% (contains 2-3%DCM) SDS Specification MOL

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Product Details of [ 1403257-80-6 ]

CAS No. :	1403257-80-6
Formula :	C₂₃H₃₀BrN₃O₃
M.W :	476.41
SMILES Code :	O=C(NCC1=C(C)C=C(C)NC1=O)C2=CC(Br)=CC(N(CC)C3CCOCC3)=C2C
MDL No. :	MFCD28167870
InChI Key :	FADJTYGNEWCCFM-UHFFFAOYSA-N
Pubchem ID :	66576790

Safety of [ 1403257-80-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338

Calculated chemistry of [ 1403257-80-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	30
Num. arom. heavy atoms	12
Fraction Csp3	0.48
Num. rotatable bonds	7
Num. H-bond acceptors	3.0
Num. H-bond donors	2.0
Molar Refractivity	124.36
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	74.43 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	3.55
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	3.78
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.85
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	2.93
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	5.41
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.9

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-5.01
Solubility	0.00467 mg/ml ; 0.00000979 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-5.04
Solubility	0.00438 mg/ml ; 0.00000919 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	-7.74
Solubility	0.00000863 mg/ml ; 0.0000000181 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Poorly 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	Yes
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	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	Yes
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	Yes
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.52 cm/s

Druglikeness

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

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<2.0
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)	3.4

Application In Synthesis [ 1403257-80-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 1403257-80-6 ]
Downstream synthetic route of [ 1403257-80-6 ]

[ 1403257-80-6 ] Synthesis Path-Upstream 1~1

1
[ 1403257-80-6 ]
[ 364794-79-6 ]
[ 1403254-99-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With sodium carbonate In 1,4-dioxane; water; acetonitrile at 100℃; for 4 h; Inert atmosphere	Step 7: Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (14 g, 29.5 mmol) in dioxane/water mixture (70 mL/14 mL) was added 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (13.4 g, 44.2 mmol) followed by addition of Na₂CO₃ (11.2 g, 106.1 mmol). The solution was purged with argon for 15 minutes and then Pd (PPh₃)₄ (3.40 g, 2.94 mmol) was added and the solution was again purged with argon for a further 10 min. The reaction mixture was heated at 100° C. for 4 h. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with 10percent MeOH/DCM. The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with methanol: DCM to the title compound as a solid (12 g, 71percent). Analytical Data: LCMS: 573.35 (M+1)⁺; HPLC: 99.5percent ( 254 nm) (R_t; 3.999; Method: Column: YMC ODS-A 150 mm4.6 mm5μ; Mobile Phase: A; 0.05percent TFA in water/B; 0.05percent TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5percent B to 95percent B in 8 min, Hold for 1.5 min, 9.51-12 min 5percent B); ¹H NMR (DMSO-d₆, 400 MHz) δ 11.46 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.36-7.39 (m, 3H), 7.21 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=2.8 Hz), 3.82 (d, 2H, J=9.6 Hz), 3.57 (bs, 4H), 3.48 (s, 2H), 3.24 (t, 2H, J=10.8 Hz), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.36 (m, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
71%	Stage #1: With sodium carbonate In 1,4-dioxane; water for 0.25 h; Inert atmosphere Stage #2: With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In 1,4-dioxane at 100℃; for 4.2 h; Inert atmosphere	[0336] Step 7: Synthesis of N-((4, 6-dimethyl-2-oxo-l, 2-dihydropyridin-3-yl) methyl)-5- (ethyl (tetrahydro-2H-pyran-4-yl) amino)-4-methyl-4'-(morpholinomethyl)-[l, l'-biphenyl]-3- carboxamide [0337] To a stirred solution of 5-bromo-N-((4, 6-dimethyl-2-oxo-l, 2-dihydropyridin-3-yl) methyl)-3-(ethyl (tetrahydro-2H-pyran-4-yl) amino)-2-methylbenzamide (14 g, 29.5 mmol) in dioxane/ water mixture (70 mL/14 mL) was added 4-(4-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) benzyl) morpholine (13.4 g, 44.2 mmol) followed by addition of Na₂C0₃ (11.2 g, 106.1 mmol). The solution was purged with argon for 15 minutes and then Pd (PPh )₄ (3.40 g, 2.94 mmol) was added and the solution was again purged with argon for a further 10 min. The reaction mixture was heated at 100°C for 4 h. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with 10percent MeOH/DCM. The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100- 200 mesh silica gel) eluting with methanol: DCM to the title compound as a solid (12 g, 71 percent). Analytical Data: LCMS: 573.35 (M + 1)⁺; HPLC: 99.5percent ( 254 nm) (R,;3.999; Method: Column: YMC ODS-A 150 mm x 4.6 mm x 5 μ; Mobile Phase: A; 0.05percent TFA in water/ B; 0.05percent TFA in acetonitrile; Inj. Vol: 10 μ, Col. Temp.: 30 °C; Flow rate: 1.4 mL/min.; Gradient: 5percent B to 95percent B in 8 min, Hold for 1.5 min, 9.51-12 min 5percent B); 1H NMR (DMSO-J₆, 400 MHz) δ 11.46 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.36-7.39 (m, 3H), 7.21 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=2.8 Hz), 3.82 (d, 2H, J=9.6 Hz), 3.57 (bs, 4H), 3.48 (s, 2H), 3.24 (t, 2H, J=10.8Hz), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.36 (m, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
71%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In 1,4-dioxane; water at 100℃; for 4 h; Inert atmosphere	N - [(4,6- dimethyl-2-carboxy-1,2-dihydro-3-pyridyl) methyl] -2-methyl-3- [ethyl (tetrahydro -2H- 4- pyran-yl) amino] -5-carboxamide bromobenzene (14g, 29.5mmol) was dissolved in dioxane / water mixture (70mL /14mL), added with stirring 4- (4-morpholino-methyl) phenylboronic acid pinacol ester (13.4g, 44.2mmol), followed by the addition of sodium carbonate (11.2g, 105.7mmol). Solution was purged with argon for 15min, then add tetrakis (triphenylphosphine) palladium (3.40g, 2.94mmol), a solution of purified argon and then 10min. The reaction mixture was heated to 100 reaction 4h. Tracking progress of the reaction TLC, eluent: methanol / dichloromethane (1:10), add water, 50mL, methanol / dichloromethane: extraction (19). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on silica gel column, eluent: methanol / dichloromethane (1:10) to give a solid product 12g, Yield 71percent

References: [1] Patent: US2012/264734, 2012, A1, . Location in patent: Page/Page column 128.
[2] Patent: WO2013/155464, 2013, A1, . Location in patent: Paragraph 0336; 0337.
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1556 - 1564.
[4] Patent: CN105440023, 2016, A, . Location in patent: Paragraph 0090; 0091; 0092.

[ 1403257-80-6 ] Synthesis Path-Downstream 1~25

1
[ 1403257-80-6 ]
[ 5720-05-8 ]
[ 1403255-82-2 ]

Yield	Reaction Conditions	Operation in experiment
73%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere;	Example 112 Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4,4'-dimethyl-[1,1'-biphenyl]-3-carboxamide To a stirred solution <strong>[1403257-80-6]5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide</strong> (200 mg, 0.42 mmol) and p-tolyl boronic acid (86 mg, 0.63 mmol) in dioxane (3 mL), aqueous 2M Na2CO3 solution (0.75 mL, 1.51 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (48 mg, 0.04 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100 C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (150 mg, 73%). LCMS: 488.20 (M+1)+; HPLC: 99.33% ( 254 nm) (Rt; 5.393; Method: Column: YMC ODS-A 150 mm4.6 mm5mu; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 muL, Col. Temp.: 30 C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) delta 11.46 (s, 1H), 8.19 (t, 1H), 7.51 (d, 2H, J=8 Hz), 7.37 (s, 1H), 7.25 (d, 2H, J=8 Hz), 7.19 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 3.81-3.83 (m, 2H), 3.22-3.27 (m, 2H), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.55 (m, 2H), 0.82 (t, 3H, J=6.8 Hz).

References: [1]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 156-157.

2
[ 1403257-80-6 ]
[ 73183-34-3 ]
[ 1403258-56-9 ]

Yield	Reaction Conditions	Operation in experiment
27%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 7h;	Step 2: Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide To a stirred mixture of <strong>[1403257-80-6]5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide</strong> (1.0 g, 2.1 mmol), bispinacolato diboron (2.67 g, 10.5 mmol) and potassium acetate (610 mg, 6.31 mmol) in dioxane (10 mL) was purged with argon for 15 min. Then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (85 mg, 0.10 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 80 C. for 7 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the desired compound (250 mg, 27%).

References: [1]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 176.

3
[ 1403257-80-6 ]
[ 59016-93-2 ]
[ 1403255-83-3 ]

Yield	Reaction Conditions	Operation in experiment
62%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere;	Example 113 Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4'-(hydroxymethyl)-4-methyl-[1,1'-biphenyl]-3-carboxamide To a stirred solution of <strong>[1403257-80-6]5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide</strong> (200 mg, 0.42 mmol) and 4-(hydroxymethyl)phenylboronic acid (96 mg, 0.63 mmol) in dioxane (2.5 mL), aqueous 2M Na2CO3 solution (0.75 mL, 1.51 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (48 mg, 0.04 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100 C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (130 mg, 62%). LCMS: 504.15 (M+1)+; HPLC: 98.86% ( 254 nm) (Rt; 4.240; Method: Column: YMC ODS-A 150 mm4.6 mm5mu; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 muL, Col. Temp.: 30 C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) delta 11.45 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.39 (s, 1H), 7.37 (d, 2H), 7.21 (s, 1H), 5.85 (s, 1H), 5.20 (t, 1H, J=5.2 Hz), 4.52 (d, 2H, J=5.6 Hz), 4.28 (d, 2H, J=3.6 Hz), 3.81-3.84 (m, 2H), 3.22-3.32 (m, 2H), 3.08-3.09 (m, 2H), 3.01 (m, 1H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.65-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).

References: [1]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 157.

4
3-fluoro-4-formylphenylboronic acid [ No CAS ]
[ 1403257-80-6 ]
[ 1403258-20-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere;	Step 1: Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3'-fluoro-4'-formyl-4-methyl-[1,1'-biphenyl]-3-carboxamide To a stirred solution of <strong>[1403257-80-6]5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide</strong> (300 mg, 0.63 mmol) and (3-fluoro-4-formylphenyl)boronic acid (160 mg, 0.94 mmol) in dioxane (6 mL), aqueous 2M Na2CO3 solution (1.15 mL, 2 3 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (72 mg, 0.06 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100 C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (288 mg, 88%).

References: [1]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 161-162.

5
[ 29943-42-8 ]
[ 1403257-80-6 ]

References: [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 1556 - 1564.
[2]Patent: CN105440023,2016,A .
[3]Patent: WO2018/81530,2018,A1 .

6
[ 1403257-80-6 ]
[ 87199-17-5 ]
[ 1403258-06-9 ]

Yield	Reaction Conditions	Operation in experiment
66%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere;	Step 3: Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4'-formyl-4-methyl-[1,1'-biphenyl]-3-carboxamide To a stirred solution of <strong>[1403257-80-6]5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide</strong> (5.0 g, 10 mmol) and (4-formylphenyl)boronic acid (2.35 g, 15.8 mmol) in dioxane/water (30 mL/10 mL) was added Na2CO3 (4.01 g, 37.9 mmol). The solution was purged with argon for 15 min., Pd(PPh3)4 (1.21 g, 1.05 mmol) and the mixture was heated at 100 C. for 2 h. The mixture was allowed to cool to room temperature, diluted with water and extracted with 10% MeOH/CH2Cl2. The combined organic layers were dried over sodium sulphate and the solvent removed under reduced pressure. The resulting crude material was purified by column chromatography over silica gel to afford N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4'-formyl-4-methyl-[1,1'-biphenyl]-3-carboxamide (3.5 g, 66%).

References: [1]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 141.

7
[ 107650-20-4 ]
[ 1403257-80-6 ]

References: [1]Patent: WO2012/142513,2012,A1 .
[2]Patent: US2012/264734,2012,A1 .
[3]Patent: WO2013/155464,2013,A1 .
[4]Patent: US2017/8904,2017,A1 .
[5]Patent: US2018/177750,2018,A1 .

8
4-(morpholine-4-carbonyl)phenylboronic acid pinacol ester [ No CAS ]
[ 1403257-80-6 ]
[ 1403255-94-6 ]

Yield	Reaction Conditions	Operation in experiment
68%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere;	Example 123 Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholine-4-carbonyl)-[1,1'-biphenyl]-3-carboxamide To a stirred solution of <strong>[1403257-80-6]5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide</strong> (300 mg, 0.63 mmol) and morpholino(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (260 mg, 0.82 mmol) in dioxane (10 mL), aqueous 2M Na2CO3 solution (1.13 mL, 2.27 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (72 mg, 0.06 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100 C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (250 mg, 68%). LCMS: 587.35 (M+1)+; HPLC: 93.85% ( 254 nm) (Rt:4.535; Method: Column: YMC ODS-A 150 mm4.6 mm5mu; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 muL, Col. Temp.: 30 C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) delta 11.46 (bs, 1H), 8.21 (t, 1H), 7.69-7.71 (m, 2H), 7.45-7.49 (m, 3H), 7.26 (s, 1H), 5.86 (s, 1H), 4.29 (d, 2H, J=4 Hz), 3.82-3.84 (m, 2H), 3.48-3.60 (m, 8H), 3.23-3.25 (m, 2H), 3.09-3.11 (m, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H), 1.52-1.68 (m, 4H), 0.83 (t, 3H, J=6.8 Hz).

References: [1]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 163.

9
[ 220514-28-3 ]
[ 1403257-80-6 ]

References: [1]Patent: WO2012/142513,2012,A1 .
[2]Patent: US2012/264734,2012,A1 .
[3]Patent: WO2013/155464,2013,A1 .
[4]Patent: US2017/8904,2017,A1 .
[5]Patent: US2018/177750,2018,A1 .

10
[ 1975-50-4 ]
[ 1403257-80-6 ]

References: [1]Patent: WO2012/142513,2012,A1 .
[2]Patent: US2012/264734,2012,A1 .
[3]Patent: WO2013/155464,2013,A1 .
[4]Patent: US2017/8904,2017,A1 .
[5]Patent: US2018/177750,2018,A1 .

11
[ 79669-49-1 ]
[ 1403257-80-6 ]

References: [1]Patent: US2012/264734,2012,A1 .

12
[ 871126-22-6 ]
[ 1403257-80-6 ]
[ 1403258-21-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere;	Step 1: Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2'-fluoro-4'-formyl-4-methyl-[1,1'-biphenyl]-3-carboxamide To a stirred solution of <strong>[1403257-80-6]5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide</strong> (300 mg, 0.62 mmol) and (2-fluoro-4-formylphenyl)boronic acid (158 mg, 0.94 mmol) in dioxane (3 mL), aqueous 2M Na2CO3 solution (1.13 mL, 2.26 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (72 mg, 0.06 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100 C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the desired compound (300 mg, 91%).

References: [1]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 162.

13
[ 1403257-80-6 ]
[ 87199-16-4 ]
[ 1403258-10-5 ]

Yield	Reaction Conditions	Operation in experiment
64%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere;	Step 1: Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3'-formyl-4-methyl-[1,1'-biphenyl]-3-carboxamide To a stirred solution of <strong>[1403257-80-6]5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide</strong> (400 mg, 0.84 mmol) and (3-formylphenyl)boronic acid (189 mg, 1.26 mmol) in dioxane (2 mL), aqueous 2M Na2CO3 solution (1.5 mL, 3.03 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (97 mg, 0.08 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100 C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (270 mg, 64%).

References: [1]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 157.

14
[ 1000342-11-9 ]
[ 1403257-80-6 ]

References: [1]Patent: WO2012/142513,2012,A1 .
[2]Patent: US2012/264734,2012,A1 .
[3]Patent: WO2013/155464,2013,A1 .
[4]Journal of Medicinal Chemistry,2016,vol. 59,p. 1556 - 1564.
[5]Patent: CN105440023,2016,A .
[6]Patent: US2017/8904,2017,A1 .
[7]Patent: WO2018/81530,2018,A1 .
[8]Patent: US2018/177750,2018,A1 .
[9]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 334 - 340.

15
[ 1073354-66-1 ]
[ 1403257-80-6 ]
[ 1403258-22-9 ]

Yield	Reaction Conditions	Operation in experiment
69.28%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere;	Step 1: Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4'-formyl-2',4-dimethyl-[1,1'-biphenyl]-3-carboxamide To a stirred solution of <strong>[1403257-80-6]5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide</strong> (400 mg, 0.84 mmol) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (310 mg, 1.26 mmol) in dioxane (2 mL), aqueous 2M Na2CO3 solution (1.5 mL, 3.03 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (97 mg, 0.08 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100 C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the desired compound (300 mg, 69.28%).

References: [1]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 163.

16
[ 1403257-49-7 ]
[ 1403257-80-6 ]

References: [1]Patent: WO2012/142513,2012,A1 .
[2]Patent: US2012/264734,2012,A1 .
[3]Patent: WO2013/155464,2013,A1 .
[4]Journal of Medicinal Chemistry,2016,vol. 59,p. 1556 - 1564.
[5]Patent: CN105440023,2016,A .
[6]Patent: US2017/8904,2017,A1 .
[7]Patent: WO2018/81530,2018,A1 .
[8]Patent: US2018/177750,2018,A1 .
[9]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 334 - 340.

17
[ 1403257-80-6 ]
[ 1403255-31-1 ]

References: [1]Patent: US2012/264734,2012,A1 .

18
[ 1403257-80-6 ]
[ 1403255-79-7 ]

References: [1]Patent: US2012/264734,2012,A1 .

19
[ 1403257-80-6 ]
[ 1403256-02-9 ]

References: [1]Patent: US2012/264734,2012,A1 .

20
[ 1403257-80-6 ]
[ 1403258-38-7 ]

References: [1]Patent: US2012/264734,2012,A1 .

21
[ 1403257-80-6 ]
[ 1403256-12-1 ]

References: [1]Patent: US2012/264734,2012,A1 .

22
[ 1403257-80-6 ]
[ 364794-79-6 ]
[ 1403254-99-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; acetonitrile; at 100℃; for 4h;Inert atmosphere;	Step 7: Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide To a stirred solution of <strong>[1403257-80-6]5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide</strong> (14 g, 29.5 mmol) in dioxane/water mixture (70 mL/14 mL) was added 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (13.4 g, 44.2 mmol) followed by addition of Na2CO3 (11.2 g, 106.1 mmol). The solution was purged with argon for 15 minutes and then Pd (PPh3)4 (3.40 g, 2.94 mmol) was added and the solution was again purged with argon for a further 10 min. The reaction mixture was heated at 100 C. for 4 h. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with methanol: DCM to the title compound as a solid (12 g, 71%). Analytical Data: LCMS: 573.35 (M+1)+; HPLC: 99.5% ( 254 nm) (Rt; 3.999; Method: Column: YMC ODS-A 150 mm4.6 mm5mu; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 muL, Col. Temp.: 30 C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) delta 11.46 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.36-7.39 (m, 3H), 7.21 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=2.8 Hz), 3.82 (d, 2H, J=9.6 Hz), 3.57 (bs, 4H), 3.48 (s, 2H), 3.24 (t, 2H, J=10.8 Hz), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.36 (m, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
71%		[0336] Step 7: Synthesis of N-((4, 6-dimethyl-2-oxo-l, 2-dihydropyridin-3-yl) methyl)-5- (ethyl (tetrahydro-2H-pyran-4-yl) amino)-4-methyl-4'-(morpholinomethyl)-[l, l'-biphenyl]-3- carboxamide [0337] To a stirred solution of 5-bromo-N-((4, 6-dimethyl-2-oxo-l, 2-dihydropyridin-3-yl) methyl)-3-(ethyl (tetrahydro-2H-pyran-4-yl) amino)-2-methylbenzamide (14 g, 29.5 mmol) in dioxane/ water mixture (70 mL/14 mL) was added 4-(4-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) benzyl) morpholine (13.4 g, 44.2 mmol) followed by addition of Na2C03 (11.2 g, 106.1 mmol). The solution was purged with argon for 15 minutes and then Pd (PPh )4 (3.40 g, 2.94 mmol) was added and the solution was again purged with argon for a further 10 min. The reaction mixture was heated at 100C for 4 h. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100- 200 mesh silica gel) eluting with methanol: DCM to the title compound as a solid (12 g, 71 %). Analytical Data: LCMS: 573.35 (M + 1)+; HPLC: 99.5% ( 254 nm) (R,;3.999; Method: Column: YMC ODS-A 150 mm x 4.6 mm x 5 mu; Mobile Phase: A; 0.05% TFA in water/ B; 0.05% TFA in acetonitrile; Inj. Vol: 10 mu, Col. Temp.: 30 C; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-J6, 400 MHz) delta 11.46 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.36-7.39 (m, 3H), 7.21 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=2.8 Hz), 3.82 (d, 2H, J=9.6 Hz), 3.57 (bs, 4H), 3.48 (s, 2H), 3.24 (t, 2H, J=10.8Hz), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.36 (m, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
71%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere;	N - [(4,6- dimethyl-2-carboxy-1,2-dihydro-3-pyridyl) methyl] -2-methyl-3- [ethyl (tetrahydro -2H- 4- pyran-yl) amino] -5-carboxamide bromobenzene (14g, 29.5mmol) was dissolved in dioxane / water mixture (70mL /14mL), added with stirring 4- (4-morpholino-methyl) phenylboronic acid pinacol ester (13.4g, 44.2mmol), followed by the addition of sodium carbonate (11.2g, 105.7mmol). Solution was purged with argon for 15min, then add tetrakis (triphenylphosphine) palladium (3.40g, 2.94mmol), a solution of purified argon and then 10min. The reaction mixture was heated to 100 reaction 4h. Tracking progress of the reaction TLC, eluent: methanol / dichloromethane (1:10), add water, 50mL, methanol / dichloromethane: extraction (19). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on silica gel column, eluent: methanol / dichloromethane (1:10) to give a solid product 12g, Yield 71%

References: [1]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 128.
[2]Patent: WO2013/155464,2013,A1 .Location in patent: Paragraph 0336; 0337.
[3]Journal of Medicinal Chemistry,2016,vol. 59,p. 1556 - 1564.
[4]Patent: CN105440023,2016,A .Location in patent: Paragraph 0090; 0091; 0092.

23
[ 1403257-80-6 ]
[ 847818-55-7 ]
[ 1403255-78-6 ]

Yield	Reaction Conditions	Operation in experiment
50%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere;	Example 109 Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)benzamide To a stirred solution of <strong>[1403257-80-6]5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide</strong> (0.2 g, 0.42 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (0.105 g, 0.505 mmol) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (0.16 g, 1.51 mmol) was added and solution purged with argon for 15 min. Pd (PPh3)4 (0.048 g, 0.042 mmol) was then added and the reaction mixture again purged with argon for 10 min. The reaction mixture was heated at 100 C. for 2 h. The reaction mixture was then diluted with water and extracted with 10% MeOH/DCM. The combined extracts were dried over Na2SO4 and the solvent removed under reduced pressure to afford the crude product which was purified by column chromatography to afford the title compound (0.100 g, 50%). LCMS: 478.20 (M+1)+; HPLC: 95.82% ( 254 nm) (Rt; 4.322; Method: Column: YMC ODS-A 150 mm4.6 mm5mu; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 muL, Col. Temp.: 30 C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) delta 11.45 (s, 1H), 8.12 (s, 1H), 8.10 (t, 1H), 7.81 (s, 1H), 7.33 (s, 1H), 7.13 (s, 1H), 5.86 (s, 1H), 4.27 (d, 2H, J=4.8 Hz), 3.81-3.83 (m, 5H), 3.21-3.26 (m, 2H), 2.98-3.08 (m, 3H), 2.20 (s, 3H), 2.17 (s, 3H), 2.10 (s, 3H), 1.63-1.66 (m, 2H), 1.48-1.52 (m, 2H), 0.86 (t, 3H, J=7.2 Hz).

References: [1]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 154.

24
[ 70799-12-1 ]
[ 1403257-80-6 ]
[ 1403255-32-2 ]

Yield	Reaction Conditions	Operation in experiment
53.8%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere;	Step 3: Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4'-((dimethylamino)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-[1,1'-biphenyl]-3-carboxamide To a stirred solution of <strong>[1403257-80-6]5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide</strong> (0.2 g, 0.42 mmol) and (4-((dimethylamino)methyl)phenyl)boronic acid (0.15 g, 0.505 mmol) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (0.16 g, 1.51 mmol) was added and the solution purged with argon for 15 min. Pd (PPh3)4 (0.048 g, 0.042 mmol) was the added and the reaction mixture again purged with argon for 10 min. The reaction mixture was heated at 100 C. for 2 h. The reaction mixture was then diluted with water and extracted with 10% MeOH/DCM. The combined extracts were dried over Na2SO4 and the solvent removed under reduced pressure to afford the crude product which was purified by column chromatography over silica gel to afford the title compound (0.120 g, 53.8%). LCMS: 531.30 (M+1)+; HPLC: 94.88% ( 254 nm) (Rt; 3.949; Method: Column: YMC ODS-A 150 mm4.6 mm5mu; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 muL, Col. Temp.: 30 C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) delta 11.45 (s, 1H), 8.19 (t, 1H, J=4.4 Hz), 7.61 (d, 2H, J=8 Hz), 7.39-7.41 (m, 3H), 7.23 (s, 1H), 5.86 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.62-3.84 (m, 4H), 3.22-3.38 (m, 2H), 3.02-3.06 (m, 3H), 2.30 (bs, 6H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.8 Hz).

References: [1]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 140.

25
[ 771579-27-2 ]
[ 1403257-81-7 ]
[ 1403257-80-6 ]

Yield	Reaction Conditions	Operation in experiment
74%		[01779] The above acid (10 g, 29 mmol) was then dissolved in DMSO (25 mL) and 3-(amino methyl)-4, 6-dimethylpyridin-2(l H)-one (8.8 g, 58 mmol) and triethyl amine (5.6 g, 58 mmol) was added. The reaction mixture was stirred at room temperature for 15 min before PYBOP (22 g, 43.8 mmol) was added and stirring was continued overnight. The mixture was poured into ice and extracted with 10 % MeOH/DCM. The combined organic layers were dried and concentrated to obtain crude material which was purified by solvent washings to afford the title compound (14 g, 74 %).
74%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In dimethyl sulfoxide; at 20℃;	Step 6: Synthesis of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide To a stirred solution of 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (14 g, 39.4 mmol) in ethanol (100 mL) was added aqueous NaOH (2.36 g, 59.2 mmol in 25 mL water) and the resulting mixture was stirred at 60 C. for 1 h. Upon completion of the reaction as determined by TLC, the solvent was removed under reduced pressure and the residue obtained was acidified with 1N HCl until a pH 7 was obtained and then aqueous citric acid solution was added until a pH 5-6 was obtained. The aqueous layer was extracted with 10% MeOH in DCM (200 mL3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the respective acid (14 g, 100%). The above acid (14 g, 40.9 mmol) was then dissolved in DMSO (70 mL) and 3-(amino methyl)-4,6-dimethylpyridin-2(1H)-one (12.4 g, 81.9 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 minutes, then PYBOP (31.9 g, 61.4 mmol) was added and stirring was continued for overnight at room temperature. Upon completion of the reaction as determined by TLC, the reaction mixture was poured onto ice-cold water (700 mL), stirred for 30 minutes and the precipitated solid was collected by filtration, washed with water (500 mL) and air dried. The solid obtained was stirred with acetonitrile (75 mL2), filtered and air dried. The solid obtained was again stirred with 5% MeOH in DCM (100 mL), filtered and dried completely under vacuum to afford the title compound as a solid (14 g, 74%). 1H NMR (DMSO-d6, 400 MHz) delta 11.47 (s, 1H), 8.23 (t, 1H), 7.30 (s, 1H), 7.08 (s, 1H), 5.85 (s, 1H), 4.23 (d, 2H, J=4.4 Hz), 3.81 (d, 2H, J=10.4 Hz), 3.20-3.26 (m, 2H), 3.00-3.07 (m, 1H), 2.91-2.96 (m, 2H), 2.18 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.58-1.60 (m, 2H), 1.45-1.50 (m, 2H), 0.78 (t, 3H, J=6.8 Hz).
74%		Carboxylic acid (13.44g, 39.4mmol) was dissolved in 70mLDMSO, and added with stirring 4,6-dimethyl-3-aminomethyl-pyridinePyridine -2 (1H) - one (12.4g, 81.9mmol). Stirred at room temperature 15min, then add hexafluorophosphate, benzotriazol-1-yl - yloxy tripyrrolidinophosphonium phosphorus (PYBOP) (31.9g, 61.4mmol), stirred at room temperature overnight, until the reaction was complete (developing solvent: ethyl acetate / ethanol = 5: 1), the reaction mixture was poured into 700mL ice water, stirred for 30min, to obtain a solid by suction filtration, washed with a 500 mL of water, and dried under vacuum dryer, the resulting solid was added with stirring acetonitrile (75mL × 2), suction, vacuum dryer. The resulting solid was combined with 100mL stirring methanol / dichloromethane (5:95), filtration, and dried under reduced pressure to obtain a solid product was thoroughly 14g, Yield 74%

30%		5-Bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl) amino)-2-methylbenzoic acid (0.5 g, 1.5 mmol) was dissolved in DMF (5 mE), and 3-(amino methyl)-4,6-dimeth- ylpyridin-2(1H)-one (0.45 g, 2.9 mmol) and DIEA (0.84 g, 5.8 mmol) were added. The reaction mixture was stirred at room temperature for 15 minutes, and then PYI3OP (1.6 g, 3.0 mmol) was added. The mixture was stirred at room temperature for 3 hours. Upon the completion of the reaction as determined by TEC, the reaction mixture was poured onto an ice-cold water (150 mE). The mixture was stirred for another 10 minutes and the solid was collected by filtration. The solid was washed with water (50 mE) and dried by air. Then the solid was slurried in 5% MeOH in DCM solution to afford desired product 5-l3romo-N-((4,6-dimethyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamideas a solid (200 mg,30%). 1H NMR: (DMSO-d6, 400 MHz) delta 11.46 (s, 1H),8.21 (s, 1H), 7.31 (s, 1H), 7.09 (s, 1H), 5.86 (s, 1H), 4.26 (d,J=4.4 Hz, 2H), 3.83 (d, J=9.60 Hz, 2H), 3.20-3.27 (m, 2H), 3.00-3.02 (m, 3H), 2.19 (s, 3H), 2.15 (s, 3H), 2.11(s, 3H),1.48-1.62 (m, 4H), 0.78 (t, J=6.8 Hz, 3H). Chemical Formula: C23H3013rN3O3; Molecular Weight: 476.41. Total H count from ?HNMR data: 30.
		[0333] Step 6: Synthesis of 5-bromo-N-((4, 6-dimethyl-2-oxo-l, 2-dihydropyridin-3-yl) methyl)-3-(ethyl (tetrahydro-2H-pyra -4-yl) amino)-2-methylbenzamide [0334] To a stirred solution of 5-bromo-3-(ethyl (tetrahydro-2H-pyran-4-yl) amino)-2- methylbenzoate (14 g, 39.4 mmol) in ethanol (100 mL) was added aqueous NaOH (2.36 g, 59.2 mmol in 25mL water) and the resulting mixture was stirred at 60 C for 1 h. Upon completion of the reaction as determined by TLC, the solvent was removed under reduced pressure and the residue obtained was acidified with IN HC1 until a pH 7 was obtained and then aqueous citric acid solution was added until a pH 5-6 was obtained. The aqueous layer was extracted with 10% MeOH in DCM (200mL X 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the respective acid (14 g, 100%). [0335] The above acid (14 g, 40.9 mmol) was then dissolved in DMSO (70 mL) and 3- (amino methyl)-4, 6-dimethylpyridin-2(lH)-one (12.4 g, 81.9 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 minutes, then PYBOP (31.9 g, 61.4 mmol) was added and stirring was continued for overnight at room temperature. Upon completion of the reaction as determined by TLC, the reaction mixture was poured onto ice- cold water (700 mL), stirred for 30 minutes and the precipitated solid was collected by filtration, washed with water (500 mL) and air dried. The solid obtained was stirred with acetonitrile (75mL X 2), filtered and air dried. The solid obtained was again stirred with 5% MeOH in DCM (lOOmL), filtered and dried completely under vacuum to afford the title compound as a solid (14 g, 74 %). 1H NMR (DMSO-J6, 400 MHz) delta 11.47 (s, 1H), 8.23 (t, 1H), 7.30 (s, 1H), 7.08 (s, 1H), 5.85 (s, 1H), 4.23 (d, 2H, J=4.4 Hz), 3.81 (d, 2H, J=10.4 Hz), I l l 3.20-3.26 (m, 2H), 3.00-3.07 (m, 1H), 2.91-2.96 (m, 2H), 2.18 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.58-1.60 (m, 2H), 1.45-1.50 (m, 2H), 0.78 (t, 3H, J=6.8 Hz).
200 mg		The acid from step 6 (0.5 g, 1.5 mmol) was dissolved in DMF (5 mL), and 3-(amino methyl)-4,6-dimethylpyridin-2(1H)-one (0.45 g, 2.9 mmol) and DIEA (0.84 g, 5.8 mmol) were added. The reaction mixture was stirred at room temperature for 15 minutes, and then PYBOP (1.6 g, 3.0 mmol) was added. The mixture was stirred at room temperature for 3 h. Upon the completion of the reaction as determined by TLC, the reaction mixture was poured onto ice-cold water (150 mL). The mixture was stirred for another 10 minutes and the solid was collected by filtration. The solid was washed with water (50 mL) and dried by air. Then the solid was slurried in 5% MeOH in DCM solution to afford desired product as a solid (200 mg, 30%). 1H NMR (DMSO-d6, 400 MHz) delta 11.46 (s, 1H), 8.21 (s, 1H), 7.31 (s, 1H), 7.09 (s, 1H), 5.86 (s, 1H), 4.26 (d, J=4.4 Hz, 2H), 3.83 (d, J=9.60 Hz, 2H), 3.20-3.27 (m, 2H), 3.00-3.02 (m, 3H), 2.19 (s, 3H), 2.15 (s, 3H), 2.11 (s, 3H), 1.48-1.62 (m, 4H), 0.78 (t, J=6.8 Hz, 3H).

References: [1]Patent: WO2012/142513,2012,A1 .Location in patent: Page/Page column 462.
[2]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 127-128.
[3]Patent: CN105440023,2016,A .Location in patent: Paragraph 0086; 0087; 0089.
[4]Patent: US2018/177750,2018,A1 .Location in patent: Paragraph 1258-1262.
[5]Patent: WO2013/155464,2013,A1 .Location in patent: Paragraph 0333; 0334; 0335.
[6]Patent: US2017/8904,2017,A1 .Location in patent: Paragraph 0422; 0430.
[7]Patent: WO2018/81530,2018,A1 .Location in patent: Page/Page column 103.
[8]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 334 - 340.

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Technical Information

• Benzylic Oxidation • Birch Reduction • Blanc Chloromethylation • Friedel-Crafts Reaction • Hydrogenolysis of Benzyl Ether • Preparation of Alkylbenzene • Preparation of Amines • Reactions of Benzene and Substituted Benzenes • Vilsmeier-Haack Reaction

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P378
P380	Evacuate area.
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H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
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H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
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Health hazards
Code	Phrase
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H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
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H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere