885693-20-9|tert-Butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate| Ambeed

Structure of 885693-20-9

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Quality Control of [ 885693-20-9 ] Purity: 97% SDS Specification

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Product Details of [ 885693-20-9 ]

CAS No. :	885693-20-9
Formula :	C₁₆H₂₈BNO₄
M.W :	309.21
SMILES Code :	O=C(N1CCC=C(B2OC(C)(C)C(C)(C)O2)C1)OC(C)(C)C
MDL No. :	MFCD10697911
InChI Key :	KEEIJBAOTMNSEN-UHFFFAOYSA-N
Pubchem ID :	49835909

Safety of [ 885693-20-9 ]

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

Computational Chemistry of [ 885693-20-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	22
Num. arom. heavy atoms	0
Fraction Csp3	0.81
Num. rotatable bonds	4
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	91.9
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	48.0 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	2.34
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.8
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.	1.54
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	1.18
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.57

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.97
Solubility	0.333 mg/ml ; 0.00108 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.	-2.99
Solubility	0.318 mg/ml ; 0.00103 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.84
Solubility	0.448 mg/ml ; 0.00145 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.	-6.52 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	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)	4.13

Application In Synthesis of [ 885693-20-9 ]

* 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 [ 885693-20-9 ]

[ 885693-20-9 ] Synthesis Path-Downstream 1~35

1
[ 180691-65-0 ]
[ 73183-34-3 ]
[ 885693-20-9 ]

Yield	Reaction Conditions	Operation in experiment
71%	With 1,1'-bis-(diphenylphosphino)ferrocene; potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 16h;	PdCl2dppf (0.16 g, 0.22 mmol), KOAc (2.18 g, 22.2 mmol), 4,4,5,5,4',4',5',5'- octamethyl-[2,2']bi[[l,3,2]dioxaborolanyl] (2.07 g, 8.13 mmol), and dppf (0.12 g, 0.22 mmol) were placed in a round-bottomed flask, and the flask was flushed with Ar. A degassed solution of 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (as prepared in the previous step, 2.45 g, 7.40 mmol) in dioxane (70 mL) was added to the flask and heated to 80 0C for 16 h. The mixture was filtered through a glass-fritted funnel to remove the solid KOAc, and the filtrate was concentrated in vacuo. Silica gel chromatography (5 percent EtOAc in hexanes) afforded the title compound (1.62 g, 71 percent) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): delta 6.69-6.60 (m, IH), 3.98 (br s, 2H), 3.49-3.42 (m, 2H), 2.24-2.16 (m, 2H), 1.47 (s, 9H), 1.27 (s, 12H). LC-MS (ESI, m/z): Calcd. for Ci8H28BNO4 310.2 (M+H), found 311.0.
71%	With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 16h;	PdCl2dppf (0.16 g, 0.22 mmol), KOAc (2.18 g, 22.2 mmol), 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (2.07 g, 8.13 mmol), and dppf(0.12 g, 0.22 mmol) were placed in a round-bottomed flask, and the flask was flushed with Ar. A degassed solution of 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 2.45 g, 7.40 mmol) in dioxane (70 mL) was added to the flask and heated to 80° C. for 16 h. The mixture was filtered through a glass-fritted funnel to remove the solid KOAc, and the filtrate was concentrated in vacuo. Silica gel chromatography (5percent EtOAc in hexanes) afforded the title compound (1.62 g, 71percent) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): delta 6.69-6.60 (m, 1H), 3.98 (br s, 2H), 3.49-3.42 (m, 2H), 2.24-2.16 (m, 2H), 1.47 (s, 12H). LC-MS (ESI, m/z): Calcd. for C18H28BNO4 310.2 (M+H), found 311.0.
71%	With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 16h;	b) 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester PdCl2dppf (0.16 g, 0.22 mmol), KOAc (2.18 g, 22.2 mmol), 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (2.07 g, 8.13 mmol), and dppf (0.12 g, 0.22 mmol) were placed in a round-bottomed flask, and the flask was flushed with Ar. A degassed solution of 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 2.45 g, 7.40 mmol) in dioxane (70 mL) was added to the flask and heated to 80° C. for 16 h. The mixture was filtered through a glass-fritted funnel to remove the solid KOAc, and the filtrate was concentrated in vacuo. Silica gel chromatography (5percent EtOAc in hexanes) afforded the title compound (1.62 g, 71percent) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): delta 6.69-6.60 (m, 1H), 3.98 (br s, 2H), 3.49-3.42 (m, 2H), 2.24-2.16 (m, 2H), 1.47 (s, 9H), 1.27 (s, 12H). LC-MS (ESI, m/z): Calcd. for C18H28BNO4 310.2 (M+H). found 311.0.

71%	With 1,1'-bis(diphenylphosphino)ferrocene; potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 16h;	PdCl2dppf (0.16 g, 0.22 mmol), KOAc (2.18 g, 22.2 mmol), 4,4,5,5,4',4',5',5'- octamethyl-[2,2']bi[[l,3,2]dioxaborolanyl] (2.07 g, 8.13 mmol), and dppf (0.12 g, 0.22 mmol) were placed in a round-bottomed flask, and the flask was flushed with Ar. A degassed solution of 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-l- carboxylic acid tert-butyl ester (as prepared in the previous step, 2.45 g, 7.40 mmol) in dioxane (70 mL) was added to the flask and heated to 80 0C for 16 h. The mixture was filtered through a glass-fritted funnel to remove the solid KOAc, and the filtrate was concentrated in vacuo. Silica gel chromatography (5 percent EtOAc in hexanes) afforded the title compound (1.62 g, 71 percent) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): delta 6.69-6.60 (m, IH), 3.98 (br s, 2H), 3.49-3.42 (m, 2H), 2.24-2.16 (m, 2H), 1.47 (s, 9H), 1.27 (s, 12H). LC-MS (ESI, m/z): Calcd. for C18H28BNO4 310.2 (M+H), found 311.0.
70%	With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 18h;Inert atmosphere;	Step 2 To a degassed solution of 5-trifluoromethanesulfonyloxy-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (340 mg, 1.0 mmol, 1 eq) in dioxane (10 mL) was added bis-(pinacolato)-diboron (287 mg, 1.1 mmol, 1.1 eq), potassium acetate (302 mg, 3.0 mmol, 3 eq), 1,1'-bis(diphenylphosphino)ferrocene (17 mg, 0.03 mmol, 0.03 eq) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium) (23 mg, 0.03 mmol, 0.03 eq) were added. The mixture was stirred at 80° C. for 18 h. After cooling down, the mixture was filtered and the filtrate was concentrated and purified by flash chromatography using cyclohexane and ethyl acetate (100/0 to 96/4) to afford the corresponding boronic ester (225 mg, 70percent yield).
64%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃;Inert atmosphere;	To a solution of tert-butyl 3-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine- l(2H)- carboxylate (503-2) (1.4 g, 4.3 mmol), BPin ( 1.3 g, 5.1 mmol) and KOAc (1.26 g, 12.9 mmol) in dioxane (10 mL) was added Pd(dppf)Cl2.DCM (351 mg, 0.43 mmol). The resulting mixture was purged with N2 X 3 and heated to 80 °C overnight. The solvent was removed in vacuo and the residue was purified by column chromatography (silica gel, 0 to 10percent EA in PE) to give tert-butyl 3-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (503-3) (850 mg, 64percent) as a yellow oil.
42%	With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-acetone complex; In 1,4-dioxane; at 80℃; for 12h;	To a high pressure vessel was added 5-trifluoromethanesulfonyloxy-3,6- dihydro-2H-pyridine- l-carboxylic acid tert-butyl ester (1.0 g, 3.0 mmol), dichloro[l ,l '- bis(diphenylphosphino)ferrocene]palladium (II) acetone adduct (0.2 g, 0.3 mmol), Iota , - bis(diphenylphosphino)ferrocene (0.2 g, 0.3 mmol), bis(pinacolato)diboron (0.84 g, 3.3 mmol) and K2OAc (0.89 g, 9.0 mmol) in 1 ,4-dioxane (7 mL, 90 mmol). The reaction was heated for 12 h at 80 °C. After cooling to RT, the mixture was diluted with EtOAc, the organic phase was concentrated in vacuo, and the residue purified by column chromatography to afford the named compound (42percent). .H NMR (CDC13, 400 MHz): delta 6.57 (br. s., 1H), 3.91 (br. s., 2H), 3.39 (t, J = 5.81 Hz, 2H), 2.13 (br. s., 2H), 1.39-1.41 (m, 9H), 1.19 (s, 12H).
41%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 85℃; for 4h;Inert atmosphere;	A mixture of tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (3.5 g, 14.5 mmol), Pd(dppf)Cl2 (0.38 g, 0.53 mmol), bis(pinacolato)diboron (3.9 g, 15.8 mmol), and KOAc (3.1 g, 31.5 mmol) in anhydrous DMF was degassed and purged with nitrogen three times. The mixture was heated at 85° C. for 4 h. After cooling down to room temperature, the reaction was diluted with ethyl acetate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography to afford tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.4 g, 41percent) as a colorless oil.
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃;	To a 25 mL round bottom flask charged with bis(pinacolato)diboron (1.50 g, 6 mmol), potassium acetate (1.5 g, 15 mmol), Pd(dppf)Cl2 (408 mg, 0.5 mmol) and DPPF (277 mg, 0.5 mmol). Compound 195 (1.55 g, 5.0 mmol) in dioxane 20 mL) was added to the above mixture. The mixture was degassed thoroughly and placed under argon. This resulting mixture was then heated at 80° C. for overnight, diluted with EtOAc (40 mL) and filtered through celite. After concentration, the residue was purified with column chromatography (silica gel, Hexane/EtOAc=60/40) to give the product (832 mg) as an oil. HPLC-MS tR=2.41 min (UV254 nm), mass calculated for formula C16H28BNO4, 309.2; observed MH+-t-Bu (LCMS) 254.2(m/z).
	With potassium acetate; In 1,4-dioxane;	Preparation 5: tert-butyl 5-(3H-pyrroIo[3,2-fJ[l,7]naphthyridin-9-yl)-3,6-dihydro-2H- pyridine-l-carboxylate (36) The compound 36 is prepared according to the procedure described in patent applications WO 2007/146838 and WO 2010/059771
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃;Inert atmosphere;	5-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester[370] A mixture of Bis(pinacolato)diboron (0.864 g, 3.40 mmol), (1 ,1'-bis-(diphenyl- phosphino)ferrocene)palladium (0.29 g, 0.39 mmol), potassium acetate (0.642 g, 6.54 mmol) and 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester(0.600 g, 1.81 mmol) in 1 ,4-dioxane (20 ml.) was degassed and refilled with N2 three times.The resulting material was stirred at 80 °C for overnight. The reaction mixture was filtrated through a celite pad, concentrated in vacuo and purified by silica gel (Hexanes: EtOAc = 9:1 , v:v) to afford the desired product. 1H NMR (400 MHz, CDCI3): delta = 1.38 (s, 9 H), 2.01-2.19 (m,2 H), 3.28-3.41 (m, 2 H), 3.89 (d, J = 2.23 Hz, 2 H), 6.55 (br. s., 1 H).

References: [1]Patent: WO2006/47277,2006,A2 .Location in patent: Page/Page column 97.
[2]Patent: US2006/281788,2006,A1 .Location in patent: Page/Page column 73.
[3]Patent: US2008/51402,2008,A1 .Location in patent: Page/Page column 60.
[4]Patent: WO2007/48088,2007,A2 .Location in patent: Page/Page column 115.
[5]Patent: US2013/102601,2013,A1 .Location in patent: Paragraph 184.
[6]Patent: WO2016/4272,2016,A1 .Location in patent: Paragraph 00654.
[7]Patent: WO2011/29046,2011,A1 .Location in patent: Page/Page column 122; 123.
[8]Patent: US2018/72743,2018,A1 .Location in patent: Paragraph 1625-1626.
[9]Patent: US2007/105864,2007,A1 .Location in patent: Page/Page column 180.
[10]Patent: WO2012/127506,2012,A1 .Location in patent: Page/Page column 68-69.
[11]Patent: WO2010/59771,2010,A1 .Location in patent: Page/Page column 47.

2
[ 885693-24-3 ]
[ 885693-20-9 ]
5-[5-(1-acetyl-piperidin-4-yl)-2-amino-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%		A solution of 5-(4,4,5,5-tetramethyl-[ 1,3, 2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester (as prepared in Example 46, step (b), 0.62 g, 2.02 mmol) and l-[4-(4-amino-3-bromo-phenyl)-piperidin-l-yl]-ethanone (as prepared in the previous step, 0.20 g, 0.67 mmol) in toluene:EtOEta (2:1, 9 mL) was treated with 2.0 M aqueous Na2CO3 (2.7 mL, 5.38 mmol) and was degassed with sonication under Ar. The mixture was heated to 80 0C, treated with Pd(PPh3)4 (54 mg, 0.05 mmol), and stirred at 80 °C for 4.5 h. The reaction was cooled to room temperature, diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and EPO <DP n="101"/>concentrated in vacuo to afford the title compound (0.25 g, 93 percent) as an off-white solid. LC-MS (ESI, m/z): Calcd. for C23H33N3O3 422.2 (M+Na), found 422.0.
93%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 4.5h;	A solution of <strong>[885693-20-9]5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester</strong> (as prepared in Example 46, step (b), 0.62 g, 2.02 mmol) and 1-[4-(4-amino-3-bromo-phenyl)-piperidin-1-yl]-ethanone (as prepared in the previous step, 0.20 g, 0.67 mmol) in toluene:EtOH (2:1, 9 mL) was treated with 2.0 M aqueous Na2CO3 (2.7 mL, 5.38 mmol) and was degassed with sonication under Ar. The mixture was heated to 80° C., treated with Pd(PPh3)4 (54 mg, 0.05 mmol), and stirred at 80° C. for 4.5 h. The reaction was cooled to room temperature, diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.25 g, 93percent) as an off-white solid. LC-MS (ESI, m/z): Calcd. for C23H33N3O3 422.2 (M+Na), found 422.0.
93%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 4.5h;	f) 5-[5-(1-Acetyl-piperidin-4-yl)-2-amino-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester A solution of <strong>[885693-20-9]5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester</strong> (as prepared in Example 46, step (b), 0.62 g, 2.02 mmol) and 1-[4-(4-amino-3-bromo-phenyl)-piperidin-1-yl]-ethanone (as prepared in the previous step, 0.20 g, 0.67 mmol) in toluene:EtOH (2:1, 9 mL) was treated with 2.0 M aqueous Na2CO3 (2.7 mL, 5.38 mmol) and was degassed with sonication under Ar. The mixture was heated to 80° C., treated with Pd(PPh3)4 (54 mg, 0.05 mmol), and stirred at 80° C. for 4.5 h. The reaction was cooled to room temperature, diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.25 g, 93percent) as an off-white solid. LC-MS (ESI, m/z): Calcd. for C23H33N3O3 422.2 (M+Na). found 422.0.

93%

With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 4.5h;

A solution of 5-(4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1 -carboxylic acid tert-butyl ester (as prepared in Example 46, step (b), 0.62 g, 2.02 mmol) and l-[4-(4-amino-3-bromo-phenyl)-piperidin-l-yl]-ethanone (as prepared in the previous step, 0.20 g, 0.67 mmol) in toluene:EtOH (2:1, 9 mL) was treated with 2.0 M aqueous Na2COs (2.7 mL, 5.38 mmol) and was degassed with sonication under Ar. The mixture was heated to 80 0C, treated with Pd(PPh3)4 (54 mg, 0.05 mmol), and stirred at 80 °C for 4.5 h. The reaction was cooled to room temperature, diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.25 g, 93 percent) as an off-white solid. LC-MS (EST, m/z): Calcd. for C23H33N3O3 422.2 (M+Na), found 422.0.

References: [1]Patent: WO2006/47277,2006,A2 .Location in patent: Page/Page column 99-100.
[2]Patent: US2006/281788,2006,A1 .Location in patent: Page/Page column 74-75.
[3]Patent: US2008/51402,2008,A1 .Location in patent: Page/Page column 61.
[4]Patent: WO2007/48088,2007,A2 .Location in patent: Page/Page column 117.

3
[ 885693-20-9 ]
[ 887475-71-0 ]
[ 887475-83-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃;	To a 25 mL round bottom flask charged with boronate 197 (456 mg, 1.5 mmol), K2CO3 (800 mg, 6 mmol), and Pd(dppf)Cl2 (160 mg, 0.2 mmol) was added a solution of product from example 177(360 mg, 1.5 mmol) in DMF (10 mL). The mixture was degassed thoroughly and placed under argon. This resulting mixture was then heated at 80° C. overnight. The reaction mixture was diluted with EtOAc (40 mL) and filtered through Celite. After concentration, the residue was purified by column chromatography (silica gel, Hexane/EtOAc=60/40) to give the product 198 (258 mg) as an oil. HPLC-MS tR=1.91 min (UV254 nm); mass calculated for formula C17H22N4O2S, 346.1; observed MH+ (LCMS) 347.2 (m/z).

References: [1]Patent: US2007/105864,2007,A1 .Location in patent: Page/Page column 180.

4
[ 98977-36-7 ]
[ 885693-20-9 ]

References: [1]Patent: WO2011/29046,2011,A1 .
[2]Patent: WO2012/127506,2012,A1 .
[3]Patent: WO2016/4272,2016,A1 .
[4]Patent: US2017/174641,2017,A1 .
[5]Patent: US2018/72743,2018,A1 .
[6]Patent: US2013/102601,2013,A1 .
[7]Patent: WO2010/59771,2010,A1 .

5
[ 885693-20-9 ]
[ 1227611-86-0 ]
[ 1227611-56-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 66: 3-[(S)-1-(2,6-Dichloro-3-fluorophenyl)ethyl]-5-(1 ,2,5,6-tetrahydropyridin- 3-yl)-1H-pyrrolo[2,3-b]pyridine[368] A mixture of 5-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2/-/-pyridine-1- carboxylic acid tert-butyl ester (0.0154 g, 0.0498 mmol), ((S)-I -{5-Bromo-3-[(S)-1 -(2,6- dichloro-3-fluorophenyl)ethyl]pyrrolo[2,3-b]pyridine-1-carbonyl}-3-methyl-butyl)-carbamic acid 9/-/-fluoren-9-ylmethyl ester (0.020 g, 0.028 mmol), Pd(PPh3)4 (0.0048 g, 0.0041 mmol) and K2CO3 (0.0172 g, 0.124 mol) in DME (1.2 mL) and H2O (0.3 mL) was stirred at 100 °C under microwave condition for 30 min. The reaction mixture was directly loaded onto Prep TLC (5percent MeOH in DCM) to afford 10 mg crude product. The crude product was dissolved in DCM (2 mL) and treated with 4 M HCl in dioxane for 2 h at rt. The resulting solution was loaded onto a Prep TLC (20x20 cm plate, silica gel 500 muM, 5percent 7 N NH3 in MeOH in DCM) to afford the desired product. 1H-NMR (CD3OD, 400 MHz): delta = 1.86 (d, J = 7.1 Hz, 3 H), 2.30 (m, 2 H), 2.99 (t, J = 5.9 Hz, 2 H), 3.58 (m, 2 H), 5.26 (m, 1 H), 5.97-6.07 (m, 1 H), 7.15-7.24 (m, 2 H), 7.37 (d, J = 1.3 Hz, 1 H), 8.15 (d, J = 2.0 Hz, 1 H). MS (ES+): m/z 390.07 (MH+, 35CI), 392.02(MH+, 37CI), HPLC: tR = 2.50 min (ZQ3, polar_5min).

References: [1]Patent: WO2010/59771,2010,A1 .Location in patent: Page/Page column 46-47.

6
[ 26218-75-7 ]
[ 885693-20-9 ]
[ 1271809-16-5 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 12h;	To a high pressure vessel was added 5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-l -carboxylic acid tert-bu yX ester (1.0 g, 3.2 mmol), methyl 6- bromopicolinate (0.77 g, 3.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.3 mmol), 1 M of sodium carbonate in water (9.7 mL, 9.7 mmol) and DME (10.1 mL, 97.0 mmol). The reaction was heated for 12 h at 80 °C,then cooled to RT and diluted with water and EtOAc. The organic phase was separated, dried (Na2SC>4), filtered and concentrated in vacuo. The crude material was purified by column chromatography (gradient hexane-EtOAc) to afford the named compound (0.71 g, 70percent yield). .H NMR (CDC13, 300 MHz): delta 7.79 (d, J = 7.55 Hz, 1H), 7.72 (t, J = 7.93 Hz, 1H), 7.44 (d, J = 8.31 Hz, 1H), 4.32-4.41 (m, 1H), 3.90-3.96 (s, 3H), 3.55-3.64 (m, 2H), 2.50 (br. s., 2H), 1.84-1.95 (m, 2H), 1.48 (s, 12H). EIMS (m/z): calcd. for Ci7H2204N2 (M-C4H9, +1H) 263, found 263.

References: [1]Patent: WO2011/29046,2011,A1 .Location in patent: Page/Page column 122; 123.

7
[ 885693-20-9 ]
[ 1271802-77-7 ]

References: [1]Patent: WO2011/29046,2011,A1 .

8
[ 885693-20-9 ]
[ 1271809-18-7 ]

References: [1]Patent: WO2011/29046,2011,A1 .

9
4,4,4',4',5,5,5'-heptamethyl-2,2'-bi(1,3,2-dioxaborolane) [ No CAS ]
[ 98977-36-7 ]
[ 885693-20-9 ]
[ 1121057-77-9 ]