70298-89-4|2,2-Dimethyl-N-pyridin-4-yl-propionamide| Ambeed

Structure of 70298-89-4

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Quality Control of [ 70298-89-4 ] Purity: 97% SDS Specification

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Product Details of [ 70298-89-4 ]

CAS No. :	70298-89-4
Formula :	C₁₀H₁₄N₂O
M.W :	178.23
SMILES Code :	CC(C)(C)C(NC1=CC=NC=C1)=O
MDL No. :	MFCD00996248
Boiling Point :	No data available
InChI Key :	JCMMVFHXRDNILC-UHFFFAOYSA-N
Pubchem ID :	427059

Safety of [ 70298-89-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 70298-89-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.4
Num. rotatable bonds	3
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	52.71
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	41.99 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.82
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	1.9
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.88
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.88
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	1.57
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.61

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.29
Solubility	0.923 mg/ml ; 0.00518 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.	-2.4
Solubility	0.702 mg/ml ; 0.00394 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	-3.23
Solubility	0.104 mg/ml ; 0.000585 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	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	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.	-6.04 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	1.0
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<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)	1.2

Application In Synthesis of [ 70298-89-4 ]

* 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 [ 70298-89-4 ]
Downstream synthetic route of [ 70298-89-4 ]

[ 70298-89-4 ] Synthesis Path-Upstream 1~1

1
[ 70298-89-4 ]
[ 138116-34-4 ]

References: [1] Patent: WO2013/13817, 2013, A1, .
[2] Patent: US2013/29961, 2013, A1, .

[ 70298-89-4 ] Synthesis Path-Downstream 1~35

1
[ 504-24-5 ]
[ 3282-30-2 ]
[ 70298-89-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; In dichloromethane; at 20℃; for 15h;	a) Synthesis of 2,2-dimethyl-N-pyridin-4-yl-propionamide 4-pyridylamine (2 g, 21.3 mmol) was dissolved in dichloromethane (20 ml), and pyvaloyl chloride (3.1 ml, 25.6 mmol) and triethylamine (8.9 mg, 63.9 mmol) were added thereto in this order at room temperature dropwise. The reaction solution was stirred at room temperature for 15 hours and the reaction was quenched by adding water. The organic layer was extracted with ethyl acetate, and then the combined organic layer was washed with saturated saline solution (50 ml), dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluding with a solvent of dichloromethane: methanol=20:1. The fractions containing the product were collected and evaporated to obtain the target compound as white solid (3.6 g, 95%). 1H-NMR (CDCl3, 300 MHz); delta=8.47 (d, J=6.1 Hz, 2H), 7.79 (br s, 1H), 7.52 (d, J=6.0 Hz, 2H), 1.32 (s, 9H).
74%	With triethylamine; In dichloromethane;	Example 25A 2,2-dimethyl-N-pyridin-4-ylpropanamide A mixture of 4-aminopyridine (10 g, 106 mmol) and pivaloyl chloride (12.9 g, 107 mmol) in 200 mL dichloromethane was cooled to 0 C. and treated slowly with triethylamine (10.9 g, 108 mmol), warmed to room temperature, stirred overnight, and diluted with water. The aqueous layer was extracted three times with dichloromethane and the combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The product was recrystallized from toluene to provide the desired product (14 g, 74%).
74%	With triethylamine; In dichloromethane; at 0 - 20℃;	Example 25A 2,2-dimethyl-N-pyridin-4-ylpropanamide A mixture of 4-aminopyridine (10 g, 106 mmol) and pivaloyl chloride (12.9 g, 107 mmol) in 200 mL dichloromethane was cooled to 0 C. and treated slowly with triethylamine (10.9 g, 108 mmol), warmed to room temperature, stirred overnight, and diluted with water. The aqueous layer was extracted three times with dichloromethane and the combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The product was recrystallized from toluene to provide the desired product (14 g, 74%).

73%	With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;	EXAMPLES EXAMPLE 1: Preparation of 2, 2-Dimethyl-N-pyridinyl-propionamides 1A : 2, 2-Dimethyl-N-pyridin-4-yl-propionamide [081] Following procedures generally taught in J. A. Turner, J. Org. Chem. 1983, 48, 3401- 3408, a solution of pivaloyl chloride (13.5 mL, 110 mmol) in CH2C12 (20 mL) was slowly added to an ice-cold solution of 4-aminopyridine (9.41 g, 100 mmol) and triethylamine (17.4 mL, 125 mmol) in CH2C12 (150 mL). After addition was complete, the resulting mixture was warmed to room temperature and stirred for 2 h. The solution was poured into water, the CH2C12 layer was washed with dilute NaHC03, dried over Na2SO4, and evaporated to leave a light brown solid. Recrystallization from EtOAc/hexanes afforded the product as a white crystal, which was collected by vacuum filtration (13.03 g, 73%). 1H NMR (400 MHz, CDC13) 8 8. 50 (d, J= 4.8 Hz, 2 H), 7.50 (d, J= 4.8 Hz, 2 H), 7.44 (br s, 1 H), 1. 33 (s, 9 H). MS (LR-APCI) calcd. for CloH1sN20 (M+H) 179.1 ; found 179.1.
73.9%	With triethylamine; In chloroform; at 0 - 20℃; for 1.16667h;	To a stirred solution of 4-amino pyridine (A; 5 g, 53.12 mmol) in CHCI3 (200 mL) were added triethylamine (TEA or Et3N) (11.5 mL, 106.2 mmol) followed by pivaloyl chloride (7.15 mL, 69 mmol) dropwise at 0C over a period of 10 minutes (min). The reaction mixture was warmed to RT and stirred for 1.5 hours (h). The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was washed with saturated sodium bicarbonate (NaHC03) solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. The obtained crude material was purified by silica gel column chromatography eluting with 10% methanol (MeOH)/dichloromethane (CH2CI2) to afford B (7 g, 73.9%) as an off-white solid. *H NMR (200 MHz, DMSO-de): delta 9.54 (bs, NH), 8.40 (d, J = 5.8 Hz, 2H), 7.67 (d, / = 6.4 Hz, 2H), 1.23 (s, 9H). MS (ESI): m/z 179 [M++l].
70%	With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;	To a solution of 1 .88 g (20.0 mmol, 1 eq.) of 4-aminopyridine and 3.6 mL (26.0 mmol, 1 .3 eq.) of triethylamine in 30 mL of DCM, cooled to 0C, were added 2.7 mL (22.0 mmol, 1 .1 eq.) of trimethylacetyl chloride in 4 mL of DCM. After 2 hours, the mixture was stirred one hour at room temperature. Then, 40 mL of water were added. The aqueous layer was extracted with 20 mL of dichloromethane. The organic phase was washed with 20 mL of aqueous NaHC03, dried, filtered and concentrated. Recrystallisation in PE/EtOAc 8:1 provided 2.50 g (14.0 mmol, 70%) of VII as a white solid. Rf=0.07 (PE/EtOAc 2:1 ). 1H NMR (300 MHz): delta = 8.46 (d, J = 5.5 Hz, 2 H), 7.73 (broad, 1 H), 7.49 (dd, J = 4.9 Hz, J = 1 .4 Hz, 2 H), 1 .30 (s, 9 H) ppm. 13C NMR (75 MHz): delta = 177.5, 150.7, 145.3, 1 13.9, 40.1 , 27.5 ppm
70%	With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;	To a solution of 1.88 g (20.0 mmol, 1 eq.) of 4-aminopyridine and 3.6 mL (26.0 mmol, 1 .3 eq.) of triethylamine in 30 mL of DCM, cooled to 0C, were added 2.7 mL (22.0 mmol, 1 .1 eq.) of trimethylacetyl chloride in 4 mL of DCM. After 2 hours, the mixture was stirred one hour at room temperature. Then, 40 mL of water were added. The aqueous layer was extracted with 20 mL of dichloromethane. The organic phase was washed with 20 mL of aqueous NaHC03, dried, filtered and concentrated. Recrystallisation in PE/EtOAc 8:1 provided 2.50 g (14.0 mmol, 70%) of VII as a white solid. Rf=0.07 (PE/EtOAc 2:1 ). 1H NMR (300 MHz): delta = 8.46 (d, J = 5.5 Hz, 2 H), 7.73 (broad, 1 H), 7.49 (dd, J = 4.9 Hz, J = 1.4 Hz, 2 H), 1.30 (s, 9 H) ppm. 13C NMR (75 MHz): delta = 177.5, 150.7, 145.3, 113.9, 40.1 , 27.5 ppm
68%	With triethylamine; In dichloromethane; at 0 - 20℃; for 18h;	A solution of trimethyl acetyl chloride (32.5 mL, 0.264 mol) in dry dichloromethane (50 mL) was added drop wise over 1 h to a stirred suspension of 4-aminopyridine (22.60 g, EPO <DP n="50"/>""0.240 ffiotra?tf &iethyf?BM?fef41.8 mL, 0.300 mol) in dry dichloromethane (360 mL) at 0 0C under nitrogen. The ice bath was removed and the reaction allowed to warm to r.t. overnight. After 17 h, the pale brown mixture was poured into water (500 mL). The organic layer was separated and washed with a dilute aqueous solution of sodium hydrogen carbonate (400 mL). The organic layer was separated, dried over sodium sulfate, filtered and the solvent evaporated in vacuo. The crude solid was recrystallized from ethyl acetate (75 mL) / hexane (50 mL), washed with diethyl ether (2 x 10 mL) and air dried to yield N-(pyridin-4-yl)pivalamide (29.11 g, 68%) as colourless plate like crystals. 1H NMR : delta (CDCl3, 400 MHz) 1.33 (s, 9 H), 7.50 (d, J = 6 Hz, 2 H), 7.56 (br. s., I H), 8.49 (d, J = 6 Hz, 2 H).
66%	With triethylamine; In dichloromethane; at 0 - 20℃; for 2.25h;	Step 1: A solution of trimethylacetylcholride (423 mg, 3.51 mmol, 1.1 eq) in dichloromethane was slowly added to an ice cooled solution of pyridin-4-amine (300 mg, 3.19 mmol) and triethylamine (0.56 mL, 3.98 mmol, 1.25 eq) of dichloromethane. The resulting mixture was stirred in and ice bath for 15 min and then at room temperature for 2 h and poured into water. The reaction mixture was washed with dilute NaHC03 dried over Na2S04, and evaporated. The crude was purified by column chromatography to give N-(pyridin-4-yl)piva.amide (377 mg, 66 %).
66%	With triethylamine; In dichloromethane; at 20℃; for 2.25h;Cooling with ice;	Step 1: A solution of trimethylacetylcholride (423 mg, 3.51 mmol, 1.1 eq) in dichloromethane was slowly added to an ice cooled solution of pyridin-4-amine (300 mg, 3.19 mmol) and triethylamine (0.56 mL, 3.98 mmol, 1.25 eq) of dichloromethane. The resulting mixture was stirred in and ice bath for 15 min and then at room temperature for 2 h and poured into water. The reaction mixture was washed with dilute NaHCO3 dried over Na2SO4, and evaporated. The crude was purified by column chromatography to give N-(pyridin-4-yl)pivalamide (377 mg, 66%).
40%		A solution of pivaloyl chloride (13.4 g, 1 1 1 mmol) in DCM (20 mL) was slowly added to a cooled (0 C) solution of pyridin-4-amine (10 g, 106 mmol) and triethylamine (26.7 g, 265 mmol) in DCM (80 mL). After addition, the icebath was removed and the resulting mixture was stirred at 20 C for 6 hours. The mixture was poured into water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic extract was washed with saturated NaHC03 solution (100 mL) and brine (100 mL), dried over MgS04, and concentrated under reduced pressure. The residue was re-crystallized from EtO Ac/petroleum ether to give the desired product as white crystals (7.9 g, 40% yield). LCMS (ESI) m/z: 179.1 [M+H+] .
	With triethylamine; In dichloromethane;	Step 1. Preparation of 2,2-Dimethyl-N-pyridin-4-yl-propionamide A solution of pivaloyl chloride (1.1 eq.) in CH2Cl2 is added to a solution of 4-aminopyridine (1 eq.) and triethylamine (1.2 eq.) in CH2Cl2, stirred at 02C for 2 h, washed with aqueous sodium bicarbonate, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography over silica gel to afford the title propionamide compound.
	With triethylamine; In dichloromethane;	Example I To a mixture of 20g of 4-Aminopyridine and 37 mL of triethylamine in 380 mL of methylene chloride is added 28.8 mL of pivaloyl chloride in a dropwise fashion. After 1 hour at room temperature the reaction mixture is washed with water and sodium bicarbonate solution, dried over magnesium sulfate and the solvent is removed in vacuo. The residue is triturated with hexane to afford 4-trimethylacetamidopyridine as a white solid.
	With triethylamine; In dichloromethane; at -78 - 20℃;	To a 1.1 M solution of 4-aminopyridine in CH2C12 at-78C was added 1.3 equiv of Et^N followed by 1.1 equiv of a 5.9 M solution of trimethylacetyl chloridein CH2C12- After allowing the reaction to warm to room temperature overnight, this mixture waspoured into a separatory funnel containing brine/CH2Cl2. The layers were separated and the aqueouslayer was extracted several times with CH2C12- The combined organic layer was dried over anhydrousNa2SO4, filtered and concentrated. The crude material was further purified by a pad of silica gel byeluting with a gradient from 60% EtOAc/hexanes to 100% EtOAc and the product was swished inhexanes twice to yield the title compound as an off-white solid. IH NMR (acetone-dg) 5 8.95 (1H, br s),8.42 (2H, dd), 7.69 (2H, dd), 1.31 (9H, s).

References: [1]Synthesis,2009,p. 2267 - 2277.
[2]Patent: US2011/28467,2011,A1 .Location in patent: Page/Page column 16.
[3]Chemistry - A European Journal,2013,vol. 19,p. 6435 - 6442.
[4]Molecules,2003,vol. 8,p. 678 - 686.
[5]European Journal of Medicinal Chemistry,2005,vol. 40,p. 15 - 23.
[6]Journal of Organic Chemistry,1983,vol. 48,p. 3401 - 3408.
[7]Patent: US2003/187026,2003,A1 .
[8]Patent: US6344/449,2002,B1 .Location in patent: Example A3a).
[9]Patent: US2003/199511,2003,A1 .Location in patent: Page/Page column 24.
[10]Patent: WO2005/56552,2005,A1 .Location in patent: Page/Page column 20-21.
[11]Patent: WO2014/117090,2014,A1 .Location in patent: Page/Page column 88-89.
[12]Patent: WO2014/198844,2014,A1 .Location in patent: Page/Page column 17; 18.
[13]Patent: WO2014/198848,2014,A2 .Location in patent: Page/Page column 16; 17.
[14]Patent: WO2006/66172,2006,A1 .Location in patent: Page/Page column 48-49.
[15]Patent: WO2013/13817,2013,A1 .Location in patent: Page/Page column 143.
[16]Patent: US2013/29961,2013,A1 .Location in patent: Paragraph 0815.
[17]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 1867 - 1880.
[18]Journal of Medicinal Chemistry,2018,vol. 61,p. 5162 - 5186.
[19]Patent: WO2012/35039,2012,A1 .Location in patent: Page/Page column 76.
[20]Tetrahedron Letters,2007,vol. 48,p. 4707 - 4710.
[21]Patent: US2003/171395,2003,A1 .
[22]Patent: EP1165555,2003,B1 .
[23]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2097 - 2102.
[24]Journal of Medicinal Chemistry,2016,vol. 59,p. 7138 - 7151.
[25]Patent: WO2004/111047,2004,A2 .Location in patent: Page 25.

2
[ 98-03-3 ]
[ 70298-89-4 ]
[ 125867-29-0 ]

References: [1]Journal of Heterocyclic Chemistry,1989,vol. 26,p. 105 - 112.

3
[ 75-77-4 ]
[ 70298-89-4 ]
[ 86847-70-3 ]

References: [1]Journal of Organic Chemistry,1983,vol. 48,p. 3401 - 3408.

4
[ 119-61-9 ]
[ 70298-89-4 ]
[ 125867-30-3 ]

References: [1]Journal of Heterocyclic Chemistry,1989,vol. 26,p. 105 - 112.

5
[ 97-77-8 ]
[ 70298-89-4 ]
[ 129333-20-6 ]

Yield	Reaction Conditions	Operation in experiment
100%		A 2.5 M solution of n-butyllithium (67.3 mL) in hexanes was added dropwise over 2 h to a stirred solution of N-(pyridin-4-yl)pivalamide (12.0 g, 0.067 mol) in tetrahydrofuran (268 mL) at -10 °C (acetone / ice 1:1) under nitrogen. The temperature was kept between -10 0C and 1 0C. Upon complete addition, the temperature returned to -10 0C and a solution of tetraethylthiuram disulfide (59.9 g, 0.202 mol) in tetrahydrofuran (180 mL) was added dropwise, rapidly. The mixture was allowed to warm to r.t., poured into water (500 mL) and extracted with diethyl ether (2 x 400 mL). The organic layers were combined, washed with brine (300 mL), then separated, dried over sodium sulfate, filtered and the solvent evaporated in vacuo to yield 4-pivalamidopyridin-3-yl diethylcarbamodithioate (21.9 g, 100percent) as an orange oil. 1H NMR : delta (CDCl3, 400 MHz) 1.28 (s, 9 H), 1.31 (t, J = 7 Hz, 3 H), 1.46 (t, J = 7 Hz, 3 H), 3.93 (q, J = 7 Hz, 2 H), 4.03 (q, /= 7 Hz, 2 H), 8.39 (d, / = 5 Hz, 1 H), 8.45 (br. s., 1 H), 8.52 (s, 1 H), 8.61 (d, J= 5 Hz, 1 H).

References: [1]Patent: WO2006/66172,2006,A1 .Location in patent: Page/Page column 49.
[2]Heterocycles,2014,vol. 88,p. 175 - 178.
[3]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 563 - 566.

6
[ 624-92-0 ]
[ 70298-89-4 ]
[ 86847-72-5 ]

References: [1]Journal of Organic Chemistry,1983,vol. 48,p. 3401 - 3408.

7
[ 6940-76-7 ]
[ 70298-89-4 ]
[ 121006-60-8 ]

References: [1]Tetrahedron Letters,1988,vol. 29,p. 5725 - 5728.

8
[ 124-38-9 ]
[ 70298-89-4 ]
[ 125867-31-4 ]

References: [1]Journal of Heterocyclic Chemistry,1989,vol. 26,p. 105 - 112.

9
[ 70298-89-4 ]
[ 100-52-7 ]
[ 125867-26-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 2.33 g (13.1 mmol, 1 eq.) of pivalamide VII and 5.9 mL (39.2 mmol, 3 eq.) of TMEDA in 105 mL of diethylether, cooled to -78°C, were added 15.7 mL (39.2 mmol, 3 eq., 2.5 M in hexane) of BuLi. After 15 minutes, the solution was brought back to -24°C and stirred 2 hours. Then, the mixture was cooled down to - 78°C before addition of 2.9 mL (28.8 mmol, 2.2 eq) of benzaldehyde in 50 mL of THF. The reaction was brought back to 0°C and stirred 2 hours before being stirred at room temperature over night. Then, 100 mL of water were added. The aqueous layer was extracted with 3 x 60 mL of dichloromethane. The organic phase was dried, filtered and concentrated. The crude mixture was purified over silica gel (PE/EtOAc 2:1 ) and the mixture (2 products, including VIII) was dissolved in 50 mL of DCM. Then, 2.30 g (26.4 mmol) of activated Mn02 were added and the reaction was refluxed 40 hours. The mixture was filtered on celite and the solvent was evaporated. The crude mixture was purified over silica gel (PE/EtOAc 1 :1 ). Then, 100 mL of 3 M aqueous HCI were added and refluxed 16 hours. The reaction was cooled down to 0°C and 50 mL of aqueous ammonia were added. The aqueous layer was extracted with 3 x 50 mL of DCM. The organic phase was dried, filtered and concentrated to yield 730 mg (3.7 mmol, 28percent) of IX as a white solid. Rf=0.12 (PE/EtOAc 1 :2). 1H NMR (300 MHz): delta = 8.58 (s, 1 H), 8.22 (d, J = 5.9 Hz, 1 H), 7.67 (m, 2 H), 7.57 (m, 1 H), 7.49 (m, 2 H), 6.60 (d, J = 5.9 Hz, 1 H), 6.56 (broad, 2 H) ppm. 13C NMR (75 MHz): delta = 198.5, 156.0, 155.6, 152.0, 139.0, 131.9, 129.3, 128.5, 115.0, 111.3 ppm
		To a solution of 2.33 g (13.1 mmol, 1 eq.) of pivalamide VII and 5.9 mL (39.2 mmol, 3 eq.) of TMEDA in 105 mL of diethylether, cooled to -78°C, were added 15.7 mL (39.2 mmol, 3 eq., 2.5 M in hexane) of BuLi. After 15 minutes, the solution was brought back to -24°C and stirred 2 hours. Then, the mixture was cooled down to - 78°C before addition of 2.9 mL (28.8 mmol, 2.2 eq) of benzaldehyde in 50 mL of THF. The reaction was brought back to 0°C and stirred 2 hours before being stirred at room temperature over night. Then, 100 mL of water were added. The aqueous layer was extracted with 3 x 60 mL of dichloromethane. The organic phase was dried, filtered and concentrated. The crude mixture was purified over silica gel (PE/EtOAc 2:1 ) and the mixture (2 products, including VIII) was dissolved in 50 mL of DCM. Then, 2.30 g (26.4 mmol) of activated Mn02 were added and the reaction was refluxed 40 hours. The mixture was filtered on celite and the solvent was evaporated. The crude mixture was purified over silica gel (PE/EtOAc 1 :1 ). Then, 100 mL of 3 M aqueous HCI were added and refluxed 16 hours. The reaction was cooled down to 0°C and 50 mL of aqueous ammonia were added. The aqueous layer was extracted with 3 x 50 mL of DCM. The organic phase was dried, filtered and concentrated to yield 730 mg (3.7 mmol, 28percent) of IX as a white solid. Rf=0.12 (PE/EtOAc 1 :2). 1H NMR (300 MHz): delta = 8.58 (s, 1 H), 8.22 (d, J = 5.9 Hz, 1 H), 7.67 (m, 2 H), 7.57 (m, 1 H), 7.49 (m, 2 H), 6.60 (d, J = 5.9 Hz, 1 H), 6.56 (broad, 2 H) ppm. 13C NMR (75 MHz): delta = 198.5, 156.0, 155.6, 152.0, 139.0, 131.9, 129.3, 128.5, 115.0, 111.3 ppm

References: [1]Journal of Heterocyclic Chemistry,1989,vol. 26,p. 105 - 112.
[2]Tetrahedron Letters,2007,vol. 48,p. 4707 - 4710.
[3]Patent: WO2014/198844,2014,A1 .Location in patent: Page/Page column 18.
[4]Patent: WO2014/198848,2014,A2 .Location in patent: Page/Page column 17.

10
[ 70298-89-4 ]
[ 874-42-0 ]
[ 125867-28-9 ]

References: [1]Journal of Heterocyclic Chemistry,1989,vol. 26,p. 105 - 112.

11
[ 70298-89-4 ]
[ 68-12-2 ]
[ 86847-71-4 ]

Yield	Reaction Conditions	Operation in experiment
69%		Example 25B N-(3-formylpyridin-4-yl)-2,2-dimethylpropanamide A mixture of Example 25A (11.4 g, 64 mmol) in 200 mL THF was cooled to -78° C., treated with 1.6 M nBuLi in hexanes (100 mL, 160 mmol), warmed to 0° C., stirred for 1 hour, treated with a solution of DMF (22 g, 215 mmol) in 100 mL THF, warmed to room temperature, stirred for 1 hour, diluted with brine, and extracted three times with ethyl acetate. The combined extracts were washed with water, washed twice with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3percent methanol/dichloromethane to provide the desired product (9.1 g, 69percent).
59%		N-(Pyridin-4-yl)pivalamide (377 mg, 2.12 mmol) was dissolved in anhydrous tetrahydrofuran under inert atmosphere and cooled to - 78 °C. Within 1 h, a 1.6 M hexane solution of buthyl-lithium (3.3 mL, 5.29 mmol, 2.5eq) was added drop wise. Then the reaction mixture was warmed to 0 °C, stirred for 3 h, and anhydrous dimethylformamide (0.5 mL, 6.35 mmol, 3eq) in anhydrous tetrahydrofuran (3 mL) was added. Subsequently, the solution was warmed to room temperature and stirred for an additional 45 min. The mixture was poured onto a mixture of 6 N HCI (5 mL) and ice (5 g). After stirring for 5 min, the solution was neutralized with K2C03 (3.3 g) and extracted with diethylether. The organic layer was dried over MgS0 and the solvent was removed in vacuo. The residue was purified bycolumnchromatography to get N-(3-formylpyridin-4-yl)pivalamide (258 mg, 59 percent).
59%		Step 2: N-(Pyridin-4-yl)pivalamide (377 mg, 2.12 mmol) was dissolved in anhydrous tetrahydrofuran under inert atmosphere and cooled to -78° C. Within 1 h, a 1.6 M hexane solution of buthyl-lithium (3.3 mL, 5.29 mmol, 2.5 eq) was added drop wise. Then the reaction mixture was warmed to 0° C., stirred for 3 h, and anhydrous dimethylformamide (0.5 mL, 6.35 mmol, 3 eq) in anhydrous tetrahydrofuran (3 mL) was added. Subsequently, the solution was warmed to room temperature and stirred for an additional 45 min. The mixture was poured onto a mixture of 6 N HCl (5 mL) and ice (5 g). After stirring for 5 min, the solution was neutralized with K2CO3 (3.3 g) and extracted with diethylether. The organic layer was dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by columnchromatography to get N-(3-formylpyridin-4-yl)pivalamide (258 mg, 59percent).

References: [1]Patent: US6344/449,2002,B1 .Location in patent: Example A3b).
[2]Patent: US2003/199511,2003,A1 .Location in patent: Page/Page column 24.
[3]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 1867 - 1880.
[4]Patent: WO2013/13817,2013,A1 .Location in patent: Page/Page column 143; 144.
[5]Patent: US2013/29961,2013,A1 .Location in patent: Paragraph 0816.
[6]Journal of Organic Chemistry,1983,vol. 48,p. 3401 - 3408.
[7]Synthesis,1999,p. 959 - 964.

12
[ 70298-89-4 ]
[ 135-02-4 ]
[ 125867-27-8 ]

References: [1]Journal of Heterocyclic Chemistry,1989,vol. 26,p. 105 - 112.

13
[ 70298-89-4 ]
[ 74-88-4 ]
[ 86847-73-6 ]

References: [1]Synthesis,2009,p. 2267 - 2277.
[2]Journal of Organic Chemistry,1983,vol. 48,p. 3401 - 3408.

14
[ 70298-89-4 ]
[ 86847-69-0 ]

References: [1]Journal of Heterocyclic Chemistry,1989,vol. 26,p. 105 - 112.
[2]Journal of Organic Chemistry,1983,vol. 48,p. 3401 - 3408.

15
[ 70298-89-4 ]
[ 113975-33-0 ]

References: [1]Journal of Organic Chemistry,1988,vol. 53,p. 2740 - 2744.

16
[ 70298-89-4 ]
[ 169205-93-0 ]

Yield	Reaction Conditions	Operation in experiment
67%		b) Synthesis of N-(3-hydroxy-4-pyridinyl)-2,2-dimethyl-propionamide 2,2-dimethyl-N-pyridin-4-yl-propionamide (1.6 g, 8.977 mol) was dissolved in anhydrous tetrahydrofuran (20 ml) under nitrogen atmosphere and then cooled to -780, and then 2.5M solution of n-butyl lithium (n-BuLi) in n-hexane (9 ml, 22.443 mmol) was added thereto dropwise and then stirred at 0.box. for 2.5 hours until yellow crystals were formed. After cooling the reaction mixture to -78.box., trimethylboron (2.5 ml, 22.443 mmol) was added thereto dropwise for 10 minutes, and the temperature was raised slowly up to .box.0. After stirring for 2 hours, acetic acid (1.9 ml) and 30percent w/w aqueous solution of hydrogen peroxide were added dropwise to the reaction solution at 0.box., and then after stirring for 30 minutes, water (1 ml) was added thereto dropwise and then stirred at room temperature for 18 hours. Water was added and the mixture was evaporated under reduced pressure, and the residue was extracted by using water and 10percent isopropanol/chloroform. The combined organic layer was treated with active carbon and the filtrate was washed with saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluding with a solvent of dichloromethane:methanol=20:1. The fractions containing the product were collected and evaporated to obtain white solid (1.16 g, 67percent). 1H-NMR (CDCl3, 300 MHz); delta=8.83 (s, 1H), 8.39 (d, J=6.0 Hz, 1H), 7.83 (s, 1H), 7.80 (d, J=6.0 Hz, 1H), 5.30 (br s, 1H), 1.35 (s, 9H).

References: [1]Patent: US2011/28467,2011,A1 .Location in patent: Page/Page column 16.
[2]Journal of Organic Chemistry,1995,vol. 60,p. 5721 - 5725.
[3]European Journal of Medicinal Chemistry,2005,vol. 40,p. 15 - 23.

17
[ 70298-89-4 ]
[ 95-92-1 ]
[ 191338-94-0 ]

Yield	Reaction Conditions	Operation in experiment
25.6%		To a stirred solution of B (3 g, 16.83 mmol) in dry THF (30 mL) was added n-BuLi (21.5 mL, 50.5 mmol, 2.3M in hexane) dropwise at -78C under an inert atmosphere. After being stirred for 30 min at 0C, a solution of diethyl oxalate (5.6 mL, 42 mmol) in dry tetrahydrofuran (THF) (5.6 mL) was added to reaction mixture at -78C. The resulting reaction mixture was warmed to room temperature (RT) and the stirring was continued for another 2 h. The reaction mixture was diluted with cold water (100 mL) and extracted with diethyl ether (2x20 mL). The combined organic phases were dried over anhydrous sodium sulfate (Na2S04), filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with 30% ethyl aceate (EtOAc)/hexane to afford C (1.2g, 25.6%) as a thick syrup. *H NMR (500 MHz, CDC13): delta 11.47 (bs, NH), 8.92 (s, 1H), 8.74 (d, / = 5.5 Hz, 1H), 8.66 (d, / = 5.5 Hz, 1H), 4.51 (q, / = 7.5 Hz, 2H), 1.45 (t, 7 = 7.5 Hz, 3H), 1.36 (s, 9H).
		To a solution of compound 13 (5.34 g, 30 mmoi) in TH (200 ml) st - ?8:0C was added dropwise / BuLi (47 ml, 75 mmoi) and the reaction was stirred for 3 hr at -10C. The reaction was cooled to ~78eC and a solution of diethyl oxalate (22 g, 150 mmoi) In THF (20 rnl) was added dropwise and the mixture was stirred overnight at room temperature. NH4CI was added, and the reaction was extracted with EtOAc, washed with brine, dried, concentrated under reduced pressure and purified by flash chromatography (silica gel/EtOAc PE 1 :10-1:8) to give the product 1.4 as a solid. MS: m/z caicd for C14H18N204 278.13, found [M+Hf 279.

References: [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 5162 - 5186.
[2]ChemMedChem,2016,vol. 11,p. 2261 - 2271.
[3]Patent: WO2014/117090,2014,A1 .Location in patent: Page/Page column 88-89.
[4]Journal of Heterocyclic Chemistry,1997,vol. 34,p. 441 - 444.
[5]Patent: WO2013/170165,2013,A1 .Location in patent: Page/Page column 88.

18
[ 70298-89-4 ]
[ 95-92-1 ]
Bis-[4-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-hydroxy-acetic acid ethyl ester [ No CAS ]

References: [1]Journal of Heterocyclic Chemistry,1997,vol. 34,p. 441 - 444.

20
[ 201230-82-2 ]
[ 70298-89-4 ]
5-Aza-3-tert-butyl-3-hydroxy-2,3-dihydroindol-2-one [ No CAS ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1999,p. 2299 - 2303.

21
[ 70298-89-4 ]
[ 239137-59-8 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1999,p. 1505 - 1510.

22
[ 70298-89-4 ]
[ 100-47-0 ]
<i>N</i>-[3-(imino-phenyl-methyl)-pyridin-4-yl]-2,2-dimethyl-propionamide [ No CAS ]

References: [1]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 3573 - 3577.

23
[ 70298-89-4 ]
[ 1122-85-6 ]
4-(N-pivaloylamino)pyridine-3-carbonitrile [ No CAS ]

References: [1]Tetrahedron Letters,2002,vol. 43,p. 6403 - 6404.
[2]Tetrahedron,2003,vol. 59,p. 5831 - 5836.

24
[ 70298-89-4 ]
[ 116332-54-8 ]
[ 223742-81-2 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In tetrahydrofuran; ethyl acetate;	Step 1 To a solution of 4-pivaloylaminopyridine (7.0 g, 39 mmol) in tetrahydrofuran (100 ml) was added n-butyllithium (39.3 ml, 98 mmol, 2.5 M solution in tetrahydrofuran) at -78° C. under a N2 atmosphere. The reaction mixture was stirred at 0° C. for 5 h, re-cooled to -78° C. and quenched with a solution of <strong>[116332-54-8]N-methoxy-N-methyl-4-fluorobenzamide</strong> (7.9 g, 43 mmol) in 100 ml tetrahydrofuran. The reaction mixture was warmed to room temperature and poured into water. The product was extracted into ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography (10percent ethyl acetate/hexanes gradient) to afford N-[3-(4-fluorobenzoyl)pyridin-4-yl]-2,2-dimethylpropanamide (10 g).

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 4702 - 4713.
[2]Patent: US6316464,2001,B1 .

25
[ 4136-91-8 ]
[ 70298-89-4 ]
[ 116990-42-2 ]

Yield	Reaction Conditions	Operation in experiment
50%		To a cooled (-78 °C) solution of N-(pyridin-4-yl)pivalamide (2.50 g, 14.0 mmol) in anhydrous THF (100 mL) was added "-BuLi (2.5 M in hexanes, 12 mL, 29.4 mmol). The mixture was allowed to warm rapidly to 0 °C and stirred at this temperature for 1.5 hours. The resulting mixture was cooled to -78 °C again and a solution of tetraisopropylthiuram disulfide (4.93 g, 14.0 mmol) in anhydrous THF (20 mL) was slowly added. After addition, the mixture was allowed to warm to room temperature, and then water (200 mL) and EtO Ac (200 mL) were added sequentially. The organic layer was separated, washed with water (2 x 200 mL), dried over Na2S04, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography, eluting with EtO Ac/petroleum ether (1 :8) to give the desired product as a yellow solid (2.46 g, 50percent yield). 3/4 NMR (500 MHz, CDC13): delta 8.60 (d, J = 7.5 Hz, 1H), 8.50-8.45 (m, 2H), 8.40 (d, J = 6.5 Hz, 1H), 1.60-1.11 (m, 14H), 1.29 (s, 9H). LCMS (ESI) m/z: 354.2 [M+H+].

References: [1]Molecules,2003,vol. 8,p. 678 - 686.
[2]Patent: WO2012/35039,2012,A1 .Location in patent: Page/Page column 76-77.
[3]Journal of Medicinal Chemistry,2016,vol. 59,p. 7138 - 7151.

26
[ 4136-91-8 ]
[ 70298-89-4 ]
3-(N,N-diisopropylthiocarbamato)-2-(pivaloylamino)pyridine [ No CAS ]

References: [1]European Journal of Medicinal Chemistry,2005,vol. 40,p. 15 - 23.

27
[ 4136-91-8 ]
[ 70298-89-4 ]
3-(N,N-diisopropylthiocarbamato)-4-(pivaloylamino)pyridine [ No CAS ]

References: [1]European Journal of Medicinal Chemistry,2005,vol. 40,p. 15 - 23.

28
[ 927-63-9 ]
[ 70298-89-4 ]
[ 253-72-5 ]

References: [1]Synlett,2006,p. 379 - 382.

29
[ 70298-89-4 ]
[ 955123-29-2 ]