161117-88-0|tert-Butyl (5-nitropyridin-2-yl)carbamate| Ambeed

Structure of 161117-88-0

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Quality Control of [ 161117-88-0 ] Purity: 95% SDS Specification

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Product Details of [ 161117-88-0 ]

CAS No. :	161117-88-0
Formula :	C₁₀H₁₃N₃O₄
M.W :	239.23
SMILES Code :	CC(C)(C)OC(=O)NC1=NC=C(C=C1)[N+]([O-])=O
MDL No. :	MFCD11977408
InChI Key :	WIRMJKZHSYNQDD-UHFFFAOYSA-N
Pubchem ID :	11064480

Safety of [ 161117-88-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H317-H319
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 161117-88-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	17
Num. arom. heavy atoms	6
Fraction Csp3	0.4
Num. rotatable bonds	5
Num. H-bond acceptors	5.0
Num. H-bond donors	1.0
Molar Refractivity	63.3
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	97.04 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.65
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	1.58
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.15
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.	0.27
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.96
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.94

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.25
Solubility	1.35 mg/ml ; 0.00563 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.	-3.23
Solubility	0.141 mg/ml ; 0.000591 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	-2.36
Solubility	1.03 mg/ml ; 0.00433 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	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	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	Yes
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.	-6.64 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	2.0 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)	2.54

Application In Synthesis of [ 161117-88-0 ]

* 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 [ 161117-88-0 ]

[ 161117-88-0 ] Synthesis Path-Downstream 1~35

1
[ 4214-76-0 ]
[ 24424-99-5 ]
[ 161117-88-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With dmap; In dichloromethane; at 20℃;Inert atmosphere;	5-Nitropyridin-2-amine (1 eq), Boc2O (1.2 eq), DMAP (0.2 eq) was added to aflask under nitrogen atmosphere. Dichloromethane was added at room temperature and the mixture was stirred overnight. Ethyl acetate was added to the crude, the precipitated was filtered and washed with ethyl acetate to obtain the desired tert-butyl (5-n itropyrid in-2-yl)carbam ate.HPLC-MS (method A): Rt= 2.88 mm, [M+H]+ m/z: 240.Yield: 80%.
70%		A. Synthesis of (tert-butoxy)-N-(5-nitro(2-pyridyl))carboxamide (0132) To a solution of 2-amino-5-nitropyridine (0.555 g, 4 mmol) in THF (10 mL) was added 1 M NaHMDS in THF (8 mL, 8 mmol). The resulting dark red suspension was stirred for 15 min, followed by addition of a solution of Boc anhydride (0.87 mL, 3.8 mmol) in THF (5 mL). The reaction mixture was stirred at room temp for 21 hr, dilute with EtOAc, washed with 1 N HCl and brine, dried and concentrated in vacuo to give (tert-butoxy)-N-(5-nitro(2-pyridyl))carboxamide (0.63 g, 70%). ES-MS (M+H-tBu)+ = 184.
63.9%		Synthesis of compound 223.2. To a solution of NaH (1.15g, 28.75mmol, l .Oeq.) in THF (20ml) was added 223.1 (4.0g, 28.75mmol, l .Oeq) at 0 C. the reaction mixture was stirred at room temperature for 30 minutes. Boc anhydride (6.26g, 28.75mmol, l .Oeq.) in THF(lOmL) was added to the reaction mixture at room temperature and reaction was allowed to stir for 3 hours. After completion of the reaction, mixture was poured in water and solid product was filtered, dried to get pure 223.2 (4.4 g, 63.9 %). MS(ES): m/z 239.23 [M+H]+.

62%		To 0.652 g (4.69 mmol) of 2-amino-5-nitropyridine in THF (5 mL) was added 3.5 mL of NaHMDS (2M solution in THF) at 0 C. After 20 min a solution of 1.085 g (4.97 mmol) of di-tert-butyl dicarbonate in THF (6 mL) was added and the mixture was slowly warmed to room temperature overnight. Water was added, and the mixture was extracted with EtOAc (×4). The organic layer was washed with brine, dried (Na2SO4), and concentrated. Chromatography on, silica with hexanes-EtOAc (7:3), gave 0.695 g (62% yield) of tert-butyl-5-nitropyridin-2-ylcarbamate as an orange powder: 1H NMR (CDCl3) 89.19 (dd, J=2.8, 0.5 Hz, 1H), 8.93 (br s, 1H), 8.46 (ddd, J=9.4, 2.8, 0.5 Hz, 1H), 8.20 (dd, J=9.5, 0.5 Hz, 1H), 1.59 (s, 9H); LCMS (APCI-) m/z: 238 (MH+, 100%).
62%		Example 37Synthesis of N5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2,5-pyridinediamineThe compound was synthesized according to Method A.To 0.652 g (4.69 mmol) of 2-amino-5-nitropyridine in THF (5 mL) was added 3.5 mL of NaHMDS (2M solution in THF) at 0 C. After 20 min a solution of 1.085 g (4.97 mmol) of di-tert-butyl dicarbonate in THF (6 mL) was added and the mixture was slowly warmed to room temperature overnight. Water was added, and the mixture was extracted with EtOAc (×4). The organic layer was washed with brine, dried (Na2SO4), and concentrated. Chromatography on, silica with hexanes-EtOAc (7:3), gave 0.695 g (62% yield) of tert-butyl-5-nitropyridin-2-ylcarbamate as an orange powder: 1H NMR (CDCl3) δ 9.19 (dd, J=2.8, 0.5 Hz, 1H), 8.93 (br s, 1H), 8.46 (ddd, J=9.4, 2.8, 0.5 Hz, 1H), 8.20 (dd, J=9.5, 0.5 Hz, 1H), 1.59 (s, 9H); LCMS (APCI-) m/z: 238 (MH+, 100%).To 0.314 g (1.31 mmol) of the above nitro compound in THF-MeOH (16 mL, 1:1) was added 0.460 g of 10% Pd/C and the mixture was stirred under hydrogen (40 in/Hg) for 4 hrs. The reaction mixture was filtered through celite, washed with MeOH and concentrated to give 0.277 g (99% yield) of tert-butyl 5-aminopyridin-2-yl-carbamate as a white powder: 1H NMR (DMSO-d6) δ9.00 (br s, 1H), 7.62 (dd, J=2.7, 0.4 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 6.94 (dd, J=8.7, 2.8 Hz, 1H), 4.92 (s, 2H), 1.44 (s, 9H).To 0.277 g (1.33 mmol) of the above amino compound in THF (3 mL) was added 0.61 mL of n-butyllithium (2.5 M solution in hexanes) and the mixture was stirred for 10 min. A solution of 0.176 g (0.44 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole in THF (5 mL) was added and the resulting mixture was stirred for 1 hr at room temperature. The reaction mixture was neutralized with acetic acid, diluted with water, and extracted with EtOAc. The organic layer was washed with water and aq. NH3, dried, and concentrated. Chromatography on silica, eluting with hexanes-EtOAc (7:3), then with CH2Cl2-EtOAc (3:1), gave 0.033 g (13% yield) of tert-butyl 5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinylcarbamate: 1H NMR (DMSO-d6) δ10.02 (s, 1H), 9.66 (s, 1H), 8.54 (s, 1H), 8.17-7.80 (m, 4H), 7.39 (d, J=8.7 Hz, 1H), 6.97-6.93 (m, 1H), 3.98 (s, 3H), 3.82 (s, 4H), 3.74-3.72 (m, 4H), 1.48 (s, 9H).To 0.033 g (0.06 mmol) of the above carbamate in CH2Cl2 (3 mL) was added 0.1 mL (1.30 mmol) of trifluoroacetic acid, and the mixture was stirred for 5 hrs. The reaction mixture was diluted with CH2Cl2 and aq. NH4OH, and the organic layer was washed with brine, dried (Na2SO4), and concentrated. The residue was recrystallized from EtOH/CH2Cl2 to give 0.0133 g (49% yield) of N5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2,5-pyridinediamine, as a brown powder: mp 267-270 C.; 1H NMR (DMSO-d6) δ9.67-9.49 (m, 1H), 8.18-7.27 (m, 5H), 6.96 (d, J=7.6 Hz, 1H), 6.48 (d, J=8.4 Hz, 1H), 5.87-5.75 (m, 2H), 3.98 (s, 3H), 3.81 (s, 4H), 3.71 (s, 4H); HRMS (ESI) M+H+ Calcd. for C21H22F2N9O2: m/z 470.1859. Found: m/z 470.1867.
	With dmap; In dimethyl sulfoxide; at 20℃; for 48h;	Preparative Example 30aPreparation of ?e^butvK5-armno-4-methylpyridm-2-yl¥2-(fl5'.2^-2-ri-(5-cMoropyrirrudin-2- yl)piperidin-4-vncvclopropyl)ethyl>carbamate.Step 1 : fert-butyl (5-nitropyridin-2-yl')carbamate.2-Amino-5-nitropyridine (Ig, 7.2mmol) and di-tert-buty dicarbonate (2.4g, 10.8ramol) were added in DMSO (1OmL), DMAP (170mg, 1.4mmol) was added and stirred at room temperature for 2 days. Water (5OmL) was added, extracted with ethyl acetate (10OmL), second wash with Brine (5OmL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 50 gram Biotage SNAP KP-Sil silica gel cartridge eluting with 13% ethyl acetate/hexanes to give the title compound as a white solid. LRMS calc: 239.23; obs: 262.34 (M+23), 184.14 (M-55), 166.11 (M-73).
	With lithium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃;	PREPARATION 46 tert-Butyl 5-nitropyridin-2-ylcarbamate 200 mL of THF was added to 5-nitropyridin-2-amine (5g, 35.90 mmol). The solution was cooled to 0 C. Sodium hexamethyldisilazide (NaHMDS, 13.18 g, 71.9 mmol) in 30 mL THF was added dropwise. At the same time, di-tert-butyl dicarbonate (8.3 mL, 35.90 mmol) in 30 mL THF was added dropwise. The reaction mixture was stirred at 0 C for 15min and then warmed to room temperature. The reaction mixture stopped stirring due to salt/product formation and was left at room temperature for 20h. 150 mL 0.5N HCl was added and 150 mL ethyl acetate was added. The layers were separated. The organic layer was washed with 50 mL brine, dried with Na2SO4, filtered and evaporated to dryness. A yellow solid was isolated, which was used in the next synthetic step without further purification. LRMS (m/z): 240 (M+1)+
	With sodium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃; for 0.25h;	200 mL of THF was added to 5-nitropyridin-2-amine (5g, 35.90 mmol). The solution was cooled to 0 C. Sodium hexamethyldisilazide (NaHMDS, 13.18 g, 71 .9 mmol) in 30 mL THF was added dropwise. At the same time, di-ie f-butyl dicarbonate (8.3 mL, 35.90 mmol) in 30 mL THF was added dropwise. The reaction mixture was stirred at 0 C for 15min and then warmed to room temperature. The reaction mixture stopped stirring due to salt/product formation and was left at room temperature for 20h. 150 mL 0.5N HCI was added and 150 mL ethyl acetate was added. The layers were separated. The organic layer was washed with 50 mL brine, dried with Na2S04, filtered and evaporated to dryness. A yellow solid was isolated, which was used in the next synthetic step without further purification.LRMS (m/z): 240 (M+1 )+
94.6 g	With dmap; triethylamine; In dichloromethane; at 20℃; for 18h;	A 3-L round-bottomed flask was charged with 5-nitro-2-pyridinamine (75.0 g, 539 mmol, Alfa Aesar, Ward Hill, MA) and 500 mL of DCM. To this was added triethylamine (82 g, 809 mmol), di-tert-butyl dicarbonate (129 g, 593 mmol, Sigma-Aldrich, St. Louis, MO), and DMAP (32.9 g, 270 mmol, Sigma- Aldrich, St. Louis, MO). After stirring at rt for 18 h, the mixture was diluted with water and the solid was collected by filtration. The yellow solid was washed with MeOH to give tert-butyl (5-nitro-2-pyridinyl)carbamate (94.6 g) as a slightly-yellow solid.
94.6 g	With dmap; triethylamine; In dichloromethane; at 20℃; for 18h;	A 3-L round-bottomed flask was charged with 5-nitro-2-pyridinamine (75.0 g, 539 mmol, Alfa Aesar, Ward Hill, MA) and 500 mL of DCM. To this was added triethylamine (82 g, 810 mmol), di-tert-butyl dicarbonate (129 g, 593 mmol, Sigma-Aldrich, St. Louis, MO), and N,N-dimethylpyridin-4-amine (32.9 g, 270 mmol, Sigma-Aldrich, St. Louis, MO). After stirring at rt for 18 h, the mixture was diluted with water and the solid was collected by filtration. The yellow solid was washed with MeOH to give tert-butyl (5-nitro-2- pyridinyl)carbamate (94.6 g) as a light yellow solid.

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2
[ 161117-88-0 ]
[ 220731-04-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With palladium 10% on activated carbon; hydrogen; In ethyl acetate; at 20℃;	tert-Butyl (5-nitropyridin-2-yl)carbamate (1 eq), Pd/C (10% w/w) and ethyl acetate was added to a flask under H2 atmosphere. The mixture was stirred at room temperature overnight. The mixture was filtered through a celite pad andthe filtrate concentrated under reduced pressure to obtain tert-butyl (5- am inopyridin-2-yl)carbamate.HPLC-MS (method A): Rt= 1.50 mm, [M+H] m/z: 210. Yield: quantitative yield.
99%	With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; methanol; at 20℃; for 4h;	To 0.314 g (1.31 mmol) of the above nitro compound in THF-MeOH (16 mL, 1:1) was added 0.460 g of 10% Pd/C and the mixture was stirred under hydrogen (40 in/Hg) for 4 hrs. The reaction mixture was filtered through celite, washed with MeOH and concentrated to give 0.277 g (99% yield) of tert-butyl 5-aminopyridin-2-yl-carbamate as a white powder: 1H NMR (DMSO-d6) δ9.00 (br s, 1H), 7.62 (dd, J=2.7, 0.4 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 6.94 (dd, J=8.7, 2.8 Hz, 1H), 4.92 (s, 2H), 1.44 (s, 9H).
99%	With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; methanol; at 20℃; under 1016.0 Torr; for 4h;	Example 37Synthesis of N5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2,5-pyridinediamineThe compound was synthesized according to Method A.To 0.652 g (4.69 mmol) of 2-amino-5-nitropyridine in THF (5 mL) was added 3.5 mL of NaHMDS (2M solution in THF) at 0 C. After 20 min a solution of 1.085 g (4.97 mmol) of di-tert-butyl dicarbonate in THF (6 mL) was added and the mixture was slowly warmed to room temperature overnight. Water was added, and the mixture was extracted with EtOAc (×4). The organic layer was washed with brine, dried (Na2SO4), and concentrated. Chromatography on, silica with hexanes-EtOAc (7:3), gave 0.695 g (62% yield) of tert-butyl-5-nitropyridin-2-ylcarbamate as an orange powder: 1H NMR (CDCl3) δ 9.19 (dd, J=2.8, 0.5 Hz, 1H), 8.93 (br s, 1H), 8.46 (ddd, J=9.4, 2.8, 0.5 Hz, 1H), 8.20 (dd, J=9.5, 0.5 Hz, 1H), 1.59 (s, 9H); LCMS (APCI-) m/z: 238 (MH+, 100%).To 0.314 g (1.31 mmol) of the above nitro compound in THF-MeOH (16 mL, 1:1) was added 0.460 g of 10% Pd/C and the mixture was stirred under hydrogen (40 in/Hg) for 4 hrs. The reaction mixture was filtered through celite, washed with MeOH and concentrated to give 0.277 g (99% yield) of tert-butyl 5-aminopyridin-2-yl-carbamate as a white powder: 1H NMR (DMSO-d6) δ9.00 (br s, 1H), 7.62 (dd, J=2.7, 0.4 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 6.94 (dd, J=8.7, 2.8 Hz, 1H), 4.92 (s, 2H), 1.44 (s, 9H).To 0.277 g (1.33 mmol) of the above amino compound in THF (3 mL) was added 0.61 mL of n-butyllithium (2.5 M solution in hexanes) and the mixture was stirred for 10 min. A solution of 0.176 g (0.44 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole in THF (5 mL) was added and the resulting mixture was stirred for 1 hr at room temperature. The reaction mixture was neutralized with acetic acid, diluted with water, and extracted with EtOAc. The organic layer was washed with water and aq. NH3, dried, and concentrated. Chromatography on silica, eluting with hexanes-EtOAc (7:3), then with CH2Cl2-EtOAc (3:1), gave 0.033 g (13% yield) of tert-butyl 5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinylcarbamate: 1H NMR (DMSO-d6) δ10.02 (s, 1H), 9.66 (s, 1H), 8.54 (s, 1H), 8.17-7.80 (m, 4H), 7.39 (d, J=8.7 Hz, 1H), 6.97-6.93 (m, 1H), 3.98 (s, 3H), 3.82 (s, 4H), 3.74-3.72 (m, 4H), 1.48 (s, 9H).To 0.033 g (0.06 mmol) of the above carbamate in CH2Cl2 (3 mL) was added 0.1 mL (1.30 mmol) of trifluoroacetic acid, and the mixture was stirred for 5 hrs. The reaction mixture was diluted with CH2Cl2 and aq. NH4OH, and the organic layer was washed with brine, dried (Na2SO4), and concentrated. The residue was recrystallized from EtOH/CH2Cl2 to give 0.0133 g (49% yield) of N5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2,5-pyridinediamine, as a brown powder: mp 267-270 C.; 1H NMR (DMSO-d6) δ9.67-9.49 (m, 1H), 8.18-7.27 (m, 5H), 6.96 (d, J=7.6 Hz, 1H), 6.48 (d, J=8.4 Hz, 1H), 5.87-5.75 (m, 2H), 3.98 (s, 3H), 3.81 (s, 4H), 3.71 (s, 4H); HRMS (ESI) M+H+ Calcd. for C21H22F2N9O2: m/z 470.1859. Found: m/z 470.1867.

97%	With hydrogen;palladium on activated charcoal; In tetrahydrofuran; methanol; for 6h;	PREPARATION 47 tert-Butyl 5-aminopyridin-2-ylcarbamate tert-Butyl 5-nitropyridin-2-ylcarbamate (4.00 g, 16.72 mmol, Preparation 46) was dissolved in THF/MeOH. Pd/C (2.03 g, 1.91 mmol) was added and the reaction mixture was put under a hydrogen atmosphere. The reaction mixture was stirred for a total of 6h. The reaction mixture was filtered and evaporated to yield the desired product as a purple solid (3.40 g, 97% yield) which was stored at -20 C. LRMS (m/z): 210 (M+1)+
97%	With hydrogen;palladium on activated charcoal; In tetrahydrofuran; methanol; for 6h;	ferf-Butyl 5-nitropyridin-2-ylcarbamate (4.00 g, 16.72 mmol, Preparation 46) was dissolved in THF/MeOH. Pd/C (2.03 g, 1 .91 mmol) was added and the reaction mixture was stirred under hydrogen atmosphere. The reaction mixture was stirred for a total of 6h. The reaction mixture was filtered and evaporated to yield the desired product as a purple solid (3.40 g, 97% yield) which was stored at -20 C.LRMS (m/z): 210 (M+1 )+
97%	With palladium 10% on activated carbon; hydrogen; triethylamine; In methanol; ethyl acetate; under 760.051 Torr; for 20h;	B. Synthesis of N-(5-amino(2-pyridyl))(tert-butoxy)carboxamide (0133) To a suspension of (tert-butoxy)-N-(5-nitro(2-pyridyl))carboxamide (0.27 g, 1.13 mmol) in methanol (2 mL), ethyl acetate (4 mL) and TEA (0.16 mL) was added 10% Pd/C (60 mg, 0.056 mmol) under argon. The reaction mixture was hydrogenated under 1 atm H2 for 20 hr, filtered through Celite and concentrated in vacuo to give N-(5-amino(2-pyridyl))(tert-butoxy)carboxamide (0.226 g, 97%). 1H-NMR (DMSO-d6): δ 1.40 (s, 9H), 4.92 (br s, 2H), 6.89-6.91 (dd, 1 H), 7.35-7.37 (d, 1 H), 7.58 (d, 1 H), 9.06 (s, 1 H).
64%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 1h;	Synthesis of compound 223.3. To a suspension of 10% Pd/C (0.0 lOg) in methanol (5ml) was added 223.2 (0.500g, 2.1mmol, l .Oeq) in M eOH (5mL). Suspension was purged with hydrogen gas for lh at room temperature. Reaction mixture was filtered through celite washed with methanol and obtained filtrate was concentrated under reduced pressure and purified by flash chromatography to get pure 223.3 (0.28 g, 64.0 %) MS (ES): m/z 209.25 [M+H]+.
38.6 g	With ammonium chloride; zinc; In tetrahydrofuran; methanol; water; at 20℃; for 12h;	A 3-L round-bottomed flask was charged with tert-butyl (5-nitro-2- pyridinyl)carbamate (96.4 g, 403 mmol), 500 mL of MeOH, 500 mL of THF, and 100 mL of sat aq NH4C1. To this was slowly added (over 10 min) zinc dust (105 g, 1612 mmol, Strem Chemical Inc, Newburyport, MA). The mixture was stirred at room temperature for 12 h, then filtered. The filtrate was concentrated and then diluted with EtOAc and washed with water. The organic extracts were dried with MgS04, filtered, and concentrated to give a solid which was recrystallized from MeOH to give tert-butyl (5-amino-2-pyridinyl)carbamate (38.6 g) as a light yellow solid.
38.6 g	With ammonium chloride; zinc; In tetrahydrofuran; methanol; water; at 20℃; for 12h;	A 3-L round-bottomed flask was charged with tert-butyl (5-nitro-2- pyridinyl)carbamate (96.4 g, 403 mmol), 500 mL of MeOH, 500 mL of THF, and 100 mL of sat aq NH4Cl. Zinc (105 g, 1610 mmol, Strem Chemical Inc, Newburyport, MA) was slowly added (over 10 min) to this solution. The mixture was stirred at room temperature for 12 h, then filtered. The filtrate was concentrated and then diluted with EtOAc and washed with water. The organic extracts were dried over MgS04, filtered, and concentrated. The resulting solid was recrystallized from MeOH to give tert-butyl(5-amino-2-pyridinyl)carbamate (38.6 g) as a light-yellow solid.

References: [1]Patent: WO2016/120808,2016,A1 .Location in patent: Page/Page column 104.
[2]Patent: US2010/249099,2010,A1 .Location in patent: Page/Page column 96.
[3]Patent: US2011/9405,2011,A1 .Location in patent: Page/Page column 54.
[4]Patent: EP2518071,2012,A1 .Location in patent: Page/Page column 41-42.
[5]Patent: WO2012/146667,2012,A1 .Location in patent: Page/Page column 95-96.
[6]Patent: EP2314593,2016,B1 .Location in patent: Paragraph 0133.
[7]Letters in drug design and discovery,2011,vol. 8,p. 401 - 405.
[8]Patent: WO2015/131080,2015,A1 .Location in patent: Paragraph 001167; 001169.
[9]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2270 - 2273.
[10]Patent: WO2013/123444,2013,A1 .Location in patent: Page/Page column 60.
[11]Patent: WO2014/35872,2014,A1 .Location in patent: Page/Page column 69.
[12]Journal of Medicinal Chemistry,2014,vol. 57,p. 3094 - 3116.

3
[ 161117-88-0 ]
tert-butyl-N-(5-amino-6-bromopyridin-2-yl)carbamate [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2270 - 2273.
[2]Patent: WO2012/146667,2012,A1 .
[3]Patent: WO2013/123444,2013,A1 .

4
[ 161117-88-0 ]
[ 884496-93-9 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2270 - 2273.

5
[ 161117-88-0 ]
5-tert-butoxycarbonylamino-2-[3'-(tert-butoxycarbonylamino-methyl)-5-methoxycarbonylmethyl-2-(2-methoxy-ethoxymethoxy)-biphenyl-3-yl]-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2270 - 2273.

6
[ 161117-88-0 ]
[ 884496-95-1 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2270 - 2273.

7
[ 161117-88-0 ]
[ 74-88-4 ]
[ 1039055-45-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium hydride; In N,N-dimethyl-formamide; at 0℃; for 2.33333h;	To 0.378 g (1.58 mmol) of the above nitro compound in DMF (6 mL) at 0 C. was added 0.067 g (2.80 mmol) of sodium hydride. After 20 min, 0.12 mL (1.93 mmol) of methyl iodide was added, and the mixture was stirred for 2 hrs. Water was added, and the mixture was extracted with EtOAc (×4). The combined organic layer was washed successively with 1M HCl, sat. NaHCO3 solution, and brine, dried (Na2SO4), and concentrated, to give 0.40 g (99% yield) of tert-butyl methyl(5-nitro-2-pyridinyl)carbamate: 1H NMR (CDCl3) δ 9.19 (d, J=2.7 Hz, 1H), 8.36 (dd, J=9.4, 2.7 Hz, 1H), 8.14 (dd, J=9.4, 0.3 Hz, 1H), 3.50 (s, 3H), 1.57 (s, 9H); LCMS (APCI-) m/z: 253 (MH+, 100%).
99%		Example 38Synthesis of N5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N2-methyl-2,5-pyridinediamineThe compound was synthesized according to Method A.To 0.652 g (4.69 mmol) of 2-amino-5-nitropyridine in THF (5 mL) was added 3.5 mL of NaHMDS (2M solution in THF) at 0 C. After 20 min, a solution of 1.085 g (4.97 mmol) of di-tert-butyl dicarbonate in THF (6 mL) was added, and the mixture was slowly warmed to room temperature overnight. Water was added, and the mixture was extracted with EtOAc (×4). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica, eluting with hexanes-EtOAc (7:3), gave 0.695 g (62% yield) of tert-butyl 5-nitro-2-pyridinylcarbamate as an orange powder: 1H NMR (CDCl3) δ9.19 (dd, J=2.8, 0.5 Hz, 1H), 8.93 (br s, 1H), 8.46 (ddd, J=9.4, 2.8, 0.5 Hz, 1H), 8.20 (dd, J=9.5, 0.5 Hz, 1H), 1.59 (s, 9H); LCMS (APCI-) m/z: 238 (MH+, 100%).To 0.378 g (1.58 mmol) of the above nitro compound in DMF (6 mL) at 0 C. was added 0.067 g (2.80 mmol) of sodium hydride. After 20 min, 0.12 mL (1.93 mmol) of methyl iodide was added, and the mixture was stirred for 2 hrs. Water was added, and the mixture was extracted with EtOAc (×4). The combined organic layer was washed successively with 1M HCl, sat. NaHCO3 solution, and brine, dried (Na2SO4), and concentrated, to give 0.40 g (99% yield) of tert-butyl methyl(5-nitro-2-pyridinyl)carbamate: 1H NMR (CDCl3) δ9.19 (d, J=2.7 Hz, 1H), 8.36 (dd, J=9.4, 2.7 Hz, 1H), 8.14 (dd, J=9.4, 0.3 Hz, 1H), 3.50 (s, 3H), 1.57 (s, 9H); LCMS (APCI-) m/z: 253 (MH+, 100%).To 0.40 g (1.58 mmol) of the above nitro compound in MeOH (25 mL) was added 0.4 g of 10% Pd/C and the mixture was stirred under hydrogen (40 in Hg) for 4 hrs. After filtration through celite the reaction mixture was concentrated, to give 0.36 g (97% yield) of tert-butyl 5-amino-2-pyridin-2-yl(methyl)carbamate, as a yellow oil: 1H NMR (DMSO-d6) δ7.70 (dd, J=2.9, 0.5 Hz, 1H), 7.07 (d, J=8.6 Hz, 1H), 6.93 (dd, J=8.6, 2.9 Hz, 1H), 3.12 (s, 3H), 1.39 (s, 9H).To 0.356 g (1.53 mmol) of the above amine in THF (3 mL) was added 0.70 mL of n-butyllithium (2.5 M solution in hexanes) and the mixture was stirred for 10 min. A solution of 0.21 g (0.52 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole in THF (5 mL) was added, and the resulting mixture was stirred for 1 hr. The reaction mixture was neutralized with acetic acid, diluted with water, and extracted with EtOAc. The organic layer was washed with water and aq. NH3, and dried. The solvent was removed under vacuum, and the product mixture was purified by flash column chromatography, eluting with CH2Cl2/EtOAc (3:1), to give 0.075 g (13% yield) of tert-butyl 5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinyl(methyl)carbamate, as a yellow powder: 1H NMR (DMSO-d6) δ10.11 (s, 1H), 8.68-7.41 (m, 5H), 7.61 (d, J=9.0 Hz, 1H), 6.97 (d, J=8.1 Hz, 1H), 3.98 (s, 3H), 3.83 (s, 4H), 3.74-3.73 (m, 4H), 3.29 (s, 3H), 1.47 (s, 9H); LCMS (APCI+) m/z: 585 (MH+, 100%).To 0.0750 g (0.13 mmol) of the above carbamate in CH2Cl2 (3 mL) was added 0.1 mL (1.30 mmol) of trifluoroacetic acid and the mixture was stirred for 5 hrs. After dilution with CH2Cl2, the mixture was treated with H2O and aq. NH3, and the organic layer was washed with brine, dried (Na2SO4), and concentrated. The residue was recrystallized from EtOH/CH2Cl2 to give 0.0472 g (75% yield) of N5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N2-methyl-2,5-pyridinediamine: mp 218-221 C.; 1H NMR (CDCl3) δ8.31-7.73 (m, 2H), 7.62 (dd, J=8.8, 2.6 Hz, 1H), 7.56-7.31 (m, 2H), 6.82-6.80 (m, 2H), 6.46 (d, J=8.8 Hz, 1H), 4.76 (br s, 1H), 4.04 (s, 3H), 3.89 (s, 4H), 3.79 (s, 4H), 2.96 (s, 3H); HRMS (ESI) M+H+ Calcd. for C22H24F2N9O2: m/z 484.2016. Found: m/z 484.2023.

References: [1]Patent: US2010/249099,2010,A1 .Location in patent: Page/Page column 97.
[2]Patent: US2011/9405,2011,A1 .Location in patent: Page/Page column 54-55.

8
[ 161117-88-0 ]
[ 1367694-75-4 ]

References: [1]Letters in drug design and discovery,2011,vol. 8,p. 401 - 405.

9
[ 161117-88-0 ]
C₂₅H₃₂N₈O₆S [ No CAS ]

References: [1]Letters in drug design and discovery,2011,vol. 8,p. 401 - 405.

10
[ 161117-88-0 ]
[ 1367695-07-5 ]

References: [1]Letters in drug design and discovery,2011,vol. 8,p. 401 - 405.

11
[ 161117-88-0 ]
[ 1404086-67-4 ]
[ 1404086-65-2 ]

References: [1]Patent: EP2518071,2012,A1 .
[2]Patent: WO2012/146667,2012,A1 .

12
[ 161117-88-0 ]
[ 1404085-44-4 ]

References: [1]Patent: EP2518071,2012,A1 .
[2]Patent: WO2012/146667,2012,A1 .

13
[ 161117-88-0 ]
[ 1404085-45-5 ]

References: [1]Patent: EP2518071,2012,A1 .
[2]Patent: WO2012/146667,2012,A1 .

14
[ 161117-88-0 ]
[ 1404085-47-7 ]

References: [1]Patent: EP2518071,2012,A1 .
[2]Patent: WO2012/146667,2012,A1 .

15
[ 161117-88-0 ]
[ 1404085-48-8 ]

References: [1]Patent: EP2518071,2012,A1 .
[2]Patent: WO2012/146667,2012,A1 .

16
[ 161117-88-0 ]
[ 1450620-41-3 ]

References: [1]Patent: WO2013/123444,2013,A1 .
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 3094 - 3116.

17
[ 161117-88-0 ]
[ 1450620-58-2 ]