514854-13-8|6-Ethyl-5-iodopyrimidine-2,4-diamine| Ambeed

Structure of 514854-13-8

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Quality Control of [ 514854-13-8 ] Purity: 97% SDS Specification

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Product Details of [ 514854-13-8 ]

CAS No. :	514854-13-8
Formula :	C₆H₉IN₄
M.W :	264.07
SMILES Code :	CCC1=NC(N)=NC(N)=C1I
MDL No. :	MFCD11655943
InChI Key :	USTNJKBQOYRJSF-UHFFFAOYSA-N
Pubchem ID :	11254067

Safety of [ 514854-13-8 ]

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

Computational Chemistry of [ 514854-13-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.33
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	2.0
Molar Refractivity	53.33
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	77.82 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.54
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	0.99
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.82
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.	0.84
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	1.19
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.08

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.44
Solubility	0.962 mg/ml ; 0.00364 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.	-2.21
Solubility	1.62 mg/ml ; 0.00613 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	-2.68
Solubility	0.553 mg/ml ; 0.00209 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	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.	-7.21 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)	2.23

Application In Synthesis of [ 514854-13-8 ]

* 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 [ 514854-13-8 ]

[ 514854-13-8 ] Synthesis Path-Downstream 1~41

1
[ 5734-66-7 ]
[ 514854-13-8 ]

References: [1]Journal of Chemical Research - Part S,2002,p. 482 - 484.

2
[ 5734-67-8 ]
[ 514854-13-8 ]

References: [1]Journal of Chemical Research - Part S,2002,p. 482 - 484.

3
[ 144104-59-6 ]
[ 514854-13-8 ]
[ 861103-12-0 ]

Yield	Reaction Conditions	Operation in experiment
70.1%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; at 100℃; for 2.0h;	The reaction mixture of <strong>[514854-13-8]6-ethyl-5-iodo-pyrimidine-2,4-diamine</strong> (60 mg, 0.23 mmol), 5-indolylboronic acid (41 mg, 0.25 mmol), tetrakis,(triphenyl-phosphine)-palladium (13 mg, 5%), Na2CO3 and toluene (2 ml) in a sealed tube was heated at 100 C. for 2 hours, and then the solvent was removed by evaporator and the residue was purified by reverse phase HPLC (070% CH3CN in aq. NH4OAc) providing the title compound (40 mg, 70.1%). 1H NMR (300 MHz, DMSO-d6) delta 11.13 (s, 1H), 7.45 (d, J=9.0 Hz, 1H), 7.36 (t, J=3.0 Hz, 1H), 7.33 (d, J=3.0 Hz, 1H), 6.86 (dd, J1=9.0 Hz, J2=3.0 Hz, 1H), 5.77 (s, 2H), 5.29 (s, 2H), 2.13 (q, J=7.5 Hz, 2H), 0.95 (t, J=7.5 Hz, 3H). MS (ESI) positive ion 254 (M+H)+; negative ion 252 (M-H)-.

References: [1]Patent: US2005/171131,2005,A1 .Location in patent: Page/Page column 47.

4
[ 931103-01-4 ]
[ 514854-13-8 ]
[ 1088496-63-2 ]

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 7532 - 7540.

5
[ 1088496-64-3 ]
[ 514854-13-8 ]
[ 1088496-65-4 ]

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 7532 - 7540.

6
[ 10147-11-2 ]
[ 514854-13-8 ]
[ 1088496-66-5 ]

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 7532 - 7540.

7
3-(2,5-dimethoxyphenyl)prop-1-yne [ No CAS ]
[ 514854-13-8 ]
[ 1088496-61-0 ]

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 7532 - 7540.

8
[ 1252013-89-0 ]
[ 514854-13-8 ]
[ 1252013-80-1 ]

References: [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 7327 - 7336.

9
[ 1252013-91-4 ]
[ 514854-13-8 ]
[ 1252013-82-3 ]

References: [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 7327 - 7336.

10
[ 1424869-74-8 ]
[ 514854-13-8 ]
[ 1424869-57-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 65℃; for 12.0h;Inert atmosphere;	To an oven-dried 8 mL screw cap vial was added ethyl-iodopyrimidine (0.060 g, 0.27 mmol), freshly purified CuI (0.009g, 0.045 mmol, 20mol%), and Pd(PPh3)2Cl2 (0.016 mg, 0.027 mmol, 10mol%). Degassed (argon purge) anhydrous DMF (0.5 mL) was added followed by alkyne 10 (0.093 g, 0.340 mmol) as a solution in DMF (0.5 mL). Degassed (argon purge) anhydrous triethylamine was added (1 mL), and the mixture was degassed once using the freeze/pump/thaw method. The vial was sealed under argon and heated at 65 C for 12 hrs. After the mixture was cooled, the orange solution was concentrated and the product was purified by flash chromatography (SiO2 6 g, 2% MeOH/CHCl2) followed by reverse phase flash chromatography (NH2 capped SiO2, CHCl2) to afford coupled pyrimidine 12 as a pale solid (0.07 g, 75%). 1H NMR (500 MHz, CDCl3) delta 9.30 (s, 1H), 8.48 (d, J = 5.97 Hz, 1H), 7.99 (dt, J = 3.62, 7.22 Hz, 1H), 7.74 (d, J = 6.00 Hz, 1H), 7.66 (m, 2H), 7.08 (s, 1H), 7.06 (m, 1H), 6.91 (m, 1H), 5.19 (bs, 2H), 4.96 (bs, 2H), 3.97 (s, 2H), 3.87 (s, 3H), 2.68 (q, J = 7.60 Hz, 2H), 1.18 (t, J = 7.61 Hz, 3H); 13C NMR (125 MHz, CDCl3) delta 173.04, 164.33, 159.96, 152.88, 143.40, 140.67, 138.83, 138.63, 134.04, 130.70, 128.90, 127.36, 126.76, 121.80, 118.42, 113.93, 112.86, 96.04, 75.71, 55.43, 29.69, 29.46, 26.29, 12.55; HRMS (DART, MH+) m/z 410.2001 (calculated for C25H24N5O, 410.1984).

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1279 - 1284.

11
[ 1424869-76-0 ]
[ 514854-13-8 ]
[ 1424869-59-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 65℃; for 12.0h;Inert atmosphere;	According to general Sonogashira coupling procedure ethyl-iodopyrimidine (0.050 g, 0.19 mmol), CuI (0.016g, 0.083 mmol, 20mol%), Pd(PPh3)2Cl2 (0.029 g, 0.041mmol, 10mol%) and alkyne 11 (0.081 g, 0.286 mmol) were reacted in DMF/Et3N (1ml each) at 65C for 12 hrs. After the mixture was cooled, the dark brown solution was concentrated and the product was purified by flash chromatography (SiO2 5 g, 2% MeOH/CHCl2) followed by reverse phase flash chromatography (NH2 capped SiO2, CHCl2) to afford coupled pyrimidine 13 as a pale solid (0.066 g, 82%). 1H NMR (500 MHz, CDCl3) delta 9.30 (s, 1H), 8.48 (d, J = 5.96 Hz, 1H), 8.02 - 7.97 (m, 1H), 7.74 (d, J = 5.98 Hz, 1H), 7.66 (d, J = 7.28 Hz, 2H), 7.11 (s, 1H), 7.09 (s, 1H), 6.91 (s, 1H), 5.17 (bs, 2H), 4.96 (bs, 2H), 4.10 (q, J = 7.11 Hz, 1H), 3.87 (s, 3H), 2.68 (q, J = 7.60 Hz, 2H), 1.65 (d, J = 7.10 Hz, 3H), 1.18 (t, J = 7.60 Hz, 3H); 13C NMR (125 MHz, CDCl3) delta 164.21, 160.41, 159.92, 152.90, 145.17, 143.41, 140.66, 138.94, 134.05, 130.72, 128.91, 127.34, 126.76, 120.88, 118.42, 113.75, 112.02, 101.38, 90.49, 75.48, 55.43, 33.08, 29.51, 24.70, 14.06, 12.49; HRMS (DART, MH+) m/z 424.2148 (calculated for C26H26N5O, 424.2137).

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1279 - 1284.

12
[ 1424869-85-1 ]
[ 514854-13-8 ]
[ 1424869-61-3 ]

Yield	Reaction Conditions	Operation in experiment
78%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 65℃; for 12.0h;Inert atmosphere;	According to general Sonogashira coupling procedure ethyl-iodopyrimidine (0.070 g, 0.26 mmol), CuI (0.009g, 0.052 mmol, 20mol%), Pd(PPh3)2Cl2 (0.019 g, 0.026mmol, 10mol%) and alkyne 16 (0.110 g, 0.392 mmol) were reacted in DMF/Et3N ( 1ml each) at 65C for 12 hrs. After the mixture was cooled, the dark brown solution was concentrated and the product was purified by flash chromatography (SiO2 10 g, 2% MeOH/CHC2) followed by reverse phase flash chromatography (NH2 capped SiO2, CHCl2) to afford coupled pyrimidine 18 as a pale solid (0.078 g, 78%). 1H NMR (500 MHz, CDCl3) delta 7.14 (s, 1H), 7.10 (d, J = 2.15 Hz, 1H), 7.07 (dd, J = 2.21, 8.35 Hz, 1H), 6.96 - 6.94 (m, 1H), 6.91 (d, J = 8.35 Hz, 1H), 6.90 (d, J = 1.46 Hz, 1H), 4.28 (s, 4H), 3.90(s, 2H), 3.84(s, 3H), 2.71 (q, J = 7.60 Hz, 2H), 1.23 (t, J = 7.60 Hz, 3H); 13C NMR (125 MHz, CDCl3) delta 173.28, 164.39, 160.58, 160.19, 143.64, 143.35, 142.36, 138.64, 134.38, 120.13, 118.83, 117.52, 115.87, 111.96, 110.77, 96.23, 90.56, 75.60, 64.45, 64.40, 55.34, 29.57, 26.32, 12.62; HRMS (DART, MH+) m/z 417.1928 ( calculated for C24H25N4O3, 417.1927).

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1279 - 1284.

13
[ 1424869-87-3 ]
[ 514854-13-8 ]
[ 1424869-63-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 65℃; for 12.0h;Inert atmosphere;	According to general Sonogashira coupling procedure ethyl-iodopyrimidine (0.065 g, 0.25 mmol), CuI (0.009g, 0.049 mmol, 20mol%), Pd(PPh3)2Cl2 (0.017 g, 0.025mmol, 10mol%) and alkyne 17 (0.110 g, 0.374 mmol) were reacted in DMF/Et3N ( 1ml each) at 65C for 12 hrs. After the mixture was cooled, the dark brown solution was concentrated and the product was purified by flash chromatography (SiO2 10 g, 2% MeOH/CHC2) followed by reverse phase flash chromatography (NH2 capped SiO2, CHCl2) to afford coupled pyrimidine 19 as a pale solid (0.085 g, 80%). 1H NMR (500 MHz, CDCl3) delta 7.17 (s, 1H), 7.11 (d, J = 2.15 Hz, 1H), 7.07 (dd, J = 2.19, 8.34 Hz, 1H), 6.97 - 6.93 (m, 2H), 6.92 (d, J = 8.36 Hz, 1H), 5.19 (s, 2H), 4.96 (s, 2H), 4.29 (s, 4H), 4.05 (q, J = 7.06 Hz, 1H), 3.85 (s, 3H), 2.71 (q, J = 7.55 Hz, 2H), 1.61 d, J = 7.1Hz, 3H), 1.24 (t, J = 7.57 Hz, 3H); 13C NMR (125 MHz, CDCl3) delta 173.27, 164.26, 160.61, 160.16, 145.23, 143.63, 143.33, 142.40, 134.53, 120.15, 117.89, 117.52, 115.89, 111.15, 110.64, 101.55, 90.57, 75.40, 64.45, 64.41, 55.34, 33.14, 29.65, 24.71, 12.54; HRMS (DART, MH+) m/z 431.2093 (calculated for C25H27N4O3, 431.2083).

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1279 - 1284.

14
[ 1569901-82-1 ]
[ 514854-13-8 ]
[ 1569901-92-3 ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2643 - 2656.

15
[ 1569901-83-2 ]
[ 514854-13-8 ]
[ 1569901-93-4 ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2643 - 2656.

16
[ 1569901-84-3 ]
[ 514854-13-8 ]
[ 1569901-94-5 ]

Yield	Reaction Conditions	Operation in experiment
79%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 14.0h;	According to the general Sonogahisra coupling procedure, ethyl-iodopyrimidine (0.036 g, 0.14 mmol), CuI (0.0075 g, 0.039 mmol, 21 mol %), Pd(PPh3)2Cl2 (0.009 g, 0.014 mmol, 10 mol %) and alkyne 20 (0.037 g, 0.15 mmol) were reacted in DMF/Et3N (0.5 mL each) at 60 C. for 14 h. After the mixture was cooled, dark reddish brown solution was concentrated and the product was purified by flash chromatography (SiO2, 5 g, 3% MeOH/CH2Cl2) to afford coupled pyrimidine 30 as a pale white powder (0.043 g, 79%) followed by reverse phase flash chromatography (NH2 capped SiO2, 3 g, 100% CH2Cl2, 1% MeOH/CH2Cl2) for biological evaluation: TLC Rf=0.06 (5% MeOH/CH2Cl2); mp 188.1-189.3 C.; 1H NMR (500 MHz, CDCl3) delta 7.52 (d, J=7.8 Hz, 1H), 7.42 (d, J=8.6 Hz, 2H), 7.11 (dd, J=7.9, 1.7 Hz, 1H), 7.01 (d, J=1.7 Hz, 1H), 6.90 (d, J=8.6 Hz, 2H), 5.31 (s, 2H), 4.99 (s, 2H), 4.40 (q, J=7.0 Hz, 1H), 3.89 (s, 3H), 2.72 (q, J=7.6 Hz, 2H), 1.53 (d, J=7.0 Hz, 3H), 1.24 (t, J=7.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) delta 173.2, 164.4, 160.3, 156.5, 156.5, 141.4, 133.2, 129.9, 128.6, 128.0, 119.4, 116.1, 109.4, 102.9, 91.4, 73.9, 55.7, 29.7, 26.9, 22.9, 12.9; IR (neat cm-1) 3470, 3371, 3337, 3173, 2970, 2930, 2871, 2341, 1726, 1547, 1438, 1217, 1028, 813; HRMS (ESI, M++H) m/z 389.1963 (calculated for C23H25N4O2, 389.1972); HPLC (a) tR=6.8 mins, 99%, (b) tR=8.23 mins, 99%.

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2643 - 2656.
[2]Patent: US2015/225353,2015,A1 .Location in patent: Paragraph 0069.

17
[ 1569901-85-4 ]
[ 514854-13-8 ]
[ 1569901-95-6 ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2643 - 2656.

18
[ 1569901-86-5 ]
[ 514854-13-8 ]
[ 1569901-96-7 ]

Yield	Reaction Conditions	Operation in experiment
78%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 70℃; for 12.0h;	According to the general Sonogahisra coupling procedure, ethyl-iodopyrimidine (0.056 g, 0.21 mmol), CuI (0.006 g, 0.031 mmol, 15 mol %), Pd(PPh3)2Cl2 (0.015 g, 0.021 mmol, 10 mol %) and alkyne 22 (0.084 g, 0.318 mmol) were reacted in DMF/Et3N (1 mL each) at 70 C. for 12 h. After the mixture was cooled, dark reddish brown solution was concentrated and the product was purified by flash chromatography (SiO2, 5 g, 2% MeOH/CHCl3) followed by reverse phase flash chromatography (NH2 capped SiO2, 3 g, 100% CH2Cl2, 1% MeOH/CH2Cl2) to afford coupled pyrimidine 32 as a pale white powder (0.065 g, 78%); TLC Rf=0.2 (5% MeOH/CH2Cl2); mp 130.9-133.1 C.; 1H NMR (500 MHz, CDCl3) delta 7.73-7.70 (m, 2H), 7.69-7.63 (m, 3H), 7.19 (dd, J=7.8, 1.7 Hz, 1H), 7.05 (d, J=1.7 Hz, 1H), 5.24 (s, 2H), 4.98 (s, 2H), 4.45 (q, J=7.0 Hz, 1H), 3.94 (s, 3H), 2.71 (q, J=7.6 Hz, 2H), 1.55 (d, J=7.0 Hz, 3H), 1.24 (t, J=7.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) delta 173.4, 164.5, 160.8, 156.8, 145.7, 139.3, 132.8, 132.5, 128.5, 127.9, 119.9, 119.1, 111.1, 109.6, 101.9, 90.8, 74.8, 55.6, 29.8, 26.9, 23.0, 12.7; IR (neat cm-1) 3464, 3428, 3332, 3188, 3029, 2925, 2775, 2546, 1651, 1548, 1445, 1286, 1008, 735, 557; HRMS (DART, M++H) m/z 398.1983, (calculated for C24H24N5O, 398.1981); HPLC (a) tR=19.2 mins, 99.6%, (b) tR=17.5 mins, 99.5%.

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2643 - 2656.
[2]Patent: US2015/225353,2015,A1 .Location in patent: Paragraph 0073.

19
[ 1569901-87-6 ]
[ 514854-13-8 ]
[ 1569901-97-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 12.0h;	According to a general Sonogahisra coupling procedure, ethyl-iodopyrimidine (0.055 g, 0.21 mmol), CuI (0.008 g, 0.04 mmol, 21 mol %), Pd(PPh3)2Cl2 (0.015 g, 0.021 mmol, 10 mol %) and alkyne 23 (0.092 g, 0.31 mmol) were reacted in DMF/Et3N (1 mL each) at 60 C. for 12 h. After the mixture was cooled, dark reddish brown solution was concentrated and the product was purified by flash chromatography (SiO2, 5 g, 2% MeOH/CHCl3) to afford coupled pyrimidine 33 as a pale white powder (0.076 g, 84%) followed by reverse phase flash chromatography (NH2 capped SiO2, 3 g, 100% CH2Cl2, 1% MeOH/CH2Cl2) for biological evaluation: TLC Rf=0.07 (5% MeOH/CH2Cl2); 1H NMR (500 MHz, MeOD) delta 7.53 (d, J=7.8 Hz, 1H), 7.46 (d, J=8.6 Hz, 2H), 7.13 (dd, J=7.8, 1.60, 1H), 7.11 (d, J=1.3 Hz, 1H), 6.85 (d, J=8.6 Hz, 2H), 4.41 (q, J=6.9 Hz, 1H), 3.93 (s, 3H), 2.67 (q, J=7.6 Hz, 2H), 1.52 (d, J=7.0 Hz, 3H), 1.22 (t, J=7.6 Hz, 3H); 13C NMR (125 MHz, MeOD) delta 173.5, 166.1, 162.2, 158.3, 157.9, 142.7, 133.8, 130.9, 129.1, 128.9, 119.9, 116.7, 110.1, 103.2, 91.4, 74.9, 56.2, 30.4, 27.9, 23.4, 13.3; 6 IR (neat cm-1) 3477, 3386, 3336, 3195, 2970, 2929, 2873, 2361, 2023, 1603, 1437, 1217, 1027, 813. HRMS (ESI, M++Na) m/z 455.1947 (calculated for C24H26N5NaO3, 455.1928); HPLC (a) tR=6.8 mins, 98%, (b) tR=8.2 mins, 98.7%.

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2643 - 2656.
[2]Patent: US2015/225353,2015,A1 .Location in patent: Paragraph 0077.

20
[ 1569901-88-7 ]
[ 514854-13-8 ]
[ 1569901-98-9 ]

Yield	Reaction Conditions	Operation in experiment
77%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 12.0h;	According to a general Sonogahisra coupling procedure, ethyl-iodopyrimidine (0.061 g, 0.23 mmol), CuI (0.009 g, 0.05 mmol, 21 mol %), Pd(PPh3)2Cl2 (0.016 g, 0.023 mmol, 10 mol %) and alkyne 24 (0.100 g, 0.34 mmol) were reacted in DMF/Et3N (1 mL each) at 60 C. for 12 h. After the mixture was cooled, dark reddish brown solution was concentrated and the product was purified by flash chromatography (SiO2, 5 g, 2% MeOH/CHCl3) to afford coupled pyrimidine 34 as a pale white powder (0.077 g, 77%) followed by reverse phase flash chromatography (NH2 capped SiO2, 3 g, 100% CH2Cl2, 1% MeOH/CH2Cl2): TLC Rf=0.1 (5% MeOH/CH2Cl2); mp 168.2-170.8 C.; 1H NMR (500 MHz, CDCl3) delta 8.08 (d, J=8.55 Hz, 2H), 7.64-7.60 (m, 3H), 7.21 (dd, J=7.8, 1.6 Hz, 1H), 7.08 (d, J=1.5 Hz, 1H), 5.15 (s, 2H), 4.84 (s, 2H), 4.43 (q, J=7.0 Hz, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 2.70 (q, J=7.6 Hz, 2H), 1.54 (d, J=7.0 Hz, 3H), 1.23 (t, J=7.6 Hz, 3H); 13C NMR (126 MHz, CDCl3) delta 173.5, 167.2, 164.5, 160.8, 156.7, 145.7, 140.2, 131.9, 130.3, 129.2, 128.3, 127.2, 120.0, 109.7, 102.1, 90.9, 74.7, 55.8, 52.4, 29.9, 26.9, 23.1, 12.8; IR (neat cm-1) 3427, 3302, 3163, 2925, 2851, 2150, 1699, 1548, 1282, 771, 698, 505; HRMS (ESI, M++H) m/z 431.2081 (calculated for C25H27N4O3, 431.2078); HPLC (a) tR=20.5 mins, 99.4%, (b) tR=18.1 mins, 99.1%.

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2643 - 2656.
[2]Patent: US2015/225353,2015,A1 .Location in patent: Paragraph 0081.

21
[ 1569901-89-8 ]
[ 514854-13-8 ]
[ 1569901-99-0 ]

Yield	Reaction Conditions	Operation in experiment
43%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 6.0h;	According to a general Sonogahisra coupling procedure, ethyl-iodopyrimidine (0.014 g, 0.05 mmol) CuI (0.002 g, 0.010 mmol, 20 mol %), Pd(PPh3)2Cl2 (0.004 g, 0.005 mmol, 10 mol %) and alkyne 25 (0.015 g, 0.050 mmol) were reacted in DMF/Et3N (0.5 mL/0.5 mL) at 60 C. for 6 h. After the mixture was cooled, dark reddish brown solution was concentrated and the product was purified by flash chromatography (SiO2, 10 g, 100% EtOAc followed by 2% MeOH/CH2Cl2) followed by reverse phase flash chromatography (NH2 capped SiO2, 5 g, 100% CH2Cl2) to afford pyrimidine 35 as an off-white solid (9 mg, 43%); TLC Rf=0.22 (5% MeOH/CH2Cl2); mp 135.2-136.1 C.; 1H NMR (500 MHz, Chloroform-d) delta 7.51 (d, J=7.8 Hz, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.14 (d, J=5.0 Hz, 1H), 7.03 (s, 1H), 6.78 (d, J=10.0 Hz, 2H), 5.24 (s, 2H), 5.01 (s, 2H), 4.40 (q, J=7.0 Hz, 1H), 3.90 (s, 3H), 2.98 (s, 6H), 2.71 (q, J=7.6 Hz, 2H), 1.53 (d, J=7.0 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) delta 164.7, 157.9, 156.6, 150.3, 141.9, 129.1, 128.7, 127.9, 119.0, 112.9, 109.2, 103.9, 92.0, 72.3, 55.7, 40.8, 28.1, 26.9, 22.7, 12.6; IR (neat cm-1) 3310, 3172, 2925, 2873, 1603, 1570, 807; HRMS (ES, M++H) m/z 416.2442 (calculated for C25H30N5O, 416.2445); HPLC was not obtained because of the instability of the compound. Biological activity was tested immediately after the synthesis.

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2643 - 2656.
[2]Patent: US2015/225353,2015,A1 .Location in patent: Paragraph 0085.

22
[ 1569901-90-1 ]
[ 514854-13-8 ]
[ 1569902-00-6 ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2643 - 2656.

23
[ 1569901-91-2 ]
[ 514854-13-8 ]
[ 1569902-01-7 ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2643 - 2656.

24
5-(1-methyl-prop-2-ynyl)-2-phenyl-pyridine [ No CAS ]
[ 514854-13-8 ]
[ 1569902-04-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 12.0h;	According to the general Sonogahisra coupling procedure, ethyl-iodopyrimidine (0.071 g, 0.27 mmol), CuI (0.011 g, 0.06 mmol, 21 mol %), Pd(PPh3)2Cl2 (0.019 g, 0.03 mmol, 10 mol %) and alkyne 43 (0.061 g, 0.3 mmol) were reacted in DMF/Et3N (1 mL each) at 60 C. for 12 h. After the mixture was cooled, dark reddish brown solution was concentrated and the product was purified by flash chromatography (SiO2, 5 g, 2% MeOH/CHCl3) to afford coupled pyrimidine 46 as a pale white hygroscopic solid (0.070 g, 75%), followed by reverse phase flash chromatography (NH2 capped SiO2, 3 g, 100% CH2Cl2, 1% MeOH/CH2Cl2) for biological evaluation: TLC Rf=0.1 (5% MeOH/CH2Cl2); 1H NMR (500 MHz, CDCl3) delta 8.72 (d, J=2.1 Hz, 1H), 7.96 (d, J=7.2 Hz, 2H), 7.81 (dd, J=8.2, 2.3 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.46 (dd, J=7.5, 7.5 Hz, 1H), 7.46 (dd, J=7.5, 7.5 Hz, 1H), 7.41-7.38 (m, 1H), 5.09 (s, 2H), 4.84 (s, 2H), 4.11 (q, J=7.1 Hz, 1H), 2.68 (q, J=7.6 Hz, 2H), 1.63 (d, J=7.1 Hz, 3H), 1.22 (t, J=7.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) delta 173.9, 164.4, 160.9, 156.4, 148.6, 139.3, 137.3, 135.3, 129.1, 128.9, 127.1, 120.6, 100.6, 90.4, 76.2, 30.6, 29.9, 24.7, 12.7; IR (neat cm-1) 3469, 3308, 3166, 2972, 2931, 1730, 1542, 1435, 1238, 1018, 739, 692; HRMS (ESI, M++H) m/z 344.1865 (calculated for C21H21N5, 344.1875); HPLC (a) tR=6.9 mins, 99.5%, (b) tR=7.1 mins, 99.2%.

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2643 - 2656.
[2]Patent: US2015/225353,2015,A1 .Location in patent: Paragraph 0090.

25
[ 1569902-02-8 ]
[ 514854-13-8 ]
[ 1569902-05-1 ]

Yield	Reaction Conditions	Operation in experiment
76%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 12.0h;	According to a general Sonogahisra coupling procedure, ethyl-iodopyrimidine (0.059 g, 0.23 mmol), CuI (0.009 g, 0.05 mmol, 21 mol %), Pd(PPh3)2Cl2 (0.016 g, 0.022 mmol, 10 mol %) and alkyne 44 (0.06 g, 0.27 mmol) were reacted in DMF/Et3N (1 mL each) at 60 C. for 12 h. After the mixture was cooled, dark reddish brown solution was concentrated and the product was purified by flash chromatography (SiO2, 5 g, 2% MeOH/CHCl3) to afford coupled pyrimidine 47 as a pale white powder (0.063 g, 76%) followed by reverse phase flash chromatography (NH2 capped SiO2, 3 g, 100% CH2Cl2, 1% MeOH/CH2Cl2) for biological evaluation: TLC Rf=0.1 (5% MeOH/CH2Cl2); mp 144-146.1 C.; 1H NMR (500 MHz, CDCl3) delta 8.74 (d, J=2.2 Hz, 1H), 7.91 (d, J=8.1 Hz, 2H), 7.82 (dd, J=8.2, 2.3 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 5.25 (s, 2H), 5.07 (s, 2H), 4.13 (q, J=7.1 Hz, 1H), 2.72 (q, J=7.6 Hz, 2H), 2.42 (s, 3H), 1.66 (d, J=7.1 Hz, 3H), 1.26 (t, J=7.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) delta 173.9, 164.5, 161.1, 156.4, 148.5, 139.1, 136.9, 136.5, 135.2, 129.7, 126.9, 120.3, 100.6, 90.3, 76.2, 30.6, 29.9, 24.6, 21.5, 12.7; IR (neat cm-1) 3459, 3319, 3152, 2973, 2933, 2873, 1542, 1443, 923, 819, 762; HRMS (ESI, M++H) m/z 358.2013 (calculated for C22H24N5, 358.2026); HPLC (a) tR=9.7 mins, 99.7%, (b) tR=9.4 mins, 99.5%.

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2643 - 2656.
[2]Patent: US2015/225353,2015,A1 .Location in patent: Paragraph 0094.

26
[ 1569902-03-9 ]
[ 514854-13-8 ]
[ 1569902-06-2 ]

Yield	Reaction Conditions	Operation in experiment
71%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 12.0h;	According to a general Sonogahisra coupling procedure, ethyl-iodopyrimidine (0.105 g, 0.4 mmol), CuI (0.028 g, 0.08 mmol, 21 mol %), Pd(PPh3)2Cl2 (0.028 g, 0.04 mmol, 10 mol %) and alkyne 45 (0.123 g, 0.6 mmol) were reacted in DMF/Et3N (1.3 mL each) at 60 C. for 12 h. After the mixture was cooled, dark reddish brown solution was concentrated and the product was purified by flash chromatography (SiO2, 5 g, 2% MeOH/CHCl3) to afford coupled pyrimidine 48 as a pale white powder (0.099 g, 71%) followed by reverse phase flash chromatography (NH2 capped SiO2, 3 g, 100% CH2Cl2, 1% MeOH/CH2Cl2) for biological evaluation: TLC Rf=0.1 (5% MeOH/CH2Cl2); mp 161.3-162.8 C.; 1H NMR (500 MHz, CDCl3) delta 8.84 (s, 2H), 8.62-8.02 (m, 2H), 7.88-7.37 (m, 3H), 5.16 (s, 2H), 4.98 (s, 2H), 4.10 (q, J=7.1 Hz, 1H), 2.67 (q, J=7.6 Hz, 2H), 1.65 (d, J=7.2 Hz, 3H), 1.22 (t, J=7.6 Hz, 3H); 13C NMR (12 MHz, CDCl3) delta 174.1, 164.4, 163.8, 161.1, 156.1, 137.5, 133.9, 130.9, 128.8, 128.3, 99.2, 89.9, 29.9, 28.7, 24.3, 12.7; IR (neat cm-1) 3401, 3312, 3159, 2970, 2933, 2871, 2222, 1623, 1563, 1427, 802, 740, 687; HRMS (ESI, M++H) m/z 345.1817 (calculated for C20H21N6, 345.1822); HPLC (a) tR=6.7 mins, 99.6%, (b) tR=7.6 mins, 99.6%

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2643 - 2656.
[2]Patent: US2015/225353,2015,A1 .Location in patent: Paragraph 0098.

27
4-[4-methoxy-3-((S)-methylprop-2-ynyl)phenyl]pyridine [ No CAS ]
[ 514854-13-8 ]
6-ethyl-5-[3S-(2-methoxy-5-pyridin-4-yl-phenyl)but-1-ynyl]pyrimidine-2,4-diamine [ No CAS ]