107867-51-6|5-(Trifluoromethyl)pyridine-2,3-diamine| Ambeed

Structure of 107867-51-6

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Quality Control of [ 107867-51-6 ] Purity: 97% SDS Specification

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Product Details of [ 107867-51-6 ]

CAS No. :	107867-51-6
Formula :	C₆H₆F₃N₃
M.W :	177.13
SMILES Code :	NC1=CC(=CN=C1N)C(F)(F)F
MDL No. :	MFCD10696252
InChI Key :	RNSZENVDZWTPPG-UHFFFAOYSA-N
Pubchem ID :	10214425

Safety of [ 107867-51-6 ]

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

Computational Chemistry of [ 107867-51-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.17
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	38.05
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	64.93 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.79
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	0.71
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.43
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.	0.72
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	0.97
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.12

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.69
Solubility	3.62 mg/ml ; 0.0204 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.65
Solubility	3.95 mg/ml ; 0.0223 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-2.19
Solubility	1.14 mg/ml ; 0.00644 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.	-6.88 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)	1.89

Application In Synthesis of [ 107867-51-6 ]

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

Downstream synthetic route of [ 107867-51-6 ]

[ 107867-51-6 ] Synthesis Path-Downstream 1~35

1
[ 79-37-8 ]
[ 107867-51-6 ]
[ 168123-87-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 2749 - 2754.

2
[ 95-92-1 ]
[ 107867-51-6 ]
[ 168123-87-3 ]

Yield	Reaction Conditions	Operation in experiment
635 mg	for 4h;Reflux;	General procedure: A mixture of 2,3-diaminopyridine in diethyl oxalate (10 mL/1 mmol phenyldiamine) was heated to reflux for 4 h before cooled to room temperature. The resulted solid was filtered,washed with ethyl acetate and 95percent ethanol, decolorized with activated charcoal and recrystallized in water and DMF or DMSO to give 5-azaquinoxalinediones as white solid. 5.2.2.6 7-Trifluoromethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (6) The title compound was prepared from 2-amino-5-trifluoromethylpyridine according to the general procedure as white solid (635 mg, 27.5percent). IR (KBr) nu 3055, 1717, 1698, 1627, 1342, 1165, 1094 cm-1; 1H NMR (400 MHz, DMSO-d6) delta 7.63 (1H, d, J = 2.0 Hz, H-8), 8.44 (1H, s, H-6), 12.13 (1H, s, NH-1), 12.71 (1H, s, NH-4); 13C NMR (100 MHz, DMSO-d6) delta 118.74 (t), 120.04 (d), 122.52, 124.18 (d), 138.99 (t), 142.95, 154.95, 156.39; HRMS-EI C8H4F3N3O2 calcd [M+Na]+ 254.0153, found 254.0150.
997 mg (94%)		8-Aza-6-trifluoromethyl-1,4-dihydroquinoxaline-2,3-dione (52) A mixture of 51 (800 mg, 4.52 mmol) and diethyl oxalate (7.0 g, 47.9 mmol) was heated at 160° C. with stirring for 2 h (the mixture turned into a solution, then more and more precipitate was formed) and cooled to room temperature. The mixture was diluted with hexane (20 mL), filtered, washed with hexane (3*5 mL), and dried to give 997 mg (94percent) of 52 as a yellow powder, mp >360° C. 1 H NMR (DMSO-d6), 7.625 (s, 1H), 8.441 (s, 1H), 12.120 (s, 1H), 12.703 (s, 1H). 19 F NMR (DMSO-d6), -131.225 ppm (The internal standard C6 F6: -162.9 ppm).

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 3679 - 3686.
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 2949 - 2961.
[3]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 2749 - 2754.
[4]European Journal of Medicinal Chemistry,2016,vol. 117,p. 19 - 32.
[5]Patent: US5620978,1997,A .

3
[ 53359-69-6 ]
[ 107867-51-6 ]

Yield	Reaction Conditions	Operation in experiment
	With tin(ll) chloride; In DMF (N,N-dimethyl-formamide); at 60℃; for 4h;	(b) 5-Trifluoromethyl-pyridine-2,3-diamine. A mixture of 3-nitro-5-trifluoromethyl-pyridin-2-ylamine from step (a) above (1.2 g, 5.59 mmol), tin (II) chloride [DIHYDRATE] (3.9 g, 17.3 mmol, Aldrich), and DMF (19 mL) was heated to [60 °C] for 4 h. The reaction mixture was cooled to room temperature and [NAHC03] (150 mL) was added. The mixture was stirred for 0.5 h, diluted with EtOAc (300 mL), stirred for 0.5 h and filtered. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 300 mL). The combined organic extracts were dried over [MGS04] and filtered. The solvent was removed in vacuo to give the title compound, which was used in the next step without additional purification. MS (ESI, positive ion) m/z : 178 [(M+1).]
	With tin(II) chloride dihdyrate; In N,N-dimethyl-formamide; at 60℃; for 12h;	3-Nitro-5-(trifluoromethyl)pyridin-2-amine (538.0 mg, 2.60 mmol) and SnCl22H2O (2340.0 mg, 10.39 mmol) were added to DMF (5.0 mL), and it was stirred at 60° C. for 12 hours. The reaction mixture was poured into saturated NaHCO3 aqueous solution and neutralized (pH=7), and it was then extracted with EtOAc (200.0 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and then evaporated under reduced pressure to obtain brown solid compound of 5-(trifluoromethyl)pyridin-2,3-diamine. [0780] LCMS ESI (+): 178 (M+1)
	In methanol;	2,3-Diamino-5-trifluoromethylpyridine (51) A mixture of 50 (950 mg, 4.59 mmol), methanol (15 mL) and Raney Ni (about 200 mg) was shaken under H2 (30-40 psi) for 2 h, then filtered. The filtrate was evaporated to dryness, giving 810 mg (100percent) of the diamine 51 as a deep yellow powder, mp 97°-99° C. 1 H NMR (CDCl3), 3.389 (bs, 2H), 4.556 (bs, 2H), 7.049 (s, 1H), 7.932 (s, 1H).

With hydrogen;nickel; In methanol; at 20℃; under 2585.81 Torr; for 1h;

Step B: 5-(trifluorornethyl)pyridine-2,3-diamine To a methanol 5mL solution of 3-nitro-5-(trifluoromethyl)pyridin~2~amine(680mg, 3,28mmol) was added Raney nickel (240 mg charged as a wet slurry, washed 3x with 10 mL OfH2O). The mixture was hydrogenated in a Parr shaker at 50psi at room temperature for lhr, purged with N2 and filtered through a pad of celite. The celite pad was washed with methanol (5mLx3). The filtrate was concentrated under reduced pressure to give the title compound (454 mg). LC/MS: m/z 178(M+H).

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 3679 - 3686.
[2]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 2749 - 2754.
[3]Journal of Medicinal Chemistry,2006,vol. 49,p. 3719 - 3742.
[4]Patent: WO2004/35549,2004,A1 .Location in patent: Page 118.
[5]Patent: US2014/315888,2014,A1 .Location in patent: Paragraph 0779-780.
[6]Patent: US5620978,1997,A .
[7]Patent: WO2009/152072,2009,A1 .Location in patent: Page/Page column 48.

4
[ 530-62-1 ]
[ 107867-51-6 ]
[ 438190-87-5 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane;	B. 6-Trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one Add 1,1'-carbonyldiimidazole (1.0 g, 6.17 mmol)to a solution of <strong>[107867-51-6]5-trifluoromethyl-pyridine-2,3 diamine</strong> (0.90 g, 5.08 mmol) in CH2Cl2 (10 mL) and stir at room temperature for 18 hours. Heat the solution to reflux for 2 hours and filter the precipitate to obtain 6-trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one.

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3719 - 3742.
[2]Patent: US2003/36652,2003,A1 .

5
[ 74784-70-6 ]
[ 107867-51-6 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3719 - 3742.
[2]Journal of Medicinal Chemistry,1997,vol. 40,p. 3679 - 3686.
[3]Patent: US2014/315888,2014,A1 .
[4]Patent: EP2865266,2015,A1 .
[5]Patent: US5620978,1997,A .

6
[ 107867-51-6 ]
2-chloro-6-trifluoromethyl-1H-imidazo[4,5-b]pyridine; hydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3719 - 3742.

7
[ 107867-51-6 ]
6-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-imidazo[4,5-b]pyridine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3719 - 3742.

8
[ 107867-51-6 ]
5-Oxy-7-trifluoromethyl-1,4-dihydro-pyrido[2,3-b]pyrazine-2,3-dione [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 3679 - 3686.
[2]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 2749 - 2754.
[3]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 2749 - 2754.

9
[ 107867-51-6 ]
[ 683242-11-7 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 20℃; for 16h;	[(C)] [6-TRIFLUOROMETHYL-1,] 3-diliydro-imidazo [4,5-b] pyridin-2-one, trifluoroacetic acid salt. A mixture of 5-trifluoromethyl-pyridine-2, 3-diamine from step (b) above and N, [N-CARBONYLDIIMIDAZOLE] (938 mg, 579 mmol, Aldrich) in THF (10 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with [HA0] (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were concentrated in vacuo and the residue was purified by preparative HPLC (gradient 0. [1 percent] trifluoroacetic acid in acetonitrile) to give the title compound. MS (ESI positive ion) m/z: 204 (M+1).

References: [1]Patent: WO2004/35549,2004,A1 .Location in patent: Page 118-119.

10
C₁₈H₁₆N₆S₂ [ No CAS ]
[ 107867-51-6 ]
C₂₁H₁₆F₃N₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: A mixture of compound 1.2 (0.2 mmol) and thiocarbonyldiimidazole (0.2 mmol) in dry THF (2.0 mL) was stirred at room temperature for 30 minutes under an atmosphere of N2. 5-Trifluoromethyl-pyridine-2,3-diamine (0.2 mmol) was added and the reaction stirred at room temperature until the reaction was deemed complete. The reaction mixture was then treated with N,N'-dicyclohexylcarbodiimide (0.2 mmol) and the resulting mixture was stirred at 40-60° C. for several hours. The solvent was removed and the residue was purified by preparative HPLC to give the titled compound. 1H NMR (CD3OD, 400 MHz): delta 8.76 (s, 1H), 8.51 (s, 1H), 8.38 (s, 1H), 7.95 (s, 1H), 7.56 (d, J=7.3 Hz, 2H), 7.48 (s, 1H), 7.38 (d, J=6.4 Hz, 2H), 4.03 (s, 2H), 3.09 (s, 2H) ppm; EIMS (m/z): 456.1 (M++H).

References: [1]Patent: US2006/35908,2006,A1 .Location in patent: Page/Page column 122.

11
[ 438191-02-7 ]
[ 53359-69-6 ]
[ 107867-51-6 ]

Yield	Reaction Conditions	Operation in experiment
	palladium-carbon; In ethanol;	A. 5-Trifluoromethyl-pyridine-2,3 diamine Add 10percent Pd/C (0.5 g) to a solution of 3 nitro-5-(trifluoromethyl) pyridin-2-amine (1.0 g, 4.83 mmol) in ethanol (10 mL). Hydrogenate the mixture at a pressure of 50 psi for 5 hours. Filter the mixture through celite, evaporate to dryness under reduced pressure to obtain 5-trifluoromethyl-pyridine-2,3 diamine.

References: [1]Patent: US2003/36652,2003,A1 .

Yield	Reaction Conditions	Operation in experiment
		Representative compounds of the present invention are:...6-dimethylamino-2,3-diaminopyridine;diethyl 2-(2,3-diamino-6-pyridyl)malonate;6(4-methyl-1-pyperazinyl)-2,3-pyridinediamine;6-(methylthio)-5-(trifluoromethyl)-2,3-pyridinediamine;5-(trifluoromethyl)-2,3-pyridinediamine;6-(2,2,2-trifluorethoxy)-5-(trifluoromethyl)-2,3-pyridinediamine;6-chloro-5-(trifluoromethyl)-2,3-pyridinediamine;5-bromo-4,6-dimethyl-2,3-pyridinediamine;...

13
[ 117550-54-6 ]
[ 107867-51-6 ]
[ 122771-62-4 ]
2-Amino-3-(2-methyl-6-methoxycarbonylaminobenzylamino)-5-trifluoromethylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		PREPARATION 17 2-Amino-3-(2-methyl-6-methoxycarbonylaminobenzylamino)-5-trifluoromethylpyridine was obtained by reacting <strong>[107867-51-6]2,3-diamino-5-trifluoromethylpyridine</strong> with 2-methyl-6-methoxycarbonylaminobenzyl chloride according to a similar manner to that of Preparation 16. mp: 157° to 159° C. IR (Nujol): 3420, 3350, 3200, 1730, 1660, 1600, 1580, 1520 cm-1. NMR (DMSO-d6, delta): 2.33 (3H, s), 3.58 (3H, s), 4.13 (2H, d, J=5Hz), 4.93 (1H, t, J=5Hz), 6.28 (2H, broad s), 6.78 (1H, broad s), 6.92-7.42 (3H, m), 7.60 (1H, broad s), 8.80 (1H, s).

References: [1]Patent: US4920129,1990,A .

14
[ 51076-95-0 ]
[ 107867-51-6 ]
[ 1201597-38-7 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at 100℃; for 0.333333h;Microwave irradiation;	Step C: 2-(chloromethyl)-6-(trifluoromethyl)-3H-imidazo[4,5-]pyridine To a DCM 2mL suspension of 5~(trifluoromethyl)rhoyridine-2,3 -diamine (454mg, 2.56mmol) was added 2~Chloro-l,l ,l-triethoxy-ethane (504mg, 2.56mmol). The mixture was heated to 1000C for 20 mill using a microwave reactor and resulting solid was suspended in 1 :1 DCM:hexanes (5mL) and gently sonicated. The precipitate was collected by suction filtration to give the title compound (324mg). LC/MS: m/z 236(M+H). 1H-NMR (500MHz, d6-DMSO): delta 4.98 (s, 2H), 8.42(d, 1H), 8.72 (d, 1H).

References: [1]Patent: WO2009/152072,2009,A1 .Location in patent: Page/Page column 48.

15
[ 1438249-45-6 ]
[ 107867-51-6 ]
[ 1438250-26-0 ]

Yield	Reaction Conditions	Operation in experiment
	With Oxone; magnesium bromide ethyl etherate; In dimethyl sulfoxide; at 50℃;	Methyl 4-(5-(3-fluoro-4-formylphenyl)pyrimidin-2-yloxy)bicyclo[2.2.2]octane- 1-carboxylate (Intermediate 2, 30 mg, 0.078 mmol, 1 equiv), 5-(trifluorornethyl)pyridine- 2,3-diamine (15.2 mg, 0.086 mmol, 1.1 equiv) and magnesium(II) bromide diethyl etherate (20 mg, 0.078 mmol, 1 equiv) were weighed to a vial then suspended in DMSO (260 muL) stirred at 50 °C for 2.5 hours then Oxone (48 mg, 0.078 mmol, 1 equiv) was added and the mixture stirred at 50 °C overnight. The reaction mixture was diluted with DMSO, filtered, and purified by preparative reverse phase HPLC on a 30 x 100 mm SunFire C I 8 column with a gradient of 20percent to 70percent acetonitrile in water containing 0.05percent TFA. This gave the TFA salt of the title compound as a white solid: LCMS calc'd [MH]+ m/z 542; found m/z 542

References: [1]Patent: WO2013/74387,2013,A1 .Location in patent: Page/Page column 64; 65.

16
methyl 2-(cis-3-[5-(3-fluoro-4-formylphenyl)pyrimidin-2-yl]oxy}cyclobutyl)acetate [ No CAS ]
[ 107867-51-6 ]
methyl 2-(cis-3-(5-(3-fluoro-4-(6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)pyrimidin-2-yloxy)cyclobutyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
143 mg	In dimethyl sulfoxide; at 70℃; for 2h;	A solution of Intermediate 18 (150 mg, 0.436 mmol) in DMSO (8.0 ml) was treated with 5-(trifluoromethyI)pyridine-2,3-diamine (85 mg, 0.479 mmol) and the mixture stirred at 70°C for 2 h. After cooling to room temperature the reaction was quenched with water to afford a precepitate. The precepitate was filtered off and washed with water. The filtered solid was dissolved in EtOAc and washed with NaHC03, brine, and dried (MgS04) and concentrated. Trituration of the solid from ether / hexane followed by filtration afforded 143 mg of Methyl 2-(Cis-3-(5-(3-fluoro-4-(6-(trifluoromethyl)-3H-imidazo[4,5-)]pyridin-2-yl)phenyl)pyrimidin-2-yloxy)cyclobutyl)acetate as a tan solid. LC-MS (M+l)

References: [1]Patent: WO2013/74387,2013,A1 .Location in patent: Page/Page column 104.

17
[ 107867-51-6 ]
tert-butyl (1-(2-chloro-7-(trifluoromethyl)pyrido[2,3-b]pyrazin-3-yl)azetidin-3-yl)(methyl)carbamate [ No CAS ]

References: [1]Patent: US2014/315888,2014,A1 .

18
[ 107867-51-6 ]
tert-butyl (1-(2-hydrazinyl-7-(trifluoromethyl)pyrido[2,3-b]pyrazin-3-yl)azetidin-3-yl)(methyl)carbamate [ No CAS ]

References: [1]Patent: US2014/315888,2014,A1 .

19
[ 107867-51-6 ]
tert-butyl methyl(1-(8-(trifluoromethyl)pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)azetidin-3-yl)carbamate [ No CAS ]

References: [1]Patent: US2014/315888,2014,A1 .

20
[ 107867-51-6 ]
N-methyl-1-(8-(trifluoromethyl)pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)azetidin-3-amine [ No CAS ]

References: [1]Patent: US2014/315888,2014,A1 .

21
[ 107867-51-6 ]
2-chloro-3-(4-methylpiperazin-1-yl)-7-(trifluoromethyl)pyrido[2,3-b]pyrazine [ No CAS ]

References: [1]Patent: US2014/315888,2014,A1 .
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 2949 - 2961.

22
[ 95-92-1 ]
[ 107867-51-6 ]
7-(trifluoromethyl)pyrido[2,3-b]pyrazin-2,3-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 120℃; for 12h;	Unpurified <strong>[107867-51-6]5-(trifluoromethyl)pyridin-2,3-diamine</strong> was added to diethyl oxalate (10.0 mL). The mixture was stirred at 120° C. for 12 hours and then cooled to room temperature. Et2O was added thereto to form a solid, and the formed solid was filtered under reduced pressure to obtain brown solid compound of 7-(trifluoromethyl)pyrido[2,3-b]pyrazin-2,3-diol. The mixture of unpurified 7-(trifluoromethyl)pyrido[2,3-b]pyrazin-2,3-diol and POCl3 (10.0 mL) was stirred at 130° C. for 12 hours and then cooled to room temperature. The reaction mixture was poured into ice water to form a solid. The formed solid was filtered and then dried under reduced pressure to obtain brown solid compound of 2,3-dichloro-7-(trifluoromethyl)pyrido[2,3-b]pyrazine (370.0 mg, 53percent in 3 steps).

References: [1]Patent: US2014/315888,2014,A1 .Location in patent: Paragraph 0781-0782.

23
[ 107867-51-6 ]
2,3-dichloro-7-(trifluoromethyl)pyrido[2,3-b]pyrazine [ No CAS ]

References: [1]Patent: US2014/315888,2014,A1 .
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 2949 - 2961.

24
[ 107867-51-6 ]
2-hydrazinyl-3-(4-methylpiperazin-1-yl)-7-(trifluoromethyl)pyrido[2,3-b]pyrazine [ No CAS ]

References: [1]Patent: US2014/315888,2014,A1 .

25
[ 107867-51-6 ]
4-(4-methylpiperazin-1-yl)-8-(trifluoromethyl)pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazine [ No CAS ]

References: [1]Patent: US2014/315888,2014,A1 .
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 2949 - 2961.

26
2-formyl-5-trifluoromethyl-phenyl ethyl sulfide [ No CAS ]
[ 107867-51-6 ]
2-(2-ethylsulfanyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12 g		Production Example 59-4 6.1 g of sodium hydrogen sulfite was added to a mixture of 8.6 g of <strong>[107867-51-6]5-trifluoromethyl-pyridine-2,3-diamine</strong>, 11 g of 2-formyl-5-trifluoromethylphenyl ethyl sulfide, and 67 mL of DMF at room temperature. After heating and stirring the mixture for 3 hours at 100°C. 1 g of copper (II) chloride dihydrate was added thereto, and the mixture was heated and stirred for 1 hour at 100°C. After allowing the mixture to cool to room temperature, the reaction mixture was added to water and was subjected to extraction using ethyl acetate. A combined organic layer was dried using sodium sulfate, and then, was condensed under reduced pressure. The residue was subjected to silicagel column chromatography to obtain yellow solid powder. The powder was washed with hexane to obtain 12 g of 2-(2-ethylsulfanyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as the present condensed heterocyclic compound 59).

References: [1]Patent: EP2865266,2015,A1 .Location in patent: Paragraph 0680; 0681.

27
2-formyl-5-trifluoromethyl-phenyl ethyl sulfide [ No CAS ]
[ 107867-51-6 ]
2-(2-ethylsulfonyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine [ No CAS ]

References: [1]Patent: EP2865266,2015,A1 .

28
1-[3-(ethylsulfonyl)-6-iodoimidazo[1,2-a]pyridin-2-yl]ethan-1-one [ No CAS ]
[ 107867-51-6 ]
3-[3-(ethylsulfonyl)-6-iodoimidazo[1,2-a]pyridin-2-yl]-7-(trifluoromethyl)pyrido[2,3-b]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
224 mg		To a mixed solution of 300 mg of 1- [3- (ethylsulfonyl) -6-iodoimidazo [1,2-a] pyridin-2-yl] ethan-1-one and 5 ml of dimethylsulfoxide was added 48 mass percent 1 ml of hydrochloric acid was added.After completion of the addition, the reaction mixture was stirred at 80 ° C. for 2 hours. After completion of the stirring, 141 mg of 5- (trifluoromethyl) pyridine-2,3-diamine was added to the reaction mixture at room temperature.After the addition was completed, the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, 10 ml of water was added to the reaction mixture at room temperature. After completion of the addition, sodium hydrogencarbonate was added to the reaction mixture for neutralization, followed by extraction with ethyl acetate (20 ml × 2).The obtained organic layer was dehydrated with anhydrous sodium sulfate and dried, and then the solvent was distilled off under reduced pressure. The precipitated solid was filtered off by filtration.The resulting solid was washed with diisopropyl ether to give the desired product 3- [3- (ethylsulfonyl) -6-iodoimidazo [1,2-a] pyridin-2-yl] - 7 - (trifluoromethyl ) Pyrido [2,3-b] pyrazine as a yellow solid.

References: [1]Patent: JP2018/27943,2018,A .Location in patent: Paragraph 0223.

29
1-(4-(3-chlorobenzamido)phenyl)cyclobutane-1-carboxylic acid [ No CAS ]
[ 107867-51-6 ]
N-(4-(1-((2-amino-5-(trifluoromethyl)pyridin-3-yl)carbamoyl)cyclobutyl)phenyl)-3-chlorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To the solution of I-B (499 mg, 1.51 mmol) in DMA (2.5 mL) at -5 °C was added thionyl chloride (0.14 mL, 1.9 mmol). After stirring for 40 min at -5 °C, a solution of 5- (trifluoromethyl)pyridine-2,3-diamine (295 mg, 1.66 mmol) in DMA (3 mL) was added to this reaction mixture. The reaction mixture was stirred at RT for 18 h. The reaction was quenched with water and extracted with DCM. Solid precipitated out from the organic phase, which was collected via filtration to afford N-(4-(l-((2-amino-5-(trifluoromethyl)pyridin-3- yl)carbamoyl)cyclobutyl)phenyl)-3-chlorobenzamide. MS (EI) m/z 489 [M+H]+.

References: [1]Patent: WO2019/27855,2019,A1 .Location in patent: Page/Page column 34-35.

30
[ 107867-51-6 ]
4-(1-(6-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)cyclobutyl)benzoic acid [ No CAS ]