81719-53-1|3,5-Dichloropyridine-2-carboxylic Acid| Ambeed

Structure of 81719-53-1

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Quality Control of [ 81719-53-1 ] Purity: 95% SDS Specification

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Product Details of [ 81719-53-1 ]

CAS No. :	81719-53-1
Formula :	C₆H₃Cl₂NO₂
M.W :	192.00
SMILES Code :	C1=C(Cl)C=NC(=C1Cl)C(=O)O
MDL No. :	MFCD03230005
InChI Key :	JYKZCYLZWZCQFP-UHFFFAOYSA-N
Pubchem ID :	219989

Safety of [ 81719-53-1 ]

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

Computational Chemistry of [ 81719-53-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	41.22
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	50.19 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.23
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	1.97
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.09
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.	0.09
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	2.04
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.48

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.61
Solubility	0.472 mg/ml ; 0.00246 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.	-2.65
Solubility	0.43 mg/ml ; 0.00224 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	-2.63
Solubility	0.446 mg/ml ; 0.00232 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.	-6.07 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.	0.56

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)	1.58

Application In Synthesis of [ 81719-53-1 ]

* 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 [ 81719-53-1 ]

[ 81719-53-1 ] Synthesis Path-Downstream 1~35

1
[ 109-06-8 ]
[ 81719-53-1 ]

References: [1]Journal of the Chemical Society,1908,vol. 93,p. 1998.

2
[ 81719-53-1 ]
[ 56-81-5 ]
[ 2457-47-8 ]

References: [1]Journal of the Chemical Society,1908,vol. 93,p. 1998.

3
[ 81719-53-1 ]
[ 70151-22-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2h;	3,5-dichloro-2-(chloromethyl)pyridine; [00376] To a 0 C solution of 5-chloropicolinic acid (5.00 g, 26.0 mmol) and N,N- dimethylformamide (1 drop) in dichloromethane (20 mL) was added oxalyl chloride (3.28 g, 26.0 mmol) dropwise, after which the reaction mixture was allowed to warm up to room temperature and stirred at that temperature for two hours. The reaction was then cooled again to 0 C, after which methanol (10 mL) was added dropwise to the reaction mixture, and the reaction was allowed to stir at room temperature for one hour where it was shown as complete by LCMS analysis. The reaction mixture was washed with saturated sodium bicarbonate solution, dried (magnesium sulfate), filtered and concentrated to afford methyl 3,5-dichloropyridine-2-carboxylate (5.36 g, 26.0 mmol, 100% yield ) as a white solid.[00377] To a 0 C solution of methyl 3,5-dichloropyridine-2-carboxylate (5.00 g, 24.3 mmol) in methanol (40 mL) was added sodium borohydride (1.80 g, 48.5 mmol), after which the reaction was warmed to room temperature and stirred at that temperature for two hours. The reaction mixture was then quenched by the addition of water (5 mL), concentrated to a residue, reconstituted in water (60 mL), extracted with ethyl acetate (2 x 60 mL), dried (magnesium sulfate), filtered and concentrated to afford (3,5-dichloropyridin-2-yl)methanol (2.90 g, 16.3 mmol, 67% yield ) as a viscous oil. This material was used in the subsequent step without any purification.[00378] To a 0 C solution of (3,5-dichloropyridin-2-yl)methanol (2.90 g, 16.3 mmol) in dichloromethane (50 mL) was added thionyl chloride (2.31 g, 19.6 mmol) dropwise, after which the reaction mixture was allowed to warm up to room temperature and stirred at that temperature for two hours. The reaction mixture was washed by the addition of saturated sodium bicarbonate solution (1 x 40 mL) and the organic layer was separated, dried (sodium sulfate), filtered and concentrated to a residue. Purification was achieved by silica gel chromatography using 9% ethyl acetate in hexanes to afford 3,5-dichloro-2- (chloromethyl)pyridine (2.40 g, 12.2 mmol, 75% yield) as an off-white solid. NMR (300 MHz, CDC13) delta (ppm): 8.36 (s, 1H), 7.56 (s, 1H), 4.66 (s, 2H).
100%	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; toluene; at 0 - 20℃; for 2.5h;	3,5-Dichloropicolinic acid (61.5 mg, 320 muiotaetaomicron) was suspended in dichloromethane (5 mL), the suspension was cooled to 0-5C (ice bath) and oxalyl chloride (56.9 mg, 39.3 mu, 448 muiotaetaomicron) as well as dimethylformamide (0.308 M in toluene, 48 mu, 15 muiotaetaomicron) were added. The mixture was stirred for 2.5 h at room temperature. Then, it was concentrated in vacuo (40C, 5 mbar) and dried azeotropically by two cycles of addition of toluene (3 mL) followed by concentration in vacuo to afford 3,5-dichloropicolinoyl chloride as yellow oil (67 mg, quant.). After that, tert-butyl ((3aS,4R,8R)-4-(5-amino-2-fluorophenyl)-4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H-isothiazolo[l,5-a][l,4]thiazin-6-yl)carbamate (Int-16ABp, 80 mg, 188 muetaiotaomicron) was dissolved in dichloromethane (5 mL), the solution cooled to 10C and N,N- diisopropylethylamine (41.4 mg, 56 mu, 320 mumol) was added, followed by a solution of 3,5- dichloropicolinoyl chloride (vide supra, 54 mg, 256 muiotaetaomicron) in dichloromethane (4 mL). The reaction mixture was stirred for 15 min at 10C. Then, methanol (2 mL) was added, the mixture was stirred for 5 min at room temperature and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 30:70 to 100:0) to yield, after drying in vacuo (40C, 5 mbar), the title compound as a light brown solid (103 mg, 92%). HPLC (method LCMS_fglm) tR = 1.34 min. MS (ES+) m/z 598.4 [M+H].
100%	With thionyl chloride; In N,N-dimethyl-formamide; at 60℃; for 2h;	N,N-Dimethylfonnamide (0.05 mL, 0.60 mmol) was added to <strong>[81719-53-1]3,5-dichloropicolinic acid</strong> (15 g, 78 mmol). The mixture was treated with thionyl chloride (45 mL, 620 mmol) and heated at 60 C for 2 hours. The solution was cooled to ambient temperature and concentrated in vacuo. Toluene (50 mL) was added and the mixture was concentrated and dried in vacuo to afford methyl 3,5-dichioropicolinic acid chloride as a light tan solid (17 g, 100% yield).1H NMR (500 MHz, chloroform-d) oe (ppm) 8.64 (d, 1 H), 7.93 (d, 1 H).

	With thionyl chloride;N,N-dimethyl-formamide; for 0.25h;Heating / reflux;	Example 54(a) 3,5-Dichloro-2-(piperidin-l-ylcarbonyl)pyridine; 3,5-Dichloro-2-pyridine carboxylic acid (1.25 g, 6.5 mmol) was suspended in thionyl chloride (10 ml). DMF (2 drops) was added and the mixture was refluxed for 15 minutes under an atmosphere of nitrogen. The solvent was evaporated. Toluene was added and the solvent was evaporated to give a solid. The solid was dissolved in DCM (8 ml) and the mixture was cooled to 0 C. Piperidine (0.64 ml, 6.5 mmol) was added dropwise followed by triethylamine (0.91 ml, 6.5 mmol). The cooling bath was removed. The mixture was <n="76"/>stirred under nitrogen atmosphere until RT was reached and then for an additional 15 minutes. The mixture was washed with aqueous sodium bicarbonate and the organic phase was dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography eluting with gradients of heptane and ethyl acetate to give the title compound (1.28 g, 76%).1H NMR (400 MHz, CDCl3) delta ppm 8.46 (d, 1 H) 7.77 (d, 1 H) 3.74 (m., 2 H) 3.11 - 3.16 (m, 2 H) 1.64 - 1.71 (m, 4 H) 1.55 (m, 2 H) MS (ESI) m/z 259; 261 (M+l).
	With thionyl chloride; N,N-dimethyl-formamide; In toluene; for 2h;Reflux;	A mixture of 3,5-dichloro-pyndme-2-carboxylic acid (5 76 g, 30 mmol) and thionyl chloride (44 mL, 60mmol) in 50 mL of anhydrous toluene and 0 5 mL of anhydrous DMF was refluxed for 2 h The solvent was removed under reduced pressure to give a mobile oil residue which was azeoptoped with toluene (2OmL) The residue was dissolved in 20 mL of anhydrous THF and this solution was added dropwise to a solution of ethyl 3-(dimethylamino)acrylate (47g, 33 mmol) and triethylamine (3 64 g, 36 mmol) in 20 mL of anhydrous THF under nitrogen, and the mixture was heated under reflux for 7 hours The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure Water (10OmL) and ethyl acetate (10OmL) was added to allow partitioning The organic layer was washed successively with saturated aqueous sodium bicarbonate(x2), water, brine, dried over sodium sulfate and was concentrated under reduced pressure The crude product was purified by ISCO (hexane/EtOAc, 0-40%, 30 mm, 100%, 20 mm) to give 5 9 g (62%) of pure product as yellow oil
110 mg	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; toluene; at 0 - 20℃; for 1.5h;	3,5-Dichloropicolinic acid (200 mg, 1.04 mmol) was suspended in dichloromethane (4 mL), the suspension was cooled to 0-5C (ice bath) and oxalyl chloride (363 mg, 250 mu, 2.86 mmol,) as well as a drop of a mixture of dimethylformamide and toluene (1:3, v/v) were added. The mixture was stirred for 1.5 h at room temperature. Then, it was concentrated in vacuo at 40C, the residue was treated with n-heptane (4 mL) and again concentrated and dried in vacuo (40C, 5 mbar) to afford 3,5-dichloropicolinoyl chloride as yellow solid (110 mg). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-7-yl)carbamate (Int-17AA, 100 mg, 228 mupiiotaomicron) was dissolved in dichloromethane (4 mL), the solution cooled to 0-5C (ice bath) and N,N- diisopropylethylamine (75.5 mg, 100 mu, 584 muiotaetaomicron) was added, followed by a solution of 3,5- dichloropicolinoyl chloride (vide supra, 60 mg, 285 muiotaetaomicron) in dichloromethane (1.2 mL).The reaction mixture was stirred at 0-5C for 1.5 h. Then, ethanol (100 mu) was added, the mixture was stirred for 45 min at room temperature, poured onto a saturated aqueous solution of sodium hydrogencarbonate (15 mL) and extracted with dichloromethane (1 x 30 mL, 2 x 20 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 60:40 to 80:20) to yield, after drying in vacuo (50C, 5 mbar), the title compound as a light yellow foam (140 mg, 99% yield). HPLC (method LCMS_gradient) tR = 3.2 min. XH NMR (CDC13, 400 MHz): delta 1.48 (s, 9 H), 1.79 (s, 3 H), 1.81-2.02 (m, 3 H), 1.85 (s, 3 H), 1.95 (s, 3 H), 2.40 (dddd, J = 3.8, 12.6, 12.6, 12.6 Hz, 1 H), 3.36-3.43 (m, 1 H), 3.58-3.66 (m, 1 H), 4.08 (dd, J = 3.2, 12.4 Hz, 1 H), 7.57 (dd, .7 = 8.9, 10.7 Hz, 1 H), 7.95 (d, 7 = 2.1 Hz, 1 H), 8.44 (dd, / = 3.1, 9.0 Hz, 1 H), 8.57 (d, J = 1.9 Hz, 1 H), 10.16 (br s, 1 H, exch), 11.23 (br s, 1 H, exch). MS (ES+) m/z 613.3, 615.3 & 617.3 [M+H, 2 CI] .

References: [1]Patent: WO2012/88469,2012,A1 .Location in patent: Page/Page column 153-154.
[2]Patent: WO2017/25491,2017,A1 .Location in patent: Page/Page column 50.
[3]Patent: WO2018/89330,2018,A2 .Location in patent: Paragraph 00263.
[4]Journal fur praktische Chemie (Leipzig 1954),1937,vol. <2> 148,p. 13,16.
[5]Patent: WO2008/2244,2008,A2 .Location in patent: Page/Page column 74-75.
[6]Patent: WO2009/89263,2009,A2 .Location in patent: Page/Page column 117.
[7]ChemMedChem,2011,vol. 6,p. 1249 - 1257.
[8]Patent: WO2016/55496,2016,A1 .Location in patent: Page/Page column 132.

4
[ 81719-53-1 ]
[ 2457-47-8 ]

References: [1]Journal fur praktische Chemie (Leipzig 1954),1937,vol. <2> 148,p. 13,16.

5
[ 5439-04-3 ]
[ 81719-53-1 ]

References: [1]Journal fur praktische Chemie (Leipzig 1954),1937,vol. <2> 148,p. 13,16.

7
[ 14482-51-0 ]
[ 124-38-9 ]
[ 81719-53-1 ]

References: [1]European Journal of Organic Chemistry,2001,p. 1371 - 1376.

8
[ 110-89-4 ]
[ 81719-53-1 ]
[ 1000848-51-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0 - 20℃; for 0.25h;	Example 54(a) 3,5-Dichloro-2-(piperidin-l-ylcarbonyl)pyridine; 3,5-Dichloro-2-pyridine carboxylic acid (1.25 g, 6.5 mmol) was suspended in thionyl chloride (10 ml). DMF (2 drops) was added and the mixture was refluxed for 15 minutes under an atmosphere of nitrogen. The solvent was evaporated. Toluene was added and the solvent was evaporated to give a solid. The solid was dissolved in DCM (8 ml) and the mixture was cooled to 0 C. Piperidine (0.64 ml, 6.5 mmol) was added dropwise followed by triethylamine (0.91 ml, 6.5 mmol). The cooling bath was removed. The mixture was <n="76"/>stirred under nitrogen atmosphere until RT was reached and then for an additional 15 minutes. The mixture was washed with aqueous sodium bicarbonate and the organic phase was dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography eluting with gradients of heptane and ethyl acetate to give the title compound (1.28 g, 76%).1H NMR (400 MHz, CDCl3) delta ppm 8.46 (d, 1 H) 7.77 (d, 1 H) 3.74 (m., 2 H) 3.11 - 3.16 (m, 2 H) 1.64 - 1.71 (m, 4 H) 1.55 (m, 2 H) MS (ESI) m/z 259; 261 (M+l).

References: [1]Patent: WO2008/2244,2008,A2 .Location in patent: Page/Page column 74-75.

9
[ 81719-53-1 ]
[ 5439-08-7 ]

References: [1]Journal fur praktische Chemie (Leipzig 1954),1937,vol. <2> 148,p. 13,16.
[2]Patent: WO2012/88469,2012,A1 .

10
[ 846045-08-7 ]
[ 81719-53-1 ]

References: [1]Journal fur praktische Chemie (Leipzig 1954),1937,vol. <2> 148,p. 13,16.

11
3,4,5-trichloro-pyridine-2-carbonyl chloride [ No CAS ]
[ 81719-53-1 ]

References: [1]Journal fur praktische Chemie (Leipzig 1954),1937,vol. <2> 148,p. 13,16.

12
[ 200711-45-1 ]
[ 81719-53-1 ]

References: [1]Journal fur praktische Chemie (Leipzig 1954),1937,vol. <2> 148,p. 13,16.

13
[ 85331-33-5 ]
[ 81719-53-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sulfuric acid; water; at 115℃;	3,5-Dichloro-pyridine-2-carbonitrile (10 g, 57 8 mmol) was dissolved in 100 mL of 95% concentrated sulfuric acid and this mixture was heated to 115 C overnight The reaction mixture was then cooled, poured over ice with strong stirring The resulting solid was filtered, washed with water and dried at 40 C under reduced pressure to give 94g (85%) of pure product as a white solid

References: [1]Patent: WO2009/89263,2009,A2 .Location in patent: Page/Page column 117.

14
[ 81719-53-1 ]
[ 1200498-17-4 ]
[ 1200498-19-6 ]

Yield	Reaction Conditions	Operation in experiment
		Ninth step To a stirred under ice-cooling solution of <strong>[81719-53-1]3,5-dichloropyridine-2-carboxylic acid</strong> in N,N-dimethylformamide (0.5 ml), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.05 mg) and triethylamine (0.01 mg) were added. After stirred for 10 minutes, a solution of the compound (116) (0.05 g) in N,N-dimethylformamide (2 ml) was added, and the mixture was stirred at room temperature for 2.5 hours. Water was added, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography to afford the compound (117) (0.05 g). 1H-NMR (CDCl3) delta: 3.89 (1H, d, J = 11.7 Hz), 3.99 (1H, d, J = 11.7 Hz), 4.26 (1H, t, J = 6.8 Hz), 4.47 (3H, d, J = 6.8 Hz), 6.96 (1H, dd, J = 8.9, 7.2 Hz), 7.10-7.14 (2H, m), 7.28-7.42 (9H, m), 7.60 (2H, d, J = 7.3 Hz), 7.74-7.76 (2H, m), 7.90 (1H, d, J = 2.0 Hz), 8.46 (1H, d, J = 2.0 Hz), 9.77 (1H, s).

References: [1]Patent: EP2305672,2011,A1 .Location in patent: Page/Page column 84-85.

15
[ 81719-53-1 ]
[ 1310374-19-6 ]
C₂₂H₂₃Cl₂FN₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 22℃; for 16h;	Synthesis of the amides H and IGeneral ProcedureTo a solution of the aniline G (0.32 mmol) in dry dichloromethane (5 ml) was added subsequently EDCI (0.35 mmol), the carboxylic acid (0.35 mmol) and stirring was continued at 22 C. for 16 h. The mixture was purified on prep. RP-18 HPLC using a gradient of acetonitrile and water (containing 0.1% of triethylamine) to give the t-butyloxycarbonyl protected intermediate H.A solution of t-butyloxycarbonyl protected intermediate H (0.27 mmol) in 4.0 ml dry dichloromethane was added CF3COOH (1 ml) and stirring was continued at 22 C. for 90 min. The mixture was evaporated, the residue was dissolved in DMSO and purified by prep. RP-18 HPLC using a gradient of acetonitrile and water (containing 0.1% of triethylamine) to give the pure amide I in yields of 10-70%.; Example 13,5-Dichloro-pyridine-2-carboxylic acid [3-((S)-2-amino-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amideThe coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and <strong>[81719-53-1]3,5-dichloro-pyridine-2-carboxylic acid</strong> followed by deprotection using procedure H yielded the title compound.MS (ESI): m/z=398.1 [M+H]+.
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 22℃; for 16h;	To a solution of the aniline G (0.32 mmol) in dry dichloromethane (5 ml) was added subsequently EDCI (0.35 mmol), the carboxylic acid acid (0.35 mmol) and stirring was continued at 22 C for 16 h. The mixture was purified on prep. RP-18 HPLC using a gradient of acetonitrile and water (containing 0.1 % of triethylamine) to give the t-butyloxycarbonyl protected intermediate H.A solution of t-butyloxycarbonyl protected intermediate H (0.27 mmol) in 4.0 ml dry dichloromethane was added CF3COOH (1 ml) and stirring was continued at 22 C for 90 min. The mixture was evaporated, the residue was dissolved in DMSO and purified by prep. RP-18 HPLC using a gradient of acetonitrile and water (containing 0.1 % of triethylamine) to give the pure amide I in yields of 10-70%.The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[l,3]oxazin-2- yl]-carbamic acid tert-butyl ester from experiment Fl (R3= Me) and 3,5-dichloro-pyridine-2- carboxylic acid followed by deprotection using procedure Eta yielded the title compound. MS (ESI): m/z = 398.1 [M+H]+.

References: [1]Patent: US2011/144098,2011,A1 .Location in patent: Page/Page column 18-19.
[2]Patent: WO2011/70029,2011,A1 .Location in patent: Page/Page column 42-43.

16
[ 81719-53-1 ]
[ 1369543-62-3 ]
[ 1369542-85-7 ]

Yield	Reaction Conditions	Operation in experiment
37%		Example B9Preparation of compound 27: rac-N-(3-r6-amino-4-methyl-2-(trifluoromethyl)-4,7- dihydropyrazolo [ 1 , 5 -a"\|pyrazin-4-yll -4-fluorophenyl I -3 , 5 -dichloropyridine-2- carboxamide and compound 28: (R)-N-(3-r6-amino-4-methyl-2-(trifluoromethyl)- 4, 7-dihydropyrazolo [ 1 , 5-a"\|pyrazin-4-yll -4-fluorophenyl I -3 , 5 -dichloropyridine-2- carboxamide and compound 29: (S)-N-{3-[6-amino-4-methyl-2-(trifluoromethyl)- 4,7-dihydropyrazolo[l,5-alpyrazin-4-yl -4-fluorophenyl}-3,5-dichloropyridine-2- carboxamide3,5-Dichloro-2-pyridinecarboxylic acid (0.54 g, 0.81 mmol) was dissolved in MeOH (4 mL) and DMTMM (0.223 g, 0.81 mmol) was added. After stirring the mixture for 5 minutes, a solution of intermediate 63 (0.22 g, 0.67 mmol) in MeOH (4 mL) was added at 0 C, and the mixture was stirred for an additional 4 h. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 7 M solution fo ammonia in methanol/DCM 0/100 to 5/95). The desired fractions were collected and concentrated in vacuo. The residue was crystallized from DIPE to yield compound 27 (0.124 g, 37% yield) as a white solid. This racemic compound was then purified by preparative SFC on Chiralpak AD-H column (20 x 250 mm), mobile phase (C02, EtOH with 0.3% iPr H2), yielding compound 28 (0.038 g, 11%) yield) and compound 29 (0.036 g, 11% yield) as pure enantiomers (both as solid compounds).
37%		3,5-Dichloro-2-pyridinecarboxylic acid (0.54 g, 0.81 mmol) was dissolved in MeOH (4 mL) and DMTMM (0.223 g, 0.81 mmol) was added. After stirring the mixture for 5 minutes, a solution of intermediate 63 (0.22 g, 0.67 mmol) in MeOH (4 mL) was added at 0 C., and the mixture was stirred for an additional 4 h. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 7 M solution of ammonia in methanol/DCM 0/100 to 5/95). The desired fractions were collected and concentrated in vacuo. The residue was crystallized from DIPE to yield compound 27 (0.124 g, 37% yield) as a white solid. This racemic compound was then purified by preparative SFC on Chiralpak AD-H column (20×250 mm), mobile phase (CO2, EtOH with 0.3% iPrNH2), yielding compound 28 (0.038 g, 11% yield) and compound 29 (0.036 g, 11% yield) as pure enantiomers (both as solid compounds).

References: [1]Patent: WO2012/38438,2012,A1 .Location in patent: Page/Page column 63.
[2]Patent: US2013/190318,2013,A1 .Location in patent: Paragraph 0245; 0246.

17
[ 81719-53-1 ]
[ 1318753-55-7 ]

References: [1]ChemMedChem,2011,vol. 6,p. 1249 - 1257.

18
[ 81719-53-1 ]
[ 1318753-30-8 ]

References: [1]ChemMedChem,2011,vol. 6,p. 1249 - 1257.

19
[ 81719-53-1 ]
[ 1318753-58-0 ]

References: [1]ChemMedChem,2011,vol. 6,p. 1249 - 1257.

20
[ 81719-53-1 ]
[ 1318753-65-9 ]

References: [1]ChemMedChem,2011,vol. 6,p. 1249 - 1257.

21
[ 81719-53-1 ]
[ 1318753-72-8 ]

References: [1]ChemMedChem,2011,vol. 6,p. 1249 - 1257.

22
[ 81719-53-1 ]
[ 1383985-65-6 ]
[ 1383982-81-7 ]

Yield	Reaction Conditions	Operation in experiment
18%		Example 20oN-[(1r,4r)-4''-Amino-4-methoxy-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-6'-yl]-3,5-dichloropyridine-2-carboxamide; N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (55.8 mg, 0.29 mmol) was added to a suspension of <strong>[81719-53-1]3,5-dichloropicolinic acid</strong> (43.0 mg, 0.22 mmol) in DCM (0.5 mL). The obtained solution was stirred for 5 min and added dropwise over 2 min to an ice-cooled solution of 4-methoxy-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4'',6'-diamine (Example 20j Step 1, 70 mg, 0.22 mmol) and 2M HCl (0.112 mL, 0.22 mmol) in DMF (0.5 mL). The mixture was stirred at 0 C. for 60 min. The mixture was stirred at r.t. for 2 days before the mixture was concentrated and diluted with DMSO and purified by preparative chromatography. The fractions were pooled and extracted with DCM (×3), and the organic phase was passed through a phase separator. Removal of the solvent provided the title compound (19.5 mg, 18% yield): 1H NMR (500 MHz, CDCl3) ppm 1.06 (td, J=13.56, 3.78 Hz, 1H), 1.26-1.43 (m, 2H), 1.56 (td, J=13.56, 3.15 Hz, 1H), 1.61-1.73 (m, 2H), 1.89-1.99 (m, 2H), 2.31 (s, 3 H), 3.03-3.10 (m, 1H), 3.10-3.20 (m, 2H), 3.33 (s, 3H), 7.25 (d, J=1.89 Hz, 1H), 7.31 (d, J=8.20 Hz, 1H), 7.41 (d, J=8.20 Hz, 1H), 7.87 (d, J=1.89 Hz, 1H), 8.44 (d, J=2.21 Hz, 1H), 9.66 (s, 1H); MS (ES+) m/z 486 [M+H]+.

References: [1]Patent: US2012/165347,2012,A1 .Location in patent: Page/Page column 62.

23
[ 81719-53-1 ]
[ 1397683-46-3 ]
[ 1397683-05-4 ]

Yield	Reaction Conditions	Operation in experiment
82%		Example B3Preparation of compound 3: rac-<strong>[81719-53-1]3,5-dichloro-pyridine-2-carboxylic acid</strong> [3-(4-amino- 6-methyl-6, 7-dihydro-pyrazolo [ 1 , 5 -a]pyrazin-6-yl)-phenyl] -amide3,5-Dichloro-pyridine-2-carboxylic acid (112 mg, 0.58 mmol) was added to a solution of 4-(4, 6-dimethoxy- 1,3,5 -triazin-2-yl)-4-methylmorpholinium chloride (176.2 mg, 0.64 mmol) in MeOH (5 mL). The mixture was stirred at room temperature for 5 min. Then the mixture was cooled to 0 C and a solution of intermediate All (128 mg, 0.53 mmol) in MeOH (5 mL) was added. The mixture was warmed to roomtemperature and stirred for 3 hours. The mixture was treated with a saturated solution of Na2C03 and H20 and extracted with DCM. The organic layer was separated, dried (MgS04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; MeOH/DCM). The desired fractions were collected and the solvents evaporated in vacuo. The crude product was triturated with Et20 and then was purified by flash column chromatography (silica gel; MeOH/DCM). The desired fractions were collected and the solvents evaporated in vacuo to yield compound 3 (180 mg, 82% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) delta ppm 1.41 (s, 3 H), 4.12 - 4.45 (m, 2 H), 6.54 (br. s., 2 H), 6.64 (d, J=2.0 Hz, 1 H), 7.25 - 7.32 (m, 2 H), 7.45 (d, J=2.0 Hz, 1 H), 7.63 (m, J=6.3, 2.5, 2.5 Hz, 1 H), 7.82(br. s, 1 H), 8.43 (d, J=2.0 Hz, 1 H), 8.72 (d, J=2.0 Hz, 1 H), 10.64 (br. s., 1 H).

References: [1]Patent: WO2012/117027,2012,A1 .Location in patent: Page/Page column 55.

24
[ 81719-53-1 ]
[ 1397683-46-3 ]
(R*)-3,5-dichloro-pyridine-2-carboxylic acid[3-(4-amino-6-methyl-6,7-dihydro-pyrazolo[1,5-a]pyrazin-6-yl)-phenyl]-amide [ No CAS ]
(S*)-3,5-dichloro-pyridine-2-carboxylic acid[3-(4-amino-6-methyl-6,7-dihydro-pyrazolo[1,5-a]pyrazin-6-yl)-phenyl]-amide [ No CAS ]

References: [1]Patent: WO2012/117027,2012,A1 .

25
[ 81719-53-1 ]
[ 1397683-52-1 ]
[ 1397683-13-4 ]

Yield	Reaction Conditions	Operation in experiment
55%		Example B7Preparation of compound 10: rac-<strong>[81719-53-1]3,5-dichloro-pyridine-2-carboxylic acid</strong> [3-(4-amino- 6-methyl-2-trifluoromethyl-6,7-dihydro-pyrazolo[l,5-a]pyrazin-6-yl)-phenyl]-amide and compound 11: (R)-<strong>[81719-53-1]3,5-dichloro-pyridine-2-carboxylic acid</strong> [3-(4-amino-6- methyl-2-trifluoromethyl-6, 7-dihydro-pyrazolo [ 1 , 5 -a]pyrazin-6-yl)-phenyl] -amide and compound 12: (S)-<strong>[81719-53-1]3,5-dichloro-pyridine-2-carboxylic acid</strong> [3-(4-amino-6-methyl-2- trifluoromethyl-6, 7-dihydro-pyrazolo [ 1 , 5 -a]pyrazin-6-yl)-phenyl] -amide3,5-Dichloro-2-pyridinecarboxylic acid (70 mg, 0.366 mmol) was added to a solution of 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (119 mg, 0.431 mmol) in MeOH (5 mL). The mixture was stirred at room temperature for 5 min. Then the mixture was cooled to 0 C and a solution of intermediate A28 (111 mg, 0.359 mmol) in MeOH (5 mL) was added. The mixture was warmed to roomtemperature and stirred for 4 hours. The mixture was treated with a saturated solution of Na2C03 and H20 and extracted with DCM. The organic layer was separated, dried (MgS04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; MeOH/DCM). The desired fractions were collected and the solvents evaporated in vacuo. The crude product was triturated with Et20, sonicated, filtered and dried in vacuo at 50C to yield compound 10 (95 mg, 55%) yield) as a white solid. This racemic compound was then further purified by preparative SFC on Chiralpak AD-H 5mu?iota (250 x 20 mm), mobile phase (0.3% iPrNH2, 70%) C02, 30%) iPrOH). The desired fractions for each enantiomer were collected and concentrated in vacuo to yield compound 11 (40 mg, 23% yield). 1H NMR (400 MHz, DMSO-i ) delta ppm 1.42 (s, 3 H), 4.35 - 4.47 (m, 2 H), 6.61 (br. s., 2 H), 7.09 (br. s, 1 H), 7.26 - 7.35 (m, 2 H), 7.59 - 7.67 (m, 1 H), 7.83 (br. s, 1 H), 8.43 (d, J=2.1 Hz, 1 H), 8.72 (d, J=2.1 Hz, 1 H), 10.67 (s, 1 H) and compound 12 (38 mg, 22% yield), for which the 1H NMR was in agreement with the one of compound 11

References: [1]Patent: WO2012/117027,2012,A1 .Location in patent: Page/Page column 58.

26
[ 81719-53-1 ]
[ 1397683-69-0 ]
[ 1397683-17-8 ]

Yield	Reaction Conditions	Operation in experiment
57%		Example B9Preparation of compound 14: rac-<strong>[81719-53-1]3,5-dichloro-pyridine-2-carboxylic acid</strong> [3-(4-amino-6- methyl-6,7-dihydro-pyrazolo[l,5-a]pyrazin-6-yl)-4-fluoro-phenyl]-amide and compound 15: (R)-<strong>[81719-53-1]3,5-dichloro-pyridine-2-carboxylic acid</strong> [3-(4-amino-6-methyl- 6,7-dihydro-pyrazolo[l,5-a]pyrazin-6-yl)-4-fluoro-phenyl]-amide and compound 16: (S )-3 , 5 -dichloro-pyridine-2-carboxylic acid [3 -(4-amino-6-methyl-6, 7-dihydro- pyrazolo[l,5-a]pyrazin-6-yl)-4-fluoro-phenyl]-amide3,5-Dichloro-2-pyridinecarboxylic acid (75.5 mg, 0.393 mmol) was added to a solution of 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (128 mg, 0.463 mmol) in MeOH (5 mL). The mixture was stirred at room temperature for 5 min. Then the mixture was cooled to 0 C and a solution of intermediate A49 (100 mg, 0.386 mmol) in MeOH (5 mL) was added. The mixture was warmed to room temperature and stirred for 4 hours. The mixture was treated with a saturated solution of Na2C03 and H20 and extracted with DCM. The organic layer was separated, dried (MgS04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; MeOH/DCM). The desired fractions were collected and the solvents evaporated in vacuo. The crude product was triturated with Et20, sonicated, filtered and dried in vacuo at 50C. The resulting compound was purified one addition time by flash column chromatography (silica gel; MeOH/DCM) to yield, after treatment with AcOEt and DIPE, compound 14 (95 mg, 57% yield) as a white solid. This racemic compound was then further purified by preparative SFC on Chiralcel OJ-H 5 muiotaeta (250 x 20 mm), mobile phase (0.3% iPr H2, 85% C02, 15% EtOH). The desired fractions for each enantiomer were collected and concentrated in vacuo to yield compound 15 (38 mg, 23% yield). 1H MR (400 MHz, CDC13) delta ppm 1.58 (s, 3 H), 2.52 (br. s., 2 H), 4.41 (br. d, J=13.2 Hz, 1 H), 4.62 (dd, J=13.2, 0.9 Hz, 1 H), 6.43 (d, J=2.1 Hz, 1 H), 7.08 (dd, J=11.7, 8.9 Hz, 1 H), 7.52 (d, J=2.1 Hz, 1 H), 7.81 (dd, J=6.9, 2.8 Hz, 1 H), 7.89 (d, J=2.1 Hz, 1 H), 7.94 (ddd, J=8.8, 4.1, 3.0 Hz, 1 H), 8.42 (d, J=2.1 Hz, 1 H), 9.71 (br. s., 1 H) and compound 16 (40 mg, 24% yield), for which the 1H NMR was in agreement with the one of compound 15.

References: [1]Patent: WO2012/117027,2012,A1 .Location in patent: Page/Page column 59-60.

27
[ 81719-53-1 ]
[ 1310350-45-8 ]
[ 1310347-44-4 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 3980 - 3995.

28
[ 81719-53-1 ]
[ 1301740-78-2 ]
[ 1310373-42-2 ]

Yield	Reaction Conditions	Operation in experiment
51%		General procedure: A solution of the carboxylic acid (0.23 mmol) in methanol (5 ml) was cooled to 0 C. 4-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate* (DMTMM) (80 mg, 0.27 mmol) was added and the solution was stirred at 0 C for 30 minutes. Thereafter, a solution of the intermediate aniline (0.21 mmol) in methanol (5 ml) was added dropwise at 0 C via syringe. The reaction mixture was stirred at 23 C for 18-60 hours. For the workup, the reaction mixture was concentrated at reduced pressure, then poured into a solution of Na2CO3 (1M) followed by the extraction with DCM. The organic layer was separated, washed with brine and dried over Na2SO4. Removal of the solvent left the crude product which was purified by chromatography on silica gel using a mixture of DCM-MeOH or heptane-EtOAc or by preparative HPLC to give the pure amides.(* The chloride salt can be replaced by the corresponding tetrafluoroborate.)

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4239 - 4243.

29
[ 81719-53-1 ]
[ 1369543-62-3 ]
(R*)-N-{3-[6-amino-4-methyl-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrazin-4-yl]-4-fluorophenyl}-3,5-dichloropyridine-2-carboxamide [ No CAS ]
(S*)-N-{3-[6-amino-4-methyl-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrazin-4-yl]-4-fluorophenyl}-3,5-dichloropyridine-2-carboxamide [ No CAS ]

References: [1]Patent: US2013/190318,2013,A1 .

30
[ 81719-53-1 ]
[ 1606165-46-1 ]
C₂₈H₂₉Cl₂FN₄O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 1h;	To a mixture of compound 3-13 (28.2 mg, 0.065 mmol), 3,5-dichioropicolinicacid (13.74 mg, 0.072 mmol), HOBt monohydrate (11.96 mg, 0.078mmol) and DMAP (0.8 mg, 0.007 mmol) in DMF (0.5 mL) was added EDC hydrochloride (14.97 mg,-0.078 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was treated with an aqueous sodium bicarbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brineand dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate). The resulting compound was dissolved in formic acid (0.225 mL, 5.86 mmol), and the solution was stirred at room temperature for 5.5 hours. To the solution was added a saturated aqueous sodium bicarbonate solution, and theaqueous layer was extracted with ethyl acetate. The organic layer was washed withbrine, and dried- over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform-methanol) to give compound (1-16) (21.9 mg, 83% yield).

References: [1]Patent: WO2014/65434,2014,A1 .Location in patent: Paragraph 0177; 0182.

31
[ 81719-53-1 ]
[ 1448793-22-3 ]

Yield	Reaction Conditions	Operation in experiment
		Example 58 Synthesis of N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-3,5-dichloropicolinamide The title compound was synthesized by procedures and steps analogous to those described in Method F (Example 32) above, but using <strong>[81719-53-1]3,5-dichloropicolinic acid</strong> (Matrix). MS m/z=483 [M+H]+. Calculated for C18H13Cl2F5N4O2: 482. H NMR (300 MHz, CHLOROFORM-d) delta ppm 9.74 (br, 1H), 8.47 (d, 1H, J=2.2), 8.10 (m, 1H), 7.91 (d, 1H, J=2.2), 7.45 (dd, 1H, J=6.8, 2.7), 7.11 (dd, 1H, J=11.5, 9.0), 4.68 (dd, 1H, J=47.5, 9.1), 4.46 (dd, 1H, J=47.0, 9.1), 4.13 (m, 1H), 2.70 (dd, 1H, J=13.3, 2.6), 2.17 (t, 1H, J=13.3).

References: [1]Patent: US2014/249104,2014,A1 .Location in patent: Page/Page column.

32
[ 81719-53-1 ]
[ 1624603-70-8 ]

Yield	Reaction Conditions	Operation in experiment
		Example 68 Synthesis of N-(5-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-6-fluoropyridin-3-yl)-3,5-dichloropicolinamide The title compound was synthesized using steps and procedures analogous to those described in Method H (Example 66) above, but using <strong>[81719-53-1]3,5-dichloropyridine-2-carboxylic acid</strong> (Matrix Scientific) in step 2. MS m/z=466 [M]+. Calculated for C17H13Cl2F4N5O2: 466.2 1H NMR (400 MHz, CHLOROFORM-d) delta=9.87 (br. s., 1H), 8.80-8.71 (m, 1H), 8.53 (d, J=2.2 Hz, 1H), 8.08 (dd, J=2.3, 8.8 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 4.14-4.03 (m, 1H), 2.89 (dd, J=2.4, 14.0 Hz, 1H), 1.98 (t, J=13.3 Hz, 1H), 1.70 (s, 3H)

References: [1]Patent: US2014/249104,2014,A1 .Location in patent: Page/Page column.

33
[ 81719-53-1 ]
[ 1624604-72-3 ]

Yield	Reaction Conditions	Operation in experiment
		Example 172 Synthesis of N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4,5-difluorophenyl)-3,5-dichloropicolinamide The titled compound was synthesized by procedure and steps analogous to those described in Method Y, Example 163 above, but using <strong>[81719-53-1]3,5-dichloropyridine-2-carboxylic acid</strong> (Matrix Scientific) in step 10. MS m/z=482.9 [M+H]+. Calculated for C18H13Cl2F5N4O2: 483.2 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.69 (s, 3H) 1.93-1.99 (m, 1H) 2.84 (d, J=11.93 Hz, 1H) 4.10 (m, J=5.48 Hz, 1H) 7.01 (br. s., 1H) 7.92 (s, 1H) 8.11-8.22 (m, 1H) 8.49 (s, 1H) 9.80 (br. s., 1H)

References: [1]Patent: US2014/249104,2014,A1 .Location in patent: Page/Page column.

34
[ 81719-53-1 ]
[ 1624604-84-7 ]

Yield	Reaction Conditions	Operation in experiment
		Example 184 Synthesis of N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinamide The title compound was synthesized using steps and procedures analogous to those described in Method K (Example 79) above, but using <strong>[81719-53-1]3,5-dichloropicolinic acid</strong> (Matrix) in step 10. MS m/z=466 [M]+. Calculated for C17H13Cl2F4N5O2: 466.2 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.67 (s, 3H) 1.80 (t, J=12.72 Hz, 1H) 3.00 (dd, J=13.45, 3.07 Hz, 1H) 4.49 (ddd, J=9.10, 6.03, 3.00 Hz, 1H) 7.49 (dd, J=10.45, 8.99 Hz, 1H) 7.92 (d, J=2.05 Hz, 1H) 8.33 (dd, J=8.84, 3.00 Hz, 1H) 8.53 (d, J=2.05 Hz, 1H) 10.10 (s, 3H).

References: [1]Patent: US2014/249104,2014,A1 .Location in patent: Page/Page column.

35
[ 81719-53-1 ]
[ 18144-47-3 ]
tert-butyl 4-(3,5-dichloropicolinamido)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	Step 1 : tert-Butyl 4-(3,5-dichloropicolinamido)benzoate N,N-Diisopropylethylamine (5.46 ml, 31.3 mmol) was added to a stirred room temperature mixture of HATU (7.9 g, 20.8 mmol), tert-butyl-4-aminobenzoate 2.4 g (12.5 mmol), and 3,5- dichloropicolinic acid (2 g, 10.4 mmol) in DMF 30 ml. The mixture was stirred at room temperature overnight. The mixture was cooled and diluted with ethyl acetate. The organic phase was washed with aqueous sodium hydrogen carbonate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Biotage 40M), eluting with ethyl acetate/isohexane to give tert-butyl 4-(3,5- dichloropicolinamido)benzoate a yellow solid. MS (ESI) m/z 367.19 (M+H).

References: [1]Patent: WO2015/54087,2015,A1 .Location in patent: Page/Page column 46; 47.

Historical Records

Technical Information

• Alkyl Halide Occurrence • Arndt-Eistert Homologation • General Reactivity • Grignard Reaction • Hiyama Cross-Coupling Reaction • Hunsdiecker-Borodin Reaction • Kinetics of Alkyl Halides • Kumada Cross-Coupling Reaction • Passerini Reaction • Preparation of Amines • Preparation of Carboxylic Acids • Reactions of Alkyl Halides with Reducing Metals • Reactions of Amines • Reactions of Carboxylic Acids • Schmidt Reaction • Specialized Acylation Reagents-Ketenes • Stille Coupling • Substitution and Elimination Reactions of Alkyl Halides • Suzuki Coupling • Ugi Reaction

Related Functional Groups of
[ 81719-53-1 ]

Chlorides

A156432 [86873-60-1]

5-Chloro-2-picolinic acid

Similarity: 0.86

A257875 [116383-98-3]

Methyl 3-chloropicolinate

Similarity: 0.85

A108879 [74840-47-4]

5-Chloro-2-methylpyrimidine-4-carboxylic acid

Similarity: 0.78

A154914 [88912-25-8]

4,6-Dichloropicolinic acid

Similarity: 0.77

A272399 [4684-94-0]

6-Chloropicolinic acid

Similarity: 0.72

Carboxylic Acids

A156432 [86873-60-1]

5-Chloro-2-picolinic acid

Similarity: 0.86

A108879 [74840-47-4]

5-Chloro-2-methylpyrimidine-4-carboxylic acid

Similarity: 0.78

A154914 [88912-25-8]

4,6-Dichloropicolinic acid

Similarity: 0.77

A272399 [4684-94-0]

6-Chloropicolinic acid

Similarity: 0.72

A137714 [1060810-03-8]

5-Chloro-2-methylisonicotinic acid

Similarity: 0.71

Related Parent Nucleus of
[ 81719-53-1 ]

Pyridines

A156432 [86873-60-1]

5-Chloro-2-picolinic acid

Similarity: 0.86

A257875 [116383-98-3]

Methyl 3-chloropicolinate

Similarity: 0.85

A154914 [88912-25-8]

4,6-Dichloropicolinic acid

Similarity: 0.77

A272399 [4684-94-0]

6-Chloropicolinic acid

Similarity: 0.72

A118489 [27330-35-4]

Ethyl 3-amino-5-chloropicolinate

Similarity: 0.72

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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CAS No.: 81719-53-1

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