19047-31-5|2-Chloro-N-cyclopropylacetamide| Ambeed

Structure of 19047-31-5

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Quality Control of [ 19047-31-5 ] Purity: 95% SDS Specification

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Product Details of [ 19047-31-5 ]

CAS No. :	19047-31-5
Formula :	C₅H₈ClNO
M.W :	133.58
SMILES Code :	O=C(NC1CC1)CCl
MDL No. :	MFCD00276391
InChI Key :	ZPWIVSGEQGESFF-UHFFFAOYSA-N
Pubchem ID :	735780

Safety of [ 19047-31-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H317-H319-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 19047-31-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	8
Num. arom. heavy atoms	0
Fraction Csp3	0.8
Num. rotatable bonds	3
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	31.83
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	29.1 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.15
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	0.72
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.44
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.	0.47
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	1.12
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.78

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.92
Solubility	15.9 mg/ml ; 0.119 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.	-0.91
Solubility	16.5 mg/ml ; 0.123 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	-1.47
Solubility	4.56 mg/ml ; 0.0341 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.	-6.6 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	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<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)	1.19

Application In Synthesis of [ 19047-31-5 ]

* 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 [ 19047-31-5 ]

[ 19047-31-5 ] Synthesis Path-Downstream 1~35

1
[ 79-04-9 ]
[ 765-30-0 ]
[ 19047-31-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	In dichloromethane; at 0℃; for 2h;	To a solution of cyclopropylamine (50.Og, 0.876mol) in dichloromethane (700ml) at O0C is added 2-chloroacetyl chloride (49.4g, 0.436mol) dropwise by addition funnel. The resulting mixture is stirred at O0C for 2 hours, then filtered through a pad of Celite. The filtrate is concentrated to an orange solid, which is slurried in 500ml of hexane, then filtered. The collected orange solid is dried under house vacuum for 30 minutes. This gives the title compound as an orange solid (58.12g, 99%). Mass (m/z): 134.1 (M++l).
74.8%	With potassium carbonate; In dichloromethane; at 20℃;Cooling with ice;	Cyclopropylamine (228.4 mg, 4.0 mmol)Was dissolved in 4 mL of dichloromethane,Anhydrous potassium carbonate (663.4 mg, 4.8 mmol) was added,The reaction flask was placed in an ice bath,Chloroacetyl chloride (451.8 mg, 4.0 mmol) was slowly added via a dropping funnel,The reaction was stirred at room temperature overnight.After completion of the reaction, 10 mL of ice water was added to quench the reaction,Dichloromethane, the combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate,The vacuum distillation was carried out without further purification to give a white solid. Yield: 74.8%
	In dichloromethane; at -10 - 20℃; for 3h;	Route 2: Step 1: Amide Formation (Int-19) Cyclopropylamine (0.35 mL, 5.0 mmol) and triethylamine (0.7 mL, 5.1 mmol) were dissolved in CH2Cl2 (10 mL). The reaction was cooled to -10 C. and chloroacetyl chloride (0.4 mL, 5.0 mmol) was added dropwise. The reaction was stirred at -10 C. for 1 hour, then at room temperature for 2 hours, followed by a quench with water. The aqueous layer was extracted with CH2Cl2, and the organic layers were dried, filtered, and concentrated to give the desired product.

	With potassium carbonate; In dichloromethane; at 20℃;Cooling with ice;	Cyclopropylamine (228.4 mg, 4.0 mmol),Potassium carbonate (663.4 mg, 4.8 mmol) was placed in 4 mL of dichloromethane solution,Ice bath,Chloroacetyl chloride (451.8 mg, 4.0 mmol) was slowly added dropwise to the above reaction flask,Room temperature overnight.After the reaction,Add the right amount of water,Extracted three times with methylene chloride,The organic phases were combined and washed with saturated brine,Dried over anhydrous magnesium sulfate,Distillation under reduced pressure to give the crude product as a white solid.
	With triethylamine; In dichloromethane; at -10 - 20℃; for 3h;	Cyclopropylamine (0.35 mL, 5.0 mmol) and triethylamine (0.7 mL, 5.1 mmol) were dissolved in CH2CI2 (10 mL). The reaction was cooled to -10C and chloroacetyl chloride (0.4 mL, 5.0 mmol) was added dropwise. The reaction was stirred at -10C for 1 hour, then at room temperature for 2 hours, followed by a quench with water. The aqueous layer was extracted with CH2CI2, and the organic layers were dried, filtered, and concentrated to give the desired product.
	With triethylamine; In dichloromethane; at 0 - 25℃; for 3.5h;	To a solution of cyclopropanamine (5.00 g, 87.58 mmol, 6.10 mL) and TEA (17.72 g, 175.16 mmol, 24.27 mL) in CH2C12 (100.00 mL) was added dropwise 2- chloroacetyl chloride (6.59 g, 58.39 mmol, 4.64 mL) at 0 C over 0.5 hour. The mixture was then stirred at 25 C for 3 hour. TLC (Petroleum ether/Ethyl acetate = 3 : 1, Rf = 0.3) indicated a major new spot formed. The reaction mixture was washed with H20 (100 mL), HC1 (1 N, 100 mL) and brine (100 mL), dried over Na2S04, filtered, and concentrated under reduced pressure to provide the title compound (3.30 g, crude) as a black-brown solid which was used in the next step reaction without further purification.
	With potassium carbonate; In tetrahydrofuran; acetonitrile; at 0 - 20℃; for 3h;	General procedure: To a solution of 9 (30mmol) in 25mL THF was added K2CO3 (6.2g, 45mmol), and stirred for 20min under the ice bath to make it well mixed. Chloroacetyl chloride (3mL, 36mmol) was added in drops and stirred for 3h under room temperature. The reaction solution was concentrated, water (100mL) was added, and extracted with EtOAc. The organic layer was collected and washed with saturated salt solution for three times, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography to afford intermediate product 10.
	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2h;	General procedure: B23-B27 or B34-B361.0 mmol, 1.0 equiv) and Et3N (1.2 mmol,1.2 equiv) were dissolved in anhydrous tetrahydrofuran (THF), thena solution of chloroacetyl chloride (1.1 mmol, 1.1 equiv) in anhydrousTHF was added dropwise at 0 C. The reaction mixture wasthen stirred at room temperature for additional 2 h. Then water(30 mL) was added, extracted with ethyl acetate (3 10 mL). Theorganic phase was combined, dried over anhydrous Na2SO4,filtered, and concentrated to yield the crude azide substituents,which was purified by flash column chromatography to afford intermediatesC23eC27 and C34eC36. To a solution of the intermediatesin DMF were added sodium azide (1.2 mmol,1.2 equiv),and the mixture was stirred for 24 h at room temperature. Thenwater (30 mL) was added, extracted with ethyl acetate (3 10 mL).The organic phase was combined, dried over anhydrous Na2SO4,filtered, and concentrated to yield the target azide substituentsN23eN27 and N34eN36, which were used for the next stepwithout further purification.
	With triethylamine; In dichloromethane;Cooling with ice;	third step:Cyclopropylamine as raw material,Dichloromethane as a solvent,Add triethylamine (1 mmol),Chloroacetyl chloride (1 mmol) diluted slowly with dichloromethane in a constant pressure dropping funnel under ice conditions,After the reaction was completed, the system was poured into water, the pH was adjusted to weakly basic with Na2CO3, and the organic phase was extracted with dichloromethane.The mixture was stirred, filtered, and dried with n-hexane to obtain 2-chloro-N-cyclopropylacetamide.

References: [1]Patent: WO2006/47124,2006,A1 .Location in patent: Page/Page column 11-12.
[2]Journal of Medicinal Chemistry,2003,vol. 46,p. 399 - 408.
[3]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 678 - 681.
[4]Patent: CN106146414,2016,A .Location in patent: Paragraph 0478; 0479; 0480.
[5]ChemMedChem,2018,vol. 13,p. 2455 - 2463.
[6]Synthesis,2013,vol. 45,p. 1039 - 1044.
[7]MedChemComm,2015,vol. 6,p. 1998 - 2003.
[8]Journal of Heterocyclic Chemistry,1994,vol. 31,p. 297 - 303.
[9]Patent: US2007/105866,2007,A1 .Location in patent: Page/Page column 63-64.
[10]RSC Advances,2015,vol. 5,p. 48368 - 48381.
[11]Patent: CN106167497,2016,A .Location in patent: Paragraph 0112; 0113; 0114.
[12]Patent: WO2018/152405,2018,A1 .Location in patent: Paragraph 00192.
[13]Patent: WO2018/201006,2018,A1 .Location in patent: Paragraph 0139; 0140.
[14]European Journal of Medicinal Chemistry,2019,vol. 178,p. 667 - 686.
[15]European Journal of Medicinal Chemistry,2019,vol. 183.
[16]Patent: CN110372531,2019,A .Location in patent: Paragraph 0029; 0031.
[17]Drug Development Research,2020,vol. 81,p. 242 - 255.

2
[ 19047-31-5 ]
[ 603-35-0 ]
<2-(cyclopropylamino)-2-oxoethyl>triphenylphosphonium chloride [ No CAS ]

References: [1]Journal of Heterocyclic Chemistry,1994,vol. 31,p. 297 - 303.
[2]Journal of Medicinal Chemistry,2003,vol. 46,p. 399 - 408.

Yield	Reaction Conditions	Operation in experiment
53.9%		General procedure: The raw material cyclohexylamine (3 g, 30 mmol) was dissolved in 25 mL of acetonitrile.Potassium carbonate (6.2 g, 45 mmol) was added.Stir for 20 min in an ice bath to mix thoroughly.Chloroacetyl chloride (3 mL, 36 mmol) was slowly added dropwise,A large amount of white smoke was generated. After stirring for 30 minutes, the white smoke disappeared and the solution was light yellow.The reaction was continued at room temperature for 3 h, and monitored by TLC until the reaction was complete.Treatment method: first remove most of the acetonitrile by distillation under reduced pressure, and then add 100 mL of water,Extracted with EA (4 × 25mL), collected the organic layer, washed three times with saturated brine,Dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure,A white crude product was obtained, which was recrystallized using a PE / EA system to obtain powdery white needle-like crystals.About 3.5 g, yield 67%.
		cyclooctylamine for 2,6-dimethylaniline, there are obtained the following substituted chlorides of formula F: ... [N-n-butyl-N-(2,6-dimethylphenyl)aminocarbonylmethyl]chloride; [N-(methyl)aminocarbonylmethyl]chloride; [N-(isopropyl)aminocarbonylmethyl]chloride; [N-(n-butyl)aminocarbonylmethyl]chloride; [N-(cyclopropyl)aminocarbonylmethyl]chloride; [N-(cyclohexyl)aminocarbonylmethyl]chloride; or [N-(cyclooctyl)aminocarbonylmethyl]chloride
	With triethylamine; In dichloromethane; at 0 - 20℃;	General procedure: 1.2.17.1. Illustrative synthesis of Intermediate Gen-13-o : 2-Chloro-N-methoxy-N-methylacetamide [00444] To a solution of chloroacetyl chloride (0.195 mL, 1.21 mmol, 1 eq.) and TEA (0.253 mL, 1.81 mmol, 1.5 eq.) in 3 mL of DCM at 0C was added the Nu,Omicron-dimethylhydroxylamine (0.081 g, 1.33 mmol, 1.1 eq.). The reaction mixture was stirred overnight at r.t., then concentrated in vacuo. The residue was suspended in acetone and stirred vigorously for 20 min, filtered and the filtrate was concentrated in vacuo to afford Intermediate Gen-13-o which was used directly without further purification. [00445] LC-MS: MW (calcd): 137 (35C1) 139 (37C1); m/z MW (obsd): 138 (35C1 M+l), 140 (37C1 M+l)

4
[ 19047-31-5 ]
[ 122-52-1 ]
diethyl ((cyclopropylcarbamoyl)methyl)phosphonate [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 399 - 408.

5
[ 19047-31-5 ]
[ 94833-31-5 ]
5-amino-4-[4-(4-bromo-phenyl)-thiazol-2-yl]-1-cyclopropyl-1,3-dihydro-pyrrol-2-one [ No CAS ]

References: [1]Russian Journal of Organic Chemistry,2005,vol. 41,p. 257 - 260.

6
[ 19047-31-5 ]
(E)-N-cyclopropyl-2-(1-indanylidene)acetamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 399 - 408.

7
[ 19047-31-5 ]
2-(6-chloro-indan-1-ylidene)-<i>N</i>-cyclopropyl-acetamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 399 - 408.

8
[ 19047-31-5 ]
2-(6-chloro-indan-1-ylidene)-<i>N</i>-cyclopropyl-acetamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 399 - 408.

9
[ 19047-31-5 ]
(E)-6-<3-(cyclopropylamino)-3-oxo-1-propenyl>-1,2-dihydro-2-oxo-3-pyridinecarboxylic acid [ No CAS ]

References: [1]Journal of Heterocyclic Chemistry,1994,vol. 31,p. 297 - 303.

10
[ 224624-80-0 ]
[ 19047-31-5 ]
(R)-1-{6-[(R)-2-(cyclopropylcarbamoyl-methoxycarbonyl)-pyrrolidin-1-yl]-6-oxo-hexanoyl}-pyrrolidine-2-carboxylic acid cyclopropylcarbamoyl-methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
190 mg (71%)	With sodium iodide; triethylamine; In N-methyl-acetamide;	EXAMPLE 5 (R)-1-{6-[(R)-2-(Cyclopropylcarbamoyl-methoxycarbonyl)-pyrrolidin-1-yl]-6-oxo-hexanoyl}-pyrrolidine-2-carboxylic acid cyclopropylcarbamoyl-methyl ester To a solution of 170 mg (0.5 mmol) (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid and 134 mg (1 mmol) N-(chloroacetyl)-cyclopropyl-amine in 3 ml dimethylformamide were added 14.9 mg (0.1 mmol) sodium iodide and 139 ml (1 mmol) triethylamine. After stirring overnight at 90 C. the solvent was distilled off, the residue was taken up with dichloromethane and extracted with water. The organic extracts were dried with sodium sulfate and the solvent was distilled off to yield 190 mg (71%) of (R)-1-{6-[(R)-2-(cyclopropylcarbamoyl-methoxycarbonyl)-pyrrolidin-1-yl]-6-oxo-hexanoyl}-pyrrolidine-2-carboxylic acid cyclopropylcarbamoyl-methyl ester as a light yellow solid, MS m/e (%): 535 (M+H+, 100).

References: [1]Patent: US2003/134891,2003,A1 .

11
1-ethyl-2-[2-[(S)-[1-((R)-pyrrolidin-2-yl)carbonyl]pyrrolidin-2-yl]ethyl]indole-6-carbonitrile [ No CAS ]
[ 19047-31-5 ]
1-ethyl-2-[2-[(S)-1-[[(R)-1-[(N-cyclopropylcarbamoyl)methyl]pyrrolidin-2-yl]carbonyl]pyrrolidin-2-yl]-ethyl]indole-6-carboxamidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 73 Synthesis of 1-ethyl-2-[2-[(S)-1-[[(R)-1-[(N-cyclopropylcarbamoyl)methyl]pyrrolidin-2-yl]carbonyl]pyrrolidin-2-yl]-ethyl]indole-6-carboxamidine (Compound 115) 250 mg of the compound II-a obtained in Example 57-b) and 92 mg of <strong>[19047-31-5]N-cyclopropyl-2-chloroethanamide</strong> were reacted under the same conditions as Example 42 to obtain 125 mg of the pale yellow solid product, which was then treated according to the same procedure as Example 1-n) to obtain 93 mg of the title compound as a pale yellow solid. 1H NMR(CDCl3, ppm): delta 8.13(d, 1H, J=3.75 Hz), 7.88(s, 1H), 7.61-7.38(m, 2H), 6.40(s, 1H), 4.27-4.13(m, 3H), 3.56-3.08(m, 3H), 2.90(s, 2H), 2.82(t, 2H, J=6.91 Hz), 2.72-2.65(m, 1H), 2.50-1.67(m, 12H), 1.35 (t, 3H, J32 7.20 Hz), 0.88-0.50(m, 4H) ES-MS: 479(M+1)+

References: [1]Patent: US6201006,2001,B1 .

12
[ 925221-77-8 ]
[ 19047-31-5 ]
[ 1056563-81-5 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃;	Example 46; Synthesis of Compound 80; Compound a from the synthesis of compound 74 (210 mg) was dissolved in 5.0 ml DMF and Cs2CO3 (730 mg) was added followed by the addition of N1-cyclopropyl-2-chloroacetamide b (300 mg). The vial was capped and the reaction was heated to 60 C. in a heat block for four hrs. The reaction was completed by LCMS. The reaction was diluted with H2O, extracted with EtOAc, dried over MgSO4, and concentrated by vacuum to give compound c. Compound c was dissolved in 3 ml 1.0 M TBAF in THF and heated to 60 C. overnight. The reaction was completed by LCMS and diluted with H2O and 0.1 N H2SO4, extracted with EtOAc, washed with brine, dried over MgSO4, concentrated under vacuum and purified by HPLC to give the final compound 80.

References: [1]Patent: US2007/37791,2007,A1 .Location in patent: Page/Page column 75.

13
[ 1056563-55-3 ]
[ 19047-31-5 ]
[ 1056562-95-8 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 4h;	Compound m (148 mg) was dissolved in 5.0 ml DMF and Cs2CO3 (330 mg) was added, followed by the addition of N1-cyclopropyl-2-chloroacetamide (130 mg). The vial was capped and the reaction was heated to 70 C. in a heat block for 4 hrs. The reaction was completed by LCMS. Diluted reaction with H2O, extracted with EtOAc, dried over MgSO4, concentrated by vacuum, and flashed by ISCO (EtOAc/hexanes) to give compound o. Compound o was dissolved in 10 ml THF and cooled to 0 C. before adding 0.14 ml 2.5 M LAH in THF. The reaction was stirred 1 hr 35 min at 0 C. and was completed by LCMS. The reaction was quenched with 400 uL 10% NaOH and 400 uL EtOH, diluted with H2O and 1 M HCl, extracted with DCM, dried over MgSO4 and concentrated under vacuum to give compound p. Compound p was dissolved in 2 ml 1.0 M TBAF in THF and 3 ml THF and heated to 60 C. overnight. Reaction was completed by LCMS and diluted with H2O, extracted with EtOAc, washed with brine, dried over MgSO4, concentrated under vacuum and purified by HPLC to give 18 mg of the final compound 85.

References: [1]Patent: US2007/37791,2007,A1 .Location in patent: Page/Page column 80-82.

14
[ 1117685-93-4 ]
[ 19047-31-5 ]
[ 1117686-02-8 ]

Yield	Reaction Conditions	Operation in experiment
44.0%	With N,N-diethylnmethylamine; In dichloromethane; at 110℃; for 0.75h;Microwave irradiation;	4-(2,6-Dimethylpyridin-3-yloxy)-N-[3-(piperazin-1-ylmethyl)phenyl]pyridin-2-amine (Example 176, 60 mg, 0.15 mmol), <strong>[19047-31-5]2-chloro-N-cyclopropylacetamide</strong> (20.58 mg, 0.15 mmol) and N,N-diethylmethylamine (0.019 mL, 0.15 mmol) were dissolved in DCM (4 mL) and sealed into a microwave tube. The mixture was heated to 110 C. for 45 mins in a microwave and was then cooled to r.t. The mixture was concentrated. The crude material was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 mum silica, 19 mm diameter, 100 mm length), eluting with decreasingly polar mixtures of water (containing 1% NH3) and MeCN to afford the title compound (33.0 mg, 44.0%) as a white solid.

References: [1]Patent: US2009/48269,2009,A1 .Location in patent: Page/Page column 55.

15
[ 1190869-00-1 ]
[ 19047-31-5 ]
[ 1190869-85-2 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5021 - 5025.

16
[ 75-15-0 ]
[ 638-07-3 ]
[ 19047-31-5 ]
[ 109-77-3 ]
[ 879033-82-6 ]

References: [1]Journal of Combinatorial Chemistry,2010,vol. 12,p. 9 - 12.

17
[ 7442-07-1 ]
[ 19047-31-5 ]
[ 312285-34-0 ]

References: [1]ChemMedChem,2011,vol. 6,p. 654 - 666.

18
[ 19047-31-5 ]
[ 2613-23-2 ]
[ 1443528-93-5 ]