[ CAS No. 54231-32-2 ] {[proInfo.proName]}

Name: 54231-32-2|3-Chloro-2-nitropyridine|98%
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Quality Control of [ 54231-32-2 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 54231-32-2 ]

CAS No. :	54231-32-2	MDL No. :	MFCD00490110
Formula :	C₅H₃ClN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PSGASDJUCYTRAD-UHFFFAOYSA-N
M.W :	158.54	Pubchem ID :	554988
Synonyms :

Calculated chemistry of [ 54231-32-2 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	38.07
TPSA :	58.71 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.1 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.19
Log Po/w (XLOGP3) :	1.64
Log Po/w (WLOGP) :	1.64
Log Po/w (MLOGP) :	0.68
Log Po/w (SILICOS-IT) :	-0.09
Consensus Log Po/w :	1.01

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.23
Solubility :	0.925 mg/ml ; 0.00583 mol/l
Class :	Soluble
Log S (Ali) :	-2.49
Solubility :	0.518 mg/ml ; 0.00327 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.01
Solubility :	1.55 mg/ml ; 0.00979 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.91

Safety of [ 54231-32-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 54231-32-2 ]

* 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.

Upstream synthesis route of [ 54231-32-2 ]
Downstream synthetic route of [ 54231-32-2 ]

[ 54231-32-2 ] Synthesis Path-Upstream 1~6

1
[ 54231-32-2 ]
[ 39620-04-7 ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: With hydrogenchloride; tin(ll) chloride In methanol; water at 20℃; Stage #2: With sodium hydroxide In methanol; water; ethyl acetate	A sample of 3-chloro-2-nitropyridine (1.00 g, 6.31 mmol) was dissolved in methanol (10 mL), treated with Tin(II) chloride (5.98 g, 31.54 mmol) followed by concentrated HCl (2.63 mL, 31.54 mmol). The reaction mixture was allowed to stir overnight at rt. The solution was then diluted with ethyl acetate and washed with IN NaOH solution. The organic phase was then washed with concentrated NaHCO₃ solution and dried over Na₂SO₄. Concentration in vacuo gave the title compound (510.0mg, 63percent). ¹H NMR (400 MHz, CD₃CN) δ 6.80 (m, 1 H), 7.60 (d, 1 H), 8.12 (d, 1 H).
41%	With hydrogenchloride; iron In ethanol; water at 0 - 20℃; for 2.5 h;	To a stirred solution of 3-chloro-2-nitropyridine (1.00 g, 6.31 mmol) in EtOH (13 ml) were added a 2 M HCl aqueous solution (1.30 ml, 2.60 mmol) and iron (2.37 g, 42.4 mmol) at 0° C. The resulting mixture was stirred for 2.5 h at room temperature. Celite (2.40 g) was added. The mixture was filtered over a celite pad and evaporated to give a dark oil that was purified by elution through a SCX cartridge. The title compound D54 (0.34 g, 2.59 mmol, 41percent yield) was obtained as a dark solid. UPLC: rt=0.27 min, peaks observed: 129 (M+1, 100percent) and 131 (M+1, 33percent). C₅H₅ClN₂requires 128.

Reference： [1] Patent: WO2006/44775, 2006, A2, . Location in patent: Page/Page column 64
[2] Patent: US2009/22670, 2009, A1, . Location in patent: Page/Page column 25

2
[ 54231-32-2 ]
[ 42753-67-3 ]

Reference： [1] Patent: WO2013/117649, 2013, A1,

3
[ 54231-32-2 ]
[ 22841-92-5 ]

Reference： [1] Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 475 - 476

4
[ 54231-32-2 ]
[ 39968-33-7 ]

Reference： [1] Journal of the Chemical Society of Pakistan, 2011, vol. 33, # 3, p. 324 - 332

5
[ 54231-32-2 ]
[ 1480-64-4 ]

Reference： [1] Journal of Organic Chemistry, 2015, vol. 80, # 24, p. 12137 - 12145

6
[ 13269-19-7 ]
[ 54231-32-2 ]

Reference： [1] Organic Process Research and Development, 2017, vol. 21, # 1, p. 44 - 51

[ 54231-32-2 ] Synthesis Path-Downstream 1~88

1
[ 54231-32-2 ]
[ 4043-87-2 ]
[ 89860-69-5 ]

Yield	Reaction Conditions	Operation in experiment
55%	With sodium hydrogencarbonate In ethanol for 5h; Heating;

Reference： [1]Adegoke, E. A.; Alo, Babajide [Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 1509 - 1512]

2
[ 54231-32-2 ]
[ 22841-92-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine hydrate In ethanol

Reference： [1]Ple, N.; Queguiner, G. [Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 475 - 476]

3
[ 54231-32-2 ]
[ 147-85-3 ]
[ 89860-68-4 ]

Yield	Reaction Conditions	Operation in experiment
53%	With sodium hydrogencarbonate In ethanol for 5h; Heating;

Reference： [1]Adegoke, E. A.; Alo, Babajide [Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 1509 - 1512]

4
[ 54231-32-2 ]
3-(4-Aminomethyl-benzoyl)-4-chloro-indole-1-carboxylic acid dimethylamide [ No CAS ]
4-Chloro-3-{4-[(2-nitro-pyridin-3-ylamino)-methyl]-benzoyl}-indole-1-carboxylic acid dimethylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In acetonitrile a) RT, 30 min, b) 60 deg C, 2 h;

Reference： [1]Curtin, Michael L.; Davidsen, Steven K.; Heyman, H. Robin; Garland, Robert B.; Sheppard, George S.; Florjancic, Alan S.; Xu, Lianhong; Carrera Jr., George M.; Steinman, Douglas H.; Trautmann, Jeff A.; Albert, Daniel H.; Magoc, Terrance J.; Tapang, Paul; Rhein, David A.; Conway, Richard G.; Luo, Gongjin; Denissen, Jon F.; Marsh, Kennan C.; Morgan, Douglas W.; Summers, James B. [Journal of Medicinal Chemistry, 1998, vol. 41, # 1, p. 74 - 95]

5
[ 110-89-4 ]
[ 54231-32-2 ]
2'-nitro-3,4,5,6-tetrahydro-2<i>H</i>-[1,3']bipyridinyl [ No CAS ]
[ 26930-71-2 ]
[ 282723-20-0 ]

Yield	Reaction Conditions	Operation in experiment
1: 58 % Spectr. 2: 18 % Spectr. 3: 24 % Spectr.	With TEA In dimethyl sulfoxide at 90℃; for 4h;

Reference： [1]Yao, Jiangchao; Blake, Paul R.; Yang, Ji [Heterocycles, 2005, vol. 65, # 9, p. 2071 - 2081]

6
[ 54231-32-2 ]
[ 103-84-4 ]
2-methyl-1-phenyl-1H-imidazo[4,5-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%		26 Example 26 Method A applied to 3-chloro-2-nitropyridine (79 mg) and N-phenylacetamide (81 mg, 0.6 mmol) afforded the title compound as brown viscous oil (45 mg, 43% yield). 1H NMR (DMSO) δ 2.54 (s, 3 H), 7.35-7.68 (m, 6 H), 7.77 (d, J = 8.8 Hz, 1 H), 8.58 (br s, 1 H); 13C NMR δ 14.0, 118.9, 120.1, 126.8, 128.5, 129.6, 130.1, 133.9, 143.0, 151.6, 156.7. HRMS (FAB): calculated for C13H12N3 [M+H+]: 210.1031; found: 210.1026.
	Multi-step reaction with 2 steps 1: palladium(II) trifluoroacetate; caesium carbonate; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl / toluene / 18 h / 80 °C / Inert atmosphere 2: iron; acetic acid / 0.5 h / Reflux

Reference： [1]Current Patent Assignee: SANOFI - EP1878724, 2008, A1 Location in patent: Page/Page column 22
[2]Alonso, Jorge; Halland, Nis; Nazare, Marc; R'Kyek, Omar; Urmann, Matthias; Lindenschmidt, Andreas [European Journal of Organic Chemistry, 2011, # 2, p. 234 - 237]

7
[ 54231-32-2 ]
[ 38042-20-5 ]
C₁₀H₁₂N₂OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃; for 0.166667h; Irradiation;

Reference： [1]Ma, Chen; Zhang, Qun; Ding, Kai; Xin, Liang; Zhang, Dongju [Tetrahedron Letters, 2007, vol. 48, # 42, p. 7476 - 7479]

8
[ 54231-32-2 ]
[ 20284-97-3 ]
C₁₃H₁₆N₂OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃; for 0.166667h; Irradiation;

Reference： [1]Ma, Chen; Zhang, Qun; Ding, Kai; Xin, Liang; Zhang, Dongju [Tetrahedron Letters, 2007, vol. 48, # 42, p. 7476 - 7479]

9
C₉H₁₇NOS [ No CAS ]
[ 54231-32-2 ]
C₁₄H₁₈N₂OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃; for 0.166667h; Irradiation;

Reference： [1]Ma, Chen; Zhang, Qun; Ding, Kai; Xin, Liang; Zhang, Dongju [Tetrahedron Letters, 2007, vol. 48, # 42, p. 7476 - 7479]

10
C₇H₁₃NO₂S [ No CAS ]
[ 54231-32-2 ]
C₁₂H₁₄N₂O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃; for 0.166667h; Irradiation;

Reference： [1]Ma, Chen; Zhang, Qun; Ding, Kai; Xin, Liang; Zhang, Dongju [Tetrahedron Letters, 2007, vol. 48, # 42, p. 7476 - 7479]

11
[ 54231-32-2 ]
[ 1009-79-6 ]
C₁₄H₁₂N₂OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃; for 0.166667h; Irradiation;

Reference： [1]Ma, Chen; Zhang, Qun; Ding, Kai; Xin, Liang; Zhang, Dongju [Tetrahedron Letters, 2007, vol. 48, # 42, p. 7476 - 7479]

12
[ 54231-32-2 ]
thioglycolic acid 2-phenylethylamide [ No CAS ]
C₁₅H₁₄N₂OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃; for 0.166667h; Irradiation;

Reference： [1]Ma, Chen; Zhang, Qun; Ding, Kai; Xin, Liang; Zhang, Dongju [Tetrahedron Letters, 2007, vol. 48, # 42, p. 7476 - 7479]

13
C₁₀H₁₃NOS [ No CAS ]
[ 54231-32-2 ]
C₁₅H₁₄N₂OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃; for 0.166667h; Irradiation;

Reference： [1]Ma, Chen; Zhang, Qun; Ding, Kai; Xin, Liang; Zhang, Dongju [Tetrahedron Letters, 2007, vol. 48, # 42, p. 7476 - 7479]

14
[ 54231-32-2 ]
[ 75484-01-4 ]
1-(3,4-dimethoxyphenethyl)-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃; for 0.166667h; Irradiation;

Reference： [1]Ma, Chen; Zhang, Qun; Ding, Kai; Xin, Liang; Zhang, Dongju [Tetrahedron Letters, 2007, vol. 48, # 42, p. 7476 - 7479]

15
[ 54231-32-2 ]
[ 4822-44-0 ]
C₁₃H₁₀N₂OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃; for 0.166667h; Irradiation;

Reference： [1]Ma, Chen; Zhang, Qun; Ding, Kai; Xin, Liang; Zhang, Dongju [Tetrahedron Letters, 2007, vol. 48, # 42, p. 7476 - 7479]

16
[ 54231-32-2 ]
6-aza-1,2,3,3a-tetrahydropyrrolo<1,2-a>quinoxalin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 53 percent / sodium hydrogen carbonate / ethanol / 5 h / Heating 2: conc. sulphuric acid / 8 h / Heating 3: 51 percent / 10percent Pd on charcoal / cyclohexene; ethanol / 2 h / Heating

Reference： [1]Adegoke, E. A.; Alo, Babajide [Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 1509 - 1512]

17
[ 54231-32-2 ]
[ 89860-70-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 53 percent / sodium hydrogen carbonate / ethanol / 5 h / Heating 2: conc. sulphuric acid / 8 h / Heating

Reference： [1]Adegoke, E. A.; Alo, Babajide [Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 1509 - 1512]

18
[ 54231-32-2 ]
[ 89860-71-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 55 percent / sodium hydrogen carbonate / ethanol / 5 h / Heating 2: 80 percent / conc. sulphuric acid / 8 h / Heating

Reference： [1]Adegoke, E. A.; Alo, Babajide [Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 1509 - 1512]

19
[ 54231-32-2 ]
[ 54231-44-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: methanol / Heating 2: aq. HCl / Heating

Reference： [1]Azev,Yu.A. et al. [Chemistry of Heterocyclic Compounds, 1974, vol. 10, p. 687 - 690][Khimiya Geterotsiklicheskikh Soedinenii, 1974, vol. 6, p. 792 - 795]

20
[ 54231-32-2 ]
[ 54231-45-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: methanol / Heating 2: aq. HBr / Heating

Reference： [1]Azev,Yu.A. et al. [Chemistry of Heterocyclic Compounds, 1974, vol. 10, p. 687 - 690][Khimiya Geterotsiklicheskikh Soedinenii, 1974, vol. 6, p. 792 - 795]

21
[ 54231-32-2 ]
[ 39620-04-7 ]

Yield	Reaction Conditions	Operation in experiment
63%		A sample of 3-chloro-2-nitropyridine (1.00 g, 6.31 mmol) was dissolved in methanol (10 mL), treated with Tin(II) chloride (5.98 g, 31.54 mmol) followed by concentrated HCl (2.63 mL, 31.54 mmol). The reaction mixture was allowed to stir overnight at rt. The solution was then diluted with ethyl acetate and washed with IN NaOH solution. The organic phase was then washed with concentrated NaHCO3 solution and dried over Na2SO4. Concentration in vacuo gave the title compound (510.0mg, 63%). 1H NMR (400 MHz, CD3CN) delta 6.80 (m, 1 H), 7.60 (d, 1 H), 8.12 (d, 1 H).
41%	With hydrogenchloride; iron; In ethanol; water; at 0 - 20℃; for 2.5h;	To a stirred solution of 3-chloro-2-nitropyridine (1.00 g, 6.31 mmol) in EtOH (13 ml) were added a 2 M HCl aqueous solution (1.30 ml, 2.60 mmol) and iron (2.37 g, 42.4 mmol) at 0 C. The resulting mixture was stirred for 2.5 h at room temperature. Celite (2.40 g) was added. The mixture was filtered over a celite pad and evaporated to give a dark oil that was purified by elution through a SCX cartridge. The title compound D54 (0.34 g, 2.59 mmol, 41% yield) was obtained as a dark solid. UPLC: rt=0.27 min, peaks observed: 129 (M+1, 100%) and 131 (M+1, 33%). C5H5ClN2 requires 128.

Reference： [1]Patent: WO2006/44775,2006,A2 .Location in patent: Page/Page column 64
[2]Patent: US2009/22670,2009,A1 .Location in patent: Page/Page column 25

22
[ 1914-02-9 ]
[ 54231-32-2 ]
[ 870072-64-3 ]

Yield	Reaction Conditions	Operation in experiment
18%	at 220℃; for 0.25h;Microwave irradiation;	4a. 3,3-dimethyl-1-(3-nitropyridin-2-yl)indoline:; To 2a (90 mg, 0.61 mmol) was added 2-nitro-3-chloropyridine (200 mg, 1.26 mmol). The reaction mixture was heated at 220 C. microwave for 15 min. The desired compound was isolated via preparative HPLC to afford 4a (30 mg, 18%) as white lyophilizes. Column: Luna 25×100 mm; Eluted from 35% CH3CN to 100% CH3CN in H2O with 0.1% TFA MS (ES) m/z 269 [M+H]+.

Reference： [1]Patent: US2006/293281,2006,A1 .Location in patent: Page/Page column 72-73

23
[ 54231-32-2 ]
[ 108-98-5 ]
[ 953045-26-6 ]

Yield	Reaction Conditions	Operation in experiment
69.8%	With caesium carbonate In dimethyl sulfoxide at 20℃; for 1.5h;	180.A Step A: Preparation of 2-nitro-3-(phenylthio)pyridine: 3-chloro-2-nitropyridine (30.6 g, 193 mmol) was dissolved in DMSO (200 mL). Benzenethiol (20.7 mL, 203 mmol) was added followed by cesium carbonate (69.3 g, 212 mmol) and stirred at ambient temperature for 1.5 hours. The solution was diluted with water (750 mL) and the solids filtered. The crude material was recrystallized from EtOAc (400 mL) and with adding hexanes (1L) to give an A-crop of 23.5 g. The filtrate was concentrated and recrystallized from EtOAc/hexanes to give 7.87 g. The solids were dried on high vacuum to provide the title compound (31.38 g, 69.8% yield).
69.8%	With caesium carbonate In dimethyl sulfoxide at 20℃; for 1.5h;	2.D Preparation of 2-nitro-3-(phenylthio^)pyridine: 3-chloro-2- nitropyridine (30.6 g, 193 mmol) was dissolved in DMSO (200 mL). Benzenethiol (20.7 mL, 203 mmol) was added followed by cesium carbonate (69.3 g, 212 mmol) and stirred at ambient temperature for 1.5 hours. The solution was diluted with water (750 mL) and the resultant solids filtered. The crude material was recrystallized from EtOAc (400ml) and with adding hexanes (IL) to give an A-crop of 23.5 g. The filtrate was concentrated and recrystallized from EtOAc/hexanes to give 7.87 g. The solids were dried on high vacuum to provide the title compound (31.38 g, 69.8% yield).

Reference： [1]Current Patent Assignee: PFIZER INC - US2009/156603, 2009, A1 Location in patent: Page/Page column 85
[2]Current Patent Assignee: PFIZER INC - WO2008/118718, 2008, A2 Location in patent: Page/Page column 45-46

24
[ 54231-32-2 ]
[ 6302-65-4 ]
[ 953045-58-4 ]

Yield	Reaction Conditions	Operation in experiment
84.1%	With caesium carbonate; In dimethyl sulfoxide; at 20℃; for 1.5h;	Step A: Preparation of methyl 4-(2-nitropyridin-3-ylthio)benzoate: Stirred a mixture of <strong>[6302-65-4]methyl 4-mercaptobenzoate</strong> (4.46 g, 26.5 mmol), 3-chloro-2-nitropyridine (4.00 g, 25.2 mmol) and cesium carbonate (9.04 g, 27.8 mmol) in DMSO (60 mL) at ambient temperature for 90 minutes. The solution was diluted with water, extracted with EtOAc, dried, and concentrated. The crude solid was suspended in MeOH (80 mL) and triturated for 0.5 hours. The solid was filtered and dried to provide the title compound (6.16 g, 84.1% yield).

Reference： [1]Patent: US2009/156603,2009,A1 .Location in patent: Page/Page column 119

25
[ 54231-32-2 ]
[ 10111-08-7 ]
[ 1252799-11-3 ]

Reference： [1]European Journal of Organic Chemistry,2010,p. 4832 - 4840

26
[ 54231-32-2 ]
[ 103-84-4 ]
C₁₃H₁₁N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium(II) trifluoroacetate; caesium carbonate; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl In toluene at 80℃; for 18h; Inert atmosphere;

Reference： [1]Alonso, Jorge; Halland, Nis; Nazare, Marc; R'Kyek, Omar; Urmann, Matthias; Lindenschmidt, Andreas [European Journal of Organic Chemistry, 2011, # 2, p. 234 - 237]

27
[ 54231-32-2 ]
[ 372-39-4 ]
[ 1338483-78-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-chloro-2-nitropyridine; 3,5-difluoroaniline With caesium carbonate In ISOPROPYLAMIDE for 0.25h; Inert atmosphere; Stage #2: With 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In ISOPROPYLAMIDE at 100℃; for 12h;	57 To a degassed solution of 3-chloro-2-nitro-pyridine (1.35 g, 8.51 mmol) and 3,5 difluoroaniline (1.0 g, 7.74 mmol) in dimethyl acetamide (23.2 mL) was added cesium carbonate (6.34 g, 19.35 mmol) and the reaction mixture was further degassed with nitrogen for 15 min. xanthophos (267 mg, 0.46 mmol) and Pd2 (dba)3 (212 mg, 0.23 mmol) were added to the reaction mixture and stirred at 100° C. for 12 h. After completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl actate (2×25 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to get the crude material, which was purified by column chromatography using silica gel (100-200 mesh) and 0-30% EtOAc in hexane to provide (3,5-difluorophenyl)-(2-nitro-pyridin-3-yl)-amine: 1H NMR (DMSO-d6, 400 MHz) δ 6.856-6.980 (m, 3H), 7.659-7.691 (m, 1H), 8.017 (dd, J=1.6 Hz, J=1.6 Hz, 1H), 8.126-8.140 (m, 1H), 9.094 (s, 1H); LC-MS (ESI) m/z 252.0 [M+H]+.

Reference： [1]Current Patent Assignee: AMGEN INC - US2011/245257, 2011, A1 Location in patent: Page/Page column 73

28
[ 54231-32-2 ]
[ 1338483-79-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: caesium carbonate / ISOPROPYLAMIDE / 0.25 h / Inert atmosphere 1.2: 12 h / 100 °C 2.1: hydrogenchloride; tin(II) chloride dihdyrate / ethanol; water / 2 h / 75 °C

Reference： [1]Current Patent Assignee: AMGEN INC - US2011/245257, 2011, A1

29
[ 54231-32-2 ]
[ 1338483-50-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: caesium carbonate / ISOPROPYLAMIDE / 0.25 h / Inert atmosphere 1.2: 12 h / 100 °C 2.1: hydrogenchloride; tin(II) chloride dihdyrate / ethanol; water / 2 h / 75 °C 3.1: HATU / dichloromethane; N,N-dimethyl-formamide / 8 h / 20 °C 4.1: 100 °C 4.2: 12 h / 70 °C

Reference： [1]Current Patent Assignee: AMGEN INC - US2011/245257, 2011, A1

30
[ 54231-32-2 ]
[ 1338483-83-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: caesium carbonate / ISOPROPYLAMIDE / 0.25 h / Inert atmosphere 1.2: 12 h / 100 °C 2.1: hydrogenchloride; tin(II) chloride dihdyrate / ethanol; water / 2 h / 75 °C 3.1: HATU / dichloromethane; N,N-dimethyl-formamide / 8 h / 20 °C 4.1: 100 °C 4.2: 12 h / 70 °C 5.1: N-ethyl-N,N-diisopropylamine / butan-1-ol / 120 °C

Reference： [1]Current Patent Assignee: AMGEN INC - US2011/245257, 2011, A1

31
[ 54231-32-2 ]
{1-[3-(3,5-difluorophenylamino)-pyridin-2-ylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: caesium carbonate / ISOPROPYLAMIDE / 0.25 h / Inert atmosphere 1.2: 12 h / 100 °C 2.1: hydrogenchloride; tin(II) chloride dihdyrate / ethanol; water / 2 h / 75 °C 3.1: HATU / dichloromethane; N,N-dimethyl-formamide / 8 h / 20 °C

Reference： [1]Current Patent Assignee: AMGEN INC - US2011/245257, 2011, A1

32
[ 54231-32-2 ]
[ 103-67-3 ]
[ 1353677-72-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine at 60℃; Inert atmosphere;	85.85a Example 851-ethyl-3-{4-[(1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 85a) N-benzyl-N-methyl-2-nitropyridin-3-amine The mixture of N-methylbenzylamine (6.085 mL), TEA (13.19 μL) and 3-chloro-2-nitropyridine (5 g) was stirred at 60° C. under N2 overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give N-benzyl-N-methyl-2-nitropyridin-3-amine (2.6 g) as dark yellow oil.MS (API+): [M+H]+244.1.1H NMR (300 MHz, DMSO-d6) δ 2.75 (3H, s), 4.44 (2H, s), 7.16-7.47 (5H, m), 7.51-7.62 (1H, m), 7.72-7.82 (1H, m), 7.92-8.02 (1H, m).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2011/319394, 2011, A1 Location in patent: Page/Page column 77

33
[ 54231-32-2 ]
[ 56291-51-1 ]

Reference： [1]Patent: US2011/319394,2011,A1

34
[ 54231-32-2 ]
[ 50339-06-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triethylamine / 60 °C / Inert atmosphere 2: hydrogen / palladium 10% on activated carbon / ethanol / 20 °C 3: tetrahydrofuran / 20 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2011/319394, 2011, A1

35
[ 54231-32-2 ]
[ 1353677-71-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: triethylamine / 60 °C / Inert atmosphere 2: hydrogen / palladium 10% on activated carbon / ethanol / 20 °C 3: tetrahydrofuran / 20 °C 4: trichlorophosphate / 5 h / 100 °C 5: sodium hydride / N,N-dimethyl-formamide / 0.33 h / 180 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2011/319394, 2011, A1

36
[ 54231-32-2 ]
[ 65550-24-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: triethylamine / 60 °C / Inert atmosphere 2: hydrogen / palladium 10% on activated carbon / ethanol / 20 °C 3: tetrahydrofuran / 20 °C 4: trichlorophosphate / 5 h / 100 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2011/319394, 2011, A1

37
[ 54231-32-2 ]
[ 39968-33-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine hydrate In ethanol for 24h; Reflux;

Reference： [1]Location in patent: experimental part Fathalla, Magda Fouad; Khattab, Sherine Nabil [Journal of the Chemical Society of Pakistan, 2011, vol. 33, # 3, p. 324 - 332]

38
[ 54231-32-2 ]
[ 68765-56-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 140 °C / Microwave irradiation 2: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 3 h / 140 °C / Microwave irradiation 2: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: ALMIRALL SA - EP2518071, 2012, A1
[2]Current Patent Assignee: ALMIRALL SA - WO2012/146667, 2012, A1

39
[ 54231-32-2 ]
[ 1393177-43-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: N,N-dimethyl-formamide / 140 °C / Microwave irradiation 2: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane; N,N-dimethyl-formamide / 20 °C 4: acetic acid / 100 °C 5: hydrogenchloride / methanol / 80 °C
	Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 3 h / 140 °C / Microwave irradiation 2.1: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3.1: HATU / dichloromethane; N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 20 °C 4.1: 100 °C 5.1: hydrogenchloride / methanol / 80 °C

Reference： [1]Current Patent Assignee: ALMIRALL SA - EP2518071, 2012, A1
[2]Current Patent Assignee: ALMIRALL SA - WO2012/146667, 2012, A1

40
[ 54231-32-2 ]
[ 1404086-73-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N,N-dimethyl-formamide / 140 °C / Microwave irradiation 2: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3: toluene-4-sulfonic acid / dichloromethane / 20 °C 4: potassium carbonate / N,N-dimethyl-formamide / 3 h / 20 °C
	Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 3 h / 140 °C / Microwave irradiation 2: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3: toluene-4-sulfonic acid / dichloromethane / 20 °C 4: potassium carbonate / N,N-dimethyl-formamide / 3 h / 20 °C

Reference： [1]Current Patent Assignee: ALMIRALL SA - EP2518071, 2012, A1
[2]Current Patent Assignee: ALMIRALL SA - WO2012/146667, 2012, A1

41
[ 54231-32-2 ]
[ 1404086-74-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N,N-dimethyl-formamide / 140 °C / Microwave irradiation 2: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3: toluene-4-sulfonic acid / dichloromethane / 20 °C 4: potassium carbonate / N,N-dimethyl-formamide / 20 °C
	Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 3 h / 140 °C / Microwave irradiation 2: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3: toluene-4-sulfonic acid / dichloromethane / 20 °C 4: potassium carbonate / N,N-dimethyl-formamide / 20 °C

Reference： [1]Current Patent Assignee: ALMIRALL SA - EP2518071, 2012, A1
[2]Current Patent Assignee: ALMIRALL SA - WO2012/146667, 2012, A1

42
[ 54231-32-2 ]
[ 1404085-62-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 140 °C / Microwave irradiation 2: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3: toluene-4-sulfonic acid / dichloromethane / 20 °C
	Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 3 h / 140 °C / Microwave irradiation 2: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3: toluene-4-sulfonic acid / dichloromethane / 20 °C

Reference： [1]Current Patent Assignee: ALMIRALL SA - EP2518071, 2012, A1
[2]Current Patent Assignee: ALMIRALL SA - WO2012/146667, 2012, A1

43
[ 54231-32-2 ]
[ 1404085-63-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N,N-dimethyl-formamide / 140 °C / Microwave irradiation 2: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane; N,N-dimethyl-formamide / 20 °C 4: acetic acid / 100 °C
	Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 3 h / 140 °C / Microwave irradiation 2.1: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3.1: HATU / dichloromethane; N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 20 °C 4.1: 100 °C

Reference： [1]Current Patent Assignee: ALMIRALL SA - EP2518071, 2012, A1
[2]Current Patent Assignee: ALMIRALL SA - WO2012/146667, 2012, A1

44
[ 54231-32-2 ]
[ 62-53-3 ]
[ 54231-46-8 ]

Yield	Reaction Conditions	Operation in experiment
65.2%	In N,N-dimethyl-formamide at 140℃; Microwave irradiation;	66 PREPARATION 66 2-Nitro-N-phenylpyridin-3-amine A mixture of 3-chloro-2-nitropyridine (100 mg, 0.62 mmol), aniline (0.57 mL, 6.18 mmol) and potassium carbonate (214 mg, 1.55 mmol) in N,N-dimethylformamide (dry, 1 mL) was heated at 140ºC in a microwave for 3 h (and was left standing overnight). The reaction mixture was added to water. The pH was set at ∼7 using aqueous 1 M HCl. Ethyl acetate was added and the layers were separated. The organic phase was dried (Na2SO4), filtered and evaporated to dryness under reduced pressure to afford 1.92 g of crude product. Purification by column chromatography (silica gel, heptane/Ethyl acetate, 9:1) afforded 2-nitro-N-phenylpyridin-3-amine (260 mg, 1.208 mmol, 65.2 % yield) as a dark brown oil. LRMS (m/z): 216 (M+1)+.
65.2%	With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 3h; Microwave irradiation;	A mixture of 3-chloro-2-nitropyridine (100 mg, 0.62 mmol), aniline (0.57 mL, 6.18 mmol) and potassium carbonate (214 mg, 1.55 mmol) in Ν,Ν-dimethylformamide (dry, 1 mL) was heated at 140°C in a microwave for 3 h (and was left standing overnight). The reaction mixture was added to water. The pH was set at -7 using aqueous 1 M HCI. Ethyl acetate was added and the layers were separated. The organic phase was dried (Na2S04), filtered and evaporated to dryness under reduced pressure to afford 1 .92 g of crude product. Purification by column chromatography (silica gel, heptane/Ethyl acetate, 9:1 ) afforded 2-nitro-N-phenylpyridin-3-amine (260 mg, 1 .208 mmol, 65.2 % yield) as a dark brown oil.LRMS (m/z): 216 (M+1 )+.

Reference： [1]Current Patent Assignee: ALMIRALL SA - EP2518071, 2012, A1 Location in patent: Page/Page column 45
[2]Current Patent Assignee: ALMIRALL SA - WO2012/146667, 2012, A1 Location in patent: Page/Page column 102

45
[ 54231-32-2 ]
[ 1393177-41-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 140 °C / Microwave irradiation 2: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane; N,N-dimethyl-formamide / 20 °C
	Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 3 h / 140 °C / Microwave irradiation 2.1: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3.1: HATU / dichloromethane; N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 20 °C

Reference： [1]Current Patent Assignee: ALMIRALL SA - EP2518071, 2012, A1
[2]Current Patent Assignee: ALMIRALL SA - WO2012/146667, 2012, A1

46
[ 54231-32-2 ]
[ 1404085-69-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: N,N-dimethyl-formamide / 140 °C / Microwave irradiation 2.1: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane; N,N-dimethyl-formamide / 20 °C 4.1: acetic acid / 100 °C 4.2: 85 °C
	Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 3 h / 140 °C / Microwave irradiation 2.1: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3.1: HATU / dichloromethane; N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 20 °C 4.1: 100 °C 5.1: hydrogenchloride; water / methanol / 85 °C 5.2: 20 °C / pH ~ 8

Reference： [1]Current Patent Assignee: ALMIRALL SA - EP2518071, 2012, A1
[2]Current Patent Assignee: ALMIRALL SA - WO2012/146667, 2012, A1

47
[ 54231-32-2 ]
[ 1404085-68-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 140 °C / Microwave irradiation 2: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane; N,N-dimethyl-formamide / 20 °C
	Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 3 h / 140 °C / Microwave irradiation 2.1: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3.1: HATU / dichloromethane; N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 20 °C

Reference： [1]Current Patent Assignee: ALMIRALL SA - EP2518071, 2012, A1
[2]Current Patent Assignee: ALMIRALL SA - WO2012/146667, 2012, A1

48
[ 54231-32-2 ]
[ 1404086-78-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: N,N-dimethyl-formamide / 140 °C / Microwave irradiation 2.1: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane; N,N-dimethyl-formamide / 20 °C 4.1: acetic acid / 100 °C 4.2: 85 °C 5.1: N-ethyl-N,N-diisopropylamine / butan-1-ol / 85 °C
	Multi-step reaction with 6 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 3 h / 140 °C / Microwave irradiation 2.1: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3.1: HATU / dichloromethane; N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 20 °C 4.1: 100 °C 5.1: hydrogenchloride; water / methanol / 85 °C 5.2: 20 °C / pH ~ 8 6.1: N-ethyl-N,N-diisopropylamine / butan-1-ol / 85 °C

Reference： [1]Current Patent Assignee: ALMIRALL SA - EP2518071, 2012, A1
[2]Current Patent Assignee: ALMIRALL SA - WO2012/146667, 2012, A1

49
[ 54231-32-2 ]
C₁₇H₁₈N₄O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 3 h / 140 °C / Microwave irradiation 2.1: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere 3.1: HATU / dichloromethane; N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 20 °C 4.1: 100 °C

Reference： [1]Current Patent Assignee: ALMIRALL SA - WO2012/146667, 2012, A1

50
[ 54231-32-2 ]
[ 270912-72-6 ]
1,1-dimethylethyl 3-[(2-nitro-3-pyridinyl)amino]methyl}-1-pyrrolidinecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 70℃;Inert atmosphere;	A solution of 3-chloro-2-nitropyridine (6.0 mmol) in dimethylsulfoxide (20 mL) was treated with 1 ,1-dimethylethyl (3S)-3-(aminomethyl)-l -pyrrolidinecarboxylate (6.0 mmol) and N,N-diisopropylethylamine (3.14 mL). The reaction was stirred under a stream of nitrogen at 70 C overnight. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (0-25% ethyl acetate/hexanes) gave the title compound as a yellow oil (400 mg, 20% yield). MS(ES)+ m e 323.2 [M+H]+.

Reference： [1]Patent: WO2011/66211,2011,A1 .Location in patent: Page/Page column 77-78

51
[ 54231-32-2 ]
2-nitro-N-[3-pyrrolidinylmethyl]-3-pyridinamine monohydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 70 °C / Inert atmosphere 2: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/66211, 2011, A1

52
[ 54231-32-2 ]
N-[1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2-nitro-3-pyridinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 70 °C / Inert atmosphere 2.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.25 h / 20 °C 3.2: 0.5 h

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/66211, 2011, A1

53
[ 54231-32-2 ]
[ 1309806-35-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 70 °C / Inert atmosphere 2.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.25 h / 20 °C 3.2: 0.5 h 4.1: hydrogen / palladium 10% on activated carbon / ethyl acetate; ethanol / 2 h / 20 °C 5.1: butan-1-ol / 2 h / 90 °C

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/66211, 2011, A1

54
[ 54231-32-2 ]
N₃-[1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,3-pyridinediamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 70 °C / Inert atmosphere 2.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.25 h / 20 °C 3.2: 0.5 h 4.1: hydrogen / palladium 10% on activated carbon / ethyl acetate; ethanol / 2 h / 20 °C

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/66211, 2011, A1

55
[ 54231-32-2 ]
4'-(1-[1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-1H-imidazo[4,5-b]pyridin-2-yl)-3-biphenylol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 70 °C / Inert atmosphere 2.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.25 h / 20 °C 3.2: 0.5 h 4.1: hydrogen / palladium 10% on activated carbon / ethyl acetate; ethanol / 2 h / 20 °C 5.1: 1-methyl-pyrrolidin-2-one / 30 h / 140 °C

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/66211, 2011, A1

56
[ 54231-32-2 ]
[ 42753-67-3 ]

Reference： [1]Patent: WO2013/117649,2013,A1

57
[ 54231-32-2 ]
potassium vinyltrifluoroborate [ No CAS ]
[ 844503-09-9 ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In tetrahydrofuran; water at 75℃; for 1.5h;	i Pd-mediated coupling The (hetero)aryl chloride (6.31 mmol), potassium vinyltrifluoroborate (7.57 mmol), cesium carbonate (18.93 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.631 mmol) are suspended in THF (50 mL) and water (5 mL) and the stirred reaction mixture is heated to 75°C for 1.5 h. The reaction mixture is filtered through celite and partitioned between diethyl ether and water. The layers are separated and the aqueous layer is extracted with diethyl ether, the organics are combined, dried (MgSO i) and concentrated in vacuo.

Reference： [1]Current Patent Assignee: GALAPAGOS - WO2013/117649, 2013, A1 Location in patent: Paragraph 00268

58
[ 54231-32-2 ]
[ 1480-64-4 ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 12137 - 12145

59
[ 54231-32-2 ]
5-chloro-4-(4-chloro-2-fluoro-5-hydroxyphenyl)-1,2-tetramethylene-4-pyrazolin-3-one [ No CAS ]
5-chloro-4-[4-chloro-2-fluoro-5-(2-nitropyridin-3-yl)oxyphenyl]-1,2-tetramethylene-4-pyrazolin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	Stage #1: 5-chloro-4-(4-chloro-2-fluoro-5-hydroxyphenyl)-1,2-tetramethylene-4-pyrazolin-3-one With sodium hydroxide In N,N-dimethyl-formamide at 50℃; for 0.25h; Cooling with ice; Stage #2: 3-chloro-2-nitropyridine In N,N-dimethyl-formamide at 50℃; for 24h;	284 Example-284 5-Chloro-4-(4-chloro-2-fluoro-5-hydroxyphenyl)-1,2-tetramethylene-4-pyrazolin-3-one (300 mg, 0.95 mmol) was added to a suspension of a 55% oil dispersion (62.2 mg, 1.43 mmol) of sodium hydride in dimethyl formamide (3 mL) under ice-cooling, followed by stirring at 50° C. for 15 minutes. 3-Chloro-2-nitropyridine (166 mg, 1.05 mmol) was added thereto at the same temperature, followed by stirring for 24 hours. After the reaction was completed, ice water was poured into the reaction solution, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water, and then, a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was eluted and purified by silica gel column chromatography (ethyl acetate:methanol=10:1), whereby 5-chloro-4-[4-chloro-2-fluoro-5-(2-nitropyridin-3-yl)oxyphenyl]-1,2-tetramethylene-4-pyrazolin-3-one (104 mg, yield: 25%) was obtained as a pale brown solid. 1H-NMR (400 MHz, CDCl3): δ1.86-1.92 (m, 2H), 1.98-2.04 (m, 2H), 3.60-3.63 (m, 2H), 3.80-3.82 (m, 2H), 6.92 (dd, J=5.07.8 and 5.07.8 Hz, 1H), 7.28 (d, J=9.2 Hz, 1H), 7.45 (d, J=6.9 Hz, 1H), 7.75 (dd, J=7.8 and 1.8 Hz, 1H), 7.98 (dd, J=5.0 and 1.8 Hz, 1H). 19F-NMR (376 MHz, CDCl3): δ-113 (s, 1F).

Reference： [1]Current Patent Assignee: SAGAMI CHEMICAL RESEARCH INSTITUTE; KAKEN PHARMACEUTICAL CO LTD - US2016/24110, 2016, A1 Location in patent: Paragraph 1203; 1204

60
[ 91-21-4 ]
[ 54231-32-2 ]
5,6-dihydropyrido[2',3':4,5]imidazo[2,1-a]isoquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	at 130℃; for 24h; Inert atmosphere;

Reference： [1]Nguyen; Ermolenko; Al-Mourabit [Chemical Communications, 2016, vol. 52, # 27, p. 4914 - 4917]

61
[ 878671-94-4 ]
[ 54231-32-2 ]
N-(4-cyclopropylnaphthalen-1-yl)-2-nitropyridin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.6%	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 20 - 90℃; for 12.25h;Inert atmosphere;	Palladium acetate (0.007 g, 0.0315 mmol)And 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.036 g, 0.063 mmol)Was dissolved in 2 mL dioxane,The mixture was stirred at room temperature for 15 minutes,While 3-chloro-2-nitropyridine (13) (0.1 g, 0.63 mmol),Cyclopropyl-1-naphthylamine (11) (0.13 g, 0.76 mmol)And cesium carbonate (0.41 g, 1.26 mmol)Was dissolved in 10 mL dioxane,The two solutions were mixed and refluxed at 90 C for 12 h under nitrogen. The reaction was complete by TLC. After the reaction was completed, the reaction mixture was cooled. To the residue was added 30 mL of methylene chloride and a saturated aqueous solution of sodium chloride (3x10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the product was purified by flash column chromatography to give yellow intermediate N- (4-cyclopropyl-1-naphthyl) -2-nitro-3-amine (16). Yield 60.6%.

Reference： [1]Patent: CN106083847,2016,A .Location in patent: Paragraph 0208; 0210

62
[ 54231-32-2 ]
[ 95-57-8 ]
C₁₁H₇ClN₂O₃ [ No CAS ]
C₁₁H₇Cl₂NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 75 %Chromat. 2: 25 %Chromat.	With caesium carbonate In N,N-dimethyl-formamide at 70℃;

Reference： [1]Maxwell, Brad D.; Bonacorsi, Samuel J. [Journal of labelled compounds and radiopharmaceuticals, 2016, vol. 59, # 14, p. 657 - 664]

63
[ 54231-32-2 ]
[ 95-57-8 ]
C₁₁H₇ClN₂O₃ [ No CAS ]
C₁₁H₇Cl₂NO [ No CAS ]
C₁₇H₁₁Cl₂NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 41.5 %Chromat. 2: 30.2 %Chromat. 3: 28.3 %Chromat.	With potassium carbonate In toluene at 70℃;

Reference： [1]Maxwell, Brad D.; Bonacorsi, Samuel J. [Journal of labelled compounds and radiopharmaceuticals, 2016, vol. 59, # 14, p. 657 - 664]

64
[ 54231-32-2 ]
[ 95-57-8 ]
C₁₁H₇Cl₂NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100 %Chromat.	With potassium carbonate In acetonitrile at 70℃;

Reference： [1]Maxwell, Brad D.; Bonacorsi, Samuel J. [Journal of labelled compounds and radiopharmaceuticals, 2016, vol. 59, # 14, p. 657 - 664]

65
[ 13269-19-7 ]
[ 54231-32-2 ]

Reference： [1]Organic Process Research and Development,2017,vol. 21,p. 44 - 51

66
[ 54231-32-2 ]
[ 953045-27-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: caesium carbonate / dimethyl sulfoxide / 1.5 h / 20 °C 2.1: acetic acid; zinc / 0.08 h / 0 °C / Cooling with ice 2.2: 0.17 h

Reference： [1]Current Patent Assignee: PFIZER INC - WO2008/118718, 2008, A2

67
[ 54231-32-2 ]
[ 953045-29-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: caesium carbonate / dimethyl sulfoxide / 1.5 h / 20 °C 2.1: acetic acid; zinc / 0.08 h / 0 °C / Cooling with ice 2.2: 0.17 h 3.1: tetrahydrofuran / 40 °C 4.1: sodium hydroxide / methanol / 8 h / 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2008/118718, 2008, A2

68
[ 54231-32-2 ]
[ 953045-28-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: caesium carbonate / dimethyl sulfoxide / 1.5 h / 20 °C 2.1: acetic acid; zinc / 0.08 h / 0 °C / Cooling with ice 2.2: 0.17 h 3.1: tetrahydrofuran / 40 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2008/118718, 2008, A2

69
[ 54231-32-2 ]
3,9-dihydro-4H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / dimethyl sulfoxide / 0 - 100 °C 2: iron / ethyl acetate / 12 h / Reflux 3: 4 h / 150 °C

Reference： [1]Current Patent Assignee: Li Mingxia - CN109223792, 2019, A

70
[ 54231-32-2 ]
[ 105-56-6 ]
2-cyano-2-(2-nitropyridin-3-yl)acetic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate In dimethyl sulfoxide at 0 - 100℃;	1.A Step A: 2-cyano-2-(2-nitropyridin-3-yl)acetate To 3-chloro-2-nitropyridine (5.00 g, 0.032 mol) and anhydrous potassium carbonate (8.72 g, 0.063 mol) at 0 °CEthyl cyanoacetate (3.57 g, 0.032 mol) was added dropwise to a suspension of dimethyl sulfoxide (60 mL). The reaction was heated to 100 ° C and allowed to react overnight.After cooling, it was poured into ice water and stirred for 15 min, and the solid was collected by filtration to afford product ( 5.80 g, 78%).

Reference： [1]Current Patent Assignee: Li Mingxia - CN109223792, 2019, A Location in patent: Paragraph 0015; 0017; 0018; 0019; 0020

71
[ 54231-32-2 ]
C₂₈H₁₈N₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate; bis-triphenylphosphine-palladium(II) chloride / water; ethanol; toluene / 24 h / 100 °C / Inert atmosphere 2: triphenylphosphine / 1,2-dichloro-benzene / 24 h / 180 °C / Inert atmosphere 3: potassium carbonate; copper / N,N-dimethyl-formamide / 48 h / 150 °C / Inert atmosphere 4: potassium carbonate; copper(l) iodide; 18-crown-6 ether; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / 48 h / 180 °C / Inert atmosphere