343781-36-2|2,4-Dichloro-3-iodopyridine| Ambeed

Structure of 343781-36-2

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]} Purity: {[proInfo.pro_purity]}

Change View

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 343781-36-2 ] Purity: 98% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support

Product Details of [ 343781-36-2 ]

CAS No. :	343781-36-2
Formula :	C₅H₂Cl₂IN
M.W :	273.89
SMILES Code :	IC1=C(Cl)C=CN=C1Cl
MDL No. :	MFCD09033756
InChI Key :	OKXJLNYZTJLVJZ-UHFFFAOYSA-N
Pubchem ID :	10636017

Safety of [ 343781-36-2 ]

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

Computational Chemistry of [ 343781-36-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	0.0
Molar Refractivity	46.97
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	12.89 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.99
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	3.09
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.99
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.	2.6
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	3.67
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.87

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.98
Solubility	0.0288 mg/ml ; 0.000105 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.	-3.03
Solubility	0.257 mg/ml ; 0.000937 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	-4.21
Solubility	0.017 mg/ml ; 0.0000622 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	Yes
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.	-5.78 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	2.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.13

Application In Synthesis of [ 343781-36-2 ]

* 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.

Downstream synthetic route of [ 343781-36-2 ]

[ 343781-36-2 ] Synthesis Path-Downstream 1~35

1
[ 26452-80-2 ]
[ 343781-36-2 ]

Yield	Reaction Conditions	Operation in experiment
81%		Description 52,4-dichloro-3-iodo-pyridine (D5)To a solution of 2,4-dichloropyridine (5.2 g, 35.137 mmol) and DIPEA (3.911 g,38.651 mmol) in dry THF (40 ml) cooled at -78 0C under a nitrogen atmosphere, was added M-butyllithium (24.157 ml, 38.651 mmol, 1.6 M in hexanes) dropwise. The resulting reaction mixture was stirred at -78 0C for 45 min. and then a solution of iodine (9.81 g, 38.651 mmol) in dry THF (20 ml) was added dropwise. The mixture was stirred at -78 0C for 1 h. The mixture was allowed to warm to room temperature, diluted with EtOAc and quenched with NH4Cl (aqueous sat. solution) and Na2S2O3 (aqueous sat. solution). The combined organic extracts were separated, washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM up to 20% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D5 (7.8 g, 81%).
81%		To a solution of 2,4-dichloropyridine (5.2 g, 35.137 mmol) and diisopropylamine (3.911 g, 38.651 mmol) in dry THF (40 ml) cooled at -78 0C under a nitrogen atmosphere, was added M-butyllithium (24.157 ml, 38.651 mmol, 1.6 M in hexanes) dropwise. The resulting reaction mixture was stirred at -78 0C for 45 min., then a solution of iodine (9.81 g, 38.651 mmol) in dry THF (20 ml) was added dropwise and the mixture was further stirred at -78 0C for 1 h. The mixture was allowed to warm to r.t., diluted with EtOAc and quenched with NH4Cl (aqueous sat. solution) and Na2S2O3 (aqueous sat. solution). The organic layer was separated, washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM up to 20% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D 12 (7.8 g, 81%)
81%		To a solution of 2,4-dichloropyridine (5.2 g, 35.137 mmol) and diisopropylamine (3.911 g, 38.651 mmol) in dry THF (40 ml) cooled at -78 0C under a nitrogen atmosphere, was added n-butyllithium (24.157 ml, 38.651 mmol, 1.6 M in hexanes) dropwise. The resulting reaction mixture was stirred at -78 0C for 45 min. and then a solution of iodine (9.81 g, 38.651 mmol) in dry THF (20 ml) was added dropwise. The mixture was stirred at -78 0C for 1 h., allowed to warm to r.t., diluted with EtOAc and quenched with NH4Cl (aqueous sat. solution) and Na2S2O3 (aqueous sat. solution). The organic layer was separated, washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM up to 20% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D24 (7.8 g, 81%).

81%		2,4-Dichloro-3 -iodo-pyridine (1-5)To a solution of 2,4-dichloropyridine (5.2 g, 35.14 mmol) and DIPEA (3.91 g, 38.65 mmol) in dry THF (40 mL) cooled at -78 C under a nitrogen atmosphere, was added n-BuLi (24.16 mL, 38.65 mmol, 1.6 M in hexanes) dropwise. The resulting r.m. was stirred at -78 C for 45 min and then a solution of iodine (9.81 g, 38.651 mmol) in dry THF (20 mL) was added dropwise. The mixture was stirred at -78 C for 1 h, allowed to warm to r. , diluted with EtOAc and quenched with H4CI (aq. sat. sol.) and Na2S203 (aq. sat. sol). The organic layer was separated, washed with NaHC03 (aq. sat. sol), dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM up to 20% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate 1-5 (7.8 g, 81%).
81%		Intermediate 1 (1-1)2,4-Dichloro-3-iodo-pyridine (1-1)To a solution of 2,4-dichloropyridine (5.2 g, 35.14 mmol) and diisopropylamine (3.91 g, 38.65 mmol) in dry THF (40 mL) cooled at -78 C under a nitrogen atmosphere, was added n-butyllithium (24.16 mL, 38.65 mmol, 1.6 M in hexanes) dropwise. The resulting reaction mixture was stirred at -78 C for 45 min. and then a solution of iodine (9.81 g, 38.651 mmol) in dry THF (20 mL) was added dropwise. The mixture was stirred at -78 C for 1 h., allowed to warm to r.t., diluted with EtOAc and quenched with H4CI (aqueous sat. solution) and Na2S203 (aqueous sat. solution). The organic layer was separated, washed with NaHC03 (aqueous sat. solution), dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM in heptane 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield intermediate compound 1-1(7.8 g, 81%).
81%		Intermediate 7 (1-7)2,4-Dichloro-3 -iodo-pyridine (1-7) To a solution of 2,4-dichloropyridine (5.2 g, 35.14 mmol) and DIPEA (3.91 g,38.65 mmol) in dry THF (40 mL) cooled at -78 C under a nitrogen atmosphere, was added n-butyllithium (24.16 mL, 38.65 mmol, 1.6 M in hexanes) dropwise. The resulting reaction mixture was stirred at -78 C for 45 min. and then a solution of iodine (9.81 g, 38.651 mmol) in dry THF (20 mL) was added dropwise. The mixture was stirred at -78 C for 1 h., allowed to warm to r.t., diluted with EtOAc and quenched with H4CI (aqueous sat. solution) and Na2S203 (aqueous sat. solution). The organic layer was separated, washed with NaHC03 (aqueous sat. solution), dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM in heptane 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield intermediate compound 1-7 (7.8 g, 81%).
81%		Intermediate 1 (1-1)2,4-Dichloro-3-iodo-pyridine (1-1)To a solution of 2,4-dichloropyridine (5.2 g, 35.14 mmol) and diisopropylamine (3.91 g, 38.65 mmol) in dry THF (40 mL) cooled at -78 C under a nitrogen atmosphere, was added n-butyllithium (24.16 mL, 38.65 mmol, 1.6 M in hexanes) dropwise. The resulting reaction mixture was stirred at -78 C for 45 min. and then a solution of iodine (9.81 g, 38.651 mmol) in dry THF (20 mL) was added dropwise. The mixture was stirred at -78 C for 1 h., allowed to warm to r.t., diluted with EtOAc and quenched with H4CI (aqueous sat. solution) and Na2S203 (aqueous sat. solution). The organic layer was separated, washed with NaHC03 (aqueous sat. solution), dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM in heptane 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield intermediate compound 1-1 (7.8 g, 81%).
81%	With n-butyllithium; iodine; diisopropylamine; In tetrahydrofuran; n-heptane; at -78℃; for 1.75h;Inert atmosphere;	2,4-Dichloro-3-iodo-pyridine (I-1) To a solution of 2,4-dichloropyridine (5.2 g, 35.14 mmol) and diisopropylamine (3.91 g, 38.65 mmol) in dry THF (40 mL) cooled at -78 C. under a nitrogen atmosphere, was added n-butyllithium (24.16 mL, 38.65 mmol, 1.6 M in hexanes) dropwise. The resulting reaction mixture was stirred at -78 C. for 45 min. and then a solution of iodine (9.81 g, 38.651 mmol) in dry THF (20 mL) was added dropwise. The mixture was stirred at -78 C. for 1 h., allowed to warm to r.t., diluted with EtOAc and quenched with NH4Cl (aqueous sat. solution) and Na2S2O3 (aqueous sat. solution). The organic layer was separated, washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM in heptane 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield intermediate compound I-1 (7.8 g, 81%).
81%		2,4-Dichloro-3-iodo-pyridine (I-5) To a solution of 2,4-dichloropyridine (5.2 g, 35.14 mmol) and DIPEA (3.91 g, 38.65 mmol) in dry THF (40 mL) cooled at -78 C. under a nitrogen atmosphere, was added n-BuLi (24.16 mL, 38.65 mmol, 1.6 M in hexanes) dropwise. The resulting r.m. was stirred at -78 C. for 45 min and then a solution of iodine (9.81 g, 38.651 mmol) in dry THF (20 mL) was added dropwise. The mixture was stirred at -78 C. for 1 h, allowed to warm to r.t., diluted with EtOAc and quenched with NH4Cl (aq. sat. sol.) and Na2S2O3 (aq. sat. sol.). The organic layer was separated, washed with NaHCO3 (aq. sat. sol.), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM up to 20% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate I-5 (7.8 g, 81%).
81%		To a solution of 2,4-dichloropyridine (5.2 g, 35.137 mmol) and diisopropylamine (3.911 g, 38.651 mmol) in dry THF (40 ml) cooled at -78 C under a nitrogen atmosphere, was added n-butyllithium (24.157 ml, 38.651 mmol, 1.6 M in hexanes) dropwise. The resulting reaction mixture was stirred at -78 C for 45 min and then a solution of iodine (9.81 g, 38.651 mmol) in dry THF (20 ml) was added dropwise. The mixture was stirred at -78 C for 1 h, allowed to warm to rt, diluted with EtOAc and quenched with NH4Cl (aqueous sat. solution) and Na2S203 (aqueous sat. solution). The organic layer was separated, washed with NaHC03 (aqueous sat. solution), dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; heptane/DCM up to 20% as eluent). The desired fractions were collected and concentrated in vacuo to yield 1-1 (7.8 g, 81%).

References: [1]European Journal of Organic Chemistry,2001,p. 1371 - 1376.
[2]Patent: WO2010/130422,2010,A1 .Location in patent: Page/Page column 53.
[3]Patent: WO2010/130423,2010,A1 .Location in patent: Page/Page column 53.
[4]Patent: WO2010/130424,2010,A1 .Location in patent: Page/Page column 104-105.
[5]Patent: WO2012/62752,2012,A1 .Location in patent: Page/Page column 26.
[6]Patent: WO2012/62751,2012,A1 .Location in patent: Page/Page column 34.
[7]Patent: WO2012/62750,2012,A1 .Location in patent: Page/Page column 38-39.
[8]Patent: WO2012/62759,2012,A1 .Location in patent: Page/Page column 37-38.
[9]Patent: US2013/252952,2013,A1 .Location in patent: Paragraph 0132; 0133.
[10]Patent: US2013/230459,2013,A1 .Location in patent: Paragraph 0162.
[11]Patent: WO2016/92002,2016,A1 .Location in patent: Page/Page column 30.

2
[ 124-38-9 ]
[ 343781-36-2 ]
[ 262423-77-8 ]
2,4-dichloro-5-iodo-3-pyridinecarboxylic acid [ No CAS ]

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

3
[ 343781-36-2 ]
[ 343781-49-7 ]

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

4
[ 109-09-1 ]
[ 343781-36-2 ]

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

5
[ 153034-86-7 ]
[ 343781-36-2 ]

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

6
[ 78607-36-0 ]
[ 343781-36-2 ]

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

7
[ 343781-36-2 ]
[ 73027-79-9 ]

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

8
[ 680-15-9 ]
[ 343781-36-2 ]
[ 1186194-98-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	Description 6 2,4-dichloro-3-trifluoromethyl-pyridine(D6)To a mixture of compound D5 (2g, 7.302 mmol) in DMF (50 ml) were added fluorosulfonyl-difluoro-acetic acid methyl ester (1.858 ml, 14.605 mmol) [C.A.S. 680- 15-9] and copper (I) iodide (2.796. g, 14.605 mmol). The reaction mixture was heated in a sealed tube at 100 0C for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D6 (1.5 g, 95%).
95%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	To a mixture of intermediate compound D12 (2g, 7.302 mmol) in DMF (50 ml) were added fluorosulfonyl-difluoro-acetic acid methyl ester (1.858 ml, 14.605 mmol)[C.A.S. 680-15-9] and copper (I) iodide (2.796. g, 14.605 mmol). The reaction mixture was heated in a sealed tube at 100 0C for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D 13 ( 1.5 g, 95%).
95%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	To a mixture of compound D24 (2g, 7.302 mmol) in DMF (50 ml) were added fiuorosulfonyl-difluoro-acetic acid methyl ester [C.A.S. 680-15-9] (1.858 ml, 14.605 mmol) and copper (I) iodine (2.796. g, 14.605 mmol). The reaction mixture was heated in a sealed tube at 100 0C for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D25 (1.5 g, 95%).

95%	copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	Intermediate 2 (1-2)2,4-Dichloro-3 -trifluoromethyl-pyridine (1-2)To a mixture of compound 1-1 (2g, 7.30 mmol) in DMF (50 mL) were added fluorosulfonyl-difluoro-acetic acid methyl ester [C.A.S. 680-15-9] (1.86 ml,14.60 mmol) and copper (I) iodide (2.79 g, 14.60 mmol). The reaction mixture was heated in a sealed tube at 100 C for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel, DCM). The desired fractions were collected and concentrated in vacuo to yield intermediate compound 1-2 (1.5 g, 95%).
95%	copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	Intermediate 8 (1-8)o-3 -trifluoromethyl-pyridine (1-2)To a mixture of compound 1-7 (2g, 7.30 mmol) in DMF (50 mL) were added fluorosulfonyl-difluoro-acetic acid methyl ester [C.A.S. 680-15-9] (1.86 ml,14.60 mmol) and copper (I) iodide (2.79 g, 14.60 mmol). The reaction mixture was heated in a sealed tube at 100 C for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel, DCM). The desired fractions were collected and concentrated in vacuo to yield intermediate compound 1-8 (1.5 g, 95%).
95%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed vessel;	Intermediate 2 (1-2)o-3-trifluoromethyl-pyridine (1-2)To a mixture of compound 1-1 (2g, 7.30 mmol) in DMF (50 mL) were added fluorosulfonyl-difluoro-acetic acid methyl ester [C.A.S. 680-15-9] (1.86 ml, 14.60 mmol) and copper (I) iodine (2.79 g, 14.60 mmol). The reaction mixture was heated in a sealed tube at 100 C for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel, DCM). The desired fractions were collected and concentrated in vacuo to yield intermediate compound 1-2 (1.5 g, 95%).
95%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	2,4-Dichloro-3-trifluoromethyl-pyridine (I-2) To a mixture of compound I-1 (2 g, 7.30 mmol) in DMF (50 mL) were added fluorosulfonyl-difluoro-acetic acid methyl ester [C.A.S. 680-15-9] (1.86 ml, 14.60 mmol) and copper (I) iodide (2.79 g, 14.60 mmol). The reaction mixture was heated in a sealed tube at 100 C. for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel, DCM). The desired fractions were collected and concentrated in vacuo to yield intermediate compound I-2 (1.5 g, 95%).
95%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	4-Dichloro-3-trifluoromethyl-pyridine (I-6) To a mixture of intermediate I-5 (2 g, 7.30 mmol) in DMF (50 mL) were added fluorosulfonyl-difluoro-acetic acid methyl ester [C.A.S. 680-15-9] (1.86 ml, 14.60 mmol) and copper (I) iodide (2.79 g, 14.60 mmol). The r.m. was heated in a sealed tube at 100 C. for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel, DCM). The desired fractions were collected and concentrated in vacuo to yield intermediate I-6 (1.5 g, 95%).
95%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	To a mixture of 1-1 (2 g, 7.302 mmol) in DMF (50 mL) were added fluorosulfonyl- difluoro-acetic acid methyl ester ([CAS 680-15-9], 1.858 mL, 14.605 mmol) and copper (I) iodide (2.796. g, 14.605 mmol). The reaction mixture was heated in a sealed tube at 100 C for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and concentrated in vacuo to yield 1-2 (1.5 g, 95%).
160 g	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;	To a solution of <strong>[343781-36-2]2,4-dichloro-3-iodopyridine</strong> ([CAS 34378 1-36-2], 290 g, 1058 mmol)in DMF (1.7 L) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate ([CAS 680-15-9], 403 g, 2098 mmol) and Cul (403 g, 2.13 mol), the reaction was then heated at100Cfor5h.The reation was cooled and filtered. The filtrate was diluted with H20 and extracted with Et20 and washed with a NH3 solution. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to yield intermediate 2 (160 g), which was used without further purification.
160 g	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;	To a solution of <strong>[343781-36-2]2,4-dichloro-3-iodopyridine</strong> ([CAS 34378 1-36-2], 290 g, 1058 mmol)in DMF (1.7 L) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate ([CAS 680-15-9], 403 g, 2098 mmol) and Cul (403 g, 2.13 mol), the reaction was then heated at i00Cfor5h.The reation was cooled and filtered. The filtrate was diluted with H20 and extracted with Et20 and washed with a NH3 solution. The organic layer was dried (Na2SO4),filtered and concentrated in vacuo to yield intermediate 2 (160 g), which was used without further purification.

References: [1]Patent: WO2010/130422,2010,A1 .Location in patent: Page/Page column 53-54.
[2]Patent: WO2010/130423,2010,A1 .Location in patent: Page/Page column 54.
[3]Patent: WO2010/130424,2010,A1 .Location in patent: Page/Page column 105.
[4]Patent: WO2012/62751,2012,A1 .Location in patent: Page/Page column 34.
[5]Patent: WO2012/62750,2012,A1 .Location in patent: Page/Page column 39.
[6]Patent: WO2012/62759,2012,A1 .Location in patent: Page/Page column 38.
[7]Patent: US2013/252952,2013,A1 .Location in patent: Paragraph 0134; 0135.
[8]Patent: US2013/230459,2013,A1 .Location in patent: Paragraph 0164.
[9]Patent: WO2016/92002,2016,A1 .Location in patent: Page/Page column 30.
[10]Patent: WO2015/32790,2015,A1 .Location in patent: Page/Page column 32.
[11]Patent: WO2015/110435,2015,A1 .Location in patent: Page/Page column 55.

9
[ 343781-36-2 ]
[ 1254981-77-5 ]

Yield	Reaction Conditions	Operation in experiment
49%	With hydrazine hydrate; In 1,4-dioxane; at 80℃; for 16h;sealed tube;	Description 32 (4-chloro-3-iodo-pyridin-2-yl)-hydrazine (D32)To a solution of <strong>[343781-36-2]2,4-dichloro-3-iodopyridine</strong> [CAS 343781-36-3] (4.7 g, 17.16 mmol) in 1,4-dioxane (240 ml), was added hydrazine monohydrate (5.096 ml, 102.962 mmol). The reaction mixture was heated in a sealed tube at 80 0C for 16 h. After cooling, the solvent was concentrated in vacuo. The white solid residue thus obtained was dissolved in DCM and washed with NaHCO3 (aqueous saturated solution). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue was washed with Et2O. The solid thus obtained was discarded. The mother liquours were concentrated in vacuo to yield intermediate compound D32 (2.31 g, 49%).
49%	With hydrazine hydrate; In 1,4-dioxane; at 80℃; for 16h;Sealed tube;	To a solution of <strong>[343781-36-2]2,4-dichloro-3-iodopyridine</strong> [CAS 343781-36-3] (4.7 g, 17.16 mmol) in 1,4-dioxane (240 ml), was added hydrazine monohydrate (5.096 ml, 102.962 mmol). The reaction mixture was heated in a sealed tube at 80 0C for 16 h. After cooling, the solvent was concentrated in vacuo. The white solid residue thus obtained was dissolved in DCM and washed with NaHCO3 (aqueous saturated solution). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue was washed with diethylether. The solid thus obtained was discarded. The mothe liquours were concentrated in vacuo to yield intermediate compound D45 (2.31 g, 49%)
49%	With hydrazine hydrate; In 1,4-dioxane; at 80℃;	To a suspension of D24 (4.7 g, 17.16 mmol) in 1,4-dioxane (240 ml), was added hydrazine monohydrate (5.096 ml, 102.96 mmol). The reaction mixture was heated at 80 0C overnight. After cooling, the resulting solution was concentrated in vacuo. The residue thus obtained was dissolved in DCM and washed with NaHCO3 (aqueous sat. solution). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue was treated with Et2O. The solid obtained was filtered off. The filtrate was concentrated in vacuo to yield intermediate D68 (2.26 g, 49%).

References: [1]Patent: WO2010/130422,2010,A1 .Location in patent: Page/Page column 66.
[2]Patent: WO2010/130423,2010,A1 .Location in patent: Page/Page column 69.
[3]Patent: WO2010/130424,2010,A1 .Location in patent: Page/Page column 124-125.

10
[ 124-41-4 ]
[ 343781-36-2 ]
[ 1163693-01-3 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 20 - 45℃;	A mixture of 4a2 (201 g, 734 mmol) and NaOMe (51.5 g, 954 mmol) in MeOH (2 L) is stirred at RT overnight then heated at 45 C for 3 h. The reaction is diluted with EtOAc, washed with water, brine, dried over MgS04, filtered and concentrated under vacuum. Upon standing crystals are formed. These are collected, washed with a small amount of (/-Pr)20 followed by heptane and dried on a stream of air to afford 4a3.

References: [1]Patent: WO2011/32277,2011,A1 .Location in patent: Page/Page column 41.

11
[ 626-03-9 ]
[ 343781-36-2 ]

References: [1]Patent: WO2011/32277,2011,A1 .

12
[ 1100932-71-5 ]
[ 343781-36-2 ]

Yield	Reaction Conditions	Operation in experiment
	With trichlorophosphate;N,N-dimethyl-formamide; at 90℃;	A mixture of 4a1 (207 g, 873 mmol), DMF (0.7 mL, 8.7 mmol) and POCI3 (1 L, 11 mol) is heated at 90 C overnight with stirring. The solution is concentrated, quenched with sat. aq. NaHC03, extracted with DCM, dried over MgS04, filtered and concentrated under vacuum. Co-evaporation with toluene affords dichloride 4a2.

References: [1]Patent: WO2011/32277,2011,A1 .Location in patent: Page/Page column 40-41.

13
[ 343781-36-2 ]
[ 1163693-02-4 ]

References: [1]Patent: WO2011/32277,2011,A1 .

14
[ 343781-36-2 ]
[ 1186194-98-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With copper(l) iodide; 2,2-difluoro-2-(fluorosulfonyl)acetate; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	Intermediate 62,4-Dichloro-3 -trifluoromethyl-pyridine (1-6)To a mixture of intermediate 1-5 (2g, 7.30 mmol) in DMF (50 mL) were added fluorosulfonyl-difluoro-acetic acid methyl ester [C.A.S. 680-15-9] (1.86 ml, 14.60 mmol) and copper (I) iodide (2.79 g, 14.60 mmol). The r.m. was heated in a sealed tube at 100 C for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel, DCM). The desired fractions were collected and concentrated in vacuo to yield intermediate 1-6 (1.5 g, 95%).

References: [1]Patent: WO2012/62752,2012,A1 .Location in patent: Page/Page column 26.

15
[ 343781-36-2 ]
[ 1254981-27-5 ]

References: [1]Patent: WO2012/62752,2012,A1 .
[2]Patent: WO2012/62751,2012,A1 .
[3]Patent: WO2012/62750,2012,A1 .
[4]Patent: WO2012/62759,2012,A1 .
[5]Patent: US2013/252952,2013,A1 .
[6]Patent: US2013/230459,2013,A1 .
[7]Patent: WO2015/32790,2015,A1 .
[8]Patent: WO2015/110435,2015,A1 .
[9]Patent: WO2016/92002,2016,A1 .

16
[ 343781-36-2 ]
[ 1254981-28-6 ]

17
[ 343781-36-2 ]
[ 1254981-29-7 ]

18
[ 343781-36-2 ]
[ 1254981-30-0 ]

19
[ 343781-36-2 ]
[ 1376334-38-1 ]

References: [1]Patent: WO2012/62752,2012,A1 .
[2]Patent: US2013/230459,2013,A1 .

20
[ 343781-36-2 ]
[ 1254982-02-9 ]

References: [1]Patent: WO2012/62751,2012,A1 .
[2]Patent: WO2012/62750,2012,A1 .
[3]Patent: WO2012/62759,2012,A1 .
[4]Patent: US2013/252952,2013,A1 .
[5]Patent: WO2015/32790,2015,A1 .
[6]Patent: WO2015/110435,2015,A1 .
[7]Patent: WO2016/92002,2016,A1 .

21
[ 343781-36-2 ]
[ 1254982-03-0 ]

References: [1]Patent: WO2012/62751,2012,A1 .
[2]Patent: WO2012/62759,2012,A1 .
[3]Patent: US2013/252952,2013,A1 .
[4]Patent: WO2015/32790,2015,A1 .
[5]Patent: WO2015/110435,2015,A1 .

22
[ 343781-36-2 ]
[ 1254982-04-1 ]

References: [1]Patent: WO2012/62751,2012,A1 .
[2]Patent: WO2012/62750,2012,A1 .
[3]Patent: WO2012/62759,2012,A1 .
[4]Patent: US2013/252952,2013,A1 .

23
[ 343781-36-2 ]
[ 1254982-05-2 ]

References: [1]Patent: WO2012/62751,2012,A1 .
[2]Patent: WO2012/62750,2012,A1 .
[3]Patent: WO2012/62759,2012,A1 .
[4]Patent: US2013/252952,2013,A1 .

24
[ 343781-36-2 ]
[ 1374765-94-2 ]

References: [1]Patent: WO2012/62751,2012,A1 .

25
[ 343781-36-2 ]
3-(cyclopropylmethyl)-7-[3-(2-fluorophenyl)-3-methylmorpholin-4-yl]methyl}-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine [ No CAS ]

References: [1]Patent: WO2012/62751,2012,A1 .
[2]Patent: US2013/252952,2013,A1 .

26
[ 343781-36-2 ]
[ 1374582-87-2 ]