141743-49-9|2,6-Difluoro-4-iodoaniline| Ambeed

Structure of 141743-49-9

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Quality Control of [ 141743-49-9 ] Purity: 97% SDS Specification

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Product Details of [ 141743-49-9 ]

CAS No. :	141743-49-9
Formula :	C₆H₄F₂IN
M.W :	255.00
SMILES Code :	NC1=C(F)C=C(I)C=C1F
MDL No. :	MFCD07774189
InChI Key :	HCUZNQLIMDDCHF-UHFFFAOYSA-N
Pubchem ID :	278943

Safety of [ 141743-49-9 ]

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

Computational Chemistry of [ 141743-49-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	43.48
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	26.02 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.79
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.09
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.0
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.	3.26
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.95
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.62

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.18
Solubility	0.168 mg/ml ; 0.000658 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.27
Solubility	1.38 mg/ml ; 0.00541 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	-3.55
Solubility	0.0717 mg/ml ; 0.000281 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.37 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)	2.04

Application In Synthesis of [ 141743-49-9 ]

* 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 [ 141743-49-9 ]

[ 141743-49-9 ] Synthesis Path-Downstream 1~36

1
[ 5509-65-9 ]
[ 141743-49-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With Iodine monochloride; In acetic acid; at 20℃; for 0.25h;	2, 6-Difluorobenzenamine (3. 0g, 22.56 mmoles) was dissolved in acetic acid (10 ml). Iodine monochloride (3.581g, 22.56 mmoles) was added to the solution. The mixture was stirred for 15 minutes at room temperature. After evaporation of the solvent, the residue was treated with an aqueous solution of sodium carbonate. The aqueous solution was extracted with dichloromethane. The organic extract was dried over MgS04 and was evaporated. Yield: 95% of intermediate 33.
95%		Example A1; a) Preparation of intermediate 1; 2,6-difluorobenzeneamine (3.0g, 22.56 mmoles) was dissolved in acetic acid (10 ml).Iodine monochloride (3.58lg, 22.56 mmoles) was added to the solution. The mixturewas stirred for 15 minutes at room temperature. After evaporation of the solvent, theresidue was treated with an aqueous solution of sodium carbonate. The aqueoussolution was extracted with dichloromethane. The organic extract was dried overMgSCU and was evaporated. Yield : 95% of intermediate 1.
51%	With silver(I) nitrite; iodine; In dichloromethane; at 0 - 20℃; for 1h;	Step 1: 4-Amino-3,5-difluoro-benzonitrile; To a suspension of iodine (5.59g, 22.0mmol) and AgNO2 (6.85g, 22.0mmol) in EPO <DP n="79"/>methylene chloride was added a solution of 2,6-difluoroaniline (2.58g, 20.0mmol) in methylene chloride at O0C, and the mixture was stirred for 30min at O0C and 30min at ambient temperature. The reaction was quenched with Na2S2O3. The reaction solution was extracted with methylenechloride, washed with water and brine, dried over anhyd. MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was column-chromatographed (hexane/ethylacetate = 15/1) to yield a yellow solid (2.57mg, 51%).

	With Iodine monochloride; In acetic acid;	Step 3: 60 g of 2,6-difluoroaniline was dissolved in 180 ml of acetic acid. A solution containing 75 g of iodine chloride dissolved in 48 ml of acetic acid was added dropwise therein, and then agitated at 80 C. for 2 hours. The reaction solution was poured into water, and the resulting deposited crystals were filtrated and washed with water. The crystals were recrystallized with methanol, vacuum distilled (125 C./22 mmHg), and recrystallized again with methanol to obtain 57 g of 2,6-difluoro-4-iodoaniline.
	With pyridine; Iodine monochloride; In chloroform; water; acetic acid;	Step 3: 2,6-Difluoroaniline (38 g) was dissolved in acetic acid (120 ml), and then pyridine (25 g) was added thereto, followed by stirring. Then, a mixture of iodine monochloride (50 g) with acetic acid (30 ml) was added dropwise thereto. After stirring at room temperature for 1 hour, the reaction solution was further stirred at 70 to 80 C. for 2 hours. Then, the reaction solution was poured into water, and the precipitated crystals were filtered, followed by washing with water. The resulting crystals were dissolved in chloroform, and then washed with water twice, further with 10% potassium hydroxide aqueous solution twice, and furthermore with water twice, followed by distilling off chloroform. The residue was distilled under reduced pressure (b.p. 120 to 130 C./20 mmHg), and then recrystallized from methanol to give 4-iodo-2,6-difluoroaniline (44 g).

References: [1]Journal of the American Chemical Society,2012,vol. 134,p. 20597 - 20600.
[2]Patent: WO2004/74266,2004,A1 .Location in patent: Page 54.
[3]Patent: WO2006/15985,2006,A1 .Location in patent: Page/Page column 54.
[4]ACS Infectious Diseases,2019.
[5]Journal of Organic Chemistry,2009,vol. 74,p. 7370 - 7382.
[6]European Journal of Organic Chemistry,2010,p. 3049 - 3067.
[7]Patent: WO2006/98554,2006,A1 .Location in patent: Page/Page column 77.
[8]Angewandte Chemie - International Edition,2017,vol. 56,p. 3349 - 3353.
Angew. Chem.,2017,vol. 129,p. 3397 - 3401,5.
[9]Patent: US5314640,1994,A .
[10]Patent: US5356558,1994,A .

Yield	Reaction Conditions	Operation in experiment
		Step 3. Using the same method as Example 2, 2,6-difluoro-4-iodoaniline was obtained.
		Step 3: Using the same method as Example 2, 2,6-difluoro-4-iodoaniline was obtained.

3
[ 141743-49-9 ]
copper(ll) sulfate pentahydrate [ No CAS ]
diazonium salt sulfuric acid [ No CAS ]
1,3-difluoro-2-cyano-5-iodobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; sodium hydrogencarbonate; acetic acid; sodium nitrite; In sulfuric acid; water; benzene;	Step 4: 12 g of sodium nitrite was dissolved in 91 ml of sulfuric acid and cooled to 10 C or less, and then 100 ml of acetic acid was added. At 20 to 25 C, 39 g of the <strong>[141743-49-9]2,6-difluoro-4-iodoaniline</strong> from Step 3 was added to the solution, and then the solution was agitated for one hour. A second solution was made by dissolving 37 g of copper sulfate pentahydrate in 91 ml of water to which was added 62 g of ice, and this solution was added to the first. A third solution containing 39 of potassium cyanide dissolved in 92 ml of water, 221 g of sodium bicarbonate, and 91 ml of benzene was added to the first solution, and a diazonium salt sulfuric acid solution was added therein. After agitation at room temperature for 3 hours, a sodium hydroxide aqueous solution was added to dissolve the crystals. After being extracted with chloroform, the crystals were washed three times alternating with a 10% sodium hydroxide solution and water. After distillation of the chloroform, the residue was extracted with hexane, and the hexane was distilled off. This residue was recrystallized with methanol to obtain 6.7 g of 1,3-difluoro-2-cyano-5-iodobenzene.

References: [1]Patent: US5314640,1994,A .

4
[ 141743-49-9 ]
2-bromo-1,3-difluoro-4-iodobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen bromide; acetic acid; sodium nitrite;copper(I) bromide; In sulfuric acid; water;	Step 4: Sodium nitrite (17 g) was dissolved in sulfuric acid (130 ml), and then acetic acid (150 ml) was added thereto at 10 C. or lower. The mixed solution was kept at 20 to 25 C., and <strong>[141743-49-9]4-iodo-2,6-difluoroaniline</strong> (44 g) was added thereto for 1 hour, followed by stirring for 2 hours. The reaction solution was added dropwise to a mixed solution of copper(I) bromide (43 g) with 48% hydrobromic acid (125 ml), and stirred overnight. Then, water (1000 ml) was added to the solution, and the resulting solution was extracted with chloroform, followed by washing with water 3 times. After distilling off chloroform, the resultant was recrystallized from methanol to give 2-bromo-1,3-difluoro-4-iodobenzene (38 g).

References: [1]Patent: US5356558,1994,A .

5
[ 141743-49-9 ]
[ 749250-09-7 ]
[ 749249-89-6 ]

Yield	Reaction Conditions	Operation in experiment
49%		Example A9; a) Preparation of intermediate 22; A mixture of intermediate 18 (lequiv.), <strong>[141743-49-9]2,6-difluoro-4-iodo-benzeneamine</strong> (1.5 equiv.), and camphorsulfonic acid (0.7 equiv.) was refluxed for 20-48 hours in 2-propanol (oil bath 120C). The precipitate formed was collected by filtration and was successively washed on the filter with an aqueous solution of Na2C03, water, and dichloromethane, yielding intermediate 22. In order to increase the yield or to have analytical samples, the 2-propanol and CH2CI2 filtrate were combined and evaporated. The residue was suspended in an aqueous solution of Na2C03 and was extracted with CH2G2. After drying over MgSC>4 and evaporation of the dichloromethane extract, the residue was purified by column chromatography using 10% ethyl acetate in dichloromethane as eluent yielding intermediate 22. Total yield : 49% (CI-MS : 485 [M+H]+).

References: [1]Patent: WO2006/15985,2006,A1 .Location in patent: Page/Page column 65.

6
[ 141743-49-9 ]
[ 544-92-3 ]
[ 110301-23-0 ]

Yield	Reaction Conditions	Operation in experiment
66%	In N,N-dimethyl-formamide; for 2h;Heating / reflux;	A mixture of the solid and CuCN in DMF was heated with reflux for 2 days and then filtered through celite. The filtrate was dissolved in methylene chloride and water, and the aqueous phase was extracted with methylene chloride. The combined organic layer was washed with brine, dried over anhyd. MgSO4, filtered, and concentrated under reduced pressure. The crude residue was column-chromatographed (hexane/ethylacetate = 4/1) to yield a yellow solid (1.03g, 66%).1HNMR (300MHz, CDC13): 7.15 (dd, 2H, J= 2.4 and 6.0 Hz), 4.28 (bs, 2H).

References: [1]Patent: WO2006/98554,2006,A1 .Location in patent: Page/Page column 78.

7
[ 141743-49-9 ]
[ 1239481-70-9 ]

References: [1]European Journal of Organic Chemistry,2010,p. 3049 - 3067.

8
[ 141743-49-9 ]
[ 1415919-96-8 ]

References: [1]Journal of the American Chemical Society,2012,vol. 134,p. 20597 - 20600.

9
[ 141743-49-9 ]
[ 1629909-30-3 ]

References: [1]Chinese Journal of Chemistry,2014,vol. 32,p. 592 - 598.

10
[ 141743-49-9 ]
[ 1629909-38-1 ]

References: [1]Chinese Journal of Chemistry,2014,vol. 32,p. 592 - 598.

11
[ 141743-49-9 ]
[ 1187977-58-7 ]

References: [1]Chinese Journal of Chemistry,2014,vol. 32,p. 592 - 598.

12
[ 141743-49-9 ]
[ 536-74-3 ]
2,6-difluoro-4-(2-phenylethynyl)phenylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; In tetrahydrofuran; at 60℃; for 1h;	Step 1: 2,6-Difluoro-4-phenylethynyl-phenylamine Bis-(triphenylphosphine)-palladium(II)dichloride (826 mg, 1.18 mmol, 0.02 equiv.) was dissolved in 100 ml THF. 2,6-Difluoro-4-iodoaniline (15 g, 58.8 mmol) and phenylacetylene (7.2 g, 7.8 ml, 70.6 mmol, 1.2 equiv.) were added at room temperature. Triethylamine (29.8 g, 41 ml, 0.29 mol, 5 equiv.), triphenylphosphine (617 mg, 2.35 mmol, 0.04 equiv.) and copper(I)iodide (112 mg, 0.58 mmol, 0.01 equiv.) were added and the mixture was stirred for 1 hour at 60C. The reaction mixture was cooled and extracted with saturated NaHC03 solution and two times with ethyl acetate. The organic layers were washed three times with water, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane gradient 0: 100 to 40:60. The desired 2,6- difluoro-4-phenylethynyl-phenylamine (12.6 g, 93 % yield) was obtained as a yellow solid, MS: m/e = 230.1 (M+H+).
93%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; In tetrahydrofuran; at 60℃; for 1h;	Bis-(triphenylphosphine)-palladium(II)dichloride (826 mg, 1.18 mmol, 0.02 equiv.) was dissolved in 100 ml THF. 2,6-Difluoro-4-iodoaniline (15 g, 58.8 mmol) and phenylacetylene (7.2 g, 7.8 ml, 70.6 mmol, 1.2 equiv.) were added at room temperature. Triethylamine (29.8 g, 41 ml, 0.29 mol, 5 equiv.), triphenylphosphine (617 mg, 2.35 mmol, 0.04 equiv.) and copper(I)iodide (112 mg, 0.58 mmol, 0.01 equiv.) were added and the mixture was stirred for 1 hour at 60C. The reaction mixture was cooled and extracted with saturated NaHC03 solution and two times with ethyl acetate. The organic layers were washed three times with water, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane 0: 100 to 40:60 gradient. The desired 2,6- difluoro-4-phenylethynyl-phenylamine (12.6 g, 93 % yield) was obtained as a yellow solid, MS: m/e = 230.1 (M+H+).
93%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; In tetrahydrofuran; at 60℃; for 1h;	Bis-(triphenylphosphine)-palladium(II)dichloride (826 mg, 1.18 mmol, 0.02 equiv.) was dissolved in 100 ml THF. 2,6-Difluoro-4-iodoaniline (15 g, 58.8 mmol) and phenylacetylene (7.2 g, 7.8 ml, 70.6 mmol, 1.2 equiv.) were added at room temperature. Triethylamine (29.8 g, 41 ml, 0.29 mol, 5 equiv.), triphenylphosphine (617 mg, 2.35 mmol, 0.04 equiv.) and copper(I)iodide(112 mg, 0.58 mmol, 0.01 equiv.) were added and the mixture was stuffed for 1 hour at 60C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with ethyl acetate. The organic layers were washed three times with water, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on asilica gel column eluting with an ethyl acetate:heptane 0:100 to 40:60 gradient. The desired 2,6- difluoro-4-phenylethynyl-phenylamine (12.6 g, 93 % yield) was obtained as a yellow solid, MS:mle = 230.1 (M+Hj.

93%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; In tetrahydrofuran; at 60℃; for 1h;	Example 1 (8S)-3'-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-l'-methyl-spiro[6,7-dihydro-5H- isoquinoline-8 6'-hexahydropyrimidine]-2',4'-dione Step 1: 2,6-Difluoro-4-phenylethvnyl-phenylamine Bis-(triphenylphosphine)-palladium(II)dichloride (826 mg, 1.18 mmol, 0.02 equiv.) was dissolved in 100 ml THF. 2,6-Difluoro-4-iodoaniline (15 g, 58.8 mmol) and phenylacetylene (7.2 g, 7.8 ml, 70.6 mmol, 1.2 equiv.) were added at room temperature. Triethylamine (29.8 g, 41 ml, 0.29 mol, 5 equiv.), triphenylphosphine (617 mg, 2.35 mmol, 0.04 equiv.) and copper(I)iodide (112 mg, 0.58 mmol, 0.01 equiv.) were added and the mixture was stirred for 1 hour at 60C. The reaction mixture was cooled and extracted with saturated NaHC03 solution and two times with ethyl acetate. The organic layers were washed three times with water, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane 0: 100 to 40:60 gradient. The desired 2,6- difluoro-4-phenylethynyl-phenylamine (12.6 g, 93 % yield) was obtained as a yellow solid, MS: m/e = 230.1 (M+H+).
93%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; In tetrahydrofuran; at 60℃; for 1h;	Bis-(triphenylphosphine)-palladium(II)dichloride (826 mg, 1.18 mmol, 0.02 equiv.) was dissolved in 100 ml THF. 2,6-Difluoro-4-iodoaniline (15 g, 58.8 mmol) and phenylacetylene (7.2 g, 7.8 ml, 70.6 mmol, 1.2 equiv.) were added at room temperature. Triethylamine (29.8 g, 41 ml, 0.29 mol, 5 equiv.), triphenylphosphine (617 mg,2.35 mmol, 0.04 equiv.) and copper(I)iodide (112 mg,0.58 mmol, 0.01 equiv.) were added and the mixture was stirred for 1 hour at 60 C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with ethyl acetate. The organic layers were washed three times with water, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane gradient 0:100 to 40:60. The desired 2,6-difluoro-4-phenylethynyl-phenylamine (12.6 g, 93% yield) was obtained as a yellow solid, MS:mle=230.1 (M+Hj.
93%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; In tetrahydrofuran; at 60℃; for 1h;	Bis-(triphenylphosphine)-palladium(II)dichloride (826 mg, 1.18 mmol, 0.02 equiv.) was dissolved in 100 ml THF. 2,6-Difluoro-4-iodoaniline (15 g, 58.8 mmol) and phenylacetylene (7.2 g, 7.8 ml, 70.6 mmol, 1.2 equiv.) were added at room temperature. Triethylamine (29.8 g, 41 ml, 0.29 mol, 5 equiv.), triphenylphosphine (617 mg, 2.35 mmol, 0.04 equiv.) and copper(I)iodide (112 mg, 0.58 mmol, 0.01 equiv.) were added and the mixture was stirred for 1 hour at 60C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with ethyl acetate. The organic layers were washed three times with water, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane gradient 0:100 to 40:60. The desired 2,6- difluoro-4-phenylethynyl-phenylamine (12.6 g, 93 % yield) was obtained as a yellow solid, MS: mle = 230.1 (M+Hj

References: [1]Patent: WO2015/104271,2015,A1 .Location in patent: Page/Page column 15.
[2]Patent: WO2015/128307,2015,A1 .Location in patent: Page/Page column 37; 38.
[3]Patent: WO2016/146600,2016,A1 .Location in patent: Page/Page column 31; 32.
[4]Patent: WO2017/9275,2017,A1 .Location in patent: Page/Page column 22.
[5]Patent: US2017/8854,2017,A1 .Location in patent: Paragraph 0104.
[6]Patent: WO2017/21384,2017,A1 .Location in patent: Page/Page column 39; 40.

13
[ 141743-49-9 ]
methyl 3-[[2,6-difluoro-4-(2-phenylethynyl)phenyl]carbamoylamino]-3-methylbutanoate [ No CAS ]

References: [1]Patent: WO2015/128307,2015,A1 .

14
[ 141743-49-9 ]
3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-6,6-dimethylhexahydropyrimidine-2,4-dione [ No CAS ]

References: [1]Patent: WO2015/128307,2015,A1 .

15
[ 141743-49-9 ]
methyl (2RS)-3-[[2,6-difluoro-4-(2-phenylethynyl)phenyl]carbamoylamino]-2,3-dimethylbutanoate [ No CAS ]

References: [1]Patent: WO2015/128307,2015,A1 .

16
[ 141743-49-9 ]
3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1,6,6-trimethylhexahydropyrimidine-2,4-dione [ No CAS ]

References: [1]Patent: WO2015/128307,2015,A1 .

17
[ 141743-49-9 ]
(2,6-difluoro-4-iodophenyl)hydrazine [ No CAS ]

References: [1]Organic Letters,2015,vol. 17,p. 6258 - 6261.

18
[ 141743-49-9 ]
(S,E)-2-((tert-butoxycarbonyl)amino)-3-(4-((2,6-difluoro-4-iodophenyl)diazenyl)phenyl)propanoic acid [ No CAS ]

References: [1]Organic Letters,2015,vol. 17,p. 6258 - 6261.

19
[ 141743-49-9 ]
[ 1885-14-9 ]
phenyl(2,6-difluoro-4-iodophenyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 60℃; for 16h;	2,6-Difluoro-4-iodoaniline (10 g, 39.2 mmol) was dissolved in 100 ml of THF. Hunig?s base(7.53 ml, 5.58 g, 43.1 mmol, 1.1 equiv.) and phenyl chloroformate (5.4 ml, 6.75 g, 43.1 mmol,1.1 equiv.) were added at room temperature and the mixture was stuffed for 16 hours at 60C.The reaction mixture was extracted with saturated NaHCO3 solution and two times with ethylacetate. The organic layers were washed with water and brine, dried over sodium sulfate andevaporated to dryness. The residue was stuffed in heptane, filtered off and dried for 2 hours at 50C and <10 mbar. The desired phenyl (2,6-difluoro-4-iodophenyl)carbamate (10.3 g, 70 % yield) was obtained as a light brown solid, MS: mle = 376.0 (M+Hj.

References: [1]Patent: WO2016/146600,2016,A1 .Location in patent: Page/Page column 63.

20
[ 141743-49-9 ]
[ 32315-10-9 ]
methyl (3S)-3-amino-3-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]butanoate [ No CAS ]
methyl (3S)-3-[[2,6-difluoro-4-(2-phenylethynyl)phenyl]carbamoylamino]-3-thiazol-2-yl-butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The title compound isolated as a byproduct was obtained as a light yellow oil, MS: mle =463.1/465.1 (M+Hj, using chemistry similar to that described in Example 1, step 5 by usingtriphosgene in toluene instead of CDI in DMF starting from 2-chloro-4-iodoaniline and methyl(35)-3-amino-3- [1- (2-trimethylsilylethoxymethyl)pyrazol-4-yl]butanoate (Example 16, step 2).2,6-Difluoro-4-phenylethynyl-phenylamine (Example], step]) (170 mg, 0.75 mmol, 1.5 equiv.) was dissolved in DMF (2.0 ml) and CDI (121 mg, 0.75 mmol, 1.5 equiv.) was added at roomtemperature. The mixture was stined for 1 hour at 100 C. To the mixture methyl (35)-3-amino-3-thiazol-2-yl-butanoate (Example], step 4) (100 mg, 0.50 mmol, 1.0 equiv.) was added and stined for 1 hour at room temperature. The reaction mixture was evaporated with isolute. The crude product was purified by flash chromatography eluting with an ethyl acetate:heptane 0:100 to 100:0 gradient. The desired methyl (35)-3-[[2,6-difluoro-4-(2-phenylethynyl)phenyl]carbamoylamino]-3-thiazol-2-yl-butanoate (155 mg, 68 % yield) was obtained as a light yellow solid, MS: mle = 456.2 (M+H

References: [1]Patent: WO2016/146600,2016,A1 .Location in patent: Page/Page column 33; 53.

21
[ 141743-49-9 ]
methyl (3S)-3-amino-3-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]butanoate [ No CAS ]
(S)-3-(2,6-difluoro-4-iodophenyl)-1,6-dimethyl-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With caesium carbonate; methyl iodide; In N,N-dimethyl-formamide; at 20℃; for 1h;	The title compound was obtained as a light brown solid, MS: mle = 577.1 (M+Hj, usingchemistry similar to that described in Example 1, step 5, 6 and 7 starting from <strong>[141743-49-9]2,6-difluoro-4-iodoaniline</strong> and methyl (35)-3-amino-3- [1 -(2-trimethylsilylethoxymethyl)pyrazol-4-yl]butanoate(Example 16, step 2).(122 mg, 0.29 mmol) (6S )-3- [2,6-Difluoro-4- (2-phenylethynyl)phenyl] -6-methyl-6-thiazol-2-yl-hexahydropyrimidine-2,4-dione (Example], step 7) was dissolved in DMF (2 ml) and cesiumcarbonate (141 mg, 0.43 mmol, 1.5 equiv.) and iodomethane (49 mg, 22 ul, 0.35 mmol, 1.2 equiv.) were added at room temperature. The mixture was stirred for 1 hour at room temperature. The reaction mixture was evaporated with isolute. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane 0:100 to 100:0gradient.The desired (65)-3- [2,6-difluoro-4- (2-phenylethynyl)phenyl] -1 ,6-dimethyl-6-thiazol-2- yl-hexahydropyrimidine-2,4-dione (95 mg, 76 % yield) was obtained as a colorless oil, MS: mle = 438.2 (M+Hj.

References: [1]Patent: WO2016/146600,2016,A1 .Location in patent: Page/Page column 34; 53.

22
[ 141743-49-9 ]
(6S)-3-[2,6-difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-6-ethyl-1-methyl-6-(1H-pyrazol-4-yl)hexahydropyrimidine-2,4-dione [ No CAS ]