[ CAS No. 3336-18-3 ]

Name: 3336-18-3|2,5-Dichloro-4-hydroxybenzonitrile|95%
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Quality Control of [ 3336-18-3 ]

COA NMR CNMR HPLC LC-MS

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Alternatived Products of [ 3336-18-3 ]

Product Details of [ 3336-18-3 ]

CAS No. :	3336-18-3	MDL No. :	MFCD22988323
Formula :	C₇H₃Cl₂NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	188.01 g/mol	Pubchem ID :	-
Synonyms :

Calculated chemistry of of [ 3336-18-3 ]

Physicochemical Properties

Num. heavy atoms :	11
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 :	43.2
TPSA :	44.02 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.45 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.7
Log Po/w (XLOGP3) :	2.81
Log Po/w (WLOGP) :	2.57
Log Po/w (MLOGP) :	1.97
Log Po/w (SILICOS-IT) :	2.6
Consensus Log Po/w :	2.33

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.18
Solubility :	0.124 mg/ml ; 0.000661 mol/l
Class :	Soluble
Log S (Ali) :	-3.39
Solubility :	0.0763 mg/ml ; 0.000406 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.14
Solubility :	0.136 mg/ml ; 0.000721 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.62

Safety of [ 3336-18-3 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P501-P261-P270-P271-P264-P280-P337+P313-P305+P351+P338-P361+P364-P332+P313-P301+P310+P330-P302+P352+P312-P304+P340+P311-P403+P233-P405	UN#:	3439
Hazard Statements:	H301+H311+H331-H315-H319	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 3336-18-3 ]

* 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 [ 3336-18-3 ]

[ 3336-18-3 ] Synthesis Path-Downstream 1~30

1
[ 3336-18-3 ]
[ 3861-52-7 ]

Yield	Reaction Conditions	Operation in experiment
	With nitric acid; acetic acid

Reference： [1]Current Patent Assignee: SANOFI - FR1375311, 1964, A [Chem.Abstr., 1965, vol. 62, # 3982][Chem.Abstr., 1965, vol. 62, # 3982]

2
[ 3861-50-5 ]
[ 3336-18-3 ]

Yield	Reaction Conditions	Operation in experiment
	With aluminium trichloride In toluene

Reference： [1]Current Patent Assignee: SANOFI - FR1375311, 1964, A [Chem.Abstr., 1965, vol. 62, # 3982][Chem.Abstr., 1965, vol. 62, # 3982]

Yield	Reaction Conditions	Operation in experiment
	2.5-Dichlor-4-brom-phenolacetat, CuCN, 1.) Δ, DMF; 2.) NH3/H2O;
	2.5-Dichlor-4-brom-anisol, CuCN, 1.) Δ, DMF; 2.) Py., HCl, Δ;

4
[ 817165-65-4 ]
[ 3336-18-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: (i) NaNO₂, aq. HCl, (ii) /BRN= 4652394/, aq. CuSO₄ 2: AlCl₃ / toluene

Reference： [1]Current Patent Assignee: SANOFI - FR1375311, 1964, A [Chem.Abstr., 1965, vol. 62, # 3982][Chem.Abstr., 1965, vol. 62, # 3982]

5
[ 3336-18-3 ]
[ 540-51-2 ]
[ 1228373-98-5 ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 12h;	26 Example 26; 3-(2,5-Dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo [ 1 ,2-a] pyridin-2-yl)- 1 ,2,4- oxadiazol-3-yl)phenoxy)-2-hydroxypropanoic acid; 2-(2,5-Dichloro-4-(5-(8-chlor o-6-(trifluoromethyl)imidazo [ 1 ,2-β] pyridin-2-yl)- l,2,4-oxadiazol-3-yl)phenoxy)ethanol.; To a stirred solution of 2,5-dichloro-4-(5-(8-chloro-6- (trifluoromethyl)imidazo(l,2-α)pyridine-2-yl)-l,2,4-oxadiazole-3-yl) phenol (1.0 g, 2.4 mmol), prepared as described in Example 13, in DMF (10 mL) was added K2CO3 (1.66 g, 12.0 mmol) and 2-bromoethanol (1.5 g, 12 mmol). The reaction mixture was stirred at 800C for 12 h and then quenched with ice water and extracted with EtOAc. The organic layer was washed with water and saturated NaCl solution, dried over Na2SO4 and concentrated in vacuo to afford of intermediate 127 (0.70 g, 59% yield) as a yellowish-brown solid.

Reference： [1]Current Patent Assignee: EXELIXIS INC - WO2010/65760, 2010, A1 Location in patent: Page/Page column 166

6
[ 3336-18-3 ]
[ 74-88-4 ]
2,5-dichloro-4-methoxybenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 2,5-dichloro-4-hydroxybenzonitrile With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 3h;	1 Example 1: Synthesis of (S)-5-((2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo [1,2- al pyridin-2-yl)- 1 ,2,4-oxadiazol-3-yl)phenoxy)methyl)pyrrolidin-2-one (11) To a stirred solution of 2,5-dichloro-4-hydroxybenzonitrile (2) (35.0 g, 186 mmol) in DMF (150 mL) was added NaH (13.7 g, 347 mmol) in small portions at 0°C and the mixture was stirred for 30 mill at 0°C. Methyl iodide (35 mL, 560 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was cooled to 0°C and ice-water was added carefully. The resulting precipitate was collected by filtration, washed with water and dried to afford compound (3) (29 g, 78%) as a white solid.
78%	Stage #1: 2,5-dichloro-4-hydroxybenzonitrile With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 3h;	[00251] To a stirred solution of 2,5-dichloro-4-hydroxybenzonitrile (2) (35.0 g, 186 mmol) in DMF (150 mL) was added NaH (13.7 g, 347 mmol) in small portions at 0°C and the mixture was stirred for 30 min at 0°C. Methyl iodide (35 mL, 560 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was cooled to 0°C and ice-water was added carefully. The resulting precipitate was collected by filtration, washed with water and dried to afford compound (3) (29 g, 78%) as a white solid.
78%	Stage #1: 2,5-dichloro-4-hydroxybenzonitrile With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 3h;	9 To a stirred solution of 2,5-dichloro-4-hydroxybenzonitrile (27) (35.0 g, 186 mmol) in DMF (150 mL) was added NaH (13.7 g, 347 mmol) in small portions at 0°C and the mixture was stirred for 30 mm at 0°C. Methyl iodide (35 mL, 560 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was cooled to 0°C and ice-water was added carefully. The resulting precipitate was collected by filtration, washed with water and dried to afford compound (28) (29 g, 78%) as a white solid.

54%

Stage #1: 2,5-dichloro-4-hydroxybenzonitrile With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 0 - 20℃;

13 2,5-Dichloro-4-methoxy benzonitrile (72).; To a stirred solution of 2,5-dichloro-4- cyanophenol 71 (11.0 g, 58.5 mmol) in DMF (40 mL) was added NaH (4.3 g, 109 mmol) in small portions at 0 0C and stirred for 30 min at 0 0C. Methyl iodide (11 rnL, 176 mmol) was added dropwise and after addition the reaction was allowed to warm to room temperature and was stirred for 3 h. After completion, the reaction mixture was cooled to 0 0C and quenched with ice water. The precipitated solid was collected by filtration, washed well with water and dried completely to afford the title intermediate 72 as a white solid (6.4 g, yield 54%).

Reference： [1]Current Patent Assignee: OPPILAN PHARMA - WO2017/83756, 2017, A1 Location in patent: Paragraph 00209
[2]Current Patent Assignee: OPPILAN PHARMA - WO2018/211324, 2018, A1 Location in patent: Paragraph 00251
[3]Current Patent Assignee: OPPILAN PHARMA - WO2018/211323, 2018, A1 Location in patent: Paragraph 00249
[4]Current Patent Assignee: EXELIXIS INC - WO2010/65760, 2010, A1 Location in patent: Page/Page column 136-137

7
[ 3336-18-3 ]
[ 106-95-6 ]
[ 1228376-23-5 ]

Yield	Reaction Conditions	Operation in experiment
59%	Stage #1: 2,5-dichloro-4-hydroxybenzonitrile With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.333333h; Stage #2: allyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃;	14 Example 14; 3-(2,5-Dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4- oxadiazol-3-yl)phenoxy)propane-l,2-diol[00406] 4-(Allyloxy)-2,5-dichlorobenzonitrile (75).; To intermediate 71 (1.72 g, 9.15 mmol) in dry DMF (20 mL), was added NaH (475 mg, 0.011 mole, 60% dispersion in oil) at 0 0C and stirred for 20 min. To the resulting reaction mixture, allyl bromide (1.5 ml, 0.018 mol) was added dropwise at 0 0C and the mixture stirred for an additional 3 h at room temperature. Excess NaH was quenched by ice, and the resulting mixture extracted with EtOAc. The combined extracts were washed with water, saturated NaCl, dried over Na2SO4, and concentrated. The resulting residue was purified by column chromatography using EtOAc:hexane as eluent to give intermediate 75 (1.22 g, 59.0%) as a white solid.

Reference： [1]Current Patent Assignee: EXELIXIS INC - WO2010/65760, 2010, A1 Location in patent: Page/Page column 138

8
[ 1940-42-7 ]
copper(l) cyanide [ No CAS ]
[ 3336-18-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	In N,N-dimethyl-formamide at 150℃; for 3h;	13 Example 13; 2,5-Dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo(l,2-«)pyridine-2-yl)-l,2,4- oxadiazole-3-yl) phenol; 2,5-Dichloro-4-hydroxy benzonitrile (71).; To a stirred solution of 2,5-dichloro-4- bromophenol 70 (10 g, 41 mmol) in DMF (50 mL) was added cuprous cyanide (4.83 g, 53.8 mmol) and the reaction was stirred at 150 0C for 3 h. After completion, the reaction mixture was concentrated in vacuo. To the residue, water and EtOAc were added and the biphasic mixture filtered through celite. The filtrate was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by column chromatography, using 15% EtOAc/hexane as eluent, to afford the title intermediate 71 as a white solid (7.7 g, yield 100%).
57%	In N,N-dimethyl-formamide at 150℃; for 4h;	1 Example 1: Synthesis of (S)-5-((2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo [1,2- al pyridin-2-yl)- 1 ,2,4-oxadiazol-3-yl)phenoxy)methyl)pyrrolidin-2-one (11) To a stirred solution of 2,5-dichloro-4-bromophenol (1) (210.0 g, 0.86 mol) in DIMF(1000 mL) was added cuprous cyanide (101.5 g, 1.13 mmol) at room temperature. The reactionmixture was stirred at 150°C for 4 h. The mixture was concentrated under vacuum. Water andEtOAc were added to the residue and then filtered through a pad of celite. The filtrate wasextracted with EtOAc and the combined organic layers were dried over anhydrous Na2504 andconcentrated under vacuum. The residue was recrystallized from petroleum ether/EtOAc (10:1,1400 mL) to afford 2,5-dichloro-4-hydroxybenzonitrile (2) (93.0 g, 57%) as a white solid.
57%	In N,N-dimethyl-formamide at 150℃; for 4h;	[00250] To a stirred solution of 2,5-dichloro-4-bromophenol (1) (210.0 g, 0.86 mol) in DMF (1000 mL) was added cuprous cyanide (101.5 g, 1.13 mmol) at room temperature. The reaction mixture was stirred at 150°C for 4 h. The mixture was concentrated under vacuum. Water and EtOAc were added to the residue and then filtered through a pad of celite. The filtrate was extracted with EtOAc and the combined organic layers were dried over anhydrous Na2S04 and concentrated under vacuum. The residue was recrystallized from petroleum ether/EtOAc (10: 1, 1400 mL) to afford 2,5-dichloro-4-hydroxybenzonitrile (2) (93.0 g, 57%) as a white solid.

57%

In N,N-dimethyl-formamide at 150℃; for 4h;

9 To a stirred solution of 2,5-dichloro-4-bromophenol (26) (210.0 g, 0.86 mol) in DMF (1000 mL) was added cuprous cyanide (101.5 g, 1.13 mmol) at room temperature. The reaction mixture was stirred at 150°C for 4 h. The mixture was concentrated under vacuum. Water and EtOAc were added to the residue and then filtered through a pad of celite. The filtrate was extracted with EtOAc and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was recrystallized from petroleum ether/EtOAc (10:1, 1400 mL) to afford 2,5-dichloro-4-hydroxybenzonitrile (27) (93.0 g, 57%) as a white solid.

Reference： [1]Current Patent Assignee: EXELIXIS INC - WO2010/65760, 2010, A1 Location in patent: Page/Page column 136
[2]Current Patent Assignee: OPPILAN PHARMA - WO2017/83756, 2017, A1 Location in patent: Paragraph 00208
[3]Current Patent Assignee: OPPILAN PHARMA - WO2018/211324, 2018, A1 Location in patent: Paragraph 00250
[4]Current Patent Assignee: OPPILAN PHARMA - WO2018/211323, 2018, A1 Location in patent: Paragraph 00248

9
[ 3336-18-3 ]
[ 1228375-15-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: hydroxylamine hydrochloride; triethylamine / ethanol / 4 h / 80 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.25 h 3.2: 12 h / 100 °C
	Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: hydroxylamine hydrochloride; triethylamine / ethanol / 20 - 80 °C 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 12 h / 100 °C
	Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: triethylamine; hydroxylamine hydrochloride / ethanol / 4.5 h / 20 - 80 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.25 h 3.2: 12 h / 100 °C

Reference： [1]Current Patent Assignee: OPPILAN PHARMA - WO2017/83756, 2017, A1
[2]Current Patent Assignee: OPPILAN PHARMA - WO2018/211324, 2018, A1
[3]Current Patent Assignee: OPPILAN PHARMA - WO2018/211323, 2018, A1

10
[ 3336-18-3 ]
[ 1228372-85-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: hydroxylamine hydrochloride; triethylamine / ethanol / 4 h / 80 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.25 h 3.2: 12 h / 100 °C 4.1: aluminum (III) chloride / dichloromethane / 0.17 h / 10 °C / Inert atmosphere 4.2: 2.5 h / 5 - 10 °C
	Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: hydroxylamine hydrochloride; triethylamine / ethanol / 20 - 80 °C 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 12 h / 100 °C 4.1: aluminum (III) chloride / dichloromethane / 0.17 h / 10 °C / Inert atmosphere 4.2: 2.5 h / 5 - 10 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: triethylamine; hydroxylamine hydrochloride / ethanol / 4.5 h / 20 - 80 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.25 h 3.2: 12 h / 100 °C 4.1: aluminum (III) chloride / dichloromethane / 0.17 h / 10 °C / Inert atmosphere 4.2: 2.5 h / 5 - 10 °C / Inert atmosphere

11
[ 3336-18-3 ]
(S)-5-((2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)methyl)pyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: hydroxylamine hydrochloride; triethylamine / ethanol / 4 h / 80 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.25 h 3.2: 12 h / 100 °C 4.1: aluminum (III) chloride / dichloromethane / 0.17 h / 10 °C / Inert atmosphere 4.2: 2.5 h / 5 - 10 °C 5.1: potassium carbonate / acetonitrile / 13 h / 76 °C

Reference： [1]Current Patent Assignee: OPPILAN PHARMA - WO2017/83756, 2017, A1

12
[ 3336-18-3 ]
(R)-5-((2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)methyl)pyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: hydroxylamine hydrochloride; triethylamine / ethanol / 4 h / 80 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.25 h 3.2: 12 h / 100 °C 4.1: aluminum (III) chloride / dichloromethane / 0.17 h / 10 °C / Inert atmosphere 4.2: 2.5 h / 5 - 10 °C 5.1: potassium carbonate / acetonitrile / 13 h / 76 °C

Reference： [1]Current Patent Assignee: OPPILAN PHARMA - WO2017/83756, 2017, A1

13
[ 3336-18-3 ]
C₂₁H₁₃Cl₃F₃N₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: hydroxylamine hydrochloride; triethylamine / ethanol / 4 h / 80 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.25 h 3.2: 12 h / 100 °C 4.1: aluminum (III) chloride / dichloromethane / 0.17 h / 10 °C / Inert atmosphere 4.2: 2.5 h / 5 - 10 °C 5.1: potassium carbonate / acetonitrile / 18 h / 76 °C

Reference： [1]Current Patent Assignee: OPPILAN PHARMA - WO2017/83756, 2017, A1

14
[ 3336-18-3 ]
(S)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)-1-methylpiperidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: hydroxylamine hydrochloride; triethylamine / ethanol / 4 h / 80 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.25 h 3.2: 12 h / 100 °C 4.1: aluminum (III) chloride / dichloromethane / 0.17 h / 10 °C / Inert atmosphere 4.2: 2.5 h / 5 - 10 °C 5.1: potassium carbonate / acetonitrile / 18 h / 76 °C 6.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 6.2: 3 h / 20 °C

Reference： [1]Current Patent Assignee: OPPILAN PHARMA - WO2017/83756, 2017, A1

15
[ 3336-18-3 ]
(R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: hydroxylamine hydrochloride; triethylamine / ethanol / 4 h / 80 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.25 h 3.2: 12 h / 100 °C 4.1: aluminum (III) chloride / dichloromethane / 0.17 h / 10 °C / Inert atmosphere 4.2: 2.5 h / 5 - 10 °C 5.1: potassium carbonate / acetonitrile / 18 h / 76 °C
	Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: hydroxylamine hydrochloride; triethylamine / ethanol / 20 - 80 °C 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 12 h / 100 °C 4.1: aluminum (III) chloride / dichloromethane / 0.17 h / 10 °C / Inert atmosphere 4.2: 2.5 h / 5 - 10 °C / Inert atmosphere 5.1: potassium carbonate / acetonitrile / 18 h / 76 °C

Reference： [1]Current Patent Assignee: OPPILAN PHARMA - WO2017/83756, 2017, A1
[2]Current Patent Assignee: OPPILAN PHARMA - WO2018/211324, 2018, A1

16
[ 3336-18-3 ]
(R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)-1-methylpiperidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: hydroxylamine hydrochloride; triethylamine / ethanol / 4 h / 80 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.25 h 3.2: 12 h / 100 °C 4.1: aluminum (III) chloride / dichloromethane / 0.17 h / 10 °C / Inert atmosphere 4.2: 2.5 h / 5 - 10 °C 5.1: potassium carbonate / acetonitrile / 18 h / 76 °C 6.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 6.2: 3 h / 20 °C

Reference： [1]Current Patent Assignee: OPPILAN PHARMA - WO2017/83756, 2017, A1

17
[ 3336-18-3 ]
2,5-dichloro-4-methoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: hydroxylamine hydrochloride; triethylamine / ethanol / 4 h / 80 °C

Reference： [1]Current Patent Assignee: OPPILAN PHARMA - WO2017/83756, 2017, A1

18
[ 3336-18-3 ]
C₈H₈Cl₂N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: hydroxylamine hydrochloride; triethylamine / ethanol / 4 h / 80 °C
	Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: hydroxylamine hydrochloride; triethylamine / ethanol / 20 - 80 °C

Reference： [1]Current Patent Assignee: OPPILAN PHARMA - WO2017/83756, 2017, A1
[2]Current Patent Assignee: OPPILAN PHARMA - WO2018/211324, 2018, A1

19
[ 3336-18-3 ]
(S)-3-(2,5-dichloro-4-(5-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)propane-1,2-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: triethylamine; hydroxylamine hydrochloride / ethanol / 4.5 h / 20 - 80 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.25 h 3.2: 20 - 100 °C 4.1: aluminum (III) chloride / dichloromethane / 0.17 h / 10 °C / Inert atmosphere 4.2: 3 h / 5 °C / Inert atmosphere 5.1: sodium hydroxide / ethanol / 0.17 h / 20 °C 5.2: 16 h / 80 °C