258273-31-3

Usage

Uses

Used in Pharmaceutical Industry:
3-Cyano-4-isopropoxybenzoic Acid is used as a reagent for the preparation of cyanoaryloxadiazolyl-substituted nitrogen heterocycles. These heterocycles serve as S1P3-sparing agonists of sphingosine phosphate receptors S1P1 and S1P5, which have potential therapeutic applications in the treatment of multiple sclerosis. The development of these agonists aims to improve the pharmacokinetics and side effect profiles, offering a more effective treatment option for patients suffering from this disease.
Used in Chemical Research:
In addition to its pharmaceutical applications, 3-Cyano-4-isopropoxybenzoic Acid is also utilized in chemical research for the synthesis of various biaryl oxadiazoles. These compounds are studied for their potential as S1P1 receptor agonists, further expanding the scope of treatment options for multiple sclerosis and other related conditions. The research on these compounds contributes to the understanding of their structure-activity relationships (SAR) and helps in the development of more effective drugs targeting sphingosine phosphate receptors.

InChI:InChI=1/C11H11NO3/c1-7(2)15-10-4-3-8(11(13)14)5-9(10)6-12/h3-5,7H,1-2H3,(H,13,14)

Synthetic route

3-cyano-4-isopropoxybenzoic acid methyl ester (213598-11-9) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Stage #1: methyl 3-cyano-4-[(1-methylethyl)oxy]benzoate With ethanol; sodium hydroxide In tetrahydrofuran at 20℃; for 4h; Stage #2: With hydrogenchloride In tetrahydrofuran; water	92%
With ethanol; sodium hydroxide In tetrahydrofuran at 20℃; for 4h;	92%
Stage #1: methyl 3-cyano-4-[(1-methylethyl)oxy]benzoate With potassium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 16h; Stage #2: With hydrogenchloride In water for 2h;	87%

3-bromo-4-hydroxy-benzoic acid (14348-41-5) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 16 h / 80 °C 2.1: 1-methyl-pyrrolidin-2-one / 16 h / 200 °C 3.1: water; lithium hydroxide / 1,4-dioxane / 1.5 h / 30 °C 3.2: 20 °C View Scheme
Multi-step reaction with 4 steps 1: hydrogenchloride / 20 °C 2: potassium carbonate / acetonitrile / Reflux 3: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 120 °C / Inert atmosphere 4: sodium hydroxide / methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water / 20 °C 2.1: potassium carbonate / acetonitrile / Reflux 3.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 120 °C / Inert atmosphere 4.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 4.2: pH 4 - 5 View Scheme

1-methylethyl 3-bromo-4-[(1-methylethyl)oxy]benzoate (1034689-05-8) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 1-methyl-pyrrolidin-2-one / 16 h / 200 °C 2.1: water; lithium hydroxide / 1,4-dioxane / 1.5 h / 30 °C 2.2: 20 °C View Scheme

1-methylethyl 3-cyano-4-[(1-methylethyl)oxy]benzoate (1261173-10-7) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Stage #1: 1-methylethyl 3-cyano-4-[(1-methylethyl)oxy]benzoate With water; lithium hydroxide In 1,4-dioxane at 30℃; for 1.5h; Stage #2: With hydrogenchloride In 1,4-dioxane; water at 20℃;
Stage #1: 1-methylethyl 3-cyano-4-[(1-methylethyl)oxy]benzoate With water; sodium hydroxide In isopropyl alcohol at 20℃; Stage #2: With hydrogenchloride In water pH=~ 2;
Stage #1: 1-methylethyl 3-cyano-4-[(1-methylethyl)oxy]benzoate With water; sodium hydroxide In isopropyl alcohol at 20℃; Stage #2: With hydrogenchloride In water pH=2;

methyl 3-iodo-4-hydroxybenzoate (15126-06-4) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium cyanide / N,N-dimethyl-formamide / 24 h / 120 °C / Inert atmosphere 2: potassium carbonate / N,N-dimethyl-formamide / 12 h / 90 °C / Inert atmosphere 3: sodium hydroxide / methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: copper(l) cyanide / N,N-dimethyl-formamide / 24 h / 120 °C / Inert atmosphere 1.2: 12 h / 90 °C / Cooling with ice 2.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 2.2: pH 4 - 5 View Scheme
Multi-step reaction with 3 steps 1: sodium cyanide / N,N-dimethyl-formamide / 18 h / 105 °C 2: potassium carbonate / N,N-dimethyl-formamide / 14 h / 90 °C 3: sodium hydroxide; ethanol / tetrahydrofuran / 4 h / 20 °C View Scheme

methyl 4-hydroxylbenzoate (99-76-3) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: Iodine monochloride; acetic acid / 20 - 65 °C 2: sodium cyanide / N,N-dimethyl-formamide / 24 h / 120 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 12 h / 90 °C / Inert atmosphere 4: sodium hydroxide / methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: Iodine monochloride / acetic acid / 65 °C 2.1: copper(l) cyanide / N,N-dimethyl-formamide / 24 h / 120 °C / Inert atmosphere 2.2: 12 h / 90 °C / Cooling with ice 3.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 3.2: pH 4 - 5 View Scheme
Multi-step reaction with 4 steps 1: acetic acid; Iodine monochloride / 24.6 h / 20 - 65 °C 2: sodium cyanide / N,N-dimethyl-formamide / 18 h / 105 °C 3: potassium carbonate / N,N-dimethyl-formamide / 14 h / 90 °C 4: sodium hydroxide; ethanol / tetrahydrofuran / 4 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: magnesium chloride / dichloromethane / 44 °C / Large scale 2: hydroxylamine hydrochloride; acetyl chloride / N,N-dimethyl-formamide; acetonitrile / 2 h / 80 °C / Large scale 3: potassium carbonate / N,N-dimethyl-formamide; acetonitrile / 80 °C / Large scale 4: sodium hydroxide / tetrahydrofuran / 1 h / 60 °C / Large scale View Scheme

methyl 3-cyano-4-hydroxybenzoate (156001-68-2) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 90 °C / Inert atmosphere 2: sodium hydroxide / methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 80 °C 2: sodium hydroxide / methanol; water / 2 h / 25 °C View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 90 °C 2: sodium hydroxide; ethanol / tetrahydrofuran / 4 h / 20 °C View Scheme

methyl 3-bromo-4-hydroxybenzoate (29415-97-2) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile / Reflux 2: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 120 °C / Inert atmosphere 3: sodium hydroxide / methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / acetonitrile / Reflux 2.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 120 °C / Inert atmosphere 3.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 3.2: pH 4 - 5 View Scheme
Multi-step reaction with 3 steps 1: copper(l) iodide / N,N-dimethyl-formamide / 120 °C 2: potassium carbonate / N,N-dimethyl-formamide / 80 °C 3: sodium hydroxide / methanol; water / 2 h / 25 °C View Scheme

3-cyano-4-fluorobenzoic acid methyl ester (676602-31-6) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hexamethyldisilazane / tetrahydrofuran / 20 °C / Cooling with ice 1.2: 16 h / 50 °C 2.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 2.2: pH ~ 2 View Scheme
Multi-step reaction with 2 steps 1.1: sodium hexamethyldisilazane / tetrahydrofuran / 17 h / 20 - 50 °C / Cooling with ice 2.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 2.2: pH 2 View Scheme

3-cyano-4-fluorobenzoic acid (171050-06-9) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / 80 - 90 °C 2.1: sodium hexamethyldisilazane / tetrahydrofuran / 20 °C / Cooling with ice 2.2: 16 h / 50 °C 3.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 3.2: pH ~ 2 View Scheme
Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / 90 °C 2.1: sodium hexamethyldisilazane / tetrahydrofuran / 17 h / 20 - 50 °C / Cooling with ice 3.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 3.2: pH 2 View Scheme

methyl 3-bromo-4-isopropoxybenzoate (213598-10-8) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 120 °C / Inert atmosphere 2: sodium hydroxide / methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 120 °C / Inert atmosphere 2.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 2.2: pH 4 - 5 View Scheme

methyl 3-formyl-4-hydroxybenzoate (24589-99-9) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride; acetyl chloride / N,N-dimethyl-formamide; acetonitrile / 2 h / 80 °C / Large scale 2: potassium carbonate / N,N-dimethyl-formamide; acetonitrile / 80 °C / Large scale 3: sodium hydroxide / tetrahydrofuran / 1 h / 60 °C / Large scale View Scheme

3-cyano-4-isopropoxybenzoic acid (258273-31-3) → 3-cyano-4-[(1-methylethyl)oxy]benzoyl chloride (1072948-37-8)

Conditions	Yield
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h;	100%
With oxalyl dichloride; N,N-dimethyl-formamide at 20℃; for 4h; Product distribution / selectivity;	100%
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 4h;	100%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + methanol (67-56-1) → 3-cyano-4-isopropoxybenzoic acid methyl ester (213598-11-9)

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid; methanol With diazomethyl-trimethyl-silane In dichloromethane at 0 - 20℃; for 1.8h; Stage #2: With acetic acid In dichloromethane at 20℃;	100%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + thiosemicarbazide (79-19-6) → 5-(5-amino-1,3,4-thiadiazol-2-yl)-2-[(1-methylethyl)oxy]benzonitrile (1258440-55-9)

Conditions	Yield
With trichlorophosphate at 90℃; for 3h;	99%
Stage #1: 3-cyano-4-isopropoxybenzoic acid; thiosemicarbazide With trichlorophosphate at 90℃; for 3h; Stage #2: With sodium hydroxide In water at 35℃; pH=10; Cooling with ice;	99%
Stage #1: 3-cyano-4-isopropoxybenzoic acid; thiosemicarbazide With trichlorophosphate at 90℃; for 3h; Stage #2: With sodium hydroxide at 35℃; pH=10; Cooling with ice;	99%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + 1,1-dimethylethyl 8-[(hydroxyamino)(imino)methyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1167416-24-1) → 1,1-dimethylethyl 8-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1167416-65-0)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; Heating;	92%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + 3-ethoxy-N-hydroxy-1H-indene-7-carboximidamide → N-((3 -cyano-4-isopropoxybenzoyl)oxy)-3 -ethoxy-1H-indene-7-carboximidamide

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 3-ethoxy-N-hydroxy-1H-indene-7-carboximidamide In N,N-dimethyl-formamide for 0.583333h;	90%
Stage #1: 3-cyano-4-isopropoxybenzoic acid With 1,1'-carbonyldiimidazole In water; N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 3-ethoxy-N-hydroxy-1H-indene-7-carboximidamide In water; N,N-dimethyl-formamide for 0.583333h;	90%
Stage #1: 3-cyano-4-isopropoxybenzoic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 3-ethoxy-N-hydroxy-1H-indene-7-carboximidamide In N,N-dimethyl-formamide for 0.583333h;	90%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + 3-ethoxy-N-hydroxy-1H-indene-7-carboximidamide → N-((3-cyano-4-isopropoxybenzoyl)oxy)-3-ethoxy-1H-indene-7-carboximidamide

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 3-ethoxy-N-hydroxy-1H-indene-7-carboximidamide In N,N-dimethyl-formamide for 0.583333h;	90%
Stage #1: 3-cyano-4-isopropoxybenzoic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 3-ethoxy-N-hydroxy-1H-indene-7-carboximidamide In N,N-dimethyl-formamide at 20℃; for 0.583333h;	90%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + tert-butyl 3-(N'-hydroxycarbamimidoyl)-4-methyl-5,6-dihydro-1,7-naphthyridine-7(8H)-carboxylate (1333996-58-9) → tert-butyl 3-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-4-methyl-5,6-dihydro-1,7-naphthyridine-7(8H)-carboxylate (1333996-60-3)

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: tert-butyl 3-(N'-hydroxycarbamimidoyl)-4-methyl-5,6-dihydro-1,7-naphthyridine-7(8H)-carboxylate In N,N-dimethyl-formamide at 20 - 100℃; for 17.5h;	88%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + 2-chloro-4-(1,3-dioxolan-2-yl)-N′-hydroxybenzimidamide → 5-(3-(2-chloro-4-(1,3-dioxolan-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid; 2-chloro-4-(1,3-dioxolan-2-yl)-N′-hydroxybenzimidamide With potassium carbonate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: With benzotriazol-1-ol In N,N-dimethyl-formamide at 110℃; for 2h; Inert atmosphere;	87%
Stage #1: 3-cyano-4-isopropoxybenzoic acid With potassium carbonate; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 2-chloro-4-(1,3-dioxolan-2-yl)-N′-hydroxybenzimidamide In N,N-dimethyl-formamide at 110℃; for 4h; Inert atmosphere;	87%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + 4-(1,3-dioxolan-2-yl)-2-fluoro-N′-hydroxybenzimidamide → 5-(3-(4-(1,3-dioxolan-2-yl)-2-fluorophenyl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid; 4-(1,3-dioxolan-2-yl)-2-fluoro-N′-hydroxybenzimidamide With potassium carbonate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: With benzotriazol-1-ol In N,N-dimethyl-formamide at 110℃; for 2h; Inert atmosphere;	81.7%
Stage #1: 3-cyano-4-isopropoxybenzoic acid With potassium carbonate; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 4-(1,3-dioxolan-2-yl)-2-fluoro-N′-hydroxybenzimidamide In N,N-dimethyl-formamide at 110℃; for 4h; Inert atmosphere;	81.7%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) → N-{(1S)-1-[(4-bromophenyl)methyl]-3-hydroxypropyl}-3-cyano-4-[(1-methylethyl)oxy]benzamide

Conditions	Yield
Stage #1: (3S)-3-amino-4-(4-bromophenyl)-1-butanol hydrochloride With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) for 0.05h; Stage #2: 3-cyano-4-isopropoxybenzoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In DMF (N,N-dimethyl-formamide) at 20℃; for 1.5h; Stage #3: With water In DMF (N,N-dimethyl-formamide)	78%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + N-hydroxybenzofuran-5-carboximidamide (1307231-09-9) → 5-(3-(benzofuran-5-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile (1307230-52-9)

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: N-hydroxybenzofuran-5-carboximidamide In N,N-dimethyl-formamide at 20 - 85℃;	69%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + (S)-1-azido-N’-hydroxy-2,3-dihydro-1H-indene-4-carboximidamide → (S)-5-(3-(1-azido-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: (S)-1-azido-N’-hydroxy-2,3-dihydro-1H-indene-4-carboximidamide In N,N-dimethyl-formamide at 115℃; for 24h; Reagent/catalyst; Solvent;	69%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + tert-butyl (1S)-4-[(E)-N’-hydroxycarbamimidoyl]-2,3-dihydro-1H-inden-1-yl N-[2-[(tert-butyldimethylsilyl)oxy]ethyl]carbamate → tert-butyl(1S)-4-[5-[3-cyano-4-(propan-2-yloxy)phenyl]-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-inden-1-yl-N-[2-[(tert-butyldimethylsilyl)oxy]ethyl]carbamate

Conditions	Yield
With benzotriazol-1-ol; 1,2-dichloro-ethane In N,N-dimethyl-formamide at 20 - 85℃; for 1.5h;	67%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + (1S)-1-({2-[(tert-butyldimethylsilyl)oxy]ethyl}[(S)-2-methylpropane-2-sulfinyl]amino)-N-hydroxy-2,3-dihydro-1H-indene-4-carboximidamide → 5-{3-[(1S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-inden-4-yl]-1,2,4-oxadiazol-5-yl}-2-(propan-2-yloxy)benzonitrile hydrochloride

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid; (1S)-1-({2-[(tert-butyldimethylsilyl)oxy]ethyl}[(S)-2-methylpropane-2-sulfinyl]amino)-N-hydroxy-2,3-dihydro-1H-indene-4-carboximidamide With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In toluene at 20 - 90℃; Inert atmosphere; Stage #2: With hydrogenchloride In water at 0 - 90℃; for 1h; Solvent;	63.6%

3-cyano-4-isopropoxybenzoic acid methyl ester (213598-11-9) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Stage #1: methyl 3-cyano-4-[(1-methylethyl)oxy]benzoate With ethanol; sodium hydroxide In tetrahydrofuran at 20℃; for 4h; Stage #2: With hydrogenchloride In tetrahydrofuran; water	92%
With ethanol; sodium hydroxide In tetrahydrofuran at 20℃; for 4h;	92%
Stage #1: methyl 3-cyano-4-[(1-methylethyl)oxy]benzoate With potassium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 16h; Stage #2: With hydrogenchloride In water for 2h;	87%

3-bromo-4-hydroxy-benzoic acid (14348-41-5) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 16 h / 80 °C 2.1: 1-methyl-pyrrolidin-2-one / 16 h / 200 °C 3.1: water; lithium hydroxide / 1,4-dioxane / 1.5 h / 30 °C 3.2: 20 °C View Scheme
Multi-step reaction with 4 steps 1: hydrogenchloride / 20 °C 2: potassium carbonate / acetonitrile / Reflux 3: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 120 °C / Inert atmosphere 4: sodium hydroxide / methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water / 20 °C 2.1: potassium carbonate / acetonitrile / Reflux 3.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 120 °C / Inert atmosphere 4.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 4.2: pH 4 - 5 View Scheme

1-methylethyl 3-bromo-4-[(1-methylethyl)oxy]benzoate (1034689-05-8) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 1-methyl-pyrrolidin-2-one / 16 h / 200 °C 2.1: water; lithium hydroxide / 1,4-dioxane / 1.5 h / 30 °C 2.2: 20 °C View Scheme

1-methylethyl 3-cyano-4-[(1-methylethyl)oxy]benzoate (1261173-10-7) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Stage #1: 1-methylethyl 3-cyano-4-[(1-methylethyl)oxy]benzoate With water; lithium hydroxide In 1,4-dioxane at 30℃; for 1.5h; Stage #2: With hydrogenchloride In 1,4-dioxane; water at 20℃;
Stage #1: 1-methylethyl 3-cyano-4-[(1-methylethyl)oxy]benzoate With water; sodium hydroxide In isopropyl alcohol at 20℃; Stage #2: With hydrogenchloride In water pH=~ 2;
Stage #1: 1-methylethyl 3-cyano-4-[(1-methylethyl)oxy]benzoate With water; sodium hydroxide In isopropyl alcohol at 20℃; Stage #2: With hydrogenchloride In water pH=2;

methyl 3-iodo-4-hydroxybenzoate (15126-06-4) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium cyanide / N,N-dimethyl-formamide / 24 h / 120 °C / Inert atmosphere 2: potassium carbonate / N,N-dimethyl-formamide / 12 h / 90 °C / Inert atmosphere 3: sodium hydroxide / methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: copper(l) cyanide / N,N-dimethyl-formamide / 24 h / 120 °C / Inert atmosphere 1.2: 12 h / 90 °C / Cooling with ice 2.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 2.2: pH 4 - 5 View Scheme
Multi-step reaction with 3 steps 1: sodium cyanide / N,N-dimethyl-formamide / 18 h / 105 °C 2: potassium carbonate / N,N-dimethyl-formamide / 14 h / 90 °C 3: sodium hydroxide; ethanol / tetrahydrofuran / 4 h / 20 °C View Scheme

methyl 4-hydroxylbenzoate (99-76-3) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: Iodine monochloride; acetic acid / 20 - 65 °C 2: sodium cyanide / N,N-dimethyl-formamide / 24 h / 120 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 12 h / 90 °C / Inert atmosphere 4: sodium hydroxide / methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: Iodine monochloride / acetic acid / 65 °C 2.1: copper(l) cyanide / N,N-dimethyl-formamide / 24 h / 120 °C / Inert atmosphere 2.2: 12 h / 90 °C / Cooling with ice 3.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 3.2: pH 4 - 5 View Scheme
Multi-step reaction with 4 steps 1: acetic acid; Iodine monochloride / 24.6 h / 20 - 65 °C 2: sodium cyanide / N,N-dimethyl-formamide / 18 h / 105 °C 3: potassium carbonate / N,N-dimethyl-formamide / 14 h / 90 °C 4: sodium hydroxide; ethanol / tetrahydrofuran / 4 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: magnesium chloride / dichloromethane / 44 °C / Large scale 2: hydroxylamine hydrochloride; acetyl chloride / N,N-dimethyl-formamide; acetonitrile / 2 h / 80 °C / Large scale 3: potassium carbonate / N,N-dimethyl-formamide; acetonitrile / 80 °C / Large scale 4: sodium hydroxide / tetrahydrofuran / 1 h / 60 °C / Large scale View Scheme

methyl 3-cyano-4-hydroxybenzoate (156001-68-2) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 90 °C / Inert atmosphere 2: sodium hydroxide / methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 80 °C 2: sodium hydroxide / methanol; water / 2 h / 25 °C View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 90 °C 2: sodium hydroxide; ethanol / tetrahydrofuran / 4 h / 20 °C View Scheme

methyl 3-bromo-4-hydroxybenzoate (29415-97-2) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile / Reflux 2: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 120 °C / Inert atmosphere 3: sodium hydroxide / methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / acetonitrile / Reflux 2.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 120 °C / Inert atmosphere 3.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 3.2: pH 4 - 5 View Scheme
Multi-step reaction with 3 steps 1: copper(l) iodide / N,N-dimethyl-formamide / 120 °C 2: potassium carbonate / N,N-dimethyl-formamide / 80 °C 3: sodium hydroxide / methanol; water / 2 h / 25 °C View Scheme

3-cyano-4-fluorobenzoic acid methyl ester (676602-31-6) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hexamethyldisilazane / tetrahydrofuran / 20 °C / Cooling with ice 1.2: 16 h / 50 °C 2.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 2.2: pH ~ 2 View Scheme
Multi-step reaction with 2 steps 1.1: sodium hexamethyldisilazane / tetrahydrofuran / 17 h / 20 - 50 °C / Cooling with ice 2.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 2.2: pH 2 View Scheme

3-cyano-4-fluorobenzoic acid (171050-06-9) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / 80 - 90 °C 2.1: sodium hexamethyldisilazane / tetrahydrofuran / 20 °C / Cooling with ice 2.2: 16 h / 50 °C 3.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 3.2: pH ~ 2 View Scheme
Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / 90 °C 2.1: sodium hexamethyldisilazane / tetrahydrofuran / 17 h / 20 - 50 °C / Cooling with ice 3.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 3.2: pH 2 View Scheme

methyl 3-bromo-4-isopropoxybenzoate (213598-10-8) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 120 °C / Inert atmosphere 2: sodium hydroxide / methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 120 °C / Inert atmosphere 2.1: sodium hydroxide; water / isopropyl alcohol / 20 °C 2.2: pH 4 - 5 View Scheme

methyl 3-formyl-4-hydroxybenzoate (24589-99-9) → 3-cyano-4-isopropoxybenzoic acid (258273-31-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride; acetyl chloride / N,N-dimethyl-formamide; acetonitrile / 2 h / 80 °C / Large scale 2: potassium carbonate / N,N-dimethyl-formamide; acetonitrile / 80 °C / Large scale 3: sodium hydroxide / tetrahydrofuran / 1 h / 60 °C / Large scale View Scheme

3-cyano-4-isopropoxybenzoic acid (258273-31-3) → 3-cyano-4-[(1-methylethyl)oxy]benzoyl chloride (1072948-37-8)

Conditions	Yield
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h;	100%
With oxalyl dichloride; N,N-dimethyl-formamide at 20℃; for 4h; Product distribution / selectivity;	100%
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 4h;	100%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + methanol (67-56-1) → 3-cyano-4-isopropoxybenzoic acid methyl ester (213598-11-9)

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid; methanol With diazomethyl-trimethyl-silane In dichloromethane at 0 - 20℃; for 1.8h; Stage #2: With acetic acid In dichloromethane at 20℃;	100%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + thiosemicarbazide (79-19-6) → 5-(5-amino-1,3,4-thiadiazol-2-yl)-2-[(1-methylethyl)oxy]benzonitrile (1258440-55-9)

Conditions	Yield
With trichlorophosphate at 90℃; for 3h;	99%
Stage #1: 3-cyano-4-isopropoxybenzoic acid; thiosemicarbazide With trichlorophosphate at 90℃; for 3h; Stage #2: With sodium hydroxide In water at 35℃; pH=10; Cooling with ice;	99%
Stage #1: 3-cyano-4-isopropoxybenzoic acid; thiosemicarbazide With trichlorophosphate at 90℃; for 3h; Stage #2: With sodium hydroxide at 35℃; pH=10; Cooling with ice;	99%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + 1,1-dimethylethyl 8-[(hydroxyamino)(imino)methyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1167416-24-1) → 1,1-dimethylethyl 8-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1167416-65-0)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; Heating;	92%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + 3-ethoxy-N-hydroxy-1H-indene-7-carboximidamide → N-((3 -cyano-4-isopropoxybenzoyl)oxy)-3 -ethoxy-1H-indene-7-carboximidamide

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 3-ethoxy-N-hydroxy-1H-indene-7-carboximidamide In N,N-dimethyl-formamide for 0.583333h;	90%
Stage #1: 3-cyano-4-isopropoxybenzoic acid With 1,1'-carbonyldiimidazole In water; N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 3-ethoxy-N-hydroxy-1H-indene-7-carboximidamide In water; N,N-dimethyl-formamide for 0.583333h;	90%
Stage #1: 3-cyano-4-isopropoxybenzoic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 3-ethoxy-N-hydroxy-1H-indene-7-carboximidamide In N,N-dimethyl-formamide for 0.583333h;	90%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + 3-ethoxy-N-hydroxy-1H-indene-7-carboximidamide → N-((3-cyano-4-isopropoxybenzoyl)oxy)-3-ethoxy-1H-indene-7-carboximidamide

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 3-ethoxy-N-hydroxy-1H-indene-7-carboximidamide In N,N-dimethyl-formamide for 0.583333h;	90%
Stage #1: 3-cyano-4-isopropoxybenzoic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 3-ethoxy-N-hydroxy-1H-indene-7-carboximidamide In N,N-dimethyl-formamide at 20℃; for 0.583333h;	90%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + tert-butyl 3-(N'-hydroxycarbamimidoyl)-4-methyl-5,6-dihydro-1,7-naphthyridine-7(8H)-carboxylate (1333996-58-9) → tert-butyl 3-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-4-methyl-5,6-dihydro-1,7-naphthyridine-7(8H)-carboxylate (1333996-60-3)

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: tert-butyl 3-(N'-hydroxycarbamimidoyl)-4-methyl-5,6-dihydro-1,7-naphthyridine-7(8H)-carboxylate In N,N-dimethyl-formamide at 20 - 100℃; for 17.5h;	88%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + 2-chloro-4-(1,3-dioxolan-2-yl)-N′-hydroxybenzimidamide → 5-(3-(2-chloro-4-(1,3-dioxolan-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid; 2-chloro-4-(1,3-dioxolan-2-yl)-N′-hydroxybenzimidamide With potassium carbonate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: With benzotriazol-1-ol In N,N-dimethyl-formamide at 110℃; for 2h; Inert atmosphere;	87%
Stage #1: 3-cyano-4-isopropoxybenzoic acid With potassium carbonate; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 2-chloro-4-(1,3-dioxolan-2-yl)-N′-hydroxybenzimidamide In N,N-dimethyl-formamide at 110℃; for 4h; Inert atmosphere;	87%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + 4-(1,3-dioxolan-2-yl)-2-fluoro-N′-hydroxybenzimidamide → 5-(3-(4-(1,3-dioxolan-2-yl)-2-fluorophenyl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid; 4-(1,3-dioxolan-2-yl)-2-fluoro-N′-hydroxybenzimidamide With potassium carbonate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: With benzotriazol-1-ol In N,N-dimethyl-formamide at 110℃; for 2h; Inert atmosphere;	81.7%
Stage #1: 3-cyano-4-isopropoxybenzoic acid With potassium carbonate; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 4-(1,3-dioxolan-2-yl)-2-fluoro-N′-hydroxybenzimidamide In N,N-dimethyl-formamide at 110℃; for 4h; Inert atmosphere;	81.7%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) → N-{(1S)-1-[(4-bromophenyl)methyl]-3-hydroxypropyl}-3-cyano-4-[(1-methylethyl)oxy]benzamide

Conditions	Yield
Stage #1: (3S)-3-amino-4-(4-bromophenyl)-1-butanol hydrochloride With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) for 0.05h; Stage #2: 3-cyano-4-isopropoxybenzoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In DMF (N,N-dimethyl-formamide) at 20℃; for 1.5h; Stage #3: With water In DMF (N,N-dimethyl-formamide)	78%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + N-hydroxybenzofuran-5-carboximidamide (1307231-09-9) → 5-(3-(benzofuran-5-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile (1307230-52-9)

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: N-hydroxybenzofuran-5-carboximidamide In N,N-dimethyl-formamide at 20 - 85℃;	69%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + (S)-1-azido-N’-hydroxy-2,3-dihydro-1H-indene-4-carboximidamide → (S)-5-(3-(1-azido-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: (S)-1-azido-N’-hydroxy-2,3-dihydro-1H-indene-4-carboximidamide In N,N-dimethyl-formamide at 115℃; for 24h; Reagent/catalyst; Solvent;	69%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + tert-butyl (1S)-4-[(E)-N’-hydroxycarbamimidoyl]-2,3-dihydro-1H-inden-1-yl N-[2-[(tert-butyldimethylsilyl)oxy]ethyl]carbamate → tert-butyl(1S)-4-[5-[3-cyano-4-(propan-2-yloxy)phenyl]-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-inden-1-yl-N-[2-[(tert-butyldimethylsilyl)oxy]ethyl]carbamate

Conditions	Yield
With benzotriazol-1-ol; 1,2-dichloro-ethane In N,N-dimethyl-formamide at 20 - 85℃; for 1.5h;	67%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + (1S)-1-({2-[(tert-butyldimethylsilyl)oxy]ethyl}[(S)-2-methylpropane-2-sulfinyl]amino)-N-hydroxy-2,3-dihydro-1H-indene-4-carboximidamide → 5-{3-[(1S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-inden-4-yl]-1,2,4-oxadiazol-5-yl}-2-(propan-2-yloxy)benzonitrile hydrochloride

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid; (1S)-1-({2-[(tert-butyldimethylsilyl)oxy]ethyl}[(S)-2-methylpropane-2-sulfinyl]amino)-N-hydroxy-2,3-dihydro-1H-indene-4-carboximidamide With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In toluene at 20 - 90℃; Inert atmosphere; Stage #2: With hydrogenchloride In water at 0 - 90℃; for 1h; Solvent;	63.6%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + 4-(1,3-dioxolan-2-yl)-N1-hydroxybenzenecarboximidamide (852691-00-0) → 5-(3-(4-(1,3-dioxolan-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid; 4-(1,3-dioxolan-2-yl)-N1-hydroxybenzenecarboximidamide With potassium carbonate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: With benzotriazol-1-ol In N,N-dimethyl-formamide at 110℃; for 2h; Inert atmosphere;	59.7%
Stage #1: 3-cyano-4-isopropoxybenzoic acid With potassium carbonate; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 4-(1,3-dioxolan-2-yl)-N1-hydroxybenzenecarboximidamide In N,N-dimethyl-formamide at 110℃; for 4h; Inert atmosphere;	59.7%
With potassium carbonate; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;	53.1%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + tert-butyl 5-(N-hydroxycarbamimidoyl)-1H-indole-1-carboxylate (1233500-95-2) → tert-butyl 5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole-1-carboxylate (1307231-08-8)

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 20℃; for 1.5h; Inert atmosphere; Stage #2: tert-butyl 5-(N-hydroxycarbamimidoyl)-1H-indole-1-carboxylate In N,N-dimethyl-formamide at 20℃; for 1h;	59%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + 1,1-dimethylethyl 7-[(hydroxyamino)(imino)methyl]-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate (1167415-97-5) → 1,1-dimethylethyl 7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate (1167416-00-3)

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: 1,1-dimethylethyl 7-[(hydroxyamino)(imino)methyl]-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate In N,N-dimethyl-formamide at 20 - 90℃; for 21h;	46%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20 - 90℃;

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + N-hydroxy-3-methylisonicotinimidamide → N-(3-cyano-4-isopropoxybenzoyloxy)-3-methylisonicotinimidamide (1307231-29-3)

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: N-hydroxy-3-methylisonicotinimidamide In N,N-dimethyl-formamide	45%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + (R)-N,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-1-carboximidamide (1307230-79-0) → (R)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile (1307230-03-0)

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 0.5h; Stage #2: (R)-N,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-1-carboximidamide In N,N-dimethyl-formamide at 20 - 90℃; for 16h;	42.4%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + (S)-N,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide → (S)-5-(3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 16h; Stage #2: (S)-N,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide In N,N-dimethyl-formamide at 20 - 85℃; for 20h;	40%

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + 1,1-dimethylethyl 5-hydroxyamino(imino)methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (1165923-57-8) → 1,1-dimethylethyl 5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate (1165923-65-8)

Conditions	Yield
Stage #1: 3-cyano-4-isopropoxybenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1.5h; Stage #2: 1,1-dimethylethyl 5-hydroxyamino(imino)methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate With dmap; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20 - 95℃; for 19h;	37%
Stage #1: 3-cyano-4-isopropoxybenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1.5h; Stage #2: 1,1-dimethylethyl 5-hydroxyamino(imino)methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate With dmap; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20 - 95℃; for 19h;

3-cyano-4-isopropoxybenzoic acid (258273-31-3) + 1,1-dimethylethyl 7-[(hydroxyamino)(imino)methyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1167416-58-1) → 1,1-dimethylethyl 7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1167416-59-2)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20 - 120℃; for 36h;	31%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20 - 120℃;

Upstream product

• 24589-99-9 methyl 3-formyl-4-hydroxybenzoate 
• 213598-10-8 methyl 3-bromo-4-isopropoxybenzoate 
• 171050-06-9 3-cyano-4-fluorobenzoic acid 
• 676602-31-6 3-cyano-4-fluorobenzoic acid methyl ester 
• 29415-97-2 methyl 3-bromo-4-hydroxybenzoate 
• 156001-68-2 methyl 3-cyano-4-hydroxybenzoate 
• 99-76-3 methyl 4-hydroxylbenzoate 
• 15126-06-4 methyl 3-iodo-4-hydroxybenzoate 
• 1261173-10-7 1-methylethyl 3-cyano-4-[(1-methylethyl)oxy]benzoate 
• 1034689-05-8 1-methylethyl 3-bromo-4-[(1-methylethyl)oxy]benzoate 
• 14348-41-5 3-bromo-4-hydroxy-benzoic acid 
• 213598-11-9 methyl 3-cyano-4-[(1-methylethyl)oxy]benzoate 

Downstream Products

• 1201146-35-1 1,1-dimethylethyl 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate 
• 1201146-44-2 5-{3-[2-(Hydroxymethyl)-1H-indol-5-yl]-1,2,4-oxadiazol-5-yl}-2-[(1-methylethyl)oxy]benzonitrile 
• 1201148-31-3 ethyl 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoate 
• 1201146-82-8 ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoate 
• 1167416-30-9 1,1-dimethylethyl 7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate 
• 1167416-59-2 1,1-dimethylethyl 7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate 
• 1167416-00-3 1,1-dimethylethyl 7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate 
• 1260021-94-0 5-[3-(2-bromo-4-pyridinyl)-1,2,4-oxadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile 
• 1260021-99-5 5-[3-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile 
• 1260022-06-7 5-{3-[3-bromo-2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-2-[(1-methylethyl)oxy]benzonitrile 
• 1260022-18-1 5-{3-[3-(hydroxymethyl)-2-methylphenyl]-1,2,4-oxadiazol-5-yl}-2-[(1-methylethyl)oxy]benzonitrile 
• 1260022-44-3 5-{3-[3-bromo-5-fluoro-2-(methyloxy)phenyl]-1,2,4-oxadiazol-5-yl}-2-[(1-methylethyl)oxy]benzonitrile 
• 1260022-76-1 ethyl 4-[3-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2-propylphenyl]butanoate 
• 1260022-93-2 ethyl 4-{[3-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2-ethylphenyl]oxy}butanoate 

Relevant academic research and scientific papers

Method for preparing 3-cyano-4-isopropoxybenzoic acid

The invention discloses a method for preparing 3-cyano-4-isopropoxybenzoic acid. A first step, 3-formyl-4-methyl hydroxybenzoate is prepared with methyl parahydroxybenzoate; a second step, 3-cyano-4-methyl hydroxybenzoate is prepared with the 3-formyl-4-methyl hydroxybenzoate; a third step, 3-cyano-4-methyl isopropoxybenzoate is prepared with the 3-cyano-4-methyl hydroxybenzoate; a fourth step, the 3-cyano-4-isopropoxybenzoic acid is prepared with the 3-cyano-4-methyl isopropoxybenzoate. The preparation method of the 3-cyano-4-isopropoxybenzoic acid, which is provided by the invention, has the advantages that 1) the use of the cuprous cyanide of hypertoxic cyanide in a previous process is avoided, and the method is more suitable for industrialization; 2) cyano is prepared by formyl, and the method is high-efficiency and direct, and is suitable for quantity production; 3) all raw materials are cheap and easily obtained, and the cost advantage is obvious.

OXADIAZOLE MODULATORS OF S1P METHODS OF MAKING AND USING

The invention is directed to Compounds of Formula (I): wherein each variable is defined herein, as well as methods of making and using the compounds as agonists of S1P1 and/or S1P5 for instance for treating graft versus host disease and autoimmune diseases.

DEUTERIUM-SUBSTITUTED OXADIAZOLES

Described are deuterated modulators of S1P1 receptors, pharmaceutical compositions thereof, and methods of use thereof.

OXADIAZOLE SUBSTITUTED INDAZOLE DERIVATIVES FOR USE AS SPHINGOSINE 1-PHOSPHATE 1 (S1P1) RECEPTOR AGONISTS

Oxadiazole substituted indazole derivatives of formula (I) or pharmaceutical salts thereof having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their uses in the treatment of various disorders mediated by S1P1 receptors are disclosed.

PYRROLOPYRAZINE-SPIROCYCLIC PIPERIDINE AMIDES AS MODULATORS OF ION CHANNELS

The invention relates to pyrrolopyrazine-spirocyclic piperidine amide compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

DISUBSTITUTED OXADIAZOLE DERIVATIVES USEFUL IN THE TREATMENT OF AUTOIMMUNE AND INFLAMMATORY DISORDERS

The present invention relates to certain disubstituted oxadiazole derivatives of Formula (Ia) and pharmaceutically acceptable salts, solvates, and hydrates thereof, which exhibit useful pharmacological properties, for example, as agonists of the S1P1 receptor. Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods of using the compounds and compositions of the invention in the treatment of S1P1-associated disorders, for example, psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, acne, myocardial ischemia-reperfusion injury, hypertensive nephropathy, glomerulosclerosis, gastritis, polymyositis, thyroiditis, vitiligo, hepatitis, biliary cirrhosis, microbial infections and associated diseases, viral infections and associated diseases, diseases and disorders mediated by lymphocytes, auto immune diseases, inflammatory diseases, and cancer.

OXADIAZOLE SUBSTITUTED INDAZOLE DERIVATIVES FOR USE AS SPHINGOSINE 1-PHOSPHATE 1 (S1P1) RECEPTOR AGONISTS

Oxadiazole substituted indazole derivatives of formula (I) or pharmaceutical salts thereof having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their uses in the treatment of various disorders mediated by S1P1 receptor are disclosed.

Modulators of S1P and Methods of Making And Using

The invention is directed to Compounds of Formula I: as well as methods of making and using the compounds.

CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS

Compounds useful for treating cellular proliferative diseases and disorders by modulating the activity of one or more mitotic kinesins are disclosed.

CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS

Compounds useful for treating cellular proliferative diseases and disorders by modulating the activity of one or more mitotic kinesins are disclosed.