2-cyclopropylaniline

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5 mmol (425 mg) of 2-pyrrolidinone and 5 mmol (766 mg) of phosphorus oxychloride are added to a solution of 5 mmol (666 mg) of 2-cyclopropylaniline in 30 ml of 1,2-dichloroethane. The whole is heated at 60° C. for 3.5 hours. After evaporation of the solvent, the residue is taken up in water, rendered alkaline with the aid of sodium carbonate, and extracted twice with 100 ml of ether. The organic phase is then dried, concentrated and purified by chromatography on silica gel to yield the expected product. The corresponding hydrochloride is obtained by the action of a titrated solution of hydrochloric acid in ethanol. After evaporation of the solvent extracted twice with 100 ml of ether The organic phase is then dried concentrated purified by chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 5 g (42 mmol) of cyclopropylbenzene in 20 ml of acetic anhydride is cooled to 15° C. While keeping the temperature below 20° C., 3.7 ml of 68% nitric acid are added slowly. The reaction mixture is stirred for one hour at that temperature, hydrolysed, rendered alkaline with 2N sodium hydroxide solution and extracted twice with 100 ml of ether. The organic phase is then dried and concentrated to yield a mixture of 2-nitrocyclo-propylbenzene and 4-nitrocyclopropylbenzene. The mixture is dissolved in 15 ml of ethanol and hydrogenated at normal temperature and pressure in the presence of 50 mg of PtO2. The residue obtained after filtering off the catalyst and evaporating off the solvent is purified by chromatography on silica gel to yield the title product. are added slowly extracted twice with 100 ml of ether The organic phase is then dried concentrated to yield The residue obtained after filtering off the catalyst evaporating off the solvent is purified by chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 21.8 mL of acetylenedicarboxylate (0.18 mol) in 50 mL of MeOH was added dropwise to a solution of 22.5 g of 2-cyclopropylaniline (0.17 mol) in 150 mL of MeOH over 1 hr and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated and the residue was taken up into 30 mL of diphenyl ether. The solution was added dropwise to 200 mL of diphenyl ether heated at 250 C and the mixture was stirred at the temperature for 30 min. The reaction mixture was concentrated in vacuo and the residue was purified on a SiO2 column chromatography (eluted with n-Hex/AcOEt=1/1) to give methyl 4-hydroxy-8-cyclopropylquinoline-2-carboxylate as a pale yellow solid. The reaction mixture was concentrated The solution was added dropwise to 200 mL of diphenyl ether heated at 250 C the mixture was stirred at the temperature for 30 min The reaction mixture was concentrated in vacuo the residue was purified on a SiO2 column chromatography (eluted with n-Hex/AcOEt=1/1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 21.8 mL of acetylenedicarboxylate (0.18 mol) in 50 mL of MeOH was added dropwise to a solution of 22.5 g of 2-cyclopropylaniline (0.17 mol) in 150 mL of MeOH over 1 hr and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated and the residue was taken up into 30 mL of diphenyl ether. The solution was added dropwise to 200 mL of diphenyl ether heated at 250 C and the mixture was stirred at the temperature for 30 min. The reaction mixture was concentrated in vacuo and the residue was purified on a SiO2 column chromatography (eluted with n-Hex/AcOEt=1/1) to give methyl 4-hydroxy-8-cyclopropylquinoline-2-carboxylate as a pale yellow solid. The reaction mixture was concentrated The solution was added dropwise to 200 mL of diphenyl ether heated at 250 C the mixture was stirred at the temperature for 30 min The reaction mixture was concentrated in vacuo the residue was purified on a SiO2 column chromatography (eluted with n-Hex/AcOEt=1/1)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5 mmol (425 mg) of 2-pyrrolidinone and 5 mmol (766 mg) of phosphorus oxychloride are added to a solution of 5 mmol (666 mg) of 2-cyclopropylaniline in 30 ml of 1,2-dichloroethane. The whole is heated at 60° C. for 3.5 hours. After evaporation of the solvent, the residue is taken up in water, rendered alkaline with the aid of sodium carbonate, and extracted twice with 100 ml of ether. The organic phase is then dried, concentrated and purified by chromatography on silica gel to yield the expected product. The corresponding hydrochloride is obtained by the action of a titrated solution of hydrochloric acid in ethanol. After evaporation of the solvent extracted twice with 100 ml of ether The organic phase is then dried concentrated purified by chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 5 g (42 mmol) of cyclopropylbenzene in 20 ml of acetic anhydride is cooled to 15° C. While keeping the temperature below 20° C., 3.7 ml of 68% nitric acid are added slowly. The reaction mixture is stirred for one hour at that temperature, hydrolysed, rendered alkaline with 2N sodium hydroxide solution and extracted twice with 100 ml of ether. The organic phase is then dried and concentrated to yield a mixture of 2-nitrocyclo-propylbenzene and 4-nitrocyclopropylbenzene. The mixture is dissolved in 15 ml of ethanol and hydrogenated at normal temperature and pressure in the presence of 50 mg of PtO2. The residue obtained after filtering off the catalyst and evaporating off the solvent is purified by chromatography on silica gel to yield the title product. are added slowly extracted twice with 100 ml of ether The organic phase is then dried concentrated to yield The residue obtained after filtering off the catalyst evaporating off the solvent is purified by chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 5 g (42 mmol) of cyclopropylbenzene in 20 ml of acetic anhydride is cooled to 15° C. While keeping the temperature below 20° C., 3.7 ml of 68% nitric acid are added slowly. The reaction mixture is stirred for one hour at that temperature, hydrolysed, rendered alkaline with 2N sodium hydroxide solution and extracted twice with 100 ml of ether. The organic phase is then dried and concentrated to yield a mixture of 2-nitrocyclo-propylbenzene and 4-nitrocyclopropylbenzene. The mixture is dissolved in 15 ml of ethanol and hydrogenated at normal temperature and pressure in the presence of 50 mg of PtO2. The residue obtained after filtering off the catalyst and evaporating off the solvent is purified by chromatography on silica gel to yield the title product. are added slowly extracted twice with 100 ml of ether The organic phase is then dried concentrated to yield The residue obtained after filtering off the catalyst evaporating off the solvent is purified by chromatography on silica gel

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 2-cyclopropylaniline (498 mg, 3.74 mmol) in acetone (10 mL) was added benzoyl isothiocyanate (0.53 mL, 3.93 mmol) and the mixture was heated at 50° C. for 8 hours. The reaction mixture was concentrated to provide N-((2-cyclopropylphenyl)carbamothioyDbenzamide as a orange oil (1.249 g, 100%): 1H NMR (400 MHz, CDCl3) δ 12.59 (s, 1H), 9.14 (s, 1H), 8.07 (dd, J=7.8, 1.3 Hz, 1H), 7.92 (dd, J=8.4, 1.2 Hz, 2H), 7.69-7.63 (m, 1H), 7.59-7.52 (m, 2H), 7.31-7.26 (m, 1H), 7.23 (td, J=7.5, 1.5 Hz, 1H), 7.13 (dd, J=7.6, 1.5 Hz, 1H), 1.95 (qt, J=12.3, 4.4 Hz, 1H), 1.09-1.01 (m, 2H), 0.76-0.69 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 178.70, 166.72, 137.59, 137.06, 133.71, 131.72, 129.22, 127.51, 127.20, 126.93, 126.12, 125.26, 11.72, 7.03; ESIMS m/z 295 ([M−H]−). The reaction mixture was concentrated to provide N-((2-cyclopropylphenyl)carbamothioyDbenzamide as a orange oil (1.249 g, 100%)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 2-cyclopropylaniline (498 mg, 3.74 mmol) in acetone (10 mL) was added benzoyl isothiocyanate (0.53 mL, 3.93 mmol) and the mixture was heated at 50° C. for 8 hours. The reaction mixture was concentrated to provide N-((2-cyclopropylphenyl)carbamothioyDbenzamide as a orange oil (1.249 g, 100%): 1H NMR (400 MHz, CDCl3) δ 12.59 (s, 1H), 9.14 (s, 1H), 8.07 (dd, J=7.8, 1.3 Hz, 1H), 7.92 (dd, J=8.4, 1.2 Hz, 2H), 7.69-7.63 (m, 1H), 7.59-7.52 (m, 2H), 7.31-7.26 (m, 1H), 7.23 (td, J=7.5, 1.5 Hz, 1H), 7.13 (dd, J=7.6, 1.5 Hz, 1H), 1.95 (qt, J=12.3, 4.4 Hz, 1H), 1.09-1.01 (m, 2H), 0.76-0.69 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 178.70, 166.72, 137.59, 137.06, 133.71, 131.72, 129.22, 127.51, 127.20, 126.93, 126.12, 125.26, 11.72, 7.03; ESIMS m/z 295 ([M−H]−). The reaction mixture was concentrated to provide N-((2-cyclopropylphenyl)carbamothioyDbenzamide as a orange oil (1.249 g, 100%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 21.8 mL of acetylenedicarboxylate (0.18 mol) in 50 mL of MeOH was added dropwise to a solution of 22.5 g of 2-cyclopropylaniline (0.17 mol) in 150 mL of MeOH over 1 hr and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated and the residue was taken up into 30 mL of diphenyl ether. The solution was added dropwise to 200 mL of diphenyl ether heated at 250 C and the mixture was stirred at the temperature for 30 min. The reaction mixture was concentrated in vacuo and the residue was purified on a SiO2 column chromatography (eluted with n-Hex/AcOEt=1/1) to give methyl 4-hydroxy-8-cyclopropylquinoline-2-carboxylate as a pale yellow solid. The reaction mixture was concentrated The solution was added dropwise to 200 mL of diphenyl ether heated at 250 C the mixture was stirred at the temperature for 30 min The reaction mixture was concentrated in vacuo the residue was purified on a SiO2 column chromatography (eluted with n-Hex/AcOEt=1/1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (42.6 mg, 0.15 mmol, 1.0 equiv; Example 31, Step 1) in anhydrous DMF (1 mL) was added N-ethyldiisopropylamine (97 mg, 128 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (67 mg, 0.18 mmol, 1.2 equiv; [CAS RN 148893-10-1]) and the reaction mixture stirred at rt for 30 min. After addition of 2-cyclopropyl-phenylamine (24 mg, 0.18 mmol, 1.2 equiv; [CAS RN 3158-73-4]) the reaction mixture was heated by microwave irradiation to 100° C. After 30 min, sodium hydride (8.6 mg, 0.2 mmol, 2.0 equiv; 55% free-flowing powder moistened with oil; [CAS RN 7646-69-7]) and iodomethane (28.4 mg, 12 μL, 0.2 mmol, 2.0 equiv; [CAS RN 74-88-4]) were added and stirring of the reaction mixture at rt continued for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 12.6 mg (20%) of the title compound. MS (ISP): 412.9 [M+H]+. was heated by microwave irradiation to 100° C After 30 min stirring of the reaction mixture at rt continued for 2 h Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 21.8 mL of acetylenedicarboxylate (0.18 mol) in 50 mL of MeOH was added dropwise to a solution of 22.5 g of 2-cyclopropylaniline (0.17 mol) in 150 mL of MeOH over 1 hr and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated and the residue was taken up into 30 mL of diphenyl ether. The solution was added dropwise to 200 mL of diphenyl ether heated at 250 C and the mixture was stirred at the temperature for 30 min. The reaction mixture was concentrated in vacuo and the residue was purified on a SiO2 column chromatography (eluted with n-Hex/AcOEt=1/1) to give methyl 4-hydroxy-8-cyclopropylquinoline-2-carboxylate as a pale yellow solid. The reaction mixture was concentrated The solution was added dropwise to 200 mL of diphenyl ether heated at 250 C the mixture was stirred at the temperature for 30 min The reaction mixture was concentrated in vacuo the residue was purified on a SiO2 column chromatography (eluted with n-Hex/AcOEt=1/1)