Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH2:10][O:9][C:8](=[O:11])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.[Cl:17][CH2:18][C:19]([CH2:21]Cl)=[CH2:20].CO>O1CCCC1.CCCCC>[Cl:17][CH2:18][C:19](=[CH2:20])[CH2:21][CH:10]1[O:9][C:8](=[O:11])[CH:7]=[C:6]1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C=C(N2CCCC2)CO1
Reactant: C=C(CCl)CCl
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCC
Product: C=C(CCl)CC1OC(=O)C=C1N1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
800 mg (5.22 mmol) of 4-pyrrolidin-1-ylfuran-2(5H)-one (Shandala, M. Y. et al. J. Heterocycl. Chem. 1984, 21, 1753-1754) are dissolved in 80 ml of tetrahydrofuran and cooled to −78° C., and 3.07 ml (5.22 mmol) of a 1.7M solution of tert-butyllithium in pentane are added. After 30 min of stirring at −78° C., 1.21 ml (10.45 mmol) of 3-chloro-2-(chloromethyl)prop-1-ene are added and the mixture is stirred at −78° C. for a further 30 minutes, warmed to room temperature over a period of about 16 hours and stirred at room temperature for a further 3 hours. After addition of methanol and concentration under reduced pressure, the residue is purified by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate. This gives 735 mg (57% of theory) of 5-[2-(chloromethyl)prop-2-en-1-yl]-4-pyrrolidin-1-ylfuran-2(5H)-one.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:12]2[N:11]([CH3:13])[C:10]3[CH2:14][CH2:15][NH:16][C:17](=[O:18])[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:20][C:21]1[O:25][CH:24]=[N:23][C:22]=1[CH3:26].O>COCCOC>[F:3][C:4]1[C:12]2[N:11]([CH3:13])[C:10]3[CH2:14][CH2:15][N:16]([CH2:20][C:21]4[O:25][CH:24]=[N:23][C:22]=4[CH3:26])[C:17](=[O:18])[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ncoc1CCl
Reactant: Cn1c2c(c3cccc(F)c31)C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ncoc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Reaction time: 6 h
Yield: 76.6 %

Procedure:
Sodium hydride (73% dispersion in oil; 167 mg) was added to a stirred suspension of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (500 mg) in dry DME (150 ml), and the suspension was stirred at 60° under nitrogen for 6 h. 5-Chloromethyl-4-methyloxazole (440 mg) was then added and the mixture was stirred overnight at 60°. A further quantity of sodium hydride (73% dispersion in oil; 84 mg) was added and the mixture was stirred for 3 h, and then cooled (0°). Water (200 ml) was added, and the mixture was extracted with dichloromethane (3×200 ml). The combined organic extracts were concentrated in vacuo and the residue was purified by FCC eluting with System A (100:8:1) to give the title compound (550 mg) as a solid, m.p. 158°-161°.
Reaction SMILES: [C:1](Cl)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:16]([O:20][C:21]([NH:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].O>C(Cl)Cl>[C:16]([O:20][C:21]([NH:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:1](=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCC1CCCCN1
Reactant: CCCCCCCCCCCCC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCC(=O)N1CCCCC1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
To a stirred, cooled (0° C.) solution of 14.3 grams (61.4 mmol) of tridecanoyl chloride in 50 mL of methylene chloride was added 7.49 grams (61.3 mmol) of N,N-dimethylaminopyridine. The resulting suspension was stirred for 10 minutes and then 11.0 grams (51.3 mmol) of 2-[N-(tert-butoxycarbonyl)aminomethyl]piperidine in 50 mL of methylene chloride was added. The mixture was allowed to warm to room temperature while stirring overnight and poured into water. The aqueous layer was extracted with methylene chloride and the combined organic layers were washed with brine and dried over MgSO4. Solvent was removed at reduced pressure and the crude product was chromatographed on 250 grams of silica gel eluting with 25% ethyl acetate in hexane to provide 20.9 grams (99%) of N-(tert-butoxycarbonyl)-N-([1-(1-oxotridecyl)-2-piperidinyl]methyl)amine as a viscous orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[O:15][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=3[CH:13]=2)=[CH:17][CH:18]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: COc1cc(O)cc(OC)c1
Product: COc1cc(OC)c2cc(-c3ccc(F)cc3)oc2c1
Yield: 49 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(4-fluorophenyl)ethanone: Yield 49% following procedure A.2; m.p. 142-143° C.; IR 2914, 1614, 1496, 1220, 1145, 1116, 1043 cm−1; 1H-NMR (200 MHz, δ ppm, CDCl3) 7.74 (dd, J=8.8 Hz, 5.4 Hz, 2H), 7.10 (t, J=8.7 Hz, 2H), 6.96 (s, 1H), 6.68 (s, 1H), 6.33 (d, J=1.7 Hz, 1H), 3.89 (d, J=11.3 Hz, 6H); 13C-NMR (126 MHz, δ ppm, CDCl3) 162.6 (d, J=247.7 Hz), 159.5, 156.8, 153.7, 153.0, 127.4 (d, J=3.0 Hz), 126.2 (d, J=8.0 Hz), 115.9 (d, J=22.0 Hz), 113.5, 98.7, 94.6, 88.5, 55.9, 55.8.
Reaction SMILES: [CH3:1][C:2]([CH3:31])=[C:3]([N:8]1[C@H:11](SC)[C@@H:10]([CH:14]([O:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[CH3:15])[C:9]1=[O:30])[C:4]([O:6][CH3:7])=[O:5].[Cl:32]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:32][CH:11]1[N:8]([C:3](=[C:2]([CH3:31])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])[C:9](=[O:30])[C@@H:10]1[CH:14]([O:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])[CH3:15]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1SC
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C1Cl
Temperature: 0 °C

Procedure:
To a solution of a mixture (1:3) of methyl 3-methyl-2-[(3S,4R)-4-methylthio-3-{(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-but-2-enoate (1.30 g) in dichloromethane (13 ml) was added a solution of chlorine (211mg) in carbon tetrachloride (2.2 ml) at -78° C. The solution was allowed to warm to 0° C. during 45 minutes and concentrated. The residue was dissolved in ethyl acetate (30 ml) and washed with a chilled aqueous sodium bicarbonate (2.5 g), water, and brine. Drying over magnesium sulfate and evaporation left an oil (1.30 g), which showed two spots on silica gel thin layer chromatography (1:1 hexane/ethyl acetate). The residue was chromatographed on silica gel (40 g) eluting with 10-30% ethyl acetate in hexane to afford firstly a mixture (5:6:4) of methyl 2-[(3S)-4-chloro-3-{1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbutenoate [a mixture (5:6:4) of (1S,4R) isomer, (1R, 4R) isomer and (1R, 4S) isomer] (550 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:22]=[CH:21][C:20]=1[N+:33]([O-:35])=[O:34])[CH2:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12].[OH-].[Na+].O.Cl>CO.CCCCC>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:22]=[CH:21][C:20]=1[N+:33]([O-:35])=[O:34])[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: Cc1ccccc1[C@@H](CCC(=O)OC(C)(C)C)Oc1cc(OCc2cccnc2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCCCC
Product: Cc1ccccc1[C@@H](CCC(=O)O)Oc1cc(OCc2cccnc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.2 %

Procedure:
A solution of tert-butyl (R)-4-(2-methylphenyl)-4-(2-nitro-5-(3-pyridylmethoxy)phenoxy)butanoate (800 mg) in methanol (20 mL) containing 5 N sodium hydroxide (10 mL) is stirred at ambient temperature for 48 hours. The reaction mixture is poured into water (50 mL), acidified to pH 5 with 1 N HCl and extracted three times with ethyl acetate (50 mL). The combined organic phases are washed with brine (50 mL), dried over magnesium sulphate, filtered and concentrated under reduced pressure The residual brown gum is purified by flash chromatography on silica eluting with ethyl acetate. Fractions homogeneous in the required product are combined and evaporated to give a yellow oil. Trituration with pentane afforded (R)-4-(2-methylphenyl)-4-(2-nitro-5-(3-pyridylmethoxy)phenoxy)butanoic acid as a white solid (150 mg), m.p. 117-119° C. [Elemental analysis:- C,65.4, H, 5.21, N, 6.64%. Calculated:- C,65.3, H, 5.17, N, 6.59%]
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][CH:10]1[CH2:14][S:13][C:12]([NH2:15])=[N:11]1.Cl>C(O)C.C(OCC)C>[ClH:1].[ClH:1].[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][C@@H:10]1[CH2:14][S:13][C:12]([NH2:15])=[N:11]1
Reactant: NC1=NC(Cc2cnccn2)CS1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: NC1=N[C@H](Cc2cnccn2)CS1
Yield: 25.6 %

Procedure:
A racemic mixture of 2.9 g of (4RS)-4-(2-pyrazinylmethyl)-4,5-dihydro-2-thiazolylamine dihydrochloride is separated on a Chiralcel OD10μ column in a heptane/ethanol/triethylamine mixture (80/20/0.1 by volume). The fractions containing the expected product are concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue obtained is dissolved in 5 cm3 of ethanol, followed by addition of 6 cm3 of hydrochloric acid dissolved in diethyl ether and 15 cm3 of diethyl ether. After filtration, washing with 15 cm3 of diethyl ether and drying, 0.371 g of (+)-(4R)-4-(2-pyrazinyl-methyl)-4,5-dihydro-2-thiazolylamine dihydrochloride is obtained in the form of a beige-coloured solid melting at 154° C. [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 3.22 (d, J=6.5 Hz: 2H); 3.45 (dd, J=11.5 and 5.5 Hz: 1H); 3.75 (dd, J=11.5 and 8 Hz: 1H); 4.73 (mt: 1H); 8.60 (broad d, J=2.5 Hz: 1H); 8.63 (dd, J=2.5 and 1.5 Hz: 1H); 8.66 (broad s; 1H); 9.09 (unresolved complex: 1H); 9.58 (unresolved complex: 1H); 9.95 (broad s: 1H); (αD20=+46.3+/−1.1 at a concentration of 0.5% in methanol)].
Reaction SMILES: [Cl-].[NH4+].Cl.[Cl:4][C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][CH:27]=1)[O:8][C:9]1[C:17]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[N+:22]([O-])=O.[OH-].[Na+]>[Fe].O>[NH2:22][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([S:18](=[O:20])(=[O:21])[NH2:19])[C:9]=1[O:8][C:7]1[CH:25]=[CH:26][CH:27]=[C:5]([Cl:4])[CH:6]=1)[C:13]([OH:15])=[O:14]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1cccc(Cl)c1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1cccc(Cl)c1
Reaction time: 6 h

Procedure:
A mixture of ammonium chloride (1.2 g), metallic iron powder (11 g), concentrated hydrochloric acid (0.05 ml), and water (30 ml) was heated on a steam bath. 4-(m-Chlorophenoxy)-3-nitro-5-sulphamyl-benzoic acid (3 g) was added while stirring, and the heating was continued for 6 hours. Then 1N sodium hydroxide (50 ml) was added, and the reaction mixture was filtered. The filter cake was washed twice with 1N sodium hydroxide (50 ml each time). The combined filtrates were adjusted to a pH of 2.5 by the addition of 4N hydrochloric acid. After cooling, the precipitated 3-amino-4-(m-chlorophenoxy)-5-sulphamyl-benzoic acid was collected by suction, and recrystallized from aqueous ethanol. The melting point was 239°-240°C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:16][C:17](O)=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.O.CCOC(C)=O>CCOCC>[CH:7]1([CH2:16][CH2:17][OH:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: O=C(O)CC1CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OCCC1CCc2ccccc21
Temperature: 25 °C
Yield: 92.5 %

Procedure:
Lithium aluminum hydride (1 M in Et2O, 14 mL, 14 mmol) was slowly added to a solution of 2-indanylacetic acid (2.5 g, 14 mmol) in Et2O. The reaction mixture was heated at reflux for 2 h and was cooled to room temperature. Water and EtOAc were added and the organic solution was washed with water (2×) and brine (1×), dried over MgSO4, filtered, and concentrated to afford 2-indanylethanol (2.1 g) which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ7.08-7.24 (m, 4H), 3.75 (t, 2H), 3.07 (m, 2H), 2.61 (m, 3H), 1.80 (m, 2H); MS 180 (M+18).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13](=[O:17])OCC)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CC1C=CC=CC=1C>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][C:13]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)=[O:17]
Reactant: CCOC(=O)Nc1nc(-c2ccccc2)cs1
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccn1)Nc1nc(-c2ccccc2)cs1
Reaction time: 2.5 h
Yield: 67 %

Procedure:
Into 45 ml of o-xylene, were added 1.5 g of ethyl N-(4-phenyl-2-thiazolyl)carbamate and 4.0 g of 2-aminopyridine. The mixture was stirred for 2.5 hours under refluxing. The reaction solution was allowed to stand for cooling. Deposited crystals were collected by filtration and washed with methyl alcohol. The crystals were then recrystallized from an N,N-dimethylformamide/methyl alcohol mixed solvent to obtain 1.2 g of N-(2-pyridyl)-N'-(4-phenylthiazol-2-yl)urea.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>CCOC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: BrCc1cccc(I)c1
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1cccc(I)c1)OCC
Temperature: 160 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
A mixture of 3-iodobenzyl bromide 12 (5 g, 16.84 mmol) and triethyl phosphite (3.3 g, 20 mmol) was stirred at 160° C. After 4 h, the mixture was cooled to room temperature. The residue was subjected to flash chromatography (EtOAc: Hex, 1:4), and gave 5.4 g of 13 (91%). 1H NMR (200 MHz, CDCl3): δ1.15 (t, J=7.05 Hz, 6H), 2.97 (d, J=21.65 Hz, 2H), 3.92 (m, 4H), 6.93 (t, J=7.76 Hz, 1H), 7.17 (m, 1H), 7.52 (m, 2H); 13C NMR (50 MHz, CDCl3): δ 16.25 (J=5.95 Hz), 33.15 (J=137.60 Hz), 62.19 (J=6.70 Hz), 94.13 (J=3.50 Hz), 128.89 (J=6.35 Hz), 130.07 (J=3.00 Hz), 133.95 (J=9.10 Hz), 135.87 (J=3.55 Hz), 138.51 (J=6.65 Hz).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:9](Br)[CH3:10].C[O-].[Na+]>CO>[C:3]([CH:2]([CH2:9][CH3:10])[C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH3:5]
Reactant: COC(=O)CC(C)=O
Reactant: CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(C(C)=O)C(=O)OC
Yield: 56.8 %

Procedure:
465 g of methyl acetoacetate and then 458 g of ethyl bromide were added under nitrogen to 720 g of 30% sodium methylate solution in 1200 ml of methanol. The reaction mixture was subsequently boiled at reflux. After distillation of the methanol the residue was poured on to ice-water. It was then extracted with n-hexane and water. The organic phases were combined and dried. After evaporation of the solvent and distillation there were obtained 328 g (56.9%) of methyl 2-acetylbutyrate, b.p. 77°-79°/15 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CC(C)CC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)C(CC(C)C)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 33.1 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (635 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.82 ml) and 1-methyl-2-chloropyridinium iodide (1 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)-4-methylpentanamide (455 mg).
Reaction SMILES: C([O:5][C:6](=[O:23])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:22])[C@H:13]([CH:19]([CH3:21])[CH3:20])[NH:14][C:15]([O:17][CH3:18])=[O:16])(C)(C)C>C1(C)C=CC=CC=1>[CH3:18][O:17][C:15]([NH:14][C@H:13]([C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:23])=[O:5])=[O:22])[CH:19]([CH3:21])[CH3:20])=[O:16]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Temperature: 120 °C
Yield: 55.3 %

Procedure:
To a solution of N-[methoxycarbonyl]-L-valyl-L-proline tert-butyl ester (813 g) in toluene (3 litres) was added Amberlyst-15 ion exchange resin (190 g). The reaction was heated at 120° C. to distill off water present in the resin via a water/toluene azeotrope. Approximately 400 ml of distillate was collected. Heating was then continued at reflux for 1.5 hours. The reaction was cooled to 0° C. and the resin was removed by filtration. The filtrate was extracted with 1M NaOH (2.5 litres) followed by saturated aqueous sodium bicarbonate solution. The combined basic extracts were extracted with a mixture of THF/ethyl acetate (1:1, 1 litre), and then cooled in an ice bath. The aqueous solution was made acidic to pH 1.5 using cold 3M hydrocloric acid (1 litre) and extracted twice with THF/ethyl acetate (1:1, 1.5 litres and 1 litre). The extracts were combined and washed with brine, dried (MgSO4), and the solvent removed by evaporation. The resulting material was dissolved in ether (1 litre) and allowed to crystallize at 0° C. over 48 hours. The resulting solid was collected by filtration, washed with cold ether and dried under vacuum to give N-[methoxycarbonyl]-L-valyl-L-proline (373 g); 1H NMR (300 MHz, DMSO) 12.4 (s, 1H), 7.37 (d, 1H), 4.25 (dd, 1H), 4.00 (t, 1H), 3.79 (m, 1H), 3.55 (m, 1H), 3.51 (s, 3H), 2.11 (m, 1H), 1.85 (m, 4H), 0.91 (d, 3H), 0.87 (d, 3H); MS m/z=273 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29]([Sn](C)(C)C)[S:28][CH2:27]1>C(O)C>[F:18][C:15]1[CH:14]=[CH:13][C:12]([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([C:29]4[S:28][CH2:27][N:26]([CH3:25])[CH:30]=4)[CH:11]=3)[C:6](=[O:24])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8]2)=[CH:17][CH:16]=1
Reactant: CN1C=C([Sn](C)(C)C)SC1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(Cl)ccc2c1=O
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(C3=CN(C)CS3)ccc2c1=O
Yield: 51.8 %

Procedure:
A mixture of 4.34 g ethyl 7-chloro-1,4-dihydro1-(4-fluorophenyl)-4-oxo-3-quinolinecarboxylate, 6.55 g 3-methyl-5-trimethylstannylthiazole and 1.52 g dichloro- bis-triphenylphosphine palladium in 150 ml absolute ethanol was heated at 150° C. in a stirred stainless steel bomb for about 16 hrs. The product was isolated and chromatographed on silica gel. Elution with 1:1 ethyl acetate/hexane and 100% ethyl acetate gave 2.67 g ethyl 1,4-dihydro-1-(4-fluorophenyl)-7-(3-methyl-5-thiazolyl)-4- oxo-3-quinolinecarboxylate as a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[C:8](=O)(OCC)[O:9]CC.C([O-])([O-])=O.[K+].[K+]>>[CH3:6][CH:5]([C@H:2]1[CH2:3][O:4][C:8](=[O:9])[NH:1]1)[CH3:7]
Reactant: CCOC(=O)OCC
Reactant: CC(C)[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)[C@H]1COC(=O)N1

Procedure:
The title compound was prepared according to Evans, Mathre and Scott (J. Org. Chem., 50, 1830 (1985)) from (S)-(+)-2-amino-3-methyl-1-butanol and diethyl carbonate in the presence of K2CO3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH-].[Na+:19]>>[CH3:17][C@H:13]([C:14]([O-:16])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1.[Na+:19]
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2cc([C@H](C)C(=O)[O-])ccc2c1

Procedure:
It has been found that, surprisingly, when neutralizing (S)-2-(6-methoxy-2-naphthyl)propionic acid having a chiral purity below 99% with less than a stoichiometric amount of aqueous sodium hydroxide solution to form naproxen sodium, it is possible to increase the chiral purity of the naproxen sodium to 99% or more by removing the water by use of a suitable organic solvent, or simply by distilling off water from an aqueous solution.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C@@H:15]2[CH:20]([CH3:22])[CH3:21])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]([CH3:32])[CH3:31].CC([O-])(C)C.[Na+].COCCOC.CCO>C1(C)C=CC=CC=1.CCOCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)C=CC=CC=1>[CH2:1]([C:8]1[CH:9]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH:30]([CH3:32])[CH3:31])[CH2:16][C@@H:15]2[CH:20]([CH3:22])[CH3:21])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccccc1Br
Reactant: CC(C)[C@H]1CNCCN1c1cccc(Cc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: CC(C)c1ccccc1N1CCN(c2cccc(Cc3ccccc3)c2)[C@@H](C(C)C)C1
Temperature: 80 °C
Yield: 60.5 %

Procedure:
110.7 mg (0.38 mmol) 4-(3′-Benzylphenyl)-3-(S)-isopropyl-piperazine (88a), 123.5 mg (0.62 mmol, 1.65 eq.) 1-Bromo-2-isopropyl-benzene 11.7 mg (12.7 μmol, 0.034 eq.) Pd2(dba)3, 7.4 mg (19.3 μmol, 0.05 eq.) 2-Diphenylphosphino-2′-dimethylamino-biphenyl and 87.3 mg (0.91 mmol, 2.42 eq.) NaOt-Bu were dissolved in 5 ml dry toluene. The resulting mixture was heated under N2 at 80° C. for 15.5 h. After cooling to room temperature the mixture was diluted with ether and washed with brine. The comb. org. fractions were dried over Na2SO4 and evaporated. Column chromatography (hexanes/EtOAc (9+1)) yielded 96.5 mg (0.23 mmol, 62.20%) 1-(3-Benzyl-phenyl)-2-(S)-isopropyl-4-(2-isopropyl-phenyl)-piperazine (89) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:14]([OH:16])=O)=[O:7])=[CH:4][CH:3]=1.Cl.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2([OH:7])[C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:14](=[O:16])[N:28]2[CH2:27][C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:30][CH:29]=2)=[CH:17][CH:18]=1
Reactant: O=C(O)C1=C(C(=O)c2ccc(Cl)cc2)CCCC1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C1C2=C(CCCC2)C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 44.4 %

Procedure:
The named compound was synthesised from, 2-(4-chlorobenzoyl)cyclohex-1-enecarboxylic acid (1.00 g, 3.78 mmol) and 4-nitrobenzylamine hydrochloride (0.78 g, 4.16 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 30% EtOAc/petrol) and obtained as a yellow solid (0.67 g, 44%).