Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1(C)C(C)(C)OB([C:28]2[CH:40]=[CH:39][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:30][CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:5]1[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:3][C:2]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:39][CH:40]=2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(CN3CCOCC3)cc2)cc(NC2CCOCC2)c1C
Temperature: 100 °C
Yield: 64.4 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (600 mg, 1.83 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (833 mg, 2.75 mmol) in dioxane (9 mL), aqueous 2M Na2CO3 solution (3.30 mL, 6.60 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (211 mg, 0.18 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (500 mg, 77%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([N:14]([CH2:18][CH2:19]O)[CH2:15][CH2:16]O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:19][CH2:18][N:14]([CH2:15][CH2:16][Cl:23])[C:12]1=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCOCc1ccccc1)N(CCO)CCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1N(CCCl)CCN1CCOCc1ccccc1

Procedure:
To 3-benzyloxypropionic acid (129.6 g) in ether (310 ml) and N,N-dimethylformamide (4ml) was added thionyl chloride (155 ml). The solution was refluxed for 2 hours, and solvents and excess thionyl chloride were removed by evaporation in vacuo. Yield 132 g of 3-Benzyloxypropionic acid chloride as an oil. To an ice cooled solution of the thus prepared acid chloride (132 g) in acetone (450 ml) was added a cold solution of sodium azide (48.5 g) in water (200 ml) at 5° C. After additional stirring at 5° C. for 30 minutes, the mixture was poured into water and toluene, and the aqueous phase was extracted twice with toluene. The combined organic phases were washed with brine. After drying (magnesium sulfate) the solution was heated slowly to 85° C. on a steam bath until evolution of nitrogen ceased. The solvent was removed in vacuo leaving 108.4 g of 2-benzyloxyethylisocyanate as an oil. A mixture of 2-benzyloxy-ethylisocyanate (10 g) and diethanolamine (5.72 g) in dichloromethane (60 ml) was refluxed for 2.5 hours. After cooling to room temperature, the solution was washed with brine. Drying (magnesium sulfate) and evaporation of the solvent yielded 11.4 g of N-(2-benzyloxyethyl)-N',N'-di-(2-hydroxyethyl)-urea as an oil. A solution of the urea derivative (11.4 g) in dichloromethane (55 ml) was cooled to 5° C., and thionyl chloride (8.3 ml) was added at a temperature below 10° C. After the addition the mixture was refluxed for 1 hour and then left over night at room temperature. The solution was washed with cold sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in 1,1,1-trichloroethane and refluxed for 3 hours. After cooling the solution was washed with sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacuo, yilding 6.6 g of the title compound 22a as an oil.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C[Si](Cl)(C)C.[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.CO.C(N(CC)CC)C>[C:13]([NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@H](CO)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 37.5 °C
Reaction time: 3 h

Procedure:
To dichloromethane (500 ml), D-serine (50 g) was added at ambient temperature under nitrogen atmosphere to form a suspension and then trimethylsilyl chloride (180.91 g) was added to the suspension in 10-15 minutes at ambient temperature. The reaction mixture was refluxed at 35-40° C. for 20 minutes and then it was cooled to ambient temperature. To the reaction mixture, a solution of triethyl amine (168.50 g) in dichloromethane (50 ml) was added in 30-45 minutes at 25-30° C. The mixture was refluxed for 45 minutes at 35-40° C. and then cooled to 0° C. To this mixture, a solution of anhydrous methanol (22.83 g) in dichloromethane (50 ml) was added at 0° C. and the mixture was allowed to reach at room temperature. Triethylamine (48.14 g) was slowly added to it at 25-30° C. and then trityl chloride (132.63 g) was added in 3 lots to the mixture at an interval of 10 minutes. The reaction mixture was then stirred for 3 hours under nitrogen at ambient temperature. After completion of the reaction, methanol (76.12 g) was added at ambient temperature in 10-15 minutes and the solvent was recovered under vacuum at 40-45° C. The crude product obtained was washed with water (750 ml) and filtered. The filtered product was further washed with 5% citric acid solution (750 ml) and filtered. The solid product obtained was partitioned between water (750 ml) and hexanes (200 ml) and then filtered. The filtered solid was washed with hexanes (200 ml) and dried to obtain the titled product. Yield=135 gm.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([F:19])[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:20]>>[ClH:20].[F:19][C:12]1[CH:11]=[C:10]([N:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)[CH:15]=[CH:14][C:13]=1[N+:16]([O-:18])=[O:17]
Reactant: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(F)c2)CC1
Agent: Cl
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cc1F

Procedure:
1-Acetyl-4-(3-fluoro-4-nitrophenyl)piperazine (1.08 g), and 2N hydrochloric acid (20 ml) were refluxed for 30 minutes. The solution was then evaporated to dryness, the residue triturated with methanol, the whole re-evaporated to remove hydrochloric acid, and the residue crystallized from methanol/ethanol, yielding the title compound, (0.78 g), m.p. 271°-3°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:5]=[CH:4][C:3]=1[C:14]([NH2:16])=[O:15].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25](OC)=O.[O-]CC.[Na+].O>C(O)C.C(OCC)(=O)C>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]1[NH:16][C:14](=[O:15])[C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:13])[C:2]=2[N:1]=1
Reactant: COC(=O)Cc1ccccc1Br
Reactant: Cc1ccccc1-n1ncc(C(N)=O)c1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1ccccc1-n1ncc2c(=O)[nH]c(Cc3ccccc3Br)nc21
Temperature: 25 °C

Procedure:
2.0 g (9.25 mmol) of 5-amino-1-(2-methylphenyl)-1H-pyrazole-4-carboxamide (Example 25A) and 9.5 g (41.62 mmol) of methyl (2-bromophenyl)acetate are dissolved in 30 ml of absolute ethanol under argon, and 3.15 g (46.6 mmol) of sodium ethoxide are added. The reaction mixture is heated to a reflux overnight. Cooling to room temperature is followed by hydrolysis with 50 ml of water and subsequent extraction with ethyl acetate (2×50 ml). The combined organic phases are dried over sodium sulphate, and the solvent is distilled off under reduced pressure. The crude product is then purified by column chromatography (silica gel; mobile phase cyclohexane/ethyl acetate, gradient 10:1→1:1). 3.01 g (82% of theory) of the product are obtained.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([O:31][CH3:32])=[O:30])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.IC1C=CC=CC=1C(OC)=O>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=3[C:29]([O:31][CH3:32])=[O:30])=[CH:25][N:26]=2)=[O:8])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccccc1-c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: COC(=O)c1ccccc1I
Product: COC(=O)c1ccccc1-c1cnc(C(=O)CCCCCCc2ccccc2)o1
Yield: 99 %

Procedure:
Methyl 2-(2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)benzoate. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (166 mg, 0.251 mmol) and methyl 2-iodobenzoate following General Procedure A. Flash chromatography (2-20% EtOAc/hexanes) yielded the title compound as a clear oil (125 mg, 99%): 1H NMR (CDCl3, 400 MHz) δ 7.75 (d, 1H, J=7.6 Hz), 7.62 (d, 1H, J=8.0 Hz), 7.53 (t, 1H, J=7.6 Hz), 7.41 (t, 1H, J=7.6 Hz), 7.28-7.24 (m, 3H), 7.17-7.15 (m, 3H), 4.83 (t, 1H, J=6.8 Hz), 3.85 (s, 3H), 2.60 (t, 2H, J=7.4 Hz), 1.92-1.90 (m, 2H), 1.64-1.60 (m, 2H), 1.38-1.33 (m, 6H), 0.90 (s, 9H), 0.11 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 173.5, 170.3, 154.6, 147.9, 136.5, 135.1, 135.0, 134.9, 133.7, 133.5, 133.4, 132.3, 130.7, 129.8, 73.8, 57.6, 41.6, 41.1, 36.6, 34.3, 34.3, 30.9, 30.1, 23.4, 0.2, 0.0.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[CH:17][O:18][CH:19]=1)C1C=CC=CC=1>ClCCl.[Pd]>[O:18]1[CH:19]=[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])[N:16]=[CH:17]1
Reactant: c1ccc(COc2ccccc2-c2cocn2)cc1
Agent: [Pd]
Solvent: ClCCl
Product: Oc1ccccc1-c1cocn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of the oxazole from above (1.99 g, 7.92 mmol) in dichloromethane (20 ml) is added 10% palladium on carbon (1.99 g). The mixture is put under an atmosphere of hydrogen, stirred at room temperature overnight, then filtered through Celite. The solvent is removed under reduced pressure to give 1.15 g of 2-(oxazol-4-yl)phenol (90%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][OH:24])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][O:24][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCC1CCCN(Cc2ccccc2)C1
Reactant: Fc1ccc(CBr)cc1
Product: Fc1ccc(COCC2CCCN(Cc3ccccc3)C2)cc1

Procedure:
Following the procedure for Example 139, 4-fluorobenzylbromide and 1-benzyl-3-(hydroxy-methyl)piperidine were reacted to give 1-benzyl-3-(4'-fluorobenzyloxymethyl) piperidine.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11]C)=[O:10])[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[CH2:17]([SH:19])[CH3:18].[OH-].[K+:21].C([S-])C.[K+].C(SC1C=C(CC(OC)=O)C=CC=1)C.C1(CC(OC)=O)C=CC=CC=1.[OH-].[Na+]>Cl.O.CO.C(OCC)C>[CH2:17]([S-:19])[CH3:18].[K+:21].[C:4]1([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: CCS
Agent: CCSc1cccc(CC(=O)OC)c1
Agent: CC[S-]
Agent: COC(=O)Cc1ccccc1
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: O=C(O)Cc1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of methyl 3-aminophenylacetate (102 g, 0.62 mole) in 1N HCl (1600 ml) cooled in an ice bath was added NaNO2 (42.7 g, 0.62 mole) portionwise and the solution stirred for 20 minutes. A solution of potassium ethanethiolate was prepared by adding ethanethiol (202 ml, 2.73 mole) dropwise over 10 minutes to a solution of 87.5% KOH (159 g, 2.48 mole) in water (1.2 l) at 0° C. The diazonium salt solution was then added via cannula to the solution of potassium ethanethiolate and the reaction mixture was stirred 30 minutes in an ice bath. Diethyl ether (~ 1.5 l) was added and the mixture was stirred 1.5 hours at room temperature. The ether layer was separated, the aqueous phase further extracted with diethyl ether (3×700 ml), and the combined ether solutions concentrated. The residue was eluted from silica gel with ethyl acetate:hexane (1:19) to give a mixture of methyl 3-ethylthiophenylacetate 1H NMR (DMSO-d6, 200 MHz) δ: 1.21 (t, J=7 Hz, 3H, ethyl CH3), 2.95 CH2), 3.60 (s, 3H, OCH3), 3.65 (s, 2H, ArCH2), 7.02-7.44 (m, Ar), and methyl phenylacetate (85.9 g). The esters (84 g) were hydrolyzed in a solution of methanol (500 ml) and 6.25N NaOH (100 ml) stirred overnight at room temperature. The solution was concentrated in vacuo to remove the methanol, the remaining solution acidified with concentrated HCl and the resulting solid was extracted into diethyl ether. The ether solution was washed with brine (3×100 ml), dried (Na2SO4) and concentrated. Vacuum distillation (0.5 mm Hg) gave a distillate (100°-115° C.) of phenylacetic acid and a residue of 3-ethylthiophenylacetic acid. The residue in the flask solidified upon cooling to give 3-ethylthiophenylacetic acid (49.8 g). Mp=49°-51° C. 1H NMR (DMSO-d6, 200 MHz) δ: 1.21 (t, J=7 Hz, 3H, CH3), 2.95 (q, J=7 Hz, 2H, SCH2), 3.54 (s, 2H, ArCH), 7.01-7.28 (m, 4H, Ar), 12.33 (br s, 1H, CO2H). Mass spectrum (CI-CH4): 197 (M+1, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:3]=1[NH2:4].Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=2[F:26])[N:19]=[C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:17]=1[CH3:34].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:3]=1[NH:4][C:16]1[C:25]2[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=2[F:26])[N:19]=[C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:17]=1[CH3:34]
Reactant: Nc1cc(N2CCOCC2)ccc1Cl
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)ccc1Cl
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 2-chloro-5-morpholinoaniline (0.14 g, 0.65 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.15 g, 0.54 mmol), 2-dicyclohexylphosphino-2,4,6,-tri-i-propyl-1,1-biphenyl, (X-Phos) (41.9 mg, 0.088 mmol), tris(dibenzylideneacetone)dipalladium (0) (20.7 mg, 0.023 mmol), and sodium tert-butoxide (0.16 g, 1.7 mmol) in dry toluene (3.0 mL) was degassed by nitrogen. The resulting reaction was heated to 100° C. and monitored with TLC and LC-MS. After 18 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-40% EtOAc in hexanes) to afford an off white solid as N-(2-chloro-5-morpholinophenyl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.73 (1H, m), 7.94 (2H, m), 7.64 (1H, d, J=9.3 Hz), 7.37 (1H, ddd, J=7.0, 5.0, 1.7 Hz), 7.33 (2H, m), 7.03 (1H, ddd, J=13.4, 8.6, 2.4 Hz), 6.46 (1H, dd, J=8.8, 2.7 Hz), 6.22 (1H, d, J=2.7 Hz), 3.87 (4H, m), 3.14 (4H, m), 2.18 (3H, s). Mass Spectrum (pos.) m/e: 467.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.[CH3:22][S:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([S:23][CH3:22])=[CH:25][CH:26]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Reactant: CSc1ccc(CCl)cc1
Product: CSc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(F)cc2)cc1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 3 (b)] with 4-methylthio-benzyl chloride [J.Org.Chem. (1988), 53(3), 561-569] there was obtained tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-(4-methylsulphanyl-benzyloxy)-piperidine-1-carboxylate as a colourless oil; MS: 432 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH:13][C:14]([CH:16]2[CH2:20][S:19][CH:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:17]2)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]1([CH3:35])[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:14]([CH:16]3[CH2:20][S:19][CH:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:17]3)=[O:15])[CH:35]2[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: O=C(NCCNCCCc1ccccc1)C1CSC(c2cccnc2)N1
Solvent: Cc1ccccc1
Product: Cc1ccc(C2N(CCCc3ccccc3)CCN2C(=O)C2CSC(c3cccnc3)N2)cc1
Temperature: 120 °C
Yield: 5.2 %

Procedure:
A mixture of 50 mg of N-(3-phenylpropylaminoethyl)-2-(3-pyridyl)thiazolidine-4-carboxamide, 17 mg of p-tolualdehyde, 100 mg of molecular sieve (4A) and 2 ml of toluene was heated in a sealed tube at 120° C. for 8 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to preparative thin layer chromatography (development with 2% methanol-ethyl acetate being made twice; Rf value=0.15) to give 3.3 mg of 1-(3-phenylpropyl)-3-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]-2-(4-tolyl)imidazolidine.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:8]=2)[CH2:3]1.C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:48][C:49]1[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=1>C(OCC)(=O)C.O>[Cl:48][C:49]1[CH:54]=[CH:53][C:52]([S:55]([NH:1][CH:2]2[CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:8]=3)[CH2:3]2)(=[O:57])=[O:56])=[CH:51][CH:50]=1
Reactant: COC(=O)Cc1ccc2c(c1)CC(N)C2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl (-)-(2-aminoindan-5-yl)acetate.(-)-dibenzoyl-L-tartaric acid salt (3.94 g) is added to a mixture of potassium carbonate (4.83 g), water (50 ml) and ethyl acetate (70 ml), and 4-chlorophenylsulfonyl chloride (1.49 g) is added thereto. The mixture is stirred at room temperature for one hour. The ethyl acetate layer is separated from the reaction mixture, washed with an aqueous sodium hydrogen carbonate solution, dried, and distilled under reduced pressure to remove the solvent. The residue is recrystallized from a mixture of ethyl acetate and hexane to give methyl (-)-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetate (2.43 g) as colorless crystals.
Reaction SMILES: [C:1]1([CH3:29])[C:2]([NH:7][C:8]2[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)=[CH:3][CH:4]=[CH:5][CH:6]=1.[H-].[Na+].[CH3:32]I>O1CCCC1>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:9]2[C:8]([N:7]([CH3:32])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:29])=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:18]([OH:20])=[O:19])[CH:15]=3)[N:10]=2)=[CH:27][CH:26]=1
Reactant: CI
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Nc3ccccc3C)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of methyl 3-(o-toluidino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (145 mg, 0.37 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (74.9 mg, 3.12 mmol) at 0° C. with stirring for 30 min, followed by the addition of CH3I (1.5 mL) dropwise. The reaction mixture was stirred overnight at room temperature. The reaction was then quenched with water (50 mL), adjusted to pH 5 with HCl (3N), and extracted with ethyl acetate (3×80 mL). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the residue, which was purified by Prep-HPLC under the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19*50 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (25% CH3CN up to 67% in 10 min); Detector, UV 220 nm] to afford 2-(4-fluorophenyl)-3-(methyl(o-tolyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (46.5 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][NH:7]C(=O)CC.Cl>C(O)C.O>[ClH:1].[NH2:7][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:15][C:14]([F:16])=[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])[CH:12]=1
Reactant: CCC(=O)NCCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCN)c(Cl)cc2F)c1=O

Procedure:
A solution of 17.0 g of N-[2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4 -trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorophenoxy}-ethyl]propionamide in 100 ml of ethanol is heated at reflux temperature for 5 hours with a solution of 75 ml of concentrated hydrochloric acid in 75 ml of water. The ethanol is subsequently distilled off at 50° C. and the clear aqueous solution is neutralized with sodium bicarbonate. The oily precipitate is dissolved in ethyl acetate and the solution is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The resinous residue is dissolved in 200 ml of 2N hydrochloric acid at 50° C., the mixture is extracted with a small amount of ethyl acetate and the aqueous phase is evaporated under reduced pressure until crystallization occurs. 50 ml of diethyl ether are subsequently added and the mixture is stirred. The crystals are filtered off under suction, washed with diethyl ether and dried at 50° C. in a vacuum. There is obtained 3-[5-(2-aminoethoxy)-4-chloro-2-fluorophenyl]-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 217°-227° C. (decomposition).