Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[S:24]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)([O:27][CH2:28][CH:29]1[O:31][CH2:30]1)(=[O:26])=[O:25]>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:30][CH:29]([OH:31])[CH2:28][O:27][S:24]([C:32]4[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=4)(=[O:26])=[O:25])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCC2CO2)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(O)COS(=O)(=O)c4ccc(C)cc4)CC3)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32.4 %

Procedure:
39.4 mg of 1-ethyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-3-quinoline carboxylic acid were mixed with 50 ml of N,N-dimethylformamide in a round flask of 100 ml and slowly stirred at room temperature for 20 minutes. 14.4 mg of glycidyl tosylate were added thereto, it was stirred at room temperature, and then washed with 30.0 ml of N,N-dimethylformamide. The reactants were held at 80° C. for 5 hours and then stirred at 25° C. for 10 minutes. The reactants were crystallized through column chromatography (20 gm silica, 10% ethylacetate/hexane), filtered, and then dried to give 11.2 mg of 1-ethyl-6-fluoro-1,4-dihydro-7-{4-[2-hydroxy-3-(toluene-4-sulfonyloxy)-propyl]-1-pip erazinyl}-4-oxo-3-quinoline carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](Cl)[C:4]=2[CH:3]=1.[C:12]1([CH:19]=[CH:18][CH:17]=[C:15]([OH:16])[CH:14]=1)[OH:13].C(N(C(C)C)CC)(C)C>O1CCOCC1>[Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:13][C:12]3[CH:19]=[CH:18][CH:17]=[C:15]([OH:16])[CH:14]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ncnc2[nH]c(Br)cc12
Reactant: Oc1cccc(O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Oc1cccc(Oc2ncnc3[nH]c(Br)cc23)c1
Temperature: 150 °C
Yield: 32.7 %

Procedure:
6-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.41 mmol), prepared as in reference 1, is mixed with resorcinol (451 mg, 4.1 mmol) and diisopropylethylamine (714 μL, 4.1 mmol) in dioxane (1.3 mL). The mixture is heated to 150° C. for 3 days, with stirring. The reaction is then cooled to ambient temperature and the solvent is removed. The resultant crude product is purified by flash column chromatography using a gradient of 3-5% MeOH in DCM to yield 5-(6-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yloxyl)-phenol (41 mg; 32%).
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1O[S:5]([CH2:8][CH2:9][CH2:10][C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:7])=[O:6].[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1.N12CCCN=C1CCCCC2.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:31][N:32]1[CH2:33][CH2:34][CH:35]([N:38]2[CH2:43][CH2:42][N:41]([S:5]([CH2:8][CH2:9][CH2:10][C@@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])(=[O:6])=[O:7])[CH2:40][CH2:39]2)[CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CCCS(=O)(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CN1CCC(N2CCNCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CN1CCC(N2CCN(S(=O)(=O)CCC[C@@H]3CCCN3C(=O)OC(C)(C)C)CC2)CC1

Procedure:
(S)-tert-Butyl 2-(3-(perfluorophenoxysulfonyl)propyl)pyrrolidine-1-carboxylate (2.8 g, 6.099 mmol) and 1-(1-methylpiperidin-4-yl)piperazine (1.676 g, 9.148 mmol) were dissolved in tetrahydrofuran (40 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (2.7 ml, 18.297 mmol) was added under an inert gas and the mixture was refluxed for 2 h. Ethyl acetate and saturated sodium bicarbonate solution (50 ml of each) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with saturated sodium bicarbonate solution (40 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/methylene chloride/ammonia (25% aq) (300:100:50:1). Yield: quantitative
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(O)C.[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:15]=1>O>[Cl:13][C:14]1[CH:19]=[C:18]([N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)[N:17]=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:15]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: OCCN1CCNCC1
Solvent: CCO
Solvent: O
Product: OCCN1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reaction time: 8 h

Procedure:
N-hydroxyethylpiperazine (7.81 g.) diluted with 20 ml. of absolute ethanol is added to a slurry obtained by adding 6.75 g. of 4,6-dichloro-2-phenylpyrimidine to 25 ml. of absolute ethanol. The resulting mixture is refluxed for fifteen minutes, then poured into 850 ml. of water. A gummy material which separates solidifies on standing overnight. The crude product weighs 7.8 g. which is recrystallized from n-heptane to afford 4-(4-chloro-2-phenylpyrimidin-6-yl)-1-piperazineethanol, m.p. 103°-105°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:23])=[CH:6][CH:7]=1
Reactant: Cc1cccnc1-c1ccc(F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: Cc1ccc[n+]([O-])c1-c1ccc(F)cc1
Temperature: 50 °C
Yield: 85 %

Procedure:
A solution of 2-(4-fluorophenyl)-3-methylpyridine (26.8 g, 0.143 mol) and m-chloroperbenzoic acid (purity 69%, 39 g, 0.157 mol) in tetrahydrofuran (100 mL) was stirred with heating at 50° C. for 5 hr. The solvent was evaporated under reduced pressure, and the obtained residue was purified 3 times by silica gel column chromatography (NH silica gel, ethyl acetate) to give a white solid. The obtained solid was washed with ethyl acetate to give the title compound (24.7 g, 85%) as a white solid.
Reaction SMILES: C=[C:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]([C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:21][CH2:22][CH3:23])[CH2:16][CH2:15]2)[CH2:3]1.Cl.CC[O:37][CH2:38][CH3:39].[CH3:40]O>>[CH3:22][CH2:21][N:20]([CH:38]([CH3:39])[CH3:40])[CH:17]([CH3:18])[CH3:16].[CH2:27]([NH:26][C:24]([N:20]([CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH:4]2[CH:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:6][C:2](=[O:37])[CH2:3]2)[CH2:15][CH2:16]1)[CH2:21][CH2:22][CH3:23])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CO
Reactant: CCOCC
Reactant: C=C1CC(CN2CCC(N(CCC)C(=O)NCc3ccccc3)CC2)C(c2ccccc2)C1
Agent: Cl
Product: CCCN(C(=O)NCc1ccccc1)C1CCN(CC2CC(=O)CC2c2ccccc2)CC1
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1 %

Procedure:
To a solution of 1-methylene-3-(SR)-((4-(N-(benzylaminocarbonyl)-N-(prop-1-yl)amino)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane from Step D (1.8 g, 4.0 mmol) in methanol (50 mL) was added 1M hydrogen chloride in ether (6.0 mL, 6.0 mmol). The solution was cooled in a dry ice/acetone bath and ozone was bubbled into the solution until the blue color persisted. The excess ozone was removed with a stream of nitrogen and then dimethylsulfide (5 mL) was added. After 10 min, the bath was removed and the reaction was allowed to warm to rt over 16 h. The volatiles were removed in vacuo and the residue was purified by FC (ethyl acetate, then 1% DIPEA in ethyl acetate) to give the title compound (1.13 g).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[N:5]2[CH:4]=[C:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+].[CH3:27][CH2:28]I>CN(C)C=O>[CH2:27]([N:9]1[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[N:6]2[C:2](=[O:1])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][N:5]2[C:10]1=[O:11])[CH3:28]
Reactant: CCOC(=O)c1cn2c(=O)[nH]c3ccccc3n2c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(=O)n(CC)c3ccccc3n2c1=O
Reaction time: 20 h

Procedure:
5.22 g of 5,6-dihydro-1,5-dioxo-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester made as in Example 1. 2.76 K2CO3 and 50 mM CH3CH2I are dissolved in 100 ml dimethylformamide and stirred for 20 hours. The crystalline 6-ethyl-5,6-dihydro-1,5-dioxo-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester is isolated after filtration and recrystallized from dimethylformamide/ethanol. The yield is 4.7 g of white crystals having a melting point of 235°-237° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[C:30](=[O:31])[CH2:29][NH:28][C:27]4=[O:32])=[CH:22][C:21]=3[F:33])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:34][CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1.CN(C=O)C>[CH2:36]([N:28]1[CH2:29][C:30](=[O:31])[N:26]([C:23]2[CH:24]=[CH:25][C:20]([O:19][C:13]3[C:12]4[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[C:10]([O:34][CH3:35])[CH:11]=4)[N:16]=[CH:15][CH:14]=3)=[C:21]([F:33])[CH:22]=2)[C:27]1=[O:32])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(Oc3ccc(N4C(=O)CNC4=O)cc3F)ccnc2cc1OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc(N4C(=O)CN(Cc5ccccc5)C4=O)cc3F)ccnc2cc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a stirring suspension of 3-(4-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)imidazolidine-2,4-dione (Example 50, 200 mg, 0.42 mmol) and benzyl bromide (0.06 mL, 0.51 mmol) in THF (2 mL) and DMF (1 mL) was added 1 M LiHMDS in THF (0.51 mL). After 3 h at RT, the solvents were removed under reduced pressure and the residue was purified on a silica gel to afford the title compound. Calc'd Mass for C33H26FN3O5, 563, MS (M+1) 564.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:11][O:10]1.[Na].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.ClCCl.CO>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH3:13])[CH2:11][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: c1nc[nH]n1
Reactant: CC(c1ccncc1)C1(c2ccc(F)cc2F)CO1
Agent: [Na]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CC(c1ccncc1)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Treatment of the product of part (i) (1.02 g) with 1H-1,2,4-triazole sodium salt (0.71 g) in N,N-dimethylformamide (10 ml) by the method of Example 1(ii), followed by chromatography of the crude product on silica gel using dichloromethane/methanol (97:3) as eluant, first gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (0.22 g), m.p. 161°-163° (from ether).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[S:6][CH:7]=[C:8]([CH2:9][N:10]3[CH2:14][CH2:13][N:12]([C:15]4[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=4)[C:11]3=[O:24])[C:4]=2[CH:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[NH2:57][CH2:58][C:59]1[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=1>CN(C)C=O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[S:6][CH:7]=[C:8]([CH2:9][N:10]3[CH2:14][CH2:13][N:12]([C:15]4[S:16][C:17]([C:21]([NH:57][CH2:58][C:59]5[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=5)=[O:23])=[C:18]([CH3:20])[N:19]=4)[C:11]3=[O:24])[C:4]=2[CH:3]=1
Reactant: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (0.55 g, 1.35 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added 1-hydroxy benzotriazole (0.22 g, 1.62 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.31 g, 1.62 mmol), diisopropylethylamine (0.85 mL, 4.87 mmol) and 3-(aminomethyl)pyridine (0.17 mL, 1.62 mmol). The resulting solution was stirred at ambient temperature for 16 hours, then concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (15 mL) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluted with 55-75% ethyl acetate in hexanes to afford the title compound as a colorless solid in 45% yield (0.30 g): mp 185-187° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.54 (d, J=6.0 Hz, 1H), 7.87 (s, 1H), 7.78 (d, J=6.0 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.45 (s, 1H), 7.36-7.28 (m, 2H), 6.09 (br s, 1H), 4.70 (s, 2H), 4.60 (d, J=3.0 Hz, 2H), 4.06 (t, J=6.0 Hz, 2H), 3.47 (t, J=6.0 Hz, 2H), 2.61 (s, 3H); MS (ES+) m/z 498.1 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[N:6]=[C:5]([C:14]([O:16]CC)=[O:15])[C:4]1=[O:19])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[N:6]=[C:5]([C:14]([OH:16])=[O:15])[C:4]1=[O:19])[CH3:2]
Reactant: CCOC(=O)c1nc2ccc(F)cc2n(CC)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCn1c(=O)c(C(=O)O)nc2ccc(F)cc21

Procedure:
4-Ethyl-6-fluoro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (8 g) and sodium carbonate (0.25 g) in methanol (20 ml) and water (10 ml) were heated under reflux for 2 hours. The methanol was distilled off and the aqueous solution was acidified with hydrochloric acid and the solid was collected. It had m.p. 162.5°-164° (39%).
Reaction SMILES: [C:1]1([CH:7]2[C:11]3([CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[O:10][C:9](=[O:17])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1.[H-].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[Cl:18][C:19]1[N:24]=[C:23]([N:8]2[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3([CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[O:10][C:9]2=[O:17])[CH:22]=[CH:21][N:20]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C1NC(c2ccccc2)C2(CCOCC2)O1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1OC2(CCOCC2)C(c2ccccc2)N1c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a mixture of 4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one (300 mg, 1.286 mmol) and 2,4-dichloropyrimidine (192 mg, 1.286 mmol) in DMF (7 mL) under argon was added NaH (60% wt., 67.9 mg, 2.83 mmol) in two portions. The mixture was stirred for ˜1 hour. The reaction mixture was carefully poured into ice-coiled 0.25N aqueous HCl solution. DCM and aqueous NaHCO3 solution were added. The separated aqueous layer was extracted with DCM (3×) and ethyl acetate (1×). The organic layers (DCM and ethyl acetate containing layers independently) were washed with brine, dried over Na2SO4 and filtered off. The organic layers were combined and concentrated under reduced pressure providing crude 3-(2-chloropyrimidin-4-yl)-4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one (330 mg) as a yellowish liquid, which was directly used in the next reaction without further purification. LCMS m/z 346.1 (M+H)+, Rt 0.83 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[CH3:37][O:38][CH2:39][CH2:40]O>O1CCCC1>[CH3:37][O:38][CH2:39][CH2:40][O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17]
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Reactant: COCCO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Product: COCCOC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1
Reaction time: 1 h

Procedure:
A suspension of 5.0 gm (16.4 millimols) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid, m.p. 164° - 165° C, in 50 ml of dry tetrahydrofuran was admixed with 2.92 gm (18.1 millimols) of carbonyldiimidazole, whereupon the acid dissolved and carbon dioxide was given off. After one hour, 1.37 gm (18.1 millimols) of glycol monomethyl ether were added, and the mixture was allowed to stand for 2 hours. For isolation of the reaction product, the mixture was evaporated, and the residue was distributed between dilute hydrochloric acid and ethyl acetate, and the organic solution was purified by chromatography on 180 gm of silicagel with cyclohexane/ethyl acetate = 1/4. For further purification, the product mixture was recrystallized from cyclohexane/ethyl acetate = 4/1. Yield: 3.8 gm (63.8% of theory); m.p. 65°-67° C.
Reaction SMILES: C([C:4]1[C:5](=[O:20])[NH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])=[N:8][CH:9]=1)(O)=O.CCOCC.C>N1C2C(=CC=CC=2)C=CC=1.C(O)C>[CH2:17]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[NH:6][C:5](=[O:20])[CH:4]=[CH:9][N:8]=1)[CH2:18][CH3:19]
Reactant: CCCOc1ccccc1-c1ncc(C(=O)O)c(=O)[nH]1
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Solvent: CCOCC
Product: CCCOc1ccccc1-c1nccc(=O)[nH]1

Procedure:
5-Carboxy-2-(2-propoxyphenyl)pyrimidin-4(3H)-one (2.03 g, U.S. Pat. No. 4,031,093) in quinoline (10 ml) was heated under reflux under nitrogen for two hours. Ether was added to the cooled reaction mixture which was then extracted with aqueous sodium hydroxide. The basic extract was washed with ether and then acidified with concentrated hydrochloric acid to pH 7. The aqueous mixture was extracted with chloroform and the chloroform extract was washed with aqueous hydrochloric acid, dried and evaporated under reduced pressure to afford a yellow solid. This solid was dissolved in ethanol and the ethanolic solution Was treated with charcoal, filtered and reduced in volume. From this precipitated a yellow solid impurity which was removed by filtration. A small quantity of the crude title compound (0.1 g) precipitated from the filtrate, however this together with another sample of crude title compound (0.54 g) similarly prepared was combined with the filtrate and eluted from a silica column with chloroform. Combined fractions containing product were evaporated under reduced pressure to afford a solid, 270 mg, which was recrystallised from ether to afford the title compound, 170 mg, m.p. 112°-113° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]([CH3:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[N+](C1C=CC([O:27][C:28]([N:30]2[CH:34]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=3)[CH2:33][O:32][C:31]2=[O:43])=O)=CC=1)([O-])=O>C1COCC1>[CH3:17][C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:28]([N:30]2[CH:34]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=3)[CH2:33][O:32][C:31]2=[O:43])=[O:27])[CH2:10][CH2:9]1
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(c2ccccc2)CCN(CCCN)CC1
Solvent: C1CCOC1
Product: CC1(c2ccccc2)CCN(CCCNC(=O)N2C(=O)OCC2c2ccc(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of 1-(3-amino-propyl)-4-methyl-4-phenyl-piperidine (60 mg, 0.258 mmol) in 10 mL of THF, 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester (60 mg, 0.165 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by MeOH:EtOAc=1:19 (Rf=0.45, MeOH:EtOAc=1:3 to obtain 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid (3-[4-methyl-4-phenyl-piperidin-1-yl)-propyl}-amide (56 mg, 74%). The compound was dissolved in CH2Cl2 (3 mL) and was treated with 1N HCl in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a pale yellow solid. M.P. 176-178°C.; [α]D=+76.9, (c=0.23, MeOH); Anal. Calcd. For C25H30N3O3F2Cl.0.60 CH2Cl2: C, 56.32; H, 5.94; N, 7.70. Found: C, 56.30; H, 5.80; N, 7.35.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH2:8]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH:31]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=3)[CH2:30][N:29]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:28][CH:27]2[CH2:51]OS(C)(=O)=O)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[CH2:8]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[CH:27]([CH2:51][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[CH2:28][N:29]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:30][CH:31]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:24][CH:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Cn2cncn2)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A solution of 22 mg (0.32 mmol) of 1,2,4-triazole in 5 ml of DMF was cooled to 0° C. and treated with 15 mg (0.29 mmol) of sodium hydride (50% dispersion in refined oil). Subsequently, the mixture was left to warm to room temperature and was stirred for a further 1 hour. 70 mg (0.105 mmol) of tert-butyl (3SR,4RS,5RS)-4-[4-(3 -benzyloxy-propoxy)-phenyl]-3-methanesulphonyloxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate were added to this solution. The reaction mixture was heated to 100° C. for 24 hours. For the working-up, the reaction mixture was evaporated under reduced pressure, the residue was partitioned between water and methylene chloride and the organic phase was separated, dried over sodium sulphate and evaporated. For purification, the crude product (70 mg) was chromatographed on silica gel using a 98:2 mixture of methylene-chloride and methanol as the eluent. There were obtained 52 mg (77% of theory) of tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-5-[1,2,4]triazol-1-ylmethyl-piperidine-1-carboxylate as a colourless solid; MS: 663 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:15]([C:14]2[CH:18]=[CH:19][C:11]([F:10])=[CH:12][CH:13]=2)=[O:16])=[C:5]([OH:9])[CH:4]=1)[CH3:2]
Reactant: CCc1cccc(O)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCc1ccc(C(=O)c2ccc(F)cc2)c(O)c1
Yield: 5.3 %

Procedure:
3-Ethylphenol (24.4g) and 4-fluorobenzoyl chloride (34.9g) were reacted together as in Example 11 giving three main fractions: B (11.4g) 126°-129°C at 0.07 mmHg; C (7.9g), 129°-132°C at 0.06 mmHg; D (5.9g), 132°-150°C at 0.06 mmHg, all containing ~80% of the required isomer. B (4.0g) was separated by preparative thin layer chromatography to give the title compound (2.6g), m.p. 44°-48°C.