Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[C@:12]1([CH2:23][F:24])[CH2:17][C@@H:16]([C:18]([F:21])([F:20])[F:19])[O:15][C:14]([NH2:22])=[N:13]1.N#N.C(O)(=O)C>CCO.[Pd]>[NH2:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([F:1])=[C:3]([C@:12]2([CH2:23][F:24])[CH2:17][C@@H:16]([C:18]([F:21])([F:19])[F:20])[O:15][C:14]([NH2:22])=[N:13]2)[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])cc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Agent: [Pd]
Agent: N#N
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(N)cc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Yield: 96.1 %

Procedure:
A solution of (4S,6S)-4-(2-fluoro-3-methyl-5-nitrophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.26 g, 3.57 mmol) in EtOH (15 mL) was purged with N2 followed by the addition of acetic acid, glacial (0.412 ml, 7.13 mmol) and palladium, 10% wt. on activated carbon (0.047 ml, 5.35 mmol). The resulting mixture was purged with N2 again and H2 was bubbled through a balloon for 1 h. The mixture was filtered through celite, concentrated, diluted washed with 10% Na2CO3, 1 N NaOH, extracted with DCM and chromatographed on silica gel using 0-5% MeOH/DCM to afford a white solid as (4S,6S)-4-(5-amino-2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.11 g, 3.43 mmol, 96% yield). MS m/z=323.9 [M+H]+. Calculated for C13H14F5N3O: 323.11.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:33])[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])[CH2:2][CH2:3][CH3:4]>C1COCC1>[CH2:1]([NH:5][C:6](=[O:33])[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C(=O)NCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CCCCNC(=O)C(=O)NCCCCCO
Yield: 93 %

Procedure:
A mixture of N1-n-butyl-N2-(5-(tert-butyldiphenylsilyloxy)pentyl)oxalamide (65 mg, 0.14 mmol) and n-tetrabutylammonium fluoride (0.41 mL, 1M soln, 0.42 mmol) in dry THF solution was stirred at room temperature under an argon atmosphere for 12 h. All volatiles were evaporated in vacuo, the residue was dissolved in EtOAc (30 mL) and the organic layer was washed with water (10 mL), brine (15 mL), dried and evaporated. Purification of the residue via SiO2 column chromatography using EtOAc/hexanes (1:2) as eluent gave the title compound (30 mg, 92%) as a colorless solid, mp 136-137° C. TLC: 50% EtOAc/hexane, Rf˜0.28; 1H NMR (300 MHz) δ 7.65 (br s, NH, 1H), 7.60 (br s, —NH, 1H), 3.65 (t, J=6.0 Hz, 2H), 3.35-3.25 (m, 4H), 1.90 (br s —OH, 1H), 1.60-1.50 (m, 6H), 1.40-1.35 (m, 4H), 0.92 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz) δ 160.25, 160.10, 62.70, 39.80, 39.65, 32.40, 31.45, 29.20, 23.25, 20.20, 13.85. HRMS calcd for C11H23N2O3 [M+1]+ 231.1709. found 231.1701.
Reaction SMILES: C1COCC1.[CH3:6][N:7]1[NH:11][N:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][C:18]([C:22]([O:24]C)=[O:23])=[CH:17][C:16]=3[CH:26]=2)[NH:8]1.[OH-].[Na+].Cl>CO>[CH3:6][N:7]1[NH:11][N:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][C:16]=3[CH:26]=2)[NH:8]1
Reactant: COC(=O)C1=Cc2cc(C3=NNN(C)N3)ccc2OCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1NN=C(c2ccc3c(c2)C=C(C(=O)O)CCO3)N1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95.6 %

Procedure:
In methanol (7 ml) and THF (7 ml) was suspended methyl 7-(2-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylate (324 mg, 1.13 mmol), and to the mixture was added 1N sodium hydroxide solution (3.4 ml). The mixture was stirred at 50° C. for 4 hours, and to the mixture was added, under ice-cooling, 1N hydrochloric acid (3.4 ml). The mixture was concentrated under reduced pressure, and to the residue was added water. Insoluble materials were filtered, which were washed with water and dried under reduced pressure to give 7-(2-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (295 mg, 1.08 mmol, 96%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15]>N1CCCCC1.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.[Cu]I>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:15]#[C:14][CH2:13][CH2:12][OH:16])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C#CCCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: OCCC#Cc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
The synthesis was performed following a procedure of Stara, Irena G.; Stary, Ivo; Kollarovic, Adrian; Teply, Filip; Saman, David; Fiedler, Pavel, Coupling reactions of halobenzenes with alkynes. The synthesis of phenylacetylenes and symmetrical or unsymmetrical 1,2-diphenylacetylenes, Collect. Czech. Chem. Commun. (1999), 64(4), 649-672. To a degassed (argon) solution of 5.0 g (17.83 mmol) 1-iodo-4-trifluoromethyl-benzene in 65 ml piperidine was added 1.03 g (0.89 mmol) Pd(PPh3)4 and 0.17 g (0.89 mmol) CuI. The reaction mixture was stirred at 50° C. for 10 min, then 2.03 ml (26.75 mmol) of but-3-yn-1-ol were added dropwise within 1 h. During the addition of but-3-yn-1-ol the oil bath was slowly heated to 80° C. starting after 30 min. The reaction mixture was stirred at this temperature for 3 h and then extracted with chilled aqueous 10% KHSO4/Et2O (three times). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification by flash-chromatography on silica gel (n-heptane/EtOAc 9:1 to 4:1) yielded 3.58 g of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([N:19]=[C:20]=[S:21])=[O:18])=[CH:15][CH:14]=1>CCOCC>[NH2:6][C:4]([C:3]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[S:21])[NH:19][C:17](=[O:18])[C:16]1[CH:22]=[CH:23][C:13]([CH3:12])=[CH:14][CH:15]=1)=[O:5]
Reactant: Cc1ccc(N)c(C(N)=O)c1
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Solvent: CCOCC
Product: Cc1ccc(C(=O)NC(=S)Nc2ccc(C)cc2C(N)=O)cc1
Yield: 91.7 %

Procedure:
To a stirred mixture of 3 g of 2-amino-5-methylbenzamide and 200 ml of ether was added dropwise, a solution of 3.7 g of 4-methylbenzoyl isothiocyanate in 100 ml of ether over 30 minutes. After 24 hours the solid was collected, giving 6 g of N-[[[2-(aminocarbonyl)-4-methylphenyl]amino]thioxomethyl]-4-methylbenzamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])=[C:4]([F:13])[CH:3]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:13])[C:9]([NH:11][CH3:12])=[O:10]
Reactant: CNC(=O)Cc1ccc(Br)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CNC(=O)C(Br)c1ccc(Br)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)-N-methylacetamide (2.479 mmol) in carbon tetrachloride (5 mL) was degassed with a stream of nitrogen for five minutes, at which point the solution was treated with N-bromosuccinimide (2.73 mmol) and azobisisobutyronitrile (0.248 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture stirred at 80° C. overnight. After stirring overnight, the reaction was cooled to room temperature. The reaction mixture was degassed again with a stream of nitrogen for three minutes and was treated with N-bromosuccinimide (0.56 mmol) and azobisisobutyronitrile (0.124 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture stirred at 80° C. for two days. The reaction was then allowed to cool and was concentrated to dryness in vacuo. Purification of the residue by silica gel chromatography (0-50% ethyl acetate/hexanes) afforded the title compound as a white solid (296 mg, 33% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 2.65 (d, J=4.55 Hz, 3 H) 5.81 (s, 1 H) 7.49 (dd, J=8.59, 1.77 Hz, 1 H) 7.61 (dd, J=9.98, 1.89 Hz, 1 H) 7.72 (t, J=8.21 Hz, 1 H) 8.49 (br. s., 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>C(O)C.O1CCCC1.[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [H][H]
Reactant: O=C(O)/C=C/C(=O)c1ccc(F)c(Br)c1
Agent: [Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1ccc(F)c(Br)c1

Procedure:
A solution of 6.2 g (0.023 mol) of (E)-4-(3-bromo-4-fluorophenyl)-4-oxo-2-butenoic acid in a mixture of 200 ml ethanol and 25 ml tetrahydrofuran was hydrogenated in the presence of 1.0 g of 10% platinum/charcoal at ambient temperature under a pressure of 50 psi until the uptake of hydrogen was complete. The residue remaining after the catalyst and solvent had been eliminated crystallised spontaneously and after being washed thoroughly with diisopropylether yielded 1.7 g (27% of theoretical) of colourless crystals, m.p. 108–110° C. and Rf 0.73 (El F).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]([C:11]([F:14])([F:13])[F:12])=[CH2:10])[C:3]=1[F:15].CO[CH2:18][N:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:20][Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:25]([N:19]1[CH2:20][CH2:10][C:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=2[F:15])([C:11]([F:14])([F:13])[F:12])[CH2:18]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1F)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1c(Cl)cc(Cl)cc1C1(C(F)(F)F)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
1,5-Dichloro-2-fluoro-3-(3,3,3-trifluoroprop-1-en-2-yl)benzene (6.2 g) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (4.7 g) were dissolved in dichloromethane (100 ml) and slowly added dropwise with a dichloromethane solution (8 ml) of anhydrous trifluoroacetic acid (0.15 ml) under ice cooling. Upon the completion of the dropwise addition, the reaction temperature was raised to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 1-benzyl-3-(3,5-dichloro-2-fluorophenyl)-3-(trifluoromethyl)pyrrolidine (3.7 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH3:10])[C:4](=[O:18])[CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH3:8][C:6]1[N:5]([CH:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH3:10])[C:4](=[O:18])[CH:3]=[C:2]([O:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(C(C)n2c(C)cc(O)cc2=O)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2cc(C)n(C(C)c3ccc(C)nc3)c(=O)c2)cc1
Reaction time: 18 h
Yield: 78.5 %

Procedure:
A stirred mixture of the product from Step 1 (475 mg, 1.947 mmol) and 4-methylbenzenesulfonyl chloride (371 mg, 1.947 mmol) in anhydrous dichloromethane (16 ml) was treated with anhydrous triethylamine (0.81 ml, 5.839 ml) and stirring was continued at ambient temperature for 18 h. The reaction mixture was diluted with dichloromethane (150 ml), washed with water (100 ml) followed by brine (100 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash silica chromatography eluting with ethyl acetate to give toluene-4-sulfonic acid 6-methyl-1-[1-(6-methyl-pyridin-3-yl)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl ester (609 mg) as a colourless gum which solidified on standing. LC-MS m/z 399 [M+H]+ Rt=2.10 min.
Reaction SMILES: [CH3:1][Mg+].[Br-].[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][N:14]=[C:13]([CH:16]=[O:17])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1>C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][N:14]=[C:13]([CH:16]([OH:17])[CH3:1])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=Cc1cc(-c2cccc(Cl)c2)on1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1cc(-c2cccc(Cl)c2)on1
Reaction time: 3 h
Yield: 124.2 %

Procedure:
MeMgBr (3M in THF, 313 mL, 937.2 mmol) was added dropwise at 0° C. to 5-(3-chlorophenyl)isoxazole-3-carbaldehyde (177 g, 252 mmol) in THF (3 L). The mixture was allowed to attain room temperature, stirred at that temperature for 3 h and then quenched with aq. NH4Cl at 0° C. and the solvent was distilled off. To the remaining was added EtOAc and filtered through a plug of celite. The organic layer was washed with water, saturated brine and concentrated. The crude product was purified by flash column chromatography on silica using heptane/EtOAc=80:20, to give the title compound (70 g, 37%) as a white-yellow solid. 1H NMR: 7.73 (m, 1H), 7.63 (m, 1H), 7.38 (m, 2H), 6.57 (s, 1H), 5.07 (q, 1H), 2.44 (s, 1H), 1.59 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O[CH2:16][CH:17]([NH:21]C(=O)OC(C)(C)C)[CH:18]([CH3:20])[CH3:19]>>[NH2:21][CH:17]([CH:18]([CH3:20])[CH3:19])[CH2:16][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1
Reactant: N#Cc1ccc(-c2cc[nH]n2)cc1Cl
Reactant: CC(C)C(CO)NC(=O)OC(C)(C)C
Product: CC(C)C(N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Yield: 22 %

Procedure:
The title compound was prepared using the method of Example 34(c) starting from 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile (0.2 g; 0.98 mmol) and tert-butyl 1-hydroxy-3-methylbutan-2-ylcarbamate (0.22 g; m 1.09 mmol). Yield 22%. 1H-NMR (400 MHz; CDCl3): δ 1.02 (m, 6H), 1.71 (m, 1H), 3.14 (m, 1H), 3.95 (m, 1H), 4.27 (m, 1H), 6.61 (d, 1H), 7.51 (d, 1H), 7.66 (d, 1H), 7.77 (dd, 1H), 7.97 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:19][NH:20][CH3:21].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([N:20]([CH3:21])[CH3:19])=[O:6]
Reactant: CNC
Reactant: COc1cc(NC(=O)C(C)(C)C)ccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NC(=O)C(C)(C)C)ccc1C(=O)N(C)C
Reaction time: 1 h

Procedure:
2-Methoxy-4-(2',2'-dimethylpropionamido)-benzoyl chloride (1.12 g) in dry THF (10 ml) was added dropwise over 30 minutes to a stirred solution of dimethylamine (1.17 g of a 40% aqueous solution) in THF (15 ml) at 0°-5° C. After completion of the addition the solution was stirred for 1 hour at 5°-10° C., stood at room temperature overnight, poured into water, and extracted with ethyl acetate. The extract was dried and evaporated to give the product as a yellow solid (0.889 g), m.p. 143°-144° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CC(O)C>[ClH:40].[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccnc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cc(C)ccn2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (333 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-ethanol to give the title compound as a white solid (yield 191 mg, 66%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[N:15]3)=[C:10]([O:18][CH2:19][C@@H:20]3[O:24][C:23](=[O:25])[NH:22][CH2:21]3)[CH:9]=2)=[CH:4][C:3]=1[O:26][CH3:27].I[CH:29]([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[N:15]3)=[C:10]([O:18][CH2:19][C@@H:20]3[O:24][C:23](=[O:25])[NH:22][CH2:21]3)[CH:9]=2)=[CH:4][C:3]=1[O:26][CH3:27])([CH3:31])[CH3:30]
Reactant: CC(C)I
Reactant: COc1cc(-c2cc(OC[C@H]3CNC(=O)O3)c3cccnc3c2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(OC[C@H]3CNC(=O)O3)c3cccnc3c2)ccc1OC(C)C
Temperature: 50 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
A mixture of 59 mg (R)-5-[7-(4-hydroxy-3-methoxy-phenyl)-quinolin-5-yloxymethyl]-oxazolidin-2-one (Example 13), 19.3 μl 2-iodopropane and 44 mg potassium carbonate in DMF (10 ml) was stirred at 50° C. for 16 hours. The mixture was poured into EtOAc and washed with water then brine and dried over Na2SO4. Purification by FCC over SiO2, eluting with EtOAc-MeOH from 100:0 to 95:5 yielded 56 mg (85%) of (R)-5-[7-(4-Isopropoxy-3-methoxy-phenyl)-quinolin-5-yloxymethyl]-oxazolidin-2-one (Example 16) as an oily residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])=[CH:23][NH:22][C:21]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11](=[CH:34][C:21]2[NH:22][CH:23]=[C:24]([C:25]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[O:26])[C:20]=2[CH3:19])[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]cc(C(=O)N4CCN(C)CC4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.7 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(3-methoxy-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (46.4 mg, 41%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][C:13]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].Cl>ClC1C=CC=CC=1Cl.C1(C)C=CC=CC=1>[CH3:22][C:20]1[CH:19]=[CH:18][C:14]([C:15](=[O:16])[C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=2)=[C:13]([CH3:12])[CH:21]=1
Reactant: Fc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(C(=O)c2ccc(F)cc2)c(C)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a suspension of anhydrous aluminum chloride (16.2 g) dispersed in 1,2-dichlorobenzene (150 ml) was added fluorobenzene (13 g), and thereto was added dropwise 2,4-dimethylbenzoyl chloride (17.0 g) at 0–20° C. The mixture was stirred at 10–30° C. for 1 hr and heated to 80° C. The mixture was stirred for 1 hr, cooled again and poured into 6N hydrochloric acid. The reaction mixture was diluted with a great excess toluene and partitioned. The obtained organic layer was washed successively with 5% aqueous sodium hydroxide solution and water, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane-ethyl acetate as eluent to give nearly pure 1,3-dimethyl-4-(4′-fluorobenzoyl)benzene (19.4 g, 85%) as pale-yellow oil. The spectrum data of this oil were the same as those confirmed in Example 7.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Reactant: Oc1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(Oc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, phenol and DBU in DME. EI-MS m/e (%): 288 (M+, 100), 287 ([M—H]+, 60).
Reaction SMILES: [N:1]1([C:6]([CH3:11])([CH3:10])[CH2:7][CH2:8][OH:9])[CH:5]=[CH:4][N:3]=[CH:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]([C@H:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([C:52](=[O:60])[C:53]3[CH:58]=[CH:57][C:56](O)=[CH:55][CH:54]=3)[C@@H:44]([CH3:61])[CH2:43]2)[C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=1.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([N:38]([C@H:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([C:52](=[O:60])[C:53]3[CH:58]=[CH:57][C:56]([O:9][CH2:8][CH2:7][C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)([CH3:11])[CH3:10])=[CH:55][CH:54]=3)[C@@H:44]([CH3:61])[CH2:43]2)[C:39](=[O:41])[CH3:40])=[CH:36][CH:37]=1
Reactant: CC(C)(CCO)n1ccnc1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)n3ccnc3)cc2)c2ccccc21
Reaction time: 0.08 h
Yield: 46 %

Procedure:
3-Imidazol-1-yl-3-methyl-butan-1-ol was dissolved in benzene at room temperature with PPh3 (0.088 g, 0.33 mmol) added (2S,4R)-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.133 g, 0.30 mmol) and stirred for 5 min. DEAD (0.058 g, 0.33 mmol) was added and the reaction was stirred for 18 h at room temperature. The reaction was concentrated and purified by silica gel chromatography (4% MeOH/96% CH2Cl2 to 5% MeOH/95% CH2Cl2 to 6% MeOH/94% CH2Cl2) to afford the product in 46% yield
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2=[N:7][N:8]([CH2:10][C:11](O)=O)[N:9]=[C:5]2[CH:4]=1.C([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=O.N1CCCCC1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2=[N:7][N:8]([CH:10]=[CH:11][C:27]3[CH:28]=[CH:29][C:24]([C:21]4[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=4)=[CH:25][CH:26]=3)[N:9]=[C:5]2[CH:4]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: COc1ccc2nn(CC(=O)O)nc2c1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COc1ccc2nn(C=Cc3ccc(-c4ccccc4)cc3)nc2c1
Yield: 60.3 %

Procedure:
21 g of 5-methoxybenzotriazole-2-acetic acid, 20 g of 4-formyl-biphenyl and 5 ml of piperidine are melted at 165° to 175° C for 10 hours. 50 ml of dimethylformamide are then added and the product is allowed to crystallise. 20 g of 5-methoxy-2-[(p-phenyl)-styryl]-benzotriazole are obtained and after recrystallisation from methylglycol this melts at 176° C.