Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[H][H].[C:11]1([CH2:17][CH2:18][CH:19]=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CS(C)=O.O.C(OCC)(=O)C>[O:20]1[CH:19]([CH2:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:2]1
Reactant: [H][H]
Reactant: O=CCCc1ccccc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CCC2CO2)cc1

Procedure:
A solution of trimethyloxosulphonium iodide (2.64 g.) in dry dimethylsulphoxide (50 ml.) is stirred at 50°-60° C. in an atmosphere of nitrogen and an 80% w/w mineral oil dispersion of sodium hydride (0.36 g.) is added. Stirring and heating are continued until the solution is clear and no more hydrogen is evolved. A solution of 3-phenylpropionaldehyde (1.34 g.) in dry dimethyl sulphoxide (10 ml.) is added and the mixture is stirred at 50°-60° C. in an atmosphere of nitrogen for 3 hours. The mixture is cooled and diluted with water (200 ml.), and the product is obtained by extraction with ethyl acetate (3 × 80 ml.). Removal of the solvent from the combined extracts gives 1,2-epoxy-4-phenylbutane as an oil which is not further purified.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CC[C:13]([O-:15])=O.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[C:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15]
Reactant: C1CNCCN1
Reactant: c1ccc2c(c1)OCCO2
Reactant: CCC(=O)[O-]
Product: O=C(C1COc2ccccc2O1)N1CCNCC1
Temperature: 110 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
1,4-benzodioxan-2-ethylcarboxylate, (31.2 g, 150 -mmol) and piperazine (15.5 g, 180 mmol) were stirred under nitrogen and heated to 110° C. After 5 hours, the reaction was completed, which was confirmed by thin film chromatography. The crude product was cooled to room temperature, extracted with chloroform, washed with NaHCO3 solution and water. The organic layer was dried with anhydrous sodium sulfate, filtered to afford 34.96 g of compound 1 (94% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>>[CH2:16]([O:15][C:13](=[O:14])[C:12](=[CH:11][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:17]
Reactant: Nc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccccc1)C(=O)OCC
Temperature: 145 °C

Procedure:
A mixture of aniline (25.6 g, 0.28 mol) and diethyl 2-(ethoxymethylene)malonate (62.4 g, 0.29 mol) was heated at 140-150° C. for 2 h. The mixture was cooled to room temperature and dried under reduced pressure to afford 2-phenylaminomethylene-malonic acid diethyl ester as a solid, which was used in the next step without further purification. 1H NMR (d-DMSO) δ 11.00 (d, 1H), 8.54 (d,J=13.6 Hz, 1H), 7.36-7.39 (m, 2H), 7.13-7.17 (m, 3 H), 4.17-4.33 (m, 4H), 1.18-1.40 (m, 6H).
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11]([CH2:14][C@H:15]([NH:19][CH:20]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:21]([F:24])([F:23])[F:22])[C:16]([OH:18])=O)(=[O:13])=[O:12].Cl.[NH2:34][C:35]1([C:38]#[N:39])[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:38]([C:35]1([NH:34][C:16](=[O:18])[C@@H:15]([NH:19][C@@H:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:21]([F:23])([F:22])[F:24])[CH2:14][S:11]([CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH:2]([F:1])[F:32])(=[O:13])=[O:12])[CH2:37][CH2:36]1)#[N:39]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)[C@H](CS(=O)(=O)Cc1ccccc1OC(F)F)NC(c1ccc(F)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@H](CS(=O)(=O)Cc2ccccc2OC(F)F)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CC1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 3-(2-difluoromethoxyphenylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethylamino]propionic acid (157 mg, 0.325 mmol) in DMF (5 mL) was added 1-aminocyclopropanecarbonitrile hydrochloride (46.4 mg, 0.39 mmol), HATU (186.3 mg, 0.49 mmol) and DIPEA (63.2 mg, 0.49 mmol). After 1 h, the reaction mixture was extracted with ethyl acetate (100 mL) and washed with satured NaHCO3 and brine. After driying with MgSO4, the solvent was removed and the residue was purified by column chromatograph yield the title compound (125 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CN(C)CCN(C)C.[C:27]1([CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Li].C([Li])(C)(C)C.BrC1C=CC=CC=1C>C1COCC1.CCCCC.C(OCC)C>[CH3:7][NH:6][C:4]([C:3]1[C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:34])=[CH:11][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1)=[O:5]
Reactant: [Li]c1ccccc1C
Reactant: CNC(=O)c1ccc(N2CCN(C)CC2)cc1Cl
Agent: CN(C)CCN(C)C
Agent: Cc1ccccc1Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCC
Product: CNC(=O)c1ccc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: -25 °C
Yield: 36 %

Procedure:
To a solution of 125 mg (0.467 mmol)2-chloro-N-methyl-4-(4-methyl-piperazin-1-yl)-benzamide and 0.22 ml (1.5 mmol) N,N,N′,N′-tetramethylethylenediamine in 2 ml THF a solution of o-tolyllithium, prepared by addition of 2.5 ml (3.8 mmol) of a 1.5 M solution of tert.-butyllithium in pentane to a solution of 0.23 ml (1.9 mmol)2-bromotoluene in 2 ml diethyl ether at −78°, was added dropwise at −78°. The reaction mixture was allowed to warm to −25° C. over a period of 2 h. After quenching with 1 ml water at −25° the mixture was warmed to room temperature followed by dilution with 10 ethyl acetate and washing with 10 ml 1 N NaOH solution. The layers were separated and the aqueous layer was extracted with 2 10ml portion of ethyl acetate. The combined organic layers were dried (Na2SO4) and evaporated. Chromatography, (SiO2, CH2Cl2/methanol 19:1) afforded 55 mg (36%) 2′-Methyl-5-(4methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid methylamide as a colorless oil MS (EI): 324(M+).
Reaction SMILES: C(O[C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13](C)=[C:14]2NC(=O)C)[CH2:6]1)(=O)C.[H][H].[Pd:31].[CH2:32]([OH:34])[CH3:33]>[Pd]>[Pd:31].[CH2:32]([OH:34])[CH2:33][C@@H:14]1[C@:15]2([CH3:16])[C@H:11]([C@H:10]3[C@H:19]([CH2:18][CH2:17]2)[C@:20]2([CH3:23])[CH:7]([CH2:6][CH2:5][CH2:22][CH2:21]2)[CH2:8][CH2:9]3)[CH2:12][CH2:13]1
Reactant: CCO
Reactant: CC(=O)NC1=C(C)C[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: [H][H]
Agent: [Pd]
Product: C[C@]12CC[C@H]3[C@@H](CCC4CCCC[C@@]43C)[C@@H]1CC[C@@H]2CCO

Procedure:
Using the procedure of Hershberg, et al JACS 73, 5073 (1951), 4 can be prepared. More specifically, selective hydrogenation of 17αethinyl-5-androsten-17β-ol (1) in pyridine with 5% palladium on Calcium Carbonate affords the vinyl carbinol (2) in high yield. Reduction of 2 in ethanol with 5% palladium on carbon gives the ethyl carbinol 3 without reducing the 5, 6-double bond. Alternatively, 3 can be prepared directly from 1 using H2 /Pd/C. Exhaustive Catalytic hydrogenation of 3 in ethanol with 5% Pd on C gives the fully saturated pregnanol, 4
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:14][CH3:15])[C:5]2[CH:6]=[CH:7][O:8][C:4]=2[C:3]=1[O:16][CH3:17].O.[OH-].[Na+].[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:14][CH3:15])[C:5]2[CH2:6][CH2:7][O:8][C:4]=2[C:3]=1[O:16][CH3:17]
Reactant: COc1c(C(=O)O)c(O)c(OC)c2occc12
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1c(O)c(C(=O)O)c(OC)c2c1OCC2
Yield: 73.4 %

Procedure:
5 g of 6-hydroxy-4,7-dimethoxybenzofuran-5-carboxylic acid in 75 ml of ethanol/25 ml of H2O/0.8 g of NaOH are hydrogenated in the presence of 1 g of Pd/C (10%) under atmospheric pressure and at 50° C. until uptake of hydrogen is complete. The mixture is filtered, the ethanol is removed by distillation, the aqueous phase is acidified, and the solid is filtered off with suction. 3.7 g of product are obtained and reacted further without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@H:8]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](O)[C:13]=1[N+:19]([O-:21])=[O:20])[CH2:9][CH3:10].CCN(C(C)C)C(C)C.Cl.P(Cl)(Cl)([Cl:34])=O.[Cl-].[Na+]>C1(C)C=CC=CC=1>[Cl:34][C:14]1[C:13]([N+:19]([O-:21])=[O:20])=[C:12]([NH:11][C@@H:8]([CH2:7][C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[CH2:9][CH3:10])[CH:17]=[CH:16][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC[C@H](Cc1sccc1Cl)Nc1ccnc(O)c1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC[C@H](Cc1sccc1Cl)Nc1ccnc(Cl)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
A toluene solution of (R)-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-2-hydroxy-3-nitro-4-pyridinamine (Compound IV) (0.1 mole in 100 mL of toluene) containing 2 equivalents of DIPEA hydrochloride is heated to 60° C. and 20.6 grams of phosphorus oxychloride is added over 10 minutes with stirring. The reaction is stirred at 60° C. until complete (3 hours). After cooling to 0° C., 245 grams of 2N sodium chloride is added at such a rate so as to maintain the reaction temperature below 10° C. The biphasic mixture is stirred 1-2 hours at 0° C. before it is allowed to warm to room temperature overnight. The bottom aqueous layer is separated from the organic layer. The organic layer is concentrated in vacuo and the residue purified by flash chromatography eluting with 25.75 ethyl acetate:heptane to give Compound V. MS (EI) m/z 345 (10%). 1HNMR (500 Mhz, CDCl3 /CD3OD)δ1.0 (2H, t); 1.5-1.8 (2H, m); 2.9-3.2 (2H, m); 3.8 (1H, m); 6.5 (1H, bd); 6.6 (1H, d); 7.15 (1H, d); 7.9 (1H, d).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:34])[CH:6]([OH:33])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]=3[C:29]([F:32])([F:31])[F:30])[O:15][N:14]=2)=[CH:9][CH:8]=1.[C:35](O)(=[O:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:35]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:34])[CH:6]([OH:33])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]=3[C:29]([F:32])([F:31])[F:30])[O:15][N:14]=2)=[CH:9][CH:8]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)O
Reactant: NCCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)NCCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
(R/S)-N-(2-Aminoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (Example 52, 30 mg, 0.063 mmol), acetic acid (7.61 mg, 0.127 mmol), HATU (36.1 mg, 0.095 mmol), and 4-methylmorpholine (32.0 mg, 0.317 mmol) were added to DMF (1 mL). This was stirred for 30 min and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, 20 mL/min, 220 nM, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 15 min (The product retention time was 18.4 min.) to yield (R/S)-N-(2-acetamidoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (10 mg, 0.019 mmol, 29.8% yield): LCMS=516.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2 H, d, J=8.35 Hz), 7.54-7.73 (7 H, m), 5.12(1 H, s), 3.34-3.39(2 H, m), 3.24-3.29(2 H, m), 1.89(3 H, s); HPLC peak RT=7.4 min (Method A).
Reaction SMILES: [C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([F:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[Br:28]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:28][C:9]1[C:8]2[CH2:23][CH2:24][CH2:25][CH2:26][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6](=[O:27])[C:7]=2[N:11]2[CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([F:20])=[CH:18][C:19]=3[C:10]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c(cc1F)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1F)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of 250 mg 27a in 7 mL dimethylformamide was added 120 mg N-bromosuccinimide. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with 2×ethyl acetate. The combined organic phases were washed with water and brine, dried and concentrated. The crude product was triturated with heptane/diisopropyl ethyl ether (1:1) to afford 230 mg of 27b as a white solid.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(Cl)([Cl:28])=O>C1C=CC=CC=1>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([Cl:28])=[O:25])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1

Procedure:
A solution of 10.0 g. p-tetradecyloxyphenylacetic acid in 100 ml. absolute benzene is treated with 19.9 g thionylchloride and refluxed for 2.5 hours. The reaction mixture is then evaporated under vacuum (i.v.) and azeotroped several times with benzene to remove residual thionylchloride, to obtain crude p-tetradecyloxyphenylacetylchloride, which may be used in Step E, below, without further refining.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[CH:18]=[C:19]([NH2:23])[CH:20]=[N:21][CH:22]=4)[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[S:32]([NH:23][C:19]1[CH:20]=[N:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[C:7]3[C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:18]=1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: Nc1cncc(-c2ccc3nccc(-c4ccncc4)c3c2)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(-c2ccc3nccc(-c4ccncc4)c3c2)c1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution of 5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinamine (82 mg, 0.27 mmol) in anhydrous pyridine (2.0 ml) was treated with neat 2,4-difluorobenzenesulfonyl chloride in one portion. The reaction was stirred at room temperature for 30 minutes then was purified directly by prep-HPLC. The combined, desired fractions were evaporated under reduced pressure to remove organic solvents then diluted with small portions of brine and saturated aqueous sodium bicarbonate. The basic solution was extracted with ethyl acetate then the extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting colorless film was crystallized from methylene chloride and diethyl ether. The solids were collected by filtration, rinsed with diethyl ether then vacuum dried to afford the title compound (219 mg, 48%) as a white solid. MS (ES)+ m/e 475 [M+H]+.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.[Br:16][C:17]1[CH:18]=[C:19]([F:24])[C:20](F)=[N:21][CH:22]=1.Cl>CS(C)=O.O>[Br:16][C:17]1[CH:18]=[C:19]([F:24])[C:20]([O:3][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)=[N:21][CH:22]=1
Reactant: Fc1cc(Br)cnc1F
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(Oc1ccc(Oc2ncc(Br)cc2F)cc1)C(=O)O
Reaction time: 0.33 h

Procedure:
A solution of NaOH (0.54 g, 0.013 mol) in a few ml of water was added to 2-(4-hydroxyphenoxy)propionic acid (1.22 g, 0.0067 mol) in 20 ml DMSO and the mixture was stirred for 20 minutes under N2. 5-Bromo-2,3-difluoropyridine (1.3 g, 0.0067 mol) was added and the mixture was stirred for 51/2 hours at 80°-90° C. The reaction mixture was poured into water, acidified with concentrated HCl to pH 1 and extracted into CH2Cl2. The solution was dried over Na2SO4 and the solvent was removed by rotary evaporation to yield a gum which became an off-white solid (0.78 g, 33%, m.p. 94°-97° C.) upon standing.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[N:12]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[CH:18]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: Nc1cccc(-n2ccnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)cnc1Nc1cccc(-n2ccnc2)c1
Temperature: 110 °C
Yield: 19.1 %

Procedure:
A mixture of 5-bromo-2-chloro-3-nitropyridine (4.1 g, 17 mmol), 3-(imidazol-1-yl)phenylamine (2.5 g, 16 mmol) and potassium carbonate (1.3 g, 9.4 mmol) in N,N-dimethylformamide (15 ml) was heated at 110° C. for 2 hours. The reaction was cooled to ambient temperature, diluted with ethyl acetate (100 ml) and methanol (100 ml) then pre-adsorbed on to silica. Purification by silica gel chromatography eluting with dichloromethane/methanol/0.880 NH3 (97:2.7:0.3) gave N-(5-bromo-3-nitropyridin-2-yl)-N-[3-(imidazol-1-yl)phenyl]amine as a red solid (1.1 g, 19%).
Reaction SMILES: C(O)(=O)C=C.[C:6]([OH:11])(=[O:10])[C:7]([CH3:9])=[CH2:8].[CH3:12][C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19](O)=[CH:20][CH:21]=1)=[O:14]>C(Cl)(=O)C(C)=C>[C:6]([O:11][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[CH3:12])=[CH:21][CH:20]=1)(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: C=C(C)C(=O)O
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: C=C(C)C(=O)Cl
Agent: C=CC(=O)O
Product: C=C(C)C(=O)Oc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In order to obtain the polymeric drug of the present invention, it is firstly required to obtain a monomer of acrylic acid or methacrylic acid derivatives by reacting a low molecular physiological active substance with acrylic acid or methacrylic acid. The above-mentioned monomer may be obtained in the manner as stated below, in case of using acetaminophen, for example. That is, acetaminophen is dissolved in an acetonitrile anhydride, and methacryloyl chloride is added drop by drop to the solution. The resulting reaction solution is stirred for 30 minutes at a room temperature, followed by the removal of a reaction solvent by distillation. The residue is dissolved in chloroform, and dried, followed by recrystallization from benzene to obtain p-methacryloyloxyacetanilide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:23])[C:20]([CH3:22])([CH3:21])[O:19][BH:18][O:17]1.C(N(CC)CC)C.O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:5]1[CH:6]=[CH:7][C:2]([B:18]2[O:19][C:20]([CH3:22])([CH3:21])[C:16]([CH3:23])([CH3:15])[O:17]2)=[CH:3][CH:4]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: C[C@H]1COCCN1c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H]1COCCN1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (3S)-4-(4-bromophenyl)-3-methylmorpholine (630 mg), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (630 mg) and triethylamine (1.03 mL) in 1,4-dioxane (10 mL) was added dichlorobis(triphenylphosphine)palladium(II) (86 mg), and the mixture was stirred overnight at 100° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (470 mg).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH:20]=[C:6]2[CH:7]=[N:8][C:9]3[CH:14]=[C:13]([CH3:15])[C:12](=O)[N:11]([CH2:17][CH2:18][CH3:19])[C:10]=3[N:5]2[CH2:4]1.P(Cl)(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][C:14]1[C:9]2[N:8]=[CH:7][C:6]3[N:5]([CH2:4][N:3]([O:2][CH3:1])[CH:20]=3)[C:10]=2[N:11]([CH2:17][CH2:18][CH3:19])[CH2:12][C:13]=1[CH3:15]
Reactant: CCCn1c2c(cc(C)c1=O)N=CC1=CN(OC)CN12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC)C=C1C=N2
Temperature: 25 °C

Procedure:
A mixture of 27 g 8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]-pyrido[3,2-e]-pyrazinone and 225 ml phosphorus oxychloride were heated to reflux for 8 hrs. To the cooled mixture 250 ml of toluene were added and then 350 ml of the liquid were distilled off. Subsequently the same procedure was performed with 150 ml toluene but 250 ml of the liquid were distilled off. The reaction mixture was allowed to cool at room temperature and then poured in a mixture of 500 g ice/500 ml water. After 30 minutes the mixture was extracted with 250 ml of dichloromethane for two times. The dichloromethane layer was then washed with 500 ml water then with sodium carbonate (3% in water) and after that with 500 ml water. The organic layer was dried with sodium sulfate. After removal of the sodium sulfate and evaporation of the dichloromethane the crude product was dried in a dry box with vacuum (40° C.).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[OH:10].[CH2:11]([CH:14]([CH2:18][CH2:19]C)[C:15](Cl)=[O:16])[CH2:12][CH3:13].[C:21](=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:21][CH:18]([CH:14]([CH2:11][CH2:12][CH3:13])[C:15]([O:10][C:3]1[C:2]([I:1])=[CH:7][C:6]([I:8])=[CH:5][C:4]=1[I:9])=[O:16])[CH3:19]
Reactant: Oc1c(I)cc(I)cc1I
Reactant: CCCC(CCC)C(=O)Cl
Reactant: O=C([O-])O
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CC#N
Product: CCCC(C(=O)Oc1c(I)cc(I)cc1I)C(C)C
Yield: 68 %

Procedure:
A mixture of 2,4,6-triiodophenol (2.0 g, 4.24 mmol), 2-propylvaleroyl chloride (2.5 ml, 12.7 mmol, 3 eq) and 4-dimethylaminopyridine (DMAP; 20 mg) in 20 ml of acetonitrile was refluxed under argon overnite. The reaction mixture was cooled and poured into excess aqueous sodium bicarbonate and then extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate, filtered, and evaporated to give the crude product (2.42 mmol, 95%) as a pink solid. Recrystallization from ethyl acetate gave 1.75 g (68%) of pure product, mp 99°-101° C.