Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.Cl>CCOCC.C1COCC1>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:21][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:15][CH:16]=1)=[O:22]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)F)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 15.6 h
Yield: 90.8 %

Procedure:
Ethyl difluoroacetate (2.78 g, 22.4 mmol) was placed in a 100 mL round bottom flask and dissolved in ether (10 mL). To the stirred solution was added 25 weight % sodium methoxide (6.02 g, 27.8 mmol ) followed by 4'-(trifluoromethyl)acetophenone (3.80 g, 20.2 mmol) and THF (20 mL). The reaction was stirred at room temperature overnight (15.6 hours), then treated with 3N HCl (20 mL). The organic layer was collected and washed with brine, dried over MgSO4, concentrated in vacuo to give a brown oil (4.88 g, 91%). 1H NMR (acetone d6) 300 MHz 15.10 (br s, 1H), 8.03 (d, J=8.7 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 6.59 (s, 1H), 6.02 (t, J=54.2 Hz, 1H); 19F NMR (acetone d6) 300 MHz: - 63.70 (s), -127.10 (d); M+ 266.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@H:14]([OH:18])[CH2:15][CH2:16][CH3:17])[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][NH2:26].C(Cl)CCl>ClCCl>[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][NH:26][C:11](=[O:13])[C@H:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@H:14]([OH:18])[CH2:15][CH2:16][CH3:17]
Reactant: NOC1CCCCO1
Reactant: CCC[C@@H](O)[C@@H](CCCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC[C@@H](O)[C@@H](CCCc1ccccc1)C(=O)NOC1CCCCO1
Temperature: 23 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
To a solution of (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxyhexanoic acid (1.53 g, 6.12 mmol) in dichloromethane (6 mL) is added 2-tetrahydropyranyloxyamine (0.93 g, 7.96 mmol) and EDC (1.29 g, 6.73 mmol). The resulting solution is stirred at 23° C. for 3 h, concentrated in vacuo, and diluted with 50 mL of EtOAc. The organic layer is washed sequentially with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, and is dried over anhydrous magnesium sulfate. Concentration under reduced pressure and purification by silica gel chromatography (elution with 2:1 EtOAc-hexanes) provides (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxyhexanoic acid 2-tetrahydropyranyloxyamide as a solid (1.62 g, 76% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][NH:13][C:14]([NH:16][C@@H:17]([C:28]([NH:30][C@H:31]([C:47]([N:49]1[CH2:54][CH2:53][N:52]([C:55]2[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=2)[CH2:51][CH2:50]1)=[O:48])[CH2:32][CH2:33][CH2:34][CH2:35][NH:36]C(OCC1C=CC=CC=1)=O)=[O:29])[CH2:18][C:19]1[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=1)=[O:15].Br.C(OCC)C>C(O)(=O)C.C1(OC)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][NH:13][C:14]([NH:16][CH:17]([C:28]([NH:30][C@H:31]([C:47]([N:49]1[CH2:50][CH2:51][N:52]([C:55]2[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=2)[CH2:53][CH2:54]1)=[O:48])[CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:29])[CH2:18][C:19]1[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=1)=[O:15]
Reactant: COc1ccc(OC)c(CCNC(=O)N[C@H](Cc2cc(Br)c(O)c(Br)c2)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2)C(=O)N2CCN(c3ccncc3)CC2)c1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: COc1ccccc1
Product: COc1ccc(OC)c(CCNC(=O)NC(Cc2cc(Br)c(O)c(Br)c2)C(=O)N[C@@H](CCCCN)C(=O)N2CCN(c3ccncc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 0.8 g (0.84 mmol) of 1-[N2—[N-[[[2-(2,5-dimethoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, 50 ml of glacial acetic acid, 25 ml of a 33% solution of hydrogen bromide in glacial acetic acid and 2 ml of anisole was stirred for 12 hours at ambient temperature. The reaction mixture was stirred into diethylether and the resulting precipitate was suction filtered. The solid residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant:ethyl acetate/methanol/conc. aqueous ammonia=8/2/0.2 (v/v/v)). 0.3 g (44% of theory) of the desired product was obtained as an amorphous solid.
Reaction SMILES: [CH3:1][S:2][C:3]([P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6]CC)=[S:4].[I-].[Na+:14]>O1CCCC1>[CH3:1][S:2][C:3]([P:5](=[O:6])([OH:12])[OH:9])=[S:4].[CH2:10]([Na:14])[CH3:11]
Reactant: CCOP(=O)(OCC)C(=S)SC
Reactant: [Na+]
Agent: [I-]
Solvent: C1CCOC1
Product: CC[Na]
Product: CSC(=S)P(=O)(O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2.3 parts of diethyl (methylthio)-thiocarbonylphosphonate in 50 parts of dry tetrahydrofuran was added 1.5 parts of sodium iodide. The solution was stirred for 18 hours at room temperature, then warmed on a steam bath for one-half hour. The desired orange ethyl sodium (methylthio)thiocarbonylphosphonate was then filtered, m.p. 288°d.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:11]1[CH:12]=[C:13]2[C:22](=[C:23]3[C:28]=1[CH:27]=[CH:26][CH:25]=[N:24]3)[NH:21][S:20](=[O:30])(=[O:29])[C:19]1[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=1.C1CCN2C(=NCCC2)CC1.C1C[O:45][CH2:44]C1>>[N:1]1([CH2:7][CH2:8][NH:9][C:44]([C:11]2[CH:12]=[C:13]3[C:22](=[C:23]4[C:28]=2[CH:27]=[CH:26][CH:25]=[N:24]4)[NH:21][S:20](=[O:30])(=[O:29])[C:19]2[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:45])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCN1CCCCC1
Reactant: O=S1(=O)Nc2c(cc(Br)c3cccnc23)-c2ccccc21
Reactant: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCCN1CCCCC1)c1cc2c(c3ncccc13)NS(=O)(=O)c1ccccc1-2
Yield: 35 %

Procedure:
In a similar fashion using route 58 general procedure 128, 2-piperidin-1-yl-ethylamine (106 mg, 0.83 mmol), 12-bromo-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 545 (100 mg, 0.28 mmol), Hermann's palladacycle (13 mg, 14 μmol, Mo(CO)6 (73 mg, 0.28 mmol), DBU (126 mg, 0.83 mmol) and THF (2 ml) gave the title compound (42 mg, 35%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:16]([N:13]1[CH2:12][CH:11]=[C:10](/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:15][CH2:14]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Fc1ccc(/C=C/c2ccncc2)cc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Fc1ccc(/C=C/C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
To a solution of (E)-4-[2-(4-fluorophenyl)ethenyl]pyridine (18.75 g, 94.2 mmol) in dimethylformamide (30 ml) at 90° C. was added benzyl bromide (11.9 ml, 100 mmol) and the reaction stirred at 90° C. for 1 hour. The reaction was cooled to room temperature, diluted with ethanol (400 ml) and sodium borohydride (4 g, 105 mmol) added in portions. The reaction was stirred at room temperature for 2 hours, after which time the solvent was evaporated to a slurry. Methanol was added, and the resultant solid filtered and dried to yield (E)-1-benzyl-4-[2-(4-fluorophenyl)ethenyl]-1,2,3,6-tetrahydropyridine (12 g, 44%) as a white solid. δH (CDCl3) 2.41 (2H, br s, tetrahydropyridinyl CH2), 2.68 (2H, t, J 5.8 Hz, tetrahydropyridinyl CH2), 3.14 (2H, br s, tetrahydropyridinyl CH2), 3.63 (2H, s, NCH2Ar), 5.80 (1H, br s, tetrahydropyridinyl 5-CH), 6.40 (1H, d, J 16.2 Hz, ArCHCHC), 6.69 (2H, d, J 16.2 Hz, ArCHCHC), 6.96-7.02 (2H, m, ArH) and 7.25-7.39 (7H, m, ArH).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([OH:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.N1CCOCC1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:24]1([CH:23]2[NH:1][C:2]3[C:15]4[CH:14]([CH2:13][CH2:12][CH2:11][C:10]=4[N:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]=[CH:7]4)[O:16]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: c1ccc(C2Nc3c4c(nc5ccccc35)CCCC4O2)cc1

Procedure:
9-Amino-1,2,3,4-tetrahydroacridine-1-ol (15.0 g) was refluxed in 1 liter of toluene that contained 12.28 g of morpholine and 9.29 g of benzaldehyde that had been freshly washed with K2CO3. The reaction mixture was refluxed overnight and allowed to cool. The crude product was then filtered off and purified by flash chromatography (20% isopropanol/ethyl acetate) to give 8.07 g of a 80:20 mixture of diastereomers after recrystallization from methanol/water. Recrystallization from dimethylformamide/water gave a 60:40 mixture of diastereomers, m.p. 225°-235° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:7]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[N:6]=[CH:5]2.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=1[F:32].C([O-])(O)=O.[Na+].CN(C=O)C>O>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[N:6][N:7]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:3][C:2]=1[O:1][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=1[F:32])=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cc2c(cnn2C2CCCCO2)cc1O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(cnn2C2CCCCO2)cc1Oc1ccc([N+](=O)[O-])cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
A mixture of ethyl 5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carboxylate (10.8 g, 37 mmol), 1,2-difluoro-4-nitrobenzene (7.1 g, 44 mmol), NaHCO3 (7.4 g, 88 mmol) and DMF (100 mL) is stirred at 80° C. for 2 hours. After it is cooled to RT, water (400 mL) and PE (50 mL) are added and the mixture is stirred for 20 min. The precipitate is collected and dried under vacuum at 50° C. to afford the product (15 g, 95% yield). MS (m/z): 430.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[C:8](=O)[CH2:7][CH2:6]2.Cl.[Br:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1.C(OCC)(=[O:28])C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(O)(=O)C.O.CC(OC)(C)C>[Br:17][C:18]1[CH:19]=[C:20]2[C:21]([C:7]3[C:6](=[O:28])[C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=4[C:9]([CH3:14])([CH3:13])[C:8]=3[NH:24]2)=[CH:22][CH:23]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(c1)CCC(=O)C2(C)C
Reactant: NNc1cccc(Br)c1
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)C(=O)c1c([nH]c3cc(Br)ccc13)C2(C)C
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 46 %

Procedure:
6-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound J2, 2.15 g, 10.5 mmol) and 3-bromophenylhydrazine hydrochloric acid salt (3.11 g, 1.3 eq.) were dissolved in acetic acid (12 mL), and stirred at 100° C. for 2.5 hr under nitrogen atmosphere. After cooling, the reaction solution was added with ethyl acetate, washed with water, saturated aqueous solution of sodium hydrogen carbonate, and saturated brine, and dried over magnesium sulfate. After the filtration, it was concentrated under reduced pressure. The resulting residues were dissolved in THF (30 mL) and water (3 mL), added with DDQ (5.96 g, 2.5 eq.) at 0° C., and then stirred at room temperature overnight. The reaction solution was added with MTBE, washed with 0.5 N aqueous solution of sodium hydroxide and saturated brine, and dried over magnesium sulfate. After filtration and the concentration under reduced pressure, the resulting residues were washed with MTBE to obtain the title compound (brown solid, 1.80 g, 46%).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.N12CCCN=C1CCCCC2>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:26]3[CH2:25][CH2:24][N:23]([C:20]4[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=4)[CH2:28][CH2:27]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(NCCC1CC1)c1ccc(N2CCN(c3ccc(F)cc3)CC2)nn1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.120 g, 0.532 mmol) in DMF (2.3 mL) was treated with 1-(4-fluorophenyl)piperazine (0.117 g, 0.638 mmol) in the presence of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (0.23 mL, 1.54 mmol) and tetra-n-butylammonium iodide (Bu4NI) (11 mg, 0.0298 mmol). The reaction mixture was heated at 75° C. to 80° C. for 15 hours, cooled to room temperature, diluted with ethyl acetate (100 mL). The organic layer was washed with water (3×10 mL), brine (3×10 mL), dried over Na2SO4, and then concentrated in vacuo. The crude product was purified by column chromatography to give the title compound as a white powder in 74% yield (0.146 g). 1H NMR (300 MHz, CDCl3) δ 8.05-7.99 (m, 2H), 7.02-6.89 (m, 5H), 3.90 (t, J=5.2 Hz, 4H), 3.55 (m, 2H), 3.23 (t, J=5.2 Hz, 4H), 1.55-1.47 (m, 2H), 0.79-0.72 (m, 1H), 0.49-0.43 (m, 2H), 0.11-0.06 (m, 2H). MS (ES+) m/z 370.3 (M+1).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([OH:12])=O.[C:13]1([NH:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([NH:19][CH2:20][CH2:21][NH:22][C:10]([C:2]2[NH:1][C:5]3=[CH:6][N:7]=[CH:8][CH:9]=[C:4]3[CH:3]=2)=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCNc1ccccc1
Reactant: O=C(O)c1cc2ccncc2[nH]1
Product: O=C(NCCNc1ccccc1)c1cc2ccncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 15) and 2-phenylaminoethylamine to give the title compound as a pale yellow solid. δH (CD3OD): 3.37 (2H, t), 3.63 (2H, t), 6.61 (1H, t), 6.69 (2H, d), 7.08-7.13 (2H, m), 7.64 (1H, d), 8.10 (1H, d), 8.78 (1H, s); m/z (ES+)=281 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH:15]([C:16](O)=[O:17])[C:14]2([CH3:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].S(Cl)([Cl:23])=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH:15]([C:16]([Cl:23])=[O:17])[C:14]2([CH3:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: CC1(C)C(C(=O)O)C1c1ccc(OC(F)(F)F)c(Br)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(C(=O)Cl)C1c1ccc(OC(F)(F)F)c(Br)c1
Yield: 93.7 %

Procedure:
9.6 g (0.027 mol) of 3-(3-bromo-4-trifluoromethoxyphenyl)-2,2-dimethyl-cyclopropanecarboxylic acid were dissolved in 100 ml of carbon tetrachloride, and 10 g of thionyl chloride were slowly added dropwise at 60° C., while stirring. The mixture was then heated under reflux for 4 hours. After the reaction period had ended, excess thionyl chloride, as well as carbon tetrachloride, were distilled off in the vacuum from a water jet. 9.4 g (93.7% of theory) of 3-(3-bromo-4-trifluoromethoxyphenyl)-2,2-dimethyl-cyclopropanecarboxylic acid-chloride were obtained as a yellow liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([C:14]2[CH:19]=[CH:18][C:17](O)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=2)([CH3:13])[CH3:12])[CH:7]=[CH:8][C:9]=1O)([O-:3])=[O:2].[Cl-].[NH4+:25].[NH3:26].[OH-].[Na+]>O>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:26])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=2)([CH3:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[NH2:25])([O-:3])=[O:2]
Reactant: N
Reactant: [NH4+]
Reactant: CC(C)(c1ccc(O)c([N+](=O)[O-])c1)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(c1ccc(N)c([N+](=O)[O-])c1)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A typical run consisted of charging the reactor with 35 grams of 2,2-bis(3-nitro-4-hydroxyphenyl)propane, 20 grams of ammonium chloride, 40 ml of water and a stirring bar. The vessel was capped and placed in a -70° C. freezer overnight to freeze the contents. Ammonia was condensed into a 100 ml flask until 63 ml had been collected. The ammonia was added to the reaction vessel and the vessel bolted shut. A variable transformer and heating tape were used to heat the contents to 140° C. for 30 hours and a stirring plate was used to keep the reaction well mixed. The vessel was then allowed to cool to room temperature and vented to release the excess ammonia. The contents were slurried with 500 ml of 1 molar sodium hydroxide solution to dissolve the unreacted starting materials. The slurry was filtered, washed with distilled water, and dried. Recrystallization from toluene and vacuum sublimation gave 32.5 grams (93%) of orange 2,2-bis(3-nitro-4-aminophenyl)propane melting at 207°-210° C. Several runs of the amination reaction were completed to produce enough material for the reduction step. Analysis calculated for C15H16N4O4 : C, 56.96%; H, 5.10%; N, 17.71%; 0, 20.23%. Found: C, 57.06%; H, 5.23%; N, 17.48%; O, 20.28%.
Reaction SMILES: [C:1](O)(=O)/[CH:2]=[CH:3]\[C:4](N)=[O:5].N1C=C[CH:12]=[CH:11][CH:10]=1.C(OC(=O)C)(=[O:17])C>CC(C)=O>[CH3:10][C:11]1([CH3:12])[O:17][CH:3]([CH:4]=[CH2:5])[CH2:2][O:1]1
Reactant: NC(=O)/C=C\C(=O)O
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: C=CC1COC(C)(C)O1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
The maleamic acid copolymer of Example 8 was cyclized as follows. The procedure described in Example 8 was repeated, but prior to precipitation pyridine (2 gram, 25 mmol) was added, the solution stirred for 15 minutes, followed by the addition of 3 grams (29 mmol) of acetic anhydride. The solution was heated to 50° C. and stirred for 1 hour. The reaction mixture was then diluted with 5 gram acetone and precipitated into a heptane/ethyl ether (2:1) mixture. The solid product was collected using suction filtration and dried under vacuum at 40° C. for 20 hours. Yield was 0.54 grams of a maleimide/dioxolane copolymer 27% theory. Mn=2900, Mw=5420, Mw/Mn=1.87. The NMR spectrum indicates that the phenyl group has been incorporated in an approximately 1 to 1 ratio with the dioxolane group. The NMR spectrum is similar to the spectrum of a copolymer obtained by polymerizing a preformed n-phenyl maleimide monomer with a 2,2-dimethyl-4-vinyl-1,3-dioxolane monomer.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])C.C([Sn](CCCC)(CCCC)[C:46]1[S:47][CH:48]=[CH:49][N:50]=1)CCC.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C(O)C.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>[C:35]([CH2:34][CH2:33][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[S:47][CH:48]=[CH:49][N:50]=3)[CH:25]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:40])([OH:37])=[O:36]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2nccs2)c1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To a solution containing 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (90 mg, 0.14 mmol) and 2-(tributylstannyl)thiazole (0.088 mL, 0.28 mmol) in toluene (4 mL) was added Pd(PPh3)4 (8 mg, 5 mol %). The reaction mixture was stirred at 110° C. for 12 h, then diluted with EtOAc. The resulting solution was washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude sample which was dissolved in hot ethanol (4 mL). To this solution, 1 N sodium hydroxide (1 mL) was added and the reaction mixture was stirred at 60° C. for 3 h. Once the hydrolysis was completed as determined by LCMS, the reaction mixture was diluted with EtOAc and washed with 10% HCl and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude sample which was purified by preparative HPLC. HR-ES(+) m/e calcd for C29H35NO8S2 (M+H)+ 590.1877, found 590.1876.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:27](Br)[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[ClH:1].[ClH:1].[CH2:27]([N:19]1[CH2:18][CH2:17][N:16]([CH:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:13][CH:12]=2)[CH3:15])[CH2:21][CH2:20]1)[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(c1ccc(-c2ccc(Cl)cc2)cc1)N1CCNCC1
Reactant: BrCC=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(c1ccc(-c2ccc(Cl)cc2)cc1)N1CCN(CC=Cc2ccccc2)CC1
Product: Cl

Procedure:
To a stirred mixture of 8g of 1[1-(4'-chloro[1,1']biphenyl-4-yl)ethyl]piperazine, 2.7g of sodium bicarbonate in 75 ml of absolute ethanol, add in a dropwise fashion 5.25g of cinnamyl bromide. Reflux the reaction mixture for 6 hours, concentrate in vacuo, and treat with 50 ml of 10% hydrochloric acid solution. Filter the dihydrochloride and recrystallize from 80% ethanol, m.p. 273°-275°. The free base has a melting point of 108°-109° after recrystallization from acetonitrile.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.C1COCC1.C(N(CC)CC)C.Cl[C:37](=[O:48])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45]>O>[O:22]=[C:20]1[NH:19][C:18](=[O:23])[CH:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][N:2]([CH3:1])[C:37]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:48])[CH:5]=3)=[CH:15][CH:14]=2)[S:21]1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: COC(=O)CCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCCCCC(=O)N(C)Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reaction time: 1 h

Procedure:
600 mg (1.36 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione, 10 ml of THF and 600 μl (4.3 mmol) of triethylamine are introduced into a round-bottomed flask and under a nitrogen stream. 220 μl (1.55 mmol) of methyl 8-chloro-8-oxooctanoate are added dropwise and the mixture is stirred for one hour. The reaction medium is poured into water, extracted with dichloromethane, the organic phase decanted off, washed with water, dried over magnesium sulphate and evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a dichloromethane and ethyl acetate (80-20) mixture. After evaporation of the solvents, 350 mg (50%) of methyl 7-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}heptanoate are recovered in the form of an oil.