Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:20])([O:3][CH2:4][CH:5]1[C:11]2=[N:12][C:13]([CH3:19])=[C:14](C(O)=O)[CH:15]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:2].C1N=CN([C:26]([N:28]2[CH:32]=[N:31]C=C2)=[O:27])C=1.[NH2:33]C(N)=N.C1COCC1>C1COCC1>[N+:1]([O-:20])([O:3][CH2:4][CH:5]1[C:11]2=[N:12][C:13]([CH3:19])=[C:14]([NH:33][C:32]([N:28]=[C:26]=[O:27])=[NH:31])[CH:15]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:2]
Reactant: N=C(N)N
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc2c(cc1C(=O)O)CCCCC2CO[N+](=O)[O-]
Solvent: C1CCOC1
Product: Cc1nc2c(cc1NC(=N)N=C=O)CCCCC2CO[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
In an atmosphere of argon, 28% sodium methoxide methanol solution (1.58 ml, 8.19 mmol) was dissolved in anhydrous methanol (8.0 ml) at room temperature, and the solution was mixed with guanidine hydrochloride (782.4 mg, 8.19 mmol) at 0° C. and stirred at the same temperature for 1 hour. The thus precipitated sodium chloride was removed by filtration using a glass filter and the resulting filtrate was evaporated under reduced pressure to obtain free guanidine. In an atmosphere of argon, (3-carboxy-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)methyl nitrate (310.0 mg, 1.17 mmol) were suspended in anhydrous THF (8.0 ml), mixed with CDI (291.2 mg, 1.76 mmol) at room temperature and then stirred at 50° C. for 1 hour. The reaction solution was added dropwise to the previously obtained guanidine THF suspension (5.0 ml), and the mixture was stirred at room temperature for 2.5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was mixed with water and extracted with ethyl acetate. The thus obtained organic layer was washed with saturated sodium bicarbonate aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=20:1) and then the thus obtained crystals were washed with ether to obtain the title compound (192.1 mg, 51.1%) as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][CH:8]=[C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][C:10]2=[O:20])=[CH:4][CH:3]=1.[C:23](Cl)(=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26]>N1C=CC=CC=1.CN(C)C=O>[O:19]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[CH:8][NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:23](=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=2)[C:10](=[O:20])[NH:11]1
Reactant: Nc1ccc(CNC=C2C(=O)NC(=O)c3ccccc32)cc1
Reactant: CC(C)CC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)CC(=O)Nc1ccc(CNC=C2C(=O)NC(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a suspension of 4-[(4-Amino-benzylamino)-methylene]-4H-isoquinoline-1,3-dione (29.3 mg, 0.1 mmol) in pyridine (250 μL) is added isovaleryl chloride (26 μL, 0.2 mmol). The reaction mixture is shaken at room temperature for 1 hour. The reaction mixture is diluted to 2 mL with N,N-dimethylformamide and purified by C18 reverse phase HPLC. The pure fractions were combined and concentrated to yield the title compound (37.2 mg).
Reaction SMILES: O[C:2]1([CH3:25])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][N:4]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:3]1.COCCN(S(F)(F)[F:36])CCOC>C(Cl)Cl.C1COCC1>[F:36][C:2]1([CH3:25])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][N:4]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:3]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCN(C(=O)OC(C)(C)C)CC(C)(O)C1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1N1CCN(C(=O)OC(C)(C)C)CC(C)(F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of tert-butyl 6-hydroxy-6-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate (100 mg, 0.28 mmol) in DCM (5 mL) was added deoxo-Fluor® (50% in THF, 0.26 mL, 0.7 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (30 mL), cooled in an ice water bath and quenched by dropwise addition of saturated aqueous NaHCO3 (40 mL). The resulting mixture was stirred for 10 min. The organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. The crude product was purified via silica gel column chromatography (0-50% EtOAc/isohexane) to give tert-butyl 6-fluoro-6-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate (70 mg, 70%) as a clear colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 3.80 (s, 3H), 3.73-3.32 (m, 6H), 3.26-3.03 (m, 2H), 1.50 (s, 9H), 1.32 (d, J=20.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].O1CCCC1.C([Li])(CC)C.[Si:30]([O:37][CH2:38][CH2:39][CH2:40]I)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH2:40][CH2:39][CH2:38][O:37][Si:30]([C:33]([CH3:34])([CH3:36])[CH3:35])([CH3:31])[CH3:32])[C:8]1=[O:12]
Reactant: CC(C)(C)[Si](C)(C)OCCCI
Reactant: COc1cc(CN2CCCC2=O)cc(OC)c1OC
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CN2CCC(CCCO[Si](C)(C)C(C)(C)C)C2=O)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-2-oxopyrrolidine (0.84 g, 3.16 mmol) and tetrahydrofuran (10 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of sec-butyl lithium (2.56 mL, 1.3 M in hexane, 3.33 mmol). After 30 minutes, add 3-(t-butyldimethylsilyloxy)propyl iodide (1.0 g, 3.33 mmol). After the addition is complete, warm to ambient temperature. After 2 hours, add water and extract three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:19]=[C:18]([CH2:20][C:21]2[C:22](=[O:45])[N:23]([C@H:33]3[CH2:38][CH2:37][C@H:36]([O:39][CH2:40][C:41]([OH:44])([CH3:43])[CH3:42])[CH2:35][CH2:34]3)[C:24]3[N:25]([N:30]=[CH:31][N:32]=3)[C:26]=2[CH2:27][CH2:28][CH3:29])[CH:17]=[CH:16][C:15]=1[C:46]1[C:47]([C:52]#[N:53])=[CH:48][CH:49]=[CH:50][CH:51]=1>C(OCC)(=O)C>[F:13][C:14]1[CH:19]=[C:18]([CH2:20][C:21]2[C:22](=[O:45])[N:23]([C@H:33]3[CH2:38][CH2:37][C@H:36]([O:39][CH2:40][C:41]([OH:44])([CH3:42])[CH3:43])[CH2:35][CH2:34]3)[C:24]3[N:25]([N:30]=[CH:31][N:32]=3)[C:26]=2[CH2:27][CH2:28][CH3:29])[CH:17]=[CH:16][C:15]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]1[NH:3][C:4](=[O:7])[O:5][N:53]=1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)c(F)c2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.47 g), sodium hydrogen carbonate (0.75 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 2′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.25 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.087 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.074 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.14 g, 49%).
Reaction SMILES: [OH-].[K+].Cl.[N:4]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[C:6](=[O:12])[CH2:5]2.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1.O>CO>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[C:5]2[C:6](=[O:12])[CH:7]3[CH2:10][CH2:11][N:4]2[CH2:9][CH2:8]3)[CH:14]=1
Reactant: O=Cc1cccnc1
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2cccnc2)N2CCC1CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
Potassium hydroxide (56 g, 0.54 mole) was dissolved in methanol (420 mL). 3-Quinuclidinone hydrochloride (75 g, 0.49 mole) was added and the mixture was stirred for 30 min at ambient temperature. 3-Pyridinecarboxaldehyde (58 g, 0.54 mole) was added and the mixture stirred for 16 h at ambient temperature. The reaction mixture became yellow during this period, with solids caking on the walls of the flask. The solids were scraped from the walls and the chunks broken up. With rapid stirring, water (390 mL) was added. When the solids dissolved, the mixture was cooled at 4° C. overnight. The crystals were collected by filtration, washed with water, and air dried to obtain 80 g of yellow solid. A second crop (8 g) was obtained by concentration of the filtrate to ˜10% of its former volume and cooling at 4° C. overnight. Both crops were sufficiently pure for further transformation (88 g, 82%).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[C:37]([OH:54])[C:36]3=[O:55])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[C:37]([O:54][CH3:3])[C:36]3=[O:55])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: O=C1C(O)=C(c2ccccc2)C(c2cccc(F)c2F)N1c1ccc2nc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: OCCO
Solvent: CO
Product: COC1=C(c2ccccc2)C(c2cccc(F)c2F)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (9 eq), ethylene glycol/Et2O (1/2.8 v/v, 34 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-3-hydroxy-4-phenyl-1H-pyrrol-2(5H)-one (1 g, 2.48 mmol, 1 eq) and MeOH (10 ml); yield: 0.160 g (60%); MS m/z: 418.1 [M+H]+; 1H-NMR: (400 MHz, CDCl3) δ: 7.87 (s, 1H), 7.74 (s, 1H), 7.58-7.50 (m, 3H), 7.36-7.2 (m, 5H), 4.18 (s, 3H); HPLC (METHOD [A]): rt 14.70 min (99.68%)
Reaction SMILES: [O:1]1[CH2:5]CCC1.C=O.[C:8](=O)([O-])[O-:9].[K+].[K+].[CH3:14][O:15][C:16]([C:18]1([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:22][CH2:21][CH2:20][C:19]1=[O:23])=[O:17]>O>[CH3:14][O:15][C:16]([C:18]1([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH2:22][CH2:21][C:20]([CH2:5][OH:1])([CH2:8][OH:9])[C:19]1=[O:23])=[O:17]
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCCC1=O
Agent: C=O
Agent: [K+]
Solvent: O
Product: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(CO)(CO)C1=O

Procedure:
Tetrahydrofuran (0.72 ml), a 37% formaldehyde aqueous solution (0.242 ml), and potassium carbonate (0.50 mmol) were added to 1-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid methyl ester (Compound VI-1) (1.0 mmol), and the mixture was allowed to react at room temperature for 5 hours. Water was added to the resultant reaction solution, and the resultant reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, and thereafter dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified with the use of a silica gel column. In this way, Compound V-1 was obtained.
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([OH:20])=[O:19])=[C:8]([CH2:11][S:12][N:13]3[CH2:17][S:16][N:15]=[CH:14]3)[CH2:9][S:10][C@H:5]12)=[O:2].[CH2:23]1OC1C.Br[C:28]1[O:29][C:30](=[O:35])[O:31][C:32]=1[CH2:33]C.Cl>CN(C=O)C.CCOC(C)=O>[CH:1]([NH:3][CH:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([O:20][CH2:23][C:28]3[O:29][C:30](=[O:35])[O:31][C:32]=3[CH3:33])=[O:19])=[C:8]([CH2:11][S:12][N:13]3[CH2:17][S:16][N:15]=[CH:14]3)[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: CC1CO1
Reactant: O=CNC1C(=O)N2C(C(=O)O)=C(CSN3C=NSC3)CS[C@H]12
Reactant: CCc1oc(=O)oc1Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1oc(=O)oc1COC(=O)C1=C(CSN2C=NSC2)CS[C@@H]2C(NC=O)C(=O)N12
Temperature: 5 °C
Reaction time: 5 h

Procedure:
A suspension of 7-formamido-3-(1,2,4-thiadiazol-4-yl)thiomethyl-3-cephem-4-carboxylic acid (1.07 g, 3 mmole), KHCO3 (1.0 g, 10 mmole) and propylene oxide (1 ml) in DMF (5 ml) was cooled to 5° C. and treated with 4-bromo-methyl-5-methyl-1,3-dioxolene-2-one (0.87 g, 4.5 mmole). After stirring at 5° C. for 5 hr, the reaction mixture was poured into a mixture of aq HCl (pH 3) (70 ml) and EtOAc (250 ml). The EtOAc layer was separated and washed successively with aq HCl (pH 3) (70 ml×2), 10% K2HPO4 buffer (pH 7) (70 ml×2) and saturated aq NaCl (50 ml). The EtOAc solution was dried (MgSO4) and concentrated in vacuo. The residue was triturated with ether (300 ml) and the resulting precipitate was filtered to give the title compound ( 0.45 g).
Reaction SMILES: [Br-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][N:39]([CH2:42][C:43]([C:45]4[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=4)=O)[CH2:38][CH2:37]3)[S:33][N:32]=2)=[CH:27][CH:26]=1.O.CCOC(C)=O>C1COCC1>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][N:39]([CH2:42][C:43]([C:45]4[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=4)=[CH2:2])[CH2:38][CH2:37]3)[S:33][N:32]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(C(=O)CN2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)cc1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(CN1CCN(c2nc(-c3ccc(Cl)cc3)ns2)CC1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyltriphenylphosphonium bromide/sodium amide (57.7 mg, 146 μmol) was combined with THF (5 mL) to give a yellow suspension and stirred for 1 h at RT. 2-(4-(3-(4-chlorophenyl)-1,2,4-thiadiazol-5-yl)piperazin-1-yl)-1-(4-methoxyphenyl)ethanone (50 mg, 117 μmol) dissolved in THF (3 mL) was added drop-wise via syringe over 5 min. The resulting orange suspension was stirred over night at RT. Water (10 mL) and EtOAc (10 mL) was added and stirred for 10 min. The aqueous layer was separated and extracted with EtOAc (1×10 mL). The organic layers were washed with brine (1×10 mL), dried over Na2SO4, filtered off and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with a gradient formed from heptane and EtOAc to yield, after evaporation of the product containing fraction, 33 mg (66%) of the title compound as off-white solid. MS (m/e): 427.2 (MH+).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:12][C:11]=1[Cl:21]>CC#N>[NH2:9][C:10]1[C:11]([Cl:21])=[CH:12][C:13]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:19][C:20]=1[Cl:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(C)C(=O)c1ccc(N)c(Cl)c1
Solvent: CC#N
Product: CN(C)C(=O)c1cc(Cl)c(N)c(Cl)c1
Yield: 93.3 %

Procedure:
NCS (38 mg, 0.288 mmol) was added to a solution of 4-amino-3-chloro-N,N-dimethylbenzamide (52 mg, 0.262 mmol) in MeCN (520 mL). The reaction mixture was refluxed for 1 hour before being concentrated under vacuum. The residue was purified via Biotage silica gel column chromatography eluting with (cyclohexane/EtOAc 80/20 to 60/40) to afford the title product as a white solid (57 mg, 93%). 1H NMR (500 MHz, CDCl3) d 3.06 (s, 6H), 4.68 (br s, 2H), 7.34 (s, 2H). LC (Method D)-MS (ESI, m/z) tR 1.50 min, 233 [(M+H+), 100%].
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([C:16]#[CH:17])=[CH:10][CH:11]=3)[C:6]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:5]=2[CH:4]=1)#[CH:2].I[C:39]1[S:43][C:42]([CH:44]=[O:45])=[CH:41][CH:40]=1>C1(C)C=CC=CC=1.CCN(CC)CC.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.[Cu]I>[CH3:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][C:6]1([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:7]2[CH:8]=[C:9]([C:16]#[C:17][C:39]3[S:43][C:42]([CH:44]=[O:45])=[CH:41][CH:40]=3)[CH:10]=[CH:11][C:12]=2[C:13]2[C:5]1=[CH:4][C:3]([C:1]#[C:2][C:39]1[S:43][C:42]([CH:44]=[O:45])=[CH:41][CH:40]=1)=[CH:15][CH:14]=2
Reactant: O=Cc1ccc(I)s1
Reactant: C#Cc1ccc2c(c1)C(CCOCCOCCOC)(CCOCCOCCOC)c1cc(C#C)ccc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCCOCCOCCC1(CCOCCOCCOC)c2cc(C#Cc3ccc(C=O)s3)ccc2-c2ccc(C#Cc3ccc(C=O)s3)cc21
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
Air was removed from a solution of 2,7-diethynyl-9,9-bis[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-9H-fluorene (0.120 g, 0.237 mmol) in 8.2 mL of toluene and 1.8 mL of Et3N by blowing argon for 20 min. Then Pd(PPh3)2Cl2 (10 mg, 6 mol %) and CuI (2.7 mg, 6 mol %), and 5-iodothiophene-2-carboxaldehyde (0.135 g, 0.568 mmol) were added, and deaeration was continued for 15 min. Thereafter the mixture was stirred at 40° C. for 17 h. After completion of the reaction, reaction mixture was filtered and evaporated to dryness. The crude product was purified by column chromatography on silica gel (CH2Cl2/AcOEt 60:40 then AcOEt) to yield 0.140 g (81%) of 5,5′-[9,9-bis[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-9H-fluorene-2,7-diyldi-2,1-ethynediyl]bis-2-thiophenecarboxaldehyde, mp 84° C.; 1H NMR (CDCl3) δ 2.43 (t, 4H, J=7.5 Hz), 2.79 (t, 4H, J=7.2 Hz), 3.21 (m, 4H), 3.33 (s, 6H), 3.39 (m, 4H), 3.54-3.46 (m, 8H), 7.37 (d, 2H, J=3.9 Hz), 7.57 (dd, 2H, J=1.5 Hz, J=7.1 Hz), 7.62 (d, 2H, J=1.2 Hz), 7.71 (d, 2H, J=7.1 Hz), 7.72 (d, 2H, J=3.9 Hz), 9.90 (s, 2H); 13C NMR (CDCl3) δ 39.6, 51.6, 59.0, 66.8, 70.1, 70.4, 70.5, 71.8, 83.0, 98.5, 120.5, 121.2, 126.6, 131.3, 132.6, 132.8, 136.2, 140.7, 143.9, 149.7, 182.5. HRMS (ESI) calcd for C41H42O8NaS2 [(M+Na)+] m/z 749.2219. found 749.2226. Anal. Calcd for C41H42O8S2 (726.90): C, 67.75; H, 5.82; S, 8.82. Found: C, 67.86; H, 5.82; S, 8.63.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:3][CH2:4][N:5]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2/[C:8]/1=[CH:9]/[C:10]([OH:12])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>O1CCCC1>[F:1][C:2]1([F:27])[CH2:3][CH2:4][N:5]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:18])=[O:19])[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:54]1[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]1)=[O:12]
Reactant: Cc1ccc(S(=O)(=O)N2CCC(F)(F)/C(=C\C(=O)O)c3ccccc32)cc1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC(F)(F)/C(=C\C(=O)N3CCN(C)CC3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 g of (Z)-(4,4-difluoro-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene)acetic acid in 100 ml of tetrahydrofuran were added 4.12 g of 1-hydroxybenzotriazole, 5.85 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride and 3.36 ml of 1-methylpiperazine, followed by stirring for two hours at room temperature. After evaporation of the solvent, ethyl acetate was added to the residue, and the mixture was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of NaCl. After drying over magnesium sulfate, the solvent was evaporated off. The resulting residue was collected by filtration to give 11.76 g of (Z)-4,4-difluoro-5-[2-(4-methylpiperazin-1-yl)-2-oxoethylidene]-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzoazepine as a colorless amorphous solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:24])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-methyl-3-phenyl-propyl)-amine (Enantiomer B) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [SH:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>C(O)C.CN(C=O)C.O>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][S:1][C:2]3[N:11]([CH3:12])[C:10](=[O:13])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cn1c(S)nc2ccccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3)cc2)nc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
2-Mercapto-3-methyl-4(3H)-quinazolinone (1.0 g) as synthesized by the method described in Chemical Pharmaceutical Bulletin 17, 2357, 1969 and sodium hydroxide (250 mg) were dissolved in 50% ethanol (15 ml)-DMF (15 ml). To this solution was added 4-(4-chlorobenzoyl)benzyl bromide (1.8 g) and the mixtrue was stirred at room temperature for 1 hour. This-reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol, and recrystallized from ethyl acetate-methanol to provide the title compound as colorless solid (1.29 g). 1H-NMR (CDCl3) δ: 3.61(3H,s), 4.62(2H,s), 7.35-7.50(3H,m), 7.55-7.80(8H,m), 8.24(1H,d,J=8.OHz).