Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1>C(O)C>[CH3:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3cccc(C)c3)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3cccc(C)c3)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product from Example 120a (32 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (14 mg, 26%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.62-1.93 (m, 2H) 2.02 (s, 3H) 2.31 (s, 3H) 2.99 (t, J=7.35 Hz, 2H) 5.11 (s, 2H) 6.30 (d, J=6.99 Hz, 1H) 6.97-7.33 (m, 8H) 7.34-7.50 (m, 3H) 7.80 (d, J=8.82 Hz, 1H) 8.36 (d, J=6.99 Hz, 1H) 8.97 (d, J=8.82 Hz, 1H) 9.97 (s, 1H) 11.01 (s, 1H) 14.36 (s, 1H); MS (ESI+) m/z 549 (M+H)+.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][C:4]([C:7]#[N:8])=[CH:3]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C@@H:2]3[CH2:6][CH2:5][C:4]([C:7]#[N:8])=[CH:3]3)[CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: N#CC1=CC(Br)CC1
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CC1=C[C@H](N2CCN(c3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
To a stirred solution of 3-bromocyclopent-1-enecarbonitrile (3 g, 17.44 mmol) in N,N-dimethylformamide (25 ml) was added 1-(4-fluorophenyl)piperazine (3.14 g, 17.44 mmol) followed by the addition of triethylamine (7.29 ml, 52.3 mmol) in a dropwise manner at 0° C. The reaction mixture was stirred at 25° C. for 3 h. The progress of reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue was then diluted with ethyl acetate (100 ml) and washed with water (4×30 ml). The organic layer was dried over sodium sulphate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column over silica gel (100-200 mesh) using 20% ethyl acetate in hexane as eluent to obtain the title compound (2.7 g, 57.1%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][CH:22]=[CH2:23])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:24])[CH:3]=1.[H-].[Na+].Br[CH:28]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[C:29]([CH:28]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[CH:3][C:4]([CH3:24])=[C:5]3[N:10]=[C:9]2[CH2:11][CH3:12])=[CH:15][C:16]=1[CH2:21][CH:22]=[CH2:23])([O:31][CH3:32])=[O:30]
Reactant: C=CCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1O
Reactant: COC(=O)C(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1OC(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.17 1 g (0.53 mmol) of the product of Step G dissolved in 2.5 mL of anhydrous DMF was added 0.023 g (0.58 mmol) of a 60% oil dispersion of sodium hydride and the reaction mixture was stirred under a nitrogen atmosphere for 30 minutes at room temperature. A solution of 0.134 g of methyl α-bromophenylacetate in 1.0 mL of DMF was then added via syringe and the reaction mixture was stirred an additional 1.5 hours. The reaction mixture was then partitioned between ethyl acetate and water, the organic layer was separated, dried (MgSO4), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted with 75% ethyl acetate-hexane to afford after evaporation of the purified fractions and drying in vacuo 0.212 g (85%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[CH2:30][O:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[N:41]1([CH2:46][CH2:47][N:48]2[CH:52]=[C:51](B3OC(C)(C)C(C)(C)O3)[CH:50]=[N:49]2)[CH2:45][CH2:44][CH2:43][CH2:42]1.C(=O)(O)[O-]>CN(C)C=O.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>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[CH2:30][O:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:51]3[CH:50]=[N:49][N:48]([CH2:47][CH2:46][N:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)[CH:52]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cnn(CCN3CCCC3)c2)OC1(C)C
Reactant: COc1ccc(COC2(c3ncc(-c4c(Cl)cnc5c4cc(I)n5S(=O)(=O)c4ccc(C)cc4)s3)COC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COc1ccc(COC2(c3ncc(-c4c(Cl)cnc5c4cc(-c4cnn(CCN6CCCC6)c4)n5S(=O)(=O)c4ccc(C)cc4)s3)COC2)cc1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(3-(4-methoxybenzyloxy)oxetan-3-yl)thiazole (Example 11G) (300 mg, 0.424 mmol) and 1-(2-(pyrrolidin-1-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Example 20A) (173 mg, 0.593 mmol) in N,N-dimethylformamide (3.97 mL) was added saturated aqueous bicarbonate solution (1.32 mL) followed by bis(triphenylphosphine)palladium dichloride (20.8 mg, 0.030 mmol). The mixture was heated to 70° C. for 4 hours, cooled to room temperature, and then quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 10% methanol in dichloromethane, to afford the title compound. MS ESI(+) m/z 745.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].[CH3:22][N:23]([CH3:29])[CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([N:26]3[CH2:27][CH2:28][CH:24]([N:23]([CH3:29])[CH3:22])[CH2:25]3)=[N:16][CH:15]=2)[C:3]=1[CH3:21]
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Reactant: CN(C)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccc(N3CCC(N(C)C)C3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 19 h

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.1 g, 0.32 mmol) in DMF (3.0 mL) was added 3-(dimethylamino)-pyrrolidine (0.041 mL, 0.32 mmol) followed by potassium carbonate (0.090 g, 0.65 mmol). The reaction was stirred at 100° C. and stirring continued for 19 h. After which, the reaction mixture was cooled to rt and water was added. The crude mixture was extracted with EtOAc and dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 1-(5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyridin-2-yl)-N,N-dimethylpyrrolidin-3-amine as a white solid. Mass Spectrum (ESI) m/e=403.1 (M+1).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].Cl>[OH-].[Na+]>[C:10]([NH:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][S:5][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@H](CSC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Cysteine HCl (2.0 g, 12.6 mmol) was dissolved in 2N NaOH and benzyl chloroformate (4.5 mL) was slowly added over 15 min. The pH value of the solution was kept at 9-10 by addition of 2N NaOH (~7 mL) at 0° C. After vigorous stirring for 1 h at 0° C., the aqueous solution was acidified with 2N HCl at pH ~2 to form a colorless syrup. The aqueous solution was decanted and the sticky syrup was triturated with petroleum ether (100 ml×3) to give N,S-diCBZ-cysteine (3.94 g, 80%) as a white solid. Analytically pure sample could also be obtained by flash chromatography (on silica gel, 5% CH3OH in EtOAc) :mp.93°-94° C.; 1H NMR (CDCl3) δ7.33 (10H, m), 5.67 (1H, d, J=7.7 Hz), 5.21 (2H, s), 5.12 (2H, s), 4.66 (1H, ddd, J=7.7, 6.7, 4.4 Hz), 3.31 (1H, dd, J=6.7, 14.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:17])=[C:13]([CH2:15][OH:16])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[H-].[Na+].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>C(#N)C>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:17])=[C:13]([CH2:15][O:16][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(CO)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cccc(C)c1CNc1cccn2c(C)c(COC(=O)CCC(=O)O)nc12
Reaction time: 0.08 h
Yield: 89.3 %

Procedure:
To a suspension of 8-(2,6-dimethylbenzylamino)-2-hydroxymethyl-3-methylimidazo[1,2-a]pyridine (0.2 g, 0.68 mmol) in acetonitrile (10 ml) was added sodium hydride (50% in oil) (0.036 g, 0.75 mmol) and the mixture was stirred for 5 min. To the mixture was added succinic anhydride (0.1 g, 1.0 mmol) and the reaction mixture was refluxed for 20 h. The solvent was evaporated under reduced pressure. To the residue was added water and the solid that formed was isolated by filtration and washed with acetonitrile to give 0.24 g (89%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.I[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25]I>>[CH2:19]([O:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:9]([B:4]2[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:1])([CH3:16])[O:3]2)[CH:14]=[CH:13][CH:12]=1)[CH2:18][O:15][CH2:11][CH2:10][O:15][C:11]1[CH:10]=[C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:14]=[CH:13][CH:12]=1
Reactant: ICCOCCOCCI
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Product: CC1(C)OB(c2cccc(OCCOCCOCCOc3cccc(B4OC(C)(C)C(C)(C)O4)c3)c2)OC1(C)C

Procedure:
By following the process described in Example R65, Example R67 is prepared by dimerization of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol with 1-iodo-2-[2-(2-iodoethoxy)ethoxy]ethane (Example R5). A white powder is obtained.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27]>>[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:27]
Reactant: O=C(Cl)c1cccs1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1cccs1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2-thienylcarbonyl chloride, there is obtained ethyl N-(2-thienylcarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a solid, mass spectrum m/e:M+ 376 (10), 347 (13), 194 (100), 111 (48); starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 1-naphthoyl chloride, there is obtained ethyl N-(1-naphthylcarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a foam, mass spectrum m/e: M+ 420 (8), 391 (6), 194 (100), 155 (32), 27 (28);
Reaction SMILES: [PH:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].Br[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.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>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CCO[PH](=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of diethyl phosphonate (3.02 g, 21.88 mmol, 1.10 equiv) in toluene (10 mL), Pd(PPh3)4 (1.15 g, 1.00 mmol, 0.05 equiv), TEA (2.21 g, 21.88 mmol, 1.10 equiv), 1-bromo-4-nitrobenzene (4 g, 19.90 mmol, 1.00 equiv). The resulting solution was stirred for 15 h at 90° C. The solids were filtered out and the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). This resulted in 3.53 g (68%) of diethyl 4-nitrophenylphosphonate as a yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[Cl-].[Li+].[O:26]1[CH2:28][CH2:27]1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:28][CH2:27][OH:26])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CO1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(I)cc2C1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(CCO)cc2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 1.80 g (5.00 mmol) 7-iodo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 7b) in 5.0 mL THF at −20° C. is added 6.34 g (5.50 mmol) of a THF-solution of 14% isopropylmagnesium-chloride*lithiumchloride under argon. The mixture is warmed to 0° C. and stirred 1 h at 0° C. The reaction mixture is cooled to −60° C. and 0.88 g (20.0 mmol) oxirane in 2.0 mL THF is added. The cooling bath is removed and the reaction is warmed to RT. The reaction mixture is poured into 50 mL aqueous ammonium chloride solution and the aqueous phase is extracted with EtOAc. The combined organic phase is washed with water, dried over MgSO4. After filtration and evaporation of the solvent, the residue is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:40]=[CH:39][C:12]([O:13][CH2:14][C:15]3([CH3:38])[CH2:24][CH:23](O)[C:22]4[C:17](=[C:18]([CH3:37])[C:19]([CH3:36])=[C:20]([O:27][CH2:28][C:29]([O:31][CH2:32]COC)=[O:30])[C:21]=4[CH3:26])[O:16]3)=[CH:11][CH:10]=2)[S:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O1CCOCC1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]3([CH3:38])[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([CH3:37])[C:19]([CH3:36])=[C:20]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:21]=4[CH3:26])[O:16]3)=[CH:39][CH:40]=2)[S:3]1
Reactant: COCCOC(=O)COc1c(C)c(C)c2c(c1C)C(O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)COc1c(C)c(C)c2c(c1C)C=CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
A mixture of 970 mg of 2-methoxyethyl α-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]4-hydroxy-2,5,7,8-tetramethylchroman-6-yloxy}acetate (prepared as described in Example 37), 50 mg of p-toluenesulfonic acid, 10 ml of benzene and 1 ml of dioxane was heated under reflux in a nitrogen stream for 60 minutes. The reaction mixture was then washed with a 5% w/v aqueous solution of sodium bicarbonate and then with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with a 7:3 by volume mixture of benzene and ethyl acetate), to give the title compound.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](N)=[O:12])=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:20].[K+].O>C(O)C>[CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:20])=[O:12])=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: NC(=O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a solution of 4-cyclohexyl-3-(trifluoromethyl)benzamide (D33) (822 mg, 3.03 mmol) in ethanol (40 ml) was added potassium hydroxide (1.700 g, 30.3 mmol) and water (5 ml) and the reaction heated to 90° C. block temperature for 3 h and stirred at room temperature for 16 h. Further potassium hydroxide (1.700 g, 30.3 mmol) was added and the reaction heated at reflux for 27 h. A further 5 mL of water was added and the reaction heated for 66 hours (weekend). The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (25 mL) and aqueous hydrochloric acid (2M, 25 mL). The aqueous layer was further extracted with ethyl acetate (25 mL) and the combined organic phases dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound as a white solid (737 mg). MS (ES): C14H15F3O2 requires 272; found 271 (M−H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N+:16]([O-])([OH:18])=[O:17].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:8]2[S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([N+:16]([O-:18])=[O:17])=[CH:5][CH:4]=1
Reactant: COc1cccc2c1sc1ccccc12
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc([N+](=O)[O-])c2c1sc1ccccc12
Reaction time: 0.75 h

Procedure:
4-Methoxy-dibenzothiophene (ii)(4.3 g, 20.0 mmol) was dissolved in glacial acetic acid (60 ml) and to this solution was added fuming nitric acid (3.37 ml) in a dropwise fashion ensuring that the temperature of the mixture did not rise above 25° C. The yellow suspension was stirred for a further 45 minutes before being poured carefully into water (200 ml) and stirred for 15 minutes. The yellow solid was removed by filtration and washed thoroughly with copious amounts of water and then hexanes. The residue thus obtained was then dried in a vacuum oven to give the title compound as a yellow solid which was used without any further purification. (5.19 g, 97%) m/z (LC-MS, ESP), RT=4.15 min, (M+H)=260.1
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([CH2:14][NH2:15])[CH2:13][CH2:12]1.O>O1CCCC1>[CH:11]1([CH2:14][NH:15][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:13][CH2:12]1
Reactant: NCC1CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccnc1NCC1CC1
Reaction time: 1 h
Yield: 95.7 %

Procedure:
3 g (18.9 mM) of 2-chloro-3-nitropyridine and 5 g (70.3 mM) of cyclopropylmethylamine in 12 ml of tetrahydrofurane were refluxed under stirring for 1 h. Water was added and the aqueous layer was extracted with ethylacetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to give 3.5 g of N-(cyclopropylmethyl)-3-nitropyridin-2-amine as a yellow oil. Yield: 95.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7](O)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:32]([C:34]2[NH:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:42]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]=2[C:32]([N:29]2[CH2:28][CH2:27][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])[CH2:31][CH2:30]2)=[O:33])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Reactant: O=C(c1cc2ccccc2[nH]1)N1CCN(c2ccccc2Cl)CC1
Product: COc1ccc(C(c2ccc(OC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Yield: 80 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 4,4'-dimethoxybenzhydrol (2.37 g, 9.71 mmol) and 1-(2-chlorophenyl)-4-(indol-2-ylcarbonyl)piperazine (3.0 g, 8.83 mmol) to give 4.0 g (yield: 81%) of the title compound.
Reaction SMILES: C(NC[S:6][CH2:7][CH:8]([CH3:19])[C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])(=O)C.S>C(O)(=O)C.O>[SH:6][CH2:7][CH:8]([CH3:19])[C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10]
Reactant: CC(=O)NCSCC(C)C(=O)N1CCC[C@H]1C(=O)O
Agent: S
Solvent: O
Solvent: CC(=O)O
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
1-[3-(acetamidomethylthio)-2-methylpropanoyl]-L-proline (1.4 g.) and mercuric acetate (1.93 g.) are dissolved in a mixture of acetic acid (25 ml.) and water (25 ml.). After 1 hour stirring on the steam bath, hydrogen sulfide is bubbled through until no more precipitation of mercuric sulfide is observed. The mixture is filtered, the precipitate is washed with ethanol, and the filtrate is concentrated to dryness in vacuo to yield 1-(3-mercapto-2-methylpropanoyl)-L-proline. Rf : 0.35 (Silica gel, Benzene/Acetic acid 3:1); Rf : 0.5 (Silica gel, Methyl-ethylketone/Acetic acid/pyridine/water 14:1:2:1) identical to the compound of Example 34.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[N:2]1.Br[CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:26]=[C:17]1[C:18]2[C:19](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:21])[N:16]1[CH2:15][CH2:14][N:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[N:2]1
Reactant: CC(C)(C)OC(=O)c1cc[nH]n1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccn(CCN2C(=O)c3ccccc3C2=O)n1
Reaction time: 12 h
Yield: 32.2 %

Procedure:
To a solution of 2.31 g of tert-butyl 1H-pyrazole-3-carboxylate and 6.98 g of N-(2-bromoethyl)phthalimide in DMF (65 mL) was added 8.95 g of cesium carbonate at room temperature, followed by stirring for 12 hours. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-hexane) to obtain 1.51 g of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-pyrazole-3-carboxylate as a colorless solid.