Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[C:15]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:16]2S(C2C=CC=CC=2)(=O)=O)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C(OCC)(=O)C.CCCCCC>O1CCCC1>[C:1]([O:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[C:15]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[NH:16]2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2ccc(OC(=O)c3ccccc3)cc2n1S(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(OC(=O)c3ccccc3)cc2[nH]1
Temperature: 0 °C
Yield: 99 %

Procedure:
To a dry 100 mL and stir bar was charged with 4.70 g ethyl 6-(benzoyloxy)-1-(phenylsulfonyl)indole carboxylate (Example 210) and dissolved in 12.5 mL of anhydrous tetrahydrofuran then cooled to 0° C. To this rapidly stirring solution was added 35.0 mL 1.0 M tetrahydrofuran solution of potassium tert-butoxide dropwise via syringe. Upon complete addition the contents were warmed to room temperature and stirred an additional ½ hour then quenched with 10 mL of 3N HCl solution followed by addition of 30 mL of water. The reaction was extracted with 3×50 mL of ethyl acetate then dried over Na2SO4 and concentrated in vacuo. The crude material was purified via column chromatography to yield 3.28g (99.0% yield) of an off white solid. The product had a Rf of 0.42 20% ethyl acetate/hexane; 1H NMR (300 MHz, Acetone-D6); 8.80 Hz, (s, 1H), 8.02 Hz, (dd, 1H), 7.95 Hz, (dd, 1H), 7.68 Hz, (dd, 1H), 7.58 Hz, (m, 2H), 7.46 Hz, (d, 2H), 7.21 Hz, (d, 1H), 6.87 Hz, (dd, 1H), 4.31 Hz (q, 2H), 1.31 Hz (t, 3H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:4]=[N:3][CH:2]=1.[OH-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>O.CCOCC>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]1[CH:6]=[N:1][CH:2]=[N:3][CH:4]=1
Reactant: OCCCCCCc1cncnc1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: BrCCCCCCOCCCCCCc1cncnc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A mixture of 5-pyrimidinehexanol (1.82 g), 50% sodium hydroxide (6 ml), 1,6-dibromohexane (6 ml) and TAB (150 mg) was vigorously stirred at room temperature for 30 h then diluted with water (20 ml) and ether (25 ml). The organic phase was dried and evaporated in vacuo. The residue was purified by FCC eluting with hexane followed by hexane-ether (1:1) and ether, to give the title compound as a colourless liquid (2.21 g), t.l.c. (ether) Rf 0.35.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[C:15](O)=[O:16].C(Cl)(=O)C([Cl:22])=O>Cl>[CH3:1][C:2]1([CH3:18])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[C:15]([Cl:22])=[O:16]
Reactant: CC1(C)C(C(=O)O)=Nc2ccc3ccccc3c21
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Product: CC1(C)C(C(=O)Cl)=Nc2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
100 mg 1,1-dimethyl-1H-benzo[e]indole-2-carboxylic acid 3 (see under Example 1) were dissolved in 1.6 mL oxalyl chloride under vigorous developement of HCl-gas. While the solution was stirred at ambient temperature slowly a bright yellow began to precipitate. After 1.5 hours the reaction was complete and the excess of oxalylchloride was removed by distillation to give a yellow solid which was used without further purification.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])[CH3:3].[C:11]([C:16](=[CH:22]OCC)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:15])[CH2:12][CH2:13][CH3:14]>>[C:11]([C:16](=[CH:22][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[CH:2]([OH:1])[CH3:3])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Reactant: CC(O)c1ccccc1N
Product: CCCC(=O)C(=CNc1ccccc1C(C)O)C(=O)OCC
Yield: 96.8 %

Procedure:
2-(1-hydroxyethyl)aniline (30 g, 0.32 mol) and ethyl 2-butyryl-3-ethoxyacrylate (47.3 g, 0.22 mol) were heated together on a rotary evaporator (bath temperature 100° C.) for 1 hour to give ethyl 2-butyryl-3-(2-(1-hydroxyethyl)-phenylamino)acrylate as an oil (65 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH3:14]O>>[CH3:14][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reaction time: 18 h

Procedure:
A 1 L round bottom flask equipped with a stir bar and reflux condenser was charged 5H2SO4 (4 mL), methanol (400 mL) and 3-fluoro-4-nitrobenzoic acid (10 g). The reaction mixture was heated at reflux temperatures with vigorous stirring for 18 h. The methanol was removed and the crude residue was triturated with hexane and concentrated to give a colorless solid (9.79 g) that was used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:3][O:4][C:5]1[C:6]([I:22])=[CH:7][C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[N:14]=[CH:15][CH:16]=3)[C:11](=[O:19])[N:10]([CH3:20])[C:9]=2[CH:21]=1.C(N(C(C)C)C(C)C)C.[C:36]1(=O)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38](=[O:45])[O:37]1>O1CCOCC1.CCOC(C)=O.C(Cl)Cl>[I:22][C:6]1[C:5]([O:4][CH2:3][C@@H:2]([N:1]2[C:36](=[O:37])[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]2=[O:45])[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:21][C:9]2[N:10]([CH3:20])[C:11](=[O:19])[C:12]3[C:17]([C:8]=2[CH:7]=1)=[CH:16][CH:15]=[N:14][C:13]=3[CH3:18]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](N)CC(C)C)c(I)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)c(I)cc21
Yield: 60 %

Procedure:
To a solution of (S)-8-((2-amino-4-methylpentyl)oxy)-9-iodo-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (130 mg, 0.140 mmol) in 1,4-dioxane (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (54.2 mg, 0.419 mmol) and isobenzofuran-1,3-dione (24.83 mg, 0.168 mmol). The reaction mixture was refluxed for 16 h. After cooling, the reaction mixture was diluted with EtOAc (10 mL). The organics were washed with water, saturated aqueous NaHCO3. The combined aqueous layers were extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC plate using 2% Methanol: DCM as a eluent system to afford (S)-2-(1-((9-iodo-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (85 mg, 0.084 mmol, 60% yield) as a pale yellow solid. LC/MS (ESI) m/e 596.5 [(M+H)+, calcd for C28H27IN3O4 596.1] LC/MS retention time (method E): tR=1.3 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][C:39](Cl)=[O:40]>>[OH:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:39](=[O:40])[CH2:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[O:31][CH3:30])=[CH:7][CH:6]=1)[CH2:9][N:10]1[C:14](=[O:15])[C:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[C:11]1[CH3:28]
Reactant: COc1ccccc1CC(=O)Cl
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Product: COc1ccccc1CC(=O)Nc1ccc(C(O)CN2C(=O)C(c3ccccc3)(c3ccccc3)N=C2C)cc1

Procedure:
Synthesis in analogy to Example 8 and Example 19 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and (2-methoxy-phenyl)-acetyl chloride to yield N-{4-[1-hydroxy-2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-ethyl]-phenyl}-2-(2-methoxy-phenyl)-acetamide. LC/MS at 254 nm; [M+H] 535: Rt=3.003 min.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: CCCCCI
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 30 °C

Procedure:
Anhydrous K2CO3 (416g, 3 mol) was added to a mixture of 4-bromo-4′-hydroxybiphenyl (300 g, 1.2 mol), 1-iodopentane (234 ml, 1.79 mol) and 2-butanbne (600 ml). The reaction mixture was refluxed for 44 h until TLC (85:15 hexanes/EtOAc) showed complete consumption of the bromo alcohol. The mixture was cooled to about 30° C., diluted with CH2C12 (600 ml) and then filtered. The filtrate was washed twice with H2O and twice with a saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered and then dried at reduced pressure to provide a solid. This solid was isolated by filtration, washed repeatedly with a total of 2 L of ice-cold heptane to remove all traces of iodopentane and then dried overnight under high vacuum. Yield: 340 g (88%) of a white powder.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH:20]=[C:21]([F:22])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:22][C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccc(F)cc4)cc(F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(-c3ccc(F)cc3)cc(F)c2O1

Procedure:
The title compound was prepared (0.12 g, 96%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-fluoro-5-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.18 g, 0.43 mmol) and methylamine (0.27 g, 8.6 mmol). mp >250° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH:23]([CH3:25])[CH3:24].C(OCC)(=O)C>CN(C)C=O.O>[CH2:22]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:23]([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1cc2cc(C)ccc2[nH]1
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C)ccc2n1CC(C)C
Temperature: 120 °C
Reaction time: 1 h

Procedure:
In 30 ml of N,N-dimethylformamide are suspended 2.81 g of ethyl 5-methyl-1H-indole-2-carboxylate, 17.0 g of potassium carbonate and 11.3 ml of isobutyl iodide. The suspension is stirred at 120° C. for one hour. The reaction mixture is added to a mixture of ethyl acetate and water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent: toluene) to obtain 1.75 g of ethyl 1-isobutyl-5-methyl-1H-indole-2-carboxylate as a light yellow oily product.
Reaction SMILES: [OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[O:21]1[CH2:23][CH:22]1[C:24]1[CH:32]=[CH:31][C:27]2=[N:28][O:29][N:30]=[C:26]2[CH:25]=1>>[N:28]1[O:29][N:30]=[C:26]2[CH:25]=[C:24]([C@@H:22]([OH:21])[CH2:23][N:7]3[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([C:10]4[CH:19]=[CH:18][C:13]5[C:14](=[O:17])[O:15][CH2:16][C:12]=5[C:11]=4[CH3:20])[OH:1])[CH2:5][CH2:6]3)[CH:32]=[CH:31][C:27]=12
Reactant: c1cc2nonc2cc1C1CO1
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Product: Cc1c([C@@H](O)CN2CCN(C[C@H](O)c3ccc4nonc4c3)CC2)ccc2c1COC2=O

Procedure:
The title compounds were prepared as described for the synthesis of EXAMPLES 57-58 starting from 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one and 5-(oxiran-2-yl)-2,1,3-benzoxadiazole. The resulting two diastereomers were resolved by prep SFC on Chiralcel OJ 30×200 mm column eluting with 70 mL/min of 30% methanol (0.2% DEA)/CO2 at 35° C. with pressure of 100 bar.
Reaction SMILES: C(O[C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([C@@H:27]([OH:31])[CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:32])[CH:22]=[CH:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=O)C.C([O-])(=O)C.[K+]>CN(C)C=O>[C:9]([O:8][CH2:7][C:6](=[O:12])[C:5]1[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([C@@H:27]([OH:31])[CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:32])[CH:22]=[CH:23]2)[CH2:18][CH2:17]3)[CH2:14][CH:13]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]12C
Temperature: 105 °C
Reaction time: 6 h
Yield: 91.8 %

Procedure:
To a solution of the product of Example 13 (21.4 g) in 250 ml dimethylformamide, potassium acetate (25 g) was added. After stirring at 105° C. under nitrogen for 6 hours, the reaction mixture was cooled down to room temperature and poured into ice water (3 L). After filtration, crystallization from acetone afforded 21-acetoxy-11β-hydroxyl-1,4,16-pregnatriene-3,20-dione (17 g, 89.8%). Recrystallization gave yellowish long cubic, m.p.=203°-205° C. NMR (CDCl3) δ 1.25 (s, 3H, 13--CH3), 1.48 (s, 3H, 10--CH3), 2.18 (s, 3H, 21--Ac), 4.40 (m, 1H, 11--H), 4.94(m, 2H, 20--CH2O--). 6.02 (S, 1H, 4--H), 6.28 (dd, 1H, J=10 and 2 Hz, 2--H), 6.74 (m, 1H, 16--H), 7.30 (d, 1H, J=10 Hz, 1--H). Upon normal saponification there was obtained 11β,21-dihydroxy-1,4,16-pregnatriene-3,20-dione. Recrystallization from acetone gave needles (VI, 50.5%). m.p.=213°-215° C.; NMR (CDCl3) δ 1.25(s, 3H, 13--CH3), 1.49 (s, 3H, 10--CH3), 4.35-4.55 (m, 3H, 20--CH2 -- and 11--H), 6.02 (S, 1H, 4--H), 6.28 (dd, 1H, J=10 and 2 Hz, 2--H), 6.73(m, 1H, 16--H), 7.32 (d, 1H, J=10 Hz, 1--H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:38])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([S:14](=[O:37])(=[O:36])[NH:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([S:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=3[F:35])(=[O:26])=[O:25])[N:17]=2)[CH2:10][CH2:9]1)C>CO>[F:35][C:29]1[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][S:24]([C:18]1[N:17]=[C:16]([NH:15][S:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:38])=[O:5])[CH2:13][CH2:12]2)(=[O:36])=[O:37])[CH:21]=[C:20]([O:22][CH3:23])[N:19]=1)(=[O:25])=[O:26]
Reactant: CCOC(=O)CN1CCN(S(=O)(=O)Nc2cc(OC)nc(S(=O)(=O)Cc3cccc(F)c3F)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(NS(=O)(=O)N2CCN(CC(=O)O)CC2)nc(S(=O)(=O)Cc2cccc(F)c2F)n1

Procedure:
The title compound was prepared by adding 1M NaOH (1 mL) to a solution of {4-[2-(2,3-Difluoro-benzylsulfonyl)-6-methoxy-pyrimidin-4-ylsulfamoyl]-piperazin-1-yl}-acetic acid ethyl ester (the product from step i) (0.31 g) in MeOH (1 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase) then titurated with Toluene, DCM followed by Et2O to give the title compound as a white solid. Yield: 85 mg
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4](Cl)[C:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[S:20])=[CH:17][CH:16]=1>C(O)C>[CH3:1][O:2][C:3]([C:4]1[S:20][C:19]([C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:24])([F:13])[F:25])=[CH:23][CH:22]=2)=[N:21][C:5]=1[CH2:6][CH2:7][CH2:8][CH3:9])=[O:12]
Reactant: CCCCC(=O)C(Cl)C(=O)OC
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)OC
Yield: 69.3 %

Procedure:
To a solution of 3-oxo-heptanoic acid methyl ester (5.0 g, 31.6 mmol) in dry dichloromethane (80 mL) add sulfurylchloride (2.82 mL). Stir the reaction mixture at room temperature for 30 minutes then add water (20 mL) and the reaction mixture extracted five times with portions of 30 mL of dichloromethane. Wash the combined organic extracts with water, saturated aqueous solution of NaHCO3 and brine and then dry over MgSO4. Remove the solvent under reduced pressure to give 2-chloro-3-oxo-heptanoic acid methyl ester (6.0 g), which was used in the next step without further purification. To a solution of 2-chloro-3-oxo-heptanoic acid methyl ester (6.0 g, 31.1 mmol) in ethanol (50 mL) add 4-(trifluoromethyl) thiobenzamide (6.4 g, 31.2 mmol). Heat the reaction mixture to reflux overnight. Remove the solvent under reduced pressure and purify the residue by chromatography on silica gel (eluting with a gradient of n-heptane:ethyl acetate (100:1 to 60:1)) to give 4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-carboxylic acid methyl ester (7.4 g) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[O:29]=[C:30]1[NH:34][C@H:33]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:32][O:31]1>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[C@H:33]([CH2:35][O:36][C:37](=[O:44])[C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:32][O:31][C:30]4=[O:29])=[CH:3][C:4]=3[S:25]([CH3:28])(=[O:27])=[O:26])=[O:9])[CH2:11][CH2:12]2)=[O:24])=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: CS(=O)(=O)c1cc(N2C(=O)OC[C@H]2COC(=O)c2ccccc2)ccc1C(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Yield: 48.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-methylsulfonylbenzoic acid (2.8 g) and (4-chlorophenyl)piperidin-4-ylmethanone (2.6 g), (4-bromo-2-methanesulfonylphenyl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (4.8 g) was obtained. By reaction and treatment in the same manner as in Preparation Example 12 and using (4-bromo-2-methanesulfonylphenyl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (1.5 g) and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (796 mg), the title compound (938 mg) was obtained.
Reaction SMILES: S1C2C=CC=CC=2N=C1NN=CC1OC([N+]([O-])=O)=CC=1.[N+:21]([C:24]1[S:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22].[NH:31]([C:33]1[S:34][C:35]2[CH:41]=[C:40]([N+:42]([O-:44])=[O:43])[CH:39]=[CH:38][C:36]=2[N:37]=1)[NH2:32]>>[N+:42]([C:40]1[CH:39]=[CH:38][C:36]2[N:37]=[C:33]([NH:31][N:32]=[CH:29][C:27]3[S:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=3)[S:34][C:35]=2[CH:41]=1)([O-:44])=[O:43]
Reactant: NNc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: O=[N+]([O-])c1ccc(C=NNc2nc3ccccc3s2)o1
Product: O=[N+]([O-])c1ccc2nc(NN=Cc3ccc([N+](=O)[O-])s3)sc2c1

Procedure:
The compound 3p was prepared according procedure described for 3a by employing 5-nitrothiophen aldehyde (157 mg, 1 mmol) and 2-hydrazino-6-nitro-benzothiazole (210 mg, 1 mmol) at 70° C. for 2 h (yield 303 mg, 87%).
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:13]([O:15][C:16](=[O:20])/[CH:17]=[C:18](/[O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][C:2]([OH:1])([CH3:12])[CH3:11])[CH:5]=1)\[CH3:19])[CH3:14]
Reactant: CC(C)(O)Cc1cccc(O)c1
Reactant: CC#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(CC(C)(C)O)c1
Temperature: 80 °C
Yield: 84.3 %

Procedure:
A mixture of 3-(2-hydroxy-2-methyl-propyl)-phenol (1.00 g, 6.01 mmol), ethyl-2-butynoate (4.00 g, 36.06 mol) and potassium carbonate (0.830 g, 6.01 mmol) in tetrahydrofuran (20 mL) in a sealed tube was heated to 80° C. for 3.75 h. The reaction mixture was then cooled and filtered. The solids were washed with a small amount of tetrahydrofuran and the combined filtrate was collected and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0% to 30% ethyl acetate/hexanes) to afford (E)-3-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester (1.41 g, 84%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][N:15]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][NH2:15]
Reactant: Cc1[nH]c(-c2ccccc2)nc1CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1[nH]c(-c2ccccc2)nc1CCN
Temperature: 0 °C
Yield: 118 %

Procedure:
To a solution of 2-[2-(5-methyl-2-phenyl-1H-imidazol-4-yl)-ethyl]-isoindole-1,3-dione (5.3 g) in ethanol (80 ml) was added hydrazine hydrate (4.0 g). The reaction mixture was stirred under reflux for 4 h, cooled to 0° C., and the precipitate was filtered off. To the filtrate was added brine and cold 2N NaOH (20 ml), and the mixture was extracted with ethyl acetate. The organic phase washed with brine, dried over magnesium sulphate and evaporated to dryness in high vacuum to obtain 2-(5-methyl-2-phenyl-1H-imidazol-4-yl)-ethylamine (3.8 g) as an off-white solid, which was sufficiently pure to be used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])[C:3]1=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])[C:3]1=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CC(=O)OCCN1CCN(C)C1=O
Reactant: Nc1ccccc1N1CCOCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)OCCN1CCN(C)C1=Nc1ccccc1N1CCOCC1

Procedure:
Reaction of 1-methyl-3-(2-acetoxyethyl)-2-imidazolidinone (13.4 g) in benzene (80 ml) with 4-(2-aminophenyl)morpholine (10.6 g) in benzene (80 ml) in the presence of phosphorus oxychloride (7 ml) for 30 hours at 80°-85° C. gave 4-{2-[1-methyl-3-(2-acetoxyethyl)-2-imidazolidinylideneamino]phenyl}morpholine.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1.FC(F)(F)C(O)=O>>[CH3:1][S:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1
Reactant: CSc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-methylmercapto-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: Cl.Cl.Cl.Cl.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C@H:12]([C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1)=[O:15])[NH2:13].[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[CH:37]=[C:36]([C:38](O)=[O:39])[S:35][C:34]=2[CH:41]=1>>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[CH:37]=[C:36]([C:38]([NH:13][C@@H:12]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:20][CH2:21]3)=[O:15])[CH2:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=3)=[O:39])[S:35][C:34]=2[CH:41]=1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)Cc3ccccn3)CC2)CC1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](Cc3ccccn3)NC(=O)c3cc4ccc(Cl)cc4s3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-[β-(2-pyridinyl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperazine tetrahydrochloride and 6-chlorobenzo[b]thiophene-2-carboxylic acid (53%).