Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:19])=[C:4]([C:14]([O:17]C)=[CH:15][CH:16]=1)[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3]([CH3:19])=[C:4]([C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: COc1ccc(F)c(C)c1C(=O)Oc1ccccc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(F)ccc(O)c1C(=O)Oc1ccccc1
Temperature: -78 °C
Reaction time: 1.23 h
Yield: 102 %

Procedure:
A 30 L 4-neck flask equipped with mechanical stirrer, thermometer and gas inlet was charged with a solution of compound 62 (1140 g, 4.38 mol) in CH2Cl2 (15 L). The brown solution was cooled to −78° C. with dry ice acetone bath under small N2 flow. A solution of BBr3 in CH2Cl2 (4.5 L, 5.26 mol) was added to the reaction at −70˜−78° C. with stirring over 74 min. The reaction mixture was the allowed to warm to 20˜25° C. over 3 h and stirred at room temperature for 16 h. Saturated aqueous NaHCO3 was added to the reaction mixture slowly to pH 2˜3. After stirring for 5 min, the layers were separated and the aqueous layer was extracted with CH2Cl2 (2×1 L). The organic layers were combined and washed with brine (2×2 L). The organic layer was dried over Na2SO4 and filtered and the filtrate was concentrated under reduced pressure to give 1100 g (>100%) of crude compound 63 as brown oil: 1H NMR (400 MHz, CDCl3) δ 10.66 (s, 1H), 7.50-7.44 (m, 2H), 7.36-7.31 (m, 1H), 7.26-7.18 (m, 3H), 6.86 (dd, J=9.3, 4.9 Hz, 1H), 2.60 (d, J=2.4 Hz, 3H); MS (ESI) m/z 245.11 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH3:19])[C:14](O)=[CH:15][CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)=[CH:4][CH:3]=1.[Br-:21].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:21][C:14]1[C:13]([CH3:19])=[C:12]2[C:17]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][C:10](=[O:20])[O:11]2)=[CH:16][CH:15]=1
Reactant: [Br-]
Reactant: Cc1c(O)ccc2c(-c3ccc(F)cc3)cc(=O)oc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(Br)ccc2c(-c3ccc(F)cc3)cc(=O)oc12

Procedure:
4-(4-fluorophenyl)-7-hydroxy-8-methyl-2-H-chromen-2-one, (4.47 g, 16.5 mol) and triphenylphosphine dibromide (7.68 g, 18.2 mmol) were heated in a sand bath at 320-350° C. for 0.5 h. The cooled mixture was dissolved in dichloromethane, silica gel was added and the mixture was evaporated. Chromatography on silica gel (hexane/EtOAC; 90:10), gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:12][CH2:11][C:10]([OH:14])=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: C=CC(=O)O
Solvent: O
Product: COc1ccc(NCCC(=O)O)cc1

Procedure:
3-(4-Methoxyanilino)propionic acid is prepared in a manner similar to that described in Example 1 but starting from p-anisidine (61 g; 0.495 mole), acrylic acid (9.5 g; 0.132 mole) and water (12 cc). After recrystallisation in toluene, the pure product (11.7 g; 0.060 mole) is obtained in the form of a white powder which melts at 89° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][O:10][C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.CS(C)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:25])[CH2:9][O:10][C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCC(O)c3ccc(F)cc3)cc2)S1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(Cc2ccc(OCC(=O)c3ccc(F)cc3)cc2)S1
Temperature: 0 °C
Reaction time: 5 h
Yield: 49.7 %

Procedure:
To a stirring solution of 5-{4-[2-(4-fluorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4-dione (0.52 g, 1.40 mmol) in DCM (15 ml) was added DMSO (0.5 ml) and the solution was cooled to 0° C. Phosphorus pentoxide (0.41 g, 1.44 mmol) was added followed by triethylamine (0.90 mL, 6.48 mmol). The reaction was allowed to slowly warm to RT and then stirred for 5 hours. The reaction mixture was partitioned between DCM and H2O, and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting white solid was chromatographed on a small silica gel column eluting with 10% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 0.25 g (48%) of the title compound as a white solid. MS (ESI+) for C18H14FNO4S m/z 359.9 (M+H)+. MS (ESI−) for C18H14FNO4S m/z 358.0 (M−H)−.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:10]2[C@H:6]([N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C(=O)[O:9]2)[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])[CH2:3]1.[Li+].[OH-]>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[OH:9][C@@H:10]1[C@H:6]([NH:7][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])[CH2:3][C@@H:2]1[CH3:1]
Reactant: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H]2[C@H]1OC(=O)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O
Temperature: 22 °C
Reaction time: 20 h
Yield: 83 %

Procedure:
To a solution of (+/−)-(3aR,7S,7aS)-tert-butyl 7-methyl-5-(3-nitropyridin-4-yl)-2-oxo-3a,6,7,7a-tetrahydrobenzo[d]oxazole-3(2H)-carboxylate (1.0 equiv.) in THF (0.20 M) was added 2M LiOH (3.0 equiv.) was added. The mixture was stirred overnight 20 hrs at 22° C. The mixture was diluted with EtOAc and NaHCO3(aq.). The layers were separated and the aqueous was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The golden foam was purified by ISCO chromatography to afford (+/−)-tert-butyl ((1R,5S,6S)-6-hydroxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-yl)carbamate in 83% yield. LC/MS (m/z)=350.2 (MH+), Rt=0.82 min.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].I[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH:19]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2)([CH3:21])[CH3:20]
Reactant: CC(C)I
Reactant: Oc1cccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc2ncccc12
Temperature: 80 °C
Yield: 91 %

Procedure:
To a mixture of quinolin-5-ol (2.00 g, 13.8 mmol) and K2CO3 (7.62 g, 55.1 mmol) in DMF (20 mL) was added 2-iodopropane (2.76 mL, 27.6 mmol). The reaction mixture was heated at 80° C. overnight before it was partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to dryness. The crude material was purified by column chromatography (10-20% EtOAc-Hex) to provide 5-isopropoxyquinoline (91%) as a light yellow oil. ESI-MS m/z calc 187.1. found 188.3 (M+1)+. Retention time: 1.06 minutes (3 min run).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:19][C:20]([OH:22])=[O:21])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24]O>O1CCOCC1>[CH3:24][O:21][C:20](=[O:22])[CH2:19][C:11]1[CH:12]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1
Reactant: CO
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (3-benzyloxy-5-trifluoromethyl-phenyl)-acetic acid (1.5 g, 4.8 mmol) in MeOH (10 mL) was added 4N HCl in 1,4-dioxane (2 mL), and the reaction was stirred at 80° C. for 1 hour. The mixture was concentrated and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][C:28](=[O:31])[C:27]=1[CH3:32].O.O.O.O.O.O.O.[Cl-].[Cl-].[Cl-].[Ce+3].[BH4-].[Na+]>O1CCCC1.CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][CH:28]([OH:31])[C:27]=1[CH3:32]
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(=O)CC1)C(=O)OC2
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(O)CC1)C(=O)OC2
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
A mixture of 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-one (0.17 g) and cerium trichloride heptahydrate (0.172 g) in tetrahydrofuran/methanol (12 mL, 4/1) was treated with sodium borohydride (0.035 g). After 0.5 hours, the reaction was diluted with ethyl acetate and washed with brine. Drying over magnesium sulfate was followed by filtration and solvent removal. Chromatography (hexanes/methylene chloride/ether, 1/1/1) gave the product 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ol (0.088 g) as a solid m.p. 108.0°-111.5° C.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[N:13]3[C:14]4[CH:20]=[CH:19][N:18](S(C5C=CC(C)=CC=5)(=O)=O)[C:15]=4[N:16]=[CH:17][C:12]3=[N:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>O1CCOCC1>[CH:3]1([C:9]2[N:13]3[C:14]4[CH:20]=[CH:19][NH:18][C:15]=4[N:16]=[CH:17][C:12]3=[N:11][CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ncc(C4CCCCC4)n23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: c1cc2c(ncc3ncc(C4CCCCC4)n32)[nH]1
Yield: 19.2 %

Procedure:
Aqueous NaOH (2N, 0.3 mL) was added to 8-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.051 g, 0.13 mmol) in 1,4-dioxane (3 mL) and the mixture was heated at reflux for about 1 h. The organic solvent was removed under reduced pressure and the aqueous phase neutralized with aqueous 1 N HCl and extracted with EtOAc (2×15 mL). The combined organic extracts were washed with brine (1×10 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The residue was suspended in MeCN (2 mL) and the precipitate was collected by filtration and dried to yield 8-cyclohexyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine as a tan solid (0.006 g, 19%): LC/MS (Table 2, Method a) Rt=2.12 min; MS m/z: 241 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:36]1[CH:41]2[CH2:42][NH:43][CH2:44][CH2:45][N:40]2[CH2:39][CH2:38][O:37]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:43]3[CH2:44][CH2:45][N:40]4[CH:41]([CH2:36][O:37][CH2:38][CH2:39]4)[CH2:42]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CN2CCOCC2CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1ccccc1-c1cc(N2CCN3CCOCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 38.2 %

Procedure:
A solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2002/16324A1] (200 mg, 0.388 mmol), octahydropyrazino[2,1-c][1,4]oxazine (EP472826, 111 mg, 0.776 mmol), and potassium carbonate (161 mg, 1.165 mmol) in 1 mL of DMSO was heated to 150° C. for 47 h. It was worked up by diluting with dichloromethane and extracting with brine. The organics were dried (Na2SO4), and the solvent removed. The product was purified by flash chromatography: silica, dichloromethane to dichloromethane: MeOH 95:5. Obtained 92 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C@H:20]3[C:37](=[O:38])[N:36]([CH3:39])[CH2:35][C:34]4[CH:40]=[C:30]([CH:31]=[CH:32][C:33]=4[C:41]([O:43]C)=[O:42])[NH:29][C:28](=[O:45])[O:27][CH2:26][C@H:25]([CH3:46])[C:24]4[CH:47]=[CH:48][C:21]3=[CH:22][C:23]=4[CH3:49])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1>[C:53]([O:52][C:50]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C@H:20]3[C:37](=[O:38])[N:36]([CH3:39])[CH2:35][C:34]4[CH:40]=[C:30]([CH:31]=[CH:32][C:33]=4[C:41]([OH:43])=[O:42])[NH:29][C:28](=[O:45])[O:27][CH2:26][C@H:25]([CH3:46])[C:24]4[CH:47]=[CH:48][C:21]3=[CH:22][C:23]=4[CH3:49])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:51])([CH3:56])([CH3:54])[CH3:55]
Reactant: COC(=O)c1ccc2cc1CN(C)C(=O)[C@H](Nc1ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c1)c1ccc(c(C)c1)[C@@H](C)COC(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1ccc(C(=O)O)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of 1C (25 mg, 0.033 mmol) in THF (1 mL) was added 1.0 N LiOH (0.5 mL) and the reaction mixture was stirred overnight. It was quenched with NH4Cl, extracted with EtOAC, washed with brine and concentrated. The crude was purified by prep HPLC (Axia Luna 5 u C18 30×100 mm) to give 1D (14 mg, 57% yield): MS (ESI) m/z: =754.3 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[C:8]([CH:10]=[CH2:11])[C:7]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:6]([F:17])[CH:5]=1)[CH3:3].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30](O)=[O:31])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].CCOC(OC(OCC)=O)=O>CN(C=O)C>[F:17][C:6]1[CH:5]=[C:4]([CH:2]([NH:1][C:30](=[O:31])[C:29]#[C:28][C:25]2[CH:26]=[CH:27][C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:23][CH:24]=2)[CH3:3])[CH:9]=[C:8]([CH:10]=[CH2:11])[C:7]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: CC(C)(C)c1ccc(C#CC(=O)O)cc1
Reactant: C=Cc1cc(C(C)N)cc(F)c1NS(C)(=O)=O
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Product: C=Cc1cc(C(C)NC(=O)C#Cc2ccc(C(C)(C)C)cc2)cc(F)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 85.1 %

Procedure:
N-[4-(1-Amino-ethyl)-2-fluoro-6-vinylphenyl]methanesulfonamide (0.03 mmol, 10.0 mg), (4-tert-butylphenyl)propynoic acid (step 2 of Example 11, 0.03 mmol, 6.52 mg), DEPC (0.03 mmol, 5.46 μl), and TEA (0.06 mmol, 8.36 μl) were added into DMF. The mixture was stirred for 12 hr. The reaction mixture was purified according to Example 12 to give a title product (11.3 mg, 95.09%).
Reaction SMILES: O1CCCCC1[O:7][C@H:8]1[C@H:22]([CH:23]=[CH:24][C@@H:25]([O:34]C2CCCCO2)[C@:26]([CH3:33])([O:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:10](=[O:41])[CH2:9]1.C([O-])(O)=O.[Na+]>C(O)=O.O.C1COCC1>[OH:7][C@H:8]1[C@H:22]([CH:23]=[CH:24][C@@H:25]([OH:34])[C@:26]([CH3:33])([O:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:10](=[O:41])[CH2:9]1
Reactant: CCCC[C@@](C)(OC)[C@@H](C=C[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CCCCCCC(=O)OC)OC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@@](C)(OC)[C@H](O)C=C[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC

Procedure:
A solution of the crude bis tetrahydropyranyl ether of Step C in formic acid, (16 ml), H2O (30 ml) and THF (35 ml) is stirred for 24 h at room temperature. The mixture is cooled in an ice-water bath, H2O (30 ml) is added, and solid NaHCO3 is added till a pH of 7 is reached. The aqueous layer is extracted with ether, the combined organic layers are washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. Column chromatograph separation on silica gel, eluting with 2% MeOH in AcOEt, gives (8R,11R,12R,15R,16R)-11,15-dihydroxy-16-methyl-l6-methoxy-9-oxo-prost-13-en-1-oic acid, methyl ester which solidifies in the freezer (m.p. 44-45° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1Cc1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 64.1 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(2-methoxybenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.075 g; 0.216 mmol), 2-methoxyphenylboronic acid (0.034 g; 0.216 mmol), tetrakis(triphenylphosphine)palladium(0) (0.013 g; 0.011 mmol), sodium carbonate (0.045 g; 0.431 mmol), sodium iodide (0.064 g; 0.431 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.058 g (53%) of the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([NH:12][CH3:13])[S:9]2)[C@@H:5]([OH:14])[C@@H:4]1[OH:15].C([O-])(O)=O.[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C1COCC1.O>[OH:15][C@@H:4]1[C@@H:3]([CH2:2][OH:1])[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([N:12]([CH3:13])[C:22](=[O:23])[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[S:9]2)[C@H:5]1[OH:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OCc1ccccc1)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.9 %

Procedure:
To a suspension of -(3aR,5R,6S,7R,7aR)-5-(hydroxymethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (1.50 g, 6.40 mmol) and NaHCO3 (1.01 g, 12.0 mmol) in THF/water (40 mL, 1:3) was added benzyl chloroformate (1.70 g, 10.0 mmol). The mixture was stirred at room temperature for 4 days. The organic solvent was removed under reduced pressure to result in a precipitate. The precipitated solid was collected by filtration, washed with Et2O and dried under vacuum, affording benzyl (-(3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white solid (1.72 g, 73%). 1H NMR (400 MHz, CD3OD) δ 7.44-7.32 (m, 5H), 6.13 (d, J=6.9 Hz, 1H), 5.27-5.20 (m, 2H), 4.14 (t, J=6.1 Hz, 1H), 4.02 (t, J=4.9 Hz, 1H), 3.74 (dd, J=2.4, 12.0 Hz, 1H), 3.63 (dd, J=6.1, 12.0 Hz, 1H), 3.53 (dd, J=4.5, 9.2 Hz, 1H), 3.47-3.43 (m, 1H), 3.39 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:27]([C:24]1[CH:25]=[CH:26][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=1)(=[O:29])=[O:28])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)-phenyl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride 1H-NMR (400 MHz, CDCl3): δ 1.21 (s, 9H), 7.30 (d, 2H, J=8.8 Hz), 7.36-7.44 (m, 4H), 7.47 (d, 1H, J=2.4 Hz), 7.54-7.63 (m, 4H), 7.21 (d, 1H, J=8.8 Hz), 9.92 (s, 1H). MS: m/z 473.4 (M++1).
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:20]=[C:19]([C:21](=[O:26])[NH:22][CH2:23][CH2:24][CH3:25])[CH:18]=[C:17]([Cl:27])[C:16]=1[C:28](Cl)=[O:29]>>[C:11]([NH:10][C:6]1[N:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:28]([C:16]3[C:17]([Cl:27])=[CH:18][C:19]([C:21]([NH:22][CH2:23][CH2:24][CH3:25])=[O:26])=[CH:20][C:15]=3[Cl:14])=[O:29])=[CH:2][NH:1][C:5]=12)(=[O:13])[CH3:12]
Reactant: CCCNC(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Reactant: CC(=O)Nc1nccc2cc[nH]c12
Product: CCCNC(=O)c1cc(Cl)c(C(=O)c2c[nH]c3c(NC(C)=O)nccc23)c(Cl)c1

Procedure:
4-{[7-(Acetylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl]carbonyl}-3,5-dichloro-N-propylbenzamide was prepared from N-(1H-pyrrolo[2,3-c]pyridin-7-yl)acetamide and 2,6-dichloro-4-(1-propylcarbamoyl)benzene carbonyl chloride (Compound No. 15).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH2:29]([N:36]1[CH2:41][CH2:40][N:39]([C:1]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[CH2:7]3)=[O:3])[CH2:38][CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Cc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 0.88 g of 5-carboxyoxindol in 10 ml of DMF was added under ice-cooling 0.82 ml of triethylamine, and 0.77 ml of isobutyl chloroformate was added thereto subsequently. The mixture was stirred at the same temperature for 1 hour. Then, 1.1 g of 1-benzylpiperazine was added thereto, and the mixture was stirred at room temperature overnight. After the reaction was completed, DMF was removed under reduced pressure, and to the residue was added an aqueous sodium hydrogencarbonate solution and extracted with chloroform. After washing with water and drying over magnesium sulfate, chloroform was distilled off under reduced pressure. The resultant residue was purified by silica-gel column chromatography (eluent: methylene chloride:methanol=50:1) and recrystallized from isopropyl alcohol to give 0.7 g of 5-(4-benzyl-1-piperazinylcarbonyl)oxindol.