Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]([C:7]1[N:12]2[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[CH:9]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:8]=1[CH3:26])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH2:27](Br)[CH:28]=[CH2:29]>C(N(CC)CC)C>[CH2:29]([C:9]1([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:8]([CH3:26])=[C:7]([C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[O:6])[N:12]2[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10]1(=[O:19])=[O:18])[CH:28]=[CH2:27]
Reactant: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(c3nnnn3C)S(=O)(=O)[C@H]12
Reactant: C=CCBr
Solvent: CCN(CC)CC
Product: C=CCC1(c2nnnn2C)C(C)=C(C(=O)C(C)(C)C)N2C(=S)[C@H](OC)[C@H]2S1(=O)=O
Reaction time: 2 h

Procedure:
A solution of 4-tert-butylcarbonyl-7α-methoxy-3-methyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-cephem 1,1-dioxide (100 mg) and allyl bromide (0.061 ml) was treated, at room temperature, with triethylamine (0.037 ml). After 2 hrs the reaction was over (TLC monitoring). Dilution with dichloromethane, washing with brine, drying over Na2SO4 and removal of the solvent left a residue which afforded the title compound as a white solide (60 mg) after flash chromatography.
Reaction SMILES: Br[C:2]1[N:11]=[C:5]2[CH:6]=[CH:7][C:8]([Br:10])=[CH:9][N:4]2[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[C:2]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:11]=2)[CH:9]=1
Reactant: Brc1ccc2nc(Br)nn2c1
Reactant: C1COCCN1
Product: Brc1ccc2nc(N3CCOCC3)nn2c1
Yield: 65.7 %

Procedure:
A mixture of 2,6-dibromo-[1,2,4]triazolo[1,5-a]pyridine (1 g, 3.61 mmol) and morpholine (10 g, 10 ml, 115 mmol) was refluxed for 4 hours under argon atmosphere. The mixture was evaporated to dryness under reduced pressure. Flash chromatography (silica gel, 50 g, 30-100% heptane/ethyl acetate) afforded 6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridine (672 mg, 66%) as a light yellow solid. Mp.: 136° C. MS: m/z=283.0/285.0 (M+H+).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[S:6][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[NH:4].[C:32]1([O:38]C(Cl)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl>ClCCl.C(#N)C.C(N(CC)CC)C>[F:29][C:28]([F:31])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[N:13]([S:10]([C:7]2[S:6][C:5]([C:3]4[NH:4][C:32](=[O:38])[O:1][N:2]=4)=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH2:14][CH2:15]3)=[CH:23][CH:24]=1
Reactant: N=C(NO)c1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)s1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccc(S(=O)(=O)N3CCc4cc(-c5ccc(C(F)(F)F)cc5)ccc43)s2)no1
Temperature: 0 °C

Procedure:
152 mg crude N-Hydroxy-5-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-thiophene-2-carboxamidine were dissolved in 10 ml dichloromethane. 1.0 ml triethylamine and 43 ml phenylchloroformate were added at 0° C. and the mixture stirred at 0° C. for thirty minutes. The mixture was diluted by the addition of 10 ml acetonitrile and 97 μl 1,8-diazabicyclo[5.4.0]undec-7-ene were added. The mixture was stirred at 0° C. for 15 minutes. Then the mixture was poured on 100 ml 1M HCl and extracted five times with portions of 50 ml dichloromethane. The combined organic extracts were washed with 100 ml saturated NaHCO3 solution. The organic layer was then dried over MgSO4. The solvent was removed in vacuo. The resulting crude material was purified by chromatography on silica gel to obtain 125 mg 3-{5-[5-(4-Trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-thiophen-2-yl}-4H-[1,2,4]oxadiazol-5-one. C21H14F3N3O4S2 (493.49), MS (ESI−): 492.2 (M−H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:11][N:10]2[C:12]3[CH:13]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=[CH:16][C:17]=3[C:18]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:9]2[C:8]2[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=2[O:6][CH2:5]1.[C:33]([O:37][C:38]([NH:40][CH2:41][CH2:42][C:43](O)=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[C:33]([O:37][C:38]([NH:40][CH2:41][CH2:42][C:43]([NH:1][CH2:2][CH2:3][CH:4]1[CH2:11][N:10]2[C:12]3[CH:13]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=[CH:16][C:17]=3[C:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[C:9]2[C:8]2[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=2[O:6][CH2:5]1)=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCN)COc1ccccc1-3
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCNC(=O)CCNC(=O)OC(C)(C)C)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 7(R,S)-(2-aminoethyl)-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.14 M) in DCM was treated with N-(tert-butoxycarbonyl)-β-alanine (2 eq) followed by HATU (1.3 eq) and DIPEA (2.5 eq) and the resulting mixture was stirred overnight at RT. The reaction was diluted with EtOAc and the combined organic layers were washed with sat. aq. NaHCO3, HCl (1N) and brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The product was used directly in the next step without further purification. (ES+) m/z 604 (M+H)+.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[CH:20]=[C:19]([C:21]([OH:23])=O)[NH:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[CH:20]=[C:19]([C:21]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])[NH:18][C:15]3=[N:16][CH:17]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C1CCNC1
Reactant: O=C(O)c1cc2cc(OCCCN3CCCCC3)cnc2[nH]1
Agent: Cl
Product: O=C(c1cc2cc(OCCCN3CCCCC3)cnc2[nH]1)N1CCCC1
Yield: 70 %

Procedure:
The title compound was synthesized in analogy to example 1 from 5-(3-piperidin-1-yl-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride and pyrrolidine to give the desired product as a colorless solid (70%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:22])=[C:4]([CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].COCCOC.Cl[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([OH:22])=[C:4]([CH:9]=[C:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(Cl)c1O
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(Cl)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of methyl 3-chloro-2-hydroxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.90 g), in a mixed solvent of DME (13.5 mL)-water (4.50 mL) were added 1-(chloromethyl)-4-methoxybenzene (0.43 g), tetrakis(triphenylphosphine)palladium(0) (0.16 g) and sodium carbonate (0.58 g), and the mixture was stirred at 80° C. overnight under argon atmosphere. The reaction mixture was allowed to be cooled to room temperature, water and ethyl acetate were added thereto, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:24]C)[C:10](=[O:23])[N:11]([CH3:22])[C:12]=2[N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[C:7]1=[O:26].C(OCC)C>Br.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:24])[C:10](=[O:23])[N:11]([CH3:22])[C:12]=2[N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[C:7]1=[O:26]
Reactant: COc1c2c(c(N(C)S(C)(=O)=O)n(C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CN(c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2)S(C)(=O)=O

Procedure:
A solution of N-[6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-methylmethane-sulfonamide (48 mg, 0.11 mmol) in 33% HBr in acetic acid (1 mL) was heated in an oil bath at 50° C. for 15 minutes. The product mixture was concentrated under vacuum, and the residue subject to preparative reverse phase HPLC purification. Collection and lyophilization of appropriate fractions afforded an oil. Trituration of the residual oil with diethyl ether provided the title compound as off white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH:14]=O)(=[O:4])=[O:3].[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:21]2[C:22](=[O:25])[CH2:23][O:24][C:20]=2[C:19]=1[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.N1CCCCC1>CO>[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:21]2[C:22](=[O:25])/[C:23](=[CH:14]/[C:8]3[C:7]4[C:11](=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=4)[NH:10][N:9]=3)/[O:24][C:20]=2[C:19]=1[CH2:28][N:29]1[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: CS(=O)(=O)c1ccc2[nH]nc(C=O)c2c1
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccc(S(C)(=O)=O)cc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
A solution of 5-(methylsulfonyl)-1H-indazole-3-carboxaldehyde (0.0392 g, 0.175 mmol) in methanol (0.7 mL) was added with tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0915 g, 0.252 mmol) synthesized in the same manner as that of Example B42, Step 5, and piperidine (0.00149 g, 0.0175 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-[(6-methoxy-2-{[5-(methylsulfonyl)-1H-indazol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0470 g, 47%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[Br:13][C:14]1[CH:15]=[C:16]([NH2:21])[CH:17]=[CH:18][C:19]=1[F:20]>>[Br:13][C:14]1[CH:15]=[C:16]([NH:21][C:2]2[CH:7]=[CH:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: Cn1ccc(Cl)c([N+](=O)[O-])c1=O
Product: Cn1ccc(Nc2ccc(F)c(Br)c2)c([N+](=O)[O-])c1=O
Yield: 40 %

Procedure:
4-Chloro-1-methyl-3-nitro-1H-pyridin-2-one was coupled to 3-bromo-4-fluorophenylamine, in the same way as in Example 1, to give 4-(3-bromo-4-fluorophenylamino)-1-methyl-3-nitro-1H-pyridin-2-one as a beige solid (2.0 g, 40%): δH (400 MHz, d6-DMSO) 3.36 (3H, s), 5.81 (1H, d, J 8), 7.33-7.37 (1H, m), 7.45 (1H, t, J 9), 7.64-7.68 (1H, m), 7.66 (1H, s), 9.73 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:9](=[O:11])([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH3:10]
Reactant: Sc1ccccc1Br
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Sc1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 2-bromothiophenol (100 g, 0.529 mol), acetic anhydride (62.4 mL, 0.661 mol), and 4-dimethylaminopyridine (3.2 g, 0.026 mol) in dichloromethane (1000 mL) was cooled in an ice-bath. Triethylamine (92.2 mL, 0.662 mol) was slowly added, and then the ice bath was removed. The mixture was stirred at room temperature for 1 hour. Water (10 mL) was added, and after a couple of minutes the mixture was washed with aqueous 1N hydrochloric acid (3×300 mL), 10% sodium hydroxide solution (3×300 mL), and 1N hydrochloric acid (300 mL), and then dried (Na2SO4), and filtered. Evaporation of the solvent left S-2-bromophenyl ethanethioate as a pale yellow oil (104 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[N:5]2.[C:13]1([C@H:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:21][C@@H:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:20])[CH:6]=[N:5]2
Reactant: C[C@@H](N)c1ccccc1
Reactant: Clc1cnc2cc(Br)ccc2n1
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H](Nc1cnc2cc(Br)ccc2n1)c1ccccc1
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of 6-Bromo-2-chloro-quinoxaline (0.45 g, 1 eq, 1.85 mmol) in DMSO (6 mL), was added (R)-1-phenylethanamine (0.67 g, 3 eq, 5.55 mmol) at room temperature. The mixture was stirred overnight. After completion of the reaction (confirmed by TLC), cold water (40 mL) was added to the reaction mixture and this was stirred for 1 hour at room temperature. The precipitate was filtered off, washed with water (10 mL) and then dried under vacuum to afford the title compound (0.48 g, 79%).
Reaction SMILES: C(S([C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)[CH:14]=[C:13]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:27][C@H:26]2[CH3:38])[N:12]=1)(=O)=O)C1C=CC=CC=1.[CH3:39][CH:40]1[CH2:44][CH2:43][CH2:42][NH:41]1>O1CCOCC1>[Cl:24][C:19]1[CH:18]=[C:17]([C:15]2[CH:14]=[C:13]([N:25]3[CH2:30][CH2:29][N:28]([C:31]4[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=4)[CH2:27][C@H:26]3[CH3:38])[N:12]=[C:11]([N:41]3[CH2:42][CH2:43][CH2:44][CH:40]3[CH3:39])[N:16]=2)[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1c1cc(-c2ccc(F)c(Cl)c2)nc(S(=O)(=O)Cc2ccccc2)n1
Reactant: CC1CCCN1
Solvent: C1COCCO1
Product: CC1CCCN1c1nc(-c2ccc(F)c(Cl)c2)cc(N2CCN(c3ncccc3Cl)C[C@H]2C)n1
Reaction time: 72 h

Procedure:
Dissolve 2-(benzylsulfonyl)-4-(3-chloro-4-fluorophenyl)-6-((R)-4-(3-chloropyridin-2-yl)-2-methylpiperazin-1-yl)pyrimidine (57 mg, 0.1 mmol) and 2-methylpyrrolidine (0.5 mmol) in dioxane (1.0 mL) under nitrogen atmosphere and beat at 110° C. for 72 hours. Concentrate under vacuum to afford crude product and purify by flash column chromatography using 5% EtOAc/hexane to afford the title product as white amorphous solid. NMR (CDCl3) δ 1.31 (3H, d, J=1.5), 1.41 (3H, dd), 1.69 (1H, m), 1.9 (1H, m), 2.0 (2H, m), 2.98 (2H, m), 3.39 (1H, m), 3.65 (2H, m), 3.82 (2H, m), 4.35 (2H, m), 4.68 (1H, m), 6.22 (1H, s), 6.86 (1H, m), 7.16 (1H, t), 7.61 (1H, d, J=1.6), 7.88 (1H, m), 8.07 (1H, m), 8.20 (1H, m). Mass spec m/z=501.13.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34]CC=C)=[CH:30][CH:29]=2)[C@H:10]([O:38][CH2:39][C@H:40]([OH:44])[CH2:41][O:42][CH3:43])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[BH4-].[Li+]>O1CCCC1.CC(O)=O.CC(O)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C@H:10]([O:38][CH2:39][C@H:40]([OH:44])[CH2:41][O:42][CH3:43])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=CCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@H](O)COC)cc1
Agent: [Pd]
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC[C@@H](O)CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(O)cc1

Procedure:
In analogy to the procedure described in example 11(c) the (3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was treated with palladium-II-acetate, triphenylphosphin and lithiumborohydride in tetrahydrofuran to yield the (3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-4-(4-hydroxy-phenyl)-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 568 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[NH:17][C:16]=2[CH:24]=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:26][NH:27][S:28]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35](=[O:40])[CH2:34]2)(=[O:30])=[O:29]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[NH:17][C:16]=2/[CH:24]=[C:34]2\[C:35](=[O:40])[NH:36][C:37]3[C:33]\2=[CH:32][C:31]([S:28](=[O:29])(=[O:30])[NH:27][CH3:26])=[CH:39][CH:38]=3)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CCOC(=O)N1CCN(CCCc2c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)NC)cc43)[nH]c3c2CCCC3)CC1
Yield: 61.5 %

Procedure:
4-[3-(2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazine-1-carboxylic acid ethyl ester (65 mg, 0.1 87 mmol) was condensed with 5-methylaminosulfonyloxindole (43 mg, 1.01 eq.) following the same condition used in Example 1 above. The precipitated solid was purified by flash chromatography, eluting with dichloromethan/methanol (50/1, 40/1, 30/1) to provide 65 mg of the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[O:9])=[CH:3][CH:2]=1.CO[CH:20]([N:23]([CH3:25])[CH3:24])OC>C1(C)C=CC=CC=1>[CH3:20][N:23]([CH3:25])/[CH:24]=[C:7](\[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)/[C:8]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14])=[O:9]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1cccc(C(=O)Cc2ccncc2)c1
Solvent: Cc1ccccc1
Product: CN(C)/C=C(/C(=O)c1cccc(C#N)c1)c1ccncc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
3-(Pyridin-4-yl-acetyl)-benzonitrile (4.91 g, 22.1 mmol) was dissolved into dry toluene (0.2 ml) and dimethoxymethyl-dimethyl-amine (10.6 g, 88.5 mmol) was added. The reaction mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. The solvent was removed under vacuum and crude 3-((E)-3-Dimethylamino-2-pyridin-4-yl-acryloyl)benzonitrile was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[C@H:13]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:12][C@@H:11]1O.C(Cl)(Cl)(Cl)[Cl:41].N1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC.CCCCCC.C(#N)C>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[C@H:13]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:12][C@H:11]1[Cl:41]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](/C=C/[C@H](CCC=C(C)C)OC2CCCCO2)[C@H](OC2CCCCO2)C[C@@H]1O
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)CCCCCC[C@@H]1[C@@H](/C=C/[C@H](CCC=C(C)C)OC2CCCCO2)[C@H](OC2CCCCO2)C[C@H]1Cl
Reaction time: 0.17 h

Procedure:
A solution of 1.0 g of (13E)-(8R,9S,11R,12R,15S)-9-hydroxy-19-methyl-11,15-bis(tetrahydropyran-2-yloxy)-13,18-prostadienoic acid methyl ester in 14 ml of a solution of 0.97 ml of carbon tetrachloride, 0.79 ml of pyridine, and 48 ml of acetonitrile was stirred together with 730 mg of triphenylphosphine for 70 hours at room temperature under argon. Thereafter the mixture was diluted with 16 ml of ether and 32 ml of hexane, further agitated for 10 minutes, filtered, and concentrated by means of a forced circulation evaporator. The evaporation residue was extracted with a mixture of 5 ml of ether and 95 ml of hexane, filtered, and concentrated to dryness under vacuum. The residue was purified by column chromatography on silica gel with hexane/20% ethyl acetate as the eluent, thus obtaining 720 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:11]([Cu])#[N:12]>CN(C=O)C.CCOC(C)=O>[C:11]([C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1)#[N:12]
Reactant: N#C[Cu]
Reactant: COc1ncc(Br)cc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ncc(C#N)cc1C
Temperature: 25 °C
Yield: 91.8 %

Procedure:
To a solution of 5-bromo-2-methoxy-3-methyl-pyridine (1.0 g, 5.0 mmol) in DMF (10 ml) was added CuCN (0.534 g, 6.0 mmol) and the resulting mixture is heated at reflux for 28 h. After cooling to room temperature the mixture is diluted with EtOAc and washed with 10% ammonia solution followed by water and brine solution. The organic layer was separated, dried over MgSO4 and evaporated under reduced pressure. The residue was purified by flash chromatography (5% EtOAc/Hexane) to give 5-cyano-2-methoxy-3-methyl-pyridine (36) (0.68 g, 93%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)=[CH:7][C:6]([C:23]2[O:24][C:25](=[O:29])[N:26]([CH3:28])[N:27]=2)=[CH:5][N:4]=1)[CH3:2].CC1(C)C(C)(C)OB(C2C=CC(NC(=O)OC(C)(C)C)=CC=2)O1.BrC1C=CC(N)=CC=1>O1CCOCC1.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>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[CH:7]=[C:6]([C:23]3[O:24][C:25](=[O:29])[N:26]([CH3:28])[N:27]=3)[CH:5]=[N:4][C:3]=2[CH2:1][CH3:2])=[CH:10][CH:11]=1
Reactant: CCc1ncc(-c2nn(C)c(=O)o2)cc1-c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Nc1ccc(Br)cc1
Solvent: C1COCCO1
Product: CCc1ncc(-c2nn(C)c(=O)o2)cc1-c1ccc(N)cc1
Temperature: 75 °C
Yield: 78 %

Procedure:
Step-1: tert-Butyl (4-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-3-yl)phenyl)carbamate: To a solution of Intermediate-1a (2.30 g, 8.10 mmol, 1.0 eq) and tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (2.58 g, 8.10 mmol, 1.0 eq; prepared from 4-bromoaniline by following the procedure described in organic and biomolecular chemistry, 2010, 8 (15), 3457) in dioxane (25 mL) was added Pd(PPh3)2Cl2 (284 mg, 0.40 mmol). The resulting mixture was thoroughly deoxygenated by subjecting to vacuum/nitrogen cycle three times and the reaction mixture was heated to 75° C. and further maintained for 15 h under nitrogen atmosphere. The resulting mixture was cooled to RT and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate-hexanes system as eluent) to afford 2.80 g (78%) of the desired compound as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 7.89 (s, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.0 Hz, 2H), 6.75 (s, 1H), 3.51 (s, 3H), 2.84 (q, J=7.0 Hz, 2H), 1.58 (s, 9H), 1.23 (t, J=7.0 Hz, 3H); ESI-MS (m/z) 397 (MH)+