Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([Cl:23])[CH:3]=1.C1COCC1.Br[C:30]1[N:31]=[CH:32][S:33][CH:34]=1>CCOC(C)=O.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:4]1[CH:3]=[C:2]([C:30]2[N:31]=[CH:32][S:33][CH:34]=2)[S:6][C:5]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3Cl)c(C)nc12
Reactant: Brc1cscn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cscn4)cc3Cl)c(C)nc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
To a 0° C. solution of 3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.60 g, 1.45 mmol) and THF (2 mL) is added 0.05 g/mL of Reike® Zn (3.80 mL, 2.91 mmol). The solution is heated at a reflux for 1 hour, and the excess Zn allowed to settle for 1 hour at ambient temperature. The solution is transferred to a flask of 4-bromo-thiazole (Kelly, T. et al. Tetrahedron, Lett. 1995, 51, 9293) (0.29 g, 1.74 mmol). PdCl2(dppf) (0.027 g, 0.036 mmol) is added and the solution heated at 65° C. overnight, diluted with EtOAc (40 mL), washed with sat. NH4Cl (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) followed by ISCO column chromatography (100% Et2O) to furnish the title compound (0.098 g, 0.24 mmol, 16%). 1H NMR (CDCl3) δ 0.88 (d, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.52 (s, 3H), 2.53 (s, 3H), 3.28-3.38 (m, 1H), 6.70 (s, 1H), 7.45 (s, 1H), 7.49 (d, J=2.0 Hz, 1H), 8.85 (d, J=2.0 Hz, 1H). LC/MS (m/z): calcd. for C20H21ClN4S2 (M+H)+: 417.1; found: 417.3.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:15])[CH2:4][C@H:5]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:6]([OH:8])=O.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH2:45]([N:52]1[CH2:56][C@H:55]2[C@H:57]([NH2:60])[CH2:58][CH2:59][C@H:54]2[CH2:53]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl>[CH2:45]([N:52]1[CH2:56][C@H:55]2[C@H:57]([NH:60][C:6](=[O:8])[C@@H:5]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[CH2:4][CH:3]([CH3:2])[CH3:15])[CH2:58][CH2:59][C@H:54]2[CH2:53]1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)C[C@@H](C(=O)O)N1CCOCC1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCOCC1
Reaction time: 0.25 h

Procedure:
(S)-4-Methyl-2-morpholinopentanoic acid hydrochloride (363 mg, 1.526 mmol) and triethylamine (0.387 mL, 2.77 mmol) were combined in dichloromethane (10 mL). 1-Hydroxybenzotriazole hydrate (234 mg, 1.526 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.270 mL, 1.526 mmol) were added, and the reaction was stirred for 15 minutes. Then (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine (300 mg, 1.387 mmol) from Example 16 Step E was added, and the reaction mixture was stirred at ambient temperature for 24 hours. The reaction was quenched with aqueous sodium bicarbonate and extracted with dichloromethane. The solvent was removed in vacuo and the crude material was purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.27 (d, J=7.3, 1H), 7.44 (d, J=7.4, 2H), 7.37 (t, J=7.5, 2H), 7.27 (dd, J=9.8, 17.3, 1H), 4.51-4.39 (m, 1H), 3.74 (t, J=4.5, 4H), 3.62 (d, J=13.1, 1H), 3.45 (d, J=13.1, 1H), 3.29-3.21 (m, 1H), 2.87 (dd, J=2.4, 9.0, 1H), 2.79 (dt, J=4.5, 9.3, 2H), 2.75-2.68 (m, 2H), 2.55 (d, J=14.8, 2H), 2.49-2.43 (m, 1H), 2.35 (dd, J=2.6, 8.9, 1H), 2.32-2.26 (m, 1H), 2.11 (dq, J=6.1, 12.1, 1H), 1.86 (dd, J=6.6, 12.2, 3H), 1.67-1.55 (m, 2H), 1.41 (dt, J=6.2, 20.1, 1H), 0.94 (dd, J=6.2, 11.1, 6H); MS (ESI+) m/z 400 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=3[OH:21])[CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[N:8]=[C:4]2[CH:3]=1.C(N(CC)C=O)C.[OH-].[Na+].[I-].[K+].[C:39]1([SH:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C)C=O>[C:39]1([S:45][C:2]2[CH:27]=[CH:26][C:5]3=[N:6][N:7]([C:9]4[CH:10]=[C:11]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=4[OH:21])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[N:8]=[C:4]3[CH:3]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)CCc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: CCN(C=O)CC
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(CCC(=O)O)cc(-n2nc3ccc(Sc4ccccc4)cc3n2)c1O
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a 1 liter, 4 necked, round-bottomed flask equipped with mechanical stirring and a nitrogen atmosphere is charged 100.0 g (0.258 mol) of methyl 3-(5-chloro-2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamate, 350 mL of N,N-diethylformamide, and 61.9 g (0.773 mol) of 50% aqueous sodium hydroxide solution. The mixture is heated at 75°-80° C. for 3 hours at which point the ester hydrolysis is complete. A catalytic mount of potassium iodide (5.0 g) is added. Thiophenol (32.2 g, 0.258 mol) is then added over a 20 minute period while the temperature remains at 75°-80° C. An additional portion of N,N-dimethylformamide (200 mL) is added during the addition of thiophenol to facilitate stirring. A 25 mL fraction of water/methanol is removed and the solution is refluxed for 48 hours. The reaction mixture is cooled, then partitioned between 1.0 L of 1N hydrochloric acid and 1.0 L of ethyl acetate. The phases are separated and the organic phase is dried over anhydrous magnesium sulfate, and the solvent is then removed under reduced pressure until the total volume is 500 mL. To this is added 200 mL of heptane and the solution is allowed to sit overnight. The resultant crystals are collected by vacuum filtration, washed with 9:1 heptane:ethyl acetate, and dried to afford 83.5 g (72% yield) of the title compound; mp 154°-156° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]([Si:40]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[SH:41])([CH3:39])[CH3:38].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:41][Si:40]([CH:42]([CH3:44])[CH3:43])([CH:45]([CH3:47])[CH3:46])[CH:37]([CH3:38])[CH3:39])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)[Si](Sc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1)(C(C)C)C(C)C
Temperature: 100 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
Bis[(2-diphenylphosphino)phenyl]ether (0.43 g; 0.80 mmol) and tris(dibenzylideneacetone)-dipalladium (0.37 mg; 0.40 mmol) were dissolved in 40 mL toluene. 4-[2-(Nonafluorobutane-1-sulfonyloxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (4.34 g; 7.76 mmol), triisopropyl-silanethiol (1.83 mL; 8.53 mmol) and sodium tert-butoxide (0.90 g; 9.3 mmol) were added and the reaction mixture was stirred under argon for 3 hours at 100° C. The reaction mixture was cooled to room temperature filtered through a pad of silica and concentrated in vacuo. The residue was purified by flash chromatography (silica gel; ethyl acetate/heptane) to give 1.58 g 4-(2-triisopropylsilanylsulfanyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (3.51 mmol; 45%).
Reaction SMILES: C([O:8][C:9](=[O:54])[C@@H:10]([NH:22][C:23](=[O:53])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([CH2:36][NH:37][CH2:38][C@H:39]([OH:52])[C:40]3[CH:45]=[CH:44][C:43]([OH:46])=[C:42]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:41]=3)[CH2:32][CH2:31]2)=[CH:26][CH:25]=1)[CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])C1C=CC=CC=1>[Pd].C(O)C.C1CCCCC=1>[OH:52][C@H:39]([C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[C:42]([NH:47][S:48]([CH3:51])(=[O:49])=[O:50])[CH:41]=1)[CH2:38][NH:37][CH2:36][CH:33]1[CH2:32][CH2:31][N:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([NH:22][C@@H:10]([CH2:11][C:12]([OH:14])=[O:13])[C:9]([OH:54])=[O:8])=[O:53])=[CH:25][CH:26]=2)[CH2:35][CH2:34]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(c3ccc(C(=O)N[C@@H](CC(=O)OCc4ccccc4)C(=O)OCc4ccccc4)cc3)CC2)ccc1O
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(c3ccc(C(=O)N[C@@H](CC(=O)O)C(=O)O)cc3)CC2)ccc1O
Temperature: 78 °C
Yield: 39.7 %

Procedure:
A mixture of (2S)-2-{[4-(4-{[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)-amino]-phenyl}-ethyl)amino]methyl}piperidin-1-yl)benzoyl]-amino}butanedioic acid dibenzyl ester (0.074 g, 0.1 mmol) and 0.08 g of 10% palladium on carbon in 4 mL ethanol-cyclohexene (3:1, v/v) was heated at 78° C. until the reduction was complete. The catalyst was filtered (Celite) and the cake was washed with hot methanol. The solvent was removed in vacuo to give 0.023 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[C:14](\Br)/[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([Zn]CC)[CH3:26]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[C:14](/[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)\[CH2:25][CH3:26])[CH2:11][O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[Zn]CC
Reactant: CC(C)(C)OC(=O)N1[C@@H](/C=C(\Br)c2ccc(Cl)cc2)COC1(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC/C(=C\[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a stirred solution of (S)-4-[(Z)-2-bromo-2-(4-chloro-phenyl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.04 g) in THF (8 ml) were added bis(tri-tert-butylphosphine)dipalladium (0) (64 mg) and diethylzinc (4.99 ml, 1.1 M solution in toluene). The mixture was stirred at r.t. for 90 min then was diluted with ethyl acetate and washed with saturated brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-[(E)-2-(4-chloro-phenyl)-but-1-enyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (824 mg, 90%) as a colourless oil. MS (ISP): 368.5 ([{37Cl}M+H]+), 366.5 ([{35Cl}M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.Cl.[CH3:46][N:47]([CH3:52])[CH2:48][C:49](O)=[O:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:46][N:47]([CH3:52])[CH2:48][C:49]([N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:24]=[CH:25][C:20]([C:17]3[CH:18]=[C:19]4[C:11]([C:9]5[CH:8]=[N:7][N:6]([CH2:5][C:4]6[CH:42]=[CH:43][CH:44]=[C:2]([F:1])[CH:3]=6)[CH:10]=5)=[CH:12][N:13]([S:32]([C:35]5[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=5)(=[O:33])=[O:34])[C:14]4=[N:15][CH:16]=3)=[CH:21][CH:22]=2)[CH2:31][CH2:30]1)=[O:50]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)CN(C)C)CC5)cc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-ii of example-124, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 1 of example 124) (75 mg, 0.123 mmol) was coupled with 2-(dimethylamino)acetic acid hydrochloride (26 mg, 0.185 mmol) using HATU (71 mg, 0.185 mmol), HOBt (25 mg, 0.185 mmol) and DIPEA (86 μL, 0.494 mmol) in DMF (2 mL) to get 80 mg (85.52%) yield of the title compound. MS: m/z=692.5 (M+1).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:15][C:14]3[C:9](=[C:10](Cl)[CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([CH:7]2[CH2:15][C:14]3[C:9](=[C:10]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: O=C1c2c(Cl)cccc2CC1C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: OCCO
Solvent: O
Product: O=C1c2c(cccc2-c2ccccc2)CC1C1CCCCC1
Temperature: 125 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Using a method similar to Example 16 d), 2.73 g (0.011 mol) of 2-cyclohexyl-7-chloro-1-indanone, 1.59 g (0.013 mol) of phenylboronic acid and 2.6 g (24.6 mmol) of sodium carbonate were placed in 55 ml of ethylene glycol/5 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 18 mg (0.09 mmol) of palladium acetate and 0.15 g (0.27 mmol) of TMSPP, the reaction mixture was stirred for 2 hours at 125° C. After addition of 60 ml of water, the aqueous phase was extracted 4 times with 60 ml each time of ether, the combined ether phases were washed with 60 ml of water and 60 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 2.9 g of 2-cyclohexyl-7-phenyl-1-indanone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cr](O)(O)(=O)=O.C(=O)(O)[O-].[Na+].O>C(O)(=O)C.CO>[CH3:23][C:20]1[CH:19]=[C:18]([C:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:24])[CH2:13][CH:14]=2)[O:22][N:21]=1
Reactant: Cc1cc(C2=CCN(CCCC(O)c3ccc(F)cc3)CC2)on1
Agent: O=[Cr](=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C2=CCN(CCCC(=O)c3ccc(F)cc3)CC2)on1
Reaction time: 3 h

Procedure:
A 1.65 g. portion of 3,6-dihydro-α-(p-fluorophenyl)-4(3-methyl-5-isoxazolyl)-1(2H)-pyridine butanol, prepared as described in Example 10, in 35 ml. of acetic acid is stirred at room temperature. A 30 ml. portion of chromic acid in acetic acid (prepared by dissolving 1.1 gm of chromium oxide in 50 ml. of acetic acid and 10 ml. of water) is added dropwise and the mixture is stirred for 3 hours and then allowed to stand overnight. A few drops of methanol are added and sufficient solid sodium bicarbonate to neutralize the solution. Water is also added. The mixture is extracted 3 times with ether. The extracts are dried over magnesium sulfate, filtered and evaporated yielding a pink solid which is recrystallized twice from methanol, m.p. 96°-98°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=[O:12])=[C:5]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[C:30]1([CH2:36]/[CH:37]=[CH:38]/B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Li+].[OH-]>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>[C:20]1([O:19][CH2:18][CH2:17][CH2:16][C:5]2[C:9]3[C:8](=[CH:4][CH:3]=[C:2](/[CH:38]=[CH:37]/[CH2:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:10]=3)[NH:7][C:6]=2[C:11]([OH:13])=[O:12])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)/C=C/Cc1ccccc1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCCOc1cccc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1[nH]c2ccc(/C=C/Cc3ccccc3)cc2c1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 11C (45.2 mg), (E)-3-phenylprop-1-enylboronic acid (21.1 mg), bis(triphenylphosphine)palladium(II) dichloride (catalytic), and 2M LiOH (0.3 mL) in 7/2/3dimethoxyethane/ethanol/H2O (2 mL) was heated under microwave (CEM Discover) conditions at 150° C. for 30 minutes. The mixture was quenched with 1 MHCl (0.4 mL) and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated. The cruconcentrate was purified by reverse phase HPLC (Zorbax SB-C18, 20-100% acetonitrile/water/0.1% trifluoroacetic acid). 1H NMR (500 MHz, DMSO-d6) δ 12.95 (brs, 1H), 11.44 (s, 1H), 8.34 (d, 1H), 7.88 (d, 1H), 7.54 (m, 2H), 7.44 (m, 2H), 7.31 (m, 5H), 7.18 (m, 3H), 6.83 (d, 1H), 6.00 (m, 2H), 4.08 (t, 2H), 2.21 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH-].[Na+].[C:17](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:17][NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Product: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Methyl 4-amino-3-nitrobenzoate (7.0 g), sodium hydroxide (5.7 g), potassium carbonate (4.9 g) and tetrabutylammonium bromide (0.22 g) were suspended in toluene (100 ml). The mixture was stirred for 1 hour at 40° C., and then dimethylsulfuric acid (7.7 ml) was added thereto and stirred for 2 hours. The reaction solution was extracted with ethyl acetate, and the extract was washed with water and dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give methyl 4-methylamino-3-nitrobenzoate (7.3 g, Y.:97%).
Reaction SMILES: [CH3:1][C:2]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=2)([CH3:6])[C:3](O)=[O:4].C(Cl)CCl.C1C=CC2N(O)N=[N:29]C=2C=1.[Cl-].[NH4+]>C(#N)C.CCN(CC)CC.O>[CH3:1][C:2]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=2)([CH3:6])[C:3]([NH2:29])=[O:4]
Reactant: CC(C)(C(=O)O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCCl
Solvent: CC#N
Product: CC(C)(C(N)=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86956.5 %

Procedure:
2-Methyl-2-(5-nitro-1H-indol-2-yl)-propanoic acid (4.12 g, 16.6 mmol) was dissolved in acetonitrile (80 mL). EDC (3.80 g, 0.020 mmol), HOBt (2.70 g, 0.020 mmol), Et3N (6.9 mL, 0.050 mmol) and ammonium chloride (1.34 g, 0.025 mmol) were added and the mixture was stirred overnight at room temperature. Water was added and the mixture was extracted with ethylacetate. Combined organic phases were washed with brine, dried over magnesium sulfate and dried to give 2-methyl-2-(5-nitro-1H-indol-2-yl)propanamide (4.3 g, 99%).
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[OH-].[K+].[BH4-].[Na+].Cl>O.C(OCC)(=O)C>[CH3:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:2]1[O:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccccc1C(=O)CCCC(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccccc1C1CCCC(=O)O1
Yield: 57.1 %

Procedure:
To a stirred suspension of 5-oxo-5-(2-methylphenyl)pentanoic acid (10 g) in water (100 mL) is added potassium hydroxide pellets (6.35 g). The temperature of the mixture is maintained at 2-20° C. whilst sodium borohydride (1.47 g) is added over 15 minutes. The reaction mixture is left at room temperature for 18 hours when 1 N hydrochloric acid (100 mL) is cautiously added followed by water (50 mL) and ethyl acetate (100 mL). The organic phase is separated and the aqueous phase extracted twice with ethyl acetate (100 mL). The combined organic phases are washed with brine (100 mL), dried over magnesium sulphate and evaporated to give 6-(2-methylphenyl)-tetrahydropyran-2-one (5.27 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11](=[O:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.CO.[BH4-].[Na+]>O>[CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(OCc2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OC1CC(OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A 100-mL round-bottom flask was charged with 3-(benzyloxy)cyclobutanone (2.00 g, 11.4 mmol), tetrahydrofuran (20 mL), and methanol (1 mL), and the solution was cooled to 0° C. Sodium borohydride (0.475 g, 12.5 mmol) was added portionwise, and the resulting mixture stirred for 30 min at room temperature. The reaction mixture was poured into water (30 mL), and extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3-(benzyloxy)cyclobutanol (1.83 g, 90%) as yellow oil. MS (ESI, pos. ion) m/z 179 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17](=[O:31])[NH:18][C:19](=O)[C:20]=2[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)=[CH:8]1>C(OCC)C.C1COCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17](=[O:31])[NH:18][CH2:19][C:20]=2[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)=[CH:8]1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1NCC(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 18 h
Yield: 18.3 %

Procedure:
20 ml of a 1M solution of LiAlH4 in diethyl ether was added to a solution of 1.0 g of 3,4-bis(3-indolyl)-1H-pyrrole-2,5-dione in 140 ml of THF. The mixture was stirred for 18 hours under nitrogen. The mixture was cooled to 0° C., quenched with 50 ml of water, then acidified to pH 2 with 2M hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was purified on silica gel with 5-10% methanol in dichloromethane. The first product eluted was triturated with ethyl acetate/hexane to give 175 mg of 3,4-bis(3-indolyl)-3-pyrrolin-2-one, m.p. 290°-293° C. (decomposition). The second product eluted was crystallized from ethyl acetate/chloroform to give 490 mg of 5-hydroxy-3,4-bis(3-indolyl)-3-pyrrolin-2-one, m.p. above 250° C. (decomposition).