Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[C:14]([C:26]([F:29])([F:28])[F:27])[CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH:2]([C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[C:14]([C:26]([F:29])([F:28])[F:27])[CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9])=[O:1]
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 88770.8 %

Procedure:
To a stirred solution of N-(3-(hydroxymethyl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (200 mg, 0.47 mmol) in CH2Cl2 (2 mL) was added freshly dried 4 Å MS and NMO (83 mg, 0.71 mmol). The mixture was stirred for 10 min before TPAP (17 mg, 0.05 mmol) was added, and the resulting reaction mixture was stirred 12 hours at room temperature. The reaction mixture was filtered through celite, concentrated under reduced pressure, and purified by flash column chromatography (3% to 7% MeOH/CH2Cl2) to afford title product (175 g, 88% yield). MS m/z: 420 [M+1].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[N:24][C:25]=1[O:26][CH3:27]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[N:24][C:25]([O:26][CH3:27])=[C:20]([Cl:19])[CH:21]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ncc(B(O)O)cc1Cl
Product: CCCNC(=O)c1nnc2c(-c3cnc(OC)c(Cl)c3)cccc2c1N
Yield: 41.2 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (119 mg, 0.385 mmol) and (5-chloro-6-methoxypyridin-3-yl)boronic acid (144 mg, 0.77 mmol) were reacted to afford the title compound (59 mg, 42% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.25 (t, J=6.0 Hz, 1H), 8.43-8.46 (m, 2H), 8.34 (d, J=2.0 Hz, 1H), 7.95 (apparent d, J=7.0, Hz, 1H), 7.80 (apparent t, J=7.8 Hz, 1H), 4.03 (s, 3H), 3.31 (apparent q, J=7.0 Hz, 2H), 1.59 (apparent sextet, J=7.0 Hz, 2H), 0.91 (t, J=7.0 Hz, 3H). MS APCI, m/z=372(M+H) HPLC 2.17 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:26])=[C:20]([CH:25]=3)[C:21]([O:23]C)=[O:22])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[OH-].[Li+]>O.C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:26])=[C:20]([CH:25]=3)[C:21]([OH:23])=[O:22])=[O:14])=[CH:27][CH:28]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1cc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)ccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.3 %

Procedure:
A reactor is charged with 0.5 g (1.3 mmol) of the solid obtained in step 2, 20 ml of a mixture water/THF (1/1) and 0.55 g (13 mmol) of lithium hydroxide. The mixture is stirred at room temperature for 6 hours. The solution is concentrated under reduced pressure and then diluted in 100 ml of water. The aqueous phase is extracted by 3*30 ml of ethyl acetate and acidified with chlorhydric acid 32% until pH comprised between 2 and 3. the aqueous phase is extracted with 3*30 ml ethyl acetate. The organic phases are combined, dried on sodium sulphate and evaporated under reduced pressure. 250 mg of a solid is obtained (52%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[N:21]=[C:20]([CH3:23])[C:19](=[O:24])[NH:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[N:36]=[C:37]=[O:38]>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[NH:36][C:37]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[N:21]=[C:20]([CH3:23])[C:19](=[O:24])[NH:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1)=[O:38]
Reactant: Cc1nc2c(Oc3ccc(N)c4ccccc34)ccnc2[nH]c1=O
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: Cc1nc2c(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c4ccccc34)ccnc2[nH]c1=O

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound as a slightly pink solid (50 mg, 61%).
Reaction SMILES: Br[C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: O=Cc1c[nH]c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccccc1-c1cc(C=O)c[nH]1
Temperature: 105 °C
Yield: 67.6 %

Procedure:
5-Bromo-1H-pyrrole-3-carbaldehyde (100 mg), 2-methylphenylboronic acid (94 mg) and sodium carbonate (146 mg) were suspended in a mixed solvent of 1,2-dimethoxyethane (5 mL) and water (2 mL), and the mixture was sufficiently degassed under a nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium (33 mg) was added, and the mixture was further degassed and refluxed at 105° C. for 24 hr. The reaction mixture was allowed to cool to room temperature, and the mixture was extracted with water and ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=8:1→3:1) to give the title compound as colorless crystals (yield 72 mg, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](O)=[O:25])[CH:19]=1>>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:25])[CH:19]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(O)c1cccnc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cccnc4)cc3c2C1
Yield: 53.8 %

Procedure:
Beginning with 9.2 mg (0.040 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 12.5 mg (0.101 mMol) 3-pyridinecarboxylic acid, 7.2 mg (54%) of the title compound were recovered as a beige solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:19]1([C:25]2[CH2:29][CH2:28][C:27](=O)[CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.O.CO>[C:2]1([C:27]2[CH2:28][CH:29]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:26]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: O=C1C=C(c2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C1=C(c2ccccc2)C=C(c2ccccc2)C1

Procedure:
A mixture of 7.9 g (0.050 mole) of bromobenzene in 15 ml tetrahydrofuran was slowly added to a mixture of 34 ml of a solution of n-butyllithium in hexane (1.6 mole/liter, 0.055 mole n-butyllithium) and 40 ml of tetrahydrofuran at -80° C. At -40° C., 4.7 g (0.030 mole) of 3-phenylcyclopent-2-en-1-one in a small amount of tetrahydrofuran, was slowly added to the mixture. The resultant mixture was allowed to reach room temperature. Methanol and water were added. The 1,3-diphenylcyclopentadiene formed was recovered by extraction and crystallization.
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.[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[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][NH:31][CH2:30][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1
Reactant: NCC1CCCCC1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CNCC2CCCCC2)cc1
Yield: 71.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-((cyclohexylmethylamino)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.070 g; 0.202 mmol), cyclohexylmethanamine (0.120 mL; 0.907 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 2 to 10% methanol in dichloromethane) furnished 0.061 g (71%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18]>N1C=CC=CC=1.O1CCCC1>[CH3:26][O:25][C:21]1[CH:20]=[C:16]([CH:15]=[C:14]([O:13][CH3:12])[C:22]=1[O:23][CH3:24])[C:17]([NH:11][C:5]1[C:6](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:7]([OH:9])=[O:8])=[O:18]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(C(=O)Nc2ccc(Cl)cc2C(=O)O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
To a solution of 1.7 g of 5-chloroanthranilic acid in 40 ml of pyridine is added a solution of 2.6 g of 3,4,5-trimethoxybenzoylchloride in tetrahydrofuran under cooling, and the mixture is stirred at room temperature for 2 hours and then heated to 80° C. for 30 minutes. The reaction mixture is concentrated under a reduced pressure and to the residue is added water. The precipitated crystals are recrystallized from acetone to obtain 1.4 g of N-(3,4,5-trimethoxybenzoyl)-5-chloroanthranilic acid as colorless needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[CH2:27][O:26]3)[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[CH3:28][NH2:29]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([OH:26])[CH2:27][NH:29][CH3:28])[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CN
Reactant: O=S(=O)(Nc1cccc(C2CO2)c1)c1ccc(-c2ccc(F)cc2F)cc1
Solvent: CCO
Product: CNCC(O)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)c1

Procedure:
Using a method analogous to Method D, using 2′,4′-difluoro-N-(3-(oxiran-2-yl)phenyl)biphenyl-4-sulfonamide and 33% methylamine in ethanol, a mixture of regioisomers was obtained. This solution was evaporated and the isomers were separated by flash chromatography (SiO2, eluting with 5% to 20% methanol/DCM, containing 0.1% concentrated aqueous NH3), giving ABD789 as a light orange powder (165 mg). With further elution (increasing the polarity slowly to 40% methanol/DCM) ABD783 was obtained as an orange gum, which was triturated with ether to give the title compound as a light orange powder (330 mg). 1H NMR (400 MHz, DMSO-d6): δ 2.47 (3H, s), 2.70-2.76 (1H, t), 2.80-2.89 (1H, dd), 4.85 (1H, d, J=8 Hz), 6.95-7.15 (2H, m), 7.10-7.25 (3H, m), 7.40 (1H, t), 7.55-7.65 (1H, m), 7.66 (2H, d, J=8 Hz) and 7.84 (2H, d, J=8 Hz). MS, m/z: Calcd, 418.11. Found, 418.28 (M).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[H-].[Na+].Cl[CH2:13][CH:14]=[CH:15][CH3:16]>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH2:13][CH:14]=[CH:15][CH3:16])[C:8]#[N:9]
Reactant: N#CCc1ccccn1
Reactant: CC=CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC=CCC(C#N)c1ccccn1
Temperature: 25 °C

Procedure:
A solution of 5.9 g. of 2-pyridylacetonitrile in 15 ml. of dimethylsulfoxide is added to a suspension of 1.2 g. of sodium hydride in 25 ml. of dimethylsulfoxide with stirring. The mixture is heated on a stream bath for 2 hours, then cooled to room temperature. 1-Chloro-2-butene (4.5 g.) is added dropwise with stirring. The mixture is heated on a steam bath, with stirring, for 10 hours, then most of the solvent is removed in vacuo. Water is added to the residue, then 100 ml. of ether is added. The ethereal solution is separated from the aqueous layer and rinsed several times with water, then dried, concentrated and distilled to give 2-(2-pyridyl)-4-hexenenitrile.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[N:10]=2)[CH:7]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:16][C:5]1[CH:4]=[C:3]([F:19])[C:2]([Br:1])=[CH:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[N:10]=1
Reactant: Nc1nccc(Nc2cc(Br)c(F)cc2[N+](=O)[O-])n1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1nccc(Nc2cc(Br)c(F)cc2N)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of 4-N-(5-bromo-4-fluoro-2-nitrophenyl)pyrimidine-2,4-diamine (713 mg, 2.17 mmol) in ethanol (30 mL) was added tin(II) chloride dihydrate (1.72 g, 7.61 mmol) The reaction mixture was stirred at 60° C. for 1 hr. Upon completion, reaction mixture was evaporated to dryness and added to ice water (20 mL). The pH was adjusted to pH10 using sat Na2CO3 solution (30 mL) and EtOAc (30 mL) was added. Saturated Rochelle's salt (20 mL) was added and the mixture stirred until separate layers were observed. The organic layer was separated and the aqueous layer extracted with EtOAc (2×5 mL). Combined organics were washed with saturated Rochelles salt (15 mL) followed by brine solution (15 mL) and dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a pale orange solid (500 mg, 68.7% yield); 1H NMR (250 MHz, DMSO) delta 8.11 (s, 1H), 7.75 (d, J=5.7 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 6.67 (d, J=11.1 Hz, 1H), 6.08 (s, 2H), 5.75 (d, J=5.7 Hz, 1H), 5.37 (s, 2H); LC-MS: m/z+299.75 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1C=CC=C[CH:3]=1.C(OC(=O)[C@@H](CC([O-])=O)NC(OC(C)(C)C)=O)(=C)C.CNC(=O)[C@H](C(C)(C)C)N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[CH:2]=[CH2:3]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: C=C(C)OC(=O)[C@@H](CC(=O)[O-])NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC(=O)[C@@H](N)C(C)(C)C
Product: C=CCOC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Yield: 84 %

Procedure:
According to Example 1(b) for 3(R)-t-butyloxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, β-allyl-N-t-butoxycarbonyl-D-aspartate (Belshaw, P.; Mzengeza, S.; Lajoie, G. Syn Commun 1990, 20, 3157-3160; 2.00 g, 7.32 mmol) and L-t-leucine N-methylamide (Malon, P.; Pancoska, P.; Budesinsky, M.; Hlavacek, J.; Pospisek, J.; Blaha, K. Coll. Czech. Chem Commun. 1983, 48, 2844-2861; 1.05 g, 7.32 mmol) were coupled with TBTU. The resultant yellow oil was routinely used without further purification. Flash column chromatography with 2% MeOH/CH2Cl2 provided 2.44 g (84%) of 3(R)-(t-butoxycarbonylamino)-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid allyl ester as a pale yellow oil. 1H NMR (CDCl3): δ 7.05 (d, 1H, J=9.0 Hz), 5.98 (d, 1H, J=4.4 Hz), 5.77 (ddt, 1H, J=5.6, 10.3, 16.2 Hz), 5.29 (ddd, 1H, J=1.5, 2.8, 15.6 Hz), 5.23 (dd, 1H, J=1.3, 10.5 Hz), 4.57 (dddd, 2H, J=1.6, 3.1, 5.6, 12.1 Hz), 4.11 (d, 1H, J=9.4 Hz), 2.77 (d, 3H, J=5.0 Hz), 1.46 (s, 9H), 0.99 (s, 9H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:29])[CH2:23][C:22]([CH3:25])([CH3:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:26](=O)[CH3:27])[CH:20]=2)[O:15]1.C([N-]C(C)C)(C)C.[Li+]>C1COCC1.CCCCCC>[CH3:13][C:14]1([CH3:29])[CH2:23][C:22]([CH3:24])([CH3:25])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:26]#[CH:27])[CH:20]=2)[O:15]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)O2
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a cooled (-78 degrees C.) solution of 522 mg (5.17 mmol) of diisopropylamine in 8 ml of dry THF was added slowly, under nitrogen, 3.23 ml of 1.6 M (5.17 mmol) n-butyl lithium in hexane. The mixture was stirred at -78 degrees C. for 40 minutes and then treated with a solution of 1.24 g (5.17 mmol) of 2,2,4,4-tetramethyl-6-acetylchroman (Compound 41) in 2 ml of dry THF. The mixture was stirred at -78 degrees C. for a further 1 h and then treated with 895 mg (5.19 mmol) of diethyclhorophosphate. The reaction mixture was allowed to warm to room temperature and transferred by double-ended needle into a solution of lithium diisopropylamide in THF at -78 degrees C. [prepared as described above from 1.04 g (10.34 mmol of diisopropylamine and 6.46 ml of 1.6 M (10.34 mmol) of n-butyl lithium in hexane]. The cooling bath was removed and the mixture was stirred at room temperature for 16 h. The mixture was then treated with 10 ml of ice water and acidified to a pH of 2 with 10% HCl. The organic layer was separated and the aqueous layer was extracted with 3×30 ml of pentane. The organic extracts were combined and washed successively with 2×30 ml of dilute HCl, water, 3×30 ml of saturated NaHCO3 solution and saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue was purified by lash chromatograph (silica; 2% ethyl acetate in hexane) to give the title compound as a pale yellow oil. PMR (CDCl3): & 1.31 (6H, s), 1.32 (6H, s), 1.50 (2H, s), 3.00 (1H, s), 6.72 (1H, d, J~8.4 Hz), 7.20 (1H, dd, J~8.4 Hz, 2.1 Hz), 7.42 (1H, d, J~2.1 Hz). MS exact mass, m/e 2.14.1251 (calcd. for C15H18O, 214.1357)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1([S:20]([NH2:23])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:13]=[C:11]([NH:23][S:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:22])=[O:21])[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.9 %

Procedure:
3-(Tert-butoxycarbonylamino)propanoic acid (4 g, 21.2 mmol, 1.0 equiv) was dissolved in DCM (100 mL). Then phenylsulfonamide (15.1 mmol, 0.7 equiv), EDCI (3.45 g, 18.2 mmol, 0.85 equiv) and DMAP (0.37 g, 3 mmol, 0.15 equiv) were added to the mixture and stirred for 2 h at room temperature. The reaction mixture was cooled down to 0° C., ice water (100 mL) was added. The mixture was stirred for 15 min, separated and the water layer was extracted twice with dichloromethane. The combined organic layer was washed by 5% HCl, brine, dried over Na2SO4, concentrated to give tert-butyl 3-oxo-3-(phenylsulfonamido)propylcarbamate 5.3 g, gray oil, 100%. EDI-MS: 329.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.52˜9.43 (brs, 1H), 8.02˜7.96 (m, 2H), 7.61˜7.55 (m, 1H), 7.50˜7.45 (m, 2H), 5.02˜4.23 (m, 1H), 3.30˜3.24 (m, 2H), 2.48˜2.41 (m, 2H), 1.34 (s, 9H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:2]=[CH2:3].B(F)(F)F.[CH3:20]COCC>CO>[CH2:1]([NH:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH2:7][CH2:8][C:9]([O:11][CH3:20])=[O:10])[CH:2]=[CH2:3]
Reactant: CCOCC
Reactant: C=CCNc1ccccc1CCC(=O)O
Agent: FB(F)F
Solvent: CO
Product: C=CCNc1ccccc1CCC(=O)OC
Temperature: 0 °C

Procedure:
A solution of 50.5 g. of 2-(allylamino)hydrocinnamic acid and 34.4 ml. of boron trifluoride etherate in 200 ml. of methanol is stirred under reflux for 44 hours, allowed to cool, and poured into 1.20 liters of ice-cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield methyl 2-(allylamino)hydrocinnamate.
Reaction SMILES: [C:1]([N:5]([OH:15])[C:6]([C:8]([CH3:14])([CH3:13])[C:9](OC)=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[C:1]([N:5]([OH:15])[C:6]([C:8]([CH3:14])([CH3:13])[CH:9]=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)(C)C(=O)N(O)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C=O)C(=O)N(O)C(C)(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
To a stirred solution of methyl 2-(tert-butyl-N-hydroxycarbamoyl)-isobutyrate (2.00 g) in dry CH2Cl2 (20 mL) at −78° C. under N2, 1M DIBAH in CH2Cl2 (17.14 mL) was added dropwise. The mixture was stirred at −78° C. for 3 hours and quenched by careful addition of MeOH (28 mL), Et2O (30 mL) and saturated aqueous solution of sodium potassium tartrate (30 mL). After 1 h the mixture was extracted three times with Et2O. The combined organic layers were washed with water, brine, dried over Na2SO4 and the solvent evaporated to dryness to give 2-(tert-butyl-N-hydroxycarbamoyl)-isobutyraldehyde (1.23 g, 71%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.02 (1H, s), 9.58 (1H, s), 1.38 (9H, s), 1.17 (6H, s).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[C:11](=O)[O:12][C:13](=[O:25])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)=[CH:2]1.[NH3:27]>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[C:11](=[O:12])[NH:27][C:13](=[O:25])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)=[CH:2]1
Reactant: Cn1cc(C2=C(c3csc4ccccc34)C(=O)OC2=O)c2ccccc21
Reactant: N
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3csc4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 140 °C

Procedure:
160 mg of 3-(1-benzothiophen-3-yl)-4-(1-methyl-3-indolyl)furan-2,5-dione were treated with 2 ml of DMF and 20 ml of 33% aqueous ammonia and the mixture was heated at 140° C. for 5 hours. The cooled mixture was filtered and the residue was washed with water and dried. The solid was purified on silica gel with 50% ethyl acetate in petroleum ether to give 20 mg of 3-(1-benzothiophen-3-yl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 250°-255° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[O:17][C:18]([F:21])([F:20])[F:19])(=[O:9])=[O:8].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1B(O)O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:26]2[CH:25]=[CH:24][C:23]([F:22])=[CH:28][C:27]=2[F:29])=[CH:12][C:11]=1[O:17][C:18]([F:21])([F:20])[F:19])(=[O:9])=[O:8]
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1OC(F)(F)F
Reactant: OB(O)c1ccc(F)cc1F
Product: O=S(=O)(NCCCCO)c1ccc(-c2ccc(F)cc2F)cc1OC(F)(F)F

Procedure:
Using a method analogous to that described in Example 40, 4-bromo-2-trifluoromethoxyphenyl-sulfonic acid-(4-hydroxybutyl)-amide and 2,4-difluorophenyl boronic acid were reacted to give the title compound as a white powder. δC (CDCl3, 62.9 MHz): 26.4, 29.5, 41.2, 62.1, 104.9 (t, J 26.0), 112.3 (dd, J 21.3, 2.9), 122.3 (dd, J 12.7, 3.9), 127.5, 131.3, 131.5, 131.5, 131.7 (d, J 2.0), 136.2, 140.6, 159.9 (dd, J 252.0, 11.7) and 163.3 (dd, J 252.0, 11.7).