Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([CH3:14])[CH:3]=1.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>O1CCCC1.C(#N)C.C(OCC)(=O)C>[CH3:14][C:4]1[CH:3]=[C:2]([NH:1][C:22](=[O:23])[O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][C:5]=1[CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cc1cc(N)ccc1CNS(C)(=O)=O
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)Oc2ccccc2)ccc1CNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a stirred solution of N-(4-amino-2-methylbenzyl)methanesulfonamide (61 mg, 0.285 mmol) in tetrahydrofuran and acetonitrile as co-solvent were added phenylchloroformate (0.04 mL, 0.299 mmol) and pyridine (0.03 mL, 0.342 mmol). The reaction mixture was stirred for 3 h at room temperature. The mixture dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to give phenyl 3-methyl-4-(methylsulfonamidomethyl)phenylcarbamate (93 mg, 98%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[CH:13][N:14](COCC[Si](C)(C)C)[C:10]=2[C:9]2[O:8][C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:6]([I:29])[C:5](=[O:30])[C:4]=2[CH:3]=1.ClC1C2N(COCC[Si](C)(C)C)C=NC=2C2OC(C3C=CC=CC=3)=C(I)C(=O)C=2C=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[N:12]=[CH:13][NH:14][C:10]=2[C:9]2[O:8][C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:6]([I:29])[C:5](=[O:30])[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc2c(Cl)cc3c(=O)c(I)c(-c4ccccc4)oc3c21
Agent: C[Si](C)(C)CCOCn1cnc2c3oc(-c4ccccc4)c(I)c(=O)c3cc(Cl)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1c(I)c(-c2ccccc2)oc2c1cc(Cl)c1nc[nH]c12
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 4-chloro-7-iodo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-chromeno[7,8-d]imidazol-6-one and 4-chloro-7-iodo-8-phenyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-chromeno[7,8-d]imidazol-6-one (80 mg, 0.14 mmol) in DCM (4 mL) was added TFA (1.0 mL) at RT. After 18 h, the reaction mixture was evaporated to dryness. The crude residue was triturated with DCM and concentrated in vacuo to afford the title compound as a white solid (59 mg, 100%). LCMS (Method A): RT=4.38 min, [M+H]+=423/425.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][C:16]3[C:11](=[N:12][C:13](SC)=[N:14][CH:15]=3)[N:10]([CH3:20])[C:9]2=[O:21])=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[N:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:29]=[C:28]([CH:37]([CH3:39])[CH3:38])[CH:27]=1)=[O:24].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:51][NH2:52]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][C:16]3[C:11](=[N:12][C:13]([NH:52][CH3:51])=[N:14][CH:15]=3)[N:10]([CH3:20])[C:9]2=[O:21])=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[N:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:29]=[C:28]([CH:37]([CH3:39])[CH3:38])[CH:27]=1)=[O:24]
Reactant: CN
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1ccc(F)c(NC(=O)Nc3cc(C(C)C)nn3-c3ccccc3)c1)C2
Agent: O=C(OO)c1cccc(Cl)c1
Product: CNc1ncc2c(n1)N(C)C(=O)N(c1ccc(F)c(NC(=O)Nc3cc(C(C)C)nn3-c3ccccc3)c1)C2
Yield: 74 %

Procedure:
Using a procedure analogous to Example A2, the sulfide was oxidized with mCPBA to the sulfone and treated with methylamine to provide 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea (74% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.13 (dd, J=8, 2.5 Hz, 1H), 7.96 (brs, 1H), 7.52 (m, 4H), 7.42 (m, 1H), 7.25 (dd, J=12.9 Hz, 1H), 7.00 (m, 2H), 6.34 (s, 1H), 4.56 (s, 2H), 3.25 (brs, 3H), 2.86 (m, 1H), 2.78 (d, J=5 Hz, 3H), 1.20 (d, J=6 Hz, 6H); MS (EST) m/z: 530.2 (M+H+).
Reaction SMILES: O[C:2]1[C:3]([C:11]2([CH2:25][OH:26])[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]3[CH:22]=[CH:23][S:24][C:12]2=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.OC1C(C2(CO)C3C(=NC=CC=3)N(CCCCC)C2=O)=CC2OCOC=2C=1>>[CH2:17]([N:14]1[C:15](=[O:16])[C:11]2([C:3]3=[CH:4][C:5]4[O:9][CH2:8][O:7][C:6]=4[CH:10]=[C:2]3[O:26][CH2:25]2)[C:12]2[S:24][CH:23]=[CH:22][C:13]1=2)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2sccc21
Agent: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2cccnc21
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2sccc21

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 6-(6-hydroxy-1,3-benzodioxol-5-yl)-6-(hydroxymethyl)-4-pentyl-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one to replace 3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, the title compound was obtained (13%): 1H NMR (300 MHz, DMSO-d6) δ 7.30 (d, 1H), 6.79 (d, 1H), 6.46 (s, 1H), 6.16 (s, 1H), 5.88-5.83 (m, 2H), 4.86 (d, 1H), 4.62 (d, 1H), 3.80-3.56 (m, 2H), 1.73-1.11 (m, 6H), 0.88 (t, 3H); MS (ES+) m/z 358.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH:12]1([N:15]=[C:16]=[O:17])[CH2:14][CH2:13]1>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:16]([NH:15][CH:12]2[CH2:14][CH2:13]2)=[O:17])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C=NC1CC1
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(NNC(=O)c1ccc(Cl)cc1)NC1CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 4.00 g (23.4 mmol) of 4-chlorobenzoic acid hydrazide are placed in 50 ml tetrahydrofuran. 1.95 g (23.4 mmol) of cyclopropyl isocyanate, dissolved in 50 ml tetrahydrofuran, are added dropwise at 50° C., and the mixture further stirred overnight at 50° C. The solvent is evaporated in vacuo, diethyl ether is added to the residue and the solid formed is isolated and purified by filtration and further washing with diethyl ether. 5.92 g (ca. 100% of theory) of the target compound are thus obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.[C:27]1([C:32](Cl)=[O:33])[S:31][CH:30]=[CH:29][CH:28]=1.C(OCC)(=O)C.O>CN(C)C(=O)C>[O:22]=[C:20]1[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[S:17][C:16]([C:14]2[N:15]=[C:10]([CH2:9][NH:8][C:32]([C:27]3[S:31][CH:30]=[CH:29][CH:28]=3)=[O:33])[CH:11]=[CH:12][CH:13]=2)=[N:21]1
Reactant: O=C(Cl)c1cccs1
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cccc(-c2nc(=O)c3ccccc3s2)n1)c1cccs1
Temperature: 60 °C
Reaction time: 15 h
Yield: 43.7 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (350 mg, 0.91 mmol) was dissolved in N,N-dimethylacetamide (10 ml), and 2-thenoyl chloride (400 mg, 2.72 mmol) was added thereto. The reaction mixture was stirred at 60° C. for 15 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (1:4, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (151 mg, 43%) as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[F:31])([C:22]#[N:23])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=[O:41].[K+].[K+].OO>CS(C)=O.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[F:31])([C:22]#[N:23])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:7][CH:8]=1)(=[O:41])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)CC1CN(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)CC1CN(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To the mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (4-cyano-phenyl)-amide (56.8 mg, 0.10 mmol) and K2CO3 (excess) in DMSO (2 mL) was added 30% H2O2 (1.0 mL, excess) and the reaction mixture was stirred at rt overnight. The reaction mixture was then diluted with EtOAc washed with sat NH4Cl, water and brine. The solvent was removed and the crude product was triturated with EtOAc and the solid was collected to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (4-carbamoyl-phenyl)-amide (55.9 mg, 95.5%). HRMS (ES+) m/z Calcd for C30H28Cl2F2N4O2+H [(M+H)+]: 585.1630, found: 585.1631.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[OH:32].ClC1C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:32][C:24]3[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:23]=3[F:22])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCc1ccccc1
Yield: 38.8 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxy-quinoline (2.04 g, 6.8 mmol), 2-fluoro-4-nitrophenol (2.34 g 14.9 mmol) and chlorobenzene (40 ml) was stirred at reflux temperature for 2 days. The reaction mixture was cooled, diluted with saturated sodium carbonate solution (30 ml) and stirred for 3 hours. The precipitate was filtered and the filtrate was separated. The aqueous layer was extracted with chloroform (3×30 ml). The organic layers were combined, washed with water and dried over sodium sulfate. The solvent was removed by evaporation under the reduced pressure. The residue was purified by column chromatography. The pure product was solidified under diisopropyl ether to give 1.11 g of product [F]. Yield: 39%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[N:22]O)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1.C(OC(=O)C)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[N:22])[C:5]2[O:10][CH:9]([C:11]([F:12])([F:14])[F:13])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C=NO)c2OC1C(F)(F)F
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C#N)c2OC1C(F)(F)F
Yield: 193.3 %

Procedure:
The oxime from Step 1 (0.61 g, 1.7 mmol) and acetic anhydride (6 mL) were stirred at 140° C. for 6.3 hours. The reaction was poured into water, extracted with ethyl acetate, washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated in vacuo to give a brown oil (1.09 g). The oil was purified by flash chromatography (10:1; hexanes: ethyl acetate) yielding upon concentration the title compound as a white solid (0.51 g, 88%): mp 114.6–115.6° C. 1H NMR (CDCl3/300 MHz) 7.65 (s, 1H), 7.53 (d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=2.4 Hz), 5.87 (q, 1H, J=6.4 Hz), 4.36 (m, 2H), 1.37 (t, 3H, J=6.5 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[N:12][C:13]([O:16][C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[CH:14][CH:15]=3)=[C:7]([C:24]([NH:26][CH3:27])=[O:25])[C:6]=2[CH:28]=1.[C:34]([O-])([O-])=O.[K+].[K+].CI>CS(C)=O.O>[Br:1][C:2]1[C:3]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:31])=[O:32])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[N:12][C:13]([O:16][C:17]4[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=4)=[CH:14][CH:15]=3)=[C:7]([C:24]([NH:26][CH3:27])=[O:25])[C:6]=2[CH:28]=1
Reactant: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)nc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)nc2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 20 °C
Yield: 19.5 %

Procedure:
To a degassed solution of 5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.187 mmol) and K2CO3 (53 mg, 0.374 mmol) in DMSO (2 mL) was added MeI (27 mg, 0.187 mmol) under N2. The mixture was heated at 20° C. for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc. It was washed with H2O, brine and dried over Na2SO4. After concentrated, the residue was purified by column chromatography (PE:EA=2:1) to give the product of 5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 20%). 1H-NMR (CDCl3, 400 MHz) δ 8.63 (d, J=2.8 Hz, 1H), 8.21˜8.24 (m, 1H), 8.02 (s, 1H), 7.65 (s, 1H), 7.06˜7.08 (m, 3H), 6.98 (d, J=8.8 Hz, 1H), 5.77 (d, J=8.8 Hz, 1H), 3.27 (s, 3H), 3.03 (s, 3H), 2.96 (d, J=4.8 Hz, 3H). MS (M+H)+: 548/550.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:15]([NH:22][C:23](=[O:40])[NH:24][C:25]1[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CS(C)=O>[CH2:15]([NH:22][C:23](=[O:40])[NH:24][C:25]1[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][CH2:33][N:32]([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:31]1)=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCCNC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCCN(C(c2ccccc2)c2ccccc2)C1
Yield: 20.3 %

Procedure:
Step 2): Bromodiphenylmethane (1.4 g, 5.6 mmol) was added to a solution of 2-(N'-n-heptylureido)-N-(piperidin-3-yl)benzamide (1.0 g, 2.8 mmol) and K2CO3 (0.4 g, 2.9 mmol) in DMSO (5 ml) at 0° C. The mixture was refluxed for 18 hours, poured into 1% NaHCO3 solution, extracted with ethyl acetate and washed with 1% NaHCO3 solution. The organic layer was dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (25% to 50% ethyl acetate in hexane) to give 2-(N'-n-heptylureido)-N-(1-diphenylmethylpiperidin-3-yl)benzamide (0.3 g, 20.5%): mp 112° C. 1H NMR (CDCl3)ppm: 0.88 (3H, t), 1.23-1.35 (8H, m), 1.47-1.85 (6H, m), 2.05-2.20 (1H, m), 2.35-2.49 (1H, m), 2.57-2.80 (2H, m), 3.24 (2H, q), 4.12-4.23 (1H, m), 4.35 (1H, s), 4.57-4.65 (1H, m), 6.90-7.55 (14H, m), 8.48 (1H, d), 10.37 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(CC(=O)C)(=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=3[C:6]=2[CH:7]=1
Reactant: Cc1ccc(Oc2ccc(C)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)CC(C)=O
Product: Cc1ccc2oc3ccc(C)cc3c2c1
Yield: 20.6 %

Procedure:
This example was carried out under the same reaction conditions as in Example 1 except that 29.0 g of 4,4'-dimethyldiphenyl ether, 0.067 g (0.30 m. mole) of palladium acetate, and 0.030 g of acetylacetone (0.30 m. mole) were employed and the mixture was reacted for 7 hours. As a result, 5.9 g (30 m. moles) of 2,8 -dimethyldibenzofuran was obtained and 1.9 g (4.7 m. moles) of the dimer also obtained.
Reaction SMILES: [CH3:1][C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:16])[C:6]([Cl:15])=[C:7]([OH:14])[C:8]=2[CH2:11][CH:12]=[CH2:13])[C:3]1=[O:17].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[Cl:15][C:6]1[C:7]2[O:14][CH:12]([CH2:13][OH:32])[CH2:11][C:8]=2[C:9]2[CH2:10][C:2]([CH3:1])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:3](=[O:17])[C:4]=2[C:5]=1[Cl:16]
Reactant: C=CCc1c(O)c(Cl)c(Cl)c2c1CC(C)(c1ccccc1)C2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(c2ccccc2)Cc2c3c(c(Cl)c(Cl)c2C1=O)OC(CO)C3
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-2-phenyl-4-allyl-5-hydroxy-6,7-dichloro-1-indanone (1.73 g., 0.005 mole) in methylene chloride (30 ml.) is added m-chloroperbenzoic acid (1.03 g., 0.006 mole) and 4,4'-thiobis-6-tert-butyl-m-cresol (10 mg.). The reaction is heated at reflux for 5 hours then cooled to 25°C. The m-chlorobenzoic acid which separates is filtered and the solution is washed with water, aqueous sodium bicarbonate and brine. The solvent is distilled at reduced pressure and the residual oil is heated at 120°C. for twenty minutes affording 4,5-dichloro-2-hydroxymethyl-6-oxo-7-methyl-7-phenyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]-furan (β-isomer) which is used in the next step without further purification.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C:15]2[NH:16][CH:17]=[CH:18][N:19]=2)=[C:6]1[CH:20]([CH3:22])[CH3:21])#[N:2].[OH-].[Na+].C([OH:27])C>Cl>[C:1]([CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C:15]2[NH:19][CH:18]=[CH:17][N:16]=2)=[C:6]1[CH:20]([CH3:22])[CH3:21])(=[O:27])[NH2:2]
Reactant: CCO
Reactant: CC(C)c1c(Cc2ncc[nH]2)c2ccccc2n1CCC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1c(Cc2ncc[nH]2)c2ccccc2n1CCC(N)=O
Reaction time: 18 h

Procedure:
1-(2-Cyanoethyl)-2-isopropyl-3-(1-imidazolylmethyl)indole (2.0 g) was dissolved in concentrated hydrochloric acid (10 ml) and the solution was allowed to stand for 18 hours at room temperature. It was cautiously basified with dilute sodium hydroxide solution and the mixture was extracted with ethyl acetate (3×25 ml). The combined ethyl acetate extracts were washed with water and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel. Elution with a mixture of chloroform and methanol (95:5) gave initially a small amount of impurity followed by pure product. Evaporation of the product containing fraction gave a gum which solidified on trituration with ethanol. The solid was crystallised from ethanol/petrol (b.p. 60°-80° C.) to give 1-(2-carbamoylethyl)-2-isopropyl-3-(1-imidazolylmethyl)indole (1.03 g), m.p. 169°-171° C. Found: C, 69.54; H, 7.25; N, 18.12. C18H22N4O4 requires: C, 69.64; H, 7.14; N, 18.05.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][CH:7]=1.[CH2:22]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH2:24]>C1(C)C=CC=CC=1.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>[CH2:24]([C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][CH:7]=1)[CH:23]=[CH2:22]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1cncc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Yield: 346 %

Procedure:
5-Bromo-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine (948 mg, 2.66 mmol) in toluene (10 mL) was added tetrakis(triphenylphosphine)palladium (15 mg) and allyltributyltin (0.18 mL, 0.56 mmol). The mixture was stirred and refluxed for two days. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to afford an oil (617 mg, 73%): 1H NMR (CDCl3, 300 MHz) δ 1.96 (m, 1H), 2.04-2.20 (m, 2H), 2.28 (m, 1H), 3.42 (t, 2H, J=7.0 Hz), 3.54 (d, 2H, J=7.0 Hz), 4.14 (m, 1H), 4.31 (dd, 1H, J=8.0, 10.5 Hz), 4.51 (dd, 1H, J=3.5, 10.5 Hz), 5.12-5.22 (m, 2H), 6.02 (m, 1H), 7.77 (s, 1H), 8.23 (s, 1H), 8.30 (d, 1H, J=2.5 Hz); MS (CI/NH3) m/e 219 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[C:12]([N+:17]([O-])=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:28][CH3:29])=[C:5]([CH3:30])[O:4][N:3]=1.O.O.Cl[Sn]Cl>C(O)C.Cl>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:28][CH3:29])=[C:5]([CH3:30])[O:4][N:3]=1
Reactant: COc1cc2c(NCc3ccccn3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1cc2c(NCc3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Temperature: 40 °C
Yield: 5.4 %

Procedure:
To a solution of this nitro intermediate (2.5 g, 24.82 mmol) in a mixture of ethanol (20 ml) and HCl (3.8 ml), was added portionwise SnCl2.2H2O (5.6 g, 24.82 mmol). The reaction mixture was heated to 40° C. for 1 h, then hydrolysed with sodium hydroxide N and extracted with DCM. The organic phase was washed with water, dried and concentrated to give the title compound as a brown powder (0.5 g, 17.8%). (APCI-MS) m/z: 376 MH+, Rt 2.46 min. 1H NMR (300 MHz, DMSO-d6, ppm) δ: 8.56 (d, 1H), 8.29 (s, 1H), 7.77 (dd, J=7.8, 7.6 Hz, 1H), 7.54 (s, 1H), 7.53-7.51 (m, 1H), 7.31-7.25 (m, 1H), 5.31 (s, 2H), 4.46 (d, J=7.2 Hz, 2H), 3.78 (s, 3H), 2.28 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1cccnc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cccnc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and methyl (S)-2-amino-3-(3-pyridyl)propionate hydrochloride (Synthetech), the title compound was prepared as a solid (mp 101-103° C.). The reaction was monitored by tlc (Rf=0.48 in 10% MeOH/DCM) and the product was purified by silica gel column chromatography.
Reaction SMILES: C(OCC)(=O)C=C.CC(C(OCCN(C)C)=O)=C.CC(C(OCCO)=O)=C.CC(C(OCCOCCOCCOC(C(C)=C)=O)=O)=C.[S:48]([O-:64])([O:51]CCCCCCCCCCCC)(=[O:50])=[O:49].[Na+:65]>O>[S:48]([O:51][O:51][S:48]([O-:64])(=[O:50])=[O:49])([O-:64])(=[O:50])=[O:49].[Na+:65].[Na+:65]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: C=C(C)C(=O)OCCN(C)C
Agent: C=C(C)C(=O)OCCO
Agent: C=C(C)C(=O)OCCOCCOCCOC(=O)C(=C)C
Solvent: O
Product: O=S(=O)([O-])OOS(=O)(=O)[O-]

Procedure:
A monomer emulsion was prepared by adding with mixing agitation about 56 parts by weight of ethyl acrylate, about 37 parts by weight of DMAEMA, about two parts by weight of HEMA, about three parts by weight of BEM25, about two parts by weight of R208 and about 0.15 parts by weight of TEGDMA into a reactor containing about 350 parts by weight of water containing about seven parts by weight C897 nonionic surfactant and about 0.3 parts by weight of sodium lauryl sulfate (30%) anionic surfactant. The resulting mixture was agitated (about 200 rpm) at a temperature in the range of about 30 to about 40° C. under a nitrogen atmosphere until an emulsion was obtained A solution of about 0.15 parts by weight of sodium persulfate in about three parts by weight of water was then added to the monomer emulsion, with mixing agitation, to initiate the polymerization reaction. The temperature of the reaction mixture was maintained at a temperature in the range of about 60 to about 62° C. for about 2.5 hours after addition of the initiator. Additional quantities of initiator were added at about 0.5 hours and about 1.5 hours after the reaction was initiated (about 0.02 parts by weight of sodium persulfate in about 3.5 parts by weight of water for each additional quantity of initiator added).