Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.I[C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)=[CH:24]\[CH2:25][O:26][C:27]2[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:29]([CH3:39])[CH:28]=2)=[CH:19][CH:18]=1>O1CCCC1.[Cu]I.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>[CH3:39][C:29]1[CH:28]=[C:27]([O:26][CH2:25]/[CH:24]=[C:23](\[C:20]2[CH:19]=[CH:18][C:17]([C:3]#[C:2][CH2:1][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)=[CH:22][CH:21]=2)/[C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)[CH:38]=[CH:37][C:30]=1[O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Reactant: C#CCN1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCCC3)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
N-Propargylpyrrolidine (113 mg, 1.04 mmol) and diisopropylamine (0.339 mL, 2.42 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)-allyloxy]-2-methylphenoxy]acetate (300 mg, 0.515 mmol; prepared as described in example 4) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (8 mg, 0.042 mmol) and bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.026 mmol) were added. The reaction mixture was stirred at ambient temperature for 21 h. Further portions of N-propargylpyrrolidine (113 mg, 1.04 mmol), diisopropylamine (0.339 mL, 2.42 mmol), copper(I) iodide (8 mg, 0.042 mmol) and bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.026 mmol) were added and reaction mixture was stirred at 50° C. for further 5 h and then evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 99:1-98:2) yielding methyl (E)-[2-methyl-4-[3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetate as brown oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:10]=[CH:9][O:8][CH:7]=1)=[O:5].[CH2:12]([Mg]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOC(C)=O.[NH4+].[Cl-]>C1COCC1>[O:8]1[CH:9]=[CH:10][C:6]([C:4](=[O:5])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7]1
Reactant: CON(C)C(=O)c1ccoc1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1ccoc1
Reaction time: 5 h
Yield: 63.2 %

Procedure:
A solution of N-methoxy-N-methylfuran-3-carboxamide (913 mg, 5.89 mmol) in anhydrous THF (10 mL) was cooled to −78° C. under nitrogen, and a solution of benzylmagnesium chloride in THF (2 mol/L, 3.53 mL) was added through a syringe. The reaction mixture was stirred at this temperature for 5 hours. TLC (PE:EtOAc=5:1) indicated reaction was nearly complete, saturated NH4Cl solution (20 mL) was added to quench the reaction, and the aqueous layer was extracted with EtOAc (80 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to afford 1-(furan-3-yl)-2-phenylethanone as a yellow oil (696 mg, yield: 63.2%).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:30][C:31](=O)[CH2:32][C:33]1[NH:37][CH:36]=[N:35][N:34]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:31](=[O:30])[CH2:32][C:33]1[NH:37][CH:36]=[N:35][N:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nnc[nH]1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Product: COc1ccc(N2CCN(C(=O)Cc3nnc[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 20 %

Procedure:
Prepared using the same procedure described in Example 275 with (S)-3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine and (4H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester as starting material. The product was obtained as an off-white solid (105 mg, 20%). LC/MS (Method B) 3.39 min, [M+1]+ 476.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([OH:8])[C@H:6]([OH:9])[C@@H:5]([CH2:10][OH:11])[O:4][C@H:3]1[N:12]1[CH:20]=[N:19][C:18]2[C:17](=[O:21])[NH:16][C:15]([NH2:22])=[N:14][C:13]1=2.O.[CH:24]1[C:36]2[CH:35]([CH2:37][O:38][C:39](ON3C(=O)CCC3=O)=[O:40])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH:24]1[C:36]2[CH:35]([CH2:37][O:38][C:39]([NH:1][C@@H:2]3[C@@H:7]([OH:8])[C@H:6]([OH:9])[C@@H:5]([CH2:10][OH:11])[O:4][C@H:3]3[N:12]3[CH:20]=[N:19][C:18]4[C:17](=[O:21])[NH:16][C:15]([NH2:22])=[N:14][C:13]3=4)=[O:40])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)c(=O)[nH]1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2NC(=O)OCC2c3ccccc3-c3ccccc32)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.5 %

Procedure:
To 3.31 g (10.61 mmol) of 9-(2-amino-2-deoxy-β-D-glucopyranosyl) guanine was added 72 mL of H2O. To this solution was added a 100 mL 1,4-dioxane solution containing 4.65 g (13.79 mmol) of N-(9-fluorenyl-methoxycarbonyloxy)succinimide. This resulted in a cloudy mixture. To this system was added 0.58 g (6.90 mmol) of NaHCO3. This mixture was stirred for 12 hours at room temperature. At this time, TLC indicated the consumption of starting material and the mixture was concentrated in vacuo to a dry residue. This residue was stirred for 3 hours in 310 mL of Et2O and 145 ml of H2O. The suspension was then filtered and the solid dried in a vacuum oven for 12 hours at 40° C. Thus was obtained 4.28 g (76%) of 9-(2-deoxy-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-β-D-glucopyranosyl)guanine. 1H NMR: (DMSO-δ6): guanine H-8 7.72 (s, 1H), anomeric H-1 5.37 (d, 1H), Fmoc-methine 4.05 (m, 1H). FAB-MS: m/z 535 for (M+1)+.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:23][C:24]([F:38])([F:37])[O:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:32](=[O:33])[CH2:31][O:30][C:29]3[CH:35]=[CH:36][C:26]([O:25][C:24]([F:37])([F:23])[F:38])=[CH:27][CH:28]=3)[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Reactant: O=C(O)COc1ccc(OC(F)(F)F)cc1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(OC(F)(F)F)cc3)CC2)c2nc(-c3cccnc3)sc2n1
Yield: 45 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-trifluoromethoxyphenoxyacetic acid in a yield of 45%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH:22]1([C:28]2[CH:33]=[CH:32][C:31](O)=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH:22]1([C:28]2[CH:33]=[CH:32][C:31]([O:1][CH2:2][C:3]3[N:8]=[CH:7][C:6]([N:9]4[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]4)=[CH:5][CH:4]=3)=[CH:30][C:29]=2[C:35]([F:36])([F:37])[F:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Oc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CO)nc2)CC1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(COc3ccc(C4CCCCC4)c(C(F)(F)F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
tert-Butyl 4-(6-hydroxymethyl-pyridin-3-yl)-piperazine-1-carboxylate (0.22 mmol), 4-Cyclohexyl-3-trifluoromethyl-phenol (0.22 mmol, synthesized in a similar manner as described in a previous example), 1,1′-azodicarbonyl dipiperdine (0.33 mmol) and Ph3P (0.33 mmol) are mixed in DCM (2 mL). The reaction mixture is stirred at room temperature for 17 h and then partitioned between saturated Na2CO3 solution and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic extracts are washed with saturated aqueous NaCl and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (6:5 hexanes/EtOAc) to give tert-butyl 4-[6-(4-cyclohexyl-3-trifluoromethyl-phenoxymethyl)-pyridin-3-yl]-piperazine-1-carboxylate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]3([CH:13]=O)[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:15]([C:17]1[N:18]=[N:19][C:20]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)=[CH:21][N:22]=1)[NH2:16].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C.C(O)(=O)C>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]4[N:18]5[N:19]=[C:20]([C:23]6[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=6)[CH:21]=[N:22][C:17]5=[N:15][N:16]=4)[CH2:11][CH2:12]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=CC1(c2ccc3ncsc3c2)CC1
Reactant: COC(=O)c1ccc(-c2cnc(NN)nn2)cc1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(1,3-benzothiazol-6-yl)cyclopropanecarbaldehyde (80.0 mg, 0.39 mmol) and methyl 4-(3-hydrazino-1,2,4-triazin-6-yl)benzoate (96.5 mg, 0.394 mol) in ethanol (2.7 mL) and acetic acid (0.53 mL) was stirred at RT for 3 h. The mixture was concentrated. The residue was dissolved in DCM (5 mL), followed by addition iodobenzene diacetate (150 mg, 0.47 mmol). The mixture was stirred at RT for 6 h, and quenched with saturated sodium bicarbonate (25 mL). The mixture was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was flash chromatographed on a silica gel column with 40% ethyl acetate in DCM to afford the desired product. Analytical LCMS: (M+H)+=429.0.
Reaction SMILES: [OH:1][C:2]1C=CC(C2C(=O)C3C(=C(C)C(O)=CC=3)OC=2)=CC=1OC.C(OC(=O)C)(=O)C.[C:30]([O:33][C:34]1[CH:55]=[CH:54][C:37]([C:38]2[C:47](=[O:48])[C:46]3[C:41](=[C:42]([CH3:53])[C:43]([O:49][C:50](=[O:52])[CH3:51])=[CH:44][CH:45]=3)[O:40][CH:39]=2)=[CH:36][CH:35]=1)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([O:33][C:34]1[CH:55]=[CH:54][C:37]([C:38]2[C:47](=[O:48])[C:46]3[C:41](=[C:42]([CH3:53])[C:43]([O:49][C:50](=[O:52])[CH3:51])=[CH:44][CH:45]=3)[O:40][CH:39]=2)=[CH:36][C:35]=1[O:1][CH3:2])(=[O:32])[CH3:31]
Reactant: COc1cc(-c2coc3c(C)c(O)ccc3c2=O)ccc1O
Reactant: CC(=O)Oc1ccc(-c2coc3c(C)c(OC(C)=O)ccc3c2=O)cc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COc1cc(-c2coc3c(C)c(OC(C)=O)ccc3c2=O)ccc1OC(C)=O

Procedure:
4′,7-Diacetoxy-3′-methoxy-8-methylisoflavone was prepared from 4′,7-dihydroxy-3′-methoxy-8-methylisoflavone (0.42 g, 1.4 mmol), acetic anhydride (2.6 ml) and pyridine (0.5 ml) as described for 4′,7-diacetoxy-8-methylisoflavone. Yield: (0.4 g, 74%) m.p. 209° C. 1H NMR (CDCl3): δ 2.22 (s, 3H, CH3), 2.32, 2.39 (each s, 3H, OCOCH3), 3.89 (s, 3H, OMe), 7.07-7.11 (m, 2H, ArH), 7.13 (d, 1H, J 8.6 Hz, H6), 7.32 (d, 1H, J 1.5 Hz, ArH), 8.09 (s, 1H, H2), 8.18 (d, 1H, J 8.7 Hz, H5).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C=O)C>[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:16][CH2:15]1
Reactant: OCCN1CCNCC1
Reactant: Clc1nc2ccccc2o1
Solvent: CN(C)C=O
Product: OCCN1CCN(c2nc3ccccc3o2)CC1
Reaction time: 1 h

Procedure:
A 300 mg portion of 2-chlorobenzoxazole was dissolved in 2 ml of DMF. Under cooling with ice, 279 mg of 1-(2 -hydroxyethyl)piperazine was added to the thus prepared solution, and the reaction was carried out for 1 hour at the same temperature and then for 24 hours at room temperature. The reaction solution was concentrated under a reduced pressure, and the resulting residue was dissolved in 100 ml of ethyl acetate and washed with sodium hydrogencarbonate aqueous solution (pH 8) and then with water. The resulting organic layer was dehydrated with sodium sulfate and concentrated under a reduced pressure to obtain 140 mg of the title compound.
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=O.[CH3:10][O:11][C:12]([C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=O)=[CH:16][CH:15]=1)=[O:13]>C(Cl)Cl>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:18][C:17]2[CH:28]=[CH:29][C:14]([C:12]([O:11][CH3:10])=[O:13])=[CH:15][CH:16]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a mixture of sodium borohydride (2.27 g) and trifluoroacetic acid (50 ml), which was previously prepared under nitrgen atmosphere, was added a solution of 4-methoxycarbonyl-4'-methoxybenzophenone (2.70 g) and methylene chloride (30 ml) at room temperature. After reacting for 24 hours, the reaciton mixture was poured into ice-water, and methylene chloride layer was sepatated. Water layer was further extracted with methylene chloride (50 ml×2).
Reaction SMILES: FC1C=CC([N+]([O-])=O)=CC=1.N1C=NN=N1.C(=O)([O-])[O-].[K+].[K+].N1(C2C=CC([N+]([O-])=O)=CC=2)C=NN=N1.[N:36]1[N:37]([C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-])=O)=[CH:43][CH:42]=2)[N:38]=[N:39][CH:40]=1>CN(C=O)C.C1COCC1.[Pt](=O)=O.O>[N:36]1[N:37]([C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[N:38]=[N:39][CH:40]=1
Reactant: O=[N+]([O-])c1ccc(-n2ncnn2)cc1
Agent: O=[Pt]=O
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(-n2cnnn2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(-n2ncnn2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-fluoro-1-nitrobenzene (12.5 g, 89 mmol) and 1H-tetrazole (6.21 g, 89 mmol) in DMF (89 mL) stirred at room temperature, potassium carbonate (12.24 g, 89 mmol) was added in one portion. The resulting mixture was stirred at 80° C. overnight, and then reaction mixture was worked up by the addition of water at 80° C., then cooled to room temperature, and stirred at room temperature for 30 minutes. The yellow solid was collected by filtration, washed with water, air-dried for 2 hours, and dried in an vacuum oven at 60° C. for 2 hours to afford a mixture of 4-(1H-tetrazol-1-yl)-1-nitrobenzene and 4-(2H-tetrazol-2-yl)-1-nitrobenzene. The product thus obtained was re-dissolved in THF (209 mL) and, while stirring at room temperature, platinum(IV) oxide (0.45 g, 1.982 mmol) was added in one portion. The resulting mixture was stirred at room temperature overnight under a hydrogen atmosphere, after which the reaction mixture was worked up by filtration through a celite pad and the solvent removed by evaporation. The residue was purified and separated by CombiFlash® (0-50% EtOAc/toluene; Teledyne Isco, Inc., Lincoln, Nebr.) to afford the desired 4-(2H-tetrazol-2-yl)aniline as a yellowish solid. 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 7.72 (d, 2H), 6.73 (d, 2H), 5.75 (s, 2H).
Reaction SMILES: C([O:5][C:6](=[O:9])CI)(C)(C)C.CCOCC.C([O:19][C:20]([CH2:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([NH:33][CH:34](OCC)[CH2:35][C:36](=C=O)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([CH3:32])[C:24]1=[O:48])=[O:21])(C)(C)C>CCCCCC>[C:20]([CH2:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([NH:33][CH:34]([C:6]([OH:9])=[O:5])[CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH3:32])[C:24]1=[O:48])([OH:19])=[O:21]
Reactant: CCOC(CC(=C=O)c1ccccc1)NC1(C)C(=O)N(CC(=O)OC(C)(C)C)c2ccccc21
Reactant: CC(C)(C)OC(=O)CI
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(NC(CCc2ccccc2)C(=O)O)C(=O)N(CC(=O)O)c2ccccc21

Procedure:
This above lactam was alkylated with t-butyliodoacetate as described in Example 1, Step B, to afford, after chromatography (silica, 2 ether: 1 hexane), 1-t-butyoxycarbonylmethyl 3-(1-ethoxy-carbonyl-3-phenylpropyl)amino-3-methyl-1,2-dihydro-2-oxo-3H-indole. NMR (CDCl3): δ1.1 (t, 3H); 1.5 (s, 9H); 1.55 (s, 3H); 1.8-3.2 (m, 6H); 3.9 (s, 2H); 4.4 (s, 2H); 7.1 (br.s., 9).
Reaction SMILES: C([O:8][CH:9]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[CH:17][N:16](C)[N:15]=2)[CH:10]1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)C1C=CC=CC=1.[CH3:27]O>[Pd]>[OH:8][CH:9]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH3:27])[CH:17]=[N:16][N:15]=2)[CH:10]1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1
Reactant: CO
Reactant: Cn1cnc(C2CCC(OCc3ccccc3)C2c2ccc(F)cc2)n1
Agent: [Pd]
Product: Cn1cnnc1C1CCC(O)C1c1ccc(F)cc1

Procedure:
A solution of 275 mg of product from Step C in 5 mL of methanol and 0.5 mL of TTA was stirred with 100 mg of 10% Pd/C under a hydrogen balloon for 60 h. The reaction was filtered and concentrated. The residue was purified by flash chromatography eluting with 5 to 10% methanol in methylene chloride to obtain 220 mg of title compound. T.l.c. (5% methanol in methylene chloride) Rf =0.25. Mass spec (NH3 /CI): 262 (M+1).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([O:4][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]#[CH:3]
Reactant: BrCCCCc1ccccc1
Reactant: C#CCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: C#CCOCCCCc1ccccc1
Reaction time: 72 h
Yield: 54.5 %

Procedure:
A mixture of propargyl alcohol (10.0 g), (4-bromobutyl)benzene (38.0 g), aqueous NaOH (80 ml, 50% w/v), and tetrabutylammonium bisulphate (1.0 g) was stirred vigorously for 3 days, treated with H2O (100 ml) and extracted with ER (2×200 ml). The dried extract was evaporated and the residue was purified on a column of silica (Merck 9385; 500 ml) [H] to give the title compound as a colourless oil (18.3 g). T.l.c. [A] Rf 0.2.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[N-:13]=[N+:14]=[N-:15].[Na+].Cl>CC(O)C.O.[Br-].[Zn+2].[Br-]>[N+:10]([C:3]1[CH:4]=[C:5]([C:6]2[N:13]=[N:14][NH:15][N:7]=2)[CH:8]=[CH:9][C:2]=1[NH2:1])([O-:12])=[O:11]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Nc1ccc(-c2nn[nH]n2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 35.9 %

Procedure:
To 4-amino-3-nitrobenzonitrile (4.98 g, 36 mol) in 2-propanol (15 ml) and water (30 ml) was added zinc bromide (13.80 g, 61 mmol) followed by sodium azide (5.81 g, 89 mmol). The reaction mixture was at heated at 80° C. for 10 hours. The reaction was cooled and then analyzed by HPLC. Water (15 ml) was added and the orange colored mixture adjusted to pH 3.0 with 50% (v/v) HCl. The solid was washed with water (50 ml) and dried in an oven at 90° C. to yield an orange yellow colored solid 2-nitro-4-(2H-tetrazol-5-yl)-phenylamine (6.59 g), Rt=8.8 mins, 1H NMR (d6-DMSO, 400 MHz) 8.47 ppm (1H, d, 2 Hz), 7.86 ppm (1H, d of d, 9 Hz, 2 Hz), 7.58 ppm (2.3H bs), 6.96 ppm (1H d, 9 Hz). MS (Electrospray+) 206 m/z (M+), 228 m/z (M+Na).
Reaction SMILES: [Li+].C[CH:3]([N-:5][CH:6]([CH3:8])[CH3:7])[CH3:4].[C:9](#N)[C:10]([CH3:12])=O>C1COCC1>[NH:5]1[C:6]2[C:7](=[CH:9][CH:10]=[CH:12][CH:8]=2)[CH:4]=[CH:3]1
Reactant: CC(C)[N-]C(C)C
Reactant: CC(=O)C#N
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2[nH]ccc2c1
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 1 (426 mg, 1.26 mmol) in THF (6 mL) at −78° C. was added dropwise a 1.8 M solution of LDA in THF (1.54 mL, 2.78 mmol) and the reaction stirred for 1 hour, then pyruvonitrile (0.208 mL, 2.78 mmol) was added dropwise and the reaction was stirred for 15 minutes turning homogeneous. The reaction was quenched by the addition of satd. NH4Cl (10 mL), the layers separated, and the aqueous extracted with Et2O (3×10 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on silica gel gradiently eluted with 20 to 40% EtOAc/hexanes to give 2 (230 mg, 48% yield) as an off-white solid. Rt=1.71 min using Phenomenex 30×4.6 5u column with flow rate of 5 mL/min over 2 min gradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%. [M+H]=380.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[CH2:12]([N:14]([CH2:18][CH3:19])[C:15](=[S:17])[S-:16])[CH3:13].[Na+]>C1COCC1>[CH3:13][CH2:12][N:14]([C:15]([S:17][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[S:16])[CH2:18][CH3:19]
Reactant: CCN(CC)C(=S)[S-]
Reactant: BrCc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=S)SCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Benzyl bromide (2.05 g, 12 mmol) in THF (10 mL) was added dropwise over 15 minutes to a supension of sodium N,N-diethyldithiocarbamate trihydrate (2.25 g, 10 mmol) in 25 mL of THF at room temperature. The solution was allowed to stir at room temperature for 3 hours when the solids were filtered off and the filtrate concentrated. The crude residue was purified by column chromatography (silica gel, 20% ethyl acetate in petroleum spirits) to obtain the title compound (2.25 g, 94%). 1H-nmr (CDCl3) δ 1.3 (6H), 3.7 (2H), 4.1 (2H), 4.6 (2H), 7.3 (5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:22]1(/[CH:28]=[CH:29]/[CH2:30]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:30]/[CH:29]=[CH:28]/[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: ClC/C=C/c1ccccc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(C/C=C/c3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 3-phenyl-2-[trans]propenylchloride as described for compound 78. Purified by chromatography (dichloromethane). Crystallized from diethyl ether at -20° C. M.p. 76°-79° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:2].C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Na+].[Na+].Br[CH2:34][CH2:35][CH2:36][CH:37]1[NH:41][C:40](=[O:42])[CH2:39][CH:38]1[CH3:43]>C1COCC1>[NH2:6][CH:5]([CH2:34][CH2:35][CH2:36][CH:37]1[CH:38]([CH3:43])[CH2:39][C:40](=[O:42])[NH:41]1)[C:4]([O:3][CH2:1][CH3:2])=[O:20]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: CC1CC(=O)NC1CCCBr
Agent: C[Si](C)(C)[NH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(N)CCCC1NC(=O)CC1C
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(diphenylmethylene)glycine ethyl ester (Aldrich, 37 mmol) in THF (20 mL) is added to -72° C. solution of sodium bis (trimethylsilylamide) (35 mmol, 0.5 M in THF), while the solution is kept below -65° C. The resulting solution is then stirred at -72° C. for 30 min.; followed by the rapid addition of a cooled solution (-72° C.) of the product from EXAMPLE 236 (24 mmol) in THF via canula. The cooling bath is removed immediately and the mixture allowed to warm to 0° C. for 4 h. The reaction mixture is partitioned between ether and 10% aqueous sodium bisulfate, then-dried and concentrated. The product is purified by column chromatography. This intermediate is then treated with 0.1 N aqueous hydrochloric acid for 3 h, followed by extraction with ether and lyophilization of the aqueous solution, to yield the title material.