Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1Br.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:38]1[NH:39][C:40]2[CH:41]=[CH:42][CH:43]=[C:44]3[C:50](=[O:51])[NH:49][CH2:48][CH2:47][C:46]=1[C:45]=23.C(=O)([O-])[O-].[Na+].[Na+]>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]>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:38]1[NH:39][C:40]2[CH:41]=[CH:42][CH:43]=[C:44]3[C:50](=[O:51])[NH:49][CH2:48][CH2:47][C:46]=1[C:45]=23
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Reactant: COC(=O)CCc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Product: COC(=O)CCc1ccccc1-c1[nH]c2cccc3c2c1CCNC3=O

Procedure:
In a manner similar to that described for Example YY, 3-(2-bromo-phenyl)-propionic acid methyl ester (243 mg, 1.00 mmol), diboron pinacol ester (279 mg, 1.10 mmol), 1,1′-bis(diphenyl phosphino)ferrocene dichloropalladium (24 mg, 0.03 mmol), and potassium acetate (294 mg, 3.00 mmol), 2-Bromo-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (239 mg, 0.90 mmol), a second portion of 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium (24 mg, 0.03 mmol), and sodium carbonate (2.5 mL of a 2.0 M aqueous solution, 5.00 mmol) were reacted to yield 3-[2-(6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-phenyl]-propionic acid methyl ester, 92 mg (29%) as a beige solid: m.p. 201-201.5° C.; 1H NMR (300 MHz, d6-DMSO) δ2.43 (t, J=7.5 Hz, 2H), 2.68 (m, 2H), 2.86 (t, J=8.1 Hz, 2H) 3.38 (m, 2H), 3.47 (s, 3H), 7.20 (t, J=7.8 Hz, 1H), 7.37 (m, 4H), 7.52 (dd, J=7.8, 0.6 Hz, 1H), 7.70 (dd, J=7.5, 0.6 Hz, 1H), 8.04 (br t, 1H), 11.41 (br s, 1H). MS (FAB, MH+): 349. Anal. (C21H20N2O3.0.3 CHCl3) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([N:14]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25](C)(C)[O:26][SiH2]C(C)(C)C)=[CH:22][CH:23]=3)[C:18](=[O:34])[N:17]([CH:35]([CH3:37])[CH3:36])[N:16]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([N:14]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[C:15]2[C:24]3[C:19](=[CH:20][C:21]([CH2:25][OH:26])=[CH:22][CH:23]=3)[C:18](=[O:34])[N:17]([CH:35]([CH3:36])[CH3:37])[N:16]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)c2nn(C(C)C)c(=O)c3cc(C(C)(C)O[SiH2]C(C)(C)C)ccc23)nn1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(N(C(=O)OC(C)(C)C)c2nn(C(C)C)c(=O)c3cc(CO)ccc23)nn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.7 %

Procedure:
3-{tert-Butoxycarbonyl-[6-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-4-oxo-3,4-dihydro-phthalazin-1-yl]-amino}-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.78, 1.25 mmol) was dissolved in tetrahydrofuran (THF) (3 ml), to this was added a 1M solution of tetrabutylammonium fluoride (TBAF) in THF (1.87 ml, 1.87 mmol) and the mixture was stirred at room temperature for 24 hours. After this time the reaction mixture was concentrated under vacuum and the residue was purified by flash column chromatography (elution: 50% heptane, 50% ethyl acetate) to give the title compound (0.39 g, 45% yield) as a brown solid MS (ESI+)=(M+H)+ 514.43.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:54]=[CH:53][C:16]([C:17]([N:19]([CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([C:32]5[CH:37]=[CH:36][C:35]([C:38]6[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=6)=[CH:34][CH:33]=5)[N:28]=4)=[CH:23][CH:22]=3)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[C:5]([C:55]([F:58])([F:57])[F:56])[CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:19]([CH2:45][C:46]([OH:48])=[O:47])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([C:32]5[CH:37]=[CH:36][C:35]([C:38]6[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=6)=[CH:34][CH:33]=5)[N:28]=4)=[CH:23][CH:22]=3)=[O:18])=[CH:53][CH:54]=2)=[O:11])=[C:5]([C:55]([F:58])([F:57])[F:56])[CH:4]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4nc(-c5ccc(-c6ccc(C)cc6)cc5)no4)cc3)cc2)c(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4nc(-c5ccc(-c6ccc(C)cc6)cc5)no4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirring solution of tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-41 (77.0 mg, 0.097 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 1 h. The solvent was concentrated and the residue re-slurried from DCM (4 mL), then washed successively with DCM (2 mL) and isohexanes (2 mL) to afford 56 mg (78%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetic acid 362. LCMS-ESI (m/z) calculated for C41H33F3N4O6: 734; no ion observed, tR=8.91 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.82 (s, 1H), 10.34 (s, 1H), 8.35-8.04 (m, 4H), 8.04-7.81 (m, 2H), 7.75-7.52 (m, 6H), 7.49-7.30 (m, 5H), 7.26-7.15 (m, 2H), 4.79 (s, 1H), 4.72 (s, 1H), 4.06 (s, 1H), 4.01 (s, 1H), 3.90-3.78 (m, 5H), 2.38 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[I:11]N1C(=O)CCC1=O>C(O)(=O)C>[I:11][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: O=C1Cc2cc(I)ccc2N1
Temperature: 10 °C

Procedure:
2-Oxindole (82.9 9) was suspended in 630 mL of acetic acid with mechanical stirring and the mixture cooled to 10° C. in an ice water bath. Solid N-iodosuccinimide (175 g) was added in portions over 10 minutes. After the addition was complete the mixture was stirred for 1.0 hour at 10° C. The suspended solid which had always present became very thick at this time. The solid was collected by vacuum filtration, washed with 100 mL of 50% acetic acid in water and then with 200 mL of water and sucked dry for 20 minutes in the funnel. The product was dried under vacuum to give 93.5 g (36%) of 5-iodo-2-oxindole containing about 5% 2-oxindole by proton NMR.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C@@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8])C.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[C:4](=[O:3])[CH2:5][C@@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8]
Reactant: CNC
Reactant: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)C(C)C
Product: CC(C)[C@@H](CC(=O)N(C)C)NC(=O)OCc1ccccc1

Procedure:
2.23 g of 3(R)-benzyloxycarbonylamino-4-methylpentanoic acid ethyl ester and 50 ml of 30% dimethylamine (in methanol) are stirred for 6 days at 75° C. in a bomb tube. The reaction mixture is concentrated by evaporation and the residue is purified by FC (dichloromethane/methanol=97:3). The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.40.
Reaction SMILES: I[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[N+:13]([C:16]1[N:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([O-:15])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[N+:13]([C:16]1[N:21]=[CH:20][C:19]([O:22][CH:2]2[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: O=[N+]([O-])c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc([N+](=O)[O-])nc2)C1
Temperature: 125 °C
Yield: 58.8 %

Procedure:
A mixture of 206a (2.24 g, 7.9 mmol), 6-nitropyridin-3-ol (1.0 g, 7.2 mmol), and Cs2CO3 (2.6 g, 7.9 mmol) in DMF (8 mL) was heated at 125° C. in a sealed tube overnight. The solid was filtered and washed with ethyl acetate (2×20 mL). The combined filtrate was evaporated in vacuo and the residue was purified on reverse-phase Combiflash to afford 206b (1.25 g, 59%). MS-ESI: [M+H]+ 296.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.[CH3:21][C:22]1[C:26]([C:27](O)=[O:28])=[C:25]([CH3:30])[O:24][N:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:19][N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:27]([C:26]4[C:22]([CH3:21])=[N:23][O:24][C:25]=4[CH3:30])=[O:28])[CH:8]=[N:7][CH:6]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:13][C:14]1=[O:20]
Reactant: Cc1noc(C)c1C(=O)O
Reactant: CN1C(=O)CCc2cc(-c3cncc(CN)c3)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C)c1C(=O)NCc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Temperature: 25 °C
Yield: 59.3 %

Procedure:
To a solution of 6-(5-aminomethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (example 36, 0.047 g, 0.177 mmol) in DMF (1 mL) were added 3,5-dimethylisoxazole-4-carboxylic acid (0.037 g, 0.266 mmol) and TBTU (0.063 g, 0.195 mmol) followed by Hünig's base (0.048 g, 0.372 mmol) and the reaction mixture was stirred at room temperature over night. The mixture was purified directly by reverse phase HPLC on a Gemini-NX column, eluting with a 20 to 98% MeOH—H2O (0.05% TEA) gradient to give the title compound (0.041 g, 59%) as a colorless solid. MS: 391.3 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[NH:17][N:18]=[CH:19][CH:20]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:20]=[CH:19][N:18]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:17]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccccc1
Reactant: BrCCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccn(CCc3ccccn3)n2)sc1C(=O)NCc1ccccc1
Temperature: 90 °C
Yield: 42.1 %

Procedure:
A solution of 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide (0.1 g, 0.33 mmol) in dimethyl sulfoxide (5 mL) was treated with 2-(2-bromo-ethyl)-pyridine (0.089 g, 0.33 mmol) and potassium carbonate (0.140 g, 1.0 mmol), and the reaction mixture was heated to 90° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue, was purified by preparative thin layer chromatography over silica gel eluting with (5% methanol, 95% methylene chloride) to provide 4-methyl-2-[1-(2-pyridin-2-yl-ethyl)-1H-pyrazol-3-yl]-thiazole-5-carboxylic acid benzylamide (56 mg, 43% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=4.0 Hz, 1H), 7.50-7.57 (m, 1H), 7.29-7.42 (m, 5H), 7.21 (s, 1H), 7.12-7.19 (m, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.68 (s, 1H), 6.01 (bs, 1H), 4.62 (d, J=8.0 Hz, 2H), 4.61 (t, J=8.0 Hz, 2H), 3.36 (t, J=8.0 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=404.2; Rt=1.25 min; HRMS (M+H)+=404.15.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][C:12]#[N:13])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#CCOc1cccc2[nH]ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCCOc1cccc2[nH]ccc12
Yield: 32.7 %

Procedure:
To a solution of 2-(1H-indol-4-yloxy)-acetonitrile (0.9 g, 5.2 mmol) in anhydrous ethyl ether (30 ml) was added lithium aluminum hydride (95%, 0.21 g, 5.2 mmol) at room temperature. The reaction was allowed to reflux for 2 hours, another equivalent of lithium aluminum hydride (0.21 g, 5.2 mmol) was added. The reaction was allowed to reflux for another 2 hours and then was quenched with 1N sodium hydroxide and water. The solid was removed by filtration and the filtrate was concentrated and dissolved in methanol and water. To a above mixture was added 2N hydrochloric acid until pH<3 and then extracted with ethyl ether. To the above aqueous layer was added sodium hydroxide until pH>9, the mixture was extracted with isopropanol-methylene (1:3). The combined organic layers were washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to afford 0.3 g (33%) of product as a brown solid. mp: 123-125° C.; MS EI m/e 177 (M+)
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][N:12]3[C:5]4[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=4[C:3]([CH3:13])=[C:2]3[CH3:1])=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: Cc1[nH]c2cnn(C)c(=O)c2c1C
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)n(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c2cnn(C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
A solution of 2,3,5-trimethyl-1H-pyrrolo[2,3-d]-pyridazin-4(5H)-one (532 mg) in DMF (45 ml) was dripped into a suspension of 60% sodium hydride-oil (144 mg) in DMF (12 ml) on an ice-water bath. The mixture was stirred at room temperature for 30 minutes, after which a solution of 4-(4-chlorobenzoyl)benzyl bromide (1.02 g) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 1.5 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:2) to provide the title compound as light-yellow powder (711 mg, yield 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[Cl:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH3:30])=[CH:25][C:24]=1[OH:31].C(=O)([O-])[O-].[K+].[K+].[Al]>CN(C=O)C.C(OCC)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:31][C:24]1[CH:25]=[C:26]([CH3:30])[C:27]([CH3:29])=[CH:28][C:23]=1[Cl:22])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: Cc1cc(O)c(Cl)cc1C
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Al]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3cc(C)c(C)cc3Cl)cc2OC1C(F)(F)F

Procedure:
To 325 mg (1.0 mmole) of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 2.5 mL of DMF was added 172 mg (1.1 mmole) of 2-chloro-4,5-dimethylphenol and 193.5 mg (1.4 mmole) of potassium carbonate. The suspension was prepared in a capped vial and placed in an aluminum heating block equipped with a shaker. The aluminum block was heated to 110° C. for 16 h. After allowing the vial to cool, the mixture was treated with 10 mL of water and 2 mL of diethyl ether. The organic layer was removed and the aqueous layer extracted two times with diethyl ether. Combined organic extracts were filtered through 5 g of silica and the silica washed with 10 mL of diethyl ether. The filtrates were concentrated under a stream of N2 to afford an off-white solid, which was used in the next step without further purification: 1H NMR (CDCl3/300 MHz) 1.36 (t, 3H, J=7.2 Hz), 2.25, (s, 3H), 2.27 (s, 3H), 4.32 (m, 2H), 5.66 (q, 1H, J=6.8 Hz), 6.27 (s, 1H), 6.93 (2, 1H), 7.25 (s, 1H), 7.33 (s, 1H), 7.66 (s, 1H); 19F NMR (CDCl3/300 MHz) −78.9 (d, 3F, J=6.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.IC.[C:20](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:13][CH2:14][C:15]([O:17][CH3:20])=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)COC1(c2ccc(Br)cc2)CCCC1
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COC1(c2ccc(Br)cc2)CCCC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To an ambient solution of Example 30B (200 mg, 0.668 mmol) in N,N-dimethylformamide (4 mL) was added iodomethane (0.208 mL, 3.34 mmol) and potassium carbonate (184 mg, 1.34 mmol). The mixture was stirred at room temperature for 40 h, and then diluted with water (10 mL) and ethyl acetate (20 mL). The layers were separated, and the organic was washed with water (3×10 mL), brine (1×10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.67-1.72 (m, 2H), 1.74-1.84 (m, 4H), 2.10 (m, 2H), 3.58 (s, 3H), 3.67-3.70 (m, 2H), 7.34-7.40 (m, 2H), 7.51-7.57 (m, 2H).
Reaction SMILES: COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:10]2)=CC=1.[NH2:23][C:24](=O)[C@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26]>COCCOC>[NH2:23][C:24](=[S:10])[C@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(N)=O
Solvent: COCCOC
Product: C[C@@H](NC(=O)OC(C)(C)C)C(N)=S
Temperature: 25 °C
Reaction time: 5 h
Yield: 203.5 %

Procedure:
2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (1.6 g, 0.0038 mol) was added to a solution of tert-butyl [(1R)-2-amino-1-methyl-2-oxoethyl]carbamate (1.45 g, 0.00770 mol) in 1,2-dimethoxyethane (40 mL). The resulting suspension was stirred at RT for 5 h. After removal of solvent the residue was taken up into ethyl acetate. It was washed with 0.1 N NaOH solution, water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 1.58 g of the product. (yield: ˜100%).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[S:20]1[CH:24]=[CH:23][C:22]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)=[CH:21]1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1ccsc1
Product: O=C(O)c1cccc(COc2ccc(-c3ccsc3)cc2)c1

Procedure:
3-(4-Thiophen-3-yl-phenoxymethyl)-benzoic acid was prepared using the procedure described above for the preparation of Example 15 from 3-(4-iodo -phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and thiophene-3-boronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). Mass spectrum MH+=311.
Reaction SMILES: [C:1]([CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)([O:3][CH2:4][CH3:5])=[O:2].Br[CH2:17][C:18](=[N:24][OH:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[OH:25][N:24]=[C:18]([CH2:17][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])[NH:11][CH:10]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(CBr)=NO
Reactant: CCOC(=O)Cc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc2[nH]cc(CC(=NO)C(=O)OCC)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
To a solution of 4-(carboethoxymethyl)indole (830 mg, 4.12 mmol) and ethyl bromopyruvate 2-oxime (866 mg, 4.12 mmol) in methylene chloride (40 mL) was added anhydrous Na2CO3 (2.40 g, 22.66 mmol) at room temperature. After stirring at room temperature for 16 hours, the mixture was filtered and concentrated to dryness. The residue was flash chromatographed on silica gel (eluting (10% MeOH/CHCl3):hexane=1:1→2:1) to give 0.98 g of the title compound; TLC Rf =0.61 (10% MeOH/CHCl3). MS(CI) m/e 333 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ8.17 (br s, --NH), 8.03 (br s, --OH), 7.26 (d, J=7.4 Hz, 1H), 7.12 (t, J=7.4 Hz, 1H), 6.98 (d, J=7.4 Hz, 1H) 6.92 (br s, 1H), 4.30 (s, 2 H), 4.28 (q, J=7.4 Hz, 2H), 4.18 (q, J=7.4 Hz, 2H), 4.13 (s, 2H), 1.30 (t, J=7.4 Hz, 3H), 1.25 (t, J=7.4 Hz, 3H).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:25])=O>>[Cl:25][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(SCCN2CCc3ccccc3C2)ccnc1CO
Product: Cc1c(SCCN2CCc3ccccc3C2)ccnc1CCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Thionyl chloride (20 ml) was dropwise added to 2-hydroxymethyl-3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)pyridine (2.8 g) under ice-cooling and the mixture was stirred at room temperature for 1.5 hours. After the completion of the reaction, the thionyl chloride was distilled away. The residue was alkali-oversaturated with potassium carbonate and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to give 2.1 g of 2-chloromethyl-3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)pyridine. The product was added to ethanol (30 ml) containing a solution of 2-mercaptobenzimidazole (1.3 g) and sodium hydroxide (1.2 g) in water (10 ml) and the mixture was refluxed under heating for 2 hours. After the completion of the reaction, the ethanol was distilled away and water was added to the residue, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled away. Acetone was added to the residue to allow crystallization. The obtained crystals were recrystallized from isopropyl alcohol to give 2-((3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole as crystals, melting point 90°-94° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cnc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCN(c2cnc3ccccc3c2)CC1

Procedure:
Prepared in analogy to example 1.16 (a) from 3-bromoquinoline and piperazine-1-carboxylic acid tert-butyl ester. Chromatography (SiO2; cyclohexane/ethyl acetate 1/1), followed by crystallization from diethyl ether/cyclohexane yields the title product as a colorless solid.