Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]4[CH:19]=3)=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[O:22].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]4[C:19]=3[CH:21]([OH:22])[C:20]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccn2cc(-c3ccc4c(c3)CCCO4)nc2c1
Reactant: CCOC(=O)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(O)c1c(-c2ccc3c(c2)CCCO3)nc2ccccn12
Temperature: 80 °C
Yield: 80 %

Procedure:
A mixture of 2-(3,4-dihydro-2H-1-benzopyran-6-yl)-imidazo[1,2-a]pyridine (19b) (50 mg, 0.2 mmol), ethyl glyoxylate 50% in toluene (0.20 mL, 1.0 mmol) and p-toluenesulfonic acid (6 mg, 0.03 mmol) in ethanol (1 mL) was heated at 80° C. for 1 hour. Ethyl glyoxylate 50% in toluene (0.10 mL, 0.5 mmol) was added and the heating was maintained for one supplementary hour. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL), washed with a saturated solution of sodium hydrogencarbonate (5 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 40/60) to provide the desired hydroxyl-ester (19c) (56 mg, 0.159 mmol, 80%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([C@H:17]1[O:19][CH2:18]1)[Cl:16]>>[Cl:16][CH2:15][C@@H:17]([OH:19])[CH2:18][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: ClC[C@@H]1CO1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1nccn1C[C@H](O)CCl

Procedure:
Alternatively, a mixture of 2-nitroimidazole, anhydrous potassium carbonate, and (S)-(+)-epichlorohydrin is refluxed for 10 minutes then filtered while hot. The filtrate is concentrated and cooled to give a solid. Crystallization from ethanol and further processing gives the product.
Reaction SMILES: N1C=CC=CC=1.[O:7]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]([OH:20])[CH:18]=[CH2:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:24][C:25]1([CH3:37])[CH:27]([CH:28]([Br:33])[C:29]([Cl:32])([Cl:31])[Br:30])[CH:26]1[C:34](Cl)=[O:35]>C1C=CC=CC=1>[O:7]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]([O:20][C:34]([CH:26]1[CH:27]([CH:28]([Br:33])[C:29]([Cl:31])([Cl:32])[Br:30])[C:25]1([CH3:37])[CH3:24])=[O:35])[CH:18]=[CH2:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1(C)C(C(=O)Cl)C1C(Br)C(Cl)(Cl)Br
Reactant: C=CC(O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C=CC(OC(=O)C1C(C(Br)C(Cl)(Cl)Br)C1(C)C)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.2 g of pyridine in 10 ml of benzene is added dropwise at 5° C., with stirring, to 8 g of 3-phenoxy-α-vinyl-benzyl alcohol in 30 ml of benzene. After the addition of 14 g of 2,2-dimethyl-3-(1-bromo-2,2-dichloro-2-bromoethyl)-cyclopropanecarboxylic acid chloride at 10° C., the mixture is stirred for 2 hours at room temperature, and is allowed to stand for a further 10 hours at this temperature. The reaction mixture is diluted with ice water; the organic layer is extracted three times with 100 ml of 3% HCl each time, and subsequently three times with 100 ml of 3% sodium bicarbonate each time; the organic phase is dried with sodium sulfate, and the benzene is distilled off. There is obtained the compound of the formula ##STR9## as colourless oil having a refractive index of nD40° =1.5776. In an analogous manner is also obtained the compound of the formula ##STR10##
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12]C(Cl)=C(Cl)[CH:9]=1)(=[O:3])[CH3:2].ClCC(=O)CC1C=C[S:23]C=1.C(O)(=O)C.C(N(CC)CC)C>>[C:1]([O:4][CH2:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][S:23][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(CCl)Cc1ccsc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)Cc1ccsc1
Yield: 52 %

Procedure:
The procedure described above for the synthesis of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate was followed, reacting 1-chloro-3-(thiophen-3-yl)propan-2-one (6.53 g, 37.4 mmol) with acetic acid (4.3 mL, 4.5 g, 75 mmol) and triethylamine (10.4 mL, 7.57 g, 74.8 mmol). Flash chromatography over silica gel (20% ethyl acetate in hexanes) gave pure product, a golden-yellow oil (3.85 g, 52% yield): 1H NMR (400 MHz, CDCl3) δ 2.16 (s, 3H) 3.77 (s, 2H) 4.70 (s, 2H) 6.98 (dd, J=4.8, 1.3 Hz, 1H) 7.14 (dd, J=1.8, 1.0 Hz, 1H) 7.32 (dd, J=4.9, 2.9 Hz, 1H).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].OS(O)(=O)=O.[Br:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][C:15]2=[O:20].[OH-].[Na+]>O.C(Cl)(Cl)Cl>[Br:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][C:15](=[O:20])[NH:1]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2c(Br)cccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1CCc2c(Br)cccc2N1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a stirred mixture of sodium azide (862 mg, 13.3 mmol) in H2O (1.7 mL) and CHCl3 (6.5 mL) was added conc. H2SO4 (0.23 mL, 4.14 mmol). The reaction mixture was stirred vigorously at 0° C. for 2.5 h. The CHCl3 layer was separated, dried over Na2SO4, and added to a solution of 4-bromo-1-indanone (1.12 g, 5.31 mmol) in CHCl3 (20 mL). To this mixture was added conc. H2SO4 (1.75 mL, 31.5 mmol) dropwise over 10 min. The reaction mixture was heated at 45 C for 1 h then poured into ice-water, neutralized with 20% aqueous NaOH, and extracted with CH2Cl2 (100 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=226 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(O[CH:16]([C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[F:31])[C:17]1[N:18]([CH3:23])[C:19]([Cl:22])=[CH:20][N:21]=1)=O)(C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([SH:39])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39][CH:16]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:17]2[N:18]([CH3:23])[C:19]([Cl:22])=[CH:20][N:21]=2)=[CH:35][CH:34]=1
Reactant: Cn1c(Cl)cnc1C(OC(=O)OC(C)(C)C)c1cc(F)ccc1F
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cn1c(Cl)cnc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
Trifluoroacetic acid (10 ml) was added to the 2-[(t-butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-methyl-5-chloro-1H-imidazole (404 mg, 1.13 mmol) obtained in Referential Example 14. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration under reduced pressure. The residue was dissolved in thionyl chloride (2.0 ml) and to the resulting solution was added a drop of dimethylformamide. The mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration under reduced pressure. The residue was dissolved in dimethylformamide (5.0 ml). To the resulting solution were added 4-chlorobenzenethiol (244 mg, 1.69 mmol) and potassium carbonate (936 mg, 6.78 mmol). The resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was allowed to stand until it became room temperature. Ethyl ether (60 ml) was added. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1 to 5:1) to give the title compound (195 mg, 89%) as a colorless oil.
Reaction SMILES: ClC(Cl)(Cl)C(Cl)=O.[CH2:8]([O:11][C:12](=[O:28])[C@@H:13]([O:18][C:19](=[O:27])[C@H:20]([CH3:26])[CH2:21][S:22][C:23](=[O:25])[CH3:24])[CH2:14][C:15]([NH2:17])=O)[CH:9]=[CH2:10].C(N(CC)CC)C>ClCCl>[CH2:8]([O:11][C:12](=[O:28])[C@@H:13]([O:18][C:19](=[O:27])[C@H:20]([CH3:26])[CH2:21][S:22][C:23](=[O:25])[CH3:24])[CH2:14][C:15]#[N:17])[CH:9]=[CH2:10]
Reactant: C=CCOC(=O)[C@H](CC(N)=O)OC(=O)[C@H](C)CSC(C)=O
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](CC#N)OC(=O)[C@H](C)CSC(C)=O
Reaction time: 8 h
Yield: 109.1 %

Procedure:
Trichloroacetyl chloride (0.3 g, 1.7 mmol) in dichloromethane (20 ml) was added at 0°-5° to a stirred solution of 2(S)-(3-(acetylthio)-2(S)-methyl-1-oxopropoxy)-4-amino-4-oxobutanoic acid 2-propenyl ester (0.48 g, 1.5 mmol) and triethylamine (0.31 g, 3 mmol) in dichloromethane (50 ml). The mixture was stirred overnight, the organic solution washed with water, dried (MgSO4) and the solvent evaporated to give the sub-title ester (0.49 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:23]2[C:5](=[CH:6][C:7]3[NH:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][C:13]=4[O:20][CH3:21])=[N:9][C:8]=3[CH:22]=2)[NH:4][C:3]1=[O:24].C(O)(=[O:28])C.OO.[OH2:32]>>[CH3:1][C:2]1([CH3:25])[C:23]2[C:5](=[CH:6][C:7]3[NH:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([S:18]([CH3:19])(=[O:28])=[O:32])=[CH:14][C:13]=4[O:20][CH3:21])=[N:9][C:8]=3[CH:22]=2)[NH:4][C:3]1=[O:24]
Reactant: CC(=O)O
Reactant: COc1cc(SC)ccc1-c1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C
Reactant: O
Agent: OO
Product: COc1cc(S(C)(=O)=O)ccc1-c1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C

Procedure:
200 mg. (0.56 mmol) 7,7-dimethyl-2-(2-methoxy-4-methylthiophenyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]-benzimidazol-6-one were stirred for 48 hours at ambient temperature in 4 ml. glacial acetic acid and 0.4 ml. 30% hydrogen peroxide. 10 ml. water were added thereto and the solvent was removed in a vacuum. There were obtained 160 mg. (75% of theory) of the title compound which, after crystallization from ethanol, had a melting point of 235°-237° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:40])[NH:10][CH2:11][CH2:12][O:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([C:21]2[N:25]=[C:24]([C:26]3[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:27]=3)[O:23][N:22]=2)=[CH:16][C:15]=1[CH2:38][CH3:39])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.CC(=O)OCC>[NH2:7][CH2:8][C:9]([NH:10][CH2:11][CH2:12][O:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([C:21]2[N:25]=[C:24]([C:26]3[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:27]=3)[O:23][N:22]=2)=[CH:16][C:15]=1[CH2:38][CH3:39])=[O:40]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OCCNC(=O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OCCNC(=O)CN
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.6 %

Procedure:
To a solution of [(2-{4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-ethylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (65 mg, 0.115 mmol) in DCM (30 mL), trifluoroacetic acid (262 mg, 2.29 mmol) is added. The mixture is stirred at rt for 16 h before it is diluted with EA and washed with sat. aq. NaHCO3-solution and brine. The org. extract is dried over Na2SO4, filtered and concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of 7 N NH3 in methanol to give the title compound (32 mg) as a yellow resin; LC-MS: tR=0.70 min; [M+1]+=467.19; 1H NMR (CDCl3): δ 1.24 (t, J=7.0 Hz, 6H), 1.32 (t, J=7.5 Hz, 3H), 2.01 (s br, 2H), 2.39 (s, 3H), 2.49 (s, 3H), 2.76 (q, J=7.5 Hz, 2H), 3.45 (s, 2H), 3.62 (q, J=7.0 Hz, 4H), 3.73-3.80 (m, 2H), 3.95 (t, J=5.0 Hz, 2H), 7.00 (s, 1H), 7.10 (s, 1H), 7.87 (s, 1H), 7.88 (s, 1H), 7.90 (s br, 1H).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O:32][C:33](=[O:62])[CH:34]([C:55]1[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=1)[CH2:35][C:36]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][C:44](Br)=[CH:43][CH:42]=2)[N:38]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:37]=1)C.[CH2:63]([NH2:66])[CH:64]=[CH2:65]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH2:63]([NH:66][C:44]1[CH:43]=[CH:42][C:41]([C:39]2[N:38]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)[N:37]=[C:36]([CH2:35][CH:34]([C:55]3[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=3)[C:33]([OH:62])=[O:32])[CH:40]=2)=[CH:46][CH:45]=1)[CH:64]=[CH2:65]
Reactant: C=CCN
Reactant: CCOC(=O)C(Cc1cc(-c2ccc(Br)cc2)n(-c2ccc(C)cc2)n1)c1cccc(C)c1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCNc1ccc(-c2cc(CC(C(=O)O)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 49.8 %

Procedure:
3-[5-(4-Allylamino-phenyl)-1-β-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester. To a mixture of Pd2(dibenzylideneacetone)3 (4 mg, 0.004 mmol, 1 mol %), 2-(di-tert-butylphosphino)biphenyl (6 mg, 0.02 mmol, 5 mol %) and K3PO4 (130 mg, 0.61 mmol, 1.5 equiv) was added a solution of 3-[5-(4-bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester (Example 77, Step C; 200 mg, 0.4 mmol) in toluene (0.6 mL) followed by allylamine (0.030 mL, 0.48 mmol, 1.2 equiv). The resulting mixture was stirred at 110° C. for 12 h and then cooled to room temperature. Ethyl acetate (2 mL) and water (3 mL) were added, and the resulting aqueous layer was back-extracted with EtOAc (3×2 mL). The combined organic layers were washed with brine (3 mL), and then dried (MgSO4). The solvent was evaporated under reduced pressure, and the residue was purified by chromatography (silica gel, 25% ethyl acetate/hexanes) to afford the desired compound (90 mg, 47%). HPLC: Rt=3.19 (Method B). MS (ESI): mass calculated for C31H33N3O2, 479.26; m/z found, 480.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.29 (s, 1H), 7.27-7.04 (m, 7H), 6.96 (d, J=8.5 Hz, 2H), 6.49 (d, J=8.5 Hz, 2H), 6.07 (s, 1H), 5.96-5.89 (m, 1H), 5.29-5.25 (m, 1H), 5.18-5.16 (m, 1H), 4.20-4.14 (m, 1H), 4.10-4.02 (m, 2H), 3.76-3.75 (m, 2H), 3.52-3.45 (m, 1H), 3.08 (dd, J=14.5, 6.0 Hz, 1H), 2.3 (s, 6H), 1.19 (t, J=7.1 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[C:11]([N+:19]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1>C(O)(=O)C.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:12]([CH2:15][C:16](=[O:17])[NH:19]3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Temperature: 100 °C
Yield: 45 %

Procedure:
Iron powder (3.6 g) was added in one portion to 7.2 g of 4′-methoxy-3-nitrobiphenyl-4-acetic acid in 50 mL of glacial acetic acid and heated at 100° C. overnight. The reaction mixture was concentrated to dryness, sonicated in ethyl acetate and filtered to remove the insolubles. The filtrate was washed twice with 1N hydrochloric acid and brine, dried over anhydrous sodium sulfate and concentrated to give 2.7 g of 6-(4-methoxyphenyl)-2-oxindole as a rose colored solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([F:21])[CH:15]=1.C([O-])([O-])=O.[K+].[K+].[C:28]1([CH3:34])[CH:33]=C[CH:31]=[CH:30][CH:29]=1>O.CCOC(C)=O.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>[F:21][C:16]1[CH:15]=[C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:20]=[C:19]2[C:17]=1[NH:18][C:28]([CH3:34])([CH3:33])[CH:29]=[C:30]2[CH3:31]
Reactant: Nc1ccc(Br)cc1F
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=CC(C)(C)Nc2c(F)cc(-c3cccc([N+](=O)[O-])c3)cc21
Temperature: 95 °C

Procedure:
A mixture of 3-nitrobenzeneboronic acid (0.70 g, 4.2 mmol), 4-bromo-2-Fluoroaniline (730 mg, 4.0 mmol), (PPh3)4Pd (93 mg, 0.08 mmol), and K2CO3 (0.69 g, 5.0 mmol) in toluene (20 mL) and water (2 mL) was heated at 95° C. for 16 h and the mixture was diluted with EtOAc (20 mL). The mixture was washed with water (10 mL) and brine (10 mL), concentrated and purified by silica gel chromatography to afford the 4-amino-3-Fluoro-3′-nitrobiphenyl (structure 82 of Scheme XXI, where R1═R3-7=H, R8=F) (0.4 g, 41%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[CH:14][C:15]1[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=1)[CH2:21][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]3)[CH:7]=[CH:6]2)#[N:2].[N+](=[CH2:34])=[N-]>C1COCC1.C(OCC)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]1[CH2:34][CH:14]1[C:15]1[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=1)[CH2:21][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]3)[CH:7]=[CH:6]2)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C=Cc3ccc4cc(C#N)ccc4c3)ccc2C1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2cc(C3CC3c3ccc4cc(C#N)ccc4c3)ccc2C1

Procedure:
A solution of Example 42I (207 mg, 0.5 mmol) and Pd(OAc)2 (5 mg) in THF (100 mL), at 0° C. was treated with a 0° C. 2M solution of diazomethane in diethyl ether (20 mL), warmed to room temperature over 10 minutes, treated with Pd(OAc)2 (5 mg) and 2M diazomethane in diethyl ether (20 mL), and treated two more times with Pd(OAc)2 and 2M diazomethane after 10 minute stirring intervals. After the final addition, the mixture was stirred for 1 hour, filtered through diatomaceous earth (Celite®) and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[C:12](=O)([O:16]CC)[O:13][CH2:14][CH3:15].[H-].[Na+].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH2:10][C:12]([O:13][CH2:14][CH3:15])=[O:16]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
To a solution of 2′,4′-Dichloroacetophenone (1.50 g, 7.93 mmol) in diethyl carbonate (24.0 mL, 198 mmol) at 0° C. was added slowly NaH (60% suspension in mineral oil, 0.657 g, 16.4 mmol). The mixture was then stirred at 80° C. for 90 minutes. The mixture was cooled to room temperature then poured into an ice cold solution of 2.0 mL acetic acid in 56 mL water. The layers were separated and the aqueous phase was extracted with ether 3 times. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (1.16 g, 56%). LCMS: (FA) ES+, 262. 1H NMR (400 MHz, d1-chloroform) δ (2 sets of signals, keto and enol): 12.49 (s, 1H), 7.61-7.29 (m, 2 sets of 3H), 5.57 (s, 1H), 4.28 (q, J=7.28 Hz, 2H), 4.19 (q, J=7.28 Hz, 2H), 4.02 (s, 2H), 1.34 (t, J=7.03 Hz, 3H), 1.25 (t, J=7.03 Hz, 3H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][N:10]=1)CCC.[C:19]([N:27]1[C:35]2[CH:34]=[CH:33][C:32](I)=[C:31]3[CH2:37][C@@H:38]([N:40]([CH2:44][CH2:45][CH3:46])[CH2:41][CH2:42][CH3:43])[CH2:39][C@H:29]([C:30]=23)[CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>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>[C:19]([N:27]1[C:35]2[CH:34]=[CH:33][C:32]([C:6]3[O:7][CH:8]=[CH:9][N:10]=3)=[C:31]3[CH2:37][C@@H:38]([N:40]([CH2:44][CH2:45][CH3:46])[CH2:41][CH2:42][CH3:43])[CH2:39][C@H:29]([C:30]=23)[CH2:28]1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: CCCN(CCC)[C@@H]1Cc2c(I)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCN(CCC)[C@@H]1Cc2c(-c3ncco3)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Yield: 67.5 %

Procedure:
A solution of 5.0 g (13.8 mmol) of the crude 2-tributylstannyloxazole prepared above and 6.8 g (13.9 mmol) of (+)(2aR,4S)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 100 ml of toluene was treated with 0.7 g (0.6 mmol) of tetrakis(triphenylphosphine)palladium then refluxed under nitrogen for 20 hours. After cooling the reaction mixture was washed with a saturated brine solution and then dried over Na2SO4. Concentration in vacuo provided a viscous oil which was chromatographed over a silica gel column using a solvent gradient progressing from toluene to 1:1 toluene/EtOAc. The product from the column was dissolved in 1M HCl. This solution was then washed with ether, made alkaline with 5M NaOH, and extracted with CH2Cl2. Concentration of the extract in vacuo gave about 4 g of a brown oil. When this oil was dissolved in pentane a small amount of a red/brown resin separated leaving a clear, yellow solution. The resin was separated and the pentane was evaporated to provide a residue. This residue was crystallized by dissolving it in a small amount of CH2Cl2 and slowly adding isoctane. The crystalline (-)(2aR,4S)-1-benzoyl-6-(2-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole, obtained in four crops, weighed 2.63 g. mp 103°-104° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][NH2:13]>C(O)C>[ClH:1].[ClH:1].[NH:12]([C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1)[NH2:13]
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Reactant: NN
Solvent: CCO
Product: Cl
Product: NNc1ccc(S(N)(=O)=O)cn1
Yield: 114 %

Procedure:
To a solution of 6-chloro-3-pyridinesulfonamide (0.64 g, 3.32 mmol) in ethanol (20 mL) was added hydrazine anhydrous (0.128 g, 3.99 mmol). After the reaction mixture was heated at reflux temperature for 5 hours, the solvent was removed. The residue was washed with methylene chloride to give the subtitle compound (0.494 g, 79.0% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([OH:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[CH:17][CH:16]=2)[C@H:10]([O:33][CH2:34][C@H:35]2[CH2:39][O:38][C:37]([CH3:41])([CH3:40])[O:36]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:43][C:44]1[CH:45]=[C:46]([O:54][CH3:55])[C:47]2[C:52]([CH:53]=1)=[CH:51][CH:50]=[CH:49][CH:48]=2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:43][C:44]2[CH:45]=[C:46]([O:54][CH3:55])[C:47]3[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:53]=2)[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[CH:17][CH:16]=2)[C@H:10]([O:33][CH2:34][C@H:35]2[CH2:39][O:38][C:37]([CH3:41])([CH3:40])[O:36]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@@H](c2ccc(OCCCOc3ccccc3Cl)cc2)[C@H](OC[C@H]2COC(C)(C)O2)C1
Reactant: COc1cc(CCl)cc2ccccc12
Product: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3COC(C)(C)O3)[C@@H]2c2ccc(OCCCOc3ccccc3Cl)cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (f) the (3S,4R,5R)-4-[4-[3-(2-chloro-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester was reacted with the 3-chloromethyl-1-methoxy-naphthalene [example 1) (α)] to yield the (3S,4R,5R)-4-[4-[3-(2-chloro-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 762.3 (M+H)+.