Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.F[C:12]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOCCOC.CCOCC>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][C:12]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:13]=3[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccc(F)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: COC(=O)c1ccc(F)cc1Oc1ccc2[nH]ccc2c1
Reaction time: 24 h

Procedure:
A mixture of 5-hydroxyindole (8.5 g), methyl 2,4-difluorobenzoate (7.05 g), and K3PO4 (9.32 g) in diglyme (40 mL) at 115° C. was stirred for 24 hours. The reaction was cooled, diluted with ether (600 mL), and washed twice with water, and brine, and concentrated. The crude product was chromatographed on silica gel with 2-50% ethyl acetate/hexanes.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[N:14][CH:13]=3)[CH2:9][C:8](=[O:18])[NH:7][C:6]=2[CH:19]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][N:15]=[N:14][CH:13]=4)[CH2:9][C:8](=[O:18])[NH:7][C:6]=3[CH:19]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: O=C1CC(c2ccnnc2)=Nc2ccc(Br)cc2N1
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2ccc3c(c2)NC(=O)CC(c2ccnnc2)=N3)cc1OC

Procedure:
The title compound was prepared from 8-bromo-4-(pyridazin-4-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one (Example 1; 1 mmol) and commercial available 3,4-dimethoxyphenylboronic acid (CAS-No: 122775-35-3; 1.5 mmol) according to the general procedure G. Obtained as a yellow solid (75%), MS (EI) 375 [(M+1)+].
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[CH2:7][C:8]([OH:10])=[O:9])=[O:4].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].Cl.[CH3:29][O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH2:33]>C(O)(=O)C>[CH3:29][O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:33][C:11](=[O:13])[C@H:6]([CH2:7][C:8](=[O:9])[OH:10])[NH:5][C:3](=[O:4])[C:2]([F:1])([F:15])[F:14]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)C[C@H](NC(=O)C(F)(F)F)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)C(F)(F)F
Reaction time: 6 h
Yield: 79 %

Procedure:
In 63.3 g of acetic acid, 22.9 g (0.1 mole) of N-trifluoroacetyl-L-aspartic acid was suspended and 10.2 g (0.1 mole) of acetic anhydride was added. The mixture was warmed to 55°-60° C. and stirred for 6 hours at the same temperature. After finishing the reaction, the resulting mixture was cooled to 15°-20° C. and then 9.2 g (0.11 mole) of sodium acetate and 20.5 g (0.095 mole) of L-phenylalanine methyl ester hydrochloride were successively added at the same temperature. The reaction was carried out for 2 hours with stirring at the same temperature. Precipitated crystals were filtered, washed and dried. Crystals of N-trifluoroacetyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained in the yield of 29.3 g (79.0% yield on L-phenylalanine methyl ester hydrochloride). The crystals thus obtained were analyzed by high performance liquid chromatography to find α-isomer alone.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S(Cl)(Cl)=O.N1C=CC=CC=1.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]1[C:49]2[C:40](=[C:41]3[C:46](=[CH:47][CH:48]=2)[CH:45]=[CH:44][CH:43]=[N:42]3)[N:39]=[CH:38][CH:37]=1>O>[C:1]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]1[C:49]2[C:40](=[C:41]3[C:46](=[CH:47][CH:48]=2)[CH:45]=[CH:44][CH:43]=[N:42]3)[N:39]=[CH:38][CH:37]=1)(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: NCCCCc1ccnc2c1ccc1cccnc12
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCCc1ccnc2c1ccc1cccnc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of octadecanoic acid (170 mg, 0.6 mmol) and thionyl chloride (4 mL) was heated at 60° C. for 1 hour. The mixture was then cooled to room temperature, whereupon it was concentrated in vacuo. Residue from this mixture was then dissolved in CH2Cl2 (10 mL), whereupon pyridine (5 equivalents) and 4-(aminobutyl)-1,10-phenanthroline (1 equivalent) (Wang et al., Adv. Funct. Mater., 12, 415-419 (2002)) were added. The resulting mixture was stirred at room temperature overnight and then poured into H2O. The resulting precipitate was collected by suction filtration and dried to a constant weight to give 4-(4-(octadecanoylamino)butyl)-1,10-phenanthroline.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][O:11][N:12]=[CH:13][C:14]2[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)=[CH:8][CH:9]=1)=[O:4].[Li+].[OH-].O>C1COCC1>[O:18]1[C:17]2[CH:22]=[CH:23][C:14]([CH:13]=[N:12][O:11][CH2:10][C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=3)=[CH:15][C:16]=2[O:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1ccc(CON=Cc2ccc3c(c2)OCCO3)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CON=Cc2ccc3c(c2)OCCO3)s1
Temperature: 70 °C
Yield: 98.3 %

Procedure:
To a solution of 200 mg (0.60 mmol) 5-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyleneaminooxymethyl)-thiophene-2-carboxylic acid methyl ester in 2.4 ml THF were added 1.2 ml 1M aqueous LiOH solution and the reaction mixture was heated to 70° C. for 5 h. Water was added, the mixture was acidified and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4 and the solvent was evaporated to give 190 mg (0.59 mmol) 5-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyleneaminooxymethyl)-thiophene-2-carbox-ylic acid; exact MW [M+H] calc'd: 320.06; MW found [M+H]: 320.2.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:37]2[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=2)=[CH:34][CH2:35]O)=[CH:29][CH:28]=1>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:35][CH:34]=[C:33]([C:30]2[CH:29]=[CH:28][C:27]([Br:26])=[CH:32][CH:31]=2)[C:37]2[CH:38]=[CH:39][C:40]([Br:43])=[CH:41][CH:42]=2)=[CH:20][CH:19]=1
Reactant: OCC=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Reaction time: 1 h
Yield: 62 %

Procedure:
Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (504 mg, 2.0 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (404 mg, 2.0 mmol), methyl 4-hydroxyphenylacetate (250 mg, 1.5 mmol) and 3,3-bis-(4-bromophenyl)prop-2-en-1-ol (552 mg, 1.5 mmol) in dry THF (10 ml), the mixture stirred for 1 h, filtered and concentrated in vacuo. The crude product was then purified by column chromatography on silica (toluene eluent). The purified product was suspended in petroleum ether, filtered to give 480 mg (62%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:13])[CH2:9][N+:10]([O-:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.Cl[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:13][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:9][N+:10]([O-:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=[N+]([O-])CC(O)c1cccc(Cl)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(C[N+](=O)[O-])c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of 1-(3-chloro-phenyl)-2-nitro-ethanol (26 g, 0.14 mol) in DMF (50 mL) were added imidazole (28.6 g, 0.42 mol) and chlorotriethylsilane (25.3 g, 0.17 mol). The reaction mixture was stirred at room temperature for 2 h. After quenching with water, the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, and filtered. After removal of solvent, the crude product was purified by flash chromatography (2% EtOAc/hexane) to yield the title compound (37 g, 91%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.40 (1H, s), 7.27-7.32 (3H, m), 5.40 (1H, dd, J=3.2, 9.5 Hz), 4.51 (1H, dd, J=9.5, 12.1 Hz), 4.36 (1H, dd, J=3.3, 12.1 Hz), 0.85 (9H, t, J=7.5 Hz), 0.54 (6H, q, J=7.5 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:6]=2[CH:19]=1.[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]1[CH2:30][CH:31]([OH:49])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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]>[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]1[CH2:30][CH:31]([OH:49])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[CH:8][N:7]([CH2:10][C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=4)[C:6]=3[CH:19]=2)[CH:35]=1
Reactant: CC1(C)OB(c2cccc(OCC(O)CN3CCc4ccccc4C3)c2)OC1(C)C
Reactant: COc1ccc(Cn2cnc3ccc(Br)cc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cnc3ccc(-c4cccc(OCC(O)CN5CCc6ccccc6C5)c4)cc32)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 24.1 %

Procedure:
A mixture of 6-bromo-1-(4-methoxybenzyl)-1H-benzo[d]imidazole (200 mg, 0.63 mmol), 1-(3,4-dihydroisoquinolin-2-(1H)-yl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol (284 mg, 0.69 mmol), K2CO3 (261 mg, 1.89 mmol) and Pd(dppf)Cl2 (50 mg) in dioxane (8 mL) and H2O (2 mL) was stirred at 100° C. for 16 h. The catalyst was filtered and the filtrate concentrated. The residue was then purified by Prep-HPLC to give the title compound (79 mg, 24.2%). 1HNMR(CH3OD, 400 MHz) δ: 8.39 (br, 1H), 8.25 (s, 1H), 7.73-7.68 (m, 1H), 7.64-7.61 (m, 1H), 7.56-7.48 (m, 1H), 7.48-7.42 (m, 1H), 7.28-7.14 (m, 8H), 6.97-6.85 (m, 3H), 5.44 (s, 2H), 4.50-4.45 (m, 1H), 4.35 (s, 2H), 4.10-4.09 (m, 2H), 3.70 (s, 3H), 3.51-3.48 (m, 2H), 3.36-3.31 (m, 2H), 3.19-3.10 (m, 2H). LCMS (m/z): 520.2 [M+H]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1)(=[O:11])=[O:10].[CH2:24]1[NH:29][CH2:28][CH2:27][N:26]2[CH2:30][CH2:31][CH2:32][C@@H:25]12.CCN(C(C)C)C(C)C>C(#N)C>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][C@H:12]([S:9]([C:3]2[CH:4]=[CH:5][C:6]([N:29]3[CH2:28][CH2:27][N:26]4[CH2:30][CH2:31][CH2:32][C@H:25]4[CH2:24]3)=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:10])[CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: C1C[C@H]2CNCCN2C1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](S(=O)(=O)c2ccc(F)cc2Cl)C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](S(=O)(=O)c2ccc(N3CCN4CCC[C@H]4C3)cc2Cl)C1
Temperature: 60 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
In a 50 mL round-bottomed flask, (S)-tert-butyl 3-(2-chloro-4-fluorophenylsulfonyl)-pyrrolidine-1-carboxylate, example 52D) (2 g, 5.5 mmol, 1 eq) was combined with acetonitrile (20 mL) to give a light yellow solution. (S)-octahydropyrrolo[1,2-a]pyrazine (1.04 g, 8.25 mmol, 1.5 eq) and DIEA (1.42 g, 1.92 mL, 11.0 mmol, 2 eq) were added. The reaction mixture was stirred for 15 h. The reaction mixture was heated to 60° C. and stirred for 5 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into EtOAc (25 mL) and extracted with aqueous 10% Na2CO3 (2×20 mL) and brine. The organic layers were dried over Na2SO4 and concentrated in vacuo to yield a colorless viscous oil (2.48 g, 96%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1>>[C:10]1([CH3:13])[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(Br)cc1
Reactant: c1cn[nH]c1
Product: Cc1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (125° C., 24 hours), 1H-pyrazole (102 mg, 1.5 mmol) is coupled with 1-bromo-4-methylbenzene (122 μL, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=70/30) to provide 90 mg (57% isolated yield) of the desired product as an uncolored oil.
Reaction SMILES: CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[C:42]([O:46][C:47]([NH:49][C@@H:50]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:51]([OH:53])=O)=[O:48])([CH3:45])([CH3:44])[CH3:43].[CH3:58][C@@H:59]1[CH2:63][NH:62][C@@H:61]2[C@@H:64]([OH:67])[CH2:65][O:66][C@H:60]12>CN(C)C=O>[OH:67][C@@H:64]1[C@H:61]2[N:62]([C:51](=[O:53])[C@@H:50]([NH:49][C:47](=[O:48])[O:46][C:42]([CH3:43])([CH3:44])[CH3:45])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:63][C@@H:59]([CH3:58])[C@H:60]2[O:66][CH2:65]1
Reactant: C[C@@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@@H]1CN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 0.08 h
Yield: 133.6 %

Procedure:
4-Methylmorpholine (1.062 mL, 9.7 mmol) was added to a suspension of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 1839 mg, 4.85 mmol), 1-hydroxybenzotriazole (654 mg, 4.85 mmol) and (S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (1.125 g, 4.85 mmol) in dimethylformamide (5 mL). The mixture was stirred for 5 minutes before adding to (3R,3aR,6R,6aR)-6-methylhexahydro-2H-furo[3,2-b]pyrrol-3-ol (107) (prepared as above with appropriate scaling of quantities, assume 4.62 mmol). The mixture was stirred for 16 hours then the solvents removed in vacuo. The crude product was dissolved in DCM (75 mL) then washed with (75 ML each) sat. NaHCO3, 0.01N HCl, brine and the organic layer dried over Na2SO4. The mixture was filtered to leave a tan oil (2.20 g). Flash chromatography over silica, eluting with ethyl acetate:pentane mixtures 15:85 to 50:50 gave desired alcohol as a white solid (1.45 g, contaminated with tetramethylurea). Analytical HPLC main peak, Rt=11.94 min., HPLC-MS 301.2 [M+2H−tBu]+, 357.2 [M+H]+, 379.2 [M+Na]+, 735.5 [2M+Na]+.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:5]([F:18])[CH:4]=1)#[N:2].[NH2:19][OH:20]>CCO>[NH2:2][C:1](=[N:19][OH:20])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[C:5]([F:18])[CH:4]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)COc1ccc(C#N)cc1F
Solvent: CCO
Product: CC(C)(C)OC(=O)COc1ccc(C(N)=NO)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
Tert-butyl (4-cyano-2-fluorophenoxy)acetate (3.50 g; 13.93 mmol; 1 eq.) was suspended in EtOH (70 mL). hydroxylamine (2.05 mL; 69.65 mmol; 5 eq.) was added in one portion. The reaction mixture was stirred at RT for 12 hours. The reaction mixture was concentrated affording the title compound as a white solid (3.57 g, 90%). 1H NMR (DMSO-d6, 300 MHz) δ 9.61 (br s, 1H), 7.51-7.41 (m, 2H), 7.09-7.03 (t, J=8.84 Hz 1H), 5.81 (br s, 2H), 4.78 (s, 2H), 1.42 (s, 9H). LC/MS (Method 13): 285.1 (M+H)+. HPLC (Method A) Rt 2.91 min (Purity: 94.3%).
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[CH3:11][N:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:13].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:18]3[CH:19]=[C:14]([N:12]([CH3:13])[CH3:11])[CH:15]=[CH:16][CH:17]=3)=[N:3]2)=[N:7][CH:8]=1
Reactant: Brc1nn2c(I)cnc2s1
Reactant: CN(C)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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)c1cccc(-c2nn3c(I)cnc3s2)c1
Temperature: 95 °C
Yield: 21.4 %

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.150 g, 0.455 mmol, 1 eq), 3-(N,N-dimethylamino)phenylboronic acid (0.113 g, 0.682 mmol, 1.5 eq), Cs2CO3 (0.296 g, 0.909 mmol, 2 eq) and Pd(PPh3)4 (0.032 g, 0.027 mmol, 0.06 eq) were dissolved in Dioxane (8 mL) and water (2 mL). The reaction mixture was heated at 95° C. for 24 h. Additional amounts of 3-(N,N-dimethylamino)phenylboronic acid (1.5 eq) and Pd(PPh3)4 (0.06 eq) were added and the reaction mixture was heated at 95° C. for 3 days. The solvent was removed in vacuo, redissolved in DCM/water (150 mL) and extracted with DCM (2×80 mL). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (20-70% EtOAc in cyclohexane) to afford the desired product (36 mg, 21%) as a yellow solid. HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.73 min, [M+H]+ m/z 371.1.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10]C)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.C[O-].[Na+]>C1COCC1>[N:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)N1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Polymer-bound piperidinecarboxylic acid, ethyl ester resin (0.25 g, 0.283 mmol) was swollen with a solution of MeOH (1 ml) in THF (4 ml) in a QUICKFIT test-tube. After addition of sodium methoxide (0.28 ml, 0.028 mmol, 1M solution in MeOH) the resulting suspension was stirred overnight at reflux. The reaction suspension was cooled down to room temperature and the resin was washed using VACMASTER station with DCM (4×3 ml), MeOH (2×3 ml) and then dried under vacuum. FT-IR (2% w/w KBr disk): C=0 1736 cm−1 (ester); 163 cm−1 (amide).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][CH:22]=[N:21][C:20]=2[C:24]#[N:25])=[CH:15][CH:14]=1.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[Cl:28][C:22]1[O:23][C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:26])[F:27])=[CH:18][CH:17]=2)=[C:20]([C:24]#[N:25])[N:21]=1
Reactant: N#Cc1ncoc1-c1ccc(C(F)(F)F)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nc(Cl)oc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
LiHMDS (1.0 M in THF, 4.5 mL, 4.5 mmol) was added dropwise to a solution of Example 56C (0.980 g, 4.11 mmol) in THF (13 mL) at −78° C. After 30 min solid hexachloroethane (0.974 g, 4.11 mmol) was added in one portion. The reaction was allowed to warm to room temperature while stirring overnight during which a solid formed. The mixture was diluted with hexanes and water, and filtered. The filtrate was diluted with EtOAc, and the phases separated. The organic phase was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was dissolved in toluene, loaded on silica gel, and eluted with 1 column length of hexanes and then 0% to 30% EtOAc:hexanes to afford 0.51 g (46%) of the title compound as a yellow milky oil. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=8.2, 2H), 7.81 (d, J=8.3, 2H).
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[CH3:9][N+:10]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24](=[S:36])[O:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[CH:15]2.C(O)(=O)C>C(Cl)Cl.C(O)(C)C.[Zn]>[CH3:9][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]([C:24](=[S:36])[O:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]1=2
Reactant: C[n+]1c2ccccc2c(C(=S)Oc2cccc3ccccc23)c2ccccc21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(C)O
Product: CN1c2ccccc2C(C(=S)Oc2cccc3ccccc23)c2ccccc21
Reaction time: 8 h
Yield: 98.2 %

Procedure:
Naphthyl 10-methylacridinium-9-thiocarboxylate triflate (65.50 g) was suspended in CH2Cl2 (1000 mL) under argon and glacial acetic acid (21.2 ml) and zinc (40.43 g) were added. After stirring overnight, TLC showed the dissappearance of the starting material and the formation of a new product. The reaction mixture was filtered through a bed of silica gel and the CH2Cl2 removed in vacuo. The slightly yellow solid obtained was stirred in isopropanol (500 ml), filtered, washed with 500 ml more isopropanol, and allowed to air dry. The pure product (46.36 g) was thereby obtained. 1H NMR (CDCl3) δ 3.47 (s, 3H) , 5.13 (s, 1H) , 7.00-7.06 (m, 4H) , 7.25-7.49 (m, 7H) , 7.70-7.79 (m, 4H).
Reaction SMILES: [C:1]1([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.O[N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30].ClC(N=C=N)CC(Cl)CCC>CS(C)=O>[C:25]1(=[O:30])[N:24]([C:2]2[CH:3]=[C:4]3[C:15]4=[C:16]5[C:11]([CH:10]=[CH:9][CH:8]=[C:7]5[CH:6]=[CH:5]3)=[CH:12][CH:13]=[C:14]4[C:1]=2[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:28](=[O:29])[CH2:27][CH2:26]1
Reactant: O=C(O)CCCc1ccc2ccc3cccc4ccc1c2c34
Reactant: O=C1CCC(=O)N1O
Agent: CCCC(Cl)CC(Cl)N=C=N
Solvent: CS(C)=O
Product: O=C(O)CCCc1c(N2C(=O)CCC2=O)cc2ccc3cccc4ccc1c2c34
Temperature: 0 °C
Yield: 62.5 %

Procedure:
SPB was prepared according to the synthesis scheme shown in FIG. 2. In 20 ml of dimethylsulfoxide (DMF), 2.25 g of 1-pyrenebutanoic acid (7.8 mmol: obtained from Molecular Probes, Inc.) and 1.2 g of N-hydroxy succinimide (10.4 mmol: obtained from Wako Pure Chemical Industries, Ltd.) were dissolved. After the mixed solution was cooled to 0° C., 2.69 g of 1,3-dichlorohexylcarbodiimide (13.1 mmol: DCC) was added thereto. Then, the mixture was reacted at 0° C. for 24 hours while stirring. After the reacted solution was filtered with a 0.45 μm filter, the filtrate was collected and dried using an evaporator. Then, the filtrate was recrystallized from 95% ethanol, thereby obtaining 1.88 g of succinimidyl-1-pyrenebutanoic acid (yield: 70%).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:10]=1C=O.N1CCCCC1.Cl>N1C=CC=CC=1>[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:1]=[CH:2][C:3]([OH:5])=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A 250 ml round-bottomed flask, Teflon stirrer, reflux condenser, and gas inlet were oven-dried for 12 hours at 160° C. The apparatus was rapidly assembled, flushed with dry nitrogen gas, and allowed to cool to room temperature. After cooling, the flask was charged with malonic acid (110 mmole), pyridine (75 ml), 2,3-dichlorobenzaldehyde (17.50 g, 100 mmole) and piperidine (2 ml, 20 mmole). The reaction mixture was stirred and brought to relux. After 16 hours of stirring under reflux, the reaction mixture was cooled to room temperature and poured onto a mixture of ice (100 ml) and concentrated hydrochloric acid (100 ml) resulting in the precipitation of a white solid to form a slurry. The resulting slurry was stirred for 2 hours, filtered, washed with cold water (2×250 ml), and dried in vacuo to give 20.01 g (92%) of 2,3-dichlorocinnamic acid.