Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2I.C([Sn](CCCC)(CCCC)[C:30]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH:38]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:37]2)[CH:33]=[N:32][CH:31]=1)CCC.N#N.O>CN(C=O)C.[Cu]I.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:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:30]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH:38]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:37]2)[CH:33]=[N:32][CH:31]=1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(I)nn2C1CCCCO1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(N2CCCC(NC(=O)OC(C)(C)C)C2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Temperature: 80 °C
Yield: 65.1 %

Procedure:
A solution of 5-(2,6-difluorophenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (400 mg, 0.91 mmol) and tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-3-ylcarbamate (520 mg, 0.91 mmol) in DMF (9.1 mL) was purged with N2 for 15 min and added CuI (225 mg, 1.18 mmol) and Pd(PPh3)4 (105 mg, 0.09 mmol). The reaction mixture was heated at 80° C. for 2 h and cooled to RT. To the reaction mixture was added water and precipitate was formed. The precipitate was collected by filtration, washed with water and dried overnight to give crude product. The crude was purified by chromatography (eluting with 0-10% MeOH and DCM) to obtain the title compound (350 mg, 66% yield). MS (ESI, pos. ion) m/z: 591 (M+1).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[NH:30][C:31](=[NH:36])[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][C:31]1[N:36]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:30]=1
Reactant: COCCC(=N)NO
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: COCCc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 300 mg (0.720 mmol) of the compound from Example 45A and 93.6 mg (0.792 mmol) of N-hydroxy-3-methoxypropanimidamide were reacted Yield: 231 mg (63% of theory, approx. 15% trans isomer)
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)(O)[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26](/[C:19](/[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20]\[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:27][CH:28]=1)(=[O:33])=[O:34]
Reactant: CC(C)(C)CC(O)(c1ccc(S(C)(=O)=O)cc1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)/C=C(\c1ccc(S(C)(=O)=O)cc1)c1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
A mixture of 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(4-methanesulfonyl-phenyl)-3,3-dimethyl-butan-1-ol (190 mg, 0.37 mmol) and tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 3 mL) was stirred at 25° C. for 16 h. The reaction was quenched with a saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (2×50 mL), washed with a saturated aqueous ammonium chloride solution (3×25 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[(E)-1-(4-methanesulfonyl-phenyl)-3,3-dimethyl-but-1-enyl]-1H-pyrrolo[2,3-b]pyridine (50 mg, 96%): LC/MS m/e calcd for C20H22N2O2S [M+H]+ 355.47, observed 355.3; 1H NMR (400 MHz, CD3OD) δ ppm 8.23 (d, J=7.6 Hz, 2H), 8.00-8.06 (m, J=8.1 Hz, 2H), 7.54-7.61 (m, J=8.1 Hz, 2H), 7.31-7.37 (m, 1H), 6.67 (s, 1H), 5.86 (s, 1H), 3.16-3.27 (s, 3H), 0.95-1.03 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([Mg]Br)[CH:12]([CH3:14])[CH3:13].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:10])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[Mg]Br
Reactant: O=CCc1cccc(F)c1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(O)Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
97 mg of 3-fluorobenzeneacetaldehyde and 0.386 mL of isobutyl magnesium bromide (2 M/diethyl ether solution) were dissolved in of 0.2 mL of THF, followed by stirring at room temperature for 1 hour. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform, and the organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using PLC (ethyl acetate:hexane=1:2) to obtain 102 mg (yield 74%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12]Br)=[CH:9]2)=[CH:4][CH:3]=1.[OH:14][C:15]1[CH:16]=[C:17]([C:21]2([O:29][CH3:30])[CH2:26][CH2:25][O:24][C:23]([CH3:28])([CH3:27])[CH2:22]2)[CH:18]=[CH:19][CH:20]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:14][C:15]3[CH:16]=[C:17]([C:21]4([O:29][CH3:30])[CH2:26][CH2:25][O:24][C:23]([CH3:27])([CH3:28])[CH2:22]4)[CH:18]=[CH:19][CH:20]=3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COC1(c2cccc(O)c2)CCOC(C)(C)C1
Reactant: Fc1ccc2ccc(CBr)cc2c1
Product: COC1(c2cccc(OCc3ccc4ccc(F)cc4c3)c2)CCOC(C)(C)C1
Yield: 99.8 %

Procedure:
Using the procedure described in Example 5, 7-fluoro-2-bromomethylnaphthalene (0.23 g) was reacted with 4-(3-hydroxyphenyl)-4-methoxy-2,2-dimethyltetrahydropyran (0.21 g) to give 4-[3-(7-fluoronaphth-2-ylmethoxy)phenyl]-4-methoxy-2,2-dimethyltetrahydropyran (0.35 g, 86%), as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]3[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1nc2ccc(Cl)cc2s1
Product: CCOC(=O)c1cn2c(n1)sc1cc(Cl)ccc12
Yield: 60.6 %

Procedure:
Ethyl 7-chloroimidazo[2,1-b]-benzthiazole-2-carboxylate was prepared according to the procedure as outlined in Example 1, (Step 1). Starting from 6-chloro-2-amino benzothiazole (9.2 g, 50 mmol) and ethyl bromopyruvate (11.6 g, 60 mmol), 8.5 g (60% Yield) of ethyl 7-chloroimidazo[2,1-b]-benzthiazole-2-carboxylate was isolated as brown solid. (M+H) 281.
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)[CH:2]=[CH2:3].[CH3:12][NH:13][CH2:14][CH:15]=[O:16]>C1C=CC=CC=1>[CH3:12][N:13]([CH2:14][CH:15]=[O:16])[C:10]([NH:9][C:7]1[S:8][C:4]([CH2:1][CH:2]=[CH2:3])=[N:5][N:6]=1)=[O:11]
Reactant: C=CCc1nnc(N=C=O)s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: C=CCc1nnc(NC(=O)N(C)CC=O)s1

Procedure:
A mixture of 5-allyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-ally-1,3,4thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].Br[CH2:16][CH:17]=[CH2:18]>ClCCl>[CH3:7][O:6][C:4](=[O:5])[C@H:3]([NH:2][CH2:18][CH:17]=[CH2:16])[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: C=CCBr
Reactant: COC(=O)[C@H](N)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: C=CCN[C@@H](C(=O)OC)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
In a 25 mL round-bottomed flask, (R)-methyl 2-amino-2-(4-chlorophenyl)acetate hydrochloride (1.000 g, 4.24 mmol, Eq: 1.00) and 3-bromoprop-1-ene (564 mg, 394 μL, 4.66 mmol, Eq: 1.1) were combined with dichloromethane (10.0 mL) to give a light yellow solution. The reaction mixture was heated to 22° C. and stirred for 1 h. The reaction mixture was stirred at 25° C. for 18 h. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 25% to 60% EtOAc in hexanes) to yield the title compound (331 mg; 33%) as a yellow oil. MS (ESI): m/z=376.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](=[S:21])[NH2:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:23]([C:29](=O)[CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CCO>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[S:21][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:29]([CH3:30])[N:20]=3)=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: COc1cccc2c(C(N)=S)cn(CC3CCCCC3)c12
Solvent: CCO
Product: CCOC(=O)c1sc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)nc1C
Temperature: 0 °C
Yield: 61 %

Procedure:
To a solution of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbothioic acid amide (604 mg, 2.00 mmol) in EtOH (5.0 ml) was added ethyl 2-chloro-3-oxobutanoate (0.332 ml, 2.40 mmol). The mixture was refluxed for 1 h. After cooling to 0° C., the precipitate was collected by filtration to afford 1-cyclohexylmethyl-3-(5-ethoxycarbonyl-4-methylthiazol-2-yl)-7-methoxy-1H-indole (505 mg, 1.22 mmol).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[CH3:17][O:18][C:19](=[O:23])[CH:20](Br)[CH3:21]>CO.CCN(C(C)C)C(C)C>[CH3:17][O:18][C:19](=[O:23])[CH:20]([N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=2)[CH2:14][CH2:13]1)[CH3:21]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: COC(=O)C(C)Br
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (0.9 g, 3.9 mmoles) in MeOH (13 mL) and DIPEA (1.5 mL) was treated with 2-bromo-propionic acid methyl ester (0.48 mL, 4.3 mmoles) and stirred overnight at 70° C. The MeOH was removed under reduced pressure and the residue was purified (silica gel, 10-40% acetone in hexane) to provide the title compound as a yellowish solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:16][C:15]([C:17]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[O:19][C:18]=4[CH2:26][CH2:27][CH2:28][CH3:29])=[N:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:30].Br[CH2:32][C:33]#[N:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:16][C:15]([C:17]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[O:19][C:18]=4[CH2:26][CH2:27][CH2:28][CH3:29])=[N:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:30][CH2:32][C:33]#[N:34]
Reactant: N#CCBr
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3c(Br)c(O)ccc3c2)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3c(Br)c(OCC#N)ccc3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A mixture of 1-bromo-6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthol (89 mg 0.192 mmol), prepared in the previous step, bromoacetonitrile (16 μL, 0.23 mmol) and cesium carbonate (127 mg, 0.389 mmol) in 20 mL of acetone was stirred under nitrogen at room temperature for 15 h (overnight). The acetone was removed under reduced pressure and the residue partitioned between methylene chloride and water. The organic layer was separated and the aqueous layer extracted two times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give ({1-bromo-6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetonitrile (95 mg, 91%) as a brown solid, mp 144-146° C. Elemental Analysis for C27H21BrN2O3 Calc'd: C, 64.68; H, 4.22; N, 5.59. Found: C, 63.90; H, 4.10; N, 5.18.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].[NH2:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1>[CH2:5]([O:4][C:2]([NH:8][C@@H:9]([CH:10]([CH3:12])[CH3:11])[C:13]([OH:15])=[O:14])=[O:3])[CH:6]=[CH2:7]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: C=CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
Allyl chloroformate (36.2 ml, 340.59 mmol, 1.2 eq) was added dropwise to a stirred solution of L-valine (I1)(33.25 g, 283.82 mmol, 1.0 eq) and potassium carbonate (59.27 g, 425.74 mmol, 1.5 eq) in water (650 mL) and THF (650 mL). The reaction mixture was stirred at room temperature for 18 hours, then the solvent was concentrated under reduced pressure and the remaining solution extracted with diethyl ether (3×100 mL). The aqueous portion was acidified to pH 2 with conc. HCl and extracted with DCM (3×100 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the product as a colourless oil (57.1 g, assumed 100% yield). LC/MS (1.966 min (ES+)), m/z: 202.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.57 (br s, 1H), 7.43 (d, 1H, J=8.6 Hz), 5.96-5.86 (m, 1H), 5.30 (ddd, 1H, J=17.2, 3.4, 1.7 Hz), 5.18 (ddd, 1H, J=10.4, 2.9, 1.6 Hz), 4.48 (dt, 2H, J=5.3, 1.5 Hz), 3.85 (dd, 1H, J=8.6, 6.0 Hz), 2.03 (oct, 1H, J=6.6 Hz), 0.89 (d, 3H, J=6.4 Hz), 0.87 (d, 3H, J=6.5 Hz),
Reaction SMILES: [CH2:1]([C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2].[H-].[Na+].[C:20]([N:39]1[C:43]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:50]2[CH:57]=[CH:56][C:53]([CH2:54]Br)=[CH:52][CH:51]=2)=[N:42][N:41]=[N:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[CH2:1]([C:3]1[S:17][C:6]2[N:7]([CH2:54][C:53]3[CH:52]=[CH:51][C:50]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[C:43]4[N:39]([C:20]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:40]=[N:41][N:42]=4)=[CH:57][CH:56]=3)[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc2sc(CC)cc2c1O
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c2sc(CC)cc2c1=O
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 76.9 %

Procedure:
To a solution of ethyl 2-ethyl-4-hydroxy-thieno[2,3-b]pyridine-5-carboxylate (1.00 g, 4 mmol) in 20 ml of DMF) was added sodium hydride (60% dispersion in oil, 160 mg) and the mixture was stirred for 10 minutes. To the reaction mixture was added 4-[2'-(N-trityltetrazol-5-yl)phenyl]benzyl bromide (2.23 g, 4 mmol) and the mixture was heated at 90° C. for 1 hour with stirring. The reaction mixture was poured into water followed by extraction with ethyl acetate. The organic layer was washed with water, dried (MgSO4), and evaporated to dryness. The resulting residue was purified by flash column chromatography on silica gel. The column was eluted with ethyl acetate/dichloromethane (1:1) to give 2.24 g (77%) of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O1CCCC1.Cl[CH2:35][C:36]([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:37]>CN(C)C=O>[CH2:14]([O:13][C:11]([C:7]1[N:8]([CH2:35][C:36](=[O:37])[N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[C:9]2[C:5]([C:6]=1[NH:16][C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1Nc1ccncc1
Reactant: CCN(CC)C(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Nc2ccncc2)c2ccc(Cl)cc2n1CC(=O)N(CC)CC
Temperature: 0 °C
Yield: 14.8 %

Procedure:
Under nitrogen, stir and cool to 0° C. a mixture of ethyl 6-chloro-3-(4-pyridinylamino)indole-2-carboxylate (0.50 g, 1.58 mmol) in dimethylformamide (5 mL). Add a 1M solution of potassium tert-butoxide in tetrahydrofuran (1.7 mL, 1.7 mmol) over a 2 min period, and stir for 10 min. Add 2-chlor-N,N-diethylacetamide (0.22 mL, 1.6 mmol) in one portion and stir at ambient temperature overnight. Quench the reaction into water (35 mL), and extract the aqueous mixture with ethyl acetate (2×20 mL). Combine the extracts, wash with water (25 mL), brine (25 mL) and dry over MgSO4. Concentrate under vacuum, and chromatograph the residue on a Redisep silica gel cartridge (10 g) eluting with 5% methanol/dichloromethane to 20% methanol/dichloromethane. Combine all homogenous fractions and concentrate to obtain a solid. Recrystallize the solid from ethyl acetate and obtain 0.1 g of the title compound as a white solid: MS 429(M+H), m.p. 212–214° C.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:41])[C@@H:6]([N:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:27])[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.C1(C)C=CC=CC=1.Cl>CO>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:28]2[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:34]3[C:29]2=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:5]([OH:41])=[O:4])=[O:27])=[CH:18][CH:17]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)c1ccc(C(=O)c2ccccc2)cc1)n1c2ccccc2c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(NCCCC[C@@H](C(=O)O)n1c2ccccc2c2ccccc21)c1ccc(C(=O)c2ccccc2)cc1
Yield: 94.6 %

Procedure:
Methanolic KOH (0.050 g, 0.88 mmol) was added to a stirred solution of 6-(4-benzoyl-benzoylamino)-2-carbazol-9-yl-hexanoic acid methyl ester 6 (0.230 g, 0.44 mmol) in a mixture (1:2) of toluene (2 mL) and methanol (4 mL). The resulting reaction mixture was refluxed for 3 h. Subsequently, it was neutralized to pH 3-4 with dil. HCl and extracted with EtOAc (20 mL×2). The combined organic extract was washed with water (15 mL×2) and dried over anhydrous Na2SO4. Removal of solvent under reduced pressure provided 6-(4-benzoyl-benzoylamino)-2-carbazol-9-yl-hexanoic acid 7 (0.210 g, 98%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12]([S-])(=[S:16])OCC.[K+].O.Cl>N1C=CC=CC=1>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:12](=[S:16])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc2oc(=S)[nH]c2c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 168.2 %

Procedure:
In accordance with well known procedures, (see Batista-Parra, A. et al. Heterocycles, 2003, 60, 1367), a suspension of 2-amino-4-nitrophenol (1.54 g, 10 mmol) and potassium O-ethyl carbonodithioate (1.68 g, 10.5 mmol) in dry pyridine (10 mL) was stirred at 120° C. for 6 h, and then at room temperature for 16 h. The solution was poured into water and aqueous hydrochloric acid was added. The resulting precipitate was collected by filtration, washed with dilute aqueous hydrochloric acid, followed by water and then dried in the vacuum oven to afford 3.3 g (84%) of the title compound.
Reaction SMILES: [CH2:1]([O:11][C:12]([CH:14]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[O:21])[N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].[Br:33]Br>C(Cl)(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([C:14]([N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)([C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:13])[Br:33])=[O:21])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)CCCCCCCOC(=O)C(C(=O)OCCCCCCCC(C)C)n1cncn1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)CCCCCCCOC(=O)C(Br)(C(=O)OCCCCCCCC(C)C)n1cncn1
Reaction time: 2 h
Yield: 107.7 %

Procedure:
1-[bis(isodecyloxycarbonyl)methyl]-1,2,4-triazole (51.8 g, 86% strength) was stirred and boiled under reflux at 78° with carbon tetrachloride (100 cm3) whilst bromine (16.0g) was added slowly beneath the liquid surface during 30 minutes. Stirring and heating at 78°-80° was continued for a further period of 2 hours, the extent of bromination being followed by disappearance of the resonance due to the methine proton at delta=5.8 ppm from tetramethylsilane in the nmr spectrum. The solution was then cooled, washed with dilute aqueous sodium sulphite solution and with water, and the solvent was distilled yielding 57.2 g of 1-[1',1'-bis(isodecyloxycarbonyl)-1'-bromomethyl]-1,2,4-triazole of strength 76% as measured by non-aqueous titration with perchloric acid. This compound was evaluated as an extractant for copper using the procedure of Example 1 and the results are presented in Table 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][C@@H:16]([CH3:25])[C:17](N1CCOCC1)=[O:18].[Mg].[Cl-].[NH4+]>O1CCCC1>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17](=[O:18])[C@@H:16]([O:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1)[CH3:25]
Reactant: C[C@H](OC1CCCCO1)C(=O)N1CCOCC1
Reactant: Fc1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](OC1CCCCO1)C(=O)c1ccccc1F
Yield: 103.6 %

Procedure:
1-Bromo-2-fluorobenzene (15 g) and 4-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (40 g) were dissolved in tetrahydrofuran (200 ml), to which magnesium (turnings: 4.4 g) was added. The mixture was stirred vigorously. The reaction flask was cooled when the temperature of the reaction solution reached to 35° C., and 1-bromo-2-fluorobenzene (16.7 g) was added thereto over the period of 10 minutes while the temperature of the reaction solution was kept at 35 to 37° C. After the reaction solution was stirred at 30 to 35° C. for 2 hours, it was cooled in an ice-bath. A saturated aqueous solution of ammonium chloride (100 ml) was added thereto and the mixture was extracted with ethyl acetate (200 ml×2, 100 ml). The extract was washed with water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=10/1 to 5/1) to give (2S)-2'-fluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (22.4 g) as a pale yellow oily substance.