Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([C@@H:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](O)=[O:9])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:56][C:57]1[S:58][CH:59]=[CH:60][N:61]=1>CN(C)C=O>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][C:4]([C@@H:7]([CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:8]([NH:56][C:57]2[S:58][CH:59]=[CH:60][N:61]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(-c2ccccc2)cc1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)[C@H](CC1CCCC1)c1ccc(-c2ccccc2)cc1
Yield: 60.1 %

Procedure:
A solution of 2(R)-biphenyl-4-yl-3-cyclopentylpropionic acid (36.9 mg, 0.13 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (52.3 mg, 0.14 mmol), N,N-diisopropylethylamine (66 μL, 0.38 mmol), and 2-aminothiazole (25.1 mg, 0.25 mmol) in dry N,N-dimethylformamide (627 μL) was stirred at 25° C. under nitrogen for 13 h. The reaction mixture was concentrated in vacuo to remove the N,N-dimethylformamide. The resulting residue was diluted with ethyl acetate (100 mL). The organic layer was washed with a 10% aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded (2R)-2-biphenyl-4-yl-3-cyclopentyl-N-thiazol-2-yl-propionamide (29.4 mg, 62%) as a white foam: mp 132-134° C.; FAB-HRMS m/e calcd for C23H24N2OS (M+H)+ 377.1687, found 377.1696.
Reaction SMILES: O1B([C@@H](NC(=O)[C@@H](NC(C2C=NC=CN=2)=O)CC2C=CC=CC=2)CC(C)C)[O:5][B:4]([C@@H:32]([NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:33][CH:34]([CH3:36])[CH3:35])[O:3]B1[C@@H](NC(=O)[C@@H](NC(C1C=NC=CN=1)=O)CC1C=CC=CC=1)CC(C)C.[C:82](O)(=[O:89])[C@H:83]([CH2:85][C:86]([OH:88])=[O:87])O>C1COCC1>[CH3:35][CH:34]([CH3:36])[CH2:33][C@@H:32]([B:4]1[O:5][C@@H:83]([CH2:85][C:86]([OH:88])=[O:87])[C:82](=[O:89])[O:3]1)[NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]1[CH:55]=[N:54][CH:53]=[CH:52][N:51]=1)=[O:49])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)O1
Reactant: O=C(O)C[C@H](O)C(=O)O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OC(=O)[C@H](CC(=O)O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N,N′,N″-(boroxin-2,4,6-triyltris{[(1R)-3-methylbutane-1,1-diyl]imino[(2S)-1-oxo-3-phenylpropane-1,2-diyl]})tripyrazine-2-carboxamide (0.500 g, 0.455 mmol) and L-malic acid (213.6 mg, 0.55 mmol) were mixed in THF (5 mL). The mixture was heated to form a solution. The solution was cooled uncontrolled until the internal temperature was about 25° C. White solid precipitated out and the resultant slurry was agitated at ambient temperature for 1 h. The slurry was filtered to collect solid 2-((S)-2-((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl)-5-oxo-1,3,2-dioxaborolan-4-yl)acetic acid (0.625 g, 95%). MS (m/z) in CH3CN: [M+H] calculated for C23H28BN4O7, 483.2051. found, 483.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[N:27]2>CCCCCC.C(OCC)(=O)C>[N:27]1[C:28]2[C:23](=[C:22]([NH:21][CH2:12][C:10]([C:13]([F:16])([F:15])[F:14])([OH:11])[CH2:9][C:8]([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:19][CH3:20])([CH3:18])[CH3:17])[CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: Nc1cccc2ncccc12
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2ncccc12)C(F)(F)F
Yield: 27.7 %

Procedure:
Analogously to Example 1, 200 mg (0.48 mmol) of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-(trifluoromethyl)oxirane is reacted with 99 mg (0.68 mmol) of 5-aminoquinoline. After chromatography on silica gel with hexane-ethyl acetate (0–70%), 58 mg of the product is obtained.
Reaction SMILES: O[CH2:2][C@@H:3]([N:10]1[C@H:23]2[C@H:13]([CH2:14][C:15]3([C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=42)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH2:12][C:11]1=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[OH-].[Li+]>CS(C)=O>[C:4]1([C:3]([N:10]2[C@H:23]3[C@H:13]([CH2:14][C:15]4([C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=53)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[CH2:12][C:11]2=[O:28])=[CH2:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C[C@H]2CC3(CCNCC3)c3ccccc3[C@H]2N1[C@H](CO)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=C(c1ccccc1)N1C(=O)C[C@H]2CC3(CCNCC3)c3ccccc3[C@H]21
Yield: 68.6 %

Procedure:
A solution of (3aR,9bS)-1-((S)-2-hydroxy-1-phenylethyl)-1,3a,4,9b-tetrahydrospiro[benzo[g]indole-5,4′-piperidin]-2(3H)-one (Step 4, 2.3 g, 6.1 mmol) and lithium hydroxide monohydrate (2.3 g, 55 mmol) in DMSO (15 ml) was heated at 170° C. for 4 h. The reaction mixture was evaporated. The residue was poured into water, extracted with EtOAc (3×). The extracts were concentrated to give the title compound as brown oil (1.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][N:8]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([NH:11][CH2:12][CH3:13])=[O:10])=O>[OH-].[K+]>[C:14]([N:8]1[C:9](=[O:10])[N:11]([CH2:12][CH3:13])[C:5]([C:4]2[CH:18]=[CH:19][CH:20]=[C:2]([Cl:1])[CH:3]=2)=[N:7]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CCNC(=O)N(NC(=O)c1cccc(Cl)c1)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Product: CCn1c(-c2cccc(Cl)c2)nn(C(C)(C)C)c1=O
Temperature: 25 °C
Yield: 6.4 %

Procedure:
A solution of 1-(3-chloro-benzoyl)-2-t-butyl-4-ethyl semicarbazide (2.0 g, 0.067 mole) in 5% potassium hydroxide (40 mL) was refluxed for 20 hours, then cooled to room temperature and extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried with sodium sulfate and filtered. The solvent was removed in vacuo to give a yellow liquid (1.2 g, 64% yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH2:23]([N:26]=[C:27]=[O:28])[CH2:24][CH3:25].CCN(C(C)C)C(C)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[O:28])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCN=C=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCNC(=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 40 °C
Yield: 21.5 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and propylisocyanate (0.26 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (2×150 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH/CH2Cl2, gradient over 15 min). The product fractions were combined, concentrated and triturated in Et2O/CH2Cl2 (50 mL) for 18 h. The product was isolated by filtration dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-propyl-urea as a white solid (0.24 g, 29% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 1.63 min (98.92%); mp: 166-168° C.; 1H NMR (DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3H, CH3), 1.31-1.46 (m, 2H, CH2), 2.03-2.08 (m, 1H, CHH), 2.45-2.62 (m, 2H, CHH, CHH), 2.82-3.01 (m, 3H, CHH, CH2), 4.36 (d, J=5.9 Hz, 2H, CH2), 5.14 (dd, J=5.3, 12.6 Hz, 1H, CH), 6.10 (t, J=5.7 Hz, 1H, NH), 6.53 (t, J=6.0 Hz, 1H, NH), 7.71-7.89 (m, 3H, Ar), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 11.31, 22.01, 23.16, 30.94, 41.20, 42.74, 48.98, 121.54, 123.39, 129.51, 131.53, 133.07, 149.53, 158.03, 167.06, 167.24, 169.84, 172.74; LCMS: MH=373; Anal Calcd for C18H20N4O5+0.1H2O: C, 57.78; H, 5.44; N, 14.97. Found: C, 57.52; H, 5.37; N, 14.76.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:24][CH:23]=2)[C:18]([O:20]C)=[O:19])[CH3:16])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]([CH:17]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:26][CH:27]=2)[C:18]([OH:20])=[O:19])[CH3:16])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(OCCCNC(=O)OCC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)O)c2ccc(OCCCNC(=O)OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A mixture of methyl [{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino}(4-{3-[(ethoxycarbonyl)amino]propoxy]phenyl)acetate (0.45 g, 0.85 mmol) and 1N NaOH (4.2 ml, 4.23 mmol) in THF (5 ml) and methanol (5 ml) was stirred at room temperature for 2 h. After removing the solvent, the residue was dissolved in water, neutralized with HCl to pH˜5-6 and extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to provide 0.36 g of [{[4-(2-butynyloxy)phenyl]-sulfonyl}(methyl)-amino}(4-{3-[(ethoxycarbonyl)amino]propoxy]phenyl)acetic acid as a solid. Yield 81.8%. Electrospray Mass Spec 519.1 (M+H)+.
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH:8]=[CH:9][C:10]1[S:14][CH:13]=[CH:12][CH:11]=1)=O)C.[C:16]([CH:21]=[C:22]1[NH:26][CH2:25][CH2:24][NH:23]1)([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:6]1[CH:8]([CH2:9][C:10]2[S:14][CH:13]=[CH:12][CH:11]=2)[C:21]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:22]2[NH:23][CH2:24][CH2:25][N:26]2[C:5]=1[CH3:4])=[O:17])[CH3:20]
Reactant: CCOC(=O)C=C1NCCN1
Reactant: CCOC(=O)CC(=O)C=Cc1cccs1
Solvent: CCO
Product: CCOC(=O)C1=C(C)N2CCNC2=C(C(=O)OCC)C1Cc1cccs1
Yield: 72 %

Procedure:
Boiling a solution of 7.4 g of then-2-ylideneacetoacetic acid ethyl ester and 5.2 g of 2-carbethoxymethylideneimidazolidine in 60 ml of ethanol for 6 hours yields 5-methyl-7-(then-2-yl)-1,2,3,7-tetrahydroimidazolo[1,2-a]pyridine-6,8-dicarboxylic acid diethyl ester of melting point 134°C (ethanol).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C@@H:7]1[N:11](C(OC)=O)[C@H:10]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][CH2:8]1)([CH3:4])[CH3:3].I[Si](C)(C)C>C(Cl)(Cl)Cl>[CH3:1][Si:2]([C:5]#[C:6][C@@H:7]1[NH:11][C@H:10]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][CH2:8]1)([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1C(=O)OC
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1
Temperature: 25 °C

Procedure:
A solution of dimethyl (2S,5R)-5-((trimethylsilyl)ethynyl)pyrrolidine-1,2-dicarboxylate (5.43 g, 19.16 mmol) and iodotrimethylsilane (3 mL, 28.74 mmol) in chloroform (100 mL) was heated to 65° C. for 3 hours, was cooled to room temperature, concentrated under reduced pressure and flash chromatographed with 35% ethyl acetate/65% hexane to provide the titled compound. MS (DCI/NH3) m/e 226 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>CCOCC>[C:2]1([CH2:1][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: C1CCNCC1
Solvent: CCOCC
Product: c1ccc(CN2CCCCC2)cc1
Reaction time: 8 h

Procedure:
A mixture of 11.9 ml of benzyl bromide in 100 ml of ether was added dropwise to a solution of 29.6 ml of piperidine in 100 ml of ether. This mixture was stirred overnight, then filtered. The organic layer was washed with water, then dried and concentrated to an oil. The oil was distilled through a Kugelrohr and the fraction boiling at 75°-85° C., 1.55 mm collected, giving 16.77 g of 1-(phenylmethyl)piperidine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([OH:14])[N:11]([CH3:15])[N:10]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:23]([F:25])[F:24].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([O:14][CH:23]([F:25])[F:24])[N:11]([CH3:15])[N:10]=1
Reactant: Cn1nc(-c2ccc(Cl)cc2Cl)cc1O
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1nc(-c2ccc(Cl)cc2Cl)cc1OC(F)F
Temperature: 90 °C
Yield: 94 %

Procedure:
9 g of 3-(2,4-dichlorophenyl)-5-hydroxy-1-methyl-1H-pyrazole from Example 4.1 were initially charged in 50 ml of dimethylacetamide, and 5.4 g of potassium carbonate were added. The mixture was heated at 90° C., and 48 g of gaseous chlorodifluoromethane were introduced over a period of 1 h. The mixture was poured into 800 ml of water and extracted twice with 300 ml of MTBE, and the combined organic phases were extracted once with 100 ml of water and once with 100 ml of saturated sodium chloride solution. Drying and concentration of the organic phase gave 10.2 g of 3-(2,4-dichlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole of a purity of 56% (yield 50.2%, based on the title compound), which was purified further by vacuum distillation.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=3)=[N:12][N:13]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:28][N:29]1[CH2:32][CH:31]([C:33]([O:35]C)=[O:34])[CH2:30]1)[CH3:2].[OH-].[Na+].Cl>C(O)(C)C.O>[CH2:1]([C:3]1[C:8]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=3)=[N:12][N:13]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:28][N:29]1[CH2:30][CH:31]([C:33]([OH:35])=[O:34])[CH2:32]1)[CH3:2]
Reactant: CCc1c(CN2CC(C(=O)OC)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a solution of methyl 1-[(2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}phenyl)methyl]-3-azetidinecarboxylate (D8) (64 mg) in isopropanol (3 mL) and water (3 mL) was added sodium hydroxide (50 mg). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with 2N HCl till pH ˜6.0. The mixture was extracted with EA/THF for 3 times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated and the residue was purified by Mass Directed AutoPrep to give 1-[(2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}phenyl)methyl]-3-azetidinecarboxylic acid (E2) (35 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.10 (3H, t), 1.33 (6H, d), 2.85 (2H, m), 3.23 (3H, m), 3.42 (2H, m), 3.67 (2H, s), 4.93 (1H, m), 7.33 (1H, t), 7.50 (3H, m), 8.23 (2H, m). δF (DMSO-d6, 376 MHz): −61.3. MS (ES): C25H26F3N3O3S requires 505. found 506.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.[H-].[Na+].Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7][CH2:6]2
Reactant: CCOC(=O)CCl
Reactant: COc1ccc2c(c1)CCNC2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-methoxy-1,2,3,4-tetrahydro-1-oxo-isoquinoline, Sall and Grunewald, J. Med. Chem. 1987, 30, 2208-2216 (0.39 mmol) and NaH (0.17 g, 0.43 mmol, 60% oil dispersion) in THF (5 mL) is heated to reflux for 1 h and then allowed to cool to RT. Ethyl chloroacetate (0.43 mmol) is added and the mixture is allowed to stir for 1 h. The mixture is quenched with H2O (10 mL) and washed with EtOAc. The organic layers are combined, washed with H2O (10 mL) and concentrated to an oil which is purified by (silica gel, gradient, 10-33% CH3OH/CH2Cl2) to afford the title compound.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([CH:20]([N:27]4[CH:31]=[CH:30][N:29]=[CH:28]4)[CH:21]([N:24]([CH3:26])[CH3:25])[CH2:22][CH3:23])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:25][N:24]([CH3:26])[CH:21]([CH2:22][CH3:23])[CH:20]([C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][CH:6]=3)[S:12][C:13]=2[CH:19]=1)[N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: CCC(C(c1ccc2nc(Nc3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(C(c1ccc2nc(Nc3ccc(C(=O)O)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of methyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)-benzo[d]thiazol-2-yl)amino)benzoate (46 mg, 0.10 mmol) and lithium hydroxide monohydrate (21 mg, 0.51 mmol) in 4 mL of dioxane and 2 mL of water was heated together with stirring at 50° C. for 4 hr. The mixture was concentrated in vacuo and the residue dissolved in about 2 mL of water. The solution was neutralized with 1N HCl then concentrated again in vacuo. The residue was purified by PTLC using two, 2 mm silica plates eluting with 20% MeOH/DCM to give 4-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoic acid. MS (ESI) m/z 436.22 [M+H]
Reaction SMILES: [CH2:1]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH2:9][NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:19]1[CH:24]=[C:23]([C:25]([OH:27])=O)[CH:22]=[CH:21][C:20]=1[C:28]([OH:30])=O>>[CH2:1]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH2:9][NH:10][C:28]([C:20]1[CH:21]=[CH:22][C:23]([C:25]([NH:10][CH2:9][CH2:8][CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:27])=[CH:24][N:19]=1)=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Reactant: CCCCCCCCC(CCN)CCCCCC
Product: CCCCCCCCC(CCCCCC)CCNC(=O)c1ccc(C(=O)NCCC(CCCCCC)CCCCCCCC)nc1

Procedure:
N,N'-bis(3-hexylundecyl)pyridine-2,5-dicarboxamide was prepared using the method of Example 1 from 3-hexylundecylamine and pyridine 2,5-dicarboxylic acid. The product which was a brown oil was not distilled but was analysed as being 92% of theoretical strength (based on MW 642) by titration of an aliquot in acetic acid with perchloric acid. It was made up as a 0.2M solution in AROMASOL H and tested for extraction of copper in the presence of chloride ion using the method of Examples 6 and 7. The results are given in Table 3. They indicated that this compound is a strong extractant for copper which would be best employed in extracting copper from solutions of relatively low chloride ion concentration and relatively low acidity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.Cl[C:21]1[N:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:21]1[N:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: N#Cc1cccnc1Cl
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2ncccc2C#N)c(OC)c1
Temperature: 80 °C
Yield: 72.2 %

Procedure:
2,4-Dimethoxybenzylamine (2.90 g, 17.3 mmol) and triethylamine (1.75 g, 17.3 mmol) were added sequentially to a solution of 2-chloronicotinonitrile (2.0 g, 14.4 mmol) in N,N-dimethylacetamide (29 mL). The reaction was heated at 80° C. for 4 h, quenched with water and extracted with diethyl ether (3×). The combined organic extracts were washed water, saturated brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 0-5% ethyl acetate (with 0.1 triethylamine) in dichloromethane gradient elution) to produce the title compound (2.80 g). MS 270.3 (M+1).
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:14])=O>ClCCl>[C:1]([Cl:14])(=[O:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cl)C=Cc1ccccc1

Procedure:
The polymeric main chain having the above repeating structure was synthesized according to the same procedures as described in Example 1. The side chain was synthesized as follows. First, 1 g (0.006 mol) of cinnamic acid was reacted with 0.71 g (0.006 mol) of thionyl chloride in dichloromethane at a temperature of 35° C. for 1 hour to form cinnamoyl chloride. Then, the cinnamoyl chloride was reacted with 0.98 g (0.006 mol) of 4-hydroxybenzoic acid and an aqueous solution of NaOH/DMSO with stirring for 1 hour at a room temperature. The product was again reacted with thionyl chloride in dichloromethane to form a side chain as follows.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]([OH:9])[CH3:8])[S:5][CH:6]=1.C1C(=O)N([Br:17])C(=O)C1>CN(C=O)C.O>[Br:17][C:6]1[S:5][C:4]([CH:7]([OH:9])[CH3:8])=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc(C(C)O)n1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C(C)O)sc1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of 1-(4-methylthiazol-2-yl)ethanol of preparation 95 (3.3 g, 22.9 mmol) in DMF (80 mL) was added NBS (4.47 g, 25.2 mmol), and the mixture was stirred at 50° C. for 2 hours. TLC (petroleum ether:EtOAc 3:1) indicated the reaction was completed. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (80 mL×3). The combined organic extracts were washed with brine (80 mL×3), dried over sodium sulfate, and concentrated in vacuum to give the residue which was purified by a silica gel column eluting with petroleum ether:EtOAc=25:1-5:1 to give the title compound as a yellow solid (3.7 g, 74%).