Azzindani/Open_Reaction_Data huggingface dataset:
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][CH2:14]OC)=[C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:7]([CH3:27])=[CH:6]2.Cl.O1CCOCC1.FC1[CH:43]=[CH:42][C:39]([CH:40]=[O:41])=[CH:38][CH:37]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:43]=[CH:42][C:39]([CH:40]=[O:41])=[CH:38][CH:37]=1)=[C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:7]([CH3:27])=[CH:6]2
Reactant: COCOc1c(-c2cccc(C(F)(F)F)c2)c(C)cc2cc(OC)ccc12
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3cccc(C(F)(F)F)c3)c(C)cc2c1
Yield: 34.5 %

Procedure:
6-Methoxy-1-methoxymethoxy-3-methyl-2-(3-trifluoromethyl-phenyl)-naphthalene (208) (0.35 g, 0.93 mmol), 4 N HCl/Dioxane (5 mL), 4-fluorobenzaldehyde (0.11 mL, 1.02 mmol), Cs2CO3 (0.364 g, 1.12 mmol) and DMF (3 mL) were reacted as described above to give 0.140 g (35%) of the title compound (209) as oil. 1H NMR (400 MHz, d-CDCl3): δ 2.26 (s, 3H), 3.95 (s, 3H), 6.68 (d, J=8.8 Hz, 2H), 7.09 (dd, J1=2.6 Hz, J2=9.2 Hz, 1H), 7.17-7.17 (m, 1H), 7.31-7.39 (m, 2H), 7.44 (s, 1H), 7.48-7.50 (m, 1H), 7.61-7.64 (m, 3H), 7.73 (d, J=9.1 Hz, 1H), 9.80 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([NH:11][NH:12][CH:13]=O)=O.C(N(CC)CC)C.Cl[Si](C)(C)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:13]=[N:12][N:11]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=CNNC=O
Reactant: Nc1ccc(Br)cc1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Brc1ccc(-n2cnnc2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 4-bromoaniline (1.71 g, 9.94 mmol), N′-formylformohydrazide (2.64 g, 30.0 mmol), and triethylamine (9.74 mL, 69.9 mmol, 7.00 equiv) in pyridine (40 mL). Chlorotrimethylsilane (19.2 mL, 151 mmol) was added drop-wise and the resulting solution was stirred for 18 h at 100° C., then cooled to room temperature. The resulting mixture was concentrated under reduced pressure and the residue was diluted with brine (50 mL) and extracted with ethyl acetate (6×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was washed with ether (30 mL) and the solids were collected by filtration to yield the title compound as a pink solid (1.6 g, 72%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]([O:14]CC)=[O:13])=[O:11])[S:7][CH:8]=1)[CH3:3].O.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[CH3:3][CH:2]([C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]([OH:14])=[O:13])=[O:11])[S:7][CH:8]=1)[CH3:1]
Reactant: CCOC(=O)C(=O)Nc1nc(C(C)C)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1csc(NC(=O)C(=O)O)n1

Procedure:
Ethyl 4-(2-propyl)thiazol-2-ylcarbamoylcarboxylate was combined with 50 ml. of water and 6.2 ml. of 1 N potassium carbonate. The mixture was clarified, cooled, acidified with acetic acid and product extracted into 150 ml. of ethyl acetate in three portions. The combined extracts were dried over anhydrous sodium sulfate, filtered and evaporated to an oil, which partially crystallized on standing. The gummy solid was recrystallized from isopropyl alcohol, affording 4-(2-propyl)thiazol-2-ylcarbamoylcarboxylic acid [216 mg.; m.p. 195°-197° C. (dec.)].
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]2[N:16]=[C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:14][N:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(OC(N1[CH2:37][CH2:36][CH:35]([C:38]2O[N:41]=[C:40](COC3C=CC(S(C)(=O)=O)=CC=3)[N:39]=2)[CH2:34]C1)=O)(C)(C)C.CCN(C(C)C)C(C)C.ClC1N=CC(CC)=CN=1>CC(O)C>[CH2:36]([C:35]1[CH:38]=[N:39][C:40]([N:20]2[CH2:21][CH2:22][CH:17]([C:15]3[O:14][N:13]=[C:12]([CH2:11][O:10][C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:24][CH:23]=4)[N:16]=3)[CH2:18][CH2:19]2)=[N:41][CH:34]=1)[CH3:37]
Reactant: CS(=O)(=O)c1ccc(OCc2noc(C3CCNCC3)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(S(C)(=O)=O)cc3)no2)CC1
Agent: CCc1cnc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCc1cnc(N2CCC(c3nc(COc4ccc(S(C)(=O)=O)cc4)no3)CC2)nc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To the crude HCl salt (0.18 g, ˜0.5 mmol) of 4-[3-(4-methanesulfonyl-phenoxymethyl)-[1,2,4]oxadiazol-5-yl]-piperidine, prepared by treatment of 4-[3-(4-methanesulfonyl-phenoxymethyl)-[1,2,4]oxadiazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 81) in dixoane with 4N HCl, was added 2-propanol (3 mL), followed by DIPEA (0.13 g, 1 mmol) and 2-Chloro-5-ethyl-pyrimidine (0.14 g, 1 mmol). The resulting mixture was stirred at 70° C. overnight. After concentration in vacuo, the residue was purified by silica column chromatography with EtOAc/hexanes to afford the desired product. 1H NMR (CDCl3): δ 8.18 (2H, s), 7.89 (2H, d, J=8.8 Hz), 7.15 (2H, d, J=8.8 Hz), 5.24 (2H, s), 4.75˜4.65 (2H, m), 3.3˜3.2 (1H, m), 3.2˜3.1 (2H, m), 3.03 (3H, s), 2.47 (2H, q, J=7.6 Hz), 2.22˜2.16 (2H, m), 1.96˜1.84 (2H, m), 1.19 (3H, t, J=7.6 Hz).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1.[NH2:14][C:15]([NH2:17])=[S:16]>>[NH2:17][C:15]1[S:16][CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[N:14]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: NC(N)=S
Product: Nc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Yield: 77.5 %

Procedure:
Using 4′-(trifluoromethyl)acetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[O:33][N:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:28][C:29]4[O:33][N:32]=[CH:31][CH:30]=4)[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])=[CH:25][CH:26]=1
Reactant: CC(C)S(=O)(=O)c1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccc(Cl)cc1
Reactant: ClCc1ccno1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1nc2c(c(=O)n(Cc3ccno3)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 50 °C
Yield: 40.8 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-8-(isopropylsulfonyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (80 mg, 0.20 mmol) in DMF (5 mL) was added 5-(chloromethyl)isoxazole (55 mg, 0.5 mmol, intermediate 41), potassium carbonate (58 mg, 0.42 mmol), and TBAI (2 mg, 0.02 mmol). The reaction was heated at 50° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-8-(isopropylsulfonyl)-1-(isoxazol-5-ylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (39 mg, 40.6% yield) as a white solid. 1H-NMR (CD3OD) δ 8.49(d, 1H), 7.41(dd, 2 H), 7.28(d, 2H), 6.43(d, 1H), 5.87(s, 2H), 5.21(s, 2H), 3.60-3.73(m, 1H), 3.47(s, 3H), 1.25(d, 6H). LCMS retention time 2.772 min; LCMS MH+ 478
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[CH:19]3)=[CH:15][CH:14]=2)[N:10]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:19]3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccco4)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4ccco4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
A mixture of ethyl 3-[1-[4-[2-(2-furyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (641 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 5 hours, and 1N hydrochloric acid (2.5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-[2-(2-furyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (485 mg, yield: 78%). This was recrystallized from ethanol-hexane. Melting point: 114–115° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21].[CH:22]([CH:24]=[CH2:25])=[O:23].OS(O)(=O)=O>CCCCCC.C1COCC1>[Br:13][C:14]1[C:15]([F:21])=[C:16]([CH:22]([CH:24]=[CH2:25])[OH:23])[C:17]([F:20])=[CH:18][CH:19]=1
Reactant: Fc1ccc(Br)c(F)c1
Reactant: C=CC=O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC(O)c1c(F)ccc(Br)c1F
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
121.1 ml (0.194 mol) of a 1.6M solution of n-butyllithium in hexane are added dropwise to a solution, cooled to -10° C., of 21.5 g (0.212 mol) of diisopropylamine in 194 ml of anhydrous THF. The mixture is stirred for 10 min at -10° C. under a nitrogen atmosphere, is then cooled to -76° C. and a solution of 37.4 g (0.194 mol) of 1-bromo-2,4-difluorobenzene in 270 ml of anhydrous THF is added dropwise over 30 minutes, at a temperature below -70° C. The mixture is stirred for 2 minutes at -70° C. and then a solution of 14.7 g (0.212 mol) of acrolein in 30 ml of anhydrous THF is added dropwise over 10 minutes at a temperature below -60° C. The mixture is then stirred for 30 minutes at -70° C., and the temperature is then allowed to return to 0° C. The mixture is poured onto a mixture of 350 g of ice and 35 ml of concentrated H2SO4. Extraction with ether, washing with water, drying over Na2SO4, filtration, evaporation under vacuum and distillation are carried out. Weight obtained: 29 g (Yd.=60%) B.p.0.5 =86°-88° C.
Reaction SMILES: I[C:2]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]=[CH:4][S:3]1.[CH2:12]([O:14][P:15]([C:20]1[CH:24]=[C:23]([Sn](CCCC)(CCCC)CCCC)[S:22][C:21]=1[C:38]1[S:39][C:40]([Sn](CCCC)(CCCC)CCCC)=[CH:41][C:42]=1[P:43]([O:48][CH2:49][CH3:50])([O:45][CH2:46][CH3:47])=[O:44])([O:17][CH2:18][CH3:19])=[O:16])[CH3:13].[F-].[K+]>CN(C=O)C>[CH2:46]([O:45][P:43]([C:42]1[CH:41]=[C:40]([C:4]2[S:3][C:2]([C:7]3[S:8][CH:9]=[CH:10][CH:11]=3)=[CH:6][CH:5]=2)[S:39][C:38]=1[C:21]1[S:22][C:23]([C:4]2[S:3][C:2]([C:7]3[S:8][CH:9]=[CH:10][CH:11]=3)=[CH:6][CH:5]=2)=[CH:24][C:20]=1[P:15]([O:17][CH2:18][CH3:19])([O:14][CH2:12][CH3:13])=[O:16])([O:48][CH2:49][CH3:50])=[O:44])[CH3:47]
Reactant: IC1(c2cccs2)CC=CS1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(P(=O)(OCC)OCC)c(-c2sc([Sn](CCCC)(CCCC)CCCC)cc2P(=O)(OCC)OCC)s1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1cc(-c2ccc(-c3cccs3)s2)sc1-c1sc(-c2ccc(-c3cccs3)s2)cc1P(=O)(OCC)OCC
Yield: 42 %

Procedure:
At room temperature, 0.0065 g (0.0056 mmols) of commercially available tetrakistriphenylphosphine palladium and 0.0818 g (0.28 mmols) of 2-iodobithiophene were dissolved in DMF. Thereafter, 0.1345 g (0.14 mmols) of 3,3′-bis(diethoxyphosphoryl)-5,5′-bis(tributylstannyl)-[2,2′]-bithiophene was added at room temperature. The reaction mixture was heated and stirred under reflux for 5 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution was added, followed by stirring for 2 hours. Thereafter, the solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a PTLC plate (developed with ethyl acetate:hexane=1:5 and ethyl acetate:hexane=1:1) to obtain the specified substance in the form of a yellow solid at a yield of 0.0451 g (yield: 42%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][C@H:16]1[NH2:26])=[O:13])=[CH:6]2.[CH3:27][N:28]1[CH2:33][CH2:32][C:31]2[N:34]=[C:35]([C:37]([O-])=[O:38])[S:36][C:30]=2[CH2:29]1.[Li+].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][C@H:16]1[NH:26][C:37]([C:35]1[S:36][C:30]3[CH2:29][N:28]([CH3:27])[CH2:33][CH2:32][C:31]=3[N:34]=1)=[O:38])=[O:13])=[CH:6]2
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: CCOC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Reaction time: 39 h
Yield: 30.3 %

Procedure:
(1S,2R,4S)-N1-[(5-Chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediamine hydrochloride (4.15 g) was dissolved in N,N-dimethylformamide (40 ml), and lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate (2.86 g), 1-hydroxybenzotriazole monohydrate (1.72 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.15 g) were added to this solution at room temperature to stir the mixture for 39 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue to conduct extraction with chloroform. The resultant organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by column chromatography on silica gel (chloroform:methanol=100:1) to obtain the title compound (1.71 g) as a colorless amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[CH2:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(-c2nc(N)nc(OCc3ccccc3)c2C#N)cc(OC)c1OC

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile, benzyl alcohol and DBU in DME. EI-MS m/e (%): 392 (M+, 40), 91 ([PhCH2]+, 100).
Reaction SMILES: CN1C2C(=CC(S(N3CCC[C@H]3COC3C=CC=CC=3)(=O)=O)=CC=2)C(=O)C1=O.[O:29]([CH2:36][C@@H:37]1[CH2:40][CH2:39][N:38]1[S:41]([C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][C:48](=[O:53])[C:47]2=[O:54])(=[O:43])=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH3:55][O:56][C:57]1[CH:64]=[CH:63][C:60]([CH2:61]Cl)=[CH:59][CH:58]=1>>[CH3:55][O:56][C:57]1[CH:64]=[CH:63][C:60]([CH2:61][N:49]2[C:50]3[C:46](=[CH:45][C:44]([S:41]([N:38]4[CH2:39][CH2:40][C@H:37]4[CH2:36][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:43])=[O:42])=[CH:52][CH:51]=3)[C:47](=[O:54])[C:48]2=[O:53])=[CH:59][CH:58]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc2C1=O
Reactant: COc1ccc(CCl)cc1
Agent: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Product: COc1ccc(CN2C(=O)C(=O)c3cc(S(=O)(=O)N4CC[C@H]4COc4ccccc4)ccc32)cc1
Yield: 50 %

Procedure:
(S)-1-(4-Methoxybenzyl)-5-(2-phenoxymethyl-azetidine-1-sulfonyl)-1H-indole-2,3-dione (18c) was prepared according to the same procedure for compound 11a, except using compound 17 and 4-methoxybenzyl chloride, and purified with hexanes-ether (1:2) to afford 62 mg (50%) of 18c as an orange solid, mp 159.8-161.5° C. 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.96 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 7.25 (m, 4H), 6.97-6.87 (m, 4H), 6.80 (d, J=7.8 Hz, 2H), 4.87 (s, 2H), 4.45 (m, 2H), 4.11 (m, 2H), 3.84 (m, 2H), 3.81 (s, 3H), 2.32 (m, 2H). Anal. Calcd for C26H24N2O6S: C, 63.40, H, 4.91; N, 5.69. Found: C, 63.65, H, 4.93; N, 5.59.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([N:27](C(OCC(Cl)(Cl)Cl)=O)[C:28](OCC(Cl)(Cl)Cl)=[O:29])=[N:19]1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([NH:27][C:28]([N:15]2[CH2:16][CH2:17][N:12]([C:9]3[S:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[CH2:13][CH2:14]2)=[O:29])=[N:19]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1noc2ccccc12
Reactant: c1ccc(-c2csc(N3CCNCC3)c2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1noc2ccccc12)N1CCN(c2cc(-c3ccccc3)cs2)CC1

Procedure:
A solution of 1-(4-phenyl-2-thienyl)piperazine (240 mg, 0.984 mmol), bis(2,2,2-trichloroethyl) 1,2-benzisoxazol-3-ylimidodicarbonate (239 mg, 0.492 mmol), diisopropylethylamine (0.0857 ml, 0.492 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 2 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (42.5 mg, 21.4%) as a solid.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[Na+].[C:11]1([CH2:17][C:18]#[N:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C)C=O>>[C:18]([CH:17]([CH:2]([CH2:3][C:4]([OH:6])=[O:5])[C:1]([O:8][CH3:9])=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:19]
Reactant: COC(=O)/C=C\C(=O)[O-]
Reactant: N#CCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC(=O)O)C(C#N)c1ccccc1
Yield: 87.9 %

Procedure:
Into a 200 ml, one-neck flask is placed 35 grams of sodium methyl maleate (0.23 moles), 85 grams (0.73 moles) of phenyl acetonitrile and 80 g (1.1 moles) dimethyl formamide. The reaction mixture is heated to 135°-140° C. for five hours and then distilled in vacuo. The residue is extracted three times with 300 ml ether. The solid (56 grams) is then dissolved in water and acidified with 23 grams conc. HCL in 50 mls water. The liquid that separates out is dissolved in ether and washed with water to remove unreacted starting materials. The ether is distilled off to give a residue of 50 grams of product (yield: 88%). The structure is verified by NMR (in CDCl3): ##STR39## CH2 (a) ABX multiplet at 2.50-3.00δ CH (b) multiplet, 3.30-3.56δ
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]([OH:23])=O)[CH:15]=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27].C(N1C=CN=C1)(N1C=CN=C1)=O>>[CH2:25]([NH:29][C:21]([C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]3)[CH:12]=2)[N:17]=1)=[O:23])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)N1CCC(Oc2ccc3nc(C(=O)O)ccc3c2)CC1
Reactant: CC(C)CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)CNC(=O)c1ccc2cc(OC3CCN(C(C)C)CC3)ccc2n1

Procedure:
According to the procedure described for the synthesis of example 1, (6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid isobutyl-amide was synthesized from 6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid 1:1 hydrochloride, isobutylamine (commercially available) and 1,1′-carbonyl-diimidazole. MS (m/e): 370.6 (M+H).
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(COS(C)(=O)=O)C(=O)N(CC(C)C)N=1.[CH2:26]([N:33]1[C:38](=[O:39])[C:37]([C:40]([O:42]C)=[O:41])=[CH:36][C:35]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[C:46]([CH3:51])[CH:45]=2)=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]1[C:38](=[O:39])[C:37]([C:40]([OH:42])=[O:41])=[CH:36][C:35]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[C:46]([CH3:51])[CH:45]=2)=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)nn(Cc2ccccc2)c1=O
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(Cc3ccccc3)n2)ccc1F
Yield: 65.2 %

Procedure:
Following the procedure of Example 1 (7), 2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as a pale yellow crystalline powder (yield: 65.2%).
Reaction SMILES: [N:1]1[C:6]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][N:4]=[C:3]2[NH:16][CH:17]=[CH:18][C:2]=12.C1C(=O)N([Br:26])C(=O)C1>CN(C=O)C>[Br:26][C:18]1[C:2]2[C:3](=[N:4][CH:5]=[C:6]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:1]=2)[NH:16][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NCc1cnc2[nH]ccc2n1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cnc2[nH]cc(Br)c2n1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
tert-Butyl (5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamate (2.45 g, 9.87 mmol) in DMF (50 mL) was treated with NBS (1.76 g, 9.87 mmol) at P. After about 15 min the solvents were removed under reduced pressure then the material was suspended in water (25 mL). The slurry was stirred for about 30 min then the solids were collected by filtration and dried to a constant weight under vacuum at about 70° C. to give tert-butyl (7-bromo-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamate (3.15 g, 98%): LC/MS (Table 2, Method b) Rt=1.99 min; MS m/z 327 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([CH2:7][O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][C:3]1=O.[CH3:16][Li].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.C(OCC)C.O>[CH3:1][N:2]1[C@H:3]([CH3:16])[CH2:4][CH2:5][C@H:6]1[CH2:7][O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN1C(=O)CC[C@H]1COc1cccnc1
Reactant: [Li]C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CC[C@@H](COc2cccnc2)N1C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 0.121 g (0.587 mmole) (S)-1-Methyl-5-((pyridin-3-yloxy)methyl)pyrrolidin-2-one in 10 ml of dry tetrahydrofuran under argon atmosphere at ice cooling, 1.10 ml (1.76 mmole) of 1.6M methyllithium solution in diethyl ether was added drop by drop for 5 minutes and stirred for 5 minutes under ice cooling, and then at room temperature for 1 hour. To this reaction mixture at room temperature and while stirring, 2.95 ml (2.95 mmole) 1M lithium aluminum hydride solution in tetrahydrofuran was added in 3 minutes and stirred for 1 hour. First 0.29 ml of 10% sodium hydroxide aqueous solution was added drop by drop and after 10 minutes stirring 0.29 ml water was added and stirred for 2 hours. The precipitate was filtered and it was washed with 5×5 ml of ethyl acetate, the combined organic solutions were evaporated at 35° C. in good vacuum. The residue (0.102 g) was separated with column chromatography on 10 g silica gel with cyclohexane-diethylamine (80-20, v/v) giving the more polar 3-(((2S,5R)-1,5-dimethylpyrrolidin-2-yl)methoxy)pyridine in pure form (5.42 mg, 4.5%). From the less polar fractions with column chromatography on 2 g silica gel we got the pure 3-(((2S,5S)-1,5-Dimethylpyrrolidin-2-yl)methoxy)pyridine (1.12 mg, 9%) isomer. The cis and trans configurations of the substituents at the 1 and 5 positions of the pyrrolidine ring were determined by nuclear Overhauser experiments.