Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1Br)=[O:5])[CH3:2].[C:17]([Cu])#[N:18].C(Cl)Cl>CN1C(=O)CCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[C:17]#[N:18])=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1c(Br)c(C(C)(C)C)nn1C
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCOC(=O)c1c(C#N)c(C(C)(C)C)nn1C
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 4-bromo-5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.00 g, 3.46 mmol) and CuCN (372 mg, 4.15 mmol) in NMP (10 mL) was stirred at 200° C. under microwave irradiation for 1 h. After cooling to room temperature, the mixture was treated with DCM (100 mL) and filtered through diatomaceous earth. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (0:100-10:90 EtOAc-hexanes) to yield the title compound as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 4.45 (q, J=7.2 Hz, 2H), 4.14 (s, 3H), 1.45 (t, J=7.2 Hz, 3H), 1.43 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C12H17N3O2: 236.1 (M+H). Measured: 236.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30](=[N:32]O)[NH2:31]>N1C=CC=CC=1>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:30]2[N:31]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[O:9][N:32]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: COc1cccc(C(N)=NO)c1
Reactant: O=C(O)c1ccccn1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: c1ccncc1
Product: COc1cccc(-c2noc(-c3ccccn3)n2)c1
Yield: 31.6 %

Procedure:
Using modifications of the method of Shine et al., J. Heterocyclic Chem. (1989) 26:125–128, a solution of picolinic acid (123 mg, 1 mmol) in pyridine (1 mL) was treated with 1,1′-carbonyldiimidazole (162 mg, 1 mmol) and the reaction stirred at ambient temperature until the evolution of carbon dioxide ceased (30 min). The intermediate acylimidazole was then treated with 3-methoxybenzamidoxime (166 mg, 1 mmol) and the reaction heated at reflux for 1 hour. Ice cold water was added to the reaction mixture to precipitate the oxadiazole. The solid was collected by filtration, washed with water and dried to afford 80 mg (32%) of 3-(3-methoxyphenyl)-5-(2-pyridyl)-1,2,4-oxadiazole: mp 90–94° C.; GC/EI-MS gave m/z (rel. int.) 253 (M+, 100), 254 (17), 179 (2), 175 (2), 149 (77), 133 (33), 119 (4), 106 (29), 78 (45), 51 (18).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:14][CH2:13][CH2:12]1>C(OCC)C>[C:11]1(=[N:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCC1
Reactant: COc1ccc(CN)cc1
Solvent: CCOCC
Product: COc1ccc(CN=C2CCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (4-methoxyphenyl)methanamine (9.26 mL, 71.3 mmol) and cyclobutanone (5.35 mL, 71.3 mmol) in anhydrous ethyl ether (70 mL) was treated with activated 4 angstrom molecular sieves (2.5 g). The mixture was stirred vigorously for 16 hours at ambient temperature. The reaction mixture was filtered, and the sieves were washed with ethyl ether. The filtrate was concentrated under reduced pressure with no heat. The title compound was stored under nitrogen and used without further purification. MS DCI(+) m/z 190.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:41])[CH2:32][CH2:31]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:9][O:8][C:6]([C:4]1[N:3]([CH:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([C:40](=[O:41])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:32][CH2:31]2)[CH:2]=[N:1][CH:5]=1)=[O:7]
Reactant: O=C(c1ccccc1)N1CCC(O)c2ccccc21
Reactant: COC(=O)c1c[nH]cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1CCN(C(=O)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
methyl 4-imidazolecarboxylate (200 mg, 1.59 mmol) and PS-triphenylphosphine (2.15 mmol/g, 0.90 g, 1.94 mmol) are added to a solution of (4-hydroxy-3,4-dihydro-2H-quinolin-1-yl)-phenyl-methanone (380 mg, 1.50 mmol) in THF (20 mL) at room temperature. The resulting mixture is stirred at room temperature for 5 minutes and then cooled to 0° C. DIAD (0.38 mL, 1.96 mmol) is added, and the mixture is slowly warmed up to room temperature. After 3 h, the reaction mixture is filtered to remove resin and washed with ethyl acetate. The combined ethyl acetate solution is washed with brine, and dried with anhydrous sodium sulfate. After concentration, the residue is purified by reverse phase HPLC (CH3CN:H2O=10 to 80% over 20 mins) to give the title compound: 1H NMR (400 MHz, CDCl3) δ ppm 2.21-2.30 (m, 1 H), 2.52-2.62 (m, 1 H), 3.75-3.82 (m, 1 H), 3.89 (s, 3 H), 4.11-4.18 (m, 1 H), 6.40 (t, J=6.1 Hz, 1 H), 6.94 (d, J=7.6 Hz, 1 H), 7.01-7.09 (m, 3 H), 7.33-7.40 (m, 3 H), 7.40-7.45 (m, 1 H), 7.46-7.50 (m, 2 H), 7.85 (d, J=0.8 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:18]=3[N+:25]([O-:27])=[O:26])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.Cl.Cl.Cl.[N:31]1([CH2:37][CH2:38][CH2:39][NH:40][CH2:41][CH2:42][CH2:43][N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:31]1([CH2:37][CH2:38][CH2:39][N:40]([CH2:23][C:21]2[CH:20]=[CH:19][C:18]([N+:25]([O-:27])=[O:26])=[C:17]([NH:16][C:10]3[S:11][C:12]([C:13]([NH2:15])=[O:14])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)[CH:22]=2)[CH2:41][CH2:42][CH2:43][N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1
Reactant: C(CNCCCN1CCOCC1)CN1CCOCC1
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1sc(Nc2cc(CN(CCCN3CCOCC3)CCCN3CCOCC3)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Reaction time: 0.33 h
Yield: 28.2 %

Procedure:
A mixture of 0.455 g (1.13 mmole) of 4-(3-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.2b), 0.860 g (2.26 mmole) of bis-(3-morpholin-4-yl-propyl)-amine trihydrochloride and 50 mL of dichloromethane was stirred for 20 minutes, then 0.479 g 2.26 mmole) of sodium triacetoxy borohydride was added. The mixture was stirred for 4 days, then quenched by the addition of 50 mL of saturated sodium bicarbonate solution. The mixture was extracted three times with 50 mL of dichloromethane. The combined dichloromethane layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (90:10) to give 0.210 g of 2-(5-{[bis-(3-morpholin-4-yl-propyl)-amino]-methyl}-2-nitro-phenylamino)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (VI.49a).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Sc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Sc2nccs2)CC1

Procedure:
By a similar manner to Reference Example 35, 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) was reacted with 2-mercaptothiazole (0.70 g, 6.0 mmol) to give the titled compound as pale yellow oily substance (1.33 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([F:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:14]>>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([F:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:14]
Reactant: N#Cc1cc(F)c(F)c(Cl)c1Cl
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cc(F)c(F)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
A solution of 2,3-dichloro-4,5-difluorobenzonitrile (1.0 g) in concentrated sulfuric acid (2.5 ml) was stirred at 90° to 100° C. for 30 minutes and then cooled. The residue was poured into ice water and the resulting precipitate was collected by filtration and recrystallized from benzene to give the title compound (0.51 g) as colorless needles, mp 153°-155° C.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][CH2:14][CH2:15][CH:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH3:13][CH2:14][CH2:15][CH:16]([NH:20][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCCC(N)CCC
Product: CCCCCCC/C=C/C(=O)NC(CCC)CCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 4-heptylamine as starting materials to give the aimed compound.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12].Br[C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=1[Cl:41]>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:31]3[CH:36]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:34]=[CH:33][C:32]=3[Cl:41])[CH2:25][C:24]2=[O:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12]
Reactant: FC(F)(F)c1ccc(Cl)c(Br)c1
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1cc2ccccc2s1
Agent: Cl
Product: O=C(NC1(C(=O)NC2CCN(c3cc(C(F)(F)F)ccc3Cl)CC2=O)CCCCC1)c1cc2ccccc2s1

Procedure:
In accordance with the same procedure as in Example 85, except that 4-[N-[1-[N-(benzothiophen-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride and 1-bromo-2-chloro-5-trifluoromethylbenzene was used instead of 1-bromo-4-fluoro-2-thiomethoxybenzene in Step 1 thereof, 222 mg of the titled compound was prepared
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8](=[O:17])[C:9]([CH3:16])([S:11][C:12]([F:15])([F:14])[F:13])[CH3:10])=[CH:4][CH:3]=1.[Br:20]Br.O>C(Cl)(Cl)Cl>[Br:20][CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=1)[C:8](=[O:17])[C:9]([CH3:16])([S:11][C:12]([F:13])([F:14])[F:15])[CH3:10]
Reactant: BrBr
Reactant: CC(C)(SC(F)(F)F)C(=O)COc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(SC(F)(F)F)C(=O)C(Br)Oc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
45 g (0.15 mol) of 1-(4-chlorophenoxy)-3-methyl-3-trifluoromethylthio-butan-2-one were dissolved in 150 ml of chloroform, and 7.5 ml (0.15 mol) of bromine were added dropwise at 20° C. at such a rate that decolorization occurred continuously. After the end of the addition, the reaction mixture was further stirred at 40° C. for 20 minutes and was then introduced into water. The mixture was extracted with chloroform and concentrated at 40° C. 1-Bromo-1-(4-chlorophenoxy)-3-methyl-3-trifluoromethylthio-butan-2-one was obtained quantitatively and was directly further reacted. ##STR15##
Reaction SMILES: [O:1]1CCO[C:2]21[CH2:21][C:10]1[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=1[CH2:8][CH2:7][CH2:6]2)[N:15]([C:18](=[O:20])[CH3:19])[N:14]=[CH:13]3.C(O)CO.CC1C=CC(S(O)(=O)=O)=CC=1.[OH-].[K+]>C1(C)C=CC=CC=1>[C:18]([N:15]1[C:16]2[C:12](=[CH:11][C:10]3[CH2:21][C:2](=[O:1])[CH2:6][CH2:7][CH2:8][C:9]=3[CH:17]=2)[CH:13]=[N:14]1)(=[O:20])[CH3:19]
Reactant: CC(=O)n1ncc2cc3c(cc21)CCCC1(C3)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: OCCO
Product: CC(=O)n1ncc2cc3c(cc21)CCCC(=O)C3
Temperature: 142 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
1-Acetyl-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (79) (30 g, 124 mmol) was added to a round bottom flask, equipped with a Dean Stark trap and condenser. Ethane-1,2-diol (27.6 mL, 495 mmol), pTSA (2.36 g, 12.38 mmol) and toluene (300 mL) were added and the resulting mixture was heated to about 142° C. for about 90 min. After cooling to rt, the mixture was concentrated and sonicated with water (˜50 mL). The resulting solids were collected by filtration and taken into MeOH (200 mL) and water (200 mL). Potassium hydroxide (13.9 g, 248 mmol) was added and the mixture was stirred at rt for about 30 min. The mixture was extracted with DCM (300 mL), washed with brine (200 mL), dried over MgSO4 and concentrated to afford 5,7,8,9-tetrahydro-M-spiro[cyclohepta[f]indazole-6,2′-[1,3]dioxolane] (81), (28.3 g, 93%); LC/MS, method 1, Rt=1.20 min, MS m/z 245 (M+H)+1H NMR (400 MHz, DMSO) δ 12.79 (bs, 1H), 7.93-7.87 (m, 1H), 7.44 (s, 1H), 7.22 (s, 1H), 3.97-3.76 (m, 4H), 3.06 (s, 2H), 2.91-2.81 (m, 2H), 1.91-1.81 (m, 2H), 1.70-1.59 (m, 2H).
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[C:8]([O:16][CH:17]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH:18]([CH3:20])[CH3:19])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C.O>[CH3:19][CH:18]([CH3:20])[CH:17]([O:16][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15])[O:21][C:22]([NH:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]1)=[O:23]
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)c1ccccc1
Reactant: NC1(C(=O)O)CC1
Solvent: O
Solvent: CC#N
Product: CC(C)C(OC(=O)NC1(C(=O)O)CC1)OC(=O)c1ccccc1
Yield: 23.2 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (0.726 g, 7.15 mmol) and 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl benzoate (2 g, 5.96 mmol) were reacted in the acetonitrile/water mixture to provide 0.445 g (25% yield) of the title compound (12) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=8.02 (d, 2H), 7.59 (t, 1H), 7.42 (t, 2H), 6.82 (d, 1H), 5.56 (br s. 0.3H), 5.44 (s, 0.7H), 2.21 (m, 1H), 1.61 (m, 2H), 1.39 (m, 2H), 1.02 (dd, 6H). MS (ESI) m/z 344.19 (M+Na)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17]O)=[C:14]([CH3:19])[C:13]=2[CH:20]=1)=[O:8]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17][Cl:3])=[C:14]([CH3:19])[C:13]=2[CH:20]=1)=[O:8]
Reactant: COC(=O)c1ccc2oc(CO)c(C)c2c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2oc(CCl)c(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (0.25 ml) was added dropwise to a stirred solution of 2-hydroxymethyl-3-methylbenzofuran-5-carboxylic acid methyl ester (0.20 g) and pyridine (2 drops) in chloroform (5 ml). The solution was stirred at room temperature for 30 minutes and then washed successively with water, sodium bicarbonate solution and dried (Na2SO4). Evaporation of the solvent gave crude 2-chloromethyl-3-methylbenzofuran-5-carboxylic acid methyl ester (0.18 g), m.p. 114°-115° which was used directly in the next stage.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[CH2:3]1.[CH3:12][C:13]1([CH3:19])[NH:17][C:16](=[O:18])[CH2:15][NH:14]1>>[CH3:12][C:13]1([CH3:19])[NH:17][C:16](=[O:18])[CH2:15][N:14]1[C:8](=[O:10])[CH2:7][N:5]1[CH2:6][CH:2]([OH:1])[CH2:3][C:4]1=[O:11]
Reactant: O=C(O)CN1CC(O)CC1=O
Reactant: CC1(C)NCC(=O)N1
Product: CC1(C)NC(=O)CN1C(=O)CN1CC(O)CC1=O

Procedure:
The same procedure of Example 10, starting from 4-hydroxy-2-oxo-1-pyrrolidineacetic acid and 2,2-dimethyl-4-imidazolidinone, afforded the title compound, m.p. 250° C. (dec).
Reaction SMILES: [NH:1]([C:5]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:6]=1[CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C(C)=O.[ClH:22].N>C(O)C>[ClH:22].[NH2:1][C:5]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:6]=1[CH2:7][N:8]([CH2:9][CH3:10])[CH2:11][CH3:12]
Reactant: CCOC(=O)c1ccc(NC(C)=O)c(CN(CC)CC)c1
Agent: Cl
Agent: N
Solvent: CCO
Product: CCOC(=O)c1ccc(N)c(CN(CC)CC)c1

Procedure:
19 gm of 2-acetamino-5-carbethoxy-N,N-diethyl-benzylamine were dissolved in 100 ml of ethanol, and after addition of 60 ml of concentrated hydrochloric acid the mixture was refluxed for 1 hour. Thereafter the mixture was poured over ice, made alkaline with ammonia and extracted three times with chloroform. The combined chloroform extracts were dried over sodium sulfate and evaporated in vacuo, and the residue was purified by chromatography on silicagel (elution agent: ethyl acetate); by addition of isopropanolic hydrochloric acid, 2-amino-5-carbethoxy-N,N-diethyl-benzylamine hydrochloride was obtained, which was recrystallized from ethanol and then had a melting point of 138-142° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>O1CCCC1>[NH:1]1[CH:5]=[C:4]([S:6]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)(=[O:8])=[O:7])[N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Solvent: C1CCOC1
Product: O=S(=O)(c1c[nH]cn1)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A dry round botton flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with a filtered solution of 8.33 g of imidazole-4-sulfonylchloride in 300 ml of tetrahydrofuran (THF). The clear solution was treated with 7.0 g of imidazole in one portion and allowed to stir overnight at room temperature. The reaction mixture was filtered and the filtrate concentrated to dryness. All the solids were triturated with water, filtered, rinsed with water and dried at high vacuum over NaOH. Recrystallization from ethanol gave 5.35 g of white crystals of 1-(4-imidazolylsulfonyl)imidazole mp 208°-10°, λmaxnujol 3.21 (HH), 7.29 (SO2N) and 8.52 μ (SO2N). NMR (DMSO, d6) 570-510 Hz, M, 1H; 497 Hz, t, J ~ 1 Hz, 2H; 481 Hz, d J ~ 1 Hz, 1H; 457 Hz, t, J ~ 1 Hz, 1H; 429 Hz, t, J ~ 1 Hz, 1 H.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][CH3:23])[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl>C(O)C.O1CCCC1.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][CH3:23])[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1cc(Nc2cccc(F)c2)ncc1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCNc1cc(Nc2cccc(F)c2)ncc1C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a solution of ethyl 6-((3-fluorophenyl)amino)-4-(propylamino)nicotinate (S15, 247 mg) in ethanol (3 mL) and tetrahydrofuran (1.5 mL), 2.0 mol/L aqueous sodium hydroxide (0.78 mL) was added at room temperature, and the mixture was stirred at 50° C. for 1 hour. To the reaction mixture, 2.0 mol/L aqueous sodium hydroxide (0.39 mL) was added at 50° C., and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was cooled to room temperature, and then 1.0 mol/L aqueous hydrochloric acid was added to the reaction mixture until the mixture became acidic. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 6-((3-fluorophenyl)amino)-4-(propylamino)nicotinic acid (S16, 130 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16](=[O:20])[C:17](Cl)=[O:18])=[CH:8]2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH2:28][O:27][C:26](=[O:29])[CH:25]=1.O>O1CCCC1>[O:29]=[C:26]1[O:27][CH2:28][C:24]([NH:23][C:17](=[O:18])[C:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:8]=2)=[O:20])=[CH:25]1
Reactant: NC1=CC(=O)OC1
Reactant: O=C(Cl)C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Solvent: O
Solvent: C1CCOC1
Product: O=C1C=C(NC(=O)C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
A solution of 2-(1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride (0.45 g) and 4-amino-5H-furan-2-one (0.30 g) in dry tetrahydrofuran (10 ml) is refluxed for 2 h. After cooling at room temperature, the reaction mixture is poured into water (200 ml) and the resulting suspension is left under stirring for 1 h. The solid is filtered off and resuspended in methanol (4.3 ml) under stirring for 1 h, then collected by filtration to give N-(5-oxo-2,5-dihydrofuran-3-yl)-2-(1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetamide (0.27 g).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12](=[O:22])[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[OH:21].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]=[CH2:31]>CC(C)=O>[NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12](=[O:22])[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[O:21][CH2:31][CH:30]=[CH2:29]
Reactant: COc1ccc(O)c(C(=O)c2oc3ccc(Cl)cc3c2N)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(OC)cc1C(=O)c1oc2ccc(Cl)cc2c1N
Temperature: 55 °C
Reaction time: 48 h

Procedure:
A suspension of 3-amino-5-chloro-2-(2-hydroxy-5-methoxybenzoyl)-benzofuran (0.06 g, 0.19 mmol), potassium carbonate (0.08 g, 0.6 mmol) and allyl bromide (0.1 g, 0.8 mmol) in dry acetone (3 ml) is stirred 55° C. for 48 h. The solids are filtered off and the solution is concentrated under reduced pressure. Purification of the residue by silicagel column chromatography yields the title compound of m.p. 115-116° C.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1>CS(C)=O>[I:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH:3]([C:2](=[O:1])[CH2:9][CH2:10][CH2:11][CH3:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:18][CH:19]=1
Reactant: CCCCC(=O)CC(=O)OCC
Reactant: BrCc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCC(=O)C(Cc1ccc(I)cc1)C(=O)OCC
Reaction time: 0.17 h
Yield: 28.9 %

Procedure:
To a solution of 3.77 g (43.8 mmol) ethyl 3-oxoheptanoate in 200 mL DMSO was added 1.75 g (43.8 mmol) 65% NaH in oil. After 10 minutes, 6.5 g (21.9 mmol) α-bromo-4-iodotoluene was added. The mixture was allowed to stir for 2 hours. It was then poured into an ice/brine mixture and extracted 3 times with ether. The combined organic material was washed with brine, dried over MgSO4, stripped of solvent in vacuo, then Still flash chromatographed in 40% CH2Cl2 /hexane to give 2.46 g of the title compound, 29% yield. Rf 0.23 in 40% CH2Cl2 /hexane, visualized by UV and ninhydrin stain;