Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[CH:8]=[C:9]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=3)[CH:10]=[CH:11][C:4]=2[O:3]1.[CH3:24][NH:25][CH3:26]>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[CH:8]=[C:9]([CH2:12][CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([N:25]([CH3:26])[CH3:24])=[O:23])=[CH:19][CH:20]=3)[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: CC1CCc2cc(CCOc3ccc(N=C=O)cc3)ccc2O1
Reactant: CNC
Solvent: Cc1ccccc1
Product: CC1CCc2cc(CCOc3ccc(NC(=O)N(C)C)cc3)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
3.1 g of 4-[(3,4-dihydro-2-methyl-2H-1-benzopyran-6-yl)ethyloxy]phenyl isocyanate was dissolved into 30 ml of toluene, and 0.9 g of dimethylamine dissolved in 5 ml of toluene was slowly added dropwise thereto at room temperature. After the mixture was stirred at room temperature for 2 hours, toluene was distilled off under a reduced pressure and the residue was recrystallized from ethyl acetate to obtain 2.7 g of Compound No. 67 shown in Table 4.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[C:4]([NH:6][CH:7]([CH2:11][CH:12]=[CH2:13])[C:8]([OH:10])=[O:9])=[O:5].S(Cl)(Cl)=O.O.[C:24](=O)([O-])O.[Na+]>CO>[CH3:24][O:9][C:8](=[O:10])[CH:7]([NH:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:18])[CH2:11][CH:12]=[CH2:13]
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CO
Product: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Allylglycine (10.11 g) was dissolved in a mixed solvent of 2N aqueous sodium hydroxide solution (176 ml) and dioxane (175 ml), and 2,6-dichlorobenzoyl chloride (15.10 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 10 hours. After concentrating the reaction solution to remove dioxane, water (150 ml) was added thereto and the resulting solution was washed with ether. Aqueous layer was acidified by adding 3N hydrochloric acid in small portions thereto, and extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain 2-(2,6-dichlorobenzamido)pent-4-enoic acid (23.48 g). (2) Under an argon atmosphere, a solution of 2-(2,6-dichlorobenzamido)pent-4-enoic acid (23.48 g) in methanol (250 ml) was cooled to 0° C. Thionyl chloride (10.70 ml) was added dropwise to the solution while keeping the reaction temperature not higher than 10° C., and thereafter the resulting mixture was stirred at room temperature for 5.5 hours. Water was added to the reaction solution, and sodium hydrogen carbonate was added thereto in small portions to neutralize it. After concentrating the reaction solution to remove methanol, aqueous layer was extracted twice with ethyl acetate. Organic layers were washed 3 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (21.70 g). NMR (H1, CDCl3): δ 2.55-2.61 (1H, m), 2.68-2.75 (1H, m), 3.72 (3H, s), 4.88 (1H, td, J=7.8, 5.4 Hz), 5.06-5.13 (2H, m), 5.64-5.74 (1H, m), 6.33 (1H, brd, J=7.1 Hz), 7.17-7.26 (3H, m)
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=O)OC(C)(C)C)=[C:11]([NH:23][C:24]2[N:29]=[C:28]([NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:27]([N+:37]([O-])=O)=[CH:26][N:25]=2)[CH:10]=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]2[N:15]=[CH:16][N:23]([C:24]3[N:29]=[C:28]4[C:27]([N:37]=[CH:1][N:30]4[CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:26][N:25]=3)[C:11]=2[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(NC2CCOCC2)n1
Product: Fc1ccc2ncn(-c3ncc4ncn(C5CCOCC5)c4n3)c2c1

Procedure:
The title compound as a TFA salt was synthesized from tert-butyl 4-fluoro-2-(5-nitro-4-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-ylamino)phenylcarbamate via the procedure described in Example 15. 1H NMR (300 MHz, CDCl3): δ 9.73 (s, 1H), 9.29 (s, 1H), 8.5-8.6 (m, 1H), 8.40 (s, 1H), 7.9-8.1 (m, 1H), 7.3-7.4 (m, 1H), 4.8-5.0 (m, 1H), 4.2-4.4 (m, 2H), 3.7-3.8 (m, 2H), 3.05 (d, 1H), 2.2-2.4 (m, 3H). 19F NMR: δ −112.4.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[F:20][CH:21]([F:30])[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>CC#N>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([O:22][CH:21]([F:20])[F:30])=[CH:24][CH:25]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(OC(F)F)cc1
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc(OC(F)F)cc2)=C(c2ccccc2)S1(=O)=O
Reaction time: 1 h
Yield: 77.6 %

Procedure:
2-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.63 g, 2.1 mmol) and 4-(difluoromethoxy)-aniline (0.67 g, 4.2 mmol) were mixed in MeCN (4 mL, dry). The mixture was put in the microwave reactor at 160° C. for 1 h, then additional 1 h and then 1 h more. It was evaporated to dryness. The residue was purified by column chromatography (ISOLUTE SI, 50 g/150 mL), eluting with DCM/heptane (50:50, then 75:25), to give the title compound (0.688 g, 78%) as a yellow solid; 1H-NMR (400 MHz; CDCl3): δ 0.99 (t, 3H), 1.42-1.52 (m, 2H), 1.82-1.90 (m, 2H), 3.77 (t, 2H), 6.34 (t, 1H), 6.67 (d, 2H), 6.76 (d, 2H), 7.11-7.17 (m, 4H), 7.22-7.26 (m, 1H); Mass Spectrum: M−H+ 421.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.S(OC)(O[CH3:25])(=O)=O.[OH-]>CO.O1CCCC1.O>[CH3:25][O:20][CH3:9].[CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2
Reactant: COS(=O)(=O)OC
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC
Reaction time: 1 h

Procedure:
Into a mixture of 1 g of estrone, 0.5 ml of dimethyl sulfate and 5 ml of tetrahydrofuran, 6 ml of 10% methanolpotassium hydroxide solution was added over a period of 1 hour. The reaction temperature was maintained at 10° - 15°C. The resulting mixture was stirred for one hour to complete the etherification. Then, 15 ml of water was added to the reaction mixture, tetrahydrofuran and methanol were distilled off under atmospheric pressure. The residue was extracted with chloroform, washed with water, and dried. Evaporation of chloroform yielded 1.032 g of the 100% purity methyl ether of estrone in a 98.4% yield.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]1[C:17](=O)[C:16]2[C:15]([C:19](OC)=[O:20])=[CH:14][CH:13]=[CH:12][C:11]=2[NH:10][CH:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2].O.[NH2:30][NH2:31]>CO>[CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]1[C:17]2=[N:30][NH:31][C:19](=[O:20])[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=32)[NH:10][CH:9]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:2]
Reactant: CCn1ccnc1C1C(=O)c2c(cccc2C(=O)OC)NC1c1ccccc1
Reactant: NN
Solvent: O
Solvent: CO
Product: CCn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
Methyl 3-(1-ethyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (190 mg, 0.49 mmol) and hydrazine monohydrate (2 mL) were added to methanol (15 mL) and the mixture was stirred room temperature for 3 hrs. Methanol was evaporated and then filtered. The filtrate was concentrated to give 9-(1-ethyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as a white solid (50 mg, yield 28%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.96 (t, 3H), 3.74-3.79 (m, 2H), 4.61 (d, 1H), 4.95 (d, 1H), 6.78 (dd, 1H), 6.91 (dd, 1H), 7.16 (d, 1H), 7.23-7.31 (m, 4H), 7.37 (s, 3H), 7.57 (t, 1H). LC-MS (ESI) m/z: 358 (M+1)+.
Reaction SMILES: Cl[CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].[F:9][C:10]([F:26])([F:25])[C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1.P(=O)(O)(O)O>O.C1(C)C(C)=CC=CC=1>[F:9][C:10]([F:25])([F:26])[C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH:2]([CH3:6])[C:3]([OH:5])=[O:4])=[CH:20][CH:21]=2)=[CH:13][CH:12]=1
Reactant: CC(Cl)C(=O)O
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
132.5 Parts of 2-chloropropionic acid (98% strength) and 199 parts of 50% sodium hydroxide solution are added simultaneously but separately at 110°-115° C. to a solution of 254 parts of 4-(4'-trifluoromethylphenoxy)-phenol in 1,000 parts of xylene. During the addition, the reaction temperature is maintained by azeotropic distillation of water in a water trap. The addition being complete, stirring is continued for 15 minutes at 110°-115° C., the batch is cooled to 90° C. and after addition of 400 parts of water, it is stirred for a further 10 minutes at 85° C., then acidified at this temperature with 120 parts of phosphoric acid, and stirred for a further 10 minutes. After elimination of the water phase, xylene is distilled off in a water jet vacuum, and the solids are dried at 60° C. and 250 mbar. 326 parts of 2-[4'-(4" -trifluoromethylphenoxy)-phenoxy]-propionic acid are obtained. The content of pure final product is 99.6% corresponding to a yield of 99.6% of theory. The residual content of 4-(4'-trifluoromethyl-phenoxy)-phenol is 0.35%.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[Br-:1].[C:7]([C:6]([CH3:11])([CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2][P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([OH:9])=[O:8]
Reactant: CC(C)(CCCCBr)C(=O)O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Product: [Br-]
Yield: 58.2 %

Procedure:
6-Bromo-2,2-dimethylhexanoic acid (3.8 g, 17 mmole) and triphenylphosphine (4.9 g, 18.7 mmole) were dissolved in acetonitrile (30 ml), and the solution was heated under reflux for 20 hours. After the completion of the reaction, the solvent was removed under reduced pressure, and the residue was treated with toluene, followed by thorough stirring. The insolubles were seperated from the toluene solution, and crystallized from ethyl acetate to give 5-carboxy-5,5-dimethylpentyltriphenylphosphonium bromide (4.8 g, 58%) [NMR (δ value): 1.10 (6H,s), 1.4-1.6 (6H), 3.4-3.8 (2H)].
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](CC2C=CC(O)=CC=2)=O)=[CH:16][CH:15]=1.[OH-:31].[K+]>C(O)C>[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:31])[CH:21]=[CH:1][C:3]2[S:7][C:6]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)=[CH:5][CH:4]=2)=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: O=C(Cc1ccc(O)cc1)Cc1ccc(O)cc1
Agent: [K+]
Solvent: CCO
Product: O=C(C=Cc1ccc(-c2cccs2)s1)c1ccc(O)cc1

Procedure:
1.94 g of 5-formyl-2,2'-bithiophene was dissolved in 15 ml of ethanol. Then 1.36 g of p-hydroxyphenyl-methyl-ketone was added in, followed by adding KOH (1 g dissolved in H2O and ethanol), the color of the mixture turned into orange. Some crude crystals were crystallized and dissolved later. The reaction solution was placed in a refrigerator overnight. The next day, it was decomposed with ice water and 2 ml of acetic acid were added. The crude product was collected and recrystallized from ethanol, 0.52 g of golden crystal product was thus obtained and the melting point thereof was 202°-205° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][CH:5]=[C:4]([C:7]2[NH:8][C:9]([CH2:18][CH3:19])=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:11]=2)[CH:3]=1.[NH3:20].Cl[S:22]([OH:25])(=[O:24])=[O:23]>>[Cl:1][C:2]1[S:6][C:5]([S:22]([OH:25])(=[O:24])=[O:23])=[C:4]([C:7]2[NH:8][C:9]([CH2:18][CH3:19])=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:11]=2)[CH:3]=1.[Cl:1][C:2]1[S:6][C:5]([S:22](=[O:25])(=[O:23])[NH2:20])=[C:4]([C:7]2[NH:8][C:9]([CH2:18][CH3:19])=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:11]=2)[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: CCc1[nH]c(-c2csc(Cl)c2)nc1-c1cccnc1
Reactant: N
Product: CCc1[nH]c(-c2cc(Cl)sc2S(=O)(=O)O)nc1-c1cccnc1
Product: CCc1[nH]c(-c2cc(Cl)sc2S(N)(=O)=O)nc1-c1cccnc1
Temperature: 25 °C

Procedure:
A mixture of 2-(5-chlorothiophen-3-yl)-5-ethyl-4-(3-pyridyl)-imidazole (2.00 g) in chlorosulfonic acid (15 ml) was stirred at room temperature for one week. The mixture was slowly added dropwise to 28% aqueous ammonia (500 ml), and the resulting mixture was stirred for 30 minutes and then concentrated under reduced pressure. The resulting residue was dissolved in methanol-tetrahydrofuran (5:1), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel flush column chromatography (solvent: chloroform:methanol=10:1→2.5:1), and then, by NH silica gel flush column chromatography (solvent: chloroform:methanol=10:1→4:1) to obtain 2-(5-chloro-2-sulfothiophen-3-yl)-5-ethyl-4-(3-pyridyl)imidazole and 2-(5-chloro-2-sulfamoylthiophen-3-yl)-5-ethyl-4-(3-pyridyl)imidazole. Each product was treated with hydrogen chloride-dioxane solution to obtain 2-(5-chloro-2-sulfothiophen-3-yl)-5-ethyl-4-(3-pyridyl)imidazole dihydrochloride (741 mg) and 2-(5-chloro-2-sulfamoylthiophen-3-yl)-5-ethyl-4-(3-pyridyl)imidazole dihydrochloride (105 mg) each as colorless powder.
Reaction SMILES: P(Br)(Br)[Br:2].O=[C:6]1[NH:22][C:10]2[CH2:11][C@H:12]3[C@H:17]([CH2:18][C:9]=2[CH:8]=[CH:7]1)[N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14][CH2:13]3>CN(C)C=O>[BrH:2].[BrH:2].[Br:2][C:6]1[CH:7]=[CH:8][C:9]2[CH2:18][C@H:17]3[C@@H:12]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:19][CH2:20][CH3:21])[CH2:11][C:10]=2[N:22]=1
Reactant: CCCN1CCC[C@H]2Cc3[nH]c(=O)ccc3C[C@@H]21
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Product: Br
Product: CCCN1CCC[C@H]2Cc3nc(Br)ccc3C[C@@H]21
Yield: 42.7 %

Procedure:
Phosphorus tribromide (30.7 mL, 87.5 g, 324 mMol) was added dropwise over 22 hours to a solution of (±)-trans-2-oxo-6-propyl-1,2,5,5a,6,7,8,9,9a,10-decahydropyrido[2,3-g]quinoline (1.50 g, 6.06 mMol) in dimethylformamide (100 mL) at 100° C. The reaction was quenched by the dropwise addition of water (50 mL). This mixture was poured over ice and made basic by addition of NH4OH and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give a brown oil. Purification by flash chromatography (7% methanol in methylene chloride, 0.5% NH4OH) gave the desired product as an orange oil (Rf=0.54, 1.22 g, 65% yield).
Reaction SMILES: [C-:1]#N.[Na+].[CH3:4][C:5]1([CH3:18])[CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH3:17])=[C:11]([OH:16])[C:12]=2[CH3:15])[CH:7]=[N:6]1>>[CH3:18][C:5]1([CH3:4])[N:6]=[CH:7][C:8]2[CH:9]=[C:10]([CH3:17])[C:11]([OH:16])=[C:12]([CH3:15])[C:13]=2[CH2:1][CH2:14]1
Reactant: Cc1cc2c(c(C)c1O)CC(C)(C)N=C2
Reactant: [C-]#N
Agent: [Na+]
Product: Cc1cc2c(c(C)c1O)CCC(C)(C)N=C2
Yield: 8 %

Procedure:
The product from the previous reaction (4.9 g, 24 mmol) is treated with NaCN as described above for compound 38. The resulting crude, cyclized imine is purified by FC (19:1 CH2Cl2/MeOH, then 9:1 CH2Cl2 /MeOH) to afford a dark orange semi-solid (370 mg, 8%). 1H NMR (CDCl3) 7.50 (s, 1), 7.00 (s, 1), 3.34 (br s, 1), 3.00-2.95 (m, 2), 2.18 (s, 3), 2.13 (s, 3), 2.00-1.95 (m, 2), 1.41 (s, 6); 13C NMR (CDCl3) 173.41, 156.30, 143.13, 141.14, 127.66, 125.74, 112.00, 57.81, 36.79, 28.50, 28.41, 16.73, 12.38; MS (MW=217.3, EI, eE=70 eV) m/z 217 (M+), 161 (base peak)
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH2:30][O:31][CH3:32])[CH:18]=3)[O:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].O>C1COCC1.CO>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH2:30][O:31][CH3:32])[CH:18]=3)[O:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)ccc1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCc1cc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.3 %

Procedure:
A solution of methyl 2-fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoate (16 g; 37 mmol) in THF (400 mL) and MeOH (400 mL) at RT was treated with NaOH (37 mL; 5 M; 184.99 mmol). The reaction mixture was stirred at RT for 12 hours. The reaction mixture was concentrated to give a yellow solid. Water (600 mL) was added and the aqueous phase was washed with EtOAc (250 mL). Then the aqueous phase was acidified with HCl cc until pH 2 and extracted with EtOAc (2×300 mL). Organics were washed with brine, dried over MgSO4 and concentrated affording the title compound as a beige solid (11.66 g, 75%). 1H NMR (DMSO, 400 MHz) δ 13.64 (br s, 1H), 8.33 (d, J=1.41 Hz, 1H), 8.17 (dd, J=7.92 Hz, 1.4 Hz, 1H), 8.13-8.03 (m, 2H), 7.96 (dd, J=11.10 Hz, 1.17 HZ, 1H), 7.43 (d, J=7.91 Hz, 1H), 7.37-7.27 (m, 3H), 7.15 (d, J=7.03 Hz, 1H), 4.25-4.14 (m, 2H), 3.25 (s, 3H), 2.04 (s, 3H). LC/MS (Method B): 419.1 (M+H)+; 417.2 (M−H)−. HPLC: Rt 5.19 min (Purity: 99.2%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][NH:4][CH:3]1[C:7]([NH2:9])=[O:8].[NH2:11][C@H:12]([C:19]([OH:21])=O)[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1.[NH2:22][C@H:23]([C:29]([OH:31])=O)[CH2:24][CH2:25][C:26](O)=[O:27]>CN(C)C=O>[NH:22]1[C:26](=[O:27])[CH2:25][CH2:24][C@H:23]1[C:29]([NH:11][C@H:12]([C:19]([N:4]1[CH2:5][CH2:6][C:2]([CH3:10])([CH3:1])[CH:3]1[C:7]([NH2:9])=[O:8])=[O:21])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:31]
Reactant: CC1(C)CCNC1C(N)=O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Solvent: CN(C)C=O
Product: CC1(C)CCN(C(=O)[C@H](Cc2c[nH]cn2)NC(=O)[C@@H]2CCC(=O)N2)C1C(N)=O

Procedure:
This was prepared from 3,3-dimethyl-dl-prolineamide (100 mg) by the method of Example 2(vi) as a white powder (195 mg) m.p. 180° (softening 135°) RF 3B 0.65. Amino acid analysis after acid hydrolysis gave the following ratios: Histidine 1.02, Glutamic acid 0.89 3,3-dimethylproline 1.02 [α]D22 + 5.9° (c = 1, dimethylformamide)
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[O:6].[C:23]1([C:29]2[N:33]=[C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[S:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:23]1([C:29]2[N:33]=[C:32]([N:34]3[CH2:39][CH2:38][N:37]([C:5]([NH:7][CH:8]4[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:9]4)=[O:6])[CH2:36][CH2:35]3)[S:31][N:30]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(NC(=O)OCC(Cl)(Cl)Cl)C1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)C1
Yield: 13 %

Procedure:
A mixed solution of tert-butyl 3-{[(2,2,2-trichloroethoxy)carbonyl]amino}piperidine-1-carboxylate (555 mg, 1.48 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (400 mg, 1.62 mmol) and diisopropylethylamine (0.257 ml, 1.48 mmol) in dimethyl sulfoxide (4.9 ml) was stirred at 70° C. for 4 days. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 90.9 mg (13.0%) of the desired product as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7](Br)[C:5]=1[NH2:6])([O-:3])=[O:2].[CH2:15]([Sn](CC)(CC)CC)[CH3:16]>CN(C=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([CH2:15][CH3:16])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC[Sn](CC)(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N
Yield: 52.5 %

Procedure:
A solution of 2,4-dinitro-6-bromoaniline (1.6 g, 6.1 mmol), tetraethyltin (2.4 ml, 12.2 mmol) and Cl2Pd(PPh3)2 (100 mg) in 10 ml of DMF was stirred at 140° C. for 12 h. Reaction mixture was concentrated in vacuo, yielding an oil which was purified on silica gel column chromatography (CH2Cl2, neat) to provide 0.68 g (3.2 mmol, 53%) of 2,4-dinitro-6-ethylaniline, which was converted to the diamine (0.45 g, 95%) on hydrogenation (H2/Pd-C).
Reaction SMILES: Cl.[CH:2]1([CH2:5]C(=N)OCC)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:18][CH2:19][C:20]#[N:21].[CH3:22][CH2:23][O:24]CC>O>[CH2:23]([O:24][C:5]([CH:2]1[CH2:3][CH2:4]1)=[N:21][CH2:20][C:19]#[N:18])[CH3:22]
Reactant: CCOCC
Reactant: N#CCN
Reactant: CCOC(=N)CC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=NCC#N)C1CC1
Reaction time: 0.08 h

Procedure:
To a suspension of ethyl cyclopropylacetimidate hydrochloride (6.0 g, 53 mmol) in ether (50 mL) was added anhydrous potassium carbonate (7.3 g, 53 mmol). After stirring for 5 min, a solution of aminoacetonitrile hydrochloride (4.9 g, 53 mmol) in water (40 mL) was added and the mixture stirred for additional 90 min. The reaction was diluted with water (100 mL) and extracted with ether (2×300 mL). The combined organic fractions were dried (Na2SO4), filtered, and concentrated to give N-cyanomethyl-cyclopropanecarboximidic acid ethyl ester as a liquid (4.54 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[OH-].[Na+].C(O)(=O)C.CN([CH:20]=[N:21][C:22]([C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)=O)C>O1CCOCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:22]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)=[N:21][CH:20]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)C=NC(=O)c1cnccn1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Clc1ccc(-n2ncnc2-c2cnccn2)cc1

Procedure:
To a solution of 12.1 g. of 4-chlorophenylhydrazine hydrochloride in a mixture of 13.5 ml. of 5 N sodium hydroxide, 100 ml. of 30% aqueous acetic acid and 50 ml. of p-dioxane is added 10.0 g. of N-(dimethylaminomethylene)pyrazinecarboxamide. The procedure of Example 2 is then followed giving 3.8 g. of the desired product as tan crystals, mp. 129°-131° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].[C:16]1(=[O:23])[CH2:21][CH2:20][CH2:19][C:18](=O)[CH2:17]1.[CH2:24]([O:26][C:27](=[O:32])[CH2:28][C:29](=[NH:31])[NH2:30])[CH3:25]>C(O)C>[CH2:24]([O:26][C:27]([C:28]1[CH:10]([C:9]2[CH:8]=[C:7]([O:12][CH3:13])[C:6]([O:14][CH3:15])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[C:17]2[C:16](=[O:23])[CH2:21][CH2:20][CH2:19][C:18]=2[NH:30][C:29]=1[NH2:31])=[O:32])[CH3:25]
Reactant: CCOC(=O)CC(=N)N
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: O=C1CCCC(=O)C1
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC2=C(C(=O)CCC2)C1c1cc(OC)c(OC)cc1[N+](=O)[O-]
Yield: 52 %

Procedure:
Boiling a solution of 8.5 g of 6-nitroveratraldehyde, 4.0 g of cyclohexane-1,3-dione and 5.2 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 1 hour yields 2-amino-4-(2-nitro-4,5-dimethoxyphenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 261°C (ethanol). Yield: 52% of theory.