Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[F:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](SC)=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][C:11]([CH3:14])=[N:10]1.[Cl:20][CH2:21][CH2:22][CH2:23][CH:24]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)[C:25](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:55][NH2:56]>>[Cl:20][CH2:21][CH2:22][CH2:23][CH:24]([C:25]1[NH:56][N:55]=[C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[N:12][C:11]([CH3:14])=[N:10]3)=[C:3]([F:2])[CH:4]=2)[N:17]=1)[C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:37])[F:38])=[CH:30][CH:29]=1
Reactant: NN
Reactant: O=C(O)C(CCCCl)c1ccc(OC(F)(F)F)cc1
Reactant: CSC(=N)Nc1ccc(-n2cnc(C)n2)c(F)c1
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCOCC1
Product: Cc1ncn(-c2ccc(Nc3n[nH]c(C(CCCCl)c4ccc(OC(F)(F)F)cc4)n3)cc2F)n1

Procedure:
Methyl 3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (0.578 g, 1.471 mmol), from preparation Q) and 5-chloro-2-(4-(trifluoromethoxy)phenyl)pentanoic acid (0.480 g, 1.62 mmol, from preparation AAK) were coupled [N-methylmorpholine (0.81 mL, 7.36 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.185 mL, 5.88 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, 5-(4-chloro-1-(4-(trifluoromethoxy)phenyl)butyl)-N-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown residue. The crude product was used in the next step without purification. LC-MS (M+H)+ 510.1.
Reaction SMILES: [C:1]1([CH:7]2[C:12](=[O:13])[NH:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([N:16]([CH2:19][CH2:20]Cl)[CH2:17][CH3:18])[CH3:15].C(N(CC)CC)C>CC(C)=O>[CH2:14]([N:16]([CH2:19][CH3:20])[CH:17]([N:8]1[CH2:9][CH2:10][NH:11][C:12](=[O:13])[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:18])[CH3:15]
Reactant: CCN(CC)CCCl
Reactant: O=C1NCCNC1c1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(C)N1CCNC(=O)C1c1ccccc1
Yield: 64 %

Procedure:
144 g. of 2-phenyl-3-keto piperazine are boiled under reflux with 121 g. of diethylamino ethylchloride, 340 cc. of triethylamine, and 1600 cc. of acetone for 24 hours. The cooled solution is filtered to remove triethylamine hydrochloride and the filtrate is evaporated to dryness. The residue is dissolved in water, 40 % sodium hydroxide solution is added thereto, and the oil which forms as upper layer, is extracted with benzene. The benzene solution is dried over anhydrous potassium carbonate, the benzene is removed by distillation, and the residue is distilled in a vacuum. A light yellow, viscous oil of the boiling point 175° C./0.05 mm. Hg is obtained. The oil is twice recrystallized from n-heptane. 145 g. of the above mentioned compound melting at 53°-56° C. are obtained. The yield is 64 % of the theoretical yield.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C(=O)C1C=CC([O:18]C)=CC=1.O1CCCC1.ClC1C=C(C=CC=1)C(OO)=O>C(OC)(C)(C)C>[OH:18][NH:10][C@@H:7]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[CH2:8][OH:9]
Reactant: N[C@H](CO)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: OC[C@@H](NO)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of (S)-phenylglycinol (15 g) and p-anisaldehyde (16.4 g) in methyl tert-butyl ether (150 mL) was heated to reflux, with a Dean-Stark trap attached, for about 3 hours. Tetrahydrofuran (60 mL) was added and the mixture cooled to 0° C. To this was added a solution of m-chloroperoxybenzoic acid (29.8 g) in methyl tert-butyl ether (80 mL), maintaining the temperature below 5° C. The mixture was stirred at 0° C. for about 3 hours. Then the reaction mixture was washed with 10% aqueous potassium carbonate (3×75 mL). The resulting organic layer was concentrated to a smaller volume. To this was added a solution of hydroxylamine hydrochloride (15.3 g) in methanol (19 mL) and water (27 mL), and the reaction was stirred at room temperature for about 3 hours. Heptane (30 mL) and water (30 mL) were added. The layers were separated, and the aqueous layer was washed with methyl tert-butyl ether (3×30 mL). The methanol was removed by vacuum distillation, and then methyl tert-butyl ether (75 ml) was added. After adjusting the pH to 7 with solid potassium carbonate, sodium chloride was added and the layers separated. The aqueous layer was further extracted with methyl tert-butyl ether (2×75 mL). The combined methyl tert-butyl ether extracts were filtered, concentrated to a small volume, and then heptane (70 mL) was added. The resulting slurry was stirred at room temperature for about 1 hour and then cooled to 0° C. After stirring for 1 hour, the mixture is filtered and the wetcake washed with heptane (20 mL). The wetcake was then dissolved in dichloromethane (100 mL) for use in the next step. 1H NMR (400 MHz, CDCl3) δ 3.83-3.91 (2H, m), 4.12 (1H, dd, J=6.9, 4.8 Hz), 4.84 (3H, br s), 7.27-7.36 (5H, m). 13C NMR (100 MHz, CDCl3) δ 63.8, 67.7, 127.5, 127.9, 128.4, 137.5.
Reaction SMILES: COC(/C=[CH:6]/[C:7]1[C:8](N)=[N:9][C:10](=[O:22])[N:11]([CH:21]=1)[C@@H:12]1[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[C@H:13]1O)=O.[OH2:24].[C:25](#[N:27])[CH3:26]>C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O.N1C=C(CC#N)N=N1>[C:25](/[CH:26]=[CH:6]/[C:7]1[C:8](=[O:24])[NH:9][C:10](=[O:22])[N:11]([CH:21]=1)[C@@H:12]1[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[CH2:13]1)#[N:27]
Reactant: COC(=O)/C=C/c1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)nc1N
Reactant: CC#N
Reactant: O
Agent: N#CCc1c[nH]nn1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: N#C/C=C/c1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h

Procedure:
2.00 g of 3', 5'-di-O-acetyl-(E)-5-(2-cyano-ethenyl) deoxyuridine (c) was dissolved in 20 ml of absolute acetonitrile, to which 9.2 ml of triethylamine, 1.12 ml of phosphorus oxychloride, and further 50 ml of 1.3 M triazole acetonitrile solution were added. The mixture was allowed to undergo a reaction at room temperature for 90 minutes. Water was added to the reaction mixture and it was left standing for 10 minutes. The reaction mixture was evaporated to dryness at reduced pressure and the residue was extracted in water-chloroform system. After the chloroform layer was dried with anhydrous sodium sulfate, chloroform was distilled away at reduced pressure. The residue was dissolved in 20 ml of dioxane, and after addition of aqueous ammonia, the mixture was left standing at room temperature for 12 hours. It was concentrated to dryness under reduced pressure. The residue was purified by C-18 reverse phase column chromatography on silica gel (20% acetone/water) to give 1.28 g of (E)-5-(2-cyanoethenyl) deoxyuridine (e).
Reaction SMILES: [C:1]1([N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([N:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:36][CH:35]=2)=[CH:30][CH:29]=1.N1[C:66]2[C:57](=[CH:58][CH:59]=[C:60]3[C:65]=2[N:64]=[CH:63][CH:62]=[CH:61]3)C=CC=1.[OH-].[K+]>C1(C)C(C)=CC=CC=1>[C:1]1([N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:20]=[CH:19][C:17]([N:18]([C:17]4[CH:19]=[CH:20][C:14]([C:11]5[CH:12]=[CH:13][C:8]([N:64]([C:65]6[CH:66]=[CH:57][CH:58]=[CH:59][CH:60]=6)[C:63]6[CH:62]=[CH:61][CH:6]=[CH:1][CH:2]=6)=[CH:9][CH:10]=5)=[CH:15][CH:16]=4)[C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][C:37]([N:40]([C:47]6[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=6)[C:41]6[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=6)=[CH:36][CH:35]=5)=[CH:30][CH:29]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Reactant: Ic1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccc(-c5ccc(N(c6ccccc6)c6ccccc6)cc5)cc4)c4ccc(-c5ccc(N(c6ccccc6)c6ccccc6)cc5)cc4)cc3)cc2)cc1
Reaction time: 6 h

Procedure:
A 250 milliliter 3-necked round bottom flask equipped with a mechanical stirrer, reflux condenser, and argon inlet was purged with argon and then charged with N,N-diphenylbenzidine (4.95 grams, 0.0147 mol), 4'-iodo-N,N-diphenyl-4-aminobiphenyl (11.0 grams, 0.0246 mol), xylene (15 milliliters), 1,10-phenanthroline (0.22 gram, 1.22 mmol), cuprous chloride (0.122 gram, 1.22 mmol), and potassium hydroxide flakes (11.04 grams, 0.197 mol). Under an argon atmosphere, the reaction mixture was heated to reflux with an oil bath and allowed to proceed at that temperature until chromatographic analysis indicated that the reaction was complete after approximately 6 hours. The oil bath was removed and 100 milliliters of toluene and 20 milliliters of water were then added with efficient stirring. The resulting two phase mixture was transferred into a separatory funnel and the layers separated. The organic phase was washed with water and treated under argon with 25 grams of alumina. After the alumina was filtered off, the organic phase was evaporated to remove the toluene. The above product compound was obtained by recrystallization of the residue from cyclohexane. Yield: 6.9 grams, m.p. 283.97° C., Tg 141° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][CH:13]([CH3:15])[CH3:14])[CH2:8][N:7]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:2].C(N(C(C)C)CC)(C)C.[CH:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:40][C:41](Cl)=[O:42])=[CH:35][CH:34]=1>ClCCl.C(Cl)(Cl)Cl>[CH2:39]([O:40][C:41]([N:12]([CH:13]([CH3:14])[CH3:15])[C@H:9]1[CH2:8][N:7]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:23])[CH2:11][CH2:10]1)=[O:42])[C:36]1[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)C[C@H]1CC[C@@H](NC(C)C)CN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C[C@H]1CC[C@@H](N(C(=O)OCc2ccccc2)C(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (2R,5R)-2-(2-ethoxy-2-oxoethyl)-5-(isopropylamino)piperidine-1-carboxylate (6.0 g) in dichloromethane (200 mL) was added diisopropylethylamine (19.1 mL), and thereto was further added dropwise under ice-cooling Z—Cl (13.0 mL) over a period of one hour. The mixture was stirred at room temperature for one hour, and then, the reaction solution was diluted with chloroform. The mixture was washed successively with an ice-cold aqueous potassium hydrogen sulfate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound (8.9 g) as a pale brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[N:20][OH:21])[CH:15]=[CH:14][C:13]=2[C:12]2[N:22](COCC[Si](C)(C)C)[N:23]=[C:24]([NH:25][CH:26]3[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:28][CH2:27]3)[C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O.N>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[N:20][OH:21])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:22][N:23]=[C:24]([NH:25][CH:26]3[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:33])=[O:34])[CH2:28][CH2:27]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3cc(C=NO)ccc3c21
Agent: N
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C=NO)ccc23)CC1
Temperature: 0 °C
Reaction time: 6 h
Yield: 44.1 %

Procedure:
A 50 ml round-bottomed flask equipped with a septum having a top-mounted argon intake is charged with 180 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde oxime in 15 ml of DCM. After cooling to 0° C. using an ice bath, 1.8 ml of TFA are added and the mixture is stirred at RT for 6 h. The mixture is concentrated under RP and the solid obtained is taken up in 50 ml of water and 2 ml of 0.75M aqueous ammonia solution. It is extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. Chromatography on silica gel (20-45 μm), eluting with a mixture of DCM and methanol (92.5/7.5 by vol.), gives 63 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde oxime (lemon yellow solid). MS (E/I): m/z=500 (M+); 1H NMR: 1.67 (m, 2H); 2.11 (m, 2H); 2.87 (s, 3H); 2.89 (m, 2H); 3.56 (m, 2H); 3.79 (m, 1H); 6.06 (d, J=7.8 Hz, 1H); 7.32 (broad t, J=7.6 Hz, 2H); 7.67 (m, 1H); 7.84 (broad s, 1H); 8.14 (broad d, J=8.5 Hz, 1H); 8.30 (s, 1H); 8.41 (d, J=8.5 Hz, 1H); 11.43 (s, 1H); 12.81 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3](=[O:25])[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:5](=[O:16])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][OH:15])[N:7]=1.[CH3:26][O-:27].[Na+]>CN(C=O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:4]2[C:3](=[O:25])[C:2]([O:27][CH3:26])=[N:7][N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH2:14][OH:15])[C:5]2=[O:16])=[CH:19][CH:20]=1
Reactant: C[O-]
Reactant: O=c1c(Br)nn(-c2ccccc2CO)c(=O)n1Cc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nn(-c2ccccc2CO)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
According to Scheme 2 Step 4: To a stirred solution of 6-bromo-4-(4-chlorobenzyl)-2-(2-(hydroxymethyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (0.330 g, 0.79 mmol) in DMF (10 ml) was added, dropwise, at 0° C., 2M solution of sodium methoxide (0.79 mmol, 0.40 ml). The mixture was stirred 1 hour at 0° C. then quenched with water and extracted with ethyl acetate (×3). The combined organic layers were successively washed with water then with brine, dried over MgSO4, filtered and concentrated. 270 mg (Yield=92.5%) of 4-(4-chlorobenzyl)-2-(2-(hydroxymethyl)phenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione were recovered. The product was pure enough to be used in the next step without any purification.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([CH:18]=O)=[CH:13][N:12]=1>>[C:1]1([C:7]2[C:8]([NH2:9])=[N:17][C:15]3[N:16]=[C:11]([NH2:10])[N:12]=[CH:13][C:14]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: Nc1ncc(C=O)c(N)n1
Product: Nc1ncc2cc(-c3ccccc3)c(N)nc2n1

Procedure:
Following the procedure of Example 1, phenylacetonitrile was reacted with 2,4-diamino-5-pyrimidinecarboxaldehyde to give the title compound; mp 317°-318° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([S:15][CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[N:12]2[CH:26]=[CH:27][N:28]=[C:11]2[CH:10]=1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].ClC1C=C(Cl)C=CC=1C1N=C(NCCS)N2C=CN=C2C=1>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([S:15][CH2:16][CH2:17][NH2:18])[N:12]2[CH:26]=[CH:27][N:28]=[C:11]2[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCCSc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Agent: SCCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCSc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12

Procedure:
2-{[7-(2,4-Dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl]thio}ethanamine trifluoroacetate (Example 47A) is prepared in analogy to Example 40A from tert-butyl (2-{[7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl]thio}ethyl)carbamate (Example 44A) (950 mg, 2.2 mmol) and trifluoroacetic acid (3.3 ml, 43 mmol) in dichloromethane (20 ml). The crude product consists of a 50:50 mixture of Example 47A and the regioisomeric product 2-{[7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl]amino}ethanethiol. The mixture is processed further without purification.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(O[CH2:20][CH:21]1[CH2:50][N:25]2[C:26]3[C:31]([C:32]([C:33]4[C:34](=[O:49])O[C:36](=[O:48])[C:37]=4[C:38]4[C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[N:40]([CH3:47])[CH:39]=4)=[C:24]2[CH2:23][CH2:22]1)=[CH:30][CH:29]=[CH:28][CH:27]=3)(=O)C.[N:51]1C(C)=CC(C)=CC=1C.[NH3:60]>ClCCl>[NH2:60][CH2:20][CH:21]1[CH2:50][N:25]2[C:26]3[C:31]([C:32]([C:33]4[C:34](=[O:49])[NH:51][C:36](=[O:48])[C:37]=4[C:38]4[C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[N:40]([CH3:47])[CH:39]=4)=[C:24]2[CH2:23][CH2:22]1)=[CH:30][CH:29]=[CH:28][CH:27]=3
Reactant: CC(=O)OCC1CCc2c(C3=C(c4cn(C)c5ccccc45)C(=O)OC3=O)c3ccccc3n2C1
Reactant: N
Reactant: Cc1cc(C)nc(C)c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CC(CN)CC4)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 mg of trifluoromethanesulfonic anhydride in 50 ml of dichloromethane were treated at 0° C. under a nitrogen atmosphere with a suspension of 150 mg of the pyrroledione product of Example 9 and 75 mg of collidine in 50 ml of dichloromethane. After 2 hours, 4 ml of 33% aqueous ammonia were added and the mixture was left to warm to room temperature overnight. The mixture was washed with water, dried and evaporated to dryness. The residue was purified by chromatography on silica gel with dichloromethane/methanol/acetone/water (90:18:3:2). Crystallization from dichloromethane/n-hexane gave 85 mg of 3-[7-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 160°-165° C.
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16](O)=O)=[CH:12][N:13]=2)CCCC1.[CH:28]1([NH:34][CH:35]2[CH2:40][CH2:39][CH:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:37][CH2:36]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C([O:49][C:50](=[O:60])CCSC1SC(N)=NC=1)C>>[CH:28]1([N:34]([C@H:35]2[CH2:36][CH2:37][C@H:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:39][CH2:40]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][CH2:16][C:50]([OH:60])=[O:49])=[CH:12][N:13]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: c1ccc(C2CCC(NC3CCCCC3)CC2)cc1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: CCOC(=O)CCSc1cnc(N)s1
Product: O=C(O)CCSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](c3ccccc3)CC2)s1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cyclohexyl-(4-phenyl-cyclohexyl)-amine and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([C:7]1[N:8]=[C:9](Cl)[C:10]2[N:11]([C:13](=[O:20])[N:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:15]=2)[CH:12]=1)([CH3:6])[CH3:5].[CH:23]([NH2:26])([CH3:25])[CH3:24]>C1COCC1.O>[CH3:1][O:2][C:3](=[O:22])[C:4]([C:7]1[N:8]=[C:9]([NH:26][CH:23]([CH3:25])[CH3:24])[C:10]2[N:11]([C:13](=[O:20])[N:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:15]=2)[CH:12]=1)([CH3:6])[CH3:5]
Reactant: CC(C)N
Reactant: COC(=O)C(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(Cl)n1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(NC(C)C)n1
Temperature: 25 °C

Procedure:
A solution of 215 mg of 2-(2-tert-butyl-8-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-2-methyl-propionic acid methyl ester and 388 mg of isopropylamine in THF (5.0 mL) was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with EtOAc. The organic extract was dried over sodium sulfate, filtered, and concentrated to provide 2-(2-tert-butyl-8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-2-methyl-propionic acid methyl ester as a light yellow solid. MS (M+H+)=350.4.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])[N:6]=1.Br[CH2:24][CH2:25][CH:26]1[O:30][CH2:29][CH2:28][O:27]1.Cl>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[N:6]=[C:7]([O:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([O:18][CH2:24][CH2:25][CH:26]2[O:30][CH2:29][CH2:28][O:27]2)=[O:17])[N:8]=1
Reactant: COc1cc(OC)nc(Oc2ccccc2C(=O)O)n1
Reactant: BrCCC1OCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2ccccc2C(=O)OCCC2OCCO2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
10 Milliliters of N,N-dimethylformamide in which 0.22 g of 60% sodium hydride in oil has been suspended was mixed with 5 ml of N,N-dimethylformamide solution of 1.38 g of 2-(4,6-dimethoxypyrimidin-2-yl)oxy benzoic acid. After stirring the mixture at room temperature for 30 minutes, 10 ml of N,N-dimethylformamide solution of 1.81 g of 2-(2-bromoethyl)-1,3-dioxolane was added thereto. The resulting solution was stirred at 100° to 110° C. for 2 hours. The reaction solution was allowed to cool, poured into diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer separated from the aqueous layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (mfd. by Merck & Co., Inc., solvent: chloroform) to obtain 1.20 g of 2-(1,3-dioxolan-2-yl)ethyl 2-(4,6-dimethoxypyrimidin-2-yl)oxybenzoate [present compound (V-2)].
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=O)=[CH:15][CH:16]=2)[CH2:11][CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][C:23]1[CH:40]=[CH:39][C:26]2[N:27]([CH2:37][CH3:38])[C:28](=[O:36])[C:29]([CH3:35])([CH3:34])[C:30](=[O:33])[N:31]([CH3:32])[C:25]=2[CH:24]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][NH:21][CH2:22][C:23]3[CH:40]=[CH:39][C:26]4[N:27]([CH2:37][CH3:38])[C:28](=[O:36])[C:29]([CH3:35])([CH3:34])[C:30](=[O:33])[N:31]([CH3:32])[C:25]=4[CH:24]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN)ccc21
Reactant: O=Cc1ccc2c(c1)CCC(=O)N2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCc3ccc4c(c3)CCC(=O)N4Cc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-carbaldehyde (0.205 g) was added to a methanol solution (10 ml) of 7-(aminomethyl)-1-ethyl-3,3,5-trimethyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (0.213 g). The mixture was stirred at room temperature overnight. Sodium borohydride (0.022 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The liquid was then condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol=9:1). The purified product was condensed under reduced pressure to give the title compound(0.400 g) as a white amorphous.