Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[C:4]2[N:9]([CH:10]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:11].C(N(C(C)C)CC)(C)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].P([O-])(O)(O)=O.[K+]>C1(C)C=CC=CC=1.C1COCC1>[CH3:12][C:3]1[C:2]([O:1][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:10][N:9]2[C:4]=1[C:5](=[O:11])[NH:6][CH:7]=[N:8]2
Reactant: Cc1c(O)cn2nc[nH]c(=O)c12
Reactant: CC(C)(C)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1c(OC(=O)C(C)(C)C)cn2nc[nH]c(=O)c12
Temperature: 5 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
A mixture of 2.9 kg 6-hydroxy-5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one, 4.6 kg of diisopropylethylamine and 17.0 kg of THF was cooled to 0-10° C., then treated with 2.6 kg pivaloyl chloride at a rate to maintain the temperature <20° C. The mixture was stirred until the reaction was complete by HPLC, then 17.8 kg of toluene was added, followed by 20.6 kg of 15% aqueous potassium dihydrogen phosphate solution. The phases were separated and the organic was washed with 10.2 kg water. The organic phase was filtered, then distilled under vacuum with a maximum temperature of 65° C. Additional toluene can be added and distillation continued until the concentration of THF was <8%, and the total reactor volume was reduced to 31 L. The resulting slurry was cooled to 20-25° C. and treated with 20.3 kg heptane over 1.5 h. The slurry was cooled to 0-5° C. and held for 1 h, then the solid was collected by filtration and dried to yield 4.0 kg of 2,2-dimethyl-propionic acid 5-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-6-yl ester with a purity of 95-99%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[S:51][C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[S:51]1[C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=[C:50]1[NH:49][C:40](=[O:42])[C@@H:39]([C:31]1[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=1)[CH2:43][CH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: Nc1nc2ccccc2s1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1Cl
Temperature: 0 °C
Yield: 72.6 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzothiazole (136 mg, 0.91 mmol) and pyridine (0.15 mL, 1.81 mmol), and the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (205 mg, 73%) as a white foam: [α]23589=−38.6° (c=0.044, chloroform); EI-HRMS m/e calcd for C22H23ClN2O3(M+) 462.0839, found 462.0839.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[Cl:37]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11]([Cl:37])=[N:10][N:9]=[C:8]2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nncn1Cc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nnc(Cl)n1Cc1ccc(Cl)cc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
To a solution of Boc-protected triazole from Example 3 (4.344 g, 12 mmol) in 20 mL of THF at −60° C. under argon was slowly added a solution of n-butyl lithium (1.6M) in hexane (7.5 mL, 1.2 eq.) and stirred at −60° C. for 30 minutes. To the mixture was added a suspension of N-chlorosuccinimide (4.67 g, 2.9 eq.) in 20 mL of THF and the mixture was kept at −60° C. for 1 hr before warming up to RT overnight. The reaction mixture was treated with sat. aqueous NaHCO3 (30 mL), then extracted with EtOAc (2×40 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Flash chromatography purification ((Hex/EtOAc) provided the desired product (1.011 g, 21.2%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:22]=2)=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:22]=2)=[CH:15][C:14]=1[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1noc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc2c(C)noc2c1
Yield: 36.9 %

Procedure:
A mixture of 6-bromo-3-methyl-1,2-benzisoxazole (11 mg), N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-pyrrolidin-1-yl-isonicotinamide (Intermediate 13, 15 mg) and aqueous sodium carbonate (0.5M, 0.25 ml) in anhydrous DME (1 ml) was degassed then stirred under nitrogen. A solution of tetrakis(triphenylphosphine)palladium(0) (2.5 mg) in DME (0.25 ml) was added and the mixture was stirred at 80° for 16 h. The solvent was removed under vacuum and the residue was partitioned between dichloromethane and water. The organic layer was separated using a hydrophobic filter, the solvent was evaporated and the residue was purified by column chromatography on silica, eluting with a cyclohexane-ethyl acetate gradient to give the title compound as an oil (5.6 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17].CCN=C=N[CH2:27][CH2:28][CH2:29][N:30](C)C.Cl.[CH3:34][N:35]([CH:37]=[O:38])C>CN(C)C1C=CN=CC=1>[C:29]([C:28]1[C:37](=[O:38])[NH:35][C:34]2[C:11]([CH:27]=1)=[C:2]([O:17][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH:14]=1)[CH:3]=[CH:4][C:5]=2[CH3:6])#[N:30]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cccc(OCc2ccc3ccccc3n2)c1
Reactant: CN(C)C=O
Agent: CN(C)c1ccncc1
Agent: Cl
Product: Cc1ccc(OC(=O)c2cccc(OCc3ccc4ccccc4n3)c2)c2cc(C#N)c(=O)[nH]c12
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A liquid mixture of 0.838 g (3 mmol) of 3-(2-quinolinylmethoxy)benzoic acid, 0.601 g (3 mmol) of 3-cyano-5-hydroxy-8-methylcarbostyryl, 50 ml of DMF, 0.931 g (6 mmol) of WSC·HCl and 0.73 g (0.6 mmol) of 4-dimethylaminopyridine was stirred under an argon gas stream at a bath temperature of 50° C. for 2 days. The solvent was distilled off from the reaction mixture under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with a 2:1 mixed solvent of CHCl3 and MeOH. The extract was washed with water, dried over MgSO4 and then concentrated. The concentrate was allowed to stand overnight, whereby 0.495 g of the title compound was obtained as yellow powder (yield: 35.8%).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH3:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:41])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[C:36]4[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=4)[N:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[S:15][CH:16]=1.S(OC)(O[CH3:46])(=O)=O>C1COCC1.CN(C=O)C>[CH3:46][N:17]([C:14]1[S:15][CH:16]=[C:12]([CH3:11])[N:13]=1)[C:18](=[O:41])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1cc2nccc(Oc3ccc(CC(=O)Nc4nc(C)cs4)cc3)c2cc1OC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(CC(=O)N(C)c4nc(C)cs4)cc3)c2cc1OC
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Under an atmosphere of argon, a 1M solution of lithium hexamethyldisilazane in THF (0.52 ml) was added dropwise to a stirred solution of N-(4-methylthiazol-2-yl)-2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]acetamide (0.205 g) in DMF (4 ml) that had been cooled to −5° C. After 5 minutes, a solution of dimethyl sulphate (0.049 ml) in DMF (1 ml) was added dropwise and the resultant mixture was stirred at 0° C. for 30 minutes. The mixture was evaporated and the residue was purified by preparative HPLC using a Waters ‘Xterra’ reversed-phase column (5 microns silica) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound (0.105 g); 1H NMR: (DMSOd6) 2.29 (d, 3H), 3.73 (s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 4.17 (s, 2H), 6.5 (d, 1H), 6.82 (s, 1H), 7.52 (d, 2H), 7.4 (s, 1H), 7.42 (d, 2H), 7.5 (s, 1H), 8.49 (d, 1H); Mass Spectrum: M+H+ 450.
Reaction SMILES: ClC1C2C3CN(C)CCC=3NC=2C=CC=1C.[Cl:17][C:18]1[C:19]([CH3:32])=[CH:20][C:21]2[C:22]3[CH2:30][N:29]([CH3:31])[CH2:28][CH2:27][C:23]=3[NH:24][C:25]=2[CH:26]=1.[H-].[Na+].[CH3:35][C:36]1([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH2:38][O:37]1>CN(C=O)C>[Cl:17][C:18]1[C:19]([CH3:32])=[CH:20][C:21]2[C:22]3[CH2:30][N:29]([CH3:31])[CH2:28][CH2:27][C:23]=3[N:24]([CH2:35][C:36]([C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)([OH:37])[CH3:38])[C:25]=2[CH:26]=1
Reactant: Cc1cc2c3c([nH]c2cc1Cl)CCN(C)C3
Reactant: CC1(c2cccnc2)CO1
Agent: Cc1ccc2[nH]c3c(c2c1Cl)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c3c(n(CC(C)(O)c4cccnc4)c2cc1Cl)CCN(C)C3
Reaction time: 0.25 h
Yield: 11.1 %

Procedure:
A mixture of 9-chloro-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and 7-chloro-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.00 g, 8.5 mmol) was dissolved in DMF (15 mL). Sodium hydride (1.708 g, 42.71 mmol) was added at 0-10° C. and stirred at the same temperature for 15 min., 3-(2-methyloxiran-2-yl)pyridine (2.309 g, 17.08 mmol) was added dropwise into the reaction mixture and the mixture was stirred at RT for 16 h. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water (100 mL) and extract with EtOAc (300 mL). The organic layer was washed with water (5×100 mL). The organic layer dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude. The crude product was purified by reverse phase column chromatography to obtain 350 mg of 1-(7-chloro-2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.68 (m, 3H), 7.95 (m, 1H), 7.29 (d, 1H), 6.9 (m, 1H), 4.68 (dd, 1H), 4.38 (m, 2H), 4.32 (dd, 1H), 3.9 (m, 1H), 3.52 (m, 2H), 3.25 (m, 1H), 3.12 (s, 3H), 2.35 (d, 3H), 1.83 (d, 3H). Separation by chiral HPLC provided enantiomers II-123a-b.
Reaction SMILES: Cl.N[C@H](C(OC)=[O:9])CC(C)C.N[C@H](C(O)=O)CC(C)C.CCC(OC(C[N+](C)(C)C)CC([O-])=O)=O.[CH:36]1([N:42]=[C:43]=[N:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>CC(C)=O.N1C=CC=CC=1>[C:43]([NH:42][CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)([NH:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)=[O:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CCC(=O)OC(CC(=O)[O-])C[N+](C)(C)C
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
To 1.82 grams (0.01 moles) of methyl leucinate hydrochloride 0.8 cc (0.01 moles) of pyridine in 15 cc of acetone were added. Pyridine hydrochloride precipitated, which was filtered off. To the methyl ester of leucine free base was added an aqueous solution of 2.54 grams (0.01 moles) of propionyl carnitine in 3.5 cc. Then, 4.12 grams of dicyclohexyl carbodiimide dissolved in 5 cc of acetone were slowly added under stirring to the solution. A precipitate of dicyclohexylurea formed which after 16 hours was filtered off. The mother liquors were concentrated under vacuum. The raw product thus obtained was crystallized from methanol-acetone, furnishing a solid, very hygroscopic product (yield: 75%).
Reaction SMILES: [F:1][C:2](I)([F:7])[C:3]([F:6])([F:5])[F:4].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1>[Cu].CS(C)=O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4])=[CH:12][CH:11]=1.[I:16][C:13]1[CH:14]=[CH:15][C:10]([C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4])=[CH:11][CH:12]=1
Reactant: Brc1ccc(I)cc1
Reactant: FC(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: CS(C)=O
Product: FC(F)(F)C(F)(F)c1ccc(Br)cc1
Product: FC(F)(F)C(F)(F)c1ccc(I)cc1

Procedure:
Pentafluoroethyl iodide (521 mg, 2.12 mmol) was condensed into a vial containing 1-bromo-4-iodobenzene (300 mg, 1.06 mmol), copper(0) powder (135 mg, 2.12 mmol), and DMSO (5 mL). The vial was then sealed and subjected to microwave irradiation at 150° C. for 60 min. GC-MS proved consumption of the starting material yielding both 1-bromo-4-pentafluoroethylbenzene and 1-iodo-4-pentafluoroethylbenzene intermediates. The mixture (1.06 mmol) was transferred to a 250 mL round bottom flask and 3-p-tolyl-1H-[1,2,4]triazole (169 mg, 1.06 mmol), Cs2CO3 (1.38 g, 4.24 mmol), CuI (202 mg, 1.06 mmol), 8-hydroxyquinoline (2 mg, 0.011 mmol), and DMF/H2O (12 mL; 10:1 solution) were added. The solution was stirred at reflux at 160° C. for 6 h. Upon completion, the cooled contents were poured into H2O and precipitation was allowed for 1 h. The precipitate was collected by vacuum filtration and dried overnight in a 45° C. vacuum oven. The crude 1-(4-pentafluoroethylphenyl)-3-p-tolyl-1H-[1,2,4]triazole intermediate was used in step 2 without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][O:12]C(=O)C)[C:9]=1[Cl:10])=[O:4].[OH-].[Na+]>O1CCOCC1.O>[C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][OH:12])[C:9]=1[Cl:10])([OH:4])=[O:2]
Reactant: COC(=O)c1scc(COC(C)=O)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1scc(CO)c1Cl
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a solution of 2-methoxycarbonyl-3-chloro-4-(acetoxymethyl)thiophene (83 g, 0.33 mol) in 1,4-dioxane (350 mL) was added a solution of sodium hydroxide (26.5 g, 0.66 mol) in water (200 mL) and the mixture stirred at ambient temperature. After 1 hour the dioxane was removed in vacuo and the aqueous solution washed with ethyl acetate (2×100 mL). The aqueous layer was brought to pH 2 by addition of concentrated HCl, then extracted with n-butanol (4×200 mL). The combined extracts were concentrated and the resulting solid dried in vacuo to afford 63 g (90% yield) of 2-carboxy-3-chloro-4-(hydroxymethyl)thiophene as a tan powder; NMR (DMSO-d6) 7.7 (s, 1), 4.4 (s, 2) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=[O:2].[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([CH2:28]C#N)=[CH:24][CH:23]=1>>[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([C:28]2[O:2][N:1]=[C:4]3[CH:9]=[CH:8][C:7]([C:10]4[N:14]([C:15]5[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=5)[N:13]=[CH:12][CH:11]=4)=[CH:6][C:5]=23)=[CH:24][CH:23]=1
Reactant: Cc1ccc(CC#N)cc1
Reactant: Cc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Product: Cc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(C)cc4)cc23)cc1

Procedure:
The title compound, yellow solid (35 mg, 27%), MS (ISP) m/z=366.2 [(M+H)+], mp 190° C., was prepared in accordance with the general method of example 1 from 5-(4-nitro-phenyl)-1-p-tolyl-1H-pyrazole (intermediate E) (100 mg, 353 μmol) and commercially available 2-(p-tolyl)-acetonitrile.
Reaction SMILES: [NH2:1][C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].CN1CCOCC1.[Cl-].[CH3:25][O:26][C:27](=[O:32])[CH2:28][C:29](O)=[O:30]>C(#N)C>[CH3:25][O:26][C:27](=[O:32])[CH2:28][C:29]([NH:1][C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]1=[O:8])=[O:30]
Reactant: NC1(c2ccccc2)C(=O)NC(=O)NC1=O
Reactant: COC(=O)CC(=O)O
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COC(=O)CC(=O)NC1(c2ccccc2)C(=O)NC(=O)NC1=O
Yield: 68 %

Procedure:
2 g 5-amino-5-phenyl-2,4,6-trioxopyrimidine is dissolved in 20 ml acetonitrile and admixed with 1.5 ml N-methyl-morpholine. 1.03 ml malonic acid monomethyl ester chloride is added dropwise while stirring and cooling on ice and the suspension is stirred for 2 hours at room temperature. The precipitate is suction filtered, washed with acetonitrile, water and again with acetonitrile and dried. 1.97 g (68%) of the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.[OH-].[Na+]>>[O:14]1[CH2:15][CH2:16][N:1]([C:2]2[CH:10]=[CH:9][C:5]3[O:6][CH:7]=[CH:8][C:4]=3[CH:3]=2)[CH2:12][CH2:13]1
Reactant: ClCCOCCCl
Reactant: Nc1ccc2occc2c1
Agent: [Na+]
Agent: [OH-]
Product: c1cc2cc(N3CCOCC3)ccc2o1

Procedure:
5-Aminobenzo[b]furan and bis-(2-chloroethyl)ether and 40% aqueous NaOH (0.073 mole) are stirred and heated to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]2[C:7]([NH:8][C:9]3[C:10]([C:19](O)=[O:20])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:22](C1C=C2C(N=C3C(=C2[Cl:39])C=CC=C3C(Cl)=O)=CC=1)([O-])=O.[CH3:43][N:44]([CH3:48])[CH2:45][CH2:46][NH2:47].N>C1(O)C=CC=CC=1>[ClH:39].[ClH:39].[CH3:43][N:44]([CH3:48])[CH2:45][CH2:46][NH:47][C:19]([C:10]1[C:9]2[C:14](=[C:15]([NH2:22])[C:16]3[C:7]([N:8]=2)=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:17]=3)[CH:13]=[CH:12][CH:11]=1)=[O:20]
Reactant: O=C(Cl)c1cccc2c(Cl)c3cc([N+](=O)[O-])ccc3nc12
Reactant: O=C(O)c1cccc2c(=O)c3cc([N+](=O)[O-])ccc3[nH]c12
Reactant: CN(C)CCN
Agent: N
Solvent: Oc1ccccc1
Product: CN(C)CCNC(=O)c1cccc2c(N)c3cc([N+](=O)[O-])ccc3nc12
Product: Cl

Procedure:
The above 7-nitro-4-carboxyacridanone was converted to 7-nitro-9-chloroacridine-4-carbonyl chloride (II, Z=Cl, R2 =7-NO2, R3 =Cl), and treated with N,N-dimethylethylenediamine followed by dry ammonia in phenol by the methods outlined in Example A above to give N-(2-dimethylaminoethyl)-9-amino-7-nitroacridine-4-carboxamide dihydrochloride (compound 20 of Table I), m.p. 316°-318° C.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]([OH:24])=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([NH2:31])[CH2:28][CH2:29][CH3:30]>>[CH:1]1([C:6]([N:8]2[CH2:9][CH:10]([C:22]3[O:24][N:31]=[C:27]([CH2:28][CH2:29][CH3:30])[N:26]=3)[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:13]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: CCCC(N)=NO
Product: CCCc1noc(C2CC(c3ccc(CC)cc3)CN(C(=O)C3CCCC3)C2)n1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 22 mg (0.22 mmol, 1.1 eq.) of N′-hydroxybutanimidamide were reacted according to the General Method 1. Yield: 12 mg (15% of theory)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1.Br[CH2:14][C:15]1[CH:34]=[CH:33][C:18]2/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:20]2=[C:21]([CH:24]=1)[O:22][CH2:23][C:17]1[CH:16]=[C:15]([CH2:14][N:8]3[C:7]4[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=4[N:5]=[C:4]3[CH2:3][O:2][CH3:1])[CH:34]=[CH:33][C:18]=1/[C:19]/2=[C:29](/[CH3:32])\[C:30]#[N:31]
Reactant: COCc1nc2ccccc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: COCc1nc2ccccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 86.8 %

Procedure:
Using 2-methoxymethyl-1H-benzo[d]imidazole (Journal of Organometallic Chemistry, 2008, vol. 26, p 3889; 244 mg, 1.51 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (550 mg, 1.54 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (576 mg, 87%) was obtained.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([NH:16][CH2:17][CH:18]=[O:19])[CH:14]=[CH2:15].C1C=CC=CC=1>C(OCC)C.CCCCC>[CH2:13]([N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1)=[O:12])[CH:14]=[CH2:15]
Reactant: C=CCNCC=O
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Solvent: CCCCC
Solvent: c1ccccc1
Solvent: CCOCC
Product: C=CCN(CC=O)C(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 0.25 h

Procedure:
A mixture of 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (8.7 grams), the diethyl acetate of 2-allylaminoacetaldehyde (8.0 grams) and benzene (30 ml) was charged into a glass reaction flask equipped with a mechanical stirrer and reflux condenser. The reaction mixture was heated with stirring for a period of about 15 minutes. After this time the reaction mixture was stripped of benzene to yield an oil. The oil was dissolved in a diethyl ether-pentane mixture and was filtered through diatomaceous earth. The filtrate was stripped of solvent to yield the desired product the diethyl acetal of 2-[1-allyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde as a dark oil.
Reaction SMILES: [F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]C(=O)C)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].[CH3:19][C:20]1[O:27][C:23](/[CH:24]=[N:25]\O)=[CH:22][CH:21]=1>N1C=CC=CC=1.CC(C)=O>[F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]/[N:25]=[CH:24]\[C:23]2[O:27][C:20]([CH3:19])=[CH:21][CH:22]=2)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: Cc1ccc(/C=N\O)o1
Reactant: CCOC(=O)C1(F)C(=O)NC(=O)NC1OC(C)=O
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCOC(=O)C1(F)C(=O)NC(=O)NC1O/N=C\c1ccc(C)o1
Temperature: 25 °C
Reaction time: 96 h
Yield: 18.5 %

Procedure:
In 75 ml of pyridine-acetone (pyridine:acetone=2:1) were dissolved 20 g (76 mmol) of ethyl 5-fluoro-6-acetoxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and 11.4 g (91 mol) of (Z)-5-methylfurfuraldoxime, and the solution was stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure, and the residue was treated with water. Crystals precipitated were collected by filtration and washed with water. The crystals were dried under reduced pressure and dissolved in acetone, and insoluble matters were filtered off. The filtrate was concentrated, and the residue was chromatographed on silica gel with chloroform-acetone (7:1), followed by recrystallization from ethyl acetate-hexane to yield 4.6 g of ethyl 5-fluoro-6-[(Z)5-methylfurfurylideneaminooxy]-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate. m.p. 163°-164° C.