Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35]>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 25 °C
Yield: 7 %

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of dichloromethane. 85 μl (2 molar equivalent) of triethylamine and 78 μl (2 molar equivalent) of isobutyl chloroformate were respectively added. The reaction mixture was maintained at room temperature for 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5) to provide 92 mg (yield=7%) of the desired product (formula shown hereinabove) as an orange powder which was characterized as follows:
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[NH3:32]>CO>[N:1]1([C:10]2[S:14][C:13]([C:15]([NH2:32])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:30])([F:31])[F:29])[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1OC(F)(F)F
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1OC(F)(F)F
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 26.8 mg of methyl 5-(1H-imidazo[4,5-c]pyridin-1-yl)-3-{[2-(trifluoromethoxy)benzyl]oxy}thiophene-2-carboxylate and 5 ml of a saturated solution of ammonia in methanol is stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture is concentrated to dryness, the resulting residue is dissolved in ethyl acetate and purified by flash chromatography [Silica gel, eluent: ethyl acetate/methanol, elution gradient of 100/0 (v/v) to 95/5 (v/v)] to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:57])[C:5](=[N:55]O)[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C@H:16]1[O:45][C@H:44]([CH2:46][O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:17]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2].[Al]>O1CCCC1.O>[CH2:1]([O:3][C:4](=[O:57])[CH:5]([NH2:55])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C@H:16]1[O:45][C@H:44]([CH2:46][O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@@H:35]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@H:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:17]1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1c([C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[nH]c2ccccc12)=NO
Agent: [Al]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(N)Cc1c([C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[nH]c2ccccc12
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
First, 1.73 g (2.25 mmol) of 2-hydroxyimino-3-[2-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)indole-3-yl]propionic acid ethyl ester [compound (IX) wherein R1 to R4 are benzyl and R6 is ethyl] was dissolved in tetrahydrofuran (225 ml)-water (25 ml). Then, aluminum amalgam prepared from 8.50 g (0.32 mmol) of aluminum was added to the mixture and stirred at 55° C. for about 0.5 hour. Then, the reacted solution was filtrated on Celite which was then washed with 10% ethanol-dichloromethane. The filtrate was then concentrated and the residue was fractionated by column chromatography on silica gel [silica gel: Merck Kieselgel 60 (230-400 mesh ASTM); elution solvent: 3% methanol-dichloromethane] to give 1.54 g (yield 90%) of 2-amino-3-[2-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)indole-3-yl]propionic acid ethyl ester [compound (x) wherein R1 to R4 are benzyl and R6 is ethyl].
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:28]1([C:34]2[CH:43]=[N:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:31]2[CH2:32][CH2:33][N:28]([C:34]3[CH:43]=[N:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)[CH2:29][CH2:30]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cnc4ccccc4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(piperazin-1-yl)-quinoxaline.
Reaction SMILES: C[O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.ClC1C=CC(C(O)=O)=CC=1.[O-:28][C:29]#[N:30].[Na+]>C1(C)C=CC=CC=1>[CH:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:29]([NH2:30])=[O:28])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:3](=[O:2])[CH2:4][C:5]=2[CH:6]=1
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Reactant: N#C[O-]
Agent: O=C(O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A mixture of 100 gms of 10-methoxyiminostilbene in 1000 mL of toluene containing 351 gms of para-chlorobenzoic acid and 370 gms of sodium cyanate were heated to reflux and refluxed for 12 hours. The reaction mixture was then cooled to room temperature and filtered. The clear toluene filtrate was then washed with 5% sodium carbonate solution followed by water. The toluene layer was then added to 1000 mL of 2N hydrochloric acid and the mixture was heated at 75-80° C. for a period of 2 hours under good agitation. It was then cooled to 0-5° C., maintained for 2 hours and the product oxcarbazepine was separated by filtration. This was then purified once in a dichloromethane methanol mixture to furnish 44 gms of pure oxcarbazepine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:4][C:5]([O:16][CH3:17])=[C:6]([C:12](OC)=[O:13])[C:7]=1[C:8](OC)=[O:9].O.[NH2:25][NH2:26].Cl>O>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:26][NH:25][C:12](=[O:13])[C:6]=2[C:5]([O:16][CH3:17])=[N:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1c(OC)nc(-c2ccccc2)c(N)c1C(=O)OC
Reactant: NN
Agent: Cl
Solvent: O
Product: COc1nc(-c2ccccc2)c(N)c2c(=O)[nH][nH]c(=O)c12
Temperature: 100 °C

Procedure:
To 0.8 g of 3-amino-4,5-dimethoxycarbonyl-6-methoxy-2-phenylpyridine was added 4 ml of hydrazine monohydrate. The mixture was heated at 100° C. in a stream of nitrogen for 1 hour. Under ice-cooling, water was added to the reaction mixture, followed by neutralization with hydrochloric acid for adjustment to pH 3. The resulting yellow crystalline precipitate was collected by filtration.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C1N=CN([C:14](N2C=NC=C2)=[O:15])C=1>CN(C)C=O>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:14]1=[O:15]
Reactant: Nc1ccccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2[nH]1
Reaction time: 22 h
Yield: 98 %

Procedure:
To a stirred solution of 1,2-phenylenediamine (10.00 g, 0.092 mol) in dimethylformamide (150 cm3) was added 1,1′-carbonyldiimidiazole (CDI, 14.99 g, 0.092 mol). After 22 hours, the reaction mixture was evaporated and then slurried in ethyl acetate. The resulting mixture was filtered, washed with ethyl acetate, and the residue dried in vacuo to give 1,3-dihydrobenzoimidazol-2-one (12.10 g, 98%) as a white solid:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[CH:4][N:3]=1.Br[CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:4][N:3]=1
Reactant: Nc1ncc(O)c(N)n1
Reactant: CCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCC(CC)COc1cnc(N)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 0.50 gram (0.003 mole) of 2,4-diamino-5-hydroxypyrimidine hydrosulfate salt, 0.47 gram (0.007 mole) of 1-bromo-2-ethylbutane and 0.95 gram (0.007 mole) of anhydrous potassium carbonate in 5 mL of N,N-dimethylformamide was heated at 84°-86° C. for about two hours. After this time the reaction mixture was allowed to cool to ambient temperature as it stirred during about a 16 hour period. The reaction mixture was then stirred with 50 mL of water and 50 mL of methylene chloride. The methylene chloride layer was separated and washed with 50 mL of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a solid residue. The residue was recrystallized from 2:1 water and methanol, yielding, when dried, 0.20 gram of 2,4-diamino-5-(2-ethylbutoxy)pyrimidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]([CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=2)[CH:7]=1)=[O:4]>C(O)C.O1CCCC1.[C].[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]([CH3:22])[C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:24])([F:1])[F:23])[CH:11]=[CH:10][CH:9]=2)=[N:14][CH:15]=1
Reactant: CN(c1cccc(NC(=O)C(F)(F)F)c1)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(c1cccc(NC(=O)C(F)(F)F)c1)c1ccc(N)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
2,2,2-Trifluoro-N-{3-[methyl(5-nitropyridin-2-yl)amino]phenyl}acetamide (5.00 g, 14.7 mmol) was dissolved in ethanol (66 mL)/tetrahydrofuran (33 mL), 10% palladium-carbon (500 mg) was added, and the mixture was stirred at room temperature for 3 hr under a hydrogen atmosphere. The insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The precipitate was collected by filtration to give the title compound (3.60 g, 79%) as a pale-violet powder.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([OH:20])[C:10]([C@@H:12]([OH:19])[C@H:13]([OH:18])[C:14]([CH2:16][OH:17])=[O:15])=O.[BH3-]C#N.[Na+]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C@:14]3([CH2:16][OH:17])[O:15][C@:10]2([C@H:12]([C@@H:13]3[OH:18])[OH:19])[CH2:9][OH:20])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(CO)[C@@H](O)[C@H](O)C(=O)CO
Agent: [BH3-]C#N
Agent: [Na+]
Product: OC[C@]12O[C@](CO)([C@@H](O)[C@@H]1O)N2c1ccc(F)cc1
Reaction time: 8 h
Yield: 6.7 %

Procedure:
A solution of 4-fluoroaniline (30 g, 0.27 mol) and 15.46 mL of HOAC in 100 mL of MEOH was added to 5-keto-D-fructose (57.7 g, 0.324 mol) in 350 mL of MEOH. To this suspension was added 32 g of NaCNBH3 (0.5 mol). The tan mixture was heated at reflux. After reacting overnight, the solution was cooled, the MeOH was largely evaporated and the residue was dissolved in ca. 200 ml. of water and treated with ca. 500 mL of Dowex 50W-X8 cation exchange resin. After stirring for 2 h, the resin and solution were added to a column with a bed of 150 mL more resin, and the supernatant was eluted. The resin was then washed with another ca. 500 mL of water. The column was then eluted with 1N NH4OH, and the water of the fractions containing the products was removed under reduced pressure. The residue was purified on two Waters Prep 500.HPLC columns (hexane/iPrOH/NH4OH, 65:34:1) to give fractions highly enriched in all three stereoisomers. The fastest eluting material was recrystallized from iPrOH/hexane to give 4.9 g white needles (7%) of the mannitol isomer (Formula XVII). Both C-13 and H-1 NMR are consistent with the assigned structure. M.p. 198° C. (browning), 205°-207° C.; (melting with decomposition).
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[CH:16][C:15]3=[CH:18][CH:19]=[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([S:27](=[O:34])(=[O:33])[NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:22]=4)[N:14]3[N:13]=2)[CH:6]=1)C.O>[OH-].[Na+].C1COCC1>[C:29]([NH:28][S:27]([C:23]1[CH:22]=[C:21]([C:20]2[N:14]3[C:15]([CH:16]=[N:17][C:12]([NH:11][C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[C:4]([OH:35])=[O:3])=[N:13]3)=[CH:18][CH:19]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:33])=[O:34])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)c1cccc(Nc2ncc3ccc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)n3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4cccc(C(=O)O)c4)nn23)c1

Procedure:
3-[7-(3-tert-Butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-benzoic acid ethyl ester (77.0 mg, 0.156 mmol) was taken up in 2 M of Sodium hydroxide in water (2.00 mL, 5.00 mmol) and 2 ml THF, heated for 72 h at 60° C. Concentrated down THF, neutralized aq layer, and extracted with CH2Cl2. Dried, filtered, and concentrated. Took residue up in DMSO and purified by Gilson RP-HPLC. LCMS=465.9 (M+H), HPLC rt=3.199, purity=98%. 1H NMR (400 MHz, CDCl3, δ, ppm): 12.95 (bs, 1H), 9.74 (s, 1H), 9.07 (s, 1H), 8.42 (d, J=7.6 Hz, 1H), 8.44 (s, 1H), 8.26 (s, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.72 (dd, J=8.3 Hz, 7.6 Hz, 1H), 7.61 (s, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.47 (dd, J=7.6 Hz, 8.3 Hz, 1H), 7.24 (d, J=4.6 Hz, 1H), 7.04 (d, J=4.9 Hz, 1H), 1.1 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]1)[CH3:2].N1CC[C@@H](NC(=O)OC(C)(C)C)C1.ICC>>[CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CCI
Product: CCN1CC[C@@H](NC(=O)OC(C)(C)C)C1

Procedure:
Prepared by proceeding in a similar manner to intermediate 82, starting from tert butyl (R)-pyrrolidin-3-yl-carbamate and iodoethane as a light coloured gum.
Reaction SMILES: [CH3:1][S:2][CH:3]1[NH:6][C:5](=[O:7])[CH2:4]1.Br[CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:19])=[CH:14][CH:13]=1>>[CH3:1][S:2][CH:3]1[N:6]([CH2:9][C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[O:19])=[CH:16][CH:17]=2)[C:5](=[O:7])[CH2:4]1
Reactant: COc1ccc(COC(=O)c2ccc(C#CCBr)cc2)cc1
Reactant: CSC1CC(=O)N1
Product: COc1ccc(COC(=O)c2ccc(C#CCN3C(=O)CC3SC)cc2)cc1

Procedure:
4-Methylthioazetidin-2-one (470 mg., 4 mmole) and 3-bromo-1-[p-(p-methoxybenzyloxycarbonyl)-phenyl]-prop-1-yne (1.44 g., 4 mmole) were converted into the title compound using the process described in Example 22.1. The title compound was obtained as a colourless gum (410 mg., 27% yield). νmax (CHCl3): 1760 (β-lactam C=O), 1720 (ester C=O), 1610 and 1515 (aromatic C=C) cm-1. δ(CDCl3): 2.10 (s, 3H, SCH3), 2.91 (dd, J 15.5, J' 2 Hz, 1H, β-lactam CHH), 3.34 (dd, J 15.5, J' 5 Hz, 1H, β-lactam CHH), 3.72 (s, 3H, OCH3), 3.92 (d, J 17 Hz, 1H, NCHH), 4.40 (d, J 17 Hz, 1H, NCHH), 4.72 (dd, J 5, J' 2 Hz, 1H, β-lactam CH), 5.35 (s, 2H, OCH2Ar), 6.93 (d, J 8 Hz, 2H, Ar-H), 7.42 (d, J 8 Hz, 2H, Ar-H), 7.48 (d, J 8.5 Hz, 2H, Ar-H), 8.03 (d, J 8.5 Hz, 1H, Ar-H).
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=3)[CH:22]=2)=[C:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>C(Cl)Cl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[C:1]1([C:7](=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:21]2[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=2)[O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][N:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Oc2cccc(C(=C3CCNCC3)c3ccccc3)c2)nc1
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of tert-butyl 4-(phenyl(3-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methylene)piperidine-1-carboxylate in CH2Cl2 (3 mL) was added trifluoroacetic acid (0.5 mL). The reaction was stirred overnight. The reaction was concentrated, redissolved in CH2Cl2 and concentrated again to give the title compound as an oil (33.7 mg, 70% yield).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[F:16][C:17]1[CH:18]=[C:19](O)[CH:20]=[CH:21][CH:22]=1>>[F:16][C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][CH:18]=1)[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: Oc1cccc(F)c1
Product: CC(C)(C)OC(=O)N1CCCC(COc2cccc(F)c2)C1

Procedure:
The title compound (D45) (244.9 mg) was prepared according to the experimental procedure described in Description 40 starting from tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (200 mg, 0.929 mmol, available at Aldrich#681318) and 3-Fluorophenol (0.083 ml, 0.929 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:3]=1[CH:4]=[N:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:14].[CH3:20][N:21]=[C:22]=[O:23]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C(OCC)(=O)C>[CH3:20][NH:21][C:22](=[O:23])[O:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:6]([N:5]=[CH:4][C:3]2[CH:15]=[CH:16][C:17]([O:19][C:22](=[O:23])[NH:21][CH3:20])=[CH:18][C:2]=2[OH:1])=[C:7]([CH3:14])[CH:8]=1
Reactant: Cc1cc(O)cc(C)c1N=Cc1ccc(O)cc1O
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOC(C)=O
Product: CNC(=O)Oc1cc(C)c(N=Cc2ccc(OC(=O)NC)cc2O)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
To a 350 milliliter glass pressure bottle equipped with a magnetic stirrer was added 5.15 grams (0.020 moles) of 4-(2,4-dihydroxybenzylideneamino)-3,5-dimethylphenol prepared in Part A, 2.40 grams (0.042 moles) of methyl isocyanate, 100 milliliters of ethyl acetate and 5 drops of dibutyltin diacetate. The resulting reaction mixture was stirred for 18 hours at room temperature, diluted with an additional 100 milliliters of ethyl acetate and washed twice with a 1% aqueous sodium bicarbonate solution followed by a single wash with saturated brine solution. After drying the reaction mixture over magnesium sulfate, it was concentrated under reduced pressure to give 7.25 grams (0.0195 moles) of 4-[2-hydroxy-4-(methylcarbamoyloxy)benzylideneamino]-3,5-dimethylphenyl methylcarbamate in the form of a yellow solid having a melting point of 70°-65° C. and the following structural formula: ##STR19##
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[CH3:32])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:33])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1/C=C/C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)OC(C)(C)C
Yield: 96 %

Procedure:
(E)-3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-acrylic acid tert-butyl ester from Example E45.2 (436 mg, 0.99 mmol) was dissolved in methanol (40 ml) and hydrogenated over 10% Pd/C catalyst (91 mg) for 5 h. The mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo and azeotroped with dichloromethane to yield the title compound (426 mg, 96%).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][NH2:10])=[N:4][N:3]=1.C([O-])(O)=O.[Na+].O=C1CCC(=O)N1[O:23][C:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]1)=O.C1COCC1.CC#N>O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][NH:10][C:24]([C@H:26]2[CH2:27][CH2:28][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:30][CH2:31]2)=[O:23])=[N:4][N:3]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)ON2C(=O)CCC2=O)CC1
Reactant: NCc1nnc(N)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nnc(N)[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-amino-6-(aminomethyl)-1,2,4-triazin-5(4H)-one [J. Heterocyclic Chem., (1984), 21 (3), 697] (2.00 g, 0.0113 mol) in H2O (60.0 mL, 3.33 mol) was cooled to 0° C. and drop wise charged with 1.00 M of NaHCO3 in H2O (22.5 mL) and allowed to warm to rt. This mixture was charged with methyl trans-4-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}cyclohexanecarboxylate (3.8 g, 0.012 mol) in 1:1 THF/MeCN (40 mL). After 30 min a precipitate began to form in the reaction. This was allowed to stir at rt for an additional 16 h and was filtered through a fritted funnel and washed with H2O (2×), diethyl ether (2×), and dried in vacuo resulting in the title compound 2.92 g, (84% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24-1.55 (m, 4H), 1.83 (s, 2H), 1.98 (d, J=10.61 Hz, 2H), 2.27 (s, 2H), 3.64 (s, 3H), 4.10 (d, J=5.81 Hz, 21H), 6.81 (br. s., 2H), 7.91 (t, J=5.56 Hz, 1H) and 11.98 (br. s., 1H); MS (ES+): m/z 310.05 [MH+].