Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](O)=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][NH:33]1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29]([N:33]4[CH2:34][C:35]5[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:32]4)=[O:30])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: c1ccc2c(c1)CNC2
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)N4Cc5ccccc5C4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2,3-dihydro-1H-isoindole.
Reaction SMILES: CN(N=O)C(N[N+]([O-])=O)=N.[OH-].[K+].[N+](=[CH2:15])=[N-].[F:16][C:17]1[CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>CCOCC.C(O)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:16][C:17]1[CH:18]=[C:19]([CH:25]2[CH2:15][CH:26]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: CCOC(=O)/C=C/c1ccc(OC)c(F)c1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C1CC1c1ccc(OC)c(F)c1
Temperature: 2.5 °C
Reaction time: 0.03 h
Yield: 83 %

Procedure:
To a mixture of N-methyl-N′-nitro-N-nitrosoguanidine (TCI-America catalogue #M0527, 3.7 g on a dry weight basis, 25.0 mmol) in ether (50 mL) at 0° C. was added a cold solution of 25% aqueous KOH (20 mL). After stifling for 2 minutes, a portion of the yellow ethereal solution of the resulting diazomethane was added to a solution of the alkene (537) (1.1 g, 5.0 mmol) in ether (25 mL) at 0° C. A portion of palladium (II) acetate (0.112 g, 0.50 mmol) was added followed by an additional portion of diazomethane solution. This process was continued until all the diazomethane solution and palladium (II) acetate was added. The resulting mixture was stirred at 0-5° C. for 4 hours and acetic acid (6 drops) was added to quench any excess reagent. The resulting mixture was concentrated in vacuo to provide ethyl 2-(3-fluoro-4-methoxyphenyl)cyclopropane carboxylate (538) (0.990 g, 83.0%) as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCc1ccccn1

Procedure:
A mixture of 5.0 g 2-(aminomethyl)pyridine, 5.02 ml acetic anhydride, 0.847 g 4-dimethylaminopyridine and 35 ml of pyridine is heated at reflux temperature for 23.5 hours. The cooled solution is poured into water and extracted with methylene chloride. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:5% methyl alcohol/ethyl acetate) to give 3.3 g of desired product as a light yellow oil.
Reaction SMILES: [CH3:1][Mg]Cl.N#N.[CH2:6]([O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[C:18](OS(C(F)(F)F)(=O)=O)=[CH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[C:18]([CH3:1])=[CH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[Mg]Cl
Reactant: COC(=O)c1ccc(-c2cc3ccc(OCc4ccccc4)cc3cc2OS(=O)(=O)C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cc3ccc(OCc4ccccc4)cc3cc2C)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
To a solution of ZnCl2 (1.32 g, 9.68 mmol) in anhydrous THF (20 mL) was added MeMgCl (1.6 mL, 4.80 mmol, 3M in THF) and the mixture was stirred at under N2 atmosphere at 10° C. for 1 hour. Then methyl 4-(6-(benzyloxy)-3-(((trifluoromethyl)sulfonyl)oxy)naphthalen-2-yl)benzoate (500 mg, 0.968 mmol) and Pd(PPh3)4 (100 mg, 0.0865 mmol) was added and the mixture was stirred at 60° C. under N2 atmosphere for 3 hours. After an aqueous/EtOAc workup, the residue was purified by silica gel column (PE/EtOAc=40/1) to give the product (250 mg, yield 68%) as an off-white solid.
Reaction SMILES: C([Li])CCC.[CH3:6][C@@H:7]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:10][C:9](=[O:18])[NH:8]1.[F:19][C:20]([F:27])([F:26])[CH2:21][CH2:22][C:23](Cl)=[O:24]>CCCCCC.O1CCCC1>[CH3:6][C@@H:7]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:10][C:9](=[O:18])[N:8]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]([F:27])([F:26])[F:19]
Reactant: O=C(Cl)CCC(F)(F)F
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
A solution of n-butyllithium (2.0 mole) in hexane was added to a stirred solution of (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (353 g) in dry tetrahydrofuran (2500 ml) at -78° C. under an inert atmosphere. The solution was stirred at -70° c. for 15 min, then 4,4,4-trifluorobutyryl chloride (320 g) was added over 30 min at -60° C. and the mixture warmed to room temperature and stirred overnight. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The ethereal layer was washed (1N hydrochloric acid, brine (twice)), dried (MgSO4), and evaporated to yield crude product (604 g, about 100%). Filtration through 3000 ml of silica gel using 1:1 methylene chloride:hexanes as the eluent afforded a white solid. Recrystallization from methylene chloride:hexanes afforded (4R,5S)-4-methyl-3-(4,4,4-trifluorobutyryl)-5-phenyl-2-oxazolidinone (519 g, 86%); m.p. 93°-95° C.; partial NMR (300 MHz, CDCl3): 0.91 (d, 3H, CH3), 2.45-2.65 (m, 2H, CF3CH2), 3.18-3.40 (m, 2H, CH2CO), 4.78 (m, 1H, 4-H oxazolidinone), 5.70 (d, 1H, 5-H oxazolidone), 7.30-7.44 (m, 5H, Ar).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]([OH:10])([CH3:9])[CH3:8])[S:5][CH:6]=1.C1C(=O)N([Br:18])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:18][C:6]1[S:5][C:4]([C:7]([OH:10])([CH3:9])[CH3:8])=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc(C(C)(C)O)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(C(C)(C)O)sc1Br

Procedure:
2-(4-Methylthiazol-2-yl)propan-2-ol (321 mg 2.04 mmol) and NBS (404 mg 2.25 mmol) was stirred in DMF (10 mL) at room temperature for 2 hours under nitrogen. The mixture was diluted with EtOAc (50 mL) and washed with water (2×20 ml), then brine, dried over sodium sulfate and concentrated to give an oil which was purified by ISCO CombiFlash® chromatography eluting with Heptane:EtOAc (100:0 to 0:100 over 20 CV) to the product as a pale yellow oil (296 mg 61%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=3)=[CH:4][C:3]=2[O:2]1.[BH4-].[Na+]>CO.C(Cl)Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]3[CH:27]=[CH:28][C:29]([CH2:32][OH:33])=[CH:30][CH:31]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(CO)cc1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Yield: 67 %

Procedure:
This product was prepared by stirring a solution of Example 23 (0.3 g, 0.66 mmol) in 40 mL of MeOH with NaBH4 (0.1 g, 4 equiv.) at rt for two hours. Evaporation of the solvent gave a residue which was dissolved in DCM (100 mL) and washed twice with water (50 mL). Extraction with DCM, drying over MgSO4 and evaporation in vacuo gave the title compound (0.2 g, 67%) as white crystals after recrystallization from EtOH.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)(=[O:19])=[O:18])[CH:7]=1.[OH-].[K+].Cl>C1COCC1>[Cl:27][C:22]1[CH:21]=[C:20]([S:17]([N:8]2[C:9]3[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:6]([S:5][CH2:4][C:3]([OH:28])=[O:2])=[CH:7]2)(=[O:19])=[O:18])[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: COC(=O)CSc1cn(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ccc(OC)cc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(SCC(=O)O)cn2S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 5 %

Procedure:
To a solution of (5-Methoxy-1H-indol-3-ylsulfanyl)-acetic acid methyl ester 26, in THF (4.0 mL) was added an aqueous solution of potassium hydroxide (1.0 mL of 1M) which was stirred at room temperature for 4 h. The acid was neutralized with aqueous HCl, extracted the product with ethyl acetate, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and purified via trituration with tetrabutyl ethyl ether to afford 27 as a white solid (4.5 mg, 5%). MS(ESI) [M+H−]+=443.95
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([CH3:18])[CH:17]=1.C(OCC)C.O>N1C=CC=CC=1>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7]([O:19][C:14]2[CH:15]=[C:16]([CH3:18])[CH:17]=[C:12]([CH3:11])[CH:13]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1cc(C)cc(O)c1
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Oc2cc(C)cc(C)c2)cc1
Yield: 84.8 %

Procedure:
p-Toluoyl chloride (154 g.) was added during 30 minutes to a solution of 3,5-dimethylphenol (122 g.) in anhydrous pyridine (200 ml.), with stirring. The temperature rose to 80° C. The mixture was stirred and heated on the steambath for 3 hours, and was then cooled and stirred with diethyl ether (500 ml.) and water (2000 ml.). The organic layer was separated, and the aqueous layer was further extracted with diethyl ether (3×250 ml.). The combined ether solutions were washed with N aqueous sodium hydroxide solution to remove unchanged starting materials and with 2 N hydrochloric acid to remove pyridine, and finally with water. The solution was dried over anhydrous sodium sulphate and evaporated in vacuo, and the residue was recrystallised from light petroleum (b.p. 40°-60° C.; 550 ml.) to give 3.5-dimethylphenyl p-toluate (203 g.). m.p. 55°-57° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][O:52][C:53](=[O:64])[CH2:54][CH:55]([NH2:63])[C:56]1[CH:61]=[CH:60][C:59]([OH:62])=[CH:58][CH:57]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.O>[OH:62][C:59]1[CH:60]=[CH:61][C:56]([CH:55]([NH:63][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]3)[CH2:19]2)=[O:25])[CH2:54][C:53]([O:52][CH3:51])=[O:64])=[CH:57][CH:58]=1
Reactant: COC(=O)CC(N)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
490.75 mg (1.33 mmol) (3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidine-3-carboxylic acid (Bioorg. Med. Chem. 13 (2005) 4343-4352, Compound 10) were suspended in 8 ml N,N-dimethylformamide and cooled to 0° C. 0.545 g (1.43 mmol) HATU, a solution of 200.0 mg (1.0 mmol) 3-amino-3-(4-hydroxy-phenyl)-propionic acid methyl ester in 12 ml N,N-dimethylformamide and 0.53 ml (3.07 mmol) N-ethyl-diisopropylamine were added. The mixture was stirred at 0° C. for 5 minutes and at room temperature for 24 hours. 20 ml water were added and the mixture extracted with dichloromethane, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuum. Chromatography over 28 g basic silica gel (dichloromethane/ethanol 100/0-95/5-90/10-80/20) gave 465 mg (83%) tert-butyl 4-[3-((3R)-3-{[1-(4-hydroxyphenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl)-3-oxopropyl]piperidine-1-carboxylate.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[C:13]2[CH:34]=[CH:35][C:36]([Cl:39])=[C:37]([CH3:38])[C:12]1=2)=[O:10])([CH3:7])[CH3:6].N1C=CC=CC=1>ClCCl>[CH:5]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]([C:1](=[O:3])[CH3:2])[CH2:19][C:20]2[CH:21]=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:25]=2)[C:13]2[CH:34]=[CH:35][C:36]([Cl:39])=[C:37]([CH3:38])[C:12]1=2)=[O:10])([CH3:7])[CH3:6]
Reactant: Cc1c(Cl)ccc2c1N(C(=O)OC(C)C)CCCC2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c1ccc(Cl)c2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
Inject titanium isopropoxide (0.176 mL, 0.60 mmol) to a mixture of 8-chloro-9-methyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (90 mg, 0.30 mmol) and 3,5-bis(trifluoromethyl)benzylamine (137 mg, 0.45 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Add methanol (1.3 mL) and sodium borohydride (28 mg, 0.75 mmol) and stir the mixture under nitrogen at room temperature for 2 h. Add 0.1M NaOH, stir for 30 min. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford (+/−)-5-(3,5-Bis-trifluoromethyl-benzylamino)-8-chloro-9-methyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (90 mg, 57%). Add acetyl chloride (0.025 mL, 0.34 mmol) dropwise to a solution of the amine (90 mg, 0.17 mmol) and pyridine (0.025 mL, 0.34 mmol) in dichloromethane (1.2 mL) at 0° C. Stir under nitrogen at room temperature for 1 h 30 min. Add water and extract with dichloromethane. Dry the organic layer over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (40 mg, 42%); MS (ES+): 565 (M+H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)[NH2:31]>>[N:35]1[CH:36]=[CH:37][C:32]([C:30]2[N:31]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:26][N:29]=2)=[CH:33][CH:34]=1
Reactant: NC(=NO)c1ccncc1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccncc3)no2)C1

Procedure:
250 mg (about 0.65 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid and 97 mg (0.71 mmol) of N′-hydroxypyridine-4-carboximidamide were reacted according to the General Method 1. Yield: 45 mg (14% of theory)
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][N:16]([CH2:26][CH3:27])[C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=O)C.C(O)(=O)C>[OH-].[Na+]>[CH2:26]([N:16]1[C:14]2[N:15]=[C:10]([N:7]3[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]3)[N:11]=[CH:12][C:13]=2[C:19](=[O:20])[C:18]([C:21]([OH:23])=[O:22])=[CH:17]1)[CH3:27]
Reactant: CCOC(=O)c1cn(CC)c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Yield: 84.6 %

Procedure:
Ethyl 2-(4-acetyl-1-piperazinyl)-5,8-dihydro-8-ethyl-5-oxopyrido[2,3 -d]pyrimidine-6-carboxylate (1.6 g) was dissolved in 30 ml of a 10% aqueous solution of sodium hydroxide by heating at 90° - 95°C for one hour. Neutralization of the reaction mixture with acetic acid under cooling yielded a crude solid, which was recrystallized from dimethylformamide to give 1.1 g of the product as a pure state.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[OH:18][C:19]1[CH:34]=[CH:33][C:22]([CH:23]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH:23]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=2)=[CH:4][CH:5]=1
Reactant: ClCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: COC(=O)C(=Cc1ccc(O)cc1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(=Cc1ccc(OCc2ccc(-c3nc4ccccc4o3)cc2)cc1)C(=O)OC
Temperature: 0 °C
Yield: 41 %

Procedure:
A mixture of 0.1 mole 2-(4-chloromethylphenyl)benzoxazole (C) and 0.1 mole dimethyl 4-hydroxybenzylidenemalonate (D) in 300 ml. 2-butanone containing 100 g. potassium carbonate was refluxed for 18 hours and poured onto 1,000 g. ice/water. Filtration, washing with water and recrystallization from methyl cellosolve/isopropyl alcohol gave a 41% yield of the light tan crystalline product II. ##STR5##
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[C:18]1(=[O:34])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:21](=[O:29])[C:20]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:19]12.Cl.O1CCOCC1>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]([NH:4][C:5]([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:22]1[C:21](=[O:29])[C:20]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:19]2[C:18]1=[O:34])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)C(CCCCCN1C(=O)c2ccccc2C1=O)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Yield: 163.1 %

Procedure:
Diethyl acetamidomalonate (2.80 g, 12.9 mmole) in 10 ml dimethylformamide (dried over 4A sieves, degassed) was added dropwise over 15 minutes to a suspension of sodium hydride (515 mg of 60% NaH/oil washed free of oil with hexane, 12.9 mmole) in 10 ml DMF with external cooling to maintain reaction temperature <10° C. The reaction mixture was warmed slowly to room temperature over 45 minutes. A solution of 5-phthalimidopentyl bromide (4.24 g, 14.3 mmole) in 10 ml DMF was added in four portions at room temperature while maintaining the internal temperature <40° C. The mixture was stirred for 24 hours until complete by TLC (product Rf =0.43, starting material Rf =0.32 (B)). Upon completion, the reaction mixture pH was adjusted to "pH 6" (pH 0-14, ColorpHast indicator strips, E. Merck, moistened) with 4N HCl/dioxane. The solvent was removed by rotary evaporation to give 9.10 g of an oil, which was purified by Still column chromatography (230-400 mesh Whatman G-60 silica gel, 320 g, CHCl3 eluant). The purified adduct 5 was crystallized from ethyl acetate/cyclohexane, 1:3. Yield: 4.35 g (78%). Mp 70°-72° C. TLC: Rf =0.43 (B). MW calc 432.19, found 432. Anal. calc for C22H28N2O7 : C, 61.10; H, 6.53; `N, 6.48. Found: C, 60.72; H, 6.61: n, 6.12. HPLC 97.4%. 1H NMR (CDCl3) 1.15 (2H, m), 1.25 (6H, t, 7 Hz), 1.33 (2H, br m), 1.56 (3H, s), 1.66 (4H, m), 2.05 (1H, s), 2.32 (2H, m), 3.65 (2H, t, 7 Hz), 4.25 (4H, q, 7 Hz), 7.72 (2H, m) and 7.90 (2H, m) for AA'BB"system.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1Cl.C([O-])([O-])=O.[Na+].[Na+].[CH3:21][NH:22][CH2:23][CH2:24][NH:25][CH3:26]>C(O)CCC.O>[CH3:21][N:22]1[C:5]2[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:14])[N:25]([CH3:26])[CH2:24][CH2:23]1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: CNCCNC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: CN1CCN(C)c2c(cccc2[N+](=O)[O-])C1=O
Temperature: 80 °C
Yield: 59.7 %

Procedure:
2-Chloro-3-nitro-benzoic acid methyl ester (500 mg, 2.32 mmol) was dissolved in n-butanol (2.5 ml). Na2CO3 (246 mg, 2.32 mmol) was added followed by N,N′ dimethylethylenediamine (250 μL, 2.32 mmol). The reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled and diluted with water (50 ml). The resulting mixture was extracted with EtOAc (3×50 mL), dried over MgSO4, and concentrated. Silica gel chromatography (0-100% EtOAc in hexanes) afforded 1,4-Dimethyl-9-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a yellow solid (326 mg, 60%). mp 146-147° C.; LCMS: m/z=236.23 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J=8.1 Hz, 1.8 Hz, 1H), 7.77 (d, J=8.1 Hz, 1.8 Hz, 1H), 7.09 (dd, J=8.1 Hz, 1H), 3.54 (t, J=5.0 Hz, 2H), 3.42 (t, J=5.0 Hz, 2H), 3.22 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][C@@H:25]3[CH2:27][O:26]3)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3].[CH3:28][N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[C:30]1=[O:44]>CCO.ClC(Cl)C>[OH:26][C@H:25]([CH2:24][N:11]1[C:8]2[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][C:7]=2[C:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=2)=[N:12]1)[CH2:27][N:41]1[CH2:40][CH2:39][CH:38]([N:31]2[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:29]([CH3:28])[C:30]2=[O:44])[CH2:43][CH2:42]1
Reactant: Cn1c(=O)n(C2CCNCC2)c2ccccc21
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2C[C@@H]2CO2)C1
Solvent: CCO
Solvent: CC(Cl)Cl
Product: Cn1c(=O)n(C2CCN(C[C@H](O)Cn3nc(-c4ccc(C(F)(F)F)cc4)c4c3CCN(S(C)(=O)=O)C4)CC2)c2ccccc21
Yield: 63.4 %

Procedure:
A solution of (R)-5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (134 mg, 0.334 mmol) and 1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (110 mg, 0.476 mmol) in EtOH (0.8 mL) and dichloroethane (0.8 mL) was heated to 80° C. for 18 h. The mixture was then concentrated and the residue purified by column chromatography (silica, 0-50% acetone/CH2Cl2) to give the title compound (134 mg, 86%). TLC (20% acetone/CH2Cl2) Rf=0.3. MS (electrospray): calculated for C30H36F3N6O4S, [M+H]+633.24. m/z found, 633.3. 1H NMR (CDCl3, 400 MHz): 7.72 and 7.66 (A and B of AA′BB′, Jab=8.3 Hz, 4H), 7.15 (dd, J=7.0, 1.7 Hz, 1H ), 7.08 (m, 2H), 6.98 (dd, J=6.6, 1.8 Hz, 1H), 4.60 and 4.55(A and B of AB, Jab=14.5 Hz, 2H), 4.34 (m, 1H), 4.23 (dd, J=13.8, 2.8 Hz, 1H), 4.15 (m, 1H), 4.23 (dd, J=13.8, 6.6 Hz, 1H), 3.71 (m, 2H), 3.40 (s, 3H), 3.08 (m, 2H), 2.96 (m, 2H), 2.89 (s, 3H), 2.56-2.36 (m, 4H), 2.23 (d, J=11.6 Hz, 1H, 1.81 (m, 2H).