Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C(OCC)C>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([Br:19])=[CH:21][CH:22]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C(Nc1ccc(Br)cc1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 4-bromo-aniline (Aldrich) according to the method described in Example 1c. Melting Point: 131-132° C. (diethylether)
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.CC(C)=O.ClC(OCC(C)C)=O.[C:29]([NH:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.C(N(CC)CC)C>[C:29]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]2[C:5](=[O:7])[CH2:6][CH:2]([OH:1])[CH:3]=2)=[CH:40][CH:39]=1)(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)CCCCCCC1=CC(O)CC1=O
Reactant: O=C(Nc1ccc(O)cc1)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(CCCCCCC1=CC(O)CC1=O)Oc1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.326 g. of 7-(3-Hydroxy-5-oxo-1-cyclopenten-1-yl)-heptanoic acid were dissolved in 20 ml. of dry acetone. At -20° C., 0.23 ml. of triehtylamine were added and then 0.216 ml. isobutyl chloroformate. After 5 minutes, the temperature was permitted to increase to 25° C., and 0.4 g. of p-benzoylaminophenol dissolved in 10 ml. of dry pyridine was added dropwise. After 2 hours, the solvent was distilled off; the residue was extracted in ethyl acetate; the organic phase was washed with water and dried over sodium sulphate. The solvent was distilled off. After chromatographic purification of the residue (silica gel/ethyl acetate), 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)-heptanoic acid p-benzoylaminophenyl ester (m.p. 168°-169° C.) was obtained.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][C:11]([C:13](=[N:19][O:20][CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=O>>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:1][CH:10]=[C:11]1[C:13](=[N:19][O:20][CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Reactant: Oc1ccccc1S
Product: CCOC(=O)C(=NOC)C1=CSc2ccccc2O1
Yield: 15.5 %

Procedure:
2-Mercaptophenol (3.5 g.) was allowed to react with ethyl 2-chloroacetyl-2-methoxyiminoacetate (6.2 g.) in a similar manner to that of Example A--(i) to give ethyl 2-(1,4-benzoxathiin-2-yl)-2-methoxyiminoacetate (syn isomer, 1.2 g.), pale yellow crystals, mp. 78° to 80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][F:17])[N:10]=[N:9]2)=[C:4]([F:18])[CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][F:17])[N:10]=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: O=c1n(CCCF)nnn1-c1ccc(Cl)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1n(CCCF)nnn1-c1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3.1 g (0.011 mole) of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one in 5 ml of concentrated sulfuric acid was added dropwise 0.9 ml (0.011 mole) of 70% nitric acid. Upon completion of addition the reaction mixture was stirred for two hours at ambient temperature then was poured into ice-water. The mixture was extracted with diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride and passed through a pad of silica gel. The eluate was concentrated under reduced pressure to yield 2.8 g of 1-(4-chloro-2-fluoro-5-nitrophenyl-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one; m.p. 80°-81° C. The reaction was repeated several times.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14]C(OCC2C=CC=CC=2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a slurry of Pd—C (10%, 170 mg) in MeOH (2 ml) was added a solution of the 3(R)-Benzyloxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester (1.0 g) in MeOH (60 ml). The mixture was stirred under H2 (1 atm) for 8 hr. After being filtered through Celite, the filtrate was evaporated to give a light yellow oil (572 mg, 99%). 1H-NMR (300 MHz, CDCl3) δ 4.00-3.78 (m, 2H), 3.80 (m, 2H), 3.60 (m, 1H), 1.90 (m, 1H), 1.70 (m, 1H), 1.60-1.40 (m, 12H), 1.30 (m, 1H) ppm; IR (film) 3485, 3361, 3292, 2975, 22931, 2862, 1692, 1608, 1548, 1479, 1427, 1367, 1266, −1242, 1162 cm−1; LRMS (calculated for C10H20N2O2) 200. found 200.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH:18]=[O:19])[N:4]=1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OCc1nc(-c2ccco2)oc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (20.0 g), 3-hydroxy-4-methoxybenzaldehyde (13.97 g), potassium carbonate (13.96 g) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-4-methoxybenzaldehyde as colorless crystals (19.4 g, yield 67%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 125-126° C.
Reaction SMILES: [CH3:1][N:2]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[C:10](=[N:11][C:12](SC)=[N:13][CH:14]=3)[C:4]2=[N:3]1.O[O:24][S:25]([O-:27])=O.[K+].O.[CH3:30]COC(C)=O>CN(C=O)C>[CH3:1][N:2]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[C:10](=[N:11][C:12]([S:25]([CH3:30])(=[O:27])=[O:24])=[N:13][CH:14]=3)[C:4]2=[N:3]1
Reactant: O=S([O-])OO
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1c2c(nn1C)-c1nc(SC)ncc1CCC2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c2c(nn1C)-c1nc(S(C)(=O)=O)ncc1CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of ethyl 2-methyl-9-(methylsulfanyl)-2,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidine-3-carboxylate (100 mg, 0.31 mmol) in DMF (15 mL), oxone (580 mg, 0.94 mmol) was added. The mixture was stirred at room temperature overnight then water and AcOEt was added and the layers separated. The organic phase was finally dried over Na2SO4 and evaporated. The residue was triturated with Et2O and collected by filtration to give 105 mg (97% yield) of the title compound.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[C:29]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])[N:9]=1)#[N:30]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cc(C)cc3C)cc2c1O
Product: Cc1cc(C)c(Oc2ccc3c(C#N)nc(C(=O)NCC(=O)O)c(O)c3c2)c(C)c1

Procedure:
The title compound was synthesized from 1-cyano-4-hydroxy-6-(2,4,6-trimethyl-phenoxy)-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=404.4.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].[Br:31][C:32]1[CH:40]=[CH:39][C:35](C(Cl)=O)=[C:34]([F:41])[CH:33]=1>C(Cl)(Cl)Cl>[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=3)[CH2:12][CH2:13]2)=[O:7])=[C:34]([F:41])[CH:33]=1
Reactant: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
4-(3-Chloro-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.4 g), which is the intermediate described in Preparation Example 48, was dissolved in chloroform (2.5 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was alkalified with 1N aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. By reaction and treatment in the same manner as in Preparation Example 8 and using the obtained residue and 4-bromo-2-fluorobenzoyl chloride (1.1 g), the title compound (1.9 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].[CH3:25][C:26](=O)[CH2:27][C:28](=[O:30])[CH3:29].Cl>C1COCC1>[C:28]([C:27]1[CH:21]([C:20]2[CH:23]=[CH:24][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)[NH:12][C:10](=[O:11])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[C:26]=1[CH3:25])(=[O:30])[CH3:29]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
265 mg (1.3 mmol) N-[3-(trifluoromethyl)phenyl]urea, 131 mg (1.0 mmol) 4-cyano-benzaldehyde, and 100 mg (1.0 mmol) 2,4-pentanedione are suspended in 2 ml of THF, and catalytic amounts of concentrated hydrochloric acid are added. The mixture is stirred at reflux for 18 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate as eluent.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20](=O)[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].C([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1>C(OCC)(=O)C.O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20](=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: CCOC(=O)CCCC(=O)C=Cc1ccc(OC)c(OC)c1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CCCC(C=Cc1ccc(OC)c(OC)c1)=C1SC(=S)NC1=O
Yield: 11.9 %

Procedure:
A mixture of 1.60 g (0.012 mol) of rhodanine, 3.06 g (0.01 mol) of ethyl 7-(3,4-dimethoxyphenyl)-5-oxo-6-heptenoate, 0.77 g (0.01 mol) of ammonium acetate and 20 ml of toluene was heated under reflux for 8 hours. After cooling, 100 ml of water were added to the reaction mixture d with ethyl acetate (3×100 ml). The ethyl acetate layer was washed three times with water and once with a saturated saline solution, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford a reddish brown oily substance. The oily substance was purified by silica gel column chromatography (eluent, chloroform) to obtain 0.5 g of ethyl 7-(3,4-dimethoxyphenyl)-5-(4-oxo-2-thioxo-5-thiazolidinylidene)-6-heptenoate. To 0.21 g of this compound was added 5 ml of water and 1 ml of 5% sodium hydroxide solution and the mixture was stirred at room temperature for 3 hours. This mixture was acidified with 10% hydrochloric acid, 100 ml of water was added to the acidified mixture which was extracted with ethyl acetate (3 ×120 ml). The ethyl acetate layer was washed three times with water and once with saturated saline solution, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, chloroform : methanol ™10:1) to obtain 0.12 g of Isomer A of 7-(3,4-dimethoxyphenyl)-5-(4-oxo-2-thioxo-5-thiazolidinylidene)-6-heptenoic acid from the first eluate and 0.03 g of Isomer B from the subsequent eluate.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C12CC(CC1)C=C2.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>CC(N(C)C)=O.CCOCC.O>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCCBr
Reactant: Cc1ccc2cc[nH]c2c1
Agent: C1=CC2CCC1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Solvent: O
Product: COC(=O)CCCc1cc2ccc(C)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.2 %

Procedure:
A round bottom flask was charged with 42 (1.76 g, 13.4 mmol), norbornene (2.53 g, 26.9 mmol), K2CO3 (3.71 g, 26.9 mmol), and PdCl2(CH3CN)2 (0.35 g, 1.34 mmol). A solution of water in DMA (0.5 M, 10 mL) was then added. The reaction mixture was evacuated, back filled with argon three times, and then added with methyl 4-bromobutyrate (4.7 mL, 26.0 mmol). The reaction mixture was placed in a preheated oil bath at 70° C., and the mixture was stirred vigorously for 16 h under N2. The reaction was cooled to rt, diluted with ether, and filtered. The filtrate was concentrated in vacuo at 60° C. to remove ether and most of DMA. The residue was purified by flash column chromatography eluting with a linear gradient ranging from 0 to 40% EtOAc-hexanes to provide 0.72 g (23%) of product 48 as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 1.98-2.07 (m, 2H), 2.40 (t, J=7 Hz, 2H), 2.43 (s, 3H), 2.80 (t, J=7 Hz, 1H), 3.66 (s, 3H), 6.18-6.19 (m, 1H), 6.91 (d, J=8 Hz, 1H), 7.09 (s, 1H), 7.40 (d, J=8 Hz, 1H), 7.90 (brs, 1H). LC-MS (CI): m/z 232.1 [(M+H)+ C14H17NO2 requires 231.13].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][N:3]=1.O.[OH-].[K+].[C:19](=S)=[S:20]>CCO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[O:7][C:19]([SH:20])=[N:9][N:8]=2)=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[CH:11]=1
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(S)o1
Temperature: 90 °C

Procedure:
6-chloro-4-(isopropylamino)nicotinohydrazide (10) (1.5 g, 8.7 mmol) was taken in EtOH (10 mL): H2O (5 mL). Added KOH (13 mmol, 1.5 equiv.) followed by the addition of CS2 (87 mmol, 10 equiv.) to the reaction mixture and heated at 90° C., overnight. The reaction mass was concentrated under reduced pressure to remove solvents from the reaction mixture. The crude material obtained was taken to next step as such without purification. LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.27 min; LCMS (ES-API), m/z 269.0 (M−H).
Reaction SMILES: [OH:1]N1C2C=CC=CC=2N=N1.[CH:11]1([N:17]=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.O=O.C1C=C2C(O)=CNC2=CC=1.C(N(CC)CC)C>O.O1CCCC1>[CH:20]1([NH:19][C:18]([NH:17][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:1])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: On1nnc2ccccc21
Agent: O=O
Agent: Oc1c[nH]c2ccccc12
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
For the reaction by the active ester process, 4.26 g. (0.02 mol) N-(furyl-(2')-methoxycarbonyl)-L-alanine and 5.4 g. (0.04 mol) N-hydroxybenzotriazole are dissolved in 50 ml. anhydrous tetrahydrofuran (THF), cooled to 0° C. and mixed with a solution of 4.4 g. (0.022 mol) dicyclohexylcarbodiimide (DCC) in 10 ml. anhydrous THF. For the formation of the active ester, the reaction mixture is stirred for 1.5 hours at 0° C. and then for 2 hours at ambient temperature. Thereafter, with the exclusion of oxygen and water, there are added thereto 2.66 g. (0.02 mol) indoxyl and 2.77 ml. (0.04 mol) anhydrous triethylamine. The reaction mixture is stirred for 18 hours at ambient temperature. The N,N'-dicyclohexylurea formed is filtered off with suction, the solvent is distilled off in a vacuum and the residue is worked up in the manner described in Example 7. The amorphous crude product obtained is then purified by column chromatography on a silica gel column with a mixture of toluene and ethyl acetate (5:1 v/v). After evaporation of the appropriate collected fractions and recrystallization of the residue from ethyl acetate-petroleum ether (1:1 v/v), there are obtained 3.0 g. (45.7% of theory) 3-[N-(furyl-(2')-methoxycarbonyl)-L-alanyloxy]-indole in the form of colorless crystals; m.p. 129° C.: [α]D20 =-51.9° (c=1% in methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9](=[O:18])[C:8]([CH2:19]Br)=[CH:7]2.N1C=[CH:24][N:23]=[N:22]1.[Na].[CH3:27][N:28](C)C=O>>[C:12]1([N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[CH:7]=[C:8]([CH2:19][N:23]3[CH:24]=[N:28][CH:27]=[N:22]3)[C:9]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1c(CBr)cc2cccc(F)c2n1-c1ccccc1
Reactant: c1c[nH]nn1
Reactant: CN(C)C=O
Agent: [Na]
Product: O=c1c(Cn2cncn2)cc2cccc(F)c2n1-c1ccccc1

Procedure:
Following the procedure of example 22, react 8-fluoro-1-phenyl-3-bromomethyl-2(1H)-quinolone with sodium triazole in dimethylformamide. Chromatograph to obtain the major product, 1-phenyl-8-fluoro-3-(1H-1,2,4-triazol-1-yl-methyl)-2-(1H)quinolone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[C:12]([N+:28]([O-])=O)[CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.C(O)C.O.[Fe]>[NH2:28][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=1)[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:31]
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2N)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A suspension of the product of Example 91B (223 mg, 0.4404 mmol) and iron powder (98 mg, 1.762 mmol) in acetic acid (5 mL) and ethanol (5 mL) was heated at reflux under a nitrogen atmosphere for 30 minutes. The reaction was cooled to room temperature, diluted with water (50 mL), and treated with solid sodium carbonate until the pH was 6. Extracted with ethyl acetate (100 mL), washed the organic with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum. Co-evaporating the resulting oil with methylene chloride/hexanes gave the title compound as a light tan solid (195 mg, 93%).
Reaction SMILES: CS(C)=O.[CH3:5][NH:6][C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:12]([C:14]1[C:19]2[N:20]=[C:21]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[O:22][C:18]=2[C:17](F)=[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15]=1[CH3:35])#[N:13].C(N(CC)CC)C>[Cl-].[Na+].O>[C:12]([C:14]1[C:19]2[N:20]=[C:21]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[O:22][C:18]=2[C:17]([N:9]2[CH2:10][CH2:11][C@H:7]([NH:6][CH3:5])[CH2:8]2)=[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15]=1[CH3:35])#[N:13]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CN[C@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CN[C@H]1CCN(c2c(-c3ccccc3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Reaction time: 4 h

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (3 ml) solution (3S)-3-methylaminopyrrolidine (139 μl, 1.40 mmol) was added at 150° C. to a dimethyl sulfoxide (18 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (350 mg, 1.08 mmol) and triethylamine (201 μl, 1.30 mmol), followed by stirring at the same temperature for 4 hours. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with chloroform/methanol (4:1, v/v) gave a crude product of the entitled compound as a solid, and the solid was suspended and washed in diisopropyl ether to obtain the entitled compound (147 mg, 34%) as a pale yellow solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:21]([NH:22][CH:23]3[CH2:25][CH2:24]3)=[CH:20][C:19]([F:26])=[CH:18][N:17]=2)[CH2:12]1.C(N(CC)C(C)C)(C)C.Cl[C:37](Cl)([O:39]C(=O)OC(Cl)(Cl)Cl)Cl.O>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([N:15]2[C:16]3=[N:17][CH:18]=[C:19]([F:26])[CH:20]=[C:21]3[N:22]([CH:23]3[CH2:24][CH2:25]3)[C:37]2=[O:39])[CH2:12]1
Reactant: Fc1cnc(N[C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c(NC2CC2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1n(C2CC2)c2cc(F)cnc2n1[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 25 °C

Procedure:
N2-(Trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-N3-cyclopropyl-5-fluoropyridine-2,3-diamine (0.051 g, 0.138 mmol) was dissolved in a mixture of dichloromethane (10 mL) and N,N-diisopropylethylamine (0.100 ml, 0.575 mmol) and cooled in an ice bath under nitrogen. Triphosgene (0.041 g, 0.138 mmol) was added in one portion. The reaction allowed to stir in the ice bath and warm to room temperature over 14 hours. Water (5 mL) and dichloromethane (10 mL) were added and the reaction stirred vigorously. The phases were separated and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (first column 0-10% methanol in dichloromethane gradient, repurify using hexane to ethyl acetate gradient) gave 3-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-1-cyclopropyl-6-fluoro-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.017 g, 0.043 mmol, 31.1% yield). M+1: 396. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.97-1.04 (m, 2 H) 1.10-1.17 (m, 2 H) 2.47-2.58 (m, 2 H) 2.88 (tt, J=6.92, 3.55 Hz, 1 H) 3.45-3.58 (m, 2 H) 4.55-4.65 (m, 1 H) 5.33 (quin, J=8.46 Hz, 1 H) 6.16 (br. s., 1 H) 7.05-7.12 (m, 1 H) 7.17 (dd, J=8.22, 2.35 Hz, 1 H) 7.25-7.35 (m, 1 H) 7.57 (d, J=8.02 Hz, 1 H) 7.60 (d, J=7.82 Hz, 1 H) 7.93 (t, J=2.15 Hz, 1 H).