Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:3]1.[O-:19][CH2:20]C.[Na+].O>C(OCC)=O>[OH:19][CH:20]=[C:8]1[C:9](=[O:11])[C:10]2[N:2]([CH3:1])[N:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]=2[CH2:6][C:7]1([CH3:13])[CH3:12]
Reactant: CC[O-]
Reactant: CCOC(=O)c1nn(C)c2c1CC(C)(C)CC2=O
Agent: [Na+]
Solvent: CCOC=O
Solvent: O
Product: CCOC(=O)c1nn(C)c2c1CC(C)(C)C(=CO)C2=O
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A solution of ethyl 1,5,5-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (1.00 g, 4 mmol) in anhydrous ethyl formate (10 mL) was treated with sodium ethoxide (0.54 g, 8 mmol) and refluxed for 3 hours. The mixture was cooled to room temperature and poured into cold water (40 mL). The aqueous layer was washed with diethyl ether (40 mL) to remove unreacted starting material, acidified with a 20% NaH2PO4 solution and extracted with ethyl acetate (50 mL×2). The organic extracts were collected, dried on Na2SO4 and evaporated to dryness to obtain the title compound (0.88 g, 78.8% yield) as a brown solid.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([F:19])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.C1COCC1.C1C(=O)N([Br:47])C(=O)C1>C(Cl)Cl.O>[Br:47][CH2:17][C:16]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[N:15]=[C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:7]([F:19])=[N:8]2)=[O:18]
Reactant: CC(=O)c1cccc2nc(F)c(NC(C)(C)C)nc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Nc1nc2c(C(=O)CBr)cccc2nc1F
Reaction time: 1 h
Yield: 58.1 %

Procedure:
A solution of 1-(3-(tert-butylamino)-2-fluoroquinoxalin-5-yl)ethanone (343b) (113 mg, 0.43 mmol), tert-butyldimethylsilyl trifluoromethanesulfonate (149 μL, 0.65 mmol), and TEA (181 μL, 1.29 mmol) in DCM (4.3 mL) was stirred at 0° C. for 30 min when silyl enol ether was observed via lcms. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated to give an oil. To a solution of the resulting oil in water (0.13 mL) and THF (4.3 mL) at RT was added NBS (92 mg, 0.52 mmol) and stirred for 1 h. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 0-15% EtOAc in hexanes to give 2-bromo-1-(3-(tert-butylamino)-2-fluoroquinoxalin-5-yl)ethanone (343c) (85 mg, 0.25 mmol, 58% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.58 (s, 9H) 4.94 (s, 2H) 5.41 (br. s., 1H) 7.44 (t, J=7.82 Hz, 1H) 7.87 (dd, J=8.02, 1.57 Hz, 1H) 7.92 (dd, J=7.43, 1.37 Hz, 1H). 19F NMR (377 MHz, CDCl3) δ ppm −79.69 (s, 1F). MS (ESI, pos. ion) m/z: 340.2/342.2 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:18]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCCCCCCc1ccccc1
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCCCCc1ccccc1

Procedure:
Batch size: 5.1 g (33.9 mmol) 3-(3-pyridyl)-acrylic acid, 6.6 ml (76.4 mmol) oxalyl chloride and 5.9 g (30.8 mmol) 7-phenyl-heptylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[C@H:20]([C:21]([O:23]CC)=[O:22])[CH2:19][CH:18]2[CH2:26][O:27][CH2:28][CH:17]12)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[C@H:20]([C:21]([OH:23])=[O:22])[CH2:19][CH:18]2[CH2:26][O:27][CH2:28][CH:17]12)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H]1CC2COCC2N1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1C2COCC2C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1 -[N-benzyloxycarbonyl- (S) -alanyl]hexahydrofuro[3,4 -b]pyrrole-2(S)-carboxylic acid, ethyl ester in methanol, add 2.5 N sodium hydroxide and stir the mixture at room temperature for 18 hours. Concentrate the mixture under nitrogen, dilute the residue with ice-water and then make the mixture acidic with concentrated hydrochloric acid. Extract the aqueous solution with ethyl acetate and dry the organic phase over magnesium sulfate. Concentrate the organic phase and place it on a column of silica gel. Elute with chloroform:glacial acetic acid 9:1 to give 1-[N-benzyloxycarbonyl-(S)-alanyl]hexahydrofuro[3,4-b ]pyrrole-2(S)-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C>C(Cl)Cl>[C:31]([O:29][C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1)(=[O:33])[CH3:32]
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@@H]1CCCC[C@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1CCCC[C@H]1n1cnc2c(cc(Cc3ccc(Cl)nc3)c3ccccc32)c1=O
Temperature: 25 °C

Procedure:
To a solution of rac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one (0.040 g, 0.095 mmol) in 2 mL of CH2Cl2 at 0° C. was added acetic anhydride (0.011 mL, 0.11 mmol) and triethylamine (0.026 mL, 0.20 mmol). The mixture was warmed to rt and after 15 h, concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 461.9 for [M+H]+.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([O:19]C)[CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:4])=[O:3].C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([OH:19])[CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(Nc2ccccc2)c(NS(C)(=O)=O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(O)ccc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
29.2 g of 3-methylsulfonylamino-4-phenylaminoanisole, 18.6 g of ethanethiol and 300 ml of methylene chloride were mixed and then ice-cooled. To the mixture was added 40 g of aluminum chloride in 20 minutes. Stirring was conducted for 3 hours at 5°-10° C. The reaction mixture was introduced into 500 ml of ice water. The resulting organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order and then dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. Ethanol was added to the residue and the resulting crystal was filtered to obtain 23.9 g (yield: 86%) of 3-methylsulfonylamino-4-phenylaminophenol having a melting point of 184°-186° C. IR (KBr) cm-1 : 3425, 3380, 3250, 1600, 1490, 1310, 1150
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:18]>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][O:19][C:17](=[O:18])[N:5]([CH2:4][C:3]2[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:2]=2[Br:1])[CH2:6][CH3:7])=[CH:26][CH:25]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Reactant: O=C(Cl)OCc1ccc(Cl)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)OCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 56, Step 2, using the following starting materials: (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine and 4-chlorobenzyl chloroformate.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([N+:12]([O-])=O)=[C:10]([SH:15])[N:9]=[C:8]([CH3:16])[C:7]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:2][CH2:3]C.[C:22](O)(=O)C>[Fe]>[NH2:12][C:11]1[C:6]([NH:5][CH:1]([CH2:2][CH3:3])[CH3:22])=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]([CH3:16])=[N:9][C:10]=1[SH:15]
Reactant: CC(=O)O
Reactant: CCCCNc1c(C(=O)OCC)c(C)nc(S)c1[N+](=O)[O-]
Agent: [Fe]
Product: CCOC(=O)c1c(C)nc(S)c(N)c1NC(C)CC

Procedure:
6.2 g. of 4-sec. butylamino-6-mercapto-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester are dissolved in 50 ml. of acetic acid. Iron dust is added carefully at relufx temperature until the mixture is colorless. The excess iron is filtered off and the filtrate is evaporated to dryness. The oily residue is dissolved in 10 ml. of methanol and precipitated by the addition of aqueous ammonia to obtain 5-amino-4-sec.butylamino-6-mercapto-2-methylpyridine-3-carboxylic acid, ethyl ester, yield 3 g. (53%), m. p. 88°-89° (ethyl acetate).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH3:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]([Cl:22])=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:22].[CH3:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: Cc1ccccc1/C=C/C(=O)Cl
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ccccc1/C=C/c1nc2ccccc2n1-c1ccccn1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-2-methylcinnamoyl chloride (Sekiya, T.; Hiranuma, H.; Hata, S.; Mizogami, S.; Hanazuka, M.; Yamada, S. J. Med. Chem., 1983, 26, 411) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound. MW: 347.85; mp: 212.0-215.0° C.; 1H-NMR (CDCl3) δ: 9.26 (1H, d, J=16.1 Hz), 8.89-8.83 (1H, m), 8.24-8.12 (2H, m), 7.72-7.64 (2H, m), 7.59-7.43 (4H, m), 7.43-7.11 (3H, m), 6.92 (1H, d, J=16.1 Hz), 2.70 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([OH:10])=[O:9])[N:6]=1.[CH2:12]([O:14][C:15]([CH:17]([O:19][NH2:20])[CH3:18])=[O:16])[CH3:13]>CN(C)C=O.CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:20]/[O:19][CH:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH3:18])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(C)ON
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)C(C)O/N=C(\C(=O)O)c1csc(N)n1
Reaction time: 12 h
Yield: 86.1 %

Procedure:
17.2 g of (2-amino-4-thiazolyl)glyoxylic acid are added whilst cooling with ice to a solution of 14.6 g of O-(1-ethoxycarbonylethyl)hydroxylamine in 20 ml of dimethylformamide. The solution is stirred for 12 hours without cooling, and then diluted with 180 ml of methanol. In order to complete crystallisation, stirring continues for 5 hours at -5°, and then the product is filtered off by suction and dried. 24.7 g (86%) of the title compound are obtained. M.p.: 166°.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH2:8][CH:7]1[N:15]1[CH:23]=[N:22][C:21]2[C:16]1=[N:17][C:18]([NH2:25])=[N:19][C:20]=2Cl)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[H][H]>[Pd].CO>[C:1]([O:4][CH2:5][CH:6]1[CH:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH2:8][CH:7]1[N:15]1[CH:23]=[N:22][C:21]2[C:16]1=[N:17][C:18]([NH2:25])=[N:19][CH:20]=2)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OCC1CC(n2cnc3c(Cl)nc(N)nc32)C1COC(C)=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)OCC1CC(n2cnc3cnc(N)nc32)C1COC(C)=O
Reaction time: 12 h
Yield: 67.1 %

Procedure:
A mixture of 2.63 g (7.15 mmol) of the product from Example 22, 1.18 g (14.3 mmol) of anhydrous sodium acetate, 1.0 g of 10% Pd on carbon and 100 mL of methanol was stirred under 1 atmosphere of hydrogen. After 12 hours, the reaction mixture was filtered and concentrated to a residue under reduced pressure. To the residue was added water and ethyl acetate, and the phases were separated. The aqueous phase was extracted with several portions of ethyl acetate and the combined organic extracts were concentrated under reduced pressure. Chromatography of the residue on silica gel with a 100:0 to 90:10/ethyl acetate:methanol gradient afforded 1.60 g (67%) of the title compound as an oil. DCI-NH3MS, m/z 334 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[O:13]>C(#N)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:23]([NH:22][S:19]([C:18]2[CH:17]=[CH:16][S:15][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:20])=[O:21])=[O:24])[N:3]=1
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C=O
Reactant: Cc1cc(C)nc(N)n1
Solvent: CC#N
Product: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Reaction time: 2 h

Procedure:
To 1.23 g of 2-amino-4,6-dimethyl pyrimidine in 30 ml of anhydrous acetonitrile was added with stirring 2.7 g of 2-methoxycarbonyl-3-thiophenesulfonylisocyanate. The mixture was heated to the boiling point, whereupon all of the insoluble material dissolved and the mixture was allowed to cool. After stirring for two hours the mixture was filtered to remove the desired product which had precipitated as a white solid. After washing with anhydrous ethyl ether the product melted at 191°-193° with decomposition and showed absorption peaks by nuclear magnetic resonance at 3.8 ppm for the methoxy group, 2.44 ppm for the two methyl groups on the pyrimidine ring, a peak at 7.0 consistent for the hydrogen in the pyrimidine ring and a peak at 7.42 for the hydrogens on the thiophene ring. The infrared absorption spectrum showed absorption peaks at 1720 and 1700 cm-1 consistent for the two carbonyl groups present in the desired product.
Reaction SMILES: C(N(CC)CC)C.[C:8]([CH:15]([CH3:19])[C@H:16]([NH2:18])[OH:17])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[C:8]([CH:15]([CH3:19])[C@:16]([NH2:18])([S:21]([CH3:20])(=[O:23])=[O:22])[OH:17])([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CC(C(=O)OC(C)(C)C)[C@H](N)O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(=O)OC(C)(C)C)[C@@](N)(O)S(C)(=O)=O
Reaction time: 1 h

Procedure:
DCM (400 mL) and triethylamine (83.9 mL, 0.60 mol) were added to a flask containing (R)-2-boc-amino-propan-1-ol. The reaction mixture was cooled in an ice bath for 30 min, and methanesulfonyl chloride (37.0 mL, 0.478 mol) was added dropwise over a five min period. The resulting mixture was stirred for 1 hour, the ice bath removed, and the mixture stirred for 18 h at RT. The resulting mixture was washed with aqueous NaOH (10%), and the organic layer dried over MgSO4, filtered, and concentrated under reduced pressure to give (R)-2-boc-amino-1-methanesulfonyl-propan-1-ol (91.93 g).
Reaction SMILES: C([O:5][C:6]([C@H:8]([C@@H:14]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:15]([NH:17][N:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:19]([CH3:22])(=[O:21])=[O:20])=[O:16])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])=[O:7])(C)(C)C.C(N(CC)CC)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>O1CCOCC1>[C:6]([C@H:8]([C@@H:14]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:15]([NH:17][N:18]([CH2:23][CH:24]([CH3:25])[CH3:26])[S:19]([CH3:22])(=[O:21])=[O:20])=[O:16])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])([OH:7])=[O:5]
Reactant: CC(C)=CC[C@H](C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)NN(CC(C)C)S(C)(=O)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)=CC[C@H](C(=O)O)[C@@H](CC(C)C)C(=O)NN(CC(C)C)S(C)(=O)=O
Yield: 99.9 %

Procedure:
A solution of 1.5 g of 2(R)-[1(S)-(tertbutoxycarbonyl)-4-methyl-3-pentenyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide, 0.51 g of triethylamine and 0.93 g trimethylsilyl triflate in 20 ml of 1,4-dioxane was heated at reflux under a nitrogen atmosphere for 4 hours. The mixture was cooled and the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with 2M aqueous hydrochloric acid, water and brine. The ethyl acetate phase was then dried over anhydrous magnesium sulphate and the solvent was evaporated to give 1.31 g of 2(R)-[1(S)-(carboxy)-4-methyl-3-pentenyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide in the form of a yellow foam.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 134.9 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[[3-(dimethylamino)propyl](methyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 83) (500 mg, 1.08 mmol) in dichloromethane (5 ml) was treated with trifluoroacetic acid (5 ml) and stirred at room temperature for 4.5 hours. The solvent was removed under reduced pressure and the residue azeotroped from dichloromethane. The residue was purified by column chromatography on silica gel eluting with a gradient system of 100:0 (dichloromethane:methanol) gradually changing to 80:20 (dichloromethane:methanol) to afford the title compound as a colourless glass (595 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.Br[C:10]1[C:11]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[N:12][CH:13]=[C:14]([CH3:16])[N:15]=1>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:11]1[C:10]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:15][C:14]([CH3:16])=[CH:13][N:12]=1)(=[O:19])=[O:20]
Reactant: OCc1cccnc1
Reactant: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1
Product: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2cccnc2)n1

Procedure:
Prepared by the method of Example 20 using pyridine-3-methanol (0.05 g) and N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (0.1 g). Yield 0.023 g.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[C:1]([N:17]1[CH2:18][CH2:19][CH:14]([CH3:13])[CH2:15][CH2:16]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC1CCNCC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCC(C)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 4-methylpiperidine as starting raw materials, to produce an intended compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[S:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:11]=1.[H-].[Na+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:20]1([CH2:19][N:6]2[CH2:5][CH2:4][N:3]([C:7]3[S:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:11]=3)[C:2]2=[O:1])[CH2:22][CH2:21]1
Reactant: COC(=O)c1cnc(N2CCNC2=O)s1
Reactant: BrCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCN(CC3CC3)C2=O)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of methyl 2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate (0.50 g, 2.20 mmol) in N,N-dimethylformamide (15 mL) was added sodium hydride (0.084 g, 3.52 mmol, 60% in mineral oil) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours, followed by the addition of (bromomethyl)cyclopropane (0.36 g, 2.64 mmol) and catalytic amount of tetra-n-butylammonium iodide. The reaction mixture was stirred at ambient temperature for 20 hours. The solvent was concentrated in vacuo, then diluted with ethyl acetate (200 mL) and washed with water (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (2/3) to afford the title compound as a colorless solid in 24% yield (0.15 g): mp 124-126° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.01 (s, 1H), 4.15-4.10 (m, 2H), 3.83 (s, 3H), 3.73-3.68 (m, 2H) 3.20 (d, J=7.1 Hz, 2H), 0.97-0.92 (m, 1H), 0.61-0.53 (m, 2H), 0.30-0.20 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.4, 162.6, 155.0, 145.2, 121.6, 52.0, 48.6, 42.2, 42.1, 8.9, 3.4; MS (ES+) m/z 282.2 (M+1).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[CH:10][N:11]=1)(=O)C.[OH-].[Na+]>O1CCOCC1.O>[O:12]1[C:9]2=[CH:10][N:11]=[C:6]([CH2:5][OH:4])[CH:7]=[C:8]2[CH:14]=[CH:13]1
Reactant: CC(=O)OCc1cc2ccoc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: OCc1cc2ccoc2cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.2 %

Procedure:
A solution of furo[2,3-c]pyridin-5-ylmethyl acetate (1.15 g) in 1,4-dioxane (30 ml) and water (10 ml) was treated with 2M sodium hydroxide (12 ml) then stirred at ambient temperature for 18 h. The mixture was then partitioned between ethyl acetate and water. The organic fractions were separated and dried then evaporated to dryness. This gave an oil (0.63 g, 70%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[NH:12][CH3:13])=[CH:4][C:3]=1[F:18].[OH:19][CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1>N1C=CC=CC=1>[F:18][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:22]1[CH2:23][CH2:24][CH:20]([OH:19])[CH2:21]1)[N:9]([NH:12][CH3:13])[CH:8]=[C:7]([C:14]([OH:16])=[O:15])[C:6]2=[O:17]
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: OC1CCNC1
Solvent: c1ccncc1
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(O)C3)cc21

Procedure:
6-Fluoro-1,4-dihydro-7-(3-hydroxy-1-pyrrolidinyl)-1-methylamino-4-oxo-3-quinolinecarboxylic acid [I; R=CH3NH, R"=H, Z=N=3-hydroxy-1-pyrrolidinyl] was prepared from 7.7 g of 7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid (Preparation 4A) and 9.75 g of 3-hydroxypyrrolidine in 30 ml of pyridine according to the procedure of Example 1. There was obtained 4.7 g of product as a yellow powder, m.p. 319°-321° C. (decompn.) when recrystallized from dimethylformamide.