Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:7]=1[NH2:8].[Cl:18][CH2:19][C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])(=O)C.[Na+]>S(=O)(=O)(O)O.C(O)(=O)C.O>[Cl:5][C:6]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:7]=1[N:8]=[N:1][CH:21]([C:20]([CH2:19][Cl:18])=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=N[O-]
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)CC(=O)CCl
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(N=Nc1c(Cl)cc(C(F)(F)F)cc1Cl)C(=O)CCl
Temperature: 25 °C

Procedure:
Sodium nitrite (9.6 g) was warmed in concentrated sulfuric acid (40 ml) to form a homogeneous mixture. The solution was allowed to cool to room temperature and a solution of 2,6-dichloro-4-trifluoromethylaniline (described in European Patent Publication 23,100:30.0 g) in glacial acetic acid (230 ml) was added dropwise, with stirring and efficient external cooling to keep the temperature below 30° C. The reaction mixture was heated at 55°-60° C. for 45 minutes, allowed to cool to room temperature, and added dropwise to a stirred solution of ethyl 4-chloroacetoacetate 21.6 g) in glacial acetic acid (100 ml) and water (200 ml). Sodium acetate (122 g) and a further 200 ml of water were added. The resultant precipitate was filtered and the filter cake was washed thoroughly with water, sucked dry and dried in a vacuum desiccator to give ethyl 2-(2,6-dichloro-4-trifluoromethylphenylazo)-4-chloroacetoacetate as a light brow solid (52.7 g), m.p. 62°-67° C.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].O1CC1C[CH:18]([O:34][CH:35]([CH2:51][CH:52]1OC1)CCCCCCCCCCCCCCC)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(OCC)(=[O:58])C>C(#N)C>[C:1]([C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:5][N:6]([CH2:52][CH:51]([OH:58])[CH2:35][O:34][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:7][CH2:8]1)#[N:2]
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: CCCCCCCCCCCCCCCC(CC1CO1)OC(CCCCCCCCCCCCCCC)CC1CO1
Reactant: CCOC(C)=O
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCC(C#N)(c2ccccc2)CC1
Temperature: 185 °C
Yield: 62 %

Procedure:
4-Cyano-4-phenylpiperidine (1.1 g, 0.0059 mol) and 2,3-epoxypropyl-n-hexadecylether (1.6 g, 0.0056 mol) were combined and heated to 185° C. for 30 minutes. After cooling, ethyl acetate (20 ml) and acetonitrile (20 ml) were added, and the resulting solid was collected by filtration (1.6 g, 62% yield): mp 69°-70° C.; ir (KBr) 2227 cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].F[C:19]1[CH:30]=[CH:29][C:22]2[C:23](=[O:28])[N:24]([CH3:27])[CH2:25][O:26][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH3:27][N:24]1[C:23](=[O:28])[C:22]2[CH:29]=[CH:30][C:19]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:20][C:21]=2[O:26][CH2:25]1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCOC2)c1
Reactant: CN1COc2cc(F)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(O[C@H]2CCOC2)c1
Temperature: 160 °C
Reaction time: 10 h
Yield: 39 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (184 mg, 0.77 mmol), 7-fluoro-3-methyl-2,3-dihydro-4H-1,3-benzoxazin-4-one (140 mg, 0.77 mmol) and potassium carbonate (214 mg, 1.54 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 160° C. for 10 hours then reduced in vacuo and ethyl acetate (50 mL) added. The organics were washed with brine (50 mL), dried (MgSO4), and reduced in vacuo and the crude oil purified by chromatography on silica, eluting with 30%-80% ethyl acetate in isohexane, to give the desired compound as a colourless oil (0.12 g).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([C:27](O)=[O:28])[CH:21]=[CH:20]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C.O>C(Cl)Cl>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([C:27]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:28])[CH:21]=[CH:20]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCCCOc1ccc2cc(C(=O)ON3C(=O)CCC3=O)ccc2c1
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a susupension of N-hydroxysuccinimide (0.56 g) and 6-heptyloxy-2-naphthoic acid (1.39 g) in methylene chloride (42 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.21 g) and stirred for 3 hours at room temparature. The reaction mixture was added to water (100 ml). The organic layer was separated and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give succinimido 6-heptyloxy-2-naphthoate (1.48 g).
Reaction SMILES: CN(C(O[N:9]1N=N[C:11]2C=CC=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][C:38]3[N:39]([C:41]([CH2:44][O:45][C:46]4[C:55]5[C:50](=[CH:51][C:52]([O:56][CH3:57])=[CH:53][CH:54]=5)[N:49]=[CH:48][CH:47]=4)=[N:42][N:43]=3)[N:40]=2)[CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.O/N=C(\N)/C>CN(C=O)C.O>[Cl:25][C:26]1[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][C:38]3[N:39]([C:41]([CH2:44][O:45][C:46]4[C:55]5[C:50](=[CH:51][C:52]([O:56][CH3:57])=[CH:53][CH:54]=5)[N:49]=[CH:48][CH:47]=4)=[N:42][N:43]=3)[N:40]=2)[CH:32]=[CH:31][C:27]=1[C:28]1[O:29][N:15]=[C:10]([CH3:11])[N:9]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)O)c(Cl)c5)nn34)ccnc2c1
Agent: C/C(N)=N/O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(-c6nc(C)no6)c(Cl)c5)nn34)ccnc2c1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
HATU (0.370 g, 0.974 mmol) and 2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzoic acid (0.300 g, 0.650 mmol) were taken up in DMF (5 mL). Added Hunig's Base (0.339 ml, 1.95 mmol). Stirred for 10 min. Added (Z)—N′-hydroxyacetamidine (0.289 g, 3.90 mmol). Stirred for an additional 30 min. Removed DMF in vacuo. Suspended in water. Isolated product by filtration. The resulting solid was allowed to try under vacuum. Split into 3 portions and separately took up in dioxane (4 mL) in a microwave tube and heated for 12 min at 150° C. Combined all 3 reactions. Concentrated. Purified on RPHPLC. Took fractions containing product and made basic with 9% sodium carbonate. Removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=500.0 [M+1]+. Calc'd for C25H18ClN7O3: 499.1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:30][CH2:31][CH2:32][O:33][C:34]4[N:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=4)=[N:12][N:13]([CH3:29])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.C[OH:42]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:30][CH2:31][CH2:32][O:33][C:34]4[N:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=4)=[N:12][N:13]([CH3:29])[C:14]=3[NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([CH3:28])([CH3:27])[CH2:26][OH:42])=[CH:23][CH:24]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: CO
Product: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)CO)cc1
Reaction time: 48 h

Procedure:
Amycolata autotrophica ATCC35203 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flasks each containing 50 ml of MY inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1″ throw. Two mls of this inoculum was then transferred to each of nine 300 ml Erlenmeyer flask containing 50 ml of MY production medium and incubated under the same conditions for a further 24 hours. At this point 5 mg of N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)4-(tert-butyl)benzenesulfonamide (GB Patent Application No 9917858.4) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 96 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].Br[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:12]
Reactant: CCOC(=O)CCCBr
Reactant: CCOC(=O)CC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCN1CCCCC1CC(=O)OCC
Reaction time: 16 h
Yield: 85.7 %

Procedure:
A stirred solution of ethyl piperidin-2-ylacetate (8.0 g, 0.047 mole) and ethyl 4-bromobutyrate (6.7 ml, 0.047 mole) in acetone (100 ml) was treated with potassium carbonate (13 g, 0.094 mole) and heated under reflux for 32 h. A further 1.5 ml of ethyl 4-bromobutyrate and 3 g of potassium carbonate was added and reflux continued for 16 h. The mixture was concentrated in vacuo and the residue treated with water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined extracts were dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with ether/petrol (60-80) to afford the title compound as a pale yellow oil (11.5 g, 86%)
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:8]1[C:12]2[CH:13]=[C:14]([Cl:21])[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:16][C:11]=2[N:10]=[C:9]1[CH3:22])[CH3:7].[N+:23]([O-])([OH:25])=[O:24].[OH-].[NH4+]>>[CH2:6]([N:8]1[C:12]2[C:13]([N+:23]([O-:25])=[O:24])=[C:14]([Cl:21])[C:15]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH3:22])[CH3:7]
Reactant: CCn1c(C)nc2cc(S(C)(=O)=O)c(Cl)cc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1c(C)nc2cc(S(C)(=O)=O)c(Cl)c([N+](=O)[O-])c21
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To a stirred, cooled solution of 40 ml. of concentrated sulfuric acid (at 0°-5° C.) was added, dropwise, 4.0 g. (0.015 mole) of 1-ethyl-2-methyl-5-methylsulfonyl-6-chlorobenzimidazole. Stirring was continued until all solid was in solution. To this stirred and cooled solution was added 6.0 g. (0.086 mole) of 90% fuming nitric acid, dropwise, over a 30 minute period. Stirring was continued while cooling for 9 hours and then the reaction mixture allowed to warm to room temperature over a 14 hour period. An additional 13.5 g. of 30% fuming sulfuric acid was then added, dropwise. The reaction mixture was stirred for about 24 hours and then stirred at about 40° C. for an additional 64 hours. The resultant reaction mixture was poured into a stirred mixture of 300 ml. of ice +200 ml. of concentrated ammonium hydroxide. The resultant aqueous mixture was extracted thrice with 100 ml. portions of chloroform and the combined chloroform extracts dried over anhydrous sodium sulfate. The resultant chloroform solution was evaporated to dryness under reduced pressure to give 3.04 g. (73.4%) of the desired product, melting at 75°-79° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23](S(C)(=O)=O)[N:22]=1.[NH:37]1[CH2:41][CH2:40][CH2:39][C:38]1=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23]([N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])[N:22]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(S(C)(=O)=O)n1
Reactant: O=C1CCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(N2CCCC2=O)n1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a solution of N-(4-methyl-3-(2-(methylsulfonyl)-6-morpholinopyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzamide (1.0 equiv.) and pyrrolidin-2-one (2.0 equiv.) in dioxane (0.10M) was added cesium carbonate (1.0 equiv.) and the allowed to stir at 120° C. for 24 hours. LCMS analysis indicated formation of the desired product. The volatiles were removed in vacuo. The crude material was purified via preparative reverse phase HPLC. Upon lyophilization of the pure fractions, N-(4-methyl-3-(6-morpholino-2-(2-oxopyrrolidin-1-yl)pyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzamide was isolated as the TFA salt in 12% yield. LCMS (m/z) (M+H)=526.3, Rt=0.83 min. 1H NMR (400 MHz, <cd3od>) δ ppm 2.25 (quin, J=7.73 Hz, 2H) 2.47 (s, 3H) 2.81 (t, J=8.02 Hz, 2H) 3.82-3.87 (m, 8H) 4.15 (t, J=7.43 Hz, 2H) 7.03 (s, 1H) 7.47 (d, J=8.61 Hz, 1H) 7.71 (dd, J=8.41, 2.15 Hz, 1H) 7.75 (t, J=7.83 Hz, 1H) 7.92 (d, J=7.83 Hz, 1H) 8.11 (d, J=2.35 Hz, 1H) 8.22 (d, J=7.83 Hz, 1H) 8.27 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1>>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])=[C:18]([F:23])[CH:17]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1F

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 4-chloro-2-fluoroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:4]1.[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17]Cl.CN(C=[O:25])C>>[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17][N:3]1[C:11]2=[N:10][CH:9]=[CH:8][CH:7]=[C:6]2[CH2:5][C:4]1=[O:25]
Reactant: c1cnc2[nH]ccc2c1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 16.2 g, 0.404 mol) was added in portions over 25 min to a solution of 7-azaindole (39.8 g, 0.337 mol) in DMF (200 mL) at 0 □C and the mixture was stirred for 1 h. 2-(Trimethylsilyl)ethoxymethyl chloride (71.8 mL, 0.404 mol) was then added slowly over 15 min, keeping the temperature of the reaction mixture below 10 □C. After 1 h, the reaction was quenched with H2O (500 mL) and the mixture was extracted with CH2Cl2 (5×300 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated and dried under high vacuum to give the title compound. MS: m/z=249 (M+1).
Reaction SMILES: CN(C=O)C.[CH:6]1([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:35])[C:18]([NH:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:19][N:20]3[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:15][C:14]=2[F:36])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:37]([N:28]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:18]1[C:17](=[O:35])[C:16]2[C:21](=[CH:22][C:13]([NH:12][CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]3)=[C:14]([F:36])[CH:15]=2)[N:20]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:19]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCOC(=O)CNc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(Cc1ccccc1)c1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 3.2 ml DMF solution of 160 mg of ethyl {[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}acetate were added 0.05 ml of benzyl bromide and 75 mg of potassium carbonate, followed by overnight stirring at room temperature. By adding water to the reaction mixture and collecting the insoluble materials by filtration, 200 mg of ethyl {benzyl[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}acetate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:35])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30]C)=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[N:15][CH:16]=1.CO.[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:35])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[N:15][CH:16]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound of example 393 (75 mg, 0.150 mmol) was taken in THF (3 mL) and MeOH (1 mL) and to this reaction mixture, 1 N LiOH (31.47 mg, 0.75 mmol) was added and stirred at room temperature for 2-3 h. After completion of the reaction, solvent was evaporated and the residue obtained was dissolved in water and acidified with 1 N HCl to obtain the title compound, which was filtered and dried.
Reaction SMILES: [C-]#N.[K+].[N+](C1C=CC(C([C@H:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)=CC=1)([O-])=O.C([OH:31])C>>[OH:31][C@@H:13]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCO
Agent: [C-]#N
Agent: [K+]
Product: CCOC(=O)[C@@H](O)CCc1ccccc1
Reaction time: 2.25 h
Yield: 74 %

Procedure:
To a suspension of potassium cyanide (0.176 g, 2.70 mmole) in absolute ethanol (43mL) was added a solution of (S)-2-[4-nitrobenzoyl]-4-phenylbutyric acid, ethyl ester (3.86 g, 10.8 mmole) in absolute ethanol (38 mL) dropwise over a period of 0.5 hours. After stirring 2.25 hours the solvent was removed and the reside was diluted with water and acidified with dilute hydrochloric acid. The organics were extracted with ether. The extracts were combined, silica gel (60 mL) was added and the solvent was removed. The adsorbate was flash chromatographed, eluent (gradient 90/10-80/20 petroleum ether/ethyl acetate) and the solvents were chased with benzene to give the title compound as a yellow oil (1.67 g, 74%): NMR (CDCl3); δ 7.38-7.16 (m, 5H), 4.30-4.10(m, 3H), 2.9-2.6 (m, 3H,), 2.2 -1.9(m, 2H), 1.15(t, 4 Hz, 3H); [a]25D +178.23 at 10.98 mg/mL CHCl3.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([O:45][CH3:46])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([O:45][CH3:46])[N:20]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(OC)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(OC)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
A mixture of hydroxylammonium chloride (2.4 g), sodium hydrogen carbonate (3.5 g) and dimethyl sulfoxide (16 mL) was stirred at 50° C. for 30 min, 4′-[(4-butyl-2-methoxy-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.6 g) was added, and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (16 mL), N,N′-carbonyldiimidazole (0.57 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.52 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.40 g, 22%) as a solid.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][C:13]=1[C:21]([F:24])([F:23])[F:22].[H-].[Na+].Cl>CN(C)C=O.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:3]2[C:4](=[O:9])[CH:5]3[CH2:8][CH:1]([CH2:7][CH2:6]3)[C:2]2=[O:10])=[O:20])=[CH:14][C:13]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)C1C(=O)C2CCC(C2)C1=O

Procedure:
A solution of bicyclo[3,2,1]octane-2,4-dione (0.552 g, 4.0 mmole), 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.77 g, 8.0 mmole), and 60% sodium hydride in mineral oil (0.176 g, 4.4 mmole) in dimethylformamide (150 mL) was stirred at 0° C. for 1 hour and heated at 45–50° C. under nitrogen for 24 hours. After cooling, the mixture was diluted with H2O and treated with 2N HCl until the mixture was clear. The clear solution was then extracted with dichloromethane. The organic layer was washed with H2O again, dried over anhydrous magnesium sulfate, and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel (30% dichloromethane/hexane) to give a clear oil as the expected product. The oily product was crystallized with ethyl acetate/hexane in a dry ice bath to afford the title compound as a white solid, mp=136–137° C.; MS (−) ESI m/z=358 (M−H)−. Analysis for C16H13ClF3NO3 Calculated: C: 53.42; H, 3.64; N, 3.89. Found: C: 53.37; H, 3.57; N, 3.67.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][Br:11])[C:3]=1[O:9][CH3:10]
Reactant: COc1c(Cl)ccnc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c(Cl)ccnc1CBr

Procedure:
4-Chloro-3-methoxy-2-methyl-pyridine (6.12 g) is dissolved in carbon tetrachloride (80 ml) then N-bromo-succinimide (7.12 g) and benzoyl peroxide (1 g) are added. The reaction mixture is refluxed under UV irradiation for 1.5 hour. The solid is filtered after cooling and the solvent evaporated. The desired product is purified by chromatography on silica gel.