Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][C:9]1[O:10][C:11]([CH3:14])=[CH:12][CH:13]=1>C(OCC)C>[CH3:8][C:9]12[O:10][C:11]([CH3:14])([CH:12]=[CH:13]1)[CH:3]1[CH:2]2[C:1](=[O:7])[O:6][C:4]1=[O:5]
Reactant: Cc1ccc(C)o1
Reactant: O=C1C=CC(=O)O1
Solvent: CCOCC
Product: CC12C=CC(C)(O1)C1C(=O)OC(=O)C12
Reaction time: 18 h
Yield: 71.9 %

Procedure:
A 100 mL 3-necked RBF is fitted with a mechanical stirrer, a condenser and a subaseal, and placed under nitrogen. Maleic anhydride (25.5 g, 0.260 mol) and anhydrous diethyl ether (35 mL) are charged to the RBF. 2,5-Dimethylfuran (27.7 mL, 0.260 mol) is added via syringe over a period of 20 mins to the suspension at 22° C. The reaction mixture is stirred for 18 h. The product is filtered off, washed with cold diethyl ether (100 mL), and dried under vacuum to yield the product 1 as a cream solid (36.32 g, 72%): 1H-NMR (300 MHz, CDCl3) δ6.35 (s, 2H), 3.16 (s, 2H), 1.76 (s, 6H).
Reaction SMILES: [SH:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][N:3]=1.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]\[C:44]([OH:46])=[O:45]>C(O)C.CC(C)=O>[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]\[C:44]([OH:46])=[O:45].[F:33][C:30]([F:31])([F:32])[C:26]1[CH:25]=[C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][S:1][C:2]3[N:6]4[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:13])([F:14])[F:12])[C:5]4=[N:4][N:3]=3)[CH2:23][CH2:22]2)[CH:29]=[CH:28][CH:27]=1
Reactant: FC(F)(F)c1cccc(N2CCN(CCCl)CC2)c1
Reactant: FC(F)(F)c1cccn2c(S)nnc12
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc(N2CCN(CCSc3nnc4c(C(F)(F)F)cccn34)CC2)c1
Yield: 44.2 %

Procedure:
A solution of 11 g of 3-mercapto-8-trifluoromethyl-1,2,4-triazolo(4,3-a)pyridine, prepared in Example 18, and 15 g of 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane in 75 ml of ethanol containing 8 ml of triethylamine is heated under reflux for 6 hours. The reaction mixture is then concentrated in vacuo, water and ice are added and the extraction is carried out with ether. The organic phase is washed with water, with a dilute solution of sodium hydroxide and then again with water. The ether phase is dried and then concentrated and the residue obtained (21.5 g) is dissolved in acetone. A solution of 5.1 g of maleic acid in acetone is added to this acetone solution. The crystals which then form are filtered off, washed with acetone and ether and dried to give 11.5 g of 3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethylmercapto]-8-trifluoromethyl-1,2,4-triazolo(4,3-a)pyridine maleate in the form of crystals melting at 144°-5° C.
Reaction SMILES: C[N:2](C)C=O.[CH3:6][O:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[O:19])=[CH:12][CH:11]=1)=[O:9].C([O-])(=O)C.[NH4+].O>C(OCC)(=O)C>[NH2:2][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:8]([O:7][CH3:6])=[O:9])=[CH:11][CH:12]=1)=[CH:17][C:18](=[O:19])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=1
Reactant: CN(C)C=O
Reactant: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCOc1ccc(C(=O)C=C(N)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dimethylformamide (50 ml), 1-(4-methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione (10.0 g) and ammonium acetate (9.9 g) were charged in 500-ml three-necked flask at room temperature and heated, and the reaction was carried out at the inner temperature of 90 to 100° C. for 4 hours. After completion of the reaction, the mixture was cooled down to room temperature, water (250 ml) and ethyl acetate (250 ml) were added, the mixture was stirred, and an ethyl acetate layer was separated. The ethyl acetate layer was further washed with water (250 ml) and a saturated saline solution (100 ml). The ethyl acetate layer was concentrated in vacuo to make 50 ml, and n-heptane (250 ml) was added to separate crystals of 1-amino-1-(4-methoxycarbonylphenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene. The crystals were filtered at room temperature and washed with a solution (50 ml) consisting of n-heptane and ethyl acetate (5:1). The crystals were dried overnight in vacuo and purified by suspending in a 70% aqueous acetone (100 ml) to give 1-amino-1-(4-methoxycarbonylphenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene (6.56 g).
Reaction SMILES: O[CH:2](C)CN(CC(O)C)CC(O)C.[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].COS(OC)(=O)=O>CC(C)=O.O.Cl>[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][C:16]=1[C:17]([O:19][CH3:2])=[O:18]
Reactant: CC(O)CN(CC(C)O)CC(C)O
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Agent: Cl
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(C(F)(F)F)ccc1Cl
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A sample of 620 g (3.25 moles) of tris-(2-hydroxypropyl)amine was melted on a steam bath. This was added slowly to a solution of 615 g (2.75 moles) of 2-chloro-5-trifluoromethylbenzoic acid and 375 g (282 ml, 2.98 moles) of dimethylsulfate in 750 ml of acetone in a 5 liter flask. (The solution began to boil during the course of the addition and was kept at 30° C. to 40° C. by intermittant cooling in an ice bath.) After addition was complete the solution was boiled on a steam bath for 30 minutes. The hot solution was diluted first with 250 ml water and, after 10 minutes, with 250 ml of 2N HCl and 750 ml of water and allowed to stir overnight. The solution was extracted with two 2 liter portions of dichloromethane and the organic extract was washed with saturated K2CO3 and water, dried over Na2SO4 and evaporated to afford 630 g (96%) of methyl 2-chloro-5-trifluoromethylbenzoate as a yellow liquid. TLC (silica gel, 10% CH2Cl2 -hexane) showed 1 spot (ester at Rf 0.4; this material was pure enough to be used in the next step without distillation. IR (NaCl, neat) 3080, 3000, 2960 (C--H), 1735 (C=O); NMR [CDCl3, (CH3)4Si] 3.78 (s, 3H, CH3 --), 7.27 (d, 1H, H--3, J3,4 =9), 7.43 (d of d, 1H, H--4, J3,4 =9, J4,6 --2.4), 7.80 (d, 1H, J4,6 --2.5); Mass Spectrum: m/e 240, 238 (1:3, M+), 209, 207 (1:3, M--OCH3), 181, 179 (1:3, M--CO22CH3). B.p. 95° C. at 4.5 torr.
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:3](=[C:4]23)[CH:2]=1.[CH3:26][O-].[Na+]>C(O)C>[CH3:26][N:22]1[C:21](=[O:25])[C:5]2[C:4]3[C:19]4[C:8](=[CH:7][CH:6]=2)[C:9]2[C:20]5[C:13]([CH:12]=[CH:11][CH:10]=2)=[CH:14][CH:15]=[CH:16][C:17]=5[C:18]=4[CH:1]=[CH:2][C:3]=3[C:23]1=[O:24]
Reactant: O=C1NC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Reactant: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CN1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.2 %

Procedure:
1.29 g (4 mmol) of perylene-3,4-dicarboximide and 0.56 g (14.7 mmol) of sodium methylate are suspended in 50 ml of ethanol and the mixture is stirred for 5 h at room temperature. After removing the solvent by evaporation under reduced pressure, 50 ml of N-methylpyrrolidone and 1.01 ml of methyl iodide are added and the mixture is stirred for 2 h at room temperature. The solvent is removed by distillation under reduced pressure and the residue is washed with 100 ml of sulfuric acid (20%) and is then collected by suction and dried at 130 ° C. under reduced pressure, giving 1.17 g (87%) of red N-methylperylene-3,4-dicarboximide.
Reaction SMILES: COC(=O)C(N1C(=O)CC[N:11]([C:16](=O)/[CH:17]=[CH:18]/[C:19]2C=CC(Cl)=C(Cl)C=2)CC1)CCO.[Cl:29][C:30]1[CH:31]=[C:32](/[CH:37]=[CH:38]/[C:39]([N:41]2[CH2:47][CH2:46][C:45](=[O:48])[N:44]([CH:49]3[CH2:53][CH2:52][O:51][C:50]3=[O:54])[CH2:43][CH2:42]2)=[O:40])[CH:33]=[CH:34][C:35]=1[Cl:36].N1CCCC1>CCO>[Cl:29][C:30]1[CH:31]=[C:32](/[CH:37]=[CH:38]/[C:39]([N:41]2[CH2:47][CH2:46][C:45](=[O:48])[N:44]([CH:49]([C:50]([N:11]3[CH2:16][CH2:17][CH2:18][CH2:19]3)=[O:54])[CH2:53][CH2:52][OH:51])[CH2:43][CH2:42]2)=[O:40])[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: O=C1OCCC1N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reactant: COC(=O)C(CCO)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Solvent: C1CCNC1
Solvent: CCO
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(C(CCO)C(=O)N2CCCC2)CC1
Yield: 88 %

Procedure:
In analogy to the procedure described in example 3, treatment of (rac)-2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-4-hydroxy-butyric acid methyl ester (with 50% of the lactone, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-oxo-tetrahydro-furan-3-yl)-[1,4]diazepan-5-one) (intermediate 6) in EtOH with pyrrolidine over night at RT gave 88% of the titled compound as white foam. MS: 468.1 (MH+, 2Cl).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O-:13])=O)[C:6]([O:8]CC)=[O:7])C.[C:14]1([CH3:34])[CH:19]=[CH:18][C:17]([S:20]([O:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH2:26][CH2:27][CH2:28][NH:29]3)(=[O:22])=[O:21])=[CH:16][CH:15]=1.P(=O)(O)(O)O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>O.C(O)C>[C:14]1([CH3:34])[CH:15]=[CH:16][C:17]([S:20]([O:23][C:24]2[C:25]3=[C:30]4[N:29]([CH2:28][CH2:27][CH2:26]3)[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[C:11](=[O:13])[C:31]4=[CH:32][CH:33]=2)(=[O:21])=[O:22])=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc3c2CCCN3)cc1
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)Oc2ccc3c(=O)c(C(=O)O)cn4c3c2CCC4)cc1
Temperature: 110 °C
Yield: 69.4 %

Procedure:
21.6 g of ethyl ethoxymethylenemalonate was added to 30.0 g of 5-(p-toluenesulfonyloxy)-1,2,3,4-tetrahydroquinoline and the mixture was heated at 110° C. on an oil bath for 30 minutes while stirring, during which time distillation of ethanol was observed. After heating, 240 g of polyphosphoric acid prepared from 120 g of phosphoric acid and 120 g of phosphorus pentoxide was added to the mixture and the mixture was allowed to react on an oil bath at 140° C. for 40 minutes. After completion of the reaction, the mixture was allowed to cool to room temperature and poured into 400 ml of water, followed by rendering the mixture neutral with a 40% aqueous sodium hydroxide to precipitate crystals. The crystals thus-obtained were mixed with 150 ml of a 10% aqueous sodium hydroxide solution and the mixture was heat refluxed for 40 minutes during which time the crystals were dissolved to form a uniform solution. The solution was filtered and the filtrate was allowed to cool and adjusted to a pH of 2 to precipitate crystals which were collected by filtration. Recrystallization of the crude crystals thus-obtained from dimethylformamide gave 27.4 g of an 8-(p-toluenesulfonyloxy)-6,7-dihydro-1-oxo-1H,5H-benzo-[ij]quinolizine-2-carboxylic acid as white needles having a melting point of not lower than 300° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[Cl:11][C:12]1[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.[Cu]I>[Cl:11][C:12]1[CH:17]=[C:16]([O:10][CH2:9][C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][N:4]=2)[CH:15]=[CH:14][N:13]=1
Reactant: OCc1ncc(F)cc1F
Reactant: Clc1cc(I)ccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Fc1cnc(COc2ccnc(Cl)c2)c(F)c1
Temperature: 105 °C
Yield: 46.9 %

Procedure:
(3,5-Difluoropyridin-2-yl)methanol (4.15 g, 28.4 mmol), 2-chloro-4-iodopyridine (7.47 g, 31.2 mmol), cesium carbonate (12.0 g, 36.3 mmol), CuI (5.40 g, 28.4 mmol) and 1,10-phenanthroline (1.02 g, 5.60 mmol) were stirred in toluene (20 mL) and purged with a nitrogen stream for 10 minutes. The mixture was heated to 105° C. for 16 h, allowed cool and filtered through a silica plug eluting with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography (80 g ISCO column column eluting with ethyl acetate/hexanes; gradient 100% hexanes to 60% ethyl acetate) to yield the title compound (3.42 g, 47%) as a yellow oil; ESI MS m/z 257 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([OH:18])[CH:13]=[CH:14][C:15]=2[CH3:17])[C:10]([CH3:20])([CH3:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](I)[CH:29]=[CH2:30]>CN(C)C=O>[CH2:30]([O:18][C:12]1[CH:13]=[CH:14][C:15]([CH3:17])=[C:16]2[C:11]=1[C:10]([CH3:19])([CH3:20])[C:9](=[O:21])[N:8]2[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:29]=[CH2:28]
Reactant: Cc1ccc(O)c2c1N(Cc1ccccc1)C(=O)C2(C)C
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C)c2c1C(C)(C)C(=O)N2Cc1ccccc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 11.6 g (41.2 mmol) of 1-benzyl-2,3-dihydro-4-hydroxy-3,3,7-trimethyl-1H-indol-2-one and 8.6 g (62.2 mmol) of potassium carbonate in 120 ml of N,N-dimethylformamide was added 8.3 g (49.4 mmol) of allyl iodide, and the mixture was stirred overnight at 70° C. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was evaporated and the residue was purified by column chromatography (silica gel, 7:1 mixture of n-hexane and ethyl acetate) to obtain 8.9 g (yield 67.2%) of colorless needles of the title compound.
Reaction SMILES: Cl[CH:2]1[C:8]([O:11][CH3:12])([O:9][CH3:10])[C:7]2([CH3:14])[O:13][C:4]([CH3:15])([CH:5]=[CH:6]2)[C:3]1=[O:16].C(#N)N(C)C.C([SnH](CCCC)CCCC)CCC.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:10][O:9][C:8]1([O:11][CH3:12])[C:7]2([CH3:14])[O:13][C:4]([CH3:15])([CH:5]=[CH:6]2)[C:3](=[O:16])[CH2:2]1
Reactant: COC1(OC)C(Cl)C(=O)C2(C)C=CC1(C)O2
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC1(OC)CC(=O)C2(C)C=CC1(C)O2

Procedure:
2.2 g (8.92 mmol) of 3-chloro-4,4-dimethoxy-1,5-dimethyl-8-oxa-bicyclo[3.2.1]oct-6-en-2-one in 240 ml of toluene are degassed, with heating at reflux temperature, and a catalytic amount of 66 mg of azaisobutyronitrile (AIBN) and a solution of 5.9 ml (22.3 mmol) of tributyltin hydride are added in succession. The reaction mixture is maintained at reflux temperature for a further 20 minutes to complete the reaction (TLC monitoring: hexane/ethyl acetate 4:1). The reaction mixture is then concentrated by evaporation under reduced pressure. The residue is then taken up in acetonitrile and the tin-containing residues are extracted by means of hexane. The acetonitrile phase is concentrated by evaporation in vacuo, 1.56 g (82.4% of theory) of 4,4-dimethoxy-1,5-dimethyl-8-oxa-bicyclo[3.2.1]oct-6-en-2-one remaining behind in the form of a yellow oil, which can be used for the next reaction step without further purification.
Reaction SMILES: C(O)C.[CH3:4][N:5]([CH3:19])[S:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)(=[O:8])=[O:7].C(=O)([O-])[O-].[Na+].[Na+]>Cl.[Fe].O>[NH2:16][C:12]1[CH:11]=[C:10]([CH2:9][S:6]([N:5]([CH3:19])[CH3:4])(=[O:8])=[O:7])[CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)S(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: CN(C)S(=O)(=O)Cc1cccc(N)c1
Temperature: 60 °C

Procedure:
To a stirred mixture of iron powder (0.5 g), ethanol (20 ml), water (1 ml) and concentrated hydrochloric acid (5 drops) at reflux was added N,N-Dimethyl-C-(3-nitro-phenyl)-methanesulfonamide (0.5 g). The mixture was then heated under reflux for a further 2 hours then basified with excess sodium carbonate solution, cooled to 60° C., then filtered. The filter cake washed with ethanol and the filtrate evaporated. The crude product was partitioned between ethyl acetate and water, separation and evaporation of the organic phase gave C-(3-Amino-phenyl)-N,N-dimethyl-methanesulfonamide, 0.4 g, sufficiently pure to use.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:19])[C:7]([C:14]([O:16]CC)=[O:15])=[CH:8][NH:9]3)=[CH:4][C:3]=2[O:2]1.[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:28][C:29]([F:32])([F:31])[F:30])(=O)=O>CN(C)C=O>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:19])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)c1c[nH]c2cc3c(cc2c1=O)OCO3
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(CC(F)(F)F)c2cc3c(cc2c1=O)OCO3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 15.6 (0.06 mole) of 6,7-methylenedioxy-4(1H)-quinolone-3-carboxylic acid, ethyl ester (J. Med. Chem. 11, 160 (1968)) and 1.5 g. (0.062 mole) of sodium hydride powder in 250 ml. of dimethyl formamide was heated with stirring for 0.5 hour at 80°-90° C. 2,2,2-Trifluoroethyl trichloromethanesulfonate (17.5 g. 0.62 mole) was then added dropwise. The temperature is maintained at 80°-90° for an additional 2 hours. The cooled mixture was poured into ice water and the solid product was isolated by filtration. It was recrystallized from ethanol. This product was identical to that obtained from Example 4.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:14]=2)[N:5]=[N:6][C:7]=1[CH2:8][C:9](OC)=[O:10].[OH-].[Na+]>CO>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][N:15]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[C:13]([C:4]2[N:5]=[N:6][C:7]3[CH2:8][C:9](=[O:10])[NH:1][C:2]=3[N:3]=2)=[N:14]1
Reactant: COC(=O)Cc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1Cc2nnc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The intermediate from Step b) was dissolved in 350 ml of methanol, and 20 drops of a 1 N aqueous sodium hydroxide solution were added (pH=6). The mixture was stirred at RT overnight and concentrated on a rotary evaporator. The residue was purified on silica gel (mobile phase: dichloromethane/methanol, 96:4). This gave 67 mg (15% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:26])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH3:23])=[N:21][N:20]=[C:19]1[CH2:24]O.P(Br)(Br)[Br:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:26])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH3:23])=[N:21][N:20]=[C:19]1[CH2:24][Br:28]
Reactant: Cc1nnc(CO)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Reactant: BrP(Br)Br
Product: Cc1nnc(CBr)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 5, 2'-chloro-5-nitro- 2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone is treated with phosphorus tribromide to give 2'-chloro-5-nitro-2-[3-(bromomethyl)-5methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26])(=[O:17])=[O:16])[CH:10]=[C:9]2[CH3:27])(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:54]>C1COCC1.C(OCC)(=O)C>[Br:54][CH2:1][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26])(=[O:17])=[O:16])[CH:10]=[C:9]2[CH3:27]
Reactant: CCOC(=O)c1ccc2c(c1)c(C)cn2S(=O)(=O)c1c(C)cc(C)cc1C
Reactant: BrC(Br)(Br)Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)n2cc(C)c3cc(CBr)ccc32)c(C)c1
Reaction time: 1 h
Yield: 93.8 %

Procedure:
Under cooling with ice, 5-carboethoxy-3-methyl-1-(2,4,6-trimethylbenzenesulfonyl)indole (1.13 g, 2.94 mmol) was added to a solution of lithium aluminum hydride (223 mg, 5.88 mmol) in THF (10 ml), followed by stirring for 1 hour. The reaction mixture was mixed with ethyl acetate and a 2N aqueous HCl solution and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and evaporated to remove the solvent. The thus obtained residue was dissolved in methylene chloride (20 ml) and mixed with triphenylphosphine (1.06 g, 4.04 mmol) and carbon tetrabromide (1.34 g, 4.04 mmol) under cooling with ice, followed by stirring for 1 hour. The reaction mixture was evaporated to remove the solvent; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:5) to give the titled compound (1.12 g, 94%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH:7]=[N:8][OH:9].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O>[OH:9][N:8]=[C:7]([Cl:15])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:13])([F:14])[F:1])[CH:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1cccc(OC(F)(F)F)c1
Solvent: CN(C)C=O
Product: ON=C(Cl)c1cccc(OC(F)(F)F)c1
Yield: 83.2 %

Procedure:
In a similar manner as described in Preparation Example 9, by using dimethylformamide (240 mL), 3-(trifluoromethoxy)benzaldehydeoxime (20.0 g, 97.50 mmol) and N-chlorosuccinimide (14.32 g, 107.26 mmol), a pale yellow solid required compound (19.43 g, 81.10 mmol, 82%) was obtained.
Reaction SMILES: [CH:1]1([N:4]([C@@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[F:18])C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1>>[CH:1]1([NH:4][C@@H:12]2[CH2:17][CH2:16][N:15]([C:20]3[N:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=3)[CH2:14][C@@H:13]2[F:18])[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N(C1CC1)[C@@H]1CCNC[C@@H]1F
Product: F[C@H]1CN(c2ncc(C(F)(F)F)cn2)CC[C@H]1NC1CC1

Procedure:
The title compound is prepared from tert-butyl N-cyclopropyl-N-[(3S,4R)-3-fluoropiperidin-4-yl]carbamate and 2-chloro-5-trifluoromethyl-pyrimidine following a procedure analogous to that described for Intermediate 87.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[C:12]=1[CH3:13].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[S:10][CH2:9][C:8](=[CH:17][N:18]([CH3:20])[CH3:19])[C:7](=[O:11])[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Reactant: COC(OC)N(C)C
Product: Cc1cc(Br)c(C)c2c1SCC(=CN(C)C)C2=O

Procedure:
20.0 g (0.074 mole) of the title compound of Step C and 100 mL of N,N-dimethylformamide dimethyl acetal (purchased from Aldrich Chemical Company) were stirred under nitrogen at reflux overnight. The mixture was concentrated, the residue was stirred in water, and filtered. The solid was dissolved in methylene chloride, dried (MgSO4), filtered, and evaporated to dryness to yield 21.54 g of the title compound of Step D as an oil. 1H NMR (CDCl3): δ2.49 (s,3H), 2.56 (s,3H), 3.16 (s,6H), 3.86 (s,2H), 7.34 (s,1H), 7.57 (s,1H).