Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.C1(C)C=CC=CC=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>ClCCl>[N:25]([C:24]1[CH:26]=[CH:27][CH:28]=[C:22]([C:21]([F:20])([F:29])[F:30])[CH:23]=1)=[C:5]=[O:11]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C=Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triphosgene (0.75 g) was added to anhydroue toluene (10 ml) under nitrogen protection, and then a solution of 3-trifluoromethylaniline (0.8 g) in dichloromethane (15 ml) was added dropwise in an ice-bath. After addition, the reaction mixture was stirred at room temperature for 15 min, and then heated to 80° C. for 6 h. The completion of the reaction was indicated by TLC. The reaction mixture was concentrated under reduced pressure to give the product as oil, which then was solidified.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:30])[N:7]([CH2:12][C:13]([CH2:15][CH:16]3[CH:21]([O:22]C)[CH2:20][CH2:19][CH2:18][N:17]3C(OCC=C)=O)=[O:14])[CH:8]=[N:9]2)=[CH:4][C:3]=1[Cl:31].Br>>[BrH:1].[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:30])[N:7]([CH2:12][C:13]([CH2:15][CH:16]3[CH:21]([OH:22])[CH2:20][CH2:19][CH2:18][NH:17]3)=[O:14])[CH:8]=[N:9]2)=[CH:4][C:3]=1[Cl:31]
Reactant: C=CCOC(=O)N1CCCC(OC)C1CC(=O)Cn1cnc2cc(Br)c(Cl)cc2c1=O
Agent: Br
Product: O=C(CC1NCCCC1O)Cn1cnc2cc(Br)c(Cl)cc2c1=O

Procedure:
Using the procedure of French Pat. No. 1,550,956, a solution of the product of Step D in an aqueous 48% hydrobromic acid solution was refluxed for an hour and was then evaporated to dryness. The residue in ethanol was refluxed for 30 minutes and the mixture was filtered to obtain dextrorotary 7-bromo-6-chloro-3-[3-(3-hydroxy-2-piperidyl)-acetonyl]-4(3H)-quinazolinone hydrobromide with a specific rotation of [α]D20 =+6°±1° (c=1% in a 1--1 methanol-water mixture).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].I[C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][CH:32]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:32]3[CH:27]=[CH:28][CH:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[N:31]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: FC(F)(F)c1ccc(I)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1cccc(C(F)(F)F)n1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 239 mg (0.66 mmol) of 75% 5-iodo-2-trifluoromethyl-pyridine in 1 mL THF with 0.37 mL 2M isopropylmagnesium chloride. Yield: 78 mg of a white powder. LC-MSD, m/z for C22H13BrF3N3O2 [M+H]+=488.0, 490.0; HPLC retention time: 2.4 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[N:11]=2)=[CH:5][CH:4]=1.[C:24](O)(=[O:27])[CH:25]=[CH2:26]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])=[CH:19][CH:18]=3)[N:11]=2)=[CH:7][CH:8]=1
Reactant: C=CC(=O)O
Reactant: COc1ccc(Sc2ccnc(Nc3ccc(N)cc3)n2)cc1
Product: C=CC(=O)Nc1ccc(Nc2nccc(Sc3ccc(OC)cc3)n2)cc1
Yield: 55.1 %

Procedure:
In a procedure analogous to Example 15, reaction of N1-(4-(4-methoxyphenylthio)pyrimidin-2-yl)benzene-1,4-diamine (80 mg, 0.23 mmol) and acrylic acid (24 μL, 0.46 mmol) furnished the product (48 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
In a nitrogen atmosphere, 4-bromophenol 5.0 g, 2-bromoethanol 5.42 g, and potassium carbonate 12.0 g were added to N,N-dimethylformamide 30 ml, and the mixture was stirred at 100° C. After 1 hour, the mixture was cooled to room temperature and partitioned by adding water and diethyl ether. The organic layer was washed with water and brine, dried over magnesium sulfate anhydride and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound 5.15 g, 82% was obtained as a colorless crystalline.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]3[C:23]([O:29]C)=[N:24][CH:25]=[C:26]([F:28])[CH:27]=3)=[N:13][C:12]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>O1CCOCC1>[C:1]([NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]3[C:23](=[O:29])[NH:24][CH:25]=[C:26]([F:28])[CH:27]=3)=[N:13][C:12]=12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC(C)(C)C)c2n1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Temperature: 80 °C
Reaction time: 120 h
Yield: 85.8 %

Procedure:
A pressure flask was charged with (R)—N-tert-butyl-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 80, 10 mg, 0.024 mmol), dioxane (0.7 mL) and 2M HCl (0.100 mL, 0.200 mmol). The flask was sealed and the reaction mixture was stirred at 80° C. for 5 days. The mixture was cooled to ambient temperature and concentrated. The residue was purified by reverse-phase column chromatography (0-50% acetonitrile/water) to afford the title compound (8.2 mg, 85%). MS (apci) m/z=399.1 (M+H).
Reaction SMILES: C[C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH2:12][CH2:13][NH:14][CH2:15][C@H:16]([OH:25])[CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:26]([OH:28])=O.[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>CO>[CH3:29][O:30][CH2:31][CH2:32][NH:33][C:26]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][NH:14][CH2:15][C@H:16]([OH:25])[CH2:17][O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:7][C:6]=2[CH:2]=1)=[O:28]
Reactant: Cc1c(C(=O)O)oc2ccc(OCCNC[C@H](O)COc3ccccc3)cc12
Reactant: COCCN
Solvent: CO
Product: COCCNC(=O)c1cc2cc(OCCNC[C@H](O)COc3ccccc3)ccc2o1

Procedure:
A solution of methyl 5-(2-(2(S)-hydroxy-3-phenoxy-propyl-amino)ethoxy)benzofuran-2-carboxylic acid (0.10 g, 0.26 mmol) and 2-methoxyethyl-amine (0.6 mL) in methanol (3 mL) were maintained at reflux temperature for 18 h. The reaction solution was concentrated in vacuo and flash chromatographed on silica gel (5% methanol:chloroform) to afford the title compound as a colorless solid. (92 mg; m.p. 95°-96° C. Analytical calculated for C23H28N2O6.0.25H2O: C, 63.79; H, 6.63; N, 6.47. Found: C, 63.59; H, 6.39; N, 6.34.)
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(COS(C)(=O)=O)C(=O)N(CC(C)C)N=1.[Cl:26][C:27]1[CH:55]=[CH:54][C:30]([CH:31]=[CH:32][CH2:33][N:34]2[C:39](=[O:40])[C:38]([C:41]([O:43]C)=[O:42])=[CH:37][C:36]([C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([F:53])[CH:46]=3)=[N:35]2)=[CH:29][CH:28]=1>>[C:41]([C:38]1[C:39](=[O:40])[N:34]([CH2:33][CH:32]=[CH:31][C:30]2[CH:54]=[CH:55][C:27]([Cl:26])=[CH:28][CH:29]=2)[N:35]=[C:36]([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([F:53])[CH:46]=2)[CH:37]=1)([OH:43])=[O:42]
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Product: COc1ccc(-c2cc(C(=O)O)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)cc1F
Yield: 98.2 %

Procedure:
Following the procedure of Example 1 (7), 2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as a pale yellow crystalline powder (yield: 98.2%).
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH2:18]([C:25]1[N:30]=[C:29]([CH3:31])[C:28]([C:32](O)=[O:33])=[CH:27][N:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>O>[CH2:18]([C:25]1[N:30]=[C:29]([CH3:31])[C:28]([C:32]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])=[O:33])=[CH:27][N:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1nc(Cc2ccccc2)ncc1C(=O)O
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCOC(=O)c1cnc(Cc2ccccc2)nc1C)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
To 10 ml of N,N-dimethylformamide were dissolved 1.00 g (5.0 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 1.30 g (5.5 mmol) of 2-benzyl-4-methylpyrimidine-5-carboxylic acid, followed by the addition of 0.50 g (6.0 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over an hydrous magnesium sulfate, the addition of “Florisil” and filtering. The solution was concentrated under reduced pressure to obtain 1.30 g (yield: 78%) of 4,4-difluoro-3-methyl-3-butenyl 2-benzyl-4-methylpyrimidine-5-carboxylate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N+](=[CH2:15])=[N-]>CCOCC>[CH3:15][O:11][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Solvent: CCOCC
Product: COC(=O)c1ccc2[nH]ccc2c1
Yield: 86 %

Procedure:
To a solution of 4.8 g (29.8 mmol) of indole-5-carboxylic acid in ether (200 ml) was added dropwise etheral diazomethane until the yellow color of diazomethane did not disappear. The mixture was concentrated and the obtained residue was chromatographed on silica gel (ethyl acetate as an eluant) to give 4.5 g of indole-5-carboxylic acid methyl ester. Yield: 86%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[F:12].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([O:20][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[F:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1,2,3-trifluoro-4-nitrobenzene (5.0 g) and benzyl alcohol (2.92 ml) in N,N-dimethylformamide (20 ml) was added potassium carbonate (5.85 g), followed by stirring at room temperature for 62 hr and 45 min. To the reaction mixture was added water (80 ml) at 0° C., followed by stirring at 4° C. for 28 hr. The precipitated crystals were collected by filtration and washed with water. These crystals were dried under reduced pressure to provide the titled compound as pale yellow crystals (6.54 g) which was a mixture of 2-(benzyloxy)-3,4-difluoro-1-nitrobenzene.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH3:12][N:13]1[CH:18]=[CH:17][C:16]([C:19]([NH2:21])=O)=[CH:15][C:14]1=[O:22].N1C=CC=CC=1>C(#N)C.O>[CH3:12][N:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:21])=[CH:15][C:14]1=[O:22]
Reactant: Cn1ccc(C(N)=O)cc1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: Cn1ccc(C#N)cc1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxalyl chloride (250 μl, 2.87 mmol) was added to an ice-cooled solution of N,N-dimethylformamide (243 μl, 3.14 mmol) in acetonitrile (3 ml). A suspension of 1-methyl-2-oxo-1,2-dihydro-4-pyridinecarboxamide (J.O.C. 24; 1959; 196) (201.5 mg, 1.32 mmol) and pyridine (470 μl, 5.82 mmol) in acetonitrile (20 ml) was added to the resulting white suspension, and the mixture stirred at room temperature for 18 hours. The mixture was diluted with water (20 ml), and extracted with ethyl acetate (2×100 ml). The combined organic solutions were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate:pentane (75:25), then dichloromethane:methanol (90:10) as eluants, to afford the title compound as a pale yellow solid, 112.3 mg.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C(=O)C.[H-].[Na+].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:18]=1[C:24]([F:27])([F:26])[F:25]>O>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:18]=1[C:24]([F:27])([F:26])[F:25]
Reactant: Fc1cccc(Br)c1C(F)(F)F
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: FC(F)(F)c1c(Br)cccc1OC1CCCCC1
Temperature: 100 °C

Procedure:
Cyclohexanol (214 mg) was added to N,N-dimethylacetamide (10 mL), and sodium hydride (60% in mineral oil, 86 mg) was added. The solution was mixed at room temperature for 15 minutes after which time 1-bromo-3-fluoro-2-(trifluoromethyl)benzene (400 mg) was added. The solution was then heated at 100° C. for 1 hour. The solution was cooled, added to water, and extracted with diethyl ether. The extract was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified on silica gel using 5% ethyl acetate in hexanes.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27](Br)[CH:28]=[CH2:29].C(I)C=C>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:29][CH:28]=[CH2:27])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C=CCBr
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: C=CCI
Agent: [Na+]
Product: C=CCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 94.2 %

Procedure:
In the same manner as in Example 81, 984 mg of the title compound was prepared from 1.00 g of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate prepared in Example 41, 538 mg of allyl bromide, and 415 mg of allyl iodide.
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH:15]=[C:16]([CH3:22])[NH:17]3)[CH2:9][CH2:8]1)=O.OP([O-])(O)=O.[K+]>[Zn].O1CCCC1>[CH3:22][C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[C:13]([N:10]1[CH2:11][CH2:12][NH:7][CH2:8][CH2:9]1)[CH:21]=[CH:20][CH:19]=2
Reactant: Cc1cc2c(N3CCN(C(=O)OCC(Cl)(Cl)Cl)CC3)cccc2[nH]1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1cc2c(N3CCNCC3)cccc2[nH]1
Yield: 44 %

Procedure:
A mixture of 4-(2,2,2-trichloroethoxycarbonyl)-1-(2-methyl-1H-indol-4-yl)piperazine (0.70 g, 1.79 mmol, used directly from above), zinc dust (2.0 g), tetrahydrofuran (15 mL), and a solution of KH2PO4 (1.0 M, 3 mL) was vigorously stirred at room temperature under nitrogen for 6 hours. The resulting reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was chromatographed using silica gel (approximately 75 g) and elution with methylene chloride/methanol/ammonium hydroxide [6:1:0.1] to afford the title compound (0.170 g, 0.79 mmol, 44%) as an off-white amorphous solid: Rf=0.2 in methylene chloride/methanol/ammonium hydroxide [6:1:0.1]; 1H NMR (CD3OD) δ7.02 (d, J=8.0 Hz, 1H), 6.94 (t, J=7.7 Hz, 1H), 6.54 (dd, J=1.0 and 7.3 Hz, 1H), 6.15 (s, 1H), 4.89 (s, exchangeable protons), 3.43 (br t, 4H), 3.40 (br t, 4H), 2.41 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]3[O:15]C=CC=3)=[CH:12][C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CC(C)=[O:25].[Mn]([O-])(=O)(=O)=O.[K+]>O>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([OH:15])=[O:25])=[CH:12][C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: FC(F)(F)c1cc(-c2ccco2)n(-c2ncc(Cl)cc2Cl)n1
Reactant: CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ncc(Cl)cc1Cl
Temperature: 65 °C
Yield: 58 %

Procedure:
To a 100 mL flask, 3,5-dichloro-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine (1.47 g, 4.22 mmol), acetone (10 mL) and a solution (10 mL) of potassium permanganate (3.33 g, 21.1 mmol) in water were added. The reaction mixture was heated to 65° C. for 4 hours and cooled to room temperature, then isolated via filtration, a cake is obtained. The cake was washed with hot solution of potassium hydroxide. To the filtrate was added ethyl acetate (80 mL), water (100 mL) and partitioned. The aqueous layer was acidified with concentrated hydrochloric acid to pH of 2-3, and extracted with ethyl acetate (200 mL). The organic extracts were washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate and concentrated by rotary evaporator to give the product (0.80 g) as yellow oil in 58% yield.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[N:5]=[C:6]([C:9]2([C:19]#[N:20])[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)[S:7][CH:8]=1.CC(=O)[O:23]CC.C1CCCCC1>O.C(O)C>[CH3:3][C:4]1[N:5]=[C:6]([C:9]2([C:19]([NH2:20])=[O:23])[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)[S:7][CH:8]=1
Reactant: CCOC(C)=O
Reactant: Cc1csc(C2(C#N)CCC3(CC2)OCCO3)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCCCC1
Product: Cc1csc(C2(C(N)=O)CCC3(CC2)OCCO3)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of KOH (12.9 g, 230 mmol) in water (200 ml) was added to 8-(4-methyl-thiazol-2-yl)-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (15.2 g, 58 mmol), dissolved in ethanol (200 ml), and the mixture was stirred at RT for 48 h. Since according to TLC (EA/cyclohexane 4:1) educt was still present, the mixture was subsequently stirred at 80° C. for a further 3 h.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:12][O:13][CH2:14][CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][O:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(=O)c1cccc(Cl)c1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1cccc(Cl)c1

Procedure:
Following a procedure similar to that described in Example 40(f), 0.18 ml of 3'-chloroacetophenone was reacted with 400 mg of 5-[4-(2-aminooxyethoxy)benzyl]-thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was mixed with a mixture of diethyl ether, diisopropyl ether and hexane, and stirred. The resulting precipitate was collected by filtration, to give 290 mg of the title compound, melting at 82°-84° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:26]1[CH2:33][CH2:32][CH2:31][C@@H:27]1[C:28]([NH2:30])=O)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[C:7]([N:26]1[CH2:33][CH2:32][CH2:31][C@@H:27]1[CH2:28][NH2:30])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NC(=O)[C@H]1CCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NC[C@H]1CCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
Under cold conditions (ice bath) and under an inert atmosphere, 60 ml (61.6 mmol) of a solution of lithium aluminium hydride (1N) in THF are added dropwise to 11 g (30.8 mmol) of the compound obtained from step 1.8 suspended in THF (60 ml). After addition, the reaction mixture is heated for 3 hours at 70° C. and then cooled to 0° C. 2.8 ml of water (formation of a precipitate), 2.8 ml of NaOH solution (1N) and 8.3 ml of water are then successively added dropwise. This mixture is stirred for 30 minutes and then filtered, the solid is rinsed with THF (10 ml) and the filtrate is then concentrated under reduced pressure. 10 g of compound are obtained in the form of a bright yellow powder, which is used without further purification in the following step. Yield=95%. Melting point: 100° C.
Reaction SMILES: [N+:1]([C:4]1[CH:46]=[CH:45][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH:14]([OH:44])[CH2:15][S:16][CH2:17][C@@H:18]2[CH2:22][C@@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][N:19]2[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:32])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[C:53](Cl)(=[O:55])[CH3:54]>ClCCl>[C:53]([O:44][CH:14]([CH2:13][NH:12][C:10]([O:9][CH2:8][C:7]1[CH:45]=[CH:46][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:11])[CH2:15][S:16][CH2:17][C@@H:18]1[CH2:22][C@@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:20][N:19]1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=1)=[O:32])(=[O:55])[CH3:54]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CSCC(O)CNC(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)CSC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of (2S,4R)-2-[3-(4-nitrobenzyloxycarbonyl)amino-2-hydroxypropyl]thiomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.24 g) in dichloromethane (40 ml) were added pyridine (0.52 ml) and acetyl chloride (0.46 ml) under ice-cooling with stirring. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with water, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, in turn, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give (2S,4R)-2-[2-acetoxy-3-(4-nitrobenzyloxycarbonyl)aminopropyl]thiomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.37 g).
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:17]#[N:18])=[O:13])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH:30]([CH3:32])[CH3:31]>CN(C=O)C>[CH:30]([N:6]1[C:5]([C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=2)[C:17]#[N:18])=[O:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[NH:8][C:7]1=[O:11])([CH3:32])[CH3:31]
Reactant: CC(C)I
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2C(C)C)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 10.3 %

Procedure:
To a stirred mixture of 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (Compound 1) (5.94 g, 20 mmol) and powdered anhydrous potassium carbonate (3.31 g, 24 mmol) in DMF (40 mL), was added 2-iodopropane (2 mL, 20 mmol). The mixture was then stirred in an oil bath (50-60° C.) overnight and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to afford 700 mg (10%) of 3-(3,5-diisopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (77) as a white solid. m.p. 278-280° C.; 1H-NMR (200 MHz, CDCl3) δ 1.11 (3H, d, J=7.0 Hz), 1.20 (3H, d, J=7.0 Hz), 1.37 (3H, d, J=6.6 Hz), 1.47 (3H, d, J=6.6 Hz), 2.19 (1H, m), 2.54 (3H, s), 3.55 (1H, m), 7.81 (1H, s), 7.98 (1H, s), 8.07 (1H, s), 9.09 (1H, s); m/z (EI) 339 (M+).