Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[O:11][C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([OH:21])=[C:16]([CH3:22])[CH:15]=3)=[N:13][C:8]2=[CH:7][CH:6]=1.O[CH2:28][C:29]([CH3:41])([CH3:40])[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[O:11][C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH2:28][C:29]([CH3:41])([CH3:40])[C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])=[C:16]([CH3:22])[CH:15]=3)=[N:13][C:8]2=[CH:7][CH:6]=1
Reactant: CC(C)(CO)C(=O)OCc1ccccc1
Reactant: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1O
Product: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(C)(C)C(=O)OCc1ccccc1
Yield: 41.5 %

Procedure:
Analogously to Example 3 (step (a)), the reaction of 250 mg of 4-[5-(2-fluorophenoxy)oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenol with 178 mg of benzyl 3-hydroxy-2,2-dimethylpropionate gave 160 mg (41%) of benzyl 3-{4-[5-(2-fluorophenoxy)oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenoxy}-2,2-dimethylpropionate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[N:6]C=1.[CH:10](=O)CC.[CH3:14][C:15]([CH3:17])=[O:16].CCCCCC>>[CH3:8][C:5]1[C:4]([CH3:9])=[N:3][C:2]([CH3:1])=[C:14]([C:15](=[O:16])[CH2:17][CH3:10])[N:6]=1
Reactant: CCC=O
Reactant: Cc1cnc(C)c(C)n1
Reactant: CC(C)=O
Solvent: CCCCCC
Product: CCC(=O)c1nc(C)c(C)nc1C
Yield: 48 %

Procedure:
The reaction of trimethylpyrazine and freshly distilled propionaldehyde is carried out as described in Example I on the same molar scale. Preparative thick layer chromatography (2000μ silica gel GF, developed in 5% acetone/hexane) of the crude reaction product gives a 48% yield of 1-(2,3,5-trimethyl-6-pyrazinyl)-1-propanone (mp 65°-67° C.).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[N+:21]([O-])=O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH:24](O)=O>C(OC)(OC)OC.[Fe]>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:11]2[C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=3[N:21]=[CH:24]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=CO
Reactant: CC(=O)Nc1cccc(Nc2ccc(C(=O)O)cc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: COC(OC)OC
Product: CC(=O)Nc1cccc(-n2cnc3cc(C(=O)O)ccc32)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 4-{[3-(acetylamino)phenyl]amino}-3-nitrobenzoic acid (1.27 g, 4.04 mmol), Fe (1.77 g, 31.6 mmol, powder) in HCO2H (30 mL) and HC(OMe)3 (20 mL) was stirred under N2 at rt for 18 h. After this time, the reaction mixture was filtered through Celite, the cake washed with EtOH and the filtrate concentrated in vacuo. The resultant crude material was purified by column chromatography over silica gel eluting with 10% MeOH in DCM to afford 1-[3-(acetylamino)phenyl]-1H-benzimidazole-5-carboxylic acid. 1H NMR (400 MHz, DMSO-d6): δ 2.07 (s, 3H), 7.36 (d, J=8.4 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 8.02 (s, 1H), 8.34 (s, 1H), 8.71 (s, 1H), 10.3 (s, 1H); MS (ES+): m/z 296 [MH+]
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].S(Cl)([Cl:21])=O>C(Cl)Cl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([Cl:21])=[O:15])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
A mixture of 2.0 g of 4-(4-propylphenyl]benzoic acid and 30 ml of thionyl chloride is stirred at reflux for 45 minutes. The reaction mixture is evaporated in vacuo to a residue which is evaporated from carbon tetrachloride (2×50 ml) to give a residue which is dissolved in methylene chloride.
Reaction SMILES: [OH-].[Na+:2].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](/[CH:29]=[CH:30]/[C:31]([O:33]CC)=[O:32])=[CH:23]4)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]>C(O)C.O1CCOCC1>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](/[CH:29]=[CH:30]/[C:31]([O-:33])=[O:32])=[CH:23]4)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].[Na+:2]
Reactant: CCOC(=O)/C=C/c1cc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]c(/C=C/C(=O)[O-])cc4c3)no2)cc1C#N
Reaction time: 1 h

Procedure:
Aqueous NaOH solution (2 N, 2 mL) was added to a solution of ethyl (2E)-3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]-2-propenoate (D27) (20 mg) in ethanol (10 mL) and dioxane (5 mL) at RT. The resulting solution was stirred for 1 hour. Ethanol and dioxane were evaporated. The solid was filtered and washed with water. The solid was collected and dried to afford sodium (2E)-3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]-2-propenoate (E10) (8 mg) as a pale yellow solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 4.99 (1H, m), 6.48 (1H, d), 6.66 (1H, s), 7.11 (1H, d), 7.46 (1H, d), 7.56 (1H, d), 7.77 (1H, d), 8.25 (1H, s), 8.42 (1H, dd) 8.51 (1H, d). MS (ES): C25H21N4O4Na requires 436; found 415.0 (M—Na++2H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([C:31]#[N:32])C(O)=O)[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(=O)=O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:31]#[N:32])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(CCCCCC(C#N)C(=O)O)oc2-c2ccc(OC)cc2)cc1
Agent: O=C=O
Solvent: CCOCC
Product: COc1ccc(-c2nc(CCCCCCC#N)oc2-c2ccc(OC)cc2)cc1
Yield: 86.2 %

Procedure:
67.5 g of 7-[4,5-bis(4-methoxyphenyl)-2-oxazolyl]-2-cyanoheptanoic acid are heated to 180° C. until the evolution of carbon dioxide has ceased (7 hours). After cooling, the residual oil is dissolved in 400 cm3 of ethyl ether. The ethereal solution is washed with 3 times 50 cm3 of saturated aqueous sodium bicarbonate solution and 100 cm3 of water, dried over magnesium sulphate and filtered, and the solvent is removed. The evaporation residue is chromatographed on a column 5.8 cm3 in diameter containing 360 g of silica gel (50 to 200μ). The column is eluted, collecting 250 cm3 fractions, with 3.5 liters of a diisopropyl ether/ethyl acetate (70:30 by volume) mixture. The fractions emerging at between 0.5 and 3.5 liters are concentrated to dryness. 52.3 g (75.9%) of 7-[4,5-bis(4-methoxyphenyl)-2-oxazolyl]heptanenitrile are thereby obtained in the form of an oil, which is used directly in the above reaction.
Reaction SMILES: [OH-].[Na+].C[C@@H](CC)CC[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>C(O)C>[C:10]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)CCc1ccc(-c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(-c2ccccc2)cc1
Reaction time: 6 h

Procedure:
0.8 g of sodium hydroxide is dissolved in a solution of 5.09 g of 4'-[(S)-3-methylpentyl]-4-biphenylol (EP-A-131373) in 40 ml of ethanol. The solution is treated with 6.26 g of (S)-2-octyl-p-toluenesulfonate and heated to boiling for 6 hours. Subsequently, the solvent is distilled off and the residue is taken up in 100 ml of diethyl ether and 50 ml of 0.5 N hydrochloric acid. The aqueous phase is separated and back-extracted with 50 ml of diethyl ether. The combined organic phase is washed in succession with 50 ml of water, with 30 ml of 3 N sodium hydroxide solution and three times with 50 ml of water each time, then dried over sodium sulfate and concentrated. Crystallization of the residue from ethanol gives 4-[(R)-1-methylheptyloxy]-4'-(S)-3-methylpentyl]biphenyl, m.p. (C-I) 12° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[NH3:14]>C(Cl)(Cl)Cl>[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])(=[O:3])[NH2:14]
Reactant: N
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
43.5 g (0.181 mole) of methyl 3-chlorosulfonylthiophene-2-carboxylate (VIII) is dissolved in 450 ml of absolute chloroform; ammonia is passed in at room temperature until the mixture has an alkaline reaction. After stirring the solution for a further 3 hours at room temperature (care being taken to keep the solution alkaline) it is extracted with water and the organic phase is dried and evaporated. The crystalline residue may be recrystallized from ethanol; however, for further reaction digestion with ether is sufficient.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7][C:8]([O-:11])(C)[CH3:9].[K+].[CH3:13][C:14]1([CH3:28])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=C(C=O)[CH:17]=[CH:16][C:15]1=2>CS(C)=O.O1CCCC1>[CH3:13][C:14]1([CH3:28])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:7]([CH:8]3[CH2:9][O:11]3)[CH:17]=[CH:16][C:15]1=2
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C3CO3)ccc21
Reaction time: 0.5 h

Procedure:
33 g (0.15 mole) of trimethylsulfoxonium iodide were added at room temperature to a solution of 17 g (0.15 mole) of potassium tert-butylate in 150 ml of dried dimethyl sulfoxide. The mixture was stirred for 0.5 hour, after which a solution of 32.5 g (0.15 mole) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthaldehyde in 100 ml of tetrahydrofuran was added dropwise. Stirring was continued for 1 hour, after which the mixture was poured onto water and extracted with ether. The organic phase was washed with water, dried over magnesium sulfate and evaporated down. 31.3 g of (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-oxirane remained. The structure was determined by H-NMR spectroscopy.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]([F:32])([F:31])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]3[NH:27][CH:28]=[CH:29][C:22]=23)=[C:16]([F:30])[CH:15]=1)=[O:12].C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:29]1[C:22]2[C:23](=[N:24][CH:25]=[CH:26][C:21]=2[O:20][C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C:10]([F:31])([F:9])[F:32])=[CH:15][C:16]=2[F:30])[NH:27][CH:28]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1)C(F)(F)F
Reaction time: 8 h

Procedure:
233 mg (1.75 mmol) of N-chlorosuccinimide are added to a solution of 540 mg (1.59 mmol) of 2,2,2-trifluoro-N-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]acetamide in anhydrous tetrahydrofuran (20 ml). The solution is stirred overnight. 20 ml of a saturated sodium bicarbonate solution are added, and the mixture is extracted with ethyl acetate (two times 20 ml). The combined organic phases are washed with a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. This gives a solid which is not purified any further.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.O[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCO)o1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OCCCc2oc(-n3ccnc3C)nc2-c2ccc(Cl)cc2)cc1
Reaction time: 1 h

Procedure:
To a mixture of (4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (100 mg), methyl 4-hydroxyphenylacetate (76 mg), tributylphosphine (93 mg) and tetrahydrofuran (5 ml) was added 1,1′-(azodicarbonyl)dipiperidine (116 mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and methyl 4-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propoxy]phenylacetate was obtained as an oil (103 mg, 70%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH2:12]O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.[CH3:25][NH2:26]>>[CH3:25][NH:26][CH2:12][CH2:11][CH2:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(CCCO)c1ccccc1
Reactant: CN
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CNCCCS(=O)(=O)c1ccccc1
Reaction time: 24 h

Procedure:
25.5 g (71.9 mmol) of 3-(phenylsulfonyl)-1-propanol-4-methylbenzenesulfonate [see H. O. Fong et al., Can. J. Chem., 57, 1206 (1979)]were dissolved in 45 ml of methylamine and stirred for 24 hours at 80° and 1000 kpa. Thereafter, the methylamine was evaporated under reduced pressure, the residue was poured into ice-water and extracted with methylene chloride. The methylene chloride extracts were dried over potassium carbonate and evaporated under reduced pressure, whereby there were obtained 14.1 g of N-methyl-3-(phenylsulfonyl)propylamine as an oil, MS: 214 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:18]=[CH:17][C:16]=1[NH2:26]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:26][C:16]1[CH:17]=[CH:18][C:19]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[CH:20][C:15]=1[Cl:14])=[O:8])=[O:5]
Reactant: Nc1ccc(-c2nnn[nH]2)cc1Cl
Reactant: O=C=NC(=O)c1ccc(F)cc1Cl
Solvent: CC#N
Product: O=C(NC(=O)c1ccc(F)cc1Cl)Nc1ccc(-c2nnn[nH]2)cc1Cl
Temperature: 40 °C
Reaction time: 1 h

Procedure:
The solution of equivalent amounts of 2-chloro-4-fluorobenzoyl isocyanate was added dropwise to the solution of 100 mg of 2-chloro-4-(1H-tetrazol-5-yl)phenylamine in 3 ml of acetonitrile and the mixture was stirred at 40° C. for 60 minutes. The solid formed was filtered off with suction and dried under reduced pressure.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[N:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[C:12]([O:21]C)=[CH:11][CH:10]=1)=[O:8]>Br>[C:17]([CH2:16][CH2:15][C:13]1[C:12]([OH:21])=[CH:11][CH:10]=[C:9]([C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]([OH:23])=[O:2])[N:14]=1)([OH:19])=[O:18]
Reactant: COC(=O)CCCC(=O)c1ccc(OC)c(CCC(=O)OC)n1
Agent: Br
Product: O=C(O)CCCC(=O)c1ccc(O)c(CCC(=O)O)n1
Yield: 66.2 %

Procedure:
A solution of 330 mg of 5-[3-methoxy-2-(2-methoxycarbonylethyl)-6-pyridyl]-5-oxopentanoic acid methyl ester in 3 ml of 48% hydrobromic acid is refluxed for 13 hours. The hydrobromic acid is distilled off, the residue is dissolved in water, adjusted to pH 4 with concentrated ammonia solution, shaken out with ethyl acetate, the organic phase is dried on sodium sulfate and concentrated by evaporation. 190 mg of 5-[2-(2-carboxyethyl)-3-hydroxy-6-pyridyl]-5-oxopentanoic acid is obtained as crude product of melting point 134°-136° C. 180 mg of this crude product is dissolved in 5 ml of methanol with 60 mg of Amberlyst 15 and stirred for 16 hours at room temperature. The reaction mixture is filtered on diatomaceous earth, the filter residue is washed with ethyl acetate, the filtrate is concentrated by evaporation, and the crude product is chromatographed on silica gel with hexane/0-15% ethyl acetate. 75 mg of 5-[3-hydroxy-2-(2-methoxycarbonylethyl)-6-pyridyl]-5-oxopentanoic acid methyl ester is obtained as yellow oil.
Reaction SMILES: C(OCC)(=O)CC(C)=O.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][NH2:17].[CH:18]1([C:21]2N(C(C)C)N=[CH:23][C:22]=2[CH:29]=[O:30])CC1>>[CH3:18][C:21]1[N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[N:17]=[CH:23][C:22]=1[CH:29]=[O:30]
Reactant: NNc1ccccn1
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Solvent: CCOC(=O)CC(C)=O
Product: Cc1c(C=O)cnn1-c1ccccn1

Procedure:
5-Methyl-1-pyridin-2-yl-1H-pyrazole-4-carbaldehyde was prepared from ethyl acetoacetate and 2-pyridyl hydrazine in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:26]([C:25]3[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(Cl)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 37.6 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 4-Chlorobenzaldehyde (39.5 mg, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 39.8 mg (38%) of the title compound. (300 MHz, DMSO-d6) 13.39 (s, 1H), 8.14 (d, J=9 Hz, 1H), 7.96 (s, 1H), 7.77 (s, 1H), 7.63 (d, J=9 Hz, 2H), 7.24 (m, 2H), 7.24 (s, 2H), 6.41 (s, 1H), 6.37 (m, 1H), 5.18 (t, J=17 Hz, 9 Hz, 1H), 2.89 (s, 1H), 2.79 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.23 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=414 (M+H), HPLC: 2.75 min (G Method)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]2[S:19][C:20]3[C:26]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:25][CH:24]=[C:23]([O:33][CH3:34])[C:21]=3[N:22]=2)=[O:17])[CH:11]([OH:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:35])[CH:12]([NH:15][C:16]([C:18]2[S:19][C:20]3[C:26]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:25][CH:24]=[C:23]([O:33][CH3:34])[C:21]=3[N:22]=2)=[O:17])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CCC3O)nc12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CCC3=O)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
To a solution of 0.56 g 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester in 10 ml dimethylsulfoxide were added 0.93 ml triethylamine, 10 ml dichlotomethane and a solution of 0.58 g sulfur trioxide pyridine complex in 8 ml dimethylsulfoxide. The mixture was stirred for 18 hours at room temperature. Extraction with water/ ethylacetate and chromatography on silicagel with dichloromethane/methanol 97:3 yielded 0.49 g (87%) 4-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-5-oxo-azepane-1-carboxylic acid tert-butyl ester as yellow solid; M.p.: 95–97° C.; MS (ISP): m/e=505 (M+H+).
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[CH:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10]>CCOCC>[OH:11][CH:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:3]#[CH:2]
Reactant: CCCCC=O
Reactant: C#CCBr
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(O)CCCC
Temperature: 30 °C

Procedure:
A suspension of 24.3 g. (1.0 mole) of magnesium in 90 ml. of dry ether is stirred at room temperature under nitrogen with 100 mg. of mercuric chloride. The reaction is initiated by the addition of 2 ml. of propargyl bromide and maintained by the dropwise addition of a solution of 119.5 g. (1.0 mole) of propargyl bromide and 107.7 g. (1.25 mole) of valeraldehyde in 300 ml. of dry ether. While the initial reaction is quite vigorous and is maintained at 30° C. only by cooling in an ice bath it may become necessary to heat the mixture to reflux temperature after about a third of the ether solution is added in order to maintain the reaction. After the addition is complete the reaction mixture is refluxed until most of the magnesium is dissolved (several hours) and the reaction mixture is decanted from excess magnesium into 1500 ml. of stirred ice-cold ammonium chloride solution. The ether layer is separated and the aqueous layer is extracted three times with 300 ml. portions of ether. The combined ether extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered. Evaporation of the ether under vacuum leaves about 115 mg. of yellow oil, which is distilled through a 15 cm. Vigreaux column at 18 mm. The fraction boiling at 81°-82° C. is collected (36 g.) and the higher-boiling and lower-boiling distillates may be redistilled to yield additional product. The infrared absorption spectrum shows at most a trace of allene (5.1 μ) and gas-liquid partition chromatography shows a purity of about 98% for the main fraction.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[CH3:19][NH:20][CH3:21]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:20]([CH3:21])[CH3:19])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: CNC
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)COC2
Solvent: CO
Product: CN(C)c1nc(Cl)nc2c1COCC2c1ccccc1
Yield: 100 %

Procedure:
A solution of 2,4-dichloro-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (135 mg, 0.480 mmol) and excess dimethylamine (216 mg, 4.80 mmol) in MeOH (2 mL) was stirred at rt for 1.5 h. The solvent was removed in vacuum to afford 2-chloro-N,N-dimethyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (139 mg, 0.480 mmol, 100% yield). LC-MS (M+H)+=290.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:16]([N+:28]([O-:30])=[O:29])=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:26])([CH3:25])[C:19]=3[CH:27]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:31]O>>[CH3:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:16]([N+:28]([O-:30])=[O:29])=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:25])([CH3:26])[C:19]=3[CH:27]=2)=[O:31])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2cc3c(cc2[N+](=O)[O-])NC(=O)OC3(C)C)cc1C
Product: Cc1ccc(S(=O)CCCCOc2cc3c(cc2[N+](=O)[O-])NC(=O)OC3(C)C)cc1C

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dimethyl-phenylmercapto)-butoxy]-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.