Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10](C=C)[N:9]2[C:16](=[O:20])[CH2:17][CH:18]=[CH2:19])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C>C(Cl)Cl.CC1C=C(C)C(N2[CH-]N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]3[N:9]2[C:16](=[O:20])[CH2:17][CH:18]=[CH:19]3)[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(=O)N1[C@H](C=C)CCC[C@@H]1c1cccc(F)c1
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1cc(C)c(N2[CH-]N(c3c(C)cc(C)cc3C)CC2)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC=C[C@@H]2CCC[C@H](c3cccc(F)c3)N12
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A solution of 1-[(2R*,6S*)-2-(3-fluorophenyl)-6-vinylpiperidin-1-yl]-3-buten-1-one (587 mg) and tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium (IV) dichloride (92 mg) in methylene chloride (250 mL) was heated under reflux in a nitrogen atmosphere for two hours. The reaction solution was left to cool to room temperature. Then, triethylamine (0.5 mL) was added thereto, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 460 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9](C2C=CC=C(F)C=2)=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].Cl.[C:19](=N)(OCC)[CH3:20]>CO>[CH3:19][C:20]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH:9]=[O:10])=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccc(C(=O)c2cccc(F)c2)cc1N
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CO
Product: Cc1nc2cc(C=O)ccc2[nH]1
Reaction time: 17 h

Procedure:
(a-1) A mixture of 20 parts of (3,4-diaminophenyl) (3-fluorophenyl) methanone, 27 parts of ethyl ethanimidate hydrochloride and 80 parts of methanol was stirred for 17 hours at reflux temperature. The reaction mixture was filtered and the filtrate was evaporated. The residue was taken up in a potassium carbonate solution 10% and the product was extracted with ethyl acetate. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 15.6 parts (70.5%) of 3-fluorophenyl) (2-methyl-1H-benzimidazol-5-yl)methanone as a residue (int. 34).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][CH:27]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[CH3:11])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].CN(C=O)C.[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[NH:1]([C:23]([O:25][CH2:26][CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[C:39]1=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:24])[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:20]([O:22][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[CH3:11])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1

Procedure:
The Fmoc-Met-Ala-Leu is added into a round bottom flask with DMF and a magnetic stirrer. After the tripeptide is dissolved, benzyl bromide, followed by cesium carbonate, is added to the solution with stirring. The reaction mixture is stirred at room temperature for 1.5 hrs. Then, the reaction mixture is slowly poured into a flask with iced water. The precipitate is collected by suction filtration. The product, Fmoc-Met-Ala-Leu-OBn, is washed with water and placed in a vacuum desiccator.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Reaction time: 16 h

Procedure:
A 2.01 g (10 mmol) sample of (S)-1-BOC-2-pyrrolidinemethanol (from Example 1a) and 1.41 g (15 mmol) of phenol (Aldrich) were added to a complex of TPP and DEAD, (prepared as in Example 5b above, 15 mmol of each) in 100 mL of THF. The reaction was stirred for 16 hr, the solvents were removed under vacuum, and the residue was extracted with hexane and chromatographed on silica gel to give 0.7 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[S:16][C:17]([C:20]([CH2:23][O:24][C:25](=[O:31])[CH2:26][O:27][C:28](=[O:30])[CH3:29])([CH3:22])[CH3:21])=[N:18][N:19]=1>C1(C)C=CC=CC=1.CCCCC>[C:28]([O:27][CH2:26][C:25]([O:24][CH2:23][C:20]([C:17]1[S:16][C:15]([NH:14][C:5](=[O:6])[C:4]2[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=2[O:12][CH3:13])=[N:19][N:18]=1)([CH3:22])[CH3:21])=[O:31])(=[O:30])[CH3:29]
Reactant: CC(=O)OCC(=O)OCC(C)(C)c1nnc(N)s1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C(=O)Nc1nnc(C(C)(C)COC(=O)COC(C)=O)s1
Temperature: 25 °C
Yield: 3 %

Procedure:
A solution of 300 mg of 2,6-dimethoxybenzoyl chloride in 20 ml of toluene containing 300 mg of 2-amino-5-[(2-acetoxy-1-acetoxymethyl)-1-methylethyl]-1,3,4-thiadiazole was heated at reflux for eighteen hours. The reaction mixture was cooled to room temperature and diluted with pentane. A solid precipitate which formed was collected by filtration and air dried to give N-[5-((2-acetoxy-1-acetoxymethyl)-1-methylethyl)-1,3,4-thiadiazol-2-yl]-2,6-dimethoxybenzamide in 3% yield.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:8]([NH:20][C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH3:29])=[N:9][C:10]([CH3:19])=[N:11][C:12]=1[O:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16].[C:30](=[O:32])=[O:31]>C1COCC1>[CH2:15]([CH:14]([O:13][C:12]1[C:7]([C:30]([OH:32])=[O:31])=[C:8]([NH:20][C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH3:29])[N:9]=[C:10]([CH3:19])[N:11]=1)[CH2:17][CH3:18])[CH3:16]
Reactant: O=C=O
Reactant: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-BuLi in THF was added a solution of [5-bromo-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine in THF at −78° C. After stirring for 10 minutes. CO2(g) was added at −78° C. and stirred at that temperature for 1 hour, then gradually warmed to room temperature. The resulting mixture was quenched with water and adjusted to pH 2 to 3 and extracted with chloroform. The organic layer was separated, dried and concentrated to dryness. The residue was purified through silica gel column chromatography to give the title compound as a solid, mp. 118-120° C., Anal. For C20H27N3O3 calc.: C, 67.20; H, 7.61; N, 11.76; found: C, 67.25; H, 7.87; N, 11.48.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:10]1[C:11]([CH3:22])=[CH:12][C:13]([C:16]([NH:18][CH2:19][CH2:20][OH:21])=[O:17])=[N:14][CH:15]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:23]([C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)=[O:39])[C:10]1[C:11]([CH3:22])=[CH:12][C:13]([C:16]([NH:18][CH2:19][CH2:20][OH:21])=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)NCCO)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C(=O)NCCO)ncc1C(c1cc(F)ccc1F)S(=O)c1ccc(F)cc1
Reaction time: 3 h
Yield: 47.7 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)thio]methyl]-N-(2-hydroxyethyl)-4-methylpyridine-2-carboxamide (478 mg, 1.11 mmol) in methylene chloride (15 ml), 3-chloroperbenzoic acid (293 mg, 1.11 mmol) was added at 0° C. After stirring for 3 hours at the same temperature, the reaction mixture was washed with 1 N aqueous sodium hydroxide, the organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=1:2 was concentrated under reduced pressure. The resulting residue was washed with hexane, and then the residue was dried under reduced pressure, to obtain the title compound (238 mg, 0.53 mmol, 48%) as a colorless foamy substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[CH2:10]([N:17]1[CH2:22][C:21](OC)=[CH:20][C:19](=[O:25])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>CCOCC.C1COCC1>[CH2:10]([N:17]1[CH2:22][C:21]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:20][C:19](=[O:25])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccc([Mg]Br)c1
Reactant: COC1=CC(=O)CN(Cc2ccccc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1C=C(c2cccc(Cl)c2)CN(Cc2ccccc2)C1
Reaction time: 1 h

Procedure:
A solution of m-chlorophenyl magnesium bromide (85 mM) in ether (50 ml) was treated dropwise with a solution of 1-benzyl-1,6-dihydro-5-methoxy-3-[2H]pyridone (16.3 g, 75 mM) in THF (75 ml) and stirred 1 hour. The reaction mixture was poured onto cold 2 N hydrochloric acid (150 ml) and stirred 30 min. Removal of the resulting precipitate by filtration, followed by air-drying and recrystallisation from ethanol gave the title compound as the hydrochloride hydrate (14.7 g) m.p. 143°-5°.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15](C(O)=O)[CH:16]=3)[CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C1(P([N:36]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CC(O)(C)C>[NH2:36][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]1=[O:1])[CH2:18]2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ccccc21

Procedure:
A solution of (±)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indole]-5-carboxylic acid from Step B (65.0 mg, 0.233 mmol), diphenylphosphoryl azide (0.060 mL, 0.279 mmol), and triethylamine (0.039 mL, 0.279 mmol) in t-BuOH (5 mL) was heated to reflux for 3 h. The reaction mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=295 (M-C4H7).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=O)=O.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.FC(F)(F)CSCC1CCN(C(OC(C)(C)C)=O)CC1>>[C:20]1([S:26][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:11][CH2:12]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: Sc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC(CSCC(F)(F)F)CC1
Product: CC(C)(C)OC(=O)N1CCC(CSc2ccccc2)CC1
Yield: 144 %

Procedure:
tert-Butyl 4-[(phenylsulfanyl)methyl]piperidine-1-carboxylate was prepared from tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate 181, 0.320 g, 1.091 mmol) and thiophenol (0.117 mL, 1.145 mmol) according to the method described for Intermediate 183 to afford the title compound (0.483 g). 1H NMR (250 MHz, CDCl3) δ ppm 7.22 (5H, m), 4.10 (2H, m), 2.83 (2H d), 2.64 (2H, t), 1.84 (2H, d), 1.63 (1H, m), 1.44 (9H, s) and 1.17 (2H, m).
Reaction SMILES: O.[SH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.C(N(CC)CC)C.[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24].O>CN(C)C=O>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([S:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2)=[O:24]
Reactant: O=C=NCCCl
Reactant: Sc1ncnc2nc[nH]c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCCl)Sc1ncnc2nc[nH]c12
Temperature: 15 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
A suspension of 6-mercaptopurine monohydrate (17.0 g, 0.1 mole) in dimethylformamide (150 ml) is treated with triethylamine (10.1 g, 0.1 mole) and the solid is dissolved by warming of the mixture to 50°-60° C. The solution is cooled to 15° C. and 2-chloroethylisocyanate (11.6 g, 0.11 mole) is dripped in under cooling with tap water to 15°-20° C. The reaction mixture is stirred at this temperature for 2 hours, and the precipitated product is collected on filter, washed with acetone and dried under reduced pressure at a temperature of approx. 50° C. to give 20.7 g (80%) of the title compound Ia, melting at 221°-223° C. UV absorption spectrum (in dimethylsulfoxide), λ max 326 nm (log ε4.33).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9](C(C1C=CC=CC=1)C1C=CC=CC=1)[C:8](=[O:24])[CH:7]2[C:25]1[C:26]([OH:34])=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:24])[C:7]12[CH2:35][O:34][C:26]2[CH:27]=[C:28]3[C:29](=[CH:33][C:25]1=2)[CH2:30][CH2:31][O:32]3
Reactant: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cccc(Cl)c2N1C(c1ccccc1)c1ccccc1
Product: O=C1Nc2c(Cl)cccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 7-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 7′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (78%) as a colorless solid: mp>250° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ11.01 (s, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.70 (d, J=7.1 Hz, 1H), 7.00-6.94 (m, 1H), 6.56 (s, 1H), 6.40 (s 1H), 4.80 (d, J=9.4 Hz, 1H), 4.68 (d, J=9.4 Hz, 1H), 4.49 (m, 2H), 2.95 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ178.5, 161.0, 160.5, 139.4, 134.7, 128.4, 123.4, 122.3, 120.1, 119.8, 118.9, 113.8, 92.3, 79.8, 72.0, 58.0, 28.2; MS (ES+) m/z 313.7 (M+1), 315.7 (M+1).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:16])/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C.[ClH:17]>O1CCOCC1>[ClH:17].[NH2:8][C@@H:9]([CH3:16])/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)/C=C/[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)/C=C/[C@H](C)N
Yield: 98 %

Procedure:
A solution of methyl(2E)(4S)-4-[(tert-butoxy)carbonylamino]pent-2-enoate (3.083 g, 13.45 mmol) in 4N hydrogen chloride in dioxane was stirred at room temperature for 1 hour. The volatiles were evaporated to give the title compound (2.2 g, 98%): ES-MS (m/z) 130.3 [M+1]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])=[N:5][N:4]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=2)C=CC=CC=1.N12CCCCC1C=NCCC2.Cl>O1CCOCC1.O>[CH3:35][O:34][C:32]1[CH:31]=[C:30]([O:36][CH3:37])[N:29]=[C:28]([NH:27][C:26]([NH:18][S:15]([CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:6]2[O:7][C:3]([S:2][CH3:1])=[N:4][N:5]=2)(=[O:17])=[O:16])=[O:25])[N:33]=1
Reactant: CSc1nnc(-c2ccccc2CS(N)(=O)=O)o1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Cc2ccccc2-c2nnc(SC)o2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
To a solution containing 0.62 g of the sulfonamide prepared in Example 3 contained in 10 ml of p-dioxane was added 0.6 g of phenyl(4,6-dimethoxy pyrimidin-2-yl)carbamate followed by dropwise addition of 0.33 g of 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU). The solution was stirred at room temperature for two hours then diluted with about 100 ml of water. The clear solution was acidified with concentrated hydrochloric acid (red to litmus paper), to give a viscous oil. The oil was triturated by decanting off the aqueous solvent and stirring the oil residue in about 5 ml of acetonitrile. After filtering the suspension, the solid residue was washed with 1×5 ml of warm ethyl acetate to give 0.26 g of the subject compound; m.p. 174°-177° C.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16])=[O:4].[N:19]([CH2:22][C@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33]C(C(O)=O)=[C:31]([F:38])[CH:30]=2)[CH2:24]1)=[N+:20]=[N-:21].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OCC)(=O)C>[N:19]([CH2:22][C@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:2]([C:3]([O:5][C:6]3[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=3[F:16])=[O:4])=[C:31]([F:38])[CH:30]=2)[CH2:24]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(=O)O)c(F)c2)C(=O)O1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.1 %

Procedure:
Pentafluorophenyl trifluoroacetate (2.2 ml, 12.9 mmol) was added dropwise with stirring to a solution of 5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one (3.0 g, 10.7 mmol; prepared as described in Example 3) and pyridine (3.5 ml, 42.8 mmol) in DMF (10 ml). The mixture was stirred at r.t. for 2.5 h, and ethyl acetate with 3% aq. citric acid added. Organic layer was washed twice with 3% citric acid, brine, and dried (Na2SO4). The crude material was washed with ether-hexanes to afford a white crystalline product (4.3 g, 90%). HPLC Rt=7.1. MS (m/z): [M+H]+=447.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].C[O:10][C:11](=O)[C:12]#[C:13][CH3:14].CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[CH3:14][C:13]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[NH:8][C:11](=[O:10])[CH:12]=1
Reactant: NNc1ccccn1
Reactant: CC#CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cc(=O)[nH]n1-c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.7 %

Procedure:
To a solution of pyridin-2-yl-hydrazine (1 g) in tert-butanol (15 mL) at 30° C. was added but-2-ynoic acid methyl ester (1 g). The reaction vessel was then cooled in an ice bath was treated with potassium tert butoxide (2 g) portionwise. The resulting suspension was stirred at ambient temperature for 16 hours. The tert-butanol was reduced in vacuo and the residue was taken up in water. The aqueous layer was extracted once with DCM. The aqueous layer was then acidified with AcOH to pH=3 and the resulting precipitate was collected by filtration and washed with water. The solid was collected and dried over P2O5 in a dessicator to give 5-methyl-1-pyridin-2-yl-1,2-dihydro-pyrazol-3-one (0.3 g) as a white solid. MS (ESI+): 176.3 [M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[S:16]1[C:20]([C:21]2[O:22][C:23]([CH3:28])=[C:24]([CH2:26]Cl)[N:25]=2)=[CH:19][C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]1=2>>[S:16]1[C:20]([C:21]2[O:22][C:23]([CH3:28])=[C:24]([CH2:26][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:25]=2)=[CH:19][C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]1=2
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: Cc1oc(-c2cc3ccccc3s2)nc1CCl
Product: Cc1oc(-c2cc3ccccc3s2)nc1COc1ccc(CCCn2ccnc2)cc1
Yield: 38 %

Procedure:
In substantially the same manner as in Working Example 37, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(2-benzo[b]thienyl)-4-chloromethyl-5-methyloxazole to give 2-(2-benzo[b]thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-methyloxazole. The yield was 38%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 142-143° C.
Reaction SMILES: [O:1]1[C:3]2([CH2:19][O:20][C:21](=[O:35])[N:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:4][CH2:5][C:6]3[C:11]([CH:2]12)=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C1C=CN=CC=1.[FH:42]>C(Cl)Cl>[F:42][CH:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1([OH:1])[CH2:19][O:20][C:21](=[O:35])[N:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)COc1cccc2c1CCC1(COC(=O)N(c3ccccc3)c3ccccc3)OC21
Reactant: F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)COc1cccc2c1CCC(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2F
Reaction time: 2 h

Procedure:
To a solution of 1,2-epoxy-2-(N,N-diphenylcarbamoyloxymethyl)-5-ethoxycarbonylmethyloxy-1,2,3,4-tetrahydronaphthalene (0.2 g) in CH2Cl2 (30 ml) was added HF-pyridine (0.5 ml) at 0° C. After being stirred for 2 hours, the solvent was removed in vacuo. The residue was extracted with ethyl acetate. The mixture was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-fluoro-2-hydroxy-2-(N,N-diphenylcarbamoyloxymethyl)-5-ethoxycarbonylmethyloxy-1,2,3,4-tetrahydronaphthalene (70 mg)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][C:4]=1[N+:26]([O-])=O>[Pd].CO.C(Cl)Cl>[NH2:26][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:3]=1[NH:2][CH3:1])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CCc1nc2ccccc2n1Cc1ccc(NC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCc1nc2ccccc2n1Cc1ccc(NC)c(N)c1

Procedure:
Prepared analogously to Example 1c from ethyl 3-[1-(4-methylamino-3-nitro-benzyl)-1H-benzimidazol-2-yl]-propionate and palladium on activated charcoal in methanol/methylene chloride.
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]([CH3:11])=[C:7]([CH2:9][CH3:10])[CH:8]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:14].O>CCCCCC>[Cl:14][C:4]1[C:3]([C:1]#[N:2])=[CH:8][C:7]([CH2:9][CH3:10])=[C:6]([CH3:11])[N:5]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCc1cc(C#N)c(=O)[nH]c1C
Solvent: CCCCCC
Solvent: O
Product: CCc1cc(C#N)c(Cl)nc1C

Procedure:
3-Cyano-5-ethyl-6-methyl-2-(1H)-pyridinone (22.9 g, .141 mol) and phosphorus pentachloride (33.1 g, 0.159 mol) were intimately mixed and heated at 110°-120° C. for one hour. The liquified solids were poured onto crushed ice and water and the semi-solid was extracted into chloroform. This extract was washed with water, saturated aqueous NaHCO3, dried (Na2SO4), filtered and evaporated. This amber oil was dissolved in hexane and the insoluble material was removed when filtered through a pad of charcoal. Removal of the solvent gave a light yellow oil which solidified (17.7 g). Trituration of this solid with cold hexane yielded pure product, m.p. 63°-64° C.