Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32]>ClCCl.CN(C)C1C=CN=CC=1>[CH:19]1([NH:18][C:16]([C:11]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:31]([N:30]([CH3:34])[CH3:29])=[O:32])=[CH:3][CH:4]=3)[C:12]=2[CH2:13][CH2:14][CH3:15])=[O:17])[CH2:20][CH2:21]1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.32 g) obtained in Example 1d) and triethylamine (1.5 ml) in dichloromethane (7 ml) was added dimethylcarbamoyl chloride (0.15 g) under ice-cooling. The mixture was stirred at room temperature for 4 hr, N,N-dimethylpyridin-4-amine (0.14 g) was added, and the mixture was further stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with 1N hydrochloric acid and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column (hexane/ethyl acetate=7/3 to ethyl acetate), and the resultant product was recrystallized from ethanol to give the title compound as a colorless powder (0.26 g, 64%).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[OH-].[Na+].Cl>CCO>[O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CCOC(=O)CCCCOc1ccc2oc3ccccc3c(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCOc1ccc2oc3ccccc3c(=O)c2c1

Procedure:
Ethyl 5-(9-oxoxanthen-2-oxy)valerate (7.0 g, 21 mmol) prepared as described above was suspended in 95% EtOH (50 mL), and 4 N aqueous NaOH (50 mL, 0.2 mmol) was added. The reaction mixture was homogeneous within 1h, and saponification proceeded at 25° C. for a total of 4 h. Subsequently, 12 N aqueous HCl (17 mL) was added with cooling to adjust the pH to 3. A light-gray precipitate formed, which was collected, washed with water (3×10 mL), and dried in vacuo over P2O5, to give the free acid product. Yield: 6.1 g (94%). A small amount of the product was recrystallized from n-hexane-EtOH (10:1) for elemental analysis in accordance with structure. Light beige needles, m.p. 151-152° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:23]([OH:25])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:30][C:31]1[S:32][CH:33]=[N:34][N:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)=[N:11][C:10]=2[C:23]([NH:30][C:31]2[S:32][CH:33]=[N:34][N:35]=2)=[O:25])=[CH:7][CH:8]=1
Reactant: Nc1nncs1
Reactant: COc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)Nc2nncs2)cc1

Procedure:
5-(4-Methoxyphenyl)-2-(4-nitrophenyl)imidazole-4-carboxylic acid, 1 M hydrochloric acid—ether solution, thionyl chloride and 2-amino-1,3,4-thiadiazole are reacted and treated in the same manner as in Example 1 to give 5-(4-methoxyphenyl)-2-(4-nitrophenyl)-N-(1,3,4-thiadiazol-2-yl)imidazole-4-carboxamide.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12](=[CH2:31])[O:11][C@H:10]1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH3:48])=[CH:42][CH:41]=2)[CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[N-]>ClCCl.O.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:55]([O:54][C:52]([CH:51]1[C:12]2([C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@H:10]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH3:48])=[CH:42][CH:41]=4)[CH:33]=3)[O:11]2)[CH2:31]1)=[O:53])[CH3:56]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CC12O[C@@H](c1ccc(Cl)c(Cc3ccc(OCC)cc3)c1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of (2S,3S,4R,5S)-3,4,5-tris-benzyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methylene-tetrahydro-pyran (See Ex. 1, step III, 100 mg, 0.15 mmole) and rhodium acetate dimmer (0.13 mg, 0.002 mmole) in dry dichloromehane (5 mL), ethyl diazoacetate in dichloromethane (2 mL) was added during 3 hours at room temperature and stirred for 18 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2×30 mL). The crude product was purified by silica gel column chromatography (20% ethyl acetate in hexane) to furnish 50 mg of (5S,6S,7R,8S)-6,7,8-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-4-oxa-spiro[2.5]octane-1-carboxylic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:40][CH:41]([CH3:43])[CH3:42])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[N:20]=[C:19]([CH:22](OC)[O:23]C)[C:18]([CH:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[CH:17][C:16]=3[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].Cl>O1CCOCC1.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[C:4]([O:40][CH:41]([CH3:43])[CH3:42])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[C:19]([CH:22]=[O:23])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COC(OC)c1nc2c(cc1C1CCN(C(=O)OC(C)(C)C)CC1)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)Oc1cc(NC(=O)N2CCCc3cc(C4CCNCC4)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butyl 4-(8-((5-cyano-4-isopropoxypyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)piperidine-1-carboxylate (intermediate 338, 55 mg) and 4N HCl in dioxane (0.35 ml) was stirred at room temperature. After 3 h, additional 4N HCl in dioxane (0.15 ml) was added. After 5 h, the reaction mixture was diluted with sat. aq. NaHCO3 and extracted with DCM (3×). The combined organic phases were dried over Na2SO4 and evaporated. The residue was triturated with Et2O to give the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].CS(O[CH2:17][C:18]([F:21])([F:20])[F:19])(=O)=O>CN(P(N(C)C)(N(C)C)=O)C.Cl>[F:19][C:18]([F:21])([F:20])[CH2:17][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.7 %

Procedure:
To a solution 4-cyanophenol (5.0 grams, 42.0 mmole) in HMPT (40 ml) was added sodium hydride (1.68 grams, 42.0 mmole) and stirred for 15 minutes at room temperature. Via syringe 2,2,2-trifluoroethyl methane sulphonate (8.98 grams, 50.4 mmole) was added and the mixture was stirred at 140° C. over night. The mixture was cooled to room temperature, diluted with 300 ml ice water and 50 ml 2 N hydrochloric acid and extracted with diethyl ether. The combined extracts were washed with water, 1N sodium hydroxide and brine, dried over Na2SO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 25% diethyl ether/hexane as eluent to give an oil (2.68 g). Synthesis 727 (1980).
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[H-].[Na+].F[C:16]1[C:21]([CH3:22])=[C:20]([I:23])[CH:19]=[CH:18][N:17]=1>O1CCCC1>[C:3]12([CH2:2][O:1][C:16]3[C:21]([CH3:22])=[C:20]([I:23])[CH:19]=[CH:18][N:17]=3)[CH2:12][CH:7]3[CH2:6][CH:5]([CH2:11][CH:9]([CH2:8]3)[CH2:10]1)[CH2:4]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1c(I)ccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(I)ccnc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Hydroxylmethyladamantane (249 mg) was dissolved in tetrahydrofuran (3.5 mL) and NaH (24 mg) was added. After the gas evolution ceased, 2-fluoro-4-iodo-3-methylpyridine (237 mg) in tetrahydrofuran (1.5 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours, quenched with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by preparative TLC, eluting with petroleum ether to provide the title compound.
Reaction SMILES: [C:1]1(C)C=CC=C[CH:2]=1.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH2:30][C:31]#[N:32])[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.BrCCCl>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].[OH-].[Na+].O>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([C:30]2([C:31]#[N:32])[CH2:2][CH2:1]2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCBr
Solvent: O
Product: N#CC1(c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 66 %

Procedure:
To a mixture of (n-C4H9)4NBr (0.50 g, 1.5 mmol), toluene (7 mL) and (3,4-bis-benzyloxy-phenyl)-acetonitrile (14 g, 42 mmol) in NaOH (50 g) and H2O (50 mL) was added BrCH2CH2Cl (30 g, 0.21 mol). The reaction mixture was stirred at 50° C. for 5 h before being cooled to room temperature. Toluene (30 mL) was added and the organic layer was separated and washed with H2O, brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by column on silica gel (petroleum ether/ethyl acetate 10:1) to give 1-(3,4-bis-benzyloxy-phenyl)-cyclopropanecarbonitrile (10 g, 66%). 1H NMR (DMSO 300 MHz) δ 7.46-7.30 (m, 10H), 7.03 (d, J=8.4 Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 6.89 (dd, J=2.4, 8.4 Hz, 1H), 5.12 (d, J=7.5 Hz, 4H), 1.66-1.62 (m, 2H), 1.42-1.37 (m, 2H).
Reaction SMILES: Cl[CH:2]([F:14])[CH2:3][CH:4]([OH:13])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C(=O)([O-])O.[Na+].[C:20]1([N:26]2[C:30]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:29](=[O:36])[NH:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I-].[K+]>C1(C)C=CC=CC=1>[O:36]=[C:29]1[C:30]2([CH2:31][CH2:32][N:33]([CH:2]([F:14])[CH2:3][CH:4]([OH:13])[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:6])[CH2:34][CH2:35]2)[N:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][NH:28]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C(c1ccccc1)C(O)CC(F)Cl
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)C(O)CC(F)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 18.75 g of γ-chloro-2-hydroxy-4-fluorobutyrophenone, 5.25 g of sodium hydrogen carbonate, 15 g of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 0.02 g of potassium iodide and 2 liters of toluene was refluxed for 80 hours. The resulting mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residual solid was washed with diethyl ether to give γ-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decan-8-yl)-2-hydroxy-4-fluorobutyrophenone, M.P. 215°-220° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13][OH:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH:6]=[CH:5]2>C(O)C.Cl.[Pd].[Pt]>[F:1][C:2]1[C:3]([CH2:13][OH:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2
Reactant: CC1C=Cc2c(ccc(F)c2CO)N1
Agent: [Pd]
Agent: [Pt]
Agent: Cl
Solvent: CCO
Product: CC1CCc2c(ccc(F)c2CO)N1
Reaction time: 5 h

Procedure:
A solid which was chiefly 1,2-dihydro-6-fluoro-5-hydroxymethylquinaldine (7.0 g) was dissolved in 200 ml of ethanol containing 1 ml of concentrated hydrochloric acid, 1.0 g of 5% palladium on charcoal, and 1.0 g 5% platinum on charcoal and the mixture was hydrogenated at 50 psi at 20° C. for 5 hours. The solution was filtered and the filtrate was evaporated to provide white solid 6-fluoro-5-hydroxymethyl-1,2,3,4-tetrahydroquinaldine as determined by nuclear magnetic resonance spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH:9]=2.[CH:27]([NH2:30])([CH3:29])[CH3:28]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:30][CH:27]([CH3:29])[CH3:28])[CH:9]=2
Reactant: COc1cc(OC)cc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)c1
Reactant: CC(C)N
Solvent: CO
Product: COc1cc(OC)cc(-c2cc(=O)c3ccc(OCC(O)CNC(C)C)cc3o2)c1

Procedure:
3′,5′-Dimethoxy-7-(2,3-epoxy-propoxy)-flavone, 32 (700 mg, 2 mmol) and iso-propyl amine (1.0 mL, 12 mmol) in dry methanol (120 mL) were reacted in a similar manner to that described under 34 to afford 44. Yield 720 mg (87%); mp 155-156° C.; MS (FAB) 414 (M++1); IR (KBr) 3426, 1630; 1H NMR (200 MHz, DMSO-d6) δ 7.95 (d, J=8.9 Hz, 1H), 7.34 (s, 1H), 7.18 (d, J=1.8 Hz, 2H), 7.09 (dd, J=8.9 Hz, 1.9 Hz, 1H), 6.96 (s, 1H), 6.70 (s, 1H), 4.20-3.90 (m, 3H), 3.85 (s, 6H), 2.84-2.58 (m, 3H), 1.03 (d, J=6.2 Hz, 6H). Analysis Calcd for C23H27NO6: C, 66.81; H, 6.58; N, 3.39. Found: C, 66.69; H, 6.13; N, 3.62.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.CN(C)[CH:26]=[O:27].P(Cl)(Cl)(Cl)=O.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH:26]=[O:27])=[C:9]2[CH3:23])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c(C=O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (Example 1) (1.55 g, 4.71 mmol) in dimethylformamide (3.65 ml, 47 mmol) and toluene (20 ml), phosphorous oxychloride (3.5 ml, 37.7 mmol) was added. After stirring for 20 minutes, the reaction mixture was heated at 70° C. for 5 hours. The reaction mixture was cooled, poured into aqueous sodium acetate solution and extracted with ethyl acetate. The organic fractions were washed with 10% aqueous potassium carbonate and water. After drying (Na2SO4), filtration and concentration, the crude yellowish liquid (2.06 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-carboxaldehyde (1.2 g, 71%): mp (DSC) 155° C. Anal Calc'd. for C19H16NSFO3 : C, 63.85; H, 4.51; N, 3.92. Found: C, 63.50; H, 4.66; N, 3.85.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][NH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[CH2:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:25]=1)(=O)=O.CN(C)C=O>O>[CH2:39]([O:38][C:26]1[CH:25]=[C:24]([CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=1)[CH2:23][N:12]1[CH:13]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COC(=O)c1c[nH]cc1-c1ccccc1
Reactant: CS(=O)(=O)OCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(Cc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Sodium hydride (60%, oily, 2.20 g) was added to a mixture of methyl 4-phenylpyrrole-3-carboxylate (11.10 g), 3,5-dibenzyloxybenzyl methanesulfonate (21.9 g) and N,N-dimethylformamide (200 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and methyl 1-(3,5-dibenzyloxybenzyl)-4-phenylpyrrole-3-carboxylate (26.4 g, yield: 95%) was obtained as an oily substance from the fraction eluted with tetrahydrofuran-hexane (1:2, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=1Br.C(N(CC)CC)C.[CH:21]#[C:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=1[C:21]#[C:22][CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)c1ccc(C=O)cc1Br
Reactant: C#CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC#Cc1cc(C=O)ccc1C(=O)OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a room temperature solution of 2-Bromo-4-formyl-benzoic acid methyl ester (500 mg, 2.05 mmol) in degassed DMF (5 mL) are added triethylamine (2.0 mL, 14.35 mmol), dichlorobis(triphenylphosphine)palladium (II) (144 mg, 0.205 mmol, 10 mol %), copper (I) iodide (20 mg, 0.103 mmol, 5 mol %), and 1-Pentyne (406 μL, 4.10 mmol). The reaction mixture is heated to 80° C. in a sealed tube. After 2 h, the reaction is concentrated and the residue is chromatographed (0% to 10% EtOAc/Hex) to yield the title compound (279 mg, 59%). 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 8.02-7.98 (m, 2H), 7.80 (dd, 1H, J=7.9, 1.8 Hz), 3.95 (s, 3H), 2.48 (t, 2H, J=7.0 Hz), 1.73-1.63 (m, 2H), 1.09 (t, 3H, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.B.C1COCC1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccc(F)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC(CO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.7 %

Procedure:
To a solution of 2-(4-fluorophenyl)propanoic acid (1 g, 5.95 mmol) in THF (20 mL) at 0° C. was added 1M BH3.THF (11.89 mL, 11.89 mmol) in THF and the resulting mixture was stirred at room temp for 3 h. Then, 1N HCl (3 mL) was added and the mixture was extracted with ethyl acetate 100 mL), washed with brine (50 mL), dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-50% EtOAc/hexane) to afford 2-(4-fluorophenyl)propan-1-ol (300 mg, 1.946 mmol, 32.7% yield) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.23 (dd, J=8.5, 5.5 Hz, 2H), 7.04 (t, J=8.7 Hz, 2H), 3.79-3.63 (m, 2H), 2.97 (sxt, J=6.9 Hz, 1H), 1.34 (t, J=5.5 Hz, 1H), 1.29 (d, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:3]1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22].O.C(OCC)(=O)C>N1C=CC=CC=1>[OH:17][CH2:16][C:15]([CH:4]1[CH2:3][CH:2]([NH:1][C:20](=[O:23])[CH2:21][CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5]1)([CH3:19])[CH3:18]
Reactant: CCC(=O)Cl
Reactant: CC(C)(CO)C1CC(N)c2cc([N+](=O)[O-])ccc2N1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)NC1CC(C(C)(C)CO)Nc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 22 (50 mg) and 0.1 ml of propionyl chloride were dissolved in 1 ml of pyridine. After 2 hours of stirring at room temperature, water and ethyl acetate were added. The ethyl acetate layer was washed with water, and then dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The residue was dissolved in 1 ml of methanol, 0.1 ml of a 4N aqueous solution of sodium hydroxide was added, and the mixture was stirred for 1 hour. Then, a phosphate buffer (pH 7.0) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 31 mg of the title compound. Its physical properties are shown below.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][NH:21][C:22](=[O:26])[CH2:23][CH2:24][SH:25])[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:27](Cl)[CH2:28][OH:29]>CN(C)C=O>[N:3]1([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][NH:21][C:22](=[O:26])[CH2:23][CH2:24][S:25][CH2:27][CH2:28][OH:29])[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(CCS)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: OCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CCSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
105 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling and in an atmosphere of nitrogen, to a solution of 0.76 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-3-mercaptopropionamide (prepared as described in Preparation 3) in 24 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, 0.16 ml of ethylene chlorohydrin were added to the reaction mixture, whilst ice-cooling. The reaction mixture was stirred at room temperature for 15 minutes, after which it was poured into ice-water and extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the residue thus obtained was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and methylene chloride as the eluent, to give 0.56 g of the title compound as an oil in a 65% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][NH2:29].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:28]([C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[F:20])[N:29]=1
Reactant: NNc1ccc(F)cc1F
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1ccccc1-c1nc(-c2ccccc2O)n(-c2ccc(F)cc2F)n1

Procedure:
5.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, 3.9 g of 2,4-difluorophenylhydrazine hydrochloride and 3 ml of triethylamine are boiled under reflux for 2 h in 25 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from ethanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 144-146C.