Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.[C:15](=O)([O-])[O-].[Cs+].[Cs+].CI>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][C:8](=[O:13])[N:7]([CH3:15])[C:6]=2[CH:14]=1
Reactant: O=C1CCC(=O)c2ccc(Cl)cc2N1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1C(=O)CCC(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.7 %

Procedure:
8-Chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-j) (0.2 g, 1 mmol) was dissolved in a mixture of THF (10 mL) and DMF (2 mL). Cesium carbonate (0.98 g, 3 mmol) and methyl iodide (0.069 mL, 1.1 mmol) were added and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure and dichloromethane (10 mL) was added. The inorganic precipitate was filtered and the filtrate was concentrated under reduced pressure to give a viscous residue. This residue was purified utilizing column chromatography, eluting with 50% ethyl acetate/hexane to afford the title compound as a white solid (0.1 g, 45%): MS m/z═224 (M+H).
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:42]1[CH:43]=[C:44]([NH:48][C:49]([O:51][CH2:52][CH2:53][C:54]2[CH:59]=[CH:58][C:57](Br)=[CH:56][C:55]=2[CH3:61])=[O:50])[CH:45]=[CH:46][CH:47]=1)[CH3:41])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:42]1[CH:43]=[C:44]([NH:48][C:49]([O:51][CH2:52][CH2:53][C:54]2[CH:59]=[CH:58][C:57]([B:25]([OH:27])[OH:26])=[CH:56][C:55]=2[CH3:61])=[O:50])[CH:45]=[CH:46][CH:47]=1)[CH3:41])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cc(Br)ccc1CCOC(=O)Nc1cccc([C@H](C)NC(=O)OCc2ccccc2)c1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: Cc1cc(B(O)O)ccc1CCOC(=O)Nc1cccc([C@H](C)NC(=O)OCc2ccccc2)c1
Yield: 22 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 59C (2.46 g, 4.8 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 59D (560 mg, 22%) as a solid. 1H NMR (400 MHz, MeOD-d4) δ ppm 1.25-1.41 (m, J=4.39 Hz, 3 H) 2.27 (s, 3 H) 2.61 (s, 2 H) 2.92 (s, 2 H) 4.22 (s, 2 H) 4.64 (s, 1 H) 6.84-7.56 (m, 12 H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4]/[C:5](/[CH3:21])=[CH:6]/[CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[C:11]([CH3:17])=[C:10]([CH3:18])[C:9]=1[O:19][CH3:20].[C-:22]#[N:23].[Na+].O.CC(OC)(C)C>CN(C=O)C>[CH3:20][O:19][C:9]1[C:10]([CH3:18])=[C:11]([CH3:17])[C:12]([O:15][CH3:16])=[C:13]([CH3:14])[C:8]=1[CH2:7]/[CH:6]=[C:5](\[CH3:21])/[CH2:4][CH2:3][CH2:2][C:22]#[N:23]
Reactant: [C-]#N
Reactant: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCI)c1C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: O
Product: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCC#N)c1C
Temperature: 45 °C
Reaction time: 25 h

Procedure:
1-((E)-6-iodo-3-methylhex-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene (412 mg, 1.024 mmol) was combined with NaCN (247.7 mg) and dissolved in DMF (2 mL). The reaction was stirred for 25 h at 45° C. then cooled to room temperature. To the mixture was added H2O (10 mL) followed by MTBE (6 mL) and the layers separated. The aqueous phase was extracted into MTBE (4×6 mL) and the combined organics washed with H2O (2×5 mL) followed by saturated NaCl solution (2×5 mL) and dried over Na2SO4. The organics were concentrated to give (E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enenitrile as a pale yellow oil, 306.4 mg (99.0%). 1H NMR (400 MHz, CDCl3) d 5.14 (t, J=6.4 Hz, 1H), 3.65 (s, 6H), 3.37 (d, J=6.8 Hz, 2H), 2.26 (t, J=7.2 Hz, 2H), 2.18 (s, 9H), 2.12 (t, J=7.2 Hz, 2H), 1.76 (m, 4H). 13C NMR (100 MHz, CDCl3) d 153.1, 152.6, 132.5, 131.0, 128.5, 128.0, 125.4, 119.7, 60.8, 60.1, 38.2, 38.2, 26.1, 23.5, 16.4, 15.9, 12.8, 12.7, 12.2.
Reaction SMILES: [CH3:1][C:2]1[NH:15][C:5]2=[N:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1.[C:16]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[C:22]([Cl:28])[CH:21]=1)(=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:15]2[C:5]3=[N:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:9]([CH3:10])=[C:4]3[N:3]=[C:2]2[CH3:1])=[C:22]([Cl:28])[CH:21]=1)(=[O:18])[CH3:17]
Reactant: COC(=O)c1cc(C)c2nc(C)[nH]c2n1
Reactant: CC(=O)Oc1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2nc(C)n(Cc3ccc(OC(C)=O)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 117.6 %

Procedure:
A mixture of methyl 2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (2.70 g), 4-acetoxy-2-chlorobenzylbromide (4.85 g), potassium carbonate (2.73 g) and N,N-dimethylformamide (27 ml) was stirred at room temperature for 5 hr and left standing overnight. The reaction mixture was partitioned between ethyl acetate and saturated brine, and the resulting precipitate was collected by filtration and washed with water and ethyl acetate to give methyl 3-(4-acetoxy-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (6.0 g) as a pale-brown powder. The mother liquor and washing were combined and the organic layer was separated, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was powdered from diethyl ether to give the second lot (680 mg) as a pale-brown powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16](OC)=[CH:15][C:14]=3OC)[C:10](=[O:23])[C@@H:9](CC(O)=O)[O:8][C@H:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3Cl)[C:6]=2[CH:35]=1.[OH-:36].[Na+]>CO.Cl>[CH2:12]([N:11]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:35][C:6]=2[C@H:7]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:8][C@H:9]([CH2:5][CH2:6][C:7]([OH:8])=[O:36])[C:10]1=[O:23])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(CN2C(=O)[C@@H](CC(=O)O)O[C@H](c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)CC[C@H]1O[C@@H](c2ccccc2)c2ccccc2N(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 20 ml of methanol was dissolved 0.5 g of ethyl ester of cis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionic acid obtained in Example 8. To the solution was added 7 ml of 1N sodium hydroxide, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was acidified with 100 ml of IN hydrochloric acid, which was subjected to extraction with 150 ml of ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure to leave 0.46 g of cis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionic acid as plates, m.p. 112°-114° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]([CH3:18])=[CH:6][C:7]1[CH:12]=[C:11]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:10]2=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>O1CCCC1>[NH2:17][C:15]1[CH:14]=[CH:13][C:11]2[C:10]([CH:16]=1)=[CH:9][CH:8]=[C:7]([CH:6]=[C:5]([CH3:18])[C:4]([OH:19])=[O:3])[CH:12]=2
Reactant: CCOC(=O)C(C)=Cc1ccc2cc(N)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=Cc1ccc2cc(N)ccc2c1)C(=O)O
Yield: 98 %

Procedure:
Into 10 ml of tetrahydrofuran (THF), 0.65 g of (E) 3-(2-amino-benzo[d]phenyl)-2-methyl-2-propenoic acid ethyl ester was dissolved; and, with 10 ml of a 1-N aqueous sodium hydroxide solution being added thereto, the mixture was reacted for 4 hours at 40° C. After the completion of the reaction, the mixture was cooled with 10 ml of 1-N hydrochloric acid being added thereto, and the precipitated crystal was filtered out, whereby 0.57 g of the aimed compound was obtained (yield: 98%).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](I)=[C:8]([F:13])[C:7]=1[F:14])([CH3:4])([CH3:3])[CH3:2].[I-].[F:16][C:17]([Zn+])=[C:18]([F:20])[F:19].[Cl-].[NH4+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:17]([F:16])=[C:18]([F:20])[F:19])=[C:8]([F:13])[C:7]=1[F:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1ccc(I)c(F)c1F
Reactant: FC(F)=C(F)[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc(C(F)=C(F)F)c(F)c1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A 1-liter reactor was charged with 31.2 g (0.10 mol) of 4-tert-butoxy-2,3-difluoro-1-iodobenzene and 100 ml of THF and heated at 60° C. To the reactor, 1.16 g (1 mmol) of tetrakis(triphenylphosphine)palladium(0) was added, then 300 ml of a THF solution of 1 M trifluorovinyl zinc iodide was added dropwise. After the completion of dropwise addition, the reaction solution was ripened for 30 minutes and poured into a saturated ammonium chloride aqueous solution. From the solution, a crude product was extracted with ethyl acetate in a conventional way. It was purified by silica gel chromatography, obtaining 21.5 g (yield 81%) the end product.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]4[O:17][CH:18]([CH2:20][OH:21])[CH2:19][C:9]=4[C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC(C)=[O:24].S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[Cr+6].O>[F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]4[O:17][CH:18]([C:20]([OH:24])=[O:21])[CH2:19][C:9]=4[C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=c1c2ccc3c(c2oc2cccc(F)c12)CC(CO)O3
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)C1Cc2c(ccc3c(=O)c4c(F)cccc4oc23)O1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled mixture of 8.0 g of the 7-fluoro-1,2-dihydro-2-hydroxymethyl-6-oxo-6H-furo[2,3-c]xanthene obtained in Example 27 and 1,000 ml of acetone, a mixture of chromium trioxide (14 g), water (80 ml) and concentrated sulfuric acid (24 g) was added dropwise under agitation. The resulting mixture was left to stand overnight and filtered. The filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from N,N-dimethylformamide (DMF) gave 8.1 g of 7-fluoro-1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 262°-265° C. This compound produced a mass spectrum having a molecular ion peak at m/e 300.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([O:24][C:25]([C@@H:27]1[CH2:31][C@@H:30]([OH:32])[CH2:29][C@H:28]1[C:33](=[O:45])[NH:34][C@:35]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][C@H:36]1[CH:38]=[CH2:39])=[O:26])([CH3:23])([CH3:22])[CH3:21].[F:46][C:47]1[CH:48]=[C:49]([C:53]2[N:62]=[C:61](O)[C:60]3[C:55](=[C:56]([CH3:66])[C:57]([O:64][CH3:65])=[CH:58][CH:59]=3)[N:54]=2)[CH:50]=[CH:51][CH:52]=1.N#N.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C=O)C.C1COCC1>[C:20]([O:24][C:25]([CH:27]1[CH2:31][CH:30]([O:32][C:61]2[C:60]3[C:55](=[C:56]([CH3:66])[C:57]([O:64][CH3:65])=[CH:58][CH:59]=3)[N:54]=[C:53]([C:49]3[CH:50]=[CH:51][CH:52]=[C:47]([F:46])[CH:48]=3)[N:62]=2)[CH2:29][CH:28]1[C:33](=[O:45])[NH:34][C:35]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][CH:36]1[CH:38]=[CH2:39])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Reactant: COc1ccc2c(O)nc(-c3cccc(F)c3)nc2c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3cccc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Reaction time: 18 h
Yield: 94.3 %

Procedure:
PPh3 (787 mg, 3.0 mmol) was added to a stirred solution of the alcohol 15 (550 mg, 1.5 mmol) and the quinazolinol 127 (430 mg, 1.5 mmol) in a mixture of dry THF (40 mL) and dry DMF 10 mL. The reaction mixture was put under inert atmosphere (N2) at room temperature and DIAD (591 μL, 3.0 mmol) was added. The reaction mixture was stirred for 18 h whereafter the solvents were evaporated. The residue was dissolved in CHCl3 and washed with brine in a separatory funnel. The organic phase was dried with Na2SO4, evaporated on silica and purified by flash chromatography (heptane:ethyl acetate 2:1 to 1:1) which gave the title compound as a white-beige solid (896 mg, 94%), LRMS (M+H) 634.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[C:24]([N+:31]([O-])=O)[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([NH2:28])[CH:25]=[C:24]([NH2:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=O)N1CCN(c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCO
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2cc(N)cc(N)c2)CC1
Reaction time: 4 h

Procedure:
1-[(2-Methoxyquinoxalin-3-yl)aminocarbonyl]-4-(3,5-dinitrophenyl)piperazine (200 mg, 0.44 mmol) was dissolved in ethanol (30 ml) and thereto 10% palladium/carbon (10 mg) was added. The mixture was hydrogenated for 4 hours, and then filtered to remove the 10% palladium/carbon. The filtrate was concentrated and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])O)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:11][C:10](=[C:20]([C:26]([F:29])([F:28])[F:27])[C:22]([F:23])([F:24])[F:25])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: OC(c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)(C(F)(F)F)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: Fc1ccc(C2=CC(=C(C(F)(F)F)C(F)(F)F)N=C2c2ccc(F)cc2)cc1

Procedure:
A mixture of 4.2 g (0.01 mole) of 4,5-bis(4-fluorophenyl)-α,α-di(trifluoromethyl)-1H-pyrrole-2-methanol and 100 ml acetic anhydride was heated at reflux under nitrogen for 3 hours. The mixture was cooled and concentrated under vacuum. The residue was purified by column chromatography on 400 g of silica gel. Eluted with 50/50 hexane/toluene was 4,5-bis(4-fluorophenyl)-2[2,2,2-trifluoro-1-(trifluoromethyl)-ethylidene]-2H-pyrrole, obtained after recrystallization from hexane as a yellow-orange solid, 1.8 g (45%), m.p. 145°-146°. The ir and nmr (proton and fluorine) spectra were consistent with the assigned structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:12]1[S:16][N:15]=[C:14]([S:17][CH3:18])[N:13]=1.[Cl-].[Na+]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:12]2[S:16][N:15]=[C:14]([S:17][CH3:18])[N:13]=2)=[CH:3][CH:2]=1
Reactant: CSc1nsc(Cl)n1
Reactant: OCc1ccncc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2ccncc2)n1
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
Into 4 g of N,N-dimethylformamide was dissolved 218 mg of 4-pyridinemethanol, 96 mg of sodium hydride (60% in oil) was added thereto at room temperature. After stirring for 30 minutes, a solution of 334 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole in 1 g of N,N-dimethylformamide was added dropwise into the mixture and the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 260 mg of 5-(4-pyridylmethyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (34)).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:20].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:20])[C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cn1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2sccc2-c2[nH]nc(-c3ccc(Br)nc3)c21
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of 6-(6-Bromo-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.32 g, 1.0 mmol) and Cs2CO3 (3.26 g, 10.0 mmol) in DMF (10 mL) was stirred under molecular oxygen at ambient temperature. The reaction mixture was stirred for 12 hr. Afterward, the mixture was poured into ice water, followed by aqueous wash and evaporation of the solvent, which provided the corresponding 6-(6-Bromo-pyridin-3-yl)-4H-1-thia-4,5-diaza-cyclopenta[a]pentalen-7-one (0.31 g, 0.92 mmol) as orange solid in 92% yield.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:19][CH3:20])[C:16]([OH:18])=[O:17])=[C:11]([F:21])[CH:10]=1)C1C=CC=CC=1>[Pd].CCO>[F:21][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[CH:15]([O:19][CH3:20])[C:16]([OH:18])=[O:17]
Reactant: COC(C(=O)O)c1ccc(OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: CCO
Product: COC(C(=O)O)c1ccc(O)cc1F

Procedure:
(RS)-(4-Benzyloxy-2-fluoro-phenyl)-methoxy-acetic acid was hydrogenated at rt and normal pressure using 10% Pd/C as a catalyst and EtOH as a solvent to give (RS)-(2-fluoro-4-hydroxy-phenyl)-methoxy-acetic acid as a light yellow oil. MS 199.2 ([M−H]−)
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][CH2:5][Mg]Br.C[Si](C)(C)CCCBr.[Mg].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.[Cl-].[Li+].[Cl-]>O1CCCC1.CCOCC>[CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Br:19]
Reactant: C[Si](C)(C)CCC[Mg]Br
Reactant: BrCCCCCCCCBr
Agent: C[Si](C)(C)CCCBr
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)CCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The 3-(trimethylsilyl)propyl magnesium bromide prepared from 40 g. 3-(trimethylsilyl)propyl bromide and 5.1 g. magnesium turnings in 150 ml. dry ether was dropwise added to a cole (-20°) solution of 42 g. 1,8-dibromooctane, 170 mg. lithium chloride, and 270 mg. cuprus chloride in 120 ml. dry tetrahydrofuran under an argon atmosphere. When addition of the Grignard reagent was complete, the reaction was warmed to room temperature and stirring was continued for 17 hr. The solution was treated with 200 ml. 10% hydrochloric acid, the layers were separated, and the aqueous phase was washed twice with 100 ml. portions of ether. The combined organic phases were washed with brine, dried with anhydrous magnesium sulfate, and evaporated to a colorless liquid. Distillation of the crude product yielded the title compound.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:25]1([CH2:28][OH:29])[CH2:27][CH2:26]1.C(OCC)(=O)C>CN1C(=O)CCC1.O>[CH:25]1([CH2:28][O:29][C:2]2[N:7]=[CH:6][C:5]([O:8][C:9]3[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=3)=[CH:4][CH:3]=2)[CH2:27][CH2:26]1
Reactant: OCC1CC1
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ccc(F)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(OCC3CC3)nc2)cc1

Procedure:
N-{3-[4-(6-Fluoropyridin-3-yloxy)phenyl]-1-methylpropyl}acetamide (105 mg, 0.35 mmol), sodium hydride (55% in oil) (42 mg, 1.04 mmol) and cyclopropylmethanol (62 mg, 0.86 mmol) were stirred in 3 ml of NMP at 130° C. under argon for 9 h. After cooling, ethyl acetate and water were added, and the organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 71 mg (58%), M+H+: 355.1.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[CH3:32])[C:12]1[C:20]2[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CS(C)=O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[C:26]([CH3:32])[CH:27]=1
Reactant: CSCc1cc(F)cc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3C)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: CSCc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3C)c[nH]c12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
174 mg (2.67 mmol) of potassium cyanide and 8.1 mg (0.07 mmol) of 4-N,N-dimethylaminopyridine were added to 608 mg (1.33 mmol) of the compound from Example 107A in 30 ml of DMSO. The mixture was stirred at 120° C. for 2 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 154 mg (30% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[O:13])[C:5](OC)=[N:6][CH:7]=1.[BH4-].[Na+].BrC1C=C(C=CC(C2C=CC(Cl)=C(Cl)C=2)O)C(OC)=NC=1.Br>O1CCCC1.C(O)C.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[O:13][C:5]2=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1/C=C/C(=O)c1ccc(Cl)c(Cl)c1
Agent: Br
Agent: COc1ncc(Br)cc1C=CC(O)c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: Clc1ccc(C2C=Cc3cc(Br)cnc3O2)cc1Cl
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 30 g of (E)-3-(5-bromo-2-methoxy-3-pyridinyl)-1-(3,4-dichlorophenyl)-2-propen-1-one in 275 ml of tetrahydrofuran and 260 ml of absolute ethanol was added 6.0 g of sodium borohydride. After 1 hour under nitrogen, the reaction mixture was partitioned between aqueous 1N sodium hydroxide solution and ether. The ether layer was washed with aqueous saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to give a pale yellow oil which was crude α-[2-(5-bromo-2-methoxy-3-pyridinyl)ethenyl]-3,4-dichlorobenzenemethanol. To a stirred solution of 25.9 g of this crude alcohol in 400 ml of acetic acid under nitrogen there was added 25 ml of 48% aqueous hydrobromic acid. The mixture was heated to 85° C. for about 30 minutes then cooled rapidly to 23° C. in an ice bath, and partitioned between water and ether. The ether layer was washed several times with water and then successively with aqueous saturated sodium bicarbonate and sodium chloride solutions. It was then dried over sodium sulfate and the solvent evaporated under reduced pressure to give a pale yellow oil. Filtration through a layer of silica gel using chloroform as eluant gave 6-bromo-2-(3,4-dichlorophenyl)-2H-pyrano[2,3-b]pyridine as a pale yellow solid which exhibited the same characteristics as the material obtained in Example 8.