Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Li+].[CH3:3][O:4][C:5]1[N:10]=[C:9]([C:11]#N)[CH:8]=[CH:7][C:6]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1.[OH2:19]>>[CH3:3][O:4][C:5]1[N:10]=[C:9]([C:11]([OH:19])=[O:1])[CH:8]=[CH:7][C:6]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1
Reactant: O
Reactant: [OH-]
Reactant: COc1nc(C#N)ccc1-n1cnc(C)c1
Agent: [Li+]
Product: COc1nc(C(=O)O)ccc1-n1cnc(C)c1
Temperature: 25 °C

Procedure:
Lithium hydroxide powder (13 g) was added to a suspension of 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carbonitrile (52.4 g) in water (464 mL), and the mixture was heated under reflux for three hours. The reaction solution was left to cool to room temperature. The reaction solution was filtered through celite, and the celite was washed with water (100 mL×4). Concentrated hydrochloric acid was added to the filtrate under ice-cooling to adjust the pH to 4 to 5. The precipitated powder was collected by filtration. The resulting powder was washed with water and then air-dried for three days to obtain 51.9 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.OS(O)(=O)=O.O.[C:23]([O-])(O)=O.[Na+]>CO>[NH2:1][C:2]1[C:3]([C:14]([O:16][CH3:23])=[O:15])=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: COc1nc(C(=O)O)c(N)cc1C(F)(F)F
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1nc(OC)c(C(F)(F)F)cc1N

Procedure:
3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Int. B) 5.5 g, 23.29 mmol) was dissolved in MeOH (90 ml). H2SO4 (6.21 ml, 116 mmol) was added dropwise and the solution was heated to reflux for 4 hours. The reaction mixture was reduced in vacuo to approx. 15 ml and water (15 ml) was added. The pH was adjusted to pH 9 by careful addition of solid NaHCO3. Water (100 ml) was added and the mixture was extracted with DCM. The combined organic extracts were concentrated in vacuo to afford the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[N:30][N:29]=[N:28]4)=[CH:23][CH:22]=3)[N:18]=2)[CH2:9]1)=O)(C)(C)C.[ClH:32]>ClCCl.CO.O1CCOCC1>[N:27]1([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:17]3[N:18]=[C:14]([CH:10]4[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)[S:15][CH:16]=3)=[CH:26][CH:25]=2)[CH:31]=[N:30][N:29]=[N:28]1.[ClH:32]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: c1cc(-n2cnnn2)ccc1OCc1csc(C2CCCNC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.13 mmol) in dichloromethane (10 mL) and methanol (2 mL) were treated with 2 mL of 4N HCl in dioxane. The resulting solution was stirred at room temperature for 30 minutes. The solvents were removed in vacuo to afford the desired product as an HCl salt.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:5]=[C:4](O)[CH:3]=1.N1C=CC=CC=1C.O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:4]1[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1cc(O)nc(SCc2ccccc2F)n1
Solvent: Cc1ccccn1
Product: Nc1cc(Cl)nc(SCc2ccccc2F)n1

Procedure:
The product of example 4, step (a) (34 g) was added to a solution of 2-picoline (20 ml) in POCl3 (150 ml) and the mixture refluxed for 24 hr. The reaction mixture was concentrated in vacuo to half its original volume and poured onto ice and then neutralized with ammonia, forming a brown gum. The aqueous phase was decanted off, and the organic residues dissolved in ethyl acetate. This solution was recombined with the aqueous phase, and refluxed for 1 hr. The organic phase was separated, evaporated, and the residue purified by silica gel chromatography, eluting with dichloromethane to afford the subtitled compound as a pale yellow solid (15.6 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12](Br)[CH:13]=[CH2:14].[H-].[Na+].C(O)(=O)C.O1C[CH2:25][CH2:24][CH2:23]1>[I-].[Na+]>[CH2:12]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:25][CH:24]=[CH2:23])[C:8]([O:10][CH3:11])=[O:9])[CH:13]=[CH2:14]
Reactant: C1CCOC1
Reactant: C=CCBr
Reactant: COC(=O)Cc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C=CCC(CC=C)(C(=O)OC)c1ccccc1
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of methyl 2-phenylacetate (12.0 g, 80 mmol), allyl bromide (17.3 mL, 200 mmol) and sodium iodide (1 g) in tetrahydrofuran (160 mL) at 0° C. was treated portionwise with sodium hydride (7.36 g, 60% in oil, 184 mmol) over 10 minutes. The solution was allowed to warm to 25° C. and heated at reflux for 18 hours. The mixture was cooled to 0° C., treated with glacial acetic acid (2 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was filtered through a plug of 70-230 mesh silica gel eluting first with hexane and then with 10% ethyl acetate in hexane to give the title compound (17.89 g, 97%). 1H NMR (300 MHz, CDCl3): δ 7.29 (m, 5 H), 5.52 (m, 2 H), 5.06 (m, 4 H), 3.65 (s, 3 H), 2.78 (m, 4 H).
Reaction SMILES: C(Cl)Cl.Cl[Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[OH:12][CH2:13][CH2:14]/[C:15](=[CH:25]\[S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)/[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].N1C=CN=C1>O>[Si:5]([O:12][CH2:13][CH2:14]/[C:15](=[CH:25]\[S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)/[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: O=C(Nc1ccccc1)/C(=C/Sc1ccccc1)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
2 ml of methylene chloride solution including 0.79 g of chloro t-butyl dimethylsilane was dropped into 6 ml of methylene chloride solution including 1.20 g of (E)-4-hydroxy-N-phenyl-2-(phenylthiomethylene)butanamide and 0.63 g of imidazole at room temperature. The resulting solution was stirred at room temperature for 2 hours and added with water, then filtered using ethyl acetate. The organic layer was washed with water 3 times, then washed with brine, and dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.63 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:13][C@@H:12]([OH:23])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:30][S:31]([O:23][C@@H:12]1[CH2:13][C@H:14]([O:15][Si:16]([C:19]([CH3:20])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[C@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11]1)(=[O:33])=[O:32]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](O)C[C@H]1COCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](OS(C)(=O)=O)C[C@H]1COCc1ccccc1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 55.3 %

Procedure:
To a stirred solution of (1S,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}cyclopentanol (2.04 g, 0.00606 mol) in CH2Cl2 (96 mL) was added pyridine (2.4 mL, 0.030 mol), DMAP (100 mg, 0.001 mol), and methanesulfonyl chloride (700 μL, 0.0091 mol) under an atmosphere of nitrogen, The mixture was stirred 23° C. for 45 minutes, then warmed to 40° C. for 3 hours. To the reaction was added DMAP (100 mg, 0.001 mol) and methanesulfonyl chloride (700 μL, 0.0091 mol). After stirring for 40 min, the reaction was cooled then concentrated in vacuo. The residue was purified by flash chromatography (0 to 15% EtOAc/hexanes) to obtain 1.39 g (55%) of the title compound as one diastereomer (separated undesired diastereomer from step a).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[I:14])=O.C1(P(=[CH:36][C:37]([O:39][CH3:40])=[O:38])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]1(C)C=CC=CC=1>>[CH2:40]([O:39][C:37](=[O:38])[CH:36]=[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[I:14])[C:2]([F:16])([F:15])[F:1])[CH3:41]
Reactant: COc1ccc(I)c(NC(=O)C(F)(F)F)c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Product: CCOC(=O)C=C(Nc1cc(OC)ccc1I)C(F)(F)F
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of 2,2,2-trifluoro-N-(2-iodo-5-methoxy-phenyl)-acetamide 76b (4.6 g, 13.3 mmole) and methyl (triphenylphosphoranylidene)acetate (8.7 g, 25 mmole) in 50 ml toluene was brought to reflux for 5 hours and cooled to room temperature. The solution was concentrated, in vacuo and purified by column chromatography (eluting with 2–6% EtOAc in hexanes) to give 4.8 g product (87% yield). 1H NMR (300 MHz, CDCl3) δ 9.57 (1H, s), 7.68 (1H, d, J=8.8 Hz), 6.83 (1H, d, J=2.8 Hz), 6.57 (1H, dd, J=2.8, 8.8 Hz), 5.43 (1H, s), 4.23 (2H, m), 3.76 (3H, s),1.55 (3H, s), 1.31 (3H, m).
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:10])[N:4]=1.[CH3:11][N:12]([CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][S:21][CH2:22][CH2:23][NH2:24])[N:19]=1)[CH3:13].COC1C=NS(=O)N=1.[CH3:33][NH:34][CH3:35]>>[CH3:13][N:12]([CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][S:21][CH2:22][CH2:23][NH:24][C:3]2[C:7]([N:34]([CH3:35])[CH3:33])=[N:6][S:5](=[O:10])[N:4]=2)[N:19]=1)[CH3:11]
Reactant: COC1=NS(=O)N=C1OC
Reactant: CNC
Reactant: CN(C)Cc1nc(CSCCN)cs1
Agent: COC1=NS(=O)N=C1
Product: CN(C)Cc1nc(CSCCNC2=NS(=O)N=C2N(C)C)cs1

Procedure:
When a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide [prepared in Example 4, Step A] is reacted with one equivalent of 2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine [prepared in Example 33, Step E] and the resultant 3-}2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1-oxide is treated with an excess of dimethylamine according to the procedure described in Example 28, the title compound is thereby produced.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Sn:11](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15]>C1COCC1>[CH2:20]([Sn:11]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH2:21][CH2:22][CH3:23]
Reactant: c1ccoc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccco1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A THF solution (100 mL) of furan (6.8 g) was cooled to -78° C. under N2 atmosphere. Butyl lithium (1.6 M×62.5 mL, 100 mmol) was added dropwise through dropping funnel in 1 hr. After stirred at -78° C. for 1 hr, the reaction mixture was warmed gradually to room temperature and stirred for 30 min. The mixture was again cooled to -78° C. and added dropwise a THF solution (25 mL) of Bu3SnCl (32.5 g, 100 mmol) with stirring. The mixture was warmed gradually to room temperature and stirred for 10-12 hrs and then concentrated. Distillation (92° C., 0.5 torr) yielded 31.3 g (87.7 mmol) of 2-(tributylstannyl) furan (87% yield).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10](=[O:13])[CH2:11]I)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:24][O:25][C@@H:26]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]1>C(#N)C>[Br:8][C:6]1[N:7]=[C:2]2[N:32]([C@H:29]3[CH2:30][CH2:31][C@@H:26]([O:25][CH3:24])[CH2:27][CH2:28]3)[CH2:11][C:10](=[O:13])[NH:9][C:3]2=[N:4][CH:5]=1
Reactant: CO[C@H]1CC[C@@H](N)CC1
Reactant: O=C(CI)Nc1ncc(Br)nc1Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CO[C@H]1CC[C@@H](N2CC(=O)Nc3ncc(Br)nc32)CC1
Temperature: 55 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To a solution of N-(3,5-dibromopyrazin-2-yl)-2-iodoacetamide (See Example 5.B) (1.0 g, 2.376 mmol) and diisopropylethylamine (1.038 mL, 5.94 mmol) in acetonitrile (10 mL) was added (cis)-4-methoxycyclohexanamine hydrochloride (0.413 g, 2.495 mmol). The solution was stirred at 55° C. for 3 h. The resulting precipitate was filtered and washed with acetonitrile and dried under reduced pressure to afford the title compound (0.442 g, 1.29 mmol, 55% yield). MS (ESI) m/z 341.3 [M]+, 343.3 [M+2]+.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][CH2:9]C(O)=O)=[CH:5][CH:4]=[C:3]([N:13]([CH2:17][CH2:18][Cl:19])[CH2:14][CH2:15][Cl:16])[CH:2]=1.C([N:22](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[Cl:16][CH2:15][CH2:14][N:13]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][CH2:9][NH2:22])=[CH:1][CH:2]=1)[CH2:17][CH2:18][Cl:19]
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NCCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
Chlorambucil (0.30 g; 0.99 mmol) was suspended in 2 ml of acetone. The resultant mixture was stirred under a nitrogen gas atmosphere and ice-cooling, to which 0.17 ml (1.22 mmol; 1.2 equivalents) of triethylamine and 0.11 ml (1.22 mmol; 1.2 equivalents) of ethyl chloroformate were added successively. Twenty minutes later, a solution of 0.13 g (2.0 mmol; 2.0 equivalents) of sodium azide in 2 ml of water was added dropwise. The resulting mixture was stirred, as was, for 1 hour, to which ice was added to terminate the reaction. The thus-obtained mixture was extracted three times with 20 ml portions of benzene. The benzene layers were combined, dried over sodium sulfate and then heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was added with 9 ml of 8N hydrochloric acid, followed by heating for 15 minutes at 100° C. The resulting mixture was concentrated under reduced pressure and the residue was diluted with water. The thus-obtained mixture was adjusted to pH 12 with concentrated aqueous ammonia, followed by extraction with ethyl acetate. The extract was dried and concentrated, whereby 0.21 g of the title compound was obtained as a crude yellow oil of high viscosity. This reaction product was provided for use in the next reaction without purification.
Reaction SMILES: Br[C:2]1([C:8]2[O:9][C:10]3[C:18]([CH2:19][C:20]#N)=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(=O)(=O)(O)[OH:23].[CH2:27]([OH:29])[CH3:28]>>[C:2]1([C:8]2[O:9][C:10]3[C:18]([CH2:19][C:20]([O:29][CH2:27][CH3:28])=[O:23])=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: N#CCc1cccc2c(=O)cc(C3(Br)CCCCC3)oc12
Reactant: O=S(=O)(O)O
Reactant: CCO
Product: CCOC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Yield: 56 %

Procedure:
2-(1-Bromocyclohexyl)-8-cyanomethyl-4-oxo-4H-[1]-benzopyran (5.0 g) and 50% sulfuric acid (4 ml) were added to ethanol (400 ml) and the mixture was refluxed for 8 hours. Then, ethanol (about 300 ml) was distilled off under reduced pressure and the residue was added to water. The mixture was extracted with ethyl acetate and the extract was washed with water, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate to obtain the title compound, yield 56%.
Reaction SMILES: CC(C)=O.C(Cl)(Cl)Cl.[CH3:9][CH2:10][C@:11]1([OH:65])[C@H:20]([OH:21])[C:19]2[C:14](=[C:15](O)[C:16]3[C:31](=[O:32])[C:30]4[C:25](=[C:26](O)[CH:27]=[CH:28][C:29]=4[OH:33])[C:23](=[O:24])[C:17]=3[C:18]=2[OH:22])[C@@H:13]([O:36][C@@H]2O[C@@H](C)[C@@H](O[C@@H]3O[C@@H](C)[C@@H](O[C@@H]4O[C@@H](C)C(=O)CC4)[C@@H](O)C3)[C@@H](N(C)C)C2)[CH2:12]1>CO>[CH3:9][CH2:10][C@:11]1([OH:65])[C@H:20]([OH:21])[C:19]2[C:18]([OH:22])=[C:17]3[C:23](=[O:24])[C:25]4[CH:26]=[CH:27][CH:28]=[C:29]([OH:33])[C:30]=4[C:31](=[O:32])[C:16]3=[CH:15][C:14]=2[C@@H:13]([OH:36])[CH2:12]1
Reactant: CC[C@@]1(O)C[C@H](O[C@H]2C[C@H](N(C)C)[C@H](O[C@H]3C[C@H](O)[C@H](O[C@H]4CCC(=O)[C@H](C)O4)[C@H](C)O3)[C@H](C)O2)c2c(O)c3c(c(O)c2[C@H]1O)C(=O)c1c(O)ccc(O)c1C3=O
Solvent: CC(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC[C@@]1(O)C[C@H](O)c2cc3c(c(O)c2[C@H]1O)C(=O)c1cccc(O)c1C3=O

Procedure:
The resulting broth (about 12 liters) was similarly subjected to acid hydrolysis, acetone extraction from the mycelia and chloroform extraction, and finally 9.8 g of a crude powder containing β-isorhodomycinone. The whole amount of the crude powder was dissolved in 100 ml of methanol and the insoluble materials were centrifuged off. After concentration, the soluble fraction was applied on a silica-gel column (diameter: 78 mm) packed with 300 g of the above-mentioned silica-gel C-200 in chloroform, and eluted with 500 ml of chloroform, 100 ml of a mixture solution of chloroform/methanol (500/1), 3400 ml of the mixture solution (400/1) and 1000 ml of the mixture solution (300/1) in this order. β-isorhodomycinone was eluted with a mixture of chloroform/methanol (400/1). The β-isorhodomycinone-containing fractions were collected and evaporated to dryness followed by washing with ether The yield of β-isorhodomycinone was 0.62 g. The identification of this compound was carried out by means of 1H--M=NMR and 13C--NMR spectra and UV and FD mass spectra thereof, referring chemical data described in the literature (Chem. Ber., Vol. 98, page 3145, 1965).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].C(O)COCCOCCO.C(OC=C)(=O)C.[CH:22]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32]OC=C)=[CH2:23].C(OCCOCCOCCO)=C>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH:22]=[CH2:23])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: C=COCCOCCOCCOC=C
Agent: C=COCCOCCOCCO
Agent: [Na+]
Solvent: OCCOCCOCCO
Solvent: Cc1ccccc1
Solvent: C=COC(C)=O
Product: C=COCCOCCOCCOC(C)=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (0.01 mmol) and sodium acetate (1.2 mmol) in toluene (2.0 ml),triethylene glycol (1 mmol) and vinyl acetate (4 mmol) were added, followed by stirring at 100° C. in an atmosphere of argon gas for 6 hours. The reaction mixture was analyzed by gas chromatography to find that triethylene glycol divinyl ether, triethylene glycol monovinyl ether, and triethylene glycol monovinyl ether monoacetate were produced in yields of 63%, 3%, and 18%, respectively, with a conversion from triethylene glycol of 100%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH2:18][CH3:19])[N:3]=1.O.[NH2:21][NH2:22]>CC#N.CCO>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH2:18][CH3:19])[CH:5]=3)=[CH:15][CH:14]=2)[NH:22][N:21]=1
Reactant: CCNc1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: CCNc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 68.9 %

Procedure:
In a 25 mL flask under argon was added 4-[2-amino-6-(ethylamino)-4-pyrimidinyl]-2-fluorobenzonitrile (0.164 g, 0.442 mmol) followed by EtOH (3.5 mL). Hydrazine monohydrate (0.87 mL, 17.7 mmol) was added and the reaction mixture was stirred for 6 hours at 80° C. The reaction was cooled to room temperature and concentrated to near dryness. Water (3 mL) was added (orange oil was formed) followed by CH3CN (8 drops), and the mixture was sonicated. A light yellow precipitate was formed. The suspension was cooled on an ice bath and the solid was filtered, washed with water and dried under vacuum at 40° C. to afford the title compound (82 mg, 68%) as a light yellow solid. LC-MS (ES) m/z=270 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.13 (t, J=7.2 Hz, 3H), 3.20-3.40 (m, 2H), 5.36 (s, 2H), 5.97 (s, 2H), 6.25 (s, 1H), 6.82 (bs, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.84 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[S:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH2:19]([Sn]CCCC)CCC.CI>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:19][O:9][C@@H:8]1[C@H:10]([OH:11])[C@@H:12]([CH2:13][OH:14])[O:15][C@H:7]1[N:6]1[CH:16]=[C:2]([CH3:1])[C:3](=[O:18])[NH:4][C:5]1=[S:17]
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=S)[nH]c1=O
Reactant: CCCC[Sn]CCCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CI
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=S
Temperature: 50 °C

Procedure:
To a stirred solution of 5-methyl-2-thiouridine (0.500 g, 1.8 mmol) in DMF (10 ml) is added dibutyltin ox-de 0.500 g, 2.0 mmol), tetrabutyl ammonium iodide (0.738 g, 2 mmol), and methyl iodide (1.022 g, 7.2 mmol). The reaction flask is sealed and heated at 50° C. for 16 hours. The mixture is cooled and another portion of methyl iodide is added (1.022 g, 7.2 mmol) and the reaction heated for an additional 16 hours. At the end of this time, the reaction mixture is cooled to room temperature and diluted with methylene chloride and chromatographed using a methylene chloride/methanol gradient. The appropriate fractions are collected and concentrated to give 2'-O-methyl-5-methyl-2-thiouridine.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH3:16])[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH3:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[C:8]1[S:7][N:6]=[C:5]([O:21][CH2:17][C:18]#[C:19][CH3:20])[N:9]=1
Reactant: CC1CCCCC1c1nc(S(C)(=O)=O)ns1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(C2CCCCC2C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.4 %

Procedure:
160 mg of 3-methylsulfonyl-5-(2-methylcyclohexyl)-1,2,4-thiadiazole and 52 mg of 2-butyn-1-ol were dissolved in 1.5 ml of N,N-dimethylformamide, 32 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 1 hour under ice-cooling and for 12 hours at room temperature. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 39 mg of 5-(2-methylcyclohexyl)-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (10)).