Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[C:18]([O:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])[CH:17]=2)=[O:15])[CH3:12])=[O:10])[CH2:5][CH2:4]1)#[N:2].N1C=CC=CC=1.C(N(CC)CC)C.[SH2:53]>C(OCC)(=O)C>[C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[C:18]([O:31][CH2:32][C:33]([OH:35])=[O:34])[CH:17]=2)=[O:15])[CH3:12])=[O:10])[CH2:5][CH2:4]1)(=[S:53])[NH2:2]
Reactant: S
Reactant: CN(CC(=O)c1ccc(OCC(=O)OC(C)(C)C)c(OCC(=O)OC(C)(C)C)c1)C(=O)[C@H]1CC[C@H](C#N)CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN(CC(=O)c1ccc(OCC(=O)O)c(OCC(=O)O)c1)C(=O)[C@H]1CC[C@H](C(N)=S)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Into the solution of the compound prepared in (a) (655 mg, 1.2 mmole) in the mixture of pyridine (15 ml) and triethylamine (1 ml) was streamed a hydrogen sulfide gas for 1 hour, and the mixture was stirred in a sealed tube at 50° C. for 5 hours. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate, and washed twice with each of a 5% aqueous sodium hydrogen carbonate and a 1M potassium hydrogen sulfate solution. After the organic layer was dried over anhydrous magnesium sulfate, the inorganic salt was removed by filtration. The filtrate was concentrated under reduced pressure, and the oily product thus obtained was purified by column chromatography on silica gel with an eluent system of chloroform:methanol =50:1 to give 71 mg of the thioamide derivative as a yellow oily product (yield, 10%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15]C)[CH:11]=2)[CH:6]1[CH:17]1[CH2:22][CH2:21][N:20]([S:23]([C:26]2[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1)=[O:4].B(Br)(Br)Br.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:32][C:2]([F:1])([F:33])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH:6]1[CH:17]1[CH2:18][CH2:19][N:20]([S:23]([C:26]2[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=2)(=[O:25])=[O:24])[CH2:21][CH2:22]1)=[O:4]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2C1CCN(S(=O)(=O)c2cn(C)cn2)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cn1cnc(S(=O)(=O)N2CCC(C3c4ccc(O)cc4CCN3C(=O)C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2,2,2-trifluoro-1-{6-methoxy-1-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethanone (0.036 g, 0.074 mmol) in CH2Cl2 (3 ml) under an atmosphere of N2 cooled to −78° C. was added boron tribromide as a 1.0 M solution in CH2Cl2 (0.3 ml, 0.3 mmol). The reaction mixture was stirred overnight slowly, while allowing it to warm to RT. MeOH (1 ml) was added to the reaction mixture and stirring was continued at RT for 10 minutes. Sat. NaHCO3 was added to the reaction mixture until the pH of the aqueous layer was 7. The mixture was then extracted with EtOAc (3×20 ml), the combined organics were washed with brine (1×20 ml), dried over MgSO4, filtered, and concentrated in vacuo to give the desired product as an off white solid (0.028 g, 0.059 mmol, 80% yield).
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:13]=[CH:12][C:10]([OH:11])=[C:7]([O:8][CH3:9])[CH:6]=1)=[O:4].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>C(O)C>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][C:10]1[CH:12]=[CH:13][C:5]([C:3](=[O:4])[CH3:2])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: BrCCCCBr
Agent: [Na]
Solvent: CCO
Product: COc1cc(C(C)=O)ccc1OCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a warm solution of 12.7 g (0.55 mole) of sodium metal in 500 ml of absolute ethanol was added a slurry of 83.1 g (0.5 mole) of acetovanillone in 250 ml of absolute ethanol. All solids dissolved and then a solid precipitated. The mixture was stirred at ambient temperature for 1 hr and then added over a 3 hr period to a solution at reflux of 177 g (0.82 mole) of 1,4-dibromobutane in 500 ml of absolute ethanol. After addition was complete, the mixture was heated at reflux overnight. The mixture was concentrated under reduced pressure and the residue was partitioned between 1.5 liter of benzene and 1 liter of water. The mixture was filtered to remove undesirable insoluble material. The filtrate layers were separated and the organic layer was washed with four 300 ml portions of a 5% sodium hydroxide solution once with water and once with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 138 g of gummy solid as residue. This solid was purified by column chromatography on 1 kg of silica gel, eluting with 2% ethyl acetate in benzene to yield 69.9 g (46%) of title compound as an off-white solid. The solid was recrystallized from isopropyl ether, m.p. 52°-54° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.O.O.O.O.O.O.C1(=O)OOOOC(=[O:42])C2=CC=CC=C12.[Mg]>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:31])=[O:42])=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Reactant: O=c1ooooc(=O)c2ccccc12
Agent: [Mg]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Reaction time: 3 h

Procedure:
To a solution of 5-(4-chloro-phenyl)-6-(4-methylsulfanyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (2.10 g, 4.72 mmol) in dry dichloromethane (36 mL) and methanol (12 mL), magnesium monoperoxy phthalate hexahydrate (1.16 g, 2.36 mmol) is added at 0° C. and the resulting mixture is stirred for 3 h at that temperature. The reaction mixture is quenched with the addition of 10% sodium bicarbonate solution and extracted with dichloromethane (3×). The organic part separated is dried (Na2SO4) and concentrated. The crude product is purified by column chromatography (silica gel, 60-120 mesh) to afford 5-(4-chloro-phenyl)-6-(4-methanesulfinyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4([NH2:26])[CH2:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[N:6][N:5]2[C:27]=1[CH:28]=[CH2:29].C(O)C>C(OCC)(=O)C.[Pd]>[CH2:28]([C:27]1[N:5]2[N:6]=[C:7]([C:16]3[CH:17]=[CH:18][C:19]([C:22]4([NH2:26])[CH2:23][CH2:24][CH2:25]4)=[CH:20][CH:21]=3)[C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:9][C:4]2=[N:3][C:2]=1[CH3:1])[CH3:29]
Reactant: C=Cc1c(C)nc2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nn12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1c(C)nc2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nn12
Reaction time: 3 h

Procedure:
14.3 mg (0.04 mmol) 1-[4-(2-Methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine, example 12, were given in five mL ethyl acetate (no complete dissolution). After addition of a catalytic amount of palladium/charcoal (10%) the reaction mixture was stirred under a hydrogen atmosphere for three hours. Due to an incomplete reaction one mL ethanol was added and stirring was continued over night. The catalyst was sucked off via a glass fibre filter and washed with ethanol. After evaporation of the solvents 11.9 mg (66.2%) of the title compound were obtained which were slightly contaminated.
Reaction SMILES: [OH:1][CH:2]([C:8]1[C:17]([CH3:18])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH3:18][C:17]1[C:8]([C:2](=[O:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:9]([O:19][S:20]([C:23]([F:24])([F:25])[F:26])(=[O:22])=[O:21])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CCOC(=O)C(O)c1c(C)cc2ccccc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C)cc2ccccc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
A solution of ethyl 2-hydroxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate (5.5 g, crude) in DCM (160 mL) was treated with Dess-Martin periodinane (7.18 g, 16.9 mmol) at 23° C. After 1 h, the reaction was added slowly over 5 min to 10% Na2S2O3 (100 mL). After 30 min, the reaction was extracted with DCM (3×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was treated with benzene, filtered, and loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product in semi pure form. 1H NMR (400 MHz, CDCl3): δ 8.11-8.08 (m, 1H), 7.86-7.83 (m, 1H), 7.76 (s, 1H), 7.66-7.60 (m, 2H), 4.41 (q, J=7.4 Hz, 2H), 2.50 (s, 3H), 1.40 (t, J=7.4 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ −73.3 (s).
Reaction SMILES: [CH2:1]([C@@H:8]1[C:15](=[O:16])[NH:14][CH2:13][C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[CH2:10][N:9]1[S:21]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:36]I>C1COCC1.O>[CH2:1]([C@@H:8]1[C:15](=[O:16])[N:14]([CH3:36])[CH2:13][C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[CH2:10][N:9]1[S:21]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)(=[O:22])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C1NCc2ccccc2CN(S(=O)(=O)c2cccc3cccnc23)[C@@H]1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1Cc2ccccc2CN(S(=O)(=O)c2cccc3cccnc23)[C@H](Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 8 (50 mg, 0.11 mmol) in THF (3 mL) at −10° C. was slowly added NaH (5.2 mg, 0.12 mmol). The mixture was warmed to rt and stirred for 1 h. To it was added CH3I (50 mg, 0.33 mmol). The reaction mixture was stirred at rt for 16 h, diluted with H2O (10 mL) and extracted with EA (2×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC to give 9 (50 mg, 96% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 9.14-9.11 (m, 1H), 8.24-8.19 (m, 2H), 7.92 (d, J=8.0 Hz, 1H), 7.59-7.54 (m, 1H), 7.44-7.36 (m, 3H), 7.22-7.13 (m, 5H), 7.08-7.04 (m, 1H), 6.72 (d, J=7.2 Hz, 1H), 5.80-5.76 (m, 1H), 5.43-5.30 (m, 2H), 4.20 (d, J=16.8 Hz, 1H), 3.46-3.30 (m, 2H), 3.06-3.00 (m, 1H), 2.75 (s, 3H); MS (ESI+) m/z: 472 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([OH:22])(=[O:21])=[O:20])[C:9](=[O:11])[CH:10]=1)=[O:5])C.[CH2:23]([CH2:25][NH2:26])[OH:24]>C(O)C>[OH:24][CH2:23][CH2:25][NH:26][C:4]([C:6]1[NH:7][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([OH:22])(=[O:20])=[O:21])[C:9](=[O:11])[CH:10]=1)=[O:5]
Reactant: CCOC(=O)c1cc(=O)n(Cc2ccccc2S(=O)(=O)O)[nH]1
Reactant: NCCO
Solvent: CCO
Product: O=C(NCCO)c1cc(=O)n(Cc2ccccc2S(=O)(=O)O)[nH]1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
14.5 g of Intermediate A and 15.3 g of ethanolamine were mixed and made to react with each other over a period of 2 hours under a pressure reduced to 30 mm Hg inside the reaction container and a temperature kept at 120° C. outside the reaction container. After cooling to room temperature, the reaction product was dissolved in 30 ml of ethanol, and separated out in a crystallized condition upon addition of 300 ml of isopropanol. After filtration, the crystals were washed with isopropanol, and dried. Thus, 13 g (yield: 86.5%) of Intermediate C was obtained. Melting Point: 215°-219° C. (decomposed).
Reaction SMILES: [O:1]([CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])P(OP([O-])([O-])=O)(=O)[O-].[CH2:15]=[CH:16][C:17](=[CH2:19])[CH3:18]>>[CH3:13][C:12]([CH3:14])=[CH:11][CH2:10][OH:1].[CH3:19][C:17]([OH:1])([CH:16]=[CH2:15])[CH3:18]
Reactant: C=CC(=C)C
Reactant: CC(C)=CCOP(=O)([O-])OP(=O)([O-])[O-]
Product: C=CC(C)(C)O
Product: CC(C)=CCO

Procedure:
Although the direct conversion of dimethylallyl diphosphate to isoprene by isoprene synthase enzymes is known in the art, we have shown that isoprene can also be produced from two different alcohols, 3-methyl-2-buten-1-ol and 2-methyl-3-buten-2-ol, using linalool dehydratase-isomerase (see Example 1 and Example 2 and FIGS. 6 and 8), an enzyme isolated from Castellaniella defragrans strain 65Phen. The linalool dehydratase isomerase permits the development of novel isoprene biosynthetic pathways of either two or three steps. In a two-step isoprene biosynthetic pathway, dimethylallyl diphosphate is converted to 2-methyl-3-buten-2-ol by an enzyme such as a 2-methyl-3-buten-2-ol synthase, followed by conversion of 2-methyl-3-buten-2-ol to isoprene. In a three-step isoprene biosynthetic pathway, dimethylallyl diphosphate is converted to 3-methyl-2-buten-1-ol by either a phosphatase or a terpene synthase capable of converting dimethylallyl diphosphate to 3-methyl-2-buten-1-ol, 3-methyl-2-buten-1-ol is converted to 2-methyl-3-buten-2-ol by a 2-methyl-3-buten-2-ol isomerase, and 2-methyl-3-buten-2-ol is converted to isoprene by a 2-methyl-3-buten-2-ol dehydratase. As demonstrated in Example 1 and Example 2, the Castellaniella defragrans linalool dehydratase-isomerase functions as both a 2-methyl-3-buten-2-ol isomerase and a 2-methyl-3-buten-2-ol dehydratase.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Br-:1].[O:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[O:5][CH2:4][CH2:3][CH2:2][P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrCCCOC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Product: [Br-]
Product: c1ccc([P+](CCCOC2CCCCO2)(c2ccccc2)c2ccccc2)cc1
Yield: 99.6 %

Procedure:
66.5 g (0.298 mol) of 2-(3-bromopropyloxy)tetrahydropyran is refluxed together with 82 g (0.312 mol) of triphenylphosphine and 1 g of tetrabutylammonium iodide in 500 ml of acetonitrile for 24 hours. After evaporation of the solvent, the residue is triturated several times with boiling diethylether. 144 g (100%) of 3-(tetrahydropyranyloxy)propyl-triphenylphosphonium bromide is obtained as heavy oil. (C26H30BrNO2P; F.W. 485.4).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)[NH2:11].N1C=CC=CC=1.Cl>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([NH:11][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccc(OCC2CC2)c(Br)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
Ethylsulfonyl chloride (233 uL, 2.4 mmol) was added to a stirred solution of 3-bromo-4-(cyclopropylmethoxy)aniline (520 mg, 2.2 mmol) and pyridine (520 uL, 6.5 mmol) in DCM (4 mL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 12 h, it was treated with 1N HCl (15 mL) and extracted with DCM (3×15 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (10 to 100%) in hexanes to afford the title compound (711 mg, 98%) as a yellow solid. LCMS (M+H)+=335.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][N:18]=[C:19]([C:21]1[O:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)[CH3:20].N1C=C(C=[N+](C)C)[CH:31]=N1>O>[N+:26]([C:23]1[O:22][C:21]([C:19]2[C:20]([CH:8]=[O:9])=[CH:31][N:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=3)[N:18]=2)=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: C[N+](C)=Cc1cn[nH]c1
Reactant: CC(=NNc1ccccn1)c1ccc([N+](=O)[O-])o1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cn(-c2ccccn2)nc1-c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Yield: 45 %

Procedure:
Add 9.4 g of phosphorus oxychloride dropwise to 16.4 g of anhydrous dimethylformamide at from 10° to 20° C and then stir the obtained reaction mixture for 30 minutes at room temperature before adding thereto (from 35° to 40° C) 5.0 g of 5-nitro-2-acetylfuran-(2-pyridyl)hydrazone. Stir the thus-prepared admixture for 28 hours under nitrogen at this temperature and then pour it and a solution comprising 4-pyrazolylmethylenedimethylammonium salt onto 250 g of ice and water. Heat the resulting reaction mixture for 2 hours at from 30° to 40° C, draw off the formed precipitate and wash the precipitate with water to obtain a 45% yield of 3-(5-nitro-2-furyl)-1-(2-pyridyl)pyrazole-4-carboxaldehyde [m.p. 191° to 191.5° C (from toluene)].
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])[CH3:5].[C:14]([O:18][C:19]([NH:21][CH:22]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36](C=O)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].[CH3:41]CCCCC>C1COCC1>[CH3:41][O:8][C:6](=[O:7])[CH:4]=[CH:5][C:36]1[CH:37]=[CH:38][C:33]([C:30]2[CH:31]=[CH:32][C:27]([CH2:26][CH:22]([NH:21][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[C:23]([OH:25])=[O:24])=[CH:28][CH:29]=2)=[CH:34][CH:35]=1
Reactant: CCCCCC
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(-c2ccc(C=O)cc2)cc1)C(=O)O
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(-c2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 93 %

Procedure:
Sodium hydride (60% in mineral oil, 1.02 g, 26.0 mmol) was washed with anhydrous hexane (3×15 mL) under an atmosphere of argon. Dry THF (20 mL) was added and cooled to 0-5° C. A solution of trimethylphosphonoacetate (2.1 mL, 13.0 mmol) in dry THF (20 mL) was added dropwise to the above mixture with stirring. After about 5 min, a solution of the aldehyde 42 (4.3 g, 10.6 mmol) in dry THF (20 mL) was added and the reaction mixture was then brought up to room temperature and stirred. After 30 min, the clear reaction mixture was quenched with 10% citric acid (25 mL) and further acidified to pH ˜2.0 with 2.0 M HCl. The THF was evaporated under reduced pressure and the resulting oily material was extracted with EtOAc (2×100 mL). The organic layer was extracted with water (3×75 mL), and brine (1×100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield the unsaturated ester 43 (4.6 g, 93%) as a crude product that was taken for the next step without further purification. 1H NMR (400 MHz, DMSO-d6): 12.66 (br, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.72 (overlapped d, J=8.8 Hz, 2H), 7.70 (overlapped d, J=16.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.18 (d, J=8.4 Hz, 1H), 6.69 (d, J=16.0 Hz, 1H), 4.13 (ddd, J=12.8, 10.4, and 4.8 Hz, 1H), 3.74 (s, 3H), 3.07 (dd, J=14.0 and 4.8 Hz, 1H), 2.88 (dd, J=13.6 and 10.0 Hz, 1H), 1.32 (s, 9H)
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:5][CH:4]=1)=O.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][C:18]=1[CH3:26].[OH-].[K+].Cl>CO.O>[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])/[CH:24]=[CH:1]/[C:3]2[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:14][CH:15]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: CCOC(=O)COc1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)/C=C/c2ccc(OCC(=O)O)cc2)ccc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
Commercially available ethyl 2-(4-formylphenoxy)acetate (20.0 g, 0.1 mol) and commercially available 4′-hydroxy-3′-methylacetophenone (15.0 g, 0.1 mol) were dissolved in 200 mL of methanol and 50 mL of water. The solution was cooled with an ice-water bath, to which was added potassium hydroxide (22.0 g, 0.392 mol). The reaction mixture was stirred overnight. The resulted mixture was poured on to 600 mL of ice-water, acidified to pH=4-5 with 1 N HCl, and extracted with ethyl acetate (4×200 mL). The combined organic layers were washed with water and brine (200 mL each), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained yellow oil was dried under high-vacuum, 10 g (33%) of yellowish solid was obtained. MS (EI): 313 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2.[I:24]I>O1CCCC1>[F:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[I:24])=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: Fc1cnc2ccccc2c1
Reactant: II
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Fc1cnc2ccccc2c1I
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 41.4 %

Procedure:
To a 0° C. solution of diisopropyl amine (2.8 mL, 27 mmol) in tetrahydrofuran (80 mL) was added dropwise butyl lithium (8.1 mL, 2.5 M solution in hexane, 27 mmol). After 10 min., the flask was cooled to −78° C. and 3-fluoro quinoline from Step B (3 g, 20 mmol) in 20 mL of tetrahydrofuran was added over 15 min. period. The stirring was continued for an additional 4 h., after which iodine (5.4 g, 21 mmol) in 10 mL of THF (tetrahydrofuran) was added and the reaction temperature was maintained at −78° C. for additional 2 h. The reaction was quenched by adding a mixture of water and tetrahydrofuran (25 mL, 1:9), and the resulting solution was extracted with ethyl acetate. The organic layers were combined, washed with water and brine. Purification by silica gel column gave the title compound (2.26 g, 40%). MS (ES) 148.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH2:42][NH2:43].C(N(C(C)C)CC)(C)C.O>CC(O)C>[C:1]([C:5]1[N:10]=[C:9]([NH:43][CH2:42][C:38]2[O:37][CH:41]=[CH:40][N:39]=2)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ncco1
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1Cl)C1CN(C(=O)OC(C)(C)C)Cc2ccccc21
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ncco1)C1CN(C(=O)OC(C)(C)C)Cc2ccccc21
Temperature: 80 °C
Reaction time: 6 h
Yield: 75.7 %

Procedure:
tert-Butyl 4-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](2-methylpropyl)amino}-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg), 1-(1,3-oxazol-2-yl)methanamine hydrochloride (54 mg) and diisopropylethylamine (0.14 ml) were dissolved in 2-propanol (2 ml), and the mixture was stirred at 80° C. for 6 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with hexane-ethyl acetate (3:1) was concentrated under reduced pressure to give the object compound (85 mg).