Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[Na+].[Na+].I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C.O.CCOC(C)=O>[CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCCC
Temperature: 45 °C
Reaction time: 48 h
Yield: 45.5 %

Procedure:
A mixture of 7-allyl-3,7-dihydro-1H-purine-2,6-dione (10.0 g, 0.052 mol), sodium carbonate (8.3 g, 0.078 mol), and 1-iodopentane (12 g, 0.062 mol) in DMF (100 mL) was stirred at 45° C. for 2 days. The reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was treated with ether and the solid formed was filtered to provide the desired product as white solid (6.2 g, 45.4%). LCMS calculated for C13H19N4O2 (M+H): 263.2. found: 263.2.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C1([Mg]Cl)C=CC=CC=1.[CH3:21][C:22]([CH3:26])([CH3:25])[CH:23]=[O:24]>C1COCC1>[CH3:12][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH:23]([OH:24])[C:22]([CH3:26])([CH3:25])[CH3:21])[CH:3]=1
Reactant: CC(C)(C)C=O
Reactant: COc1ccc([N+](=O)[O-])c(I)c1
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(C(O)C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a solution of 3-iodo-4-nitroanisole (2.79 g, 10.0 mmol) in anhydrous THF (10 mL) at minus 40° C. under a nitrogen atmosphere, phenylmagnesium chloride (2 M in THF, 4.2 mL, 8.3 mmol) was added dropwise at a rate such that the temperature would not exceed minus 35° C. Upon completion of the addition, the mixture was stirred at minus 40° C. for two hours, followed by addition of trimethylacetaldehyde (1.1 mL, 10 mmol). The mixture was stirred at minus 40° C. for two hours and then at room temperature for another one hour. The reaction was then quenched with brine (100 mL), and the mixture was extracted with CH2Cl2 (40 mL) three times. The combined organic phase was dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield racemic (R/S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propanol (1.76 g, 88%). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, 1H, J=9.2 Hz, Ph-H), 7.27 (d, 1H, J=2.8 Hz, Ph-H), 6.84 (dd, 1H, J=8.8 and 2.8 Hz, Ph-H), 5.62 (d, 1H, J=4.0 Hz, PhCH), 3.89 (s, 3H, OCH3), 2.08 (d, 1H, J=4.0 Hz, OH), 0.89 (s, 9H, C(CH3)3).
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C@@:7]2(O)[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]2)=[CH:3][CH:2]=1.[CH2:33]([SH:36])[CH:34]=[CH2:35]>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH2:33]([S:36][C@:7]1([C:4]2[CH:5]=[CH:6][C:1]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:2][CH:3]=2)[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]1)[CH:34]=[CH2:35]
Reactant: C=CCS
Reactant: COC(=O)[C@@H]1C[C@@](O)(c2ccc(-c3ccccc3)cc2)CN1C(=O)OCc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: C=CCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Reaction time: 20 h
Yield: 22.1 %

Procedure:
To a clear solution of (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate (3236 mg, 7.5 mmol) and prop-2-ene-1-thiol (834 mg, 9.00 mmol) in Acetonitrile (40 mL) was added Scandium(III) trifluoromethanesulfonate (369 mg, 0.750 mmol) as solid by one portion at room temperature. The formed pink solution was stirred at this temperature for 20 h. Quenched with sat. ammonium chloride, extracted with EtOAc. Washed the organic layer with brine, dried over MgSO4, filtered, evaporated in vacuo. The residue was purified by Biotage column, eluted with 5%˜50% EtOAc-Hexane to afford a mixture of diastereomers (2.88 g, 79%) and recovered starting material (0.600 g, 18%). This mixture was purified by Biotage column again, eluted with 2%˜8% EtOAc-Toluene to afford the desired product (2S,4R)-1-benzyl 2-methyl 4-(allylthio)-4-(biphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (900 mg, 1.661 mmol, 22.15% yield) as an viscous oil and the undesired diastereomer plus some overlapped fraction (1.80 g) as an viscous oil. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 2.59-2.75 (m, 1 H), 2.77-2.93 (m, 3 H), 3.60 (s, 1.5 H), 3.77 (s, 1.5 H), 3.92 (d, J=11.60 Hz, 1 H), 4.20-4.30 (m, 1 H), 4.37-4.47 (m, 1 H), 4.92-5.34 (m, 4 H), 5.55-5.72 (m, 1 H), 7.20-7.65 (m, 14 H). LC-MS (retention time: 3.34 min, method B), MS m/z 488 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([S:14]([NH2:17])(=[O:16])=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH:9]=1)[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH:28][C:29](=O)[O:30]C2C=CC=CC=2)[N:21]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.O>[CH3:27][O:26][C:24]1[CH:25]=[C:20]([O:19][CH3:18])[N:21]=[C:22]([NH:28][C:29]([NH:17][S:14]([C:10]2[N:8]3[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[CH:6][C:7]3=[N:12][C:11]=2[CH3:13])(=[O:15])=[O:16])=[O:30])[N:23]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CCOc1ccc2nc(C)c(S(N)(=O)=O)n2c1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1ccc2nc(C)c(S(=O)(=O)NC(=O)Nc3nc(OC)cc(OC)n3)n2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
As shown in the above reaction scheme, 6-ethoxy-2-methylimidazo[1,2-a]pyridin-3-sulfonamide (0.04 g, 0.156 mmol) and phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate (0.048 g, 0.172 mmol) were suspended in acetonitrile (1 ml) and stirred at room temperature, during which DBU (0.026 g, 0.172 mmol) was added thereto. After the mixture was stirred at room temperature for 2 hours, the reaction solution was poured into water (20 ml) and adjusted to pH 3 with dilute hydrochloric acid. The precipitated crystals were collected by filtration, and washed with water and ether in this order. The crystals were dried under reduced pressure to give the title compound as pale brown crystals. The yield was 0.06 g (87%), and the melting point was 159 to 164° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH2:24][C:25]4([OH:33])[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]4)=[CH:18][C:17]=3[CH3:34])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38].CO.[OH-].[Na+].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH2:24][C:25]4([OH:33])[CH2:26][CH2:27][S:28](=[O:32])(=[O:31])[CH2:29][CH2:30]4)=[CH:18][C:17]=3[CH3:34])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:35][CH2:36][C:37]([OH:39])=[O:38]
Reactant: CCOC(=O)CCc1ccc(NCc2cccc(-c3c(C)cc(OCC4(O)CCS(=O)(=O)CC4)cc3C)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCC2(O)CCS(=O)(=O)CC2)cc(C)c1-c1cccc(CNc2ccc(CCC(=O)O)c(F)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
To a mixture of ethyl 3-(2-fluoro-4-[({4′-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl)methyl)amino]phenyl}propanoate (1.99 g, 3.40 mmol), methanol (24 mL) and tetrahydrofuran (7 mL) was. added 1 M aqueous sodium hydroxide solution (10.2 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, and concentrated under reduced pressure to evaporate the organic solvent. The residue was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1-hexane/ethyl acetate=1/1) and recrystallized from ethyl acetate-hexane to give the title compound (1.47 g, yield 78%) as colorless crystals.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: NCCCSc1ccncc1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)NCCCSc1ccncc1
Yield: 72.2 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 1.15 ml (4.96 mmol) of lauroyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.05 g of the desired compound (72.2%, colorless powder), mp: 71.0°-72.0° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li][CH2:12][CH2:13]CC.C(=O)C>C1COCC1.CCCCCC>[CH3:12][CH:13]1[C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[O:6]1
Reactant: O=C(O)c1ccccc1Br
Reactant: [Li]CCCC
Agent: CC=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1OC(=O)c2ccccc21
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 35 %

Procedure:
To a solution of 2-bromobenzoic acid (0.50 g, 2.49 mmol) in THF (12.0 ml) cooled at −78° C. was added 2.5M n-BuLi in hexane (2.0 ml). After stirring for 25 minutes, a solution of acetaldehyde (0.142 g, 3.23 mmol) in THF (0.3 ml) was added. The reaction was allowed to warm to room temperature after 8 minutes at −78° C., and then quenched into 10% HCl aqueous solution (30 ml). The acidic solution was rapidly stirred for 1.5 hours, and then extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3 aqueous solution, brine, dried with anhydrous Na2SO4, and rotary evaporated to an oily residue. Gradient chromatography of the oil residue through a silica gel column with 20% to 30% EtOAc in hexane afforded 3-methyl-2-benzofuran-1(3 H)-one as a clear oil (130 mg, 35%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:46][NH2:47]>ClCCl.CO>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:47][OH:46])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: CN(C)CCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
A solution (3R)-6-cyclohexyl-3-(3-{[[2-(dimethylamino)ethyl](methyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 82) (450 mg, 0.72 mmol) and N-methylmorpholine (284 μl, 2.53 mmol) in dichloromethane (10 ml) was cooled to 0° C., treated with isobutyl chloroformate (112 μl, 0.87 mmol) and stirred under an argon atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (355 μl, 2.90 mmol) was added and the mixture was stirred for 3.5 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol (2.5 ml) and stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and washed with water (20 ml), dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The solid was purified by column chromatography on silica gel eluting with a gradient system of 97:3:0.3 (dichloromethane:methanol:ammonia) gradually changing to 90:10:1 (dichloromethane:methanol:ammonia) to afford the title compound as a gum (123 mg).
Reaction SMILES: [OH-].[Na+:2].C([O:5][C:6]([C:8]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][O:9]1)=[O:7])C.CC(C)=O>O1CCCC1>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]2([C:6]([O-:7])=[O:5])[CH2:10][O:9]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1.[Na+:2]
Reactant: CCOC(=O)C1(CCCCCc2ccccc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C([O-])C1(CCCCCc2ccccc2)CO1
Reaction time: 0.75 h

Procedure:
A mixture of 166 ml of 1 N sodium hydroxide solution and 90 ml of tetrahydrofuran is added dropwise to a solution of 43.6 g of 2-(5-phenylpentyl)oxirane 2-carboxylic acid ethyl ester in 90 ml of tetrahydrofuran. When the addition has ended, the mixture is stirred for about 45 minutes, until a clear solution has formed. 1.6 l of acetone are now added dropwise in the course of 3 hours, a crystalline precipitate, which is filtered off and washed with acetone, separating out. The product is recrystallized from water to give 42.9 g of the title compound as the dihydrate of m.p. 82° to 86° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19](=[O:27])[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:3]=1.Br[CH2:29][CH:30]1[CH2:32][CH2:31]1>>[CH:30]1([CH2:29][N:24]2[CH2:25][CH2:26][CH:21]([NH:20][C:19](=[O:27])[CH2:18][O:17][C:4]3[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=3)[CH2:22][CH2:23]2)[CH2:32][CH2:31]1
Reactant: BrCC1CC1
Reactant: Cc1nc(OCC(=O)NC2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OCC(=O)NC2CCN(CC3CC3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 57 and bromomethyl cyclopropane in the same manner as in Example 32.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[O:22][CH2:21][CH2:20][NH:19][C:18]=3[CH:17]=[C:16](C(C)(C)C)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30].FC(F)(F)C(O)=O.[ClH:49]>C(O)C>[Cl:49][C:16]1[CH:15]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:23]2[O:22][CH2:21][CH2:20][N:19]([S:38]([C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH:33]=3)(=[O:40])=[O:39])[C:18]=2[CH:17]=1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C(C)(C)C)cc3c2OCCN3)CC1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1cccc(S(=O)(=O)N2CCOc3c(N4CCNCC4)cc(Cl)cc32)c1

Procedure:
Similarly, but replacing 4-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester with 4-(6-tert-butyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester, and replacing 3-methylsulfonyl-benzenesulfonyl chloride with the appropriate aryl- or heteroaryl-sulfonyl chlorides followed by de-protection using trifluoracetic acid or hot hydrogen chloride in ethanol, the following was prepared:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10].[C:12]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])[CH2:13][C:14]([O-])=[O:15].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.C1COCC1>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:14](=[O:15])[CH2:13][C:12]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])(=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)c1ccccc1N
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)c1ccccc1NC(=O)CC(=O)OCc1ccccc1
Yield: 17.9 %

Procedure:
To a mixture of 1-(2-aminophenyl)propan-1-one (CAS1196-28-7) (4.6 g), monobenzyl malonate (7.2 g), and THF (46 mL) were added EDC.HCl (7.1 g) and HOBt.H2O (7.1 g), and the mixture was stirred at room temperature for 14 h and then heated to reflux for 8 h. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9:1) to obtain benzyl N-(2-propionylphenyl)malonamate (1.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[C:16]([C:18](=[CH:27]OCC)[C:19]([NH:21][C:22](OCC)=[O:23])=[O:20])#[N:17]>>[C:16]([C:18]1[C:19](=[O:20])[NH:21][C:22](=[O:23])[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:27]=1)#[N:17].[C:16]([C:18]1[C:19](=[O:20])[NH:21][C:22](=[O:23])[N:13]([C:12]2[CH:14]=[CH:15][C:9]([Br:8])=[CH:10][CH:11]=2)[CH:27]=1)#[N:17]
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Reactant: Nc1ccccc1
Reactant: Nc1ccc(Br)cc1
Product: N#Cc1cn(-c2ccc(Br)cc2)c(=O)[nH]c1=O
Product: N#Cc1cn(-c2ccccc2)c(=O)[nH]c1=O

Procedure:
Following procedures hereinabove, each of aniline and 4-bromoaniline is reacted with α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide and cyclized to yield 5-cyano-1-phenyluracil, m.p. 290°, and 5-cyano-1-(4-bromophenyl)uracil, m.p. 257°-260°. The foregoing two compounds have been reported by Atkinson et al., J. Chem. Soc. 4118-4123 (1956) and Senda et al., Chem Pharm. Bull. 22(1), 189-195 (1974), respectively.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16](=[O:17])[N:11]3[CH2:12][CH:13]=[CH:14][CH2:15][N:10]3[CH:9]2[C:18]2[CH:23]=[CH:22][N:21]=[C:20](SC)[N:19]=2)=[CH:4][CH:3]=1.[CH3:26]O.O[O:29][S:30]([O-:32])=O.[K+]>C1COCC1.O.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16](=[O:17])[N:11]3[CH2:12][CH:13]=[CH:14][CH2:15][N:10]3[CH:9]2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([S:30]([CH3:26])(=[O:32])=[O:29])[N:19]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: CSc1nccc(C2C(c3ccc(F)cc3)C(=O)N3CC=CCN23)n1
Reactant: O=S([O-])OO
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1nccc(C2C(c3ccc(F)cc3)C(=O)N3CC=CCN23)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of 2-(4-fluorophenyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-2,3,5,8-tetrahydro-pyrazolo[1,2-a]pyridazin-1-one, 11, (2.4 g, 6.8 mmol) in THF:MeOH (80 mL of 1:1 mixture) is added dropwise a solution of OXONE® (16.8 g, 27.2 mmol) in H2O (80 mL). After stirring 2 hours at room temp, the reaction mixture is diluted with aqueous saturated NaHCO3 and extracted with EtOAc (3×). The combined organic phases are dried, filtered, and concentrated in vacuo to afford 1.5 g (58% yield) of the desired product as a yellow solid.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH:75]([O:78][CH3:79])[O:76][CH3:77])[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([O:58][C:59]1[CH:64]=[CH:63][C:62]([S:65]([CH3:68])(=[O:67])=[O:66])=[CH:61][CH:60]=1)=[CH:53][C:52]=2[O:69][CH:70]([CH3:74])[CH2:71][O:72][CH3:73])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1>C(#N)C>[CH3:77][O:76][CH:75]([O:78][CH3:79])[CH:44]1[S:43][C:47]([C:49]2[NH:50][C:51]3[C:56]([CH:57]=2)=[CH:55][C:54]([O:58][C:59]2[CH:60]=[CH:61][C:62]([S:65]([CH3:68])(=[O:66])=[O:67])=[CH:63][CH:64]=2)=[CH:53][C:52]=3[O:69][CH:70]([CH3:74])[CH2:71][O:72][CH3:73])=[N:46][CH2:45]1
Reactant: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)NCC(SCc3ccccc3)C(OC)OC)[nH]c12
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: CC#N
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(C(OC)OC)S3)[nH]c12
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 10.1 %

Procedure:
To an ice-cooled and stirred solution of triphenylphosphine oxide (0.43 g) in acetonitrile (8 mL) was added trifluoromethanesulfonic anhydride (0.13 mL), and the mixture was stirred at 4° C. for 30 min, followed by an addition of a solution of N-[2-(benzylsulfanyl)-3,3-dimethoxypropyl]-7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (0.25 g) and thioanisole (0.093 mL) in acetonitrile (5 mL). After stirring at 4° C. for 30 min, the reaction mixture was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution, and the organic layer was washed with brine, dried (MgSO4), filtered, and concentrated. The resulting precipitate was removed by filtration and washed with ethyl acetate-hexane. The combined filtrate and washings were concentrated and the residue was purified by basic silica gel chromatography (ethyl acetate:hexane=25:75 to 35:65, volume ratio) and then by silica gel chromatography (ethyl acetate:hexane=25:75 to 80:20) to give a colorless oil, which was crystallized from diethyl ether-hexane to give the title compound (21 mg, 10%) as colorless crystals. MS 535 (MH+). mp 109-112° C.
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[CH2:3][N:4]1[CH2:10][CH2:9][CH:8]([OH:11])[C:7]2[CH:12]=[CH:13][O:14][C:6]=2[CH2:5]1.[Br:17][C:18]1[C:19]([Cl:25])=[C:20](F)[CH:21]=[CH:22][CH:23]=1>>[ClH:25].[Br:17][C:18]1[C:19]([Cl:25])=[C:20]([O:11][CH:8]2[CH2:9][CH2:10][N:4]([CH2:3][C:2]([OH:1])([CH3:16])[CH3:15])[CH2:5][C:6]3[O:14][CH:13]=[CH:12][C:7]2=3)[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(O)CN1CCC(O)c2ccoc2C1
Reactant: Fc1cccc(Br)c1Cl
Product: CC(C)(O)CN1CCC(Oc2cccc(Br)c2Cl)c2ccoc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 7-(2-hydroxy-2-methyl-1-propyl)-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 43) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:8][C:7]2[C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH:5]=1)O.[Br-:17].[C:18]1([PH+:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[Br-:17].[CH3:13][C:12]1([CH3:14])[C:6]2[CH:5]=[C:4]([CH:2]([P+:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:1])[S:8][C:7]=2[C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11]1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: CC(O)c1cc2c(s1)C(C)(C)CCC2(C)C
Agent: [Br-]
Solvent: CC#N
Product: CC(c1cc2c(s1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 103.4 %

Procedure:
20.2 g of 4,5,6,7-tetrahydro-α,4,4,7,7-pentamethylbenzo[b]thiophene-methanol are dissolved in 260 ml of acetonitrile and the solution is treated with 29.2 g of triphenylphosphonium bromide. After stirring at 50° C. for 3 hours, the mixture is evaporated to dryness, the residue is taken up with 80% aqueous ethanol and extracted twice with hexane. The ethanol phase is evaporated, the residue is dissolved in methylene chloride, the solution is dried over sodium sulphate and evaporated. There are obtained 49.4 g of [1-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo-[b]thien-2-yl)ethyl]triphenylphosphonium bromide as an amorphous white powder.