Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH2:12][CH2:13][N:14]([CH2:22][CH2:23]O)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])[CH2:23][CH2:22][N:14]([C:15]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:21])[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCO)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Yield: 73.5 %

Procedure:
The t-butyl N-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]-N-(2-hydroxyethyl)carbamate (200 mg, 0.404 mmol) obtained in Example 257 was dissolved in toluene (10 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (200 mg, 0.829 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 8 hours. After the reaction mixture was allowed to cool down, cyanomethylenetri-n-butylphosphorane (200 mg, 0.829 mmol) was added thereto. Under an argon atmosphere, the mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, the residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with diethyl ether, whereby the title compound (140 mg, 0.297 mmol, 74%) was obtained as a white powder.
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].CO[C:11](=[O:35])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)=[N:22][O:23][C:24]=2[CH2:25][OH:26])=[N:14][CH:13]=1>O1CCOCC1>[F:34][C:29]1[CH:28]=[C:27]([C:21]2[C:20]([CH2:19][O:18][C:15]3[CH:16]=[CH:17][C:12]([C:11]([NH:8][CH:5]([CH3:7])[CH3:6])=[O:35])=[CH:13][N:14]=3)=[C:24]([CH2:25][OH:26])[O:23][N:22]=2)[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
A trimethylaluminium solution (2M in toluene, 798 ul, 1.60 mmol) was added to a solution of isopropylamine (63.2 mg, 1.06 mmol) in dioxane (5 mL). 6-[3-(3,4-Difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.27 mmol) in dioxane (5 mL) was added after 1 h at 50° C. The reaction mixture was stirred at 85° C. overnight. The solvent was removed by distillation. The residue was purified by chromatography (silica, ethyl acetate:heptane=2:3 to 7:3) to afford the title compound (30 mg, 28%) as a light brown solid. MS: m/e=404.3 [M+H]+.
Reaction SMILES: [N+]([O-])(O)=O.N([O-])=O.[Na+].[OH:9][CH2:10][C:11]1[N:15]([CH:16]([CH3:18])[CH3:17])[C:14](S)=[N:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O>[OH:9][CH2:10][C:11]1[N:15]([CH:16]([CH3:18])[CH3:17])[CH:14]=[N:13][CH:12]=1
Reactant: CC(C)n1c(CO)cnc1S
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CC(C)n1cncc1CO
Reaction time: 2 h
Yield: 38.4 %

Procedure:
To 5.0M nitric acid (81 ml) was added sodium nitrite (248 mg), and 5-hydroxymethyl-1-isopropyl-2-mercaptoimidazole (15.5 g) was added by portions at 0° C. The mixture was allowed to be at room temperature and the mixture was stirred for 2 hours, and water (100 ml) was added to the mixture. The mixture was neutralized with potassium carbonate at 0° C., and the solvent was distilled off under reduced pressure. Ethanol was added to the mixture, and the insolubles were filtered off, and the solvent was distilled off under reduced pressure. To the obtained residue was added methanol-ethyl acetate, and basic silica gel was added to the mixture. This mixture was purified by basic silica gel column chromatography (methanol-ethyl acetate=1:8) to obtain solid, which was recrystallized from diisopropyl ether-ethyl acetate, to give 5-hydroxymethyl-1-isopropylimidazole (4.84 g) as brown crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](OC)=[O:8])=[CH:5][C:4]([N+:11]([O-:13])=[O:12])=[N:3]1.[BH4-].[Li+]>C1COCC1>[CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][C:4]([N+:11]([O-:13])=[O:12])=[N:3]1
Reactant: COC(=O)c1cc([N+](=O)[O-])nn1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1nc([N+](=O)[O-])cc1CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a magnetic stirrer, addition funnel and nitrogen inlet was purged with nitrogen and charged with 156b (0.67 g, 3.6 mmol), THF (20 mL) and cooled to 0° C. using an ice bath. 2 M lithium borohydride solution (3.6 mL, 7.2 mmol) was added dropwise at a rate that maintained the internal reaction temperature below 5° C. After the addition was complete, the cooling bath was removed and the reaction was stirred at room temperature for 3 h. The reaction was cooled to 0° C. using an ice bath, and saturated aqueous sodium bicarbonate (30 mL) was added dropwise. The layers were separated, and aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, ethyl acetate/hexanes) to afford a quant. yield (0.56 g) of (1-methyl-3-nitro-1H-pyrazol-5-yl)methanol (156c) as an off-white solid: MS (ESI+) m/z 158.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][CH:4]([OH:24])[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([S:22][CH3:23])[N:17]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[F:26][C:2]([F:25])([F:1])[CH2:3][CH:4]([OH:24])[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([S:22]([CH3:23])=[O:35])[N:17]=1
Reactant: CSc1nccc(-n2ccc3c(OCC(O)CC(F)(F)F)cccc32)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nccc(-n2ccc3c(OCC(O)CC(F)(F)F)cccc32)n1
Yield: 89.6 %

Procedure:
4,4,4-Trifluoro-1-[1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yloxy]-butan-2-ol (1.5 g) in CHCl3 (200 mL) at 0° C. was stirred for 3 h with MCPBA (0.962 g) at 0° C., then quenched with 10% aqueous sodium thiosulfate. The organic layer was separated, washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered, concentrated in vacuo and purified on a column with 100% DCM to 15% MeOH/DCM (product eluting at 5% MeOH) to yield 4,4,4-trifluoro-1-[1-(2-methylsulfinyl-pyrimidin-4-yl)-1H-indol-4-yloxy]-butan-2-ol (˜1.4 g).
Reaction SMILES: [Na].[NH2:2][C:3]1[N+:8]([O-:9])=[C:7]([CH3:10])[CH:6]=[C:5](Cl)[N:4]=1.[OH-].[Na+].[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17]>>[NH2:2][C:3]1[N+:8]([O-:9])=[C:7]([CH3:10])[CH:6]=[C:5]([O:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH3:14])[N:4]=1
Reactant: CC(C)(C)CO
Reactant: Cc1cc(Cl)nc(N)[n+]1[O-]
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Product: Cc1cc(OCC(C)(C)C)nc(N)[n+]1[O-]
Reaction time: 22 h

Procedure:
0.32 g of sodium is dissolved in 50 ml of 2,2-dimethyl-1-propanol in the heated state. 2 g (0.0125 mole) of 2-amino-4-methyl-6-chloropyrimidine 3-oxide are added and the reaction medium is brought to 105° C. for 22 hours. The mixture, still hot, is poured into 300 ml of 10% aqueous sodium hydroxide solution. The product is extracted with ethyl acetate and the organic phase is dried with sodium sulphate. It is concentrated and a brown oil is obtained. The latter is filtered on silica gel using an elution gradient with ethyl acetate and methanol. After evaporation, a solid crude product is obtained, which is recrystallized in an acetonitrile/water (98:2) mixture.
Reaction SMILES: ClC1C=C([C@H]2OC(=O)N([C@H](C)C[C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=3)C2)C=CC=1.Br[C:26](Br)([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:22]1[C:19]2[CH:20]=[CH:21][CH:16]=[CH:17][C:18]=2[O:23][C:26]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: C[C@H](Cc1ccc(O)c(O)c1)N1C[C@@H](c2cccc(Cl)c2)OC1=O
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccccc2O1

Procedure:
More specifically, the chiral synthesis may be carried out by performing the synthetic reaction sequence outlined in Scheme III. L-DOPA 19 is treated with di-t-butyl-dicarbonate in dimethylformamide, giving (S)-N-(1-(1,1-dimethylethoxy)carbonyl)-3-hydroxy-L-tyrosine 20 which is reacted with methyl iodide and anhydrous potassium carbonate in acetone, giving (S)-N-(1,1-dimethylethoxy)carbonyl)-3,4-dimethoxy-L-phenylalanine methyl ester 21 which is reduced with lithium borohydride giving (S)-1,1-dimethylethyl-(2-(3,4-dimethoxyphenyl)-1-(hydroxymethyl)ethyl)carbonate 22, which is reacted with methane sulfonyl chloride and triethylamine in methylene chloride, giving (S)-1,1-dimethylethyl-(2-(3,4-dimethoxyphenyl)-1(((methylsulfonyl) oxy)methyl)ethyl)carbamate 23. Compound 23 is treated with trifluoroacetic acid and then is reduced using 10% Pd/C and hydrogen giving (R)-3,4-dimethoxy- -methylbenzeneethanamine 24. The compound 24 is treated with 3-chlorostyrene oxide 25 and N-(trimethylsilyl) acetamide giving a mixture of (R,S)- and (S,S)-3-chloro-(((2-(3,4-dimethoxyphenyl)-1-methylethyl)amino)methyl) benzenemethanol 26. Reaction of 26 with carbonyl diimidazole and triethylamine in tetrahydrofuran, followed by chromatographic separation of the diastereomers gives cyclized derivative 27, which is reacted with boron tribromide in dichloromethane, giving (R,R)-5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidinone 28. Compound 28 is then reacted with diethyl dibromomalonate and anhydrous potassium carbonate in acetone, giving (R,R)-5-(2-5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3benzodioxole-2,2-dicarboxylic acid, diethyl ester 29. Compound 29 is reacted with 5N sodium hydroxide in ethanol and then isolated by reverse phase chromatography to give (R,R)-1,3-benzodioxole-2,2-dicarboxylic acid, 5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-, disodium salt 15.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:40]=[O:41].O>C(OCC)C.O1CCCC1>[Si:10]([O:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH:40]=[O:41])[CH:7]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](OCc1ccnc(Br)c1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](OCc1ccnc(C=O)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of 2-bromo-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)pyridine (8.50 g) in diethyl ether (80 mL) was slowly added a 1.6M n-butyllithium hexane solution (13.0 mL) at −78° C. The reaction mixture was stirred for 30 min, a solution of N,N-dimethylformamide (1.85 mL) in tetrahydrofuran (20 mL) was added, and the mixture was warmed to room temperature and stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (2.16 g, yield 29%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). MS: 376 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Si:18]([O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
3-Aminophenol (21.8 g, 0.200 mol) and imidazole (34 g, 0.50 mol) were dissolved in DMF (200 mL), the solution was cooled with an ice-water bath, and TBDMSCl (36.1 g, 0.24 mol) was added in one portion. The cooling bath was removed, the reaction mixture was allowed to warm-up to room temperature, and stirred for 1 h. DMF (ca. 150 mL) was evaporated in vacuo at +55° C., the residue was diluted with AcOEt (250 mL), washed with sat. aq. NaHCO3 (twice), water (several times), brine and dried over MgSO4. After evaporation of solvents, the oily residue was dried in vacuo (0.5 Torr) to a constant weight. Purification by column chromatography (gradient elution with hexane to hexane/ether=5/1) afforded compound 2 (Rf=0.24 in hexane/ether=8/1) as a clear oil (34.1 g, 76%). 1H NMR (300 MHz, CDCl3): δ=0.21 (s, 6 H, SiMe2But), 0.99 (s, 9 H, SiMe2But), 3.60 (br. s, 2 H, NH2), 6.18 (m, 1 H), 6.28 (m, 2 H), 6.98 (m, 1 H) ppm.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH3:23])=[C:16]([F:24])[CH:15]=1.[Cl-].[NH4+].[O:27]1CCC[CH2:28]1>CN(C)C=O>[Br:13][C:14]1[C:15]([CH:28]=[O:27])=[C:16]([F:24])[C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:18][CH:19]=1
Reactant: COCOc1ccc(Br)cc1F
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)c(C=O)c1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of diisopropylamine (364 μl) in tetrahydrofuran (1 ml) was cooled to −78° C., and thereto was added dropwise n-butyl lithium (0.86 ml, 2.77M hexane solution), and the mixture was stirred at 0° C. for 10 minutes. The reaction mixture was cooled to −78° C., and thereto was added dropwise a solution of 1-bromo-3-fluoro-4-(methoxymethoxy)benzene (470 mg) in tetrahydrofuran (1 ml), and the mixture was stirred for 30 minutes. To the mixture was added dropwise N,N-dimethyl-formamide (210 μl), and the mixture was stirred at room temperature for one hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (48 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH:8]1[C:16](O)=[O:17].O.[OH-].[Na+]>C(OCC)C>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH:8]1[CH2:16][OH:17]
Reactant: O=C(O)C1Cc2ccccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCC1Cc2ccccc2O1
Reaction time: 8 h
Yield: 90 %

Procedure:
A three-necked flask is charged with 17 g of lithium aluminum hydride dissolved in anhydrous ethyl ether. 3 g of 2,3-dihydro-2-benzofurancarboxylic acid (Chim. Ler., (1973), 3, p. 259), dissolved in 1,140 ml of ethyl ether, are then introduced. The reaction medium is left stirring overnight. It is then hydrolyzed in an ice bath with 15.2 ml of water, 15.2 ml of 4N sodium hydroxide and then 45.2 ml of water. The complex is drained and washed with ethyl ether and the filtrate is dried and distilled to obtain the expected compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)N)=[CH:5][CH:4]=1.O=[C:20]([CH2:28][CH3:29])[CH2:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25]>C(O)(C)(C)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:12]3[C:17](=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:28]([CH3:29])=[C:20]2[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: CCC(=O)CCCC(=O)OC
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: CC(C)(C)O
Product: Cc1c(CCCC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the method of Example 2, but using 1-[(4-chlorophenyl)methyl]-1-(4-fluorophenyl)hydrazine hydrochloride and methyl 5-oxoheptanoate as the starting materials and tert-butanol as the solvent, the title compound was prepared.
Reaction SMILES: CS(O)(=O)=O.O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=3[S:15][CH:14]=2)=[CH:9][CH:8]=1>>[C:10]1([C:13]2[C:17]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=3[S:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=[CH:12][CH:11]=1
Reactant: COc1ccc2c(-c3ccc(O)cc3)csc2c1
Agent: CS(=O)(=O)O
Product: COc1ccc2c(-c3ccccc3)csc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 80 ml. of methanesulfonic acid (cooled to about 15° C.) were added 20.0 g. of the above product. The resulting mixture was stirred for two hours, and the dark red solution was poured over about 2 liters of ice. The mixture was extracted with 1 liter of ether. The ether extract was washed twice with 100 ml. of aqueous sodium chloride solution and once with 100 ml. of aqueous sodium bicarbonate solution. The ether layer was dried over magnesium sulfate, filtered, and evaporated to give an oil. The oil was crystallized from a mixture of ether and hexane to obtain 12.0 g. of 3-(4-hydroxyphenyl)-6-methoxybenzothiophene as white crystals, m.p. 140°-140.5° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6]O[C:4]([C:16]([OH:18])=[O:17])=[CH:3]1.[NH4+:19].[OH-].Cl>>[O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][NH:19][C:4]([C:16]([OH:18])=[O:17])=[CH:3]1
Reactant: [NH4+]
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Agent: Cl
Agent: [OH-]
Product: O=C(O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Reaction time: 3 h

Procedure:
300 g (1.22 mol) of 4-oxo-5-(phenylmethoxy)-4H-pyran-2-carboxylic acid was put into a flask and 5 1 of 33% NH4OH was carefully added with stirring. The reaction mixture was then stirred under reflux. After 3 hours, one additional liter of 33% NH4OH was added slowly. Stirring was continued for further 2 hours under reflux. The reaction solution was then evaporated until the product crystallized. The product was transferred back into the reaction flask and water added until a clear solution was obtained (approximately 5 1, pH 6.38). This solution was stirred vigorously while concentrated hydrochloric acid was added dropwise until a pH of 3 was obtained. The precipitated white product was removed by filtration, thoroughly washed with water and dried. Yield: 273 g (1.12 mol)=91.8%.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[CH:13]=[CH:12][CH:11]=[CH:10][N:5]2[C:6](=[O:9])[C:7]=1[Cl:8].CN1NCCCCCCC(C2CCCCCCCCC=2)=N1.Br[CH2:36][N:37]1[C:47](=[O:48])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[S:38]1(=[O:40])=[O:39].O>CN(C=O)C>[Cl:8][C:7]1[C:6](=[O:9])[N:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[O:1][CH2:36][N:37]1[C:47](=[O:48])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[S:38]1(=[O:39])=[O:40]
Reactant: O=c1c(Cl)c(O)nc2ccccn12
Reactant: O=C1c2ccccc2S(=O)(=O)N1CBr
Agent: CN1N=C(C2=CCCCCCCCC2)CCCCCCN1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1COc1nc2ccccn2c(=O)c1Cl
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a mixture of 2-hydroxy-3-chloropyrido[1,2-a]pyrimidine-4-one (0.324 g), and methyltriazabicyclodecene (0.24 mL) in DMF (15 mL) was added 2-bromomethylsaccharin (0.414 g). The mixture was stirred overnight, poured into water and the precipitate which formed was collected by filtration and recrystallized from DMF to afford 0.371 g (65%) of 2-[3-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-yl]oxymethyl-saccharin.
Reaction SMILES: [CH2:1]([C:8]1[S:14][CH:13]2[CH:10]([C:11](=[O:32])[N:12]2[C:15](=[C:29]([OH:31])[CH3:30])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=[O:35].N1CCOCC1.BrBr.Cl>O1CCCC1.CO.N1C=CC=CC=1.C(N(CC)CC)C>[C:2]1([CH2:1][C:8]([NH:9][CH:10]2[C:11](=[O:32])[N:12]3[C:15]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=4)=[O:17])=[C:29]([OH:31])[CH2:30][S:14][C@H:13]23)=[O:35])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Agent: BrBr
Agent: Cl
Solvent: CO
Solvent: C1COCCN1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 0 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
One adds triethylamine (5.68 ml) to a stirred suspension of p-nitrobenzyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (9.06 g) in tetrahydrofuran (120 ml) under nitrogen atmosphere at -20° C to give clear solution, adds methanesulfonyl chloride (1.65 ml) to the solution, stirs for 30 minutes at the same temperature, adds morpholine (1.92 ml), warms to 0° C, stirs for 5 hours, cools to -30° C, adds pyridine (1.54 ml) and bromine (3.12 g), stirs for 20 minutes, warms to ice-water temperatur, adds 5% hydrochloric acid (144 ml) and methanol (120 ml), stirs for 3 hours at room temperature, and lets stand overnight at 0° C. Collection of the separated crystals in the reaction mixture by filtration gives p-nitrobenzyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate (6.678 g). m.p. 201° C. Yield: 71 %.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:7]2[CH:8]=[CH:9][C:10]3[C:14](=[O:15])[O:13][CH2:12][C:11]=3[C:6]=2[CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.I([O-])(=O)(=O)=O>C(Cl)Cl>[O:15]=[C:14]1[O:13][CH2:12][C:11]2[C:6]3[CH2:5][CH2:4][CH:3]([CH:2]=[O:1])[C:7]=3[CH:8]=[CH:9][C:10]1=2
Reactant: O=C1OCc2c1ccc1c2CCC1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: O=CC1CCc2c1ccc1c2COC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-(hydroxymethyl)-1,6,7,8-tetrahydro-3H-indeno[4,5-c]furan-3-one (55 mg, 0.27 mmol) in DCM (5 mL) was added Dess-Martin Periodate (171 mg, 0.400 mmol). The reaction was allowed to stir at RT for 3 hours. LC analysis showed formation of the desired product, and there was little SM left. The solution was diluted with DCM (30 mL), and to that was added Na2S2O3 (10% aq solution, 15 mL) to consume the excess Dess-Martin reagent. The mixture was stirred until the two layers separated. The bottom DCM layer was collected, washed with aq Na2CO3, dried over sodium sulfate, and concentrated to give 3-oxo-3,6,7,8-tetrahydro-1H-indeno[4,5-c]furan-6-carbaldehyde. LC-MS (IE, m/z): 203 [M+1]+; tR=0.58 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:20])[C:8]=1[N+:21]([O-])=O)(=[O:6])=[O:5]>C(O)C.[Pt](=O)=O>[NH2:21][C:8]1[C:9](=[O:20])[N:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]([CH3:13])=[CH:12][C:7]=1[S:4]([CH2:3][CH2:2][Cl:1])(=[O:6])=[O:5]
Reactant: CCOC(=O)Cn1c(C)cc(S(=O)(=O)CCCl)c([N+](=O)[O-])c1=O
Agent: O=[Pt]=O
Solvent: CCO
Product: CCOC(=O)Cn1c(C)cc(S(=O)(=O)CCCl)c(N)c1=O
Reaction time: 16 h

Procedure:
A mixture of platinum (IV) oxide (24 mg) and 4-(2-chloroethylsulfonyl)-1-ethyloxycarbonylmethyl-6-methyl-3-nitro-2-pyridinone (120 mg, 0.33 mmol) in ethanol (3.0 mL) was stirred under hydrogen for 16 h. The reaction was filtered through celite and evaporated to give the title compound as a glass: