Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)#[CH:11]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]#[C:11][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)=[CH:13][CH:14]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: CSc1nccc(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CSc1nccc(C#Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
4-Iodo-2-(methylthio)pyrimidine (35.7 g, 142 mmol) and 1-ethynyl-4-fluorobenzene (17.0 g, 142 mmol) were added to triethylamine (200 mL) at room temperature. To the resulting solution were added dichlorobis(triphenylphosphine)palladium(II) (1.0 g, 1.4 mmol) and copper iodide (1.0 g, 5.2 mmol). Then the reaction mixture was stirred under a nitrogen atmosphere at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure to remove excess triethylamine. The residue was partitioned between water (400 mL) and dichloromethane (400 mL). The organic layer was washed with water (2×400 mL) and dried (MgSO4), and the solvent was evaporated under reduced pressure to give an oil. Flash chromatographic purification on silica gel with 0 to 50% ethyl acetate/hexanes as eluant gave 18.3 g of the title compound as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:17]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11](=[O:18])[S:10]2)=[CH:4][C:3]=1[O:19]C(C)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:17]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11](=[O:18])[S:10]2)=[CH:4][C:3]=1[OH:19]
Reactant: CC(C)Oc1cc(N=c2sc(=O)n3n2CCCC3)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=c1sc(=Nc2ccc(Cl)c(O)c2)n2n1CCCC2

Procedure:
Into a reaction flask equipped with a Dimroth condenser, 1.7 g (5 mmol) of 9-(4-chloro-3-isopropoxyphenylimino)-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-one, 1.3 g (10 mmol) of aluminum chloride and 50 ml of chloroform, were charged, and refluxed under heating for 2 hours to complete the reaction.
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.C.[CH2:8]([C:15]#[N:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[C:9]1([CH2:8][C:15]([NH2:2])=[NH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CCc1ccccc1
Reactant: [NH4+]
Agent: C
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: N=C(N)Cc1ccccc1
Temperature: 0 °C
Yield: 91.9 %

Procedure:
Ammonium chloride (2.9 g, 54 mmol) was suspended in 20 mL of anhydrous toluene, stirred under argon, and cooled to 0° C. To this suspension was added 25 ml (50 mmol) of a 2M solution of trimethylaluminum in toluene. The reaction was allowed to warm to room temperature and stirring continued until the evolution of methane ceased (˜1 hour). Then, 3.46 mL (30 mmol) of benzyl cyanide in 10 mL of anhydrous toluene was added and the reaction was heated to 80° C. for 18 hours. The reaction was then cooled to room temperature and slowly poured into a slurry of 15 g of silica gel in 50 mL of chloroform and stirred for 5 minutes. The silica was filtered and washed with methanol. The filtrate and washings were combined and reduced to a volume of ˜15 mL and refiltered. Then, 18 mL (54 mmol) of a 3N solution of methanolic HCl was added to the filtrate followed by 400 mL of diethyl ether. After 16 hours of stirring at room temperature, a white precipitate formed and was subsequently filtered. This crude solid was then added to 150 mL of a 4:1 mixture of isopropanol-acetone and stirred for an additional 16 hours at room temperature. Undissolved ammonium chloride was then removed by filtration and the filtrate reduced to ˜15 mL, and 300 mL of diethyl ether was added and the mixture stirred for ˜1 hour. The white precipitate was then filtered and dried to yield 3.7 g (72%) of the objective compound as the hydrochloride salt. MS: (ESI, Pos) m/z 157.9 (M+23) 1H NMR (500 MHz, DMSO-d6): δ (ppm) 9.06 (br.d, 3H), 7.49 (d, 2H), 7.36 (t, 2H), 7.31 (t, 1H), 3.74 (s, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([N:15]1[C:20]2[CH:21]=[C:22]([C:26]([O:28][CH2:29]C)=[O:27])[CH:23]=[C:24](I)[C:19]=2[O:18][CH2:17][CH2:16]1)[CH2:12][CH2:13][CH3:14]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:11]([N:15]1[C:20]2[CH:21]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[C:24]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)[C:19]=2[O:18][CH2:17][CH2:16]1)[CH2:12][CH2:13][CH3:14]
Reactant: c1cocn1
Reactant: CCCCN1CCOc2c(I)cc(C(=O)OCC)cc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN1CCOc2c(-c3ncco3)cc(C(=O)OC)cc21
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a −70° C. solution of oxazole (227 mg) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexanes, 2 mL). After stirred at −70° C. for 30 min, zinc chloride (1 M in ethyl ether, 13 mL) was added. The mixture was warmed to 0° C. for 1 h. To this mixture was then added ethyl 4-butyl-8-iodo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (600 mg, 1.6 mmol) in THF (5 mL) followed by tetrakis triphenylphosphine palladium (0) (115 mg). The mixture was heated at reflux for 3 h, diluted with ethyl acetate (300 mL) and washed with water followed by brine. The organic solution was dried (sodium sulfate) and concentrated under reduced pressure. Purification by silica gel plug (1:1 acetate/hexanes) provided 363 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.96, 7.73, 7.40, 7.28, 4.44, 3.90, 3.43, 3.34, 1.61, 1.41, 0.98.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[C:5]([Cl:15])[CH:6]=[CH:7][C:8]=2[F:14])[N:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)CCC>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[C:5]([Cl:15])[CH:6]=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1c(Cl)nc2c(Cl)ccc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(Cl)ccc(F)c2c1Cl

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4,8-trichloro-5-fluoro-3-methylquinoline (0.61 g, 2.306 mmol), 2-(tributylstannyl)-pyridine (0.89 g, 2.42 mmol), palladium tetrakistriphenylphosphine (0.27 g, 0.23 mmol) in toluene (2 mL) to give 4,8-dichloro-5-fluoro-3-methyl-2-(pyridin-2-yl)-quinoline as a white solid. Mass Spectrum (ESI) m/e=307.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:7]2[C:8](=[O:17])[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]23[CH2:5][CH:4]=1.CO.[BH4-].[Na+]>O.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:16]=[CH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]([OH:17])[C:7]=2[CH:18]=1
Reactant: COC1=CCC23C=CC=CC2=CC=CC(=O)C3=C1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)C(O)c1ccccc1C=C2

Procedure:
The 3-methoxy-5H-dibenzo[a,b]cyclohepten-5-one intermediate (6.4 grams, 0.027 mole) was dissolved 140 milliliters of methanol and added to and caused to react with a solution of 2.57 grams (0.0678 mole) of sodium borohydride in 29 milliliters of water and 0.1 milliliter of 10N sodium hydroxide at reflux temperature to obtain 3-methoxy-5H-dibenzo[a,d]cyclohepten-5-ol intermediate which was recovered by vaporizing some of the methanol in vacuo and chilling to obtain a solid which after filtering and drying amounted to 5.3 grams.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=1.[C:12]([O:23][CH3:24])(=[O:22])[C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:24][O:23][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:18]([O:19][CH2:2][C:3]2[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=2)=[C:15]([O:16][CH3:17])[CH:14]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: Cc1nc(C)c(CBr)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2nc(C)c(C)nc2C)c(OC)c1
Temperature: 85 °C
Yield: 69.3 %

Procedure:
Adding 2-bromomethyl-3,5,6-trimethylpyrazine (0.5 g, 2.33 mmol), methyl vanillate (0.6 g, 3.30 mmol), anhydrous potassium carbonate (1.0 g, 7.25 mmol), and DMF (40 mL) into a 100 mL three-necked bottle in turn, heating to 85° C. with oil bath, stifling to react for 8 hours, TLC [V(cyclohexane):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.6, Rf of product=0.35), filtering to obtain filtrate, adding 30 mL water, extracting with chloroform (3×30 mL), incorporating the chloroform layer and wishing with water (2×20 mL), drying with anhydrous sodium sulfate, recycling chloroform under reduced pressure to obtain a light yellow oily matter, separating with a silica column, wherein eluant is V(petroleum ether):V(ethyl acetate)=3:1, collecting product, recycling the solution under reduced pressure to obtain solid, 0.51 g white crystalloid of 4-((3,5,6-trimethylpyrazine-2-yl)methoxyl)-3-methoxybenzoic methyl ester, a yield is 69.3%, m.p. 129.8-130.4° C.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([NH:10][C:11]([C:13]2[S:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[O:12])[CH2:7][N:6]1[CH2:19][C:20](=[O:36])[NH:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]2=[O:34])=[CH:24][C:23]=1[F:35])=[O:4].[OH-].[Na+].Cl>C1COCC1>[Cl:18][C:15]1[S:14][C:13]([C:11]([NH:10][C@H:8]2[CH2:7][N:6]([CH2:19][C:20](=[O:36])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]4=[O:34])=[CH:24][C:23]=3[F:35])[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]2)=[O:12])=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H]1C[C@@H](NC(=O)c2ccc(Cl)s2)CN1CC(=O)Nc1ccc(-n2ccccc2=O)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1C(=O)O)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
A solution of 394 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid methyl ester (example 11.4) in 10 ml THF was treated with 1.5 ml 1N NaOH. The reaction mixture was stirred for 4 hrs at r.t., then brought to pH 7 with 3N HCl and concentrated. The crude product was purified by chromatography (silica gel; CH2Cl2/MeOH 4:1, then MeOH). The product-containing fractions were concentrated, triturated with water and dried to give 290 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid as an off-white solid. MS 519.3 ([M+H]+)
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[CH:30]=[CH:29][C:6]([CH:7]([C:17]2[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])[C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[OH-].[Na+].OO>>[CH3:16][N:14]([CH3:15])[C:11]1[CH:10]=[CH:9][C:8]([C:7]2([C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:31])=[CH:30][CH:29]=3)[C:17]3[C:18](=[CH:22][C:23]([N:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=3)[C:19](=[O:21])[O:20]2)=[CH:13][CH:12]=1
Reactant: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3cc(N(C)C)ccc32)cc1
Temperature: 70 °C

Procedure:
To 1,500 wt. parts of an aqueous solution containing 41.7 wt. parts of 2-[4,4'-bis-(dimethylamino)-benzhydryl]-5-dimethylaminobenzoic acid and 4.4 wt. parts of sodium hydroxide was added 0.4 wt. part of cobaltous chloride. The mixture was heated at 70° C. and 51 wt. parts of 10% aqueous solution of hydrogen peroxide was added dropwise during 1 hour (pH=9.9). The precipitate was separated and dissolved into toluene and the catalyst was separated by a filtration and toluene was distilled off to obtain 39.8 wt. parts of 3,3-bis-(4-dimethylaminophenyl)-6-dimethylaminophthalide having a melting point of 180° to 183° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:26]([O:27][CH3:28])=[CH:25][C:6]2[CH2:7][C:8](=[O:24])[N:9]([CH2:12][CH2:13][CH2:14][N:15](C)[C:16](=O)OC(C)(C)C)[CH:10]=[CH:11][C:5]=2[CH:4]=1.Cl.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[C:26]([O:27][CH3:28])=[CH:25][C:6]2[CH2:7][C:8](=[O:24])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C(=O)OC(C)(C)C)C=C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNCCCN1C=Cc2cc(OC)c(OC)cc2CC1=O
Temperature: 60 °C
Yield: 78 %

Procedure:
Dissolve 1.9 g (4.86 mmol) of the product obtained in Step 1 in 30 ml of ethanol and add to that solution 7 ml (24.3 mmol, 5 equivalents) of HCl in ethanol (3.5N). Heat overnight at 60° C. and evaporate the reaction mixture to dryness. The residue obtained is taken up in water, and the aqueous phase is then adjusted to pH=8 by adding 20% sodium hydroxide solution and extracted with dichloromethane. The organic phase is washed with water, dried over MgSO4, filtered and then evaporated to dryness. 1.1 g of the title product are obtained in the form of a colourless oil.
Reaction SMILES: C(OC(=O)[CH:5]=[CH:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=3)[N:18]=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])[N:16]=2)[CH2:11][CH2:10]1)=[O:8])C.C[Mg]Br>C(OCC)C.O.C(Cl)Cl>[OH:32][C:27]([CH3:28])([CH3:26])[CH:5]=[CH:6][C:7]([N:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=3)[N:18]=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])[N:16]=2)[CH2:13][CH2:14]1)=[O:8]
Reactant: CCOC(=O)C=CC(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Agent: C[Mg]Br
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(C(=O)C=CC(C)(C)O)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C

Procedure:
To 4-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-oxo-but-2-enoic acid ethyl ester (655 mg, 1.47 mmol) in 2 mL of diethyl ether at −20° C. was added methyl magnesium bromide (8.4 mL, 11.7 mmol, 1.4 M THF/Toluene), and the reaction mixture was allowed to warm to 0° C. over 15 minutes The mixture was diluted with 10 mL of water and 15 mL of CH2Cl2. The resulting emulsion was filtered, and the organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure to give the alcohol. LC/MS: m/z 433.5 (M+H)+ at 2.56 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])(=O)=O.O>CC(C)=O>[I:1][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CS(=O)(=O)OCCCCCCC(F)(F)C(F)(F)F
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)C(F)(F)CCCCCCI
Yield: 90.2 %

Procedure:
Sodium iodide (19.62 g, 130 mmol) was added to a solution of 1-methanesulfonyloxy-7,7,8,8,8-pentafluorooctane (14 g, 47.01 mmol) in acetone (200 ml), followed by heating under reflux for 12 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with ether. The combined organic layers were washed with 1% aqueous sodium thiosulfate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give 1-iodo-7,7,8,8,8-pentafluorooctane (14 g, Yield 89%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+].O>CS(C)=O>[C:11]1([S:17]([C:8]2[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([Br:1])[CH:9]=2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1Br
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1Br
Temperature: 125 °C
Yield: 32.4 %

Procedure:
A mixture of 2-bromo-4-fluorobenzaldehyde (10.2 g, 50 mmol) and sodium benzenesulfinate (8.21 g, 50 mmol) in DMSO (100 mL) was heated at 125° C. overnight. Upon cooling the mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified via flash chromatography (hexane/EtOAc, 4/1) to give 4-benzenesulfonyl-2-bromo-benzaldehyde (5.26 g, 32% yield) as white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:8][C:5]2=[N+:6]([O-:29])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ncc(Br)cc32)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2cc(Br)c[n+]3[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a stirred solution of 6-bromo-1-tosyl-1H-pyrrolo[3,2-b]pyridine (6.87 g, 19.56 mmol) in DCM (100 mL) at 0° C. was added 3-chloroperbenzoic acid (77 wt %, 5.26 g, 23.47 mmol). The reaction mixture was stirred at RT until the starting material was completely consumed, as monitored by HPLC. After 8 h, the solution was washed with saturated aqueous NaHCO3 (2×). The organic phase was dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (2% to 4% MeOH/DCM) to give the title compound as a white solid (5.66 g, 79%). 1H NMR (500 MHz, CDCl3) δ ppm 8.30 (s, 1H), 8.06 (s, 1H), 7.78 (d, 2H, J=8.0 Hz), 7.65 (d, 1H, J=3.5 Hz), 7.33 (d, 2H, J=8.0 Hz), 7.06 (d, 1H, J=3.5 Hz), 2.41 (s, 3H); ESI-MS m/z [M+H]+ calc'd for C14H11BrN2O3S, 367, 369; found 367, 369.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH:9]=[CH2:10])=[C:3]1[CH3:11].N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Si:21]([O:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH:9]=[CH2:10])=[C:3]1[CH3:11])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCC1=C(C)C(O)CC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCC1=C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O
Temperature: 0 °C
Yield: 96.9 %

Procedure:
1 (RS)-4-hydroxy-3-methyl-2-(2-propenyl)-cyclopent-2-ene-1-one (5.0 g) and imidazole (2.91 g) were dissolved in dry dimethylformamide (20 ml), and tert-butyldimethylchlorosilane (5.45 g) was added thereto at room temperature and the resulting mixture was allowed to react for 14 hours at room temperature. The reaction solution was poured into an ice-cooled aqueous citric acid solution, and extracted three times with diethyl ether. The organic layers were combined, and the combined layer was washed with saturated aqueous sodium bicarbonate solution and brine in sequence, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resultant residue was subjected to column chromatography (eluent; n-hexane: ethy acetate=4:1) to afford (RS)-4-tert-butyldimethylsilyloxy-3-methyl-2-(2-propenyl)cyclopent-2-ene-1-one (8.48 g, yield 97.0%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]12[O:8][CH:7]1[CH2:6][CH2:5][C:4]([CH3:10])([CH3:9])[C:3]2=[CH:11][C:12](=O)[CH:13]=[CH2:14].CC[O:18]CC>C[O-].[Na+].[Cl-].[Na+].O>[CH3:1][C:2]1[CH:7]([OH:8])[CH2:6][CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1[CH:11]=[CH:12][C:13](=[O:18])[CH3:14]
Reactant: CCOCC
Reactant: C=CC(=O)C=C1C(C)(C)CCC2OC12C
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(=O)C=CC1=C(C)C(O)CCC1(C)C
Reaction time: 0.5 h

Procedure:
Retro-ionone (1.9 g) was added to a solution of m-chloroperbenzoic acid (2.2 g) dissolved in dichloromethane. This resulted in an exothermic reaction (~40°). After cooling, the mixture was washed with an aqueous sodium carbonate solution dried over MgSO4 and taken to dryness to yield the epoxide, the 1-(2,6,6-Trimethyl-2,3-epoxy-1-cyclohexylidene)-buten-2-one. This epoxide (~2 g) was dissolved in a solution of methanolic sodium methoxide (1.4 Molar; 20 ml) and left at RT for 1/2 hour (instant color change and probably complete reaction). Dilution with ether followed by a brine washing yielded 1-(2,6,6,-trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-oxo-1-butene, upon chromatography over silica gel.
Reaction SMILES: CC1(C)C2C3C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=3C=CC=2N(CCCS([O-])(=O)=O)/C/1=C/C=C(\C1C=CC=C(CCCCC(O[N:78]2[C:82](=[O:83])[CH2:81][CH2:80][C:79]2=[O:84])=O)C=1)/C=C/C1C(C)(C)C2C3C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=3C=CC=2[N+]=1CCCS([O-])(=O)=O.[Na+:86].[Na+].[Na+].[Na+].[Na+].[C:91]([CH2:94][CH2:95][CH2:96][CH2:97][C:98]1[CH:103]=[CH:102][CH:101]=[CH:100][C:99]=1/[C:104](=[CH:129]\[CH:130]=[C:131]1\[N:132]([CH2:146][CH2:147][CH2:148][S:149]([O-:152])(=[O:151])=[O:150])[C:133]2[C:138]([C:139]\1([CH3:141])[CH3:140])=[CH:137][C:136]([S:142]([O-:145])(=[O:144])=[O:143])=[CH:135][CH:134]=2)/[CH:105]=[CH:106]/[C:107]1[C:115]([CH3:117])([CH3:116])[C:114]2[C:109](=[CH:110][CH:111]=[C:112]([S:118]([O-:121])(=[O:120])=[O:119])[CH:113]=2)[N+:108]=1[CH2:122][CH2:123][CH2:124][S:125]([O-:128])(=[O:127])=[O:126])([OH:93])=[O:92].[Na+].[Na+].[Na+]>>[CH3:117][C:115]1([CH3:116])[C:114]2[C:109](=[CH:110][CH:111]=[C:112]([S:118]([O-:121])(=[O:119])=[O:120])[CH:113]=2)[N:108]([CH2:122][CH2:123][CH2:124][S:125]([O-:128])(=[O:127])=[O:126])/[C:107]/1=[CH:106]/[CH:105]=[C:104](\[C:99]1[CH:100]=[CH:101][CH:102]=[CH:103][C:98]=1[CH2:97][CH2:96][CH2:95][CH2:94][C:91]([O:93][N:78]1[C:82](=[O:83])[CH2:81][CH2:80][C:79]1=[O:84])=[O:92])/[CH:129]=[CH:130]/[C:131]1[C:139]([CH3:140])([CH3:141])[C:138]2[C:133](=[CH:134][CH:135]=[C:136]([S:142]([O-:145])(=[O:144])=[O:143])[CH:137]=2)[N+:132]=1[CH2:146][CH2:147][CH2:148][S:149]([O-:152])(=[O:151])=[O:150].[Na+:86].[Na+:86].[Na+:86]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)ON3C(=O)CCC3=O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2ccccc2CCCCC(=O)O)=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2ccccc2CCCCC(=O)ON2C(=O)CCC2=O)=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21

Procedure:
Compound 34 is prepared analogously to compound 9 (Example 9), except that compound 33 is used as a starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1.I[CH2:31][C:32]([NH2:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH2:31][C:32]([NH2:34])=[O:33])[CH:17]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(S(C)(=O)=O)cc1
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(CC(N)=O)c1)c1ccc(S(C)(=O)=O)cc1

Procedure:
In analogy to example 161, step 1, 5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)pyridin-2(1H)-one (example 339, step 2) was reacted with 2-iodoacetamide in the presence of potassium carbonate to give the title compound as a light yellow solid, MS (ESI+): m/z=487.3 [M+H]+.