Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([OH:17])=[O:16])[C:9](=[O:18])[C:8]=2[CH:19]=1)([O-])=O.[CH2:20]([N:27]=[C:28]=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28](=[O:29])[NH:1][C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([OH:17])=[O:16])[C:9](=[O:18])[C:8]=2[CH:19]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=C(O)CN1CCOc2ccc([N+](=O)[O-])cc2C1=O
Product: O=C(O)CN1CCOc2ccc(NC(=O)NCc3ccccc3)cc2C1=O

Procedure:
Catalytic hydrogenation of (7-nitro-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetic acid (Example 15 c) followed by treatment of the resulting amine with benzylisocyanate yielded [7-(3-benzyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetic acid: mp. 60-70° C. (dec.); MS (ISP): 370 (M+1)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:28][CH2:29][NH2:30])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].O>ClCCl>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:28][CH2:29][NH:30][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(O)CCCCCCCCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CCNC(=O)CCCCCCCCc2ccccc2)cc1OC
Reaction time: 18 h

Procedure:
A solution of 9-phenylnonanoic acid (1.934 g) and N,N'-carbonyldiimidazole (1.34 g) in dry dichloromethane (20 ml) was stirred at 20° for one hour and a solution of 3,4-dimethoxybenzeneethanamine (1.4 ml) in dry dichloromethan (10 ml) then added. The mixture was stirred at 20° for 18 hours and water added. The organic phase was separated, washed with dilute hydrochloric acid, aqueous sodium bicarbonate and brine, dried over magnesium sulphate and evaporated to leave a solid. Crystallisation from 2-propanol gave the amide as colourless prisms (2.7 g); mp, 117°-119°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]([CH2:15][CH3:16])[CH:9]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]2=[O:22])[CH3:2].[Se](=O)=[O:24]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH:14]=[O:24])[N:10]([CH2:15][CH3:16])[CH:9]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]2=[O:22])[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2nc(C)c(OCC)cc2c1=O
Reactant: O=[Se]=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CC)c2nc(C=O)c(OCC)cc2c1=O
Yield: 62.5 %

Procedure:
20.2 g of the Compound VIII obtained as above was heated at 175°-185° C. under a nitrogen stream to melt and 10 g of selenium dioxide was added in several portions. Under a nitrogen stream, the mixture was reacted under the same conditions for 20 minutes. After allowing to cool, chloroform was added to the reaction mixture and the insoluble materials were removed by filtration and the filtrate was concentrated in vacuo. The resulting residue was recrystallized from ethanol to yield 13.2 g of ethyl 1,4-dihydro-6-ethoxy-1-ethyl-7-formyl-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 169°-170° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:7]([S:26]([CH3:29])(=[O:28])=[O:27])[N:6]=1)(=O)=O.C([Li])CCC.[CH:35]1([OH:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH:35]1([O:41][C:5]2[N:6]=[C:7]([S:26]([CH3:29])(=[O:28])=[O:27])[C:8]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[N:10]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Reactant: OC1CCCCC1
Agent: [Li]CCCC
Product: CS(=O)(=O)c1nc(OC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
2,4-Bis(methylsulfonyl)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine (Reference Example 5) (196 mg, 0.4 mmol) was reacted with 1 equivalent each of n-butyl lithium and cyclohexanol by the procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel (eluted with 90/10 hexanes/ethyl acetate) afforded 2-cyclohexyloxy-4-(methylsulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Higher Rf product): 1H-NMR 500 MHz (CDCl3): δ 1.30 (m, 5H), 1.45 (m, 1H), 1.55 (m, 1H), 1.64 (m, 1H), 1.75 (m, 1H), 1.90 (m, 1H), 2.15 (m, 1H), 3.38 (s, 3H), 5.09 (m, 1H), 7.0 (d, J=7 Hz, 1H), 7.18-7.22 (m, 4H), 7.36 (d over m, J=2 Hz, 2H); and 2-methylsulfonyl-4-cyclohexyl-oxy-5-(4chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Lower Rf product): 1H-NMR 500 MHz (CDCl3): δ 0.87-0.9 (m, 1H), 0.95-1.07 (m, 2H), 1.1-1.3 (m, 2H), 1.33 (m, 2H), 1.7-1.82 (m, 4H), 3.40 (s, 3H), 4.37 (d, J=6 Hz, 2H), 7.08 (d, J=8 Hz, 2H), 7.12 (d, J=8 Hz, 1H), 7.22-7.30 (m, 3H), 7.37 (d, J=2 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=2)[CH:2]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36])(=[O:31])=[O:30]>CN(C=O)C>[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:14]([C:10]1[C:11]([CH3:13])=[N:12][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8][CH:9]=1)=[O:16])(=[O:30])=[O:31]
Reactant: Cc1nc(-c2cccnc2)ncc1C(=O)O
Reactant: CNS(=O)(=O)c1cccc(CN)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3cccnc3)nc2C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A mixture of 2-(3-pyridyl)-4-methylpyrimidine-5-carboxylic acid (215 mg, 1 mmol, prepared according to the general procedure described in Example 42, steps 1 and 2) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (380 mg, 1 mmol) in dry DMF (12 mL) is treated with of diisopropylethylamine (0.18 mL) and stirred at room temperature for 30 min. 3-Methylsulfamoylbenzylamine hydrochloride (355 mg, 1.5 mmol) is added and the mixture is stirred at room temperature for 24 hours. The solvent is removed and the residue partitioned between EtOAc and saturated NaHCO3. The organic phase is separated, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 2% MeOH in EtOAc to afford 2-(3-pyridyl)-4-methyl-pyrimidine-5-carboxylic-acid-3-methylsulfamoyl-benzylamide (180 mg, 45%) as a solid. MS: 398 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.43 (s, 3H), 2.65 (s, 3H), 4.60 (d, 2H), 7.57-7.71 (m, 4H), 7.79 (s, 1H), 8.68-8.72 (d, 1H), 8.72-8.78 (d, 1H), 8.93 (s, 1H), 9.34 (t, 1H), 9.53 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:14]1[N:13]=[C:12]([NH:16][C:17]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:18])[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:11]2[CH:12]=[N:13][C:14]([CH3:15])=[CH:9][CH:10]=2)[CH:7]=1
Reactant: Cc1nc(NC(=O)NC(=O)C(C)(C)C)ccc1Oc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3C)ccn2)cn1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 129.8 %

Procedure:
A suspension of Example C1 (0.20 g, 0.551 mmol), Example C2 (0.254 g, 1.158 mmol) and satd. NaHCO3 (1.1 mL) in dioxane (4.4 mL) was sparged with Ar under sonication, treated with Pd(PPh3)4 (0.064 g, 0.055 mmol), sparged again with Ar, heated at 80° C. for 3 h, then 90° C. for 1.5 h. The mixture was cooled to RT, diluted with EtOAc and filtered through diatomaceous earth. The filtrate was concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was further purified via reverse-phase silica gel chromatography (MeCN/H2O with 0.1% TFA). Pure fractions were combined and concentrated under reduced pressure. The aqueous residue was neutralized with satd. Na2CO3 and the solid collected via filtration, dissolved in MeCN/H2O, frozen and lyophilized to afford N-((6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (150 mg, 65%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.15 (s, 1H), 10.39 (s, 1H), 9.08 (d, J=2.4 Hz, 1H), 8.52 (d, J=5.7 Hz, 1H), 8.26 (dd, J=8.1, 2.4 Hz, 1H), 7.91 (m, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 6.78 (dd, J=5.7, 2.4 Hz, 1H), 2.49 (s, 3H), 2.26 (s, 3H), 1.20 (s, 9H); MS (ESI) m/z: 420.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]([N:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]([OH:24])=O)=[CH:21][C:16]=2[N:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C(N(CC)C(C)C)(C)C.CN(C(O[N:43]1N=N[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.NC1C=CC=CC=1>CN(C=O)C>[NH:43]([C:22]([C:20]1[CH:19]=[CH:18][C:17]2[N:13]([CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:25])[CH:14]=[N:15][C:16]=2[CH:21]=1)=[O:24])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(C(=O)Nc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3-ethoxy-3-oxo-1-phenylpropyl)-1H-benzimidazole-5-carboxylic acid (50 mg, 148 μmol) in DMF (3 μL) was added N,N-diisopropylethylamine (50 μL, 287 μmol) and TBTU (57 mg, 177 μmol). The solution was stirred at room temperature for 0.5 hour, aniline (20 μL, 220 μmol) was added, and stirring continued at room temperature for 72 hours. The solution was evaporated in vacuo, and the residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (98:2) to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=5.30 min, MH+ 414].
Reaction SMILES: [CH2:1](I)I.[CH3:4][C:5]([CH:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:6][CH2:7][CH3:8]>C(OC)(C)(C)C>[CH2:7]([CH:6]1[CH2:4][C:5]1([CH3:1])[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[OH:15])[CH3:8]
Reactant: CCC=C(C)C(O)CCCCC
Reactant: ICI
Solvent: COC(C)(C)C
Product: CCCCCC(O)C1(C)CC1CC
Reaction time: 0.08 h

Procedure:
To a dry 2 liter multi-neck round bottom flask fitted with an air stirrer, nitrogen inlet condenser and an addition funnel 8 g of a ZnCu and 75 ml of Methyl Tertiary Butyl Ether (MTBE) was added. The resulting mixture was stirred for 5 minutes. After the temperature of the mixture was stabilized, 24 g of CH2I2 was added over 10 minutes while stirring. After the temperature of the mixture was stabilized, the mixture was heated to reflux. As the temperature of the mixture reached 44° C., 17 g of 4-methyl-3-decene-5-ol was added over 30 minutes. After the addition of 4-methyl-3-decene-5-ol, a first sample was taken. Additional samples were taken every hour for three hours. Then the sample was quenched with saturated NH4Cl, aqueous layer separated and the organic layer filtered through celite.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl>CC(N(C)C)=O>[CH3:21][N:22]([CH2:23][CH2:24][CH2:25][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH3:27]
Reactant: CN(C)CCCCl
Reactant: Oc1ccccc1CCCCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(C)CCCOc1ccccc1CCCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
96 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling and stirring, to a solution of 226 mg of 2-(4-phenylbutyl)phenol (prepared as described in Preparation 3) in 10 ml of dimethylacetamide, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, 174 mg of 3-dimethylaminopropyl chloride hydrochloride were added, and the reaction mixture was stirred at 70° C. for 14 hours. It was then poured into ice-water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The oily residue was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 210 mg (yield 67%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[N:8][N:9]([CH2:11][CH2:12][C@@:13]([CH3:28])([S:24]([CH3:27])(=[O:26])=[O:25])[C:14]([NH:16][O:17]C3CCCCO3)=[O:15])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1.C(Cl)Cl.O>[CH:1]1([C:6]2[CH:7]=[N:8][N:9]([CH2:11][CH2:12][C@@:13]([CH3:28])([S:24]([CH3:27])(=[O:25])=[O:26])[C:14]([NH:16][OH:17])=[O:15])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@](CCn1cc(C2CCCC2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@](CCn1cc(C2CCCC2)cn1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
To a solution of (2R)-4-(4-cyclopentyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (100 mg, 0.242 mmol) in dioxane (2 mL), DCM (2 mL) and water (500 uL) was added a 4.0M sol of HCl in dioxane (0.36 mL, 1.45 mmol). The reaction mixture was stirred at RT for 30 minutes. The solvent was removed and the crude mixture was purified by HPLC (Column: Phenomenex Luna (2) C18 150×3.0 mm 5μ; flow rate 0.75 mL/min; Gradient: 5-100% MeOH/Water containing 0.1% TFA) to give (2R)-4-(4-cyclopentyl-1H-pyrazol-1-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (4 mg, 5% yield). LC-MS M+H+330.1.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](Cl)(=O)C(Cl)=O.CO>O1CCCC1>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To a solution of 2-chloro-3-nitrobenzoic acid (100 g, 0.496 mol) in tetrahydrofuran (1000 mL) was added dropwise oxalyl chloride (46.8 mL, 0.546 mol) at 0° C., and the mixture was stirred at room temperature for 3 hr. To the mixture was added dropwise methanol (300 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. The mixture was concentrated and the residue was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was washed with n-hexane to give the title compound as a yellow powder (103 g, 0.478 mol, 96%).
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].[OH2:7].O.[Na+].[SH:10][C:11]1[CH2:16][O:15][CH2:14][CH2:13][C:12]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)(=O)C>[CH2:20]([O:19][C:17]([C:12]1[CH2:13][CH2:14][O:15][CH2:16][C:11]=1[S:10]([OH:7])(=[O:6])=[O:5])=[O:18])[CH3:21]
Reactant: O
Reactant: CCOC(=O)C1=C(S)COCC1
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(S(=O)(=O)O)COCC1
Reaction time: 3 h
Yield: 219.9 %

Procedure:
Sodium perborate tetrahydrate (24.5 g) was added to acetic acid (130 ml) and the mixture was heated to 50–55° C. Thereto was added dropwise a solution of ethyl 5-sulfanyl-3,6-dihydro-2H-pyran-4-carboxylate (10.0 g) in acetic acid (30 ml) over 2 h. The mixture was stirred at 50–55° C. for 3 h, and the reaction mixture was concentrated under reduced pressure. To the residue was added acetonitrile (230 ml) and the mixture was stirred at room temperature for 2 days, and the resultant insoluble material was removed off by filtration and washed with acetonitrile (70 ml). The filtrate and washing were combined and the mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile (160 ml) and the mixture was stirred at room temperature for 6 h. The obtained insoluble material was removed off by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added diisopropyl ether (100 ml), and the precipitated insoluble material was filtered off to give 4-(ethoxycarbonyl)-5,6-dihydro-2H-pyran-3-sulfonic acid as a pale-yellow oil (27.6 g) containing an inorganic product.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[C:7]1=[O:16])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:17]1[O:25][C:24]2[C:19](=[CH:20][CH:21]=[C-:22][CH:23]=2)[O:18]1.[Mg+2].[Br-]>C1COCC1>[O:18]1[C:19]2[CH:20]=[CH:21][C:22]([C:8]3([OH:15])[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]3=[O:16])=[CH:23][C:24]=2[O:25][CH2:17]1
Reactant: CCCCCN1C(=O)C(=O)c2ccccc21
Reactant: [c-]1ccc2c(c1)OCO2
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(O)(c2ccc3c(c2)OCO3)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of 1-pentyl-1H-indole-2,3-dione (2.80 g, 12.8 mmol) in THF (50.0 mL) was added 3,4-(methylenedioxy)phenylmagnesium bromide (14.0 mL, 1 M THF solution, 14.0 mmol) slowly at −78° C. The mixture was stirred at 0° C. for 1 h and quenched with ammonium chloride solution. The mixture was poured into water (150 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash column chromatography to afford the title compound (3.10 g, 71%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 7.34-7.23 (m, 2H), 7.05 (t, 1H), 6.91-6.85 (m, 2H), 6.83-6.78 (m, 1H), 6.71 (d, 1H), 5.92-5.89 (m, 2H), 3.82-3.55 (m, 2H), 3.40 (br, 1H), 1.76-1.61 (m, 2H), 1.39-1.28 (m, 4H), 0.87 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:15]3[C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[CH:12]=[N:11][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]#[C:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1>CC(C)=O>[F:45][C:42]1[CH:43]=[CH:44][C:39]([C:38]#[C:37][CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:15]4[C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[CH:12]=[N:11][C:10]=4[N:9]=3)=[CH:6][CH:7]=2)=[CH:40][CH:41]=1
Reactant: Fc1ccc(C#CCBr)cc1
Reactant: CCCn1cnc2nc(-c3ccc(O)cc3)n(COCC[Si](C)(C)C)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1cnc2nc(-c3ccc(OCC#Cc4ccc(F)cc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 80 °C
Yield: 24.8 %

Procedure:
A mixture of 8-(4-hydroxy-phenyl)-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.100 g, 0.25 mmol), potassium carbonate (0.086 g, 0.50 mmol), 1-(3-bromo-prop-1-ynyl)-4-fluoro-benzene (0.107 g, 0.50 mmol) were taken in acetone (10 ml). The reaction mixture was heated at 80° C. for 2 hour. The mixture was cooled to room temperature and filtered through sintered funnel, washed with acetone. Solvent was evaporated and the residue was purified by preparative TLC to obtain pure 8-{4-[3-(4-fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.033 g, 25%) as pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([Br:16])[C:7]2[O:11][C:10]([C:12]([O-:14])=[O:13])=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[K+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([Br:16])[C:7]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: O=C([O-])c1cc2cc([N+](=O)[O-])cc(Br)c2o1
Agent: [K+]
Solvent: CO
Product: O=C(O)c1cc2cc([N+](=O)[O-])cc(Br)c2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A mixture of 11.5 gm (35.5 mMol) potassium 5-nitro-7-bromobenzofuran-2-carboxylate and 36 gm Dowex 50WX8-200 resin in 1.6 L methanol was stirred for 1 hour at room temperature. The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was diluted with about 80 mL of methanol and heated on the steam bath with stirring. The mixture was cooled to room temperature and filtered. The residual solid was dried under vacuum to provide 6.7 gm (66%) of the desired compound as a gold solid.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:45])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:42][CH3:43])([C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[C:25]([CH3:41])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:44])[CH:13]=1)C.Cl>CO.O>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:13]=[C:8]([CH2:7][C:6]([OH:45])=[O:5])[CH:9]=[N:10][CH:11]=2)=[C:15]([CH3:44])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:40])([C:36]([F:37])([F:38])[F:39])[C:32]([F:34])([F:35])[F:33])=[C:25]([CH3:41])[CH:24]=1)[CH2:42][CH3:43])[CH3:22]
Reactant: CCOC(=O)Cc1cncc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c3)cc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Reaction time: 2 h
Yield: 61.6 %

Procedure:
A 6 N sodium hydroxide aqueous solution (0.009 mL) was added to a solution of [5-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester (Example 75-(1); 5.0 mg, 0.0084 mmol) in methanol (0.3 mL) and water (0.030 mL), and the mixture was stirred for two hours. 2 N hydrochloric acid aqueous solution and water were added to the reaction mixture, followed by extraction with diethyl ether and ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (dichloromethane/methanol=5/1) to give the title compound (3.0 mg, 60%).
Reaction SMILES: BrC1C=CC(N2C=CC=N2)=CC=1.[N:13]1([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH:26]([OH:30])[CH2:25]3)=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[N:14]1>>[N:13]1([C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]3)=[CH:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: OC1CCCN(c2ccc(-n3cccn3)cc2)C1
Agent: Brc1ccc(-n2cccn2)cc1
Product: O=C1CCCN(c2ccc(-n3cccn3)cc2)C1

Procedure:
1-(4-(1H-Pyrazol-1-yl)phenyl)piperidin-3-one (300 mg, 1.243 mmol) was synthesized as described in General Procedure B using 1-(4-bromophenyl)-1H-pyrazole. The resulting product 1-(4-(1H-pyrazol-1-yl)phenyl)piperidin-3-ol was oxidized using General Procedure D to give the title compound.