Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][CH2:2]C.[Na+].[CH2:5]([O:7][C:8](=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)[CH3:6].C=O.C(O)(=O)C>C(O)C.CS(C)=O>[CH2:5]([O:7][C:8](=[O:19])[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)[CH2:2][OH:1])[CH3:6]
Reactant: CCOC(=O)Cc1ccc(OCC)cc1
Reactant: CC[O-]
Agent: C=O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCOC(=O)C(CO)c1ccc(OCC)cc1
Reaction time: 0.08 h

Procedure:
Sodium ethoxide solution in ethanol (0.5 M, 18 ml) was added to a solution of ethyl-p-ethoxyphenylacetate (30 g) in dry dimethyl sulphoxide (180 ml) under argon cover. The mixture was stirred for 5 minutes and dry paraformaldehyde (5.4 g) added. After 19 h stirring, acetic acid (1.5 ml) was added, the solution quenched in ice and extracted with ether. The ether layer was washed with sodium bicarbonate solution and water, dried over anhydrous sodium sulphate, and the solvent evaporated. The resulting oil crystallized from petroleum ether (40°-60°) to yield 27.8 g product m.p. 35°-36° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:17]2[CH2:19][CH2:18]2)=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.S([O-])(O[O-])(=O)=[O:21].[K+].[K+]>CC(C)=O.O.CC(OC)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:21])[CH:5]=[N:4][C:3]=1[CH:17]1[CH2:19][CH2:18]1
Reactant: CC1(C)OB(c2cnc(C3CC3)c(Cl)c2)OC1(C)C
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: Oc1cnc(C2CC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
3-Chloro-2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 41, 3.092 mmol assuming 100% in previous step) was dissolved in acetone (10.0 mL) and cooled to 0° C. with an ice bath. Then potassium peroxymonosulfate (2.55 g, 4.15 mmol) in water (10.0 mL) was added dropwise to the mixture and stirred at this temperature for 1 hour. The reaction was then diluted in TBME (25.0 mL) and washed with brine (3×25.0 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified with silica gel chromatography eluting with 0 to 30% EtOAc in heptane to yield the title compound as a pale yellow solid (0.220 g, 1.28 mmol, 42% over 2 steps).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:28]1([C:31]([O:33]C)=[O:32])[CH2:30][CH2:29]1)([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:16][CH:15]=1)[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Li+].Cl>N1C=CC=CC=1.O.CCOC(C)=O>[CH2:1]([NH:8][C:9]([C:28]1([C:31]([OH:33])=[O:32])[CH2:29][CH2:30]1)([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[CH:16][CH:15]=1)[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1(C(NCc2ccccc2)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)CC1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(O)C1(C(NCc2ccccc2)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)CC1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To a solution Intermediate 14D (558 mg, 1.140 mmol) in pyridine (5.7 mL) was added lithium iodide (1.53 g, 11.4 mmol). The reaction was heated to reflux overnight. The reaction was cooled to rt and diluted with water and EtOAc. The aqueous layer was made acidic with 1 N HCl and the layers were separated. The organic layer was washed with sat'd aq NaCl, dried over MgSO4, filtered and concentrated to provide Intermediate 14E (506 mg, 84%) which was used in the next step without further purification. LCMS Anal. Calc'd for C23H23F6NO3 475.42, found [M+H] 476.2.
Reaction SMILES: CS[C:3]1[C:8]2[C:9](=[O:24])[C:10]3[C:11]([CH:22]=[CH:23][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[N:12][CH:13]=[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:15]=3.O[O:26][S:27]([O-:29])=O.[K+].[CH2:31]1COCC1>CO>[CH3:31][S:27]([C:3]1[C:8]2[C:9](=[O:24])[C:10]3[C:11]([CH:22]=[CH:23][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[N:12][CH:13]=[C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:15]=3)(=[O:29])=[O:26]
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Reactant: CSc1cccc2ccc3ncc(-c4ccccc4)cc3c(=O)c12
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)c1cccc2ccc3ncc(-c4ccccc4)cc3c(=O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 6-(methylthio)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (7.4 mg, 0.022 mmol) in THF (0.7 mL) and MeOH (0.2 mL) was added oxone (0.3 mL, 0.138 M in water). The mixture was then stirred at room temperature. After 2 hours, the reaction mixture was concentrated to dryness. The crude residue was diluted with EtOAc and washed with brine. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by reverse phase HPLC (30-100% acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 9.10 (d, 1H), 8.40 (d, 1H), 8.26 (d, 1H), 8.00 (d, 1H), 7.85 (t, 1H), 7.75 (d, 2H), 7.53 (t, 2H), 7.47 (m, 2H), 7.38 (d, 1H), 3.52 (s, 31). LRMS (APCI) calculated for C21H16NO3S [M+H]+, 362.0; found 362.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12](=[O:15])[CH2:13]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([CH2:30][C:31]1[CH:47]=[CH:46][C:34]([O:35][CH2:36][CH2:37][NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:33][CH:32]=1)(=[O:29])[NH2:28].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:39]([N:38]([CH2:37][CH2:36][O:35][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C:27](=[O:29])[NH2:28])=[CH:47][CH:46]=1)[CH2:13][C:12](=[O:15])[C:11]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: NC(=O)Cc1ccc(OCCNCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)Cc1ccc(OCCN(CC(=O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)Cc2ccccc2)cc1

Procedure:
A mixture 3,4-dibenzyloxyphenacyl bromide (32.8 g.), N-[2-(4-carbamoylmethylphenoxy)ethyl]benzylamine (22.8 g.), anhydrous sodium carbonate (8.4 g.) and ethanol (1 liter) was boiled under reflux for 3 hours, then filtered hot to remove the inorganic sediment and evaporated in vacuo to afford a thick syrup. The latter was crystallized upon trituration in diethyl ether and a sample of the resultant solid was recrystallized from ethanol to give N-benzyl-N-(3,4-dibenzyloxybenzoyl)methyl-2-(4-carbamoylmethylphenoxy)ethylamine, m.p. 99°-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH2:23][CH3:24].[H-].[Na+].[F:27][C:28]([F:41])([O:32][C:33]1[CH:34]=[C:35]([CH2:39]Br)[CH:36]=[CH:37][CH:38]=1)[CH:29]([F:31])[F:30].O>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:22])[CH:16]([CH2:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([O:32][C:28]([F:27])([F:41])[CH:29]([F:30])[F:31])[CH:34]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[CH2:23][CH3:24]
Reactant: CCOC(=O)CC(=O)c1ccc(Oc2ccc(Cl)c(CC)c2)cc1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(Oc2ccc(Cl)c(CC)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (6.0 g, 28.8 mmol) in carbon tetrachloride (60 ml) were added N-bromosuccinimide (5.65 g, 31.7 mmol) and 2,2′-azobis(isobutyronitrile) (237 mg, 1.44 mmol), and the mixture was heated under reflux for 6 hrs. After cooling, the reaction solution was filtered, and the filtrate was concentrated to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-oxopropionate (10 g, 28.8 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 1.15 g, 28.8 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (10 ml), and the reaction solution was stirred at room temperature for 1 hr. The reaction solution was poured into water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene) to give ethyl 3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-oxo-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate (9.26 g, 58%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].N1C=CC=CC=1.Cl.[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39](Cl)=[O:40])[CH2:35][CH2:34]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:39]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)=[O:40])[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N3CCN(C)CC3)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (441 mg, 1.36 mmol) in dichloromethane (5 mL) and pyridine (1.1 mL, 13.6 mmol) was added 4-methyl-piperazine-1-carbonyl chloride hydrochloride (297 mg, 1.49 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was extracted with dichloromethane (2×50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-{3-[(4-methyl-piperazine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (612 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C26H34N4O3 (M+H)+: 451.59, observed: 451.2.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC1C=C(C=CC=1)C(OO)=[O:19]>ClCCl>[CH:12]12[O:19][CH:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13]2
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-boc-1,2,3,6-tetrahydropyridine (3.63 g, 21.0 mmol) in 40 mL of dichloromethane was added 3-chloroperoxybenzoic acid (2.75 g, 15.0 mmol). The reaction was stirred at room temperature for 4 h, then washed 3× with saturated aqueous potassium carbonate and once with brine. The solution was dried over sodium sulfate, filtered, and concentrated in vacuo to provide crude tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate that gave a proton NMR spectra consistent with theory.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][N:3]1[C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O.Cl.[NH2:20][CH2:21][C:22]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][N:3]1[C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14]([NH:20][CH2:21][C:22]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:16]
Reactant: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)O
Reactant: NCC1(O)CCCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)NCC1(O)CCCCCC1
Yield: 41.2 %

Procedure:
A slurry of 5-(3,5-Dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-methyl-benzoic acid (5.0 g, 20.2 mmol), 1-aminomethyl-cycloheptanol HCl (5.4 g, 30.3 mmol), EDCI (5.8 g), and DMAP (7.4 g, 60.6 mmol) in DMF (67.3 mL) was stirred at ambient temperature for 14 hours. The reaction was then poured into 1N HCl (50 mL) and diluted with water (15 fold). The aqueous was extracted with CH2Cl2 (3×). The organics were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a tan solid. The crude was recrystallized from CH2Cl2 to give the title compound as an off-white solid (3.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:33])=[C:8]2[C:14]([Br:15])=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:12]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[CH3:34][C:35]([CH3:40])([CH3:39])[C:36](Cl)=[O:37].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:33][C:36](=[O:37])[C:35]([CH3:40])([CH3:39])[CH3:34])=[C:8]2[C:14]([Br:15])=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:12]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(-c1ccc(Cl)cc1)n2Cc1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ncc2c(c(Br)c(-c3ccc(Cl)cc3)n2Cc2ccc3c(c2)OCO3)c1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a suspension mixture of 1-benzo[1,3]dioxol-5-ylmethyl-3-bromo-2-(4-chloro-phenyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (320 mg, 0.60 mmol)(from Example 35(e)) in CH2Cl2 (3 mL) at 0° C. was added 2,2-dimethyl-propionyl chloride (87.4 mg, 0.73 mmol) and triethylamine (122 mg, 1.20 mmol). Resulting mixture was stirred at room temperature for 1.5 h. It was diluted with CH2Cl2 and washed with 0.1 N HCl aqueous solution, water and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (eluting with 5%-20% EtOAc in CH2Cl2) to give the title compound 361 mg. MS-(+)-ion: M+1=614.98, 613.02.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([OH:23])[C:21]=1[OH:22])[C:5]1[O:6][C:7]2[C:12]([C:13](=[O:18])[C:14]=1[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2.C(O[C:28](=[O:30])[CH3:29])(=O)C.Cl>N1C=CC=CC=1.ClCCl>[C:2]([O:23][C:20]1[CH:19]=[C:4]([CH:3]=[C:2]([O:1][C:28](=[O:30])[CH3:29])[C:21]=1[O:22][C:5](=[O:6])[CH3:4])[C:5]1[O:6][C:7]2[C:12]([C:13](=[O:18])[C:14]=1[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:1])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1c(-c2cc(O)c(O)c(O)c2)oc2ccccc2c1=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(-c2oc3ccccc3c(=O)c2C(=O)O)cc(OC(C)=O)c1OC(C)=O
Reaction time: 2 h

Procedure:
3',4',5'-Trihydroxyflavone-3-carboxylic acid was dissolved in 4 ml absolute pyridine, and the solution was reacted with 0.57 ml acetic anhydride and stirred for two hours. Then it was worked up by diluting with 20 ml dichloromethane, pouring onto a mixture of dilute hydrochloric acid/ice water and shaking with dichloromethane. Here care must be taken that the aqueous phase remains acid (if necessary some dilute hydrochloric acid must be added). The dichloromethane phase was separated, washed with water, dried over sodium sulfate and evaporated. 0.8 g crude 3',4',5'-triacetoxyflavone-3-carboxylic acid were obtained which was immediately processed further without additional purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]=[C:10]2[CH3:34])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH:36]1[CH2:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:36]1([O:8][C:7]2[CH:6]=[CH:5][C:4]([N:9]3[C:14](=[O:15])[C:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][CH:18]=4)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]=[C:10]3[CH3:34])=[CH:3][C:2]=2[F:1])[CH2:39][CH2:38][CH2:37]1
Reactant: BrC1CCC1
Reactant: CCCc1nc(C)n(-c2ccc(O)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC3CCC3)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 85.8 %

Procedure:
To a solution of 4′-{[1-(3-fluoro-4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and bromocyclobutane (0.90 g) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.44 g), and the mixture was stirred at 80° C. for 15 hr. After allowing to cool, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.96 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1cc(Br)ccc1Br
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Br)ccc1Br
Yield: 75.1 %

Procedure:
Into a 2 L flask fitted with a reflux condenser and magnetic stir-bar was introduced 2,5-dibromobenzoic acid (50.0 g, 0.1786 mol) and thionyl chloride (150 mL, 2.04 mol). The mixture was refluxed for 8 hours. Most of the thionyl chloride was distilled off followed by removal of the remainder by rotary evaporation. Distillation gave 40 g of 2,5-dibromobenzoyl chloride. (pot temperature 110° C.; distillation temp 70° C./0.70 mm Hg).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C.O>CN(C)C=O>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
Potassium phthalimide (20 g, 0.108 mol) was added to a solution obtained by dissolving 4-benzyloxybenzyl chloride (25 g, 0.107 mol) in N,N-dimethylformamide (75 mL), and the solution was stirred for 3 hours under reflux. The reaction solution was allowed to room temperature, then, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, and 2-(4-benzyloxybenzyl)-isoindol-1,3-dione (37 g, quantitatively) was obtained as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([N:15]3[CH:19]=[C:18](I)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][CH:3]=1.[C:21]([NH:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][S:26]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[CH:11]=[C:12]([CH3:14])[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:19]=2)[CH:34]=1)(=[O:28])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)c1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)c1

Procedure:
The title compound was prepared from 2-(4-chloro-phenyl)-6-(4-iodo-imidazol-1-yl)-4-methyl-pyridine (example E.95) (0.198 g, 0.5 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.141 g, 0.55 mmol) according to the general procedure VI. Obtained as a white solid (0.028 g, 12%). MS (ISP) 482.4 [(M+H)+].
Reaction SMILES: C([O:3][C:4](=O)[C:5]([S:8](=[O:17])(=[O:16])[NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:7])[CH3:6])C.[NH2:19][NH2:20]>C(O)C>[CH:10]1([NH:9][S:8]([C:5]([C:4]([NH:19][NH2:20])=[O:3])([CH3:7])[CH3:6])(=[O:17])=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NN
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)NC1CCCCC1
Solvent: CCO
Product: CC(C)(C(=O)NN)S(=O)(=O)NC1CCCCC1
Reaction time: 12 h

Procedure:
Using a method similar to that described by S. Paik and E. H. White (Tetrahedron, 1996, 52, 5303), 2-cyclohexylsulfamoyl-2-methylpropionic acid ethyl ester DF1 (which is prepared by the method of A. De Blic et al. (Synthesis, 1982, 281)) in ethanol is treated with 1.2 equivalent of 95% hydrazine under N2 and the mixture is allowed to stand at RT for 12 h. The reaction mixture is concentrated to give the title compound DF2 which is used directly in Step 2.
Reaction SMILES: C(OC(NC[C@H]1CC[C@H:13]([C:16]([NH:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH2:21])=O)CC1)=O)(C)(C)C.C(N(CC)CC)C.[Cl:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[O:43]1CCCC1>>[ClH:37].[NH2:21][C@H:20]([C:19]([NH:18][C@H:16]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:13][OH:43])=[O:29])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(=O)[C@@H](N)Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1ccccc1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-(t-butoxycarbonyl)-3-phenoxy-DL-phenylalanine (I) (7.42 g) obtained in (4) was dissolved in dry tetrahydrofuran (80 ml), triethylamine (3 ml) was added to the solution, and further, ethyl chloroformate (2.40 g) was added under ice-cooling, followed by stirring for 30 minutes. To the solution, 4-acetylanilide (2.70 g) was added and the mixture was stirred under room temperature for 10 hours. To the reaction mixture, ice-water (300 ml) was added, and the crystalline substance precipitated was collected by filtration, thoroughly washed with water, and then dried to obtain N-(t-butoxycarbonyl)-3-phenoxy-DL-phenylalanine 4-acetylanilide (II) 7.07 g) as a white powder. The structure was confirmed by IR and NMR.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[S:13].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:17]2[NH:11][C:12](=[S:13])[NH:14][C:15]2=[O:16])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: O=C1CNC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)NC1=Cc1ccc(O)c(Br)c1
Yield: 75.8 %

Procedure:
Prepared according to the procedure described in Example 1 using 3-bromo-4-hydroxybenzaldehyde (3.1 g, 15 mmoles), 2-thiohydantoin (1.7 g, 15 mmoles), sodium acetate (4.5 g, 55 mmoles), and acetic acid (35 ml), to afford the pure product (3.4 g), mp 262° C (dec).