Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:17]([NH:19][C@H:20]([C:29]([NH:31][C@H:32]([C:40]([NH:42][C@H:43]([C:51]([OH:53])=[O:52])[CH2:44][CH2:45][CH2:46][NH:47][C:48](=[NH:50])[NH2:49])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].CC(O)=O.CC(O)=O.N[C@H](C(O)=O)CC1C=CC(O)=CC=1.N[C@H](C(O)=O)CC1C=CC=CC=1.N[C@H](C(O)=O)CCCCN.N[C@H](C(O)=O)CCCNC(=N)N.C(O)(=O)C>>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:17]([NH:19][C@H:20]([C:29]([NH:31][C@H:32]([C:40]([NH:42][C@H:43]([C:51]([OH:53])=[O:52])[CH2:44][CH2:45][CH2:46][NH:47][C:48](=[NH:49])[NH2:50])=[O:41])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH3:43][C:51]([OH:53])=[O:52].[CH3:43][C:51]([OH:53])=[O:52]
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)OCc1ccccc1)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: CC(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCCN)C(=O)O

Procedure:
500 mg of Z-Lys-Lys-Tyr-Phe-Arg diacetate are dissolved in 20 ml of 90% strength acetic acid and subjected to catalytic hydrogenation analogously to Example 1 h. The residue is chromatographed in 90% strength methanol over a crosslinked, hydroxypropylated dextran gel. The eluate containing the peptide is concentrated and the residue is dissolved in water and freeze-dried. Yield 244 mg. Aminoacid analysis (hydrolysis in 6N HCl for 24 hours at 120° C.): Tyr 0.93, Phe 1.0, Lys 2.06 and Arg. 0.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc(CBr)cc1
Yield: 65.1 %

Procedure:
39.7 g (287 mmmol) of p-toluylic acid, 51.2 g (287 mmmol) of N-bromosuccinimide and 2.8 g (11.5 mmol) of dibenzoyl peroxide were suspended in 350 ml of carbon tetrachloride. Then, the resultant mixture was heated with vigorously stirring to perform a reaction under reflux for 2 hours. After completion of the reaction, the reaction mixture was cooled in ice bath. The deposited crystalline product was collected by filtration, which was then washed with hexane and water, followed by drying. The resultant crystalline product was recrystallized from ethanol to obtain 40.3 g of 4-bromomethylbenzoic acid as a white needle crystal (isolated yield: 65%).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:18]3[CH:30]=[CH:29][N:28]=[C:19]3[S:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl.C(Cl)CCl>[C:1]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:18]3[CH:30]=[CH:29][N+:28]([O-:39])=[C:19]3[S:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:15][CH2:16]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1CCN(C2=Nc3ccccc3Sc3nccn32)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)N1CCN(C2=Nc3ccccc3Sc3n2cc[n+]3[O-])CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To the solution of 0.5 g of 5-(4-carbobenzoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine in 5 ml of methylene chloride, cooled at 0° C., is added dropwise a solution of 0.26 g of m-chloroperbenzoic acid dissolved in 2 ml of ethylene chloride. The mixture is stirred at 0° C. for 1.5 hrs., the solids are filtered, and the filtrates are washed with 10% aqueous potassium carbonate and water, then dried over magnesium sulfate and evaporated to dryness to give 5-(4-carbobenzoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine 1-oxide.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1>[OH-].[OH-].[Pd+2].C1COCC1>[F:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:16])[CH3:15])[CH2:12][CH2:13]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)N1CC=C(c2cccnc2F)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2cccnc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 196.2 %

Procedure:
A 2 L Parr shaker bottle was charged with 1-(2-fluoro-5′,6′-dihydro-[3,4′-bipyridin]-1′(2′H)-yl)ethanone (see PREPARATION P14.1; 44.7 g, 0.203 mol), THF (600 mL), and palladium hydroxide on carbon, 20% wet type (22 g, 50 wt %). The bottle was purged three times with H2 and was shaken at room temperature under 50 psi of H2. At 1 hour, crude 1HNMR indicated full conversion (aliquot syringe filtered and concentrated). This reaction was filtered (along with another 44.7 g batch) through a CELITE® pad. The pad was washed with THF (2×250 mL). The filtrate was concentrated under vacuum to afford 88.5 g white solid (98% yield, >99% purity by LCMS, excellent purity by 1HNMR).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=2[CH:17]=1.B([O-])([O-])O[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.O.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>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=3[CH:17]=2)=[CH:21][CH:22]=1
Reactant: [O-]B([O-])Oc1ccc(Cl)cc1
Reactant: CCOC(=O)C1=Cc2cc(Br)ccc2OCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Product: CCOC(=O)C1=Cc2cc(-c3ccc(Cl)cc3)ccc2OCC1
Temperature: 25 °C
Yield: 83 %

Procedure:
Under argon atmosphere, a solution of ethyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (500 mg), 4-chloro-phenyl borate (289 mg) and potassium carbonate (464 mg) in toluene-ethanol-water (20-2-2 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakistriphenyl-phosphinepalladium (0.06 g), and the mixture was refluxed for 24 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:19) to give ethyl 7-(4-chlorophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (459 mg) as colorless crystals.
Reaction SMILES: C(Cl)(=O)C.[CH3:5][Si:6]([CH2:9][OH:10])([CH3:8])[CH3:7].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]([OH:39])[CH2:19][NH:20][CH:21]([CH3:38])[CH2:22][C:23]2[CH:37]=[CH:36][C:26]3[O:27][C:28]([C:33]([OH:35])=[O:34])([C:30](O)=[O:31])[O:29][C:25]=3[CH:24]=2)[CH:15]=[CH:16][CH:17]=1>C(=O)(O)[O-].[Na+]>[CH3:5][Si:6]([CH:9]([O:10][C:30]([C:28]1([C:33]([OH:35])=[O:34])[O:27][C:26]2[CH:36]=[CH:37][C:23]([CH2:22][CH:21]([NH:20][CH2:19][CH:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[CH:13]=3)[OH:39])[CH3:38])=[CH:24][C:25]=2[O:29]1)=[O:31])[Si:6]([CH3:8])([CH3:7])[CH3:5])([CH3:8])[CH3:7]
Reactant: C[Si](C)(C)CO
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)OC([Si](C)(C)C)[Si](C)(C)C)O2)NCC(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Acetyl chloride (0.59 g, 7.5 mmol) was added to trimethylsilylmethanol (4.03 g, 37.5 mmol) with stirring at room temperature. After 0.5 h, 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid (1.05 g, 2.5 mmol) was added in portions. The resulting solution was stirred for 3 days, and then treated with 50 ml of 50% sodium bicarbonate solution, followed by extraction with ethyl acetate (50 ml). The organic extract was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was passed through a pad of silica gel, eluting with hexanes, and ether-hexanes/1:1 until no more trimethylsilylmethanol could be detected. The filter pad was then eluted with ethyl acetate, and the solvent was evaporated to give 1.14 g of the desired product as a colorless gum. Conversion to the HCl salt yielded 1.16 g of white foam; 1H NMR (CDCl3) δ 0.06 (s, 18H), 1.33 (d, J=6.5 Hz, 3H), 2.80 (m, 1H), 3.15 (m, 1H), 3.20 (m, 1H), 3.48 (m, 2H), 4.014 (s, 2H), 4.015 (s, 2H), 5.45 (bd, J=9.7 Hz, 1H), 5.60 (bs, 1H), 6.80 (m, 3H), 7.25 (m, 2H), 7.45 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1H); IR (KBr): 1763 cm-1 (C=O); MS (ES) m/z 594 (MH+); [α]D25 -23° (c, 1.0, CHCl3). Anal. Calcd. for C28H40ClNO7Si2 ·HCl: C, 53.32; H, 6.39; N, 2.22; Cl, 11.24; Si, 8.91. Found: C, 52.65; H, 6.70; N, 2.11; Cl, 11.47; Si, 9.00.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].[F:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[N:31]=[C:30]([CH2:32]O)[CH:29]=[CH:28][CH:27]=2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH2:32][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([O:25][C:24]2[CH:34]=[CH:35][C:21]([F:20])=[CH:22][CH:23]=2)[N:31]=1)=[O:15]
Reactant: OCc1cccc(Oc2ccc(F)cc2)n1
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)OCc1cccc(Oc2ccc(F)cc2)n1

Procedure:
The acid chloride of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid is reacted with [6-(4-fluorophenoxy)-2-pyridyl]methanol using the procedure of Example 1 to give [6-(4-fluorophenoxy)-2-pyridyl]methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:24]1[CH:25]=[C:26]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>[Cu]I.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:21][N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[C:19](=[O:22])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(C2CC(=O)N(c3cccc([N+](=O)[O-])c3)C2)cc1OCc1ccccc1
Temperature: 110 °C
Yield: 56.7 %

Procedure:
To a round bottom flask was added 4-(3-benzyloxy-4-methoxyphenyl)-pyrrolidin-2-one (1.76 g, 5.9 mmol), 3-iodonitrobenzene (2.64 g, 10.6 mmol), K3PO4 (2.79 g, 13 mmol), trans-cyclohexanediamine (50 μL), DMF (8 mL) and dioxane (8 mL). The mixture was stirred under N2 for 5 min before the addition of CuI (150 mg). After heating to 110° C. for 20 h, the mixture was cooled to r.t. After filtration, the reaction mixture was diluted with EtOAc (100 mL), washed with saturated NH4Cl, brine and dried over Na2SO4. Concentration and purification by column chromatography on silica gel (EtOAc:hexane=1:3) gave 1.4 g of the desired product. Yield: 57%.
Reaction SMILES: [CH2:1]([O:5][N:6]1[C:15]([C:16](O)=[O:17])=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:25])[CH:12]=2)[C:7]1=[O:26])[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C([Cl:30])=O>C1COCC1.CN(C=O)C>[CH2:1]([O:5][N:6]1[C:15]([C:16]([Cl:30])=[O:17])=[C:14]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:25])[CH:12]=2)[C:7]1=[O:26])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOn1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCOn1c(C(=O)Cl)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
2-Butoxy-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (370 mg) was dissolved in THF(6.0 ml), and oxalyl chloride (170 μl) and DMF (1 drop) were added at 0° C. with stirring. The mixture was stirred at room temperature for 2 hrs. and concentrated under reduced pressure. Toluene was added to the residue and they were boiled together several times to give 2-butoxy-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonyl chloride.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:12]=1)[CH:10]=[O:11]>O1CCCC1>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:10]([OH:11])[CH3:1])[CH:12]=1
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 31.4 %

Procedure:
Methyl magnesium bromide (7.97 mL of 3.0 M in tetrahydrofuran, 23.91 mmol) was added dropwise to 5-bromo-2-nitro-benzaldehyde (5.00 g, 21.73 mmol) in tetrahydrofuran (72 mL) at −78° C. After the addition was complete, the reaction was stirred for 15 min at −78° C. Then, the mixture was quenched with water and diethyl ether was added. The reaction was allowed to warm to room temperature and 10% citric acid solution was added. The layers were separated and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:7 ethyl acetate:hexanes to give 1.68 g (31%) of 1-(5-bromo-2-nitrophenyl)-ethanol as a solid. 1H NMR (400 MHz, d6-DMSO): δ 7.95 (d, J=2 Hz, 1H), 7.87 (d, J=9 Hz, 1H), 7.71 (dd, J=9, 2 Hz, 1H), 5.64 (d, J=4 Hz, 1H), 5.16-5.09 (m, 1H), 1.36 (d, J=6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10](N)[CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=2)[CH:5]=[CH:4][N:3]=1.B(Br)(Br)Br.C(Cl)Cl.C([O-])(O)=[O:26].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([OH:26])[CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(-c2cc(N)cc([N+](=O)[O-])c2)ccn1
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(-c2cc(O)cc([N+](=O)[O-])c2)ccn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
To 0° C. flask charged with 65.B (2.85 g, 11.7 mmol) was added a solution of BBr3/CH2Cl2 (1.0 M, 25 mL). The solution was allowed to warm to rt and stirred for 45 mins. The resulting mixture was treated with MeOH (7 mL), neutralized with solid NaHCO3 to PH=7 and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel using 0-10% of MeOH/CH2Cl2 for elution gave the title product 65.C as solid (1.83 g, 68%).
Reaction SMILES: C([Mg:3][Br:4])C.Br[C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16].CI>COCCOC>[F:12][C:11]1[C:6]([Mg:3][Br:4])=[C:7]([F:16])[C:8]([F:15])=[C:9]([F:14])[C:10]=1[F:13]
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Reactant: CC[Mg]Br
Solvent: COCCOC
Solvent: CI
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Air inside a reaction vessel of the same type as the one used in Example 1 was replaced with a nitrogen gas in a satisfactory manner, after which 60 ml of a 1,2-dimethoxy ethane (chain ether solvent) solution containing 0.088 mol of suspended ethyl magnesium bromide was charged to the reaction vessel. Meanwhile, 0.081 mol of bromopentafluorobenzene was charged to the dropping funnel. Further, 0.5 g of methyl iodide was charged to the reaction vessel through a micro-syringe, and the reaction solution was stirred for 10 minutes at room temperature. Then, bromopentafluorobenzene in the dropping funnel was dropped to the reaction vessel over 45 minutes at room temperature, and the reaction solution was stirred for 4 hours at room temperature. Consequently, pentafluorophenyl magnesium bromide was obtained in the form of a colorless 1,2-dimethoxy ethane solution. The yield of pentafluorophenyl magnesium bromide measured in the same manner as Example 1 was 98.5 mol % based on bromopentafluorobenzene.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[O:7][CH:6]=[C:5]([CH:8]=[O:9])[CH:4]=1.B(F)(F)F.CCOCC.[CH3:21][C:22]([CH:29]=[CH2:30])=[CH:23][O:24][Si](C)(C)C>C(Cl)Cl>[OH:9][CH:8]([C:5]1[CH:4]=[C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])[O:7][CH:6]=1)[CH2:30][CH:29]=[C:22]([CH3:21])[CH:23]=[O:24]
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: C=CC(C)=CO[Si](C)(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C=O)=CCC(O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-trimethylsilyl-3-furaldehyde (0.382 g., 2.27 mmol) in dry methylene chloride (15 ml) at -50° under argon was added dropwise boron trifloride etherate (0.28 ml, 2.3 mmol). This addition was followed by the dropwise addition of 2-methyl-l-trimethylsilyloxy-1,3-butadiene (0.356 g., 2.3 mmol). The solution was stirred at -50° to -60° for 18 hours, quenched by the addition of several ml saturated sodium bicarbonate solution, warmed to room temperature and poured into methylene chloride. The organic portion was washed once with saturated bicarbonate solution, once with water, once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a yellow oil which consisted of several components by TLC. The mixture was applied to a chromatography column (silica) and eluted with 30% ethyl acetate/hexane. Eluted last was the desired alcohol, which was concentrated to give a yellow gum.
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:23])(P(=O)(OC)OC)P(=O)(OC)OC)[CH:6]=[CH:7][CH:8]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:26]([NH:33][C:10](=[O:23])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COP(=O)(OC)C(O)(Cc1cccc([Si](C)(C)C)c1)P(=O)(OC)OC
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccccc1)NCc1ccccc1
Reaction time: 2 h

Procedure:
The iodo derivative 53 was hydrolysed as described under general procedures to give the title compound as an orange colored powder in quantitative yield. Reaction of dimethyl phenylacetylphosphonate (50b) with benzylamine To a solution of the phosphonate 50b in CHCl3 (5 ml) was added molecular sieves (4A, 0.25 g) followed by benzylamine (0.11 g, 1 mmol). After 0.5 h a catalytic amount of TsOH was added and the mixture was stirred for 2 h. The mixture was filtered and flash chromatography (silica, 3:7 EtOAc/hexane) of the filtrate provided N-benzylphenylacetamide (61), as determined by comparison with an authentic sample.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][CH:22]=[CH2:23])[CH:15]=2)([CH3:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].[OH-].[K+].Cl>>[CH:21]([C:16]1[CH:15]=[C:14]([C:11]([C:6]2[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([CH:1]=[CH:2][CH3:3])[CH:5]=2)([CH3:12])[CH3:13])[CH:19]=[CH:18][C:17]=1[OH:20])=[CH:22][CH3:23]
Reactant: C=CCc1cc(C(C)(C)c2ccc(O)c(CC=C)c2)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC=Cc1cc(C(C)(C)c2ccc(O)c(C=CC)c2)ccc1O

Procedure:
2,2-Bis(3-allyl-4-hydroxyphenyl)propane (1 mole) was mixed with potassium hydroxide pellets (2.2 moles) and the mixture was stirred and heated at 110° for 30 minutes. The mixture was cooled, neutralised with dilute hydrochloric acid, and the product was extracted into methylene chloride. The solution was dried and evaporated to give substantially pure 2,2-bis(3-(1-propenyl)-4-hydroxyphenyl)propane.
Reaction SMILES: NC1C=CC(Cl)=C(C2C=C(C=CN=2)C(OC)=O)C=1.CC1N=C(C(F)(F)F)C=CC=1C(Cl)=O.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:53])[C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[N:44][C:43]=2[CH3:52])=[CH:36][C:35]=1[C:54]1[CH:55]=[C:56]([CH:61]=[CH:62][N:63]=1)[C:57](OC)=[O:58].[BH4-].[Na+]>CCO>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:53])[C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:50])([F:49])[F:51])=[N:44][C:43]=2[CH3:52])=[CH:36][C:35]=1[C:54]1[CH:55]=[C:56]([CH2:57][OH:58])[CH:61]=[CH:62][N:63]=1
Reactant: COC(=O)c1ccnc(-c2cc(NC(=O)c3ccc(C(F)(F)F)nc3C)ccc2Cl)c1
Agent: COC(=O)c1ccnc(-c2cc(N)ccc2Cl)c1
Agent: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Agent: [BH4-]
Solvent: CCO
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2cc(CO)ccn2)c1

Procedure:
75 mL of (4-methylpyridin-2-yl)zinc(II) bromide was reacted with 4 g of 1-chloro-2-iodo-4-nitrobenzene via Procedure B. To 300 mg of 2-(2-chloro-5-nitrophenyl)-4-methylpyridine in 1.5 mL of Sulfuric Acid was slowly added 362 mg of Chromium (III) Oxide and the reaction was stirred for several hours at room temperature until complete. Icewater was added to dilute the reaction and the aqueous layer was extracted 3 times with Ethyl Acetate. The organic layers were combined, dried over Magnesium Sulfate, filtered and concentrated to give 2-(2-chloro-5-nitrophenyl)isonicotinic acid. 300 mg of 2-(2-chloro-5-nitrophenyl)isonicotinic acid was esterified with 750 μL of 4N HCl in Dioxane in 10 mL of MeOH at 55° C. for 16 hours. The reaction was concentrated and subjected to basic workup, dried over Magnesium Sulfate, filtered and concentrated to give methyl 2-(2-chloro-5-nitrophenyl)isonicotinate. 259 mg of methyl 2-(2-chloro-5-nitrophenyl)isonicotinate was treated with 200 mg of Tin (II) Chloride and 500 μL of HCl in 10 mL of EtOH. Upon completion, EtOH was concentrated and the reaction was extracted with Ethyl Acetate and water with TEA to decrease emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give crude methyl 2-(5-amino-2-chlorophenyl)isonicotinate. 240 mg of methyl 2-(5-amino-2-chlorophenyl)isonicotinate was treated with 204 μL of 2-methyl-6-(trifluoromethyl)nicotinoyl chloride via Procedure D. To 100 mg of methyl 2-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)isonicotinate at 0° C. in 5 mL of EtOH was slowly added 135 mg of Sodium Borohydride. The reaction was subsequently refluxed for 1 hour until complete, quenched with water and extracted with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate, filtered, concentrated and purified by reverse phase HPLC to give pure N-(4-chloro-3-(4-(hydroxymethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide. MS (Q1) 422.1 (M)+.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CN(C)C=O>ClCCl>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([Cl:21])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Benzoylbenzoic acid (226 mg, 1.0 mmol) in dichloromethane (1.5 mL) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacuo to afford 3-benzoylbenzoyl chloride.