Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][Cl:24])=[O:21]>C(OCC)C>[C:20](=[O:21])([O:22][CH2:23][Cl:24])[O:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCCl
Reactant: OCCCOCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(OCCl)OCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-(benzyloxy)propanol (synthesized by a procedure described in Wei et al., J. Org. Chem, 54, 5768-5774 (1989):15.1 g) and pyridine (7.18 g) in diethyl ether (150 ml), a solution of chloromethyl chloroformate (11.7 g) in diethyl ether (50 ml) was added dropwise under ice cooling over the period of 20 minutes. After stirring at room temperature for 15 hours, the resulting solid was removed off by filtration and washed with ethyl acetate (100 ml). The filtrate and the washings were combined, and washed with water (100 ml×2) and a saturated sodium chloride aqueous solution (50 ml). After drying the solution over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by subjecting to silica gel chromatography (silica gel 200 g, eluent: ethyl acetate-hexane=1:4) to obtain [3-(benzyloxy)propyl] chloromethyl carbonate (21.0 g) as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(F)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-{3-[1-(6-hydroxy-6-phenylhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.05 (s, br, 1H), 7.72-6.70 (m, 13H), 5.06-4.96 (m, 1H), 3.66-3.51 (m, 2H), 3.01-2.82 (m, br, 2H), 2.82-2.57 (m, br, 4H), 2.57-2.34 (m, br, 2H), 2.05-1.78 (m, br, 6H), 1.64-1.52 (m, br, 1H), 1.52-1.16 (m, br, 3H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 517.0 (M+H)+.
Reaction SMILES: C([O:4][C:5]([C:7]1[C:12]([CH2:13][N:14]([CH2:25][C:26]([O:28][CH3:29])=[O:27])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)=O)(C)C.C[O-].[Na+]>CO.C(OCC)(=O)C>[OH:4][C:5]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[N:14][CH:13]=[C:12]2[C:7]=1[N:8]=[CH:9][CH:10]=[CH:11]2
Reactant: COC(=O)CN(Cc1cccnc1C(=O)OC(C)C)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc2cccnc2c1O
Reaction time: 1.5 h

Procedure:
3-{[Methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-pyridine-2-carboxylic acid isopropyl ester (1.02 mol) was dissolved in dry methanol (4000 ml) and cooled to zero degrees under nitrogen. Then via addition funnel, sodium methoxide (137.8 g, 2.5 mol) was added slowly to avoid any exotherm. The reaction was stirred at zero degrees, and checked by HPLC after 1.5 hours and was found to be completed. The solvent was removed in vacuo to obtain a reddish-orange oil, which was partitioned between water (1L) and ethyl acetate (1L). The organic layer was back extracted with saturated sodium bicarbonate solution. The pH of the aqueous layer was adjusted to 7, and the layer was maintained at this pH while extracting with methylene chloride. The organic layer was dried with Na2SO4, filtered, and the solvent was removed in vacuo to obtain a tan solid. The solid was dissolved in hot ethyl acetate, and the solution was filtered while hot to filter out any insoluble material. The product precipitated upon cooling. The precipitate was then filtered and dried in a vacuum oven. The filtrate was recrystallized by concentrating the filtrate and redissolving the resulting solid in a minimal amount of methylene chloride. Sufficient ethyl acetate was added to turn the solution slightly cloudy, after which the solution was boiled to reduce the volume, cooled, and the resulting crystals were filtered out and dried in a vacuum oven.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2(C#N)[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1.[CH3:24][NH:25][CH3:26]>C1COCC1.O>[CH3:24][N:25]([CH3:26])[C:9](=[O:10])[C:11]1[C:6]([C:7]([C:12]2[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[N:17]=2)=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[Cl:1]
Reactant: COc1cc(OC)nc(C2(C#N)OC(=O)c3c(Cl)cccc32)n1
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)nc(C(=O)c2cccc(Cl)c2C(=O)N(C)C)n1
Reaction time: 0.25 h

Procedure:
1.0 g of 7-chloro-3-cyano-3-(4,6-dimethoxy-2-pyrimidinyl)phthalide is dissolved in 15 ml of THF. 0.7 ml of a 40% aqueous dimethylamine solution is then added via syringe whereupon the solution darkens. Stirring is continued at R.T. for 15 minutes and the mixture diluted with water and partitioned between ethyl acetate and water. The organic phase is separated, washed with 2N H2SO4, then brine, dried and concentrated. The residue is purified on silica gel, eluant 200 ml of 50% ethyl acetate/hexane then 100% ethyl acetate. Fractions 12 to 15 yielded the title compound, m.p. 141°-142° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:26][C:27]1[C:32]([OH:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37].Cl>ClCCl>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([O:33][C:32]3[C:27]([F:26])=[C:28]([F:37])[C:29]([F:36])=[C:30]([F:35])[C:31]=3[F:34])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(OCc2ccccc2)cc1
Temperature: -15 °C
Reaction time: 1.75 h

Procedure:
To a stirred solution of 4-[(phenyhnethyl)oxy]benzenesulfonyl chloride (D48) (13.77 g, 48.70 mmol) in dichloromethane (265 ml) was added triethylamine (9.16 ml, 65.75 mmol) under argon and the mixture cooled to −15° C. A solution of pentafluorophenol (9.86 g, 53.57 mmol) in dichloromethane (20 ml+20 ml wash) was then added quickly and the reaction allowed to wami slowly to room temperature over 1.75 h. Hydrochloric acid (2M, 250 ml) was then added and the mixture stirred for 20-30 min and the layers separated. The aqueous layer was then re-extracted with dichloromethane (100 ml) and the combined organic fractions washed with saturated aqueous sodium hydrogen carbonate (200 ml). The layers were separated and the aqueous re-extracted with dichloromethane (100 ml). All the dichloromethane layers were combined and dried over sodium sulfate, filtered and evaporated. The resulting solid was then dissolved in dichloromethane (40 ml) with warming, and allowed to cool and then purified by chromatography on silica gel eluting with 10-15% diethyl ether/hexane to afford the title compound (D49). 1H-NMR (d6-DMSO) d 7.97-7.94 (2H, m), 7.50-7.31 (7H, m), 5.29 (2H, s).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:21][CH2:22][CH2:23][CH2:24]O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:20][CH2:24][CH2:23][CH2:22][OH:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)O
Reactant: OCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCO

Procedure:
A solution of z,z,z-octadeca-6,9,12-trienoic acid (150 g) in methylene chloride (500 ml) was added dropwise to a mixture of 1,3-dihydroxypropane (205 g), 1,3-dicyclohexylcarbodiimide (130 g) and 4-(N,N-dimethylamino)pyridine (87 g) in methylene chloride (2500 ml) at room temperature under nitrogen. When tlc indicated that the reaction had gone to completion the reaction mixture was filtered. The filtrate was washed with dilute hydrochloric acid, water and saturated sodium chloride solution. The solution was dried, concentrated and purified by dry column chromatography to yield 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane as a pale yellow oil.
Reaction SMILES: [Cl:1]C1C=C(C(C)C(O)=O)C=CC=1.Cl[C:14]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:15]=1[CH2:16][NH:17][C:18](=[O:28])[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[CH3:20]>>[Cl:1][C:32]1([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:30][CH:29]=[C:15]([CH2:16][NH:17][C:18](=[O:28])[CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[CH3:20])[CH2:14]1
Reactant: CC(C(=O)NCc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Reactant: CC(C(=O)O)c1cccc(Cl)c1
Product: CC(C(=O)NCC1=CC=CC(Cl)(C(F)(F)F)C1)c1ccccc1Cl
Yield: 22 %

Procedure:
The titled compound was prepared from 2-(3-Chlorophenyl)propionic acid in 22% yield in the same manner as the preparation of N-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propionamide in Example 184b. MS (ESI) 376 (MH+).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O>CN(C)C=O>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:8]=1
Reactant: Ic1cn[nH]c1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCn1cc(I)cn1
Reaction time: 0.5 h

Procedure:
To a slurry of NaH (60% in mineral oil, 271 mg, 6.77 mmol) in N,N-dimethylformamide (20 mL) was added 4-iodo-1H-pyrazole (1.25 g, 6.44 mmol), and the reaction was stirred for 30 minutes. 1-Octyl bromide (1.22 mL, 7.08 mmol) was then added and the reaction stirred for 24 hours. The mixture was poured into water (200 mL), and the resulting solution was extracted three times with ether. The combined ether extracts were washed three times with water and brine, dried over Na2SO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[C:18]1([C:15]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][N:8]([CH3:7])[C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:17][CH2:16]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=C1CC(=O)O1
Reactant: CNCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)N(C)CCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 8.943531518538547e+16 %

Procedure:
Diketene (0.98 mL, 12.7 mmol, 1.50 equiv) was added at 0° C. to a stirred solution of 1-[3-(N-methylamino)propyl]-4,4-diphenylpiperidine (2.61 g, 8.46 amol, 1.00 equiv) in anhydrous toluene (30 mL) under argon, and stirring was continued for 1 hour. After removal of the solvent, the residue was purified by flash chromatography (SiO2, EtOAc-MeOH-isopropylamine 9:1:0 to 6:1:0.1) to afford 2.97 g (89%) of brown oil, which was characterized spectroscopically.
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][C:12](=[O:14])[O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1>C(Cl)Cl>[CH2:22]([NH:23][C:12]([CH2:13][C:8](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([OH:11])=[O:10])=[O:14])[CH2:21][C:18]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CC(=Cc2ccccc2)C(=O)O1
Reactant: NCCc1ccccc1
Solvent: ClCCl
Product: O=C(CC(=Cc1ccccc1)C(=O)O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
226 mg (1.2 mmol) of benzalsuccinic acid anhydride were treated in 20 ml of methylene chloride with 0.15 ml of 2-phenethylamine and subsequently stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel, to obtain 260 mg (70%) of α-[(phenethylcarbamoyl)methyl]cinnamic acid, MS: 309 (M)+.
Reaction SMILES: Br[C:2]1[N:6]([C@@H:7]2[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([CH2:14][OH:15])[CH2:8]2)[C:5]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>C(O)C>[C:22]([NH:26][C:2]1[N:6]([C@@H:7]2[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([CH2:14][OH:15])[CH2:8]2)[C:5]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N
Reactant: OC[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Solvent: CCO
Product: CC(C)(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1C[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 148 °C
Yield: 61 %

Procedure:
A solution of (1R, 2S, 3S, 5S)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol (500 mg, 1.26 mmole) was stirred in tert-butylamine (Aldrich, 98%, 20 mL) in a Parr bomb maintained at 148° C. (oil bath) for 48 hours. The bomb was cooled and the resulting pale yellow solution diluted with ethanol containing 1N sodium hydroxide (1.2 mL). Volatiles were evaporated in vacuo and the residue was chromatographed on silica gel. Title compound was eluted with 10% methanol-chloroform as a colorless oil. The oil was dissolved in absolute ethanol, concentrated to an oil, and triturated with water (3 mL) to give (1R, 2S, 3S, 5S)-5-[2-(tert-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol as white powder (303 mg, 61%), m.p.: collapses to glass at 116°-150° C.; 1H-NMR(DMSO-d6)δ: 7.63 and 7.43 (both s, 2, aromatic CH), 6.15 (s, 1, NH), 5.08 (t, J=4.3 Hz, 1, OH), 4.85 (d, J=7.4 Hz, 1, OH), 4.71 (d, J=3.8 Hz, 1, OH), 4.7-4.5 (m, 1, NCH), 4.45-4.3 (m, 1, OCH), 3.80 (m, 1, OCH), 3.7-3.4 (m, 2, OCH2), 2.2-1.85 (m, 3, CH2 and CH of cyclopentane), 1.47 (s, 9, 3 CH3); mass spectrum (CI): 388(M+1); [α]20589 -4.0°, [α]20578 -4.3°, [α]20546 -6.0°, [α]20436 -22.6°, [α]20365 -82.1° (c=0.420, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[F-].[K+].[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH3:24])=[C:16]1[C:25]([NH:27][C@H:28]([C:32]([NH:34][CH:35]([C:44](=[O:47])[CH2:45]Br)[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:26]>>[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH3:24])=[C:16]1[C:25]([NH:27][C@H:28]([C:32]([NH:34][CH:35]([C:44](=[O:47])[CH2:45][O:5][C:4](=[O:6])[C:3]1[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:11])[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:26]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CBr)C(C)C)n(C)c2ccccc12
Agent: [F-]
Agent: [K+]
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COC(=O)c2c(Cl)cccc2Cl)C(C)C)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
To a mixture of 2,6-dichlorobenzoic acid (0.023 g, 0.12 mmol) and potassium fluoride (0.015 g, 0.25 mmol) at room temperature under nitrogen was added N-[(1,3-dimethyl-indole-2-carbonyl)valinyl]-3-amino-5-bromo-4-oxo-pentanoic acid, tert-butyl ester (0.054 g, 0.10 mmol) in one portion. After stirring at room temperature for further 16 hrs, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated NaHCO3 solution, and brine, dried over sodium sulfate, and concentrated. Trituration with ether gave the title compound as a white powder (0.051 g, 79%). TLC(CH2Cl2/MeOH, 95/5): Rf=0.88.
Reaction SMILES: [C:1]1([NH:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:25]=[CH:24][C:13]([CH:14]=NC2C=CC(Cl)=CC=2C)=[CH:12][CH:11]=1>CCOCC>[Cl:9][C:10]1[CH:25]=[CH:24][C:13]([CH:14]=[N+:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O-:8])=[CH:12][CH:11]=1
Reactant: Cc1cc(Cl)ccc1N=Cc1ccc(Cl)cc1
Reactant: ONc1ccccc1
Solvent: CCOCC
Product: [O-][N+](=Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
N-phenylhydroxylamine (0.052 mole) was dissolved in ether (20 cc). This solution was treated with N-(p-chlorobenzylidene)-2-methyl-4-chloroaniline (13.8 g.) dissolved in ether (50 cc). After 15 min., white crystals had begun to form. Filtration and washing with ether gave α-p-chlorophenyl-N-phenylnitrone.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72].O>CN(C=O)C>[OH:52][C:49]1[CH:48]=[CH:47][C:46]([C:14]2[C:12]3[NH:13][C:9]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH3:60])=[CH:3][CH:4]=4)=[C:28]4[N:29]=[C:25]([C:24]([C:30]5[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=5)=[C:23]5[NH:37][C:20](=[C:19]([C:38]6[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=6)[C:18]6[CH:17]=[CH:16][C:15]=2[N:45]=6)[CH:21]=[CH:22]5)[CH:26]=[CH:27]4)=[CH:10][CH:11]=3)=[CH:51][CH:50]=1
Reactant: Oc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Reactant: CCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCOc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Temperature: 25 °C

Procedure:
5,10,15.20-tetrakis-(4-Hydroxy-phenyl)-porphyrin (400 mg, 0.59 mmol) is dissolved and K2CO3 (1.0 g, 7.1 mmol) is suspended in DMF (75 mL). To the vigorously stirred reaction mixture a solution of 1-bromotridecane (0.1 mL, 0.45 mmol) in DMF (10 mL) is added dropwise at 50° C. during 30 mins and the mixture is then heated for 1.5 h. The reaction mixture is cooled to room temperature and poured into water (150 mL). The porphyrins are extracted with ethyl acetate (100 mL) and the extract washed with brine (3×50 mL) and dried (Na2SO4). After evaporation of solvent, the residue is dissolved in toluene:ethanol (1:1, by vol., ca. 10 mL) and purified by chromatography using a column (200 g) of silica gel (Merck 60) with toluene as the eluent. After the elution of the first three compounds, the eluent is changed to toluene:ethyl acetate (2:1, by vol.). The fifth compound eluted is collected and dried under high vacuum to yield product as violet crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]2[CH2:12][CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20]1(C2CC(C(C)C(OCC)=O)C2)C=CC=CC=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[CH2:9][CH:12]([CH:11]([CH3:10])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:20]2)=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C)C1CC(c2ccccc2)C1
Reactant: CCOC(=O)C1CC(Cc2ccc([N+](=O)[O-])cc2)C1
Product: CCOC(=O)C(C)C1CC(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
Following the general procedure described for ethyl 3-(4-nitrobenzyl)cyclobutanecarboxylate (Intermediate 93i), replacing ethyl 3-benzylcyclobutanecarboxylate with ethyl 2-(3-phenylcyclobutyl)propanoate the title compound was obtained which was used directly in the next step.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16](=[O:23])[NH:17][C:18]([CH3:22])([CH3:21])[CH:19]=O)([CH3:14])([CH3:13])[CH3:12].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:11]([O:15][C:16](=[O:23])[NH:17][C:18]([CH3:22])([CH3:21])[CH:19]=[CH2:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of methyl triphenylphosphonium bromide (1.9 g, 5 mmol) in THF (25 mL) at −78° C. is added dropwise KHMDS (5 mmol, 11 mL of 0.5M solution). The mixture is stirred at 0° C. for 30 min then is recooled to −78° C. To this is added dropwise a solution of (1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (1.0 g, 5 mmol) in THF (5 mL). The mixture is stirred at −78° C. for 10 min then is allowed to warm to RT overnight. Water is added and the mixture is extracted with EtOAc. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure. The resulting oil is purified by flash chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26](Br)=[CH:25][CH:24]=[C:23]([Cl:28])[N:22]=3)[C@@H:15]([CH3:29])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:32][C:33]1[C:38]([CH:39]([CH3:41])[CH3:40])=[CH:37][C:36](B(O)O)=[C:35]([O:45][CH3:46])[CH:34]=1>C(=O)([O-])[O-].[K+].[K+].C1COCC1>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26]([C:36]4[CH:37]=[C:38]([CH:39]([CH3:41])[CH3:40])[C:33]([F:32])=[CH:34][C:35]=4[O:45][CH3:46])=[CH:25][CH:24]=[C:23]([Cl:28])[N:22]=3)[C@@H:15]([CH3:29])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(Cl)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C

Procedure:
A mixture of (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 2, 49 mg, 0-092 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Intermediate 6, 21 mg, 0.101 mmol) and 1,1-bis(ditbutylphosphino)ferrocene palladium dichloride (6 mg, 0.0092 mmol) in aqueous potassium carbonate/THF (3 mL, 3 mL) was heated at reflux for 2 h under N2. After cooling to room temperature, the aqueous phase was separated and extracted with EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography on silica gel (0-15% EtOAc in hexanes gradient) to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-chloro-3-(4-fluoro-5-isopropyl-2-methoxyphenyl)pyridin-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one as a colorless oil. LCMS=619.0 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.88 (br s, 2H), 7.84 (s, 1H), 7.68 (brs, 2H), 7.49 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.28 (br s, 1H), 6.71 (d, J=12.1 Hz, 1H), 5.88 (brs, 1H), 5.25 (br d, J=16.7 Hz, 1H), 4.21 (br m, 2H), 3.95 (br m, 2H), 3.81 (s, 3H), 3.21 (m, 1H), 2.39 (m, 2H), 1.92 (m, 1H), 2.11 (3H, s), 1.29 (br d, 9H).