Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4](Cl)[N:3]=1.[OH-:13].[Na+].[CH3:15]O>CO>[CH3:15][O:13][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: [OH-]
Reactant: CO
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Agent: [Na+]
Product: COc1cc(C(F)(F)F)cc(Cl)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 2,6-dichloro-4-trifluoromethylpyridine (10 g, 46.3 mmol) in methanol (200 mL) was added 25% NaOH/MeOH (12.5 g, 13.2 mL, 231 mmol), which was then stirred at 50° C. for 2 h and then at room temperature overnight. The reaction mixture was extracted with pentane, and the extract was concentrated in vacuo to afford 2-methoxy-6-chloro-4-trifluoromethylpyridine (9.79 g), used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[C:40]([C:46]([F:49])([F:48])[F:47])[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][N:52]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[C:40]([C:46]([F:47])([F:48])[F:49])[CH:39]=2)[C:35]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][N:52]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1ccc([N+](=O)[O-])cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2ccc([N+](=O)[O-])cn2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
A solution of triphenylphosphine (393 mg, 1.5 mmol) in methylene chloride (10.0 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (303 mg, 1.7 mmol). After stirring at 0° C. for 10 min, the reaction mixture was treated with 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid (332 mg, 1.0 mmol). The reaction mixture was stirred at 0° C. for 20 min and at 25° C. for 30 min. At this time, the reaction mixture was treated with 2-amino-5-nitropyridine (290 mg, 1.5 mmol) and pyridine (0.14 mL, 1.8 mmol). The resulting reaction mixture was stirred at 25° C. for 20 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 200-400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-(5-nitro-pyridin-2-yl)-propionamide (425 mg, 60%) as an off-white solid: mp 109-110° C.; EI-HRMS m/e calcd for C21H22F3N3O3S (M+) 453.1334, found 453.1334.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29].[I-].[Na+]>CN(C=O)C>[CH2:28]([N:30]([CH2:31][CH3:32])[CH2:26][CH2:25][CH2:24][O:23][C:16]1[C:15]2[C:14]3[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:21]4[C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH:11]=[CH:12][CH:13]=3)[CH3:29]
Reactant: CCNCC
Reactant: ClCCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 50 °C
Yield: 43.4 %

Procedure:
To a mixture of 3-chloropropyl 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl ether (0.45 g, 1.2 mmol) in dry DMF (10 mL) is added diethylamine (1.2 mL, 12 mmol) and sodium iodide (0.18 g, 1.2 mmol). The mixture is heated at 50° C. overnight. The mixture is partitioned between water and CH2Cl2. The layers are separated and the organic layer washed with brine (50 mL) followed by water (100 mL). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography with silica gel (60 mL) using CH3OH/CH2Cl2 (3/97) as eluent gave 0.216 g (43%) of the title compound.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.[CH2:13](Br)[CH:14]=[CH2:15]>>[CH2:15]([C:5]1([OH:12])[CH:6]2[CH2:11][C:2]3([OH:1])[CH2:9][CH:8]([CH2:10][CH:4]1[CH2:3]3)[CH2:7]2)[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Product: C=CCC1(O)C2CC3CC1CC(O)(C3)C2

Procedure:
The title compound is prepared from 5-hydroxy-adamantan-2-one and allyl bromide following a procedure analogous to that described in Step 1 of Intermediate 2. Yield: quantitative; Mass spectrum (ESI+): m/z=226 [M+NH4]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][CH:12]([CH2:17][N:18]([CH3:20])[CH3:19])[C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH3:21][I:22]>C(O)(C)C>[I-:22].[Cl:1][C:2]1[C:3]([CH2:11][CH:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:17][N+:18]([CH3:21])([CH3:19])[CH3:20])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: COC(=O)C(Cc1cc2c(cc1Cl)OCO2)CN(C)C
Reactant: CI
Solvent: CC(C)O
Product: COC(=O)C(Cc1cc2c(cc1Cl)OCO2)C[N+](C)(C)C
Product: [I-]

Procedure:
The operation is carried out as in Stage 2 of Example 1, starting with 436 mg of the product obtained in Stage 2 above, 6 ml isopropanol and 0.27 ml of methyl iodide. In this way 501 mg of expected product is obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:9][C:10]([O:12][CH3:13])=[O:11].COC1C=CC=CC=1OC>CO>[CH3:13][O:12][C:10]([CH2:9][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11]
Reactant: COC(=O)CCl
Reactant: Oc1ccccc1
Solvent: COc1ccccc1OC
Solvent: CO
Product: COC(=O)COc1ccccc1

Procedure:
Illustrative Embodiment 1 is repeated with a mixture of 32 g of phenol, 56 g of methyl chloroacetate, 13 g of methanol and 8 g of dimethoxy benzene (as a gas chromatograph standard). Methyl phenoxy acetate is formed.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C([Li])CCC.CCCCCC.[B:26]([O:35]C(C)C)([O:31]C(C)C)[O:27]C(C)C.Cl>O1CCCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([O:27][B:26]([OH:35])[OH:31])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)[CH3:10]
Reactant: CCOc1ccc(Br)c(C(F)(F)F)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(OB(O)O)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Compound (c) (10.0 g) dissolved in tetrahydrofuran (THF) (40 mL) was cooled to −78° C., a 1.6 M butyllithium/hexane solution (30 mL) was slowly added dropwise and the mixture was stirred at the same temperature for 2 hours. Triisopropyl borate (14.0 g) dissolved in THF (20 mL) was then slowly added dropwise at −78° C., and the mixture was stirred at the same temperature for 1 hour. The temperature was increased to room temperature and the final solution was stirred. After adding 3 M hydrochloric acid (200 mL) dropwise at ice-cooling temperature, the aqueous layer was extracted three times with ether. The organic layers were combined, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 8.28 g of Compound (d).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]([C:18]2[NH:19][N:20]=[CH:21][CH:22]=2)=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:39])(=[N:32][C:33](=[O:38])[NH:34][CH:35]([CH3:37])[CH3:36])=[O:31])=[CH:26][CH:25]=1>>[CH:35]([NH:34][C:33]([N:32]=[S:30]([C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:5]([C:18]3[NH:19][N:20]=[CH:21][CH:22]=3)=[CH:4][N:3]=2)=[CH:29][CH:28]=1)([CH3:39])=[O:31])=[O:38])([CH3:37])[CH3:36]
Reactant: Clc1ncc(-c2ccn[nH]2)c(NCCCN2CCOCC2)n1
Reactant: CC(C)NC(=O)N=S(C)(=O)c1ccc(N)cc1
Product: CC(C)NC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3ccn[nH]3)c(NCCCN3CCOCC3)n2)cc1
Yield: 34 %

Procedure:
In the reaction of [2-chloro-5-(2H-pyrazol-3-yl)-pyrimidin-4-yl]-(3-morpholin-4-yl-propyl)-amine (212.8 mg, 0.66 mmol) with (RS)—S-(4-aminophenyl)-N-(isopropylcarbamoyl)-S-methylsulphoximide (153 mg, 0.6 mmol) according to procedure 5c, the desired product is obtained in 34% yield (109 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])(=[O:5])=[O:4].CS(C)=O.[OH-:23].[K+].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36]>O>[CH2:26]=[CH:27][CH2:28][CH2:29][C:30]([OH:4])=[O:23].[CH2:26]([N:2]([CH3:1])[S:3]([C:6]([F:17])([F:18])[C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:10])([F:12])[F:11])(=[O:5])=[O:4])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36]
Reactant: [OH-]
Reactant: CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=CCCCCCCCCCBr
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCC(=O)O
Product: C=CCCCCCCCCCN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A 500 mL three-necked round-bottom flask equipped with magnetic stirring, oil bath heat, and connection to a nitrogen bubbler was charged with 17.2 g of N-methylperfluorobutanesulfonamide (C4F9SO2NHCH3) and 250 mL dimethyl sulfoxide. Stirring was begun, and the solid dissolved within a few minutes. A solution of 4.0 g of potassium hydroxide in 5 mL of water was added via pipette, and stirring was continued for another 30 min while the oil bath was heated to 80° C. By the end of this period most of the potassium hydroxide had dissolved. 11-Bromo-1-undecene, obtained from Aldrich Chemical Co. (95 percent purity, 12.3 g) was then added to the flask via pipette, and the reaction mixture was left to stir for 19 hr at 80° C. The oil bath was then removed to allow the mixture to cool, and the flask contents were poured into a separatory funnel. The mixture separated into two liquid phases, and the lower layer was drawn off. The upper phase was diluted with an equal volume of water, causing separation of a small amount of lower phase. This was also drawn off and combined with the first batch. The combined crude product (18.0 g) was dissolved in 150 ml dichloromethane and washed successively with 100 ml portions of water, 10 weight percent aqueous potassium hydroxide solution, water, and brine. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered, then solvent was removed on a rotary evaporator at water aspirator pressure. This left 17.9 g light straw-colored liquid product. Bulb-to-bulb vacuum distillation of 17.3 g crude product at 160-180° C. and 0.3 torr (4 Pa) gave 16.2 g of N-(10-undecenyl)-N-methylperfluorobutanesulfonamide as a clear, colorless liquid distillate.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5](O)=[O:6])=[O:2].S(Cl)([Cl:18])=O>>[CH:1]([C:3]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5]([Cl:18])=[O:6])=[O:2]
Reactant: O=Cc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: O=S(Cl)Cl
Product: O=Cc1ccc(C(F)(F)F)cc1C(=O)Cl
Temperature: 25 °C

Procedure:
A solution of Example 375A (0.6 g) and thionyl chloride (3.27 g, 27.5 mmol) was refluxed for 2 hr. The reaction solution was cooled to room temperature, concentrated, azeotroped with toluene, and used without further purification.
Reaction SMILES: [H-].[Na+].CN(C)C=[O:6].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1.Br[CH2:28][C:29](=[O:31])C>C(OCC)(=O)C>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:29](=[O:31])[CH3:28])[C:17]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[O:6])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)Cc2ccc(SC)cc2)cc1
Reactant: CN(C)C=O
Reactant: CC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(C(C(C)=O)C(=O)c2ccc(SC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
0.44g (11.0 mol) of 60% sodium hydride was added to 27 ml of N,N-dimethylformamide solution containing 2.72 g (10.0 mmol) of 1-(4-methoxyphenyl)-2-(4-methylthiophenyl)ethanone, and stirred at the room temperature for 30 minutes, then 1.51 g (11.0 mol) of bromoacetone was added and further stirred at room temperature for 1 hour. 400 ml of ethyl acetate was added thereto and the mixture was washed three times with 200 ml of saturated saline. The organic layer was dried over anhydrous magnesium sulfate, then concentrated under reduced pressure followed by subjected to chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain 2.27 g of 2-(4-methoxyphenyl)-1-(4-methylthiophenyl)butane-1,3-dion as colorless oil (yield: 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19](OC)=O)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:23].FC1C=CC(C2C=C(COS(C)(=O)=O)[C:34](=O)[N:35](CC(C)C)N=2)=CC=1C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19][NH:35][CH3:34])[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)nn(CC(C)C)c1=O
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Product: CNCc1cc(-c2ccc(F)c(C)c2)nn(CC(C)C)c1=O
Yield: 96.2 %

Procedure:
Following the procedure of Example 9 (4), 6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as a pale yellow oil (yield: 96.2%).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:8]=[N+:9]=[N-:10].[Na+].C(Cl)Cl.[Cl-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[N:8]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CCl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CN=[N+]=[N-]

Procedure:
A solution of 55.7 grams (0.45 moles) of 99% pure ethyl chloroacetate (Aldrich Chemical Company, Milwaukee, Wis.), 0.64 grams(1.6 millimoles) of Aliquat 336 and 30.16 grams (0.46 moles) of sodium azide (Aldrich) in 50 ml. of methylene chloride and 50 ml. of water was heated to reflux for 16 hours in a 250 ml. round bottom 3-neck flask. The mixture was allowed to cool, whereupon an additional 30 ml. of water was added to dissolve the precipitated sodium chloride. The organic phase was separated and the aqueous phase was washed twice with 10 ml. aliquots of methylene chloride. The aqueous phase was discarded and the organic phases were combined and used as a solvent for the following reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[CH:6][C:4]=1[NH2:5].[I-].C[N+]1(CC2C=CC=CC=2)[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1.C(Cl)Cl>CCO.O>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[CH:6][C:4]=1[N:5]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1
Reactant: CCCOc1ccc(N)c(OC)c1
Reactant: C[N+]1(Cc2ccccc2)CCC(=O)CC1
Agent: [I-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCCOc1ccc(N2CCC(=O)CC2)c(OC)c1
Reaction time: 1 h

Procedure:
1.20 g (6.62 mmol) 2-methoxy-4-propoxyaniline (Example XXXI) in 8.5 mL EtOH and 1.8 mL water are stirred under reflux. During 30 min 2.19 g (6.62 mmol) N-methyl-N-benzyl-4-oxopiperidinium iodide (Org. Lett. 1999, 1, 1261-1262) are added by several portions. Stirring under reflux is continued for 1 h. Then the reaction mixture is cooled down to rt before water and DCM are added. The layers are separated and the org. layer is dried with MgSO4, filtered and the solvent is removed in vacuo. The resulting residue is purified by column chromatography (silica gel, PE/EtOAc 8/2).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[C:7]([N+:25]([O-:27])=[O:26])[CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:28])[C:3]([OH:29])=[O:2])=[CH:6][C:7]=1[N+:25]([O-:27])=[O:26]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)c([N+](=O)[O-])c1
Yield: 79.2 %

Procedure:
A solution of 4-[2-(2-naphthalenyloxy)ethoxy]-3-nitro-alpha-oxobenzeneacetic acid methyl ester (0.55 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 5 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from acetone-hexane provided 0.42 g of purified 4-[2-(2-naphthalenyloxy)ethoxy]-3-nitro-alpha-oxobenzeneacetic acid as a yellow solid, mp 164° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:16])[C:8]=1[O:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[NH2:5].C1(C)C=CC=CC=1.[C:24](Cl)(Cl)=[O:25].O1CCOCC1>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]=[C:24]=[O:25])[CH:6]=[C:7]([Cl:16])[C:8]=1[O:9][C:10]([F:14])([F:15])[CH:11]([F:13])[F:12]
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(Cl)c(OC(F)(F)C(F)F)c(Cl)c1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Product: O=C=Nc1cc(Cl)c(OC(F)(F)C(F)F)c(Cl)c1

Procedure:
33.4 g of 3,5-dichloro-4-(1,1,2,2,-tetrafluoroethoxy)aniline are dissolved in 130 ml of chlorobenzene. With stirring, this solution is added dropwise at 22° C. to a solution consisting of 90 g of toluene containing 20% by weight of phosgene and of 100 ml of dioxane and 300 ml of chlorobenzene. The reaction mixture is stirred for 1 hour at room temperature, 1 hour at 50° C. and then 1 hour at 80° C. The reaction mixture is subsequently concentrated in a water-jet vacuum and then distilled under high vacuum, affording the title compound of the formula ##STR8## as a colourless oil. Boiling point 81°-83° C./2.5 mbar.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:15]([F:16])=[CH:14][C:13](Br)=[CH:12][C:11]=2[F:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24](B(O)O)[CH:25]=1>>[C:1]1([S:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:22]3[CH:21]=[C:20]([Cl:19])[CH:25]=[CH:24][C:23]=3[O:29][CH3:30])=[CH:12][C:11]=2[F:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: O=S(=O)(c1ccccc1)c1c(F)cc(Br)cc1F
Product: COc1ccc(Cl)cc1-c1cc(F)c(S(=O)(=O)c2ccccc2)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (i) and 5-chloro-2-methoxybenzene boronic acid which was used directly in step (iv) without further characterisation.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:28])[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([Li])CCC.[O:34]=[C:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:37][CH2:36]1>O1CCCC1>[Si:11]([O:10][CH2:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:35]1([OH:34])[CH2:36][CH2:37][N:38]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:39][CH2:40]1)[OH:28])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)[Si](OCC(O)c1ccccc1Br)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(O)(c2ccccc2C(O)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 25.9 %

Procedure:
To a stirred solution of 1-(2-bromophenyl)-2-{[tert-butyl (diphenyl)silyl]oxy}ethanol (step 2, 5.63 g, 12.4 mmol) in tetrahydrofuran (36 mL) was added dropwise a 1.59 M solution of butyllithium in tetrahydrofuran (15.9 mL, 25.3 mmol) at −78° C. for 5 min and the mixture was stirred for 5 h at the same temperature. To the mixture was added dropwise a solution of ethyl 4-oxopiperidine-1-carboxylate (2.33 g, 13.6 mmol) in tetrahydrofuran (10 mL) at −78° C. and the mixture was stirred for 2 h at the same temperature. This resulting mixture was slowly warmed up to room temperature and stirred for 16 h at the same temperature. The reaction mixture was quenched by the addition of saturated ammonium chloride aqueous solution, and concentrated to give a yellow residue. The crude material was partitioned between ethyl acetate and water, and then the organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (150 g) eluting with hexane/ethyl acetate (2/1) to afford 1.76 g (26%) of the title compound as a colorless solid:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[Mg].C([N:16]1[CH2:21][CH2:20][CH:19]([C:22]#N)[CH2:18][CH2:17]1)(=O)C.[Cl-].[NH4+].CC[O:28]CC>O1CCCC1>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:22]([CH:19]1[CH2:18][CH2:17][NH:16][CH2:21][CH2:20]1)=[O:28]
Reactant: CC(=O)N1CCC(C#N)CC1
Reactant: CCOCC
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1cccc(C(F)(F)F)c1)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-trifluoromethylbenzoyl)piperidine is prepared in the following manner: A solution of 102.5 g of 3-bromobenzotrifluoride in 25 ml of ether is added dropwise to a stirring mixture of 11.5 g of magnesium turnings in 300 ml of anhydrous ether to maintain a moderate reflux. After total addition the resulting dark mixture is stirred for 1 hour at ambient temperature. A solution of 60.0 g of 1-acetyl-4-cyanopiperidine in 100 ml of tetrahydrofuran is slowly added to this mixture and the mixture is stirred for 16 hours. An excess of an aqueous solution of ammonium chloride is added and the mixture is heated on a steam bath for 3 hours. The mixture is allowed to cool, extracted with benzene and the combined extracts are dried. The solvent is removed and the residue is dissolved in ethanol and basified with sodium hydroxide. The alkaline solution is refluxed for 3 hours, cooled and extracted with benzene. The combined benzene extracts are dried and the benzene is removed, leaving the oil, 4-(3 -trifluoromethylbenzoyl)piperidine, which is converted to the hydrochloride, mp 196°-198° C.
Reaction SMILES: [NH:1]([C:35]([O:37]C(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:25]([O:27]N1C(=O)CCC1=O)=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[O:19]C(C)(C)C)=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6]C(C)(C)C.[NH2:42][C@H:43](C(O)=O)[CH2:44][CH2:45][C:46](=[O:48])[OH:47].[CH3:52][N:53]1[C@@H:70]2[CH2:71][C:58]3[CH:59]=[CH:60][C:61]([O:72][CH3:73])=[C:62]4[O:63][C@H:64]5[C:65]([CH2:67][CH2:68][C@@H:69]2[C@:56]5([C:57]=34)[CH2:55][CH2:54]1)=[O:66]>>[NH2:42][C@H:43]([C:35]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:25]([OH:27])=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[OH:19])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[OH:6])=[O:37])[CH2:44][CH2:45][C:46](=[O:47])[OH:48].[CH3:52][N:53]1[C@@H:70]2[CH2:71][C:58]3[CH:59]=[CH:60][C:61]([O:72][CH3:73])=[C:62]4[O:63][C@H:64]5[C:65]([CH2:67][CH2:68][C@@H:69]2[C@:56]5([C:57]=34)[CH2:55][CH2:54]1)=[O:66]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Product: N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Glu-Glu-Glu-Hydrocodone was prepared by a similar method to 9 except the amino acid starting material was Boc-Glu(OtBu)-Glu(OtBu)-OSu and the conjugate starting material was Glu-Hydrocodone.