Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C(=O)(O)[O-:3].[Na+].[C:7]([O:12][CH2:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])Cl)(=[O:11])[C:8]([CH3:10])=[CH2:9]>C(OCC)C>[C:7]([O:12][CH2:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[OH:3])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C=C(C)C(=O)OCCC[Si](C)(C)Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: C=C(C)C(=O)OCCC[Si](C)(C)O

Procedure:
After 60 mL of water, 60 ml of diethyl ether, and 7 g (83 mmol) of sodium bicarbonate had been placed into a four-necked flask, the temperature was lowered to 0° C. Next, 15 g (68 mmol) of 3-methacryloxypropyldimethylchlorosilane were added dropwise into the resulting mixture, which was being agitated, via a dropping funnel. After the reaction had been completed, the ether layer was separated and then washed with water once. After the ether had subsequently been distilled and removed at room temperature and reduced pressure, 3-methacryloxypropyldimethylsilanol (hereafter, "MPOH") was obtained. The structure of said compound was verified by gas chromatographic analysis (GLC) and nuclear magnetic resonance analysis (NMR).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27]/[CH:28]=[C:29]1/[C:30]2[CH:43]=[C:42]([C:44]([OH:47])([CH3:46])[CH3:45])[CH:41]=[CH:40][C:31]=2[O:32][CH2:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][C:35]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:8]2[CH2:12][CH2:11][N:10]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Reactant: CC(C)CN(Cc1ccc(Cl)cc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)CN(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of (4-chloro-benzyl)-isobutyl-pyrrolidin-3-yl-amine (0.16 g, 0.6 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.8 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 24 h. The reaction was concentrated, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by flash chromatography using ethyl acetate/methanol (5%). 1H-NMR (CDCl3) δ: 0.80 (6H, d), 1.55(6H, s), 1.60–1.90 (4H, m), 2.15 (1H, d), 2.20–2.60 (6H, m), 3.25–3.60 (2H, m), 5.30 (2H, br, s), 6.10 (1H, t), 6.80 (1H, dd), 7.15–7.30 (6H, m), 7.40 (1H, d), 7.55 (1H, dd), 8.45 (1H, dd). ESI-MS m/z: 560 (M+1), UV retention time: 1.66 min.
Reaction SMILES: [CH2:1]([P:5](Cl)([CH:7]([CH2:9][CH3:10])[CH3:8])=[O:6])[CH:2]([CH3:4])[CH3:3].[CH2:12]([Mg]Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:1]([P:5](=[O:6])([CH:7]([CH2:9][CH3:10])[CH3:8])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCCCC[Mg]Br
Reactant: CCC(C)P(=O)(Cl)CC(C)C
Product: CCCCCCCP(=O)(CC(C)C)C(C)CC

Procedure:
Iso-butyl sec-butyl phosphinyl chloride prepared as in Part A and n-heptyl magnesium bromide were allowed to react together as in Preparative Example A to give iso-butyl sec-butyl n-heptyl phosphine oxide bp. 123°-5°/0.004 mm.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH2:24]([O:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][CH:28]=[C:18]([O:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:19]=1)[CH3:25]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(OCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
N-Boc-4-piperidine ethanol (15 g, 65 mmol) and ethyl 3-hydroxybenzoate (11 g, 65 mmol) were dissolved in dry THF (750 ml) under N2. To this was added tri-n-butylphosphin (24 ml, 98 mmol) and ADDP (25 g, 98 mmol) resulting in a suspension, which was stirred overnight at 20° C. The mixture was concentrated in vacuo to ˜100 ml, filtered, and the filtrate was evaporated with silica gel. Flash chromatography (EtOAc/heptane 1:4) afforded 24 g of the title compound. LC-MS (m/z): 401 (M+23).
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[Br:15]Br>C(O)(=O)C>[Br:15][C:9]1[C:10]([O:13][CH3:14])=[N:11][CH:12]=[C:7]([Cl:6])[CH:8]=1
Reactant: COc1ccc(Cl)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ncc(Cl)cc1Br
Temperature: 80 °C
Reaction time: 64 h

Procedure:
To a stirred suspension of 2.5 g of anhydrous sodium acetate in 10 ml of acetic acid was added 4.3 g of 5-chloro-2-methoxypyridine followed by a solution of 3.1 ml of bromine in 10 ml of acetic acid. The mixture was warmed to 80° C. for 6 hours and then allowed to cool and stirred at 23° C. for 64 hours. It was then partitioned between ether and water and the resulting ether layer was washed with aqueous 1N sodium hydroxide solution and then with aqueous 5% sodium bisulfite solution, dried over potassium carbonate and concentrated at reduced pressure to leave a residual brown solid. This residue was bulb-to-bulb distilled with the material distilling at 140°-150° C. at 20 torr collected to give 3-bromo-5-chloro-2-methoxypyridine as a solid melting at about 45°-47.5° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F-].[K+]>C1COCC1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccccc2)cc1
Yield: 96.8 %

Procedure:
4-Chlorobenzaldehyde (144 mg, 1.02 mmol) reacted with phenylboronic acid (185 mg, 1.36 mmol) using 1/2 mol % of Pd(OAc)2/Ph5FcP(t-Bu)2 and KF (178 mg, 3.18 mmol) in THF at 50° C. to give the title compound (180 mg, 96%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 8.05 (s, 1H), 7.96 (d, 2H, J=8.32 Hz), 7.76 (d, 2H, J=8.22 Hz), 7.65 (d, 2H, J=7.08 Hz), 7.52-7.14 (m, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 191.88, 147.10, 139.62, 135.11, 130.21, 128.96, 128.42, 127.61, 127.30. GC/MS(EI): m/z 182 (M+), 152. Anal. Calcd for C13H10O: C, 85.69; H. 5.53. Found: C, 85.69; H, 5.77.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][CH2:6][C:5]2=[O:22].Br[Zn][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27]>>[CH2:25]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][CH2:6][C:5]2=[O:22])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)C[Zn]Br
Reactant: O=C1CCN(C(=O)OCc2ccccc2)c2ccc(Br)cc21
Product: CC(C)(C)Cc1ccc2c(c1)C(=O)CCN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Benzyl 6-bromo-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (3.10 g) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.35 g) were combined in a round bottom flask. The mixture was put under high vacuum and purged with nitrogen. A 0.5 M solution of bromo(neopentyl)zinc (55 mL) prepared using the procedure of Negishi et al. Tet Lett. 1983, 24, 3823–3824, was added to the mixture and was stirred at room temperature for two days. The reaction had not gone to completion, so an additional 10 mL of bromo(neopentyl)zinc solution was added and the mixture was stirred for one additional day. The mixture was then partitioned between ethyl acetate and aqueous ammonium chloride, dried with magnesium sulfate, filtered, and concentrated. Silica gel chromatography using a 20% ethyl acetate in heptane solvent solution gave 2.17 g of the title compound. MS (ESI+) for C22H25NO3 m/z 353.17 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H+].[B-:7]([F:11])([F:10])([F:9])[F:8]>ClCCl.C(OCC)C>[F:8][B-:7]([F:11])([F:10])[F:9].[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1
Reactant: c1c[nH]cn1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: ClCCl
Product: c1c[nH+]c[nH]1

Procedure:
To a solution of imidazole (20 mmol) in dichloromethane (30 mL) at 0° C. HBF4 (20 mmol, 3.8 g of a diethyl etherate) in dichloromethane is added dropwise. The reaction mixture is diluted with diethyl ether (100 mL) to precipitate the title compound. It is then filtered, washed with ether and recrystallized from ether.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[Li+].[CH3:14]CC[CH2-].IC>O1CCCC1>[CH3:14][C:3]1[C:4]2[O:5][CH2:6][O:7][C:8]=2[CH:9]=[CH:10][C:2]=1[C:1]([OH:12])=[O:11]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: [CH2-]CCC
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc2c1OCO2
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a round bottom flask equipped with an overhead stirrer and a nitrogen inlet was added piperonylic acid (50.0 g, 301 mmol) and tetrahydrofuran (753 mL). This was cooled to −75° C. in a dry ice-acetone bath. N-Butyllithium (1.6 M in hexanes) (414 mL, 662 mmol) was added dropwise maintaining the temperature of the reaction at or below −65° C. When the addition was complete the cooling bath was removed and the reaction was allowed to warm to −20° C. The reaction was returned to the bath and cooled to at least −60° C. at which time iodomethane (37.5 mL, 602 mmol) was added dropwise. Cooling was removed and the reaction allowed to warm to 10° C. at which time the reaction was placed in an ice bath and stirred at 0° C. for 30 minutes. The reaction was quenched by addition of 1N HCl and the tetrahydrofuran removed by evaporation. The residue was slurried in 1N HCl and filtered. The filtrate was washed with water, and dried at 50-60° C. in vacuo to give a pale yellow solid, 4-methyl-benzo[1.3]dioxole-5-carboxylic acid (52.8 g, 293 mmol) in 97% yield. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.44 (s, 3H), 6.10 (s, 2H), 6.77 (d, 1H), 7.64 (d, 1H). TLC Rf=0.54 (1:1 ethyl acetate/hexane, piperonylic acid=0.41).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)C.Cl.[NH2:13][OH:14].[OH-].[Na+].Cl>O.C(O)C>[OH:14][N:13]=[CH:9][C:3]1[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[OH:1]
Reactant: NO
Reactant: CC(=O)c1ccc(O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 2.0 grams (0.013 mole) of 1-(2,4-dihydroxyphenyl)ethan-1-one (commercially available) and 1.4 grams (0.019 mole) of hydroxylamine hydrochloride in 20 mL of water and 100 mL of ethanol was cooled to about 0° C. to 4° C. and 2.7 grams (0.068 mole) of sodium hydroxide was added. Upon completion of addition the reaction mixture was warmed to reflux where it stirred during a 30 minute period. After this time the reaction mixture was cooled to ambient temperature and 400 mL of aqueous 5% hydrochloric acid was added. The mixture was extracted with diethyl ether, and the extract was washed with water. The organic layer was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, yielding 1.5 grains of the subject compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5](I)=[CH:4][N:3]=1.[C:14]([C:16]1[CH:17]=[N:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=1)#[CH:15].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=3)[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]=2[CH:7]=1
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
Reactant: C#Cc1cnn(C(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2S(C)(=O)=O)cn1
Temperature: 60 °C

Procedure:
To a mixture of N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide (8) (419 mg, 1.11 mmol) and tert-butyl 4-ethynyl-1H-pyrazole-1-carboxylate (4) (277 mg, 1.44 mmol, 1.3 equiv) was added copper(I) iodide (7.4 mg 0.039 mmole) and DMF (4 mL), followed by triethylamine (0.69 mL, 497 mg, 4.92 mmol). The reaction was flushed twice with nitrogen. Bis(triphenylphosphine)palladium chloride (27 mg, 0.038 mmole) was added and the reaction flushed twice more with nitrogen, it was heated at 60° C. for 70 minutes. The reaction was added to water (40 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with water (3×20 mL) and with brine, dried and evaporated. The residue was purified on four 2 mm 20×20 cm silica prep tlc plates, eluted with 3:1 ethyl acetate:cyclohexane. The product band was recovered with acetone giving the title compound (251 mg, 51%). 1H-NMR (CDCl3, 500 MHz): δ 1.73 (s, 9H), 3.02 (s, 3H), 6.81 (s, 1H), 7.97 (s, 1H), 8.26 (s, 1H), 8.43 (s, 1H), 8.69 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.[OH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[F:19][C:18]([F:21])([F:20])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:3]1[C:2]([C:27]2[CH:28]=[CH:29][C:24]([CH2:23][OH:22])=[CH:25][CH:26]=2)=[N:7][CH:6]=[CH:5][N:4]=1)(=[O:11])=[O:10]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=S(=O)(Nc1nccnc1Cl)c1ccccc1C(F)(F)F
Product: O=S(=O)(Nc1nccnc1-c1ccc(CO)cc1)c1ccccc1C(F)(F)F
Yield: 85 %

Procedure:
Following the general method as outlined for Intermediate 4, starting from N-(3-chloropyrazin-2-yl)-2-(trifluoromethyl)benzenesulfonamide and 4-hydroxymethyl benzene boronic acid, the title compound was isolated, after evaporation and recrystallization, as a yellowish solid in 85% yield (97% purity by HPLC).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].Cl[C:11]([O:13][CH3:14])=[O:12]>C(Cl)Cl.C(N(C(C)C)CC)(C)C>[CH3:14][O:13][C:11]([NH:1][CH2:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])=[O:12]
Reactant: NCc1ccccc1N
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NCc1ccccc1N

Procedure:
The amine component employed is obtained starting from 2.0 g of 2-(aminomethyl)aniline, dissolved in 30 ml of methylene chloride, by reaction with 1.3 ml of methyl chloroformate in the presence of 3.1 ml of diisopropylethylamine at 5° C. After purification over 80 g of silica gel (mobile phase A), 2-(methoxycarbonylaminomethyl)aniline is obtained: Rf (A)=0.23; Rf (Z)=0.31.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[N:24]=[CH:25][C:26]4[CH:31]=[CH:30][NH:29][C:27]=4[N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH:15]2[CH2:17]C2)[CH2:12][CH2:11][CH2:10][CH2:9]1.[H][H]>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:31]4[CH:26]=[CH:25][NH:24][C:30]=4[N:29]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH2:15][CH3:17])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: c1cc2cnc(-c3cnn(C(CC4CC4)C4CCCC4)c3)nc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 2 h
Yield: 68.9 %

Procedure:
4-[1-(1-Cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoro-acetate salt (prepared in Example 729) (20 mg, 0.048 mmol) was dissolved in methanol (2 mL) and a catalytic amount of 5% Pd—C was added. The mixture was stirred under 1 atmosphere of hydrogen via an affixed balloon. After 2 hours, the mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) to afford the product (14 mg, 69%).
Reaction SMILES: BrC1C=C([O:8]C)C=CC=1.C([Li])(CC)C.[CH2:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:19][CH2:18]1)[CH3:16]>O1CCCC1.CCCCCC>[CH2:15]([N:17]1[CH2:22][CH2:21][C:20]([OH:8])([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:19][CH2:18]1)[CH3:16]
Reactant: COc1cccc(Br)c1
Reactant: CCN1CCC(c2cccc(OC)c2)CC1
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN1CCC(O)(c2cccc(OC)c2)CC1
Temperature: -50 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a stirred solution of 3-bromoanisole (12.83 g, 0.069 mol) in dry tetrahydrofuran (70 ml) at -50° C. under an atmosphere of nitrogen was added sec-butyllithium (1.3M in hexanes, 68.5 ml, 0.089 mol) dropwise, ensuring that the temperature in the reaction vessel did not rise above -50° C. After complete addition of the sec-butyllithium, a white precipitate formed, and the reaction was stirred for 1 hour at -50° C. N-Ethyl-4-(3-methoxyphenyl)piperidine (10.5 ml, 0.079 mol) in dry tetrahydrofuran (50 ml) was added dropwise at a rate to maintain the reaction temperature below -40° C., resulting in an orange solution. The reaction mixture was allowed to warm to -20° C. over 1.5 hours, and then to room temperature over a further 1 hour. After this time, the reaction mixture was quenched by the addition of saturated brine (21 ml) and water (30 ml). The quenched reaction was stirred for a further 30 minutes, and then the two phases separated, and the organic phase retained. The aqueous phase was extracted with dichloromethane (3×75 ml), and the two organics combined and washed with hydrochloric acid (1N, 2×50 ml). The aqueous layer was separated, basified with ammonium hydroxide to pH 10, and extracted with dichloromethane (3×40 ml). The dichloromethane extracts were concentrated to yield a thick oil, which was triturated in cold hexane until a solid was obtained. This crude solid was stirred in hot hexane, allowed to cool, and filtered to yield N-ethyl-4-hydroxy-4-(3-methoxyphenyl)piperidine (5.5 g, 33.7%) as a white solid. m.p.=86.7-91.1° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([CH:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:13][C:14]([O:16][CH3:17])=[O:15])([O:10][CH3:11])=[O:9]>C(Cl)Cl>[C:8]([CH:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[CH2:27][NH:28][CH2:29][C:30]([F:31])([F:33])[F:32])[CH2:13][C:14]([O:16][CH3:17])=[O:15])([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CC(Cc1ccc(OC)cc1CN(CC(F)(F)F)C(=O)OC(C)(C)C)C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC(Cc1ccc(OC)cc1CNCC(F)(F)F)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
TFA (55 mL) was added all at once to a solution of methyl (±)-3-carbomethoxy-4-[2-[N-(tert-butoxycarbonyl)-N-(2,2,2-trifluoroethyl)amino]methyl-4-methoxyphenyl]butanoate (7.98 g, 16.71 mmole) in anhydrous CH2Cl2 (42 mL) at 0° C. under argon, and the reaction was warmed to RT. After 1.5 hr, the reaction was concentrated, and the residue was reconcentrated from xylenes. Drying in high vacuum at 40° C. left the title compound (8.70 g, quantitative) as a yellow solid: MS (ES) m/e 378 (M+H)+.
Reaction SMILES: [CH-:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+].CCOCC.[C:16]1([P:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH:1]1([P:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: c1ccc2[cH-]ccc2c1
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C1=CC(P(c2ccccc2)c2ccccc2)c2ccccc21
Reaction time: 8 h
Yield: 83.5 %

Procedure:
In the drybox lithium indenide (8.00 g, 65.52 mmol) dissolved in 50 mL of THF was added within 15 minutes to a 180 mL ether solution of diphenylchlorophosphine (14.46 g, 65.52 mmol) (diphenylchlorophosphine was distilled before use (97° C. @ 0.4 torr)). After stirring overnight, LiCl was separated by filtration giving a yellow solution. Solvent was removed under vacuum leaving an off-white solid. This solid was triturated with 40 mL of hexane. Hexane was removed by decanting and the solid was dried under reduced pressure to give 16.43 g of off-white solid. Yield 84 percent.
Reaction SMILES: C[C:2]1[CH:8]=[C:7](C)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][CH2:11][C:12](Cl)=[O:13].O>C(O)(=O)C>[Cl:10][CH2:11][C:12]([NH:4][C:3]1[CH:2]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:13]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(N)c(C)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCl)Nc1ccccc1
Yield: 80 %

Procedure:
In accordance with the present invention there is provided a method for the preparation of a scintillographic agent which comprises dissolving 2,4-dimethylaniline in acetic acid at room temperature, mixing the resulting solution with chloracetyl chloride under vigorous mixing. The solution then is kept several hours at a temperature of 4° C. The reaction mixture is poured into water with ice. The sediment is crystallized from alcohol and from post-crystallizatic bases, diluted in water, a further quantity of sediment is regained which gives a total yield 80 to 82 %. The ω-chloracetanilide produced in this way is dissolved, together with the sodium salt of iminodiacetic acid, in aqueous ethanol wherein the proportion by volume of water to ethanol is 1:1.2. The mixture is warmed during several hours under a water circulation cooler. After the evaporation of solvent, the dry sediment is dissolved in water, the non-reacted component is separated, and the residual water solution is adjusted to the pH value about 2.5. The precipitated sediment is dissolved in absolute ethanol, non-reacted component is separated and, after the evaporation of solvent, the derivative of iminodiacetic acid is crystallized from water at pH about 2.5. The yield is 25 to 35 %. Further, the derivative of iminodiacetic acid, produced in this way, is dissolved in water with a possible addition of stannous chloride in hydrochloric acid and the pH value is adjusted to 4 to 6 depending on the supplied chelating radiometal. The solution is then passed through a sterile filter, freeze-dried and stored in sterile ampoules fixed in nitrogen or filled at a reduced pressure. At least half an hour prior to an intravenous administration the sterile solution of pertechnetate 99 m Tc or another radiometal is added to the derivative of iminodiacetic acid. The scintillographic agent according to the invention is durable up to 24 hours.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (270 mg, 70%).