Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]([CH3:26])[C:19]([C@H:21]1[CH2:25][CH2:24][CH2:23][NH:22]1)=[O:20]>C(#N)C>[CH3:17][N:18]([CH3:26])[C:19]([C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)=[O:20]
Reactant: CN(C)C(=O)[C@H]1CCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)C(=O)[C@H]1CCCN1c1ccc([N+](=O)[O-])cc1

Procedure:
4-Fluoronitrobenzene (0.47 g, 3.34 mmol), potassium carbonate (1.39, 10 mmol) and (R)-pyrrolidine-2-carboxylic acid dimethylamide (0.50, 3.52 mmol) were pre-mixed in acetonitrile (40 ml) and heated at reflux for 36 hours. The reaction was quenched with saturated ammonium chloride (40 ml), extracted with DCM (2×100 ml), dried and solvent removed in vacuo to yield the title compound as a yellow solid. Ether was added and the solid was stirred, filtered and dried (0.85 g, 96%). M/z 264.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[CH3:21][S:22]([O:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (806 mg) in tetrahydrofuran (25 ml) was added triethylamine (1.80 ml). This was cooled in an ice bath under a nitrogen atmosphere, and methanesulfonyl chloride (0.499 ml) was added dropwise, followed by stirring at the same temperature for 30 min. The reaction mixture was partitioned after addition of ethyl acetate (100 ml) and water (70 ml). The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate). Fractions containing the target compound were concentrated to provide the titled compound as a colorless oil (1.05 g, 92.0%).
Reaction SMILES: [O:1]1[CH:6]([CH2:7][OH:8])[CH2:5][O:4][C:3]2=[CH:9][S:10][CH:11]=[C:2]12.O1CCCC1.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(OCC)(=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][O:8][CH2:7][CH:6]1[O:1][C:2]2=[CH:11][S:10][CH:9]=[C:3]2[O:4][CH2:5]1)[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: OCC1COc2cscc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)COCC1COc2cscc2O1
Reaction time: 0.5 h

Procedure:
(2,3-Dihydro-thieno[3,4-b][1,4]dioxin-2-yl)-methanol (6.9 g, 40 mmol) was dissolved into tetrahydrofuran (100 mL), blanketed by nitrogen. Sodium hydride (1.9 g) was added in portions after which the reaction mixture was stirred for another 30 min. Then ethyl bromoacetate (5.3 mL) was added dropwise and stirring was continued for another hour at 25° C. The reaction mixture was then poured into ethyl acetate, washed with 1M hydrochloric acid, washed with a 1M aqueous solution of sodium hydrogen carbonate and concentrated. This resulted in quantitative formation of pure (2,3-dihydro-thieno[3,4-b][1,4]dioxin-2-ylmethoxy)-acetic acid ethyl ester as demonstrated by NMR and mass spectroscopy.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:6]([C:24]2[N:28]([CH3:29])[C:27]([CH2:30][CH3:31])=[N:26][N:25]=2)[CH:5]=1.[NH3:33]>O>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([S:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH2:33])=[O:2])=[CH:5][C:6]=2[C:24]2[N:28]([CH3:29])[C:27]([CH2:30][CH3:31])=[N:26][N:25]=2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)([CH3:22])([CH3:23])[CH3:21]
Reactant: N
Reactant: CCc1nnc(-c2cc(C(=O)OC)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Solvent: O
Product: CCc1nnc(-c2cc(C(N)=O)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A 10 mL scintillation vial was charged with 4-(4-tert-butyl-benzenesulfonylamino)-3-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-benzoic acid methyl ester (20 mg, 0.044 mmol) and 30% NH3 in H2O (1.5 mL). The reaction was heated to 60° C. and stirred overnight. The following day, the volatiles were removed in vacuo to about 200 μL at which point the solution was purified by preparative TLC to afford 4-(4-tert-butyl-benzenesulfonylamino)-3-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-benzamide as a colorless oil: MS (ES) M+H expected 442.2, found 442.4.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([F:15])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH3:16]>CO>[NH2:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([F:15])=[CH:8][C:3]=1[C:4]([NH2:16])=[O:5]
Reactant: COC(=O)c1cc(F)c([N+](=O)[O-])cc1N
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(F)c([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
4.0 g (18.7 mmol) of methyl 2-amino-5-fluoro-4-nitro-benzoate were dissolved in 250 ml of methanol and saturated with ammonia at -40° C. Subsequently, the mixture was stirred at room temperature overnight. The solution was concentrated and ther residue was triturated with methylene chloride. The precipitate was filtered off under suction and dried. 3.17 g (85%) of 2-amino-5-fluoro-4-nitro-benzamide were obtained as yellow crystals;
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.OCCC1C=C[N+:16]([O-])=[CH:15]C=1.C[Si](C#N)(C)C>>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:15]#[N:16])[CH:5]=1
Reactant: [O-][n+]1ccc(CCO)cc1
Reactant: OCCc1ccncc1
Agent: C[Si](C)(C)C#N
Product: N#Cc1cc(CCO)ccn1

Procedure:
4-(2-hydroxyethyl)-pyridine is oxidized to 4-(2-hydroxyethyl)-pyridine-N-oxide which is in turn treated with trimethylsilyl cyanide to yield 4-(2-hydroxyethyl)-2-cyanopyridine which is converted to ethyl 4-(2-hydroxyethyl)-2-pyridine carboxylate and then hydrogenated to yield ethyl 4-(2-hydroxyethyl)-piperidine-2-carboxylate.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:23]([OH:30])[CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23](=[O:30])[CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCCC2)cc2cc(C(F)(F)F)cnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(CC1CCCC1)c1cc2cc(C(F)(F)F)cnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of 1-(1-benzenesulfonyl-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-ethanol (1.34 g, 3.07 mmol) in dichloromethane (50 ml) was added Dess-Martin periodinane (2.6 g, 6.14 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (3×20 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 50% dichloromethane/hexanes) to afford 1-(1-benzenesulfonyl-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-ethanone (1.33 g, 100%) as a light yellow solid: LC/MS m/e calcd for C21H19F3N2O3S [M+H]+ 437.46, observed 436.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[C:5]([CH3:12])[CH:4]=1.[ClH:13].[H][H]>C(O)C.[Pd]>[ClH:13].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[C:5]([CH3:12])[CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(CC#N)c(C)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(CCN)c(C)c1
Reaction time: 20 h
Yield: 50 %

Procedure:
4-Methoxy-2-methylphenylacetonitrile (3.0 g, 18.6 mmol) was dissolved in 2B ethanol (65 mL). To the solution was added con. HCl (2.4 mL) and 10% Pd/C (300 mg). The suspension was deaerated in a 500 mL Parr hydrogenation bottle and then pressurized with 55 psi H2, and shaken. After 20 h, the reaction was recharged with hydrogen and 10% Pd/C. After a total of 96 h, the reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The off-white solid residue was recrystallized from isopropanol and collected by suction filtration to afford 1.86 g (50% yield) 2-(4-methoxy-2-methylphenyl)-ethylamine hydrochloride as a white solid, melting point (M.P.) 220-222° C. (gradual softening and discoloration from 104-220° C.). The filtrate was concentrated in vacuo and the residue was washed with ethyl acetate and filtered, providing an additional 1.34 g for a total yield of 3.2 g (85% yield). GC/MS: m/z 165; 1H NMR (DMSO) 8.25 (bs, 3H), 7.09 (d, 1H), 6.75 (m, 2H), 3.71 (s, 3H), 2.87 (m, 4H), 2.27 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])/[C:3](/OS(C(F)(F)F)(=O)=O)=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)#[N:29]>O1CCOCC1>[C:28]([C:30]1[CH:35]=[C:34](/[C:3](/[C:2]([F:19])([F:18])[F:1])=[CH:4]\[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:33]=[CH:32][CH:31]=1)#[N:29]
Reactant: CCOC(=O)/C=C(\OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)/C=C(\c1cccc(C#N)c1)C(F)(F)F
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of ethyl (Z)-4,4,4-trifluoro-3-{[(trifluoromethyl)sulfonyl]-oxy}-2-butenoate (250 mg, 0.79 mmol) in 5 ml anhydrous dioxane was added potassium phosphate (251 mg, 1.19 mmol), 3-cyanophenyl boronic acid (116 mg, 0.79 mmol), and tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol). Reaction mixture was heated to reflux and stirred overnight. Mixture was filtered through a pad of Celite, diluted with 50 ml ethyl acetate, washed with 2×50 ml water, 2×50 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Residue was chromatographed on silica gel using 20% EtOAc in hexane as the eluent to give ethyl (2E)-3-(3-cyanophenyl)-4,4,4-trifluorobut-2-enoate (150 mg, 79%) as a yellow residue after drying. H1NMR (CDCl3) 1.107-1.142 (t, 3H); 4.04-4.107 (m, 2H); 6.684 (s, H); 7.38-7.72 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([Cl:11])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:12].[Cl:13]N1C(=O)CCC1=O.[Cl-].[Li+]>CN(C)C=O>[NH2:1][C:2]1[C:10]2[S:9][C:8]([Cl:11])=[N:7][C:6]=2[C:5]([Cl:13])=[CH:4][C:3]=1[Cl:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1c(Cl)ccc2nc(Cl)sc12
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(Cl)c2nc(Cl)sc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.3 %

Procedure:
Under a nitrogen atmosphere a solution of 6.0 grams (27 mmole) of 7-amino-2,6-dichlorobenzothiazole in 75 mL of N,N-dimethylformamide was stirred and cooled in an ice bath. To this was then added 4.3 grams (32 mmole) of N-chlorosuccinimide. Upon completion of the addition the reaction mixture was stirred for 20 minutes and then warmed to ambient temperature and stirred for an additional 18 hours. After this time the reaction mixture was poured into 250 mL of ice-water, and about 15 grams of lithium chloride was added, after which the reaction mixture was stirred for 30 minutes. The resulting precipitate was collected by filtration and dried under reduced pressure, yielding a dark solid, which was purified by column chromatography on silica gel. Elution was accomplished with 4:1 hexane:ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 4.4 grams of 7-amino-2,4,6-trichlorobenzothiazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]([O:20]C)=[O:19])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+:31]>O1CCOCC1>[C:22]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]([O-:20])=[O:19])[CH2:12][CH2:11]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1.[Na+:31]
Reactant: COC(=O)CN1CCCN(CCC(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C([O-])CN1CCCN(CCC(c2ccccc2)c2ccccc2)CC1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Methyl [4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (0.327 g, 0.89 mmol) was dissolved in a mixture of dioxane (3.1 mL). MeOH (1.1 mL) and 4N NaOH (0.22 mL). After stirring for 30 min. 5 more drops of 4N NaOH were added and stirring was, continued until hydrolysis of the methyl ester was complete. The mixture was concentrated in vacuo and the residue subjected to flash silica gel column chromatography (eluent: CH2Cl2/MeOH, 1/1, v/v) to give sodium [4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (0.278 g) in 88% yield, TLC Rf=0.22 (10% CH3OH—CH2Cl2); RPLC tR=1.98 min (>85%), 220 nm (Method B); ESI/MS m/e 353.3 (M++H, C22H29N2O2).
Reaction SMILES: [OH-].[Na+].[CH:3]([C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]3[N:22]=[C:21]([CH3:23])[C:20]([CH:24]([CH2:29][CH2:30][CH3:31])[C:25]([O:27]C)=[O:26])=[C:19]([C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)[N:18]=3)[CH2:12]2)[O:8][N:7]=1)([CH3:5])[CH3:4]>CO>[CH:3]([C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]3[N:22]=[C:21]([CH3:23])[C:20]([CH:24]([CH2:29][CH2:30][CH3:31])[C:25]([OH:27])=[O:26])=[C:19]([C:32]4[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=4)[N:18]=3)[CH2:12]2)[O:8][N:7]=1)([CH3:5])[CH3:4]
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCC(c3nc(C(C)C)no3)C2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCC(c3nc(C(C)C)no3)C2)nc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 331.8 %

Procedure:
A solution of sodium hydroxide 5N (1 mL) was added to a mixture of methyl 2-(2-(3-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.026 g; 0.053 mmol) in methanol (1 mL). The mixture was heated in a sealed tube at 100° C. for 18 h and then concentrated under reduced pressure. The residue was dissolved in water and the pH of the solution was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N. The precipitate was collected by filtration and dried under reduced pressure over phosphorus pentoxide to give 0.084 g (33%) of the title compound as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][C:9]=1[O:20][CH3:21])=O)C.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>C1(C)C(C)=CC=CC=1>[CH3:21][O:20][C:9]1[CH:10]=[CH:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:13][C:8]=1[NH:7][C:5](=[S:24])[C:4]([OH:3])=[O:22]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)C(=O)Nc1cc(N2CCOCC2)ccc1OC
Solvent: Cc1ccccc1C
Product: COc1ccc(N2CCOCC2)cc1NC(=S)C(=O)O
Temperature: 25 °C
Yield: 170.4 %

Procedure:
To 33.9 g (110 mmol) N-(2-methoxy-5-morpholin-4-yl-phenyl)-oxalamic acid ethyl ester in 652 ml boiling xylene was added 8.80 g (40 mmol) phosphorus pentasulfide in small portions over a period of 30 minutes. The mixture was refluxed for 5 hours, cooled to room temperature and filtered. The solution was extracted 7 times with 100 ml 1N NaOH. The aqueous phase was washed twice with 100 ml toluene, filtered, and treated at 0–5° C. with concentrated hydrochloric acid until pH 1 was reached. Filtration of the precipitate yielded 20.2 g (62%) (2-methoxy-5-morpholin-4-yl-phenylamino)-thioxo-acetic acid as yellow crystals with M.p.: 156–158° C., MS m/e (%): 297 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1Cl.[NH:10]1[CH2:18][CH2:17][CH:13]([C:14]([NH2:16])=[O:15])[CH2:12][CH2:11]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[N:10]1[CH2:18][CH2:17][CH:13]([C:14]([NH2:16])=[O:15])[CH2:12][CH2:11]1
Reactant: Clc1c(Br)cncc1Br
Reactant: NC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: NC(=O)C1CCN(c2c(Br)cncc2Br)CC1
Yield: 44.4 %

Procedure:
General procedure C was followed using 3,5-dibromo-4-chloropyridine 18 (50 mg, 0.18 mmol), isonipecotamide (24 mg, 0.18 mmol), NMP (2 mL) and triethylamine (51 μL, 0.37 mmol). The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 9:1) to furnish the title compound as a pale yellow solid (29 mg, 43%), m.p. 158-160° C.; umax (CHCl3)/cm−1 3053, 2985, 1687, 1591; m/z (ESI) C11H14Br2N3O requires 361.9498 found [M+H]+ 361.9500.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH:4]([N:6]1[CH2:11][CH2:10][NH:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]1=O)[CH3:5])[CH3:2].C(N(CC)C(N1CCNC(=O)C1C1C=CC=CC=1)C)C>>[CH2:19]([N:3]([CH2:1][CH3:2])[CH:4]([N:6]1[CH2:11][CH2:10][NH:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)[CH3:5])[CH3:20]
Reactant: CCN(CC)C(C)N1CCNC(c2ccccc2)C1=O
Agent: CCN(CC)C(C)N1CCNC(=O)C1c1ccccc1
Product: CCN(CC)C(C)N1CCNC(c2ccccc2)C1

Procedure:
1-Diethylamino ethyl-2-keto-3-phenyl piperazine prepared according to Example 1 B (a), is reduced by following the procedure described hereinabove in Example 8a whereby, in place of 1-diethylamino ethyl-3-keto-2-phenyl piperazine, the equimolecular amount of said 1-diethylamino ethyl-2-keto-3-phenyl piperazine is used. The resulting 3-phenyl piperazine compound is obtained in the form of a light yellow oil boiling at 102° C./0.02 mm. Hg.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13](=[O:31])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42]O)=[CH:37][CH:36]=1)([O-:34])=[O:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:15]([NH:14][C:13]([C:3]1[CH:4]=[C:5]([O:12][CH2:42][CH2:41][C:38]2[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:40][CH:39]=2)[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[OH:1])=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: CCCCCCCCCCCCCCCCNC(=O)c1cc(O)c2ccccc2c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNC(=O)c1cc(OCCc2ccc([N+](=O)[O-])cc2)c2ccccc2c1O
Yield: 48.9 %

Procedure:
A mixture composed of 42.7 g (0.1 mol) of 1,4-dihydroxy-2-(N-hexadecylcarbamoyl)naphthalene, 50.1 g (0.3 mol) of 2-(p-nitrophenyl)ethanol, 19 g of p-toluenesulfonic acid and 600 ml of toluene was refluxed by heating for 5 hours and the resulting water was removed by azeotropic distillation. After allowing to cool, toluene was distilled from the reaction mixture under a reduced pressure and the residue was dissolved in ethyl acetate. After washing with water, the thyl acetate was distilled off under a reduced pressure to concentrate and the residue was purified by a silica gel chromatography to obtain 28.2 g of 2-(N-hexadecylcarbamoyl)-4-[2-(p-nitrophenyl)ethoxy]-1-naphthol.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:3]=1[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1C=CC(P([C:43]2[CH:48]=[CH:47]C=CC=2)C2C=CC=CC=2)=CC=1.C1(B(O)O)CC1.O.NN.[OH-].[Na+]>C1(C)C=CC=CC=1.O.CCO.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[Cl:21][C:16]1[CH:17]=[C:18]([Cl:20])[CH:19]=[C:2]([CH:47]2[CH2:48][CH2:43]2)[C:3]=1[CH2:4][NH2:5]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1Cc1c(Cl)cc(Cl)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: NN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: NCc1c(Cl)cc(Cl)cc1C1CC1
Temperature: 80 °C
Reaction time: 96 h

Procedure:
To a soln. of 2-(2-bromo-4,6-dichlorobenzyl)isoindoline-1,3-dione (1.96 mmol) in 16 mL toluene and 0.8 mL water were added K3PO4 (6.85 mmol), PPh3 (0.23 mmol), cyclopropylboronic acid (2.35 mmol) and Pd(OAc)2 (0.15 mmol). The mixture was stirred at 80° C. for 24 h when another portion of cyclopropylboronic acid (1.96 mmol) and Pd(OAc)2 (0.15 mmol) were added. The reaction mixture was stirred at 80° C. for further 4 days, cooled to RT, quenched with sat. aq. NaHCO3 solution and extracted with EtOAc. The comb. org. layers were dried over MgSO4 and conc. in vacuo to give a crude white solid. This solid was dissolved in 15 mL EtOH and 12.6 mL of hydrazine monohydrate was added. After stirring at RT for 30 min, EtOAc was added. The aq. phase was basified with 1M NaOH soln. and extracted 3 times with EtOAc. The comb. org. layers were dried over MgSO4 and conc. Purification with CC (KP-NH™ from Biotage) gives the desired compound as red/brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][N:27]2[C:23](=[O:33])[C:24]3=[CH:32][CH:31]=[CH:30][CH:29]=[C:25]3[C:26]2=[O:28])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2CO)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 41.3 %

Procedure:
1-(tert-Butoxycarbonyl)-4-[(2-hydroxymethylphenyl)amino]piperidine (716 mg) was dissolved in tetrahydrofuran (7 ml), added with phthalimide (349 mg), triphenylphosphine (736 mg) and diethyl azodicarboxylate (0.43 ml) and stirred at room temperature for 21 hours. The reaction mixture was added with water (10 ml) and extracted twice with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=4:1) to obtain crude 1-(tert-butoxycarbonyl)-4-[(2-phthalimidylmethylphenyl)amino]piperidine (420 mg).