Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:4])#[C-:2].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=1[F:24].C([O-])([O-])=O.[K+].[K+].O>CO.[N+](C(S(C1C=CC(C)=CC=1)(=O)=O)C)#[C-]>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[O:21][CH:2]=[N:1][C:3]=2[CH3:4])=[CH:18][C:17]=1[F:24]
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ncoc1-c1ccc(Br)c(F)c1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A mixture of 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1.67 g, 7.97 mmol), 4-bromo-3-fluorobenzaldehyde (1.62 g, 7.97 mmol), and K2CO3 (2.20 g, 15.9 mmol) in MeOH (40 mL) was heated to reflux. After 1.5 hr additional 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (106 mg, 0.51 mmol) was added and the reaction mixture was again heated at reflux for 1.5 hr. The reaction was cooled to ambient temperature, water (200 mL) was added and the product was extracted with EtOAc (200 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (Analogix® SF25-40G column, 0%-30% EtOAc/hexanes, 30 mL/min), which yielded 1.86 g (91%) of the title compound as an orange solid. 1H NMR (300 MHz, CH3OH-d4) δ 8.18 (s, 1H), 7.73 (dd, J=8.4, 7.3 1H), 7.49 (dd, J=9.9, 2.0 1H), 7.41 (dd, J=8.3, 1.8 1H), 2.42 (s, 3H). MS (DCI+) m/z 256/258 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][NH:13][CH3:14].O>C1COCC1>[CH3:12][N:13]([CH3:14])[CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
In THF (250 ml) was dissolved 4-nitrobenzyl bromide (25.0 g), and to the mixture was added 50% dimethylamine solution (29 ml) at 0° C. The reaction mixture was stirred at room temperature for 60 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give dimethyl-4-nitrobenzylamine (20.7 g) as orange oil.
Reaction SMILES: [OH:1][OH:2].[OH-].[Na+].[CH3:5][C:6]1[CH2:11][CH2:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1>CO>[CH3:13][CH:12]([C:9]12[O:2][O:1][C:6]([CH3:5])([CH:11]=[CH:10]1)[CH2:7][CH2:8]2)[CH3:14]
Reactant: OO
Reactant: CC1=CC=C(C(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C12C=CC(C)(CC1)OO2
Reaction time: 3.5 h
Yield: 90 %

Procedure:
At 30° C., 230 μl of H2O2 (50%) and 200 μl of 5M NaOH were successively added to a solution of 325 μl of α-terpinene and 143.6 mg of La(NO3)3.xH2O in 4 ml of methanol, whereupon a white precipitate formed. After 3.5 hours and after 21 hours, two further 230 μl portions of H2O2 (50%) were added to the mixture. After 24.5 hours, the reaction mixture was centrifuged, and the solution was decanted from the catalyst. The solvent was evaporated and the residue was dissolved in CDCl3 and analyzed using NMR. The reaction mixture was also analyzed by means of HPLC (MeOH/H2O 90/10; 260 nm). The analyses gave a conversion of 10% and a yield of >90% of ascaridol.
Reaction SMILES: O[C@H:2]1[C@H:6]([CH:7]=[CH2:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C(N(CC)C(C)C)(C)C.F.F.F.C(N(CC)CC)C.[F:38]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F>C1(C(F)(F)F)C=CC=CC=1>[F:38][C@@H:2]1[C@H:6]([CH:7]=[CH2:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1
Reactant: C=C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Solvent: CCN(C(C)C)C(C)C
Solvent: FC(F)(F)c1ccccc1
Solvent: CCN(CC)CC
Product: C=C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of (3S,4R)-benzyl 3-hydroxy-4-vinylpyrrolidine-1-carboxylate (5.0 g, 20.2 mmol) in PhCF3 (81 mL, 0.25 M solution) was added N,N-diisopropylethylamine (53 mL, 303 mmol), triethylamine trihydrofluoride (19.8 mL, 121 mmol) and perfluoro-1-butanesulfonyl fluoride (PBSF, 3.6 mL, 20.2 mmol). The resulting mixture was stirred at room temperature. After 60 and 120 minutes, additional perfluoro-1-butanesulfonyl fluoride (3.6 mL, 20.2 mmol) was added. After 18 hours, the reaction mixture was transferred to a separatory funnel and was washed twice with 50 mL of 1.0 N HCl (Caution! lots of heat produced), twice with saturated NaHCO3 aqueous solution, and once with H2O and brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to provide a crude brown oil. The pure (3R,4R)-benzyl 3-fluoro-4-vinylpyrrolidine-1-carboxylate was obtained in 81% yield (4.1 g) as a yellow oil by flash column chromatography. 1H NMR (CDCl3, 400 MHz): δ 7.37-7.25 (5H, m), 5.9 (1H, m), 5.24 (2H, m), 5.14 (2H, m), 5.03 (1H, m), 3.9-3.5 (3H, m), 3.53 (1H, m), 2.83 (1H, m). LC/MS (uplc): MH+ 250.0, 0.93 min.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[O:11][CH:10]=[C:9]([C:19](O)=[O:20])[C:8]2=[O:22])(=[O:3])[CH3:2].C1C=CC=CC=1.S(Cl)([Cl:31])=O>CN(C)C=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[O:11][CH:10]=[C:9]([C:19]([Cl:31])=[O:20])[C:8]2=[O:22])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)Oc1cc2occ(C(=O)Cl)c(=O)c2cc1OC(C)=O

Procedure:
A mixture of 6,7-Diacetoxychromone-3-carboxylic acid (918 mg, 3 mmol), benzene (20 ml), thionyl chloride (260 μl, 3.6 mmol) and N,N-dimethylformamide (0.2 ml) was refluxed for 2 hours and the solvent was removed. Benzene (5 ml) was added and then evaporated. This was repeated twice to remove traces of thionyl chloride. The residual solid was collected to afford the desired compound.
Reaction SMILES: C(ON=O)(C)(C)C.[O:8]1[CH2:12][CH2:11][C:10]([C:13]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=2N)=[N:9]1.[CH3:21][S:22]SC>[Cu]>[CH3:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:14]([S:22][CH3:21])[C:13]=1[C:10]1[CH2:11][CH2:12][O:8][N:9]=1
Reactant: CSSC
Reactant: Cc1cccc(N)c1C1=NOCC1
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: CSc1cccc(C)c1C1=NOCC1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
19.5 g (170 mmol) of tert-butylnitrite and 20 g of copper powder are initially charged in 30 ml of dimethyl disulfide, and a solution of 20 g (114 mmol) of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline in 100 ml of dimethyl disulfide is added dropwise at from 50 to 55° C. The mixture is subsequently stirred at 60° C. for 1.5 hours. For work-up, the solid is filtered off with suction, and the filtrate is diluted with methylene chloride and extracted with dilute hydrochloric acid. The organic phase is washed with saturated aqueous NaHCO3 solution and dried over sodium sulfate, the drying agent is filtered off and the filtrate is concentrated. Excess dimethyl disulfide is removed under oil pump vacuum.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].I[CH3:14]>C1COCC1>[CH3:14][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: CI
Reactant: Cc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc2c1ccn2C
Temperature: 0 °C
Reaction time: 0.27 h

Procedure:
To a solution of 4-methyl-1H-indole (CAS#16096-32-5, 2.82 mL, 22.9 mmol) in THF (100 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 1.37 g, 34.3 mmol). The reaction was permitted to stir for 16 minutes at 0° C. and was then warmed to room temperature for 60 minutes. The reaction mixture was then re-cooled to 0° C. and iodomethane (1.86 mL, 29.7 mmol) was added. The reaction was then put at room temperature and permitted to stir for 45 minutes. The reaction was then quenched with saturated aqueous ammonium chloride and concentrated to approximately half of its original volume. The mixture was then diluted with water and dichloromethane and the layers were separated. The aqueous layer was then extracted two additional times with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane 0 to 30%) to afford 1,4-dimethyl-1H-indole; 1H NMR (400 MHz, CDCl3) δ ppm 2.57 (s, 3H), 3.80 (s 3H), 6.51 (d, J=3.0 Hz, 1H), 6.93 (d, J=6.7 Hz, 1H), 7.06 (d, J=3.0 Hz, 1H), 7.13-7.21 (m, 2H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].O=S(Cl)Cl.[CH3:15]O>>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:15])=[O:9]
Reactant: CO
Reactant: O=C(O)c1ccccc1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccccc1O
Temperature: 25 °C

Procedure:
To a ice cold solution of salicylic acid (10 g, 0.072 mol) in methanol (100 mL), was added drop wise SOCl2 (12.8 g, 0.1 mol). After the addition, the mixture was warmed to room temperature and heated to reflux for 12 h. After reaction is completed the reaction mixture was cooled to room temperature and the excess methanol was evaporated under reduced pressure to obtain 9 g of methyl 2-hydroxybenzoate as a white solid. (81%). A solution of methyl 2-hydroxybenzoate (9 g, 0.059 mol) in glacial acetic acid (90 mL) was cooled to 15° C., fuming nitric acid (11.2 mL) was added drop wise. The reaction mixture was warmed to room temperature and stirred for 4 h. When the reaction is completed, the reaction mixture was poured into crushed ice. The precipitate was collected by filtration and washed several times with chilled water, then dried in a vacuum oven to the required product as a yellow coloured solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:12]O>>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(O)c1ccccc1O
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccccc1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxybenzoic acid (110 g, 796 mmol) in MeOH (400 mL) was bubbled HCl (gas) for 1 h. The resulting mixture was stirred at 50° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude methyl 2-hydroxybenzoate that was used directly without further purification.
Reaction SMILES: [S:1]([Cl:5])(=O)(=[O:3])[OH:2].S(=O)(=O)(O)O.[C:11]([OH:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.S(Cl)(Cl)=O>S(=O)(=O)(O)N>[Cl:5][S:1]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[C:11]([OH:19])=[O:18])(=[O:3])=[O:2]
Reactant: O=C(O)c1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Agent: NS(=O)(=O)O
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
349.5 g=199.7 ml (3.0 mol) of chlorosulfuric acid and 20.0 g of 96% strength sulfuric acid are placed in a 2 l four-neck flask fitted with stirrer, internal thermometer, reflux condenser with gas outlet and dropping-funnel, at 25° C., and 1.0 g of sulfamic acid is added. Subsequently 122.1 g (1.0 mol) of benzoic acid are introduced into this mixture. The reaction mixture is heated to 120° C. over 3 hours and stirred further until evolution of HCl has ended (about 30 minutes). Then it is cooled to 70° C. and 119.0 g (1.0 mol) of thionyl chloride are added dropwise over 2 hours. The reaction solution is then heated to 80° C. and stirred further for about 30 minutes until gas evolution has ended. The mixture is added dropwise to 1000 g of ice-water at 10° C. over 2 hours. The precipitated product is filtered off with suction and washed with 500 g of ice-water. 321.2 g of crude 3-(chlorosulfonyl)benzoic acid (water content: 33.9%; chlorine: 10.8%) are obtained, corresponding to 212.3 g (0.96 mol) of 100% 3-(chlorosulfonyl)benzoic acid. 1115 g of mother liquor and 538 g of wash-water are produced.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18](=[O:24])[N:19]([CH2:21][CH2:22][OH:23])[CH3:20])([CH3:16])([CH3:15])[CH3:14].O[N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:13]([O:17][C:18](=[O:24])[N:19]([CH2:21][CH2:22][O:23][N:26]1[C:30](=[O:31])[C:29]2[C:28](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]1=[O:36])[CH3:20])([CH3:16])([CH3:14])[CH3:15]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCON1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 98.7 %

Procedure:
Diethylazodicarboxylate was added dropwise over 45 min to a stirring solution of (2-hydroxy-ethyl)-methyl-carbamic acid tert-butyl ester (7.10 g, 40.5 mmol), N-hydroxyphthalimide (7.17 g, 44.0 mmol) and triphenylphosphine (11.5 g, 43.8 mmol) in tetrahydrofuran (150 mL). The resultant reaction mixture was stirred 22 h at ambient temperature and was concentrated in vacuo to a thick oil. Chloroform (200 mL) was added and the resultant solution was chilled to affect crystallization of diethyl 1,2-hydrazaine dicarboxylate. The precipitate was filtered and the filtrate was concentrated and further diluted with hexanes. A single crystal of triphenylphosphine oxide was added. The resultant crystals of triphenylphoshine oxide were removed by filtration and the filtrate was concentrated in vacuo and chromatographed on silica gel to afford [2-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (12.8 g, 98% yield) as a colorless oil: 1H NMR (400 MHz, DMSO-d6) δ 7.86 (bs, 4 H), 8.55 (bs, H), 4.24 (t, J=5.5 Hz, 2 H), 3.50 br t, J=5.4 Hz, 2 H), 2.92 and 2.88 (br s, 3 H), 1.39 and 1.36 (br s, 9 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:11][C@H:10]([OH:12])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][NH:20]2)=[CH:16][C:15]=1B1OCC(C)(C)CO1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][NH:20]2)=[CH:16][C:15]=1[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:11][C@H:10]([OH:12])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: O[C@H]1C[C@H](c2ccc(Br)cc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc([C@H]4C[C@H](O)C4)cc3)cc12
Temperature: 110 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a solution of trans-3-(4-bromophenyl)cyclobutanol (200 mg, 0.88 mmol) in toluene/ethanol (4 mL, v/v=1/1) was added methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (296 mg, 0.968 mmol), potassium carbonate (360 mg, 2.64 mmol), water (1 mL) and Pd(dppf)Cl2 (46 mg, 0.06 mmol) under nitrogen. The mixture was stirred at 110° C. for 2 hours. The mixture was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by silica gel combiflash to give the title compound (190 mg, 61%) as a light yellow solid. 1H NMR (500 MHz, CD3OD) δ 8.02 (s, 1H), 8.01 (s, 1H), 7.60 (s, 1H), 7.40-7.35 (m, 4H), 4.52 (m, 1H), 3.88 (s, 3H), 3.66 (m, 1H), 2.57-2.44 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][C@@:8]1([C:24]([O:26]CC2C=CC(OC)=CC=2)=[O:25])[C@H:12]([CH3:13])[CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6](=[O:36])[CH2:7][C@@:8]1([C:24]([OH:26])=[O:25])[C@H:12]([CH3:13])[CH2:11][NH:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(COC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@H]2C)cc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CNC[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Reaction time: 8 h
Yield: 95.3 %

Procedure:
Methanol (3 ml) and 10% Pd/C (30 mg) were added to 1-benzyl 3-(4-methoxyphenyl)methyl (3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-1,3-dicarboxylate which is obtained in Example 4d and which is without silica gel column chromatography purification (104 mg, 0.21 mmol), followed by stirring at mom temperature overnight under a hydrogen atmosphere. Water was added to the reaction liquid, which was stirred and filtered. The filtrate was concentrated to give the title compound (48.7 mg, yield: 95.3%).
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:38])[CH2:9][C@@:10]1([C:26]([O:28]CC2C=CC(OC)=CC=2)=[O:27])[C@H:14]([CH3:15])[CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11]1)([CH3:6])([CH3:5])[CH3:4]>[Pd].O>[C:3]([O:7][C:8](=[O:38])[CH2:9][C@@:10]1([C:26]([OH:28])=[O:27])[C@H:14]([CH3:15])[CH2:13][NH:12][CH2:11]1)([CH3:4])([CH3:5])[CH3:6]
Reactant: COc1ccc(COC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@H]2C)cc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: C[C@@H]1CNC[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Reaction time: 72 h
Yield: 71.3 %

Procedure:
Methanol (70 ml) and 10% Pd/C (600 mg) were added to 1-benzyl 3-(4-methoxyphenyl)methyl (3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-1,3-dicarboxylate obtained by the method of Example 4e (3.3 g, 6.63 mmol), followed by stirring at mom temperature for three days under a hydrogen atmosphere. Water (70 ml) was added to the reaction liquid, which was stirred and filtered. The filtrate was concentrated to give the title compound (1.15 g, yield: 71.3%).
Reaction SMILES: BrC1C=CC(N2CCN(S(CC(C(C)C)C(O)=O)(=O)=O)CC2)=CC=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[CH:33][CH:32]=2)[CH:26]=1.[CH3:43][O:44][C:45]([C:47]1([CH2:53][S:54](Cl)(=[O:56])=[O:55])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)=[O:46]>>[CH3:43][O:44][C:45]([C:47]1([CH2:53][S:54]([N:40]2[CH2:41][CH2:42][N:37]([C:34]3[CH:33]=[CH:32][C:31]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)=[CH:36][CH:35]=3)[CH2:38][CH2:39]2)(=[O:56])=[O:55])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)=[O:46]
Reactant: COC(=O)C1(CS(=O)(=O)Cl)CCOCC1
Reactant: c1cncc(-c2ccc(N3CCNCC3)cc2)c1
Agent: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)O
Product: COC(=O)C1(CS(=O)(=O)N2CCN(c3ccc(-c4cccnc4)cc3)CC2)CCOCC1
Yield: 55 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-bromophenyl)piperazine-1-sulfonylmethyl]-3-methyl-butyric acid tert-buryl ester, from 1-(4-pyridin-3-yl-phenyl)piperazine (0.18 g) and 4-chlorosulfonylmethyl tetrahydropyran-4-carboxylic acid methyl ester (0.23 g), to yield the title compound as a white solid (0.19 g, 55%).
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.C(OCCN(C1C=CC(C([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:28][CH2:27]2)=O)=CC=1)C(=O)CCl)(C)C.C1([S-])C=CC=CC=1.[Na+]>C(O)C>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][N:29]2[CH2:28][CH2:27][NH:26][CH2:31][CH2:30]2)=[CH:35][CH:36]=1
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [S-]c1ccccc1
Solvent: CCO
Product: Clc1ccc(CCN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 g of 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine (Example 3) are dissolved in 50 ml of absolute ethanol, and 1.471 g of sodium thiophenolate are added. The mixture is stirred for one hour at room temperature and a further 1 g of sodium thiophenolate is added. The mixture is stirred for a further 3 hours at RT and then the reaction solution is concentrated by evaporation. The oily residue is extracted with ether and the ethereal phases are washed in succession with water, soda solution and water a concentrated by evaporation, and the light-yellow oil is crystallised from ether and hexane, yielding 1-{4-[N-(2-isopropyloxyethyl)-N-phenylmercaptoacetylamino]benzoyl{-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 47°-49°.
Reaction SMILES: [C:1]1([C:7]([CH3:18])([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C)(C)C.N.[H][H]>[Ru].[Pd].O>[C:1]1([C:7]([CH3:18])([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(CCCC#N)(CCCC#N)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Ru]
Agent: N
Solvent: CC(C)(C)O
Solvent: O
Product: CC(CCCCN)(CCCCN)c1ccccc1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
A one liter autoclave was charged with 50 g 0.21 mol of a dinitrile consisting essentially of 5-phenyl-5-methylnonanedinitrile. Also charged to the reactor was 300 mL 237 g t-butyl alcohol, 25 ml water, 5 g of 5 percent by weight ruthenium on alumina, and 2 g of 5 percent by weight palladium on alumina. The reactor was flushed with nitrogen and charged with 70 g 4.1 mol of ammonia. The reactor was pressured to 1200 psig with hydrogen and heated with stirring at 170° C. for two hours. Hydrogen uptake indicated only reduction of nitrile groups to amino groups had taken place thus producing the aralkylenediamine, 5phenyl-5methyl-1,9-nonanediamine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3][C:4]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: Sc1ccccc1
Product: O=C(O)CNC(=O)c1nc(Sc2ccccc2)c2ccccc2c1O
Temperature: 140 °C

Procedure:
The title compound was prepared as follows: To a solution of 250 mg of [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid, (U.S. Pat. No. 6,093,730, disclosed as N-((1-chloro-4-hydroxyisoquinoline-3-yl)carbonyl)glycine), in 1 ml 1-methyl-2-pryrrolidinone was added 1.2 ml of benzenethiol. The solution was heated at 130 to 150° C. in a sealed tube for 16 h. The solution was concentrated under vacuum. The resultant residue was crystallized from methanol to yield 91 mg of a tan solid; MS (−) m/z 353.07 (M−1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][C:16]=1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC>CS(C)=O.CO.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:5][C:6](=[O:7])[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:16]([CH3:22])[CH:17]=1
Reactant: Cc1cc(I)ccc1OCC1CCCN1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)OC(C)(C)C)c(C)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 111.7 %

Procedure:
To a stirred solution of 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-1-iodo-3-methylbenzene (645.3 mg, 1.546 mmol) in DMSO (7 mL) and MeOH (6 mL) was added Et3N (0.47 mL, 3.401 mmol), Pd(OAc)2 (17.4 mg, 0.077 mmol) and 1,3-bis(diphenylphosphino) propane (31.46 mg, 0.077 mmol). To the stirred mixture was induced CO gas for 10 min. The mixture was stirred at 70° C. for 2 days and concentrated. The residue was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure, and the residue was chromatographed on silica-gel with n-hexane-EtOAc (5:1, v/v) as eluent to afford 301.6 mg (56%) methyl-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-methylbenzoate as an oil. 1H-NMR (400 MHz, CDCl3) δ1.47 (s, 9H), 1.86-2.10 (br m, 4H), 2.33 (s, 3H), 3.32-3.50 (br m, 2H), 3.88 (s, 3H), 3.88, 4.04 (br m each, 1H), 4.13-4.20 (m, 2H), 6.89 (br m, 1H), 7.82 (s, 1H), 7.85 (dd, J=2.0, 8.8 Hz, 1H); MS (FAB) m/z 350 (M++1).