Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[N:7]([CH:9]([C:13]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21](=[O:30])[C:20]3[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=3)[N:14]=2)[CH:10]([CH3:12])[CH3:11])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]>CN(C=O)C.O>[C:50]([O:49][C:47](=[O:48])[CH2:46][NH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[N:7]([CH:9]([C:13]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21](=[O:30])[C:20]3[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=3)[N:14]=2)[CH:10]([CH3:12])[CH3:11])[CH:8]=1)([CH3:53])([CH3:52])[CH3:51]
Reactant: Cc1ccc(-c2nc(CCN)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2nc(CCNCC(=O)OC(C)(C)C)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Yield: 49.6 %

Procedure:
A solution of 2-{1-[4-(2-Amino-ethyl)-2-p-tolyl-imidazol-1-yl]-2-methyl-propyl}-3-benzyl-7-chloro-3H-quinazolin-4-one (181 mg, 0.343 mmol), potassium carbonate (47 mg., 0.343 mmol), and tert-butyl bromoacetate (67 mg., 0.343 mmol) in DMF (2.0 mL) was stirred at room temperature for 4.5 h. The reaction was diluted with water and the resulting white precipitate was filtered and purified by flash chromatography (silica gel, 95:5 methylene chloride:methanol) to provide the title compound as a white solid (109 mg., 50%). MS(ES+) m/e 640 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].S([O:20][CH2:21][C:22]1([CH:28]=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(C)(=O)=O.C(N(CC)CC)C.Cl>COCCOCCOC>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[S:1][CH2:28][C:22]1([CH:21]=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccccc1S
Reactant: CS(=O)(=O)OCC1(C=O)CCCCC1
Agent: Cl
Solvent: COCCOCCOC
Solvent: CCN(CC)CC
Product: O=CC1(CSc2ccccc2C(=O)c2ccccc2)CCCCC1
Yield: 18.1 %

Procedure:
A mixture of 69 g (0.303 mole) of 2-mercaptobenzophenone, 82 g (0.303 mole) of mesylate 55, 32 g of triethylamine, and 150 ml of diglyme was stirred and held at reflux for 24 h. The mixture was cooled, poured into dil. HCl and extracted with methylene chloride. The organic layer was washed with 10% NaOH, water, brine, and dried over sodium sulfate and concentrated under vacuum to remove excess diglyme. This was purified by silica gel flush column (5% EtOAc:Hexane) and gave 18.6 g (75.9%) of yellow oil. Proton NMR and mass spectra were consistent with the product.
Reaction SMILES: N#N.[CH3:3][S:4]([C:7]1[O:11][C:10]([CH2:12]O)=[CH:9][CH:8]=1)(=[O:6])=[O:5].CCN(CC)CC.S([Cl:25])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:25][CH2:12][C:10]1[O:11][C:7]([S:4]([CH3:3])(=[O:6])=[O:5])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1ccc(CO)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CCl)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.5 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (5-methanesulfonyl-furan-2-yl)-methanol (692 mg, 3.93 mmol) in dry CH2Cl2 (7.0 mL) was treated at 0° C. with Et3N (0.71 mL, 5.11 mmol) followed by DMAP (50 mg, 0.39 mmol) and Ms-Cl (0.37 mL, 4.71 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give 868 mg of crude 2-chloromethyl-5-methanesulfonyl-furan as a yellow oil. 150 mg of this crude material in acetone (2.0 mL) was added, under inert atmosphere (N2) to a solution of 4-nitro-1H-pyrazole (87 mg, 0.77 mmol) in acetone (2.0 mL). K2CO3 (320 mg, 2.13 mmol) followed by TBA bromide (50 mg, 0.15 mmol) were added and the reaction mixture was stirred at rt overnight. Water (10 mL) and EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (40:60 hept-EA) gave the title compound as a yellow oil. TLC: rf (40:60 hept-EA)=0.27. LC-MS-conditions 02: tR=0.82 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17](OCC)=[O:18])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1.[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([CH2:17][OH:18])[CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1
Reactant: CCOC(=O)C1(CCCCl)CC=CCC1c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: OCC1(CCCCl)CC=CCC1c1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
Ethyl 1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-carboxylate (8.65 g, 29.4 mmol) dissolved in toluene (200 ml) was added dropwise to a 1.0M stock solution of diisobutylaluminum hydride (DIBAL, 2.2 equiv., 64.6 ml). The contents were stirred for 16 hrs. under N2 at ambient temperature. The reaction was then chilled to 0° C. and water (100 ml) added. The resulting precipitate was filtered off and the filtrate was dried over MgSO4, filtered, and concentrated in vacuo to afford 7.21 g (92% yield) of 1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-methanol as a clear mobile oil. Infrared spectroscopy indicated the disappearance of an ester carbonyl band and the appearance of hydroxyl stretching between 3200-3400 cm-1. To this alcohol (27 mmol) dissolved in acetone (100 ml) and cooled to 0° C. was added Jones reagent (2.67M, 2.0 equiv., 20.3 ml). The contents were stirred for 2 hr. at which time isopropyl alcohol (20 ml) was added to quench unreacted Jones reagent. The solution was concentrated in vacuo. The residue was washed with water and extracted three times with 100 ml of ethyl ether. The combined organic extracts were dried over MgSO4, filtered through celite and concentrated in vacuo to afford 1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-carboxylic acid (4.95 g, 87% yield) as a clear viscous oil. Infrared spectroscopy indicated the appearance of the carboxyl stretch at 1700 cm-1.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10](OC)(OC)OC>>[CH3:10][O:9][C:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC(OC)OC
Reactant: O=C1CCCCCCC1
Product: COC1=CCCCCCC1
Yield: 75.2 %

Procedure:
In the presence of 0.2 g of paratoluenesulfonic acid, 16.5 g (0.13 mol) of cyclooctanone and 16.5 g (0.15 mol) of trimetyl orthoformate were stirred at room temperature for four hours. The resultant mixture was heated at 100° C. for 14 hours. The vacuum distillation of the mixture gave 13.7 g (75% yield) of 1-methoxycyclooctene having a boiling point of 83° to 88° C./27 mmHg.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C@@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[C@H:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[C@H:15]1[C:36]([OH:38])=[O:37])([OH:3])=[O:2].[OH-].[Na+:40]>C(O)C.O>[Na+:40].[Na+:40].[C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C@@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[C@H:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[C@H:15]1[C:36]([O-:38])=[O:37])([OH:3])=[O:2].[C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C@@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[C@H:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[C@H:15]1[C:36]([O-:38])=[O:37])([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCC(=O)O)[C@H](C(=O)O)[C@H]2c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCC(=O)O)[C@H](C(=O)[O-])[C@H]2c1ccc2c(c1)OCO2
Reaction time: 0.25 h

Procedure:
A solution of (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid in absolute ethanol/water (12 to 1) was titrated to pH=11-12 with 1.25 N sodium hydroxide solution then after stirring for 15 minutes, concentrated to an oil. Absolute ethanol was added and the solution reconcentrated to a solid which was triturated with hexane, and filtered. The solid was dried to constant weight to afford (+) (1S, 2R, 3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid disodium salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CC(C)=O>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2
Reactant: Oc1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: BrCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(-n2ccc3cc(OCCCCCCCBr)ccc32)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
410 mg (1.8 mmol) 1-(4-Fluoro-phenyl)-1H-indol-5-ol in 6 ml acetone were treated with 500 mg (3.6 mmol) powdered K2CO3 and 610 μl (3.6 mmol) 1,7-dibromoheptane. The suspension was stirred at 60° C. overnight, cooled to RT, filtered and concentrated. Column chromatography on silica gel with hexane/EtOAc 49:1 yielded 526 mg (72%) 5-(7-Bromo-heptyloxy)-1-(4-fluoro-phenyl)-1H-indole as colorless solid, mp 63-65° C., MS: 403 (M, 1Br).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:8][CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Reaction time: 0.25 h

Procedure:
Triethylamine (10 cc) is added with stirring to a solution, cooled to a temperature in the region of 5° C., of 10-(1-hydroxy-2-propyl)-2-phenothiazinecarbonitrile, L series (12.6 g), in methylene chloride (126 cc), a solution of methanesulphonyl chloride (5.6 cc) in methylene chloride (56 cc) is then introduced dropwise during 25 minutes and stirring is continued for 1 hour 15 minutes at a temperature in the region of 10°-15° C. The reaction mixture is washed successively with distilled water (2×100 cc) and with saturated aqueous sodium chloride solution (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 2-(2-Cyano-10-phenothiazinyl)-1-propyl methanesulphonate, L series (16.2 g), is thereby obtained in the form of an orange-colored oil
Reaction SMILES: [C:1]([O:10][C:11]1[C:12]([O:17][CH3:18])=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:19](O)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22].P(Cl)(Cl)(Cl)=O.Cl.[OH-].[Na+]>CN(C)C=O>[CH3:18][O:17][C:12]1[C:11]([O:10][C:1]([C:2]2[C:3]([O:4][C:19]([C:20]3[C:21]([OH:22])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:27])=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:9])=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1O
Reactant: COc1ccccc1OC(=O)c1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccccc1OC(=O)c1ccccc1OC(=O)c1ccccc1O
Yield: 60 %

Procedure:
244 g of guaiacol salicylate (1.0 mole) and 138 g of salicylic acid (1.0 mole) are suspended in 1 liter of dimethylformamide. 80 g of phosphorus oxychloride are added over a period of about one hour to the solution, which is kept heated under agitation to 60°-70° C., and the mixture is maintained at this temperature until hydrochloric acid ceases to be evolved. The homogeneous dense mass, of straw colour, is poured under energetic agitation into 5 liters of a water-ice mixture and the suspension is neutralised slowly with dilute sodium hydroxide. The crystalline white solid which precipitates is filtered off, washed abundantly with water and then crystallised from isopropanol to obtain an overall yield of 60%. The product has a melting point of 85°-86° C.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([C@@H:19]([NH3+:21])[CH3:20])=[N:7]2.Cl[C:23]1[C:24]2[C:31]([S:32][C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[O:40][CH3:41])=[CH:30][N:29]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:25]=2[N:26]=[CH:27][N:28]=1.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[F:39][C:37]1[CH:36]=[CH:35][C:34]([O:40][CH3:41])=[C:33]([S:32][C:31]2[C:24]3[C:23]([NH:21][C@H:19]([C:8]4[N:9]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)[C:10](=[O:12])[C:11]5=[C:3]([CH3:2])[CH:4]=[CH:5][N:6]5[N:7]=4)[CH3:20])=[N:28][CH:27]=[N:26][C:25]=3[N:29]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:48])([CH3:47])[CH3:49])[CH:30]=2)[CH:38]=1
Reactant: COc1ccc(F)cc1Sc1cn(COCC[Si](C)(C)C)c2ncnc(Cl)c12
Reactant: Cc1ccn2nc([C@H](C)[NH3+])n(-c3ccccc3)c(=O)c12
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1Sc1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Temperature: 125 °C
Yield: 72.1 %

Procedure:
(S)-1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethanaminium chloride (39 mg, 0.13 mmol) was treated with 4-chloro-5-((5-fluoro-2-methoxyphenyl)thio)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (56 mg, 0.13 mmol), cesium fluoride (8 mg, 0.05 mmol), N,N-diisopropylethylamine (201 μl, 1.15 mmol) and tert-butanol (0.78 ml) as a solvent according to Preparation 13 but heating the reaction mixture at 125° C. overnight. The residue was purified using SP1® Purification System (0% to 40%, hexane-ethyl acetate) to give 63 mg (73% yield) of the title compound.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.C(O[C:13](=O)[NH:14][C:15]([C:18]1[N:22]([CH3:23])[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[N:20][N:19]=1)([CH3:17])[CH3:16])(C)(C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:21]1[N:22]([CH3:23])[C:18]([C:15]([N:14]2[CH2:2][C:3]3[C:26](=[CH:25][CH:24]=[CH:29][CH:28]=3)[CH2:13]2)([CH3:16])[CH3:17])=[N:19][N:20]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (2 ml) was added to a chloroform (4 ml) solution of tert-Butyl-{1-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methylethyl}carbamate (500 mg), followed by stirring at room temperature for 2 hours. The reaction solution and chloroform were added to an aqueous saturated sodium hydrogen carbonate solution and then the organic layer was separated. Furthermore, the organic layer washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. Potassium carbonate (394 mg) and 1,2-bis(bromomethyl)benzene (376 mg) were added to a DMF (10 ml) solution of the resulting residue, followed by stirring at 60° C. for 14 hours. Distilled water and chloroform were added to the reaction solution and then the organic layer was separated. Furthermore, the organic layer washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by flash chromatography (chloroform:methanol=25:1) to obtain 35 mg of 2-{1-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methylethyl} isoindoline (colorless solid).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[C:16]([F:25])[CH:15]=2)[CH2:11][CH:10]([C:26](O)=[O:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:30]=[C:31]([O:33][CH2:34][CH3:35])[NH2:32]>O1CCOCC1.CN(C=O)C>[CH2:34]([O:33][C:31]1[N:32]=[C:26]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[C:16]([F:25])[CH:15]=3)[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]2)[O:27][N:30]=1)[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(c2ccc(OC(F)(F)F)c(F)c2)C1
Reactant: CCOC(N)=NO
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOc1noc(C2CC(c3ccc(OC(F)(F)F)c(F)c3)CN(C(=O)OC(C)(C)C)C2)n1
Reaction time: 3 h

Procedure:
442 mg (1.09 mmol) of 1-(tert-butoxycarbonyl)-5-[3-fluoro-4-(trifluoromethoxy)phenyl]-piperidine-3-carboxylic acid were dissolved in 11.8 ml of dioxane and 5.9 ml of DMF, heated to 60° C. and admixed with 264 mg (1.63 mmol) of 1,1″-carbonyldiimidazole. The reaction mixture was stirred at this temperature for three hours and then admixed with 170 mg (1.63 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390]. The mixture was left to stir at 50° C. for one hour and thereafter at 115° C. for nine hours. The reaction mixture was concentrated under reduced pressure, taken up in ethyl acetate and washed three times with water. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 387 mg (75% of theory, purity 61%)
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[C:30]1([OH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[K+].[OH-].[Na+]>>[O:36]([C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2cnc3c(Cl)nc4ccccc4c32)CC1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(CCn2cnc3c(Oc4ccccc4)nc4ccccc4c32)CC1
Temperature: 120 °C
Reaction time: 7 h
Yield: 70.7 %

Procedure:
A mixture of 4.46 g of tert-butyl 4-[2-(4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-1-piperidinecarboxylate, 10.1 g of phenol and 1.80 g of potassium hydroxide was stirred at 120° C. for 7 hours. The reaction mixture was adjusted to pH 10 with 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed successively with 10% aqueous sodium hydroxide solution and saturated brine, and dried, and then the solvent was evaporated to give a brown liquid. The resulting brown liquid was purified by silica gel column chromatography using ethyl acetate as an eluting solvent to give 3.59 g of a colorless solid. Recrystallization from a mixture of ethyl acetate and n-hexane gave colorless crystals having the melting point of from 130.5 to 132.5° C.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:30](=[O:32])N)[CH2:10][C@H:11]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:14]([C:23]([O:25]C(C)(C)C)=[O:24])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=[O:37])C>C(O)C.O>[C:19]([O:18][C:16]([N:15]1[C@H:11]([CH2:10][CH:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:30]([OH:37])=[O:32])[CH2:12][CH2:13][C@H:14]1[C:23]([OH:25])=[O:24])=[O:17])([CH3:21])([CH3:22])[CH3:20]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](CC(NCc2ccccc2)C(N)=O)N1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@H](CC(NCc2ccccc2)C(=O)O)CC[C@H]1C(=O)O

Procedure:
2.2 g of di-tert-butyl (2S,5S)-5-(2-benzylamino-2-carbamoylethyl)pyrrolidine-1,2-dicarboxylate were dissolved in 20 ml of ethanol and 5 ml of water. 1.2 g of solid sodium hydroxide were added thereto. The solution was then boiled under reflux for 36 h. For workup, it was cooled to room temperature and neutralized with acetic acid, and the ethanol was removed in vacuo. The residue was diluted with 20 ml of water and adjusted to a pH of 3 with acetic acid. The mixture was extracted 3 times with 30 ml of 5:1 ethyl acetate/butanol each time. The organic phases were combined and concentrated in vacuo. The residue was chromatographed on silica gel.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:11]#[CH:12])=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]>C(O)C.O=[Pt]=O>[C:1]([O:4][C:5]1[C:6]([CH2:11][CH3:12])=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: C#Cc1ncccc1OC(C)=O
Agent: O=[Pt]=O
Solvent: CCO
Product: CCc1ncccc1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 2-ethynylpyridin-3-yl acetate (5.0 g, 31 mmol) in ethanol (50 mL) was added PtO2 (0.50 g, 2.2 mmol). The mixture was degassed with nitrogen and placed under a double-layer balloon of hydrogen. The reaction was stirred at ambient temperature for 30 minutes, then filtered and concentrated in vacuo to give 2-ethylpyridin-3-yl acetate (5.1 g, 31 mmol) which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:27]1>CN(C)C=O>[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([N:35]2[CH2:36][CH2:37][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:39][CH2:40]2)=[N:27]1
Reactant: c1ccc2c(N3CCNCC3)noc2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2noc3ccccc23)CC1
Temperature: 20 °C

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (3.6 g), triethylamine (1.8 cc) and 4(1,2-benzisoxazol-3-yl)piperazine (2.69) in dimethylformamide (200 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on silica gel, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallization from boiling acetonitrile (30 cc), 2-{3-[4-(1,2-benzisoxazol-3-yl) -1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.4 g) is obtained, m.p. 263° C.