Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][O:12]CN.C1(N=C=[N:23][CH:24]2CCCCC2)CCCCC1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:11][O:12][N:23]([CH3:24])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[OH:1]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COCN
Reactant: O=C(O)c1cccnc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)c1cccnc1O
Yield: 83.1 %

Procedure:
2-Hydroxynicotinic acid (2.00 g, 14.4 mmol) and methoxymethylamine (2.80 g, 28.8 mmol) were dissolved in methylene chloride (70 mL). The resultant mixture was added with dicyclohexylcarbodiimide (5.90 g, 28.8 mmol), triethylamine (4.00 mL), and 4-N,N-dimethylaminopyridine (176 mg, 1.44 mmol) at 0° C. The resultant mixture was stirred at room temperature overnight. Then the reaction solution was added with a small amount of water and concentrated in vacuo. Ethyl acetate was added and the generated crystal was filtered. Ethyl acetate was further added and the generated crystal was filtered in the same manner. The obtained residue was purified using silica-gel column chromatography (n-hexane/ethyl acetate=1/1) and N-methoxy-N-methyl-2-hydroxynicotinamide (2.18 g, yield 84%) was obtained as a colorless solid.
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:24])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.Cl.[CH3:34][S:35](Cl)(=[O:37])=[O:36].CCN(C(C)C)C(C)C>CO>[F:1][C:2]1[C:3]([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:7][CH2:6]2)=[CH:18][CH:19]=[CH:20][C:21]=1[NH:22][C:23]([NH:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)=[O:24]
Reactant: Cc1ccc(NC(=O)Nc2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2F)cn1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)Nc2cccc(CN3CCN(S(C)(=O)=O)CC3)c2F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
To a solution of tert-butyl 4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate (1.3 g, 2.9 mmol, 1.0 equiv) in MeOH (10 mL) was added by syringe HCl (4.0 M in dioxane, 10 mL, 40 mmol, 13.8 equiv) After 30 minutes, the reaction mixture was concentrated in vacuo. The resulting solid was then suspended in THF (10 mL) and methanesulfonyl chloride (220 μL, 2.9 mmol, 1.0 equiv) and DIPEA (2.0 mL, 11.5 mmol, 4.0 equiv) were added by syringe. The reaction mixture was allowed to stir at room temperature for 0.5 h and then quenched by the addition of aq. satd. NaHCO3. The organic layer was separated, dried over sodium sulfate and purified by flash chromatography on silica gel (1%-10% MeOH/DCM) to provide 1-(2-fluoro-3-((4-(methylsulfonyl)piperazin-1-yl)methyl)phenyl)-3-(6-methylpyridin-3-yl)urea (930 mg, 76%). LCMS m/z (APCI)=422.2 (M+H).
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)[C:19](Cl)=[O:20].[NH2:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>ClCCl.CN(C)C=O.C(=O)(O)[O-].[Na+].O1CCCC1>[O:20]=[C:19]([NH:24][CH:25]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:33]([OH:35])=[O:34])[CH2:11][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(CC(c1ccccc1)c1ccccc1)NC(Cc1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a magnetically stirred suspension of 5.00 g (22.1 mmol) of diphenylpropionic acid in 25 ml of dry dichloromethane under nitrogen was added 2.12 ml (24.3 mmol) of oxalyl chloride followed by two drops of dimethylformamide. After stirring for one hour, the solution was rotary evaporated and the residue placed under high vacuum to further remove any remaining volatiles. The resulting yellow oil was added to a solution of 3.65 g (22.1 mmol) of racemic phenylalanine in 50 ml of saturated aqueous sodium bicarbonate and 10 ml of tetrahydrofuran. The mixture was allowed to stir for three hours while maintaining the pH at 8. The mixture was then acidified to pH 2 with concentrated hydrochloric acid and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with 10% aqueous hydrochloric acid, water, brine, dried over magnesium sulfate, filtered and rotary evaporated. Recrystallization of the residue from toluene gave 4.60 g of the title compound as an off-white solid, melting point 138°-140° C.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C>C1C=CC=CC=1>[F:13][C:10]1[CH:9]=[CH:8][C:7]2[O:6][CH:5]=[CH:4][C:12]=2[CH:11]=1
Reactant: CCOC(COc1ccc(F)cc1)OCC
Solvent: c1ccccc1
Product: Fc1ccc2occc2c1
Temperature: 25 °C

Procedure:
To a mixture of benzene (200 mL) containing polyphosphoric acid (80 g, 236.69 mmol) was added 2-(4-fluoro-phenoxy)-acetaldehyde diethyl acetal (45 g, 197.37 mmol). The mixture was stirred vigorously while being heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature and decanted from the polyphosphoric acid. The solvent was removed under vacuum to give the residue, which was purified by a silica gel column (1% ethyl acetate in petroleum ether) to afford 5-fluorobenzofuran as colorless oil (14.0 g, crude).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[N:5]1([CH2:4][CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCCCn1ccc2ccccc21
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCn3ccc4ccccc43)CC2)c1

Procedure:
Prepared by Procedure AH and Scheme P using 1-(3-chloropropyl)-1H-indole and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 404.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:12])=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([Cl:21])[C:3]=1[OH:22].[N+]([O-])(O)=[O:24].O>C(O)(=O)C>[Cl:21][C:4]1[C:3](=[O:22])[C:2](=[O:24])[C:7]2[C:8]([C:11](=[O:12])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:9][O:10][C:6]=2[CH:5]=1
Reactant: COc1ccc(C(=O)c2coc3cc(Cl)c(O)c(Cl)c23)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)c2coc3c2C(=O)C(=O)C(Cl)=C3)cc1
Temperature: 60 °C

Procedure:
To a suspension of compound 10d (100 mg, 0.29 mmol) in glacial acetic acid (1.5 mL) at room temperature was added nitric acid (0.1 mL, d 1.35) dropwise with vigorous stirring. The mixture was heated at 60° C. for 30 min, allowed to cool to room temperature, and poured into cold water. The resulting precipitate was filtered and recrystallized (CH2Cl2-pet. ether) to furnish compound SKC-BF-04 (50 mg, 53%) as a red solid. TLC Rf=0.4 (petroleum ether-EtOAc, 7:3); 1H NMR (CDCl3) δ 7.86-7.80 (m, 3H), 7.54 (s, 1H), 6.95 (d, J=9.0 Hz, 2H), 3.88 (s, 3H); MS (ES) m/z 317 (M+H)+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=[O:16].[Na+]>S(=O)(=O)(O)O.O>[OH:16][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(C2CCC(=O)CC2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1CCC(c2ccc(O)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
200 ml of 4 N sulfuric acid were heated to 80° C. in a sulfonation flask and then treated with about 5% of a solution of 37.9 g of 4-(4-aminophenyl)cyclohexanone in 200 ml of 4 N sulfuric acid. Subsequently, the remaining solution of 4-(4-aminophenyl)cyclohexanone as well as a solution of 15.2 g of sodium nitrite in 45 ml of water were simultaneously added dropwise to the reaction mixture at 80° C. within 1.5 hours. Thereafter, the mixture was treated dropwise at 80° C. within 30 minutes with a solution of 9 g of sodium nitrite in 27 ml of water and stirred at 80° C. for a further 1 hour. After cooling the reaction mixture to 0° C. the separated crystals were removed by filtration under suction, washed with 200 ml of cold water and dried up to constant weight at 60° C. in a drying oven under a water-jet vacuum. The crystalline crude product (34.6 g) was suspended in 520 ml of ethyl acetate. The suspension was heated to reflux for 1 hour, then treated with 1.7 g of active carbon and then heated to reflux for a further 1 hour. The mixture was subsequently suction filtered (rinsing with 40 ml of warm ethyl acetate) and the filtrate was evaporated under a water-jet vacuum at a bath temperature of 40° C. Drying of the evaporation residue up to constant weight at 60° C. in a drying oven under a water-jet vacuum gave 32.2 g of 4-(4-hydroxyphenyl)cyclohexanone as yellow-brown crystals with m.p. 165°-166° C.
Reaction SMILES: [SH:1][CH:2]1[N:5]([C:6](=[C:20]([OH:23])[CH2:21]Br)[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C:4](=[O:24])[CH:3]1[NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.CO>[OH:23][C:20]1[CH2:21][S:1][C@@H:2]2[CH:3]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4](=[O:24])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1S
Solvent: CO
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of p-nitrobenzyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)-acetate (70 mg) prepared by the method of Example 4.--III(2) in a mixture of methylene chloride (2 ml) and methanol (2ml) is stirred for 3 hours at room temperature. The reaction mixture is poured into ice water, and is extracted with methylene chloride. The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give p-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (42 mg), identical with the product of Example 4(3). Yield: 70%.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][O:8][CH3:9])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:9][O:8][CH2:7][C:5]1[O:6][C:2]([C:19]2[CH:18]=[N:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=2)=[CH:3][C:4]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COc1ccc(B(O)O)cn1
Reactant: COCc1oc(Br)cc1C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COCc1oc(-c2ccc(OC)nc2)cc1C(=O)OC
Yield: 83.8 %

Procedure:
A mixture of methyl 5-bromo-2-(methoxymethyl)furan-3-carboxylate (3.0 g), 2-methoxy-5-pyridineboronic acid (2.1 g), tetrakis(triphenylphosphine)palladium(0) (0.7 g), 2N aqueous sodium carbonate solution (14 mL) and 1,2-dimethoxyethane (30 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 25% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.8 g, 84%) as a white crystal.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:13])[CH:3]=1.C(N(CC)CC)C.[CH2:21]([S:25](Cl)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]>ClCCl>[CH2:21]([S:25]([O:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:13])[CH:3]=1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]
Reactant: Cn1cc(O)c(=O)c2ccccc21
Reactant: CCCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)Oc1cn(C)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxy-1-methyl-4-quinolone (3 g) was suspended in dichloromethane (200 ml), triethylamine (5.6 ml) was added to the suspension and the mixture was stirred at ambient temperature for hour. 1 -Butanesulphonyl chloride (2.6 ml) was added to the suspension, the mixture stirred for 90 minutes and then left to stand overnight. The resultant mixture was washed with water (400 ml), aqueous sodium hydroxide (1M, 400 ml) and then further water (3×300 ml). The dichloromethane layer was dried over magnesium sulphate and evaporated to give a solid which was crystallised from methanol (100 ml) to give the novel compound 1-methyl-4-oxo-1,4-dihydroquinol-3-yl 1-butanesulphonate, m.p. 143°-144°.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br>C(OCC)(=O)C.CN(C=O)C>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:2]1[C:1]([NH:5][C:4](=[O:6])[CH:3]=1)=[O:7]
Reactant: BrCCCCCBr
Reactant: O=C1C=CC(=O)N1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1C=C(CCCCCBr)C(=O)N1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
12 g (0.124 mole) maleimide were dissolved in 60 ml ethyl acetate and 22.4 g (0.33 mole) distilled furane were added over 10 minutes, whereupon the mixture became slightly warm, and the batch was stirred for 25 hours at room temperature. The precipitate was subsequently filtered off under suction and was dried under vacuum at room temperature. Yield: 10.5 g=51.3% theoretical. The substance was pure as determined by GC and its IR, NMR and mass spectra corresponded to the desired 7-oxabicycloheptene-1,2-dicarboxylic acid imide. 10 g (0.06 mole) of this imide were is dissolved in 300 ml distilled DMF, an amount of KI which covered the tip of a spatula was added, and 8.1 g (0.072 mole) K-tert-butylate were added under N2. After 2 hours 69.6 g (0.303 g) 1,5-dibromopentane in 100 ml DMF were added drop-wise over 7 hours with stirring and at room temperature. The batch was subsequently stirred for 50 hours at room temperature. The DMF solution was filtered from the precipitated KBr and the DMF was substantially removed by distillation in a rotary evaporator under vacuum. The liquid residue was distilled in a microdistillation apparatus under a vacuum of 1×10−3 mbar, whereupon at a boiling temperature of 50-55° C. it was solely the excess 1,5-dibromopentane which distilled over. The temperature of the oil bath was then slowly raised to 140° C. After a preliminary flow of 2.3 g, 5.5 g product distilled over at a boiling temperature of 113° C./3×103 mbar. This product was pure as determined by G C, and its IR, NMR and mass spectra corresponded to the desired 5-bromopentylmaleimide. Yield: 5.5 g=37.4%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[N:11]#[C:12][NH2:13].O1CCOCC1.[ClH:20]>CCOCC>[ClH:20].[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12](=[NH:11])[NH2:13])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: N#CN
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(C(=N)N)c1
Temperature: 100 °C
Yield: 93 %

Procedure:
To a solution of 1H-pyrazole-4-carboxylic acid ethyl ester (5.00 g, 35.7 mmol), cyanamide (1.50 g, 35.7 mmol), and dioxane (25 mL) was added a solution of 4M HCl in dioxane (9.80 mL, 39.3 mmol). The reaction mixture was heated to 100° C. for 3 h. The reaction was cooled to 23° C. and Et2O (20 mL) was added. The resulting white precipitate was filtered to yield the titled compound (7.26 g, 93%). 1H NMR (400 MHz, DMSO-d6): 9.65 (br m, 4H), 9.29 (s, 1H), 8.43 (s, 1H), 4.31 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([NH:9][C:10]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[CH:7][CH:6]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([CH:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[O:11])=[CH:18][CH:19]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=C(Nc1ccc(OCCO)cc1)C1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(NC(=O)C3CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.4 %

Procedure:
4′-(2-Hydroxyethoxy)-3,4,5,6-tetrahydro-2H-pyran-4-carboxanilide (5.7 g) solution in pyridine (50 ml) was added with p-toluenesulfonylchloride (4.92 g). The mixture was stirred for 6 hours at room temperature and allowed to stand for one night. The reaction mixture was concentrated under vacuum and dissolved into chloroform (50 ml). This solution was washed water (50 ml) two times. After concentrated under vacuum, the organic layer was added with methanol (50 ml) and mixed. Crystals formed were collected by filtration, washed with water and then dried under vacuum at 60° C. to obtain 4′-[2-(p-toluenesulfonyloxy)ethoxy]-3,4,5,6-tetrahydro-2H-pyran-4-carboxanilide (5.17 g) as yellowish crystal.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH3:8][C:3]([CH3:9])([CH:2]=[O:1])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(C)CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)C(C)(C)C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 3-hydroxy-2,2-dimethylpropanoate (8.6 g, 65.1 mmol) in 100 mL DCM was cooled to 0° C. under N2. PCC (24.8 g, 115.2 mmol) was added portionwise over several minutes. The mixture was allowed to gradually warm to room temperature and was stirred overnight. The mixture was filtered through silica gel. Enough Celite is added to the remaining oil so that all is adsorbed. This is added to the top of a silica pad and this is washed with about 1.5 L DCM. The solution is then carefully concentrated in vacuo, maintaining the water bath at about 30° C. to obtain methyl 2,2-dimethyl-3-oxopropanoate as a clear colorless oil. 1H (300 MHz, CDCl3, δ) 9.60 (s, 1H), 3.70 (s, 3H), 1.29 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([SH:9])[N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][CH:28]([CH2:33][CH:34]3[O:36][CH2:35]3)[C:29]([O:31]C)=[O:30])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:27][CH:28]([CH2:33][CH:34]([OH:36])[CH2:35][S:9][C:4]3[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=3)[C:29]([OH:31])=[O:30])(=[O:25])=[O:26])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Cc1cc(C)nc(S)n1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc(C)cc(C)n3)C(=O)O)cc2)cc1

Procedure:
Example 46 is prepared from 4,6-dimethyl-2-mercaptopyrimidine and 1d using the procedure described for compound 20.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[C:32]#[CH:33])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>ClCCl.CO>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[C:32]#[C:33][C:2]3[CH:16]=[CH:15][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][C:10]([OH:13])([CH3:14])[CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC1(O)CCN(Cc2ccc(I)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CC1(O)CCN(Cc2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared analogously to Example 1.1.d. from 1-(4-iodobenzyl)-4-methylpiperidin-4-ol and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 25 mg (13% of theory); melting point: 192° C.-193° C.; C28H27ClN2O2 (M=458.99); calc.: molecular ion peak (M+H)+: 459/461; found: molecular ion peak (M+H)+: 459/461; Rf value: 0.2 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:38]=[CH:39][CH:40]=1)[CH2:8][NH:9][C@@H:10]1[C@@H:15]([OH:16])[C@H:14]([CH2:17][C:18]2[CH:23]=[C:22]([O:24][C@H:25]([CH2:30][O:31][CH3:32])[C:26]([F:29])([F:28])[F:27])[C:21]([N+:33]([O-])=O)=[C:20]([F:36])[CH:19]=2)[CH2:13][S@:12](=[O:37])[CH2:11]1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CO>[NH2:33][C:21]1[C:22]([O:24][C@H:25]([CH2:30][O:31][CH3:32])[C:26]([F:29])([F:27])[F:28])=[CH:23][C:18]([CH2:17][C@H:14]2[C@H:15]([OH:16])[C@@H:10]([NH:9][CH2:8][C:7]3[CH:38]=[CH:39][CH:40]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)[CH2:11][S@@:12](=[O:37])[CH2:13]2)=[CH:19][C:20]=1[F:36]
Reactant: COC[C@@H](Oc1cc(C[C@@H]2C[S@](=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Product: COC[C@@H](Oc1cc(C[C@@H]2C[S@](=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1N)C(F)(F)F

Procedure:
The title compound was prepared in an analogous manner as described for example 41d) from (1S,3R,4S,5S)-3-(3-tert-butyl-benzylamino)-5-[3-fluoro-4-nitro-5-((R)-2,2,2-trifluoro-1-methoxymethyl-ethoxy)-benzyl]-1-oxo-tetrahydro-thiopyran-4-ol as an amorphous solid: TLC (EtOAc-MeOH 9:1) Rf=0.48; HPLC RtH1=0.91 min; ESIMS [M+H]+=561; 1H NMR (600 MHz, CDCl3): δ 7.36 (s, 1H), 7.24 (m, 2H), 7.13 (d, 1H), 6.74 (s, 1H), 6.65 (d, 1H), 5.15 (s, 1H), 5.06 (s, 1H), 4.58 (s, 2H), 3.83-3.79 (m, 2H), 3.73 (m, 2H), 3.63 (dd, 1H), 3.53 (d, 1H), 3.30 (s, 3H), 3.03 (m, 1H), 2.97 (m, 2H), 2.49-2.32 (m, 4H), 1.70-2.62 (m, 1H), 1.25 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:8])[C:5](Cl)=[O:6].[F:9][C:10]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH2:12][OH:13].O>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:3][N:4]([CH3:8])[C:5](=[O:6])[O:13][CH2:12][CH:11]=[C:10]([F:9])[S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCSC(F)=CCO
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCSC(F)=CCOC(=O)N(C)C
Reaction time: 1 h

Procedure:
To a slurry of sodium hydride (125 mg, 5.2 mmol) in 5 ml of THF and 2 ml of HMPA under N2 is added dimethylcarbamoyl chloride (0.37 ml, 430 mg, 4.0 mmol). The slurry is cooled in an ice bath and 3-fluoro-3-hexylthio-2-propen-1-ol (450 mg, 2.34 mmol) is added gradually. After 1 hour, the mixture is cautiously poured into water, extracted with ether and stripped to give 3-fluoro-3-hexylthio-2-propenyl dimethylcarbamate.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([CH:11]1[CH2:20][CH2:19][CH:18]2[CH:13]([CH2:14][CH2:15][CH:16]([CH:21]3[CH2:30][CH2:29][C:24]4(OCC[O:25]4)[CH2:23][CH2:22]3)[CH2:17]2)[CH2:12]1)[CH2:9][CH3:10]>C(O)=O>[CH2:8]([CH:11]1[CH2:20][CH2:19][CH:18]2[CH:13]([CH2:14][CH2:15][CH:16]([CH:21]3[CH2:22][CH2:23][C:24](=[O:25])[CH2:29][CH2:30]3)[CH2:17]2)[CH2:12]1)[CH2:9][CH3:10]
Reactant: CCCC1CCC2CC(C3CCC4(CC3)OCCO4)CCC2C1
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCCC1CCC2CC(C3CCC(=O)CC3)CCC2C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 100.1 %

Procedure:
Sixth step: Toluene (300 ml) and formic acid (98%; 15 g) were added to 8-(6-propyldecahydronaphthalene-2-yl)-1,4-dioxaspiro[4.5]decane (27.9 g) obtained in the fifth step, and the mixture was stirred for 7 hours. After the reaction mixture had been cooled to room temperature, it was washed with aqueous sodium hydroxide solution (1M) and water, and dried over anhydrous magnesium sulfate. The toluene was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-heptane=1/9 by volume) to give 4-(6-propyldecahydronaphthalene-2-yl)cyclohexanone (24.1 g).