Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CO.[C:5]1(/[C:11](/[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12]\[C:13]([O:15]CC)=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[C:5]1(/[C:11](/[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12]\[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)/C=C(\c1ccccc1)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)/C=C(\c1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
20 ml of a 10% w/v aqueous solution of sodium hydroxide were added to 35 ml of a methanol solution containing 3,41 g of ethyl (E)-3-phenyl-3-(4-pyridyl)-acrylate (prepared as described in Preparation 2), and the mixture was stirred for 1 hour an room temperature. At the end of this time, the reaction solution was poured into 50 ml of water and washed with methylene chloride. Sufficient hydrochloric acid was added to the aqueous phase to adjust the pH to a value of 2.8. The resulting precipitate was collected, giving 2.131 g of the title compound, as a white powder, melting at 239°-241° C.
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:21][NH:22][C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1.[C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49](Cl)(=[O:51])=[O:50])#[N:42]>O1CCCC1.O>[C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49]([N:22]1[C:23]([C:24]2[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=2)=[C:19]([F:18])[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:21]1)(=[O:51])=[O:50])#[N:42]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2ccccc2C#N)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26 mg) in tetrahydrofuran (4 mL) were added dropwise 15-crown-5 (0.13 mL), a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (162 mg) in tetrahydrofuran (1 mL) and 2-cyanobenzenesulfonyl chloride (151 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:4) to give the title compound as a pale-yellow oil (yield 238 mg, 98%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:29])C(=O)C1>>[Br:29][C:11]1[C:10]2[NH:9][C:8]3[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[C:15]=2[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccc2[nH]c3ccc(C(C)(C)C)cc3c2c1
Product: CC(C)(C)c1ccc2[nH]c3c(Br)cc(C(C)(C)C)cc3c2c1
Yield: 80 %

Procedure:
The reaction of 3,6-di-tert-butyl-9H-carbazole with NBS produced 1-bromo-3,6-di-tert-butyl-9H-carbazole as a white-glassy solid in 80% yield after purification by flash chromatography on silica gel (FIG. 13).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:5][CH:4]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Si:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([NH:2][CH3:1])=[CH:8][CH:7]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CNc1ccc(CCCCOCCCCCCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNc1ccc(CCCCOCCCCCCO[Si](C)(C)C(C)(C)C)cc1

Procedure:
A solution of Intermediate 56 (0.92 g, 3.3 mmol) in dichloromethane was treated successively with tert-butyldimethylsilyl chloride (0.75 g, 5.0 mmol), DMAP (50 mg), and triethylamine (1.4 mL, 10 mmol). After a few minutes, additional quantities of tert-butyldimethylsilyl chloride (0.75 g, 5.0 mmol) and triethylamine (1 mL) were added. The mixture was filtered through a pad of Celite and concentrated. The residue was purified via automated flash silica gel chromatography, using a 40 g Silicycle SiliSep flash column (hexanes/ethyl acetate). Concentration of the desired fractions under reduced pressure provided the title compound as clear, colorless syrup (0.99 g, 76%). ES/MS calcd. for C23H44NO2Si+ 394.3. Found m/z=394.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[N-:16]=[N+:17]=[N-].[Na+]>Cl.O>[N:1]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(C(=O)O)cc1N
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Amino-4-methyl benzoic acid (2.28 g, 15.1 mmol) was suspended in 65 mL of 2N HCl and chilled to 0° C. A chilled solution of 1.25 g (18.1 mmol) of NaNO2 in 5 mL of water was added slowly, and the solution was stirred for 30 min. The mixture was filtered through a plug of diatomaceous earth, and then returned to a 0° C. bath where 1.08 g (16.6 mmol) of NaN3 dissolved in about 5 mL of water was slowly added. Gas evolved immediately, and a precipitate formed. The precipitate was filtered, washed with water, and dried under a stream of air to provide 2.34 g (13.4 mmol; 88%) of Compound 2 as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=O>[Ti](Cl)(Cl)(Cl)Cl.CCCCC>[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2ccccc2C1
Reactant: C1CCNC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCC
Product: C1=C(N2CCCC2)Cc2ccccc21
Reaction time: 2 h

Procedure:
To a 100 ml reaction tube equipped with a stirrer bar, Suba.Seal™ stopper, and a nitrogen balloon, was added pyrrolidine (1.3 ml) and pentane (8 ml). Titanium tetrachloride (0.2 ml) was added slowly to each tube. 2-Indanone (0.2 g, 1.33 mmol) was added as a solid and the reaction stirred vigorously for 2 h. The reaction mixture was filtered through Celite and the solvent removed in vacuo to give the title compound as a dark solid. m/z (ES+) 186 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[F:31][C:32]([F:44])([F:43])[C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:18][N:19]([S:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:31])([F:43])[F:44])[CH:34]=3)(=[O:41])=[O:40])[C:20](=[O:28])[N:21]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(C(F)(F)F)c4)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 3-trifluoromethylbenzenesulphonyl chloride to give the title compound as a colorless solid. MS: 586.8 ([M+H]+)
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[NH2:2][C:1](=[N:17][OH:18])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(N)=NO)CC1

Procedure:
A mixture of tert-butyl 4-cyano-1-piperidinecarboxylate (2.69 g, 12.8 mmol), hydroxylamine hydrochloride (4.45 g, 64 mmol) and sodium carbonate (6.78 g, 64 mmol) in water (40 ml) and methanol (40 ml) was heated under reflux for 5 hours. The cooled mixture was concentrated under reduced pressure and the remaining aqueous solution extracted with ethyl acetate (3×). The combined organic extracts were washed with water and brine, dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a white solid, 2.60 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][N:22]=[C:21]([CH3:24])[C:20]=3[CH:25]=[O:26])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH3:2].[C:28]([Mg]Br)#[CH:29]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][N:22]=[C:21]([CH3:24])[C:20]=3[CH:25]([OH:26])[C:28]#[CH:29])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: C#C[Mg]Br
Reactant: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3C=O)cc2)cc1
Product: C#CC(O)c1c(C)noc1-c1ccc(-c2ccc(CCC(=O)OCC)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 25, Step 1, using 3-[4′-(4-formyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-propionic acid ethyl ester and ethynylmagnesium bromide.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13]C)=[O:12])[C:5]=2[C:4]([CH2:15][NH:16][CH:17]2[CH2:23][CH:22]3[N:24]([CH3:25])[CH:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:3]1.O.[OH-].[Li+:28]>C1COCC1.O>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O-:13])=[O:12])[C:5]=2[C:4]([CH2:15][NH:16][CH:17]2[CH2:23][CH:22]3[N:24]([CH3:25])[CH:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:3]1.[Li+:28]
Reactant: COC(=O)c1cccc2c1c(CNC1CC3CCC(C1)N3C)nn2C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1C2CCC1CC(NCc1nn(C)c3cccc(C(=O)[O-])c13)C2
Temperature: 90 °C
Yield: 287.9 %

Procedure:
To a solution of methyl 1-methyl-3-((8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)methyl)-1H-indazole-4-carboxylate (0.54 g, 1.6 mmol) from Step A above in THF (5 mL) was added lithium hydroxide monohydrate (1.6 g, 38 mmol) in water (5 mL). The mixture was heated at 90° C. for 1 h and then concentrated under reduced pressure. The residue was dried overnight under vacuum to afford crude lithium 1-methyl-3-((8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)methyl)-1H-indazole-4-carboxylate (1.54 g), which was used in the next step without further purification: LC/MS (ESI+) m/z 329 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][C:23]=1[C:36]([NH2:38])=[O:37]>CN(C=O)C>[C:36]([C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:22]=1[O:1][C:2]1[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)(=[O:37])[NH2:38]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C(N)=O)c(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A resealable tube was charged with 6-hydroxy-1-naphthoic acid (0.035 g, 0.187 mmol), cesium carbonate (0.183 g, 0.561 mmol), and DMF (1.0 mL). The system was flushed with argon, the tube was sealed, and the mixture stirred at RT for 15 min. 4-Chloro-6,7-dimethoxyquinoline-3-carboxamide (0.050 g, 0.187 mmol) mL) was added (along with a 1 mL DMF rinse), and the system was again flushed with argon. The tube was sealed and the mixture stirred at 60° C. for 26 h. The reaction mixture was diluted with water (2.5 mL) and 6 N HCl (aq) was added dropwise with stirring until the pH of the solution was 5-6. The resulting precipitate was filtered and washed with water. The filter cake was dried under vacuum to afford 6-(3-carbamoyl-6,7-dimethoxyquinolin-4-yloxy)-1-naphthoic acid as a tan solid. MS (ESI, pos. ion) m/z: 419.0 (M+H). Mass Calc'd for C23H18N2O6: 418.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[CH2:13]2)[CH2:11]1
Reactant: CN1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C2CNC2)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A mixture of 3-(4-methyl-3-oxopiperazin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (211 mg, 0.78 mmol) and TFA (2 mL) in DCM (4 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 4-Azetidin-3-yl-1-methylpiperazin-2-one as a white solid (125 mg, 95%). 1H NMR (CDCl3, 300 MHz): δ 3.63 (m, 4H); 3.37-3.27 (m, 3H); 3.03 (s, 2H); 2.96 (s, 3H); 2.58 (t, J=5.6 Hz, 2H); 2.13-1.97 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3](O)([C:10]#[C:11][CH:12]([OH:14])[CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(OC)(C)(C)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10]#[C:11][CH:12]([O:14][C:22](=[O:24])[CH3:23])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=CCCC(C)(C)C1(O)C#CC(C)O
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Product: CC(=O)OC(C)C#CC1=C(C)C=CCC1(C)C
Temperature: 25 °C
Reaction time: 27 h
Yield: 45 %

Procedure:
In a 500 ml. three-necked flask fitted with a mechanical stirrer, a dropping funnel, a thermometer and a reflux condenser protected by a calcium chloride tube is placed a mixture of 66 g. of 2,6,6-trimethyl-1-hydroxy-1-(3-hydroxy-but-1-ynyl)cyclohex-2-ene and 76 g. of pyridine in 200 ml. of tertiary butylmethyl ether. To the stirred solution is added 34 g. of acetic anhydride at room temperature. The reaction mixture is stirred for a period of 27 hours at ambient temperature. The reaction mixture is then poured into 200 ml. of water and the organic layer is separated, washed with 10% hydrochloric acid, subsequently with water, 10% sodium bicarbonate solution and water, and finally dried over sodium sulfate. Concentration yields a residue which gives on distillation 33 g. or 45% yield of 2,6,6-trimethyl-1-(3-acetoxy-but-1-ynyl)cyclohexa-1,3-diene, b.p. 125° C./1 mm., nD20 1.5045.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:13][N:6]2[C:7](=[O:12])[CH2:8][CH2:9][NH:10][CH2:11][C@@H:5]2[CH2:4]1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[OH:2][C@H:3]1[CH2:13][N:6]2[C:7](=[O:12])[CH2:8][CH2:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=3)[CH2:11][C@@H:5]2[CH2:4]1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: O=C1CCNC[C@@H]2C[C@@H](O)CN12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@@H]2C[C@@H](O)CN12
Temperature: 100 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A mixture of (8R,9aS)-8-hydroxyoctahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (90 mg, 0.435 mmol, Part A), 2-bromo-5-(trifluoromethyl)pyridine (148 mg, 0.635 mmol) and sodium carbonate (138 mg, 1.306 mmol) in dimethyl sulfoxide (0.4 mL) was stirred at 100° C. overnight. The mixture was purified by chromatography on silica gel (ethyl acetate/methanol=15:1) to give 135 mg (98% yield) of the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77 (m, 1H), 2.09 (m, 1 H), 2.50-2.66 (m, 2 H), 3.08 (m, 1 H), 3.35 (m, 2 H), 3.50 (m, 1 H), 3.98 (m, 2H), 4.20 (m, 1H), 4.44 (m, 1H), 4.55 (m, 1H), 4.88 (br s, 1H), 7.01 (d, J=8 Hz, 1 H), 7.81 (d, J=8 Hz, 1 H), 8.43 (s, 1H); MS (ESI) m/z 316.0 (M+H)+.
Reaction SMILES: [Na+].[CH3:2][S:3]([O-:5])=[O:4].F[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=1[C:15]([F:18])([F:17])[F:16]>CS(C)=O>[CH3:2][S:3]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=1[C:15]([F:16])([F:18])[F:17])(=[O:5])=[O:4]
Reactant: CS(=O)[O-]
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C=O)cc1C(F)(F)F
Temperature: 75 °C
Reaction time: 2 h

Procedure:
Methane sulfinic acid sodium salt (6.65 g, 65.1 mmol) is added to a stirred solution of 4-Fluoro-3-trifluoromethyl-benzaldehyde (10.0 g, 52.1 mmol) in dry DMSO (200 ml) and the mixture is heated at 75° C. After 2 hours the reaction is allowed to cool and poured onto ice-water (300 ml). The precipitate is collected by filtration, washed with water and dissolved in dichloromethane (200 ml). The organic extract is washed with water (3×200 ml), dried over MgSO4, filtered, and the solvent is removed to give the title compound as a white solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7]C(O)=[CH:4][CH:3]=1)O.B(F)(F)F.[CH3:13][CH2:14][O:15][CH2:16][CH3:17].O1CCOCC1>C(OCC)C>[O:15]1[C:16]2[C:8](=[CH:1][CH:3]=[CH:4][CH:17]=2)[CH2:7][CH2:13][CH2:14]1
Reactant: Oc1ccc(O)cc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 0 h

Procedure:
To a solution of hydroquinone 1 (0.01 mol) and a catalyst, preferably boron trifluoride diethyl etherate (0.016 mol) in an organic solvent, preferably dry dioxane (10 mL), is added vinyl lactone 2 (0.016 mol) in an organic solvent, preferably dry dioxane (5.0 mL) over 1-60 minutes, preferably 60 minutes, at 0-150° C., preferably 110° C., under an inert gas. The reaction mixture is stirred for 0 to 8 hours, preferably 0 hours, at the selected temperature, cooled to room temperature, and diluted with an organic solvent, preferably diethyl ether (200 mL). The reaction mixture is then washed with water (100 mL, 2×50 mL), dried over sodium sulfate (Na2SO4), and solvent is removed under reduced pressure to afford a brown oily residue. The residue is dissolved in alcohol, preferably methanol (30 mL), and the alcohol is then removed under reduced pressure. The brown oily liquid or semisolid is further purified by chromatography, preferably on silica gel, to afford pure racemic chroman derivative 3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:21][CH3:22])[C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][OH:20])[N:13]=1.[H-].[Na+].I[CH3:26].O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:21][CH3:22])[C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][O:20][CH3:26])[N:13]=1
Reactant: CCN(c1nc(C)cc(CO)n1)c1ccc(C(C)C)cc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(c1nc(C)cc(COC)n1)c1ccc(C(C)C)cc1Br

Procedure:
To the product of Example 24 and sodium hydride (1.1 eq.) in dry THF under nitrogen was added iodomethane (1.1 eq.) and after four hours the reaction was poured into H2O and extracted three times with CHCl3. The combined extracts were dried over MgSO4, filtered, and evaporated under vacuum. The material was purified by chromatography on silica gel using 10% EtOAc in hexanes to give a light yellow oil. (Rf=0.37)
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:20][CH3:21])=[C:10]([C:12]3[C:13](=[O:19])[CH2:14][CH2:15][C:16]=3[O:17]C)[CH:11]=2)=[CH:4][CH:3]=1>CC(C)=O.Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:20][CH3:21])=[C:10]([CH:12]3[C:13](=[O:19])[CH2:14][CH2:15][C:16]3=[O:17])[CH:11]=2)=[CH:22][CH:23]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1C1=C(OC)CCC1=O
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)CCC1=O

Procedure:
A solution of 2-(4′-chloro-4-ethylbiphen-3-yl)-3-methoxycyclopent-2-enone (200 mg, 0.61 mmol) in acetone (4 ml) and 2M aqueous hydrochloric acid (4 ml) is heated at 120° C. for 20 minutes under microwave irradiation. The reaction mixture is diluted with water (20 ml) and 2M aqueous hydrochloric acid (10 ml), and the crude product is extracted with ethyl acetate (3×15 ml). The organic extracts are combined, washed with brine (10 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to dryness under reduced pressure to give 2-(4′-chloro-4-ethylbiphen-3-yl)-1,3-cyclopentanedione.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)=[C:3]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1cnc2cc(Cl)ccc2c1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=S(=O)(c1ccc(Cl)cc1)c1cnc2cc(Cl)ccc2c1-c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A mixture of 4-bromo-7-chloro-3-(4-chloro-benzenesulfonyl)-quinoline (0.42 g, 1 mmol), 4-fluorophenylboronic acid (0.21 g, 1.5 mmol) and tetrakis-(triphenylphosphin)palladium(0) (0.08 g, 0.07 mmol) in 30 ml 1,2-dimethoxyethane and 8 ml of 2M aqueous sodium carbonate solution was stirred for 2 hours at 70° C. After cooling the mixture was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (Kieselgel 60, eluent: chloroform) and crystallized from methanol to obtain 0.29 g of the title compound in 67% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[N:23]1[CH2:32][C:31]2[C:26](=[N:27][C:28](S(C)(=O)=O)=[N:29][CH:30]=2)[N:25]([CH3:37])[C:24]1=[O:38].[NH3:39]>O1CCCC1>[NH2:39][C:28]1[N:27]=[C:26]2[N:25]([CH3:37])[C:24](=[O:38])[N:23]([C:3]3[CH:4]=[C:5]([NH:8][C:9]([C:11]4[CH:16]=[CH:15][C:14]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:13][CH:12]=4)=[O:10])[CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:32][C:31]2=[CH:30][N:29]=1
Reactant: CN1C(=O)N(c2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: N
Solvent: C1CCOC1
Product: CN1C(=O)N(c2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2Cl)Cc2cnc(N)nc21
Reaction time: 2 h
Yield: 31 %

Procedure:
0.079 g Biphenyl-4-carboxylic acid[4-chloro-3-(7-methanesulfonyl-1-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-phenyl]-amide were dissolved in 10 mL tetrahydrofuran. 10 mL of liquid ammonia were added in an autoclave and the reaction mixture was stirred for 2 h. The organic solvent was evaporated, and the crude product was purified by reverse phase chromatography (acetonitrile/water with 1% acetic acid) to give the title product in 31% yield.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]2[C:24](=[O:25])[C:23]3[CH:26]=[CH:27][C:28]([N+:30]([O-])=O)=[CH:29][C:22]=3[CH2:21][O:20][C:19]=2[CH:33]=1>C(O)C>[NH2:30][C:28]1[CH:27]=[CH:26][C:23]2[C:24](=[O:25])[C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[O:7][CH3:6])=[CH:33][C:19]=3[O:20][CH2:21][C:22]=2[CH:29]=1
Reactant: COc1ccccc1Nc1ccc2c(c1)OCc1cc([N+](=O)[O-])ccc1C2=O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1ccccc1Nc1ccc2c(c1)OCc1cc(N)ccc1C2=O

Procedure:
In accordance with general method Y, 0.10 g (0.44 mmol) of tin(II) chloride dihydrate is dissolved in 15 ml of ethanol, and 0.04 g (0.10 mmol) of (14) is added. Yield: 0.0046 g (13.3%); melting point: 68.4° C.; C21H18N2O3 (Mr=346.39); LC 18.55 min