Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([S:17](Cl)(=[O:19])=[O:18])=[CH:10][CH:9]=1.Cl.[NH2:22][C@H:23]([C@H:26]1[O:30][C:29](=[O:31])[C@H:28]([CH3:32])[CH2:27]1)[CH2:24][OH:25].O1CCCC1>O>[OH:25][CH2:24][C@H:23]([NH:22][S:17]([C:11]1[CH:10]=[CH:9][CH:8]=[CH:13][C:12]=1[N+:14]([O-:16])=[O:15])(=[O:19])=[O:18])[C@@H:26]1[CH2:27][C@@H:28]([CH3:32])[C:29](=[O:31])[O:30]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@@H]([C@H](CO)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reaction time: 2 h
Yield: 56 %

Procedure:
8.66 g of triethylamine (85.7 mmol) and 9.67 g of O-nitrobenzenesulfonyl chloride (41.3 mmol) were added to a solution of (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-methyldihydrofuran-2-one hydrochloride obtained in the above reaction in a mixed solvent of tetrahydrofuran (120 ml) and water (12.0 ml) at 0° C., and the mixture was stirred at the same temperature for two hours. The reaction mixture was concentrated under reduced pressure and 200 ml of water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with water, a saturated sodium bicarbonate aqueous solution and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:ethyl acetate). Further, 10 ml of diisopropyl ether and 20 ml of ethyl acetate were added, and the precipitated solid was collected by filtration to obtain 5.27 g of the title compound (total yield over two steps: 56%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.Br[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32]>CN(C=O)C>[CH2:29]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:17]=[CH:18][C:19]([C@@H:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3cccc(O)c3)CC2)cc1
Reactant: CC(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3cccc(OCCC(C)C)c3)CC2)cc1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
8 mg (0.2 mmol) NaH (60% in mineral oil) are added to a mixture of 34 mg (0.10 mmol) (S)—N-{1-(4-[1-(3-hydroxyphenyl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (compound 1.27) and 23 mg (0.15 mmol) 1-bromo-3-methylbutane in 2 mL DMF at 0° C. The mixture is stirred at 70° C. for 3 d. The reaction mixture is quenched with water, filtered and the solvent is evaporated. The residue is purified using reversed phase HPLC (water/MeOH, 0.1% TFA) to yield the desired product.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)=[CH2:22].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:21]=[CH2:22])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Yield: 91 %

Procedure:
Methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in WO 2004065367) and (2-vinylphenyl)boronic acid (1.5 eq) were dissolved in dioxane (0.07 M) and 2M aqueous Na2CO3 (6 eq) was added. The solution was degassed by bubbling argon, Pd(PPh3)2Cl2 (0.2 eq) was added, and the reaction mixture was refluxed for 1 h; after cooling, EtOAc was added, and the solution washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The title compound was isolated by chromatography (PE/EtOAc 9:1) in 91% yield; MS (ES+) m/z 360 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[SH:11]CC(OCC)=O.C(=O)([O-])[O-].[K+].[K+].O.[O:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH2:2]([CH2:27][C:26]([O:25][CH2:29][CH3:28])=[S:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CCl)c1ccccc1
Reactant: C1CCOC1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=S)CCC(=O)c1ccccc1

Procedure:
Part A. A solution of 2-chloroacetophenone (Aldrich, 14.1 g, 91.2 mmol), ethyl 2-mercaptoacetate (Aldrich, 10.0 mL, 91.2 mmol), and potassium carbonate (13.9 g, 100 mmol) in tetrahydrofuran (200 mL) was stirred at ambient temperature for 10 hours. The mixture was poured into water (400 mL), and extracted with methylene chloride (2×400 mL). The extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual oil was separated by flash chromatography (1:4 ethyl acetate-hexane) to afford the product, ethyl 2-phenacylthioacetate, as an oil (16.1 g, 67.7 mmol, 74%). 1H NMR (CDCl3): δ 7.97 (2H, dd, J=8.0, 1.5 Hz); 7.62 (1H, tt, J=5.1, 1.4 Hz); 7.48 (2H, t, J=7.7 Hz); 4.19 (2H, q, J=7.3 Hz); 4.04 (2H, s); 3.33 (2H, s); 1.27 (3H, t, J=7.3 Hz). Mass spectrum (NH3 -CI/DDIP): m/z 256 (100%); 240 (6%);239 (42%); 210 (1%); 193 (1%).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([CH:8]([N:11]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][N:26](C(OCC)=O)[CH2:25][CH2:24]4)=[N:21][CH:22]=3)[CH:13]=[N:12]2)[CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1>Br.O>[ClH:1].[Cl:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([CH:8]([N:11]2[C:15](=[O:16])[N:14]([C:17]3[CH:22]=[N:21][C:20]([N:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)=[CH:19][CH:18]=3)[CH:13]=[N:12]2)[CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCN(c2ccc(-n3cnn(C(CC)C(=O)c4ccc(Cl)cc4)c3=O)cn2)CC1
Agent: Br
Solvent: O
Product: CCC(C(=O)c1ccc(Cl)cc1)n1ncn(-c2ccc(N3CCNCC3)nc2)c1=O
Product: Cl
Yield: 15.3 %

Procedure:
A mixture of (±)-ethyl 4-[5-[2-[1-(4-chlorobenzoyl)propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl]-2-pyridinyl]-1-piperazinecarboxylate (24 g) in hydrobromic acid, 48% solution in water (250 ml) was stirred and refluxed overnight. The solvent was evaporated and the residue was dissolved in CH2Cl2, neutralized with NH4OH/H2O and extracted with CH2Cl2. The organic layer was washed with water, dried, filtered off and evaporated. A sample (3.5 g) of the residue (total 18 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 99/1). The pure fractions were collected and evaporated. The residue was dissolved in 2-propanol and converted into the hydrochloric acid salt (1:1) in 2-propanol. The precipitate was filtered off, washed with 2-propanol and dried at 150° C. The product was dissolved in 2-propanol. Pyridine was added dropwise until all the product was dissolved and crystallized out. The precipitate was filtered off and dried, yielding 1.7 g (±)-2-[1-(4-chlorobenzoyl) propyl]2,4-dihydro-4-[6-(1-piperazinyl)-3-pyridinyl]-3H-1,2,4-triazol-3-one monohydrochloride (39.4%); mp. 209.8° C. (interim. 1).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:25][OH:26]>C(O)C>[CH2:1]([CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[N:25][OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1c2ccccc2CCC1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1c2ccccc2CCC1Cc1ccccc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To a solution of 2-benzyl-1-tetralone (prepared according to Org. Prep. Proc. Inter., 2, 37 (1970)), (58.95 g, 0.250 mol) and 95% ethanol (500 mL) was added sodium acetate (45.1 g, 0.55 mol) and hydroxylamine hydrochloride (20.8 g, 0.30 mol). The reaction was heated to reflux overnight and then allowed to cool to room temperature and concentrated under vacuum. The residue was partitioned between water (300 mL) and ethryl acetate (500 mL), the organic layer was then sequentially washed with water (300 mL), and brine (500 mL). This was then dried over sodium sulfate and concentrated to give 61.1 g of an orange solid. Recrystalization from ethyl acetate/hexanes gave the title compound as a white solid, m.p. 123-124° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH2:26]([O:28][C:29](=[O:33])[C@H:30]([CH3:32])[NH2:31])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:33])[CH:30]([NH:31][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:22])([F:23])[F:24])[CH:4]=1)[CH3:32])[CH3:27]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(C)NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.536 g (10 mmol) of L-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C1(S([CH:21]2[C:29]3C(=CC=CC=3)C(=O)[O:22]2)(=O)=O)C=CC=CC=1.C1(=O)C2C(CC3C(C=2)=CC2C(=CC=CC=2)C3)CCC1>CN(C)C=O>[C:21]([CH:7]1[CH2:8][CH2:9][CH:10]2[CH:5]([CH2:4][CH:3]=[CH:2][C:1]2=[O:11])[CH2:6]1)(=[O:22])[CH3:29]
Reactant: O=C1CCCC2CCCC=C12
Reactant: O=C1OC(S(=O)(=O)c2ccccc2)c2ccccc21
Agent: O=C1CCCC2CC3Cc4ccccc4C=C3C=C12
Solvent: CN(C)C=O
Product: CC(=O)C1CCC2C(=O)C=CCC2C1

Procedure:
reacting the hexahydronaphthalenone product with phenylsulfonyl isobenzofuranone to create a hexahydronaphthacenone product having the formula ##STR21## and heating the hexahydronaphthacenone product in dimethylforamide under an oxygen atmosphere to produce the compound.
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[CH:7]=[C:6]([CH3:19])[C:5]=1[OH:20])[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>O>[CH3:19][C:6]1[C:5]2[O:20][CH:2]([C:36]([OH:37])=[O:39])[CH2:1][C:4]=2[C:17]2[O:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:18])[C:8]=2[CH:7]=1
Reactant: C=CCc1c(O)c(C)cc2c(=O)c3ccccc3oc12
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(=O)c3ccccc3oc2c2c1OC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.2 %

Procedure:
A mixture of 4-allyl-3-hydroxy-2-methyl-9-oxo-9H-xanthene (12 g), m-chloroperbenzoic acid (12 g) and chloroform (700 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, 20 g of potassium carbonate and 400 ml of water were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (2,000 ml) and, to the stirred solution, a mixture of chromium trioxide (34 g), water (70 ml) and concentrated sulfuric acid (30 ml) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from a mixed solvent of ethanol and DMF gave 8.7 g of 1,2-dihydro-4-methyl-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 292°-295° C. This compound produced a mass spectrum having a molecular ion peak at m/e 296.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH:15]=O)[C:12]([OH:17])=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>>[ClH:1].[C:26]([NH:30][CH2:15][C:13]1[C:12]([OH:17])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N
Reactant: O=Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Product: CC(C)(C)NCc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Product: Cl

Procedure:
5′-((tert-Butylamino)methyl)-3,3″,4,4″-tetrachloro-[1,1′:3′,1″-terphenyl]-4′-ol hydrochloride was prepared as a white solid using the procedure described in Example 5 from 3,3″,4,4″-tetrachloro-4′-hydroxy-[1,1′:3′,1″-terphenyl]-5′-carbaldehyde and tert-butylamine.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:29])[C@:7]1([OH:28])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[CH:18]2)[C@@H:13]([CH3:27])[CH2:12]3)[CH2:9][CH2:8]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O.C(OCC)(=O)C>[OH:28][C@:7]1([C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[CH:18]2)[C@@H:13]([CH3:27])[CH2:12]3)[CH2:9][CH2:8]1)[C:6](=[O:29])[CH2:5][OH:4]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H]1C[C@@H]2C(=CC[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)CO)[C@@]2(C)C=CC(=O)C=C12

Procedure:
A 13.58 g sample of 21-acetoxy-17α-hydroxy-6α-methylpregna-1,4,9-(11)-triene-3,20-dione in methanol (850 ml) was hydrolyzed with 10% potassium carbonate (34 ml). The reaction mixture was acidified, diluted with water and concentrated to give a gummy precipitate which was dissolved in ethyl acetate. The extract was washed with water and brine, then dried over sodium sulfate and evaporated. Crystallization of the residue from acetone-hexane gave the title compound Example 2(a), m.p. 204°-206° C.; one spot by TLC (10% CH3OH--CHCl3).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)N.[CH3:9][O:10][CH2:11][C:12](=O)[CH3:13]>C(O)C>[CH3:9][O:10][C:11]1[C:8]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[NH:1][C:12]=1[CH3:13]
Reactant: COCC(C)=O
Reactant: NNc1ccccn1
Solvent: CCO
Product: COc1c(C)[nH]c2ncccc12
Yield: 40.8 %

Procedure:
A solution of 7,4 g (68 mmol) 2-hydrazinopyridine and 6,0 g (68 mmol) methoxyaceton in 50 ml of ethanol was refluxed for 1 h. The solvent was removed under reduced pressure. The resulting oil was dissolved in diethylene glycol and refluxed for 1,5 h. The mixture was allowed to cool and was poured into ice-water. Extraction with methylene chloride gave an black oily residue which was treated with boiling petroleumether (60-80). After decanting the solvent was allowed to cool and the precipitated product filtered of affording 4,5 g (41%) pure title compound as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:4].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C.Br.C(N(CC)CC)C.[ClH:44]>O1CCCC1.C(OCC)C>[ClH:44].[ClH:44].[OH:15][C:8]1[CH:7]=[CH:6][C:5]([C:3](=[O:4])[CH2:2][N:26]2[CH2:27][CH2:28][N:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH3:16])[CH2:24][CH2:25]2)=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: COC(=O)c1cc(C(=O)CBr)ccc1O
Agent: Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(=O)CN2CCN(c3ccccc3C)CC2)ccc1O

Procedure:
A solution of 10.9 g (0.04 mol) of methyl 5-(2-bromoacetyl)-2-hydroxybenzoate in 100 ml of dry tetrahydrofuran is added dropwise over 4 hours to a stirred solution of 7.1 g (0.04 mol) of 1-(2-methylphenyl)piperazine and 4.0 g (0.04 mol) of triethylamine in 75 ml of tetrahydrofuran at room temperature. Stirring is continued for 2-12 hours or until the theoretical amount (7.3 g) of triethylamine hydrobromide precipitates. The precipitates is removed by filtration and the filtrate is evaporated to dryness. Addition of 2 equivalents of methanolic HCl and precipitation by addition of ethyl ether at room temperature affords the crude methyl 2-hydroxy-5-[2-[4-(2-methylphenyl)-1-piperazinyl]acetyl]benzoate dihydrochloride (9.4 g). Attempts to purify this product by recrystallization frequently led to decomposition and were subsequently avoided.
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][C:4]([O:10]C(=O)C)(OC(=O)C)[CH3:5].[CH3:15][C:16]([CH3:20])=[CH:17][CH2:18]O.C(O)(=O)CC>>[CH3:14][C:2]([CH2:1][CH2:18][CH:17]=[C:16]([CH3:20])[CH3:15])=[CH:3][C:4](=[O:10])[CH3:5]
Reactant: CC(C)=CCO
Reactant: CC(=O)OC(C)(C=C(C)C)OC(C)=O
Solvent: CCC(=O)O
Product: CC(=O)C=C(C)CCC=C(C)C
Temperature: 200 °C
Yield: 81 %

Procedure:
A mixture of 25 parts of 4-methyl-2,2-diacetoxy-3-pentene, 10 parts of 3-methyl-2-buten-1-ol (prenol) and 0.3 part of propionic acid is heated for 3 hours at about 200°C in a vibratory autoclave at a pressure 30 atmospheres. After cooling, the reaction product is distilled off to give 9.4 parts of 4,8-dimethyl-3,7-nonadien-2-one having a boiling point of 60°-62°C/0.2 mm. The yield is 81% of theory at a conversion of 60% based on the prenol introduced.
Reaction SMILES: C(NC(C)C)(C)C.C[Li].CCOCC.[C:15]1([S:21]([CH3:24])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CON(C)[C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[C:31]([CH3:36])[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:15]1([S:21]([CH2:24][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[C:31]([CH3:36])[CH:30]=2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CON(C)C(=O)c1ccc(Br)c(C)c1
Reactant: CS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Li]C
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CS(=O)(=O)c2ccccc2)ccc1Br
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
A stirred solution of diisopropylamine (3.6 ml, 0.026 mole) in dry THF (60 ml) at -60° C. under argon was treated with 1.5M methyllithium in ether (15.3 ml, 0.023 mole). After 15 minutes, the solution was treated dropwise over 5 minutes with a solution of methyl phenyl sulphone (2.8 g, 0.020 mole) in dry THF (20 ml). The mixture was kept at -60° C. for a further 10 minutes, then treated with a solution of N-methoxy-N-methyl-4-bromo-3-methylbenzamide (D41, 4.4 g, 0.017 mole) in dry THF (30 ml) and allowed to warm to room temp. over 1.5 h. The reaction mixture was treated with 10% Na2CO3 solution (70 ml), then concentrated in vacuo to approx. 100 ml volume and extracted with ethyl acetate (2×100 ml). The combined extract was dried and concentrated in vacuo to afford the title compound as a pale orange solid (6.0 g, 100%).
Reaction SMILES: C[O:2][C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH2:8]Cl)=[O:7].[CH2:11]([O:13][C:14](=[O:22])[CH2:15][CH:16](Cl)[C:17]([CH2:19]Cl)=[O:18])C.COC(=O)CCC(C)=O>>[C:3]([OH:10])(=[O:2])[CH2:4][CH2:5][C:6]([CH3:8])=[O:7].[CH3:11][O:13][C:14](=[O:22])[CH2:15][CH2:16][C:17]([CH3:19])=[O:18]
Reactant: CCOC(=O)CC(Cl)C(=O)CCl
Reactant: COC(=O)CCC(=O)CCl
Agent: COC(=O)CCC(C)=O
Product: CC(=O)CCC(=O)O

Procedure:
Preparation of 5-chlorolevulinic acid methyl ester from a mixture of 3-chloro-, 5-chloro-, 3,5-dichlorolevulinic acid ethyl ester and levulinic acid methyl ester consisting of the same product ratio, which is obtained by the bromination of both levulinic acid and levulinic acid methyl ester according to the Examples 1 and 2.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:48][C:18]2[N:19]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=4)=[CH:36][CH:35]=3)[C:20](=[O:32])[N:21]([CH2:24][C:25]3([OH:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:48][C:18]2[N:19]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[C:46]4[NH:3][C:4](=[O:7])[O:5][N:47]=4)=[CH:36][CH:35]=3)[C:20](=[O:32])[N:21]([CH2:24][C:25]3([OH:31])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCc1cc2c(=O)n(CC3(O)CCOCC3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(CC3(O)CCOCC3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.27 g), sodium hydrogencarbonate (0.4 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.16 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride (10 mL), N,N′-carbonyldiimidazole (0.046 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.038 ml) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.04 g, 22%).
Reaction SMILES: [C:1]([C:14]1[CH:15]=[C:16]([C:33]([O:35]C)=[O:34])[N:17]([CH2:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=2)[CH:18]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>C1COCC1.[Pd]>[C:28]([CH2:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:17]2[CH:18]=[C:14]([C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:15]=[C:16]2[C:33]([OH:35])=[O:34])=[CH:21][CH:22]=1)([OH:30])=[O:29]
Reactant: CCCCCCCCCCCC(=O)c1cc(C(=O)OC)n(Cc2ccc(/C=C/C(=O)OCC)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)c1cc(C(=O)O)n(Cc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C

Procedure:
50 mg (0.1 mmol) of methyl (E)-4-dodecanoyl-1-{4-[2-(ethoxycarbonyl)ethenyl]benzyl}pyrrole-2-carboxylate are dissolved in 5 ml of THF. After addition of a spatula tip of Pd/C, hydrogenation is carried out with vigorous stirring at room temperature under a hydrogen atmosphere produced using a hydrogen-filled balloon fitted onto the reaction flask for 4 h. Addition of kieselguhr is followed by filtration, the solvent is distilled off, the residue is mixed with 12 ml of ethanol and 4 ml of 10% strength aqueous KOH, and the resulting mixture is boiled under reflux for 1 h. Cooling is followed by dilution with water, acidification with dilute HCl and extraction with ether. The organic phase is washed with dilute HCl, dried over Na2SO4 and concentrated. The product is precipitated from petroleum ether.