Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])S[C@@H:5]2[CH2:7][C:8](=[O:9])[N:4]2[C@H:3]1[C:10]([OH:12])=[O:11].C(OO)(=O)C.[S:19](=[O:22])(O)[O-:20].[Na+]>O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:13])[S:19](=[O:22])(=[O:20])[C@@H:5]2[CH2:7][C:8](=[O:9])[N:4]2[C@H:3]1[C:10]([OH:12])=[O:11]
Reactant: O=S([O-])O
Reactant: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O
Agent: CC(=O)OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)[C@H](C(=O)O)N2C(=O)C[C@H]2S1(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 1.78 g. of penicillanic acid in water, at pH 7.5, was added 1.46 ml. of 40% peracetic acid, followed by an additional 2.94 ml. of 40% peracetic acid 30 minutes later. The reaction mixture was stirred for 3 days at room temperature and then it was diluted with ethyl acetate and water. Solid sodium bisulfite was added to decompose excess peracid, and then the pH was adjusted to 1.5. The ethyl acetate layer was removed, dried (Na2SO4) and evaporated in vacuo. The residue was a 3:2 mixture of penicillanic acid 1,1-dioxide and penicillanic acid 1-oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10]C)[CH:5]=[C:6]([O:8]C)[CH:7]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:10])[CH:3]=1
Reactant: COc1cc(Cl)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(O)cc(Cl)c1
Temperature: -78 °C
Reaction time: 48 h
Yield: 58.6 %

Procedure:
A solution 5-chloro-1,3-dimethoxybenzene (20.71 g) in dichloromethane (50 ml) at -78° C. was treated dropwise with a solution of boron tribromide (56 ml) in dichloromethane (250 ml), maintaining the temperature at -78° C. The mixture was slowly warmed to room temperature then left at ambient temperature for 48 hours. The reaction mixture was quenched with water (100 ml), (sodium hydroxide scrubber required) and partitioned between water (1000 ml) and dichloromethane (1000 ml). The organic layer was separated and the aqueous layer was extracted twice with a mixture of dichloromethane and methanol (500 ml, 98:2, v/v). The combined organic extracts were washed with saturated brine (200 ml), dried over magnesium sulphate and evaporated affording the title compound (10.17 g) as a yellow/orange oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:25])[NH:23][CH3:24])[CH:17]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1([CH3:26])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:25])[NH:23][CH3:24])[CH:17]=1
Reactant: CNC(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNC(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Yield: 43.1 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(methylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (85 mg, 0.24 mmol) in methanol (4.6 mL) and 1N sodium hydroxide aqueous solution (3.6 mL, 3.6 mmol) was heated to reflux for 1 h. LC-MS showed the reaction was complete. The solvent was removed in vacuo to give white solid, which was dissolved in water and acidified with 1N hydrochloric acid solution to pH=2. The precipitated white solid was collected by filtration and back-dissolved in aqueous sodium hydroxide solution, then was acidified with 1 M hydrochloric acid solution again to pH=7. The white precipitated solid was collected by filtration and dried in vacuo to afford 35 mg of 3,3-dimethyl-2-(3-(methyl carbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 42.9%. LC-MS(M+1)=339.2.
Reaction SMILES: [CH2:1]([C:8]1[CH:34]=[CH:33][CH:32]=[CH:31][C:9]=1[C:10](=[O:30])[CH2:11][CH2:12][NH:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:24])=[CH:20][C:21]=2[Cl:23])[NH:16][C:15]=1[C:25]([O:27]CC)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[CH2:1]([C:8]1[CH:34]=[CH:33][CH:32]=[CH:31][C:9]=1[C:10](=[O:30])[CH2:11][CH2:12][NH:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:24])=[CH:20][C:21]=2[Cl:23])[NH:16][C:15]=1[C:25]([OH:27])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccccc1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccccc1Cc1ccccc1
Temperature: 60 °C
Yield: 93.9 %

Procedure:
Dissolve 3-[(2-benzylphenacyl)methylamino]-2-carbethoxy-4,6-dichloroindole (200 mg, 0.41 mmol) in tetrahydrofuran (3 mL) and add water (3 mL). Add lithium hydroxide monohydrate (1.2 mmol) and heat at 60° C. overnight. Add addition lithium hydroxide monohydrate (1.2 mmol) and heat at 60° C. for 5 hours. Allow some of the tetrahydrofuran to evaporate and add methanol to form a homogeneous solution. Heat for 3 days, adding additional lithium hydroxide monohydrate (2.4 mmol). Dilute with water and filter. Acidify, extract into ethyl acetate and dry (MgSO4). Evaporate the solvent in vacuo and recrystallize (ethyl acetate/hexane) to give the title compound as a white powder (180 mg, 97%); mp 280°-83° C.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][C:7]1[CH:20]=[CH:19][C:18]2[C:17](=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:22])[C:9]=2[CH:8]=1>O1CCCC1>[Br:2][CH2:6][C:7]1[CH:20]=[CH:19][C:18]2[C:17](=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:22])[C:9]=2[CH:8]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(CO)ccc21
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)c2cc(CBr)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A solution of PBr3 (82 mg, 302 μmole) in 5 mL of tetrahydrofuran (THF) was placed in ice bath. 2-Hydroxymethylanthraquinone (100 mg, 421 μmole) obtained from Aldrich Chemical Co., St. Louis, Miss., in 10 mL of THF was added to the mixture slowly over 10 minutes. After 1 hour at 0° C., the reaction temperature was raised to room temperature and the mixture was stirred for 48 hours. The mixture was evaporated and then redissolved in ethyl acetate for H2O extraction. The organic layer was dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. 2-Bromomethylanthraquinone was purified by flash silica column chromatography (Yield=52%). 1H NMR (300 MHz, CDCl3) δ 8.24 (2H, m), 8.14 (1H, s), 8.01(1H,d), 7.70 (1H, d), 7.57 (2H, m), 4.68 (2H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li][CH2:12]CCC.CI>C1COCC1>[CH3:12][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1C(=O)Nc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
A solution of oxindole (665 mg, 5.0 mmol) in THF (10 ml) was treated dropwise with n-BuLi (4.4 ml, 11.0 mmol) at −78° C., stirred for 30 min. at −78° C. To the reaction methyliodine (2 ml) was added dropwise at −78° C. The resulting solution was warmed up to room temperature. The mixture was quenched with water. The reaction solution was partitioned between ethylacetate and water. The organic layer was washed (brine), dried (Na2SO4), filtered and concentrated under vacumm. Purification on silica gel with 30% ethyl acetate/hexane to provide the title compound (630 mg, 86%). MS (DCI/NH3) m/e 148 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([NH2:13])[CH2:6][CH2:5]2.[C:14](N1C=CN=C1)(N1C=CN=C1)=[S:15]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([N:13]=[C:14]=[S:15])[CH2:6][CH2:5]2
Reactant: NC1CCc2cc(F)c(F)cc2C1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: Fc1cc2c(cc1F)CC(N=C=S)CC2
Yield: 79.1 %

Procedure:
A mixture of (-)-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine (0.56 g, 3.06 mmol), prepared as in Example 8, and 1,1'-thiocarbonyldiimidazole (0.82 g, 4.59 mmol) in 15 mL of ethyl acetate was stirred until the reaction was complete. The solvent was removed by evaporation. Purification of the residue by column chromatography on silica gel (solution: 5% acetone/methylene chloride) gave (-)-6,7-difluoro-2-isothiocyano-1,2,3,4-tetrahydronaphthalene (0.55 g, 2.42 mmol). [α]D25 -15.5° (c=1.0, CH3OH)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)c(Br)c1

Procedure:
3-Bromo-4-chlorobenzoic acid (200 mg, 0.849 mmol) was refluxed in the presence of concentrated sulfuric acid (5.49 mg, 0.042 mmol) in methanol (10 mL) at 70° C. for overnight. The reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum, and the compound was purified by column chromatography affording the title compound (130 mg). 1H NMR (400 MHz, CDCl3): δ 8.29 (d, 1H, J=2.0 Hz), 7.91 (dd, 1H, J=2.0 & 8.4 Hz), 7.52 (d, 1H, J=8.4 Hz), 3.92 (s, 3H). ESI-MS: 250.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([S:24](Cl)(=[O:26])=[O:25])[CH3:23]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:24]([CH2:22][CH3:23])(=[O:26])=[O:25])=[CH:6][CH:7]=1
Reactant: Clc1ccc(NCc2cccnc2)cc1
Reactant: CCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(Cl)cc1

Procedure:
A 4.37 g. portion of 3-(4-chlorophenylaminomethyl)pyridine was dissolved in 20 ml. of dichloromethane, and 4.1 g. of potassium carbonate and 3.8 g. of ethanesulfonyl chloride were added. The mixture was stirred under gentle reflux overnight, and was then allowed to stand for several days at ambient temperature. The mixture was extracted with water, dried over magnesium sulfate and filtered. The residue was taken up in chloroform and purified over silica gel, eluting with chloroform. The product-containing fractions were collected and evaporated under vacuum to obtain 1 g. of the desired product, m.p. 104°-106°.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[S:3]([O:6][C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])(C)C)=[O:14])[CH2:9][CH:8]=1)(=[O:5])=[O:4].FC(F)(F)C(O)=O.C(N(CC)CC)C.ClC(OC[C:41]1[CH:46]=[CH:45]C=[CH:43][CH:42]=1)=O>ClCCl>[F:21][C:2]([F:1])([F:20])[S:3]([O:6][C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:19]2[CH:45]=[CH:46][CH:41]=[CH:42][CH:43]=2)=[O:14])[CH2:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50 mL roundbottom flask, was placed tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (3.5 g, 10.00 mmol). To this was added dichloromethane (20 mL) followed by the addition of trifluoroacetic acid (5 mL). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. This was followed by the addition of dichloromethane (20 mL). This was followed by the addition of triethylamine (3.03 g, 29.94 mmol). To the mixture was added benzyl chloroformate (2.05 g, 12.02 mmol). The resulting solution was allowed to react overnight at room temperature. The reaction mixture was filtered and the filtrate was concentrated under vacuo. The crude mixture was purified by silica gel chromatography (1:40 EtOAc/petroleum ether) to yield the title compound as a yellow liquid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]([C:23]1[CH:24]=[CH:25][C:26]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([CH2:33]O)[CH:27]=2)([CH3:22])[CH3:21].C(Cl)(Cl)(Cl)[Cl:36]>>[Cl:36][CH2:33][C:28]1[CH:27]=[C:26]2[C:30](=[CH:31][CH:32]=[C:23]([CH:20]([CH3:22])[CH3:21])[CH:24]=[CH:25]2)[CH:29]=1
Reactant: CC(C)c1ccc2cc(CO)cc-2cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)c1ccc2cc(CCl)cc-2cc1

Procedure:
Triphenylphosphine (0.66 g) was added to a solution of (6-isopropylazulen-2-yl)methanol (0.5 g) in carbon tetrachloride (10.0 ml) and the mixture was refluxed with heating for 15 hours. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (n-hexane-diethyl ether) to obtain 2-(chloromethyl)-6-isopropylazulene (0.38 g).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](=[S:11])[NH2:10])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].Cl[CH2:15][C:16]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]2([CH3:31])[CH3:30])=O.O>C(O)(C)C.N1C=CC=CC=1>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]2[S:11][CH:15]=[C:16]([C:18]3[CH:27]=[CH:26][C:25]4[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=4[CH:19]=3)[N:10]=2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CCl)ccc21
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(-c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)cc1
Yield: 46.2 %

Procedure:
3.2 g (16.5 moles) of 4-carbomethoxybenzothiamide and 4.2 g (16 millimoles) of 6-chloroacetyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (for preparation see Example 28) in 40 ml of isopropanol were refluxed for 1 hour with the addition of 2 drops of pyridine. The mixture was cooled, water was added and the crystals formed were filtered off under suction. Recrystallization from isopropanol and a trace of water gave 3.0 g the title compound of melting point 138°-140° C.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:38][CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([C:48](=[O:55])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:44][CH2:43]1.C1CCN2C(=NCCC2)CC1.C(N(CC)CC)C>C(#N)C>[C:48]([N:45]1[CH2:44][CH2:43][N:42]([CH2:41][CH2:40][CH2:39][NH:38][C:13]([C:5]2[S:6][C:7]3[N:12]4[C:3](=[CH:2][N:1]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[CH:4]=2)=[O:15])[CH2:47][CH2:46]1)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: NCCCN1CCN(C(=O)c2ccccc2)CC1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCCCN1CCN(C(=O)c2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 0.8 g (3.67 mmol.) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 0.84 g (8.8 mmol.) of N-hydroxysuccinimide in acetonitrile (15 ml) was added, at room temperature, 1.41 g (7.36 mmol.) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride. The mixture was stirred for 2 hours. To the reaction system was added a solution of 1.41 g (4.4 mmol.) of 4-(3-aminopropan-1-yl)-1-benzoylpiperazin dihydrochloride, 1.34 g (8.8 mmol.) of 1,8-diazabicyclo[5.4.0]unde-7-cene (DBU) and 1.0 ml (7.17 mmol.) of triethylamine in acetonitrile (15 ml). The mixture was stirred for further 2 hours. The solvent was distilled off under reduced pressure. To the residue was added water, which was subjected to extraction with ethyl acetate (a small volume of ethanol was also used). The organic layer was washed with a saturated aqueous saline solution, dried over magnesium sulfate and subjected to to distillation under reduced pressure. The residue was subjected to fractional purification by means of a column chromatography (methanol/ethyl acetate 30-40%), followed by distilling off the solvent under reduced pressure to afford the object compound as a reddish purple crystalline product. The yield was 0.738 g (45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[O:16][CH3:17]>C(#N)C.C(Br)C1C=CC=CC=1>[CH2:8]([N:13]1[CH2:14][CH2:15][C:10]([CH2:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([O:16][CH3:17])[CH2:12]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: COc1cnccc1CCc1ccccc1F
Agent: BrCc1ccccc1
Solvent: CC#N
Product: COC1=C(CCc2ccccc2F)CCN(Cc2ccccc2)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 159.9 %

Procedure:
After dissolving 1.12 g of 4-[2-(2-fluorophenyl)ethyl]-3-methoxypyridine in 10 ml of acetonitrile, 0.63 ml of benzyl bromide was added, the mixture was stirred for 2 hours at 50° C., and the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml of methanol, and then 552 mg of sodium borohydride was added while cooling on ice and the mixture was stirred for 1 hour. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered with NH silica gel. The solvent was distilled off under reduced pressure to obtain the title compound (1.26 g, 80% yield).
Reaction SMILES: [CH2:1]([CH:3]([CH2:12][CH3:13])[CH2:4][CH:5](C(O)=O)[C:6]([OH:8])=[O:7])[CH3:2]>C(Cl)Cl.CO>[CH2:1]([CH:3]([CH2:12][CH3:13])[CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCC(CC)CC(C(=O)O)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: CCC(CC)CCC(=O)O
Temperature: 25 °C
Yield: 0 %

Procedure:
2-(2-Ethyl-butyl)-malonic acid (3.55 g, 18.8 mmol) was heated at 195° C. for 2 h. After this time, the solution was cooled to 25° C. and diluted with a 90/10 methylene chloride/methanol solution. The organics were then washed with a saturated aqueous sodium chloride solution, concentrated in vacuo and azeotroped with acetonitrile (2×50 mL) to afford 4-ethyl-hexanoic acid (1.24 mg, 45%) as yellow oil, which was used without further purification; EI+-HRMS m/e calcd for C8H16O2 [M−H]+ 143.1072, found 143.1074. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.81 (t, J=7.2 Hz, 6H) 1.02-1.35 (m, 5H) 1.32-1.59 (m, 2H) 2.16 (t, J=7.8 Hz, 2H) 11.98 (br. s., 1H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].[CH3:14][N:15]([CH3:21])[CH2:16][CH2:17][CH2:18][NH:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:14][N:15]([CH3:21])[CH2:16][CH2:17][CH2:18][N:19]([CH3:20])[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6]
Reactant: CNCCCN(C)C
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)CCCN(C)c1cc(C#N)cc(C(F)(F)F)c1

Procedure:
500 mg (2.64 mmol) of 3-fluoro-5-(trifluoromethyl)benzonitrile, 338 mg (2.91 mmol) of N,N,N′-trimethylpropane-1,3-diamine and 767 mg (5.52 mmol) of potassium carbonate in 5.0 ml of DMSO were stirred at 110° C. for 8 h. The reaction mixture was then separated directly into its components by preparative HPLC (Method 12). The product fractions were freed from the solvent, the residue was suspended in ethyl acetate and the suspension was washed successively with saturated aqueous potassium carbonate solution and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate and concentrated. This gave 290 mg (38% of theory) of the title compound.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:9][CH:8]=1)[CH3:6].OS(O)(=O)=O>C1C=CC=CC=1>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([C:5]([CH3:6])=[CH:4][CH2:3][OH:2])=[CH:8][CH:9]=1
Reactant: COC(=O)C=C(C)c1ccc(-c2ccc(F)cc2F)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC(=CCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
33.4 ml. of a 70% solution of NaAl(OCH2CH2OCH3)2H2 in benzene is added dropwise to a stirred mixture of 20.8 g. of 3-(2',4'-difluoro-4-biphenylyl)-2-butenoic acid methyl ester and 100 ml. of benzene and the reaction mixture is stirred overnight at 80°. The mixture is poured into 130 ml. of 20% H2SO4, stirred for one hour and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)-2-buten-1-ol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[C:5]1[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(Cl)(Cl)Cl.CC(C)=O>ClCCl>[S:26]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[C:5]1[CH2:13][C:14]([O:16][CH3:17])=[O:15])([CH3:25])(=[O:28])=[O:27]
Reactant: COC(=O)Cc1c(C(=O)OC)ccn1CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1c(C(=O)OC)ccn1CCOS(C)(=O)=O
Yield: 77.7 %

Procedure:
To a stirred solution of 4.1 g of methyl N-(2-hydroxyethyl)-3-carbomethoxypyrrole-2-acetate in 35 ml of dry dichloromethane cooled to -10° C., are added 2.65 ml of triethylamine and thereafter, in a dropwise fashion, 1.46 ml of methanesulfonyl chloride, maintaining the temperature of the reaction mixture at -10° to -5° C. The course of the reaction is followed by t.l.c. analysis using chloroform:acetone (90:10). When the reaction appears to be complete (about 30 minutes after the addition of the methanesulfonyl chloride is terminated) there is added slowly 10 ml of water. The organic phase is separated, washed with water (3×30 ml), dried over sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from dichloromethane affords 4.75 g (77.7%) of methyl N-(2-mesyloxyethyl)-3-carbomethoxypyrrole-2-acetate (V,R=H), m.p. 99°-101° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:26].[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(O)C.C(Cl)Cl.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][C:25]([N:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH2:29][CH2:28]4)=[O:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(CBr)N1CCc2ccccc21
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1CCc2ccccc21

Procedure:
A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (10 g, 45.4 mmol), K2CO3 (7.2 g, 52.5 mmol) and N-(2-bromoacetyl)indoline (12 g, 50 mmol) in acetronitrile (300 ml) was heated at reflux for 4 hours. The mixture was cooled and filtered. The solution was concentrated down until solid appeared. The crystals were collected: weight 12.68 g. The mother liquor was concentrated to dryness. The residues were purified further by flash chromatography to yield an additional 1.35 g. Total yield was 14.03 g. A 2 g sample was dissolved in ethanol/methylene chloride and was treated with a solution of fumaric acid (612 mg) in ethanol to yield 2.58 g, m.p. 226°-227° C.