Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:15][CH2:16][CH2:17][Cl:18]>CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][O:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1ccccc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCOc1ccccc1
Yield: 96.8 %

Procedure:
To a suspension of 44 g (0.318 mol) of K2CO3 in 300 ml of acetone, 15 g (0.159 mol) of phenol and 18.9 ml (0.191 mol) of 1-bromo-3-chloropropane are added successively at r.t. under N2 atmosphere. The mixture is refluxed for 6 h and concentrated under reduced pressure. The crude mixture is diluted with cold 1N aqueous NaOH and extracted with AcOEt. The combined extracts are washed with H2O, dried over MgSO4 and concentrated under reduced pressure to give 26.25 g of (3-chloro-propoxy)-benzene (yield 83%); NMR (CDCl3): 2.20-2.27 (m, 2H), 3.75 (t, 2H, J=6.04 Hz), 4.11 (t, 2H, J=6.04 Hz), 6.9-6.97 (m, 3H), 7.25-7.31 (m, 2H).
Reaction SMILES: [SH:1][C:2]1[N:3]=[N:4][NH:5][CH:6]=1.[Cl-].[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH2:9].[CH2:16](O)C>>[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][S:1][C:2]2[NH:3][N:4]=[N:5][CH:6]=2)=[CH:12][CH:11]=1)=[CH2:9]
Reactant: C=Cc1ccccc1
Reactant: Sc1c[nH]nn1
Reactant: CCO
Agent: [Cl-]
Product: C=Cc1ccc(CSc2cnn[nH]2)cc1

Procedure:
10 mmole of 4-mercapto-1H-1,2,3-triazole (sodium salt) was dissolved in 20 ml of ethanol in stirring. 10 mmole of 4-vinylbenzene chloride was added, and stirred overnight. The precipitate was removed by filtration, the solvent in the filtrate was removed in vacuum. The obtained solid was separated with a Si gel column (solvents: 1 ethylacetate/1 hexane in volume). 2.1 g product was obtained. 1H NMR (CD3Cl): 7.46 (1H, s), 7.31 (2H, d, JH-H=8.16), 7.18 (2H, d, JH-H=8.16), 6.67 (1H, m), 5.71 (1H, d, JH-H=16.68), 5.22 (1H, d, JH-H=11.68), 4.09 (2H, S).
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].O=[C:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1>CN(C=O)C.CCOCC>[Br:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.6 %

Procedure:
To [(3-bromophenyl)methyl](triphenyl)phosphonium bromide (1.13 mg, 2.2 mmol) in DMF (4 mL) was added NaH (52.8 mg, 2.2 mmol). This mixture was stirred at RT for 5 min, then 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (400 mg, 2.0 mmol) was added and the pot stirred at RT for 1 h. The resultant mixture was diluted with Et2O (25 mL), washed with H2O (12+2×8 mL), brine (8 mL), dried over NaSO4, and filtered. The mixture was concentrated and purified with CombiFlash chromatograph to afford the title compound (0.2014 g, 28%). LC-MS m/z 352 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH:9]2[CH2:11][CH:10]2[CH2:12][C:13]#N)[C:3]=1[CH3:15].Cl.O.C([O-])(O)=[O:19].[Na+].[CH2:23]([OH:25])[CH3:24]>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH:9]2[CH2:11][CH:10]2[CH2:12][C:13]([O:25][CH2:23][CH3:24])=[O:19])[C:3]=1[CH3:15]
Reactant: O=C([O-])O
Reactant: Cc1c(C2CC2CC#N)ncc(F)c1Cl
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC1CC1c1ncc(F)c(Cl)c1C
Reaction time: 1 h

Procedure:
A sample of 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile (3.26 g, 14.51 mmol) was dissolved in 10 mL of ethanol, and gaseous HCl was introduced until 4 g had been dissolved. The solution was heated to reflux, and 0.36 mL of water was added, then the mixture was stirred for 1 hour. The reaction was cooled, then poured into water, and the mixture was adjusted to pH7 with NaHCO3. The mixture was then extracted with methylene chloride, which was washed with water, dried over MgSO4 and concentrated. The residue was triturated with 1:4 ethyl acetate:hexane, and filtered. The filtrate was concentrated and the residue was purified by flash chromatography with 1:4 ethyl acetate:hexane to give 2.262 g of ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetate after removal of the solvent. MS 272, 274 (M+H)+ ; 1H NMR (CDCl3)∂: 0.12 (m, 1H), 0.38 (m, 1H), 0.53 (m, 1H), 0.76 (m, 1H), 1.20 (t, 3H, J=7 Hz), 1.67 (m, 1H), 2.40 (s, 3H), 3.23 (d, 1H, J=9 Hz), 4.16 (q, 2H, J=7 Hz), 8.36 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:5][N:4]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:5][N:4]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CC(=O)c1ccc(CO)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)c1ccc(COS(C)(=O)=O)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Dissolve 2-hydroxymethyl-5-(3-methyl-butyryl)-pyridine (190 mg, 0.98 mmol) in dichloromethane (10 mL). Cool to 0° C. and add triethylamine (0.151 mL, 1.08 mmol) and methanesulfonyl chloride (0.083 mL, 1.08 mmol). Allow the mixture to warm to room temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane and wash with saturated aqueous NaHCO3. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to provide the title compound as oil (263 mg, 98%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C@@H:26]([C@@H:28]2[CH2:32][O:31]C(C)(C)[O:29]2)[CH3:27])[N:12]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C@H:26]([CH3:27])[C@@H:28]([OH:29])[CH2:32][OH:31])[N:12]=1
Reactant: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Agent: Cl[Fe](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@@H](O)CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product of step ii) (0.13 g) in DCM (5 mL) was added iron (III) chloride hexahydrate (0.24 g). The reaction mixture was stirred at ambient temperature for 1 h, then saturated aqueous sodium bicarbonate (10 mL) was added. The layers were separated and the aqueous material extracted with DCM (3×10 mL) and EtOAc (3×10 mL). The combined organic extracts were washed with saturated sodium chloride, dried (MgSO4), filtered and evaporated. The residual pale yellow solid was slowly precipitated from DCM, filtered and the resulting material washed with minimal cold DCM (2×1 mL) to afford the title compound as a white powder. Yield: 45 mg.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH3:14])=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[NH:25][CH2:26][C:27]([O:29]CC)=O)=[CH:19][CH:18]=1)#[N:2].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1COCC1>[O:32]=[C:24]1[NH:25][CH2:26][C:27](=[O:29])[N:23]1[C:20]1[CH:19]=[CH:18][C:17]([C:4]2[N:5]([CH2:15][CH3:16])[C:6]3[C:11]([C:3]=2[C:1]#[N:2])=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH3:14])[CH:7]=3)=[CH:22][CH:21]=1
Reactant: CCOC(=O)CNC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCC)cc3n2CC)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOc1ccc2c(C#N)c(-c3ccc(N4C(=O)CNC4=O)cc3)n(CC)c2c1
Reaction time: 8 h

Procedure:
A solution of ethyl {3-[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-ureido}-acetate (compound 773, 101 mg, 0.232 mmol) in THF (10 mL) is treated with a solution of potassium tert-butoxide in tert-butanol (0.30 mL, 1.0 M, 0.30 mmol), and the resulting mixture is allowed to stir overnight. The reaction mixture is partitioned between water and ethyl acetate (50 mL each), and the organic phase is washed with saturated brine. The aqueous phases are extracted with more ethyl acetate, and the extracts are combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is separated by column chromatography (eluting 2/1 ethyl acetate/hexane on silica gel 60) to afford 2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile, compound 779, which is purified further by trituration with ether, collection by filtration and drying under high vacuum (76 mg, 0.196 mmol, 84%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH:28]#[C:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)Cl.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.[Cu]I>[C:28]([C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1)#[C:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reactant: C#CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC#Cc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
To a solution of 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 54b (180 mg, 0.48 mmol), bis(triphenylphosphine)palladium(II) chloride (7 mg, 0.05 mmol), copper (I) iodide (2 mg) and triethylamine (1.0 mL) in methylene chloride (3 mL) was added 1-hexyne (8.3 mL, 0.72 mmol). The mixture was refluxed overnight and cooled to room temperature. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with ethyl acetate:hexane 1:1 to afford the title compound (102 mg, 56% yield). MS (CI/NH3) m/z 379 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ0.96 (t, J=6.6 Hz, 3H), 1.43 (s, 9H), 1.46-1.69 (m, 4H), 2.20-2.40 (m, 2H), 2.44-2.56 (m, 2H), 3.83-3.92 (m, 2H), 4.06-4.15 (m, 1H), 4.26-4.38 (m, 1H), 4.45-4.57 (m, 1H), 7.34 (br s, 1H), 7.51-7.58 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)=[O:20]>O>[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:2]2[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])=[CH:24][CH:23]=1)(=[O:20])[CH3:18]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: CC(=O)Nc1ccc(N)cc1
Solvent: O
Product: CC(=O)Nc1ccc(Nc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 25 °C

Procedure:
The starting material is prepared as follows: The mixture of 5.6 g of 4-chloro-3-nitro-5-sulfamoylbenzoic acid, 200 ml of water and 9 g of 4-aminoacetanilide is refluxed for four hours while stirring under nitrogen. It is cooled to room temperature and the precipitate formed filtered off, to yield the 4-(4-acetamidophenylamino)-3-nitro-5-sulfamoylbenzoic acid, melting above 275°.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:19].[CH3:20][S:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>C1COCC1>[CH3:9][CH:10]1[CH:18]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([S:21][CH3:20])=[CH:23][CH:24]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:19]
Reactant: CSc1ccc(CCl)cc1
Reactant: CC1Cc2ccccc2C1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(CC2c3ccccc3C(=O)C2C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cooled solution (-70° C.) of LDA (1M) in THF (37 mL) was added dropwise a solution of 2-methyl-1-indanone (J.A.C.S. Vol. 98, 8119-8124 (1976)) (2.5 g, 17 mmol) in THF (20 mL). The resulting dark red solution was stirred at room temperature for 3 hours, then cooled to -20° C. and a solution of 4-methylthiobenzyl chloride (3.1 g, 18 mmol) in THF (15 mL) was added slowly. The addition completed, the reaction mixture was stirred at -20° C. for 30 minutes before being quenched with 3N aqueous HCl (50 mL) and brine (50 mL). The product was extracted with ether, dried over MgSO4 and evaporated to dryness. The oily residue was chromatographed on silica gel eluting with a 1:5 mixture of ethyl acetate-hexane to afford the pure title compound as an oil.
Reaction SMILES: [C:1]([C:5]#[CH:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:12]([CH:14]=[CH2:15])=[O:13]>>[CH3:2][C:1]([CH3:4])([CH3:3])[C:5]#[C:6][CH:12]([OH:13])[CH:14]=[CH2:15]
Reactant: C=CC=O
Reactant: C#CC(C)(C)C
Agent: [Li]CCCC
Product: C=CC(O)C#CC(C)(C)C
Temperature: -75 °C

Procedure:
Reacting t-butylacetylene at −20° C. with butyllithium, cooling the reaction mixture to −75° C. and reacting it with acrolein to give 6,6-dimethylhept-1-en-4-yn-3-ol.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[O:21])[CH:15]=2)=[C:9]([CH3:22])[CH:8]=1)[CH3:2].[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][OH:21])[CH:15]=2)=[C:9]([CH3:22])[CH:8]=1)[CH3:2]
Reactant: CCOCCSc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOCCSc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Temperature: 0 °C
Yield: 95.8 %

Procedure:
To a solution of 4′-[(2-ethoxyethyl)thio]-2′,6′-dimethylbiphenyl-3-carbaldehyde (0.97 g, 3.10 mmol) in a mixture of tetrahydrofuran (4 mL) and methanol (2 mL) was added sodium borohydride (0.07 g, 1.59 mmol) under stirring at 0° C., and the mixture was stirred at the same temperature for 10 min. The reaction solution was concentrated under reduced pressure, the residue was diluted with ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=5/1) to give the title compound (0.94 g, yield 96%) as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[CH:8][CH:7]=[CH:6]2.N.[Li]>C(O)C>[OH:13][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH2:12][C:3](=[O:2])[CH2:4]2
Reactant: COc1ccc2c(O)cccc2c1
Agent: N
Agent: [Li]
Solvent: CCO
Product: O=C1CCc2c(O)cccc2C1
Reaction time: 0.17 h

Procedure:
To a stirred slurry of 8.0 g. (0.048 mole) of 6-methoxy-1-naphthol and 200 ml. of liquid ammonia held below the reflux temperature by external cooling there is added 1.05 g. (0.15 g. - atom) of lithium ribbon over 25 minutes. After a further 10 minutes at this temperature, 20 ml. of ethanol is added over 30 minutes. As the blue color fades, the ammonia is evaporated and the residue stirred overnight under nitrogen with 50 ml. of water, 50 ml. of tetrahydrofuran and 35 ml. of conc. hydrochloric acid. Extraction with three 100 ml. portions of chloroform followed by drying and solvent removal gives 7.24 g. of solid. Recrystallization (4:1) hexane-ethyl acetate gives 5.04 g. (68%) of ketone, m.p. 168°-171° (lit m.p. 155°-162° dec.), JACS 80, 2887 (1958).
Reaction SMILES: ClC[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].[CH2:8]([O:10][C:11](=[O:23])[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:13])[CH3:9].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:8]([O:10][C:11](=[O:23])[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:3][CH2:4][N:5]([CH3:7])[CH3:6])[CH:15]=1)=[O:13])[CH3:9]
Reactant: CN(C)CCCCl
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(=O)c1cn(CCN(C)C)c2ccccc12
Yield: 63.3 %

Procedure:
The general procedure 1 was then followed using 1-chloro-3-dimethylaminopropane (7 mmol, 0.75 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (6 mmol, 1.3 g) and Cs2CO3 (6.6 mmol, 2.15 g). The purification was achieved by column chromatography (petrolether:ethylacetate:diethylamine 6:3:1) to yield ethyl-2-{1-[2-(dimethylamino)ethyl]-1H-indol-3-yl}-2-oxoacetate (3.8 mmol, 63%) as an pale yellow oil. IR {tilde over (ν)} [cm−1]=3023; 2962; 2917; 1732; 1630. EI-MS m/z (rel. int.)=302 (8.21%; M+•). 1H NMR (300 MHz, CDCl3) 8.43 (m; 1H; indole-H); 8.39 (s; 1H; indole-H); 7.33 (m; 3H; indole-H); 4.40 (q; 3J=7.1 Hz; 2H; OCH2CH3); 4.27 (t; 3J=6.8 Hz; 2H; indole-CH2CH2CH2N); 2.22 (s; 6H; N(CH3)2); 2.20 (m; 2H; indole-CH2CH2CH2N); 2.00 (quint; 3J=6.7 Hz; 2H; indole-CH2CH2CH2N); 1.42 (t; 3J=7.1 Hz; 3HOCH2CH3).
Reaction SMILES: C1(S(CC[CH2:12][C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=O)=O)C=CC=CC=1.Cl.[F:23][C:24]1[CH:38]=[CH:37][C:27]2[C:28]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[N:29][O:30][C:26]=2[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:45][C:46](=O)[CH2:47]C>O>[F:23][C:24]1[CH:38]=[CH:37][C:27]2[C:28]([CH:31]3[CH2:32][CH2:33][N:34]([CH2:45][CH2:46][CH2:47][C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[NH:14][C:13]=4[CH3:12])[CH2:35][CH2:36]3)=[N:29][O:30][C:26]=2[CH:25]=1
Reactant: O=S(=O)(CCCc1cc2ccccc2[nH]1)c1ccccc1
Reactant: CCC(C)=O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1[nH]c2ccccc2c1CCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 31.5 %

Procedure:
A stirred mixture of 3.1 g of 2-methyl-3-(3-phenylsulfonylpropylindole, 2.1 g of 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, 6.3 g of potassium carbonate and 50 ml of 2-butanone was heated under reflux for 24 hrs. The reaction mixture was poured into water and the aqueous mixture was extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resultant oil was triturated with isopropyl ether and the solid was collected. The solid was combined with a 1.6 g sample of previously prepared material and the combined sample was chromatographed on 100 g silica gel, using 2% methanol-chloroform as eluent. The eluent was evaporated and the solid was dissolved in 125 ml toluene and a saturated hydrogen chloride-toluene solution was added until no more precipitate formed. The precipitate was filtered and dried. Recrystallization from acetone afforded 2.7 g (31.5%) of product, mp 208°-210°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:17])[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: [NH4+]
Agent: [Cl-]
Product: CC(C)(C)OC(=O)N1CCCCC1CC(N)=O
Yield: 46.2 %

Procedure:
The title compound (0.92 g) wvas prepared from 2-(RS)-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) and ammonium chloride (0.86 g) according to the method of Example 97.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][S:6]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:21])(=[O:8])=[O:7].[CH3:22][O:23]C(Cl)Cl>C(Cl)Cl>[CH3:5][S:6]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[C:16]([CH:22]=[O:23])[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:21])(=[O:8])=[O:7]
Reactant: COC(Cl)Cl
Reactant: COc1ccc2c(c1)CCC(=O)N2S(C)(=O)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)N(S(C)(=O)=O)C(=O)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a flame dried round bottom flask equipped with a nitrogen cap was added 180 mg (1.35 mmol) aluminum chloride and 10 ml of methylene chloride. The mixture was stirred at ambient temperature for 0.25 hour and then cooled to 0° C. followed by the addition of 177 mg (0.69 mmol) 1-methanesulfonyl-6-methoxy-3,4-dihydro-1H-quinolin-2-one. The reaction mixture was stirred for 10 minutes at this temperature and was then treated with 171 μl (1.89 mmol) of α,α-dichloromethyl methyl ether before allowing the reaction to slowly warm to room temperature over 16 hours. The reaction mixture was quenched with 30 ml of 2M HCl and extracted with ethyl acetate (3×30 ml). The combined organics were then washed with saturated aqueous bicarbonate solution and brine followed by drying over sodium sulfate and evaporation in vacuo. The crude residue was purified on silica gel eluting with 95/5 methylene chloride/methanol to afford an off white solid in 66% yield (130 mg). Mass spectrum APCI m/e 284 (p+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.[C:18]([O-:21])([O-:20])=O.[K+].[K+].Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([C:35](=[O:37])[CH3:36])[CH:32]=[CH:33][CH:34]=1>>[C:5]([OH:28])(=[O:9])/[CH:6]=[CH:16]/[C:18]([OH:21])=[O:20].[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:30]=[C:31]([C:35](=[O:37])[CH3:36])[CH:32]=[CH:33][CH:34]=4)[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cccc(OCCCCl)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: [K+]
Product: CC(=O)c1cccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c1
Product: O=C(O)/C=C/C(=O)O
Yield: 48.2 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.53 g, 20.5 mmol), K2CO3 (4.5 g), 1-[3-(3-chloropropoxy)phenyl]ethanone (6.4 g, 29 mmol) in acetronile (60 ml) was heated at reflux for 5 hours. At the end of the reaction, the solvent was removed and the residue was extracted into dichloromethane (300 ml). The inorganic insolubles were filtered off. The dichloromethane solution was concentrated to a small volume (10 ml) and purified on a flash chromatographic column (SiO2, 75 g, eluted with dichloromethane, 900 ml; and 2% methanol in dichloromethane, 800 ml). The fractions containing the pure product were combined and concentrated to an oil (2.87 g, 35%). The oil was dissolved into ethanol and treated with a solution of fumaric acid (841 mg). Recrystallization (twice) from ethanol afforded 2.53 g of 1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone fumarate as white crystals, m.p.=172-174° C.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].S(Cl)(Cl)=O.N1C=CC=CC=1.[CH:27]1(O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1C=CC=CC=1>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:16])[C:13]([O:15][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:14])=[CH:10][CH:11]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: CC(C)=CCc1ccc(C(C)C(=O)O)cc1
Reactant: OC1CCCCC1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)=CCc1ccc(C(C)C(=O)OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To an ice-cooled solution of 26.0 g of 2-(p-prenylphenyl)propionic acid in 200 ml of benzene were added dropwise 15.7 g of thionyl chloride and 10.4 g of pyridine at the same time with stirring over one hour, and then the mixture was stirred at room temperature for 30 minutes. After ice-cooling, to this mixture were added 13.0 g of cyclohexanol and 10.4 g of pyridine. The resulting mixture was stirred for 2 hours at room temperature, and then washed with 1 N hydrochloric acid, water, 5% aqueous sodium hydroxide and water successively, and dried over anhydrous mangesium sulfate. The solvent was evaporated to give 23.5 g of cyclohexyl 2-(p-prenylphenyl)propionate. b.p. 142° C./0.06 mmHg, IR νmaxneat ; 1730 cm-1.