Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:8](=[O:9])[C:7]([CH:11]([CH3:13])[CH3:12])([CH3:10])[N:6]=[C:5]1[C:14]1[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:33])C=1.CCOCC>C(Cl)Cl>[C:1]([N:4]1[C:8](=[O:9])[C:7]([CH:11]([CH3:13])[CH3:12])([CH3:10])[N:6]=[C:5]1[C:14]1[N+:23]([O-:33])=[C:22]([CH3:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(C)nc1C1=NC(C)(C(C)C)C(=O)N1C(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1ccc(C)[n+]([O-])c1C1=NC(C)(C(C)C)C(=O)N1C(C)=O

Procedure:
A solution of 29 g of methyl 2-(1-acetyl-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-6-methylnicotinate and 28.7 g of 80% M-chloroperbenzoic acid in 250 mL of methylene chloride is stirred and heated at reflux for 31/2 hours. The reaction mixture is filtered, and the solid is thoroughly washed with methylene chloride. The combined filtrates are cooled and treated cautiously with saturated aqueous sodium bisulfite until a negative starch-iodide test is obtained. The mixture is again filtered, and the organic layer is washed with saturated sodium bicarbonate solution, dried, and concentrated in vacuo to give an oil. Trituration of this oil with ether affords the desired product as a pale yellow solid, mp 135°-138.5° C.
Reaction SMILES: O.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[C:11]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[OH-].[K+]>CC1C=CC(C(C)C)=CC=1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]([OH:18])=[O:17])=[CH:3]1
Reactant: O=C1CCCCCO1
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: O
Product: O=C(O)CCCCCc1c[nH]c2ccccc12
Reaction time: 96 h

Procedure:
In a water separator, indole (50 g, 0.43 mol.), ε-caprolactone (oxepan-2-one, 55.9 g, 0.49 mol.), potassium hydroxide (35.9 g, 0.64 mol.) in p-cymene (1-isopropyl-4-methylbenzene, 250 ml) were heated at boiling for 4 d, with stirring. For working up, water (200 ml) was added to the mixture, the phases were separated, and the aqueous phase was adjusted to pH 4 with 2M HCl and stored for 2 d at 4° C. in a refrigerator. The resulting solid was filtered off with suction and washed with water (3×20 ml). Recrystallisation from ether (50 ml) yielded 6-(1H-indol-3-yl)hexanoic acid in the form of a white solid having a melting point of 124–126° C. in a yield of 16.9 g.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[F:14])[N:5]=[C:4]([CH3:15])[C:3]=1[C:16]#[N:17].[I:18]CI.N(OCCC(C)C)=O>CC#N.C(Cl)Cl>[F:14][C:8]1[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=1[N:6]1[C:2]([I:18])=[C:3]([C:16]#[N:17])[C:4]([CH3:15])=[N:5]1
Reactant: Cc1nn(-c2ccc(O)cc2F)c(N)c1C#N
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1nn(-c2ccc(O)cc2F)c(I)c1C#N
Temperature: 50 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
To a stirred solution of 5-amino-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (114 mg, 0.49 mmol) in MeCN (2.5 mL) was added diiodomethane (0.293 mL, 3.63 mmol) followed by isoamyl nitrite (0.029 mL, 0.216 mmol). The reaction vessel was heated using a heating gun to initiate the reaction. After the rest of isoamyl nitrite (0.261 mL, 1.94 mmol) was added and the reaction was stirred for 1 hour at 50° C. The reaction was diluted with DCM and concentrated into silica and purified using silica gel (Heptane-EtOAc 1:0 to 0:1) to give 1-(2-fluoro-4-hydroxyphenyl)-5-iodo-3-methyl-1H-pyrazole-4-carbonitrile (90.0 mg, 53%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].FC(F)(F)C(O)=O.[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=[C:39]([CH:60]=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.[F:61][C:62]1[CH:70]=[C:69]([F:71])[CH:68]=[CH:67][C:63]=1[C:64](Cl)=[O:65]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=[C:39]([CH:60]=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:55][CH2:56][N:57]([C:64](=[O:65])[C:63]2[CH:67]=[CH:68][C:69]([F:71])=[CH:70][C:62]=2[F:61])[CH2:58][CH2:59]1
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Clc1cnc2nc1Nc1ccc(NCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(F)cc1F)N1CCC(CCNc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 30 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-N-(2-piperidin-4-ylethyl)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tetrakis(trifluoroacetate) and 2,4-difluorobenzoyl chloride as the starting materials in 30% yield. LCMS for C31H31ClF2N7O (M+H)+: m/z=590.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH2:40])[CH:37]([CH3:39])[CH3:38]>C(Cl)(Cl)Cl.C(N(CC)CC)C.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:40][CH2:36][CH:37]([CH3:39])[CH3:38])=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)CN
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCC(C)C)c(F)c3)c2cc1OC

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml), and a solution of triphosgene (104 mg) in dichloromethane was then added to the solution. The mixture was heated under reflux for 5 min. Next, isobutylamine (50 μl) was added to the reaction solution, and the mixture was heated under reflux for 10 min. The reaction solution was purified by chromatography on silica gel by development with chloroform/acetone (4/1). Thus, the title compound was quantitatively obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:24]=3[N:25]=2)=[C:15]([Cl:32])[CH:14]=1)(=[O:11])=[O:10].[OH-:33].[K+].Cl>C(O)(C)(C)C>[Cl:19][C:17]1[CH:18]=[C:13]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:10])[CH:14]=[C:15]([Cl:32])[C:16]=1[S:20][C:21]1[S:22][C:23]2[CH:29]=[CH:28][C:27]([C:30]([NH2:31])=[O:33])=[CH:26][C:24]=2[N:25]=1
Reactant: [OH-]
Reactant: N#Cc1ccc2sc(Sc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)nc2c1
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1ccc2sc(Sc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)nc2c1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
To a solution of 2,4-dichloro-N-[3,5-dichloro-4-(5-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-benzenesulfonamide (297) (250 mg, 0.45 mmol) in tert-butanol (10 mL), was added KOH (EM Science Product, 126 mg, 2.25 mmol). The resulting mixture was refluxed for 1 hour. After cooling to room temperature, a 1M aqueous solution of HCl (50 mL) was added and the crude reaction mixture was extracted 3× with EtOAc (50 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (20% EtOAc in CH2Cl2, then 10% MeOH in CH2Cl2) to yield 207 mg (80%) of compound 303 as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]2=[N:8][C:7]=1[NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:5])[CH3:2].C(N(CC)CC)C.[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[F:37])[C:31](Cl)=[O:32]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]2=[N:8][C:7]=1[N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:36]([F:37])=[C:28]([F:27])[CH:29]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCCCNc1nc2n(c1C(=O)OCC)CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN(C(=O)c1ccc(F)c(F)c1)c1nc2n(c1C(=O)OCC)CCCC2
Temperature: 0 °C

Procedure:
Compound F (3.2 g, 12.1 mmol) and triethylamine (2.54 mL, 18.1 mmol, 1.5 eq.) were dissolved in DCM (70 mL) and the solution was cooled to 0° C. 3,4-difluorobenzoylchloride (1.66 mL, 13.3 mmol, 1.1 eq.) was added dropwise. After 90 minutes the reaction mixture was diluted with DCM (130 mL) and washed with 0.5 M KHSO4 in water (200 mL), saturated aqueous NaHCO3 solution (200 mL) and saturated aqueous NaCl solution (200 mL). The combined organic phases were dried over sodium sulphate and the solvent was removed under vacuum and the untreated product 2-[butyl-(3,4-difluoro-benzoyl)-amino]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester was used directly in the next stage.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](F)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:18][NH2:19].CS(C)=O>O>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]([NH:18][NH2:19])[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1cccc(F)c1
Reactant: NN
Solvent: O
Solvent: CS(C)=O
Product: NNc1cccc(S(=O)(=O)c2ccccc2)c1
Temperature: 118 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A mixture of 1-benzenesulfonyl-3-fluoro-benzene (1.34 g, 5.7 mmol), hydrazine hydrate (1.4 mL) and dimethyl sulfoxide (2 mL) was stirred at 118° C. for 18 h, then cooled and poured into water (100 mL). The resulting colourless crystals were collected by filtration to give the title compound (1.34 g, 95%). 1H NMR (DMSO-d6): 7.95-7.84 (2H, m), 7.73-7.56 (3H, m), 7.37-7.21 (3H, m), 7.06 (1H, d), 6.96 (1H, dd), 4.14 (2H, br m).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH:6](N)[CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:2]1.CS(OC1CCOCC1)(=O)=O.[Li+].CC([N-:30]C(C)C)C>>[O:1]1[CH2:2][CH2:3][CH:6]([CH:7]([NH2:30])[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:5]1
Reactant: CC(C)[N-]C(C)C
Reactant: NC(Cc1cccnc1)C1CCOC1
Agent: CS(=O)(=O)OC1CCOCC1
Agent: [Li+]
Product: NC(c1cccnc1)C1CCOCC1
Yield: 52 %

Procedure:
The 1-(4-oxanyl)-1-(3-pyridyl)methylamine was synthesized essentially according to the procedure described above for the synthesis of 1-(3-oxolanyl)-2-(3-pyridyl)ethylamine. Thus, 4-oxanyl methanesulfonate (0.99 g, 5.5 mmol), prepared according to the procedure of Suto et al., J. Med. Chem., 34: 2484 (1991), was treated with the imine anion generated by reacting N-(diphenylmethylidene)-3-(aminomethyl)pyridine (1.36 g, 5.0 mmol) with LDA (5.5 mmol in 5.0 mL THF). A work up similar to the one described for the synthesis of 1-(3-oxolanyl)-2-(3-pyridyl)ethylamine, followed by purification by column chromatography (15% methanol in chloroform), yielded 1-(4-oxanyl)-1-(3-pyridyl)methylamine (499 mg, 52% yield).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[N+:6]([C:9]1[N:14]=[CH:13][C:12]([C:15](=O)[CH2:16][NH:17]C(=O)C)=[CH:11][CH:10]=1)([O-:8])=[O:7].[OH-].[K+]>CO>[NH2:4][C:3]1[NH:17][CH:16]=[C:15]([C:12]2[CH:13]=[N:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=2)[C:2]=1[C:1]#[N:5]
Reactant: N#CCC#N
Reactant: CC(=O)NCC(=O)c1ccc([N+](=O)[O-])nc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1c(-c2ccc([N+](=O)[O-])nc2)c[nH]c1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
0.022 g (0.336 mmol) of malononitrile is added at a temperature in the region of 20° C., under an argon atmosphere, to 0.050 g (0.224 mmol) of N-[2-(6-nitropyridin-3-yl)-2-oxoethyl]acetamide in solution in 5 cm3 of methanol. The reaction medium is cooled to a temperature in the region of 0° C. and then 0.1 cm3 of a 50% aqueous potassium hydroxide solution is added. After stirring for 15 minutes at a temperature in the region of 20° C. and then for 1.15 hours at a temperature in the region of 65° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and then diluted in 50 cm3 of ethyl acetate. The organic phase is washed with 10 cm3 of water and 10 cm3 of a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.043 g of 2-amino-4-(6-nitropyridin-3-yl)-1H-pyrrole-3-carbonitrile in the form of a brown solid. ES+: m/z=230 (MH+).
Reaction SMILES: [OH:1][C:2]([CH3:15])([CH2:13][CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8](SC)=[CH:7][CH:6]=1)=[O:4].O[O:17][S:18]([O-:20])=O.[K+].[CH2:22](Cl)Cl>CO.O>[OH:1][C:2]([CH3:15])([CH2:13][CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:18]([CH3:22])(=[O:20])=[O:17])=[CH:7][CH:6]=1)=[O:4]
Reactant: ClCCl
Reactant: CCC(C)(O)C(=O)c1ccc(SC)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the tertiary alcohol from Step 2 (4.5 g, 20.1 mmol) in CH2Cl2 (100 mL), MeOH (100 mL) and H2O (25 mL) was added Oxone® (9 g). After 3 h at r.t. a second 9 g portion of Oxone® was added and the mixture was stirred overnight at r.t. The solvent was then removed under vacuum, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O and brine, and was then dried (MgSO4), filtered, and evaporated. Purification was effected by flash chromatography (1:2 EtOAc: hexane) to give 5.5 g of the title compound as a tan coloured oil.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([O:24][CH2:25][C:26]([O:28]C)=[O:27])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:30](=[O:32])[NH2:31])[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+]>C(O)C>[F:33][C:2]([F:1])([F:34])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([O:24][CH2:25][C:26]([OH:28])=[O:27])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:30](=[O:32])[NH2:31])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.4 %

Procedure:
A suspension of the {9-[(3-trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (22.4 mg, 0.047 mM) and 0.065 mL (0.065 mM) of 1 N NaOH in 5 mL of ethanol was stirred for 24 hours at 25° C. The solvent was removed in vacuo and the residue suspended in EtOH. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 9 mg (41%) of the {9-[(3-trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. MS (ES) m/e 457, 459.
Reaction SMILES: C(O[CH:6]1[O:10][N:9]=[C:8]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7]1)CCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([C:8]2[CH:7]=[CH:6][O:10][N:9]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: CCCCOC1CC(C(=O)c2ccc(OC)cc2)=NO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)c2ccon2)cc1

Procedure:
20.4 g of 5-butoxy-3-(4-methoxybenzoyl)-2-isoxazoline and 1.4 g of p-toluenesulfonic acid in 200 ml of toluene are stirred under reflux for 8 hours. Stirring with 50 ml of sodium hydrogen carbonate solution is then carried out and the aqueous phase is separated off. After concentration of the organic phase and purification over silica gel, 3-(4-methoxybenzoyl)isoxazole is obtained in the form of colourless crystals, m.p: 71-73° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C1CCN2C(=NCCC2)CC1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CC(O)C>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:3]=2)[NH:7]1
Reactant: CCOC(=O)CBr
Reactant: O=C1Cc2cc(O)ccc2N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Product: CCOC(=O)COc1ccc2c(c1)CC(=O)N2
Temperature: 80 °C

Procedure:
To a stirred solution of 5-hydroxyindolin-2-one (1 g, 6.70 mmol) in 2-Propanol (10 mL) was added DBU (1.52 mL, 10.06 mmol) and ethyl bromoacetate (1.12 mL, 10.06 mmol) at room temperature. The reaction mixture was refluxed at 80° C. for 12 h. After completion of the reaction as monitored by TLC, the reaction mixture was concentrated and water (100 mL) was added. The solid which precipitated was filtered and dried to yield ethyl 2-((2-oxoindolin-5-yl)oxy)acetate as an off white solid (0.75 g, 47.6%) LCMS: RT 0.67 min. LCMS (ES-API), m/z 236.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:3]=1[C:4]=23.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[N:8]1[C:9]2[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:2]([O:1][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:3]3[CH2:18][CH2:17][CH2:16][C:5]([C:4]=23)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1c2c3c(ccnc3c3ccccc13)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c2c3c(ccnc3c3ccccc13)CCC2
Temperature: 20 °C
Yield: 46 %

Procedure:
7-Hydroxy-5,6-dihydro-4H-dibenzo[de,h]quinoline (27 g) [prepared as described in Example 2] is added to a suspension of sodium hydride (50% dispersion in mineral oil; (5.75 g) in anhydrous dimethylformamide (520 cc) and then, after stirring for 4 hours, ethyl bromoacetate (21.3 g) in solution in anhydrous dimethylformamide (20 cc) is added. The reaction mixture is maintained for 22 and a half hours at about 20° C., is distilled water (10 cc) is added, the mixture is concentrated to a volume of 400 cc, distilled water (4600 cc) is added and the mixture is extracted eight times with diethyl ether (total 3500 cc). The combined organic solutions are washed four times with distilled water (total 4000 cc), dried over anhydrous sodium sulphate, treated with decolourising charcoal (5 g), filtered and evaporated to dryness. The residue is dried by azeotropic distillation with methylene chloride (150 cc) and then crystallised from ethanol (16 cc). After cooling for 21 hours at about 5° C., the resulting crystals are filtered off, washed twice with ethanol (total 18 cc), which has been cooled to -20° C., and dried under reduced pressure (20 mm Hg) at 20° C. Ethyl (5,6-dihydro-4H-dibenzo[de,h]quinol-7-yloxy)acetate (16.95 g), melting at 70° C., is thus obtained.
Reaction SMILES: C([N:9]1[CH:14]=[CH:13][C:12](=[O:15])[CH2:11][CH:10]1[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20])(=O)C1C=CC=CC=1.C[O-].[Na+].P([O-])([O-])([O-])=O>CO>[C:19]([C:18]1[CH:17]=[C:16]([CH:10]2[CH2:11][C:12](=[O:15])[CH:13]=[CH:14][NH:9]2)[CH:23]=[CH:22][CH:21]=1)#[N:20]
Reactant: N#Cc1cccc(C2CC(=O)C=CN2C(=O)c2ccccc2)c1
Agent: C[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cccc(C2CC(=O)C=CN2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3-(1-Benzoyl-4-oxo-1,2,3,4-tetrahydro-pyridin-2-yl)-benzonitrile (350 mg) was dissolved in 50 ml methanol at 0° C. and 1.5 ml of 0.5 M sodium methoxide in methanol was added. The solution was stirred at 0° C. for 3 hours, and then 25 ml of pH 7 phosphate buffer was added. The mixture was concentrated under reduced pressure and partitioned between buffer and ethyl acetate. The organic layer was dried over sodium sulfate and the drying agent filtered off. Racemic 2-(3-cyanophenyl)-2,3-dihydro-pyridin-4-one was crystallized by addition of hexane to give 131 mg.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:22]=[N:23][N:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:25]=2[CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:38]([OH:40])=O)[CH2:9]1)=O)(C)(C)C.[CH3:41][C:42]1NN=[N:44][N:43]=1.C1(N=C=NC2CCCCC2)CCCCC1.O>C1(C)C=CC=CC=1>[CH3:31][O:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]1[N:24]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:23]=[N:22][C:21]=1[C:19]([N:14]([C@H:12]1[CH2:11][C@@H:10]([C:38]2[O:40][C:42]([CH3:41])=[N:43][N:44]=2)[CH2:9][NH:8][CH2:13]1)[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:20]
Reactant: Cc1nnn[nH]1
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](c3nnc(C)o3)C2)nnn1-c1ccccc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 47.8 %

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (200 mg) was dissolved in toluene (5 ml), 5-methyl-1H-tetrazole (36 mg) and N,N′-dicyclohexylcarbodiimide (96 mg) were added and the mixture was stirred at 80° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:3-1:1) was concentrated under reduced pressure. The residue was dissolved in toluene (1 ml), trifluoroacetic acid (1 ml) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, basified with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted twice with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (1 ml), fumaric acid (12 mg) was added and the mixture was concentrated under reduced pressure to give the object product (85 mg).
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:15])[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]1([N:23]2[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:17]1([N:23]2[CH2:24][CH2:25][CH:26]([NH:29][C:7](=[O:15])[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:27][CH2:28]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NC1CCN(c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(NC1CCN(c2ccccc2)CC1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Pyridine (24 μL) and phenyl chlorocarbonate (32 μL) were added to a solution of 1-phenyl-4-piperidylamine (35 mg) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/chloroform=1/1) to give the title compound (37 mg).