Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br[CH:3]1[C:8](=[O:9])[CH:7](Br)[C:6]([CH3:12])([CH3:11])[NH:5][C:4]1([CH3:14])[CH3:13].[CH3:15][C:16]1([CH3:23])[O:20][CH:19]([CH2:21][NH2:22])[CH2:18][O:17]1.CC([O-:28])(C)C.[K+]>C(O)(C)C>[CH3:15][C:16]1([CH3:23])[O:20][CH:19]([CH2:21][NH2:22])[CH2:18][O:17]1.[CH3:12][C:6]1([CH3:11])[C:7]([C:8]([OH:9])=[O:28])=[CH:14][C:4]([CH3:3])([CH3:13])[NH:5]1
Reactant: CC1(C)NC(C)(C)C(Br)C(=O)C1Br
Reactant: CC(C)(C)[O-]
Agent: Br
Agent: CC1(C)OCC(CN)O1
Agent: [K+]
Solvent: CC(C)O
Product: CC1(C)C=C(C(=O)O)C(C)(C)N1
Reaction time: 1 h
Yield: 57.3 %

Procedure:
Under agitation, cooling between -5° and 0° C., and covering with argon, 68.94 g (175 mmol) of 3,5-dibromo-2,2,6,6-tetramethylpiperidin-4-one hydrobromide is added in portions to a solution of 22.93 g (175 mmol) of (2,2-dimethyl-1,3-dioxolan-4-yl)methylamine and 58.9 g (525 mmol) of potassium tert-butylate in 700 ml of isopropanol. A white paste is thus obtained which is stirred for one hour without cooling, suctioned off from the solid matter, and concentrated to dryness under vacuum. The residue is distributed between dichloromethane and water. The organic phase is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized. After recrystallization from pentane, 30.1 g (60.9% of theory) of 2,2,5,5-tetramethyl-3-pyrroline-3-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amine is obtained, mp 55°-57° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[N:12][CH:13]=1.C(OO)(=[O:18])C.S(=O)(=O)(O)O.[OH-].[Na+]>CC(C)=O.C(Cl)Cl>[F:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:13]([OH:18])=[N:12][CH:11]=[N:10][CH:9]=1
Reactant: CC(=O)OO
Reactant: N#Cc1nccc(-c2cncnc2)c1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: N#Cc1nccc(-c2cncnc2O)c1F
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a vial charged with 3-fluoro-4-(pyrimidin-5-yl)picolinonitrile (0.400 g, 1.998 mmol) in acetone (Volume: 11.89 ml) were added peroxyacetic acid (0.841 ml, 4.00 mmol) and sulfuric acid (0.222 ml, 4.00 mmol). The reaction mixture was refluxed for 1 h, and then allowed to cool to room temperature. The reaction mixture was neutralized with 4 M NaOH and extracted with CH2Cl2 (5×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 0-25% MeOH in CH2Cl2 over 25 min, tr=16 min) gave the title compound (263 mg, 1.204 mmol, 60.3% yield) as a yellow solid. ESI MS (M+H)+=217.1.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].CN(C)C=O.[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:8])[F:9])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1sc(C(F)(F)F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc(C(F)(F)F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64 %

Procedure:
A mixture of 5B (5.0 g) and dimethylformamide (50 ml) is treated with sodium hydride (1.06 g). Benzylbromide (3.15 ml) was slowly added to the resulting reaction mixture and stirred at room temperature for 20 hours. The reaction mixture was poured into water. The mixture was extracted with diethyl ether twice. The combined organic phases were washed with water, dried and concentrated in vacuo. The crude product was chromatographed (hexane/dichloromethane, 1/1) to give the product as a white solid (4.5 g, 64%) with a melting point of 52-53.5° C.
Reaction SMILES: [CH2:1]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([OH:20])=O)[CH2:13][CH2:12]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[N+:44]([C:47]1[CH:48]=[CH:49][C:50]([O:53][C:54]2[CH:59]=[CH:58][C:57]([NH2:60])=[CH:56][CH:55]=2)=[N:51][CH:52]=1)([O-:46])=[O:45]>CN(C=O)C>[N+:44]([C:47]1[CH:48]=[CH:49][C:50]([O:53][C:54]2[CH:59]=[CH:58][C:57]([NH:60][C:18](=[O:20])[CH2:17][N:14]3[CH2:13][CH2:12][N:11]([CH2:1][C:2]4[CH:10]=[CH:9][C:8]5[O:7][CH2:6][O:5][C:4]=5[CH:3]=4)[CH2:16][CH2:15]3)=[CH:56][CH:55]=2)=[N:51][CH:52]=1)([O-:46])=[O:45]
Reactant: O=C(O)CN1CCN(Cc2ccc3c(c2)OCO3)CC1
Reactant: Nc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCN(Cc2ccc3c(c2)OCO3)CC1)Nc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (4-piperonylpiperazin-1-yl)acetic acid (13.9 g, 50 mmol) was suspended in DMF (400 mL), and to the resulting suspension were added 1-hydroxybenzotriazole monohydrate (8.42 g, 55 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.5 g, 55 mmol) and 4-(5-nitropyridin-2-yloxy)phenylamine (11.6 g, 50 mmol) under ice cooling. The resulting solution was stirred for 6 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and washed with a saturated sodium bicarbonate solution and brine. The organic layer was left for standing overnight at room temperature, and the resulting precipitated crystals were collected by suction filtration, to thereby yield 12.8 g of the title compound.
Reaction SMILES: BrBr.[OH-:3].[Na+].[Cl:5][C:6]1[C:11]([CH2:12][CH3:13])=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[C:15](=[O:17])C.O>O1CCOCC1>[Cl:5][C:6]1[C:11]([CH2:12][CH3:13])=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[C:15]([OH:17])=[O:3]
Reactant: [OH-]
Reactant: CCc1c(F)ccc(C(C)=O)c1Cl
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1c(F)ccc(C(=O)O)c1Cl
Temperature: 10 °C
Yield: 88.2 %

Procedure:
Bromine (8.94 g) was added to an aqueous solution (35.6 mL) of sodium hydroxide (7.61 g) with stirring at 10° C., and a solution (37.4 mL) of 1-(2-chloro-3-ethyl-4-fluorophenyl)ethanone (3.74 g) in dioxane was added under ice-cooling (sodium chloride-ice bath). The mixture was warmed to room temperature and, after stirring for 1 hr, poured into water and partitioned with chloroform. The aqueous layer was adjusted to pH=3 with concentrated hydrochloric acid, and extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as colorless crystals (yield: 3.33 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4ccc(Cl)c(Cl)c4)c3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 78.9 %

Procedure:
A mixture of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.50 g, 1.6 mmol), 3,4-dichlorophenyl isocyanate (0.29 g, 1.6 mmol), and diisopropylethylamine (0.40 g, 3.1 mmol) in 10 mL pyridine was warmed to 40° C. with stirring under N2, and the resulting solution was stirred at the same temperature for 2 hours. The mixture was cooled, and the solvent was evaporated under vacuum. The residue was chromatographed using a methylene chloride-methanol gradient, eluting with 97:3 methylene chloride-methanol, to provide 0.60 g of the product in 82% yield: mp 241-243° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H), 2.54-2.64 (m, 2H), 2.84-2.97 (m, 1H), 4.71 (d, J=6.0 Hz, 2H), 5.17 (dd, J=12.5 Hz, d=5.4 Hz, 1H), 6.92 (t, J=6.0 Hz, 1H), 7.25 (dd, J=8.8 Hz, J=2.5 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.75-7.88 (m, 4H), 9.15 (s, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.8, 48.9, 117.8, 118.8, 121.9, 122.4, 127.2, 130.4, 130.9, 131.6, 133.7, 134.8, 139.9, 140.5, 154.9, 167.0, 167.6, 169.8, 172.8; Anal. calcd. for C21H16Cl2N4O5.0.25H2O: C, 52.57; H, 3.47; N, 11.68. Found: C, 52.78; H, 3.41; N, 11.37.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([N:12]2[CH2:18][CH:17]3[O:19][CH:14]([CH2:15][CH2:16]3)[CH2:13]2)[N:3]=1.[OH:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][N:8]1[C:6]2=[N:7][C:2]([C:25]3[CH:26]=[C:21]([OH:20])[CH:22]=[CH:23][CH:24]=3)=[N:3][C:4]([N:12]3[CH2:18][CH:17]4[O:19][CH:14]([CH2:15][CH2:16]4)[CH2:13]3)=[C:5]2[CH:10]=[N:9]1
Reactant: OB(O)c1cccc(O)c1
Reactant: Cn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3cccc(O)c3)nc21
Temperature: 120 °C

Procedure:
A mixture of 3-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (95 mg, 0.34 mmol), 3-hydroxyphenylboronic acid (70 mg, 0.51 mmol), and tetrakis(triphenylphosphine)palladium(0) (39 mg, 10 mol %) in toluene/ethanol (1:1, 3 mL) and 2 M aqueous sodium carbonate solution (2 mL) was heated in a Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was acidified with 1 M aqueous hydrochloric acid and then extracted three times with ethyl acetate. The combined extracts were washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The extracts were then dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 90% acetonitrile to provide, after concentration, 3-[1-methyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenol. MS (ES+): 338.0 (M+H)+
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:17]1[C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=[C:18]1[C:25]([OH:27])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:22]([C:21]1[O:17][C:18]([C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:27])=[CH:19][CH:20]=1)=[O:24])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(C(=O)O)o1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)c1ccc(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)o1
Yield: 78.1 %

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 640 mg (4.1 mmol) furan-2,5-dicarboxylic acid afforded, after flash chromatography (EtOAc), 1.7 g (78%) of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([OH:12])=[CH:5]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc2cc(Br)ccc2cn1
Solvent: CN(C)C=O
Product: Brc1ccc2cnc(OCc3ccccc3)cc2c1
Temperature: 80 °C
Yield: 18.8 %

Procedure:
To a 25 mL round-bottomed flask containing 6-bromoisoquinolin-3-ol (500 mg, 2.23 mmol) was added TEA (0.467 mL, 3.35 mmol) and benzyl bromide (0.319 mL, 2.68 mmol) in DMF (10 mL) to give a brown solution. The reaction was heated to 80° C. overnight. After cooling to RT, the reaction mixture was concentrated in vacuo, and taken up in DCM and water. The water was extracted with DCM (2×), and the combined organic fractions were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purify by flash column chromatography (10-30-50% EtOAc/Heptanes), providing the title compound (132 mg, 0.420 mmol, 19% yield). M+1=316.0. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.92 (s, 1H), 7.85 (d, J=1.25 Hz, 1H), 7.74 (d, J=8.78 Hz, 1H), 7.31-7.52 (m, 6H), 6.99 (s, 1H), 5.48 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2O[C:12](=O)[C:11]([C:15]#[N:16])=[C:10]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:24]1[CH2:28]O[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:4]3[C:3]4[C:25](=[CH:24][CH:28]=[CH:7][CH:2]=4)[CH2:26][C:12]=3[C:11]([C:15]#[N:16])=[C:10]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCC2)cc(-c2ccc(Cl)cc2)oc1=O
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCC2)cc(-c2ccc(Cl)cc2)c2c1Cc1ccccc1-2

Procedure:
A mixture of 6-(4-chlorophenyl)-2-oxo-4-(pyrrolidin-1-yl)-2H-pyran-3-carbonitrile (300 mg), indanone-2 (132 mg) and NaH (33 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 197-199° C.; FAB MS 370 (M+); IR (KBr) 2217 cm−1 (CN).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:14]=2[N:15]=1.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1B(O)O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:22]3[O:21][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH:23]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(Br)ccc3o2)c1
Product: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4cc5ccccc5o4)ccc3o2)c1

Procedure:
Prepared by the method of Example 15d), from 2-(2-fluoro-5-nitrophenyl)-5-bromobenzoxazole (1.00 g, 3.0 mmol) and benzofuran-2-boronic acid (728 mg, 4.50 mmol) the subtitle compound was obtained (208 mg, 18%). The product was used directly in the next step without purification.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])C1C=CC=CC=1.N1C=CC=CC=1.[CH2:26]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[CH3:27]>ClCCl.CN(C1C=CC=CN=1)C>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[NH:10][S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH2:26][CH3:27])=[CH:29][CH:30]=1)(=[O:36])=[O:35]
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(Nc1ccc(F)cc1F)OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccc(S(=O)(=O)Nc2ccc(F)cc2F)cc1
Yield: 94.3 %

Procedure:
To 2,4-difluoro-phenylamine (30, 2.0 g, 15.5 mmol) in 20 mL of dichloromethane, pyridine (1.326 mL, 16.4 mmol) and dimethylaminopyridine (0.076 g, 0.62 mmol) are added followed by the dropwise addition of 4-ethyl-benzenesulfonyl chloride (59, 3.357 g, 16.4 mmol) and the reaction is heated to reflux overnight. The reaction is concentrated under vacuum to dryness, then brought up in ethyl acetate and water for extraction. The organic layer is isolated and concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with a gradient of 10-20% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (60, 4.344 g).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[S:18])=[CH:12][CH:11]=1>ClCCl>[CH3:22][C:21]([CH3:24])([CH3:23])[CH2:20][N:19]1[C:2](=[O:8])[C:3](=[O:5])[N:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[C:17]1=[S:18]
Reactant: CC(C)(C)CNC(=S)Nc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)CN1C(=O)C(=O)N(c2ccc(F)cc2)C1=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
Ethyl chlorooxoacetate (0.60 mL, 5.41 mmol) was added to a stirring solution of the above thiourea (1.00 g, 4.16 mmol) in dichloromethane (20 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and recrystallization from boiling methanol afforded 0.77 g (62%) 1-(2,2-dimethyl-propyl)-3-(4-fluoro-phenyl)-2-thioxo-imidazolidine-4,5-dione as an orange-yellow solid: mp 165.2–166.3° C.; 1H NMR (DMSO-d6): δ 7.40 (m, 4H), 3.73 (s, 2H), 0.98 (s, 9H); IR (KBr): 3500, 2980, 1770 cm1; MS (m/z) 294 (M+).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH2:24][CH2:23]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=1)[CH2:24][CH2:23]2
Reactant: Clc1ccc2c(c1)CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2cc(Cl)ccc21
Yield: 68.1 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 307 mg of 5-chloroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of dimethylformamide. 255 mg of 2-[2-(5-chloro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=O)=[CH:16][CH:15]=2)[CH:10]([O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:36][CH2:37][C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:39].C(N(CC)CC)C.F[B-](F)(F)F.O=C1C=CC=CN1OC(N(C)C)=[N+](C)C>CN(C)C=O>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:10]1[CH:11]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21](=[O:23])[NH:36][CH2:37][C:38](=[O:39])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: NCC(=O)c1ccccc1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)NCC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
A solution of 150 mg (0.32 mmol) of (3RS,4RS)-[4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-phenyl]-acetic acid and 55 mg (0.32 mmol) of 2-amino-1-phenyl-ethanone in 5 ml of dimethylformamide was treated in sequence with 44.6 μl (0.32 mmol) of triethylamine and 96 mg (0.32 mmol) of O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU) and the mixture was stirred at room temperature for 18 hours. For the working-up, the reaction was evaporated in an oil pump vacuum, the residue was taken up in 20 ml of methylene chloride and washed with 5 ml of water. The organic phase was dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude material was chromatographed on silica gel using a 95:5 mixture of methylene chloride and methanol as the eluent. There were obtained 120 mg (64% of theory) of tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[(2-oxo-2-phenyl-ethylcarbamoyl)-methyl]-phenyl}-piperidine-1-carboxylate as a colourless oil; MS: 615 (M+Na)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH2:11][CH2:10]3)=[CH:3][CH:2]=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[C:16]1([NH:22][C:23]([N:12]2[C:13]3[C:9](=[CH:8][C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccccc1
Reactant: c1cc(-c2ccc3c(c2)CCN3)ccn1
Solvent: CC#N
Product: O=C(Nc1ccccc1)N1CCc2cc(-c3ccncc3)ccc21
Temperature: 80 °C
Reaction time: 6 h
Yield: 46.7 %

Procedure:
To a solution of 5-(4-pyridinyl)indoline (80 mg) in acetonitrile (10 mL) was added phenyl isocyanate (53 mg) and the mixture was stirred at 80° C. for 6 hours. The mixture was evaporated to dryness and the residue was purified by column chromatography on silica gel eluting with ethyl acetate/methanol (10:1) to give N-phenyl-5-(4-pyridinyl)-1-indolinecarboxamide (60 mg) as a light-brown powder.