Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:20][CH2:21][S:22][CH3:23]>CN(C=O)C>[Br:16][C:6]1[C:5]2[C:10](=[CH:11][C:2]([S:1][CH2:20][CH2:21][S:22][CH3:23])=[CH:3][CH:4]=2)[C:9](=[O:12])[N:8]([CH:13]([CH3:14])[CH3:15])[N:7]=1
Reactant: CC(C)n1nc(Br)c2ccc(S)cc2c1=O
Reactant: CSCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCSc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 90.7 %

Procedure:
To a solution of crude 7-mercapto-2-isopropyl-4-bromo-2H-phthalazin-1-one (0.40 g, 1.3 mmol) in DMF (8 ml), was added NaH (60%, 0.064 g, 1.6 mmol) portion-wise. After stirring for 5 min, chloroethyl methylsulfide (0.17 g, 1.6 mmol) was added dropwise. The mixture was heated to 60° C. for two hours, after which time the mixture was concentrated under vacuum and the residue was subjected to flash column chromatography (elution: 90% heptane, 10% EtOAc) to give the title compound (0.44 g, 54% yield) as a white solid. δH (400 MHz, DMSO), 8.03 (1H, d), 7.92 (1H, d), 7.81 (1 H, d), 5.26-5.15 (1H, m), 3.41 (2H, t), 2.78 (2H, t), 2.15 (3H, s), 1.36 (6H, d).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]2)=[C:5]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([CH3:27])[O:24][N:23]=2)=[O:21])[CH:4]=1)=O.C(O)(=O)C.[C:32]1([C@H:38]([NH2:40])[CH3:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CCOC(C)=O>[CH3:27][C:25]1[O:24][N:23]=[C:22]([C:20]([NH:19][C:5]2[CH:4]=[C:3]([CH2:1][NH:40][C@@H:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:39])[CH:8]=[CH:7][C:6]=2[N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]2)=[O:21])[CH:26]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COC(=O)C1CCN(c2ccc(C=O)cc2NC(=O)c2cc(C)on2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2ccc(CN[C@H](C)c3ccccc3)cc2NC(=O)c2cc(C)on2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67 %

Procedure:
To a solution of methyl 1-(4-formyl-2-(5-methylisoxazole-3-carboxamido)phenyl)piperidine-4-carboxylate 60 (0.268 g, 0.72 mmol) in DCE (10 mL) was added acetic acid (0.045 mL, 0.78 mmol), (R)-1-phenylethanamine (0.11 mL, 0.88 mmol), and NaBH(OAc)3 (0.186 g, 0.88 mmol). The reaction mixture was stirred at room temperature for 15 h and diluted with EtOAc. The organic phase was washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 70% to 100% EtOAc in hexanes) gave (R)-methyl 1-(2-(5-methylisoxazole-3-carboxamido)-4-((1-phenylethylamino)methyl)phenyl)piperidine-4-carboxylate 61 (0.230 g, 67% yield) as a white solid. Mass spectrum: calculated for C27H32N4O4 476.2. found 477.3 (M++1).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][CH:22](O)[CH3:23].[OH2:25]>C(#N)C>[C:1]1([C:7]([NH:21][CH2:22][CH2:23][OH:25])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(N)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O
Solvent: CC#N
Product: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
Triphenylchloromethane (1.00 g, 3.58 mmol) (Wako Pure Chemical Industries, Ltd.) and aminoethanol (2.00 g, 32.7 mmol) were dissolved in acetonitrile (5 mL), and the solution was stirred at room temperature overnight. Water (100 mL) was poured into the reaction solution, and the precipitates were suction-filtered and then dried. The solid product was recrystallized from a mixed solvent of ethanol (Wako Pure Chemical Industries, Ltd.) and water, to thereby obtain the title compound (0.43 g, 39% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:18]Br)=[O:5])[CH3:2].[CH2:20]([O:22][C:23](=[O:33])[CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:21].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:18][N:25]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:33])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)nc1CBr
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)OCC)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 32.3 %

Procedure:
A mixture of 4-bromomethyl-2-(4-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (2.22 g, 6.18 mmol), tert-butoxycarbonylamino-acetic acid ethyl ester (1.32 g, 6.48 mmol) and sodium hydride (60% in mineral oil, 296 mg, 7.4 mmol) in anhydrous dimethylformamide (30 mL) was stirred at 0° C. for one hour and room temperature for four hours before it was quenched with brine. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (964 mg): 1H NMR (CDCl3, 200 MHz): δ=7.87 (d, 2H), 7.39 (d, 2H), 4.99 (m, 2H), 4.21 (m, 6H), 1.45 (s, 9H), 1.26 (t, 3H).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1O[C@H]1CCl.[CH:26]1([C:32]2C=C[C:35]([OH:38])=[CH:34][CH:33]=2)CCCCC1.C(OCC)(=O)C#CCC>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:35](=[O:38])[CH:34]=[C:33]([CH2:32][CH3:26])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: Oc1ccc(C2CCCCC2)cc1
Agent: CCC#CC(=O)OCC
Agent: ClC[C@H]1CO1
Solvent: CCO
Product: CCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2
Temperature: 25 °C

Procedure:
To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (1.0 g, 3.64 mmol), prepared in accordance with the procedures as set forth in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-cyclohexylphenol, in ethanol (18.2 mL) was added ethyl 2-pentynoate (0.92 g, 7.28 mmol). The reaction mixture was heated at reflux for 14 hrs and then gradually cooled to room temperature. The resulting crystalline solid was isolated by filtration, washed with heptane 3 times, and dried under vacuum to afford 560 mg of (S)-2-(4-cyclohexyl-phenoxymethyl)-5-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as a white solid. [α]D25 −27.96 (c 0.526, CHCl3).
Reaction SMILES: [CH3:1][C:2](=C)[C@@H:3]([N:20]1[C:26](=[O:27])[C@H:25]2[C@@H:21]1[O:22][C:23]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[N:24]2)[C:4]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C(N(CC)CC)C>C(Cl)Cl>[C:8]1([CH:7]([O:6][C:4](=[O:5])[C:3]([N:20]2[C:26](=[O:27])[C@H:25]3[C@@H:21]2[O:22][C:23]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:24]3)=[CH:2][CH3:1])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C(C)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(Cc3ccccc3)O[C@@H]21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(Cc3ccccc3)O[C@@H]21
Yield: 95 %

Procedure:
In a manner similar to the above (1), a solution of 75 mg of diphenylmethyl (2R)-3-methyl-2-[(1R,5S)-3-benzyl-7-oxo-4-oxa-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-3-butenoate in 5 ml of methylene chloride is stirred at room temperature for 1 hour in the presence of 0.03 ml of triethylamine to afford diphenylmethyl-2-[(1R,5S)-3-benzyl-7-oxo-4-oxa-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-2-butenoate in 95% yield. mp. 104.5°-106° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:29])[CH2:15][NH:16][CH2:17][C:18]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH3:3].C(N(CC)CC)C.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14](=[O:29])[CH2:15][N:16]([S:43]([C:40]1[CH:41]=[CH:42][C:37]([CH3:47])=[CH:38][CH:39]=1)(=[O:45])=[O:44])[CH2:17][C:18]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH3:1]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(c2ccccc2)CCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N(CC(=O)Nc2c(C(C)C)cccc2C(C)C)CC2(c3ccccc3)CCCC2)cc1
Reaction time: 120 h

Procedure:
To a mixture of the product of Example 6 (0.45 g) and excess triethylamine at room temperature was added 0.22 g p-toluene sulfonyl chloride. This mixture was diluted with ethyl acetate, concentrated, and triethylamine and ethyl acetate added a second time. The reaction mixture was then concentrated to a brown oil. After sitting 5 days at room temperature, the oil was taken up in ethyl acetate, washed with NaHCO3 and NaCl solutions, dried over MgSO4, filtered, and concentrated to an oil. The oil was purified by chromatography on silica gel using hexane/EtoAc, 8/21 as eluant. The appropriate fractions were concentrated to an oil which crystallized upon trituration with hexane. 0.44 g (69%). NMR (CDCl3) δ 1.17 (6H, d), δ 1.64-1.82 (4H, m), δ 2.03 (4H, m), δ 2.42 (3H, s), δ 2.97 (2H, m), δ 3.42 (2H, s), δ 3.55 (2H, s), δ 7.13-7.65 (12H, m). IR (KBr) 3370, 2965, 2870, 1673, 1497, 1328, 1158, 1092, 755, 550 cm-1.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH2:8][NH:9]C(=O)C(F)(F)F)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[ClH:26]>CO.O.CCOCC>[ClH:26].[CH2:1]([S:3]([C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH2:8][NH2:9])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccccc1CNC(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CCS(=O)(=O)c1ccccc1CN
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(ethylsulfonyl)benzyltrifluoroacetamide (88 mg, 0.30 mmol) in methanol (11 mL) and water (0.74 mL) was added potassium carbonate (124 mg, 0.90 mmol). The mixture was heated to 65° C. and stirred under Ar overnight. The mixture was then concentrated to a colorless oil which was taken up in EtOAc and washed with a small amount of brine. The aqueous layer was extracted twice with CHCl3 and was then saturated with sodium chloride and further extracted with THF. The combined organic extracts were dried over MgSO4 and concentrated at reduced pressure. The residue was treated with 2 equivalents of 1.0 M HCl in ether. The resulting precipitate was collected by filtration and was dried on a high vacuum line to give the title compound as an off-white solid:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:3]1.[CH3:17][N:18]([CH3:21])[S:19]Cl.O>N1C=CC=CC=1>[CH3:17][N:18]([CH3:21])[S:19][N:14]([CH3:15])[C:12](=[O:13])[O:11][C:8]1[C:9]2[O:10][C:2]([CH3:16])([CH3:1])[CH2:3][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: CN(C)SCl
Solvent: O
Solvent: c1ccncc1
Product: CN(C)SN(C)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 18 h

Procedure:
A mixture of 16 g of carbofuran and 8.5 g of (dimethylamino)sulfenyl chloride in 50 ml of pyridine was allowed to stand at room temperature for about 18 hours. The mixture was poured into water, the aqueous mixture extracted with chloroform, the extracts washed with dilute hydrochloric acid, followed by water and saturated sodium chloride solution. Concentration under reduced pressure gave an oil which was found by nuclear magnetic resonance spectroscopy to contain about 20% unreacted carbofuran. This oil was subjected to column chromatography on silica gel using diethyl etherhexane (3:1) as eluting solvent to obtain 2,3-dihydro-2,2-dimethyl-7-benzofuranyl (dimethylaminosulfenyl)(methyl)carbamate
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.B(F)(F)F.CCOCC.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[C:3]2[O:4][C:5]3[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:7](=[O:9])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1Br
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=c1c2ccccc2oc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a solution of 2-(2-bromophenoxy)-benzoic acid 2j (11.8 g, 40.3 mmol) in dichloromethane (200 mL) was added trifluoroacetic anhydride (6.3 mL, 44.6 mmol), and the mixture was stirred for 30 min at rt. Boron trifluoride etherate (0.51 mL, 4.03 mmol) was added, and the mixture was stirred for 2 h at rt. The mixture was cooled in an ice bath, and a 3N sodium hydroxide solution (100 mL) was added under vigorous stirring. The organic layer was separated, washed with water and brine, dired over magnesium sulfate, filtered, and evaporated. The residue was purified over silica gel using dichloromethane as eluent. The desired fractions were collected, and evaporated to yield 10.18 g (91.8%) of title compound 3j.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][N:11]([C:16]3[CH:21]=[C:20](B(O)O)[CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.I[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][N:11]([C:16]3[CH:21]=[C:20]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2cn(-c3cc(B(O)O)ccn3)ccc2=O)cc1
Reactant: Ic1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(COc2cn(-c3cc(-c4ccccc4)ccn3)ccc2=O)cc1
Temperature: 135 °C

Procedure:
To a 20 mL microwave vial (Biotage) was added {3-[(4-methoxybenzyl)oxy]-4-oxo-4H-1,2′-bipyridin-4′-yl}boronic acid (300 mg, 0.85 mmol), iodobenzene (348 mg, 1.70 mmol), cesium carbonate (6 mL of a 1.0 M aq solution, 6.0 mmol), and 69.6 mg (0.085 mmol) I,Γ-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex. The vial was sealed and the reaction mixture was heated at 135° C. under microwave irradiation for 15 minutes, then cooled. The organic layer was separated, washed with 5 mL water, dried over Na2S04, filtered, and concentrated in vacuo. Purification by flash chromatography (silica gel, 0-10% MeOH in EtOAc gradient) afforded 3-[(4-methoxybenzyl)oxy]-4′-phenyl-4H-1,2′-bipyridin-4-one. LCMS (M+H)+=385.4.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17](O)=[O:18])[CH:13]=3)[C:8]2=[O:20])=[CH:4][CH:3]=1.[N:23]1([CH2:29][CH2:30][NH2:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl-:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([NH:31][CH2:30][CH2:29][NH+:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:18])[CH:13]=3)[C:8]2=[O:20])=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(Cc1ccc(Cl)cc1)C2=O
Reactant: NCCN1CCCCC1
Product: O=C(NCC[NH+]1CCCCC1)c1ccc2c(c1)C(=O)N(Cc1ccc(Cl)cc1)C2=O
Product: [Cl-]

Procedure:
2-(4-chloro-benzyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-carboxylic acid (100 mg, 0.316 mmol) and 2-piperidin-1-yl-ethylamine (113 μL, 0.792 mmol) were reacted with each other. Target compound in the amount of 77 mg (53%) was obtained by following the procedure described in Example 1.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=CC=C[CH:9]=2)[CH:6]=CC=C[CH:2]=1.CC1(C)O[C:19](=[O:21])[C:18](=[CH:22][NH:23][C:24]2[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:28]=2)C(=O)O1>>[CH:1]([O:7][CH:8]([CH3:13])[CH3:9])([CH3:6])[CH3:2].[C:29]1([C:27]2[C:28]3[C:19](=[O:21])[CH:18]=[CH:22][NH:23][C:24]=3[S:25][CH:26]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CC1(C)OC(=O)C(=CNc2cc(-c3ccccc3)cs2)C(=O)O1
Product: CC(C)OC(C)C
Product: O=c1cc[nH]c2scc(-c3ccccc3)c12
Temperature: 25 °C

Procedure:
Diphenyl ether (15 ml) was heated to reflux and 2,2-dimethyl-5-[(4-phenyl-thiophen-2-ylamino)-methylene]-[1,3]dioxane-4,6-dione (1.41 g, 4.29 mmol) was added in portions with evolution of gas. The reaction mixture was kept at reflux for a further 45 min, before cooling to room temperature. Trituration with diisopropyl ether and petroleum ether (40-60°) gave 3-phenyl-7H-thieno[2,3-b]pyridine-4-one. Yield=0.7 g, (72%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:40][C:37]3[C:38]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Br)c3)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3cccc(Br)c3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 572 (M+H)+.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)([OH:5])=[O:4].[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15].Cl>O.C(O)C>[C:3]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:8][CH:7]=1)([OH:5])=[O:4]
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(C=CC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.4 %

Procedure:
To a solution of 2.0 g of sodium hydroxide in 25 ml of water and 10 ml of ethanol was added 4.50 g of 4-carboxybenzaldehyde (supplied by the Aldrich Chemical Company, Milwaukee, Wis.) in one portion. After stirring for 15 min. at room temperature, 3.60 g of acetophenone was added and the resulting solution was stirred at room temperature for 3 hrs. The reaction mixture was cooled in an ice-bath and acidified with 75 ml of 1N hydrochloric acid. The precipitate was collected, washed with water and air-dried. Recrystallization from methanol gave 4.64 g (61%) of 4-carboxybenzalacetophenone as yellow crystals, m.p. 227°-229° C. after drying at 90°-95° C. under vacuum for 4 hrs.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[NH:3][C:2]1=O.[CH2:13]([N:15](CC)[CH2:16][CH3:17])[CH3:14].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[C:2]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Product: CCN(CC)c1nc(Cl)c2ccccc2n1

Procedure:
20.0 g of 1H,3H-quinazoline-2,4-dione were dissolved in 280 ml of phosphorus oxychloride, and 60 ml of triethylamine were added. After refluxing for 75 minutes, the excess phosphorus oxychloride was distilled off under vacuum and the residue was slowly introduced into 200 ml of ice-cold 1N sodium hydroxide solution. Extraction with dichloromethane (three times 150 ml), washing of the organic phase with water (three times 100 ml), drying over magnesium sulfate and distillation of the solvent on a rotary evaporator gave a brown oil, which could be used in the next reaction without further purification. Yield: 17.7 g (60%)
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12](OC)(=[O:14])C>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8](=[NH:9])[O:14][CH3:12])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: COC(C)=O
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: COC(=N)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Part A: 4-Nitrobenzonitrile (5.4 g, 36.5 mmol) was dissolved in 200 mL of anhydrous methyl acetate and 20 mL of MeOH. The whole mixture was cooled to 0° C. and bubbled with dry HCL gas for 1 hour. The resulting mixture was placed at 5° C. for 12 hours, the solvent was removed to obtain 5.8 g of methyl 4-nitrobenzimidate as its HCl salt.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:36]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:41][CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNC2CCCC2)no1
Yield: 53 %

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and cyclopentylamine (170 mg, 1.98 mmol) as starting materials to afford the title compound as a colourless oil (220 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C(OCC)(=O)C.[NH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]([CH3:32])[CH2:24][C:25]2([CH3:31])[CH3:30]>C(N(CC)CC)C>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([NH:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]([CH3:32])[CH2:24][C:25]2([CH3:31])[CH3:30])=[O:9]
Reactant: Cc1ncsc1C(=O)O
Reactant: CC1CC(C)(C)c2cccc(N)c21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: Cc1ncsc1C(=O)Nc1cccc2c1C(C)CC2(C)C
Yield: 51.7 %

Procedure:
A mixture of 1.7 g (10.3 mmols) of 4-methyl-5-thiazole carboxylic acid and 10 ml of thionyl chloride was refluxed for 1 hour. The reaction solution was distilled under reduced pressure to remove excess thionyl chloride. The residue was dissolved in 10 ml ethyl acetate. The solution was added to 10 ml of an ethyl acetate solution of 1.8 g (10.3 mmols) of 4-amino-1,1,3-trimethylindane and 4 ml of triethylamine, and the resultant solution was stirred at room temperature for 3 hours. The solution was washed sequentially with water, aqueous sodium hydrogen carbonate solution, water, and saturated brine. The solution was dried with magnesium sulfate and then concentrated under reduced pressure. The concentrated residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane =1/2), to obtain 1.6 g of amorphous solid substance (Compound No. 6 shown in Table 4). The yield was 50.2%.