Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].O1CCCC1.[Cl:8][C:9]1[C:10]([CH3:15])=[N:11][O:12][C:13]=1[NH2:14].Cl[S:17]([C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]([O:27]C)=[O:26])(=[O:19])=[O:18]>CCCCCC>[Cl:8][C:9]1[C:10]([CH3:15])=[N:11][O:12][C:13]=1[NH:14][S:17]([C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]([OH:27])=[O:26])(=[O:18])=[O:19]
Reactant: Cc1noc(N)c1Cl
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)O)c1Cl
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a mixture of sodium hydride (60%, 2.1 g, 52 mmol) and tetrahydrofuran (20 mL) was added a mixture of 4-chloro-3-methyl-1,2-oxazol-5-amine (3.0 g, 23 mmol) and tetrahydrofuran (20 mL) at 0° C., followed by stirring at that temperature for 30 minutes. Methyl 3-(chlorosulfonyl)thiophene-2-carboxylate (5.3 g, 22 mmol) was added at that temperature to the reaction mixture, which was then stirred for 1 hour at 0° C., and then stirred for 4 hours at room temperature. Hexane (100 ml) was added at room temperature to the reaction mixture, and the precipitated solid was collected by filtration. Methanol (20 mL) was added to the solid, followed by a 2N aqueous solution of sodium hydroxide (20 mL), and the reaction mixture was stirred for 5 hours at room temperature. The solvent was distilled away under reduced pressure, and ice water (20 mL) was added to the residue, followed by a 2 N aqueous solution of hydrochloric acid (20 mL). The precipitated solid was collected by filtration to give the title compound (2.5 g, 35% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12](Br)[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:20]([Sn](CC)(CC)CC)[CH3:21]>>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([CH2:20][CH3:21])[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC[Sn](CC)(CC)CC
Reactant: CCCCOC(=O)c1nc(Br)c2c(C)nsc2c1O
Product: CCCCOC(=O)c1nc(CC)c2c(C)nsc2c1O

Procedure:
The title compound was synthesized in analogy to Example 28 from 4-bromo-7-hydroxy-3-methyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester and tetraethyltin: MS (m/z) 295.2 (M+1).
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[C:16]([O-:19])(=[O:18])[CH3:17].[Na+]>C(O)C>[C:16]([O:19][CH:2]([CH3:15])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4])(=[O:18])[CH3:17]
Reactant: CC(Br)C(=O)c1cccc2ccccc12
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)OC(C)C(=O)c1cccc2ccccc12

Procedure:
2-bromo-1-(napth-1-yl)-1-propanone (2 g) and sodium acetate (0.63 g) were boiled under reflux in anhydrous ethanol (10 ml) for 16 hours. The mixture was cooled and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried with sodium sulphate, filtered and evaporated in vacuo. The title compound was obtained as an oil (0.75 g) following silica gel column chromatography of the residue in 50% dichloromethane in petroleum ether.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: NCCc1ccccn1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCc2ccccn2)cc1
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
4-geranyloxybenzoic acid(1.37 g) was dissolved in chloroform(30 ml) and triethylamine(1.53 ml), and then diphenylphosphinic chloride(1.05 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 2-(2-aminoethyl)pyridine(0.67 g) added thereto, was stirred for 1.5 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=40:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 1.39 g of the aimed compound.
Reaction SMILES: CO[C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[OH:11].[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH:7]2[OH:11])[C:3]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCCC1O)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCCC1O)c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Yield: 55.1 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(2-hydroxy-cyclopentyl)-propionic acid methyl ester (262.2 mg, 0.82 mmol) and 2-aminothiazole (165 mg, 1.65 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. % , 2.60 mL, 1.81 mmol) was heated to 100° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and filtered through a pad of celite (ethyl acetate as eluent). The filtrate was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 ethyl acetate/hexanes) afforded the 2-(3,4-dichloro-phenyl)-3-(2-hydroxy-cyclopentyl)-N-thiazol-2-yl-propionamide (174 mg, 54.6%) as a white solid: mp 86-88° C.; EI-HRMS m/e calcd for C17H18Cl2N2O2S (M+Na)+ 407.0358. found 407.0361.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Mg].II.CON(C)[C:17](=[O:19])[CH3:18].Cl>O1CCCC1>[S:7]1[CH:8]=[CH:9][C:10]2[C:2]([C:17](=[O:19])[CH3:18])=[CH:3][CH:4]=[CH:5][C:6]1=2
Reactant: Brc1cccc2sccc12
Reactant: CON(C)C(C)=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)c1cccc2sccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Approximately 5 ml of a solution of 4-bromobenzo[b]thiophene (4.10 g; prepared in a manner similar to that described in Bull. Soc. Chim. Fr., 1966, 111, 3667) in tetrahydrofuran (44 ml) was added under nitrogen to magnesium turnings (0.486 g). Two crystals of iodine were added and the mixture was heated to initiate the reaction. The remainder of the 4-bromobenzo[b]thiophene solution was added at reflux temperature over 20 minutes then the mixture was heated under reflux for 15 minutes and allowed to cool to ambient temperature. A solution of N-methoxy-N-methylacetamide (1.98 g; prepared in a manner similar to that described in Example 15) in tetrahydrofuran (20 ml) was added, the mixture was heated under reflux for 1 hour, then it was allowed to cool to ambient temperature. 2M Hydrochloric acid (40 ml) was added, the mixture was stirred at ambient temperature for 1 hour, then the product was extracted into ethyl acetate (250 ml). The extract was washed with water (2×50 ml) and saturated aqueous sodium chloride solution (2×50 ml), dried (Na2SO4), and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 97:3 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-4-yl]ethan-1-one (1.76 g) as a yellow oil which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2.C(N(C(C)C)CC)(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:34]([NH:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCN)c3ccccc23)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCNC(=O)c3ccccc3)c3ccccc23)CC1
Reaction time: 19 h
Yield: 75.2 %

Procedure:
tert-Butyl 6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0401 g, 0.122 mmol) was dissolved in THF (2 mL) at rt under N2. Diisopropylethylamine (0.028 mL, 0.0205 g, 0.158 mmol, 1.30 equiv.) and benzoyl chloride (0.017 mL, 0.0205 g, 0.146 mmol, 1.20 equiv.) were added, then the reaction mixture was stirred for 19 h. Citric acid (10%) was added and the reaction mixture was stirred for 15 min. The reaction mixture was extracted with EtOAc and the organic layer was washed sequentially with 10% citric acid, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude product (0.056 g) was chromatographed (SiO2 25 g, eluted with 1:1 hexane:EtOAc) to give tert-butyl 6-[2-(benzoylamino)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0398 g) in 75% yield. 1H NMR (300 MHz, CDCl3) δ 1.45, 1.48, 2.96-3.05, 3.60-3.70, 3.74, 4.36-4.42, 6.29, 7.10-7.19, 7.31-7.43, 7.46-7.53, 7.63; MS (ESI+) for C26H31N3O3 m/z 434.1 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].F[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]>C1COCC1>[CH:1]1([CH2:4][O:5][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
Cyclopropyl methanol (15 g, 207 mmol) was added to a stirred suspension of NaH (60% in mineral oil, 8.37 g) in 200 mL THF over a period of 15 min at 0° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 1 h at RT. The mixture was cooled to 0° C. and a solution of 2,4-difluoro-1-nitrobenzene (30 g, 187 mmol) in 200 mL THF was added in a drop wise manner. The reaction mixture was stirred at 0° C. for 2 h and then poured onto ice water. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give 22.0 g of 2-(cyclopropylmethoxy)-4-fluoro-1-nitrobenzene as an orange oil (86%).
Reaction SMILES: C(=O)([O-])O.[Na+].[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14]([O:18][C:19]([CH2:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].O>CN(C)C=O>[CH2:6]([O:25][C:23]([C@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:20])=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCCC[C@H](CC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC[C@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydrogencarbonate (305 mg) and benzyl bromide (1.0 ml) were added Successively to a solution of 2-(R)-(tert-butoxycarbonylmethyl)heptanoic acid (440 mg), prepared in Referential Example 5, in 18 ml of dimethylformamide (DMF), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was successively washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After the solvent had been distilled off under reduced pressure, the residue was purified by column chromatography through silica gel, using a 20:1 mixture of hexane and ethyl acetate as an eluent, to give 476 mg of the desired compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([CH3:12])[CH3:11])=[C:7]([C:13](=[O:29])[C:14]3[CH:19]=[C:18]([I:20])[C:17]([CH2:21][CH3:22])=[C:16]([I:23])[C:15]=3[O:24][CH2:25][C:26]([OH:28])=[O:27])[C:6]=2[CH:30]=1.[C:31](Cl)(=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1>>[CH:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:40])[C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[CH:30][C:6]=2[C:7]=1[C:13](=[O:29])[C:14]1[CH:19]=[C:18]([I:20])[C:17]([CH2:21][CH3:22])=[C:16]([I:23])[C:15]=1[O:24][CH2:25][C:26]([OH:28])=[O:27])([CH3:12])[CH3:11]
Reactant: CCc1c(I)cc(C(=O)c2c(C(C)C)oc3ccc(N)cc23)c(OCC(=O)O)c1I
Reactant: COc1ccc(C(=O)Cl)cc1
Product: CCc1c(I)cc(C(=O)c2c(C(C)C)oc3ccc(NC(=O)c4ccc(OC)cc4)cc23)c(OCC(=O)O)c1I
Yield: 83 %

Procedure:
5-amino-2-isopropyl-3-(3 ,5-diiodo-4-ethyl carboxymethoxybenzoyl)-benzofuran (prepared as in Example 6(d), 150 mg, 0.25 mmol) was treated with anisoyl chloride as described in Example 3(a) to produce 160 mg (yield 83%) of 2-isopropyl-3-(3,5-diiodo-4-ethyl carboxymethoxybenzoyl)-5-(4-methoxybenzamido)benzofuran.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[Cl:25][C:26]1[CH:27]=[C:28]([NH:32][NH2:33])[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[C:2]3[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=3)[C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:33]2)[CH:29]=[CH:30][CH:31]=1
Reactant: NNc1cccc(Cl)c1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1ccc(-c2nn(-c3cccc(Cl)c3)c3cc(O)ccc23)c(O)c1
Yield: 87.9 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (2.46 g, 10 mmol), sodium acetate (0.82 g, 10 mmol) and 3-chlorophenylhydrazine hydrochloride (1.97 g, 11 mmol) to give 3.1 g of product as a tan solid Crystallized from EtOAc/hexane to give 1.4 g of an off-white solid (mp 228–230° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[CH2:37][CH2:36][CH:35]([OH:38])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[ClH:39]>C(Cl)Cl.O1CCOCC1>[ClH:1].[ClH:39].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:30]4[CH2:37][CH2:36][CH:35]([OH:38])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2CCC3O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)NCC(C(=O)N1CCN(c2ncnc3c2CCC3O)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 2-(4-chlorophenyl)-3-(4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (49 mg, 0.09 mmol) in DCM (10 mL) was added HCl in dioxane (4M, 2 mL). The mixture was stirred at room temperature overnight. The solvent was removed to afford the 2-(4-chlorophenyl)-1-(4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one dihydrochloride (46 mg, 99%). 1H NMR (D2O, 400 MHz) δ 8.38-8.36 (m, 1H), 7.37-7.34 (m, 2H), 7.22-7.19 (m, 2H), 5.18-5.10 (m, 1H), 4.34-4.28 (m, 1H), 4.10-3.00 (m, 12H), 2.50-2.40 (m, 1H), 1.85-1.75 (m, 1H), 1.28-1.26 (m, 6H), 1.20-1.13 (m, 3H). MS (APCI+) [M+H]+444.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([CH3:11])=[N:6][C:5]=1[CH:12]1[CH2:14][CH2:13]1.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[C:7]([CH3:11])=[N:6][C:5]=1[CH:12]1[CH2:13][CH2:14]1
Reactant: N#Cc1cccc(CBr)c1
Reactant: COC(=O)c1cc(O)c(C)nc1C1CC1
Product: COC(=O)c1cc(OCc2cccc(C#N)c2)c(C)nc1C1CC1
Yield: 72.7 %

Procedure:
The coupling of 2-cyclopropyl-5-hydroxy-6-methyl-nicotinic acid methyl ester (183) (605 mg, 2.9 mmol) and α-bromo-m-tolunitrile (629 mg, 3.2 mmol), as described in Example 1, gave 5-(3-cyano-benzyloxy)-2-cyclopropyl-6-methyl-nicotinic acid methyl ester (184) (680 mg, 72% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (3.0 g, 21 mmol) in DMSO (30 mL) was added ethyl piperidine-4-carboxylate (5.0 g, 32 mmol) and K2CO3 (5.9 g, 43 mmol). The resulting mixture was stirred at 100° C. for 8 h, and allowed to cool to rt. EtOAc (300 mL) was added. The organic layer was washed with water (3×100 mL) and brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:2 v/v)). Compound 54a was obtained as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C14H18N2O4: 279.1 (M+H). Found 279.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:40])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:27](COCC[Si](C)(C)C)[C:26]4[C:25](=[O:36])[N:24]([CH2:37][CH2:38][CH3:39])[CH:23]=[N:22][C:21]=4[N:20]=3)=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:40])[CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[NH:27][C:26]4[C:25](=[O:36])[N:24]([CH2:37][CH2:38][CH3:39])[CH:23]=[N:22][C:21]=4[N:20]=3)=[CH:17][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCCn1cnc2nc(-c3ccc(OCC(=O)Nc4ccc(C#N)cc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCn1cnc2nc(-c3ccc(OCC(=O)Nc4ccc(C#N)cc4)cc3)[nH]c2c1=O
Yield: 57.2 %

Procedure:
The above compound N-(4-Cyano-phenyl)-2-{4-[6-oxo-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-6,7-dihydro-1H-purin-8-yl]-phenoxy}-acetamide (0.110 g, 0.20 mmol) was taken in DCM (6 ml) and TFA (3 ml), stirred for 4 hrs at 27° C. The solvent was evaporated and the residue was washed with saturated NaHCO3 followed by water and n-pentane to obtain N-(4-cyano-phenyl)-2-[4-(6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-phenoxy]-acetamide (0.049 g, 58%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27])(=[O:23])[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[C:24]([C:21](=[O:23])[CH3:22])[CH:25]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(=O)c1cccc(N)c1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: CC(=O)c1cccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)c1
Yield: 87.7 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and m-acetylaniline (80 mg, 0.59 mmol) to give 200 mg of the title compound (85%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (bs, 1H), 10.23 (s, 1H), 8.12 (bs, 1H), 7.85 (d, 1H, J=8.1 Hz), 7.68 (d, 1H, J=8.1 Hz), 7.47 (t, 1H, J=8.1 Hz), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 5.18~5.28 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.55~2.70 (m, 2H), 2.56 (s, 3H), 2.12 (dm, 1H, J=13.5 Hz), 1.81~1.96 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH2:31][CH2:32]I)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.CC(C)([O-])C.[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH2:31][CH2:32][O:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1cccnc1
Reactant: CCOC(=O)CCC(CCI)CCCCN(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(CCCCN(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1

Procedure:
To a solution of 3.1 g (5 mmol) of ethyl 8-[N-(p-chlorophenylsulfonyl)-N-(t-butoxycarbonyl)amino]-4-(2-iodoethyl)octanoate in 10 ml dimethylformamide at 0° C. under an inert atmosphere is added a solution of 0.62 g (6.5 mmol) 3-hydroxypyridine and 0.73 g potassium-t-butoxide in 20 ml dimethylformamide, dropwise. After 24 hours at room temperature the reaction is evaporated to dryness. The residue is dissolved in ethyl acetate and the solution is washed with cold 5% Na2CO3 solution and brine, dried and evaporated to yield ethyl 8-[N-(p-chlorophenylsulfonyl)-N-(t-butoxycarbonyl)-amino]-4-[2-(3-pyridyloxy)-ethyl]-octanoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[Si:16]([CH3:19])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[CH3:17][Si:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:19])[CH3:18]
Reactant: Oc1cccc(Br)c1
Reactant: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromophenol (17.3 g, 0.100 mol) and 9 ml of pyridine together with 100 ml of toluene were placed in a 3-necked 250 ml round-bottomed flask equipped with a reflux condensor, an addition funnel and thermometer/adaptor. Chlorotrimethylsilane (12.8 g, 15 ml, 0.12 mol) was added dropwise to the vigorously stirred solution. The resultant white reaction mixture was subsequently refluxed for 4 hrs and then stirred at room temperature overnight. The white precipitate was removed by filtration and the colorless filtrate was subjected to rotary evaporation to remove the solvent. The residual liquid was purified by simple distillation. The pure product was collected at 232°-233° C. Yield: 23.0 g (93%). Calc. for C9H13BrOSi: 44.08% C; 5.34% H; 32.59% Br. Found: 43.98% C; 5.36% H; 32.35% Br. Mass Spectroscopy: 244,246 (77%, 78%, M+) Proton NMR (δ in ppm, CHCl3); 0.27 (singlet, Me3Si--); 6.66-7.32 (complex, aromatic protons).