Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:23]=[CH:22][C:8]([CH2:9][O:10][C:11](=[O:21])[CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11](=[O:21])[CH:12]([P:13]([O:15][CH2:16][CH3:17])([O:18][CH2:19][CH3:20])=[O:14])[CH2:25][CH:26]2[CH2:28][CH2:27]2)=[CH:22][CH:23]=1
Reactant: CCOP(=O)(CC(=O)OCc1ccc(OC)cc1)OCC
Reactant: BrCC1CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(CC1CC1)C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a suspension of 60% sodium hydride in mineral oil (0.840 g, 21.0 mmol) in DMF (100 mL) was added a solution of 2-(diethoxyphosphoryl)acetic acid para-methoxybenzyl ester (6.04 g, 19.1 mmol) from Step A in DMF (10 mL). The reaction mixture was stirred for 30 min at room temperature. Bromomethylcyclopropane (2.4 mL, 24.8 mmol) was added and the reaction mixture was stirred at rt for 12 h. The reaction mixture was diluted with diethyl ether, poured into saturated sodium bicarbonate, and extracted three times with diethyl ether. The organic layers were combined, washed with saturated sodium chloride, dried over sodium sulfate, and filtered. The volatiles were removed in vacuo and the residue was purified by FC (40% ethyl acetate in hexanes) to afford 4.31 g of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]=1[OH:16])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:17][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]([OH:16])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(O)c(C(C)C)ccc2c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(O)c(C(C)C)cc(Br)c2c1
Yield: 91.3 %

Procedure:
In 100 ml of DMF was dissolved 5 g of 2-isopropyl-6-methoxy-1-naphthol, and a solution of 4.03 g of N-bromosuccinimide in DMF (50 ml) was added under ice-cooling. The mixture was stirred under ice-cooling for 3 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent:diethyl ether:n-hexane:chloroform=10:50:1) to provide 6.1 g of 4-bromo-2-isopropyl-6-methoxy-1-naphthol. m.p. 81.5°-83.5° C.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22]>C(OCC)(=O)C>[CH3:26][C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH:11]=1)([CH3:25])[C:21]([O:23][CH3:24])=[O:22]
Reactant: NC(=O)c1ccccc1
Reactant: COC(=O)C(C)(C)OCCCCCCC(=O)CCl
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)OCCCCCCc1coc(-c2ccccc2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
A mixture of 956 mg of benzamide and 1.1 g of methyl 2-(8-chloro-7-oxooctyloxy)-2-methylpropionate was stirred for 2 hours at 120° C. The reaction solution was cooled, dissolved in ethyl acetate, washed by adding sodium hydrogencarbonate, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=9:1) to provide 658 mg of the objective compound as colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.C[O:9][C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=O>>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=[O:9]
Reactant: OCC1CCCN1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CCCC2CO)n1
Yield: 15 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 2-hydroxymethyl-pyrrolidine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (15%) as sticky yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([OH:13])[CH:9]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:13][C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[O:12][N:11]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1cc(-c2ccccc2Cl)on1
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2Cl)on1
Yield: 87.9 %

Procedure:
5-(2-Chlorophenyl)-3-hydroxy-isoxazole (0.23 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.20 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.35 g, 88%) as a colorless powder.
Reaction SMILES: O[C:2]1[C:11]2[CH2:10][CH:9]([CH2:12][CH3:13])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[C:11]2[CH2:10][CH:9]([CH2:12][CH3:13])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(c1O)CC(CC)CC2
Product: CCOC(=O)c1cnc2c(c1Cl)CC(CC)CC2

Procedure:
A solution of 3.5 g of ethyl 4-hydroxy-6-ethyl-5,6,7,8-tetrahydroquinoline-3-carboxylate in 35 ml phosphorus oxychloride is heated to reflux under nitrogen for five hours. The POCl3 is removed under vacuum, the residue is dissolved in CHCl3, and the solution is washed with cold 2N NaOH, saturated NaCl, then dried over anhydrous MgSO4, and evaporated to dryness. The crude product is purified through a short column of silica gel eluting with EtOAc. Removal of solvent under vacuum affords ethyl 4-chloro-6-ethyl-5,6,7,8-tetrahydroquinoline-3-carboxylate as an oil, which is used directly in the next step.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O+](CC)CC)[CH3:7].[CH:13]1([CH2:16][O:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]1>C(Cl)Cl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH:13]1([CH2:16][O:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20](=[NH:22])[O:21][CH2:6][CH3:7])[CH2:15][CH2:14]1
Reactant: CC[O+](CC)CC
Reactant: NC(=O)c1ccccc1OCC1CC1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=N)c1ccccc1OCC1CC1
Reaction time: 18 h
Yield: 66 %

Procedure:
A solution of triethyloxonium fluoroborate (99.1 g., 0.522 mole) in methylene chloride (225 ml.) was added to a stirred solution of 2-cyclopropylmethoxybenzamide (99.2 g., 0.518 mole) in methylene chloride (450 ml.). The mixture was stirred at 22° for 18 hours. The solution was concentrated to about one-fifth volume and then diluted with diethyl ether. The precipitated solid was recrystallized from methylene chloride - diethyl ether to give ethyl 2-cyclopropylmethoxybenzimidate fluoroborate (104.7 g., 65.7%), m.p. 120°-121°. To a stirred, cooled (ice-water) mixture of the fluoroborate (104.7 g.) in ethanol (100 ml.) was added 400 ml. of 6% ethanolic ammonia. The mixture was stirred for 18 hours at 20°. The mixture was concentrated and the residue partitioned between diethyl ether and 3N sodium hydroxide. The ether layer was washed with brine and dried over sodium sulfate. The dried solution was treated with hydrogen chloride. The precipitate was recrystallized from methylene chloride-diethyl ether to give 2-cyclopropylmethoxybenzamidine hydrochloride (71.5 g., 92.5% from fluoroborate), m.p. 166°-171°.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:36])[CH2:17][CH2:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[C:26]([O:28]CC1C=CC=CC=1)=[O:27])=[O:20])=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:26]([C@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:36])([OH:28])=[O:27]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)CCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CCCN1C(=O)CCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 108.9 %

Procedure:
A solution of 256 mg (0.5 mmol) (R)-1-[4-[(R)-2-benzyloxycarbonyl-pyrrolidin -1-yl]-4-oxo-butyryl]-pyrrolidine-2-carboxylic acid benzyl ester in 5 ml ethanol as stirred with 13 mg 10% Palladium on carbon under 1 atm of hydrogen for 16 h at room temperature. After filtration to remove the catalyst, concentration in vacuo afforded 170 mg (100%) of the title compound (R)-1- [4-[(R)-2-carboxy-pyrrolidin-1-yl]-4-oxo-butyryl]-pyrrolidine-2-carboxylic acid as a colorless viscous oil. MS m/e (%): 313 (M+H)+, 100).
Reaction SMILES: N#N.O[CH2:4][C:5]1[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=1.CCN(CC)CC.S([Cl:24])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][CH2:4][C:5]1[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(CO)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(CCl)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 173.7 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(5-hydroxymethyl-furan-2-yl)-ethanone (2.00 g, 14.27 mmol) in dry CH2Cl2 (29 mL) was treated at 0° C. with Et3N (2.58 mL, 18.55 mmol) followed by DMAP (178 mg, 1.43 mmol) and Ms-Cl (1.33 mL, 17.13 mmol). After stirring at rt for 3 h, the reaction was quenched with water. The layers were separated and the aq. layer extracted with CH2Cl2 (3×) The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give 3.93 g (quant.) of crude 1-(5-chloromethyl-furan-2-yl)-ethanone as a brown oil. Part of this crude material (1.718 g, 10.83 mmol) in DMF (10.3 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (10.30 g of a 10% solution in acetone, 9.03 mmol) in DMF (10.3 mL) pre-treated for 30 min with DIPEA (3.09 mL, 18.06 mmol) and the reaction mixture was stirred overnight at 50° C. Water (32 mL), followed by EA (65 mL) were added. The aq. layer was extracted with EA (65 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound as a yellow solid: TLC:rf (2:1 hept-EA)=0.20. LC-MS-conditions 02: tR=0.85 min, [M+H]+=237.46.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.C(=O)=O.CC(C)=O.[OH-].[Na+]>C(Cl)Cl>[Cl:12][CH2:13][CH2:14][CH2:15][S:16]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:6]
Reactant: O=[N+]([O-])c1ccc(SCCCCl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)CCCCl)cc1
Reaction time: 2 h
Yield: 4.2 %

Procedure:
A solution of m-chloroperoxybenzoic acid (80% 16.6 g, 86.3 mmol) in methylene chloride (100 mL) was added dropwise to a solution of 1-[(3-chloropropyl)thio]-4-nitrobenzene (20.0 g, 86.3 mmol) in methylene chloride (20 mL) maintained at -78° C. (dry ice/acetone bath). After 2 h the reaction was allowed to warm to ambient temperature (~1 h) and 200 mL of 10% aqueous sodium hydroxide was added. The layers were allowed to separate and the aqueous layer was extracted (100 mL) with methylene chloride. The combined organic extracts were washed (water, 100 mL), dried (MgSO4) and concentrated in vacuo. A 1.0 g sample of the residue (21.2 g) was chromatographed (Chromatatron, SiO2 4000 μ, 99/1 methylene chloride:methanol) to give 0.89 g (88%) of white solid, mp 72.5°-74.5° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2(O)[C:12]3[C:13]([CH3:32])=[C:14]([N:19]4[CH2:24][CH2:23][N:22]([CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:21][CH2:20]4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:34])[CH3:33])=[CH:4][CH:3]=1>CCCCCC>[CH2:25]([N:22]1[CH2:21][CH2:20][N:19]([C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]3[O:10][C:9]([CH3:34])([CH3:33])[CH:8]([C:5]4[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:12]=3[C:13]=2[CH3:32])[CH2:24][CH2:23]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1c(C)c(N2CCN(Cc3ccccc3)CC2)c(C)c2c1OC(C)(C)C2(O)c1ccc(F)nc1
Solvent: CCCCCC
Product: Cc1c(C)c(N2CCN(Cc3ccccc3)CC2)c(C)c2c1OC(C)(C)C2c1ccc(F)nc1
Yield: 78 %

Procedure:
Using 3-(6-fluoropyridine-3-yl)-5-(4-benzylpiperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Example 125, the title compound was synthesized in the same manner as in Example 46. Yield 78%. mp. 76–79° C. (hexane).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:14]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO>[Br:14][CH:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10]
Reactant: BrBr
Reactant: O=C(CCC1CCCCC1)C1CC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: O=C(C(Br)CC1CCCCC1)C1CC1
Temperature: -5 °C
Yield: 100 %

Procedure:
3-Cyclohexyl-1-cyclopropylpropan-1-one (61.0 mg, 0.338 mmol) obtained in step 2 was dissolved in methanol (1.0 mL), and the mixture was cooled to −5° C., and a dilute solution of bromine (0.0200 mL, 0.372 mmol) in methanol (1.0 mL) was slowly dropped to the mixture. After the dropping, the mixture was stirred at room temperature for hours. Under ice-cooled condition, a sodium thiosulfate aqueous solution was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95) to give 2-bromo-3-cyclohexyl-1-cyclopropylpropan-1-one (87.6 mg, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]([O:15]C)=[O:14])=[CH:10][C:9]=2[S:17][C:18]([F:21])([F:20])[F:19])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[S:17][C:18]([F:20])([F:19])[F:21])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(SC(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(SC(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 106 %

Procedure:
A mixture of methyl 5-(p-chlorophenyl)-4-[(trifluoromethyl)thio]pyrrole-2-carboxylate (4.89 g, 0.0146 mol) and sodium hydroxide (1.75 g, 0.0437 mol) in a 2:1 methanol/water solution (150 mL) is warmed to 60° C., stirred for three hours, cooled to room temperature with stirring overnight and concentrated in vacuo to remove most of the methanol. The resulting aqueous solution is treated with 10% hydrochloric acid and a white precipitate forms. Ethyl acetate is added and the organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as an off-white solid (4.98 g, mp 176°-178° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:13][C:14]=1[CH3:15].[Cl:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:17]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([NH:8][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[C:27]([CH2:26][Cl:25])[CH:28]=2)[CH:10]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: Cc1ccc(NC(=O)c2ccccc2)cc1N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccccc2)cc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.5 %

Procedure:
Triethylamine (2.0 ml) was added to a stirred mixture of N-(3-amino-4-methylphenyl)benzamide (3.0 g), 3-chloromethylbenzoyl chloride (2.76 g), 4-dimethylaminopyridine (0.162 g) and methylene chloride (50 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under 2N aqueous hydrochloric acid solution. The solid so obtained was isolated, washed in turn with a saturated aqueous sodium bicarbonate solution, water and isohexane and dried under vacuum at 55° C. There was thus obtained the title compound (5.1 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 4.85 (s, 2H), 7.23 (d, 1H), 7.55 (m, 5H), 7.66 (d, 1H), 7.84 (s, 1H), 7.95 (m, 3H), 8.05 (s, 1H), 9.96 (s, 1H), 10.22 (s, 1H); Mass Spectrum: M−H− 377.
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][CH2:22][CH:23]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])=[CH:14][CH:13]=1)=O.C([O-])(O)=O.[Na+].[C:41]([NH:48][CH2:49][CH2:50][NH2:51])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>O.CC#N>[C:44]([O:43][C:41]([NH:48][CH2:49][CH2:50][NH:51][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][CH2:22][CH:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]3[C:35]2=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:20])=[CH:14][CH:13]=1)=[O:8])=[O:42])([CH3:45])([CH3:46])[CH3:47]
Reactant: O=C(Nc1ccc(NC(=O)ON2C(=O)CCC2=O)cc1)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NCCNC(=O)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A solution of N-{4-[(2,5-dioxoazolidinyloxy)carbonylamino]phenyl}(fluoren-9-ylmethoxy)carboxamide (16.10 g, 34.15 mmol, 1.0 eq) in H2O/CH3CN (1/1, v/v, 360 mL) is reacted at room temperature with NaHCO3 (2.86 g, 34.15 mmol, 1.0 eq) and N—BOC-ethylenediamine (5.47 g, 34.15 mmol, 1.0 eq). After stirring overnight at room temperature, the reaction mixture is filtered to afford 16.36 g of the expected crude product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4](Cl)[N:3]=1.[NH2:13][C@H:14]1[CH2:18][C:17]([CH2:19][OH:20])=[CH:16][CH2:15]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:13][C@H:14]2[CH2:18][C:17]([CH2:19][OH:20])=[CH:16][CH2:15]2)[C:5]([NH:9][CH:10]=[O:11])=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: N[C@@H]1CC=C(CO)C1
Product: Nc1nc(Cl)c(NC=O)c(N[C@@H]2CC=C(CO)C2)n1

Procedure:
By the method of Exaple 7, N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 2.56 g, 52.4 mmol) was reacted with (4R)-4-amino-1-cyclopentene-1-methanol (1.4 g, 52.4 mmol), available from (-)-2-azabicyclo[2.2]hept-5-en-3one (Chiroscience) by methods described in Examples 1-4 and 42 of U.S. Pat. No. 5,049,671. Crystallization from ethyl acetate--methanol gave title compound as white crystals, m.p. 148-150° C.; mass spectrum (CI/CH4): 286, 284 (M+1), 190, 188 (B+M); 1H-NMR (DMSO-d6)δ: 8.97 and 8.55 (s and d with J=11.3 Hz, total 1, NHCHO), 8.12 and 7.80 (s and d with J=11.5 Hz, total 1, CHO), 7.00 and 7.78 (both d, J=7.4 Hz, total 1, NH), 6.60 and 6.40 (both 8, total 2, NH2), 5.48 (s, 1, =CH), 4.74 (t, J=5.5 Hz, 1, OH), 4.74-4.60 (m, 1, NCH), 4.0-3.90 (m, 2, CH2O), 2.75-2.55 and 2.40-2.15 (both m, 2 each, 2CH2); [α]58920 -4.4°, [60 ]57820 -5.2°, [α]54620 -4.8°, [α]43620 -20.0°, [α]36520 -60.4°, (c 0.25, methanol).
Reaction SMILES: C([Sn](CCCC)(CCCC)[CH:6]1[CH2:11][CH2:10][CH:9]=[CH:8][O:7]1)CCC.Br[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:25]=[C:24]2[CH:38]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39]1>C1(C)C=CC=CC=1>[O:7]1[CH:8]=[CH:9][CH2:10][CH2:11][CH:6]1[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:25]=[C:24]2[CH:38]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39]1
Reactant: CCCC[Sn](CCCC)(CCCC)C1CCC=CO1
Reactant: CN1CCC(c2cn(C(=O)c3ccccc3)c3ccc(Br)cc23)C1
Solvent: Cc1ccccc1
Product: CN1CCC(c2cn(C(=O)c3ccccc3)c3ccc(C4CCC=CO4)cc23)C1
Yield: 566.9 %

Procedure:
To a stirred solution of 2-tributylstannyl-2,3-dihydropyran (Example 6, 0.41 g, 0.11 mmol) in anhydrous toluene (15 mL) was added 5-bromo-3-(N-methylpyrrolidin-3-yl)-1-benzoylindole (Example 5b, 0.280 g, 0.729 mmol) and Pd[PPh3 ]4 (0.09 g, 0.076 mmol). The mixture was heated to reflux for 6.5 hours, cooled, filtered through celite and concentrated by reduced pressure. The crude product was purified by column chromatography [95:5 CH2Cl2 : NH3 (2M in MeOH)] to yield the title compound (0.241 g, 85%) as a yellow oil; HRMS-FAB+ for C25H26N2O2 ; calc. MH+ :387.2072; found MH+ :387.2092.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[NH:11][C:10]2[CH2:20][O:21][C:22](=[O:23])[C:9]1=2.[CH:24]([N-]C(C)C)(C)[CH3:25].[Li+].C(I)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]([CH2:24][CH3:25])[C:10]2[CH2:20][O:21][C:22](=[O:23])[C:9]1=2
Reactant: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1Cl
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCOC(=O)C1=C(C)N(CC)C2=C(C(=O)OC2)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 mmol of ethyl 4-(2-chlorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro-[3,4-b]pyridine-3-carboxylate are dissolved in tetrahydrofuran, and 50 mmol of lithium diisopropylamide followed by 50 mmol of ethyl iodide are added at -78° C. The mixture is heated to room temperature and stirred for 1 hour, and is worked up analogously to Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH2:11]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[N:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(O)cn1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
To a solution of 3-hydroxy-6-methylpyridine (5.00 g, 45.8 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (2.02 g, 50.4 mmol, 60% in oil) at 0° C., and the solution was stirred for 15 minutes at 0° C. Then, benzyl bromide (5.99 mL, 50.4 mmol) was added at 0° C., and the solution was stirred for 3.5 hours at room temperature. The reaction solution was partitioned in water and ethyl acetate. This organic layer was separated, washed with water and brine and dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (heptane/ethyl acetate=2/1), and the title compound (5.99 g, 66%) was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13]C(=O)C)=[CH:6][C:7]2[CH2:11][CH2:10][O:9][C:8]=2[CH:12]=1)([O-:3])=[O:2]>C(O)C.Cl>[N+:1]([C:4]1[C:5]([NH2:13])=[CH:6][C:7]2[CH2:11][CH2:10][O:9][C:8]=2[CH:12]=1)([O-:3])=[O:2]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OCC2
Agent: Cl
Solvent: CCO
Product: Nc1cc2c(cc1[N+](=O)[O-])OCC2

Procedure:
89 g of N-(6-nitro-2,3-dihydrobenzo[b]furan-5-yl)acetamide in 1 l of ethanol and 400 ml of hydrochloric acid is refluxed for 2 hours and concentrated. The residue is combined with 2 N sodium hydroxide solution/ethyl acetate, the aqueous phase is again extracted once with ethyl acetate, and the combined organic phases are concentrated, thus obtaining from ethyl acetate 66 g of 6-nitro-2,3-dihydrobenzo[b]furan-5-amine, mp 152° C.