Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[N:7]([CH2:8][C:9]([N:11]([CH:18]([CH3:20])[CH3:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[C:6]2[CH:21]=[CH:22][CH2:23][CH2:24][C:5]=2[C:4](=[O:25])[O:3]1.[NH2:26][CH2:27]C(O)=O.C(N(CC)CC)C>O>[O:3]=[C:2]1[N:7]([CH2:8][C:9]([N:11]([CH:18]([CH3:20])[CH3:19])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])[C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[C:4](=[O:25])[NH:26][CH2:27]1
Reactant: NCC(=O)O
Reactant: CC(C)N(C(=O)Cn1c2c(c(=O)oc1=O)CCC=C2)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)CN1C(=O)CNC(=O)c2ccccc21)c1ccccc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
A suspension of 2-(2,4-dioxo-6H-benzo[d][1,3]oxazin-1-yl)-N-isopropyl-N-phenylacetamide (10 g, 31 mmol), glycine (2.32 g, 31 mmol) and triethylamine (4.32 mL, 31 mmol) in water (50 mL) is stirred at 50° C. for 5 h. The reaction mixture is concentrated to a brown viscous oil, acetic acid (100 mL) is added and the mixture heated at reflux for 6 h. The reaction mixture is concentrated to a brown viscous oil, dissolved in ethyl acetate (300 mL) and washed with water, saturated aqueous sodium bicarbonate and brine. The resulting solution is dried over magnesium sulfate and concentrated to a yellow foam. Recrystallization from ethyl acetate/petroleum ether (4:1, 100 mL) gave the title compound (7.55 g, 21.5 mmol) as an off-white powder. 1H NMR (300M Hz, CDCl3): 1.12 (d, J=6.7 Hz, 6H); 3.6-6.4 (m, 4H); 5.05 (m, J=6.7 Hz, 1H); 6.62 (m, 1H); 7.1-7.6 (m, 7H); 7.84 (d, J=7.5 Hz, 1H). MS (FAB): [M+H]+ =352.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])(=O)=O>C1CCCCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To the product of step (b) (70.2 g, 189 mmol) was added N,N-dimethylformamide (260 mL) and this mixture was cooled in an ice bath under nitrogen. 2,6-Lutidine (40.3 g, 376 mmol) was added over 5 min and then tert-butyldimethylsilyl trifluoromethanesulfonate (99.8 g, 378 mmol) was added slowly while maintaining the temperature below 20° C. The mixture was allowed to warm to room temperature for 45 min. Methanol (45 mL) was added to the mixture dropwise over 10 min and the mixture was partitioned between ethyl acetate/cyclohexane (1:1, 500 mL) and water/brine (1:1, 500 mL). The organics were washed twice more with water/brine (1:1, 500 mL each). The combined organics were evaporated under reduced pressure to give a light yellow oil. Two separate portions of cyclohexane (400 mL) were added to the oil and distillation continued until a thick white slurry was formed. Cyclohexane (300 mL) was added to the slurry and the resulting white crystals were filtered, washed with cyclohexane (300 mL) and dried under reduced pressure to give the title compound (75.4 g, 151 mmol, 80% yield, 98.6% ee).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[CH2:17]([O:16][C:14]([CH:11]1[CH2:12][CH2:13][CH:8]([CH2:7][C:6]([OH:19])=[O:5])[CH2:9][CH2:10]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1CCC(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1CCC(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 100 mL round-bottom flask was charged ethyl 4-(2-tert-butoxy-2-oxoethyl)cyclohexanecarboxylate (Int-4b, 2.00 g, 7.40 mmol) and 4N HCl in 1,4-dioxane. The resulting solution was stirred at room temperature for 2 hours. At this point the solvent was removed in vacuo and the resulting residue was diluted with DCM and washed with H2O. The organic layer was dried over Na2SO4 and reduced in vacuo. The resulting residue was taken on without further purification.
Reaction SMILES: [CH3:1][N:2]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[C:25]([CH3:33])[CH:24]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH:4]1[C:9]([OH:11])=O.[NH2:34][OH:35]>>[OH:35][NH:34][C:9]([C@H:4]1[C@H:3]([N:2]([CH3:1])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7][O:6][CH2:5]1)=[O:11]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N(C)C3CCOCC3C(=O)O)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@@H]3CCOC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 40 %

Procedure:
According to the procedure of Example 24, Step 3, 4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-pyran-3-carboxylic acid (0.120 g, 0.255 mmol) and hydroxylamine provided (3S,4R)-4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-pyran-3-carboxylic acid hydroxyamide as an amorphous white solid (0.050 g, 40%) after purification by Biotage Flash 40S chromatography, eluting with 4% methanol in ethyl acetate. MS: 486 (M+H)+.
Reaction SMILES: CN(C)C=O.[C:6]([NH:25][C:26]1[S:27][CH:28]=[C:29](/[C:31](=[N:36]/[OH:37])/[C:32]([O:34][CH3:35])=[O:33])[N:30]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:44](Br)[CH:45]=[CH2:46]>O>[C:6]([NH:25][C:26]1[S:27][CH:28]=[C:29](/[C:31](=[N:36]/[O:37][CH2:46][CH:45]=[CH2:44])/[C:32]([O:34][CH3:35])=[O:33])[N:30]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCO/N=C(\C(=O)OC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 91.1 %

Procedure:
To 70.5 ml of N,N-dimethylformamide are added 7.05 g of methyl 2-(2-tritylamino-4-thiazolyl)-(Z)-2-hydroxyiminoacetate and 3.3 g of potassium carbonate. Then, under ice-cooling and stirring 2.12 g of allyl bromide is added dropwise over a period of 5 minutes. The mixture is further stirred under ice-cooling for 4 hours. To this reaction mixture are added 1.65 g of potassium carbonate and 1.06 g of allyl bromide, and the mixture is stirred for an additional 4 hours. The reaction mixture is diluted with 150 ml of water and extracted three times with 100 ml portions of ether. The ether extract is washed twice with 100 ml portios of aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is then distilled off and the residue is purified by column chromatography [silica gel: 300 g; eluent: hexane-ethyl acetate (1:1)] and crystallized from ether-hexane to give 7.0 g of methyl 2-(2-tritylamino-4-thiazolyl)-(Z)-2-allyloxyiminoacetate, m.p. 115°- 116° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[CH2:5]2.[OH:15][C@:16]1([C:23]2[CH:24]=[C:25]([SH:28])[S:26][CH:27]=2)[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]1>>[OH:15][C@:16]1([C:23]2[CH:24]=[C:25]([S:28][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[CH2:5]4)[S:26][CH:27]=2)[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]1
Reactant: CN1Cc2cc(I)ccc2N(C)C1=O
Reactant: C[C@H]1C[C@@](O)(c2csc(S)c2)CCO1
Product: C[C@H]1C[C@@](O)(c2csc(Sc3ccc4c(c3)CN(C)C(=O)N4C)c2)CCO1
Yield: 74 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-iodo-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline was reacted with (2S,4R)-4-hydroxy-4-(2-mercaptothien-4-yl)-2-methyltetrahydropyran to give (2S,4R)-4-hydroxy-2-methyl-4-[2-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-ylthio)thien-4-yl]tetrahydropyran in 74% yield as a gum;
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH:9](C(=O)C2C=CC=CC=2)[OH:10])[O:7][C@@H:6]([N:19]2[CH:26]=[C:25]([F:27])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:5]1)=[N+:2]=[N-:3].N>CO>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:19]2[CH:26]=[C:25]([F:27])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2cc(F)c(=O)[nH]c2=O)O[C@@H]1C(O)C(=O)c1ccccc1
Agent: N
Solvent: CO
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cc(F)c(=O)[nH]c2=O)O[C@@H]1CO

Procedure:
3′-Azido-5′-benzoyl-2′,3′-dideoxy-5-fluorouridine prepared in step B above (2.5 g) was suspended in methanol saturated with ammonia (200 mL) and stirred using a magnetic stirrer at room temperature for 12 hours. Subsequently, the methanol was removed using a vacuum evaporator, and the solid residue was subjected to column chromatography on silica gel with chloroform-methanol (40:1, v/v) as the mobile phase. Yield of AddFU: 1.64 g, 91%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([I:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.O(C)[Na].CO.[Cl-].[Zn+2:22].[Cl-]>CO>[Zn:22].[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([I:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: [Zn+2]
Agent: CO[Na]
Agent: Nc1nc(O)c(I)c(-c2ccccc2)n1
Agent: [Cl-]
Solvent: CO
Product: [Zn]
Reaction time: 0.08 h

Procedure:
To 1.56 g. (5 mmole) of 2-amino-5-iodo-6-phenyl-4-pyrimidinol in 15 ml. of methanol under nitrogen with stirring at room temperature is added 1.1 ml. of a 25% NaOCH3 /CH3OH solution. After five minutes 340 mg. (2.5 mmole) of anhydrous zinc chloride (ZnCl2)) was added. After one hour the heterogeneous solution is concentrated to dryness, washed with 2×50 ml. water, filtered, and dried in vacuo at 60° C. for 18 hours. The product is a white solid with m.p. at 285° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:25][C:26]([O:28]C)=[O:27])[CH:7]=[CH:8][C:9]=1[NH:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH:22]([CH3:24])[CH3:23])[CH:14]=1)=[O:12]>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:25][C:26]([OH:28])=[O:27])[CH:7]=[CH:8][C:9]=1[NH:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH:22]([CH3:23])[CH3:24])[CH:14]=1)=[O:12]
Reactant: COC(=O)Cc1ccc(NC(=O)c2cn(C(C)C)c3ccccc23)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)n1cc(C(=O)Nc2ccc(CC(=O)O)cc2Cl)c2ccccc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
In THF (6.0 ml) was dissolved the methyl 3-chloro-4-((1-isopropyl-3-indolylcarbonyl)amino)phenylacetate obtained in the above-described (Step 3). To the resulting solution was added 0.25N NaOH (6.0 ml), followed by stirring at 50° C. for 18 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The resulting residue was acidified with 1N HCl (2.0 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give 3-chloro-4-((1-isopropyl-3-indolylcarbonyl)amino)phenylacetic acid (246.2 mg, 93%) as a brown amorphous substance.
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:29][CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[ClH:29].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: ClCCN1CCCC1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: O=C1N(CCN2CCCC2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 179° C. and MS: m/e=467.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 1-(2-chloroethyl)-pyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.Br[CH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25]C)=[O:24].C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+].Cl>C1COCC1.CO.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([OH:25])=[O:24])=[CH:13][CH:12]=2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Oc1ccc(-c2cc(F)cc3ccoc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(COc2ccc(-c3cc(F)cc4ccoc34)cc2)c1
Reaction time: 8 h
Yield: 94 %

Procedure:
To the compound (170 mg, 0.745 mmol) of Step 2, methyl 3-(bromomethyl)benzoate (256 mg, 1.12 mmol), and potassium carbonate (206 mg, 1.49 mmol), DMF (4 mL) was added, and stirred overnight. The solvent was distilled away under reduced pressure, and after diluted with ethyl acetate, the resultant was washed with the water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate). To the resulting compound (267 mg, 0.709 mmol), methanol (5 mL) and THF (5 mL) were added. A 1 N lithium hydroxide aqueous solution (1.5 mL) was added thereto under ice-cooling, and stirred at room temperature overnight. After a 1N hydrochloric acid aqueous solution (2 mL) were added thereto under ice-cooling, the solid obtained by concentrating the solvent was collected by filtration to thus obtain the title compound.
Reaction SMILES: [I:1][C:2]1[S:3][C:4]([C:13]([O:15]CC)=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[OH-].[Na+].Cl>C(O)C>[I:1][C:2]1[S:3][C:4]([C:13]([OH:15])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: CCOC(=O)c1sc(I)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1sc(I)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Ethyl 2-iodo-4-phenyl-1,3-thiazole-5-carboxylate (5 g, 13.9 mmol) was dissolved in 96% ethanol (30 ml), treated with solid sodium hydroxide (1.1 g) and stirred at room temperature for 1 hour. The solution was acidified with 3 N HCl solution, and extracted with ethyl acetate (5×50 ml). The organic layers were combined, dried over Na2SO4 and evaporated to give the title compound as a solid. Yield: 92% yield.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>BrC1C=C2C(=CC=1)NN=C2.O1CCCC1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[CH3:9][N:8]([CH3:10])[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19])[N:7]=1
Reactant: CN(C)c1cccc(Br)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Brc1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(N(C)C)n1
Temperature: 0 °C
Yield: 50 %

Procedure:
Add dropwise a solution of (6-bromo-pyridin-2-yl)-dimethyl-amine (8; g, 39.8 mmol) in anhydrous tetrahydrofuran (10; mL) to a stirring cooled solution of n-butyl-lithium in hexanes (2.5; M, 19.1; mL, 47.7; mmol) in anhydrous tetrahydrofuran (160; mL) under nitrogen at −75° C. at a rate so that the internal reaction temperature does not exceed −70° C. After 1; h at −75° C., add dropwise tri-n-butyltin chloride (13; g, 39.8; mmol), stir for 30; min and warm to 0° C. Add water (200; mL) and then dilute with a saturated aqueous solution of sodium bicarbonate (50; mL) and diethyl ether (200; mL) and separate the layers. Extract the organic phase once with brine (200; mL), dry over sodium sulfate, filter and concentrate to give a liquid (25.4; g). Purify by silica gel chromatography eluting with iso-hexane:ethyl acetate:triethylamine 90:9:1, to give the title product as a colorless liquid (8.16; g, 50%). MS (m/z): 409-414; cluster (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19](O)=[O:20])[CH2:14]2)=[CH:9][CH:8]=1.CN.[CH3:27][N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:27][NH:28][C:19]([C@@H:15]1[CH2:16][C:17](=[O:18])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]3[CH:22]=[CH:23][CH:24]=[C:2]([Cl:1])[CH:3]=3)=[CH:8][CH:9]=2)[CH2:14]1)=[O:20]
Reactant: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(Cl)c3)cc2)C1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(Cl)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 24f), the condensation of the (R)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid with methylamine using HBTU as the condensation agent yields the (R)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a white solid. MS: m/e=359 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:17])=[O:12])=[CH:6][CH:5]=1.[C:23]([Mg]Br)#[C:24][CH3:25]>COCCOC.C1COCC1>[F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[C:11]([C:13]2[CH:20]=[CH:19][CH:18]=[C:15]([CH:16]([OH:17])[C:23]#[C:24][CH3:25])[CH:14]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: CC#C[Mg]Br
Reactant: O=Cc1cccc(C(=O)C(=O)c2ccc(OC(F)F)cc2)c1
Solvent: COCCOC
Solvent: C1CCOC1
Product: CC#CC(O)c1cccc(C(=O)C(=O)c2ccc(OC(F)F)cc2)c1
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A stirred solution of 3-[2-(4-difluoromethoxyphenyl)-2-oxo-acetyl]-benzaldehyde (0.1 g, 0.33 mmol) in dry DME at 0° C. under nitrogen was treated over 10 min with 0.5 M 1-propynyl magnesium bromide in THF. The reaction was stirred for 0.5 h, quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The combined extracts were dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue by flash chromatography (20% to 40% ethyl acetate/petroleum ether) gave 1-(4-difluoromethoxyphenyl)-2-[3-(1-hydroxybut-2-ynyl)phenyl]ethane-1,2-dione as a clear oil, 55 mg (49% yield). Using essentially the same procedure described as described in Example 1, step c, and employing 1-(4-difluoromethoxyphenyl)-2-[3-(1-hydroxy-but-2-ynyl)phenyl]-ethane-1,2-dione (0.055 g, 0.16 mmol), the title product was obtained as a slight yellow foam, 0.044 g (69% yield), identified by NMR and mass spectral analyses. MS (ES+): 400 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4](=[N:8][O:9][N+:10]=2[O-:11])[N:5]=[CH:6][N:7]=1.[H-].[Li+].[CH3:14]I>C1COCC1.C(OCC)(=O)C>[CH3:14][N:7]1[C:2](=[O:1])[C:3]2=[N+:10]([O-:11])[O:9][N:8]=[C:4]2[N:5]=[CH:6]1
Reactant: [O-][n+]1onc2ncnc(O)c21
Reactant: CI
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cnc2no[n+]([O-])c2c1=O
Temperature: 40 °C
Reaction time: 48 h

Procedure:
A solution of 3.0 g (20 mmol) of 7-hydroxy-[1,2,5]oxadiazolo[3,4-d]pyrimidine-1-oxide (C. Temple, C. L. Kussner, J. A. Montgomery, J. Org. Chem. 33 (1968) 2086) in 30 ml of THF is added dropwise to a suspension of 0.18 g (22.5 mmol) of lithium hydride in 20 ml of THF. The mixture is heated at 40° C. for 30 minutes, then 11.5 g (80 mmol) of methyl iodide in 10 ml of THF are added dropwise at room temperature and it is allowed to stand for 2 days. The mixture is diluted with 300 ml of ethyl acetate, washed three times with water, dried over magnesium sulphate and concentrated in vacuo. After recrystallisation from isopropanol, 1.9 g (57%) of 6-methyl-[1,2,5]oxadiazolo[3,4-d]pyrimidine-7(6H)-one-1-oxide are obtained.
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH2:20][CH2:21][CH3:22])[C:11]2[CH:17]=[C:16]([CH2:18]O)[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]1(=[O:55])[NH:49][C:48](=[O:50])[C:47]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:46]12.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:23]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH2:20][CH2:21][CH3:22])[C:11]2[CH:17]=[C:16]([CH2:18][N:49]3[C:45](=[O:55])[C:46]4[C:47](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:48]3=[O:50])[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:24][CH3:25]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCN(CCC)CCCCc1nc2ccc(CO)cc2n1CCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCN(CCC)CCCCc1nc2ccc(CN3C(=O)c4ccccc4C3=O)cc2n1CCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
The compound (302 mg) obtained in Example 125-4 was dissolved in toluene (6.0 ml) and added with triphenylphosphine (275 mg) and phthalimide (193 mg), followed by cooling to 0° C. In this solution, a 40% diethyl azodicarboxylate/toluene solution (452 mg) was dropped. After that, the solution was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with water. Then, the solution was subjected to extraction with chloroform and the extract was then washed with saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (174 mg) as a pale-yellow solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:30])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[CH3:29][O:28][CH2:27][CH2:26][O:25][C:23]1[CH:22]=[CH:21][C:20]2[C:10]3([CH2:17][O:18][C:19]=2[CH:24]=1)[C:11]1[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:9]3=[O:30]
Reactant: COCCOc1ccc2c(c1)OCC21C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: COCCOc1ccc2c(c1)OCC21C(=O)Nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-6-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 6-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (69%): mp 172-174° C.; 1H NMR (300 MHz, CDCl3) δ8.56 (s, 1H), 7.23-7.18 (m, 1H), 7.15-7.06 (m, 1H), 7.06-6.97 (m, 1H), 6.97-6.89 (m, 1H), 6.89-6.82 (m, 1H), 6.82-6.74 (m, 1H), 6.38 (s, 1H), 4.80 (ABq, 2H), 4.03-3.80 (m, 2H), 3.67-3.54 (m, 2H), 3.35 (s, 3H); MS (ES+) m/z 312.0 (M+1).