Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:28][C:29]1([CH3:35])[CH2:33][O:32][C:31](=[O:34])[NH:30]1>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:30]5[C:29]([CH3:35])([CH3:28])[CH2:33][O:32][C:31]5=[O:34])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC1(C)COC(=O)N1
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: CC1(C)COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1
Yield: 43 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 95 and 4,4-dimethyloxazolidin-2-one (138 mg), the title compound (198 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)=O.Cl.[C:15](=[O:18])([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.O>[CH3:4][C:5]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]2[C:15](=[O:18])[C:6]=1[CH2:7][CH3:2]
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1c(C)nc2ccc(Cl)cn2c1=O
Yield: 91 %

Procedure:
12.8 g. of 2-amino-5-chloropyridine are reacted with 15.8 g. of ethyl-2-ethylacetacetate in a mixture of 46 g. of phosphorus oxychloride and 7 g. of polyphosphoric acid at 120° to 130° C. for 3 hours. The initially violent hydrogen chloride gas evolution gradually ceases. The reaction mixture is treated with 100 ml. of water at 70° to 80° C. Upon cooling the pH-value of the mixture is adjusted to neutral with sodium carbonate. The aqueous reaction mixture is shaken with four 100-ml. portion of chloroform. The combined chloroform solutions, dried on sodium sulphate, are evaporated and ethyl acetate is distilled through the residue. 20.2 g. (91%) of 2-methyl-3-ethyl-7-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidine are obtained, melting at 114° to 116° C. after recrystallization from a mixture of ethanol and ether.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH3:9][CH:10]([CH2:12][C@@H:13]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:14](ON1C(=O)CCC1=O)=[O:15])[CH3:11].N(CC)(CC)CC>Cl.CN(C=O)C>[NH:24]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C@@H:13]([C:14]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:15])[CH2:12][CH:10]([CH3:11])[CH3:9]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 58.3 %

Procedure:
Proline (0.842 g, 7.31 mmoles), in its HCl salt form, is dissolved in DMF and stirred with Boc-D-Leu-OSU (2.4 g, 7.31 mmoles) and (C2H5)3N (1.02 ml, 7.31 mmoles), prepared in Step C above, at room temperature overnight. The reaction mixture is filtered and the filtrate is concentrated under vacuum to dryness. The residue is dissolved in ethyl acetate washed with 0.1 N HCl, and then washed twice with H2O. The organic layer is dried over anhydrous Na2SO4 and the solvent removed by evaporation. The crude product is purified by silica gel column, yielding 1.4 g of pure Boc-D-Leu-Pro-OH.
Reaction SMILES: [OH-].[K+].Cl.[CH:4]1([CH2:7][NH2:8])[CH2:6][CH2:5]1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]3[C:20]([CH2:23]Cl)=[N:21][N:22]=[C:18]3[CH2:17][N:16]=[C:15]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])[C:14]=2[CH:33]=1.[I-].[K+]>O1CCCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]3[C:20]([CH2:23][NH:8][CH2:7][CH:4]4[CH2:6][CH2:5]4)=[N:21][N:22]=[C:18]3[CH2:17][N:16]=[C:15]([C:25]3[C:26]([F:32])=[CH:27][CH:28]=[CH:29][C:30]=3[F:31])[C:14]=2[CH:33]=1
Reactant: NCC1CC1
Reactant: Fc1cccc(F)c1C1=NCc2nnc(CCl)n2-c2ccc(Cl)cc21
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1cccc(F)c1C1=NCc2nnc(CNCC3CC3)n2-c2ccc(Cl)cc21

Procedure:
In the manner given in Example 3, a solution of potassium hydroxide and (cyclopropylmethyl)amine hydrochloride is treated with a solution of 8-chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine and potassium iodide in tetrahydrofuran to give 8-chloro-1-[[(cyclopropylmethyl)amino]methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][NH:7][C:8](=[O:31])[C:9]=2[CH:10]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[O:27][C:26]([CH3:29])=[CH:25][C:24]3=[O:30])[C:11]=1[C:12]([O:14][CH2:15][CH2:16][C:17]#[N:18])=[O:13].C(OCC)(OCC)O[CH2:34][CH3:35]>S(=O)(=O)(O)O>[CH2:34]([O:31][C:8]1[N:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=1[O:27][C:26]([CH3:29])=[CH:25][C:24]3=[O:30])[C:11]([C:12]([O:14][CH2:15][CH2:16][C:17]#[N:18])=[O:13])=[C:2]([CH3:1])[NH:3]2)[CH3:35]
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc3c(=O)cc(C)oc23)c2c(cc[nH]c2=O)N1
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Product: CCOc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(=O)OCCC#N)=C(C)N2
Temperature: 130 °C
Reaction time: 8 h

Procedure:
2.20 g (5.27 mmol) of the compound from Example 31A are suspended in 80 ml of triethyl orthoformate and heated to 130° C. Then, over a total period of 8 hours, 5 drops of concentrated sulfuric acid are added each hour to the reaction mixture. It is then stirred at the same temperature overnight. After cooling, excess orthoester is removed in a rotary evaporator, and the crude product is purified by column chromatography (silica gel; mobile phase: initially dichloromethane, then ethyl acetate, finally ethyl acetate/methanol 20:1). The product fractions are concentrated to a volume of about 5 ml. The precipitated product is filtered off and, after washing with ethyl acetate and diethyl ether, dried under high vacuum. 282 mg (12% of theory) of the title compound are obtained in the form of brown crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[CH:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[CH2:11]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:12]#[C:13][CH3:14]>>[CH3:2][O:3][C:4](=[O:10])[CH:5]([NH:6][S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:11][C:12]#[C:13][CH3:14])=[CH:21][CH:20]=1)(=[O:24])=[O:23])[CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)C(N)C(C)C
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1

Procedure:
According to the procedure of Example 20, 1.500 g (8.95 mmol) of D,L-valine methyl ester hydrochloride and 2.19 g (8.95 mmol) of 4-but-2-ynyloxybenzenesulfonyl chloride provided 2.15 g of the NH-sulfonamide ester, 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid methyl ester, as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>O>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:21]=[CH:22][C:13]=1[NH:12][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=1
Reactant: Nc1ccc2cccnc2n1
Reactant: COc1ccc(C(=O)O)cc1
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3cccnc3n2)cc1
Temperature: 4 °C
Yield: 82.6 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (4.55 g), N,N'-carbonyldiimidazole (6.55 g) and 2-amino-1,8-naphthyridine (5.2 g). The product produced by precipitation in water (8.35 g; m.p. 85° C., viscous) is filtered and then dissolved in boiling 1-propanol (50 cc). After 1 hour's cooling at 4° C., the crystallised solid is separated by filtration, washed with 1-propanol (2×5 cc) and dried at 35° C. under reduced pressure (0.067 kPa). N-(1,8-naphthyridin-2-yl)-4-methoxybenzamide (6.9 g) is produced, m.p. 150° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][CH2:31][CH2:32][C:33]3[CH:34]=[CH:35][C:36]([S:39]([NH2:42])(=[O:40])=[O:41])=[CH:37][CH:38]=3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NCCc3ccc(S(N)(=O)=O)cc3)n2)cc1
Yield: 49 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 μL of triethylamine and 4-(2-aminoethyl)benzene-sulfonamide (23 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (30 mg, 49% yield.) MS/ES+: m/z=514.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12.[CH3:11][O-:12].[Na+]>O1CCOCC1.O>[CH3:11][O:12][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12
Reactant: Clc1nccc2ccoc12
Reactant: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1nccc2ccoc12
Yield: 89.9 %

Procedure:
A solution of 7-chlorofuro[2,3-c]pyridine (1.1 g) was stirred at room temperature under dry nitrogen in 1,4-dioxane (40 ml). Sodium methoxide (1.2 g) was added and the resulting mixture heated at reflux overnight. The mixture was diluted with water (100 ml) then extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the title compound (0.96 g) as a brown oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C([O:12][P:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C>O1CCCC1>[C:14]1([P:13]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[OH:9])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:12])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOP(c1ccccc1)c1ccccc1
Reactant: OCc1ccccc1O
Solvent: C1CCOC1
Product: O=P(Cc1ccccc1O)(c1ccccc1)c1ccccc1
Yield: 73.1 %

Procedure:
In a reactor equipped with a thermometer, a stirrer and a condenser were placed 99.2 g of o-(hydroxymethyl)phenol and 400 ml of tetrahydrofuran. They were made into a uniform solution. Thereto was added 184 g of ethyldiphenylphosphinite. The resulting mixture was subjected to reaction for 3 hr with heating and stirring. The reaction mixture was cooled and the resulting white crystal precipitate was separated by filtration and then dried to obtain 180 g of o-(diphenylphosphinylmethyl)phenol. Yield: 73% Melting point: 179° C.
Reaction SMILES: [C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([C:32](O)=[O:33])[CH:28]=4)=[CH:23][CH:22]=3)[C:10](=[O:35])[C:7]=2[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[BH4-].[Na+]>O.CO.C1COCC1>[C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([CH2:32][OH:33])[CH:28]=4)=[CH:23][CH:22]=3)[C:10](=[O:35])[C:7]=2[NH:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1C1c2c(C(C)(C)C)n[nH]c2C(=O)N1c1ccc(-c2cc(C(=O)O)no2)cc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1C1c2c(C(C)(C)C)n[nH]c2C(=O)N1c1ccc(-c2cc(CO)no2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To a mixture of 3-t-butyl-5-[4-(3-carboxy-5-isoxazolyl)phenyl]-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.080 g, 0.17 mmol), triethylamine (0.031 mL, 0.22 mmol) and THF (2 mL), ethyl chlorocarbonate (0.019 mL, 0.20 mmol) was added under ice-cooling conditions and the mixture stirred at r.t. for 2 hr. Sodium borohydride (0.026 g, 0.68 mmol), water (0.3 mL) and methanol (1 mL) were added to the mixture and the mixture was stirred at r.t. for 10 min. Water was added to the mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from dichloromethane, diethyl ether and ethyl acetate, and the precipitate was collected by filtration to give 3-t-butyl-5-[4-(3-hydroxymethyl-5-isoxazolyl)-phenyl]-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.068 g, 88%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:17](Br)[CH:18]([CH3:20])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c2ccccc2c2ccc(Br)cc21
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 88.4 %

Procedure:
2-bromo-9H-carbazole (4.1 g, 16.74 mmol) was dissolved in DMF. To the stirred solution was slowly added NaH (1.8 g, 75.5 mmol) in 3 portions. Isobutylbromide (4.8 mL, 43.2 mmol) was added to the stirred slurry and after waiting for 20 minute, warmed up to 60° C. for 4 h. Reaction mixture was cooled to room temperature and carefully quenched with drop wise addition of saturated NH4Cl solution. Content was then partitioned in brine and ethylacetate. Organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum. The crude product was flashed over silica gel with 10% ethylacetate/hexane. Final product (4.45 g, 14.8 mmol) was isolated as white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[S:7][C:8]([C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][C:10]=1[NH2:11])=[O:5].[CH2:18]([O:25][CH:26]1[CH2:29][C:28](=O)[CH2:27]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C:6]1[S:7][C:8]([C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][C:10]=1[NH:11][CH:28]1[CH2:29][CH:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:27]1)=[O:5]
Reactant: O=C1CC(OCc2ccccc2)C1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 115.7 %

Procedure:
A mixture of 3-amino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester, hydrochloride salt (750 mg, 2.74 mmol) and 3-benzyloxy-cyclobutanone (2.5 g, 14.3 mmol) in DCM (40 mL) was treated with sodium triacetoxyborohydride (3.34 g, 15.8 mmol) portionwise. The mixture was stirred at room temperature for 3 hours. The solution was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate, water, and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% ethyl acetate:hexanes). This resulted in 1.26 g (quant. yield) of 3-(3-benzyloxy-cyclobutylamino)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester as a mixture of cis- and trans-isomers.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[C:12]=2[Cl:19])[N:8]=[C:7]1[CH:20]=O)(=[O:5])=[O:4].Cl.[CH2:24]([O:27][NH2:28])[CH:25]=[CH2:26].Cl.NO>>[CH2:24]([O:27][N:28]=[CH:20][C:7]1[N:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:22])[CH3:1])[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[C:12]=2[Cl:19])[N:8]=1)[CH:25]=[CH2:26]
Reactant: CN(C)S(=O)(=O)n1cc(-c2ccc(Cl)c(Cl)c2Cl)nc1C=O
Reactant: C=CCON
Agent: Cl
Agent: NO
Product: C=CCON=Cc1nc(-c2ccc(Cl)c(Cl)c2Cl)cn1S(=O)(=O)N(C)C

Procedure:
1-(Dimethylsulphamoyl)-2-formyl-4-(2,3,4-trichlorophenyl)imidazole was reacted with O-allylhydroxylamine hydrochloride in a similar manner to the reaction with hydroxylamine hydrochloride described in Example 1, to give 2-allyloxyiminomethyl-1-(dimethylsulphamoyl)-4-(2,3,4-trichlorophenyl)imidazole, m.p. 87°-88°. (Compound 9)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:15][CH:16]=2)[NH:11][C:10]1=[O:23].[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([N:11]1[C:12]2=[N:13][C:14]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:15][CH:16]=[C:17]2[CH2:18][N:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]1=[O:23])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CS(=O)(=O)c1ncc2c(n1)NC(=O)N(c1c(Cl)cccc1Cl)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ncc2c(n1)N(Cc1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Temperature: 90 °C
Yield: 79.9 %

Procedure:
A solution, cooled in ice, of 100 mg (0.27 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one in 6 ml of dimethylformamide was treated with 11 mg (0.27 ml) of sodium hydride (60% w/w). After 30 minutes the mixture was treated with 0.04 ml (0.3 mmol) of benzyl bromide and then heated to 90° C. for 2 hours. The mixture was evaporated and 30 ml of dichloromethane and 30 ml of water were added to the residue. The phases were separated and the organic phase was washed with 30 ml of water, dried over magnesium sulfate, filtered and evaporated to give 100 mg (80%) of 1-benzyl-3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow solid.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7]O)[C@@H:4]([OH:5])[C@H:2]1[OH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:37]=[N+:38]=[N-:39].[Li+].C(Br)(Br)(Br)Br>CN(C=O)C.C(Cl)(Cl)Cl.CO.CO>[N:37]([CH2:7][C@H:6]1[O:9][C@@H:1]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@H:2]([OH:3])[C@@H:4]1[OH:5])=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: BrC(Br)(Br)Br
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Uridine (5.5 g, 22.5 mmol), triphenylphosphine (11.8 g, 45.0 mmol) and lithium azide (5.51 g, 112.6 mmol) were dissolved in dried DMF (120 ml). Then, carbon tetrabromide (14.92 g, 45.0 mmol) was added with vigorous stirring and after 2 hours of stirring, about 5 ml of methanol was added to terminate the reaction. The DMF was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel; chloroform-methanol (30:1 v/v) to give 5′-azido-5′-deoxyuridine (5.40 g, 21.2 mmol, yield 94%). A white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.[CH3:44][O:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][C:53]=1[O:54][CH3:55])[CH2:49]Br.BrCC1CCCCO1>>[CH3:44][O:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][C:53]=1[O:54][CH3:55])[CH2:49][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: COc1ccc(CBr)cc1OC
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1OC

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 3,4-dimethoxybenzyl bromide (Oguri, T., et al., Chem. Pharm. Bull. (1977), 25:2287-91) to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(3,4-dimethoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (100%) as a colorless solid: mp 209-211° C. (hexanes/diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.23-7.14 (m, 2H), 7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.92-6.80 (m, 4H), 6.51 (s, 1H), 6.21 (s, 1H), 5.09 (d, J=15.3 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.68 (d, J=15.3 Hz, 1H), 4.67 (d, J=9.0 Hz, 1H), 4.22-4.16 (m, 2H), 4.13-4.08 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.7, 155.3, 149.5, 148.8, 144.7, 142.2, 138.4, 132.4, 128.9, 128.4, 124.0, 123.5, 121.3, 120.0, 111.5, 111.2, 110.5, 109.5, 99.6, 80.1, 64.6, 64.0, 58.2, 56.02, 55.99, 44.1; MS (ES+) m/z 446.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=[C:6]([Br:8])[CH:7]=1.C[Si]([CH2:18][C:19]#[N:20])(C)C>CN(C=O)C.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[F-].[F-].[Zn+2].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:8][C:6]1[CH:7]=[C:2]([CH2:18][C:19]#[N:20])[CH:3]=[C:4]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=1
Reactant: Brc1cc(Br)cc(C2OCCO2)c1
Reactant: C[Si](C)(C)CC#N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#CCc1cc(Br)cc(C2OCCO2)c1
Temperature: 90 °C
Yield: 104.8 %

Procedure:
To a screw-capped vial containing 2-(3,5-dibromophenyl)-1,3-dioxolane (4.g, 12.99 mmol), Xantphos (0.15 g, 0.26 mmol), Pd2(dba)3 in anhydrous DMF (5.0 mL) was added trimethylsilyl acetonitrile (2.20 mL, 16.07 mmol) and the reaction mixture was degassed with nitrogen for 15 min to give an orange-red suspension. To the above mixture was added ZnF2 under nitrogen atmosphere and the vial sealed with a cap containing a PTFE/silicone septum under nitrogen. The heterogeneous mixture was heated with stirring at 90° C. in an oil bath to give an olive green suspension. The reaction mixture was let stirred at 90° C. for 22 h to give a dark brown suspension/solution. The reaction mixture cooled to room temperature and diluted with diethyl ether (100 mL). The resulting solution was washed with water (2×75 mL). The organic layer was removed and evaporated in vacuo and the residue was dissolved in ethyl acetate (50 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo to afford an orange-red viscous liquid (3.65 g). Purification of the crude product by Silica-gel flash chromatography on silica gel column and elution with 10-80% ethyl acetate in hexanes afforded the desired product as a pale yellow viscous liquid (1.95 g). LC-MS analysis of the liquid shows the desired product's mass: m/z 268 (79BrM+H), m/z 270 (81BrM+H), m/z 290 (79BrM+Na), and m/z 292 (81BrM+Na); GC-MS (EI mode) analysis also shows the desired product's mass: m/z 266 (79BrM+) and m/z 268 (81BrM+), Calcd for C11H10BrNO2: 268.11. 1H NMR (400 MHz, CDCl3): δ 3.72 (s, 2H, —CH2CN), 3.98-4.05 (M, 2H, —CH2—O—), 4.06-4.13 (M, 2H, —CH2—O—), 5.75 (s, 1H, O—CH—O), 7.36 (s, 1H), 7.47 (s, 1H), 7.58 (s, 1H). 1H NMR spectrum of the liquid was consistent with the suggested structure of the product.