Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(CN)[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.[C:11](C1C=CC(CN)=CC=1)#[N:12]>>[C:3]1([CH2:11][NH2:12])[C:4]([CH2:7][NH2:8])=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: N#Cc1ccc(CN)cc1
Reactant: NCc1ccc(CN)cc1
Product: NCc1ccccc1CN

Procedure:
After releasing the pressure, MX and methanol were removed from the recovered reaction liquid in a rotary evaporator. By distilling the resultant solution under 0.5 kPa, p-xylylenediamine was obtained as the major distillate. The obtained p-xylylenediamine contained 0.4% by weight of 4-cyanobenzylamine.
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24](=[S:26])[NH2:25])[CH2:7]1)(=[O:4])=[O:3].Br[CH2:28][C:29](=O)[C:30]([O:32]CC)=[O:31]>ClCCl.C(O)C>[C:30]([C:29]1[N:25]=[C:24]([C@@H:8]2[CH2:7][C@@H:6]([O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][N:9]2[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[S:26][CH:28]=1)([OH:32])=[O:31]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=S)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CCOC(=O)C(=O)CBr
Solvent: ClCCl
Solvent: CCO
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2nc(C(=O)O)cs2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-thiocarbamoylpyrrolidine (2.0 g) in dichloromethane (40 ml) was added a solution of ethyl bromopyruvate (1.04 ml) in absolute ethanol (10 ml) at 0° C. After stirring at room temperature for 2 hours, the mixture was evaporated. The residue was dissolved in ethyl acetate, and washed with saturated sodium bicarbonate and brine successively. The dried organic layer was evaporated and the residue was dissolved in tetrahydrofuran (15 ml) and 1N sodium hydroxide (15 ml). After stirring at 35°-45° C. for 1 hour, the mixture was evaporated and poured into ethyl acetate. To this mixture was added 1N hydrochloric acid (20 ml), and then organic layer was separated, and washed with brine. The dried organic layer was evaporated to give (2S,4R)-2-(4-carboxythiazol-2-yl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.54 g).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:7]([O-:9])=O)[CH2:6][CH2:5][CH2:4]1.[C:10](#[N:12])[CH3:11].Cl>C1COCC1.O>[CH:3]1([C:7](=[O:9])[CH2:11][C:10]#[N:12])[CH2:4][CH2:5][CH2:6]1
Reactant: CC#N
Reactant: O=C([O-])C1CCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCC1

Procedure:
A 50 mL three necked round bottom flask containing NaH (980 mg, 60%, 24.50 mmol, 1.57 eq.) and THF (10 mL) was heated to reflux under nitrogen for about 30 min. Then a mixture of cyclobutanecarboxylate [CCLXVII] (2 g, 15.6 mmol, 1.00 eq.) and acetonitrile (1 g, 24.3 mmol, 1.56 eq.) in 20 mL of THF was added dropwise to the refluxing suspension. After addition, the resulting mixture was refluxed for 16 h and worked up with water. The pH value of the reaction solution was adjusted to 4 with aqueous HCl solution and extracted with ethyl acetate. The combined organic phases were dried and concentrated, the residue was applied onto a silica gel column with ethyl acetate/petroleum ether as the eluent to give Compound [CCLXVIII] as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 3.40-3.60 (m, 1H), 3.43 (s, 2H), 2.25-2.36 (m, 4H), 2.01-2.15 (m, 1H), 1.82-1.96 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([NH:19][CH3:20])=[O:18])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH2:16])=[NH:15])[CH:9]=2)=[CH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:17]([NH:19][CH3:20])=[O:18])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[NH:16][CH:6]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:15]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(C(=N)N)c2)cnc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1nc(-c2cccc(-c3nc(-c4ccccc4)c[nH]3)c2)cnc1N
Temperature: 70 °C
Yield: 62.6 %

Procedure:
To a stirred solution of 3-amino-6-{3-[amino(imino)methyl]phenyl}-N-methylpyrazine-2-carboxamide (0.13 6 mg, 0.5 mmol) in DMF (5 mL) was added bronoacetophenone (0.11 g, 0.55 mmol ) followed by K2CO3 (0.276 g). The resulting mixture was heated at 70 ° C. for 0.5 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL). The extract was washed with brine, dried (Na2SO4), and concentrated. The product was purified by hplc to provide 3-amino-N-methyl-6-[3-(4-phenyl-1H-imidazol-2-yl)phenyl]pyrazine-2-carboxamide (58 mg): 1H NMR (400 MHz; DMSO-d6): 8.94 (s, 1H); 8.82 (m, 1H); 8.62 (s, 1H); 8.2 (d, 1H); 8.04 (d, 1H); 7.9-7.78 (m, 3H); 7.58 (t, 1H); 7.38 (m, 2H); 7.24 (t, 1H); 2.82 (d, 3H); MS (EI) for C21H18N6O: 371 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:16](C(O)=O)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:25]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:25][C:16]1[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2nn3ccccc3c2C(=O)O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nn3ccccc3c2Br)n1
Yield: 87.7 %

Procedure:
A solution of 2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.92 g, 3.6 mmol), sodium bicarbonate (1.04 g, 12.4 mmol), and N-bromosuccinimide (0.71 g, 4.0 mmol) in DMF (25 mL) is stirred for 2 hours at room temperature. The reaction is then diluted with water (50 mL) and extracted with EtOAc (3×15 mL). The organic layer is washed with brine and dried over sodium sulfate. The solvent is removed in vacuo to afford 0.91 g (87%) of desired product as a dark green solid. UV (95% EtOH) λmax 282 nm (ε 12089), 233 nm (ε 21813). TOF MS ES+ exact mass calculated for C13H10BrN3 (p+1): m/z=288.0136. Found: 287.0058. Anal. Calcd for C13H10BrN3: C, 54.19; H, 3.50; N, 14.58. Found: C, 54.10; H, 3.60; N, 14.48.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][C:9]1[CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=2[CH:10]=1.[CH2:23]([N:25](CC)[CH2:26]C)C.CNC>O1CCCC1.CN(C)C=O>[CH3:23][N:25]([CH3:26])[CH2:7][CH2:8][C:9]1[CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=2[CH:10]=1
Reactant: CCN(CC)CC
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CCO)=C2
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)CCC(CCN(C)C)=C2
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
Methanesulfonyl chloride (0.0393 ml, 0.469 mmol) was added to a dimethylformamide solution (2 ml) of N-[6-(2-hydroxyethyl)-7,8-dihydro-2-naphthalenyl]acetamide (102 mg, 0.426 mmol) obtained in Reference Example 102 and triethylamine (0.0652 ml, 0.469 mmol) under ice-cooling, which was stirred for 30 minutes. A tetrahydrofuran solution (0.64 ml) of 2N dimethylamine was added to the reaction mixture, which was stirred at 60° C. for 5 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, and extraction was conducted using 1N hydrochloric acid. Potassium carbonate was added to the extract to make it alkaline, and extraction was conducted using ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resulting residue was purified by alumina column chromatography (development solvent; ethyl acetate), to give the titled compound (57.5 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([C:12]2[O:11][CH:15]=[CH:14][CH:13]=2)[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccco1
Reactant: CCc1c(Cl)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCc1c(Cl)ncnc1-c1ccco1
Temperature: 80 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
A mixture of 4,6-dichloro-5-ethylpyrimidine (10 g), 2-furylboronic acid (6.33 g) tetrakis(triphenylphosphine)palladium (1.94 g), dimethoxyethane (100 ml), and sodium carbonate solution (2 mol/l) (60 ml) was stirred at 70° C. for 2 hours and at 80° C. for 2 hours. After standing to cool the reaction mixture to room temperature, to the reaction mixture, water was added, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6.06 g of 4-chloro-5-ethyl-6-(furan-2-yl)-pyrimidine.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[S:11])[CH3:2].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:12]([N:14]1[CH2:15][C:16](=[O:17])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])[C:10]1=[S:11])[CH3:13]
Reactant: CCNCC(=O)O
Reactant: CCc1ccccc1N=C=S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1ccccc1N1C(=O)CN(CC)C1=S
Yield: 36.8 %

Procedure:
The title compound was prepared by the procedure described in Example 16 using 16.3 g of 2-ethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 200 mL of chloroform. Purification was achieved by flash chromatography on silica gel (5-10 % ethyl acetate in hexane) Crystallization from diethyl ether afforded the title compound (9.12 g) as a white solid, m.p. 71°-73° C. Anal. Calcd. for. C13H16N2O S: C,62.87; H, 6.49; N, 11.28. Found: C, 62.81; H, 6.43; N, 11.17. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[C:10](=O)[C:11]4[C:16]([S:17](=[O:21])(=[O:20])[C:18]=3[CH:19]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:4][N:3]=[N:2]1.Cl>[Zn].C(O)(=O)C>[NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[CH2:10][C:11]4[C:16]([S:17](=[O:21])(=[O:20])[C:18]=3[CH:19]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:4][N:3]=[N:2]1
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: O=S1(=O)c2ccccc2Cc2ccc(-c3nnn[nH]3)cc21
Reaction time: 4 h

Procedure:
To 3-(5-tetrazolyl)thioxanthone-10,10-dioxide (1.25g.), zinc wool (2.50g.) and mercuric acetate (0.10g.) was added acetic acid (25 ml.) and concentrated hydrochloric acid (25 ml.), and the mixture boiled under reflux for 2hr. After this time a further amount of hydrochloric acid (1.5ml.) was added and the mixture boiled for a further 4 hr., filtered while hot, cooled, the diluted with water. The crude product was filtered off, recrystallised three times from methanol, and dried at 80° C. in vacuo to give 3-(5-tetrazolyl)thioxanthene-10,10-dioxide m.pt. 233° C. with decomposition.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[CH3:31][C:32]1[C:36](B2OC(C)(C)C(C)(C)O2)=[C:35]([CH3:46])[NH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:36]4[C:32]([CH3:31])=[N:33][NH:34][C:35]=4[CH3:46])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2c(-c3c(C)n[nH]c3C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 100 °C
Yield: 25 %

Procedure:
To a solution of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (140 mg, 0.267 mmol) in 1,4-dioxane (2 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (89 mg, 0.401 mmol), bis(triphenylphosphine)palladium(II) chloride (18.76 mg, 0.027 mmol) and potassium carbonate (111 mg, 0.802 mmol). Water (1 mL) was added and the mixture heated at 100° C. in a microwave for 15 min (×2). Another portion of bis(triphenylphosphine)palladium(II) chloride (18.76 mg, 0.027 mmol) was then added and the reaction mixture degassed with nitrogen for 5 min and then heated at 100° C. in a microwave for 15 min (×2). The solvent was then removed in vacuo and the residue dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The aqueous phase was re-extracted with ethyl acetate (20 mL×2). All organic phases were combined, dried over MgSO4, filtered and concentrated. The residue was purified on silica, eluting with a gradient of 0-80% ethyl acetate in cyclohexane and then further purified using MDAP (acidic conditions), to give the title compound (36 mg). LCMS (A) m/z: 539 [M+1]+, Rt 1.47 min (acidic).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1>C1COCC1.CN(C=O)C>[CH3:28][O:27][CH2:26][CH2:25][O:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([CH:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])=[N:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: COCCOc1ccc2c(Cl)ncnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOc1ccc2c(C3C(=O)Nc4ccccc43)ncnc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
A solution of oxindole (319 mg, 2.4 mmol) in THF (3 ml) was added dropwise under nitrogen to sodium hydride (58 mg, 2.4 mmol, pre-washed with hexane) and the mixture stirred for 20 minutes at ambient temperature. A solution of 4-chloro-7-(2-methoxyethoxy)quinazoline (191 mg, 0.8 mmol) in DMF (3 ml) was added and the mixture then heated at 70° C. for 1 hour. The mixture was allowed to cool and the solvent removed by evaporation. The mixture was partitioned between water and ether. The aqueous phase was separated and adjusted to pH7 with 2M hydrochloric acid. The resulting solid was collected by filtration and washed with water and ethanol. This solid was then suspended in ether, recollected by filtration, washed with ether and dried under vacuum to give 7(2-methoxyethoxy)-4-(oxindol-3-yl)quinazoline (200 mg, 75%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:8]2[C:7](=[O:23])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][NH:2][C:26](=[O:27])[N:25]([CH3:29])[CH3:24])[CH:5]=3)[N:10]=[C:9]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2ccc(CNC(=O)N(C)C)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) in acetonitrile (10 mL), was added dimethyl carbamyl chloride (0.21 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.62 mL, 3.8 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-1,1-dimethyl-urea as an off-white solid (290 mg, 52% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10190 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 4.66 min (98.7%); mp, 264-268° C.; 1HNMR (DMSO-d6) δ 2.14-2.20 (m, 1H, CH), 2.56-2.86 (m, 12H, N(CH3)2, CHCH2, CH3), 4.31 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.00 (t, J=5 Hz, 1H, CH2NH), 7.54-7.89 (m, 3H, Ar), 11.03 (s, 1H. NH); 13C NMR (DMSO-d6) δ 20.95, 23.38, 30.61, 35.85, 43.20, 56.49, 119.88, 123.54, 126.30, 133.91, 139.98, 145.59, 154.27, 158.09, 160.50, 169.49, 172.62. LCMS MH=372; Anal Calcd For C18H21N5O4+0.5H2O: C, 56.83; H, 5.83; N, 18.41. Found: C, 56.71; H, 5.81; N, 18.18.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:34])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([CH2:11][NH:12][CH2:13][C:14]([C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=2)=[O:15])=[CH:6][C:5]=1[O:31][CH2:32][CH3:33].[C:35](OC([O-])=O)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>O1CCCC1>[Br:10][C:8]1[CH:9]=[C:4]([C:3]([NH:2][CH3:1])=[O:34])[C:5]([O:31][CH2:32][CH3:33])=[CH:6][C:7]=1[CH2:11][N:12]([CH2:13][C:14]([C:16]1[CH:17]=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:19]([OH:26])=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)=[O:15])[C:35](=[O:36])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CCOc1cc(CNCC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Br)cc1C(=O)NC
Solvent: C1CCOC1
Product: CCOc1cc(CN(CC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)OC(C)(C)C)c(Br)cc1C(=O)NC
Yield: 94.8 %

Procedure:
After dissolving the N1-methyl-5-bromo-4-[({2-[3,5-di(tert-butyl)-4-hydroxyphenyl]-2-oxoethyl}amino)methyl]-2-ethoxybenzamide (1.75 g) in tetrahydrofuran (20 ml), tert-butyl dicarbonate (770 mg) was added. The mixture was heated to reflux for 2 hours, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.97 g) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([N:17]=[O:18])[C:5]([NH:7][C@@H:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(O[C:23](=[O:25])[CH3:24])(=O)C>N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][N:4]([N:17]=[O:18])[C:5]([NH:7][C@@H:8]1[O:16][CH2:15][C@@H:13]([O:14][C:23](=[O:25])[CH3:24])[C@H:11]([O:12][C:11](=[O:12])[CH3:13])[C@H:9]1[O:10][C:9](=[O:10])[CH3:8])=[O:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=NN(CCCl)C(=O)N[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1NC(=O)N(CCCl)N=O
Yield: 29.4 %

Procedure:
1-(2-chloroethyl)-1-nitroso-3-(β-D-xylopyranosyl) urea (99 mg) was acetylated with acetic anhydride and pyridine in the same manner as that used in Example 1(b). Crystallization from a mixture of chloroform and n-propanol yielded the titled compound (42 mg). Yield 29.4%. mp. 124.5°-125° C (with decomposition). [α]D17 -19.0° (c 0.9, chloroform).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[NH2:6][C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O>N1C=CC=CC=1>[S:1]([NH:6][C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:4])(=[O:3])=[O:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1NS(C)(=O)=O
Yield: 24.2 %

Procedure:
A solution of mesyl chloride (0.95 g) in pyridine (3 ml) was added to a solution of ethyl 2-[2-amino-3-(2-chlorophenoxy)phenyl]acetate (2.3 g) in pyridine (10 ml), and the mixture was stirred for an hour. The reaction mixture was poured into water (100 ml) and extracted with diethyl ether (80 ml×2). The extract was washed with 5% hydrochloric acid (50 ml×2) and saline, dried over magnesium sulfate and then evaporated in vacuo. The oily residue (2.5 g) was crystallized by treating with ethanol and the resultant solid substance was recrystallized from ethanol to give ethyl 2-[2-mesylamino-3-(2-chlorophenoxy)phenyl]acetate (0.7 g). mp 145°-149° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[O:6])[CH:2]=[CH2:3].[C:8](OCC)(=[O:13])[CH2:9][C:10]([CH3:12])=O.[OH-].[K+]>C(O)C.Cl.CO>[CH2:1]([N:4]1[C:8](=[O:13])[CH:9]=[C:10]([CH3:12])[NH:7][C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: CCOC(=O)CC(C)=O
Reactant: C=CCNC(N)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: C=CCn1c(=O)cc(C)[nH]c1=O
Reaction time: 288 h

Procedure:
To allylurea (25 g, 0.25 mol) in ethanol (10 mL) was added ethyl acetoacetate (31.86 mL, 0.25 mol) and 10 drops conc. HCl. After 12 days at room temperature, concentration gave an oil which was dissolved in MeOH. KOH (22.5 g, 0.34 mol) was added and the solution refluxed for 1 hour. After neutralization, the resulting solid 1 was collected. Yield 2.7 g (7%). NMR (CDCl3) δ: 2.16 (3H, s), 4.52 (2H, d), 5.18 (1H, d), 5.23 (1H, d), 5.60 (1H, s), 5.82–5.93 (1H, m), 10.3 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:16](N(CC)CC)[CH3:17].ICC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC1(c2cc(F)cc(Cl)c2)CCNC1
Reactant: CCN(CC)CC
Solvent: CCI
Solvent: C1CCOC1
Product: CCN1CCC(OC)(c2cc(F)cc(Cl)c2)C1

Procedure:
Preparation according to Example 22. (+)-3-(3-chloro-5-fluorophenyl)-3-methoxypyrrolidine (0.01 g, 0.043 mmol), triethylamine (12.1 μL, 0.086 mmol), tetrahydrofuran (2 ml) and iodoethane (5.2 μL, 0.065 mmol). The crude product analyzed by GCMS. Analysis showed 74% conversion. MS m/z (relative intensity, 70 eV) 257 (M+, 10), 242 (94), 227 (39), 157 (40), 71 (bp).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Br:31])[C:27]([Br:30])=[C:28]([Br:29])[C:4]=2[N:3]=1.[C-]#N.[K+]>CCO.CCOC(C)=O>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([Br:31])[C:27]([Br:30])=[C:28]([Br:29])[C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3c(Br)c(Br)c(Br)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3c(Br)c(Br)c(Br)cc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 0.430 g (0.664 mmol) of the blocked nucleoside (102) and 0.216 g (3.317 mmol) of KCN in 13 mL of 70% EtOH was stirred at room temperature for 6 hr. The reaction mixture was diluted with 75 mL of EtOAc. The EtOAc solution was washed with H2O (50 mL), sat. NaCl solution (50 mL), dried (Na2SO4), and evaporated. The residue was chromatographed on a silica column (1.9×15 cm, eluted successively with CHCl3, 1%, 2%, 3% MeOH/CHCl3). Evaporation of fractions 43-60 (10 mL per fraction) and recrystallization from MeOH/MeCN gave 0.157 g (2 crops, 44%) of 103 as white crystals. MP: 168°-170° C. MS: (FAB) m/e 518.7947 (28%, MH+ =518.7957). 1H NMR (DMSO-d6): d 8.76 (s, 1,7-H), 5.87 (d, 1, 1 '-H, J1'-2' =8.0 Hz), 5.51 (d, 1,2'-OH, J2'-2'OH =6.0 Hz), 5.42 (t, 1, 5'-OH, J5'-5'OH =4.5 Hz), 5.30 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.37 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.14 (m, 1,3'-H, J3'-4' =2.0 Hz), 4.02 (m, 1,4'-H, J4'-5' =J4'-5" =2.5 Hz), 3.71 (m, 2, 5'-H and 5"-H, J5'-5" =12.0 Hz). 13C NMR (DMSO-d6l ): d 142.32 (C2), 140.94 (C3a), 132.50 (C7a), 120.62 (C5), 118.44 (C6), 117.10 (C7), 115.34 (C4), 89.58 (C1'), 86.50 (C4'), 71.93 (C2'), 69.63 (C3'), 60.89 (C5'). Anal. Calcd. for C12 H10Br3ClN2O4 0.3 MeCN: C, 28.36; H, 2.06; N, 6.04. Found: C, 28.25; H, 1.84; N, 5.90. (the Content of 0.3 MeCN was also indicated by 1H NMR.)