Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH2:24]([O:23][C:21](=[O:22])[C:20]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:10](=[O:12])[CH3:11])=[C:2]([F:1])[C:7]=1[CH3:8])([CH3:27])[CH3:26])[CH3:25]
Reactant: CC(=O)c1ccc(O)c(C)c1F
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)c(F)c1C
Temperature: 50 °C
Reaction time: 11 h
Yield: 27.4 %

Procedure:
A suspension of 0.21 g (0.62 mmol) of crude 1-(2-fluoro-4-hydroxy-3-methyl-phenyl)-ethanone, 0.45 g (1.37 mmol) of cesium carbonate and 0.24 ml (1.25 mmol) of ethyl 2-bromo-2-methylpropionate in 5 ml of DMF was heated at 50° C. for 7 h. Additional 0.10 g (0.31 mmol) of cesium carbonate and 0.06 ml (0.31 mmol) of ethyl 2-bromo-2-methylpropionate were added and stirred at 50° C. for 11 h. The mixture was neutralized with aqueous 10% KHSO4 and extracted with ether (three times). The organic phases were washed with aqueous 10% KHSO4, aqueous 10% NaCl solution, dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography over silica gel with n-heptane/AcOEt 95:5 to give 0.048 g of the title compound as yellow liquid.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[C:13]1([CH2:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CS(C)=O>[CH2:19]([NH:20][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ccc2nc(Cl)cnc2c1
Reactant: NCc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: Clc1ccc2nc(NCc3ccccc3)cnc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,6-Dichloroquinoxaline (0.500 g, 2.5 mmol) was dissolved in DMSO (10 mL) at RT and phenylmethanamine (1.3 g, 12.56 mmol) was added. The reaction mixture was stirred at RT for 16 h. After completion of reaction (confirmed by TLC), water (100 mL) was added to the reaction mixture and this layer was extracted with ethyl acetate (50 mL×3). The organic layer was washed with water (15 mL), brine (15 mL) and dried over Na2SO4. The organic layer was concentrated under vacuum to give crude product.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11](O)=[O:12])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:65])[CH2:41][C@H:42]([OH:64])[C@@H:43]([NH:51][C:52](=[O:63])[C@H:53]([C@H:59]([CH2:61][CH3:62])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[CH3:62][CH2:61][C@@H:59]([C@H:53]([NH:54][C:55]([O:57][CH3:58])=[O:56])[C:52]([NH:51][C@H:43]([C@@H:42]([OH:64])[CH2:41][N:40]([NH:65][C:11]([C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:12])[CH2:39][C:36]1[CH:35]=[CH:34][C:33]([C:32]2[S:28][CH:29]=[N:30][CH:31]=2)=[CH:38][CH:37]=1)[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:63])[CH3:60]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)[C@@H](NC(=O)OC)[C@@H](C)CC

Procedure:
Analogously to Example 7, 175 mg (0.92 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 332 mg (1.7 mmol) of EDC and 156 mg (1.15 mmol) of HOBT in 2.5 ml of DMF and 483 μl (3.47 mmol) of TEA are reacted with 0.578 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5 (S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane (Example 11b) in 5.2 ml of DMF to form the title compound: m.p: 213°-216° C.; HPLC20-100 : tret =14.7; FAB MS (M+H)+ =711.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[O:10]
Reactant: OCc1cccc(Cl)c1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1cccc(Cl)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
A solution of (2-bromo-3-chloro phenyl)methanol (4.73 g, 21.24 mmol), which had been obtained in Reference example 7 (7a), in methylene chloride (120 mL) was added with 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (10.8 g, 25.49 mmol) under ice cooling, and stirred at room temperature for 2 hours. The reaction solution was added with a mixture of saturated aqueous sodium hydrogen carbonate solution (60 mL) and saturated aqueous sodium thiosulfate solution (30 mL), and then stirred at room temperature for 0.5 hours. The mixture obtained was extracted with dichloromethane (90 mL×2). After that, the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=5/1) to give the title compound as a white solid (4.36 g, yield 94%).
Reaction SMILES: [Cl:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4](Cl)=[O:5].N1C=CC=CC=1.[CH:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH2:18].O>C(Cl)(Cl)Cl>[CH2:20]([O:19][CH:17]=[CH:18][C:4](=[O:5])[C:3]([F:8])([F:7])[C:2]([Cl:1])([F:10])[F:9])[CH2:21][CH2:22][CH3:23]
Reactant: O=C(Cl)C(F)(F)C(F)(F)Cl
Reactant: C=COCCCC
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCOC=CC(=O)C(F)(F)C(F)(F)Cl
Temperature: 0 °C
Reaction time: 15 h

Procedure:
With stirring and at 0° C., 10.0 g (50.2 mmol) of 3-chlorotetrafluoropropionyl chloride—dissolved in ml of chloroform—were added to a mixture of 3.97 g (50.2 mmol) of pyridine and 5.03 g (50.2 mmol) of butyl vinyl ether in 80 ml of chloroform. After the addition, stirring was continued at room temperature for a further 15 h. 100 ml of water were then added to the mixture, and the organic phase was separated off, dried and concentrated. This gave 10.4 g (78% of theory) of a yellowish oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](O)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([Br:16])[CH:18]=2)[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2cccc(Br)c2)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with 3-bromo-benzoic acid. LC-MS (acidic): tR=1.08 min; [M+H]+=394.9.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>N1CCCCC1.C(O)C>[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:12][C:9]1[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=1[CH3:11]
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)c(C)c32)c(C)c1CCC(=O)O
Yield: 55.6 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (98 mg), 91 mg 5-chloro-4-methyl-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 90° C. for 4 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 100 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].OO.FC(F)(F)C(O)=[O:15]>ClCCl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:15])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1ccncc1Cl
Agent: OO
Solvent: ClCCl
Product: N#Cc1cc[n+]([O-])cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
9.6 g of 3-chloro-4-cyanopyridine was dissolved in 70 ml of dichloromethane. Then, 23.2 g of a 31% hydrogen peroxide aqueous solution and 16.0 g of trifluoroacetic acid were added thereto, and the mixture was stirred overnight at room temperature. After completion of the reaction, the reaction solution was extracted with dichloromethane. The organic layer was washed sequentially with an aqueous sodium hydrogen carbonate solution and an aqueous sodium hydrogen sulfite solution and the dried over anhydrous magnesium sulfate. Then, dichloromethane was distilled off under reduced pressure. The obtained residue was washed with isopropyl ether to obtain 7.2 g of 3-chloro-4-cyanopyridine N-oxide as a white powder (melting point: 172° to 174° C.). Then, 20 ml of phosphorus oxychloride was added to this 3-chloro-4-cyanopyridine N-oxide, and the mixture was refluxed under heating for 5 hours. After cooling, the reaction solution was gradually poured into an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) to obtain 3.2 g of 4-cyano-2,5-dichloropyridine (melting point: 55° to 58° C.) and 2.5 g of 4-cyano-2,3-dichloropyridine (melting point: 65° to 69° C.).
Reaction SMILES: [NH2:1][C:2](=[N:23]O)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)[CH:4]=1.[CH3:25][N:26]=[C:27]=[S:28]>CN(C)C=O.C(OCC)(=O)C>[CH3:25][NH:26][C:27]1[S:28][N:23]=[C:2]([C:3]2[CH:8]=[CH:7][N:6]=[C:5]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]3)[CH:4]=2)[N:1]=1
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Reactant: CN=C=S
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1nc(-c2ccnc(N3CCN(C(=O)OCC(C)(C)C)CC3)c2)ns1
Temperature: 100 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
2,2-Dimethylpropyl 4-{4-[amino(hydroxyimino)methyl]pyridin-2-yl}piperazine-1-carboxylate (122 mg) obtained in Example 26-1) was dissolved in dimethylformamide (1 mL), and methyl isothiocyanate (41 mg) was added thereto and stirred at 100° C. for 1 hour. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 31.3 mg of the entitled compound as a colorless solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:11]CN(CC)CC.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[CH3:11][NH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCN(CC)CC
Reactant: N[C@H]1CCc2ccccc21
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CN[C@H]1CCc2ccccc21
Reaction time: 72 h
Yield: 76.9 %

Procedure:
To a solution of (S)-(+)-1-aminoindan (176 mg, 1.29 mmol) in THF (10.0 mL) was added Et3N (0.200 mL, 1.43 mmol) followed by di-tert-butyldicarbonate (286 mg, 1.31 mmol). The mixture was stirred under an atmosphere of nitrogen for 3 days, concentrated, diluted with DCM (100 mL), and washed with 0.1 N aq hydrochloric acid (50.0 mL) and aq NaCl. The organic layer was dried (MgSO4), filtered and concentrated. The tan solid was taken up in tetrahydrofuran (10.0 mL) and to this was added with a 1.00 M solution of lithium aluminum hydride (1.0 M in THF, 5.80 mL). The mixture was heated at reflux for 6 hours, quenched with water (0.300 mL), 15% aq NaOH solution (0.300 mL) and water (0.900 mL). This was stirred for 10 minutes, filtered through celite, diluted with EtOAc (100 mL), dried (MgSO4), filtered and concentrated. The residue was purified via flash chromatography (0 to 100% EtOAc/hexanes to 10% MeOH/DCM) to afford the title compound as a black solid (146 mg, 77%).
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].N[CH2:15][CH2:16][OH:17].N>O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C.C(O)CCC>[CH2:1]([C:12]1[O:17][CH2:16][CH2:15][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: NCCO
Reactant: CCCCCCCCCCCC#N
Agent: CC(=O)[O-]
Agent: N
Agent: [Cd+2]
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCCCCC1=NCCO1
Temperature: 125 °C
Yield: 88 %

Procedure:
The reaction was carried out under nitrogen atmosphere in a three neck flask equipped with a magnetic stirring bar, reflux condenser, addition funnel and thermometer. 50 ml of 1-butanol and 667 mg (2.5 mmoles) of cadmium acetate dihydrate was introduced and the catalyst was dissolved by slight warming. 18.13 g (100 mmoles) of undecyl cyanide was added and the solution was heated to 125° C. 7.33 g (120 mmoles) of 2-aminoethanol was then added dropwise controlling the evolution of ammonia. At the end of the reaction (ca. 48 hrs.) the solvent was removed under vacuo. The residue was treated with 100 ml of petroleum ether and filtered after keeping for several hours. The filtrate was washed with water, dried over anhydrous magnesium sulfate, concentrated and the residue was distilled 114° C./0.5 mm to give 19.83 g (88%) of 2-undecyl-2-oxazoline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([F:16])=[CH:14][N:13]=[C:12]([NH:17][C:18]3[CH:19]=[CH:20][C:21]4[O:25][CH:24]([C:26]([O:28]C)=O)[CH2:23][C:22]=4[CH:30]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.CN.[CH:34]([N:37](C(C)C)CC)(C)C>CO.O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([F:16])=[CH:14][N:13]=[C:12]([NH:17][C:18]3[CH:19]=[CH:20][C:21]4[O:25][CH:24]([C:26]([NH:37][CH3:34])=[O:28])[CH2:23][C:22]=4[CH:30]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(F)c(F)c4)n3)ccc2O1
Agent: CN
Agent: Cl
Solvent: CO
Solvent: O
Product: CNC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(F)c(F)c4)n3)ccc2O1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of (±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine, methylamine Hydrogen Chloride (5 equivalents) and diisopropylethylamine (5 equivalents) in MeOH was shaken in a sealed tube at 80° C. for 24 h. The resulting solution was diluted with water and the precipitate obtained was filtered, washed with water, dried and analyzed to afford (±)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.46 (s, 1H), 9.07 (s, 1H), 8.05 (m, 3H), 7.48 (m, 2H), 7.35 (m, 1H), 7.22 (m, 1H), 6.72 (d, 1H, J=8.1 Hz), 5.07 (dd, 1H, J=6.6 and 6.3 Hz), 3.40 (dd, 1H), 3.15 (dd, 1H), 2.60 (d, 3H, J=4.5 Hz); LCMS: purity: 98%; MS (m/e): 416 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]2([C:18]([O:20]CC)=[O:19])[CH2:17][CH2:16]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH:13]([C:15]2([C:18]([OH:20])=[O:19])[CH2:17][CH2:16]2)[CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(C2CN(C(=O)OCc3ccccc3)C2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CC(C2(C(=O)O)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To 2.68 g (8.83 mmol) of ethyl 1-(1-benzyloxycarbonyl-3-azetidinyl)cyclopropanecarboxylate dissolved in 27 ml of ethanol was added 27 ml of 1N sodium hydroxide aqueous solution, followed by overnight stirring at room temperature. After evaporation of the solvent, the resulting residue was mixed with 10% citric acid aqueous solution, extracted with chloroform (50 ml×3) and then dried over anhydrous sodium sulfate. By evaporating the solvent, 2.35 g (97%) of the title compound was obtained.
Reaction SMILES: [OH:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl.CCOC(C)=O>[C:21]([O:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5]([CH3:13])([CH3:14])[CH2:4][CH2:3]1)(=[O:23])[CH3:22]
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(Br)cc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(OC(C)=O)CCC(C)(C)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (+/-) ethyl 2-(1-hydroxy-1,2,3,4-tetrahydro-4,4-dimethyl-7-bromo-naphthalen-1-yl)acetate (Compound E47, 200.0 mg, 0.586 mmol) and 4-N,N-dimethylaminopyridine (86.0 mg, 0.703 mmol) in 4.0 mL CH2Cl2 at 0° C. was added acetic anhydride (239.3 mg, 2.344 mmol). The resulting solution was warmed to room temperature and stirred overnight. The reaction was warmed to 50° C. for 3 h, cooled to room temperature, and diluted with EtOAc (70 mL). The solution was washed with H2O, saturated aqueous NaHCO3, 10% aqueous HCl, and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure followed by column chromatography afforded the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][C:42]=5[CH3:49])=[CH:35][CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([S:39]([CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][C:42]=5[CH3:49])=[O:59])=[CH:37][CH:38]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4c(C)ncn4CCC)cc2)CCCN3CC(C)C)cc1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4c(C)ncn4CCC)cc2)CCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (300 mg) in dichloromethane (10 ml) was added dropwise a 70% solution of 3-chloro-per-benzoic acid (117 mg) in dichloromethane (10 ml) at −78° C. After stirring as such for 1 hour, the dry ice-acetone bath was removed, and an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and saturated aqueous brine, and was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified with basic silica gel column chromatography (hexane:ethyl acetate=1:4→ethyl acetate) to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (230 mg) as a yellow amorphous material (Compound 37).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1>CN(C=O)C>[CH3:22][S:21][C:17]1[N:18]=[C:19]([N:11]2[CH:10]=[CH:9][N:8]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:20]=[CH:15][N:16]=1
Reactant: CSc1nccc(Cl)n1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-n2ccnc2-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-Phenylimidazole (1-2, 50 g, 347 mmol) was dissolved in 400 ml DMF and the resulting solution was cooled to 0° C. Sodium hydride (8.32 g of solid NaH, plus 13.9 g of a 60% dispersion in mineral oil, 347 mmol) was added and the mixture was stirred for 10 minutes. 4-Chloro-2-(methylthio)pyrimidine (1-1, 55.7 g, 347 mmol) was then added over 2 minutes. The reaction was then heated to 100° C. After stirring overnight the reaction was partitioned between water and EtOAc. The organic phase was washed 2× with water, dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (eluting with 50:50 to 70:30 EtOAc/Hexane) afforded 2-(methylthio)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidine.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:23])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH3:22])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:24]#[C:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[C:24]([C:2]1[N:3]=[C:4]([NH2:23])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH3:22])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[C:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C#CCCCC
Reactant: CCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: CCCCC#Cc1nc(N)c2nc(NCC)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
The reaction was performed with 2-iodo-8-ethylaminoadenosine (8, 67 mg, 0.15mmol) and 1-hexyn (0.73 mmol). The mixture was purified by column chromatography (EtOAc-10% MeOH in EtOAc). Yield 49 mg (0.12 mmol, 83%), mp230–232÷C; 1H NMR (DMSO-d6) δ 6.97 (t, 1H, J=4.80 Hz, NH), 6.57 (s, 2H, NH2), 5.86 (d, 1H, J=7.55 Hz, H-1′), 5.74 (t, 1H, J=4.80 Hz, OH-2′), 5.25 d, 1H, J=6.52 Hz, OH-5′), 5.15 (d, 1H, J=4.12 Hz, OH-3′), 4.57 (q, 1H, J=6.18 Hz, H-2′), 4.08 (m, 1H, H-3′), 3.95 (m, 1H, H4′), 3.64–3.60 (m, 2H, H-5′), 3.05 (m, 2H, NHCH2), 2.36 (t, 2H, J=7.21 Hz, ≡CHCH2), 1.51–1.40 (m, 4H, CH2CH2CH3), 1.16 (t, 3H, J=7.20 Hz, NHCH2CH3), 0.89 (t, 3H, J=5.15 Hz, CH3); MS m/z 391 (M+H)+; Anal. (C18H26N6O4) C, H, N.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:22][CH2:23][N:24]([C:2]3[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=3[N+:10]([O-:12])=[O:11])[CH2:25][CH2:26]2)=[CH:17][CH:16]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
In analogy to the procedure described in example 1, the 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (as prepared in Eur. Pat. Appl. EP 1 074 549 A2) was treated with the 4-(4-fluoro-phenyl)-piperidine hydrochloride in N,N-dimethylformamide in the presence of N-ethyldiisopropylamine at room temperature to yield the 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one as yellowish solid;