Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)C>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:15][CH2:14]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: -5 °C
Yield: 99 %

Procedure:
5-Chloro-2-nitroaniline (401 g, 2.32 mol) was added to a 4-neck 12 L round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The flask was then purged with N2. 1-Methylpiperazine (977 g, 1.08 L, 9.75 mol) and 100% ethanol (650 mL) were added to the reaction flask with stirring. The flask was again purged with N2, and the reaction was maintained under N2. The flask was heated in a heating mantle to an internal temperature of 97° C. (+/−5° C.) and maintained at that temperature until the reaction was complete (typically about 40 hours) as determined by HPLC. After the reaction was complete, heating was discontinued and the reaction was cooled to an internal temperature of about 80° C. with stirring, and water (3.15 L) was added to the mixture via an addition funnel over the period of 1 hour while the internal temperature was maintained at 82° C. (+/−3° C.). After water addition was complete, heating was discontinued and the reaction mixture was allowed to cool over a period of no less than 4 hours to an internal temperature of 20-25° C. The reaction mixture was then stirred for an additional hour at an internal temperature of 20-30° C. The resulting mixture was then filtered, and the flask and filter cake were washed with water (1×1 L), 50% ethanol (1×1 L), and 95% ethanol (1×1 L). The golden yellow solid product was placed in a drying pan and dried to a constant weight of 546 g (99% yield) under vacuum at about 50° C. in a vacuum oven.
Reaction SMILES: [C:1]([C:4]1[C:8]2[C:9]([Cl:27])=[CH:10][C:11]([F:26])=[C:12]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[C:7]=2[O:6][C:5]=1[CH3:28])(=O)[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30]>C1(C)C=CC=CC=1>[Cl:27][C:9]1[C:8]2[C:4]([C:1](=[S:30])[CH3:2])=[C:5]([CH3:28])[O:6][C:7]=2[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:11]([F:26])[CH:10]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(=O)c1c(C)oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c12
Solvent: Cc1ccccc1
Product: CC(=S)c1c(C)oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c12
Reaction time: 2 h
Yield: 9 %

Procedure:
100 ml of toluene was added to 0.50 g (1.2 mmol) of 3-(3-acetyl-4-chloro-6-fluoro-2-methylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil and 1.5 g (6.7 mmol) of phosphorus pentasulfide, followed by stirring for 2 hours under heating and refluxing. After completion of the reaction, 100 ml of toluene was further added to the reaction solution. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 47 mg (yield: 9%) of the desired product as an orange colored glassy substance. Refractive index: 1.5967 (20° C.).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6](=[O:17])[N:7]([N:9]=[CH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=1.Cl[CH2:19][C:20]#[N:21]>CN(C)C=O>[C:20]([CH2:19][N:5]1[C:4]([CH3:3])=[CH:8][N:7]([N:9]=[CH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:6]1=[O:17])#[N:21]
Reactant: Cc1cn(N=Cc2cccnc2)c(=O)[nH]1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(N=Cc2cccnc2)c(=O)n1CC#N
Reaction time: 0.5 h

Procedure:
0.72 g of sodium hydride are added to a suspension of 4.1 g of 2,3-dihydro-4-methyl-2-oxo-1-pyrid-3-ylmethyleneamino-1H-imidazole in 80 ml of N,N-dimethylformamide. The mixture is heated to 50°, treated with a solution of 1.89 g of chloroacetonitrile in 20 ml of N,N-dimethylformamide, and stirred for 30 minutes. The N,N-dimethylformamide is then removed on a rotary evaporator. In a mixer, the residue is mixed intimately with water. The crystals are filtered off, yielding the title compound melting at 195°-198°.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.NC1C=C(C=CC=1)C#N>C(O)(=O)C>[O:13]=[C:12]1[N:7]([C:1]2[CH:6]=[C:5]([CH:4]=[CH:3][CH:2]=2)[C:24]#[N:23])[CH:8]=[N:9][C:10]2[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][S:14][C:11]1=2
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: N#Cc1cccc(N)c1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: N#Cc1cccc(-n2cnc3c(-c4ccccc4)csc3c2=O)c1
Yield: 14 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1 ml), 3-aminobenzonitrile (96 mg, 0.81 mmol), and acetic acid (0.1 ml) were used to give 20 mg (0.061 mmol, 14% yield) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11]Br)=[CH:2]1.N1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].[C:25](#[N:27])C>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:16]2[CH2:15][CH2:14][CH:25]([NH2:27])[CH2:18][CH2:17]2)=[CH:2]1
Reactant: C1CNCCN1
Reactant: CC#N
Reactant: BrCCc1coc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC1CCN(CCc2coc3ccccc23)CC1

Procedure:
84 mmol of 2-(benzofuran-3-yl)-1-bromoethane, 67 mmol of piperazine and 56 mmol of potassium carbonate are added to 200 ml of acetonitrile. After refluxing for 4 hours, the reaction mixture is cooled and then concentrated. The residue is taken up in dichloromethane, is washed with water, dried, filtered and then concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethanol: 90/10) allows the expected product to be isolated.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][NH:8][CH:7]([CH3:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:12].[Cl:13]N1C(=O)CCC1=O.[Cl-].[Li+]>CN(C=O)C>[NH2:1][C:2]1[C:10]2[O:9][NH:8][CH:7]([CH3:11])[C:6]=2[C:5]([Cl:13])=[CH:4][C:3]=1[F:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1NOc2c1ccc(F)c2N
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC1NOc2c(N)c(F)cc(Cl)c21
Reaction time: 18 h
Yield: 64.2 %

Procedure:
A solution of 7-amino-6-fluoro-3-methyl-1,2(2H)-benzisoxazole (3.5 g, 0.021 mole) in DMF (50 mL) was stirred, and a solution of N-chlorosuccinimide (2.8 g, 0.02 mole) in a minimum amount of DMF was added dropwise. Upon completion of addition, the reaction mixture was stirred for about 18 hours. After this time, the reaction mixture was poured into aqueous 10% lithium chloride and then thoroughly extracted with ether. The combined extracts were washed with aqueous 10% lithium chloride, dried with magnesium sulfate, and concentrated to a residue. The residue was subjected to silica gel column chromatography using 9:1 to 4:1 hexane and ethyl acetate to provide 2.6 grams of 7-amino-4-chloro-6-fluoro-3-methyl-1,2(2H)-benzisoxazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)=[O:16]
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)CCCCCBr
Product: O=C(CCCCCBr)Nc1ccc(O)cc1
Yield: 88 %

Procedure:
was prepared in 88% yield from 148.4 g (1.36 mol) of p-aminophenol and 145 g (0.68 mol) of 6-bromohexanoyl chloride according to the procedure of Example 1, part a, except that the addition was made at ambient temperature and the reaction was refluxed one hour, mp 124°-125° C.
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)([Cl:16])=O>>[C:1]12([C:11]([Cl:16])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-adamantanecarboxylic acid (0.27 g, 1.5 mmol) in 5 mL of thionyl chloride was warmed to reflux and stirred for 2 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with 5 mL of toluene and concentrated under reduced pressure three times to afford the title compound, which was used without additional purification or characterization.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[H][H].C(O)(=O)C.[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:22])[CH3:21]>O>[CH3:3][N:4]([CH3:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:22])=[CH:7][CH:6]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: [H][H]
Reactant: CCCCCCCCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCOC(=O)C=Cc1ccc(N(C)C)cc1
Reaction time: 48 h
Yield: 93.6 %

Procedure:
Sodium hydride (1.9 g of an 80% dispersion in oil) was added portionwise with stirring over 0.5 hour to 4-dimethylaminobenzaldehyde (7.46 g) in 1-octyl acetate (158 g) at 25° C. The temperature was raised until a steady evolution of hydrogen was observed (40° C.) and held at this temperature for 48 hours. The cooled mixture was treated with glacial acetic acid (4 ml) and then water (50 ml) added. The upper layer was separated, washed with 10% sodium carbonate solution, water, and dried (MgSO4). The excess 1-octyl acetate was removed by distillation at 15 mm pressure. the residue solidified on cooling. It was crystallised from petroleum ether (B.P. 40°-60°) at 0° C., giving 14.2 g pale yellow crystals, m.p. 48°-49.5° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=2[F:26])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.[Cl-].[NH4+].O1CCCC1.C(O)C>[Fe].O>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:3]2[C:2]([Br:1])=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][C@H:7]([CH3:15])[N:8]3[C:12](=[O:14])[CH3:13])=[C:18]([F:26])[CH:19]=1
Reactant: CC(=O)N1c2ccc(Br)c(Oc3ccc([N+](=O)[O-])cc3F)c2CC[C@@H]1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(=O)N1c2ccc(Br)c(Oc3ccc(N)cc3F)c2CC[C@@H]1C
Temperature: 80 °C
Reaction time: 12 h
Yield: 79.7 %

Procedure:
A 100-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen, and charged with 1-[(2S)-6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (500 mg, 1.18 mmol), iron powder (331 mg, 5.91 mmol), ammonium chloride (128 mg, 2.37 mmol), tetrahydrofuran (9 mL), ethanol (3 mL), and water (9 mL). The resulting mixture stirred for 12 h at 80° C. and was then filtered. The filtrate was concentrated, and the residue was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1-[(2S)-5-(4-amino-2-fluorophenoxy)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (370 mg, 80%) as a light brown solid. MS (ESI, pos. ion) m/z 393, 395 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:26][C@@H:27]1[CH2:31][O:30][C:29]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[O:28]1)(=O)=O>C(O)C.O.CN(C)C=O>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:26][C@@H:27]1[CH2:31][O:30][C:29]2([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[O:28]1)=[O:8])(=[O:3])[CH3:2]
Reactant: O=S(=O)(OC[C@@H]1COC2(CCCCC2)O1)C(F)(F)F
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)OC[C@@H]1COC2(CCCCC2)O1
Reaction time: 0.5 h

Procedure:
The solution from 2-acetoxy-benzoic acid (0.6 g, 3.33 mmol) in ethanol (3.5 ml) is treated with a solution of caesium carbonate (0.54 g, 1.67 mmol) in water (35 ml) and stirred. After 30 min, the mixture is freeze-dried. The residue is added with stirring to a solution of [2S]-1,4-dioxa-spiro[4,5]dec-2-yl-methyl trifluoromethanesulphonate (1.15 g, 3.79 mmol) in N,N-dimethylformamide (10 ml). After 16 h at 20° C., the mixture is concentrated, the residue is taken up in dichloromethane (50 ml), and the solution is washed twice with water, dried over magnesium sulphate and concentrated. The residue is purified by column chromatography (toluene/ethyl acetate=50/1). Yield: 601 mg.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.[Br:26][C:27]1[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[CH:29][C:28]=1[S:38][C@@H:39]([CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[C:40](O)=[O:41].CN1CCOCC1>ClCCl.O>[Br:26][C:27]1[CH:32]=[C:31]([CH:30]=[CH:29][C:28]=1[S:38][C@H:39]([C:40]([NH:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])=[O:41])[CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)c1ccc(S[C@@H](CCCc2ccc(OC)cc2)C(=O)O)c(Br)c1
Reactant: CC(C)(C)OC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc(S[C@@H](CCCc2ccc(OC)cc2)C(=O)NCC(=O)OC(C)(C)C)c(Br)c1
Reaction time: 1.5 h

Procedure:
Glycine tert-butyl ester hydrochloride (2.03 g) and dicyclohexylcarbodiimide (DCC) (2.5 g) were added to a solution of (2S)-2-{[2-bromo-4-(ethoxycarbonyl)phenyl]thio}-5-(4-methoxyphenyl)pentanoic acid (the compound of Reference Example 8) (96% e.e.) in dichloromethane (56.4 ml) at −5° C., and N-methylmorpholine (1.26 ml) was added dropwise thereto. After stirring at the same temperature for 1.5 hours, water was added thereto and the resulting mixture was filtered through Celite. The filtrate was extracted with chloroform and the extract solution was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the solvent was distilled off under reduced pressure. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain ethyl 3-bromo-4-({(1S)-4-(4-methoxyphenyl)-1-[(tert-butoxycarbonylmethylamino)carbonyl]butyl}thio)benzoate (4.83 g, 98% e.e.). The optical purity analysis conditions are as follows. [Optical purity analysis conditions: column=AD-H (Chiralcel, DAICEL Chemical Industries Ltd.); detecting wavelength (UV)=254 nm; flow rate: 1.0 ml/min; mobile phase=n-hexane/isopropyl alcohol/TFA (90/10/0.1)]
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17]
Reactant: NCC(=O)CCC(=O)O
Reactant: OCCc1ccccc1
Agent: Cl
Product: NCC(=O)CCC(=O)OCCc1ccccc1
Reaction time: 3 h

Procedure:
From 2-phenylethanol (5.0 g; 41 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after 3 h. The yield was 1.43 g (88%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]([C@@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:16]([OH:19])[CH2:17][OH:18])=[N+:13]=[N-:14]>CN(C)C1C=CN=CC=1.ClCCl.N1C=CC=CC=1>[N:12]([C@@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:16]([OH:19])[CH2:17][O:18][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])=[N+:13]=[N-:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=N[C@@H](Cc1ccccc1)[C@H](O)CO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](Cc2ccccc2)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.4 %

Procedure:
1.05 g (5.5 mmol) of p-toluenesulphonyl chloride were added to a solution of 0.95 g (4.6 mmol) of 3(S)-azido-4-phenyl-1,2(S)-butanediol and 30 mg of 4-dimethylaminopyridine in a mixture of 30 ml of dichloromethane and 5 ml of pyridine. The resulting solution was stirred at room temperature for 48 hours. The solvents were removed under reduced pressure and the oily residue was partitioned between water and ethyl acetate. The aqueous phase was back-extracted twice with ethyl acetate. The organic phases were combined, washed with 10% aqueous sulphuric acid and with sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated to dryness. Purification of the crude product by flash chromatography on silica gel using n-hexane/ethyl acetate (3:1) for the elution gave 1.37 g of 3(S)-azido-4-phenyl-1-(p-toluenesulphonyloxy)-2(S)-butanol in the form of a viscous oil: MS: m/e 362 [M+H]+.
Reaction SMILES: [NH:1]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C@H:2]([C:7]([NH:9][C@H:10]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([O:46]C)=O)[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].O.[NH2:59][NH2:60]>CN(C)C=O.CO>[NH:1]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C@H:2]([C:7]([NH:9][C@H:10]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([NH:59][NH2:60])=[O:46])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: NN
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)NN
Reaction time: 20 h

Procedure:
3.97 g of Z-Asn-Lys(BOC)-Phe-His-OMe are dissolved in 8 ml of warm dimethylformamide and 12 ml of methanol. 2.5 ml of hydrazine hydrate are added to the solution whilst it is still at about 30°C and the mixture is allowed to stand for 20 hours at room temperature. The peptide-hydrazide is precipitated by adding water, filtered off and washed with water until free of hydrazine. The product is recrystallised from ethanol, melting point = 200°-201°C. In a thin layer chromatogram on silica gel RF43C = 0.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[N:14]([CH3:21])[C:15](=[O:20])[C:16]([CH3:19])=[C:17]([OH:18])[C:12]=3[C:11](=[O:22])[N:10]([CH:23]3[CH2:25][CH2:24]3)[C:9]2=[O:26])=[CH:4][CH:3]=1.C(#N)C.[S:30](Cl)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[N:14]([CH3:21])[C:15](=[O:20])[C:16]([CH3:19])=[C:17]([O:18][S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:12]=3[C:11](=[O:22])[N:10]([CH:23]3[CH2:24][CH2:25]3)[C:9]2=[O:26])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(O)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(Br)cc3)c2n(C)c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2c(C)c(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
To 1-(4-bromo-phenyl)-3-cyclopropyl-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 38 (400 mg) obtained in Step 5 was added acetonitrile (8.0 ml), tosyl chloride 11 (458 mg) and triethylamine (0.34 ml) were added under a nitrogen atmosphere, and the mixture was stirred under reflux for 30 hrs. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:acetone=25:1→20:1) to give toluene-4-sulfonic acid 1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 39 (407 mg, yield 74%) as ocher crystals.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22](SC)=[N:23][C:24]=2Cl)(=O)C.Cl.[O:32]([CH2:39][CH2:40][O:41]ON)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([N:46](CC)CC)C.N>O1CCOCC1.C(OCC)(=O)C.CO>[O:32]([CH2:39][CH2:40][O:41][C:22]1[N:23]=[C:24]([NH2:46])[C:25]2[N:26]=[CH:27][N:19]([C:20]=2[N:21]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CSc1nc(Cl)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Reactant: NOOCCOc1ccccc1
Reactant: CCN(CC)CC
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc(OCCOc2ccccc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 65 h
Yield: 20.3 %

Procedure:
9-(2,3,5-Tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-methylthio-9H-purine (0.50 g, 1.1 mmol) (prepared by Method C, using the procedure described in PCT Publication No. WO 93/08206, O-[2-(phenoxy)ethoxy]hydroxylamine hydrochloride (0.41 g, 2.16 mmol) (see Example 9) and triethylamine (0.45 g, 4.4 mmol) were stirred at 100° C. in dioxan (20 ml) for 6 h, and at ca. 95° C. for 65 h. The product, after column chromatography, was deprotected using methanolic ammonia, to provide the title 2-methylthio-N-[2-(phenoxyethoxy]adenosine (0.09 g, 18%), (after column chromatography) as a colourless foam, tic Rf 0.26 [(SiO2, dichloromethane/methanol (9/1)], 1H NMR (DMSO-d6)γ 2.51 (3H, s,--SCH3), 3.52-3.60 (1H, m, H-5'a), 3.62-3.69 (1H, m, H-5'b), 3.94 (1H, q, H- 4'), 4.16 (1H, q, H-3'), 4.30 (4H, br d,--OCH2CH2O--), 4.61 (1H, q, H-2'), 5.04 (1H, t, 5'-OH), 5.23, 5.50 (2H, 9d, 9'- and 3'-OH), 5.90 (1H, d, H-1'), 6.92-7.01 (3H, m, Ar-H), 7.32 (2H, dd, Ar-H), 8.36 (1H, s, H-8), 11.20 (1H, s, N-H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.[CH3:12][C:13]1([CH3:31])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][C:15]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[O:14]1.C(N(CC)CC)C>C(#N)C>[OH:11][CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:28]1[CH2:29][CH2:30][C:15]2([O:14][C:13]([CH3:12])([CH3:31])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)OC2(CCNCC2)C1
Reactant: OCCc1cccc(CBr)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(C)(C)OC2(CCN(Cc3cccc(CCO)c3)CC2)C1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
2-(3-(Bromomethyl)phenyl)ethanol (0.416 g) was added portionwise over 1 hour to a solution of tert-butyl 2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (Example 271, step c) (0.55 g) and triethylamine (0.809 mL) in acetonitrile (20 mL). The mixture was stirred for 2 hours at 20° C. The solvent was evaporated under reduced pressure and the residue partitioned between saturated sodium bicarbonate solution and DCM, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with 2% methanol in dichloromethane with 1% triethylamine to afford the subtitled compound. Yield 0.78 g.