Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]Br)=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH:13]([OH:15])[CH3:14]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:11][CH2:12][CH:13]([OH:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: Clc1ccc(CCBr)cc1
Reactant: CC(O)CN
Product: CC(O)CNCCc1ccc(Cl)cc1

Procedure:
In Stage 2, 2-(4′-chlorophenyl)ethyl bromide was reacted with 1-amino-2-propanol to form the secondary amine, 1-[2-(4-chloro-phenyl)-ethylamino]-propan-2-ol. 1-[2-(4-Chloro-phenyl)-ethylamino]-propan-2-ol was separated from excess 1-amino-2-propanol and water soluble byproducts by extraction into toluene and removing water from the toluene containing 1-[2-(4-Chloro-phenyl)-ethylamino]-propan-2-ol by azetropic distillation and can be used directly into the next step without further purification and without isolation.
Reaction SMILES: Cl.Cl.[N+]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2)([O-])=O.Cl.[N+](C1C=CC=C2C=1N=CC=C2)([O-])=O>C(OCC)(=O)C.CN(C)C=O>[N:11]1[C:12]2[C:7](=[CH:6][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1cccc2ncccc12
Agent: Cl
Agent: O=[N+]([O-])c1cccc2cccnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc2ncccc2c1
Temperature: 25 °C

Procedure:
A crude nitration mixture (50 g) created in the manner of Preparation I was dissolved in 500 mL of ethyl acetate. Approximately 10.4 g (0.29 mole) of hydrogen chloride gas was added giving a yellow precipitate. (Note: The amount of hydrogen chloride gas added could only be approximated as it was measured by weighing the flask.) This precipitate was analyzed and found to contain 5-nitroquinoline hydrochloride and 8-nitroquinoline hydrochloride in a ratio of 51:41. The precipitate was collected by filtration and dried affording 54 g. The crude product was suspended in 270 mL of wet dimethylformamide (0.5 parts water in 99.5 parts dimethylformamide) to form a slurry. The slurry was heated to dissolution (95° C.-100° C.) to form a solution and this solution was cooled to 25° C. Crystallization of a cream colored solid commenced at about 85° C.-95° C. The solid was collected by filtration, washed with ethyl acetate (2×25 mL) and dried and found to be 99.0% 5-nitroquinoline hydrochloride and 0.41% 8-nitroquinoline hydrochloride. The yield of 5-nitroquinoline hydrochloride was 20.8 g (34.5% overall yield from quinoline).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:5])[CH3:4].[OH-].[Na+].I[CH2:9][CH:10]=[CH:11][C:12]1[CH2:13][S:14][C@@H:15]2[CH:35]([NH:36][C:37](=[O:67])/[C:38](=[N:64]\[O:65][CH3:66])/[C:39]3[N:40]=[C:41]([NH:44]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:42][CH:43]=3)[C:34](=[O:68])[N:16]2[C:17]=1[C:18]([O:20]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19]>C(OCC)(=O)C.CCCCCC>[NH2:44][C:41]1[S:42][CH:43]=[C:39](/[C:38](=[N:64]/[O:65][CH3:66])/[C:37]([NH:36][CH:35]2[C:34](=[O:68])[N:16]3[C:17]([C:18]([O-:20])=[O:19])=[C:12](/[CH:11]=[CH:10]/[CH2:9][N+:3]([CH3:5])([CH3:4])[CH3:2])[CH2:13][S:14][C@H:15]23)=[O:67])[N:40]=1
Reactant: CN(C)C
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(/C=C/C[N+](C)(C)C)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylamine hydrochloride (6.31 g, 66 mmole) was added to an aqueous NaOH solution (2N, 33 ml) covered with ethyl acetate (100 ml). The organic layer was separated, dried over NaOH pellets, and added to a suspension of diphenylmethyl 3-(3-iodo-1-propen-1-yl)-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (X-1, 32 g, 33 mmole) in a mixture of ethyl acetate and n-hexane (300 ml/150 ml). The mixture was stirred for one hour at room temperature and then filtered to give the blocked title compound, which was treated with trifluoroacetic acid (50 ml) and anisole (10 ml) for one hour at room temperature. The mixture was concentrated under reduced pressure and the residue was triturated with ether to give 10.3 g of dark brown solid, which was treated with water (100 ml) at room temperature. After removal of insolubles by filtration, the filtrate was chromatographed on a column of HP-20 (200 ml) by eluting with 30% aqueous methanol. The eluate was concentrated and lyophilized to give 2.3 g of the crude title compound, which was purified by preparative HPLC (Waters Associates, System 500, PrepPAK 500/C18, 15% CH3OH) to afford 880 mg (5%) of the title compound I-1D. Estimated purity 75% (by HPLC).
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.[CH3:17][C:18](C)([O-])C.[Na+].C(Br)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl:1][C:2]1[C:6]([N:7]([CH2:17][CH3:18])[C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCN(C(C)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 38 °C
Reaction time: 0.08 h

Procedure:
In a 125 mL 3-neck round-bottomed flask was added N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (2.57 g, 9.44 mmol), tetrahydrofuran (55 mL), and sodium tert-butoxide (1.81 g, 18.9 mmol). The suspension was stirred for 5 minutes then ethyl bromide (1.41 mL, 18.9 mmol), and tetrabutylammonium iodide (67 mg, 0.2 mmol) were added. The resulting gray colored suspension was then heated to 38° C. The reaction was analyzed after 3 hours and found to have gone to 81% completion, after 24 hours the reaction was found to have gone to completion. The reaction mixture was allowed to cool to ambient temperature and quenched with ammonium hydroxide/formic acid (HCO2H) buffer (10 mL). The mixture was then diluted with tetrahydrofuran (40 mL), ethyl acetate (120 mL), and saturated sodium bicarbonate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The organic layers were combined and silica gel (37 g) was added. The solvent was removed in vacuo to give a solid that was purified using semi-automated silica gel chromatography (RediSep Silica 220 g column; hexanes (0.2% triethylamine)/ethyl acetate, 40/60 to 0/100 gradient elution system, flow rate 150 mL/minutes) to give, after concentration, an orange solid weighing (2.19 g, 88%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:20][CH:21](O)[CH2:22][CH2:23][CH3:24].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:21]([CH3:20])[CH2:22][CH2:23][CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCC(C)O
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCC(C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg, 0.661 mmol) obtained in Example 5 and 2-pentanol (0.144 ml, 1.33 mmol) were dissolved in toluene (3 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (0.320 ml). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. The reaction mixture was then allowed to cool down. The residue obtained by concentrating the reaction mixture under reduced pressure was separated and purified by flash silica gel chromatography (hexane:ethyl acetate=50:1), whereby obtained were the title Isomer 292-A (low polarity) (67 mg, 0.18 mmol, 27%) as a white powder and the title Isomer 292-B (high polarity) (45 mg, 0.12 mmol, 19%) as a white solid.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15]([NH:17][C:18]([CH2:20][NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:32]([O:34][CH3:35])=[O:33])=[C:26]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:27]=1)=[S:19])=[O:16])[CH3:13].[CH3:36][O:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[N:41]=[C:40]([NH:46][C:47](OC2C=CC=CC=2)=[O:48])[N:39]=1>C(#N)C>[CH3:45][O:44][C:42]1[CH:43]=[C:38]([O:37][CH3:36])[N:39]=[C:40]([NH:46][C:47]([NH:31][S:28]([C:26]2[CH:27]=[C:22]([NH:21][CH2:20][C:18]([NH:17][C:15]([O:14][CH2:12][CH3:13])=[O:16])=[S:19])[CH:23]=[CH:24][C:25]=2[C:32]([O:34][CH3:35])=[O:33])(=[O:29])=[O:30])=[O:48])[N:41]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CCOC(=O)NC(=S)CNc1ccc(C(=O)OC)c(S(N)(=O)=O)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)NC(=S)CNc1ccc(C(=O)OC)c(S(=O)(=O)NC(=O)Nc2nc(OC)cc(OC)n2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1.2 ml of DBU is added to a suspension of 0.69 g (1.84 mmol) of 5-[N-(ethoxycarbonylaminothiocarbonyl)methylamino]-2-methoxycarbonylbenzenesulfonamide and 0.55 g (1.99 mmol) of 4,6-dimethoxy-2-phenoxycarbonylaminopyrimidine in 5 ml of acetonitrile. The mixture is stirred for 17 h at room temperature and the solvent is then removed by distillation. The residue is taken up in water and washed with diethyl ether. The aqueous phase is acidified with concentrated hydrochloric acid (pH=1) and produces a colorless precipitate, which is filtered off and induced to crystallize by stirring with a little methanol. The resulting product is 0.61 g (60% of theory) of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-5-[N-(ethoxycarbonylaminothiocarbonyl)methylamino]-2-methoxycarbonylbenzenesulfonamide. m.p.: 144°-145° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.Cl[C:21]1[N:29]=[C:28]([NH2:30])[N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(CC)CC>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH:19][C:21]3[N:29]=[C:28]([NH2:30])[N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:18])=[C:8]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[CH:9]=2)[CH:4]=[CH:3]1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
To a 10 mL vial were added (S)-1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (100 mg, 0.384 mmol), 6-chloro-9H-purin-2-amine (65.1 mg, 0.384 mmol) and Et3N (0.11 mL, 0.77 mmol) in DMF (3 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The reaction mixture was purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium formate). The fractions containing the desired product were combined and lyophilized to give the title compound as a white solid (38 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.52 (m, 4 H), 2.68-2.86 (m, 3 H), 3.01-3.18 (m, 3 H), 3.69-3.95 (m, 9 H), 5.62-5.82 (m, 2 H), 5.88-6.08 (m, 1 H), 6.46-6.59 (m, 2 H), 6.74-6.92 (m, 1 H), 7.52-7.59 (m, 1 H), 7.59-7.74 (m, 1 H), 7.76-7.90 (m, 1 H), 12.00-12.22 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H23N9O, 394. found 394.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.C([O-])(O)=O.[Na+].CO>O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][N:7]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=[C:6]2[CH:5]=1)=[O:11]
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)c1ccnc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccn2cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-amino-isonicotinic acid methyl ester (5 g, 32 mmol), w-bromoacetophenone (6.47 g, 32 mmol), NaHCO3 (2.95 g, 35 mmol) and methanol (30 ml) was heated under an atmosphere of argon to reflux (3 h). After cooling, water (20 ml) was added, the mixture was stirred at r.t. (15 min), and filtered. The obtained solid was washed (water, methanol, diethyl ether) and dried under vacuum. The product (6.8 g, 85%) was used in the next step without further purification. MS (m/e)=253.2 [M+H+].
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1([CH3:23])[O:9][N:8]=[C:7]([S:10][CH2:11][C:12]2[C:13]([C:19]([F:22])([F:21])[F:20])=[N:14][N:15]([CH3:18])[C:16]=2F)[CH2:6]1.O>CN(C)C=O>[C:1]([C:16]1[N:15]([CH3:18])[N:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[C:12]=1[CH2:11][S:10][C:7]1[CH2:6][C:5]([CH3:23])([CH3:4])[O:9][N:8]=1)#[N:2]
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1C#N
Temperature: 40 °C
Reaction time: 1 h
Yield: 176.7 %

Procedure:
0.2 g (4.0 mmoles) of sodium cyanide was added to a solution of 0.5 g (1.6 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 30 ml of N,N-dimethylformamide. The mixture was stirred at 40° C. for 1 hour to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.9 g of crude 3-(5-cyano-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl.[F:35][CH:36]([F:42])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:39]4[CH2:40][CH2:41][CH:37]([CH:36]([F:42])[F:35])[CH2:38]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: FC(F)C1CCNC1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CCC(C(F)F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and 3-Difluoromethyl-pyrrolidine hydrochloride. 1H NMR (400 MHz, DMSO-d6): δ 8.75 (t, J=5.81 Hz, 1H), 7.75 (dd, J=9.31, Hz, 1H), 7.51-7.58 (m, 2H), 7.01 (d, J=9.01 Hz, 1H), 6.05-6.34 (m, 1H), 3.67-3.76 (m, 2H), 3.51-3.57 (m, 2H), 3.22-3.24 (m, 2H), 2.84-2.93 (m, 1H), 2.13-2.21 (m, 1H), 1.99-2.06 (m, 3H), 1.73-1.86 (m, 5H), 1.23-1.32 (m, 2H). m/z: 458.2 [M+H]+
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[Cl:18][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CCOC(=O)N1CCC(CCCO)CC1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(CCCCl)CC1
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a stirred mixture of 36 parts of ethyl 4-(3-hydroxypropyl)-1-piperidinecarboxylate and 261 parts of benzene were added dropwise 21.5 parts of thionyl chloride at 5°-10° C. Upon complete addition, stirring was continued overnight at this temperature. The reaction mixture was evaporated and the residue was taken up in methylbenzene. The solvent was evaporated (this was repeated twice), yielding 33 parts (83.8%) of ethyl 4-(3-chloropropyl)-1-piperidinecarboxylate as a residue (int. 58).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C:12]1[N:13]([CH3:23])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([O:21][CH3:22])[CH:15]=2)[CH3:2].[Cl:26]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:26][C:20]1[C:19]2[C:14](=[CH:15][C:16]([O:21][CH3:22])=[CH:17][CH:18]=2)[N:13]([CH3:23])[C:12]=1[C:5]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=1[N:3]([CH2:1][CH3:2])[CH2:24][CH3:25]
Reactant: CCN(CC)c1cc(OC)ccc1-c1cc2ccc(OC)cc2n1C
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)c1cc(OC)ccc1-c1c(Cl)c2ccc(OC)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of diethyl [5-methoxy-2-(6-methoxy-1-methyl-1H-indol-2-yl)phenyl]amine (110 mg) in tetrahydrofuran (5 ml) was added N-chlorosuccinimide (50 mg), and the solution was stirred for 1 hour at room temperature. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate-methanol system) to provide the title compound (96 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:34]([OH:37])(=[S:36])[CH3:35].[CH3:38][C@:39]12[CH2:56][CH2:55][C@H:54]3[C@@H:44]([CH2:45][C@H:46]([OH:58])[CH:47]4[C@:52]3([CH3:53])[CH2:51][CH2:50][C@H:49](O)[CH2:48]4)[C@@H:43]1[CH2:42][CH2:41][C@@H:40]2[OH:59]>C1COCC1.CCOC(C)=O>[C:34]([S:36][C@@H:49]1[CH2:50][CH2:51][C@@:52]2([CH3:53])[CH:47]([C@@H:46]([OH:58])[CH2:45][C@@H:44]3[C@@H:54]2[CH2:55][CH2:56][C@@:39]2([CH3:38])[C@H:43]3[CH2:42][CH2:41][C@@H:40]2[OH:59])[CH2:48]1)(=[O:37])[CH3:35]
Reactant: CC(O)=S
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@H](O)C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)S[C@@H]1CC[C@@]2(C)C(C1)[C@@H](O)C[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of triphenylphosphine (2.38 g) in THF (140 mL) cooled at 0° C., diisopropyl azodicarboxylate (1.79 mL) was added dropwise. After stirring for 30 minutes, thioacetic acid (0.65 mL) and androstane-3β,6α,17β-triol (2.00 g) were added. After 2 hrs at 0° C. and overnight at room temperature EtOAc was added. The mixture was washed with water and the organic layer evaporated to dryness. The crude product was purified by flash chromatography (SiO2, cyclohexane:EtOAc 55:45) to give 3α-acetylthioandrostane-6α,17β-diol (1.60 g, 66%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.42 (1H, bb), 4.28 (1H, bb), 3.91 (1H, bb), 3.42 (1H, m), 3.11 (1H, m), 2.28 (3H, s), 2.00-0.80 (20H, m), 0.74 (3H, s), 0.60 (3H, s).
Reaction SMILES: [CH:1]1[N:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:4]2[N:11]=[C:12]([NH2:16])[N:13]=[C:14]([OH:15])[C:3]=2[N:2]=1.N1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:22]=[CH:21]\[CH2:20]/[CH:19]=[CH:18]\[CH2:22]/[CH:21]=[CH:20]\[CH2:19][CH2:18][CH2:4][CH2:3][C:14]([O:10][CH2:9][CH2:8][O:7][CH2:6][N:5]1[C:4]2[NH:11][C:12]([NH2:16])=[N:13][C:14](=[O:15])[C:3]=2[N:2]=[CH:1]1)=[O:15]
Reactant: c1ccncc1
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCOCn1cnc2c(=O)nc(N)[nH]c21

Procedure:
Acyclovir (ACV, 0.5 g, 2.22 mmol, used as a dry white powder) was suspended in anhydrous pyridine (10 ml) and to the mixture stirred under dry nitrogen was added GLA acid chloride (0.788 g, 2.664 mmol). The reaction mixture was stirred overnight at room temperature after which period TLC indicated conversion to the required product. The pyridine was removed in vacuo and the residual syrup was dissolved in chloroform. This was introduced into a column of silica gel (30 g) pre-equilibrated in chloroform:ethanol (30:1, v:v). Elution with chloroform followed by chloroform: ethanol (30:1) , (20:1) and finally (15:1), gave the required product, AK-5, as a TLC homogeneous semi-solid. Yield, 48% (0.517 g, 1.065 mmol).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:9]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:29]1[C:30]2[C:37]([CH3:38])=[CH:36][S:35][C:31]=2[N:32]=[CH:33][N:34]=1>C(O)C>[CH3:20][C:17]1[CH:16]=[CH:15][C:14](/[CH:13]=[CH:12]/[C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH2:4][CH:3]([NH:2][C:29]2[C:30]4[C:37]([CH3:38])=[CH:36][S:35][C:31]=4[N:32]=[CH:33][N:34]=2)[CH2:11]3)=[CH:19][CH:18]=1
Reactant: Cc1ccc(/C=C/c2ccc3c(c2)CC(N)C3)cc1
Reactant: Cc1csc2ncnc(Cl)c12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(/C=C/c2ccc3c(c2)CC(Nc2ncnc4scc(C)c24)C3)cc1
Yield: 58.3 %

Procedure:
Using 2-amino-5-[(E)-2-(4-methylphenyl)ethenyl]indan hydrochloride (16 mg, 0.06 mmol), ethanol (0.6 ml), triethylamine (50 μl, 0.36 mmol), and 4-chloro-5-methylthieno[2,3-d]pyrimidine (11 mg, 0.060 mmol), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (14 mg, 0.035 mmol) having the following physical properties:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@:13]([CH2:23][OH:24])([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:10]1[OH:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C@@H:9]1[C@@:13]([CH2:23][O:24][S:40]([C:37]2[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=2)(=[O:42])=[O:41])([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:10]1[O:33][S:40]([C:37]1[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=1)(=[O:42])=[O:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1ccn([C@@H]2O[C@](CO)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@]2(COCc3ccccc3)O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]2OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 78 %

Procedure:
To a stirred solution of 1-(3,5-di-O-benzyl-4-C-hydroxymethyl-β-D-ribofuranosyl)uracil 41 (3.55 g, 7.81 mmol) in dichloromethane (50 cm3) were added DMAP (3.82 g) and p-toluenesulphonyl chloride (4.47 g, 23.5 mmol) at room temperature. Stirring was continued for 2 h, and dichloromethane (100 cm3) was added. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (2×75 cm3) and dried (Na2SO4). The organic phase was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99.5:0.5, v/v) as eluent to give nucleoside 75 (4.65g, 78%) as a white solid material. δH (CDCl3) 8.49 (1H, br s, NH), 7.67 (1H, d, J 8.3, 6-H), 7.51-7.03 (18H, m, Bn, Ts), 6.0 (1H, d, J 7.6, 1′-H), 5.05 (1H, m, 2′-H), 4.91 (2H, m, 5-H, Bn), 4.56 (2H, m, Bn), 4.42 (1H, d, J 10.4, Bn), 4.31 (1H, d, J 4.9, 3′-H), 4.05 (2H, m, 1″-H), 3.75-3.64 (2H, m, 5′-H), 2.41 (3H, s, CH3), 2.34 (3H, s, CH3). δC (CDCl3) 162.2 (C-4), 149.5 (C-2), 146.0, 145.3 (Ts), 139.0 (C-6), 136.7, 131.9, 130.0, 129.9, 128.9, 128.7, 128.5, 128.4, 128.3, 128.2, 128.0, 127.6 (Bn, Ts) 102.7 (C-5), 85.5 (1′-C), 84.4 (4′-C), 79.2, 78.3, 75.1, 74.3, 72.4, 69.1 (Bn, 3′-C, 2′-C, 5′-C, 1″-C ), 21.7, 21.6 (Ts). FAB-MS m/z 763. Found: C, 61.2; H, 4.4; N, 3.3; C38H38N2O11S2 requires C, 59.8; H,5.0; N,3.6.