Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([N:20]([CH:23](C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl.Cl.[C:39](OC(C)C)(=[O:41])C>C1COCC1>[CH3:39][O:41][N:20]([CH3:23])[C:14](=[O:16])[C@@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:13]
Reactant: CC(=O)OC(C)C
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
CBZ-L-Alanine (6.5 kg, 28.5 mol), HOBT-hydrate (4.8 kg, 34.8 mol), Me(MeO)NH2Cl (3.4 kg, 36.2 mol) and THF (32 L) were charged to a clean flask under nitrogen. The mixture was cooled to 0-10° C. and diisopropylethylamine (12.4 L) was slowly added at a temperature less than 20° C. EDC-HCl (7 kg, 36.2 mol) was added slowly with slight cooling at 15°-25° C. The slurry was aged overnight at 20°-25° C. The mixture was cooled to 0°-10° C. and 3N HCl (13 L) is added slowly. Isopropyl acetate (45.5 L) was added and the layers were separated. The organic layer was washed once with HCl (13 L) and twice with 8% NaHCO3 (13 L). The organic layer was concentrated under vacuum to <20 L at 50° C. The clear solution was cooled slowly to room temperature, allowing the product to crystallize. Heptane (˜70 L) was added slowly. The slurry was filtered, washed with heptane (18 L), and dried at room temperature on the filter pot. Benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate was obtained with >99.9% ee measured by chiral HPLC.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[NH:2][NH2:3].Br[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].N1C=CC=CC=1.II>CN(C=O)C.C(OCC)(=O)C>[CH2:18]([O:17][C:15](=[O:16])[C:14]([NH:3][NH:2][C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])([CH3:21])[CH3:20])[CH3:19]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: NNC(=O)OCc1ccccc1
Agent: II
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)NNC(=O)OCc1ccccc1
Temperature: 97.5 °C
Reaction time: 1.25 h

Procedure:
Benzyl carbazate (25 g, 0.15 mol) was dissolved in 50 mL of DMF in a round bottom flask. The solution was heated to 95-100° C. From two separate addition funnels, ethyl 2-bromoisobutyrate (58.5 g, 0.3 mol) and pyridine (29.7 g, 0.375 mol, 30 mL) were added drop-wise separately and simultaneously over 30-120 minutes. Heating was continued if necessary to propel the reaction to completion. The reaction was monitored by TLC (30% ethyl acetate in hexanes, I2 visualization). The mixture was allowed to cool, and then poured onto ice water. The aqueous mixture was extracted with ethyl ether, and the solvent was removed in vacuo. 2-(N′-benzyloxycarbonyl-hydrazino)-2-methyl-propionic acid ethyl ester was isolated, optionally after silica gel chromatography. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.36(br s, 5H), 6.6 (br s, 1H), 5.15 (br s, 2H), 4.2 (q, 2H), 1.3 (s, 6H), 1.25 (t, 3H). 1H NMR analysis alone is insufficient to ascertain the extent of the reaction.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])[CH3:12].C(N(C(C)C)CC)(C)C>CCO>[CH2:11]([O:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:18][CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CC[C@@H](Nc2nc3ccccc3[nH]2)CC1
Temperature: 200 °C

Procedure:
A mixture of 2-Chlorobenzimidazole (I) (0.9 g, 5.9 mmol) and ethyl-4-amino-cyclohexane carboxylate (1.1 g, 5.4 mmol) were placed in a glass high pressure a tube. Diisopropylethylamine (2.8 mL, 16.2 mmol) was added, the reaction vessel was sealed and heated to 200° C. for 4 h and allowed to cool to room temperature. Next was added 5 mL EtOH and heated to dissolve the reaction mixture. The reaction mixture was partitioned between aqueous NaHCO3 and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. Purification of the crude product on silica gel (gradient, 1:1 hexanes:EtOAc to EtOAc) gave the cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (J) (0.5 g) and the trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (K) (0.5 g) Data for (J): 1H NMR (300 MHz, CDCl3) δ 7.28 (br s, 2H), 7.02 (m, 2H), 5.16 (br s, 1H), 4.15 (q, 2H), 3.97 (br s, 1H), 2.40 (br s, 1H), 1.80-1.54 (m, 8H), 1.22 (t, 3H); mass spectrum m/z 288 [(M+H)+; calcd for C16H22N3O2: 288]. Later fractions gave the trans isomer (K) (0.5 g): 1H NMR (300MH, CDCl3) δ 7.28 (br s, 2H), 7.02 (m, 2H), 4.82 (br s, 1H), 4.15 (q, 2H), 3.64 (m, 1H), 2.20 (br d, 3H), 1.96 (br d, 2H), 1.42 (m, 2H), 1.22 (t, 3 H), 1.20 (m, 2H); mass spectrum m/z 288 [(M+H)+; calcd for C16H22N3O2: 288].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:44])[CH2:19][C:20]2[N:21]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:44])[CH2:19][C:20]2[N:21]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C@H:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C(CC(O)c2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C(CC(=O)c2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a cold (−70° C.) solution of oxalyl chloride (0.27 mL, 3.06 mmol) in dichloromethane (15 mL) is added DMSO (0.32 mL, 6.11 mmol) followed by the alcohol 256 (1.28 g, 2.48 mmol) in dichloromethane (5 mL). The mixture is stirred for at −70° C. solution 15 min., and triethylamine (1.03 mL, 13.9 mmol) is added and the mixture is allowed to come to RT and is stirred for 4 h. The reaction mixture is washed with water, brine, then dried (MgSO4), and filtered. The filtrate is rotary evaporated, and the residue is recrystallized from Et2O to give 1.02 g of the product 257. 1H NMR (CDCl3) δ 10.60 (s, 1 H), 8.10-7.95 (m, 2 H), 7.10-6.90 (m, 12 H), 6.90-6.70 (m, 2 H), 5.40 (s, 2 H), 1.25 (s, 9 H); MS: m/z 459 (M++1).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)(C)=O.FC1C=CC([N:20]2[C:28]3[C:23](=[CH:24][C:25]4[C@@:33]5([CH2:39]C6C=CC=CN=6)[CH2:34]CC(=O)C[C@H]5CCCC=4C=3)[CH:22]=[N:21]2)=CC=1.FC1C=CC(N2C3C(=CC4[C@:66]5([CH2:72][C:73]6C=CC=CN=6)[CH2:67][CH2:68][C:69](=[O:71])[CH2:70][C@@H:65]5[CH2:64][CH2:63]CC=4C=3)C=N2)=CC=1>C1COCC1.CCOC(C)=O>[CH2:72]([C:66]12[CH2:67][CH2:68][C:69]3([CH2:8][O:71]3)[CH2:70][CH:65]1[CH2:64][CH2:63][CH2:39][C:33]1[C:25]2=[CH:24][C:23]2[CH:28]=[N:20][NH:21][C:22]=2[CH:34]=1)[CH3:73]
Reactant: O=C1CC[C@@]2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@H]2C1
Reactant: C[S+](C)(C)=O
Reactant: O=C1CC[C@]2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@@H]2C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCC12CCC3(CO3)CC1CCCc1cc3[nH]ncc3cc12
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 139.6 %

Procedure:
A mixture of DMSO (1 mL) and sodium hydride (60 wt % in oil, 0.020 g, 0.51 mmol) was heated to about 65° C. for about 45 min then cooled to rt and diluted with THF (1 mL). The mixture was cooled to about 0° C. and trimethylsulfoxonium iodide (0.112 g, 0.509 mmol) was added. The mixture was stirred for about 15 min and (4aS,12bR)-9-acetyl-12b-ethyl-1,2,4a,5,6,7,9,12b-octahydro-4H-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-one; compound with (4aR,12bS)-9-Acetyl-12b-ethyl-1,2,4a,5,6,7,9,12b-octahydro-4H-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-one (10, R1=Acetyl, R2=Ethyl) (0.066 g, 0.203 mmol) dissolved in THF (1.5 mL) was added. The mixture was warmed to rt and stirred for about 14 h. In a separate flask a mixture of DMSO (1 mL) and sodium hydride (60 wt % in oil, 0.020 g, 0.51 mmol) was heated to about 65° C. for about 45 min then cooled to rt and diluted with THF (0.5 mL). The mixture was cooled to about 0° C., trimethylsulfoxonium iodide (0.112 g, 0.51 mmol) was added and the mixture was stirred for about 15 min. The mixture was added to the epoxidation reaction and stirring was continued for about 2 h at rt. The reaction mixture was diluted with EtOAc (25 mL) and washed successively with sat. aq. NH4Cl (15 mL), water (15 mL), and brine (15 mL). The organic solution was died over MgSO4, filtered and concentrated under reduced pressure to provide crude rac-(2′R,4aS,12bR)-12b-ethyl-2,4,4a,5,6,7,9,12b-octahydro-1H-spiro[benzo[6,7]cyclohepta[1,2-f]indazole-3,2′-oxirane] (12, R1═H, R2=Ethyl) (0.084 g); LC/MS, method 3, Rt=2.32 min, MS m/z 297 (M+H)+. The material was used directly in Step #13 without further purification
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][Cl:24]>CN(C)C=O>[Cl:24][CH2:23][CH2:22][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(CCCl)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-methoxyphenyl)piperazine was dissolved in N,N-dimethylformamide, and potassium carbonate and 1-bromo-2-chloroethane were added. The resulting mixture was stirred at room temperature overnight, the solid material filtered off, and the solvent removed from the filtrate under reduced pressure. The residue was purified by biotage chromatography eluting with 3:7 ethyl acetate:hexanes, to provide 1-[4-(2-chloroethyl)piperazinyl]-4-methoxybenzene.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[F:13][C:14]([F:43])([F:42])[C:15](Cl)([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH3:40])=[CH:34][CH:33]=1)[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1.C([SnH](CCCC)CCCC)CCC.O>C1(C)C=CC=CC=1>[F:13][C:14]([F:42])([F:43])[CH:15]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH3:40])=[CH:36][CH:37]=1)[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1
Reactant: CCOc1ccc(C(Cl)(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ccc(C(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Yield: 90.2 %

Procedure:
A few crystals of α,α-azoisobutyronitrile (AIBN) were added to a solution of 1,1,1-trifluoro-2-chloro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propane (0.36 g) in toluene (15 cm3), and the mixture was cooled in an ice bath whilst tri-n-butyl tin hydride (0.25 cm3) was added. The reaction mixture was heated at the reflux temperature for 1.5 hours under an atmosphere of nitrogen. Analysis by gas liquid chromatography at this time showed no trace of the starting chloro compound. The mixture was cooled, poured I into water (50 cm3), and extracted with diethyl ether (4×30 cm3). The combined organic layers were dried over anhydrous sodium sulphate and the residual oil after evaporation of the solvent under reduced pressure was purified by column chromatography on a silica gel support, eluting with n-hexane containing 6% by volume diethyl ether, to give 1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)-propane (0.3 g) as an oil.
Reaction SMILES: C([Li])(CC)C.[N:6]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.CN(C)CCN(C)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(OCC)C.O>[N:6]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc21
Reactant: CCOC(=O)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cccc2c1N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Yield: 37.6 %

Procedure:
A 1.3 M solution of sec-butyl lithium in cyclohexanes (1642 mL, 2.13 mol) was added dropwise to a solution of 1,1-dimethylethyl 2,3-dihydro-1H-indole-1-carboxylate (300 g, 1.37 mol) and N,N,N′,N′-tetramethyl-1,2-ethanediamine (248 mL, 1.64 mol) in dry diethyl ether (2.5 L) at −78° C. The reaction mixture was stirred for 2 hours at this temperature and ethyl chloroformate (143.9 mL, 1.50 mol) was added dropwise to the mixture at −78° C. After the addition, the reaction was allowed to warm to room temperature overnight. Water (1 L) was added carefully to the mixture and the organic layer was separated and dried (Na2SO4). The solution was concentrated and the residue was purified by silica-gel column chromatography (PE: EA=10:1), giving 150 g (38%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([Cl:11])=[C:9]([C:12](OC)=[O:13])[S:8][C:7]=2[CH:16]=1.CO.[NH2:19][NH2:20].II>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([Cl:11])=[C:9]([C:12]([NH:19][NH2:20])=[O:13])[S:8][C:7]=2[CH:16]=1
Reactant: COC(=O)c1sc2cc(OC)ccc2c1Cl
Reactant: NN
Agent: II
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2c(Cl)c(C(=O)NN)sc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 57 %

Procedure:
A 100 ml, round bottomed flask, reflux condenser, gas inlet and Teflon stirrer were oven dried for 12 hours at 160° C. The apparatus was rapidly assembled, flushed with dry nitrogen gas, and cooled to room temperature. The reaction flask was charged with methyl 6-methoxy-3-chlorobenzo[b]thiophene-2-carboxylate (1.50 g, 5.85 mmole), anhydrous methanol (Aldrich, 50 ml), and anhydrous hydrazine (Aldrich, 2.5 equivalents, 0.47 g, 0.45 ml, 14.61 mmole). The stirred reaction mixture was brought to reflux and the progress of the reaction monitored by TLC (Silica, 1:1 hexane:ethyl acetate, and 100% ethyl acetate, iodine and UV visualization). After 72 hours, the completed reaction was cooled to room temperature, and further cooled to 5° C. for 1 hour. The resulting solid was filtered, washed with cold methanol (2×10 ml), and dried in vacuo. This resulted in 0.856 g of the desired material, as a white amorphous powder which was used directly.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:10][CH2:11][C:12](Cl)=[O:13].CCN(C(C)C)C(C)C>ClCCl>[Br:10][CH2:11][C:12]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])=[O:13]
Reactant: O=C(Cl)CBr
Reactant: Nc1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)Nc1ccc(F)cc1F
Reaction time: 4 h

Procedure:
5.16 g (40 mmol) of 2,4-difluoroaniline and 6.3 g (40 mmol) of bromoacetyl chloride are treated in 200 ml of dichloromethane with 5.17 g (40 mmol) of Hunig base. After 4 h, the mixture is washed twice with 1N hydrochloric acid and once with water, dried (MgSO4) and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12](=[O:15])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][NH:9][C:8]=3[C:7](=[O:21])[C:6]=2[CH:22]=1.[CH2:23](I)[CH3:24]>>[CH2:23]([N:9]1[CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[C:13]2[O:14][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=3[C:7](=[O:21])[C:8]1=2)[CH3:24]
Reactant: CCOC(=O)c1c[nH]c2c(=O)c3cc(Cl)ccc3oc2c1=O
Reactant: CCI
Product: CCOC(=O)c1cn(CC)c2c(=O)c3cc(Cl)ccc3oc2c1=O
Yield: 77.6 %

Procedure:
Prepared from ethyl 8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate (3.19 g, 0.01 mole) and ethyl iodide (6.24 g, 0.04 mole) by the method described for Example 9. Recrystallization from DMF gave white crystals (2.7 g, 78%), m.p. 257°-259°.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH3:23][CH:24]([NH2:27])[CH2:25][OH:26]>>[CH2:18]([C:13]1[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:27][C@@H:24]([CH3:23])[CH2:25][OH:26])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)OC)cn1
Reactant: CC(N)CO
Product: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)N[C@@H](C)CO)cn1
Yield: 36 %

Procedure:
As described in example 10, 6-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (100 mg, 0.28 mmol), and L-2-amino-1-propanol instead of DL-2-amino-1-propanol, was converted to the title compound (41 mg, 36%) which was obtained as a colorless oil after purification by chromatography (silica, dichloromethane:methanol 100:0 to 96.5:3.5). MS: m/e=364.4 [M+H]+.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:16]=[CH:15][C:13](=O)[NH:12][C:10]2=O)[CH2:3]1.[N-:17]=[N+]=[N-].[K+].[C@@H:21]1([N:29]2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1.CO>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:21]=[N:29][C:15]3[C:16]2=[N:17][CH:10]=[N:12][CH:13]=3)[CH2:3]1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3cncnc32)C[C@@H]1F
Temperature: 45 °C
Reaction time: 96 h
Yield: 57 %

Procedure:
2-Amino-6-(cycloropylmethoxy)-9H-purine (0.53 g, 2.6 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in 50 ml, 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky et al., Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 4 days, 182 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (9:1). Solvent was removed and lyophilization yielded 0.414 g of 2-amino-6-cyclopropylmethoxy)-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-9H-purine (57%): mp 80°-81° C.; TLC Rf 0.75 (silica gel, MeCN:15N NH4OH:H2O/85:5:10); [α]D20 -19.0 (c=0.5, DMF);UV λmax (ε×10-3) at pH 7, 247 (9.7); at pH 13, 247 (9.3);1H NMR (200 MHz, DMSO-d6) δ8.13 (s, 1H, H8), 6.47 (b, 2H, NH2), 6.27 (dd, 1H, H1', J=9.3 Hz, J=5.6 Hz), 5.43 (dd, 1H, H3', J=54 Hz, J=4.2 Hz), 5.24 (t, 1H, OH5'J=5.6 Hz), 4.26 (d, 2H, OCH2, J=7.2 Hz), 4.11-4.27 (m, 1H, H4'), 3.59 (t, 2H, H5' and H5", J=5.2 Hz), and 2.62-3.01 (m, 2H, H2' and H2"), 1.25-1.35, 0.55-0.64, and 0.35-0.40 (m, 5H, cyclopropyl group);
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH2:19])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:20][C:21]1[NH:22][CH:23]=[C:24]([CH:26]=O)[N:25]=1.[C:28](O)(=[O:30])C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:4]([N:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][N:19]2[CH2:26][C:24]3=[CH:23][N:22]=[C:21]([CH3:20])[N:25]3[C:28]2=[O:30])[CH2:15][CH2:16]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)O
Reactant: Cc1nc(C=O)c[nH]1
Reactant: NCCN1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ncc2n1C(=O)N(CCN1CCN(Cc3ccccc3)CC1)C2
Yield: 8.5 %

Procedure:
A suspension of 2-(1-benzyl-4-piperazinyl)ethanamine trihydrochloride (2.5 g) obtained in Example 97a), 2-methylimidazole-4-carbaldehyde (0.84 g) and acetic acid (0.5 ml) in 1,2-dichloroethane (50 ml) was mixed at room temperature for 40 minutes, and then sodium triacetoxyborohydride (2.4 g) was added thereto under ice-cooling. The reaction mixture was returned to room temperature, and mixed for 2 days. Then, the reaction solution was washed with an aqueous potassium carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in THF (60 ml). To the reaction solution were added N,N′-carbonyldiimidazole (1.4 g) and DBU (1.3 g), and mixed at room temperature for 4 days. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, then washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified with basic silica gel column (ethyl acetate) to obtain the title compound as a colorless oil (0.22 g, 8.5%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][S:16](=[O:19])[CH2:15][CH2:14]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([SH:12])[C:6]=2[N:7]=1.[CH:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21]>>[CH:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:3]=[C:4]([N:13]3[CH2:18][CH2:17][S:16](=[O:19])[CH2:15][CH2:14]3)[C:5]3[N:11]=[CH:10][N:9]=[C:8]([SH:12])[C:6]=3[N:7]=2)[CH2:24][CH2:23]1)=[O:21]
Reactant: O=S1CCN(c2nc(Cl)nc3c(S)ncnc23)CC1
Reactant: O=CN1CCNCC1
Product: O=CN1CCN(c2nc(N3CCS(=O)CC3)c3ncnc(S)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 93 from 2-chloro-8-mercapto-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: >280° C., decomp.) and N-formyl-piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][S:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[Cl:26])(=[O:14])=[O:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[CH:27](N(CC)C(C)C)(C)[CH3:28].C(OS(C(F)(F)F)(=O)=O)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([S:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[CH:18][C:17]=2[Cl:26])(=[O:13])=[O:14])[CH2:27][CH3:28])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1nccnc1NS(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Agent: CCOS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CCN(c1nccnc1C(=O)OC)S(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-(2-chloro-5-trifluoromethyl-phenylmethanesulfonylamino)-pyrazine-2-carboxylic acid methyl ester (Example 2.1) (1.5 g) in acetonitrile (20 ml) was added N,N-diisopropylethylamine (“Hunig's base”) (0.71 ml) at ambient temperature. The mixture was stirred for 5 minutes at ambient temperature before dropwise addition of a solution of ethyltrifluoromethanesulfonate (0.71 ml) in acetonitrile (5 ml) at ambient to temperature. The reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated and the residue purified by column chromatography on silica gel (eluent: dichloromethane) to give 3-[(2-chloro-5-trifluoromethyl-phenyl-methanesulfonyl)-ethyl-amino]-pyrazine-2-carboxylic acid methyl ester as a beige solid (0.968 g). 1H-NMR (400 MHz, CDCl3): 8.57 (d, 1H), 8.52 (d, 1H), 7.77 (m, 1H), 7.50-7.56 (m, 2H), 4.64 (m, 2H), 4.01 (q, 2H), 4.00 (s, 3H), 1.23 (t, 3H) ppm.