Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([OH:24])[CH:23]=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29]([F:34])([F:33])C([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([O:24][CH:29]([F:34])[F:33])[CH:23]=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(O)cc21
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(OC(F)F)cc21
Yield: 32.2 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-6-hydroxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg), sodium chlorodifluoroacetate (253 mg), K2CO3 (172 mg), DMF (3 mL), and water (0.60 mL) was refluxed overnight. The reaction mixture was poured into water, and the mixture was extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 10%-40% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-6-(difluoromethoxy)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (110 mg) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.CO[CH:22](N(C)C)[N:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)=[CH:22][N:23]([CH3:25])[CH3:24]
Reactant: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: COC(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C(=CN(C)C)c1ccc(OCc2ccccc2)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
According to a modified literature procedure (Wasserman, H. H.; Ives, J. L. J. Org. Chem. 1985, 50, 3573–3580) a solution of 1.0 g (3.9 mmol) of (4-benzyloxy-phenyl)-acetic acid methyl ester in 4 mL of toluene was flushed with argon. To this solution was added 0.842 mL g (5.5 mmol) of methoxy bis(dimethylamino)methane, and the resulting mixture was stirred at 65° C. under argon overnight. The reaction mixture was concentrated to give 1.21 g of desired 2-(4-benzyloxy-phenyl)-3-dimethylamino-acrylic acid methyl ester as indicated by 1H NMR (containing traces of starting material). The product was used without any further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[S:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[S:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=1)=[O:5]
Reactant: Nc1ncc([N+](=O)[O-])s1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])s1)c1ccccc1Cl

Procedure:
By following the procedure of the first part of Example 1, but using 2-chlorobenzoyl chloride (26.3 g), 2-amino-5-nitrothiazole (21.8 g) and pyridine (ca 150 ml), there was obtained 2-chloro-N-(5-nitro-2-thiazolyl)benzamide, m.pt 221°-222°, after recrystallisation from acetic acid.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:37])[C@@H:15]4[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]4[C:17]=3[C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])[S:10][C:9]=12.[NH2:38][C:39]([NH2:41])=[S:40]>C(#N)C.CN(C=O)C>[OH:35][C@@H:33]([C@H:32]1[C:31](=[O:36])[N:16]2[C:17]([C:18]([OH:20])=[O:19])=[C:13]([C:11]3[S:10][C:9]4=[C:5]([S:4][CH2:3][CH2:2][NH:41][C:39](=[NH:38])[SH:40])[N:6]=[CH:7][N:8]4[CH:12]=3)[C@H:14]([CH3:37])[C@H:15]12)[CH3:34]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCBr)c4s3)[C@H](C)[C@H]12
Reactant: NC(N)=S
Solvent: CC#N
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(c3cn4cnc(SCCNC(=N)S)c4s3)[C@H](C)[C@H]12
Temperature: 50 °C
Reaction time: 18 h
Yield: 14.7 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[7-(2-bromoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (128 mg) was dissolved in 3 ml of acetonitrile and 0.5 ml of DMF. Thiourea (222 mg) was added to the solution. The mixture was stirred at 50° C. for 18 hr. The reaction solution was concentrated under the reduced pressure. The residue was purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1), followed by a reaction and purification in the same manner as in Example 1c). Thus, 14.5 mg of the title compound was prepared.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][C:8]1([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[O:24])[CH:12]([CH3:13])[CH2:11][N:10]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CCCCCC.C(O)C>[C:1]([O:5][C:6](=[O:39])[CH2:7][C@@:8]1([C:23]([NH:25][CH:26]2[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]2)=[O:24])[C@H:12]([CH3:13])[CH2:11][N:10]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(Cc2c(Cl)cccc2Cl)CC1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCO
Solvent: CCCCCC
Product: C[C@@H]1CN(Cc2c(Cl)cccc2Cl)C[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl 4-[(3RS,4SR)-3-[2-(tert-butoxy)-2-oxoethyl]-1-[(2,6-dichlorophenyl)methyl]-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 5a (2.04 g, 3.49 mmol) was optically resolved repeatedly by HPLC (CHIRALPAK IA (3 cm diameter×25 cm), elution solvent: hexane/ethanol=94/6, flow rate: 22 ml/min.) to give the title compound (a chiral form corresponding to the peak with a shorter retention time) (859 mg, 42.1%) and the optical isomer (a chiral form corresponding to the peak with a longer retention time) (817 mg, 40%), respectively.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4].[C:25]([O:29][C:30](=[O:49])[NH:31][C@H:32]([CH:47]=O)[CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])([CH3:28])([CH3:27])[CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:25]([O:29][C:30](=[O:49])[NH:31][C@H:32]([CH2:47][NH:1][C@@H:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4])[CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:38])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)[C@@H](N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CCCNC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@@H](NC[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 2-((R)-1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H -quinazolin-4-one (a compound of Formula 107, 366 mg, 1.07 mmol) and ((S)-4-benzyloxycarbonylamino-1-formyl-butyl)-carbamic acid tert-butyl ester (prepared as previously described: Hamada, Y.; Shioro, T. Chem. Pharm. Bull. 1982, 30, 1921) (452 mg, 1.29 mmol) in CH2Cl2 (25 mL) was added sodium triacetoxyborohydride (341 mg, 1.61 mmol). The resultant cloudy mixture was stirred overnight and quenched with saturated brine (50 mL). The aqueous layer was extracted with CH2Cl2 (20 mL) and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (2:1 hexanes:ethyl acetate) to provide 550 mg (76%) of the title compound as a yellow oil. MS(ES+) m/e 676.4 [M+H]+.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[NH:6]1[CH2:10][CH2:9][CH:8](OS(C2C=CC(C)=CC=2)(=O)=O)[C:7]1=[O:22]>CC(C)=O>[C:1]([O:4][CH:8]1[CH2:9][CH2:10][NH:6][C:7]1=[O:22])(=[S:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OC2CCNC2=O)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=S)OC1CCNC1=O
Yield: 23 %

Procedure:
A mixture of 855 mg. (7.5 mmoles) potassium thioacetate and 1.27 g (5 mmoles) crude 2-pyrrolidon-3-yl-p-toluenesulfonate in 40 ml. acetone was refluxed under nitrogen for ca. 20 hr. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was partitioned between 50 ml. ethyl acetate and 50 ml. water and the ethyl acetate layer was washed with 40 ml. water and 40 ml. saturated aqueous sodium chloride solution. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel, eluting with ethyl acetate, to yield 180 mg. (23% yield) of the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=[O:12])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH3:23]O>>[O:17]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([O:13][CH3:23])=[O:12])[CH2:6][CH2:7]1
Reactant: CO
Reactant: O=C(O)c1cccc(N2CCS(=O)(=O)CC2)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(N2CCS(=O)(=O)CC2)c1
Yield: 90 %

Procedure:
3-(1,1-dioxidothiomorpholino)benzoic acid (100 mg, 0.392 mmol) was refluxed in the presence of con. Sulfuric acid (2.53 mg, 0.020 mmol) in methanol (5 mL) at 70° C. for overnight. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by flash chromatography afforded the methyl 3-(1,1-dioxidothiomorpholino)benzoate (99 mg, 0.353 mmol, 90% yield). 1H NMR (CDCl3, 400 MHz): δ 7.58 (m, 2H), 7.36 (t, 1H, J=8.0 Hz), 7.09 (m, 1H), 3.91 (s, 3H), 3.89 (m, 4H), 3.11 (m, 4H). Mass [M+H]+: 270.1
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.[C:29]1(=O)[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([NH:1][CH2:2][CH2:3][NH:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]3[CH2:20][C:19]4[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=4[O:17][B:16]3[OH:28])=[O:13])[CH2:7][CH2:6]2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: O=C1CCCC1
Product: O=C(C[C@H]1CC[C@H](NCCNC2CCCC2)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
Prepared from (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid and cyclopentanone following the procedure described in Example 71. The product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 458 (MH)+.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([CH3:7])[O:5][C:4]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([OH:25])[CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=3)=[CH:10][CH:9]=2)=[N:3]1.Cl[C:27]1[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH3:1][C@@H:2]1[C@H:6]([CH3:7])[O:5][C:4]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=3)[O:25][C:27]3[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=3)=[CH:10][CH:9]=2)=[N:3]1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=N[C@H](C)[C@H](C)O3)[nH]2)c1
Reactant: CS(=O)(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H](C)[C@H](C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
3-{5-[(4R,5S)-4,5-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol (420 mg, 1.22 mmol) synthesized in Example (109c) was dissolved in acetonitrile (20 mL), and 2-chloro-5-(methylsulfonyl)pyrazine (345 mg, 1.46 mmol) synthesized in Example (97c) and cesium carbonate (1.02 g, 3.13 mmol) were added at room temperature, followed by stirring at room temperature overnight under nitrogen atmosphere. To this reaction solution, water (30 mL) was added, and extraction was carried out with methylene chloride (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-3%) to afford the desired compound (513 mg, yield 84%) as a white solid.
Reaction SMILES: [C:1]([C:5]([C:7]1[N:12]2[C:13](=[O:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[CH2:9][C:8]=1[CH2:20][S:21][C:22]1[N:26]([CH3:27])[N:25]=[N:24][N:23]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[Br:28]N1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[Br:28][CH:9]1[C:8]([CH2:20][S:21][C:22]2[N:26]([CH3:27])[N:25]=[N:24][N:23]=2)=[C:7]([C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[O:6])[N:12]2[C:13](=[O:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10]1(=[O:19])=[O:18]
Reactant: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(CSc3nnnn3C)CS(=O)(=O)[C@H]12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(CSc3nnnn3C)C(Br)S(=O)(=O)[C@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-tert-butylcarbonyl-7α-methoxy-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-3-cephem 1,1 dioxide (350 mg) in dichloromethane (30 ml), N-bromosuccinimide (200 mg) and triethylamine (0.13 ml) were added sequentially. The mixture was stirred for 15 min at room temperature. Following dilution with dichloromethane, the organic phase was sequentially washed with 4% aqueous NaHSO3, saturated NaHCO3 and water. After drying over Na2SO4 and removal of the solvent, the residue was purified by flash chromatography (eluting with hexane-EtOAc mixtures) affording 2-bromo-4-tert-butylcarbonyl-7α-methoxy-3-(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl-3-cephem 1,1-dioxide as a waxy solid (200 mg), IR (KBr) νmax 1800, 1700 cm-1. A portion of this material (180 mg) was dissolved in acetonitrile (10 ml) and treated with silver benzoate (95 mg). The mixture was stirred for 30 min at room temperature, then filtered and rotoevaporated. Following flash chromatography (eluting with gradient of EtOAc in hexane) the title product was obtained as a light yellow solid (80 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:16]2[CH2:17][O:18][CH2:19][CH:9]1[C:10]1[CH:11]=[N:12][O:13][C:14]=1[CH:15]2O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:27])CC>C(Cl)Cl.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH:16]2[CH2:17][O:18][CH2:19][CH:9]1[C:10]1[CH:11]=[N:12][O:13][C:14]=1[CH:15]2[F:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C2COCC1C(O)c1oncc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2COCC1C(F)c1oncc12
Reaction time: 6 h

Procedure:
To a solution of 7-Hydroxy-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene-12-carboxylic acid tert-butyl ester 106d (141 mg, 0.5 mmol, 1.0 eq) in DCM (5 mL) was added DAST (166 mg, 1 mmol, 2.0 eq) at −78° C. Then mixture was stirred for 6 h from −78° C. to room temperature. The reaction was diluted with EA (20 mL), and washed with aqueous NaHCO3 (5%, 20 mL). The organic layer was dried and concentrated to give 7-Fluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene-12-carboxylic acid tert-butyl ester as an oil, 150 mg, crude yield: 100%. MS: calc'd (MH+) 285, measured (MH+) 285.
Reaction SMILES: [C@@H:1]1([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@H:3]2[O:4][C@@H:2]12.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>N1C=CC=CC=1>[Si:19]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[CH:10]2)[C@@H:2]2[O:4][C@H:3]12)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]2O[C@H]21
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2O[C@@H]21
Reaction time: 3.5 h
Yield: 96 %

Procedure:
To a stirred solution of 9.5 g (38.1 mmol) of 2',3'-anhydroadenosine (Robins, M. J.; Hansske, F; Low, N. H.; Park, J. I. Tetrahedron Lett. 1984, 367-370) in 114 mL of pyridine was added 11.5 g (76.2 mmol) of t-butyldimethylsilyl chloride. After 3.5 h at room temperature, an additional 5.75 g (38.1 mmol) of t-butyldimethylsilyl chloride was added. After a total of 4.25 h, the reaction mixture was diluted into 2 L of water and extracted with 3×500 mL of dichloromethane. The combined dichloromethane extracts were washed with one liter of saturated aqueous sodium bicarbonate, with 3×500 mL of water, and then dried over magnesium sulfate. Concentration under reduced pressure afforded 13.3 g of 5'-O-(t-butyldimethylsilyl)-2',3'-anhydroadenosine. To a stirred solution of 2.0 g (5.50 mmol) of 5'-O-(t-butyldimethylsilyl)-2',3'-anhydroadenosine in 55 mL of THF at 0° C. was added 22 mL (22 mmol) of a 1M solution of lithium triethyl borohydride in THF. The reaction mixture was then allowed to warm to room temperature. After 3 hours, the reaction mixture was recooled to 0° C. and then carefully treated with 4.0 mL of 5% aqueous acetic acid. The resulting mixture was diluted with 150 mL of EtOAc, washed with 3×100 mL of saturated aqueous NaCl, dried over magnesium sulfate, concentrated under reduced pressure, and then coevaporated with three portions of chloroform. Chromatography of the residue on silica gel with a 100:0 to 97:3 chloroform/methanol gradient afforded 1.8 g (90%) of the title compound: colorless glass; Rf =0.10 (silica gel 60 F-254, 0.25 mm, E. Merck (SG), 95:5 CHCl3 :MeOH); [α]D23 -47.8° (c 2.47, CHCl3); IR (CDCl3) 3480, 3415, 3320, 3165, 3125, 2960, 2935, 2860, 1635, 1595, 1575, 1470, 1415, 1330, 1290, 1255, 1210, 1135, 1090, 995 cm-1 ; 1H NMR (300 MHz, CDCl3, TMS=0.00 ppm) δ0.08, 0.09 (2s, 6H, (CH3)2Si), 0.88 (s, 9H, (CH3)3CSi), 2.10 (ddd, 1H, J=13.5 Hz, J'= 6.5 Hz, J"=4.0 Hz, 3'-H), 2.34 (ddd, 1H, J=13.5 Hz, J'=7.5 Hz, J"=6.0 Hz, 3'-H), 3.74 (dd, 1H, J=12.0 Hz, J'=3.0 Hz, 5'-H), 4.05 (dd, 1H, J=12.0 Hz, J'=3.0 Hz), 4.62 (dddd, 1H, J=7.5 Hz, J'=6.5 Hz, J"=J'"=3.0 Hz, 4'-H), 4.70 (ddd, 1H, J=6.0 Hz, J'=4.0 Hz, J"=2.5 Hz, 2'-H), 5.88 (bs, 1H, OH), 6.01 (d, 1H, J=2.5 Hz, 1'-H), 6.15 (bs, 2H, NH2), 8.30, 8.33 (2s, 2H, H-2, H-8); FAB MS, m/z 366 (M+H)+ , 136.
Reaction SMILES: [F:1][CH:2]([CH3:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.Cl.[C:13](=[NH:18])([NH2:17])[CH2:14][CH2:15][CH3:16].C[O-].[Na+]>CO.C(OCC)(=O)C>[F:1][CH:2]([C:3]1[N:17]=[C:13]([CH2:14][CH2:15][CH3:16])[NH:18][C:5](=[O:7])[CH:4]=1)[CH3:11]
Reactant: CCCC(=N)N
Reactant: CCOC(=O)CC(=O)C(C)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1nc(C(C)F)cc(=O)[nH]1
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A mixture of ethyl 4-fluoro-3-oxopentanoate (5.0 g), butanimidamide hydrochloride (4.6 g) and sodium methoxide (28% methanol solution, 16 mL) in methanol (50 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (5.7 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH3:12]>CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH2:12])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: N
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)nc2[nH]ccc12
Temperature: 100 °C

Procedure:
A mixture of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.1 g, 0.53 mmol) in Ammonia (7 N in MeOH, 1 mL) was heated at 100° C. for 24 h, then it was diluted with EtOAc, washed with Sat. NaHCO3, brine, dried and concentrated to give 2-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-amine (0.06 g).
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([C:23]2[CH:24]=[CH:25][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:28]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:19][CH:20]=1
Reactant: O=C(O)C1CCCc2ccccc21
Reactant: CC(C)c1ccc(NCc2ccc(Cl)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(Cl)cc2)C(=O)C2CCCc3ccccc32)cc1
Yield: 4.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) and [(4-chlorophenyl)methyl](4-isopropylphenyl)amine (1.3 g) as starting materials, N-[(4-chlorophenyl) methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.1 g) was obtained. melting point: 122-123° C.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH:6]([CH3:9])[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])(S(C3C=CC=CC=3)(=O)=O)[CH2:4]2)[O:2]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CC(C)=O>[OH:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:5]1[CH:6]([CH3:9])[CH2:7][CH2:8][C:3](=[O:2])[CH:4]=1
Reactant: CC1CCC2(CC1(CCCCCCCCCCCCCCO)S(=O)(=O)c1ccccc1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC1CCC(=O)C=C1CCCCCCCCCCCCCCO

Procedure:
Paratoluenesulfonic acid (20 mg) was added to a solution of 235 mg of 1,1-(ethylenedioxy)-3-(14-hydroxytetradecyl)-4-methyl-3-(phenylsulfonyl)-cyclohexane in 20 ml of chloroform and 4 ml of acetone. The resulting mixture was reacted at 50° C. for 24 hours. To the reaction mixture was added 10 ml of a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane. The organic layer was washed with saturated saline, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column while using hexane-ethyl acetate, whereby 3-(14-hydroxytetradecyl)-4-methyl-2-cyclohexen-1-one was obtained in the form of a colorless oil (yield: 75%).
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33].ClC(OCC)=O>>[C:1]1([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:23][CH2:24][N:25]([C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27]3)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC1CCCCC1)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Reactant: CCCC(=O)Cl
Agent: CCOC(=O)Cl
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)Nc3ccccc3)c3ccccc23)CC1

Procedure:
The title compound was prepared according to the general procedure in Scheme 11, substituting 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid m-tolylamide for 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid cyclohexylamide, and butyryl chloride for ethyl chloroformate. 1H NMR (300 MHz, CDCl3) δ 8.65 (d, 1H), 8.35 (d, 1H), 8.27 (m, 2H), 7.70 (m, 2H), 7.60 (s, 1H), 7.52 (m, 1H), 7.28 (m, 2H), 7.02 (d, 1H), 5.10 (d, 1H), 4.07 (m, 1H), 3.58 (m, 1H), 3.23 (m, 1H), 2.90 (m, 1H), 2.50 (m, 1H), 2.14 (m, 2H), 1.57 (m, 4H), 1.21 (m, 1H), 1.04 (m, 1H), 0.89 (t, 3H); LC/MS m/z 494 (M+H)+.