Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8].C(N(C(C)C)C(C)C)C.[N:60]([C@@H:63]([CH3:68])[C:64]([O:66][CH3:67])=[O:65])=[C:61]=[O:62].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C1COCC1>[CH3:68][C@H:63]([NH:60][C:61](=[O:62])[N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[C:64](=[O:65])[O:66][CH3:67]
Reactant: CCC(CC)N(CCNC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Reactant: COC(=O)[C@H](C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)N(CCN(C)C(=O)N[C@@H](C)C(=O)OC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a mixture of 250 mg of methyl 4-[2-(4-{[(2-{[3-({[2-(methylamino)ethyl](pentan-3-yl)amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 0.20 mL of N-ethyl-N-isopropylpropan-2-amine and 10 mL of THF under ice cooling was added 70 mg of methyl(S)-(−)-2-isocyanatopropionate, followed by stirring for 1 hour at the same temperature and then for 2 hours at room temperature. Ethyl acetate and an aqueous sodium hydrogen carbonate solution were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (10% methanol/chloroform), thereby obtaining 290 mg methyl 4-{2-[4-({[2-({3-[(4S)-4,7-dimethyl-3,6-dioxo-10-(pentan-3-yl)-2-oxa-5,7,10-triazaundecan-11-yl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.C(N(CC)CC)C.[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:13][C:7]1([CH3:12])[C:6]2[CH:14]=[C:2]([O:1][S:30]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=3[Cl:22])(=[O:32])=[O:31])[CH:3]=[CH:4][C:5]=2[NH:10][C:9](=[O:11])[O:8]1
Reactant: CC1(C)OC(=O)Nc2ccc(O)cc21
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OC(=O)Nc2ccc(OS(=O)(=O)c3cccc(Cl)c3Cl)cc21
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
To a stirred solution of 6-hydroxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (1.00 g, 5.17 mmol), prepared according to the procedure in example 69, in methylene chloride (25 mL) at 0° C. was added triethylamine (0.9 mL, 6.45 mmol). After 10 minutes, 2,3-dichlorobenzenesulfonyl chloride (1.27 g, 5.17 mmol) was added. The solution was stirred for one hour, then partitioned between ammonium chloride solution (sat.) and methylene chloride. The organic layer was dried over magnesium sulfate and concentrated. Trituration with ether gave (4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,3-dichlorobenzenesulfonate as a white solid (1.55 g, 75%). 1H NMR (DMSO-d6): δ 10.37 (s, 1H), 8.13 (dd, J=8.2, 1.6 Hz, 1H), 7.90 (dd, J=7.9, 1.5 Hz, 1H), 7.60 (t, J=8.05 Hz, 1H), 7.02 (dd, J=8.7, 2.6 Hz, 1H), 6.96 (d, J=2.7 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 1.48 (s, 6H). MS (ESI) m/z 400/402/404 ([M−H]−); Anal. calcd for C16H13Cl2NO5S: C, 47.78; H, 3.26; N, 3.48. Found: C, 47.14; H, 3.46; N, 3.49.
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[OH:4])[CH3:2].[C:27]([O:35][CH2:36]Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:4])[O:5][CH2:36][O:35][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:2]
Reactant: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C(OCCl)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCP(=O)(OCOC(=O)c1ccccc1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid (0.40 g, 0.97 mmol), chloromethyl benzoate (0.23 g, 1.36 mmol) and triethylamine (0.27 g) in 4 ml of DMF is stirred at RT for 4 days. The reaction mixture is poured into water and extracted with methylene chloride. The combined extracts are washed, dried, evaporated to dryness and purified by prep. TLC (eluting with 50% ethyl acetate/hexane) to yield benzoyloxymethyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate.
Reaction SMILES: [Na].[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].Br[CH:10]([OH:13])[CH2:11][CH3:12]>N>[OH:13][CH2:10][CH2:11][CH2:12][S:5][CH2:4][C@@H:3]([C:6]([OH:8])=[O:7])[NH2:2]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CCC(O)Br
Agent: N
Agent: [Na]
Product: N[C@@H](CSCCCO)C(=O)O
Yield: 190.1 %

Procedure:
The compound was prepared in a similar manner to that described by J. F. Carson, et al, J. Org. Chem., 1964, 29, 2203. To a solution of sodium (6.44 g, 0,281 mol) in liquid ammonia (300 mL) was added cysteine (15.0 g, 62.5 mmol) over a 30 minutes period until permanent discharge of blue. Bromopropanol (15,8 mL, 0.175 mol) was added dropwise over 1 hour. The ammonia was allowed to evaporate and the resulting solid was dissolved in 1M HCl and passed through a column of Dowex 50 (H+) (5×30 cm) eluting with 1N ammonium hydroxide. Lyopholyzation yielded 21.3 g of the title compound as a white solid. MS(CI) m/e 180 (M+H)+. 1H NMR (DMSO-d6, 300 MHz) δ1.70-2.00 (m, 3H), 2.70 (t, J=7.5 Hz, 2H), 3.00-3.21 (m, 3H), 3.58-3.84 (m, 3H), 3.93 (dd, 1H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[N:3]=[CH:2]1.N1C=CC(=O)N=C1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[S:28])[N:3]=[CH:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=c1nc[nH]c2ccccc12
Agent: O=c1cc[nH]cn1
Product: S=c1nc[nH]c2ccccc12

Procedure:
In the next step the carbonyl function of the 1H-quinazolin-4-one derivative, or the 1H-pyrimidin-4-one derivative with a condensed 5-membered heterocyclic ring structure is reacted further e.g. with phosphorous pentasulfide or Lawesson's reagent to yield the 1H-quinazolin-4-thion derivatives, or the 1H-pyrimidin-4-thion one derivatives with a condensed 5-membered heterocyclic ring structure.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1ccc(CBr)cc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(Cl)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-4-chlorobenzene (0.69 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.84 g, 62%).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:13]([O:14][Si](C(C)(C)C)(C)C)[C@@H:12]([CH2:22][O:23][Si](C(C)(C)C)(C)C)[O:11][C@H:10]1[N:31]1[C:40]2[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=2[N:33]=[C:32]1[NH:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[OH:55])=[CH:45][CH:44]=1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:63][C:64]([O:66][CH3:67])=[O:65]>CN(C)C=O>[CH3:67][O:66][C:64]([CH2:63][O:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[C:46]1[CH:45]=[CH:44][C:43]([CH2:42][NH:41][C:32]2[N:31]([C:40]3[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=3[N:33]=2)[C@@H:10]2[O:11][C@H:12]([CH2:22][OH:23])[C@@H:13]([OH:14])[C@H:9]2[OH:8])=[CH:48][CH:47]=1)=[O:65]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4ccccc4O)cc3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1-c1ccc(CNc2nc3c(N)ncnc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2′,3′,5′-tris-O-(tert-butyl-dimethylsilyl)-8-(2′-hydroxybiphenyl-4-ylmethylamino)-adenosine (0.313 g) in N,N-dimethylformamide (1.9 mL) was added potassium carbonate (0.080 g). Then methyl bromoacetate (0.048 mL) was added, and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was partitioned between diethyl ether (35 mL) and water (10 mL). The organic layer was washed successively with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue (0.337 g) was dissolved in methanol (1.7 mL). Ammonium fluoride (0.379 g) was added, and the resulting mixture was stirred at 60° C. for 19 hours. The reaction mixture was cooled to room temperature. Dichloromethane (10 mL) was added, and the insoluble material was filtered out. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (0.053 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[O:17][C:16]([C:18]([O:20]CC)=[O:19])=[CH:15][CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[OH-].Cl>C1COCC1.O>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[O:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
Ethyl 5-[3,5-bis(trifluoromethyl)phenyl]furan-2-carboxylate (61 mg, 0.17 mmol) and LiOH (9.4 mg, 0.22 mmol) were diluted with THF/H2O=1:1 (1.5 mL), and then stirred for 2 hrs at room temperature. The mixture was acidified with 1N HCl, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to yield the crude title compound as a white solid (30 mg, 54%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[C:36]2[C:43]([I:44])=[CH:42][NH:41][C:37]=2[N:38]=[CH:39][N:40]=1.[Si:45]([O:62][CH2:63][C@@H:64]1[CH2:68][C@@H:67](O)[CH2:66][N:65]1[C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])([C:58]([CH3:61])([CH3:60])[CH3:59])([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1COCC1.O.C(OCC)(=O)C>[Si:45]([O:62][CH2:63][C@@H:64]1[CH2:68][C@H:67]([N:41]2[C:37]3[N:38]=[CH:39][N:40]=[C:35]([Cl:34])[C:36]=3[C:43]([I:44])=[CH:42]2)[CH2:66][N:65]1[C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])([C:58]([CH3:60])([CH3:61])[CH3:59])([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](n2cc(I)c3c(Cl)ncnc32)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of triphenylphosphine (443 mg) in THF (25 ml) was cooled to 0° C., and DIAD (340 μl) was added thereto dropwise. The reaction mixture was stirred at 0° C. for 1 hour. 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (363 mg) and the (2S,4R)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-4-hydroxypyrrolidine-1-carboxylate (651.6 mg) obtained in Example 28 (Step 1) were added thereto, and stirred at room temperature overnight. Ethyl acetate and water were added to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow, amorphous substance (400 mg). m/z [M+H]+ 718.5
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[I-:24].[Na+]>[Cu]I>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[N:7][C:2]([I:24])=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: [I-]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Agent: [Cu]I
Agent: [Na+]
Product: Cc1ccc(N2CCN(C(=O)c3ccc(I)nc3)CC2)c(C)c1
Yield: 62.1 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (487 mg) described in Preparation Example 115, sodium iodide (389 mg) and copper(I) iodide (123 mg) and by the reaction and treatment in the same manner as in Preparation Example 154, the title compound (340.6 mg) was obtained.
Reaction SMILES: FC1C=CC2C(C3CCNCC3)=NOC=2C=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:28][CH:29]1[O:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1)(=O)=O>C(#N)C>[CH3:28][CH:29]1[O:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1
Reactant: CS(=O)(=O)OCC1COc2ccccc2O1
Agent: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1COc2ccccc2O1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 3.6 mmol), K2CO3 (2.45 g, 17.7 mmol), 2-methanesulfonyloxymethyl-1,4-benzodioxan (3.35 g, 13.7 mmole) in acetonitrile (100 ml) was heated at reflux for 12 hours. At the end of the reaction, the insolubles were filtered and rinsed with dichloromethane. The organic solution was concentrated. The crude oil was purified by flash chromatography on a silica gel column. The fractions containing the pure product were pooled and concentrated to a light yellow oil (3.94 g, 74%). Crystallization from ethanol and petroleum ether gave 2-[4-(6-fluoro-1,2-benzisoxazolyl)-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan as off-white crystals, 2.22 g, m.p.=86°-87° C.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]1>CN(C=O)C.C(N(CC)CC)C>[C:1]([NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
A solution of benzoic acid (0.123 g) in DMF (5 ml) was treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.231 g), HOBT (0.163 g) and triethylamine (0.56 ml) and stirred at room temperature for 1 h. A solution of 3-amino-1-N-Boc-piperidine (0.3 g) in DMF (1 ml) was then added and stirring continued for 18 h. The solution was concentrated under reduced pressure to give an oil which was partitioned between ethyl acetate and water. The separated organic extracts were washed with water, hydrochloric acid (2N), saturated sodium bicarbonate solution and brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (0.120 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]2[CH:9]=[CH:10][N:11]=[C:4]2[N:3]=1.C[Si](C)(C)N[Si](C)(C)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C(O[C@@H:32]1[O:54][C@H:53]([CH2:55][O:56][C:57](=[O:64])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C@@H:43]([O:44][C:45](=[O:52])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@H:33]1[O:34][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=O)C>ClCCCl.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]2[N:11]([C@@H:32]3[O:54][C@H:53]([CH2:55][O:56][C:57](=[O:64])[C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C@@H:43]([O:44][C:45](=[O:52])[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C@H:33]3[O:34][C:35](=[O:42])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:10]=[CH:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: Nc1nc2nccn2c(=O)[nH]1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: Nc1nc(=O)n2ccn([C@@H]3O[C@H](COC(=O)c4ccccc4)[C@@H](OC(=O)c4ccccc4)[C@H]3OC(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A mixture of dry 2-aminoimidazo[1,2-a]-s-triazin-4-one (V) 3.02 g, 0.020 mol), freshly distilled hexamethyldisilazane (15.0 mL), and a few crystals of ammonium sulfate (25 mg) was heated at reflux temperature for 15 h. with the exclusion of moisture. The clear, slightly brown solution was fractionated by distillation to remove excess of hexamethyldisilazane and the residual gum was presumed to be the bis(trimethylsilyl) derivative which was used without further prification. To a solution of the above trimethylsilyl derivative in anhydrous 1,2-dichloroethane (100 mL) was added 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (10.09 g, 0.02 mol) followed by stannic chloride (7.0 g, 0.027 mol). The reaction mixture was protected from moisture and stirred for 30 h. at ambient temperature. The brown reaction solution was then poured into 200 mL of chloroform, with efficient stirring and keeping the mixture basic at all times. The resulting emulsion was filtered through a Celite pad which was washed with chloroform (3×25 mL). The combined organic layer was washed with water (2×100 mL) before it was dried over anhydrous sodium sulfate. The solvent was evaporated to a light brown foam which was chromatographed on an open-bed, silica gel column (5×75 cm) prepacked in ethyl acetate and eluted with ethyl acetate-water-1-propanol (4:2:1, v/v, upper phase). The band containing the requisite product was collected and the solvent evaporated to leave 6.8 g (56.30%) of a light yellow, chromatographically homogeneous foam: [α]25D -32.0° (cl.O.Me2SO); UVλmax (pH 1) 233 nm (ε=45800), 268 (18800); UVλmax (pH 7) 235 nm (ε=39400), 263 sh (24700); UVλmax (pH 11) 234 nm (ε=42300), 260 sh (20600). Anal. (C31H25N5O8.0.5H2O, 604.57) C, H, N.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:67]=[N:68][N:69]([CH3:71])[CH:70]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[N:67]=[N:68][N:69]([CH3:71])[CH:70]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: Cn1cc(SCC2=C(C(=S)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)[C@H]3SC2)nn1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Solvent: O
Product: Cn1cc(SCC2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)nn1
Reaction time: 1 h
Yield: 27.5 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1-methyl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (708 mg: 0.683 mMol.) in a mixture of anisole (2 ml) and nitromethane (8 ml) is added dropwise a solution of aluminum chloride (727 mg: 5.47 mMol.) in anisole (2 ml) at -40° C., and the mixture is stirred for 1 hour at -30°--40° C. The reaction mixture is diluted with 1N-hydrochloric acid (5.5 ml) and water and washed with ethyl acetate. The aqueous layer is concentrated under reduced pressure to remove organic solvent and passed through a column of styrene-divinylbenzene copolymer adsorbent. The product is eluted with methanol-water (4:1) to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1-methyl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4carboxylic acid as pale yellow powder (96.3 mg). Yield: 27%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)(=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:2]3[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=3)=[CH:28][CH:29]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1N
Solvent: CC(=O)O
Product: Cc1cnc(Nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1N
Temperature: 70 °C

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.35 g, 2.4 mmol) and 4-(4-amino-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (0.80 g, 2.8 mmol) in acetic acid (20 mL) was heated at 70° C. for 1 d. After cooling to room temperature, the mixture was concentrated. The residue was taken in water (30 mL) and neutralized with 10% NaOH solution until pH˜10. The resulting aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the title compound used in the next step without purification. MS (ES+): m/z 399 (M+H)+.