Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:26][C:27]([O:29]CC2C=CC=CC=2)=[O:28])[CH2:18][CH2:17][CH2:16][N:15]([CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-])=O)=[CH:41][CH:40]=2)[CH2:14][CH2:13]1)=[O:10])C1C=CC=CC=1.CCOCC>C(O)C.[Pd]>[C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:26][C:27]([OH:29])=[O:28])[CH2:18][CH2:17][CH2:16][N:15]([CH2:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([NH2:45])=[CH:43][CH:44]=2)[CH2:14][CH2:13]1)([OH:10])=[O:8]
Reactant: O=C(CN1CCCN(CCc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)OCc2ccccc2)CCCNCC1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: Nc1ccc(CCN2CCCN(CC(=O)O)CCNCCCN(CC(=O)O)CC2)cc1
Yield: 98.4 %

Procedure:
To a solution of compound (16) (0.86 g, 1.33 mmol) in absolute ethanol (100 ml) was added 10% Pd/C (0.26 g). The resultant mixture was stirred at an ambient temperature under H2 atmosphere for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×20 ml). The solvent was evaporated from the combined filtrate in vacuo to give an oily residue, which was then treated with Et2O to obtain a white solid of compound (12) (0.57 g, 98% yield). 1H NMR (500 MHz, D2O): δ 7.45-7.43 (dd, 2H), 7.38-7.36 (dd, 2H), 3.49-3.12 (m, 18H), 2.82-2.62 (m, 6H), 1.91 (brs, 4H); 13C NMR (125 MHz, D2O): δ 177.0, 176.6, 163.4, 163.1, 162.8, 162.5, 137.4, 130.4, 128.9, 123.4, 119.9, 117.5, 115.2, 112.9, 56.0, 54.9, 54.4, 53.3, 51.6, 50.5, 48.8, 47.3, 45.0, 31.5, 27.6, 22.8, 21.3; FIRMS (FAB) calculated for C22H38N5O4: 436.2924 [(M+H)+], measured value: 436.2925 [(M+H)+].
Reaction SMILES: Cl[C:2]([F:8])([F:7])C(OC)=O.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16](O)=[CH:15][CH:14]=[CH:13]2.C(=O)([O-])[O-:22].[K+].[K+]>CN(C=O)C>[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([O:22][CH:2]([F:8])[F:7])[CH:14]=[CH:13]2
Reactant: Oc1cccc2cc(Br)ccc12
Reactant: COC(=O)C(F)(F)Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc2cc(Br)ccc2c1
Yield: 38 %

Procedure:
Methyl chlorodifluoroacetate (5.3 mL) was added dropwise to 6-bromonaphthol (10.25 g; 45.9 mmol) and potassium carbonate (7.61g; 55.1 mmol) at 90 C in 160 mL of DMF for 6 h. Purification by gel silica chromatography (3% EtOAc in hexane) gave 4.80 g (38%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=C[N:20](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CN(C=O)C>[C:14]([C:11]1([CH3:17])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)(=[O:15])[NH2:20]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(N)=O)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (2.85 g, 11.7 mmol) in DMF (57 mL) was added CDI (2.28 g, 14.1 mmol). The mixture was stirred at 60° C. for 30 minutes, then cooled to room temperature. Ammonium hydroxide (18.2 mL, 117 mmol) was added cautiously and stirring continued for 1 hour. The mixture was then evaporated to give a colourless oil. It was extracted with ethyl acetate and the organic layer washed with HCl (1 M), with water, sodium hydrogen carbonate solution, brine, dried over sodium sulfate, filtered and evaporated. The residue was taken up in toluene, then hexane was added and the mixture was stirred at room temperature for 15 minutes. The precipitate was filtered, washed with hexane and dried to give the title compound (2.55 g, 90%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28]O)[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][N:34]4[C:30](=[O:40])[C:31]5[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:33]4=[O:35])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethanol (prepared as described in Example 4/500 mg, 1.21 mmol), phthalimide (534 mg, 3.63 mmol) and triphenylphosphine were dissolved in a 1:1 mixture of THF and DMF (10 ml). Ditertbutyl azodicarboxylate (698 mg, 3.03 mmol) was added at 0° C. and mixture was stirred at room temperature for 4 hours. After evaporation, the crude mixture was purified by silica gel chromatography (6% methanol/CH2Cl2) to give the title compound (33% yield); NMR Spectrum: 4.09 (t, 2H), 4.50 (t, 2H), 5.31 (s, 2H), 7.31 (d, 1H), 7.38 (t, 1H), 7.60 (d, 1H), 7.77 (dd, 1H), 7.83-7.90 (m, 4H), 7.99 (s, 1H), 8.05 (d, 1H), 8.31 (s, 1H), 8.61 (d, 1H); Mass Spectrum: 542 (MH+).
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@@H:9]([O:10][C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C@H:15]([O:21][N+:22]([O-:24])=[O:23])[CH2:16][O:17][N+:18]([O-:20])=[O:19])[C@H:5]2[O:4][CH2:3]1.CCN(CC)CC.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:35]>C1COCC1>[N+:43]([C:40]1[CH:41]=[CH:42][C:37]([O:36][C:34]([O:1][C@H:2]2[C@H:6]3[O:7][CH2:8][C@@H:9]([O:10][C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C@H:15]([O:21][N+:22]([O-:24])=[O:23])[CH2:16][O:17][N+:18]([O-:20])=[O:19])[C@H:5]3[O:4][CH2:3]2)=[O:35])=[CH:38][CH:39]=1)([O-:45])=[O:44]
Reactant: O=C(CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a solution of (S)-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)5,6bis(nitrooxy)hexanoate (0.80 g, 2.18 mmol) and Et3N (0.66 g, 6.54 mmol) in THF (30 mL) was added 4-Nitrophenyl chloroformate (0.44 g, 2.18 mmol) as solid. After stirring at rt over night, the mixture was concentrated. The residue was diluted with EtOAc and washed with NaH2PO4 5%. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash chromatography (Biotage SP1; column SNAP 50; TLC method: n-hexane/ethyl acetate 1/1; Rf=0.38), affording the title product as a pale yellow oil. 1H-NMR (300 MHz, CDCl3); δ 8.32-8.29 (2H, m), 7.44-7.28 (2H, m), 5.33 (1H, m), 5.21-5.05 (2H, m), 4.89-4.65 (3H, m), 4.50 (1H, m), 4.20-3.95 (4H, m), 3.94-3.85 (1H, m), 2.50 (2H, m), 1.84 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][C:10]([OH:12])=[O:11])=[C:4]([F:13])[CH:3]=1.[CH:14](OCC)(OCC)OCC.[N-:24]=[N+:25]=[N-:26].[Na+]>CC(O)=O>[F:13][C:4]1[CH:3]=[C:2]([N:1]2[CH:14]=[N:26][N:25]=[N:24]2)[C:7]([F:8])=[CH:6][C:5]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: Nc1cc(F)c(CC(=O)O)cc1F
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)Cc1cc(F)c(-n2cnnn2)cc1F
Temperature: 100 °C

Procedure:
A solution of (4-amino-2,5-difluorophenyl)acetic acid (380 mg, 2.0 mmol) and triethyl orthoformate (902 mg, 6.1 mmol) in HOAc (10 mL) was added sodium azide (158 mg, 2.44 mmol) and the mixture was heated to 100° C. for 3 hours. After the reaction was completed, the reaction mixture was cooled to ambient temperature. The solvent was removed under vacuum. The residue was dissolved in EtOAc, washed with water, dried over anhydrous sodium sulfate, and concentrated. The [2,5-difluoro-4-(1H-tetrazol-1-yl)phenyl]acetic acid was directly used in next step.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:49]=[CH:48][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:27]=[C:28]([N:32]5[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:34](=[O:47])[CH2:33]5)[CH:29]=[CH:30][CH:31]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:50]1([CH2:56][CH2:57][OH:58])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>>[CH:50]1([CH2:56][CH2:57][O:58][C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][C:13]4[N:14]([C:26]5[CH:27]=[C:28]([N:32]6[S:36](=[O:37])(=[O:38])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:34](=[O:47])[CH2:33]6)[CH:29]=[CH:30][CH:31]=5)[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=5[Cl:25])[N:17]=4)=[CH:48][CH:49]=3)=[CH:4][CH:3]=2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: OCCC1CCCCC1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)c2)S1(=O)=O
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCCC5CCCCC5)nn4)cc3)c2)S1(=O)=O

Procedure:
5-{3-[2-[4-(6-Chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (38 mg, 0.05 mmol) was treated as described in general procedure L using 2-cyclohexyl ethanol (35 μL, 0.25 mmol) to give 5-{3-[2-{4-[6-(2-cyclohexyl-ethoxy)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [N:1]([CH:4]1[C:30](=[O:31])[N:6]2[CH:7]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[C:8]([CH2:12][O:13][C:14](=[O:16])[CH3:15])([OH:11])[CH2:9][S:10][C@:5]12[S:32][CH3:33])=[N+:2]=[N-:3].CCN(CC)CC.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[N:1]([CH:4]1[C:30](=[O:31])[N:6]2[CH:7]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[C:8]([CH2:12][O:13][C:14](=[O:16])[CH3:15])([O:11][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:9][S:10][C@:5]12[S:32][CH3:33])=[N+:2]=[N-:3]
Reactant: CS[C@]12SCC(O)(COC(C)=O)C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N=[N+]=[N-]
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS[C@]12SCC(COC(C)=O)(OS(C)(=O)=O)C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N=[N+]=[N-]
Temperature: 0 °C
Yield: 68.3 %

Procedure:
To an ice-cold, stirring solution of p-nitrobenzyl 7-azido-6-methylthio-3-acetoxymethyl-3-hydroxy-cepham-4-carboxylate (2.72 g., 5.47 mMol) and Et3N (1.15 ml., 8.25 mMol) in anhydrous CH2Cl2 (20 ml.) is added dropwise a solution of methanesulfonyl chloride (0.51 ml., 6.56 mMol) in anhydrous CH2Cl2 (15 ml.). After stirring 15 more mins. in the cold, the solution is washed with H2O, 5% HCl, 5% NaHCO3, and brine, dried with MgSO4, filtered, and evaporated in vacuo. The residual oil is crystallized from CH2Cl2 --MeOh to afford p-nitrobenzyl 7-azido-6-methylthio-3-acetoxymethyl-3-methylsulfonyloxycepham-4-carboxylate (2.15 g.) as yellow crystals: mp 147° C.; ir (CHCl3) 4.72, 5.59, 5.71, 6.58 and 7.42μ; nmr (CDCl3)δ 2.17 (s, 3, COCH3), 2.20 (s, 3, SCH3), 3.00 (s, 3, SO2CH3), 3.22, 4.28 (ABq, 2, J=14Hz, SCH2, 4.67, 4.95 (ABq, 2, J=13Hz, CH2OAc), 4.88 (s, 1, H7), 5.20 (s, 1, H4), 5.35 (s, 2, CH2Ar), and 7.63, 8.25 (ABq, 4, J=9, ArH).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:39]12([C:45]3[C:46]([O:50][C:51]4[N:56]=[CH:55][C:54]([NH2:57])=[CH:53][CH:52]=4)=[CH:47][CH:48]=[CH:49][C:44]=3[O:43][CH2:42]1)[CH2:41][CH2:40]2>CN(C)C=O>[CH3:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:10])[C:11](=[O:13])[NH:57][C:54]1[CH:55]=[N:56][C:51]([O:50][C:46]2[C:45]3[C:39]4([CH2:42][O:43][C:44]=3[CH:49]=[CH:48][CH:47]=2)[CH2:41][CH2:40]4)=[CH:52][CH:53]=1
Reactant: Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
To a solution of N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalanine (80 mg, 0.393 mmol) in dry N,N-dimethylformamide (1.5 mL) DIPEA (0.096 mL, 0.551 mmol) and then HATU (150 mg, 0.393 mmol) were added and the reaction mixture was stirred for 15 minutes at room temperature This solution was added to a solution of 6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinamine (Intermediate 89, 40 mg) in dry N,N-dimethylformamide (0.5 ml) and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with water (2 ml), diluted with brine (10 ml) and extracted with ethyl acetate (2×20 ml). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 1:1 as eluents affording the title compound as a white solid (52 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH3:28][O:29][CH:30]([C:34]([NH:36][CH2:37][C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])=[O:35])[C:31](O)=[O:32]>>[CH2:13]([O:12][CH2:11][CH2:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:31](=[O:32])[CH:30]([O:29][CH3:28])[C:34]([NH:36][CH2:37][C:38]([F:43])([F:44])[C:39]([F:40])([F:42])[F:41])=[O:35])[C:3]2[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=2[C:5]2[CH:23]=[CH:22][CH:21]=[CH:20][C:6]1=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: COC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2-methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid, the title compound was prepared in the same manner as example 1c (99%). White solid. MS: m/e=606(M+H+).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[H][H].[O:12]([C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25]Br)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O.O>[O:12]([C:19]1[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH2:25][O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)=[CH:27][CH:28]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1ccccn1
Reactant: [H][H]
Reactant: BrCCOc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(Oc2ccc(OCCOc3ccccn3)cc2)cc1
Yield: 28.6 %

Procedure:
To a suspension of sodium hydride (132 mg, 3.3 mmol; 60% in oil) in dimethylformamide (5 ml), a solution of 2-hydroxypyridine (314 mg, 3.3 mmol) in dimethylformamide (3 ml) was dropwise added with stirring, and stirring was continued at room temperature until the generation of hydrogen gas ceased. To the resultant solution, there was dropwise added a solution of 2-(4-phenoxyphenoxy)ethyl bromide (879 mg, 3.0 mmol) in dimethylformamide (3 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water (70 ml) and extracted with toluene (25 ml) three times. The toluene layer was dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation. The residue was purified by silica gel column chromatography to give 2-[2-(4-phenoxyphenoxy)ethoxy]pyridine (264 mg) as white crystals. M.P., 94.2° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH2:12]O)=[CH:10][CH:9]=[CH:8][N:7]=1.CCN(C(C)C)C(C)C.S(Cl)(C)(=O)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]#[CH:38])=[CH:31][C:30]=1[C:39]([C:41]1[CH:46]=[CH:45][C:44]([CH:47]([CH3:49])[CH3:48])=[CH:43][CH:42]=1)=[O:40]>O1CCOCC1>[CH:47]([C:44]1[CH:43]=[CH:42][C:41]([C:39]([C:30]2[CH:31]=[C:32]([O:35][CH2:36][C:37]#[CH:38])[CH:33]=[CH:34][C:29]=2[NH:28][CH2:12][C:11]2[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:7][CH:8]=[CH:9][CH:10]=2)=[O:40])=[CH:46][CH:45]=1)([CH3:49])[CH3:48]
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: COCCOc1ncccc1CO
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C#CCOc1ccc(NCc2cccnc2OCCOC)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a solution of 400 mg (2.18 mmol) [2-(2-methoxy-ethoxy)-pyridin-3-yl]-methanol in 4 ml dioxane at r.t. is added 1.12 ml (6.55 mmol) Hünig's base followed by 170 μl (2.18 mmol) mesyl chloride and the mixture is stirred for 5 min. 641 mg (2.18 mmol) (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone is added to this mixture with the addition of 1 ml of dioxane. The reaction mixture is then heated to 100° C. and stirred overnight. The mixture is partitioned between ether/water and the organic layer is washed with brine, dried with Na2SO4, filtered and evaporated. Flash-chromatography (ethyl acetate/ether 1:1) yields a yellow oil
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:6]=2[C:5](=[O:27])[NH:4][C:3]1=[O:28].C(=O)([O-])[O-].[K+].[K+].[CH2:35](I)[CH2:36][CH2:37][CH3:38]>CN(C=O)C.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][N:7]3[C:6]4[C:5](=[O:27])[N:4]([CH2:35][CH2:36][CH2:37][CH3:38])[C:3](=[O:28])[N:2]([CH3:1])[C:10]=4[N:9]=[CH:8]3)=[CH:17][CH:16]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: CCCCI
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Yield: 21 %

Procedure:
A solution of 3-methyl-7-[4-(4-chlorobenzoyl)-benzyl]xanthine (612 mg), potassium carbonate (228 mg) and butyl iodide (430 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:1) and recrystallized from ethyl acetate to provide the title compound as colorless solid (147 mg).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:13]([O:26][C:27]([C:29]1[N:30]2[CH:33]([S:34][CH2:35][C:36]=1[CH:37]=[CH:38][O:39][S:40]([C:43]1[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=1)(=[O:42])=[O:41])[CH:32]([NH:50]C(OC(C)(C)C)=O)[C:31]2=[O:58])=[O:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[NH2:50][CH:32]1[C:31](=[O:58])[N:30]2[CH:33]1[S:34][CH2:35][C:36]([CH:37]=[CH:38][O:39][S:40]([C:43]1[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=1)(=[O:42])=[O:41])=[C:29]2[C:27]([O:26][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:28]
Reactant: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)cc1
Temperature: 35 °C
Reaction time: 0.75 h
Yield: 90.8 %

Procedure:
A solution of p-toluenesulphonic acid hydrate (3.49 g) in acetonitrile (25 cc) is added dropwise, in the course of 25 minutes, to a solution, at 35° C., of 2-benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (E-form) (6.1 g) in acetonitrile (75 cc). The mixture is stirred for 45 minutes at 35° C. and is then poured into a saturated sodium bicarbonate solution (500 cc). After 30 minutes' contact, with stirring, the mixture is extracted with ethyl acetate (500 cc) and the organic phase is washed with water (100 cc), dried over sodium sulphate, filtered and concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). 7-Amino-2-benzhydryloxycarbonyl-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (E-form) (4.7 g) is obtained in the form of a brown froth.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:8]=2[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+].O.Cl>CO.O1CCCC1>[O:15]=[C:11]1[C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[C:7]=2[CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)c1csc2c1CCCC2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1csc2c1CCCC2=O
Reaction time: 0.75 h
Yield: 95.8 %

Procedure:
To a mixture solution of 7-Oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (21.6 g) in methanol (50 mL) and tetrahydrofuran (50 mL) was added in several portions an aqueous solution of 2N sodium hydroxide (77 mL) on an ice bath. After the solution was stirred for 45 minutes and the pH of solution was adjusted to 2 with 2N hydrochloric acid water, the organic solvent was removed by evaporation. Water was added to the residue to suspend, the solid was collected by filtration, and washed with water and then with ethanol, and then was dried to provide the title compound (18.1 g).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([O:10]C)=O)=[C:6]([OH:12])[C:5]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:4]=2[S:3]1(=[O:19])=[O:18].[NH2:20][C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:7]([C:8]([NH:20][C:21]2[S:22][C:23]([CH3:26])=[CH:24][N:25]=2)=[O:10])=[C:6]([OH:12])[C:5]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:4]=2[S:3]1(=[O:19])=[O:18]
Reactant: COC(=O)C1=C(O)c2ccc(C)cc2S(=O)(=O)N1C
Reactant: Cc1cnc(N)s1
Solvent: Cc1ccccc1C
Product: Cc1ccc2c(c1)S(=O)(=O)N(C)C(C(=O)Nc1ncc(C)s1)=C2O
Yield: 84.8 %

Procedure:
2.83 gm (0.01 mol) of methyl 2,7-dimethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 1.25 gm (0.011 mol) of 2-amino-5-methyl-thiazole were reacted in xylene analogous to Example 8, and 3.1 gm (84% of theory) of 2,7-dimethyl-4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained