Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:17])[C:9]2[N:10]=[CH:11][N:12]3[CH:16]=[CH:15][S:14][C:13]=23)[CH:5]=[N:6][CH:7]=1.C(B(CC)[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)C.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.[O-2].[O-2].[Mn+4].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:6]1[CH:5]=[C:4]([C:8]([C:9]2[N:10]=[CH:11][N:12]3[CH:16]=[CH:15][S:14][C:13]=23)=[O:17])[CH:3]=[C:2]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:7]=1
Reactant: CCB(CC)c1cccnc1
Reactant: OC(c1cncc(Br)c1)c1ncn2ccsc12
Agent: [Mn+4]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cncc(-c2cccnc2)c1)c1ncn2ccsc12
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 34.9 %

Procedure:
A ketone compound (1.96 g) was prepared in substantially the same manner as in step b) of Synthesis Example 1, except that 2.77 g of 7-[(5-bromopyridin-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole and 2.00 g of manganese dioxide were used as the starting compounds. The ketone compound (616 mg) was dissolved in 20 ml of N,N-dimethylformamide to prepare a solution. Diethyl(3-pyridyl)borane (588 mg), 232 mg of tetrakis(triphenylphosphine)palladium(0), and 552 mg of potassium carbonate were added to the solution at room temperature under an argon atmosphere. The mixture was stirred at 90° C. for 2.5 hr. Ethyl acetate (200 ml) was added to the reaction solution, and the organic layer was washed four times with 80 ml of water and once with saturated brine. The washed organic layer was dried over anhydrous magnesium sulfate and was filtered. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel (chloroform/methanol=20/1 →10/1) to give 428 mg of 7-([3,3′]bipyridinyl-5-yl)carbonylimidazo[5,1-b]thiazole.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:20]I>O1CCCC1.O>[CH3:20][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][CH2:3]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCNc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(C(=O)OC(C)(C)C)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl 3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Reference Example 28 (1.06 g) in tetrahydrofuran (20 ml), sodium hydride (60% suspension in oil, 181 mg) was added and stirred for 5 minutes, followed by addition of methyl iodide (281 μl). After stirring at room temperature for 1 hour, sodium hydride (60% suspension in oil, 181 mg) was further added and stirred for 30 minutes, followed by addition of methyl iodide (281 μl). After stirring overnight at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=10:1 to 5:1) to give tert-butyl 4-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (331 mg) as a brown powder. To a solution of tert-butyl 4-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate thus obtained (331 mg) in ethyl acetate (2 ml), 4N hydrochloric acid (in ethyl acetate, 1.1 ml) was added and stirred overnight at room temperature. The reaction mixture was diluted with 8M aqueous sodium hydroxide and then extracted with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to give the titled compound, i.e., 1-methyl-1,2,3,4-tetrahydroquinoxaline (179 mg) as a brown oil.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[N:8]2)=[C:4]([NH2:22])[N:3]=1.C1C(=O)N([Cl:30])C(=O)C1>CN(C=O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[CH:13]=[C:14]([O:20][CH3:21])[C:15]([O:18][CH3:19])=[CH:16][C:17]=3[Cl:30])=[N:8]2)=[C:4]([NH2:22])[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC

Procedure:
A solution of 2-Fluoro-8-(3,4-dimethoxy-benzyl)adenine (40 mg, 0.132 mmol), NCS (77.8 mg, 0.58 mmol) in anhydrous DMF (0.7 mL) was stirred at room temperature for 5.5 h. Following solvent removal, the product (22 mg, 49.4%) was collected through silica gel column purification (CHCl3:EtOAc at 8:2 to 4:6). MS m/z 338.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:18]2[NH:26][C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=2)=[CH:12]/[CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>[Pd].CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:18]2[NH:26][C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=2)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(/C(=C/C2CCCO2)c2cc3cccnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCO2)c2cc3cccnc3[nH]2)cc1
Temperature: 50 °C
Yield: 25.3 %

Procedure:
A mixture of (Z)-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 70, 60 mg, 0.16 mmol) and 10% palladium on activated carbon (18 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 16 h. The mixture was cooled to 25° C., the catalyst filtered off, washed with ethyl acetate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (15 mg, 24%) as a mixture of stereoisomers: LC/MS m/e calcd for C20H22N2O3S [M+H]+ 371.47, observed 371.3; 1H NMR (400 MHz, CD3OD) δ ppm 8.12 (d, J=3.8 Hz, 1H), 7.90-8.00 (m, 3H), 7.62-7.67 (m, 2H), 7.06-7.11 (m, 1H), 6.43-6.48 (m, 1H), 4.50-4.61 (m, 2H), 3.83-3.97 (m, 1H), 3.65-3.78 (m, 2H), 3.11-3.19 (m, 3H), 2.43-2.55 (m, 1H), 2.21-2.36 (m, 1H), 1.85-2.11 (m, 3H), 1.57-1.67 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C@@H:11]2[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[C:14]=3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[CH2:4][CH2:3]1.O.[C:22]([OH:30])(=[O:29])[CH:23]([CH2:25][C:26]([OH:28])=[O:27])[OH:24]>>[CH3:1][N:2]1[C@@H:11]2[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[C:14]=3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[CH2:4][CH2:3]1.[C:22]([O-:30])(=[O:29])[CH:23]([CH2:25][C:26]([O-:28])=[O:27])[OH:24].[CH3:1][N:2]1[C@@H:11]2[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[C:14]=3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[CH2:4][CH2:3]1
Reactant: O=C(O)CC(O)C(=O)O
Agent: CN1CCc2cccc3c2[C@H]1Cc1ccc(O)c(O)c1-3
Solvent: O
Product: O=C([O-])CC(O)C(=O)[O-]

Procedure:
Apomorphine malate solution was prepared by dissolving apomorphine base in 0.1M Malic acid solution. Water was added to obtain solutions with a molar ratio of 1:1 apomorphine:malic acid, at a concentration of 2% apomorphine. The pH of each solution was 4.0. Table 5 shows the composition of each apomorphine organic salt solution.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.N1C=CN=N1.[C@@H:14]1(N2C=CC(=O)NC2=O)[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]1[OH:16].[C@@H]1(N2C3N=CN=C(O)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O.[C@@H]1(N2C=CC(N)=NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O.[C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O.P([O-])(O)(O)=O.[K+]>>[CH:5]1[N:1]([C@@H:14]2[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]2[OH:16])[N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: NC(=O)c1nc[nH]n1
Agent: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1

Procedure:
By using a substrate solution (pH 6.0) containing 40 mM 1,2,4-triazole-3-carboxamide (hereinafter called "triazole") as the base donor, 40 mM uridine, inosine, cytidine, adenosine or guanosine as the saccharide residue donor and 40 mM potassium dihydrogenphosphate, ribavirin was produced in the same manner as in Example 1. The results are shown in Table 7.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[N:8][C:9]([N:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)=[N:10][CH:11]=2)=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[OH:18][CH:15]1[CH2:14][CH2:13][N:12]([C:9]2[N:8]=[CH:7][C:6]([C:5]3[N:4]=[N:3][N:2]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:1]=3)=[CH:11][N:10]=2)[CH2:17][CH2:16]1
Reactant: CCOC(=O)CBr
Reactant: OC1CCN(c2ncc(-c3nnn[nH]3)cn2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(O)CC3)nc2)n1
Temperature: 80 °C

Procedure:
A mixture of 1-[5-(1H-tetrazol-5-yl)pyrimidin-2-yl]piperidin-4-ol (550 mg, 2.224 mmol), triethylamine (0.62 mL, 4.45 mmol), ethyl bromoacetate (371 μL, 3.34 mmol) in THF (77.4 mL) was heated at 80° C. for 1 h. The solvent was evaporated, diluted with water (5 mL) and slurried with Et2O (5 mL). The mixture was filtered and washed with water followed by Et2O. The solid was dried under high vacuum to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9](=[O:12])[NH:10][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]2[N:4]([C:9](=[O:12])[N:10]([CH2:14][C:15]3[C:16]([CH3:25])=[N:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]nc2c(Br)c(Cl)ccn12
Reactant: Cc1nc(C(F)(F)F)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(Cl)ccn2c1=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
To a solution of 8-bromo-7-chloro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (456 mg, 2.0 mmol) in anhydrous DMF (7 mL) was added 3-(chloromethyl)-2-methyl-6-(trifluoromethyl)pyridine (627 mg, 3.0 mmol), followed by anhydrous potassium carbonate (415 mg, 3.0 mmol). The resulting suspension was stirred under argon at 80° C. for 1.5 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc (30 mL×2). The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried over Na2SO4, and evaporated under reduced pressure to provide crude product as a brown solid. The crude product was purified using a silica gel cartridge (40 g) eluted with a gradient of EtOAc (0-60%) in hexanes to afford the title compound as an off-white solid (733 mg, 87%). HPLC/MS: retention time=3.36 min, [M+H]+=420.1.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:9]2[O:10][CH2:11][C@@H:12]([O:13]S(C)(=O)=O)[C@H:8]2[O:7][C@H:4]1[O:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][C:45](O)=[C:46]([O:49][CH3:50])[CH:47]=3)[N:42]=[CH:41][N:40]=2)=[CH:34][C:33]=1[Cl:52]>CN(C=O)C.C(OCC)(=O)C>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][C:45]([O:13][C@H:12]4[CH2:11][O:10][C@@H:9]5[C@@H:3]([O:2][CH3:1])[C@@H:4]([O:7][C@H:8]45)[O:5][CH3:6])=[C:46]([O:49][CH3:50])[CH:47]=3)[N:42]=[CH:41][N:40]=2)=[CH:34][C:33]=1[Cl:52]
Reactant: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2OS(C)(=O)=O)[C@H]1OC
Reactant: COc1cc2c(Nc3ccc(Br)c(Cl)c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(Br)c(Cl)c3)ncnc2cc1O[C@H]1CO[C@@H]2[C@@H](OC)[C@H](OC)O[C@@H]21
Temperature: 135 °C
Yield: 28 %

Procedure:
Methyl 3,6-anhydro-2-O-methyl-5-O-(methylsulfonyl)-β-D-glucofuranoside (314 mg, 1.1 mmol) was dissolved in DMF (3 mL). To this solution was added potassium carbonate (404 mg, 2.9 mmol) and 4-[(4-bromo-3-chlorophenyl)amino]-6-methyloxy-7-hydroxyquinazoline trifluoroacetate (280 mg, 0.59 mmol). The resulting mixture was heated at 135° C. for 18 h. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (15 mL), washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 2-7% methanol in 1:1 ethyl acetate:hexanes) to give methyl 3,6-anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-O-methyl-α-L-idofuranoside as a white solid, 181 mg, 28% yield. 1H NMR (400 MHz; Methanol-d4): 8.75 (s, 1H), 8.04-8.06 (d, 1H), 7.99 (s, 1H), 7.78-7.75 (d, 1H), 7.64-7.61 (d, 1H), 7.35 (s, 1H), 5.16-5.14 (d, 1H), 5.02 (s, 1H), 4.89 (br, 1H), 4.69-4.68 (d, 1H) 4.46-4.42 (dd, 1H), 4.09 (br, 1H), 4.06 (s, 3H), 3.69 (s, 1H), 3.48 (s, 3H), 3.42 (s, 3H); MS (EI) for C23H23BrClN3O6: 551.88 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C:9]1[N:10]=[C:11]([NH2:13])[S:12][C:8]=1[CH2:7][CH2:6]2.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[C:21]=1[S:28]([NH:13][C:11]1[S:12][C:8]2[CH2:7][CH2:6][C:5]3[C:14](=[CH:15][C:16]([O:17][CH3:18])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[N:10]=1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: COc1cc2c(cc1OC)-c1nc(N)sc1CC2
Product: COc1cc2c(cc1OC)-c1nc(NS(=O)(=O)c3c(Cl)cc(Cl)cc3Cl)sc1CC2

Procedure:
The title compound was prepared from 7,8-dimethoxy-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-amine (100 mg, synthesized according to METHOD I from 6,7-dimethoxytetralone) and 2,4,6-trichlorobenzenesulfonyl chloride (213 mg) as described in the synthetic METHOD A to give a yellow powder (6.5 mg) with a purity of 86%: MS-ES (neg) m/z 505.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16]C)[CH:14]=2)[CH2:9][CH2:8][CH:7]1[N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.B(Br)(Br)Br>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][CH:6]1[C:15]2[CH:14]=[C:13]([OH:16])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[N:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N1CCCC1)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N1CCCC1)CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
1-(1-(3,4-Dichlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)pyrrolidine (1.6 g, 4.10 mmol) was dissolved in CH2Cl2 (100 ml) and BBr3 (1 molar in CH2Cl2, 12.3 ml, 12.3 mmol) was added at −10° C. It was stirred for 2 h after which time the temperature rose to room temperature. Ice water was added, the organic phase separated and the aqueous phase extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 and NaCl solution, dried over Na2SO4, and concentrated to afford a residue. The beige solid product (1.2 g, 78%) was obtained from precipitation in ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].CI.[H-].[Na+].[CH3:34]COC(C)=O>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([O:10][CH3:34])[CH2:7][N:6]1[C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@@H](OC)CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 26 h

Procedure:
Into a solution of 2 (5.71 g, 14.7 mmol) in anhydrous DMF (20 mL) and anhydrous THF (20 mL) was added MeI (3.67 mL, 58.9 mmol). The solution was cooled to 0° C. in an ice bath and NaH (0.766 g, 19.2 mmol) was added in one portion. The mixture was stirred at RT for 26 h before adding EtOAc and washing sequentially with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. Purification of the crude material by flash chromatography revealed 3 (4.67 g, 79%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[F:48][C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][NH:57][C:58](=[O:60])[CH3:59])=[C:51]([OH:61])[CH:50]=1>>[C:58]([NH:57][CH2:56][CH2:55][C:52]1[CH:53]=[CH:54][C:49]([F:48])=[CH:50][C:51]=1[O:61][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1)(=[O:60])[CH3:59]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(=O)NCCc1ccc(F)cc1O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2cc(F)ccc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.45 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.27 g of N-[2-(4-fluoro-2-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.63 (EtOAc); Rt=5.61.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][S:13]([OH:16])(=[O:15])=[O:14].C(OCC)(=[O:19])C>>[CH3:12][S:13]([OH:16])(=[O:15])=[O:14].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][OH:19])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: CS(=O)(=O)O
Product: Nc1ccc(CC(=O)OO)cc1
Yield: 98.5 %

Procedure:
The procedures of Example 8 were repeated, by substituting 3-amino-benzoic acid with 4-amino-phenyl-acetic acid (3 g: 0.0198 mole) and by using 19 g of CH3SO3H instead of 30 g, 2.2 g of H2O2 at 85% (0.055 mole) instead of 2.9 g, and ethyl acetate (300 moles) instead of THF. 5.2 g of crystalline and substantially pure 4-amino-phenyl-peracetic acid methanesulphonate were obtained. Yield: 98.5%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C@H:17]([NH:19][C@@H](C2C=CC=CC=2)C)[CH3:18])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CCO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C@H:17]([NH2:19])[CH3:18])[CH:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](Cc1cccc(CCNC(=O)OC(C)(C)C)c1)N[C@H](C)c1ccccc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: C[C@@H](N)Cc1cccc(CCNC(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A stirred solution of (2-{3-[(R)-2-((R)-1-phenylethylamino)propyl]phenyl}ethyl)carbamic acid tert-butyl ester (1.54 g, 4.02 mmol), palladium hydroxide on carbon (10 wt. %, ˜50% water, 2.24 g, 0.805 mmol), and ammonium formate (1.27 g, 20.1 mmol) in EtOH (50.0 mL) was heated gradually to 50° C. and then stirred at 50° C. for 1.5 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give the title compound, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:7][C:6]2([CH3:16])[CH3:15].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[NH:1]([C:2]1[CH:3]=[N:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:7][C:6]2([CH3:16])[CH3:15])[C:17]([CH3:18])=[O:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Nc2ccccc2-c2c(N)cnn21
Solvent: c1ccncc1
Product: CC(=O)Nc1cnn2c1-c1ccccc1NC2(C)C
Reaction time: 24 h
Yield: 82 %

Procedure:
16.1 g (0.075 mole) of 1-amino-5,5-dimethyl-5,6-dihydropyrazolo[1,5-c]quinazoline are dissolved in 100 ml of pyridine. 80 ml of acetic anhydride are added and the reaction mixture is left to stand at room temperature for 1 day. The crystals separated spontaneously are filtered off and the mother liquor is evaporated. The collected crystals are washed with water and dried. Thus, 16.7 g (82%) of 1-acetamino-5,5-dimethyl-5,6-dihydropyrazolo[1,5-c]quinazoline are obtained. M.p.: 228°-230° C.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:26][CH:25]([S:27][C:28]3[C@H:29]([CH3:52])[C@@H:30]4[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]4[C:32]=3[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[CH2:24]2)[S:21][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C@@H:10]([NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:24][CH:25]([S:27][C:28]3[C@H:29]([CH3:52])[C@@H:30]4[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]4[C:32]=3[C:33]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:34])[CH2:26]2)[S:21][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CO)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Yield: 55.3 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (640 mg, 0.827 mmol) (obtained as described in Example 42(1)) in tetrahydrofuran (32 ml) were added acetic acid (142 μl, 2.48mmol) and a solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran (2.48 ml, 2.48 mmol) in an ice bath and the mixture was stirred for 2 days at room temperature. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate and ethyl acetate:methanol (9:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-((1S)-1-hydroxymethyl-3-methylbutylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (302 mg, yield 55%) as a pale yellow solid.