Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH:20]([CH2:22][C:23]([O:25]CC)=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1.[OH-].[Na+]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH:20]([CH2:22][C:23]([OH:25])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1Cc2ccc(OCCCNc3ccccn3)cc2Cc2ccccc21
Reaction time: 28.5 h
Yield: 79.8 %

Procedure:
A mixture of ethyl (±)-10,11-dihydro-3-[3-(2-pyridylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (0.94 g, 2.18 mmole) and 1.0 N NaOH (2.6 mL, 2.62 mmole) in absolute EtOH (19.2 mL) is warmed in an oil bath set at 50° C. After 28.5 hr, the reaction was concentrated on the rotavap and the residue was purified by ODS chromatography (1:1 MeOH/H2O). Concentration left a cloudy, aqueous solution, which was made homogeneous by addition of a little 1.0 N NaOH. The pH was adjusted to 7 with 1.0 N HCl, and the solid precipitate was collected and washed with H2O. The mother liquors were concentrated, and the residue treated similarly to afford a small second crop. The combined materials were dried in high vacuum at 40° C. to afford the title compound (0.70g, 79%) as a nearly colorless solid: HPLC (Hamilton PRP-1®, 40% CH3CN/H2O containing 0.1% TFA) k′=1.2; 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=4.4 Hz, 1H), 7.32-7.41 (m, 1H), 7.03-7.22 (m, 4H), 6.97 (d, J=8.4 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 6.60-6.74 (m, 2H), 6.41-6.50 (m, 2H), 4.20 (d, J=14.7 Hz, 1H), 4.00 (t, J=6.2 Hz, 2H), 3.88 (d, J=14.7 Hz, 1H), 3.60-3.70 (m, 1H), 3.26-3.40 (m, 2H, partially obscured by residual solvent signal), 3.20 (dd, J=15.1, 4.3 Hz, 1H), 2.83 (dd, J=15.1, 10.3 Hz, 1H), 2.60 (dd, J=15.9, 5.3 Hz, 1H), 2.50 (dd, 1H, partially obscured by residual solvent signal), 1.88-2.00 (m, 2H); MS (ES) m/e 403 (M+H)+. Anal. Calcd for C25H26N2O3 .0.25 H2O: C, 73.78; H, 6.56; N, 6.88. Found: C, 73.85; H, 6.47; N, 6.75.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([NH:12][CH2:13][CH2:14][OH:15])[CH:9]=[C:8]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=O.C(N(CC)C(C)C)(C)C>C(#N)C>[OH:15][CH2:14][CH2:13][N:12]1[C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]=2[C:9]2[C:8]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[N:7][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:11][C:10]1=2
Reactant: O=C1CCCCC1Br
Reactant: OCCNc1cc(N2CCCC2)nc(N2CCCC2)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: OCCn1c2c(c3c(N4CCCC4)nc(N4CCCC4)nc31)CCCC2

Procedure:
A mixture of 2-[(2,6-di-(1-pyrrolidinyl)pyrimidin-4-yl)amino]ethanol (VI, Example1, 5.55 g), 2-bromocyclohexanone (3.54 g), N,N-diisopropylethylamine (2.65 g) and acetonitrile (60 mL) is heated at reflux for 44 hr. The reaction mixture is cooled to 20°-25° and concentrated under reduced pressure. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered, and concentrated. Chromatography (silica gel, 2.5% acetone/chloroform) gives the title compound, NMR (CDCl3) 7.64, 4.05, 3.91, 3.67, 3.55, 2.72, 2.56, 2.0-1.7 δ; MS (m/z) calc'd=355.2372, found=355.2368.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 31.1 %

Procedure:
Following general procedure D, (S)-tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.17 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (75 mg, 0.26 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (29 mg, 31% over 2 steps) as a light orange solid: 1H NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.25-8.19 (m, 2H), 8.11 (br s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.65 (dd, J=9.1, 2.8 Hz, 1H), 7.32 (s, 2H), 7.7 (d, J=9.1 Hz, 1H), 4.53 (br s, 1H), 4.00 (dt, J=12.8, 4.0 Hz, 1H), 3.39-3.23 (m, 3H), 2.86 (br s, 1H), 2.22-2.12 (m, 1H), 1.98-1.88 (m, 1H), 1.78-1.64 (m, 2H), 1.26-1.16 (m, 4H). ESI MS m/z 548 [C29H27Cl2N5O2+H]+; HPLC>99.0% (AUC), tR=10.97 min.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12]([NH:14][C@@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16]I)=[O:13])([CH3:10])([CH3:9])[CH3:8].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=1>CN(C=O)C>[C:7]([O:11][C:12]([NH:14][CH:15]([CH2:16][CH:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=1)[C:30](=[O:32])[CH3:31])[C:18]([O:20][CH3:21])=[O:19])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)[C@@H](CI)NC(=O)OC(C)(C)C
Reactant: CC(=O)Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC(C(C)=O)c1cccc(Cl)c1)NC(=O)OC(C)(C)C
Reaction time: 2.5 h

Procedure:
A mixture of cesium carbonate (9.80 g, 30.1 mmol) and methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (9.90 g, 30.1 mmol) in DMF (75 mL) was stirred at 23° C. for 45 min before 1-(3-chlorophenyl)propan-2-one (6.09 g, 36.1 mmol) and additional cesium carbonate (9.80 g, 30.1 mmol) were added. The resulting mixture was stirred for 2.5 h. The majority of the DMF was then removed under reduced pressure at a bath temperature of <40° C. The concentrated mixture was partitioned between water (500 mL) and ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give the title compound as a 1:1 racemic mixture of diastereomers, which was used without further purification. MS: m/z=314.1 (M−t-Bu+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)(=O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:29]B(O)O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[NH4+].[Cl-].CC([O-])=O.CC([O-])=O.[Pd+2].O.C1(C)C=CC=CC=1>[CH3:18][O:17][C:12]1[C:11]2[C:16](=[C:7]([CH3:29])[CH:8]=[CH:9][CH:10]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc2c(OS(=O)(=O)C(F)(F)F)cccc12
Reactant: CB(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c(C)cccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
In a 500 mL 2-neck round bottom flask, toluene (300 mL) and deionized water (14 mL) were added and degassed under nitrogen for 20 minutes. Then, 5-methoxynaphthalen-1-yl trifluoromethanesulfonate (above Step-2 intermediate) (14 g, 45.75 mmol) was added to the above mixture. After stirring for 10 min at RT, K3PO4 (34 g, 160 mmol) and methylboronic acid (4.1 g, 68.6 mmol) were added followed by Pd(OAc)2 (1.03 g, 4.6 mmol) and BINAP (5.7 g, 9.15 mmol) and the reaction mixture was stirred at RT for 15 min under nitrogen and then heated to 100° C. overnight. It was cooled and diluted with saturated NH4Cl solution (150 mL). The aqueous layer was extracted with EtOAc (4×100 mL) and the combined organic layer was washed with water (100 mL), brine (100 mL), dried and filtered. After solvent removal, the crude product obtained was purified by column chromatography (5% EtOAc:Hexanes) to yield the desired compound (7 g, 87%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH3:19]>CN(C=O)C>[Br:1][C:2]1[C:9]([O:10][CH2:18][CH3:19])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CCBr
Reactant: O=Cc1cccc(O)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(C=O)c1Br
Temperature: 70 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
The suspension of 2-bromo-3-hydroxybenzaldehyde (120 g, 0.60 mol), K2CO3 (247 g, 1.79 mol) and bromoethane (135 mL, 1.79 mol) in DMF (700 mL) was stirred at 70° C. for 3 h. After the reaction was quenched with water (50 mL), the resulting mixture was extracted with EtOAc (3×60 mL). The combined organic layers were washed with water (50 mL) and aqueous LiCl solution (50 mL), dried over anhydrous Na2SO4 and concentrated to dryness in vacuo. The residue was purified by column chromatography on silica gel to give the target compound (128 g, yield 94%). 1H NMR (400 MHz, DMSO-d6 δ 10.45 (s, 1H), 7.52-7.50 (d, 1H), 7.38-7.34 (t, 1H), 7.13-7.10 (d, 1H), 4.18-4.13 (m, 2H), 1.53-1.50 (m, 3H).
Reaction SMILES: [H-].[Na+].O[CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11]S(C2C=CC(C)=CC=2)(=O)=O)[N:6]1C(OC(C)(C)C)=O.[NH4+].[Cl-:30].Cl>CN(C)C=O.O1CCOCC1.O>[ClH:30].[CH:7]12[NH:6][CH:5]([CH2:9][CH2:8]1)[CH2:4][O:11][CH2:10]2
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(CO)N2C(=O)OC(C)(C)C)cc1
Reactant: [Cl-]
Agent: Cl
Agent: [H-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: C1CC2COCC1N2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil) (0.284 g, 7.10 mmol) in N,N-Dimethylformamide (5 mL), cooled in an ice bath under argon, was added dropwise a solution of 1,1-dimethylethyl 2-(hydroxymethyl)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarboxylate (Intermediate 26, 2.28 g, 5.91 mmol) in N,N-Dimethylformamide (10 mL). The reaction was allowed to warm to room temperature and stirred for 5 hours. The reaction was cooled in an ice-water bath before the addition of sat. NH4Cl (30 mL) and water (30 mL). The mixture was extracted with diethyl ether (3×60 mL). The ether layers were combined, washed with water:brine (1:1, 2×60 mL), passed through a hydrophobic frit and the solvent removed to yield a colourless gum, which was dried under vacuum for 18 hours to yield a white solid. The crude intermediate was dissolved in 1,4-Dioxane (5 mL) before the addition of HCl (4M in 1,4-dioxane) (14.8 mL, 59.1 mmol). The reaction was stirred at room temperature for 3 hours then the solvent was removed under vacuum to yield the title compound as a white solid (904 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:11][CH2:10][C:9]2=[O:26])[CH2:4][CH2:3]1.[N+:27]([O-])([O-:29])=[O:28].[K+].C(Cl)Cl>S(=O)(=O)(O)O>[N+:27]([C:17]1[CH:16]=[CH:15][C:14]2[N:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[C:9](=[O:26])[CH2:10][N:11]=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:13]=2[CH:18]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])[O-]
Reactant: CN1CCC(N2C(=O)CN=C(c3ccccc3F)c3ccccc32)CC1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: CN1CCC(N2C(=O)CN=C(c3ccccc3F)c3cc([N+](=O)[O-])ccc32)CC1
Temperature: -8 °C
Reaction time: 6 h
Yield: 24.3 %

Procedure:
To conc. sulfuric acid (10 ml) is added 1-(1-methyl-4-piperidinyl)-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzdiazepin-2-one (2.09 g; 5.95 m mol) under cooling at temperature of -8° C. A solution of potassium nitrate (571 mg, 5.95×0.95 m mol) in conc. sulfuric acid (5 ml) is dropwise added to the mixture at the same temperature, which is allowed to stand at -5° C. over a period of 6 hours and then at room temperature over a period of 15 hours. The reaction mixture is poured onto ice (200 g), neutralized with conc. aqueous ammoniac solution, and shaken with methylene chloride. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a column of alumina, which is eluted with ethyl acetate. The eluate is concentrated in vacuo and the residue is crystallized from methylene chloride-ether to give 7-nitro-1-(1-methyl-4-piperidinyl)-1,3-dihydro-5-(2 -fluorophenyl)-2H-1,4-benzdiazepin-2-one (544 mg) as crystals melting at 199° to 201° C. (dec.). The yield is 23%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C@H:12]1[O:16][C:15](=[O:17])[C@H:14]([CH2:18][CH3:19])[CH2:13]1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]([O:11][S:28]([CH3:27])(=[O:30])=[O:29])[C@@H:12]1[CH2:13][C@@H:14]([CH2:18][CH3:19])[C:15](=[O:17])[O:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H]1C[C@@H]([C@H](O)COCc2ccccc2)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC[C@@H]1C[C@@H]([C@@H](COCc2ccccc2)OS(C)(=O)=O)OC1=O
Reaction time: 3 h
Yield: 96.2 %

Procedure:
A solution of 25.0 g of (3R,5S)-5-[(R)-2-benzyloxy-1-hydroxyethyl]-3-ethyldihydrofuran-2-one obtained in Example (106c) (94.7 mmol) in methylene chloride (600 ml) was cooled in an ice bath. Then, 28.7 g of triethylamine (284 mmol) and 15.9 g of methanesulfonyl chloride (139 mmol) were added thereto, and the mixture was stirred at the same temperature for three hours. 500 ml of water was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=4/1-1/1) to obtain 31.2 g of the title compound (yield: 96%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[NH:15]1[CH2:21][CH2:20][CH2:19][C@H:16]1[CH2:17][OH:18].C(N(C(C)C)CC)(C)C.CN1CCCC1=O>O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:21][CH2:20][CH2:19][CH:16]2[CH2:17][OH:18])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: OC[C@@H]1CCCN1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(N2CCCC2CO)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 13 h
Yield: 998.4 %

Procedure:
A mixture of 4-chloro-2-nitrobenzoic acid methyl ester 100 mg, prolinol 56 mg, diisopropylethylamine 90 mg and 1-methyl-2-pyrrolidinone 3 ml is stirred at 100° C. for 13 hours. Ethyl acetate and water are added to the mixture, and the organic layer is washed with water (twice) and brine, and dried over sodium sulfate. After removal of the sodium sulfate, the filtrate is concentrated in vacuo, and the residue is purified with column chromatography (silica gel 100 g, solvent; hexane:ethyl acetate=4:1→2:1→1:1→100% ethyl acetate) to give 4-(2-hydroxymethyl-1-pyrrolidinyl)-2-nitrobenzoic acid methyl ester 1.298 g as a pale yellow viscosity oil. MS(m/z): 285(M+H)+
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[S:6]1[C:10]2[C:11]3[CH:17]=[N:16][NH:15][C:12]=3[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:18].S(=O)(=O)(O)O>>[N+:1]([C:14]1[C:9]2[N:8]=[C:7]([NH2:18])[S:6][C:10]=2[C:11]2[CH:17]=[N:16][NH:15][C:12]=2[CH:13]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1nc2ccc3[nH]ncc3c2s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1nc2c([N+](=O)[O-])cc3[nH]ncc3c2s1
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
Under ice-cooling, 184 mg (2.17 mmol) of sodium nitrate was added to a mixture of 191 mg (1.01 mmol) of 6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-ylamine and 3 ml of concentrated sulfuric acid, and the mixture was stirred for 0.5 hours. The reaction mixture was poured onto ice, and the precipitated solid was collected by filtration, and then washed with water and methanol to give 160 mg (yield: 68%) of 4-nitro-6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-ylamine.
Reaction SMILES: OCC1C(O)C(O)C(O)[CH:5]([O:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH:18]=CC2C=CC(OC)=CC=2)O1.C[OH:29]>[Pd]>[CH3:5][O:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[CH:18]=[O:29]
Reactant: COc1ccc(C=Cc2sccc2OC2OC(CO)C(O)C(O)C2O)cc1
Reactant: CO
Agent: [Pd]
Product: COc1ccsc1C=O
Reaction time: 18 h

Procedure:
50 mg of 2-hydroxymethyl-6-{2-[2-(4-methoxy-phenyl)-vinyl]-thiophen-3-yloxy}-tetrahydro-pyran-3,4,5-triol were dissolved in 10 ml of methanol. 20 mg of palladium on activated carbon were added and the solution was stirred under a hydrogen atmosphere for 18 h. The catalyst was filtered off and washed with 60 ml of methanol, and the organic phase was concentrated. The residue was chromatographed on silica gel (ethyl acetate). 18 mg of the product with the molecular weight of 396.46 (C19H24O7S); MS (ESI): 419.05 (M+Na+), 414.10 (M+NH4+).
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:6][C@@H:7]1[C:12](=O)[O:11][C:9](=[O:10])[CH2:8]1)(=[O:5])[CH3:4].O>O1CCCC1>[O:10]=[C:9]1[O:11][CH2:12][C@@H:7]([NH:6][C:3](=[O:5])[CH3:4])[CH2:8]1
Reactant: CC(=O)N[C@H]1CC(=O)OC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N[C@@H]1COC(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
To a stirred suspension of sodium borohydride (1.264 g, 33.41 mmol) in tetrahydrofuran (100 mL), N-acetyl-L-aspartic anhydride (5.0 g, 31.82 mmol, prepared as described in example A) was added in five portions at 0° C. over 1 h. The white suspension was warmed to room temperature, stirred for 3 h and cooled again to 0° C. Cold water (˜50 mL) was slowly added to the stirred mixture while the temperature was allowed to reach 15° C. After stirring overnight at room temperature, tetrahydrofuran was evaporated in vacuo. The residual aqueous solution was diluted with water to a volume of 100 mL and passed through a Dowex 50X8 ion exchange column (100 g). The ion exchange column was rinsed with water (3×100 mL). The resulting aqueous solution was concentrated in vacuo and the residue was taken up in a mixture of toluene (30 mL) and methanol (70 mL). The solvent was evaporated in vacuo. This procedure was repeated, i.e. the residue was taken up in toluene-methanol and concentrated again another three times. The remaining colorless oil (5.4 g) which consisted of a mixture of hydroxy-acid and lactone was dissolved in acetic acid (54 mL). Toluene (54 mL) was added and the solution was stirred at 110° C. for 2.5 h. After this time, all hydroxy-acid was cyclized to the desired lactone according to GC analysis of a reaction sample which had been concentrated and silylated. The reaction mixture was concentrated in vacuo. Three times the residue was taken up in toluene and concentrated again to give the crude product (4.2 g) as a white solid. For purification, the crude product was dissolved in acetonitrile (30 mL). Toluene (60 mL) was added to the solution and acetonitrile was partly removed from the mixture in vacuo, until the product started to crystallize. The product was collected by filtration, washed with toluene and tert-butyl methyl ether and dried in vacuo to afford (S)-N-(5-oxo-tetrahydro-furan-3-yl)-acetamide (3.8 g, 83% based on N-acetyl-L-aspartic anhydride) as white crystals. The structure of the compound was confirmed by 1H-NMR, MS, IR. and elemental analysis.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])[S:10][C:9]=12)=[O:2].[Na+].[C:29]([O:35][CH2:36]I)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.ClCCl>[CH:1]([NH:3][CH2:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O:20][CH2:36][O:35][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:19])[S:10][C:9]=12)=[O:2]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(CNC=O)c4s3)[C@H](C)[C@H]12
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3cn4cnc(CNC=O)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 33 mg of sodium (1S,5R,6S)-2-(7-formylaminomethyl imidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 0.8 ml of DMF was added 29 mg of pivaloyloxymethyl iodide at −30° C., and the mixture was stirred for 1 hour during which the temperature was raised up to room temperature. The reaction mixture was diluted with 30 ml of dichloromethane, washed with semi-saturated aqueous saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue thus obtained was purified by column chromatography on silica gel (ethyl acetate:methanol=4:1) to give the title compound in a yield of 29 mg.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][CH:34]=[CH:35][CH:36]=2)=[CH:28][C:8]=1[C:9]([NH:11][C:12]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15])=[O:10])(=O)C.Cl>O1CCOCC1>[O:33]1[CH:34]=[CH:35][CH:36]=[C:32]1[C:29]1[CH:30]=[CH:31][C:7]([OH:6])=[C:8]([CH:28]=1)[C:9]([NH:11][C:12]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][C:13]=1[C:14]([OH:16])=[O:15])=[O:10]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccco2)ccc1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(-c2ccco2)ccc1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.1 %

Procedure:
Dioxane (2 mL) and a 2 mol/L aqueous solution of sodium hydroxide (0.79 mL) were added to the obtained methyl 2-(2-acetoxy-5-(furan-2-yl)benzamido)-4-phenylbenzoate (0.072 g), followed by stirring at room temperature for 6 hours. The reaction mixture was adjusted to a pH of 1.5 with 2 mol/L hydrochloric acid, and the solid substance was collected by filtration to obtain 0.055 g of 2-(5-(furan-2-yl)-2-hydroxybenzamido)-4-phenylbenzoic acid as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH:6]=[CH2:7].[CH3:17][C:18]1[CH:27]=[C:26]([CH2:28][O:29][C:30]2[CH:38]=[CH:37][C:33]([CH:34]=[N:35][OH:36])=[CH:32][CH:31]=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>>[CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH:6]1[O:36][N:35]=[C:34]([C:33]2[CH:32]=[CH:31][C:30]([O:29][CH2:28][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[C:18]([CH3:17])[CH:27]=3)=[CH:38][CH:37]=2)[CH2:7]1
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)OC
Product: COC(=O)C(CC1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1)NC(=O)OC(C)(C)C
Yield: 65 %

Procedure:
Following a procedure analogous to that used in Example step 1c, but using the product from step 8b and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime from step 1b, the crude product was prepared and purified by FCC on silica gel eluting ethyl acetate:hexanes (gradient) to give 2-tert-butoxycarbonylamino-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid methyl ester (1.15 g, 65%) as an oil. MS found: (M+H)+=520.