Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:44])=O.CN(C)C=O>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C@@H:10]1[Cl:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cl[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 80.7 %

Procedure:
3.0 g (5.5 mmol) of 2,3,4,6-tetra-O-benzyl-D-glucopyranose were dissolved in 30 ml of anhydrous methylene chloride and the solution was stirred with 1.45 ml (2.11 g; 16.5 mmol) of oxalyl dichloride and 0.3 ml of dimethylformamide at room temperature. After one hour, the solution was concentrated under a high vacuum, the residue was taken up in 10 ml of methylene chloride and the mixture was filtered over about 10 g of silica gel. Renewed concentration gave 2.48 g (80%) of 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride as a colorless syrup. The crude product was taken up in 20 ml of anhydrous acetonitrile and the mixture was heated under reflux with 3.0 g (38 mmol) of potassium hydrogen fluoride (24 hours at 100° C., dried over P2O5) for 8 hours. It was possible to purify the crude product by column chromatography on silica gel (methylene chloride/ether, 20:1). Yield: 1.1 g (47%) of 2,3,4,6 -tetra-O-benzyl-α-D-glucopyranosyl fluoride.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH3:16])[CH:6]=1)(=O)C.[H-].[Na+].F[C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28].O>CN1CCCC1=O>[CH3:16][C:12]1[N:11]([C:7]2[CH:6]=[C:5]([NH:4][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[N+:27]([O-:29])=[O:28])[CH:10]=[CH:9][CH:8]=2)[CH:15]=[CH:14][N:13]=1
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Reactant: CC(=O)Nc1cccc(-n2ccnc2C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nccn1-c1cccc(Nc2ccc(I)cc2[N+](=O)[O-])c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a solution of 2j from Example 5 (2 g, 9.3 mmol) in dry N-methyl-2-pyrrolidone (20 ml) is added sodium hydride (0.37 g of a 60% dispersion in mineral oil) in portions at 0° C. under nitrogen. The mixture is stirred for 1 hour, the last 30 min. at room-temperature. 1c from Example 1 (2.67 g, 10 mmol) is added and the temperature is raised to 40-50° C. over night. After cooling the mixture is poured into water (100 ml) and extracted with dichloromethane. The organic phase is extracted with 4M hydrochloric acid. The acidic extract is cooled in ice, rendered alkaline by addition of sodium hydroxide (12M) and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is extracted with a mixture of dichloromethane and diethyl ether (1:1). This extract is concentrated under reduced pressure and the residue is dissolved in dimethoxyethane (60 ml). Aqueous sodium hydroxide (28 ml, 1 M) is added and the mixture is stirred at ambient temperature over night. The mixture is poured into water (200 ml) and a small volume of ethanol is added with stirring. The product is filtered off, washed with water and dried to leave 6j (2 g, 51%). Mp 135-136° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].S(O[CH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1)(=O)(=O)C>CN(C=O)C>[C:46]([O:45][C:43]([N:40]1[CH2:41][CH2:42][CH:37]([CH2:36][O:17][C:11]2[CH:10]=[C:9]3[C:14]([C:5]([O:4][C:3]4[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:2]=4[F:1])=[CH:6][CH:7]=[N:8]3)=[CH:13][C:12]=2[O:15][CH3:16])[CH2:38][CH2:39]1)=[O:44])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To a solution of the 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-hydroxyquinoline (609 mg, 1.8 mmol) in DMF (9 mL) was added K2CO3 (1.24 g, 9.0 mmol) and N-Boc-4-piperidinemethanol mesylate (732 mg, 2.5 mmol). The mixture was then stirred at 80° C. for 2.5 h. After it was cooled to it, the mixture was loaded directly to a Biotage column, and eluted with solvents (hexanes:EtOAc=1:3). The resulting product, 4-[4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester, was obtained as a solid (556 mg, 56%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]([C:13]1[N:14]=[C:15]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:16]2[C:17](=[O:20])[C:18]=1Br)[CH3:12].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.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>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]([C:13]1[N:14]=[C:15]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:16]2[C:17](=[O:20])[C:18]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:12]
Reactant: Cc1cccc2nc(C(C)n3cnc4c(N)ncnc43)c(Br)c(=O)n12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc2nc(C(C)n3cnc4c(N)ncnc43)c(-c3ccccc3)c(=O)n12
Temperature: 100 °C

Procedure:
To a mixture of 2-[1-(6-amino-9H-purin-9-yl)ethyl]-3-bromo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.030 g, 0.075 mmol) and phenylboronic acid (11.0 mg, 0.0899 mmol) in 1,4-dioxane (0.6 mL) was added a 1 M solution of sodium carbonate (9.53 mg, 0.0899 mmol) in water (0.089 mL) and tetrakis(triphenylphosphine)palladium (0) (4.33 mg, 0.00375 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to rt, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on RP-HPLC at pH 10 (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to provide the desired product. LCMS calculated for C22H20N7O (M+H)+: m/z=398.2. Found: 398.3. 1H NMR (DMSO-d6, 300 MHz) δ 8.37 (1H, s), 7.97 (1H, s), 7.56 (1H, dd, J=8.7 and 6.6 Hz), 7.41-7.36 (5H, m), 7.26 (1H, br d, J=9.0 Hz), 7.09 (2H, br s), 6.85 (1H, br d, J=7.2 Hz), 5.59 (1H, q, J=7.2 Hz), 2.80 (3H, s), 1.64 (3H, d, J=7.2 Hz) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Br[C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:16]=1[C:17]([OH:19])=[O:18]>>[C:17]([C:16]1[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:15]=1[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[C:2]([CH3:1])=[N:3]1)([OH:19])=[O:18]
Reactant: COc1cccc(Br)c1C(=O)O
Reactant: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Product: COc1cccc(-n2nc(C)c3ccc([N+](=O)[O-])cc32)c1C(=O)O
Yield: 75.9 %

Procedure:
3-Methyl-6-nitroindazole (5.31 g) and 6.93 g of 2-bromo-6-methoxybenzoic acid were subjected to reaction in the same manner as in Example 11 to obtain 1-(2-carboxy-3-methoxyphenyl)-3-methyl-6-nitroindazole (yield: 75.9%). The nitro group of the compound was reduced to give 6-amino-(2-carboxy-3-methoxyphenyl)-3-methylindazole (yield: 100%), which was then cyclized to obtain 1.83 g (28.9%) of 5-amino-7-methoxy-2-methyl-6H-pyrazolo[4,5,1-d,e]acridin-6-one.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH2:26][CH2:27][O:28][CH2:29][CH:30]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].C([O-])=O.[NH4+]>C1COCC1.CO.[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:17]=1)[OH:11]
Reactant: O=C(c1ccc(Oc2ncccc2C2=CCOCC2)cc1)c1nc2ccccc2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: OC(c1ccc(Oc2ncccc2C2CCOCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A 350 ml heavy-walled vessel was charged with (1H-benzo[d]imidazol-2-yl)(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanone (1.2 g, 3.02 mmol) and ammonium formate (5.71 g, 91 mmol) in THF (20 mL) and MeOH (20.00 mL). The reaction was evacuated 2× and treated with palladium on carbon 10% (0.321 g, 0.302 mmol) under nitrogen. The vessel was capped and the mixture was heated to 70° C. After 6 hours, the reaction was allowed to cool down to RT and filtered through celite. The filtrate was reduced under vacuum and the resulting residue was partition with DCM and water. The DCM layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 2 to 12% MeOH in DCM to give (1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanol as a white solid. MS (ESI, pos. ion) m/z: 401.9 (M+1).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:24])[C:16](=[O:23])N2CCSC2=S)[NH:13][C:12]1=[O:25])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:26]([O:29][C:30]([N:32]1[CH2:36][CH:35]([SH:37])[CH2:34][CH:33]1[CH2:38][O:39][CH2:40][CH2:41][F:42])=[O:31])[CH:27]=[CH2:28].C(N(CC)CC)C.C(O)(=O)C>O1CCCC1>[CH2:26]([O:29][C:30]([N:32]1[CH2:36][C@@H:35]([S:37][C:16](=[O:23])[C@@H:15]([C@H:14]2[NH:13][C:12](=[O:25])[C@@H:11]2[C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH3:10])[CH3:24])[CH2:34][C@H:33]1[CH2:38][O:39][CH2:40][CH2:41][F:42])=[O:31])[CH:27]=[CH2:28]
Reactant: C=CCOC(=O)N1CC(S)CC1COCCF
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1CCSC1=S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: C=CCOC(=O)N1C[C@@H](SC(=O)[C@H](C)[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)C[C@H]1COCCF
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 42.3 %

Procedure:
To a solution of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]- 4-{(1R)-1-methyl-2-oxo-2-(2-thioxothiazolidin-3-yl)ethyl]-2-azetidinone (3.17 g) in tetrahydrofuran (30 ml) were added 1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)-4-mercaptopyrrolidine (2.21 g) and triethylamine (1.46 ml) at 5° C., and the mixture was stirred at room temperature for 8.5 hours. Acetic acid (0.63 ml) was added to the mixture and the mixture was evaporated. The residue was dissolved in water and ethyl acetate. The organic layer was separated, washed with water, dried and evaporated. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane and ethyl acetate (2:1 V/V) to give (3S,4S)-4-[(1R)-2-{(2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)pyrrolidin-4-yl-thio}-1-methyl-2-oxoethyl]-3-{(1R)-1-(t-butyldimethylsilyl-oxy)ethyl}-2-azetidinone (1.82 g).
Reaction SMILES: CC1C=CC(CN)=CC=1.[CH3:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][NH:16][C:17]2[C:18]([NH2:32])=[CH:19][CH:20]=[C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)[CH:22]=2)=[CH:13][CH:12]=1.[C:35]1(=[O:45])[C@@H:43]2[C@@H:38]([CH2:39][CH2:40][CH2:41][CH2:42]2)[C:37](=O)[O:36]1>>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[C:17]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=4)[CH:20]=[CH:19][C:18]=3[N:32]=[C:37]2[C@H:38]2[CH2:39][CH2:40][CH2:41][CH2:42][C@H:43]2[C:35]([OH:45])=[O:36])=[CH:33][CH:34]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: Cc1ccc(CNc2cc(OCc3ccc(C)cn3)ccc2N)cc1
Agent: Cc1ccc(CN)cc1
Product: Cc1ccc(Cn2c([C@H]3CCCC[C@H]3C(=O)O)nc3ccc(OCc4ccc(C)cn4)cc32)cc1

Procedure:
The title compound was prepared using analogous conditions described for Example 1 using p-tolylmethanamine in Step A then for Intermediate I using N1-(4-methylbenzyl)-5-((5-methylpyridin-2-yl)methoxy)benzene-1,2-diamine and racemic cis-hexahydroisobenzofuran-1,3-dione followed by the hydrolysis according to Example 111. MS (ESI): mass calcd. for C29H31N3O3, 469.24; m/z found, 470.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.50 (s, 1H), 8.02 (d, J=8.1, 1H), 7.74 (d, J=9.0, 1H), 7.69 (d, J=8.1, 1H), 7.36 (dd, J=9.0, 2.3, 1H), 7.25 (d, J=2.2, 1H), 7.17 (d, J=8.0, 2H), 7.00 (d, J=8.1, 2H), 5.77 (d, J=16.9, 1H), 5.71 (d, J=17.0, 1H), 5.36-5.19 (m, 2H), 3.63 (dt, J=12.1, 3.7, 1H), 2.90 (d, J=3.7, 1H), 2.45 (s, 3H), 2.37-2.25 (m, 4H), 2.19 (d, J=14.2, 1H), 2.05 (d, J=12.9, 1H), 1.96 (t, J=12.1, 1H), 1.82-1.72 (m, 1H), 1.72-1.63 (m, 1H), 1.59-1.35 (m, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[CH3:8].[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([C@@H:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:18])[CH3:8])=[CH:17][CH:16]=3)=[O:15])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: C[C@@H](c1ccc(C(=O)O)cc1)N1CCCS1(=O)=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc([C@H](C)N4CCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 80.8 %

Procedure:
Using (S)-4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)ethyl]benzoic acid (162 mg) described in Preparation Example 44 and 1-(3,5-dimethylpyridin-2-yl)piperazine (126 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (215 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15](=[O:28])[N:6]2[C:7]=1[C:8]([O:10]C(C)(C)C)=[O:9].Cl>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:15](=[O:28])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A stirred solution of tert-butyl (6R,7R)-3-methyl-7-phenoxyacetamido-ceph-3-em-4-carboxylate (0.41 g, 1.0 mmol) in dichloromethane (25 ml) was cooled to 0° C. Titanium tetrachloride (0.38 ml, 3.5 mmol) was added in 1 min. A yellow precipitate was formed which was stirred for 2 h at 0° C. To the suspension was added a chilled 1 M solution of hydrochloric acid in water (40 ml). The organic phase was separated, washed with water and brine, dried over magnesium sulphate, and evaporated to give 0.30 g of (6R,7R)-3-methyl-7-phenoxyacetamidoceph-3-em-4-carboxylic acid (purity 63%, yield 54.3%).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12](N(OC)C)=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1.[C:31]([Mg]Br)#[CH:32]>O1CCCC1>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:12](=[O:13])[C:31]#[CH:32])[CH:18]=[CH:19][C:20]=2[CH3:21])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1
Reactant: C#C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Cl)c2=O)c1
Solvent: C1CCOC1
Product: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Cl)c2=O)c1

Procedure:
To a solution of 3-[5-chloro-2-methyl-4-(2-methyl-thiazol-4-ylmethoxy)-6-oxo-6H-pyrimidin-1-yl]-N-methoxy-4,N-dimethyl-benzamide from Step B (93 mg, 0.21 mmol) in tetrahydrofuran (2 mL), cooled using an ice water bath, was added ethynylmagnesium bromide, 0.5M in tetrahydrofuran, (0.62 mL, 0.31 mmol) in a drop-wise manner. Additional Grignard reagent was added as necessary to ensure full product formation. After thirty minutes, the reaction was quenched into ice cold water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride, water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated. The crude material was used without any additional purification.
Reaction SMILES: [NH2:1][C:2](=[O:38])[CH:3]([OH:37])[CH:4]([NH:12][C:13](=[O:36])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[NH2:1][C:2](=[O:38])[C:3](=[O:37])[CH:4]([NH:12][C:13](=[O:36])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[N:21]1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2CCc3ccccc3C2)n1
Solvent: ClCCl
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2CCc3ccccc3C2)n1

Procedure:
Oxidation of N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(3-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-1H-pyrazol-1-yl)nicotinamide (200 mg, 0.392 mmol) as described in example 1.4, recrystallization of the crude product from CH2Cl2/MTB gave the title compound as white amorphous solid; 52 mg, ESI-MS [M+H]+: 509.2. 1H-NMR (400 MHz, DMSO), δ[ppm]: 8.98 (m, 1H), 8.59 (m, 1H), 8.42 (m, 1H), 8.07 (m, 1H), 7.83 (m, 1H), 7.74 (m, 1H), 7.44 (m, 1H), 7.29-7.15 (m, 5H), 7.10-7.00 (m, 4H), 6.43 (m, 1H), 5.43 (m, 1H), 3.48 (m, 4H), 3.17 and 2.91 (each dd, 1H), 2.91 (m, 2H), 2.61 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[C:19]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20]1.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: O=C1CCCC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.7 %

Procedure:
N1-(4-Methoxybenzoyl)-1,2-benzenediamine (3.0 g, 12 mmol), glutaric anhydride (1.7 g, 15 mmol), and pyridine (7 mL) were dissolved in methylene chloride (2 mL) and allowed to stir at ambient temperature for 5 h. The reaction mixture was quenched with water (2 mL) and concentrated in vacuo. The resultant residue was acidified with aqueous sulfuric acid. The resulting white solid was collected and dried at 60° C. in vacuo to yield 3.88 g (88%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[C:6]([CH3:24])=[C:5]2[CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+:31]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[C:6]([CH3:24])=[C:5]2[CH2:25][C:26]([O-:28])=[O:27].[Na+:31]
Reactant: COc1cc(C=C2C(C)=C(CC(=O)O)c3cc(F)ccc32)cc(OC)c1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C=C2C(C)=C(CC(=O)[O-])c3cc(F)ccc32)cc(OC)c1OC
Reaction time: 0.33 h

Procedure:
5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-3-indenylacetic acid (1.79 g, 4.65 mmol) in methanol (10 ml) is added to a solution of sodium methoxide (0.25 g, 4.65 mmol) in methanol (5 ml). The reaction mixture is stirred for 20 minutes and evaporated to dryness to yield sodium 5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-3-indenylacetate.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Br:39])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Br:39])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cccc(Br)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(c1cccc(Br)c1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
0.271 g (0.444 mmol) of (2R*,4S*)-2-benzyl-1-(3-bromobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is reacted with 0.067 g (1.78 mol) of sodium borohydride in analogy to Example 2. The title compound ##STR72## is obtained (0.212 g, 93%) as oil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.29, FD-MS: M+ =513, 515.
Reaction SMILES: C([O:8][C:9](=[O:46])[CH2:10][C@@H:11]([N:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)=[CH:30]1)[C:12]([NH:14][C@H:15]([C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1.CC(O)=O>CCO>[CH3:17][C:16]([CH3:19])([CH3:18])[C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:41]=[CH:42][N:43]=[CH:44][CH:45]=3)=[CH:36][CH:35]=2)=[CH:30]1)[CH2:10][C:9]([OH:46])=[O:8])[C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)C(=O)Nc1ccncc1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)C(=O)Nc1ccncc1
Yield: 40.8 %

Procedure:
According to the procedure described in Example 7(a), N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester (185 mg, 0.280 mmol) was hydrogenolyzed in EtOH (10 mL) and HOAc (1 mL) and furnished a solid that was triturated with EtOAc to give 60 mg(41%) of N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid as a yellow solid. 1H NMR (CD3OD): δ 8.54 (d, 2H, J=6.6 Hz), 8.33 (d, 2H, J=6.6 Hz), 7.73-7.68 (m, 4H), 7.64-7.59 (m, 4H), 7.32 (s, 1H), 6.91 (t, 1H J=2.4 Hz), 6.52 (dd, 1H, J=1.8, 2.9 Hz), 5.31 (t, 1H, J=7.5 Hz), 4.41 (s, 1H), 2.99 (dd, 1H, J=6.8, 16.7 Hz), 1.03 (s, 9H). Anal. Calculated for C30H31N5O4.0.6H2O.0.2EtOAc: C, 66.77; H, 6.15; N, 12.64. Found: C, 66.72; H, 5.99; N, 12.62.