Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=1[Cl:44])[CH3:35]>CN(C=O)C.[Cu]I>[Cl:44][C:37]1[CH:38]=[C:39]([F:43])[C:40]([F:42])=[CH:41][C:36]=1/[C:34](/[CH3:35])=[CH:33]/[N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]1=2
Reactant: CC(=CBr)c1cc(F)c(F)cc1Cl
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-2-chloro-4,5-difluorobenzene (321 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The product was further purified by HPLC. Yield: 12 mg as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.50 (m, 2H), 7.32 (s, 1H), 7.25 (d, 1H), 7.15 (d, 1H), 6.70 (s, 1H), 4.75 (m, 1H), 4.38 (m, 1H), 3.90 (m, 1H), 3.60 (m, 1H), 3.25 (m, 2H), 3.15 (s, 3H), 2.42 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: Cl.Cl.[CH:3]([N:6]([CH3:13])[CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)([CH3:5])[CH3:4].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[CH:20][CH:19]=1)=[O:16]>CN(C)C=O>[F:33][C:31]([F:32])([F:34])[C:28]1[CH:29]=[CH:30][C:25]([O:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][C:15]([N:10]3[CH2:9][CH2:8][CH:7]([N:6]([CH:3]([CH3:5])[CH3:4])[CH3:13])[CH2:12][CH2:11]3)=[O:16])=[CH:19][CH:20]=2)=[N:26][CH:27]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CC(C)N(C)C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)N(C)C1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title product was prepared from isopropyl-methyl-piperidin-4-yl-amine, dihydrochloride and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate; dimethylformamide as solvent, preparative HPLC (method C) (77%, light yellow oil). HPLC-MS m/z=438.3 (M+1), Rt: 2.77 min.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[Cl:24][C:25]1[CH:26]=[C:27]([CH2:32][CH2:33][C:34](Cl)=[O:35])[CH:28]=[CH:29][C:30]=1[Cl:31]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH2:32][CH2:33][C:34]([NH:23][S:20]([C:5]2[CH:6]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[C:8]([O:9][CH3:10])=[C:3]([CH:1]=[O:2])[CH:4]=2)(=[O:22])=[O:21])=[O:35])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)CCc1ccc(Cl)c(Cl)c1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCc2ccc(Cl)c(Cl)c2)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and 3-(3,4-dichlorophenyl)-propanoyl chloride, gave N-[3-(3,4-dichlorophenyl)-propanoyl]-5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[OH:44][C:45]([CH3:49])([CH3:48])[CH2:46][NH2:47].[Cl-].[Na+]>CN(C=O)C>[OH:44][C:45]([CH3:49])([CH3:48])[CH2:46][NH:47][C:20]([C:17]1[NH:18][N:19]=[C:15]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22]
Reactant: CC(C)(O)CN
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)[nH]n1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)NCC(C)(C)O)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
To a solution of 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2H-pyrazole-3-carboxylic acid (0.212 mmol) in DMF (5 mL) was added 1-hydroxybenzotriazole hydrate (0.318 mmol), N-ethyldiisopropylamine (0.848 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (0.318 mmol) and 2-hydroxy-2-methylpropylamine (0.318 mmol) and the resulting mixture stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by preparative HPLC afforded the title compound (15 mg, 29%) as an off white solid. MS: m/e=388.4 [M+H]+.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:22]=[C:16]1[CH:15]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[CH2:4][N:3]([CH3:2])[C:32]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)=[O:33])[C:9]2=[O:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CNCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccc(N=C=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)N(C)Cc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a suspension of 3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and 4-methoxy-phenyl-isocyanate (0.29 mL, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with MeOH and filtered. The resulting solid was rinsed with CH2Cl2 (5 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(4-methoxy-phenyl)-1-methyl-urea (0.38 g, 46%): mp 245-247° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=1.91 (98%); 1H NMR (DMSO-d6): δ 1.99-2.04 (m, 1H), 2.30-2.37 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.87 (m, 1H), 2.95 (s, 3H), 3.70 (s, 3H), 4.37 (d, J=17.3 Hz, 1H), 4.44 (d, J=17.4 Hz, 1H), 4.63 (s, 2H), 5.11-5.18 (dd, J=4.9, 13.1 Hz, 1H), 6.84 (d, J=8.9 Hz, 2H), 7.32 (d, J=8.9 Hz, 2H), 7.45 (d, J=7.4 Hz, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.64 (d, J=7.3 Hz, 1H), 8.31 (s, 1H), 11.02 (s, 1H). 13C NMR (DMSO-d6) δ: 22.58, 31.17, 34.64, 46.26, 48.36, 51.57, 55. 10, 113.46, 121.69, 122.01, 128.41, 129.91, 131.91, 133.29, 133.98, 140.13, 154.64, 155.91, 168.02, 171.02, 172.85. Anal Calcd for C23H24N4O5+0.1H2O: C, 63.03; H, 5.57; N, 12.78. Found: C, 62.96; H, 5.48; N, 12.49.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:42])([CH3:41])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:40])([C@@:18]4([CH3:39])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([CH:37]=O)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[NH2:43][CH2:44][CH2:45][CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][C:48]1=[O:52]>>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:42])([CH3:41])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:40])([C@@:18]4([CH3:39])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([CH2:37][NH:43][CH2:44][CH2:45][CH2:46][N:47]2[CH2:51][CH2:50][CH2:49][C:48]2=[O:52])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: NCCCN1CCCC1=O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCCC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 82 %

Procedure:
The title compound was prepared in 82% yield following steps 5 and 6 described above, using methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 1-(3-aminopropyl)pyrrolidin-2-one as the reactant amine MS: m/e 687.5 (MH+), 1.71 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.96 (s, 3H) 0.98 (s, 3H) 1.02 (s, 3H) 1.08 (s, 3H) 1.17 (s, 3H) 1.73 (s, 3H) 0.90-1.91 (m, 20H) 1.96-2.20 (m, 6H) 2.44 (t, J=8.03 Hz, 2H) 2.47-2.55 (m, 1H) 2.83 (d, J=13.05 Hz, 1H) 3.06 (t, J=7.03 Hz, 2H) 3.20 (d, J=13.55 Hz, 1H) 3.43 (t, J=6.53 Hz, 2H) 3.51 (t, J=7.15 Hz, 2H) 4.62-4.66 (m, 1H) 4.75 (d, J=1.76 Hz, 1H) 5.35 (dd, J=6.15, 1.88 Hz, 1H) 6.94 (dd, J=11.80, 1.25 Hz, 1H) 7.02 (dd, J=8.03, 1.51 Hz, 1H) 7.83 (t, J=7.91 Hz, 1H). 19F NMR (376 MHz, MeOD) δ ppm −112.76 (s, 1 F).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([OH:23])[CH2:20][C@H:19]1[CH2:24][O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)C(C)C)(C)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:22][C:21](=[O:23])[CH2:20][C@H:19]1[CH2:24][O:25][C:26](=[O:36])[C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1COC(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1COC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (23.5 ml, 246 mmol) in dichloromethane (400 ml), which was cooled to −75° C., dimethyl sulfoxide (35 ml, 492 mmol) in dichloromethane (60 ml) was added in 20 minutes. After 30 minutes at −70° C., a solution of (2S,4R)-4-hydroxy-2-(4-nitro-benzoyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 55, 45 g, 123 mmol) in dichloromethane (300 ml) was added dropwise. After 2 hours at −70° C., N,N-diisopropylethylamine (60 ml) was added in 10 minutes. After 25 minutes at −60° C. and 30 minutes at room temperature dichloromethane (200 ml) was added. The organic solvent was washed with 0.5N HCl (500 ml), water (500 ml) and brine (500 ml), dried (Na2SO4) and evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 5/1 to 3/1). (S)-2-(4-Nitro-benzoyloxymethyl)-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester was obtained as white solid (28.5 g, yield: 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[N:10]([C@H:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:9]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:32](Br)[CH:33]=[CH2:34].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:34]([C@@H:12]1[CH2:13][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:9]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[N:10]([C@@H:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:11]1=[O:14])[CH:33]=[CH2:32]
Reactant: C=CCBr
Reactant: CC[C@H](C(=O)OC(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 1.45 g (3.14 mmol) of tert-butyl (2S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-1-piperidinyl)butanoate (Example 1, Step F) and allyl bromide (0.326 mL, 3.76 mmol) in 12.5 mL of THF was added dropwise at −78° C. 3.3 mL of a 1 M solution of lithium bis(trimethylsilyl)-amide in THF (3.3 mmol). After being stirred at −78° C. for 3 h, the reaction was quenched with sat. aqueous NH4Cl solution, extracted with ethyl acetate. The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (50 g SiO2, eluent: 5 to 20% EtOAc/hexanes, gradient elution) provided tert-butyl (2S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate as the faster eluting major isomer.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[N:23][C:18]3=[CH:17][CH:16]=2)SCCCS1.CC(C)=[O:30].CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O.Cl[Hg]Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:30])[CH2:14][C:15]1[N:20]=[C:19]2[S:21][C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[N:23][C:18]2=[CH:17][CH:16]=1
Reactant: CC(C)Nc1nc2ccc(CC3(c4ccccc4F)SCCCS3)nc2s1
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl[Hg]Cl
Solvent: O
Solvent: CO
Product: CC(C)Nc1nc2ccc(CC(=O)c3ccccc3F)nc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
To a solution of 5-((2-(2-fluorophenyl)-1,3-dithian-2-yl)methyl)-N-isopropylthiazolo[5,4-b]pyridin-2-amine (0.61 g, 1.45 mmol, 1.0 eq.) in MeOH (73 mL) and water (6 mL) were added HgO (0.83 g, 3.83 mmol, 2.6 eq.) and HgCl2 (1.83 g, 6.74 mmol, 4.6 eq.). After stirring for 15 min., the solution was refluxed for another 15 min. and cooled to room temperature. The precipitate was removed, and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc and water, and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. Acetone (7 mL), water (0.1 mL, 5.56 mmol, 3.8 eq.), and TsOH.H2O (0.0342 g, 0.180 mmol, 0.1 eq.) were added, and the reaction was stirred overnight and concentrated in vacuo. The residue was diluted with CH2Cl2 and water, and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography using CH2Cl2:MeOH (15:0.1) as eluent afforded 1-(2-fluorophenyl)-2-(2-(isopropylamino)thiazolo[5,4-b]pyridin-5-yl)ethanone as a yellow solid (0.1994 g, 42% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:23])[CH:13]([OH:14])[CH:12]([N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=2)[O:5]1>CO.[Pd]>[CH3:1][O:2][CH2:3][C:4]1([CH3:23])[CH:13]([OH:14])[CH:12]([N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1
Reactant: COCC1(C)Oc2ccc(Br)cc2C(n2ccccc2=O)C1O
Agent: [Pd]
Solvent: CO
Product: COCC1(C)Oc2ccccc2C(n2ccccc2=O)C1O

Procedure:
A solution of 280 mg of 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-bromo-3-chromanol is hydrogenated on 140 mg of 20% Pd-C in 80 ml of methanol at 20° and 1 bar, the mixture is filtered, the filtrate is evaporated and 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-3-chromanol m.p. 244°-246° C. is obtained after chromatographic purification on silica gel.
Reaction SMILES: O[N:2]=[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[ClH:15].O>CO.[Pd]>[ClH:15].[NH2:2][CH:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4]
Reactant: COC(=O)c1ccc(C(C)=NO)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C(C)N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a degassed solution of methyl 4-(1-(hydroxyimino)ethyl)benzoate (1.1 g, 5.6 mmol) and 12.0 M of hydrochloric acid in water (0.6 mL, 7.3 mmol) in methanol (50 mL) was added 10% palladium on carbon (0.20 g, 0.18 mmol). The reaction mixture was stirred overnight at room temperature. All insolubles were removed via filtration through celite and subsequent evaporation of the filtrate to dryness afforded the title compound as a white solid (1.12 g, 83%). LC-MS: (FA) ES+ 180; 1H NMR (400 MHz, MeO D) δ 8.09 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 4.55 (q, J=6.8 Hz, 1H), 3.91 (s, 3H), 1.65 (d, J=6.9 Hz, 3H).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:41])[C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:23]([OH:33])=[C:22]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[CH:21]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:48]([O:50][C:51](=[O:57])[CH2:52][CH2:53][CH2:54][CH2:55]Br)[CH3:49].O>CN(C=O)C>[Cl:32][C:28]1[CH:27]=[C:26]([C:24]2[CH:25]=[C:20]([C:19](=[O:41])[NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)[CH:21]=[C:22]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:23]=2[O:33][CH2:55][CH2:54][CH2:53][CH2:52][C:51]([O:50][CH2:48][CH3:49])=[O:57])[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CCCCBr
Reactant: O=C(NCCCCCCCCn1ccc2ccccc21)c1cc(-c2cccc(Cl)c2)c(O)c(-c2cccc(Cl)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCn2ccc3ccccc32)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
A mixture of N-(8-indol-1-yl-octyl)-3,5-bis(3-chlorophenyl)-4-hydroxybenzamide (0.399 g, 0.68 mmol), K2CO3 (0.116 g, 0.84 mmol), and ethyl-5-bromovalerate (0.176 g, 0.84 mmol) in DMF was stirred at room temperature under nitrogen. After ˜48 h, the reaction mixture was poured into water (40 ml) and extracted with EtOAc (1×20 ml, 4×10 ml). The combined extracts were washed with water (3×10 ml), brine (2×10 ml), dried over Na2SO4, filtered and the filtrate concentrated in vac and dried. The crude product was purified by flash chromatography (alumina, hexane, 10% and 60% EtOAc/Hex) to give the desired product as a light yellow oil (0.432 g, 86%); (400 MHz, DMSO-d6) δ 1.12–1.30 (m, 15H), 1.44–1.55 (m, 2H), 1.67–1.76 (m, 2H), 1.92 (t, J=7 Hz, 2H), 3.16–3.27 (m, 4H), 3.98 (q, J=7 Hz, 2H), 4.12 (t, J=7.2 Hz, 2H), 6.38 (d, J=3.1 Hz, 1H), 6.95–6.99 (m, 1H), 7.06–7.10 (m, 1H), 7.32 (d, J=3.3 Hz, 1H), 7.40–7.52 (m, 6H), 7.56–7.59 (m, 2H), 7.68 (t, J=1.8 Hz, 2H), 7.87 (s, 2H), 8.53 (t, J=5.7 Hz, 1H); IR (film) 3320, 2940, 2950, 1730, 1630, 1540, cm−1; mass spectrum [(+)APCI], m/z 713 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([C:13]1[N:14]([S:21]([C:24]2[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:15]=[CH:16][C:17]=1[C:18]([OH:20])=O)[CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[CH2:6]([O:5][CH2:4][CH2:3][C@@H:2]1[C:13]2[N:14]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:22])=[O:23])[CH:15]=[CH:16][C:17]=2[C:18](=[O:20])[NH:1]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)O)c2[C@H](N)CCOCc2ccccc2)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2[C@@H](CCOCc2ccccc2)NC3=O)cc1
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of (R)-2-(1-amino-3-(benzyloxy)propyl)-1-tosyl-1H-pyrrole-3-carboxylic acid compound with TFA (1:1) (504d, 5.43 g, 10.01 mmol) and DIEA (5.22 mL, 30.0 mmol) in EtOAc (50 mL) was added 1-propanephosphonic acid cyclic anhydride (50 wt. % in EtOAc, 5.96 mL, 10.01 mmol) dropwise via syringe. All solids dissolved to give a light brown solution. After 1 h, the reaction was partitioned between sat'd NaHCO3 and EtOAc. The organic layer was washed with sat'd NaHCO3 once, sat'd NaCl once, and the organics were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give (R)-6-(2-(benzyloxy)ethyl)-1-tosyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (724e) (3.51 g, 8.55 mmol, 85% yield) as a light brown foam. m/z (ESI, +ve) 411.1 (M+Na)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([C:13]([CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]5[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=5)[CH2:20][CH2:19]4)=[C:14]([CH3:15])[N:9]3[CH2:8][CH2:7][CH2:6]2)[CH:12]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([C:13]([CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]5[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=5)[CH2:20][CH2:19]4)=[C:14]([CH3:15])[N:9]3[CH2:8][CH2:7][CH2:6]2)[CH:12]=1
Reactant: COc1cc2c3c(c1)c(CCN1CCN(c4cc(C)ccn4)CC1)c(C)n3CCC2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccnc(N2CCN(CCc3c(C)n4c5c(cc(O)cc35)CCC4)CC2)c1
Temperature: -10 °C
Yield: 57.7 %

Procedure:
7.9 g of 8-hydroxy-2-methyl-1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl]ethyl}-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (preparation see Example 5) were dissolved in 110 ml of dichloromethane. The solution was cooled to -10° C. A solution of 24.42 g of boron tribromide in 35 ml of dichloromethane was then added while the temperature was kept between -10° and 0° C. The mixture was allowed to react at about 0° C. for 30 minutes. To work up the reaction mixture it was added to a mixture of ice and saturated aqueous sodium bicarbonate solution. The organic phase was separated from the alkaline aqueous phase, washed until neutral, dried and evaporated. As a residue, 9.3 g of a pale grey, solid crude product remained, which was purified by chromatography on a small silica gel column. 4.4 g of cream-colored 8-hydroxy-2-methyl-1-{2-[4-(4-methylpyridin-2 -yl) piperazin-1-yl]ethyl}-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline having a melting point of 110° C. were obtained.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:30][O:31][CH2:32][CH2:33][NH:34]C(OC(C)(C)C)=O)[C:10]([NH:12][CH:13]2[C:28](=[O:29])[N:15]3[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:30][O:31][CH2:32][CH2:33][NH2:34])[C:10]([NH:12][CH:13]2[C:28](=[O:29])[N:15]3[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1csc(N)n1
Yield: 81.8 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer, 1.7 g.) and conc. hydrochloric acid (1.5 g.) in methanol (30 ml.) was stirred at room temperature for 3 hours. After evaporating the solvent in vacuo, methanol was added to the residue and then evaporated in vacuo again. The residue was dissolved in water (30 ml.) and adjusted to pH 3.5 with a sodium bicarbonate saturated aqueous solution under ice-cooling. The solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (trademark, manufactured by Mitsubishi Chemical Industries Ltd.) and eluted with 30% aqueous isopropyl alcohol. The eluate was concentrated in vacuo, and the residue was lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-(2-aminoethoxyimino)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer, 1.1 g.).