Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:4][CH:5](O)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)([O-:3])=[O:2].CS(Cl)(=O)=O.C(N(CC)CC)C.O>C(Cl)Cl>[N+:1]([CH:4]=[CH:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1ccc(CCC(O)C[N+](=O)[O-])cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CCC=C[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.9 %

Procedure:
To a solution of 4.89 g (18.1 mmol) of 1-nitro-4-(4-ethoxycarbonylphenyl)-2-butanol in 24 mL of dry methylene chloride at 0° C. was added 2.1 g (18.1 mmol) of methanesulfonyl chloride followed by addition of 3.66 g (36.2 mmol) of triethylamine. The mixture was stirred at 0° C. for 20 minutes, poured into 40 mL of water, extracted with 50 mL of methylene chloride, dried over anhydrous, and concentrated under reduced pressure. The residual solid was purified by column chromatography on silica gel, eluting with 1:9 ethyl acetate:hexanes, to afford 4.1 g (90%) of 1-nitro-4-(4-ethoxycarbonylphenyl)-1-butene as a light yellow solid: IR (KBr) 3112, 2982, 1713, 1647, 1610, 1519, 1424, 1417, 1353, 1277, 1178, 1104, 1021, 954, 935, 857, 766, 706 cm-1. 1H NMR (CDCl3) δ 8.02 (2H, d, J=8.5 Hz), 7.28 (1H, dt, J=14.0 and 7.5 Hz), 7.27 (2H, d, J=8.5 Hz), 6.98 (1H, d, J=14.0 Hz), 4.39 (2H, q, J=7.0 Hz), 2.92 (2H, t, J=7.5 Hz), 2.64 (2H, q, J=8.0 Hz), 1.42 (3H, t, J=7.0 Hz); 13C NMR (CDCl3) δ 166.55, 144.90, 140.91, 140.39, 130.23, 129.27, 128.49, 61.16, 34.12, 29.89, 14.52; EIMS m/z 249 (M+), 204, 202, 163, 135, 129, 118, 107, 90, 77; HRMS calc'd for C13H15NO4 249.1001 found 249.1029.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)c2ccc(I)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O
Product: O=C(c1ccc(O)cc1)c1ccc(I)cc1
Temperature: 0 °C
Yield: 94.5 %

Procedure:
A mixture of (4-Iodophenyl)[4-(methyloxy)phenyl]methanone (142) (1.50 g, 4.44 mmol) and AlCl3 (2.40 g, 17.74 mmol) were refluxed in benzene (50 mL) for 1.5 h and then cooled to 0° C. in an ice bath. Water (50 mL) was added slowly, and the mixture was extracted with ether (2×100 mL). The combined ethereal extracts were washed with water, brine, and dried over Na2SO4. Concentration and trituration with hot hexanes afforded 1.36 g (95%) of the title compound as light brown solid. 1H NMR (400 MHz, CDCl3): δ 5.37 (br s, 1H), 6.90 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.6 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H). LCMS (ESI): m/z, 325 (M+H)+, 323 (M−H)−.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[CH2:12]([CH2:14][CH2:15][CH2:16][C:17](CC([O-])=O)=[O:18])[CH3:13]>>[O:18]=[C:17]1[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=[C:15]([CH2:14][CH2:12][CH3:13])[CH2:16]1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CCCCCC(=O)CC(=O)[O-]
Product: CCCC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1

Procedure:
From the reaction of 4-hydrazinobenzoic acid and ethylbutyrylacetate, 4-(4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzoic acid is obtained. Subsequent reaction with 2-ethylaniline yields 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzoic acid, Mp 254.5° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.Cl.[CH3:33][O:34][C:35](=[O:40])[C@H:36]([CH2:38][OH:39])[NH2:37].C1C=CC2N(O)N=NC=2C=1.O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([NH:37][C@H:36]([C:35]([O:34][CH3:33])=[O:40])[CH2:38][OH:39])=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@@H](CO)C(=O)OC)[nH]2)c1
Reaction time: 15 h
Yield: 97.4 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.60 g, 3.58 mmol) synthesized in Example (78k), L-serine methyl ester hydrochloride (0.61 g, 3.94 mmol), HOBT.H2O (0.53 g, 3.94 mmol) and N-methylmorpholine (0.79 mL, 7.17 mmol) were dissolved in a mixed solvent of methylene chloride (30 mL) and N,N-dimethylformamide (7 mL), and WSCI.HCl (0.82 g, 4.30 mmol) was added at room temperature, followed by stirring for 15 hours under nitrogen atmosphere. The reaction solution was diluted with methylene chloride (100 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-80%) to afford the desired compound (1.91 g, 97%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](O)=[O:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:54][CH:55]([F:66])[O:56][C:57]1[CH:64]=[CH:63][C:60]([CH2:61][NH2:62])=[CH:59][C:58]=1[F:65]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](=[O:29])[NH:62][CH2:61][C:60]2[CH:63]=[CH:64][C:57]([O:56][CH:55]([F:54])[F:66])=[C:58]([F:65])[CH:59]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NCc1ccc(OC(F)F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)NCc2ccc(OC(F)F)c(F)c2)C1
Yield: 109.2 %

Procedure:
To a solution of the compound (1.83 g) obtained in Example 783, Step 2 in N,N-dimethylformamide (10 ml) were successively added, with stirring under ice-cooling, 1-hydroxybenzotriazole hydrate (677 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (847 mg) and a solution of 4-difluoromethoxy-3-fluorobenzylamine (806 mg) in N,N-dimethylformamide (3 ml). After stirring overnight at room temperature, the mixture was partitioned by adding ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate, the combined organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give the title compound (2.76 g).
Reaction SMILES: [CH2:1]([C:3]1[N:15]2[C:6]([C:7](=[O:28])[NH:8][C:9]3[C:10]([N:16]([CH2:18][CH2:19][O:20]CC4C=CC=CC=4)[CH3:17])=[N:11][CH:12]=[N:13][C:14]=32)=[CH:5][N:4]=1)[CH3:2].CO.[OH-].[Na+]>[Pd]>[CH2:1]([C:3]1[N:15]2[C:6]([C:7](=[O:28])[NH:8][C:9]3[C:10]([N:16]([CH2:18][CH2:19][OH:20])[CH3:17])=[N:11][CH:12]=[N:13][C:14]=32)=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncc2c(=O)[nH]c3c(N(C)CCOCc4ccccc4)ncnc3n12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1ncc2c(=O)[nH]c3c(N(C)CCO)ncnc3n12

Procedure:
Prepared by hydrogenation of the product of Example 24 with palladium on carbon in methanol containing 1.1 eq. NaOH at 50 psi for 8 hr.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[N:9]2)[CH:5]=[N:4][C:3]=1[CH3:17].[Cl:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([CH3:27])=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([CH3:27])=[CH:21][C:20]=1[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[N:9]2)[CH:5]=[N:4][C:3]=1[CH3:17]
Reactant: COc1cc(Cl)c(B(O)O)cc1C
Reactant: Cc1ncc(-n2nnc3ccccc32)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(Cl)c(-c2nc(-n3nnc4ccccc43)cnc2C)cc1C
Temperature: 110 °C
Yield: 50 %

Procedure:
To a stirred solution of 83 mg 1-(6-Chloro-5-methyl-pyrazin-2-yl)-1H-benzotriazole (0.29 mmol) and 58 mg 2-chloro-4-methoxy-5-methyl-phenyl boronic acid (0.29 mmol) in 0.3 mL toluene was added 0.29 mL 2 M Na2CO3 (aq). After 10 min 10 mg (pbbp)Pd(Cl)2 was added as a solid and the resulting suspension was heated at 110° C. for 16 h. The organic phase was directly subjected to column chromatography eluting with hexane ethyl acetate (0.1% Et3N) to provide the title compound in 50% yield.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30]C)=[O:29])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[C:24]4[N:25]=[C:26]([CH3:27])[N:17]([C:18]=24)[CH2:16][CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O.CO.C1COCC1.O[Li].O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([OH:30])=[O:29])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[C:24]4[N:25]=[C:26]([CH3:27])[N:17]([C:18]=24)[CH2:16][CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCn1c(C)nc2cccc-3c21
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2cccc3c2n1CCn1c-3c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 60 °C
Yield: 68 %

Procedure:
Methyl 14-cyclohexyl-5-methyl-7,8-dihydroimidazo[4,5,1-jk]indolo[1,2-d][1,4]benzodiazepine-11-carboxylate was dissolved in a mixture of H2O/MeOH/THF (1/1/1) (0.015 M) and LiOH.H2O added (4.4 eq). The reaction was stirred with heating at 60° C. for 3 h, before being allowed to cool to RT, acidified with 1N HCl (aq). The volatiles were removed in vacuo and the residue purified by RP-HPLC (stationary phase: column WATERS X-TERRA prep. C18, 5 microns. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (68%). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 8.30 (s, 1H), 7.99 (d, 1H, J 8.6), 7.79 (d, 1H, J 7.6), 7.68 (d, 1H, J 8.6), 7.67-7.56 (m, 2H), 5.39-5.29 (m, 1H), 4.80-4.72 (m, 1H), 4.38-4.29 (m, 1H), 4.23-4.14 (m, 1H), 3.14-3.06 (m, 1H), 2.73 (s, 3H), 2.19-2.06 (m, 3H), 1.98-1.90 (m, 1H), 1.78-1.72 (m, 2H), 1.55-1.42 (m, 3H), 1.24-1.14 (m, 1H); MS (ES+) m/z 400 (M+H)+.
Reaction SMILES: B.[CH3:2]SC.[C:5]([O:9][C:10]([N:12]1[CH2:24][C@@H:23]([CH3:25])[N:22]2[C@H:14]([CH2:15][C:16]3[C:21]2=[N:20][C:19]([CH2:26][O:27]CCO)=[CH:18][CH:17]=3)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C1COCC1>[C:5]([O:9][C:10]([N:12]1[CH2:24][C@@H:23]([CH3:25])[N:22]2[C@H:14]([CH2:15][C:16]3[C:21]2=[N:20][C:19]([C@@H:26]([OH:27])[CH3:2])=[CH:18][CH:17]=3)[CH2:13]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Reactant: CSC
Agent: B
Solvent: C1CCOC1
Product: C[C@H](O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.08 h

Procedure:
To a stirred solution of (R)-Me-CBS-oxazaborolidine (770 μl, 1M in toluene) in THF (3 ml) was added borane-dimethylsulfide (770 μl, 2M in THF) at 0° C. under nitrogen. A solution was stirred for 5 mins, then 6-acetyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 34, intermediate b) (255 mg) in THF (2.5 ml) was added dropwise over 45 mins. A solution was stirred at 0° C. for 3 hours, quenched with methanol and partitioned between aqueous ammonium chloride and EtOAc. The phases were separated and the organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography [SiO2; isohexane-ethyl acetate (1:1)] to afford 6-((1S)-1-hydroxy-ethyl)-(4R,9aR)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (185 mg) as a colorless oil: 1H NMR (400 MHz, CDCl3): 7.16 (1H, d, J 7 Hz), 6.35 (1H, d, J 7 Hz), 4.37–4.31 (1H, br s), 4.31–4.19 (1H, br s), 4.09–3.95 (1H, m), 3.95–3.85 (1H, m), 3.13–2.94 (2H, m), 2.79–2.55 (1H, br s), 2.54 (1H, dd, J 6 and 16 Hz), 1.48 (9H, s), 1.44 (3H, d, J 6.5 Hz) and 1.24 (3H, d, J 6.5 HZ); MS (ES) 334.3 (MH+).
Reaction SMILES: O=[C:2]1[CH:11]2[CH2:12][CH2:13][CH:14]=[C:9]3[C:10]2=[C:4]([CH2:5][NH:6][C:7]([O:15][CH3:16])=[CH:8]3)[CH:3]1[CH3:17].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C(OCC)C>[CH3:17][CH:3]1[C:4]2[CH2:5][NH:6][C:7]([O:15][CH3:16])=[CH:8][C:9]3[C:10]=2[CH:11]([CH2:12][CH2:13][CH:14]=3)[CH2:2]1
Reactant: COC1=CC2=CCCC3C(=O)C(C)C(=C23)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COC1=CC2=CCCC3CC(C)C(=C23)CN1
Reaction time: 24 h

Procedure:
A sample of 550 mg (2.7 mmol) of 1-oxo-2-methyl-5-methoxy-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine, a compound of Formula 10 prepared, for example, as described in Preparation 10A, was dissolved in 100 ml of diethylether followed by the addition of 750 mg (19 mmol) of LAH. The reaction was allowed to proceed for 24 hours at ambient temperature. The reaction mixture is treated dropwise with about 1 ml of water, 1 ml of 15% NaOH, and then 3 ml of water. Insoluble inorganic materials are removed by filtration and the filtrate concentrated to give 2-methyl-5-methoxy-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine, a compound of Formula I, as the free base; (HBr salt, mp 250°-252° C.).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.CON(C)[C:21]([C:23]1[N:24]=[N:25][N:26]([CH2:34][C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=2)[C:27]=1[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:22].Cl>C1COCC1.CCOCC.CCOC(C)=O>[F:44][C:41]([F:42])([F:43])[C:39]1[CH:40]=[C:35]([CH:36]=[C:37]([C:45]([F:46])([F:48])[F:47])[CH:38]=1)[CH2:34][N:26]1[C:27]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[C:23]([C:21]([C:14]2[N:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[Cl:6])[CH:17]=[CH:16][N:15]=2)=[O:22])[N:24]=[N:25]1
Reactant: CON(C)C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Reactant: Clc1ccccc1-n1ccnc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1)c1nccn1-c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Add BuLi (0.80 mL, 1.28 mmol) to a −78° C. solution of 1-(2-chloro-phenyl)-1H-imidazole (200 mg, 1.12 mmol) in THF (3 mL). Stir at −78° C. for 20 min., then add a solution of 1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid methoxy-methyl-amide (261 mg, 0.57 mmol) in THF (2 mL) via cannula. Stir the resulting solution at −78° C. for 10 min., then allow to warm to RT and stir for 2 h. Add 1N HCl (1.3 mL) and stir for 30 min. Dilute reaction with EtOAc (50 mL) and wash with water (20 mL), saturated NaHCO3 (20 mL) and brine (20 mL). Dry, filter and concentrate the organic solution and purify the crude material by silica gel chromatography (20% to 80% EtOAc/hexanes) to give a brown solid. Trituration with cold ether gives the title compound as a fine white powder. MS [ES] 577.2 (M+H)+. 1H NMR (400 MHz, CHCl3) δ 8.68 (dd, 1H, J=1.4, 4.8 Hz), 8.48 (d, 1H, J=1.8 Hz), 7.81 (s, 1H), 7.48 (m, 3H), 7.46 (m, 1H), 7.44 (m, 1H), 7.34 (m, 4H), 7.17 (m, 1H), 5.60 (s, 2H).
Reaction SMILES: C(C1CCCCC1=O)=O.[C:10]1([C:16]2([CH2:25][CH2:26][C:27]#[N:28])[CH2:21][CH2:20][CH2:19][CH:18](C=O)[C:17]2=[O:24])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC(S([N:38]=[N+:39]=[N-])(=O)=O)=CC=1.CNC.C(NCC)C>C(OCC)C>[C:10]1([C:16]2([CH2:25][CH2:26][C:27]#[N:28])[CH2:21][CH2:20][CH2:19][C:18](=[N+:38]=[N-:39])[C:17]2=[O:24])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: N#CCCC1(c2ccccc2)CCCC(C=O)C1=O
Agent: CNC
Agent: O=CC1CCCCC1=O
Solvent: CCNCC
Solvent: CCOCC
Product: N#CCCC1(c2ccccc2)CCCC(=[N+]=[N-])C1=O

Procedure:
Reaction of a formyl cyclohexanone derivative with para-toluenesulfonylazide effects displacement of the formyl group by a diazo moiety to provide a diazocyclohexanone derivative. For example, a formyl cyclohexanone derivative such as 2-phenyl-2-(2-cyanoethyl)-6-formylcyclohexanone can be reacted with about an equimolar quantity of para-toluene-sulfonylazide in the presence of dimethylamine or diethylamine, in an organic solvent such as diethyl ether, to provide, for instance, 2-phenyl-2-(2-cyanoethyl)-6-diazocyclohexanone.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][N:14]([CH3:27])[S:15]([C:18]1[C:23]([Cl:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:19]=1[Cl:26])(=[O:17])=[O:16])C1C=CC=CC=1>[Pd].C1COCC1>[Cl:26][C:19]1[CH:20]=[C:21]([Cl:25])[CH:22]=[C:23]([Cl:24])[C:18]=1[S:15]([N:14]([CH2:13][O:12][CH2:11][CH2:10][CH2:9][OH:8])[CH3:27])(=[O:16])=[O:17]
Reactant: CN(COCCCOCc1ccccc1)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(COCCCO)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl

Procedure:
10% palladium on charcoal (350 mg) was added to a soln. of N-(3-benzyloxypropoxymethyl)-2,4,6-trichloro-N-methylbenzenesulfonamide (2.60 g, 5.7 mmol) in THF (100 ml) under argon and hydrogenation was carried out at RT under 3 bar. The reaction soln. was then filtered through Celite, the residue on the filter was washed with THF (50 ml) and the filtrate was concentrated i. vac. The crude product (1.63 g) was purified by means of flash chromatography with cyclohexane/EtOAc (1:1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26].[NH2:27][CH2:28][CH:29]([OH:36])[CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:27][CH2:28][CH:29]([OH:36])[CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:13])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[C:20]([Cl:26])=[CH:21][CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: NCC(O)CN1CCCC1
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1c(Cl)cccc1Cl
Product: Nc1ncc(-c2ccc(C(=O)NCC(O)CN3CCCC3)cc2)cc1OCc1c(Cl)cccc1Cl

Procedure:
4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamide was prepared from 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid and 1-amino-3-pyrrolidin-1-yl-propan-2-ol following procedure 4.
Reaction SMILES: CO.[CH3:3][CH:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[N:7]2[C:13](=[O:32])[CH:14]([NH:15][C:16](=[O:31])[C:17](=[N:26][O:27][CH:28]([CH3:30])[CH3:29])[C:18]3[N:19]=[C:20]([NH:23]C=O)[S:21][CH:22]=3)[C@H:6]2[S:5]1.Cl>O1CCCC1>[CH3:3][CH:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[N:7]2[C:13](=[O:32])[CH:14]([NH:15][C:16](=[O:31])[C:17](=[N:26][O:27][CH:28]([CH3:29])[CH3:30])[C:18]3[N:19]=[C:20]([NH2:23])[S:21][CH:22]=3)[C@H:6]2[S:5]1
Reactant: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(NC=O)n1
Agent: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(=NC=O)[nH]1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of methanol (13 ml) and tetrahydrofuran (13 ml) was dissolved 2-methyl-7-[2-isopropoxyimino-2-(2-formylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-isopropoxyimino-2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (1.7 g) and thereto was added concentrated hydrochloric acid (1.5 ml) with stirring at room temperature and then stirring was continued for 2 hours at room temperature. The reaction mixture was concentrated to dryness and the solid was dissolved in water (100 ml) by adding sodium bicarbonate, whereby the resulting mixture was adjusted to pH 7.0. The solution was adjusted to pH 3.0 with concentrated hydrochloric acid under ice-cooling. Precipitates were collected by filtration, washed with water and then dried to give 2-methyl-7-[2-isopropoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-isopropoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (1.2 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:21]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCc1ccc([C@@H]2CCCN2)cc1
Product: CCc1ccc(C2CCCN2S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound, white solid, m.p. 94° C. and MS: m/e=350.3 (M+) was prepared in accordance with the general method of example 1e from (S)-2-(4-ethyl-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CCCCCC.C[O:18][C:19](=O)[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[CH:21]=1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:26][C:22]1[CH:21]=[C:20]([CH2:19][OH:18])[CH:25]=[CH:24][N:23]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCc1ccnc(Cl)c1
Yield: 95 %

Procedure:
A 0.95 M solution of diisobutylaluminum hydride in hexane (200 mL, 190 mmol) was added dropwise to a solution of 2-chloroisonicotinic acid methyl ester (11 g, 62 mmol) in anhydrous tetrahydrofuran (300 mL) under a nitrogen atmosphere under ice-cooling, and then the mixture was stirred under ice-cooling for 2 hours. After that, 1 N hydrochloric acid (200 mL) was added thereto, the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogencarbonate solution (400 mL) was added to the reaction mixture, then the whole was extracted with ethyl acetate (100 mL) three times. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give 8.5 g of the title reference compound as a white solid. (Yield 95%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]3C=CC=CC=3)[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:28](O)(=O)C.IC(C)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:22])[CH3:28])[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cc2cc(O[C@H]3CCN(Cc4ccccc4)C3)ccc2[nH]1
Agent: [Pd]
Solvent: CC(C)I
Solvent: CCO
Product: CCOC(=O)c1cc2cc(O[C@H]3CCN(C(C)C)C3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a mixture of 5-((S)-1-benzyl-pyrrolidin-3-yloxy)-1H-indole-2-carboxylic acid ethyl ester (18.0 g, 1.0 eq.) and acetic acid (28 mL, 10 eq.) in ethanol (500 mL) was added palladium on activated charcoal (10% in mass, 2.0 g, 0.04 eq.) and the reaction vessel was flushed with hydrogen (1 Atm). The reaction mixture was stirred 18 h at room temperature and then filtered off and concentrated in vacuo. The residue (28.4 g) was dissolved in dimethylformamide (500 mL) and potassium carbonate was added. The mixture was stirred 15 min at room temperature. Then 2-iodopropane (42 g, 5.0 eq.) was added and the mixture was stirred 4 h at 50° C. The reaction mixture was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in acetone, filtered and the filtrate was evaporated in vacuo then purified on silica eluting with dichloromethane/methanol/ammoniac. One fraction was isolated and dried in vacuo, to yield 9.3 g (59%) of the desired product as light brown solid. MS (m/e): 317.4 (MH+, 100%).