Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C@@H:31](O)[CH2:32][N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C@H:31]([O:1][C:2]1[C:3]([CH2:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2)[CH2:32][N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1
Reactant: O[C@@H](Cn1ccnc1)c1ccc(F)cc1F
Reactant: O=C1CCCc2c1ccc(O)c2CS(=O)(=O)c1ccccn1
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1ccc(F)cc1F)c2CS(=O)(=O)c1ccccn1

Procedure:
The title compound was prepared using the procedure of Example 10, step (b) using 6-Hydroxy-5-(pyridine-2-sulfonylmethyl)-3,4-dihydro-2H-naphthalen-1-one and (R)-1-(2,4-difluoro-phenyl)-2-Imidazol-1-yl-ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:22])[CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:7]2=1.[CH3:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].CCN=C=NCCCN(C)C>N1C=CC=CC=1>[Cl:22][C:4]1[CH:5]=[C:6]2[C:14](=[C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[N:32][C:24]=3[CH3:23])[CH:3]=1)[NH:13][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:7]2=1
Reactant: Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12
Reactant: Cc1ncccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: Cc1ncccc1C(=O)Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
N-(8-amino-6-chloro-9H-β-carbolin-4-yl)-2,2,2-trifluoro-acetamide (90 mg, 0.274 mmol, 1 equiv.) and 2-methylnicotinic acid (45 mg, 0.329 mmol, 1.2 equiv.) were dissolved in 1.5 ml of anhydrous pyridine under N2. EDCI (84 mg, 0.438 mmol, 1.6 equiv.) was added in one portion and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and the resulting dark solids captured by filtration. These solids were titurated in a 3:1 methanol—DMSO solution to give N-[6-chloro-4-(2,2,2-trifluoro-acetylamino)-9H-β-carbolin-8-yl]-2-methyl-nicotinamide as light yellow solids (41 mg, 3%). 1H-NMR (300 MHz, DMSO-d6): δ 11.94 (br, 1H), 11.78 (s, 1H), 10.61 (s, 1), 9.00 (s, 1), 8.64 (d, 1), 8.38 (s, 1H), 8.13 (d, 1), 8.01 (s, 1H), 7.73 (s, 1H), 7.45 (m, 1H), 2.68 (s, 3H). Formic acid standard conditions. DAD RT=1.98 min. M+H=448.
Reaction SMILES: [N:1]([C@@H:4]([CH:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:5]([OH:7])=[O:6])=[N+]=[N-].CCOC(C)=O>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[NH2:1][C@@H:4]([CH:8]([C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[C:5]([OH:7])=[O:6]
Reactant: [N-]=[N+]=N[C@H](C(=O)O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@H](C(=O)O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 100.1 %

Procedure:
(S)-2-Azido-3,3-bis-(4-chloro-phenyl)-propionic acid (0.98 g, 2.9 mmol), Lindlar's catalyst (307 mg, 5 mol % Pd), and EtOAc (29 mL) was placed in a 500 mL Parr bottle. The bottle was pressurized with 50 psi of H2 and shaken overnight in a Parr shaker apparatus. The mixture was diluted with MeOH, and the catalyst was removed by filtration through diatomaceous earth, rinsing with MeOH. The filtrate was concentrated to provide 0.90 g (100%) of the desired amino acid as a white solid. MS (ESI−): mass calcd. for C15H13Cl2NO2, 309; m/z found, 308 [M−H]−. 1H NMR (400 MHz, CD3OD): 7.41-7.22 (m, 8H), 4.46 (d, J=9.1, 1H), 4.26 (d, J=9.1, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][OH:19])[C:11]=2[CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:29]([N:31]=C=O)=[O:30]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][O:19][C:29](=[O:30])[NH2:31])[C:11]=2[CH2:20][C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)n1nc(CO)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: CC(C)n1nc(COC(N)=O)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution containing 100 mg of 5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazole-3-methanol in 3 ml of anhydrous dichloromethane was stirred under nitrogen at 0° C. while 35 μl of trichloroacetyl isocyanate was added dropwise. The mixture was stirred at 0° C. for 2 h. The mixture was evaporated under reduced pressure and then the residue was treated with 2 ml of methanol, 1 ml water and 100 mg of potassium carbonate under nitrogen at 0° C. The mixture was then stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water then extracted with ethyl acetate three times. The combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane (1:49) for the elution to give 67 mg of carbamic acid [5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazol-3-yl]methyl ester as a white solid. Mass spectrum (ESI) m/z 451 [M+H]+. 1H NMR (DMSO) 1.30 (d, 6H), 3.91 (s, 2H), 4.77 (m, 1H), 5.05 (s, 2H), 6.55 (br s, 1H), 6.78 (br s, 1H), 6.79 (s, 2H), 7.08 (d, 2H), 7.39 (s, 1H), 8.30 (d, 2H).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([F:12])=[CH:7][CH:6]=2)[CH3:2].[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.[OH-].[Na+]>C(O)(=O)C.P(=O)(O)(O)O>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1)=[CH:9][C:8]([F:12])=[CH:7][CH:6]=2)[CH3:2]
Reactant: O=C1CCNCC1
Reactant: CCc1cc2cc(F)ccc2[nH]1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1[nH]c2ccc(F)cc2c1C1=CCNCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
2.83 g 2-ethyl-5-fluoro-1H-indole are suspended in 50 ml acetic acid and heated to 90° C. A suspension of 6.66 g 4-piperidone in 15 ml phosphoric acid 2N is added. The reaction mixture is stirred for 3 hours at 90° C., combined with sodium hydroxide solution and the product is extracted with ethyl acetate. 2.85 g product are obtained in the form of a solid. 1H NMR (400 MHz, DMSO): 5.63 (1H, s); 2.73 (2H, q); 1.23 (3H, t).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH3:2].[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[NH:41][CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[N:41]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C#Cc1cccc(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C=C(c1cccc(OC)c1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 90 %

Procedure:
The title compound was synthesized from (3-methoxy-phenyl)-propynoic acid ethyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in a 90% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] δ 7.45–6.68 (m, 9H), 6.49 (m, 2H), 6.23 (s, 1H), 4.37 (m, 2H), 4.13 (q, 2H, J=7.2 Hz), 3.76 (t, 2H, J=5.2 Hz), 3.68 (s, 2.1H), 3.58 (s, 0.9H), 3.20 (m, 2H), 2.73 (t, 2H, J=6.8 Hz), 1.90 (m, 2H), 1.51 (s, 9H), 1.26 (t, 2.1H, J=7.2 Hz), 1.13 (t, 0.9H, J=7.2 Hz). Mass Spectrum (LCMS, ESI) calculated for C30H32N3O4 498.2 (M-Boc+1); found 498.4.
Reaction SMILES: S(Cl)(C)(=O)=O.[C:6]([N:9]1[CH2:14][CH2:13][C:12](O)([Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]1)(=[O:8])[CH3:7].C(N(CC)CC)C.[Na+].[Cl-]>ClCCl>[C:6]([N:9]1[CH2:10][CH:11]=[C:12]([Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:13][CH2:14]1)(=[O:8])[CH3:7]
Reactant: CCCC[Sn](CCCC)(CCCC)C1(O)CCN(C(C)=O)CC1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)C1=CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Under an inert atmosphere, 1.3 equivalents of mesyl chloride in 15 ml of dichloromethane are added dropwise to a solution of 0.16 mmol of the compound obtained in Step A and 2.8 equivalents of triethylamine in 1 litre of dichloromethane at 0° C. After stirring the mixture at ambient temperature for 4 days, a saturated aqueous solution of NaCl is added. After extraction, drying, filtration and concentration of the organic phase under reduced pressure, chromatography of the residue on silica gel (dichloromethane/ethanol: 97/3) enables the expected product to be isolated.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]([C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH:13]([CH3:18])[C:14]2=[O:17])=[CH:10][C:9]=1[O:19][C:20]1[C:25]([F:26])=[C:24]([F:27])[C:23]([F:28])=[C:22]([F:29])[C:21]=1[F:30])([CH3:7])[CH3:6].[Br:31]Br>ClCCl.[O-]S([O-])=O.[Na+].[Na+]>[Br:31][C:10]1[C:9]([O:19][C:20]2[C:21]([F:30])=[C:22]([F:29])[C:23]([F:28])=[C:24]([F:27])[C:25]=2[F:26])=[C:8]([CH:5]([CH3:6])[CH3:7])[CH:16]=[C:15]2[C:11]=1[CH2:12][CH:13]([CH3:18])[C:14]2=[O:17]
Reactant: CC1Cc2cc(Oc3c(F)c(F)c(F)c(F)c3F)c(C(C)C)cc2C1=O
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2c(cc(C(C)C)c(Oc3c(F)c(F)c(F)c(F)c3F)c2Br)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 17.5 g (131 mmol) of AlCl3 in 28 ml of dichloromethane cooled to −20° C. a solution of 32.4 g (87.5 mmol) of 6-isopropyl-2-methyl-5-(pentafluorophenoxy)indan-1-one in 46 ml of dichloromethane was added dropwise. Further on, this solution was warmed to 0° C., and 4.80 ml (96.0 mmol) of bromine was added dropwise by vigorous stirring for 0.5 h. This mixture was stirred for 24 h at room temperature and then poured in cold aqueous Na2SO3 to remove an excess of bromine. The product was extracted with 3×50 ml of dichloromethane. The combined extract was evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: n-hexane-dichloromethane-ether 50:50:1, vol.). Yield 20.1 g (51%). Additionally, 15.0 g of the starting indanone was recovered.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[C:4]([OH:11])[CH:3]=1.Cl[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])=[O:15].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]([CH3:9])=[C:13]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[O:15])[O:11][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1O
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Temperature: 90 °C
Reaction time: 38 h
Yield: 44.1 %

Procedure:
To a stirred solution of 1-(4-Bromo-2-hydroxy-phenyl)-ethanone (2.81 g, 13.1 mmol, from step 1) and 2-chloro-1-(2,4-dichlorophenyl)ethanone (6.88 g, 30.8 mmol, 2.3 eq) in anhydrous N,N-dimethylformamide (50 mL) was added K2CO3 (7.42 g, 53.7 mmol, 4.0 eq). The dark brown reaction mixture was stirred at 90° C. for 38 h. The reaction was poured into ethyl acetate (100 mL) and water (100 mL) after cooled down to rt. Extracted with ethyl acetate (3×50 mL). The organic layer was dried (Na2SO4), filtered, and evaporated in vacuo. The crude product was washed by hexane (2×30 mL) followed by ethyl ether (2×30 mL) to provide 2.22 g (44%) of the desired compound as light yellow solid. 1H-NMR (CDCl3) δ 7.64 (d, J=1.9 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.49 (d, J=1.9 Hz, 1H), 7.45-7.36 (m, 3H), 2.57 (s, 3H); MS LC-MS (MH+=385).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[Li]C(C)(C)C.CCCCCC.[I:26]I>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]([I:26])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
To a solution of N-(6-chloropyridin-2-yl)-2,2-dimethylpropionamide (20 g, 94 mmol) in dry THF (500 mL) at −78° C., 1.3 M t-BuLi in hexane (220 mL, 282 mmol) is added dropwise. The reaction mixture is stirred for 30 min and a solution of iodine (29 g, 114 mmol) in dry THF is added. The reaction mixture is stirred for 3 h at −78° C. then is warmed to ambient temperature and stirred for another 1 h. The reaction mixture is quenched with 1N HCl and is extracted with ethyl acetate (2×250 mL). The organic layers are separated and washed with Na2S2O3 solution and saturated NaHCO3 solution, respectively. The combined organic layers are dried (Na2SO4) and evaporated under reduced pressure. The crude residue is purified by flash column chromatography using 20% EtOAc/petroleum ether to afford the title compound as a pale yellow solid (15 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH:20]=[C:19]([C:21]([NH2:23])=[O:22])[C:18]([C:24]([F:27])([F:26])[F:25])=[N:17]1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:23][C:21]([C:19]2[C:18]([C:24]([F:25])([F:27])[F:26])=[N:17][N:16]([CH3:15])[CH:20]=2)=[O:22])=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1c1ccc(Cl)cc1
Reactant: Cn1cc(C(N)=O)c(C(F)(F)F)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)NC2=C(c3ccc(Cl)cc3)CCCC2)c(C(F)(F)F)n1
Yield: 57.4 %

Procedure:
0.521 g 2-(4-chlorophenyl)-cyclohexanone (prepared as described in J. Org. Chem. 70, 2005, page 2967) and 0.482 g 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid amide were suspended with 5 mg p-toluenesulfonic acid in 20 ml toluene and heated to reflux temperature of the solvent for 24 hours under continuos removal of water. The reaction mixture was washed with 5% sodium bicarbonate and water, dried and the solvent was removed under vacuum. The reaction product was purified by chromatography on a silica gel column (eluent: ethylacetate:hexane 1:1). 0.55 g 1-Methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [2-(4-chlorophenyl)-cyclohex-1-enyl]-amide was obtained in the form of crystals (m.p. 145-148° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=[O:18])[CH2:13][CH:12]1[CH:24]([NH:26][C:27]1[N:32]=[C:31]([N:33]2[C:37]3[CH:38]=[CH:39][C:40]([N:42]4[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[C:43]4=[O:49])=[CH:41][C:36]=3[N:35]=[CH:34]2)[CH:30]=[CH:29][N:28]=1)[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:50]1([N:60]=C=O)[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52][CH:51]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:18])[NH:60][C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH:53]=[CH:52][CH:51]=2)[CH2:13][CH:12]1[CH:24]([NH:26][C:27]1[N:32]=[C:31]([N:33]2[C:37]3[CH:38]=[CH:39][C:40]([N:42]4[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[C:43]4=[O:49])=[CH:41][C:36]=3[N:35]=[CH:34]2)[CH:30]=[CH:29][N:28]=1)[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1CCN(c2ccc3c(c2)ncn3-c2ccnc(NC(C)C3CN(C(=O)OC(C)(C)C)CCN3C(=O)OCc3ccccc3)n2)C1=O
Reactant: O=C=Nc1cccc2ccccc12
Product: CCN1CCN(c2ccc3c(c2)ncn3-c2ccnc(NC(C)C3CN(C(=O)Nc4cccc5ccccc45)CCN3C(=O)OCc3ccccc3)n2)C1=O

Procedure:
The title compound was prepared from 2-[1-(1-(benzyloxycarbonyl)-4-(tert-butyloxycarbonyl)-piperazine-2-yl)-ethylamino]-4-[5-(3-ethyl-imidazolidin-2-on-1-yl)benzimidazol-1-yl]pyrimidine (35 mg) and naphthyl isocyanate (10 mg) according to the procedure described in EXAMPLE 14, Step F. Mass spectrum (ESI) 739.5 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1.[H-].[Na+].[CH2:15](OS(OCC)(=O)=O)[CH3:16].O>CS(C)=O>[CH2:15]([O:1][CH2:2][C@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1)[CH3:16]
Reactant: OCC1Cc2ccccc2CN1
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC[C@H]1Cc2ccccc2CN1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 500 mg (3.06 mmol) of (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline in 10 mL of DMSO was added 122 mg (3.06 mmol) of NaH (60% in oil) and the mixture was stirred for 45 minutes at room temperature. Then 0.403 mL (3.06 mmol) of diethylsulfate was added via syringe. Foaming occurred and subsided in approximately 15 minutes. The reaction mixture was then stirred at room temperature overnight and poured into water. The product was extracted into ethyl acetate and dried and evaporated to an oil. This was chromatographed on silica gel to give the desired product as an oil, 190 mg. 1H-NMR (CDCl3) δ 1.22 (3H, t, J=7), 2.29 (1H, broad s), 2.55-2.70 (2H, m), 3.09-3.18 (1H, m), 3.41 (1H, t, J=7), 3.50-3.59 (3H, m), 4.06 (2H, ABq, J=5, 21), 7.00-7.13 (4H, m).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:35][C:36]1[S:37][CH:38]=[C:39]([C:41](=[N:45][O:46][CH2:47][C:48]2[NH:52][N:51]=[N:50][N:49]=2)[C:42](O)=[O:43])[N:40]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:53][CH:54]1[C:73](=[O:74])[N:56]2[C:57]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])=[C:58]([CH2:61][O:62][C:63](=[O:65])[CH3:64])[CH2:59][S:60][C@H:55]12.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C>[C:63]([O:62][CH2:61][C:58]1[CH2:59][S:60][C@@H:55]2[CH:54]([NH:53][C:42](=[O:43])[C:41]([C:39]3[N:40]=[C:36]([NH:35][C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[S:37][CH:38]=3)=[N:45][O:46][CH2:47][C:48]3[NH:52][N:51]=[N:50][N:49]=3)[C:73](=[O:74])[N:56]2[C:57]=1[C:66]([O:68][C:69]([CH3:70])([CH3:72])[CH3:71])=[O:67])(=[O:65])[CH3:64]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)C(=NOCc1nnn[nH]1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOCc3nnn[nH]3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.5 g of dicyclohexylcarbodiimide in 5 ml of methylene chloride was added to a mixture of 1.024 g of the product of Step C, 0.656 mg of tert.-butyl 7-amino-3-acetoxymethyl-ceph-3-eme-4-carboxylate and 2 ml of pyridine and the mixture was stirred for one hour at room temperature. The mixture was vacuum filtered and 25 ml of N hydrochloric acid were added to the filtrate. The mixture was stirred for 5 minutes and the decanted organic phase was washed with 25 ml of water, was dried and evaporated to dryness under reduced pressure. The residue was taken up in isopropyl ether and efflorescenced. The mixture was vacuum filtered and the recovered product was rinsed with isopropyl ether and dried to obtain 1.778 g of raw product. The latter was dissolved in 4 ml of ethyl acetate and the solution was treated with activated carbon and was filtered. 20 ml of isopropyl ether were added to the filtrate over 5 minutes with stirring and after stirring for another 5 minutes, the mixture was vacuum filtered. The recovered product was rinsed with isopropyl ether and dried to obtain 1.412 g of the syn isomer of tert.-butyl 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(tetrazol-5-yl-methyloxyimino)-acetamido]-ceph-3-eme-4-carboxylate in the form of a white product melting at 158° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
6 g of Boc-Phe-PAM resin (substitution 0.36 mmol/g) was suspended and shaken in TFA/CH2Cl2 (1:1 by volume, 3×50 mL) 10 min. each time at room temperature to remove the Boc-group. The product was isolated by filtration and washed (3×50 mL each) with CH2Cl2 8% DIEA in CH2Cl2 and CH2Cl2 to give the free base of Phe-PAN-resin. This was subjected to sequential solid phase synthesis using the Fmoc-protocol. All couplings were performed using the DCC/HOBT procedure. At step 7 the Fmoc-amino acid, DCC, and HOBT were added with the corresponding reaction times as follows: Fmoc-Asp(OtBu)-OH (2.46 g. 6 mmol), DCC (1.24 g. 6 mmol) and HOBT (1.2 g, 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min at room temperature. Fmoc-Met-OH (2.2 g, 6 mmol), DCC (1.24 g. 6 mmol) and HOBT (1.2 g, 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2 - and allowed to couple for 60 min at room temperature. Fmoc-Trp-OH (2.6 g, 6 mmol), DCC (1.24 g. 6 mmol) and HOBT (1.2 g, 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2 - and allowed to couple for 60 min at room temperature. Fmoc-Gly-OH (1.8 g. 6 mmol), DCC (1.24 g. 6 mmol) and HOBT (1.2 g. 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min. Fmoc-Met-OH (2.2 g. 6 mmol), DCC (1.24 g. 6 mmol) and HOBT (1.2 g. 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min at room temperature. At this point the peptide-resin was dried under high vacuum to provide 7.98 g of Fmoc-Met-Gly-Trp-Met-Asp(OtBu)-Phe-PAM resin.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:15][C:14](=S)[CH2:13][CH2:12][S:11](=[O:18])(=[O:17])[CH:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:9]=2[CH:26]=1>O1CCCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:15]=[C:14]([NH:2][NH2:3])[CH2:13][CH2:12][S:11](=[O:18])(=[O:17])[CH:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:9]=2[CH:26]=1
Reactant: NN
Reactant: O=S1(=O)CCC(=S)Nc2ccc(Cl)cc2C1c1ccccc1F
Solvent: O
Solvent: C1CCOC1
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of 0.9 ml of hydrazine hydrate in 134 ml of tetrahydrofuran is treated with 6.2 g of 8-chloro-6-(2-fluorophenyl)-1,3,4,6-tetrahydro-2-thiono-2H-5,1-benzothiazocine 5,5-dioxide. The solution is stirred at room temperature under a stream of argon for 1.25 hours and then evaporated in vacuo. The residue is crystallized from diisopropyl ether, there being obtained 8-chloro-6-(2-fluorophenyl)-2-hydrazino-3,6-dihydro-4H-5,1-benzothiazocine 5,5-dioxide of melting point 159°.