Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[O:17][CH2:18][C:19]([N:21]1[CH2:26][C@H:25]([CH3:27])[N:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:23][C@H:22]1[CH3:36])=[O:20])=[O:9])C.O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH2:18][C:19]([N:21]2[CH2:26][C@H:25]([CH3:27])[N:24]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:23][C@H:22]2[CH3:36])=[O:20])=[C:10]([C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]([OH:37])=[O:3])[CH:15]=1
Reactant: CCOC(=O)CCCC(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)CCCC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
To a solution of 5-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-5-oxo-pentanoic acid ethyl ester (0.089 g, 0.17 mmol) in 2:2:1 tetrahydrofuran:methanol:H2O (2 mL) was added lithium hydroxide hydrate (0.025 g, 0.60 mmol). The reaction was stirred at ambient temperature for 4 hours. The pH was then adjusted to 4 with 0.2 M hydrochloric acid. The solution was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Anion exchange chromatography (MCX) provided the title compound (0.014 g, LRMS: 505.5, 507.5).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]O)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].S(Cl)([Cl:23])=O>>[Cl:23][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCO
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCCl
Temperature: 80 °C
Yield: 4805.9 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 5-[(3-nitroquinolin-4-yl)amino]pentan-1-ol (5.0 g, 18.16 mmol), and thionyl chloride (40.78 g, 0.34 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 80° C. to give a homogeneous solution that was maintained at 80° C. for 1 hour at which time the starting material was completely consumed. The volatiles were removed under reduced pressure and the resulting oil stirred in water made basic (pH 10) with solid sodium carbonate. The resulting solid was collected by filtration to afford N-(5-chloropentyl)-3-nitroquinolin-4-amine (4.80 g, 16.34 mmol) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]([F:17])([F:16])[C:11]([N:13]([CH3:15])[CH3:14])=[O:12].C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O.C1(C)C=CC=CC=1>[F:16][C:10]([F:17])([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12]
Reactant: CN(C)C(=O)C(F)(F)Br
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)C(F)(F)Oc1cccc(F)c1
Temperature: 100 °C
Yield: 89 %

Procedure:
A mixture of 3-fluoro-phenol (9.8 g, 87.4 mmol), 2-bromo-2,2-difluoro-N,N-dimethyl-acetamide (18.3 g, 89.6 mmol) and K2CO3 (13.3 g, 96.2 mmol) in 75 g of dimethylacetamide (DMAC) was heated to 100° C. for 1 h and then heated to 120° C. for 2 h. The reaction mixture was then cooled to room temperature and poured on 250 mL of H2O and 50 mL of toluene. The aqueous phase was extracted with 25 g of toluene. The combined organic layers were extracted with 5% NaOH (20 g) and H2O (2×20 g) and dried over Na2SO4. The product (18.5 g, >98% purity by quant. HPLC, 77.8 mmol, 89% yield) was obtained after removal of all volatiles under reduced pressure as a slightly yellow liquid. The material could be used in subsequent steps without further purification or purified by fractionated distillation.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][O:27]CC)[N:14]([CH2:15][C:16]([NH:19][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.B(Br)(Br)Br.[OH-].[Na+]>ClCCl.C(#N)C.Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][OH:27])[N:14]([CH2:15][C:16]([NH:19][C:20]([NH:22][CH:23]([CH3:24])[CH3:25])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NC(=O)NC(C)C
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)NC(=O)NC(C)(C)Cn1c(CO)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 30244.4 %

Procedure:
Under a nitrogen atmosphere, a suspension of 1-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-3-(1-methylethyl)urea (1.19 g, 2.99 mmol) in dichloromethane (30 mL) was chilled in an ice bath. Boron tribromide (7.47 mL of 1 M in dichloromethane) was added. The reaction mixture was allowed to warm slowly to ambient temperature and then stirred for 18 hours. Additional boron tribromide (2 eq) was added. After 2 hours the reaction mixture was diluted with acetonitrile (10 mL) and the reaction mixture was stirred overnight. The reaction mixture was diluted with dichloromethane (10 mL) and acetonitrile (10 mL), stirred for an additional 16 hours, quenched with methanol (25 mL), and then concentrated under reduced pressure to provide an orange foam. The foam was dissolved in hydrochloric acid (25 mL of 6 N) and heated at 50° C. for 2 hours. The solution was neutralized with 50% sodium hydroxide. The resulting gummy precipitate was extracted with chloroform (3×15 mL). The combined organics were washed with brine (15 mL), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide an off white solid. This material was purified by prep HPLC (HORIZON HPFC system, eluting with a gradient of 15-50% CMA in chloroform) and then recrystallized from acetonitrile to provide 335 g of 1-[2-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-3-(1-methylethyl)urea as a white crystalline solid, mp 196-199° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.38 (d, J=8.0 Hz, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.43-7.38 (m, 1H), 7.24-7.19 (m, 1H), 6.54 (s, 2H), 5.72 (s, 1H), 5.63 (d, J=7.6 Hz, 1H), 5.46 (t, J=5.7 Hz, 1H), 5.01 (s, 2H), 4.78 (s, 2H), 3.78-3.67 (m, 1H), 1.17 (bs, 6H), 1.05 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 157.2, 154.2, 152.3, 145.6, 134.3, 126.8, 126.7, 121.5, 120.9, 115.8, 56.5, 54.2, 52.1, 26.4, 23.6; MS (APCI) m/z 371 (M+H)+; Anal. Calcd for C19H26N6O2.0.3H2O: % C, 60.72; % H, 7.13; % N, 22.36. Found: % C, 60.44; % H, 7.42; % N, 22.52.
Reaction SMILES: [ClH:1].C[C:3]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([CH3:21])[C:4]=1[CH2:5][C@@H:6]([C:8]([NH:10][C@@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[NH2:7]>CO>[ClH:1].[CH3:21][C:16]1[CH:17]=[C:18]([OH:20])[CH:19]=[CH:3][C:4]=1[CH2:5][C@@H:6]([C:8]([NH:10][C@@H:11]([C:13]([NH:10][CH2:8][CH2:6][CH2:5][C:4]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:3]=1)=[O:15])[CH3:12])=[O:9])[NH2:7]
Reactant: Cc1cc(O)cc(C)c1C[C@H](N)C(=O)N[C@H](C)C(=O)O
Agent: Cl
Solvent: CO
Product: Cc1cc(O)ccc1C[C@H](N)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1

Procedure:
The title compound was prepared by the method of Example 4 from diastereomer F of the title compound of Example 11, Route B. [α]D -23.8 (MeOH)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C@:17]23[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:18]2[C@@H:19]2[C@@:32]([CH3:35])([CH2:33][CH2:34]3)[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:38])([CH3:37])[C:26]([C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:55](N1CCNCC1)([CH3:58])([CH3:57])[CH3:56]>>[C:55]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][C@:17]23[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:18]2[C@@H:19]2[C@@:32]([CH3:35])([CH2:33][CH2:34]3)[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:38])([CH3:37])[C:26]([C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20]2)[CH2:12][CH2:13]1)([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)N1CCNCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)amino)-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)benzoic acid using 1-(tert-butyl)piperazine as the alkylating reagent in Step 3. The product was isolated as a white solid (9 mg, 40%). LCMS: m/e 698.67 (M+H)+, 2.27 min (method 11). 1H NMR (500 MHz, Acetic) δ 8.04 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 5.38 (d, J=5.2 Hz, 1H), 4.84 (s, 1H), 4.74 (s, 1H), 3.77 (br. s., 2H), 3.51-2.82 (m, 11H), 2.41-1.16 (m, 22H), 1.77 (s, 3H), 1.49 (s, 9H), 1.30 (s, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[C:3]=1[CH2:11][CH3:12].[NH2:13][C@@H:14]([C:18]([OH:20])=[O:19])[C@H:15]([CH3:17])[OH:16].C(=O)([O-])[O-].[K+].[K+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CS(C)=O>[Cl:10][C:4]1[C:3]([CH2:11][CH3:12])=[C:2]([NH:13][C@H:14]([C@@H:15]([OH:16])[CH3:17])[C:18]([OH:20])=[O:19])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: CCc1c(F)ccc(C#N)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reaction time: 0.17 h
Yield: 467.3 %

Procedure:
4-Fluoro-2-chloro-3-ethyl benzonitrile (1.0 g, 5.45 mmol), D-threonine (779 mg, 6.54 mmol), potassium carbonate (1.51 g, 10.9 mmol) and DMSO (6 mL) were heated at 85° C. for 17.5 h. The reaction mixture was allowed to cool to room temperature whereupon water (20 mL) was added followed by citric acid monohydrate (2 g). After stirring for 10 min the mixture was partitioned between EtOAc (40 mL) and water. The organic phase was then washed with water (15 mL), brine (15 mL), dried (Na2SO4) and concentrated to furnish a pale yellow solid (7.2 g). This crude product was then passed through a silica-plug [hexanes-EtOAc (95:5) as eluent] to furnish a white solid (928 mg), which was used directly in the next step.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[C:7]1([S:17](Cl)(=[O:19])=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1>O>[C:7]1([S:17]([OH:19])=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S(O)c1cccc2ccccc12
Reaction time: 5 h
Yield: 95.4 %

Procedure:
189 g of sodium sulfite was dissolved in 600 ml of water, the solution was warmed at a temperature ranging from 60° to 70° C., 68 g of 1-naphthalenesulfonyl chloride was added and then the mixture was reacted at a temperature ranging from 50° to 60° C. for 5 hours. Insolubles were filtered off, the temperature of the reaction solution was brought back to room temperature and the solution was acidified by addition of conc. hydrochloric acid. The resulting precipitates were collected by filtration to give 55 g of 1-naphthalene sulfinic acid.
Reaction SMILES: [C@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[NH2:7].O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@@H:1]1[NH:8][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: N[C@H]1CCCC[C@@H]1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N[C@H]2CCCC[C@@H]2N)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.1 %

Procedure:
To a solution of (1S,2S)-cyclohexane-1,2-diamine (4 g, 35.08 mmol) in dichloromethane (80 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (3.49 g, 17.54 mmol) followed by sodium triacetoxy borohydride (11.15 g, 52.60 mmol) and stirred at room temperature for 5 hours. A saturated solution of sodium hydrogen carbonate (10 mL) was then added and the reaction diluted in dichloromethane (100 mL). The phases were separated and aqueous phase was extracted with dichloromethane (2×60 mL). Combined organic layers was washed with brine, dried and concentrated in vacuo. The crude compound was purified by flash chromatography to provide the titled compound as yellow oil (3.5 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[CH:27][C:28]([OH:33])=[C:29]([CH:32]=2)[CH:30]=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CN1CCCC1=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:26]=[CH:27][C:28]3[O:33][C:2]([C:3]([NH2:5])=[O:4])=[CH:30][C:29]=3[CH:32]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: NC(=O)CCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)c(C=O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3oc(C(N)=O)cc3c2)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
5 ml of 1-methyl-2-pyrrolidone, 0.16 g of chloroacetamide and 0.25 g of potassium carbonate are added at 20° C. with stirring/under nitrogen to 0.5 g of 5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde. The mixture is stirred at 60° C. for 16 hours, cooled and then filtered, and the solvent is removed under reduced pressure. The residue is taken up in MTB ether, re-filtered and concentrated, and the residue is crystallized from toluene. The isolated yield is 0.34 g (60%).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a suspension of adenine (5) (5.00 g, 37.0 mmol) in dry DMF (120 mL) was added NaH (1.77 g, 44.4 mmol) at room temperature. The reaction mixture was stirred for 30 min and the resulting white suspension was warmed to 60° C. for an additional 30 min. Benzyl bromide (7.59 g, 44.4 mmol) was added and the mixture was stirred for 24 h at 60° C. TLC of the reaction mixture indicated the formation of two products. DMF was distilled off under reduced pressure and the resulting residue was treated with water (20 mL). The white solid that separated out, was filtered and dried under vacuum. Separation and purification was through flash column chromatography using CHCl3:MeOH (9:1) for elution. 9-Benzyladenine: yield 5.5 g. (66%); mp 231-232° C.; 1H NMR (DMSO-d6: δ 5.38 (s, 2H, CH2), 7.29-7.33 (m, 7H, Ar—H and NH2), 8.17 (s, 1H, purine C8—H), 8.28 (s, 1H, purine C2—H). 7-Benzyladenine: yield 1.8 g. (21%). Mp 252-255° C. 1H NMR (DMSO-d6): δ 5.53 (s, 2H, CH2), 7.29-7.48 (m, 5H, Ar—H), 7.81 (s, 1H, purine C8—H), 8.0-8.1 (br, 2H, NH2), 8.6 (s, 1H, purine C2—H).
Reaction SMILES: [N+](C1C=CC(COC([NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]3[CH2:24][C@H:23]([S:25][C:26]4[C@H:27]([CH3:50])[C@@H:28]5[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]5[C:30]=4[C:31]([O:33]CC4C=CC([N+]([O-])=O)=CC=4)=[O:32])[CH2:22][N:21]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:19])[CH2:14]2)=O)=CC=1)([O-])=O.[ClH:66]>O1CCCC1.O>[ClH:66].[NH2:12][C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]2[CH2:24][C@H:23]([S:25][C:26]3[C@H:27]([CH3:50])[C@@H:28]4[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]4[C:30]=3[C:31]([OH:33])=[O:32])[CH2:22][NH:21]2)=[O:19])[CH2:14]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CC[C@@H](N)C4)C3)[C@H](C)[C@H]12

Procedure:
730 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3R)-3-(4-nitrobenzyloxycarbonyl)aminopyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.75 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 1.0 g of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 18(b), to give 120 mg of the title compound, as a powder.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=[N:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].C(O)C>[CH2:26]([NH:25][C:23]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])=[CH:21][N:20]=1)=[O:24])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCNC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccccc3)CC2)cn1
Agent: [Pd]
Solvent: CCO
Product: CCCCNC(=O)Nc1ccc(C(=O)N2CCNCC2)cn1
Yield: 98 %

Procedure:
1-(5-(4-Benzylpiperazine-1-carbonyl)pyridin-2-yl)-3-butylurea (58 mg, 0.147 mmol) and palladium on carbon 10% (15.61 mg, 0.015 mmol) were stirred in ethanol (2.5 mL containing 3 drops of 5M hydrochoric acid) under a hydrogen atmosphere at 5 bar at room temperature overnight. The mixture was filtered and the residue was taken up in dichloromethane/methanol and loaded on to a strong cation exchange column (2 g) and washed with dichloromethane/methanol. Elution of the column with 2M ammonia in methanol gave the title compound (44 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[CH3:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=1.C[Si](C)(C)N[Si](C)(C)C.[Li]>O1CCCC1.C(OCC)(=O)C.O.C1CCCCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:14]([C:13]2[CH:18]=[CH:19][C:10]([CH3:9])=[CH:11][CH:12]=2)=[O:15])[CH:3]=1
Reactant: Cc1cc(Br)ccn1
Reactant: COC(=O)c1ccc(C)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Cc2cc(Br)ccn2)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
1 g (5.81 mmol) of 4-bromo-2-methylpyridine and 1.75 g (11.60 mmol) of methyl 4-methylbenzoate are placed in a round-bottomed flask and dissolved in 30 ml of anhydrous tetrahydrofuran under a stream of nitrogen. The solution is cooled to 5° C. and 14 ml (14 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at ambient temperature for 2 h 30 and then cooled to 5° C., before gradually adding 20 ml of water. The medium is subsequently diluted with 200 ml of ethyl acetate and 200 ml of water. The organic phase is separated, dried over sodium sulphate and filtered. 5 g of silica are subsequently added to the filtrate before concentrating it under reduced pressure. The powder obtained is used as solid deposit for chromatography on silica gel with a mixture of cyclohexane and ethyl acetate (95/5) as eluent. 1.03 g (61%) of compound are obtained in the form of a yellow powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si:22]([O:29][C@@H:30]([CH3:60])[C@@H:31]([NH:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[C:49]([C:55]([F:58])([F:57])[F:56])[C:48]=1[CH3:59])[C:32]([NH:34][NH:35][C:36](=O)[C:37]1[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=1)=[O:33])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl>[Si:22]([O:29][C@@H:30]([CH3:60])[C@@H:31]([NH:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[C:49]([C:55]([F:58])([F:56])[F:57])[C:48]=1[CH3:59])[C:32]1[O:33][C:36]([C:37]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=2)=[N:35][N:34]=1)([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:23])[CH3:24]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Yield: 98.8 %

Procedure:
Triphenylphosphine (374 mg, 1.43 mmol) was dissolved in 25 mL of DCM followed by addition of I2 (362 mg, 1.43 mmol) and TEA (289 mg, 2.85 mmol) at 0° C. N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)butanoyl)-4-cyanobenzohydrazide (400 mg, 0.71 mmol) in 15 mL DCM was added to the precooled solution mixture of PPh3/I2/TEA system and stirred. The temperature was allowed to rise to room temperature and stirred for an additional 10 min. The reaction was quenched with 50 mL saturated sodium thiosulfate and extracted with EtOAc. The crude mixture was chromatographed to give the product (380 mg) 1H NMR (400 MHz, acetone-d6, δ in ppm): 8.39 (d, J=9 Hz, 2H), 8.19 (d, J=9 Hz, 2H), 7.79 (d, J=9 Hz, 1H), 7.32 (d, J=9 Hz, 1H), 5.88 (d, J=9 Hz, 1H), 5.53 (m, 1H), 4.99 (m, 1H), 2.61 (m, 3H), 1.67 (d, J=6 Hz, 3H), 1.02 (s, 9H), 0.29 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C.[F:31][C:32]([F:53])([F:52])[C:33]1[O:37][N:36]=[C:35]([C:38]2[CH:39]=[C:40]([CH:49]=[CH:50][CH:51]=2)[C:41]([NH:43][CH2:44][CH2:45][C:46]([OH:48])=O)=[O:42])[N:34]=1.O[N:55]=[C:56]([NH2:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>ClCCl.CN(C=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:57]1([C:56]2[N:63]=[C:46]([CH2:45][CH2:44][NH:43][C:41](=[O:42])[C:40]3[CH:49]=[CH:50][CH:51]=[C:38]([C:35]4[N:34]=[C:33]([C:32]([F:31])([F:53])[F:52])[O:37][N:36]=4)[CH:39]=3)[O:48][N:55]=2)[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: NC(=NO)c1ccccc1
Reactant: O=C(O)CCNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(NCCc1nc(-c2ccccc2)no1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 6.7 %

Procedure:
HOBt (47 mg, 0.35 mmol), EDCI (67 mg, 0.35 mmol), and diisopropylethylamine (0.7 mL, 1.0 mmol) were added to a solution of 3-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamido)propanoic acid (115 mg, 0.35 mmol) and N′-hydroxybenzimidamide (47 mg, 0.35 mmol) in dichloromethane (3.5 mL) with a few drops of DMF. The reaction was stirred 1 h and then toluene was added and the reaction was heated to 90° C. for 1 h. The reaction was diluted with ethyl acetate and the organic layer was washed with saturated sodium bicarbonate and dried over sodium sulfate. The product was purified on reverse phase using water/acetonitrile to give N-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide (10 mg, yield 7%). 1H NMR (CDCl3) δ 8.60 (s, 1H), 8.22 (m, 1H), 8.10 (m, 3H,) 7.60 (m, 1H), 7.55-7.45 (m, 3H), 4.05 (m, 2H), 3.26 (m, 2H). MS (ESI) m/z: Calculated for C20H14F3N5O3: 429.10. found: 430.1 (M+H)+.