Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:19]([CH3:21])=[C:18]([CH3:22])[N:17]=[C:16]([NH2:23])[C:15]=2[N:14]=[C:13]1[CH3:24].[N:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)(Cl)Cl>[NH2:23][C:16]1[C:15]2[N:14]=[C:13]([CH3:24])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:31]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:32])[C:20]=2[C:19]([CH3:21])=[C:18]([CH3:22])[N:17]=1
Reactant: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(N)c2nc(C)n(CCCNC(=O)N3CCOCC3)c2c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.9 %

Procedure:
Triethylamine (0.78 mL, 5.6 mmol) was added to a solution of 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (1.00 g, 4.3 mmol) in chloroform (50 mL). The solution was cooled in an ice bath and then 4-morpholinecarbonyl chloride (0.55 mL, 4.7 mmol) was added. After 15 minutes the reaction mixture was removed from the ice bath and allowed to stir at ambient temperature for 2 days. The reaction mixture was diluted with water (30 mL) and the pH was adjusted to 11 with potassium carbonate. The resulting precipitate was isolated by filtration and then recrystallized from isopropanol/water to provide 0.61 g of N-[3-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]morpholine-4-carboxamide as a white solid, m.p. 128.9-129.7° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCCC2)c(C#N)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N4CCCCC4)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-cyano-5-piperidin-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J33) (316 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (420 mg, 77%).
Reaction SMILES: CO[C:3]([CH:5]1[C:9](=O)[CH2:8][O:7][CH2:6]1)=[O:4].[F:11][C:12]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:13]=1[C:14]([NH2:16])=[NH:15]>C(O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:12]([F:11])=[C:13]([C:14]2[N:16]=[C:3]([OH:4])[C:5]3[CH2:6][O:7][CH2:8][C:9]=3[N:15]=2)[CH:17]=1
Reactant: N=C(N)c1cc(Cl)ccc1F
Reactant: COC(=O)C1COCC1=O
Solvent: CCO
Product: Oc1nc(-c2cc(Cl)ccc2F)nc2c1COC2
Temperature: 80 °C
Yield: 29.7 %

Procedure:
To a suspension of 4-oxo-tetrahydrofuran-3-carboxylic acid methyl ester (prepared according to Dowd, P.; Choi, S-C. Tetrahedron, 1991, 47, 4847-4860; 800 mg, 5.55 mmol, 1 eq) in ethanol (20 ml) was added a solution of 2-fluoro-5-chloro-benzamidine (961 mg, 5.55 mmol, 1 eq) in EtOH (10 ml). The reaction mixture was heated to 80° C. overnight. The reaction mixture was cooled to r.t. and the white precipitate was filtered and washed with cold ethyl actetate (2×20 ml). The crude residue was partitioned between chloroform and water. The aqueous layer was acidified to pH 4 and the product was extracted with chloroform (3×50 ml). The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude solid which was purified by flash column chromatography (5% MeOH in EtOAc) to give a white solid 2-(5-chloro-2-fluoro-phenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol (440 mg, 30%).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([NH2:18])=[O:17])[CH2:15][C@@:9]1([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:10]([O:19][CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:42][C:43](=O)[CH3:44].CN(C)C=O>C(OCC)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[O:17][CH:42]=[C:43]([CH3:44])[N:18]=3)[CH2:15][C@@:9]1([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:10]([O:19][CH2:20][C:21]1[CH:22]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reactant: CC(=O)CCl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1coc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Temperature: 120 °C
Reaction time: 24 h
Yield: 12 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl) phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxamide (Example 75; 250 mg, 0.44 mmol), chloroacetone (1 ml) and N,N-dimethylforamide (4 ml) was stirred at 120° C. for 24 hours. After cooling to room temperature the reaction mixture was diluted with diethyl ether (70 ml), washed with saturated aqueous NaHCO3, water and brine. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (53 mg, 12%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C)[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][C:31](=[O:46])[CH:32]([O:41][CH2:42][CH2:43][O:44][CH3:45])[CH2:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:29][O:30][C:31](=[O:46])[CH:32]([O:41][CH2:42][CH2:43][O:44][CH3:45])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:17][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:14][CH:13]=2)=[CH:38][CH:39]=1
Reactant: COCCOC(Cc1ccc(O)cc1)C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(N(C)C(=O)OC(C)(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)OC
Yield: 57 %

Procedure:
2-[4-{tert-Butoxycarbonyl(methyl)amino}phenyl]ethyl-4-methylbenzenesulfonate (described in Example 40a) (0.50 g; 1.26 mmole), 3-(4-hydroxyphenyl)-2-(2-methoxyethoxy)propanoic acid methyl ester(0.32 g; 1.26 mmole) and potassium carbonate (0.35 g; 2.64 mmole) were mixed in acetonitrile (20 ml) and refluxed over night. Water was added, acetonitrile evaporated and the residue extracted three times with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated. Purification of the crude product with preparativ HPLC (Kromasil C8, 7 μm, 50×250 mm) using acetronitrile (50-70%) in ammonium acetate buffer (pH 7) as mobil phase gave 0.34 g (58% yield) of 3-[4-(2-(4-tert-butoxycarbonylaminophenyl}ethoxy)phenyl]-2-(2-methoxyethoxy)propanoic acid methyl ester
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:21]1([C:9]([C:8]2[C:7]([O:6][C:5]3[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:1])([F:20])[F:19])[CH:4]=3)=[N:15][CH:14]=[CH:13][CH:12]=2)=[O:11])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)c1cccnc1Oc1cccc(C(F)(F)F)c1
Reactant: c1ccc2c(c1)CCCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cccnc1Oc1cccc(C(F)(F)F)c1)N1CCCc2ccccc21
Temperature: 100 °C
Yield: 55.5 %

Procedure:
To a solution of 2-(3-trifluoromethyl-phenoxy)-nicotinic acid (200 mg, 0.71 mmol, 1.0 equiv) in anhydrous DMF (3 mL) was added 1,2,3,4-tetrahydro-quinoline (113 mg, 107 μL, 0.85 mmol, 1.2 equiv; [CAS RN 635-46-1]), N-ethyldiisopropylamine (457 mg, 617 μL, 3.53 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (322 mg, 0.85 mmol, 1.2 equiv; [CAS RN 148893-10-1]). The reaction mixture was heated by microwave irradiation to 100° C. for 5 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 157 mg (56%) of the title compound. MS (ISP): 399.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([NH2:17])[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:7]=1.Cl.CN(C)CCC([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O.O>CN(C=O)C>[C:25]1([C:3]2[CH2:2][CH2:7][N:6]3[N:8]=[C:9]([NH2:17])[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)=[C:5]3[N:4]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)CCC(=O)c1ccccc1
Reactant: Nc1nn2cc(Br)cnc2c1-c1ccccn1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nn2c(c1-c1ccccn1)N=C(c1ccccc1)CC2
Temperature: 160 °C
Yield: 90.7 %

Procedure:
6-Bromo-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidin-2-ylamine (0.52 g, 3.01 mmol) and 3-dimethylamino-1-phenyl-propan-1-one hydrochloride (0.64 g, 3.01 mmol) were suspended in dry DMF (10 mL). The mixture was heated at 160° C. for 3 hours with stirring. After allowing the reaction to cool down to room temperature, the mixture was poured into cold water. The resulting precipitate was filtered and dried to afford the title compound as a yellow solid (0.79 g, 93% yield). MS (ES+) 290. δH (DMSO-d6) 3.3 (2H, m), 4.1 (2H, m), 6.1 (2H, s), 7.2 (1H, m), 7.7 (4H, m), 7.9 (1H, t), 8.2 (1H, m), 8.4 (1H, d), 8.6 (1H, d).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: COC(=O)CBr
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)COc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 100 °C
Yield: 27 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (31 mg, 0.23 mmol) and methyl bromoacetate (16 μL, 0.17 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 100° C. for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3.5:0.5:4 followed by trituration with diethyl ether afforded 10 mg (26%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-methoxy-2-oxoethoxy) phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.87 (d, 1H), 8.23 (d, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.92 (t, 1H), 7.50 (t, 1H), 7.42 (s, 1H), 4.81 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [C:1]([O:10]N1C(=O)CCC1=O)([O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7])=O.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:27][NH:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[Na+].[Na+].O>C(Cl)Cl>[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:33][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[CH2:27][N:28]([CH2:29][CH2:30][CH2:31][CH3:32])[C:1]([O:3][CH2:4][CH2:5][Si:6]([CH3:7])([CH3:8])[CH3:9])=[O:10])=[O:24])([CH3:19])([CH3:20])[CH3:21]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CCCCNC[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCN(C[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106.5 %

Procedure:
Solid Teoc-OSu (390 mg, 1.5 mmol) was added to a vigorously stirred 2-phase mixture of (2S)-2-(tert-butoxycarbonylamino)-1-butylamino-3-cyclohexylpropane (312.8 mg, 1.0 mmol), Na2CO3 (525 mg, 5.0 mmol), H2O (5.0 mL), and CH2Cl2 (25.0 mL). The mixture was stirred for 90 min at rt and the reaction was taken up in CH2Cl2 (50 mL), washed with brine (3×10 mL), dried over Na2SO4, decanted, and stripped to give a clear oil. This oil was separated on a 4 g SiO2 column to give crude (2S)-2-(tert-butoxycarbonylamino)-1-(N-butyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropane (486.5 mg, 106%) as a clear oil (quant). MS ESI+ve m/z 479 (M+Na). The crude product was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:17][CH2:16]2)=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc(COc2ccc(N3CCNCC3)nc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(OCc3ccccc3)cn2)CC1
Reaction time: 3 h

Procedure:
A stirred solution of 1-[5-(benzyloxy)pyridin-2-yl]piperazine (104 g, 278 mmol) in CH2Cl2 (1.1L) at 0° C. was treated sequentially with triethylamine (94 mL, 672 mmol) and methanesulfonyl chloride (31 mL, 400 mmol). The reaction was brought to room temperature and stirred for 3 hour. The reaction was then diluted with DCM (3L) and washed with water (1L), HCl (0.5 M, 2×800 mL) and sat. NaHCO3 (800 mL), back-extracting with DCM (500 mL). The combined organic extracts were then dried (MgSO4), filtered and concentrated in vacuo to give 1-[5-(benzyloxy)pyridin-2-yl]-4-(methylsulfonyl)piperazine as a dark liquor (120 g, 278 mmol @ 81 wt %, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Ba+2].[OH-].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:9]1([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccccc2)nc1

Procedure:
A mixture of 2-bromo-5-methylpyridine (2.00 g, 11.63 mmol), phenylboronic acid (1.56 g, 12.79 mmol), barium hydroxide (5.50 g, 17.4 mmol), DME (80 mL) and water (15 mL) was purged with dry argon. Tetrakis(triphenylphosphine)palladium(0) (672 mg, 0.58 mmol) was added, and the resultant solution was stirred at 80° C. for 4 hours. The solvents were evaporated in vacuo, and the residue partitioned between EtOAc and water and acidified with 1M aq. HCl. The aqueous extract was separated, and extracted with EtOAc. The organic extracts were combined, washed with NaHCO3 and 5% aq. Na2S2O3, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, CH2Cl2) to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:15]=[C:14]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[N:13]=[CH:12][C:11]=3[N:28]=2)=[CH:4][CH:3]=1.CS(O[CH2:34][CH2:35][CH:36]1[CH2:38][C:37]1([F:40])[F:39])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:39][C:37]1([F:40])[CH2:38][CH:36]1[CH2:35][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:15]=[C:14]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH3:19])[N:13]=[CH:12][C:11]=3[N:28]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](COc1cc2oc(-c3ccc(O)cc3)nc2cn1)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCCC1CC1(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COc1cc2oc(-c3ccc(OCCC4CC4(F)F)cc3)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A mixture of tert-butyl ((2S)-1-((2-(4-hydroxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate (300 mg), 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (312 mg), potassium carbonate (215 mg) and DMF (5 mL) was stirred overnight at 70° C. The reaction mixture was allowed to cool to room temperature, and 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (935 mg) and potassium carbonate (645 mg) were added thereto. The obtained mixture was stirred overnight at 70° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (239 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=CC(O)=C[CH:5]=1.N[C@H](C(O)=O)CCCNC(=N)N>>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH:4]([CH3:9])[CH3:5]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
Tyr 0.92 (1); Glu 1.02 (1); Arg 0.93 (1)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:13]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:13]=2[CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
To a solution of [(S)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (1.6 g, 4.5 mmol) in DCM (24 mL) was added TFA (12 mL) and the mixture stirred at RT for 1 h. The volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to give the crude material as yellow oil (764 mg, 66%) which was used without further purification. LCMS (Method B): RT 1.63 min [M+H]+ 256.9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:40])[CH2:25][CH2:26][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:64]1[C:69](=[O:70])[CH2:68][CH2:67][C:65]1=[O:66])=[N+](C)C)C>C1COCC1>[C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:40])[CH2:25][CH2:26][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][CH2:29][C:30]([O:32][N:64]1[C:69](=[O:70])[CH2:68][CH2:67][C:65]1=[O:66])=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCNC(=O)CCN(CCC(=O)O)C(=O)OC(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCNC(=O)CCN(CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
17-{3-[tert-Butoxycarbonyl (2-carboxyethyl)amino]propionylamino}heptadecanoic acid tert-butyl ester (0.122 g, 0.2 mmol) was dissolved in THF (5 mL). DIEA (39 ul) was added and the mixture was cooled to 0° C. TSTU (66 mg, 0.22 mmol) was added. The mixture was stirred at 0° C. for 30 min, then for 16 h at RT. The mixture was concentrated under vacuum. AcOEt (15 mL) and the solution was washed with 0.2 N HCl (5 ml) and sat. NaCl (5 ml), dried over MgSO4, and dried under vacuum. The residue was purified by flash chromatography (silica) eluting with AcOEt/heptane (9:1) and AcOEt. The appropriate fractiones were pooled and concentrated under vacuum to yield 58 mg.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=O.[CH3:9][C:10]1[N:11]=[C:12]([NH2:21])[S:13][C:14]=1[CH2:15][CH2:16][O:17][N+:18]([O-:20])=[O:19]>>[CH3:9][C:10]1[N:11]=[C:12]([NH:21][C:6]([CH:2]2[CH2:3][CH2:4][CH2:5][NH:1]2)=[O:8])[S:13][C:14]=1[CH2:15][CH2:16][O:17][N+:18]([O-:20])=[O:19]
Reactant: Cc1nc(N)sc1CCO[N+](=O)[O-]
Reactant: O=C(O)C1CCCN1
Product: Cc1nc(NC(=O)C2CCCN2)sc1CCO[N+](=O)[O-]
Yield: 55 %

Procedure:
Pet-160 was prepared according to the general procedure described hereinabove and the procedure described above for the preparation of Pet-154, using pyrrolidine-2-carboxylic acid and 4-methyl-5-(2-nitrooxy-ethyl)-thiazol-2-ylamine (Pet-10) as the starting materials, in an overall yield of 55%.
Reaction SMILES: O.[Na].[Na].[Na].[C:5]([C:8]1[N:9]=[N:10][NH:11][C:12]=1[SH:13])([OH:7])=[O:6].CC(O[CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O.O.Cl>CC(C)=O>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][S:13][C:12]3[NH:11][N:10]=[N:9][C:8]=3[C:5]([OH:7])=[O:6])[CH2:28][S:27][C@H:22]12
Reactant: O=C(O)c1nn[nH]c1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3[nH]nnc3C(=O)O)CS[C@H]12

Procedure:
4-Carboxy-1,2,3-triazole-5-thiol trisodium salt hydrate (4.4 g., 20 mmol.) was added to a stirred suspension of 4.08 g. (15 mmol.) of 7-aminocephalosporanic acid in 30 ml. of water and 15 ml. of acetone. The reaction mixture was quickly acidified to pH 7.3 with dilute hydrochloric acid, then heated at 65° for 4.5 hours. The mixture was cooled (ice bath), brought to pH 2.4 with dilute hydrochloric acid and the precipitate was collected, washed with water and acetone and dried in vacuo over phosphorus pentoxide to give the title compound.
Reaction SMILES: C1(S([C:10]2(SC)[CH2:15][C@H:14]3[C@:12]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=4)([CH2:13]3)[CH2:11]2)(=O)=O)C=CC=CC=1.C[OH:27].Cl>C(OCC)(=O)C.CCCCCC>[Cl:23][C:18]1[CH:17]=[C:16]([C@:12]23[CH2:13][C@H:14]2[CH2:15][C:10](=[O:27])[CH2:11]3)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: CSC1(S(=O)(=O)c2ccccc2)C[C@@H]2C[C@]2(c2ccc(Cl)c(Cl)c2)C1
Reactant: CO
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1C[C@@H]2C[C@]2(c2ccc(Cl)c(Cl)c2)C1
Yield: 99 %

Procedure:
(1S,5S)-3-Benzenesulfonyl-1-(3,4-dichlorophenyl)-3-methylsulfanyl-bicyclo[3.1.0]hexane (3.5 g, 8.4 mmol), methanol (15 mL) and concentrated hydrochloric acid (3 mL) were heated to reflux for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane(20:80)). The reaction mixture was concentrated under reduced pressure to remove methanol. The pH of the reaction mass was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous layer was extracted with diethyl ether (300 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 3 g of crude oil, which was purified by preparative HPLC to give 900 mg (45%) of 99% pure product. 1H NMR δ(300 MHz,CDCl3) 0.68-0.70 (1H,t, J=4 Hz), 1.25-1.35 (1H,m), 1.94-2.15 (1H,m), 2.36-2.42 (1H, d, J=10 Hz), 2.59-2.66 (1H,d,J=10 Hz), 2.83-2.89 (2H,m), 6.99-7.03 (1H,dd,J=9,3 Hz), 7.25-7.26 (1H,d,J=3 Hz), 7.36-7.39 (1H,d,J=9 Hz). 13CNMR(CDCl3)δ: 215.28, 143.49, 132.57, 130.4, 130.07, 128.09, 125.41, 45.35, 42.08, 27.20, 23.31, 22.23.