Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:15][N:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:15][N:14]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Product: O=C(Nc1cc(-c2ccccc2)[nH]n1)c1cc(Br)ccc1O
Yield: 9.2 %

Procedure:
Using 5-bromosalicylic acid and 3-amino-5-phenylpyrazole as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([NH:16][C:17]1[C:18]([CH3:26])=[C:19]3[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[CH:20]3)[CH2:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH:9]12[NH:8][CH:13]([CH2:14][CH2:15]1)[CH2:12][CH:11]([NH:16][C:17]1[C:18]([CH3:26])=[C:19]3[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[CH:20]3)[CH2:10]2
Reactant: Cc1c(NC2CC3CCC(C2)N3Cc2ccccc2)ccc2[nH]ncc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1c(NC2CC3CCC(C2)N3)ccc2[nH]ncc12
Yield: 87.4 %

Procedure:
To a solution of the N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1H-indazol-5-amine (130 mg, 0.375 mmol) obtained in Example 500 in ethanol (10 ml) were added 10% Pd-C (26 mg) and then ammonium formate (118 mg, 1.87 mmol), and the resulting mixture was heated under reflux for 1 hour. The solid was removed by filtration using Celite, and the solvent was distilled off under reduced pressure. Ethyl acetate/aqueous ammonia was added to the residue, followed by extraction with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby N-(8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1H-indazol-5-amine (84 mg, 88%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]=O.[CH3:13][N:14]1C2C(=CC=CC=2)C(C)=C1C=O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][NH:14][CH3:13]
Reactant: Cc1c(C=O)n(C)c2ccccc12
Reactant: O=Cc1c[nH]c2c(F)cccc12
Product: CNCc1c[nH]c2c(F)cccc12
Yield: 90 %

Procedure:
According to the procedure of Preparation 13 (c),except substituting 7-fluoro-1H-indole-3-carboxaldehyde (0.5 g, 3.1 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.5 g, 90%) was prepared as a viscous oil: MS (ES) m/e 179 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[O:7][CH:8]=[C:9]([C:11]([NH:13][CH2:14][C@@H:15]([N:17]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([Cl:30])[C:23]=3[CH3:31])=[N:18]2)[CH3:16])=[O:12])[N:10]=1)(=[O:5])[CH3:4]>C(O)C>[Cl:30][C:24]1[C:23]([CH3:31])=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([C@@H:15]([CH3:16])[CH2:14][NH:13][C:11]([C:9]3[N:10]=[C:6]([CH:3]([OH:5])[CH3:4])[O:7][CH:8]=3)=[O:12])[N:18]=2)[CH:27]=[CH:26][C:25]=1[C:28]#[N:29]
Reactant: CC(=O)c1nc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3C)n2)co1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(-c2ccn([C@@H](C)CNC(=O)c3coc(C(C)O)n3)n2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Sodium borohydride (0.055 g, 1.462 mmol) was added into a flask and the atmosphere was replaced with nitrogen. Dry ethanol was added and the reaction mixture was cooled to 0° C. (S)-2-acetyl-N-(2-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propyl)oxazole-4-carboxamide (0.301 g, 0.731 mmol) was added and the reaction mixture was warmed slowly to RT while stirring overnight. The crude product was cooled to 0° C., the pH was adjusted to 6 and the mixture was evaporated. 5% of methanol/DCM was added and the crude product was washed with 1M NaHCO3 and with water. The mixture was dried and evaporated. Yield 94%. 1H-NMR (400 MHz; CDCl3): δ 1.57 (d, 3H), 1.61 (d, 3H), 3.78-3.83 (m, 1H), 3.87-3.94 (m, 1H), 4.59-4.68 (m, 1H), 4.87-4.96 (m, 1H), 6.43 (d, 1H), 7.34-7.42 (m, 1H), 7.51 (d, 1H), 7.54-7.61 (m, 2H), 8.14 (s, 1H).
Reaction SMILES: [OH-].[Li+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[CH:10]=2)[CH:5]=[CH:4]1>O.O1CCCC1>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4]1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2cc[nH]c2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
Lithium hydroxide (0.72 g, 17.2 mmol, 3 equiv.) in water (10 mL) was added to methyl indole-6-carboxylate (1 g, 5.7 mmol, 1 equiv.) in tetrahydrofuran (10 mL) and the mixture stirred at 80° C. for 16 hours. The solution was concentrated under vacuum then diluted with dichloromethane (10 mL) and the organic layer extracted with water (3×10 mL). The aqueous phase was acidified to pH<1 with concentrated HCl forming a precipitate. The precipitate was filtered and washed with 1 M aqueous HCl (3×10 mL) to afford 1H-indole-6-carboxylic acid as a white solid, 0.807 g (88% yield). LC @215 nm; Rt 1.02: 100%, m/z (ES+): 162 (M+H+.); δH (400 MHz; MeOD) 8.15 (1H, d), 7.72 (1H, m), 7.67 (1H, m), 7.45 (1H, m), 6.53 (1H, m).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][CH:10]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[O:13]C(=O)[NH:11]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[OH-].[Na+]>C(O)C.O>[NH2:11][CH:10]([CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:2]([F:4])([F:1])[CH3:3])=[CH:24][CH:23]=1)[CH:14]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[OH:13]
Reactant: CC(F)(F)c1ccc(CC2NC(=O)OC2c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(F)(F)c1ccc(CC(N)C(O)c2ccc(F)cc2)cc1

Procedure:
(4RS,5SR)-4-[4-(1,1-Difluoroethyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one (1.557 g, 4.643 mmol) and sodium hydroxide (0.74 g, 18.6 mmol) were heated under reflux in ethanol (20 ml) and water (1 ml) for 6 hrs. The reaction solution was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel (APS type) column chromatography (hexane/ethyl acetate=3/1-ethyl acetate) to give the objective substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.[F:16][C:17]([F:26])([F:25])[C@H:18]1[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(Cl)Cl.CCO>CN(C=O)C>[F:16][C:17]([F:25])([F:26])[C@H:18]1[CH2:19][CH2:20][C@H:21]([NH:24][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]([NH2:12])=[CH:11][C:3]=2[O:2][CH3:1])[CH2:22][CH2:23]1
Reactant: COc1cc(N)c([N+](=O)[O-])cc1C(=O)O
Reactant: N[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(N)c([N+](=O)[O-])cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The sub-title compound was prepared from 2-methoxy-4-amino-5-nitro benzoic acid and trans-4-trifluoromethyl-cyclohexylamine with TBTU and TEA in DMF in analogy to example 3e._Yield: quantitative; TLC: silica gel, DCM/EtOH 9:1, Rf=0.68.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:44])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][C:21]=3[CH:35]([C:40]([O:42]C)=[O:41])[O:36]C(=O)C)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.C1COCC1.CO>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:44])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][C:21]=3[CH:35]([C:40]([OH:42])=[O:41])[OH:36])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COC(=O)C(OC(C)=O)c1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)c(C(O)C(=O)O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.2 %

Procedure:
A solution of (5S)-9-bromo-5-[p-tert-butoxycarbonylaminomethyl-o-(1-methoxycarbonyl-1-acetoxymethyl)phenylcarbamoylmethyl]-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (310 mg, 0.46 mmol) in a mixture of 1N aqueous sodium hydroxide (6 mL), THF (5 mL), and methanol (5 mL) was stirred for 6 h at room temperature. The mixture was concentrated to ca. 6 mL and acidified with 5% aqueous potassium hydrogen sulfate. The precipitates formed were collected and dried to give 276 mg of the title compound (97%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[C:15]([O-:18])(=[O:17])[CH3:16].[Na+]>CN(C=O)C>[C:15]([O:18][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:4])(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Bromo-1-[4-(methylsulfonyl)phenyl]ethanone (2.4 g, 8.7 mmol) was added over a period of 30 min to the suspension of sodium acetate (0.7 g, 8.7 mmol) in DMF (25 mL) at RT. The mixture was stirred at 25° C. for 16 h, and was partitioned between H2O (100 mL) and EtOAc/hexane (20/100 mL). The organic layer was separated and washed with water (3×100 mL), dried with anhydrous Na2SO4, and concentrated to give 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl acetate. LCMS: m/e=256 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][CH:4]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>[Ag]=O.CN(C=O)C>[C:15]([O:14][C:12](=[O:13])[CH2:11][O:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][OH:1])[N:8]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=c1cccc(CO)[nH]1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.8 %

Procedure:
A mixture of 1.38 g of 6-(hydroxymethyl)pyridin-2(1H)-one, 2.15 g of tert-butyl bromoacetate, 3.07 g of silver oxide, and 33 mL of DMF was stirred at room temperature for 12 hours, and then at 60° C. for 12 hours. The insoluble material was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, followed by washing with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 1.92 g of tert-butyl{[6-(hydroxymethyl)pyridin-2-yl]oxy}acetate as a yellow oily substance.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].C([O-])([O-])=O.[Na+].[Na+].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][O:23][C:24](=O)[O:25]C1C=CC([N+]([O-])=O)=CC=1>O.C1COCC1.Cl>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][O:23][C:24]([NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9])=[O:25]
Reactant: O=C(OCc1cccs1)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@H]1CCCC[C@H]1C(=O)O)OCc1cccs1
Temperature: 25 °C

Procedure:
To a solution of Trans-2-amino-1-cyclohexane carboxylic acid (100 mg, 0.7 mmol) in 1 mL of water is added 2M aqueous Na2CO3 until pH=9-10 (2 mL). A solution of the carbonic acid 4-nitro-phenyl ester thiophen-2-ylmethyl ester (195 mg, 0.7 mmol) in THF (1 mL) is added at 0° C. and, after 10 minutes, 1 ml of the 2M Na2CO3 is added to the reaction. The mixture is allowed to warm to RT and vigorously stirred overnight. The reaction mixture is diluted with 0.5N HCl until pH=4-3 and the water layer is extracted three times with CH2Cl2 (10 ml). The organic phases are combined, dried (MgSO4), and concentrated under reduced pressure. The resulting product is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[CH2:4][CH2:5][C:6]=1[O:7][CH3:8].[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21](B(O)O)=[C:20]([CH3:28])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([C:2]2[C:3](=[O:9])[CH2:4][CH2:5][C:6]=2[O:7][CH3:8])=[C:20]([CH3:28])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1B(O)O
Reactant: COC1=C(Br)C(=O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: COC1=C(c2c(C)cc(OCc3ccccc3)cc2C)C(=O)CC1
Temperature: 90 °C

Procedure:
To a suspension of 2-bromo-3-methoxycyclopent-2-enone (5.00 g, 26.0 mmol), 4-benzyloxy-2,6-dimethylphenyl boronic acid (7.20 g, 28 mmol) (described in EP1726580) and potassium phosphate (9.55 g, 45 mmol) in degassed toluene (125 ml) is added palladium (II) acetate (0.135 g, 0.6 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.492 g, 1.2 mmol). The reaction mixture is then heated at 90° C. under a nitrogen atmosphere for 4 hours, then allowed to cool to room temperature. After partitioning between ethyl acetate (500 ml) and distilled water (500 ml), the organic phase is separated and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/hexane eluant) to afford 2-(4-benzyloxy-2,6-dimethylphenyl)-3-methoxycyclopent-2-enone as a white solid.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][C:9]1[CH:14]([C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[N:13]2[C:31](=[O:42])[C@@H:32]([NH:33][C:34](=[O:41])[CH2:35][C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[C@H:12]2[S:11][CH:10]=1>[O-2].[O-2].[O-2].[Cr+6].C(Cl)Cl>[CH:8]([C:9]1[CH:14]([C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[N:13]2[C:31](=[O:42])[C@@H:32]([NH:33][C:34](=[O:41])[CH2:35][C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[C@H:12]2[S:11][CH:10]=1)=[O:7]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CO)=CS[C@H]12
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
In this preparation 31 g. of dried chromium trioxide is added to a mixture of 51 g. of dry pyridine and 800 ml. of dry methylene chloride and stirred at 15°C under nitrogen for 20 minutes. 26 Grams of benzhydryl 3-hydroxymethyl-7β-(thiophen-2-yl-acetamido)-ceph-2-em-4carboxylate in 250 ml. of dry methylene chloride is added in one portion. The resulting mixture is stirred for 30 minutes and then filtered through diatomaceous earth. The contents of the reaction flask and the diatomaceous earth are washed with 500 ml. of methylene chloride and combined with the preceding filtrate and then washed with 400 ml. of 5% aqueous potassium hydroxide solution, 500 ml. of 20% aqueous hydrochloric acid and twice with 400 ml. brine. The aqueous washings are back extracted with 500 ml. of methylene chloride and the extracts added to the previously washed methylene chloride filtrate, then dried over sodium sulfate and then stirred for one hour with 30 g. of silica gel. The mixture is filtered and the silica gel washed with 400 ml. 1:1 vol. ethyl acetate/methylene chloride. The combined filtrates are evaporated to dryness under reduced pressure and the resulting residue (26 g.) is recrystallized from ethyl ether/methylene chloride affording 21.4 g. of benzhydryl 3-formyl-7β-(thiophen-2-yl-acetamido)-ceph-2-em-4-carboxylate.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.[Cl:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][C:23]2=[O:26])=[CH:18][CH:17]=1.Br[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>C(Cl)(Cl)Cl.[Cu](I)I.CO>[Cl:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][N:22]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[C:23]2=[O:26])=[CH:18][CH:17]=1
Reactant: O=C1NCCc2ccc(Cl)cc21
Reactant: Brc1cccnc1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1c2cc(Cl)ccc2CCN1c1cccnc1
Temperature: 110 °C
Yield: 42.2 %

Procedure:
Copper iodide (15.6 mg, 0.0824 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (28.3 mg, 0.2472 mmol) and potassium phosphate (437.3 mg, 2.0604 mmol) were added to 1,4-dioxane (20 mL) degassed with argon for 30 minutes. The reaction mixture was purged with argon for a further 20 minutes followed by the addition of 7-chloro-3,4-dihydro-2H-isoquinolin-1-one (I-1d: 150 mg, 0.82417 mmol) and 3-bromo-pyridine (88.9 mL, 0.9065 mmol). The reaction mixture was heated to reflux at 110° C. for 12 hours. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mixture was filtered and the filtrate was concentrated. Purification by column chromatography on silica gel (10% methanol in CHCl3) afforded 90 mg of the product (42.2% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:20][C:21]1[CH:29]=[C:28]([I:30])[CH:27]=[C:26]([F:31])[C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Cl:20][C:21]1[CH:29]=[C:28]([I:30])[CH:27]=[C:26]([F:31])[C:22]=1[C:23]([NH:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])=[O:24]
Reactant: Nc1ccnc(Cl)c1F
Reactant: O=C(Cl)c1c(F)cc(I)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccnc(Cl)c1F)c1c(F)cc(I)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of 2-chloro-3-fluoro-pyridin-4-amine (3.31 g, 22.6 mmol) in THF (50 mL) at 0° C. was slowly added LiHMDS in THF (1.0 M, 45 mL). The mixture was warmed to room temperature and allowed to stir for 1 hour. It was then cooled to −78° C. A THF solution of 2-chloro-6-fluoro-4-iodo-benzoyl chloride (15.1 mmol, 15 mL) was added dropwise. The mixture was stirred at −78° C. for 1 hour. The reaction was then quenched with sat. NH4Cl, extracted with EtOAc (3×). The combined organics were dried over Na2SO4, concentrated. The crude product was purified by silica gel column chromatography (0-25% EtOAc/hexane) to give the title compound (4.97 g, 76.8% yield) as an off-white solid. 1H NMR (400 MHz, methanol-d4) δ 8.37 (t, J=5.4 Hz, 1H), 8.18 (d, J=5.5 Hz, 1H), 7.80 (s, 1H), 7.69 (dd, J=8.2, 1.2 Hz, 1H). LCMS (ESI) m/z 429.0 [M+H+].
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([PH:10](=O)[C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([N:18]([CH3:20])[CH3:19])=[C:13]([CH3:21])[CH:12]=2)=[CH:5][C:4]=1[CH3:23].[BH3:25].O1CCCC1>C1(C)C=CC=CC=1>[CH3:24][N:2]([CH3:1])[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([PH:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([N:18]([CH3:19])[CH3:20])=[C:13]([CH3:21])[CH:12]=2)=[CH:5][C:4]=1[CH3:23].[BH3:25]
Reactant: Cc1cc([PH](=O)c2cc(C)c(N(C)C)c(C)c2)cc(C)c1N(C)C
Agent: B
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(Pc2cc(C)c(N(C)C)c(C)c2)cc(C)c1N(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
Under an argon atmosphere, to a solution of bis(4-dimethylamino-3,5-dimethylphenyl)phosphine oxide (4.6 g, 14 mmoL) synthesized in Example 1 in toluene (30 mL) was added borane-tetrahydrofuran solution (71 mL, 5.4 equivalents) at room temperature over 2 hr. Then, silica gel (8.7 g, 10.8 equivalents) was added to the mixture, and the mixture was stirred at room temperature for 1.5 hr. The silica gel was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 20 g, toluene) and the residue was recrystallized from n-hexane to give the title compound (3.0 g, white crystals). yield 65%.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:11][CH:12]=2)=[CH:5][N:6]=1
Reactant: Cc1ncc(-c2ccccc2)o1
Reactant: O=S(=O)(O)Cl
Product: Cc1ncc(-c2ccc(S(=O)(=O)Cl)cc2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Methyl-5-phenyl-oxazole (1.6 g, 10 mmol), prepared according to the literature procedure (Varma, R. S.; Kumar, D. J. Heterocyclic Chem., 1998, 35,1533), was dissolved in chlorosulfonic acid (10 mL) and stirred at room temperature for 16 h. The reaction mixture was added to crushed ice (50 g) and the product was extracted with ether (3×50 mL). The combined organic extract was dried over anhydrous Na2SO4 and ether was evaporated. The product was purified by flash chromatography (silica-gel, 5-20% ethylacetate/hexane mobile phase) to yield 0.82 g of the desired title compound as tan solid. MS: m/z 258.0 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:19])[N:12]=3)[N:9]=[C:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:5]2=[N:6][CH:7]=1.Cl[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>N1C=CC=CC=1>[NH2:19][C:13]1[C:14]([NH:18][C:29](=[O:30])[O:31][CH:32]([CH3:34])[CH3:33])=[C:15]([NH2:17])[N:16]=[C:11]([N:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:9]2)[N:12]=1
Reactant: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc(N)c1N
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1c(N)nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
300 mg (0.81 mmol) of the compound from example 8A were initially charged in 10 ml of pyridine, and the mixture was cooled to 0° C. 0.81 ml (0.81 mmol) of isopropyl chloroformate was then added dropwise, and the mixture was stirred at 0° C. for a further 60 min. The reaction mixture was brought to RT and purified directly by means of preparative RP-HPLC (acetonitrile:water (+0.1% formic acid) gradient). This gave 88 mg of the target compound (24% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:35])[O:14][CH2:15][C@@H:16]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:5]2.[CH:36]1[CH:41]=[CH:40][C:39]([O:42][C:43](OC2C=CC=CC=2)=[N:44][C:45]#[N:46])=[CH:38][CH:37]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:35])[O:14][CH2:15][C@@H:16]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:17][CH2:18][CH2:19][NH:20]/[C:43](=[N:44]/[C:45]#[N:46])/[O:42][C:39]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1)=[CH:5]2
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN)COC(=O)Nc1cc2cc(F)ccc2cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN/C(=N/C#N)Oc1ccccc1)COC(=O)Nc1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentyl 6-fluoroisoquinolin-3-ylcarbamate (190 mg, 0.35 mmol) and diphenyl cyanocarbonimidate (83 mg, 0.35 mmol) in DCM (10.0 mL) was added DIEA (0.12 mL, 0.70 mmol). The reaction mixture was stirred at RT for 4 h. The mixture was concentrated under reduced pressure to give (S,Z)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-((cyanoimino)(phenoxy)methylamino)pentyl 6-fluoroisoquinolin-3-ylcarbamate, which was used without further purification. LRMS (M+H+) m/z 650.2.