Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.Br[C:25]1[CH:26]=[C:27]2[C:31](=[C:32]([CH3:34])[CH:33]=1)[C:30](=[O:35])[N:29]([CH2:36][CH:37]1[CH2:39][CH2:38]1)[CH2:28]2.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:25]2[CH:26]=[C:27]3[C:31](=[C:32]([CH3:34])[CH:33]=2)[C:30](=[O:35])[N:29]([CH2:36][CH:37]2[CH2:39][CH2:38]2)[CH2:28]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)cc2c1C(=O)N(CC1CC1)C2
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CC2CCN(C(=O)OC(C)(C)C)CC2)cc2c1C(=O)N(CC1CC1)C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
To a purged (Argon) sample of 4-Methylene-piperidine-1-carboxylic acid tert-butyl ester (727 mg, 3.68 mmol) was added 9-BBN (11.32 mL, 5.66 mmol). The mixture was stirred at 60° C. for two hours. After cooling to room temperature this solution was added to 5-Bromo-7-methyl-2-cyclopropylmethyl-2,3-dihydro-isoindol-1-one (794 mg, 2.83 mmol), Pd(dppf)Cl2 (115 mg, 0.142 mmol), DMF (25 mL), potassium carbonate (1.17 g, 8.49 mmol) and water (2.5 mL). The mixture was allowed to stir at 75° C. for 1.5 hours. The mixture was then cooled to room temperature and poured into water (3 mL). The product was extracted with ethyl acetate. The combined organic layers were washed with water three times, brine, dried over sodium sulphate, filtered and concentrated. Column chromatography (30% Ethyl acetate/hexanes) provided the title compound as a light yellow oil (777 mg, 53%). 1H NMR (300 MHz, CDCl3): δ 7.01 (s, 1H), 6.94 (s, 1H), 4.39 (s, 2H), 3.42 (d, 2H), 2.68 (s, 3H), 2.57 (s, 2H), 2.54 (d, 2H), 1.70-1.62 (m, 4H), 1.43 (s, 9H), 1.09 (d, 1H), 1.01 (m, 1H), 0.56-0.5 (m, 2H), 0.31-0.29 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:19]([O:21][CH3:22])=[O:20])=[N:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[N:4]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CCC(C)=O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:13]([C:19]([O:21][CH3:22])=[O:20])=[N:14][C:15]([NH:18][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:16][CH:17]=2)[N:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1nc(N)ccc1Oc1nc(OC)cc(OC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1nc(NS(C)(=O)=O)ccc1Oc1nc(OC)cc(OC)n1
Yield: 19.7 %

Procedure:
3.1 g (10 mmol) of methyl 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-aminopicolinate, 2.4 g (21 mmol) of methanesulfonyl chloride and 1.5 g (11 mmol) of potassium carbonate were added to 10 ml of MEK, and the mixture was stirred and refluxed for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residual oily product was purified by column chromatography and then crystallized from diisopropyl ether to obtain the desired product as a slightly yellow powder.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[C:15]([N+:16]([O-])=O)=[CH:14][C:13]([N+:19]([O-])=O)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl[Sn]Cl>C(O)C>[NH2:19][C:13]1[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]2[CH:4]=[CH:3][NH:16][C:15]=2[CH:14]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1/C=C/N(C)C
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCOC(=O)c1cc(N)cc2[nH]ccc12
Yield: 41.3 %

Procedure:
A mixture of (E)-ethyl 2-(2-(dimethylamino)vinyl)-3,5-dinitrobenzoate (11 g, 0.037 mot) and SnCl2 (83 g, 0.37 mol) in ethanol was heated at reflux for 4 h. The mixture was concentrated to dryness and the residue was poured into water and basified using sat. aq. Na2CO3 to pH 8. The precipitated solid was filtered and the filtrate was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water (2×100 mL) and brine (150 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by column on silica gel to give ethyl 6-amino-1H-indole-4-carboxylate (3.0 g, 40%). 1HNMR (DMSO-d6) δ 10.76 (br s, 1H), 7.11-7.14 (m, 2H), 6.81-6.82 (m, 1H), 6.67-6.68 (m, 1H), 4.94 (br s, 2H), 4.32-4.25 (q, J=7.2 Hz, 2H), 1.35-1.31 (t, J=7.2, 3H); MS (ESI) m/e (M+H+) 205.0.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:29][O:30][C:31]1[CH:44]=[CH:43][C:34]([CH2:35][N:36]2[CH:40]=[C:39]([CH:41]=O)[CH:38]=[N:37]2)=[CH:33][CH:32]=1.O>O1CCCC1>[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:20][C:19]=1[CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:35][N:36]2[CH:40]=[C:39](/[CH:41]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:38]=[N:37]2)=[CH:43][CH:44]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cnn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Sodium hydride (60%, oily, 336 mg) was added at 0° C. to a solution of ethyl diethylphosphonoacetate (1.67 ml) in tetrahydrofuran (20 ml), which was stirred at 0° C. for 30 minutes. To this solution, a solution of 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-carbaldehyde (2.61 g) in tetrahydrofuran (20 ml) was added dropwise at 0° C., and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and ethyl (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole-4-yl]propenoate (2.78 g, yield: 90%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 112–113° C.
Reaction SMILES: C(O[C:4]1([O:10]CC)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)C.C(Cl)(Cl)Cl.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(N(CC)CC)C>[C:18]([N:6]1[CH2:7][CH2:8][CH2:9][C:4](=[O:10])[CH2:5]1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC1(OCC)CCCNC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 8.7 g. of 3,3-diethoxypiperidine in 100 ml. of dry chloroform is treated at 0° C. with 5 g. of triethylamine followed by 5.4 g. of ethyl chloroformate. After stirring at 25° C. for two hours, the solvent is removed in vacuo. The residue is extracted with ether and the extract concentrated in vacuo. This residue is treated with dilute hydrochloric acid for two hours. The solution is then saturated with sodium chloride and extracted with chloroform. The chloroform extract is washed with 5% aqueous sodium bicarbonate solution, dried and concentrated in vacuo to give 1-carbethoxy-3-piperidone.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[N+:7]([C:10]1[O:14][C:13]([CH:15]=[CH:16][C:17]2[NH:26][C:25](=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:12][CH:11]=1)([O-:9])=[O:8]>P(Cl)(Cl)(Cl)=O>[N+:7]([C:10]1[O:14][C:13]([CH:15]=[CH:16][C:17]2[N:26]=[C:25]([Cl:2])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1[nH]c(C=Cc2ccc([N+](=O)[O-])o2)nc2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(C=Cc2nc(Cl)c3ccccc3n2)o1
Yield: 67 %

Procedure:
A 500 ml 3 necked flask fitted with a stirrer, reflux condenser and protected by a calcium chloride trap was charged with 9.0 g of phosphorus pentachloride (0.043 mole) and 70 ml of phosphorus oxychloride and the mixture stirred. To this 11.3 g (0.04 mole) of 2-[2-(5-nitro-2-furyl)vinyl] -4-(3H)quinazolinone was added and rinsed into the flask with 15 ml of phosphorus oxychloride. The mixture was heated under reflux for 4 hours, cooled in an ice bath and diluted with 150 ml of diethyl ether. The 2-[2-(5-nitro-2-furyl)vinyl]-4-chloroquinazoline which precipitated was collected by filtration, washed with 100-150 ml of diethyl ether, slurried in 100 ml of diethyl ether and then refiltered to obtain 8.09 g of the desired product melting at 252°-4°C with decomposition. The product was recrystallized from toluene (large volumes are required) or was extracted in a Soxhlet extractor with toluene to obtain yellow crystals of 2-[2-(5-nitro-2-furyl)vinyl)-4-chloroquinazoline melting at 264°-5°C with decomposition.
Reaction SMILES: Cl.[C:2]1([C:8]2([OH:29])[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([N+:25]([O-])=O)[CH:21]=4)[C:16]3=[O:28])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[NH4+]>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].O>[C:2]1([C:8]2([OH:29])[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([NH2:25])[CH:21]=4)[C:16]3=[O:28])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2CCC1CN1CCC(O)(c2ccccc2)CC1
Agent: [Fe+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Nc1ccc2c(c1)CCC(CN1CCC(O)(c3ccccc3)CC1)C2=O

Procedure:
A mixture of 4.17 g. of 2-(4-phenyl-4-hydroxypiperidinomethyl)-6-nitro-1-tetralone hydrochloride, 20 g. of iron-(II) sulfate heptahydrate, 45 ml. of water and 0.15 ml. of concentrated hydrochloric acid is heated at 100° with stirring. 10 ml. of concentrated ammonium hydroxide solution are added at 80° and the mixture is heated for 10 minutes more on a steam bath. It is allowed to cool, extracted with chloroform and worked up to give 2-(4-phenyl-4-hydroxypiperidinomethyl)-6-amino-1-tetralone.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12][C:7]=3[CH:8]=2)[NH:3]1.[H-].[Na+].CI.[C:26](=O)([O-])O.[Na+]>CN(C=O)C>[CH3:26][N:3]1[C:4]2[C:9](=[CH:8][C:7]3[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:16][C:6]=3[CH:5]=2)[CH2:10][CH2:11][C:2]1=[O:1]
Reactant: CCOC(=O)N1CCc2cc3c(cc2CC1)NC(=O)CC3
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)N1CCc2cc3c(cc2CC1)N(C)C(=O)CC3
Reaction time: 1 h

Procedure:
287 mg of ethyl 2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate was dissolved in 5 ml of DMF, and 65 mg of 60% sodium hydride was added thereto in an ice-bath, followed by stirring for 1 hour. 0.3 ml of methyl iodide was added thereto, followed by stirring at room temperature for 3 hours. Then, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 94 mg of ethyl 1-methyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([NH:14]C(=O)C)([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)[CH3:3].[OH-].[K+].Cl>C(O)CO.CCOCC>[CH3:3][C:2]([NH2:14])([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:11])[F:12])=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(=O)NC(C)(C)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: OCCO
Product: CC(C)(N)c1ccc(C(F)(F)F)cc1
Temperature: 170 °C
Yield: 72.4 %

Procedure:
To a solution N-{1-methyl-1-[4-(trifluoromethyl)phenyl]ethyl}acetamide (2.0 g, 8.16 mmol) in ethylene glycol (5 mL) was added KOH (3.66 g, 8.16 mmol) and the resulting mixture was heated for 48 h at 170° C. After cooling to rt, the reaction mixture was extracted with Et2O (3×20 mL). The combined organic layers were washed with water (4×), dried over MgSO4, filtered and evaporated to give a colorless oil. This oil was dissolved in Et2O (30 mL) and a saturated solution of HCl in Et2O (10 mL) was added. The white precipitate was collected, washed with Et2O (3×10 mL) and dried under vacuo. This solid was then poured into Et2O (50 mL) and a 1N aqueous solution of NaOH (20 mL) were added. The organic layer was separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with water (2×20 mL), dried over MgSO4, filtered and evaporated to give the title compound as colorless oil (1.2 g, 72%). 1H NMR (CDCl3, 300 MHz) δ 7.60-7.46 (m, 4H), 1.53 (br s, 2H), 1.43 (s, 6H). HPLC (Condition A), Rt: 1.73 min (HPLC purity: 94.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:16]([O:18]C)=O)[C:8]([C:12]([O:14]C)=O)=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[C:7]3[C:16]([OH:18])=[N:31][N:30]([C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[C:12](=[O:14])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(NN)cc1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Yield: 112 %

Procedure:
To a stirred suspension of dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (0.500 g, 1.69 mM) in ethanol (17mL) was added 4-methoxyphenyl hydrazine hydrochloride (2.07 g, 11.83 mM). Triethylamine (1.88 mL, 13.52 mM) was added, and the mixture was heated to reflux for 40 hours. The resulting suspension was filtered hot, and the collected solids were washed with ethanol to give the 4-methoxyphenyl hydrazine salt of the title compound (0.700 g) as a light tan solid. This material was heated to reflux in glacial acetic acid (20 mL) for 2 hours to give a brown suspension. The suspension was cooled to room temperature. The solids were collected and washed with glacial aceticacid, methanol and ether to give the title compound (0.331 g, 53%) as a tanpowder, mp 365° C. (decomp.); MS(CI): 370 (M+H). Analysis for C18H12ClN3O4 : Calculated: C, 58.50; H, 3.27; N, 11.36; Found: C, 58.29; H, 3.41; N, 11.14; NMR: 13.79 (br s, 1H, exchangeable), 8.22 (br d, J=8.70 Hz, 2H, 1H exchangeable), 7.88 (d, J=1.79 Hz, 1H), 7.57 (dd, J=1.79, 8.70 Hz, 1H), 6.78 (s, 4H), 3.67 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[O:14][C:15]1[S:19][C:18]([C:20]#[N:21])=[CH:17][CH:16]=1.N.S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1>[Cl:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[O:14][C:15]1[S:19][C:18]([CH2:20][NH2:21])=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(Oc2ccccc2Cl)s1
Agent: N
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Product: NCc1ccc(Oc2ccccc2Cl)s1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of lithium aluminum hydride (1.79 g, 47.1 mmol) in tetrahydrofuran was added aluminum chloride (7.54 g, 56.5 mmol) on an ice bath, which was then stirred for 10 minutes. To the suspension was 5-(2-chloro-phenoxy)-thiophene-2-carbonitrile described in Preparation Example 158 (2.22 g, 9.42 mmol) was added on an ice bath, and the solution was stirred for 1 hour. An aqueous ammonia was added to the reaction solution, then, anhydrous magnesium sulfate was added for drying, and the solution was filtered through Celite pad. The filtrate was concentrated in vacuo, the residue was purified by NH silica gel column chromatography (heptane/ethyl acetate=1/2), and the title compound (2.26 g, 9.42 mmol, 100%) was obtained as a light brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:14])C1C=CC=CC=1.[H-].[Na+].Cl[C:18]1[CH:23]=[CH:22][N+:21]([O-:24])=[CH:20][CH:19]=1>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:14][C:18]1[CH:23]=[CH:22][N+:21]([O-:24])=[CH:20][CH:19]=1
Reactant: OC(c1ccccc1)c1ccccn1
Reactant: [O-][n+]1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: [O-][n+]1ccc(OCc2ccccn2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
2-Pyridylbenzylalcohol (1.67 g, 15.3 mmol) was dissolved in 1,4-dioxane (25 mL) and NaH (60% weight dispersion in mineral oil, 0.92 g, 23 mmol) was added. After stirring for 30 minutes, 4-chloropyridine-N-oxide (2.27 g, 17.5 mmol) was added and the reaction mixture was heated for 1 h at 120° C. Upon cooling, the mixture was purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 40 mL/min) to provide the title compound (600 mg, 38%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 8.62-8.61 (m, 1H), 8.13-8.10 (m, 2H), 7.74 (overlapping ddd, J=7.8, 1.4 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.30 (d, J=4.8 Hz, 1H), 6.92-6.89 (m, 2H), 5.23 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]#[N:21])=[C:8]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:9]=1)([O-])=O.[H][H]>C1(C)C=CC=CC=1.O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:20]#[N:21])=[C:8]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:9]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1NC(=O)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N)cc1NC(=O)c1ccc(F)cc1
Temperature: 80 °C
Yield: 74.9 %

Procedure:
To a solution of N-(5-nitro-2-cyano-phenyl)-4-fluoro-benzamide (1.79 g) (Example 18) in a mixture of toluene (100 ml) and water (10 ml) was added palladium on charcoal (5%) (180 mg). The reactor was charged with hydrogen (471.72 ml, 10 bar) and the reaction mixture was heated to 80° C. for 4 hours. The reaction mixture was filtered to remove the palladium catalyst and the filtrate concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/tetrahydrofuran 1:1) to give N-(5-amino-2-cyano-phenyl)-4-fluoro-benzamide (1.2 g, 75% yield). 1H-NMR (CDCl3, 400 MHz): 8.28 (s, 1H), 7.98 (m, 3H), 7.40 (d, 1H), 7.22 (t, 1H), 6.43 (m, 1H), 4.3 (s, 2H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][C@H:18]2[NH:24][C:25](=[O:33])[O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([NH2:39])([CH3:38])([CH3:37])[CH3:36].C([BH3-])#N.[Na+].[OH-].[Na+]>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:39][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:19][C@H:18]2[NH:24][C:25](=[O:33])[O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:31])[CH3:32])[C:13]1=[O:34])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOC(=O)N[C@@H]1CC(=O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CC(C)(C)N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl (1R,2S)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-oxocyclohexylcarbamate (0.550 g, 1.123 mmol) in methylene chloride (0.4 mL) was added t-butylamine (1.180 ml, 11.23 mmol) and Titanium(IV) isopropoxide (6.63 ml, 22.47 mmol). This mixture was stirred for 2 h before sodium cyanoborohydride (127 mg, 2.022 mmol) and MeOH (1 mL) were added. After 2 h, methylene chloride (50 mL) was added, followed by 1N NaOH. The mixture was filtered through Celite to remove the titanium salts. The filtrate was dried and concentrated in vacuo to give 2-(trimethylsilyl)ethyl (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexylcarbamate and its 5S diastereomer as a mixture (510 mg, 0.933 mmol, 83% yield). LC/MS found [M+H]+=547.31.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:35][N:36]([CH:45]=[O:46])[O:37]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=3[O-:24])=[O:16])[CH2:13][CH2:12][N:11]2C(OCC2C=CC=CC=2)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:6][C@H:7]([CH2:35][N:36]([CH:45]=[O:46])[OH:37])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=3[O-:24])=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2cccc[n+]2[O-])CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1cccc[n+]1[O-]
Reaction time: 72 h
Yield: 51.5 %

Procedure:
To a solution of phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-{[(1-oxido-2-pyridinyl)amino]carbonyl}-1-pyrazolidine carboxylate (105 mg, 0.167 mmol) in methanol (10 ml) was added 10% palladium on carbon (17.75 mg, 0.017 mmol). The mixture was hydrogenated under balloon pressure for 72 h and then filtered. The mixture was purified by reverse-phase HPLC to yield (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-(1-oxido-2-pyridinyl)-3-pyrazolidinecarboxamide (35 mg, 0.086 mmol, 52% yield). LC/MS: (M+H)+: 06.4. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.07-1.28 (m, 3H) 1.39-1.69 (m, 5H) 1.69-1.84 (m, 2H) 1.84-2.02 (m, 2H) 2.29-2.46 (m, 1H) 2.46-2.64 (m, 1H) 2.84-3.00 (m, 1H) 3.19-3.31 (m, 1H) 3.46-3.61 (m, 1H) 3.76-3.90 (m, 1H) 3.93-4.14 (m, 1H) 4.76-4.87 (m, 1H) 7.10-7.34 (m, 1H) 7.58 (t, J=8.08 Hz, 1H) 7.90 (s, 1H) 8.34 (d, J=6.32 Hz, 1H) 8.49 (dd, J=8.59, 1.52 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2=[N:15][C:16]([C:21](OC)=[O:22])=[C:17]([OH:20])[C:18](=[O:19])[N:13]2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>CO>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:21]([C:16]2[N:15]=[C:14]3[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][CH:11]=[CH:12][N:13]3[C:18](=[O:19])[C:17]=2[OH:20])=[O:22])=[CH:28][CH:27]=1
Reactant: COC(=O)c1nc2c(OCc3ccccc3)cccn2c(=O)c1O
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1nc2c(OCc3ccccc3)cccn2c(=O)c1O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 9-(benzyloxy)-3-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylate in MeOH was added p-fluorobenzylamine. The solution was stirred at 80° C. for 24 hours. The solvent was removed under reduced pressure and the residue washed with diethylether. The product was purified by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluants (column: C18). The product was obtained after lyophilization of the pooled product fractions as bright yellow fluffy material.