Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[O:16][C:11]1([CH2:15][CH2:14][NH:13][CH2:12]1)[CH2:10][C:9]2=[O:20].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[O:16][C:11]1([CH2:15][CH2:14][N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12]1)[CH2:10][C:9]2=[O:20]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2

Procedure:
(−)-(E)-3-[4-Oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (110 mg, 0.38 mmol) was treated with benzaldehyde and NaBH(OAc)3 according to the procedure used for Example 2, Step A to give (+)-(E)-3-[1′benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (45 mg).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([Cl:22])[CH:13]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1.[OH-].[K+]>C(O)C.O>[Cl:22][C:14]1[CH:13]=[C:12]([CH:4]([O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]2)[C:3]([OH:23])=[O:2])[CH:17]=[CH:16][C:15]=1[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: COC(=O)C(OC1C=CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(OC2C=CCCC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
A solution of rac-(3-chloro-4-methanesulfonyl-phenyl)-(cyclohex-2-enyloxy)-acetic acid methyl ester (350 mg, 0.98 mmol) in ethanol (15 mL) at 25° C. was treated with a solution of potassium hydroxide (273 mg, 4.88 mmol) in water (2.5 mL) and the solution was stirred at 25° C. After 3 h, the reaction was diluted with water and concentrated under reduced pressure. The concentrate was acidified to pH 2 with an aqueous solution of 1N hydrochloric acid and extracted with dichloromethane (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residual material was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate plus 1% acetic acid) to give rac-(3-chloro-4-methanesulfonyl-phenyl)-(cyclohex-2-enyloxy)-acetic acid (265 mg, 79% yield) as a colorless oil: EI-HRMS m/e calcd for C15H17ClSO5 (M+) 344.0485, found 344.0494.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:22][NH:23][CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH3:22][N:23]([CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH2:6][CH2:5][C:4]#[C:3][C:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: CC(C)(C)C#CCCO
Reactant: CNCc1cccc2ccccc12
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CCC#CC(C)(C)C)Cc1cccc2ccccc12

Procedure:
To a solution of 540 mg 5,5-dimethyl-3-hexyn-1-ol in dimethylformamide (DMF) are added, at 0° 1.2 ml triethylamine. Then are added, dropwise, with stirring, 0.335 ml methanesulfonylchloride. After 2 hours of stirring at room temperature are added 740 mg N-methyl-1-naphthylmethylamine and the mixture is heated overnight at 80°. The solvent is evaporated in vacuum, the residue distributed between saturated aqueous NaHCO3 solution and ethyl acetate, the organic phase washed, dried and evaporated. The crude residue is chromatographed over silicagel (with toluene/ethylacetate 9/1) and the title compound (Compound 1) obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>CS(C)=O>[CH2:20]([NH:22][C:23]([NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=2[N:7]=1)=[O:24])[CH3:21]
Reactant: COc1ccc2nc(N)sc2c1
Reactant: CCN=C=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(OC)cc2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-Methoxy-1,3-benzothiazol-2-amine (5.00 g, 27.74 mmol) was dissolved in anhydrous DMSO (20 mL) and triethylamine (15.50 mL, 110.97 mmol) followed by ethyl isocyanate (4.39 mL, 55.49 mmol). The mixture was stirred at rt under N2 for 4 h then quenched with water (˜200 mL) and stirred for 1 h. A white solid formed, was collected by filtration, rinsed with water then washed with acetone (100 mL) and the filtrate collected separately to the aqueous filtrate. The solid was partially soluble in acetone so the filtrate was concentrated to dryness under reduced pressure and combined with the solid collected by filtration to obtain the desired compound as a white solid, 6.27 g (90%). m/z: 251.96 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[N+:24]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.C(Cl)Cl>[NH2:24][C:10]1[CH:11]=[C:12]([O:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)c1ccccc1
Reactant: [H][H]
Solvent: ClCCl
Solvent: CO
Product: Nc1cc(OC(=O)c2ccccc2)ccc1OCc1ccccc1
Yield: 79.3 %

Procedure:
A Parr hydrogenator was charged with platinum(IV) oxide(PtO2) (0.3 g) and a solution of benzoic acid 4-benzyloxy-3-nitro-phenyl ester (5.23 g, 15 mmol) (which was obtained in Example 15) in methanol (80 mL) and CH2Cl2(40 mL). This mixture was then hydrogenated at 5 psi of hydrogen at 0˜10° C. for 2 hours. The reaction mixture was filtered through a short pad of celite and concentrated. Recrystallization from CH2Cl2/hexanes gave the title compound as a white solid (3.80 g, 79%); 1H NMR (300 MHz, CDCl3) δ 5.09 (s, 2H), 6.57 (dd, J=10.1, 2.7 Hz, 1H), 7.10 (d, J=2.7 Hz, 1H), 7.30-7.50 (m, 8H), 7.55-7.65 (m, 1H), 8.15-8.25 (m, 2H); MS (ES) m/z: 320.0 (MH+, 100%); HRMS Calcd. for C20H18NO3 (MH+): 320.1281. Found: 320.1278.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12].[H][H]>CO.[Ni]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[CH:4][C:3]=1[OH:12]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(O)c(F)cc1F
Agent: [Ni]
Solvent: CO
Product: Nc1cc(O)c(F)cc1F
Yield: 90.5 %

Procedure:
24 g of 2,4-Difluoro-5-nitrophenol, dissolved in 120 ml of methanol, are subjected to hydrogenation at a hydrogen pressure of 20-40 bar at 25°-45° C. in the presence of 2 g of Raney nickel. When constant pressure is reached (i.e. when the take-up of hydrogen is complete), the pressure is released and the mixture is cooled, the solution is free from catalyst by filtration, and the methanol is subsequently removed by distillation at reduced pressure. 18 g (GC purity 97.5%) of 2,4-difluoro-5-aminophenol are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[C:14]2[CH2:17][N:16]([C@@H:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=3)[CH2:15]2)[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=3)[CH2:15]2)[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1)c1cc(F)cc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: -2.5 °C

Procedure:
To a solution of 27.15 g (51.64 mmol) of methyl (3-bromo-5-fluorophenyl){1-[(S)-(4-chlorophenyl)(3-cyanophenyl)methyl]azetidin-3-ylidene}acetate in 120 mL of THF and 220 mL of MeOH, were added small portions of sodium borohydride (total: 740 mg, 31.05 mmol) at −5-0° C. The mixture stirred at −5-0° C. and the reaction was followed by HPLC. Then the reaction was quenched with 2N HCl at 0° C. (to pH=7-7.5) and concentrated to remove the organic solvents. The residue was dissolved in 300 mL of CH2Cl2 and 300 mL water, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (100 mL×2). The combined organic layer was dried over Na2SO4 and concentrated. The residue was separated by silica gel chromatography with cyclohexane/ethyl acetate to afford the methyl (2S)-(3-bromo-5-fluorophenyl){1-[(S)-(4-chlorophenyl)(3-cyanophenyl)methyl]azetidin-3-yl}acetate; 1H-NMR(CDCl3) δ 2.66(t, 1H, J=6.2 Hz), 2.92(dd, 1H, J1=7.5 Hz, J2=5.7 Hz), 3.08-3.16(m, 2H), 3.41(t, 1H, J=7.2 Hz), 3.69(s, 3H), 3.83(d, 1H, J=10.7 Hz), 4.34(s, 1H), 6.96 (d, 1H, J=8.9 Hz), 7.17(d, 1H, J=8.0 Hz), 7.20 (d, 1H, J=12 Hz), 7.27-7.32 (m, 5H), 7.39 (t, 1H, J=7.6 Hz), 7.50 (d, 1H, J=7.5 Hz), 7.60 (d, 1H, J=7.5 Hz), 7.70 (s, 1H); Mass Spectrum: m/e=527(M+1, 35Cl79Br), 529 (M+1, 37Cl79Br/35Cl81Br), 531 (M+1, 37Cl81Br).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[N:22]1([C:28]2[CH:37]=[C:36]([C:38](O)=[O:39])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:38]([C:36]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=[C:28]([N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)[CH:37]=4)=[O:39])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1cc(N2CCCCC2)nc2ccccc12
Product: Cc1ccc(NC(=O)c2cc(N3CCCCC3)nc3ccccc23)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-piperidin-1-ylquinoline-4- carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1, 1′-biphenyl-4-carboxamide and 2-(piperidin-1-yl)quinoline-4-carboxylic acid using method B. NMR; δH CDCl3 7.90,(1H, d), 7.83-7.78,(4H, m), 7.67,(1H, b), 7.52,(1H, t), 7.42,(2H, d), 7.33,(1H, d), 7.26, (1H, m), 7.21,(1H, t), 7.01,(1H, s), 6.30,(1H, t), 3.63,(4H, s), 3.31,(2H, m), 2.27,(3H, s), 1.62,(6H, m), 1.07,(1H, m), 0.57,(2H, m), 0.28,(2H, m). LCMS: retention time 3.32 min, MH+519.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:19](O)[CH2:20][OH:21].CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:21][CH2:20][CH2:19][O:18]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: OCCO
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)N1CCC(C2(c3ccc(F)cc3)OCCO2)CC1
Reaction time: 108 h
Yield: 56.8 %

Procedure:
A mixture of 74.7 parts of 1-acetyl-4-(4-fluorobenzoyl)piperidine, 46.5 parts of 1,2-ethanediol, 3 parts of 4-methylbenzenesulfonic acid and 810 parts of benzene was stirred for 108 hours at reflux temperature using a water separator. After cooling, the reaction mixture was washed successively with 250 parts of water, 22.5 parts of ammonium hydroxide and 250 parts of water. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3COCH3 50:50). The eluent of the desired fraction was evaporated, yielding 50 parts (56.8%) of 1-acetyl-4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]piperidine (interm 45).
Reaction SMILES: [Cl-:1].[Cl-].[Ca+2].[CH2:4]([N:6]1[C:14]2[N:13]=[C:12]3[CH:15](O)[C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[CH2:18][CH2:19][C:11]3=[CH:10][C:9]=2[CH:8]=[N:7]1)[CH3:5].Cl>C1C=CC=CC=1>[Cl:1][CH:15]1[C:12]2=[N:13][C:14]3[N:6]([CH2:4][CH3:5])[N:7]=[CH:8][C:9]=3[CH:10]=[C:11]2[CH2:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]1=2
Reactant: CCn1ncc2cc3c(nc21)C(O)c1ccccc1CC3
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: CCn1ncc2cc3c(nc21)C(Cl)c1ccccc1CC3
Reaction time: 8 h

Procedure:
6 g. of pulverized CaCl2 are added with stirring to a solution of 11 g. of 1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-ol (0.04 mol.), from example 2, in 175 ml. of dry benzene. The suspension is saturated for 15 hours with anhydrous hydrogen chloride at room temperature. After standing overnight, the mixture is filtered and the benzene is evaporated in vacuo. The residue is extracted with ether, treated with charcoal, and refrigerated to crystallize 8.3 g. of 11-chloro-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine; m.p. 107°-110° (ether).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[O:56][N:55]=[CH:54][C:53]=2[C:57](O)=[O:58])=[CH:48][CH:47]=1>CN(C=O)C>[CH3:45][C:46]1[CH:47]=[CH:48][C:49]([C:52]2[O:56][N:55]=[CH:54][C:53]=2[C:57]([N:10]2[CH2:11][C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]([CH2:12][OH:13])[CH2:9]2)=[O:58])=[CH:50][CH:51]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: OCC1CNCC1c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2oncc2C(=O)N2CC(CO)[C@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
A solution of (4-phenylpyrrolidin-3-yl)methanol (7 mg, 0.033 mmol), TBTU (13 mg, 0.039 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (11 μL, 0.066 mmol, 2 equ.) in DMF (0.3 mL) was added to 5-(4-methylphenyl)isoxazole-4-carboxylic acid (7 mg, 0.033 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (4 mg). MS (ESI, pos. ion) m/z calcd for C22H22N2O3: 362.1630, found 362.1629.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:32][N:33]1[C:39](=[O:40])[N:38]2[CH2:41][C@H:34]1[CH2:35][CH2:36][C@H:37]2[C:42]([NH:44][NH2:45])=[O:43])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH2:46][C:47](=[O:51])[C:48](O)=[O:49].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:25]([O:32][N:33]1[C:39](=[O:40])[N:38]2[CH2:41][C@H:34]1[CH2:35][CH2:36][C@H:37]2[C:42]([NH:44][NH:45][C:48](=[O:49])[C:47]([NH2:46])=[O:51])=[O:43])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NC(=O)C(=O)O
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
HATU (0.95 g, 2.5 mmol) was added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (1.00 g, 2.5 mmol), 2-amino-2-oxoacetic acid (0.18 g, 2.1 mmol) and DIPEA (1.08 g, 8.4 mmol) in DMF (10 mL). The reaction mixture was stirred at 0° C. for 1 h then quenched with saturated sodium chloride (50 mL) and the organic layer was separated. The aqueous layer was exacted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (1:1 EtOAc/hexane) to give 2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoacetamide (0.57 g, 64%). ESI-MS (EI+, m/z): 362 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].[CH3:12][C:13]1[N:18]=[C:17]2[C:19]([O:21][C:22](=O)[C:16]2=[CH:15][CH:14]=1)=[O:20].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[Cl:10][C:9]1[C:2]([N:1]2[C:22](=[O:21])[C:16]3[C:17](=[N:18][C:13]([CH3:12])=[CH:14][CH:15]=3)[C:19]2=[O:20])=[C:3]([C:4]#[N:5])[C:6]([CH3:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc(Cl)c(N)c1C#N
Reactant: Cc1ccc2c(n1)C(=O)OC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: Cc1ccc2c(n1)C(=O)N(c1c(Cl)ccc(C)c1C#N)C2=O
Temperature: 170 °C
Reaction time: 8 h

Procedure:
3.1 g (18.61 mmol) of the compound from example 4 were added to 2.9 g (17.7 mmol) of 6-methylpyridine-2,3-dicarboxylic anhydride and, with warming to 170° C., the mixture was stirred for a total of 8 h as a melt. After cooling, the residue was taken up in methylene chloride, and the solution was treated with active carbon and magnesium sulfate. After filtering off with suction, the filtrate was chromatographed on silica gel, 1.3 g (24.4% of theory) of the title compound being obtained after concentration as beige crystals of m.p. 173-176° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([OH:3])=[O:2].[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:11]1[CH:12]=[CH:13][C:5]([CH2:4][C:1]([OH:3])=[O:2])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])([O-:16])=[O:15]
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: O=[N+]([O-])O
Product: O=C(O)Cc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.0 g of 2-carboxymethyl-benzoic acid were dissolved in 16 ml of fuming nitric acid. 16 ml of ice water was added into the resulting solution after stirred at room temperature for 2 hr, then filtrated to obtain a precipitation, dried in vacuum to obtain 1.99 g of 5-nitro-2-carboxymethyl-benzoic acid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:19])[C:15]([O:17]C)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].B(Br)(Br)Br>ClCCl>[F:20][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:19])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.50 g, 4.10 mmol) in dichloromethane (80 mL) was treated dropwise with BBr3 (9.4 mL of a 1.0M solution in CH2Cl2, 9.4 mmol), and the mixture stirred overnight while warming to 20 C. The excess BBr3 was quenched with the dropwise addition of water, the mixture diluted with ether (200 mL), washed with Na2CO3 (100 mL) and brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 1.25 g of a white solid foam. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.25 (s, 1 H), 6.79 (m, 1 H), 3.79 (m, 1 H), 3.7-3.3 (m, 2 H), 3.2-2.8 (m, 4 H), 1.32 (m, 3 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][CH2:42][CH2:43]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[F:41][CH2:42][CH2:43][O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: OCCF
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CO)cc2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(COCCF)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
To a solution of tert-butyl 4-(4-(hydroxymethyl)phenyl)piperazine-1-carboxylate (100 mg, 0.34 mmol) in THF (1 mL) was added triphenylphosphine (135 mg, 0.51 mmol), 2-fluoroethanol (24 μL, 0.41 mmol) and diisopropylazodicarboxylate (99 μL, 0.51 mmol). The reaction mixture stirred at room temperature overnight. The next day the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated to obtain a crude oil. Purification of the crude material using silica gel chromatography (gradient of 0% to 100% EtOAc in hexanes) afforded tert-butyl 4-(4-((2-fluoroethoxy)methyl)phenyl)piperazine-1carboxylate as a colorless oil (26 mg, 22% yield). 1H NMR (300 MHz, CDCl3) δ 7.27 (d, 2H, J=9.0 Hz), 6.89 (d, 2H, J=9.0 Hz), 4.65 (m, 1H), 4.52 (s, 2H), 4.49 (m, 1H), 3.74 (m, 1H), 3.64 (m, 1H), 3.58 (dd, 4H, J=6.0, 3.0 Hz), 3.13 (dd, 4H, J=6.0, 3.0 Hz), 1.49 (s, 9H); 19F NMR (282.4 MHz, CDCl3): δ−223.01 (m, 1F); 13C NMR (75.5 MHz, CDCl3); δ 154.7, 150.9, 129.4, 129.2, 116.5, 84.3 (82.0), 79.9, 73.0, 68.8 (68.7), 49.3, 44.0, 28.4; HRMS calcd for C18H27FN2O5: 339.20785 found 339.20790.
Reaction SMILES: Br[CH:2]([C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>CN(C)C=O.O>[CH:15]1([NH:18][CH:2]([C:4]2[NH:13][C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH3:3])[CH2:17][CH2:16]1
Reactant: CC(Br)c1nc2ccccc2c(=O)[nH]1
Reactant: NC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC1CC1)c1nc2ccccc2c(=O)[nH]1
Reaction time: 18 h

Procedure:
To a suspension of 2-(1-bromoethyl)quinazolin-4(3H)-one (2.53 g) in N,N-dimethylformamide (30 mL) was added cyclopropylamine (3.46 mL), and the mixture was diluted with N,N-dimethylformamide (20 mL) and water (1 mL), and then stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added aqueous sodium hydrogen carbonate solution, and then the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with diisopropyl ether/ethyl acetate (20:1) to give 2-[1-(cyclopropylamino)ethyl]quinazolin-4(3H)-one [REx(33-1)] (1.71 g) as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[C@H](C(O)=O)CC1C=CC=CC=1)=O)(C)(C)C.[N+:39]([C:42]1[CH:62]=[CH:61][C:45]([CH2:46][NH:47][C:48](=[O:60])[C@H:49]([CH3:59])[NH:50][C:51](=[O:58])[C@H:52]([CH2:54][CH:55]([CH3:57])[CH3:56])[NH2:53])=[CH:44][CH:43]=1)([O-:41])=[O:40].C(Cl)Cl>C(OCC)(=O)C>[N+:39]([C:42]1[CH:62]=[CH:61][C:45]([CH2:46][NH:47][C:48](=[O:60])[C@H:49]([CH3:59])[NH:50][C:51](=[O:58])[C@H:52]([CH2:54][CH:55]([CH3:56])[CH3:57])[NH:53][C:17](=[O:19])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:44][CH:43]=1)([O-:41])=[O:40]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCc1ccc([N+](=O)[O-])cc1
Yield: 71 %

Procedure:
Parallel syntheses for the D-isomer (R1 =H, R2 =benzyl) and L-isomer (R1 =benzyl, R2 =H) were performed. The following procedure was used for each. The procedure of Example 2, Section B was followed, using t-butoxycarbonyl-D-phenylalanine for one isomer and t-butoxycarbonyl-L-phenylalanine for the other, and using L-leucyl-L-alanine 4-nitrobenzylamide of the formula ##STR28## instead of (-)N-(L-2-hydroxy-4-methylpentanoyl)-L-alanine 4-nitrobenzyl amide. The reaction was carried out on a 2.0 mmol scale, using methylene chloride (10 mL) instead of dimethylformamide as the solvent. After the extractions, the crude product was purified by silica gel chromatography, eluting with 7:3 methylene chloride:ethyl acetate to afford the products as white solids (D-isomer: 0.83 g, 1.42 mmol, 71% yield; L-isomer: 0.77 g, 1.3 mmol, 62% yield). Verification of the structures was as follows: