Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][Si](C(C)(C)C)(C)C.C([C:14]1[CH:19]=[C:18]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH2:32][N:33]([CH2:35][CH3:36])[CH3:34])[CH:26]=3)[O:22][N:21]=2)[CH:17]=[C:16]([CH3:37])[C:15]=1[OH:38])C.[C:39]([O-])([O-:41])=[O:40].[K+].[K+]>C(#N)C>[CH2:35]([N:33]([CH2:32][C:27]1[CH:26]=[C:25]([C:23]2[O:22][N:21]=[C:20]([C:18]3[CH:17]=[C:16]([CH3:37])[C:15]([O:38][CH2:2][CH2:3][OH:4])=[C:14]([CH3:39])[CH:19]=3)[N:24]=2)[CH:30]=[C:29]([CH3:31])[CH:28]=1)[CH3:34])[CH3:36].[CH:39]([O-:41])=[O:40]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1O
Agent: [K+]
Solvent: CC#N
Product: CCN(C)Cc1cc(C)cc(-c2nc(-c3cc(C)c(OCCO)c(C)c3)no2)c1
Product: O=C[O-]
Temperature: 70 °C
Reaction time: 16 h

Procedure:
(2-bromoethoxy)-tert-butyl-dimethylsilane (104 mg, 435 μmol) was added to a suspension of 2-ethyl-4-(5-{3-[(ethyl-methyl-amino)-methyl]-5-methyl-phenyl}-[1,2,4]oxadiazol-3-yl)-6-methyl-phenol (53 mg, 145 μmol) and K2CO3 (60 mg, 435 μmol) in acetonitrile (2 mL). The mixture was stirred at 70° C. for 16 h before it was filtered. The filtrate was diluted with 1N aq. HCl (0.1 mL) and 2N aq. HCl (0.1 mL). The mixture was allowed to stand at rt for 10 min before the solvent was removed in vacuo. The crude product was purified by prep. HPLC to give the title compound as a formate salt in the form of a white lyphilisate (29 mg). LC-MS: tR=0.59 min; [M+1]+=410.26; 1H NMR (D6-DMOS): δ 1.06 (t, J=7.3 Hz, 3H), 1.23 (t, J=7.3 Hz, 3H), 2.15 (s, 3H), 2.36 (s, 3H), 2.42-2.48 (m, 5H), 2.75 (q, J=7.5 Hz, 2H), 3.56 (s, 2H), 3.73-3.77 (m, 2H), 3.84-3.89 (m, 2H), 7.47 (s, 1H), 7.80 (s, 2H), 7.90 (s, 1H), 7.92 (s, 1H), 8.17 (s, 1H, formate).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH3:33])[CH:18]=[CH:17][C:16]([S:19]([N:22]2[C:26]3[N:27]=[CH:28][CH:29]=[C:30]([C:31]#[N:32])[C:25]=3[CH:24]=[CH:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[I:34]I>O1CCCC1.O>[I:34][C:23]1[N:22]([S:19]([C:16]2[CH:15]=[CH:14][C:13]([CH3:33])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[C:26]2[N:27]=[CH:28][CH:29]=[C:30]([C:31]#[N:32])[C:25]=2[CH:24]=1
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C#N)ccnc32)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(C#N)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
A stirred solution of diisopropylamine (0.38 mL) in tetrahydrofuran (7 mL), at −70° C. and under nitrogen, was treated with a solution of n-butyllithium in hexanes (1.06 mL, 2.5M) over 5 minutes, whilst maintaining the temperature below −65° C. After stirring for 20 minutes the mixture was added, at −70° C., to a solution of 1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (0.65 g, Reference Example 63) in tetrahydrofuran (15 mL) and stirred at −70° C. for 45 minutes. A solution of iodine (0.9 g) in tetrahydrofuran (10 mL) was then added at −70° C. The reaction mixture was allowed to warm up to room temperature over 1 hour, and stirred for 18 hours, then treated with water (10 mL). The reaction mixture was evaporated in vacuo and the residue partitioned between ethyl acetate (75 mL) and water (50 mL). The insoluble material was filtered, washed with ether and dried in vacuo to give the title compound (0.45 g) as a white solid. The filtrate was separated and the organics washed sequentially with saturated sodium thiosulfate solution (2×30 mL), water (30 mL) and brine (30 mL), dried over sodium sulfate and evaporated. The residue was triturated with diethyl ether to give a further quantity of the title compound (0.25 g) as a cream solid. TLC RF=0.43 (ethyl acetate/heptane 1:1). MS: 424 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN(OC)[C:18](=[O:22])[CH2:19][CH2:20][CH3:21].O>C1COCC1.C(OCC)(=O)C>[CH3:9][N:8]([CH3:10])[C:4]1[CH:3]=[C:2]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)c1cccc(Br)c1
Reactant: CCCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)c1cccc(N(C)C)c1
Temperature: -35 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a stirred solution of (3-bromophenyl)dimethylamine (7.5 g, 37.5 mmol) in THF (50 mL) at −78° C., was added n-butyllithium (2.88 g, 45.0 mmol). The resulting solution was stirred at −35° C. for 1 h and was then cooled to −78° C. and treated dropwise with a solution of N-methyl-N-(methyloxy)butanamide (4.92 g, 37.5 mmol) (Description 25) in dry THF (15 mL). The resulting mixture was stirred for 45 min at −78° C. and then worked up using water (100 mL) and ethyl acetate (200 mL). The crude material was purified by chromatography on silica gel, eluting with a gradient of 0-20% ethyl acetate in hexane, to afford the title compound (3.48 g). LCMS (B) m/z: 192 [M+1]+, Rt 2.29 min.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.O.C(O)(=O)C>C1COCC1.[Fe]>[N:10]1([C:7]2[CH:8]=[N:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cn1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(N2CCCCC2)cn1
Temperature: 45 °C
Reaction time: 12 h

Procedure:
To 6′-Nitro-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl (0.25 g) in THF (8 mL) was added iron (0.539 mg) and water (2.5 mL). Then acetic acid (0.35 mL) was added dropwise and the mixture was allowed to stir at 45° C. for 12 hours. TLC analysis confirmed complete consumption of the starting material. The suspension was filtered through celite and the filter cake was washed well with ethyl acetate. The filtrate was concentrated in vacuo prior to addition of 2N NaOH. The aqueous layer was saturated with NaCl and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4 and evaporated to give a residue that was purified by flash chromatography on silica gel (gradient of MeOH in DCM containing 0.5% NH4OH). 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamine was obtained as a black oil (0.196 g). MS (ESI): 178.1 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].[Li]CCCC.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C1COCC1.O>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])(=[O:4])=[O:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)S(=O)(=O)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Imidazole (Intermediate L1, available from Aldrich, 20.0 g, 0.29 mol), triethylamine (41.0 mL, 0.29 mol) and N,N-dimethylsulfamoyl chloride (31.6 mL, 0.29 mol) were added to benzene (320 mL). The reaction was stirred for 48 h at rt and then filtered. The filtrate was collected and concentrated under reduced pressure. Vacuum distillation of the crude produc (˜0.5 mmHg, 115-118 EC) afforded dimethylsulfamoyl) imidazole (Intermediate L2) 38.7 g (76%) as a clear and colorless oil. Upon cooling the product solidifies to give white crystals. 1-(Dimethylsulfamoyl) imidazole (Intermediate L2) (18.8 g, 0.11 mol) was added to THF (430 mL). The solution was cooled to −78 EC. A solution of n-BuLi (70.9 mL, 1.6 M in hexane) was added dropwise to the reaction mixture. Upon completion, the solution was stirred for 1 h at −78 EC. t-Butyldimethylsilylchloride (TBSCl) (17.8 g, 0.12 mol) in THF (50 mL) was added via cannula to the mixture. After the addition was completed the reaction mixture was warmed slowly to rt and stirred for 24 h. The mixture was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over Na2SO4. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography on SiO2 with 20% ethyl acetate/hexane afforded 1-dimethylsulfamoyl-2-t-butyldimethylsilyl imidazole (Formula 13) as a light yellow solid. Recrystallization from pentane gave 30 g (94%) of white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[C:11](Cl)(Cl)=[O:12].C1(C)C=CC=CC=1>C1COCC1>[CH:7]1[C:3]2[CH2:4][CH2:5][O:6][C:11](=[O:12])[NH:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccccc1CCO
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2CCO1
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a solution of 2-aminophenethyl alcohol (4.0 g, 29.16 mmol) in THF (200 mL) was added a solution of 2M phosgene in toluene (17 mL, 34 mmol) at room temperature. The reaction was stirred for 15 minutes, concentrated, and purified with flash chromatography using ethyl acetate (5% 20%) in hexanes to yield 8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (4 g, 84%): 1H NMR (300 MHz, CDCl3) δ 8.02 (bs, 1H), 7.17 (dt, 1H), 7.09 (d, 1H), 6.99 (dt, 1H), 6.90 (d, 1H), 4.51 (t, 2H), 3.21 (t, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[CH3:8][C:9]1([CH3:17])[O:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[O:10]1.[CH2:18](OC(OCC)OCC)C>CCO>[CH3:8][C:9]1([CH3:17])[O:14][C:13](=[O:15])[C:12](=[CH:18][NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[C:11](=[O:16])[O:10]1
Reactant: CCOC(OCC)OCC
Reactant: Cn1ccc(N)n1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCO
Product: Cn1ccc(NC=C2C(=O)OC(C)(C)OC2=O)n1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
A mixture of 1-methyl-1H-pyrazol-3-ylamine (1.05 g, 10.8 mmol), 2,2-dimethyl-[1,3]dioxane-4,6-dione (1.71 g, 11.9 mmol), and triethylorthoformate (1.60 g, 10.8 mmol,) in a 25 mL round bottomed flask was heated in a 100° C. oil bath for 15 min. The mixture was cooled to room temperature and EtOH (10 mL) was added. The reaction mixture was heated to dissolve all solids and then cooled back to room temperature. The solid that was formed was isolated by filtration, rinsed with ethanol, and dried to provide the title compound (1.81 g, 66% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([C:25]([OH:27])=O)[CH2:21][CH2:22][CH2:23][CH3:24])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28]N1CCOCC1.ClC(OCC)=O.[N+](=C)=[N-]>C1COCC1.C(OCC)C>[C:25]([CH:20]([NH:19][C:17](=[O:18])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:21][CH2:22][CH2:23][CH3:24])(=[O:27])[CH3:28]
Reactant: CN1CCOCC1
Reactant: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Agent: C=[N+]=[N-]
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 150 g of anhydrous THF were dissolved 5.4 g of N-benzyloxycarbonyl-L-leucyl-L-norleucine prepared in the same manner as in Example 1-(b) and 3.4 ml of N-methylmorpholine, and 1.6 g of ethyl chloroformate was added thereto under ice-cooling, followed by stirring at 0° C. for 30 minutes. The reaction mixture was added to an excess diazomethane solution in diethyl ether, and the solution was allowed to stand at 0° C. for 1 hour. The solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 4.0 g of the titled compound as a colorless crystal.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:46][C:47]([O:49][CH3:50])=[O:48]>CN(C=O)C>[CH3:50][O:49][C:47](=[O:48])[CH2:46][O:35][C:32]1[CH:33]=[CH:34][C:29]([N:7]([CH2:6][C:5]2[CH:36]=[CH:37][CH:38]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:26])[CH2:10][CH2:9]2)=[CH:30][CH:31]=1
Reactant: COC(=O)CBr
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)cccc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of COMPOUND 117 (102 mg, 0.20 mmol) in DMF (1 mL) were added K2CO3 (86 mg, 0.62 mmol) followed by methyl bromoacetate (40 μL, 0.42 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 147 as a tan solid (97 mg, 82%) following work-up and purification. 1H NMR (CDCl3) δ 0.90-1.13 (m, 2H), 0.99 (d, 3H, J=6.3 Hz), 1.49-1.54 (m, 1H), 1.69-1.81 (m, 3H), 2.12 (t, 1H, J=12.0 Hz), 2.31 (s, 6H), 2.53 (t, 1H, J=11.7 Hz), 2.73-2.88 (m, 3H), 3.24-3.31 (m, 1H), 3.41-3.49 (m, 1H), 3.71 (s, 2H), 3.78 (s, 3H), 3.86-3.90 (m, 1H), 4.52 (s, 2H), 6.51 (d, 2H, J=8.1 Hz), 6.73 (d, 2H, J=8.4 Hz), 6.94-7.00 (m, 3H), 7.42-7.50 (m, 4H), 8.42 (br s, 1H). 13C NMR (CDCl3) δ 13.79, 19.51, 29.43, 30.68, 31.28, 40.19, 44.01, 49.03, 52.51, 58.07, 60.86, 66.52, 112.73, 116.20, 116.37, 119.42, 127.62, 128.72, 129.51, 130.61, 130.78, 131.56, 134.42, 139.02, 142.79, 143.83, 150.85, 162.90, 170.14, 170.22. ES-MS m/z 583 (M+H). Anal. Calcd. for C35H422N4O4.0.3H2O: C, 71.48; H, 7.30; N, 9.53. Found. C, 71.42; H, 7.23; N, 9.40.
Reaction SMILES: C[CH:2]1[C:7](=[O:8])[O:6][CH2:5][C:3]1=O.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>CCO>[N:9]1([C:3]2[CH2:5][O:6][C:7](=[O:8])[CH:2]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC1C(=O)COC1=O
Reactant: C1CCNC1
Solvent: CCO
Product: O=C1C=C(N2CCCC2)CO1
Temperature: 25 °C

Procedure:
A mixture of methyl tetronate (2.0 g, 17.5 mmol) and pyrrolidine (4.0 mL, 48 mmol) in EtOH (20 mL) was heated at reflux for 2 hours. The mixture was cooled to room temperature, and evaporated to dryness. The resulting solid was recrystallized with benzene/hexanes to give 4-pyrrolidin-1-ylfuran-2(5H)-one as white crystals. Yield: 2.60 g, 96%.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([NH2:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>C(#N)C>[NH2:8][C:6]([C@H:2]([NH:1][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH:3]([CH3:5])[CH3:4])=[O:7]
Reactant: CC(C)[C@@H](N)C(N)=O
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Product: CC(C)[C@@H](NCCCS(=O)(=O)O)C(N)=O
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To a solution of D-valinamide (1.76 g, 14.7 mmol) in acetonitrile (30 mL) was slowly added 1,3-propanesultone (1.75 g, 14.4 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetonitrile (2×25 mL). The solid product was dissolved in water (75 mL). Dowex Marathon C resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid material was suspended in acetone (50 mL), filtered and dried in vacuo, affording the title compound (1.57 g, 51%). 1H NMR (D2O, 500 MHz) δ ppm 3.80 (m, 1H), 3.19 (m, 2H), 3.00 (m, 2H), 2.25 (m, 1H), 2.16 (m, 2H), 1.08 (d, 3H, J=6.8 Hz), 1.02 (d, 3H, J=6.8 Hz). 13C (D2O, 125 MHz) δ ppm 169.94, 65.86, 48.10, 46.27, 29.54, 21.23, 17.99, 17.02. [α]D=−12.4° (c=0.0037 in water), ES-MS 237 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:12][C:13]([F:17])([F:16])[CH2:14][NH2:15]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH2:14][C:13]([F:17])([F:16])[F:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NCC(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(NCC(F)(F)F)c1ccc(Br)cc1
Yield: 26.2 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and 2,2,2-trifluoroethylamine (0.32 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-(2,2,2-trifluoroethyl)benzenesulfonamide (0.13 g) was provided after purification. MS (ESI) m/z 318. HPLC purity 100.0% at 210-370 nm, 8.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][NH:26][C:25]4=[O:29])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1.[CH2:31]1COC[CH2:32]1.[H-].[Na+].C(I)C>O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][N:26]([CH2:31][CH3:32])[C:25]4=[O:29])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: COc1ccc(Cc2ccc(CN3CCNC3=O)nc2)c(F)c1-c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCI
Product: CCN1CCN(Cc2ccc(Cc3ccc(OC)c(-c4cccc(Cl)c4)c3F)cn2)C1=O
Product: Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Into an 18 mL vial was added P-374 (65 mg, 0.16 mmol), THF (3 mL), and the solution was cooled to 0° C. NaH (9 mg, 0.23 mmol) was added and the suspension was stirred at room temperature for 15 minutes. EtI (25 uL, 0.31 mmol) was added and the reaction was stirred for 1 hour at room temperature. Water was added and the product was extracted with EtOAc (3×3 mL). The organics were washed with water, brine, and concentrated. To the residue was added 2 mL of 4N HCl/dioxane. After stirring to dissolve, the solution was concentrated. The resulting residue was triturated with ether, filtered, washed with ether, and dried to give P-461 (51 mg, 65%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) 8.63 (br s, 2H), 8.07 (br s, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.50-7.33 (m, 4H), 7.29 (d, J=5.8 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H), 4.51 (s, 2H), 4.09 (br s, 2H), 3.74 (s, 3H), 3.57 (s, 2H), 3.31 (s, 2H), 3.19-3.10 (m, 2H), 1.10-0.97 (m, 3H) ppm. LC/MS=84.2%, 454.2 (APCI+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](Cl)[CH:15]=[CH:14]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:15]=[CH:14]2
Reactant: Clc1ccc2cccc(Br)c2n1
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Brc1cccc2ccc(Nc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of aniline (0.76 g, 8.16 mmol) and 8-bromo-2-chloroquinoline (Biofine International, Vancouver, BC; 1.1 g, 4.54 mmol) in THF (7 mL) at 0° C. was added LiHMDS (1.0 M solution in THF, 13.61 mL, 13.61 mmol) drop wise via a syringe. The resulting brown mixture was stirred at RT for 1 h, and then quenched with sat. NH4Cl solution (15 mL) and extracted with EtOAc (2×50 mL). The combined organic solution was concentrated and the residue was purified on a silica gel column (25-45% EtOAc in hexanes) to afford 8-bromo-N-phenylquinolin-2-amine (Ex. 165c, 1.03 g, 3.44 mmol, 76% yield) as a brown crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.69 (1H, s), 8.21 (2H, d, J=7.8 Hz), 8.10 (1H, d, J=8.8 Hz), 7.94 (1H, m), 7.77 (1H, d, J=7.0 Hz), 7.35 (2H, t, J=7.8 Hz), 7.21 (1H, t, J=7.7 Hz), 7.13 (1H, d, J=9.0 Hz), 6.98 (1H, t, J=7.3 Hz). m/z (ESI, +ve) 299/301 (M+H)+.
Reaction SMILES: S([O-])(O)(=O)=O.[K+].C([O:10][C:11]1[O:12][CH2:13][C:14](=O)[C:15]=1C(OC(C)C)=O)(C)C.[Cl:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:32][CH:33]([F:35])[F:34])=[CH:26][CH:25]=1>C(#N)CCC>[Cl:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:32][CH:33]([F:35])[F:34])[C:14]2[CH2:13][O:12][C:11](=[O:10])[CH:15]=2)=[CH:26][CH:25]=1
Reactant: FC(F)CNCc1ccc(Cl)nc1
Reactant: CC(C)OC(=O)C1=C(OC(C)C)OCC1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCC#N
Product: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Temperature: 25 °C
Yield: 95 %

Procedure:
0.6 g of potassium hydrogensulphate was added at room temperature to a suspension of 1.0 g of isopropyl 2-isopropoxy-4,5-dihydro-4-oxofuran-3-carboxylate and 0.85 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethylamine in 15.8 g of butyronitrile. The mixture was heated to reflux for 5 hours. Subsequently, it was cooled to room temperature and washed with 10 ml of water. The solvent was removed under reduced pressure. This gave 1 g of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one (this corresponds to 95% yield).
Reaction SMILES: C(O[C:9](=[O:24])[CH:10]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[NH:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])C1C=CC=CC=1.[NH2:25][C@H:26]1[C@H:29]([CH2:30][CH:31](C)C)N[C:27]1=[O:34].C(=NC(CCC)C(=O)C(OOCCCC)=O)=[O:36]>>[CH2:15]([O:14][C:12]([NH:11][CH:10]([C:9]([N:25]1[CH2:31][CH2:30][CH2:29][C@H:26]1[C:27]([OH:34])=[O:36])=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])=[O:13])[CH2:16][CH2:17][CH3:18]
Reactant: CC(C)C[C@@H]1NC(=O)[C@H]1N
Reactant: CCCCOOC(=O)C(=O)C(CCC)N=C=O
Reactant: CCCCOC(=O)NC(CCCCN)C(=O)OCc1ccccc1
Product: CCCCOC(=O)NC(CCCCN)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
N-α-[4-(2-methylpropyl)-2-oxo-3-azetidinyl]-N-ε-3°-butoxycarbonyl-D,L-lysine benzyl ester can be prepared from trans-3-amino-4-(2-methylpropyl)-2-azetidinone (Example 78) and benzyl ε-3°-butoxy carbonylamino-2-oxohexanoate. The benzyl group can be removed by hydrogenation and the product coupled with L-proline benzyl ester. The product, N-α-[4-(2-methylpropyl)-2-oxo-3-azetidinyl]-N-ε-3°-butoxycarbonyl-D,L-lysyl-L-proline benzyl ester, can then be debenzylated with hydrogen and the β-lactam hydrolyzed with dilute base to obtain N-α-(2-amino-1-carboxy-4-methylpentyl)-N-ε-3°-butoxycarbonyl-D,L-lysyl-L-proline. After benzoylation with benzoyl chloride in organic solvent, the t-Boc protecting group can be removed with trifluoroacetic acid so that one can obtain N-α-(2-benzamido-1-carboxy-4-methylpentyl)-D,L-lysyl-L-proline.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[C:27]([O:31][CH3:32])[CH:28]=[CH:29][CH:30]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: COc1cccc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Yield: 59 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3-bromoanisole, the hydrochloride salt of the title compound was formed in 59% yield as a white solid, mp 260-261 C. elemental Analysis for C28H29 NO2.HCl.0.4H2O: Calculated: C, 73.88; H, 6.82; N, 3.08 Found: C, 73.87; H, 6.70; N, 3.14