Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:4][C:2]([N:7]1[CH2:8][CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6]1)=[O:3]
Reactant: c1ccc2c(c1)CCNC2
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCc2ccccc2C1
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A solution of methyl chloroformate (15.45 mL, 200 mmol) in CH2Cl2 (50 mL) was added to a solution of 1,2,3,4-tetrahydroisoquinoline (13.3 g, 100 mmol) and triethylamine (57 mL, 400 mmol) in CH2Cl2 (200 mL) at 0° C. The reaction mixture was stirred for 3 hours then was quenched with water. The organic layer was separated and washed with water (2×50 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered and the resultant filtrate was concentrated in vacuo to provide the title compound (19.1 g). The crude material thus obtained was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[C:6]([C:12]([NH:14][CH3:15])=[O:13])=[C:7]([CH:9]3[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl.N1C=CC=CC=1.O>[Br:18][C:17]1[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:3][C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[C:6]([C:12]([NH:14][CH3:15])=[O:13])[C:5]=2[CH:16]=1
Reactant: CNC(=O)c1c(C2CC2)oc2cc(N)c(Br)cc12
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNC(=O)c1c(C2CC2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a degassed solution of 6-amino-5-bromo-2-cyclopropyl-N-methylbenzofuran-3-carboxamide (4.0 g, 13 mmol) in DCM/Pyridine (80 mL/10 mL) was added MsCl (4.5 g, 39 mmol) under N2 at 0° C. over a period of 30 min. The reaction mixture was stirred at 25° C. for 8 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine and dried over Na2SO4. After concentration, the residue was purified by column chromatography (PE) to give crude product of 5-bromo-2-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (4.5 g, yield: 90%). 1H-NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.71 (s, 1H), 6.79 (s, 1H), 5.93 (s, 1H), 3.06 (d, J=4.8 Hz, 3H), 2.96 (s, 3H), 2.59˜2.61 (m, 1H), 1.13˜1.14 (m, 2H), 1.16˜1.20 (m, 2H). MS (M+H)+: 387/389.
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([CH:21]=[C:22]([C:24]2[NH:25][C:26]([C:29]3[O:30][C@@H:31]([CH3:34])[CH2:32][N:33]=3)=[CH:27][CH:28]=2)[CH:23]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH:19][CH3:20])(=[O:18])=[O:17])=[N:14][CH:15]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:2][CH2:3][C@H:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([CH:21]=[C:22]([C:24]2[NH:25][C:26]([C:29]3[O:30][C@@H:31]([CH3:34])[CH2:32][N:33]=3)=[CH:27][CH:28]=2)[CH:23]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH:19][CH3:20])(=[O:18])=[O:17])=[N:14][CH:15]=1
Reactant: CNS(=O)(=O)c1ccc(Oc2cc(O[C@@H](C)COC)cc(-c3ccc(C4=NC[C@H](C)O4)[nH]3)c2)cn1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Oc2cc(O[C@@H](C)CO)cc(-c3ccc(C4=NC[C@H](C)O4)[nH]3)c2)cn1
Reaction time: 1.5 h
Yield: 76.4 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridine-2-sulfonamide (166 mg, 0.32 mmol) synthesized in Example (121d) was dissolved in methylene chloride (5 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 0.34 mL, 0.34 mmol) was added at −78° C. under nitrogen atmosphere. Subsequently, the temperature was brought back to room temperature, followed by stirring for 1.5 hours. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with methylene chloride. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-4%) to afford the desired compound (119 mg, yield 78%) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl-].[Mg+2].[Cl-].[CH2:24]([O:26][C:27](=[O:32])[CH2:28]C([O-])=O)[CH3:25]>O1CCCC1.O>[O:8]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:32]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1cccs1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
To a suspension of 2-thiophenecarboxylic acid (6.48 g, 50.57 mmol) in tetrahydrofurane (100 ml) at 5. was added 1,1′-Carbonyldiimidazole (8.61 g, 53.09 mmol) by portions. The mixture was allowed to warm to room temperature, and the stirring was continued for 1 hour. The reaction mixture was added into a suspension mixture of magnesium chloride (4.86 g, 51.07 mmol) and pottasium 3-ethoxy-3-oxopropanoate (12.91 g, 75.85 mmol) in tetrahydrofurane (50 ml). After being stirred at 50. for 2 hours and at room temperature overnight, the reaction mixture was poured into water, and then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (ethyl acetate/hexane, 15/85) to give ethyl 3-oxo-3-(2-thienyl)propanoate (7.83 g, 78% yield) as a yellow oil.
Reaction SMILES: C([CH:3]([O:7][C:8]1[CH:12]=[C:11]([C:13](O)=O)[N:10]([CH3:16])[N:9]=1)[C:4]([OH:6])=[O:5])C.CCN=C=NCCCN(C)C.Cl.[CH2:29]([N:33]1[C:40]([NH2:41])=[C:39]([NH2:42])[C:37](=[O:38])[N:36]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:34]1=[O:35])[CH:30]([CH3:32])[CH3:31]>CO>[CH2:43]([N:36]1[C:37](=[O:38])[C:39]2[NH:42][C:13]([C:11]3[N:10]([CH3:16])[N:9]=[C:8]([O:7][CH2:3][C:4]([OH:6])=[O:5])[CH:12]=3)=[N:41][C:40]=2[N:33]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:34]1=[O:35])[CH:44]([CH3:46])[CH3:45]
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(CC(C)C)c1=O
Reactant: CCC(Oc1cc(C(=O)O)n(C)n1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CC(C)Cn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CC(C)C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetic acid (0.5 mmol) and EDCl (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-diisobutyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-diisobutyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[NH2:16])([O-])=O>[Pd].C(O)C.CC(=O)OCC>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]2[CH:9]=[C:4]([NH2:1])[C:5]([NH2:16])=[CH:6][CH:7]=2)[CH:11]=1
Reactant: Nc1ccc(-c2cccnc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(-c2cccnc2)cc1N
Yield: 102.8 %

Procedure:
4-Amino-3-nitrophenylboronic acid pinacol ester (1.60 g, 6.06 mmol), 3-bromopyridine (1.10 g, 6.96 mmol), cesium carbonate (3.33 g, 10.22 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride DCM complex (491 mg, 0.60 mmol) were suspended in dimethylformamide (20 mL). The solution was degassed by vacuum several times and placed in an argon atmosphere. It was then heated to 65° C. for 6 hr. After cooling, EA (100 mL) and water (40 mL) were added. When additional water (50 mL) was added to the organic layer, a precipitate was formed in the separatory funnel. The biphasic solution was filtered, and the filtrate was transferred to the separatory funnel and separated. The organic phase was washed twice with water (50 mL each), then with brine, and then dried with sodium sulfate and concentrated under reduced pressure to give 2-nitro-4-(pyridin-3-yl)benzenamine (1.18 g). 2-Nitro-4-(pyridin-3-yl)benzenamine (700 mg, 3.26 mmol) in 1:1 ethanol/EA (40 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (90 mg, 0.08 mmol) at room temperature for 2 days. Filtration and concentration under reduced pressure gave 4-(pyridin-3-yl)-benzene-1,2-diamine (621 mg).
Reaction SMILES: [CH2:1]([Sn:5]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1[S:10][C:9]([Si](C)(C)C)=[N:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].Cl>C1COCC1>[CH2:19]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1[S:10][CH:9]=[N:8][CH:7]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([Si](C)(C)C)s1
Agent: Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cncs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-tributylstannanyl-2-trimethylsilanylthiazole (4.0 g, 9.0 mmol) in THF is added slowly HCl (1.0N, 3 mL) and the solution is stirred at RT for 1 h. The reaction mixture is extracted with ether, washed with sat. NaHCO31 dried over anhydrous MgSO4 and concentrated to afford the title compound as a yellow oil which is used in the next step without further purification: (M+1)+=375.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([CH:15]2[CH2:17][CH2:16]2)[OH:14])[CH2:9]1)=O)(C)(C)C.C1C=NC2C3N=CC=CC=3C=CC=2C=1.I[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.CCO>[Cu]I>[CH:15]1([C@H:13]([O:14][C:41]2[C:42]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:38]=[CH:39][CH:40]=2)[C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](O)C2CC2)C1
Reactant: Ic1cccc2ccccc12
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc2c(O[C@@H](C3CC3)[C@H]3CCNC3)cccc2c1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
(S)-3-((S)-Cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (35 mg, 140 μmmol), copper(I) iodide (8.3 mg, 43.5 μmmol), o-phenanthroline (15.7 mg, 87 μmmol), and 1-iodonaphthalene (73.7 mg, 290 μmmol) were combined. Toluene (463 μL, 4.4 mmol) was added, followed by the addition of cesium carbonate (94.5 mg, 290 μmmol). Air was bubbled through the mixture, the vessel was sealed, and the mixture was heated at 105° C. for 72 hours. The mixture was filtered, rinsed with DCM, and concentrated. The crude material was treated with 1.25M HCl in EtOH (1.2 mL, 1.5 mmol) and stirred overnight. The mixture was concentrated, redissolved in 1:1 AcOH:H2O and purified by preparative HPLC to yield the title compound as a mono-TFA salt (3.5 mg, 99% purity). MS m/z: [M+H]+ calcd for C18H21NO, 268.16; found 268.2.
Reaction SMILES: [CH2:1]([C@:8]1([OH:32])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)[CH2:10][C@@H:9]1[OH:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[Pd]>[CH2:1]([C@:8]1([OH:32])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[CH2:10][C@@H:9]1[OH:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@H]1CN(CCOc2ccc(OCc3ccccc3)cc2)CC[C@@]1(O)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(OCCN2CC[C@@](O)(Cc3ccccc3)[C@@H](O)C2)cc1
Reaction time: 4 h

Procedure:
(3R,4R) and (3 S,4S)-4-benzyl-1-[2-(4-benzyloxy-phenoxy)-ethyl]-piperidine-3,4-diol 550 mg (1.3 mmol) was dissolved in 10 ml EtOH and hydrogenated in the presence of 100 mg Pd/C (10%) under atmospheric pressure at 50° C. After 4 hours the reaction was complete and the catalyst was filtered off and the solvent was removed under reduced pressure to give the crude product. Purification by chromatography (CH2Cl2/MeOH 9:1) yielded 249 mg (0.73 mmol, 56%) (3R,4R) and (3S,4S)-4-benzyl-1-[2-(4-hydroxy-phenoxy)-ethyl]-piperidine-3,4-diol as a solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:7]=2)=[N:2]1.Br[CH2:44][CH2:45][OH:46].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[OH:46][CH2:45][CH2:44][N:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[CH:7]=2)=[N:2]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc[nH]n3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccn(CCO)n3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 75 °C
Reaction time: 2 h

Procedure:
(S)-2-(1-((5-(1H-Pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (38 mg, 0.07 mmol) and 2-bromoethanol (15 mg, 0.12 mmol) were dissolved in DMF (1.5 ml) and cesium carbonate (102 mg, 0.31 mmol) was added. After stirring the mixture at 75° C. for 2 h, the solvent was evaporated under reduced pressure and the residue was suspended in water, basified with sodium carbonate and extracted with ethyl acetate (×3). The organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The residue (31 mg, 96% purity) was used in the next synthetic step without further purification.
Reaction SMILES: CO[C:3]([S:5][S:6][CH2:7][C:8]([NH:10][CH:11]([CH2:15][C:16]([OH:18])=[O:17])[C:12]([OH:14])=[O:13])=[O:9])=O.S[CH:20]([OH:22])C>CO>[OH:22][CH2:20][CH2:3][S:5][S:6][CH2:7][C:8]([NH:10][CH:11]([CH2:15][C:16]([OH:18])=[O:17])[C:12]([OH:14])=[O:13])=[O:9]
Reactant: CC(O)S
Reactant: COC(=O)SSCC(=O)NC(CC(=O)O)C(=O)O
Solvent: CO
Product: O=C(O)CC(NC(=O)CSSCCO)C(=O)O
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 74.6 %

Procedure:
A round bottomed flask was charged with 399.6 mg (1 eq., 1.495 mmole) (methoxycarbonyldithio)ethylamidosuccinic acid dissolved in 5 ml methanol, cooled to 0° C., purged with argon, and then treated dropwise with a solution of 110.9 mg (0.95 eq., 995.9 μl, 1.42 mmole) mercaptoethanol in 4 ml methanol over a 30 min period. The stirred solution was allowed to warm to room temperature over 1 hour and then stirred at this temperature for an additional 3.5 hours, after which, the solvent was evaporated on the rotary evaporator (bath temp. 30° C.). The residue was subjected to vacuum transfer for 0.5 hours to ensure that all mercaptoethanol was removed. The resultant white solid was then titurated with 3 ml ether and then the solid was pumped on the high vacuum for 10 min. (bath temp. 40° C.) to yield approximately 0.3 g of (2-hydroxyethyldithio)ethylamidosuccinic acid as a pure white solid. 1NMR (d6MDSO/TMS) δ: 2.31 (2H, t, J=6.02 Hz, CH2), 2.41 (2H, t, J=6.39 Hz, CH2), 2.77 (4H, q, J=6.86 Hz, 2×CH2), 3.35 (2H, t, J=6.75 Hz, CH2), 3.60 (2H, t, J=6.46 Hz, CH2), 8.06 (1H, T, NH). 13C NMR (d6DMSO/TMS) δ: 30.53 (CH2), 31.62 (CH2), 38.46 (CH2), 39.68 (CH2), 42.11 (CH2), 61.27 (CH2), 174.76 (Q), 176.63 (Q)
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][C:11]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(OC(F)F)cc1
Agent: O=S(=O)(O)O
Product: O=Cc1ccc(OC(F)F)c([N+](=O)[O-])c1

Procedure:
10 4-Difluoromethoxybenzaldehyde (1.7 g, 10 mmol) was dissolved in concentrated sulfuric acid (8 mL) at 0 ° C. followed by dropwise addition of 70 % nitric acid (1,1 mL).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:34]=[CH:33][C:20]([C:21]([NH:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[O:22])=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:34]=[CH:33][C:20]([C:21]([NH:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[O:22])=[CH:19][CH:18]=1)=[O:16]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(C(=O)Nc2ccc(C(=O)O)cc2)cc1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(C(=O)Nc2ccc(C(=O)O)cc2)cc1
Temperature: 100 °C
Yield: 75 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-{[4-(hydrazinocarbonyl)benzoyl]amino}benzoic acid. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 126 mg of the title compound (75%) as a orange solid in 83.3% purity by HPLC (Rt: 3.78, gradient of 8 min. MaxPlot detection between 230 and 400 nm).
Reaction SMILES: CC(C)=O.[C:5]([OH:9])(=[O:8])[CH2:6][OH:7].[C:10](Cl)(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1>[C:10]([O:7][CH2:6][C:5]([OH:9])=[O:8])(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C(O)CO
Reactant: CCCCCCCC(=O)Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCC(=O)OCC(=O)O
Reaction time: 1 h
Yield: 66.7 %

Procedure:
15.8 gm (0.20 mole) pyridine and 50 ml. acetone were combined in a 250 ml. round bottomed-three necked flask equipped with magnetic stir bar and two addition funnels, and cooled in an ice water bath with stirring. One addition funnel was charged with 15.5 gm (0.20 mole) glycolic acid dissolved in approximately 75 ml. acetone. The other addition funnel was charged with 32.5 gm (0.20 mole) octanoyl chloride. The contents of each addition funnel were added simultaneously to the cooled, stirred pyridine solution so that the complete addition of each component was continuous over one hour. The resultant slurry (a precipitation of pyridine hydrochloride was noted) was stirred an additional 45 minutes at ice bath temperature, and then at room temperature for another 30 minutes. Solvent was then removed by rotary evaporation at reduced pressure and 45C. The residual oil was dissolved in 200 ml dichloromethane and this was extracted with 3×150 ml. of 4% aqueous HCl. The dichloromethane layer was dried over sodium sulfate, decanted and the solvent removed by rotary evaporation. Drying on high vacuum for 4 hours left OOAA and 8.0% octanoic acid by weight, giving a crude yield for OOAA of 84%(mole). Recrystallization from 200 ml. hexane gave 27 g of a white crystalline product melting at 50 to 52° C., which was determined to be 99% wt. OOAA, giving a 67% (mole) yield of pure octanoxyloxyacetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH:13][C:14](=O)[C:15]3[CH:20]=[CH:19][C:18]([C:21]([C:24]#[N:25])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1>CC(O)=O.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]3[N:9]2[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:23])([CH3:22])[C:24]#[N:25])=[CH:17][CH:16]=2)=[N:13][N:12]=3)=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)c1ccc(C(=O)NNc2cnc3ccc(Br)cc3n2)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C#N)c1ccc(-c2nnc3cnc4ccc(Br)cc4n23)cc1
Temperature: 25 °C
Yield: 8.5 %

Procedure:
A solution of N′-(7-bromoquinoxalin-2-yl)-4-(2-cyanopropan-2-yl)benzohydrazide (2.2 g, 0.054 mol) in 3 mL of AcOH was stirred at 100° C. overnight. After cooling to room temperature, the reaction mixture was diluted with water (5 mL). The solid was collected on a filter, and washed with Sat. NaHCO3 (5 mL) to give 2-(4-(8-bromo-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl) phenyl)-2-methylpropanenitrile as a yellow solid (1.8 g, yield 85.0%). MS (m/z): 392 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.Br[CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:26]([N:23]1[CH2:22][CH2:21][C@H:20]2[N:15]3[C:16]4[C:11](=[CH:10][C:9]([C:3]5[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=5[Cl:1])=[CH:18][C:17]=4[C@H:19]2[CH2:24]1)[CH2:12][CH2:13][CH2:14]3)[CH2:27][CH2:28][CH3:29]
Reactant: Clc1cccc(-c2cc3c4c(c2)[C@H]2CNCC[C@H]2N4CCC3)c1Cl
Reactant: CCCCBr
Product: CCCCN1CC[C@@H]2[C@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (28 mg, 82%) from (±)-cis-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol) and 1-bromobutane (23 mg, 0.17 mmol). 1H NMR (CDCl3, 300 MHz) δ 0.92(t, J=7.3 Hz, 3H), 1.32 (se, J=7.3 Hz, 2H), 1.53-1.65 (br, 2H), 2.02-2.25 (m, 5H), 2.38-2.53 (br, 2H), 2.58-2.68 (m, 1H), 2.75 (t, J=6.4 Hz, 2H), 2.80-2.92 (br, 1H), 2.95-3.07 (br, 1H), 3.31 (dt, J=10.3, 3.6 Hz, 1H), 3.37-3.45 (br, 2H), 6.94 (s, 1H), 6.99 (s, 1H), 7.15-7.21 (m, 2H), 7.35-7.40 (m, 1H) ppm.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH:14]=2)[CH:6]=[N:7][CH:8]=1>Cl.O1CCOCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:6]=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cncc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1cncc(C2=CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 115.3 %

Procedure:
tert-Butyl 5-(trifluoromethyl)-3′,6′-dihydro-3,4′-bipyridine-1′(2′H)-carboxylate (50.0 mg, 0.152 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (2 mL) to form a light yellow clear (then cloudy) solution. After being stirred at room temperature for 1 h, the reaction mixture was concentrated in vacuo to afford 40.0 mg (87%) of product as a yellow gum. LC-MS calculated for C11H11F3N2: (M+H) 229; found 229.0.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[CH2:66][C:65](=[O:67])[N:64]([CH3:68])[C:63]2=[O:69])[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:54]=[CH:55][C:56]([N+:59]([O-:61])=[O:60])=[CH:57][CH:58]=4)=[O:50])[C@H:46]([CH:62]4[CH2:66][C:65](=[O:67])[N:64]([CH3:68])[C:63]4=[O:69])[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: CN1C(=O)CC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CC(=O)N(C)C4=O)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 89.4 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (220 mg, 0.37 mmol) and (2S,4S)-4-mercapto-2-(N-methyl-2,5-dioxopyrrolidin-3-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer B (140 mg, 0.36 mmol) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(N-methyl-2,5-dioxopyrrolidin-3-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate diastereomer B (244 mg, yield: 89.4%).