Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:55](=[O:56])[N:6]2[C:7]([C:42]([O:44]CC3C=CC([N+]([O-])=O)=CC=3)=[O:43])=[C:8]([S:11][C@@H:12]3[CH2:16][N:15]([CH3:17])[C@H:14]([C:18]([N:20]4[CH2:25][CH2:24][N:23]([C:26](=[NH:41])[NH:27]C(OCC5C=CC([N+]([O-])=O)=CC=5)=O)[CH2:22][CH2:21]4)=[O:19])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[H][H]>O1CCCC1.O.[Pd]>[C:26]([N:23]1[CH2:24][CH2:25][N:20]([C:18]([C@@H:14]2[CH2:13][C@H:12]([S:11][C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:55](=[O:56])[N:6]4[C:7]=3[C:42]([OH:44])=[O:43])[CH2:16][N:15]2[CH3:17])=[O:19])[CH2:21][CH2:22]1)(=[NH:27])[NH2:41]
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=N)NC(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C)C3)[C@H](C)[C@H]12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=N)N)CC4)N(C)C3)[C@H](C)[C@H]12

Procedure:
500 ml of 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-{(2S,4S) -1-methyl-2-[4-(4-nitrobenzyloxycarbonylamidino)piperazin-1-ylcarbonyl]-pyrrolidin-4-yl-thio}-1-carbapen-2-em-3-carboxylate [prepared as described in step (1) above] were dissolved in 75 ml of a 1:1 by volume mixture of tetrahydrofuran and water, and 2400 mg of a 10% w/w palladium-on-carbon catalyst were added to the resulting solution. The mixture was then hydrogenated in an atmosphere of hydrogen at 28° C. for 1 hour. At the end of this time, the catalyst was removed by filtration, and the filtrate was washed with diethyl ether. The filtrate was then concentrated to 20 ml by evaporation under reduced pressure. The solution was then subjected to reverse phase silica gel column chromatography (Cosmosil 75C18 -prep, manufactured by Nacalai Tesque, 100 ml), eluted with mixtures of acetonitrile and water in proportions of 0:100, 2:98, 4:96, 6:94 and 8:92 by volume, in that order. The fractions containing the desired compound were collected, concentrated to 3 ml by evaporation under reduced pressure, and cooled to precipitate colorless needle-like crystals. The crystals were filtered off and dried to obtain 435 mg of the title compound as crystals, melting at 218°-220° C. (with decomposition).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH3:17])[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:18]([O-])=[O:19].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:18]=[O:19])[C:5]([N:7]([CH3:17])[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Product: CN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 1 h
Yield: 63.2 %

Procedure:
2 g of 1-(2-chloroethyl)-3-methyl-3-D-ribofuranosylurea are dissolved in 10 ml of formic acid, and 1.1 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, the mixture is treated in the same manner as described in Example 1-(2). 1.4 g of 1-(2-chloroethyl)-1-nitroso-3-methyl-3-D-ribofuranosylurea are thereby obtained as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:25]2[CH2:24][CH2:23][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:27][CH2:26]2)=[CH:3][CH:4]=1)([OH:14])[CH3:13]
Reactant: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(C)(O)C(F)(F)F)cc2)CC1
Temperature: 100 °C
Yield: 85.8 %

Procedure:
A 350 mL pressure tube was charged with 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (7.22 g, 26.8 mmol, Example 27, step 1), N-Boc-piperazine (5.00 g, 26.8 mmol), sodium tert-butoxide (3.87 g, 40.3 mmol), 50 mL of toluene, dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (1.253 g, 2.68 mmol, Strem Chemical Inc, Newburyport, Mass.) and tris(dibenzylideneacetone)dipalladium (0) (1.229 g, 1.342 mmol, Strem Chemical Inc, Newburyport, Mass.). The tube was sealed and heated at 100° C. for 2 h. After that time, the mixture was diluted with water (50 mL) and extracted with EtOAc (2×100 mL) to give a dark oil. Purification via column chromatography (120 g of silica gel, 0 to 40% EtOAc in hexanes) gave tert-butyl 4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (8.61 g) as an off-white brittle foam.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 50 °C
Yield: 100.1 %

Procedure:
A mixture of methyl 4-hydroxy-benzoate (10.0 g, 0.066 mol) and potassium carbonate (12 g, 0.086 mol), were taken in acetone (50 ml) and heated at 50° C. for 1 hour. To the reaction mixture benzyl bromide (8.2 ml, 0.072 mol) was added. The mixture was heated at 80° C. for 5 hours. The mixture was cooled to room temperature and filtered through sintered funnel, washed with acetone. Solvent was removed to obtain pure 4-benzyloxy-benzoic acid methyl ester as white solid (16 g, 100%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11](=[O:16])[C:10]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.Br>C1COCC1.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])([CH3:15])[C:11](=[O:16])[C:10]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:19][CH:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Agent: Br
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC(c2ccc(O)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 8.8 %

Procedure:
To a stirred 0° C. solution of 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (1.0 g, 2.61 mmol) in THF (10 mL), aqueous HBr (908 mg, 5.2 mmol) was added under a nitrogen atmosphere. The reaction mixture was then stirred for 12 h at RT, diluted with water and extracted with hexane (2×50 mL). The organic layers were concentrated in vacuo to afford 5-(4-hydroxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (100 mg) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 10.25 (s, 1H), 8.48 (d, J=7.8 Hz, 1H), 8.16-8.00 (m, 2H), 7.95 (t, J=7.8 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.63 (t, J=7.2 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H); 7.18 (d, J=7.2 Hz, 2H), 7.12 (d, J=7.2 Hz, 2H), 6.89 (d, J=7.6 Hz, 2H), 5.32 (s, 2H), 1.37 (s, 6H). MS: M+H: m/z=438.2; and LC MS: 88%, (Condition-H).
Reaction SMILES: [C:1](=[O:10])([O:7][CH2:8]Cl)[O:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:11]([O-:16])(=[O:15])[C:12]([CH3:14])=[CH2:13].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[C:1](=[O:10])([O:7][CH2:8][O:16][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])[O:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=C(C)C(=O)[O-]
Reactant: CCCCOC(=O)OCCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCOC(=O)OCCCC
Yield: 60.4 %

Procedure:
The intermediate n-butyl chloromethyl carbonate (2.5 g 15.0 mmol) was dissolved in dimethyl formamide (80 ml), and potassium methacrylate (1.77 g, 15.0 mmol) was added together with a catalytic amount of 18-crown-6 (0.2 g, 7.5 mmol). After 3 days at 25° C. the solvent was removed under reduced pressure, cholorform (30 ml) and water (20 ml) were added and the product was extracted into chloroform. The solvent was removed under reduced pressure after drying (MgSO4). Flash chromatography gave 1.96 g (61%) of butyl methacryloyloxymethyl carbonate.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[O:6][CH2:7][CH:8]([OH:24])[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH2:12][CH2:11]1)(=[O:3])N.Cl.C(=O)([O-])[O-:31].[K+].[K+]>>[C:1]([C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[O:6][CH2:7][CH:8]([OH:24])[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH2:12][CH2:11]1)([OH:3])=[O:31]
Reactant: COc1ccccc1N1CCN(CC(O)COc2ccccc2C(N)=O)CC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Product: COc1ccccc1N1CCN(CC(O)COc2ccccc2C(=O)O)CC1
Temperature: 25 °C

Procedure:
A solution consisting of 45 g. of 1-(2-carbamoylphenoxy)-3-[4-(2-methoxyphenyl)piperazinyl]propan-2-ol dissolved in 200 ml. of 40% aqueous hydrochloric acid was refluxed for a period of 2 hours and then allowed to cool to room temperature. Upon completion of this step, the resulting reaction mixture was adjusted to approximately pH 6-7 with aqueous potassium carbonate and the solid material which precipitated at this point was thereafter collected by means of suction filtration and subsequently recrystallized from aqueous ethanol to afford pure 1-(2-carboxyphenoxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-2-ol, m.p. 198°-202°C. (analytical sample). The yield of crude product before recrystallization was 44 g. (98%).
Reaction SMILES: O=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][C:5]1([C:10]([O:12]C)=O)[CH2:9][CH2:8][CH2:7][CH2:6]1.Cl.[CH2:21]([O:23][C:24](=[O:27])[CH2:25][NH2:26])[CH3:22].CC(O)=O.[BH3-]C#N.[Na+]>CCO>[O:12]=[C:10]1[C:5]2([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][C@@H:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:26]1[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:27]
Reactant: CCOC(=O)CN
Reactant: COC(=O)C1(NCC(=O)c2ccccc2)CCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CN1C(=O)C2(CCCC2)NC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred mixture of methyl 1-[(2-oxo-2-phenylethyl)amino]cyclopentanecarboxylate from Step A (1.10 g, 2.67 mmol) and glycine ethyl ester hydrochloride (881 mg, 6.31 mmol) in EtOH (10 mL) was added AcOH (0.72 mL, 12.6 mmol). The resulting mixture was stirred at ambient temperature for 5 min, then NaCNBH3 (397 mg, 6.31 mmol) was added. The reaction mixture was heated to 70° C. for 3 h then allowed to cool. The reaction mixture was quenched with saturated aqueous NaHCO3 and then extracted with EtOAc (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The product-containing fractions were combined, basified with saturated aqueous NaHCO3, and extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the racemic product. The enantiomers were separated by HPLC, using a Chiralcel OD column and eluting with hexane:EtOH—60:40. The first major peak to elute was ethyl [(8S)-10-oxo-8-phenyl-6,9-diazaspiro[4.5]dec-9-yl]acetate and the second major peak to elute was ethyl [(8R)-10-oxo-8-phenyl-6,9-diazaspiro[4.5]dec-9-yl]acetate, the title compound. MS: m/z=317 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])[OH:4])[CH3:2].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:36])[C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([O:23][CH3:24])[C:17]=2[NH:25][C:26]([C:28]2[S:29][CH:30]=[C:31]([CH2:34]Cl)[C:32]=2[Cl:33])=[O:27])=[N:12][CH:13]=1.CS(C)=O.C([O-])([O-])=O.[K+].[K+]>O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:36])[C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([O:23][CH3:24])[C:17]=2[NH:25][C:26]([C:28]2[S:29][CH:30]=[C:31]([CH2:34][O:4][N:3]([CH2:5][CH3:6])[CH2:1][CH3:2])[C:32]=2[Cl:33])=[O:27])=[N:12][CH:13]=1
Reactant: CCN(O)CC
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CCl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCN(CC)OCc1csc(C(=O)Nc2c(OC)cc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c1Cl
Temperature: 40 °C
Reaction time: 48 h

Procedure:
In a manner similar to that described in Paragraph J above, to a solution of N,N-diethylhydroxylamine (0.45 g, 5.0 mmol), N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (0.51 g, 1.0 mmol), and DMSO (10 mL) was added K2CO3 (0.68 g, 4.9 mmol). The mixture was stirred at 40° C. for 2 days, then it was poured into water. The resulting mixture was extracted with CH2Cl2 (2×50 mL). The organic layer was washed with 1% K2CO3, brine, treated with charcoal and concentrated. Purification by silica gel chromatography using 10:1 CH2Cl2:CH3OH with 1% NH4OH followed by precipitation from CH2Cl2 and hexane afforded N-(5-chloropyridin-2-yl)-2-[((4-(((diethylamino)oxy)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide, as a white solid; NMR (DMSO-d6) 8.35 (s, 1H), 8.20 (s, 1H), 8.10 (d, 1H), 7.90 (dd, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 4.20 (s, 2H), 3.85 (s, 3H), 3.20-2.80 (m, 4H), 1.20 (t, 6H) ppm.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][C:10](OCC)=[O:11])[CH:6]=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cc1cccc(NC)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1cccc(CCO)n1
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
A solution of ethyl 2-[6-(methylamino)-2-pyridyl]acetate (2.2 g, 12.5 mmol) in THF (30 ml) was added dropwise to a suspension of lithium aluminum hydride (1.24 g, 31.2 mmol) in TEF (25 ml) under argon at 0° C. The reaction was stirred for 30 minutes and quenched carefully with water (4 ml) and 1 N NaOH (4 ml). The mixture was filtered through a pad of Celite and washed several times with ethyl acetate. The filtrate was dried with sodium sulfate, filtered, and evaporated under vacuum. The crude product was chromatographed over silica gel to yield 1.50 g (79%) of 2-[6-(Methylamino)-2-pyridyl]ethan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17]OS(C)(=O)=O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[NH:33][N:32]=1>C(#N)C>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:35]=[C:31]([C:30]([F:29])([F:40])[F:41])[N:32]([CH2:17][C:10]2[CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=2)[N:33]=1
Reactant: FC(F)(F)c1cc(C(F)(F)F)[nH]n1
Reactant: COC(=O)c1cc(COS(C)(=O)=O)nn1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 700 mg (2.03 mmol) of methyl 2-(3-chloropyridin-2-yl)-5-methanesulphonyloxymethyl-2H-pyrazole-3-carboxylate in 15 ml of acetonitrile is admixed in succession with 336 mg (2.43 mmol) of potassium carbonate and 413 mg (2.03 mmol) of 3,5-bis(trifluoromethyl)pyrazole and the mixture is subsequently stirred at 60° C. for 1 h. After the mixture has cooled to room temperature, the solvent is concentrated on a rotary evaporator, water is added and extraction is carried out with three times 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate and then the solvent is removed on a rotary evaporator.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([N+:21]([O-])=O)[C:17]([O:19][CH3:20])=[CH:18][C:11]=2[CH2:10][CH2:9]1>[Pd].CCO>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][N:8]1[CH2:9][CH2:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH2:21])=[CH:15][C:12]=2[CH2:13][CH2:14]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCN(CC1COCCO1)CC2
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1N)CCN(CC1COCCO1)CC2

Procedure:
3-1,4-Dioxinan-2-ylmethyl-7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine was treated under standard hydrogenation conditions (H2, EtOH, 10% Pd/C) to yield desired 3-1,4-Dioxinan-2-ylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine as a crude oil, which was used for the subsequent reaction without further purification; LC/MS (m/e) 293.15 (M+H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:13])[CH2:11][NH2:12])[CH:5]=[CH:4][N:3]=[CH:2]1.I.CS[C:17]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:23]3[C:24]=2[C:19](=[CH:20][CH:21]=[CH:22]3)[N:18]=1>C(O)C>[N:18]1[C:19]2[C:24]3[C:23](=[CH:28][CH:27]=[CH:26][C:25]=3[C:17]=1[NH:12][CH2:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:13])[CH:22]=[CH:21][CH:20]=2
Reactant: CSC1=Nc2cccc3cccc1c23
Reactant: NCC(=O)NCCCn1ccnc1
Agent: I
Solvent: CCO
Product: O=C(CNC1=Nc2cccc3cccc1c23)NCCCn1ccnc1
Yield: 43.2 %

Procedure:
A mixture of 3.7 g of N-[3-(1H-imidazol-1-yl)propyl]glycinamide, 425 ml of ethanol, and 5.0 g of 2-(methylthio)benz[cd]indole hydroiodide was reacted as described in Example 19, giving 2.2 g of the desired product, mp 145°-146° C.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([CH2:25][CH3:26])=[C:12]2[CH2:27][C:28]([NH2:30])=[O:29])C.[OH-].[Na+]>CCO.O>[NH2:30][C:28](=[O:29])[CH2:27][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:31])=[O:3])[CH:10]=2)[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]=1[CH2:25][CH3:26]
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(CC)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1c(CC(N)=O)c2cc(OCCCC(=O)O)ccc2n1Cc1ccccc1
Reaction time: 1.5 h
Yield: 61 %

Procedure:
A mixture of 200 mg (0.5 mmol) of [4-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1-H-indol-5-yl]oxy]butanoic acid ethyl ester and 4 mL of 1N NaOH in 10 mL of EtOH was stirred for 1.5 hours, diluted with water and extracted with EtOAc. The aqueous layer was made acidic to pH 5 with 1N HCl, extracted with EtOAc, the EtOAc solution washed with brine and dried (MgSO4). The solvent was evaporated at reduced pressure, the residue stirred with ether/MeOH and the insoluble material filtered to give 120 mg (61% yield) of [4-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1-H-indol-5-yl]oxy]butanoic acid, mp, 196°-199° C.
Reaction SMILES: [NH:1]([C:31]([O:33]C(C)(C)C)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1)=[O:20])[CH2:15][C:16](=[O:18])[OH:17])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH3:38]C(ON1C(=O)CCC1=O)=O.C([O-])(O)=O.[Na+].CN(C=O)C>C(O)(C(F)(F)F)=O.Cl>[NH:1]([C:31]([CH3:38])=[O:33])[C@H:2]([C:6]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1)=[O:20])[CH2:15][C:16](=[O:18])[OH:17])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)O)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)O)C(=O)Nc1ccc([N+](=O)[O-])cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-BOCValAlaAsp-p-nitroanilide (174 mg, 0.33 mmole) was dissolved in neat TFA (5 mL) and stirred at room temperature for 1 hour. The TFA was removed in vacuo and the residue was then dissolved in 5 mL of CH2Cl2 which was then evaporated in vacuo. This dissolution with CH2 Cl2 and subsequent evaporation repeated two more times. The residue was dissolved in dioxane/water (5 mL, 4:1) and treated with acetic acid N-hydroxysuccinimide ester (63 mg, 0.40 mmole) and NaHCO3 (139 mg, 1.65 mmole). After 18 hours, the mixture was diluted with 1N HCl (25 mL) and extracted three times with ethyl acetate. The combined extracts were dried with MgSO4, filtered and concentrated to a yellow solid which was recrystallized from ethyl acetate/ethanol to give 33 mg (21%) of light yellow powder: mp 196°-200° C. (dec.); 1H NMR (DMSO-d6) δ 0.80 (d, J=6.6 Hz, 3H), 0.82 (d, J=5.1 Hz, 3H), 1.20 (d, J=7.2 Hz, 3H), 1.85 (s, 3H), 1.85-2.0 (m, 1H), 2.60 (dd, J=7.5, 16.6 Hz, 1H), 2.75 (dd, J=6.2, 16.6 Hz, 1H), 4.1-4.2 (m, 1H), 4.2-4.3 (m, 1H), 4.6-4.7 (m, 1H), 7.8-7.9 (m, 3H), 8.11 (d, J=6.8 Hz, 1H), 8.21 (d, J=9.3 Hz, 2H), 8.27 (d, J=7.2 Hz, 1H), 10.51 (s, 1H), 12.45 (br s, 1H); MS (LSIMS) m/e 488 (6, M+ +Na), 466 (23, M+ +1), 449 (7) 328 (15), 213 (44), 142 (100); [α]D20 -24.9° (c=1.0, DMF); Analysis calculated for C20H27N5O8 : C, 51.60; H, 5.85; N, 15.05; found: C, 50.16; H, 5.79; N, 14.06.
Reaction SMILES: CO.[OH-].[K+].[C:5](I)([C:8]([C:11]([C:14]([C:17]([C:20]([C:23]([C:26]([F:29])([F:28])[F:27])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.O>[CH:5]([C:8]([C:11]([C:14]([C:17]([C:20]([C:23]([C:26]([F:27])([F:28])[F:29])([F:24])[F:25])([F:21])[F:22])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
Into a 1 l four-necked flask equipped with a stirrer, a reflux condenser, a dropping funnel and a thermometer, 250 cc of methanol and 3 g of tetrabutylphosphonium bromide and 74.3 g (1.1 mols) of 85% potassium hydroxide were charged. The reactor was heated to bring the internal temperature to 60° C. Then, 273 g (0.5 mol) of C8F17I was dropwise added thereto over a period of one hour. After completion of the dropwise addition, heating and refluxing were continued for 8 hours. The conversion at that time was 99.6%. The reactor was cooled to room temperature. Then, 300 g of water was added to dissolve precipitated potassium iodide. The crude reaction solution was separated into two layers, and the fluorocarbon layer (lower layer) was further washed with 300 g of water to recover a fluorocarbon. Thus, 197 g of C8F17H having a purity of 99.0%, was obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:10]3[CH2:11][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[OH:1][C:2]1[C:3]2[C:10]3[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOC(=O)C1CCc2sc3ncnc(O)c3c2C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2sc3ncnc(O)c3c2c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 55.7 %

Procedure:
To a 250-mL round-bottom flask was placed a solution of ethyl 4-hydroxy-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate (4.0 g, 14.39 mmol, 1.00 equiv) in 1,4-dioxane (50 mL) was added DDQ (8 g, 35.24 mmol, 2.45 equiv) at room temperature. The resulting solution was stirred for 3 h at 90° C. under nitrogen. After cooling, the reaction was quenched with saturated aqueous Na2CO3. The solids were filtered out and the filtration was extracted with 3×100 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to give the resulted ethyl 3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaene-12-carboxylate (2.2 g, 56%) as a brown solid.