Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:7]=1.[OH-].[Na+]>CCO.O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][CH:10]([C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)[CH2:9][C:8]2=[O:17]
Reactant: O=C(/C=C/c1ccncc1)c1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CC(c2ccncc2)Oc2ccc(Br)cc21
Reaction time: 8 h
Yield: 51.9 %

Procedure:
To a solution of (E)-1-(5-bromo-2-hydroxyphenyl)-3-(pyridin-4-yl)prop-2-en-1-one (20 g, 63.3 mmol) in EtOH (160 mL) and H2O (480 mL) was added NaOH (2.53 g, 63.3 mmol). The reaction mixture was stirred overnight. The mixture was filtered to give a solid residue. The solid residue was dissolved in EtOAc. The resulting solution was dried over Na2SO4 and concentrated in vacuo to give 6-bromo-2-(pyridin-4-yl)chroman-4-one (10 g, 50%). 1H-NMR (CDCl3): 3.00 (t, 2H), 5.51 (dd, 1H), 7.02 (d, 1H), 7.39 (d, 2H), 7.63 (t, 1H), 8.04 (s, 1H), 8.72 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)=[O:4].S(Cl)(Cl)=O.O.[NH2:18][NH2:19]>>[NH:18]([C:10]([C:8]1[S:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)=[O:12])[NH2:19]
Reactant: COC(=O)c1ccc(C(=O)O)s1
Reactant: NN
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)NN)s1
Yield: 72 %

Procedure:
The known procedure disclosed in the literature (J. Heterocyclic Chem., 28, 17, (1991).) was followed using 5-methoxycarbonyl-2-thiophenecarboxylic acid synthesized in Reference Synthetic Example 38, thionyl chloride and hydrazine monohydrate to give 144 mg of the desired product as a white solid (yield 72%).
Reaction SMILES: II.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:18])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1.Br[CH:20]([C:22]1[N:27]=[CH:26][N:25]=[C:24]([Cl:28])[C:23]=1[F:29])[CH3:21]>O1CCCC1.[Zn]>[Cl:28][C:24]1[C:23]([F:29])=[C:22]([CH:20]([CH3:21])[C:11]([C:5]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=2[F:3])([OH:18])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[N:27]=[CH:26][N:25]=1
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(Br)c1ncnc(Cl)c1F
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(c1ncnc(Cl)c1F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
A solution of iodine (2.25 g) in tetrahydrofuran (6 ml) was added dropwise to a stirred slurry of zinc (Britannia Alloys) (3.00 g) and lead (0.15 g) in tetrahydrofuran (19 ml) under a nitrogen atmosphere at 25° C. The reaction temperature was allowed to rise during the addition. The mixture was then cooled to 2° C. A solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (2.00 g), 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine (see Preparation 1) (2.84 g) and iodine (0.02 g) in tetrahydrofuran (16 ml) was added dropwise over 10 minutes. The reaction temperature was limited to a maximum of 16° C. during the addition by cooling. Further cooling was then applied to obtain a temperature below +5° C. The reaction was stirred below +5° C. for 30 minutes. A sample of the reaction mixture was taken and subjected to HPLC analysis according to the conditions set out in Example 1. The analysis showed a 10.3:1 molar ratio of the 2R,3S/2S,3R to the 2R,3R/2S,3S enantiomeric pair of the title compound. The yield of the 2R,3S/2S,3R enantiomeric pair was calculated to be 90% using an internal standard.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][C:13](=[O:20])[C:12]2=[O:21].Br[CH2:23][CH2:24][Cl:25]>CN(C=O)C>[Cl:25][CH2:24][CH2:23][N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH3:7])=[C:17]([O:18][CH3:19])[CH:16]=2)[C:12](=[O:21])[C:13]1=[O:20]
Reactant: COc1cc2c(cc1OC)C(=O)C(=O)N2
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)N(CCCl)C(=O)C2=O
Temperature: 70 °C

Procedure:
Anhydrous potassium carbonate (2.44 g) was added to a solution of 5,6-dimethoxy-1H-indole-2,3-dione (1.2 g) in dry DMF (5 ml). 2-Bromo-1-chloroethane (4.1 g) was added and the mixture was heated at 70° C. for 2 hours. The mixture was evaporated to dryness under reduced pressure and the residue was purified by flash chromatography on silica gel. The 1-(2-chloroethyl)-5,6-dimethoxy-1H-indole-2,3-dione thus obtained was dissolved in dry DMF (5 ml) and anhydrous potassium carbonate (2.44 g), potassium iodide (100 mg) and 1-(phenylmethyl)piperazine (3.06 g) were added. The mixture was stirred and heated at 70° C. for 2 hours and then evaporated to dryness under reduced pressure. The residue was purified by chromatography to yield a red oil which on treatment with ethanolic HCl afforded 5,6-dimethoxy-1-[2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-1H-indole-2,3-dione dihydrochloride (33%), m.p. 205°-207° C. (dec.).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#N)[CH:2]([CH3:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].Cl.CC[O:28]CC>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:28])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cccc(C#N)c1
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)Cc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-isobutylbenzonitrile (7.0 g) in toluene (150 ml) was added a 1.5M solution of diisobutylaluminum hydride in toluene (88 ml) at 25° C. over 30 minutes and the mixture was stirred at 25° C. for 2 hours. Another 1.5M solution of diisobutylaluminum hydride in toluene (30 ml) was added, and the mixture was stirred at 25° C. for 1 hour. The mixture was poured into a mixture of ether, aqueous ammonium chloride and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (150 g) eluting with a mixture of toluene and hexane (2:1) to give 3-isobutylbenzaldehyde (4.72 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:36][CH3:37])=[C:25]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=2)[CH:26]=1>>[Cl:34][C:33]1[C:28]([NH:27][C:25]2[CH:26]=[C:21]([Cl:20])[CH:22]=[CH:23][C:24]=2[O:36][CH3:37])=[N:29][C:30]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:31][CH:32]=1
Reactant: COc1ccc(Cl)cc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3cc(Cl)ccc3OC)n1)CCN(CC(C)(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (5-Chloro-2-methoxy-phenyl)-(2,5-dichloro-pyrimidin-4-yl)-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.063 g, 71%). MP: 170-173° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.48 (s, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.78 (s, 1H), 7.42 (s, 1H), 7.03-6.98 (m, 1H), 6.86-6.82 (m, 1H), 6.65 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 2.89-2.78 (m, 10H), 1.68 (t, 3H, J=18.7 Hz). MS: 538 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH:10]([O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([NH:42][C:18]([C:17]1[CH:21]=[CH:22][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH:10]2[O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:15][CH:16]=1)=[O:20])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: NCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)NCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 36(b), by condensing (3RS,4RS)-4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-benzoic acid with benzylamine there was obtained tert-butyl (3RS,4RS)-4-(4-benzylcarbamoyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless foam; MS: 551 (M+H)+.
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:29])[CH3:28])[C@@H:22]([CH3:30])[CH2:21][C@H:20]3[NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=2)[CH:14]=[N:13]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O.[ClH:46].CCOCC>ClCCl>[ClH:46].[C:27]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH2:11][CH2:10][NH:6][CH3:5])[CH:16]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=2)[CH2:21][C@@H:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(CC(C)(C)C)C(=O)[O-])c3)cc2[C@H](Nc2ccc(F)cn2)C[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2ccc(F)cn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
A solution of 1,1-dimethylethyl[2-(4-{(2S,4R)-1-acetyl-4-[(5-fluoro-2-pyridinyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}-1H-pyrazol-1-yl)ethyl]methylcarbamate (for a preparation see intermediate 76) (51 mg, 0.098 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (TFA) (1 ml, 12.98 mmol) and the resulting mixture was stirred at room temperature for 1 h then concentrated in vacuo. The residue was loaded onto a 2 g SCX cartridge and eluted with MeOH (45 mL) followed by 2M NH3 in MeOH (45 mL). The ammonia fractions were combined and concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and the solution was treated with HCl (1M in Et2O, 0.11 mmol, 0.11 ml) then was concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-N-(5-fluoro-2-pyridinyl)-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (52 mg, 0.102 mmol, 104%) as an orange solid.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][O:7][C:8](=[O:28])[C:9]1[CH:14]=[C:13]([C:15]2[CH:19]=[CH:18][O:17][CH:16]=2)[C:12]([C:20]([F:23])([F:22])[F:21])=[CH:11][C:10]=1[NH:24]C(=O)C>CO>[CH3:6][O:7][C:8](=[O:28])[C:9]1[CH:14]=[C:13]([C:15]2[CH:19]=[CH:18][O:17][CH:16]=2)[C:12]([C:20]([F:22])([F:23])[F:21])=[CH:11][C:10]=1[NH2:24]
Reactant: COC(=O)c1cc(-c2ccoc2)c(C(F)(F)F)cc1NC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(-c2ccoc2)c(C(F)(F)F)cc1N
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Concentrated H2SO4 (1.4 mL) was added to a solution of 2-acetylamino-5-furan-3-yl-4-trifluoromethyl-benzoic acid methyl ester (156 mg, 0.47 mmol) in MeOH (15 mL). The mixture was stirred for 1 h (TLC control) at 90° C. The mixture was filtered over Celite and evaporated under reduced pressure. The yellow solid obtained was used in the next step without further purification (rt 5.95 min.).
Reaction SMILES: C(OC(=O)[NH:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH:14]3[SH:21])[CH2:12]1)[CH2:18]2)C1C=CC=CC=1.Br>CCOCC>[NH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH:14]3[SH:21])[CH2:12]1)[CH2:18]2
Reactant: O=C(NC12CC3CC(C1)C(S)C(C3)C2)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Product: NC12CC3CC(C1)C(S)C(C3)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 11A (51 mg, 0.16 mmol) was added HBr (33% in HOAc) 2 mL and the mixture was stirred at rt for 2 h. Ether (10 mL×2) was added and the resulting precipitate was collected and dried under vacuum to give the title compound as hydrogen bromide salts (11). LC-MS (ESR): m/z=184 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>>[CH:14]1([NH:17][C:4](=[O:6])[C:3]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:2]=2[OH:1])[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(OC)cc1O
Product: COc1ccc(C(=O)NC2CC2)c(O)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A suspension of methyl 2-hydroxy-4-methoxybenzoate (5.1 g, 28.0 mmol) in cyclopropyl amine 24 mL) was stirred at room temperature for 5 days. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-60% ethyl acetate in petroleum ether) to give the subtitled compound (1.8 g).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[O:13]([CH2:20][C:21]([NH:23][CH:24]1[C:55](=[O:56])[N:26]2[C:27]([C:39]([O:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[C:28](OS(C(F)(F)F)(=O)=O)[CH2:29][S:30][C@H:25]12)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[O:13]([CH2:20][C:21]([NH:23][CH:24]1[C:55](=[O:56])[N:26]2[C:27]([C:39]([O:41][CH:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[O:40])=[C:28]([S:1][C:2]3[S:3][C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=3)[CH2:29][S:30][C@H:25]12)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CS[C@H]12
Reactant: Sc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3nc4ccccc4s3)CS[C@H]12
Temperature: -20 °C
Reaction time: 16 h

Procedure:
To a solution of 2-mercaptobenzothiazole (0.26 g. 1.54 mmol) in dry tetrahydrofuran (5.0 ml) at -78° C. was added sodium hydride (98%) (0.0369 g. 1.54 mmol). followed by diphenylmethyl 7-phenoxyacetamido-3-(trifluoromethylsulfonyloxy)-3-cephem-4-carboxylate (1.0 gm, 1.54 mmol). The reaction was warmed up to -20° C. and stirred for 16 hours before quenching in 0.5 N solution of hydrochloric acid (5 ml). The aqueous layer was extracted with dichloromethane (3×5 ml), dried (magnesium sulfate) and evaporated in vacuo to give the title compound as an oil which was purified by flash chromatography (silica, 40% ethylacetate in haxanes); yield isolated 0.7 g (70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([O:22][CH3:23])[CH:11]=2)=[O:8])[NH:5][CH:6]=1.Br[CH2:25][CH2:26]Br.[OH-].[Na+]>ClC(Cl)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[O:8])[N:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:26][CH2:25][N:5]2[CH:6]=1
Reactant: COc1cc(NC(=O)c2cc(Br)c[nH]2)ccc1OCC(C)(C)O
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cc(N2CCn3cc(Br)cc3C2=O)ccc1OCC(C)(C)O
Temperature: 50 °C
Reaction time: 16 h
Yield: 40.1 %

Procedure:
A mixture of 4-bromo-N-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide (1.50 g, 3.92 mmol), 1,2-dibromoethane (1.68 mL, 19.6 mmol), NBu4Br (1.26 g, 3.93 mmol) and 1N NaOH (19.6 mL, 19.6 mmol) in dichloroethane (19.6 mL) was allowed to stir at 50° C. for 16 h. The reaction mixture was cooled to rt, diluted with EtOAc (150 mL), washed with water, brine, dried over anhydrous Na2SO4 and concentrated. To the resulting brown oil was triturated with EtOAc (25 mL) to give 643 mg of the title compound as a light gray solid: 1H NMR (500 MHz, CDCl3) δ 1.34 (s, 6H), 2.67 (br. s., 1H), 3.83 (s, 2H), 3.85 (s, 3H), 4.04-4.08 (m, 2H), 4.22-4.26 (m, 2H), 6.78 (t, J=5.5 Hz, 2H), 6.90-6.95 (m, 2H), 6.99 (s, 1H); HPLC a) column: Phenomenex Luna 5μ 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% H3PO4 to 90% MeOH/10% H2O/0.1% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 2.730 min retention time, (99%); HPLC b) column: Phenomenex Luna C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 2.748 min retention time; MS (ES) 409 [M+H]+
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5](N1C=CN=C1)([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)=[O:6]>ClCCl>[N:7]1([C:5]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: C=CCN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C=CCNC(=O)n1ccnc1
Reaction time: 8 h

Procedure:
Allylamine (1.0 g, 17.5 mmol) was dissolved in dichloromethane (30 ml), 1,1′-carbonyldiimidazole (7.37 g, 15 mmol) was added, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([NH:14][C@H:15]([C:37]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)=[O:38])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23]S(C4C5C=CN=CC=5C=CC=4)(=O)=O)=[CH:19][CH:18]=3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[CH2:45]([O:52][C:53](Cl)=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[Cl-].[Na+].[OH-].[Na+]>C(Cl)Cl.CO.C(N(CC)CC)C>[CH2:45]([O:52][C:53]([N:42]1[CH2:41][CH2:40][N:39]([C:37](=[O:38])[C@H:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[NH:14][S:11]([C:6]2[C:5]3[CH:4]=[CH:3][N:2]=[CH:1][C:10]=3[CH:9]=[CH:8][CH:7]=2)(=[O:12])=[O:13])[CH2:44][CH2:43]1)=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C([C@H](Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)NS(=O)(=O)c1cccc2cnccc12)N1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCN(C(=O)[C@H](Cc2ccc(O)cc2)NS(=O)(=O)c2cccc3cnccc23)CC1

Procedure:
620 mg of the crude product obtained in Example 28 was dissolved in 10 ml of methylene chloride, and to the solution were sequentially added 0.29 ml of benzyloxycarbonyl chloride and 3.04 ml of triethylamine with ice cooling. After stirring for two hours with ice cooling, 40 ml of saturated sodium chloride aqueous solution was added to the reaction mixture, which was then extracted twice with 20 ml of chloroform, and the extract was dried over magnesium sulfate and concentrated under a reduced pressure to obtain a residue. The residue was dissolved in 6 ml of methanol, and after the addition of 2 ml of 1N sodium hydroxide aqueous solution, the mixture was refluxed for two hours, dried over magnesium sulfate and concentrated under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform/methanol (80:1 to 50:1) to obtain 336 mg of the title compound as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1.N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>ClCCl.C(OCC)(=O)C>[C:16]([O:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OCC(CO)O1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)OCC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
To a mixture of 4-hydroxymethyl-2,2-dimethyl-1,3-dioxolane (5.35 g) and pyridine (15.65 g) in dichloromethane (200 ml) was added acetic anhydride (20.56 g), and the mixture was stirred at ambient temperature for 12 hours. The mixture was poured into a mixture of water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate and brine successively, dried over magnesium sulfate, and evaporated in vacuo to give 4-acetoxymethyl-2,2-dimethyl-1,3-dioxolane (6.02 g).
Reaction SMILES: [NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:7]([NH:9][C@@H:10]([C:25](O)=[O:26])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([O:23][CH3:24])=[O:22])[CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:35][C@@H:36]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[CH2:37][CH2:38][CH2:39][CH3:40].CC1C=CC(S(O)(=O)=O)=CC=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.O>[NH:1]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C@H:2]([C:7]([NH:9][C@@H:10]([C:25]([NH:35][C@@H:36]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[CH2:37][CH2:38][CH2:39][CH3:40])=[O:26])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([O:23][CH3:24])=[O:22])[CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)n1cc(C[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Reactant: CCCC[C@@H](N)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CCCC[C@@H](NC(=O)[C@@H](Cc1cn(C(=O)OC)c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of Boc-Leu-DTrp(COOMe)-OH (50 mg), H-DNle-OBzl.TsOH (46 mg), NMM (13 μl) and HOBT.H2O (16 mg) in dichloromethane (1 ml) was added EDCI.HCl (22 mg) under ice cooling. After being stirred at room temperature for 2 h, the mixture was diluted with dichloromethane, washed with water, 10% aq. citric acid, sat. aq. NaHCO3 and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was purified by preparative TLC (Merck, Kieselgel 60 F254) with chloroform/methanol/acetic acid=100/10/1 for development to give Boc-Leu-DTrp(COOMe)-DNle-OBzl (67 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21](O)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([NH:30][NH2:31])=[O:29].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21]([NH:31][NH:30][C:28](=[O:29])[C:27]1[CH:32]=[CH:33][CH:34]=[C:25]([CH3:24])[CH:26]=1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2nc(C(=O)O)c(OCc3ccccc3)c(=O)n2c1
Reactant: Cc1cccc(C(=O)NN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)NNC(=O)c2nc3ccc(C)cn3c(=O)c2OCc2ccccc2)c1
Yield: 53 %

Procedure:
To a solution of the product from Example 8.2 (200 mg, 0.644 mmol) in tetrahydrofuran (10 mL), was added 3-methylbenzoyl hydrazine (94.8 mg, 0.632 mmol), 1-hydroxybenzotriazole (6.98 mg, 0.0576 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98 mg, 0.632 mmol) successively at room temperature. After 12 h the reaction solution was quenched with water (20 mL) and extracted with ethyl acetate. The extract was washed with 2N aqueous hydrochloric acid (20 mL), 2N aqueous sodium hydroxide (20 mL) dried (Na2SO4) and concentrated in vacuo to afford the desired compound (53%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.OS(O)(=O)=O.[N+:18]([O-])([OH:20])=[O:19]>CCOC(C)=O>[F:1][C:2]1[C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C1COc2cc(F)ccc2N1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: O=C1COc2cc(F)c([N+](=O)[O-])cc2N1
Temperature: 0 °C

Procedure:
To a stirred solution of the compound of Step B, Example 3, (48.9 gm, 292.8 mmol) and concentrated H2SO4 (100 mL), under N2, was added a 26 mL mixture of HNO3 (69-71%) and concentrated H2SO4 dropwise at 25°-35° C. (ice-bath). The resultant solution was stirred at room temperature for 10 minutes. 400 mL of ice water was added portionwise to the solution at 0° C. (ice-bath) followed by the addition of EtOAc (1.5 L). The organic layer was separated, dried (MgSO4) and evaporated to dryness to give the title compound of Step C as a tan solid (60.0 gm), 96%; m.p. 200°-202° C.; IR (nujol, cm-1): 1703.5 (C=O); 1H NMR δ: 4.79 (s,2H), 7.26-7.29 (d,1H), 7.63-7.64 (d,1H), 11.05 (s,1H).