Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH2:15])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.[C:37]([NH:44][C@H:45]([C:47](O)=[O:48])C)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH:15][C:47](=[O:48])[CH2:45][NH:44][C:37](=[O:38])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:30]=[CH:31][C:32]([C:33]#[N:34])=[CH:35][CH:36]=2)=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NN)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc(NNC(=O)CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.1 %

Procedure:
To a round bottom flask was added 4-(5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (70 mg, 0.1367 mmol), N-Boc-alanine (24 mg, 0.1367 mmol), EDAC (30 mg, 0.150 mmol), HOBT (20.3 mg, 0.150 mmol) THF (5 ml) and diisopropyl ethyl amine (0.026 ml, 0.150 mmol). The reaction was stirred at rt for 5 hr. After this time the reaction mixture was diluted with EtOAc (25 ml). The resulting solution was washed with water (2×15 ml) and saturated NaCl (15 ml). The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (8 g silica gel) eluting with a gradient of 20%-100% EtOAc/Hex to give product tert-butyl 2-(2-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)hydrazinyl)-2-oxoethylcarbamate as a light yellow solid (54 mg, 60% yield)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]=[C:13]=[S:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[CH3:37].C1(C)C=CC=CC=1>C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:13]([NH:12][C:10](=[O:11])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[S:14])=[CH:32][C:31]=1[CH3:37]
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.7 %

Procedure:
Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (79 mg, yield 94%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:13][C:12]([C:27]([C:33]([F:36])([F:35])[F:34])([C:29]([F:32])([F:31])[F:30])[OH:28])=[N:11]1.[CH3:37][N:38]([CH3:43])[S:39](Cl)(=[O:41])=[O:40]>>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:22][CH2:23][N:24]([S:39](=[O:41])(=[O:40])[N:38]([CH3:43])[CH3:37])[CH2:25][CH2:26]3)=[CH:19][CH:20]=2)[CH2:13][C:12]([C:27]([C:29]([F:30])([F:32])[F:31])([C:33]([F:34])([F:35])[F:36])[OH:28])=[N:11]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(N3CCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Product: CN(C)S(=O)(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)CC1

Procedure:
The titled compound was prepared in accordance with the same procedures as in Example 406, except for using 1-(2,4-difluoro-phenyl)-5-[4-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride prepared in Example 405; and using dimethylsulfamoyl chloride instead of methanesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:33]=[C:32]4[C:13]([CH2:14][CH2:15][C:16]5[N:20]=[C:19]([C@@H:21]6[CH2:25][C@H:24]([O:26][CH2:27][CH3:28])[CH2:23][N:22]6[C:29]([O-:31])=[O:30])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:33]=[C:32]4[C:13]([CH:14]=[CH:15][C:16]5[N:20]=[C:19]([C@@H:21]6[CH2:25][C@H:24]([O:26][CH2:27][CH3:28])[CH2:23][N:22]6[C:29]([O:31][C:5]([CH3:11])([CH3:6])[CH3:4])=[O:30])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1
Reactant: CCO[C@H]1C[C@@H](c2nc3c([nH]2)-c2cc4c(cc2CC3)-c2ccc(Cl)cc2CO4)N(C(=O)[O-])C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(Cl)ccc2-5)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 143.7 %

Procedure:
To a solution of (2S,4S)-2-(9-chloro-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate (0.99 g, 1.9 mmol) in CH2Cl2 (18 mL) was added MnO2 (4.52 g, 52.0 mmol). The resulting slurry was stirred at room temperature for 18 h. The reaction was filtered through celite, washed with CH2Cl2, and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 75% EtOAc (w/5% MeOH)/Hexanes) to afford tert-butyl (2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate (0.71 g, 72%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.CCCCCC.[N:24]1([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[CH:32]=[O:33])[CH:28]=[CH:27][CH:26]=[CH:25]1>C1COCC1.O>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([CH:32]([C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([N:24]3[CH:28]=[CH:27][CH:26]=[CH:25]3)[CH:30]=2)[OH:33])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:12]
Reactant: CCOc1cc(Br)ccc1OC
Reactant: O=Cc1cccc(-n2cccc2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1cc(C(O)c2cccc(-n3cccc3)c2)ccc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.3 %

Procedure:
To a solution of 4-bromo-2-ethoxy-1-methoxy-benzene (1.5 g, 6.5 mmol) in THF (30 mL) was added a solution of n-butyllitium in hexane (2.4 mL, 2.5 N, 6.0 mmol) at −78° C. and kept for 20 min. To the mixture was added 3-pyrrol-1-yl-benzaldehyde (1.0 g, 5.8 mmol) at −78° C. After 18 h, water (30 mL) was added to the mixture, and the cold bath was removed. The mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with HCl (0.5 N, 50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent gave (3-ethoxy-4-methoxy-phenyl)-(3-pyrrol-1-yl-phenyl)-methanol (1.9 g, 100% crude yield). The sample was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:9]=[CH:8][C:7](=[O:10])[C:6]([OH:11])=[C:5]1[CH3:12].[CH2:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:14]#[CH:15]>>[CH2:13]([N:16]1[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][N:4]2[CH:9]=[CH:8][C:7](=[O:10])[C:6]([OH:11])=[C:5]2[CH3:12])[CH2:18][CH2:17]1)[C:14]#[CH:15]
Reactant: C#CCN1CCNCC1
Reactant: Cc1c(O)c(=O)ccn1CCCl
Product: C#CCN1CCN(CCn2ccc(=O)c(O)c2C)CC1

Procedure:
The title compound was prepared as described in Scheme D by reaction of N-(2-chloroethyl)-2-methyl-3-hydroxy-4-pyridinone (H2, Appendix VII) (prepared as described in Bijaya L. Rai, Lotfollah Dekhordi, Hicham Khodr, Yi Jin, Zudong Liu, and Robert C. Hider J. Med. Chem. 1998, 41,3347-3359) with N-propargylpiperazine (obtained as in step (iii) in Example 2):
Reaction SMILES: [F:1][C:2]([F:10])=[CH:3][CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[C:16]2[C:22]([CH2:23]Br)=[N:21][N:20](C(OC(C)(C)C)=O)[C:17]2=[N:18][CH:19]=1>CN(C=O)C.O>[Br:13][C:14]1[CH:15]=[C:16]2[C:22]([CH2:23][N:7]3[CH2:8][CH:4]([CH:3]=[C:2]([F:10])[F:1])[CH2:5][C:6]3=[O:9])=[N:21][NH:20][C:17]2=[N:18][CH:19]=1
Reactant: O=C1CC(C=C(F)F)CN1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cc(Br)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC(C=C(F)F)CN1Cc1n[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.9 %

Procedure:
To a solution of 4-(2,2-difluorovinyl)pyrrolidin-2-one x98 (2.86 mmol, 2 eq, 0.42 g) in dry DMF (5 ml) maintained at 0° C. is added natrium hydride (60% dispersion in oil; 2.86 mmol, 2 eq, 0.114 g). The resulting mixture is stirred at room temperature for 0.5 hour and tert-butyl 5-bromo-3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate x155 (1.43 mmol, 1 eq, 0.56 g) dissolved in DMF (2 ml) is added. The resulting mixture is stirred overnight at room temperature. The mixture is poured in water and extracted with AcOEt. The cumulated organic layers are dried over MgSO4, filtered and evaporated under reduced pressure. The crude mixture is purified twice by chromatography on silicagel (CH2Cl2/MeOH/NH4OH 98/2/0.2) to afford pure 1-[(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one 221 (0.025 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.[NH2:16]C1C=CC=CC=1>O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][N:16]=[C:15]2[CH:14]=[N:13][N:12]=[C:11]2[NH2:10])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1cc[nH]n1
Reactant: Nc1ccc(F)c(F)c1
Reactant: Nc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: NC1=NN=CC1=NNc1ccc(F)c(F)c1

Procedure:
4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine was prepared from 3,4-difluoroaniline (0.62 g, 4.8 mmol) and 3-aminopyrazole (0.4 g, 4.8 mmol) according to the procedure described above except that the aniline was initially dissolved in a mixture of water (7.2 mL) and DMF (1.16 mL) prior to being acidified. The solvents were removed under reduced pressure and the resulting crude material was purified by column chromatography eluting with (CHCl3:MeOH=10:1) to yield 0.41 g (38%) of the compound as a yellow solid. 1H NMR (ppm, 200 MHz, DMSO-d6) δ 12.0 (br s, 1H), 7.2-8.0 (m, 4H), 6.9 (m, 2H).
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[K+].CS(C)=O>O>[C:13]([C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:2][C:3]#[N:4])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CC(Cl)Cc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC=Cc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 50.9 g (0.168 mol) of α,4-dichloro-2-(benzoyl)benzenepropanenitrile, 17 g (0.14 mol) of potassium carbonate, 50.9 g (0.5 mol) of potassium bicarbonate and 510 ml of dimethyl sulfoxide was stirred at room temperature for 48 hours. The mixture was diluted with 1.5 liters of water, and the resulting precipitate was collected by filtration. Recrystallization from a mixture of methylene chloride and ether gave off-white prisms, mp 89°-91° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:16])[C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[C:26](Cl)(=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[C:1]1([CH2:7][O:8][C:9](=[O:16])[C:10]([CH3:14])([CH3:15])[CH2:11][CH2:12][O:13][C:26](=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC(C)(CCO)C(=O)OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OCCC(C)(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a solution of 4-hydroxy-2,2-dimethylbutanoic acid phenylmethyl ester (1.11 g), in dichloromethane in an ice bath, was added dimethylaminopyridine (0.72 g) followed by a solution of decanoyl chloride (0.95 g) in dichloromethane (5 mL). The mixture was stirred at room temperature for 2 hours and was filtered. The filtrate was evaporated and the residue was chromatographed on silica gel eluting with dichloromethane to afford 1.4 g (74.5%) of 2,2-dimethyl-4-[(1-oxodecyl)oxy]butanoic acid phenylmethyl ester. A portion was evaporatively distilled to give an analytical sample as a colorless oil: bp 190° C./0.15 mm; IR (CHCl3) 1720 (C=O) and 697 cm-1 (Ph); NMR (CDCl3) δ 0.87 (t, 3, CH3), 1.25-1.60 (m, 20, CH2 and CH3), 1.93 (t, 2, CH2), 2.23 (t, 2, CH2), 4.11 (t, 2, CH 2), 5.11 (s, 2, CH2) and 7.33 (s, 5, Ph); MS m/e 376 and 91.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@:4]([N:9]=[C:10]=[O:11])([CH:6]([CH3:8])[CH3:7])N.[CH2:13]([N:15]([C:18]1[S:19][CH:20]=[C:21]([CH2:23][OH:24])[N:22]=1)[CH2:16][CH3:17])[CH3:14]>ClCCl.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:9][C:10]([O:24][CH2:23][C:21]1[N:22]=[C:18]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[S:19][CH:20]=1)=[O:11]
Reactant: COC(=O)[C@](N)(N=C=O)C(C)C
Reactant: CCN(CC)c1nc(CO)cs1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCN(CC)c1nc(COC(=O)N[C@H](C(=O)OC)C(C)C)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A solution of 5.11 mmol of α-isocyanato-valine methyl ester in 10 ml of dichloromethane was treated with 0.864 g (4.65 mmol) of 2-(N,N-diethylamino)-4-(hydroxymethyl)thiazole and 0.46 mmol of 4-dimethylaminopyridine. The resulting solution was stirred at ambient temperature for 16 h, after which it was diluted with 200 ml of chloroform, washed successively with 10% citric acid, aqueous NaHCO3, and saturated brine. After drying over Na2SO4, the solvent was removed in vacuo, and the residue was chromatographed on silica gel using 1-2% methanol in chloroform to provide 1.31 g (82%) of the desired compound, Rf 0.51 (4% methanol in chloroform) as an oil. 1H NMR (CDCl3) δ 0.89 (d, J=7 Hz, 3 H), 0.96 (d, J=7 Hz, 3 H), 1.24 (t, J=7 Hz, 6 H), 2.15 (m, 1 H), 3.51 (q, J=7 Hz, 4 H), 3.74 (s, 3 H), 4.29 (dd, J=8, 4 Hz, 1 H), 5.03 (s, 2 H), 5.34 (br d, J=8 Hz, 1 H), 6.42 (s, 1 H). Mass spectrum: (M+H)+ =344.
Reaction SMILES: C[C@@H]1[C@H]2[C@@]3(C)[C@H](C(C)=CC[C@H](O[C@@H]4O[C@H](C)[C@H](NC(OC)=O)[C@]([N+]([O-])=O)(C)C4)C(C)=C[C@H]4[C:23]5([O:31]C(=O)[C:26](=C3O)[C:24]5=[O:25])[CH:22]=[C:21]([CH:32]=[O:33])C[C@@H]4O)C=C[C@@H]2[C@@H]([O:55][C@@H:56]2[O:61][C@@H:60]([CH3:62])[C@H:59]([O:63]C(C)=O)[C@H:58]([O:67][C@@H]3O[C@@H](C)[C@H](O[C@@H]4O[C@@H](C)[C@H](O[C@@H]5O[C@@H](C)[C@H](O)CC5)[C@H](O)C4)CC3)[CH2:57]2)[C@@H](C)C1>C(OCC)(=O)C>[O:33]=[CH:32][CH2:21][CH2:22][C@H:23]([C@H:24]([CH3:26])[OH:25])[OH:31].[O:55]=[CH:56][CH2:57][C@H:58]([C@H:59]([C@H:60]([CH3:62])[OH:61])[OH:63])[OH:67]
Reactant: COC(=O)N[C@H]1[C@@H](C)O[C@@H](O[C@H]2CC=C(C)[C@@H]3C=C[C@@H]4[C@@H](O[C@H]5C[C@@H](O[C@H]6CC[C@@H](O[C@H]7C[C@@H](O)[C@@H](O[C@H]8CC[C@@H](O)[C@H](C)O8)[C@H](C)O7)[C@H](C)O6)[C@@H](OC(C)=O)[C@H](C)O5)[C@@H](C)C[C@H](C)[C@H]4[C@]3(C)C(O)=C3C(=O)OC4(C=C(C=O)C[C@H](O)[C@H]4C=C2C)C3=O)C[C@]1(C)[N+](=O)[O-]
Agent: COC(=O)N[C@H]1[C@@H](C)O[C@@H](O[C@H]2C/C=C(/C)[C@@H]3C=C[C@@H]4[C@@H](O[C@H]5C[C@@H](O[C@H]6CC[C@@H](O[C@H]7C[C@@H](O)[C@@H](O[C@H]8CC[C@@H](O)[C@H](C)O8)[C@H](C)O7)[C@H](C)O6)[C@@H](OC(C)=O)[C@H](C)O5)[C@@H](C)C[C@H](C)[C@H]4[C@]3(C)/C(O)=C3\C(=O)OC4(C=C(C=O)C[C@H](O)[C@H]4/C=C/2C)C3=O)C[C@]1(C)[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: C[C@H](O)[C@H](O)CCC=O
Product: C[C@H](O)[C@H](O)[C@H](O)CC=O

Procedure:
The forementioned studies involved obtaining tetrocarcin A by dissolving DC-11 in ethyl acetate, washing the solution with dilute hydrochloric acid and subjecting the resulting solution to column chromatography using silica gel. The resulting tetrocarcin A is subjected to hydrolysis to obtain L-amicetose, L-digitoxose and a compound represented by the following formula: ##STR2## Based on the physicochemical properties of tetrocarcin A, DC-11 and antlermicin A (the free form of which is considered to be identical to tetrocarcin A; see J. Antibiotics, 33, 244-246, 1980) as shown in Table A below and the results of the hydrolysis above referred to, the above formula for tetrocarcin A was obtained.
Reaction SMILES: C(OC(N1C[C@@H](N=[N+]=[N-])[C@H](F)[C@H]1C(=O)N[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)(C)(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:38][C@H:37]([F:39])[C@@H:36]([N:40]=[N+]=[N-])[C@H:35]1[C:43](=[O:52])NCC1C=CC=CC=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].CP(C)C.[OH2:57]>C1COCC1>[C:27]([O:31][C:32]([N:34]1[CH2:38][C@H:37]([F:39])[C@@H:36]([NH2:40])[C@H:35]1[C:43]([O:52][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:57])=[O:33])([CH3:28])([CH3:29])[CH3:30]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)[C@@H](N=[N+]=[N-])[C@H]1C(=O)NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])[C@H](F)[C@H]1C(=O)NCc1ccccc1
Agent: CP(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](F)[C@@H](N)[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (2R,3R,4R)-4-azido-2-benzylcarbamoyl-3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester and (2S,3S,4S)-3-azido-2-benzylcarbamoyl-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (3.52 g, 8.98 mmol) (described in Scheme B22), trimethylphosphine in THF (17.97 mL, 17.97 mmol) and water (0.32 mL, 17.97 mmol) in THF (100 mL) was stirred for 16 h at RT. The reaction mixture was quenched with water and extracted twice with EtOAc. The organic phases were joined, washed with brine, dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography on silica gel (c-hexane/EtOAc 1:1) gave (2S,3S,4S)-3-amino-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester: MS (UPLC/MS): 339 [M+H]+; tR (HPLC conditions f): 1.59 min and (2R,3S,4R)-4-amino-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester: MS (UPLC/MS): 339 [M+H]+; tR (HPLC conditions f): 1.62 min.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].CN(C)C=O.[I-].C[N+](C)(C)[CH2:17][C:18]([C:20]1[C:29]2[CH:28]=[N:27][C:26]([O:30][CH3:31])=[CH:25][C:24]=2[CH2:23][CH2:22][CH:21]=1)=[CH2:19]>C(N(CC)CC)C>[CH3:31][O:30][C:26]1[N:27]=[CH:28][C:29]2[C:20]([C:18]([CH2:17][C:2]3([CH3:1])[C:6](=[O:7])[CH2:5][CH2:4][C:3]3=[O:8])=[CH2:19])=[CH:21][CH2:22][CH2:23][C:24]=2[CH:25]=1
Reactant: CC1C(=O)CCC1=O
Reactant: C=C(C[N+](C)(C)C)C1=CCCc2cc(OC)ncc21
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(CC1(C)C(=O)CCC1=O)C1=CCCc2cc(OC)ncc21
Temperature: 25 °C

Procedure:
A solution containing 0.75 part of 2-methylcyclopentane-1,3-dione in 19 parts of dimethylformamide is treated sequentially with 1.0 part by volume of triethylamine and 1.9 parts of N,N,N-trimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)ammonium iodide. The resulting homogeneous solution is heated at about 135° for 43/4 hours. It is allowed to cool to room temperature and solvent is removed under reduced pressure. The remaining material is diluted with water-ether and enough 5% sodium hydroxide solution is added to bring the pH to 10. The aqueous and organic layers are separated and the aqueous layer is extracted with ether. The extracts are washed sequentially with 5% sodium hydroxide solution, 2.5% aqueous formic acid and saturated sodium chloride solution, then dried over anhydrous sodium sulfate. Upon solvent removal, an oil remains which is taken into ether. Then n-hexane is added until the solution becomes turbid. Charcoal is added and the mixture is filtered. Solvent is removed under reduced pressure to yield an oil which crystallizes upon standing. Recrystallization from acetone-water gives pure 5,6-dihydro-3-methoxy-8-[3-(2-methyl-1,3-dioxocyclopent-2-yl)prop-1-en-2-yl]isoquinoline, which is identical to the product obtained in Example 18A.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[CH:7]=1.[NH3:19].CO>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH:15]([F:17])[F:16])[CH2:9][O:10][CH2:11][C:12]([NH2:19])=[N:13]2)[CH:7]=1
Reactant: Fc1ccc(Br)cc1C1(C(F)F)COCC(=S)N1
Reactant: N
Solvent: CO
Product: NC1=NC(c2cc(Br)ccc2F)(C(F)F)COC1

Procedure:
A solution of 6.14 g (18.05 mmol) 5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-morpholine-3-thione in 77 ml 7M NH3/MeOH was stirred at rt for 6 h. The mixture was evaporated and purified chromatographed on silica gel (DCM/1-5% MeOH followed by DCM/MeOH/aqueous NH3 95:4.5:0.5) to give the desired product as yellowish resin.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>C1COCC1>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:6]=[CH:5]2
Reactant: COc1c(Br)ccc2[nH]ncc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(Br)ccc2c1cnn2COCC[Si](C)(C)C
Reaction time: 0.08 h
Yield: 56.4 %

Procedure:
To a stirred solution of 5-bromo-4-methoxy-1H-indazole (1.33 g, 5.9 mmol) in THF (20 mL) at 0° C., under a nitrogen atmosphere, was added sodium hydride (280 mg, 7 mmol) portionwise. After 5 min, (2-chloromethoxy-ethyl)-trimethylsilane (1.36 mL, 7.7 mmol) was added dropwise. After 3 hours, the reaction mixture was quenched with water (20 mL). The resulting biphasic mixture was separated, extracted with ethyl acetate (2×50 mL) and the combined organic layers were washed with brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, gradient 10-20% ethyl acetate in cyclohexane) to give the title compound as a yellow oil (1.19 g, 56%). LCMS (Method B): RT=4.91 min, [M+H]+=357.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.Br[CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].[C:41](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:20]([O:19][C:18]([NH:17][CH2:16][C:6]1[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:8][C:9]2[C:4]([C:5]=1[C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH3:41])=[CH:29][CH:30]=1)=[CH:3][C:2]([O:1][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:11][CH:10]=2)=[O:24])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(O)cc23)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(CC)cc3)c2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
A mixture of tert-butyl {[6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.7 g, 6.3 mmol), ethyl 4-bromobutanoate (1.4 g, 7.0 mmol), potassium carbonate (0.97 g, 7.0 mmol) and N,N-dimethylformamide (30 ml) was stirred at 50° C. for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 4-{[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-ethylphenyl)quinolin-6-yl]oxy}butanoate (2.2 g, yield 67%) as crystals.