Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:11]3)=[CH:4][CH:3]=1.C(=O)([O-])O.[K+].[I:25]I>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[I:25])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:11]3)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Reactant: II
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: Clc1ccc(-c2nc3sc4ccccc4n3c2I)cc1
Yield: 83.2 %

Procedure:
In 100 ml of methylene chloride was dissolved 2 g of 2-(p-chlorophenyl)imidazo[2,1-b]benzothiazole and after adding thereto 20 ml of an aqueous 10% potassium hydrogencarbonate solution and 1.8 g of iodine, the mixture was stirred overnight vigorously at room temperature. The crystals which formed were recovered by filtration and recrystallized from a mixture of methylcellosolve and water to provide 2.4 g of 2-(p-chlorophenyl)-3-iodoimidazo[2,1-b]benzothiazole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=O)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[BH4-].[Na+].B(F)(F)F.CCOCC>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:13][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([O-:3])=[O:2]
Reactant: O=C(c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)N1CCOCC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a mixture of (3,4-dinitro-phenyl)-morpholin-4-yl-methanone (2.84 g) in dry THF (50 ml) was added NaBH4 (954 mg) followed drop-wise by BF3.Et2O (3.2 ml). The mixture was stirred at ambient temperature for 3 hours and then quenched though addition of MeOH. The mixture was reduced in vacuo, partitioned between EtOAc and water and the organic portion washed with brine, dried (MgSO4) and reduced in vacuo. The residue was purified via flash column chromatography eluting with EtOAc to give 4-(3,4-dinitro-benzyl)-morpholine (1.08 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14](C2OC(C)(C)C(C)(C)O2)=[CH:13][C:12]=1[S:27]([N:30]1[CH2:36][CH2:35][CH2:34][CH2:33][C:32]2[CH:37]=[CH:38][CH:39]=[CH:40][C:31]1=2)(=[O:29])=[O:28])([CH3:4])([CH3:3])[CH3:2].Br[C:43]1[C:48]([C:49]#[N:50])=[CH:47][C:46]([C:51]([F:54])([F:53])[F:52])=[N:45][CH:44]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([C:43]2[CH:44]=[N:45][C:46]([C:51]([F:54])([F:53])[F:52])=[CH:47][C:48]=2[C:49]#[N:50])=[CH:13][C:12]=1[S:27]([N:30]1[CH2:36][CH2:35][CH2:34][CH2:33][C:32]2[CH:37]=[CH:38][CH:39]=[CH:40][C:31]1=2)(=[O:29])=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(C2OC(C)(C)C(C)(C)O2)cc1S(=O)(=O)N1CCCCc2ccccc21
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1S(=O)(=O)N1CCCCc2ccccc21
Temperature: 100 °C
Yield: 85.5 %

Procedure:
4-[5-Chloro-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenoxy]-butyric acid tert-butyl ester (60.0 mg, 0.1 mmol), 5-bromo-2-trifluoromethyl-isonicotinonitrile (23 mg, 0.09 mmol), Pd(Ph3P)4 (12 mg, 0.01 mmol) and K2CO3 (56 mg, 0.4 mmol) in a mixture of dioxane (1.5 mL) and water (0.15 mL) was degassed with N2 for 5 min. The reaction vessel was sealed and heated at 100° C. for 16 hrs. Ethyl acetate (5 mL) and water (5 mL) were added. The organic layer was separated, washed with brine (2×5 mL), dried over MgSO4, filtered, concentrated and purified by TLC plates eluting with ethyl acetate in hexanes (1/3) to give 4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-butyric acid tert-butyl ester 6-1 as a white foam (50 mg). MS: 593.9 (M+H-tBu)*; tR=6.98 min (method 4). NMR (CDCl3), δ, 8.791 (1H, s), 7.738-8.101 (2H, m), 7.060-7.272 (4H, m), 6.774-6.828 (1H, m), 4.213 (2H, m), 3.780 (2H, m), 2.833 (2H, m), 2.404 (2H, t), 1.912-2.029 (4H, m), 1.591-1.657 (2H, m), 1.448 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[NH:15][N:14]=[N:13][N:12]=2)[CH:8]=[C:7]([Cl:16])[C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:41]([O:43][C:44](=[O:66])[C@@H:45]([NH2:65])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([N:53]2[C:61](=[O:62])[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][C:59]=3[CH3:63])[C:54]2=[O:64])=[CH:49][CH:48]=1)[CH3:42]>ClCCl.C(N(CC)CC)C>[CH2:41]([O:43][C:44](=[O:66])[C@@H:45]([NH:65][C:4](=[O:6])[C:3]1[C:7]([Cl:16])=[CH:8][C:9]([C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[CH:10][C:2]=1[Cl:1])[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([N:53]2[C:61](=[O:62])[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][C:59]=3[CH3:63])[C:54]2=[O:64])=[CH:51][CH:52]=1)[CH3:42]
Reactant: O=C(O)c1c(Cl)cc(-c2nnn[nH]2)cc1Cl
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(N2C(=O)c3cccc(C)c3C2=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(N2C(=O)c3cccc(C)c3C2=O)cc1)NC(=O)c1c(Cl)cc(-c2nnn[nH]2)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The mixture of 35 mg of 2,6-dichloro-4-tetrazolyl benzoic acid, 30 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 23 mg of 1-hydroxybenzotriazol hydrate, 15 mg of triethylamine, 35 mg of (2S)-2-amino-3-[4-(4-methyl-1,3-dioxo-1,3-dihydroisoindole-2-yl)phenyl]propionic acid ethylester hydrochloride and 5 ml of dichloromethane was stirred at room temperature for 3 days. The mixture was concentrated and suspended in a mixed solvent of water-acetonitrile containing 0.1% trifluoroacetic acid and then filtered to obtain the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([OH:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:20]([CH2:25][CH3:26])[C:21](=[O:24])[CH2:22]Cl)[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>CC(=O)CC>[CH2:18]([N:20]([CH2:25][CH3:26])[C:21](=[O:24])[CH2:22][O:17][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:16]=1)[CH3:19]
Reactant: Oc1nc(-c2ccccc2)nc2ccccc12
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCN(CC)C(=O)COc1nc(-c2ccccc2)nc2ccccc12
Reaction time: 22 h
Yield: 59.6 %

Procedure:
A mixture of 2-phenyl-4-quinazolinol (4.45 g), N,N-diethylchloroacetamide (3.3 g), sodium carbonate (4.25 g) and cuprous iodide (1 g) in 2-butanone (70 cc) is brought to boiling for 22 hours. The solvent is evaporated off under reduced pressure, water (100 cc) is added, the mixture is alkalinised with ammonia solution and the aqueous phase is extracted with methylene chloride (3×100 cc). The organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel with a cyclohexane/ethyl acetate (1:1 by volume) mixture as eluant. After crystatllization in isopropyl ether, N,N-diethyl-(2-phenyl-4-quinazolinyl)oxyacetamide (4 g), m.p. 113° C., is obtained.
Reaction SMILES: [CH:1]1[CH:20]=[CH:19][C:17](=[O:18])/[C:3](=[CH:4]\[NH:5][CH2:6][CH2:7][NH:8]/[CH:9]=[C:10]2\[C:11]([CH:13]=[CH:14][CH:15]=[CH:16]\2)=[O:12])/[CH:2]=1.[O-]CC.[O-]CC.[O-]CC.[Al+3]>C1(C)C=CC=CC=1>[CH:15]1[CH:14]=[CH:13][C:11](=[O:12])/[C:10](=[CH:9]/[NH:8][CH2:7][CH2:6][NH:5]/[CH:4]=[C:3]2/[CH:2]=[CH:1][CH:20]=[CH:19][C:17]/2=[O:18])/[CH:16]=1
Reactant: O=C1C=CC=C/C1=C/NCCN/C=C1/C=CC=CC1=O
Agent: CC[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: O=C1C=CC=C/C1=C/NCCN/C=C1\C=CC=CC1=O

Procedure:
Salen ligand (C0) (1.0 g, 3.9 mmol) and aluminium triethoxide (1.2 g, 7.4 mmol) were dissolved in dry toluene (25 mL). The reaction mixture was refluxed for 4 hours after which the toluene was evaporated and the resulting yellow residue taken up in dichloromethane and washed with water (3×100 mL) and saturated brine (100 mL). After evaporation of the organic phase, a light yellow powder was obtained which was washed with diethyl ether (ca. 50 mL) and dried to give salen complex (C1) (1.2 g, 49%). 1H NMR 3.87 (8H, s, 2×CH2CH2), 6.7-6.9 (8H, m, 8×HAr), 7.1-7.3 (8H, m, 8×HAr), 8.29 (4H, s, 4×CHN). 13C NMR 60.14, 65.09, 117.36, 119.00, 131.81, 132.74, 161.46, 166.85. m/z (ESI) Found: 603.1775 C32H25N4O5Al2 (MH+), Requires 603.1769.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:14]=2)=[N:5][C:4]([CH2:26]O)=[N:3]1.S(Cl)([Cl:30])=O>>[Cl:30][CH2:26][C:4]1[N:5]=[C:6]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:14]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cn1nc(CO)nc1NCCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=S(Cl)Cl
Product: Cn1nc(CCl)nc1NCCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-methyl-5-[4-[3-(1-piperidinylmethyl)phenoxy]butyl]amino-1H-1,2,4-triazole-3-methanol (0.75 g) and thionyl chloride (4 ml) was stirred at room temperature for 2 h. The mixture was evaporated in vacuo and the residue was dissolved in chloroform and washed with sodium bicarbonate. The organic extract was dried and evaporated to give the title compound as an oil (0.75 g) T.l.c. System E Rf 0.65.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.IC.[C:40]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][CH:23]([N:26]([CH3:40])[S:27]([CH3:30])(=[O:29])=[O:28])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(NS(C)(=O)=O)CC2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(N(C)S(C)(=O)=O)CC2)n1
Yield: 84.4 %

Procedure:
Reaction of N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide (Example 17) (114 mg, 0.21 mmol) with iodomethane (0.5 mL, 8.1 mmol) and K2CO3 (2 g, 14.5 mmol) in DMF (5 mL) gave N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-methylmethanesulfonamide (98 mg) in 84% yield: mp (CH2Cl2/MeOH) 231-233° C.; 1H NMR (DMSO-d6) δ 7.89 (d, J=8.2 Hz, 1H), 7.69 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 4.82-4.72 (m, 2H), 3.98 (s, 3H), 3.98-3.90 (m, 2H), 3.82-3.79 (m, 4H), 3.70-3.69 (m, 4H), 3.11-2.98 (m, 2H), 2.94 (s, 3H), 2.68 (s, 3H), 1.77-1.70 (m, 4H); Anal. Calcd. for C23H30F2N8O4S: C, 50.0; H, 5.5; N, 20.3. Found: C, 49.9; H, 5.6; N, 20.3%.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[N:10]=[C:11]([NH2:12])[C:5]=2[CH:4]=1.[CH3:19][O:20][CH2:21][CH2:22][C@H:23]1[CH2:28]N[CH2:26][CH2:25][NH:24]1.C(N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[N:10]=[C:11]([N:12]3[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:22][CH2:21][O:20][CH3:19])[CH2:28]3)[C:5]=2[CH:4]=1
Reactant: COCC[C@H]1CNCCN1
Reactant: Cc1ccc2c(c1)C(N)=Nc1ccccc1N2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C)cc32)CCN1
Temperature: 110 °C
Reaction time: 46 h
Yield: 52.6 %

Procedure:
Combine 2-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (600.0 mg, 2.31 mmol), (S)-2-(2-methoxy-ethyl)-piperazine (666.3 mg, 4.62 mmol), N,N-diisopropylethylamine (298.6 mg, 2.31 mmol), DMSO (1.0 ml), and toluene (4.0 ml) and stir and heat the mixture at 110° C. After 46 hours, cool the mixture to ambient temperature and dilute with ethyl acetate. Wash the organic layer with 0.1N NaOH and brine, dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 425.5 mg (53%) of a yellow foam: mp 63° C., dec; mass spectrum (ion spray): m/z 351.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:10][C@H:9]2[CH3:33])[CH:5]=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].Cl.O>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:33])[CH:5]=[CH:4][C:3]=1[C:34]([F:37])([F:35])[F:36]
Reactant: C[C@@H]1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1c1ccc(C(F)(F)F)c(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: O
Product: C[C@@H]1CNCCN1c1ccc(C(F)(F)F)c(Cl)n1
Temperature: 80 °C
Yield: 57.4 %

Procedure:
A suspension of 1-(6-chloro-5-trifluoromethyl-pyridin-2-yl)-2-(R)-methyl-4-trityl-piperazine (from Step 1 above; 5.70 g, 10.9 mmol) in EtOH (70 mL) was heated to 80° C. Aqueous HCl (4 M; 6 mL) was added and the mixture was heated in an open vessel for one hour. To the clear solution was water added (100 mL) and the precipitate was filtered off. The solvent from the filtrate was evaporated down to about 10 mL, the crystals were filtered off and the evaporation continued down to 3 mL and another portion of slightly pinkish crystals were filtered off. The combined crystal fractions were taken up between alkaline water (NaOH)/CHCl3. The aqueous phase was washed twice with CHCl3 and the combined, dried (MgSO4), organic phases were evaporated at reduced pressure to give a light yellow oil (1.75 g, 69%). A NOE between the methylene protons at C-2 in the piperazine ring and the C3-hydrogen in the pyridine ring was observed. Purity 99% (HPLC). Fragmenting MS analysis supports the stated structure. HRMS m/z calcd for C11H13ClF3N3 (M)+ 279.0750. found 279.0744.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[N:18]1C=CC=C[CH:19]=1.CN>C(Cl)Cl>[CH3:19][NH:18][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: c1ccncc1
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)Cc1cccc(O)c1
Reaction time: 1.5 h
Yield: 24 %

Procedure:
A solution of 3-hydroxyphenylacetic acid (1.00 g, 6.57 mmol) and oxalyl chloride (0.63 mL, 7.22 mmol) in methylene chloride (20 mL) was treated dropwise with pyridine (0.6 mL, 7.37 mmol), stirred for 90 min, poured into 40% aqueous methylamine (30 mL), stirred for 15 min, concentrated, dissolved into 1M HCl and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with ethyl acetate to provide 260 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=2[CH2:6][CH2:5]1.[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:17][O:16][C:13]1[C:14](=[O:15])[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:1][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:10][CH2:9][C:8]=2[C:11](=[O:20])[C:12]=1[O:18][CH3:19]
Reactant: COC1=C(OC)C(=O)C2=C(CCC(CCO)CC2)C1=O
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 2.33 h
Yield: 61.3 %

Procedure:
To a solution of 7-(2-hydroxyethyl)-2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo[a]cycloheptene-1,4-dione (100 mg), phenol (109 mg), and triphenylphosphine (127 mg) in THF (2 ml) was added a solution of diethyl azodicarboxylate (82 mg) in THF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 140 min and concentrated. The residue was purified by alumina column chromatography (eluent:ethyl acetate/hexane=1/10) and then with recrystallization from ethyl acetate-hexane to obtain the entitled compound (78 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C:12]([F:15])([F:14])[CH2:11][CH:10]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:21]([O-])=O>C(O)C.[Pd]>[NH2:21][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][C:12]([F:15])([F:14])[CH2:11][CH:10]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH2:9]2)=[N:7][C:2]=1[NH2:1]
Reactant: CN(C)C(=O)C1CN(c2ccc([N+](=O)[O-])c(N)n2)CC(F)(F)C1
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)C1CN(c2ccc(N)c(N)n2)CC(F)(F)C1
Reaction time: 2 h

Procedure:
To a solution of 1-(6-amino-5-nitropyridin-2-yl)-5,5-difluoro-N,N-dimethylpiperidine-3-carboxamide (400 mg, 1.21 mmol) in ethanol (50 mL) was added 10% palladium-on-carbon (300 mg). After 2 h under hydrogen, the mixture was filtered through Celite which was then washed with ethanol to afford 1-(5,6-diaminopyridin-2-yl)-5,5-difluoro-N,N-dimethylpiperidine-3-carboxamide as a filtrate that was directly used for the next step.
Reaction SMILES: COC1C=CC(C[O:8][C@H:9]([C@H:63]([O:78]CC2C=CC(OC)=CC=2)[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])[C@@H:10]([N:52]2[CH:56]=[C:55]([CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[N:54]=[N:53]2)[CH2:11][O:12][C@@H:13]2[C@H:18]([O:19]CC3C=CC=CC=3)[C@@H:17]([O:27]CC3C=CC=CC=3)[C@@H:16]([O:35]CC3C=CC=CC=3)[CH:15]([CH2:43][O:44]CC3C=CC=CC=3)[O:14]2)=CC=1.[H][H]>C(O)C.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[CH2:57]([C:55]1[N:54]=[N:53][N:52]([C@H:10]([C@H:9]([OH:8])[C@H:63]([OH:78])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])[CH2:11][O:12][C@@H:13]2[C@H:18]([OH:19])[C@@H:17]([OH:27])[C@@H:16]([OH:35])[CH:15]([CH2:43][OH:44])[O:14]2)[CH:56]=1)[CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCC[C@@H](OCc1ccc(OC)cc1)[C@@H](OCc1ccc(OC)cc1)[C@H](CO[C@H]1OC(COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)n1cc(CCCCCC)nn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@H](CO[C@H]1OC(CO)[C@H](O)[C@H](O)[C@H]1O)n1cc(CCCCCC)nn1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
The compound (1.0 eq.) obtained in Step 1 was dissolved in a mixed solvent of ethylalcohol/methylene chloride (3:1, 0.01˜0.1 M) to which Pd(OH)2 (500 massa) was then added. The resulting reaction mixture was stirred for 5˜8 hrs at room temperature under 1 atm of hydrogen gas. After the filtration of the metal catalyst through a Celite pad, the reaction mixture was washed with a solution of ethylalcohol/methylene:chloride (3:1). After two rounds of centrifugation at 1000 rpm for 10 min, the supernatant was concentrated and dried in a vacuum. The concentrate was precipitated in a mixed solvent of hexane/ethyl acetate (1:1) to afford the object compound as a white wax solid (24 mg, 80%).
Reaction SMILES: [CH2:1]1[C@:6]([OH:9])([CH2:7][OH:8])[C@@H:5]([O:10][C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H:4]([OH:22])[C@@H:3]([OH:23])[C@H:2]1[NH:24][C@@H:25]1[C@H:30]([OH:31])[C@@H:29]([OH:32])[C@H:28]([OH:33])[C:27]([CH2:34][OH:35])=[CH:26]1.[NH4+].[OH-]>N1C=CC=CC=1>[CH2:1]1[C:6]([OH:9])([CH2:7][OH:8])[CH:5]([OH:10])[CH:4]([OH:22])[CH:3]([OH:23])[CH:2]1[NH:24][CH:25]1[CH:30]([OH:31])[CH:29]([OH:32])[CH:28]([OH:33])[C:27]([CH2:34][OH:35])=[CH:26]1
Reactant: OCC1=C[C@H](N[C@H]2C[C@](O)(CO)[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: OCC1=CC(NC2CC(O)(CO)C(O)C(O)C2O)C(O)C(O)C1O

Procedure:
One hundred grams of the crude powder containing validamycin G and validoxylamine G obtained in Example 1a) was submitted to column chromatography on Dowex 1×2 (OH- form, manufactured by Dow Chemicals; 1.8L), eluted with water to give validoxylamine G-containing fractions (eluate fractions 3-5 L; abbreviated as eluate fraction I' hereafter) and validamycin G-containing fractions (eluate fractions 6-8 L; abbreviated as `eluate fraction II` hereafer). The eluate fraction I and the eluate fraction II were separately concentrated to dryness to give 2.7 and 3.0 g of a crude powder, respectively. The crude powder from the eluate fraction I (2.7 g) was submitted to column chromatography on Dowex 50W x 8 (pyridine form, manufactured by Dow Chemicals Co.; 200 mL) and eluted with 0.2 M pyridine-acetate buffer (pH 6.0). In succession to the fractions containing validoxylamine B and validamycin D (eluate fractions 100-420 mL), validoxylamine G-containing fractions (eluate fractions 520-1140 mL) were eluted. The validoxylamine G-containing eluate fractions were concentrated to dryness under reduced pressure, to give a white powder (0.8 g) of validoxylamine G.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[N:15][CH:16]=[C:10]3[CH:9]=2)[CH2:4][CH2:3]1.Br[C:18]1C=CN=C(C(N)C)C=1.BrC1C=CN=C(CN)C=1>>[ClH:1].[CH3:18][C:16]1[N:15]=[CH:14][N:11]2[CH:12]=[CH:13][C:8]([CH:5]3[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]3)=[CH:9][C:10]=12
Reactant: CC(N)c1cc(Br)ccn1
Reactant: c1cn2cncc2cc1C1CCNCC1
Agent: Cl
Agent: NCc1cc(Br)ccn1
Product: Cc1ncn2ccc(C3CCNCC3)cc12

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 39.5, except 1-(4-bromopyridin-2-yl)ethanamine (compound 66.1) was used in place of (4-bromopyridin-2-yl)methanamine (compound 39.1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[N:32][CH:33]=4)=[C:14]([C:16]#[C:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[H-].[Na+].[C:44]([O:48][C:49]([CH2:51]C(OC(C)(C)C)=O)=[O:50])([CH3:47])([CH3:46])[CH3:45].O>CN(C=O)C>[C:37]([O:36][C:35]([N:34]([C:31]1[CH:30]=[CH:29][C:28]([C:13]2[N:9]3[N:10]=[CH:11][CH:12]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:8]3=[N:15][C:14]=2[C:16]#[C:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:33][N:32]=1)[CH2:51][C:49]([O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:50])=[O:41])([CH3:38])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 38a (1.0 g, 1.7 mmol) in DMF (20 mL), was added sodium hydride (60%, 0.11 g, 2.7 mmol) in portions at 0° C. The resulting mixture was stirred at rt for 30 min, and treated with tert-butyl 2-(tert-butoxycarbonyl)acetate (0.53 g, 2.7 mmol). The resulting mixture was stirred at rt for 4 h, and treated with water (100 mL). The solids formed were collected by filtration, washed with Et2O (2×50 mL), and further purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether (2:1)) to obtain compound 38b as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C37H39N7O5: 662.3 (M+H). found: 662.2.