Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccccc1N1CCCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1N1CCCNCC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To 2.03 g (6.62 mmol) of 4-(2-methoxy-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester in 30 mL CH2Cl2 at 23° C. was added 5 mL trifluoroacetic acid. After stirring at 23° C. for 30 min, 4 additional mL of trifluoroacetic acid were added. After a total of 1 h, the reaction solution was poured into 200 mL of saturated aqueous NaHCO3 and extracted with 3×100 mL of EtOAc. The combined organics were washed with 1×200 mL H2O, 1×200 mL brine, dried over Na2SO4, filtered and evaporated to give 1.01 g (4.90 mmol, a 74% yield) of the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3): δ1.99 (pent, J=4.5 Hz, 2H), 2.82 (brs, 1H), 3.06 (t, J=4.4 Hz, 2H), 3.08-3.13 (m, 2H), 3.29-3.36 (m, 4H), 3.84 (s, 3H), 6.83-6.96 (m, 4H); IR (KBr, cm−1): 3335w;, MS (ES) m/z (relative intensity): 207 (M++H, 100).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH:25]([OH:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.CCN(CC)CC.[C:37](Cl)(=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>C(Cl)Cl>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]4[O:27][C:37](=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C1c2ccccc2C(O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)OC1c2ccccc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-2,3-dihydro-3-hydroxy-1H-isoindol-1-one (1.4 g, 3.5 mmol) in DCM (30 ml) was added Et3N (1.2 ml, 8.8 mmol) followed by decanoyl chloride at 0 C. under nitrogen. After stirring for 1 h in the cooling bath, the solvent was removed using a stream of nitrogen. The remaining residue was diluted with EtOAc and the precipitated triethylamine hydrochloride was filtered off. The filtrate was concentrated and the remaining oil was flushed through alumina with ether to give 1.6 g (83%) of the desired product as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N=C2CCCC(=O)C2)=[CH:4][CH:3]=1.[OH2:17]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:3]1[CH2:4][CH2:5][CH2:6][C:7](=[O:17])[C:2]2=1
Reactant: O
Reactant: O=C1CCCC(=NNc2ccc(Br)cc2)C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: O=C1CCCc2[nH]c3ccc(Br)cc3c21

Procedure:
The product of Stage (i) (1.5 g) was heated under reflux with dry zinc chloride (16 g) in glacial acetic acid (75 ml) for 24 h. The mixture was cooled, poured into water (200 ml), and the resulting solid filtered off and dried (0.95 g). Purification by flash chromatography (E) gave the title compound as a solid (125 mg). T.l.c. (F), Rf 0.65
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[CH:21]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Reactant: BrC1CCCCC1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1C1CCCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclohexyl bromide according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-cyclohexyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10](OB(O)O)=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.Br[C:18]1[N:19]=[C:20]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH3:35])[CH2:30][CH2:29]2)[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:34]([N:31]1[CH2:30][CH2:29][N:28]([C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:27]=[C:18]([C:10]3[CH:11]=[CH:12][C:7]([C:2]4([CH3:1])[O:6][CH2:5][CH2:4][O:3]4)=[CH:8][CH:9]=3)[N:19]=2)[CH2:33][CH2:32]1)[CH3:35]
Reactant: CC1(c2ccc(OB(O)O)cc2)OCCO1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
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: [Na+]
Solvent: Cc1ccccc1
Product: CCN1CCN(c2nc(-c3ccc(C4(C)OCCO4)cc3)cc3ccccc23)CC1

Procedure:
4-(2-Methyl-1,3-dioxolan-2-yl)phenylboric acid (0.41 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.62 g) were reacted in the presence of tetrakistriphenylphosphinepalladium(0) (0.11 g) in toluene (50 ml) and a 10% aqueous solution of sodium carbonate (30 ml) in nitrogen atmosphere at 120° C. for 30 min. The organic layer was separated, washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1-(4-ethylpiperazin-1-yl)-3-[4-(2-methyl-1,3-dioxolan-2-yl)phenyl]isoquinoline.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]#[N:17])=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[F:18].[CH3:19][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][C:3]([F:18])=[C:2]([CH3:19])[CH:10]=3)[C:6]([C:16]#[N:17])=[CH:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C[Zn]C
Reactant: N#Cc1cn(C2CCCC2)c2cc(Br)c(F)cc12
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1F)c(C#N)cn2C1CCCC1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
Into a solution of 6-bromo-1-cyclopentyl-5-fluoro-1H-indole-3-carbonitrile (6.6 g, 21.5 mmol) and PdCl2dppf (0.31 g, 0.43 mmol) in dioxane (45 mL) was added a solution of dimethylzinc in toluene (1.2 M, 35.8 mL, 43 mmol). The atmosphere was replaced with nitrogen. The mixture was stirred at 90° C. for 90 min and then cooled to room temperature. The reaction was quenched by careful addition of methanol. Ethyl acetate (200 mL) was added and the mixture washed with aq. 2 N HCl, water and brine, dried over Na2SO4 and concentrated. The residue was purified on silica gel eluting with a gradient of 5 to 35% ethyl acetate in hexane to provide 1-cyclopentyl-5-fluoro-6-methyl-1H-indole-3-carbonitrile (4.4 g, 85%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[N+:21]([O-])=O>[Pd].CO.[H][H]>[NH2:21][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Reaction time: 2 h
Yield: 110.2 %

Procedure:
To a mixture of N-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)benzamide 66 (12 g, 37.0 mmol) and palladium on activated carbon (0.438 g, 3.70 mmol) in methanol (800 mL), hydrogen (gas) was bubbled through for 2 h. Excess of Pd/C (5 g) was added and stirred for additional 2 h. Filtered over decalite and concentrated to give N-(3-amino-4-methylphenyl)-3-(trifluoromethyl)benzamide 67 (12 g, 88%). (m/z)=295 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[C:8]([O:19][CH3:20])[C:7]=2[CH:21]([OH:32])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>ClCCl.[O-2].[Mn+4].[O-2]>[CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:16])([CH3:17])[O:13]3)=[C:8]([O:19][CH3:20])[C:7]=2[C:21](=[O:32])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1c2c(cc(C3CCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)OC(C)(C)CC2=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1c2c(cc(C3CCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)OC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.22 mmol) of 7-cyclopentyl-6-{hydroxy[4-(trifluoromethyl)phenyl]methyl}-5-methoxy-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 7A) are dissolved in 5 ml of dichloromethane, 194 mg (2.23 mmol) of manganese(IV) oxide are added and the mixture is stirred at room temperature overnight. The mixture is filtered through a layer of silica gel, the filter cake is washed thoroughly with ethyl acetate and the filtrate is concentrated to dryness. The crude product is chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). This gives 82.5 mg (83% of theory) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([CH2:7][NH:8][C:9](=[O:30])[CH:10]([C:13]2[CH:18]=[C:17]([O:19][CH2:20][CH3:21])[CH:16]=[C:15]([O:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:14]=2[F:29])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.CCOC(C)=O>C1COCC1>[C:33]1([S:39]([N:26]2[CH2:25][CH2:24][CH:23]([O:22][C:15]3[C:14]([F:29])=[C:13]([CH:10]([O:11][CH3:12])[C:9]([NH:8][CH2:7][C:6]4[CH:31]=[CH:32][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)=[O:30])[CH:18]=[C:17]([O:19][CH2:20][CH3:21])[CH:16]=3)[CH2:28][CH2:27]2)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOc1cc(OC2CCNCC2)c(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1cc(OC2CCN(S(=O)(=O)c3ccccc3)CC2)c(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)c1
Temperature: 0 °C
Yield: 100.2 %

Procedure:
To a solution of (RS)-N-(4-cyano-benzyl)-2-[5-ethoxy-2-fluoro-3-(piperidin-4-yloxy)-phenyl]-2-methoxy-acetamide (300 mg) in THF (3 ml) were added benzenesulfonyl chloride (127 mg) and triethylamine (138 mg). The mixture was stirred over the weekend. Ice-water and EtOAc were added and the pH of the aqueous phase was adjusted to 2. The mixture was extracted with EtOAc. The organic phase was washed with saturated NaHCO3 soln. and water, dried, filtered and evaporated to give (RS)-2-[3-(1-benzenesulfonyl-piperidin-4-yloxy)-5-ethoxy-2-fluoro-phenyl]-N-(4-cyano-benzyl)-2-methoxy-acetamide (396 mg) as an off-white solid. MS 582.2 ([M+H]+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:40]3[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=3)[C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.[ClH:47].C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:72]([NH:74][CH2:75][C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][N:77]=4)=[O:73])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1>>[ClH:47].[OH:46][C:43]1[CH:44]=[CH:45][C:40]([CH:32]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:72]([NH:74][CH2:75][C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][N:77]=4)=[O:73])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[CH:41][CH:42]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-{2-((R)-3-amino-pyrrolidin-1-yl)-6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-purin-9-yl}-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 106) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113). MS (ES+) m/e 762.53 (MH+).
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[CH2:27](Br)[C:28]#[CH:29].C1(C)C=CC=CC=1>C(OCC)(=O)C.CN(C)P(=O)(N(C)C)N(C)C>[C:1]1([N:7]([C:27]#[C:28][CH3:29])[NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CCBr
Reactant: NS(=O)(=O)c1cc(C(=O)NNc2ccccc2)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CC#CN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Reaction time: 21 h

Procedure:
In a three necked 1 liter round bottom reaction vessel equipped with a mechanical stirrer and reflux condenser were placed 97.5 g (0.3 mol) of the compound of Example 8 and 200 ml of hexamethylphosphoric-triamide. The mixture was heating with stirring under nitrogen at 80°-90° C. till the solid dissolved. To this solution was added with stirring 252 g (3 mol) sodium bicarbonate powder. Over a period of about 0.5 hour 29.4 ml of an 80% w/w solution of propargyl bromide in toluene (0.315 mol propargyl bromide) were added with stirring. After the reaction had run for 21 hours an additional 4 ml of the propargyl bromide solution in toluene (0.043 mol propargyl bromide) was added and the reaction continued for an additional 68 hours. The reaction mixture was then cooled and diluted with 1 liter of ethyl acetate. The mixture was transferred to a separatory funnel, cross-washed with water/brine, then with a 2 molor aqueous citric acid and again with brine. The organic layer was dried over anhydrous magnesium sulfate, clarified and evaporated to yield 108 g of a dark oil which was purified by chromatography over silica gel to yield a solid which was recrystallized from ethyl acetate/hexane. M.p. 168°-170° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:7](=O)[C:6]=2[CH:5]=[C:4]2[NH:20][C:21]([C:23]3[C:24](=[O:43])[NH:25][CH:26]=[CH:27][C:28]=3[NH:29][CH:30]([CH3:42])[CH2:31][C:32]3[C:37]([F:38])=[C:36]([F:39])[CH:35]=[C:34]([F:40])[C:33]=3[F:41])=[N:22][C:3]=12>[Zn].C(O)(=O)C>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH:12]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]3)[CH2:7][C:6]=2[CH:5]=[C:4]2[NH:20][C:21]([C:23]3[C:24](=[O:43])[NH:25][CH:26]=[CH:27][C:28]=3[NH:29][CH:30]([CH3:42])[CH2:31][C:32]3[C:33]([F:41])=[C:34]([F:40])[CH:35]=[C:36]([F:39])[C:37]=3[F:38])=[N:22][C:3]=12
Reactant: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)CN(C1CCN(C)CC1)C2=O
Yield: 34.3 %

Procedure:
A mixture of 4-methyl-6-(1-methylpiperidin-4-yl)-2-(2-oxo-4-(1-(2,3,5,6-tetrafluorophenyl)propan-2-ylamino)-1,2-dihydropyridin-3-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.93 g, 1.65 mmol), zinc dust (1.02 g, 15.6 mmol), and 30 mL of acetic acid was heated at reflux for 14 h under an argon atmosphere. Product was separated by a silica gel column using methylene chloride and methanol (85:15 v/v) as eluent to afford 0.33 g (36.3%) of the designed compound as yellowish solid. NMR (500 MHz, DMSO-d6) δ 12.95 (s, 1H, NH), 11.32 (d, J=8.5 Hz, 1H, NH), 11.25 (d, J=4.1 Hz, 1H, NH), 7.80 (s, 1H, ArH), 7.77-7.75 (m, 1H, ArH), 7.63 (t, J=7.0 Hz, 1H, ArH), 6.19 (d, J=7.5 Hz, 1H, ArH), 4.41 (d, J=3.5 Hz, 2H, CH2), 4.29-4.21 (m, 1H, CH), 4.06-4.01 (m, 1H, CH), 3.07-3.06 (m, 2H, CH2), 2.92-2.90 (m, 2H, CH2), 2.43 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.09 (m, 2H, CH2), 1.91-1.83 (m, 2H, CH2), 1.72-1.69 (m, 2H, CH2), 1.36 (d, J=6.5 Hz, 3H, CH3); Mass (ESI, positive) m/z 583.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:6]=2[C:5]1=[O:16])[CH:2]=[CH2:3].[N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]OS(C1C(C)=CC=CC=1)(=O)=O)=[N+:18]=[N-:19].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:13]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:17]=[N+:18]=[N-:19])=[CH:14][C:6]=2[C:5]1=[O:16])[CH:2]=[CH2:3]
Reactant: Cc1ccccc1S(=O)(=O)OCCCCCCCCN=[N+]=[N-]
Reactant: C=CCN1CCCc2ccc(O)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1CCCc2ccc(OCCCCCCCCN=[N+]=[N-])cc2C1=O
Temperature: 65 °C
Yield: 50.7 %

Procedure:
A suspension of 2-allyl-8-hydroxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (1.0 g, 0.0049 mol), 8-azido-1-(toluenesulfonyloxy)octane (1.50 g, 0.0049 mol) and K2CO3 in N,N-dimethylformamide (20 mL) was stirred vigorously under argon, and heated at 65° C. for 18 hours. The solution was then partitioned between ethyl acetate and brine, and the combined organic layers were washed with water, dried (K2CO3), filtered, and concentrated in vacuo. The residue was purified by chromatography over silica gel to yield 920 mg (51%) of 2-allyl-8-(8-azidooctyloxy)-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one as a colorless oil; 1H NMR(CDCl3) d7.47(s, 1H), 6.95(d, J=6 Hz, 1H), 6.84(dd, J=3, 6 Hz, 1H), 5.89(m, 1H), 5.22(m, complex, 2H), 4.20(d, J=6 Hz, 2H), 3.95(t, J=6 Hz, 2H), 3.22(t, J=6 Hz, 2H) 2.66(t, J=6 Hz, 2H), 1.90(t, J=6 Hz, 2H), 1.79(t, J=6 Hz, 2H), 1.60(m, 4H), 1.35(m, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-])=O)=[CH:4][C:3]=1[N+:15]([O-])=O.[OH:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1.[OH-].[Na+]>O>[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[CH2:19][O:18][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH2:12])=[CH:4][C:3]=1[NH2:15]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: OCC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(N)c(OCC2CCCCO2)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
27 g of 4-chloro-5-trifluoromethyl-1,3-dinitrobenzene are initially introduced into 36 g of 2-hydroxymethyltetrahydropyran, and 8.8 g of 50 percent strength aqueous sodium hydroxide solution are added at 45° C. in the course of 30 minutes. The mixture is then subsequently stirred at 45° for one hour and 30 ml of water are added. The oil which has separated out is separated off, washed twice with 20 ml of water each time and dried. This gives 18.3 g (53% of the theoretical value) of yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([OH:49])=O)[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.ON1C2C=CC=CC=2N=N1.[NH2:61][CH2:62][C:63]1[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=1.[ClH:69]>C1COCC1.CO>[ClH:69].[OH:1][C:2]1[C:7]2[C:8]3([OH:45])[C:21]([O:25][CH3:26])([CH:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([NH:61][CH2:62][C:63]1[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=1)=[O:49])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: NCc1cccnc1
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)C3(OC)C(O)Cc5cc(C)c(C(=O)NCc6cccnc6)c(O)c5C3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (60 mg, 0.09 mmol) in THF (2 mL) was added polystyrene-carbodiimide (156 mg, 0.18 mmol), 1-hydroxybenzotriazole hydrate (24 mg, 0.18 mmol) and 3-(aminomethyl)pyridine (11 mg, 0.10 mmol). The reaction mixture was stirred at room temperature under nitrogen for 7 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) to afford a dark red solid. The solid was dissolved in methanol (2 mL) and treated with HCl (0.20 mL, 1.25 M solution in methanol) at 0° C. The solution was concentrated and triturated with diethyl ether to afford 6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-(pyridin-3-ylmethyl)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide hydrochloride as a mixture of diastereomers (12 mg, 21%) and as a red solid: 1H NMR (500 MHz, CD3OD) δ 8.84-8.80 (m, 1H), 8.80-8.65 (m, 1H), 8.64-8.58 (m, 1H), 8.10 (s, 1H), 8.09-8.06 (m, 1H), 6.63 (s, 1H), 6.16 (s, 0.3H), 6.01 (s, 0.7H), 5.20 (s, 0.3H), 4.95 (s, 0.7H), 4.67 (br s, 1H), 3.92-3.89 (m, 1H), 3.75 (s, 3H), 3.70-3.67 (m, 0.3H), 3.64-3.62 (m, 0.7H), 3.57 (s, 3H), 3.54 (s, 1H), 3.50 (s, 1H), 3.49-3.37 (m, 5H), 3.24-3.17 (m, 1H), 3.10-3.02 (m, 1H), 2.23 (s, 3H), 1.28 (d, J=6.5 Hz, 2H), 1.23 (d, J=6.5 Hz, 1H); MS (ESI−) m/z 772 (M−H); HPLC 96.7% (AUC), tR 10.53 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=O)[CH:6]=[CH:7][CH:8]=1.NC1C=C(C=CC=1)CO>CC(O)=O.Cl.C1(S)C=CC=CC=1>[N+:14]([C:11]1[CH:10]=[N:9][C:5]2[C:6]([CH:12]=1)=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=2)([O-:16])=[O:15]
Reactant: O=CC(=CNc1cccc(CO)c1)[N+](=O)[O-]
Agent: Cl
Agent: Nc1cccc(CO)c1
Agent: Sc1ccccc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnc2cc(CO)ccc2c1
Yield: 12.6 %

Procedure:
3-(3-(Hydroxymethyl)phenylamino)-2-nitroacrylaldehyde (4.3 g, 19.4 mmol) was placed in 20 mL HOAc. 4.8 g of 3-aminobenzyl alcohol (4.8 g, 38.7 mmol) was dissolved in 5 mL conc HCl, then 20 mL HOAC was added to the HCl solution. This mixture was added to the reaction flask containing the 3-(3-(hydroxymethyl)phenylamino)-2-nitroacrylaldehyde in HOAc. The mixture was heated to reflux under nitrogen and after 20 min, benzene thiol (0.19 mL, 0.19 mmol) was added. The mixture was refluxed for 28 h (m/z=208.1). After allowing to cool, acid was removed under vacuum. The residue was dissolved in EtOAc/MeOH and loaded on a silica gel cartridge. Purification by column chromatography on silica gel using hexane/EtOAc (0-50%) then 10% MeOH/EtOAc as eluent gave the product (500 mg, 9%) as a brown solid.