Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCc1cccc(C#CCCCCO)c1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCc1cccc(CCCCCCO)c1)(c1ccccc1)c1ccccc1
Reaction time: 17 h
Yield: 660.4 %

Procedure:
To a solution of 6-[3-(t-Butyldiphenylsilyloxymethyl)-phenyl]-hex-5-ynol (880 mg, 2 mmol) in ethyl acetate (10 mL) is added Pd on Carbon (120 mg, 10% Pd by wt.). The mixture is stirred under a hydrogen atmosphere for 17 h, purged with argon filtered through celite concentrated to give the title compound (5.9 g) as an oil. MS (EI) 389 (M-tBu)+.
Reaction SMILES: Br[C:2]1[C:6]([N+:7]([O-])=O)=[C:5]([NH:10][CH3:11])[N:4]([CH3:12])[N:3]=1.S(=O)(=O)(O)O>O>[NH2:7][C:6]1[CH:2]=[N:3][N:4]([CH3:12])[C:5]=1[NH:10][CH3:11]
Reactant: CNc1c([N+](=O)[O-])c(Br)nn1C
Agent: O=S(=O)(O)O
Solvent: O
Product: CNc1c(N)cnn1C
Yield: 137.7 %

Procedure:
0.5 g (2.13 mmoles) of 3-bromo-1-methyl-5-methylamino-4-nitropyrazole are hydrogenated in a solution of 220 mg (2.13 mmoles) sulfuric acid in 20 ml water for 14 hours after adding the catalyst as described in method (2). After filtering the catalyst, the filtrate is reduced until dry and the residue is recrystallized from ethanol. 370 mg (78 percent of theory) of 4-amino-1-methyl-5-methylaminopyrazole hydrosulfate are obtained in the form of colorless crystals with a melting point of 185° to 188° C.
Reaction SMILES: [N+:1]([CH:4]([N+:8]([O-:10])=[O:9])[N+:5]([O-:7])=[O:6])([O-:3])=[O:2].[CH:11]([CH:13]=[CH2:14])=[O:12]>O>[N+:1]([C:4]([N+:8]([O-:10])=[O:9])([N+:5]([O-:7])=[O:6])[CH2:14][CH2:13][CH:11]=[O:12])([O-:3])=[O:2]
Reactant: C=CC=O
Reactant: O=[N+]([O-])C([N+](=O)[O-])[N+](=O)[O-]
Solvent: O
Product: O=CCCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Temperature: 9 °C
Yield: 90.7 %

Procedure:
A 12 L three-necked, round-bottom flask with a thermometer, mechanical stirrer, and 1000 ml addition funnel was charged with 6377 g of an 11% aqueous trinitromethane solution (701.5 g; 4.675 mol) and cooled in a dry-ice bath at 9° C. A solution of acrolein (274.1 g, 4.90 mol) in 2000 ml of water was added at a rate that maintained the temperature at 0° C. The dry-ice bath was removed and the stirred solution allowed to warm to room temperature overnight. The two phases were separated and the aqueous layer was extracted with CH2Cl2 (2×2000 ml). The combined organic layers were washed with water (2×2000 ml). The product was dried (MgSO4) and concentrated to give 878 g (91%) of the aldehyde as a yellow oil; nD =1.4731 (26C). The infrared spectrum showed bands at 1725 cm-1 (C=O), 1590, 1300, and 800 cm-1 (NO2).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]#[C:11][NH2:12].[Na]>C(OCC)C>[C:1]([NH:12][C:11]#[N:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#CN
Agent: [Na]
Solvent: CCOCC
Product: N#CNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
Benzoylcyanamide was prepared by the addition of benzoyl chloride (6.33 g, 0.045 mol) in 100 ml of diethyl ether to a suspension of monosodium cyanamide (5.76 g, 0.090 mol) in 100 ml of ether at 4° C. The reaction was stirred overnight at room temperature and the pale yellow solid which formed was collected and dissolved in water. On acidification of the solution to pH 1, a precipitate formed which was collected and recrystallized from ethyl acetate (EtOAc)/petroleum ether (30°-60° C.) to give 2 (5.89 g, 89.7% yield), mp 140°-142° C. [reported mp 139°-140° C⟧ Anal. Calcd for C8H6H2O: C, 65.75; H, 4.11; N, 19.18. Found: C, 65.79; H, 4.35; N, 19.04.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([N:10]=[C:11]=[O:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.[CH3:13][NH:14][CH3:15]>C(OCC)C>[CH3:13][N:14]([CH3:15])[C:11]([NH:10][CH:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:9][CH2:8][CH2:7]1)=[O:12]
Reactant: CNC
Reactant: O=C=NC1CCCc2sccc21
Solvent: CCOCC
Product: CN(C)C(=O)NC1CCCc2sccc21

Procedure:
A solution of 6.27 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate in 200 ml. of diethyl ether is charged with gaseous dimethylamine introduced via a capillary tube with stirring. After 0.5 hour of bubbling, the gas flow is terminated, and the mixture is evaporated to dryness to give a solid residue. This is crystallized from acetone-hexane-ether to give 1,1-dimethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea melting at 117° C. to 120° C.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]([C:26]3[C:27](=[O:44])[N:28]([CH2:42][OH:43])[C:29](=[O:41])[C:30]=3[C:31]3[C:39]4[C:34](=[C:35]([CH3:40])[CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:9]21[CH2:11][CH2:10]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCCl>[CH2:10]1[C:9]2([CH2:12][N:13]([C:16]3[N:17]=[C:18]([C:26]4[C:27](=[O:44])[N:28]([CH2:42][OH:43])[C:29](=[O:41])[C:30]=4[C:31]4[C:39]5[C:34](=[C:35]([CH3:40])[CH:36]=[CH:37][CH:38]=5)[NH:33][CH:32]=4)[C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][CH2:15][NH:8]2)[CH2:11]1
Reactant: Cc1cccc2c(C3=C(c4nc(N5CCN(C(=O)OC(C)(C)C)C6(CC6)C5)cc5ccccc45)C(=O)N(CO)C3=O)c[nH]c12
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2c(C3=C(c4nc(N5CCNC6(CC6)C5)cc5ccccc45)C(=O)N(CO)C3=O)c[nH]c12
Reaction time: 1.5 h

Procedure:
To a solution of 7-{1-[1-hydroxymethyl-4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-isoquinolin-3-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (500 mg, 0.842 mmol) in 1,2-dichloroethane (5 mL) was added TFA (1.44 g, 0.973 mL, 12.7 mmol) under argon at 0° C. The reaction mixture was stirred for 1 h under argon at 0° C. after which additional TFA (0.768 g, 0.52 mL, 6.74 mmol) was added. Stirring was continued for 1.5 h at 0° C. The reaction mixture was evaporated to dryness at reduced pressure and the crude product was crystallised from MeOH to afford the title compound as a red solid (TFA salt) as a dark red solid. 1H-NMR (400 MHz, DMSO-d6): 12.01 (d, 1H), 9.06 (bs, 2H), 8.11 (d, 1H), 7.71-7.66 (m, 2H), 7.51 (t, 1H), 7.27 (s, 1H), 7.14 (t, 1H), 6.77 (d, 1H), 6.45-6.39 (m, 2H), 5.92 (d, 1H), 5.00 (d, 2H), 3.84-3.54 (m, 6H), 2.39 (s, 3H), 0.96-0.67 (m, 4H). LCMS: [M+1]+=493.7, Rt(1)=1.84 min.
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]2[C:26]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:25](Cl)[N:24]=[C:23]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:22]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.ClCCl.CS(C)=O>[CH3:8][C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]2[C:26]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:25]([O:5][CH2:4][CH2:3][OH:6])[N:24]=[C:23]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:22]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([CH3:10])[CH3:9]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Sodium hydroxide (26.66 g), ethylene glycol (400 mL), tetrabutylammonium bromide (10 g), 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidin-4-yl]benzenesulfonamide (100 g) and dimethylsulphoxide (400 mL) were mixed together at 25° C. The reaction mixture was heated to 60° C. to 65° C. and the mixture was stirred for 12-14 hours at 60° C. to 65° C. The reaction mixture was cooled to 25° C. followed by the addition of dichloromethane (600 mL) and de-ionized water (1000 mL). The pH of the mixture was adjusted to 2 to 3 with concentrated hydrochloric acid and the mixture was stirred for 10 minutes. The organic layer of the reaction mixture was separated. The aqueous layer was extracted with dichloromethane (200 mL). Both the organic layers were combined, washed with de-ionized water (500 mL) and the solvent was recovered. The residue was dried under vacuum at 40° C. to 50° C. to obtain bosentan.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([OH:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O.[H][H]>[Pt].C(O)(C)C>[CH3:1][C:2]([CH3:19])([OH:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15]
Reactant: [H][H]
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Solvent: CC(C)O
Product: CC(C)(O)CNc1c(N)cnc2cccnc12

Procedure:
A catalytic amount of 5% platinum on carbon was added to a suspension of 1,1-dimethyl-2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethanol (7 g, 26 mmol) in isopropanol (300 mL). The mixture was hydrogenated on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure for 3 hours. The reaction mixture was fileted to remove the catalyst. The filtrate was concentrated under vacuum. Toluene was added to the residue and the mixture was concentrated under vacuum to remove all of the alcohol and provide crude 1,1-dimethyl-2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethanol.
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][C:18](=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.[OH-].[Na+]>CO.C(Cl)(Cl)Cl>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH:21]=[C:18]1[CH2:17][CH2:16][N:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([C@H:7]([OH:6])[CH3:8])[N:14]=2)[CH2:20][CH2:19]1
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCC(=Cc3cccc(Cl)c3)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@@H](O)c1nccc(N2CCC(=Cc3cccc(Cl)c3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-1-{4-[4-(3-chloro-benzylidene)-piperidin-1-yl]-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 176, Step C, 0.62 g, 1.55 mmol) in methanol (8 mL) was added 1 N aqueous sodium hydroxide (1 mL) then stirred for 4 h at ambient temperature. The mixture was diluted with chloroform and washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product which was purified by flash chromatography (95:5 dichloromethane:methanol) to give the title compound as a white solid, 0.31 g (61%). 1H NMR (CDCl3, 300 MHz) δ1.51 (d, 3H), 2.46 (m, 2H), 2.56 (m, 2H), 3.07 (m, 2H), 3.77 (m, 2H), 4.35 (d, 1H), 4.69 (q, 1H), 6.36 (s, 1H), 6.40 (d, 1H), 7.07 (m, 1H), 7.12-7.28 (m, 3H), 8.18 (m, 1H); mp: 45-55° C.; MS (CI) 330 (MH+); [α]D +16.8 (c, 1.0, MeOH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.C([CH:48](O)[CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]1)(C)(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:48][CH2:49][CH2:50][N:51]4[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: CN1CCN(CCC(O)C(C)(C)C)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2cc(F)cc(F)c2)CC1
Reaction time: 34 h

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, t-butyl 3-(4-methylpiperazin-1-yl)propan-1-ol (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, being stirred for 34 h, and being purified by prep. HPLC (20% H2O/CH3CN) to provide 3-(3,5-difluorophenyl)-6-(3-(4-methylpiperazin-1-yl)propoxy)-2-(pyridin-3-yl)-1H-inden-1-one, which was treated with HCl/dioxane following the same procedure in Step 8 of Example 1 (50% for 2 steps).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:34])([F:33])[C:5]1[CH:6]=[C:7]([N:15]([CH3:32])[C:16]([N:18]([C@H:20]2[C@H:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=3)[CH2:23][NH:22][CH2:21]2)[CH3:19])=[O:17])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.[CH3:35][O:36][C:37]([NH:39][C@H:40]1[CH2:45][CH2:44][C@H:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)=[O:38]>>[F:34][C:4]([F:3])([F:33])[C:5]1[CH:6]=[C:7]([N:15]([CH3:32])[C:16]([N:18]([CH3:19])[C@H:20]2[C@H:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=3)[CH2:23][N:22]([C:46]([C@H:43]3[CH2:42][CH2:41][C@H:40]([NH:39][C:37](=[O:38])[O:36][CH3:35])[CH2:45][CH2:44]3)=[O:47])[CH2:21]2)=[O:17])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: COC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CN(C(=O)N(C)[C@@H]1CNC[C@H]1c1ccc(F)cn1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: COC(=O)N[C@H]1CC[C@H](C(=O)N2C[C@@H](N(C)C(=O)N(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccc(F)cn3)C2)CC1

Procedure:
By reaction and purification in the same manner as in the method described in Example 4 and using the compound obtained in Example 191 and trans-4-[(methoxycarbonyl)amino]cyclohexanecarboxylic acid, the title compound was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:32][CH3:33])=[CH:12][C:13]([O:30][CH3:31])=[C:14](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])[CH:15]=1.CCN(CC)CC.[CH2:41]1[CH2:45][O:44][CH2:43][CH2:42]1.C(OC(=O)CCC)(=O)CCC>CN(C1C=CN=CC=1)C.O>[C:43]([NH:29][S:26]([C:23]1[CH:22]=[CH:21][C:20]([C:18](/[CH:17]=[CH:16]/[C:14]2[CH:15]=[C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:11]([O:32][CH3:33])=[CH:12][C:13]=2[O:30][CH3:31])=[O:19])=[CH:25][CH:24]=1)(=[O:28])=[O:27])(=[O:44])[CH2:42][CH2:41][CH3:45]
Reactant: C1CCOC1
Reactant: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Agent: CCCC(=O)OC(=O)CCC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC(=O)NS(=O)(=O)c1ccc(C(=O)/C=C/c2cc(-c3cc4ccccc4[nH]3)c(OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-35E, 0.92 g, 2 mmol), DMAP(0.024 g, 0.2 mmol) and Et3N (0.2 g, 2.1 mmol) in 100 ml o THF was added butyric anhydride (0.64 g, 4 mmol). The reaction mixture was stirred at room temperature overnight. The clear solution was then poured into 150 ml of H2O and extracted with CH2Cl2. The combined organic phase was washed with water, dried over MgSO4, and concentrated to dryness. Recrystallization from EtOAc/hexenes gave 0.80 g (75%) of the title compound as a red solid, mp 155–165° C. 1H-NMR (300 MHz, Acetone-d6) δ 10.55 (br, 1H), 8.35 (s, 1H), 8.27 (d, J=8 Hz, 2H), 8.13–8.20 (m, 3H), 7.89 (d, J=16 Hz, 1H), 7.52 (d, J=7 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.02–7.07(m, 1H), 6.95–7.00 (m, 2H), 6.90 (s, 1H), 4.10 (s, 3H), 4.04 (s, 3H), 2.29 (t, J=8 Hz, 2H), 1.48–1.56 (m, 2H), 0.81(t, J=8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[F:34][C:35]1[C:43]([F:44])=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][CH2:38][NH:39]2>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([N:39]2[C:40]3[C:36](=[C:35]([F:34])[C:43]([F:44])=[CH:42][CH:41]=3)[CH2:37][CH2:38]2)=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: Fc1ccc2c(c1F)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)ccn1)N1CCc2c1ccc(F)c2F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.50 g (3.2 mmol) 4-chloropicolinic acid, 1.1 g (3.4 mmol) TBTU and 0.91 mL (6.5 mmol) TEA were placed in 10 mL DMF. 0.63 g (3.3 mmol) 4,5-difluoroindoline hydrochloride were added. The reaction mixture was stirred overnight at RT and then extracted successively with a 15% potassium carbonate solution, water, a 1M HCl solution and EtOAc. The organic phase was dried, filtered and concentrated to dryness by rotary evaporation. The residue was stirred with diisopropylether and the undissolved solid was suction filtered and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23][C:22]2[C:21]([O:24][CH3:25])=[C:20]3[C:11]([CH:12]=[C:13]4[C:18](=[C:19]3[OH:26])[CH:17]=[CH:16][CH:15]=[C:14]4[O:27][CH3:28])=[C:10]([O:29][CH3:30])[C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cr](O)(O)(=O)=[O:37].S(=O)(=O)(O)O.O>C(Cl)Cl.C(OC(=O)C)C.[O-2].[O-2].[O-2].[Cr+6]>[CH2:34]([O:33][C:31]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:23][C:22]2[C:21]([O:24][CH3:25])=[C:20]3[C:11]([C:12](=[O:37])[C:13]4[C:14]([O:27][CH3:28])=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]3=[O:26])=[C:10]([O:29][CH3:30])[C:9]=2[CH2:8][CH2:7]1)=[O:32])[CH3:35]
Reactant: CCOC(=O)C1(C(=O)OCC)CCc2c(c(OC)c3c(O)c4cccc(OC)c4cc3c2OC)C1
Reactant: O=[Cr](=O)(O)O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)OCC)CCc2c(c(OC)c3c(c2OC)C(=O)c2c(OC)cccc2C3=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
The product of the principal reaction of example VII (compound VI) has added thereto ice (3 g) and there is added thereto a chromic acid solution of (4 ml.) from a previously prepared solution comprising chromium trioxide (24 g.), concentrated sulfuric acid 30 g, and water to 100 ml. The chromic acid solution is added dropwise with agitation while holding the mixture at 0° C. Thirty minutes after reaction is complete the reaction mixture is removed from the cooling bath and permitted to warm to ambient temperature at which it remains for 2 hours. The reaction mixture is then diluted with distilled water (20 ml.) and extracted with ethyl acetate (20 ml.). The aqueous phase is further extracted with ethyl acetate (20 ml.) and the organic phases iare combined. To the organic phase is added zinc dust (1 g) and the mixture shaken briefly, the zinc dust is removed by filtration and the organic filtrate washed successively with dilute aqueous hydrochloric acid (3 N. 20 ml.) saturated aqueous sodium bicarbonate (20 ml.) and distilled water (20 ml.) The organic extract is dried over anhydrous magnesium sulfate, filtered, and the solvent removed from the filtrate by evaporation under reduced pressure to yield an orange residue which was taken up in methylene-chloride/ethylacetate (17:3, 20 ml.) and passed through a silica gel column: (20 g). The solvent is removed from the eluate under reduced pressure and the residue recrystallized (from aqueous methanol) to give 9,9-Bis(ethoxycarbonyl)-4,6,11-trimethoxy-7,8,9,10-tetrahydronaphthacene-5,12-quinone (VII) (860 mg., 0.017 moles 62%) as yellow needle crystals m.p. 123°-125° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7]2.[OH-].[K+]>>[Br:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2
Reactant: COC(=O)c1cc2ccc(OC)c(Br)c2[nH]1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2cc(C(=O)O)[nH]c2c1Br

Procedure:
Following the general procedure of PREPARATION 63 and making non-critical variations but starting with methyl 7-bromo-6-methoxyindole carboxylate (PREPARATION 81, 0.36 g) and potassium hydroxide (0.11 g), the title compound is obtained, NMR (300 MHz, CD3OD), 7.58, 7.20, 6.96 and 3.93 δ.
Reaction SMILES: [H-].[Na+].C(=N[OH:6])C.[Cl:7][C:8]1[C:17]([Cl:18])=[C:16]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([N+]([O-])=O)=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:9]=1[O:10][CH:11]([OH:13])[CH3:12]>CN(C=O)C>[Cl:7][C:8]1[C:17]([Cl:18])=[C:16]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([OH:6])=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:9]=1[O:10][CH:11]([OH:13])[CH3:12]
Reactant: CC(O)Oc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)c(Cl)c1Cl
Reactant: CC=NO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)Oc1ccc(C(=O)c2ccc(O)cc2)c(Cl)c1Cl
Reaction time: 0.17 h

Procedure:
Dry DMF (40 ml.) was cooled in an ice bath to 10°-15° C. Sodium hydride (7.2 g., 0.15 mole) was then added. The suspended mixture was stirred for 10 minutes and acetaldoxime (11.8 g., 0.2 mole) was added portionwise. After stirring for another 10 minutes the compound from Example 1 (17.8 g., 0.05 mole) in 30 ml. dry DMF was added dropwise. When the addition was completed, the ice bath was removed and the reaction mixture was stirred at room temperature for 21/2 hours. The mixture was poured into ice water and was filtered. The filtrate was acidified with concentrated HCl to obtain a precipitate. The crude solid was purified from aqueous ethanol to yield 11 g. (67%), m.p. 169°-170° C.
Reaction SMILES: [NH:1]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:22][C@H:23]([C:28]([NH:30][C@H:31]([C:35]([OH:37])=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([CH:52]([C:57]([CH:75]([O:80][SiH](C)C)C(C)(C)C)([CH:66]([O:71][SiH](C)C)C(C)(C)C)[NH:58][C:59]([CH2:61][CH2:62][CH2:63][CH2:64][NH-:65])=[O:60])[O:53][SiH](C)C)(C)(C)C>C(O)(=O)C.O>[NH:1]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:22][C@H:23]([C:28]([NH:30][C@H:31]([C:35]([OH:37])=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[OH:71][CH2:66][C:57]([CH2:52][OH:53])([CH2:75][OH:80])[NH:58][C:59]([CH2:61][CH2:62][CH2:63][CH2:64][NH-:65])=[O:60]
Reactant: C[SiH](C)OC(C(C)(C)C)C(NC(=O)CCCC[NH-])(C(O[SiH](C)C)C(C)(C)C)C(O[SiH](C)C)C(C)(C)C
Agent: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C
Solvent: O
Solvent: CC(=O)O
Product: [NH-]CCCCC(=O)NC(CO)(CO)CO

Procedure:
83 mg of Z-Phe-His-Leu-Val-4-[-tris-(tert.-butyldimethylsilyloxymethyl)-methylaminocarbonyl]-butyl amide (Example 19) are stirred at room temperature for 2 hours with 6 ml of glacial acetic acid/water 2:1. After evaporating off the solvent and medium-pressure chromatography (60 g of Lichroprep® Si60, 40-60 μm, system B8), the title compound is obtained in the form of a colourless powder. Rf (methylene chloride/methanol/concentrated ammonia 70:10:1)=0.11.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl.O>CN(C=O)C>[CH3:14][N:13]1[CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[N:12]1
Reactant: CCOC(=O)c1cnn(C)c1N
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(C)c1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of 90% t-butyl nitrite (50 mL, 0.37 mol) in 200 mL DMF was added in portions ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (39 g, 0.23 mol), maintaining the temperature at around 30° C. After the addition, the resulting mixture was warmed to 50° C. and stirred at that temperature for 0.5 h. The mixture was poured into 100 mL conc HCl and 40 mL water and extracted with CH2Cl2. The organic solution was washed with water, brine, dried and concentrated. Vacuum distillation of the residue gave 32.4 g of ethyl 1-methyl-1H-pyrazole-4-carboxylate as a clear liquid. b.p. 65°-80° C. at 0.1 torr.