Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:26]=[CH:25][C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH2:24])[CH3:23])[CH2:16][CH2:15]4)[O:13][C:9]=3[CH:8]=2)[CH2:4][CH2:3]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1.O>[CH:2]1([CH2:5][O:6][C:7]2[CH:26]=[CH:25][C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH:24][C:27](=[O:29])[CH3:28])[CH3:23])[CH2:16][CH2:15]4)[O:13][C:9]=3[CH:8]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](N)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N[C@@H](C)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-1-({1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)propan-2-amine monohydrochloride (17.6 g) in pyridine (85 mL) was added acetic anhydride (12.6 mL) at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, 1M hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was recrystallized from hexane/ethyl acetate to give the title compound (12.0 g) as white crystals.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[N:48]=[C:47]([CH3:52])[C:46]([S:53]([CH3:56])(=[O:55])=[O:54])=[C:45]2[C:57]1[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=1.[NH:67]1[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1>C(O)(C)(C)C.CCCCCCC>[CH3:56][S:53]([C:46]1[C:47]([CH3:52])=[N:48][C:49]2[C:44]([C:45]=1[C:57]1[CH:58]=[CH:59][C:60]([C:63]([F:64])([F:66])[F:65])=[CH:61][CH:62]=1)=[CH:43][C:42]([N:67]1[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1)=[CH:51][CH:50]=2)(=[O:54])=[O:55]
Reactant: C1COCCN1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(C(F)(F)F)cc2)c1S(C)(=O)=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCCCCCC
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccc(C(F)(F)F)cc2)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 36.4 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (51 mg, 0.05 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (47 mg, 0.10 mmol) and cesium carbonate (1.21 g, 3.71 mmol). 6-Bromo-3-methanesulfonyl-2-methyl-4-(4-trifluoromethyl-phenyl)-quinoline (compound of example 20) (800 mg, 1.95 mmol) in tert.-butanol (20 ml) was added, followed by morpholine (0.259 g, 2.97 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate with a gradient 100:0 to 40:60 to give a yellow solid (320 mg, 29%). MS: m/z=451 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]=O)=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[N:18]([NH2:19])[CH:17]=[N:16][N:15]=1.C([O-])(=O)C.[Na+].C(O)(=O)C>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:11]=[N:19][N:18]3[CH:17]=[N:16][N:15]=[C:14]3[N:13]=2)=[CH:5][CH:4]=1
Reactant: Nc1nncn1N
Reactant: COc1ccc(C(=O)C=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2cnn3cnnc3n2)cc1

Procedure:
A solution of 9.1 g. of p-methoxyphenylglyoxal, 6.7 g. of 3,4-diamino-4H-1,2,4-triazole and 4.1 g. of sodium acetate in 90 ml. of 67% acetic acid is heated on a steam bath for 1/2 hour. Water is added and heating is continued until crystals separate. The mixture is cooled and filtered. The precipitate is washed with water, ethanol and then hexane giving the desired product as yellow plates, m.p. 282.5°-284.5° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[N:6][O:7][C:8]=1[CH3:9])[CH3:2].C(N(CC)CC)C.[CH3:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl>[C:20]([N:3]([C:4]1[CH:5]=[N:6][O:7][C:8]=1[CH3:9])[CH2:1][CH3:2])(=[O:21])[CH2:19][CH2:18][CH3:17]
Reactant: CCCC(=O)Cl
Reactant: CCNc1cnoc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N(CC)c1cnoc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred, ice cooled solution of 4-ethylamino-5-methylisoxazole (Method 5 of WO 03/76436; 49.6 g, 305 mM) and triethylamine (77.0 g, 763 mM, 107 ml) in DCM (800 ml), was slowly added a solution of n-butyryl chloride (35.5, 333 mM, 35 ml) in DCM (100 ml). There was a moderate exotherm. The solution was allowed to warm to ambient temperature and stir for 1 hour. The reaction mixture was washed with water, 2N HCl, brine, sat. NaHCO3 and brine. It was dried and the solvent was evaporated to give the title compound as an oil, which crystallized to a waxy solid (45.1 g, 75%). NMR (300 Mz, DMS0-d6): 0.78 (t, 3H), 0.96 (t, 3H), 1.44 (sext, 2H), 1.93 (t, 2H), 2.33 (s, 3H), 3.49 (q, 2H), 8.68 (s, 1H); m/z 197.
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[NH2:28][C:29]([NH2:31])=[O:30].[Na].CC(C)=O>C(Cl)Cl>[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:28][C:29]([NH2:31])=[O:30])=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: NC(N)=O
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NC(N)=O)cc1

Procedure:
The 12.6 g. of 4-(hexadecylamino)benzoyl chloride hydrochloride in methylene chloride is added to 5 g. of sodium urea in 30 ml. of acetone and the mixture is stirred at 20° C. for 18 hours. Dilute alkali is added and the solid washed with alkaline aqueous acetone. Recrystallization from ethanol gives pure white crystals of product.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([CH3:13])[C:3]=1[NH2:4].Cl.[N:15]([O-])=O.[Na+].C([O-])(=O)C.[Na+].CC(S)(C)C.CC(C)([O-])C.[K+]>O.C(O)C.CS(C)=O>[Br:1][C:2]1[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=[C:5]2[C:3]=1[NH:4][N:15]=[CH:13]2
Reactant: Cc1cc(C(F)(F)F)cc(Br)c1N
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CC(C)(C)S
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1cc(Br)c2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 2-bromo-6-methyl-4-(trifluoromethyl)aniline (1 1.3 g, 44.5 mmol) in hydrochloric acid (8 M, 40 mL, 320 mmol) at −10° C. was added a solution of sodium nitrite (3.22 g, 46.7 mmol) in water (ca. 10 mL) dropwise. After 10 min, the resulting solution was neutralized by addition of solid sodium acetate. The resulting solution was added to a solution of 2-methyl-2-propanethiol (5.01 mL, 44.5 mmol) in ethanol (100 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The resulting mixture was poured onto ice and the resulting mixture was extracted into diethyl ether (2×). The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. The resulting residue was dissolved in dimethylsulfoxide (25 mL) and transferred to a solution of potassium tert-butoxide (39.9 g, 356 mmol) in dimethylsulfoxide (250 mL) in a cool water bath (ca. 10° C.) via canula. The bath was removed and stirring continued for 30 min. The reaction mixture was poured onto ice/concentrated hydrochloric acid to give a precipitate. After 30 min, the resulting solid was collected by filtration and air dried on the filter overnight to give 10.1 g (86%) as a tan solid. 1H-NMR (CDCl3, 500 MHz) δ 8.24 (s, 1H), 8.01 (s, 1H), 7.73 (s, 1H), 2.83 (bs, 1H); 13C-NMR (CDCl3, 126 MHz) δ 140.7, 136.3, 125.8 (q, J=2.9 Hz), 124.9 (q, J=33 Hz), 123.8 (q, J=273 Hz), 123.2, 118.4 (q, J=3.8 Hz), 104.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][OH:18]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: OCCCBr
Product: OCCCN1CCN(Cc2ccccc2)CC1

Procedure:
Alkylation of 1-benzylpiperazine (16 g, 0.091 mole) with 3-bromopropan-1-ol (13.88 g; 0.01 mole) as described in Example 1(c) gave, after chromatography, 12.9 g (61%) of the product as a colourless oil. νmax (film) 3300, 2920, 2800, 1595 cm-1 ; (Found; C, 69.41; H, 9.60; N, 11.75; C14H22N2O.O.5H2O requires; C, 69.10; H, 9.52; N, 11.51%).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH3:10][CH:11]1[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][C:12]1=[O:18].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:10][C:11]1([CH2:1][CH2:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8])[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][C:12]1=[O:18]
Reactant: CC1C(=O)CCCC1=O
Reactant: C=CCCCC(=O)C=C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCCCC(=O)CCC1(C)C(=O)CCCC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1,7-Octadien-3-one(0.24 g), 2-methyl-1,3-cyclohexanedione(0.5 g) and triethylamine (1 ml) are added to ethyl acetate (10 ml), and the mixture is stirred at room temperature for 24 hours. The triethylamine and acetic acid are evaporated off and the residue is purified by silica gel column chromatography(methylene chloride) to recover 0.39 g of the above-indicated compound. [IR 1700-1730 cm-1, 920 cm-1 ; NMR 1.10 ppm(3H, singlet, --CH3), 4.6-6.0 ppm(3H, multiplet, vinyl)].
Reaction SMILES: [C:1]1([N:7]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Mg]Br.C1C[O:44][CH2:43][CH2:42]1>>[C:43]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:44])[CH3:42]
Reactant: C1CCOC1
Reactant: [N-]=[N+]=Nc1ccccc1
Agent: C[Mg]Br
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: CC(=O)Nc1ccccc1
Temperature: 120 °C

Procedure:
In a capped vial (1 mL) containing a solution of phenylazide (6.6 mg, 55 μmol) in dry THF (300 μL), was added [RhCl(cod)]2 (0.27 mg, 0.55 μmol), and 1,2-bis(diphenylphosphino)ethane (0.66 mg, 1.65 μmol), and was shaken until the solution was homogeneous. After addition of a solution of methyl magnesium bromide (18.5 μL of 3M solution in ether, 55 μmol), the resulting mixture was transferred to the micro-autoclave, which was pre-charged with [11C]CO. The micro-autoclave was heated at 120° C. for 5 min under 35 MPa and the crude product was transferred to a reduced pressure vial. The radioactivity was measured before and after the vial was flushed with N2 (the [11C]CO-trapping efficiency of 96% was determined based on these values). The solution was dissolved in ammonium formate (0.5 mL, pH=3.5) and heated at 120° C. for 1 min. A small amount of crude product was collected and analyzed by the reversed phase HPLC. Yield of product: 91%. The product was identified by HPLC with an added authentic reference compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([Br:27])=[CH:20][C:19]=1Br)[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2].[CH2:29]=[N:30]O.N1C(C)=CC=CC=1C.[N+](C1C=CC=CC=1)([O-])=O>[Cu]I>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([Br:27])=[CH:20][C:19]=1[C:29]#[N:30])[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc(Br)cc2[N+](=O)[O-])c(NC(C)=O)c1
Reactant: C=NO
Agent: [Cu]I
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1cccc(C)n1
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc(Br)cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 90 °C
Yield: 18.3 %

Procedure:
A stirred mixture of 3-acetylamino-4-(2',4'-dibromo-6'-nitrophenylazo)-N,N-diethylaniline (5.3 parts), copper (I) iodide (1.9 parts), formaldoxime trimer (1.8 parts), 2,6-lutidine (2.15 parts), and nitrobenzene (100 parts), was heated to 90° C. for 10 hours when thin layer chromatography showed reaction to be effectively complete. The mixture was filtered, cooled, and the solvent was removed by steam distillation. Crystallisation of the solid product from ethanol gave 3-acetylamino-4-(2'-cyano-4'-bromo-6'-nitrophenylazo)-N,N-diethylaniline (Found; C, 49.5; H, 4.3; Br, 17.7; N, 18.3. C19H19BrN6O3 requires C, 49.65; H, 4.15; Br, 17.4; N, 18.3%)
Reaction SMILES: C(C1N(CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)C(C(OC(OC(=O)CCC[C@@H](O[N+]([O-])=O)CO[N+]([O-])=O)C)=O)=C(Cl)N=1)CCC.[CH2:69]([O:71][C:72]1[N:76]([CH2:77][C:78]2[CH:83]=[CH:82][C:81]([C:84]3[CH:89]=[CH:88][CH:87]=[CH:86][C:85]=3[C:90]3[N:94](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:93]=[N:92][N:91]=3)=[CH:80][CH:79]=2)[C:75]2[C:114]([C:118]([O:120][CH:121]([O:123][C:124](=[O:138])[CH2:125][CH2:126][CH2:127][C@@H:128]([O:134][N+:135]([O-:137])=[O:136])[CH2:129][O:130][N+:131]([O-:133])=[O:132])[CH3:122])=[O:119])=[CH:115][CH:116]=[CH:117][C:74]=2[N:73]=1)[CH3:70]>>[CH2:69]([O:71][C:72]1[N:76]([CH2:77][C:78]2[CH:79]=[CH:80][C:81]([C:84]3[CH:89]=[CH:88][CH:87]=[CH:86][C:85]=3[C:90]3[NH:91][N:92]=[N:93][N:94]=3)=[CH:82][CH:83]=2)[C:75]2[C:114]([C:118]([O:120][CH:121]([O:123][C:124](=[O:138])[CH2:125][CH2:126][CH2:127][C@@H:128]([O:134][N+:135]([O-:137])=[O:136])[CH2:129][O:130][N+:131]([O-:133])=[O:132])[CH3:122])=[O:119])=[CH:115][CH:116]=[CH:117][C:74]=2[N:73]=1)[CH3:70]
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
The title compound was prepared by following step D in example 14, except that the reagent 1-{[(5R)-5,6-bis(nitrooxy)hexanoyl]oxy}ethyl 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate was replaced by the individual diastereomerically pure 1-{[(5R)-5,6-bis(nitrooxy)hexanoyl]oxy}ethyl 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][CH2:26][NH:27][C:28](=O)[CH3:29])[C:5]2=3)[CH:14]=1.CO>C1COCC1>[CH2:28]([NH:27][CH2:26][CH2:25][O:24][C:6]1[C:5]2[C:4]3[C:12]4=[C:13]([O:15][CH2:16][CH:17]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:11]4[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:14]=[C:2]([CH3:1])[CH:3]=3)[CH3:29]
Reactant: CC(=O)NCCOc1cccc2c1c1cc(C)cc3c1n2C(c1ccccc1)CO3
Solvent: C1CCOC1
Solvent: CO
Product: CCNCCOc1cccc2c1c1cc(C)cc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 72.3 %

Procedure:
To a mixture of N-{2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethyl}acetamide (0.212 g, 0.53 mmol) in THF (10 mL) is added borane-methylsulfide complex (0.15 mL, 1.6 mmol). The mixture is refluxed at 85° C. for 16 hours. After cooling, methanol is slowly added until gas evolution ceased. The solvents are removed under vacuum and methanol (5 mL) is added then removed. The residue is dissolved in CH2Cl2/CH3OH (1:5, 15 mL). Conc. HCl is added and the mixture is heated at 65° C. for 1 h. The mixture is removed from heat, neutralized with aqueous potassium carbonate and then partitioned between water and CH2Cl2. The organic layer is washed with water, dried over magnesium sulfate, and concentrated. Column chromatography (70 g silica gel) using CH3OH/CH2Cl2 (5:95) as eluent gave 0.148 g (70%) of N-ethyl-2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine (TLC: MeOH/CH2Cl2, 5/95, Rf=0.38); conversion to the maleic acid salt and recrystallizing from absolute ethanol gave 0.0223 g of N-ethyl-2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine, maleic acid salt
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])#[N:2].[Cl:13][C:14]1[C:19](O)=[C:18]([Cl:21])[C:17]([Cl:22])=[C:16]([Cl:23])[C:15]=1[Cl:24].O=P(Cl)(Cl)Cl.Cl>C(Cl)(Cl)(Cl)Cl>[Cl:13][C:14]1[C:19]([O:5][C:4](=[O:6])[CH:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])=[C:18]([Cl:21])[C:17]([Cl:22])=[C:16]([Cl:23])[C:15]=1[Cl:24]
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: N#CC(C(=O)O)c1ccccc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccccc1
Temperature: 25 °C

Procedure:
8 g. (0.05 moles) of α-cyanophenylacetic acid, 13 g. (0.05 moles) of pentachlorophenol are mixed together. 4.3 g. (0.05 moles) of phosphoroxychloride are added dropwise. The obtained mixture is heated slowly to 85°-90° C. on an oil-bath and the mixture is kept at this temperature until the HCl evolution ceases. When the reaction is completed, the mixture is cooled to room temperature, and the melt is taken up in 100 ml. of carbon tetrachloride. The solution is washed three times with 30 ml. of water, treated with decolorizing charcoal, dried and evaporated. The product is recrystalized from diisopropyl ether, and crystalline pentachlorophenyl ester is precipitated.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[N:15](CC3C=CC(OC)=CC=3)[CH:16]=[CH:17][C:9]=2[C:8]=1[C:27]1[C:28]([CH3:37])=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][CH2:32][CH2:31][CH2:30]2)[C:3]([O:5][CH3:6])=[O:4].OS(O)(=O)=O.C1(OC)C=CC=CC=1.CO.C(Cl)Cl>FC(F)(F)C(O)=O>[OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[NH:15][CH:16]=[CH:17][C:9]=2[C:8]=1[C:27]1[C:28]([CH3:37])=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][CH2:32][CH2:31][CH2:30]2)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(O)c1c(-c2ccc3c(c2C)CCCO3)c2ccn(Cc3ccc(OC)cc3)c2c(=O)n1C
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(O)c1c(-c2ccc3c(c2C)CCCO3)c2cc[nH]c2c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
An ice cold solution of methyl 2-hydroxy-2-(1-(4-methoxybenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (880 mg, 1.751 mmol) in Trifluoroacetic acid (TFA) (3.5 mL) was treated with conc. H2SO4 (0.262 mL, 4.92 mmol) and anisole (0.525 mL, 4.81 mmol). After stirring for 1 hour, the reaction was warmed to rt for 2 hours, and then quenched with sat. NaHCO3 until neutral. The mixture was extracted with EtOAc, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/Hexane, then 0-20% MeOH/DCM) afforded methyl 2-hydroxy-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (421.4 mg, 1.102 mmol, 62.9% yield) as yellow oil: LCMS (m/z) ES+=383 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:46])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:47])[C:3]=1[C:48]([O:50][CH3:51])=[O:49])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:44])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C:35](=[N:39][OH:40])[C@@H:34]([O:41][CH3:42])[C@H:33]([CH3:43])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:45].[N:52]1C=CC=[CH:54][CH:53]=1>CO>[NH2:52][CH2:53][CH2:54][O:40]/[N:39]=[C:35]1\[C@@H:36]([O:37][CH3:38])[C@@H:31]([NH:30][C:14]2[C:13](=[O:44])[C:12]3[CH:11]=[C:10]4[C:19]([C:20](=[O:27])[C@@:21]5([O:25][CH3:26])[C@@:8]([OH:46])([C:9]4=[O:45])[C:7]4[C:2]([OH:1])=[C:3]([C:48]([O:50][CH3:51])=[O:49])[C:4]([CH3:47])=[CH:5][C:6]=4[CH2:23][C@H:22]5[OH:24])=[C:18]([OH:28])[C:17]=3[C:16](=[O:29])[CH:15]=2)[O:32][C@@H:33]([CH3:43])[C@@H:34]\1[O:41][CH3:42]
Reactant: c1ccncc1
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)C(=NO)[C@H]1OC)C4=O
Solvent: CO
Product: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)/C(=N/OCCN)[C@H]1OC)C4=O
Reaction time: 6 h
Yield: 33 %

Procedure:
To a solution of the ketone from Step A of the preparation of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,5R,6S)-4-(hydroxyimino)-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-carboxylate [Isomer A](Example 48) (50 mg, 0.072 mmol) in methanol (1 mL) was added 2-(aminooxy)-1-ethanaminum dihydrochloride (10.7 mg, 0.072 mmol) and pyridine (0.1 mL) at room temperature. The mixture was stirred under nitrogen for 6 h. The reaction mixture was quenched with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC (silica gel, 90:10 chloroform/methanol) to afford (6R,6aS,14aR)-methyl 11-((2S,3R,5R,6S,Z)-4-(2-aminoethoxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6,8,14a-tetrahydroxy-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (18 mg, 33%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.00 (br s, 1H), 6.53 (s, 1H), 5.93 (s, 1H), 4.98 (d, J=1.5 Hz, 1H), 4.95 (d, J=6.0 Hz, 1H), 4.87 (br s, 1H), 4.29-4.26 (m, 3H), 3.83 (s, 3H), 3.74-3.70 (m, 2H), 3.61-3.54 (m, 2H), 3.58 (s, 3H), 3.47 (s, 3H), 3.40 (s, 3H), 3.34 (d, J=19.5 Hz, 1H), 3.11-3.06 (m, 2H), 2.40 (s, 3H), 1.37 (d, J=6.0 Hz, 3H), 1.24 (t, J=7.0 Hz, 2H); MS (ESI+) m/z 754 (M+H); HPLC 95.6% (AUC), tR 10.86 min.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[C:22]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][CH:26]([F:27])[C:24]1[CH:23]=[C:22]([C:29]2[CH:30]=[N:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=2)[N:21]=[C:20]([N:18]2[CH:19]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[N:16]=[CH:17]2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.8 %

Procedure:
To a cooled and stirred solution of 3-{1-[4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonic acid tert-butylamide (0.06 g) in dichloromethane (2 ml) was added TFA (2 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by column chromatography on silica gel (dichloromethane/MeOH/NH4OH 16:1:0.1) and crystallization (diethyl ether) yielded the title compound as a white solid (0.022 g, 4%). MS (ISP) 497.2 [(M+H)+]; mp 219.5° C.