Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13][CH:12]=1)[C:3](=O)OC(C)(C)C.[H-].[Na+].[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:32][C:27]=2[CH2:26][CH2:25]1>CN(C)C=O>[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([S:33]([N:13]3[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:15][C:11]([CH2:10][NH:2][CH3:3])=[CH:12]3)(=[O:35])=[O:34])=[CH:32][C:27]=2[CH2:26][CH2:25]1
Reactant: CN(Cc1c[nH]c(-c2ccccc2)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc3c(c2)CCO3)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a solution (5 mL) of tert-butyl methyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (28 mg) in N,N-dimethylformamide was added sodium hydride (60% in oil, 40 mg) at room temperature and the mixture was stirred for 30 min. 2,3-Dihydro-1-benzofuran-5-sulfonyl chloride (65 mg) was added at room temperature and the mixture was stirred for 1 hr. To the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1), and dissolved in methanol (10 mL). 4 mol/l Hydrogen chloride-ethyl acetate solution (1.5 mL) was added and the mixture was stirred at 65° C. for 30 min. The reaction mixture was concentrated under reduced pressure to give a free form, which was crystallized from ethyl acetate as a 0.5 oxalic acid salt to give the title compound as pale-red crystals (yield 26 mg, 63%).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([O:22][N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][C:26]([NH:33]C=O)=[N:27][C:28]=2Cl)[CH2:11][O:12][CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])(C(C)(C)C)(C)C.C(O)=[O:37]>>[CH2:17]([O:16][P:14]([CH2:13][O:12][CH2:11][CH:10]([O:22][N:23]1[CH:31]=[N:30][C:29]2[C:28](=[O:37])[NH:27][C:26]([NH2:33])=[N:25][C:24]1=2)[CH2:9][OH:8])([O:19][CH2:20][CH3:21])=[O:15])[CH3:18]
Reactant: CCOP(=O)(COCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(Cl)nc(NC=O)nc21)OCC
Reactant: O=CO
Product: CCOP(=O)(COCC(CO)On1cnc2c(=O)[nH]c(N)nc21)OCC
Temperature: 20 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A solution of 9-(1-t-butyldimethylsilyloxy-3-diethoxyphosphorylmethoxyprop-2-oxy)-6-chloro-2-formamidopurine (280 mg, 0.51 mmol) in 80% aqueous formic acid (5 ml) was stirred at 120° C. for 3 hours. The acid was evaporated, the residue dissolved in methanol (1 ml) and 0.88 ammonia (1 ml) and stirred for 1 hour at 20° C. After evaporation, the residue was dissolved in hot water (5 ml) and extracted with ether (3×5 ml). The aqueous solution was passed down a reverse-phase silica column eluting with up to 15% methanol affording 9-(1-diethoxyphosphorylmethoxy-3-hydroxyprop-2-oxy)guanine (105 mg, 53%) m.p. 238°-240° C. νmax (KBr) 3380, 1700, 1600, 1380, 1380, 1240, 1030 and 960 cm-1 ; δH [(CD3)2SO] 1.24(6H, t, J7.2 Hz, 2×(CH2CH3 ), 3.61(2H, t, J5.2 Hz, CH2OH), 3.81(2H, d, J4.7 Hz, CH2OCH2P), 3.89(2H. d, J8.0 Hz,CH2P), 4.04 (4H, m, 2×CH2CH3, 4.39(1H, t, J4.7 Hz,CHON), 5.06(1H, t, J6.0 Hz, D2O exchangeable, OH), 6.61(2H, br.s, D2O exchangeable, NH2), 7.86(1H, s, H-8), 10.67(1H, br.s, D2O exchangeable, NH); m/z (FAB+veIon), 392(MH+, 2%), 414(MNa+, 100%). Found: C,39.27; H,5.60; N,17.78%; C13H22N5O7P.0.3H2O requires C,39.36; H,5.74; N,17.66%.
Reaction SMILES: OO.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:14]=[C:13]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)[N:12]=2)=[CH:6][CH:5]=1.C([O-])(O)=[O:36].[Na+]>C(Cl)Cl>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:14]=[C:13]([N:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N+:30]=4[O-:36])[CH2:27][CH2:28]3)[N:12]=2)=[CH:6][CH:5]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(Nc2cc(N3CCCCC3)nc(N3CCN(c4ccccn4)CC3)n2)cc1
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(Nc2cc(N3CCCCC3)nc(N3CCN(c4cccc[n+]4[O-])CC3)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-cholorperbenzoic acid (450 mg, 2.6 mmol), and 30% H2O2 (0.1 mL) in CH2Cl2 (2 mL) was added to a solution of N-(4-methylphenyl)-6-(1-piperidinyl)-2-[4-(2-pyridinyl)-1-piperazinyl]-4-pyrimidinamine (150 mg, 0.300 mmol) in CH2Cl2 at 0° C. The resulting mixture was gradually warmed to room temperature and stirred for 24 h, crude product was treated with saturated NaHCO3 (50 mL) and extracted with EtOAC (3×50 mL). Combined organic layers were washed with brine (2×50 mL), dried over Na2SO4, filtered, concentrated in vacuo, and purified by chromatography on silica using hexane/EtOAc (1:3) to give the desired product.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C@H:3]1[O:8][C:7](=[O:9])[C@@H:6]([CH3:10])[C@@H:5]([CH3:11])[O:4]1.S(=O)(=O)(O)O.[CH3:19]C(O)C>O>[CH3:10][C@@H:6]([C@H:5]([OH:4])[CH3:11])[C:7]([O:8][CH:3]([CH3:19])[CH3:2])=[O:9]
Reactant: C[C@@H]1C(=O)O[C@H](C(Cl)(Cl)Cl)O[C@@H]1C
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)[C@@H](C)[C@@H](C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.0 g of (2R, 5S, 6R)-2-trichloromethyl-5,6-dimethyl-1,3-dioxan-4-one obtained by a procedure similar to Example 1-(4) were added 0.1 ml of concentrated sulfuric acid and 10 ml of 2-propanol, stirred at room temperature for one hour, and 20 ml of water was added followed by ether extraction. The ether phase was dried over anhydrous sodium sulfate and ether was distilled off, and then the residue was subjected to distillation to obtain 0.4 g of isopropyl (2S, 3R)-2-methyl-3-hydroxybutanoate. ##STR54##
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].C(O[C@@H:13]1[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@@H:24]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:14]1[O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)C.C[Si](N[Si](C)(C)C)(C)C.Cl[Sn](Cl)(Cl)Cl>C(#N)C>[C:16]([O:15][C@@H:14]1[C@H:24]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:34]([CH2:36][O:37][C:38](=[O:45])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:35][C@H:13]1[N:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[S:3])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1cc[nH]c(=S)[nH]1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC#N
Product: O=C(OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=S)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 64 %

Procedure:
0.64 g. (5 mmol) of 2-thiouracil, 2.52 g. (5 mmol) of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose were combined in 75 ml. of absolute acetonitrile with 0.65 g. (4 mmol) of HMDS, 0,43 g. (4 mmol) of TCS, and 1.56 g. (6 mmol) of SnCl4 and after 7 hours at 24° C. the mixture was worked up as set forth in Example 1, thus obtaining 64% of crystalline 2-thiouridine tribenzoate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:51])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][C:27]=4[C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:21][CH2:20]3)=[CH:15][C:14]=2[O:41][C:42]2[CH:43]=[C:44]3[CH:50]=[CH:49][NH:48][C:45]3=[N:46][CH:47]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:52]([O-:54])=[O:53].[NH2:55][CH:56]1[CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]1.CCN(C(C)C)C(C)C>O1CCOCC1.C(OCC)(=O)C>[NH:48]1[C:45]2=[N:46][CH:47]=[C:42]([O:41][C:14]3[CH:15]=[C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH2:25][C:26]5[CH2:31][CH2:30][C:29]([CH3:32])([CH3:33])[CH2:28][C:27]=5[C:34]5[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=5)[CH2:23][CH2:24]4)[CH:17]=[CH:18][C:13]=3[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:55][CH:56]4[CH2:57][CH2:58][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:60][CH2:61]4)=[C:3]([N+:52]([O-:54])=[O:53])[CH:4]=3)(=[O:10])=[O:9])=[O:51])[CH:43]=[C:44]2[CH:50]=[CH:49]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(Cl)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCN(C(=O)OC(C)(C)C)CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 82 (800 mg) and tert-butyl 4-aminopiperidine-1-carboxylate (203 mg) in dioxane (10 mL) was added Hunig's Base (1 mL). The mixture was stirred at 120° C. overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with water, brine and dried over Na2SO4. After filtration and evaporation of solvent, the residue was loaded on a silica gel cartridge and eluted with 3% methanol in dichloromethane to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:10]([NH2:12])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]([CH2:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][CH3:20])[N:15]=2)[N:4]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:31][C:32]1[CH:37]=[CH:36][N:35]2[C:38]([C:41](OC)=[O:42])=[CH:39][N:40]=[C:34]2[CH:33]=1>C1COCC1.CO.C(Cl)Cl>[Br:31][C:32]1[CH:37]=[CH:36][N:35]2[C:38]([C:41]([NH:12][C:10]3[CH:9]=[CH:8][CH:7]=[C:6]4[C:11]=3[C:3]([CH2:1][CH3:2])=[N:4][N:5]4[CH2:13][C:14]3[CH:18]=[CH:17][N:16]([CH2:19][CH3:20])[N:15]=3)=[O:42])=[CH:39][N:40]=[C:34]2[CH:33]=1
Reactant: COC(=O)c1cnc2cc(Br)ccn12
Reactant: CCc1nn(Cc2ccn(CC)n2)c2cccc(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CCc1nn(Cc2ccn(CC)n2)c2cccc(NC(=O)c3cnc4cc(Br)ccn34)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
To a solution 3-ethyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-amine (328 mg, 1.22 mmol) in anhydrous THF (3 mL) was added under a nitrogen atmosphere at ambient temperature lithium bis(trimethylsilyl)amide (1.0 M in THF, 1.15 mL). The resulting mixture was stirred at ambient temperature for 10 minutes, then added dropwise to a chilled (ice-water bath) solution of methyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (140 mg, 0.55 mmol) in anhydrous THF (3 mL). The cold bath was removed, and the reaction mixture was allowed to warm to ambient temperature, and quenched with water. The resulting suspension was extracted thoroughly with DCM, the combined organic extracts were dried over anhydrous sodium sulfate, and concentrated to afford the crude product. The crude product was subjected to preparative thin-layer chromatography on silica with 5% MeOH-DCM as eluent to afford 219 mg of desired product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][O:16][CH3:17])[C:9]([F:13])=[C:10](F)[F:11])=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].Cl>O1CCCC1.C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:14][CH2:15][O:16][CH3:17])/[C:9](/[F:13])=[CH:10]\[F:11])=[CH:6][CH:7]=1
Reactant: COCCC(C(F)=C(F)F)c1ccc(Cl)cc1
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: COCCC(/C(F)=C\F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a stirred solution of 1-chloro-4-[2,3,3-trifluoro-1-(2-methoxyethyl)-2-propenyl]benzene (2.25 g, 8.5 mmol) in tetrahydrofuran (56 ml) at −5° C. was added sodium bis(2-methoxyethoxy)aluminum hydride (RedAl, 6.7 ml of a 65% solution in toluene). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to −5° C., and water (6.5 ml) was added dropwise with stirring, followed by 10% hydrochloric acid (30 ml). The resulting mixture was stirred for 45 minutes, diluted with water (50 ml) and extracted with methylene chloride (3×50 ml). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate, and water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound as a brown oil (1.92 g) which was characterized by IR, 1HNMR and mass spectral analysis and used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[CH:19]=[C:18]([O:21][CH3:22])[CH:17]=[CH:16]3)=[CH:12][CH:11]=[C:10]([O:23][CH3:24])[CH:9]=2.[CH:28]([N:31]=[C:32]=[O:33])([CH3:30])[CH3:29].C(N(CC)CC)C>C(Cl)Cl>[CH:28]([NH:31][C:32]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[CH:19]=[C:18]([O:21][CH3:22])[CH:17]=[CH:16]3)=[CH:12][CH:11]=[C:10]([O:23][CH3:24])[CH:9]=2)=[O:33])([CH3:30])[CH3:29]
Reactant: COc1ccc2nc3ccc(OC)cc3c(Nc3cccc(CO)c3)c2c1
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2nc3ccc(OC)cc3c(Nc3cccc(COC(=O)NC(C)C)c3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A mixture of 9-(3'-hydroxymethylanilino)-2,7-dimethoxyacridine, (300 mg, 0.66 mmol), isopropyl isocyanate (1 ml) and triethylamine (2 ml) in methylene chloride (20 ml) is stirred at room temperature for 90 minutes, and then concentrated in vacuo. The residue is chromatographed on a silica gel column using commerical chloroform as the eluent to give the 9-[3'-(isopropylaminocarbonyloxymethyl)-anilino]-2,7-dimethoxyacridine, (246 mg, 84%) as a yellow solid, mp 148°-149° C.
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](O)=[O:48])[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].[CH2:50]([NH2:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.O.ON1C2C=CC=CC=2N=N1>C1COCC1>[CH2:50]([NH:57][C:47]([C:3]1[C:4]([CH3:46])=[CH:5][C:6]2[CH2:23][C@@H:22]([OH:24])[C@:21]3([O:25][CH3:26])[C@@:8]([OH:45])([C:9](=[O:44])[C:10]4[C:19]([C:20]3=[O:27])=[C:18]([OH:28])[C:17]3[C:16](=[O:29])[CH:15]=[C:14]([NH:30][CH:31]5[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]5)[C:13](=[O:43])[C:12]=3[CH:11]=4)[C:7]=2[C:2]=1[OH:1])=[O:48])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: NCc1ccccc1
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: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: 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)NCc6ccccc6)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.7 %

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 (50 mg, 0.073 mmol) in THF (5 mL) was added benzyl amine (15 μL, 0.15 mmol), polystyrene carbodiimide (130 mg, 0.147 mmol, 1.12 mmol/g), and 1-hydroxybenzotriazole hydrate (20 mg, 0.15 mmol). The reaction mixture was stirred at room temperature under nitrogen for 12 h. The reaction was quenched by adding 1N HCl solution (5 mL) and brine (25 mL). The aqueous layer was extracted with methylene chloride (2×50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the crude product. 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) and lyophilized to afford (6R,6aS,14aR)—N-benzyl-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-carboxamide (19 mg, 33%) as a red-brown powder and as a mixture of diastereomers: 1H NMR (500 MHz, CD3OD) δ 8.12 (s, 1H), 7.32-7.21 (m, 5H), 6.61 (s, 1H), 5.99 (s, 1H), 4.96-4.87 (m, 2H), 4.53-4.33 (m, 2H), 3.75 (s, 3H), 3.75-3.72 (m, 1H), 3.64 (s, 2H), 3.57 (s, 3H), 3.47-3.38 (m, 4H), 3.25 (d, J=18.7 Hz, 1H), 3.06 (t, J=9.5 Hz, 1H), 2.19 (s, 3H), 1.27 (d, J=6.5 Hz, 3H); MS (ESI−) m/z 771 (M−H); HPLC >99% (AUC), tR 13.83 min.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[N:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: CC#N
Product: Clc1ccc(-c2cnc3[nH]ccc3n2)cc1
Temperature: 120 °C
Yield: 61.5 %

Procedure:
In a microwave tube containing 2-bromo-5H-pyrrolo[2,3-b]pyrazine (1, 0.165 g, 0.833 mmol), 4-chlorophenylboronic acid (6, 0.118 g, 0.757 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (0.028 g, 0.038 mmol), 1.5 mL of acetonitrile and 1.5 mL of 1.00 M potassium carbonate in water were added. The resulting mixture was heated at 120° C. in the microwave for 10 minutes. The reaction was poured into 1M aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography eluting with 1% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to give the desired compound (7, 107 mg). MS (ESI) [M+H+]+=229.8.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].CN(C1C=CC=CN=1)C.[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32](O)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH:32]1[CH2:31][CH2:30][N:29]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:34][CH2:33]1)=[O:7]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)c1cccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c1
Reaction time: 2 h
Yield: 67.1 %

Procedure:
0.33 g (0.002 mol) of 3-dimethylaminobenzoic acid was dissolved in 10 ml of dimethylformamide, treated with 0.122 g (0.001 mol) of dimethylaminopyridine and 0.383 g (0.002 mol) of 1-benzyl-4-hydroxypiperidine and cooled to 0°. 0.422 g (0.0022 mol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride was added and the mixture was stirred at 0° for a further 2 hrs. Subsequently, the mixture was stirred at room temperature for 3 days, the solvent was distilled off and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.454 g (67%) of 1-benzyl-piperidin-4-yl 3-dimethylamino-benzoate was obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]#[N:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:15])[CH3:16])[C:11]([C:17]#[N:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C#N

Procedure:
The title compound was prepared from (2-amino-4-cyano-5-dimethylamino-phenyl)-carbamic acid tert-butyl ester (Example J23) (276 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (402 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (360 mg, 59%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:19])[C:3]=1[CH2:4][OH:5].[F:20][C:21]1[CH:22]=[C:23](O)[CH:24]=[C:25]([F:28])[C:26]=1[F:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:20][C:21]1[CH:22]=[C:23]([O:5][CH2:4][C:3]2[C:2]([F:1])=[CH:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[F:19])[CH:24]=[C:25]([F:28])[C:26]=1[F:27]
Reactant: Oc1cc(F)c(F)c(F)c1
Reactant: CCCc1ccc(-c2cc(F)c(CO)c(F)c2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1ccc(-c2cc(F)c(COc3cc(F)c(F)c(F)c3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
In a nitrogen atmosphere, 10.00 g of 2,6-difluoro-4-(4-propylphenyl)benzyl alcohol, 5.65 g of 3,4,5-trifluorophenol, and 13.01 g of triphenylphosphine were dissolved in 30 mL of THF, the resultant solution was cooled to −20° C., and 8.48 g of DIAD was added dropwise at such a rate that the inside temperature did not exceed −10° C. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Then, the residue was suspended by adding hexane, and precipitated triphenylphosphine was filtered off. An organic layer was washed with saturated brine and dried by adding sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and then recrystallized from ethanol to yield 11.32 g of (3,4,5-trifluorophenyloxy)-[2,6-difluoro-4-(4-propylphenyl)phenyl]methane.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1.C(OCC)(=O)C>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Cc1ccnc(N)c1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: Cc1ccnc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)c1
Yield: 55.3 %

Procedure:
5.0 gm (0.016 mol) of 4-hydroxy-2-methyl-2H-naphtho[ 2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide were reacted with 2.2 gm (0.02 mol) of 2-amino-4-methylpyridine in 220 ml of xylene analogous to Example 10, and yielded 3.5 gm (58% of theory) of 4-hydroxy-2-methyl-N-(4-methyl-2-pyridyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 221° C (decomp.; from ethyl acetate).