Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1.Cl.Cl[C:15]1[C:16]2[C:23]([CH3:24])=[C:22]([S:25]([NH:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])(=[O:27])=[O:26])[S:21][C:17]=2[N:18]=[CH:19][N:20]=1.O.[OH-].[NH4+]>O1CCOCC1.O>[CH3:34][N:32]([CH3:33])[CH2:31][CH2:30][CH2:29][NH:28][S:25]([C:22]1[S:21][C:17]2[N:18]=[CH:19][N:20]=[C:15]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=3[O:9][CH:10]([CH3:12])[CH3:11])[C:16]=2[C:23]=1[CH3:24])(=[O:27])=[O:26]
Reactant: CC(C)Oc1cc(F)ccc1N
Reactant: Cc1c(S(=O)(=O)NCCCN(C)C)sc2ncnc(Cl)c12
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(S(=O)(=O)NCCCN(C)C)sc2ncnc(Nc3ccc(F)cc3OC(C)C)c12
Temperature: 25 °C
Yield: 28.9 %

Procedure:
4-Fluoro-2-iso-propoxyaniline (0.049 g, 0.28 mmol) and 4-chloro-N-(3-(dimethylamino)propyl)-5-methylthieno[2,3-d]pyrimidine-6-sulfonamide hydrochloride salt (0.1 g, 0.28 mmol) were heated at 70° C. in anhydrous 1,4-dioxane (1.5 mL) for 4 hours. The solution was cooled to ambient temperature and diluted with water (2.0 mL) and adjusted to pH 9 (4:1 water/ammonium hydroxide solution). The precipitate was collected, washed with water and diethyl ether to yield the title compound as beige solid (0.039 g, 28%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([F:9])=[CH:6][C:7]=1[NH2:8].O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl.[OH-].[Na+]>[F:9][C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][C:4]=1[C:10]([F:13])([F:11])[F:12])[NH:1][C:17](=[O:18])[C:16](=[O:20])[NH:8]2
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(F)c(C(F)(F)F)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2cc(F)c(C(F)(F)F)cc2[nH]c1=O
Temperature: 25 °C
Yield: 40.3 %

Procedure:
A mixture of 3,4-diamino-6-fluorobenzotrifluoride (270 mg, 1.38 mmol) and oxalic acid dihydrate (200 mg, 1.60 mmol, used as received) in 4N HCl (5 mL) was refluxed at 120°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed twice with cold water (2×2 mL), collected by filtration, and dried at 60° C. under reduced pressure for 2 h, affording 152 mg of crude title compound (40%) as a light yellow powder. The crude compound was dissolved in 1N NaOH (4 mL) and filtered. The filtrate was acidified to pH=5, affording 138 mg of title compound as a yellow powder. Mp: 330°-333° C. IR (KBr, cm-1) 3398, 3170, 2959, 1701, 1641, 1515; 1398. 1H NMR (DMSO-d6): δ7.079 (d, 1H, J=11.4 Hz); 7.376 (d, 1H, J=5.1 Hz); 12.022 (s, 1H); 12.225 (s, 1H). HRMS: calcd for C9H4F4N2O2 (M+) m/z: 248.0208; found: 248.0220.
Reaction SMILES: COCC(O)C.Cl[C:8]1[N:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[C:10](Cl)[C:9]=1[Cl:17].[OH-].[NH4+]>O.C1(C)C=CC=CC=1.[Zn]>[Cl:14][C:12]1[C:11]([Cl:15])=[CH:10][C:9]([Cl:17])=[CH:8][N:13]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: COCC(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1cnc(Cl)c(Cl)c1
Yield: 164.4 %

Procedure:
To a 500 milliliter, 3-neck flask which was fitted with a reflux condenser, thermometer, stirrer and heater was added 100 milliliters of 1-methoxy-2-propanol, 25.1 grams (0.10 mole) of pentachloropyridine and 39.0 grams (0.60 gram atom) of zinc dust. The flask was heated, with stirring, to 90° C. until all the pentachloropyridine was dissolved. At this time, 100 milliliters of concentrated ammonium hydroxide was added over a 5 hour period. The pH of the mixture was ~12. The mixture was refluxed for 32 hours and the reaction mixture was diluted with two volumes of water and 100 milliliters of toluene. The mixture was filtered to remove insolubles. The toluene was removed by fractionation leaving 30.0 grams of crude 2,3,5-trichloropyridine as an amber-colored oil. Analysis by gas-liquid chromatography showed a yield of 2.1 grams of the desired product (12 percent of theoretical).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[N:31]=[C:30]([C:32](O)=[O:33])[CH:29]=[CH:28][N:27]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:32]([C:30]5[CH:29]=[CH:28][N:27]=[C:26]([C:25]([F:36])([F:24])[F:35])[N:31]=5)=[O:33])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1ccnc(C(F)(F)F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccnc(C(F)(F)F)n1
Yield: 54.9 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol), 2-(trifluoromethyl)pyrimidine-4-carboxylic acid (150 mg, 0.83 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (100 mg, 0.53 mmol), 1-hydroxybenzotriazole (72 mg, 0.53=mol) and N,N-dimethylformamide (6.0 mL) as starting materials and in the same manner as in Example 318, the title compound (130 mg, 54%) was obtained as a white powder.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:42]=[C:43]1[CH2:47][CH2:46][CH2:45][N:44]1[CH2:48][CH2:49][O:50][C:51](=[O:72])[C@@:52]([CH2:70][OH:71])([CH3:69])[CH2:53][C@H:54]([NH2:68])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[CH:58][CH:57]=1>CN(C=O)C>[O:42]=[C:43]1[CH2:47][CH2:46][CH2:45][N:44]1[CH2:48][CH2:49][O:50][C:51](=[O:72])[C@@:52]([CH2:70][OH:71])([CH3:69])[CH2:53][C@H:54]([NH:68][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:55][C:56]1[CH:57]=[CH:58][C:59]([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)=[CH:60][CH:61]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCCN1CCCC1=O
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)OCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 20.2 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-(2-oxo-pyrrolidin-1-yl)-ethyl ester (52.6 mg, 124 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (13 mg; purity 95%). MS m/z [M+H]+ calc'd for C28H33N5O5, 520.25. found 520.4.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:18])[CH:11]([F:25])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[Si:35](OS(C(F)(F)F)(=O)=O)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].O>ClCCl>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:18][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:11]([F:25])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: OC(COC1CCC(OCc2ccccc2)CC1F)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC(COC1CCC(OCc2ccccc2)CC1F)c1ccccc1
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
To a solution of 2-{[4-(Benzyloxy)-2-fluorocyclohexyl]oxy}-1-phenylethanol (8.46 g, 24.6 mmol) in dichloromethane (100 mL) at 0° C. was added diisopropylethylamine (17.1 mL, 98.8 mmol) and TBSOTf (13.0 mL, 49.4 mmol). The reaction mixture was stirred for 5 min and then poured into water. The layers were separated and the aqueous extracted with dichloromethane (3×). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (5% ethyl acetate in hexanes) gave (2-{[4-(Benzyloxy)-2-fluorocyclohexyl]oxy}-1-phenylethoxy)(tert-butyl)dimethylsilane (11.3 g, 100% yield) as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[C:3]=1[C:11]1[C:12](=[O:32])[NH:13][C:14](=[O:31])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:17]=1.C(N(CC)CC)C.[N:40]1[CH:45]=[CH:44][N:43]=[CH:42][C:41]=1[C:46](O)=[O:47].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[C:3]=1[C:11]1[C:12](=[O:32])[NH:13][C:14](=[O:31])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH:25]2[CH2:26][CH2:27][N:28]([C:46]([C:41]3[CH:42]=[N:43][CH:44]=[CH:45][N:40]=3)=[O:47])[CH2:29][CH2:30]2)[CH:17]=1
Reactant: O=C(O)c1cnccn1
Reactant: O=C1NC(=O)C(c2cn(C3CCNCC3)c3ccccc23)=C1c1c(F)ccc2c1OCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C(c2cn(C3CCN(C(=O)c4cnccn4)CC3)c3ccccc23)=C1c1c(F)ccc2c1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.5 %

Procedure:
Mix 3-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-[1-(piperidin-4-yl]-1H-indol-3-yl)pyrrole-2,5-dione (180 mg, 0.42 mmol) in dimethylformamide with triethyl amine (0.2 mL, 1.4 mmol), 2-pyrazinecarboxylic acid (57 mg, 0.46 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimid hydrochloride (106 mg, 0.55 mmol), and 1-hydroxybenzotriazole (74 mg, 0.55 mmol). Stir the reaction mixture at ambient temperature for 18 hours. Dilute with ethyl acetate, and wash the organic layer with water/brine (×4). Dry over magnesium sulfate and concentrate. Purify by chromatography (silica gel; hexane/EtOAc; 1:1 to 0:1) to give an orange solid (105 mg, 49%). MS (MSI) m/z 538 (M+H)+.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:16])[CH:14]=[CH2:15].[Cl:17][CH2:18][CH2:19][N:20]=[C:21]=[O:22]>>[Cl:17][CH2:18][CH2:19][NH:20][C:21]([N:16]([CH2:13][CH:14]=[CH2:15])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:22]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: C=CCN
Reactant: O=C=NCCCl
Product: C=CCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 66.3 %

Procedure:
3.6 g of D-galactose, 1.5 g of 2-propenylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 4.3 g of 1-(2-chloroethyl)-3-(2-propenyl)-3-D-galactopyranosylurea are obtained as colorless caramel. IRνmaxnujol (cm-1): 3400, 1640, 1535, 1070
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=[O:5])C.CO.C1COCC1.CO.[N+:37]([C:40]1[NH:41][CH:42]=[C:43]([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][C:48](=[O:52])[CH2:47]2)[N:44]=1)([O-])=O>[Ni].C(Cl)Cl.CO>[O:52]=[C:48]1[NH:49][CH2:50][CH2:51][N:46]([CH2:45][C:43]2[N:44]=[C:40]([NH:37][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:5])[NH:41][CH:42]=2)[CH2:47]1
Reactant: O=C1CN(Cc2c[nH]c([N+](=O)[O-])n2)CCN1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Agent: [Ni]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nc(CN4CCNC(=O)C4)c[nH]3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, and 4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazin-2-one (Step 142.1) instead of 2-nitroimidazole in Step 14.3. Title compound: ESI-MS: 540.0 [M+H]+; tR=3.18 min (System 1); TLC: Rf=0.18 (DCM/MeOH, 9:1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:31]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4([NH:42]C(=O)OC(C)(C)C)[CH2:41][CH2:40][CH2:39]4)=[CH:34][CH:33]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[Cl:57]CCl>>[ClH:57].[NH2:42][C:38]1([C:35]2[CH:34]=[CH:33][C:32]([N:31]3[C:11]4=[N:12][C:13]([C:16]5[CH:17]=[C:18]([NH:22][C:23]([CH:25]6[CH2:30][CH2:29][O:28][CH2:27][CH2:26]6)=[O:24])[CH:19]=[CH:20][CH:21]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:37][CH:36]=2)[CH2:39][CH2:40][CH2:41]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(NC(=O)C6CCOCC6)c5)nc43)cc2)CCC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Nc1ncccc1-c1nc2ccc(-c3cccc(NC(=O)C4CCOCC4)c3)nc2n1-c1ccc(C2(N)CCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[(tetrahydro-2H-pyran-4-ylcarbonyl)amino]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (29 mg) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL) dropwise at room temperature. After being stirred at the same temperature for 1 h, the reaction mixture was concentrated under reduced pressure. Dichloromethane (5 mL) and MP-carbonate (Argonaout technologies 2.91 mmol/g, 400 mg) were added. The mixture was stayed for 30 min. with occasional shaking then filtered. The filtrate was concentrated under reduced pressure. To a solution of the residue in dichloromethane (5 mL) and methanol (0.4 mL) was added hydrogen chloride in ethyl acetate (4 M, 0.055 mL) at room temperature. After being stirred for 10 min., the mixture was concentrated under reduced pressure. The resulting solid was suspended with ethyl acetate and filtered to give the product (19 mg).
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:19])[N:11]([CH3:18])[C:12](=[O:17])[N:13]([CH3:16])[C:14]=1[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20]Br>C(Cl)(Cl)Cl>[C:1]([C:9]1[C:10](=[O:19])[N:11]([CH3:18])[C:12](=[O:17])[N:13]([CH3:16])[C:14]=1[CH2:15][Br:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: Cc1c(C(=O)c2ccccc2)c(=O)n(C)c(=O)n1C
Solvent: ClC(Cl)Cl
Product: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 57.6 %

Procedure:
(See, e.g., Tsupak et al., Khimiya Geterotsiklicheskikh Soedinenii. 7:1096-1102 (2003); Tsupak et al., Russ. Chem. Bull. 55:2265-2270 (2006)). To a solution of 3 (2.61 g, 10.1 mmol) in chloroform (13 mL) was added bromine (1.62 g, 0.52 mL, 20.3 mmol in 3 mL chloroform) dropwise over 30 min at room temperature. The reaction mixture was further stirred for 1 min at room temperature before concentrated in vacuo. The crude reaction mixture was purified by flash chromatography to yield 4 (1.96 g, 57%); mp 164-167° C.; MS (ES+) (m/z): [M+1]+ calculated for C14H14BrN2O3, 338.18. found 337.15, 338.93. This compound matched analytical data as reported (see, e.g., Tsupak et al., Khimiya Geterotsiklicheskikh Soedinenii., supra; Tsupak et al., Russ. Chem. Bull., supra).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[N+:14]([O-])([O:16]C(=O)C)=[O:15].[N+]([O-])(O)=O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(=O)O[N+](=O)[O-]
Reactant: Cc1cc(Cl)n(-c2ccccc2)n1
Solvent: CC(=O)OC(C)=O
Solvent: O=[N+]([O-])O
Product: Cc1nn(-c2ccccc2)c(Cl)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of 9.6 g (0.05 mole) of 5-chloro-3-methyl-1-phenylpyrazole and 25 ml of acetic anhydride was added at 10°C to a solution of acetyl nitrate prepared from 25 ml of 90% nitric acid and 10 ml of acetic anhydride. The solution was stirred 2 hours at 20°-30°C and carefully poured onto ice water. The solid was filtered off and washed with cold water. One recrystallization from ethanol gave long white needles of product.
Reaction SMILES: N1C(C)=CC=CC=1C.O[C:10]1[C:11]2[C:16]([C:17]([O:25][CH3:26])=[C:18]3[C:23]=1[C:22](=[O:24])[CH2:21][CH2:20][CH2:19]3)=[CH:15][C:14]([CH3:27])=[C:13](/[CH:28]=C/C)[C:12]=2[O:31][CH2:32][O:33][CH3:34].I([O-])(=O)(=O)=[O:36].[Na+].[OH2:41]>O1CCCC1>[OH:41][C:10]1[C:23]2[C:22](=[O:24])[CH2:21][CH2:20][CH2:19][C:18]=2[C:17]([O:25][CH3:26])=[C:16]2[C:11]=1[C:12]([O:31][CH2:32][O:33][CH3:34])=[C:13]([CH:28]=[O:36])[C:14]([CH3:27])=[CH:15]2
Reactant: O
Reactant: C/C=C/c1c(C)cc2c(OC)c3c(c(O)c2c1OCOC)C(=O)CCC3
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: COCOc1c(C=O)c(C)cc2c(OC)c3c(c(O)c12)C(=O)CCC3
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
2,6-Lutidine (130 μL, 1.12 mmol, 2.0 equiv) was added to an ice-cooled mixture of (E)-9-hydroxy-10-methoxy-8-(methoxymethoxy)-6-methyl-7-(prop-1-enyl)-3,4-dihydroanthracen-1-one (200 mg, 0.56 mmol, 1 equiv), potassium osmate dihydrate (10 mg, 0.028 mmol, 0.05 equiv), and sodium periodate (480 mg, 2.24 mmol, 4.0 equiv) in a mixture of tetrahydrofuran (10 mL) and water (5 mL). After 10 min, the cooling bath was removed and the reaction flask was allowed to warm to 23° C. After 2.5 h, the reaction mixture was partitioned between water (50 mL) and ethyl acetate (100 mL). The layers were separated. The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography (15% ethyl acetate-hexanes initially, grading to 20% ethyl acetate-hexanes) to provide 142 mg of the product, 9-hydroxy-10-methoxy-1-(methoxymethoxy)-3-methyl-8-oxo-5,6,7,8-tetrahydroanthracene-2-carbaldehyde, as an orange foam (74%). 1H NMR (500 MHz, CDCl3): 15.10 (s, 1H), 10.72 (s, 1H), 7.59 (s, 1H), 5.26 (s, 2H), 3.81 (s, 3H), 3.62 (s, 3H), 3.08 (t, 2H, J=6.6 Hz), 2.77 (t, 2H, J=6.6 Hz), 2.73 (s, 3H), 2.12 (m, 2H). 13C NMR (125 MHz, CDCl3): 205.1, 193.2, 163.4, 161.7, 143.1, 141.6, 137.0, 132.4, 126.8, 120.0, 116.4, 111.4, 102.8, 61.1, 58.3, 38.8, 23.7, 22.3, 21.9. FTIR, cm−1: (thin film) 2959 (m), 1674 (m), 1610 (s), 1560 (m), 1375 (s), 1246 (s), 1153 (m), 1038 (s), 1015 (s), 900 (s). HRMS (ESI): Calcd for (C19H20O6+H)+ 345.1333; Found 345.1329. TLC: (20% ethyl acetate-hexanes) Rf=0.22 (CAM).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:37]1([CH3:49])[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[C:38]=1[S:45](Cl)(=[O:47])=[O:46].[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[CH3:49][C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[C:38]=1[S:45]([N:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:14][CH:13]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)(=[O:46])=[O:47]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: c1ccc(OC2CCCCO2)c(CNc2ccc(OCCN3CCCC3)cc2)c1
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccccc2OC2CCCCO2)c2ccc(OCCN3CCCC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.5 %

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[2-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.060 g, 0.19 mmol) in 0.4 mL methylene chloride was added triethylamine (0.06 mL, 0.43 mmol) and 2-mesitylene sulfonyl chloride (0.066 g, 0.30 mmol). The reaction mixture was stirred at room temperature for 24 hr. PS-isocyanate resin (0.050 g), PS-trisamine resin (0.050 g), and 1.5 mL methylene chloride were added and the mixture was stirred for 2 hr. at room temperature. The resin was filtered off with the aid of methylene chloride. The filtrate was concentrated. The residue was purified by preparative TLC (1.0 mm silica gel layer, eluting with 10% methanol/methylene chloride) to afford the title compound of Step A (0.039 g). MS 579.3 (M+1)+
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH3:21])[C:10]([NH:12][N:13]1[C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=[CH:14]1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CCO.O>[CH2:1]([O:8][CH:9]([C:10]1[NH:20][C:18](=[O:19])[C:17]2=[CH:16][N:15]=[CH:14][N:13]2[N:12]=1)[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OCc1ccccc1)C(=O)Nn1cncc1C(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(OCc1ccccc1)c1nn2cncc2c(=O)[nH]1
Temperature: 100 °C
Yield: 75.4 %

Procedure:
To a solution of compound 10 (1.5 g, 5.2 mmol) in EtOH (10 mL) was added a solution of KOH (870 mg, 15.6 mmol) in H2O (4 mL). Then the resulting mixture was heated at 100° C. under microwave heating for one hour. After removal of the solvent, the mixture was poured into ice water and pH was adjusted to 7 with 1M aqueous HCl solution. The suspension was filtered and the solid was dried to give compound 11 (1.06 g, 75% yield) as a white solid. LC-MS: m/z 271 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.70 (br. s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.39˜7.32 (m, 5H), 4.60 (m, 2H), 4.46 (q, J=6.4 Hz, 1H), 1.57 (d, J=6.4 Hz, 3H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:21]([O:20][C:14](=[O:19])[CH2:15][CH:16]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)[CH3:18])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC(C)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A solution of tert-butyl piperazine-1-carboxylate (1 g, 5.37 mmol), ethyl acetoacetate (883 μl, 6.98 mmol) in DCM (30 ml) was stirred for 30 min at rt under nitrogen, then (2.4 g, 10.74 mmol) NaBH(OAc)3 was added. The reaction mixture was stirred at rt overnight, quenched by addition of water, stirred for 15 min and slowly diluted with a saturated aqueous solution of sodium bicarbonate (pH around 8-9). The reaction mixture was shaken for 1 h. After separation, the aqueous layer was extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (Snap 50 g cartridge, MeOH/DCM: 0/100 to 5/95 over 20 CV, not UV active) to afford the desired product 513 (1.03 g, 3.43 mmol, 63% yield) as a colorless sticky oil. MS (m/z): 301.4 (M+H).