Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:12])[NH:6][C:5]2=[O:13].[Cl:14][C:15]1[C:20]([CH:21]=O)=[C:19]([O:23][CH3:24])[N:18]=[CH:17][CH:16]=1>CO.CC(O)=O.O>[Cl:14][C:15]1[CH:16]=[CH:17][N:18]=[C:19]([O:23][CH3:24])[C:20]=1[C:21]1[NH:11][C:10]2=[CH:9][C:8]3[C:7](=[O:12])[NH:6][C:5](=[O:13])[C:4]=3[CH:3]=[C:2]2[N:1]=1
Reactant: COc1nccc(Cl)c1C=O
Reactant: Nc1cc2c(cc1N)C(=O)NC2=O
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1nccc(Cl)c1-c1nc2cc3c(cc2[nH]1)C(=O)NC3=O
Reaction time: 8 h
Yield: 87.5 %

Procedure:
5,6-Diaminoisoindoline-1,3-dione (2.88 g, 16.26 mmol) and 4-chloro-2-methoxynicotinaldehyde (2.79 g, 16.26 mmol) were suspended in MeOH/HOAc (200 mL, 3/1 v/v) at rt under air. The reaction mixture was stirred under air overnight and diluted with 200 mL of water. The solid was filtered, washed with acetone and recrystallized from hot EtOAc to give a pale-yellow solid product, 4.67 g, 87.5% yield. MS: 329.0 [M+H]+. 1H NMR (DMSO-d6, 500 MHz): δ 13.23 (s, 1H), 8.36 (d, 1H, J=5.5 Hz), 8.02 (S, 2H), 7.39 (d, 1H, J=6.0 Hz), 3.89 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:7]([CH3:16])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][O:19]1>>[CH3:1][NH:2][S:3]([C:6]1[C:7]([CH3:16])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:26]1[NH:25][CH:24]=[C:23]2[C:18](=[O:17])[O:19][CH2:20][CH2:21][C:22]=12)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1C)CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: CNS(=O)(=O)c1ccc2c(c1C)C(=Cc1[nH]cc3c1CCOC3=O)C(=O)N2
Yield: 96.4 %

Procedure:
4-Methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (0.2 g, 0.83 mmol) was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde (1.2 eq, 0.17 g) to give 0.31 g (97%) of the title compound as a yellow solid.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.[ClH:36]>O1CCCC1.ClCCl>[ClH:36].[OH:1][C@H:2]([CH2:3][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@H]2CO2)c1
Reactant: C1CCNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@H](O)CN2CCCC2)c1
Temperature: 45 °C
Yield: 83.1 %

Procedure:
To (S)-1-(1-(oxiran-2-ylmethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)-pyridin-2(1H)-one (200 mg, 0.48 mmol) in tetrahydrofuran (5 mL) was added LiClO4 (775 mg, 7.28 mmol) followed by pyrrolidine (0.41 mL, 4.9 mmol). The reaction mixture was heated in a 45° C. oil bath for 4.5 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml), washed with water (25 mL) and brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The material was purified by column chromatography (silica gel, 9:1 CH2Cl2/MeOH to 90:9:1 CH2Cl2/MeOH/conc. NH4OH). The dried residue (197 mg, 0.41 mmol) was dissolved in dichloromethane (10 mL) and HCl (1.25 M solution in methanol, 0.36 mL, 0.45 mmol) was added. The mixture was concentrated under reduced pressure and dried to afford the title compound (194 mg, 78%) as a yellow solid: mp 116-119° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.65 (br s, 1H), 8.21 (s, 1H), 8.02-8.00 (m, 2H), 7.89-7.82 (m, 5H), 7.47 (dd, J=9.0, 2.0 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.74 (dd, J=7.0, 2.0 Hz, 1H), 5.75 (br s, 1H), 4.57-4.47 (m, 2H), 4.33 (br s, 1H), 3.56-2.90 (br m, 6H), 1.89 (br s, 4H); ESI MS m/z 483 [M+H]+; HPLC (Method B)>99% (AUC), tR=14.5 min; [α]23D +10.8° (c 0.11, Methanol).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:6]([CH2:7][CH:8]=[C:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@@:10]3([CH2:32][CH3:33])[C:11](=[O:31])[CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5]1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].[Na+].[Cl-].C(O[C@H]1CC[C@@]2(C)[C@@H](CC=C3[C@@H]2CC[C@@]2(C)[C@@]3(CC)[C@@H](O)C[C@@H]2[C@H](C)CCCC(C)C)C1)C>CCOCC>[CH2:1]([O:3][C@H:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:6]([CH2:7][CH:8]=[C:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@@:10]3([CH2:32][CH3:33])[C@H:11]([OH:31])[CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:5]1)[CH3:2]
Reactant: CCO[C@H]1CC[C@@]2(C)[C@@H](CC=C3[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC(=O)[C@@]32CC)C1
Agent: CCO[C@H]1CC[C@@]2(C)[C@@H](CC=C3[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)C[C@H](O)[C@@]32CC)C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCO[C@H]1CC[C@@]2(C)[C@@H](CC=C3[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)C[C@@H](O)[C@@]32CC)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To 3β-ethoxy-14α-ethyl-5α-cholest-7-en-15-one (1.0 g; 2.19 mmol) in ether (100 ml) was added lithium aluminum hydride (2.0 g; 52.7 mmol). After stirring for 2 hours at room temperature, the reaction mixture was cooled to 0° C. and ice was cautiously added to decompose the unreacted hydride. The resulting mixture was poured into a 0.35 M NaCl solution and extracted thoroughly with ether containing methylene chloride (5%). The combined extracts were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting residue (0.97 g) was crystallized from acetone-water to give a mixture (0.94 g; 94% yield) of 3β-ethoxy-14α-ethyl-5α-cholest-7-en-15β-ol and 3β-ethoxy-14α-ethyl-5α-cholest-7-en-15α-ol. The following structures for the compounds were shown by i.r., n.m.r., and m.s. analyses: ##STR38##
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[CH:43]1[O:55][C@@H:54]([CH2:56][O:57][C:58](=[O:60])[CH3:59])[C@H:49]([O:50][C:51](=[O:53])[CH3:52])[C@@H:44]1[O:45][C:46](=[O:48])[CH3:47])(=O)C>ClCCCl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@H:43]3[O:55][C@@H:54]([CH2:56][O:57][C:58](=[O:60])[CH3:59])[C@H:49]([O:50][C:51](=[O:53])[CH3:52])[C@@H:44]3[O:45][C:46](=[O:48])[CH3:47])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@@H]1OC(OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)Nc1nc2c(Cl)cccc2[nH]1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Product: CC(=O)OC[C@@H]1O[C@H](n2c(NC(C)C)nc3c(Cl)cccc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 46.8 %

Procedure:
4-Chloro-2-(isopropylamino)-1H -benzimidazole (2.24 g, 10.68 mmol), N,O-bis(trimethylsilyl)acetamide (3.00 mL, 2.47 g, 12.14 mmol), trimethylsilyl trifluoromethanesulfonate (1.2 mL, 1.42 g, 6.00 mmol), 1,2,3,5-tetra-O-acetyl-L-ribofuranose (4.46 g, 14.01 mmol) and 1,2-dichloroethane (35 mL) were used according to general procedure II. The product was purified by silica gel chromatography using 95:5 dichloromethane/acetonitrile to afford 2.34 g (47%) of an off-white foam. MS (EI): m/z 46.82 (M+H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:46][C:47]([F:50])([F:49])[F:48])(=O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH:34]5[CH2:39][CH2:38][N:37]([CH2:46][C:47]([F:50])([F:49])[F:48])[CH2:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC1CCNCC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC1CCN(CC(F)(F)F)CC1
Yield: 11 %

Procedure:
The title compound was prepared as described in Example 103C, using 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-yloxy]phenyl}urea (0.213 g, 0.4 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.139 g, 0.6 mmol), and N,N-diisopropylethylamine (0.5 mL) in CH2Cl2 (10 mL) at room temperature for 4 hours, which was purified by silica gel chromatography with EtOAc/hexane as eluants and preparative HPLC (C18 column and 60-90% MeCN/H2O with 0.05% AcOH) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-{6-methoxy-7-[1-(2,2,2-trifluoroethyl)piperidin-4-yloxy]quinazolin-4-yloxy}phenyl)urea as a solid (0.027 g, 11%). 1H NMR (300 MHz, CDCl3) δ 9.42 (s, 1H), 8.61 (s, 1H), 7.66 (t, 1H), 7.59 (m, 1H), 7.55 (s, 1H), 7.40 (t, 1H), 7.31 (m, 2H), 7.02 (d, 1H), 5.83 (s, 1H), 4.60 (m, 1H), 4.04 (s, 3H), 3.04 (q, 2H), 3.00 (m, 2H), 2.67 (m, 2H), 2.15 (m, 2H), 2.02 (m, 2H), 1.33 (s, 9H); LC-MS (ESI) m/z 615 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[C:26]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[CH2:21][CH:13]([CH2:12][NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH2:14]2)(=[O:28])[CH3:27]
Reactant: O=S(=O)(NCC1Cc2ccccc2C1)c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
369 mg (1.15 mmol) of 2-[(4-chlorophenyl)sulfonylaminomethyl)indan was dissolved in 5 ml of methylene chloride, to which were added 460 mg (4.20 mmol) of anhydrous aluminum chloride under ice-cooling and then 302 mg (3.80 mmol) of acetyl chloride dropwise. After stirring for 30 minutes at the same temperature, the reaction solution was admixed with ice, and the organic phase was washed with water and saturated-aqueous sodium bicarbonate, dried and the solvent was removed. The residue was recrystallized from a solvent mixture of ethyl acetate and isopropylether to obtain 310 mg of colorless crystals. Yield: 75%
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:9])([CH3:6])[CH3:5].O.O[Li].O>CO>[Cl:28][C:25]1[CH:24]=[CH:23][C:22](/[CH:21]=[CH:20]/[C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:29])=[O:2])=[O:9])=[CH:27][CH:26]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1/C=C/c1ccc(Cl)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(NC(=O)c1ccc2ccccc2c1/C=C/c1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.4 %

Procedure:
38 mg 2-({1-[(E)-2-(4-chloro-phenyl)-vinyl]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid methyl ester were dissolved in 3 ml of MeOH and 1 ml of water was added. After addition of 5 mg of LiOH.H2O the reaction was stirred at room temperature for 14 h. Filtration of the crude mixture, RP-HPLC and freeze-drying gave 35 mg of 2-({1-[(E)-2-(4-Chloro-phenyl)-vinyl]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid (96%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])=[O:20])[CH2:16][CH2:17]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reactant: Nc1ccccc1O
Product: O=C(N[C@H]1CC[C@H](C(=O)Nc2ccccc2O)CC1)OCc1ccccc1

Procedure:
By treating trans-4-(benzyloxycarbonylamino)cyclohexanecarboxylic acid and 2-aminophenol in the same manner as in Reference Example 8-40, trans-4-benzyloxycarbonylamino-N-(2-hydroxyphenyl)cyclohexanecarboxamide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[C:4]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:3]=1>CCOC(C)=O.CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[C:4]([NH:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:3]=1
Reactant: CC(C)(O)CNS(=O)(=O)c1ccc(C=CC(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(O)CNS(=O)(=O)c1ccc(CCC(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 4-[3-(4-chloro-2-phenylaminophenyl)-3-oxo-propenyl]-N-(2-hydroxy-2-methylpropyl)-benzene sulfonamide (0.535 g) in EtOAc (100 mL) and EtOH (50 mL) was added Pt(IV)O2, and the mixture stirred under H2 for 1.5 h. The product was filtered and concentrated under reduced pressure to provide 4-[3-(4-chloro-2-phenylaminophenyl)-3-oxo-propyl]-N-(2-hydroxy-2-methylpropyl)-benzene sulfonamide as a yellow oily solid.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][CH:21]=[N:20][C:19]=2[CH3:23])=[CH:14][C:13]=1[F:24].[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.CCOCC>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([Cl:25])=[N:20][C:19]=2[CH3:23])=[CH:14][C:13]=1[F:24]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ncoc1-c1ccc(Br)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nc(Cl)oc1-c1ccc(Br)c(F)c1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
LiHMDS (1 M in THF, 4.4 mL, 4.4 mmol) was added dropwise via syringe to a solution of Example 29A (1.03 g, 4.02 mmol) in THF (20 mL) at −78° C. After 30 min solid hexachloroethane (1.90 g, 8.04 mmol) was added in one portion and the reaction mixture was allowed to gradually warm to ambient temperature over 16 hr. The reaction was diluted with Et2O and quenched with half-saturated aqueous NH4Cl solution. The separated aqueous phase was extracted with Et2O, and the combined organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (Analogix® Intelliflash 280™; 0% to 15% EtOAc/hexanes eluant; SF25-120 g column) afforded 1.07 g (92%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.84 (dd, J=8.4, 7.4 1H), 7.57 (dd, J=9.9, 2.0 1H), 7.39 (dd, J=8.5, 2.0 1H), 2.36 (s, 3H). MS (DCI+) m/z 290/292 (M+H).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]([CH3:22])[C:20]#[N:21])[CH:15]=[CH:16][C:17]=1[OH:18]>N1C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]([CH3:22])[C:20]#[N:21])[CH:15]=[CH:16][C:17]=2[OH:18])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C#N)c1ccc(O)c(N)c1
Solvent: c1ccncc1
Product: CC(C#N)c1ccc(O)c(NC(=O)Cc2ccccc2)c1
Temperature: 100 °C

Procedure:
Phenyl acetyl chloride (28.0 g.) was added over 20 minutes to a cooled stirred solution of 2-(3-amino-4-hydroxyphenyl) propionitrile (29.0 g.) in anhydrous pyridine (200 ml.) at 0°-3° C. After addition was complete, the mixture was heated at 100° C. for 1 hour. After evaporation under reduced pressure, 2-(3-phenylacetamido-4-hydroxyphenyl)propionitrile was isolated as an oil.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH3:13])[C:10](=[O:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].OC(C)C(=O)C.[Si](Cl)(C(C)(C)C)(C)C.N1C=CN=C1.[CH2:33]([O:40][C:41]1[CH:42]=[C:43]([Mg]Br)[CH:44]=[C:45]([F:47])[CH:46]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.BrC1C=C(OCC2C=CC=CC=2)C=C(F)C=1.[Mg]>C(OCC)C.O1CCCC1>[CH2:33]([O:40][C:41]1[CH:42]=[C:43]([C:10]([OH:12])([CH:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2])[CH3:13])[CH3:11])[CH:44]=[C:45]([F:47])[CH:46]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Fc1cc(OCc2ccccc2)cc([Mg]Br)c1
Reactant: CC(=O)C(C)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)C(C)O
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: Fc1cc(Br)cc(OCc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O[Si](C)(C)C(C)(C)C)C(C)(O)c1cc(F)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41 %

Procedure:
A solution of 3-tert-butyldimethylsilyloxybutan-2-one (5.56 g; prepared by reacting 3-hydroxybutan-2-one with tert-butyldimethylsilyl chloride in diethyl ether and using imidazole as a suitable base) in tetrahydrofuran (5 ml) was added to a solution of 3-benzyloxy-5-fluorophenylmagnesium bromide [prepared by heating a mixture of benzyl 3-bromo-5-fluorophenyl ether (6.7 g), magnesium powder (0.58 g) and tetrahydrofuran (50 ml) to 40° C. for 1 hour] in tetrahydrofuran (50 ml) and the mixture was stirred at ambient temperature for 2.5 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 3:2 v/v mixture of petroleum ether (b.p. 40°-60° C.) and methylene chloride as eluent. There was thus obtained an erythro isomer, (2RS,3SR)-2-(3-benzyloxy-5-fluorophenyl)-3-(tert-butyldimethylsilyloxy)butan-2-ol (3.8 g, 41%), as an oil; and a threo isomer, the corresponding (2RS,3RS)-isomer (1.73 g, 18%), as an oil.
Reaction SMILES: Br[CH:2]1[CH2:19][CH:18]([OH:20])[CH2:17][C:16]2[C:15]([OH:21])=[C:14]3[C:5]([C:6](=[O:29])[C:7]4[CH:8]=[CH:9][CH:10]([CH2:27][CH3:28])[C:11]5([O:26][CH2:25][CH2:24][O:23]5)[C:12]=4[C:13]3=[O:22])=[C:4]([OH:30])[C:3]1=2.[CH2:31]([CH2:33][NH2:34])[OH:32]>>[OH:32][CH2:31][CH2:33][NH:34][CH:2]1[CH2:19][CH:18]([OH:20])[CH2:17][C:16]2[C:15]([OH:21])=[C:14]3[C:5]([C:6](=[O:29])[C:7]4[CH:8]=[CH:9][CH:10]([CH2:27][CH3:28])[C:11]5([O:26][CH2:25][CH2:24][O:23]5)[C:12]=4[C:13]3=[O:22])=[C:4]([OH:30])[C:3]1=2
Reactant: NCCO
Reactant: CCC1C=CC2=C(C(=O)c3c(O)c4c(c(O)c3C2=O)C(Br)CC(O)C4)C12OCCO2
Product: CCC1C=CC2=C(C(=O)c3c(O)c4c(c(O)c3C2=O)C(NCCO)CC(O)C4)C12OCCO2

Procedure:
In the same manner as in Example 1 (2), 7-bromo-9-(1,1-ethylenedioxy)ethyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (1.0 g) prepared in Example 1 (1) and ethanolamine (20 ml) were subjected to reaction to give 7-(2-hydroxyethyl)amino-9-(1,1-ethylenedioxy)ethyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione as orange crystals. M.P., 190° C. (decomp.).
Reaction SMILES: CS(O[CH2:6][C:7]1([F:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)(=O)=O.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O.C(OCC)(=O)C>[F:13][C:7]1([CH2:6][N:18]2[C:14](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]2=[O:19])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CS(=O)(=O)OCC1(F)CCOCC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1(F)CCOCC1

Procedure:
A mixture of EXAMPLE 409A (1.8 g) and potassium phthalimide (2.356 g) in N,N-dimethylformamide (30 mL) was heated at 150° C. overnight, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, concentrated and chromatographed on silica gel with 30% ethyl acetate in hexanes as eluent to give the product.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=O)[CH2:7][C:8]([O:10]CC)=[O:9].[N:14]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)=[N+:15]=[N-:16].[O-]CC.[Na+].[OH-].[Na+]>C(O)C.O>[CH2:24]([NH:23][C:21]([C:20]1[CH:26]=[CH:27][C:17]([N:14]2[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][F:1])=[C:7]([C:8]([OH:10])=[O:9])[N:16]=[N:15]2)=[CH:18][CH:19]=1)=[O:22])[CH3:25]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)CCCCF
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCCCF)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
Ethyl 7-fluoro-3-oxoheptanoate (0.920 g, 4.84 mmol, 1.17 eq.) obtained in Example 108a) and 4-azido-N-ethylbenzamide (0.790 g, 4.15 mmol) were dissolved in ethanol (25 ml), sodium ethoxide (366 mg, 4.84 mmol, 1.17 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 11 hr. 1N Aqueous sodium hydroxide solution (4.15 ml, 1.0 eq.) was added to the reaction mixture and the mixture was further stirred for 1 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and washed with ethyl acetate-hexane (1:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, and acidified (pH<3) with 6N hydrochloric acid. The precipitate was collected by filtration, washed with water and dried to give the title compound as a pale-gray powder (1.26 g, 3.77 mmol, 90.8%).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[CH:21]=[N:22][C:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:35]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[O:36])[CH:33]=4)[C:28]([S:43][CH3:44])=[CH:27]3)=[N:24][CH:25]=2)[CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[CH:21]=[N:22][C:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:35]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[O:36])[CH:33]=4)[C:28]([S:43]([CH3:44])=[O:6])=[CH:27]3)=[N:24][CH:25]=2)[CH:15]=1
Reactant: COc1ccnc(-c2cnc(-n3cc(SC)c4ccc(C(=O)N5CCOCC5)cc43)nc2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccnc(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N5CCOCC5)cc43)nc2)c1
Reaction time: 0.5 h

Procedure:
m-Chloroperoxybenzoic acid (65%; 91.6 mg, 0.345 mmol, 0.8 eq,) was added at 0° C. to a stirred solution of the product 141b) (200 mg, 0.432 mmol, 1.0 eq) in dichloromethane (10 mL). Stirring was continued at this temperature for 30 min and the reaction mixture was then diluted with dichloromethane (10 mL), washed with saturated natrium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography [100-200 mesh silica gel; methanol/ethyl acetate=1:9]. White solid. Yield 70 mg (34% of theory). Melting range: 216-220° C. HPLC (method 6): Rt=7.24 min. Mass spectroscopy: m/z: [M+H]+=478.2.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27]([SH:29])[CH3:28]>C(C(C)=O)C(C)C>[CH2:27]([S:29][C:7]1[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:28]
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)c1c(SCC)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 69.7 %

Procedure:
A mixture of 3.0 g (0.009 mol) of product of Example 9, 1.55 g (0.011 mol) of K2CO3 and 3.5 ml (0.047 mol) of ethanethiol in 15 ml of methyl isobutyl ketone was stirred at reflux for 60 hours. The reaction mixture was concentrated. The residue was taken up in ether, washed with 10% NaOH and water, dried (MgSO4) and concentrated in vacuo to 2.98 g of dark oil which was purified by HPLC using 5% ethyl acetate/cyclohexane as eluting solvent affording 2.18 g (69.8%) of product as a tan solid; mp 36°-37.5° C. Anal. Calc'd. for C12H11F6N1O2S1 : C, 41.50; H, 3.19; N, 4.03. Found: C, 41.45; H, 3.22; N, 4.01.