Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].Cl[CH2:23][C:24]1[O:25][CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[O:21]=[C:2]1[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:23][C:24]1[O:25][CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:28]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: COC(=O)c1coc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)n1
Yield: 91.4 %

Procedure:
A suspended mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.60 g, 5.70 mmol), methyl 2-(chloromethyl)oxazole-4-carboxylate (1.00 g, 5.70 mmol) and cesium carbonate (3.71 g, 11.4 mmol) in tetrahydrofuran (10 mL) was refluxed for 16 h. The reaction mixture was cold down to ambient temperature and concentrated in vacuo. The residue was treated with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic solution was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with a 20% to 30% gradient of ethyl acetate in hexanes to afford methyl 2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate (2.19 g, 92%) as a colorless solid: mp 183-185° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.86 (s, 1H), 7.28 (t, J=7.2 Hz, 1H), 7.16 (d, J=7.0 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 7.03 (t, J=7.5 Hz, 1H), 6.66 (s, 1H), 6.41 (S, 1H), 5.90 (d, J=2.1 Hz, 2H), 5.23-5.17 (m, 2H), 4.74 (ABq, 2H), 3.74 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 8177.2, 161.3, 160.2, 155.6, 148.8, 146.9, 142.3, 142.0, 132.8, 132.4, 129.4, 124.1, 123.9, 120.4, 109.7, 103.9, 101.9, 93.7, 80.0, 57.9, 52.3, 37.4; MS (ES+) m/z 421.2 (M+1).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])=[CH:5][N:6]=1.[NH2:13][C:14]1[CH:19]=[C:18]([Br:20])[N:17]=[C:16]([CH3:21])[N:15]=1>>[Br:20][C:18]1[N:17]=[C:16]([CH3:21])[N:15]=[C:14]([NH:13][C:2]2[S:3][C:4]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])=[CH:5][N:6]=2)[CH:19]=1
Reactant: Cc1nc(N)cc(Br)n1
Reactant: CC(C)OC(=O)c1cnc(Cl)s1
Product: Cc1nc(Br)cc(Nc2ncc(C(=O)OC(C)C)s2)n1
Yield: 76.9 %

Procedure:
Prepared from isopropyl 2-chlorothiazole-5-formate and Compound 9: isopropyl 2-(6-bromo-2-methylpyrimidin-4-ylamino)thiazole-5-formate was yielded (yield: 76.9%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[C@H:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:30])CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([F:30])[C@H:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H]1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
The title compound was prepared in a similar manner as described by L. Demange et al., Tetrahedron Letters 2001, 42, 651-653: To a solution of (2S,3R)-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (360 mg, 1.12 mmol) in CH2Cl2 (30 mL), cooled to −78° C., was added dropwise DAST (0.740 mL, 5.60 mmol). The reaction mixture was stirred at −78° C. for 5 h, and then was allowed to warm to RT and stirred overnight. After cooling to 0° C., the reaction was quenched with MeOH, followed by addition of aqueous NaHCO3 solution. Volatiles were removed under reduced pressure and the residue was taken up in EtOAc. The organics were washed with aqueous NaHCO3 (3×), water and brine, dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:9) to give the title compound (99% purity by HPLC/215 nm). TLC Rf (EtOAc/c-hexane 1:4)=0.2; MS (LC/MS): 346 [M+Na]+, 268 [MH−tBu]+, 224 [MH−Boc]+; tR (HPLC conditions b): 5.01 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2].[CH2:25]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[C:26]#[CH:27]>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:16]=[C:17]([C:27]#[C:26][CH2:25][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:18]=[C:19]([OH:21])[CH:20]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(SCc2cc(O)cc(Br)c2)cc1C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(SCc2cc(O)cc(C#CCN3CCOCC3)c2)cc1C

Procedure:
[4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (2.3 g; 5.6 mmol), 4-prop-2-ynyl-morpholine (2.1 g; 16.8 mmol), bis(triphenylphosphine)palladium (II) chloride (0.31 g; 0.45 mmol) and copper iodide (0.06 g; 0.34 mmol) were dissolved in a mixture of triethylamine (5 mL) and DMF (10 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100° C. for 1 h. The reaction mixture was purified by preparative HPLC (method A). Yield: 0.9 g. HPLC-MS: m/z: 456.1 (M+); Rt: 1.53 min.
Reaction SMILES: [ClH:1].C([O:4][C:5](=[O:42])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:9]=1[NH:25][C:26](=[O:41])[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:39][CH2:38][CH2:37][N:36]([CH3:40])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1)C.[OH-].[Na+].Cl>CO>[ClH:1].[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([NH:14][C:10]2[C:9]([NH:25][C:26](=[O:41])[C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:39][CH2:38][CH2:37][N:36]([CH3:40])[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)=[C:8]([CH:13]=[CH:12][CH:11]=2)[O:7][CH2:6][C:5]([OH:42])=[O:4])=[O:24])=[CH:21][CH:20]=1
Reactant: CCOC(=O)COc1cccc(NC(=O)c2ccc(OC)cc2)c1NC(=O)c1ccc(N2CCCN(C)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)Nc2cccc(OCC(=O)O)c2NC(=O)c2ccc(N3CCCN(C)CC3)cc2)cc1
Reaction time: 2 h
Yield: 76.1 %

Procedure:
Ethyl(3-[(4-methoxybenzoyl)amino]-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}phenoxy)acetate hydrochloride (350 mg) was dissolved in 6 ml of methanol, then 1.8 ml of a 1N aqueous solution of sodium hydroxide was added at room temperature and the mixture was stirred for 2 hours. 1N hydrochloric acid (1.8 ml) was further added and the mixture was concentrated in vacuo. The resulting residue was purified by ODS column chromatography using 0.001N hydrochloric acid-acetonitrile (1:1) as an eluting solvent to give 254 mg of (3-[(4-methoxybenzoyl)amino]-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}phenoxy)acetic acid hydrochloride.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([O:25][CH3:26])[CH:5]=1.CO.C(O)C.[OH-].[K+]>O>[CH3:26][O:25][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:3]([OH:27])=[O:2]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1OC
Yield: 83.1 %

Procedure:
The title compound is prepared by the procedure of Example 32 using 40 g of the product from Example 46, 320 ml of methyl alcohol, 125 ml ethyl alcohol, 20 ml of water and 17.8 g of potassium hydroxide. The residue is recrystallized from chloroform/hexane to give 32 g of the desired product as white crystals.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[H-].[Na+].I[CH3:15]>O1CCCC1>[CH3:15][O:11][C:7]1[C:5]2[N:6]=[C:2]([NH2:1])[O:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CI
Reactant: Nc1nc2c(O)cccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2oc(N)nc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a stirred solution of 10 g (66 mmol) 2-amino-benzooxazol-4-ol in 100 ml tetrahydrofuran at room temperature was added portionwise 3.49 g (79.9 mmol) sodium hydride (55% dispersion in oil), and the mixture was then stirred for 1 h at 50° C. A solution of 14.5 ml (233 mmol) iodomethane in 500 ml tetrahydrofuran was then added dropwise over 3 h, while the reaction mixture was maintained at 50° C. The mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (dichloromethane then 2/98 methanol/dichloromethane) afforded 7.5 g (69%) 4-methoxy-benzooxazol-2-yl-amine as a brown crystalline solid. EI-MS m/e (%): 164 (M+, 100), 149 ([M−CH3]+, 23), 135 (46).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10].C(C1C=C(C=C(C)C=1O)[C:16]([NH:18][OH:19])=[NH:17])C>>[OH:10][C:4]1[C:5]([CH3:9])=[CH:6][C:7]([C:16]([NH:18][OH:19])=[NH:17])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: COc1cccc(C)c1O
Product: COc1cc(C(=N)NO)cc(C)c1O

Procedure:
The title compound is prepared from commercially available 2-methoxy-6-methyl-phenol in analogy to literature procedures (see 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine); LC-MS: tR=0.50 min; [M+H]+=197.23.
Reaction SMILES: [CH2:1]([C:3]1([C:11](Cl)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH3:10])C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>CCOCC>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:11]([C:3]2([CH2:9][CH3:8])[CH2:1][CH2:7][CH2:6][CH2:5][CH:4]2[CH3:10])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: CCC1(C(=O)Cl)CCCCCC1C
Solvent: CCOCC
Product: CCC1(C(=O)Nc2ccc(OC)cc2)CCCCC1C

Procedure:
1-Ethyl-2-methylcycloheptanecarbonyl chloride (1.5 g, 0.007 mole) in ether (10 ml.) was added to a stirred solution of p-anisidine (0.01 mole) in ether (30 ml.). A further quantity of ether (100 ml.) was added and the solution was washed with dilute hydrochloric acid, dilute sodium hydroxide and then with water. The ether solution was dried (MgSO4) and the solvent was removed by distillation. The residue was recrystallised from 40-60 petroleum ether to give N-(p-Methoxyphenyl)-1-ethyl-2-methylcyclohexanecarboxamide, mp. 107°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][CH2:7][CH2:8][CH2:9][O:10][C:11]12[CH:20]=[CH:19][CH:18]=[CH:17][CH:12]1[CH2:13][CH:14]2[CH2:15][OH:16].C(N(CC)CC)C>C(Cl)Cl>[S:2]([OH:4])(=[O:10])(=[O:3])[CH3:1].[Cl:6][CH2:7][CH2:8][CH2:9][O:10][C:11]12[CH:20]=[CH:19][CH:18]=[CH:17][CH:12]1[CH2:13][CH:14]2[CH2:15][OH:16]
Reactant: CS(=O)(=O)Cl
Agent: OCC1CC2C=CC=CC21OCCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methane sulfonylchloride (1.13 g) is added dropwise to a stirred solution of 3-(3-chloropropoxy)-1-hydroxymethylbenzocyclobutene (1.83 g) and triethylamine (1.58 ml) in methylene chloride (32 ml) at 5° C. under nitrogen. The reaction mixture is stirred at RT for about 2 hours, washed with water, saturated NaCl, dried over Na2SO4, filtered and evaporated in vacuo yielding the desired product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]([O:12][CH3:17])=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:7]=1
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1c(C(C)(C)C)cc(Br)cc1C(C)(C)C
Yield: 107.1 %

Procedure:
Under an argon atmosphere, to a solution of 4-bromo-2,6-di-tert-butylphenol (50 g, 0.175 mol) and potassium carbonate (96.7 g, 4.0 equivalents) in acetone (750 mL) was added dimethyl sulfate (38.6 g, 1.75 equivalents) at 22° C., and the mixture was stirred under reflux for 13 hrs. Insoluble materials were filtered off and the solvent was evaporated under reduced pressure. Ethyl acetate (150 mL) and water (100 mL) were added, the mixture was partitioned, and the organic layer was washed successively with water (100 mL), 5% aqueous NaHCO3 solution (100 mL) and 5% aqueous NaCl solution (100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered by gravity, and the filtrate was concentrated under reduced pressure to give the title compound (56.1 g, brown oil). yield 95.2%
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:8]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCCCCCC
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCC[Si](OCC)(OCC)OCC
Temperature: 50 °C
Yield: 1.5 %

Procedure:
224 mg Of octene-1, 328 mg of triethoxysilane, and 56 mg of toluene were placed in a glass reaction tube. Next, 0.001 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 wt %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of octene-1 was 2.5% and n-octyltriethoxysilane was produced at a yield of 1.5%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15](=[O:30])[CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[NH2:41][CH2:42][C:43]([NH2:45])=[O:44]>>[NH2:45][C:43](=[O:44])[CH2:42][NH:41][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15](=[O:30])[CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[CH:3]=1
Reactant: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1cc(Cl)nc(-c2ccccc2)n1
Reactant: NCC(N)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CNc1cc(NC(=O)CN2CCC(Cc3ccccc3)CC2)nc(-c2ccccc2)n1
Temperature: 100 °C
Yield: 39.9 %

Procedure:
To a crude sample of N-(6-chloro-2-phenylpyrimidin-4-yl)-2-(4-benzylpiperidin-1-yl)acetamide (22.55) (0.75 g in 60 ml DMSO) were added glycinamide hydrochloride (1.85 g in 10 ml DMSO) and N,N-diisopropylethylamine (2.96 ml) and the mixture heated to 100° C. for 16 hrs. The solvent was then removed in vacuo and the residue purified by flash chromatography on silica gel using mixtures of dichloromethane and methanol (97:3, 95:5 then 93:7 v/v/v). Further purification by recrystallization from methanol furnished the title compound (326 mg over 2 steps).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.CCN(CC)CC.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:25]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2cccc(-c3ccccc3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (30.4 mg, 0.090 mmol) (Starting Material 1), Et3N (38 μL, 0.271 mmol), tri-o-tolylphosphine (1.7 mg, 0.006 mmol) (Aldrich), Pd(OAc)2 (0.6 mg, 0.003 mmol)(Aldrich), and phenylboronic acid (16.5 mg, 0.136 mmol) (Aldrich) in 362 μL of dry N,N-dimethylformamide (Fisher Scientific) was heated at 100° C. for 24 h. The reaction mixture was allowed to cool to room temperature, concentrated in vacuo to remove N,N-dimethylformamide, and then directly purified by flash chromatography (Merck Silica gel 60, 70-230 mesh, 10% ethyl acetate-hexanes then 25% ethyl acetate-hexanes elution) to provide pure (Z)-1,3-dihydro-4-phenyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Yield 21.9 mg, 85%) as an orange solid (mp 184-185° C.).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]([O:9]CC)=[O:8])=[N:2]1.[OH-].[Na+].O.CO>C1COCC1>[NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]([OH:9])=[O:8])=[N:2]1
Reactant: CCOC(=O)Cc1nc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1nc[nH]n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A mixture of ethyl 1H-1,2,4-triazol-3-ylacetate obtained in Reference Example 14 (900 mg, 5.80 mmol), 4N aqueous sodium hydroxide solution (7.25 mL, 29.0 mmol), water (10 mL), methanol (10 mL) and THF (10 mL) was stirred at 100° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was acidified with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure. Ethanol was added to the residue, and the insoluble material was filtered off, and the filtrate was concentrated. The residue was crystallized from toluene to give the title compound as a white powder (369 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O1[CH2:13][C:12](=O)[N:11]=[C-]1.C(=O)=O>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:13][CH2:12][NH2:11])=[CH:4][CH:3]=1
Reactant: O=C1CO[C-]=N1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C=O
Product: NCCNc1ccc(Cl)cc1
Temperature: 160 °C
Yield: 70.9 %

Procedure:
The hydrochloride salt of 4-chloroaniline (6.2 g, 38 mmol) and 2-oxazolidone (3.29 g, 38 mmol) was suspended in a minimal amount of di(ethyleneglycol)methyl ether and the resulting suspension heated at 160° C. After 4 h CO2 evolution ceased and the reaction mixture was cooled to ambient temperature. The resulting solid was crystallized from EtOH/ether to yield 4.6 g (58%) of 4-chloroanilinoethylamine as its HCl salt. MS (CI) (M+H)+ at m/z 171. The free amine was prepared by partitioning the HCl salt between CH2Cl2 and NaHCO3 (sat.), drying the organic layer (Na2SO4), filtering and concentrating.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([Cl:15])=[CH:7][C:6]=1[Cl:16])=[O:4].[CH3:17][NH:18][C:19]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[S:20]>>[BrH:1].[Cl:16][C:6]1[CH:7]=[C:8]([Cl:15])[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:5]=1[C:3]1([OH:4])[CH2:2][S:20][C:19](=[N:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:18]1[CH3:17]
Reactant: CNC(=S)NCCc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)c(Cl)cc1Cl
Product: Br
Product: CN1C(=NCCc2ccccc2)SCC1(O)c1cc(S(N)(=O)=O)c(Cl)cc1Cl

Procedure:
was obtained in a manner analogous to the method described in Example 10 from 3.5 g of 2-bromo-2',4'-dichloro-5'-sulfamoylacetophenone and 2 g of 1-methyl-3-(2-phenylethyl)-thiourea. M.p. 164°-165° C (decomposition)
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2OC)[C:9]([OH:18])=[C:8]2[C:3]=1[C:4](=[O:20])[CH:5]=[CH:6][C:7]2=[O:19].[Br:21]Br.[C:23]([OH:26])(=O)C>>[Br:21][C:6]1[C:7](=[O:19])[C:8]2[C:3]([C:4](=[O:20])[CH:5]=1)=[C:2]([Cl:1])[C:15]1[C:10](=[C:11]([O:26][CH3:23])[CH:12]=[CH:13][CH:14]=1)[C:9]=2[OH:18]
Reactant: COc1cccc2c(O)c3c(c(Cl)c12)C(=O)C=CC3=O
Reactant: CC(=O)O
Reactant: BrBr
Product: COc1cccc2c(Cl)c3c(c(O)c12)C(=O)C(Br)=CC3=O
Reaction time: 2 h

Procedure:
10-Chloro-9-hydroxy-5-methoxy-1,4-anthracenedione (compound 12) (50 mg) was dissolved in acetic acid (5 ml) to saturation by warming. The mixture was cooled to room temperature before addition of bromine (27 mg) in acetic acid (0.15 ml). The mixture was stirred for 120 min. then excess acetic acid was evaporated under reduced pressure. The crude solid dibromide was dissolved in ethanol (5 ml) containing boron trifluoride etherate (5 drops) and heated at reflux for 20 min. The resulting red-purple solution which deposited some crystals was cooled and diluted with distilled water (20 ml). After standing overnight, the precipitated red-black solid was filtered off to give the product (compound 13) (58 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:29][CH2:30][CH:31]=[C:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[N:42][C:37]=2[CH2:36][O:35][C:34]2[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:29][CH2:30][CH:31]=[C:32]3[C:38]4[CH:39]=[CH:40][CH:41]=[N:42][C:37]=4[CH2:36][O:35][C:34]4[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]3=4)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: O=[N+]([O-])c1cc(C2(O)CCNCC2)ccc1Cl
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)c([N+](=O)[O-])c3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 14 h
Yield: 30.3 %

Procedure:
To a solution of the 4-(4-Chloro-3-nitro-phenyl)-piperidin-4-ol (0.295 g, 1.2 mmol) in isopropanol was added 2,6-lutidine (0.225 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.224 g, 0.6 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.100 g, 30%). 1H-NMR (CDCl3): δ 1.53 (s, 6H), 1.70 (d, 2H), 1.81-2.18 (m, 4H), 2.3-2.44 (m, 4H), 2.56 (t, 2H), 2.69 (d, 2H), 5.32 (bs, 2H), 6.16 (t, 1H), 6.81 (d, 1H), 7.28 (t, 2H), 7.48 (t, 2H), 7.58 (t, 2H), 8.06 (s, 1H). ESI-MS m/z: 550 (M+1), retention time 1.51
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([OH:23])=[CH:15][C:14]=1[CH2:13][C@H:12]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])(=[O:3])[CH3:2].[O:33]1[CH:38]=[CH:37][CH2:36][CH2:35][CH2:34]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>O1CCCC1.C(OCC)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([O:23][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][O:33]2)=[CH:15][C:14]=1[CH2:13][C@H:12]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12

Procedure:
A solution of 21.3 g of 17β-acetoxy-7α-(5-acetoxypentyl)-estra-1,3,5(10)-trien-3-ol in 213 ml of tetrahydrofuran is allowed to stand with 21.3 ml of 3,4-dihydro-2H-pyran and 1.065 g of p-toluenesulfonic acid for 8 hours at room temperature. The reaction solution is mixed with 3 ml of pyridine, then diluted with diethyl ether, washed with water and dried. The residue that is obtained after the concentration by evaporation is chromatographed on silica gel, and 24.3 g of 17β-acetoxy-7α-(5-acetoxypentyl)-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene is obtained as oil. [α]D22=+31.5°(c=0.535% in chloroform)