Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@H:9](C)[C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([N:42]2[CH2:46][CH2:45][C@@H:44]([NH:47][C:48]([NH:50]C4C=NC=CC=4)=[O:49])[CH2:43]2)=[N:22][C:23]=3[NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:15]([OH:57])[C@@H:14]1[OH:58])=[O:11])C1C=CC=CC=1.N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)[C@H:82]([O:84]CC4C=CC=CC=4)C)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.C1(OC(=O)N[C:119]2[CH:124]=[CH:123][C:122]([S:125](=[O:128])(=[O:127])[NH2:126])=[CH:121][CH:120]=2)C=CC=CC=1.C1(OC(=O)NC2C=NC=CC=2)C=CC=CC=1>>[C:30]1([CH:29]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:28][NH:27][C:23]2[N:22]=[C:21]([N:42]3[CH2:46][CH2:45][C@@H:44]([NH:47][C:48]([NH:50][C:119]4[CH:124]=[CH:123][C:122]([S:125](=[O:127])(=[O:128])[NH2:126])=[CH:121][CH:120]=4)=[O:49])[CH2:43]3)[N:20]=[C:19]3[C:24]=2[N:25]=[CH:26][N:18]3[C@@H:16]2[CH2:17][C@H:13]([NH:12][C:10](=[O:11])[CH2:9][CH2:82][OH:84])[C@@H:14]([OH:58])[C@H:15]2[OH:57])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NS(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Agent: O=C(Nc1cccnc1)Oc1ccccc1
Product: NS(=O)(=O)c1ccc(NC(=O)N[C@@H]2CCN(c3nc(NCC(c4ccccc4)c4ccccc4)c4ncn([C@@H]5C[C@H](NC(=O)CCO)[C@@H](O)[C@H]5O)c4n3)C2)cc1

Procedure:
The title compound was prepared analogously to (R)-2-benzyloxy-N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 181, step 5), by substituting N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-3-hydroxy-propionamide (Intermediate ZG) for (R)—N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4) and (4-Sulfamoyl-phenyl)-carbamic acid phenyl ester (Intermediate ZE) for pyridin-3-yl-carbamic acid phenyl ester (Intermediate ZB).
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4].[CH3:37][C:38]1([CH3:41])[CH2:40][O:39]1.CCN(C(C)C)C(C)C>CC#N>[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][N:22]([CH2:37][C:38]([OH:39])([CH3:41])[CH3:40])[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4]
Reactant: CC1(C)CO1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCNC3)n(C)c2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCN(CC(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.4 %

Procedure:
A mixture of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-3-ol dihydrochloride (150 mg, 0.28 mmol), 2,2-dimethyloxirane (100 μL, 1.12 mmol) and DIPEA (192 μL, 1.12 mmol) in MeCN (4 mL) was stirred at r.t. for 20 h then heated at 70° C. for 24 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient acetonitrile 5-30%) affording 746 (35 mg, 23%). LCMS (method I): RT 2.57 min, [M+H]+ 535.2. 1H NMR (DMSO, 400 MHz): δ 8.03-7.98 (1 H, m), 7.65-7.61 (1 H, m), 7.28-7.21 (2 H, m), 5.46 (1 H, s), 4.45-4.05 (5 H, m), 3.96 (3 H, s), 3.77-3.76 (4 H, m), 3.30-3.22 (2 H, m), 3.07-2.99 (1 H, m), 2.91-2.83 (1 H, m), 2.70-2.60 (1 H, m), 2.45-2.35 (1 H, m), 2.26 (2 H, s), 2.15-2.00 (1 H, m), 1.96-1.69 (3 H, m), 1.32 (3 H, t, J=7.43 Hz), 1.01 (6 H, d, J=15.78 Hz)
Reaction SMILES: [CH:1]1([N:7]2[C:11]([OH:12])=[CH:10][C:9]([CH3:13])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].C>O.C(Cl)Cl>[CH:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([CH3:13])[N:8]2[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(O)n(C2CCCCC2)n1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(=O)n(C2CCCCC2)n1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 17.9 %

Procedure:
A mixture of 2-cyclohexyl-3-hydroxy-5-methylpyrazole (16.5 g) and dimethyl sulfate (10.9 g) was heated with stirring at 150°-160° for 6 hours and then allowed to cool to room temperature. A solution of sodium carbonate (6.5 g) in water (100 ml) was added, and the reaction mixture was heated at reflux temperature for 2 hours, cooled, and extracted with chloroform. The layer was dried and concentrated to give a dark oil, which was dissolved in methylene chloride, treated with charcoal and diatomaceous earth, filtered and concentrated. The concentrate was fractionally distilled, and the portion distilling at 118°/0.020 mm Hg was further purified by column chromatography on silica gel. Elution with chloroform-ethyl acetate (7:3), chloroform-ethyl acetate gradients, ethyl acetate, and ethanol afforded product from the ethyl acetate-rich chloroform-ethyl acetate gradient fractions and the ethyl acetate and ethanol fractions as determined by thin-layer chromatography and nuclear magnetic resonance spectroscopy. Product-rich fractions which were shown by gas chromatography to be highly pure were combined and concentrated to give 2-cyclohexyl-1,5-dimethyl-1,2-dihydro-3H-pyrazol-3-one (3.0 g) as an oil. The assigned structure was confirmed by infrared and nuclear magnetic resonance spectral analysis.
Reaction SMILES: [OH-].[Na+].[CH:3]([N:6]1C[CH2:9][CH2:8][C:7]1=O)([CH3:5])[CH3:4].Cl.[C:13](=[O:16])([O-])[O-:14].[Na+].[Na+].[Br:19][C:20]1[CH:21]=[CH:22][C:23](F)=[C:24]([CH:27]=1)[CH:25]=[O:26]>CS(C)=O>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([N:6]([CH:3]([CH3:5])[CH3:4])[CH2:7][CH2:8][CH2:9][C:13]([OH:14])=[O:16])=[C:24]([CH:25]=[O:26])[CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)N1CCCC1=O
Reactant: O=Cc1cc(Br)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)N(CCCC(=O)O)c1ccc(Br)cc1C=O
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 7.8 %

Procedure:
4N sodium hydroxide (36 ml) was added to 1-isopropyl-2-pyrrolidone (9.2 g), and the mixture was stirred for 3.5 hours. After cooled to 0° C., the mixture was neutralized with concentrated hydrochloric acid. After sodium carbonate (15.3 g) was added thereto, a solution of 5-bromo-2-fluorobenzaldehyde (7.3 g) in dimethyl sulfoxide (96 ml) was added thereto, and the mixture was heated to reflux for 5 hours. After cooled to room temperature, pH was adjusted to approximate 4 with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate/THF. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=4/1→3/2) to give 4-(4-bromo-2-formylisopropylanilino)butyric acid (0.92 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[CH2:11][CH:10]([NH:12]C(=O)C)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:16]3[C:21](=[O:22])[C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[C:36]5[NH:40][C:39](=[O:41])[O:38][N:37]=5)=[CH:26][CH:25]=4)=[C:19]([CH2:42][CH2:43][CH3:44])[N:18]=[C:17]3[CH3:45])[CH:8]=2)[O:3]1>Cl.O1CCOCC1.C(OCC)(=O)C>[NH2:12][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:16]3[C:21](=[O:22])[C:20]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[C:36]5[NH:40][C:39](=[O:41])[O:38][N:37]=5)=[CH:28][CH:29]=4)=[C:19]([CH2:42][CH2:43][CH3:44])[N:18]=[C:17]3[CH3:45])[CH:8]=2)[O:3][C:2]([CH3:1])([CH3:46])[CH2:11]1
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)C(NC(C)=O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)C(N)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Yield: 89.4 %

Procedure:
N-{2,2-Dimethyl-6-[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]-3,4-dihydro-2H-chromen-4-yl}acetamide (0.30 g) was dissolved in 6 M hydrochloric acid (1 mL) and 1,4-dioxane (2 mL), and the mixture was stirred at 90° C. for 2 days. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.25 g, 90%) as a colorless solid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14][CH2:15][CH2:16][CH3:17]>CC1C=CC=CC=1C>[C:4]1(=[O:5])[O:6][C:1](=[O:7])[C:2]2=[CH:13][CH:8]=[CH:9][CH:10]=[C:3]12.[CH:8]1[C:13]2[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CCCC
Reactant: c1ccccc1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1C
Product: O=C1OC(=O)c2ccccc21
Product: c1ccc2ccccc2c1

Procedure:
It is well known that maleic anhydride is prepared by the catalytic oxidation of benzene, naphthenes, butenes, or butane in the vapor phase, and that it is also obtained as a by-product of the preparation of phthalic anhydride by oxidation of o-xylene or naphthalene. It is usual to isolate maleic anhydride from the crude product by fractional distillation; crystallization of the distillate gives colorless, almost pure maleic anhydride. It has been found however that even the colorless, crystalline maleic anhydride obtained in this way is prone to discolor when it is stored for some time, and molten maleic anhydride discolors quicker.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:19]=[C:18]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][OH:25])[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1>C(O)C.[Pd]>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCCCO)oc21
Agent: [Pd]
Solvent: CCO
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCCCO)oc21
Temperature: 25 °C
Yield: 48.3 %

Procedure:
N-(4-Chlorobenzyl)-2-(5-hydroxypent-1-ynyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 84, 0.125 g) was dissolved in ethanol (40 mL) with heating and then allowed to cool to room temperature. The mixture was hydrogenated over 10% Pd/C (0.038 g) at 35 psi for 2 h. The reaction mixture was filtered through a Celite pad and the pad was washed with CH2Cl2 (75 mL). The filtrate was concentrated in vacuo and then resubjected to the reaction conditions for 1 h. The resulting solid was purified by column chromatography (CH2Cl2/methanol, 98/2) followed by recrystallization from ethyl acetate to yield 0.061 g of the title compound as a white solid. Physical characteristics. M.p. 151-152° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.69, 8.51, 7.41-7.32, 6.67, 4.54, 4.37, 3.92, 3.41-3.37, 2.73, 1.68-1.63, 1.49-1.42, 1.40-1.33; MS (ESI+) m/z 403 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:38])([CH3:37])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]=[C:12]2[CH3:36])=[CH:7][CH:6]=1.[H-].[Na+].CI.[C:43](OCC)(=O)C>CN(C)C=O.O>[CH3:43][O:1][CH2:2][C:3]([CH3:37])([CH3:38])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]=[C:12]2[CH3:36])=[CH:7][CH:6]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)COC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
To a solution of 4′-({1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.69 g) in N,N-dimethylformamide (7 mL) were added 60% sodium hydride (0.065 g) and then methyl iodide at 0° C., and the mixture was stirred for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.52 g, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[C@H:28]([CH3:39])[CH2:27]3)=[O:25])=[CH:21][N:22]=2)[N:19]=1.[ClH:40]>>[ClH:40].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][NH:29][C@H:28]([CH3:39])[CH2:27]3)=[O:25])=[CH:21][N:22]=2)[N:19]=1
Reactant: C[C@@H]1CN(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)CCN1C(=O)OC(C)(C)C
Agent: Cl
Product: C[C@@H]1CN(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)CCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a reaction vial containing (R)-tert-butyl 4-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-2-methylpiperazine-1-carboxylate (Example 36; 12 mg, 0.022 mmol) was added 0.5 mL 4 N HCl (dioxane) solution in one portion. After stirring at ambient temperature for 4 hours, the reaction was concentrated. The resulting solid residue was treated with ether and concentrated again to yield the final product salt form as a pale-yellowish powder. MS (apci) m/z=442.2 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]1)=[O:6].[H-].[Na+]>C1COCC1.CCOCC>[F:14][C:11]1([F:15])[CH2:12][CH2:13][CH:8]([N:7]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[CH2:9][CH2:10]1
Reactant: O=C(CCCCl)NC1CCC(F)(F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1CCCN1C1CCC(F)(F)CC1
Yield: 55 %

Procedure:
Heat the mixture of 4-chloro-N-(4,4-difluoro-cyclohexyl)-butyramide (0.41 g, 1.7 mmol) and 0.69 g of NaH in 17 mL of THF to 70° C. for overnight. Dilute the reaction mixture with Et2O. Filter the precipitate through a pad of celite. Wash the organic layer with saturated aqueous NaCl, dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford 0.19 g of the title compound: mass spectrum (m/z): 204 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]1[OH:21].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C1(=O)CCCCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]1=[O:21]
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: O=C1CCCCC1
Product: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Yield: 88.1 %

Procedure:
Dissolve dl-3-methoxyestra-2,5(10)-dien-17β-ol (4 g) in cyclohexanone (40 ml) and toluene (140 ml) and add a solution of aluminum isopropoxide (4 g) in toluene (56 ml). Reflux in an atmosphere of nitrogen for two hours and cool. Add water (7.5 ml), shake, and then dry by adding sodium sulfate (10 g). Filter and evaporate under vacuum and recrystallize the residue from methanol to obtain dl-3-methoxyestra-2,5(10)-dien-17-one (3.5 g); m.p. 116°-118°; infrared absorption maxima at 5.76 μ, 5.9 μ, 6.01 μ.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[C:12](=[O:22])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:12](=[O:22])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(N2C(=O)CCCC2c2ccc(Cl)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: O=C1CCCC(c2ccc(Cl)cc2)N1c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a stirred mixture of 2.95 g of 6-(4-chlorophenyl)-1-(4-methoxyphenyl)-2-piperidone, 3 ml of ethanethiol, and 50 ml of methylene chloride was added, under ice-cooling 5.06 g of anhydrous aluminum chloride. After stirring at room temperature for 1 hour, the mixture was poured into ice-cold water and extracted with chloroform. The extract was washed with an aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried, and concentrated. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 2.75 g of 6-(4-chlorophenyl)-1-(4-hydroxyphenyl)-2-piperidone as colorless needles.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15](O)=[O:16])[CH:12]=[CH:11][C:10]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:5][C:4]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30].ON1C(=O)CCC1=O.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.[NH2:61][C@H:62]([C:71]([CH3:74])([CH3:73])[CH3:72])[CH2:63][C:64]([O:66]C(C)(C)C)=[O:65].Cl>CN(C=O)C.C(O)=O>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]([NH:61][C@H:62]([C:71]([CH3:74])([CH3:73])[CH3:72])[CH2:63][C:64]([OH:66])=[O:65])=[O:16])[CH:12]=[CH:11][C:10]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:5][C:4]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(C)(C)C
Reactant: CN(C)CCCOc1cc(-c2nc(C(=O)O)ccc2-c2ccccc2Cl)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCCOc1cc(-c2nc(C(=O)N[C@@H](CC(=O)O)C(C)(C)C)ccc2-c2ccccc2Cl)ccc1Cl
Reaction time: 18 h
Yield: 117.3 %

Procedure:
To a mixture of 674 mg (1.4 mmol) of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridine-2-carboxylic acid hydrochloride in 7 mL of anhydrous DMF are successively added, under argon and at room temperature, 240 mg (2.1 mmol) of N-hydroxysuccinimide and 401 mg (2.1 mmol) of EDC.HCl. After stirring for 18 hours, 1.31 mL (7.7 mmol) of DIEA and 304 mg (1.51 mmol) of tert-butyl(3S)-3-amino-4,4-dimethylpentanoate (J. Org. Chem., 1999, 64, 6411-6417) are successively added to the reaction medium. Stirring is continued for 18 hours at room temperature and the reaction mixture is then concentrated under reduced pressure. The residue obtained is then treated for 18 hours at room temperature with 0.25 mL (3 mmol) of aqueous 12N HCl solution in 30 mL of formic acid and then concentrated under reduced pressure. After purification by reverse-phase HPLC (RP18), eluting with an aqueous 10−2N HCl/acetonitrile gradient of from 5% to 100% acetonitrile, and after freeze-drying, 500 mg of (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}-amino)-4,4-dimethylpentanoic acid hydrochloride are obtained in the form of a white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:31](O)=[O:32].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:12]([C:10]1[N:9]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:31]([C:23]3[N:22]([CH3:21])[C:30]4[C:25]([CH:24]=3)=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:32])=[CH:18][CH:19]=2)[N:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:11]=1)[CH3:13]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(NC(=O)c2cc3ccccc3n2C)cc1
Reaction time: 18 h

Procedure:
A DMF (2 mL) solution of 3-(3-pyridyl)-5-ethyl-1-(4′-aminophenyl)pyrazole (264 mg, 1 mmol), N-methylindole-2-carboxylic acid (192.5 mg, 1.1 mmol), PyBOP (570 mg, 1.1 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) was stirred at room temperature. for 18 hr. The reaction mixture was poured into crushed ice, and extracted with methylene chloride (3×50 mL). The combined extracts were washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated. Chromatography of the residue over silica gel (4% methanol/methylene chloride) followed by preparative TLC (silica gel, developer 5% methanol/methylene chloride) gave the title compound as a light, cream colored solid, m.p. 178-179° C. 1H NMR (DMSO-d6) δ 1.2 (3H, t, J=7.5), 2.73 (2H, q, J=7.5 Hz), 4.05 (3H, s), 6.93 (1H, s), 7.16 (1H, t, J=7.5), 7.34 (1H, t, J=7.5), 7.37 (1H, s), 7.44-7.48 (1H, dd, J=3.1 & 4.7 Hz), 7.57-7.61 (3H, m), 7.74 (1H, d, J=7.9 Hz), 7.98 (2H, d, J=8.8 Hz), 8.2-8.22 (1H, m), 8.53-8.54 (1H, m), 9.07 (1H, d, J=1.8 Hz), 10.56 (1H, s).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[O:20])=[CH:18][CH:17]=1
Reactant: COC(=O)CCCCCCCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(N(CCCCCCCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1

Procedure:
As described in example 1(b), the reaction is carried out with 125 g (0.3 mol) of 8-[4-chloro-N-(4-methoxyphenyl)-benzamido]-caprylic acid methyl ester, 500 cc. of methanol and 12 g (0.3 mol) of sodium hydroxide. Reaction time: 2 days, reaction temperature: 25° C. 40 g of the crude product (96.3 g) are purified chromatographically on silicic acid using a mixture of chloroform and methanol (99:1) as eluant.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1Cl)[CH3:2].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:16][CH:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:22]1)[CH3:2]
Reactant: CCOCCn1c(Cl)nc2ccccc21
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOCCn1c(NC2CCN(C(=O)OCC)CC2)nc2ccccc21
Temperature: 170 °C
Reaction time: 12 h

Procedure:
Combine 1-(2-ethoxyethyl)-2-chloro-1H-benzimidazole (3.06 g, 13.62 mmol) and ethyl 4-aminopiperidine-1-carboxylate (5.16 g, 30 mmol) and heat to 150° C. After 12 hours, heat to 170° C. After 8 hours, cool the reaction mixture and partition between dichloromethane (150 mL) and water. Separate the layers and extract the organic layer with water. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate/hexane 1/1 to give (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonyl-piperidin-4-yl)amine: Rf=0.15 (silica gel, ethyl acetate/hexane).