Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6](I)[CH:5]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([C:18](=[O:20])[CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc(N)c(I)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N)c(C(C)=O)c1
Temperature: 105 °C
Reaction time: 7 h
Yield: 81.4 %

Procedure:
To a solution of 4-amino-3-iodo-benzoic acid methyl ester (11.30 g, 40.77 mmol) in toluene (300 mL) were added tributyl(1-ethoxyvinyl)tin (16.5 mL, 48.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (9422 mg, 8.154 mmol) under nitrogen atmosphere, and the solution was stirred at 105° C. for 7 hours. After cooling to room temperature, water was added, the mixture was extracted with ethyl acetate-tetrahydrofuran, the organic layer was washed with water, and then, evaporated. The residue was dissolved in 280 mL of tetrahydrofuran, 2N hydrochloric acid (80 mL) was added thereto, followed by stirring for 3 hours at room temperature. The reaction mixture was cooled on an ice bath, an aqueous solution of 2N sodium hydroxide (80 mL) was added, an aqueous solution of saturated sodium bicarbonate was further added, and the solution was extracted with ethyl acetate. An aqueous solution of 10% potassium fluoride was added to the organic layer, and the solution was stirred for 3 hours at room temperature. The organic layer was separated, washed with brine, then evaporated, the residue was purified by silica gel column chromatography (hexane-ethyl acetate), and title compound (6.42 g, 33.2 mmol, 81.4%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([Br:21])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Br)c2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 103.1 %

Procedure:
To a solution of 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.71 mmol) (as prepared in the previous step) in DCM (3 mL) was added N-bromosuccinimide (NBS) (0.13 g, 0.71 mmol), and the reaction stirred at RT for 10 h. The reaction was diluted with EtOAc (10 mL) and washed with NaHCO3 (2×10 mL) and brine (10 mL). Concentration of the organic layer gave 0.26 g (100%) of the title compound as a yellow foam. Mass spectrum (ESI, m/z): Calcd. for C16H23BrN2O2, 355.1 (M+H), found 355.1.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N+:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=2)[CH2:6][CH2:5]1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3[N+](=O)[O-])CC2)cc1

Procedure:
Ethyl 4-(piperazin-1-yl)benzoate (1.5 g), 1-(bromomethyl)-2-nitrobenzene (1.383 g) and sodium carbonate (2.036 g) were suspended in anhydrous N,N-dimethylformamide (20 mL) at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and concentrated. The residue was purified by flash column purification with 10-40% ethyl acetate/hexane to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[OH:11]O>C(O)(=O)C>[CH3:1][C:2]1[NH:10][C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[N+:3]=1[O-:11]
Reactant: Cc1nc2cnccc2[nH]1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1[nH]c2cnccc2[n+]1[O-]

Procedure:
Following the method of Chem. Pharm. Bull., 12, 866 (1964), a solution of 2-methylimidazo[4,5-c]pyridine (5.65 g, 42.5 mmol) in 30% aqueous hydrogen peroxide (15 ml) and glacial acetic acid was stirred at 60° C. for 6 days. The volatiles were removed under reduced pressure and the residue was dissolved in ethanol and treated with solid anhydrous potassium carbonate. The solid was filtered off, washed with ethanol, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with 10-30% water in acetone. Fractions containing the product were concentrated under reduced pressure, redissolved in isopropanol/toluene, 1:1 (200 ml) and re-evaporated to give the title compound, as a hygroscopic solid, (2.94 g, 46%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][CH:12]([CH3:15])[NH:13][CH3:14].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][C:27](Cl)=[O:28])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][CH:12]([N:13]([CH3:14])[C:27](=[O:28])[CH2:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=1)[CH3:15]
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: CNC(C)CCc1cc(OC)ccc1I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(I)c(CCC(C)N(C)C(=O)Cc2ccc(OC)c(OC)c2)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 17.87 g (0.056 mole) of 2-iodo-5-methoxy-N,alphadimethylbenzenepropanamine in 58 ml of dry methylene chloride was added dropwise to a cooled (5° C.) solution of 3,4-dimethoxyphenylacetyl chloride in 68 ml of dry methylene chloride over a period of five minutes while stirring under an atmosphere of nitrogen. After about two minutes of stirring, 5.67 g (0.056 mole) of triethylamine was added followed by an additional 20 ml of dry methylene chloride. The reaction mixture was allowed to warm to room temperature while stirring overnight. An additional 80 ml of methylene chloride was added and the mixture washed successively with 200 ml of water, 300 ml of 5% hydrochloric acid, and 200 ml of sodium hydroxide solution. The organic phase was dried over anhydrous magnesium sulfate and evaporated in vacuo to yield 27.5 g (99%) of N-[3-(2-iodo-5-methoxyphenyl)-1-methylpropyl]-3,4-dimethoxy-N-methylbenzeneacetamide as an orange gum, MS (high resolution):
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=2)[CH2:4]1.[F:17][CH:18]([F:22])[C:19](O)=[O:20].C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:17][CH:18]([F:22])[C:19]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=2)[CH2:4]1)=[O:20]
Reactant: O=C(O)C(F)F
Reactant: NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1)C(F)F
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A suspension of (5S)-5-Aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one (1022, 5.0 g, 14.88 mmol) in methylene chloride (CH2Cl2, 50 mL) was treated with difluoroacetic acid (2.14 g, 1.41 mL, 22.32 mmol, 1.5 equiv) and N,N-diisopropylethylamine (DIEA or Hunig's base, 3.85 g, 5.18 mL, 29.76 mmol, 2.0 equiv), and the resulting reaction mixture was cooled down to 0-5° C. before being treated with EDCI (4.30 g, 22.32 mmol, 1.5 equiv) at 0-5° C. The reaction mixture was subsequently stirred at 0-5° C. for 1 h before being gradually warmed up to room temperature for 12 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H2O (50 mL) and CH2Cl2 (50 mL). The two layers were then separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed H2O (50 mL) and the saturated aqueous NaCl solution (50 mL), dried over MgSO4, and concentrated in vacuo to afford the crude (5S)-2,2-difluoro-N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (1026, 5.64 g, 6.16 g theoretical, 91.6%) as off-white powders, which by HPLC/MS and 1H NMR was found to be essentially pure and was directly used in the subsequent reactions without further purification. For 1026: 1H NMR (300 MHz, DMSO-d6) δ 3.54 (t, 2H, J=5.5 Hz), 3.77 (dd, 1H, J=6.3, 9.2 Hz), 4.15 (t, 1H, J=9.2 Hz), 4.77-4.86 (m, 1H), 6.25 (t, 1H, J=53.52 Hz, —CHCF2), 7.18 (dd, 1H, J=2.4, 8.7 Hz), 7.55 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (t, 1H, J=8.5 Hz), 9.19 (t, 1H, J=5.5 Hz, —CONH); C12H10F3IN2O3, LCMS (EI) m/e 415 (M++H), 456 (M++H+CH3CN).
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH3:18][C:19]([CH3:21])=O>>[CH2:4]([C@:2]12[CH2:7][C:6](=[CH2:21])[C@@H:5]3[C@@H:19]4[C:21]([CH2:19][CH2:18][C@H:4]3[C@@H:3]1[CH2:7][CH2:6][CH2:12]2)=[CH:3][CH2:2][CH2:12][CH2:18]4)[CH3:5]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=C1C[C@]2(CC)CCC[C@H]2[C@@H]2CCC3=CCCC[C@@H]3[C@@H]12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1.3 g (3.79 mmoles) of 13-ethyl-11-methylen-17,17-(1,3-propilendioxy)-gon-4-ene (compound XVIIa) were dissolved in acetone (21 ml) under stirring at room temperature. 250 mg of p-toluensulfonic acid monohydrate were added to the solution so obtained and the stirring at room temperature was continued for 17 hours. After this period a saturated solution of sodium bicarbonate (21 ml) was added to the reaction mixture and the organic solvent was evaporated under vacuum. The so obtained aqueous suspension was extracted with dichloromethane (3×30 ml) and the organic extracts dried on sodium sulfate, filtered and evaporated under vacuum to give 0.88 g (3.11 mmoles; yields 82%) of the intermediate 13-ethyl-11-methylen-gon-4-ene (compound XVIII).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][O:19][CH2:20][CH3:21].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][O:19][CH2:20][CH3:21])=[C:4]([F:9])[CH:3]=1
Reactant: CCOCCBr
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOc1ccc(Br)cc1F
Reaction time: 18 h

Procedure:
To a mixture of 4-bromo-2-fluorophenol (10.07 g) and potassium carbonate (9.5 g) in DMF (100 ml) was added at room temperature 2-bromoethylethyl ether (6.0 ml), and the mixture was stirred for 18 hours. To the mixture was added 2-bromoethylethyl ether (1.2 ml), and the mixture was stirred at 55° C. for 5 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (thrice) and saturated brine (once), and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give pale yellow oil of 4-bromo-1-(2-ethoxyethoxy)-2-fluorobenzene (13.79 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH:35]1[CH2:44][CH:43]([OH:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([OH:46])[CH:41]=2)[O:36]1>>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH:35]1[CH2:44][CH:43]([OH:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:46][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:41]=2)[O:36]1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccc(F)cc1F)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2ccc(F)cc2F)O3)nc1

Procedure:
2-(2,4-Difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 520 mg of 2-(2,4-difluorophenyl)chroman-4,6-diol (Example 69(b)). The product was recrystallised from a mixture of 2-propanol and diethyl ether. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.8 Hz), 8.61 (dd, 1H, J 9.1, 2.8 Hz), 7.66 (m, 1H), 7.32 (m, 1H), 7.26 (d, 1H, J 2.9 Hz), 7.23 (d, 1H, 9.1 Hz), 7.17 (m, 1H), 7.02 (dd, 1H, J 8.9, 2.9 Hz), 6.88 (d, 1H, J 8.9 Hz), 5.70 (bs, 1H), 5.52 (dd, 1H, J 11.9, 1.5 Hz), 5.00 (m, 1H), 2.31 (m, 1H), 2.09 (m, 1H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1>CN(C=O)C>[C:1]1(=[O:11])[N:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1ccc(CBr)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a suspension of 37 g (0.2 mol) of potassium phthalimide in 200 ml of DMF was added 50 ml of a solution of 19.6 g (0.1 mol) of α-bromo-p-tolunitrile in DMF at room temperature in argon atmosphere. The reaction mixture was stirred at 90° C. for 3 hours, then cooled to room temperature and poured into 400 ml of ice-water, followed by extraction with benzene-ether (1:1). The organic layer was washed with saturated aqueous solution of sodium chloride, dried over Na2SO4 and concentrated, giving 24.9 g (yield 95%) of 4-phthalimidomethylbenzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]#[N:16].[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)C.CO>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([N:21]1[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]1)=[NH:16]
Reactant: OC1CCNCC1
Reactant: N#CNc1ccccc1-c1ccccc1F
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: N=C(Nc1ccccc1-c1ccccc1F)N1CCC(O)CC1

Procedure:
A mixture of 2'-fluoro-2-biphenylylcyanamide (2.5 g) and 4-hydroxypiperidine (1.4 g) in ethanol (30 ml) was heated at reflux on a steam bath for 2 hours gave a yellow foamy solid which was reacted with fumaric acid (1.3 g) in methanol (10 ml) to give N-(2'-fluoro-2-biphenylyl)-4-hydroxypiperidine-1-carboxamidine fumarate as a colourless solid (m.p. 214°-215° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16](O)=[O:17].[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN>CN(C=O)C>[F:1][C:2]([F:20])([F:19])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]([NH:23][CH3:21])=[O:17]
Reactant: O=C(O)c1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
5-(Trifluoromethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid (1.50 grams, 0.0046 mole) and carbonyldiimidazole (0.94 gram, 0.0058 mole) were dissolved in DMF. The reaction mixture was stirred for 10 minutes, then 7 ml. of 40% aqueous methylamine were added. The reaction mixture was stirred for three hours at room temperature, then poured into 150 ml. of water and filtered. The precipitate was dried to 1.51 grams, then recrystallized from 10:1 cyclohexane/toluene, yielding 1.23 grams of 5-(trifluoromethyl)-1-(2,4-dichlorophenyl)-N-methyl-1H-pyrazole-4-carboxamide, mp=143°-144° C.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[CH:41]([S:43]([CH:46]=[CH2:47])(=[O:45])=[O:44])=[CH2:42]>CCO>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][CH2:47][CH2:46][S:43]([CH:41]=[CH2:42])(=[O:45])=[O:44])[CH2:19][CH2:18]2
Reactant: C=CS(=O)(=O)C=C
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCO
Product: C=CS(=O)(=O)CCN[C@]12CC[C@@H](C(=C)C)[C@@H]1[C@H]1CC[C@@H]3[C@@]4(C)CC=C(c5ccc(C(=O)OC)cc5)C(C)(C)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Temperature: 100 °C
Yield: 68.7 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (30 mg, 0.055 mmol), TEA (0.023 mL, 0.165 mmol) and vinylsulfonylethene (19.5 mg, 0.165 mmol) in EtOH (1 mL) was heated for 3 h at 100° C. The reaction mixture was quenched with water, extracted with DCM (3×2 mL). The organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a brown oil (25 mg, 68%). LCMS: m/e 662.42 (M+H)+, 3.45 min (method 10).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11][CH3:12])=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[F:27][C:26]([F:28])([F:29])[C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:30])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH3:12])=[CH:19][CH:18]=2)=[CH:25][CH:24]=1
Reactant: CCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cc1

Procedure:
To a solution of 4-(1-hydroxy-propyl)-benzoic acid methyl ester (300 mg, 1.55 mmol) in toluene (10 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 585 mg, 2.32 mmol) at 0° C., followed by the addition of tributylphosphine (0.58 mL, 2.32 mmol) and 4′-trifluoromethyl-biphenyl-4-ol (442 mg, 1.86 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4′-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid methyl ester. The ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 hours at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4′-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid (570 mg).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]([C:19]([O:21][CH3:22])=[O:20])=[C:11]([CH2:23][CH3:24])[N:10]=1)C1C=CC=CC=1.C1COCC1.[H][H]>[C].[Pd].C(O)C>[CH2:23]([C:11]1[C:12]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:9]([OH:8])[N:10]=1)[CH3:24]
Reactant: CCc1nc(OCc2ccccc2)c(C(=O)OC)cc1C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1nc(O)c(C(=O)OC)cc1C(=O)OC
Yield: 72.6 %

Procedure:
A mixture of dimethyl 2-(benzyloxy)-6-ethylpyridine-3,5-dicarboxylate (2.37 g), 10% palladium carbon (containing 55% water, 2.00 g), THF (20 mL), and ethanol (20 mL) was stirred at room temperature for 1 hour in a hydrogen atmosphere. The catalyst was filtered off, and then, the obtained filtrate was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to obtain the title compound (1.25 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14]CC)=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(Cl)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1OB(O)c2cc(O)cc(Cl)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
To a solution of ethyl 2-(4-chloro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (150 mg, 0.55 mmol) in THF (2 mL) was added an aqueous solution of lithium hydroxide (116 mg, 2.77 mmol) in water (1 mL) at 0° C. The resulting mixture was stirred at ambient temperature for 3 h and acidified with diluted hydrochloric acid at 0° C. to pH=1˜2. The mixture was extracted with EtOAc (2×20 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as a white powder (78 mg. Yield: 69%). 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.40 (s, 1H), 8.15 (s, 1H), 7.06 (d, J=1.6 Hz, 1H), 6.91 (d, J=1.6 Hz, 1H), 5.38-5.41 (m, 1H), 3.14-3.19 (m, 1H), 2.15-2.22 (m, 1H). MS (ESI) m/z=243 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.Cl.[CH3:18][NH:19][CH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[CH3:18][N:19]([CH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:15]
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: CNCCc1cccnc1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N(C)CCc2cccnc2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-[2-(methylamino)ethyl]pyridine dihydrochloride (12.5 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.6 mg). Calcd for C19H19N3O2: 321.1477, found 321.1491.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:26]1[C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]2[C:35]([O:37][C:38](=O)[C:28]=2[CH:27]=1)=[O:36]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:35](=[O:36])[C:29]2[C:28](=[CH:27][CH:26]=[C:31]([C:32]([OH:34])=[O:33])[CH:30]=2)[C:38]1=[O:37]
Reactant: COc1ccc(-c2nc3cc(-c4ccc(Cl)cc4)ccc3o2)cc1N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(-c2nc3cc(-c4ccc(Cl)cc4)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-4-methoxyphenyl)-5-(4-chlorophenyl)benzoxazole (104 mg, 0.30 mmol) and 1,2,4-benzenetricarboxylic anhydride (58 mg, 0.33 mmol) the title compound was obtained (67 mg, 43%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.38–8.33(m, 3H), 8.12(d, 1H), 8.05(d, 1H), 7.86(d, 1H), 7.77(d, 1H), 7.70(dd, 1H), 7.55–7.48(m, 3H), 3.89(s, 3H). MS m/z 525.1 (M+H)+.