Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14](SC)=[N:15][CH:16]=2)[N:11]2[CH:22]=[CH:23][N:24]=[C:10]12.ClC1C=C(C=CC=1)C(OO)=O.[NH2:36][C:37]1[CH:38]=[N:39][C:40]2[CH2:41][CH2:42][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:44][C:45]=2[CH:46]=1>C(Cl)Cl.C(OCC)(=O)C>[C:50]([O:49][C:47]([N:43]1[CH2:42][CH2:41][C:40]2[N:39]=[CH:38][C:37]([NH:36][C:14]3[N:13]=[C:12]4[C:17]([C:18](=[O:19])[N:9]([C:3]5[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[C:10]5[N:11]4[CH:22]=[CH:23][N:24]=5)=[CH:16][N:15]=3)=[CH:46][C:45]=2[CH2:44]1)=[O:48])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)N1CCc2ncc(N)cc2C1
Reactant: CSc1ncc2c(=O)n(-c3c(F)cccc3Cl)c3nccn3c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ncc(Nc3ncc4c(=O)n(-c5c(F)cccc5Cl)c5nccn5c4n3)cc2C1
Reaction time: 5 h

Procedure:
A mixture of Example 95C (70.0 mg, 0.193 mmol) and m-chloroperoxybenzoic acid (52.0 mg, 0.232 mmol) in CH2Cl2 (2 ml) was stirred for 20 minutes. tert-Butyl 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (57.9 mg, 0.232 mmol) was added to the reaction mixture. After 5 hours, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with ethyl acetate to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[S:29]
Reactant: COC(=O)c1cccc(OCc2cccc(Cl)c2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: COC(=S)c1cccc(OCc2cccc(Cl)c2)c1
Yield: 145.9 %

Procedure:
In an analogous manner to that described in Example 1(B), 36.5 g(131.9 mmol) of methyl 3-[(3-chlorobenzyl)oxy]benzoate were heated at reflux for 16 hours with 26.7 g (66 mmol) of Lawesson reagent in xylene and thereafter chromatographed on silica gel. Elution with hexane/toluene (2%, 5% and 10%) yielded 28.2 g (73%) of O-methyl 3-[(3-chlorobenzyl)oxy]thiobenzoate as an orange, crystallizing oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[F:5][C:6]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:7]=1[CH:8]=O.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>CO.C(Cl)Cl>[F:5][C:6]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:7]=1[CH2:8][NH:4][CH2:3][CH2:1][OH:2]
Reactant: NCCO
Reactant: O=Cc1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCCNCc1ccc(F)cc1F
Temperature: 0 °C
Yield: 68 %

Procedure:
Ethanolamine (0.86 g, 14.07 mmol) was added to a solution of 2,4-difluorobenzaldehyde (2.0 g, 14.07 mmol) in methanol (50 mL) at RT. Sodium bicarbonate (7.0 g, 83.33 mmol) was added and the reaction mixture was stirred at reflux for 24 hours. The mixture was cooled to 0° C. and sodium borohydride (0.32 g, 8.42 mmol) was then added in lots, maintaining the temperature of the mixture at 0-5° C. The reaction mixture was allowed to warm to RT over a period of 4 hours. The reaction mixture was then diluted with DCM (50 mL), washed with brine (2×30 mL), dried (Na2SO4) and the solvents removed under reduced pressure to afford the title compound (1.79 g, 69%). The product was used in the next step without further purification.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[C:2]=[S:3].[Cl:15][C:16]1[CH:17]=[C:18]([NH2:30])[C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:21]=1>O1CCCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:18]([NH:30][C:2]([NH:1][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]2)=[S:3])[CH:17]=1
Reactant: CCOC(=O)N1CCC(N=C=S)CC1
Reactant: Nc1cc(Cl)ccc1NCc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(NC(=S)Nc2cc(Cl)ccc2NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 10.6 parts of ethyl 4-isothiocyanato-1-piperidinecarboxylate, 11.6 parts of 4-chloro-N1 -(phenylmethyl)-1,2-benzenediamine and 90 parts of tetrahydrofuran is stirred overnight at room temperature. The reaction mixture is evaporated, yielding 21 parts (100%) of ethyl 4-[{[{5-chloro-2-[(phenylmethyl)amino]phenyl}amino]thioxomethyl}amino]-1-piperidinecarboxylate; mp. 162° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24]([O:26]C)=O)#[N:2].Cl.[OH-].[NH4+:30]>C1COCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:30])#[N:2]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1C#N
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1Cn1c2cccc(O)c2c2c(C(N)=O)cccc21
Yield: 49 %

Procedure:
A solution of the 9-[(2-cyanophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (295 mg, 0.83 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 22 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 140 mg (49%) of the 9-[(2-cyanophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a tan solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.9 (d, 1H, J=8 Hz), 7.75 (d, 1H, J=8 Hz), 7.5-7.4 (m, 4H), 7.25 (t, 1H, J=8 Hz), 7.0 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.4 (m, 1H), and 5.85 (s, 2H). IR (KBr, cm−1) 3448, 3356, 2225, 1628, and 1600. MS (ES) m/e 340, 342.
Reaction SMILES: CC1CC([OH:8])CC=1C.[Si:9]([O:16][CH:17]1[CH2:21][C:20]([CH2:25][CH:26]=[CH2:27])(COC)[CH:19]=[CH:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[Si:9]([O:16][CH:17]1[CH2:21][C:20]([CH2:25][CH:26]=[CH2:27])([OH:8])[CH:19]=[CH:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: C=CCC1(COC)C=CC(O[Si](C)(C)C(C)(C)C)C1
Reactant: CC1=C(C)CC(O)C1
Product: C=CCC1(O)C=CC(O[Si](C)(C)C(C)(C)C)C1
Yield: 92 %

Procedure:
From 4.50 g of (1RS,4RS)-4-allyl-4-hydroxy-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether was obtained by the same procedures as in (3) of the intermediate preparation example 1 (1RS,4RS)-4-allyl-4-methoxymethyl-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether in an amount of 4.88 g. Yield 92%
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[O:1]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCOc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)CCOc1ccccc1
Yield: 2255.8 %

Procedure:
A solution of 3-phenoxypropionic acid (25 g, 150.4 mmol) and p-toluenesulfonic acid (1.23 g, 6.46 mmol) in 500 mL of methanol was heated to reflux under nitrogen atmosphere in a 1 L round-bottom flask though 3 Å, 8-12 mesh molecular sieves which is equipped with a soxhlet extractor and condenser. The mixture was heated at reflux for 21 hr and then cooled. Methanol was removed on a rotary evaporator to leave a light yellow oil which was taken up in 50 mL of water and then extracted with ether (3×75 mL). The combined ether extracts were washed with NaHCO3 solution, water and brine and dried over MgSO4. Removal of the solvent and then Kugelrohr distillation (80° C., 0.8 mm Hg) gave a yield of 26.26 g (97%) of the named product.
Reaction SMILES: C=O.[C:3](O)(=O)C.[Cl:7][C:8]1[C:9]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:36][CH2:35]2)=[N:10][CH:11]=[C:12]([C:14](=[O:33])[NH:15][C:16]2[S:17][C:18]([CH2:27][NH:28][CH:29]3[CH2:32][CH2:31][CH2:30]3)=[C:19]([C:21]3[S:22][CH:23]=[C:24]([Cl:26])[CH:25]=3)[N:20]=2)[CH:13]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl.ClCCCl>[Cl:7][C:8]1[C:9]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:36][CH2:35]2)=[N:10][CH:11]=[C:12]([C:14](=[O:33])[NH:15][C:16]2[S:17][C:18]([CH2:27][N:28]([CH:29]3[CH2:32][CH2:31][CH2:30]3)[CH3:3])=[C:19]([C:21]3[S:22][CH:23]=[C:24]([Cl:26])[CH:25]=3)[N:20]=2)[CH:13]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(CNC4CCC4)s3)cc2Cl)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(CN(C)C4CCC4)s3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
110 μl of a formaldehyde aqueous solution (35%) and 76 μl of acetic acid were added to 2 ml of 1.2-dichloroethane solution of 79 mg of ethyl 1-[3-chloro-5-({4-(4-chlorothiophen-2-yl)-5-[(cyclobutylamino)methyl]thiazol-2-yl}carbamoyl)-2-pyridyl]piperidine-4-carboxylate, and the mixture was stirred at room temperature for 1 hour. Subsequently, 45 mg of NaBH(OAc)3 was added, and the solution was stirred at room temperature for 1 hour. Chloroform was added to the reaction solution, and the organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution, with water and with brine, and then dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane:EtOAc=4:1 to 2:1) to obtain 58 mg of ethyl 1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[cyclobutyl(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N+]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15])([OH:3])=[O:2].N([O-])=O.[Na+].[BrH:21]>[Pd].O>[Br:21][C:8]1[CH:7]=[CH:6][C:5]([CH2:13][C:14]([OH:16])=[O:15])=[C:4]([C:1]([OH:3])=[O:2])[CH:9]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: Br
Agent: [Pd]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccc(Br)cc1C(=O)O

Procedure:
A mixture of 2-carboxy-4-nitrophenylacetic acid (described by H. E. Ungnade et al., J. Org. Chem., 10, 533 (1945), 50 g, 0.22 mol) and 5% palladium on carbon (5 g) is rapidly stirred under an atmosphere of hydrogen until the nitro group is reduced. Water (300 ml) is added and the mixture is warmed to dissolve the precipitate. The mixture is filtered through diatomaceous earth. The filtrate is evaporated and 375 ml of 2 N hydrobromic acid is added. The resulting solution is cooled in an ice-bath to 0°-5° C. Sodium nitrite (15.2 g, 0.22 mol) in 50 ml of water is added while stirring. The latter solution is added slowly to a cold (0°-5° C.) stirring freshly prepared solution of cuprous bromide (150 g, 0.105 mol) in 230 ml of 49% hydrobromic acid. The reaction is stirred at room temperature for 2 hr and the precipitate is collected by filtration. The precipitate is washed with water and dried to obtain 4-bromo-2-carboxyphenylacetic acid (53 g), mp 210°-213° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]1[C:9]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:10]([C:15]([N:17]2[CH2:20][C:19](=O)[CH2:18]2)=[O:16])[CH:11]=[CH:12][C:13]=1[F:14].C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([C:15]([N:17]2[CH2:20][C:19](=[CH2:1])[CH2:18]2)=[O:16])[C:9]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[F:30]
Reactant: O=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reaction time: 15 h
Yield: 21.2 %

Procedure:
Methyl triphenylphosphonium bromide (508 mg, 1.42 mmol) was treated with potassium tert-butoxide (159 mg, 1.42 mmol) in tetrahydrofuran (5 mL) at 0° C. for 10 minutes. 1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (270 mg, 0.605 mmol), prepared using procedures similar to those described in Example 6, was dissolved in tetrahydrofuran (2 mL) and was added to the mixture. The mixture was stirred at ambient for 15 h and then the mixture was filtered and the filtrate was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 20% ethyl acetate in hexanes) gave 2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-[(3-methylideneazetidin-1-yl)carbonyl]aniline (57 mg, 0.128 mmol, 21% yield): 1H NMR (400 MHz, CDCl3): 8.56 (br s, 1H), 7.39 (dd, 1H), 7.35-7.30 (m, 1H), 7.18-7.12 (m, 1H), 6.86-6.76 (m, 1H), 6.62 (ddd, 1H), 5.14-5.00 (br, 2H), 4.74 (br d, 4H); MS (EI) for C17H12F3IN2O: 445 (MH+).
Reaction SMILES: [CH2:1]([O:11][CH:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].P(Br)(Br)[Br:21].CO.C(=O)([O-])O.[Na+]>C(OCC)C>[CH2:1]([O:11][CH:12]([Br:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCCOC(O)c1ccccc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: C=CCCCCCCCCOC(Br)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 223.9 %

Procedure:
First, 16.05 g (0.061 M) of 9-decenoxybenzyl alcohol (compound (23)) prepared in Synthetic example 1-2 was dissolved in 85 mL of diethyl ether, and the solution was cooled to 0° C. After cooling, 6.76 g (0.022 M) of phosphorus tribromide (compound (21)) was added dropwise thereto at 5° C. or less. The mixture was aged at 5° C. for 2 hours and then at 15° C. for 1.5 hours. After aging, the solution was cooled to 5° C. Then, 38 mL of methanol was added dropwise at 5° C. or less. After dropwise addition, 73.4 g of a sodium hydrogen carbonate aqueous solution (1 M) was added dropwise at 10° C. or less, and then phase separation was performed. After the separation, the separated organic layer was washed with 32 mL of deionized water and then concentrated. Thereby, 18.19 g of 9-decenoxybenzyl bromide (compound (24)) was produced (yield: 91.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[OH:14].[Br:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:12])([F:13])[F:11])[CH:5]=[CH:4][C:3]=1[O:14][CH2:18][CH2:17][CH2:16][Br:15]
Reactant: BrCCCBr
Reactant: Oc1ccc(OCC(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(OCCCBr)c(Cl)c1
Temperature: 70 °C
Yield: 56.9 %

Procedure:
To a 110 ml DMF solution of 2-chloro-4-(2,2,2-trifluoroethoxy)phenol (5 g, 22.1 mmol) was added 1,3-dibromopropane (11.2 ml, 110 mmol) and cesium carbonate (9.34 g, 28.7 mmol). The resulting suspension was heated to 70° C. for 5 hr. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel eluting with 10% dichloromethane/hexanes to give the title compound as a clear oil 4.37 g (57%).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[N:14]=[N:13][C:12]([NH2:15])=[CH:11][CH:10]=1>N1C=CC=CC=1.O>[Br:8][C:9]1[N:14]=[N:13][C:12]([NH:15][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:11][CH:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Br)nn1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(Br)nn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Pivaloyl chloride (2.85 ml, 23.2 mmol) was added dropwise to a solution of 6-bromopyridazin-3-amine (2.00 g, 15.4 mmol) in pyridine (8 mL). The mixture stirred 12 h at room temperature, then was diluted with water and extracted with dichloromethane (3×). The combined organic layers were washed with water (2×) and brine, then dried (sodium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (2−>20% EtOAc:Hex) to give title compound.
Reaction SMILES: [C:1]1([NH:7]/[N:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([C:18]([CH3:45])=[CH:19][C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=1[C:33]([N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36]1)=[O:34])([O-])=O>>[C:27]([O:26][C:24]([C:23]1[CH:31]=[CH:32][C:20]([C:19]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:18]=2[CH3:45])=[C:21]([C:33]([N:35]2[CH2:44][CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36]2)=[O:34])[CH:22]=1)=[O:25])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Reactant: CCOC(=O)/C=N/Nc1ccccc1
Product: CCOC(=O)c1nn(-c2ccccc2)c(C)c1-c1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1
Yield: 67.5 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 224E, (E)-ethyl 2-(2-phenylhydrazono)acetate (22 mg, 0.11 mmol) and tert-butyl 4-(2-nitroprop-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (48 mg, 0.11 mmol) were converted to the title compound (42 mg, 65%) as a colorless oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.10 (dd, J=8, 2 Hz, 1H), 8.06-8.04 (m, 1H), 7.49-7.40 (m, 6H), 7.21-6.81 (m, 4H), 5.02-4.96 (m, 1H), 4.49-4.28 (m, 3H), 4.17-4.03 (m, 1H), 3.54-3.33 (m, 1H), 2.82-2.43 (m, 2H), 2.19 (s, 3H), 1.61 (s, 9H), 1.28 (t, J=8 Hz, 1.5H), 1.23 (t, J=8 Hz, 1.5H); MS(ESI+) m/z 566.3 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCNC[CH2:28]1>>[N:19]1([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:20][CH2:21][CH2:28][NH:22][CH2:23][CH2:24]1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Reactant: C1CNCCNC1
Product: O=c1c2c[nH]c3ccc(N4CCCNCC4)nc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described for 6a using perhydro-[1,4]-diazepine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 1.82 (2H, m), 2.65 (2H, m), 2.90 (2H, m), 3.88 (4H, m), 6.89 (1H, d, J=9.07 Hz), 7.05 (1H, t, J=7.41 Hz), 7.35 (2H, dd, J=8.52, 7.41 Hz), 7.74 (1H, d, J=9.07 Hz), 8.25 (2H, m), 8.29 (1H, s). m/z 361.4 (MH+).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:44])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:43])[CH2:12][CH2:13][C@@:14]3([C:30]([N:32]4[CH2:37][CH2:36][C:35]([CH2:41][CH3:42])([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]4)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:46])[CH3:45])(=O)C.C1COCC1.[OH-].[Na+]>CO>[CH2:41]([C:35]1([C:38]([OH:40])=[O:39])[CH2:34][CH2:33][N:32]([C:30]([C@:14]23[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]2[C@@H:16]2[C@@:11]([CH3:43])([CH2:12][CH2:13]3)[C@@:10]3([CH3:44])[C@@H:19]([C@:20]4([CH3:23])[C@@H:7]([CH2:8][CH2:9]3)[C:6]([CH3:46])([CH3:45])[C@@H:5]([OH:4])[CH2:22][CH2:21]4)[CH2:18][CH2:17]2)=[O:31])[CH2:37][CH2:36]1)[CH3:42]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.6 %

Procedure:
1-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)-4-ethylpiperidine-4-carboxylic acid (Example 83, 2.0 g) was taken in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (1.5 g in 4 ml water) was added and the contents were stirred for 6 hours at room temperature. Completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure and the residue was taken in water and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (1.45 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 10H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.15-4.18 (m, 2H); 4.56 (s, 1H); 4.71 (s, 1H); MASS: 595 (100%).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1ccnc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(OCc3cc(C(CC(=O)O)C4CC4)ccn3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(2-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)methyl)pyridin-4-yl)propanoate (71 mg) in THF (1.0 mL) and methanol (0.50 mL) was added 1N aqueous sodium hydroxide solution (1.0 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1N hydrochloric acid (1.0 mL) at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (62 mg) as a white amorphous solid.