Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([S+](N(C)C)N(C)C)C.C[Si-](F)(F)(C)C.[Si]([O:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][C@@H:45]([NH:54][C:55]2[CH:60]=[CH:59][C:58]([S:61]([NH:64][C:65](=[O:99])[C:66]3[CH:71]=[CH:70][C:69]([N:72]4[CH2:77][CH2:76][CH:75]([C@H:78]([C:86]5[CH:91]=[CH:90][CH:89]=[CH:88][C:87]=5[C:92]5[CH:97]=[CH:96][C:95]([Cl:98])=[CH:94][CH:93]=5)[NH:79][S@:80]([C:82]([CH3:85])([CH3:84])[CH3:83])=[O:81])[CH2:74][CH2:73]4)=[CH:68][CH:67]=3)(=[O:63])=[O:62])=[CH:57][C:56]=2[S:100]([C:103]([F:106])([F:105])[F:104])(=[O:102])=[O:101])[CH2:46][S:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:39][CH2:38]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[Cl:98][C:95]1[CH:94]=[CH:93][C:92]([C:87]2[CH:88]=[CH:89][CH:90]=[CH:91][C:86]=2[C@H:78]([NH:79][S@:80]([C:82]([CH3:85])([CH3:84])[CH3:83])=[O:81])[CH:75]2[CH2:74][CH2:73][N:72]([C:69]3[CH:68]=[CH:67][C:66]([C:65]([NH:64][S:61]([C:58]4[CH:59]=[CH:60][C:55]([NH:54][C@H:45]([CH2:44][CH2:43][N:40]5[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][OH:34])[CH2:42][CH2:41]5)[CH2:46][S:47][C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)=[C:56]([S:100]([C:103]([F:106])([F:105])[F:104])(=[O:101])=[O:102])[CH:57]=4)(=[O:63])=[O:62])=[O:99])=[CH:71][CH:70]=3)[CH2:77][CH2:76]2)=[CH:97][CH:96]=1
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCN(CCO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: C[Si-](C)(C)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCN(CCO)CC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Reaction time: 1 h
Yield: 128.1 %

Procedure:
A solution of TASF (0.58 ml. 0.58 mmol, 1.0M in DMF) was added to a solution of N-(4-((R)-4-(4-(2-(tert-butyldiphenylsilyloxy)ethyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)-4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzamide (EXAMPLE 13, STEP 2, 0.39 g, 0.29 mmol) in DMF (2.3 ml) and the reaction mixture was stirred at r.t for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with DCM and washed with H2O. The organic layer was dried (Na2SO4), concentrated under reduced pressure, after filtration, and dried under vacuum to give 4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)-N-(4-((R)-4-(4-(2-hydroxyethyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide (EXAMPLE 13, STEP 2, 0.41 g) which was used in the preparation of EXAMPLE 13, STEP 3 without further purification.
Reaction SMILES: [CH2:1]([CH:3]([OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)[CH3:2].[OH-].[Na+].[CH3:16]S(C)=O.[OH-].[NH4+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[CH3:16][O:13][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)[CH2:1][CH3:2]
Reactant: CS(C)=O
Reactant: CCC(O)c1cccc([N+](=O)[O-])c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC(OC)c1cccc([N+](=O)[O-])c1
Reaction time: 0.83 h

Procedure:
A 500-milliliter flask equipped with a reflux condenser, an addition funnel and a magnetic stirring bar was charged with 31.6 grams (0.1749 mole) of α-ethyl-3-nitrobenzyl alcohol and 0.4 gram tetrabutylammonium iodide in 100 milliliters of diethyl ether. To this stirred mixture was added 36.4 grams (0.4546 mole) of 50 percent aqueous sodium hydroxide solution. Exothermic heating was observed. This mixture was vigorously stirred for 50 minutes, after which was added dropwise 26.6 grams (0.21 mole) of dimethyl sulfoxide. The mixture was stirred for 18 hours, after which an additional 2.0 grams of dimethyl sulfoxide was added and stirring continued for 2 hours. To this stirred mixture, 20 milliliters of concentrated ammonium hydroxide solution was carefully added and stirring continued for 1 hour. The mixture was then transferred to a separatory funnel, diluted with 100 milliliters of diethyl ether, thoroughly shaken, and the organic phase was withdrawn. The organic phase, after washing with 50 milliliters of water, was dried over magnesium sulfate and concentrated on a rotary evaporator at 55° C., leaving an amber liquid. The amber liquid was charged to a distillation flask and distilled at a pressure of 2.0 millimeters of mercury. A main fraction (21.0 grams) was collected, said fraction having a boiling point of 112° C.-115° C. at 2.0 mm Hg pressure. This main fraction was identified by NMR spectroscopy as 1-(1-methoxyprop-1-yl)-3-nitrobenzene.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH2:15])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[CH:8]=1)C>C1COCC1>[NH2:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[CH:8]=1)[CH2:4][OH:3]
Reactant: CCOC(=O)C(C)(N)Cc1cccc(I)c1
Solvent: C1CCOC1
Product: CC(N)(CO)Cc1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
BH3.THF Complex 1 M soln. in THF (9 mL, 9 mmol) was added dropwise to a 0° C. solution of rac-2-amino-3-(3-iodo-phenyl)-2-methyl-propionic acid ethyl ester H-5 (1.2 g, 3.6 mol) in THF (10 mL) under argon and the resulting mixture was stirred for 5 min at 0° C. before being warmed to RT and stirred overnight. The reaction mixture was cooled to 0° C. and quenched with MeOH before being evaporated in vacuo. The residue was partioned between 2M aq. HCl and TBME and stirred for 30 min. The phases were separated and the aqueous phase was re-extracted with TBME (2×) and the combined organic extracts were discarded. The aqueous layer was basified with 2M aq. NaOH and re-extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the title compound as a white solid. LC-MS D: tR=0.74 min; [M+H+MeCN]+=333.02.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.Cl[C:18](OCC)=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>C(Cl)(Cl)Cl.CN(C)C=O.O>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:18](=[O:19])[NH:1][C:2]=2[CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(O)c(N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc2oc(=O)[nH]c2c1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
2-Amino-4-methylphenol (5.00 g, 40.6 mmol) and triethylamine (17 ml, 122 mmol) were dissolved in chloroform (100 ml), ethyl chloroformate (5.8 ml, 61 mmol) was added at room temperature with stirring, and thereafter the mixture was stood at the same temperature overnight. Water was added to the reaction mixture, the mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. N,N-Dimethylformamide (35 ml) and potassium carbonate (11.2 g, 81.2 mmol) were added to the obtained residue, and the mixture was stirred at 70° C. for 9 hr. The reaction mixture was cooled to room temperature, and 3N hydrochloric acid was added with stirring. The precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (4.94 g, yield 82%) as a pale-bistered solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:12][CH:13]=C)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.I([O-])(=O)(=O)=[O:16].[K+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[CH2:5]([O:4][CH2:3][C@H:2]([CH3:1])[CH2:12][CH:13]=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CCC(C)COCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@H](CC=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.7 %

Procedure:
A 250 mL round-bottomed flask, equipped with a magnetic stirring bar and a thermometer was fitted with a septum and a nitrogen inlet. The apparatus was charged with benzyl 2-methyl-4-penten-1-yl ether (2.39 g, 12.5 mmol) in 75 mL of acetone and 25 mL of water. Osmium tetroxide (0.833 mL of an 0.15M aqueous solution, 0.125 mmol) was added in one portion, followed by potassium periodate (6.04 g, 26.2 mmol) in three equal portions. The resulting slurry was stirred for 6 hours at room temperature and decanted into a 500 mL separatory funnel. The aqueous layer was extracted with 3×200 mL of diethyl ether. Each washing was stirred over the solids for 5 minutes, washed with 150 mL of saturated aqueous sodium thiosulfate and 100 mL of saturated aqueous sodium chloride. The combined organic layers were dried over sodium sulfate, filtered, concentrated and chromatographed (4×20 cm column; 4:1 hexane:ethyl acetate) to afford 1.94 g (81%) of aldehyde 4 as a colorless oil. Rf =0.37 (4:1 hexane:ethyl acetate).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:16](=[O:17])[N:15]2[CH:18]([C:21](=[O:40])[NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[NH:31])=[CH:26][CH:25]=3)[CH2:19][CH2:20][C:14]2=[N:13][CH:12]=1)C1C=CC=CC=1>CO.[Pd]>[C:36]([O:35][C:33](=[O:34])[NH:32][C:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:21]([C@H:18]2[N:15]3[C:16](=[O:17])[C:11]([NH2:10])=[CH:12][N:13]=[C:14]3[CH2:20][CH2:19]2)=[O:40])=[CH:25][CH:26]=1)=[NH:31])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)C2CCc3ncc(NC(=O)OCc4ccccc4)c(=O)n32)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Reaction time: 24 h
Yield: 84 %

Procedure:
To a solution of intermediate 1i (74.8 mg, 0.134 mmol) in 3 mL MeOH, was added 80 mg 10% Pd/C. The mixture was evacuated and flushed with H2 (3×), then it was stirred under an atmosphere of H2 for 24 h. The mixture was filtered and concentrated to afford 48 mg (84%) of intermediate 1j. MS (ESI) 427.08 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:4][CH:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:4][CH:3]=2)=[CH:24][CH:23]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cccc(-c2cccc(Br)n2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cccc(-c2cccc(-c3ccc(C(C)C)cc3)n2)c1
Temperature: 80 °C
Yield: 69.5 %

Procedure:
Part B. A solution of ethyl 3-(6-bromo-pyridin-2-yl)-benzoate (154 mg, 0.5 mmol) and 4-isopropylbenzeneboronic acid (83 mg, 0.5 mmol) in acetonitrile is treated with a solution of sodium carbonate (160 mg) in water (1 mL). The mixture is degassed twice, and a catalytic amount of tetrakis(triphenylphosphine)palladium is added under the protection of nitrogen. The reaction mixture is stirred at 80° C. until the consumption of starting material is observed by TLC. The mixture is cooled, filtered and evaporated, and the residual material is partitioned between water and ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate, filtered and evaporated. The residue is purified by column chromatography to afford ethyl 3-[6-(4-isopropyl-phenyl)-pyridin-2-yl]-benzoate (120 mg, 69%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:13]=[C:12]([O:27][CH3:28])[N:11]=2)=[CH:6][C:3]=1[CH:4]=O.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:48]>C(Cl)Cl.CCOC(C)=O>[ClH:48].[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([O:27][CH3:28])[N:13]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH:15]=2)=[CH:6][C:3]=1[CH2:4][NH:33][CH2:32][CH2:31][O:30][CH3:29]
Reactant: COc1ccc(CCNc2cc(-c3ccc(F)c(C=O)c3)nc(OC)n2)cc1
Reactant: COCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCNCc1cc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)ccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
A mixture of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde [300 mg, 0.787 mmol, Example 35(j)], 2-methoxyethylamine (170 μL, 1.97 mmol), sodium triacetoxyborohydride (500 mg, 2.36 mmol) and 3 Å sieves (500 mg) in DCM (7 mL) is stirred at room temperature under a nitrogen atmosphere for 5 hours. The reaction mixture is filtered and the filter cake is washed with DCM (50 mL). The combined filtrate and washings are extracted with water (50 mL). The aqueous extract is extracted with DCM (50 mL). The new organic extract is washed with water (30 mL), with brine (30 mL), dried over sodium sulfate, filtered and concentrated by rotary evaporator. The resulting solid is subjected to flash column chromatography on silica (4.5 g) eluting with 0 to 8% MeOH in DCM gradient to afford a solid. This material is treated with hydrogen chloride in EtOAc and concentrated to afford (6-{4-fluoro-3-[(2-methoxy-ethylamino)-methyl]-phenyl}-2-methoxy-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine hydrochloride [260 mg, 75%, Example 13(b)] as a solid. LCMS: RT=1.98 minutes, MS: 441 (M+H). 1H NMR (300 MHz, CDCl3): δ 9.65 (1H, s), 8.27 (1H, s), 7.91 (1H, s), 7.47 (1H, t, J=0.03 Hz), 7.21 (2H, d, J=0.027 Hz), 6.85 (2H, d, J=0.027 Hz), 4.26 (2H, s), 4.03 (2H, s), 3.72 (6H, s), 3.31 (3H, s), 3.17 (2H, m), 2 (2H, t, J=0.024), 2.5 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=1.[C:17](OC)(OC)(OC)[CH3:18].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO.C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:17]([CH3:18])[N:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:3]=2[CH:4]=1
Reactant: COC(C)(OC)OC
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Temperature: 70 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (300 mg, 1.07 mmol) in a mixture of methanol (5 mL) and THF (20 mL) was added trimethyl orthoacetate (2.02 ml, 0.02 mol) and TsOH (0.02 ml, 0.11 mmol). The reaction mixture was stirred at 70° C. for 40 min then allowed to stand at RT for 3 days. A saturated aqueous solution of NaHCO3 was added. The product was extracted into DCM (×3) and the organic layers were washed with brine and then dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Isolute column, 1-2% MeOH in DCM) to give the title compound as a yellow solid; 1H NMR (500 MHz, DMSO) δ 2.67 (3H, s), 6.88 (1H, d, J=5.20 Hz), 7.13 (2H, br. s.), 7.41 (1H, dd, J=8.51, 1.89 Hz), 7.58 (1H, d, J=8.51 Hz), 7.86 (1H, d, J=1.89 Hz), 8.48 (1H, d, J=5.20 Hz); LC-MS: m/z=+303.9, 305.7 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].C[O:13][C:14]1[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:15]=1C(O)=O>>[OH:10][C:8]1[CH:7]=[CH:6][C:4]2[N:5]=[C:1]([C:20]3[CH:19]=[CH:15][C:14]([OH:13])=[CH:22][C:21]=3[OH:23])[O:2][C:3]=2[CH:9]=1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: COc1ccc(N)c(OC)c1
Product: Oc1ccc(-c2nc3ccc(O)cc3o2)c(O)c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 2,4-dimethoxybenzoic acid and was obtained as a white solid, m.p. 293-296° C.; MS m/e 242 (M−H)+.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[CH:11]1([CH2:14][C:15]#[N:16])[CH2:13][CH2:12]1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[C:15]([CH:14]([CH:11]1[CH2:13][CH2:12]1)[C:3]([O:7][CH2:8][CH3:9])=[O:10])#[N:16]
Reactant: N#CCC1CC1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)C1CC1

Procedure:
To a solution of sodium hydride (60% in mineral oil, 38 g) and diethyl carbonate (97 mL) in toluene (240 mL) was added dropwise a solution of cyclopropylacetonitrile (32 g) in toluene (120 mL) over 40 min with heating under reflux, and the mixture was heated under reflux for additional 2 hr. The mixture was neutralized with acetic acid (120 mL) in an ice bath, water was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was distilled (boiling point 69-72° C., 4.0 mmHg) to give the title compound (50 g).
Reaction SMILES: CO[N:3]=[CH:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][OH:12].B.C1COCC1.[OH-].[Na+]>C1COCC1.O>[NH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][OH:12]
Reactant: CON=Cc1cc(-c2ccccc2)ccc1CO
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(-c2ccccc2)ccc1CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the oxime from step B (0.51 g, 2.1 mmol) in THF (15 mL) at 0° C. was added BH3.THF (1M in hexane; 8 mL, 8 mmol) and the resulting solution was stirred at room temperature for 16 h then heated to reflux for 24 h. The solution was cooled to 0° C. and 1N NaOH (10 mL) was added slowly. After 1 h, the mixture was diluted with water, extracted with EtOAc (3×), washed with brine, dried and evaporated to give the title compound as an oil. This was used as such in the next step.
Reaction SMILES: C(CCC1C=CC([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=CC=1)(O)=O.B([C:47]1[CH:55]=[CH:54][C:50]([C:51]([OH:53])=[O:52])=[C:49]([Cl:56])[CH:48]=1)(O)O.B(O)O>>[C:51]([C:50]1[CH:54]=[CH:55][C:47]([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=[CH:48][C:49]=1[Cl:56])([OH:53])=[O:52]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)c1ccc(B(O)O)cc1Cl
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(Cl)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-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]chrysene-3a-carboxylic acid (example 4a) using 4-borono-2-chlorobenzoic acid as the reactant boronic acid. Purification of the product was accomplished by first using Biotage flash chromatography with a 0-50% ethyl acetate in hexanes gradient with 0.1% acetic acid added to the mixture. The compound was not sufficiently pure, so further purification by prep HPLC followed (acetonitrile/water mobile phase with TFA buffer on a C18 reverse phase column). After concentrating the desired fractions, the title compound was isolated as a white film (6.1 mg, 6.8% yield over two steps). LCMS: m/e 591.60 (M−H)−, 1.54 min (method 1). 1H NMR (500 MHz, Pyr) δ ppm 0.92 (br. s., 6H), 0.96 (s, 3H), 1.10 (s, 3H), 1.11 (s, 3H), 1.18-1.84 (m, 15H), 1.83 (s, 3H), 1.89 (t, J=13.28 Hz, 1H), 1.99 (br. s., 1H), 2.09 (dd, J=17.09, 6.10 Hz, 1H), 2.24-2.33 (m, 2H), 2.66 (d, J=12.51 Hz, 1H), 2.81 (t, J=11.75 Hz, 1H), 3.54-3.63 (m, 1H), 4.82 (s, 1H), 5.00 (s, 1H), 5.37 (d, J=5.80 Hz, 1H), 7.24 (d, J=8.24 Hz, 1H), 7.51 (s, 1H), 8.21 (d, J=7.63 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:13][C:12]([CH:22]=[O:23])=[CH:11][C:10]=1[C:24]([CH3:27])([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([Mg]Br)#[CH:29].[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[CH:13][C:12]([CH:22]([OH:23])[C:28]#[CH:29])=[CH:11][C:10]=1[C:24]([CH3:27])([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(C=O)cc(C(C)(C)C)c2OCc2ccccc2)cc1
Reactant: C#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)c1cc(-c2ccc(C)cc2)c(OCc2ccccc2)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
780 mg (2.2 mmol) of 6-benzyloxy-5-tert-butyl-4′-methyl-3-biphenylcarbaldehyde are dissolved in 50 mL of THF, and the reaction medium is cooled to 0° C. 5.7 mL (2.8 mmol) of 0.5 M ethynylmagnesium bromide solution are added slowly. The medium is stirred at 0° C. for 2 hours and the reaction is then treated with a saturated ammonium chloride solution. The residue obtained is purified by chromatography on a column of silica (eluent: 9 heptane/1 ethyl acetate). A yellow oil is obtained (m=740 mg; yield=89%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][N:8]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[C:19]([CH2:26][CH2:27][NH:28][C:29](=[O:37])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH2:9][CH2:10][C:11]([O:13]CC)=[O:12].Cl>CO>[CH3:7][N:8]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[C:19]([CH2:26][CH2:27][NH:28][C:29](=[O:37])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)CCN(C)c1ccc2cccc(CCNC(=O)Cc3ccccc3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(CCC(=O)O)c1ccc2cccc(CCNC(=O)Cc3ccccc3)c2c1

Procedure:
An aqueous 0.5N solution of K2CO3 (10 ml) is added to the product obtained in Step A (4 mmol) dissolved in methanol (10 ml). When the reaction has ceased, the solution is acidified to pH 6–7 using 1N hydrochloric acid solution. The reaction mixture is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue is chromatographed on silica gel to yield the title product.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][C:20]([C:26]([O:28]C)=[O:27])=[CH:19][C:18]=3[CH:30]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][C:20]([C:26]([OH:28])=[O:27])=[CH:19][C:18]=3[CH:30]=2)=[CH:31][CH:32]=1)[CH2:2][CH3:3]
Reactant: CCCOCCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOCCOc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 65 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
Into a solution of methyl 7-[[4-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.54 g) in THF-methanol (10-5 ml) was added at room temperature 2.4 ml of a 1 M aqueous solution of potassium carbonate (2.6 mmol), and the resulting mixture was stirred at 65° C. for 20 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. To the aqueous layer was added 1 N hydrochloric acid (10 ml), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[[4-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (321 mg) as light yellow crystals.