Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH2:18][O:19]C1CCCCO1)[CH2:3][N:4]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[N:5]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>CCO>[CH3:1][C:2]([CH3:26])([CH2:3][N:4]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[N:5]1)[CH2:18][OH:19]
Reactant: CC(C)(COC1CCCCO1)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(CO)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.2 %

Procedure:
1-[2,2-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Compound 47C, 539 mg, 1.48 mmol) was dissolved in EtOH (2.64 mL) and p-TsOH.H2O (56.3 mg, 0.296 mmol) was added to the reaction mixture. The reaction was left to stir at rt for 16 hrs. Solid NaHCO3 (1.24 g, 14.8 mmol) was added to the reaction mixture and left to stir at rt for an additional 30 min. The reaction mixture was quenched with water and then extracted with EtOAc. The organic layer was washed with sat. NaHCO3 (1×), brine (2×), extracted, dried over sodium sulfate, filtered, concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [0-30% Acetone/Heptanes] to afford 237 mg of the title compound (57%). MS (ESI): m/z=281.38 [M+H]+. UPLC: tR=1.12 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.Br[CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33].N>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][N:23]([CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:26])[F:27])[CH:4]=1
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Reactant: CC(C)=CCBr
Agent: N
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(CC=C(C)C)CC[C@@H]2N4CCC3)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (25 mg, 71%) from (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) and 4-bromo-2-methyl-2-butene (23 mg, 0.15 mmol). 1H NMR (CDCl3, 300 MHz) δ1.65 (s, 3H), 1.79 (s, 3H), 2.12-2.22 (m, 3H), 2.24-2.40 (m, 1H), 2.57 (se, J=7.7 Hz, 2H), 2.72 (t, J=6.6 Hz, 2H), 2.74-2.84 (br, 1H), 3.05-3.45 (m, 6H), 3.59-3.77 (m, 1H), 3.86 (s, 3H), 5.42-5.55 (br, 1H), 6.83 (s, 1H), 6.85 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 7.17-7.25 (m, 2H) ppm. MS (CI, NH3): 457.2 (base, M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][CH:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:26]([CH:24]([CH3:25])[CH3:23])(=[O:28])=[O:27])[CH:3]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Reaction time: 8 h
Yield: 36.5 %

Procedure:
2-(3-Aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (100 mg, 0.34 mmol) was dissolved in 2 mL of dry pyridine under nitrogen. Then propane-2-sulfonyl chloride (0.1 mL, 0.89 mmol) was added drop wise to the reaction mixture. The reaction mixture was allowed to stir overnight. Thin layer chromatography (petroleum ether:ethyl acetate=1:1, Rf=0.5) showed the reaction was complete. Pyridine was removed in vacuo and the residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to afford 50 mg of 3,3-dimethyl-2-(3-(1-methylethylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 36.8%. MS (ES+APCI) M+1=403.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.CCOC(C)=O>C1COCC1.O>[C:1]([O:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCCCCCCCSc1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(SCCCCCCCCCC(=O)O)cc1
Reaction time: 24 h
Yield: 106 %

Procedure:
4-(9-Methoxycarbonyl nonylsulfanyl) benzoic acid tert-butyl ester (2.46 g, 6.2 mmol) was dissolved in THF (25 ml). 1 N NaOH (6.2 ml, 6.2 mmol) was added and the mixture was stirred under N2 for 1 d. 1 N HCl (6.5 ml) diluted with water (100 ml) was added, and then AcOEt (100 ml) was added. The organic phase was dried over MgSO4 and concentrated under vacuum to yield a white solid (2.5 g).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[CH2:7][CH2:6]1)[CH2:2][C:3]#[CH:4].I[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>C(N)CCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:23][C:22]1[CH:21]=[C:20]([C:4]#[C:3][CH2:2][CH2:1][N:5]2[CH2:10][CH2:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)([OH:11])[CH2:7][CH2:6]2)[CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cccc(I)c1
Reactant: C#CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Product: Nc1cccc(C#CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c1
Yield: 68.5 %

Procedure:
A solution of 1-(3-butynyl)-4-(4-chlorophenyl)-4-hydroxypiperidine (263 mg, 1.00 mmol), 3-iodoaniline (208 mg, 0.950 mmol) and tetrakis(triphenylphosphine) palladium (0) (46 mg) in n-butylamine (5 mL) is allowed to reflux for 15 hr. The solvent is evaporated in vacuo to give a residue, which is purified by flash chromatography giving the product as an off white solid (231 mg, 69%): mp 139-140° C.; 1H NMR (CDCl3) 1.71 (m, 3 H), 2.12 (m, 2 H), 2.56 (m, 4 H), 2.73 (m, 2 H), 2.84 (m, 2 H), 3.60 (bs, 2 H), 6.59 (d, J=7.5 Hz, 1 H), 6.72 (s, 1 H), 6.79 (d, J=7.5 Hz, 1 H), 7.07 (dd, J1=J2=7.5 Hz, 1 H), 7.33 (d, J=9.7 Hz, 2 H), 7.46 (d, J=9.7 Hz, 2 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[N:7]2)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[N:7]2
Reactant: CCOC(=O)c1cnc2cc([N+](=O)[O-])ccc2n1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(N)ccc2n1
Reaction time: 3 h
Yield: 65.5 %

Procedure:
To a flask containing compound 7 (2.93 g, 11.9 mmol) in ethanol (500 mL) was added 10% Pd/C (300 mg). The mixture was degassed and stirred under a H2 atmosphere for 3 h 45. The catalyst was removed by filtration through Celite® 545, washed with ethanol (50 mL) and the filtrate was evaporated. The resulting crude product was purified by chromatography (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to afford the title product 8 (1.69 g, 7.79 mmol) as a dark yellow solid. Yield 66%; Rf (Al2O3, CH2Cl2/EtOH, 99/1, v/v) 0.55; mp 181-183° C.; IR (KBr)□ ν 1299, 1487, 1613, 1701, 3202, 3431 □cm−1; 1H NMR (200 MHz, CDCl3) δ 1.49 (t, 3H, J=7 Hz), 4.38 (m, 2H), 4.56 (q, 2H, J=7 Hz), 7.16 (d, 1H, J=2.5 Hz), 7.26 (dd, 1H, J=2.5, 9 Hz), 8.05 (d, 1H, J=9 Hz), 9.35 (s, 1H); MS m/z 217 (M+, 23), 145 (100), 117 (19), 90 (16), 63 (14).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.Cl.O.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:17]1[CH2:18][CH2:19][NH:14][CH2:15][CH2:16]1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: COc1ccc2[nH]cc(C3CCNCC3)c2c1

Procedure:
This compound was prepared following the procedure described in Example 1 (parts A and B) starting with 5 g (33.9 mmol) of 5-methoxyindol and 13.2 g (86.2 mmol) of 4-piperidone monohydrate hydrochloride. After the usual work-up 6.5 g (83% of yield) of the desired product were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([F:13])[C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]([C@@H:18]1[O:20][CH2:19]1)=[O:17].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[F:13][C:11]1[C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=[C:2]([NH:1][CH2:19][C@@H:18]([OH:20])[C:16]([O:15][CH3:14])=[O:17])[CH:12]=1
Reactant: COC(=O)[C@H]1CO1
Reactant: Cn1c(=O)oc2cc(N)cc(F)c21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](O)CNc1cc(F)c2c(c1)oc(=O)n2C
Temperature: 90 °C
Yield: 99.6 %

Procedure:
A mixture of 6-amino-4-fluoro-3-methyl-1,3-benzoxazol-2(3H)-one (Step 7, 0.630 g, 3.46 mmol), methyl (2R)-glycidate (0.353 g, 3.46 mmol) and lithium trifluoromethanesulfonate (0.540 g, 3.46 mmol) in acetonitrile (10 ml) is stirred and heated at 90° C. overnight. The reaction mixture is diluted with ethyl acetate, washed with water and saline, dried (MgSO4), and evaporated under reduced pressure. Final purification by flash column chromatography (50% ethyl acetate/hexane) gives pure product as a white solid (0.98 g, 60%); MS for C12H13FN2O5 m/z 285 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8]2)=[C:4]([CH3:14])[CH:3]=1.[CH3:15][O:16]C(Cl)Cl>ClCCl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:12])([CH3:13])[CH2:8]2)=[C:4]([CH3:14])[C:3]=1[CH:15]=[O:16]
Reactant: Cc1cc(Cl)c(C)c2c1CC(C)(C)C2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(Cl)c(C=O)c(C)c2c1CC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of 19.8 g of the 6-chloro-2,2,4,7-tetramethylindane in 100 ml of dry dichloromethane was continuously added 13 ml of α,α-dichloromethyl methyl ether and 12.4 ml of TiCl4 at 0° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with 200 ml of water, and separated the organic layer. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 21.8 g of the title compound as yellow solid.
Reaction SMILES: [S:1]1[C:5]([CH2:6][C:7]2[C:8](C)=[CH:9][C:10]([OH:23])=[C:11]([CH:13]3[CH:18]([OH:19])[CH:17]([OH:20])[CH2:16][CH:15]([CH2:21][OH:22])[O:14]3)[CH:12]=2)=[CH:4][C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2.[C:29](Cl)(=[O:36])C1C=CC=CC=1>N1C=CC=CC=1>[S:1]1[C:5]([CH2:6][C:7]2[C:8]([O:36][CH3:29])=[CH:9][C:10]([OH:23])=[C:11]([CH:13]3[CH:18]([OH:19])[CH:17]([OH:20])[CH2:16][CH:15]([CH2:21][OH:22])[O:14]3)[CH:12]=2)=[CH:4][C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(O)c(C2OC(CO)CC(O)C2O)cc1Cc1cc2ccccc2s1
Solvent: c1ccncc1
Product: COc1cc(O)c(C2OC(CO)CC(O)C2O)cc1Cc1cc2ccccc2s1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
To a solution of allyl α-D-glactonpyranoside (1, 5.0 g, 22.7 mmol) in 100 mL of dry pyridine at −35˜−30° C. was added benzoyl chloride dropwise with stirring. The reaction mixture was stirred at that temperature for 20 mins, then warmed to room temperature and stirred at room temperature for 48 h. The reaction was quenched by the dropwise addition of the reaction mixture to 200 ml of ice-cold saturated aqueous sodium bicarbonate with stirring. The aqueous mixture was extracted with EtOAc three times (150 ml each time). The combined extracts were washed with 1N HCl six times, brine, dried over Na2SO4, then evaporated to dryness in vacuo to give the crude product as light orange oil, which was purified by flash column chromatography on silica gel (150 g AnaLogix column, EtOAc/heptane: 0>>>5%>>>15%>>>35%) to yield compound 2 (8.55 g, 70.7%) as a white solid. 1H NMR (CDCl3) δ 8.07 (s, 1H), 8.05 (d, J=1.01 Hz, 1H), 8.01 (dd, J=3.03, 1.52 Hz, 2H), 7.99 (dd, J=3.03, 1.52 Hz, 2H), 7.59 (m, 1H), 7.52 (m, 2H), 7.46 (t, J=7.58 Hz, 2H), 7.35-7.42 (4H), 5.86 (ddd, J=16.67, 11.12, 5.56 Hz, 1H), 5.79 (dd, J=11.12, 0.03 Hz, 1H), 5.70 (dd, J=10.61, 3.54 Hz, 1H), 5.35 (d, J=3.54 Hz, 1H), 5.27 (dq, J=17.18, 1.52 Hz, 1H), 5.12 (dq, J=10.61, 1.52 Hz, 1H), 4.68 (dd, J=11.62, 6.57 Hz, 1H), 4.55 (dd, J=11.12, 6.57 Hz, 1H), 4.42 (m, 2H), 4.25 (m, 1H), 4.10 (m, 1H), 2.47 (d, J=4.04 Hz, 1H). MS (ES) 554.8 (M+Na+).
Reaction SMILES: CON(C)[C:4](=[O:22])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][O:9][CH2:8]1.[CH:24]([Mg]Br)=[CH2:25].Cl>O1CCCC1>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:5]([CH2:6][CH:7]2[CH2:11][CH2:10][O:9][CH2:8]2)[C:4](=[O:22])[CH:24]=[CH2:25])=[CH:17][CH:16]=1)(=[O:19])=[O:20]
Reactant: CON(C)C(=O)C(CC1CCOC1)c1ccc(S(C)(=O)=O)cc1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCOC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
A solution of N-methoxy-N-methyl-2-[4-(methylsulfonyl)phenyl]-3-(tetrahydrofuran-3-yl)propanamide (2.96 g) in tetrahydrofuran (34.6 mL) was cooled to 0° C., vinylmagnesium bromide (1.0M tetrahydrofuran solution, 34.6 ml) was added dropwise thereto. The reaction mixture was stirred at room temperature for 4 hr, and poured into 1M hydrochloric acid, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (2.06 g, yield 77%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][CH:35]([CH2:38][CH3:39])[CH2:36][CH3:37])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][CH:35]([CH2:36][CH3:37])[CH2:38][CH3:39])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OC(CC)CC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(CC)Oc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1-ethylpropoxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (190 mg) is dissolved in ethanol (5 ml), and thereto is added a 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 3 hours and 30 minutes. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→93:7) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1-ethylpropoxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (158 mg). The resulting 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1-ethylpropoxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (158 mg) is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (237 μl) and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1-ethyl-propoxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (149 mg). MS (m/z): 666 [M−Na]−
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C([O-])([O-])=O.[K+].[K+].[F-].[K+].N>C1COCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:9]12[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10]1)[CH:7]([O:6][C:5]1[CH:15]=[CH:16][C:2]([C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[NH:17][CH:18]=[CH:19]4)=[CH:3][CH:4]=1)[CH2:8]2
Reactant: Ic1ccc(OC2CN3CCC2CC3)cc1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: [Pd]
Agent: N
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1cc2cc(-c3ccc(OC4CN5CCC4CC5)cc3)ccc2[nH]1

Procedure:
Under N2, the product of Example 1A (329 mg, 1 mmol), 5-indolylboronic acid (Frontier, 193 mg, 1.2 mmol), Pd2(dba)3 (Aldrich, 24 mg, 0.025 mmol), (tBu3P)2 Pd (26 mg, 0.05 mmol), K2CO3 (276 mg, 2 mmol) and KF (80 mg, 1.4 mmol) in THF(8 mL) was stirred at 60° C. overnight. The reaction was monitored with TLC. After the reaction was complete, it was diluted with EtOAc (30 mL) and washed with brine (2×5 mL). The organic solution was concentrated under reduced pressure and the title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (80 mg, yield, 25%). 1H NMR (300 MHz, CD3OD) δ 1.44-1.58 (m, 1H), 1.62-1.90 (m, 2H), 2.01-2.15 (m, 1H), 2.16-2.24 (m, 1H), 2.74-3.04 (m, 5H), 3.27-3.40 (m, 1H), 4.51-4.59 (m, 1H), 6.46 (dd, J=3.4, 1.1 Hz, 1H), 6.95 (dt, J=8.8, 2.6 Hz, 2H), 7.22 (d, J=3.1 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.40 (dt, J=8.5, 1.0 Hz, 1H), 7.54 (dt, J=9.2, 2.6 Hz, 2H), 7.71 (dd, J=1.7, 0.7 Hz, 1H) ppm. MS (DCI/NH3): m/z 319 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10](Cl)(=[O:12])[CH3:11].[OH:14][CH:15]1[C:24]2[N:23]=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH2:18][CH:17]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:16]1>CN(C)C1C=CN=CC=1.ClCCl>[C:10]([O:14][C@@H:15]1[C:24]2[N:23]=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH2:18][C@H:17]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH2:16]1)(=[O:12])[CH3:11]
Reactant: COc1ccc(CC2Cc3cc(C)cnc3C(O)C2)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C[C@H]2Cc3cc(C)cnc3[C@@H](OC(C)=O)C2)cc1
Reaction time: 8 h
Yield: 115 %

Procedure:
Diisopropylethylamine (0.51 g, 3.9 mmol), a catalytic amount of 4-dimethylaminopyridine and a solution of acetyl chloride (0.31 g, 3.9 mmol) in dichloromethane (5 ml) were added slowly to a solution of 5,6,7, 8-tetrahydro-8-hydroxy-6-((4-methoxyphenyl)methyl)-3-methylquinoline (1.12 g, 3.9 mmol) in dichloromethane (7 ml) at room temperature. The mixture was stirred overnight before further additions of acetyl chloride (0.32 g, 4 mmol) and diisopropylethylamine (0.51 g, 4 mnmol) were made. The mixture was again stirred overnight then diluted with dichloromethane (15 ml) and washed with water (1×15 ml), sodium hydrogen carbonate (1×15 ml), brine (1×15 ml) and water (1×15 ml). After drying (MgSO4) the reaction mixture was concentrated under reduced pressure to give an oil (1.46 g). This product was chromatographed on silica gel eluting with ethyl acetate/hexane (1:1) to give a fraction which on evaporation gave a solid (0.8 g). The solid was recrystallised from hexane to afford the title compound, (0.45 g), mp 113°-115° C., [α]D27 =+46° (1%CHCl3).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:11][C:12]2[C:19]([CH3:20])=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:21])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>C(OCC)(=O)C>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([NH:29][C:2]2[N:3]=[C:4]([O:11][C:12]3[C:19]([CH3:20])=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=3[CH3:21])[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:31][CH:32]=1)#[N:35]
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Cl)nc2ccsc12
Reactant: N#Cc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccsc12
Temperature: 90 °C
Reaction time: 15 h
Yield: 34 %

Procedure:
To a solution of 4-(2-chlorothieno[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (187 mg, 0.6 mmol), TFA (0.37 mL, 4.8 mmol) in TFE (3 mL) was added 4-aminobenzonitrile (283 mg, 2.4 mmol) in a sealed tube. The reaction was stirred at 90° C. for 15 h. Reaction mixture was diluted with ethyl acetate (5 mL) and washed with saturated NaHCO3 (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep HPLC afforded the product as a white solid (81 mg, 34%):
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13](N2[C@H](C3C=CC=CC=3)[C@H](C)N(C)C2=O)=[O:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:29][C:30]1[CH:31]=[C:32]([Mg]Br)[CH:33]=[C:34]([F:36])[CH:35]=1.C1([C@@H](C2C=CC(S(C)(=O)=O)=CC=2)CC=O)C=CC=CC=1>>[F:29][C:30]1[CH:31]=[C:32]([C@@H:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)[CH2:12][CH:13]=[O:14])[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)N(C(=O)C=Cc2ccc(S(C)(=O)=O)cc2)C(=O)N1C
Reactant: Fc1cc(F)cc([Mg]Br)c1
Agent: CS(=O)(=O)c1ccc([C@@H](CC=O)c2ccccc2)cc1
Product: CS(=O)(=O)c1ccc([C@@H](CC=O)c2cc(F)cc(F)c2)cc1

Procedure:
This was prepared from (4S,5R)-1-(3-[4-methanesulfonylphenyl]acryloyl)-3,4-dimethyl-5-phenyl-imidazolidin-2-one and 3,5-difluorophenylmagnesium bromide using a method similar to that used to prepare (S)-3-phenyl-3-(4-methanesulfonyl-phenyl)propionaldehyde from phenylmagnesium bromide (Method N).