Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:24]=[CH:23][C:10]([CH2:11][O:12][C:13]([CH3:22])([C:18]([F:21])([F:20])[F:19])[C:14]([O:16]C)=[O:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].CO>O>[C:1]1([C:7]2[CH:24]=[CH:23][C:10]([CH2:11][O:12][C:13]([CH3:22])([C:18]([F:19])([F:20])[F:21])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(C)(OCc1ccc(-c2ccccc2)cc1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(OCc1ccc(-c2ccccc2)cc1)(C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42 %

Procedure:
A mixture of (±)-methyl 2-[(4-phenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionate (28.1g.), potassium hydroxide (5.6g.), methanol (200ml.) and water (25ml.) is stirred at ambient temperature for 2.5 hours. The suspension is separated by filtration and the filtrate evaporated in vacuo. The residue is mixed with water, and the solution is washed with light petroleum (b.p. 60°-80° C). The aqueous phase is acidified with concentrated hydrochloric acid then extracted with ether. The extracts are dried (Na2SO4) and evaporated. The residue is crystallised from light petroleum (b.p. 80-100° C.) to give (±)-2-[(4-phenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionic acid (11.3g.), m.p. 132°-134° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:16]([O-])([OH:18])=[O:17]>>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([N+:16]([O-:18])=[O:17])([C:12]([O:14][CH3:15])=[O:13])[CH2:11][C:2]=1[OH:1]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(C(=O)OC)c(O)c1
Product: COC(=O)C1=C(O)CC(C(=O)OC)([N+](=O)[O-])C=C1

Procedure:
Dimethyl hydroxyterephthalate (3.00 g, 14.3 mmol) was cooled to 5° C. and mixed with 7 mL fuming nitric acid for 40 min. The reaction mixture was poured onto ice and extracted with ethyl acetate. The organic layer was washed with pH 7 phosphate buffer, saturated NaCl, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to yield crude 3.0 g dimethyl-2-hydroxy-4-nitroterephthalate. IR: 1739, 1688, 1549, 1442, 1338 and 1254 cm−1
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>>[F:13][C:12]1[C:7]([F:6])=[C:8]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:9]=[CH:10][C:11]=1[B:23]([OH:28])[OH:24]
Reactant: CCCCCCCCOc1cccc(F)c1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CCCCCCCCOc1ccc(B(O)O)c(F)c1F

Procedure:
Quantities: n-butyllithium (10 cm3, 10.0M in hexanes, 0.1 mol), compound from Example 41 (23.4 g, 0.1 mol) and triisopropyl borate (37.6 g, 0.2 mol). The experimental procedure was as described in Example 28.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[C:10]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)C(=O)OCC(C)C
Product: CC(C)COC(=O)[C@H](C)Nc1cc(Cl)cc(Cl)c1

Procedure:
Following General Procedure AA above and using 3,5-dichloroaniline (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[C:32]1([CH3:44])[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:41]3[CH2:42][CH2:43][N:38]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH3:44])[CH2:39][CH2:40]3)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Reactant: Cc1ccccc1N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(F)cc2c1NC(c1cccc(N3CCN(c4ccccc4C)CC3)c1)C(C)(C)C2
Temperature: 120 °C
Reaction time: 12 h
Yield: 63.1 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (1.0 g, 2.6 mmol), palladium acetate (17.5 mg, 0.078 mmol), cesium carbonate (1.7 g, 5.2 mmol), xantphos (60.2 mg, 0.10 mmol) and 1-(ortho-tolyl)piperazine hydrochloride (830 mg, 3.9 mmol) in toluene (30 mL) was stirred at 120° C. for 12 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with saturated aqueous sodium chloride (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(20% ethyl acetate/hexanes) to afford 6-fluoro-3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.80 g, 63%) as a white solid: LC/MS m/e calcd for C30H34FN3O2 (M+H)+: 488.6, observed: 488.3.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C:22]4([CH2:28][CH2:27][N:26](CC5C=CC=CC=5)[CH2:25][CH2:24]4)[O:21][CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C:22]4([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[O:21][CH2:20][CH2:19]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCOC2(CCN(Cc3ccccc3)CC2)C1
Solvent: CCO
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCOC2(CCNCC2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.4 %

Procedure:
To a solution of compound 403 (1.43 g, 3.05 mmol) in ethanol (27 mL) was added palladium hydroxide, 20 wt % pd (dry basis) on carbon, wet (1.51 g, 2.15 mmol), followed by hydrochloric acid (0.10 mL). The sealed glass tube was then evacuated and purged with hydrogen three times. The sealed tube was then charged with hydrogen (50 psi), and allowed to stir at room temperature for three days. HPLC showed ˜85% conversion to the desired product. After filtering the mixture through a plug of celite, the filtrate was concentrated to a solid and purified by flash chromatography (0-20% methanol in DCM with 1% NH4OH) to give compound 404 (709 mg, 61%) as a white solid. LCMS-ESI (POS), M/Z, M+1: Found 379.1, Calculated 379.2.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].O1CCCC1.[OH-].[Na+]>CO>[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-[5-(methoxycarbonyl)-2-thiazolyl]-1-piperazinecarboxylate (i.e. the product of Example 4, Step A) (2.56 g, 8 mmol) in 15 mL of methanol and 15 mL of tetrahydrofuran was added 1 N aqueous NaOH solution (10 mL), and the mixture was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure, diluted with water, washed with ether, and acidified with excess 20% aqueous citric acid solution to give a precipitate. The precipitate was filtered, washed with water and dried to give 2.12 g of the title compound as a slightly pink solid.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:18]1CCO[CH:19]1[C:23]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]2[C:24]=1[CH2:25][CH2:26][C:27](=[O:50])[N:28]2[CH2:35][C:36]1[CH:37]=[N:38][C:39]([N:42]([CH3:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:40][CH:41]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CC(C)=O.O>[CH3:34][O:33][C:30]1[C:29]2[N:28]([CH2:35][C:36]3[CH:37]=[N:38][C:39]([N:42]([CH3:49])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:40][CH:41]=3)[C:27](=[O:50])[CH2:26][CH2:25][C:24]=2[C:23]([CH:19]=[O:18])=[CH:32][CH:31]=1
Reactant: COc1ccc(C2OCCO2)c2c1N(Cc1ccc(N(C)c3ccccc3)nc1)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C=O)c2c1N(Cc1ccc(N(C)c3ccccc3)nc1)C(=O)CC2
Yield: 80.6 %

Procedure:
Pyridinium p-toluene sulfonate (PPTS) (0.54 g) was added to a mixed solution of 5-(1,3-dioxolan-2-yl)-8-methoxy-1-[6-(N-methyl-N-phenylamino)pyridin-3-ylmethyl]-3,4-dihydro-1H-quinolin-2-one (0.95 g) in acetone (19 ml) and water (9.5 ml), followed by heating under reflux for 2 hours. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and extraction with ethyl acetate was performed. The extract was washed twice with water, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1). The purified product was concentrated under reduced pressure to thereby obtain 0.69 g (yield: 81%) of 8-methoxy-1-[6-(N-methyl-N-phenylamino)pyridin-3-ylmethyl]-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a light yellow amorphous solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].[Cu][C:11]#[N:12]>C(Cl)Cl>[CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([C:11]#[N:12])=[O:6]
Reactant: N#C[Cu]
Reactant: C[Si](C)(C)CCC(=O)Cl
Solvent: ClCCl
Product: C[Si](C)(C)CCC(=O)C#N
Temperature: 25 °C
Yield: 30.2 %

Procedure:
In a flask were placed 5.0 g (0.032 mole) of 4,4-dimethyl-4-silapentanoic acid chloride and 2.89 g (0.032 mole) of copper(I) cyanide. This mixture was heated at approximately 150°-200° C. for a period of 50 minutes after which it was cooled to ambient temperature. Methylene chloride was added to the reaction mixture which was then filtered. The solvent was evaporated from the filtrate under reduced pressure, leaving 1.5 g of 4,4-dimethyl-4-silapentanoyl cyanide as a residue.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([CH:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8](Cl)=[O:9])[CH3:6].[F:15][C:16]1[C:17]2[CH2:23][S:22][CH2:21][C:18]=2[S:19][CH:20]=1>C(Cl)Cl>[CH2:5]([CH:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8]([C:20]1[S:19][C:18]2[CH2:21][S:22][CH2:23][C:17]=2[C:16]=1[F:15])=[O:9])[CH3:6]
Reactant: Fc1csc2c1CSC2
Reactant: CCCCC(CC)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(CC)C(=O)c1sc2c(c1F)CSC2
Temperature: 0 °C
Yield: 70 %

Procedure:
2.31 mmol of AlCl3 was added to 20 ml DCM with 2.31 mmol 2-ethylhexanoyl chloride at about 0° C. Compound 7 from the previous step was added to the mixture. The mixture was reacted at about 0° C. for about 4 hours. After reacting, the reactant was poured into ice water. The organic phase was extracted by ether 3 times. Compound 8 was purified by silica gel. The yield was about 70%.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[O:4][C@@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([NH:34][C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([NH:34][C@H:35]([C:37]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]3[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=3[O:4][C@@H:3]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:38])[CH3:36])=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: CC(C)N1C(=O)[C@@H](N)[C@@H](c2ccccc2)Oc2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)N1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)[C@@H](c2ccccc2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.7 %

Procedure:
To a stirred solution of (2R,3S)-3-amino-5-isopropyl-2-phenyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (69b) (59 mg, 0.199 mmol) in dichloromethane (2 mL) was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (1e) (59 mg, 0.242 mmol), HOBt (33 mg, 0.245 mmol), NMM (30 mg, 0.297 mmol) and EDAC-HCl (47 mg, 0.245 mmol). After stirring at ambient temperature under nitrogen for 90 min. the solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic solution was separated, washed with 1N aqueous HCl then dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1:1 (v/v) hexane:ethyl acetate to afford the title compound (64 mg, 62%) as a white solid. TLC Rf=0.17 (1:1 hexane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ1.21 (d, 3H, J=7.0 Hz), 1.29 (d, 3H, J=7.0 Hz), 1.54 (d, 3H, J=7.0 Hz), 3.47 (s, 2H), 4.22 (m, 1H), 4.77 (m, 1H), 4.93 (t, 1H, J=7.2 Hz), 5.60 (d, 1H, J=7.4 Hz), 5.87 (br d, 1H, J=7.4 Hz), 6.25 (br d, 1H, J=7.0 Hz), 6.67-6.86 (m, 3H), 7.21-7.43 (m, 9H). MS APCI, m/z=522 (M+1). LC/MS: 2.75 min.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)[C:10]([CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:31][CH2:30]1)=[C:9]2[C:41]([OH:43])=O)(=[O:5])=[O:4])[CH3:2].[F:44][C:45]([F:55])([F:54])[C@@H:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[NH2:47].C(N(CC)C(C)C)(C)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(OCC)(=O)C.ClCCl.C([O-])(O)=O.[Na+]>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=1)[C:10]([CH2:28][N:29]1[CH2:30][CH2:31][CH:32]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[CH2:33][CH2:34]1)=[C:9]2[C:41]([NH:47][C@H:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:45]([F:44])([F:54])[F:55])=[O:43])(=[O:5])=[O:4])[CH3:2]
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Reactant: CCS(=O)(=O)c1cc2c(C(=O)O)c(CN3CCC(N4CCOCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1cc2c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c(CN3CCC(N4CCOCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A solution of 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.200 g, 0.303 mmol), (1R)-2,2,2-trifluoro-1-phenylethanamine (0.069 g, 0.393 mmol), N,N-diisopropylethylamine (10.57 μL, 0.061 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (0.252 mL as a 50% solution in ethyl acetate, 0.424 mmol) in dichloromethane (2 mL) was stirred at 0° C. for 2 h, then warmed to room temperature overnight. The solution was diluted with saturated aqueous NaHCO3 and extracted with methylene chloride (3 times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in DMSO and purified via HPLC (Waters, Sunfire, 30×75 mm column, 50 mL/min, 20-60% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to afford 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.166 g, 67% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 9.79 (br. s., 1H), 8.78 (s, 1H), 7.81 (s, 1H), 7.76-7.80 (m, 1H), 7.65-7.69 (m, 2H), 7.60 (s, 1H), 7.53-7.59 (m, 2H), 7.42-7.49 (m, 3H), 6.20-6.31 (m, 1H), 4.11 (s, 3H), 3.65-3.71 (m, 4H), 3.54-3.65 (m, 2H), 3.47 (q, J=7.28 Hz, 2H), 2.59-2.71 (m, 1H), 2.38-2.46 (m, 4H), 2.17-2.28 (m, 1H), 2.04 (t, J=11.04 Hz, 1H), 1.49-1.65 (m, 6H), 1.32 (t, J=7.53 Hz, 3H); MS (m/z) 779.2 (M+H+).
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:28])[C@@H:7]1[C@:23]2([CH3:24])[CH:10]([CH:11]3[C:20](=[CH:21][CH2:22]2)[C@:19]2([CH3:25])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][C@H:8]1[CH3:27])(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>C(Cl)Cl.CO>[OH:4][CH2:5][C:6]([C@@H:7]1[C@:23]2([CH3:24])[CH:10]([CH:11]3[C:20](=[CH:21][CH2:22]2)[C@:19]2([CH3:25])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@H:8]1[CH3:27])=[O:28]
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C)CC2C3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C[C@@H]1CC2C3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CO
Temperature: 5 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
A solution of 2-oxo-2-((10S,13S,16R,17S)-10,13,16-trimethyl-3-oxo-2,3,6,7,8,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl acetate (1.0 g, 2.6 mM) in methylene chloride (5 mL) and methanol (15 mL) was put under an inert atmosphere and cooled in an ice bath. 1 mL of 1 M aqueous potassium carbonate was added by syringe. The reaction was stirred at 5° C. for 2 h. The reaction was then neutralized with 1N HCl and concentrated. After partitioning between water and methylene chloride, the product solution was dried over anhydrous magnesium sulfate, filtered and evaporated. Crystallization from ethyl acetate yielded a first crop of 0.33 g product. NMR (500 MHz, CDCl3, TMS): δ 0.67 (s, 3H), 1.01 (d, 3H, J=7 Hz), 1.13 (m, 1H), 1.33 (s, 3H), 1.47-1.80 (m, 3, H), 2.00 (m, 1H), 2.06-2.24 (m, 6H), 2.37 (d, 1H), 2.45-2.60 (m, 3H), 2.82 (m, 1H), 3.30 (m, 1H), 4.20 (m, 2H), 5.50 (d, 1H, J=5 Hz), 5.76 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.C(=O)C1C(=CC=CC=1)O>[C:9]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(N)C(=O)O
Agent: C[C@H](NC(=O)c1ccccc1)C(=O)O
Solvent: O
Solvent: O=Cc1ccccc1O
Product: CC(C)[C@H](N)C(=O)O
Temperature: 95 °C
Reaction time: 48 h

Procedure:
Twenty four grams of DL-valine and 19.3 g of N-benzoyl-L-alanine were suspended in 200 mL of deionized water. The suspension was heated to 95° C. to form a clear solution, to which 0.2 g of salicylaldehyde was added. The solution was cooled slowly to room temperature and stirred for another 48 hours at 25° C. The precipitated crystals were then separated by filtration, washed with 50 mL of deionized water, and dried to obtain 29.2 g of crystalline L-valine N-benzoyl-L-alanine complex (L-valine to N-benzoyl-L-alanine molar ratio of 1:1).
Reaction SMILES: [NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]=2)=[CH:5][CH:4]=1.[F:45][C@@H:46]1[CH2:51][CH2:50][CH2:49][CH2:48][C@H:47]1[O:52][C:53](=[O:59])[O:54][CH:55](Cl)[CH2:56][CH3:57].[I-].[Na+].C(=O)([O-])O.[K+]>O.CN(C=O)C>[F:45][C@@H:46]1[CH2:51][CH2:50][CH2:49][CH2:48][C@H:47]1[O:52][C:53](=[O:59])[O:54][CH:55]([O:16][C:14]1[N:13]([C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)[N:12]=[C:11]([C@H:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([NH2:1])=[N:36][C:37](=[O:44])[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:4][CH:5]=2)[C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[N:15]=1)[CH2:56][CH3:57]
Reactant: CCC(Cl)OC(=O)O[C@@H]1CCCC[C@H]1F
Reactant: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(OC(=O)O[C@@H]1CCCC[C@H]1F)Oc1nc([C@H](Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2cc(OC)cc(OCCO)c2F)nn1-c1ncccn1
Temperature: 40 °C
Reaction time: 76 h

Procedure:
To a mixture of N-[1-amino-1-(4-{[(R)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H[1,2,4]-triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide (Example 12b, 500 mg) and DMF (5 mL), carbonic acid 1-chloropropyl ester trans-2-fluorocyclohexyl ester (998 mg), sodium iodide (625 mg), and potassium hydrogen carbonate (100 mg) were added, and the resulting mixture was stirred at 40° C. for 76 hours. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was sequentially washed twice with water and with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was crudely purified by silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain a crudely purified product.