Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:16]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH3:16][O:1][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc2ccccc2cc1O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccccc2cc1OC
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K2CO3 (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temp. for 15 min., then treated with iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room temp. overnight, then was treated with water (200 mL). The resulting mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO4), concentrated under reduced pressure (approximately 0.4 mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil (10.30 g): 1H-NMR (DMSO-d6) δ 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J=8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (app t, J=8.09 Hz, 1H), 7.84 (d, J=8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:23][CH3:24])[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]2[NH:16][C:17]([CH:20]=O)=[C:18]([CH3:19])[C:12]=2[C:11]1=[O:22])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)N[C:31](=[O:36])[CH2:30]2.N1CCCC[CH2:38]1>C(O)C>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:23][CH3:24])[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]2[NH:16][C:17]([CH:20]=[C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=4)[CH2:38][C:31]3=[O:36])=[C:18]([CH3:19])[C:12]=2[C:11]1=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCN(CCN1CCc2[nH]c(C=O)c(C)c2C1=O)C(=O)OC(C)(C)C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CCO
Product: CCN(CCN1CCc2[nH]c(C=C3C(=O)Cc4ccc(F)cc43)c(C)c2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A stirred solution of ethyl-[2-(2-formyl-3-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-5-yl)-ethyl]-carbamic acid tert-butyl ester (160 mg, 0.458 mmol), 5-fluoro-1,3-dihydro-indol-2-one (65.76 mg, 0.435 mmol), in. 0.803 ml of ethanol was added dropwise with anhydrous piperidine (0.022 ml). The mixture was stirred overnight at room temperature until a precipitate was formed. The precipitate was filtered under reduced pressure and washed with ethanol (0.3 ml×3) to give ethyl-{2-[2-(6-fluoro-2-oxo-indan-1-ylidenemethyl)-3-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-5-yl]ethyl}-carbamic acid tert-butyl ester (111 mg, 50%) as a yellow solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9]([F:18])([F:17])[C:8]2=[O:19])[CH2:4]1.Cl[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.O>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[NH:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9]([F:18])([F:17])[C:8]2=[O:19])[CH2:4]1
Reactant: Clc1nc2ccccc2s1
Reactant: N[C@H]1C[C@H](N2C(=O)C(F)(F)c3cc(F)cnc32)C1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C1N([C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c2ncc(F)cc2C1(F)F
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
1-(Trans-3-aminocyclobutyl)-3,3,5-trifluoro-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrochloride (0.105 g, 0.358 mmol), 2-chlorobenzothiazole (0.0728 g, 0.429 mmol), and N,N-diisopropylethylamine (0.249 mL, 1.430 mmol) were mixed in DMSO (0.5 mL) in a sealed tube. The reaction mixture was stirred at 120° C. for 1.5 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography eluting with EtOAc in hexanes to yield the title compound (0.032 g, 0.082 mmol, 22.9% yield) as a white solid. M+1: 391.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.46-2.56 (m, 2 H) 3.37-3.48 (m, 2 H) 4.58 (m, J=3.50 Hz, 1 H) 5.23 (quin, J=8.61 Hz, 1 H) 5.76 (br. s., 1 H) 7.12 (t, J=7.53 Hz, 1 H) 7.32 (t, J=7.73 Hz, 1 H) 7.56-7.66 (m, 3 H) 8.30 (s, 1 H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.[OH-].[Na+].[C:12]([O:16][C:17](OC([O-])=O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CC(O)(C)C.O>[C:12]([O:16][C:17]([N:5]1[CH2:6][CH2:7][CH2:8][C:2](=[O:1])[CH2:3][CH2:4]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1CCCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirred solution of 4-oxohomopiperidine.HCl (1.2 g, 8.05 mmol), NaOH (0.68 g, 16.9 mmol) in t-BuOH/H2O (1:1, 10 mL) was added t-butyldicarbonate (1.93 mL, 8.9 mmol) drop-wise. The reaction was stirred at RT overnight, extracted with EtOAc (2×10 mL) and the organic layer separated. The organic layer was dried over Na2SO4 and concentrated under vacuo. Pure 1-t-butoxycarbonyl-4-oxohomopiperidine (1.42 g, 84%) was isolated via silica gel flash chromatography eluting with 50% EtOAc/hexane. 1H NMR CDCl3 δ: 44 (9H, s), 1.72–1.84 (2H, m), 2.60–2.65 (4H, m), 3.55–3.61 (4H, m).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][N:7]=1.[O:8]=[C:9]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(N(CC)CC)C>[O:8]=[C:9]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[C:10](=[C:3]1[CH2:4][CH2:5][CH2:6][NH:7]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: COC1=NCCC1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)c1cc(F)c(F)cc1F)=C1CCCN1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
5-Methoxy-3,4-dihydro-2H-pyrrole and triethylamine were added to ethyl 3-oxo-3-(2,4,5-trifluorophenyl)propanoate, for stirring at 60° C. for 4 days, to obtain ethyl 3-oxo-2-pyrrolidin-2-ylidene-3-(2,4,5-trifluorophenyl)propanoate.
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17].[Br:25][C:26]1[CH:27]=[C:28]([F:36])[CH:29]=[C:30]2[C:34]=1[NH:33][C:32](=[O:35])[CH2:31]2.N1CCCCC1>C(O)C>[Br:25][C:26]1[CH:27]=[C:28]([F:36])[CH:29]=[C:30]2[C:34]=1[NH:33][C:32](=[O:35])/[C:31]/2=[CH:15]\[C:12]1[NH:11][C:7]2[CH2:8][CH2:9][CH2:10][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5](=[O:17])[C:6]=2[C:13]=1[CH3:14].[OH:1][CH:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][CH:12]=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CCC2
Reactant: O=C1Cc2cc(F)cc(Br)c2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3c(Br)cc(F)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CCC2
Product: Cc1c[nH]c2c1C(=O)N(CC(O)CN1CCOCC1)CCC2
Temperature: 25 °C
Yield: 260.3 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexa hydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (40 mg, 0.12 mmol) and 7-bromo-5-fluoro-1,3-dihydro-indol-2-one 4b (27 mg, 0.12 mmol) were dissolved in 1.5 ml of ethanol, and added with 6 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was reacted at 45° C. for 16 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (1 ml×2) and dried to obtain the title compound (S,Z)-2-(7-bromo-5-fluoro-2-oxoindolin-3-ylidene)methyl)-5-(2-hydroxy-3-morpholinopropyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 82 (48 mg, yield 73.8%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([Cl:34])[C:13]([N:20]3[CH2:24][CH2:23][C@H:22]([N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:26])[CH2:21]3)=[C:14]([F:19])[CH:15]=2)[N:10]([CH:35]2[CH2:37][CH2:36]2)[C:9]1=[O:38])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:43]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:39])[N:7]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([Cl:34])[C:13]([N:20]3[CH2:24][CH2:23][C@H:22]([N:25]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH3:26])[CH2:21]3)=[C:14]([F:19])[CH:15]=2)[N:10]([CH:35]2[CH2:36][CH2:37]2)[C:9]1=[O:38])[CH3:43])([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2c(F)cc3c(=O)n(NC(=O)OC(C)(C)C)c(=O)n(C4CC4)c3c2Cl)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2c(F)cc3c(=O)n(N(C)C(=O)OC(C)(C)C)c(=O)n(C4CC4)c3c2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of {7-[(S)-3-(tert-butoxycarbonyl-N-methylamino)-pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid tert-butyl ester from Example 8 (0.238 g, 0.421 mmol) in N,N-dimethylformamide (5 mL) at −78° C. under nitrogen atmosphere is added sodium hydride (60% dispersion in mineral oil, 0.025 g, 0.631 mmol). After 30 minutes, iodomethane (0.052 mL, 0.842 mmol) is added, and the reaction mixture is warmed to room temperature. After 1 hour, the reaction mixture is diluted with ethyl acetate and washed with saturated ammonium chloride solution, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate concentrated. The resulting residue is purified by flash column chromatography (1:1 ethyl acetate/hexanes) to afford the title compound (0.118 g). 1H NMR (CDCl3): δ 7.63 (dd, 1H), 4.78 (bs, 1H), 3.87–3.45 (m, 6H), 2.62–2.44 (m, 6H), 2.31–2.12 (m, 2H), 1.49–1.47 (m, 18H), 1.23–1.07 (m, 2H), 0.75–0.53 (m, 2H). MS CI: m/z 582 (MH+).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[N+:13]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][NH2:22])=[O:20])([O-:15])=[O:14].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[N+:13]([C:16]1[CH:17]=[C:18]([C:19]2[O:20][C:1]([OH:2])=[N:22][N:21]=2)[CH:23]=[CH:24][CH:25]=1)([O-:15])=[O:14]
Reactant: NNC(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(-c2nnc(O)o2)c1
Reaction time: 4 h

Procedure:
1,1′-Carbonyldiimidazole (641.2 mg; 3.95 mmol; 1 eq.) is added to a 0° C. solution of 3-nitrobenzohydrazide (715.9 mg; 3.95 mmol; 1 eq.) and triethylamine (822 μl; 5.93 mmol; 1.50 eq.) in DMF (30 ml). The reaction mixture is stirred between 0° C. and rt for 4 hours. Solvents are removed under vacuo affording an orange oil which is solubilized in DCM and washed with HCl 0.1 M. The organic phase is concentrated. The resulting precipitate is recovered by filtration, affording 5-(3-nitrophenyl)-1,3,4-oxadiazol-2-ol as a white solid (469.9 mg; 58%). 1H NMR (DMSO-d6) δ: 7.84 (s, 1H), 8.19 (m, 1H), 8.41 (m, 2H), 12.91 (s, 1H). HPLC (method A), Rt: 2.06 min (purity: 97.5%).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C1C[O:37][CH2:36]C1>>[OH:16][C@H:15]([CH2:17][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:37][CH3:36])([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H]1CO1
Reactant: C1CCNC1
Product: COC1(Oc2ccc3[nH]c(C)cc3c2)NC=Nc2cc(OC[C@H](O)CN3CCCC3)ccc21
Temperature: 75 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A mixture of the (2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (250 mg, 0.66 mmol), (prepared as described for the starting material in Example 269), and pyrrolidine (1.5 ml) in THF (10 ml) was stirred at 75° C. for 3 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatography using gradient elution with dichloromethane/methanolic ammonia (7M) (100/0 to 90/10) to give (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)4-methoxy-4-(2-methylindol-5-yloxy)quinazoline (165 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([CH2:8][O:9][C:19](=[O:21])[CH3:20])=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: COc1cc(Br)cnc1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Br)cnc1COC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (5-bromo-3-methoxy-pyridin-2-yl)-methanol (Stage 194.1.3, 2.79 mmol) and triethylamine (4.18 mmol) in dichloromethane was added slowly acetyl chloride (3.35 mmol) and the RM was stirred for 1 h at rt. The RM was diluted with dichloromethane, washed with saturated aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 60%). The fractions containing product were evaporated together to give the title compound as a white solid. (HPLC: tR 2.72 min (Method A); M+H=260, 262 MS-ES)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCOc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(OCCCC(=O)O)cc2)CC(C)(C)C1
Yield: 94.7 %

Procedure:
The hydrolysis conditions described for 191 was followed. A solution of ethyl 4-({4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)butanoate (222) (0.760 g, 1.7 mmol) in THF/EtOH (1:1, 40 mL) was treated with 1 N NaOH (20 ml, excess) at 70° C. for 1 h. The reaction mixture was poured into 20% aqueous HCl (200 mL). The precipitated product was filtered and dried under reduced pressure to afford 0.68 g (95%) of compound 223 as an off-white solid. mp 203-204° C. 1H NMR (300 MHz, CD3OD): δ 7.05 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 4.00 (t, J=6.3 Hz, 2H), 2.50 (t, J=7.2 Hz, 2H), 2.06 (quintet, J1=13.5, J2=6.9 Hz, 2H), 2.00 (d, J=4.2 Hz, 4H), 1.31 (s, 2H), 0.94 (s, 12H). LCMS (ESI): m/z 421 (M−H)−. Anal. Calcd for C27H34O4. C, 76.75; H, 8.11; Found: C, 75.63; H. 8.03.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19](OC([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:18][C@:14]2(O)[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4](OC(C)=O)[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2OC(C2C=CC=CC=2)=O)[C@:11]2(OC(C)=O)[CH2:51]O[C@@H:10]2[CH2:9][C@@H:8]1O)=O.C/C=C(/C(N[C@H]([C@@H](O)C(O[C@@H]1C(C)=C2C(C)(C)[C@](O)([C@@H](OC(C3C=CC=CC=3)=O)[C@@H]3[C@]4(OC(C)=O)CO[C@@H]4C[C@H](O)[C@@]3(C)C([C@@H]2OC(C)=O)=O)C1)=O)C1C=CC=CC=1)=O)\C>C(OCC)(=O)C.C(Cl)Cl>[CH3:51][C@H:11]1[C@H:12]2[CH2:13][C@H:14]3[C:15]([CH3:16])([CH3:17])[C@@H:3]([CH2:4][CH2:5][C@:7]2([CH3:58])[CH2:8][CH2:9][CH2:10]1)[C@H:2]([CH3:1])[CH2:19][CH2:18]3
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: C/C=C(\C)C(=O)N[C@@H](c1ccccc1)[C@@H](O)C(=O)O[C@H]1C[C@@]2(O)[C@@H](OC(=O)c3ccccc3)[C@@H]3[C@]4(OC(C)=O)CO[C@@H]4C[C@H](O)[C@@]3(C)C(=O)[C@H](OC(C)=O)C(=C1C)C2(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1CCC[C@@]2(C)CC[C@H]3[C@H](C)CC[C@@H](C[C@H]12)C3(C)C

Procedure:
dissolving any fraction comprising taxol and cephalomannine from step (7) in a mixture of about 20% ethyl acetate and 80% methylene chloride to form a taxane-containing solution;
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:67]=[C:68]([CH:72]=[CH:73][CH:74]=1)[C:69]([NH2:71])=[O:70]>C(Cl)Cl.CO>[C:69]([C:68]1[CH:67]=[C:66]([NH:65][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])[CH:74]=[CH:73][CH:72]=1)(=[O:70])[NH2:71]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: NC(=O)c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(N)=O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.258 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 3-amino benzamide (Oakwood, 35 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 30% EtOAc/methylene chloride) to give a white solid. 58 mg. The solid was resolved on a Berger SFC system on a Whelk column under 100 bar, 30° C., and 35% of methanol to give two peaks: Peak 1, undesired enantiomer, 19 mg; Peak 2, 21 mg as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](C)=[CH:4][C:3]=1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].[C:17](=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH:26](Cl)[C:27]([OH:29])=[O:28]>CC(O)C>[CH3:17][C:15]1[C:10]2[CH2:9][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:1][CH:26]([C:27]([OH:29])=[O:28])[O:16][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)C(Cl)Cl
Reactant: Cc1ccc(O)c(Cc2ccccc2O)c1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: Cc1cccc2c1Cc1ccccc1OC(C(=O)O)O2
Reaction time: 24 h
Yield: 126.4 %

Procedure:
(2-Hydroxy-5-methylphenyl)(2-hydroxyphenyl)methane (1.66 g, 7.7 mmol) was combined with 2.07 g (15 mmol) of potassium carbonate, 0.56 g (3.4 mmol) of potassium iodide, 0.99 g (7.7 mmol) of dichloroacetic acid and 50 ml of 2-propanol and the mixture heated at reflux with stirring for 24 hours. Another 7.7 mmol of dichloroacetic acid was added and the reaction continued for 2 days. The volatiles were removed by evaporation under reduced pressure and water added. The mixture was acidified with 1N hydrochloric acid and extracted with ether. The ether extract was dried over magnesium sulfate and the ether removed by evaporation under reduced pressure to obtain 2.63 g of the title compound in impure form as a brown oil. The proton nmr spectrum was consistent with the presence of desired product. A sample of the title compound prepared by hydrolysis of the product of Example 7 with potassium hydroxide in an aqueous methanol mixture at ambient temperature overnight melted at 61° C. and had a proton nmr spectrum consistent with the assigned structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[O:13])OC(=O)[NH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21].C(Cl)Cl>C1(C)C=CC=CC=1>[NH2:9][C:8]1[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[C:12]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[O:17][CH3:16])=[O:13]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Reactant: COc1ccccc1CN
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccccc1CNC(=O)c1ccc([N+](=O)[O-])cc1N
Reaction time: 0.5 h

Procedure:
A mixture of 9.3 g 7-nitro-1H-benzo[d][1.3]oxazine-2,4-dione (45 mmol) and 12.3 g 2-methoxybenzylamine (90 mmol) in 200 mL toluene was stirred for 30 minutes at reflux, then mixed with methylene chloride and washed repeated with water. The organic phase was dried, concentrated and the solid residue was dried and reacted further without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CO
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC)c(OC)c(OC)c1

Procedure:
A solution of 50 g of 3,4,5-trimethoxybenzoic acid in 500 ml dry methanol containing 4.8 ml of conc. sulfuric acid was refluxed under anhydrous condition for 18 hr and concentrated to half the volume. The solution was poured into ice water and extracted with methylene chloride. The organic extract was washed with cold 0.5 N sodium hydroxide and water, dried over sodium sulfate, evaporated and crystallized from hexane to give 3,4,5-trimethoxybenzoic acid methyl ester, mp 65°-66° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][N:9]([CH3:34])[CH2:10][CH:11]([OH:33])[CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1COCC1>[CH3:34][N:9]([CH3:8])[CH2:10][CH:11]([O:33][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOCCC(O)CN(C)C
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCCC(CN(C)C)OC(=O)CCC(=O)O

Procedure:
Succinic anhydride (0.60 g, 5.99 mmol, 1.1 equiv) was added in one portion to a dry THF (11 mL) solution of 1-(dimethylamino)-4-((9Z,12Z)-octadeca-9,12-dienyloxy)butan-2-ol (2.0 g, 5.45 mmol, 1.0 equiv) and the resultant was refluxed for 18 hours under argon. The mixture was concentrated and the residue was partitioned between EtOAc (10 mL) and deionized water (20 mL). The layers were separated and the aqueous layer was extracted with two additional portions of EtOAc (25 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to provide crude 4-(1-(dimethylamino)-4-((9Z,12Z)-octadeca-9,12-dienyloxy)butan-2-yloxy)-4-oxobutanoicacid, a thick, yellow oil, which was used without further purification.