Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[C:3](O)=[O:4].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.[NH:56]1[CH2:61][CH2:60][CH:59]([NH:62][C:63]2[CH:70]=[CH:69][C:66]([C:67]#[N:68])=[C:65]([C:71]([F:74])([F:73])[F:72])[CH:64]=2)[CH2:58][CH2:57]1>CN(C)C=O.ClCCl.O1CCCC1>[CH3:1][CH:2]([CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[C:3]([N:56]1[CH2:61][CH2:60][CH:59]([NH:62][C:63]2[CH:70]=[CH:69][C:66]([C:67]#[N:68])=[C:65]([C:71]([F:72])([F:73])[F:74])[CH:64]=2)[CH2:58][CH2:57]1)=[O:4]
Reactant: N#Cc1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: C[C@@H](CN1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(CN1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=O)N1CCC(Nc2ccc(C#N)c(C(F)(F)F)c2)CC1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
2-Methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propionic acid (57 mg; 0.18 mmol, prepared in accordance with Example 67), diisopropylethyl amine (140 μL; 0.8 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (65 mg; 0.17 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of 4-(Piperidin-4-ylamino)-2-trifluoromethyl-benzonitrile (50 mg; 0.17 mmol) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 1 hour at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. Upon addition of acetonitrile to the residue obtained a precipitation is observed. The precipitate is filtered, washed with acetonitrile (2×3 mL) and dried under high vacuum to afford the desired product (98 mg; 0.17 mmol). The structure was confirmed using Protocol II-B. Calculated mass=568; observed mass=568; HPLC retention time=4.812 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][CH:3]=1.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][NH:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:12]2[CH2:11][C@H:10]([CH3:9])[O:15][C@H:14]([CH3:16])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H]1CN(c2ccc(Br)cc2)C[C@H](C)O1
Temperature: 150 °C
Reaction time: 25 h

Procedure:
A mixture of 1-bromo-4-fluorobenzene (10 g), cis-2,6-dimethylmorpholine (7.74 ml) and potassium carbonate (15.8 g) in dimethylsulfoxide (50 ml) was stirred for 25 hours at 150° C. The reaction mixture was cooled and poured into water (500 ml), and stirred for 10 minutes. The reaction mixture was extracted with ethyl acetate (100 ml×2), washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give a crude yellow oil (680 mg). The crude oil was purified by silica gel chromatography (1:0-10:1 hexane-ethyl acetate) to give 4-(4-bromophenyl)-cis-2,6-dimethylmorpholine (360 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][CH:8]=[CH:9][C:2]=12.[Br:10]Br>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:10][C:9]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][N:1]=2)[NH:7][CH:8]=1
Reactant: BrBr
Reactant: c1cnc2[nH]ccc2n1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Brc1c[nH]c2nccnc12
Reaction time: 1.5 h

Procedure:
7-Bromo-5H-pyrrolo[2,3-b]pyrazine (4) is prepared by dissolving 5H-pyrrolo[2,3-b]pyrazine (3) in chloroform and slowly adding Br2 in carbon tetrachloride at 0° C. After stirring for 1-2 hours, the reaction may be quenched in aqueous hydrochloric acid. Isolation by conventional means (e.g. extraction and silica gel chromatography) provides compound 4.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][OH:14])=[CH:7][CH:6]=1)[CH2:2][CH3:3].C1COCC1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(OCC)(=O)C>[CH3:27][S:28]([O:14][CH2:13][CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCCOc1ccc(CCCO)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCOc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 3-(4-propoxyphenyl)-1-propanol (735 mg) and THF (20 ml) were added at 0° C. triethylamine (1.58 ml) and methanesulfonyl chloride (0.44 ml). The resulting mixture was stirred at 0° C. for 20 minutes and at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 3-(4-propoxyphenyl)propyl methanesulfonate (1.02 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[CH:15]=[C:16]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc(Cl)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-chlorobenzenesulfonyl chloride according to METHOD A, giving 0.47 g (65%) of a pink powder: MS (electrospray, [M−H]−) m/z 359.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[NH:14][N:13]=[N:12][N:11]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[N:11]=[N:12][N:13]([CH3:15])[N:14]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cc(Cl)cc(Br)c1-c1nnn[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnc(-c2c(F)cc(Cl)cc2Br)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the above tetrazole (16.0 g, 57.7 mmol), potassium carbonate (12.0 g, 86.5 mol), and iodomethane (11.5 g, 80.7 mol) in 15 mL DMF was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water, and the organic extract was washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0-10% ethyl acetate in hexanes to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 293.0 for M+H+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11]O>Cl>[CH3:11][O:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=1)=[O:10]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Product: COC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a slurry of 2.0 g of 6-chloro-3-pyridinecarboxylic acid (Aldrich, 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233 USA) in methanol (200 ml) was added two drops of concentrated aqueous hydrochloric acid and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and evaporated to give 1.5 g (71%) of product as a white solid. mp 90°-92° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([O:25]C(C)C)=[CH:18][C:11]=3[C:12]=2[C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)=[CH:4][CH:3]=1.ClB(Cl)Cl>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([OH:25])=[CH:18][C:11]=3[C:12]=2[C:13]2[NH:17][CH:16]=[CH:15][N:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)Oc1cc2c(-c3ncc[nH]3)c(-c3ccc(F)cc3)oc2cc1[N+](=O)[O-]
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-(4-fluorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-yl)-1H-imidazole (800 mg, 2.098 mmol) in dichloromethane (DCM) (80 mL) at −78° C. under an nitrogen atmosphere was added a 1.0 M solution of trichloroborane in DCM (5.24 mL, 5.24 mmol). The reaction mixture was allowed to warm to room temperature and stirring continued at rt overnight. The reaction mixture was then concentrated completely to remove the volatiles. The residue was diluted with ice-cold water, and the solid filtered to obtain the title compound as a yellow solid. Yield: 650 mg (91%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 14.59-15.34 (m, 1H) 11.07 (br s, 1H) 8.35-8.52 (m, 1H) 8.07 (d, J=1.76 Hz, 1H) 7.87-7.99 (m, 1H) 7.59-7.77 (m, 1H) 7.30-7.55 (m, 4H). LCMS: (ES+) m/z=340.15 (M+H)+; Column—ACQUITY UPLC BEH C8 (50×2.1 mm; 1.7 μm); M phase A: 5 mM Ammonium Acetate:MeCN (95:5); M phase B: 5 mM Ammonium Acetate:MeCN (5:95)
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>O1CCCC1>[OH:10][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1ccc(O)c(C=O)n1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(O)c(C(O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
3-Hydroxy-6-methyl-pyridine-2-carbaldehyde (350 mg) was dissolved in tetrahydrofuran (13 ml) to prepare a solution which was brought to −78° C. Phenylmagnesium bromide (7.4 ml) was slowly added dropwise thereto, and the mixture was stirred at room temperature for one hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give 2-(hydroxyphenyl-methyl)-6-methyl-pyridin-3-ol (553 mg, yield 100%).
Reaction SMILES: C(O)(=O)C.[NH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[C:7]#[N:8].[C:20]([NH:23][C:24]1[CH:34]=[CH:33][CH:32]=[C:26]2[C:27]([O:29][C:30](=O)[C:25]=12)=[O:28])(=[O:22])[CH3:21]>C(O)(=O)C.CCOC(C)=O>[C:7]([CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[N:5]1[C:30](=[O:29])[C:25]2[C:26](=[CH:32][CH:33]=[CH:34][C:24]=2[NH:23][C:20](=[O:22])[CH3:21])[C:27]1=[O:28])#[N:8]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc(C(N)C#N)ccc1OC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOc1cc(C(C#N)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 85.3 %

Procedure:
To a mixture of 2-amino-2-(3-ethoxy-4-methoxyphenyl)ethanenitrile acetate (4.1 g, 14.6 mmol) and 3-acetamidophthalic anhydride (3.0 g, 14.6 mmol) in glacial acetic acid (60 mL), was heated to reflux for 17 hours. The mixture was concentrated in vacuo to provide an oil. The oil was dissolved in EtOAc and washed with water, brine and dried over MgSO4. Solvent was removed, and the residue was purified by chromatography (SiO2, Hexane:EtOAc 6:4) to give 4.9 g (83%) of N-{2-[cyano(3-ethoxy-4-methoxyphenyl)methyl]-1,3-dioxoisoindolin-4-yl}acetamide as a white solid; mp 118-120° C.; 1H NMR (CDCl3) δ 9.43 (s, 1H), 8.76 (d, J=8.4 Hz, 1H), 7.67 (t, J=7.7 Hz, 1H), 7.51 (d, J=7.2 Hz, 1H), 7.05-6.82 (m, 3H), 5.60-5.54 (dd, J=6.63 and 10.0 Hz, 1H), 4.10 (q, J=6.8 Hz, 2H), 3.81 (s, 3H), 3.81-3.74 (m, 1H), 3.29-3.20 (dd, J=6.2 and 16.8 Hz, 1H), 2.27 (s, 3H), 1.46 (t, J=7 Hz, 3H); 13C NMR (CDCl3) δ 169:56, 169.12, 167.19, 149.92, 148.64, 137.73, 136.30, 130.87, 128.70, 125.11, 119.92, 118.29, 116.76, 114.94, 112.14, 111.98, 64.56, 55.94, 51.08, 24.92, 21.04, 14.68. Aanly. Calculated for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 65.01; H, 5.10; N, 10.19.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:10]([C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)=[O:9])=[O:11]
Reactant: O=C(C(=O)c1ccco1)c1ccc(O)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)C(=O)c4ccco4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Under argon, 2-furoyl 4-hydroxyphenyl ketone (205 mg) obtained in Example 129 and 4-dimethylaminopyridine (146 mg) were added to xylene (5 ml), and the admixture was stirred at room temperature for 1 hour. 4-Chloro-6,7-dimethoxyquinoline (244 mg) was added, and the admixture was then refluxed with heat for 20 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, and the chloroform layer was dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate and then with chloroform, followed by thin layer chromatography on silica gel eluting with chloroform/ethyl acetate (5/1), to obtain 192 mg of the title compound (yield: 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([CH2:16][CH2:17][OH:18])[C:8]=23)=[C:4]([F:21])[CH:3]=1.Cl[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:26]=[C:25]([NH2:33])[N:24]=1.Cl.[OH-].[Na+]>O>[NH2:33][C:25]1[N:24]=[C:23]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([CH2:16][CH2:17][OH:18])[C:8]=34)=[C:4]([F:21])[CH:3]=2)[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[N:26]=1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]cc(CCO)c23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]cc(CCO)c34)c(F)c2)cc(C(F)(F)F)n1

Procedure:
130 mg (0.45 mmol) of 2-[4-(4-amino-2-fluorophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]ethanol and 107 mg (0.54 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 6 ml of water. 0.6 ml (0.6 mmol) of 1N hydrochloric acid is added and the mixture is heated at reflux overnight. Using 1N aqueous sodium hydroxide solution, the suspension is adjusted to pH 10, resulting in the precipitation of crystals. The crystals are filtered off with suction, washed with water and purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol (7N ammonia) 100:1 to 100:3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH3:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[N+](C1C=CC([O:28][C:29]([C:31]2[C:32]3[CH:41]=[C:40]([CH2:42][CH3:43])[O:39][C:33]=3[C:34]([O:37][CH3:38])=[N:35][CH:36]=2)=O)=CC=1)([O-])=O>CN(C)C=O>[CH3:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:1][C:29]([C:31]1[C:32]2[CH:41]=[C:40]([CH2:42][CH3:43])[O:39][C:33]=2[C:34]([O:37][CH3:38])=[N:35][CH:36]=1)=[O:28]
Reactant: Cc1cnccc1N
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc2c(C(=O)Nc3ccncc3C)cnc(OC)c2o1
Reaction time: 0.17 h
Yield: 36.3 %

Procedure:
A solution of 4-amino-3-methylpyridine (76 mg) in dry N,N-dimethylformamide (20 ml) was stirred at 0° C. under an atmosphere of dry nitrogen. Sodium bis(trimethylsilyl)amide (1.0M solution in tetrahydrofuran, 0.77 ml) was added and stirring continued at 0° C. for 10 minutes. 2-Ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.20 g) was added and stirring continued at room temperature for 90 minutes. The solvent was then removed in vacuo, the residue taken up in water (100 ml) and extracted with ethyl acetate (3×75 ml). The combined organic extracts were washed with water (100 ml) then brine (50 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with ethyl acetate followed by trituration with diethyl ether gave the title compound (66 mg) as a white solid.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.[OH-].[Na+]>C1COCC1.O>[CH:16]1[CH:15]=[C:14]2[C:13]([CH:4]=[O:5])=[CH:12][NH:11][C:19]2=[CH:18][CH:17]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=Cc1c[nH]c2ccccc12

Procedure:
[a-2H; a-13C]-DMF (7.52 mmol) was dissolved in THF (4 ml), phosphorus oxychloride (3.76 mmol) was added to the resulting solution with stirring in an ice bath, a solution (50 ml) of the indole (35) (3.76 mmol) in THF was further added to the resulting mixture, followed by stirring of the mixture at room temperature for 3 hours. After the confirmation of the completion of the reaction using the TLC method, the reaction system was cooled in an ice bath, water (30 ml) and 2M NaOH aqueous solution were added till an alkaline solution was obtained, the resulting alkaline solution was extracted with methylene chloride-methanol (95:5) mixed solvent (100 ml×3), the extract was washed with a saturated sodium chloride aqueous solution (100 ml×3) and then dried over anhydrous magnesium sulfate. After filtration under reduced pressure, the solvent was distilled off from the filtrate and the resulting residue was purified by silica gel chromatography (developing solvent: methylene chloride/methanol=94/6) to thus give an aldehyde (36) in a yield of 2.68 mmol (71%).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:28]([CH3:29])[C@@H:27]2[C@@:5]([C:31]([OH:33])=[O:32])([CH2:6][CH2:7][C@@:8]3([CH3:30])[C@:13]4([CH3:26])[CH2:14][CH2:15][C@H:16]5[C:21]([CH3:23])([CH3:22])[C@@H:20]([OH:24])[CH2:19][CH2:18][C@:17]5([CH3:25])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:29][CH:28]1[CH:27]2[C@@:5]([C:31]([OH:33])=[O:32])([CH2:6][CH2:7][C@:8]3([CH3:30])[C:9]2=[CH:10][CH2:11][CH:12]2[C@@:13]3([CH3:26])[CH2:14][CH2:15][CH:16]3[C@:17]2([CH3:25])[CH2:18][CH2:19][C:20](=[O:24])[C:21]3([CH3:22])[CH3:23])[CH2:4][CH2:3][CH:2]1[CH3:1]
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@H]12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1CC[C@]2(C(=O)O)CC[C@]3(C)C(=CCC4[C@@]5(C)CCC(=O)C(C)(C)C5CC[C@]43C)C2C1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.2 %

Procedure:
To a mixture of ursolic acid (2a, 1.0 g, 2.18 mmol) and CH2Cl2 (55 mL) was added the Dess-Martin reagent (1.2 g, 2.83 mmol) under nitrogen at room temperature. After stirring at room temperature for 2.5 hours, the starting material was consumed as indicated by TLC (1:1 hexanes:diethyl ether). The reaction mixture was quenched with the addition of a solution of sodium thiosulfate and NaHCO3 (6.3 g sodium thiosulfate in 25 mL saturated NaHCO3 solution). The mixture was stirred at room temperature for 10 minutes. The layers were separated and the aqueous layer was extracted with EtOAc (3×250 mL). The combined organics were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 3:1 hexanes/diethyl ether) to provide the sub-title compound (924 mg, 92%) as a white foam solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:5][CH2:6][CH:7]1[C:12]2([C:13]3[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=3)[CH:8]1[CH2:9][N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11]2.[NH:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:5][CH2:6][CH:7]1[C:12]2([C:13]3[CH:18]=[CH:17][C:16]([N:31]4[CH2:35][CH2:34][CH2:33][C:32]4=[O:36])=[CH:15][CH:14]=3)[CH:8]1[CH2:9][N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11]2
Reactant: O=C1CCCN1
Reactant: CC(C)(C)OC(=O)N1CC2C(COc3ccc(Cl)c(Cl)c3)C2(c2ccc(Br)cc2)C1
Product: CC(C)(C)OC(=O)N1CC2C(COc3ccc(Cl)c(Cl)c3)C2(c2ccc(N3CCCC3=O)cc2)C1

Procedure:
The title compound was prepared from tert-butyl 6-((3,4-dichlorophenoxy)methyl)-1-(4-bromophenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate obtained in Step 1 of Example XXXV and 2-pyrrolidinone using the method described for Step 1 (Example XXXIII)
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([CH2:20][C:21]([OH:23])=[O:22])[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C[O-].[Na+:26].CO.CCOC(C)=O>CO>[O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[C:11]1\[O:12][CH:13]([CH2:20][C:21]([O-:23])=[O:22])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]\1=3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Na+:26]
Reactant: O=C(O)CC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C([O-])CC1O/C(=C2/C(=O)Nc3ccccc32)c2ccccc21
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a slurry of [3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-acetic acid (430 mg, 1.40 mmol) in MeOH (100.0 ml) at room temperature was added 0.5M NaOMe/MeOH (2.80 ml). The solution was rapidly stirred for 15 minutes and then rotary evaporated (combined 116 mg of product obtained from previously run reaction). The solid was chased with MeOH (20 ml), and then with EtOAc (2×15 ml) to give sodium [(3E)-3-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,3-dihydro-2-benzofuran-1-yl]acetate as a yellow solid (576 mg, 100%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[O:7]([C:14]([O:16][C@@H:17]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])=O)C1C=CC=CC=1.C(OCC)(=O)C.[Cl-].[Na+]>CN(C)C=O>[CH3:1][NH:2][CH2:3][CH2:4][N:5]([C:14]([O:16][C@@H:17]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:7])[CH3:6]
Reactant: COC(=O)[C@H](Cc1ccccc1)OC(=O)Oc1ccccc1
Reactant: CNCCNC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNCCN(C)C(=O)O[C@@H](Cc1ccccc1)C(=O)OC
Yield: 97.9 %

Procedure:
To N,N'-dimethylethylenediamine (7.93 g) in N,N-dimethylformamide (27 ml) was dropwise added methyl 2(S)-phenoxycarbonyloxy-3-phenylpropionate (9.0 g) in N,N-dimethylformamide (9 ml) under cooling at -5°-10° C. over 30 minutes. After the dropwise addition, the mixture was stirred at said temperature for 60 minutes and poured into a mixture of ethyl acetate and 20% aqueous sodium chloride for partition. The water layer was re-extracted with ethyl acetate, the organic layer was combined, and 5% hydrochloric acid was added thereto for partition. The water layer was washed with ethyl acetate, added with methylene chloride, and adjusted to pH 9.0 with an aqueous solution of 24% sodium hydroxide. The organic layer was separated, washed with 20% aqueous sodium chloride, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 8.64 g of methyl 2(S)-[N-(2-methylaminoethyl)-N-methylaminocarbonyloxy]-3-phenylpropionate (yield 97.9%).