Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[C:11]4[CH:17]=[CH:18][CH:19]=[CH:20][C:10]4=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]=[C:4]([OH:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[C:31]([CH3:35])([CH3:34])[C:32]#[CH:33]>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]2[O:21][C:31]([CH3:35])([CH3:34])[CH:32]=[CH:33][C:5]2=[C:6]2[C:15]=1[C:14](=[O:16])[C:13]1[CH:12]=[C:11]3[CH:17]=[CH:18][CH:19]=[CH:20][C:10]3=[CH:9][C:8]=1[NH:7]2
Reactant: O=c1c2cc3ccccc3cc2[nH]c2cc(O)cc(O)c12
Reactant: C#CC(C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C=Cc2c(cc(O)c3c(=O)c4cc5ccccc5cc4[nH]c23)O1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 44.4 %

Procedure:
To a solution of 2 g of the product of Step A in 50 ml of anhydrous dimethylformamide, under an inert atmosphere, there are added 2 g of anhydrous potassium carbonate. After stirring for 15 minutes at 65° C., 2.4 g of anhydrous potassium iodide and 4.4 g of 3-chloro-3-methyl-1-butyne are added, and the reaction mixture is held at 65° C. for 24 hours and then at 130° C. for 1 hour. After cooling, the solution is hydrolysed and then extracted with dichloromethane. The combined organic phases are washed with water and then with 1M potassium hydroxide solution, dried over sodium sulphate and then evaporated. After chromatography over silica gel (cyclohexane/acetone: 90/10), 1.10 g of the expected product are isolated.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29](=O)[CH:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=2)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:22][C:29](=[O:30])[CH2:28][C:27]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc([N+](=O)[O-])c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc([N+](=O)[O-])c1
Yield: 49.5 %

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) (1.1 g, 4.0 mmol) and 2,2-dimethyl-6-(3-nitro-phenyl)-[1,3]dioxin-4-one (Example J12) (1.23 g, 4.4 mmol) according to the general procedure K. Obtained as a light yellow solid (989 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH3:13][O:14][C:15]1[C:16]([N+]([O-])=O)=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.O>CN(C=O)C>[CH3:13][O:14][C:15]1[C:16]2[S:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:18][C:17]=2[CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CS
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cccc(OC)c2s1
Temperature: 70 °C

Procedure:
550 mg (3.97 mmol) of potassium carbonate and 350 mg (3.31 mmol) of methyl mercaptoacetate are added to a solution of 600 mg (3.31 mmol) of 3-methoxy-2-nitrobenzaldehyde in 8 ml of DMF. The reaction mixture is heated at 70° C. for 4 h. After cooling, water is added. The resulting precipitate is filtered off, washed with water and dried under reduced pressure. This gives 387 mg (45.7% of theory) of the title compound.
Reaction SMILES: CON(C)[C:4]([CH2:6][C:7]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8]1)=[O:5].[CH3:15][Li]>C1COCC1>[O:5]=[C:4]([CH3:15])[CH2:6][C:7]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:8][CH2:9]1
Reactant: [Li]C
Reactant: CON(C)C(=O)CC1(CC(=O)O)CC1
Solvent: C1CCOC1
Product: CC(=O)CC1(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3.6 g crude {1-[(methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acid (18 mmole) in 54 ml of THF are added 24.5 ml of methyllithium (1.6 M solution in diethyl ether, 39.2 mmole, 2.2 eq) at <−75° C. Stirring is continued for 2 hours, then the mixture is quenched by addition of 2 ml of methanol and warmed to room temperature. 54 ml of water are added and the phases are separated. The aqueous product phase is washed with 27 ml of methyl tert-butyl ether, acidified to pH 2.5 by addition of conc. HCl and extracted three times with 27 ml ethyl acetate each. The combined organic phases are concentrated to dryness and the residue is directly used in the next step (esterification to [1-(2-oxo-propyl)-cyclopropyl]-acetic acid methyl ester).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=O)=[CH:5]2.[N+]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)N[C:23]([C:28]([O:30]CC)=O)=[CH:22]2)([O-])=O>>[C:4]([C:27]1[CH:19]=[CH:20][C:21](/[CH:22]=[CH:23]/[C:28]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([CH2:11][OH:13])=[CH:5]3)=[O:30])=[CH:25][CH:26]=1)([CH3:8])([CH3:5])[CH3:3]
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Product: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3[nH]c(CO)cc3c2)cc1

Procedure:
Ethyl 5-aminoindole-2-carboxylate. Analogous to the procedure used to prepare Example 3, step (a), ethyl 5-nitroindole-2-carboxylate (2.3 g, 9.9 mmol, Acros) provided the title product. MS (ESI, pos. ion) m/z: 205 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14](=O)[CH2:15]Br>O1CCOCC1>[Cl:8][C:7]1[C:2]2[N:3]([CH:15]=[C:14]([C:13]3[CH:18]=[CH:19][CH:20]=[C:11]([O:10][CH3:9])[CH:12]=3)[N:1]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: Nc1nccnc1Cl
Solvent: C1COCCO1
Product: COc1cccc(-c2cn3ccnc(Cl)c3n2)c1
Temperature: 25 °C
Yield: 19.5 %

Procedure:
To a solution of 2-amino-3-chloropyrazine (0.20 g, 1.5 mmol, 1.00 equiv) and 3-methoxyphenacyl bromide (0.71 g, 3.1 mmol, 2.0 equiv) in dioxane (10 mL) was heated at 90° C. for 3 hr. The resulting mixture was cooled to rt and filtered. The filtrate was partitioned between 10% IPA/DCM and 1 N NaOH. The aqueous extract was washed with 10% IPA/DCM (2×) and the combined organic extracts were washed with brine and dried with sodium sulfate. Concentration afforded 8-chloro-2-(3-methoxy-phenyl)-imidazo[1,2-a]pyrazine (76 mg, 19%). MH+ (LCMS) 260.1 (m/z).
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:27])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:26]=[CH:25][C:18]([O:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.N1C(C)=CC=CC=1C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[C:36]([O:23][CH2:22][C@@H:21]([OH:24])[CH2:20][O:19][C:18]1[CH:17]=[CH:16][C:15]([C:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][C@H:3]([OH:27])[CH2:2][Cl:1])=[CH:11][CH:10]=2)([CH3:14])[CH3:13])=[CH:26][CH:25]=1)(=[O:38])[CH3:37]
Reactant: CC(C)(c1ccc(OC[C@H](O)CO)cc1)c1ccc(OC[C@H](O)CCl)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(=O)OC[C@@H](O)COc1ccc(C(C)(C)c2ccc(OC[C@H](O)CCl)cc2)cc1
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of (R)-3-(4-(2-(4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol (1000 mg, 2.53 mmol) in anhydrous dichloromethane (8.0 mL) at −78° C. were successively added 2,6-lutidine (590 μL, 5.06 mmol) and acetic chloride (144 μL, 2.02 mmol) dropwise. After 1 h, the reaction mixture was quenched with an aqueous solution of sodium chloride and stirred for 15 min, and the resulting mixture was extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate and filtered. Solvents were evaporated, and the resulting crude material was purified by silica gel flash chromatography (eluent: 2% methanol in dichloromethane) to provide the title compound (300 mg, 27%) as a sticky solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[NH:16][C:17]1[N:22]=[CH:21][C:20]2=[CH:23][CH:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]2[N:18]=1.[O:38]1[CH2:40][C@H:39]1[CH2:41][OH:42].CO>>[OH:38][C@@H:39]([CH2:41][OH:42])[CH2:40][N:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:7]2[CH:6]=[CH:5][C:4]([NH:16][C:17]3[N:22]=[CH:21][C:20]4=[CH:23][CH:24]=[C:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]4[N:18]=3)=[C:3]([O:2][CH3:1])[CH:8]=2)[CH2:11][CH2:12]1
Reactant: OC[C@@H]1CO1
Reactant: COc1cc(CN2CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Solvent: CO
Product: COc1cc(CN2CCN(C[C@@H](O)CO)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Yield: 16.8 %

Procedure:
Into an 8-dram vial, N-{2-[2-(2-Methoxy-4-piperazin-1-ylmethyl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide (80 mg, 0.2 mmol), (R)-Oxiranemethanol (0.0350 g, 0.472 mmol), and Methanol (5.87 mL, 145 mmol) were added. The reaction was stirred at room temperature over the weekend. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The selected fractions were concentrated. The residue was partitioned with DCM and sat. NaHCO3. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered wand washed with DCM. The solvent was removed under vacuum to give N-[2-(2-{4-[4-((R)-2,3-Dihydroxy-propyl)-piperazin-1-ylmethyl]-2-methoxy-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a yellow solid (20 mg, 21%). LCMS (E/I+) 596.11 (M+H). NMR 1H (DMSO-d6)-8.97 (s, 1H), 7.90-7.98 (m, 1H), 7.88 (d, 1H, J=8.21 Hz), 7.72 (s, 1H), 7.62-7.66 (m, 1H), 7.51-7.56 (m, 1H), 7.00 (d, 1H, J=4.67 Hz), 6.96 (d, 1H, J=4.67 Hz), 6.92 (bs, 1H), 6.72 (d, 1H, J=8.01 Hz), 4.51 (t, 1H, J=5.55), 4.34 (d, 1H, J=4.34 Hz), 3.82 (s, 3H), 2.18-3.70 (bm, 21H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21]CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(O)=O)[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[F:47][C:48]([F:76])([C:66]([F:75])([F:74])[C:67]([F:73])([F:72])[C:68]([F:71])([F:70])[F:69])[CH2:49][CH2:50][CH2:51][CH:52]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH:64]=C)[C:53]([O:55]CC)=[O:54]>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH:52]([CH2:51][CH2:50][CH2:49][C:48]([F:47])([F:76])[C:66]([F:74])([F:75])[C:67]([F:72])([F:73])[C:68]([F:70])([F:69])[F:71])[C:53]([OH:55])=[O:54])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 8 and the ethyl 2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-9-decenoate prepared in Example 7, a procedure analogous to that as shown in Example 8 was repeated to give 11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)undecanoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:41])[N:27]3[C:30]([O:32][CH:33](Cl)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.[C:42]([OH:47])(=[O:46])[CH2:43][CH2:44][CH3:45].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:41])[N:27]3[C:30]([O:32][CH:33]([O:47][C:42](=[O:46])[CH2:43][CH2:44][CH3:45])[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)OC(Cl)c1ccccc1
Reactant: CCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(=O)OC(OC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of chloro(phenyl)methyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (4.11 g, 6.66 mmol) in dimethyl formamide (40 mL) was added butyric acid (0.91 mL, 9.99 mmol) and cesium carbonate (1.63 g, 4.99 mmol). The reaction was stirred at room temperature for 20 hours then diluted with ethyl acetate (40 mL) and washed with 1:1 water/brine (3×50 mL). The organics were dried (MgSO4) and concentrated. The crude product was purified by column chromatography on silica eluting with 0.5% Et3N/ethyl acetate to give butyryloxy(phenyl)methyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate, Compound-91 (1.12 g). The material was determined to be 67% pure by LCMS.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[N:11]([C:18](N2C=CN=C2)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:26][O:27][CH2:28][CH2:29][OH:30]>>[CH3:26][O:27][CH2:28][CH2:29][O:30][C:18]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:25])=[O:19]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Reactant: COCCO
Product: COCCOC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 31 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-1-(imidazol-1-ylcarbonyl)-1,3-dihydro-indol-2-one (200 mg, 0.6 mmol) in 6 mL of 2-methoxyethanol was stirred at room temperature for 20 h and partitioned between water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified on a silica gel column eluting with ethyl acetate-hexane (1:3) to give 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-methoxy-ethyl ester (63 mg, 31%) as an red solid. 1H NMR (400 MHz, CDCl3) δ 12.71 (s, 1H, NH-1′), 7.85 (d, J=7.05 Hz, 1H), 7.50 (d, J=7.05 Hz, 1H), 7.40 (s, 1H, H-vinyl), 7.16-7.23 (m, 2H), 6.03 (s, br, 1H, H-4′), 4.62 (t, J=4.70 Hz, 2H, CH2), 3.81 (t, J=4.70 Hz, 2H, CH2), 2.38 (s, 3H, CH3), and 2.34 (s, 3H, CH3). MS m/z (relative intensity, %) 341 (100, [M+1]+.)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[C:12]1(=[O:26])[N:16]([CH2:17][C:18](Cl)=[O:19])[C:15](=[O:21])[C:14]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:13]12>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:18](=[O:19])[CH2:17][N:16]3[C:15](=[O:21])[C:14]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:13]4[C:12]3=[O:26])=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11]
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: CN1C(=O)Cc2ccccc21
Product: CN1C(=O)Cc2cc(C(=O)CN3C(=O)c4ccccc4C3=O)ccc21
Yield: 65.3 %

Procedure:
1-Methyl-2-indolinone (34.0 g) and 2-phthalimidoacetyl chloride (37.3 g) was reacted according to a similar manner to that of Example 8-(1). The object compound was purified by column chromatography on silica gel (300 g) using chloroform as an eluent to give 36.41 g of 1-methyl-5-phthalimidoacetyl-2-indolinone.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6]2[CH:11]=[C:12]([C:15](OC)=[O:16])[CH:13]=[N:14][C:5]1=2)([CH3:3])[CH3:2].[H-].[Na+]>O1CCCC1>[OH:16][CH2:15][C:12]1[CH:13]=[N:14][C:5]2[N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: COC(=O)c1cnc2c(c1)NC(=O)CN2C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N1CC(=O)Nc2cc(CO)cnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl 4-isopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate (1.3 g, 5.45 mmol) was suspended in tetrahydrofuran (68 mL). The white suspension was cooled to 0° C. and NaH (60% dispersion in mineral oil, 0.327 g, 8.17 mmol) was added. The reaction was removed from the ice bath and allowed to stir at RT for 0.5 h. The solution was then cooled to −78° C. and LiAlH4 was added over two min. A temperature between −30 and −20° C. was maintained. The reaction was cooled to −78° C. and MeOH (2 mL) was added. The reaction was stirred at room temperature 30 min. The reaction was poured into ethyl acetate (400 mL) and water (100 mL), and stirred for 1 hr. The mixture was filtered through medium frit to remove tan solids. The aqueous layer was extracted with ethyl acetate (1×100 mL). The organic fractions were combined, washed once with brine (100 mL), dried with sodium sulfate and concentrated to the title compound (1.10 g, 91%) as a white solid. [M+H] calc'd for C11H15N3O2, 222; found, 222.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[CH2:16][NH:17][C:18]1[C:27]2[S:26][CH2:25][C:24](=[O:28])[NH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.CI.[C:34]([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CN(C=O)C>[CH3:34][N:23]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:17][CH2:16][C:15]3[CH:29]=[CH:30][CH:31]=[C:13]([O:12][CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[CH:14]=3)[C:27]=2[S:26][CH2:25][C:24]1=[O:28]
Reactant: O=C1CSc2c(NCc3cccc(OCc4ccc5ccccc5n4)c3)cccc2N1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)CSc2c(NCc3cccc(OCc4ccc5ccccc5n4)c3)cccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.3 %

Procedure:
After a mixture of 1.690 g (3.95 m-mol) of 8-[3-(2-quinolinylmethoxy)benzylamino]-3,4-dihydro-2H-1,4-benzothiazin-3-one obtained in Example 95, 0.673 g (4.74 mmol) of CH3I, 1.311 g (9.5 mmol) of K2CO3, 0.129 g (0.4 mmol) of (n-Bu)4NBr and 50 ml of DMF was stirred at room temperature for 3 days, the solvent was distilled off under reduced pressure. Water was added to the residue, followed by extraction with CHCl3. The extract was washed with water, dried over MgSO4 and then concentrated. The residue was subjected to chromatography on a silica gel column. Subsequent to elution with CHCl3, recrystallization was conducted from an acetone-n-hexane mixed solvent, whereby 1.000 g of the title compound was obtained (yield: 57.3%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][C:9]([SH:11])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:7]2[O:8][C:9]([S:11][CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1nc2ccnc(Br)c2o1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nc2ccnc(Br)c2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.21 g (5.24 mmol) 4-bromo-oxazolo[5,4-c]pyridine-2-thiol, 0.8 g (5.76 mmol) K2CO3, 0.9 g (6.28 mmol) MeI in 12 ml DMF is stirred at room temperature for 1 h. The reaction mixture is then poured on water and extracted 2× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo to afford the title compound in quantitative yield.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[C:7]=1[CH3:32])C.Cl>CO.[OH-].[Na+].O>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:6]([CH2:5][C:4]([OH:33])=[O:3])=[C:7]2[CH3:32])=[CH:19][CH:20]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccc(OCc3ccccc3)cc2)c2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccc(OCc2ccccc2)cc1
Reaction time: 16 h
Yield: 32 %

Procedure:
1-[(4-Benzyloxyphenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid. Using the method described in Example 6, Part A, 2.0 g (8.12 mmol) of 5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester, 0.325 g (8.12 mmol) of 60% NaH/mineral oil, and 1.88 g (8.12 mmol) of 4-benzyloxy-1-chloromethylbenzene were reacted to give on workup 800 mg of crude 1-[(4-benzyloxyphenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester. The crude ester in 50 mL of MeOH and 15 mL of 1N NaOH was heated at reflux temperature for 3 hours and left standing for 16 hours. After diluting with water, the mixture was made acidic with 1N HCl and extracted with EtOAc. The EtOAc solution was dried (Na2SO4) and concentrated. The residue was crystallized from MeOH to give 280 mg (32% yield) of 1-[(4-benzyloxyphenyl)-methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid, mp, 175-179° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[N:6]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:33][O:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38].Cl>C1COCC1.O>[C:17]1([S:14]([N:6]2[C:7]3[C:12](=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=3)[C:4]([C:1](=[O:3])[CH2:2][C:37]([C:36]3[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=3[O:34][CH3:33])=[O:38])=[CH:5]2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: CC(=O)c1cn(S(=O)(=O)c2ccccc2)c2ccc(Cl)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1C(=O)CC(=O)c1cn(S(=O)(=O)c2ccccc2)c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
A solution of 500 mg (1.5 mmol) of 3-acetyl-1-benzenesulfonyl-5-chloroindole in THF (5 ml) was cooled at −78° C. Subsequently, to the reaction mixture was added 1.8 ml (1.8 mmol) of 1M LHMDS in THF. The solution was gradually warmed to 0° C. and cooled again to −78° C. To the solution was added 310 mg (1.8 mmol) of 2-methoxybenzoylchloride. The reaction mixture was warmed to room temperature. After 30 minutes, the mixture was treated with water and acidified with 6 N hydrochloric acid. The mixture was extracted with ethyl acetate and washed with water, and then dried. The solvent was removed and the obtained residue was chromatographed on silica gel with ethyl acetate-n-hexane as eluent. The fraction of the objective was concentrated to give 160 mg of the titled compound as a foam. Yield: 23%.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[CH2:17][C:18](O)=[O:19])=[O:8])=[CH:3][CH:2]=1.O[N:28]=[C:29]([NH2:31])[CH3:30].CC(C)N=C=NC(C)C>ClCCl>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([CH2:17][C:18]2[O:19][N:31]=[C:29]([CH3:30])[N:28]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CC(N)=NO
Reactant: CON=C1C[C@@H](CC(=O)O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CON=C1C[C@@H](Cc2nc(C)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 102.4 %

Procedure:
To a solution of [(2S,4EZ)-1-biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]acetic acid (Intermediate 7, 50 mg, 0.14 mmol) in dichloromethane (3 ml) was added N′-hydroxyethanimidamide (12 mg, 0.16 mmol) followed by DIC (36 mg, 0.28 mmol). The reaction mixture was stirred 1 h30. The precipitate was filtered and the solution was concentrated in vacuo. Pyridine (1 ml) was added and the reaction mixture was stirred at reflux overnight The solvent was removed and dichloromethane was added. The organic phase was washed with HCl 1N then NaHCO3. The organic phase was dried (MgSO4), concentrated and purified on silica gel column chromatography (Ethyl acetate/cyclohexane, 40:60) to afford (3EZ,5S)-1-(biphenyl-4-ylcarbonyl)-5-[(3-methyl-1,2,4oxadiazol-5-yl)methyl]pyrrolidin-3-one O-methyloxime (56 mg). Yield: 91%. HPLC purity: 90%