Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:27]([CH3:29])[CH3:28])[C:3]1[C:4]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([CH3:26])=[CH:20]3)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH:27]([CH3:29])[CH3:28])[C:3]1[C:4]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([CH3:26])=[CH:20]3)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2cc(-c3nc4ccc(C(=O)O)cc4nc3N(C)C(C)C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylate (660 mg, 1.70 mmol) in methanol (40 ml) was added a solution of NaOH (340 mg, 8.50 mmol) in water (5 ml). The resulting solution was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in water (20 ml), adjusted to pH 4 with HCl (3N). The product was precipitated from water and collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylic acid as a orange solid (500 mg, 78%).
Reaction SMILES: C(OCC)C.C([Mg]Br)C.[C:10]1([S:16]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=3[F:28])[C:21](I)=[CH:20]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:31]([N:38]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@@H:39]([CH3:42])[CH:40]=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH2:43]([N:38]([CH:39]([CH3:42])[CH:40]([C:21]1[C:22]2[C:27](=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[N:19]([S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[CH:20]=1)[OH:41])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(F)cc(F)c21
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C(O)c1cn(S(=O)(=O)c2ccccc2)c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.8 %

Procedure:
A 3.0 M diethyl ether solution of ethylmagnesium bromide (7.3 ml, 21.8 mmol) is added under N2 at 0° C. to a 95 ml tetrahydrofuran solution of N-benzenesulfonyl-3-iodo-5,7-difluoro-indole (8.4 g, 20 mmol). The resulting mixture is stirred for 20 minutes at 0° C., allowed to warm to room temperature over 20 minutes, then recooled to 0° C. A 20 ml tetrahydrofuran solution of (S)N,N dibenzyl-2-aminopropanal (Syn. Lett., 1997,2, 223-224, 5.1 g, 22 mmol) is added to the reaction mixture and the resulting mixture is stirred 1 hour as it warmed to room temp. The reaction is quenched with aqueous NH4Cl, extracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, concentrated, and the residue is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 8.4 g of 2-(N,N-dibenzylamino)-1-(1-benzenesulfonyl-5,7-difluoro-1H-indol-3-yl)-propan-1-ol. (77%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:16]([NH2:18])[CH3:17]>>[Cl:1][C:2]1[C:3]([F:15])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][CH:10]=1)[C:5]([NH:18][CH2:16][CH3:17])=[O:7]
Reactant: C[Si](C)(C)c1ccc(Cl)c(F)c1C(=O)O
Reactant: CCN
Product: CCNC(=O)c1c([Si](C)(C)C)ccc(Cl)c1F
Product: O=C(O)c1cccc(Cl)c1F
Yield: 84 %

Procedure:
The trimethylsilyl ester of 3-chloro-2-fluorobenzoic acid (11.66 g) was prepared in 84% yield using the method described in Example 207. This ester (2.47 g) was converted to 0.45 g of 3-chloro-2-fluoro-6-(trimethylsilyl)benzoic acid in 18% yield using the method of Example 207. The crude product was converted to the acid chloride by the procedure of example b. The acid chloride was reacted with 70% aq ethylamine using General Method E1 to afford the title compound. Purification by flash chromatography (ethyl acetate/hexanes) followed by recrystallization from pentane gave 84 mg of the title compound as an off-white solid (18%). m.p. 96-97° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2.[H-].[Na+].Br[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2c(c1)CCN2
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2CCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
To a solution of 5-methoxyindoline (175 mg, 1.17 mmol) in 3.6 mL of dry N,N-dimethylformamide was added sodium hydride (55%, 70 mg, 1.6 mmol) at 0° C. After the reaction mixture was stirred at the same temperature for 30 min, (2-bromoethyl)benzene (0.22 mL, 1.6 mmol) was added with additional stirring at room temperature overnight. After the reaction mixture was quenched with water at 0° C., the solution was extracted with diethyl ether (20 mL) twice. The combined extracts were washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 85/15) to obtain 5-methoxy-1-phenethylindole (95 mg, 32%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10]Br.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>CC(C)=O>[Br:7][CH2:8][CH2:9][CH2:10][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCCCBr)cc1
Yield: 61 %

Procedure:
K2CO3 (1.82 g, 13 mmol) and 1,3-dibromopropane (3.05 mL, 30 mmol) were added to a solution of 4-hydroxy-benzaldehyde (1.22 g, 10 mmol) in acetone (30 mL). The mixture was heated under reflux for 8.5 hrs. Then the reaction mixture was filtered and the solvent was removed by evaporation. The resulting residue was mixed with ether and then washed consecutively with 5% NaOH, water, and brine. After drying with MgSO4 and evaporation of the solvent, flash column chromatography (silica gel, hexane 100%>EtOAc:hexane=10:90>20:80) gave the desired compound as a pale yellow oil: Rf=0.71 (silica gel, EtOAc:hexane=35:65); yield 61%; 1H-NMR (300 MHz, CDCl3) δ9.86 (1H, s), 7.82-7.79 (2H, dd, J=6.9 and 1.8 Hz), 7.00-6.97 (2H, dd, J=7.1 and 1.6 Hz), 4.19-4.15 (2H, t, J=5.8 Hz), 3.61-3.56 (2H, t, 6.4 Hz), 2.37-2.28 (2H, qui, 6 Hz).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[C:18]([OH:24])=[C:17]([CH:25]([CH3:27])[CH3:26])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=1)(=[O:33])=[O:32]>>[CH2:1]([C:8]1[O:9][C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=1[C:13]([C:15]1[CH:16]=[C:17]([CH:25]([CH3:27])[CH3:26])[C:18]([O:24][S:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=2)(=[O:33])=[O:32])=[C:19]([CH:21]([CH3:22])[CH3:23])[CH:20]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(Cc2ccccc2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1oc(Cc2ccccc2)c(C(=O)c2cc(C(C)C)c(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C(C)C)c2)c1C
Yield: 8.8 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (2-benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone (0.300 g, 0.768 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.218 g, 0.922 mmol) to give 0.04 g (9%) of the title compound as a tan solid, mp 142-143° C.; 1H NMR (DMSO-d6) δ 1.04 (d, 12 H), 1.81 (s, 3 H), 2.19 (s, 3 H), 3.07 (septet, 2 H), 3.81 (s, 2 H), 6.95-6.97 (m, 2 H), 7.14-7.20 (m, 3 H), 7.40-7.46 (m, 2 H), 7.47 (s, 2 H), 8.03 (d, 1 H). IR (KBr) 3400, 2950, 1675, 1375, 1180 cm-1. mass spectrum (EI), m/z 590 (M+). Anal. Calcd. for C33H34O8S.1.1H2O: C, 64.92; H, 5.98; N, 0.00. Found: C, 64.92; H, 5.76; N, -0.03.
Reaction SMILES: [CH2:1]([C:8]1[S:14][CH:13]2[CH:10]([C:11](=[O:32])[N:12]2[C:15](=[C:29](O)[CH3:30])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.[Br:44]N1C(=O)CCC1=O.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl.O.C(N(CC)CC)C>[CH2:1]([C:8]1[S:14][CH:13]2[CH:10]([C:11](=[O:32])[N:12]2[C:15](=[C:29]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH2:30][Br:44])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C(=C(CBr)N1CCOCC1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reaction time: 1.08 h
Yield: 65 %

Procedure:
One dissolves p-nitrobenzyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (827 mg) in methylene chloride (10 ml), cools to -20° C., adds a solution of methanesulfonyl chloride (1 M in methylene chloride; 2.2 ml) and a solution of triethylamine (1 M in methylene chloride; 2.2 ml), stirs for 90 minutes, cools to -25° C., adds morpholine (0.35 ml), stirs for 65 minutes, adds N-bromosuccinimide (340 mg), and stirs for 1 hour. One washes the reaction mixture with water, dries over magnesium sulfate, and evaporates. Purification of the obtained residue by chromatography over silica gel containing 10% water (30 g) gives p-nitrobenzyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholino-2-bromoethylidene)acetate (710 mg). Yield: 65%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]([O:24]CC)=O)[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C([NH2:29])=O.C[O-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]([NH2:29])=[O:24])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)o1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(-c2nc(C(N)=O)oc2-c2ccc(OC)cc2)cc1
Yield: 71.9 %

Procedure:
In WO2004/065374 is disclosed a method in which ethyl 4,5-bis(4-methoxyphenyl)-1,3-oxazole-2-carboxylate, which is a carboxylic acid ester, is allowed to react with formamide in the presence of sodium methoxide, which is a metal alkoxide, to give 4,5-bis(4-methoxyphenyl)-1,3-oxazole-2-carboxamide, which is a carboxamide, in a yield of 71.9% (see Example 2).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[H-].[Na+].Cl[S:22]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>CN(C=O)C.CCOC(C)=O>[C:14]([O:13][C:12]([N:11]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:2]=1[CH3:1])[S:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=1)(=[O:24])=[O:23])=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: Cc1c(NC(=O)OC(C)(C)C)nc2ccccn12
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3ccccn3c2C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a solution of compound 1-E (0.174 g, 0.703 mmol) in DMF (5 mL), cooled to 0° C., was added 60% NaH (0.028 g, 0.703 mmol) and the reaction mixture was stirred at 0° C. for 20 min. Methyl 4-(chlorosulfonyl)benzoate (0.247 g, 1.06 mmol) was added in one-portion and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with EtOAc, washed with H2O (2×), brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford a crude solid. The crude material was purified by flash column chromatography (SiO2) eluting with a heptanes-EtOAc gradient to afford compound 1-F as a white solid (0.188 g, 60%). 1H-NMR (CDCl3): δ 8.22-8.35 (dd, 2H), 7.90-7.92 (d, 1H), 7.61-7.64 (d, 1H), 7.22-7.24 (m, 1H), 6.90-6.93 (m, 1H), 3.98 (s, 3H), 2.55 (s, 3H), 1.32 (s, 9H); MS: m/z 446.1 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])([NH:8][C:9]([C:11]2[O:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:30][I:31]>>[I-:31].[CH2:28]([O:27][C:25](=[O:26])[CH2:24][C:5]1([NH:8][C:9]([C:11]2[O:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4][CH2:3][N+:2]([CH3:30])([CH3:1])[CH2:7][CH2:6]1)[CH3:29]
Reactant: CCOC(=O)CC1(NC(=O)c2ccc(CCc3ccccc3)o2)CCN(C)CC1
Reactant: CI
Product: CCOC(=O)CC1(NC(=O)c2ccc(CCc3ccccc3)o2)CC[N+](C)(C)CC1
Product: [I-]
Yield: 94 %

Procedure:
Ethyl 2-(1-methyl-4-(5-phenethylfuran-2-carboxamido)piperidin-4-yl)acetate (25 mg, 0.063 mmol) was treated with MeI (38 uL, 0.630 mmol) as described in Example 2a to yield crude title compound (32 mg, 94%) which was used without further purification. NMR (400 MHz, CD3OD) δ 7.29-7.16 (m, 5H), 7.07 (s, 1H), 6.20 (s, 1H), 4.10 (q, 2H, J=7.2 Hz), 3.56-3.46 (m, 4H), 3.23 (s, 3H), 3.21 (s, 3H), 3.03 (s, 4H), 3.01 (s, 2H), 2.91-2.83 (m, 2H), 2.29-2.19 (m, 2H), 1.17 (t, 3H, J=7.2 Hz); MS ESI 414.1 [M+H]+, calcd for [C24H32N2O4+H]+ 413.53.
Reaction SMILES: FC(S(O[C:9]1[CH2:14][CH2:13][C:12]([C:29]#[N:30])([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:16]=2)[CH2:11][CH:10]=1)(=O)=O)(F)F.CN.[CH3:33][OH:34].CN(C)[CH:37]=[O:38]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([C:12]1([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:16]=2)[CH2:13][CH2:14][C:9]([C:33]([O:38][CH3:37])=[O:34])=[CH:10][CH2:11]1)#[N:30]
Reactant: CN(C)C=O
Reactant: CO
Reactant: COc1ccc(C2(C#N)CC=C(OS(=O)(=O)C(F)(F)F)CC2)cc1OC1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN
Product: COC(=O)C1=CCC(C#N)(c2ccc(OC)c(OC3CCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1cyclohexenyl trifluoromethylsulfonate (1.0 g, 2.24 mmol) in 1:1 methanol/N,N-dimethylformamide (8 mL) were added methylamine (0.66 mL, 4.72 mmol) and tetrakis(triphenylphosphine)palladium (0.13 g, 0.11 mmol). The resulting mixture was stirred at room temperature in the dark under a carbon monoxide atmosphere for 3h. The mixture was partitioned between water and ethyl acetate, the organic extract was washed three times with water, once with brine, was dried (potassium carbonate) and was evaporated.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:28]=[C:29]([NH2:32])[NH:30][N:31]=2)[CH:24]=[CH:25][CH:26]=1>O1CCCC1>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:28]=[C:29]([NH:32][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[NH:30][N:31]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: COc1cccc(-c2cc(N)[nH]n2)c1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: COc1cccc(-c2cc(NC=C3C(=O)Nc4ccccc43)[nH]n2)c1

Procedure:
The named compound is prepared by substituting 5-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2367 gms. 5-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.0 mL) over the weekend.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:22][C:21](=[O:23])[O:20][N:19]=2)=[C:14]([O:24][CH3:25])[CH:13]=1.[CH2:36]([N:38](CC)[CH2:39][CH3:40])[CH3:37].C[S:44](Cl)(=O)=O>CN(C)C=O>[CH3:25][O:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10][C:9]2[S:8][C:7]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[N:6][C:5]=2[CH2:4][CH2:3][CH2:2][N:38]2[CH2:39][CH2:40][S:44][CH2:37][CH2:36]2)[CH:17]=[CH:16][C:15]=1[C:18]1[NH:22][C:21](=[O:23])[O:20][N:19]=1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCO)ccc1-c1noc(=O)[nH]1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCN2CCSCC2)ccc1-c1noc(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 50 mg of 3-{4-[4-(3-hydroxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one in 1.5 mL of dimethylformamide at 0° C. were added 0.015 mL of triethylamine and 0.008 mL of methanesulfonyl chloride. The resulting mixture was stirred at 0° C. for 30 minutes and then concentrated under reduced pressure, taken into dichloromethane, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was dissolved in 4 mL of dimethylformamide. To the resulting solution were added 0.012 mL of thiomorpholine, 0.017 mL of diisopropylethyl amine and 29 mg of potassium iodide. The reaction mixture was heated to 90° C. for 10 minutes under microwave irradiation in a sealed tube. It was then concentrated under reduced pressure, taken into dichloromethane, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient of methanol in dichloromethane), triturated in acetonitrile and filtered to give 5.3 mg of 3-{2-methoxy-4-[4-(3-thiomorpholin-4-yl-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-1,2,4-oxadiazol-5-one.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].C[N+]([O-])=O.Cl[CH:21](Cl)[O:22]C>C(Cl)CCl>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[C:8]([CH:21]=[O:22])[CH:9]=1)=[O:4]
Reactant: COC(Cl)Cl
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: C[N+](=O)[O-]
Product: O=Cc1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)-ethanone (5.0 g, 23.53 mmol) and AlCl3 (3.8 g, 28.50 mmol) in co-solvents of EDC (20 mL) and MeNO2 (20 mL) was cooled to −10° C. A solution of dichloro-methoxy-methane (3.25 g, 28.27 mmol) in EDC (5 mL) was added fairly rapidly and the mix was then stirred at −10° C. to room temperature for overnight. It was poured over crushed ice, the layer were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed, dried over MgSO4, and concentrated, yielding a slightly reddish solid (3.6 g, 64%). 1H NMR (500 MHz, CDCl3) δ10.10 (s, 1H), 10.06 (br, 1H), 7.96 (m, 2H) ppm. MS (ES−): m/e=238 (M−H); LC/Method A/3.15 min.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].CC1C=CC(S(O[CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: Cc1cc(O)c(F)c(C)c1-c1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCCCS(C)(=O)=O)c(F)c(C)c1-c1cccc(C=O)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
To a solution of 3′-fluoro-4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (2.44 g, 10.0 mmol) and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (3.51 g, 12.0 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.80 g, 13.0 mmol), and the mixture was stirred at 90° C. for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (3.45 g, yield 95%) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][S:23]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:14]([CH:43]=O)[CH:13]=3)[CH2:9]1)=O)(C)(C)C>C(O)=O>[NH3:8].[CH3:21][C@@H:19]1[CH2:20][NH:8][CH2:9][C@@H:10]2[N:18]1[C:17]1[N:16]=[C:15]3[CH2:22][S:23][CH2:43][C:14]3=[CH:13][C:12]=1[CH2:11]2
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(C=O)c(CSC(c4ccccc4)(c4ccccc4)c4ccccc4)nc3N21
Solvent: O=CO
Product: C[C@@H]1CNC[C@H]2Cc3cc4c(nc3N21)CSC4
Product: N
Yield: 166.9 %

Procedure:
A solution of 0.270 g (4R,9aR)-7-formyl-4-methyl-6-tritylsulfanylmethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 5 ml 90% aqueous formic acid was kept at room temperature for 6 h. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the aqueous phase was mixed with dichloromethane. The pH of the mixture was adjusted to 12.00 by addition of 2N aqueous sodium hydroxide and the phases were separated. The organic phase was evaporated and the residue was purified by chromatography on silica gel with dichloromethane:methanol:ammonia=90:10:1 to yield 0.092 g of the title compound as brownish solid (MS: 246.3 (M+H+)).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].Cl[C:22]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[O:23]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[O:23])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: COC(=O)CCC(=O)Cl
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 96.8 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added methyl 3-(chlorocarbonyl)propanoate (0.63 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.75 g (97%) of product as an off-white solid: mp 224-226° C.; 1H NMR (DMSO-d6) δ 11.18 (s, 1H), 9.79 (s, 1H), 8.43 (d, J=8.4 Hz, 1H), 7.83 (t, J=7.8 Hz, 1H), 7.62 (d, J=7.3 Hz, 1H), 5.16 (dd, J=5.2 and 12.6 Hz, 1H), 3.61 (s, 3H), 2.99-2.48 (m, 7H), 2.11-2.06 (m, 1H); 3C NMR (DMSO-d6) δ 172.84, 172.66, 170.94, 169.75, 167.61, 166.70, 136.39, 136.15, 131.52, 126.39, 118.43, 117.04, 51.51, 48.95, 31.22, 30.96, 28.39, 22.03; Anal. Calcd. For C18H17N3O7: C, 55.82; H, 4.42; N, 10.85. Found: C, 55.68; H, 4.41; N, 10.61.