Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:27][CH2:28][C@H:29]([CH2:30][C:31]([O:33]CC)=[O:32])[C:3]=12.[OH-].[Na+]>O1CCOCC1.CO>[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:27][CH2:28][C@H:29]([CH2:30][C:31]([OH:33])=[O:32])[C:3]=12
Reactant: CCOC(=O)C[C@H]1CCn2c1c(Cl)c1cc(OCc3ccc(OC(C)C)c(C(F)(F)F)c3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(Cl)c2n3CC[C@@H]2CC(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.4 %

Procedure:
To a solution of (R)-ethyl 2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (54.6 g, 107 mmol) in dioxane (750 mL) and MeOH (75 mL) was added NaOH (aq. 3N, 89.0 mL, 268 mmol). The mixture was stirred at room temperature for 17 h, concentrated in vacuo to approx 150 mL, and acidified with aqueous 3N HCl (300 mL). The resulting slurry was shaken and the solid filtered, washed with H2O (twice), hexanes and dried in a vacuum oven (50° C., 2 Torr, 15 h) to give (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid (51.3 g, 101 mmol, 94% yield, >98% ee) as a white solid. Exact mass calculated for C24H23ClF3NO4: 481.1, found: LCMS m/z=482.2, [M+H+]; 1H NMR (400 MHz, CD3CN) δ ppm 1.33 (d, J=6.0 Hz, 6 H), 2.34 (m, 1 H), 2.58 (dd, J1=16.5, J2=9.7 Hz, 1 H), 2.86 (m, 1 H), 3.06 (dd, J1=16.5, J2=4.2 Hz, 1 H), 3.73 (m, 1 H), 4.01 (m, 1 H), 4.14 (ddd, J1=9.9, J2=8.5 Hz, J3=4.9 Hz 1 H), 4.75 (sep, J=6.0 Hz, 1 H), 5.08 (s, 2 H), 6.87 (dd, J1=8.8, J2=2.4 Hz, 1 H), 7.01 (d, J=2.4 Hz, 1 H), 7.18 (d, J=8.6 Hz, 1 H), 7.21 (d, J=8.8 Hz, 1 H), 7.63 (dd, J1=8.6, J2=2.1 Hz, 1 H), 7.68 (d, J=2.1 Hz, 1 H), 9.10 (bs, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14]([OH:16])=O.CCN=C=NCCCN(C)C.Cl.O[NH:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)=[NH:35]>ClCCCl>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14]1[O:16][N:35]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[N:33]=1
Reactant: N=C(NO)c1ccccn1
Reactant: N#Cc1ccc2c(cc(C(F)F)n2CC(=O)O)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCCl
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2nc(-c3ccccn3)no2)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.3 %

Procedure:
To a suspension of [4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]acetic acid (0.020 g, 0.070 mmol) in DCE (2 mL), under N2 was added EDCl (0.015 g, 0.077 mmol) and the resulting mixture was stirred at rt. After 5 min, N-hydroxy-2-pyridinecarboximidamide (0.011 g, 0.077 mmol) was added. After stirring at rt for 30 min, the mixture was heated in a microwave at 150° C. for 20 min. Upon cooling, the mixture was partitioned between EtOAc and 0.1N HCl. The organic phase was washed with sat'd NaHCO3 solution and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-100% EtOAc-hexanes gradient) and the product was crystallized from CH2Cl2-MeOH-hexanes to give the title compound as a white solid (0.016 g, 59% yield): MS (ES) m/z 386 (M+1).
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:16](=[O:17])[CH2:15][CH2:14][C@@H:13]2[C:18]([OH:20])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:21][CH:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:23]([OH:27])[C:24]([NH2:26])=[O:25].O[NH-].O=[N-]>>[NH2:26][C:24](=[O:25])[C:23](=[O:27])[CH:22]([NH:21][C:18]([C@H:13]1[CH2:14][CH2:15][C:16](=[O:17])[N:12]1[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:20])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1cccc2ccccc12
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1cccc2ccccc12

Procedure:
Coupling of (R)-1-naphthalen-1-ylmethyl-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([N:27]2[CH:31]=[CH:30][C:29]([NH2:32])=[N:28]2)[CH:24]=[CH:25][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([NH:32][C:29]1[CH:30]=[CH:31][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:33])([F:19])[F:34])[CH:22]=2)[N:28]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Reactant: Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 2-nitro-5-(piperidin-1-yl)benzoic acid (5 g, 20.00 mmol, 1.19 equiv) in N,N-dimethylformamide (50 mL), 1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine (3.8 g, 16.74 mmol, 1.00 equiv), HATU (9.5 g, 25.00 mmol, 1.49 equiv), and N,N-diisopropylethylamine (3.3 g, 25.58 mmol, 1.53 equiv). The resulting solution was stirred overnight at 50° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 200 mL of water, extracted with 4×50 mL of ethyl acetate, and the organic layers combined. The resulting mixture was washed with 2×50 mL of water and 2×50 mL of brine. The mixture was dried over sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (5:1) to yield 2.8 g (36%) of product as a yellow solid.
Reaction SMILES: [CH3:1]I.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH2:5][CH2:4]1>C(#N)C.CO>[CH3:1][N:3]1[CH2:4][CH2:5][CH:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH2:7][CH2:8]1
Reactant: CI
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Solvent: CC#N
Solvent: CO
Product: CN1CCC(c2cccc3c2CC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
Methyl iodide (130.6 mg, 0.92 mmol) was added to a solution of 4-piperidin-4-yl-1,3-dihydroindol-2-one (199 mg, 0.92 mmol) in acetonitrile (10 mL) and methanol (1 mL). The reaction was stirred at room temperature under nitrogen for 2 days. The solvents were removed and the residue was purified on a silica gel column to give 150 mg (70%) of 4-(1-methylpiperidin-4-yl)-1,3-dihydroindol-2-one as a tan solid.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][C@@H:21]([CH2:26][O:27][CH2:28][CH3:29])[C:22](OC)=[O:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[Si:13]([O:20][C@@H:21]([CH2:26][O:27][CH2:28][CH3:29])[C:22]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Cc1ccc(N)nc1
Reactant: CCOC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)OC
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
A solution of trimethylaluminium (2M in hexane, 2.75 mL, 5.49 mmol) was added dropwise to a stirred solution of 5-methylpyridin-2-amine (0.594 g, 5.49 mmol) in toluene (10 mL) cooled to 0° C., over a period of 5 minutes under nitrogen. The resulting solution was stirred for 15 minutes. A solution of (S)-methyl 2-(tert-butyldimethylsilyloxy)-3-ethoxypropanoate (Intermediate G3) (1.31 g, 4.99 mmol) in toluene (5 mL) was added dropwise over a period of 2 minutes. The resulting solution was allowed to warm to ambient temperature and then heated to reflux for 7 hours then allowed to cool to room temperature and 1M citric acid (20 mL) added, diluted with water (25 mL) and the mixture extracted with ethyl acetate (25 mL). The aqueous was re-extracted with ethyl acetate (25 mL), the organic phases combined, washed with water (5 mL) and brine (20 mL), dried over MgSO4, filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 10 to 100% EtOAc in isohexane to give (2S)-2-(tert-butyl-dimethylsilyl)oxy-3-ethoxy-N-(5-methylpyridin-2-yl)propanamide (1.1 g, 65%). 1H NMR (400 MHz, CDCl3) δ 0.18 (3H, s), 2.00 (3H, s), 0.99 (9H, s), 1.18 (3H, t), 2.30 (3H, s), 3.51-3.61 (2H, m), 3.63-3.67 (1H, m), 3.78-3.81 (1H, m), 4.41-4.43 (1H, m), 7.51 (1H, dd), 8.13-8.18 (2H, m), 9.03 (1H, s); m/z (ESI+) (M+H)+=339; HPLC tR=3.31 min.
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23].O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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:10]([C:4]1[C:3]([O:13][CH3:14])=[C:2]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:16]([F:15])[CH:17]=2)[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)(=[O:12])[CH3:11]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2c(C)c(Cl)cc(C(C)=O)c2OC)cc1F
Temperature: 100 °C

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (1.0 g, 3.6 mmol) and [3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid (0.85 g, 4.3 mmol) in 1,4-dioxane (12 mL) and 10% sodium carbonate in water (5.73 mL, 5.40 mmol) was bubbled with N2 to degas. After tetrakis(triphenylphosphine)palladium(0) (166 mg, 0.144 mmol) was added, the mixture was bubbled with N2 for 5 min. more and heated at 100° C. overnight. The mixture was cooled to room temperature and diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give crude product.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C@H:3]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(C(C)C)C(C)C.[C:30](C1CC(=O)NC1=O)([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>CN(C)C=O>[CH2:33]([O:32][C:30]([NH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C@H:3]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C1CC(C(=O)OCc2ccccc2)C(=O)N1
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 105.1 %

Procedure:
To a solution of (3R,4R)-di-tert-butyl 4-aminopyrrolidine-1,3-dicarboxylate (Org. Biomol. Chem. 2004, 2, 2763-2776) (765 mg, 2.67 mmol) and Hunig's base (465 uL, 2.67 mmol) in N,N-dimethylformamide (5 mL) was added Cbz succinimide (665 mg, 2.67 mmol). The mixture was stirred for 3 hours and partitioned between EtOAc and water. The organic layer was washed repeatedly with brine, dried (Na2SO4) and concentrated to a clear oil (1.18 g, quantitative yield). MS (DCI/NH4) m/z=438 (M+NH4)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:13]=1)[O:10][C:9]([C:21](O)=[O:22])=[CH:8][C:7]2=[O:24].[CH3:25][CH:26]1[O:31][CH:30]([CH3:32])[CH2:29][N:28]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:27]1>>[CH3:32][CH:30]1[O:31][CH:26]([CH3:25])[CH2:27][N:28]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:21]([C:9]3[O:10][C:11]4[C:6]([C:7](=[O:24])[CH:8]=3)=[CH:5][C:4]([O:3][CH3:2])=[CH:13][C:12]=4[N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[O:22])=[CH:35][CH:34]=2)[CH2:29]1
Reactant: CC1CN(c2ccc(N)cc2)CC(C)O1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)O)cc(=O)c2c1
Agent: Cl
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CC(C)OC(C)C4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) and commercially available 4-(2,6-dimethyl-morpholin-4-yl)-phenylamine (Maybridge) as prepared in Example 12, yielding a yellow solid. (70 mg=49%), LCMS-m/z=507.5.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[OH:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29].Cl>N1C=CC=CC=1>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[O:27][C:28](=[O:30])[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1sc2cc3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1C1CCCC1
Yield: 99.7 %

Procedure:
To 2-cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (2.8 g, 7.5 mmol) in anhydrous pyridine (20 mL) at room temperature under nitrogen was added dropwise acetic anhydride (0.92 mL, 9.8 mmol). The reaction mixture was placed in the refrigerator. After 41 h the reaction was diluted and acidified with 10% aqueous hydrochloric acid to a pH of 1. The mixture was extracted with diethyl ether (500 mL), and the diethyl ether layer was washed with 5% aqueous hydrochloric acid (100 mL), twice with water (100 mL), brine (100 mL), and then dried (MgSO4). Concentration under reduced pressure gave the title compound as a white solid (3.1 g, 98%): (DMSO-d6): δ8.48 (s, 1H), 7.97 (d, 1H), 7.47-7.43 (m, 1H), 7.38-7.36 (m, 2H), 7.28 (s, 1H), 7.19 (d, 2H), 3.14 (quintet, 1H), 2.40 (s, 3H), 2.37 (s, 3H), 1.99-1.91 (m, 2H), 1.69-1.40 (m, 6H), 1.56 (s, 3H); MS(EI): [M+] 414; Anal. Calc. for C27H26O2S: C, 78.23; H, 6.32; N, 0.00. Found: C, 77.68; H, 6.39; N, 0.04.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:9](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)\[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cccc(/C(=C/C=C/C(=O)O)c2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.4 %

Procedure:
As in Example 115, (2E,4E)-5-(3 methoxyphenyl)-5-phenyl-2,4-pentadienoic acid (3.2 g) and 4-nitrophenol (1.73 g) in dichloromethane (50 mL) was treated with 1,3-dicyclohexylcarbodiimide (2.35 g) and the mixture was stirred at room temperature for 1.5 hours. The usual work up furnished 4.2 g of crude product which was crystallized from 2-propanol to give 3.5 g of (2E,4E)-5-(3-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid 4-nitrophenyl ester mp 101°-103° C. Anal. Calculated for C24H19NO5 : C, 71.81; H, 4.77; N, 3.49 Found: C, 72.12; H, 5.02; N, 3.42.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[CH3:11].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH:16]=O.[C:22](#[N:26])[CH2:23][C:24]#[N:25]>>[NH2:26][C:22]1[O:1][C:2]2[C:10]([CH:16]([C:15]3[CH:14]=[C:13]([F:12])[CH:20]=[C:19]([F:21])[CH:18]=3)[C:23]=1[C:24]#[N:25])=[CH:9][CH:8]=[C:7]1[N:6]([CH3:11])[CH2:5][CH2:4][C:3]=21
Reactant: CN1CCc2c(O)cccc21
Reactant: N#CCC#N
Reactant: O=Cc1cc(F)cc(F)c1
Product: CN1CCc2c1ccc1c2OC(N)=C(C#N)C1c1cc(F)cc(F)c1

Procedure:
The title compound was prepared from 4-hydroxy-2,3-dihydro-1-methylindole (30 mg, 0.2 mmol), 3,5-difluoro-benzaldehyde (29 mg, 0.2 mmol) and malononitrile (13 mg, 0.2 mmol) similar to Example 22 to yield 20 mg (29%) of white solids. 1H NMR (CDCl3): 6.74-6.65 (m, 4H), 6.20 (d, J=7.8 Hz, 1H), 4.62 (s, 3H), 3.40 (t, J=8.1 Hz, 2H), 2.99 (t, J=8.7 Hz, 2H), 2.74 (s, 3H).
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([CH2:12][O:13][CH2:14][C@@H:15]1[CH2:19][C@@H:18]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][N:16]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:26])(O)=[O:10].C([N:40](CC)CC)C.O.N>O1CCCC1.O>[C:9]([CH2:12][O:13][CH2:14][C@@H:15]1[CH2:19][C@@H:18]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][N:16]1[C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=1)=[O:26])(=[O:10])[NH2:40]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
A solution of isobutyl chloroformate (0.60 g) in tetrahydrofuran (1 ml) was dropwise added to a solution of (2S,4R)-2-(carboxymethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.28 g) and triethylamine (0.82 ml) in tetrahydrofuran (13 ml) at -10°~-5° C., and the mixture was stirred at the same temperature for 30 minutes. The mixture was dropwise added to concentrated ammonia water (10 ml) at 0°-5° C. and the solution was stirred at the same temperature for 1 hour. The mixture was poured into water (50 ml) and extracted with chloroform (50 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (25 g) and eluted with a mixture of methanol and chloroform (2:98 V/V) to give (2S,4R)-2-(carbamoylmethyloxymethyl)4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.00 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:17]([OH:19])=O)=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C=O)C.[O:37]([C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O>[CH2:1]([O:8][C:9]1[C:10]([C:17]([NH:48][C:47]2[CH:46]=[CH:45][C:44]([O:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:50][CH:49]=2)=[O:19])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccnc(C(=O)O)c1OCc1ccccc1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1OCc1ccccc1
Reaction time: 8 h
Yield: 71.3 %

Procedure:
3-Benzyloxy-4-methoxypicolinic acid (0.65 g, 2.5 mmol) and 0.50 g (3.0 mmol) of carbonyldiimidazole were mixed into anhydrous DMF to prepare a suspension (8 ml). An anhydrous DMF solution (2 ml) of 0.56 g (3.0 mmol) of 4-phenoxyaniline was added dropwise to this suspension, and a reaction was allowed to proceed at room temperature overnight. Water (10 ml) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the dried organic layer was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 0.76 g (yield 71%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([C:29](=[O:31])[CH3:30])=[CH:26][C:25]=2[CH:32]=1>CN(C=O)C>[C:29]([C:27]1[O:28][C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:2]3[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:32][C:25]=2[CH:26]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)c1cc2cc(N)ccc2o1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Product: COCCN1C(=O)C(Nc2ccc3oc(C(C)=O)cc3c2)=C(c2ccccc2)S1(=O)=O
Yield: 34.5 %

Procedure:
A solution of 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.245 g, 0.81 mmol) and 1-(5-amino-1-benzofuran-2-yl)ethanone (0.285 g, 1.63 mmol) in DMF (4 mL) was heated at 130° C. for 4 h in a microwave reactor. The product was purified by preparative HPLC [0.1M NH4OAc/MeCN, gradient A:B (8:2 to 3:7)]. The product fractions were evaporated and the residue was extracted with DCM. The organic layer was washed with saturated NaHCO3, dried through a phase separator and evaporated to give the title compound (0.123 g, 34%) as a solid; 1H NMR (500 MHz, CD3CN): δ 7.32 (ds, 1H), 7.24 (d, 1H), 7.02-7.16 (m, 7H), 3.93 (t, 2H), 3.73 (t, 2H), 3.38 (s, 3H), 2.49 (s, 3H); Mass Spectrum: M+H+ 441.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([Br:10])[CH:3]=1.F[C:12](F)(F)C(O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>C(OC(OCC)OCC)C.C(O)(=O)C>[Br:10][C:4]1[CH:3]=[C:2]([N:1]2[CH:12]=[N:20][N:19]=[N:18]2)[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: COc1ccc(N)cc1Br
Reactant: O=C(O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: COc1ccc(-n2cnnn2)cc1Br

Procedure:
4-Amino-2-bromoanisole (4.7 g) was suspended in triethylorthoformate (50 ml), trifluoroacetic acid (1.8 ml) was added, and the reaction was heated at reflux for 36 hrs. The triethylorthoformate was removed in vacuo to afford a brown oil, which was dissolved in acetic acid (25 ml), sodium azide (2.25 g) was added and the mixture was heated for 4 hrs. The solvent was removed in vacuo and the residue dispersed between ethyl acetate and saturated sodium hydrogen carbonate. The organic layer was washed with water, brine, dried (MgSO4) and the solvent removed. Purification on flash silica eluting with 100% dichloromethane→0.25%→0.5%→0.75% methanol in dichloromethane afforded the title compound (4 g) as a brown solid. 1H NMR (250 MHz, DMSO) δ 4.06 (3H, s), 7.48 (1H, d, J=8.9) 8.03 (1H, dd, J=8.9, 2.7), 8.31 (1H, d, J=2.5), 10.15 (1H, s).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:33])[C@H:21]([CH3:32])[NH:22][C:23](=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[F:34]C1C=C(CC(O)=O)C=CC=1>>[F:34][C:29]1[CH:30]=[C:25]([CH2:24][C:23]([NH:22][C@H:21]([C:20]([NH:19][C@@H:3]2[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C@@H:4]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:33])[CH3:32])=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Reactant: O=C(O)Cc1cccc(F)c1
Product: C[C@H](NC(=O)Cc1cccc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (113) was used except that 3-fluorophenylacetic acid (77 mg) was used in place of phenylacetic acid to afford the title, compound as a 1:1 mixture with the (2S,3R) diastereomer (140 mg), white solid, m.p. 130-140° C. 1H NMR (300 MHz, CDCl3) δ 0.97 (d, 1.5H, J=5 Hz), 1.27 (d, 1.5H, J=5 Hz), 3.45 (two peaks, 2H), 4.52 (m, 0.5H), 4.67 (m, 0.5H), 4.91 (t, 1H, J=6 Hz), 5.12 (t, 1H, J=6 Hz), 5.79 (dd, 1H, J=7 Hz, J=10 Hz), 6.15 (d, 0.5H, J=8 Hz), 6.28 (d, 0.5 Hz, J=8 Hz), 6.63 (d, 0.5h, J=6 Hz), 6.70 (d, 0.5H, J=7 Hz), 6.86-7.70 (m, 13H), 7.96 (s, 1H). MS APCI, m/z=484 (M+Na). LC/MS: 2.09 min.