Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[CH:17](=[O:23])/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH3:22]>C(O)C>[C:2]([N:5]1[CH:17]([OH:23])[CH2:18][CH:19]([CH2:20][CH2:21][CH3:22])[C:6]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCC/C=C/C=O
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCC1CC(O)N(C(C)=O)C1(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Sodium metal (3.48 g, 0.15 mol) was dissolved in a stirred solution of diethyl acetamidomalonate (201.6 g, 0.93 mol) in anhydrous ethanol (1200 mL) at room temperature under nitrogen. The reaction mixture was cooled to 0° C. and trans-2-hexenal (100.0 g, 1.02 mol) was then added dropwise. The resulting mixture was allowed to warm to room temperature. After stirring for 3 hours at 23° C., the reaction was quenched with 24 mL of acetic acid. The solution was concentrated in vacuo and the resulting residue was taken up in ethyl acetate and washed with saturated aqueous NaHCO3 (2×) and brine. Dried over anhydrous magnesium sulfate, concentation and recrystallization of the residue from EtOAc/Hexane gave 271.4 g (93% yield) of the title compound as fine needles, mp 105°-106° C. TLC, Rf =0.43 (9:1 CHCl3 /MeOH). MS(CI) m/e 316 (M+1)+, 298 (MH-H2O)+ . 1H NMR (CD3OD, 300 MHz) δ0.94 (t, J=7.2 Hz, 3H), 1.47-1.11 (m, 9H), 1.90-1.78 (m, 1H), 1.94 (dd, J=12.8, 5.2 Hz, 1H), 2.08 (dd, J=12.8, 6.4 Hz, 1H), 2.21 (s, 3H), 2.83 (m, 1H), 4.10-4.26 (m, 4H), 5.64 (d, J=5.2 Hz, 1H). IR (CDCl3) 3460, 1750, 1665 cm-1. Anal. calcd. for C15H25NO6 : C, 57.13; H, 7.99; N, 4.44. Found: C, 57.28; H, 8.08; N, 4.42.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:17]1(=[O:22])[CH2:21][CH2:20][CH:19]=[CH:18]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:18]2[C:17](=[O:22])[CH2:21][CH2:20][CH:19]=2)=[CH:6][C:7]([CH2:10][CH3:11])=[CH:8][N:9]=1
Reactant: O=C1C=CCC1
Reactant: CCc1cnc(Cl)c(C=O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Product: CCc1cnc(Cl)c(C(O)C2=CCCC2=O)c1
Yield: 97 %

Procedure:
The clear solution of 2-Chloro-5-ethylnicotinaldehyde (10 mmol, 1.69) and imidazole (10 mmol, 0.68 g) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 97% yield (2.47 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(N)ccc2s1
Reaction time: 96 h

Procedure:
A suspension of 5-nitro-benzo[b]thiophene-2-carboxylic acid ethyl ester (10.52 g, 41.89 mmol) and 10% Pd/C (1.1 g) in 450 mL of EtOH was hydrogenated under 1 atm of H2 for 4 d at rt. The reaction mixture was filtered and the filtrate was concentrated and dried to give 5-amino-benzo[b]thiophene-2-carboxylic acid ethyl ester as a green solid. A parallel reaction was preformed on 10.61 g of 5-nitro-benzo[b]thiophene-2-carboxylic acid ethyl ester in the same manner. 5-amino-benzo[b]thiophene-2-carboxylic acid ethyl ester was obtained. MS (EI): cal'd 222.0 (MH+), exp 222.2 (MH+).
Reaction SMILES: [F:1][C:2]1([F:15])[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.Br[CH:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:18]1=[O:33].C(N(CC)CC)C>CN(C=O)C>[F:15][C:2]1([F:1])[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH:17]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=3)[C:18]2=[O:33])[CH2:3]1
Reactant: O=C1C(Br)CCN1Cc1ccc(C(F)(F)F)cc1
Reactant: Oc1ccc(C2CCNCC2(F)F)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1C(N2CCC(c3ccc(O)cc3)C(F)(F)C2)CCN1Cc1ccc(C(F)(F)F)cc1
Temperature: 120 °C
Yield: 35.1 %

Procedure:
A mixture of 4-(3,3-difluoropiperidin-4-yl)phenol (200 mg, 0.94 mmol, E-2a from step D), 3-bromo-1-(4-(trifluoromethyl)benzyl)pyrrolidin-2-one (604 mg, 1.9 mmol), triethylamine (0.65 mL, 4.7 mmol), and 2 mL of DMF was heated in a microwave reactor at 120° C. for 1 h. The cooled reaction mixture was partitioned between water and 30 mL of ethyl acetate, and the aqueous phase was again extracted with 30 mL of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford 150 mg of 3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)-benzyl)pyrrolidin-2-one (0.33 mmol, 35%, 2 diastereoisomers) which was purified and separated in step F. LCMS (method J) RT 0.8 min (60% AP), m/z 455.4 (M+H+).
Reaction SMILES: Cl[O-:2].[Na+].[OH-].[Na+].[C:6]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:19])[CH:15]=2)[CH:10]=1)(=[O:8])C>O.O1CCOCC1>[Br:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:6]([OH:8])=[O:2])[CH:18]=[CH:17]2
Reactant: [O-]Cl
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc2cc(Br)ccc2c1
Temperature: 70 °C
Yield: 87.8 %

Procedure:
To a solution of sodium hypochlorite (62 ml, 5.25% in water (w/w), 3.6 g, 48.18 mmol) and sodium hydroxide (6.4 g, 160.6 mmol) in 50 ml of water was added a solution of 2-acetyl-6-bromonaphthalene (Compound L) 4 g, (16.06 mmol) in 50 ml of 1,4-dioxane. The yellow solution was heated to 70° C. in an oil bath for 2 hours, cooled to ambient temperature, and extracted with ethyl ether (2×50 ml). The aqueous layers were diluted with NaHSO3 solution (until KI indicator solution remained colorless) and then acidified (pH<2) with 1N sulfuric acid to give a white precipitate. The mixture was extracted with ethyl ether, and the combined organic phase washed with saturated aqueous NaCl, dried (MgSO4) and concentrated to give 3.54 g (88%) of the title compound as a solid. 1H NMR (DMSO-d6): δ 8.63 (1H, br s), 8.32 (1H, d, J=2.0 Hz), 8.10 (1H, d, J=8.8 Hz), 8.00-8.05 (2H, m), 7.74 (1H, dd, J=2.0, 8.8 Hz).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH3:27][O:28][C:29]([O:31][CH:32](I)[CH3:33])=[O:30]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:32]([O:31][C:29]([O:28][CH3:27])=[O:30])[CH3:33])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: COC(=O)OC(C)I
Agent: [Na+]
Product: COC(=O)OC(C)OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 74.3 %

Procedure:
In the same manner as in Example 81, 145 mg of the title compound was prepared from 163 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 140 mg of 1-(methoxycarbonyloxy)ethyl iodide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:28])[C@@H:13]([NH:20]C(=O)OC(C)(C)C)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:28])[C@@H:13]([NH2:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC(Oc2ccc(F)c(F)c2)CC1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](C(=O)N1CCC(Oc2ccc(F)c(F)c2)CC1)c1ccccc1

Procedure:
The product from Example 20, step a (0.650 g) was dissolved in dichloromethane (7 ml) and trifluoroacetic acid (2 ml) was added. After 3 hr at room temperature the solution was evaporated and aqueous NaOH (2M) added. The product was extracted with ethyl acetate, the combined organic extracts dried with Na2SO4 and concentrated to give the sub-title product as an oil (0.544 g).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)[Cl:11]>>[C:1]([Cl:11])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: O=C(O)c1ccccc1
Product: O=C(Cl)c1ccccc1

Procedure:
Shaking once with 300 ml of methylene chloride completely removes small quanitites of benzoic acid formed by the hydrolysis of adhering benzoyl chloride. The hydrolysis solution is neutralized with sodium hydroxide and made up with water to 750 ml. The 1,3-dimethyl-1-oxophospholine is isolated from the neutral solution in the same way as in Example 1. Yield: 109 g of 1,3-dimethyl-1-oxophospholine (41.9% of the theoretical yield).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]([O:16][CH3:17])=[C:14]2[C:10]([CH:11]=[N:12][NH:13]2)=[CH:9][CH:8]=1)=[O:6].[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21]>C1COCC1>[CH3:3][O:4][C:5]([C:7]1[C:15]([O:16][CH3:17])=[C:14]2[C:10]([CH:11]=[N:12][N:13]2[S:20](=[O:22])(=[O:21])[N:19]([CH3:24])[CH3:18])=[CH:9][CH:8]=1)=[O:6]
Reactant: COC(=O)c1ccc2cn[nH]c2c1OC
Reactant: CN(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cnn(S(=O)(=O)N(C)C)c2c1OC
Reaction time: 0.08 h
Yield: 75.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.27 g, 31.66 mmol) was added to anhydrous THF (100 mL) with stirring under an atmosphere of nitrogen. After 5 min, a solution of 7-methoxy-1H-indazole-6-carboxylic acid methyl ester (5.44 g, 26.38 mmol, prepared as described in J. Med. Chem. 2006, 49, 4762-4766) in anhydrous THF (50 mL) was added dropwise over 15 min. After stirring for 30 min, a solution of dimethylsulfamoyl chloride (3.68 mL, 34.3 mmol) in anhydrous THF (20 mL) was added dropwise over 10 min. After stirring for 2 h, the reaction mixture was quenched by addition of water (50 mL) and transferred to a separating funnel using EtOAc. The organic layer was washed with water. The aqueous layers were combined and extracted using EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 20% EtOAc in DCM) to afford the title compound as a yellow solid (6.23 g, 75%). 1H NMR (400 MHz, DMSO-d6): δ 8.98 (s, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 4.29 (s, 3H), 3.85 (s, 3H), 2.97 (s, 6H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[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>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(I)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(I)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
Under argon, 4-hydroxyphenyl 4-iodophenyl ketone (380 mg) obtained in Example 177 and 4-dimethylaminopyridine (158 mg) were added to xylene (11 ml), and the admixture was stirred at room temperature. After 2 hours, 4-chloro-6,7-dimethoxyquinoline (262 mg) was added, and the admixture was refluxed with heat overnight. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, and the chloroform layer was then 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/ethyl acetate, followed by thin layer chromatography on silica gel eluting with chloroform/ethyl acetate (5/1), to obtain 459 mg of the title compound (yield: 77%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:22]=[N:23][NH:24][CH:25]=1.O>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:25]=[N:24][N:23]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:3])[CH:22]=1
Reactant: Clc1ccccc1-c1cn[nH]c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)n1cc(-c2ccccc2Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
4-Nitrophenyl chloroformate (2.3 g, 11.5 mmol) and 4-(2-chlorophenyl)-1H-pyrazole (2.0 g, 11.0 mmol) are dissolved in 30 mL CH2Cl2 and cooled to 0° C. TEA (1.7 mL, 12.0 mmol) is added, and the reaction is allowed to warm to RT. After 30 min, additional 4-nitrophenyl chloroformate (0.25 g) and TEA are added. After 1 h, water is added. The mixture is extracted with CH2Cl2, dried (MgSO4), filtered and concentrated to give a solid. The solid is triturated with hexanes, filtered and dried to provide 1.7 g (45%) of the crude 4-nitrophenyl 4-(2-chlorophenyl)-1H-pyrazole-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([NH2:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].N1C=CC=CC=1.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:34]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:34]=1[C:35]([NH:23][C:14]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:11]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:24][CH3:25])[CH:4]=2)([CH3:10])[CH3:9])=[CH:12][N:13]=1)=[O:36]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: COc1cc(C(C)(C)c2cnc(N)n2-c2ccc(F)cc2)ccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(C)(C)c2cnc(NC(=O)c3c(F)cccc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.7 %

Procedure:
To a 0° C. solution of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-amine (93 mg, 0.26 mmol) and pyridine (0.05 mL, 0.52 mmol) in DCM (1.5 mL) was added 2-chloro-6-fluorobenzoyl chloride (0.050 g, 0.26 mmol) in DCM (0.5 mL). After stirring 2 h at ambient temperature, the reaction was quenched with water. The mixture was extracted with DCM (3×5 mL) and dried with MgSO4. The residue was purified by HPLC (10-99%, MeCN/H2O with 0.05% TFA) to afford the title compound (9 mg) as a white solid. MS (EI) m/z 516 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]([O:11]CC)=[O:10])[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)on1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(C2CC2)on1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.8 %

Procedure:
The mixture of ethyl 5-cyclopropylisoxazole-3-carboxylate (0.550 g; 3.04 mmol) and 1M aqueous sodium hydroxide (9.11 mL; 9.11 mmol) was stirred at room temperature during the weekend (72 h). The pH of the solution was adjusted to 1 by addition of 6N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and was evaporated to furnish 0.446 g (96%) of 5-cyclopropylisoxazole-3-carboxylic acid as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][C@H:16]([CH2:19][NH2:20])[CH2:15]1)=[N:9][C:8]([O:21][CH3:22])=[CH:7][CH:6]=2.C(N(CC)CC)C.[O:30]=[C:31]1[NH:36][C:35]2[CH:37]=[C:38]([S:41](Cl)(=[O:43])=[O:42])[CH:39]=[CH:40][C:34]=2[S:33][CH2:32]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][C@H:16]([CH2:19][NH:20][S:41]([C:38]3[CH:39]=[CH:40][C:34]4[S:33][CH2:32][C:31](=[O:30])[NH:36][C:35]=4[CH:37]=3)(=[O:43])=[O:42])[CH2:15]1)=[N:9][C:8]([O:21][CH3:22])=[CH:7][CH:6]=2
Reactant: O=C1CSc2ccc(S(=O)(=O)Cl)cc2N1
Reactant: COc1ccc2ncc(F)c(CCN3CC[C@H](CN)C3)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(CCN3CC[C@H](CNS(=O)(=O)c4ccc5c(c4)NC(=O)CS5)C3)c2n1
Reaction time: 24 h
Yield: 91.2 %

Procedure:
To a stirred solution of [((3R)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine (0.50 g, 1.65 mmole) in dry CH2Cl2 (25 mL) at RT was added triethylamine (0.34 mL, 2.48 mmole) and 3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-sulfonyl chloride (0.47 g, 1.80 mmole). After 24 h, the reaction solution was concentrated under vacuum. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.80 g, 91%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.16 (d, J=9.0 Hz, 1H), 7.34 (m, 3H), 7.03 (d, J=9.0 Hz, 1H), 4.04 (s, 3H), 3.47 (s, 2H), 3.34 (m, 2H), 2.95 (m, 3H), 2.79 (m, 2H), 2.61 (m, 1H), 2.52 (m, 2H), 2.34 (m, 1H), 1.97 (m, 1H), 1.55 (m, 1H). LC-MS (ES) m/e 532 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[CH:37]=[CH:36][C:14]([O:15][C:16]([C:18]2[O:22][C:21]([CH2:23][CH2:24][C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])CC(O)=O)=[O:26])=[CH:20][CH:19]=2)=[O:17])=[C:13](OC)[CH:12]=1)(=[NH:10])[NH2:9].F[C:41](F)(F)[C:42]([OH:44])=[O:43]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]([C:18]2[O:22][C:21]([CH2:23][CH2:24][C:25]([N:27]([CH2:2][CH2:41][C:42]([OH:44])=[O:43])[CH2:28][C:33]([OH:35])=[O:34])=[O:26])=[CH:20][CH:19]=2)=[O:17])=[CH:36][CH:37]=1)(=[NH:10])[NH2:9]
Reactant: COc1cc(C(=N)N)ccc1OC(=O)c1ccc(CCC(=O)N[C@@H](CC(=O)O)C(=O)O)o1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(OC(=O)c2ccc(CCC(=O)N(CCC(=O)O)CC(=O)O)o2)cc1
Reaction time: 0.5 h

Procedure:
To 5-(2-tert-butoxycarbonylethenyl)furan-2-carboxylic acid benzyl ester (0.15 g, 0.46 mmol) obtained in Example 41, step 2 was added trifluoroacetic acid (3 ml), and the mixture was stirred for 30 minutes. The solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18].C([O-])([O-])=O.[Na+].[Na+].[NH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[NH2:26][C:27]1[CH:32]=[C:31]([C:3]2[C:2]([F:1])=[CH:10][CH:9]=[C:8]3[C:4]=2/[C:5](=[CH:12]/[C:13]2[NH:17][CH:16]=[N:15][C:14]=2[CH3:18])/[C:6](=[O:11])[NH:7]3)[CH:30]=[CH:29][CH:28]=1
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(-c3cccc(N)c3)c21

Procedure:
A solution of (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 11), 2M aqueous Na2CO3 solution (0.14 mL), (Ph3P)2PdCl2 (11 mg, 0.0135 mmol) and 3-aminobenzeneboronic acid (52.5 mg, 0.339 mmol) (Lancaster) in a 1:4 mixture of DMF:1,2-dimethoxyethane (5 mL) was heated at 104° C. for 4 days. The reaction mixture was concentrated and the crude material was purified by C18 reverse phase chromatography to give (Z)-4-(3-Aminophenyl)-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 18 mg, 40%).
Reaction SMILES: O.[CH3:2][O:3][C:4]1[C:9](B(O)O)=[CH:8][CH:7]=[CH:6][N:5]=1.Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:2][O:3][C:4]1[C:9]([C:14]2[CH:15]=[C:16]([NH2:17])[CH:18]=[CH:19][CH:20]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Nc1cccc(Br)c1
Reactant: COc1ncccc1B(O)O
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: O
Solvent: COCCOC
Product: COc1ncccc1-c1cccc(N)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
2-methoxypyridine-3-boronic acid hydrate (0.133 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (10-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.092 g in 80% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:18]([NH:20][CH:21]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]2[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=2[N:23]([CH3:38])[C:22]1=[O:39])=[O:19])[CH:15]([CH3:17])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:18]([NH:20][CH:21]2[N:27]=[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=3[N:23]([CH3:38])[C:22]2=[O:39])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CC(C)[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-valinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-Y), the title compound was prepared as a solid (mp.=228–229° C.). The product was purified by slurrying in ether/hexanes (80:20).
Reaction SMILES: [Cu](C#N)[C:2]#[N:3].[Cl:6][C:7]1[C:12](I)=[CH:11][N:10]=[C:9]([C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1>CN(C=O)C>[Cl:6][C:7]1[C:12]([C:2]#[N:3])=[CH:11][N:10]=[C:9]([C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C(c1cc(Cl)c(I)cn1)N1CCc2cc(F)ccc21
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: N#Cc1cnc(C(=O)N2CCc3cc(F)ccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere 45 mg (0.50 mmol) copper cyanide were added to 0.10 g (0.25 mmol) (4-chloro-5-iodo-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone in 1.5 mL DMF and the mixture was stirred for 2 h at RT. The reaction mixture was stirred overnight at 100° C. and then mixed with d-water. The precipitate formed was suction filtered and dried.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)=[C:5]([O:18][CH2:19][C:20]#[CH:21])[CH:4]=1.C([O-])(=O)/C=C/[C:25]([O-])=[O:26]>>[CH3:25][O:26][C:8]1[CH:7]=[C:6]([C:9]2[NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([O:18][CH2:19][C:20]#[CH:21])=[CH:4][CH:3]=1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: C#CCOc1cc(OC)ccc1-c1nc2cnccc2[nH]1
Product: C#CCOc1ccc(OC)cc1-c1nc2cnccc2[nH]1

Procedure:
2-(4-Methoxy-2-propargyloxyphenyl)imidazo(4,5-c)pyridine, fumarate, m.p. 210°.