Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:31])[NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=4)[CH:17]=[CH:16][C:15]=3[F:32])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[Br-].[CH2:52]([O:54][C:55](=[O:59])[CH2:56][CH2:57][Zn+])[CH3:53]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[F:29])[CH2:22][NH:21][C:20]([C:18]1[CH:17]=[CH:16][C:15]([F:32])=[C:14]([NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([CH2:57][CH2:56][C:55]([O:54][CH2:52][CH3:53])=[O:59])=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[CH:19]=1)=[O:31]
Reactant: O=C(NCc1ccc(F)c(F)c1)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Reactant: CCOC(=O)CC[Zn+]
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccn2c(C(=O)Nc3cc(C(=O)NCc4ccc(F)c(F)c4)ccc3F)cnc2c1
Temperature: 60 °C

Procedure:
7-Bromo-N-(5-(3,4-difluorobenzylcarbamoyl)-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (Intermediate 3A) (1 g, 1.987 mmol), Pd2(dba)3 (0.091 g, 0.099 mmol) and tritertbutylphosphonium tetrafluoroborate (0.058 g, 0.199 mmol) were combined in THF (60 ml) under nitrogen and the mixture was degassed thoroughly refilling with nitrogen (×3). (3-Ethoxy-3-oxopropyl)zinc(II) bromide (19.87 ml, 9.93 mmol) was added and the mixture was heated at 60° C. for 100 mins. After cooling to RT, the mixture was absorbed onto silica and purification by chromatography eluting with 0-6% MeOH in DCM afforded a yellow oil which was triturated with EtOAc to give the title compound;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][NH:22][C:21]3=[O:25])[N:17]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:12][CH:11]=1.[H-].[Na+].I[CH3:36].O>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][N:22]([CH3:36])[C:21]3=[O:25])[N:17]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3F)cc2)CC[C@]12CCNC2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CC[C@]2(CC[C@H](c3ccc(OCc4ccccc4F)cc3)N2C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
To a solution of 1,1-dimethylethyl (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D26) (70 mg, 0.159 mmol) in dry DMF (1 ml) at 0° C. was added NaH 60% wt dispersion in mineral oil (10 mg, 0.238 mmol); after 15 minutes of stirring at room temperature, iodomethane (30 μl, 0.477 mmol) was added and the resulting mixture was stirred at room temperature for 2.5 hours. The mixture was cooled to 0° C., and water (4 ml) and ethyl acetate (10 ml) were added, the organic layer was washed with ice cold brine (3×10 ml), dried over Na2SO4 and evaporated. The crude material was purified by chromatography on silica gel using cyclohexanes/ethyl acetate (7:3) to afford the title compound as a white solid (63 mg, 88%); Rt (HPLC): 5.99 min; Rf (cyclohexane:ethyl acetate=1:1): 0.28; MS: (ES/+) m/z: 477 [M+Na+]; C26H31FN2O4 requires 454. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.66 (d, 2H); 7.56-7.49 (m, 1H); 7.35-7.25 (m, 1H); 7.20-7.13 (m, 1H); 7.12-7.04 (m, 1H); 6.97 (dd, 2H); 5.14 and 5.12 (s, s, 2H); 5.02 and 4.88 (d, d, 1H); 3.52-3.45 and 3.41-3.22 (m, m, 2H); 2.96 and 2.92 (s, s, 3H); 2.67-2.56 and 2.53-2.42 (m, m, 1H); 2.40-2.22 (m, 2H); 2.08-1.79 (m, 2H); 1.77-1.68 (m, 1H), 1.40 and 1.16 (s, s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2].[CH3:21][S:22]([NH:25][C:26]1[CH:41]=[CH:40][C:29]2[NH:30][C:31]([CH2:36][C:37](O)=[O:38])=[N:32][S:33](=[O:35])(=[O:34])[C:28]=2[CH:27]=1)(=[O:24])=[O:23].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[C:37](=[O:38])[CH2:36][C:31]2[NH:30][C:29]3[CH:40]=[CH:41][C:26]([NH:25][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:27][C:28]=3[S:33](=[O:34])(=[O:35])[N:32]=2)[CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C1CC=CCC1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CC=CCC1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 121.6 %

Procedure:
The crude 6-(4-fluoro-benzylamino)-cyclohex-3-enecarboxylic acid ethyl ester (113.7 mg, 0.41 mmol) was mixed with (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 150 mg, 0.45 mmol) and dissolved in N,N-dimethylformamide (3.4 mL). N-methylmorpholine (100 μL, 0.9 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol). The reaction mixture was stirred at 25° C. for 16 h. LC-MS analysis indicated that the reaction was incomplete and thus additional (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (30 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17 mg) were added and the resulted mixture was stirred at 25° C. for 1.5 h. A 1.0 M aqueous hydrochloric acid solution (6.7 mL) was added. The product was extracted with ethyl acetate (3×15 mL) and the combined organic layers were washed with water (10 mL) and saturated aqueous brine solution (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and further dried under high vacuum for 16 h to afford the crude product, 6-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohex-3-enecarboxylic acid ethyl ester (295.4 mg). LC-MS (ESI) calcd for C26H29FN4O7S2 592.15, found 593.4 [M+H+]. This crude product was directly used in next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:9]=[C:8]2[C:18](=[O:20])[CH3:19])=[CH:4][CH:3]=1.C1COCC1.[C:28](OCC)(=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].CC[O-].[Na+]>CCOC(C)=O>[CH2:32]([O:31][C:29](=[O:30])[C:28](=[O:34])[CH2:19][C:18]([C:8]1[N:7]([CH2:6][C:5]2[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=2)[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=1)=[O:20])[CH3:33]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(-c2ccccc2)n1Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)c1ccc(-c2ccccc2)n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 1-[1-(4-fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]ethanone AV-8-1 (0.628 g, 2.14 mmol), dry THF (10 mL), diethyl oxalate (0.41 mL, 3.00 mmol) and NaOEt (0.204 g, 3.00 mmol). The resulting mixture was stirred 1 h at ambient temperature. The mixture was diluted with EtOAc and washed with 1N HCl, H2O (2×) and brine. Drying (MgSO4) filtration and removal of the solvent in vacuo gave 4-[1-(4-fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AV-9-1 as an oil. This material was used without further purification. 1H NMR (CDCl3) δ 1.38 (3H, t, j=7.1 Hz), 4.38 (2H, q, j=7.1 Hz), 5.65 (2H, s), 6.38 (1H, d, j=4.1 Hz), 6.79 to 6.94 (4H, m), 7.29 (2H, m), 7.39 (3H, m).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([CH3:34])[CH:28]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:22]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:21]=2)=[CH:28][C:29]=1[CH3:34]
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(4-chloro-3-methyl-phenyl)-4-methyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.405 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 ml), diethylether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (diethyl ether/heptane) to yield the title compound as an off-white solid (0.093 g, 20%). MS (ISP) 456.1 [(M+H)+]; mp 240° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:5]=[CH:6][CH:7]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(-c2cccc3[nH]ccc23)c1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To the suspension of 4-(3-fluoro-phenyl)-1H-indole (1.40 g, 6.63 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (81 mL) was added pyridinium tribromide (90% purity from Aldrich, 7.07 g, 19.88 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (30 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (1.34 g, 89%) as a tan solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:13].[C:14]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=2B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:23]2[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:22]=2[O:21][CH2:20][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:3]([CH3:13])[CH:4]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: CCS(=O)(=O)c1ccc(Br)c(C)c1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Product: CCS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)ccc2OCc2ccccc2)c(C)c1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and (ii), yield 2.72 g.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[N:25]([CH3:26])[CH:24]=[CH:23][C:10]3=[N:11][C:12]=2[C@@H:13]([NH:15]C(=O)OC(C)(C)C)[CH3:14])=[C:5]([CH3:27])[NH:4][N:3]=1.[ClH:28]>C1COCC1.O1CCOCC1>[ClH:28].[CH3:27][C:5]1[C:6]([C:7]2[CH:8]=[C:9]3[N:25]([CH3:26])[CH:24]=[CH:23][C:10]3=[N:11][C:12]=2[C@@H:13]([NH2:15])[CH3:14])=[C:2]([CH3:1])[NH:3][N:4]=1
Reactant: Cc1n[nH]c(C)c1-c1cc2c(ccn2C)nc1[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1n[nH]c(C)c1-c1cc2c(ccn2C)nc1[C@H](C)N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl ((1S)-1-(6-(3,5-dimethyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (149 mg, 0.403 mmol) in THF (4 mL) was added dropwise 4 M HCl (1 mL, 4.00 mmol) in dioxane. The mixture was stirred at RT for 2 hours and then concentrated in vacuo to give an HCl salt of the title compound as an off-white solid. ESI-MS m/z [M+H]+ calc'd for C15H19N5, 270.16; found 270.6.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(=O)=O.CC(C)=O.C(OCC)(=O)C>[CH3:21][S:22]([CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc2c(Cl)ccnc2c1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Cc1ccc2c(Cl)ccnc2c1
Reaction time: 0.33 h

Procedure:
7-Hydroxymethyl-4-chloroquinoline (930 mg, 4.82 mmol) dissolved in anhydrous methylene chloride (40 ml) was added with triethylamine (679 mg, 6.72 mmol). The mixture was cooled in dry ice/acetone bath, added dropwise with methanesulfonyl chloride (770 mg, 6.7 mmol) and the reactant was stirred for 20 minutes without the cooling bath. Then, the reactant was added under ice-water cooling with cool aqueous solution of saturated sodium bicarbonate (40 ml) and ethyl acetate (150 ml) and shaken to separate the organic layer. The separated organic layer was washed with saturated saline solution and dried over magnesium sulfate. The solvent was removed to obtain 7-methanesulfonylmethyl-4-chloroquinoline as oily product.
Reaction SMILES: C(O)C.[Na].[N:5]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:24](OCC)(=[O:30])[C:25](OCC)=[O:26]>C(O)(=O)C.O>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][N:5]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:25]([OH:26])[C:24]([OH:30])=[C:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:17]
Reactant: CCOC(=O)CN(CC(=O)OCC)CC(=O)OCC
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(C(=O)OCC)c(O)c(O)c1C(=O)OCC
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a 1000-mL round bottom flask was added containing a stir bar, and argon atmosphere, and outfitted with a reflux condenser was added ethanol (200 proof, 500 mL) and sodium metal (21.31 g, 927 mmol). When the sodium was completely dissolved, a mixture of triethyl nitrilotriacetate (56.20 g, 204 mmol) and diethyl oxalate (29.44 g, 204 mmol) was added. The mixture was refluxed overnight, whereupon it became a clear, gelatinous solution. After cooling to room temperature, the mixture was poured into 1200 mL of DI water, chilled in an ice bath and acidified with glacial acetic acid (200 mL). The resulting white precipitate was isolated via vacuum filtration and washed with several portions of DI water to yield 59.75 g (89%) of a white solid. mp 121.3-121.8° C.; 1H NMR (300 MHz, CDCl3): δ 7.51 (s, 2H), 5.32 (s, 2H), 4.39 (q, 4H, J=7.7 Hz), 4.20 (q, 2H, J=7.7 Hz), 1.38 (t, 6H, J=7.7 Hz), 1.27 (t, 3H, J=7.7 Hz); 13C NMR (75 MHz, CDCl3): δ 169.5, 162.4, 139.6, 111.1, 61.6, 47.9, 14.5, 14.4; HRMS (EI): Calcd for C14H19NO8 ([M]+), 329.1111, found m/z, 329.1111; Anal. Calcd for C14H19NO8: C, 51.06; H, 5.82; N, 4.25%, found: C, 50.79; H, 5.83; N, 4.22%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]4[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][C:13]=4[C:14](=[O:17])[C:15]=3[OH:16])=[CH:9][C:4]=2[O:3][CH2:2]1>C(Cl)(Cl)Cl.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]4[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][C:13]=4[C:14](=[O:17])[C:15]=3[O:16][CH2:10][C:8]3[CH:9]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)Nc1ccc2oc(-c3ccc4c(c3)OCO4)c(O)c(=O)c2c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc2oc(-c3ccc4c(c3)OCO4)c(OCc3ccccc3)c(=O)c2c1
Yield: 85 %

Procedure:
Prepared analogously to Example 5d) starting from 2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-6-acetamido-4H-1-benzopyran-4-one. Yield: 85%; TLC (9/1 Chloroform/Methanol) Rf: 0.57.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.C1CCCCC1.CN(C)[CH:28]=[O:29]>C1COCC1.O>[C:1]([N:5]1[CH:28]([OH:29])[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([CH3:13])[CH:9]=2)[C:6]1=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)NC(C)(C)C)cc1
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1ccc2c(c1)C(O)N(C(C)(C)C)C2=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 102.4 %

Procedure:
To a solution of N-tert-butyl-4-methylbenzamide (9.02 g, 47.2 mmol) in THF (132 ml), charged to a 250 mL round bottom, sec-butyl lithium, 1.4 m in cyclohexane (74.1 ml, 104 mmol) was added at −78° C. The reaction mixture was stirred at −78° C. for 30 min, then warmed to 0° C. for 45 min, before cooling back to −78° C. Then N,N-dimethylformamide (12.0 ml, 156 mmol) was added. The reaction mixture was stirred at −78° C. for 30 min, then allowed to warm to 23° C. The reaction mixture was diluted with water and extracted with EtOAc 3×. The combined organics were washed with brine, dried over magnesium sulfate and concentrated under vacuum to give 2-tert-butyl-3-hydroxy-5-methylisoindolin-1-one (10.6 g, 100% yield). MS (M+H)+ 220.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=O)[CH2:3]2.Cl.[NH2:12][OH:13].CC(O[Na])=O.O.O.O.[Na+].[Cl-]>O>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[N:12][OH:13])[CH2:3]2
Reactant: NO
Reactant: O=C1CN2CCC1CC2
Agent: CC(=O)O[Na]
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: ON=C1CN2CCC1CC2
Temperature: 70 °C
Reaction time: 1 h
Yield: 107 %

Procedure:
32.33 g (200 mmol) of 3-Quinuclidinone hydrochloride was dissolved in 75 ml of water, and to the solution of hydroxylamine hydrochloride (16.4 g; 236 mmol) and CH3CO2Na.3H2O (80 g; 588 mmol) was added. The mixture was stirred at 70° C. for 1 hour. Then NaCl (10 g) was dissolved in the mixture and was cooled to 0° C. Separated crystals were filtered and carefully dried. The obtained crude 3-quinuclidone oxime (approx. 30 g) was used in the next step of the synthesis without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([NH:12][C:13]([N:15]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17][CH2:16]2)=[O:14])([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:8][C:7]1[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3][C:4]([C:9]([NH:12][C:13]([N:15]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17][CH2:16]2)=[O:14])([CH3:11])[CH3:10])=[CH:5][CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(NC(=O)N1CCN2CCC1CC2)c1ccc(F)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)N1CCN2CCC1CC2)c1ccc(F)c(-c2ccccc2)c1
Yield: 66.3 %

Procedure:
Using general procedure E, N-[2-(3-bromo-4-fluorophenyl)propan-2-yl]-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide (100 mg, 0.261 mmol), phenylboronic acid (79 mg, 0.65 mmol) and palladium (II) acetate gave the title compound as an off-white solid (66 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 7.54 (m, 2H), 7.44-7.40 (m, 5H), 7.08(m, 1H), 4.78(br s, 1H), 4.00 (br s, 1H), 3.60 (m, 2H), 3.11-2.92 (m, 6H), 2.00 (m, 2H) 1.67(m, 7H), 1.26 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 159.6, 155.6, 144.6, 136.5, 129.3, 128.6, 128.5, 127.8, 127.5, 125.7, 125.6, 116.1, 115.9, 57.9, 55.3, 48.2, 46.4, 46.4, 41.6, 30.6, 30.5, 29.9, 27.6 ppm. Purity: >99% UPLCMS (210 nm); retention time 0.88 min; (M+1) 382.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:42][N:43]1[C:52]2[C:47](=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=2)[CH:46]=[C:45]([C:54]2[CH:55]=[C:56]([NH:61]/[C:62](/[NH2:65])=[N:63]/O)[CH:57]=[CH:58][C:59]=2[CH3:60])[C:44]1=[O:66]>CN(C=O)C>[CH3:42][N:43]1[C:52]2[C:47](=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=2)[CH:46]=[C:45]([C:54]2[CH:55]=[C:56]([NH:61][C:62]3[N:63]=[C:6]([C@@H:2]4[CH2:3][CH2:4][CH2:5][O:1]4)[O:8][N:65]=3)[CH:57]=[CH:58][C:59]=2[CH3:60])[C:44]1=[O:66]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: O=C(O)[C@@H]1CCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc([C@@H]4CCCO4)n3)ccc1C)c(=O)n2C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
(S)-Tetrahydrofuran-2-carboxylic acid (75.7 mg, 0.65 mmol), HATU (247 mg, 0.65 mmol), and DIPEA (0.11 mL, 0.65 mmol) were stirred in dry DMF (6 mL) for 1 h before 17 (200 mg, 0.59 mmol) was added at rt. The stirring was continued for 1 h before it was heated at 100° C. for 5 h. After cooling and filtration, the mixture was purified by preparative LC/MS to give (S)-1,7-dimethyl-3-(2-methyl-5-(5-(tetrahydrofuran-2-yl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (A77) as a solid. 1H NMR (400 MHz, d4-MeOH) δ 9.07 (s, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 7.45 (d, J=4 Hz, 1H), 7.36 (dd, J=8, 4 Hz, 1H), 7.25 (d, J=4 Hz, 1H), 5.10 (dd, J=8, 4 Hz, 1H), 4.03 (dd, J=12, 8 Hz, 1H), 3.96 (dd, J=12, 8 Hz, 1H), 3.83 (s, 3H), 2.85 (s, 3H), 2.41-2.34 (m, 1H), 2.28-2.20 (m, 1H), 2.16 (s, 3H), 2.12-2.03 (m, 2H). MS m/z 417.5, 418.5 (M+1).
Reaction SMILES: [CH:1]1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CB(O)O.Cl[C:44]1[CH:52]=[C:51]2[C:47]([C:48]([CH:53]=[O:54])=[CH:49][NH:50]2)=[CH:46][C:45]=1[C:55]1[CH:60]=[CH:59][C:58]([C:61]2([OH:65])[CH2:64][CH2:63][CH2:62]2)=[CH:57][CH:56]=1.[Cl-].[NH4+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:65][C:61]1([C:58]2[CH:57]=[CH:56][C:55]([C:45]3[CH:46]=[C:47]4[C:51](=[CH:52][C:44]=3[CH3:1])[NH:50][CH:49]=[C:48]4[CH:53]=[O:54])=[CH:60][CH:59]=2)[CH2:64][CH2:63][CH2:62]1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4(O)CCC4)cc3)cc12
Agent: [Pd+2]
Agent: CB(O)O
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2[nH]cc(C=O)c2cc1-c1ccc(C2(O)CCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphane (62.8 mg, 0.153 mmol), palladium acetate (13.7 mg, 0.061 mmol), tribasic potassium phosphate monohydrate (566 mg, 2.46 mmol), and methyl boronic acid (184 mg, 3.07 mmol) was sealed in a microwave tube and evacuated and backfilled with nitrogen three times. Deoxygenated 1,4-dioxane (1.5 mL) was added and the mixture was stirred vigorously at room temperature for one hour. A solution of 6-chloro-5-[4-(1-hydroxy-cyclobutyl)-phenyl]-1H-indole-3-carbaldehyde (400 mg, 1.23 mmol) in 1,4-dioxane (2.5 mL) was degassed with nitrogen for 10 minutes then added to the reaction mixture. The reaction mixture was heated at 120° C. for three hours under microwave irradiation, and then allowed to stir at room temperature for 12 hours. The reaction mixture was poured into saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. Flash silica gel chromatography was performed on the crude product utilizing a solvent system of heptanes/ethyl acetate (9:1 to 1:1) to give the title compound. MS (ES+) 306.5 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 9.86 (s, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.55 (d, 2H), 7.38 (s, 1H), 7.36 (d, 2H), 2.61 (m, 2H), 2.39 (m, 2H), 2.34 (s, 3H), 2.05 (m, 1H), 1.75 (m, 1H).