Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=CC=1.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[OH:19])([CH3:11])([CH3:10])[CH3:9].[CH3:20][O:21]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.O>[C:8]([C:12]1[C:13]([OH:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH:17]=1)[CH:20]=[O:21])([CH3:11])([CH3:10])[CH3:9]
Reactant: Cc1ccc(C(C)(C)C)c(O)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: Clc1ccccc1
Product: Cc1cc(O)c(C(C)(C)C)cc1C=O
Temperature: 5 °C

Procedure:
Chlorobenzene (100 mL) and 2-tert-butyl-5-methylphenol (20.6 gm, 125 mmol) were combined and the mixture stirred and cooled to 5° C. Titanium tetrachloride (27.5 mL) and dichloromethyl methyl ether (19 mL, 210 mmol) were added separately and simultaneously over 45 minutes while holding the reaction temperature between 4 and 7° C. The resulting mixture was stirred at 0-5° C. for 3 hours. Water (100 mL) was cautiously added over 18 minutes to the reaction mixture while holding the temperature below 14° C. The mixture was extracted with ethyl acetate (200 mL) and the resulting organic layer was extracted with 12% hydrochloric acid (2×75 mL). The combined aqueous acid layers were diluted with water (50 mL) and back extracted with ethyl acetate (100 mL). This extract was combined with the first ethyl acetate extract and the whole extracted with 15% KOH (3×100 mL). The KOH extracts were combined and the pH adjusted to 3 with 37% hydrochloric acid (62.8 gm). The resulting mixture was extracted with 1:1 ethyl acetate/toluene (2×150 mL). These organic extracts were combined and back extracted with water (2×50 mL) and the organic solution concentrated to approximately 75 mL. 5-tert-Butyl-4-hydroxy-2-methylbenzaldehyde seed crystals were added and the mixture stirred and cooled to 25° C. The mixture was filtered and the product washed with toluene (30 mL) and vacuum dried at 40° C. to give 5-tert-butyl-4-hydroxy-2-methylbenzaldehyde (1): 15 g (78 mmol, 62%): mp: 168-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH:5]=[C:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[OH:21]O.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:6]3([C:14](=[O:15])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:16])[O:21]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: OO
Reactant: O=C1C(=Cc2ccc(Cl)c(Cl)c2)C(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1c2ccccc2C(=O)C12OC2c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a suspension of 2-(3,4-dichloro-benzylidene)-indane-1,3-dione (1c) (1.6 g, 5.2 mmol) in MeOH (13 mL) was added hydrogen peroxide (30% solution, 3 mL). The mixture was cooled to 0° C. and sodium hydroxide (1N, 300 μL) was added dropwise. After addition was completed, stirring was continued at room temperature for 1 h. The mixture was then poured into water (5 mL) and the resulting solid was collected by filtration and washed with water and MeOH. After drying under high vacuum 3-(3,4-dichlorophenyl)-spiro (oxirane-2,2′-indan)-1′,3′-dione (Id) (1.6 g, 95% yield) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]4[CH:17]([C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:15][CH2:14]4.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:35]=[C:36]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[CH3:37]>CN(C=O)C>[F:44][C:41]1[CH:42]=[CH:43][C:38]([C:36]([CH3:37])=[CH:35][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5]3[CH:17]4[N:13]([CH2:12][CH2:11][C:6]2=3)[CH2:14][CH2:15][CH2:16]4)=[CH:39][CH:40]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: CC(=CBr)c1ccc(F)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=Cn1c2c(c3cc(C)ccc31)C1CCCN1CC2)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a degassed solution of 10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (50 mg, 0.22 mmol), potassium phosphate (93 mg, 0.44 mmol), L-proline (2 mg, 0.01 mmol) and Cu(I)iodide (8 mg, 0.04 mmol) in DMF (1 mL) was added 1-(1-bromoprop-1-en-2-yl)-4-fluorobenzene (95 mg, 0.44 mmol). The reaction mixture was stirred at 120° C. for 18 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was filtered through Celite. The filtrate was diluted with water (50 mL), extracted with EtOAc (2×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 7-(2-(4-fluorophenyl)prop-1-enyl)-10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole. 1H NMR, (CD3OD, TFA salt) δ (ppm): 7.65 (t, 2H), 7.35 (s, 1H), 7.19 (t, 2H), 7.1 (m, 2H), 6.95 (s, 1H), 5.1 (t, 1H), 3.79 (m, 1H), 3.62 (m, 2H), 3.41 (m, 1H), 3.1 (m, 2H), 2.75 (m, 1H), 2.41 (s, 3H), 2.28 (m, 3H), 1.95 (s, 3H). Chiral HPLC provided the enantiomers 194a and 194b.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[Br:24]NC(=O)CCC(N)=O>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][C:3]=1[Br:24]
Reactant: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Reactant: NC(=O)CCC(=O)NBr
Solvent: CN(C)C=O
Product: Nc1nc2[nH]c(-c3ccc(F)cc3)c(-c3ccncc3)c2cc1Br
Temperature: 23 °C
Reaction time: 24 h

Procedure:
6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (250 mg, 0.822 mmol), N-bromosuccinamide (146 mg, 0.822 mmol), and DMF (4 mL) were allowed to stir at 23° C. After 24 h, the reaction was concentrated in vacuo and the residue was purified by flash chromatography (ethyl acetate:hexane 1:1) to afford 6-Amino-5-bromo-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (27): Mass Spectrum (CI) 385 (MH+Br81).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:19][CH2:18]1)[C:10]([F:17])([F:16])[S:11][CH2:12][CH2:13][O:14][CH3:15].[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH2:18][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[C:10]([F:17])([F:16])[S:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: c1nc[nH]n1
Reactant: COCCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-methoxyethyl)thio]-2,3-epoxypropane (13.0 g, 0.044 mol) in DMSO (100 ml), 1,2,4-triazole (7.6 g, 0.11 mol) and potassium carbonate (15.2 g, 0.11 mol) were added and the resulting mixture was stirred at room temperature for 12 hours and at an external temperature of 50° C. for one hour. After the completion of the reaction, the reaction mixture was diluted with ether and insoluble matter was filtered off. The ether solution was washed with water, dried over magnesium sulfate and distilled off under reduced pressure. The residue was recrystallized from isopropyl ether-ethyl acetate, whereby 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-methoxyethyl)thio]-3-(1H-1,2,4-triazol-1-yl)-2-propanol (2.0 g, yield: 12.0%) was obtained as colorless crystals.
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=1.Cl>C(OCC)C>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:18])=[CH2:4])=[CH:13][CH:12]=1
Reactant: CCOCC
Reactant: COc1ccc(C(C)=O)cc1
Agent: C[Mg]Br
Agent: Cl
Product: C=C(C)c1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
To a 1000 mL three-necked flask equipped with a mechanical stirrer, methyl magnesium bromide/diethyl ether solution (200 mL, 3.0 mol) is added. A solution of 85.3 g of 4′-methoxy-acetophenone dissolved in 80 mL of anhydrous diethyl ether is charged to the Grignard reagent over 90 minutes at ambient temperature. Diethyl ether (200 mL) and 250 mL of 3N hydrochloric acid are added slowly to the reaction mixture. The solution is stirred for another 30 minutes. The aqueous layer is separated and washed twice with 100 mL of diethyl ether. The ethereal layers are combined and vacuum distilled. The desired product is obtained in a yield of 91.7 g as a yellow oil whose structure is verified by 1Hnmr and mass spectroscopy.
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.O=[C:10]1[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>>[F:2][C:3]1([F:8])[CH2:7][CH2:6][N:5]([CH:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)[CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: FC1(F)CCNC1
Agent: Cl
Product: NC1CCC(N2CCC(F)(F)C2)CC1
Yield: 106.1 %

Procedure:
Following General procedure I, 3,3-difluoropyrrolidine hydrochloride (468 mg, 3.26 mmol) was reacted with tert-butyl 4-oxocyclohexylcarbamate (500 mg, 2.34 mmol) to afford the desired product (507 mg, quant.) as a colorless oil: ESI MS m/z 205 [C10H18F2N2+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(c1cccc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A suspension of 1-(3-(trifluoromethyl)phenyl)ethanone (0.100 g, 0.532 mmol), tert-butyl piperazine-1-carboxylate (0.148 g, 0.797 mmol), acetic acid (0.046 mL, 0.797 mmol) and sodium cyanoborohydride (0.050 g, 0.797 mmol) in ethanol (0.5 mL) was heated under nitrogen at 75° C. After stirring overnight the reaction was concentrated, saturated sodium bicarbonate (0.7 mL) was added, and the product was extracted into ethyl acetate (2×0.7 mL). The combined organic layers were concentrated, dissolved in a minimal amount of dichloromethane, loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 2% to 20% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute).
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:38])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)=[CH:29][CH:28]=2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(OC)cc4)cc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc(-c3nc(CCOc4ccc(OC(C)(C)C(=O)O)cc4)c(C)o3)cc2)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4′-methoxybiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4′-methoxybiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 8.02 (2H, m), 7.64 (4H, m), 7.01(2H, m), 6.97 (2H, m), 6.91 (2H, m), 6.79 (2H, d), 4.20 (2H, t), 3.86 (3H, s), 3.00 (2H, t) 2.39 (3H, s), 1.52 (6H, s).
Reaction SMILES: N([O-])=[O:2].[Na+].[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](N)=[O:11])#[N:6]>S(=O)(=O)(O)O>[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:2])=[O:11])#[N:6]
Reactant: N#Cc1cccc(C(N)=O)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N#Cc1cccc(C(=O)O)c1
Yield: 91.2 %

Procedure:
Sodium nitrite (2.07 g) was dissolved in a 70 wt. % aqueous sulfuric acid solution (100 ml), and m-cyanobenzamide (2.92 g) was added to the resultant solution. The mixture was allowed to react at 40° C. for one hour with stirring. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 2.68 g of m-cyanobenzoic acid (yield 92%). The m-cyanobenzoic acid obtained had a purity of 99% or more.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][C:12]([NH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25](Cl)[N:24]=4)=[O:22])([CH2:13]3)[CH2:11]1)[CH2:17]2)=[O:8].[CH3:30][O:31][CH2:32][CH2:33][CH2:34][NH2:35].C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]=O.CC(N(C)C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][C:12]([NH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([NH:35][CH2:34][CH2:33][CH2:32][O:31][CH3:30])[N:24]=4)=[O:22])([CH2:13]3)[CH2:11]1)[CH2:17]2)=[O:8]
Reactant: O=C(NC12CC3CC(C1)CC(NC(=O)c1cccc(Cl)n1)(C3)C2)c1ccccn1
Reactant: COCCCN
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COCCCNc1cccc(C(=O)NC23CC4CC(CC(NC(=O)c5ccccn5)(C4)C2)C3)n1
Temperature: 230 °C

Procedure:
To a microwave vial was added a stir bar, 6-chloro-pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide (Intermediate 4, 20 mg, 0.05 mmol), copper (II) oxide (20 mg, 0.2 mmole), DMA (1 mL), 3-methoxy-propylamine (0.05 mL) and cesium carbonate (120 mg, 0.3 mmol). The mixture was heated at 230° C. under microwave irradiation for 30 min. Solvent was removed in Genevac. The residue was dissolved in DCM (2 mL), washed with aq. 1 N NaOH (2 mL), and water (2×2 mL). After removing the solvent, the crude product was purified on a RP-HPLC/MS system (Gradient: acetonitrile in water with a cycle time of 5 min. Flow rate: 100 mL/min. Mobile phase additive: 25 mM of ammonium acetate. Column: Inertsil® C8, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo, Japan)) to afford 3.9 mg of the title compound, 6-(3-methoxy-propylamino)-pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide. The product was quality checked (QC) by LC-MS (Gradient: acetonitrile in water, 30-90%, in 1.7 minutes with a cycle time of 2 min. Flow rate: 5.0 mL/min. Mobile phase additive: 30 mM of ammonium formate. Column: Inertsil® C8, 50×4.6 mm, 3 μm particle size (GL Sciences, Tokyo, Japan)): Retention time: 1.29 min; purity (UV254): 94%; ESI-MS m/z: 464.6 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[C:10]([CH3:13])=[CH:11][O:12][C:8]=2[CH:7]=1.[CH2:16]([O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)[CH3:17].O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:16]([O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:15]=[CH:14][C:9]4[C:10]([CH3:13])=[CH:11][O:12][C:8]=4[CH:7]=3)=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)[CH3:17]
Reactant: Cc1coc2cc(OCCCBr)ccc12
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc4c(C)coc4c3)ccc21
Temperature: 80 °C
Reaction time: 68 h
Yield: 108.3 %

Procedure:
To a mixture of 6-(3-bromopropoxy)-3-methyl-1-benzofuran (87 mg, 0.32 mmol) (Example 63) and ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (59 mg, 0.269 mmol) (Example 6) in DMF containing 1 vol % water (2.4 mL) was added Cs2CO3 (105 mg, 0.323 mmol). The mixture was stirred for 68 h at 80° C., and the reaction mixture cooled to rt, then concentrated under reduced pressure. The residue was suspended in EtOAc and filtered through a small plug of silica to give 119 mg (90%) of a light-yellow solid that was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][C:5]2[N:10]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:9](=[O:16])[CH2:8][O:7][C:6]=2[N:17]=1.CC1(C)C(C)(C)OB([C:32]2[CH:46]=[CH:45][C:35]([CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:34][CH:33]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[O:16]=[C:9]1[CH2:8][O:7][C:6]2[N:17]=[C:2]([C:32]3[CH:46]=[CH:45][C:35]([CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[CH:34][CH:33]=3)[C:3]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][C:5]=2[N:10]1[CH2:11][C:12]([F:15])([F:14])[F:13]
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1CC(F)(F)F
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(cc2-c2ccccc2)N(CC(F)(F)F)C(=O)CO3)cc1
Temperature: 50 °C
Yield: 85.1 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-7-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (40 mg, 0.103 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (41.3 mg, 0.124 mmol), and cesium carbonate (168 mg, 0.517 mmol) in a mixture of 1,4-Dioxane (1937 μl) and water (646 μl) to give a colourless solution. This was degassed by bubbling nitrogen for 15 minutes, followed by the addition of PdCl2(dppf)-CH2Cl2Adduct (16.87 mg, 0.021 mmol) and degassing for a further 5 minutes. The reaction mixture was heated to 50° C. under a nitrogen atmosphere for one hour. LC-MS analysis showed reaction completion. The reaction mixture was allowed to cool to room temperature, diluted with water (5 mL) and extracted into ethyl acetate (3×5 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a brown solid. The resulting residue was purified via Biotage (0-45% cyclohexane:EtOAc; 10 g column) to give the title compound (45 mg, 85%) as off-white solid. 1H NMR (500 MHz, CDCl3): 7.36 (1H, s), 7.32-7.26 (5H, m), 7.17-7.13 (4H, m), 4.96 (2H, s), 4.77 (1H, br), 4.63-4.58 (2H, q), 4.28 (2H, s), 1.48-1.45 (9H, br).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[CH3:28][NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:32])=[O:31].C(=O)(O)[O-].[Na+].O>COCCOC.O.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>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=[C:2]([C:36]2[CH:35]=[CH:34][C:33]([S:30]([NH:29][CH3:28])(=[O:31])=[O:32])=[CH:38][CH:37]=2)[CH:3]=1)=[O:16]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNS(=O)(=O)c1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3c(C)nn(C(C)C)c3n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol), {4-[(methylamino)sulfonyl]phenyl}boronic acid (66.5 mg, 0.31 mmol) and bis(triphenylphosphine)palladium(II) chloride (8.4 mg, 0.01 mmol) were suspended in DME/water (4 mL, 3:1) and stirred for 10 min under nitrogen at room temperature. Sodium bicarbonate (52 mg, 0.62 mmol) was added and the heterogenous mixture was irradiated (microwave) at 150° C. for 30 min. After cooling to room temperature, water was added to the black mixture, and the contents were vacuum filtered. The crude product was dissolved in DCM/MeOH (1:1) and preabsorbed onto silica gel. The product was purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH, gradient of 0 to 90:10:1). The light beige solid that was collected was suspended in EtOH, sonicated, and filtered. The solid was then air-dried for 15 min, and then in vacuum oven overnight. The final product was collected as 77 mg (70%). LCMS E-S (M+H)=523.2 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (br. s., 1 H) 8.78 (t, J=5.05 Hz, 1 H) 8.43 (m, J=8.59 Hz, 2 H) 7.93 (m, J=8.59 Hz, 2 H) 7.78 (s, 1 H) 7.58 (br. s., 1 H) 5.89 (s, 1 H) 5.29 (quin, J=6.63 Hz, 1 H) 4.40 (d, J=4.80 Hz, 2 H) 2.46 (d, J=1.26 Hz, 6 H) 2.25 (s, 3 H) 2.12 (s, 3 H) 1.52 (s, 3 H) 1.51 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]#[CH:18])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([CH:14]1[CH2:16][CH2:15]1)[CH3:13])[CH2:7]2.C(=O)([O-])O.[K+].O.Cl[C:26](=[N:32][OH:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[O:33][N:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:18]=2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([CH:14]1[CH2:16][CH2:15]1)[CH3:13])[CH2:7]2
Reactant: CCOC(=O)C(Cl)=NO
Reactant: C#Cc1cc(Cl)c2c(c1)CN([C@@H](C)C1CC1)C2=O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(-c2cc(Cl)c3c(c2)CN([C@@H](C)C2CC2)C3=O)on1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.2 %

Procedure:
7-chloro-2-((S)-1-cyclopropylethyl)-5-ethynylisoindolin-1-one (28.66 g, 110.35 mmol) and potassium hydrogen carbonate (110.0 g, 1103.45 mmol) were dissolved in a solution consisting of 1200 mL of ethyl acetate and 400 mL of water. To this solution was added ethyl 2-chloro-2-(hydroxyimino)acetate (66.9 g, 441.38 mmol). The ethyl 2-chloro-2-(hydroxyimino)acetate was added at room temperature as a solution in 160 mL of ethyl acetate via syringe pump at a rate of 5 mL/Hr. Following the addition of the ethyl 2-chloro-2 (hydroxyimino)acetate, the reaction was allowed to continue stirring at room temperature for an additional 12 hours. The ethyl acetate layer was extracted in a separatory funnel, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel eluting with a gradient of 0 to 25% ethyl acetate in hexane to afford the title compound as a white solid (17.05 g, 41.2%). 1H NMR (300 MHz, CDCl3) δ ppm 0.36-0.53 (m, 3H) 0.63-0.73 (m, 1H) 0.98-1.12 (m, 1H) 1.38 (d, 3H) 1.47 (t, 3H) 3.80 (dq, 1H) 4.43-4.65 (m, 4H) 7.05 (s, 1H) 7.83 (s, 2H). MS ESI, m/z=375 (M+H). HPLC Method B: 0.82 min