Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].FC(F)(F)C1C=CC(C(=O)C(C2C=CC(C(F)(F)F)=CC=2)O)=CC=1.CN1CCOCC1.[OH:37][CH:38]([C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=1)[C:39]([C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH3:48])=[CH:43][CH:42]=1)=[O:40]>ClCCl>[Br:1][CH2:2][C:3]([O:40][CH:39]([C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH3:48])=[CH:43][CH:42]=1)[C:38]([C:49]1[CH:50]=[CH:51][C:52]([CH2:55][CH3:56])=[CH:53][CH:54]=1)=[O:37])=[O:4]
Reactant: CCc1ccc(C(=O)C(O)c2ccc(CC)cc2)cc1
Reactant: O=C(Cl)CBr
Agent: O=C(c1ccc(C(F)(F)F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCc1ccc(C(=O)C(OC(=O)CBr)c2ccc(CC)cc2)cc1
Reaction time: 1 h
Yield: 65 %

Procedure:
A solution of bromoacetyl chloride (2.00 mL, 24.2 mmol) in anhydrous dichloromethane (20 mL) was added dropwise to a cold (0° C.) mixture of 2-hydroxy-1,2-di-(4-ethylphenyl)ethanone (IX; 6.5 g, 24.2 mmol) and N-methylmorpholine (NMM; 2.7 mL, 24.2 mmol) in anhydrous dichloromethane (180 mL). The mixture was stirred at 0° C. for 1 h and at ambient temperature for 2 h before additional 2-hydroxy-1,2-di-(4-ethylphenyl)ethanone (0.5 mL) and NMM (0.6 mL) were added to aid in completion. After 1 h, the mixture was washed with saturated sodium bicarbonate solution, 1N HCl and brine. Following drying and solvent evaporation, the residue was purified by flash chromatography on silica gel (gradient elution with 10% ethyl acetate in hexanes followed by 25% ethyl acetate in hexanes) and furnished 6.10 g (65%) of bromoacetoxy-1,2-di-(4-ethylphenyl)ethanone as a pale-yellow oil which was carried on directly. A portion of bromoacetoxy-1,2-di-(4-ethylphenyl)ethanone (3.15 g, 8.09 mmol) was treated with anhydrous sodium carbonate (0.86 g, 8.09 mmol), sodium iodide (0.12 g) and N-(2,6-dimethylphenyl)-1-piperazineacetamide (2.0 g, 8.09 mmol) in anhydrous acetonitrile (120 mL) and the resulting mixture was heated to 80° C. for 5 h before it was cooled and concentrated down in vacuo. Purification of the residue by flash chromatography on silica gel with absolute ethyl acetate gave 3.40 g (76%) of 2-oxo-1,2-di-(4-ethylphenyl)ethyl 4-[[[(2,6-dimethylphenyl) amino]carbonyl]-methyl]-1-piperazineacetate as pale-yellow foam. A portion of 2-oxo-1,2-di-(4-ethylphenyl)ethyl 4-[[[(2,6-dimethylphenyl)amino]carbonyl]-methyl]-1-piperazineacetate (2.50 g, 4.50 mmol) was dissolved in glacial acetic acid (75 mL) and ammonium acetate (1.65 g, 22.5 mmol) was added. The mixture was gently refluxed under nitrogen for 6 h before the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and 1N sodium hydroxide solution (until basic) and the organic phase was separated, washed with brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (gradient elution with ethyl acetate followed by 10% methanol in ethyl acetate) and yielded 0.61 g (22%) of the oxazole product I as a white solid and 0.85 g (30%) of the imidazole product I as a white solid after salt formation with ethereal hydrogen chloride.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:33])=[CH:11][C:12]([F:32])=[C:13]([CH:31]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][OH:30])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[F:32][C:12]1[CH:11]=[C:10]([CH3:33])[C:9]([OH:8])=[CH:31][C:13]=1[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][OH:30])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1
Reactant: COc1cc2c(Nc3cc(OCc4ccccc4)c(C)cc3F)ncnc2cc1OCCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCCO
Yield: 42.2 %

Procedure:
A mixture of 4-(5-benzyloxy-2-fluoro-4-methylanilino)-7-(2-hydroxyethoxy)-6-methoxyquinazoline (150 mg, 0.33 mmol), (prepared as described for the starting material in Example 13), and 10% palladium-on-charcoal catalyst (20 mg) in ethyl acetate (8 ml) was stirred under 1 atmosphere of hydrogen at ambient temperature for 18 hours. The catalyst was removed by filtration through diatomaceous earth and most of the solvent removed by evaporation and hexane added to the residue. The resulting precipitate was collected by filtration and dried to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-hydroxyethoxy)-6-methoxyquinazoline (50 mg, 41%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.CCN(CC)CC.[C:39](Cl)(=[O:47])[O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:12]([C:11]1[CH:15]=[CH:16][C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:39](=[O:47])[O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:3]2)=[N:9][C:10]=1[NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:23]=1)(=[O:13])[NH2:14]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)Oc3ccccc3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
To a suspension of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (140 mg, 0.330 mmol) and Et3N (0.069 mL, 0.495 mmol) in CH2Cl2 (3 mL) was added phenyl carbonochloridate (51.6 mg, 0.330 mmol) at 0° C. and stirred for 10 min. The reaction mixture was quenched with satd. NaHCO3, extracted with CH2Cl2, separated, and concentrated. The residue was purified (ISCO, 100% ethyl acetate, 12 g silica gel column) to obtained 93 mg of (R)-phenyl 1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyridin-2-yl)piperidin-3-ylcarbamate as a white solid. LCMS: (M+H)+=545.31. 1H NMR (400 MHz, CDCl3) δ ppm 11.20 (1H, s), 7.69 (2H, d, J=8.79 Hz), 7.50 (1H, d, J=8.79 Hz), 7.31-7.39 (4H, m, J=7.91, 7.91 Hz), 7.19 (1H, t, J=7.47 Hz), 7.08 (2H, d, J=7.47 Hz), 6.10 (1H, d, J=8.79 Hz), 5.64 (1H, s), 5.35 (1H, d, J=7.47 Hz), 5.30 (1H, s), 4.03 (1H, dd, J=12.96, 2.86 Hz), 3.78-3.91 (1H, m), 3.64 (7H, s), 3.38-3.53 (2H, m), 1.98-2.12 (1H, m), 1.76-1.87 (1H, m), 1.63-1.76 (1H, m), 1.19-1.34 (1H, m).
Reaction SMILES: [C:1]([CH:3]([CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:13])[C:11]#[N:12])=[CH:6][CH:5]=1)#[N:2].[ClH:15].CO>C1COCC1>[ClH:15].[ClH:15].[NH2:2][CH2:1][CH:3]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:13])[CH2:11][NH2:12])=[CH:6][CH:5]=1)[CH3:14]
Reactant: CC(C#N)c1ccc(C(C)C#N)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(CN)c1ccc(C(C)CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
2-[4-(Cyano-methyl-methyl)-phenyl]-propionitrile (3.25 g, 17.7 mmol) was dissolved in anhydrous THF (30 mL). The solution was heated to reflux and a 2M THF solution of borane-methyl sulfide complex (19.5 mL, 38.9 mmol) was added dropwise. Heating at reflux was continued for 30 minutes and then allowed to cool to room temperature. An HCl saturated solution of methanol (30 mL) was slowly added until pH=2. The mixture was concentrated in vacuo, redissolved in methanol and concentrated again to provide the intermediate title compound (4.5 g, 96%). TLC and HPLC indicated the starting material had been consumed and produced a mixture of more polar products. This material was used crude in the next step without further characterization.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[CH2:4][CH2:5][C:6]=1[O:7][CH2:8][CH3:9].C([O-])([O-])=O.[K+].[K+].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C1C=CC=CC=1.O.CCO.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.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.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].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].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:8]([O:7][C:6]1[CH2:5][CH2:4][C:3](=[O:10])[C:2]=1[C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)[CH3:9]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC1=C(Br)C(=O)CC1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC1=C(c2ccc(F)cc2)C(=O)CC1
Temperature: 100 °C
Yield: 69.6 %

Procedure:
2-Bromo-3-ethoxy-cyclopent-2-enone (Intermediate NINE2) (10.5 g, 51.2 mmol) and K2CO3 (14.2 g, 102 mmol) in toluene (100 mL), benzene (100 mL) and H2O (50 mL) was treated with a solution of 4-fluorophenylboronic acid (9.31 g, 66.5) in EtOH (100 mL). Tetrakis(triphenylphosphine)palladium(0) Pd(PPh3)4 (3 g, 2.6 mmol), bis(dibenzylideneacetone)palladium(0), Pd2(dba)3 (0.47 g, 0.5 mmol) and triphenylphosphine (0.27 g, 1.0 mmol) were added and the mixture was purged with N2 for 15 m. The mixture was heated to 100° C. for 15 h. The mixture was diluted with water and EtOAc:hexane. After extracting with EtOAc:hexane, the combined organic layers were dried over MgSO4, filtered and evaporated to dryness. The crude oil was purified by column chromatography on silica gel with 2.5% EtOAc:CH2Cl2 to give 3-ethoxy-2-(4-fluoro-phenyl)-cyclopent-2-enone (Intermediate NINE3) 7.85 g (70%).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]2[CH:12]=[CH:13][N:14]=[C:8]2[CH:7]=1)C.[OH-].[Na+].Cl>O1CCOCC1>[N:14]1[CH:13]=[CH:12][N:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:15])=[O:3])=[CH:7][C:8]=12
Reactant: CCOC(=O)Cc1ccn2ccnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)Cc1ccn2ccnc2c1
Temperature: 90 °C
Yield: 70 %

Procedure:
To a solution of imidazo[1,2-a]pyridin-7-yl-acetic acid ethyl ester (180 mg, 0.65 mmol) (Preparation 130) in dioxane (4 mL) at 0° C. was added 2 N aqueous sodium hydroxide solution (4 mL). Then reaction mixture was heated at 90° C. for 6 hours. After cooling to 0° C., the mixture was acidified to pH 4 with 2 N aqueous hydrochoric acid and extracted with 20% isopropanol in dichoromethane (8×10 mL). The combined organics were dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as an off-white solid in 70% yield, 80 mg.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:49])[CH2:19][CH2:20][C:21]1[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:25][CH:24]=[CH:23][C:22]=1[O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47]C)=[O:46]>>[C:45]([CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:38][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])[C:21]=1[CH2:20][CH2:19][C:18]([OH:49])=[O:17])([OH:47])=[O:46]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCCCCCOc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Product: CCCc1c(OCCCCCCc2cccc(OCCCCCCC(=O)O)c2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 184, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 2-[(7-methoxy-7-oxoheptyl)oxy]-6-[6-(methylsulfonyl)oxyhexyl]benzenepropanoic acid methyl ester from the preceding example, followed by saponification, in 55% overall yield. The product was a colorless solid, mp 91°-93° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[C:21]2[CH3:29])=[CH:16][C:15]=1[F:30])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].CN(C)[CH:35]=[O:36]>>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH:35]=[O:36])=[C:21]2[CH3:29])=[CH:16][C:15]=1[F:30])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Cc1cc2ccccc2n1-c1ccc(OCc2ccccc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)c2ccccc2n1-c1ccc(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Phosphorous oxychloride (3 mL) was added to anhydrous dimethylformamide (6 mL) and the mixture allowed to stir at room temperature for 15 min. A mixture of 1-(4-benzyloxy-3-fluorophenyl)-2-methyl-1H-indole (1.03 g, 3.1 mmol) in dimethylformamide (10 mL) was added and the mixture heated to 80° C. and held for 18 hr. The reaction mixture was poured onto ice and adjusted to a pH of 7 by the addition of 2 N NaOH. The mixture was extracted with ethyl acetate (2×100 mL), the organic layer washed with water and brine and dried over MgSO4, and evaporated to provide the product as a dark solid. Purification by silica gel chromatography (25% EtOAC-hexanes) provided a white solid (0.84 gr, 76%): mp 166-168-152° C.; 1H NMR (DMSO-d6): δ 2.55 (3H, s), 5.30 (2H, s), 7.04 (1H, d, J=6.9 Hz), 7.19-7.28 (2H, m), 7.23-7.52 (7H, m), 7.44 (2H, dd, J=6.0 Hz, J=1.4 Hz), 7.59 (1H, dd, J=11.7 Hz, J=2.5), 8.17 (1H, dd, J=7.0 Hz, J=1.0), 10.20 (1H, s) Hz; MS m/z (M+H)+ 360: Anal. for C23H18FNO2 (0.1H2O): Calc'd: C, 76.48; H, 5.08; N, 3.88. Found: C, 76.39; H, 4.81; N, 3.69
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH2:20][CH2:21][CH:22]([OH:24])[CH3:23]>>[OH:24][CH:22]([CH3:23])[CH2:21][NH:20][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: CC(O)CN
Product: CCc1cc(-c2ccc(S(=O)(=O)NCC(C)O)s2)c(C)[nH]c1=O
Yield: 59 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 1-aminopropan-2-ol as described in Step 5, Example 24 to give the title compound as a yellow solid (59% yield). LC/MS: RT 2.33 min; m/e 357 (M+H); 1H NMR (CDCl3, δ, ppm): 11.13 (1H, br), 7.52 (1H, d), 7.23 (1H, s), 6.91 (1H, d), 5.27 (1H, m), 4.00 (1H, m), 3.20 (1H, m), 2.90 (1H, m), 2.53 (2H, q), 2.40 (3H, s), 2.01 (1H, s), 1.20 (6H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])O[C:5]2=[O:12].[CH3:13][O:14][C:15](=[O:21])[C@H:16]([CH:18]([CH3:20])[CH3:19])[NH2:17].C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:17]([CH:16]([CH:18]([CH3:20])[CH3:19])[C:15]([O:14][CH3:13])=[O:21])[C:5]2=[O:12]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C(C(C)C)N1C(=O)c2ccc(Br)cc2C1=O
Temperature: 80 °C

Procedure:
5-bromoisobenzofuran-1,3-dione (3 g, 13.21 mmol), L-valine methyl ester (3.31 g, 19.82 mmol) and triethyl amine (2.75 mL, 19.82 mmol) were taken in acetonitrile and heated at 80° C. for 24 h. The solvent was removed by distillation and the crude material obtained was purified using column chromatography (silicagel, 20% dichloromethane in petroleum ether) to afford the title compound.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C(=O)=O.CC(C)=O.[Li]CCCC.[C:20]1([C:26]23[CH2:33][CH2:32][C:29]([CH2:34][C:35]([O:37][CH3:38])=[O:36])([CH2:30][CH2:31]2)[CH2:28][CH2:27]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CI.[Cl-].[NH4+]>C1COCC1>[C:20]1([C:26]23[CH2:27][CH2:28][C:29]([CH:34]([CH3:1])[C:35]([O:37][CH3:38])=[O:36])([CH2:32][CH2:33]2)[CH2:30][CH2:31]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CC12CCC(c3ccccc3)(CC1)CC2
Reactant: CC(C)NC(C)C
Agent: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)C12CCC(c3ccccc3)(CC1)CC2
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of diisopropylamine (0.9 mL, 6.39 mmol) in anhydrous THF (10 mL) cooled to −78° C. (CO2/acetone) was added nBuLi (2M solution in cyclohexane; 3.2 mL, 6.4 mmol) and the reaction mixture was allowed to stir at −78° C. for 5 mins. Methyl (4-phenylbicyclo[2.2.2]oct-1-yl)acetate (Intermediate 1(ii); 1.5 g, 5.81 mmol) in anhydrous THF (2 mL) was added and the mixture immediately became dark brown/black. It was allowed to stir for ˜30 mins at −78° C. then methyl iodide (0.4 mL, 6.39 mmol) was added and the reaction mixture was allowed to warm to ambient temperature over 4 hrs. Saturated aqueous ammonium chloride solution (50 mL) was added and the mixture extracted into EtOAc (2×150 mL), the organic extracts were combined, dried (MgSO4) and concentrated to leave crude product which was an inseparable mixture of the title compound and starting material which was taken directly through to the next stage without further characterisation.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:13][CH3:14])[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.[F:15][CH:16]([F:43])[C:17]([N:19]1[C@H:23]([CH2:24][F:25])[C@@H:22]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[O:21][C:20]1([CH3:42])[CH3:41])=[O:18].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[F:43][CH:16]([F:15])[C:17]([N:19]1[C@H:23]([CH2:24][F:25])[C@@H:22]([C:26]2[CH:31]=[CH:30][C:29]([C:2]3[CH:7]=[N:6][C:5]([CH:8]([NH:13][CH3:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=3)=[CH:28][CH:27]=2)[O:21][C:20]1([CH3:41])[CH3:42])=[O:18]
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: CNC(c1ccc(Br)cn1)C(F)(F)F
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CNC(c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1)C(F)(F)F
Temperature: 80 °C
Yield: 90.5 %

Procedure:
To a stirred solution of [1-(5-Bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl]-methyl-amine (0.075 g, 0.279 mmol) and 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (0.115 g, 0.279 mmol) in toluene:ethanol:water (3:3:3 mL) is added Na2CO3 (0.073 g, 0.697 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 30 minutes followed by addition of Pd(PPh3)4 (0.032 g, 0.028 mmol) and heated to 80° C. for 3 h. The reaction mixture is concentrated in vacuo then is diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate and evaporated in vacuum. The crude material is purified by Combi-flash eluting in 20% ethyl acetate in hexane afford the title compound (0.120 g). 1H-NMR (400 MHz, DMSO) δ: 1.52 (s, 3H), 1.60 (s, 3H), 2.25 (d, J=5.76 Hz, 3H), 3.01-3.05 (m, 1H), 4.44-4.48 (m, 1H), 4.56-4.58 (m, 0.5H), 4.67-4.72 (m, 1H), 4.81-4.88 (m, 0.5H), 4.90-5.00 (m, 1H), 5.27 (d, J=3.68 Hz, 1H), 6.65 (t, J=52.36 Hz, 1H), 7.60 (d, J=8.24 Hz, 2H), 7.98-8.00 (dd, J1=2.04 Hz, J2=8.2 Hz, 1H), 8.06 (d, J=8.24 Hz, 1H), 8.15 (d, J=8.32, 2H), 8.73 (d, J=1.8 Hz, 1H). LC-MS (m/z): [M−H]=476.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:3]=12.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[C:27]([C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[N:26]1.N#N>O1CCOCC1.C([O-])(O)=O.[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>[CH3:24][N:25]1[CH:29]=[C:28]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:17])=[O:16])[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:3]=23)[C:27]([C:39]2[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=2)=[N:26]1
Reactant: C[Si](C)(C)c1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccnc3c2cc([Si](C)(C)C)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 105 °C
Yield: 36 %

Procedure:
A mixture of 4-bromo-1-(phenylsulfonyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (37 mmol) and 1-methyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (37 mmol) in 1,4-dioxane (300 ml) and saturated NaHCO3(aq) (100 ml) was degassed with N2 for 10 minutes after which time tetrakis(triphenylphosphine)palladium(0) (1.85 mmol) was added and the resulting mixture was heated at 105° C. overnight. The reaction was then concentrated, diluted with CHCl3 (200 ml) and EtOAc (200 ml), sonicated for 10 minutes, filtered through Celite 545, and concentrated to yield a red oil which was purified on 400 g silica gel (CHCl3/EtOAc w/0.1% MeOH) to give the title product as a light yellow foam (36%). ESMS [M+H]+: 532.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:43]=[CH:42][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:39]([OH:41])=O)[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.[NH2:45][C@@H:46]([C:54]([O:56]C(C)(C)C)=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:39]([NH:45][C@@H:46]([C:54]([OH:56])=[O:55])[CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:41])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:31])=[CH:42][CH:43]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccccc1
Reactant: NC(=O)CC[C@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: NC(=O)CC[C@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N2-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-glutamine (15 mg, 0.0244 mmol), tert-butyl D-phenylalaninate hydrochloride (8 mg, 0.0310 mmol) and N-methylmorpholine (10 mg, 0.099 mmol) were dissolved in methylene chloride (0.5 ml). TBTU (10 mg, 0.0313 mmol) was added and the mixture was stirred for 1 h at room temperature. The solvent was evaporated and the residue was dissolved in formic acid (0.5 ml). The mixture was heated to 45-50° C. and stirred at this temperature for 6 h. The reaction mixture was evaporated under reduced pressure. Methanol (5 ml) was added and evaporated. The residue was dissolved in methanol (1 ml). Two drops of TEA was added and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by preparative HPLC using acetonitrile/ammonium acetate buffer (40:60) as eluent. After freeze-drying 12 mg (64%) of the title compound was obtained. 1H-NMR, 300 MHz, DMSO): 1.55-1.97 (m, 4H), 2.77-3.10 (m, 4H), 4.20-4.38 (m, 3H), 4.49 (s, 2H), 4.66-4.78 (m, 1H), 4.99-5.07 (m, 1H), 6.70 (s, 1H), 6.88-7.40 (m, 19H), 8.00-8.20 (m, 2H).