Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>CCOC(C)=O.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.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(NC(=O)c1coc(-c2cccc(C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
In a glass tube were placed 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (100 mg, 0.26 mmol), 3-trifluoromethyl phenyl boronic acid (60 mg, 0.32 mmol), 2N—Na2CO3 (0.5 mL), Pd(PPh3)4 (4.6 mg, 0.004 mmol), toluene (1.0 mL), ethanol (0.5 mL), and a magnetic stir bar. The mixture was stirred overnight at 110° C. and was diluted with EtOAc and water. The organic layer was washed with saturated ammonium chloride, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (gradient 12% to 100% EtOAc in n-hexane) to give title compound (30 mg, 29%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:20]4[CH:27]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=5)[NH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41].C(=O)(O)[O-].[K+].O>CN(C)C=O>[CH2:38]([N:39]([CH2:42][CH3:43])[CH2:40][CH2:41][O:34][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[NH:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([O:18][C:15]4[CH:14]=[CH:13][C:12]([NH:11][C:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)=[O:10])=[CH:17][CH:16]=4)[C:20]=3[CH:27]=2)=[CH:33][CH:32]=1)[CH3:37]
Reactant: CCN(CC)CCCl
Reactant: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccc(O)cc4)cc23)cc1)Nc1cccc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc(-c2cc3c(Oc4ccc(NC(=O)Nc5cccc(F)c5)cc4)ncnc3[nH]2)cc1
Reaction time: 16 h

Procedure:
After dissolving 114 mg of 1-(3-fluorophenyl)-3-{4-[6-(4-hydroxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yloxy]phenyl}urea in 2 ml of dimethylformamide, there were added 44 mg (ca. 1 equivalent) of 2-chloroethyldiethylamine hydrochloride and 63 mg (2.5 equivalents) of potassium bicarbonate, and the mixture was stirred at 50–60° C. for 16 hours. There were then added 17 mg of 2-chloroethyldiethylamine hydrochloride, 20 mg of potassium bicarbonate and 1 ml of dimethylformamide, and the mixture was stirred overnight at the same temperature. It was then returned to room temperature, water was added, and liquid separation and extraction were performed with ethyl acetate-tetrahydrofuran. The organic layer was washed with water and saturated brine, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 33 mg of a crude solid containing the title compound. This was washed with ethyl acetate to obtain 5 mg of the title compound.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].O=C1[CH2:13][C@H:12]2[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H]([CH2:10][CH2:11]2)C1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:5]=[C:4]1[CH2:13][CH:12]2[N:14]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH:2]([CH2:10][CH2:11]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)C2
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (2.38 g, 6.6 mmol) in dry THF at 0° C. was added n-BuLi (2.7 mL, 2.5 M) dropwise. After stirring at 0° C. for 30 min, (1R,5S)-tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.2 mmol) was added and the mixture was stirred at 0° C. for additional 16 hrs. The reaction was quenched by sat. NH4Cl and extracted with EtOAc (50 mL×3) and purified by SGC (eluting with petroleum ether/ethyl acetate=20/1) to give target compound (130 mg, 27%). 1H NMR (500 MHz, CDCl3) δ 4.77 (t, J=4.0 Hz, 2H), 4.21 (br s, 1H), 4.11 (br s, 1H), 2.43-2.33 (m, 2H), 2.01 (s, 1H), 1.98 (s, 1H), 1.79 (d, J=3.0 Hz, 2H), 1.53-1.49 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=[CH:26][CH:25]=4)=[N:23][C:16]=23)[CH2:11][C@H:10]1[CH2:34][OH:35])(C(C)(C)C)(C)C.Cl[S:37]([NH2:40])(=[O:39])=[O:38].Cl.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.O>[S:37](=[O:39])(=[O:38])([O:35][CH2:34][C@@H:10]1[CH2:11][C@@H:12]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=[CH:26][CH:25]=4)=[N:23][C:16]=23)[CH2:13][C@@H:9]1[OH:8])[NH2:40]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](Oc2ccnc3[nH]c(-c4cccc5ccccc45)nc23)C[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: NS(=O)(=O)OC[C@@H]1C[C@@H](Oc2ccnc3[nH]c(-c4cccc5ccccc45)nc23)C[C@@H]1O
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
To a solution of ((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{[2-(1-naphthyl)-3H-imidazo[4,5-b]pyridin-7-yl]oxy}cyclopentyl)methanol (0.0624 g, 0.000127 mol) in DMA (2.00 mL) was added chlorosulfonamide (0.0736 g, 0.000637 mol) and the mixture was stirred for 10 min. To this was added 12 M of hydrochloric acid in water (2.00 mL) dropwise at 0° C. and the mixture was stirred for 10 min. The mixture was added dropwise to 50 mL of a 2N Na2CO3 solution, and was extracted by CH2Cl2 (3×30 ml). The combined organic layers were concentrated and the residue was purified by flash chromatography (0 to 10% MeOH/EtOAc) to provide the title compound (14.5 mg, 25%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ: 8.49 (m, 1H), 8.28 (m, 1H), 8.06 (d, 1H, J=8.3 Hz), 7.97 (m, 1H), 7.87 (dd, 1H, J=7.0 Hz, J=1.0 Hz) 7.63-7.54 (m, 3H), 6.89 (d, 1H, J=5.8 Hz) 5.40 (bs, 1H), 4.45 (dt, 1H, J=4.9 Hz, J=1.9 Hz), 4.35 (dd, 1H, J=7.2 Hz, J=2.5 Hz), 4.19 (dd, 1H, J=7.2 Hz, J=2.5 Hz), 2.62 (m, 1H), 2.44-2.39 (m, 1H), 2.31-2.25 (m, 1H), 2.18-2.14 (m, 2H). LC/MS: Rt=1.55 min, ES+ 455 (AA standard).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:14]=2)[NH:9][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:3]=2)[CH2:17]1
Reactant: C1COCCN1
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(S(=O)(=O)N3CCOCC3)cc21
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(S(=O)(=O)N3CCOCC3)cc21
Temperature: 120 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
The mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-6-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydro-quinoline (150 mg, 0.33 mmol), copper(I) iodide (20 mg, 0.1 mmol), morpholine (1.3 mL, 14.7 mmol), N,N-dimethylglycine hydrochloride (34.0 mg, 0.24 mmol) and potassium carbonate (110 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL). was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 4,4-dimethyl-6-(morpholine-4-sulfonyl)-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline (124.3 mg, 80.0%) as a white solid: MS (ESI) M+1=472.2.
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[C:7]([NH:13][NH2:14])=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1.[C:15](OCC)(=[O:23])/[CH:16]=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(O)(=O)C>O.C(O)C>[Cl:5][C:6]1[C:7]([N:13]2[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][C:15](=[O:23])[NH:14]2)=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: NNc1ncc(Cl)cc1Cl
Reactant: CCOC(=O)/C=C\C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CC(=O)NN1c1ncc(Cl)cc1Cl
Temperature: 65 °C
Yield: 47 %

Procedure:
To a 500 mL flask, 300 mL anhydrous ethanol, sodium ethoxide (4.1 g, 61 mmol) and 3,5-dichloro-2-hydrazinylpyridine (10.00 g, 56 mmol) were added. The reaction mixture was heated to reflux for 5 minutes. Diethyl maleate (10.64 g, 61.0 mmol) was added dropwise and heated to reflux for 10 minutes. After being cooled to 65° C., the reaction mixture was neutralized with glacial acetic acid (13 g, 224 mmol) and diluted with 300 mL water. The mixture was cooled down to room temperature and the a precipitate formed. The solid was isolated via filtration, washed with 40% aqueous solution of ethanol (3×50 mL) and dried to give the product (8.00 g) as an orange solid in 47% yield. Melting point: 105-108° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([CH2:35][CH3:36])([OH:34])[CH2:32][CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][CH:15]=2)[CH:10]=[C:11]([F:13])[CH:12]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:21]([C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:9]2[CH:10]=[C:11]([F:13])[CH:12]=[C:7]([CH2:6][C:5]([OH:40])=[O:4])[CH:8]=2)=[CH:19][CH:18]=1)([C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([CH2:32][CH3:33])([OH:34])[CH2:35][CH3:36])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cc(F)cc(CC(=O)OC)c3)cc2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cc(F)cc(CC(=O)O)c3)cc2)cc1C)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.335 mL, 0.335 mmol) was added to a solution of (4′-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-5-fluoro-biphenyl-3-yl)-acetic acid methyl ester (Example 127-(2); 57.7 mg, 0.112 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (38.5 mg, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[NH:9]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O>CN(CCO)C.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: O[C@H]1CCNC1
Reactant: Brc1ccc(I)cc1
Agent: [Cu]I
Agent: CN(C)CCO
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: O[C@H]1CCN(c2ccc(Br)cc2)C1
Temperature: 55 °C
Reaction time: 60 h
Yield: 84.2 %

Procedure:
A mixture of 1-bromo-4-iodo-benzene (50.0 g, 177 mmol), (S)-pyrrolidin-3-ol (28.6 mL, 353 mmol), CuI (6.73 g, 35.3 mmol) and K3PO4.H2O (81.4 g, 353 mmol) in N,N-dimethylaminoethanol (177 mL) was stirred at 55° C. for 60 h. The mixture was allowed to cool to rt, and water was added. The mixture was extracted several times with CH2Cl2. The combined org. extracts were washed with a 1:1 mixture of aq. conc. NH3 and water. The NH3-containing aq. layer was extracted with CH2Cl2. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Crystallization of the crude from EtOAc/heptane yielded the title compound (36.1 g, 84%).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[H-].[Na+].[CH:9]([N:12]1[C:16]([C:17]2[N:18]=[C:19]3[C:25]4[CH:26]=[CH:27][C:28]([C:30](OC)=O)=[CH:29][C:24]=4[O:23][CH2:22][CH2:21][N:20]3[CH:34]=2)=[N:15][CH:14]=[N:13]1)([CH3:11])[CH3:10].C(Cl)Cl.S(Cl)(Cl)=O>O1CCCC1.C1COCC1.CN(C=O)C>[CH3:5][C:2]1([CH3:6])[CH2:3][O:4][C:30]([C:28]2[CH:27]=[CH:26][C:25]3[C:19]4[N:20]([CH:34]=[C:17]([C:16]5[N:12]([CH:9]([CH3:11])[CH3:10])[N:13]=[CH:14][N:15]=5)[N:18]=4)[CH2:21][CH2:22][O:23][C:24]=3[CH:29]=2)=[N:1]1
Reactant: CC(C)(N)CO
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=NC(C)(C)CO3)cc1OCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
2-Amino-2-methyl-1-propanol (0.20 g, 2.3 mmol) was dissolved in tetrahydrofuran (2.2 mL) and NaH (60% in mineral oil, 0.0942 g) was added. The resulting mixture was stirred for 1 h at room temp. To this mixture was added methyl 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate 184 (0.40 g, 1.1 mmol) in THF/DMF (1:1, 10 mL). The entire reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with water and diluted with EtOAc. Extracted, dried over MgSO4, filtered and concentrated. Dissolved in Methylene chloride (10 mL, 200 mmol) and cooled to at 0° C. and treated with thionyl chloride (0.314 mL, 4.30 mmol) dropwise. Following the addition, the reaction was warmed to room temp and stirred for 3 h. Concentrated in vacuo and purified by reverse phase HPLC to provide 199 (209 mg, 48% yield). LC/MS (ESI+): m/z 393 (M+H). 1H NMR (400 MHz, DMSO) δ 8.47 (d, J=8.4, 1H), 7.99 (s, 1H), 7.92 (d, J=3.5, 1H), 7.59 (dd, J=8.4, 1.6, 1H), 7.45 (d, J=1.6, 1H), 5.85 (dt, J=13.2, 6.6, 1H), 4.55 (dd, J=10.6, 6.4, 4H), 4.12 (s, 2H), 1.49 (d, J=6.6, 6H), 1.30 (s, 6H)
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]([CH3:12])=[N:10][C:9]2[N:5]([N:6]=[C:7]3[C:15]([CH3:17])([CH3:16])[N:14]([C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:19])[CH2:13][C:8]3=2)[C:4]=1[CH3:33].[CH3:34][C:35]([CH3:37])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O.[OH-].[Na+]>ClCCCl>[Cl:2][C:3]1[C:11]([CH3:12])=[N:10][C:9]2[N:5]([N:6]=[C:7]3[C:15]([CH3:16])([CH3:17])[N:14]([C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH:27]4[CH2:28][CH2:29][N:30]([CH:35]([CH3:37])[CH3:34])[CH2:31][CH2:32]4)=[O:19])[CH2:13][C:8]3=2)[C:4]=1[CH3:33]
Reactant: CC(C)=O
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)C(C)(C)N(C(=O)c1ccccc1OC1CCNCC1)C3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1nc2c3c(nn2c(C)c1Cl)C(C)(C)N(C(=O)c1ccccc1OC1CCN(C(C)C)CC1)C3
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.5 %

Procedure:
A mixture of Example 100 (98 mg; 0.22 mmol; 1 eq.), acetone (95 μL; 1.3 mmol; 6 eq.), sodium triacetoxyborohydride (183 mg; 0.86 mmol; 4 eq.) and AcOH (15 μL; 0.26 mmol; 1 eq.) in DCE (5 mL) was stirred at room temperature for 16 hours. Acetone (95 μL; 1.3 mmol; 6 eq.), sodium triacetoxyborohydride (183 mg; 0.86 mmol; 4 eq.) and AcOH (15 μL; 0.26 mmol; 1 eq.) were added and the resulting mixture was stirred at room temperature for 24 hours. 1M NaOH was added and the two phases separated. The aqueous layer was extracted with DCM (2×). The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (5% to 20% MeOH in DCM) afforded the title compound (78 mg, 72%) as a colourless oil. 1H NMR (DMSO-d6) δ 7.44-7.33 (m, 1H), 7.24 (dd, J=7.4, 1.7 Hz, 1H), 7.18-7.09 (m, 1H), 7.00 (t, J=7.4 Hz, 1H), 4.61-4.42 (m, 2H), 4.42-4.27 (m, 1H), 2.83 (s, 3H), 2.63-2.52 (m, 4H), 2.36-2.21 (m, 2H), 1.98-1.74 (m, 8H), 1.68-1.44 (m, 2H), 0.79 (d, J=6.2 Hz, 6H). HPLC (max plot) 86.3%, Rt 3.27 min. UPLC/MS: (MS+) 496.5 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.C(N(CC)CC)C.[C:24]([O:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30])(=[O:26])[CH3:25]>CN(C)C(=O)C.C(OCC)(=O)C>[C:24]([O:27][C:28]([CH3:33])([CH3:32])[C:29](=[O:30])[NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:10]=1)(=[O:26])[CH3:25]
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(=O)OC(C)(C)C(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (220 mg) and triethylamine (0.182 mL) in N,N-dimethylacetamide (1.5 mL) chilled to 0° C. was added 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.175 mL) dropwise. After being stirred at room temperature for 1 h, the reaction mixture was diluted with ethyl acetate and washed with 1 M citric acid aqueous solution 3 times then brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (10-100% ethyl acetate in hexanes) gave the product (290 mg, 83%).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16](=[O:25])[NH:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CCO.[Pd].[Fe+3]>[OH:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16](=[O:25])[NH:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cn1cccc(OCc2ccccc2)c1=O)NOc1ccccc1
Reactant: [H][H]
Agent: [Fe+3]
Agent: [Pd]
Solvent: CCO
Product: O=C(Cn1cccc(O)c1=O)NOc1ccccc1
Yield: 57 %

Procedure:
17 (350 mg, 0.8 mmol) was suspended in 175 mL of EtOH. 10% (w/w, 38 mg) of 10% Pd/C catalyst was added to the hydrogenation flask (500 mL Pyrex® Parr reaction bottle tested to 120 psi, max. working pressure of 60 psi). The Parr hydrogenation system located in the VanNieuwenhze lab was used for the deprotection reactions. The hydrogen pressure was set to 35 psi with agitation, and the process went on for 41 h. A white precipitate was present even after the reaction was stopped, but this white product reacted with iron(III) to give a reddish product instead of no reaction as seen with the protected starting material. The catalyst was removed by vacuum filtration and separated from the product by dissolving the white precipitate in 125 mL hot CH2Cl2 and MeOH and THF. The clear solution was concentrated by rotary evaporation to yield a white solid. The solid was washed with MeOH to remove residual DCU to yield a white, feathery microcrystalline solid. Yield: 57%. 1H NMR (d6-DMSO, 400 MHz, 25° C.): δ 4.75 (s, 2H, —CH2—), 6.11 (t, J=7.0 Hz, 1H, Ar—H), 6.72 (d, J=7.2 Hz, 1H, Ar—H), 6.97 (m, 4H, Phenoxy-H), 7.11 (m, 2H, Ar—H, Phenoxy-H), 7.36 (t, J=7.2 Hz, 2H, Phenoxy-H), 7.58 (d, J=6.8 Hz, 2H, Phenoxy-H), 9.03 (s, 1H, —OH), 10.36 (s, 1H, —NH—). APCI-MS: m/z 336.9 [M+H]+. Anal. Calcd for C19H16N2O4: C, 67.85; H, 4.79; N, 8.33. Found: C, 67.75; H, 5.07; N, 8.49.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.Cl.[CH2:31]([C:38]([OH:40])=O)[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1.FC(F)(F)C(O)=O.[NH2:48][C@H:49]([CH2:68][C:69]1[CH:74]=[CH:73][C:72]([O:75][CH3:76])=[CH:71][CH:70]=1)[C:50]([N:52]1[CH2:55][C:54]([O:63][CH2:64][CH2:65][CH2:66][CH3:67])([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])[CH2:53]1)=[O:51]>CN(C)C=O>[CH2:64]([O:63][C:54]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])[CH2:53][N:52]([C:50](=[O:51])[C@H:49]([NH:48][C:38](=[O:40])[CH2:31][CH2:32][C:33]2[N:37]=[CH:36][NH:35][CH:34]=2)[CH2:68][C:69]2[CH:74]=[CH:73][C:72]([O:75][CH3:76])=[CH:71][CH:70]=2)[CH2:55]1)[CH2:65][CH2:66][CH3:67]
Reactant: CCCCOC1(c2ccccc2F)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Reactant: O=C(O)CCc1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCCCOC1(c2ccccc2F)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)CCc2c[nH]cn2)C1
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
81 mg (0.3 mmol) of TBTU and 0.1 ml (0.6 mmol) of triethylamine are added to a solution of 42 mg (0.25 mmol) of desamino-histidine hydrochloride in 1 ml of dimethylformamide. After stirring for 10 minutes, 119 mg (0.2 mmol) of (R)-2-amino-1-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-3-(4-methoxyphenyl)propan-1-one trifluoroacetate are added and the reaction medium is stirred for 64 h at ambient temperature. After extraction with a 1/2 heptane/ethyl acetate mixture, the organic phase is washed with 1N aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated. The crude product is purified by silica gel chromatography, elution being carried out with a 90/10 dichloromethane/methanol mixture. 59 mg of N—[(R)-2-[3-butoxy-3-(2-fluoro-phenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white solid with a yield of 57%.
Reaction SMILES: [OH-].[Na+].[CH:3](=O)[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[BH4-].[Na+].[NH2:14][C@H:15]([C:22]([OH:24])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1>>[OH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[CH2:3][NH:14][C@H:15]([C:22]([OH:24])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: O=Cc1ccccc1O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H](Cc1c[nH]cn1)NCc1ccccc1O
Reaction time: 1 h

Procedure:
To 20 ml of a 2N aqueous solution of sodium hydroxide in which 5 g of L-histidine had been dissolved, 3.5 ml of salicylaldehyde and 0.4 g of sodium borohydride were successively added. After stirring for 1 hour, additional 3.5 ml of salicylaldehyde and 0.4 g of sodium borohydride were successively added. After stirring at room temperature for 1 hour, the unsolubles were filtered out and the filtrate was extracted with diethyl ether. The pH was adjusted to 6 with hydrochloric acid to give 8 g of N-(2-hydroxybenzyl)-L-histidine.