Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH:3]1[CH2:6][N:5]([C:7]([C@@H:9]2[CH2:13][C@H:12]([S:14]CC3C=CC(OC)=CC=3)[CH2:11][N:10]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])=[O:8])[CH2:4]1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>C1(OC)C=CC=CC=1>[CH3:1][N:2]([CH3:37])[CH:3]1[CH2:4][N:5]([C:7]([C@@H:9]2[CH2:13][C@H:12]([SH:14])[CH2:11][N:10]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])=[O:8])[CH2:6]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(N(C)C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN(C)C1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h
Yield: 88.9 %

Procedure:
1.47 g of (2S,4S)-2-(3-dimethylaminoazetidin-1-ylcarbonyl)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (a) above] were dissolved in 3.02 ml of anisole, and 10.71 ml of trifluoroacetic acid and 0.488 ml of trifluoromethanesulfonic acid were added to the resulting solution, after which the mixture was stirred at the same temperature for 1 hour. The solvent was then removed by distillation under reduced pressure, and the residue was washed by repeated decantation, in turn, with hexane and with diethyl ether. Ethyl acetate was added to the residue and the mixture was made alkaline by the addition of a saturated aqueous solution of sodiumhydrogencarbonate. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 1.01 g of the title compound as a powder.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=23)=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[C:24]([NH2:32])[N:23]=1.Cl.[OH-].[Na+]>O.CO.C(O)C>[NH2:32][C:24]1[N:23]=[C:22]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([CH2:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=34)=[C:4]([F:20])[CH:3]=2)[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[N:25]=1
Reactant: N#Cc1c[nH]c2nccc(Cc3ccc(N)cc3F)c12
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CO
Product: N#Cc1c[nH]c2nccc(Cc3ccc(Nc4cc(C(F)(F)F)nc(N)n4)cc3F)c12

Procedure:
82 mg (0.31 mmol) of 4-(4-amino-2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile and 67 mg (0.34 mmol) of 4-chloro-6-trifluoromethylpyrimidine-2-amine are suspended in 3 ml of water, 1.5 ml of ethanol and 0.15 ml of 4N hydrochloric acid. The reaction mixture is heated at reflux for 2 hours. After cooling, the mixture is made alkaline using dilute aqueous sodium hydroxide solution, a little methanol is added, the mixture is extracted with ethyl acetate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC. This gives crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([NH:24][CH2:25][CH3:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:24]([CH2:25][CH3:26])[C:12]1[C:13]([CH:21]2[CH2:23][CH2:22]2)=[CH:14][C:15]2[C:10]([CH:11]=1)=[N:9][N:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:16]=2[C:17]([NH:19][CH3:20])=[O:18])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CCNc1cc2nn(-c3ccc(Br)cc3)c(C(=O)NC)c2cc1C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(C(C)=O)c1cc2nn(-c3ccc(Br)cc3)c(C(=O)NC)c2cc1C1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.6 %

Procedure:
To a solution of compound (ii) (6 mg, 0.015 mmol) in DCM was added DIPEA (7 μL, 0.040 mmol), followed by acetyl chloride (7 μL, 0.098 mmol) and the reaction was stirred at RT for 20 min. After concentrating to dryness, the residue was purified by flash column chromatography eluting with MeOH/DCM (0-20%) to give Compound (48) as a white solid (4 mg, 61%). ESI-MS m/z calculated for [M+H]+: 455.1/457.1; found: 455.4/457.4; 1H NMR (400 MHz, CDCl3) δ 7.71-7.63 (m, 2H), 7.56 (brs, 1H), 7.52-7.46 (m, 2H), 7.43 (s, 1H), 5.77 (brs, 1H), 4.32 (dq, J=14.3, 7.2 Hz, 1H), 3.25 (dq, J=14.2, 7.1 Hz, 1H), 3.01 (d, J=4.9 Hz, 3H), 1.96-1.74 (m, 4H), 1.21 (t, J=7.2 Hz, 3H), 1.10-0.97 (m, 2H), 0.86-0.70 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[F:13][C:14]([F:19])([F:18])C([O-])=O.[K+]>>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[C:14]([F:19])([F:18])[F:13]
Reactant: O=C([O-])C(F)(F)F
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: [K+]
Product: COc1ccc(C(=O)O)cc1C(F)(F)F

Procedure:
The title compound was prepared from 3-bromo-4-methoxybenzoic acid and potassium trifluoroacetate in a manner similar to that of Procedures 3 and 4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:7]=2)[CH:3]=1.C(NC1C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1)(=O)C.N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[N+:37]=[N-:38])[C:12]([O:14][CH3:15])=[O:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[N:7]=2)[CH:3]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COC(=O)Cc1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(=[N+]=[N-])c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)acetate (1.95 g, 5.49 mmol) and 4-acetamidobenzenesulfonyl azide (1.52 g, 6.32 mmol) in acetonitrile (11 mL) at 0° C. was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.04 mL, 6.87 mmol) dropwise over 20 min. The ice bath was removed and stirring continued at room temperature for 1 h. The reaction was partitioned between water and ethyl acetate. The organics were washed with saturated sodium bicarbonate, dried over sodium sulfate, and concentrated. The resulting residue was purified by column chromatography (8%→25% ethyl acetate/n-hexane) to give 1.39 g (66%) as a yellow oil. 1H-NMR (CDC13, 500 MHz) δ 8.01 (s, 1H), 7.79 (d, J=1.5 Hz, 1H), 7.45 (d, J=1.8 Hz, 1H), 5.64 (s, 2H), 3.89 (s, 3H), 3.64 (t, J=8.2 Hz, 2H), 0.93 (t, J=8.4 Hz, 2H), −0.03 (s,9H; 13C NMR (126 MHz, CDCl3) δ ppm 165.9, 143.2, 128.7, 125.3, 123.1, 122.7, 122.5, 116.5, 116.4, 81.8, 67.9, 52.1, 17.8, −1.4.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:16]1[C:35]([I:36])=[CH:34][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([Cl:33])([F:32])[F:31])=[CH:25][CH:24]=2)=[O:21])=[CH:18][N:17]=1.CCOC(C)=O>CC(O)C>[Cl:33][C:30]([F:31])([F:32])[O:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:20](=[O:21])[C:19]2[CH:34]=[C:35]([I:36])[C:16]([N:4]3[CH2:5][CH:2]([OH:1])[CH2:3]3)=[N:17][CH:18]=2)=[CH:24][CH:25]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Reactant: OC1CNC1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(O)C2)c(I)c1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
3-Hydroxyazetidine (164 mg, 2.18 mmol) and DIPEA (0.419 mL, 2.396 mmol) were added to a suspension of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 48.3, 500 mg, 1.089 mmol) in iPrOH (2 mL). and stirred at 140° C. for 16 h. EtOAc (80 mL) was added and the solution was washed with 1 M HCl (30 mL), aq. sat. NaHCO3 solution (30 mL) and water (30 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as yellow foam. HPLC (Condition 7) tR=6.64 min, UPLC-MS (Condition 3) tR=1.08 min, m/z=496.0/498.0 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.S(O[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1
Reactant: OC[C@H]1CCCCN1
Reactant: COc1ccc(CCCOS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCCN2CCCC[C@@H]2CO)cc1
Temperature: 90 °C

Procedure:
(R)-2-hydroxymethylpiperidine (288 mg, 2.50 mmol), 3-(4-methoxyphenyl)propyl mesylate (915 mg, 3.75 mmol), sodium carbonate (398 mg, 3.75 mmol) and sodium iodide (30 mg, 0.20 mmol) were added to acetonitrile (25 ml), and they were heated under reflux at 90° C. for 6 hours. The solvent was evaporated under reduced pressure. The residue was distributed in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and dried over magnesium sulfate. Then the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane as the eluent and then with dichloromethane and methanol (20:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-2-hydroxymethyl-1-[3-(4-methoxy-phenyl) propyl]piperidine in the form of a light yellow oil (422 mg, 64%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].Cl[C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([CH2:23][N:24]3[CH2:29][CH2:28][N:27]([C:30]([CH3:35])([CH2:33][OH:34])[CH2:31][OH:32])[CH2:26][CH2:25]3)[N:19]2[CH3:22])=[C:15]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:14]=1>>[CH2:1]([C:3]1[N:4]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[C:18]([CH2:23][N:24]4[CH2:25][CH2:26][N:27]([C:30]([CH3:35])([CH2:31][OH:32])[CH2:33][OH:34])[CH2:28][CH2:29]4)[N:19]3[CH3:22])=[C:15]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[N:14]=2)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: Cn1c(CN2CCN(C(C)(CO)CO)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2[nH]1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(CO)CO)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-ethylbenzimidazole and 2-(4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropane-1,3-diol were reacted to give 440. LCMS m/z: 550.3 (MH+)
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([F:13])=[CH:5][CH:4]=1)#[N:2].[ClH:14]>C(O)C.[Pd]>[ClH:14].[F:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([CH2:1][NH2:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(F)c2ccccc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc(F)c2ccccc12
Yield: 44 %

Procedure:
A solution of 1-cyano-4-fluoronaphthalene (1.05 g, 6.12 mmol) and 1.5 mL of HCl (aq.) in absolute ethanol (50 mL) was stirred under a hydrogen atmosphere (balloon) with 10% palladium on carbon (0.20 g) for 16 hours. The catalyst was removed by filtration through Celite, and the filtrate concentrated under vacuum. The resulting solid was triturated with ether and collected by filtration to give the title compound (0.575 g, 44% yield) as an off white solid.
Reaction SMILES: [C:1]1([CH:7]([CH:15]2[O:20][CH2:19][CH2:18][NH:17][CH2:16]2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>ClCCl>[CH2:32]([O:31][C:29]([N:17]1[CH2:18][CH2:19][O:20][CH:15]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:16]1)=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: c1ccc(CC(c2ccccc2)C2CNCCO2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCOC(C(Cc2ccccc2)c2ccccc2)C1
Reaction time: 24 h

Procedure:
To a solution of 2-(1,2-Diphenyl-ethyl)-morpholine (2 g, 7.49 mmol) in dry dichloromethane (15 ml) at 0° C. under nitrogen atmosphere is added neat triethylamine (2.2 ml, 15.5 mmol, 2.07 equiv.) followed by the addition of neat benzyl chloroformate (1.61 ml, 11.23 mmol, 1.5 equiv.). The reaction is left to reach room temperature over 24 hours and then quenched by addition of a saturated bicarbonate (NaHCO3) aqueous solution. The resulting mixture is extracted with dichloromethane and the resulting organic phases are mixed, dried (MgSO4) and concentrated under reduced pressure to give an oil containing the four possible diastereoisomers (2.3 g, 78%). The diastereoisomers are separated using preparative HPLC, followed by each single enantiomer being resolved by preparative chiral HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:16][CH2:15][C:14]3[CH:17]=[C:18]([CH2:21]O)[CH:19]=[CH:20][C:13]=3[CH2:12][O:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.C1(C)C=CC(S([Cl:39])(=O)=O)=CC=1>ClCCl>[Cl:39][CH2:21][C:18]1[CH:19]=[CH:20][C:13]2[CH2:12][O:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[O:16][CH2:15][C:14]=2[CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(C2OCc3ccc(CO)cc3CO2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(C2OCc3ccc(CCl)cc3CO2)cc1
Yield: 37.5 %

Procedure:
1.5 g (5 mmol) of [7-(4-nitrophenyl)-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl]methanol in 15 ml of dichloromethane are introduced into a flask. 0.76 g (7.5 mmol) of triethylamine is added and 1 g (5.4 mmol) of p-toluenesulfonyl chloride is added in small solid portions at room temperature. After 20 hours of reaction, the solvent is evaporated off and the crude product is purified by silica gel chromatography (heptane/ethyl acetate: 4/1) to give 0.6 g of 2-chloromethyl-7-(4-nitrophenyl)-(5H,9H)-6,8-dioxabenzocycloheptene.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)ccc1Oc1ccccc1
Reaction time: 8 h

Procedure:
2-Methyl-4-nitro-1-phenoxybenzene and 10% Pd/C (3.35 g) were dissolved in 200 mL EtOH and stirred under 1 atmosphere of H2 overnight. The reaction mixture was filtered through Celite with the aid of 50 mL EtOH and concentrated to provide 3-methyl-4-phenoxybenzenamine as an oil, which was used in Step C without further purification.
Reaction SMILES: [CH2:1]1[CH2:8][O:7][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2]1.[CH2:9]([NH2:11])[CH3:10].CCO>O1CCCC1.CC(C)=O.CCO>[CH2:9]([NH:11][CH2:8][CH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])[CH3:10]
Reactant: CCN
Reactant: O=S1(=O)CCCCO1
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCNCCCCS(=O)(=O)O
Temperature: 5 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A solution of 1,4-butanesultone (2.66 g, 18.6 mmol) in tetrahydrofuran (total volume: 4 mL) was added via syringe pump over a 4 hour period to ethylamine (70% w/w in water, 24 mL, 372 mmol) at 5° C. The solution was stirred at 5° C. for an additional 3 hours before it was warm up to room temperature. The reaction was stirred in these conditions overnight. The solvent was coevaporated with EtOH (1×25 mL). The solid was suspended in 50% acetone/EtOH (50 mL). The suspension was stirred for 5 minutes, the solid was filtered and dried in vacuo. Yield: 75%. 1H NMR (D2O, 500 MHz) δ ppm 2.95 (m, 4H), 2.82 (m, 2H), 1.68 (m, 4H), 1.13 (t, 3H, J=7.3 Hz), 1.14 (t, 3H, J=7.3 Hz). 13C (D2O, 125 MHz) δ ppm 50.27, 46.68, 42.99, 24.66, 21.48, 10.64. ES-MS182 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(N=C=NCCCN(C)C)C.[NH2:48][C:49]1[C:50]([OH:60])=[C:51]([CH:57]=[CH:58][CH:59]=1)[C:52]([O:54][CH2:55]C)=[O:53]>C.[Cl-].[Cl-].O>[OH:60][C:50]1[C:51]([C:52]([O:54][CH3:55])=[O:53])=[CH:57][CH:58]=[CH:59][C:49]=1[NH:48][C:15]([CH:13]1[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:14]1)=[O:17]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reactant: CCOC(=O)c1cccc(N)c1O
Agent: C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1cccc(NC(=O)C2CN(C(=O)OCc3ccccc3)C2)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid (2.4 g) in dichloride methane (15 ml) was added 1-hydroxybenzotriazole (1.48 mg, 11 mmol), diisopropylethylamine (4 g, 30 mmol) and 1-ethly-3-(3-dimethylaminopropyl)carbodiimide hydrochloric (2 g, 11 mmol). The mixture was stirred at room temperature for 30 min. Then ethyl 3-amino-2-hydroxybenzoate (700 mg, 4 mmol) was added. The mixture was stirred at room temperature for 2 h. To the resulting mixture, water (10 ml) was added and hydrochloride acid (1N) to pH=3, then extracted with ethyl acetate (100 ml×4). The organic phase was washed with sodium bicarbonate (saturated) and brine and concentrated, dried with sodium sulfate. The crude was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1). 820 mg of benzyl 3-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)azetidine-1-carboxylate was obtained. Yield 52%. LC-MS (ESI) m/z: 385 (M+1)+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]=[C:37]=[O:38])=[CH:31][CH:30]=1>CN(C=O)C.Cl>[ClH:28].[NH2:3][C:4]([CH:15]1[CH2:16][CH2:17][N:18]([C:37](=[O:38])[NH:36][CH2:35][C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)[CH2:19][CH2:20]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6]
Reactant: O=C=NCc1ccc(Cl)cc1
Reactant: NC(CCCCB(O)O)(C(=O)O)C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(CCCCB(O)O)(C(=O)O)C1CCN(C(=O)NCc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
A stirred solution of crude 2-amino-6-borono-2-(piperidin-4-yl)hexanoic acid dihydrochloride (Example 26-A, Step 1, 0.240 g, 0.594 mmol) in dry DMF (12 mL) under nitrogen was treated with triethylamine (0.662 mL, 4.75 mmol) to give a white slurry. 1-chloro-4-(isocyanatomethyl)benzene (0.177 mL, 1.34 mmol) was added dropwise, and the resulting opaque mixture was stirred at room temperature for 1 h. The mixture was diluted with 1 N HCl (15 mL) and washed with ethyl acetate (2×20 mL), and the aqueous layer was concentrated under reduced pressure to give the crude product which was purified by reverse phase HPLC [Phenomenex Luna 250×30.00 mm, 10 micron column. 40 mL/min flow rate. Gradient: solvent A is 0.07% TFA in acetonitrile; solvent B is 0.10% TFA in water; 5% to 50% A over 24 min, then 50% to 100% A over 1 min]. Product fractions were pooled and concentrated, and the residue was taken up in 0.5N HCl (5 mL)/acetonitrile (8 mL) and concentrated. The residue was once again treated with 0.5N HCl (5 mL)/acetonitrile (8 mL) and concentrated and dried under high vacuum overnight to give 2-amino-6-borono-2-{1-[(4-chlorobenzyl)carbamoyl]-piperidin-4-yl}hexanoic acid hydrochloride (92 mg, 34%) as an off-white solid. 1H NMR (D2O, 400 MHz) δ 7.26 (m, 2H), 7.15 (m, 2H), 4.19 (s, 2H), 3.95 (bt, J=14.6 Hz, 2H), 2.75 (bt, J=12.8 Hz, 2H), 2.06 (bt, J=12.4 Hz, 1H), 1.81 (m, 3H), 1.53 (bd, J=12.8 Hz, 1H), 1.32 (m, 4H), 1.11 (m, 2H), 0.69 (t, J=7.6 Hz, 2H). ESI+ MS found for C19H29BClN3O5 m/z 408.4 (M−18+H); ESI− MS m/z 424.4 (M−H), 406.4 (M−18−H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23]>CC(C)=O>[CH3:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOCCOc1cccc(C=O)c1
Yield: 19.6 %

Procedure:
A mixture of 3.66 g of 3-hydroxybenzaldehyde, 4.6 g of powdered potassium carbonate, and 5.5 g of 1-bromo-2-(2-methoxyethoxy)ethane in 40 ml of acetone is stirred and refluxed under nitrogen for 18 h, then cooled and filtered. The filtrate is concentrated under reduced pressure, and the residue partitioned between CH2Cl2 and 1N NaOH. The aqueous phase is extracted with two additional portions of CH2Cl2, and the combined organic extracts dried (MgSO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 20% EtOAc in CH2Cl2 affords 1.32 g of the title compound as a pale yellow oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:11]([C:20]([F:23])([F:22])[F:21])[CH:10]=2)O1.[NH2:25][C:26]1[C:27]([C:35]#[N:36])=[N:28][C:29](Cl)=[CH:30][C:31]=1[NH:32][CH3:33].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.O.C(OCC)(=O)C.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]>[NH2:25][C:26]1[C:27]([C:35]#[N:36])=[N:28][C:29]([C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:11]([C:20]([F:21])([F:22])[F:23])[CH:10]=2)=[CH:30][C:31]=1[NH:32][CH3:33]
Reactant: CNc1cc(Cl)nc(C#N)c1N
Reactant: CC1(C)OB(c2ccc(OCCCO)c(C(F)(F)F)c2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CNc1cc(-c2ccc(OCCCO)c(C(F)(F)F)c2)nc(C#N)c1N
Temperature: 100 °C

Procedure:
A mixture of 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoro-methyl)phenoxy)propan-1-ol (34 g), 3-amino-6-chloro-4-(methylamino)picolinonitrile (16.2 g), potassium phosphate (56.5 g), tricyclohexylphosphine (2.98 g), and tris(dibenzylideneacetone)dipalladium(0) (4.06 g) in dioxane (340 ml) and water (170 ml) under N2 was heated to 100° C. for 2 hours then diluted with ethyl acetate and filtered through celite. The organic layer was separated, dried over magnesium sulphate and solvent removed under reduced pressure to give expected product clean enough for use in the next step (49.6 g). 1H NMR (CD3OD) δ: 8.06 (s, 1H), 8.01 (d, 1H), 7.23 (d, 1H), 6.86 (s, 1H), 4.23 (t, 2H), 3.78 (t, 2H), 2.98 (s, 3H), 2.04 (quin, 2H). MS m/z 367 (M+H).