Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:17][C:18]([O-:20])=[O:19])[O:3]1.[Li+].[OH-].Cl>CCO>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:17][C:18]([OH:20])=[O:19])[O:3]1
Reactant: Cc1cc(OS(C)(=O)=O)cc2c1C(CC(=O)[O-])OB2O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OS(C)(=O)=O)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 3 h
Yield: 17.2 %

Procedure:
To a solution of 2-(1-hydroxy-4-methyl-6-(methylsulfonyloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in EtOH (10 mL) was added an aqueous solution of LiOH (3 mL, 10% aq.). The reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was acidified with 1N HCl to pH=2 and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as an off-white powder (64 mg, yield: 17.2%, two steps). 1H NMR (400 MHz, DMSO) δ 12.36 (s, 1H), 9.36 (s, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 5.53-5.55 (m, 1H), 3.38 (s, 3H), 3.06-3.10 (m, 1H), 2.34 (s, 3H), 2.14-2.20 (m, 3H); MS (ESI) m/z=323 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([N:9]=[CH:10]N(C)C)=[C:4]([Cl:14])[N:3]=1.P([O-])([O-])([O-])=[O:16].[K+].[K+].[K+].OP([O-])(O)=O.[K+].P(=O)(O)(O)O>P(=O)(O)(O)O.CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:16])=[C:4]([Cl:14])[N:3]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: CN(C)C=Nc1c(Cl)nc(N)nc1Cl
Agent: O=P(O)(O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1nc(Cl)c(NC=O)c(Cl)n1
Temperature: 125 °C
Yield: 68 %

Procedure:
A slurry of 2-amino-4,6-dichloro-5-{[(dimethylamino)methylene]amino}pyrimidine (Example 2, 1.50 g, 6.41 mmol) and 1.5 M aqueous potassium phosphate buffer (35 mL, prepared by adjusting the pH of a 1.5 M solution of KH2PO4 to 3.2 by addition of 85% phosphoric acid) was gently refluxed (in an oil bath at 125° C.) After 4 hours of reflux, the pH of the mixture was adjusted from 4 to 3 by addition of 4 drops of 85% phosphoric acid. After a total of 6 hours of reflux, TLC (silica gel plated developed in 5% methanol-chloroform) showed that the starting material had been largely converted to a lower-Rf product. The solid was filtered and washed with water (5 mL), methanol (5 mL), and dried to give the title compound as a white solid (0.900 g, 68%), m.p.>250° C. dec.; mass spectrum (Cl/CH4): 209, 207 (M+1); 1H-NMR (DMSO-d6)δ: 9.81 and 9.46 (s and d, J=11 Hz, total 1, NH), 8.25 and 8.00 (s and d, J=11 Hz, total 1, CHO), 7.69 and 7.63 (both s, total 2, NH2).
Reaction SMILES: [CH:1]([Si:4]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[SH:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19](Br)[CH:18]=1>C1COCC1.C1(C)C=CC=CC=1.CCOC(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>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:8])[CH3:7])[CH:9]([CH3:11])[CH3:10])[CH:18]=1
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(S[Si](C(C)C)(C(C)C)C(C)C)c1
Reaction time: 0.25 h

Procedure:
Triisopropylsilane-thiol (97%, 1.29 mL, 6.0 mmol) in THF (15 mL) was cooled to 0° C. and then sodium hydride (60% in mineral oil, 0.240 g, 6.0 mmol) was added. After 15 minutes, 2-bromo-isonicotinic acid methyl ester (1 g, 4.6 mmol) in toluene was added and the mixture was purged with N2 (g). Tetrakis(triphenylphosphine)palladium(0) (0.531 g, 4.6 mmol) was added and the reaction was heated to reflux. After cooling the reaction was diluted with EtOAc then washed with H2O and brine. The organic portion was dried and concentrated to afford the title compound, which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([O:7][C:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:9])([CH3:6])[CH3:5].[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([CH2:27][Br:28])[CH:24]=[C:23]([CH2:29]Br)[CH:22]=1.[Cl-].[NH4+]>CN(C)C=O>[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:22]=[C:23]([CH2:29][N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:8]([O:7][C:4]([CH3:3])([CH3:5])[CH3:6])=[O:9])[CH:24]=[C:25]([CH2:27][Br:28])[CH:26]=1
Reactant: COC(=O)c1cc(CBr)cc(CBr)c1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CBr)cc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
A mixture of sodium hydride (3.6 g, 90 mmol) and N,N-dimethylformamide (150 ml) was cooled to 0° C. and treated with solid di-tert-butyliminodicarboxylate (17.4 g, 76.0 mmol) with vigorous stirring. The mixture was stirred at 0° C. for 15 minutes, the ice bath was removed and a solution of methyl-3,5-bis(bromomethyl)-benzoate (23.6 g, 73.2 mmol) in N,N-dimethylformamide was added dropwise over 30 minutes. After 12 hours the mixture was poured into 100 ml 1/4 saturated aqueous ammonium chloride and extracted with the three 100 ml portion of hexanes. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure and chromatographed using a gradient of 10-20% ethyl acetate/hexanes to yield the product (22.0 g, 66% yield). TLC (20% ethyl acetate/hexanes): Rf =0.55 (UV active, CAM stain)
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([C:20]([C:23]4[CH:24]=[CH:25][C:26]5[O:30][CH2:29][CH2:28][C:27]=5[CH:31]=4)([F:22])[F:21])=[N:18][N:19]=3)[N:16]=2)=[CH:9][CH:10]=1)=[O:5])C.[OH-].[Na+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:77][N:78]1[CH2:83][CH2:82][NH:81][CH2:80][CH2:79]1>C1COCC1.CO.ClCCl.O>[O:30]1[C:26]2[CH:25]=[CH:24][C:23]([C:20]([F:21])([F:22])[C:17]3[N:15]4[N:16]=[C:11]([C:8]5[S:7][C:6]([C:4]([N:81]6[CH2:82][CH2:83][N:78]([CH3:77])[CH2:79][CH2:80]6)=[O:5])=[CH:10][CH:9]=5)[CH:12]=[CH:13][C:14]4=[N:19][N:18]=3)=[CH:31][C:27]=2[CH2:28][CH2:29]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1ccc(-c2ccc3nnc(C(F)(F)c4ccc5c(c4)CCO5)n3n2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN1CCN(C(=O)c2ccc(-c3ccc4nnc(C(F)(F)c5ccc6c(c5)CCO6)n4n3)s2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound prepared in step b was dissolved in a 2:1 THF/methanol (3 mL) mixture and treated with 2N NaOH (0.15 mL). The mixture was stirred for 3 hours at RT, evaporated in vacuo, diluted with water (10 mL), and acidified with 6 N HCl to pH 2. The white solid precipitates were collected, dried under reduced pressure, dissolved in DMF (3 mL) and treated with HATU (0.12 g, 0.31 mmol), HOBt (24 mg, 0.18 mmol) and DIEA (0.1 mL, 1.04 mmol) respectively. The resulting mixture was stirred at RT for 30 minutes and N-methylpiperazine (0.027 mL, 0.24 mmol) was added. Stirring was continued for an additional hour and water (20 mL) was added. dichloromethane (20 mL) was added and layers separated. The CH2Cl2 layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by reverse phase HPLC (Varian Prostar HPLC, Pursuit prep column, CH3CN/H2O containing 0.1% TFA). The final compound was filtered through a HCO3 cartridge and dried under reduced pressure to provide the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([CH:11]1[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[O:12]1)[CH3:10]>ClCCl>[Br:1][C:17]1[CH:18]=[CH:19][C:13]2[O:12][CH:11]([CH2:9][CH3:10])[CH2:15][C:14]=2[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC1Cc2ccccc2O1
Solvent: ClCCl
Product: CCC1Cc2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Bromosuccinimide (8.66 g, 48.6 mmol) was added to a solution of 2-ethyl-2,3-dihydrobenzofuran (preparation 98) in dichloromethane (70 mL) and the mixture was stirred at room temperature for 18 hours. The mixture was then diluted with dichloromethane (200 mL) and washed with water (200 mL) and sodium meta-bisulphite (200 mL). The organic solution was dried over magnesium sulfate and concentrated in vacuo to give a yellow oil that was purified by HPLC using a Chiralcel OJ 250*20 mm column and hexane:isopropanol (95:5) as the eluant to afford the first enantiomer of the title compound. Further elution provided the second isomer of the title compound, 2.95 g. 1H NMR (400 MHz, CDCl3) δ: 7.24 (1H, m), 7.18 (1H, m), 6.62 (1H, d), 4.75 (1H, m), 3.30-3.20 (1H, m), 2.92-2.80 (1H, m), 1.77-1.88 (1H, m), 1.75-1.65 (1H, m) 1.00 (3H, m) ppm.
Reaction SMILES: [O:1](CC=C)[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4].OCCOC(=O)C=C.Cl.NCCCNC(=O)C(C)=C.Cl.Cl.N(C(C1NCCN=1)(C)C)=NC(C1NCCN=1)(C)C>O>[O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: C=CCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Agent: C=C(C)C(=O)NCCCN
Agent: C=CC(=O)OCCO
Agent: CC(C)(N=NC(C)(C)C1=NCCN1)C1=NCCN1
Solvent: O
Product: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C

Procedure:
A 40 mol % mannose polymer was prepared as follows. Allyl α-D-mannopyranoside (1.77 g, 8.0 mmol), 2-hydroxyethylacrylate (1.36 g, 11.7 mmol), N-(3-aminopropyl)methacrylamide hydrochloride (89.6 mg, 0.5 mmol) and 2,2′-Azobis-[2-(2-imidazolin-2-yl)-propane]dihydrochloride (23.7 mg, 0.073 mmol) were added into a 50 ml round bottom flask, followed by addition of water (28.8 ml). The mixture was dissolved under magnetic stirring at room temperature. After purging with nitrogen for 5 min, the mixture was heated to 60° C. and polymerized at that temperature for 12 hours. Upon cooling a slightly yellow and viscous solution was obtained. This solution was dialysed (25 k MWCO regenerated cellulose) overnight against water, and freeze-dried to obtain a white fluffy polymer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][CH2:10][C@H:9]2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:27]1[N:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:27]3[N:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[CH2:10][C@H:9]2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: Cc1ccc(Cl)nn1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CN(c2ccc(C)nn2)C[C@H]1c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 75 %

Procedure:
The product of Step A, methyl (3S,4R)-4-(4-chlorophenyl)pyrrolidine-3-carboxylate (0.46 g, 1.92 mmol) was dissolved in dioxane (2 ml). DIPEA (1.34 ml, 7.67 mmol) and 3-chloro-6-methylpyridazine (0.74 g, 5.76 mmol) were added. The reaction was conducted at 180° C. for 5 minutes with microwave. Then, the reaction mixture was concentrated in vacuo. EtOAc was added to the obtained residue. The mixture was diluted with EtOAc, washed with water and purified by column chromatography (eluent: EtOAc/Hex=1/2) to give the title compound (0.48 g, 75%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:7](B(O)O)=[CH:6][NH:5][N:4]=1.Br[C:14]1[N:19]=[C:18]2[S:20][C:21]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)=[N:22][C:17]2=[CH:16][CH:15]=1>>[OH:34][C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:24]([NH:23][C:21]2[S:20][C:18]3[C:17]([N:22]=2)=[CH:16][CH:15]=[C:14]([C:7]2[C:3]([C:2]([F:12])([F:11])[F:1])=[N:4][NH:5][CH:6]=2)[N:19]=3)=[O:35])=[CH:30][CH:29]=1)([CH3:32])[CH3:33]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: OB(O)c1c[nH]nc1C(F)(F)F
Product: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(-c4c[nH]nc4C(F)(F)F)nc3s2)cc1
Yield: 7 %

Procedure:
The titled compound (yield=7%) was prepared using a procedure analogous to that described in connection with 10 (Example 10) except 3-(trifluoromethyl)-1H-pyrazol-4-ylboronic acid and 1D (Example 1) were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 6H) 7.67 (d, J=8.34 Hz, 2H) 7.76 (d, J=8.34 Hz, 1H) 8.11 (d, J=8.34 Hz, 2H) 8.20 (d, J=8.59 Hz, 1H) 8.57 (s, 1H) 12.97 (s, 1H) 13.88 (br. s., 1H); ESI-MS: m/z 448.0 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=1[C:17]#[N:18].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:15]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=2[C:17]#[N:18])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2C#N)CC1
Temperature: 85 °C
Yield: 15 %

Procedure:
A mixture of Boc-piperazine (573 mg, (3.08 mmol), 2-bromo-5-trifluoromethylbenzonitrile (700 mg, 2.80 mmol), Pd2(dba)3 (256 mg, 0.28 mmol), xantphos (486 mg, 0.84 mmol), sodium t-butoxide (660 mg, 7.0 mmol) in degassed anhydrous dioxane (10 mL) was heated at 85° C. for 1 h. The mixture was allowed to cool and filtered through celite. The filtrate was concentrated and purified by chromatography (EtOAc/hexanes) to yield the title compound (150 mg, 15%). m/z (M+1) 356.37.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][N:5]=1)[CH3:2].Br[C:20]1[N:25]2[CH:26]=[CH:27][N:28]=[C:24]2[C:23]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[CH:32][CH:31]=2)=[N:22][CH:21]=1.CC([O-])(C)C.[Na+]>CN(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>[CH3:42][N:39]1[CH2:40][CH2:41][N:36]([C:33]2[CH:34]=[CH:35][C:30]([NH:29][C:23]3[C:24]4[N:25]([CH:26]=[CH:27][N:28]=4)[C:20]([C:8]4[CH:7]=[CH:6][N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=4)=[CH:21][N:22]=3)=[CH:31][CH:32]=2)[CH2:37][CH2:38]1
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(-c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)c3nccn23)ccn1
Temperature: 85 °C

Procedure:
A mixture of 2-ethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (97 mg, 0.31 mmol), (5-bromoimidazo[1,2-a]pyrazin-8-yl)-(4-(4-methylpiperazin-1-yl)phenyl)amine (100 mg, 0.259 mmol), Pd(PPh3)4 (29 mg, 0.026 mmol) and NaOtBu (99 mg, 1.0 mmol) in DMF (3 mL) and water (1 mL) is heated at 85° C. for 18 hours. After this time the reaction mixture is cooled to room temperature and the solvents removed in vacuo. The residue is chromatographed on silica gel, eluting with DCM followed by 96:4 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated to afford the title ethoxypyridine as a solid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([N:12]1[CH2:23][CH2:22][CH2:21][C@@H:13]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:24]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:25]([C:28](O)=[O:29])([CH3:27])[CH3:26]>>[NH:24]([C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[C:25]([C:28]([NH:1][C@H:2]([C:10]([N:12]1[CH2:23][CH2:22][CH2:21][C@@H:13]1[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:29])([CH3:27])[CH3:26]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)[C@@H](N)Cc1ccccc1
Product: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)C(C)(C)NC(=O)OCc1ccccc1
Yield: 85.4 %

Procedure:
H-L-Phe-D-Pro-OtBu (0.853 g, 2.68 mmol) and Z-Aib-OH (954 mg, 4.02 mmol) were condensed as described in Step 1 above. The oily product was purified by flash chromatography on silica gel (CHCl3/MeOH=99/1) to yield 1.23 g (85%) of the titled compound.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[OH:13][CH:14]([C:44]([NH:46][O:47][CH3:48])=[O:45])[CH:15]([NH:23][C:24](=[O:43])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[N:31]1[CH:35]=[C:34]([CH3:36])[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:32]1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH3:48][O:47][NH:46][C:44](=[O:45])[C:14](=[O:13])[CH:15]([NH:23][C:24]([C:25]1[C:26]([N:31]2[CH:35]=[C:34]([CH3:36])[C:33]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:43])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc(C)c(-c2ccccc2)n1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: ClCCl
Product: CONC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc(C)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To polymer-supported IBX (Novabiochem, 1.1 mmol/g; 300 mg, 0.330 mmol) dichloromethane (5 ml) was added and the mixture was left for 10 min. Then N-(3-hydroxy-4-(methoxyamino)-4-oxo-1-phenylbutan-2-yl)-2-(4-methyl-3-phenyl-1H-pyrazol-1-yl)nicotinamide (77 mg, 0.159 mmol) in 10 ml of dichloromethane was added and the mixture was shaken for 1 day at room temperature. Additional portions of the polymer-supported IBX were added after 2 days and 3 days (120 mg, 0.132 mmol and 100 mg, 0.110 mmol). After 4 days the mixture was filtered off, evaporated under reduced pressure and the crude product purified via chromatography on silica gel (eluent: CH2Cl2+2-4% (v/v) methanol). After evaporation of the combined product fractions 45 mg of an amorphous solid were obtained. ESI-MS [M+H]+: 484.2
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:15])[CH3:14])[CH2:10][C:9]1=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([O:15][C:23](=[O:25])[CH3:24])[CH3:14])[CH2:10][C:9]1=[O:16])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(O)CC1CC(=O)N1[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(C)CC1CC(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-(t-butyldimethylsilyl)-4-(2-hydroxypropyl)-2-azetidinone (2.46 g) is dissolved in 20 ml CH2Cl2 cooled to 0° and treated with 0.90 g pyridine and 0.080 g of acetyl chloride (added dropwise). The reaction mixture is stirred at 0° for 15 min, allowed to warm to r.t. during the next 15 min and then worked up by dilution with CH2Cl2 and washing with water, drying and evaporating. The residue on chromatography on silica gel gives 1-(t-butyldimethylsilyl)-4-(2-acetoxypropyl)-2-azetidinone.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C@H:5]2[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C@H:4]2[N:3]1[CH2:15][C:16]([O:18]CC)=[O:17].[Li+].[OH-].Cl>C1COCC1.O>[O:1]=[C:2]1[CH2:7][O:6][C@H:5]2[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C@H:4]2[N:3]1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)CN1C(=O)CO[C@H]2Cc3ccccc3[C@H]21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)CO[C@H]2Cc3ccccc3[C@H]21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl [(4aR,9aS)-3-oxo-2,3,9,9a-tetrahydroindeno[2,1-b][1,4]oxazin-4(4aH)-yl]acetate from Step C (480 mg, 1.74 mmol) in THF (7.5 mL) and H2O (2.5 mL) was added 1 N aqueous LiOH (2.1 mL, 2.09 mmol) and the resulting mixture was stirred at ambient temperature for 4 h. The mixture was adjusted to pH 4 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=248 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(=[O:17])[CH3:16]>>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:16]/[C:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)=[O:17]
Reactant: O=Cc1ccc(-c2cccs2)cc1F
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(C(=O)/C=C/c2ccc(-c3cccs3)cc2F)cc1
Yield: 71 %

Procedure:
The title compound was prepared by condensing 2-fluoro-4-thiophen-2-yl-benzaldehyde (Ex-30A) and 4-acetylbezoic acid in a similar manner as described in Ex-3. Yellow solid, 71% yield, m.p.>260° C. 1H-NMR (300 MHz, d6-DMSO): 8.19 (d, 2H, J=8.4 Hz), 8.12 (d, 1H, J=8 Hz), 8.06 (d, 2H, J=8 Hz), 7.95 (d, 1H, J=16 Hz), 7.80 (d, 1H, J=16 Hz), 7.71 (d, 1H, J=3.5 Hz), 7.62 (m, 2H), 7.56 (d, 1H, J=8 Hz), 7.15 (m, 1H). MS m/z=352 ([M]+, 100%). HRMS (EI) Calcd. for C20H13NO3S: 352.0569. Found: 352.0560.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:6].[CH3:22][O:23][C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)=[O:25].O>C(O)(=O)C>[CH2:16]([C:15]1[CH:14]=[CH:13][C:4]([C:5]([N:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)=[O:6])=[CH:3][C:2]=1[NH:1][CH2:30][C:29]1[CH:28]=[CH:27][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:33][CH:32]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCCCCCc1ccc(C(=O)N2CCOCC2)cc1N
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCc1ccc(C(=O)N2CCOCC2)cc1NCc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound ([5]-(55)-75) (600 mg) prepared in Example 63 was dissolved in acetic acid (6.0 ml). Then, 4-methoxycarbonylbenzaldehyde (373 mg) was added. The mixture was stirred at room temperature for 4 hours. Then, boranediethylamine complex (146 mg) was added to the solution. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, water was added to the solution. The solution was extracted with ethyl acetate, washed with distilled water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Kieselgel 60=30 g, hexane/ethyl acetate=1/1) to obtain the above-captioned compound ([5]-(57)-75') (841 mg) as a white solid.