Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([C@H:13]3[CH2:18][CH2:17][CH2:16][CH2:15][N:14]3[C:19](=[O:28])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:38](Cl)(=[O:40])[CH3:39].O>C1COCC1>[O:21]([CH2:20][C:19]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]1[C:11]1[O:10][N:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:40])[CH3:39])[CH:7]=[CH:6][CH:5]=2)[N:12]=1)=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)c1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cccc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1 mmol (R)-1-{2-[3-(3-Amino-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-2-phenoxy ethanone were dissolved in THF. 2 eq. of DIPEA were added. The reaction was cooled to 0° C. 1 eq. of acetylchloride in THF was added dropwise and the reaction stirred for 30 min. The product was isolated by extraction from ethylactetade/water and subsequent purification via preparative HPLC.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[Br:12][C:13]1[CH:14]=[N:15][C:16]2[C:17]3[N:25]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])[C:24]([CH2:31][O:32][CH2:33][CH3:34])=[N:23][C:18]=3[CH:19]=[N:20][C:21]=2[CH:22]=1.[OH-].[NH4+:36].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:36][C:19]1[C:18]2[N:23]=[C:24]([CH2:31][O:32][CH2:33][CH3:34])[N:25]([CH2:26][C:27]([CH3:28])([OH:29])[CH3:30])[C:17]=2[C:16]2[N:15]=[CH:14][C:13]([Br:12])=[CH:22][C:21]=2[N:20]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
mCPBA (35.5 g of 77% purity, 158 mmol) was added to a stirred solution of 1-[7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (15 g, 0.040 mol) in chloroform (400 mL), and the reaction was stirred at room temperature for 2.5 hours. Concentrated ammonium hydroxide (200 mL) was added, and then p-toluenesulfonyl chloride (18.9 g, 98.9 mmol) was added over a period of five minutes. The reaction mixture was stirred at room temperature for 2.5 hours, and an analysis by LC/MS indicated the presence of starting material. Additional p-toluenesulfonyl chloride (11 g) was added, and the reaction mixture was stirred at room temperature for one hour. An analysis by LC/MS indicated the reaction was still incomplete. Additional ammonium hydroxide (100 mL) and p-toluenesulfonyl chloride (10 g) were added, and the mixture was stirred for 30 minutes at room temperature. The aqueous layer was separated and extracted with dichloromethane (2×300 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (41.4 g) was purified by chromatography using a Biotage Horizon™ High-Performance Flash Chromatography instrument (65I cartridge, eluting with ethyl acetate:methanol in a gradient from 97:3 to 85:15) to provide 5.96 g of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a yellow solid.
Reaction SMILES: F[C:2]1[C:9]([Si](C)(C)C)=[C:8]([I:14])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][SH:20])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:17][C:18]([C:19]1[S:20][C:2]2[CH:9]=[C:8]([I:14])[CH:7]=[CH:6][C:3]=2[CH:4]=1)=[O:21])[CH3:16]
Reactant: CCOC(=O)CS
Reactant: C[Si](C)(C)c1c(I)ccc(C=O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(I)cc2s1
Temperature: 75 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A solution of 2-fluoro-4-iodo-3-trimethylsilanyl-benzaldehyde (14.2 g, 44.1 mmol) (Tetrahedron Letters 1992, p 7499-7502) in DMF (50 mL) is treated with mercapto-acetic acid ethyl ester (5.80 mL, 52.9 mmol) and K2CO3 (12.2 g, 88.2 mmol). The resulting suspension is stirred at 75° C. for 60 min and quenched with water (300 mL). The mixture is extracted with EtOAc (3×50 mL,) and the organic layer is dried over Na2SO4, concentrated, and purified by silica gel column chromatography (5-20% EtOAc/Hex), to give the title compound as an oil (9.40 g, 64%).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=[O:32].O>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:31]([C:30]1[CH:33]=[CH:34][CH:35]=[C:28]([F:27])[CH:29]=1)[OH:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1cccc(F)c1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1cccc(F)c1)c1ccccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.44 M, 5.65 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (3.3 g, 12.5 mmol) in THF (40 mL) at −78° C. and the mixture solution was stirred at the same temperature for 30 minutes. To this mixture, a solution of 3-fluorobenzaldehyde (1.40 g, 11.3 mmol) in THF (5 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for one hour, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (2.26 g, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=2)=[CH:4][CH:3]=1.C([O:22][N:23]=O)(C)(C)C.Cl>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=2)=[N:23][OH:22])=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccnc(F)c1)c1ccc(Br)cc1
Reactant: CC(C)(C)ON=O
Agent: Cl
Solvent: CCO
Product: O=C(C(=NO)c1ccnc(F)c1)c1ccc(Br)cc1
Temperature: -5 °C

Procedure:
To a solution of the intermediate from Example 1 Step A (48 g, 0.163 mol) in ethanol (800 mL) at −10° C. was added dropwise t-butylnitrite (22.1 mL, 0.18 mol) over 10 minutes, followed by 2.5 N HCl in absolute ethanol (52 mL, 0.13 mol). The reaction temperature was maintained at −5° C. during these additions. After the addition was completed, the dry ice bath was removed and the reaction was allowed to warm to RT overnight. The ethanol was removed under reduced pressure and the residue was diluted with H2O. The aqueous phase was made basic with saturated NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was taken up in methanol/isopropanol and mixed with toluene. The methanol/isopropanol mixture was concentrated under reduced pressure and the title compound was recrystallized from hexane/toluene. 1H NMR (400 MHz, CDCl3): δ8.22 (m, 1H), 7.78 (m, 2H), 7.65 (m, 2H), 7.32 (m, 1H), 7.08(s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:22])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.BrC1C=CC(NC(=O)CC2C=CC=CC=2)=C(C=1)C([O-])=O.BrC1C=C2C(=CC=1)NC(=O)C(C1C=CC=CC=1)=C2O>>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:22])[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])=[C:7]2[OH:9]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)Cc1ccccc1Cl
Agent: O=C(Cc1ccccc1)Nc1ccc(Br)cc1C(=O)[O-]
Agent: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1ccccc1
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1ccccc1Cl

Procedure:
The title compound was prepared using methyl 5-bromo-2-(2-(2-chlorophenyl)acetamido)benzoate (Intermediate 2, step a) in place of 5-bromo-2-(2-phenylacetamido)benzoate using the procedure described for Intermediate 1, step b.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CS([C:21]1[N:26]=[C:25]([C:27]2[C:28]([CH3:34])=[N:29][C:30]([NH2:33])=[N:31][CH:32]=2)[CH:24]=[CH:23][N:22]=1)=O>C1COCC1>[CH3:34][C:28]1[C:27]([C:25]2[CH:24]=[CH:23][N:22]=[C:21]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[N:26]=2)=[CH:32][N:31]=[C:30]([NH2:33])[N:29]=1
Reactant: Cc1nc(N)ncc1-c1ccnc(S(C)=O)n1
Reactant: Nc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(N)ncc1-c1ccnc(Nc2ccncc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 1.8 %

Procedure:
To a solution of 4-aminopyridine (423 mg, 4.49 mmol) in THF (0.562 mL) cooled to −10° C. was added LHMDS (1M in THF) (1.123 mL, 1.123 mmol). The resulting suspension was warmed to rt and stirred for 15 minutes, after which time it was cooled back to −10° C. and 2-Methanesulfinyl-4′-methyl-[4,5′]bipyrimidinyl-2′-ylamine (20) (70 mg, 0.281 mmol) was then added. The reaction mixture was again warmed to rt and stirred for 1.5 hours. The reaction was quenched by slow addition of saturated ammonium chloride and the volatiles evaporated. The mixture was then diluted with DCM, the layers separated, and the organic layer washed with brine, dried with sodium sulfate, and concentrated. The crude residue was purified by flash column chromatography with a gradient of 2-20% MeOH in DCM. The product was further purified by reverse phase HPLC with a gradient of 10-90% MeCN in water over 15 minutes, to give the desired product as a white solid (1.39 mg, 0.44%). 1H NMR (400 MHz, MeOD) δ ppm 2.57 (s, 3 H) 7.13 (d, J=5.56 Hz, 1 H) 7.84 (d, J=6.57 Hz, 2 H) 8.30 (d, J=6.57 Hz, 2 H) 8.50 (s, 1 H) 8.57 (d, J=5.05 Hz, 1 H). HRMS (ES+) for C14 H13N7.H+ [MH+]: calcd, 280.1311. found, 280.1318. UV-LC: 100/100% UV purity at 214/254 nm; tR=2.93 minutes over 7.75 minutes.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9][OH:10])[CH:7]=1.[CH3:12][C:13]1[CH:14]=[C:15](B(O)O)[S:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:10][CH2:9][CH2:8][N:6]1[CH:7]=[C:2]([C:15]2[S:16][CH:17]=[C:13]([CH3:12])[CH:14]=2)[N:3]=[CH:4][C:5]1=[O:11]
Reactant: O=c1cnc(Br)cn1CCO
Reactant: Cc1csc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1csc(-c2cn(CCO)c(=O)cn2)c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
5-Bromo-1-(2-hydroxyethyl)pyrazin-2(1H)-one (199.6 mg, 911 μmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (66.6 mg, 91 μmol), and 4-methylthiophen-2-ylboronic acid (253.7 mg, 1787 μmol) were suspended in DME (5.0 mL) and sodium carbonate (1.2 mL, 2.0 M in water, 2.4 mmol) was added. The reaction flask was fit with a reflux condensor and placed in a preheated oil bath (85° C.) and stirred under argon for 1 hour The reaction was then cooled to room temperature and quenched with saturated sodium bicarbonate (5 mL) and allowed to stand at room temperature overnight. It was then extracted with CH2Cl2 and with 10:1 CH2Cl2/MeOH, and the organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and filtered through silica gel (30:1 CH2Cl2/MeOH) to afford the desired product (110.6 mg, 0.468 mmol, 51% yield). MS (ESI pos. ion) m/z (MH+): 237. Calc'd exact mass for C11H12N2O2S: 236. 1H NMR (400 MHz, CDCl3): 8.21 (s, 1H), 7.53 (s, 1H), 7.12 (s, 1H), 6.88 (s, 1H), 4.14 (t, J=5.0 Hz, 2H), 4.02 (q, J=5.0 Hz, 2H), 2.33 (s, 1H, J=5.0 Hz, 1H), 2.28 (s, 3H).
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:22][CH3:23])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH3:21])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CN(C=O)C>[C:2]1([S:8]([C:11]2[C:12]([S:22][CH3:23])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([CH3:21])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
10 ml of a 50% solution of NH3 in MeOH were added to a solution of 0.40 g (1.13 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 10 ml of DMF and stirred at RT for 2 hrs. The reaction solution was evaporated in a high vacuum and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/AcOEt 7:1) and crystallization from EtOH yielded 0.25 g (66%) of (3-benzenesulphonyl-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-yl)amine as colorless crystals, m.p. >230°.
Reaction SMILES: CCN(CC)CC.[Cl:8][CH2:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:22]/[O:23][CH3:24])/[C:19](Cl)=[O:20])[N:17]=1)=[O:11].[NH2:25][CH:26]1[C:55](=[O:56])[N:28]2[C:29]([C:39]([O:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[C:30]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:31]([CH3:33])[S:32][C@H:27]12>C(Cl)Cl>[Cl:8][CH2:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:22]/[O:23][CH3:24])/[C:19]([NH:25][CH:26]2[C:55](=[O:56])[N:28]3[C:29]([C:39]([O:41][CH:42]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)=[O:40])=[C:30]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:31]([CH3:33])[S:32][C@H:27]23)=[O:20])[N:17]=1)=[O:11]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2S[C@H]1C
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(C)=O)[C@H](C)S[C@H]12)c1csc(NC(=O)CCl)n1
Reaction time: 0.75 h
Yield: 59.6 %

Procedure:
A 0.5 ml portion of Et3N, along with 1.13 g of 2-(2-chloroacetylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetyl chloride, was added to a solution of 1.6 g of diphenylmethyl 7-amino-2β-methyl-3-acetoxymethylceph-3-em-4-carboxylate in 50 ml of CH2Cl2 at -40° C., and the mixture was stirred at from -20° C. to -15° C. for 45 minutes. The reaction solution was washed with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl solutions, and dried over MgSO4, followed by distilling off the CH2Cl2 under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.AcOEt (5:1) were collected to distill off the solvent, thus yielding 1.5 g (61%) of diphenylmethyl 7-[2-(2-chloroacetylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-2β-methyl-3-acetoxymethylceph-3-em-4-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:5]2[N:6]=[CH:7][C:8]3[NH:9]C(=O)[NH:11][C:12]=3[N:4]2[N:3]=1.Cl>>[CH3:1][C:2]1[CH:14]=[C:5]2[N:6]=[CH:7][C:8]([NH2:9])=[C:12]([NH2:11])[N:4]2[N:3]=1
Reactant: Cc1cc2ncc3[nH]c(=O)[nH]c3n2n1
Agent: Cl
Product: Cc1cc2ncc(N)c(N)n2n1
Temperature: 100 °C

Procedure:
A 40 mL scintillation vial containing Compound (10-2) (0.72 g, 3.8 mmol) and 10% aqueous HCl (25 mL) was heated at 100° C. for 3 hours. The mixture was allowed to cool, the solvent was removed in vacuo and water (˜40 mL) was added. The resulting solid (starting material) was filtered to recover Compound (10-2). The filtrate was then concentrated and dried to furnish Compound (10-3) as a yellowish solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:19](=[O:21])[CH3:20].[Li]CCCC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:19](=[O:21])[CH3:20])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCc2ccccc2)cn1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2ccccc2)cn1

Procedure:
A mixture of 5-benzyloxy-2-bromo-pyridine (1.0 g), N-methoxy-N-methyl-acetamide (780 mg) and THF (20 mL) under argon at −60° C. was added n-BuLi (2.6 M in toluene, 2.9 mL). After 1 hour the cooling bath was removed. After reaching room temperature the mixture was quenched by addition of saturated NH4Cl-solution. The mixture was distributed between EA and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (silica gel, heptane to EA/heptane 3:7) to provide the subtitle compound. MS ESI+: m/z=228 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:18][CH3:19].O.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: COc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Oc2ccc(N)cc2)ccc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-methyl-2-(methyloxy)-4-[(4-nitrophenyl)oxy]benzene (Intermediate 19, 1.43 g) in tetrahydrofuran (65 mL)/water (32.5 mL) iron (1.540 g, 27.6 mmol) and then ammonium chloride (1.475 g, 27.6 mmol) were added and the reaction mixture was stirred for 5 hours at room temperature. The catalyst was filtered off and the solution was diluted with a saturated solution of Na2CO3 (10 mL) and extracted with ethyl acetate (2 times 60 mL). Combined organic layers were dried over sodium sulphate, filtered and evaporated to the title compound (1.25 g) as a brown/red solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:21]Br>>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:21][N:10]([C:11]1[CH:16]=[N:15][CH:14]=[N:13][CH:12]=1)[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)nc1
Reactant: Fc1ccc(CBr)cc1F
Product: O=[N+]([O-])c1ccc(N(Cc2ccc(F)c(F)c2)c2cncnc2)nc1

Procedure:
Starting compounds: 5-[N-(5-nitro-2-pyridyl)amino]pyrimidine and 3,4-difluorobenzyl bromide
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[OH:13][C@H:14]([CH2:21][CH2:22][CH3:23])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH2:24](Br)[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:27]1(/[CH:26]=[CH:25]/[CH2:24][C@H:15]([C@H:14]([OH:13])[CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCC[C@@H](O)CC(=O)OCC
Reactant: BrCC=Cc1ccccc1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC[C@@H](O)[C@@H](C/C=C/c1ccccc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a solution of diisopropylamine (2.28 g, 20.63 mmol) in THF (20 mL) cooled to 0° C. is added n-butyllithium (20.63 mmol, 2.5 M in hexanes) and the resulting solution is stirred at 0° C. or 0.5 h. The reaction mixture is cooled to −50° C. followed by slow addition of ethyl (3R)-3-hydroxyhexanoate (1.5 g, 9.38 mmol). After 0.5 h a solution of cinnamyl bromide (2.67 g, 14.06 mmol) in HMPA (2 mL) is added and the reaction mixture is allowed to warm to −20° C. and stirred for 16 h. The reaction mixture is quenched by addition 3 mL of saturated aqueous ammonium chloride solution, is poured into 20 mL of 1 N hydrochloric acid, and is extracted with two 50-mL portions of EtOAc. The combined organic layers are dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 25% EtOAc-hexanes) to afford ethyl (2R,3R)-2-[(2E)-3-phenyl-2-propen-1-yl]-3-hydroxyhexanoate as a yellow oil (1.82 g, 70% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:27]3[CH:28]=[CH:29][C:24]([C:21](=[O:23])[CH3:22])=[CH:25][CH:26]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(C(C)=O)cc3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 4-acetyl-phenylboronic acid (53 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound. Yield: 26 mg, 23%; LC/MS tr 1.45 min; MS(ES+) m/z 378 (M+H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([NH2:19])=[O:18].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([NH2:19])=[O:18])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCC[C@H]1C(N)=O
Reaction time: 17 h
Yield: 33.8 %

Procedure:
A mixture of 6.28 g (0.0332 m) of N-tert.-butoxycarbonyl-β-alanine, 5.0 g (0.0332 m) of L-proline amide hydrochloride, 8.96 g (0.0664 m) of 1-hydroxybenzotriazole, 12 ml of N-methylmorpholine, 75 ml of tetrahydrofuran, 40 ml of dimethylformamide and 6.84 g (0.0332 m) of dicyclohexylcarbodiimide was stirred at 25° for 17 hours. The solvents were evaporated in vacuo and the residue dissolved in ethyl acetate and water. The separated organic layer was washed with small volumes of dilute hydrochloric acid, brine, 5% bicarbonate and brine. The dried extract was concentrated to give 3.2 g of syrupy N-tert.-butoxycarbonyl-β-alanyl-L-proline amide. The methane chemical ionization mass spectrum was in agreement with the dipeptide structure.