Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH2:13]O)[CH:10]=[CH:11][CH:12]=1.P(Br)(Br)([Br:17])=O.C([O-])(O)=O.[Na+]>C1COCC1>[Br:17][CH2:13][C:9]1[CH:8]=[C:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=P(Br)(Br)Br
Reactant: OCc1cccc(-c2ncccn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCc1cccc(-c2ncccn2)c1
Temperature: 60 °C
Yield: 80.5 %

Procedure:
To a stirred solution of (3-(pyrimidin-2-yl)phenyl)methanol [892502-12-4] (2.48 g, 12.92 mmol) in THF (25 mL), POBr3 (4.81 g, 16.79 mmol) was added and the mixture was heated at 60° C. for 90 min. The mixture was cooled to rt, poured into saturated aqueous NaHCO3 solution and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash-column chromatography over silicagel (eluent: gradient 5%-40% ethyl acetate/heptane) to yield the title compound (2.59 g, 80%). [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.92 (d, J=5.0 Hz, 2H), 8.48 (t, J=1.6 Hz, 1H), 8.32 (dt, J=7.7, 1.4 Hz, 1H), 7.58-7.62 (m, 1H), 7.49-7.54 (m, 1H), 7.47 (t, J=4.8 Hz, 1H), 4.82 (s, 2H); LCMS RtA=1.04, [M+H]+=249.2/251.2].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]([C:18]([OH:20])=[O:19])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=2)=[C:5]([F:21])[CH:4]=1)#[CH:2].FC(F)(F)C(O[C:27]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37])=O.N1C=CC=CC=1>CN(C=O)C>[F:33][C:32]1[C:27]([O:19][C:18]([C:11]2[C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[CH:2])=[CH:4][C:5]=3[F:21])=[CH:15][C:14](=[O:16])[N:13]([CH3:17])[CH:12]=2)=[O:20])=[C:28]([F:37])[C:29]([F:36])=[C:30]([F:35])[C:31]=1[F:34]
Reactant: C#Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)O)c(F)c1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C#Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (0.70 g, 2.44 mmol) was reacted with pentafluorophenyl trifluoroacetate (1.30 mL, 7.36 mmol) in the presence of pyridine (0.60 mL) in DMF. The solution was allowed to stir at room temperature for 15 hours, to afford the 4-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid pentafluorophenyl ester which was reacted directly with 2-aminoethanol (0.74 mL, 12.20 mmol) that is stirred at room temperature for 4 hours. The resulting precipitate was filtered and purified by column chromatography on silica gel (5% MeOH/CH2Cl2 as eluant) to give 4-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (2-hydroxy-ethyl)-amide as a yellow solid (0.24 g, 30%). 1H NMR [(CD3)2SO, 400 MHz] δ 10.27 (s, 1H), 8.41 (t, 1H), 8.13 (s, 1 H), 7.48 (dd, J=10.2, 1.8 Hz, 1H), 7.40 (dd, J=8.6 Hz, 1H), 7.31 (dd, J=8.5 Hz, 1H), 5.73 (s, 1H), 4.76 (t, 1 H, OH), 4.24 (s, 1H), 3.51 (t, J=4.9 Hz, 2H), 3.35 (s, 3H), 3.25 (t, J=8.3 Hz, 2H). (APCI+) calcd for C17H16FN3O3 329.33 (M+1), found 330.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20]4[N:24]=[C:23]([CH:25]5[CH2:28][C:27]([F:30])([F:29])[CH2:26]5)[O:22][N:21]=4)[CH:17]=[CH:16][C:15]=3[CH3:31])=[O:12])=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][NH:43][CH:44]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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:29][C:27]1([F:30])[CH2:28][CH:25]([C:23]2[O:22][N:21]=[C:20]([C:18]3[CH:17]=[CH:16][C:15]([CH3:31])=[C:14]([NH:13][C:11]([C:8]4[N:6]5[CH:7]=[C:2]([C:40]6[CH:41]=[N:42][NH:43][CH:44]=6)[CH:3]=[CH:4][C:5]5=[N:10][CH:9]=4)=[O:12])[CH:19]=3)[N:24]=2)[CH2:26]1
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(Br)cn12
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(-c3cn[nH]c3)cn12
Temperature: 130 °C

Procedure:
6-Bromo-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (42a) (98.0 mg, 0.2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (60.0 mg, 0.3 mmol), K3PO4(42.0 mg, 0.2 mmol) and Pd(PPh3)4(46.2 mg, 0.04 mmol) were added to a flask equipped with a stir bar. The flask was evacuated and backfilled with nitrogen several times. 1,4-Dioxane (1 mL) and the reaction was heated at 130° C. for 20 minutes in a microwave reactor. The reaction was filtered and purified by preparative HPLC to afford N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (F40). MS m/z 476.1 (M+1)+.
Reaction SMILES: [NH2:1][OH:2].[CH3:3]/[C:4](/[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[F:19])[N:10]=[C:9]([CH3:20])[C:8]=1[C:21]#[N:22])=[CH:5]/[CH3:6].CC1SC=C(C)C=1C1N(C2C=CC(O)=CC=2F)N=C(C)C=1C#N>CO>[CH3:3]/[C:4](/[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[F:19])[N:10]=[C:9]([CH3:20])[C:8]=1[C:21](=[NH:22])[NH:1][OH:2])=[CH:5]/[CH3:6]
Reactant: NO
Reactant: C/C=C(/C)c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Agent: Cc1csc(C)c1-c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Solvent: CO
Product: C/C=C(/C)c1c(C(=N)NO)c(C)nn1-c1ccc(O)cc1F
Temperature: 150 °C
Yield: 47 %

Procedure:
Hydroxylamine (50 wt % solution in water, 0.5 mL, 8.11 mmol) was added to (Z)-5-(but-2-en-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (22 mg, 0.08 mmol) dissolved in MeOH (1.0 mL) or Hydroxylamine (50 wt % solution in water, 0.24 mL, 3.97 mmol) was added to 5-(2,4-dimethylthiophen-3-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (13 mg, 0.04 mmol) dissolved in MeOH (0.8 mL). The reaction was heated at 150° C. in the microwave for 15 min. Purification using preparative HPLC gave 5-((Z)-but-2-en-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-N-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide (E51) (11.44 mg, 46%), ES/MS m/z: 305.08 (M+H), 303.13 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.22 (m, 1H), 6.76-6.71 (m, 2H), 5.65 (m, 1H), 2.30 (s, 3H), 1.83 (s, 3H) and 1.39 (d, 3H, J=6.7 Hz) or 5-(2,4-dimethylthiophen-3-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide (E52) (4.31 mg, 30%) ES/MS m/z: 361.05 (M+H), 359.17 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.14 (t, 1H, J=8.8 Hz), 6.83 (q, 1H, J=1.0 Hz), 6.66 (m, 1H), 6.61 (dd, 1H, J=11.9, 2.7 Hz), 2.38 (s, 3H), 2.16 (s, 3H) and 1.94 (d, 3H, J=1.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[C:4](I)[C:5]([O:21][CH2:22][CH3:23])=[C:6]([CH:8]([N:10]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:19])=[C:13]3[C:12]([CH3:20])=[N:11]2)[CH3:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([O:49][CH3:50])(=[O:48])[CH:46]=[CH2:47].C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:19][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:10]([CH:8]([C:6]3[C:5]([O:21][CH2:22][CH3:23])=[C:4](/[CH:47]=[CH:46]/[C:45]([O:49][CH3:50])=[O:48])[C:3]([CH3:25])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:11]=[C:12]([CH3:20])[C:13]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1I
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1/C=C/C(=O)OC
Temperature: 100 °C
Yield: 71.6 %

Procedure:
A suspension of 1-[1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (peak 1 single isomer from step 2) (0.61 g, 1.3 mmol) in acetonitrile (7.4 mL) in a sealed tube was degassed with nitrogen and treated with triphenylphosphine (0.048 g, 0.18 mmol), methyl acrylate (0.41 mL, 4.5 mmol), and palladium acetate (0.029 g, 0.13 mmol) followed by triethylamine (0.54 mL, 3.9 mmol) and heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature, filtered, and the solids washed with acetonitrile. The filtrate was concentrated to a residue. The crude material was purified by flash column chromatography using ethyl acetate (containing 3% methanol) in hexanes (0%-100%) to give the desired product (0.40 g, 72%). LCMS for C21H25ClN5O3 (M+H)+: m/z=430.2; Found: 430.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C([Li])CCC.Cl>O1CCCC1.CCCCCC>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:17]([OH:22])[OH:18]
Reactant: Brc1ccccc1CCOC1CCCCO1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccccc1CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
To a solution of 2-[2-(2-bromophenyl)ethoxy]tetrahydropyran (3.58 g, 12.5 mmol) and triisopropyl borate (3.70 ml, 16.1 mmol) in tetrahydrofuran (10.0 ml) was added a solution (10.0 ml) of 1.6M n-butyllithium in hexane at −78° C., and the mixture was stirred for 2 hr while gradually raising the temperature to 0° C. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1-2:1) to give 2-[2-(tetrahydropyran-2-yloxy)ethyl]phenylboronic acid (1.77 g, yield 56.6%).
Reaction SMILES: [Br:1][C:2]1[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=[C:15]([Br:26])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([CH3:14])[CH3:13])[CH:6]=1.C1N2CN3CN(C2)CN1C3.Cl.[C:38](O)(C(F)(F)F)=[O:39]>>[Br:1][C:2]1[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=[C:15]([Br:26])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:12]([CH3:13])[CH3:14])[C:8]([OH:11])=[C:9]([CH:10]=1)[CH:38]=[O:39]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)c1cc(Oc2c(Br)cc([N+](=O)[O-])c(C(F)(F)F)c2Br)ccc1O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CC(C)c1cc(Oc2c(Br)cc([N+](=O)[O-])c(C(F)(F)F)c2Br)cc(C=O)c1O
Temperature: 98 °C
Reaction time: 5 h
Yield: 57 %

Procedure:
4-(2,6-dibromo-4-nitro-3-trifluoromethylphenoxy)-2-isopropylphenol of Part 11C (220 mg, 0.44 mmol) was dissolved in TFA (3 mL) and hexamethylenetetramine (154 mg, 1.1 mmol) was added to the reaction. The reaction mixture was heated at 98° C. for 12 hours, cooled down and 1N HCl (4 mL) was added. The reaction mixture was stirred for 5 hours at room temperature, extracted with EtOAc, washed with H2O, NaHCO3 and brine. The organic layer was dried by MgSO4 and concentrated. The residue was purified on column (silica gel, gradient elution with n-heptane/EtOAc) to give 130 mg (57%) of 5-(2,6-dibromo-4-nitro-3-trifluoromethylphenoxy)-2-hydroxy-3-isopropylbenzaldehyde.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].I[C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH3:34])=[CH:29][N:28]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:27]3[CH:32]=[C:31]([CH3:33])[C:30]([CH3:34])=[CH:29][N:28]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cnc(I)cc1C
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cnc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 86 mg (0.21 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 125 mg (0.54 mmol) of 2-iodo-4,5-dimethyl-pyridine in 1 mL THF with 0.28 mL 2M isopropylmagnesium chloride using. Yield: 21 mg of a white powder. LC-MSD, m/z for C23H18BrN3O2 [M+H]+=448.0, 450.0; HPLC retention time: 2.2 min.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]3N=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH:22]=[C:21]([C:32]([F:35])([F:34])[F:33])[N:20]=3)[CH:18]=2)=[N:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.[C:36](O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[CH:22]=[C:21]([C:32]([F:34])([F:33])[F:35])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:12]4[S:13][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][N:11]=4)[N:15]=[CH:16]3)[CH:36]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)s1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cnc(-c2cn(-c3cc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 14 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-2-{1-[4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.088 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (THF/hexane) to yielded the title compound as a light brown solid (0.03 g, 14%). MS (ISN) 485.2 [(M−H)−]; mp 263° C.
Reaction SMILES: [O:1]=[C:2]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.[F:24][C:25]1[CH:26]=[C:27]([NH2:47])[CH:28]=[CH:29][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]2[CH:38]=[C:39]([C:41]3[N:42]([CH3:46])[CH:43]=[CH:44][N:45]=3)[S:40][C:33]=12.C(Cl)CCl.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:24][C:25]1[CH:26]=[C:27]([NH:47][C:4](=[O:6])[CH2:3][C:2]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:1])[CH:28]=[CH:29][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]2[CH:38]=[C:39]([C:41]3[N:42]([CH3:46])[CH:43]=[CH:44][N:45]=3)[S:40][C:33]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(O)CC(=O)Nc1cccnc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4cccnc4)cc3F)c2s1
Reaction time: 0.08 h

Procedure:
To a solution of the acid 39 (58 mg, 0.32 mmol) and HOBt (47 mg, 0.35 mmol) in DMF (5 mL), was added amine 9 (108 mg, 0.32 mmol). After stirring for 5 min, EDC (75 mg, 0.39 mmol) was added and the reaction mixture was stirred overnight at room temperature then poured into dilute NaHCO3 solution and extracted with EtOAc. The extract was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Aquasil C-18, gradient: MeOH in water 60% to 95%) to afford the title compound 40 as a white solid. (20 mg, 12%) 1H NMR (DMSO-d6) δ (ppm): 10.65 (s, 1H), 10.50 (s, 1H), 8.73 (d, 1H), 8.50 (d, 1H), 8.26 (dd, 1H), 8.05 (m, 1H), 7.88 (s, 1H), 7.87 (dd, 1H), 7.48 (t, 1H), 7.41 (m, 2H), 7.35 (m, 1H), 6.69 (d, 1H), 3.99 (s, 3H), 3.56 (s, 2H). MS (m/z): 503.1 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([OH:29])=[CH:21][CH:20]=1.O>CN(C=O)C>[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([O:29][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(O)c2ccccc12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc([N+](=O)[O-])cc2)c2ccccc12
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-methoxy-1-naphthol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100 mL), extracted with EtOAc (2×50 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-methoxynaphthalen-1-yloxy)-1-nitrobenzene. The crude product was used for further transformation .
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:28])[CH2:23][CH2:24][C:25](O)=[O:26])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:29]([NH:33][C:25](=[O:26])[CH2:24][CH2:23][C:22]([N:19]1[CH2:18][CH2:17][C:16](=[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1)=[O:28])([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C(O)CCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)CCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 8 h

Procedure:
100 mg (0.268 mmol) of 4-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-4-oxobutanoic acid, 23.5 mg (0.321 mmol) of t-butylamine, 3 mg (0.03 mmol) of 4-dimethylaminopyridine and 77.1 mg (0.402 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in 1 ml of dichloromethane. 35.2 mg (0.348 mmol) of triethylamine was added to the obtained solution, and they were stirred overnight. The obtained product was purified by the silica gel chromatography (hexane:ethyl acetate=2:1 to 4:6) to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:25])[CH2:15][O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1>>[OH:25][CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:34]2[CH:35]=[CH:36][C:37]([C:40]3([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH2:42][CH2:41]3)=[CH:38][CH:39]=2)=[CH:3][CH:4]=1)[CH2:15][O:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCCc1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1C(O)COCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-phenethyloxy-ethanol and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropane carbonyl}-methanesulfonamide.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:36][C@@H:35]([CH2:37][N:38]([CH:55]([CH3:57])[CH3:56])[C:39](=[O:54])[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:41]=2)[C@H:34]([CH2:58][N:59]([C:63]([O:65][CH2:66][C:67]([C:70]([OH:72])=O)([CH3:69])[CH3:68])=[O:64])[CH:60]2[CH2:62][CH2:61]2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN.C(N(CC)CC)C>CC#N>[C:25]([O:29][C:30]([N:32]1[CH2:36][C@@H:35]([CH2:37][N:38]([CH:55]([CH3:57])[CH3:56])[C:39](=[O:54])[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:41]=2)[C@H:34]([CH2:58][N:59]([CH:60]2[CH2:61][CH2:62]2)[C:63]([O:65][CH2:66][C:67]([CH3:69])([C:70](=[O:72])[NH:2][CH3:1])[CH3:68])=[O:64])[CH2:33]1)=[O:31])([CH3:27])([CH3:28])[CH3:26]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)OCC(C)(C)C(=O)O)C2CC2)C(C)C)ccc1OC
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=O)C(C)(C)COC(=O)N(C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C)C1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
HBTU (161 mg, 0.43 mmol) is added to a solution of (3S*,4R*)-3-{[(2-carboxy-2-methyl-propoxycarbonyl)-cyclopropyl-amino]-methyl}-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (240 mg, 0.35 mmol) in CH3CN (10 mL) at 0° C. After 5 min a solution of methylamine (44 μL, 0.35 mmol, 8M in EtOH) and triethylamine (493 μL, 3.54 mmol) in CH3CN (10 mL) is added at 0° C. and the reaction solution is stirred at RT for 5 h. Another portion of methylamine (0.22 mL, 1.75 mmol) is added and stirring is continued for another 16 h. Then, triethylamine (247 μL, 1.77 mmol) and HBTU (268 mg, 1.02 mmol) are added and the reaction mixture is stirred at 50° C. for another 16 h. The solvent is evaporated and the crude product purified by HPLC (Interchrom C18 ODB 10 μm, 28×250 mm, eluent: CH3CN/H2O 5%/2.5 min, CH3CN/H2O 5-100%/23 min, 100% CH3CN/4.5 min, flow 40 mL/min) to give the title compound. MS (LC-MS): 691.4 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.38 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][C@@H:10]1[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl.C(OCC)(=O)C>N1C=CC=CC=1>[C:24]([O:15][CH:12]1[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@@H:10]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(O)CC[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OC1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
(1R*,2S*)-N1,N2-Bis(tert-butoxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine (Stereoisomer B) (1.74 g) was dissolved in pyridine (15 ml), and acetic anhydride (5 ml) was added to stir the mixture at room temperature for 4 days. 1N Hydrochloric acid was added to the reaction mixture, extraction was conducted with ethyl acetate, and the resultant organic layer was successively washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:3) to obtain the title compound (1.96 g) as a colorless oil.