Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](O)([CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH3:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]1(/[C:7](=[CH:9]/[CH:10]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH3:11])/[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1(/[C:7](=[CH:9]\[CH:10]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH3:11])/[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(CC(C)(O)c1ccccc1)c1ccncc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: C/C(=C/C(C)c1ccncc1)c1ccccc1
Product: C/C(=C\C(C)c1ccncc1)c1ccccc1
Temperature: 100 °C
Yield: 17 %
Yield: 4 %

Procedure:
To the said oily substance, that is , 8.83 g (36.6 mmol) of 2-phenyl-4-(4-pyridyl)-2-pentanol, 15 ml of 65% sulfuric acid was added and the mixture was heated for 2 hours at 100° C and after cooling, water was added. The mixture was alkalized with sodium carbonate and was extracted with ethyl acetate. Subsequently, layer a of ethyl acetate was dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure and purified by silica gel column chromatography to obtain 0.45 g of (E)-2-phenyl-4-(4-pyridyl)-2-pentene (yield: 17%) and 0.10 g of (Z)-2-phenyl-4-(4-pyridyl)-2-pentene (yield: 4%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][CH:3]=1.CC#N.C([O-])([O-])=O.[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:15]([CH3:20])[CH:14]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCC(CC)(c1ccc(Br)cc1)c1ccc(O)c(C)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CCC(CC)(c1ccc(Br)cc1)c1ccc(OCc2ccccc2)c(C)c1
Reaction time: 20 h
Yield: 82.5 %

Procedure:
To a solution of 4-[1-(4-bromophenyl)-1-ethylpropyl]-2-methylphenol (2.1 g, 6.3 mmol) in anhyd MeCN (30 mL) added anhyd K2CO3 (2.9 g, 21 mmol) and benzyl bromide (0.83 mL, 7.0 mmol). The reaction mixture was heated at reflux. After 20 h, the reaction mixture was cooled, diluted with Et2O (100 mL) and filtered. The filtrate was washed with H2O (2×50 mL) and brine, dried (anhyd Na2SO4), concentrated under reduced pressure and chromatographed (silica, EtOAC/Hex, 0:100 to 15:85) to give 5-[1-(4-bromophenyl)-1-ethylpropyl]-2-benzyloxytoluene (2.2 g, 82%), as a colorless liquid: 1H-NMR (CDCl3) δ 7.43-7.48 (2H, m), 7.31-7.42 (5H, m), 7.06 (2H, d, J=8.6), 6.94 (1H, dd, J=2.3, 8.3), 6.89 (1H, d, J=2.3), 6.79 (1H, d, J=8.3), 5.05 (2H, s), 4.23 (1H, s), 2.23 (3H, s), 2.05 (4H, q, J=7.3), 0.62 (6H, t, J=7.3).
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:13][NH2:14])(=O)[CH:9]([CH3:11])[OH:10].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=O)[C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([C:24]2[N:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[C:8]([CH:9]([CH3:11])[OH:10])=[N:13][N:14]=2)=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: CC(O)C(=O)NN
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(-n2c(-c3ccc([N+](=O)[O-])cc3)nnc2C(C)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3 ml of triethylamine were added at ambient temperature to a solution of 2 equivalents of -lactic acid hydrazide in 60 ml of toluene and then, 4.3 g of N-(4-methoxyphenyl)-4-nitrobenzene carboximidoyl chloride (Step A of Example 1) were added in two lots with stirring for 4 hours at ambient temperature. The mixture was then refluxed for 4 hours to obtain cyclization and the toluene was eliminated under reduced pressure. After washing with water, filtering and drying, 4.34 g of crude product were obtained which was purified by chromatography under pressure (eluent-chloroform-ethyl acetate-methanol: 47:50:3) to obtain 3 g of 5-[4-nitrophenyl]-4-(4-methoxyphenyl)-methyl-4H-1,2,4-triazol-3-methanol melting at 140° C.
Reaction SMILES: [F:1]C(F)(F)C1NN=C(O)C=1.[F:11][C:12]([F:22])(F)[C:13](=O)[CH2:14][C:15](OCC)=[O:16].[CH3:23][NH:24][NH2:25].OC1NNC(=O)C1.S(=O)(=O)(O)O>CCOCC.C(Cl)(Cl)Cl>[CH3:23][N:24]1[C:13]([CH:12]([F:22])[F:11])=[C:14]([F:1])[C:15]([OH:16])=[N:25]1
Reactant: Oc1cc(C(F)(F)F)[nH]n1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CNN
Agent: O=C1CC(O)NN1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cn1nc(O)c(F)c1C(F)F

Procedure:
Another method of making 5-trifluoromethyl-3-hydroxypyrazole involves reacting the ethyl 4,4,4-trifluoroacetoacetate directly with the methylhydrazine in ether to form a mixture of the intermediates 5-hydroxypyrazolidin-3-one and 3-hydroxypyrazolidin-5-one and dehydration of these intermediates by the addition of sulfuric acid in chloroform to form a mixture of the 3- and 5-hydoxypyrazoles. The desired isomer can be separated as described above. Alternatively, 2,4,4 trifluoroacetoacetate can be reacted in a like manner to give 1-methyl-3-hydroxy-4-fluoro-5-difluoromethylpyrazole.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[N:49]1([CH2:55][CH2:56][CH2:57][NH-:58])[CH2:53][CH2:52][CH2:51][C:50]1=[O:54].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:49]1([CH2:55][CH2:56][CH2:57][NH-:58])[CH2:53][CH2:52][CH2:51][C:50]1=[O:54]
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]CCCN1CCCC1=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 221 mg of Z-Phe-His-OH, 150 mg of H-Leu-Val-3-(2-pyrrolidinon-1-yl)-propyl amide, 77 mg of HOBt and 122 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B7). Rf (B7)=0.26, Rf (N12)=0.34.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8]1)(=O)=O.[ClH:17].Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27]([C:29]2[S:39][C:38]3[N:40]4[C:31](=[CH:32][N:33]=[C:34]4[CH:35]=[CH:36][CH:37]=3)[CH:30]=2)=[O:28])[CH2:21][CH2:20]1.[CH2:41]([N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])[CH3:42]>C(O)C>[O:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8][C@H:7]1[CH2:6][N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27]([C:29]2[S:39][C:38]3[N:40]4[C:31](=[CH:32][N:33]=[C:34]4[CH:35]=[CH:36][CH:37]=3)[CH:30]=2)=[O:28])[CH2:21][CH2:20]1.[ClH:17].[CH2:41]([N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])[CH3:42]
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: CS(=O)(=O)OC[C@@H]1COc2ccccc2O1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCC1CCN(C[C@@H]2COc3ccccc3O2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
A solution of the above crude (S)-2-methanesulfonyloxymethyl-1,4-benzodioxane, 1.05 g (2.71 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride, and 1.20 ml (8.64 mM) of triethylamine in 30 ml of ethanol was refluxed for 3 days. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate-methanol=4/1 to 3/1) to provide the title compound and triethylamine hydrochloride as a mixture. This mixture was diluted with ethyl acetate and washed serially with aqueous solution of sodium hydrogen carbonate, water, and saturated aqueous solution of NaCl. The organic layer was dried over MgSO4 and the solvent was distilled off to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2([NH:14][CH:15]=[O:16])[CH2:10][CH:9]([C:11]([OH:13])=O)[CH2:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl.[CH3:29][O:30][NH:31][CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2([NH:14][CH:15]=[O:16])[CH2:8][CH:9]([C:11]([N:31]([O:30][CH3:29])[CH3:32])=[O:13])[CH2:10]2)=[CH:17][CH:18]=1
Reactant: O=CNC1(Cc2ccc(Cl)cc2)CC(C(=O)O)C1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)C1CC(Cc2ccc(Cl)cc2)(NC=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
A solution of 3-(4-chlorobenzyl)-3-formamidocyclobutanecarboxylic acid (1.3 g, 4.87 mmol), DIPEA (2.17 mL, 12.6 mmol), O,N-dimethylhydroxylamine hydrochloride (617 mg, 6.33 mmol) in dichloromethane (20 mL) was treated with HATU (2.2 g, 5.84 mmol) and stirred at room temperature for 16 h. The solution was diluted with dichloromethane (20 mL), washed successively with 1 M HCl (2×), 5% aqueous NaHCO3 and saturated aqueous sodium chloride, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (gradient 0.5-1.0% methanol in dichloromethane) to give the subject compound (0.5 g, 33.3%). ESI MS found for C15H19ClN2O3 m/z [211.4 (M+1), 233.4 (M+Na+)].
Reaction SMILES: N#N.[CH:3](/[C:11]1[O:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=1)=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1>C(Cl)Cl.O>[Si:22]([O:17][CH2:16][C:14]1[N:15]=[C:11](/[CH:3]=[CH:4]/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:12][CH:13]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1coc(/C=C/c2ccccc2)n1
Agent: N#N
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (E)-(2-styryloxazol-4-yl)methanol (5.40 g, 26.8 mmol) in CH2Cl2 (56.0 mL) was treated at rt with tert-butylchlorodimethylsilane (8.52 g, 53.67 mmol) followed by imidazole (3.69 g, 53.67 mmol) and the resulting suspension was stirred for 1 h at rt. Water was added. The aq. layer was extracted with and the combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (gradient from hept to 9:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (9:1 hept-EA)=0.35. LC-MS-conditions 07: tR=1.08 min, [M+H]+=316.13.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:40]([CH3:42])[CH3:41])[C:10]([NH:12][C@@H:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:27]=1)[C:14]([N:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([OH:24])=[O:23])[NH:17]1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:43]([C:45]1[CH:53]=[C:52]2[C:48]([CH2:49][CH2:50][C@H:51]2O)=[CH:47][CH:46]=1)=[CH2:44].C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH:43]([C:45]1[CH:53]=[C:52]2[C:48]([CH2:49][CH2:50][C@H:51]2[O:23][C:22]([C@@H:18]2[CH2:19][CH2:20][CH2:21][N:16]([C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:40]([CH3:42])[CH3:41])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH:27]=3)[NH:17]2)=[O:24])=[CH:47][CH:46]=1)=[CH2:44]
Reactant: C=Cc1ccc2c(c1)[C@H](O)CC2
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)O)N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=Cc1ccc2c(c1)[C@H](OC(=O)[C@@H]1CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)N1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
A solution of (S)-1-{(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (658 mg, 1.086 mmol) 2f, prepared as described earlier, (R)-6-vinyl-indan-1-ol (208.7 mg, 1.303 mmol) and 4-dimethylaminopyridine (132.7 mg, 1.086 mmol) in anhydrous dichloromethane (20 mL) was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (340.6 mg, 1.738 mmol). After overnight stirring at room temperature the volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 to afford the title compound (762 mg, 95%) as a white solid. 1H NMR (300 MHz, CDCl3) δ0.13-0.22 (m, 6H), 0.86-0.99 (m, 15H), 1.47 (s, 10H), 1.72-1.91 (m, 3H), 1.99-2.20 (m, 2H), 2.43-2.60 (m, 2H), 2.66-2.78 (m, 1H), 2.81-3.01 (m, 3H), 3.04-3.17 (m, 1H), 3.91-4.01 (m, 1H), 4.33 (br d, J=12.7 Hz, 1H), 5.03-5.11 (m, 1H), 5.22-5.33 (m, 1H), 5.70-5.82 (m, 2H), 6.21 (dd, J=3.6, 6.9 Hz, 1H), 6.49 (d, J=8.5 Hz, 1H), 6.57-6.65 (m, 2H), 6.68-6.74 (m, 1H), 6.75-6.85 (m, 2H), 6.92 (app t, J=7.6 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.48 (s, 1H). LCMS (m/z) 771.4 [M+Na], Tr=6.05 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC(F)(F)F)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1.[CH:30]([C@@H:32]1[CH2:36][O:35][C:34]([CH3:38])([CH3:37])[N:33]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH2:31].[CH2:46](N(CC)CC)C.CN(C)C=O>CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.[Pd].O>[O:28]=[S:20]1(=[O:29])[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH2:23][N:17]([C:4]2[CH:3]=[C:2](/[CH:31]=[CH:30]/[C@@H:32]3[CH2:36][O:35][C:34]([CH3:38])([CH3:37])[N:33]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:46])[CH:10]=3)[N:5]=2)[CH2:18][CH2:19]1
Reactant: CCN(CC)CC
Reactant: C=C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(/C=C/[C@@H]3COC(C)(C)N3C(=O)OC(C)(C)C)c2c1
Temperature: 110 °C
Yield: 60 %

Procedure:
To a vial containing a mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (200 mg, 0.536 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1), tert-butyl (4R)-4-ethenyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (146 mg, 0.643 mmol), triethylamine (0.5 mL) and N,N-dimethylformamide (1 mL), which was evacuated and filled with argon, di(tri-tert-butylphosphine)palladium(0) (13.7 mg, 0.0268 mmol) was added. The vial was caped and heated at 110° C. for 30 minutes under microwave irradiation. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL×3). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 50% ethyl acetate in hexanes) to afford 180 mg of the desired product as a white solid (yield was 60%).
Reaction SMILES: [CH3:1][C@@H:2]([NH:13]C(OC(C)(C)C)=O)[C:3](ON1C(=O)CCC1=O)=[O:4].[NH2:21][C@H:22]([C:30]([NH:32][C@H:33]([C:41]([OH:43])=O)[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:40])[NH2:39])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.Cl.[CH:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48][C:47]=1[NH-:56].[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60]>>[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60].[CH:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48][C:47]=1[NH:56][C:41](=[O:43])[C@H:33]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:40])[NH2:39])[NH:32][C:30](=[O:31])[C@H:22]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH:21][C:3](=[O:4])[C@@H:2]([CH3:1])[NH2:13]
Reactant: [NH-]c1ccc2ccccc2c1
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc2ccccc2c1

Procedure:
This was similarly prepared, as described in Example 1. Boc-D-alanine N-hydroxysuccinimide ester was coupled to Phe-Arg-β-naphthylamide dihydrochloride; the resultant Boc-D-Ala-Phe-Arg 2-naphthylamide was deprotected with trifluoroacetic acid to afford a white solid: 1H NMR (400 MHz, D2O ) δ1.43 (d, J=8.8 Hz, 3H), 1.74 (m, 2H), 1.90 (m, 1H), 1.99 (m, 1H), 3.17 (dd, J=12.9; 8.2 Hz, 1H), 3.21 (dd, J=12.3; 8.2 Hz, 1H), 3.29 (t, J=7.1 Hz, 2H), 4.13 (q, J=8.8 Hz, 1H), 5.50 (t, J=8.0 Hz, 1H), 4.81 (HOD with proton hidden), 7.18 (m, 1H), 7.29 (m, 4H), 7.58 (d, J=10.6 Hz, 1H), 7.63 (m, 2H), and 8.01 (m, 4H).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>CN(C=O)C.C(OCC)C>[C:2]([O:6][C:7](=[O:17])[C@@H:8]([N:9]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: BrCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)N1CCCCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
To a solution of L-phenylalanine tert-butyl ester hydrochloride (3.05 g) in DMF (50 ml) were added potassium carbonate (5.38 g) and 1,5-dibromopentane (2.98 g), and the mixture was stirred at 80° C. for 2 hours, and then at room temperature for 22 hours. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluate: methylene chloride-methanol) to give 1.24 g of the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:41]=[CH:40][C:30]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:29][CH:28]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:5]1[CH:4]=[CH:3][C:2]([CH2:1][NH:8][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:27]3[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[CH:40][CH:41]=3)=[CH:13][N:12]=2)=[O:18])=[CH:7][CH:6]=1
Reactant: CC1(C)OB(c2ccc(OCCN3CCOCC3)cc2)OC1(C)C
Reactant: O=C(Cc1ccc(Br)cn1)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Temperature: 150 °C
Yield: 78.8 %

Procedure:
A 10 mL reaction tube with a septum closure and stir bar was charged with N-benzyl-2-(5-bromopyridin-2-yl)acetamide (123 mg, 0.403 mmol), 4-(2-(4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenoxy)ethyl)morpholine (171 mg, 0.513 mmol), and FibreCat 10071 (30 mg, 0.015 mmol). Ethanol (3 mL) was added, followed by aqueous potassium carbonate solution (0.60 mL, 1.0 M, 0.60 mmol). The tube was sealed and heated under microwave conditions at 150° C. for 10 minutes. The reaction was cooled and concentrated to remove the majority of the ethanol, and then taken up in 10 mL of ethyl acetate and washed successively with water and saturated sodium chloride solution. The organic layer was dried with MgSO4, filtered and concentrated to a white solid. This white solid was triturated with ethyl ether to give KX2-391 as a white solid (137 mg, 79%): mp 135-137° C.; 1H NMR (300 MHz, CDCl3) δ 8.70 (d, 1H, J=2.0 Hz), 7.81 (dd, 1H, J=2.4 Hz, J=8.0 Hz), 7.65 (br s, 1H), 7.49 (d, 2H, J=8.8 Hz), 7.37-7.20 (m, 6H), 7.01 (d, 2H, J=8.8 Hz), 4.49 (d, 2H, J=5.8 Hz), 4.16 (t, 2H, J=5.7 Hz, 3.82 (s, 2H), 3.78-3.72 (m, 4H), 2.84 (t, 2H, J=5.7 Hz), 2.62-2.58 (m, 4H); HPLC (Method B) 98.0% (AUC), tR=1.834 min.; APCI MS m/z 432 [M+H]+. 1 Polymer bound di(acetato)dicyclohexylphenylphosphinepalladium(II), manufactured by Johnson Matthey, Inc. and available from Aldrich (catalog #590231).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[N:9][NH:8][C:7]=12.Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[C:7]2=[N:8][N:9]([CH:12]([F:17])[F:16])[CH:10]=[C:6]2[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Clc1nccc2cn[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)n1cc2ccnc(Cl)c2n1
Temperature: 95 °C
Yield: 21.3 %

Procedure:
A mixture of 7-chloro-1H-pyrazolo[3,4-c]pyridine (4.99 g, 32.5 mmol), sodium chlorodifluoroacetate (14.86 g, 97 mmol), and cesium carbonate (40.2 g, 123 mmol) in DMF (81 ml) was heated at 95° C. for 4 h. The reaction was allowed to cool to rt and the solids were filtered. The filtrate was diluted with water and extracted with EtOAc. The organic extract was washed with water, satd NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (100 g), eluting with a gradient of 5% to 60% EtOAc in hexane, to provide a white solid (1.4117 g, 6.93 mmol, 21.34% yield). MS m/z=203.9 [M+H]+. Calculated for C7H4ClF2N3: 203.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][C:15]([C:20]#N)=[C:16]([C:18]#[N:19])[N:17]=1.[CH2:22]([OH:24])[CH3:23].Cl.[OH2:26]>>[C:18]([C:16]1[NH:17][C:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:5][C:4]=2[Cl:12])=[N:14][C:15]=1[C:20]([O:24][CH2:22][CH3:23])=[O:26])#[N:19]
Reactant: CCO
Reactant: O
Reactant: N#Cc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1C#N
Agent: Cl
Product: CCOC(=O)c1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1C#N

Procedure:
A mixture of 2-(2,6-dichloro-4-trifluoromethylphenyl)-4,5-dicyanoimidazole (3.3 g, 0.01 mol), ethanol (10 ml) and concentrated hydrochloric acid (10 ml) was stirred and heated at reflux for 24 hours. After cooling the mixture was poured into water (50 ml) and extracted with dichloromethane (2×50 ml). The combined extracts were washed with water (50 ml), dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by mplc of silica eluted with a mixture of ethyl acetate and petroleum spirit (b.p. 60°-80° C.) (1:1) to give ethyl 5-cyano-2-(2,6-dichloro-4-trifluoromethyl-phenyl)-imidazole-4-carboxylate (0.35 g) m.p. 180°-181° C., after recrystallisation from a mixture of toluene and petroleum spirit (b.p. 60°-80° C.) (1:2), as a white solid.