Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][Mg])[CH3:2].C([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13]Br)C.BrC1C=CC=CC=1>>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][C:13]1[CH:12]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCCCC(CC)C[Mg]
Reactant: CCCCC(CC)CBr
Solvent: Brc1ccccc1
Product: CCCCC(CC)Cc1ccccc1

Procedure:
19.3 g of 2-ethylhexyl-magnesium prepared from 2-ethylhexyl bromide, are reacted with 15.7 g of bromobenzene in the presence of a catalyst based on bis[bis(diphenylphosphionethane]palladium(0). 19 g of 2-ethylhexyl-benzene thus obtained were dissolved in 60 ml of an equal volume mixture of trifluoroacetic acid and anhydride maintained at 0° C. under stirring, to which 3.5 g of sodium iodide and 4.2 g of iodic anhydride are added. The solvent is removed with a rotary evaporator. Then the residual product is dissolved in 30 ml of acetonitrile and poured in 200 ml of water containing 10 g of sodium acetate and 2 g of sodium sulfite and 14 g of potassium bis-fluorosulfonylimide. The organic phase is extracted with dichloromethane and washed with water. The solvent is eliminated by means of a rotary evaporator to leave an oily liquid of bis-fluorosulfonylimide of bis-[4-(2-ethylhexyl)]phenyl-iodonium. This ionic compound presents characteristics of solubility in hydrocarbons and silicon oils comparable to those of compounds with longer alkyl chains such as bis(dodecylbenzene) iodonium associated to the anion PF6-. It has a lipophilic character more noticeable than that of the compound of Example 3. It is particularly advantageous to catalyze the cross-linking of antiadhesive silicon coating and the polymerization of the monomers of low polarity such as cyclohexanedimethanoldivinylether, 2-ethylhexylglycidylether or 2-ethylhexylvinylether.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9](=[O:13])/[CH:10]=[CH:11]/[CH3:12].[Cl-].[NH4+]>O1CCCC1.CCOCC>[C:1]1([CH:9]([OH:13])[CH:10]=[CH:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: C/C=C/C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC=CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.9 %

Procedure:
To a cooled (0-55° C.) 927 mL of 1 M solution of phenyl magnesium bromide in tetrahydofuran was added dropwise a solution of crotonaldehyde (65.0 g) in 130 mL of anhydrous ether over a period of 2 hours and 45 minutes. The reaction was stirred for an additional 45 minutes and then warmed to room temperature. After four more hours of stirring, saturated ammonium chloride aqueous solution (750 mL) was added to the reaction. The mixture was extracted with 750 mL of ether twice. The combined extract was dried over anhydrous potassium carbonate and filtered. The solvent was evaporated to give 135.88 g (99.9%) of the desired 1-phenyl-2-buten-1-ol as an oil which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[O:8])[CH3:2].Br[C:15]1[CH:24]=[CH:23][C:18]2[O:19][CH2:20][CH2:21][O:22][C:17]=2[CH:16]=1.C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[O:19]1[C:18]2[CH:23]=[CH:24][C:15]([CH:7]([C:6]3[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[OH:8])=[CH:16][C:17]=2[O:22][CH2:21][CH2:20]1
Reactant: Brc1ccc2c(c1)OCCO2
Reactant: CCOc1cc(C=O)ccc1OC
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: CCOc1cc(C(O)c2ccc3c(c2)OCCO3)ccc1OC
Yield: 56.2 %

Procedure:
3-ethoxy-4-methoxybenzaldehyde (0.92 g, 5.12 mmol), 6-bromo-2,3-dihydro-benzo[1,4]dioxine (1.21 g, 5.63 mmol), and n-butyl lithium (2.25 ml, 5.63 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3-ethoxy-4-methoxy-phenyl)-methanol as a yellow solid (0.91 g, 56%): 1HNMR (CDCl3) 6.92-6.80 (m, 6H, Ar), 5.68 (d, J=3 Hz, 1H, CHOH), 4.23 (s, 4H, 2CH2), 4.07 (q, J=6.90, 14 Hz, 2H, CH2CH3), 3.85 (s, 3H, OCH3), 2.13 (d, J=2 Hz, 1H, OH), 1.44 (t, J=7 Hz, 3H, CH2CH3). The product was carried over to the next step.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:38][CH:35]1[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][NH:29][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:33][CH2:34]1
Reactant: NCCN1CCC(O)CC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCN3CCC(O)CC3)ccc21
Yield: 38.2 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)ethyl]-amide (50.0 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 1-(2-amino-ethyl)-piperidin-4-ol (72.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 421. 1H NMR (DMSO-d6, 400 MHz): δ 8.00 (1H, m), 7.80-7.77 (1H, m), 7.65 (1H, m), 7.41-7.39 (1H, m), 7.26-7.24 (1H, m), 3.90 (1H, m), 3.75-3.72 (2H, t), 3.69 (3H, s), 3.37 (1H, m), 3.18 (2H, m), 2.07-2.02 (2H, m), 1.83-1.78 (2H, m), 1.32-1.29 (2H, m), 0.90-0.87 (2H, m), 2 —NH and —OH proton signals were not observed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1O.[Cl:10][CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:14]([C:12](=[O:13])[CH2:11][Cl:10])[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1
Reactant: Cc1ccc(NC(=O)CCl)cc1
Reactant: Oc1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(N(C(=O)CCl)c2c(Cl)cccc2Cl)cc1

Procedure:
Same procedure as example 6a starting from 2,6-dichlorophenol and 2-chloro-N-(4-methylphenyl)acetamide. At the end of the acetylation reaction the mixture was diluted with a small amount of toluene (0.2 part) to prevent solidification.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][S:12][C:13]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][NH:22][C:21](=[O:25])[CH:20]=2)[CH:16]=[CH:15][N:14]=1.CS(O[C@H:31]([C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([F:48])[CH:42]=1)[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])(=O)=O>C1COCC1>[Si:34]([O:33][CH2:32][C@@H:31]([N:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([S:12][CH3:11])[N:18]=2)=[CH:20][C:21]1=[O:25])[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([F:48])[CH:42]=1)([C:37]([CH3:39])([CH3:40])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccc(Cl)c(F)c1
Reactant: CSc1nccc(-c2cc[nH]c(=O)c2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1nccc(-c2ccn([C@H](CO[Si](C)(C)C(C)(C)C)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
1.0M KHMDS (5.09 mL, 5.09 mmol) as a solution in THF was added to a cold (0° C.) suspension of 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (0.93 g, 4.24 mmol) in THF (20 mL) The reaction mixture was stirred at 0° C. for 10 minutes before (R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (2.44 g, 6.36 mmol) was added as a solution in THF (5 mL) The reaction was heated to reflux for 30 hours and then cooled to room temperature and concentrated. The residue was taken up in ethyl acetate (200 mL) and washed with water. The organics were dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (4:1) to give (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (1.35 g, 63%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J=5.0 Hz, 1H), 7.43 (m, 2H), 7.34 (d, J=5.0 Hz, 1H), 7.32-7.28 (m, 2H), 7.16 (m, 1H), 6.85 (m, 1H), 6.24 (m, 1H), 4.35 (m, 1H), 4.23 (m, 1H), 2.65 (s, 3H), 0.88 (s, 9H), 0.03 (s, 3H), −0.03 (s, 3H); m/z (APCI-pos) M+1=506.1, 508.1.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+].[N+:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21]>CN(C)C=O.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>[NH2:1][C:2]1[C:3]([S:10]([OH:13])(=[O:12])=[O:11])=[CH:4][C:5]([Br:9])=[CH:6][C:7]=1[C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:28]=1
Reactant: Nc1c(I)cc(Br)cc1S(=O)(=O)O
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(-c2cccc([N+](=O)[O-])c2)cc(Br)cc1S(=O)(=O)O
Temperature: 70 °C
Yield: 80.4 %

Procedure:
To a solution of 1.9 g (5 mmol) of 2-amino-5-bromo-3-iodobenzenesulphonic acid and 1.6 g (15 mmol) of sodium carbonate in 25 ml of dimethylformamide and 12.5 ml of water are added successively, under a nitrogen atmosphere, 0.231 g (0.2 mmol) of tetrakis(triphenylphosphine)palladium (0) and 1.42 g (8.5 mmol) of 3-nitrobenzeneboronic acid. The reaction medium is heated for 2 hours at 70° C. and is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on an RP 18 reverse-phase column, eluting with an acetonitrile/water mixture (1:9). 1.5 g of compound are obtained in sodium sulphonate form.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[N:13]=2)[CH:10]=1)=O.[NH2:23][C:24]([NH2:26])=[S:25]>CO>[NH2:26][C:24]1[S:25][CH:2]=[C:3]([C:5]2[CH:6]=[CH:7][C:8]3[N:9]([CH:11]=[C:12]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:15])[N:13]=3)[CH:10]=2)[N:23]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Solvent: CO
Product: Nc1nc(-c2ccc3nc(C(=O)Nc4ccccc4)cn3c2)cs1
Yield: 35.6 %

Procedure:
To a suspension of 60 mg of crude 6-(2-bromoacetyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in 10 mL of methanol are added 14 mg of thiourea. The reaction mixture is heated for 45 minutes at reflux and then concentrated to dryness under reduced pressure. The residue is chromatographed on a silica cartridge, eluting with a mixture of dichloromethane and methanol (gradient of from 100/0 to 90/10). The fractions containing the expected product are combined and evaporated to dryness under reduced pressure to give 20 mg of 6-(2-aminothiazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[C:16]([O:21][CH3:22])[N:15]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8]([NH:20][C:18]2[CH:17]=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:13][CH3:12])[CH:19]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1cc(N)cc(OC)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(NS(=O)(=O)c2cccnc2Cl)cc(OC)n1
Yield: 75.6 %

Procedure:
The title compound (623 mg, 1.89 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (530 mg, 2.5 mmol), 2,6-dimethoxy-4-pyridinamine (424 mg, 2.8 mmol) and pyridine (0.6 mL, 7.5 mmol) in DCM (10 mL) using the methods of (IntC1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8]CCO.[CH2:12]([O:19][C:20]([C@H:22]1[NH:25][C:24](=[O:26])[CH2:23]1)=[O:21])[C:13]1C=CC=CC=1>[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4]>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:13][CH2:12][O:19][C:20]([C@H:22]1[NH:25][C:24](=[O:26])[CH2:23]1)=[O:21]
Reactant: O=C1C[C@@H](C(=O)OCc2ccccc2)N1
Reactant: COCCOCCOCCO
Agent: [Ti+4]
Agent: CCCC[O-]
Product: COCCOCCOCCOC(=O)[C@@H]1CC(=O)N1
Temperature: 90 °C

Procedure:
3 was prepared by transesterification of 1 with triethyleneglycol monomethyl ether following the procedure reported by Muñoz-Guerra et al.21 A vigorously stirred solution of 1 (2.05 g, 10 mmol) and titanium(IV) tetrabutoxide (0.1 g, 0.3 mmol) in dry tri(ethylene glycol) monomethyl ether (20 mL) was heated at 90° C. for 12 h. The course of transesterification was followed by TLC. The reaction was assumed to be complete when no trace of UV absorption indicative of 1 was detectable. The unreacted tri(ethylene glycol) monomethyl ether was distilled off under vacuum and can be reused. The remaining brown residue was purified by passage through a silica gel column (ethyl acetate and hexane, 1:1). The eluent fractions containing product were combined and the solvent was evaporated under vacuum to afford a light yellow oil. Pure compound 3 was obtained by vacuum distillation of this oil (1.21 g, 46%). FTIR (THF): 1779 cm−1 (νCO, lactam, s), 1745 cm−1 (νCO, ester, s). 1H NMR (CDCl3, 500 MHz) δ 6.73 (br, 1H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)), 4.36 (m, 2H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)), 4.19 (dd, 1H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)), 3.71 (m, 2H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)), 3.63 (m, 6H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)), 3.54 (m, 2H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)), 3.37 (s, 3H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)), 3.26 (ddd, 1H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)), 3.08 (ddd, 1H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)). 13C NMR (CDCl3, 200 MHz) δ 171.4, 166.4, 72.2, 71.0, 70.9, 70.8, 69.1, 64.9, 59.3, 47.6, 43.9. [α]25D: −15.1 (C 0.52 in THF) MS calcd: 261.28; found: 262.33 (MH+).
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].[CH3:8][O:9][C:10]1[CH:19]=[C:18]([NH:20][C:21]2[S:22][C:23]3[CH2:29][CH2:28][CH2:27][CH:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]=3[N:25]=2)[CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13]>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:19]=[C:18]([NH:20][C:21]2[S:22][C:23]3[CH2:29][CH2:28][CH2:27][CH:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]=3[N:25]=2)[CH:17]=[CH:16][C:11]=1[C:12]1[O:13][C:1]([CH3:2])=[N:15][N:14]=1
Reactant: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1C(=O)NN
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-c1nnc(C)o1
Reaction time: 40 h
Yield: 65 %

Procedure:
At room temperature, acetic anhydride (108 μL) was added to a suspension of 2-methoxy-4-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-ylamino)-benzoic acid hydrazide (130 mg, 0.33 mmol) in dimethylformamide (5 mL). The mixture was stirred for 40 hours and evaporated to dryness. The residue was taken up in 10% w/w (3 mL) phosphorous pentoxide in methanesulfonic acid (prepared by mixing 5 g phosphorous pentoxide and 30 mL methanesulfonic acid and stirring for 2 h at 90° C.) and stirred for 18 hours. The mixture was poured into 75 ml water, neutralized to pH 5-6 with 32% aqueous sodium hydroxide and the precipitate filtered off. The solid was dissolved in ethyl acetate (30 mL), washed four times with water and once with brine, dried with magnesium sulfate and concentrated in vacuo, affording the title compound (69 mg, 65%) as an off-white solid. NMR (CDCl3, 300 MHz): δ (ppm)=7.74 (d, 1H), 7.61 (d, 1H), 7.31-7.15 (m, 5H), 6.82 (dd, 1H), 4.03 (m, 1H), 3.34 (m, 3H), 2.73 (m, 2H), 2.50 (m, 3H), 2.14 (m, 1H), 1.79 (m, 3H). MS ISP (m/e): 419.1 (100) (M+H)+.
Reaction SMILES: Br[C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:28]2[C@H:30]([C:31]([O:33]CC)=[O:32])[C:29]2([CH3:37])[CH3:36])=[CH:4][CH:3]=1.[S:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[N:42]=[CH:41]1>>[CH3:36][C:29]1([CH3:37])[C@H:28]([C:8]2[N:7]([CH2:6][C:5]3[CH:38]=[CH:39][C:2]([C:43]4[N:42]=[CH:41][S:40][CH:44]=4)=[CH:3][CH:4]=3)[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=2)[C@@H:30]1[C:31]([OH:33])=[O:32]
Reactant: CC1(C)OB(c2cscn2)OC1(C)C
Reactant: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)C1(C)C
Product: CC1(C)[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3cscn3)cc2)[C@@H]1C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 97 using racemic cis-ethyl 3-(1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropanecarboxylate and thiazole-4-boronic acid pinacol ester in Step A. MS (ESI): mass calcd. for C33H28N4O3S, 560.19; m/z found, 561.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.89-8.85 (m, 1H), 8.20 (d, J=8.5, 1H), 8.11 (d, J=8.5, 1H), 7.92 (d, J=8.3, 2H), 7.85-7.81 (m, 1H), 7.77-7.71 (m, 1H), 7.68 (d, J=8.5, 1H), 7.57-7.53 (m, 2H), 7.34-7.31 (m, 1H), 7.25-7.23 (m, 1H), 7.16-7.08 (m, 3H), 5.47-5.33 (m, 4H), 2.30 (d, J=8.2, 1H), 2.08 (d, J=8.2, 1H), 1.21 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([OH:27])[CH:23]=[CH:24][C:25]=1[Cl:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:27][C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2cccc(Br)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2cccc(Oc3ccc(Cl)c(Cl)c3)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.1 %

Procedure:
To a solution of (6-bromo-pyridin-2-yl)-(4-isopropyl-piperazin-1-yl)-methanone (76.7 mg, 0.25 mmol) in DMF (2.5 mL) was added 3,4 dichlorophenol (40.07 mg, 0.25 mmol) and K2CO3 (101.93 mg, 0.74 mmol). After 18 h at 120° C., the mixture was cooled to rt, diluted with water, and extracted with DCM. Purification by FCC followed by reverse phase HPLC (basic conditions) provided the desired product (10.0 mg, 3.5%). MS (ESI): mass calcd. for C19H21Cl2N3O2, 393.10; m/z found, 394.3 [M+H]+. 1H NMR (CDCl3): 7.82 (dd, J=8.2, 7.4 Hz, 1H), 7.52-7.44 (m, 2H), 7.26 (d, J=2.7 Hz, 1H), 7.06-6.98 (m, 2H), 3.75-3.67 (m, 2H), 3.50-3.44 (m, 2H), 2.70-2.61 (m, 1H), 2.55-2.48 (m, 2H), 2.23-2.15 (m, 2H), 1.01 (d, J=6.6 Hz, 6H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[NH2:35])[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].CO[CH:39]1[CH2:43][CH2:42][CH:41](OC)O1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[N:35]3[CH:39]=[CH:43][CH:42]=[CH:41]3)[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(F)cc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Product: O=C(NC1(C(=O)NC2CCN(c3cc(F)ccc3-n3cccc3)CC2O)CCCCC1)c1cc2ccccc2o1

Procedure:
The mixture of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-amino-5-fluorophenyl)piperidin-3-ol (2 g) obtained in Step 1 and 0.96 ml of 2,5-dimethoxytetrahydrofuran was refluxed for 1 hour and concentrated under reduced pressure. The resulting residue was diluted with 70 ml of dichloromethane, washed with a saturated sodium bicarbonate solution and brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 1.8 g of the titled compound as white color.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[CH:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1)([CH3:13])[CH3:12].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=2)[C:5]([OH:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: CCc1cc(Cl)ccc1O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1cc(Cl)cc(Cc2ccc(C(C)C)cc2)c1O
Temperature: 60 °C
Reaction time: 5.5 h

Procedure:
117.5 g (0.75 mol) 4-chloro-2-ethylphenol are dissolved with 42.25 g (0.25 mol) 4-isopropylbenzylchloride in 200 ml chloroform. 22.5 g water-free zinc chloride are added thereto for the alkylation reaction. Already at 30° C. a powerful reaction takes place. The entire mixture is after-stirred 5-6 h at 60° C. for completion of the alkylation. After a cooling it is subsequently washed three times each with 200 ml water, and then dried across sodium sulfate, after which the solvent chloroform is driven off.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:43]1[S:44][CH:45]=[CH:46][N:47]=1)CCC.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:44]1[CH:45]=[CH:46][N:47]=[C:43]1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:27][CH2:28][CH2:29]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4nccs4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 130 °C

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (300 mg, 0.54 mmol), 2-(tributylstannyl)thiazole (337 μA, 1.1 mmol), and PdCl2(PPh3)2 (38 mg, 0.047 mmol) in 1,2-dimethoxyethane (10 ml) was added to a crimp top microwave vial, which was then sealed and heated under microwave irradiation conditions at 130° C. for 60 min. After cooling to room temperature the mixture was poured into water and extracted into ethyl acetate. The organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography (hexane/ethyl acetate; 0-100% ethyl acetate over 60 min) to give a yellow amorphous (quant.). 1HNMR (CDCl3) 400 MHz δ: 8.18 (1H, dd, J=7.7, 1.4 Hz), 8.02 (1H, d, J=4.0 Hz), 7.75 (1H, d, J=2.9 Hz), 7.44-7.37 (3H, m), 7.32 (1H, td, J=7.5, 1.7 Hz), 7.24 (1H, d, J=2.9 Hz), 7.15 (1H, td, J=7.4, 1.2 Hz), 6.97 (1H, d, J=8.0 Hz) 6.89-6.81 (1H, m), 6.61 (1H, dd, J=7.7, 4.9 Hz), 6.48 (1H, s), 5.18 (1H, s), 2.60-2.32 (4H, m), 2.17-2.08 (1H, m), 1.93-1.84 (1H, m), 1.48-1.21 (9H, m); LC/MS [M+H]: 563.