Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[C:10](=[O:24])[NH:11][C:12](=[O:23])[N:13]([CH:22]=1)[C@@H:14]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]1)=[O:4].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1>CN(C=O)C>[Si:27]([O:20][CH2:19][C@H:18]1[O:21][C@@H:14]([N:13]2[CH:22]=[C:9]([C:8]#[C:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:25])([F:1])[F:26])[C:10](=[O:24])[NH:11][C:12]2=[O:23])[CH2:15][C@@H:16]1[OH:17])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: O=C(NCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1) (656 mg, 1.74 mmol) in dry DMF (15 ml) was added t-butyldimethylsilylchloride (288 mg, 1.91 mmol) in small portions, followed by imidazole (130 mg, 1.91 mmol). The reaction was followed by TLC and was completed after stirring for 8 h at room temperature. The reaction was quenched with sat. aq. NaCl solution. EtOAc (25 ml) was added to the reaction mixture and the aqueous layer was extracted with EtOAc three times. After drying the combined organics (MgSO4), the solvent was removed under vacuum. Purification by chromatography on silica (EtOAc:petroleum ether 8:2) gave (2) as slightly yellow crystals (676 mg, 83%). 1H NMR (d6 DMSO) δ 0.00 (s, 6H, CH3), 0.79 (s, 9H, tBu), 1.93-2.00 (m, 1H, H-2′), 2.06-2.11 (m, 1H, H-2′), 3.63-3.75 (m, 2H, H-5′), 3.79-3.80 (m, 1H, H-4′), 4.12-4.14 (m, 3H, H-3′, CH2N), 5.22 (d, J=4.1 Hz, 1H, OH), 6.03 (t, J=6.9 Hz, 1H, H-1′), 7.86 (s, 1H, H-6), 9.95 (t, J=5.4 Hz, 1H, NH), 11.61 (br s, 1H, NH). Mass (−ve electrospray) calcd for C20H28F3N3O6Si 491.17, found 490.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.Cl[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23].C1(C)C=CC=CC=1>CCCCCC>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:11]1[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: Fc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2F)cc1
Reaction time: 24 h
Yield: 68 %

Procedure:
Using a THF solution of p-methoxyphenylmagnesium bromide (2.34 mL, 0.64 M, 1.5 mmol) and 1-chloro-2-fluorobenzene (130.6 mg, 1.0 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 60° C. for 24 hours, then at 80° C. for 12 hours in the same manner as in Example 15. After performing silica gel column chromatography (toluene=15, 30 and 50% in hexane), the above compound (0.135 g, yield=68%, purity=>97% (GC analysis)) was obtained as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[N:11][C:4]=2[NH:3]1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]3)=[N:24]2)=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([NH:36][C:12]([C:10]4[CH:9]=[CH:8][C:5]5[S:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=5[N:11]=4)=[O:14])[CH2:34][CH2:35]3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4ccc5c(n4)NC(=O)CS5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow solid (7 mg, 10% yield) following Scheme 3 and in analogy to Example 35 using 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (26 mg, 0.12 mmol, 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (40 mg, 0.12 mmol, 1.0 eq) as starting materials.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1>CN1CCCC1=O>[NH:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=[C:2]1[NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CN1CCCC1=O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1

Procedure:
A solution of 2-chlorobenzimidazole (1 g) and ethyl 4-amino-1-piperidinecarboxylate (2 g) in 1-methyl-2-pyrrolidinone was heated at 130° C. for 24 h. The mixture was partitioned between water and ethyl acetate, the organic layer washed with water, dried and evaporated under reduced pressure. Purification was by chromatography eluting with 1% triethylamine/5% methanol in dichloromethane. Yield 0.630 g as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([N:9]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[Br:26][C:27]1[CH:28]=[C:29]([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[S:30][C:31]=1[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>C(#N)C.CCO.O>[Br:26][C:27]1[CH:28]=[C:29]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:2][CH2:3][O:4][C:5]3[CH:25]=[CH:24][C:8]([N:9]([C:10]4[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=4)[C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[CH:7][CH:6]=3)=[CH:42][CH:41]=2)[S:30][C:31]=1[C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1
Reactant: COc1ccc(-c2sc(-c3ccc(O)cc3)cc2Br)cc1
Reactant: Clc1ccc(N(c2ccc(Cl)cc2)c2ccc(OCCBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2sc(-c3ccc(OCCOc4ccc(N(c5ccc(Cl)cc5)c5ccc(Cl)cc5)cc4)cc3)cc2Br)cc1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
4-(2-bromoethoxy)-N,N-bis-(4-chlorophenyl)aniline (70, 1.40 g, 3.20 mmol) and 4-(4-bromo-5-(4-methoxyphenyl)thiophen-2-yl)phenol (65, 1.16 g, 3.20 mmol) were dissolved in acetonitrile (40 mL) and the cesium carbonate (2.09 g, 6.41 mmol) was added. The reaction mixture was heated to reflux for 20 hours. After cooling to RT, the reaction mixture was poured into DCM (100 mL) and water (150 mL). The mixture was mixed well and the aqueous portion extracted with DCM (2×100 mL). The combined organics were washed with water (2×150 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation. The resulting off-white solid was sonicated in MeOH (100 mL), filtered and air dried to afford an off-white powder which still contained some minor impurities by TLC. This material was allowed to stir in refluxing EtOH (150 mL) for 15 minutes, cooled slightly, filtered and air dried to afford 71 as an off-white powder (1.60 g, 70%).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([CH3:18])[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])O1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].ClCCl.O1CCOCC1>[OH:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([CH3:18])[CH:3]=1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: Cc1cc(Br)ccc1C(=O)OCc1ccccc1
Agent: [Fe+2]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccccc2O)ccc1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a 1,4-dioxane solution (99 ml) of benzyl 4-bromo-2-methylbenzoate (6.63 g) were added at room temperature 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenol (4.86 ml), tripotassium phosphate hydrate (16.8 g), a [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (860 mg) and 1,1′-bis(diphenylphosphino)ferrocene (584 mg), followed by stirring at 80° C. for 8 hours. After the reaction solution was brought back to room temperature, a 10% aqueous citric acid solution and dichloromethane were added, and the solution was separated. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford benzyl 2′-hydroxy-3-methylbiphenyl-4-carboxylate (6.01 g).
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([C:17]([O:19]CC1C=CC=CC=1)=[O:18])[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]>[Pd].C(O)C>[C:1]([O:7][CH2:8][C@@H:9]([C:17]([OH:19])=[O:18])[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)CC(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
A mixture of benzyl O-acetoacetyl-N-trifluoroacetyl-L-serinate (320 mg) and 10% palladium on activated carbon (40 mg) in ethanol (10 ml) was hydrogenated under hydrogen at one atom for 20 minutes. The mixture was filtered with Celite (filter aid, trade mark, made by Nakarai Chemicals) and the filtrate was concentrated to give O-acetoacetyl-N-trifloroacetyl-L-serine (232 mg).
Reaction SMILES: [Cl:1][C:2]([Cl:22])([Cl:21])[C:3](=[O:20])[C:4](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:23][C:24]([CH3:31])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(O)(C)(C)C>[OH:20][C:3]1([C:2]([Cl:21])([Cl:22])[Cl:1])[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH3:31])[NH:23]1
Reactant: CCOC(=O)C=C(C)N
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)C(Cl)(Cl)Cl
Solvent: CC(C)(C)O
Product: CCOC(=O)C1=C(C)NC(O)(C(Cl)(Cl)Cl)C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 40747.3 %

Procedure:
Ethyl 4,4,4-trichloro-2-(3-nitrophenylmethylene)-3-oxobutanoate (7.19 g, 0.02 mmoles) and ethyl 3-amino-2-butenoate (2.53 g) were heated at 60° for 24 hours in tert-butanol (60 ml). The solvent was evaporated and the residue chromatographed on silica eluting with ether/petroleum ether (60°-80°) mixtures to give the title compound (4.04 g). Recrystallised from 2-propanol. mp 125°-6.5°.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[F:12].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>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.C1(C)C=CC=CC=1>[CH2:15]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[F:12])[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1OCc2c1ccc(Br)c2F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1F)COC2=O

Procedure:
To a flask charged with 5-bromo-4-fluoro-2-benzofuran-1(3H)-one (52 mg, 0.22 mmol) and a stir bar was added allyl tri-n-butyltin (0.10 mL, 0.34 mmol), palladium tetrakis (39 mg, 0.034 mmol), lithium chloride (29 mg, 0.68 mmol), and toluene (5 mL). The mixture was purged three times with nitrogen, and heated to reflux for 4 hours. LC showed formation of the desired product, which was purified by silica gel chromatography to deliver 5-allyl-4-fluoro-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 193 [M+1]+;
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].C(=O)([O-])[O-].[Na+].[Na+]>>[N+:9]([C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[CH3:12])([O-:11])=[O:10]
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(NCCN(C)C)c([N+](=O)[O-])c1

Procedure:
17.2 g. of 4-chloro-3-nitrotoluene, 9 g. of 2-dimethylaminoethylamine, and 21.5 g. of anhydrous sodium carbonate are agitated for 7 hours at 135° C. Excess starting material is removed by steam distillation. The distillation residue is extracted with chloroform, the chloroform solutions are dried, filtered, and concentrated under a vacuum. By distilling the residue at 0.05 mm Hg and 133°-137° C., 10.5 g. of 3-nitro-4-(2-dimethylaminoethylamino)-toluene is obtained, m.p. 59° C. 3.5 g. of this compound is reduced as described in Example 27, and 3 g. of crude 3-amino-4-(2-dimethylaminoethylamino)-toluene is thus obtained. 400 mg. of this compound is reacted with 400 mg. of the ethyl ester of 5-nitro-1-methyl-2-imidazolyliminocarboxylic acid, as described in Example 1, thus producing 172 mg. of 1-(2-dimethylaminoethyl)-5-methyl-2-(5-nitro-1-methyl-2-imidazolyl)-benzimidazole hydrochloride, m.p. 249°-251° C.
Reaction SMILES: [CH3:1][C:2]([N:4]([OH:39])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([CH2:13][CH2:14][C:15]([N:17]([OH:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][CH2:27][C:28]([N:30]([OH:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:29])=[O:25])=[O:16])=[O:12])=[O:3].[CH3:40][S:41]([OH:44])(=[O:43])=[O:42].[Cl-].[Zn+2:46].[Cl-]>>[Zn:46].[CH3:1][C:2]([N:4]([OH:39])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([CH2:13][CH2:14][C:15]([N:17]([OH:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][CH2:27][C:28]([N:30]([OH:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:29])=[O:25])=[O:16])=[O:12])=[O:3].[CH3:40][S:41]([OH:44])(=[O:43])=[O:42]
Reactant: [Zn+2]
Agent: CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN
Agent: CS(=O)(=O)O
Agent: [Cl-]
Product: [Zn]
Temperature: 25 °C

Procedure:
A zinc chloride solution (7.6 mM) in sterile saline is prepared by dissolving 1.043 gm of high purity zinc chloride (Aldrich Chemical Co., Inc.) in one liter of saline, autoclaving and cooling to room temperature. 10 ml of the zinc chloride sterile solution is added to a vial of 500 mg of Desferal, the mixture is shaken until the contents are completely dissolved and used for either a bolus or continuous injection.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: OB(O)c1ccccc1F
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
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: [K+]
Solvent: O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1F
Temperature: 95 °C
Yield: 69 %

Procedure:
A solution of N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (120 mg, 0.281 mmol), 2-fluorophenylboronic acid (472 mg, 0.337 mmol, CAS RN 1993-03-9) and K2CO3 (155 mg, 1.124 mmol) in a mixture of water:ethanol:toluene (10 mL; 0.5:1:3) was thoroughly degassed for 30 min at 25° C. under an atmosphere of argon in a sealed tube. Pd(PPh3)4 (32.5 mg, 0.0281 mmol, CAS RN 14221-01-3) was then added to the mixture, and continued degassing for another 15 min. The reaction mixture was heated to 90-100° C. for 14 hours. After the completion of reaction, the mixture was filtered though a bed of celite and the residue washed with EtOAc. The combined filtrates were evaporated in vacuo and the resultant residue was diluted with EtOAc. The organic layer washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue thus obtained was purified by preparative HPLC to afford the desired compound as an off-white solid (69%). MS (ESI): m/z=443.2 [M+H]+.
Reaction SMILES: ClC(OCC)=O.[OH:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[C:15](=O)[CH:16]([CH3:18])[CH3:17].C(N(CC)CC)C.[BH4-].[Na+].[OH-].[Na+].Cl>C1COCC1.O>[CH2:15]([C:9]1[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=1[OH:7])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C(=O)c1ccc(O)cc1O
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl chloroformate (3 eq) was added slowly to a cooled (0° C.) solution of 1-(2,4-dihydroxy-phenyl)-2-methyl-propan-1-one (1 eq) and triethylamine (3 eq) in THF. The mixture was warmed to ambient temperature and stirred for three hours before being filtered and the solids washed with cold THF. The combined filtrates were cooled to 0° C. and sodium borohydride (4 eq) in a volume of water equal to the THF filtrates added slowly. The mixture was warmed to ambient temperature, stirred for three hours and diluted with water. The mixture was twice extracted with diethyl ether, the combined extracts concentrated to dryness and re-suspended in 10% aqueous sodium hydroxide solution (4 eq). After refluxing for 90 minutes, the mixture was cooled, acidified with 5M aq HCl and twice extracted with diethyl ether. The organic extracts were dired over magnesium sulphate, filtered and concentrated to dryness to give 4-isobutyl-benzene-1,3-diol as a cloudy oil, which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:13]([O:15]C)=[O:14])=[C:10]([CH3:12])[S:11][C:5]=2[N:4]([CH:17]([CH3:19])[CH3:18])[C:3]1=[O:20].CO.[OH-].[Na+].Cl>C1COCC1>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:13]([OH:15])=[O:14])=[C:10]([CH3:12])[S:11][C:5]=2[N:4]([CH:17]([CH3:18])[CH3:19])[C:3]1=[O:20]
Reactant: COC(=O)c1c(C)sc2c1c(=O)n(C)c(=O)n2C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc2c(c1C(=O)O)c(=O)n(C)c(=O)n2C(C)C
Reaction time: 18 h

Procedure:
To a solution of the product of step b) (3.81 g) in THF (50 ml) and methanol (5 ml) was added 1N NaOH (25.7 ml) and the mixture stirred under nitrogen for 18 hr. It was acidified with 2.5N HCl and extracted with DCM, the organic extracts washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the sub-title compound as a solid (3.40 g)
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH2:16][CH2:17][CH2:18]O)[C:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1.S(Cl)([Cl:24])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH2:16][CH2:17][CH2:18][Cl:24])[C:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCn1c(Cc2ccccc2)nc2cc(Cl)ccc21
Solvent: ClC(Cl)Cl
Product: ClCCCn1c(Cc2ccccc2)nc2cc(Cl)ccc21
Reaction time: 6 h

Procedure:
To a stirred mixture of 45 parts of 5-chloro-2-(phenylmethyl)-1H-benzimidazole-1-propanol and 225 parts of trichloromethane are added dropwise 29.75 parts of sulfinyl chloride. Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated and the residue is taken up in water. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The reisude is purified by columnchromatography over silica gel using a mixture of trichloromethane and methanol (98:2) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 5-chloro-1-(3-chloropropyl)-2-(phenylmethyl)-1H-benzimidazole as a solid residue.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[C@H:15]2[CH2:21][NH2:22])=[O:13])[N:3]=[CH:4][CH:5]=1.F[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1>>[N:1]1[N:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[C@H:15]2[CH2:21][NH:22][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)=[O:13])[N:3]=[CH:4][CH:5]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: C[C@@H]1CCCN(C(=O)c2ccccc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2ccccc2-n2nccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using (2-(2H-1,2,3-triazol-2-yl)phenyl)((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 445 [M+1]. 1H NMR (300 MHz, DMSO-d6) δ 8.35-6.60 (m, 10H), 4.85-2.70 (m, 5H), 1.85-0.65 (m, 8H).
Reaction SMILES: [N+](C1C=CC=CC=1O[C:11](=[O:35])[C@@H:12]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O.Cl.[CH3:37][O:38][C:39]1[CH:48]=[CH:47][C:42]([C@H:43]([NH2:46])[CH2:44][OH:45])=[CH:41][CH:40]=1.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.[Cl-].[Na+].O.O.C(N(CC)CC)C>[C:14]([NH:13][C@H:12]([C:11]([NH:46][C@H:43]([C:42]1[CH:47]=[CH:48][C:39]([O:38][CH3:37])=[CH:40][CH:41]=1)[CH2:44][OH:45])=[O:35])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1ccccc1[N+](=O)[O-]
Reactant: COc1ccc([C@H](N)CO)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc([C@H](CO)NC(=O)[C@H](CCCNC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)cc1
Yield: 78.3 %

Procedure:
Prepared according to the method described in Example 11(a) above from Nα -Boc-Nδ -Cbz-(R)-ornithine o-nitrophenyl ester (4.83 g; 9.91 mmol; see Example 4(a) above) with (S)-4-methoxy-α-hydroxymethylbenzylamine hydrochloride (2.22 g; 10.90 mmol) and triethylamine (1.50 g; 14.87 mmol; instead of DiPEA) in CH2Cl2 (150 mL), 18 hours reaction time. The reaction mixture was submitted to aqueous work up using water, 1N HCl and brine. The organic solution was dried, filtered and concentrated to give the sub-title compound as a yellow solid (4.0 g) which was used without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6]([CH3:8])=[CH:5][C:4](=[O:9])[CH2:3]1.N(CCO)(CCO)CCO>>[CH3:1][C:2]1([CH3:10])[CH:7]=[C:6]([CH3:8])[CH2:5][C:4](=[O:9])[CH2:3]1
Reactant: CC1=CC(=O)CC(C)(C)C1
Solvent: OCCN(CCO)CCO
Product: CC1=CC(C)(C)CC(=O)C1

Procedure:
A mixture of 500 g of 3,3,5-trimethyl-cyclohex-5-en-1-one (isophorone) and 50 g of triethanolamine was refluxed for 4 hours, whereupon it was fractionally distilled to give a fraction at b.p. 170°. The isomerization was performed in a reaction vessel equipped with a lateral distillation column having the following characteristics:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[OH:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14]>>[OH:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([CH3:18])=[C:11]([OH:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Cc1ccc(N)cc1O
Reactant: Fc1cnc(Cl)nc1Cl
Product: Cc1ccc(Nc2ncc(F)c(Nc3ccc(C)c(O)c3)n2)cc1O

Procedure:
In like manner to N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-hydroxy-4-methylaniline were reacted to yield N2,N4-bis(-3-hydroxy-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.83 (d, 1H J=4 Hz), 7.11 (m, 4H), 6.81 (m, 2H), 2.19 (m, 6H); LCMS: ret. time: 20.69 min.; purity: 98%; MS (m/e): 341 (MH+).