Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[N:26]3)=[CH:21][C:20]=2[CH3:34])[C:8]2[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40].C(=O)=O.C(O)C>>[CH:1]1([N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([C:30]([F:31])([F:33])[F:32])[CH:27]=[N:26]3)=[CH:21][C:20]=2[CH3:34])[C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCN
Reactant: COC(=O)c1ccc(N(Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2C)C2CCCCC2)nc1
Agent: Cl
Agent: O=C=O
Solvent: CCO
Product: COC(=O)CCNC(=O)c1ccc(N(Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2C)C2CCCCC2)nc1

Procedure:
The title compound was prepared by a method analogous to that described in Steps B-C of Example 82, using (+/−)-methyl 6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinate in Step B and methyl 3-aminopropanoate hydrochloride in Step C. Racemic methyl 3-(6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinamido)propanoate was purified by chiral SFC to afford Isomer 1 and Isomer 2, which were used in conversion to the final enantiopure products. Chiral SFC: Chiralpak AD-H, 4.6×250 mm, 5 μm. Modifier: 0.05% DEA. Mobile Phase: 60/40 CO2/ethanol. Flow: 2.35 mL/min. Retention time: 5.19 minutes (Isomer 1) and 7.83 minutes (Isomer 2).
Reaction SMILES: O1C2C=CC(C3C(=O)OC(O)(C4C=CC(OC)=CC=4)C=3[CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][N:38]=[N+:39]=[N-:40])[CH:17]=3)=CC=2OC1.CCCCCCCCCCN.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[O:82][C:83]1C(OC)=CC(C=O)=C[C:84]=1[OH:93].N(CCOCCOCCOCCOC1C=C(C=C(OC)C=1OC)C=O)=[N+]=[N-]>C1COCC1.C(O)CO.O>[N:38]([CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][C:18]1[CH:17]=[C:16]([CH:15]2[O:93][CH2:84][CH2:83][O:82]2)[CH:21]=[C:20]([O:22][CH3:23])[C:19]=1[O:24][CH3:25])=[N+:39]=[N-:40]
Reactant: COc1cc(C=O)cc(O)c1OC
Reactant: COc1ccc(C2(O)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OCCOCCOCCOCCN=[N+]=[N-])c2)cc1
Agent: CCCCCCCCCCN
Agent: COc1cc(C=O)cc(OCCOCCOCCOCCN=[N+]=[N-])c1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: OCCO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C2OCCO2)cc(OCCOCCOCCOCCN=[N+]=[N-])c1OC

Procedure:
Compound 9 is then converted to the free amine 10 by Staudinger-Reaction with triphenylphosphine and water in THF (scheme 3). Regrettably, the yields in this step were disappointing (<20%) and several byproducts made the purification rather difficult. This probably occurred due to reaction of the phosphine with one of the oxygen-containing moieties of the butenolide ring structure. To circumvent these difficulties a second reaction sequence was chosen, where the amine was generated earlier and then protected for further conversion. This second sequence (scheme 4) also starts with the reaction of 3,4-dimethoxy-5-hydroxybenzaldehyde 1 with PEG-derivative 7. The aldehyde function of azide 8 is then protected with ethylene glycol, giving dioxolane 11 in nearly quantitative yield after purification. This kind of protection allows subsequent reduction of the azide and BOC protection of the generated amine 12 without the risk of intermolecular imine formation. The dioxolane protecting group of 13 then can easily be destroyed by reaction with catalytic amounts of iodine in acetone without affecting the BOC protecting group. The product benzaldehyde 14 and ketoester 3 are then converted to the desired butenolide derivative by the same procedure as described above for the azide functionalised aldehyde 8 (scheme 3). The product of this rection is the PEG-modified, N-Boc-protected butenolide 15, which in the finishing step is deprotected by treatment with trifluoroacetic acid (TFA) in methylene chloride. The final product 16 can be isolated as the TFA salt which can be handled and stored easily at 4° C.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([CH3:26])[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[C:19]([CH3:26])[CH:18]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cc1cc(Cl)ccc1-c1c(-c2cc(C#N)ccn2)ncn1C

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro-2-methylphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C17H13ClN4, 310. Found, 309, 311.
Reaction SMILES: CC1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:39])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28](/[CH:32]=[CH:33]/[S:34]([NH:37][CH3:38])(=[O:36])=[O:35])[CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1>CO>[OH:39][C@H:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28](/[CH:32]=[CH:33]/[S:34]([NH:37][CH3:38])(=[O:35])=[O:36])[CH:29]=[CH:30][CH:31]=1
Reactant: CNS(=O)(=O)/C=C/c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc3c(c2)COC(C)(C)O3)c1
Solvent: CO
Product: CNS(=O)(=O)/C=C/c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1
Yield: 75.2 %

Procedure:
A solution of (E)-2-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-N-methylethenesulfonamide (100 mg) in methanol (15 ml) was administered onto a Bond Elut SCX2 cartridge (10 g), which had been preconditioned in methanol. The cartridge was eluted with methanol (2×25 ml) followed by 15% aq. ammonia-methanol (2×20 ml). Evaporation of the latter fractions gave the title compound (70 mg) LCMS RT=2.59 min, ES+ve 535 (MH)+
Reaction SMILES: [C:1]([C:9]([OH:11])=[O:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:12][CH:13](O)[C:14]#[CH:15].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[I:12][C:13]#[C:14][CH2:15][O:10][C:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: C#CC(O)I
Reactant: O=C(O)C(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(OCC#CI)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a cold, stirred solution of benzoyl formic acid (1.5 g, 0.01 mole) in methylene chloride (75 mL) at 4° C. were added iodopropargyl alcohol (1.9 g, 0.0105 mole) followed by 4-dimethylaminopyridine (0.122 g, 0.001 mole) and ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2 g, 0.0104 mole). After stirring at 0° to 10° C. for one hour, the reaction mixture was diluted with methylene chloride (100 mL) and was washed with water (3×50 mL) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to a residue. The residue was triturated with hexane and the product, a pale yellow solid, was collected by suction-filtration yielding 1.75 g (60%), mp=48°-50° C. An nmr spectrum showed the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[N:7]=[C:8]([C:12]([O:14]CC)=[O:13])[O:9][C:10]=1[CH3:11].[OH-].[Na+].O>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[N:7]=[C:8]([C:12]([OH:14])=[O:13])[O:9][C:10]=1[CH3:11]
Reactant: CCOC(=O)c1nc(Cc2cccc(Br)c2)c(C)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1oc(C(=O)O)nc1Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A mixture of ethyl 4-(3-bromobenzyl)-5-methyloxazole-2-carboxylate (500 mg, 1.5 mmol) and 2 N NaOH (2 mL, 4 mmol) in EtOH (6 mL)/H2O (2 mL) was stirred at 0° C. for 2 h. The mixture was neutralized with aqueous critic acid (10%), concentrated and purified by Combiflash reverse phase chromatography (50%˜60% MeCN/H2O containing 0.01% TFA) to afford 4-(3-bromobenzyl)-5-methyloxazole-2-carboxylic acid as a yellow oil (320 mg, 65%). MS (ES+) C12H10BrNO3 requires: 295, 297, found: 296 [M+H]+, 298 [M+2+H]+(1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[O:11]=[C:12]1[C:17](=O)[CH:16]([C:19](=O)[C:20]([F:23])([F:22])[F:21])[CH2:15][CH2:14][N:13]1[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[O:11])[N:13]([C:25]4[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=4)[CH2:14][CH2:15][C:16]=3[C:19]([C:20]([F:23])([F:21])[F:22])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NN)cc1
Reactant: N#Cc1ccc(N2CCC(C(=O)C(F)(F)F)C(=O)C2=O)cc1
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C#N)cc2)CC3)cc1

Procedure:
Condensation of 4-methoxyphenylhydrazine with 4-[2,3-dioxo-4-(2,2,2-trifluoro-acetyl)-piperidin-1-yl]-benzonitrile afforded the desired intermediate 4-[1-(4-methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-benzonitrile. This intermediate was dissolved in anhydrous methanol and HCl gas was bubbled through for 15 min. The reaction mixture was stirred at room temperature for 18 h and concentrated. The residue was re-dissolved in methanol and 2 equivalents of N-methyl-ethylenediamine were added. The reaction mixture was stirred at room temperature for 18 h and concentrated. Pure product was obtained via reverse phase HPLC. ESI mass spectrum 470 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]1([C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:13]1[CH:14]=[CH:15][C:10]([C@H:16]2[CH2:17][CH2:18][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:20][CH2:21]2)=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)[C@H]1CC[C@H](c2ccccc2)CC1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A mixture of 65% nitric acid (6.2 mL) and 95% sulphuric acid (7.8 mL) in carbon tetrachloride (10 mL) was added dropwise to a solution of methyl trans-4-phenylcyclohexanecarboxylate (6940 mg) keeping the internal temperature below 5° C. The mixture was allowed to warm and stirred for 16 h. Ice/water (50 mL) was added and the mixture was extracted with DCM (2×75 mL). The extracts were combined, washed with brine (50 mL), dried and concentrated in vacuo to give an oil. This oil was chromatographed on an 80 g Biotage™ silica column, using a gradient of 0-20% EtOAc/hexane as the eluent to give crude methyl trans-4-(4-nitrophenyl)cyclohexanecarboxylate (4445 mg); MS m/e MH+ 264.10% Pd/C (450 mg) was added to a solution of this material (4440 mg) in EtOAc (50 mL) and the suspension was stirred for 16 hours under an atmosphere of hydrogen then filtered through diatomaceous earth and concentrated in vacuo. The residue was purified by chromatography on an 80 g Biotage™ silica column using a gradient of 0-50% EtOAc/hexane as eluent to give crude methyl trans-4-(4-aminophenyl)cyclohexanecarboxylate (2900 mg). A solution of this material (2890 mg) and pyridine (1.67 mL) in DCM (50 mL) was cooled to 5° C. Methyl chloro(oxo)acetate (1.48 mL) was added and the solution was allowed to warm up with stirring for 16 h. Water (75 mL) was added and the mixture was extracted with DCM (2×75 mL). The extracts were combined, dried, and concentrated in vacuo to give a solid. This solid was purified by flash chromatography on 80 g Biotage™ silica column eluting with a gradient of 0-50% EtOAc/hexane to give the title compound (919 mg) as a solid; 1H NMR δ 10.66 (1H, s), 7.60 (2H, d), 7.20 (2H, d), 3.83 (3H, s), 3.60 (3H, s), 2.56-2.30 (2H+DMSO, m), 2.00 (2H, m), 1.80 (2H, m), 1.46 (4H, m); MS m/e MH+ 320.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([NH:18][C@H:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1)[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[ClH:33]>C1COCC1.CO>[ClH:33].[O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([NH:18][C@H:19]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=1)[CH3:20])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2CCOc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](NC(=O)[C@H]1CCCCN1CCOc1ccccc1)c1ccc(C(=O)O)cc1
Yield: 66.1 %

Procedure:
Dissolve methyl 4-[(1S)-1-[[(2R)-1-(2-phenoxyethyl)piperidine-2-carbonyl]amino]ethyl]benzoate (930 mg, 2.27 mmol) in THF (4.0 mL) and CH3OH (4.0 mL) at room temperature. Add NaOH (1 M aqueous solution, 4.5 mL, 4.5 mmol), then stir the resulting mixture at room temperature for three days. Concentrate the reaction mixture under reduced pressure to furnish a gummy solid. Add hydrogen chloride (4 M solution in dioxane, 2 mL, 8 mmol), and stir vigorously for 10 minutes. Remove the suspended solids by filtration, and concentrate the filtrate under reduced pressure to furnish a white solid. Triturate the solid in boiling diethyl ether (25 mL), and isolate the suspended solids by filtration to furnish the title compound (650 mg, 66% yield) as a white solid. Mass spectrum (m/z): 397 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.89 (br s, 1H), 10.08 (br s, 1H), 9.41 (d, J=7.6 Hz, 1H), 7.88 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.2 Hz, 2H), 7.26 (dd, J=8.4, 7.6 Hz, 2H), 6.96 (t, J=7.2 Hz, 1H), 6.90 (d, J=7.9 Hz, 2H), 5.02 (app pentet, J=7.1 Hz, 1H), 4.34-4.21 (m, 2H), 4.03 (app t, J=10.2 Hz, 1H), 3.57 (d, J=12.4 Hz, 1H), 3.48-3.39 (m, 1H), 3.37-3.18 (m, 2H), 2.15 (d, J=13.5 Hz, 1H), 1.82-1.66 (m, 4H), 1.50-1.43 (m, 1H), 1.39 (d, J=7.2 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[N:15]1([CH2:2][C:3]([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][CH:6]=2)=[O:4])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1
Reactant: O=C(CBr)c1cccc2ccccc12
Reactant: c1ccc2[nH]nnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(Cn1nnc2ccccc21)c1cccc2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 2-bromo-1-(naphthalen-1-yl)ethanone (1 g, 4.02 mmol), benzotriazole (530 mg, 4.42 mmol) and K2CO3 (560 mg, 4.02 mmol) in toluene (100 mL) was heated at reflux for 16 hours. The reaction was cooled to room temperature, washed with water, dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (100% DCM) afforded 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1-(naphthalen-1-yl)ethanone as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[C:17]([C:18]4[CH:23]=[CH:22][C:21](Cl)=[CH:20][CH:19]=4)=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[Br:25]N1C(=O)CCC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:16]([Br:25])[NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc(-c2c[nH]c3ncnc(Nc4cccc(Br)c4)c23)cc1
Product: Brc1cccc(Nc2ncnc3[nH]c(Br)c(-c4ccccc4)c23)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28 %

Procedure:
Utilizing an analogous procedure as described in Example 26, 4-chloro-(5-phenyl)-7H-pyrrolo[2,3-d] pyrimidine, the intermediate, was made in 74% yield from 7-benzenesulfonyl-4-chloro-5iodo-7H-pyrrolo[2,3-d]pyrimidine and 3-bromo benzene boronic acid: TS-MS: 230 (MH+) This second intermediate was coupled with 3-bromoaniline in methanol in a sealed tube to provide (3-bromo-phenyl)-[5-(4-chloro-phenyl)7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine in 75% yield: TSMS: 365 (MH+). (3-bromo-phenyl)-[5-(4-chloro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine was brominated with N-bromosuccinimide impregnated onto silica gel. The reaction was complete after stirring at room temperature under nitrogen for 1.5 hours. The reaction was filtered and concentrated in vacuo to provide the title compound as a gray solid in 28% yield (128 mg): MP.: dec 300° C.; TSMS: 445/447 (MH+/MH+2); anal. RP1 8-HPLC RT=7.223 minutes.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][CH2:23][CH2:24][C:25]([OH:32])([CH2:29][CH:30]=[CH2:31])[CH2:26][CH:27]=[CH2:28])[CH3:21])=[CH:16][CH:15]=1.C(N(C(C)C)C(C)C)C>ClCCl>[CH2:29]([C:25]1([CH2:26][CH:27]=[CH2:28])[O:32][C:2](=[O:4])[N:22]([C@H:20]([C:17]2[CH:16]=[CH:15][C:14]([Br:13])=[CH:19][CH:18]=2)[CH3:21])[CH2:23][CH2:24]1)[CH:30]=[CH2:31]
Reactant: C=CCC(O)(CC=C)CCN[C@@H](C)c1ccc(Br)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC1(CC=C)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphosgene (6.90 g) is added to a solution of 4-{2-[(S)-1-(4-bromo-phenyl)-ethylamino]-ethyl}-hepta-1,6-dien-4-ol (7.86 g) and ethyl-diisopropyl-amine (4 mL) in dichloromethane (150 mL) chilled in an ice bath. The cooling bath is removed and the solution is stirred at room temperature overnight. Water is added and the organic phase is then separated. The organic phase is dried (Na2SO4) and concentrated to give the crude title compound that is used without further purification. Yield: 8.65 g (ca. 90% pure); LC (method 1): tR=4.03 min; Mass spectrum (ESI+): m/z=364/366 (Br) [M+H]+.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].O[C:17]1[C:18]([C:23]([O:25][CH3:26])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:17]1[C:18]([C:23]([O:25][CH3:26])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=1)(=[O:3])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ncccc1O
Solvent: ClCCl
Product: COC(=O)c1ncccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triflic anhydride (5.0 g, 18.0 mmol) was added dropwise to a cold (0° C.) solution of methyl 3-hydroxypicolinate (2.5 g, 16.3 mmol) and TEA (2.5 mL, 18.0 mmol) in CH2Cl2 (80 mL). The mixture was stirred at 0° C. for 1 h before it was allowed to warm up to room temperature where it stirred for an additional 1 h. The mixture was then quenched with saturated NaHCO3 solution (40 mL) and the organic layer was separated, washed with brine, dried over MgSO4 and concentrated to give methyl 3-(trifluoromethylsulfonyloxy)picolinate (i.e., Cap-174, step a) (3.38 g, 73%) as a dark brown oil (>95% pure) which was used directly without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 8.72-8.79 (1 H, m), 7.71 (1 H, d, J=1.5 Hz), 7.58-7.65 (1 H, m), 4.04 (3 H, s). Rt=1.93 min (Cond.-MD1); LC/MS: Anal. Calcd. for [M+H]+ C8H2F3NO5S: 286.00; found: 286.08.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:35])[NH:23][CH2:24][CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C=O)C>[C:17]([O:21][C:22](=[O:35])[NH:23][CH2:24][CH2:25][N:26]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=2)=[CH:16][CH:15]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCN(Cc1ccc(Cl)cc1)C(=O)c1ccc(-c2ccncc2)cc1
Reaction time: 8 h
Yield: 78.7 %

Procedure:
The 4-pyridin-4-yl-benzoic acid hydrochloride salt (100 mg, 0.502 mmol), [2-(4-chlorobenzylamino)-ethyl]-carbamic acid tert-butyl ester (143 mg, 0.502 mmol), HOBt (77 mg, 0.502 mmol), and EDCI (56 mg, 0.552 mmol) were dissolved in 1.7 mL DMF, then treated with triethyl amine (77 μL, 0.552 mmol) to room temperature. The reaction was allowed to stir overnight to completion and partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with hexanes/ethyl acetate gradients plus 2% triethylamine) to afford the {2-[(4-chlorobenzyl)-(4-pyridin-4-yl-benzoyl)-amino]-ethyl}-carbamic acid tert-butyl ester as a colorless oil (184 mg, 93%). 1H NMR (CDCl3, 400 MHz) δ 8.68 (d, J=4.8 Hz, 2H), 7.65 (m, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.48 (d, J=4.4 Hz, 2H), 7.34 (m, 2H), 7.13 (m, 2H), 4.91 (m, 1H), 4.59 (brs, 2H), 3.62 (m, 2H), 3.44 (m, 2H), 1.46 (s, 9H). LCMS (APCI+) m/z 466 [M+H]+; Rt=3.19 min.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23](Br)[CH:22]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[C:11]([F:20])[CH:10]=2)[N:3]=1.[CH3:29][N:30]([CH3:33])C=O>C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:9]3[CH:29]=[N:30][CH:33]=[C:11]([F:20])[CH:10]=3)[CH:22]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[C:11]([F:20])[CH:10]=2)[N:3]=1
Reactant: CN(C)C=O
Reactant: CN1C(=O)C(c2ccc(OC(F)(F)F)c(F)c2)(c2ccc(F)c(Br)c2)N=C1N
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CN1C(=O)C(c2ccc(OC(F)(F)F)c(F)c2)(c2ccc(F)c(-c3cncc(F)c3)c2)N=C1N
Temperature: 150 °C
Yield: 74 %

Procedure:
A mixture of 2-amino-5-(3-bromo-4-fluorophenyl)-5-[3-fluoro-4-(trifluoromethoxy)phenyl]-3-methyl-3,5-dihydroimidazol-4-one (0.17 g, 0.366 mmol), 5-fluorpyridin-3-yl-tri(n-butyl)stannate (0.212 g, 0.55 mmol) and bis(triphenylphosphino)palladium(II) chloride (0.013 g, 0.018 mmol) in dimethyl formamide is degassed, heated at 150° C. for 1 h, cooled to room temperature and diluted with ethyl acetate and 2% aqueous lithium chloride. The organic phase is separated, washed with 2% aqueous lithium chloride, dried over sodium sulfate and concentrated in vacuo. Purification of the resultant residue by flash chromatography (silica, 97:3:0.25 methylene chloride/methanol/concentrated ammonium hydroxide as eluent) affords the title compound as a white solid, 0.130 g (74% yield), mp 91-97° C.; identified by HNMR and mass spectral analyses. 1H NMR (300 MHz, CD3OD) 8.55 (m, 1H), 8.49 (d, J=3.0 Hz, 1H), 7.83 (d, J=9.6 Hz, 1H), 7.60-7.21 (m, 6H), 3.13 (s, 3H); IR (ATR) 3352, 3070, 1732, 1669, 1598, 2502, 1479, 1421, 1252, 1217, 1171, 883, 817, 794, 703 cm−1; ESI MS m/z 481