Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:11].FC(F)(F)C(O)=O>C(OCC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(c1nc2ccccc2s1)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Mix 4-[(2-benzothiazolyl)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (10.5 g, 30.31 mmol) and trifluoroacetic acid (75 mL) and stir at room temperature for 2 hours. Cool in an ice/water bath and add ethyl ether until a solid begins to precipitate. Stir at 0° C. for 30 minutes, collect the solid by filtration and wash with ethyl ether and recrystallize (methanol/ethyl ether) to give the title compound as a white powder; mp 195°-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20](=[N:26][OH:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[OH:27][N:26]=[C:20]([CH2:19][C:4]1[C:3]2[C:7](=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=2[Cl:1])[NH:6][CH:5]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(CBr)=NO
Reactant: Clc1cc(Cl)c2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(Cc1c[nH]c2cc(Cl)cc(Cl)c12)=NO
Yield: 70 %

Procedure:
Mix 4,6-dichloroindole (5.90 g, 31.72 mmol), potassium carbonate (1.81 g, 47.6 mmol) and anhydrous methylene chloride (200 mL). Stir and add a solution of ethyl 3-bromo-2-hydroxyiminopropanoate (7.00 g, 33.31 mmol) in methylene chloride (75 mL). Stir under a nitrogen atmosphere for 48 hours. Take the solution up in methylene chloride (100 mL) and wash with water (300 mL), saturated sodium hydrogen carbonate (200 mL) and brine (100 mL). Dry (MgSO4) and evaporate the solvent in vacuo to give a tan solid. Purify by silica gel chromatography (1 to 3% acetone in chloroform) to give the title compound as a yellow solid (7.00 g, 99% based on consumed starting material). Recrystallize (diethyl ether/hexane) to give the title compound as white crystals (4.0 g, 56%); mp 175°-176° C.
Reaction SMILES: C(Cl)Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[C:13]([C:16]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:17]=1[C:18]([OH:20])=O)([CH3:15])[CH3:14].FC(F)(F)C(OC(=O)C(F)(F)F)=O>O>[CH3:26][O:25][C:22]1[CH:21]=[C:17]2[C:16]([C:13]([CH3:15])([CH3:14])[C:5]3[O:4][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[C:6]=3[C:18]2=[O:20])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(C)(C)c2cc3ccccc3o2)c(C(=O)O)c1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: COc1ccc2c(c1)C(=O)c1c(oc3ccccc13)C2(C)C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To the DCM solution (1 ml) of 2-(1-benzofuran-2-yl-1-methylethyl)-5-methoxy benzoic acid (63 mg), trifluoroacetic anhydride (0.03 ml) was added at room temperature under nitrogen atmosphere. The mixture was stirred for 30 min. The reaction mixture was then added with water and extracted with DCM. The organic layer was dried over sodium sulfate. The residues obtained after concentration under reduced pressure were purified by silica gel column (DCM) to obtain the title compound (50 mg, 84%).
Reaction SMILES: [N+]([O:4][C@H:5]([CH2:12][O:13][N+]([O-])=O)[CH2:6][CH2:7][CH2:8][C:9](O)=[O:10])([O-])=O.[N+:17]([O:20][C@@H:21]([CH3:28])[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])([O-:19])=[O:18]>>[N+:17]([O:20][C@@H:21]([CH3:28])[CH2:22][CH2:23][CH2:24][C:25]([O:27][C@@H:8]1[CH2:9][O:10][C@@H:6]2[C@H:5]([OH:4])[CH2:12][O:13][C@H:7]12)=[O:26])([O-:19])=[O:18]
Reactant: O=C(O)CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Reactant: C[C@@H](CCCC(=O)O)O[N+](=O)[O-]
Product: C[C@@H](CCCC(=O)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O)O[N+](=O)[O-]

Procedure:
The title compound was prepared by following the procedure for the synthesis of EXAMPLE 4, except that in Step F the reagent (S)-5,6-di(nitrooxy)hexanoic acid was replaced by (S)-5-(nitrooxy)hexanoic acid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([C:19]1C=C[C:22]([O:25][CH3:26])=[CH:21][C:20]=1CCN)[CH2:13][CH2:12]2)(C(C)(C)C)(C)C.Cl.[N:31]1([CH2:38][CH2:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](O)=O)=[CH:42][CH:41]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:38][CH2:39][C:40]2[CH:48]=[CH:47][C:43]([CH2:44][CH2:36][CH2:37][NH:31][C:32]3[CH:33]=[C:22]([O:25][CH3:26])[CH:21]=[CH:20][C:19]=3[CH:14]3[CH2:13][CH2:12][C:11]4[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:42][CH:41]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1ccc(CCN2CCCCCC2)cc1
Reactant: COc1ccc(C2CCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(CCN)c1
Agent: Cl
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(CCN3CCCCCC3)cc2)c1

Procedure:
Synthesized from {2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methoxyphenyl}ethylamine and 4-(2-azepan-1-ylethyl)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, 4-(2-azepan-1-ylethyl)benzyl]{2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methoxyphenyl}ethylamine (59 mg) was used according to an analogous synthetic method to Example 325 described below to provide the title compound (38 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[CH:31][CH:30]=3)[CH:3]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 5′-bromo-6-methyl-4-(4-trifluoromethylphenyl)-[2,3′]bipyridinyl (example E.24) (0.15 g, 0.38 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.092 g, 0.42 mmol) according to the general procedure VI. Obtained as a white solid (0.085 g, 54%). MS (ISP) 407.2 [(M+H)+]; mp 161-177° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:14][NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[O:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)(=O)C.CO>[C:26]1([C:11]2([CH2:14][NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[O:17])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: [H][H]
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCNCC1

Procedure:
A mixture of 1.3 g (3.1 mmol) of 1-N-Benzyl-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)piperidine (Example 1), 100 mg of Pearlman's catalyst (palladium hydroxide on carbon, purchased from Aldrich Chemical Co., Milwaukee, Wis.) and 3 drops of acetic acid in 20 mL of methanol was stirred in a hydrogen atmosphere (50 psi) for 18 hr. The reaction mixture was filtered and the filtrate was concentrated to afford the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[Br:13][C:14]1[C:15](Cl)=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20]>C1COCC1>[Br:13][C:14]1[C:15]([O:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1ccnc(Cl)c1Br
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2nccc(C)c2Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-bromo-2-(4-methoxybenzyloxy)-4-methylpyridine was prepared by the procedure described in J. Med. Chem., 2008, 51, 3065. A pressure vessel was charged with anhydrous THF (25 ml) and sodium hydride (1.44 g, 36.18 mmol, 60% dispersion). To this stirred mixture was added portionwise a solution of 4-methoxybenzyl alcohol (5.0 g, 36.18 mmol) in anhydrous THF (15 ml). After addition was complete, the mixture was stirred at room temperature for 30 minutes and a solution of 3-bromo-2-chloro-4-picoline (4.97 g, 24.08 mmol) in anhydrous THF (15 ml) was added. The vessel was sealed and the reaction mixture was heated at 75° C. for 6 hours. Upon cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with water, sat'd NaCl(aq.), dried over MgSO4, filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 4:1 hexanes: EtOAc) gave the title compound as a clear oil which crystallized on standing (6.71 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH:17](O)[CH2:18][N:19]3[N:23]=[N:22][C:21]([C:24]([F:27])([F:26])[F:25])=[N:20]3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C(N2C(C(OC)=O)=CC(C(O)CN3C(C(F)(F)F)=NN=N3)=N2)=NC=CC=1.CS(Cl)(=O)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10](/[CH:17]=[CH:18]/[N:19]3[N:23]=[N:22][C:21]([C:24]([F:26])([F:25])[F:27])=[N:20]3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C(O)Cn2nnc(C(F)(F)F)n2)nn1-c1ncccc1Cl
Agent: COC(=O)c1cc(C(O)Cn2nnnc2C(F)(F)F)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(/C=C/n2nnc(C(F)(F)F)n2)nn1-c1ncccc1Cl
Yield: 61.2 %

Procedure:
225 mg (0.54 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-{1-hydroxy-2-[5-(trifluoromethyl)-2H-tetrazol-2-yl]ethyl}-1H-pyrazole-5-carboxylate and methyl 1-(3-chloropyridin-2-yl)-3-{1-hydroxy-2-[5-(trifluoromethyl)-1H-tetrazol-1-yl]ethyl}-1H-pyrazole-5-carboxylate in a ratio of 66:34 were initially charged in 7.0 ml of toluene, 75.3 mg (0.65 mmol) of methanesulphonyl chloride and 166 mg (1.64 mmol) of triethylamine were added at 0° C. and the mixture was stirred at reflux temperature for 10 hours. The reaction mixture was diluted with toluene and washed with sodium bicarbonate solution. The organic phases were dried over magnesium sulphate and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel, which gave 132 mg (45% of theory) of methyl 1-(3-chloropyridin-2-yl)-3-{(E)-2-[5-(trifluoromethyl)-2H-tetrazol-2-yl]vinyl}-1H-pyrazole-5-carboxylate and methyl 1-(3-chloropyridin-2-yl)-3-{(E)-2-[5-(trifluoromethyl)-1H-tetrazol-1-yl]vinyl}-1H-pyrazole-5-carboxylate in a ratio of 69:31. (logP: 3.37/3.49; MH+: 400.1; 1H-NMR (400 MHz, CD3CN, δ, ppm): 3.78 (s, 3H), 7.35 (m, 1H), 7.60 (m, 1H), 7.75 (m, 1H), 8.08 (m, 1H), 8.32 (m, 1H), 8.55 (m, 1H).)
Reaction SMILES: C([Al](CC(C)C)CC(C)C)C(C)C.[NH2:14][C:15]1[S:16][CH2:17][CH2:18][N:19]=1.[C:20]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([C:34]=1[OH:35])=[CH:32][CH:31]=[CH:30][CH:29]=2)(OCC)=[O:21]>C1(C)C=CC=CC=1>[S:16]1[CH2:17][CH2:18][N:19]=[C:15]1[NH:14][C:20]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([C:34]=1[OH:35])=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:21]
Reactant: CCOC(=O)c1cnc2ccccc2c1O
Reactant: NC1=NCCS1
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: Cc1ccccc1
Product: O=C(NC1=NCCS1)c1cnc2ccccc2c1O
Temperature: 8 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
167 ml of a solution of 25% by weight of triisobutyl aluminum in toluene were added with stirring over 20 minutes at 8° to 10° C. to a mixture of 37.4 g of 2-amino-thiazoline and 800 ml of methylene chlorideand the mixture was stirred at 8° C. for 30 minutes. 15.89 g of 3-carbethoxy-4-hydroxy-quinoline were added to the mixture which was then stirred for 30 minutes and then refluxed for 16 hours. The mixture was evaporated to dryness under reduced pressure and the residue was taken up in 1 liter of N aqueous hydrochloric acid. The solution was filtered and the filtrate was iced for 16 hours and was filtered. The product was washed with water and the filtrate was made alkaline with sodium carbonate. The mixture was filtered and the product was washed with water and dried to obtain 11.7 g of N-(4,5-dihydro-thiazol-2-yl)-4-hydroxy-3-quinoline-carboxamide.
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].C(N(CC)CC)C.Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=1.C(=O)([O-])O.[Na+]>C(O)CC>[F:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:1]=[CH2:2])[N:17]=1
Reactant: Fc1cccc(Br)n1
Reactant: C=C[B-](F)(F)F
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCCO
Solvent: CCN(CC)CC
Product: C=Cc1cccc(F)n1
Temperature: 100 °C
Reaction time: 11 h
Yield: 35.7 %

Procedure:
Potassium vinyltrifluoroborate (2.28 g), triethylamine (2.38 mL) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex (928 mg) were added in that order to an n-propanol solution (12 mL) of 2-bromo-6-fluoropyridine (2.0 g), and stirred at 100° C. for 11 hours, and then at room temperature for 2 days. Saturated sodium hydrogencarbonate solution was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried, concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain the entitled compound (500 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].S(Cl)(Cl)=O.[OH-].[Na+].Cl.Cl.[CH:20]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21]1>C1(C)C=CC=CC=1.O.CN(C=O)C>[CH:20]1([N:23]2[CH2:28][CH2:27][N:26]([C:7]([C:6]3[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=3)=[O:9])[CH2:25][CH2:24]2)[CH2:22][CH2:21]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: C1CN(C2CC2)CCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C(=O)N2CCN(C3CC3)CC2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-formyl-benzoic acid (54.4 g), toluene (500 mL), DMF (3.6 mL), and thionyl chloride (30.4 mL) was heated at 60° C. for 2 h and then was cooled to 5° C. In a separate flask, a 5° C. mixture of NaOH (50.7 g), water (550 mL), and toluene (150 mL) was treated with 1-cyclopropyl-piperazine dihydrochloride (70.0 g) in portions while the temperature was maintained below 10° C. After the addition was complete, the mixture was cooled to 5° C. and treated with the crude acyl chloride solution prepared as above at a rate such that the temperature did not exceed 10° C. After the addition was complete, the mixture was allowed to warm to room temperature and was stirred overnight. The biphasic mixture was basified to pH ˜10 with 1 N NaOH (300 mL). The layers were separated and the aqueous layer was extracted with toluene (100 mL×2). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated to yield the title compound as pale yellow viscous oil.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][P:7]([CH2:27][NH2:28])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[CH3:29][C:30]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:32]2[C:33]([O:35][C:36](=O)[C:31]=12)=[O:34]>>[CH3:5][O:6][P:7]([CH2:27][N:28]1[C:33](=[O:34])[C:32]2=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:30]([CH3:29])=[C:31]2[C:36]1=[O:35])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Reactant: COc1ccc(C)c2c1C(=O)OC2=O
Solvent: CC(=O)O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)c2c(C)ccc(OC)c2C1=O)OC
Yield: 47.1 %

Procedure:
In a manner analogous to that described in Example 3(A), from 0.41 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate and 0.21 g of 3-methyl-6-methoxyphthalic anhydride there was obtained 0.245 g of [(3-methoxy-6-methylphthalimido)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester in the form of a white foam.
Reaction SMILES: [Cl-:1].[CH3:2][N:3]1[CH:7]=[CH:6][N+:5]([CH3:8])=[C:4]1/[N:9]=[N:10]/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1>CN(C=O)C.BrCCCCCCBr>[Cl-:1].[CH3:8][N:5]1[CH:6]=[CH:7][N+:3]([CH3:2])=[C:4]1/[N:9]=[N:10]/[C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:18][CH2:19][N:20]([CH2:15][CH2:16][CH2:11][CH2:12][CH2:13][CH2:14][N:20]3[CH2:21][CH2:22][N:17]([C:14]4[CH:13]=[CH:12][C:11](/[N:10]=[N:9]/[C:4]5[N:5]([CH3:8])[CH:6]=[CH:7][N+:3]=5[CH3:2])=[CH:16][CH:15]=4)[CH2:18][CH2:19]3)[CH2:21][CH2:22]2)=[CH:15][CH:16]=1.[Cl-:1]
Reactant: Cn1cc[n+](C)c1/N=N/c1ccc(N2CCNCC2)cc1
Agent: BrCCCCCCBr
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cn1cc[n+](C)c1/N=N/c1ccc(N2CCN(CCCCCCN3CCN(c4ccc(/N=N/c5n(C)cc[n+]5C)cc4)CC3)CC2)cc1

Procedure:
2-[(E)(4-{4-[6-(4-{4-[(E)(1,3-dimethyl-1H-imidazol-3-ium-2-yl)diazenyl]phenyl}piperazin-1-yl)hexyl]piperazin-1-yl}phenyl)diazenyl]-1,3-dimethyl-1H-imidazol-3-ium chloride (I) was synthesized by dissolving 1,3-Dimethyl-2-[(E)(4-piperazin-1-ylphenyl)diazenyl]-1H-imidazol-3-ium chloride (0.9 g) in DMF (20 ml), Br(CH2)6Br (0.5 mol
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[Br:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1.C([O-])([O-])=O.[K+].[K+].N#N>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:36])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:41]3[CH:42]=[CH:43][C:38]([Br:37])=[CH:39][CH:40]=3)=[CH:25][CH:26]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: Brc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(Br)cc3)cc2)[nH]1)C(C)C
Temperature: 85 °C
Yield: 52.5 %

Procedure:
A solution of [2-methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (300 mg, 0.60 mmol), 1,4-dibromo-benzene (95 mg, 0.40 mmol) and aqueous K2CO3 (800 μl of a 2M solution) in dimethoxyethane (4 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 and the reaction was heated to 85° C. overnight. After cooling to room temperature, the reaction was quenched with acetic acid, filtered, and then concentrated. The crude product was purified by reverse phase preparative HPLC (10-85% MeCN—H2O; 0.1% formic acid modifier) to afford both the monosubstituted product (1-{2-[5-(4′-bromo-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (111 mg, 0.21 mmol, 53% yield) and the desired bis substituted product (1-{2-[5-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl]-[1,1′;4′,1″]terphenyl-4″-yl)-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (24 mg, 0.074 mmol, 19% yield): 1H-NMR: 400 MHz, (DMSO-d6) δ: 11.79 (s, 2H), 7.85-7.62 (m, 12H), 7.53 (s, 2H), 7.29 (d, 2H), 5.02 (m, 2H), 4.07 (t, 2H), 3.82 (m, 4H), 3.54 (s, 6H), 2.15-1.90 (m, 10H), 0.91 (d, 6H), 0.86 (d, 6H). LCMS-ESI+: calc'd for C46H55N8O6: 815.4 (M+H+). Found: 815.7 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([OH:16])[CH:13]=[CH:12]2)=[C:4]([Cl:17])[N:3]=1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1COCC1>[CH2:28]([O:27][C:25](=[O:26])[O:16][C@H:14]1[CH2:15][C@@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[Cl:17])[CH:12]=[CH:13]1)[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1S,4R)-4-(2,6-Dichloro-purin-9-yl)-cyclopent-2-enol (9.5 g, 35.05 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry THF (200 mL) is added followed by dry pyridine (5.54 g, 70.1 mmol). Ethyl chloroformate (15.21 g, 140.2 mmol) is added slowly so that the temperature does not rise above 40° C. and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 1 hour. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (200 mL) and water (200 mL). The organic layer is washed with water (150 ml) and brine (150 ml), dried over MgSO4, filtered and the solvent is removed in vacuo. The title compound is obtained after crystallisation from methanol. 1H nmr (CDCl3, 400 MHz); 8.20 (s, 1H), 6.45 (m, 1H), 6.25 (m, 1H), 5.75 (m, 1H), 5.70 (m, 1H), 4.25 (q, 2H), 3.20 (m, 1H), 2.05 (m, 1H), 1.35 (t, 3H), MS (ES+) m/e 343 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13].C(N(CC)CC)C>C(Cl)Cl>[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(O)c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 57.7 %

Procedure:
A solution of benzoyl chloride (16.9 ml, 0.146 moles) in 200 ml of methylene chloride was added under nitrogen dropwise over approximately 1 hour to a solution of 2-amino-1-phenylethanol (20.0 g, 0.146 moles) and triethylamine (20.0 ml, 0.146 moles) in 300 ml of methylene chloride at ice bath temperature. After the addition the reaction was stirred at ice bath temperature for 2 hours and then at room temperature for approximately 2 hours. The solid formed was collected by filtration and dried to give N-(2-hydroxy-2-phenyl-ethyl)-benzamide (20.33 g, 58%) as a white solid, mp 140-143° C.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C(=O)(SC)O[CH2:22][CH2:23][CH:24]1CCCCC1>>[CH:2]1([C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]2[CH2:18][C:17](=[O:19])[NH:16][C:14]2=[O:15])=[O:11])[CH3:8])=[O:5])[CH2:4][CH2:24][CH2:23][CH2:22][CH2:3]1
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Reactant: CSC(=O)OCCC1CCCCC1
Product: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C1CCCCC1

Procedure:
Following the procedures for synthesizing [(1-isobutanoyloxyethoxy)carbonyloxy]succinimide (17) and replacing compound (2) with compound (6) affords [(1-cyclohexanoyloxyethoxy)carbonyloxy]succinimide (20).