Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.C([Li])(C)(C)C.CN(C)[CH:17]=[O:18].C(=O)=O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:8][CH3:9])[C:5]([CH:17]=[O:18])=[CH:6][CH:7]=1
Reactant: COc1cccc(Cl)n1
Reactant: CN(C)C=O
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1nc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To 2-Chloro-6-methoxypyridine (25, 0.511 g, 3.56 mmol) in tetrahydrofuran (10 mL) cooled in a −78° C. acetone/dry ice bath was added tert-butyllithium (1.7M in pentane, 5.0 mL, 7.66 mmol). The reaction was allowed to stir for 1 hour. Dimethylformamide (0.673 mL, 17.4 mmol) was added and the reaction was allowed to continue for an additional 30 minutes at −78° C., then stirred for 30 minutes outside of the dry-ice bath. The reaction was placed back in the dry-ice bath and quenched with 6 N HCl (1.5 mL) followed by water and allowed to warm to room temperature. The reaction was extracted with diethyl ether and aqueous (1M) sodium bicarbonate. The organic layer was separated, dried with anhydrous magnesium sulfate, filtered and volatiles removed by rotary evaporation, and the resulting yellow solid was dried under vacuum to provide 561 mg of compound 26 (3.27 mmol, 92% yield). MS (ESI) [M+H+]+=172.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:24]([OH:26])=[O:25])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CC(=O)CC>[CH3:37][C:36]([CH3:39])([CH3:38])[C:35](=[O:40])[CH2:34][O:25][C:24]([C:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:12]1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)OCC(=O)C(C)(C)C)(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of piperidine-1,3,3-tricarboxylic acid 1-tert-butyl 3-benzyl ester (2.85 g 7.85 mmol), potassium carbonate (1.4 g 10 mmol) and bromopinacolone (1.73 mL 17 mmol) in butan-2-one is stirred at room temperature for 6 h. The mixture is washed with water, dried over magnesium sulphate and concentrated under reduced pressure. After purification by column chromatography, the product is crystallized in heptane to give piperidine-1,3,3-tricarboxylic acid 1-tert-butyl 3-benzyl 3-(3,3-dimethyl-2-oxobutyl)ester melting at 60° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH3:6][C:7](=[CH:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15]O)[CH3:13])[CH3:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][CH2:15][CH2:14][CH:12]([CH2:11][CH2:10][CH:9]=[C:7]([CH3:8])[CH3:6])[CH3:13])(=[O:4])[CH:2]=[CH2:3]
Reactant: CC(C)=CCCC(C)CCO
Reactant: C=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCC(C)CCC=C(C)C
Temperature: 150 °C

Procedure:
24 g of acrylic acid, 31 g of citronellol and 1.5 g of p-toluenesulfonic acid in 500 mL of toluene were heated to reflux at a oil temperature of 150° C. for 19 h. Subsequently, the reaction mixture was quenched by the addition of salt saturated sodium bicarbonate solution. The mixed solution was extracted with ether. The organic layers were combined and washed with salt saturated sodium bicarbonate solution, an aqueous solution of sodium hydroxide, and then salt saturated ammonium chloride solution, and then dried over salt saturated brine and sodium sulfate anhydrous. Finally, the resultant oily product was evaporated under reduced pressure to obtain citronellyl acrylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Sn](CCCC)(CCCC)CCCC)[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:33]=[C:32]2I>CN(C=O)C.C(Cl)Cl.[Cu]I.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>[Cl:1][C:2]1[N:3]=[C:4]([C:32]2[C:31]3[C:35](=[CH:36][CH:37]=[C:29]([C:23]4[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=4[F:21])[CH:30]=3)[N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:33]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cc(-c3c(F)cccc3F)ccc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cc(-c2cncc(Cl)n2)c2cc(-c3c(F)cccc3F)ccc21
Temperature: 100 °C
Yield: 35.1 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-6-(tributylstannyl)pyrazine (177 mg, 0.439 mmol) and tert-butyl 5-(2,6-difluorophenyl)-3-iodo-1H-indole-1-carboxylate (200 mg, 0.439 mmol) in DMF (2.5 mL) followed by CuI (18 mg, 0.044 mmol) and Pd(PPh3)4 (50.8 mg, 0.044 mmol). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 40 min, and then the mixture was diluted with DCM. The organic layer was separated, washed with water (20 mL×4), dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 0-5% EtOAc in Hexanes) to give tert-butyl 3-(6-chloropyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indole-1-carboxylate (68.0 mg, 0.154 mmol, 35.0% yield) as a white solid. MS (ESI, pos. ion) m/z: 442 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=[O:2].[CH:16]([N:18]1[CH:27](C(O)=O)[CH:26]([CH3:31])[CH:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH2:24]2)[CH2:19]1)=O>C(OC(=O)C)(=O)C>[CH3:31][CH:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][N:18]2[CH:16]=[C:7]3[C:8]([C:9](=[O:14])[C:10]4[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=4[C:6]3=[O:15])=[C:27]12
Reactant: CC1C2CC=CC=C2CN(C=O)C1C(=O)O
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: CC1c2ccccc2Cn2cc3c(c21)C(=O)c1cccc([N+](=O)[O-])c1C3=O
Yield: 138.9 %

Procedure:
A mixture of 5-nitro-1,4-naphthoquinone (4.7 g) and N-formyl-4-methyl-3-tetrahydroisoquinolinecarboxylic acid (2.4 g) suspended in acetic anhydride (15 ml) was stirred and heated at 70°-75° for 21/2 hours. The mixture was cooled and the solid formed was collected by filtration, washed with acetic anhydride, then with ether and finally dried to give the title compound (5.4 g) as a yellow crystalline solid. N.m.r. in DMSOd6 (ppm) δ 1.49(14-CH3);4.88(14-H); 5.37, 5.47(5-CH2); 8.39(10-H). U.v. λmax 246 nm, E11 481; 376 nm, E11 83.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:13])=[CH:4][C:3]=2[O:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH:27]([CH3:30])[CH2:28][OH:29]>C(Cl)Cl>[OH:13][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:12][C:11]2=[CH:10][C:6]=1[C:7]([NH:26][CH:27]([CH3:30])[CH2:28][OH:29])=[O:9]
Reactant: CC(N)CO
Reactant: O=C(O)c1cc2c(cc1O)OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(CO)NC(=O)c1cc2c(cc1O)OCO2
Yield: 52 %

Procedure:
4,5-Methylenedioxysalicylic acid was activated by carbonyldiimidazole in methylene chloride and combined with 2-amino-1-propanol in essentially an identical manner as for Example 1 above. An acidic quench and subsequent purification by flash chromatography (SiO2) using (1:1) hexane-ethyl acetate gave 2-(2-hydroxy-4,5-methylenedioxybenzamido)-1-propanol as a waxy white solid in 52% yield.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH2:20][N:19]([CH3:21])[CH2:18][CH2:17][CH:16]=3)[CH:10]=2)=[C:6]([N+:24]([O-])=O)[CH:5]=1)(=[O:3])[CH3:2].[CH2:27](O)C>[Pd]>[C:1]([C:4]1[CH:23]=[CH:22][C:7]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]4[CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH2:20]4)[CH:10]=3)[CH:27]=[N:24][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Nc2cccc(C3=CCCN(C)C3)c2)c([N+](=O)[O-])c1
Reactant: CCO
Agent: [Pd]
Product: CC(=O)c1ccc2c(c1)ncn2-c1cccc(C2CCCN(C)C2)c1
Temperature: 80 °C
Yield: 50 %

Procedure:
To a solution of 4-acetyl-N-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]-2-nitroaniline (6, Ex. 12a) (1 g, 3 mmol) in ethanol (50 ml) was added a catalytic amount of palladium on charcoal and the mixture was hydrogenated at ambient pressure over night. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. To this concentrate formic acid (10 ml) was added and the resulting solution was stirred at 80° C. over night. Excess formic acid was removed by evaporation. The residue was dissolved in water and rendered alkaline by addition of solid sodium carbonate. Extraction with ethyl acetate and treatment of the extract with activated carbon in ethanol afforded 5-acetyl-1-[3-(1-methylpiperidin-3-yl)phenyl]-benzimidazole (9) (0.5 g, 50%) as an oil. m/e 333.
Reaction SMILES: [CH3:1][C:2]([CH:6]1[CH2:11][CH2:10][O:9][C:8]([CH3:13])([CH3:12])[O:7]1)([CH3:5])[CH:3]=C.P([O-])([O-])([O-])=[O:15]>C1COCC1.O=[Os](=O)(=O)=O>[CH3:12][C:8]1([CH3:13])[O:7][CH:6]([C:2]([CH3:1])([CH3:5])[CH:3]=[O:15])[CH2:11][CH2:10][O:9]1
Reactant: O=P([O-])([O-])[O-]
Reactant: C=CC(C)(C)C1CCOC(C)(C)O1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: CC1(C)OCCC(C(C)(C)C=O)O1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
286 mg (1.55 mmol) of acetonide 44 is dissolved in 18 ml of THF, and 14 ml of aqueous phosphate buffer at pH 7 is added. 400 μl (0.031 mol, 0.02 equivalent) of OsO4 solution (2.5% in tert-butanol) is added in drops to the reaction mixture that is stirred vigorously. After 10 minutes, 996 mg (4.656 mmol, 3 equivalents) of NalO4 is added in portions over a period of 20 minutes. The mixture is stirred vigorously at room temperature and, after 24 and 48 hours in each case, another 332 mg (1.55 mmol, 2×1.0 equivalents each) of NalO4 is added. After 55 hours, the phases are separated, the aqueous phase is extracted with ether, the combined organic phases are dried on MgSO4 and concentrated by evaporation. The residue is purified by column chromatography with pentane:DE=1:1. 221 mg (1.19 mmol) of aldehyde 45 corresponding to a yield of 76% is obtained.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][SH:35].CC(C)([O-])C.[Na+]>CS(C)=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:35][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CN(C)CCS
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(I)cc3F)c2C#N)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(SCCN(C)C)cc3F)c2C#N)CC1
Temperature: 120 °C

Procedure:
In a microwave reaction tube was placed 4-[5-cyano-6-(2-fluoro-4-iodo-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (10 mg, 0.19 mmol), 2-dimethylamino-ethanethiol (27 mg, 0.19 mmol), di-m-bromobis (tri-t-butylphosphino)dipalladium (I) (8 mg, 0.0095 mmol), sodium t-butoxide (55 mg, 0.57 mmol), and DMSO (0.5 mL). The reaction mixture was heated at 120° C. under microwave for 4 hours. The resulting mixture was filtered through a syringe filter and purified by preparative HPLC. 1H NMR (CDCl3, 400 MHz) δ 1.26 (d,6H), 1.86 (m, 2H), 2.00 (m, 2H), 2.86 (s, 6H), 3.20 (m, 2H), 3.30 (m, 2H), 3.43 (m, 2H), 3.78 (m, 2H), 4.94 (m, 1H), 5.44 (m, 1H), 7.22 (s, 1H), 7.24 (s, 1H), 7.35 (s, 1H), 8.11 (t, 1H), 8.45 (s, 1H). Exact mass calculated for C24H31 FN6O3S 502.22, found 503.2 (MH+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[O:44][N:43]=[CH:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[O:44][N:43]=[CH:42][CH:41]=5)=[O:54])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ccno4)cc2)CCN3CC(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ccno4)cc2)CCN3CC(C)C)cc1
Yield: 50.2 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(isoxazol-5-ylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (20 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (118 mg) in dichloromethane (20 ml) at −78° C. After finishing the dropping, water was added to the mixture, an aqueous solution of saturated sodium bicarbonate was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:4), and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(isoxazol-5-ylmethyl) sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (103 mg) (Compound 328) as yellow crystals, and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(isoxazol-5-ylmethyl) sulfonyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (72.8 mg) (Compound 329) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(CO)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.7 %

Procedure:
To a solution of 2-fluoro-4-nitrobenzaldehyde (1.0 g, 5.92 mmol) in CH3OH (10 mL) was added NaBH4 (814 mg, 22 mmol). After stirring at RT for 15 min, the mixture was concentrated. The residue was partitioned between 100 mL of EA and 100 mL of brine. The combined organic layers were washed with brine (100 mL×2), dried over Na2SO4, and concentrated to afford 1.0 g of (2-fluoro-4-nitrophenyl) methanol (99%) as a red solid. MS (ESI) m/e [M+1]+ 172.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH2:33][CH2:32]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)Nc2nc3ccc(F)cc3nc2OC)CC1
Yield: 82 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-methoxyphenyl) piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 82%). 1H NMR (200 MHz, CDCl3): δ 3.14-3.17 (m, 4H), 3.78-3.81 (m, 4H), 3.88 (s, 3H), 4.14 (s, 3H), 6.88-7.41 (m, 7H), 7.81 (dd, J=9.0 and 5.7 Hz. 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:33])[C:18]([CH3:32])([CH3:31])[CH2:19][NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S.[N:36]1C=CC=CC=1>>[CH2:1]([O:8][C:9](=[O:34])[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:33])[C:18]([CH3:31])([CH3:32])[CH2:19][NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([C:28](=[NH:36])[NH2:29])=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: CC(C)(CNC(=O)c1ccc(C#N)cc1)C(=O)N1CCC(CC(=O)OCc2ccccc2)CC1
Agent: S
Product: CC(C)(CNC(=O)c1ccc(C(=N)N)cc1)C(=O)N1CCC(CC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
N-(N-4-Cyanobenzoyl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid benzyl ester (0.6 g) was dissolved in pyridine (15 ml) and hydrogen sulfide gas was introduced for 1 hour. The reaction container was sealed and the reaction mixture was stirred at a room temperature for 12 hours. The solvent was distilled off and methyl iodide (2 g) was added, followed by refluxing in acetone for 3 hours. After the solvent and excess methyl iodide were distilled off from the reaction solution, ammonium acetate (0.2 g) was added and the mixture was refluxed in methanol for 6 hours. After the solvent was distilled off, the residue was dissolved in a small amount of methylene chloride and reprecipitated from hexane to yield N-(N-4-amidinobenzoyl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid benzyl ester (0.25 g, 40.0%).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][OH:19])[CH:13]=[C:12]([CH2:20]N(CC)CC)[C:11]=2[OH:26])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[N:27]1[N:28]([C:36]2[CH:41]=[C:40]([CH2:42][CH2:43][CH2:44][OH:45])[CH:39]=[CH:38][C:37]=2[OH:46])[N:29]=[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=12.CO.C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:20]([C:12]1[CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][OH:19])[CH:15]=[C:10]([N:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1]2)[C:11]=1[OH:26])[C:38]1[CH:39]=[C:40]([CH2:42][CH2:43][CH2:44][OH:45])[CH:41]=[C:36]([N:28]2[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]3=[N:27]2)[C:37]=1[OH:46]
Reactant: OCCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: CCN(CC)Cc1cc(CCCO)cc(-n2nc3ccccc3n2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Product: OCCCc1cc(Cc2cc(CCCO)cc(-n3nc4ccccc4n3)c2O)c(O)c(-n2nc3ccccc3n2)c1
Yield: 61.2 %

Procedure:
In 100 ml of xylene were dissolved 35.9 g (97.0 mmols) of crude 2-(2H-benzotriazole-2-yl)-4-(3-hydroxypropyl)-6-(N,N-diethylaminomethyl)phenol synthesized in Example 11 and 26.1 g (97.0 mmols) of the purified product of 2-(2H-benzotriazole-2-yl)-4-(3-hydroxypropyl)phenol synthesized in Example 6. 5 ml of a methanol solution of 28% sodium methylate was added, and the mixture was refluxed in a nitrogen stream for 10 hours. The subsequent treatment was carried out in the same manner as in Example 12, giving 33.0 g of 2,2'-methylenebis[6-(2H-benzotriazole-2-yl)-4-(3-hydroxypropyl)phenol] as white crystals (yield 61.2%, purity 99.0%).
Reaction SMILES: [ClH:1].C(O)(C(F)(F)F)=O.C(OC([N:16]1[C@@H:20]([CH3:21])[CH2:19][CH2:18][C@H:17]1[C:22]1[NH:23][C:24]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH:33]=[C:32]([C:37]#[C:38][C:39]2[NH:43][C:42]([C@@H:44]4[CH2:49][C@@H:48]5[C@@H:46]([CH2:47]5)[N:45]4C(OC(C)(C)C)=O)=[N:41][CH:40]=2)[CH:31]=[CH:30]3)=[CH:25][N:26]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:21][C@@H:20]1[NH:16][C@H:17]([C:22]2[NH:26][CH:25]=[C:24]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[CH:33]=[C:32]([C:37]#[C:38][C:39]3[N:43]=[C:42]([C@@H:44]5[CH2:49][C@@H:48]6[C@@H:46]([CH2:47]6)[NH:45]5)[NH:41][CH:40]=3)[CH:31]=[CH:30]4)[N:23]=2)[CH2:18][CH2:19]1
Reactant: C[C@H]1CC[C@@H](c2ncc(-c3ccc4cc(C#Cc5cnc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]5)ccc4c3)[nH]2)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: C[C@H]1CC[C@@H](c2nc(-c3ccc4cc(C#Cc5c[nH]c([C@@H]6C[C@H]7C[C@H]7N6)n5)ccc4c3)c[nH]2)N1
Reaction time: 2 h
Yield: 135.2 %

Procedure:
4M HCl (0.611 mL, 2.445 mmol) in dioxane was added to a mixture of a TFA salt of (1R,3S,5R)-tert-butyl 3-(5-((6-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (53.6 mg, 0.061 mmol) in dioxane (1.5 mL) and the reaction was vigorously stirred for 2 h. The reaction was concentrated under a steam of nitrogen overnight to yield an HCl salt of (1R,3S,5R)-3-(4-((6-(2-((2S,5S)-5-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (37 mg) which was used without further purification. LC-MS retention time 2.302 min; m/z 449.40 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].[Br:13]Br>CC(O)=O>[CH2:1]([C:3]1[NH:4][C:5]2[C:11]([Br:13])=[C:10]([NH2:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2ccc(N)cc2[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCc1nc2ccc(N)c(Br)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 1.3 g (7.7 mmol) of 2-ethyl-5-aminobenzimidazole in 50 ml of AcOH was added 0.40 ml of Br2 (7.5 mmol) dropwise and resulting reaction mixture was stirred for 1 h at 25° C. The reaction mixture was concentrated in vacuo and purified on silica gel column chromatography (20% isopropanol/EtOAC) to yield 1.5 g (6.3 mmol, 82%) of the desired product.
Reaction SMILES: [O:1]([CH:8]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:27](I)[CH3:28]>CN(C)C=O.C(OCC)(=O)C>[O:1]([C:8]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH2:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(OCC)C(Oc1ccccc1)P(=O)(OCC)OCC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(CC)(Oc1ccccc1)P(=O)(OCC)OCC
Reaction time: 0.75 h

Procedure:
Tetraethyl (phenoxymethylene)-bisphosphonate (1.14 g) was added to a suspension of 55% sodium hydride (0.15 g) in dimethylformamide (10 ml). After 45 minutes at room temperature, ethyl iodide (0.49 ml) was added, and the mixture was left overnight at room temperature, diluted with ethyl acetate and washed with 40% aqueous calcium chloride. The organic phase was dried and evaporated to leave an oil which was purified by chromatography on silica gel. The title compound was isolated as a colourless oil.