Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H][H].C([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[OH:22][CH:17]([C:14]1[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=1)[C:18]([F:20])([F:21])[F:19]
Reactant: [H][H]
Reactant: OC(c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: CC(=O)O
Product: Oc1ccc(C(O)C(F)(F)F)cc1

Procedure:
At 50° C. and a hydrogen pressure of 5 bar, 65.7 g (233 mmol) of 1-benzyloxy-4-(1-hydroxy-2,2,2-trifluoroethyl)benzene were hydrogenated in the presence of 5.2 g of palladium (10% on carbon) in 500 ml of glacial acetic acid. The catalyst was filtered off and the mixture was concentrated. This gave 44.1 g (99% of theory) of the product as a colourless oil.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5](Br)=[CH:4][C:3]=1[F:12].[Mg].C[O:15][B:16](OC)[O:17]C>O1CCCC1>[F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([B:16]([OH:17])[OH:15])=[CH:4][C:3]=1[F:12]
Reactant: COB(OC)OC
Reactant: Fc1cc(Br)c2occc2c1F
Agent: [Mg]
Solvent: C1CCOC1
Product: OB(O)c1cc(F)c(F)c2ccoc12
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 123.7 %

Procedure:
A mixture of 2.0 gm (8.58mMol) 4,5-difluoro-7-bromobenzofuran and 0.202 gm (8.58 mMol) magnesium in 10 mL tetrahydrofuran was heated at reflux for 50 minutes. The resulting mixture was then cooled to −5° C. and treated dropwise with 1.01 mL (8.93 mMol) trimethylborate over 20 minutes. The reaction mixture was stirred at room temperature for 1.5 hours and was then concentrated under reduced pressure. The residue was partitioned between 50 mL deionized water and 50 mL ethyl acetate. The mixture was treated with 0.3 mL acetic acid to adjust to a neutral pH. The phases were separated and the aqueous phase was extracted well with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure to provide 2.1 gm of the title compound.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].[CH2:7]([C:9]1[N:10]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[N:11]=[C:12]2[C:17](=[O:18])[NH:16][C:15]([C:19]3[C:20](OCCC)=[N:21][CH:22]=[C:23]([S:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)(=[O:27])=[O:26])[CH:24]=3)=[N:14][C:13]=12)[CH3:8]>CC(O)C>[CH2:7]([C:9]1[N:10]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[N:11]=[C:12]2[C:17](=[O:18])[NH:16][C:15]([C:19]3[C:20]([O:4][CH:2]([CH3:3])[CH3:1])=[N:21][CH:22]=[C:23]([S:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)(=[O:26])=[O:27])[CH:24]=3)=[N:14][C:13]=12)[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CCCOc1ncc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Agent: [K+]
Solvent: CC(C)O
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(C)CC4)cnc3OC(C)C)[nH]c(=O)c2nn1Cc1ccccn1
Yield: 35.3 %

Procedure:
Potassium t-butoxide (290 mg, 2.60 mmol) was added to a stirred solution of the title compound of Example 20 (239 mg, 0.43 mmol) in propan-2-ol (7 ml) under nitrogen and the reaction mixture heated under reflux for 48 hours, then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue partitioned between water (20 ml) and ethyl acetate (20 ml). The phases were separated, the aqueous phase extracted with ethyl acetate and the combined organic solutions dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100:0 to 95:5), to afford the title compound (84 mg, 35%) as a foam. δ (CDCl3): 1.28 (3H, t), 1.56 (6H, 2×d), 2.28 (3H, s), 2.50 (4H, m), 3.04 (2H, q), 3.14 (4H, m), 5.68 (3H, m), 7.09 (1H, d), 7.22 (1H, m), 7.62 (1H, m), 8.57 (1H, d), 8.62 (1H, s), 9.02 (1H, s), 10.68 (1H, s). LRMS: m/z 553 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCCSc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCSc1ccncc1)c1ccccc1
Yield: 34.3 %

Procedure:
To a solution of 1.00 g (5.49 mmol) of 4-(4-aminobutylthio)pyridine and 0.92 ml (6.60 mmol) of triethylamine in 30 ml of methylene chloride, 0.67 ml (5.77 mmol) of benzoylchloride was added with stirring under ice-cooling and the mixture was stirred at room temperature for 13 hours. The mixture was washed with saturated aqueous sodium bicarbonate and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent:ethyl acetate) to give 0.54 g of the desired compound (34.4% yield, colorless crystals), mp. 75°-77° C.
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])[CH2:5][CH3:6].O>CCOCC>[CH2:4]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH:9][C:2]#[N:1])[CH2:5][CH3:6]
Reactant: N#CBr
Reactant: CCCc1ccccc1N
Solvent: CCOCC
Solvent: O
Product: CCCc1ccccc1NC#N
Reaction time: 2.5 h
Yield: 41.8 %

Procedure:
A mixture of cyanogen bromide (1.89 g, 17.9 mmol), and 2-n-propylaniline (3.87 g, 28.65 mmol) in ether (50 mL) was stirred for 2.5 hours under nitrogen atmosphere. The mixture was poured into water and extracted with diethylether. The solvent was dried over magnesium sulfate and concentrated in vacuo at room temperature to give 2-propylphenylcyanamide (1.2 g, 26%) as an off white solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][N:27]2[C:31]([C:32](=[O:35])[CH2:33]Br)=[C:30]([CH2:36][CH3:37])[N:29]=[C:28]2[CH2:38][CH2:39][CH3:40])=[C:24]([F:43])[CH:23]=1.O>CC(C)=O>[Br:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][N:27]2[C:31]([C:32](=[O:35])[CH2:33][O:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:30]([CH2:36][CH3:37])[N:29]=[C:28]2[CH2:38][CH2:39][CH3:40])=[C:24]([F:43])[CH:23]=1
Reactant: CCCc1nc(CC)c(C(=O)CBr)n1Cc1ccc(Br)cc1F
Reactant: Oc1ccccc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCc1nc(CC)c(C(=O)COc2ccccc2Oc2ccccc2)n1Cc1ccc(Br)cc1F
Yield: 13 %

Procedure:
To a solution of 0.63 g (3.36 mmol) of 2-phenoxyphenol and 0.62 g (4.48 mmol) of K2CO3 in 75 mL acetone at ambient temperature was added 1.00 g (2.24 mmol) of 1-(4-bromo-2-fluorobenzyl)-2-(n-propyl)-4-ethyl-5-bromoacetyl-1H-imidazole obtained from Part B of Example 11 in 25 mL acetone. After stirring at reflux overnight, the reaction mixture was poured into water and extracted with 3×100 mL ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvents evaporated under reduced pressure. The crude product was purified by flash column chromatography using 10-40% ethyl acetate in hexane, which provided 0.16 g (6.3%) of a clear oil after evaporation of solvents under reduced pressure. 1H NMR (300 MHz, CDCl3): δ 0.95 (t, 3H, J=7.3 Hz); 1.29 (t, 3H, J =7.3 Hz); 1.66 (m, 2H); 2.60 (m, 2H); 2.81 (q, 2H, J=7.3 Hz); 5.00 (s, 2H); 6.38 (t, 1H, J=7.8 Hz); 6.89-7.29 (m, 10H). ##STR106##
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][N:13]3[CH:17]=[C:16]([C:18]([OH:20])=O)[N:15]=[N:14]3)[CH:8]=2)[N:3]=1.[NH2:21][CH2:22][C:23]1[C:24]([Cl:31])=[CH:25][C:26]([NH2:30])=[N:27][C:28]=1[CH3:29]>>[NH2:30][C:26]1[N:27]=[C:28]([CH3:29])[C:23]([CH2:22][NH:21][C:18]([C:16]2[N:15]=[N:14][N:13]([CH2:12][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)[CH:17]=2)=[O:20])=[C:24]([Cl:31])[CH:25]=1
Reactant: Cc1ccc2cc(Cn3cc(C(=O)O)nn3)ccc2n1
Reactant: Cc1nc(N)cc(Cl)c1CN
Product: Cc1ccc2cc(Cn3cc(C(=O)NCc4c(Cl)cc(N)nc4C)nn3)ccc2n1

Procedure:
The title compound was prepared from 1-((2-Methylquinolin-6-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 5-(aminomethyl)-4-chloro-6-methylpyridin-2-amine in analogy to Example 20c). HPLC-MS (Method F) Rt=0.44 min. [M+H]+=422.1.
Reaction SMILES: [Si]([O:8][CH:9]1[C:17]2[C:12](=[C:13]([CH3:41])[C:14]([CH:18]([OH:40])[C:19]([N:22]3[CH2:39][CH2:38][C:25]4([C:29](=[O:30])[N:28]([C:31]5[CH2:32][O:33][C:34](=[O:37])[C:35]=5[CH3:36])[CH2:27][CH2:26]4)[CH2:24][CH2:23]3)([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[CH2:11][O:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[OH:40][CH:18]([C:14]1[C:13]([CH3:41])=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:9]([OH:8])[O:10][CH2:11]2)[C:19]([N:22]1[CH2:39][CH2:38][C:25]2([C:29](=[O:30])[N:28]([C:31]3[CH2:32][O:33][C:34](=[O:37])[C:35]=3[CH3:36])[CH2:27][CH2:26]2)[CH2:24][CH2:23]1)([CH3:21])[CH3:20]
Reactant: CC1=C(N2CCC3(CCN(C(C)(C)C(O)c4ccc5c(c4C)COC5O[Si](C)(C)C(C)(C)C)CC3)C2=O)COC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1=C(N2CCC3(CCN(C(C)(C)C(O)c4ccc5c(c4C)COC5O)CC3)C2=O)COC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the product of Step I (1.282 g, 2.192 mmol) in tetrahydrofuran (50 ml) was added TBAF (2.63 mL, 2.63 mmol) at 0° C., and the resulting solution was stirred at 0° C. for 2 h. After concentration, the residue was purified on TLC eluting with 10% MeOH/DCM to give the title compound. LC/MS: (M+1)+: 471.20.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH:14]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH3:34])[CH:27]=2)(=[O:25])=[O:24])[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:35])=[CH:10][N:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:35][C:11]1[C:12]([CH:14]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH3:34])[CH:27]=2)(=[O:25])=[O:24])[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH2:7])=[N:9][CH:10]=1
Reactant: COc1cc(S(=O)(=O)C(c2cc(F)ccc2F)c2cc(NC(=O)OC(C)(C)C)ncc2Cl)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(S(=O)(=O)C(c2cc(F)ccc2F)c2cc(N)ncc2Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a dichloromethane (5 ml) solution of t-butyl[5-chloro-4-[(4-chloro-3-methoxyphenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbamate (300 mg, 0.54 mmol) was added trifluoroacetic acid (5 ml) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was dissolved in dichloromethane. The resulting solution was washed with a 1N aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was washed with diethyl ether and then collected by filtration to give the title compound (208 mg, 0.45 mmol, 84%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCI
Reactant: CC1(C)CC(=O)c2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc2c(c1)C(=O)CC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Under nitrogen, a solution of 28.5 g (0.16 mol) of 6-hydroxy-3,3-dimethylindan-1-one (J. Org. Chem. 19; 1954; 305) in 200 ml of DMF was added dropwise to a solution of 5.6 g (0.19 mol) of 80% sodium hydride in 250 ml of DMF. After 1 h at RT, 30.4 g (0.17 mol) of 1-iodobutane were added, and the mixture was stirred at RT for 2 h. The solvent was distilled off under reduced pressure, the residue was taken up in EA and water and the organic phase was washed successively with dil. hydrochloric acid and dil. sodium hydroxide solution. This procedure gave 31.3 g of 6-butoxy-3,3-dimethylindan-1-one.
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1)[C:23]#[N:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[C:23]([C:22]1[CH:25]=[C:26]([C:2]2[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[CH:13][C:3]=2[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:27]=[C:20]([F:19])[CH:21]=1)#[N:24]
Reactant: CC1(C)OB(c2cc(F)cc(C#N)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)COc1ccc(C=O)cc1-c1cc(F)cc(C#N)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
To solution of tert-butyl 2-(2-bromo-4-formylphenoxy)acetate (1) (120 g, 0.38 mol) in dioxane/H2O (4:1, 700 mL) was added 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (20) (158 g in 60% purity, 0.38 mol), Na2CO3 (81 g, 0.76 mol) and Pd(PPh3)4 (22 g, 19 mmol) under N2. The mixture was stirred at 80° C. for 3 h. After cooling to room temperature, the mixture was concentrated in vacuo and purified by column chromatography (PE:EA=10:1 v/v) to give 90 g of t-butyl 2-(2-(3-cyano-5-fluorophenyl)-4-formylphenoxy)acetate (21) (90 g, 67%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:11]=3)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:35]([O:38][C:39](Cl)=[O:40])([CH3:37])[CH3:36]>C(Cl)Cl>[CH:35]([O:38][C:39](=[O:40])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:25]3[CH2:26][CH2:27][CH2:28]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:11]=3)=[CH:4][CH:3]=1)([CH3:37])[CH3:36]
Reactant: N#Cc1c(-c2ccc(N)cc2)n(C2CCC2)c2cc(N3CCOCC3)ccc12
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(N4CCOCC4)cc3n2C2CCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.2 %

Procedure:
A solution of 2-(4-amino-phenyl)-1-cyclobutyl-6-morpholin-4-yl-1H-indole-3-carbonitrile (0.112 g, 0.3 mmol), pyridine (1.0 mL) in CH2Cl2 (2.0 mL) was treated with isopropylchloroformate (1.0 M in toluene, 0.6 mL, 0.6 mmol). The mixture was stirred at room temperature for 5 h and diluted with CH2Cl2 (5 mL). The organic layer was separated, washed with HCl (1.0 N, 3×2 mL), water (5 mL×2) and brine (5 mL), and purified on silica gel (CH2Cl2/EtOAc, 9:1) to provide [4-(3-cyano-1-cyclobutyl-6-morpholin-4-yl-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (0.12 g, 87%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])(=[O:11])=[O:10])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.[CH:22]([O:35][C:36]([NH:38][C:39]1[CH:44]=[CH:43][N:42]([CH2:45][C:46](O)=[O:47])[C:41](=[O:49])[N:40]=1)=[O:37])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH:22]([O:35][C:36]([NH:38][C:39]1[CH:44]=[CH:43][N:42]([CH2:45][C:46]([N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][C:5]=3[N+:19]([O-:21])=[O:20])(=[O:11])=[O:10])[C:13](=[O:18])[CH2:14]2)=[O:47])[C:41](=[O:49])[N:40]=1)=[O:37])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Reactant: O=C1CNCCN1S(=O)(=O)c1ccc(F)cc1[N+](=O)[O-]
Agent: Cl
Product: O=C(Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3ccc(F)cc3[N+](=O)[O-])C(=O)C2)c(=O)n1)OC(c1ccccc1)c1ccccc1
Yield: 59.7 %

Procedure:
The title compound (1.19 g, 60%) was synthesized by reaction of 1-(4-fluoro-2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (1.02 g, 3.0 mmol) with [4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetic acid (1.14 g, 3.0 mmol), as per the procedure of example 77. 1H NMR (DMSO-d6) δ 10.98 (s, 1H), 8.41 (m, 1H), 8.24 (dd, 1H), 7.87 (m, 2H), 7.50˜7.25 (m, 10H), 6.96 (m, 1H), 6.79 (s, 1H), 4.81 (s, 1.2H), 4.73 (s, 0.8H), 4.45 (s, 0.8H), 4.27 (s, 1.2H), 4.06˜3.95 (m, 2.4H), 3.90˜3.80 (m, 1.6H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44].C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][N:11]([CH2:32][CH2:33][N:34]2[C:38](=[O:39])[C:37]3=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]3[C:35]2=[O:44])[C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
(2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (0.73 g, 1.8 mmol), N-(2-bromoethyl)phthalimide (0.686 g, 2.7 mmol), triethylamine (0.5 ml, 3.6 mmol) and a catalytic amount of potassium iodide was dissolved in dry dimethylformamide (30 ml). The mixture was stirred for 24h at 70° C., cooled to room temperature and evaporated in vacuo. Water (60 ml) was added and extraction with methylene chloride (3×60 ml), drying of the organic phases with magnesium sulphate and evaporation of the solvent in vacuo afforded an oil. Purification twice on silica gel (Eluent 1: Heptane/ethyl acetate (1:1) and eluent 2: Petroleum ether/diethylether (2:1)) gave (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethyl-1-(2-phthalimidoethyl)pyrrolidine (0.64 g, yield: 61%) as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH3:24])=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][N:9]=[C:8]2[CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:23])=[O:4].[OH-].[K+]>CO>[O:23]=[C:15]1[CH:14]([C:8]2[C:7]3=[C:6]([CH3:24])[C:5]([C:3]([OH:4])=[O:2])=[CH:13][N:12]3[N:11]=[CH:10][N:9]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1
Reactant: COC(=O)c1cn2ncnc(C3C(=O)Nc4ccccc43)c2c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)cn2ncnc(C3C(=O)Nc4ccccc43)c12
Temperature: 60 °C
Yield: 92.2 %

Procedure:
To a solution of Example 77 (3.3 g, 10.2 mmol) in methanol (600 mL) was added potassium hydroxide (1N aqueous solution, 200 mL) and the mixture was deoxygenated by purging with argon. The reaction mixture was heated to 60° C. for 20 hrs. The reaction mixture was cooled and concentrated to about 50 mL and the residue was acidified with concentrated HCl to pH 4. The yellow solid was collected, washed with water, and dried in vacuo to afford the title compound (2.9 g, 92%). MS: [M+H]+=307.1; 1H NMR (CD3OD): δ 7.94 (s, 1H), 7.71 (s, 1H), 7.18-7.10 (m, 2H), 6.94-6.86 (m, 2H), 2.45 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][NH:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH3:2].Br[CH2:19][CH2:20][CH2:21]Cl>C1(C)C(C)=CC=CC=1>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:7]2=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]2[CH2:21][CH2:20][CH2:19]1)[CH3:17]
Reactant: ClCCCBr
Reactant: CCN(CC)CCNc1nc2ccccc2[nH]1
Solvent: Cc1ccccc1C
Product: CCN(CC)CCN1CCCn2c1nc1ccccc12

Procedure:
Heat at reflux for 12 hours a mixture of 1.16 g (5 mmol) of 2-(2-diethylaminoethylamino) benzimidazole and 0.6 ml (5 mmol) of 1-bromo-3-chloropropane in 10 ml of xylene. After cooling, the xylene is decanted off and the residual oil is treated with petroleum ether. Evaporate the remaining petroleum ether and treat with ammonium hydroxide. Extract with chloroform. The combined organic phases are concentrated and passed over a column of alumina eluted with chloroform. The evaporation of the solvent allows the title compound to be obtained.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:17][C:16]3[NH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>CN(C)C=O>[CH3:19][S:20]([N:15]1[C:16]2[CH2:17][CH:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:10][C:11](=[O:18])[C:12]=2[CH:13]=[CH:14]1)(=[O:22])=[O:21]
Reactant: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1ccc2c1CC(c1ccccc1)CC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a suspension of 60% sodium hydride (0.18 g, washed with hexane thrice) in dimethylformamide (10 ml was added 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of methanesulfonylchloride (0.48 g) in dimethylformamide (3 ml), and the mixture was stirred at the same temperature for 3 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) and recrystallized from ethyl acetate-hexane to give colorless crystals of 1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.51 g).
Reaction SMILES: O=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(OC(OCC)OCC)C>CCO>[O:25]1[CH2:24][CH2:23][CH:22]([N:3]2[CH:2]=[N:10][C:9]3[C:4]2=[N:5][C:6]([C:11]2[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=24)=[N:7][CH:8]=3)[CH2:27][CH2:26]1
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Solvent: CCO
Solvent: CCOC(OCC)OCC
Product: N#Cc1ccn2ncc(-c3ncc4ncn(C5CCOCC5)c4n3)c2c1
Temperature: 123 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a suspension of the compound obtained in example 1 section d (100 mg, 0.30 mmol) in EtOH (1 mL), PTSA monohydrate (5.7 mg, 0.03 mmol) and triethylorthoformate (1 mL) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 123° C. and 270 W for 30 min. Then, it was evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using MeOH/EtOAc mixtures of increasing polarity as eluent, to afford 81 mg of the desired compound (79% yield).
Reaction SMILES: [C:1]([C:3]1([NH:9][C:10]([CH:12]([NH:20]C(OC(C)(C)C)=O)[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].[ClH:28]>O1CCOCC1>[ClH:28].[C:1]([C:3]1([NH:9][C:10]([CH:12]([NH2:20])[CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:11])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1)#[N:2]
Reactant: CC(C)(C)OC(=O)NC(CC1CCCCC1)C(=O)NC1(C#N)CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(NC(=O)C(N)CC2CCCCC2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-Butoxycarboxylic acid [1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide (1000 mg, 2.62 mmol) was dissolved in 15 mL of 4 M HCl in dioxane. The solution was stirred at ambient temperature for 1 hr. The volatiles were removed in vacuo and the resulting paste was triturated with 25 mL of diethyl ether to give a fine white solid that was collected by filtration and dried in vacuo. The product was used without further purification.