Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:4][C:3]=1[C:36]#[C:37][C:38]([OH:41])([CH3:40])[CH3:39].[CH:42]1[C:51]2[C:46](=[CH:47][C:48](B(O)O)=[CH:49][CH:50]=2)[CH:45]=[CH:44][N:43]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1>[OH:41][C:38]([CH3:40])([CH3:39])[C:37]#[C:36][C:3]1[N:4]=[C:5]([N:7]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=2)[S:6][C:2]=1[C:48]1[CH:47]=[C:46]2[C:51](=[CH:50][CH:49]=1)[CH:42]=[N:43][CH:44]=[CH:45]2
Reactant: CC(C)(O)C#Cc1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc1Br
Reactant: OB(O)c1ccc2cnccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(O)C#Cc1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc1-c1ccc2cnccc2c1
Temperature: 120 °C
Yield: 37 %

Procedure:
(S)-tert-butyl 1-(N-(5-bromo-4-(3-hydroxy-3-methylbut-1-ynyl)thiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.025 g, 0.038 mmol) was taken up in 1 mL of dioxane in a microwave safe tube. Isoquinolin-6-ylboronic acid (0.0098 g, 0.057 mmol), sodium carbonate, 2M in water (0.075 mL, 0.15 mmol), and tetrakistriphenylphosphine palladium(0) (0.0044 g, 0.0038 mmol) were added. The mixture was degassed with nitrogen and the tube was sealed. The tube was then heated to 120° C. in a Personal Chemistry microwave unit for 20 minutes. The mixture was diluted with 10 mL of EtOAc, washed with 5 mL of water and 5 mL of brine, and then dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (pipette column, 25% to 70% EtOAc/hexanes), afforded (S)-tert-butyl 1-(N-(4-(3-hydroxy-3-methylbut-1-ynyl)-5-(isoquinolin-6-yl)thiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.010 g, 37% yield) as a white solid.
Reaction SMILES: N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)[Cl:8].[CH3:13][CH:14]1[CH:19]=[C:18]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[N:17]2[C:28](=[O:40])[CH:29]([NH:30]C(=O)CC3C=CC=CC=3)[C@H:16]2[S:15]1.CO>ClCCl>[ClH:8].[CH3:13][CH:14]1[CH:19]=[C:18]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:25])[Cl:26])=[O:21])[N:17]2[C:28](=[O:40])[CH:29]([NH2:30])[C@H:16]2[S:15]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Product: Cl

Procedure:
Pyridine (0.55 g.) and phosphorus pentachloride (1.43 g.) were added in turn under cooling at -5° to -10° C. to a suspension of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate (2.14) in dried dichloromethane (20 ml.), and the mixture was stirred. After dissolution of the starting material, the reaction temperature was elevated to at room temperature, and stirred for 4 hours. To this solution was dropwise added absolute methanol (1.47 g.) under cooling at -10° to -15° C. After stirring for 1 hour at the same temperature and 1.5 hours at 2° to 3° C., the precipitated crystals were collected by filtration, washed with a small amount of dichloromethane and ether, and dried to give colorless crystals of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (1.26 g.), mp 185° to 187° C. (dec.). Similar results were obtained by using the following compounds as a starting compound instead of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:33]Cl>O>[OH2:17].[ClH:29].[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:33][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:2][CH2:3]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cl
Product: O=C1CCc2c(cccc2N2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)N1
Reaction time: 3 h
Yield: 16.7 %

Procedure:
To a mixture of 1.2 g of 5-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.17 g of potassium carbonate and 20 ml of DMF was added 895 mg of 3,4-dichlorobenzyl chloride and the mixture was stirred at 60°-70° C. for 3 hours. The reaction mixture was poured into a large amount of water and extracted with chloroform. After washing with water the extract was dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified through silica gel column chromatography. After conversion to hydrochloric acid salt with methanol-hydrochloric acid the product was recrystallized from methanol to give 0.17 g of 5-[4-(3,4-dichlorobenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril monohydrochloride monohydrate, m.p. 298.5°-300° C. (decomp.), colorless granules.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[NH2:14].[CH2:15]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=O)[CH3:16].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.N1C=CC=CC=1>[CH2:15]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]1[N:2]([CH3:1])[C:3]2[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:11])([F:12])[F:13])=[CH:5][C:4]=2[N:14]=1)[CH3:16]
Reactant: CCSc1ccccc1C(=O)O
Reactant: CNc1c(N)cc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cc(N)c2n1C
Temperature: 110 °C
Reaction time: 5 h
Yield: 15.2 %

Procedure:
To a mixture of N′-methyl-5-trifluoromethyl-benzene-1,2,3-triamine (1.3 g), 2-ethylsulfanylbenzoic acid (1.3 g), and pyridine (12 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.4 g) and 1-hydroxybenzotriazole (86 mg) were added at room temperature. The mixture was stirred at room, temperature for 5 hours, then heated to 110° C., and stirred with heating for 8 hours. After the reaction mixture was allowed to cool to room temperature, the reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 339 mg of 2-(2-ethylsulfanyl-phenyl)-3-methyl-6-trifluoromethyl-3H-benzimidazole-4-ylamine (hereinafter, Present Compound 336).
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH3:27])[C:4]=1[CH3:28].C(N(S(F)(F)[F:35])CC)C.O.[Cl:39]CCl>>[ClH:39].[CH3:28][C:4]1[C:5]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH3:27])=[N:6][C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:8][C:3]=1[CH2:2][F:35]
Reactant: Cc1c(CO)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C
Reactant: CCN(CC)S(F)(F)F
Reactant: ClCCl
Solvent: O
Product: Cc1c(CF)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C
Product: Cl
Temperature: -75 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
The solution of 6-hydroxymethyl-5-methyl-2-(4-fluorophenyl-amino)4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (0.19 g, 0.5 mmol) prepared in accordance with WO 98/43968 in dichloromethane (5 ml) and cooled to −75° C. and (diethylamino)sulfur trifluoride (0.15 ml, 2.26mmol) was dropwise added thereto. The reaction mixture was stirred for 2 hours at −75° C., further stirred for 2 hours at −45 ° C., and slowly heated to room temperature. The reaction mixture was stirred for 18 hours at room temperature, and then water was added thereto to terminate the reaction. The extracted organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was subjected to silica gel column column chromatography (eluent:ethyl acetate/hexane=⅓), and then treated with ethyl ether solution saturated with hydrochloric acid to afford 72 mg (34.5%) of the titled compound.
Reaction SMILES: [C:1]([NH:4]/[C:5](=[CH:10]\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2].[H][H].[CH3:19]O>[Rh]>[CH3:19][N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([C:6]([OH:8])=[O:7])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CO
Reactant: [H][H]
Reactant: COC(=O)/C(=C/c1ccccc1)NC(C)=O
Agent: [Rh]
Product: CC(=O)N(C)[C@H](Cc1ccccc1)C(=O)O
Temperature: 20 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A 100 mL Fisher-Porter tube was charged with methyl (Z)-α-acetamidocinnamate (300 mg, 1.36 mmol), rhodium catalyst [(COD)Rh(1,2-Bis((2R,5R)-2,5-diethylphospholano)benzene)]+CF3SO3- prepared as in Example 15 (1.0 mg, 0.00136 mmol), MeOH (6.0 mL), and a stir bar. After sealing, the pressure head was then connected to a hydrogen tank (Matheson, 99.998%) and the lines were purged of air by four vacuum/H2 cycles. After two vacuum/H2 cycles on the reaction mixture, the tube was pressurized to an initial pressure of 30 psig H2. The reaction was allowed to stir at 20° C. for 2 h after which no further H2 uptake was observed. Complete conversion to product was indicated by capillary GC (methyl silicone column). The reaction was concentrated on a rotovap and the residue was chromatographed on a short SiO2 column (ca. 6×0.5 cm) using 80% ethyl acetate/hexane as eluent. The fractions containing product were concentrated on a rotovap to give methyl (R)-N-acetylphenylalanine as a colorless crystalline solid (270 mg, 90%). Enantiomeric excess analysis by HPLC using Daicel Chiralcel OJ column as described above indicated 99% enantiomeric purity. Other substrates were hydrogenated using the above procedure and the resulting data is summarized in Tables 1 and 2.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:12](=[O:15])([O-])[O-].[K+].[K+].O.[C:19](#N)[CH3:20]>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:19][C@H:20]2[CH2:12][O:15]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC#N
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C1CCN(C[C@H]2CO2)CC1

Procedure:
A mixture of 5.7 g (2R)-glycidyl-tosylate (Fluka GmbH), 4 ml piperidine-4-carboxylic acid ethyl ester and 3.5 g potassium carbonate in 100 ml acetonitrile is heated for 2 h under reflux. After cooling the reaction mixture is admixed with 50 ml water and extracted three times each with 50 ml methylene chloride and 50 ml diethyl ether. After drying the combined organic phases over sodium sulfate and removing the solvent on a rotary evaporator, the residue is purified by means of column chromatography on silica gel (ethyl acetate/saturated methanolic ammonia 95/5). In this way 2.5 g (2S)-l-oxiran-2-ylmethyl-piperidine-4-carboxylic acid ethyl ester is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([O:8][C:15](=[O:18])[CH2:16][CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: Oc1cccc(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Oc1cccc(F)c1
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a solution of 3-fluorophenol (22.4 g, 0.2 mol), pyridine (24 ml, 0.3 mol) and dichloromethane (200 ml) at room temperature was added 20 ml (0.225 mol) propionyl chloride over a period of 5 min. The reaction was exothermic. The solution was stirred for another 30 min. After addition of dichloromethane, the organic phase was washed with sat. NaHCO3 solution and water, dried over MgSO4 and concentrated in vacuo. 33.8 g (100%) of 3-fluoro-1-propionyloxybenzene was obtained. This compound was reacted with 33.3 g (0.25 mol) AlCl3 at 150° C. for a period of 10 min. After careful quenching with water, the reaction mixture was extracted three times with ether. The ether phase was dried (MgSO4) and evaporated to give 29.5 g (0.176 mol, 88%) rearranged product. This intermediate was dissolved in 200 ml of acetone and K2CO3 (42, 0.3 mol) and MeI (25 ml, 0.4 mol) were added. The reaction mixture was heated at 40° C. for a period of 12 h. The reaction mixture was filtered and the acetone was evaporated. The residue was dissolved in ether and the ether phase washed with a 0.5 M NaOH solution and water. Drying (MgSO4) and evaporation gave 31.2 g (0.17 mol, 86% yield for three steps) of 4-fluoro-2-methoxypropiophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=2)[CH:15]=[N:14]1.C(N(CC)CC)C.[CH3:30][O:31][C:32](Cl)=[O:33].O>ClCCl>[C:32](=[O:33])([O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[N:14][N:13]2[C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:5][C:4]=2[Cl:12])=[CH:17][CH:18]=1)[O:31][CH3:30]
Reactant: COC(=O)Cl
Reactant: Oc1ccc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2c1
Yield: 94.2 %

Procedure:
To a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-6-hydroxyindazole [Compound No. 80] (10 g) in dichloromethane (30 ml), triethylamine (5 g) and methoxycarbonyl chloride (7 g) were added, and the resultant mixture was refluxed for 3 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give methyl 1-(2,6-dichloro-4-trifluoromethylphenyl)indazol-6-yl carbonate (11 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:16]([C:22](O)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]([CH3:33])[C:22]([C:16]1[C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:9]=2)(=[O:12])=[O:13])=[CH:20][C:19]([Cl:21])=[CH:18][N:17]=1)=[O:23]
Reactant: CNc1ccccc1F
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1)c1ccccc1F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
3-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-pyridine-2-carboxylic acid (75 mg, 0.20 mmol), (2-fluoro-phenyl)-methyl-amine (23 mg, 0.61 mmol), HATU (193 mg, 0.51 mmol), TEA (114 μL, 0.81 mmol) and 0.5 mL NMP were combined in a 4 mL vial and stirred overnight at 60° C. HPLC purification (10 to 95% gradient of MeCN-water) provided 3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridine-2-carboxylic acid (2-fluoro-phenyl)-methyl-amide: 1H NMR (400 MHz, CDCl3) 9.98 (s, 1H), 8.01 (s, 1H), 7.82 (d, 2H), 7.63 (s, 1H), 7.51 (d, 2H), 7.13 (m, 1H), 6.92 (t, 1H), 6.84 (t, 1H), 6.37 (m, 1H), 3.38 (t, 3H), 1.26 (s, 9H); MS m/z 476.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]2[C:8](=[O:12])[C:7](=[O:13])[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[C:4]=2[O:3]1.[OH:19][CH2:20][CH:21]([CH2:23][OH:24])O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[OH:19][CH2:20][CH:21]1[CH2:23][O:24][C:7]2([C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[C:4]3[O:3][C:2]([CH3:18])([CH3:1])[CH2:11][CH2:10][C:9]=3[C:8]2=[O:12])[O:13]1
Reactant: OCC(O)CO
Reactant: CC1(C)CCC2=C(O1)c1ccccc1C(=O)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(CO)O1)C2=O
Yield: 36 %

Procedure:
To a solution of 2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (1.21 g, 5 mmol) in benzene (12 ml) is added glycerol (0.92 g, 10 mmol) and p-toluenesulfonic acid monohydrate (0.28 g, 1.5 mmol). The resulting mixture is refluxed for 6 hours. After removal of the solvent, product is purified by column chromatography on silica gel eluting with 30% ethyl acetate in methylene chloride to provide 0.57 g (36% yield) as a light yellow solid, which is a mixture of diasteromers. M.p. 44-46° C.; 400 MHz 1H NMR (CDCl3) δ: 1.41 (s, 6H), 1.73-1.82 (m, 2H), 2.36-2.42 (m, 1H), 2.48-2.54 (m, 1H), 3.72-3.78 (m, 1H), 4.18 (d, J=2.5 Hz, 1H), 4.20-4.29 (m, 1H), 4.40 (t, J=8.0 Hz, 1H), 4.71-4.74 (m, 1H), 4.85 (d, J=8.8 Hz, 1H), 7.38-7.44 (m, 2H), 7.54-7.56 (m, 1H), 7.75-7.78 (m, 1H); LCMS: Calc. for C18H21O5: 217; Found 217.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:29]([OH:31])=O)=[C:21]5[C:25]=4[O:24][CH:23]([CH2:26][O:27][CH3:28])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:32])[C:8](=[O:33])[C@H:7]2[CH2:34][CH3:35])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.[N:41]1(OC(N(C)C)=[N+](C)C)[C:45]2[CH:46]=[CH:47]C=[CH:49][C:44]=2N=N1.[CH:58]([N:61](C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:29]([NH:41][CH:45]5[CH2:44][CH2:49][N:61]([CH3:58])[CH2:47][CH2:46]5)=[O:31])=[C:21]5[C:25]=4[O:24][CH:23]([CH2:26][O:27][CH3:28])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:32])[C:8](=[O:33])[C@H:7]2[CH2:34][CH3:35])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OC(COC)C4)nc2N1C1CCCC1
Reactant: CCN(C(C)C)C(C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)c4c3OC(COC)C4)nc2N1C1CCCC1
Reaction time: 1 h
Yield: 69.2 %

Procedure:
7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylic acid 40e (50 mg, 0.10 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (33 mg, 0.10 mmol) were dissolved in 40 mL of dichloromethane followed by the addition of diisopropylethylamine (38 μL, 0.23 mmol) and 1-methyl-piperidyl-4-yl-amine (12 mg, 0.10 mmol) successively. The reaction solution was stirred for 1 hour, added with 20 mL of saturated sodium carbonate solution and extracted with dichloromethane (30 mL×3). The combined organic phase was washed with water (20 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(methoxymethyl)-N-(1-methyl-4-piperidyl)-2,3-dihydrobenzofuran-4-carboxamide 40 (40 mg, yield: 69.0%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[CH:29][CH:30]=2)[CH:25]=[CH:24]1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:20][CH2:21][CH2:22][N:23]1[C:31]3[C:26](=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[CH:29][CH:30]=3)[CH:25]=[CH:24]1)[CH:7]=[CH:6]2
Reactant: O=[N+]([O-])c1ccc2c(ccn2CCCCl)c1
Reactant: COc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(ccn2CCCn2ccc3cc([N+](=O)[O-])ccc32)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To 926 mg of 5-methoxyindole was added 30 ml of dimethylformamide and 230 mg of sodium hydride (in oil), this mixture was stirred under nitrogen gas stream at 60° C. for 1 hour. Then 1.5 g of 1-(3-chloropropyl)-5-nitroindole was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was further stirred at 60° C. for 5.5 hours, then water was added thereto, and the crystals being separated were collected by filtration, and washed with water. The washed crystals were subjected to a silica gel column chromatography (eluent: dichloromethane), there was obtained 1.8 g of 1-[3-(5-methoxyindol-1-yl)propyl]-5-nitroindole as in the form of yellow powdery product.
Reaction SMILES: C([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:11]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[C:23]([N:30]([CH:33]([CH:35](C)C)C)[C:31]#[N:32])[CH:22]=2)[N:10]=[C:9]1[CH3:38])C1C=CC=CC=1.[CH:39]1CC=CCC=1.[CH2:45](O)[CH3:46]>[Pd]>[CH3:39][CH:45]([CH3:46])[CH:33]([N:30]1[C:23]2[CH:22]=[C:21]([C:11]3[NH:10][C:9]([CH3:38])=[N:8][C:12]=3[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH:26]=[CH:25][C:24]=2[N:27]=[C:31]1[NH2:32])[CH3:35]
Reactant: CCO
Reactant: C1=CCC=CC1
Reactant: Cc1nc(-c2ccc([N+](=O)[O-])c(N(C#N)C(C)C(C)C)c2)c(-c2ccc(F)cc2F)n1Cc1ccccc1
Agent: [Pd]
Product: Cc1nc(-c2ccc(F)cc2F)c(-c2ccc3nc(N)n(C(C)C(C)C)c3c2)[nH]1
Temperature: 25 °C

Procedure:
Combine 1-benzyl-2-methyl-4-(3-(N-[3-methylbut-2-yl]-N-[cyano]amino)-4-nitrophenyl)-5-(2,4-difluorophenyl)-1H-imidazole-(0.122 g, 0.24 mmol), 10% palladium on carbon (90 mg), and 1,4-cyclohexadiene (2 mL) in absolute ethanol (10 mL) and heat to 95° C. in a sealed vessel for 18 hours. Cool to room temperature, filter through celite, and concentrate the filtrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with dichloromethane/methano/ammonia mixtures to give 0.077 g (0.195 mmol) of 1-(3-methylbut-2-yl)-2-amino-6-(2-methyl-4-(2,4-difluorophenyl)-1H-imidazol-5-yl)-1H-benzimidazole. Dissolve in 10% methanol/dichloromethane, add 1.0 equivalent methanesulfonic acid, remove solvent under a stream of nitrogen and finally under high vacuum to give 0.094 g of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([NH:15][CH:16]([CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:22]=[N:23][C:24]([NH2:28])=[C:25]([CH3:27])[CH:26]=1)[CH3:17])=O)(C)(C)C>C1(OC)C=CC=CC=1>[CH3:13][NH:15][CH:16]([CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:22]=[N:23][C:24]([NH2:28])=[C:25]([CH3:27])[CH:26]=1)[CH3:17]
Reactant: Cc1cc(/C=C/CC(C)NC(=O)OC(C)(C)C)cnc1N
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CNC(C)C/C=C/c1cnc(N)c(C)c1
Reaction time: 0.75 h
Yield: 12.2 %

Procedure:
Under a nitrogen atmosphere, trifluoroacetic acid (17.76 g, 155.76 mmol) was added dropwise, via addition funnel, over 30 min to a cold (0–5° C.), stirring solution of (4E)-N-(tert-butoxycarbonyl)-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine (1.11 g, 3.47 mmol) in anisole (15 mL). The resulting solution was stirred for 45 min at 0–5° C. and was then concentrated by rotary evaporation. The viscous, brown oil was further dried under high vacuum for 18 h. The crude product was cooled (0–5° C.), basified with 10% NaOH solution (10 mL), treated with saturated NaCl solution (10 mL), and extracted with CHCl3 (5×10 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation, followed by further drying under high vacuum yielding a dark-brown oil. The crude product was purified by column chromatography on silica gel (50 g), eluting with CHCl3—CH3OH-Et3N (4:1:1, v/v/v). Selected fractions containing the product (Rf 0.13) were combined and concentrated by rotary evaporation, and the residue was re-chromatographed on silica gel (50 g) eluting with CHCl3—CH3OH (7:3, v/v). Fractions containing the product (Rf 0.12) were combined and concentrated by rotary evaporation. The residue was dissolved in CHCl3, and the CHCl3 solution was dried (Na2SO4), filtered, concentrated by rotary evaporation, and vacuum dried affording a yellow oil (0.087 g) which tended to crystallize. The semi-crystalline material was dissolved in a warm solution of hexane containing a small amount of ethyl acetate. The warm solution was decanted from an insoluble gum. The solution was allowed to cool to ambient temperature and was further cooled at 5° C. for 18 h. The resulting crystalline solids were collected, washed with hexane, and vacuum dried at 40° C. for 16 h. The yield was 30.8 mg (4.3%) of a light-yellow powder, mp 78–81° C.