Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=2)=[C:9]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: COC(=O)c1cc(Nc2ccc(F)cc2)c(Nc2ccc(F)cc2)cc1C(=O)OC

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 2.3 ml (24 mmol) of 4-fluoroaniline in 60 ml of glacial acetic add is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane the solution is washed in succession with 20 ml of 1N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with ethyl acetate/hexane 2:1 and the product fractions are concentrated by evaporation and recrystallized from ethyl acetate/hexane, yielding the title compound in the form of yellow crystals, 1H-NMR (CDCl3): δ7.40 (s, 2H), 7.10-6.80 (m, 8H), 5.70 (br s, 2H) 3.83 (s, 6H).
Reaction SMILES: [NH2:1][OH:2].C(=O)([O-])O.[Na+].[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OCC)(=O)C>[C:8]([NH:1][OH:2])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(NO)c1ccccc1

Procedure:
To 281 mg of the compound (6) were added 2 ml of ethyl acetate, 2 ml of aqueous saturated sodium hydrogencarbonate, and 0.077 ml of benzoyl chloride and the mixture was reacted at room temperature for 1. 5 hours to obtain a benzoylamino-alcohol compound (compound (7), C51H63NO13Si, molecular weight of 926.14).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.C[O:23][C:24](=O)[C:25]([CH3:28])([CH3:27])[NH2:26]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:24](=[O:23])[C:25]([CH3:28])([CH3:27])[NH:26][C:12]2=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1(C)NC(=O)N(c2ccc(C(C)(C)C)cc2)C1=O
Temperature: 25 °C
Yield: 79.6 %

Procedure:
To a suspension of 15 g of 4-tert-butylphenyl-isocyanate in 200 mL of toluene are successively added 31.52 mL of triethylamine and 13.15 g of 2,2-dimethylglycine methyl ester hydrochloride. The reaction mixture is refluxed for 24 h, cooled to room temperature, poured into distilled water and extracted with ethyl acetate. The organic phase is washed successively with water and with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is taken up in diethyl ether and the solid formed is filtered off and dried to give 17.75 g of 3-(4-tert-butylphenyl)-5,5-dimethyl-imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9](OS(C(F)(F)F)(=O)=O)=[C:4]2[CH:3]=[CH:2]1.[CH3:18][C:19]1[C:23](B(O)O)=[C:22]([CH3:27])[O:21][N:20]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:18][C:19]1[C:23]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[NH:1][CH:2]=[CH:3][C:4]=23)=[C:22]([CH3:27])[O:21][N:20]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: O=S(=O)(Oc1ccnc2[nH]ccc12)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1ccnc2[nH]ccc12
Temperature: 110 °C
Reaction time: 5 h

Procedure:
To a solution of trifluoro-methanesulfonic acid-1H-pyrrolo[2,3-b]pyridin-4-yl ester [4.05 g, Reference Example 18(g)] and 3,5-dimethylisoxazole-4-boronic acid (2.31 g) in dimethylformamide (100 mL) was added tetrakis(triphenylphosphine)palladium[0] (0.1 g) and saturated sodium bicarbonate solution (30 mL). The resulting mixture was stirred at 110° C. for 5 hours. The reaction mixture was cooled and filtered through celite. The filtrate was evaporated to dryness and the residue partitioned between ethyl acetate (100 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate and the combined organic fractions were washed twice with brine (30 mL), then dried over magnesium sulfate and then evaporated to afford the title compound as an orange oil which was used immediately without further purification for the preparation of Reference Example 9(i).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3F)cc2)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3F)cc1)nn2C[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
Into a 100 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (2R)-2-([4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (200 mg, 0.40 mmol, 1.00 equiv) in dichloromethane (20 mL), and trifluoroacetic acid (10 g, 87.70 mmol, 221.25 equiv). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The resulting solution was diluted with 10% aqueous sodium carbonate and the solution was extracted with dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 0.1 g (62%) of 3-[4-(2-fluorophenoxy)phenyl]-1-((2R)-pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a light yellow solid.
Reaction SMILES: [CH2:1]=[CH:2][S:3]([O-:6])(=[O:5])=[O:4].[Na+].N([O-])=O.[Na+].NC(N)=O.Cl.[C:17]([NH2:21])(=[O:20])[CH:18]=[CH2:19].C(#N)C=C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O=O.C(O)C.O>[C:17](#[N:21])[CH:18]=[CH2:19].[C:17]([NH2:21])(=[O:20])[CH:18]=[CH2:19].[CH2:1]=[CH:2][S:3]([OH:6])(=[O:5])=[O:4]
Reactant: C=CS(=O)(=O)[O-]
Agent: C=CC(N)=O
Agent: Cl
Agent: NC(N)=O
Solvent: O
Solvent: C=CC#N
Solvent: CCO
Product: C=CS(=O)(=O)O
Reaction time: 24 h

Procedure:
A water-soluble copolymer of acrylonitrile, acrylamide and ethylene sulfonic acid was prepared in the following way: 57.5 g of an aqueous 47% solution of sodium ethylene sulfonate, stabilized against polymerization by 0.2% sodium nitrite, was destabilized by adding 3 g urea and acidified with concentrated hydrochloric acid to pH 2. The developing gases were repeatedly drawn off. 7.1 g Acrylamide and 13.6 ml acrylonitrile were added and the monomer mixture was dissolved in 76 ml of oxygen-free water. 1 ml of a 5% sodium pyrosulfite solution and the same amount of ammonium persulfate were stirred in, and the somewhat turbid solution was left standing under carbon dioxide at room temperature for 24 hours. The viscous solution thus obtained was poured into 2 liters of anhydrous ethanol. The white coagulate was purified by dissolving it in water and again precipitating it in anhydrous ethanol, broken to small pieces and dried at 70° C.
Reaction SMILES: S=C1N([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])CCS1.[CH2:23]([CH:25]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:26][NH2:27])[CH3:24].C(N(CC)CC)C>C1COCC1.C(OCC)C>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:27][CH2:26][CH:25]([CH2:23][CH3:24])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: CCCCC(CC)CN
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC(CC)CNC(=O)OCc1ccc(OC(C)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred yellow solution of VII (298.2 mg, 0.873 mmol) in anhydrous THF (10 mL) was added 2-ethylhexylamine (124 mg, 157 μL 1.1×0.873 mmol) and then, dropwise, triethylamine (97 mg, 135 μL, 1.1×0.873 mmol). The solution was stirred for 3 hours at room temperature. The colorless solution was then diluted with diethyl ether and washed with 1N HCl, distilled water, and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel using hexanes/ethyl acetate (6:4, v/v) to give 9 as 207.2 mg (68%) of a clear, light yellow oil: Rf=0.60 (hexanes/ethyl acetate, 1:1, v/v); 1HNMR (CDCl3) δ 6.99 (d, 3J=8.0 Hz, 1H), 6.95 (d, 4J=1.75 Hz, 1H), 6.92 (dd, 3J=8.0 Hz, 4J=1.72 Hz, 1H), 5.04 (s, 2H), 4.67 (bs, 1H, NH), 3.82 (s, 3H), 3.16-3.08 (m, 2H), 2.29 (s, 3H), 1.43-1.35 (m, 1H), 1.33-1.119 (m, 8H) and 0.867 (apparent triplet, 3J=7.2 Hz, 6H). Exact mass (FAB+) calculated for C19H30NO5 [M+H] 352.2118. found 352.2101.
Reaction SMILES: [Cl:1][CH2:2][O:3][C:4](Cl)=[O:5].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>>[Cl:1][CH2:2][O:3][C:4]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:5]
Reactant: C1COCCN1
Reactant: O=C(Cl)OCCl
Product: O=C(OCCl)N1CCOCC1

Procedure:
Using chloroformic acid chloromethyl ester and morpholine as the raw materials, the same operation as the Example 101(1) gave the title compound as a crude product, and the crude product was used for the next reaction without further purification.
Reaction SMILES: C([O:8][C:9](=[O:23])[NH:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16]([F:20])[CH:17]=2)[C:12]1=O)C1C=CC=CC=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>>[F:20][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[F:21])[CH:12]1[CH:11]([NH:10][C:9](=[O:8])[O:23]1)[CH2:19]2
Reactant: O=C(NC1Cc2cc(F)c(F)cc2C1=O)OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC2Cc3cc(F)c(F)cc3C2O1
Reaction time: 24 h

Procedure:
To (5,6-difluoro-1-oxoindan-2-yl)carbamic acid benzyl ester (Preparation 79) (238 mg, 0.75 mmol) was added TFA (5 mL) and triethylsilane (0.59 mL, 3.75 mmol). The reaction mixture was stirred for 24 h. Solvent was removed in vacuo and the residue purified by column chromatography (MeOH:DCM 5:95) to give the title compound: δH (CDCl3) 3.06-3.15 (1H, m), 3.29 (1H, dd), 4.79 (1H, t), 5.98 (1H, d), 7.10 (1H, dd), 7.27-7.35 (1H, m), 12.02 (1H, s).
Reaction SMILES: O[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([NH:13][C:8]1[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]2[O:4][C:3]([CH3:21])([CH3:22])[CH:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[C:6]=2[CH:7]=1)=[O:20]
Reactant: Cc1ccccc1C1(O)c2cc(NC(=O)CC(C)(C)C)c(C)c(C)c2OC1(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccccc1C1c2cc(NC(=O)CC(C)(C)C)c(C)c(C)c2OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of N-(3-hydroxy-2,2,6,7-tetramethyl-3-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (120 mg, 0.3 mmol) obtained in Example 242 in trifluoroacetic acid (2 mL) was added triethylsilane (71 mg, 0.6 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to water and the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 1 N sodium hydroxide solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) and recrystallized from ethyl acetate-hexane to obtain 93 mg (yield: 79%) of the title compound. Melting point: 161-162° C.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[CH:3]([CH:22]1[CH2:27][CH2:26][N:25](C(OCC2C=CC=CC=2)=O)[CH2:24][CH2:23]1)[O:4][C:5]1[C:6]([NH:15][S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.C(O)C>O1CCCC1.[Pd]>[F:39][C:2]([F:1])([F:38])[CH:3]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[O:4][C:5]1[C:6]([NH:15][S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(C1CCN(C(=O)OCc2ccccc2)CC1)C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(C1CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.5 %

Procedure:
Ten percent palladium/carbon (15.0 mg) was suspended in tetrahydrofuran (1.0 mL). To this, a tetrahydrofuran solution (2.0 mL) of N-{3-[2,2,2-trifluoro-1-(1-benzyloxycarbonylpiperidin-4-yl)ethoxy]quinoxalin-2-yl}propane-1-sulfonamide (150 mg, 0.245 mmol) was added and the mixture was stirred under hydrogen stream at room temperature for 3 days. To the reaction mixture, 10% palladium/carbon (15.0 mg) and ethanol (2.0 mL) were added and the mixture was stirred under hydrogen stream at room temperature for 8 hours. The reaction mixture was filtered through Celite and the solvent was evaporated off under reduced pressure. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=9/1) to give Compound 327 (38.7 mg, yield: 37%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[C:4]([N+:10]([O-])=O)[C:3]=1[NH2:13].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:22](OC)(OC)OC.CN(C=O)C>C(O)(=O)C>[Cl:1][C:2]1[C:3]2[N:13]=[CH:22][NH:10][C:4]=2[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: Nc1c([N+](=O)[O-])cc(Cl)c(Cl)c1Cl
Reactant: COC(OC)OC
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Clc1cc2[nH]cnc2c(Cl)c1Cl
Temperature: 100 °C
Yield: 43 %

Procedure:
A mixture of 2,3,4-trichloro-6-nitro-phenylamine (0.250 g, 1.04 mmol), sodium dithionite (0.907 g, 5.21 mmol), trimethyl orthoformate (4 ml), DMF (4 mL), and acetic acid (0.5 mL) was heated in a sealed tube for 15 h at 100° C. The reaction mixture was cooled to 23° C. and partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was collected and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated to yield the titled compound (0.098 g, 43%). MS (ESI/CI): mass calcd. for C7H3Cl3N2, 219.9; m/z found, 221.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.16 (s, 1H), 8.43 (s, 1H), 7.90 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]2)[CH:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][N:3]1[CH2:25][C:26]([F:29])([F:28])[F:27].[ClH:30].O1CCOCC1>C(Cl)Cl>[ClH:30].[C:19]1([CH:5]2[C:6]3([CH2:11][CH2:10][CH2:9][NH:8][CH2:7]3)[C:2](=[O:1])[N:3]([CH2:25][C:26]([F:28])([F:29])[F:27])[CH2:4]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)N(CC(F)(F)F)CC2c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1N(CC(F)(F)F)CC(c2ccccc2)C12CCCNC2
Temperature: 25 °C
Reaction time: 9 h

Procedure:
Tert-butyl 1-oxo-4-phenyl-2-(2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]decane-7-carboxylate (0.874 g, 2.119 mmol) in DCM (10 ml) was treated with 4M HCl in 1,4-dioxane (4.5 ml, 0.018 mmol). The reaction mixture was stirred at room temperature for 9 hours. The solvent was removed in vacuo to give the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.C(OC([NH:40][C@@H:41]([C:45](O)=O)[CH:42]([CH3:44])[CH3:43])=O)(C)(C)C>>[ClH:28].[NH2:40][C@H:41]([CH:42]([CH3:44])[CH3:43])[CH2:45][N-:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: CC(C)[C@@H](N)C[N-]c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The titled compound can be synthesized from 1-[4-(6-amino-purin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and tert-butoxycarbonyl-D-valine by using the same method as in Example 96.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH3:44])=[CH:39][CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([CH2:43][CH3:44])=[CH:39][CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: CCc1ccc(C(=O)CCCCCBr)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(C(=O)CCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1
Yield: 22.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.1 g) as starting compound, potassium carbonate (1.0 g) and 6-bromo-1-(4-ethylphenyl)-1-hexanone (0.94 g) were reacted and treated in the same manner as in Example 172 to give 0.34 g of 4-amino-5-chloro-N-((1-(6-(4-ethylphenyl)-6-oxohexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][NH2:49])=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C.Cl.CO>>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][NH2:49])=[CH:38][CH:37]=2)=[CH:19][CH:18]=1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCN)CCC3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCNC[C@@H]2OCc2ccc3c(c2)N(CCCN)CCC3)cc1

Procedure:
In analogy to the procedure described in example 4(b), the (3R,4R)-3-[1-(3-amino-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl/methanol to yield the (3R,4R)-3-[7-(4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl)-3,4-dihydro-2H-quinolin-1-yl]-propylamine as yellow oil; MS: 574 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11]([NH2:13])=O)=[CH:4][C:3]=1[N+:14]([O-])=O.CC1C2NC=NC=2C(C#N)=CC=1[N+]([O-])=O>>[NH2:14][C:3]1[CH:4]=[C:5]([C:11]#[N:13])[C:6]2[N:10]=[CH:9][NH:8][C:7]=2[C:2]=1[CH3:1]
Reactant: Cc1c([N+](=O)[O-])cc(C(N)=O)c2nc[nH]c12
Agent: Cc1c([N+](=O)[O-])cc(C#N)c2nc[nH]c12
Product: Cc1c(N)cc(C#N)c2nc[nH]c12

Procedure:
As to General Reaction Scheme 3, intermediate (22) (produced via, inter alia, General Scheme 2) is nitrated by a nitrating agent to yield intermediate 7-Methyl-6-nitro-1H-benzimidazole-4-carboxylic acid (23). In turn, intermediate (23) may either be amidated/dehydrated by an amidating/dehydrating agent to yield intermediate 7-Methyl-6-nitro-1H-benzimidazole-4-carbonitrile (24), or amidated by an amidating agent to yield intermediate 7-Methyl-6-nitro-1H-benzimidazole-4-carboxamide (25). Intermediate (24) is reduced by a nitro group reducing agent to yield intermediate (10). In turn, intermediate (25) is reduced by a nitro group reducing agent to yield intermediate 6-Amino-7-methyl-1H-benzimidazole-4-carboxamide, hydrochloric acid salt (26), and thereafter dehydrated by an amide dehydrating agent to yield intermediate (10). See Examples 13 and 14.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([F:8])[N:3]=1.[CH2:9]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH2:10][CH2:11][CH2:12][CH3:13]>>[F:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:23]2[CH:22]=[CH:21][C:20]([C@H:17]3[CH2:18][CH2:19][C@H:14]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16]3)=[CH:25][CH:24]=2)[N:3]=1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(B(O)O)cc2)CC1
Reactant: Fc1cncc(Cl)n1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3cncc(F)n3)cc2)CC1

Procedure:
In an analogous reaction to Example 1b, 2.17 g (16.41 mmol) of 2-chloro-6-fluoropyrazine (prepared as described in Example 1a) and 4.50 g (16.41 mmol) of 4-(trans-4-pentylcyclohexyl)phenylboronic acid gives 3.36 g of 2-fluoro-6-[4-(trans-4-pentylcyclohexyl)-phenyl]pyrazine. ##STR19## 3b
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][NH:10][C:11](=[O:29])[C@H:12]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=2)[C@H:13]([OH:15])[CH3:14])=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CN=C1.[CH3:37][C:38]([Si:41](Cl)([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CN(C=O)C>[Si:41]([O:15][C@H:13]([CH3:14])[C@@H:12]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1)[C:11]([NH:10][NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:31][CH:30]=1)=[O:29])([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:43])[CH3:42]
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 79 %

Procedure:
To a pre-cooled (0° C.) solution of 4-cyano-N′-((2R,3R)-2-(4-cyano-3-(trifluoromethyl)phenylamino)-3-hydroxybutanoyl)benzohydrazide (1.57 g, 3.64 mmol) in DMF (100 mL) was added imidazole (1.98 g, 29.4 mmol) then TBSCl (2.20 g, 14.58 mmol). The reaction was warmed slowly to room temperature, stirred for 19 h, cooled to 0° C. and quenched with H2O (300 mL). The solution was extracted with EtOAc (250 mL). The organic extract was washed with H2O (2×100 mL) and 5% aq. citric acid (3×80 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (20-30% EtOAc in hexanes) to provide the title compound as a colourless solid (1.57 g, 79%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.06 (dm, J=8.6 Hz, 2H), 7.91 (dm, J=8.6 Hz, 2H), 7.73 (d, J=8.8 Hz, 1H), 7.36 (d, J=2.2 Hz, 1H), 7.14 (dd, J=2.4, 8.6 Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 4.49-4.39 (m, 2H), 1.36 (d, J=6.1 Hz, 3H), 0.85 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H).