Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:3]=1.O.[NH2:25][NH2:26].O>O1CCOCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:4]2[N:5]=[C:6]([C:8]3[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=3[F:15])[N:7]=[C:2]([NH:25][NH2:26])[N:3]=2)=[CH:18][CH:19]=1
Reactant: NN
Reactant: Fc1cccc(F)c1-c1nc(Cl)nc(Nc2ccc(Cl)cc2)n1
Solvent: C1COCCO1
Solvent: O
Product: NNc1nc(Nc2ccc(Cl)cc2)nc(-c2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 165.6 %

Procedure:
General Method 1A Step 3A.1 part a. To a solution of 151 mg (0.4 mmol) of triazine (XXVI) in 4 mL of 1,4-dioxane was quickly added 100 uL (2 mmol) of hydrazine monohydrate. The reaction was stirred at room temperature for 12 hours and 30 mL of water was added and the mixture stirred for an additional 30 minutes. The resultant solid was collected by filtration and washed with several portions of water. The white solid was dried overnight to afford 231 mg of N-(4-chlorophenyl)-4-(2,6-difluorophenyl)-6-hydrazinyl-1,3,5-triazin-2-amine (XXVII). If the hydrazine did not form a solid that could be filtered, then the mixture was extracted three times with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to yield the hydrazine intermediate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (271 mg, 66%).
Reaction SMILES: [C:1](C([O-])=O)([C:10]([O-:12])=[O:11])=[C:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[Na+].[Na+].[Na+].[Na+].Cl.C(=O)=O>O>[CH2:3]([C:4]([OH:6])=[O:5])/[C:2](/[C:7]([OH:9])=[O:8])=[CH:1]\[C:10]([OH:12])=[O:11]
Reactant: O=C([O-])CC(C(=O)[O-])=C(C(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: O
Product: O=C(O)/C=C(\CC(=O)O)C(=O)O

Procedure:
Nine grams of the product as prepared in Example XXIII, i.e. tetrasodium propene-1,1,2,3-tetracarboxylate, is dissolved in 10 mls water and acidified with dilute HCl (10%). Liberation of CO2 is instantaneous. The residue, after evaporation of water, is extracted with acetone. The acetone is evaporated to leave a residue consisting of a 1:1 by weight mixture of cis-trans aconitic acid. The structure of the product is confirmed by NMR analysis (D2O): ##STR73##
Reaction SMILES: I[Si](C)(C)C.COC([N:10]([CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:23]3[CH2:24][CH2:25][C:26](=[O:29])[NH:27][N:28]=3)[CH:20]=2)[CH2:15]1)[CH2:11][CH2:12][CH3:13])=O.N>C(Cl)(Cl)Cl>[CH2:11]([NH:10][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:23]3[CH2:24][CH2:25][C:26](=[O:29])[NH:27][N:28]=3)[CH:20]=2)[CH2:15]1)[CH2:12][CH3:13]
Reactant: CCCN(C(=O)OC)C1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: C[Si](C)(C)I
Agent: N
Solvent: ClC(Cl)Cl
Product: CCCNC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Yield: 71.8 %

Procedure:
Iodotrimethylsilane (9 ml) was added to 13.16 g of 2-(N-methoxycarbonyl-N-propylamino)-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane dissolved in 130 ml of chloroform. The mixture was refluxed under heating for 2 hours. After cooling, aqueous ammonia was added to the solution. The organic layer was collected by separation, washed with water and dried, and the solvent was removed. The resulting crude crystals were recrystallized from acetone to obtain 7.78 g of 2-propylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:20]1[CH:21]=[C:22]([CH:38]=[CH:39][CH:40]=1)[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[Cl:37])[CH2:26][CH2:25]1.CC(C(CC(C(C)(C)C)=O)=O)(C)C>CN1C(=O)CCC1.Cl[Cu]>[Cl:37][C:31]1[C:32]([Cl:36])=[CH:33][CH:34]=[CH:35][C:30]=1[N:27]1[CH2:26][CH2:25][N:24]([CH2:23][C:22]2[CH:21]=[C:20]([CH:40]=[CH:39][CH:38]=2)[O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)[CH2:29][CH2:28]1
Reactant: Clc1cccc(N2CCN(Cc3cccc(Br)c3)CC2)c1Cl
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: O=C1CCc2ccc(Oc3cccc(CN4CCN(c5cccc(Cl)c5Cl)CC4)c3)cc2N1
Temperature: 120 °C
Yield: 38 %

Procedure:
To a solution of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (196 mg, 1.2 mmol in NMP was added Cs2CO3 (391 mg, 1.2 mmol). The slurry was degassed by evacuating and filling the reaction flask with N2 three times. Intermediate 53 (240 mg, 0.6 mmol) and TMHD (11 mg, 0.06 mmol) were added followed by the addition of CuCl (60 mg, 0.6 mmol). The reaction mixture was degassed by evacuating and filling the reaction flask with N2 three times, and then warmed to 120° C. under N2 for 7.5 h. The reaction mixture was cooled to rt and diluted with Et2O. The slurry was filtered and the filtercake was washed with Et2O. Combined filtrates were washed with 2 N HCl, 0.6 N HCl, 2 M NaOH, and 10% aq NaCl. The resulting organic layer was dried, concentrated, and purified by flash chromatography on a silica gel column (elution with PE/EtOAc=1:1) to give 7-(3-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)phenoxy)-3,4-dihydro quinolin-2(1H)-one (compound 30) (110 mg, 38%). 1H NMR (300 MHz, CDCl3): δ 7.62 (s, 1H), 7.31 (d, J=7.2 Hz, 2H), 7.15-7.05 (m, 4H), 6.96-6.89 (m, 2H), 6.62 (dd, J=2.1 Hz, 8.1 Hz, 1H), 6.41 (d, J=2.1 Hz, 1H), 3.57 (s, 2H), 3.06 (m, 4H), 2.94 (t, J=7.5 Hz, 2H), 2.66-2.61 (m, 5H). HPLC: 99%, RT 2.637 min. MS (ESI) m/z 482.1 [M+H]+. mp: 182-183° C.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[N:13]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O.[NH:28]1[CH2:41][CH2:40][CH2:39][C@H:29]1[C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]>C1COCC1>[N:13]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([N:28]1[CH2:41][CH2:40][CH2:39][C@H:29]1[C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31])=[O:17]
Reactant: O=C(Nc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.6 %

Procedure:
201 mg (1.05 mmol) of EDCl was added to 5 ml of THF solution of 100 mg (0.526 mmol) of Boc-Pro-OH (manufactured by Tokyo Chemical Industry Co., Ltd), and 113 mg (0.526 mmol) of H-Pro-NHPh (manufactured by Tokyo Chemical Industry Co., Ltd), followed by stirring for 6 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with a diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water (one time for each), it was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1 (volume ratio)), thereby obtaining 150 mg of the product with a yield of 73.6%.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:16]=1)[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].Cl[C:34]1[CH:44]=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]=1.C(N(CCCC)CCCC)CCC.O>CN1C(=O)CCC1>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]([N:2]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:34]4[CH:44]=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]=4)[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:1])=[O:13])=[O:12])([CH3:11])([CH3:9])[CH3:10]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CN(Cc1cccc(-c2cnc(N3CCNCC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Solvent: CN1CCCC1=O
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN(c3ncc(-c4cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c4)cn3)CC2)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
tert-Butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (200 mg) and ethyl 6-chloronicotinate (169 mg) were dissolved in NMP (4 ml), and N,N-dibutylbutan-1-amine (252 mg) was added thereto, followed by stirring at 100° C. overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with saturated brine and dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 8% CHCl3/MeOH) to obtain ethyl 6-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)nicotinate (100 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[C:10](=[O:19])[CH:11]2C(OC)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CCN(CC)CC.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[Cl-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[C:10](=[O:19])[CH2:11]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1C(=O)C2CCC1N2C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C2CCC1C(=O)C2
Temperature: 100 °C
Reaction time: 12 h
Yield: 44.4 %

Procedure:
To 180 mg (0.970 mmol) of the diastereomer mixture obtained in Example 10, 7-(t-butoxycarbonyl)-3-methoxycarbonyl-7-azabicyclo[2.2.1]heptan-2-one, was added 3 ml of 10% HCl and the resulting mixture was heated under reflux at 100° C. for 3.5 hours. After completion of the reaction the solvent was evaporated in vacuo and the remaining water was removed by azeotropic distillation with ethanol. The crude product obtained was dissolved with 10 ml of dry methylene chloride, 169 ml (1.68 mmol) of Et3N and 292 mg (1.34 mmol) of (Boc)2O were added to the solution and the resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was poured into a saturated aqueous sodium chloride solution, then extracted with chloroform, the extract was dried with Na2SO4, then filtrated and the solvent was evaporated in vacuo. The crude product thus obtained was purified by silica gel chromatography (AcOEt:hexane=1:3) to obtain 91.0 mg of 7-(t-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-one. Yield 64%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=S)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CI.[CH3:23][C:24]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[C:25]=1[NH2:26]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=[N:26][C:25]3[C:27]([CH3:32])=[CH:28][C:29]([CH3:31])=[CH:30][C:24]=3[CH3:23])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: COc1ccc(-c2cc(=S)n(C)c(=O)n2C)cc1OC
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)cc1OC
Yield: 70.9 %

Procedure:
To a solution of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-thioxo-2(1H)-pyrimidinone (1.51 g) in tetrahydrofuran (150 ml) was added methyl iodide (30 ml) and the mixture was refluxed for 90 minutes. The precipitate was added to 2,4,6-trimethylaniline (6 g) and the mixture was heated at 110°-120° C. for 3 hours. The reaction mixture was washed with a mixture of hexane and diisopropyl ether to remove excess 2,4,6-trimethylaniline. The resulting precipitate was collected by filtration and then dissolved in chloroform. The solution was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure to give crude product, which was purified by silica gel column chromatography to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (1.44 g); mp 68°-70° C. Thus obtained compound was recrystallized from a mixture of methanol and water (5:1) to give the desired compound as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[O:13][CH3:14].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[OH:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:10])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C(=O)C(C)C)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(C(=O)C(C)C)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
15.0 g of 4'-hydroxy-3'-methoxy-2-methyl-propiophenone are dissolved in 300 ml of glacial acetic acid and 7.65 ml of 50.5 percent nitric acid (11.2N) in 40 ml of glacial acetic acid are added dropwise thereto while stiring within 15 minutes. After 15 minutes the reaction mixture is poured into ice-water and the separated crystals are filtered under suction, washed with water and dissolved in methylene chloride. The solution is dried over sodium sulfate and evaporated. The crude product obtained is taken up on methylene chloride and filtered over 100 g of silica gel. The thus-obtained crystals are recrystallized from methylene chloride/n-hexane. There is obtained 4'-hydroxy-3'-methoxy-2-methyl-5'-nitropropiophenone in the form of yellow crystals of m.p. 85°-87°.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].N1C=CC=CC=1.[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.S(=O)(O)[O-:57].[Na+]>O.O1CCCC1>[CH3:1][S:2]([C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=[O:57]
Reactant: O=S([O-])O
Reactant: CSc1ccc(-n2cnnn2)cc1C(=O)O
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)c1ccc(-n2cnnn2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 2-methylthio-5-(1H-tetrazol-1-yl)benzoic acid (0.50 g, 2.0 mmol), pyridine (20 mL) and water (20 mL). Cool in an ice bath. Add phenyltrimethylammonium tribromide (0.75 g, 2 mmol) and tetrahydrofuran (20 mL). Warm to ambient temperature. After 1 hour, add a solution of sodium bisulfite (1 g) in water (1 mL). Extract the reaction mixture with ethyl acetate and then dichloromethane. Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give a residue. the title compound. Chromatograph the residue on silica gel eluting sequentially with ethyl acetate and then 10% methanol/ethyl acetate to give methyl 2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoate.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[F:26][C:14]([F:13])([F:25])[C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:23])=[O:22])=[CH:19][CH:20]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-trifluoromethylbenzenesulfonyl chloride according to METHOD A, giving 0.14 g (33%) of an off-white solid after recrystallization from acetone/ether/petroleum ether: mp 174° C.; MS (Ionspray, [M+H]+) m/z 395; Anal. Calcd (found) for C14H13F3N2O4S2: C, 42.6 (42.4)%, H, 3.3 (2.8)%, N, 7.1 (6.8)%
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[CH:12]=[CH:13][N:14]=[CH:15][C:10]3=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.O=[Pt]=O>[CH:1]1([C:7]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][C:10]3=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1cn2c(C3CCCCC3)ncc2cn1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: c1nc(C2CCCCC2)n2c1CNCC2
Yield: 87.5 %

Procedure:
A solution of 3-cyclohexyl-imidazo[1,5-a]pyrazine 8a (960 mg, 4.4 mmol) in 25 ml ethanol was treated with 100 mg Adam's catalyst and stirred vigorously under one atmosphere of hydrogen for 18 hr. The mixture was filtered through a pad of Celite®. The filtrate was concentrated in vacuo to yield 790 mg of 3-cyclohexyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine 9a as a greenish-yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:42])[CH2:10][C@@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43](OC(=O)C[C@@H](NC(OC(C)(C)C)=O)C(N[C@@H](CC1C=CC=CC=1)COC)=O)C1C=CC=CC=1.C1(C2C=CC=CC=2)C=CC(C2CC(OC)OC2OC)=CC=1>CC(O)=O>[CH2:1]([O:8][C:9](=[O:42])[CH2:10][C@@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:32][CH:31]=2)=[CH:26]1)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][O:17][CH3:43])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC[C@H](Cc1ccccc1)NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=C(C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1)OCc1ccccc1
Agent: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Solvent: CC(=O)O
Product: COC[C@H](Cc1ccccc1)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Yield: 54 %

Procedure:
According to the procedure described in Example 1(a) for the preparation of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester, N-(1(S)-benzyl-2-methoxy-ethyl)-3(R)-(t-butoxycarbonylamino)succinamic acid benzyl ester was deprotected and the crude salt condensed in HOAc with 3-(biphenyl-4-yl)-2,5-dimethoxytetrahydrofuran (prepared as described in Example 1(a)) to provide in 54% yield N-(1(S)-benzyl-2-methoxyethyl)-3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester as an oil, which was used without further purification. 1H NMR (CDCl3): ∂ 7.65-7.62 (m, 6H), 7.57 (t, 2H, J=7.4 Hz), 7.48-7.16 (m, 9H), 7.10 (d, 2H, J=7.7 Hz), 6.98 (s, 1H), 6.69 (s, 1H), 6.57 (s, 1H), 5.78 (d, 1H, J=8.5 Hz), 5.10 (s, 2H), 5.01 (dd, 1H, J=5.5, 9.2 Hz), 4.20-4.16 (m, 1H), 3.43 (dd, 1H, J=5.3, 16.7 Hz), 3.28-3.15 (m, 5H), 3.02 (dd, 1H, J=9.2, 16.6 Hz), 2.76 (d, 2H, J=7.4 Hz); IR: 3315, 3063, 3030, 2930, 2891, 1738, 1682, 1526, 1495, 1204, 1167, 764, 737, 698 cm-1. HRFABMS: Calculated for C37H36N2O4 (M+H+): 572.2675. Found: 572.2674.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[OH:18])[O:9][C:6]2=[N:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:32](I)[CH3:33]>O>[CH2:32]([O:18][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[C:10]1[O:9][C:6]2[C:5]([N:11]=1)=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=2)[CH3:33]
Reactant: CCI
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Temperature: 60 °C
Yield: 21.8 %

Procedure:
To a mixture of 0.25 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol, 0.14 g of potassium carbonate and 3 ml of DMF, a mixture of 0.15 g of ethyl iodide and 1 ml of DMF was added at room temperature and stirred while heating at 60° C. for 1.5 hours. To the reaction mixture, 70 mg of potassium carbonate and 53 mg of iodoethane were added, and the reaction solution was stirred while heating at 60° C. for 3.5 hours. The reaction solution was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 60 mg of 2-(3-ethoxypyridin-4-yl)-6-trifluoromethyl-oxazolo[5,4-b]pyridine (hereinafter, referred to as “active compound 161”).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:10]2[C:11]([CH2:14][O:15][C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[C:19]([C:25]([OH:27])=O)[NH:20]4)=[CH:12][O:13][C:9]=2[CH:8]=1.[NH2:30][CH:31]1[CH2:36][CH2:35][C:34]([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][C@H:43]([OH:46])[C@@H:42]([CH3:47])[CH2:41]2)([OH:37])[CH2:33][CH2:32]1>>[OH:37][C:34]1([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][C@H:43]([OH:46])[C@@H:42]([CH3:47])[CH2:41]2)[CH2:35][CH2:36][CH:31]([NH:30][C:25]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[C:16]([O:15][CH2:14][C:11]2[C:10]4[CH:28]=[CH:29][C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:8][C:9]=4[O:13][CH:12]=2)[CH:24]=[CH:23][CH:22]=3)=[O:27])[CH2:32][CH2:33]1
Reactant: COCCCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: COCCCOc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-[6-(3-methoxy-propoxy)-benzofuran-3-ylmethoxy]-1H-indole-2-carboxylic acid 30f and amine 14.
Reaction SMILES: [I:1][C:2]1[C:10]2[NH:9][C:8](=O)[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:8]1[NH:7][C:6]2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=[C:2]([I:1])[C:10]=2[N:9]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)cc(I)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(I)c2nc(Cl)[nH]c2c1

Procedure:
4-Iodo-6-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one (328 mg, 1 mmol) reacted with POCl3 under the conditions of Example 1c to give the title compound as a off-white solid. MS (ESI, pos. ion) m/z: 347(M+1).