Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)(=[O:22])=[O:21])=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)(C)(C)C.[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[NH2:7][CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([N:19]([CH3:31])[S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]1=2
Reactant: CC(C)(C)OC(=O)NCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccc2c(c1)CCCC2CN)S(=O)(=O)c1cccc(F)c1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.22 grams (0.524 mmole) (+/−)-[6-(3-fluoro-benzenesulfonylamino)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamic acid tert-butyl ester in 10 mL DMF was added 0.08 grams (0.576 mmole) potassium carbonate and 0.033 mL (0.524 mmole) iodomethane. The reaction mixture was stirred at 23° C. for 0.5 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water saturated aqueous sodium chloride, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was dissolved in 3 mL warm TFA and immediately concentrated under reduced pressure. The residue was partitioned between saturated aqueous sodium carbonate ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. N-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-fluoro-N-methyl-benzenesulfonamide was isolated as the crystalline oxalate salt, 0.06 grams (18%), m.p. 176-177° C., M+H=349.
Reaction SMILES: Cl[C:2]([O:5][C:6](=[O:12])[O:7][C:8](Cl)(Cl)Cl)(Cl)Cl.[N:13]1[CH:18]=CC=C[CH:14]=1.[O:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:6](=[O:12])([O:7][CH:8]1[CH2:22][CH2:23][O:19][CH2:20][CH2:21]1)[O:5][CH2:2][CH2:18][NH:13][CH3:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CCOC1
Reactant: c1ccncc1
Product: CNCCOC(=O)OC1CCOCC1
Reaction time: 0.33 h

Procedure:
To a solution of bis(trichloromethyl)carbonate (0.48 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.39 mL) in tetrahydrofuran (1 mL) under ice-cooling. The reaction solution was stirred for 20 minutes under ice-cooling, and 2-(methylamino)ethyl tetrahydropyran-4-yl carbonate hydrochlride (0.96 g) obtained in Reference Synthetic Example 17 was added. A solution of triethylamine (0.67 mL) in tetrahydrofuran (1 mL) was added dropwise, and stirred at room temperature for 2 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2 N hydrocloric acid (20 mL), and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL). To the solution were added (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.26 g), triethylamine (0.71 mL) and 4-dimethylaminopyridine (0.042 g), and stirred at 60° C. for 6 hrs, and then at room temperature for 8 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate:hexane=3:7, then ethyl acetate). The purified material was crystallized from diethyl ether, and further recrystallized from acetone-diisopropyl ether to give title compound as colorless solid (1.45 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[O:28]=[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[CH:16][CH:17]=1)[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 84.4 %

Procedure:
In a manner similar to Example 12, Step (b), (4-trifluoromethyl-phenyl)boronic acid (1.285 g, 0.00676 mol) was allowed to react with 4-(4′-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.356 g, 0.00500 mol) in the presence of tetrakis(triphenylphosphine)palladium(0) (0.173 g, 0.000150 mol) and 2.0 M aqueous sodium carbonate (5.0 mL, 0.010 mol) in toluene (10 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluting with chloroform to give 1.42 g of 4-oxo-4-(4′-trifluoromethyl-biphenyl-4-yl)-butyric acid, methyl ester as a white solid; mp 140-142° C.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Bi](Br)(Br)Br.O[CH:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)[CH3:14]>C(Cl)(Cl)(Cl)Cl>[CH:1]1([O:7][CH:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: OC1CCCCC1
Agent: Br[Bi](Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(C)OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
To the solution of cyclohexanol (167 mg, 1.67 mmol) in carbon tetrachloride (50 mL) was added bismuth (III) bromide (744.4 mg, 1.67 mmol), the mixture was stirred for 30 minutes at room temperature, the methyl 4-(1-hydroxyethyl)benzoate (300 mg, 1.67 mmol) was added, the mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give methyl 4-(1-(cyclohexyloxy)ethyl)benzoate (60 mg, 14%) as oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC>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.O1CCOCC1>[N:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:2]1[C:10]2[NH:9][C:8]([N:11]3[CH2:12][CH2:13][N:14]([C:17]4[C:22]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:15][CH2:16]3)=[N:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:28])[F:29])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(-c2ccccn2)c2[nH]c(N3CCN(c4ncccc4C(F)(F)F)CC3)nc2c1
Reaction time: 1 h

Procedure:
A mixture of 4-bromo-6-trifluoromethyl-2-[4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1H-benzoimidazole (148 mg, 0.3 mmol, Example 7), 2-tributylstannylpyridine (148 mg, 0.5 mmol, Frontier), Pd(PPh3)4 (46 mg, 0.04 mmol, Aldrich) and 1,4-dioxane (1 mL) was subjected to microwave irradiation at 140° C. with stirring for 60 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 60% EtOAc/hexane, to give the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 493 (M+1).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[O:34][C@H:33]([CH2:35][OH:36])[C@@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([O:4][C@H:5]1[O:34][C@H:33]([CH2:35][O:36][S:43]([C:40]2[CH:41]=[CH:42][C:37]([CH3:47])=[CH:38][CH:39]=2)(=[O:45])=[O:44])[C@@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: C=CCO[C@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the compound (4) (25.1 g, 51.2 mmol) in anhydrous pyridine (250 ml) were added p-toluenesulfonyl chloride (14.6 g, 1.5 equivalents) and 4-dimethylaminopyridine (626 mg, 0.1 equivalents), and the reaction liquid was stirred at room temperature for 16 hours. After the sufficient progress of the reaction was confirmed, water (10 ml) was added to stop the reaction, and the reaction liquid was concentrated under reduced pressure. The residue was suspended in a minor amount of ethyl acetate, poured to 0.5 M hydrochloric acid (200 ml), and extracted with ethyl acetate (3×200 ml). The organic layers were combined, washed with a saturated sodium hydrogen carbonate solution (2×100 ml) and saturated saline (2×100 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was crystallized twice from heated ethanol to obtain the title compound (5) in the form of colorless needle crystals (25.0 g). The filtrate was concentrated, purified with silica gel chromatography (hexane-ethyl acetate, 5:1→4:1→3:1) to obtain the compound (5) (4.00 g). {29.0 g (45.0 mmol) in total, 87.9%}.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20](F)(F)F)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.BrC1C=C[C:30]2[C:31]3[N:32]=C(C(N)=O)SC=3CCO[C:29]=2[CH:28]=1.N1C=CC=CC=1CNN>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]5[CH:28]=[CH:29][CH:30]=[CH:31][N:32]=5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: NNCc1ccccn1
Product: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3Cc3ccccn3)nc1-2

Procedure:
Following the procedure for 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 was reacted with Pyridin-2-ylmethyl-hydrazine to give 8-Bromo-2-(2-pyridin-2-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene. MS (ESI+) 440.0/442.0.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[C:15]1(=[O:19])[CH2:18][CH2:17][CH2:16]1>C(OCC)C>[OH:19][C:15]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: N#Cc1ccc(I)cc1
Reactant: O=C1CCC1
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Product: N#Cc1ccc(C2(O)CCC2)cc1

Procedure:
Analogously to the process described in Example 5A/Step 1, 32.67 g (143 mmol) of 4-iodobenzonitrile, 75 ml (150 mmol) of 2 M isopropylmagnesium chloride solution in diethyl ether and 15.0 g (214 mmol) of cyclobutanone were used to obtain 13.31 g (78% of theory) of the title compound. The reaction time at RT in this case was 16 h, and, after the aqueous workup, the crude product was purified by means of suction filtration through 150 g of silica gel with 10:1→4:1 cyclohexane/ethyl acetate as the eluent.
Reaction SMILES: C1(C(C2[C:14]([CH2:15][O:16][CH2:17][C:18]3[C:23](C4C(=CC=C(O)C=4)O)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=CC(=CC=1)O)O.[CH3:32][CH:33]([O:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[OH2:50]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:17]([O:16][C:15]1[CH:10]=[CH:11][C:12]([O:46][C:45](=[O:50])[C:44]2[CH:48]=[CH:49][C:41]([O:40][CH:33]([CH3:32])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:42][CH:43]=2)=[CH:13][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCCCCC(C)Oc1ccc(C(=O)Cl)cc1
Reactant: O
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCC(C)Oc1ccc(C(=O)Oc2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 2 h

Procedure:
Hydroquinone monobenzyl ether (100.0 g, 0.50 mol) was dissolved in pyridine (600 ml), followed by dropwise adding to the solution, a solution of p-(1-methyl-heptyloxy)benzoic acid chloride (122.2 g, 0.45 mol) dissolved in toluene (600 ml), under ice cooling, agitating the mixture for 2 hours while keeping the temperature at about 50°-60° C., allowing it to stand overnight, thereafter adding toluene (3,000 ml) and water (2,000 ml), agitating the mixture, washing the toluene layer with 6N-HCl, then with 2N-NaOH aqueous solution and further with water until the wash water became neutral, distilling off toluene and recrystallizing the residue from ethanol to obtain p-(1-methyl-heptyloxy)-benzoic acid p-benzyloxyphenyl ester (121.0 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[N:11]=[C:10]([CH:12]=[C:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
tert-Butyl 4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylene)piperidine-1-carboxylate (0.72 g) was brought up in ethanol (80 mL) and ethyl acetate (80 mL) and the flask was purged with nitrogen before addition of 10% Palladium on carbon (10 mol %). The reaction was placed under a hydrogen balloon and stirred at room temperature overnight. The reaction was filtered thru celite and purified by flash column chromatography to obtain 0.55 g tert-butyl 4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidine-1-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[C:14]1([CH2:13][O:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][NH:6]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1cccc2[nH]ncc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2cccc3[nH]ncc23)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxyindazole (702 mg, 5.24 mmol) in DMF (10 mL) at ambient temperature under argon was added sodium hydride (231 mg of a 60% dispersion in mineral oil, 5.76 mmol). The mixture was stirred for 10 minutes and then benzyl bromide (0.622 mL, 5.24 mmol) was added via syringe. After stirring for 2 hours at ambient temperature, the mixture was quenched with ammonium chloride solution, the solvents were evaporated and ethyl acetate and water were added. The product was extracted into ethyl acetate and the organic solution was dried (Na2SO4) and evaporated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Mg]Br)C.[C:36](=[O:38])=[O:37].O>C1COCC1.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([C:36]([OH:38])=[O:37])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Reactant: O=C=O
Agent: CC[Mg]Br
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1nc(C(=O)O)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a cooled (−30° C.) solution of 3-ethyl-1-iodo-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (500 mg; 0.910 mmol) in anhydrous THF (10 ml) was added dropwise 1M ethylmagnesium bromide in THF (2.0 ml; 2 mmol). The resulting colorless suspension was allowed to warm-up to rt in 30 min., and was again cooled to −35° C. before continuous injection of carbon dioxide during 2 h. Water and EA were then added, and the resulting reaction mixture was allowed to warm-up to rt. The organic layer was further washed with aq. sat. NH4Cl, dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give the expected product 3-ethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester as a colorless foam (350 mg; 0.748 mmol; 82%).
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([OH:24])=O.[OH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([NH2:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1>>[OH:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]([NH:39][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:24])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:30][CH:31]=1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Reactant: NC(c1ccccc1)c1ccc(O)cc1
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)NC(c4ccccc4)c4ccc(O)cc4)[C@@]3(C)CC[C@@H]12
Yield: 25 %

Procedure:
The title compound was prepared in a yield of 25% in a similar manner to that described in Example 37 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and α-(4-hydroxyphenyl)benzylamine.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C([O:17][C:18](=O)[CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C>CC(O)=O>[C:1]([N:5]1[C:9]2[NH:10][C:18](=[O:17])[CH:19]=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:8]=2[C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(C2CCC2)cc1N
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)n1nc(C2CCC2)c2c(-c3ccccc3)cc(=O)[nH]c21
Temperature: 110 °C
Yield: 15 %

Procedure:
To a stirring solution of crude 2-tert-butyl-5-cyclobutyl-2H-pyrazol-3-ylamine (4.0 g, 20.7 mmol) in AcOH (20 mL) was added 3-oxo-3-phenyl-propionic acid ethyl ester (3.5 g, 20.7 mmol). The reaction was then heated to 110° C. for 14 hr, at which time the reaction was cooled to room temperature and concentrated under reduced pressure. Purification of the resulting material was accomplished by flash chromatography using a 75 g short Biotageo column, eluting with a gradient of 5%, 10% EtOAc/hexanes. The product-containing fractions were collected and concentrated to give the title compound (1.0 g, 15% yield) as a colorless solid. Rf=0.31 (20% EtOAc/hexanes); LRMS m/z (APCl) 322 (M+1); 500 MHz 1H NMR (CDCl3) δ 7.46-7.44 (m, 3H), 7.38-7.36 (m, 2H), 6.17 (s, 1H), 3.16 (dddd, J=7.9, 7.9, 7.9, 7.9 Hz, 1H), 2.17-2.11 (m, 2H), 1.76 (s, 9H), 1.71-1.67 (m, 4H); 125 MHz 13C NMR (CDCl3) δ 163.1, 151.0, 147.5, 141.8, 138.5, 128.9, 128.4, 128.2, 112.5, 110.6, 105.7, 59.7, 34.2, 29.2, 27.6, 18.4.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][N:11]=[N+:12]=[N-:13])([O:3]C(C)(C)C)=O.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].C(Cl)(=O)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1>O1CCOCC1.O>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([C:1]([NH:8][C@H:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][N:11]=[N+:12]=[N-:13])=[O:3])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN=[N+]=[N-])c1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C(=O)N[C@@H](CN=[N+]=[N-])c2ccccc2)cc1
Temperature: -15 °C
Yield: 85.9 %

Procedure:
(R)-2-(Boc-amino)-2-phenylethyl azide (47.8 g, 0.182 mole) was added to trifluoroacetic acid (500 mL) with stirring and ice-water bath cooling. The cooling bath was removed, the reaction was allowed to stir 1 h, and the solvent was removed in vacuo at 35° C. water bath temperature. The residue was co-evaporated with toluene to give a weight of 75.0 g. The residue was dissolved in 1,4-dioxane (500 mL) and water (500 mL), with ice-water bath cooling, and then potassium carbonate (113.5 g, 0.82 mol), and anisoyl chloride (37.3 g, 0.219 mol) were added. Another portion of 1,4-dioxane (300 mL) was added to facilitate stirring. After stirring over the weekend, water (1 L) was added. The mixture was cooled to −15° C., and vacuum filtered to collect a white solid. The solid was washed with water, air dried, and then dried under vacuum at 50° C. for 4 h to afford 46.3 g (86%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]3[O:29][C:28]([C:30]([NH2:32])=[O:31])=[CH:27][C:26]=3[CH:33]=2)[CH2:18][CH2:17]1)#[N:2].Cl.CC(C)=[O:37]>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:37])[CH:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:23]=[CH:24][C:25]3[O:29][C:28]([C:30]([NH2:32])=[O:31])=[CH:27][C:26]=3[CH:33]=2)[CH2:20][CH2:21]1)#[N:2]
Reactant: N#Cc1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(C(N)=O)cc5c4)CC3)c2c1
Reactant: CC(C)=O
Agent: Cl
Solvent: CS(C)=O
Product: N#Cc1ccc2c(c1)C(CCCCN1CCN(c3ccc4oc(C(N)=O)cc4c3)CC1)C(=O)N2
Temperature: 25 °C

Procedure:
4.78 g (10 mmol) of 5-{4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl}benzo-furan-2-carboxamide are dissolved in 28.4 ml of hot DMSO. After cooling to room temperature, 66.4 ml of conc. HCl are added dropwise with stirring. The batch temperature is held at 24° C. by cooling by means of an ice bath. When the addition of HCl is complete, the batch is stirred at room temperature for 10 h. The crystal slurry is subsequently stirred with 50 ml of acetone, filtered off with suction and rinsed with acetone, isopropanol and diethyl ether. The resultant crystals were dried in air.