Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12](=[O:14])[CH3:13])[N:4]=1.[C:17]([O:21][C:22]([NH:24][C@H:25]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:26][C:27](O)=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:26][C:27]([N:10]1[CH2:9][CH2:8][N:7]2[C:3]([C:2]([F:1])([F:15])[F:16])=[N:4][C:5]([C:12](=[O:14])[CH3:13])=[C:6]2[CH2:11]1)=[O:28])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2

Procedure:
1-(3-Trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl)-ethanone 27g (192 mg, 0.72 mmol) and (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid if (0.24 g, 0.72 mmol) were dissolved in 20 mL of dichloromethane under stirring, and triethylamine (0.4 mL, 2.88 mmol) was then added to the solution. After stirring to mix well, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.275 g, 1.08 mmol) was then added. The reaction mixture was reacted overnight at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-acetyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 27h (0.3 g) as a white solid.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[CH2:16]([N-:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:17]([CH3:19])[CH3:18].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[CH2:16]([N-:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CC(C)C[N-]CC(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1
Yield: 73 %

Procedure:
Under N2 atmosphere, the Boc-DPro-diisobutylamide was dissolved in 25 ml of CH2Cl2 and 1-ml of trifluoracetic acid was added while being stirred. The reaction mixture was stirred for 30 min. Volatiles were removed under vacuum and the residue was dissolved in 30 ml of CH2Cl2 and washed with 10 ml saturated NaHCO3 aqueous solution. The organic layer was removed and the aqueous layer was extracted with CH2Cl2 (3×10 ml). The organic layer was dried over anhydrous sodium sulfate and filtered and the solvent was removed in vacuum. The residue was further purified by column chromatography (SiO2, CHCl3/MeOH, 85:15) to afford 0.73 mmol (73%) of compound (1) which was characterized by TLC on mass spectra, M+=225.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH:28]([CH3:32])[C:29]([NH2:31])=[O:30])[C:17]([C:33]([F:36])([F:35])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:39][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH:28]([CH3:32])[C:29]([NH2:31])=[O:30])[C:17]([C:33]([F:34])([F:36])[F:35])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)nc2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C)CC3)nc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a mixture of 2-(2-(2-(2-((6-(piperidin-4-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)propanamide 62 (0.064 g, 0.13 mmol) in anhydrous MeOH (2.0 mL) was added 37% aqueous formaldehyde (0.04 mL, 0.5 mmol) and sodium triacetoxyborohydride (0.138 g, 0.649 mmol). The mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere and then quenched by the addition of sat. aq. NaHCO3 (30 mL). The aqueous phase was extracted with EtOAc (2×20 mL), the combined organics were dried using a phase separation cartridge and then concentrated under reduced pressure. The organic residues were purified by prep-LCMS to give the title compound 63 (0.020 g, 30%) as the formic acid salt (2 equivs. determined by 1H NMR). LCMS-A: rt 4.786 min; m/z 513.3 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([O:37][CH2:38][CH3:39])[CH2:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[CH2:38]([O:37][CH:27]([C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]3)=[CH:14][CH:13]=2)=[CH:16][CH:17]=1)[CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH3:39]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(CCCc4ccccc4)OCC)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(CCCc1ccccc1)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)O)CC3)cc2)cc1
Temperature: 70 °C

Procedure:
1-{4′-[4-(1-Ethoxy-4-phenyl-butyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.070 g, 0.133 mmol) was dissolved in THF (3 mL) and MeOH (0.3 mL) then NaOH (3 N aq., 0.150 mL) was added. The reaction was heated to 70° C. overnight then an additional portion of NaOH (3 N aq., 0.150 mL) was added and the reaction was heated overnight again. After cooling the reaction was submitted to standard aqueous workup then purified by preparatory HPLC to afford a separable mixture of products, of which the major product was the title compound.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]1[NH:11][C:12]2[C:17]([C:18](=[O:21])[C:19]=1[CH3:20])=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].ClC1C=CC=C(C(OO)=[O:30])C=1.[OH-:33].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([S:8]([CH2:9][C:10]1[NH:11][C:12]2[C:17]([C:18](=[O:21])[C:19]=1[CH3:20])=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:30])=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCSCc1[nH]c2ccccc2c(=O)c1C
Reactant: [OH-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCS(=O)(=O)Cc1[nH]c2ccccc2c(=O)c1C
Reaction time: 5 h

Procedure:
To a solution of 2-[(heptylsulfanyl)methyl]-3-methylquinolin-4(1H)-one (110 mg) in chloroform (5 mL) was added m-chloroperbenzoic acid (75%, 200 mg) at room temperature, and the mixture was stirred for 5 hours. A 0.2M aqueous sodium hydroxide solution (20 mL) was added to the reaction mixture, followed by extraction with chloroform (50 mL). The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting powder was washed with diethyl ether and dried to obtain 2-[(heptylsulfonyl)methyl]-3-methylquinolin-4(1H)-one (70 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](C[Br:12])=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:32]1C=CC=CC=1>>[Br-:12].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:32][P+:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:7][CH:6]=1)([O:2][CH3:1])=[O:4]
Reactant: c1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccccc1CBr
Product: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 46 g (0.2 mole) of methyl-α-bromotoluate and 105 g (0.4 mole) of triphenyl phosphine in 800 ml of dry benzene was refluxed for two hours. After 15 minutes, the phosphonium bromide started precipitating out from the solution. After cooling the flask to room temperature, the solid was filtered, washed with plenty of petroleum ether and dried. The yield was 98 g m.p. 258°-260° C. The infrared spectrum showed absorption at 1720 cm-1 ##STR10## NMR (CDCl3) showed 3.8 ##STR11## 5.5-5.8 (d, --CH2 -p+, 2), and 7-8 (m,aromatic, 19). The phosphonium bromide was used in the next stop without further purification.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=1[CH2:5]Br.[CH3:12][N:13]([CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22])[CH3:14].[Cl-:29].[NH4+]>CCOCC>[ClH:29].[F:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=1[CH2:5][C:17]1([OH:22])[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH:15]([N:13]([CH3:12])[CH3:14])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccccc1)C1CCCCC1(O)Cc1cc(F)ccc1F
Product: Cl
Temperature: 25 °C
Yield: 56.4 %

Procedure:
0.29 g (11.9 mmole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 2.47 g (11.9 mmole) of 2,5-difluorobenzyl bromide dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.30 g (9.9 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.49 g of crude base (97.8% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 30 ml of water and 10 ml of ammonia solution (25 vol. %), extracted three times, each time with 20 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.75 g of crude base (77.0% of theory) were obtained, from which 2.21 g of 1-(2,5-difluoro-benzyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride (56.4% of theory) with a melting point of 219° C.-221° C. were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1)[CH3:2].C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)Cl>[Br:17][C:4]1[CH:5]=[CH:6][C:7]([NH2:9])=[N:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cccc(N)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCc1nc(N)ccc1Br
Reaction time: 0.75 h
Yield: 68.3 %

Procedure:
A 0° C. solution of 6-ethylpyridin-2-amine (3.37 g, 27.6 mmol) in CHCl3 (30 mL) was treated portion-wise with NBS (4.91 g, 27.6 mmol) over 30 min, stirred for 45 min, then concentrated to dryness. The residue was treated with EtOAc (8 mL), filtered to remove solids and purified via silica gel chromatography (EtOAc/Hex) to afford 5-bromo-6-ethylpyridin-2-amine (3.79 g, 68%). 1H NMR (400 MHz, DMSO-d6): δ 7.43 (d, J=8.6 Hz, 1 H), 6.21 (d, J=8.7 Hz, 1 H), 6.03 (s, 2 H), 2.61 (q, J=7.5 Hz, 2 H), 1.11 (t, J=7.5 Hz, 3 H);
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].Cl.CN(C)CCCN=C=N.ON1C2C=CC=CC=2N=N1.[CH2:32]([N:34]([CH2:37][CH2:38][NH2:39])[CH2:35][CH3:36])[CH3:33]>CN(C=O)C>[CH2:32]([N:34]([CH2:35][CH3:36])[CH2:37][CH2:38][NH:39][C:8]([C:6]1[NH:7][C:3]([CH:1]=[O:2])=[C:4]([CH3:11])[CH:5]=1)=[O:10])[CH3:33]
Reactant: CCN(CC)CCN
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Agent: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Reaction time: 12 h
Yield: 78 %

Procedure:
To a solution of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2.50 g, 16.32 mmol) in DMF (54 mL) was added 1-ethyl-3-(3-dimethylamino-propylcarbodiimide hydrochloride (EDC, 3.76 g, 19.59 mmol), 1-hydroxybenzotriazole (HOBt, 2.65 g, 19.59 mmol) followed by diethylaminoethyl amine (2.75 mL, 19.59 mmol). The reaction solution was stirred for 12 h, and then DMF solvent was removed. The residue was purified on a silica gel column eluting with 1-5% methanol in dichloromethane to provide 3.2 g (78%) of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH:16](C(O)=O)C)[C:10]1=[O:21])=O)(C)(C)C.S(Cl)([Cl:24])=[O:23].[CH2:26]([OH:28])[CH3:27]>>[ClH:24].[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]([O:28][CH2:26][CH3:27])=[O:23])[C:10]1=[O:21]
Reactant: CC(C(=O)O)N1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Reactant: O=S(Cl)Cl
Reactant: CCO
Product: CCOC(=O)N1CCCC[C@H](N)C1=O
Product: Cl

Procedure:
3-(S)-t-Butoxycarbonylamino-1-(1-carboxyethyl)perhydroazepin-2-one (Isomer A) (2 g), prepared as in Example 12, was treated with thionyl chloride in absolute ethyl alcohol to provide 2.07 g of the 3-(S)-amino-1-(1-ethoxycarbonyl)perhydroazepin-2-one hydrochloride. This material, following careful neutralization with ethanolic sodium ethoxide, was condensed with benzyl 2-keto-4-phenylbutyrate in the same manner as Example 1, the keto ester having been prepared by thionyl chloride treatment of the ketoacid in benzyl alcohol and purified via the sodium bisulfite addition product. The diastereoisomeric mixture resulting from the reductive amination (10.6 g) was chromatographed over silica gel to yield the individual isomers:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([CH2:14]Cl)=[CH:4][N:3]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:16]([CH2:14][C:5]1[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[N+:17]=[N-:18]
Reactant: CC(C)(C)CNc1nc(Cl)ncc1CCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)CNc1nc(Cl)ncc1CN=[N+]=[N-]
Temperature: 30 °C
Reaction time: 2.5 h

Procedure:
A solution of 1.47 g (5.92 mmol) of (2-chloro-5-chloromethyl-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine and 0.46 g (7.1 mmol) NaN3 is dissolved in 6 ml of DMF and was stirred at 30° C. for 2.5 hours. Then the reaction mixture is cooled to rt., diluted with ethyl acetate and twice extracted with H2O. The organic layer is separated and dried over Na2SO4. Evaporation of the ethyl acetate yielded (5-azidomethyl-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine as white crystalls.
Reaction SMILES: C(#N)C.[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=1)([O-:6])=[O:5].[CH:15](O)=[O:16]>>[CH:15]([NH:14][NH:13][C:10]1[CH:9]=[CH:8][C:7]([N+:4]([O-:6])=[O:5])=[CH:12][CH:11]=1)=[O:16]
Reactant: O=CO
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: O=CNNc1ccc([N+](=O)[O-])cc1
Reaction time: 0.33 h
Yield: 929.9 %

Procedure:
Then, according to the method described in Japanese Patent Application (OPI) No. 74729/79, 1-formyl-2-(4-aminophenyl)hydrazine was produced. That is, to 1.6 liters of acetonitrile was added 45 g of 4-nitrophenylhydrazine and then 322 g of formic acid was gradually added to the mixture with stirring, whereby a homogeneous solution was obtained. After 20 minutes, crystals began to deposit. After further performing the reaction for 2 hours at an inside temperature of 80° C., the reaction mixture was cooled and crystals thus formed were collected by filtration, washed with acetonitrile and dried to provide 495 g of 1-formyl-2-(4-nitrophenyl)hydrazine having a melting point of 184°-186° C.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[CH2:14]([C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C:15]1[CH:20]=[CH:19][C:18]([CH:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH2:3]2)=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:14]([C:15]1[CH:20]=[CH:19][C:18]([C:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH:3]=2)=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: Br[Mg]c1ccc(Cc2ccccc2)cc1
Product: COC(=O)c1cc2c([nH]1)CC=C2c1ccc(Cc2ccccc2)cc1
Product: COC(=O)c1cc2c([nH]1)CCC2c1ccc(Cc2ccccc2)cc1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.64 g, 3.6 mmol) and (4-benzylphenyl)magnesium bromide were reacted according to General Procedure 3 to give methyl 4-(4-benzylphenyl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate. (4-Benzylphenyl)magnesium bromide was synthesized from 1-benzyl-4-bromobenzene. (In an inert Ar atmosphere, to a suspension of Mg (0.44 g, 18.2 mmol) turnings in 50 mL of THF was added very slowly (dropwise) 1-benzyl-4-bromobenzene, then catalytic amount of iodine was added. The reaction mixture was stirred for 30 min at room temperature, then 25 mL of THF was added and the mixture was stirred for 3 hours at 75-80° C. (gentle reflux of THF).) The methyl 4-(4-benzylphenyl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate was hydrogenated according to General Procedure 6 with 5% Pd/C and a hydrogen balloon, and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.23-2.35 (m, 1H), 2.71-2.97 (m, 3H), 3.82 (s, 3H), 3.96 (s, 2H), 4.20 (t, J=7.32 Hz, 1H), 6.63 (d, J=1.76 Hz, 1H), 7.09-7.15 (m, 5H), 7.16-7.23 (m, 2H), 7.28-7.32 (m, 2H), 8.84 (br. s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6](=[O:18])[C:5]=2[NH:4][N:3]=1.[C:19](=[O:22])([O-])[O-].[K+].[K+].ClC[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=O>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6](=[O:18])[C:5]=2[N:4]([C:19](=[O:22])[CH2:27][CH2:28][N:30]2[CH2:31][CH2:32][N:33]([C:36]3[CH:37]=[CH:38][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:40][CH:41]=3)[CH2:34][CH2:35]2)[N:3]=1
Reactant: O=C(CCCl)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: Cc1ccc(N2CCc3c(N)n[nH]c3C2=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(c5ccc(C(F)(F)F)cc5)CC4)c3C2=O)cc1

Procedure:
A target compound (176.3 mg, 0.334 mmol, 85.4%) was yielded as solid in the same manner as Example 1 by reacting 3-amino-5,6-dihydro-6-N-(p-tolyl)-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (95 mg, 0.392 mmol) with potassium carbonate (81.2 mg, 0.588 mmol) and 3-chloro-1-[4-{4-(trifluoromethyl)phenyl}piperazin-1-yl]propan-1-one (138.2 mg, 0.431 mmol).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][N:12]([CH:29]([CH3:31])[CH3:30])[C:13](=[O:28])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH:15]=2)[CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1)=[O:5])C.O[Li].O.Cl>CO.C(Cl)Cl>[C:35]([O:34][C:32]([N:8]1[CH2:9][C@@H:10]([CH2:11][N:12]([CH:29]([CH3:30])[CH3:31])[C:13](=[O:28])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH:15]=2)[C@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[O:33])([CH3:36])([CH3:38])[CH3:37]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)C(C)C)ccc1OC
Reaction time: 8 h

Procedure:
To a solution of (3S*,4R*)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.41 g, 2.63 mmol) in MeOH (25 mL) cooled at 0° C., 662 mg of LiOH.H2O is added. The reaction mixture is stirred overnight. The mixture is taken up in CH2Cl2, an aqueous HCl (5%) solution is added and the resulting mixture is extracted 3 times with CH2Cl2, dried over Na2SO4, filtered and concentrated. The crude material is used in the next step without purification. TLC, Rf (CH2Cl2/MeOH 95:5)=0.15. MS (LC-MS): 409.0 [M-H-Boc]−; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mumin): 4.96 min.
Reaction SMILES: N1C=CC=CC=1.[Br-:7].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:28][N:29]([CH3:53])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]3[CH:44]=[CH:43][N:42]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:39]3=[N:40][CH:41]=2)=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:7][C:44]1[C:38]2[C:39](=[N:40][CH:41]=[C:36]([C:33]3[CH:34]=[CH:35][C:30]([N:29]([CH3:53])[CH3:28])=[CH:31][CH:32]=3)[CH:37]=2)[N:42]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:51])([CH3:50])[CH3:52])[CH:43]=1
Reactant: [Br-]
Reactant: CN(C)c1ccc(-c2cnc3c(ccn3COCC[Si](C)(C)C)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)c1ccc(-c2cnc3c(c2)c(Br)cn3COCC[Si](C)(C)C)cc1
Yield: 70.3 %

Procedure:
Pyridine (0.180 mL, 2.23 mmol) and pyridinium tribromide (0.832 g, 2.34 mmol) were added to a stirred and cooled (−70° C.) solution of 59 (0.820 g, 2.23 mmol) in CH2Cl2 (10 mL). The mixture was stirred at −70° C. for 30 min., poured into saturated aqueous NaHCO3 solution and extracted with CH2Cl2. The organic extract was washed with brine, dried (MgSO4), and concentrated. The residue was purified by means of SGC with hexane:AcOEt as eluent to afford 60 (0.700 g, 70%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 0.00 (s, 9H), 0.94-1.01 (m, 2H), 3.07 (s, 6H), 3.58-3.64 (m, 2H), 5.71 (s, 2H), 6.88-6.93 (m, 2H), 7.43 (s, 1H), 7.56-7.62 (m, 2H), 8.01 (d, J=0.21 Hz, 1H), 8.62 (d, J=0.21 Hz, 1H).
Reaction SMILES: Cl.[F:2][CH:3]([F:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([N:29]2[CH2:28][CH2:27][N:26]([C:24]([C:6]3[N:5]([CH2:4][CH:3]([F:2])[F:32])[C:13]4[C:8]([CH:7]=3)=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=4)=[O:25])[CH2:31][CH2:30]2)=[O:37])[CH2:35][CH2:34]1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3CC(F)F)CC1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(C(=O)C4CC4)CC2)n3CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-(2,2-difluoro-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and cyclopropanoyl chloride. Off-white solid. MS (m/z): 503.2 (M+H)+.