Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([Br:56])=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([Br:56])=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1Cl
Temperature: 0 °C
Yield: 82.7 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it was completely dissolved and became light purple in color. The reaction mixture was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 92, 200 mg, 0.61 mmol) and stirred at 0° C. for 20 min and then warmed to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-amino-5-bromopyridine (157 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09 mmol), and reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-bromo-pyridin-2-yl)-propionamide (245 mg, 83%) as a white foam: EI-HRMS m/e calcd for C20H22Br ClN2O3S (M+) 484.0223, found 484.0222.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH2:28][CH2:29][CH3:30])=[C:7]([CH:22]=[CH:23][C:24]=1[C:25](=[O:27])[CH3:26])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[Br:21])(=[O:3])[CH3:2].C(O)(=[O:33])C.[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[C:1]([O:4][C:5]1[C:6]([CH2:28][CH2:29][CH3:30])=[C:7]([CH:22]=[CH:23][C:24]=1[C:25](=[O:27])[CH3:26])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([OH:33])=[O:18])=[CH:15][C:14]=1[Br:21])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc(C=O)cc2Br)ccc(C(C)=O)c1OC(C)=O
Reactant: CC(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Br)ccc(C(C)=O)c1OC(C)=O

Procedure:
To a solution of 4-[3-(3-acetoxy-4-acetyl-2-propylphenoxy)propoxy]3-bromobenzaldehyde (2.39 g) in acetone (50 ml) was added acetic acid (50 ml). To the well stirred mixture was added pulverized potassium permanganate (1.58 g) by portions at room temperature. The reaction was allowed to proceed while stirring for one hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was subjected to extraction with chloroform. Insoluble materials were filtered off, and the filtrate was washed with a dilute aqueous solution of hydrogen peroxide, then with water. The resulting solution was dried and concentrated to give colorless and clear syrup. Crystallization from aqueous alcohol gave 4-[3-(3-acetoxy-4-acetyl-2 propylphenoxy)propoxy]-3-bromobenzoic acid (2.0 g), m.p. 155°-156° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]([CH3:25])([CH3:24])[C:21]([NH2:23])=[O:22])[CH2:16][CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=1.[CH3:32][C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][C:20]([N:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=[C:2]([N:34]2[C:35]4[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=[C:33]2[CH3:32])[N:10]=3)[CH2:19][CH2:18]1)([CH3:25])[C:21]([NH2:23])=[O:22]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cn1c(CCN2CCN(C(C)(C)C(N)=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3CCN(C(C)(C)C(N)=O)CC3)n(C)c2n1
Temperature: 120 °C
Yield: 64 %

Procedure:
A mixture of 2-{4-[2-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]piperazin-1-yl}isobutyramide (80 mg, 0.18 mmol), 2-methylbenzimidazole (26 mg, 0.20 mmol), Pd2(dba)3 (4 mg, 2.5 mol %), Xphos (8 mg, 10 mol %) and Cs2CO3 (87 mg, 0.27 mmol) in dioxane (1.0 mL) was purged with argon gas then heated at 120° C., for 19 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PCC, 0-10% MeOH in DCM) to give 368 (63 mg, 65%) as a pale yellow solid. LCMS: (Method G): RT 5.34 min; [M+H]+ 547.3. 1H NMR (400 MHz, CHCl3-d): δ 8.09-8.05 (m, 1 H), 7.73-7.69 (m, 1 H), 7.29-7.24 (m, 1 H), 7.06 (s, 1 H), 5.23 (s, 1 H), 4.47-4.14 (m, 4 H), 3.87 (t, J=4.7 Hz, 4 H), 3.79 (s, 3 H), 3.49 (s, 1 H), 3.19-3.0 (m, 2 H), 2.94 (s, 3 H), 2.78-2.54 (m, 6 H), 1.78-1.48 (m, 4 H), 1.25 (s, 6 H)
Reaction SMILES: [CH2:1]([C:3]([C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[C:27]([CH3:40])[CH:26]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH3:24])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:41][O:42][C:43](=[O:52])[CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[C:49](Br)[CH:50]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>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.CN(C)C=O>[CH3:41][O:42][C:43](=[O:52])[CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[C:49]([C:28]2[CH:29]=[CH:30][C:25]([C:3]([CH2:4][CH3:5])([C:6]3[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]4([O:19][Si:20]([CH3:22])([CH3:23])[CH3:21])[CH2:18][CH2:17][CH2:16][CH2:15]4)=[C:8]([CH3:24])[CH:7]=3)[CH2:1][CH3:2])=[CH:26][C:27]=2[CH3:40])[CH:50]=1
Reactant: CCC(CC)(c1ccc(CCC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(CCC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 95 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
2-[4-(1-ethyl-1-{3-methyl-4-[2-(1-trimethylsilanyloxy-cyclopentyl)-ethyl]-phenyl}-propyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 34-(1); 35.7 mg, 0.063 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 19.0 mg, 0.082 mmol), tetrakis(triphenylphosphine)palladium (0) (9.2 mg, 0.080 mmol), potassium phosphate (26.3 mg, 0.124 mmol) and N,N-dimethylformamide (0.38 mL) were placed in a reaction vessel and stirred in a nitrogen atmosphere at 95° C. for three hours. A saturated aqueous ammonium chloride solution (0.1 mL) and water (0.1 mL) were added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane only to hexane/ethyl acetate=3/1) to give the title compound (26.8 mg, 72%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[C:16]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:17]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:18]=1[C:19](OCC)=[O:20])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][CH2:36][C:15]2[C:16]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:17]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[C:18]3[C:19](=[O:20])[N:8]4[C@@H:9]([CH2:10][CH2:11][CH2:12]4)[C:13]=3[N:14]=2)=[CH:39][CH:40]=1
Reactant: CCOC(=O)C1=C(CCc2ccc(F)cc2)NC([C@@H]2CCCN2C(=O)OC(C)(C)C)=C(C(=O)OCC)C1c1ccc(C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1ccc(C)cc1)C(=O)N1CCC[C@@H]21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.3 %

Procedure:
To the flask containing crude diethyl 2-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-6-[2-(4-fluorophenyl)ethyl]-4-(4-methylphenyl)-1,4-dihydro-3,5-pyridinedicarboxylate (B, 1.0 mmol), 14.2 ml premixed trifluoroacetic acid and dichloromethane (10 ml/4.2 ml) were added. The resulting mixture was stirred at room temperature for 20 minutes. The solvents were removed in vacuo. The resulting residue was dissolved in a 30 ml mixture of triethylamine and dichloromethane (10 ml/20 ml) and was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water, brine subsequently. After removing the solvent, the residue was purified with flash chromatography. 125 mg of solid was obtained. 1H NMR (400 MHz, CDCl3) δ 7.22 (m, 4H), 7.18 (t, 2H), 6.95 (t, 2m), 4.64 (m, 1H), 4.02 (q, 2H), 3.70 (m, 1H) 3.35 (m, 1H), 3.15 (m, 2H), 3.05 (m, 2H), 2.42 (m, 1H), 2.35 (s, 3H), 2.30 (m, 2H), 1.38 (m, 1H) ppm. ESI-MS m/z 459 (M+H)+, 917 (2M+1)+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH:9]([S:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH3:11])[CH3:10].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.CCOC(C)=O.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:9]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:17][CH:16]=1)(=[O:13])=[O:14])([CH3:11])[CH3:10]
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Nc1cnc(Br)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)cn2)cc1
Temperature: 60 °C
Yield: 80.7 %

Procedure:
5-Bromopyrazin-2-amine (5 g, 28.74 mmol), (4-isopropylsulfonylphenyl)boronic acid (7.866 g, 34.49 mmol) and K3PO4 (12.20 g, 57.48 mmol) were combined in MeCN (100 mL)/Water (25 mL) and Pd[P(tBu)3]2 (734.4 mg, 1.437 mmol) was added. The reaction was heated at 60° C. for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with EtOAc and water. The layers were separated and the aqueous layer extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated from DCM and isolated by filtration to give the sub-title compound as an orange solid (6.43 g, 76% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.17 (d, 6H), 3.43 (sept, 1H), 6.86 (s, 2H), 7.87 (d, 2H), 8.00 (s, 1H), 8.20 (d, 2H) and 8.67 (s, 1H) ppm; MS (ES+) 278.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.Cl[C:21]1[CH:30]=[CH:29][N:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][C:25]([CH3:31])=[N:26]2>>[CH3:17][NH:16][C:14](=[O:15])[C:13]1[CH:18]=[CH:19][C:10]([S:9][C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[NH:1][C:21]2[C:22]3[C:27](=[N:26][C:25]([CH3:31])=[CH:24][CH:23]=3)[N:28]=[CH:29][CH:30]=2)=[CH:11][CH:12]=1
Reactant: CNC(=O)c1ccc(Sc2ccc(C)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: CNC(=O)c1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 85b (0.277 g, 1.05 mmol) was reacted with the product from Example 1d (0.09 g, 0.504 mmol) for 41 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid salt (0.078 g, 28%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.41 (s, 3H) 2.70-2.82 (m, 6H) 6.36 (d, J=6.99 Hz, 1H) 7.20 (d, J=8.46 Hz, 2H) 7.35-7.45 (m, 2H) 7.51 (d, 1H) 7.64 (d, J=8.46 Hz, 2H) 7.75 (d, J=8.82 Hz, 1H) 8.33-8.45 (m, 2H) 8.90 (d, J=8.82 Hz, 1H) 11.03 (s, 1H); MS (ESI+) m/z 415.0 (M+H)+; (ESI−) m/z 413.1 (M−H)−.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH:11]=[C:10]([F:21])[C:9]=1/[CH:22]=[CH:23]/[C:24](OC)=[O:25]>C1COCC1>[F:7][C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:16])[O:17][CH:18]([CH3:19])[CH3:20])[CH:11]=[C:10]([F:21])[C:9]=1/[CH:22]=[CH:23]/[CH2:24][OH:25]
Reactant: COC(=O)/C=C/c1c(F)cc(NC(=O)OC(C)C)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)OC(=O)Nc1cc(F)c(/C=C/CO)c(F)c1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of LiAlH4 (26 mL of a 1.0 M THF solution, 26 mmol) was added to a cooled (−78° C.) solution of methyl (2E)-3-{2,6-difluoro-4-[(isopropoxycarbonyl)amino]phenyl}acrylate (7.77 g, 26 mmol) in THF (130 mL). The solution was allowed to warm slowly to −20° C. and maintained at that temperature for 2 hours. The reaction mixture was then quenched by slow addition of saturated NH4Cl and then treated with 30 mL of dilute citric acid. The resulting mixture was stirred for 15 minutes and then extracted with three portions of ethyl acetate. Combined organic phases were washed with H2O, brine and dried (MgSO4), filtered and concentrated to give a red oil. The crude product was purified by column chromatography (0-1% methanol-dichloromethane) to afford the title compound as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12]1)C1C=CC=CC=1>CCO.[Pd]>[C:22]([O:21][C:19](=[O:20])[NH:18][CH2:17][C@H:14]1[CH2:13][CH2:12][C@H:11]([NH2:10])[CH2:16][CH2:15]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of trans-[4-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acid benzyl ester (5.32 g, 0.015 mol) in EtOH (200 mL) was added 10% Pd/C (50 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 4 hr. The resulting mixture was filtered through a pad of celite and concentrated. The residue was purified by column chromatography (silica gel, 3% 2 M NH3/MeOH in CH2Cl2) to give trans-(4-amino-cyclohexylmethyl)-carbamic acid tert-butyl ester as a colorless solid (3.197 g, 95.4%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]([CH3:15])[C:6]1=[O:16])[CH:2]([CH3:4])[CH3:3].[Br:17][CH2:18][CH2:19]N.[OH-].[Na+]>CO>[Br:17][CH2:18][CH2:19][N:10]1[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:13]=2[N:12]=[CH:11]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2[nH]cnc21
Reactant: NCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c1ncn2CCBr

Procedure:
The process of preparing the compound of formula I comprises the steps of dissolving 3-isobutyl-1-methylxanthine (IBMX) into methanol and stirring with 2-bromoethylamine upon a mantle heater, reacting this mixture with NaOH and then recrystallizing this mixture with methanol to obtain N7-bromoehtyl 3-isobutyl-1-methylxanthine.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].O.[Li+].[OH-]>O1CCOCC1>[OH:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([N:10]([C:11]([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[C:7]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:21][CH2:22]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-[(trans-4-Hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (34 mg, 0.075 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (1 ml) and then LiOH 1N (375 ul, 0.375 mmol) was added. After 4 hours of stirring at room temperature, solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 21 mg (64%) of 3-[(trans-4-Hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (Compound 15).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C([O-])(=O)C.[Na+].[CH3:20][C:21]1([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:30][CH2:29][C:28]([NH:27][C:21]2([CH3:20])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:31])[CH2:11][CH2:10]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: C=CC(=O)NC1(C)CCCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC1(NC(=O)CCN2CCN(c3ncccn3)CC2)CCCCC1
Yield: 41.9 %

Procedure:
The title compound was prepared from -1-(2-pyrimidyl)piperazine dihydrochloride (2.77 g, 0.0117 mol), sodium acetate (1.92 g, 0.0234 mol) and the mixture of 3-N-1-methylcyclohexyl-bromopropanamide and N-1-methylcyclohexyl acrylamide (1.8 g, 0.0098 mol) in the manner described in Example 16 to give 1.36 g of the title compound as the dihydrochloride (32%, based on the amide mixture), mp. 204°-209° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:39]N1C(=O)CCC1=O>C(Cl)Cl>[Br:39][CH:13]1[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a cooled (0° C.) solution of N-benzyloxycarbonyl-4-piperidone (501, 27.3 g 117 mmol) in DCM (3 ml/mmol) was added DIPEA (25.5 ml, 146.2 mmol, 1.25 eg) and trimethylsilyl trifluoromethane sulfonate (25.4 ml, 141 mmol, 1.2 eg). The mixture was stirred for 30 minutes at 0° C. Next, N-bromosuccinimide (21.2 g, 119.3 mml, 1.02 eg) was added and stirring was continued for 16 hrs at room temperature. The reaction mixture was washed with 5% NaHCO3 and the organic layer was dried (MgSO4) and subsequently concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography (diethyl ether/petroleum ether, 1/1 to 1/0, v/v, Rf 0.1) giving 502 in a yield of 90% as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[C:10]([F:21])[C:11]([CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=3)[CH:8]([OH:22])[CH:7]([OH:23])[C:6]=2[C:5]=1[F:24])[CH3:2]>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[C:10]([F:21])[C:11]([CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=3)[C:8](=[O:22])[C:7](=[O:23])[C:6]=2[C:5]=1[F:24])[CH3:2]
Reactant: CCCc1ccc2c(c1F)C(O)C(O)c1c-2ccc(OCC)c1F
Solvent: CS(C)=O
Product: CCCc1ccc2c(c1F)C(=O)C(=O)c1c-2ccc(OCC)c1F
Yield: 34.5 %

Procedure:
IBX (31.5 g, 112.5 mmol) was added to 100 mL of DMSO, and the resultant mixture was agitated at room temperature for 30 minutes, and then compound (57) (9.4 g, 28.11 mmol) was added and the resultant mixture was further agitated for 3 hours. The reaction mixture was filtered, 200 mL of water was added to a filtrate, and the resultant mixture was extracted with 100 mL of ethyl acetate three times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was recrystallized from toluene, and thus 2-ethoxy-1,8-difluoro-7-propylphenanthrene-9,10-dione (58) (3.2 g, yield 34.5%) was obtained.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:68])[C:49]4[C:50]([O:60][C:61]=3[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[C:51]([C:55]3[CH:56]=[N:57][NH:58][CH:59]=3)[N:52]=[CH:53][CH:54]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:77]>CO.O>[ClH:77].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:68])[C:49]4[C:50]([O:60][C:61]=3[C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[C:51]([C:55]3[CH:56]=[N:57][NH:58][CH:59]=3)[N:52]=[CH:53][CH:54]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cn[nH]c5)nccc4c3=O)cc2)CCC1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cn[nH]c5)nccc4c3=O)cc2)CCC1
Yield: 81 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[4-oxo-2-phenyl-8-(1H-pyrazol-4-yl)-4H-pyrano[2,3-c]pyridin-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (0.75 mL), water (4.25 mL) and 1 M HCl (0.1 mL) and then chromatographed on a 2 g C18 cartridge {gradient 15 to 50% MeOH in water+1 M HCl (60 μL in each 5 mL of eluent)} to give the title compound as a white solid (12.1 mg, 81%, 2 steps). 1H NMR (400 MHz, DMSO-d6): δ 8.66 (d+br s, J=5.1 Hz, 4H), 8.29 (s, 2H), 7.80 (d, J=5.0 Hz, 1H), 7.55-7.41 (m, 7H), 7.30 (d, J=8.2 Hz, 2H), 2.59-2.51 (m, 4H), 2.23-2.12 (m, 1H), 1.85-1.74 (m, 1H). LCMS (Method E): RT=2.79 min, [M+H]+=435.
Reaction SMILES: [OH-].[Na+].[CH:3]1[N:4]=[C:5]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([NH:24][C:25](=[O:30])[NH:26][CH2:27][CH2:28][CH3:29])=[C:18]([CH:23]=2)[C:19]([O:21]C)=O)=[O:13])[N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12>CO>[CH:3]1[N:4]=[C:5]([C:12]([C:14]2[CH:23]=[C:18]3[C:17](=[CH:16][CH:15]=2)[NH:24][C:25](=[O:30])[N:26]([CH2:27][CH2:28][CH3:29])[C:19]3=[O:21])=[O:13])[N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12
Reactant: CCCNC(=O)Nc1ccc(C(=O)c2ncc3ccccn23)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCn1c(=O)[nH]c2ccc(C(=O)c3ncc4ccccn34)cc2c1=O
Yield: 67.4 %

Procedure:
1.38 ml (1.38 mmol) of a 1N aqueous solution of sodium hydroxide are added, at ambient temperature, to a suspension of 0.436 g (1.15 mmol) of methyl 5-(imidazo[1,5-a]pyridin-3-ylcarbonyl)-2-[(propylcarbamoyl)amino]benzoate in 10 ml of methanol. After refluxing for 2 hours, the methanol is concentrated under reduced pressure. A 1N aqueous solution of hydrochloric acid is added. The precipitate obtained is filtered off, rinsed with water and then dried, overnight at 40° C. under reduced pressure. 0.27 g of a yellow solid is obtained.