Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]([N:21]1[CH2:25][C@H:24]([F:26])[CH2:23][C@H:22]1[C:27](=[O:38])[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[F:37])=[O:20])[CH:13]=[C:12]2[C:39]([NH2:41])=[O:40])C1C=CC=CC=1.C1(SC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:36][C:32]1[C:31]([F:37])=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][NH:28][C:27]([C@@H:22]1[CH2:23][C@@H:24]([F:26])[CH2:25][N:21]1[C:19](=[O:20])[CH2:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[C:12]([C:39]([NH2:41])=[O:40])=[CH:13]1)=[O:38]
Reactant: NC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(OCc3ccccc3)cc12
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(O)cc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 5-benzyloxy-1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-1H-indole-3-carboxylic acid amide Example 503 (148 mg, 0.255 mmol) in TFA (2.5 mL), cooled to 0° C., was added thioanisole (0.301 mL, 2.55 mmol), and the reaction mixture was stirred at RT for 3 h. Volatiles were evaporated under reduced pressure, and the residue was suspended in a saturated aqueous NaHCO3 solution, followed by freeze-drying in vacuo. The residue was suspended in a small amount of methanol and the solid was filtered off. The filtrate was purified by preparative HPLC (Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA). The title compound was obtained as a white solid. MS (LC/MS): 491 [M+H]+; 983 [2M+H]+; tR (HPLC, conditions b): 3.75 min.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH:5]=[CH:4]1.[O:27]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:33]([CH:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)=[O:34])[CH2:24][CH2:25]2)[CH:5]=[CH:4]1
Reactant: O=C(O)C1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1)C1CCOCC1

Procedure:
The title compound, off-white solid (87 mg, 78%), MS (ISP) m/z=439.4 [(M+H)+], mp 217° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl-amine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and tetrahydropyran-4-yl-carboxylic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][CH2:10][CH2:11][S:12][CH2:13][CH2:14][CH:15]1OCC[O:16]1>C(O)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][CH2:10][CH2:11][S:12][CH2:13][CH2:14][CH:15]=[O:16]
Reactant: c1ccc(CCOCCSCCC2OCCO2)nc1
Solvent: O=CO
Product: O=CCCSCCOCCc1ccccn1
Reaction time: 22 h

Procedure:
The material from step b) (0.850 g) was dissolved in 80% formic acid (10 ml) and left to stand at room temperature for 22 hours. The mixture was partitioned between ether and water. The layers were separated and the aqueous layer extracted with ether. The ethereal extracts were combined, washed with brine, dried (MgSO4) and evaporated under reduced pressure to yield the subtitled compound as an oil (0.70 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([CH:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[C:31](=[O:32])[CH2:30][O:29][C:28]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[N:27]3)=[CH:21][CH:20]=2)[C:16](O)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1.[NH2:39][CH:40]([CH3:54])[CH2:41][CH2:42][CH2:43][C:44]1([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:46][CH2:45]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:10]1([CH:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[C:31](=[O:32])[CH2:30][O:29][C:28]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[N:27]3)=[CH:21][CH:20]=2)[C:16]([NH:39][CH:40]([CH3:54])[CH2:41][CH2:42][CH2:43][C:44]2([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:45][CH2:46]2)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Reactant: CC(N)CCCC1(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCCC1(C(=O)OC(C)(C)C)CC1)NC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
At RT, 253 μl (1.45 mmol) of DIEA were added to a solution of 517.9 mg (1.32 mmol) of (+)-cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetic acid and 450 mg (about 1.98 mmol, crude material) of tert-butyl 1-(4-aminopentyl)cyclo-propanecarboxylate in 2.5 ml of DMF. The resulting mixture was cooled to 0° C., and four portions of altogether 186.4 mg (0.49 mmol) of HATU were then added. The reaction mixture was slowly warmed to RT, stirred at RT for 16 h and then added to water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. Purification of the crude product by preparative RP-HPLC (acetonitrile/water gradient) gave 540.0 mg (68.0% of theory) of the target compound as a diastereomer mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]#[C:26][CH2:27][N:28]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[O:29]C(OC(C)(C)C)=O)[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:11]=3)=[N:7][C:6]=2[CH:24]=1.N>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:25]#[C:26][CH2:27][N:28]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[OH:29])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)[CH:11]=3)=[N:7][C:6]=2[CH:24]=1
Reactant: COc1ccc(-c2nc3cc(Cl)cc(C#CCN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3o2)cc1OC1CCCC1
Agent: N
Solvent: C1CCOC1
Product: COc1ccc(-c2nc3cc(Cl)cc(C#CCN(O)C(=O)OC(C)(C)C)c3o2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 57.3 %

Procedure:
1.00 g (1.6 mmol) of 5-chloro-2-(3-cyclopentyloxy-4-methoxy-phenyl)-7-[3-(N-t-butyloxycarbonyl-N-t-butoxycarbonyloxy-amino)-1-propynyl]-benzoxazole was dissolved in 20 ml of THF and treated with 20 g of ammonia in a reactor. The pressure rose to 100 psi. After 2 hours, the solvents were removed in vacuo. Crystallization from methanol and recrystallization from di-isopropyl ether gave the title compound (0.47 g, 56.2%), mp 157-61° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[OH-].[Na+].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH2:41]([O:43][C:44]([C:46]1([NH2:49])[CH2:48][CH2:47]1)=[O:45])[CH3:42].CCN(C(C)C)C(C)C>CCOC(C)=O.[Cl-].[Na+].O.Cl.C(Cl)Cl.C1COCC1.CO>[CH2:41]([O:43][C:44]([C:46]1([NH:49][C:3]([C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:23])[N:10]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:11]=[CH:12][C:13]=3[C:14]=2[OH:15])=[O:4])[CH2:48][CH2:47]1)=[O:45])[CH3:42]
Reactant: CCOC(=O)C1(N)CC1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(NC(=O)c2ncc3c(=O)n(Cc4ccccc4)ccc3c2O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.2 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (53 mg, 0.17 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to dryness. The residue was dissolved in water and acidified to pH about 2 with 1 M HCl. The resulting precipitate was isolated by filtration. To the crude solid were added CH2Cl2 (3 mL), HOBt (29 mg, 0.22 mmol), and EDC (47 mg, 0.24 mmol), and the resulting mixture was stirred for 10 min. 1-Amino-cyclopropanecarboxylic acid ethyl ester HCl salt (36 mg, 0.22 mmol) and Hunig's base (0.086 mL, 0.49 mmol) were added, and the mixture was stirred for 16 h. The mixture was diluted with EtOAc and brine, and 1 M HCl was added until pH was about 2. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH) to give 23 mg of the title compound. MS: (+) m/z 408.29 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[C:19]([C:29]#[N:30])[CH:18]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:32][CH2:33][CH2:34][OH:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][N:26]([CH2:32][CH2:33][CH2:34][OH:35])[CH2:27][CH2:28]4)=[C:19]([C:29]#[N:30])[CH:18]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: Cc1c(C(=O)Nc2ccc(N3CCNCC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(N3CCN(CCCO)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 54.9 %

Procedure:
1-(4-Chlorophenyl)-N-[3-cyano-4-(piperazin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide (4.0 g), 3-bromopropanol (1.6 g) and potassium carbonate (1.6 g) were added to dimethylformamide (25 ml) and the mixture was stirred at 60° C. for 3 h. The reaction mixture was added into water, and the obtained crystals were recrystallized from hydrous dimethylformamide to give the title compound (2.5 g), melting point: 213° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH3:13])[C:14](=[O:16])[O:15][CH2:17]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
Benzyloxycarbonyl-L-alanine (19.3 g), paraformaldehyde (6.56 g) and p-toluenesulfonic acid monohydrate (0.17 g) were suspended in toluene (190 mL), and the mixture was heated at reflux while removing water produced. At the end of the reaction, the reaction mixture was cooled to room temperature, washed with saturated aqueous sodium hydrogen carbonate solution and then saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, the resulting crystals were filtrated to give the title compound (19.0 g) as white crystals in an yield of 93%.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[C:5](=[CH:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[NH2:6].[OH:15]O>C(O)(=O)C>[CH3:1][S:2]([CH2:3][C:4]1[C:5](=[CH:7][CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[NH2:6])=[O:15]
Reactant: OO
Reactant: CSCc1cc(C(F)(F)F)ccc1N
Solvent: CC(=O)O
Product: CS(=O)Cc1cc(C(F)(F)F)ccc1N
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cooled (ice/water) solution of 8.7 g. of α-methylthio-4-trifluoromethyl-o-toluidine predissolved in 50 ml. of acetic acid is added 4.1 ml. of a 30% solution of hydrogen peroxide. The ice/water bath is removed and the reaction mixture is stirred for 90 minutes, after which examination by TLC indicates the presence of essentially all of the sulfinyl compound (reaction complete). The reaction mixture is then treated with 50 ml. of a 10% solution of sodium sulfite and concentrated on a rotary evaporator. The residue is then taken up in chloroform and a 15 % solution of sodium hydroxide. After separation of the phases, the aqueous phase is back-extracted with chloroform and the combined chloroform solution is washed successively with water and brine, dried, evaporated in vacuo to dryness, and the residue recrystallized from chloroform/petroleum ether to yield α-methylsulfinyl-4-trifluoromethyl-o-toluidine, m.p. 121.5°-125° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25](OC)=[O:26])=[CH:23][N:22]=1)[C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:9][CH:10]=1.[OH-].[Na+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:68][CH2:69][CH2:70][C:71]([O:73][CH3:74])=[O:72]>CO.[Cl-].[Na+].O>[CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:68][CH2:69][CH2:70][C:71]([O:73][CH3:74])=[O:72])=[O:26])=[CH:23][N:22]=1)[C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[N:12]2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCN
Reactant: COC(=O)c1ccc(NC(CC(C)C)c2ccc(-n3cc(C(F)(F)F)cn3)nc2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: O
Product: COC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2ccc(-n3cc(C(F)(F)F)cn3)nc2)nc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of (+\−)-methyl 6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinate (800 mg, 1.85 mmol) in methanol (5 mL) was added 2N aqueous sodium hydroxide (9.2 mL, 18.4 mmol). The resulting mixture was stirred at 20° C. for 2 h. Methanol was removed under reduced pressure and the residue was acidified by addition of 1N aqueous HCl to pH 3-4 and extracted with dichloromethane (30 mL×2). The combined organic layers were concentrated under reduced pressure. The residue was dissolved in DMF (10 mL). HATU (1.36 mg, 3.58 mmol) and N,N-di-iso-propylethylamine (1.15 mg, 8.95 mmol) were added. Methyl 3-aminopropanoate hydrochloride (370 mg, 2.68 mmol) was added. The resulting mixture was stirred at 30° C. for 1 h. The mixture was poured into brine (30 mL) and extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with 1N aqueous HCl (30 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The crude residue was purified silica gel chromatography to give (+\−)-methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinamido)propanoate (850 mg) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.37 (d, J=12.0 Hz, 2H), 7.87 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.76-7.70 (m, 2H), 6.52 (s, 1H), 6.22 (d, J=8.4 Hz, 1H), 5.07 (d, J=4.0 Hz, 1H), 4.86 (d, J=9.2 Hz, 1H), 3.62-3.58 (m, 5H), 2.54 (t, J=5.6 Hz, 2H), 1.77-1.59 (m, 3H), 1.75-1.63 (m, 2H), 0.95 (d, J=6.0 Hz, 3H), 0.91 (d, J=6.0 Hz, 3H). (+\−)-methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinamido)propanoate was resolved by SFC (column: Chiralpak AD-3, 50×4.6 mm×3 μm; mobile phase: 40% methanol in CO2; modifier: 0.05% diethylamine; flow rate: 4 mL/min) to give methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinamido)propanoate, Isomer 1 (450 mg, retention time: 0.62 min) and methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinamido)propanoate, isomer 2 (400 mg, retention time: 1.30 min).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7](SC)=[N:8][CH:9]=2)[N:4]([CH2:13][CH:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]2)[N:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH3:39][NH2:40]>C(Cl)Cl.CCOC(C)=O.C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:40][CH3:39])=[N:8][CH:9]=2)[N:4]([CH2:13][CH:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]2)[N:3]=1
Reactant: CN
Reactant: CSc1ncc2c(Br)nn(CC3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNc1ncc2c(Br)nn(CC3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of tert-butyl 4-((3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.91 g, 2.0 mmol) in CH2Cl2 (30 mL) was added meta-Chloroperoxybenzoic acid (1.34 g, 77%, 6 mmol) at room temperature. The color of the solution changed to light purple from colorless. After 2 h, the reaction was diluted with EtOAc. The organic solution was then washed with 1 N NaOH (3×), dried (NaSO4), and concentrated. The resulting residue was dissolved in THF (10 mL) before a 2.0 M methylamine solution in THF (10 mL, 20 mmol) was added at room temperature. The resulting solution was heated at 60° C. for 2 h. After removal of the solvent, it was purified by Isco to provide tert-butyl 4-((3-bromo-6-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.75 g, 85%) as a white solid. MS m/z 439.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O>>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Nc1ccc(Br)nc1
Product: Nc1ccc(-c2ccccc2C(F)(F)F)nc1
Yield: 59 %

Procedure:
Obtained (2.05 g, yield 59%) following the procedure described in Intermediate 27, starting with 6-bromopyridin-3-amine, 2-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21].C>C(O)C>[F:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Nc1ccc(F)c(F)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Agent: C
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(F)c(F)c1
Yield: 71.6 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 250 ml ethanol and 2.55 ml (25.8 mmol) 3,4-difluoroaniline was heated to reflux under N2. Removed heat at 3.5 hours and made basic with saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solids and air dried. Washed with water and dried in vacuo. Dissolved in ethyl acetate, stirred with Darco, filtered, stripped solvent and dried in vacuo, giving ethyl acetate, stirred with Darco, filtered, stripped solvent and dried in vacuo, giving 5.02 g of yellow solid: mass spectrum (electrospray m/e): M+H=327.1.
Reaction SMILES: C(OC(=O)[CH2:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][S:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:12])=[O:11])C.CCCCCCCC>>[CH2:13]([S:10]([CH2:9][CH2:8][CH2:7][C:6](=[O:25])[CH3:5])(=[O:11])=[O:12])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCS(=O)(=O)CCCC(=O)CC(=O)OCC
Solvent: CCCCCCCC
Product: CCCCCCCCCCCCS(=O)(=O)CCCC(C)=O

Procedure:
The title compound was prepared from 6-(dodecylsulfonyl)-3-oxo-hexanoic acid ethyl ester (2.30 g, 0.005 mol), 1,4-diazebicyclo[2.2.2]octane (6.60 g, 0.058 mol) and zylenes (10.7 ML, 15.0 eq) using the procedure described in Example 3, Step B. 1H NMR (ppm, CDCl3): 0.85-0.90 (t, 3H), 1.17-1.43 (m, 20H), 1.76-1.88 (m, 2H), 2.03-2.14 (m, 2H), 2.16 (s, 3H) 2.96-3.03 (m, 4H),
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.C(N)=O.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=1)=O.[CH:30]([NH2:32])=[S:31].[OH-].[Na+]>O1CCOCC1>[F:29][C:24]1[CH:23]=[C:22]([C:20]2[N:32]=[CH:30][S:31][CH:19]=2)[CH:27]=[CH:26][C:25]=1[OH:28]
Reactant: NC=S
Reactant: O=C(CBr)c1ccc(O)c(F)c1
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: NC=O
Product: Oc1ccc(-c2cscn2)cc1F
Temperature: 25 °C
Yield: 83 %

Procedure:
To a stirred solution of phosphorus pentasulfide (8.6 g, 19.3 mmol) in dioxane (53 ml) was added formamide (5.2 g, 115.5 mmol), and the mixture was heated at reflux temperature for 2 hours. The mixture was cooled down to room temperature, and the solution was decanted away from solids. To a stirred solution of 2-bromo-1-(3-fluoro-4-hydroxyphenyl)-1-ethanone (3.02 g, 12.98 mmol) in dioxane (50 ml) was added the thioformamide solution, and the mixture was heated at reflux temperature for 6 hours. The mixture was cooled down to room temperature, and made basic by addition of 0.5M NaOH aqueous solution. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:3) to give title compound (2.11 g, 83% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].ClC1C=CC=[C:22]([C:26]([O:28]O)=[O:27])C=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:26]([O:28][C:12]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:18])[C:6]3([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:17][CH2:16][CH2:15][C:13]=1[C:14]=23)(=[O:27])[CH3:22]
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1ccc2c3c1CCCC3(CCCCBr)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A 2 ml portion of methylene chloride solution of 2a-(4-bromobutyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (94 mg, 0.26 mmol) was cooled to 0° C. and then mixed with 93 mg (0.52 mmol) of m-chloroperbenzoic acid and 21 μl (0.26 mmol) of trifluoroacetic acid. After 2 hours of stirring in the dark at a room temperature, the reaction solution was extracted with chloroform and washed with sodium sulfite and sodium bicarbonate in that order. After drying (Na2SO4), the solvent was evaporated under a reduced pressure, and the thus obtained oily substance was purified by a silica gel column chromatography (20 cc; elution with ethyl acetate-hexane=1:2) to obtain 88 mg of the title compound (89% in yield).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@@H:5](/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[OH:6])[NH2:4].[C:22]([NH:25][CH2:26][C:27](O)=[O:28])(=[O:24])[CH3:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[C:22]([NH:25][CH2:26][C:27]([NH:4][C@H:3]([C@@H:5](/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[OH:6])[CH2:2][OH:1])=[O:28])(=[O:24])[CH3:23]
Reactant: CC(=O)NCC(=O)O
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO)NC(=O)CNC(C)=O

Procedure:
5.0 gr of sphingosine (16.70 mM), prepared according to Example 4, 2.1 gr of N-acetylglycine (18.37 mM) and 3.8 gr of dicyclohexylcarbodiimide (18.40 mM) are left to react in 150 cc of chloroform, under warm conditions overnight. The reaction mixture is placed in a freezer to precipitate. The urea is filtered, and the chloroform solution is washed with H2O. The raw material is purified by chromatography using a mixture of CH2Cl2 /ethyl acetate/CH3OH, 70:30:10 v/v/v.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[Cl:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(F)cc1Cl

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-4-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.