Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([N:13]([CH3:33])[C:14](=[O:32])[C:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)([CH3:17])[CH3:16])=[C:9]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])[CH:8]=2)[CH2:3]1.C(N(CC)C(C)C)(C)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>ClCCl.CN(C1C=CN=CC=1)C>[F:27][C:24]([F:25])([F:26])[C:22]1[CH:23]=[C:18]([C:15]([CH3:16])([CH3:17])[C:14]([N:13]([C:10]2[CH:11]=[N:12][C:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][S:52]([CH3:51])(=[O:54])=[O:53])[CH2:3]3)=[CH:8][C:9]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:33])=[O:32])[CH:19]=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:21]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CC[C@H](N)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CC[C@H](NS(C)(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
To a solution of 600 mg (1.03 mmol) (S)—N-[6-(3-amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 6 ml dichloromethane were added 6 mg (0.05 mmol) 4-(N,N-dimethylamino)pyridine, 266 mg (2.06 mmol) N,N-diisopropylethylamine and 153 mg (1.34 mmol) methanesulfonyl chloride. After stirring at room temperature for 18 h the reaction mixture was diluted with 20 ml dichloromethane and washed with 20 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography to give 553 mg (81%) of the title compound as an off-white foam.
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]([CH2:33][C:34](O)=[O:35])[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:34](=[O:35])[CH2:33][CH:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[CH2:24][CH2:25]2)[CH:5]=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Reactant: O=C(O)CC1CCOCC1
Agent: Cl
Product: O=C(CC1CCOCC1)N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1

Procedure:
The title compound, off-white solid (77 mg, 68%), MS (ISP) m/z=453.4 [(M+H)+], mp 181° 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-acetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH2:11][N:12]([CH2:19][C:20]1[CH:36]=[CH:35][C:23]([O:24][C:25]([CH3:34])([CH3:33])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:22][CH:21]=1)[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1.B.CSC.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][N:12]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][C:25]([CH3:34])([CH3:33])[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:35][CH:36]=1)[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(NC(=O)CN(Cc2ccc(OC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)c(C)c1
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(NCCN(Cc2ccc(OC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)c(C)c1
Yield: 37 %

Procedure:
In 5 ml toluene, 0.25 g (0.50 mmol) of the compound from Example 3-1 is treated with 0.30 ml of 2 M borane-dimethyl sulphide solution in tetrahydrofuran, and the mixture is heated at the boil for 2 hours. The mixture is then stirred in the presence of 5 ml of 2 N sodium carbonate solution for 1 hour and the organic phase is washed with water and with saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and the solvent is distilled off, and the residue is then purified using silica gel flash chromatography (cyclohexane/dichloromethane 3:1→cyclohexane/ethyl acetate 10:1). This gives the target compound in a yield of 37%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Cl[C:37]1[CH:38]=[C:39]([C:49]([NH:51][CH2:52][C:53]2[C:54](=[O:61])[NH:55][C:56]([CH3:60])=[CH:57][C:58]=2[CH3:59])=[O:50])[C:40]2[CH:45]=[N:44][N:43]([CH:46]([CH3:48])[CH3:47])[C:41]=2[N:42]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.COCCOC>[CH3:59][C:58]1[CH:57]=[C:56]([CH3:60])[NH:55][C:54](=[O:61])[C:53]=1[CH2:52][NH:51][C:49]([C:39]1[C:40]2[CH:45]=[N:44][N:43]([CH:46]([CH3:48])[CH3:47])[C:41]=2[N:42]=[C:37]([C:2]2[CH:7]=[N:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:38]=1)=[O:50]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CNS(=O)(=O)c1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: COCCOC
Solvent: C1COCCO1
Solvent: O
Product: CNS(=O)(=O)c1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3cnn(C(C)C)c3n2)cn1
Temperature: 100 °C

Procedure:
5-Bromo-N-methyl-2-pyridinesulfonamide (225 mg, 0.896 mmol), Bis(pinacolato)diboron (296 mg, 1.165 mmol), Pd(dppf) (35.7 mg, 0.044 mmol) and potassium acetate (264 mg, 2.69 mmol) were suspended in 1,4-Dioxane (8 mL), and stirred with heating at 100° C. for 1 h. After cooling to room temperature, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (368 mg, 0.986 mmol), bis(triphenylphosphine)palladium(II) chloride (73.2 mg, 0.090 mmol) and sodium bicarbonate (226 mg, 2.69 mmol) were added, followed by DME (5 mL) and water (3 mL). The reaction mixture was irradiated (microwave) at 120° C. for 2 h. The reaction mixture was cooled to room temperature and filtered through Na2SO4. The contents were purified directly by silica gel chromatography (eluent: 15% MeOH/CH2Cl2) to furnish the desired product as a grey solid after evaporation and preciptation from warm EtOAc/MeOH (1:9). The product was again purified by silica gel chromatography (eluent: 5% MeOH/CH2Cl2) to afford the final product as a white solid, 83 mg (18%). LCMS E-S (M+H)=510.0 1H NMR (400 MHz, DMSO-d6) δ ppm 11.59 (br. s., 1 H), 9.56 (d, J=1.52 Hz, 1 H), 8.96 (s, 1 H), 8.86 (dd, J=8.34, 2.27 Hz, 1 H), 8.46 (s, 1 H), 8.34 (s, 1 H), 8.12 (d, J=8.34 Hz, 1 H), 7.85 (br. s., 1 H), 5.91 (s, 1 H), 5.27-5.46 (m, 1 H), 4.43 (d, J=4.80 Hz, 2 H), 2.60 (s, 3 H), 2.23 (s, 3 H), 2.13 (s, 3 H), 1.56 (d, 6 H).
Reaction SMILES: [H-].[Na+].ClC1C=CC([C:8](=O)[CH2:9][NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=CC=1.CI.[O:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1.CN(C)C=O>>[Cl:20][C:18]1[CH:17]=[CH:16][C:42]([C:43](=[O:39])[CH2:8][CH2:9][NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:12]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:41][CH:40]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1c(NCC(=O)c2ccc(Cl)cc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(NCCC(=O)c2ccc(Cl)cc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Suspend sodium hydride (160 mg of a 60% dispersion, 4 mmol) in anhydrous tetrahydrofuran/dimethylformamide (3 mL/2:1) and cool to 0° C. under a nitrogen atmosphere. Add 3-[(p-chlorophenacyl)amino]-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole (2 g, 3.9 mmol) in tetrahydrofuran/dimethylformamide (10 mL/2:1) dropwise to the suspension. Stir at 0° C. for 30 minutes. Add methyl iodide (0.137 mL, 2.2 mmol) and stir for 30 minutes at 0° C. Warm the reaction to room temperature and after 4 hours quench with water (20 mL). Extract with ethyl acetate (20 mL), wash with saturated sodium chloride, dry over magnesium sulfate, filter and concentrate in vacuo to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=1.B([O-])[O-:15]>>[CH:10]1([CH2:9][O:8][C:5]2[N:6]=[CH:7][C:2]([OH:15])=[CH:3][C:4]=2[CH3:13])[CH2:12][CH2:11]1
Reactant: [O-]B[O-]
Reactant: Cc1cc(Br)cnc1OCC1CC1
Product: Cc1cc(O)cnc1OCC1CC1

Procedure:
Following Typical Procedures 4 and 5a, conversion of 5-bromo-2-cyclopropylmethoxy-3-methyl-pyridine to the boronate and oxidation with NaBO3 provided the title compound. MS ESI+: m/z=180 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[C:27]([C:32]([O:34]C)=[O:33])[CH:28]=[N:29]4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1.C1COCC1.O.[OH-].[Na+]>CCO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[C:27]([C:32]([OH:34])=[O:33])[CH:28]=[N:29]4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1
Reactant: COC(=O)c1cnc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3cc(C(=O)O)cnc3c2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
To 47 mg (0.09 mmol) of methyl 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-quinolinecarboxylate in a mixture of 3 mL of EtOH, 1 mL THF and 1 mL H2O was added 35 mg (0.86 mmol) of NaOH and the mixture stirred at 50° C. for 16 hr. The mixture was concentrated to ⅓ volume then added dropwise to a a stirred solution of 10 mL of 0.5 M HCl (aq.). The resulting solids were collected by suction filtration, washed with water then dried to yield 32 mg (70%) of 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-quinolinecarboxylic acid as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.97 (s, 1H), 8.24-8.21 (m, 2H), 7.99 (d, J=8 Hz, 1H), 7.76 (d, J=8 Hz, 2H), 7.63-7.61 (m, 2H), 7.55-7.52 (m, 1H), 6.93 (d, J=9 Hz, 2H), 4.88 (s, 2H), 3.50-3.44 (septet, J =7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). ESI-LCMS m/z 534 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][C:20]([OH:22])=[O:21].[CH2:23](O)[CH2:24][CH3:25].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][C:20]([O:22][CH2:23][CH2:24][CH3:25])=[O:21]
Reactant: CCCO
Reactant: Cc1cc2c(cc1C)C(CC(=O)O)N(c1cccnc1)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCOC(=O)CC1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
To a solution of 5,6-dimethyl-3-carboxymethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: 2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetic acid] (74 mg, 0.25 mmol), n-propyl alcohol (16 mg, 0.27 mmol) and 4-dimethylaminopyridine (3 mg, 0.025 mmol) in dichloromethane was added 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (53 mg, 0.27 mmol) at 5° C. and the temperature was raised to 25° C. over a period of 1.5 hrs. The reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extracting with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, successively water, dried, and concentrated under reduced pressure to give 34 mg of the title compound.
Reaction SMILES: [O:1]1[C:9]2[CH:10]=[CH:11][C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:31][CH:32]=O)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28].[BH3-]C#N.[Na+]>>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([CH2:31][CH2:32][N:4]2[CH2:3][CH2:2][O:1][C:9]3[CH:10]=[CH:11][C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=3[O:7][CH2:6][CH2:5]2)[CH:22]=[C:21]([O:20][CH3:19])[C:26]=1[O:27][CH3:28]
Reactant: COc1cc(CC=O)cc(OC)c1OC
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OCCNCCO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1cc(CCN2CCOc3ccc(NS(C)(=O)=O)cc3OCC2)cc(OC)c1OC

Procedure:
In a manner similar to example 4, react N-(3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonin-9-yl)methanesulfonamide, 3,4,5-trimethoxybenzeneacetaldehyde, and NaBH3CN to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]4([OH:33])[CH2:32][CH2:31][CH2:30]4)[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3([OH:33])[CH2:30][CH2:31][CH2:32]3)[CH2:25][CH2:24]2)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:34]1[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C3(O)CCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C4(O)CCC4)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 1-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)cyclobutanol were reacted to give 260. LCMS m/z: 517.3 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:16]([S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[C:15]([C:31]#[N:32])=[N:14]1.C(N(C(C)C)CC)(C)C.O1CCOCC1.[CH3:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54].C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([N:18]2[CH2:19][CH2:20][N:21]([CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:22][CH2:23]2)=[C:16]([S:24]([C:27]([F:28])([F:30])[F:29])(=[O:26])=[O:25])[C:15]([C:31]#[N:32])=[N:14]1
Reactant: CCCCCCC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N2CCNCC2)c1S(=O)(=O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N2CCN(Cc3ccccc3)CC2)c1S(=O)(=O)C(F)(F)F

Procedure:
To a mixture of 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-piperazin-1-yl-4-[(trifluoromethyl)sulfonyl]-1H-pyrazole-3-carbonitrile (0.40 g, 0.8 mmol) and diisopropylethylamin (0.13 g, 1.0 mmol) in dioxane (5 mL) benzylbromide (0.14 g, 0.8 mmol) was added and refluxed for 5 h. Extractive workup (heptane-ethyl acetate, water) and chromatography gave the title product (Compound 01-45, 0.31 g) as an oil; 1H-NMR: 2.30(4H), 3.19 (4H), 3.45 (2H), 7.25 (5H), 7.82 (2H); 19F-NMR: −64.1 (PhCF3); −79.6 ppm (SO2CF3).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:24]=[C:25]2[CH2:31][C:30](=[O:32])[NH:29][C:26]2=[N:27][CH:28]=1>>[Br:22][C:23]1[CH:24]=[C:25]2[C:31](=[CH:20][C:3]3[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)[C:7](=[O:19])[C:6]=4[C:2]=3[CH3:1])[C:30](=[O:32])[NH:29][C:26]2=[N:27][CH:28]=1
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3ncc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 33 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (prepared according to Heterocycles, 60 (4), 865-877, 2003) as starting materials to give 2-(5-bromo-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 33%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:28])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:35]([O:41][CH2:42]Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:28])[N:17]([CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[7-(2-Butynyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (1.1 g) and potassium carbonate (0.43 g) were dissolved in N,N-dimethylformamide (15 ml), and chloromethyl pivalate (0.60 ml) was added to the solution while cooling on ice. After the mixture was stirred at room temperature overnight, the reaction mixture was diluted with ethyl acetate and washed with water. Insoluble white solid was collected by filtration, and washed with a mixture of hexane-ethyl acetate (1:1) to give 0.57 g of the title compound.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[C:4]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][N+:16]([CH2:31][C:32]([O:34]CC)=[O:33])([CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH2:15]2)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1>Cl>[Cl-:10].[C:32]([CH2:31][N+:16]1([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:17][CH2:18][CH2:19][CH:14]([NH:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])[CH2:15]1)([OH:34])=[O:33]
Reactant: CCOC(=O)C[N+]1(CCCc2ccc(OC)cc2)CCCC(NC(=O)c2nc(Cl)c(N)nc2N)C1
Agent: Cl
Agent: [Cl-]
Product: COc1ccc(CCC[N+]2(CC(=O)O)CCCC(NC(=O)c3nc(Cl)c(N)nc3N)C2)cc1

Procedure:
A solution of 3-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-1-ethoxycarbonylmethyl-1-[3-(4-methoxy-phenyl)-propyl]-piperidinium chloride (Example 3.1, 30 mg, 0.06 mmol) in hydrochloric acid (6 M, 1 mL) is heated at 60° C. for 36 hours. Volatiles are removed by freeze-drying. The resulting amorphous solid is triturated with diethyl ether and dried under vacuum at 50° C. Yield: 21 mg. IC50>1 μM
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1.[F:11][C@@H:12]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][C@H:13]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:13]2[O:14][C@H:15]([CH2:18][OH:19])[C@@H:16]([OH:17])[C@H:12]2[F:11])=[CH:4][N:3]=1
Reactant: Nc1ncc2[nH]cnc2n1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1ncc2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3F)c2n1
Temperature: 37 °C

Procedure:
2-Aminopurine (Vega Biochemicals, 0.4 g, 3.0 mmoles) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.2 g, 0.71 mmoles) which may be prepared according to J. F. Codington et al. (J. Org. Chem. 29:558, 1964) were suspended in 35 ml of 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. Thymidine phosphorylase (1,930 I.U.) and purine nucleoside phosphorylase (1,880 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,344) were added and the suspension stirred at 37° C. On day 24, the reaction was diluted to 200 ml with water and 1,390 I.U. of thymidine phosphorylase, and, 1,880 I.U. of purine nucleoside phosphorylase were added. On day 35, the suspension was evaporated. The residue was dissolved in water/methanol (7/3) and applied to a 1.5×15 cm column of anion exchange resin (Bio-Rad AG1X2-hydroxide form). The product was eluted with water/methanol (7/3). The product-containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in water and lyophilized to obtain title compound that analyzed as a 0.6 hydrate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][C:11]2([F:14])[F:13])=[CH:6][C:5]([N+:15]([O-])=O)=[C:4]([F:18])[CH:3]=1.C.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][C:11]2([F:13])[F:14])=[CH:6][C:5]([NH2:15])=[C:4]([F:18])[CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(OCC2CC2(F)F)c(Cl)cc1F
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(OCC2CC2(F)F)c(Cl)cc1F

Procedure:
36.9 g 4-Chloro-2-fluoro-5-(2,2-difluorocyclopropylmethoxy)nitrobenzene in 600 ml ethanol was hydrogenated by the addition of 5 g of 10% palladium metal on activated charcoal at room temperature and normal pressure. After the uptake of hydrogen is complete the catalyst is filtered off, the solvent evaporated to give 29.3 g(=89% of theory) of an oil, whose nmr spectrum is as follows: δ=1.1-2.2 ppm (m) 3H, δ=4.0 ppm (d 10 Hz wide) 2H, δ=5 ppm (s wide) 2H, δ=6.5 ppm (d 7 Hz) 1H, δ=7.0 ppm (d 10 Hz) 1H.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:3]=1.CN.[C:27]([BH3-])#[N:28].[Na+].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>CO.C(O)(=O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:28][CH3:27])[C:12]=2[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1OCC(F)(F)F
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(Oc2cc(Cl)ccc2C#N)c1OCC(F)(F)F
Yield: 47.6 %

Procedure:
4-Chloro-2-[3-formyl-2-(2,2,2-trifluoroethoxy)phenoxy]benzonitrile (0.12 g, 0.33 mmol), methylamine (33% in ethanol, 0.4 mL, 3.2 mmol) and sodium cyanoborohydride (40 mg, 0.6 mmol) were stirred at ambient temperature in a solution of glacial acetic acid (0.5 mL) in methanol (25 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (39 mg, 0.34 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration and dried to give 4-chloro-2-[3-methylaminomethyl-2-(2,2,2-trifluoroethoxy)phenoxy]-benzonitrile fumarate (76.5 mg, 47%) as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: OB(O)c1cccc(Cl)c1
Product: O=C(O)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (200 mg, 0.99 mmol) was coupled to 3-chloro-phenylboronic acid (130 mg, 0.83 mmol) using Method F to give the title compound.