Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20](Cl)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[F:32])[C:14]2=[O:33])[CH2:9][CH2:8]1)(C)(C)C.[NH2:36][C:37]1[CH:38]=[C:39]([O:45][CH3:46])[C:40]([O:43][CH3:44])=[CH:41][CH:42]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[N:15]1[CH2:16][C:17]2[C:18](=[N:19][C:20]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=3)=[N:21][CH:22]=2)[N:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([OH:6])[CH2:8][CH2:9]2)[C:14]1=[O:33]
Reactant: COc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)c(F)c1
Reactant: COc1ccc(N)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(N2Cc3cnc(Nc4ccc(OC)c(OC)c4)nc3N([C@H]3CC[C@H](O)CC3)C2=O)c(F)c1
Temperature: 160 °C

Procedure:
A mixture of 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-7-chloro-3-(2-fluoro-4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.20 g, 0.38 mmol) (from Example 17c supra), 4-amino-veratrole (76.6 mg, 0.50 mmol) (Aldrich) and p-toluenesulfonic acid monohydrate (95.1 mg, 0.50 mmol) (Aldrich) in 2-propanol (4 mL) was placed in a microwave reactor (SmithSynthesizer™). The reaction mixture was heated at 160° C. for 15 minutes. After cooling, it was concentrated under reduced pressure and purified by RP-HPLC (C-18, eluted with acetonitrile-water) to give 3-(2-fluoro-4-methoxy-phenyl)-1-(trans-4-hydroxy-cyclohexyl)-7-(3,4-dimethoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.13 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[CH:4][C:3]=1[NH:20][CH:21]([CH3:24])[CH2:22][OH:23].[N:25]([O-])=O.[Na+].C(OCC)(=O)C>C(O)(=O)C.O>[Cl:14][C:13]1[C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[N:25][N:20]([CH:21]([CH3:24])[CH2:22][OH:23])[C:3]=3[CH:4]=2)=[N:10][N:11]([CH3:19])[C:12]=1[C:15]([F:18])([F:17])[F:16]
Reactant: CC(CO)Nc1cc(Oc2nn(C)c(C(F)(F)F)c2Cl)ccc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(CO)n1nnc2ccc(Oc3nn(C)c(C(F)(F)F)c3Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.9 %

Procedure:
The diamine obtained in Step C (1.08 g) was dissolved in glacial acetic acid (20 cm3) and water (2 cm3) and cooled to below 5° C. in an ice/salt bath. A solution of sodium nitrite (0.41 g, 5.9 mmol) in water (5 cm3) was added dropwise, at such a rate that the internal temperature was maintained below 5° C., and when the addition was complete the reaction mixture was stirred for 4 hours, during which it was allowed to warm to room temperature. The mixture was poured into ethyl acetate (100 cm3) and washed successively with water (2×100 cm3) and saturated aqueous sodium bicarbonate solution (100 cm3). The organic phase was dried (MgSO4), filtered and the filtrate evaporated under reduced pressure. The residue was further purified by flash column chromatography on silica gel, eluting with diethyl ether, to give compound 9, DL 2-[6-(4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol-3-yloxy) benzotriazol-1-yl]-propan-1-ol (0.90 g) as an off white solid m.p. 153°-154° C.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]([F:16])([F:15])[C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.Cl[C:18]1[C:23]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:22]([CH3:31])[N:21]=[N:20][C:19]=1[CH3:32]>C(OCC)(=O)C>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]2[C:18]([N:12]3[CH:13]=[CH:14][C:10]([C:9]([F:16])([F:15])[F:8])=[N:11]3)=[C:19]([CH3:32])[N:20]=[N:21][C:22]=2[CH3:31])=[CH:29][CH:28]=1
Reactant: Cc1nnc(C)c(-c2ccc(Cl)cc2)c1Cl
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nnc(C)c(-n2ccc(C(F)(F)F)n2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.5 %

Procedure:
87 mg of sodium hydride (55% oil dispersion) was added to 5 ml of DMF, and to this was added 0.27 g of 3-trifluoromethylpyrazole, and the mixture was stirred for 5 hours at room temperature. To the resultant mixture was added 0.25 g of 4-chloro-5-(4-chlorophenyl)-3,6-dimethylpyridazine, and the mixture was stirred for 3 hours on an oil bath of 80° C. To the reaction mixture was added ethyl acetate, and the mixture was washed with brine four times. The organic layer was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.57 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.27 g of 5-(4-chlorophenyl)-4-(3-trifluoromethyl-1-pyrazolyl)-3,6-dim ethylpyridazine (hereinafter, described as compound (4) of the present invention.).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([N:13]([CH3:26])[C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[NH:27]([C:29]([O:31]CC)=O)N.C[N:35]1C(=O)CCC1>CCOC(C)=O>[CH3:26][N:13]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:3]([C:1]2[NH:27][C:29](=[O:31])[NH:35][N:2]=2)[N:4]=1)[C@H:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15]1
Reactant: CN(c1nc(C#N)cc2ccccc12)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: CCOC(=O)NN
Reactant: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN(c1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 175 °C
Yield: 32 %

Procedure:
To crude (S)-tert-butyl 3-((3-cyanoisoquinolin-1-yl)(methyl)amino)pyrrolidine-1-carboxylate (0.245 g) in NMP (1 mL) was added ethyl hydrazinecarboxylate (0.289 g, 2.78 mmol). The reaction mixture was heated at 175° C. for 2 days and was subsequently cooled, diluted with EtOAc, and washed with aqueous NH4Cl. The organic phase was separated, dried, and concentrated. The crude product was purified by HPLC to give the title compound (91 mg, 32% over 2 steps).
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:21])[CH:12]=[C:13]([C:16](OCC)=[O:17])[O:14][CH:15]=2)=[CH:6][CH:5]=1>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:21])[CH:12]=[C:13]([C:16]([NH2:1])=[O:17])[O:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: N
Reactant: CCOC(=O)c1cc(=O)c(-c2ccc(OC)cc2)co1
Solvent: CCO
Product: COc1ccc(-c2coc(C(N)=O)cc2=O)cc1
Reaction time: 0.5 h

Procedure:
Cold concentrated ammonia solution (30%, 80 ml) was added to a stirred suspension of ethyl 5-(4-methoxyphenyl)-4-oxo-4H-pyran-2-carboxylate (12.4 g) in ethanol (120 ml) at 5°-10° C. The mixture was stirred for a further 30 minutes at 0°-5° C. then the solid title product was washed with water and dried (mp 262°-263° C. with decomposition).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][P:7](=[O:14])([O:11]CC)[O:8][CH2:9][CH3:10].O.Cl>C(O)C.[OH-].[K+]>[CH2:9]([O:8][P:7]([CH2:6][C:5]1[CH:15]=[CH:16][CH:17]=[C:3]([C:2]([F:19])([F:1])[F:18])[CH:4]=1)(=[O:11])[OH:14])[CH3:10]
Reactant: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(O)Cc1cccc(C(F)(F)F)c1
Yield: 94.8 %

Procedure:
The diethyl 3-trifluoromethylbenzylphosphonate (10.0 g, 34.0 mmol) was dissolved in a mixture of 300 mL of 75% aqueous ethanol and 18.9 g of KOH and the resultant mixture was heated at reflux for 3 hours. The reaction mixture was poured into H2O, acidified with hydrochloric acid, and extracted with CHCl3 (3×500 mL). The chloroform extract was dried with anhydrous Na2SO4 and evaporated to yield 8.64 g (94.7%) of white solid product, mp=48°-51° C.; D.C.I.M.S.[MH+, 269].
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=[O:7])(C)(C)C.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30].CCOC(C)=O.C[N:39](C=O)C>O>[CH:29]([NH:39][C:6](=[O:7])[NH:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])([CH3:30])[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: C=CCBr
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)NC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Reaction time: 1 h

Procedure:
2-(tert-Butoxycarbonyl)amino-5-trifluoromethylbenzoic acid (2 g) was dissolved in DMF prior to the addition of K2CO3 (1.08 g) and allyl bromide (0.68 mL). The mixture was stirred for 18 h before EtOAc and water were added. The organic layer was washed with brine, dried, filtered, and concentrated (2.05 g). The resulting material was dissolved in CH2Cl2 (4 mL) and TFA (4 mL). After 1 h, the solution was concentrated. This material was dissolved in THF and added dropwise to a THF (50 mL) solution of trichloromethyl chloroformate (1.9 mL). After stirring for 18 h, the solution was concentrated and a THF (30 mL) solution of iso-propylamine (4.3 mL) was added. After 18 h, the solution was diluted with EtOAc and was washed with brine solution and 1N HCl. The organic layer was dried (MgSO4), filtered, and concentrated to a white solid. This solid was dissolved in CH3CN (22 mL) prior to the addition of pyrrolidine (0.41 mL) and Pd(PPh)4 (105 mg). After 18 h, the solution was diluted with EtOAc and was washed 1N HCl. The organic layer was dried (MgSO4), filtered, and concentrated to give the title compound (1.1 g) as a white solid: 1H NMR (DMSO, δppm, 300 mHz) 1.11 (d, 6H), 3.78 (m, 1H), 7.63 (br d, 1H), 7.81 (dd, 1H), 8.14 (d, 1H), 8.64 (d, 1H), 10.27 (s, 1H), 13.83 (br s, 1H).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:23]=[C:24]([CH2:32][OH:33])[N:25]5[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=45)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:23]=[C:24]([CH2:32][OH:33])[N:25]5[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=45)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nc(CO)n4cc(F)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nc(CO)n4cc(F)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-3-hydroxymethyl-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (82 mg, 0.138 mmol) was dissolved in dichloromethane (0.7 ml) and trifluoroacetic acid (0.43 ml, 5.6 mmol) was added. The reaction was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.7 ml) and ethylenediamine (0.56 ml, 8.3 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water and diluted with dichloromethane. The resulting precipitate was filtered, washing with water and dichloromethane then dried under high vacuum to provide 46 mg (68%) of 2-(6-fluoro-3-hydroxymethyl-imidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow powder. MS: (M+H)+=463; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.30 (br. s, 1H), 9.12 (s, 1H), 8.79 (dd, J=9.6, 3.2 Hz, 1H), 8.55 (d, J=4.9 Hz, 1H), 8.44 (d, J=7.9 Hz, 1H), 8.40 (d, J=5.7 Hz, 1H), 7.07-7.17 (m, 1H), 5.61 (t, J=5.7 Hz, 1H), 4.94 (d, J=5.3 Hz, 2H), 4.50-4.81 (m, 3H), 4.20-4.32 (m, 1H), 4.14 (dt, J=10.3, 5.2 Hz, 1H), 3.81-3.93 (m, 1H), 1.40 (t, J=6.0 Hz, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:9][CH2:8]1.[CH3:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:28][CH:29]=1.CN(C1C=CC=CN=1)C.CCN=C=NCCCN(C)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][C:16]([NH:33][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)(=[O:31])=[O:32])=[O:18])[CH2:11][CH2:12]1
Reactant: O=C(O)CCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)CCCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 12.8 %

Procedure:
4-(3,4-Dichlorophenoxy)-1-piperidinebutanoic acid hydrochloride (0.250 g) was dissolved in dichloromethane (10 mL) containing p-toluenesulfonamide (0.142 g), dimethylaminopyridine (92 mg) and EDCI (0.158 g) were added. The solution was stirred at room temperature for 4 days. The solvent was evaporated. The crude product was dried in vacuo and then purified by HPLC (at column dilution, gradient ammonium acetate/acetonitrile 75% to 5% ;Waters Xterra® column) and to give the title compound (42 mg).
Reaction SMILES: P([C:9]#[N:10])(=O)(OCC)OCC.CN(C=O)C.[CH3:16][N:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]([CH2:42][C:43]3[CH:51]=[CH:50][C:46]([C:47]([OH:49])=O)=[CH:45][CH:44]=3)[CH2:34][CH2:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]1=[O:52].[ClH:53].CN>C(OCC)(=O)C.C(N(CC)CC)C>[ClH:53].[ClH:53].[CH3:9][NH:10][C:47](=[O:49])[C:46]1[CH:50]=[CH:51][C:43]([CH2:42][N:33]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:23]2[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=2)[N:17]([CH3:16])[C:18](=[O:52])[CH:19]=[CH:20]3)[CH2:34][CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[CH:44][CH:45]=1
Reactant: CCOP(=O)(C#N)OCC
Reactant: Cn1c(=O)ccc2cc(OCCCCCN(CCc3cccnc3)Cc3ccc(C(=O)O)cc3)ccc21
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(CN(CCCCCOc2ccc3c(ccc(=O)n3C)c2)CCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
Diethyl phosphorocyanidate (39.1 mg) was added to a DMF solution (1 ml) of 4-{[N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid (0.10 g), methylamine hydrochloride (27 mg), and triethylamine (0.07 ml), and the mixture was stirred at room temperature overnight. Ice water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1). The purified product was concentrated under reduced pressure. A 1N-hydrogen chloride ethanol solution (0.16 ml) was added to the solution of the residue in ethanol, and stirred for 30 minutes at room temperature. The precipitated insoluble matter was collected by filtration, washed with ethyl acetate, and dried to give the title compound (81.3 mg) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[CH:29]=O)=[O:8].[CH2:35]([NH2:38])[CH2:36][NH2:37].C1C(=O)N(Br)C(=O)C1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:20])[CH3:21])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[C:29]1[NH:37][CH2:36][CH2:35][N:38]=1)=[O:8]
Reactant: NCCN
Reactant: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C=O)n(Cc3ccccn3)c2c1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C3=NCCN3)n(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(3,4-difluorobenzyl)-2-formyl-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 105, 27 mg, 0.058 mmol) in CH2Cl2 (2 ml) was added 1,2-ethylene-diamine (5 μl, 0.070 mmol). The reaction was stirred at room temperature for 1 h and NBS (13 mg, 0.070 mmol) was added. The reaction was stirred for 16 h and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (9:1 EtOAc-Et3N, then 8:2:1 EtOAc-MeOH-Et3N) followed by PTLC eluted with EtOAc to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[CH:23][C:6]1=2
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CN1CCC(O)CC1
Product: CN1CCC(Oc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 1-methylpiperidin-4-ol.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](=[O:6])[CH3:5].O.C(=O)([O-])[O-].[K+].[K+].[C:20](Cl)(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(OCC)(=O)C>[C:20]([NH:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](=[O:6])[CH3:5])(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCC(=O)Cl
Reactant: CC(=O)C(N)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCC(=O)NC(C(C)=O)c1ccccc1

Procedure:
To a mixture of 1-amino-1-phenyl-2-propanone hydrochloride (5.55 g), water (40 ml), ethyl acetate (75 ml) and potassium carbonate (4.55 g) was added dropwise hexanoyl chloride (4.42 g) under ice-cooling and stirring. The mixture was further stirred for an hour with ice-cooling. The ethyl acetate layer was separated, washed with water, diluted hydrochloric acid and water in that order, and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was recrystallized from isopropyl ether to give crystals of 1-hexanoylamino-1-phenyl-2-propanone, yield 5.80 g (78.2%), m.p. 77°-78° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].Cl[C:12](OC(Cl)(Cl)Cl)=[O:13].[C:19]([C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([C:29](=[O:31])[CH3:30])[CH:28]=1)[NH2:25])(=[O:21])[CH3:20]>C1(C)C=CC=CC=1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:12]([NH:25][C:24]2[CH:26]=[C:27]([C:29](=[O:31])[CH3:30])[CH:28]=[C:22]([C:19](=[O:21])[CH3:20])[CH:23]=2)=[O:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(NC(=O)Nc2cc(C(C)=O)cc(C(C)=O)c2)cc1
Reaction time: 16 h

Procedure:
4-Aminoacetophenone (1.35 g) in toluene (20 mL) was treated with trichloromethyl chloroformate (1.2 mL). The mixture was heated at reflux for 2 hr. 3,5-diacetylaniline (1.77 g) was added and the mixture was heated at reflux for 1 hr then allowed to stand 16 hr at room temp. The product was filtered off and washed with ethanol and dried to give 0.93 g of N-(4-acetylphenyl)-N'-(3,5-diacetylphenyl)urea, mp 251°-2° C.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[N:10][C:11](S(C)(=O)=O)=[N:12][C:13]=3[NH:15][CH2:16][C@H:17]([OH:19])[CH3:18])[NH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32].[OH-].[K+]>>[CH:1]1([C:6]2[C:14]3[C:9](=[N:10][C:11]([O:32][C:26]4[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=4[F:24])=[N:12][C:13]=3[NH:15][CH2:16][C@H:17]([OH:19])[CH3:18])[NH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H](O)CNc1nc(S(C)(=O)=O)nc2[nH]nc(C3CCCC3)c12
Reactant: Oc1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Product: C[C@@H](O)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]nc(C3CCCC3)c12

Procedure:
(R)-1-(3-Cyclopentyl-6-methylsulfonyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-propan-2-ol was treated with 2,4-difluorophenol in the presence of KOH using the procedure of step 6 of Example 4 to afford 0.56 mg of (R)-1-[3-Cyclopentyl-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol. Mass Spec. M+H=390.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[C:8]([C:14]([NH2:16])=O)=[N:9][C:10]([I:13])=[CH:11][N:12]=1.O.[CH3:18][N:19]([CH3:22])[CH:20]=O>>[C:14]([C:8]1[C:7]([N:6]=[CH:18][N:19]([CH3:22])[CH3:20])=[N:12][CH:11]=[C:10]([I:13])[N:9]=1)#[N:16]
Reactant: CN(C)C=O
Reactant: NC(=O)c1nc(I)cnc1N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN(C)C=Nc1ncc(I)nc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
13.59 ml (146 mmol) of phosphorus oxychloride is added drop by drop at 0° C. to 11 g (41.7 mmol) of a solution of 3-amino-6-iodopyrazine-2-carboxamide in 80 ml of dimethylformamide. The reaction mixture is stirred at room temperature overnight and then poured in a beaker containing ice and a little water. The pH is adjusted to 8 with 1 N soda solution; a precipitate is formed. The mixture is allowed to gradually return to room temperature and then the solid formed is filtered, rinsed with water and dried at 50° C. to yield 10.50 g of N′-(3-cyano-5-iodopyrazine-2-yl)-N,N-dimethyl formimidamide (84%) in the form of a beige solid.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][NH2:15].[C:16](O)(=[O:23])[CH2:17][C:18]([C:20]([OH:22])=[O:21])=O>O>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:16]([OH:23])=[CH:17][C:18]([C:20]([OH:22])=[O:21])=[N:15]1
Reactant: O=C(O)CC(=O)C(=O)O
Reactant: NNc1ccccc1F
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(O)n(-c2ccccc2F)n1
Temperature: 5 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Sulfuric acid (400 ml) was added slowly to water (400 ml). After cooling to 5° C., 2-fluoro-phenylhydrazine hydrochloride (123 g, 757 mmol) was added resulting in a brown suspension. Then a solution of oxalacetic acid (100 g, 757 mmol) in water (400 ml) was added slowly during a period of 25 min. After 2 h the conversion was complete and the solid was filtered. After washing with water the solid was dried. The product was obtained as light brown solid (151 g, 90%).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1(C)C=CC(S(O[CH:36](C)[CH:37]([C:42]#[N:43])[CH2:38][CH2:39][CH2:40][CH3:41])(=O)=O)=CC=1.[CH3:46]N(C)C=O>>[C:42]([C:37]([CH3:36])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:46][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[N:17]=[CH:18][C:13]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][N:15]=2)=[CH:24][CH:23]=1)#[N:43]
Reactant: CCCCC(C#N)C(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCc1cnc(-c2ccc(OCC(C)(C#N)CCCC)cc2)nc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 48.8 %

Procedure:
28 mg (0.7 mM) of sodium hydride and 1.5 ml of dimethylformamide were stirred, and 220 mg (0.7 mM) of p-(5-n-decyl-2-pyrimidyl)phenol was added, followed by stirring for 10 minutes. Further, 218 mg (0.7 mM) of 2-cyano-methylhexyl p-toluenesulfonate and dimethylformamide were added, followed by 6 hours of stirring under heating at 100° C. After the reaction, the solvent was distilled off and distilled water was added thereto, followed by extraction with diethyl ether. The organic layer was washed with distilled water and dried on sodium sulfate. After distilling off the solvent, the product was purified by thin layer chromatography (developer solvent: hexane/methylene chloride=1/5) to obtain 149 mg of 4-(5-n-decyl-2-pyrimidyl)-phenyl 2-cyano-2-methylhexyl ether. Yield: 48.8%, [α]25D -1.47 (C 1.494, methylene chloride) m.p.: 43° C.