Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C@H:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[CH2:14]/[C:15](/[C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)=[N:16]\[OH:17])=[CH:9][CH:8]=2)[CH2:4]1.[ClH:32].C(=O)([O-])O.[Na+].[Cl-].[NH4+]>O1CCOCC1.C(OCC)(=O)C>[Cl:32][CH2:4][CH:3]([O:2][CH3:1])[CH2:6][NH:5][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:14][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=2)=[N:16][OH:17])=[CH:9][CH:8]=1
Reactant: COC1CN(c2ccc([C@@H](C/C(=N\O)c3ccnc(C)c3)c3ccccc3C)cc2)C1
Reactant: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(CCl)CNc1ccc([C@@H](CC(=NO)c2ccnc(C)c2)c2ccccc2C)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
To a solution of (R)-3-[4-(3-methoxy-azetidin-1-yl)-phenyl]-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one oxime (example 270, 31 mg) in 1,4-dioxane (2 mL) was added at room temperature hydrochloric acid 4 M in 1,4-dioxane (187 μL). The reaction mixture was heated at 50° C. and stirred for 4 hours. A saturated solution of sodium hydrogencarbonate (2 mL) was added to neutralized the crude solution followed by a saturated aq. ammonium chloride solution. Ethyl acetate was added, the phases were separated and the inorganic one was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (25% to 100% ethyl acetate in n-heptane) to yield the title compound as a light yellow foam (89%), MS (ESI+): m/z=452.3 ([M+H]+).
Reaction SMILES: [H-].[Na+].C1C=CC=CC=1.Cl[C:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:21])[N:13]=[C:12]2[N:22]([CH3:25])[CH:23]=[N:24][C:11]=12.[CH3:26][CH:27]([CH3:31])[CH2:28][CH2:29][OH:30]>>[CH3:25][N:22]1[C:12]2=[N:13][C:14]([CH3:21])=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([O:30][CH2:29][CH2:28][CH:27]([CH3:31])[CH3:26])=[C:11]2[N:24]=[CH:23]1
Reactant: CC(C)CCO
Reactant: CCOC(=O)c1c(C)nc2c(ncn2C)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)c1c(C)nc2c(ncn2C)c1OCCC(C)C
Reaction time: 12 h

Procedure:
0.3 g. of sodium hydride are suspended in 100 ml. of anhydrous benzene. The mixture is heated with stirring at reflux temperature while 8.8 g. of 3-methylbutane-1-ol are dropped in. After the addition is completed, the mixture is refluxed for an additional 10 hours. After this time 25.3 g. of 7-chloro-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester obtained in Example 2 c are added and refluxing is continued for 12 hours. The inorganic precipitate is filtered off and the solvent removed in vacuo. The oily residue is dissolved in 50 ml. of ether and, on cooling, 3,5-dimethyl-7-(3-methylbutoxy)-3H-imidazo[4,5-b]-pyridine-6-carboxylic acid, ethyl ester is obtained. Yield 24.3 g. (80%), m.p. 64°-66° (diethyl ether).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][NH:14][C:15]3[CH:49]=[CH:48][C:18]([C:19]([NH:21][C@H:22]([C:44]([O:46]C)=[O:45])[CH2:23][CH2:24][C:25](=[O:43])[NH:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:20])=[CH:17][CH:16]=3)[N:8]=2)[N:3]=1.[OH-].[Li+].C1COCC1.O>Cl>[NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:21][C@@H:22]([CH2:23][CH2:24][C:25]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][NH2:35])=[O:43])[C:44]([OH:46])=[O:45])=[O:20])=[CH:48][CH:49]=3)[N:8]=2)[N:3]=1
Reactant: COC(=O)[C@H](CCC(=O)NCCOCCOCCNC(=O)OC(C)(C)C)NC(=O)c1ccc(NCc2cnc3nc(N)nc(O)c3n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCCOCCOCCNC(=O)CC[C@H](NC(=O)c1ccc(NCc2cnc3nc(N)nc(O)c3n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
(S)-methyl 18-(4-((2-amino-4-hydroxypteridin-6-yl)methylamino)benzamido)-2,2-dimethyl-4,15-dioxo-3,8,11-trioxa-5,14-diazanonadecan-19-oate (225 mg, 0.33 mmol, crude) in 6 M aqueous hydrochloric acid (20 mL) was stirred at ambient temperature for 2 hours. After this time, the reaction was purified by semi-preparative HPLC (0-70% H2O/CH3CN with 0.05% TFA over 25 minutes) to give a mixture of the desired acid and the methyl ester (190 mg) as a yellow solid. To this mixture lithium hydroxide (30 mg, 1.25 mmol) was added along with a 1:1 THF/H2O mixture (6 mL). This mixture was stirred at ambient temperature for 2 hours. After this time, the THF was removed under reduced pressure, and the reaction was purified by semi-preparative HPLC (0-70% H2O/CH3CN with 0.05% TFA over 25 min) to afford (S)-2-(4-((2-amino-4-hydroxypteridin-6-yl)methylamino)benzamido)-5-(2-(2-(2-aminoethoxy)ethoxy)ethylamino)-5-oxopentanoic acid (185 mg, 100%) as a yellow solid that was obtained from lyophilization: 1H NMR (500 MHz, DMSO-d6) δ 12.47 (vbs, 1H), 11.44 (vbs, 1H), 8.64 (s, 1H), 8.17 (d, J=7.5 Hz, 1H), 7.87 (t, J=5.5 Hz, 1H), 7.72 (bs, 2H), 7.65 (d, J=9.0 Hz, 2H), 6.93 (bs, 2H), 6.64 (d, J=9.0 Hz, 2H), 4.48 (s, 2H), 4.30-4.26 (m, 1H), 3.57-3.49 (m, 6H), 3.37 (t, J=6.0 Hz, 2H), 3.22-3.13 (m, 2H), 2.99-2.94 (m, 2H), 2.19 (t, J=7.5 Hz, 2H), 2.08-2.01 (m, 1H), 1.93-1.85 (m, 1H), exchangeable proton not observed (1H); ESI MS m/z=570 [M−H]−.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=S)[CH:6]=[CH:7][CH:8]=1.[NH3:18]>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[NH:18])[CH:6]=[CH:7][CH:8]=1
Reactant: OCc1cccc(NC(=S)NCC(F)(F)F)c1
Reactant: N
Product: N=C(NCC(F)(F)F)Nc1cccc(CO)c1

Procedure:
The above thiourea (1.32 g.) was stirred in 1.6N alcoholic ammonia (50 ml.) with mercuric oxide (3.4 g.) for 17 hours at 20°. The resulting mixture was clarified on the centrifuge and the supernatant was evaporated in vacuo to a syrup which was further dried at 70°/0.1 m.m. to give 1-(3-hydroxymethylphenyl)-3-(2,2,2-trifluoroethyl)guanidine. The n.m.r. spectrum in d6 dimethylsulphoxide using tetramethyl silane as internal standard (δ=0) had the following resonances (δ): 6.9 (4H, multiplet); 4.4 (2H, singlet); 3.9 (2H, quartet).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])(=[O:10])=[O:9]>P(Cl)(Cl)(Cl)=O>[F:14][C:13]([F:16])([F:15])[C:12]1[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[N:11]=1
Reactant: Nc1ccncc1S(=O)(=O)NC(=O)C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Product: O=S1(=O)N=C(C(F)(F)F)Nc2ccncc21

Procedure:
A mixture of 1 g of 4-amino-3-trifluoroacetylaminosulfonylpyridine (Preparation 18) and 20 cm3 of phosphorus oxychloride is brought to reflux for 18 hours. The solvent is removed under partial vacuum and the oil obtained, triturated with 5 ml of ice-cold water, produces a precipitate. The latter is collected on a filter, washed with water and dried. It is then purified by dissolving in the minimum amount of methanol and then adding 3 volumes of diethyl ether and 3 volumes of petroleum ether (40°-60° ). The crystals obtained are collected on a filter, washed with diethyl ether and dried.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:16]=3)[C:11]2=[O:24])[C:3]=1[CH:4]=[O:5].C([BH-](CC)CC)C.[Li+].C([O-])(O)=O.[Na+].O>C1COCC1>[Br:1][C:2]1[C:3]([CH2:4][OH:5])=[C:6]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:23])([CH3:21])[CH3:22])[CH:16]=3)[C:11]2=[O:24])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(O)c1ccc2c(c1)CCN(c1cccc(Br)c1C=O)C2=O
Agent: CC[BH-](CC)CC
Agent: O=C([O-])O
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)CCN(c1cccc(Br)c1CO)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Intermediate 42 (320 mg, 0.824 mmol) in THF (10 ml) under argon atmosphere was added lithium triethylborohydride (1M in THF, 0.989 ml, 0.989 mmol) dropwise. The resulting mixture was stirred for 2 hrs at r.t. before adding sat. aqueous NaHCO3 solution (5 ml). Additional water was added and the mixture was extracted three times with EtOAc. The combined organic layers were dried, filtered, and evaporated to dryness. The crude product was purified by flash chromatography (silica gel, cyclohexane/EtOAC gradient) to yield Intermediate 43.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CC(O)=O>C(Cl)(Cl)Cl>[CH3:7][O:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:1][C:2]([Cl:4])=[O:3])=[O:20]
Reactant: COC(=O)CCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCCCCCC(=O)Cl
Temperature: 50 °C

Procedure:
In a separate process, 23.9 g of azelaic monomethylester was dissolved in 30 ml chloroform. Oxalylchloride (15 ml) was added, all at once, and the mixture refluxed 2 hours at 50° C. The mixture was cooled; excess solvent and oxalylchloride were evaporated. After distillation, 25.8 g of CH3OCO(CH2)7COCl was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.Br[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([NH:1][C:2]2[C:3]3[CH:4]=[CH:5][N:6]=[CH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[N:14][CH:15]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Nc1cccc2cnccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: Brc1ccc(Nc2cccc3cnccc23)nc1
Temperature: 130 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
To a mixture of 5-aminoisoquinoline (2.53 g, 17.5 mmol) and 2,5-dibromopyridine (3.62 g, 15.3 mmol) was added palladium acetate (0.17 g, 0.76 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.47 g, 0.76 mmol). The flask was flushed with nitrogen and p-xylene was added followed by sodium tert-butoxide (2.2 g, 22.9 mmol). Nitrogen was bubbled through the mixture for 5 minutes and the reaction was then heated with stirring at 130° C. for 12 hours under an atmosphere of nitrogen. The mixture was allowed to cool to room temperature and poured onto a mixture of chloroform/water (200 ml/20 ml). The phases were separated and the aqueous phase was extracted twice with chloroform. The combined organic layers were washed with brine, dried over sodium sulfate and adsorbed onto silica gel. Purification by flash chromatography (50% ethyl acetate-isohexane) followed by recrystallisation from ethanol gave N-(5-bromopyridin-2-yl)isoquinolin-5-amine (3.4 g, 74%). A portion (0.71 g, 2.37 mmol) was added to 4(trifluoromethyl) phenylboronic acid (0.68 g, 3.59 mmol) in anhydrous dioxane (10 ml) and tetrakis(triphenylphosphino)-palladium (0) (0.14 g, 0.12 mmol) and saturated aqueous sodium carbonate solution (4 ml) were added. Nitrogen was bubbled through the mixture for 5 minutes and the reaction was then heated with stirring at 100° C. for 12 hours under an atmosphere of nitrogen. The mixture was allowed to cool to room temperature and poured into a mixture of ethyl acetate/water (100 ml/30 ml). The phases were separated and the aqueous phase was extracted two times more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and adsorbed onto silica gel. Purification by flash chromatography (50% ethyl acetate-iso-hexane) followed by recrystallisation from methanol/water (1:1) yielded the title compound (0.22 g, 25%). m/z (ES+) 366 (M+H+).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:13][CH:12]=2)[CH2:9][CH:8]([OH:10])[CH2:7]1)=O.[OH-].[Na+]>CCO.O>[NH2:5][C:6]1([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:22][C:35]([C:36]6[N:37]=[CH:38][CH:39]=[CH:40][N:41]=6)=[N:34][N:33]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)[CH2:9][CH:8]([OH:10])[CH2:7]1
Reactant: O=C(NC1(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)CC(O)C1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC1(c2ccc(-c3nc4ccn5nc(-c6ncccn6)nc5c4cc3-c3ccccc3)cc2)CC(O)C1
Temperature: 100 °C

Procedure:
To a mixture of 2,2,2-trifluoro-N-(3-hydroxy-1-{4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-3) (10 mg, 0.016 mmol) in EtOH (1.0 mL) was added NaOH (2M in water, 1.0 mL, 2.00 mmol), and the mixture was heated under microwave irradiation at 100° C. for 1 hour. The mixture was diluted with water, extracted with CHCl3, washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by preparative TLC, eluting with 10% MeOH in CHCl3 to give 3-amino-3-{-4-[9-phenyl-2-(2-pyrimidinyl)[1,2,4]triazolo[5,1-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanol (6-1) as a colorless solid. MS (M+H)+: observed=486, calculated=486.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([S:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)=[CH:20]2.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([S:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:12]([C:9]3[CH:10]=[CH:11][C:5]4[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)=[O:14])[CH2:32][CH2:31]1)=[CH:20]2
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.5 %

Procedure:
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (21 mg, 0.09 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-ylamine (30 mg, 0.09 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by 1-hydroxybenzotriazole (13 mg, 0.10 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (20 mg, 0.10 mmol, 1.15 eq) and N,N-diisopropylethylamine (35 μL, 0.20 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×5 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide as a white solid (30 mg, 59% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([NH2:27])[CH:17]=2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:7]=1.[O:28]=[C:29]1[NH:33][CH2:32][C@@H:31]([C:34](O)=[O:35])[CH2:30]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([NH:27][C:34]([C@H:31]3[CH2:30][C:29](=[O:28])[NH:33][CH2:32]3)=[O:35])[CH:17]=2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:14])([F:12])[F:13])[CH:7]=1
Reactant: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccccc2)c1)C(F)(F)F
Reactant: O=C1C[C@H](C(=O)O)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@@H](OCc1cc(F)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccccc2)c1)C(F)(F)F
Reaction time: 5.2 h
Yield: 41.8 %

Procedure:
To a solution of 5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine (37 mg) in N,N-dimethylacetamide (1.0 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (16 mg) prepared in Preparation 14 and WSC.HCl (23 mg) at room temperature, the mixture was stirred for 5.2 hours. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. This solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (20 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][C:9]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:25][C:24](=O)[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N:33]3[CH:37]=[CH:36][N:35]=[C:34]3[CH3:38])[CH:28]=2)[O:21]1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:15])[CH3:16])=[CH:10][C:9]=1[NH:17][C:24](=[O:25])[CH2:23][C:22]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[C:34]2[CH3:38])[CH:28]=1)=[O:21])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reactant: Cc1nccn1-c1cccc(C2=CC(=O)OC(C)(C)O2)c1
Product: Cc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(C(C)C)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
Prepared from (2-amino-4-isopropyl-phenyl)-carbamic acid tert.-butyl ester (Example G47) and 2,2-dimethyl-6-[3-(2-methyl-imidazol-1-yl)-phenyl]-[1,3]dioxin-4-one (Example J15) according to the general procedure K. Obtained as a yellow oil (186 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[NH3:18]>C(O)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4]([NH2:18])[N:3]=1
Reactant: N
Reactant: Nc1nc(Cl)cnc1-c1cc(Cl)cc(Cl)c1Cl
Solvent: CCO
Product: Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Temperature: 180 °C

Procedure:
A suspension of 2-amino-6-chloro-3-(2,3,5-trichlorophenyl)pyrazine (0.3 g, 9.71×10−4 mole) in absolute ethanol (4 ml) and 0.880 aqueous ammonia (8.24 ml) was stirred and heated in an autoclave at 180° C. for 44 hrs. The cooled mixture was evaporated in vacuo, and the residue extracted with chloroform (3×30 ml). The combined chloroform extracts were dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated down in vacuo. The residue was purified by ‘flash chromatography’ using chloroform to 98:2 chloroform:methanol as the eluent. The product was triturated with 40-60° C. petroleum ether, filtered and dried in vacuo. Yield 0.155 g (56%), M.p. 178-180° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.[Br:10][C:11]1[N:16]=[C:15](Br)[C:14]([C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[C:13]([CH3:24])[N:12]=1>C(O)C>[Br:10][C:11]1[N:16]=[C:15]([NH:9][C:7]2[CH:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:5][N:6]=2)[C:14]([C:18]#[C:19][Si:20]([CH3:21])([CH3:23])[CH3:22])=[C:13]([CH3:24])[N:12]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Cc1nc(Br)nc(Br)c1C#C[Si](C)(C)C
Solvent: CCO
Product: Cc1nc(Br)nc(Nc2cc(C3CC3)[nH]n2)c1C#C[Si](C)(C)C
Temperature: 21.5 °C
Reaction time: 20 h
Yield: 19.9 %

Procedure:
At 20° C. (using an ice bath for the temperature control), 3-cyclopropyl-1H-pyrazol-5-amine (1.192 g, 9.68 mmol, 1.5 eq) in ethanol (15 ml) was added into a solution of compound 2,4-dibromo-6-methyl-5-((trimethylsilyl)ethynyl)pyrimidine (2.246 g, 6.45 mmol, 1.0 equiv.) in ethanol (15 mL). The reaction was stirred at for 20 h at 20-23° C. Ethanol was removed under reduced pressure 10-20° C. Purified by silica-gel column chromatography (mobile phase: petroleum ether/ethyl acetate=20/1; 5/1) afforded solid product 2-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-5-((trimethylsilyl)ethynyl)pyrimidin-4-amine (500 mg, 22%). LC-MS (m/z)=392.0 [M+2H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16](=O)[C:11]2[C:12]([CH3:15])=[CH:13][O:14][C:10]=2[CH2:9]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl>C(O)C>[ClH:24].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17]/[C:16](=[N:23]\[NH:22][C:19]([NH2:21])=[NH:20])/[C:11]2[C:12]([CH3:15])=[CH:13][O:14][C:10]=2[CH2:9]1
Reactant: Cc1coc2c1C(=O)CC(c1ccccc1Br)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1coc2c1/C(=N/NC(=N)N)CC(c1ccccc1Br)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a mixture of 6-(2-bromophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.28 g) and aminoguanidine hydrochloride (102 mg) were added ethanol (20 ml) and 6N hydrochloric acid (0.080 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2-bromophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 45) (0.31 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26]C)[CH:22]=3)[C:17]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]1.Br>>[Cl:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=3)[C:17]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]1
Reactant: COc1ccc2c(c1)CCN(c1ccc(N3CCC(N(C)C)C3)c(Cl)c1)C2=O
Agent: Br
Product: CN(C)C1CCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2Cl)C1

Procedure:
According to Method L, 2-[3-chloro-4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-6-methoxy-3,4-dihydro-2H-isoquinolin-1-one was treated with hydrogen bromide. In this way the product was obtained with molecular weight 385.90 (C21H24ClN3O2); MS (ESI): 386 (M+H+).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1)#[CH:10]>C(#N)C.[Cu]I.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>[CH2:17]([C:14]1[CH:13]=[CH:12][C:11]([C:9]#[C:10][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1)[CH2:18][CH2:19][CH3:20]
Reactant: Nc1ccc(I)cc1
Reactant: C#Cc1ccc(CCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: CCCCc1ccc(C#Cc2ccc(N)cc2)cc1
Temperature: 85 °C
Reaction time: 24 h
Yield: 48.5 %

Procedure:
To a stirred solution of 4-iodoaniline (20 g, 91 mmol, Aldrich) and 1-eth-1-ynyl-4-butylbenzene (16.7 g, 105 mmol, Aldrich) in dry acetonitrile (300 mL) under nitrogen was added CuI (0.83 g, 4.3 mmol), TEA (27.7 g, 273 mmol) followed by Pd(PPh3)2Cl2 (3 g, 4.3 mmol). The reaction mixture was stirred at 85° C. for 24 hours and the solvent was removed under reduced pressure. The residue was diluted with Et2O (200 mL) and washed with water, brine and dried (MgSO4). The solvent was removed under reduced pressure and the crude product was purified by chromatography (Pet Ether/EtOAc (4/1) to give 11 g (47%) of the title compound as a solid. TLC-Pet ether/EtOAc (4/1): Rf=0.35. HPLC purity >98%.