Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C([Li])CCC.CCCCCC.[CH3:22][N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29]>O1CCCC1>[CH3:22][NH:23][C:24](=[O:29])[CH2:25][CH2:26][C:27](=[O:28])[C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[O:9][CH3:10]
Reactant: CN1C(=O)CCC1=O
Reactant: COc1cccc(OC)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)CCC(=O)c1c(OC)cccc1OC
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A solution of 1,3-dimethoxybenzene (89 ml, 0.064 mole) in dry tetrahydrofuran (480 ml) was added during 10 minutes to a stirred solution of n-butyl lithium in hexane (350 ml, 0.6 mole) under an atmosphere of nitrogen. The stirred mixture was heated under reflux for 90 minutes, then a solution of N-methyl succinimide (77 g, 0.68 mole) in dry tetrahydrofuran was added dropwise. The mixture was heated under reflux for an additional hour and then allowed to stand overnight. The supernatant was decanted and the residue was hydrolysed with 20% aqueous ammonium chloride solution (280 ml) and extracted with chloroform. The washed and dried extract was evaporated and the residue recrystallised from ethyl acetate to give N-methyl 3-(2,6-dimethoxybenzoyl)propionamide (15 g, 10%, m.p. 134°).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.O.[NH2:26][NH2:27]>CCO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([NH:26][NH2:27])=[O:20])=[CH:17][CH:16]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(=O)CCc2ccc3c(c2)OCO3)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(NC(=O)CCc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a suspension of methyl 4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoate (200 mg, 0.61 mmol) in EtOH (3.5 mL) was added hydrazine hydrate (0.5 mL). After stirring for 15 hrs at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (2×1 mL) and water (3×1 mL), and drying under vacuo at 70° C. for 1 hr gave 130 mg of the title compound (65%) as a white solid in 95.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([O:36][CH3:37])[CH:30]=3)(=[O:28])=[O:27])[CH2:21][CH2:20]2)=[O:18])[CH3:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[C:31]([O:36][CH3:37])[CH:30]=3)(=[O:28])=[O:27])[CH2:21][CH2:20]2)=[O:18])[CH3:15])=[CH:10][CH:9]=1
Reactant: BrC1CCCC1
Reactant: COc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)ccc1OC1CCCC1
Temperature: 50 °C

Procedure:
Cyclopentylbromide (10.45 mg, 0.07 mmol) was added to solution of trans-4-(4-hydroxy-3-methoxy-benzenesulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 2, 31.6 mg, 0.07 mmol) and potassium carbonate (19.4 mg, 0.14 mmol) in dimethylformamide (700 ul). The reaction was heated 50° C. for 16 h, cooled to room temperature, diluted with ethyl acetate and rinsed with 1:1 water:brine. The organic layer was concentrated and purified by reverse-phase chromatography followed by lyophilization to yield title compound (18 mg, 0.035 mmol). MS MH+ 519.1
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:10](N(CC)CC)C.ClC1C=CC(S(ON2C3C=C(Cl)C=CC=3N=N2)(=O)=O)=CC=1.CO>C(Cl)(Cl)Cl>[C:1]([O:9][CH3:10])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCN(CC)CC
Reactant: CCCCCCC(=O)O
Agent: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCC(=O)OC
Reaction time: 0.17 h

Procedure:
Heptanoic acid (1.30 g) is dissolved in chloroform (15 ml) and thereto are added triethylamine under ice-cooling and further 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1,2,3-benzotriazole (3.44 g), and the mixture is stirred for 3 hours. To the solution are added methanol (0.61 ml) and triethylamine (1.40 ml), whereby exothermic reaction occurs. After stirring for 10 minutes, chloroform is distilled off and to the resulting residue are added water and ether. The ether layer is washed with water, an aqueous sodium hydrogen carbonate and water in order, dried over anhydrous magnesium sulfate and the solvent is distilled off to give methyl heptanoate (1.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[N:20]1([C:26]2[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([C:26]2[N:31]=[CH:30][C:29]([NH:32][C:13]([C:11]3[N:12]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[O:9][C:10]=3[C:16]([F:19])([F:18])[F:17])=[O:15])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2Cl)oc1C(F)(F)F
Product: O=C(Nc1ccc(N2CCOCC2)nc1)c1nc(-c2ccccc2Cl)oc1C(F)(F)F

Procedure:
With a procedure similar to example 16 above, 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C20H16ClF3N4O3 (m/e) 452, obsd 453 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[C:13](=[O:16])([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:16][CH3:13])=[CH:7][CH:6]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccccc2OC)cc1
Temperature: 100 °C
Yield: 179.7 %

Procedure:
A mixture of 4-bromo benzoic acid ethyl ester (2.7 mL, 16.5 mmol), 2-methoxy boronic acid (2.5 g, 16.5 mmol) and sodium carbonate (7.7 g, 72.6 mmol) in toluene: ethanol:water (75 mL:37 mL:37 mL), was flushed with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine)palladium(0) catalyst (0.96 g, 0.83 mmol), the reaction mixture was heated at 100° C. overnight. After cooling, the mixture was filtered through Celite which was then rinsed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification of the residue by flash chromatography with a solvent gradient from 25% to 50% dichloromethane in hexane provided the title compound (3.8 g, 89.9%) as a pale yellow oil.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](Cl)(=[O:14])[CH2:12][CH3:13].O.O.CN(C=O)C>CN(C=O)C>[C:11]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])(=[O:14])[CH2:12][CH3:13]
Reactant: Nc1ccccc1C(=O)O
Reactant: CCC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)Nc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.2 %

Procedure:
To a room temperature solution of 50.22 g anthranilic acid (I) (370 mmol, 1.00 equiv) dissolved in 200 mL dry DMF was added 35.0 mL propionyl chloride (400 mmol, 1.10 equiv) dropwise by addition funnel over 1.5 h. The addition rate was slow enough to maintain internal temperature of the reaction below 38° C. Upon completed addition of the acid chloride, the heterogeneous reaction mixture was stirred for 2.5 h at ambient temperature and then poured into 1600 mL water. The resulting water/DMF mixture, with white precipitate, was stirred vigorously at ambient temperature for one h, after which time the solid was collected by vacuum filtration, rinsing the solid with cold water (2×100 mL). The product was dried in vacuo over phosphorous pentoxide overnight affording 48.04 g of a white solid. m.p. 120.1° C. 1H NMR (CDCl3) δ 1.30 (t, 3H, J=7.4 Hz), 2.52 (q, 2H, J=7.4 Hz), 7.12 (t, 1H, J=7.2 Hz), 7.60 (t, 1H, J=7.1 Hz), 8.13 (d, 1H, J=6.3 Hz), 8.76 (d, 1H, J=7.8 Hz) ppm. MS (ESI−) 192.1 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([CH3:28])[CH:20]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH2:14][N:13]([C:23]([C:22]4[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[CH:20][C:21]=4[CH3:28])=[O:24])[CH2:12][CH:11]3[CH2:10]2)[N:3]=1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Reactant: COc1ccc(C(=O)O)c(C)c1
Product: COc1ccc(C(=O)N2CC3CN(c4nc(C)cc(C)n4)CC3C2)c(C)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 23 and 4-methoxy-2-methylbenzoic acid. MS (ESI): mass calculated for C21H26N4O2, 366.21; m/z found 367.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.11 (d, J=7.9, 1H), 6.77-6.67 (m, 2H), 6.29 (s, 1H), 4.01-3.83 (m, 2H), 3.83-3.72 (m, 4H), 3.72-3.55 (m, 2H), 3.46 (dt, J=11.9, 6.0, 2H), 3.21-2.89 (m, 3H), 2.37-2.25 (m, 9H).
Reaction SMILES: [CH:1]1([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]#[N:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.C(N(S(F)(F)[F:28])CC)C.C([O-])(O)=O.[Na+]>>[CH:1]1([CH:6]([F:28])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]#[N:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1(c2ccc(C(O)C3CCCC3)cc2)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CC1(c2ccc(C(F)C3CCCC3)cc2)CC1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
1-{4-[Cyclopentyl(hydroxy)methyl]phenyl}cyclopropanecarbonitrile (600.0 mg, 0.002486 mol) was dissolved in methylene chloride (10 mL, 0.2 mol), cooled to −78° C., and to the solution was added diethylaminosulfur trifluoride (0.328 mL, 0.00249 mol) (DAST). The resulting reaction mixture was warmed to rt and stirred at rt for 18 h. The reaction mixture then was poured into ice-water containing NaHCO3 and the resulting mixture was extracted with CH2Cl2 (3×). The combined organic phase was dried over Na2SO4, and concentrated to afford the product.
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([N:28]([CH3:37])[C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].C1C=C(C([O-])=[O:46])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO>[F:38][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([N:28]([CH3:37])[C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:17]=[CH:18][N+:19]([O-:46])=[CH:20][CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: COc1ccc(N(C)c2ccc(C(Cc3ccncc3)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(N(C)c2ccc(C(Cc3cc[n+]([O-])cc3)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.2 %

Procedure:
To a solution of 4-[2-[3,4-bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-4-methoxyphenylamino)3-pyridyl]ethyl}pyridine from Example 112 (60 mg, 0.11 mmol) in a mixture of 3.0 mL of CH2Cl2 and 0.3 mL MeOH, was added 84 mg (0.136 mmol) of 80% MMPP. Reaction was stirred for 24 h at room temperature, quenched with a saturated solution of NaHCO3 and diluted with ethyl acetate. The organic layer was then washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Gradient 40% to 50% EtOH/ethyl acetate) to afford 27 mg (45%) of the title compound
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][C:40](O)=[O:41]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[C:40](=[O:41])[CH2:39][O:38][CH2:37][CH2:36][O:35][CH3:34])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Reactant: COCCOCC(=O)O
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)COCCOC)cc2)cc1

Procedure:
The titled compound was prepared following the procedure H using methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]phenoxy}acetate and (2-methoxyethoxy)acetic acid as a yellow oil (96%). HPLC, Rt: 5.17 min (Purity: 94.8%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:14]=[CH:13][C:11]([OH:12])=[CH:10][C:9]=1[OH:15].[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>CC(C)=O>[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:16]([O:12][C:11]2[CH:13]=[CH:14][C:8]([Br:7])=[C:9]([OH:15])[CH:10]=2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)Oc2ccc(Br)c(O)c2)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
K2CO3 (3 eq) was added to a stirred mixture of 4-bromoresorcinol (0.35 M) and TsCl (1.2 eq) in acetone and the mixture stirred at 50° C. for 18 h. Volatiles were removed in vacuo and the residue partitioned between 6 N HCl (aq) and EtOAc. The combined organic fractions were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound. The product was used in the next step without further purification. (ES+) m/z 343, 345 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH:3]=[CH:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1CCc2cc(C=CCCl)ccc2N1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(C=CCN3CCN(Cc4ccccc4)CC3)ccc2N1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
2.3 Grams of 6-(3-chloro-1-propenyl)-3,4-dihydrocarbostyril, 2.0 g of 4-benzylpiperazine and 2.0 ml of triethylamine were mixed in 50 ml of dimethylformamide and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was poured into a mixture of 50 ml of a saturated sodium chloride aqueous solution with 50 ml of 5% of sodium hydrogencarbonate aqueous solution, and the organic layer was extracted with chloroform. The chloroform layer was washed with water and dried, then chloroform was removed by distillation to obtain a residue. The residue was recrystallized from ethanol-water to obtain 2.1 g of 6-[3-(4-benzylpiperazinyl)-1-propenyl]-3,4-dihydrocarbostyril, having the melting point of 151°-153° C. in colorless needle-like crystals. Then 2.1 g of 6-[3-(4-benzylpiperazinyl)-1-propenyl]-3,4-dihydrocarboxtyril, 0.2 g of platinum black and 2 ml of concentrated hydrochloric acid were mixed with 100 ml of ethanol and the mixture was subjected to catalytic reduction under 3 kg/cm2 of hydrogen gas at a room temperature for 5 hours. The reaction mixture was filtered and the mother liquor was concentrated to obtain a residue. The residue was recrystallized from methanol to obtain 1.8 g of 6-(3-piperzinopropyl)-3,4-dihydrocarbostyril dihydrochloride in colorless needle-like crystals. Melting point: 275° -278° C. (decomposed).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(O)=O.C([NH2:16])=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:16])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: NC=O
Solvent: O
Solvent: O=CO
Product: CC(N)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
1-(3-Chlorophenyl)ethanone (11.9 g, 77.5 mmol) and formic acid (3.72 g, 77.5 mmol) were heated in formamide (10 mL) at 170-180° C. for 20 h. The mixture was cooled to room temperature, diluted with water and extracted with benzene. After removal of benzene by rotary evaporation the crude mixture was heated under reflux conditions in 3M HCl for 30 h. After cooling, the reaction was added to ether and extracted. The aqueous layer was basified with NaOH to pH 9 and extracted with dichloromethane. The dichloromethane was evaporated to collect the title compound (3.93 g, 33%). 1H NMR (400 MHz, CDCl3): δ 7.34 (s, 1H), 7.21 (m, 3H), 4.07 (m, 1H), 1.35 (d, 3H); MS (ESI) m/z: Calculated for C8H11ClN: 156.06; Observed: 156.0 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([SH:11])[CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([SH:11])[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1S
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)cc1S
Yield: 70 %

Procedure:
A mixture of 4-fluoro-2-sulfanylbenzoic acid (6.0 g, 34.9 mmol), concentrated sulfuric acid (6 mL) in methanol (200 mL) was refluxed for 18 hours under argon atmosphere. The resulting mixture was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water, basified with a saturated aqueous solution of sodium bicarbonate to about pH 8. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 4.54 g of the crude product as a brown oil (yield was 70%), which was used directly for the next step without further purification. MS obsd. (ESI−) [(M−H)−] 185.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][CH:30]([F:41])[O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[N:36][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:34]1[CH:35]=[N:36][CH:37]=[C:32]([O:31][CH:30]([F:41])[F:29])[CH:33]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1cncc(OC(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cncc(OC(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.17 mmol) were added 48 mg (0.26 mmol) of (5-(difluoromethoxy)pyridin-3-yl)boronic acid, 13 mg (0.02 mmol) of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex and 170 μl of a 2M aqueous solution of cesium carbonate in dioxane. The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography (0% to 100% hexane/AcOEt, 0-8% AcOEt/MeOH) to give 70 mg (81% yield) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:29]=[CH:28][C:11]3[N:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:13]([C:15]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=4[C:17]#[N:18])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.[NH2:30][OH:31]>CCO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:29]=[CH:28][C:11]3[N:12]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:13]([C:15]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=4[C:17]([NH:30][OH:31])=[NH:18])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)n1c(-c2cc(F)ccc2C#N)nc2cc(-c3cnc(N)nc3)ccc21
Reactant: NO
Solvent: CCO
Product: CC(C)(C)n1c(-c2cc(F)ccc2C(=N)NO)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 75 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a suspension of 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-4-fluoro-benzonitrile (500 mg, 1.29 mmol) in EtOH (8 mL) is added hydroxylamine 50% aqueous solution (1.71 mL, 25.88 mmol) at room temperature. The solution is stirred at 75° C. for 18 hours. The reaction mixture is cooled to room temperature and the ethanol removed in vacuo. Water (30 mL) is added to the reaction mixture and the resultant precipitate is filtered and washed with 10% EtOAc/heptane (10 mL) to afford 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-4-fluoro-N-hydroxy-benzamidine (485 mg, 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][CH2:45][NH2:46]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:46][CH2:45][CH2:44][CH:40]3[CH2:41][CH2:42][CH2:43][N:39]3[CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CN1CCCC1CCN
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CN1CCCC1CCNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-(1-methyl-pyrrolidin-2-yl)ethylamine according to conditions described in general procedure C. Mp: 112-114° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.30-1.61 (m, 10 H), 1.37-2.10 (m, 5 H), 2.84 (bs, 2 H), 3.11-3.36 (m, 7 H), 6.15-6.30 (m, 1 H), 6.96 (d, J=12.4 Hz, 1 H), 7.08-7.20 (m, 2 H), 7.37 (d, J=8.0 Hz, 1 H), 7.43 (s, 1 H), 7.52-7.59 (m, 3H), 7.79 (d, J =8.4 Hz, 1 H), 7.96 (d, J=7.7 Hz, 1 H), 8.21 (s, 1 H), 10.40 (s, 1 H).