Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[NH2:19]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[S:3][C:4]3[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(Nc2nc3ccc([N+](=O)[O-])cc3s2)cc1OC

Procedure:
The title compound was synthesised from 2-Chloro-6-nitro-benzothiazole (commercially available) and 3,4-dimethoxyaniline (commercially available) according to the procedure described for Example 1a) above. MS (m/e): 332.2 (MH+, 100%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:28]=[CH:27][C:11]2[NH:12][C:13]([CH:15]3[CH2:18][N:17]([C:19]4[C:24]([Cl:25])=[CH:23][N:22]=[C:21](Cl)[N:20]=4)[CH2:16]3)=[N:14][C:10]=2[CH:9]=1.ClCCl.O>O1CCOCC1>[Cl:25][C:24]1[C:19]([N:17]2[CH2:18][CH:15]([C:13]3[NH:12][C:11]4[CH:27]=[CH:28][C:8]([Cl:7])=[CH:9][C:10]=4[N:14]=3)[CH2:16]2)=[N:20][C:21]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:22][CH:23]=1
Reactant: Clc1ccc2[nH]c(C3CN(c4nc(Cl)ncc4Cl)C3)nc2c1
Reactant: C1COCCN1
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Clc1ccc2[nH]c(C3CN(c4nc(N5CCOCC5)ncc4Cl)C3)nc2c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 72.2 %

Procedure:
A mixture of morpholine (0.062 mL, 0.711 mmol) and 5-chloro-2-(1-(2,5-dichloropyrimidin-4-yl)azetidin-3-yl)-1H-benzo[d]imidazole (0.063 g, 0.18 mmol) in dioxane (1 mL) was heated to 60° C. under argon and stirred for 6 h. The mixture was cooled to RT, dichloromethane and water were added, and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil that was purified by silica gel chromatography to give 4-(5-Chloro-4-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-2-yl)morpholine (0.052 g, 0.13 mmol, 72%) as a white solid. [M+1] 405. IC50 (uM) 0.1554.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([C:10]2[N:14]=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[NH:12][N:11]=2)=[N:8][CH:7]=[CH:6][N:5]=1.[N:20]#[C:21]Br>CN(C)C=O>[NH2:20][C:21]1[N:11]2[N:12]=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:10]2[C:9]2[N:8]=[CH:7][CH:6]=[N:5][C:4]=2[N:3]=1
Reactant: N#CBr
Reactant: Nc1nccnc1-c1n[nH]c(-c2ccco2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc2nccnc2c2nc(-c3ccco3)nn12

Procedure:
To a suspension of 50% sodium hydride in oil (300 mg) in dry dmethylformamide (16 ml) is added 3-(2-aminopyrazin-3-yl)-5-(2-furyl)-1,2,4-triazole (1.37 g) and the whole stirred under nitrogen at 60° until a solution forms. To this is added cyanogen bromide (700 mg) in dimethylformamide (9 ml) and the whole stirred under nitrogen over 66 hours at 60°. It is cooled to 0° and the solid collected, washed with dimethylformamide, then water, then ethanol and finally ether and air dried. It is recrystallized from dimethylacetamide (70 ml) to which methanol (50 ml) is added to form pure 5-amino-(2-furyl)-pyrazino[2,3-e][1,2,4]-triazolo[1,5-c]pyrimidine, melting in the range 347°-351°.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH2:19]([C:21]1[N:22]([CH2:34][C:35]#[CH:36])[C:23]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[CH:25][C:24]=2[N:33]=1)[CH3:20]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:19]([C:21]1[N:22]([CH2:34][C:35]#[C:36][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)[C:23]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[CH:25][C:24]=2[N:33]=1)[CH3:20]
Reactant: C#CCn1c(CC)nc2cnc3ccccc3c21
Reactant: FC(F)(F)c1cccc(I)c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCc1nc2cnc3ccccc3c2n1CC#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (66 mg, 0.03 eq.), 3-iodobenzotrifluoride (336 μL, 1.1 eq.), triethylamine (889 μL, 3.0 eq.), and copper (I) iodide (24.3 mg, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinoline (500 mg, 2.13 mmol, 1.0 eq.) in DMF (10.6 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 2/98 methanol/chloroform) to provide 0.73 g of 2-ethyl-1-[3-(3-trifluoromethylphenyl)-2-propynyl]-1H-imidazo[4,5-c]quinoline as a light tan solid.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:27][CH2:28][NH2:29]>C(Cl)Cl>[C:1]1([O:7][C:8](=[O:9])[NH:29][CH2:28][CH2:27][C:21]2[C:20]3[C:24](=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=3)[NH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCc1c[nH]c2ccc(F)cc12)Oc1ccccc1
Reaction time: 24 h

Procedure:
Chloroformic acid phenyl ester (310 μl, 2.45 mmole) and pyridine (415 μl, 5.13 mmole) were added to a solution of 2-(5-fluoro-1H-indol-3-yl)-ethylamine (0.5 g, 2.33 mmole) in abs. DCM (10 ml). Stirring was then performed for 24 h at RT. Working up was performed by extracting the batch with water (2×20 ml), with 1M HCl (2×20 ml) and with 1M NaOH (2×20 ml). The organic phase was dried with Na2SO4 and evaporated. [2-(5-Fluoro-1H-indol-3-yl)-ethyl]-carbamic acid phenyl ester was obtained as a colorless solid in a yield of 0.69 g (100%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]=[N+]=[N-])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCCCN1CCC(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: NCCCN1CCC(Cc2ccccc2)CC1
Reaction time: 4 h
Yield: 59.8 %

Procedure:
To a solution of 4-benzyl-1-(3-azidopropyl)piperidine (0.14 g, 0.54 mmol) in methanol (5 mL) was added Pd/C 5% (6 mg) and the resulting heterogeneous mixture was hydrogenated at 1 atm for 4 h. then filtered through a celite pad and concentrated in vacuum. The crude compound was purified by trituration with diethyl ether (5 mL) to give the title compound as a white solid (0.075g, 60%), mp 140-141° C. 1H-NMR (DMSO): 1.05-1.21 (m, 2H), 1.35-1.55 (m, 3H), 1.55-1.70 (m, 2H), 1.746 (t, J=11.1 Hz, 2H), 2.281 (t, J=6.6 Hz, 2H), 2.4-2.5 (m, 2H), 2.5-2.85 (m, 4H), 7.06-7.18 (m, 3H), 7.23 (t, J=7.2 Hz, 2H), 7.8 (bs, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:38])[NH:28][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)([CH3:31])[CH3:30])[CH:22]=4)=[C:17]([N+:39]([O-])=O)[C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1>C(O)C.CC(O)=O.CCOC(C)=O.[Fe]>[NH2:39][C:17]1[C:11]2[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[O:9][C:10]=2[CH:20]=[CH:19][C:18]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:38])[NH:28][C:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([CH3:31])[CH3:30])[CH:22]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)c([N+](=O)[O-])c12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)c(N)c12
Reaction time: 1 h
Yield: 59 %

Procedure:
Iron (25 mg, 0.453 mmol) was added to a stirring solution of 2-(4-fluorophenyl)-N-methyl-4-nitro-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide (50 mg, 0.091 mmol) in ethanol (1 mL) and AcOH (1 mL) at rt. It was placed in a reaction block set to 100° C. It was allowed to stir for 1 hr. The mixture was allowed to cool and was diluted with EtOAc and washed with 1M HCl, followed by 1N NaOH and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and triturated with Et2O to give the titled compound (28 mg, 56%). 1H NMR (300 MHz, CD3OD) δ ppm 7.83-7.89 (1H, m), 7.73-7.81 (3H, m), 7.52-7.64 (2H, m), 7.42-7.49 (2H, m), 7.10-7.35 (6H, m), 6.98 (1H, d, J=8.42 Hz), 2.87 (3H, s), 1.76 (6H, s). LC-MS retention time: 2.33 min; m/z (MH+): 522. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=14.17 min, purity=97%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=12.84 min, purity=98%.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:35]=[CH:34][C:19]([CH2:20][C:21]2[CH:25]=[C:24]([C:26]3[C:27]([NH2:33])=[N:28][CH:29]=[C:30]([F:32])[CH:31]=3)[O:23][N:22]=2)=[CH:18][CH:17]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>>[NH2:33][C:27]1[C:26]([C:24]2[O:23][N:22]=[C:21]([CH2:20][C:19]3[CH:34]=[CH:35][C:16]([OH:15])=[CH:17][CH:18]=3)[CH:25]=2)=[CH:31][C:30]([F:32])=[CH:29][N:28]=1
Reactant: Nc1ncc(F)cc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(F)cc1-c1cc(Cc2ccc(O)cc2)no1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
To a trifluoroacetic acid (5 mL) solution of 3-(3-(4-benzyloxy-benzyl)-isoxazol-5-yl)-5-fluoro-pyridin-2-ylamine (180 mg, 0.48 mmol) described in Example 173 was added thioanisole (225 μL, 1.92 mmol), which was stirred for 6 hours at room temperature. A saturated sodium hydrogencarbonate aqueous solution was added to this reaction solution at 0° C., which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2˜ethyl acetate) to obtain the title compound (134.0 mg, 98%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([F:46])([F:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:34]([C:47]([F:50])([F:49])[F:48])[CH:33]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CC(=O)OCC>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][C:39]([F:45])([F:46])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:34]([C:47]([F:48])([F:49])[F:50])[CH:33]=3)=[O:28])=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[CH3:2]
Reactant: CCOC(=O)C(F)(F)Cc1ccc(N)cc1C(F)(F)F
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)Cc1ccc(NC(=O)Cc2ccc(-c3cnc(OCc4ccc(OC)cc4)c(OCC)c3)cc2F)cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
To a mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (150 mg, 0.365 mmol) in pyridine (2 mL) were added ethyl 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-difluoropropanoate (108 mg, 0.365 mmol) and T3P® (EA solvate) (464 mg, 0.729 mmol). The mixture was stirred at 20° C. for 1 h. LCMS and TLC (PE/EA=1:1, Rf=0.5) showed the reaction was finished. The mixture was concentrated and then purified by TLC (PE/EA=1:1, Rf=0.5) to give ethyl 3-(4-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-difluoropropanoate (120 mg, 0.150 mmol, 41.2% yield): 1H NMR (400 MHz, CD3OD-d4) δ 8.08-8.02 (m, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.78 (s, 1H), 7.54-7.33 (m, 7H), 6.90 (d, J=8.8 Hz, 2H), 5.35 (s, 2H), 4.26 (q, J=7.3 Hz, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.81 (s, 2H), 3.78 (s, 3H), 3.63-3.52 (m, 2H), 1.41 (t, J=7.1 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H); ES-LCMS m/z 691 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
A solution of (4-nitro-phenyl)-acetic acid ethyl ester (Preparation 266, 3.4 g, 16.1 mmol) in methanol (100 mL) was degassed with argon for 15 min, treated with 10% palladium on charcoal (700 mg), and then stirred at room temperature under hydrogen (balloon pressure) for 16 hours. The reaction mixture was filtered through celite, washed with methanol (2×20 mL) and the filtrate was evaporated in vacuo to afford the title compound as an oil in 96% yield, 2.8 g.
Reaction SMILES: [CH:1]([C@:4]1([C:16]([N:18]2[CH2:23][CH:22]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:5]1)([CH3:3])[CH3:2]>CO.[Pd]>[CH:1]([C@:4]1([C:16]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)=[O:17])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3)CC2)CC[C@@H](NC2CCOCC2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@]1(C(=O)N2CCC(c3ccccc3)CC2)CC[C@@H](NC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 91.2 %

Procedure:
To a solution of N-{(1R,3S)-3-isopropyl-3-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclopentyl}tetrahydro-2H-pyran-4-amine (22 mg, 0.055 mmol) in methanol (2.0 mL) under N2 was added palladium (10 mg) (10% dry weight on wet activated carbon). The reaction mixture was stirred at room temperature under H2 (1 atm) overnight (22 h) and filtered through celite. The celite was washed with methylene chloride and the filtrate was concentrated to give 20 mg of desired product after lyophilization. MS calculated for C25H38N2O2: (M+H) 399; found 399.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>C(O)C>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:15]=[C:16]([CH2:20][NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Clc1ncnc2ccccc12
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: FC(F)(F)c1cccc(CNc2ncnc3ccccc23)c1

Procedure:
A mixture of 1.65 g of 4-chloroquinazoline, 1.5 g of [3-(trifluoromethyl)phenyl]methyl amine, and 1.0 g of triethylamine in 50 ml of ethanol was refluxed for 6 hours. The mixture was then cooled, and washed with water. After removing solvents in vacuo the product was crystallized from a mixture of ethyl acetate and hexane. Yield: 1.0 g. M.P. 145°-146° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[O:31]=[C:32]1[NH:37][CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:37]5[CH2:36][CH2:35][NH:34][CH2:33][C:32]5=[O:31])[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cc(-c3cccnc3)ncc21
Product: O=C1CNCCN1c1cccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)n1
Yield: 20 %

Procedure:
Following the procedure of Example 224, 3-(6-bromopyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl 3-oxopiperazine-1-carboxylate were reacted. The product was deprotected by the procedure of Example 225 and purified via reverse phase HPLC using a gradient of MeOH in water with 0.1% NH4OH to afford 8.0 mg (20%) of 301 over two steps. ESI MS m/z 372.1 (M+1). 1H NMR (400 MHz, DMSO); 14.08 (s, 1H), 9.29 (d, J=2.0 Hz, 1H), 9.25 (s, 1H), 8.94 (s, 1H), 8.61 (dd, J=4.7, 1.3 Hz, 1H), 8.47-8.40 (m, 1H), 8.07-7.92 (m, 3H), 7.56 (dd, J=7.9, 4.8 Hz, 1H), 6.48 (s, 1H), 4.22 (t, J=5.4 Hz, 2H), 3.56 (s, 2H), 3.18 (t, J=5.4 Hz, 2H). m/z 372.1 (M+1)
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[CH3:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: COCc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCc1ccccc1-c1ccc(C(=O)O)cc1
Temperature: 90 °C
Yield: 58.5 %

Procedure:
To a suspension of 4-iodobenzoic acid (0.82 g, 3.31 mmol) and 2-methoxymethylphenylboronic acid (0.55 g, 3.31 mmol) in dry acetonitrile (30 mL) was added a 0.4 M aqueous sodium carbonate solution (30 mL) and the reaction mixture purged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.078 mmol) was then added and the reaction mixture heated to 90° C. for 19 hours. The hot reaction mixture was filtered through celite, concentrated in vacuo to remove acetonitrile and the resulting aqueous suspension washed with ethyl acetate (2×30 mL). The aqueous phase was acidified to pH 1 by the addition of concentrated hydrochloric acid, the resulting white suspension cooled to 4° C. for 1 hour and the solid product filtered. Recrystallization from dichloroethane gave the title compound (0.469 g, 59%) as a white solid, m.p. 164.5-165.5° C.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:38])/[C:13](=[N:27]\[O:28][C@H:29]([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])/[C:14]3[N:15]=[C:16]([NH:19]C(OC(C)(C)C)=O)[S:17][CH:18]=3)[C:9](=[O:39])[N:8]2[S:40]([OH:43])(=[O:42])=[O:41])[CH:5]=[N:4][CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:38])/[C:13](=[N:27]\[O:28][C@H:29]([CH3:37])[C:30]([OH:32])=[O:31])/[C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)[C:9](=[O:39])[N:8]2[S:40]([OH:43])(=[O:41])=[O:42])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[C@@H](O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cncn1)c1csc(NC(=O)OC(C)(C)C)n1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cncn1)c1csc(N)n1)C(=O)O
Yield: 33.2 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-3-((Z)-2-((((R)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (141 mg, 0.219 mmol), DCM (2.19 mL) and TFA (1.0 mL, 13 mmol). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (35.5 mg, 29%) as a white powder. LCMS: Rt=0.42 min, m/z=489.0 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, D2O) δ 8.58 (s, 1H), 8.06 (s, 1H), 7.06 (s, 1H), 5.41 (d, J=5.6 Hz, 1H), 4.81-4.52 (m, 4H assumed; partly obscured by solvent peak), 1.29 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[C:23]([CH3:29])[N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][N:8]=2)[C:5](=[O:30])[NH:4][C:3]1=[O:31].[CH3:32]C(C)([O-])C.[K+].CI.O>O1CCCC1>[CH3:32][N:4]1[C:3](=[O:31])[CH:2]([CH3:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[C:23]([CH3:29])[N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][N:8]=2)[C:5]1=[O:30]
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)nc3)CC2)nc1C
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C)nc3)CC2)nc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.7 %

Procedure:
5-Methyl-1-{5-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}imidazolidine-2,4-dione (60 mg) described in Example 549 was dissolved in tetrahydrofuran, potassium tert-butoxide (17 mg) and methyl iodide (9.3 μL) were added under ice-cooling, and the mixture was stirred at the same temperature for 15 min and at room temperature for 24 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (50 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10]>>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:9](=[O:10])[O:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccncc1
Product: O=C(Nc1ccncc1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Prepared as Example 27d from pyridin-4-amine and p-nitrophenyl chloroformate to provide the compound as an off white solid. MS=260 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:3]=1.C1N2CC[N:20](CC2)[CH2:19]1.C(#N)C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:19]#[N:20])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:3]=1
Reactant: C1CN2CCN1CC2
Reactant: Nc1nc(Cl)nc(Nc2cccc(F)c2F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1nc(N)nc(Nc2cccc(F)c2F)n1
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To 2-amino-4-chloro-6-(2,3-difluorophenylamino)-[1,3,5]triazine (Intermediate 55, 1.0 g, 3.89 mmol) was added DABCO (540 mg, 4.67 mmol), tetra n-butylammonium cyanide (1.15 g, 4.28 mmol) and anhydrous acetonitrile (15 mL). The reaction mixture was stirred at 50 C for 1 h, diluted with 50 mL ethyl acetate, extracted with 1M aq. citric acid (2×50 mL), water (2×50 mL), saturated brine (50 mL) and dried further over anhydrous sodium sulfate. Evaporation of the solvent gave a red gum which was purified by column chromatography on silica eluting with DCM-2% ethyl acetate to give the desired compound (429 mg, 69%). Method B HPLC-MS: MH+ requires m/z=249. Found: m/z=249, Rt=1.64 min (91%).