Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@H]1CC2C(=CC=CC=2)[C@H]1NC1C(CC)=NC(C2C=CC(Cl)=CC=2Cl)=C(CC)N=1)(=[O:3])C.[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[C:41]1[C:42]([C:62]([O:64][CH3:65])=[O:63])=[N:43][C:44]([NH:49][C@@H:50]2[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[CH2:52][C@@H:51]2[O:59][CH2:60][CH3:61])=[C:45]([O:47][CH3:48])[N:46]=1>>[C:60]([O:59][C@H:51]1[CH2:52][C:53]2[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@H:50]1[NH:49][C:44]1[N:43]=[C:42]([C:62]([O:64][CH3:65])=[O:63])[C:41]([C:35]2[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:34]=2[Cl:33])=[N:46][C:45]=1[O:47][CH3:48])(=[O:3])[CH3:61]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C(=O)OC)c(-c2ccc(Cl)cc2Cl)nc1OC
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OC(C)=O
Product: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2OC(C)=O)c(OC)nc1-c1ccc(Cl)cc1Cl

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl acetate but substituting methyl 3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxylate and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 2.03, 3.10-3.143.31-3.36, 3.75, 4.05, 5.68-5.77, 6.07-6.11, 7.31-7.48; MS (ESI+) for C24H21Cl2N3O5 m/z 502 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]1[N:12]=[C:11]([SH:13])[C:10]2[C:5](=[CH:6][C:7]([CH3:14])=[CH:8][CH:9]=2)[N:4]=1.[OH-].[Na+].I[CH3:26]>C(O)(C)C>[F:22][C:2]([F:1])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]1[N:12]=[C:11]([S:13][CH3:26])[C:10]2[C:5](=[CH:6][C:7]([CH3:14])=[CH:8][CH:9]=2)[N:4]=1
Reactant: CI
Reactant: Cc1ccc2c(S)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(C)ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.4 %

Procedure:
To a solution of 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methylquinazoline-4-thiol (243 mg, ˜0.75 mmol) in isopropanol (5 mL) was added 1N NaOH (1.13 mL, 1.13 mmol), and the mixture was stirred at rt for 5 min. Iodomethane (0.06 mL, 0.90 mmol) was then added and the mixture was stirred at room temperature for 5 min. The mixture was concentrated under reduced pressure to afford a yellow solid that was collected and washed with water and methanol to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methyl-4-(methylthio)quinazoline as a light yellow solid (152 mg, 60%). (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 8.57-8.66 (m, 1H), 7.93-8.12 (m, 3H), 7.85 (s, 1H), 7.62-7.71 (m, 1H), 2.56 (s, 3H), 2.53 (s, 3H). LCMS (ESI) m/z 336 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([Cl:18])[C:13]([CH3:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:26])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([Cl:18])[C:13]([CH2:17][Br:26])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(ccn2C(=O)OC(C)(C)C)c1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CBr)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
To a stirred solution of 314 (38.1 g, 0.143 mol) in CCl4 (300 mL) at 80° C. was added NBS (30.6 g, 0.172 mol) followed by AIBN (1.2 g, 7.31 mmol), and the reaction mixture was stirred at 80° C. overnight. The cooled reaction mixture was diluted with EtOAc, and the organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (2 to 20% EtOAc) to afford 16.1 g (33%) of tert-butyl-5-(bromomethyl)-4-chloro-1H-indole-1-carboxylate (316) as a white solid: NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 6.71 (d, J=3.8 Hz, 1H), 4.75 (s, 2H), 1.67 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[NH2:26][C@H:27]1[CH2:32][CH2:31][CH2:30][C@H:29]([OH:33])[CH2:28]1.O>CN(C=O)C>[C:11]1([C:9]2[O:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:26][C@@H:27]4[CH2:32][CH2:31][CH2:30][C@H:29]([OH:33])[CH2:28]4)[C:3]=3[CH:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@H]1CCC[C@H](O)C1
Reactant: Clc1ncnc2oc(-c3ccccc3)cc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@H]1CCC[C@@H](Nc2ncnc3oc(-c4ccccc4)cc23)C1
Temperature: 120 °C

Procedure:
Heat a mixture of 4.0 g (17.34 mmol) of 4-chloro-6-phenylfuro[2,3-d]pyrimidine, 4.5 ml (26 mmol) of DIEA and 2.8 g of (+/−)-cis/trans-3-aminocyclohexanol (approx. 85% strength, approx. 20.8 mmol; approx. 3:1 cis/trans mixture; prepared according to J. Chem. Soc. Perkin Trans. I, 1994, 537) in 15 ml of DMF is heated to 120° C. overnight. After cooling, add the reaction mixture to water and extract three times with ethyl acetate. Wash the combined organic phases with saturated sodium chloride solution, dry over magnesium sulphate and concentrate under reduced pressure. Repeated stirring of the crude product with a mixture of methyl tert-butyl ether and dichloromethane enriches the product in the mother liquor. After concentrating the mother liquor, filter off the product with suction after crystallization from dichloromethane/methanol (10:1) and dry it under reduced pressure. 1.11 g (20.7% of theory) of the target product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([CH2:16][OH:17])[N:13]=[C:12]([CH3:18])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:21][CH3:22].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([CH:16]=[O:17])[N:13]=[C:12]([CH3:18])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: COc1cc(CNC(=O)c2cc(CO)nc(C)n2)ccc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(CNC(=O)c2cc(C=O)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a cold solution of N-(4-fluoro-3-methoxybenzyl)-6-(hydroxymethyl)-2-methylpyrimidine-4-carboxamide (7.23 g, 23.71 mmol, Preparation #7) in DCM (150 mL) was added Dess-Martin periodinane (16.10 g, 37.93 mmol, Spectrochem) portion wise over about 45 min at about 0° C. The resulting suspension was allowed to warm to RT and stirred for about another 2 h. The reaction mixture was re-cooled to about 0° C. and quenched with sodiumthiosulphate solution (150 mL) and stirred vigorously for about 30 min. The organic layer was separated, washed successively with saturated sodiumbicarbonate (1×100 mL), water (1×150 mL) and brine (1×150 mL), dried over sodium sulphate and concentrated under reduced pressure to afford N-(4-fluoro-3-methoxybenzyl)-6-formyl-2-methylpyrimidine-4-carboxamide 6.75 g (crude 94%), 1H NMR (400 MHz, DMSO): δ 9.99 (s, 1H), 9.586-9.556 (t, J=6.4 Hz, 1H), 8.09 (s, 1H), 7.18-7.11 (m, 2H), 6.90-6.87 (m, 1H), 4.495-4.479 (d, J=6.4 Hz, 2H), 3.81 (s, 3H), 2.84 (s, 3H), MS m/z: 304.2 (M+H)+.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].[Na].[O-2].[Ba+2].[H-].[Na+].CN(C)[CH:17]=[O:18]>[Ag]=O.O1CCCC1.CS(C)=O.CCOCC.C(N(CC)CC)C>[C:1]1([O:18][CH2:17][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: Oc1ccccc1
Agent: O=[Ag]
Agent: [Ba+2]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CS(C)=O
Product: c1ccc(COc2ccccc2)cc1

Procedure:
In Scheme 3, the starting phenol is reacted with a benzyl halide in the presence of a base (e.g. sodium amide, triethylamine, sodium hydroxyde, barium oxide, silver oxide, sodium hydride) in an inert solvent (e.g. ether, dimethylsulfoxide, dimethylformamide, tetrahydrofuran) to give a benzyl phenyl ether, which is an example of the derivative of the alkoxyiminocarboxylic acid (V).
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:39]([O:40][CH2:41][CH:42]([F:44])[F:43])=[CH:38][C:15]3[N:16]([CH3:37])[C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH2:27][NH:28]C(OC(C)(C)C)=O)[C:21]=4[Cl:36])=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1.Cl>C1COCC1>[F:45][C:2]([F:1])([F:46])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:39]([O:40][CH2:41][CH:42]([F:43])[F:44])=[CH:38][C:15]3[N:16]([CH3:37])[C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH2:27][NH2:28])[C:21]=4[Cl:36])=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)OC(C)(C)C)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)cc21
Agent: Cl
Solvent: C1CCOC1
Product: Cn1c(Nc2c(Cl)ccc(CN)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)cc21
Reaction time: 8 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-{2,6-dichloro-3-[(tert-butoxy-carbonylamino)-methyl]-phenylamino}-6-(2,2-difluoroethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide (350 mg, 0.504 mmol), 6 M aq. HCl-solution (15 mL) and THF (15 mL) is stirred overnight, the mixture is concentrated and directly used in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.[C:11](O)(C(F)(F)F)=[O:12].FC(F)(F)C([O-])=O.[Tl+].[Cl-].[Li+].[O-2].[Mg+2]>[Pd](Cl)Cl.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:11](=[O:12])[O:9][CH2:8][C:4]=2[C:3]=1[CH3:10]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c(Br)cccc1CO
Agent: Cl[Pd]Cl
Agent: O=C([O-])C(F)(F)F
Agent: [Cl-]
Solvent: CO
Product: Cc1c(Br)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of thallium trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To the residue was then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The solution was filtered through a Celite pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford the title compound: 1H-NMR (500 MHz, CDCl3) δ ppm 7.71 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])[NH2:22]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Product: CC(C)C[C@H](NC(=O)c1cc(OCC2CC2)c(C2CC2)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and (S)-2-Amino-4-methyl-pentanoic acid amide (CAN 687-51-4) as starting materials and isolated (10.5 mg, 20%) as colorless oil; MS (ESI, m/z): 346.6 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[F:12][C:13]([F:23])([F:22])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.C(N(C(C)C)CC)(C)C.[BH3-]C#N.[Na+].[OH-].[Na+]>ClCCl.CO.Cl[Ti](Cl)(Cl)Cl>[F:12][C:13]([F:22])([F:23])[CH:14]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(C)C)NC(c1ccccc1)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of L-leucine methyl ester hydrochloride (975 mg, 5.37 mmol) in dichloromethane (30 mL) was added 2,2,2-trifluoroacetophenone (0.75 mL, 5.34 mmol) and diisopropylethylamine (3.5 mL, 20 mmol). TiCl4 (0.55 mL, 5.0 mmol) in 0.45 mL dichloromethane was added dropwise, and the mixture was stirred overnight. Additional TiCl4 (0.4 mL, 3.6 mmol) was then added and the mixture was stirred 3 h. A solution of NaCNBH3 (1050 mg, 16.7 mmol) in MeOH (20 mL) was added and the mixture was stirred 2 h. Poured into 1N NaOH and extracted with ethyl acetate (2×). The organic phase was washed with 1N NaOH and brine, then dried over MgSO4 and evaporated. Purification by ISCO column chromatography (gradient 30% to 90% ethyl acetate/hexanes) provided methyl N-(2,2,2-trifluoro-1-phenylethyl)-L-leucinate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].CC([N-]C(C)C)C.[I:17]I>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[I:17]
Reactant: Clc1cncc(Cl)c1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1cncc(Cl)c1I
Reaction time: 1 h

Procedure:
To a stirred solution of 3,5-dichloropyridine (3.0 g, 20.4 mmol) in THF (15 mL) was added LDA (2.0 M solution in THF/heptane/ethylbenzene, 12.14 mL, 24.4 mmol) dropwise at 0° C. and the mixture was stirred at the same temperature for 1 h. A solution of iodine (2.7 g, 21.4 mmol) in THF (10 mL) added dropwise to above mixture. Upon completion of addition, the mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (4×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide compound B15-1 (3.2 g, 57%) as a yellow gum.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[CH3:18][O:19][CH2:20]/[CH:21]=[CH:22]/B1OC(C)(C)C(C)(C)O1>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.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>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](/[CH:22]=[CH:21]/[CH2:20][O:19][CH3:18])=[CH:8][C:6]=2[N:7]=1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC/C=C/c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Yield: 67.9 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (150 mg), 85 mg of (E)-2-(3-methoxy-1-propen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 14 mg of bis(triphenylphosphine)palladium(II) dichloride in 1 mL of 1M Na2CO3 aqueous solution and 1 mL of acetonitrile was heated to 100° C. in a sealed microwave reactor for 10 min. The reaction mixture was evaporated. The crude product was purified by flash chromatography eluting with 5-50% EtOAc/hexane to yield 2-chloro-6-((E)-3-methoxyprop-1-enyl)-4-morpholinothieno[3,2-d]pyrimidine (87 mg, 68%). 2-Chloro-6-((E)-3-methoxyprop-1-enyl)-4-morpholinothieno[3,2-d]pyrimidine (40 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 29.1 mg of 334. MS (Q1) 408.1 (M)+
Reaction SMILES: [CH2:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[CH2:30][CH2:29][C:26]([CH2:31][C:32]([O:34]C)=[O:33])([CH2:27][CH2:28]4)[O:25][CH2:24]5)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[N:7][N:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>>[CH2:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[CH2:28][CH2:27][C:26]([CH2:31][C:32]([OH:34])=[O:33])([CH2:29][CH2:30]4)[O:25][CH2:24]5)=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[N:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(CC(C)C)o5)cc4)cc3)(CC1)CO2
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Cc1nnc(Nc2ccc(-c3ccc(C45CCC(CC(=O)O)(CC4)OC5)cc3)cc2)o1

Procedure:
The title compound was prepared analogous to Example 4, Step 4 starting from methyl 2-(4-(4′-(5-isobutyl-1,3,4-oxadiazol-2-ylamino)biphenyl-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (56 mg, 0.12 mmol) and NaOH (0.35 ml, 0.35 mmol). After acidification with 1N HCl, the slurry was filtered and washed with water to afford the title compound as white solid after drying (52 mg, 97% yield). HR/MS (M+H)+ found 462.2399. calc. 462.2406. RT: 2.40 (Condition L). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.02-10.86 (m, 1H) 7.62 (s, 5H) 7.53-7.59 (m, 2H) 7.37 (d, J=8.59 Hz, 2H) 3.85 (s, 2H) 2.65 (d, J=7.07 Hz, 2H) 2.11-2.25 (m, 2H) 2.00-2.09 (m, 3H) 1.90-2.00 (m, 2H) 1.81 (d, J=13.39 Hz, 4H) 0.97 (d, J=6.82 Hz, 6H)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([NH2:8])=[O:7].[CH2:9](O)[CH3:10].C(N(CC)CC)C.C(Br)C>C1(C)C=CC=CC=1>[CH2:9]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([NH2:8])=[O:7])[CH3:10]
Reactant: CCO
Reactant: NC(=O)[C@@H]1CCCN1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCBr
Product: CCN1CCC[C@H]1C(N)=O

Procedure:
To a solution of (S)-2-pyrrolidine carboxamide (13.2 g, 116 mmol) in ethanol (140 ml) K2CO3 (17.6 g, 128 mmol) and triethylamine (1.2 ml, 8.6 mmol) were added. The mixture was heated to 30 C. and stirred vigorously. Then ethylbromide (10.4 ml, 138 mmol) were added during 0.5 hours. After 30 hours the mixture was diluted with toluene (50 ml) and washed with water (50 ml). The organic layer was concentrated at reduced pressure. The residue was dissolved in toluene (150 ml) and washed with a small amount of aqueous sodium hydroxide, dried with magnesium sulfate, and evaporated to dryness in vacuo. Yield 10.7 g (65%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=O)[CH:4]=[CH:5][N:6]=1.[ClH:22].Cl.[NH2:24][CH2:25][CH2:26][O:27][NH2:28].N1C=CC=CC=1.C(O)C>[OH-].[Na+].C(OCC)(=O)C>[ClH:22].[ClH:22].[NH2:24][CH2:25][CH2:26][O:27][N:28]=[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH2:9][CH2:8][CH2:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: NCCON
Reactant: Cc1nccn1CCCC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nccn1CCCC(=NOCCN)c1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 61 %

Procedure:
A mixture of 4-(2-methyl-1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-butanone (2.65 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.60 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for three hrs. The reaction mixture was diluted with 10% sodium hydroxide solution and ethyl acetate. The layers were separated. The aqueous phase was extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized from absolute ethanol/ether to give 1.4 g (37%) of product, mp 181°-184° C. (dec).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[C:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]3[CH:30]=[N:31][CH:32]=[C:28]3[C:27]([Br:33])=[CH:26][C:25]=2[CH:34]([NH2:36])[CH3:35])[CH2:20][CH2:19]1)(=[O:17])[CH3:16].Br[C:38]1[N:46]=[CH:45][N:44]=[C:43]2[C:39]=1[N:40]=[CH:41][N:42]2[CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][O:48]1.C(N(CC)C(C)C)(C)C>C(O)C>[C:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]3[CH:30]=[N:31][CH:32]=[C:28]3[C:27]([Br:33])=[CH:26][C:25]=2[CH:34]([NH:36][C:38]2[N:46]=[CH:45][N:44]=[C:43]3[C:39]=2[N:40]=[CH:41][N:42]3[CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[CH3:35])[CH2:20][CH2:19]1)(=[O:17])[CH3:16]
Reactant: CC(=O)N1CCN(c2c(C(C)N)cc(Br)c3cncn23)CC1
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(=O)N1CCN(c2c(C(C)Nc3ncnc4c3ncn4C3CCCCO3)cc(Br)c3cncn23)CC1
Yield: 57.6 %

Procedure:
A solution of 1-[5-(4-acetylpiperazin-1-yl)-8-bromoimidazo[1,5-a]pyridin-6-yl]ethanamine bis(trifluoroacetate) (67 mg, 0.11 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (48 mg, 0.17 mmol), and N,N-diisopropylethylamine (98 mL, 0.56 mmol) in ethanol (0.87 mL) was heated at 95° C. overnight. Purification via preparative HPLC on a C-18 column eluting acetonitrile: water gradient buffered with ammonia to pH 10 gave the desired product (36 mg, 56%). LCMS for C25H31BrN9O2 (M+H)+: m/z=568.2, 570.2. Found: 568.0, 570.0.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:30]1[C:31]([C:36]#[N:37])=[N:32][CH:33]=[CH:34][N:35]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:36]([C:31]1[C:30]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)=[N:35][CH:34]=[CH:33][N:32]=1)#[N:37]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: N#Cc1nccnc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2nccnc2C#N)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0506 g, 0.132 mmol) and 3-chloropyrazine-2-carbonitrile (0.0338 g, 0.242 mmol) were combined then added dry N,N-Dimethylformamide (0.910 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.80 (s, 1H), 8.50 (d, J=2.2, 1H), 8.21 (d, J=8.7, 2H), 8.15 (d, J=2.2, 1H), 7.50 (d, J=8.7, 2H), 6.30 (t, J=5.5, 1H), 4.86 (s, 2 H), 4.00 (s, 2H), 3.74 (d, J=4.3, 4H), 3.49 (d, J=4.2, 4H), 3.12 (dt, J=13.8, 7.1, 3H), 2.85 (s, 2H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+486.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:9](=[O:11])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[N+:12]([O-:14])=[O:13])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)Cc1cccc(F)c1[N+](=O)[O-]
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: O=C(Cc1cccc(F)c1[N+](=O)[O-])NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
2-(3-Fluoro-2-nitrophenyl)acetic acid (1.17 g, 5.88 mmol) was dissolved in tetrahydrofuran (50 ml). N,N′-Carbonyldiimidazole (1.06 g, 6.54 mmol) was added to the mixture in one portion. Reaction stirred at room temperature for 30 minutes. 1-Benzylpiperidin-4-amine (1.15 ml, 6.09 mmol) was added to the mixture in one portion. Reaction stirred at room temperature for 1.25 hours. Reaction was quenched with water. Material was extracted twice with diethyl ether and the aqueous phase was discarded. Material was washed once with water and once with brine and the aqueous phases were discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as amber oil in 99% yield. MS (M+H)+=372.4.