Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([OH:30])=[O:29])[CH:23]=[C:24]([CH3:26])[CH:25]=1.[Br:31]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:31][CH2:26][C:24]1[CH:23]=[C:22]([CH2:27][C:28]([OH:30])=[O:29])[CH:21]=[C:20]([F:19])[CH:25]=1
Reactant: Cc1cc(F)cc(CC(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C(O)Cc1cc(F)cc(CBr)c1

Procedure:
Benzoyl peroxide (0.05 g) was added to a mixture of 2-(3-fluoro-5-methylphenyl)acetic acid (0.518 g) and N-bromosuccinimide (0.6 g) in DCM (10 mL). The reaction was heated at reflux for 1 h. DCM (10 mL) and water (20 mL) were added and the organic phase separated. The organic layer was washed with brine (20 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was triturated with toluene and the resulting white solid removed by filtration. The mother liquors were evaporated in vacuo to give the subtitled compound as a white solid which was used in the next step without further purification. Yield 0.38 g.
Reaction SMILES: S(O[CH2:6][CH2:7][C:8]1[O:9][CH:10]=[CH:11][C:12]=1[C:13]([O:15]C)=O)(C)(=O)=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C.O>C(#N)C>[CH2:17]([N:24]1[CH2:6][CH2:7][C:8]2[O:9][CH:10]=[CH:11][C:12]=2[C:13]1=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1ccoc1CCOS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: O=C1c2ccoc2CCN1Cc1ccccc1

Procedure:
A solution of the above crude methyl 2-(2-mesyloxyethyl)furan-3-carboxylate, 0.65 g (6.1 mmol) of benzylamine and 2.33 ml (13.4 mmol) of N,N-diisopropylethylamine in 50 ml of acetonitrile was refluxed for 1 week. The reaction mixture was poured into water and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield the desired product.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]([Cl:14])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[O:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:14][C:13]1[C:4]([O:15][CH:19]([C:18]2[CH:4]=[N:5][CH:6]=[CH:16][CH:17]=2)[CH:8]([CH3:9])[CH3:7])=[N:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:12]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)C(Oc1nc2ccccc2nc1Cl)c1cccnc1
Yield: 94 %

Procedure:
According to Reference Example 7-4, by use of Compound CE (360 mg, 2.4 mmol), tetrahydrofuran (17 mL), 60% sodium hydride (in oil) (168 mg, 4.2 mmol) and 2,3-dichloroquinoxaline (418 mg, 2.1 mmol), the mixture was stirred and reacted at room temperature for 1 hour. Then, purification by silica gel column chromatography (hexane/ethyl acetate=1/0 to 2/1) was performed to give 2-chloro-3-[2-methyl-1-(pyridin-3-yl)propoxy]quinoxaline (Compound BP) (620 mg, yield: 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18]([O:23][C:24]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][N:28]=[C:29]4Cl)=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1.[Cl:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18]([O:23][C:24]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][N:28]=[C:29]4[NH:43][C:42]3[CH:44]=[CH:45][C:39]([Cl:38])=[CH:40][CH:41]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1ccc(Cn2cnc3c(-c4cccnc4Oc4c(C)ccc5c(Cl)nccc45)ncnc32)cc1
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1ccc(Cn2cnc3c(-c4cccnc4Oc4c(C)ccc5c(Nc6ccc(Cl)cc6)nccc45)ncnc32)cc1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
A mixture of 5-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-yloxy)-1-chloro-6-methylisoquinoline (0.250 g, 0.491 mmol) and 4-chloroaniline (0.0752 g, 0.589 mmol) in anhydrous 1,4 dioxane (10 mL) was vacuum purged with Ar three times, then 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.0309 g, 0.0786 mmol) and tris(dibenzylideneacetone)palladium (0) (0.0180 g, 0.0196 mmol) were added. The suspension was sonicated for 2 min, then treated dropwise with lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 0.69 mL, 0.69 mmol). The resulting brown solution was stirred in a 50° C. oil bath for 45 min. The reaction mixture was allowed to cool to RT (22° C.) and quenched with 1N aq HCl (5 mL). After stirring at RT for 10 min, the mixture was added to satd NaHCO3 (70 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with water (50 mL), satd NaCl (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 530 mg as a yellow residue. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 30% to 60% EtOAc in CH2Cl2, to provide 5-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-yloxy)-N-(4-chlorophenyl)-6-methylisoquinolin-1-amine as a clear film. MS (ESI, pos. ion) m/z: 600.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9]2[C:10]([N+:27]([O-])=O)=[C:11]([CH:24]=[CH:25][CH:26]=2)[NH:12][CH:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1.O.NN>C(O)C.[Ni]>[NH2:27][C:10]1[C:9]([NH:8][CH2:7][C:6]2[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:26][CH:25]=[CH:24][C:11]=1[NH:12][CH:13]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:14][C:15]([OH:17])=[O:16]
Reactant: COc1ccc(CNc2cccc(NC(CC(=O)O)c3ccccc3)c2[N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(CNc2cccc(NC(CC(=O)O)c3ccccc3)c2N)cc1
Temperature: 25 °C
Reaction time: 0.6 h

Procedure:
To a solution of 3-{3-[(4-methoxybenzyl)amino]-2-nitroanilino}-3-phenylpropanoic acid (176 mg, 418 μmol) in ethanol (6 mL) was added Raney-nickel (Aldrich22, 167-8, catalytic, ca. 5 mg) and hydrazine hydrate (200 μL, 4.12 mmol). The resulting suspension was stirred at room temperature for 0.6 hour. The suspension was filtered through Celite®, and the pad washed with ethanol. The combined filtrates were evaporated in vacuo, and the residue purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (19:1) to afford the title compound, 1H NMR: (CD3OD), 7.76-7.74 (m, 1H), 7.66-7.61 (m, 1H), 7.41-7.20 (m, 7H), 6.91-6.87 (m, 2H), 6.50-6.46 (m, 1H), 6.23-6.21 (m, 1H), 6.07-6.05 (m, 1H), 4.81 (br t, J=6.59, 1H), 4.27-4.24 (m, 3H), 3.80 (s, 3H), 2.90 (dd, J=15.38, 8.79, 1H), 2.76 (dd, J=15.38, 9.89, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20]([O:22]CC)=[O:21])[C:9]1=[S:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20]([OH:22])=[O:21])[C:9]1=[S:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1c(=S)n(Cc2ccccc2)c(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1c(=S)n(Cc2ccccc2)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 2-[2-(N-benzylcarbamoyl)anilino]acetate (1.5 g) and N,N'-thiocarbonyldiimidazole (2.85 g) was stirred at 120° C. for 30 minutes. After cooling, the reaction mixture was diluted with chloroform and chromatographed on silica gel. Elution with chloroform gave ethyl 2-(3-benzyl-1,2,3,4-tetrahydro-4-oxo-2-thioxoquinazolin-1-yl)acetate. A mixture of ethyl 2-(3-benzyl-1,2,3,4-tetrahydro-4-oxo-2-thioxoquinazolin-1-yl)acetate and 1N sodium hydroxide (2 ml) in methanol (10 ml) was stirred for 4 hours at room temperature. The reaction mixture was poured into dilute hydrochloric acid and extracted with chloroform. The extract was washed with brine and dried. Removal of the solvent gave 2-(3-benzyl-1,2,3,4-tetrahydro-4-oxo-2-thioxoquinazolin-1-yl)acetic acid (280 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[CH:4][C:3]=1[O:17]C.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[CH:4][C:3]=1[OH:17]
Reactant: COc1cc(-c2cccc([N+](=O)[O-])c2)ccc1N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ccc(-c2cccc([N+](=O)[O-])c2)cc1O

Procedure:
4-Amino-3-methoxy-3′-nitro-biphenyl was then stirred with boron tribromide in dichloromethane to give 4-amino-3′-nitro-biphenyl-3-ol as an orange solid: mp 175-176° C.; 1H-NMR (DMSO-d6) δ 9.3 (s, 1H), 8.25 (bs, 1H), 8.05 (d, 1H, J=8.33 Hz), 7.95 (d, 1H, J=8.33 Hz), 7.66 (t, 1H, J=7.5 Hz), 7.06-7.02 (m, 2H), 6.70 (d, 1H, J=8.33 Hz), 4.9 (s, 2H); MS (ES) m/z 229 ([M−H]−, 100%).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18](=[O:31])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:16]=2)[N:11]([S:32]([C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=2[O:42][CH3:43])(=[O:34])=[O:33])[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[CH2:29]([O:28][C:26](=[O:27])[C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:18]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[NH:8][CH2:9][CH2:10][N:11]3[S:32]([C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=2[O:42][CH3:43])(=[O:34])=[O:33])=[O:31])=[CH:21][CH:22]=1)[CH3:30]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCN3C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCN3)cc1

Procedure:
A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-6-(4-ethoxycarbonyl-phenylcarbamoyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester (95 mg, 0.15 mmol) in trifluoroacetic acid (2 mL) was stirred at room temperature 2 hours. The volatiles were removed and the residue was purified by trituration in dichloromethane. 4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-benzoic acid ethyl ester was obtained as a white solid, 61 mg (76%), MS (ISP): m/e=530.3, 532.3 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]([F:12])[C:6]([C:7]([OH:9])=O)=[C:5]([F:13])[CH:4]=1)#[N:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[N:49]1([CH2:55][CH:56]([N:60]2[CH:64]=[C:63]([C:65]3[C:66]4[CH:73]=[CH:72][N:71](COCC[Si](C)(C)C)[C:67]=4[N:68]=[CH:69][N:70]=3)[CH:62]=[N:61]2)[CH2:57][C:58]#[N:59])[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>CN(C=O)C.C(OCC)(=O)C>[C:58]([CH2:57][CH:56]([N:60]1[CH:64]=[C:63]([C:65]2[C:66]3[CH:73]=[CH:72][NH:71][C:67]=3[N:68]=[CH:69][N:70]=2)[CH:62]=[N:61]1)[CH2:55][N:49]1[CH2:50][CH2:51][N:52]([C:7]([C:6]2[C:5]([F:13])=[CH:4][C:3]([C:1]#[N:2])=[CH:11][C:10]=2[F:12])=[O:9])[CH2:53][CH2:54]1)#[N:59]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Reactant: N#Cc1cc(F)c(C(=O)O)c(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCC(CN1CCN(C(=O)c2c(F)cc(C#N)cc2F)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 16 h

Procedure:
4-Cyano-2,6-difluorobenzoic acid (82 mg, 0.32 mmol), Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (110 mg, 0.00025 mol) and triethylamine (180 uL, 0.0013 mol) were stirred together in DMF (0.5 mL) for 15 minutes. 4-Piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (125 mg, 0.211 mmol; from Example 12, Step 2) was added and the reaction stirred for 16 hours. To push the reaction to completion, additional 4-cyano-2,6-difluorobenzoic acid (82 mg, 0.32 mol) and triethylamine (58.9 uL, 0.000422 mol) were mixed, in a separate vial, in N,N-Dimethylformamide (1.6 mL) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (110 mg, 0.25 mmol) was added. This mixture was stirred separately for 15 minutes, and then was added to the incomplete original reaction mixture. The reaction was continued for 1.5 hours, then was diluted with a large quantity of ethyl acetate. The solution was washed with three portions of water, once with brine, dried over sodium sulfate and concentrated. The residue was stirred in a mixture of 1:1 dichloromethane (DCM):TFA for one hour, was concentrated, then was stirred in methanol (3 mL) containing ethylenediamine (0.5 mL) until deprotection was complete as evidenced by LCMS. Two successive purifications vial HPLC-MS (eluting first with a gradient of MeCN/H2O containing 0.1% TFA, then repurification eluting with a gradient of MeCN/H2O containing 0.15% NH4OH afforded clean product (46 mg, 43%). 1H NMR (400 MHz, d6-dmso): δ 12.11 (br s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 7.98-7.91 (m, 2H), 7.60 (d, 1H), 6.97 (d, 1H), 5.02-4.93 (tt, 1H), 3.66-3.54 (m, 2H), 3.25-3.16 (m, 4H), 2.91-2.78 (m, 2H), 2.63-2.54 (m, 1H), 2.52-2.38 (m, 2H), 2.37-2.28 (m, 1H); LCMS (M+H)+: 502.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.CCOCC>[CH2:25]([O:16][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:13]=1[N:12]([CH2:15][C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:13]=1)[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(C)ccc2C(=O)O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2cc(C)ccc2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 155 %

Procedure:
To a solution of 1.82 g (5.66 mmol) of the product of Example 4 in 20 ml DMF, was added NaH (60% suspension in oil, 498 mg, (12.5 mmol). The resulting mixture was stired for 15 minutes and benzyl bromide (4.84 g, 0.028 mol) was then added. The mixture was heated to 80-84° with stirnng for 18 hr under N2. The motion was then cooled to room temperature, diluted with ether, washed with H2O and brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated with EtOAc to afford 2.2 g (77%) of the desired product as a white solid. Electrospray Mass Spec: 502 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2cccc(Cl)c2)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.182 mmol) was used in general procedure 1 with 3-chlorobenzoyl chloride (0.228 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(3-chlorobenzoamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide. MS (Q1) 469 (M)+
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][NH:6][C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[C:27]([CH3:29])[C:26](Br)=[C:25]([CH3:31])[CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[C:34]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([C:38]1[CH:43]=[CH:42][C:41]([C:26]2[C:25]([CH3:31])=[CH:24][C:23]([O:22][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:33])=[O:32])=[CH:13][CH:12]=3)[CH2:15][CH2:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[CH:28][C:27]=2[CH3:29])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2cc(C)c(Br)c(C)c2)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: Cc1cc(OC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(C)(C)C)cc1

Procedure:
The title compounds are prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. Isomer 1 MS: 568.2 [M−H]−; Isomer 2 MS: 568.2 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([CH3:22])[CH3:21])[N:9]=[C:10]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13](F)[CH:12]=3)[C:3]=12.O.[NH2:24][NH2:25]>CCCCO>[NH2:16][C:15]1[C:14]2[C:13](=[CH:12][C:11]([C:10]3[C:3]4[C:4](=[N:5][CH:6]=[N:7][C:2]=4[NH2:1])[N:8]([CH:20]([CH3:22])[CH3:21])[N:9]=3)=[CH:18][CH:17]=2)[NH:25][N:24]=1
Reactant: CC(C)n1nc(-c2ccc(C#N)c(F)c2)c2c(N)ncnc21
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: CC(C)n1nc(-c2ccc3c(N)n[nH]c3c2)c2c(N)ncnc21
Temperature: 110 °C
Yield: 70 %

Procedure:
4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorobenzonitrile (BA150, 20 mg, 0.07 mmol) was dissolved in n-BuOH (2 ml). Hydrazine monohydrate (0.400 ml) was added and the reaction was heated to 110° C. under an argon atomosphere and left stirring over night. Reaction mixture was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA154 (15 mg, 70% yield). ESI-MS (M+H)+ m/z calcd 309.2, found 309.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=3[CH3:22])[CH2:12][CH2:13][CH2:14][N:7]21.[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([N:11]2[C:8]3=[N:9][C:10]4[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([CH:23]([OH:24])[C:26]([F:28])([F:27])[F:25])[C:6]=4[N:7]3[CH2:14][CH2:13][CH2:12]2)=[C:16]([CH3:22])[CH:17]=1
Reactant: Cc1cc(Br)ccc1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1N1CCCn2c1nc1c(Cl)ccc(C(O)C(F)(F)F)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To a suspension of 9-chloro-1-(4-bromo-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (4.54 g, 11.2 mmol), trifluoromethyltrimethylsilane (4.97 mL, 33.7 mmol) in tetrahydrofuran (150 mL) was added tetrabutylammonium fluoride (1M solution in tetrahydrofuran 1.12 mL, 1.12 mmol), and the mixture was stirred at 0° C. for 15 min. To the reaction mixture was added tetrabutylammonium fluoride (1M solution in tetrahydrofuran 1.12 mL, 1.12 mmol), and the mixture was stirred at 0° C. for 15 min. To the reaction mixture was added trimethyl(trifluoromethyl)silane (4.97 mL, 33.7 mmol), and the mixture was stirred at 0° C. for 30 min. 1N hydrochloric acid (20 mL 20 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 min. The reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-60% ethyl acetate/n-hexane gradient mixture. The desired fractions were concentrated in vacuo to give the title compound as a colorless powder (3.24 g, 6.83 mmol, 61%).
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[CH2:8][CH2:7]2.C([Li])CCC.[C:25](=[O:27])=[O:26]>C1COCC1>[CH3:19][N:16]1[CH2:17][CH2:18][N:13]([C@@H:9]2[C:10]3[C:6](=[CH:5][C:4]([C:25]([OH:27])=[O:26])=[CH:12][CH:11]=3)[CH2:7][CH2:8]2)[CH2:14][CH2:15]1
Reactant: O=C=O
Reactant: CN1CCN([C@H]2CCc3cc(Br)ccc32)CC1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCN([C@H]2CCc3cc(C(=O)O)ccc32)CC1
Temperature: -78 °C
Yield: 100 %

Procedure:
Under the protection of N2, 1-((1S)-5-bromo-2,3-dihydro-1H-inden-1-yl)-4-methylpiperazine (660 g, 2.235 mol) and THF (3.3 L) were added to a 10 L three-neck flask, and the solution was stirred until dissolved. The system temperature was cooled to −78° C. in liquid nitrogen-acetone bath. n-butyllithium (n-BuLi) (2.5 M in hexane solution) (1072 mL, 2.682 mol, 1.2-fold) was added dropwise into the solution at −78° C.˜−82° C. After being stirred for 10 minutes, when the LC-MS assay shown that the reaction of the raw materials was completed, dry ice (170 g, 3.86 mol, 1.73-fold) was added carefully. The solution was then stirred for 10 minutes at −60° C.˜−75° C. After the reaction was completed, the cold bath was removed and aqueous solution of 2 N HCl was then added to adjust the pH value till pH=2. Most of the water was removed using rotary evaporator. The system was further dried overnight at 50° C.˜60° C. in a vacuum drying oven to obtain the title compound (1289 g, the actual product of 583 g providing 100% yield). This crude product was used in the next step of reaction directly.
Reaction SMILES: O[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][N:5]=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[N:3]=1.P(Cl)(Cl)([Cl:25])=O.CN(C)C1C=CC=CC=1>>[Cl:25][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][N:5]=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[N:3]=1
Reactant: COC(=O)Cc1cnc(Cc2ccc([N+](=O)[O-])cc2)nc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COC(=O)Cc1cnc(Cc2ccc([N+](=O)[O-])cc2)nc1Cl
Temperature: 150 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
A mixture of methyl [4-hydroxy-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (4.0 g, 13.19 mmol), phosphorus oxychloride (6.15 mL, 65.95 mmol) and N,N-dimethylaniline (2.51 mL, 19.78 mmol) was stirred at 150° C. for 3 hours. After the removal of the excess phosphorus oxychloride, the residue was dissolved with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica-gel, (hexane:ethyl acetate, 7/3) to give methyl [4-chloro-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (2.70 g, 64%) as orange solid.
Reaction SMILES: [CH:1]1([N:16]([CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([OH:31])(=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28]>CO>[C:24]([OH:31])(=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28].[C:24]([OH:31])(=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28].[CH:6]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:1][N:16]([CH2:18][CH2:19][CH2:20][N:21]([CH3:22])[CH3:23])[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CCCN(C)C1CCCCCCCCCCCCCC1
Agent: O=C(O)CCC(=O)O
Solvent: CO
Product: CN(C)CCCN(C)CCCCCCCCCCC1CCCC1
Reaction time: 18 h

Procedure:
The diamine of Example 40 (274 mg) in methanol (3 ml) is treated with succinic acid (283 mg) in methanol (3 ml). The reaction is stirred at 20°-25° for 18 hours. A white precipitate forms which is collected by filtration. This is then recrystallized from methanol-diethyl ether to give a solid, mp 164°-166° C. Second crop mp 164°-165° C. (PLA2)