Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:22])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([N:15]3[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]3)[CH:9]=2)[CH2:4][CH2:3]1.[K+].[C:24]([C:26]1[N:27]=[C:28]([C:39]([O-])=[O:40])[N:29](COCC[Si](C)(C)C)[CH:30]=1)#[N:25].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[O:22]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:39]([C:28]3[NH:29][CH:30]=[C:26]([C:24]#[N:25])[N:27]=3)=[O:40])=[C:10]([N:15]3[CH2:16][CH2:17][CH:18]([CH3:21])[CH2:19][CH2:20]3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1CCN(c2cc(C3CCS(=O)(=O)CC3)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1CCN(c2cc(C3CCS(=O)(=O)CC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68 %

Procedure:
To a mixture of 4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-2-(4-methyl-piperidin-1-yl)-phenylamine (as prepared in the previous step, 16 mg, 0.050 mmol), 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium (as prepared in Example 3, step (d), 17 mg, 0.055 mmol) and PyBroP (35 mg, 0.075 mmol) in 1 mL of DCM was added DIEA (17 μL, 0.10 mmol). The resulting mixture was stirred at RT for 20 h under Ar. Treated with 30 mL of EtOAc, the mixture was washed with H2O (3×10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-2% EtOAc/DCM) gave 19 mg (68%) of the title compound as a colorless oil: 1H-NMR (CDCl3; 400 MHz): δ 10.4 (s, 1H), 8.29 (d, 1H, J=8.4 Hz), 7.79 (s, 1H), 7.02 (d, 1H, J=1.9 Hz), 6.99 (dd, 1H, J=8.4, 1.9 Hz), 5.97 (s, 2H), 3.67 (app t, 2H, J=8.3 Hz), 3.14 (m, 4H), 2.99 (d, 2H, J=12.0 Hz), 2.67-2.80 (m, 3H), 2.40 (m, 2H), 2.22 (m, 2H), 1.79 (m, 2H), 1.52-1.67 (m, 3H), 1.08 (d, 3H, J=5.9 Hz), 0.98 (app t, 2H, J=8.3 Hz), 0.001 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C28H41N5O4SSi, 572.3 (M+H), found 572.0.
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17])#[C:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH2:18]>Cl>[CH2:7]([C:6]1[N:1]=[N:17][C:12]2[C:11]([C:5]=1[OH:18])=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCC#Cc1ccccc1N
Reactant: O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: CCCCc1nnc2ccccc2c1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 2 g of sodium nitrite in 60 ml of water was added at 0° C. to a suspension at 0° C. of 3.2 g of the product of Step A in 100 ml of concentrated hydrochloric acid, and the mixture was stirred for 90 minutes at 0° C., then for one hour at 100° C. The reaction medium was poured into 100 ml of ice-cooled water, separated and washed with ice-cooled water. The moist product was taken up in 100 ml of water and alkalized with concentrated ammonium hydroxide. After separation, the residue was washed with water and dried at 70° C. under reduced pressure to obtain 1.47 g of the expected product melting at 180° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].COC1[CH:9]=[C:10]([CH2:16][C:17](N)=O)[CH:11]=[CH:12]C=1OC.[CH:20]1C=CC=CC=1>>[CH3:1][NH:2][C:3]([N:5]1[CH:12]=[CH:11][C:10]([CH3:9])([CH3:20])[CH:16]=[CH:17]1)=[O:4]
Reactant: COc1ccc(CC(N)=O)cc1OC
Reactant: c1ccccc1
Reactant: CNC(N)=O
Product: CNC(=O)N1C=CC(C)(C)C=C1

Procedure:
The title compound was prepared using the method of Example 2b after substituting an equivalent amount of methylurea for (3,4-dimethoxyphenyl)acetamide as a starting material and diluting the solution three-fold with benzene. The crude product was purified by silica gel flash chromatography eluting with a 25% ethyl acetate/hexane solution. The eluate was evaporated in vacuo to yield the title compound as a white solid, mp 129°-131° C.
Reaction SMILES: [I-].[Na+].[Br:3][C:4]1[C:5]([CH3:11])=[N:6][C:7](Br)=[CH:8][CH:9]=1.[I:12][Si](C)(C)C>C(#N)CC.C(OCC)(=O)C.O>[Br:3][C:4]1[C:5]([CH3:11])=[N:6][C:7]([I:12])=[CH:8][CH:9]=1
Reactant: Cc1nc(Br)ccc1Br
Reactant: C[Si](C)(C)I
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCC#N
Solvent: CCOC(C)=O
Product: Cc1nc(I)ccc1Br
Temperature: 95 °C
Reaction time: 0.08 h
Yield: 95 %

Procedure:
Sodium iodide (2 equiv) and 3,6-dibromo-2-methylpyridine (1 equiv) were combined in propionitrile and the resulting slurry was stirred under nitrogen for 5 min. Iodotrimethylsilane (0.2 equiv) was added and the reaction was heated at 95° C., with stirring, under nitrogen for 24 h. The slurry was cooled to room temperature, diluted with a 1:1 mixture of ethyl acetate and water. The mixture was agitated for 15 min and the aqueous and organic phases were then separated. The organic layer was washed sequentially with equal volumes of saturated aqueous sodium bicarbonate solution, sodium thiosulfate (5% aqueous solution), and saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the desired product in 95% yield, as an oil, which crystallized to an off-white solid. MS (ESI) m/z 297.8 [M]+, 299.8 [M+2]+.
Reaction SMILES: C(Cl)(C(Cl)=O)=O.CS(C)=O.[CH3:11][C:12]1([CH3:42])[O:16][C@H:15]([C@H:17]([OH:39])[CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:14]([CH:40]=[CH2:41])[O:13]1.C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl>[CH3:11][C:12]1([CH3:42])[O:16][C@H:15]([C:17](=[O:39])[CH2:18][O:19][C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:14]([CH:40]=[CH2:41])[O:13]1
Reactant: C=C[C@@H]1OC(C)(C)O[C@@H]1[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=C[C@@H]1OC(C)(C)O[C@@H]1C(=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a stirred solution of (COCl)2 (28.69 ml, 57.38 mmol, 2 M solution in CH2Cl2) in CH2Cl2 (200 ml) was dropwise added a solution of DMSO (8.9 ml, 125.51 mmol) in CH2Cl2 (30 ml) at −78° C., and the reaction mixture was stirred at the same temperature for 30 minutes. A solution of alcohol 3 (15.44 g, 35.86 mmol) in CH2Cl2 (30 ml) was added and the reaction mixture was stirred at −78° C. for 1 hour. Triethylamine (32.99 ml, 236.68 mmol) was added at −78° C. and then the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. A saturated ammonium chloride solution was added carefully at 0° C. and the reaction mixture partitioned between CH2Cl2 and water. The organic layer was dried, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using hexane and ethyl acetate (6:1) to give ketone 4 (13.83 g, 90%) as a white solid; 1H NMR (400 MHz, CDCl3) δ 7.46-7.23 (m, 15H), 5.56 (ddd, J=17.2, 10.4, 6.8 Hz, 1H), 5.26 (td, J=16.8, 1.2 Hz, 1H), 5.13 (td, J=10.4, 1.2 Hz, 1H), 4.88-4.84 (m, 1H), 4.76 (d, J=7.6 Hz, 1H), 4.06 (d, J=18.0 Hz, 1H), 3.72 (d, J=18.4 Hz, 1H), 1.41 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([CH2:13][OH:14])[CH:3]=1.[N+:15]([O-:18])(O)=[O:16]>S(=O)(=O)(O)O>[F:1][C:2]1[C:7]([N+:15]([O-:18])=[O:16])=[CH:6][C:5]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([CH2:13][O:14][S:9]([OH:11])(=[O:10])=[O:8])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)Oc1ccc(F)cc1CO
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)Oc1cc([N+](=O)[O-])c(F)cc1COS(=O)(=O)O

Procedure:
To a mixture of 7.53 g (34 mmole) of methanesulfonic acid 4-fluoro-2-hydroxymethyl-phenyl ester and 60 mL of concentrated sulfuric acid at 0 degrees was added dropwise, a cold mixture of 2.5 mL of concentrated nitric acid and 3 mL of concentrated sulfuric acid. The mixture was poured on ice and extracted three times with 50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether to give 3.5 g of methanesulfonic acid 4-fluoro-5-nitro-2-sulfooxymethyl-phenyl ester as a white solid. The white solid was heated to reflux for 1 hour with 100 mL of methanol, 2 mL of trimethylorthoformate and 0.10 g of p-toluenesulfonic acid monohydrate. The mixture was neutralized by addition of saturated sodium bicarbonate solution and then concentrated under reduced pressure. The residue was partitioned between 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 2.6 g of methanesulfonic acid 4-fluoro-2-hydroxymethyl-5-nitro-phenyl ester as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=S)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:24][CH2:25][CH:26]([OH:32])[CH2:27][C:28]([F:31])([F:30])[F:29].C(N(CC)CC)C>C(O)C.[Hg](Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=[N:24][CH2:25][CH:26]([OH:32])[CH2:27][C:28]([F:31])([F:30])[F:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1NC(=S)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Reactant: NCC(O)CC(F)(F)F
Agent: Cl
Agent: Cl[Hg]Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@H]1NC(=NCC(O)CC(F)(F)F)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl[(3S,5S,6R)-6-methyl-5-phenyl-2-thioxopiperidin-3-yl]carbamate (75 mg, 0.23 mmol) in ethanol (2.3 mL) was added 1-amino-4,4,4-trifluorobutan-2-ol hydrochloride (105 mg, 0.59 mmol), mercury(II) chloride (83 mg, 0.30 mmol), and triethylamine (78 μL, 0.56 mmol). The mixture was stirred 30 min, filtered, and then concentrated, giving the crude title compound. MS 430.3 (M+1).
Reaction SMILES: [O:1]=[C:2]([CH3:17])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]([OH:16])=O)=[CH:12][N:13]=2)[CH:10]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[F:29][C:30]1([F:47])[CH2:33][CH:32]([C:34]2[O:38][N:37]=[C:36]([C:39]3[CH:40]=[CH:41][C:42]([CH3:46])=[C:43]([CH:45]=3)[NH2:44])[N:35]=2)[CH2:31]1>ClCCl.N1C=CC=CC=1>[F:47][C:30]1([F:29])[CH2:31][CH:32]([C:34]2[O:38][N:37]=[C:36]([C:39]3[CH:40]=[CH:41][C:42]([CH3:46])=[C:43]([NH:44][C:14]([C:11]4[N:9]5[CH:10]=[C:5]([CH2:4][CH2:3][C:2](=[O:1])[CH3:17])[CH:6]=[CH:7][C:8]5=[N:13][CH:12]=4)=[O:16])[CH:45]=3)[N:35]=2)[CH2:33]1
Reactant: CC(=O)CCc1ccc2ncc(C(=O)O)n2c1
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)CCc1ccc2ncc(C(=O)Nc3cc(-c4noc(C5CC(F)(F)C5)n4)ccc3C)n2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirring suspension of 6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxylic acid (78) (150 mg, 0.646 mmol) in anhydrous dichloromethane (5 mL) at 0° C. under Argon was added dropwise oxalyl chloride (60 μL, 0.710 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at room temperature for 45 minutes. The solvent was concentrated. A stirring mixture of the acid chloride and 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (37) (86 mg, 0.323 mmol) in anhydrous pyridine (3 mL) was stirred at room temperature for 3 hours. The crude product was purified by silica chromatography to give N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxamide (F53). 1H NMR (400 MHz, d6-DMSO) δ 10.19 (s, 1H), 9.37 (s, 1H), 8.70 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.86-7.83 (m, 2H), 7.66 (dd, J=1.6, 9.2 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 3.92-3.84 (m, 1H), 3.24-3.05 (m, 4H), 2.89-2.86 (m, 4H), 2.37 (s, 3H), 2.11 (s, 3H). MS m/z 480.18 (M+1)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]=[N+]=[N-])[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.O>[O:25]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH2:20])[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:6][CH2:7]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: NC[C@H]1CN(c2ccc(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Yield: 95.7 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl) oxazolidin-2-one (Intermediate 2) (3 g, 8.2 mmol) was dissolved in acetonitrile/water (10:1, 50 ml). Triphenylphosphine (2.6 g, 9.9 mmol) was added and the resulting mixture was stirred over night with evolution of nitrogen. The reaction mixture was applied onto a silica gel column and eluted with acetonitrile/water (15:1 to 5:1) to give the title compound (2.67 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[C:34](OCCCC)(=O)[CH:35]=[O:36].CC(O)=O>CCO>[C:24]([O:23][C:21]([NH:20][CH:17]1[CH2:18][CH2:19][N:15]([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:5]3[N:6]=[CH:7][C:2]4[N:1]=[CH:34][C:35](=[O:36])[N:28]([CH:29]5[CH2:30][CH2:31][CH2:32][CH2:33]5)[C:3]=4[N:4]=3)=[CH:14][CH:13]=2)[CH2:16]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCCCOC(=O)C=O
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc(N)c(NC4CCCC4)n3)cc2)C1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc4ncc(=O)n(C5CCCC5)c4n3)cc2)C1
Yield: 28.5 %

Procedure:
A mixture of 0.70 g (1.5 mmol) of 5-amino-2-[[4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]phenyl]amino]-4-(cyclopentylamino)-pyrimidine, 0.52 g (4 mmol) of butyl glyoxylate (F. J. Wolf, J. Weijlard, Org. Synth. Coll., 1963;4:124–125) and 0.5 mL HOAc in 15 mL of EtOH is heated under reflux for 14 hours, and the solvent is removed under vacuum. The residue is diluted with aqueous ammonia solution and extracted into EtOAc. Chromatography on silica, eluting with hexane/EtOAc (3:2), gives 0.21 g (28%) of the title compound (Compound 53): mp (MeOH) 226–228° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18](Cl)=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5](C(O)CC)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[C:34](=[O:36])[CH3:35].[O:38]1[CH2:42][CH2:41][CH2:40]C1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:34](=[O:36])[CH3:35])[CH:5]=[CH:6][C:10]=1[N:9]1[C:8]2=[N:11][C:15]3[C:16]([Cl:22])=[CH:17][CH:18]=[C:19]([CH:42]([OH:38])[CH2:41][CH3:40])[C:20]=3[N:7]2[CH2:14][CH2:13][CH2:12]1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC(=O)N(C)C
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(C(C)=O)cc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (700.0 mg, 1.538 mmol) in tetrahydrofuran (12.0 mL) was added n-butyllithium (1.60 M solution in n-hexane, 2.57 mL, 4.12 mmol) at −78° C., and the mixture was stirred for 30 min. To the mixture was added N,N-dimethylacetamide (0.77 mL, 8.24 mmol) at −78° C. The mixture was stirred at room temperature for 3 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-100% ethyl acetate/n-hexane gradient mixture to give the title compound as a pale yellow amorphous (130.2 mg, 0.311 mmol, 20%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].[NH:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14].NCCC(O)=O.C(O)(=O)C>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:18]2[NH:12][C:13](=[O:14])[NH:15][C:16]2=[O:17])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: O=C1CNC(=O)N1
Reactant: COc1cc(C=O)ccc1O
Agent: NCCC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C=C2NC(=O)NC2=O)ccc1O
Yield: 42.7 %

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (4.6 g, 30 mmoles), hydantoin (3.0 g, 30 mmoles), β-alanine (1.4 g, 16 mmoles), and acetic acid (40 ml) is stirred under an inert atmosphere and heated to reflux. After 4 hours the mixture is stirred into water (350 ml) and the precipitate is filtered off, rinsed successively with water (3×), ethanol (2×), and ether (2×), and dried. Recrystallization from methanol afforded the pure product (3.0 g), mp 272°-273° C.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.C[O:13][C:14](=O)[C:15]([NH2:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C=O)C.O>[Br:2][C:3]1[CH:8]=[N:7][C:6]2[NH:9][C:14](=[O:13])[C:15]([CH3:17])([CH3:16])[NH:18][CH2:10][C:5]=2[CH:4]=1
Reactant: COC(=O)C(C)(C)N
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)NCc2cc(Br)cnc2NC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.2 %

Procedure:
A solution of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (11.0 g, 31.7 mmol) and 2-amino-2-methyl-propionic acid methyl ester (5.80 g, 49.5 mmol) in DMF (220 mL) was treated with triethylamine (9.0 mL, 18.5 mmol). After stirring at room temperature for 3 d, the mixture was diluted with H2O (400 mL) and then extracted with EtOAc (4×200 mL). The combined organic layers were washed with H2O (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 99:1) gave the title compound (3.87 g, 40%) as a light yellow solid: MS (ESI) m/e 302 (M+H)+.
Reaction SMILES: [N:1]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:5][CH:4]([N:7]2[C@@H:15]3[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[CH2:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25].Cl>>[O:16]=[C:8]1[CH2:9][C@@H:10]2[C@H:15]([CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]1[CH:4]1[CH2:3][CH2:2][N:1]([CH:17]2[CH2:18][CH2:19][N:20]([C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:22]2)[CH2:6][CH2:5]1
Reactant: CC(C)OC(=O)Cl
Reactant: O=C1C[C@H]2CCCC[C@@H]2N1C1CCN(C2CCNCC2)CC1
Agent: Cl
Product: CC(C)OC(=O)N1CCC(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CC1

Procedure:
Following procedure similar to Example 82, the title compound was prepared from (3aR,7aS)-1-(1,4′-bipiperidin-4-yl)octahydro-2H-indol-2-one and isopropyl chloroformate. 1H NMR (400 MHz, METHANOL-D4) HCl salt: 6 ppm 1.24 (d, J=5.86 Hz, 6H), 1.27-1.53 (m, 4H), 1.53-1.83 (m, 4H), 1.84-2.00 (m, 4H), 2.04-2.17 (m, 3H), 2.26 (d, J=6.64 Hz, 1H), 2.28-2.37 (m, 1H), 2.35-2.68 (m, 2H), 2.74-2.95 (m, 2H), 3.03-3.23 (m, 3H), 3.34-3.46 (m, 1H), 3.60 (d, J=12.89 Hz, 2H), 3.78-3.94 (m, 1H), 4.29 (d, J=14.06 Hz, 2H), 4.76-4.88 (m, 1H). MS (M+1): 392.3
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2F)/[N:7]([CH2:24][C@@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH:32]1[CH2:38][OH:39]>>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[O:39][CH2:38][CH:32]2[CH2:33][N:34]([CH3:37])[CH2:35][CH2:36][N:31]2[CH3:30])/[N:7]([CH2:24][C@@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(C)C(CO)C1
Reactant: CC(C)(C)c1cn(C[C@@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Product: CN1CCN(C)C(COc2ccc(C(F)(F)F)cc2C(=O)/N=c2\sc(C(C)(C)C)cn2C[C@@H]2CCCO2)C1

Procedure:
A mixture of Example 32B (108 mg, 0.25 mmol) and (1,4-dimethylpiperazin-2-yl)methanol (72 mg, 0.5 mmol) were processed using method described in Example 32B to afford the title compound. 1H NMR (500 MHz, pyridine-d5) δ ppm 1.17-1.26 (m, 9 H), 1.50-1.72 (m, 3 H), 1.86 (dd, J=12.5, 6.1 Hz, 1 H), 2.25 (s, 3 H), 2.31-2.55 (m, 7 H), 2.62 (d, J=10.1 Hz, 1 H), 2.74 (d, J=11.3 Hz, 1 H), 3.19 (d, J=10.7 Hz, 1 H), 3.65 (q, J=7.2 Hz, 1 H), 3.82 (q, J=6.9 Hz, 1 H), 4.16-4.38 (m, 3 H), 4.43-4.56 (m, 2 H), 7.20 (s, 1 H), 7.27 (d, J=8.5 Hz, 1 H), 7.71-7.80 (m, 1 H), 8.55 (s, 1 H); MS (DCI/NH3) m/z 555 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].C(N(CC)CC)C.Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[N+:30]([O-:32])=[O:31]>CC(C)=O>[N+:27]([C:24]1[CH:23]=[C:22]([N+:30]([O-:32])=[O:31])[CH:21]=[CH:26][C:25]=1[O:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1 L four-necked flask equipped with an overhead stirrer, thermocouple and a condenser was charged with 2-hydroxyisoindoline-1,3-dione (25 g, 153 mmol) and acetone (500 mL). To this stirred suspension was added triethylamine (15.7 g, 154 mmol). The reaction mixture turned dark red and 2-hydroxyisoindoline-1,3-dione slowly dissolved and became a homogeneous solution after 10 minutes. 1-Chloro-2,4-dinitrobenzene (31 g, 153 mmol) was added and the reaction was stirred at room temperature for 2 hours. After this time, a bright yellow suspension formed, and the reaction mixture was poured into 500 mL of ice-water. The precipitate was filtered and washed three times with cold MeOH (100 mL). The solid was compressed and washed with heptanes (3×100 mL) and dried under vacuum to give 2-(2,4-dinitrophenoxy)isoindoline-1,3-dione (I-33). 1H NMR (400 MHz, CDCl3) δ 8.99 (d, 1 H), 8.44 (dd, 1 H), 8.03-7.97 (m, 2 H), 7.95-7.90 (m, 2 H), 7.46 (d, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>>[CH:24]([C:20]1[CH:19]=[C:18]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:31]4[CH:32]=[N:27][CH:28]=[N:29][CH:30]=4)[CH:3]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:23]=[CH:22][N:21]=1)([CH3:25])[CH3:26]
Reactant: OB(O)c1cncnc1
Reactant: CC(C)c1cc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)ccn1
Product: CC(C)c1cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3ccccc32)ccn1
Yield: 58 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-isopropylpyridin-4-yl)-1H-isoindol-3-amine (Example 113) as described in Example 67 Scheme #10, D in 58% yield using pyrimidine-5-boronic acid. 1H NMR (DMSO-d6) δ 9.11 (s, 1 H), 8.93 (s, 2 H), 8.30 (d, J=5.30 Hz, 1 H), 7.90-7.82 (m, 1 H), 7.81-7.69 (m, 1 H), 7.65-7.53 (m, 2 H), 7.49-7.33 (m, 4 H), 7.17-7.11 (m, 1 H), 7.07 (dd, J=5.31, 1.77 Hz, 1 H), 6.86 (br s, 2 H), 2.97-2.75 (m, 1 H), 1.08 (d, J=6.82 Hz, 6 H); MS (ESI) m/z 406 [M+1]+.