Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([N:12]2[CH2:16][C@@H:15]3[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C@@H:14]3[CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O.C(OCC)(=O)C>[C:23]([O:22][C:20]([N:18]1[CH2:19][C@H:14]2[CH2:13][N:12]([C:8]3[CH:9]=[N:10][CH:11]=[C:6]([CH:7]=3)[C:4]([OH:5])=[O:3])[CH2:16][C@H:15]2[CH2:17]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)c1cncc(N2C[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
The product from Example 33A (3.20 g, 8.90 mmol) was dissolved in a solvent mixture of ethanol (40 mL) and water (20 mL). Sodium hydroxide (2.0 M, 13 mL) was added, and the reaction mixture was stirred at ambient temperature for 1 hour. The mixture was then diluted with ethyl acetate (100 mL) and partitioned between ethyl acetate (250 mL) and water (30 mL). The aqueous layer was acidified to pH 4 and repartitioned between dichloromethane (200 mL) and water (250 mL). The organic layer was dried (Na2SO4) and concentrated under vacuum to afford the title compound (3.0 g, 102%). 1H NMR (400 MHz, CD3OD) δ ppm 1.45 (s, 9H), 3.06-3.14 (br s, 2H), 3.27-3.34 (m, 4H), 3.61 (dd, J=10.0, 7.5 Hz, 2H), 3.64-3.71 (m, 2H), 7.57 (dd, J=2.8, 1.8 Hz, 1H), 8.04 (d, J=1.5 Hz, 1H), 8.39 (s, 1H). MS (APCI) m/z 334 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[C:15](=N)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:16]1([C:15](=[N:2][CH2:3][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([O:7][CH3:8])=[O:6])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(CN)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(CN=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 3-amino-2-phenylpropanoate hydrochloride in CH2Cl2 was added benzophenone imine, and the solution was stirred overnight at room temperature. The mixture was then washed with H2O and the organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 5-20% EtOAc/Hexanes) gave pure methyl 3-(diphenylmethyleneamino)-2-phenylpropanoate (E320).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].Br[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:20][N:19]1[C:15]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[O:4])=[CH:16][CH:17]=[N:18]1
Reactant: Cn1nccc1Br
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2ccnn2C)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
A mixture of (3-(methoxycarbonyl)phenyl)boronic acid (270 mg, 1.5 mmol), 5-bromo-1-methyl-1H-pyrazole (200 mg, 1.25 mmol), K2CO3 (518 mg, 3.75 mmol) and Pd(dppf)Cl2 (10 mg) in a mixture solution of dioxane (8 mL) and H2O (2 mL) was stirred at 120° C. for 30 min under microwave heating. The catalyst was filtered and the filtrate concentrated. The residue was then purified by column chromatography to give provide the desired product as a colorless oil (226 mg, Yield 60%). It was used directly in the next step. LCMS (m/z): 217.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][C:39](=[O:50])[NH:40][CH2:41][CH:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:49][CH:42]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[CH2:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:50])[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Reactant: CS(=O)c1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1
Product: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1)c1ccccc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 48 supra) (170 mg, 0.36 mmol) and (2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester (from Example 51 supra) (341 mg, 1.44 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford crude (4-{3-[2-(2-tert-butoxycarbonylamino-1-phenyl-ethylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 100 mg). LC-MS: [M+H]+ 644.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:20])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:29][C:30]1[N:31]=[CH:32][S:33][CH:34]=1.O>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl>[CH3:19][C@@H:15]1[N:14]2[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([O:20][CH2:29][C:30]5[N:31]=[CH:32][S:33][CH:34]=5)[CH:8]=4)[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:18][O:17][CH2:16]1
Reactant: C[C@H]1COCc2nc3c(N)nc4ccc(O)cc4c3n21
Reactant: ClCc1cscn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@H]1COCc2nc3c(N)nc4ccc(OCc5cscn5)cc4c3n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
A solution of (11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-2-ol (500 mg, 1.85 mmol) dissolved in 15 mL of DMF was treated with cesium carbonate (1.80 g, 5.55 mmol), 4-chloromethyl thiazole hydrochloride (345 mg, 2.03 mmol), and tetrabutylammonium bromide (715 mg, 2.22 mmol). After stirring overnight at ambient temperature, the brown mixture was poured into 150 mL of H2O and stirred for 30 minutes. The reaction mixture was extracted with CHCl3 (3×75 mL) and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give a brown solid. Chromatography (SiO2, 0-20% CMA/CHCl3) gave an off-white solid which was crystallized from acetonitrile to give 179 mg of the title compound as an off-white solid, mp 240-242° C. 1H NMR (500 MHz, DMSO-d6) δ 9.16 (d, J=2.0 Hz, 1H), 7.82 (d, J=1.9 Hz, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.51 (d, J=2.7 Hz, 1H), 7.21 (dd, J=2.6, 9.1 Hz, 1H), 6.35 (br s, 2H), 5.36 (m, 2H), 5.14 (m, 1H), 5.09 (d, J=15.5 Hz, 1H), 4.95 (d, J=15.5 Hz, 1H), 4.13 (m, 2H), 1.52 (d, J=6.5 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 154.4, 152.8, 152.7, 150.3, 145.0, 139.6, 130.9, 127.3, 126.7, 118.0, 116.9, 114.3, 102.8, 68.2, 65.6, 64.5, 49.8, 18.9; MS (APCI) m/z 368 (M+H)+. Anal. calcd for C18H17N5O2S: C, 58.84; H, 4.66; N, 19.06. Found: C, 58.88; H, 4.63; N, 19.29.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[CH:10](C(OCC)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=[O:23].[Na+]>Cl>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([OH:16])([OH:23])[C:12]([F:14])([F:15])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC(F)(F)C1=O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: OC1(O)CCN(Cc2ccccc2)CC1(F)F
Temperature: 25 °C

Procedure:
A solution of ethyl 1-benzyl-5,5-difluoro-4-oxopiperidine-3-carboxylate (4.272 g, 14.4 mmol) dissolved in 3 N HCl (175 mL) was heated at reflux for 14 hours. The reaction mixture was cooled to room temperature, then solid NaHCO3 was added until pH 8 and extracted three times with ethyl acetate, the combined organic layers were dried over Na2SO4 and the solvents were evaporated. The title compound was obtained as white solid (3.5 g, 100%).
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:14]=1[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:8]([O:7][P:5]([O:11][CH2:12][C:13]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:14]=1[C:15]([OH:17])=[O:16])([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCOP(=O)(OCC=C)OCc1cccc(F)c1C(=O)OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CCOP(=O)(OCC=C)OCc1cccc(F)c1C(=O)O

Procedure:
According to a similar procedure to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-6-fluorobenzoate (1.07 g, 2.39 mmol) obtained from Example 9-(1) was reacted with anisole (1.8 g, 16.6 mmol) and trifluoroacetic acid (5 ml), and the reaction mixture was worked up to afford 2[[bis(allyloxy)phosphoryl]oxymethyl]-6-fluorobenzoic acid as a crude product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[CH2:28]([NH2:31])[CH2:29][NH2:30]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:30][CH2:29][CH2:28][NH2:31])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: NCCN
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.5 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H cyclopenta[d]pyrimidine (0.5 g, 1.77 mmol) in acetonitrile (5 mL) was added diisopropylethylamine (0.343 g, 2.659 mmol) followed by ethane-1,2-diamine (0.138 g, 2.30 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was taken in dichloromethane (5 mL) and silica (1 g). The resultant slurry of the compound on silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, 10% methanol in chloroform) to get the title compound N1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)ethane-1,2-diamine (0.35 g, 64.5%) as a dark brown solid. LC-MS (M+H)+=307.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.11-7.08 (2H, m), 6.99-6.95 (2H, m), 5.40 (1H, br s), 4.25-4.22 (1H, m), 3.61-3.57 (2H, m), 2.99-2.98 (2H, m), 2.78-2.62 (3H, m), 2.10-2.09 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH2:19][O:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25]C)=[O:24])=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].C(O)(=O)C>O.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH2:19][O:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([OH:25])=[O:24])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1OCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1OCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
0.65 g (1.542 mmol) of methyl 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)benzoate were solubilized with magnetic stirring in 30 ml of a mixture consisting of ethanol and of tetrahydrofurane (1/1, v/v) and then 15.42 ml (15.42 mmol) of a 1N NaOH aqueous solution were added. The mixture was stirred at r.t. for 16 h before adding 20 ml of water and then 0.883 ml (15.42 mmol) of acetic acid. The formed precipitate was isolated by filtration, washed with 10 ml of water and dried in a vacuum bell jar in order to obtain 0.518 g (yield=81%) of 2-((3-((4-fluoro-phenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)benzoic acid as a pale yellow solid. LC-MS: m/z=387 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 12.72 (s, 1H), 8.64 (d, J=5.5 Hz, 1H), 7.78-7.59 (m, 4H), 7.45 (d, J=6.2 Hz, 2H), 7.41-7.24 (m, 3H), 7.14 (t, J=6.8 Hz, 1H), 7.00 (t, J=7.3 Hz, 1H), 5.42 (s, 2H).
Reaction SMILES: Cl.Cl.[NH2:3][NH2:4].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13](=O)[O:14][C:15](=[O:17])[CH:16]=2)=[CH:8][CH:7]=1>O>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13](=[O:14])[NH:3][NH:4][C:15](=[O:17])[CH:16]=2)=[CH:8][CH:7]=1
Reactant: NN
Reactant: O=C1C=C(c2ccc(Cl)cc2)C(=O)O1
Agent: Cl
Solvent: O
Product: O=c1cc(-c2ccc(Cl)cc2)c(=O)[nH][nH]1
Temperature: 120 °C
Reaction time: 0.67 h
Yield: 81.4 %

Procedure:
To a solution of hydrazine dihydrochloride (5.6 g, 53.3 mmol) in H2O (60 mL) at 120° C. was added 3-(4-chlorophenyl)-2,5-furandione (10 g, 48 mmol) in one portion. After addition, the reaction mixture was stirred at 120° C. for 40 min. After cooling to room temperature, the reaction became a pale yellow suspension. The precipitate was collected by filtration, washed with water (30 mL×3), hexanes (30 mL×3), and dried in a 50° C. vacuum oven for 16 h to afford 8.7 g (81%) of the title compound as a pale yellow solid. LC/MS (method A): retention time=2.57 min, (M+H)+=223.
Reaction SMILES: [CH2:1]([O:21][CH:22]([CH2:30][CH3:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[CH:32](NC(C)C)(C)[CH3:33].[Li].C(I)C.[NH4+].[Cl-]>O1CCCC1>[CH2:30]([C:22]([O:21][CH2:1][CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20])([CH2:32][CH3:33])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH3:31]
Reactant: CC(C)NC(C)C
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(CC)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(CC)(CC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
tert-Butyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoate (480 mg, 1.11 mmol) was added dropwise over 30 minutes to a solution of lithium diisopropylamine (LDA) (2.0 M, 750 μL, 1.50 mmol) in dry tetrahydrofuran (10 mL) held at −70° C. under nitrogen. The reaction mixture was stirred for 30 minutes. Ethyl iodide (312 mg, 2.00 mmol) was added in one portion and the resulting mixture was warmed to ambient temperature during 1 hour. The reaction mixture was stirred at ambient temperature for 17 hours. The mixture was poured into saturated NH4Cl (aq.) (50 mL) and extracted with heptane (2×50 mL). The combined organic phases was washed succesively with brine (50 mL), 0.25 M HCl (50 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (100:0→95:5) as eluent. Concentration of the appropriate fractions afforded 343 mg (67% yield) of the title compound as an oil. 1H NMR (300 MHz, CDCl3): δ 0.84 (t, 6H), 0.99 (td, 3H), 1.35-1.55 (m, 11H), 1.54-1.69 (m, 2H), 1.68-1.87 (m, 4H), 1.99-2.24 (m, 4H), 2.74-2.99 (m, 8H), 3.31 (t, 2H), 5.23-5.52 (m, 10H); MS (electro spray): 401.3 [M−H]−
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][N:6]=1.[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[NH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[C:21]2[CH:20]=[CH:19][C:18]([C:32]3[CH:37]=[N:36][C:35]([NH2:38])=[N:34][CH:33]=3)=[C:17]([F:16])[CH:22]=2)[N:10]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Nc1ccnc(Oc2ccccc2Br)n1
Product: Nc1ccnc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)n1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)pyrimidin-4-amine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H15FN6O, 374.13; m/z found, 375.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.49-8.43 (d, J=1.4, 2H), 7.79-7.72 (d, J=5.9, 1H), 7.51-7.47 (dd, J=7.6, 1.7, 1H), 7.47-7.41 (m, 2H), 7.39-7.28 (m, 3H), 7.22-7.17 (dd, J=8.1, 1.2, 1H), 6.16-6.05 (d, J=105.9, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[O:9])=[CH:4][C:3]=1[F:24].[I:25]I>[O-]S([O-])(=O)=O.[Ag+].[Ag+].C(O)C>[NH2:1][C:2]1[C:23]([I:25])=[CH:22][C:5]([CH2:6][NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:14][CH:13]=2)=[O:9])=[CH:4][C:3]=1[F:24]
Reactant: CC(C)(C)c1ccc(CNC(=O)NCc2ccc(N)c(F)c2)cc1
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CC(C)(C)c1ccc(CNC(=O)NCc2cc(F)c(N)c(I)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the 50 ml of round bottom flask were put 1-(4-amino-3-fluoro-benzyl)-3-(4-t-butyl-benzyl)-urea (0.25 g, 0.76 mmol) and Ag2SO4 (1.1 eq, 0.26 g) and then cooled to 0° C. And to this mixture was poured 20 ml ethanol and added I2 (1.0 eq, 0.193 g) portionwise and stirred for 3 hours at room temperature. After confirming the completion of the reaction with TLC, the reaction mixture was filtered through celite and concentrated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].C(Cl)(=O)C(Cl)=O.[CH2:28]([NH:30][CH3:31])[CH3:29]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([S:9][C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:18])[N:30]([CH3:31])[CH2:28][CH3:29])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C(O)c1ccc(Sc2ccc([N+](=O)[O-])c(Cl)c2F)cc1
Reactant: CCNC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(C)C(=O)c1ccc(Sc2ccc([N+](=O)[O-])c(Cl)c2F)cc1
Reaction time: 8 h
Yield: 34.9 %

Procedure:
2-Chloro-3-fluoro-4-(4-carboxyphenylsulphanyl)nitrobenzene (Method 24; 5.5 g, 16.8 mmol) was suspended with stirring in DCM (100 ml) and oxalyl chloride (3.22 ml) was added. A couple of drops of DMF were added to initiate the reaction and it was left to stir overnight. The mixture was evaporated to dryness and then redissolved in DCM (20 ml). N-ethyl-N-methylamine (0.46 ml, 5.28 mmol) was dissolved in DCM (1 ml) and to this with stirring was added some of the above acid chloride solution (2.4 mmol). The solution was left to stir overnight and then washed with water, brine and dried by pouring onto a Chem Elut column eluting with EtOAc. The resulting solution was evaporated down to dryness and then purified by chromatography on a Mega Bond Elut column eluting with a graduated solvent of hexane/EtOAc to yield the title compound (680 mg). NMR: 1.1 (s, 3H), 2.9 (d, 3H), 3.2 (s, 1H), 3.4 (s, 1H), 7.2 (m, 1H), 7.5 (d, 2H), 7.6 (d, 2H), 8.0 (m, 1H); m/z 369.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1F.[CH3:17][C:18]1[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:19]=1[NH2:29].Cl>C(OCC)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:29][C:19]1[CH:20]=[CH:21][C:22]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:23][C:18]=1[CH3:17]
Reactant: Cc1cc(OC(F)(F)F)ccc1N
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Agent: Cl
Solvent: CCOCC
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccc(OC(F)(F)F)cc1C
Temperature: 140 °C

Procedure:
4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4 (0.50 g, 2.15 mmol) is suspended in xylenes (3 mL) and 2-methyl-4-trifluoromethoxy-phenylamine (1.00 g, 5.23 mmol) is added. The reaction mixture is stirred at 140° C. under N2. After stirring for 7 days, the reaction is a mixture of starting material and product. The reaction mixture is cooled to room temperature. The reaction mixture is poured into a separatory funnel and diethyl ether and 10% aqueous HCl are added and the layers separated. The aqueous phase is extracted with three portions of diethyl ether. The combined diethyl ether layers are dried (MgSO4) and concentrated under reduced pressure. The residue is redissolved in methylene chloride and flushed through a plug of silica gel eluting with methylene chloride. The filtrate is concentrated under reduced pressure to give a bright yellow solid. The solid is washed with diethyl ether and the filtrate is concentrated under reduced pressure and the residue is further purified by FCC (eluting with 100% methylene chloride) to yield 0.39 g (45%) of the desired pure product as a yellow solid. MS APCI (−) m/z 402 (M−1) detected.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].S(OC)(O[CH3:23])(=O)=O.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:23][O:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1OC

Procedure:
A mixture of compound 68b (0.543 mmol, 150 mg), dimethyl sulfate (0.608 mmol, 0.058 mL), and sodium bicarbonate (0.57 mmol, 48 mg) in acetone was heated at reflux overnight. The reaction mixture was cooled and filtered. The filtrate was concentrated and the residue was partitioned between EtOAc and water. The organic solution was concentrated and purified by flash column chromatography (silica gel, 10% EtOAc/hexanes) to give compound 68c.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:7][OH:8])[CH2:4][CH2:5][OH:6].CO[C:11](OC)([CH3:13])[CH3:12].C(N(CC)CC)C>O1CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:6][CH2:5][CH2:4][CH:3]1[CH2:7][O:8][C:11]([CH3:13])([CH3:12])[O:1][CH2:2]1
Reactant: COC(C)(C)OC
Reactant: OCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CCO)CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
To a solution of 1,4-dihydroxy-2-hydroxymethylbutane (12 g, 100 mmol) in tetrahydrofuran (25 ml), 2,2-dimethoxypropane (13.5 g, 110 mmol) and p-toluenesulphonic acid monohydrate (0.57 g, 3 mmol) were added. The solution was stirred for 0.5 hour at room temperature and was then neutralised by addition of triethylamine. The solvent was removed and the residue purified by column chromatography on silica gel eluting with chloroform-methanol mixtures to afford 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan as a clear colourless liquid (6.5 g, 41%).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[C:9]([N:17]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH:18]1[CH2:22][N:21]([CH2:23][CH3:24])[CH2:20][CH:19]1[OH:25])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+].O>CO>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[C:9]([N:17]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]1[CH2:22][N:21]([CH2:23][CH3:24])[CH2:20][C@H:19]1[OH:25])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN1CC(O)C(N(C(=O)c2ccccc2)C2CCCCC2)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN1C[C@@H](O)[C@H](N(C(=O)c2ccccc2)C2CCCCC2)C1

Procedure:
A mixture of 4.8 g (9 mmole) of trans-benzoic acid ester with 4-[(benzoyl)(cyclohexyl)amino]-1-ethyl-3-pyrrolidinol fumarate [1:1], 1.7 g (30 mmole) of potassium hydroxide, 10 ml of water and 40 ml of methanol was heated on a steam bath for 1 hr. then concentrated to approximately 5-10 ml volume under reduced pressure. The residue was partitioned between water and methylene chloride and the organic layer was dried and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and 1.0 g fumaric acid added and the precipitate was collected. After recrystallization from ethyl acetate, 2.7 g (72%) of white powder, m.p. 145.0°-146.5° C. was obtained.