Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N[C:5](=[CH:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=1)[C:6]([O:8]C)=[O:7])(=O)C.Cl.[O:26]1CCOCC1>>[F:22][C:21]([F:24])([F:23])[C:13]1[CH:12]=[C:11]([CH2:10][C:5](=[O:26])[C:6]([OH:8])=[O:7])[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=1
Reactant: C1COCCO1
Reactant: COC(=O)C(=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC(C)=O
Agent: Cl
Product: O=C(O)C(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
19.5 g (54.9 mmol) methyl 2-acetylamino-3-(3,5-bis-trifluoromethyl-phenyl)-acrylate in 100 mL 1,4-dioxane were heated to 100° C. bath temperature, combined with 100 mL 4 M HCl and stirred for 8 h at 100° C. bath temperature. The reaction mixture was evaporated down i. vac., the crystals were suction filtered, washed with water and dried in the drying cupboard at 50° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=1.Cl[C:28]1[N:33]=[CH:32][C:31]([Br:34])=[CH:30][N:29]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:34][C:31]1[CH:30]=[N:29][C:28]([N:24]2[CH2:25][CH2:26][CH:21]([CH2:20][O:19][C:16]3[CH:15]=[CH:14][C:13]([C:4]4[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:3]=4[F:2])=[CH:18][CH:17]=3)[CH2:22][CH2:23]2)=[N:33][CH:32]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cc2)c(F)c1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(c4ncc(Br)cn4)CC3)cc2)c(F)c1
Temperature: 100 °C
Yield: 91 %

Procedure:
A mixture of 4-({[2′-fluoro-4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (Example 66, Step 1, 0.12 g, 0.30 mmol), 2-chloro-5-bromopyrimidine (89 mg, 0.45 mmol) and K2CO3 (0.13 g, 0.90 mmol) in DMSO (5 mL) was degassed, purged with N2 and heated at 100° C. overnight. The mixture was allowed to cool to ambient temperature, and was poured into water (50 mL) and extracted with EtOAc. The combined organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow solid. The crude product was triturated with hot hexanes containing 1% of MeOH to give 0.142 g (91%) of the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 2H), 7.80-7.70 (m, 2H), 7.65-7.55 (m, 1H), 7.50 (d, 2H, J=7.6 Hz), 6.99 (d, 2H, J=8.7 Hz), 4.85-4.75 (m, 2H), 3.88 (d, 2H, J=6.3 Hz), 3.09 (s, 3H), 3.00-2.90 (m, 2H), 2.20-2.05 (m, 1H), 2.00-1.90 (m, 2H), 1.45-1.30 (m, 2H); LRMS (ESI), m/z 520/522 (M+H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:33][CH:32]2[NH:34][CH2:35][CH:27]1[CH2:28][CH:29]=[CH:30][CH2:31]2.CCN(C(C)C)C(C)C>C(O)C>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:33][CH:32]2[N:34]([CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]3[CH:15]=[CH:14][CH:13]=[C:12]4[C:7]=3[CH:8]=[CH:9][CH:10]=[N:11]4)[CH2:35][CH:27]1[CH2:28][CH:29]=[CH:30][CH2:31]2
Reactant: c1cc(OCC2CO2)c2cccnc2c1
Reactant: C1=CCC2CNC(C1)CN2c1ccc2ccccc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: OC(COc1cccc2ncccc12)CN1CC2CC=CCC1CN2c1ccc2ccccc2c1

Procedure:
5-Oxiranylmethoxy-quinoline (13 mg, 0.065 mmol), 7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (20 mg, 0.042 mmol), DIPEA (0.1 mL, 0.55 mmol) and ethanol (2 mL) were μW for 900 sec at 130° C. in a μW reaction tube. The solvent was evaporated in vacuo to yield a crude solid that was purified with flash chromatography gradient [30% EtOAc/heptane to 100% EtOAc] to yield the title compound as its free base, as a residue.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9](=[N:12][OH:13])[C:8]2[N:14]([CH3:17])[CH:15]=[CH:16][C:7]=2[S:6]1(=[O:19])=[O:18].Cl.[F:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].[I-].[Na+]>C(#N)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:11][CH2:10][C:9](=[N:12][OH:13])[C:8]4[N:14]([CH3:17])[CH:15]=[CH:16][C:7]=4[S:6]3(=[O:19])=[O:18])[CH2:30][CH2:29]2)=[O:27])=[CH:34][CH:35]=1
Reactant: Cn1ccc2c1C(=NO)CCN(CCCCl)S2(=O)=O
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: Cn1ccc2c1C(=NO)CCN(CCCN1CCC(C(=O)c3ccc(F)cc3)CC1)S2(=O)=O
Yield: 95 %

Procedure:
A suspension of 112 mg (0.4 mmol) of Compound 20, 97 mg (0.4 mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride, 134 mg (1.6 mmol) of sodium hydrogencarbonate and 120 mg (0.8 mmol) of sodium iodide in 5 ml of acetonitrile was refluxed for 14 hours. Post treatment and purification were conducted as in Example 15, whereby 181 mg of the title compound were obtained (yield: 95%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][OH:7])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:27]1([CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][C:41]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:35][CH2:34][CH2:33][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH3:3]
Reactant: Oc1ccccc1CCCc1ccccc1
Reactant: CN(C)CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)CCCOc1ccccc1CCCc1ccccc1
Yield: 35.7 %

Procedure:
134 mg of 3-(N,N-dimethylamino)propanol and 342 mg of triphenyl phosphine were added to a solution of 230 mg of 2-(3-phenylpropyl)phenol (prepared as described in Preparation 29) in 10 ml of methylene chloride, and the mixture was cooled with ice and stirred. 227 mg of diethyl azodicarboxylate were then added dropwise to the solution, and the mixture was stirred at room temperature for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and ethyl acetate and water were added to the residue and shaken. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 115 mg (yield 36%) of the title compound as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:22]=3)=[CH:19][N:20]=2)=[CH:11][C:10]=1[CH2:32][CH3:33])C1C=CC=CC=1>C1COCC1.CCO.[Pd]>[CH2:32]([C:10]1[CH:11]=[C:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([CH2:28][CH:29]([CH3:30])[CH3:31])[CH:22]=3)=[CH:19][N:20]=2)[CH:13]=[C:14]([CH3:15])[C:9]=1[OH:8])[CH3:33]
Reactant: CCc1cc(-c2ncc(-c3cc(C)nc(CC(C)C)c3)o2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cc(-c2ncc(-c3cc(C)nc(CC(C)C)c3)o2)cc(C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
To a solution of 4-[2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-oxazol-5-yl]-2-isobutyl-6-methyl-pyridine (29 mg, 66 μmol) in THF (0.5 mL) and EtOH (0.5 mL), Pd/C (10 mg, 10% Pd) is added. The mixture is stirred at rt under 1 bar of H2 for 16 h. The catalyst is filtered off and the filtrate is concentrated. The residue is again treated with Pd/C and H2 at rt for 24 h as described before. The catalyst is filtered off and the filtrate is evaporated. The crude product is purified on prep. TLC using heptane:EA 1:1 to give 2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-oxazol-2-yl]-6-methyl-phenol (11 mg) as a pale yellow glass; LC-MS: tR=0.97*, [M+1]+=351.11; 1H NMR (CDCl3): δ 0.99 (d, J=6.5 Hz, 6 H), 1.33 (t, J=7.5 Hz, 3 H), 2.12-2.22 (m, 1 H), 2.37 (s, 3 H), 2.63 (s, 3 H), 2.66-2.79 (m, 4 H), 5.35 (s br, 1 H), 7.21 (s, 1 H), 7.29 (s, 1H), 7.58 (s, 1 H), 7.80 (s, 2 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH3:15][C:16]1[S:17][C:18]([CH3:26])=[CH:19][C:20]=1/[CH:21]=[CH:22]/[C:23]([Cl:25])=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:25].[CH3:15][C:16]1[S:17][C:18]([CH3:26])=[CH:19][C:20]=1/[CH:21]=[CH:22]/[C:23]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Cc1cc(/C=C/C(=O)Cl)c(C)s1
Reactant: Nc1ccccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1cc(/C=C/c2nc3ccccc3n2-c2ccccn2)c(C)s1

Procedure:
To a solution of (E)-3-(2,5-dimethylthiophene-3-yl)acrylic acid (328 mg, 1.8 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-3-(2,5-dimethylthiophene-3-yl)acryloyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (250 mg, 1.4 mmol) and (E)-3-(2,5-dimethylthiophene-3-yl)acryloyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound. MW: 367.91; mp:>230° C.; 1H-NMR (CDCl3) δ: 8.98-8.83 (2H, m), 8.25-8.16 (1H, m), 8.10-8.02 (1H, m), 7.76-7.68 (2H, m), 7.60-7.42 (3H, m), 6.78-6.73 (1H, m), 6.61 (1H, d, J=16.1 Hz), 2.75 (3H, s), 2.38 (3H, s).
Reaction SMILES: [CH:1]([N-:3][CH:4]=[O:5])=[O:2].[Na+].C(#N)C.Cl[CH2:11]/[C:12](=[CH:22]/[F:23])/[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[Cl-].[Na+]>C1(C)C=CC=CC=1.O.CN(C)C=O>[F:23]/[CH:22]=[C:12](\[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)/[CH2:11][N:3]([CH:4]=[O:5])[CH:1]=[O:2]
Reactant: O=C[N-]C=O
Reactant: F/C=C(/CCl)CCc1ccc(F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=CN(C=O)C/C(=C/F)CCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Combine sodium diformylamide (70 lb) and acetonitrile (903 lb). With agitation, add N,N-dimethylformamide (119 lb). Add a solution of (E)-1-chloro-2-(fluoromethylene)-4-(p-fluorophenyl)butane (126 lb) in toluene. Warm to 80° C. After 6 hours, add a 10% by weight solution of sodium chloride in water (1168 lb). Agitate for 15 minutes, separate the layers. Remove the organic layer to give the title compound as a solution in acetonitrile/N,N-dimethylformamide.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+]>CCOCC>[C:7]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: COc1cc(C(C)(C)C)ccc1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1cc(C(C)(C)C)ccc1CN
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
Lithium aluminium hydride (50 mg) was suspended in ether (2 ml) and the suspension was cooled to 0° C. To the suspension was added dropwise a solution of the compound 13-2a (167 mg) prepared by Step 1 in ether (2 ml) and the mixture was refluxed for 2 hours. After the completion of the reaction, the reaction solution was basified with 5 N aqueous sodium hydroxide solution. Then, aqueous Rochel solution was added thereto and stirred for 1 hour, at room temperature. Then, resulting mixture was extracted with ether (50 ml×3) and concentrated under reduced pressure to yield the compound 13-3a (120 mg, 71%). The following Step 3 was proceeded using the compound 13-3a which was not purified.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C@H:10]2[C@@H:14]3[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@@H:13]3[C@@H:12]([CH2:20][N:21]([CH3:36])[CH2:22][CH2:23][CH2:24][N:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])[CH2:11]2)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[CH:37]([O-])([O-])OCC>C(O)(=O)C>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]2[C:2]=1[N:1]=[CH:37][N:9]2[C@H:10]1[C@@H:14]2[O:15][C:16]([CH3:18])([CH3:19])[O:17][C@@H:13]2[C@@H:12]([CH2:20][N:21]([CH3:36])[CH2:22][CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]2=[O:34])[CH2:11]1
Reactant: CCOC([O-])[O-]
Reactant: CN(CCCN1C(=O)c2ccccc2C1=O)C[C@H]1C[C@@H](Nc2ncnc(Cl)c2N)[C@@H]2OC(C)(C)O[C@H]12
Solvent: CC(=O)O
Product: CN(CCCN1C(=O)c2ccccc2C1=O)C[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A solution of 2-(3-((((3aR,4R,6R,6aS)-6-((5-amino-6-chloropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)propyl)isoindoline-1,3-dione (0.22 g, 0.39 mmol) in ethyl orthoformate (2.3 mL, 14 mmol) was treated with acetic acid (8 drops) and heated at reflux for 3.25 h; HPLC indicated nearly complete consumption of starting material. The reaction mixture was cooled to rt, diluted with toluene (10 mL), and concentrated in vacuo to remove most of the volatiles, and further concentrated under the flow of air. The resulting clear, dark brown oil was purified by column chromatography (2×22 cm silica; 0-1% 7 N NH3 in CH3OH/CH2Cl2) to afford the title compound (0.19 g, 85%) as a pale yellow foam: MS (ESI+) for C26H29ClN6O4 m/z 525.2 [M+H]+; HPLC purity 92% (ret. time, 2.917 min).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]1[CH2:14][CH:13]([CH3:15])[C:12](=[N:16]O)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C.[Ni]>[CH2:3]([N:10]1[CH2:14][CH:13]([CH3:15])[CH:12]([NH2:16])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC1CN(Cc2ccccc2)CC1=NO
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1CN(Cc2ccccc2)CC1N
Yield: 712.6 %

Procedure:
90 ml of a 20% w/v aqueous solution of sodium hydroxide were added to a solution of 12 g (0.059 mole) of 1-benzyl-3-(hydroxyimino)-4-methylpyrrolidine [prepared as described in Step (5) above] dissolved in 100 ml of ethanol. 23.9 g of Raney nickel (about 50%) were gradually added to the mixture, whilst vigorously stirring it. After the reaction mixture had been stirred for 3 hours, it was filtered. The upper layer of the filtrate was separated and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel eluted with methanol, to give 80 g of 1-benzyl-3-amino-4-methylpyrrolidine as a pale yellow liquid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH2:16][NH2:17])[C:10]=2[N:9]=[CH:8]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:30]=[C:29]([CH:31]3[CH2:33][CH2:32]3)[NH:28][N:27]=2)[C:22]([F:34])=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:31]1([C:29]2[CH:30]=[C:26]([NH:25][C:23]3[C:22]([F:34])=[CH:21][N:20]=[C:19]([NH:17][CH2:16][C:15]4[C:10]5[N:9]=[CH:8][N:7]([CH:2]6[CH2:3][CH2:4][CH2:5][CH2:6][O:1]6)[C:11]=5[CH:12]=[CH:13][CH:14]=4)[N:24]=3)[NH:27][N:28]=2)[CH2:33][CH2:32]1
Reactant: Fc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Reactant: NCc1cccc2c1ncn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cnc(NCc2cccc3c2ncn3C2CCCCO2)nc1Nc1cc(C2CC2)n[nH]1
Temperature: 120 °C
Yield: 56.7 %

Procedure:
A tube was charged with 58 (273 mg, 1.18 mmol), 55 (150 mg, 0.59 mmol), DIPEA (0.5 ml) and IPA (4 mL), degassed, sealed and heated at 120° C. for 72 h. The solvent was evaporated in vacuo to afford 150 mg (57%) of N4-(3-cyclopropyl-1H-pyrazol-5-yl)-5-fluoro-N2-((1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)methyl)pyrimidine-2,4-diamine (280)—as yellow solid: MS (ESI) m/z=449.7 [M+1]+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([CH3:26])[NH:7][C:8](=[O:25])[C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH:1]1([C:4]2[N:5]=[C:6]([CH3:26])[N:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:8](=[O:25])[C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:2][CH2:3]1
Reactant: OB(O)c1ccccc1
Reactant: Cc1nc(C2CC2)c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc(C2CC2)c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.3 %

Procedure:
A mixture of 4′-[(4-cyclopropyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.02 g), phenylboronic acid (0.73 g), molecular sieves 4 A (0.51 g), triethylamine (2.1 mL), pyridine (1.0 mL), copper(II) acetate (1.09 g) and methylene chloride (20 mL) was stirred at room temperature for 24 hr. Ethyl acetate was added to the reaction mixture, and the insoluble solid was filtered off. The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.44 g, 35%).
Reaction SMILES: [CH3:1][N:2]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)[NH:4][C:3]1=[O:27].I[C:29]1[C:30]([O:35][CH3:36])=[N:31][O:32][C:33]=1[CH3:34].C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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>[CH3:36][O:35][C:30]1[C:29]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3](=[O:27])[N:2]([CH3:1])[CH:11]3[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:33]([CH3:34])[O:32][N:31]=1
Reactant: CN1C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1c1ccccc1
Reactant: COc1noc(C)c1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)N(C)C(=O)N2
Temperature: 120 °C

Procedure:
3-Methyl-4-phenyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinazolin-2-one (457 mg, 1.255 mmol), 4-Iodo-3-methoxy-5-methyl-isoxazole (150 mg, 0.628 mmol), potassium carbonate (173 mg, 1.255 mmol) and Pd(dppf)Cl2 (102.5 mg, 0.126 mmol) are added to a microwave vessel. Dimethoxyethane (0.1 mL) and water (0.1 mL) are added and the vessel flushed with argon. The mixture is heated in a microwave reactor at 120° C. for 3.5 hours. The reaction mixture is extracted with ethyl acetate from water. The organic phase is dried over Na2SO4 and the solvent is removed on a rotary evaporator. The residue is purified by reversed phase HPLC.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH3:16][Si:17]([CH3:21])([CH3:20])[CH2:18][NH2:19].Cl.CN(C)CCCN=C=NCC.O>ClCCl>[Br:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:19][CH2:18][Si:17]([CH3:21])([CH3:20])[CH3:16])=[O:15])=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)CN
Reactant: O=C(O)c1ccc(CBr)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CNC(=O)c1ccc(CBr)c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.7 %

Procedure:
4-(bromomethyl)naphthalen-1-carboxylic acid (7 g), 1-(trimethylsilyl)methylamine (2.7 g), N,N-dimethylaminopyridine (0.1 g) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (6.6 g) were dissolved in dichloromethane (30 ml), and stirred for 5 hours at room temperature. Water was added to the reaction mixture, and then organic layers, were separated and dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 4-(bromomethyl)-N-[(trimethylsilyl)methyl]naphthalene-1-carboxamide (3 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[O:15])=[C:9]3[N:8]=[C:7]([C:16]3[S:20][C:19]([C:21]([OH:23])=O)=[CH:18][CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1.C[N:25](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[O:15])=[C:9]3[N:8]=[C:7]([C:16]3[S:20][C:19]([C:21]([NH2:25])=[O:23])=[CH:18][CH:17]=3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(C(=O)O)s3)nc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(-c2cc(NC3CC3)n3ncc(C=O)c3n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.2 %

Procedure:
To 5-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid (40 mg, 0.122 mmol), HATU (70 mg, 0.183 mmol), HOBt (4 mg, 0.024 mmol) and DIEA (85 μL, 0.488 mmol) in 2 mL of DMF was added ammonium chloride (20 mg, 0.366 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate washed with saturated NaHCO3 solution, brine, dried over MgSO4, filtered, and evaporated to dryness to provide 42 mg of 5-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxamide (100%). LCMS (M+1=328).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]([CH2:16][CH2:17][CH2:18][CH3:19])[C:5]=2[NH:4][N:3]=1.Br[CH2:21][CH2:22][Cl:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:3]([CH2:21][CH2:22][Cl:23])[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]2[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: ClCCBr
Reactant: CCCCn1c(=O)n(CCC)c(=O)c2c(N)n[nH]c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCC)c(=O)c2c(N)n(CCCl)nc21
Reaction time: 12 h
Yield: 66 %

Procedure:
A mixture of 3-amino-7-butyl-5-propylpyrazolo[3,4-d]pyrimidine-4,6(5H, 7H)-dione(8 g), 1-bromo-2-chloroethane(3.7 ml) and potassium carbonate(6.2 g) in DMF(100 ml) was stirred at 50°-60° C. for 12 hr. The reaction mixture was concentrated to dryness, and the concentrate was extracted with chloroform/water. The chloroform layer was washed with water, dried and concentrated to obtain a brown syrup, which was purified by flash chromatography(silica gel 100 g, chloroform). The purified syrupy product was crystallized from isopropylether to obtain colorless needles(21.5 g,66%), m.p. 118°-121° C.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]=[CH:20][CH:21]([CH3:23])[CH3:22])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)C=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)CCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4fluorophenyl)-5-(3-methyl-1-butenyl)pyridine (Example 27) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.14 (m, 4 H) 4.33 (d, J=5.5 Hz, 2 H), 3.41 (sept, J=6.6 Hz, 1 H), 3.22 (sept, J=6.6 Hz, 1 H), 2.27 (m, 2 H), 1.35 (m, 1 H), 1.33 (d, J=7 Hz, 6 H), 1.30 (d, J=7 Hz, 6 H), 1.17 (m, 3 H), 0.70 (d, J=6.6 Hz, 6 H). FAB-MS: calculated for (C23H32FNO) 357, found 358 (M+H). Anal. Calcd for C23H32FNO: C, 77.27; H, 9.02; N, 3.92. Found: C, 77.34; H, 9.15; N, 3.69. mp 43-45° C. Rf=0.2 (20% ethyl acetate/hexane).