Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([OH:18])=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])[CH3:3].Cl.[CH2:20]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>ClCCl>[CH2:20]([O:27][C:28]([C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:16](=[O:18])[C@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:34])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Boc-D-α-phenylglycine (2 mmol), L-proline benzyl ester hydrochloride (2.2 mmol), and DIPEA (5 mmol) in dry dichloromethane (10 mL) was added TBTU (2.2 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and the residue was passed through a SCX-2 column and further chromatographied to yield compound 2a. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.40 (s, 9H), 1.76-1.82 (m, 1H), 1.92-2.07 (m, 3H), 3.09-3.15 (m, 1H), 3.70-3.77 (m, 1H), 4.47-4.51 (m, 1H), 5.16 (d, J=12.35 Hz, 1H), 5.23 (d, J=12.35 Hz, 1H), 5.43 (d, J=7.20 Hz, 1H), 6.12 (d, J=7.20 Hz, 1H), 7.27-7.41 (m, 10H); and MS (ESI, EI+) m/z=439 (MH+).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:36]1[N:40]=[C:39]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[S:38][N:37]=1.[F:47][C:48]1[CH:57]=[C:56]2[C:51]([C:52]([NH2:65])=[C:53]([CH3:64])[C:54]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=3)=[N:55]2)=[CH:50][CH:49]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:47][C:48]1[CH:57]=[C:56]2[C:51]([C:52]([NH:65][C:36]3[N:40]=[C:39]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[S:38][N:37]=3)=[C:53]([CH3:64])[C:54]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=3)=[N:55]2)=[CH:50][CH:49]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N
Reactant: Brc1nsc(N2CCOCC2)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1nsc(N2CCOCC2)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.018 g, 0.038 mmol), 4-(3-bromo-1,2,4-thiadiazol-5-yl)morpholine (0.059 g, 0.24 mmol), 7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.06 g, 0.24 mmol) and Pd2 dba3 (0.009 g, 9.48 μmol) in toluene (2.4 mL) was added sodium tert-butoxide (0.057 g, 0.592 mmol). The reaction mixture was heated to 100° C. and stirred for 1 hour. The crude reaction mixture was filtered through a plug of alumina eluting with (dichloromethane/methanol; 3/1), the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on alumina (0-60% ethyl acetate/hexanes) to give the desired product. The desired product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions were concentrated then diluted with ethyl acetate. After washing twice with saturated aq. sodium bicarbonate solution, the solvent was removed under reduced pressure to yield pure product N-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-5-morpholino-1,2,4-thiadiazol-3-amine. 1H NMR (400 MHz, CD2Cl2) δ ppm 8.65 (1H, d, J=3.9 Hz), 8.03 (1H, dd, J=9.2, 5.9 Hz), 7.94 (1H, td, J=7.7, 1.8 Hz), 7.74 (1H, d, J=7.8 Hz), 7.67 (1H, dd, J=10.0, 2.7 Hz), 7.39-7.49 (1H, m), 7.32 (1H, ddd, J=9.3, 8.2, 2.4 Hz), 3.71-3.83 (4H, m), 3.37-3.50 (4H, m), 2.28 (3H, s). Mass Spectrum (ESI) m/e=423.2 (M+1). Biological Assays Recombinant Expression of PI3Ks Full length p110 subunits of PI3k α, β and δ, N-terminally labeled with polyHis tag, were coexpressed with p85 with Baculo virus expression vectors in sf9 insect cells. P110/p85 heterodimers were purified by sequential Ni-NTA, Q-HP, Superdex-100 chromatography. Purified α, β and δ isozymes were stored at −20° C. in 20 mM Tris, pH 8, 0.2M NaCl, 50% glycerol, 5 mM DTT, 2 mM Na cholate. Truncated PI3Kγ, residues 114-1102, N-terminally labeled with polyHis tag, was expessed with Baculo virus in Hi5 insect cells. The γ isozyme was purified by sequential Ni-NTA, Superdex-200, Q-HP chromatography. The γ isozyme was stored frozen at −80° C. in NaH2PO4, pH 8, 0.2M NaCl, 1% ethylene glycol, 2 mM β-mercaptoethanol.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([S:10](Cl)(=[O:12])=[O:11])[CH3:9].[NH2:14][C:15]1[C:16]([NH:30][CH2:31][CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)=[CH:17][C:18]([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]#[N:29])=[CH:24][N:23]=2)=[N:19][CH:20]=1>CN(C=O)C>[C:28]([C:25]1[N:26]=[CH:27][C:22]([NH:21][C:18]2[N:19]=[CH:20][C:15]([NH:14][S:10]([CH2:8][CH3:9])(=[O:12])=[O:11])=[C:16]([NH:30][CH2:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:17]=2)=[N:23][CH:24]=1)#[N:29]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)CC1
Reactant: CCS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
Triethylamine (15 μL, 0.11 mmol) and ethylsulfonylchloride (8 μL, 0.78 mmol) were added to a stirred solution of tert-butyl 4-((5-amino-2-(5-cyanopyrazin-2-ylamino)-pyridin-4-ylamino)-methyl)-piperidine-1-carboxylate (30.3 mg, 0.071 mmol) in DMF (1 mL) at 0° C. After 1.5 hours at room temperature, further ethylsulfonylchloride (5.5 μL, 0.53 mmol) and triethylamine (7.5 μL, 0.53 mmol) were added. After 1 hour the reaction mixture was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and concentrated. Preparative HPLC gave N-(6-(5-cyanopyrazin-2-ylamino)-4-(1-Boc-piperidin-4-ylmethylamino)pyridin-3-yl)ethanesulfonamide as a solid. The material was dissolved in 20% trifluoroacetic acid in dichloromethane. After 20 minutes the mixture was loaded onto a MP-TsOH SPE cartridge and eluted with 2M ammonia in methanol. The basic fractions were combined to give N-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)ethanesulfonamide (2.28 mg, 8%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)[CH:19]=[N:18][CH:17]=4)=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1.Cl>O1CCOCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[C:20]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[N:21]=4)=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3[nH]cc(-c4cncc(N5CCN(C(=O)OC(C)(C)C)CC5)n4)c3c2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3[nH]cc(-c4cncc(N5CCNCC5)n4)c3c2)cn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-butyl 4-{6-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl}piperazine-1-carboxylate (0.047 g, 0.10 mmol) was suspended in dioxane (1.0 ml). 4M HCl in dioxane (1.0 ml) was added, and the reaction mixture was stirred at room temperature for 45 min. The reaction mixture was filtered to afford 5-(1-methyl-1H-pyrazol-4-yl)-3-(6-piperazin-1-ylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine as an orange/yellow solid (hydrochloride salt). 1H NMR (600 MHz, DMSO-D6) 12.4 (br s, 1H); 9.41 (br s, 2H); 8.71 (br d, 1H); 8.56 (s, 1H); 8.55 (d, 1H); 8.39 (d, 1H); 8.19 (s, 1H); 8.18 (s, 1H); 7.89 (s, 1H); 3.93 (br t, 4H); 3.87 (s, 3H); 3.25 (br m, 4H). LRMS calculated for C19H20N8 [M+H]+, 361.2; found 361.2.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[O:20]=[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccccn1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(Cn2ccccc2=O)cc1)c1ccccc1
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 2-hydroxypyridine. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.12 (s, 2H), 6.13 (t, 1H), 6.60 (d, 1H), 7.10 (br s, 2H), 7.22-7.41 (m, 9H); HPLC-MS: m/z=335.2 (M+1); Rt=2.97 min.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:22])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH2:23]([OH:45])[C@H:24]1[O:29][C@H:28]([O:30][C@H:31]2[C@H:36]([OH:37])[C@@H:35]([OH:38])[C@H:34]([OH:39])[O:33][C@@H:32]2[CH2:40]O)[C@H:27]([OH:42])[C@@H:26]([OH:43])[C@@H:25]1[OH:44]>[Pd].CO>[CH2:6]([O:5][CH2:4][CH:3]([OH:22])[CH2:2][N:1]([C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:40][C@@H:32]([C@H:31]([C@@H:36]([C@@H:35]([CH2:34][OH:39])[OH:38])[OH:37])[O:30][C@H:28]1[O:29][C@H:24]([CH2:23][OH:45])[C@@H:25]([OH:44])[C@H:26]([OH:43])[C@H:27]1[OH:42])[OH:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCCCCCCCCCOCC(O)CN(C[C@H](O)[C@@H](O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)[C@H](O)CO)C(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
A 1-liter eggplant type flask equipped with a reflux condenser was charged with 22.7 g (72 mmol) of 1-amino-3-hexadecyloxy-2-propanol, 23.5 g (69 mmol) of maltose and 350 g of methanol. After stirring the mixture for 20 hours at room temperature under a nitrogen atmosphere, it was heated and stirred at 80° C. for 1 hour. The thus-obtained solution was transferred to a 970-ml autoclave, and 2.26 g of palladium on carbon was added, thereby subjecting the solution to hydrogenolysis at 50° C. for 16 hours under a hydrogen pressure of 100 kg/cm2. The catalyst was removed by filtering the hot mixture, and the filtrate was allowed to cool to form crystals. The crystals were recrystallized again from methanol, thereby obtaining 15.2 g (yield: 33%) of the title compound (2Be) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[S:17][C:18]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:19]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:15][C:16]2[S:17][C:18]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:7])[CH:8]=[CH:9][N:10]=1
Reactant: Nc1nc(-c2ccco2)c(N2CCOCC2)s1
Reactant: O=C(O)c1ccnc(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccnc(Cl)c1
Yield: 53.7 %

Procedure:
2-Chloroisonicotinic acid (5.00 g, 31.7 mmol) was added to thionyl chloride (40 mL), followed by stirring under heating and reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (1 mL). The resulting solution was added to a pyridine (16 ml) solution of 2-amino-4-(2-furyl)-5-morpholinothiazole (880 mg, 5.00 mmol) obtained in Step 1 of Example 29, and then N,N-dimethylaminopyridine (48.8 mg, 0.400 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:3 to ethyl acetate) to afford the entitled Compound 39 (1.05 g, 66%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:30]1[CH:31]=[CH:32][C:33]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[CH:34][CH:35]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(N2CCOCC2)cc1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2c(cc(-c3ccc(N4CCOCC4)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 44.4 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.21 mmol), 4-(4-tributylstannanyl-phenyl)-morpholine (0.12 mL, 0.31 mmol), and PdCl2(PPh3)2 (29 mg, 0.041 mmol) in DMF (5 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine (10 mL) and EtOAc (20 mL) were added. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent, the crude product was purified by silica gel chromatography (5-70% EtOAc/hexanes+2% AcOH) to give 44 mg of the title compound. MS: (+) m/z 472.34 (M+1).
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([C:29]2[S:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[N:23][C:24]=3Cl)[O:7]1)(=O)C.[NH3:35]>>[NH2:35][C:24]1[N:23]=[C:22]([C:29]2[S:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[N:21]=[C:20]2[C:25]=1[N:26]=[CH:27][N:19]2[C@H:8]1[C@H:9]([OH:15])[C@H:10]([OH:11])[C@@H:6]([CH2:5][OH:4])[O:7]1
Reactant: N
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(-c4ccc(C)s4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1ccc(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)s1
Temperature: 40 °C

Procedure:
Compound 12 (50 mg, 0.1 mmol) was dissolved in 5 mL methanolic ammonia (saturated at 0° C.) and the mixture was heated at 40° C. for 24 h. After concentration in vacuo, the residue was purified using prep. TLC (10% MeOHIDCM) to afford 13 1HNMR (CD3OD)δ2.5 (s, 3 H) 3.75 (d, 1 H), 3.85 (d, 1 H), 4.15 (d, 2 H) 4.45 (m, 1 H), 4.85 (m, 1 H), 6.0 (d, 1 H), 6.75 (d, 1 H), 7.7 (d, 1 H), 8.25 (s, 1 H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]=[C:12]([CH2:15][CH2:16][C:17]#[N:18])[C:13]#[N:14]>C(OCC)C>[CH2:3]([O:10][CH2:11][CH:12]([CH2:15][CH2:16][C:17]#[N:18])[C:13]#[N:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=C(C#N)CCC#N
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: N#CCCC(C#N)COCc1ccccc1
Reaction time: 24 h

Procedure:
A 50% dispersion of sodium hydride in mineral oil (200 mg.) was added to benzyl alcohol (32.4 g.) and the mixture was stirred until effervescence had ceased. The solution was treated with 2-methyleneglutaronitrile (15.9 g.)and the mixture was kept at room temperature for 24 hours. The reaction mixture was diluted with diethyl ether and the solution was washed three times with water, and then dried and evaporated to dryness to give 2-(benzyloxymethyl)glutaronitrile (32 g.). The crude 2-(benzyloxymethyl)glutaronitrile was reduced with borane-dimethyl sulphide complex in a similar process to that described in Example 1 to give 2-(benzyloxymethyl)pentane-1,5-diamine dihydrochloride, m.p. 159°-161° (after crystallisation from ethanol).
Reaction SMILES: OC(C(F)(F)F)=O.[CH2:8]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19](Cl)=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][C:33]=4[F:40])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:42][CH:43]([NH2:45])[CH3:44].CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:8]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:45][CH:43]([CH3:44])[CH3:42])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][C:33]=4[F:40])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(OC2CCN(c3nc4c(nc3Cl)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Reactant: CC(C)N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CCN(Cc1ccccc1)C2
Temperature: 90 °C

Procedure:
A solution of 4-((1-(6-benzyl-3-chloro-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile TFA salt (213.9 mg, 0.361 mmol) in toluene (1.44 mL) was treated with propan-2-amine (0.118 mL, 1.445 mmol), sodium tert-butoxide (69.4 mg, 0.723 mmol), BINAP (22.5 mg, 0.036 mmol), and Pd2(dba)3 (16.5 mg, 0.018 mmol). Nitrogen gas was bubbled through the solution for 5 min. The reaction mixture was then sealed and the reaction mixture was heated to 90° C. overnight. The reaction mixture was allowed to cool to room temperature. Solvent was removed under reduced pressure and the residue was purified by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 40% to 70% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (105 mg, 47.3%). ESI-MS m/z [M+H]+ 501.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH2:15][CH3:16])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[N:32]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:34][CH2:33]1)[CH3:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH2:15][CH3:16])[C:11]=1[O:12][CH3:13])[C:6]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:35]2[CH2:36][CH2:37][CH2:38][N:32]([C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:33][CH2:34]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:8]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: CCOc1cc(C(=O)O)cc(OC)c1OC
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OCC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 3,4-dimethoxy-5-ethoxybenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[Si:29]([O:36][C@@H:37]([CH3:64])[C@@H:38]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[C:56]([Cl:62])[C:55]=1[CH3:63])[C:39]([NH:41][NH:42][C:43](=O)[C:44]1[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=1)=[O:40])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl.CCOC(C)=O>[Si:29]([O:36][C@@H:37]([CH3:64])[C@@H:38]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[C:56]([Cl:62])[C:55]=1[CH3:63])[C:39]1[O:40][C:43]([C:44]2[CH:45]=[CH:46][C:47]([C:50]#[N:51])=[CH:48][CH:49]=2)=[N:42][N:41]=1)([C:32]([CH3:33])([CH3:35])[CH3:34])([CH3:30])[CH3:31]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
To a 1 L round bottom flask equipped with a magnetic stir bar and septum was added triphenylphosphine (12.3 g, 47.0 mmol) under an atmosphere of nitrogen. To this was added methylene chloride (500 mL) followed by addition of solid iodine (11.91 g, 47.0 mmol). This was allowed to stir at room temperature for a period of 10 min. then cooled to 0° C. Triethylamine (13.1 mL, 94 mmol) was then slowly added to this reaction (CAUTION: Exotherm). This mixture was allowed to stir at room temperature for an additional ten min., during which the reaction became a thick slurry. N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenyl-amino)butanoyl)-4-cyanobenzohydrazide (12.35 g, 23.5 mmol) was taken up in methylene chloride (200 mL) and slowly added to the heavily stirred reaction mixture. After a period of 10 min, TLC (1:1 EtOAc:hexanes) showed product formation and no starting material. The reaction was then quenched by slow addition of 10% Na2S2O3/H2O (500 mL). The organic layer was then isolated and washed with additional 10% sodium thiosulfate/water (1×200 mL), brine (1×200 mL), then dried (Na2SO4). The solution was then filtered and concentrated under reduced pressure to reveal a brown oil/so lid. This was purified via silica gel chromatography eluted with 25% EtOAc/hexanes to provide the title compound as a white solid (9.98 g, 84%): 1H NMR (400 MHz, CDCl3, δ in ppm) (AA′XX′, J=8.8 Hz, 2H), 7.79 (AA′XX′, J=8.8 Hz, 2H), 7.33 (d, J=8.7 Hz, 1H), 6.44 (d, J=8.7 Hz, 1H), 5.35 (d, J=8.8 Hz, 1H), 4.82 (dd, J=2.0, 8.7 Hz, 1H), 3.54 (m, 1H), 2.37 (s, 3H), 1.42 (d, J=6.2 Hz, 3H), 0.85 (s, 9H), 0.07 (s, 3H), −0.22 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:36]4[CH:37]=[CH:38][C:33]([O:32][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:34][CH:35]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(OCc5ccccc5)cc4)cc32)N=C1N
Temperature: 120 °C
Yield: 6.9 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL of flask under Ar2 was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(benzyloxy)phenylboronic acid (24 mg, 0.104 mmol). The mixture was heated under 120° C. at Ar2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 2′-amino-6-(4-(benzyloxy)phenyl)-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (1.75 mg, 7%). 1H-NMR (MeOD): 2.46 (m, 1H), 2.59 (m, 1H), 3.29 (s, 3H), 5.12 (s, 2H), 5.83 (m, 1H), 7.04 (m, 2H), 7.09 (m, 1H), 7.31 (m, 1H), 7.38 (m, 4H), 7.45 (m, 4H), 7.50 (m, 4H), 7.56 (m, 1H).