Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[CH:23]([C:29]#[N:30])C(OCC)=O)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].O>CS(C)=O.CCOC(C)=O>[C:29]([CH2:23][C:15]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=1[CH2:13][N:11]([CH3:12])[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)#[N:30]
Reactant: CCOC(=O)C(C#N)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(Cc1cc([N+](=O)[O-])ccc1CC#N)C(=O)OCc1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
36B (2.609 g, 6.34 mmol) was dissolved in DMSO (40 mL), lithium chloride (0.538 g, 12.68 mmol) and water (0.114 mL, 6.34 mmol) were added. The reaction mixture was stirred at 130° C. for 2 h, then cooled to rt, diluted with EtOAc (250 mL), washed with water (2×100 mL), brine (1×100 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (0-70% EtOAc/hexanes) to give 36C (1.803 g, 5.31 mmol, 84% yield) as a yellowish film. MS (ESI) m/z: 340.1 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 8.20 (1H, d, J=7.07 Hz), 8.09 (1H, br. s.), 7.67 (1H, d, J=5.05 Hz), 7.29-7.46 (5H, m), 5.19 (2H, s), 4.59 (2H, br. s.), 3.91 (2H, br. s.), 2.94 (3H, br. s.).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C(O[CH2:14][O:15][CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20])(=O)C.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.Cl[Sn](Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:19]([O:18][CH2:17][CH2:16][O:15][CH2:14][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])(=[O:21])[CH3:20]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: CC(=O)OCCOCOC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCOCn1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Yield: 36 %

Procedure:
Thymine (0.63 g, 5 mmol) was added to 2-acetoxyethyl acetoxymethyl ether (1.32 g, 7.5 mmol) dissolved in 2 (15 mL). The reaction mixture was stirred at room temperature and N,O-bis(trimethylsilyl)acetamide (2.96 mL, 12 mmol) was added dropwise. After 3 hours of stirring, the clear solution was cooled to 0° C., and SnCl4 (0.12 mL, 1 mmol) was added. The reaction mixture was allowed to come to room temperature and stirred overnight. A mixture of saturated aqueous NaHCO3 (25 mL) and CHCl3 (50 mL) was prepared and cooled in ice. The reaction mixture was added slowly with vigorous stirring; a white foam formed immediately. After filtration, the aqueous layer was further extracted with ethyl acetate (3×25 mL) and CHCl3 (25 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration of drying agent and removal of solvents in vacuo, an oily liquid was obtained. It was purified on a silica gel column using 2:1 CHCl3/CH3COCH3 as the eluent to give the desired product. Yield 36%; Wt. 4.0 g; mp 105°-107° C.; 1H NMR (DMSO-d6) 1.8 (s, CH3 C5 thymine), 2.0 (s, CH3 CO), 3.65 (m, CO O CH2 CH2), 4.1 (m, CO O CH2 CH2), 5.05 (s, O CH2 N) , 7.55 (s, H C6 thymine), 11.3 (s, HN thymine).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=1.[OH-].[K+].O.Br[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[Br:15]>CS(C)=O>[Br:15][C:14]([F:17])([F:16])[C:13]([F:19])([F:18])[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[Br:15])[CH:3]=1
Reactant: Oc1cccc(O)c1
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(Br)C(F)(F)Oc1cccc(OC(F)(F)C(F)(F)Br)c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 80 %

Procedure:
Into a 250 mL round-bottom flask were placed 18.72g (0.17 mol) of 1,3-dihydroxybenzene (resorcinol) and 75 mL of DMSO. The solution was purged with nitrogen gas for one hour followed by adding 223.62 mL of 1.52M (0.34 mol) KOH-water solution dropwise to the solution, with the reaction flask resting in an ice-bath. The reaction mixture was then heated at 100° C. for one day followed by distilling off most of the water from the reaction solution. The rest of reaction solvents were evaporated slowly under vacuum. The salt was dried at 120° C. under the vacuum line for at least two days. Then 75 mL of dry DMSO and 109.2 g (0.42 mol) of 1,2-dibromo tetrafluoroethane was transferred to the flask via a closed system. The mixture was stirred at 35° C. for 3 days. The reaction mixture was filtered to remove the KBr, then the reaction mixture was washed with acetone in a 500 mL separatory funnel and the organic layer was diluted with 150 mL of methylene chloride. The combined organic layer was washed first with 10% of sodium bicarbonate water solution, and then with 0.01N HCl and finally with distilled water until neutral. The solution was dried over sodium sulfate overnight. After the removal of the sodium sulfate by filtration and the evaporation of the solvents, the crude product was purified by distillation under reduced pressure with an oil bath at a temperature of 100-110° C. A total of 64 g (0.136 mol) of 1,3-di(2-bromotetrafluoro ethoxy)benzene was obtained in 80.4% yield, which had a boiling point of 76-80° C. (at 10−2 torr). The amount of hydrogen by-product in the product was about 5.4%.
Reaction SMILES: [C:1]([CH:8]([NH2:15])[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:1]([CH:8]([NH2:15])[CH:9]1[CH2:10][CH2:11][N:12]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:13][CH2:14]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C1CCCC1
Reactant: CC(C)(C)OC(=O)C(N)C1CCNCC1
Product: CC(C)(C)OC(=O)C(N)C1CCN(C2CCCC2)CC1
Yield: 77.4 %

Procedure:
Using Alkylation Method B, 4-(Boc-aminomethyl)piperidine (15 g, 70 mmol) and cyclopentanone (36 g, 450 mmol) afforded 15.3 g (77%) of the title compound.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[Na+].Cl[C:50]1[N:55]=[CH:54][C:53]([N:56]2[CH2:61][CH2:60][N:59]([CH2:62][CH2:63][O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:58][CH2:57]2)=[CH:52][CH:51]=1.[CH:72]1([N:77]2[C:81]3[N:82]=[C:83]([NH2:86])[N:84]=[CH:85][C:80]=3[C:79]3[CH:87]=[CH:88][N:89]=[C:90]([F:91])[C:78]2=3)[CH2:76][CH2:75][CH2:74][CH2:73]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]>[CH:72]1([N:77]2[C:81]3[N:82]=[C:83]([NH:86][C:50]4[CH:51]=[CH:52][C:53]([N:56]5[CH2:61][CH2:60][N:59]([CH2:62][CH2:63][O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:58][CH2:57]5)=[CH:54][N:55]=4)[N:84]=[CH:85][C:80]=3[C:79]3[CH:87]=[CH:88][N:89]=[C:90]([F:91])[C:78]2=3)[CH2:73][CH2:74][CH2:75][CH2:76]1
Reactant: Nc1ncc2c3ccnc(F)c3n(C3CCCC3)c2n1
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCN(c2ccc(Cl)nc2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 105 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To tris(dibenzylideneacetone)dipalladium (0) (0.0289 g, 0.0316 mmol), xantphos (0.0366 g, 0.0632 mmol), NaOtBu (0.0486 g, 0.506 mmol), compound 247 (0.150 g, 0.421 mmol), and compound 245 (0.114 g, 0.421 mmol) was added degassed dioxane (2.0 mL). The reaction vessel was sealed and stirred at 105° C. overnight. The reaction was loaded directly to silica. Silica gel chromatography (gradient elution 1.5 to 5% 2 M methanolic NH3 in DCM) afforded compound 248 (0.120 g, 48.2% yield). 1H NMR (400 MHz, CDCl3) δ 0.09 (s, 6 H) 0.83-1.00 (m, 9 H) 1.75-1.90 (m, 2 H) 2.05-2.25 (m, 4 H) 2.36-2.53 (m, 2 H) 2.63 (br. s., 2 H) 2.75 (br. s., 4 H) 3.22 (br. s., 4 H) 3.82 (br. s., 2 H) 5.54 (quin, J=9.00 Hz, 1 H) 7.38 (dd, J=9.00, 2.74 Hz, 1 H) 7.72 (dd, J=5.09, 3.13 Hz, 1H) 8.00-8.04 (m, 1 H) 8.06 (d, J=2.74 Hz, 1 H) 8.10 (s, 1 H) 8.36 (d, J=9.00 Hz, 1 H) 9.08 (s, 1 H) ppm.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:19][C@H:18]([F:20])[C@@H:17]([O:21][CH3:22])[C@H:16]1[C:23](=[O:34])[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[F:33])=O)(C)(C)C>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[Cl:32][C:28]1[C:27]([F:33])=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][NH:24][C:23]([C@@H:16]1[C@H:17]([O:21][CH3:22])[C@@H:18]([F:20])[CH2:19][NH:15]1)=[O:34]
Reactant: CO[C@H]1[C@@H](C(=O)NCc2cccc(Cl)c2F)N(C(=O)OC(C)(C)C)C[C@@H]1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1[C@@H](C(=O)NCc2cccc(Cl)c2F)NC[C@@H]1F
Reaction time: 8 h

Procedure:
TFA (0.86 mL, 11.12 mmol) was added to a solution of (2S,3S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (450 mg, 1.12 mmol) in CH2Cl2 (20 mL). The reaction mixture was stirred overnight then was concentrated. The residue was triturated with Et2O (10 mL) to give a precipitate which was filtered off, washed with Et2O (10 mL) then dried under high vacuum. The absolute stereochemistry was confirmed by X-ray. tR (HPLC conditions f): 0.40 min; MS (UPLC): 349 [M+HCOO]−, 305 [M+H]+.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH3:17][C:18]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:23])[CH2:19][C:20](O)=[O:21]>>[CH3:23][C:18]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:17])[CH2:19][C:20]([NH:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16])=[O:21]
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: CC(C)(CC(=O)O)c1ccccc1
Product: CC(C)(CC(=O)Nn1nc(C(F)(F)F)c2ccccc2c1=O)c1ccccc1

Procedure:
The product of Example 11B and 3-methyl-3-phenylbutanoic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.58-11.60 (bs, 1H), 8.43 (dd, J=7.9, 1.3 Hz, 1H), 8.11-8.15 (m, 1H), 7.97-8.07 (m, 2H), 7.43-7.46 (m, 2H), 7.28-7.36 (m, 2H), 7.16-7.21 (m, 1H), 2.66 (s, 2H), 1.46 (s, 6H); MS (ESI) m/z 390 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)N>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:20]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)=[CH:19][C:18]=1[CH3:17]
Reactant: Cc1cc(N)ccc1OCc1cccc(F)c1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCO)c23)ccc1OCc1cccc(F)c1
Yield: 57.8 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (2.0 g, 8.96 mmol) and 3-methyl-4-[(3-fluorobenzyl)oxy]aniline (2.5 g, 10.8 mmol) to give the title compound as a white solid (2.12 g, 58%); NMR Spectrum: 2.24 (s, 3H), 3.79 (s, 2H), 4.30 (t, 2H), 5.17 (s, 2H), 7.02 (d, 1H), 7.15 (td, 1H), 7.31 (m, 2H), 7.42 (m, 3H), 7.85 (t, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 8.33 (s, 1H); Mass Spectrum: 410 (MH+).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:14][N:15]1[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][C:16]1=[O:23].O>CN(C=O)C>[N:1]1([CH2:14][N:15]2[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][C:16]2=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCCC1CC(=O)N(CCl)C1
Reactant: c1ccc2c(c1)CCCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC1CC(=O)N(CN2CCCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline x158 (400 mg, 3 mmol, 1 eq) in DMF (7 ml) maintained under argon is added NaH (60% in mineral oil; 120 mg, 3 mmol, 1 eq). The reaction mixture is stirred for three hour at room temperature, then a solution of 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 in DMF (1 M, 3 ml, 3 mmol, 1 eq) is added. The reaction mixture is stirred for 20 hours at the same temperature. Water (70 ml) is added and the resulting mixture is extracted with ethyl acetate (30 ml). The organic phase is washed twice with water and dried over Na2SO4. After filtration and evaporation, the crude product is purified by two consecutive chromatographs on silicagel (CH2Cl2/MeOH gradient, then CH2Cl2). Pure 1-(3,4-dihydroquinolin-1(2H)-ylmethyl)-4-propylpyrrolidin-2-one 295 is obtained as syrup (231 mg).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:37][CH3:38])=[C:7](/[CH:20]=[CH:21]/[C:22]2[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][C:23]=2[C:24]([O:26]C)=[O:25])[CH:8]=[C:9]([C:11]2[C:12](=[O:19])[NH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].O>>[C:1]([C:5]1[C:6]([O:37][CH3:38])=[C:7](/[CH:20]=[CH:21]/[C:22]2[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:34])=[O:35])=[CH:28][C:23]=2[C:24]([OH:26])=[O:25])[CH:8]=[C:9]([C:11]2[C:12](=[O:19])[NH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-c2ccc(OC)[nH]c2=O)cc(C(C)(C)C)c1OC
Agent: [Li]O
Solvent: O
Product: COc1ccc(-c2cc(/C=C/c3ccc(NS(C)(=O)=O)cc3C(=O)O)c(OC)c(C(C)(C)C)c2)c(=O)[nH]1

Procedure:
The title compound was prepared by saponification of 328 with LiOH.H2O. The product was purified by SiO2 chromatography eluting with 5% MeOH/DCM to afford I-211.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[OH:12])[CH:5]=[CH:6][CH:7]=1.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C.N1C=CC=CC=1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[O:12][C:21]2=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(CCNc1cccc(Br)c1)c1ccccc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C1OC(c2ccccc2Cl)CCN1c1cccc(Br)c1
Reaction time: 0.5 h
Yield: 164 %

Procedure:
Half of the crude 3-(3-bromophenylamino)-1-(2-chlorophenyl)propan-1-ol (0.074 mmol) was mixed with triphosgene (7.5 mg, 0.34 equiv), i-Pr2NEt (26 μL, 2 equiv), pyridine (30 μL, 5 equiv) and acetonitrile (5 mL). The mixture was put in the microwave oven for 30 min at 110° C. LC-MS found the reaction completed. The mixture was concentrated, redissolved in EtOAc (5 mL), washed with 1% aq HCl (2×2 mL), concentrated and purified by preparative HPLC to afford 3-(3-bromo-phenyl)-6-(2-chloro-phenyl)-[1,3]oxazinan-2-one (15.2 mg). LC-MS (3 min) tR=1.86 min., m/z 368,369(M+1). 1H NMR (CDCl3) δ 7.63(d, 1H), 7.56 (s, 1H), 7.43-7.26 (m, 6H), 5.83 (d, 1H), 3.88 (q, 1H), 3.67 (m, 1H), 2.55 (d, 1H), 2.17 (m, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Br>C(#N)C>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:26][CH:28]3[O:30][CH2:29]3)[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCC1CO1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: c1ccc(C(c2ccccc2)N2CCN(CC3CO3)CC2)cc1
Yield: 48.3 %

Procedure:
After 1-(diphenylmethyl)piperazine (10.0 g) was dissolved in acetonitrile (50 ml), sodium carbonate (6.5 g) and epibromohydrin (6.8 g) were added thereto, and the mixture was heated under reflux for 2.5 hours. Salts were separated by filtration, and then the resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Wako gel C-200, 200 g) and eluted with a mixed solvent of 99 parts of chloroform and 1 part of methanol to obtain 1-(diphenylmethyl)-4-(1-(2,3-epoxy)propyl)piperazine (5.9 g).
Reaction SMILES: CC(C)([O-])C.[CH2:6]([P:9]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)([CH2:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH3:8].Cl[C:22]1[N:30]=[C:29]([I:31])[N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1>C1COCC1>[CH2:6]([P:9]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:22]2[N:30]=[C:29]([I:31])[N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][N:26]3[CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)=[CH:18][CH:19]=1)([CH2:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH3:8]
Reactant: CCCP(=O)(CCC)c1ccc(N)cc1
Reactant: Clc1nc(I)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Product: CCCP(=O)(CCC)c1ccc(Nc2nc(I)nc3c2ncn3C2CCCCO2)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Patasium tert-Butoxide (0.19 g, 1.65 mmol) was suspended in 4.5 mL anhydrous THF under nitrogen and cooled to −10° C. in an ice-salt bath. 4-(Dipropylphosphoryl)benzenamine (0.12 g, 0.55 mmol) was added to the suspension and the mixture was stirred at −10° C. for 30 min. 6-Chloro-2-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Tetrahedron 2002, 58, 7911-7923, 0.18 mg, 0.5 mmol) was then added to the reaction mixture and the content was warmed to room temperature and stirred over night. The reaction mixture was cooled to 0° C., and quenched by the addition of 0.1N HCl (˜500 mL). The mixture was concentrated on a rotavapor. The residue was partitioned between ethyl acetate (10 mL)/water (4 mL), organic layer was separated and washed with 0.1N HCl (4×4 mL), saturated NaHCO3 (4 mL), brine (4 mL), and dried over Na2SO4. The final product was obtained by flash column chromatography on silica gel (7.5% MeOH/DCM).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C:10]1([C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([CH:55]=[CH2:56])=[CH:51][CH:50]=2)[CH:42]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>C(Cl)Cl.CC#N>[CH2:24]([O:23][C@H:13]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:10]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([CH2:48][C:49]3[CH:50]=[CH:51][C:52]([CH:55]=[CH2:56])=[CH:53][CH:54]=3)[CH:42]=2)[O:11][C@@H:12]1[CH2:31][O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=Cc1ccc(Cc2cc(C3(O)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOCC
Product: C=Cc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-(4-chloro-3-(4-vinylbenzyl)phenyl)tetrahydro-2H-pyran-2-ol (intermediate AN) (350 mg) in 4 mL of CH2Cl2:CH3CN (1:1) at −15° C. was added Et3SiH (0.146 mL), followed by BF3.Et2O (0.09 mL). During the period of addition, the temperature was maintained at approximately −5° C. to −10° C. The stirred solution was allowed to warm to 0° C. over 5 h. The reaction was monitored by TLC, and after the starting material was consumed, the reaction was quenched by addition of saturated aqueous NaHCO3. The solvent was removed under reduced pressure. The residue was then dissolved in a mixture of 40 mL of ethyl acetate and water (1:1). After separation of the organic layer, the aqueous phase was extracted 2× with 20 mL of ethyl acetate. The organic phases were combined and washed with brine and water before drying over Na2SO4. Concentration of the solution yielded a yellow gel, which was purified by preparative TLC to obtain pure intermediate AO (100 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:8]=2)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[H-].[Na+].CN(C=O)C.Cl[CH2:37][O:38][CH:39]=[O:40]>O>[CH3:37][O:38][C:39]([NH:1][C:2]1[N:6]([C:7]2[N:8]=[C:9]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:10]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:12]=2)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1)=[O:40]
Reactant: O=COCCl
Reactant: Nc1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Nc1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Yield: 45.4 %

Procedure:
0.19 g (0.50 mmol) of 2-(2-aminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine synthesized in (1) of the Example 6 and 60% sodium hydride (24 mg, 0.60 mmol) added to DMF (2 ml) were reacted at room temperature for 1 hour. The reaction mixture was added and reacted with 0.040 ml (0.55 mmol) of chloromethylformate at room temperature for 16 hours. The reaction solution was poured into water and extracted with methyl acetate. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 100 mg (yield: 46%) of the titled compound as colorless crystals.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC#N>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][CH:13]=1
Reactant: Cc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-c2ccccc2)nc1
Temperature: 25 °C

Procedure:
Phenylboronic acid (732 mg, 6 mmol), 2-bromo-5-methylpyridine (1.03g, 5.99 mmol), and Pd (PPh3)4 (350 mg, 0.303 mmol) were heated in 0.4 M K2CO3 (30 mL, 12 mmol) and CH3CN (30 mL) at 90° overnight. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between brine and ethyl acetate. The organic layer was separated, dried (Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (9:1 hexanes:ethyl acetate) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (m, 1H), 8.05 (m, 2H), 7.85 (d, J=8.4 Hz, 1H), 7.68–7.71 (m, 1H), 7.37–7.50 (m, 3 H), 2.34 (s, 3H); MS (APCI+) m/z 170 (M+H)+.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([C:25]([NH2:27])=[O:26])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:28][C:29]1[CH:30]=[C:31]([NH:35][C:36]([C@@H:38]2[CH2:42][CH2:41][CH2:40][N:39]2[CH3:43])=[O:37])[CH:32]=[CH:33][CH:34]=1>CN1C(=O)CCC1>[CH2:18]([NH:17][C:15]1[C:14]([C:25]([NH2:27])=[O:26])=[CH:13][N:12]=[C:11]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([C@@H:38]3[CH2:42][CH2:41][CH2:40][N:39]3[CH3:43])=[O:37])[CH:30]=2)[N:16]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN1CCC[C@H]1C(=O)Nc1cccc(N)c1
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1NCc1ccccc1
Solvent: CN1CCCC1=O
Product: CN1CCC[C@H]1C(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCc3ccccc3)n2)c1
Temperature: 100 °C
Yield: 77 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(benzylamino)pyrimidine-5-carboxamide (50 mg, 0.14 mmol) in NMP (1 mL) was added (S)-N-(3-aminophenyl)-1-methylpyrrolidine-2-carboxamide (33 mg, 0.152 mmol) and pTsO.RH2O (60 mg, 0.28 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, and purified by preparative HPLC to give of (S)-4-(benylamino)-2-(3-(1-methylpyrrolidine-2-carboxamido)phenylamino)pyrimidine-5-carboxamide (48 mg). MS found for C24H27N7O2 as (M+H)+ 446.5. λ=247.5.