Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1[C@H:12]([CH3:13])[C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)OC1=O)(=O)CCCCC.Cl.[CH2:22]([O:24][C:25](=[O:36])[C@H:26]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH2:27])[CH3:23].CN(C([O:44]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH2:11]([C@H:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C:19]([NH:27][C@@H:26]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:25]([O:24][CH2:22][CH3:23])=[O:36])=[O:44])[CH:12]=[CH2:13]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)[C@@H](N)CCc1ccccc1
Reactant: CCCCCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=CC[C@H](CCCC)C(=O)N[C@@H](CCc1ccccc1)C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of the compound of step G (3) (421 mg, 2.69 mmol) and homophenylalanine ethyl ester hydrochloride (789 mg, 3.24 mmol) in DMF (30.1 mL) was added HATU (1.54 g, 3.24 mmol) and N-Methyl morpholine (1.24 mL, 9.42 mmol). The reaction was stirred at rt until LC showed conversion to product (<30 min). DMF was removed in vacuo, the residue suspended in water, and the product extracted 3 times to ethyl acetate. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was suspended in a minimal amount of methylene chloride and filtered through glass wool. The solution was loaded onto a silica gel column, and pure product was obtained following elution with a ethyl acetate/hexane gradient (836 mg, 90%). 1H NMR (500 MHz, CDCl3) δ ppm 0.88 (t, J=7.02 Hz, 3H) 1.19-1.38 (m, 7H) 1.40-1.50 (m, 1H) 1.57-1.69 (m, 1H) 1.92-2.06 (m, 1H) 2.08-2.26 (m, 3H) 2.28-2.41 (m, 1H) 2.52-2.75 (m, 2H) 4.18 (q, J=7.32 Hz, 2H) 4.61-4.74 (m, 1H) 4.95-5.11 (m, 2H) 5.69-5.84 (m, 1H) 5.96 (d, J=7.63 Hz, 1H) 7.10-7.34 (m, 5H). HPLC retention time: 1.76 min (method A). MS (ESI) (M+H)+ 346.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH2:18][C:17]([CH3:20])=[CH:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C([Cu])#N.[C:29]([C:33]1[CH:41]=[C:40]2[C:36]([CH:37]=[C:38]([CH3:46])[CH:39]2[Si:42](Cl)([CH3:44])[CH3:43])=[C:35]([C:47]2[CH:52]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[CH:50]=[C:49]([C:57]([CH3:60])([CH3:59])[CH3:58])[CH:48]=2)[C:34]=1[O:61][CH3:62])([CH3:32])([CH3:31])[CH3:30]>CCOCC.O>[C:29]([C:33]1[CH:41]=[C:40]2[C:36]([CH:37]=[C:38]([CH3:46])[CH:39]2[Si:42]([CH:16]2[C:15]3[C:19](=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=4)[CH:12]=[CH:13][CH:14]=3)[CH:18]=[C:17]2[CH3:20])([CH3:44])[CH3:43])=[C:35]([C:47]2[CH:48]=[C:49]([C:57]([CH3:60])([CH3:59])[CH3:58])[CH:50]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[CH:52]=2)[C:34]=1[O:61][CH3:62])([CH3:31])([CH3:30])[CH3:32]
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1cc(C(C)(C)C)cc(C(C)(C)C)c1)C=C(C)C2[Si](C)(C)Cl
Reactant: CC1=Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1
Agent: N#C[Cu]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1c(C(C)(C)C)cc2c(c1-c1cc(C(C)(C)C)cc(C(C)(C)C)c1)C=C(C)C2[Si](C)(C)C1C(C)=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 5.54 g (21.1 mmol) of 7-(4-tert-butylphenyl)-2-methyl-1H-indene in 150 ml of ether 8.50 ml (21.3 mmol) of 2.5 M nBuLi in hexanes was added in one portion at −40° C. This mixture was stirred overnight at room temperature, then cooled to −40° C., and 190 mg of CuCN was added. The resulting mixture was stirred for 1 h at −20° C., then cooled to −40° C., and a solution of 10.5 g (21.1 mmol) of [6-tert-butyl-4-(3,5-di-tert-butylphenyl)-5-methoxy-2-methyl-1H-inden-1-yl](chloro)dimethyl-silane in 150 ml of ether was added in one portion. Further on, this mixture was stirred overnight at ambient temperature, then 0.5 ml of water was added. This solution was filtered through a pad of silica gel 60 (40-63 um) which was additionally washed by 2×75 ml of dichloromethane. The combined elute was evaporated to dryness, and the residue was triturated with 70 ml of n-hexane. The obtained suspension was filtered on glass frit, the precipitate was washed with 30 ml of n-hexane and dried in vacuum to give a white powder. Additionally, the mother liquor was evaporated to small volume. The formed suspension was filtered through glass frit (G3), and the precipitate was washed with 2×15 ml of n-hexane and then dried in vacuum. Again, the mother liquor was evaporated to give a yellowish oil which was re-crystallized at −30° C. for two months. Crystals precipitated from this solution were collected and dried in vacuum. Thus, 12.2 g (80%) of the title product was isolated. Assignment in NMR spectra was made using the following abbreviations: L1 for 4-(4-tert-butylphenyl)-2-methyl-1H-inden-1-yl and L2 for 6-tert-butyl-4-(3,5-di-tert-butylphenyl)-5-methoxy-2-methyl-1H-inden-1-yl.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:22]([C:23]#[N:24])[C:19]2[CH:20]=[CH:21][C:16]([O:15][C:14]([F:13])([F:25])[F:26])=[CH:17][CH:18]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: N#CCc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(C=C(C#N)c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
4-Formylbenzoic acid methyl ester (8.60 g, 52.39 mmol) was dissolved in warm methanol (50 mL) and 4-trifluoromethoxyphenylacetonitrile (10.54 g, 52.39 mmol) was added. The mixture was stirred and potassium carbonate (7.75 g, 56.05 mmol) was added. The mixture was heated to 60° C. and more methanol (20 mL) was added and stirring was continued for 1 hour. The precipitate was filtered off and added in small portions to a stirred and cold 4 M hydrochloric acid solution. The precipitate was filtered off, washed with water and dried to afford 14.4 g (79%) of 4-[2-cyano-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.O=[C:22]1[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:31]([OH:33])=[O:32])[C:25]=2[CH2:24][CH2:23]1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:22]3[C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([C:31]([OH:33])=[O:32])[C:25]=4[CH2:24][CH2:23]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: O=C(O)c1cccc2c1CCC2=O
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CCc4c(C(=O)O)cccc43)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 1-oxo-indan-4-carboxylic acid using decaborane yielded a mixture of epimers of the title compound as a light yellow foam. MS (ESI): m/z=439.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][CH3:22])[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:23](=[O:26])[C:24]=2[OH:25])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][C:37]1[O:41][N:40]=[C:39]([C:42](Cl)=[O:43])[CH:38]=1.CNC>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([N:21]([CH3:22])[C:42]([C:39]5[CH:38]=[C:37]([CH3:36])[O:41][N:40]=5)=[O:43])[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:23](=[O:26])[C:24]=2[OH:25])=[O:9])=[CH:27][CH:28]=1
Reactant: CNC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Reactant: Cc1cc(C(=O)Cl)no1
Agent: CNC
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)C23CCC(CC2)Cn2c3nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)no1
Temperature: 25 °C
Yield: 16.5 %

Procedure:
To a solution of N-(4-fluorobenzyl)-3-hydroxy-10-(methylamino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (25 mg, 0.061 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.051 mL, 0.365 mmol) followed by 5-methylisoxazole-3-carbonyl chloride (17.69 mg, 0.122 mmol) and the resulting mixture was stirred at room temperature. After 16 at room temperature the reaction mixture was concentrated to give crude product which was dissolved in methanol (2 mL) and treated with 2M dimethylamine in methanol (0.5 mL). The resulting reaction mixture was stirred at 60° C. for 2 h, then cooled and purified by preparative HPLC to afford the title compound (5 mg, 17% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 11.81 (1 H, brs), 8.70 (1 H, d, J=5.19 Hz), 7.31 (2 H, dd, J=8.55, 5.49 Hz), 6.92-7.01 (2 H, m), 6.09 (1 H, s), 4.75-4.86 (1 H, m), 4.58-4.67 (1 H, m), 4.38-4.47 (1 H, m), 3.67 (1 H, d, J=15.56 Hz), 3.35-3.46 (1 H, m), 3.13 (3 H, s), 2.50 (1 H, brs), 2.41 (3 H, s), 2.07-2.16 (3 H, m), 1.95-2.05 (1 H, m), 1.72-1.86 (2 H, m), 1.37-1.50 (1 H, m). LCMS (M+H)=496.66. HPLC purity: >95%.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH2:15][OH:16])[C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C(N(CC)[P:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])C.N1C=NN=N1.C1C=C(Cl)C=C(C(OO)=[O:46])C=1.S(=O)(O)[O-].[Na+]>C1COCC1>[C:27]([O:26][P:20]([O:16][CH2:15][CH2:14][N:3]([CH2:1][CH3:2])[C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:46])([CH3:28])([CH3:29])[CH3:30]
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Reactant: CCN(CCO)C(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: C1CCOC1
Product: CCN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 59.1 %

Procedure:
A solution of benzyl ethyl(2-hydroxyethyl)carbamate (INTERMEDIATE 47, 1.0 g, 4.48 mmol) and di-tert-butyl diethylphosphoramidite (4.47 ml, 16.1 mmol) in THF (146 ml) was treated with tetrazole (1.57 g, 22.39 mmol) in one portion. The resulting mixture was stirred at r.t for 50 minutes and the clear solution became cloudy. The mixture was cooled using an acetone/dry ice bath (˜−77° C.) and m-CPBA (6.96 g) was added over the course of ˜1 minute. The mixture was stirred under these conditions for 20 minutes and subsequently allowed to warm to r.t. over 10 minutes. Sodium bisulfite (aq., 10% w/v, 3.41 ml) was added and the mixture was stirred for 10 minutes, concentrated in vacuo, diluted with EtOAc (200 ml), and washed with sodium bisulfite (aq., 100 ml), and NaHCO3 (aq., 5% w/v, 100 ml). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure. The concentrate was purified by column chromatography (ISCO, silica gel column, eluting with 0→100% EtOAc in hexanes) to give the title compound (1.1 g, yield: 60%).
Reaction SMILES: [Se-2:1].[Na+].[Na+].Cl[C:5]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:7]([O:9]C)=O.Cl[CH2:16][C:17]#[N:18].C[O-].[Na+].Cl>CN(C=O)C.CO>[C:11]([C:5]1[Se:1][C:16]([C:17]#[N:18])=[C:7]([OH:9])[CH:6]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)C=C(Cl)C(C)(C)C
Reactant: [Se-2]
Reactant: N#CCCl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(O)c(C#N)[se]1
Temperature: 65 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a suspension of sodium selenide (5.35 g, 42.49 mmol) in DMF (43 mL) was added a solution of methyl 3-chloro-4,4-dimethylpent-2-enoate (7.5 g, 42.49 mmol) in DMF (10 mL) at rt for 5 min and stirred the mixture at 60-70° C. for 2 h. Then chloroacetonitrile (2.785 mL, 42.49 mmol) was added dropwise to the reaction mixture and again stirred at 60-70° C. for 2 h. Then, a solution of sodium methoxide (2.29 g, 42.49 mmol) in dry methanol (26 mL) was added dropwise and stirring was continued for 1 h at the same temperature. The reaction mixture was poured into ice cold water and acidified with dil. HCl. The solution was extracted with chloroform (3×200 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtoAc (80:20) as eluents to give the product as a red color oil (7.5 g, 77%). 1H NMR (400 MHz, CDCl3): δ 6.76 (1H, s), 1.35 (9H, s); LC-MS (negative ion mode): m/z 226, 228 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=1[CH3:24].[O:25]1[CH2:30][CH:29]=[C:28]([C:31]2[CH:32]=[C:33]([NH2:37])[CH:34]=[N:35][CH:36]=2)[CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[O:25]1[CH2:26][CH:27]=[C:28]([C:31]2[CH:32]=[C:33]([NH:37][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=3[CH3:24])[CH:34]=[N:35][CH:36]=2)[CH2:29][CH2:30]1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(C2=CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Nc1cncc(C2=CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (50.0 mg, 0.140 mmol) and 5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-amine in toluene to give N-(5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.23 (2H, d, J=2.2 Hz), 8.20 (1H, dd, J=8.0, 1.2 Hz), 7.75-7.82 (1H, m), 7.68 (1H, td, J=7.7, 1.4 Hz), 7.50 (1H, ddd, J=9.3, 2.5, 1.3 Hz), 7.42 (1H, dd, J=7.6, 1.2 Hz), 7.15 (1H, d, J=13.7 Hz), 7.01-7.11 (2H, m), 6.22 (1H, dt, J=2.9, 1.4 Hz), 4.28 (2H, q, J=2.6 Hz), 3.89 (2H, td, J=5.4, 2.1 Hz), 3.14 (3H, s), 2.33-2.58 (2H, m), 1.86 (3H, s). Mass Spectrum (ESI) m/e=508.1 (M+1).
Reaction SMILES: Br[CH:2]([C:4]1[N:8]=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[S:6][N:5]=1)[CH3:3].[C-:17]#[N:18].[Na+].[Na+].[I-]>CN(C=O)C>[C:17]([CH:2]([C:4]1[N:8]=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[S:6][N:5]=1)[CH3:3])#[N:18]
Reactant: CC(Br)c1nsc(NC(=O)OC(C)(C)C)n1
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)c1nsc(NC(=O)OC(C)(C)C)n1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
DMF was added to tert-butyl [3-(1-bromoethyl)-1,2,4-thiadiazol-5-yl]carbamate (1.9 mmol), NaCN (1.1 eq) and NaI (1 eq). The reaction mixture was stirred for 30 min at 140° C. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Standard work-up and recrystallization from EtOH afforded tert-butyl [3-(1-cyanoethyl)-1,2,4-thiadiazol-5-yl]carbamate.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][O:7][C:6]1=[O:15]>CO>[OH:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[CH:5]([O:4][CH3:3])[C:6]([NH:2][CH3:1])=[O:15].[CH3:3][O:4][CH:5]([C:14]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:6]([NH:2][CH3:1])=[O:7]
Reactant: CN
Reactant: COC1C(=O)OCc2ccccc21
Solvent: CO
Product: CNC(=O)C(OC)c1ccccc1
Product: CNC(=O)C(OC)c1ccccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
40% methylamine--methanol solution (9.80 g, 126 mmol) was added to 4-methoxy-3-isochromanone (7.50 g, 42.1 mmol) in methanol (40 ml), and the mixture was stirred at room temperature for 1 hour. Evaporation of the solvent gave the desired compound 2-hydroxymethyl-(α-methoxy-N-methylphenyl-acetamide (8.50 g, 96.5%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C@@H:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:24][C:25]1[C:30]([F:31])=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1.[F-].[Cs+]>CO.O>[F:24][C:25]1[C:30]([F:31])=[C:29]([C:2]2[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([O:9][C@@H:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[N:19]3[N:23]=[CH:22][CH:21]=[N:20]3)[CH3:11])[CH:3]=2)[CH:28]=[CH:27][N:26]=1
Reactant: C[C@@H](Oc1cc(Br)cnc1N)c1cc(F)ccc1-n1nccn1
Reactant: OB(O)c1ccnc(F)c1F
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: O
Product: C[C@@H](Oc1cc(-c2ccnc(F)c2F)cnc1N)c1cc(F)ccc1-n1nccn1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
5-Bromo-3-[(R)-1-(5-fluoro-2-[1,2,3]triazol-2-yl-phenyl)-ethoxy]-pyridin-2-ylamine (example 45) (200 mg, 0.529 mmol, 1.0 eq) and 2,3-difluoropyridin-4-ylboronic acid (168 mg, 1.06 mmol, 2.0 eq) were dissolved in MeOH (5 mL), followed by the addition of freshly prepared aqueous solution of CsF (563 mg, 3.5 mmol, 7 eq) in water (3.34 mL) and Pd-132 (64 mg, 0.09 mmol, 0.17 eq), then degassed for three times. The mixture was heated up to 80° C. for overnight. LCMS showed >80% conversion to desired product, and ˜10% of des-bromation of example 45. The reaction mixture was filtered. The filtrate was concentrated and purified via a Biotage silica gel cartridge to provide the title compound (174 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:18]1([CH2:24][CH2:25][CH2:26][NH2:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([NH:27][CH2:26][CH2:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: NCCCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc(NCCCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.7 %

Procedure:
2-Chloro-5-nitropyrimidine (100 mg, 0.627 mmol) and triethylamine (96 μL, 0.690 mmol) were added successively to a solution of 3-phenylpropylamine (98 μL, 0.690 mmol) in tetrahydrofuran, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and 0.5 mol/L hydrochloric acid and dried over anhydrous magnesium sulfate. Thereafter, the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to afford 5-nitro-N-(3-phenylpropyl)pyrimidin-2-amine as a colorless solid (108 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=O)=[C:6]([NH:11][O:12][CH2:13][C@H:14]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]2)[N:5]=[C:4]([NH:21][CH:22]=[O:23])[N:3]=1>C(OC(OCC)OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH:22]=[O:23])[N:5]=[C:6]2[C:7]=1[N:8]=[CH:9][N:11]2[O:12][CH2:13][C@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1
Reactant: CC1(C)OC[C@H](CONc2nc(NC=O)nc(Cl)c2NC=O)O1
Agent: CCOC(OCC)OC(C)=O
Product: CC1(C)OC[C@H](COn2cnc3c(Cl)nc(NC=O)nc32)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
A solution of (R)-4-chloro-2,5-diformamido-6-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxyamino)pyrimidine 11 (900 mg, 2.6 mmol) in diethoxymethyl acetate (20 ml) was stirred at 120° C. for 3 hours. The solvent was removed under reduced pressure, the residue dissolved in methanol (20 ml) containing 0.88 ammonia solution (0.5 ml) and the mixture stirred for 1 hour at 25° C. The solvents were evaporated under reduced pressure and the residue chromatographed on silica, eluting with ethyl acetate-hexane (2:1), affording (R)-6-chloro-9-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)-2-formamidopurine (530 mg, 62%), m.p. 145°-8° C. UV: λmax (MeOH) 232 (ε 26,800), 291 (ε 9,600)nm; 1R: υmax (nujol) 1700, 1600, 1580 cm-1 ; 1H NMR: δH (CDCl3) 1.37 (3H,s, CH3), 1.42 (3H s, CH3), 3.87 (1H, m, CH2OC), 4.12 (1H, m, CH2OC), 4.46 (3H, m, CH+CH2ON), 8.20 (1H, s, H-8), 8.44 (1H, br. d, J=11.5 Hz, D2O exchangeable, NH), 9.55 (1H, J=11.5 Hz, HCONH).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][C:8]1[N:9]=[CH:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)=O.[OH-].[Na+]>O1CCCC1.CO.O>[C:13]([N:11]1[CH:12]=[C:8]([CH2:7][CH2:6][NH2:5])[N:9]=[CH:10]1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
The above amide (45.54 g; 0.101 mmol) was dissolved in tetrahydrofuran (1000 mL) and methanol (1200 mL). A solution of sodium hydroxide (20.26 g; 0.507 mol) in water (500 mL) was added. Mixture was stirred for 2 hrs at room temperature and then it was concentrated in vacuo. The residue was separated between chloroform (1200 mL) and water (800 mL). Aqueous layer was extracted with chloroform (3×400 mL). Organic layers were combined and dried over anhydrous magnesium sulfate. Evaporation of the solvent yielded brown oil, which was dried for 3 days in vacuo to give the title product as beige solid.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([CH:13]=[O:14])[CH:9]=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6].C[Mg+].[Br-].[CH3:18]C(O)=O>C1COCC1>[F:1][C:2]1[C:11]([F:12])=[C:10]([CH:13]([OH:14])[CH3:18])[CH:9]=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)Nc1ccc(C=O)c(F)c1F
Reactant: CC(=O)O
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(C)O)c(F)c1F
Temperature: 15 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 7.7 g of 2',3'-difluoro-4'-formylacetanilide in 190 mL of THF under an N2 atmosphere is added 29 mL of a 2.85M solution of MeMgBr at a temperature of 10°-20° C. The thick suspension is stirred 20 minutes at 20°-25° C., cooled to 15° C. and 5 mL of AcOH cautiously added. The mixture is then poured onto 500 mL of ice/H2O and the product extracted into 500 mL of CH2CL2. This extract is washed with H2O, saturated NaHCO3 and H2O (100 mL each) and stripped to give 8.1 g of yellow gummy 2',3'-difluoro-4'-(1-hydroxyethyl)-acetanilide. 8.1 g of the crude 2',3'-difluoro-4'-(1-hydroxyethyl)-acetanilide is stirred in acetone (175 mL) while 54 mL of Kilianis' reagent (Fieser and Fieser, "Reagents for Organic Synthesis", Vol. I p144) is added dropwise during 30 min. at a temperature of 20°-25° C. After stirring 30 min. longer, the reaction mixture is poured onto 200 mL of ice/H2O containing 5 g of Na2S2O5. The green suspension is extracted three times with CH2Cl2 (total volume 1 L) and the organic extract is washed with H2O, saturated NaHCO3, H2O (100 mL each) and stripped in vacuo. There is obtained 5.8 g of off-white solid which is slurried with 75 mL of Et2O to afford 5.23 g (65% yield) of 4'-acetyl-2',3'-difluoroacetanilide, m.p. 149°-152° C., (Mass spectrum shows an ion of 214).