Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[N:14]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:13](=[O:33])[NH:12]2)=[CH:7][CH:6]=1)#[N:4].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41]Br)[CH:36]=1>CCCCC.O1CCCC1>[Br:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[CH2:41][N:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[CH:6][CH:7]=2)[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[N:14]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[CH:24]=2)[C:13]1=[O:33]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(Cc2cccc(Br)c2)C1c1ccc(C#N)cc1
Reaction time: 0.08 h

Procedure:
Sodium hydride (55.9 mg 1.397 mmol; 60% dispersion in mineral oil) is washed with pentane (2×10 ml) and suspended in tetrahydrofuran (10 ml). A solution of ethyl 4-(4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 4A) (500 mg, 1.164 mmol) in tetrahydrofuran (5 ml) is added with stirring. After 5 minutes at room temperature, a solution of 1-bromo-3-(bromomethyl)benzene (320 mg, 1.23 mmol) in tetrahydrofuran (5 ml) is added, and the reaction is stirred at room temperature for 16 h. The solution is quenched with water (50 ml) and extracted with ethyl acetate (3×150 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The yellow residue (approximately 1.05 g) is purified by flash chromatography over silica gel 60 (50 g) with cyclohexane/ethyl acetate (5:1) as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10](Cl)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][C:22]([CH3:28])([CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:30][CH:31]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNS(=O)(=O)CCc2ccc(Cl)cc2)cc1
Yield: 77 %

Procedure:
from 2-(4-chlorophenyl)-ethanesulphonyl chloride and ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate; colorless oil; yield 77% of theory, and from this, by hydrolysis:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(C(Cl)=O)=O.[NH2:24][C:25]1[C:26]([CH3:34])=[C:27]([OH:33])[CH:28]=[C:29]([CH3:32])[C:30]=1[F:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([NH:24][C:25]1[C:26]([CH3:34])=[C:27]([OH:33])[CH:28]=[C:29]([CH3:32])[C:30]=1[F:31])=[O:6]
Reactant: Cc1cc(O)c(C)c(N)c1F
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)c(C)c(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
To a solution of 2-fluoro-5-(3-fluorophenyl)benzoic acid (Intermediate III(a)) (248 mg, 1.06 mmol, 1.1 eq) in CH2Cl2 (4 mL) and DMF (1 drop) at 0° C. was added (COCl)2 (403 mg, 3.18 mmol, 3.3 eq) dropwise. The reaction mixture was stirred at room temperature for 2 h. The solvent and excess reagent were then removed under reduced pressure and the residue obtained dissolved in THF (4 mL) and added dropwise to a mixture of 3-amino-4-fluoro-2,5-dimethylphenol (X(h)) (150 mg, 0.97 mmol, 1.0 eq) and NaHCO3 (407 mg, 4.85 mmol, 5.0 eq) in THF (3 mL) at 0° C. After the addition was completed, the reaction mixture was stirred at room temperature for 30 min. Water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with aqueous NaHCO3, water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 6:1 to 5:1) to give an impure product. The crude material was triturated with a mixture of petroleum ether and EtOAc (3 mL:1 mL) and the solid collected by filtration to afforded the title compound as a white solid (233 mg, 65%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH2:13][OH:14])[C:9]=2[CH3:15])=[CH:6][CH:5]=[CH:4][N:3]=1.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[C:9]=2[CH3:15])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(CO)c[nH]c1-c1cccnc1F
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: Cc1c(C=O)c[nH]c1-c1cccnc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.3 %

Procedure:
To a suspension of [5-(2-fluoropyridin-3-yl)-4-methyl-1H-pyrrol-3-yl]methanol (1.70 g) in acetonitrile (35 mL) were added tetra-n-propylammonium perruthenate (103 mg), N-methylmorpholine N-oxide (1.44 g) and molecular sieves 4A powder (0.89 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:2) to give the title compound as colorless crystals (yield 527 mg, 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[C:7](=[O:24])/[C:8](=[CH:10]/[C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:18]=4)[NH:13][N:12]=3)/[O:9][C:5]=2[C:4]=1[CH2:27][N:28]1[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[C:7](=[O:24])/[C:8](=[CH:10]/[C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:18]=4)[NH:13][N:12]=3)/[O:9][C:5]=2[C:4]=1[CH2:27][N:28]1[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccc(S(C)(=O)=O)cc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1CN1CCNCC1)O/C(=C\c1n[nH]c3ccc(S(C)(=O)=O)cc13)C2=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.8 %

Procedure:
A solution of tert-butyl (Z)-4-[(6-methoxy-2-{[5-(methylsulfonyl)-1H-indazol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0462 g, 0.0812 mmol) in methylene chloride (1 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted five times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain (Z)-6-methoxy-2-{[5-(methylsulfonyl)-1H-indazol-3-yl]methylene}-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0277 g, 72%).
Reaction SMILES: [C:1]1([C:7]#[C:8][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCCCCCCCCCCCC>C1COCC1.[Zn+2].[Br-].[Br-]>[C:1]1([C:7]#[C:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]C#Cc1ccccc1
Reactant: N#Cc1ccccc1
Agent: CCCCCCCCCCCCC
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
A solution of phenylethynylmagnesium bromide (4.0 ml; 4.00 mmol; 1.0 M in THF) in was treated at room temperature with a solution of ZnBr2 (0.473 g; 2.10 mmol) in THF (1 ml) and stirred for 30 min. This solution was then added to a room temperature solution of benzonitrile (0.204 ml; 0.206 g; 2.00 mmol), dichlorobis(trimethylphosphine)nickel (0.0282 g; 5 mol %), and tridecane (0.244 ml; 0.184 g; 1.00 mmol) in THF (1 ml). The reaction mixture was then heated to 65° C. and stirred for 46 h; then a sample was withdrawn and quenched in a mixture of 1 M sodium citrate (aq) and MTBE. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 0.63 mmol (31% yield) of diphenylacetylene and 0.36 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[N:14]([CH3:16])[CH3:15])[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O1CCCC1.O>[CH3:16][N:14]([CH3:15])[C:13]1[CH:12]=[CH:11][C:4]([C:5](=[O:6])[N:7]([O:9][CH3:10])[CH3:8])=[CH:3][C:2]=1[NH:1][C:24](=[O:25])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CON(C)C(=O)c1ccc(N(C)C)c(N)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)c1ccc(N(C)C)c(NC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of EXAMPLE 458B in a mixture of tetrahydrofuran (20 mL) and water (20 mL) was added cesium carbonate (6.02 g, 18.58 mmol) and benzyl chloroformate (1.5 mL, 10.16 mmol). The reaction mixture was stirred at room temperature for 16 hours, and concentrated. The residue was partitioned between ethyl acetate (100 mL) and brine (75 mL). The organic layer was washed with brine, and concentrated. The residual oil was purified by flash chromatography eluting with 40% ethyl acetate in hexanes to provide the title product. MS (DCI/NH3) m/z 358 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[OH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C1CCN2C(=NCCC2)CC1.O>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]([C:9]#[N:10])=[C:6]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:7]=1
Reactant: CSc1nc(N)nc(Br)c1C#N
Reactant: OCc1ccccn1
Solvent: COCCOC
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1nc(N)nc(OCc2ccccn2)c1C#N
Reaction time: 16 h
Yield: 16.1 %

Procedure:
To a stirred suspension of 1.00 g (4.08 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 10 ml DME were added 0.33 ml (4.08 mmol) 2-(hydroxymethyl)pyridine and 0.62 ml (4.08 mmol) DBU and stirring continued for 16 hours at room temperature. 50 ml water was then added and the resulting crystals collected by filtration. Chromatography (ethyl acetate) followed by trituration in ether afforded 180 mg (16%) 2-amino-4-methylsulfanyl-6-(pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 273 (M+, 100), 258 (89), 108 (63), 92 (95), 65 (70), 39 (36).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][OH:19])[CH2:13]1.C(N(CC)CC)C>ClCCl>[OH:19][CH2:18][CH:14]1[CH2:15][CH2:16][CH2:17][N:12]([C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13]1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: OCC1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)N1CCCC(CO)C1
Temperature: 0 °C
Reaction time: 22 h

Procedure:
A solution of 3-phenylpropionyl chloride (29.7 ml) in dichloromethane (100 ml) was added dropwise to a stirred solution of 3-piperidinemethanol (23 g) and triethylamine (22.2 g) in dichloromethane (200 ml) at 0° C. over 1.25 hours, maintaining the temperature at 0° C. The mixture was stirred at 0°-5° C. for 22 hours. After washing (saturated sodium bicarbonate solution), the organic layer was separated off, dried and evaporated to give 3-hydroxymethyl-1-(3-phenylpropionyl)piperidine as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:20]=1[CH:21]=[CH:22][C:23](O)=O>>[CH3:17][O:18][C:19]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:20]=1/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: COc1cccc(C=CC(=O)O)c1OC
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cccc(OC)c3OC)nc2n(CCC)c1=O
Yield: 35.7 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.0 g (8.85 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.2 g (10.6 mmol) of 2,3-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from chloroform/cyclohexane to give 1.26 g (yield 36%) of Compound 28 as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:10]2[N:11]=[C:12]([S:15][CH3:16])[N:13]=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]1=[O:17].[CH:22]1(B(O)O)[CH2:24][CH2:23]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[CH:22]1([C:2]2[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=2[CH2:4][N:5]2[C:10]3[N:11]=[C:12]([S:15][CH3:16])[N:13]=[CH:14][C:9]=3[CH:8]=[CH:7][C:6]2=[O:17])[CH2:24][CH2:23]1
Reactant: OB(O)C1CC1
Reactant: CSc1ncc2ccc(=O)n(Cc3ccccc3Br)c2n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CSc1ncc2ccc(=O)n(Cc3ccccc3C3CC3)c2n1
Temperature: 140 °C
Yield: 65.9 %

Procedure:
8-(2-bromobenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (150 mg, 0.41 mmol, Example 30), cyclopropylboronic acid (107 mg, 1.25 mmol), K3PO4 (264 mg, 1.24 mmol) and PdCl2(Pcy3)2 (15 mg, 0.02 mmol) were mixed as solids and placed under argon. Argon was bubbled through a mixture of toluene:water (20:1, 1.5 mL) for 20 min. The solvent was added to the solid and the suspension was heated under microwave irradiation at 140° C. for 1.5 h. The reaction mixture was then diluted with toluene (10 mL) and water (1×5 mL), the two phases were separated, and the aqueous layer was extracted with toluene (1×10 mL). The combined organic layers were washed with water (1×10 mL) and evaporated to dryness. The crude compound was purified by silica gel column chromatography using dichloromethane:methanol (100:0.5) to yield 8-(2-cyclopropylbenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as an off-white solid (88 mg, 0.27 mmol, 66%). ESMS m/z 324 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([C:12]#[C:13][CH2:14][OH:15])[O:9][N:8]=1.N1C=CC=NC=1C1C=CC(C#CCO)=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([C:12]#[C:13][CH:14]=[O:15])[O:9][N:8]=1
Reactant: OCC#Cc1cc(-c2ccccn2)no1
Agent: OCC#Cc1ccc(-c2ncccn2)cc1
Product: O=CC#Cc1cc(-c2ccccn2)no1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 300 by substituting 3-[3-(2-pyridinyl)-5-isoxazolyl]-2-propyn-1-ol (prepared as described in Reference Example 294) for the 3-[4-(2-pyrimidinyl)phenyl]-2-propyn-1-ol of Reference Example 300. MS 199 (M+H)+.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH2:5]([N:7]([CH2:14][CH2:15][OH:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6].Cl.[OH-].[Na+]>O.C1C=CC=CC=1>[CH2:5]([N:7]([CH2:14][CH2:15][OH:16])[C:8]1[CH:9]=[CH:10][C:11]([N:1]=[O:3])=[CH:12][CH:13]=1)[CH3:6]
Reactant: O=N[O-]
Reactant: CCN(CCO)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCN(CCO)c1ccc(N=O)cc1
Yield: 59.6 %

Procedure:
A solution was prepared by dissolving 18.5 g (0.26 mol) of sodium nitrite, of a purity of 97%, in 30 ml of water. This solution was added dropwise to a solution composed of 41.3 g (0.25 mol) of N-ethyl-N-2-hydroxyethylaniline, 200 g of water and 105 ml of conc HCl with stirring at a temperature between 5° and 10° C. for one-half hour. After stirring the solution obtained at a temperature between 10° and 20° C. for one hour, the solution was neutralized to pH 8 with a 15% aqueous solution of sodium hydroxide. 100 ml of benzene was added to the neutralized solution with stirring. After standing, the organic phase of the solution was separated. The benzene of the organic phase obtained was removed under reduced pressure. 28.9 g of N-ethyl-N-2-hydroxyethyl-p-nitrosoaniline which is a dark brown colored viscous liquid was obtained. The yield was 59.6%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[O:4].[C:17](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Li+]>C(O)C>[CH2:30]([O:29][C:27]([CH:26]([NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])[CH2:25][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)/C=C/C(=O)c1ccccc1
Reactant: N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 191 %

Procedure:
To 100 ml of ethanol were added 9.69 g of N6-trifluoroacetyl-L-lysine and 8.16 g of trans-ethyl β-benzoylacrylate. Thereto was added 40 ml of 1N aqueous solution of lithium hydroxide over about 2 hours with stirring, while maintaining the temperature at about −5° C., and the stirring was further continued for 30 minutes. The reaction was terminated by adding 10 ml of concentrated hydrochloric acid thereto. To the reaction mixture were added 130 ml of ethanol and 5 g of 10% palladium-carbon, and a reduction reaction was carried out at about 40° C. under ordinary pressure. After the reaction, the catalyst was removed by suction filtration. The obtained ethanol solution was adjusted to about pH 4 with sodium hydroxide, added with water and concentrated under reduced pressure to distil away ethanol so as to replace the solvent with water. The resulting crystals were filtered with suction and dried under vacuum to give 33 g of N2-(1-ethoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl-L-lysine (1S/1R ratio =80/20).
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH2:13]([C:17](=[CH2:23])[C:18](OCC)=[O:19])[CH2:14][CH2:15][CH3:16].C(O)(=O)C>C(OCC)C.O1CCCC1>[O:19]=[C:18]([C:17](=[CH2:23])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: C=C(CCCC)C(=O)OCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=C(CCCC)C(=O)CP(=O)(OC)OC
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A 2N solution (400 ml.) of n-butyllithium in diethyl ether was added dropwise to a solution of dimethyl methylphosphonate (110 g.) in pure anhydrous tetrahydrofuran (700 ml.) with stirring under nitrogen, while the reaction temperature was kept within the range of -50° to -60°C. After 10 minutes, a solution of ethyl 2-n-butylacrylate (prepared as described in (1) above; 60 g.) in tetrahydrofuran (150 ml.) was added dropwise to the reaction mixture at -65° to -70°C. and stirred for 4 hours at the same temperature. The reaction mixture was further stirred overnight at 0°C, acidified with acetic acid and concentrated under reduced pressure. Diethyl ether and water were added to the residue in order to remove the water soluble materials. The ethereal solution was dried over magnesium sulphate and concentrated. The residue was distilled under reduced pressure to give pure dimethyl 2-oxo-3-methylene-n-heptylphosphonate (67 g; 69%), having the following physical characteristics:-
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][C:4]=1[CH3:11].FC1C=C(CN)C=CC=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:25][C:21]1[CH:20]=[C:19]([C:3]2[C:4]([CH3:11])=[CH:5][C:6]([CH2:9][NH2:10])=[CH:7][N:8]=2)[CH:24]=[CH:23][N:22]=1
Reactant: Cc1cc(CN)cnc1Cl
Reactant: Cc1cc(-c2ccc(CN)cc2F)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: Cc1cc(-c2ncc(CN)cc2C)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a reaction vial was added (6-chloro-5-methylpyridin-3-yl)methanamine 30-4 (500 mg, 2.6 mmol), 2-methylpyridin-4-ylboronic acid 15-1 (460 mg, 3.38 mmol), Pd(OAc)2 (58 mg, 0.26 mmol), S-Phos (150 mg, 0.37 mmol) and K3PO4 (1.65 g, 7.8 mmol). The vial was evacuated and backfilled with nitrogen. 2-butanol (5 mL) was added via syringe. The reaction was stirred at room temperature for 10 mins and then 110° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted into 10% methanol in DCM, and filtered through celite pad. The filtrate was dried and the crude product was purified by silica gel flash chromatography, and eluted with 10% methanol in DCM to give (2′,3-dimethyl-2,4′-bipyridin-5-yl)methanamine 63-2 as an oil. MS m/z 214.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][C@H:13]1[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[NH:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH2:6][N:14]2[C@@H:15]([CH3:19])[CH2:16][O:17][CH2:18][C@@H:13]2[CH3:12])=[C:4]([F:11])[CH:3]=1
Reactant: O=Cc1cc(F)c(Cl)cc1F
Reactant: C[C@H]1COC[C@H](C)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1COC[C@H](C)N1Cc1cc(F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.8 %

Procedure:
4-Chloro-2,5-difluorobenzaldehyde (0.177 g, 1.0 mmol) and (3S,5S)-3,5-dimethylmorpholine (0.167 g, 1.10 mmol) were dissolved in dichloromethane (10 mL). Sodium triacetoxyborohydride (0.307 g, 1.45 mmol) was added and the mixture was stirred under argon atmosphere at RT for 20 h. The mixture was diluted with dichloromethane and washed with NaHCO3 (aq). The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica eluting with gradients of ammonia in methanol and dichloromethane. The fractions containing product were pooled and evaporated to give (3S,5S)-4-(4-chloro-2,5-difluorobenzyl)-3,5-dimethylmorpholine (0.118 g, 43%) as a liquid.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH2:2][C:3]2[O:4][C:5](=[O:9])[O:6][C:7]=2[CH3:8])=[CH:14][CH:13]=1
Reactant: COc1ccc(S)cc1
Reactant: Cc1oc(=O)oc1CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(SCc2oc(=O)oc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
In 40 ml of dichloromethane was dissolved 2.0 g of 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and 1.9 g of 4-methoxybenzenethiol was added. Then, 1.4 g of triethylamine was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate. The insoluble materials were separated by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to medium-pressure silica gel column chromatography as in Example 1. The eluate was evaporated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 2.3 g of the captioned compound as pale yellow crystals.