Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH2:8][C:7]1=[O:22])(=O)[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:24]([O:26][NH3+:27])[CH3:25].C([O-])(=O)C.[Na+]>C(O)C>[CH2:24]([O:26][NH:27][CH2:4][CH2:3][CH2:2][CH:1]=[C:6]1[C:7](=[O:22])[CH2:8][CH:9]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=2)[CH2:10][C:11]1=[O:12])[CH3:25]
Reactant: CCO[NH3+]
Reactant: CCCC(=O)C1C(=O)CC(c2ccc(CCC)cc2)CC1=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1ccc(C2CC(=O)C(=CCCCNOCC)C(=O)C2)cc1

Procedure:
15.0 parts by weight of 2-butyryl-5-(4-n-propylphenyl)-cyclohexane-1,3-dione is reacted with 5.1 parts by weight of ethoxyammonium chloride and 4.5 parts by weight of anhydroud sodium acetate in 120 parts by volume of ethanol, and worked up as in Example 1. There is obtained 2-(ethoxyaminobutylidene)-5-(4-n-propylphenyl)-cyclohexane-1,3-dione (active ingredient No. 4).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.CCCCCC.C([Li])CCC.[C:19]1(=[O:24])[O:23][CH2:22][CH2:21][CH2:20]1>CCOCC>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][OH:24])[CH:3]=1
Reactant: O=C1CCCO1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(CCCO)c1cccnc1
Yield: 76.5 %

Procedure:
A solution of 10.0 g (63.3 mmol) of 3-bromopyridine in 100 ml of ether was cooled to -78° C., to which 40 ml (64 mmol) of 1.6 M n-butyllithium hexane solution was added dropwise with stirring. After completion of the addition, the mixture was stirred for further 15 minutes, to which the solution of 5.45 g (63.3 mmol) of γ-butyrolactone in 15 ml of ether was added dropwise, and stirred for further 1 hour at -78° C.-room temperature. To the reaction mixture an aqueous solution of ammonium chloride, and the resultant substance was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was evaporated off. The residue was purified with silica gel column chromatography (CHCl3 -MeOH (9:1)) and recrystallized from ethyl acetate-isopropyl ether, to give 8.0 g (77%) of 4-(3-pyridyl)-4-oxobutanol. m.p. 36°-37° C.
Reaction SMILES: Cl[CH:2]([CH3:4])[CH3:3].[Mg].[C:6]1([C:12]2[NH:13][C:14]([CH3:19])=[C:15]([CH:17]=[O:18])[N:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)C.C1COCC1>[C:6]1([C:12]2[NH:13][C:14]([CH3:19])=[C:15]([CH:17]([OH:18])[CH:2]([CH3:4])[CH3:3])[N:16]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)Cl
Reactant: Cc1[nH]c(-c2ccccc2)nc1C=O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2ccccc2)nc1C(O)C(C)C
Yield: 57.9 %

Procedure:
35 Grams (0.45 mol) of 2-chloropropane was added to 10.8 g (0.45 mol) of magnesium in 100 ml of diethyl ether. Then 55.8 g (0.3 mol) of 2-phenyl-4-formyl-5-methyl-1H-imidazole in 100 ml of THF were added. At the end of the addition, the mixture was refluxed for 30 minutes and then cooled and poured on ice water. The aqueous layer was extracted twice with 100 ml of diethyl ether. Evaporation of the solvent gave a residue which was recrystallized in ethanol to yield 40 grams of 2-phenyl- 4-(1-hydroxy-2-methylpropyl)-5-methyl-1H-imidazole, which melted at 214° C.
Reaction SMILES: [CH:1]([NH:3][NH2:4])=O.[N:5]([CH2:8][C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[C:6]=[S:7].C(O)C>N1C=CC=CC=1>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[CH2:8][N:5]1[CH:1]=[N:3][N:4]=[C:6]1[SH:7]
Reactant: S=C=NCc1ccco1
Reactant: NNC=O
Solvent: CCO
Solvent: c1ccncc1
Product: Sc1nncn1Cc1ccco1
Yield: 83.7 %

Procedure:
A solution of formic acid hydrazide (439 mg, 7.809 mmol) in pyridine (20 ml) was added to a solution of 2-isothiocyanatomethyl-furan (1 g, 7.185 mmol) in pyridine (20 ml). Reaction took place at room temperature overnight, and ethanol (20 ml) was added directly to the reaction and placed in 80 C bath overnight. Solvent was evaporated and the title compound (1.09 g, 83%) was obtained from purification by SPE chromatography on silica gel with 500 ml 20%, 250 ml 25%, 250 ml 30%, 250 ml 35%, 250 ml 40%, and 250 ml 50% ethyl acetate in hexanes. 1H NMR (CD3OD), δ (ppm): 14.0 (bs, 1H), 8.19 (s, 1H), 7.52 (q, 1H), 6.52 (m, 1H), 6.42 (m, 1H), 4.90 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11](I)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15].CCN(CC)CC>C1COCC1.[Cu]I.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[C:11]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cc(I)c(N)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of compound 70n (0.642 mmol, 200 mg), CuI (0.064 mmol, 12.2 mg) and Pd(PPh3)2Cl2 (0.064 mmol, 45 mg) in THF (2 mL) was added ethynyltrimethylsilane (0.963 mmol, 95 mg) followed by Et3N (7.19 mmol, 1 mL) under N2. The reaction mixture was stirred at room temperature for 1.5 h and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 70p.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C@H:11]([C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=O)[C@@H:12]([OH:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C@H:24]([C@@H:30]([OH:52])[C@H:31]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@H:33]([N:44]2[CH:49]=[CH:48][C:47](=[O:50])[NH:46][C:45]2=[O:51])[O:32]1)[C:25]([O:27][CH2:28][CH3:29])=[O:26].N[C@H]([C@@H](O)[C@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](N2C=CC(=O)NC2=O)O1)C(OCC)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[C:37]([O:36][C@H:35]1[C@@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([N:44]2[CH:49]=[CH:48][C:47](=[O:50])[NH:46][C:45]2=[O:51])[O:32][C@@H:31]1[C@H:30]([OH:52])[CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:23][CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:21])[C@H:11]([C@@H:12]([OH:14])[CH3:13])[NH:10][C:9](=[O:22])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:39])[CH3:38]
Reactant: C[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Reactant: CCOC(=O)[C@H](N)[C@@H](O)[C@@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCOC(=O)[C@H](N)[C@@H](O)[C@@H]1O[C@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(NCCCNC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@H](C)O)[C@@H](O)[C@H]1O[C@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
A solution of [(1S,2S)-2-hydroxy-1-(3-oxo-propylcarbamoyl)-propyl]-carbamic acid benzyl ester (215 mg, 0.699 mmol, obtained from Reference Example 18) and a mixture of ethyl (2R,3R)-2-amino-3-hydroxy-3-[(2S,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]propanoate and ethyl (2R,3R)-2-amino-3-hydroxy-3-[(2S,3R,4R,5S)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]propanoate (300 mg, 0.699 mmol) in anhydrous tetrahydrofuran (3 ml) were stirred at room temperature under a nitrogen atmosphere for 15 minutes. Acetic acid (40 μl) and sodium triacetoxyborohydride (0.296 mg, 1.4 mmole) were added and the resulting solution was stirred under nitrogen for an additional 2.5 hours. The reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution, and the aqueous layer was separated and extracted with ethyl acetate (2×75 ml). The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (flash column, silica gel, 5% methanol in methylene chloride) to provide ethyl (5S)-12-[(R)-[(2R,3R,4R,5S)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (230 mg, 46%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@@H:16]([F:44])[CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:43])([F:42])[C:25]([F:41])([F:40])[O:26][C:27]([F:39])([F:38])[C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])([F:22])[F:21])=[C:10]([F:45])[C:9]=2[F:46])=[N:6][CH:7]=1.[CH2:47](Br)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:47]([O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@@H:16]([F:44])[CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:42])([F:43])[C:25]([F:40])([F:41])[O:26][C:27]([F:38])([F:39])[C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])([F:21])[F:22])=[C:10]([F:45])[C:9]=2[F:46])=[N:4][CH:3]=1)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCBr
Reactant: Oc1cnc(-c2ccc(OC[C@@H](F)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCCCCCOc1cnc(-c2ccc(OC[C@@H](F)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)nc1

Procedure:
The title compound was prepared essentially as in Example 18 by combining 5-hydroxy-2-[4-(3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-(S)-2-fluoropropoxy)-2,3-difluorophenyl]pyrimidine (0.89 g, 1.24 mmol), octyl bromide (0.3 g, 1.5 mmol), and potassium carbonate (0.2 g, 1.5 mmol) in acetonitrile (12 mL). The resulting mixture was heated to reflux overnight, deionized water (20 mL) was added, and the resulting crude product was collected by filtration. The product was recrystallized from methanol to yield 0.35 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:49])[C:23]([CH3:48])=[C:24]([CH2:30][C:31]2[C:32]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:49])[C:23]([CH3:48])=[C:24]([CH2:30][C:31]2[C:32]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:35])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OCc2ccccc2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCOCC3)c2OCc2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.2 %

Procedure:
Morpholine (0.033 g, 0.38 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.109 g, 0.57 mmol) were added to a methylene chloride solution (10 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-benzyloxybenzoic acid (0.080 g, 0.19 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) to obtain the titled compound (0.057 g, 0.12 mmol, 61%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:13][C:14]([NH2:16])=[NH:15])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:17]([O:21][C:22](=[O:37])/[C:23](/O)=[C:24](\[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[C:25](O)=[O:26])([CH3:20])([CH3:19])[CH3:18].C[O-].[Na+]>CO>[C:17]([O:21][C:22]([C:23]1[C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([OH:26])[N:16]=[C:14]([CH2:13][C:8]2([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:15]=1)=[O:37])([CH3:20])([CH3:18])[CH3:19]
Reactant: N=C(N)CC1(c2ccccn2)CCCC1
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
To a stirred solution of 2-(1-pyridin-2-yl-cyclopentyl)-acetamidine hydrochloride (435) (1 g, 3.55 mmol) and 2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (1.638 g, 5.319 mmol) in methanol (15 mL), sodium methoxide (25% in methanol) (2.3 mL, 10.638 mmol) was dropwise added at 0° C. Then reaction mixture was allowed to stir at room temperature for 16 h. Then reaction mixture was quenched with aqueous HCl (1N; 5 mL) and the methanol was removed under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic part was dried, concentrated and the residue was purified by nor mal silica gel (100-200 mesh) column chromatography using 30% ethyl acetate in hexane as eluent to obtain 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (436) (1.2 g, 73%) as a yellow sticky liquid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:3]=1[NH2:16].CN(C)[C:19](=O)[CH3:20].C(C(CC)(CC)C([O-])([O-])[O-])C>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[C:3]=1[N:16]=[C:19]([CH3:20])[N:9]2[CH:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: CC(=O)N(C)C
Reactant: Nc1nc(Cl)c(N)c(NC2CCOCC2)n1
Agent: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CC(=O)O
Product: Cc1nc2c(Cl)nc(N)nc2n1C1CCOCC1
Temperature: 160 °C
Reaction time: 72 h

Procedure:
In an alternative procedure, the reaction was carried out in parallel using 10 vials. To each vial was added 6-chloro-N4-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4,5-triamine (preparation Route A) (400 mg, 1.64 mmol), N,N-dimethyl acetamide (8 mL), glacial acetic acid (16 μL, 0.2% vol) and triethylorthoacetate (0.8 mL, 5.32 mmol) and the mixture was stirred at 160° C. After 3 days, the reaction was complete (by LC-MS) and the reaction mixture, containing desired product MS (EI) m/z 268.1 (MH)+, as well as acetylated product MS (EI) m/z 310.2 (MH)+, was cooled to room temperature. To each vial was then added 1 mL of a 1 M aqueous solution of HCl, with stirring at 100° C. After 1 h at 100° C., LC-MS analysis indicated only desired product, in a clean reaction. Upon cooling to room temperature, a white precipitate formed. Filtration under vacuum, followed by washing of the precipitate with portions of methanol provided the desired product (combined yield 2.98 g for 10 vials, 68% yield) as a white solid in pure form. 1H NMR (300 MHz, d6-DMSO) δ, ppm: 6.76 (s, 2H), 4.41 (m, 1H), 3.97 (m, 2H), 3.45 (m, 2H), 3.33 (s, 3H), 2.63 (m, 2H), 1.74 (m, 2H); MS (EI) m/z 268.1 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:18])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.Cl[CH2:20][C:21](=O)[CH2:22]C(OC)=O.FC1C=CC(N=C=O)=CC=1>C(O)CCC.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:18])[C:13]=2[C:14]([O:16][CH2:17][CH2:20][CH2:21][CH3:22])=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2)OCC1=O
Reactant: COC(=O)CC(=O)CCl
Agent: O=C=Nc1ccc(F)cc1
Agent: [Zn]
Solvent: CCCCO
Product: CCCCOC(=O)C1=C(Nc2ccc(F)cc2)OCC1=O
Temperature: 80 °C
Reaction time: 72 h

Procedure:
Under a nitrogen atmosphere, a solution of methyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.13 g, 0.50 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and 4-fluorophenyl isocyanate, and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0062 g, 0.0065 mmol) in 1-butanol (2.0 mL) was stirred at 80° C. for 3 days then stirred at ambient temperature for further 3 days. The precipitate was collected by filtration, washed with 2-propanol and diisopropyl ether then dried to afford n-butyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.078 g, y. 53%).
Reaction SMILES: [Li]C(C)(C)C.[C:6]1([NH:12][C:13]2[N:14]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=[CH:16][N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([O:50][CH3:51])[C:47]=1[O:48][CH3:49])[C:42](Cl)=[O:43]>C1COCC1>[C:6]1([NH:12][C:13]2[N:14]([C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:15]=[C:16]([C:42]([C:41]3[CH:45]=[C:46]([O:50][CH3:51])[C:47]([O:48][CH3:49])=[C:39]([O:38][CH3:37])[CH:40]=3)=[O:43])[N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(Nc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(Nc3ccccc3)n2)cc(OC)c1OC
Reaction time: 8 h
Yield: 43.6 %

Procedure:
At −78° C., t-BuLi in THF (1.7 M, 0.34 mL, 0.58 mmol) was added to a solution of trityl protected compound (d) (116 mg, 0.289 mmol) in THF. Then 3,4,5-trimethoxybenzoyl chloride (66.5 mg, 0.289 mmol) was added and stirred overnight. The reaction mixture was quenched with saturated NR4Cl, and dried with MgSO4. Filtration and evaporation of the solvent followed by chromatography afforded compound (e) (75 mg, 43.7%). 1H NMR (500 MHz, CDCl3) δ 7.55-7.41 (m, 5H), 7.32 (s, 1H), 7.28-7.18 (m, 15H), 6.94 (s, 2H), 3.78 (s, 6H), 3.70 (s, 3H). MS: 594.2 (M−H)−; 596.3 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH3:16][NH:17][C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19]>>[C:14]([C:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:3]2[N:4]=[CH:5][N:6]([CH3:7])[C:2]=2[C:24]2[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH:17][CH3:16])=[O:19])[CH:13]=1)#[N:15]
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: CNC(=O)c1cccc(B(O)O)c1
Product: CNC(=O)c1cccc(-c2c(-c3cc(C#N)ccn3)ncn2C)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 3-(N-methylaminocarbonyl)phenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H15N5O, 318. Found, 318.
Reaction SMILES: [N+:1](=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[C:12](N)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCCl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Rh+3].[Rh+3]>[C:12]([NH:1][CH:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=[N+]=[N-])C(C)=O
Reactant: NC(=O)c1ccccc1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Product: CCOC(=O)C(NC(=O)c1ccccc1)C(C)=O
Yield: 75 %

Procedure:
A solution of ethyl 2-diazo-3-oxobutanoate (20 g, 128 mmol) in 1,2-dichloroethane (100 mL) was added over 16 h to a refluxing solution of benzamide (13 g, 107 mmol) and dirhodium tetraacetate (1.4 g, 3.2 mmol) in 1,2-dichloroethane (200 ml). The mixture was evaporated in vacuo and purified by flash chromatography to give ethyl 2-benzamido-3-oxobutanoate as a yellow oil (20 g, 50% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH3:43][Mg]Br.Cl>O1CCCC1>[O:42]=[C:17]1[C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:13]=2)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]2[N:25]=[CH:26][N:27]=[C:19]2[N:18]1[C@H:28]1[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](=[O:37])[CH3:43])[CH2:30][CH2:29]1
Reactant: C[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ncnn12
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.75 g) was dissolved in tetrahydrofuran (10 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 4 mL) was added at room temperature. The reaction mixture was warmed to 70° C. and stirred for 3 hr. 1 N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.48 g, 69%).
Reaction SMILES: CCN(CC)CC.[CH3:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1OS(C(F)(F)F)(=O)=O)[C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13].[CH3:30][C:31]1([CH3:38])[C:35]([CH3:37])([CH3:36])[O:34][BH:33][O:32]1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:30][C:31]1([CH3:38])[C:35]([CH3:37])([CH3:36])[O:34][B:33]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:9]([CH3:8])[C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[O:32]1
Reactant: CC(C#C[Si](C)(C)C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)OBOC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2Oc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C#C[Si](C)(C)C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Temperature: 60 °C
Yield: 86.5 %

Procedure:
A mixture of 547 mg (2.44 mmol, 0.03 eq) of Pd(OAc)2 and 2.63 grams (4.88 mmol, 0.06 eq) of bis[2-(diphenylphosphino)phenyl]ether (DPEphos) was stirred in 163 mL of dioxane in a 500 mL round bottom flask under argon at room temperature. To this heterogenous mixture was sequentially added 22.7 mL (163 mmol, 2.0 eq) of Et3N and 28.5 grams (81.3 mmol, 1.0 eq) of triflate 7. Lastly, 17.6 mL (122 mmol, 1.5 eq) of 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane was added and the mixture was sparged with argon for 10 minutes. The reaction was then heated to 60° C. in a silicon oil bath and stirred until complete by 1H-NMR (aliquots removed periodically). Upon completion (˜19 hours) the mixture was cooled to room temperature and diluted with Et2O. The solution was then washed with water and the water layer was back extracted with Et2O. The combined Et2O layers were washed with brine and dried over MgSO4. Concentration and silica gel chromatography (hexane/EtOAc) gave 23.1 grams (86%) of 9 as a yellow oil, Rf 0.64 (1:1 hexane:EtOAc). 1H-NMR (500 MHz, CDCl3): 7.81 (1H, d, J=7.1 Hz), 7.75 (1H, d, J=7.8 Hz), 7.47 (1H, d, J=7.6 Hz), 7.24 (1H, d, J=7.4 Hz), 4.73 (1H, q, J=7.1 Hz), 1.45 (3H, d, J=7.1 Hz), 1.36 (6H, s), 1.35 (6H, s), 0.215 (9H, s). 13C-NMR (500 MHz, CDCl3): 150.25, 136.35, 131.64, 126.85, 125.94, 111.34, 85.66, 83.77, 31.52, 26.29, 25.17, 24.93, 0.45. IR (cm−1): 2975 (m), 2165 (m), 1598 (m), 1441 (m), 1380 (m), 1346 (s), 1249 (m), 1145 (m), 842 (s) HRMS (EI) calcd. for C19H29BO2Si: 328.2030. found: 328.2028.