Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8](N(OC)C)=[O:9])=[C:4]([O:16][CH3:17])[CH:3]=1.[CH:18]1([Mg]Br)[CH2:20][CH2:19]1.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([CH:18]2[CH2:20][CH2:19]2)=[O:9])=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: COc1cc(Br)ccc1OCC(=O)N(C)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1OCC(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 2-(4-bromo-2-methoxyphenoxy)-N-methoxy-N-methylacetamide Part A (2 g, 6.58 mmol) in THF (25 mL) was slowly added cyclopropylmagnesium bromide (39.5 mL, 19.73 mmol). After stirring for 1 hour at RT, the reaction mixture was added to a sat. NH4Cl solution which was subsequently extracted with EtOAc, dried (Na2SO4), and concentrated. The crude product was purified using ISCO flash chromatography (silica gel/hexanes-ethyl acetate 100:0 to 50:50 gradient) to afford the desired product 2-(4-bromo-2-methoxyphenoxy)-1-cyclopropylethanone 16B (1.72 g, 6.03 mmol, 92% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 7.01 (2H, dddd), 6.65 (1H, d, J=8.53 Hz), 4.72 (2H, s), 3.89 (3H, s), 2.24-2.35 (1H, m), 1.15 (2H, quin, J=3.83 Hz), 0.98 (2H, dq, J=7.56, 3.67 Hz).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[O:49][N:48]=[C:47]([CH3:50])[N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[O:49][N:48]=[C:47]([CH3:50])[N:46]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Cc1noc(CCl)n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1noc(Cn2nc3nc(C(C)(C)C)nc(N4CCC(F)(F)C4)c3n2)n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole and isolated as light yellow gum. MS (m/e): 379.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][C:16]([NH:18][CH:19]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[CH2:20][C:21]([O:23]C)=[O:22])=[O:17])=[O:13])[CH:3]=1.[OH-].[Na+]>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][C:16]([NH:18][CH:19]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:29][CH:30]=2)[CH2:20][C:21]([OH:23])=[O:22])=[O:17])=[O:13])[CH:3]=1
Reactant: COC(=O)CC(NC(=O)CNC(=O)CCCNc1cc(C)ccn1)c1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccnc(NCCCC(=O)NCC(=O)NC(CC(=O)O)c2ccc(OC(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
280 mg of methyl 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionate (crude material) are dissolved in 30 ml of dioxane, and 0.61 ml of NaOH (2 mol/l) is added. Stirring at room temperature overnight is followed by removal of the solvent by distillation and the usual workup. 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid is obtained. If an excess of NaOH is used, the sodium salt of 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid is obtained. Preparative HPLC results in 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid trifluoroacetate, RT 24.93 min, FAB-MS (M+H)+ 483.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.B(Cl)(Cl)Cl.ClCCl.CS[C:20]#[N:21].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>ClC(Cl)C>[OH:10][C:6]1[CH:5]=[C:4]2[C:9]([CH2:1][CH2:2][CH2:3]2)=[CH:8][C:7]=1[C:20]#[N:21]
Reactant: Oc1ccc2c(c1)CCC2
Reactant: CSC#N
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: N#Cc1cc2c(cc1O)CCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.7 %

Procedure:
To a stirred solution of Indan-5-ol (5.0 g, 32.3 mmol) in anhydrous dichloroethane (21.5 mL) was added, at 0° C., 1.0 M boron trichloride in dichloromethane (41.0 mL, 41.0 mmol, 1.2 eq), followed by methyl thiocyanate (2.43 mL, 35.5 mmol, 1.1 eq) and aluminum chloride (4.30 g, 2.3 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 2 d and then cooled to 0° C. To the dark brown reaction mixture was added 50% aqueous sodium hydroxide solution (100 mL) until pH=11. The resulting yellow biphasic layers were stirred at reflux for 3 h. The biphasic layers were separated, and the aqueous layer was adjusted to pH=1 with 50% aqueous hydrogen chloride solution at 0° C. The acidified aqueous mixture was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate and concentrated at reduced pressure. Crystallization from ether-hexane afforded the cyanophenol as a white solid (3.02 g, 50.9%). 1H-NMR (DMSO-d6) δ 10.67 (s,1H), 7.36 (s, 1H), 6.84 (s,1H), 2.81 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 1.99 to 1.93 (m, 2H); Rf=0.23, 25% ethyl acetate-hexane.
Reaction SMILES: C(C1OC[C@H](C(C)(C)C)N=1)(C1OC[C@H](C(C)(C)C)N=1)(C)C.[Cl:22][C:23]([F:25])=[CH2:24].[N+](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N-]>C1CCCCC1.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[Cl:22][C:23]1([F:25])[CH2:24][CH:28]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C(F)Cl
Agent: [Cu+2]
Agent: CC(C)(C1=N[C@@H](C(C)(C)C)CO1)C1=N[C@@H](C(C)(C)C)CO1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1CCCCC1
Product: CCOC(=O)C1CC1(F)Cl
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Cyclohexane (76.6 g), 2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (64.8 mg, 0.22 mmol), and copper (II) trifluoromethanesulfonate (72.1 mg, 0.20 mmol) were charged in an autoclave, and then 1-chloro-1-fluoroethylene (76.8 g, 0.95 mol) was charged under elevated pressure. After the mixed solution was cooled to 10° C., a mixed solution containing 95% of ethyl diazoacetate (12.0 g, 100 mmol) and cyclohexane (50 g) was charged under elevated pressure over five hours. Cyclohexane (20 ml) was further charged under elevated pressure and stirring was continued at the same temperature for 1 hour, and then the internal pressure was released to give a solution of ethyl 2-chloro-2-fluorocyclopropanecarboxylate in cyclohexane (179.3 g). This solution was analyzed by gas chromatography to find that the content of the ethyl 2-chloro-2-fluorocyclopropanecarboxylate was 6.52% (yield based on ethyl diazoacetate: 70.1%), and the ratio of cis-isomer/trans-isomer was 64.4/35.6.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[Si:23]([O:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 95.7 %

Procedure:
A mixture of (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 40.7 mmol), imidazole (5.54 g, 81.4 mmol) and t-butyldimethylsilyl chloride (6.6 g, 45 mmol) in DMF (50 ml) was stirred and r.t. for 4 days. The mixture was diluted with EtOAc and washed with H2O and sat. NH4Cl. The organic layer was dried over MgSO4 and concentrated. 14 g of an oil product was obtained and used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:13][CH:12]([CH2:14][C:15]([O:17]CC)=[O:16])[N:11]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])[C:10]1=[NH:28]>C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:13][CH:12]([CH2:14][C:15]([OH:17])=[O:16])[N:11]([C:20]2[C:21]([CH3:27])=[CH:22][CH:23]=[CH:24][C:25]=2[CH3:26])[C:10]1=[NH:28]
Reactant: CCOC(=O)CC1CN(c2c(C)cccc2C)C(=N)N1c1c(C)cccc1C
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1N1CC(CC(=O)O)N(c2c(C)cccc2C)C1=N

Procedure:
When the above product is allowed to stand at room temperature in ethyl acetate for 2 days, a transesterification reaction occurs, the ethyl 1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-acetate, melting at 142°-144° C., is obtained.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]([CH3:13])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[Na+].Cl>O>[O:16]=[C:17]1[CH:22]=[CH:21][N:20]([C:2]2[CH:15]=[CH:14][C:5]([C:6]([CH:8]([CH3:13])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=2)[CH:19]=[CH:18]1
Reactant: CC(CC(=O)O)C(=O)c1ccc(F)cc1
Reactant: Oc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)C(=O)c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
A solution of 3-(4-fluorobenzoyl)butanoic acid (8 g), 4-hydroxypridine (8 g) and sodium hydroxide (4.6 g) in water (80 ml) was heated in an autoclave at 140° C. for 20 hours. The reaction mixture was cooled and on acidification to pH3 with dilute hydrochloric acid afforded as a white crystalline precipitate 3-[4-(4-oxo-1,4-dihydropyridin-1-yl)benzoyl]butanoic acid, 9.45 g, m.p. 250°-252° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:21][C@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[N:18][C:17](Br)=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[CH3:22][O-:23].[Na+].O.Cl>CO>[CH3:22][O:23][C:17]1[N:18]=[CH:19][C:14]([N:12]2[C:11]3[C@@H:10]4[CH2:21][C@@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:3])=[O:5])=[N:13]2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1nn(-c2cnc(Br)cn2)c2c1C[C@H]1C[C@@H]21
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)cn1
Temperature: 140 °C
Yield: 74.7 %

Procedure:
To a reaction vial containing (1aR,5aR)-2-(5-bromopyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (120 mg, 0.344 mmol) in methanol was added sodium methoxide (74 mg, 1.375 mmol). The reaction mixture was heated at 140° C. for 1 h under microwave irradiation, poured into water, acidified with HCl solution and extracted with solution of DCM:IPA (4:1). The combined organics were dried and concentrated to give the title compound (70 mg). LCMS m/z=273.3 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:12])[NH:8][C:9]=1[CH2:10]C)(=[O:3])[CH3:2].[CH3:13]C(=O)CC(=O)CC.[OH-].[NH4+]>C(O)C>[CH3:10][C:9]1[NH:8][C:7](=[O:12])[CH:6]=[CH:5][C:4]=1[C:1](=[O:3])[CH2:2][CH3:13]
Reactant: CCC(=O)CC(C)=O
Reactant: CCc1[nH]c(=O)ccc1C(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCC(=O)c1ccc(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
C-6. 6-Methyl-5-(n-propanoyl)-2(1H)-pyridinone (and 5-Acetyl-6-ethyl-2(1H)-pyridinone)--A mixture containing 50 g of 2,4-hexanedione, 100 ml of ethanol and 50 ml of concentrated aqueous ammonium hydroxide was allowed to stand at room temperature overnight and then concentrated on a rotary evaporator at 50°-60° C. to a constant weight of 48.8 g, a pale yellow oil that solidified on standing at room temperature. The nmr spectrum of this solid in CDCl3 indicated it to be a mixture of 5-amino-4-hexen-3-one and 4-amino-3-hexen-2-one in a weight ratio of 65:35. The mixture of amino-hexen-ones was dissolved in 100 ml of dimethylformamide and treated with methyl 2-propynoate and the resulting mixture was first gently heated with stirring on a steam bath for 2 hours and then refluxed for 24 hours. The reaction mixture was allowed to cool to room temperature and allowed to stand at room temperature overnight. The crystalline material that separated was collected, washed with isopropyl alcohol and dried in vacuo at 90°-95° C. to yield 11.9 g of 6-methyl-5-(n-propanoyl)-2(1H)-pyridinone, m.p. 173°-175° C. The mother liquor was concentrated on a rotary evaporator and the residue was crystallized from isopropyl alcohol, washed with ether and dried to yield another 10.4 g of 6-methyl-5-(n-propanoyl)-2(1H)-pyridinone, m.p. 173°-175° C. (The filtrate was concentrated in vacuo to yield 57.8 g of an oily residue which was chromatographed on silica gel (700 g) using ether as eluant. Evaporation of the ether fractions yielded 22.4 g of the least polar component, an oily material, a middle fraction of 16.4 g, a viscuous gummy oil, and as the most polar component, 7.8 g, a solid which was recrystallized from isopropyl alcohol to yield a white amorphous powder, m.p. 140°-145° C., whose nmr spectrum showed it to consist of 90% 5-acetyl-6-ethyl-2(1H)-pyridinone. Six further recrystallizations of this product resulted in 1.5 g of pure 5-acetyl-6-ethyl-2(1H)-pyridinone, m.p. 162°-164° C., as shown by its nmr spectrum.)
Reaction SMILES: [Li+].[CH-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[F:7][C:8]1[CH:25]=[CH:24][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=O)=[CH:10][CH:9]=1>O1CCCC1>[C:2]1(=[C:12]([C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:25][CH:24]=2)[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3]1
Reactant: c1cc[cH-]c1
Reactant: CS(=O)(=O)c1ccc(C(=O)c2ccc(F)cc2)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(=C2C=CC=C2)c2ccc(F)cc2)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
A solution of 3.7 g (50 mmol) of lithium cyclopentadienylide in 90 ml of anhydrous tetrahydrofuran is added to a solution of 11.1 g (40 mmol) of 4-fluoro-4'-methylsulfonylbenzophenone, prepared in Example 2, in 70 ml of anhydrous tetrahydrofuran, cooled to 10° C. The reaction medium is stirred for 2 hours at this temperature and then for 24 hours at room temperature. It is subsequently poured onto ice. After dilution with water, the mixture is extracted with t-butyl methyl ether. The organic phase is dried over magnesium sulfate and then concentrated in the cold. The residue obtained is chromatographed on silica gel in dichloromethane. The resulting oil crystallizes from a petroleum ether/t-butyl methyl ether mixture to give 3.6 g of 4-[(cyclopenta-2,4-dienylidene)(4-fluorophenyl)methyl]methylsulfonylbenzene in the form of orange crystals melting at 110° C.
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:5].[Cu](C#N)[C:20]#[N:21]>CN(C)C(=O)C>[NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([C:20]#[N:21])=[CH:13][C:3]=1[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:5]
Reactant: CCCCCCOC(=O)c1cc(Br)cc(C)c1N
Reactant: N#C[Cu]C#N
Solvent: CC(=O)N(C)C
Product: CCCCCCOC(=O)c1cc(C#N)cc(C)c1N
Yield: 93.9 %

Procedure:
The above-described method (Example 2) was repeated to react hexyl 2-amino-5-bromo-3-methylbenzoate (2.2 g, 6.79 mmol) with copper cyanide (0.62 g, 6.93 mmol) in N,N-dimethylacetamide at 170° C. for 6 hours. Following working up similar to Example 2 and additional extraction with ethyl acetate and washing with aqueous 5% ethylenediamine solution, hexyl 2-amino-5-cyano-3-methylbenzoate (1.66 g, 85.5% of theory, 91.1 area % LC) was obtained as a brown oil.
Reaction SMILES: [C:1]([Si:5]([CH3:11])([CH3:10])[O:6][CH2:7][C:8]#[CH:9])([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[Li+].[Cl-].CON(C)[C:22](=[O:24])[CH3:23].[NH4+].[Cl-]>C1COCC1>[Si:5]([O:6][CH2:7][C:8]#[C:9][C:22](=[O:24])[CH3:23])([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:10])[CH3:11]
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Reactant: CON(C)C(C)=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)C#CCO[Si](C)(C)C(C)(C)C
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 70.6 %

Procedure:
To a −40° C. solution of tert-butyl(dimethyl)(prop-2-yn-1-yloxy)silane (1.70 g, 10 mmol) in THF (6 mL) was added iPrMgCl.LiCl (8.46 mL, 11 mmol) dropwise keeping the internal temperature below −20° C. A solution of the N-methoxy-N-methylacetamide (1.13 g, 11.0 mmol) in THF (4 mL) was cooled to −10° C. and the alkyne solution was added to the Weinreb amide solution via cannula. The reaction mixture was stirred at −10° C. for 10 minutes. The reaction mixture was poured into a mixture of saturated NH4Cl and ice. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried with Mg2SO4, filtered, then concentrated under vacuum to give 5-{[tert-butyl(dimethyl)silyl]oxy}pent-3-yn-2-one (Cpd G, 1.5 g, 64%) as an oil.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]2=[N:9][CH:8]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:6]([C:7]1[N:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]2=[N:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cnc2cnccn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cnc2cnccn12
Reaction time: 0.25 h
Yield: 77.8 %

Procedure:
To a solution of 3-((Trimethylsilyl)ethynyl)imidazo[1,2-a]pyrazine (0.15 g, 0.7 mmol) in 3.5 mL of THF was added 1.05 mL (1.05 mmol) of tetrabutylammonium fluoride (1.0M in THF) at ambient temperature. The solution was stirred for 15 min, concentrated, and the crude product purified by silica gel flash chromatography (eluted with 50% EtOAc/hexanes) to provide 0.078 g of product.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:28])[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([N:39]=[C:40]=[O:41])=[O:38])=[CH:32][CH:31]=1>O1CCCC1>[CH3:24][N:23]([CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:40]([NH:39][C:37](=[O:38])[CH2:36][C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=4)=[O:41])=[CH:3][C:4]=3[F:28])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1)[CH3:25]
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ccn2)CC1
Reaction time: 72 h
Yield: 15 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine (61.1 mg) in tetrahydrofuran (2.0 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 1.6 ml) at room temperature, followed by stirring for 3 days. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate) to provide the titled compound (13.3 mg, 15%) as white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[N+:18]([C:21]1[CH:32]=[CH:31][C:24]([O:25][CH:26]([CH3:30])[C:27](Cl)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:27](=[O:28])[CH:26]([O:25][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:32][CH:31]=2)[CH3:30])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a mixture of 4-nitrophenol (21.8 g) and triethylamine (33 ml) in ethyl acetate (360 ml) at 0° C. was added 2-(4-nitrophenoxy)-propionyl chloride (36 g) dropwise, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was filtered to remove the salts, washed with 5% sodium bicarbonate, followed by water, and the ethyl acetate layer was dried over anhydrous sodium sulphate. The solvent was distilled off under vacuum and the compound was precipitated by adding cold methanol. Filtration and drying gave pure 2-(4-nitrophenoxy)-propionic acid-4-nitrophenyl ester (35 g) as white powder. The product had a melting point of 136-139° C., with a purity of 99%. The product was characterized by 1H NMR (CDCl3) δ 1.85 (d, 3H, CH3), 5.15 (q, 1H, CH), 7.05 (d, 2H, Ar), 7.28 (d, 2H, Ar), 8.30 (m, 4H, Ar).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](Br)=[CH:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:17]([Sn](CCCC)(CCCC)CCCC)=[CH2:18]>C1COCC1.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>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH:17]=[CH2:18])=[CH:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc(Br)n(-c2ccc([N+](=O)[O-])cc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1cc(C)nn1-c1ccc([N+](=O)[O-])cc1
Yield: 91.7 %

Procedure:
To a solution of 1-(4′-nitrophenyl)-5-bromo-3-methylpyrazole (138 mg, 0.49 mmol) in THF (5 mL) was added Pd(PPh3)4 (21 mg, 0.018 mmol) followed by vinyl tributyltin (0.16 mL, 0.54 mmol). The mixture was heated at reflux for 6 hr under N2, and was then quenched with saturated KF and extracted with EtOAc. The extract was dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/acetate, 10:1) to give the title compound (103 mg, 92%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([F:15])[C:9]=1[CH2:16][C:17]([OH:19])=O.CN(C)C=O.[CH3:25][O:26][C:27]([C:29]1[C:34]([NH2:35])=[N:33][CH:32]=[CH:31][N:30]=1)=[O:28]>ClCCl.C(#N)C>[CH3:25][O:26][C:27]([C:29]1[C:34]([NH:35][C:17](=[O:19])[CH2:16][C:9]2[C:10]([F:15])=[CH:11][CH:12]=[C:13]([F:14])[C:8]=2[Cl:7])=[N:33][CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: COC(=O)c1nccnc1N
Reactant: O=C(O)Cc1c(F)ccc(F)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)c1nccnc1NC(=O)Cc1c(F)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 244.7 %

Procedure:
Oxalyl chloride (1.30 ml) was added dropwise to a solution of (2-chloro-3,6-difluoro-phenyl)-acetic acid (3.151 g) in dichloromethane (20 ml) and a drop of N,N-dimethylformamide was added to initiate the reaction. The reaction mixture was stirred at ambient temperature for 1 hour. The solvent was evaporated to produce a colourless oil which was dissolved in acetonitrile (30 ml). This solution was then divided into three portions and each portion was added to a slurry of 3-amino-pyrazine-2-carboxylic acid methyl ester (0.76 g) in acetonitrile (15 ml). The reaction mixtures were heated in the microwave at 130° C. for 40 minutes to produce dark red solutions that was stored at ambient temperature for 16 hours. The samples were combined and concentrated to produce 3-[2-(2-chloro-3,6-difluoro-phenyl)-acetylamino]-pyrazine-2-carboxylic acid methyl ester as a dark orange solid (4.15 g). 1H-NMR (400 MHz, CDCl3): 4.02 (s, 3H), 4.22 (s, 2H), 7.02-7.10 (m, 1H), 7.11-7.17 (m, 1H), 8.41 (d, 1H), 8.61 (d, 1H), 10.8 (s, 1H) ppm.