Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C:4](=O)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:39](O)(=[S:41])[CH3:40]>O1CCCC1>[C:2]([C@@H:3]1[CH2:4][NH:5][C:39](=[S:41])[CH2:40]1)(=[O:1])[CH3:6]
Reactant: O=C1C[C@@H](O)CN1
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1CNC(=S)C1
Reaction time: 0.17 h

Procedure:
(4R)-4-Hydroxy-2-pyrrolidone (4.5 g) is suspended in tetrahydrofuran (300 ml), and thereto is added triphenylphosphine (23.4 g). After stirring the mixture for 10 minutes, diethyl azodicarboxylate (14 ml) is added dropwise to the mixture below -10° C., and the mixture is stirred at the same temperature for 10 minutes. Thioacetic acid (6.3 ml) is added dropwise to the reaction mixture below -10° C., and the mixture is stirred at the same temperature for 2 hours, and the solvent is evaporated under reduced pressure. The residue is crystallized from diisopropyl ether, and the precipitate is removed by filtration. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent, chloroform:ethanol=98:2) to give (4S)-4-acetylthio-2-pyrrolidone (3.8 g) as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][C@H:29]([N:31]([CH3:35])[C:32](=[O:34])[CH3:33])[CH3:30])[N:20]=[CH:19][N:18]=2)=[CH:12][C:11]=1[CH3:36]>>[CH3:35][N:31]([C@H:29]([CH3:30])[CH2:28][O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[C:11]([CH3:36])[CH:12]=1)=[N:18][CH:19]=[N:20]2)[C:32](=[O:34])[CH3:33]
Reactant: CC(=O)N(C)[C@H](C)COc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Reactant: ClCc1ccccn1
Product: CC(=O)N(C)[C@H](C)COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c12
Yield: 43 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine and N-[(1R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-N-methylacetamide to give the title compound as a light beige solid in 43% yield; NMR spectrum (DMSO-d6 373K) 1.21 (d, 3H), 1.85 (s, 3H), 2.27 (s, 3H), 2.84 (s, 3H), 4.34 (m, 1H), 4.40 (t, 1H), 5.07 (m, 1H), 5.20 (s, 2H), 7.01 (d, 1H), 7.17 (d, 1H), 7.33 (m, 2H), 7.42 (d, 1H), 7.47 (dd, 1H), 7.55 (d, 1H), 7.67 (t, 1H), 7.82 (td, 1H), 8.41 (s, 1H), 8.57 (d, 1H), 9.50 (s, 1H); Mass spectrum MH+ 472.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([C:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[O:15][C:14]=3[CH3:24])O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.S(Cl)([Cl:27])=O.N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:27][CH:11]([C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:15][C:14]=1[CH3:24])[CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)cc1C(O)C1CCC2(CC1)OCCO2
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1oc(-c2ccccc2)cc1C(Cl)C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]dec-8-yl(2-methyl-5-phenylfuran-3-yl)methanol (0.7 g) in toluene (20 mL) were added thionyl chloride (0.2 mL) and pyridine (0.2 mL), and the mixture was stirred at 0° C. for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.7 g, 100%) as an oil.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[C:9]([OH:18])(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12]>C(OC(=O)C)(=O)C>[C:9]([O-:18])(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12].[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5]
Reactant: O=C(O)c1ccccc1O
Reactant: O=C(O)/C=C/C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C([O-])/C=C/C(=O)[O-]
Product: O=C([O-])c1ccccc1O

Procedure:
The procedure described in Example 1, above, was used with fumaric acid (58 g, 0.5 mol), salicylic acid (69 g, 0.5 mol) and 200 mL acetic anhydride. The reaction mixture formed a clear solution and then a clear melt and the final product was a dark colored, transparent glass which weighed 70.5 g NMR spectra indicated very little acetate and no starting materials were present.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[N:25]1([C:32](=[O:34])[CH3:33])[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CN(C=O)C.CS(C)=O.CO>[C:32]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:27][CH2:26]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CS(C)=O
Product: CC(=O)N1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)CC1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol) and 1-(1,4-diazepan-1-yl)ethanone (101 mg, 0.75 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (25-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (87.7 mg, 78%). 1H NMR (DMSO-d6) [1:1 ratio of rotamers: δ: 10.93 (s, 1H); 10.91 (s, 1H)], 7.99 (d, J=8.3 Hz, 2H), 7.62 (dd, 2H), [1:1 ratio of rotamers: 7.13 (s, 1H); 7.07 (s, 1H)], [1:1 ratio of rotamers: 6.19 (s, 1H); 6.18 (s, 1H)], [1:1 ratio of rotamers: 4.37 (t, J=5.6 Hz, 2H); 4.20 (t, J=5.4 Hz, 2H)], [1:1 ratio of rotamers: 4.03 (t, J=5.6 Hz, 2H); 3.97 (t, J=5.9 Hz, 2H)], 3.63-3.78 (m, 2H), [1:1 ratio of rotamers: 3.58 (t, J=5.9 Hz, 2H); 3.52 (t, J=5.8 Hz, 2H)], 2.37 (s, 3H), [1:1 ratio of rotamers: 2.03-2.11 (m, 2H); 1.94 (quin, J=5.9 Hz, 2H)], [1:1 ratio of rotamers: 2.02 (s, 3H); 1.89 (s, 3H)], 1.46 (s, 6H); ESI-MS: m/z 451.3 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][C:4]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2C=C[N:15]=[C:14]3[N:18]([S:21]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:19]=[CH:20][C:13]=23)[N:11]=1)=[O:5].[H-].[Na+].[CH2:34](I)[CH2:35][CH3:36].[CH3:38][N:39](C=O)C>>[CH3:1][CH:2]([CH3:31])[CH2:3][C:4]([N:6]([CH2:34][CH2:35][CH3:36])[C:7]1[S:8][CH:9]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18]([S:21]([C:24]4[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=4)(=[O:23])=[O:22])[C:14]=3[N:15]=[CH:38][N:39]=2)[N:11]=1)=[O:5]
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4csc(NC(=O)CC(C)C)n4)ccnc32)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Product: CCCN(C(=O)CC(C)C)c1nc(-c2ncnc3c2ccn3S(=O)(=O)c2ccc(C)cc2)cs1
Temperature: 40 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
[100 mg; 0.22 mmol] of 3-Methyl-N-{4-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-thiazol-2-yl}-butyramide was dissolved in 1 mL of dry DMF and to this solution was added [13.0 mg; 0.27 mmol] of sodium hydride (60% in oil dispersion) and the reaction was stirred at 40° C. for 10 minutes before addition of [21.5 uL; 37.37 mg; 0.22 mmol] of n-propyliodide, in one portion. The reaction was stirred for one hour more at 40° C. After reaction was determined to be complete, the solvent was removed under reduced pressure and residue triturated with methyl t-butyl ether and filtrate decanted away from oil. The trituration was performed again and the crude reaction mixture stirred overnight at ambient temperature, the material solidifies. The material was isolated via suction filtration and washed with more ether, again with petroleum ether and air dried. This provides a dark beige powder; 83 mg representing a 76% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1)=O.O=[C:12]([CH3:20])[CH2:13][C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15].[F:21][C:22]([F:34])([F:33])[C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH2:32])=[O:31])[CH:26]=[CH:27][CH:28]=1>O1CCCC1>[C:9]([C:6]1[N:7]=[CH:8][C:3]([CH:1]2[C:13]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])=[C:12]([CH3:20])[N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:33])([F:34])[F:21])[CH:24]=3)[C:30](=[O:31])[NH:32]2)=[CH:4][CH:5]=1)#[N:10]
Reactant: N#Cc1ccc(C=O)cn1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: C=CCOC(=O)CC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)nc1

Procedure:
To a stirred solution of Example 3A (29.3 g, 70.4 mmol) in tetrahydrofuran (450 ml) is given allyl 3-oxobutanoate (10.0 g, 70.4 mmol), N-[3-(trifluoromethyl)phenyl]urea (14.4 g, 70.4 mmol) and polyphosphoric acid ethyl ester (33 mg) [freshly prepared according to the procedure of Cava et al., J. Org. Chem. 34, 2665 (1969)]. The reaction mixture is refluxed for 24 hours after which time the solvent is removed in vacuo, and the residue is purified by column chromatography (silica, eluent: cyclohexane/ethyl acetate mixtures).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][Br:15])=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2ccccc2F)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccccc1-c1ccc(CBr)cc1
Yield: 39.8 %

Procedure:
A mixture of 8.70 g of 2-fluoro-4'-methylbiphenyl, 8.32 g of N-bromosuccinimide, 0.10 g of 2,2'-azobisisobutylonitrile and 150 ml of carbon tetrachloride was heat-refluxed for 5 hours. The reaction solution was washed with water, and the organic layer was concentrated. The resulting residue was purified through silica-gel column chromatography (eluent: a mixture of hexane and ethyl acetate at a ratio of 9:1) to obtain crude 2-fluoro-4'-bromomethylbiphenyl. Further, this compound was crystallized from hexane to give 4.93 g of 2-fluoro-4'-bromomethylbiphenyl.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[N:3][C:2]([C:24]3[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)=[N:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)Oc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cc1
Yield: 5.2 %

Procedure:
2-Chloro-5-(4-trifluoromethoxyphenyl)-pyrimidine (4.22 mmol), 4-formylphenyl boronic acid (5.1 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.05 mmol), 2 M potassium carbonate (4.2 mL) and dioxane (21 mL) were combined in a vial and irradiated by microwave for 20 min at 150° C. The organic layer from the reaction mixture was loaded directly onto silica and dried in vacuo. Purification by silica gel chromatography (EtOAc/hexanes) yielded 75 mg of a white solid. 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 9.06 (s, 2H), 8.68 (d, J=8.8 Hz, 2H), 8.03 (d, J=8.3 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.7 Hz, 2H); EIMS 344 m/z (M+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][C:13]3[C:18]([CH2:19][CH2:20][CH2:21][CH3:22])=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:16]=[N:15][C:14]=3[Cl:29])=[CH:9][C:4]=2[O:3][CH2:2]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:44][CH2:45][CH2:46][CH2:47][CH2:48]C.[CH3:50][CH2:51][O:52][C:53](C)=[O:54]>CC(O)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([CH2:48][C:47]3[CH:46]=[CH:45][C:44]4[O:54][CH2:53][O:52][C:51]=4[CH:50]=3)[CH2:12][C:13]3[C:18]([CH2:19][CH2:20][CH2:21][CH3:22])=[C:17]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:16]=[N:15][C:14]=3[Cl:29])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCCc1c(-c2ccccc2)nnc(Cl)c1CNCc1ccc2c(c1)OCO2
Reactant: CCOC(C)=O
Reactant: CCCCCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCc1c(-c2ccccc2)nnc(Cl)c1CN(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Piperonyl (0.06 g, 0.4 mmol) is added to a solution of benzo[1,3]dioxol-5-ylmethyl-(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine (0.042 g, 0.1 mmol) in CH2ClCH2Cl (5 mL) and HOAc (0.5 mL). The mixture is stirred at room temperature for 45 minutes, NaBH(OAc)3 (0.127 g, 0.6 mmol) is then added and the mixture is stirred overnight. The solvent is removed in vacuo, the residue is partitioned between saturated aqueous NaHCO3 solution (20 mL) and EtOAc (20 mL), and the organic layer is washed with water (15 mL), brine (15 mL), and then dried (Na2SO4). Evaporation of the solvent in vacuo provides the compound shown above as a yellow oil. Preparative TLC (3:1 Hexane, EtOAc) of the residue provides a light yellow oil. LC-MS (M+1) 544. 1H NMR (δ, CDCl3) 7.37–7.48 (m, 5H), 6.77 (s, 2H), 6.72 (s, 4H), 5.91 (s, 4H), 3.78 (s, 2H), 3.49 (s, 4H), 2.69 (t, J=7.2 Hz, 2H), 0.85–1.02 (m, 4H), 0.59 (t, J=7.0 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH2:16][O:17][CH2:18][CH2:19][OH:20])=[CH:10][CH:9]=2)[CH:2]=1.[CH2:21]=[C:22]1[O:26][C:24](=[O:25])[CH2:23]1>O1CCCC1.C(N(CC)CC)C>[C:24]([O:20][CH2:19][CH2:18][O:17][CH2:16]/[CH:15]=[CH:14]/[C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:9][CH:10]=1)(=[O:25])[CH2:23][C:22]([CH3:21])=[O:26]
Reactant: C=C1CC(=O)O1
Reactant: OCCOC/C=C/c1ccc(Cc2cccnc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)CC(=O)OCCOC/C=C/c1ccc(Cc2cccnc2)cc1
Yield: 72 %

Procedure:
In 50 ml of tetrahydrofuran was dissolved 5.4 g of 2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]allyloxy]ethanol, and one drop of triethylamine was added to the resulting solution. To this solution was dropwise added a mixture of 1.8 g of diketene and 4 ml of tetrahydrofuran under reflux over one hour, and then the resulting mixture was subjected to reaction at the same temperature for a further 30 minutes. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (2:1 by volume)] to obtain 5.1 g (yield 72.2%) of oily 2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]allyloxy]ethyl acetoacetate.
Reaction SMILES: [CH:1](OCC)=O.[H-].[Na+].C([O:11][CH2:12][CH2:13][F:14])(=O)C.[C:15]([CH2:17][C:18]([NH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)=[NH:19])#[N:16]>C(O)C.CCCCCC>[F:14][C:13]1[C:12](=[O:11])[NH:19][C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[CH:24]3)=[C:17]([C:15]#[N:16])[CH:1]=1
Reactant: CC(=O)OCCF
Reactant: CCOC=O
Reactant: N#CCC(=N)Nc1ccc2ncccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Product: N#Cc1cc(F)c(=O)[nH]c1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl formate (16.1 ml) was added to a hexane (40 ml) suspension containing sodium hydride (60% in oil, 2.4 g) at room temperature, and then fluoroethyl acetate (3.86 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 15 minutes. Ethanol (50 ml) was added to the reaction mixture, and then an ethanol (50 ml) solution containing 2-cyano-N-(quinolin-6-yl)acetamidine (4.20 g) was added dropwise, followed by stirring at 80° C. for 2 hours. The reaction mixture was cooled to room temperature. Then, solid matter was collected by filtration and washed with ethyl acetate, and a yellow solid of 5-fluoro-6-oxo-2-(quinolin-6-ylamino)-1,6-dihydropyridin-3-carbonitrile (3.71 g) was thus obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[Br:7][C:8]1[CH:9]=[C:10]([S:14]([Cl:17])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1>C(OCC)C>[ClH:17].[Br:7][C:8]1[CH:9]=[C:10]([S:14]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CN(C)CCN
Solvent: CCOCC
Product: CN(C)CCNS(=O)(=O)c1cccc(Br)c1
Product: Cl
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
N,N-Dimethylethylenediamine (1.76 g) was added dropwise to a solution of 3-bromobenzenesulfonyl chloride (5.11 g) in diethyl ether (100 ml) at room temperature. The resulting suspension was stirred for 30 minutes and filtered to afford the sub-title compound as a solid (4.31 g).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([NH:8][C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[O:10])=[N:5][CH:4]=1)#[N:2].CC(C)([O-])C.[K+].[CH3:27][O:28][CH2:29][CH2:30]Br>O1CCCC1.CN(C)C=O>[C:1]([C:3]1[S:7]/[C:6](=[N:8]\[C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[O:10])/[N:5]([CH2:30][CH2:29][O:28][CH3:27])[CH:4]=1)#[N:2]
Reactant: N#Cc1cnc(NC(=O)C23CC4CC(CC(C4)C2)C3)s1
Reactant: COCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCn1cc(C#N)s/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of Example 183B (240 mg, 0.84 mmol) in N,N-dimethylformamide tetrahydrofuran (1:4, 10 mL) were added a solution of potassium tert-butoxide (Aldrich, 133 mg, 1.2 mmol) and commercially available, 2-bromoethyl methyl ether (Aldrich, 104 μL, 1.2 mmol). The reaction mixture was stirred at 80° C. for 16 hours, cooled to room temperature, quenched with saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (3×10 mL,). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.59-1.77 (m, 6 H), 1.84-1.91 (m, 6 H), 1.95-2.04 (m, 3 H), 3.26 (s, 3 H), 3.71 (t, J=5.3 Hz, 2 H), 4.36 (t, J=5.1 Hz, 2 H), 8.54 (s, 1 H); MS (ESI+) m/z 346 (M+H)+; Anal. Calculated for C18H23N3O2S: C, 62.58; H, 6.71; N, 12.16. Found: C, 62.15; H, 6.89; N, 11.95.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:15]=[C:14]([C:16]3[N:20]([CH:21]4[CH2:23][CH2:22]4)[CH:19]=[N:18][N:17]=3)[S:13][CH:12]=2)=[O:9])[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:21]1([N:20]2[CH:19]=[N:18][N:17]=[C:16]2[C:14]2[S:13][CH:12]=[C:11]([NH:10][C:8]([C:4]3[CH:3]=[C:2]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH:7]=[CH:6][N:5]=3)=[O:9])[CH:15]=2)[CH2:23][CH2:22]1
Reactant: O=C(Nc1csc(-c2nncn2C2CC2)c1)c1cc(Br)ccn1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(Nc1csc(-c2nncn2C2CC2)c1)c1cc(-c2cccnc2)ccn1
Temperature: 90 °C
Yield: 20.2 %

Procedure:
A suspension of 4-bromo-N-(5-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiophen-3-yl)picolinamide (55 mg, 0.14 mmol), 3-pyridine boronic acid (17 mg, 0.14 mmol), dppf(Pd)C12 (5.2 mg, 0.0071 mmol), potassium carbonate (49 mg, 0.35 mmol) in degassed toluene (0.70 mL), degassed water (0.35 mL) and degassed ethanol (0.35 mL) was heated at 90° C. for 3 hours. The aqueous layer was separated, the organic layer was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC to give N-(5-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiophen-3-yl)-3,4′-bipyridine-2′-carboxamide as a white powder (11 mg, 20% yield). N-(5-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiophen-3-yl)-3,4′-bipyridine-2′-carboxamide; C20H16N6OS. 389.2 (M+1). 1H NMR (DMSO) δ 11.45 (s, 1H), 9.11 (d, J=2 Hz, 1H), 8.85 (d, J=5 Hz, 1H), 8.70-8.74 (m, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.31-8.36 (m, 2H), 8.10 (dd, J=2, 5 Hz, 1H), 8.06 (s, 1H), 7.60 (dd, J=5, 8 Hz, 1H), 3.56-3.59 (m, 1H), 1.11-1.27 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[CH2:7][S:8][C@H:9]([CH:10]=[O:11])[C@H]2O1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.S([O:39][CH3:40])(OC)(=O)=O.[C:41](=O)([O-])[O-:42].[K+].[K+]>CN(C)C=O.CC(C)=O.O>[CH3:41][O:42][C:10]([C@@H:9]1[C@@H:40]2[C@@H:5]([O:6][C:2]([CH3:1])([CH3:12])[O:39]2)[CH2:7][S:8]1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)OC
Reactant: CC1(C)O[C@H]2[C@H](CS[C@@H]2C=O)O1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1SC[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 20 h
Yield: 132 %

Procedure:
2.8 g (0.015 mol) of (3aS,4S,6aR)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxole-4–Carbaldehyde from the aforementioned Experimental Example 6 were dissolved in 200 mL of anhydrous N,N-dimethylformamide to which 26.7 g (0.070 mol) of pyridinium dichromate was added. The reaction mixture was stirred at ambient temperature for 20 h. After 0.3 L of water were added, it was extracted with 2.5 L of ethyl acetate (0.5 L×5). The extract was dried, filtered, and concentrated under reduced pressure to obtain the concentrate which was (3aS,4S,6aR)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxole-4-carboxylic acid. The concentrate was dissolved in 65 mL of acetone to which 2 mL (21.14 mmol) of dimethyl sulfate and 1.2 g (8.68 mmol) of potassium carbonate were added. The resulting mixture was stirred for 2 h. Acetone was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, followed by washing with water and saturated saline solution. The organic layer was dried and filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography using the eluant (hexane:ethyl acetate=3:1) mixture to obtain 2.5 g (yield: 78%) of (3aS,4S,6aR)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxole-4-carboxylic acid methyl ester as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].[C:9](O)(=[O:31])[CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH3:30].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[C:9]([NH:6][C@@H:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])(=[O:31])[CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH3:30]
Reactant: COC(=O)[C@H](C)N
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N[C@@H](C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
L-Alanine methyl ester hydrochloride (0.85 g, 6.1 mmol) was taken up in CH3CN (20 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (2.0 g, 6.1 mmol), EDCI (1.3 g, 6.72 mmol) and DIEA (1.3 mL). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed with dilute aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford (S)-methyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoate (2.0 g, 79%).