Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:3][C@@H:4]([OH:7])[CH2:5][CH3:6].N1C=CC=CC=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:7][C@H:4]([CH2:3][CH:2]([CH3:1])[CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:5][CH3:6])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCCC(C)C[C@@H](O)CC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCCC(C)C[C@H](CC)OS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a solution of (S)-5-methylnon-8-en-3-ol (9.5 g, 60.8 mmole) in DCM (100 mL) was added pyridine (20 mL) followed by DMAP (0.74 g, 6.08 mmole) and the solution was stirred for 10 min. p-Toluenesulfonyl chloride (17.39 g, 91 mmole) was added to the reaction mass at 0° C. The reaction mass was allowed to come to room temperature and stirred for overnight. Solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (100 mL). The organic solution was washed with aqueous 1.5 N HCl solution, saturated bicarbonate solution, brine solution, dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound (15 g, 79%). The crude compound was taken to the next step without further purification. MS: MS m/z 328.4 (M++18).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.ClC1C=CN=CN=1.ClC1C=CC(B(O)O)=CC=1.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1B(O)O>>[CH:39]1[C:40]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=[CH:37][C:38]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Clc1ccc(-c2ccncn2)cc1
Agent: Clc1ccncn1
Agent: OB(O)c1ccc(Cl)cc1
Product: c1ccc2cc(-c3ccc(-c4ccncn4)cc3)ccc2c1

Procedure:
It is easy to synthesize the following compounds in the same manner as in Example 11 except that 4-(4-chlorophenyl)pyrimidine is synthesized from 4-chloropyrimidine prepared in Example 13 and 4-chlorophenylboronic acid (made by Aldrich Co.) and was reacted with 2-naphthaleneboronic acid (made by Lancaster Co.) to obtain 4-[4-(2-naphthyl)phenyl]-pyrimidine, which is used instead of 2-(benzo[b]thienyl)-5-phenylpyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([CH2:15][C:16](=[O:18])[CH3:17])(=[O:14])[CH3:13].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1.C(OCC)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH:13][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[O:14])([O-:3])=[O:2]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(=O)CC(=O)C=Cc1cccc([N+](=O)[O-])c1

Procedure:
A mixture of 3-nitrobenzaldehyde (20 g), acetylacetone (13.25 g), acetic acid (1.58 g), and piperidine (0.45 g) in benzene (20 ml) was refluxed for 1 hr under azeotropic dehydration. To the reaction mixture was added diethyl ether (100 ml). The mixture was washed with water (50 ml) and a saturated aqueous solution of sodium chloride (50 ml) successively, dried over magnesium sulfate, and evaporated in vacuo. The residual substance was recrystallized from ether to afford 3-(3-nitrobenzylidene)acetylacetone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(Nc2ccccc2C(=O)O)cc1Cl
Agent: BrB(Br)Br
Product: O=C(O)c1ccccc1Nc1ccc(O)c(Cl)c1

Procedure:
2-(3-Chloro-4-hydroxyphenylamino)benzoic acid [XI; R=H, R"=3-Cl, OH at 4-position] was prepared by reaction of 2-(3-chloro-4-methoxyphenylamino)benzoic acid (prepared from 3-chloroanisidine and 2-chlorobenzoic acid) with boron tribromide according to the procedure of Example 3, part (b), and was obtained as a pale yellow powder, m.p. 180°-183° C. (decompn.).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[CH:16]=[C:17]([CH2:22][C:23]([C:25]3[C:26]([C:32]([O:34]C)=O)=[C:27]([CH3:31])[NH:28][C:29]=3[CH3:30])=O)[CH:18]=[CH:19][C:20]=2[F:21])=[O:14])[CH2:9][CH2:8]1)[CH3:5]>C(O)(=O)C>[CH2:4]([O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=2[F:21])[CH2:22][C:23]2[C:25]3[C:26](=[C:27]([CH3:31])[NH:28][C:29]=3[CH3:30])[C:32](=[O:34])[NH:2][N:3]=2)=[O:14])[CH2:9][CH2:8]1)[CH3:5]
Reactant: CCOC1CCN(C(=O)c2cc(CC(=O)c3c(C)[nH]c(C)c3C(=O)OC)ccc2F)CC1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCOC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c(C)[nH]c(C)c34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.4 %

Procedure:
Hydrazine hydrate (0.037 mL, 0.49 mmol) was added to methyl 4-(2-(3-(4-ethoxypiperidine-1-carbonyl)-4-fluorophenyl)acetyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (53) (0.200 g, 0.45 mmol) in acetic acid (8 mL). The resulting solution was stirred at room temperature for 2 days. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford a crude gum, which was triturated with a mixture of NMP, DMSO and water to give a solid which was collected by filtration, washed with ether and dried under vacuum to give the desired compound as a white solid (0.112 g, 58.4% yield); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.29 (1H, m), 1.42 (1H, m), 1.71 (1H, m), 1.86 (1H, m), 2.27 (3H, s), 2.51 (3H, s), 3.04 (1H, m), 3.24-3.39 (2H, m), 3.46 (2H, m), 3.52 (1H, m), 3.97 (1H, s), 4.07 (2H, s), 7.13-7.30 (3H, m), 11.07 (1H, s), 11.94 (1H, s); m/z (LC-MS, ESI+), RT=1.62 min (M+H=427.12).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[C:11]([C:21]([NH2:23])=[O:22])[CH:12]=[C:13]([C:16]4[S:17][CH:18]=[CH:19][CH:20]=4)[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:31][CH2:32][CH2:33][S:34]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[C:11]([C:21]([NH2:23])=[O:22])[CH:12]=[C:13]([C:16]4[S:17][CH:18]=[CH:19][CH:20]=4)[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1)(=[O:36])=[O:35]
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCNCC3)c[nH]c12
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCl)CC3)c[nH]c12

Procedure:
3-{1-[(2-chloroethyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indole-7-carboxamide was prepared according to the procedure for intermediate 11. 3-(4-piperidinyl)-5-(2-thienyl)-1H-indole-7-carboxamide (30 mg, 0.09 mmol) was reacted with triethyl amine (0.04 mL, 0.27 mmol) and 2-chloroethylsulfonyl chloride (0.02 mL, 0.18 mmol) to give 3-{1-[(2-chloroethyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indole-7-carboxamide, which was used in the next step without further purification.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][C:21](=[O:27])[NH:22]2>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:17]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][C:21](=[O:27])[NH:22]2)=[C:8]=[S:9]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Nc1cccc2c1CC(=O)N2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C1Cc2c(N=C=S)cccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
4-Dimethylaminopyridine (0.086 g, 0.706 mmol) and di-2-pyridyl thionocarbonate (0.983 g, 4.23 mmol) are added to a solution of 4-aminooxindole (0.523 g, 3.53 mmol) in methylene chloride. The resulting mixture is stirred at room temperature for two hours during which time a soluble solution forms. The methylene chloride is removed by rotary evaporation and the crude residue is purified via silica gel column chromatography using 40% ethyl acetate/hexanes as the eluent. The appropriate fractions are combined and the solvents removed by rotary evaporation to yield 0.531 g of 4-isothiocyanatooxindole as a dark orange solid (79%, impure).
Reaction SMILES: I[C:2]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([CH3:12])[C@H:7]1[CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])=[O:5].C([Sn](CCCC)(CCCC)[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1)CCC.[F-].[Cs+]>CN(C=O)C.[Cu]I.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>[CH3:12][C@@H:8]1[CH2:9][CH2:10][CH2:11][N:6]([C:4](=[O:5])[C:3]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:2]=2[C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C@@H:7]1[CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24]
Reactant: Cc1ccc(I)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Temperature: 120 °C
Yield: 60.5 %

Procedure:
A mixture of 2-(((2S,3R)-1-(2-iodo-5-methylbenzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.20 g, 0.40 mmol), 2-(tributylstannyl)pyrimidine (0.15 mL, 0.48 mmol), CsF (121 mg, 0.80 mmol), CuI (15 mg, 0.08 mmol) and Pd(PPh3)4 (46 mg, 0.04 mmol) in DMF (10 mL) was degassed and heated at 120° C. for 1 h in a microwave reactor. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0˜100% EtOAc/hexanes) to yield the title compound as a brown oil (0.11 g, 61%). MS (ESI) 455 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14]>Br>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: COc1cc(F)c(CCC(=O)OC(C)(C)C)c(F)c1
Agent: Br
Product: O=C(O)CCc1c(F)cc(O)cc1F
Reaction time: 16 h
Yield: 36.5 %

Procedure:
tert-Butyl 3 (2,6-difluoro-4-methoxyphenyl)propanoate (11.7 g) was suspended in 48% aqueous hydrogen bromide (200 mL), followed by stirring at 120 □ C for 16 hours. The reaction mixture was concentrated under reduced pressure, and then to the residue was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3-(2,6-difluoro-4-hydroxyphenyl)propanoic acid (3.17 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14].Cl.[CH:18]1([CH2:21][NH2:22])[CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:22]([CH2:21][CH:18]1[CH2:20][CH2:19]1)[CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: NCC1CC1
Reactant: COC(=O)c1coc(=O)c2ccc(Br)cc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)c1cn(CC2CC2)c(=O)c2ccc(Br)cc12
Temperature: 25 °C

Procedure:
A mixture of the product of step ii) (5.5 g), cyclopropylmethanamine hydrochloride (2.09 g) and N,N-diisopropylethylamine (5.1 mL) in methanol (40 mL) was heated at reflux for 17 hours. The reaction mixture was allowed to cool to room temperature and filtered. The solid was washed with methanol and dried under vacuum at 60° C. to yield the sub-titled compound (4.55 g)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[N:5]=[C:4]([N:17]=[C:18]2[N:22]([CH2:23][O:24][CH3:25])[CH:21]=[CH:20][S:19]2)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH3:68][N:69](C)C(=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Zn]>[Si:10]([O:9][CH2:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([N:17]=[C:18]2[N:22]([CH2:23][O:24][CH3:25])[CH:21]=[CH:20][S:19]2)[N:5]=1)[C:68]#[N:69])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(=O)N(C)C
Reactant: COCn1ccsc1=Nc1cc(Br)cc(CO[Si](C)(C)C(C)(C)C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: COCn1ccsc1=Nc1cc(C#N)cc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
A mixture of 2.04 g of 4-bromo-6-(((tert-butyl(dimethyl)silyl)oxy)methyl)-N-(3-(methoxymethyl)-thiazol-2(3H)-ylidene)pyridin-2-amine, 379 mg of zinc cyanide, 266 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 133 mg of bis(dibenzylideneacetone)palladium(0), 92 mg of zinc and 9.2 ml of N,N-dimethylacetamide was stirred at 140° C. for 3 hours. The resulting reaction mixture was diluted with ethyl acetate, and then an insoluble matter was filtered off using Celite. The filtrate was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by a silica gel column chromatography (eluent: hexane to hexane/ethyl acetate=3/1) to give the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C@@H:16]([CH3:17])[CH2:15][C@@H:14]2[OH:19])(=O)=O)=CC=1.CN(C)C=O.[N-:25]=[N+:26]=[N-:27].[Na+]>C(OCC)C.O.[Cl-].[Na+]>[N:25]([CH2:12][C@H:13]1[O:18][C@@H:16]([CH3:17])[CH2:15][C@@H:14]1[OH:19])=[N+:26]=[N-:27]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](C)C[C@@H]2O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1C[C@H](O)[C@@H](CN=[N+]=[N-])O1
Yield: 77.4 %

Procedure:
A mixture, under argon, of 0.560 g of product from Example 337, 2 ml of N,N-dimethylformamide and 0.250 g of sodium azide is stirred at 75°C. for 12 hours. The reaction mixture is diluted with diethyl ether, washedwith water and saturated sodium chloride, dried and concentrated in vacuo to give 0.238 g of the desired product.
Reaction SMILES: O1CCN(C[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])CC1.C([O:23]C1(OC)C=CC(C(O)=O)=CC1OC)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:8]([NH2:9])(=[O:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC1C=C(C(=O)O)C=CC1(OC)OCc1ccccc1
Reactant: NC(CN1CCOCC1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2-morpholino-1-phenylethanamine represented by Formula 113 (516.3 mg, 2.50 mmol, purchased from Enamine Co.) was slowly added to 4-benzyloxy-3,4-dimethoxybenzoic acid represented by Formula 89 (793.75 mg, 2.75 mmol) prepared in Preparative Example 1 and diisopropylethylamine (1.75 mL, 10.01 mmol) in DMF (12 mL) at room temperature. After cooling the reaction mixture to 0° C. and adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 1.05 g, 2.75 mmol) thereto, the mixture was agitated at room temperature for 24 hours. The reaction solvent was removed under reduced pressure and chloroform (25 mL) was added to the remaining concentrate to prepare a solution. The solution was washed with a potassium carbonate solution, followed by separation to form an organic layer. After drying the organic layer with sodium sulfate (Na2SO4), the solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) using silica gel (SiO2), resulting in a benzamide compound represented by Formula 20 as a desired product (VVZ-021; 355.2 mg, 30% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:10])[CH3:9].[Br-:20].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)(=O)C>[Br:20][CH2:9][C:8]([C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:3][C:2]=1[CH3:1])=[O:10]
Reactant: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: Cc1cc(-c2ccc([N+](=O)[O-])cc2)ccc1C(=O)CBr
Temperature: 110 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
A mixture of 1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone (5.66 g, 22 mmol), pyridinium tribromide (10.63 g, 33.0 mmol), and glacial acetic acid (60 mL) was stirred at 110° C. for 3 h. The reaction mixture was cooled to 0-5° C., and the precipitated product was collected by filtration and washed with small amounts of water, ethanol, and diethyl ether. The crude material was purified by flash chromatography (5:95 ethyl acetate/hexane) to give 2-bromo-1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone as a light yellow solid (4.33 g, 59% yield). HPLC ret. time 3.63 min; 1H NMR (CDCl3) δ: 2.63 (s, 3H), 2.25 (s, 2H), 7.52-7.58 (m, 2H), 7.72-7.83 (m, 3H), 8.32 (d, 2H).
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C=O)C.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>[CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Reactant: C=Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nccn2c(C3CCC3)nc(/C=C/c3ccccc3)c12
Temperature: 75 °C

Procedure:
A solution of 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine (50 mg, 0.159 mmol), styrene (0.022 mL, 0.191 mmol) and triethylamine (0.044 mL, 0.318 mmol) in DMF (3.0 mL) was degassed three times, charged with tetrakis(triphenylphosphine)palladium (0) (18 mg, 0.0159 mmol) degassed twice more and then heated at 75° C. for 16 h. The reaction mixture was then concentrated in vacuo dissolved in MeOH/CH3CN (1:1)(4 mL) and was filtered through a 0.45 μM fritted autovial prior to purification via mass directed preparative HPLC which afforded the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 1.87-1.99 (m, 1H), 2.02-2.17 (m, 1H), 2.37-2.47 (m, 4H), 3.18 (s, 2H), 3.83-3.94 (m, 1H), 6.94 (d, J=4.9 Hz, 1H), 7.25 (t, J=7.33 Hz, 1H), 7.32-7.40 (m, 3H), 7.45 (d, J=15.5 Hz, 1H), 7.63 (d, J=15.45 Hz, 1H), 7.73 (d, J=7.46 Hz, 2H); MS (ES+): m/z 291.15 [MH30 ].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH2:23])[C:17]3[O:21][N:20]=[C:19]([CH3:22])[N:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:25]([C:27]1[CH:28]=[C:29]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH:30]=[CH:31][C:32]=1[O:33][C:34](=[O:36])[CH3:35])=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:23][C:25]([C:27]3[CH:28]=[C:29]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:44])([F:46])[F:45])=[CH:39][CH:38]=4)[CH:30]=[CH:31][C:32]=3[O:33][C:34](=[O:36])[CH3:35])=[O:26])[C:17]3[O:21][N:20]=[C:19]([CH3:22])[N:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Reactant: CC(=O)Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)Cl
Product: CC(=O)Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)c1nc(C)no1
Yield: 70.5 %

Procedure:
Acetic acid 3-[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylcarbamoyl]-4′-trifluoromethyl-biphenyl-4-yl ester (45 mg) was prepared from 2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine (33 mg, 0.1 mmol) and acetic acid 3-chlorocarbonyl-4′-trifluoromethyl-biphenyl-4-yl ester (34 mg, 0.1 mmol) following the general procedure M.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:5])[C:2]([CH3:4])=[O:3].[C:15](OC(=O)C)(=[O:17])[CH3:16]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C>[C:15]([O:3][C:2](=[CH2:4])[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:5])(=[O:17])[CH3:16]
Reactant: CCCCCCCCOC(=O)C(C)=O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: C=C(OC(C)=O)C(=O)OCCCCCCCC
Temperature: 120 °C
Reaction time: 27 h
Yield: 59.2 %

Procedure:
Next, in a mixture of the obtained octyl pyruvate (300 g, 1.5 mol) and acetic anhydride (306 g, 3.0 mol), p-toluenesulfonic acid monohydrate (5 g) was added. Then, the mixture was stirred under a nitrogen gas stream at 120° C. for 27 hours, thereby obtaining a second reaction solution. Next, acetic acid generated by a reaction with excess acetic anhydride under reduced pressure (5 mmHg) was removed from the second reaction solution. Thereafter, the residue was purified by reduced pressure distillation (1 mmHg or less, 80 to 102° C.), thereby obtaining octyl α-acetoxyacrylate (215 g, yield 59%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([CH:10]1[O:12][CH2:11]1)[Cl:9]>Cl.N1CCCCC1>[Cl:9][CH2:8][CH:10]([OH:12])[CH2:11][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCC1CO1
Reactant: Oc1ccccc1
Agent: Cl
Solvent: C1CCNCC1
Product: OC(CCl)COc1ccccc1
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
A mixture of phenol (94 g; 1.0 mole) and epichlorhydrin (138.8 g; 1.5 mole) was vigorously stirred at 100° C. in the presence of piperidine hydrochloride (2.0 g) for 6 hours, cooled, and the excess epichlorohydrin removed at 100° in vacuo. The residue was cooled, dissolved in an equal volume of chloroform and stirred vigorously with excess concentrated hydrochloric acid for 0.5 hours. After separation of the phases the organic layer was washed with water, dried and evaporated to a colourless oil. Distillation gave 116.4 g (62.5%) of 1-chloro-3-phenoxy-2-propanol of bp0.6 112° as a GLC pure material, νmax (film) 3310, 1603, 1590, 1495, 1245 cm-1 ; τ(CDCl3); 7.40 (broad exchangeable s); 6.25 (2H, d, J 3.5 Hz); 5.90 (2H, s); 5.90 (1H, m); 3,21-2.56 (5H, m).