Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]#N)=[CH:15][CH:16]=3)[NH:11][N:10]=2)[CH:2]=1.CC(O)=[O:22].CN(C=O)C.[PH2]([O-])=O.[Na+]>N1C=CC=CC=1.O.[Ni]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[O:22])=[CH:15][CH:16]=3)[NH:11][N:10]=2)[CH:2]=1
Reactant: N#Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Reactant: CC(=O)O
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: O=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a suspension of (E)-3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-carbonitrile (984 mg, 3 mmol) in pyridine (30 mL) was added HOAc (8 mL), followed by DMF (30 mL). The resulting mixture was heated and sonicated to make a clear solution. After cooling to 0° C., a solution of sodium hypophosphite (1.408 g, 16 mmol) in H2O (8 mL) was added, followed by Raney-Nickel 2400 (slurry in H2O, 0.8 mL). The resulting mixture was heated at 60° C. (oil temp.) for 1 h before cooling to rt. H2O (50 mL) was added and the mixture was extracted with EtOAc (100 mL+50 mL×2). The combined extracts were dried (Na2SO4). Removal of low boiling point solvents gave a yellow solution in DMF (30 mL); H2O (500 mL) was added with swirling and a yellow precipitate formed. After standing 10 min, the resulting precipitate was collected by suction filtration, rinsed with H2O and dried under high vacuum to give the title compound (500 mg, 50%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.79 (s, 1H, NH), 10.14 (s, 1H, CHO), 8.90 (s, 1H), 8.48 (d, J=4.8 Hz, 1H), 8.39 (d, J=8.0 Hz, 1H), 8.19 (d, J=9.2 Hz, 1H, partially overlapping with the singlet at 8.18 ppm), 8.18 (s, 1H, partially overlapping with the doublet at 8.19 ppm), 7.75 (d, J=16.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.59 (d, J=16.8 Hz, 1H), 7.43 (dd, J=8.0 Hz, 5.2 Hz, 1H); MS ESI 250.0 [M+H]+, calcd for [C15H11N3O+H]+ 250.1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=O.[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:3]2[N:13]=[C:14]([NH2:16])[S:15][CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NC(N)=S
Reactant: COc1cccc(C(=O)CBr)c1
Solvent: CCO
Product: COc1cccc(-c2csc(N)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
2-Bromo-1-(3-methoxy-phenyl)-ethanone (0.7291 g, 3.183 mmol) and thiourea (0.2665 g, 3.501 mmol) were dissolved in a 20 mL of ethanol. The reaction mixture was allowed to stir overnight at room temperature. The ethanol was evaporated to dryness and the crude product was dissolved in a minimum of dichloromethane. The crude product was then extracted twice with 1M sodium hydroxide and once with a saturated aqueous solution of sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and evaporated to dryness to yield the product (0.619 g, 3.00 mmol, 94.3%). ESI-MS m/z calc. 206.3. found 207.0 (M+1)+ Retention time 1.86 minutes. 1H NMR (400 MHz, CD3CN) δ 3.84 (s, 3H), 5.67 (s, 2H), 6.85-6.91 (m, 2H), 7.31 (t, J=7.9 Hz, 1H), 7.36-7.43 (m, 2H).
Reaction SMILES: [OH:1][B:2]1[C@@H:7]([NH:8][C:9](=[O:16])[CH2:10][C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][C@@H:4]([CH2:17][C:18]([OH:20])=[O:19])[O:3]1.Cl.[CH3:22][CH2:23]OC(C)=O.CCOCC>C(O)C>[OH:1][B:2]1[C@@H:7]([NH:8][C:9](=[O:16])[CH2:10][C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][C@@H:4]([CH2:17][C:18]([O:20][CH2:22][CH3:23])=[O:19])[O:3]1
Reactant: CCOC(C)=O
Reactant: O=C(O)C[C@@H]1CC[C@H](NC(=O)Cc2cccs2)B(O)O1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CC[C@H](NC(=O)Cc2cccs2)B(O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.1 %

Procedure:
To a solution of 5 (400 mg, 1.35 mmol) in 4 mL of absolute ethanol was added anhydrous 1M HCl in EtOAc (4 mL, 4 mmol). The reaction was stirred at room temperature for 16 h. The mixture was then concentrated and azeotroped with acetonitrile (3×10 mL) to give a sticky solid. Ether (10 mL) was added to the azeotroped sticky solid and the resulting precipitate was filtered. The filtered solid was rinsed with additional ether (5 mL) and dried to give ethyl 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetate 65 (300 mg, 0.92 mmol, 68.5% yield). 1H NMR (CD3OD) δ ppm 0.98-1.09 (q, J=14 Hz, 1H), 1.23-1.26 (t, J=7 Hz, 3H), 1.49-1.54 (dd, J=14 Hz, J=3 Hz, 1H), 1.57-1.64 (dt, J=11 Hz, J=2 Hz, 1H), 1.72-1.78 (brd, J=14 Hz, 1H), 2.24-2.28 (dd, J=15 Hz, J=6 Hz, 1H), 2.34-2.39 (dd, J=15 Hz, J=8 Hz, 1H), 2.63 (brs, 1H), 3.99 (s, 2H), 4.07-4.13 (q, J=4 Hz, 3H), 6.99-7.01 (t, J=4 Hz, 1H), 7.05-7.06 (d, J=3 Hz, 1H), 7.35-7.36 (dd, J=5 Hz, J=1.3 Hz, 1H); ESIMS found for C14H20BNO5S m/z 308.1 (M−H2O)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([CH3:10])[CH:3]=1.[C-:11]#[N:12].[Na+].O.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a solution of 4-bromo-1-bromomethyl-2-methyl-benzene (3.96 g, 15 mmol) dissolved in DMF (16 mL) were added sodium cyanide (0.85 g, 17.25 mmol) and water (1.8 mL). The reaction was stirred for overnight at room temperature. To the reaction was added 100 mL water; 80 mL saturated NaHCO3, and 100 mL EtOAc. The layers were separated, and the aqueous layer was extracted with 3×100 mL EtOAc. The combined organics were washed with 100 mL water, and then dried over Na2SO4. After filtering off the solids, the mother liquor was concentrated to the desired product by rotary evaporation (2.92 g, 92.7% yield). 1H NMR (400 MHz, CDCl3): δ 2.32 (2 H, s), 3.62 (1 H, s), 7.20–7.27 (1 H, m), 7.32–7.41 (1 H, m).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[CH2:2].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1.F[K].C(P)(C)(C)C.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:17][CH:18]=2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: Clc1ccc(-c2ccccn2)cc1
Reactant: C=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: CC(C)(C)P
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2ccc(-c3ccccn3)cc2)cc1
Temperature: 80 °C
Yield: 45 %

Procedure:
Under a nitrogen stream, 23.42 g (0.158 mol) of 4-vinyl-phenyl boronic acid, 20.0 g (0.1055 mol) of 2-(4-chloro-phenyl)pyridine, 500□ of 1,4-dioxane, 27.54 g (0.474 mol, 3.3 equivalent) of fluoro-potassium, 1.69 g (0.0084 mol, 5.3 mol %) of t-butylphosphine [P(t-Bu)3)], and 2.6 g (0.0028 mol, 1.8 mol %) of palladium tris(dibenzylidene acetone) [Pd2(dba)3] were placed into a 2-neck round flask 250□. After the resulting solution was heated to reflux at 80° C. for 24 hours, the reaction was terminated. The resulting mixture was filtered, the catalyst and fluoro-potassium that were black solids were removed, and then the dioxane was removed by rotary evaporation. After extraction with 300□ of dichloromethane and 400□ of distilled water, the residue was subjected to column chromatography using a mixed solution of hexane and ethylacetate (7:3) as a developing solvent and then recrystallized at 0° C. using ethylacetate to give the 2-(4′-vinyl-biphenyl-4-yl)pyridine. The yield was 45%. As the structural characteristics of the thus prepared 2-(4′-vinyl-biphenyl-4-yl)pyridine, the 1H-NMR spectrum is shown in FIG. 2, the UV/Vis is shown in FIG. 3, the GC-Mass is shown in FIG. 4, and the FT-IR is shown in FIG. 5. Moreover, the analysis data of the 2-(4′-vinyl-biphenyl-4-yl)pyridine is shown in the following table 1:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:13][C:14]=1[CH2:15][CH3:16].C(C1C(N[CH:41]2[C:46]3[CH:47]=[CH:48][O:49][C:45]=3[CH2:44][CH2:43][CH2:42]2)=NC(CC)=CN=1)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:41]2[C:46]3[CH:47]=[CH:48][O:49][C:45]=3[CH2:44][CH2:43][CH2:42]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1cnc(CC)c(NC2CCCc3occc32)n1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCCc2occc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzofuran-4-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.50, 7.34, 5.30, 4.53, 2.68, 2.62, 2.51, 2.09, 1.94 1.26, 1.20; HRMS (EI) calcd for C22H23Cl2N3O 415.1218, found 415.1217.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:9]1[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=1)[CH2:7][NH2:8])[CH2:2][CH3:3].C(N(CC)CC)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].O>ClCCl>[Cl:15][C:14]1[C:9]([C:6](=[N:5][O:4][CH2:1][CH2:2][CH3:3])[CH2:7][NH:8][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[C:25]([F:24])([F:35])[F:36])=[N:10][CH:11]=[C:12]([Cl:16])[CH:13]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCCON=C(CN)c1ncc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Yield: 87.2 %

Procedure:
In a solution of 151 mg of 2-amino-1-(3,5-dichloropyridin-2-yl)ethanone-O-propyloxime and 86 mg of triethylamine in 4 ml of dichloromethane, 154 mg of 2-(trifluoromethyl)benzoyl chloride was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 2 hours. After completion of the reaction, the reaction mixture was mixed with 10 ml of water and extracted with chloroform (30 ml×1), the resulting organic layer was washed with water (10 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 2:8 to 3:7) as the eluent to obtain 218 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.CCOC(C)=O.[Cl-].[Na+].O.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>[C:25]([O:24][C:22](=[O:23])[CH2:21][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)[C:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]1[C:34]1[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)OC(C)(C)C)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3)n(CC(=O)OC(C)(C)C)c2c1
Temperature: 80 °C
Yield: 81 %

Procedure:
A solution (0.1 M) of methyl 2-bromo-1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-1H-indole-6-carboxylate (from Step 1) in DME and EtOH (5:2) was treated with 4-methoxyphenylboronic acid (1.5 eq.). Aqueous Na2CO3 (2 N, 8.5 eq.) was added and the solution was degassed, and then heated with Pd(PPh3)4 (0.1 eq.). The mixture was heated at 80° C. for 2 h, then cooled and diluted with EtOAc and brine. The organic phase was separated, dried and concentrated under reduced pressure. The residue was purified by filtration through silica gel (5:95 EtOAc/PE) to give the title compound (81%) as a solid. 1H NMR (300 MHz, DMSO-d6, 300K) δ 1.13-1.38 (m, 3H), 1.33 (s, 9H), 1.61-1.96 (m, 7H), 2.55-2.67 (m, 1H), 3.86 (s, 3H), 3.88 (s, 3H), 4.73 (s, 2H), 7.11 (d, J 8.6, 2H), 7.27 (d, J 8.6, 2H), 7.69 (dd, J 8.4, 1.1, 1H), 7.86 (d, J 8.4, 1H), 8.06 (d, J 1.1, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH:13]2[CH2:25][N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)(=[O:11])=[O:10])[CH:8]=1)#[N:2].Cl>C(Cl)Cl.O1CCOCC1>[ClH:38].[Cl:39][C:34]1[CH:33]=[C:32]([CH:37]=[C:36]([Cl:38])[CH:35]=1)[O:31][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=1[S:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[CH2:25][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1)(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc(C#N)ccc2Oc2cc(Cl)cc(Cl)c2)C(Cn2cncn2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)N2CCNCC2Cn2cncn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 179.3 %

Procedure:
To a solution of tert-butyl 4-{[5-cyano-2-(3,5-dichlorophenoxy) phenyl]sulfonyl}-3-(1H-1,2,4-triazol-1-ylmethyl)-1-piperazinecarboxylate (37 mg, 0.06 mmol) in CH2Cl2 (1 ml) was added 4N HCl in 1,4-dioxane (1 ml). The mixture was stirred for 2 hours at room temperature. The solvent was evaporated in vacuo, the residue was triturated with Et2O and the white solid was collected by filtration to give 4-(3,5-dichlorophenoxy)-3-{[2-(1H-1,2,4-triazol-1-ylmethyl)-1-piperazinyl]sulfonyl}benzonitrile hydrochloride (28.5 mg, 86.3%).
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH3:18])=[O:16])=[CH:4][NH:3][CH2:2]1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:3]2[CH2:2][CH2:1][C:14]3[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[NH:7][C:6]=3[C:5]([C:15]([O:17][CH3:18])=[O:16])=[CH:4]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)C1=CNCCc2c1[nH]c1ccccc21
Product: COC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using methyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (Kuehne et al. (1985) J. Org. Chem. 50:919-924) and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.51 (1H, br s), 7.99 (1H, s), 7.62 (2H, m), 7.53 (1H, d), 7.23 (1H, d), 7.10-7.24 (4H, m), 4.22 (2H, t), 3.80 (3H, s), 3.27 (2H, m); MS (ES): 365 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[CH:16]=[C:15](I)[CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[NH:26]([C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:6][C:5]2[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc(I)cc1Nc1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Nc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 2.0 mL suspension of methyl 2-(4-fluoroanilino)-4-iodobenzoate 0.20 g, rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 10 mg, palladium acetate 4 mg and cesium carbonate 0.35 g was added aniline 0.074 mL, and it was heated and refluxed under nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 10 mg and palladium acetate 4 mg were added to it, and it was heated and refluxed under nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, insoluble matter was filtrated, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=10:1] to give methyl 4-anilino-2-(4-fluoroanilino)benzoate 0.13 g of pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC=C(Cl)C=2F)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[Cl:28][C:24]1[C:23]([F:29])=[C:22]([N:15]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:8][N:9]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(Cl)c2F)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: Fc1c(Cl)cccc1NCC1CCCC1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(Cl)c2F)s1

Procedure:
The title compound was prepared via {2-[3-(3-chloro-2-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-chloro-2-fluoro-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3][N:2]1C(OC(C)(C)C)=O>C(O)(C(F)(F)F)=O.ClCCl>[CH2:3]1[C:4]2([CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:8][CH2:9]2)[CH2:1][NH:2]1
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)OCc3ccccc3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CNC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Benzyl 2-tert-butyl 2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate (33.4 g, 92.8 mmol) was dissolved in a solution of TFA (50 mL) and dichloromethane (200 mL) and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo and the residue was neutralized with saturated aqueous Na2CO3 (100 mL). The aqueous solution was washed with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4) and concentrated to give a yellow oil, which upon co-evaporation with dichloromethane provided benzyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (SM-2a) as a white solid. (17.6 g, 73%). MS (ES+) 261.4 (M+H)+. 1H NMR (CDCl3) δ 1.67-1.89 (m, 4H), 2.86-3.18 (m, 2H), 3.40-3.64 (m, 7H), 5.12 (s, 2H), 7.30-7.39 (m, 5H).
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[O:3]1.C(N(CC)CC)C.[C:20](Cl)(=[O:28])[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24]>ClCCl>[CH3:1][CH:2]1[N:6]([C:20](=[O:28])[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[O:3]1
Reactant: CCCC(CCC)C(=O)Cl
Reactant: CC1NCC2(CCN(C)CC2)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(CCC)C(=O)N1CC2(CCN(C)CC2)OC1C
Temperature: 0 °C

Procedure:
2,8-Dimethyl-1-oxa-3,8-diaza-spiro[4.5]decane (1.52 g, 8.95 mmol) was dissolved in dry dichloromethane (5 ml) under an argon atmosphere. Distilled triethylamine (1.87 ml, 13.42 mmol) was added and the resulting solution was cooled to 0° C. Valproyl chloride (1.46 g, 8.95 mmol) was added dropwise with a syringe. The reaction flask was allowed to warm to room temperature with stirring, and a white solid started to precipitate. After 4 h of stirring, dichloromethane (100 ml) was added and the resulting solution was washed with water (10 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic phase was dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 130/10/1) to give AF712 (389 mg, 98.7% chemical purity) as a yellow powder. 1H NMR (CDCl3, 300 MHz) δ 5.43 (q, J=5.2 Hz, 1H, CHCH3), 4.13, 3.63 (2d, J=11.35 and J=9.6 Hz, 1H, CHHNCO), 3.22, 3.00 (2d, J=9.6 and J=11.35 Hz, 1H, CHHNCO), 2.56-2.38 (m, 5H), 2.30, 2.29 (2s, 3H, NCH3), 1.84-1.53 (3m, 6H), 1.44, 1.43 (2d, J=5.2 Hz, 3H, CH3CH), 1.4-1.19 (m, 6H), 0.90 (app t, J=7.11 Hz, 6H, CH3CH2) ppm; 13C NMR (CDCl3, 300 MHz) δ 173.92, 173.68 (C), 84.75, 84.20 (CH), 78.32, 78.09 (C), 54.24 (CH2), 52.34 (CH2), 52.02 (CH2), 46.03 (CH3), 44.34, 43.64 (CH), 35.63 (CH2), 35.05 (CH2), 34.92 (CH2), 32.83 (CH2), 23.52, 20.91 (CH3), 20.59 (CH2), 20.43 (CH2), 14.30 (CH3), 14.16 (CH3) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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.CN(C=O)C>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[C:4]([NH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH:5]=[N:6][CH:7]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Nc1cncc(Br)c1)c1ccccc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cncc(-c2cccc(C(F)(F)F)c2)c1)c1ccccc1
Temperature: 85 °C
Reaction time: 12 h

Procedure:
At 50° C., 1.95 g (7.02 mmol) of N-(5-bromopyridin-3-yl)benzamide, 2.00 g (10.5 mmol) of [3-(trifluoromethyl)phenyl]boronic acid and 1.49 g (14.04 mmol) of sodium carbonate were dissolved in 12 ml of 1,2-dimethoxyethane, 3.5 ml of water and 261 ml of DMF. The mixture was flushed with argon, 41 mg (0.04 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was stirred at 85° C. for 12 h. The reaction mixture was concentrated slightly on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography (cyclohexane/ethyl acetate 2:1). Yield: 860 mg (35% of theory)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][C:22]=2[F:27])[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: Oc1ccc(Cl)cc1F
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2ccc(Cl)cc2F)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 90.5 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate and 0.19 g of 4-chloro-2-fluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.29 g of 4-(2-butynyloxy)-6-(4-chloro-2-fluorophenoxy)pyrimidine (the present compound (4)), m.p.: 117.7° C.