Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:14]=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:23][CH3:24].[Li]CCCC.S([N:40]=[N+:41]=[N-:42])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[N:40]([C:14]1[N:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:11]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:23][CH3:24])[CH:4]=2)([CH3:9])[CH3:10])=[CH:12][N:13]=1)=[N+:41]=[N-:42]
Reactant: COc1cc(C(C)(C)c2cncn2-c2ccc(F)cc2)ccc1Cl
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)c2cnc(N=[N+]=[N-])n2-c2ccc(F)cc2)ccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a −78° C. solution of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (0.215 g, 0.62 mmol) in 3 mL of THF (3 mL) was added 1.67 M BuLi (0.45 mL, 0.75 mmol). The reaction was stirred at −78° C. for 30 min and then tosyl azide (0.160 g, 0.81 mmol) in THF (0.5 mL) was added dropwise. The reaction was stirred at −78° C. for 1 h when it was determined to be complete by LCMS. The reaction was quenched at −78° C. with pH 7 buffer and allowed to warm to room temperature. The mixture was extracted with DCM (3×10 mL) and dried with MgSO4. The residue was purified by column chromatography using Hex:EtOAc as eluents to afford 2-azido-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (131 mg) as a yellow oil. MS (EI) m/z 386 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1([OH:15])[CH2:10][CH2:9][CH2:8][N:7](C(OC)=O)[CH2:6]1)[CH3:2]>O>[CH2:1]([NH:3][CH2:4][C:5]1([OH:15])[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1)[CH3:2]
Reactant: CCNCC1(O)CCCN(C(=O)OC)C1
Solvent: O
Product: CCNCC1(O)CCCNC1

Procedure:
10 g (46.2 mmol) of methyl 3-ethylaminomethyl-3-hydroxypiperidine-1-carboxylate are heated under reflux overnight with 28.5 g of Ba(OH)2. 8H2O in 280 ml of water. The product is filtered off from BaCO3 with suction and concentrated. The residue is boiled five times using 120 ml of dioxane each time, and the dioxane solution is concentrated and distilled.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH2:11])=[N:6]2.Br[C:23]1[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:11][C:23]1[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)=[N:6]2
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)ncc12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(Nc3cccc(S(N)(=O)=O)c3)ncc12
Yield: 19.8 %

Procedure:
A mechanical mixture of 5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (Intermediate 45) (0.025 g, 0.09 mmol), 3-bromobenzenesulfonamide (0.02 g, 0.09 mmol), Pd2(dba)3 (0.008 g, 0.01 mmol), 2-(Di-t-butylphosphino)biphenyl (0.008 g, 0.03 mmol), and NaOtBu (0.011 g, 0.11 mmol) in 1,4-dioxane (1 mL) was irradiated with microwave radiation for 1000 seconds at a temperature of 150° C. Filtration of the resultant through celite, followed by concentration and purification by preparative HPLC gave 3-({5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-yl}amino)benzenesulfonamide (0.008 g) as a yellow solid. 1H NMR (Acetone-d6): δ9.19 (s, 1H), 8.98-8.93 (m, 1H), 8.81 (bs, 1H), 8.42-8.37 (m, 1H), 8.10-8.05 (m, 1H), 7.95-7.90(m, 1H), 7.81-7.75 (m, 1H), 7.67-7.50 (m, 2H), 6.63 (bs, 1H), 2.60 (s, 3H). MS m/z 449 (M+1).
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17](O)[C:18]2[N:19]([CH:27]3[CH2:29][CH2:28]3)[CH:20]=[CH:21][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[CH:13][CH:12]=1.C(N(CC)CC)C.[NH2:38][C:39]1[CH:40]=[C:41]([CH3:47])[C:42](=[O:46])[N:43]([CH3:45])[CH:44]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH:38][C:39]2[CH:40]=[C:41]([CH3:47])[C:42](=[O:46])[N:43]([CH3:45])[CH:44]=2)[C:18]2[N:19]([CH:27]3[CH2:29][CH2:28]3)[CH:20]=[CH:21][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[CH:13][CH:12]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: COC(=O)c1ccn(C2CC2)c1C(O)c1ccc(Cl)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccn(C2CC2)c1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
Methanesulfonic anhydride (3.42 g, 19.62 mmol) was added at −40° C. to a stirred solution of methyl 2-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-1H-pyrrole-3-carboxylate (Step 240.5) (3 g, 9.81 mmol) and triethylamine (6.84 mL, 49.1 mmol) in CH2Cl2 (60 mL). After 15 min at −40° C., 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 240.7) (1.762 g, 12.76 mmol) was added. The resulting mixture was allowed to warm from −40° C. to rt over 18 hr under stirring, diluted in CH2Cl2//water, and extracted twice with CH2Cl2. The combined organic extracts were dried and concentrated. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH 97.5:2.5) to afford the title compound (2.2 g, 51.6% yield) as a brown foam. tR: 1.13 min (LC-MS 6); ESI-MS: 426.2 [M+H]+ (LC-MS 6); TLC (CH2Cl2/MeOH 97.5:2.5): Rf=0.29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.FC(F)(F)C(O)=O.[CH3:28][N:29]([CH3:34])[CH2:30][C:31](Cl)=[O:32].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][N:13]([C:31](=[O:32])[CH2:30][N:29]([CH3:34])[CH3:28])[CH2:12][CH2:11]1
Reactant: NS(=O)(=O)c1cnc(OCC2(F)CCNCC2)c(Cl)c1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC(=O)N1CCC(F)(COc2ncc(S(N)(=O)=O)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide, 2.trifluoroacetic acid (0.131 g), 2-(dimethylamino)acetyl chloride, hydrochloric acid (0.139 g), and sodium carbonate (0.048 g) were combined in a 5-mL vial with N,N-dimethylformamide (3 mL) and stirred overnight at room temperature. Additional sodium carbonate (0.048 g) was added followed by 2-(dimethylamino)acetyl chloride, hydrochloric acid (0.139 g) and stirring was continued over a second night. The reaction mixture was concentrated under high vacuum, slurried in CH2Cl2, filtered, concentrated, chromatographed on amine functionalized silica gel with 0 to 4% methanol in CH2Cl2 as the eluent and dried in a vacuum oven at 80° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH2:10])(=[NH:3])[NH2:2].[Cl-:11].[NH4+].C[Al](C)C.NC1C=CN=CC=1C#N>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[ClH:11].[C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH2:10])(=[NH:2])[NH2:3]
Reactant: [Cl-]
Agent: C[Al](C)C
Agent: N#Cc1cnccc1N
Agent: N=C(N)c1cnccc1N
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Amidino-4-aminopyridine To ammonium chloride (430 mg, 8.1 mmol) in toluene was added trimethylaluminium (2M in hexane, 4 ml, 8.1 mmol) at 5° C. and the mixture was stirred at room temperature for 2 h. 4-Amino-3-cyanopyridine (320 mg, 2.7 mmol) was added and the reaction mixture was heated at 80° C. overnight. The mixture was cooled, poured onto alumina in chloroform, quenched with ethanol and filtered. The filtrate was concentrated and triturated with ether to give a solid. MS (+EI) m/z 119 (M−NH3)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH2:20][OH:21])[CH:5]=[CH:6][CH:7]=1>C1(C)C=CC=CC=1.CCCCCC.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH:20]=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2nc(CO)c(-c3cccc(F)c3)c(=O)n12
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cccc2nc(C=O)c(-c3cccc(F)c3)c(=O)n12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(3-fluorophenyl)-2-(hydroxymethyl)-6-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one (2.0005 g, 7.037 mmol, Prepared in Example 1) and manganese(IV) oxide (6.118 g, 70.37 mmol) in toluene (46.91 mL) was heated to reflux. After 3 h, the mixture was cooled to rt and filtered through a pad of Celite™. The pad was rinsed with DCM (200 mL). The filtrate was concd under reduced pressure to give an orange solid. The orange solid was suspended in hexane (50 mL), sonicated, and filtered to give 3-(3-fluorophenyl)-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carbaldehyde as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (1 H, s), 7.78 (1 H, dd, J=8.6, 7.0 Hz), 7.18-7.68 (5 H, m), 7.06 (1 H, d, J=6.7 Hz), 2.92 (3 H, s); Mass Spectrum (ESI) m/e=283.0 (M+1).
Reaction SMILES: C(O)C.Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([S:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:15]([CH3:24])=[CH:14][C:13]=1[CH3:25].[S-:26][C:27]#[N:28].[K+].CCCCCC>C(OCC)(=O)C>[S:26]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([S:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:15]([CH3:24])=[CH:14][C:13]=1[CH3:25])[C:27]#[N:28]
Reactant: N#C[S-]
Reactant: Cc1cc(C)c(SCC(F)(F)F)cc1OCCCCCCBr
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: Cc1cc(C)c(SCC(F)(F)F)cc1OCCCCCCSC#N
Temperature: 25 °C
Yield: 77.5 %

Procedure:
To 60 ml of ethanol were added 1.87 g (4.68 mmol) of 6-bromohexyl-[2,4-dimethyl-5-(2,2,2-trifluoroethylthio)phenyl]ether and 2.28 g (23.46 mmol) of potassium thiocyanate. The mixture was refluxed for 8 hours under heating. The mixture was allowed to cool to room temperature, and the solvent was distilled off under reduced pressure. Then extraction was conducted by adding ethyl acetate and water. The organic phase obtained was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=20:1), to obtain 1.37 g (yield: 77%) of an intended product.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:16](Br)=[N:15][C:14]([Br:18])=[CH:13][N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=1>>[Br:18][C:14]1[N:15]=[C:16]([O:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:11]([NH:10][S:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:8])=[N:12][CH:13]=1
Reactant: O=S(=O)(Nc1ncc(Br)nc1Br)c1ccc(Cl)s1
Reactant: COc1ccc(CO)cc1
Product: COc1ccc(COc2nc(Br)cnc2NS(=O)(=O)c2ccc(Cl)s2)cc1
Yield: 90.1 %

Procedure:
Prepared by the method of Example 20b using 5-chloro-N-(3,5-dibromo-2-pyrazinyl)-2-thiophenesulphonamide (Example 8) (0.32 g) and 4-methoxybenzylalcohol (0.1 g) to give the product (0.32 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[C:6]([Cl:12])[CH:5]=1)=[O:3].[C:13](Cl)(Cl)=[O:14]>C1(C)C=CC=CC=1>[C:2]([C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([N:11]=[C:13]=[O:14])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:1]
Reactant: O=C(Cl)Cl
Reactant: CC(=O)c1cc(Cl)c(N)c(Cl)c1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(N=C=O)c(Cl)c1

Procedure:
A mixture of 5 g. of 4-amino-3,5-dichloroacetophenone, 5 ml. of phosgene, and 30 ml. of toluene was heated to 150° C. for 24 hours in a sealed tube. The reaction mixture was cooled and concentrated under reduced pressure to provide crude 4-acetyl-2,6-dichlorophenyl isocyanate. The crude product was dissolved in 150 ml. of toluene and then 5 ml. of aniline was added to the solution. The crystals thus formed were recovered by filtration and recrystallized from ethanol to provide 4.56 g. of 3,5-dichloro-4-phenylcarbamoylaminoacetophenone having a melting point of 239°-240° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)[CH3:2].[CH2:14](I)[CH3:15]>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:14][CH3:15])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)Cc1ccc(S)cc1
Product: CCOC(=O)Cc1ccc(SCC)cc1

Procedure:
Alkylation of ethyl(4-mercaptophenyl)acetate (20 g, 102 mmol) with EtI (9.8 mL, 122 mmol), using a similar procedure to that described in Preparation 39, furnished ethyl(4-ethylsulfanylphenyl)acetate: m/z (ES+)=225.2 [M+H]+. Oxidation of this compound (22.6 g, 101 mmol) with mCPBA (222 mmol), employing a protocol similar to that described in Preparation 22, provided the title compound: m/z (ES+)=298.2 [M+MeCN+H]+.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([O:23]C)=[C:17]([CH2:25][CH3:26])[CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[CH3:28][C:10]1[S:9][C:8]2[CH:1]=[C:2]3[C:3](=[C:13]([C:15]4[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([OH:23])=[C:17]([CH2:25][CH3:26])[CH:16]=4)[C:12]=2[C:11]=1[CH3:27])[CH:4]=[CH:5][CH:6]=[CH:7]3
Reactant: CCc1cc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc(CC)c1OC
Agent: BrB(Br)Br
Product: CCc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(CC)c1O

Procedure:
The title compound was prepared according to the procedure in Example 1, step 5, using (2-benzyl-4,5-dimethylthiophen-3-yl)-(3,5-diethyl-4-methoxy-phenyl)-methanone (17.67 g, 45.0 mmol) and boron tribromide (12.8 mL, 0.135 mol) to give 16.63 g, of the title compound. 1H NMR (DMSO-d6) δ 1.15 (t, 6 H), 1.61 (s, 3 H), 2.40 (s, 3 H), 2.59-2.73 (m, 4 H), 6.86 (s, 2 H), 7.32 (ddd, 1 H), 7.42 (ddd, 1 H), 7.47 (d, 1 H), 7.93 (d, 1 H), 8.31 (s, 1 H), 8.41 (s, 1 H). mass spectrum (+ESI) m/z 360 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][O:9][CH3:10].P(Cl)(Cl)([Cl:14])=O>C(Cl)Cl>[Cl:14][C:3]1[C:2]([CH3:1])=[C:7]([CH2:8][O:9][CH3:10])[N:6]=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1ncnc(O)c1C
Solvent: ClCCl
Product: COCc1ncnc(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
5-Methyl-6-[(methyloxy)methyl]-4-pyrimidinol (Intermediate 48, 2.10 g, 13.62 mmol) was dissolved in DCM (20 ml), treated with phosphorus oxychloride (12.04 ml, 129 mmol) and the resulting mixture was heated under reflux for 3 hours, allowed to cool to room temperature and left to stand overnight. The solvent was removed under reduced pressure, the residue taken up in ice water and the pH was adjusted to 7 using aqueous 2M sodium hydroxide solution. The mixture was extracted with chloroform (×3) and the chloroform layers were separated, combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by SP4 Biotage column chromatography eluting with a gradient of 0-50% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow oil (2.14 g);
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]=[C:11]([NH:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25]C)=[O:24])[C:5]=2[C:6]([O:9][CH3:10])=[N:7][CH:8]=1)#[N:2].CO.C1COCC1.[OH-].[Na+]>O>[C:1]([C:3]1[C:4]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]=[C:11]([NH:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([OH:25])=[O:24])[C:5]=2[C:6]([O:9][CH3:10])=[N:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cccc(Nc2cn(C3CCCC3)c3c(C#N)cnc(OC)c23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ncc(C#N)c2c1c(Nc1cccc(C(=O)O)c1)cn2C1CCCC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
To a mixture of methyl 3-((7-cyano-1-cyclopentyl-4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)benzoate (90 mg) in a mixed solvent of methanol (1 mL) and THF (1 mL) was added 8N aqueous sodium hydroxide solution (0.288 mL), and the mixture was stirred at 80° C. for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The aqueous layer was neutralized with 1N hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (80 mg).
Reaction SMILES: [OH-].[Na+].[CH:3]([NH:5][C:6]1[N:11]=[C:10]([C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:9]=[CH:8][CH:7]=1)=[O:4].Cl.[CH3:20][O:21][NH2:22]>C(O)C>[CH:3]([NH:5][C:6]1[N:11]=[C:10]([C:12](=[N:22][O:21][CH3:20])[C:13]([OH:15])=[O:14])[CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: CON
Reactant: CCOC(=O)C(=O)c1cccc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(C(=O)O)c1cccc(NC=O)n1
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
2N Sodium hydroxide solution [solvent:water (1 part)+ethanol (4 parts)] (14.87 ml.) was added to a solution of ethyl 2-(6-formamidopyridin-2-yl)glyoxylate (6.00 g.) in ethanol (180 ml.) at room temperature and stirred at the same temperature for 20 minutes. Methoxyamine hydrochloride (2.71 g.) was added to the resultant solution, stirred at room temperature for 1.5 hours and then concentrated to a small volume under reduced pressure. The precipitates were collected by filteration washed with ethyl acetate and water, dissolved in methanol and then treated with activated charcoal. The solution was concentrated under reduced pressure and then the precipitates were collected by filtration to give 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (3.63 g.), mp 170° to 171° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[CH:5]=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O.C(Cl)Cl>[CH3:13][C:12]1[O:11][N:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1ccnc(Br)c1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1-c1ccnc(Nc2ccccc2)c1
Temperature: 80 °C
Yield: 61.1 %

Procedure:
To a stirred solution of the above Compound 17a (20 mg, 0.063 mmol), aniline (7.0 μL, 0.076 mmol) and BINAP (5.6 mg, 0.009 mmol) in toluene (0.6 mL) at 25° C. was added Pd2(dba)3 (2.7 mg, 0.003 mmol) followed by NaOtBu (9.1 mg, 0.095 mmol). The solution was heated to 80° C. for 2 h. The solution was cooled, filtered and concentrated. Preparative thin layer chromatography (SiO2, 5% EtOAc/CH2Cl2) provided the title compound (12.6 mg, 0.0385 mmol, 61%).
Reaction SMILES: [CH3:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:34](C([Sn])=C(CCCC)CCCC)[CH2:35]CC.[Cl-].[Li+].[F-].[K+]>CN(C=O)C.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>[CH3:1][C:2]1[C:3]([CH:34]=[CH2:35])=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COC(=O)c1cc(Cc2ccc(-c3ccn(C)n3)cc2)c(C)c(C)c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1c(C(=O)OC)cc(Cc2ccc(-c3ccn(C)n3)cc2)c(C)c1C
Yield: 98.8 %

Procedure:
A solution of methyl 3,4-dimethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (1.30 g), tributylvinyltin (1.28 g), trans-dichlorobis(triphenylphosphine)palladium(II) (0.10 g) and lithium chloride (0.80 g) in DMF (12.0 mL) was stirred at 90° C. for 2 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.96 g).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[O:32])=[N:22]1.C(N(CC)CC)C.O>CN(C)C=O>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:2]3[S:6][N:5]=[C:4]([C:7]4[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=4)[N:3]=3)[CH2:35][CH2:34]2)=[O:32])=[N:22]1
Reactant: Cc1ccc(-c2nsc(Cl)n2)cc1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of 5-chloro-3-(4-methylphenyl)-1,2,4-thiadiazole (117 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to water, and the precipitated solid was separated by filtration, which was recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran to give 91.0 mg (39.1%) of the desired product.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].S(Cl)(Cl)=O.[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1.[Cl-].[NH4+]>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][Br:26])=[CH:35][CH:36]=2)=[O:18])=[CH:20][CH:21]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: Oc1ccc(OCCCCCCBr)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(OCCCCCCBr)cc2)cc1
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
4-{[6-(acryloyloxy)hexyl]oxy}benzoic acid (4) (2.8 g (grams)) was dissolved in tetrahydrofurane (THF, 100 ml (milliliters)) at a room temperature, and a temperature of the resulting mixture was adjusted to a temperature of 0° C. (Celsius). Then, thionyl chloride (12 ml (milliliters), 1M in THF) was added to the mixture, and stirred for 30 minutes. Then, 4-(6-bromohexyloxy)phenol (2.5 g (grams)) and triethyl amine (13 ml (milliliters)) were added to the resulting reaction mixture, stirred at 0° C. (Celsius) for 1 hour, and then stirred at a room temperature overnight. Next day, a saturated ammonium chloride aqueous solution was poured into the reaction mixture, and the reaction was completed. The resulting reaction mixture was extracted three times with ethyl acetate (50 ml (milliliters)), and waster was removed over magnesium sulfate. Then, the solvents were evaporated, and the resulting reaction mixture was then purified using a column chromatography (developer solution: ethylacetate/hexane=1/2 volume ratio) to obtain 4-(6-bromo hexyloxy)phenyl 4-{[6-(acryloyloxy)hexyl]oxy}benzoate (5) (3 g (grams)).