Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.F[C:15]1[CH:20]=[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])[C:18]([F:34])=[CH:17][C:16]=1[N+:35]([O-:37])=[O:36].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[F:34][C:18]1[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:20][C:15]([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=2)=[C:16]([N+:35]([O-:37])=[O:36])[CH:17]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: COC(=O)COc1ccc(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2[N+](=O)[O-])cn1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
To a mixture of 0.5 g of 5-hydroxy-2-(methoxycarbonyl)methoxypyridine, 0.80 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-y]nitrobenzene and 5 ml of N,N-dimethylformamide was added 0.35 g of potassium carbonate, and the mixture was stirred for 1.5 hours at 50° C. The solution was cooled to room temperature, poured into a mixture of water, hydrochloric acid and saline, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.93 g of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:24][CH:25]([OH:28])[C:26]#[CH:27].CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:27]#[C:26][CH:25]([OH:28])[CH3:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CC(C)O
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(O)C#Cc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C
Yield: 20 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example No. 40 (800 mg), 3-butyn-2-ol (0.20 mL), PdCl2 (PPh3)2 (32.3 mg), and 1.16 mL Et3N in 4.64 mL anhydrous DMF is heated at 90° C. for 1 hr. The reaction mixture is cooled to room temperature and partitioned between EtOAc and H2O. The aqueous layer is washed with EtOAc (3×). The combined organic layers are dried over Na2SO4 and condensed to obtain a red-brown residue. The residue is chromatographed eluting with 3% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 139.2 mg (20%) of the title compound as a brown solid.
Reaction SMILES: C(OCC)(=O)C.[N+:7]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=1[CH:20]1[CH2:25][CH2:24][O:23][C:21]1=[O:22])([O-])=O.[H][H]>[Pt]=O.C(O)C>[CH3:19][O:18][C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][C:14]=1[O:16][CH3:17])[NH:7][C:21](=[O:22])[CH:20]2[CH2:25][CH2:24][OH:23]
Reactant: COc1cc(C2CCOC2=O)c([N+](=O)[O-])cc1OC
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)C(CCO)C(=O)N2
Yield: 99.1 %

Procedure:
An ethyl acetate solution containing 2.0 g of α-(2-nitro-4,5-dimethoxyphenyl)-butyrolactone and 500 mg of platinum oxide was stirred in a 2.0 atm. hydrogen gas atmosphere. Ethanol was added to the reaction mixture, followed by filtration. The solvent was evaporated to yield 1.76 g of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]3[C:14](=[CH:15][C:5]=2[N:4]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.SC[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.O>C(O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:1][S:2][C:3]1[NH:4][C:5]2[CH:15]=[C:14]3[C:9](=[CH:8][C:6]=2[N:7]=1)[CH:10]=[CH:11][CH:12]=[CH:13]3
Reactant: SCc1ccccn1
Reactant: CSc1nc2cc3ccccc3cc2[nH]1
Solvent: CCO
Solvent: O
Product: c1ccc(CSc2nc3cc4ccccc4cc3[nH]2)nc1
Yield: 81.7 %

Procedure:
0.45 g of 2-methylthio-1H-naphth[2,3-d]imidazole and 0.64 g of 2-mercaptomethylpyridine were heated for 40 hours under reflux in 10 ml of ethanol. 10 ml of water were added to the homogeneous solution and the precipitate formed was filtered off. 0.50 g of 2-[(2-pyridylmethyl)thio]-1H-naphth[2,3-d]imidazole having a m.p. of 170° was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[F:15][CH2:16][CH:17]([OH:20])[CH2:18][F:19]>C1COCC1>[Cl:1][C:2]1[C:3]([O:20][CH:17]([CH2:18][F:19])[CH2:16][F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: OC(CF)CF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OC(CF)CF)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
Methyl 5,6-dichloronicotinate (1.5 g) and 60% sodium hydride (640 mg) were dissolved in THF (45 mL). 1,3-Difluoropropan-2-ol (1.5 g) was added thereto at 0° C., followed by stirring at 0° C. for 3 hours, and the reaction solution was quenched with aqueous NH4Cl. After extraction with EtOAc, the organic layer was dried over MgSO4 and then filtered, and the desiccant was removed. The vehicle was evaporated under reduced pressure, followed by purification by silica gel column chromatography (hexane:AcOEt=100:0 to 50:50) to obtain methyl 5-chloro-6-[(1,3-difluoropropan-2-yl)oxy]nicotinate (1.56 g) as a colorless liquid.
Reaction SMILES: [C:1](=[O:14])([O-])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=C(C#CCC)C=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCCCCC>C(OCC)(=O)C>[CH2:3]([O:2][C:1]([N:19]1[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]1)=[O:14])[CH2:8][C:7]#[CH:6]
Reactant: CCC#Cc1cccc(OC(=O)[O-])c1
Reactant: OC1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C#CCCOC(=O)N1CCC(O)CC1
Yield: 101.7 %

Procedure:
10.0 g of 3-butynylphenyl carbonate and 5.8 g of 4-hydroxypiperidine were heated in a solvent-free condition at 100° C. of 30 minutes. After completion of the reaction, silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:1-1:2) was used for purification to obtain 10.6 g of the intended compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.N.[CH3:24][N:25](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([C:24]#[N:25])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: N
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
Under a nitrogen stream, 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.13 g) was dissolved in N,N-dimethylformamide (30 mL), zinc cyanide (1.03 g) and tetrakistriphenylphosphine palladium(0) (0.51 g) were added, and the mixture was stirred at 120° C. for 4 hr. After completion of the reaction, to the reaction mixture was added water/saturated aqueous ammonium chloride solution/28% aqueous ammonia (4:4:1), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (2.46 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:10]([CH2:12]O)[CH:11]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:10]([CH2:12][Cl:3])[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Br)ccc1OCCN1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: ClCc1cc(Br)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mL (2.20 mmol) of thionyl chloride was added at −10° C. to a solution of 0.60 g (2.00 mmol) of [5-bromo-2-(2-pyrrolidin-1-ylethoxy)phenyl]methanol and 0.42 mL (3.00 mmol) of triethylamine in 30 mL of THF and the mixture was stirred for 16 hours at RT. Ice and dilute aqueous sodium bicarbonate solution was added to the reaction mixture and the phases were separated. The aqueous phase was exhaustively extracted with DCM, and the combined organic phases were washed with water, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 0.39 g (62% of theoretical); C13H17BrClNO (M=318.637); calc.: molpeak (M+H)+: 318/320/322 (BrCl); found: molpeak (M+H)+: 318/320/322 (BrCl); HPLC-MS: 5.84 minutes (method A).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:18].[Na+]>CC(C)=O.C(OCC)C>[CH2:1]([O:8][C@H:9]1[CH2:12][C@H:11]([I:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CS(=O)(=O)O[C@H]1C[C@@H](OCc2ccccc2)C1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: I[C@H]1C[C@H](OCc2ccccc2)C1
Yield: 86 %

Procedure:
A solution of cis-3-benzyloxy-1-methanesulfonyloxycyclobutane (1.25 g, 4.8 mmol) and sodium iodide (2.16 g, 14.4 mmol) in dry acetone (20 ml) was refluxed under nitrogen for 3.5 days. The mixture was cooled and diluted with diethyl ether (150 ml). The suspension was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and filtered through a plug of silica gel, eluting with ethyl acetate to give trans-3-benzyloxy-1-iodocyclobutane (1.19 g, 86%) as an orange oil; 1H NMR (250 MHz, CDCl3) δ2.54-2.65 (2H, m), 2.94-3.04 (2H, m), 3.85-4.06 (2H, m), 4.40 (2H, s), 7.26-7.38 (5H1 m).
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.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:25][C:26]1[CH:27]=[C: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)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: COc1ccc(B(O)O)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)cc1Cl
Temperature: 120 °C
Yield: 20.4 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 90 mg, 0.261 mmol), 3-Chloro-4-methoxyphenylboronic acid (97 mg, 0.522 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17 mg, 21 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.5 mL of 1,4-dioxane and 1 mL of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 120° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (60-70% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (24 mg, 20%). 1H NMR (DMSO-d6) δ: 11.19 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 7.90-8.17 (m, 4H), 7.54-7.73 (m, 2H), 7.41 (d, J=8.8 Hz, 1H), 6.39 (s, 1H), 5.19 (s, 1H), 3.99 (s, 3H), 2.42 (s, 3H), 1.46 (s, 6H). ESI-MS: m/z 451.0 (M+H)+.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][O:4][CH2:3][C@H:2]1[C:7]([O:9]C)=O.[NH2:18][CH2:19][CH2:20][OH:21]>CO>[OH:21][CH2:20][CH2:19][NH:18][C:7]([C@@H:2]1[CH2:3][O:4][CH2:5][CH2:6][N:1]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:9]
Reactant: COC(=O)[C@@H]1COCCN1C(=O)OC(C)(C)C
Reactant: NCCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)NCCO
Temperature: 80 °C
Reaction time: 7 h
Yield: 76.7 %

Procedure:
A mixture of (S)-4-tert-butyl 3-methyl morpholine-3,4-dicarboxylate (0.93 g, 3.8 mmol) and 2-aminoethanol (5 g, 81.9 mmol) in methanol (2 mL) was stirred at 80° C. for 7 hours under N2. The mixture was concentrated in vacuo, diluted with EtOAc (100 mL) and acetic acid (5 mL). The organic layer was washed with brine (80 mL×6), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the title compound as a white solid (0.8 g, 77%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[C:21]([CH2:22]Br)=[CH:20][S:19][C:18]=2[CH:24]=1)=[O:13].O>CN(C)C=O>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[C:21]([CH2:22][O:3][C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)=[CH:20][S:19][C:18]=2[CH:24]=1)=[O:13]
Reactant: COC(=O)c1ccc2c(CBr)csc2c1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(COc3cccnc3)csc2c1
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
Sodium hydride (0.12 g of 50% dispersion in mineral oil) was added to a solution of 3-hydroxypyridine (0.24 g) in dry N,N-dimethylformamide (5 ml) and the mixture was stirred for 30 minutes. 3-Bromomethylbenzo[b]thiophene-6-carboxylic acid methyl ester (0.71 g) in a small volume of N,N-dimethylformamide was added and the mixture was stirred at room temperature for 2 hours and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave a gummy solid which was chromatographed on silica gel. Elution with chloroform first gave some impurity followed by pure product. Evaporation of the product containing fractions gave 3-(3-pyridyloxymethyl)benzo[b]thiophene-6-carboxylic acid methyl ester (0.27 g) which was used directly in the next stage.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>C1COCC1>[OH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([B:22]([OH:27])[OH:23])=[CH:3][CH:4]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCCc1ccc(B(O)O)cc1
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a stirred solution of 4-bromophenethylalcohol (5.00 g, 24.9 mmol) in THF (80 ml) was added a solution of 1.5M n-BuLi in hexane (39.8 ml, 59.7 mmol) at −78° C. over 30 min. After 1 hour, a solution of B(OiPr)3 (8.61 ml, 37.3 mmol) in THF (20 ml) was added slowly to the mixture at −78° C. The resultant mixture was warmed to room temperature, and treated with 2M HCl (100 ml) for 1 hour. This was extracted with CH2Cl2 and dried over MgSO4, then filtered. After evaporation in vacuo, the residue was purified by silica-gel column chromatography eluting with CH2Cl2/MeOH=20/1 to afford 2.61 g (63%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:8][CH2:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1ccnc1CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1ccnc1COS(C)(=O)=O

Procedure:
A solution of (1-methyl-1H-imidazol-2-yl)-methanol (Bionet Research, 66 mg, 0.59 mmol), triethylamine (0.25 mL, 0.89 mmol), and methanesulfonyl chloride (69 μL, 0.89 mmol) in 5 mL THF were processed as described in Example 1C to give the crude material which was used directly in the next reaction.
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21].O>CN(C=O)C>[CH2:19]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:11][CH2:10][CH:2]=[CH2:3])[C:2]([Br:1])=[C:3]([O:12][CH2:6][CH:5]=[CH2:4])[CH:4]=1)[CH:20]=[CH2:21]
Reactant: C=CCBr
Reactant: O=C(O)c1cc(O)c(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cc(OCC=C)c(Br)c(OCC=C)c1
Reaction time: 15 h
Yield: 194.8 %

Procedure:
To a solution of 4-Bromo-3,5-dihydroxybenzoic acid (20.43 g, 87.5 mmol, 1.0 equiv) in DMF (120 mL) at room temperature was added solid K2CO3 (60.5 g, 438 mmol, 5 equiv). To the suspension was added allylbromide (31 ml, 358 mmol, 4.1 equiv) dropwise over 25 minutes. After 15 hours, water (150 mL) was added and the slurry was poured into water (300 mL). The precipitate was separated by filtration, washed with water, and dissolved in ether. The solution was washed with brine, dried over MgSO4, filtered, and concentrated to afford 16 as a white powder (30.1 g, 97%). Rf=0.52 (15% EtOAc/hexane); FTIR (neat, cm−1) 3088, 2900, 1717, 1649, 1582, 1424, 986; 1H NMR (400 MHz, CDCl3) δ, 7.24 (s, 2H), 6.12-5.98 (m, 3H), 5.51 (dd, J=17.6, 1.6 Hz, 2H), 5.40 (dd, J=17.2, 1.2 Hz, 1H), 5.32 (dd, J=10.2, 1.2 Hz, 2H), 5.30 (dd, J=8.4, 1.6 Hz, 1H), 4.81 (d, J=6.0 Hz, 2H), 4.66 (d, J=3.4 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ132.2, 132.0, 129.9, 118.4, 117.9, 107.9, 106.9, 69.9, 65.7; MS EI+ calculated for C16H17BrO4 (M−H+): 351, found: 351.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][N:6]1[C:14]2[CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][NH:25][CH3:26])=[C:17]([C:27]([F:30])([F:29])[F:28])[CH:16]=3)[N:11]=[C:10]([C:31]#[N:32])[C:9]=2[N:8]=[CH:7]1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:1]([N:25]([CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:11]=[C:10]([C:31]#[N:32])[C:9]3[N:8]=[CH:7][N:6]([CH3:5])[C:14]=3[CH:13]=2)=[CH:16][C:17]=1[C:27]([F:30])([F:29])[F:28])[CH3:26])(=[O:3])[CH3:2]
Reactant: CNCCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C)CCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (0.011 ml) was added dropwise to a solution of 1-methyl-6-(4-(3-(methylamino)propoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg) and diisopropylethylamine (0.045 ml) in THF (2 ml). The reaction mixture was stirred at room temperature for 1 hour. The product was then purified by acidic prep HPLC to give 6-{-4-[3-(N-acetyl-N-methylamino)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (9.2 mg).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:26])[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][NH:18]3)=[CH:13][CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][F:36]>CN(C)C=O.C(OCC)(=O)C>[F:36][CH2:35][CH2:34][N:18]1[C:19]2[C:14](=[CH:13][CH:12]=[C:11](/[CH:10]=[CH:9]/[C:6]3[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)[CH:20]=2)[C:15](=[O:26])[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17]1
Reactant: CCOC(=O)c1c[nH]c2cc(/C=C/c3nc(C(C)C)cs3)ccc2c1=O
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCF)c2cc(/C=C/c3nc(C(C)C)cs3)ccc2c1=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
Ethyl 7-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate (368 mg, 1.00 mmol) was dissolved in dimethylformamide (6 ml), added with potassium carbonate (276 mg, 2.00 mmol) and 1-bromo-2-fluoroethane (0.223 ml, 3.00 mmol), and then the mixture was stirred overnight at 65° C. The reaction mixture was left stand for cooling and then diluted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=100:1) to obtain the title compound (254 mg, 61%) as colorless transparent oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][NH2:8])[S:5][CH:6]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29](O)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29]([NH:8][CH2:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=3)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1csc(CN)c1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1csc(CNC(=O)c2sc(-n3ccc(OCc4ccccc4)cc3=O)nc2C)c1
Yield: 46 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (4-methylthiophen-2-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 46% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.83 (t, J=5.8 Hz, 1H), 8.60 (d, J=8.1 Hz, 1H), 7.50-7.31 (m, 5H), 6.91 (s, 1H), 6.77 (s, 1H), 6.38 (dd, J=8.1, 2.6 Hz, 1H), 6.22 (d, J=2.6 Hz, 1H), 5.15 (s, 2H), 4.46 (d, J=5.7 Hz, 2H), 2.53 (s, 3H), 2.12 (s, 3H); MS (ES+) m/z 452.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][N:14]([CH2:57][CH:58]=O)[C:15](=[O:56])[C:16]1[CH:55]=[CH:54][CH:53]=[C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)=[O:20])[CH:17]=1.CC(O)=O.C([BH3-])#N.[Na+]>C(O)C>[CH3:13][N:14]([CH2:57][CH2:58][N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:12])[C:15](=[O:56])[C:16]1[CH:55]=[CH:54][CH:53]=[C:18]([C:19](=[O:20])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)[CH:17]=1
Reactant: CN(CC=O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(CCN1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 47.8 %

Procedure:
To a solution of L-proline-t-butyl ester (0.096 mmol, 16 mg) in ethanol (0.2 mL) were added (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide (0.032 mmol, 20 mg) and HOAc (0.064 mmol, 4 mg). The mixture was stirred at room temperature for 25 minutes, and then sodium cyanoborohydride (0.16 mmol, 10 mg) was added. The mixture was stirred for an additional 20 minutes and quenched with water. The yellow solid was collected via filtration and was purified by prep HPLC to give a yellow solid (12 mg, 37%). MS (ES, m/z): 786.1 [M+H]+.