Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[C:22](C(O)=O)=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.SCC(O)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH:22]=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1
Reactant: CC(C)c1cc(Cc2c(Cl)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Agent: O=C(O)CS
Solvent: O
Product: CC(C)c1cc(Cc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Temperature: 155 °C
Yield: 39.4 %

Procedure:
2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (49) (101.5 mg, 0.224 mmol) was treated with mercaptoacetic acid (2.2 mL). The reaction mixture was stirred with a magnetic stirrer and was heated to 155° C. for 24 h. The reaction mixture was then cooled to room temperature, diluted with water (25 mL) and extracted with ethyl acetate (25 mL). The organic layer was separated and washed with a 1N aqueous sodium hydroxide solution (3×10 mL). The aqueous layers were combined and acidified to pH=4. The resulting solids were filtered and rinsed well with water followed by petroleum ether. The solids were dried under vacuum to afford dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-[1,2,4]triazine-3,5-dione (50) (36 mg, 40%) as a tan solid; EI(+)-HRMS m/z calcd for C17H15Cl2N5O3 (M+H)1+ 408.0625, found 408.0626. Molecular Weight=408.2468; Exact Mass=407.0552
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[C:21]([C:28]#[N:29])[N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:30])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH2:28][NH2:29])[N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc([N+](=O)[O-])c(C#N)n2)c(OC)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(CN)n2)c(OC)c1
Reaction time: 8 h
Yield: 130.7 %

Procedure:
To a solution of (6-cyano-5-nitro-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (1.06 g, 2.56 mmol) in THF (10 mL) and acetic acid (20 mL) was added Pd/C (10%, 200 mg) and the reaction mixture was hydrogenated overnight. The catalyst was filtered and the filtrate evaporated to afford (5-amino-6-aminomethyl-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (1.3 g) as the acetate salt, which was used without further purification. MS: [M+H]+=389.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]([CH:16]([CH3:18])[CH3:17])=[C:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13](=[O:26])[NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:33]([O:39][C@@H:40]1[C@@H:45]([O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@H:44]([O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:43]([CH2:60][O:61][C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])[O:42][C@@H:41]1Br)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].O>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[C:15]([CH:16]([CH3:18])[CH3:17])=[C:14]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:13]([O:26][C@@H:41]2[O:42][C@H:43]([CH2:60][O:61][C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])[C@@H:44]([O:53][C:54](=[O:59])[C:55]([CH3:56])([CH3:57])[CH3:58])[C@H:45]([O:46][C:47](=[O:52])[C:48]([CH3:49])([CH3:50])[CH3:51])[C@H:40]2[O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:35])[CH3:36])=[N:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(Cc2ccccc2)c(=O)[nH]n1C(=O)OCc1ccccc1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)c1c(Cc2ccccc2)c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)nn1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 58.8 %

Procedure:
To a solution of 1-benzyloxycarbonyl-4-benzyl-5-isopropyl-1,2-dihydro-3H-pyrazol-3-one (0.16 g) in acetonitrile (5 mL) were added potassium carbonate (0.0757 g) and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (0.278 g) successively under stirring at room temperature. In addition, the mixture was stirred at 50° C. for 4 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/6) to give 1-benzyloxycarbonyl-4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole (0.228 g).
Reaction SMILES: CN(C)C(=O)[O:4][CH:5]([C:12]1[N:13]([CH3:33])[C:14]([C:23]2[S:24][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH2:32])[C:30]=3[N:31]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)(C(F)(F)F)=O.O>C1COCC1.CCOC(C)=O>[NH2:32][C:29]1[C:30]2[N:31]=[C:23]([C:14]3[N:13]([CH3:33])[C:12]([CH:5]([C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)[OH:4])=[N:16][C:15]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:24][C:25]=2[N:26]=[CH:27][N:28]=1
Reactant: CN(C)C(=O)OC(c1ccccc1)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C(O)c2ccccc2)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
[5-(7-Amino[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-1-methyl-4-phenyl-1H-imidazol-2-yl](phenyl)methyl dimethylcarbamate (Intermediate 97) (25 mg) was dissolved in THF (4 mL), TFA (0.1 mL) and water (0.1 mL) added then heated at reflux under an inert atmosphere. After 2 hours, cooled to ambient temperature, diluted with EtOAc (10 mL), washed with saturated aqueous NaHCO3 (10 mL), organic layer dried (MgSO4), filtered and concentrated in vacuo. Residue was purified by flash chromatography on silica eluting with 4% MeOH/DCM to give the title compound as a colourless foam (21 mg, 99%);
Reaction SMILES: NC1N=[C:6](N2CCC3(CN[C@H](C(OC(C)C)=O)C3)CC2)[CH:5]=[C:4](O[C@H](C2C=CC(C3C=CC(C)=C(C)C=3)=CC=2N2C=CC(C)=N2)C(F)(F)F)N=1.[NH2:50][C:51]1[N:56]=[C:55]([N:57]2[CH2:69][CH2:68][C:60]3([CH2:64][NH:63][C@H:62]([C:65]([OH:67])=[O:66])[CH2:61]3)[CH2:59][CH2:58]2)[CH:54]=[C:53]([O:70][C@H:71]([C:76]2[CH:81]=[CH:80][C:79]([Cl:82])=[CH:78][C:77]=2[C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:72]([F:75])([F:74])[F:73])[N:52]=1>>[NH2:50][C:51]1[N:56]=[C:55]([N:57]2[CH2:58][CH2:59][C:60]3([CH2:64][NH:63][C@H:62]([C:65]([O:67][CH:5]([CH3:6])[CH3:4])=[O:66])[CH2:61]3)[CH2:68][CH2:69]2)[CH:54]=[C:53]([O:70][C@H:71]([C:76]2[CH:81]=[CH:80][C:79]([Cl:82])=[CH:78][C:77]=2[C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:72]([F:75])([F:74])[F:73])[N:52]=1
Reactant: Cc1ccn(-c2cc(-c3ccc(C)c(C)c3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)OC(C)C)C4)nc(N)n2)C(F)(F)F)n1
Reactant: Nc1nc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1
Product: CC(C)OC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1

Procedure:
The title compound was prepared as described for (S)-isopropyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (Example 67a) starting with (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34c).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([OH:23])[CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])C.[CH3:25][NH2:26]>C(O)C>[CH3:25][NH:26][C:4](=[O:3])[CH:5]([OH:23])[CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: CCOC(=O)C(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Reactant: CN
Solvent: CCO
Product: CNC(=O)C(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Yield: 94.2 %

Procedure:
40 g of ethyl-2-hydroxy-3-phenyl-3-(2-nitro-phenoxy)-propionate in 1 liter of 95° ethyl alcohol and 250 ml of 35% methylamine was heated in a stopped vessel at 40°-50° C. for 24 hours. The whole was evaporated to dryness under vacuum, taken up with 200 ml of absolute ethyl alcohol, again evaporated to dryness and the residue crystallized from isopropanol. There was in this way obtained 36 g (94.2%) of N-methyl-2-hydroxy-3-phenyl-3-(2-nitro-phenoxy)-propionamide, melting point 162°-163° C.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][OH:16])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[CH2:17](Br)[C:18]#[CH:19]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+]>[CH2:19]([O:16][CH2:15][CH2:14][N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1)[C:18]#[CH:17]
Reactant: C#CCBr
Reactant: OCCn1cnc2cnc3ccccc3c21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: C#CCOCCn1cnc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
2-(1H-Imidazo[4,5-c]quinolin-1-yl)-1-ethanol (28.5 g, 0.133 mol) was added in portions over a period of 1 hour to a mixture of sodium hydroxide (240 mL of 50%), dichlorometbane (240 mL), propargyl bromide (39.6 g of 80%, 0.266 mol) and benzyltrimethylammonium chloride (2.46 g, 0.013 mmol). The resulting reaction mixture was allowed to stir at ambient temperature for 16 hours at which time the reaction mixture was homogeneous. The layers were separated. The aqueous fraction was extracted with additional dichloromethane. The organic fractions were combined, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was combined with diethyl ether and the mixture was allowed to stir. An orange solid was isolated by filtration. This material was recrystallized from ethyl acetate to provide 19.8 g of 2-(1H-imidazo[4,5-c]quinolin-1-yl)ethyl (2-propynyl) ether as a yellow crystalline solid, m.p. 124-126° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:34])=[C:24]([C:27]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])[CH:25]=2)[NH:20][C:19](=[O:35])[C:18]=1[C:36]1[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([CH3:43])[CH:37]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[Cl:34][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:36]3[CH:37]=[C:38]([CH3:43])[CH:39]=[C:40]([CH3:42])[CH:41]=3)[C:19](=[O:35])[NH:20]2)=[CH:25][C:24]=1[C:27]([N:29]1[CH2:30][CH2:31][CH2:32][CH2:33]1)=[O:28]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C(=O)N4CCCC4)c(Cl)cc3[nH]c2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc(C(=O)N4CCCC4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(pyrrolidine-1-carbonyl)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (8.0 mg in 2.0 dry methylene chloride) was added a few drops of anisole followed by 1.0 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 30 minutes the solvents were removed in vacuo and the resulting residue purified by flash chromatography on silica gel (methylene chloride: 10% ammonium hydroxide in methanol, 95:5; then 90:10) to give the title compound (5 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:14])[CH:12]=O>>[CH3:10][N:11]([CH3:14])[CH:12]=[CH:1][C:2]1[CH:3]=[CH:4][N:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CN(C)C=O
Reactant: Cc1ccncc1C#N
Product: CN(C)C=Cc1ccncc1C#N
Reaction time: 16 h
Yield: 63 %

Procedure:
A solution of 4-methylnicotinonitrile (13.8 g, 0.12 m), dimethylformamide (DMF) (100 mL) and DMF acetal (14.0 g, 0.12 m) was heated at reflux under N2. After 16 hours, the reaction mixture was concentrated at atmospheric pressure until the internal temperature reached 150°. The mixture was then cooled, poured into H2O (1 L) and extracted with C6H6 (6×200 mL). The combined organic extracts were washed with H2O (2×200 mL), dried, filtered and evaporated to dryness. The residue was distilled at 150°-160° (0.2 mm) to yield 12.6 g (63%) of N,N-dimethyl-2-(3-cyano-4-pyridyl)ethenamine. An analytical sample was prepared by crystallization from C6H6 --C6H14, mp 88°-90°.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(OCC)(=O)C>[CH3:10][CH:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: N#Cc1ccc(F)cc1
Reactant: CC1CCNCC1
Solvent: CCOC(C)=O
Product: CC1CCN(c2ccc(C#N)cc2)CC1

Procedure:
4-Fluorobenzonitrile (1.21 g) was heated with 4-methylpiperidine (1.00 g) at 180° C. for 1 hour. The mixture was then taken up in ethyl acetate, washed with water, 2N sodium hydroxide solution and saturated sodium bicarbonate solution, dried over sodium sulfate, concentrated and crystallized from n-pentane. This resulted in the product with the molecular weight of 200.29 (C13H16N2); MS(ESI): 201 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[CH2:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1)[CH2:11][CH3:12].Cl>C(NCC)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.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]#[C:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=2)=[C:4]([F:9])[CH:3]=1
Reactant: C#Cc1ccc(CCC)cc1
Reactant: Fc1cc(Br)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: CCCc1ccc(C#Cc2ccc(Br)cc2F)cc1
Temperature: 5 °C
Yield: 66.1 %

Procedure:
4-Bromo-2-fluoro-1-iodobenzene (33 g) was dissolved in diethylamine (37 ml) under nitrogen atmosphere, and then bis(triphenylphosphine)palladium(II) chloride (0.1 g) and copper(I) iodide (0.1 g) were added thereto, followed by stirring. The flask was cooled to 5° C. or lower, and then 4-propylphenylacetylene (16 g) was added dropwise thereto. After stirring at room temperature for 5 hours, the reaction solution was poured into a mixture of concentrated hydrochloric acid (23 ml) and ice (150 g). After extraction with chloroform, the resultant was washed twice with water, followed by distilling off chloroform therefrom. The residue was distilled under reduced pressure (b.p. 190° to 200° C./4 mmHg), and then recrystallized from a mixed solvent of acetone and methanol to give 4-bromo-2-fluoro-4'-propyltolane (23 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([OH:17])=[C:11]([CH3:18])[C:10]=2[CH3:19])[CH:6]=[CH:7][CH:8]=1.CC1C=CC(S(O[CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:19][C:10]1[C:11]([CH3:18])=[C:12]([O:17][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: Cc1c(C)c(-c2cccc(CO)c2)c(C)c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)c(-c2cccc(CO)c2)c(C)c(C)c1OCCCS(C)(=O)=O
Temperature: 90 °C
Reaction time: 12 h
Yield: 63.9 %

Procedure:
To a solution of 3′-(hydroxymethyl)-2,3,5,6-tetramethylbiphenyl-4-ol (0.616 g, 2.40 mmol) and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (1.05 g, 3.60 mol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (0.597 g, 4.32 mmol), and the mixture was stirred at 90° C. for 12 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.577 g, yield 85%) as colorless crystals.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=O)(C)(C)C.[OH:16][CH2:17][CH2:18][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH:21]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[C:20]1=[O:37]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11].[OH:16][CH2:17][CH2:18][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH:21]([N:26]2[C:27](=[O:36])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]2=[O:35])[C:20]1=[O:37]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoate (410 mg) was dissolved in 30% TFA/DCM (5 mL), the mixture was stirred on a magnetic stirrer for 4 hrs at room temperature. White foam was obtained after reduced pressure distillation to distill off the solvent. The foam was dissolved in DCM (30 mL). The resultant solution washed with aqueous saturated sodium bicarbonate solution and brine (30 mL), dried over anhydrous magnesium sulfate, and filtered. Title compound was obtained as a white solid (260 mg) after rotary evaporation. 1H NMR (CDCl3, ppm) δ 7.87-7.91 (m, 2H), 7.76-7.79 (m, 2H), 4.97-5.08 (m, 1H), 4.38-4.43 (m, 1H), 4.05-4.30 (m, 3H), 3.25 (dd, 1H, J=4.8, 13.2 Hz), 2.95-3.05 (m, 1H), 2.80-2.95 (m, 2H), 2.10-2.20 (m, 1H), 1.90-2.10 (m, 2H), 1.00-1.20 (m, 1H), 0.95-0.98 (m, 3H), 0.87-0.91 (m, 3H). MS (m/e): 402 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([O:26]C)[CH:20]=[C:19]3[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][CH3:36])[CH:29]=2)([C:10]2[N:11]([CH3:15])[CH:12]=[N:13][CH:14]=2)[OH:9])=[CH:4][CH:3]=1.Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:9])([C:10]2[N:11]([CH3:15])[CH:12]=[N:13][CH:14]=2)[C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH:20]=[C:19]3[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][CH3:36])[CH:29]=2)=[CH:4][CH:3]=1
Reactant: CCOc1cccc(-c2cc(OC)nc3ccc(C(O)(c4ccc(Cl)nc4)c4cncn4C)cc23)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4ccc(Cl)nc4)c4cncn4C)cc23)c1
Yield: 85.1 %

Procedure:
Following the same procedure as described in example 1F, (6-chloro-pyridin-3-yl)-[4-(3-ethoxy-phenyl)-2-methoxy-quinolin-6-yl]-(3-methyl-3H-imidazol-4-yl)-methanol (1.458 g, 2.92 mmol) was treated with HCl in aqueous THF to yield the title compound (1.21 g, 85% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:9](=[O:12])[CH2:10][CH3:11])[C:5]([O:7][CH3:8])=[O:6].[Li]CCCC.[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27]([O:29]C)=O.OS([O-])(=O)=O.[K+]>C1COCC1>[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27](=[O:29])[CH:10]([CH3:11])[C:9](=[O:12])[CH:4]([CH3:3])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc2ccccc2o1
Reactant: CCC(=O)C(C)C(=O)OC
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C)C(=O)C(C)C(=O)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
After adding 60% NaH (220 mg) to a solution of methyl 2-methyl-3-oxopentanoate (750 mg) in THF (5 ml) at 0° C. and stirring at 0° C. for 5 minutes, the mixture was cooled to −78° C. To this reaction solution there was added 1.63 M n-BuLi (3.3 ml), and the mixture was stirred at −78° C. for 30 minutes to prepare a dienolate. A solution of methyl 2-benzofurancarboxylate (300 mg) in THF (10 ml) was added to the dienolate, and the mixture was stirred at −78° C. for 20 minutes. The reaction solution was allowed to return to 0° C., aqueous KHSO4 was added for quenching, and extraction was performed with AcOEt. The organic layer was rinsed with saturated saline and dried with MgSO4, and then filtered and concentrated. The residue was crudely purified by silica gel column chromatography (n-hexane/AcOEt=3/1→2/1) to obtain methyl 5-(benzofuran-2-yl)-2,4-dimethyl-3,5-dioxopentanoate.
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].ClC1C(CCl)=NC=C(C(F)(F)F)C=1>CN(C)C=O>[C:6]1(=[O:7])[NH:2][C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: FC(F)(F)c1cnc(CCl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc21
Reaction time: 1 h

Procedure:
To a solution of N-hydroxyphthalimide (3.55 g) in dimethylformamide (50 ml) was added potassium carbonate (3.0 g) to give a thick yellow suspension which was stirred for 1 hour. 3-Chloro-2-chloromethyl-5-trifluoromethylpyridine (5.0 g) was added and the reaction stirred at room temperature for 20 hours. The mixture was filtered and the filtrate poured into water. The resulting white solid was isolated by filtration, washed with water, redissolved in ethyl acetate and the organic solution dried and evaporated to yield the intermediate phthalimide as a white solid. The phthalimide (2.0 g) was dissolved in methanol (20 ml) and the resulting solution treated with hydrazine hydrate (0.42 g). The reaction was left to stand for 19 hours before heating at reflux for 3 hours to yield a white precipitate. The reaction mixture was filtered and the methanol filtrate evaporated. The residue was treated with diethyl ether and refiltered. Evaporation of the filtrate yielded the title compound as a green yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([OH:3])=[O:2].[S:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[S:28]>>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[C:32]2[S:26][C:27](=[S:28])[NH:29][C:30]2=[O:31])=[CH:20][CH:21]=1)([OH:3])=[O:2]
Reactant: O=Cc1ccc(OCc2ccccc2-c2ccccc2C(=O)O)cc1
Reactant: O=C1CSC(=S)N1
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2ccccc2-c2ccccc2C(=O)O)cc1
Yield: 79085.6 %

Procedure:
The 4-[2-(2-carboxyphenyl)benzoxy]benzaldehyde (93.7 mg, 0.28 mmol) was then coupled with rhodanine (37.5 mg, 0.28 mmol) as described supra to yield the title product (99.1 g, 79%).