Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.NC1C=CC(F)=C2C=1C=CC(=O)N2.[NH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[C:39]([F:47])[CH:40]=[CH:41][C:42]=2[NH2:46])[N:37]=1>[Ti](Cl)(Cl)(Cl)Cl>[NH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[C:39]([F:47])[CH:40]=[CH:41][C:42]=2[NH:46][CH:11]2[C:5]3[C:4](=[C:3]([O:20][CH3:21])[C:2]([F:1])=[CH:7][CH:6]=3)[C:8]([CH3:19])([CH3:18])[CH2:9][C:10]2([OH:17])[C:13]([F:16])([F:14])[F:15])[N:37]=1
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1ccc2c(N)ccc(F)c2n1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Nc1ccc(F)c2[nH]c(=O)ccc12
Product: COc1c(F)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1ccc(F)c2nc(N)ccc12

Procedure:
Analogously to Example 10, a mixture of the corresponding imines is produced starting from 237 g of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 137 mg of a mixture that consists of 5-amino-8-fluoroquinolin-2(1H)-one and 2,5-diamino-8-fluoroquinoline. Analogously to Example 3, the mixture of imines with 2.5 ml of titanium tetrachloride solution (1 M in dichloromethane) is reacted, and the two title compounds are obtained after chromatography on silica gel.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:52][O:53][CH2:54][CH2:55]Cl>>[CH3:52][O:53][CH2:54][CH2:55][N:2]([CH3:1])[S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: COCCCl
Reactant: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Product: COCCN(C)S(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1

Procedure:
100 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methylamide (compound in Example 745) and 15 μL 2-chloroethyl methyl ether were reacted in the same manner as in Example 746, to give 90 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid (2-methoxyethyl)-methylamide. This product was subjected to the same reaction as in Example 618, dissolved in dichloromethane/methanol and recrystallized from ethanol/ether, to give 35 mg of the title compound as orange crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:49][C:50]([NH2:52])=[O:51]>CN(C)C=O.C(OCC)(=O)C>[NH2:52][C:50](=[O:51])[CH2:49][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]2[C@H:35]3[C@H:31]([O:32][CH2:33][CH2:34]3)[O:30][CH2:29]2)[C@H:15]([OH:37])[CH2:14][N:13]([S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:38][CH:39]([CH3:41])[CH3:40])=[CH:19][CH:20]=1
Reactant: NC(=O)CBr
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCC(N)=O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (47 mg, 0.08 mmol) in anhydrous dimethylformamide (2 mL) was added cesium carbonate (78 mg, 0.24 mmol) and 2-bromoacetamide (22 mg, 0.16 mmol). After 1 h at ambient temperature, the mixture was diluted with ethyl acetate, washed with water (3×), brine, dried (sodium sulfate), and evaporated. The residue was purified by chromatography (silica gel, dichloromethane/methanol, 97:3) to afford the title product as a white solid (45 mg). 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.4 (1H, quintuplet), 1.9-2.0 (1H, m), 2.35 (1H, t), 2.6-2.8 (3H, m), 2.9 (1H, d), 2.95 (1H, dd), 3.25-3.30 (1H, m), 3.45 (1H, br s), 3.5-3.6 (3H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.3 (2H, s), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.8 (2H, d), 7.0-7.15 (3H, m), 7.22 (1H, s), 7.24 (1H, d), 7.26 (1H, d), 7.32 (1H, s), 7.42 (1H, s); MS: 650 (MH+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[OH:25][CH2:26][C:27]1[S:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.O>O1CCOCC1.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>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:30]4[S:31][C:27]([CH2:26][OH:25])=[CH:28][CH:29]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: OCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CO)s4)cc23)CC1
Reaction time: 0.33 h
Yield: 203.8 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (200 mg, 0.49 mmol) in dioxane (4.5 mL) and H2O (1.5 mL) was added [5-(hydroxymethyl)-2-thienyl]boronic acid (232 mg, 1.47 mmol), potassium carbonate (406 mg, 2.94 mmol) and tetrakis(triphenylphosphine)palladium (0) (57 mg, 0.049 mmol). Reaction was run in the microwave at 150° C. for 20 min. Aqueous work-up with EtOAc/H2O gave 447 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(hydroxymethyl)-2-thienyl]-1H-indole-7-carboxamide.
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][C:25]([NH2:29])=[C:26]([OH:28])[CH:27]=3)=[CH:18][CH:17]=2)[CH2:10][CH:9]1[CH3:31])=O)(C)(C)C.Br[CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=1)[CH3:34].[H-].[Na+]>CN(C=O)C>[NH2:29][C:25]1[N:24]=[CH:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:15]([N:11]3[CH2:12][CH:13]([CH3:14])[NH:8][CH:9]([CH3:31])[CH2:10]3)=[O:30])=[CH:17][CH:18]=2)=[CH:27][C:26]=1[O:28][CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=1)[CH3:34]
Reactant: CC1CN(C(=O)c2ccc(-c3cnc(N)c(O)c3)cc2)CC(C)N1C(=O)OC(C)(C)C
Reactant: CC(Br)c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(C(=O)c2ccc(-c3cnc(N)c(OC(C)c4cccc(C(F)(F)F)c4)c3)cc2)CC(C)N1
Reaction time: 8 h
Yield: 26.2 %

Procedure:
To a mixture of 4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.23 mmol) and 1-(1-bromo-ethyl)-3-trifluoromethyl-benzene (64 mg, 0.25 mmol) in DMF (2 ml) was added NaH (12 mg, 0.47 mmol) at 0° C. The mixture was stirred overnight. LCMS showed that the reaction was completed, DMF and water were removed. TFA (2 mL) was added to the residue and stirred at room temperature for 3 hr. TFA was removed followed by addition of methanol. The residue was purified by prep-HPLC to afford (4-{6-Amino-5-[1-(3-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone (30 mg, yield 25.7%).
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:20][C:21]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([Cl:32])[C:22]=1[C:23](Cl)=[O:24]>CO>[Cl:20][C:21]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([Cl:32])[C:22]=1[C:23]([C:3]1[C:4]2[C:5](=[C:6]([NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)=[O:24]
Reactant: N#Cc1cc(Cl)c(C(=O)Cl)c(Cl)c1
Reactant: O=C(Nc1nccc2cc[nH]c12)C1CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Product: N#Cc1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
N-(1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide (1 g, 4.9 mmol) was added to a stirred suspension of aluminium chloride (3.30 g, 24.8 mmol) in dry dichloromehane (100 mL) and the mixture was stirred at room temperature for about 1 hour, followed by drop-wise addition of 2,6-dichloro-4-cyanobenzoyl chloride (1.16 g, 4.9 mmol). The resulting reaction mixture was stirred at room temperature for about 8 hours. Methanol (25 mL) was added cautiously to quench the reaction mass followed by concentration under vacuum. The resulting residue was taken up in water followed by partitioning with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography using ethyl acetate and hexane gradient elution to afford N-[3-(2,6-dichloro-4-cyanobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7yl]cyclopropane carboxamide (0.75 g, 37.87%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:16]1([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:16]1([CH:22]2[CH2:23][CH2:24][N:25]([CH2:2][CH:3]3[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)[CH2:26][CH2:27]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCC(c3ccccc3)CC2)CC1

Procedure:
A mixture of 3.081 g (11.075 mM) of tert-butyl 4-(bromomethyl)piperidine-1-carboxylate, 1.96 g (12.2 mM) of 4-phenylpiperidine, and 3.06 g (22.2 mM) of potassium carbonate was stirred in 20 ml of N,N-dimethylformamide at 110° C. for 4 hours. This reaction mixture was poured in water and extracted with 2 portions of diethyl ether. The organic layers were combined and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to provide the title compound.
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].Cl>C(#N)C.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>[F:12][C:3]1[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([F:13])[CH:19]=2)=[CH:10][C:9]([CH3:11])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Cc1cc(Br)c(F)c(C(=O)O)c1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C(=O)O)c(F)c(-c2cccc(F)c2)c1
Yield: 37.9 %

Procedure:
A mixture of 3-bromo-2-fluoro-5-methyl-benzoic acid (400 mg, 1.7 mmol, 1.0 eq), (3-fluorophenyl)boronic acid (720 mg, 5.2 mmol, 3.0 eq), K2CO3 (356 mg, 2.6 mmol, 1.5 eq) and Pd(PPh3)4 (396.0 mg, 0.40 mmol, 0.2 eq) in acetonitrile (5 mL) and H2O (4 mL) was heated at reflux overnight. The reaction was acidified to pH 3 by addition of 1M HCl and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound as a solid (160 mg, 75%).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Sn](Cl)(Cl)(Cl)Cl>C(=S)=S>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: c1ccc(Cc2cc3ccccc3s2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: S=C=S
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)sc3ccccc23)cc1
Yield: 85 %

Procedure:
The known compound, 2-benzyl-benzo[b]thiophene (CA reg. no. 3407-15-6) was acylated with one equilvalent of anisoyl chloride using one equivalent of a tin (IV) chloride promoter in carbon disulfide solvent to afford (2-benzyl-benzo[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone (85% yield). This compound was demethylated using six equivalents of pyridinium hydrocholide at 228° C. to afford (2-benzyl-benzo[b]thiophen-3-yl)-(4-hydroxy-phenyl)-methanone (90% yield). This compound was brominated according to the procedure in Example 4 to afford the title compound as a white solid (95% yield): mp 155.5-156.5; ; MS m/e 500 (M)+ ; Analysis for: C22H14Br2O2S Calc'd: C, 52.61; H, 2.80 Found: C, 52.43; H, 2.71
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.CO>C1COCC1.CCOCC>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)C1CC1
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)C4CC4)c3C2=O)C(=O)N1
Yield: 83.9 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.60 g, 2.2 mmol) and cyclopropanecarbonyl chloride (0.4 mL, 4.4 mmol) in THF (20 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL). The solvent was removed in vacuo to give a solid. The solid was slurried in ether (30 mL0 for 1 h. The suspension was filtered and washed with ether (30 mL) to give cyclopropanecarboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-amide as a solid (630 mg, 84% yield): mp, 237–239° C.; 1H NMR (DMSO-d6) δ 0.87–0.90 (m, 4H, 2CH2), 1.93–2.09 (m, 2H, CH, CHH), 2.49–2.65 (m, 2H, CH2), 2.64–2.96 (m, 1H, CHH), 5.15 (dd, J=5.2, 12.6 Hz, 1H, NCH), 7.61 (d, J=7.2 Hz, 1H, Ar), 7.82 (t, J=7.7 Hz, 1H, Ar), 8.41 (d, J=8.3 Hz, 1H, Ar), 9.99 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) δ 8.10, 14.93, 22.00, 30.93, 48.92, 117.07, 118.30, 126.69, 131.49, 135.97, 136.43, 166.67, 167.57, 169.77, 172.55, 172.74; Anal Calcd for C17H15N3O5: C, 59.82; H, 4.43; N, 12.31. Found: C, 59.50; H, 4.39; N, 12.04.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.I[C:18]1[CH:23]=[C:22](I)[CH:21]=[CH:20][C:19]=1[C:25]([CH3:28])([CH3:27])[CH3:26].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O1CCOCC1>[C:25]([C:19]1[CH:20]=[CH:21][C:22]([N:6]2[CH2:5][CH2:4][N:3]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=3)[C:2]2=[O:1])=[CH:23][CH:18]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)c1ccc(I)cc1I
Reactant: COC(=O)c1ccc(N2CCNC2=O)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCN(c3ccc(C(C)(C)C)cc3)C2=O)cc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
Methyl 4-(2-oxoimidazolidin-1-yl)benzoate (220 mg, 1.0 mmole) was mixed with iodo-1-tert-butyl-4-iodobenzene (260 mg, 1.0 mmol), CuI (38 mg, 0.2 mmol), K3PO4 (426 mg, 2 mmol), N,N′-dimethyl ethylenediamine (17 mg, 0.2 mmol) and 1,4-dioxane (5 ml). The mixture was heated at 110° C. with stirring for 12 hours, and the solvent was removed in vacuum. The residue was suspended in dichloromethane and purified on ISCO system (5% methanol in dichloromethane) to give a pure product as a white crystalline (275 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 8.05 (dd, 2H), 7.70 (dd, 2H), 7.36 (dd, 2H), 7.20 (dd, 2H), 4.02 (s, 4H), 3.90 (s, 3H), 1.30 (s, 9H). MS (ESI) m/z: Calculated: 352.18; Observed: 353.10 (M++1).
Reaction SMILES: [CH:1]1([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].S(Cl)([Cl:21])(=O)=O>>[Cl:21][C:1]1([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(c1ccccc1)C1CCCCCC1
Reactant: O=S(=O)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1ccccc1)C1(Cl)CCCCCC1
Temperature: 0 °C

Procedure:
Sulfuryl chloride (210 mL) was added dropwise to neat cycloheptyl-phenyl-methanone (Example 14a) (86.5 g) at 0° C. over approximately 1 hour. Gas evolution and an exotherm were observed. The internal temperature was kept below 15° C. during the addition and the evolved gas was scrubbed by passing through a 10.2M aqueous solution of NaOH. The reaction mixture was heated to reflux overnight. The reaction mixture was cooled to 0° C and poured slowly onto ice (1 L) with stirring. The layers were separated and the aqueous layer was extracted with ether (2×400 mL). The combined organic layers were washed with water (600 mL), saturated aqueous sodium hydrogen carbonate (600 mL), and brine (600 mL), dried over magnesium sulphate, filtered and evaporate to give the sub-titled compound as a brown oil (100 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[CH3:10][C:11](N)=[S:12]>CN(C=O)C.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.[Fe+2].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]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:11]([CH3:10])[S:12][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1I
Reactant: CC(N)=S
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cc1nc2ccc(Br)cc2s1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A solution of 4-bromo-2-iodo-phenylamine (1.5 g, 5.0 mmol), thiacetamide (381 mg, 5.0), cupric oxide (280 mg, 3.5 mmol), dppf (56 mg, 0.10 mmol), Pd2(dba)3 (48 mg, 0.052 mmol) in DMF was heated at 60° C. for 1 hour, cooled to room temperature, partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and concentrated. The concentrate was purified by flash chromatography on silica gel using 20% hexanes/methylene chloride to give 550 mg (40% yield) of the desired product. MS (ESI(+)) m/e 227.8, 229.8 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([S:14][C:15]2[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:27].C(N(CC)CC)C.[CH:35]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36]1>C(Cl)Cl>[NH2:27][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([S:14][C:15]1[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][S:38]([CH:35]1[CH2:37][CH2:36]1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCN)OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCNS(=O)(=O)C1CC1)OCO2

Procedure:
9-(3-Aminopropyl)-8-(6-(dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine (61 mg, 0.158 mmol), triethylamine (18 mg, 24 μL, 0.174 mmol), cyclopropane sulfonyl chloride (22 mg, 17 μL, 0.158 mmol) in CH2Cl2 (3 mL) was stirred for 2 h at rt. The mixture was dried under reduced pressure and the residue purified by preparatory TLC (CH2Cl2:MeOH—NH3(7N), 20:1) to give MRP-I-31 (55 mg, 71%). 1H NMR (600 MHz, CDCl3): δ 8.30 (s, 1H), 6.78 (s, 1H), 6.66 (t, J=6.8 Hz, 1H), 6.51 (s, 1H), 6.29 (br s, 2H), 5.91 (s, 2H), 4.31 (t, J=6.0 Hz, 2H), 3.02 (q, J=6.1 Hz, 2H), 2.70 (s, 6H), 2.34-2.38 (m, 1H), 1.95-1.99 (m, 2H), 1.15-1.17 (m, 2H), 0.93-0.96 (m, 2H); 13C NMR (150 MHz, CDCl3): δ 154.9, 153.1, 151.7, 148.4, 147.6, 146.3, 144.8, 119.8, 119.4, 109.6, 102.4, 101.8, 45.4, 40.0, 39.0, 30.4, 30.2, 5.26; HRMS (ESI) m/z [M+H]+ calcd. for C20H26N7O4S2, 492.1488. found 492.1468.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.[C].[Pd]>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)/C=C/[C@H](NC(=O)c1c(C)nc2c(OCC3CCCCC3)cccn12)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@H](NC(=O)c1c(C)nc2c(OCC3CCCCC3)cccn12)c1ccccc1
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 185 mg of methyl (2E,4S)-4-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-4-phenylbuta-2-enoate in 3.7 ml of ethyl acetate was added 20 mg of 10% palladium-carbon, followed by stirring for 8 hours under a hydrogen atmosphere. The reaction mixture was filtered over Celite and the solvent was evaporated under reduced pressure to obtain 165 mg of methyl (4S)-4-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-4-phenylbutanoate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].O1CCCC1>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
3-Nitro-5-(trifluoromethyl)benzoic acid (5.0 g, 21.2 mmol) was combined with tetrahydrofuran (43 mL) and cooled to 0° C. To this solution was added a 1 M borane tetrahydrofuran complex (42 mL, 42 mmol) cautiously over 15 min and the reaction mixture allowed to warm to room temperature overnight. The mixture was cooled to 0° C., treated with excess methanol and concentrated in vacuo to afford 4.0 g (85%) which was used without further purification. 1H-NMR (CDCl3, 300 MHz) δ 8.39 (s, 1H), 8.35 (s, 1H), 7.94 (s, 1H), 4.87 (s, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.N1CCCCC1>C(O)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:13][CH:14]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1
Yield: 70.4 %

Procedure:
2.0 g of oxindole was dissolved in 40 ml of ethanol, and 2.0 g of p-anisaldehyde was added thereto at room temperature. Subsequently, 1.5 ml of piperidine was added, and the mixture was refluxed with heat for 13 hours. After completion of reaction, the reaction mixture was cooled. Crystals that precipitated were collected by filtration. The resultant crude product was washed with methanol, to thereby obtain 2.6 g (yield 71%) of the title compound in the form of yellow crystals. The melting point and elementary analysis data are shown in Table 13, and NMR and MS spectrum data are shown in Table 14.