Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:26])[NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH2:27][C:28]([OH:30])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:26])[NH:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:14][CH:15]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccccc3)cc2)c(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2ccccc2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of tert-butyl 2-(3-cyano-4-(4-(phenethylcarbamoyl)phenoxy)phenyl)acetate 0.120 g) in 2 ml of dichloromethane was added 2 ml of TFA and the reaction was stirred at ambient temperature. After 1 hour the reaction was concentrated and dried under vacuum to give 2-(3-cyano-4-(4-(phenethylcarbamoyl)phenoxy)phenyl)acetic acid (0.100 g). MS−355.3 [M−CO2H].
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([N:13]=[C:14]=[O:15])[CH3:12].[CH3:16][C:17]([CH3:19])=O>>[CH3:16][C:17]1([CH3:19])[N:13]([CH2:11][CH3:12])[C:14](=[O:15])[N:6]2[C:2](=[N:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=32)[NH:1]1
Reactant: CCN=C=O
Reactant: CC(C)=O
Reactant: Nc1nc2ccccc2[nH]1
Product: CCN1C(=O)n2c(nc3ccccc32)NC1(C)C

Procedure:
The title compound was prepared from 2-aminobenzimidazole, acetone and ethyl isocyanate by the procedure described in the first paragraph of Example 1. In this preparation, a 10-N-methylcarbamoyl derivative was not isolated and the subject compound was recovered from the Soxhlet extraction and recrystallized from acetone to give a solid, mp above 300° C. (dec). The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: [CH:1]([C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:8])=[CH:5][CH:4]=1)=O.[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38](=[O:40])[CH3:39])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C(C1C=CC=CC=1)(=O)C.[OH-].[Na+]>CO>[N:29]1([C:32]2[CH:33]=[CH:34][C:35]([C:38](=[O:40])[CH:39]=[CH:1][C:3]3[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:8])=[CH:24][CH:25]=3)=[CH:36][CH:37]=2)[CH2:28][CH2:27][O:26][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(N2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)c1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=CC(=O)c2ccc(N3CCOCC3)cc2)cc1
Reaction time: 72 h
Yield: 90 %

Procedure:
To a stirred solution at room temperature of XI (210 mg, 0.62 mmol), 4′-morpholino acetophenone (227 mg, 1.11 mmol) or acetophenone derivative (1.5–2.0 equiv.) in MeOH (10 ml) was added a solution of NaOH (1.9 ml, 1N in H2O). A precipitate appeared. After 3 days, the reaction mixture was filtered off, rinsed with MeOH, air-dried and dried under vacuum to afford the title compound XXVf (295 mg, 0.56 mmol, 90% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:32][CH2:33][C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:23][CH:24]=1)=[O:35]
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
1.7 g of 1-(4-aminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine and 0.55 g of triethylamine are introduced into 25 ml of methylene chloride. A solution of 0.6 g of chloroacetyl chloride is added dropwise thereto. The dark solution is left to stand overnight, diluted with 50 ml of methylene chloride, washed with 1N sodium hydroxide solution, dried over magnesium sulfate and concentrated by evaporation. The crystallisate so obtained is recrystallised from acetone, yielding 1-(4-chloroacetylaminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 146°-147°.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].Br[CH2:27][C:28]([CH3:30])=[CH2:29]>C1COCC1>[CH3:29][C:28](=[CH2:27])[CH2:30][Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C=C(C)CBr
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C(C)C[Sn](CCCC)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
n-Butyllithium (16.5 mL of a 2.5 M hexanes solution, 41.2 mmol)was added to a 0° C. solution of diisopropylamine (5.4 mL, 41.3 mmol) in THF (40 mL). After stirring for 5 minutes, tributyltin hydride (10 g, 34.4 mmol) was added. After stirring for 15 minutes at 0° C., the reaction mixture was cooled to −78° C. and 3-bromo-2-methylpropene (4.0 mL, 39.7 mmol) was added dropwise. After stirring for an additional hour, the cold reaction mixture was quenched with dilute ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate layer was dried (MgSO4), filtered and concentrated to afford a colorless liquid, 2-methylallyl tributyltin (11.6 g, 98%) which was used without purification for the next step.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:34](Cl)=[O:35]>>[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([C:34]([N:8]2[CH2:13][CH2:12][C@H:11]([N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[C@H:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH2:9]2)=[O:35])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccc(F)cc1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccc(F)cc2)CC1

Procedure:
The title compound, MS: m/e=518.2 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-(4-fluoro-phenyl)-piperidin-4-one, N-methyl-piperazine and 3,5-bistrifluoromethyl-benzoyl chloride.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([C:13]2[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]3[C:20]([C:21]=2[NH2:22])=[CH:19][CH:18]=[C:17]([Cl:23])[CH:16]=3)=[O:12])[O:9][CH:10]=1)(=[O:3])[CH3:2].[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([C:13]2[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]3[C:20]([C:21]=2[NH:22][C:29](=[O:32])[CH2:30][CH3:31])=[CH:19][CH:18]=[C:17]([Cl:23])[CH:16]=3)=[O:12])[O:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(N)c2ccc(Cl)cc21
Reactant: CCC(=O)Cl
Product: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(NC(=O)CC)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) employing 2-(4-acetoxymethyl-2-furoyl)-3-amino-6-chloro-1-(ethoxycarbonyl)indole (Exampe 373, step 2) and propionyl chloride.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]2([CH3:21])[CH3:20])[C:3]1=[O:22].F[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=1[F:34].C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[F:34][C:25]1[CH:26]=[C:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=[CH:29][C:24]=1[NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9][C:8]2([CH3:21])[CH3:20])[C:3]1=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](N)C2=O)C(C)(C)C1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Nc3ccc(S(C)(=O)=O)cc3F)C2=O)C(C)(C)C1
Temperature: 120 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
tert-Butyl 4-((S)-3-amino-2-oxopyrrolidin-1-yl)-3,3-dimethylpiperidine-1-carboxylate (0.40 g, 1.3 mmol) was dissolved in DMSO (5 mL). 1,2-Difluoro-4-(methylsulfonyl)benzene (0.32 g, 1.7 mmol) and powdered Na2CO3 (0.18 g, 1.7 mmol) were added. The reaction mixture was bubbled under nitrogen for 15 minutes. The mixture stirred overnight at 120° C. The reaction mixture was cooled to ambient temperature and partitioned between brine and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated. Flash chromatography of the crude material on silica gel followed by reverse phase HPLC purification gave tert-butyl 4-((S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)-3,3-dimethylpiperidine-1-carboxylate (0.10 g, 0.21 mmol, 16% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:16])[F:15])=[CH:11][CH:12]=2)[O:4][N:3]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: Oc1cc(-c2ccc(C(F)(F)F)cc2)on1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(C(F)(F)F)cc2)on1
Yield: 80 %

Procedure:
3-Hydroxy-5-(4-trifluoromethylphenyl)isoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.15 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.26 g, 81%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:8]=2)[N:3]=1.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>N1C=CC=CC=1>[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:1]([C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)[C:2]2[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:8]=3)[N:3]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1c(N)nc2ccc(N3CCOCC3)cc2c1NCc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N(C(=O)c2ccc(OC)cc2)c2nc3ccc(N4CCOCC4)cc3c(NCc3ccccc3)c2C#N)cc1
Temperature: 0 °C

Procedure:
To the solution of 0.4 g of 2-amino-3-cyano-4-benzylamino-6-(morpholin-4-yl)quinoline in 2 mL of pyridine, 0.4 mL of 4-methoxybenzoyl chloride is added under stirring and cooling. The reaction mixture is stirred at 80° C. for 8 hours, and then poured onto 5 mL of ice-water. The precipitated material is filtered off, washed twice with 3 mL of water. After drying 0.53 g of the title compound is obtained, m.p.: 157° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[C:13]3[CH2:14][CH:15]([CH2:17][OH:18])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:22]([O:21][C:19]1[C:13]2[CH2:14][CH:15]([CH2:17][O:18][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=3)(=[O:33])=[O:32])[O:16][C:12]=2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[CH:20]=1)([CH3:24])[CH3:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(CO)O2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(OC(C)C)cc(C(=O)Nc4ccn(C)n4)cc3O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 2-hydroxymethyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (215) (506 mg, 1.530 mmol) in pyridine (10 mL) was added DMAP (20 mg), followed by p-toluenesulfonyl chloride (533 mg, 2.79 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with 3×EtOAc, dried over Na2SO4, concentrated and purified by flash column chromatography with 35-60% EtOAc in hexanes to give a white solid (580 mg, 78% yield). 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1 H) 7.78 (d, J=8.34 H) 7.35 (d, J=8.08 Hz, 2 H) 7.29 (d, J=2.27 Hz, 1 H) 6.96 (s, 1 H) 6.80 (d, J=2.27 Hz, 1 H) 6.69 (d, J=1.26 Hz, 1 H) 5.01 (dd, J=4.93, 1.89 Hz, 1 H) 4.56-4.66 (m, 1 H) 4.19 (dd, J=5.05, 2.27 Hz, 2 H) 3.81 (s, 3 H) 3.24 (dd, J=16.55, 9.73 Hz, 1 H) 2.95 (dd, J=16.42, 6.82 Hz, 1 H) 2.45 (s, 3 H) 1.30-1.35 (m, 6 H); LCMS for C24H27N3O6S m/z 486.20 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>O1CCCC1>[C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cc(-c2ccccc2)no1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cc(-c2ccccc2)no1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
To a solution of 3-phenylisoxazole-5-amine (420 mg, 2.62 mmol) and pyridine (0.636 ml, 7.87 mmol) in tetrahydrofuran (5 ml) was added 2,2,2-trichloroethyl chloroformate (0.542 ml, 3.93 mmol) with ice-cooling, the mixture was stirred for 30 minutes with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (750 mg, 85.3%) as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[C:18]1(C)[CH:23]=[CH:22][C:21]([S:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.[Na+].Cl[CH2:30]Cl.C(OCC)(=O)C>>[C:20]1([CH3:30])[CH:19]=[CH:18][CH:23]=[CH:22][C:21]=1[S:24]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:25])=[O:26]
Reactant: ClCCl
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCS(=O)(=O)c1ccccc1C
Yield: 94 %

Procedure:
As in Example 2a, 9.15 g (30 mmol) of 1-bromohexadecane and 5.88 g (33 mmol) of sodium p-toluenesulfinate (anhydrous) are reacted. After chromatography on a short silica gel column (dichloromethane/ethyl acetate 10:1) 10.7 g (94%) of 5a are obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].Cl[C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:18])[C:8]=1[NH:19][C:20](=[O:22])[CH3:21].O>C1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:18])[C:8]=1[NH:19][C:20](=[O:22])[CH3:21]
Reactant: COCCN
Reactant: CC(=O)NC1=C(Cl)C(=O)c2ccccc2C1=O
Solvent: O
Solvent: c1ccccc1
Product: COCCNC1=C(NC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methoxyethylamine (0.8 ml) was added to a solution of N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)acetamide (1.0 g) in benzene (20 ml) and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was recrystallized from ethyl acetate to give N-[3-(2-methoxyethyl)amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl]acetamide (0.87 g) as a red powder.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[CH:8]1.[OH-].[Na+].CN([CH:22]=[O:23])C>O>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[C:8]1[CH:22]=[O:23]
Reactant: Cc1cn(C)c2ccccc12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution of phosphorus oxychloride (7.0 mL, 75 mmole) in DMF (25 mL) was added dropwise a solution of 1,3-dimethylindole (12.0 g, 83 mmole) in dry DMF (6.0 mL). The reaction was stirred at RT for 2 hr then was poured onto ice. The mixture was basified with a solution of NaOH (13.2 g, 330 mmole) in H2O (44 mL), then was extracted with Et2O (2×50 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated under vacuum. Flash chromatography on silica gel (10% ethyl acetate/hexanes) gave the title compound (13.03 g, 91%) as an off-white solid: LCMS (ES) m/e 174.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 10.16 (s, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.42 (t, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.15 (t, 1H), 4.04 (s, 3 H), 2.63 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[C:17]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CCN2
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 11.9 g of indoline in 100 ml of chloroform is cooled to 0° C. 13.9 ml of triethylamine are added and a solution of 10.4 ml of acetic anhydride in 10 ml of chloroform is then added dropwise, followed by 0.1 g of 4-dimethylaminopyridine. After stirring for two hours at RT, water is added to the reaction mixture, extraction is carried out with chloroform, the organic phase is dried over sodium sulfate and the solvent is evaporated off under vacuum to give 15.44 g of the expected product, which is used as such.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:22]1[N:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1.CO.C(Cl)[Cl:34]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:34][C:26]1[N:27]=[CH:22][CH:23]=[CH:24][C:25]=1[C:28]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:29]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccnc2Cl)CC1
Temperature: 0 °C
Yield: 89 %

Procedure:
To a stirred ice-cooled solution of tert-butyl 1-piperazinecarboxylate (2.2 g, 12 mmol), triethylamine (3.2 mL, 23 mmol), and 4-dimethylaminopyridine (0.014 g, 0.11 mmol) in DCM (15 mL) was added 6-chloropyridine-3-carbonyl chloride (2.0 g, 11 mmol) in one portion. The resulting mixture was stirred at 0° C. and gradually warmed up to ambient temperature for 20 h. Upon workup, the mixture was subjected to combi-flash column chromatography (methanol/DCM) to give compound 351 (3.3 g, 89% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.46 (1 H, d, J=2.0 Hz), 7.74 (1 H, dd, J=8.2, 2.3 Hz), 7.42 (1 H, dd, J=8.2, 0.8 Hz), 3.20-4.02 (8 H, m), 1.48 (9 H, s). LCMS-ESI (POS), M/Z, M+1: Found 326.0.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]=O.[NH2:20][CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1>CO>[CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16][NH:20][CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCc2cccnc21
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Solvent: CO
Product: C[Si](C)(C)CCOCn1c(CNC2CCCc3cccnc32)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a stirred solution of 1-(2-trimethylsilylethoxymethyl)-2-formyl-benzimidazole (4.26 g, 15.4 mmol) in dry MeOH (50 mL) was added a solution of 8-amino-5,6,7,8-tetrahydroquinoline (2.20 g, 14.8 mmol) in dry MeOH (20 mL) and the mixture stirred for 2 h at room temperature under an argon atmosphere. The reaction mixture was concentrated under reduced pressure and the resultant residue analyzed by 1H NMR to confirm imine formation. The residue was re-dissolved in dry MeOH (80 mL) and to the resultant solution was added sodium borohydridc (1.17 g, 30.8 mmol). The mixture was stirred for 5 h, concentrated in vacuo and diluted with CH2Cl2 (100 mL) and saturated aqueous NaHCO3 (125 mL). The phases were separated and the aqueous layer was extracted with CH2Cl2 (2×75 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude material through a plug of silica gel (CH2Cl2/MeOH 96:4) afforded the desired amine (5.91 g, 98%) as an orange oil. 1H NMR (CDCl3) δ −0.07 (s, 9H), 0.90 (t, 2H, J=9 Hz), 1.72-1.83 (m, 2H), 1.95-2.01 (m, 1H), 2.76-2.85 (m, 2H), 3.54 (t, 2H, J=9 Hz), 4.33 (m, 2H), 5.68 (d, 1H, J=12 Hz), 5.75 (d, 1H, J=12 Hz), 7.05-7.09 (m, 1H), 7.25-7.30 (m, 2H), 7.38 (d, 1H, J=9 Hz), 7.44-7.46 (m, 1H), 7.71-7.73 (m, 1H), 8.36-8.38 (m, 1H).
Reaction SMILES: [CH3:1][S:2](O)(=O)=O.CS(O)(=O)=O.[CH2:11]([O:18][CH2:19][C:20]([CH2:27]O)([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:21]O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:29]([S:36]CC1(C(C)(C)C)COC(C)(C)OC1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:11]([O:18][CH2:19][C:20]([CH2:27][S:2][CH2:1][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH2:21][S:36][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)OCC(CSCc2ccccc2)(C(C)(C)C)CO1
Reactant: CS(=O)(=O)O
Reactant: CC(C)CC(CO)(CO)COCc1ccccc1
Product: CC(C)CC(COCc1ccccc1)(CSCc1ccccc1)CSCc1ccccc1

Procedure:
1-Benzyloxy-2,2-di-benzylthiomethyl-4-methyl-pentane was prepared from 2-benzyloxymethyl-2-hydroxymethyl-4-methyl-pentan-1-ol dimethanesulphonate in a manner analogous to that described for the synthesis of 5-benzylthiomethyl-5-t-butyl-2,2-dimethyl-1,3-dioxane.