Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[O:8][C:9]([CH3:32])=[C:10]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:11]=1.[CH:33]([C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1)=O>>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[O:8][C:9]([CH3:32])=[C:10](/[CH:12]=[CH:33]/[C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)[N:11]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Cc1oc(-c2ccco2)nc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: COC(=O)c1ccc(/C=C/c2nc(-c3ccco3)oc2C)cc1

Procedure:
[2-(2-Furyl)-5-methyl-4-oxazolylmethyl]triphenylphosphonium chloride and methyl 4-formylbenzoate were reacted in the same manner as in Reference Example 10 to yield methyl (E)-4-[2-[2-(2-furyl)-5-methyl-4-oxazolyl]vinyl]benzoate, which was then recrystallized from ethyl acetate to yield colorless prisms having a melting point of 142°-143° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:13](=O)(=[O:16])([OH:15])[OH:14].OS(O)(=O)=O.O=S(=O)=O.[Na+:27].[Cl-]>>[Na+:27].[CH:7]1([C:1]2[CH:2]=[CH:3][C:4]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=S(=O)(O)O
Reactant: c1ccc(C2CCCCC2)cc1
Agent: O=S(=O)=O
Agent: [Cl-]
Agent: [Na+]
Product: O=S(=O)([O-])c1ccc(C2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Cyclohexyl benzene (500 gm, 3.12M) is stirred in a five liter 3-necked flask equipped with a condenser and a thermowatch, and is warmed to 70° C. Sulfuric acid (381 gm, 3.74M) and 30% oleum (38.2 gm) are added dropwise to the stirred reaction at a rate sufficient to maintain a temperature of approximately 70°-75° C. When the addition is complete, the reaction is aged at 70° C. for three hours and then cooled. The resulting reaction mixture, which is deep red in color, then is drowned in two liters of a saturated NaCl solution that is cooled to approximately 5° C. The solid precipitated in the salt solution then is filtered and washed with hexane, following which the precipitate is dried in a vacuum oven at 75° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH3:29])=[CH:23][CH:22]=4)=[O:19])=[CH:13][C:12]=3[CH:36]=2)=[CH:4][CH:3]=1.[CH3:37][I:38]>CN(C)C=O>[I-:38].[CH3:29][N+:28]([CH3:37])([CH2:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18]([C:14]2[CH2:15][CH2:16][CH2:17][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[CH:36][C:12]=3[CH:13]=2)=[O:19])=[CH:22][CH:23]=1)[CH:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCC3)cc1
Reactant: CI
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+](C)(C)C4CCOCC4)cc2)CCC3)cc1
Product: [I-]

Procedure:
A solution of 2-(4-methylphenyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (0.11 g) and methyl iodide (0.02 ml) in dimethylformamide (4 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added ethyl acetate. Precipitated crude crystal was filtered, which was recrystallized from ethanol-ethyl acetate to give N,N-dimethyl-N-(4-((2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl)carbonyl)aminobenzyl)-N-(4-tetrahydropyranyl)ammonium iodide (Compound 220) (0.13 g) as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)=[O:5].ClC1N=CC=CC=1C(NC1C=CC=C(Cl)C=1)=O.[O:41]([C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.NC1CCN(CC2C=CC=CC=2)CC1>>[O:41]([C:48]1[CH:49]=[CH:50][C:51]([NH:52][C:2]2[N:23]=[CH:22][CH:21]=[CH:20][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)=[O:5])=[CH:53][CH:54]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=C(Nc1ccc(Oc2ccccc2)cc1)c1cccnc1Cl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: NC1CCN(Cc2ccccc2)CC1
Agent: O=C(Nc1cccc(Cl)c1)c1cccnc1Cl
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1cccnc1Nc1ccc(Oc2ccccc2)cc1
Yield: 77.8 %

Procedure:
The title compound was prepared in the same manner as in Example 1, with the exception that 2-chloro-(N-4-phenoxyphenyl)nicotinamide of Preparation Example 6, instead of 2-chloro-(N-3-chlorophenyl)nicotinamide, and 4-phenoxyaniline, instead of 4-amino-1-benzylpiperidine, were used in the same molar amounts (Yield: 77.8%). 1H NMR (DMSO-d6) δ 10.50 (s, 1H), 10.33 (s, 1H), 8.35 (d, 1H), 8.25 (d, 1H), 7.69˜7.82 (m, 4H), 7.30˜7.46 (m, 4H), 6.88˜7.18 (m, 11H) ppm.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([F:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]#[N:21])=[O:14]>>[F:10][C:5]12[CH2:8][CH2:9][C:2]([NH:1][CH2:12][C:13]([N:15]3[CH2:19][CH2:18][CH2:17][C@H:16]3[C:20]#[N:21])=[O:14])([CH2:7][CH2:6]1)[CH2:3][CH2:4]2
Reactant: NC12CCC(F)(CC1)CC2
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Product: N#C[C@@H]1CCCN1C(=O)CNC12CCC(F)(CC1)CC2
Yield: 76.4 %

Procedure:
Using 4-amino-1-fluorobicyclo[2,2,2]octane (50.0 mg) and (2S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile (73.5 mg), the same procedure was followed as in Example 10 to obtain (2S)-1-[[N-(4-fluorobicyclo[2,2,2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (72.3 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.Cl.[F:15][C:16]1[CH:17]=[CH:18][C:19]([C@@H:22]([NH2:24])[CH3:23])=[N:20][CH:21]=1.C(N(C(C)C)CC)(C)C.O>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:24][C@H:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][N:20]=2)[CH3:23])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Reactant: C[C@H](N)c1ccc(F)cn1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1cnc(Cl)nc1N[C@@H](C)c1ccc(F)cn1
Yield: 115.2 %

Procedure:
A solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (prepared as described in WO2009/131687, 0.29 g, 1.31 mmol), (S)-1-(5-fluoropyridin-2-yl)ethanamine hydrochloride (prepared as described in WO2006/123113, 0.28 g, 1.59 mmol) and diisopropylethylamine (0.69 mL, 3.96 mmol) in acetonitrile (3 mL) was stirred overnight at ambient temperature. Water was then added and the reaction mixture was extracted with diethyl ether. The organic phase was washed with water and brine, dried (MgSO4), filtered and the solvents evaporated under reduced pressure to yield the title compound (0.49 g, 85%) as an oil.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][C:12]([C:15](O)=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH2:30]>>[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH:30][C:15]([C:12]1[S:11][C:10]([NH:9][C:8]([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])=[N:14][CH:13]=1)=[O:16]
Reactant: O=C(O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: COC(=O)CN
Agent: Cl
Product: COC(=O)CNC(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 75 %

Procedure:
Prepared in 75% yield as described in general procedure (K) using 2-(3,3-dicyclohexylureido)-thiazole-5-carboxylic acid and glycine methyl ester hydrochloride.
Reaction SMILES: [CH2:1](OC(=O)C(NC1C=CC(=O)C(O)=CC=1)=O)C.[CH2:18]([O:20][C:21](=[O:34])[C:22]([NH:24][C:25]1[C:26](=[O:33])[C:27]([OH:32])=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])C>>[CH3:18][O:20][C:21](=[O:34])[C:22]([NH:24][C:25]1[C:26](=[O:33])[C:27]([O:32][CH3:1])=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23]
Reactant: CCOC(=O)C(=O)Nc1ccccc(O)c1=O
Reactant: CCOC(=O)C(=O)Nc1ccc(O)c(=O)cc1
Product: COC(=O)C(=O)Nc1ccccc(OC)c1=O

Procedure:
In the same manner but replacing [(5-hydroxy-4-oxo-2,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl ester with an equivalent amount of [(3-hydroxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl ester (described in Example 5), [(3-methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid methyl ester is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O[NH:30][C:31](=[NH:48])[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[CH:34]=[CH:35][N:36]2[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:14][N:48]=[C:31]([C:32]3[CH:40]=[CH:39][CH:38]=[C:37]4[C:33]=3[CH:34]=[CH:35][N:36]4[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:30]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reactant: CCOC(=O)CCn1ccc2c(C(=N)NO)cccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)CCn1ccc2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cccc21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
To 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (D61) (1.504 g, 6.97 mmol) in dry DMF (30 ml) was added EDC (1.604 g, 8.37 mmol) and HOBT (1.282 g, 8.37 mmol). Stirred solution at RT for 10 minutes then added ethyl 3-{4-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (N4111-31-A4) (D57) (1.92 g, 6.97 mmol). The mixture was stirred for 30 minutes. LC/MS showed one product (intermediate). The solution was heated at 80° C. for 2 hours. Left standing overnight at RT then heated 80° C. for further 2 hours to give complete reaction. Cooled and added EtOAc (250 ml). The EtOAc was washed with sat. NaHCO3 (150 ml) followed by water (2×200 ml). Dried over MgSO4 and evaporated off the solvent. The residue was subjected to chromatography on the biotage (EtOAc/hexane 1:2). On evaporation of most of the solvent from clean fractions and addition of hexane a white precipitate was formed. The solid was filtered off to obtain 1.1 g of the title product. MS (ES) C23H2335ClN4O4 requires 454; found 455 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:11]2[CH2:16][CH2:15][O:14][C@@H:13]([CH2:17][NH:18]C(=O)OC(C)(C)C)[CH2:12]2)[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[ClH:26].CO>O1CCOCC1>[ClH:1].[ClH:26].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:11]2[CH2:16][CH2:15][O:14][C@@H:13]([CH2:17][NH2:18])[CH2:12]2)[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CNC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CN)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate 32 was treated with 4M hydrogen chloride in dioxane (15 ml) and the solution stirred for 2 h at room temperature. The solution was treated with methanol (20 ml) and concentrated in vacuo to give the title compound as an off-white solid (1.53 g).
Reaction SMILES: [H-].[Na+].[CH3:3]N(C=O)C.[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:15]2[C:10]=1[C:11](=[O:43])[C:12]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[CH:13][N:14]2[CH2:23][C:24]([NH:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:25].CI>C(OCC)(=O)C.O>[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:15]2[C:10]=1[C:11](=[O:43])[C:12]([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)=[CH:13][N:14]2[CH2:23][C:24]([N:26]([CH3:3])[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:25]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CC(=O)NCCN3CCOCC3)c12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CC(=O)N(C)CCN3CCOCC3)c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
Sodium hydride (60% oil base, 61 mg, 1.4 mmol) was added to a DMF solution (2 ml) of 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-(2-morpholin-4-ylethyl)acetamide (580 mg, 1.16 mmol), and the resulting mixture was stirred at room temperature for 5 minutes. Methyl iodide (230 mg, 1.62 mmol) was added thereto, and the thus-obtained mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added to the reaction mixture, followed by separation. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=30:1→15:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, giving a white powder of 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-methyl-N-(2-morpholin-4-ylethyl)acetamide (440 mg, yield: 74%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:24]=[CH:23][C:9]([CH2:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=3[N:12]=2)=[CH:8][CH:7]=1)[CH3:4].Cl[CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30]>O1CCOCC1>[CH2:3]([O:5][C:6]1[CH:24]=[CH:23][C:9]([CH2:10][C:11]2[N:12]([CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:13]3[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:8][CH:7]=1)[CH3:4]
Reactant: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3[nH]2)cc1
Reactant: CCN(CC)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOc1ccc(Cc2nc3ccc([N+](=O)[O-])cc3n2CCN(CC)CC)cc1
Temperature: 65 °C
Yield: 13.6 %

Procedure:
To a small, argon purged flask fitted with a condenser and magnetic stirbar is charged Sodium Hydride (60 wt %, 74 mg, 1.850 mmol) and anhydrous dioxane (5 mL) and stirring begun. A solution of 2-(4-Ethoxy-benzyl)-5-nitro-1H-benzimidazole 42 (550 mg, 1.850 mmol) in anhydrous dioxane (10 mL) was added dropwise to the suspension of sodium hydride and the mixture heated to 65° C. for 90 minutes at which time a solution of (2-Chloroethyl)-diethyl-amine (251 mg, 1.850 mmol) in anhydrous dioxane (5 mL) is added dropwise to the hot solution. After 60 minutes at 65° C. the mixture is cooled to room temperature, filtered and solvent removed under reduced pressure to afford crude. The product was purified using dry silica gel column chromatography eluting with 25 mL portions of solvent system (1.25% 2M NH3 in methanol/98.75% dichloromethane to 2.5% 2M NH3 in methanol/97.5% dichloromethane). The enriched fractions were further purified using silica gel column chromatography eluting with 50% ethyl acetate/50% hexanes to 70% ethyl acetate/30% hexanes to afford a pale yellow-colorless solid 43 {2-[2-(4-Ethoxy-benzyl)-6-nitro-benzoimidazol-1-yl]-ethyl}-diethyl-amine Yield: 100 mg (13.6%). 1H NMR (DMSO) δ: 0.70 (t, 6H, J=7.1), 1.30 (t, 3H, J=6.9), 2.39 (q, 4H, J=7.1), 2.50 (m, 2H), 3.98 (q, 2H, J=6.9), 4.28-4.36 (s, 2H; m, 2H) 6.87 (d, 2H, J=8.7), 7.20 (d, 2H, J=8.6), 7.72 (d, 1H, J=9.0), 8.06 (dd, 2H, J=8.9, 2.1), 8.51 (d, 1H, J=2.1); MS (ESI): 397 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16]1([CH2:22][CH2:23][CH2:24]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([CH2:24][CH2:23][CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1c(N)sc2c1CCNC2
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(N)sc2c1CCN(CCCc1ccccc1)C2
Yield: 51.2 %

Procedure:
10.0 g (44.2 mmol) of 2-amino-3-carboethoxy-4,5,6,7-tetra-hydrothieno[2,3-c)pyridine [sic] in 100 ml of toluene were mixed with 9.0 g (45 mM) of 1-phenyl-3-bromopropane, 400 mg of potassium iodide and 6.1 g (44.2 mmol) of finely powdered potassium carbonate and refluxed for 6 h. The residue after concentration in a rotary evaporator was taken up in water, adjusted to pH=10 and extracted twice with methylene chloride. The crude product after drying and concentration of the organic phase was extracted by stirring in 50 ml of isopropanol. The pale solid was filtered off with suction and washed with isopropanol. 7.8 g (51%) of product with melting point 108-110° C. were isolated.
Reaction SMILES: OS(O)(=O)=O.[CH:6]([O:11][CH3:12])([O:9]C)OC.[Cl:13][C:14]1[CH:30]=[CH:29][C:17]([C:18]([C:20]2C(=O)[O:22][C:23]([CH3:27])=[CH:24][C:25]=2[OH:26])=O)=[CH:16][CH:15]=1.C(OC)=O>CO>[CH3:12][O:11][C:6]([C:20]1[C:25](=[O:26])[CH:24]=[C:23]([CH3:27])[O:22][C:18]=1[C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:30][CH:29]=1)=[O:9]
Reactant: Cc1cc(O)c(C(=O)c2ccc(Cl)cc2)c(=O)o1
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Solvent: COC=O
Solvent: CO
Product: COC(=O)c1c(-c2ccc(Cl)cc2)oc(C)cc1=O
Temperature: 25 °C
Yield: 84 %

Procedure:
A 5000 ml 3-neck flask is fitted with a N2 inlet, magnetic stirring bar, thermometer and a Dean-Stark trap with condenser. 2300 mls of dry methanol is added to the flask along with 244 gms of 96% H2SO4 and 352 gms of trimethyl orthoformate. 173 gms of 3-(4'-chlorobenzoyl)-4-hydroxy-6-methyl-2-pyrone is added and the reaction mixture is gently brought to reflux. The most volatile by-product of the reaction (methyl formate) is condensed and collected in the Dean-Stark trap. After 281/2 hours of reflux the reaction mixture is cooled to room temperature and poured into 6000 mls of brine. The resulting suspension is extracted with methylene chloride (6×250 mls). Evaporation of the solvent yields 153 gms of 3-methoxycarbonyl-6-methyl-2-(4'-chlorophenyl)-4-pyrone. mp (methylene chloride/ether)=131-2.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH2:8][C:7]([CH3:17])([CH3:16])[C:6]=2[CH:5]=1)(=O)[CH3:2].C(OP([CH2:26][C:27]([O:29][CH3:30])=[O:28])(OCC)=O)C.[CH3:31][O-].[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:14][C:10]1([CH3:15])[CH2:9][CH2:8][C:7]([CH3:17])([CH3:16])[C:6]2[CH:5]=[C:4](/[C:1](/[CH3:2])=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:13]=[CH:12][C:11]1=2
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: C[O-]
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C(\C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 14 h
Yield: 108.2 %

Procedure:
A solution of 2-acetyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (33, 4.60 g, 20.0 mmol) and methyl diethylphosphonoacetate (7.33 g, 34.9 mmol) in anhydrous toluene (80 mL) was treated dropwise via syringe with sodium methoxide (25 wt % in methanol, 5.5 mL, 24.0 mmol) at room temperature under argon. The reaction mixture was stirred for 14 h and then poured into a separatory funnel containing diethyl ether and saturated ammonium chloride solution. The layers were agitated and separated, and the organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 6.5 g of a pale yellow oil. Purification by column chromatography (20:1 ratio silica gel/crude product; elution with 10% ethyl acetate/hexanes) gave 4.10 g (72%) of 34 as a clear, colorless oil. 1H NMR (300 MHz, CDCl3) δ7.40 (d, J=2 Hz, 1H, ArH), 7.30 (d, J=7 Hz, 1H, ArH), 7.25 (dd, J=2, 8 Hz, 1H, ArH), 6.15 (br s, 1H, C=CH), 3.75 (s, 3H, CO2CH3), 2.58 (s, 3H, CH3C=C), 1.67 (s, 4H, CH2CH2), 1.26 (s, 6H, 2×CH3), and 1.28 (s, 6H, 2×CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16](=[O:33])[CH2:17][CH2:18][C:19]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)=[O:20])[CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[C:8]=1[O:9][CH2:10][CH2:11][CH3:12].[BH4-].[Na+]>CO.O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]([OH:33])[CH2:17][CH2:18][CH:19]([C:21]2[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=2)[OH:20])[CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[C:8]=1[O:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCOc1c(OC)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1c(OC)cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a solution of 1-(3-methoxy-4-propoxy-5-nitrophenyl)-4-(3,4,5 -trimethoxyphenyl)-butane-1,4-dione (11.53 g, 25 mmol) in 350 mL of methanol and 250 mL of tetrahydrofuran was added dropwise a solution of sodium borohydride (3.076 g, 81.34 mmol) in 140 mL of water. After the addition was completed, the mixture was stirred at room temperature for 3 hours, quenched with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and evaporated to provide a foam (11.53 g, 99.24%). 1H NMR (CDCl3): 1.05 (t, 3H), 1.80-1.95 (m, 6H), 3.80-3.98 (m, 12H), 4.1 (t, 2H), 4.72. (m, 2H), 6.6 (s, 2H), 7.15 (s, 1H), 7.35 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1[C:17]2[N:16]=[C:15]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:14]([CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.[H-].[Na+].[CH:45](Br)([CH3:47])[CH3:46]>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:45]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:14]([CH2:27][CH2:28][CH2:29][CH:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:47])[CH3:46]
Reactant: CC(C)Br
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole trifluoroacetate (300 mg, 0.6 mmol, 1 eq) in anhydrous N,N-dimethylformamide (3 m) was treated with sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol, 1.1 eq). The resulting mixture was stirred for thirty minutes at room temperature. Isopropyl bromide (0.66 mmol, 1 eq) was added to the reaction and the resulting mixture was stirred for two hours at room temperature. The reaction was quenched with the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (2×10 ml), then brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by flash column chromatography to yield the title product as a crystalline product.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](Cl)=[O:33].O>O1CCCC1.C(OCC)(=O)C>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32]([N:9]1[C:8](=[O:13])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:11][C:10]1=[O:12])=[O:33]
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
0.5 g of 5,5-diphenylimidazolidine-2,4-dione was dissolved in tetrahydrofuran (5 mL), and sodium hydride (60%, in oil) (87 mg) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 2-naphthoyl chloride (415 mg) was added at 0° C., followed by stirring at room temperature for 2.5 hours. After water was carefully added, ethyl acetate (200 mL) was added, and the layers were separated. The resulting organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=3:1) afforded white crystals. The resulting fraction was recrystallized from isopropyl ether (IPE) to obtain 441 mg of white crystals.