Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[NH2:41][C@@H:42]([CH3:45])[CH2:43][OH:44]>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:41][C@@H:42]([CH3:45])[CH2:43][OH:44])=[O:40])=[CH:15][CH:14]=3)[CH:21]=2)[CH:27]=1
Reactant: C[C@H](N)CO
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Product: C[C@@H](CO)NC(=O)Nc1ccc(-c2cc(-c3cc(F)ccc3S(C)(=O)=O)nc(N3CCOC[C@@H]3C)n2)cc1

Procedure:
Method as described for example 58 using intermediate 32 (100 mg, 0.18 mmol) and (S)-2-aminopropan-1-ol (20 mg, 0.267 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound. (51 mg, 53%)
Reaction SMILES: CC(C)([O-])C.[K+].[K].[CH3:8][C@@:9]12[C:25](=[O:26])[CH2:24][CH2:23][C@H:22]1[C@H:21]1[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:27])=[CH:17][C:18]=3[CH2:19][CH2:20]1)[CH2:11][CH2:10]2.[N:28](OCCC(C)C)=[O:29]>C(O)(C)(C)C.O>[CH3:8][C@@:9]12[C:25](=[O:26])/[C:24](=[N:28]/[OH:29])/[CH2:23][C@H:22]1[C@@H:21]1[CH2:20][CH2:19][C:18]3[CH:17]=[C:16]([OH:27])[CH:15]=[CH:14][C:13]=3[C@H:12]1[CH2:11][CH2:10]2
Reactant: CC(C)CCON=O
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C/C(=N\O)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of potassium tert-butoxide under an atmosphere of N2, freshly prepared by dissolving potassium metal (80 mg, 2.05 mmol) in 2 mL tert-butanol, oestrone (200 mg, 740 mmol) was added. The reaction mixture was then stirred for 1 hour at room temperature under N2 and isoamyl nitrite (180 μmol, 1.34 mmol) was added dropwise. The deep red mixture obtained was stirred overnight and then poured into water (20 mL). The resulting solution was extracted with ether (2×20 mL) and the aqueous layer was acidified with glacial acetic acid. (10 mL) to give a light yellow precipitate. This was left separating for two hours after which the solid was filtered (140 mg, 63%): mp 223–225° C. (lit. 226–227° C.);43 TLC (chloroform/acetone, 9:1) Rf 0.27 cf. Rf 0.69 (E1); IR (KBr) 3385 (NOH), 2920–2860 (aliph CH), 1735 (C═O), 1605–1500 (arom C═C) cm−1; δH (DMSO-d6, 400 MHz) 0.89 (3H, s, C-18-H3), 1.30–2.85 (11H, m), 2.70–2.81 (2H, m, C-6-H2), 6.46 (1H, d, JC-2-H,C-4-H=2.3 Hz, C-4-H), 6.52 (1H, dd, JC-1-H,C-2-H=8.4 Hz and JC-4-H,C-2-H=2.3 Hz, C-2-H), 7.05 (1H, d, JC-2-H,C-1-H=8.2 Hz, C-1-H), 9.05 (1H, s, exchanged with D2O, OH) and 12.39 (1H, s, exchanged with D2O, NOH); δc (DMSO-d6, 100.4 MHz) 14.09 (q, C-18), 25.09 (t); 25.46 (t), 26.18 (t), 29.02 (t), 30.92 (t), 37.20 (d), 43.20 (d), 44.59 (d), 48.50 (s, C-13), 112.70 (d), 114.83 (d), 125.82 (d), 129.59 (s), 136.88. (s), 154.84 (s, C-3 or C-16), 155.23 (s, C-3 or C-16) and 204.64 (s, C═O); MS m/z (FAB+) 453.2 [30, (M+H+NBA)+], 300.1 [100, (M+H)+]; MS m/z (FAB−) 451.3 [38, (M−H+NBA)−], 298.2 [100, (M−H)−]; Acc MS m/z (FAB+) 300.15963, C18H22NO3 requires 300.115997. CHN,
Reaction SMILES: [C:1]([S:7][CH2:8]/[C:9](=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:10]([OH:12])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[O:12]=[C:10]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])/[C:9](/[CH2:8][S:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[CH:13]\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CCN
Reactant: CC(C)(C)C(=O)SC/C(=C/c1ccccc1)C(=O)O
Product: COC(=O)CCNC(=O)/C(=C\c1ccccc1)CSC(=O)C(C)(C)C
Yield: 69 %

Procedure:
The (E)-2-pivaloylthiomethyl-3-phenylpropenoic acid described in Example 8 (step B) is coupled with methyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield: 69% (after flash chromatography, eluent: ether/petroleum ether 55/45) oil IR: 3300, 1730, 1660, 1630 cm-1 1H NMR (CDCl3): 7.20 (s, 5H); 6.75 (s, 1H); 5.90 (broad t, 1H); 3.80 (s, 2H); 3.50 (s, 3H); 3.60 to 3.25 (m, 2H); 2.40 (t, 2H, J=6.5 Hz); 1.20 (s, 9H) Microanalysis: C19H25NO4S Calc. % C=62.79 H=6.93 N=3.85 Found. % C=63.20 H=7.10 N=3.92
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCN2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
In DMF (100 ml) was dissolved 4-(2-bromoethyl)nitrobenzene (25.0 g), and to the solution were added piperidine (12.9 ml) and potassium carbonate (18.0 g). The mixture was stirred at 70° C. for 15 hours, and to the mixture was added water (900 ml), and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give 1-[2-(4-nitro-phenyl)ethyl]piperidine (24.8 g) as orange oil.
Reaction SMILES: O[N:2]1[C:10]2[C:5](=[N:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].S(Cl)([Cl:18])=O>>[Cl:11][C:7]1[N:6]=[C:5]2[N:4]=[C:3]([C:12]([F:15])([F:14])[F:13])[NH:2][C:10]2=[CH:9][C:8]=1[Cl:18]
Reactant: On1c(C(F)(F)F)nc2nc(Cl)ccc21
Reactant: O=S(Cl)Cl
Product: FC(F)(F)c1nc2nc(Cl)c(Cl)cc2[nH]1

Procedure:
1-Hydroxy-5-chloro-2-(trifluoromethyl)-1H-imidazo [4,5-b] pyridine (100 milligrams) was mixed with 10milliliters of thionyl chloride and the mixture refluxed on a steam bath for ten hours. The thionyl chloride was then evaporated and the residue, the desired 5,6-dichloro-2-(trifluoromethyl) -1H-imidazo [4,5-b] pyridine product, was shaken with water and separated by filtration, m.p. 222° -24° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH2:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[NH2:1][C:2]1[C:7]([NH:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[CH3:9])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccccc1CN
Reactant: Nc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1CNc1nccnc1N
Yield: 19.7 %

Procedure:
A mixture of 2-amino-3-chloropyrazine (4.3 g), 2-methylbenzylamine (4.6 g), potassium carbonate (5.5 g), and potassium iodide (0.4 g) in N,N-dimethylformamide (43 ml) was refluxed for 24 hours under a nitrogen atmosphere and allowed to stand at room temperature. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (110 g) with a mixture of chloroform and methanol (100:3) as an eluent to give 2-amino-3-(2-methylbenzylamino)pyrazine (1.4 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:16]=[CH:15][C:14]2[NH:13][C:12](=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=1.C(=O)(O)[O-].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(OCC)(=O)C>[O:17]=[C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[CH:4]=[C:3]([NH:2][C:25](=[O:26])[CH2:24][Cl:23])[CH:16]=[CH:15][C:14]=2[NH:13]1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
To a suspension of HCl salt of 2-amino-6(5H)-phenanthridinone (3.4 g, 0.014 mol) in ethyl acetate (200 mL) was added saturated solution of sodium bicarbonate (200 mL), followed by addition of chloroacetyl chloride (5.6 mL, 0.07 mol). The reaction mixture was stirred at room temperature for 2 days. The solid that separated out was filtered and washed thoroughly with cold water. It was then dried under vacuum to give N-(6-oxo-5, 6-dihydro-phenanthridin-2-yl)-chloroacetamide (3.35 gm, 85%).
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Sb](F)(F)[F:19].C>C1(C)C(C)=CC=CC=1.CO>[C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([F:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: F[Sb](F)F
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1C
Solvent: CO
Product: O=C(F)N(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
DPFC was prepared according to a published method of Metzger and Wilson (Biochem., 1964, Vol. 3, pp 926-931). Diphenylcarbamyl Chloride was obtained from Aldrich Chemical Co. Inc., Milwaukee, Wis., USA. DFPC was prepared from the chloride by reaction with 50% excess antimony trifluoride in hot xylene for one hour. The mixture was cooled to room temperature. Antimony halides were then precipitated with ether and the solution decolorized with charcoal, filtered and evaporated to dryness. The solids thus obtained were dissolved in Methanol, decolorized with charcoal, filtered and crystalized by cooling the solution to about 0° C. This process was repeated again and yielded white crystals with melting point of 81°-82° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([N:14]1[C:18]2[CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26]Cl)[CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(C1C=CC=CC=1N(C(C)C)CC)(C)C>C(#N)C>[CH2:7]([N:14]1[C:18]2[CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: Cc1cccc(-c2nc3ccc(OCCCCl)cc3n2Cc2ccccc2)c1
Agent: CCN(c1ccccc1C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(-c2nc3ccc(OCCCN4CCOCC4)cc3n2Cc2ccccc2)c1
Reaction time: 8 h

Procedure:
The title compound was prepared by first adding morpholine (1.02 g, 11.77 mmol) and the compound of Example 97, supra, (0.39 g, 1.00 mmol) to 125 ml of acetonitrile while stirring under nitrogen purge. To this mixture is then added diisopropylethyl aniline (1.51 ml, 8.67 mmol) dropwise. This reaction mixture is then allowed to stir overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10]1(C(O)=O)[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1.CCN(CC)CC>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1)[C:8]#[N:9]
Reactant: N#Cc1ccc(C2(C(=O)O)CCc3cncn32)c(Cl)c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C2CCc3cncn32)c(Cl)c1

Procedure:
The 5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid (0.02 g, 70 pmol) is dissolved in DMSO (2 mL) and Et3N (0.2 mL) and heated at 100° C. for 2 h. The solution is evaporated to dryness and residue purified via reverse phase HPLC (5-100% MeCN/water w/0.1% TFA) to give 3-chloro-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile as a white solid. MS (ESI) m/z 244.2, 246.2 (M+H); 1H NMR (400 MHz, CDCl3) (TFA salt) δ ppm 2.60-2.73 (m, 1 H), 3.08-3.20 (m, 2 H), 3.22-3.36 (m, 1 H), 6.04 (dd, J=7.6, 5.8 Hz, 1 H), 6.91 (d, J=8.1 Hz, 1 H), 7.24 (s, 1 H), 7.61 (d, J=8.1 Hz, 1 H), 7.81 (d, J=1.5 Hz, 1 H), 8.53 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[C:12]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][CH2:28][C:29](O)=[O:30])[CH:19]=2)=[CH:3]1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH2:48]([O:50][C:51](=[O:55])[C@H:52]([CH3:54])[NH2:53])C.C(N(CC)CC)C>O1CCCC1>[CH3:48][O:50][C:51](=[O:55])[C@H:52]([CH3:54])[NH:53][C:29](=[O:30])[CH2:28][CH2:27][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([C:12]2[C:13](=[O:17])[NH:14][C:15](=[O:16])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:19]1
Reactant: CCOC(=O)[C@H](C)N
Reactant: Cn1cc(C2=C(c3cn(CCC(=O)O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)NC(=O)CCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-[3-[4-(1-Methylindol-3-yl)-1H-pyrrole-2,5-dion-3-yl]-indol-1-yl)-propionic acid 272 mg (0.65 mmol) are dissolved in 3 mL anhydrous tetrahydrofuran and mixed with 145 mg (0.70 mmol) dicyclohexylcarbodiimide and a mixture of 90 mg (0.8 mmol) alanine ethyl ester hydrochloride and 85 mg triethylamine dissolved in 5 mL anhydrous tetrahydrofuran. The reaction mixture is stirred for 24 hours at ambient temperature, the solvent is then distilled off in a vacuum, the residue is taken up in 100 mL ethyl acetate, and the organic phase is washed with water. After drying over anhydrous sodium sulphate and distilling off the solvent in a vacuum, the crude product obtained is separated by thick layer chromatography (silica gel, dichloromethane/methanol=90:10%). The fraction with the RF of 0.31 is separated, the product is extracted and, after removal of the solvent in a vacuum, there are isolated 130 mg (40% of theory) of the desired product;
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13]>ClCCl>[CH:1]([NH:4][S:21]([C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1)(=[O:22])=[O:23])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
To a stirred solution of isopropylamine (6.8 mL, 79.6 mmol) and triethylamine (16.6 mL, 119.4 mmol) in dichloromethane (300 mL) was added the solution of 4-nitro-benzenesulfonyl chloride (8.8 g, 39.8 mmol) in dichloromethane (50 mL) at 0° C. The mixture solution stirred at room temperature for 4 h. The mixture solution was stirred at room temperature for 4 h and then washed with brine (50 mL×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford N-isopropyl-4-nitro-benzenesulfonamide (9.3 g, 96%) as a white powder: MS (ESI) M+1=245.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH3:12][C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=1)=[O:14].[OH-].[Na+]>CO>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6](/[CH:7]=[CH:12]/[C:13]([C:15]3[CH:16]=[C:17]([O:23][CH3:24])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=3)=[O:14])=[CH:5][C:4]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COc1cc(OC)cc(C(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)cc(C(=O)/C=C/c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.4 %

Procedure:
To a stirred solution of Piperonal (1.00 g, 6.67 mmol) and 3,5-dimethoxyacetophenone (1.20 g, 6.67 mmol) in methanol (30 ml) was added a 50% w/v solution of aqueous NaOH (8 ml, 15 eq). A colourless solution had formed initially following the dissolution of the two starting materials in the solvent, but upon addition of NaOH, the solution became a yellow, creamy suspension. A pale yellow precipitate was noticed approximately 2 or 3 mins after adding the aqueous NaOH. A further 3 ml (˜5 eq) of base was added, after 5 h, in order to drive the reaction to completion. The mixture was stirred for a total of 6 h at room temperature. The precipitate was collected via vacuum filtration and the filtrate discarded. The solid was purified by recrystallisation from hot methanol and hot filtration. The product was collected and allowed to be dried under vacuum to afford the title compound as a pale yellow solid (0.53 g, 25%). 1H-NMR (CDCl3) δ 7.25 (1H, d, CH(9)), 7.30(2H, d, CH(6&8)), 6.85 (1H, d, CH(3)), 6.65 (1H, t, CH(4)), 6.00 (2H, s, CH2(1)), 3.85 (6H, s, OCH3(5&7)); 13C-NMR (CDCl3) δ 189.958 (C═O), 160.870, 149.928, 148.401, 144.756, 140.403, 129.325, 125.221, 120.112, 108.650, 106.659, 106.253, 104.879, 101.621, 55.608 (OCH3); Infrared Spectrum Vmax (KBr)/cm−1 1668.3 (C═O); Mass Spectrum (FAB) m/e 313 (m+1); Elemental Analysis: Molecular Compound C18H16O5, calculated C=69.23, H=5.19 and found C=69.15, H=5.18.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:14]=[C:15]([CH:36]=[C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:38]=1[OH:39])[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([NH:26][C:27](=[O:35])[CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=1)=[O:17])([CH3:12])([CH3:11])[CH3:10].CCCCCC>C(Cl)(Cl)Cl>[C:40]([C:37]1[CH:36]=[C:15]([CH:14]=[C:13]([C:9]([CH3:10])([CH3:11])[CH3:12])[C:38]=1[OH:39])[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([NH:26][C:27](=[O:35])[CH:28]([Cl:1])[C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[CH:20]=1)=[O:17])([CH3:43])([CH3:42])[CH3:41]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)C(=O)CC(=O)Nc1cc(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1Cl
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)C(Cl)C(=O)Nc1cc(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1Cl
Reaction time: 18 h

Procedure:
N-chlorosuccinimide (16.3 g; 0.122 mole) was added with stirring to a solution of the compound (55.7 g; 0.1 mole) from (c) in chloroform (480 ml) and stirring continued for 18 hr. The volume of the mixture was reduced to approximately 100 ml and hexane (250 ml) added. The mixture was washed with water (2×100 ml) and the organic solution dried and evaporated to give a solid. This material was crystallized from dichloromethane (100 ml) and hexane (500 ml), to give the product (44.5 g; 83%) as a white solid, m.p. 185°-187° C.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]=[C:23]=[O:24].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:21][NH:22][C:23](=[O:24])[O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:9]2[C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:15]=1
Reactant: CN=C=O
Reactant: O=C(c1ccccc1)N1CCCC1c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCCN2C(=O)c2ccccc2)c1
Reaction time: 22 h
Yield: 60 %

Procedure:
To a solution of 3-[1-benzoyl-2-pyrrolidinyl]phenol (0.69 g) in dry tetrahydrofuran (35 ml) was added methyl isocyanate (0.16 ml) followed by milled potassium carbonate (0.46 g) at ambient temperature, under nitrogen. The reaction mixture was stirred for 22 hrs, at which time it was filtered through a pad of celite, and the solids washed with ethyl acetate. The combined filtrates were concentrated. Recrystallization of the residue from ethyl acetate afforded 0.50 g (60%) of product, mp 117°-121° C.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:23](I)[CH2:24][CH2:25][CH3:26].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:23]([CH2:4][CH2:3][CH2:2][C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:5])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCI
Reactant: CCCC(=O)Nc1cc(C(=O)OCC)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)Nc1cc(C(=O)OCC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116 %

Procedure:
A solution of 1.86 g of ethyl 3-butyrylamino-4-nitrobenzoate in 10 ml of N,N-dimethylformamide was added dropwise to a slurry of 0.428 g of 60% sodium hydride and 10 ml of N,N-dimethylformamide at room temperature, and the mixture was stirred at room temperature for 30 minutes. Subsequently, a solution of 1.97 g of n-butyl iodide in 10 ml of N,N-dimethylformamide was added dropwise thereto, and the mixture was heated at 50° C. for 13 hours. The reaction solution was poured into a mixed solution of 70 g of dilute hydrochloric acid and 70 g of ethyl acetate for extraction. The resulting organic layer was washed twice with water, dried, and then concentrated under reduced pressure to obtain 2.59 g of crude ethyl 3-(N-n-butylbutyrylamino)-4-nitrobenzoate. Then, 0.81 g of 1-n-butyl-6-ethoxycarbonyl-2-n-propylbenzimidazole (94) were formed in the same manner as in Example 24.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:18][CH3:19])[CH2:8][CH2:7][C:6]([C:14](OC)=[O:15])([C:9](OCC)=[O:10])[CH2:5][CH2:4]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.C1COCC1>[CH3:19][O:18][C:3]1([O:2][CH3:1])[CH2:4][CH2:5][C:6]([CH2:9][OH:10])([CH2:14][OH:15])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1(C(=O)OC)CCC(OC)(OC)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC1(OC)CCC(CO)(CO)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 102.9 %

Procedure:
To a solution of 1-ethyl 1-methyl 4,4-dimethoxycyclohexane-1,1-dicarboxylate (4.7 g, 17.13 mmol) in dry Et2O (250 mL) at 0° C. was added LiAlH4 (17.1 mL of a 2 M solution in THF; 34.3 mmol) dropwise over 15 min. The reaction mixture was stirred at 0° C. for 15 min, then warmed to rt and stirred for 1 h. It was then cooled to 0° C. and carefully quenched with aqueous NaOH (7.3 mL of a 1N solution; 7.3 mmol). The mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound (3.6 g, 100% yield) as a semisolid. 1H NMR (500 MHz, CDCl3) δ 3.65 (d, J=4.4 Hz, 4H), 3.20 (s, 6H), 2.42 (t, J=4.6 Hz, 2H), 1.67 (dd, J=7.3, 4.9 Hz, 4H), 1.53-1.41 (m, 4H).