Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19](O)=[O:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=[CH:25]1)=O.CNC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:17]([CH2:18][C:19]([N:24]([CH3:25])[CH3:22])=[O:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:7][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(-c2nc3cccnc3n2CC(=O)O)cc1
Agent: CNC
Solvent: C1CCOC1
Product: COc1ccc(-c2nc3cccnc3n2CC(=O)N(C)C)cc1
Reaction time: 2 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-methoxyphenyl-3-H-imidazo[4,5-b]pyridine-3-acetic acid (4.2 g, 0.0148 mole) and 1,1'-carbonyldiimidazole (2.43 g, 0.015 mole) in 120 ml of tetrahydrofuran was stirred at room tempeature for 31/2 hrs. A solution of dimethylamine in tetrahydrofuran (60 ml of 0.5M) was added, and the reaction was allowed to stir at room temperature overnight.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7][C:6]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21]([O:28][C:29]([NH:31][CH2:32][CH2:33]Br)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>CN(C)C=O.O>[CH2:21]([O:28][C:29]([NH:31][CH2:32][CH2:33][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7][C:6]=2[CH:14]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(NCCBr)OCc1ccccc1
Reactant: Oc1ccc2c(c1)sc1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCOc1ccc2c(c1)sc1ccccc12)OCc1ccccc1
Temperature: 60 °C
Yield: 91.2 %

Procedure:
To a solution of 370.6 mg of 3-hydroxydibenzothiophene [prepared by the method reported by H. Kudo in J. Heterocycl. Chem., 22 (1), 215-218 (1985)] and 768 mg of potassium carbonate in 4 ml of dimethylformamide, 720 mg of Intermediate 0 were added and the mixture was heated at 60° C. for 30 hours. Thereto were added ethyl acetate and water to effect extraction, whereupon the organic layer was dried and the solvent was distilled off under a reduced pressure to thereby obtain 637 mg of the above-identified compound after purification by a column chromatography (mathanol/chloroform of 1/100). Rf=0.17 (ethyl acetate/n-hexane of 1/5).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Yield: 45.4 %

Procedure:
A mixture containing methyl 4-hydroxybenzoate (45.6 g), octadecylbromide (100 g), and potassium carbonate (41.4 g) in 2-butanone (200 ml) was heated at reflux for 16 hours. The solvent was then removed until 125 ml of 2-butanone had been collected. While it was still warm, the remaining material was poured into methanol (400 ml). The product was filtered and recrystallized from 2000 ml of methanol to give methyl 4-octadecyloxybenzoate (55 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1)[CH3:2].ClN1C(=O)CCC1=O.[F:20][C:21]([F:39])([F:38])[C:22]1[CH:23]=[C:24]([C:32]([C:34]([F:37])([F:36])[F:35])=[CH2:33])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.C(=O)([O-])O.[K+]>CN(C)C=O.O>[F:20][C:21]([F:38])([F:39])[C:22]1[CH:23]=[C:24]([C:32]2([C:34]([F:37])([F:36])[F:35])[O:9][N:8]=[C:7]([C:6]3[CH:10]=[CH:11][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:33]2)[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1
Reactant: CCc1ccc(C=NO)cc1
Reactant: C=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Reaction time: 14 h

Procedure:
To a solution of 1.49 g of 4-ethylbenzaldoxime in 10 mL of N,N-dimethylformamide, 1.60 g of N-chlorosuccinimide was added and the resultant mixture was stirred at room temperature for 2 hours. Next, to the reaction mixture, 3.00 g of 3,5-bis(trifluoromethyl)-1-(1-trifluoromethylethenyl)benzene and 3.00 g of potassium hydrogen carbonate were added and the stirring of the resultant reaction mixture was continued at room temperature further for 14 hours. After the completion of the reaction, 10 mL of water was added to the reaction mixture and the resultant reaction mixture was extracted with ethyl acetate (50 mL×1). The organic phase was washed with 20 mL of water and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order, and the solvent was distilled off under reduced pressure. To the resultant residue, hexane was added and a deposited crystal was filtered off to obtain 3.00 g of the objective substance as a white crystal.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]2[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=2)=[CH:27][CH:26]=1>CCOCC>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]2[CH:46]=[CH:47][C:48]([C:49]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:50])=[CH:52][CH:53]=2)=[CH:29][CH:30]=1
Reactant: C1CCNCC1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1)N1CCCCC1
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperidine, 2.5 ml. of triethylamine and 0.6 g. of dimethylaminopyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.3 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with water and dried. The solvent is removed in vacuo and the solid is recrystallized from diethyl ether to yield 1-{4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl}piperidine.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][NH2:7])=O.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9]>C1(C)C=CC=CC=1>[CH2:8]([N:10]1[C:4]([CH2:3][O:2][CH3:1])=[N:6][NH:7][C:11]1=[O:12])[CH3:9]
Reactant: CCN=C=O
Reactant: COCC(=O)NN
Solvent: Cc1ccccc1
Product: CCn1c(COC)n[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methoxyacetic acid hydrazide (3.0 g) was heated and dissolved in toluene (60 ml), and then ethyl isocyanate (2.56 ml) was added dropwise. After stirring for at room temperature for one day, the reaction mixture was concentrated under reduced pressure. The residue was added to a 2% aqueous solution of potassium hydroxide (100 ml) that had been heated to 95° C., and the mixture was stirred at 95° C. for 45 minutes. After cooling to room temperature, concentrated hydrochloric acid (2.9 ml) was added and the mixture was stirred at room temperature for one day. Silica gel was then added to the reaction mixture, and it was concentrated under reduced pressure and purified by silica gel column chromatography. The obtained solid was washed with diethyl ether to obtain the title compound (3.56 g).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].[H-].[Na+].[CH3:18]I>C1COCC1>[NH:1]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[O:4][CH3:18]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a THF solution containing 0.8 g of Boc-Thr-OH, 100 mg of sodium hydride (60% in oil) was added under ice cooling and the resultant mixture was stirred for 30 min at room temperature. Further, 2.8 ml of methyl iodide was added and the obtained reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated under reduced pressure and the resultant residue was redissolved in ethyl acetate, washed with 5% sodium hydrogensulfite aqueous solution, water and saturated sodium chloride aqueous solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure, dissolved in methanol, mixed with DCHA and reevaporated. Ether-hexane was added to the residue to give 0.55 g of the title compound as its DCHA salt.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8]2)=[O:4].[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([N:14]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1NC(=O)OC(C)C)CCC2
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCN(C(=O)OC(C)C)c1c(C(=O)OC)ccc2c1CCC2
Temperature: 65 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
Add a solution of 4-isopropoxycarbonylamino-indan-5-carboxylic acid methyl ester (570 mg, 2.1 mmol) in dimethylformamide (8.2 mL) to a suspension of sodium hydride 60% dispersion mineral oil (82 mg, 2.1 mmol) in dimethylformamide (8.2 mL) at 0° C. under an atmosphere of nitrogen and allow to reach room temperature over 1 h. Add ethyl 4-bromobutyrate (0.44 mL, 3.09 mmol) and stir at room temperature for 14 h, then heat at 65° C. for 2 h. Cool the mixture to room temperature, dilute with ethyl acetate, wash with 1M HCl, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to provide the title compound (651 mg, 81%). 1H NMR (MeOD, 300 MHz) δ 1.03-1.34 (m, 9H), 1.85 (m, 2H), 2.10 (m, 2H), 2.30 (m, 2H), 2.82-3.01 (m, 4H), 3.32 (m, 1H), 3.68 (m, 1H), 3.86 (s, 3H), 4.08 (m, 2H), 4.91 (m, 1H), 7.19 (d, J=7.7 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H). MS (ES+): 392 (M+H).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][C:12]2[CH2:18][N:17]([CH2:19][C:20](=[O:31])[NH:21][CH:22]3[CH2:26][C:25](=[O:27])[O:24][CH:23]3[O:28]CC)[C:16](=[O:32])[CH:15]([NH:33][C:34]([C:36]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:39]=[CH:38][N:37]=3)=[O:35])[CH2:14][CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>CC#N.O>[C:1]1([S:7]([NH:10][CH2:11][C:12]2[CH2:18][N:17]([CH2:19][C:20](=[O:31])[NH:21][CH:22]3[CH2:26][C:25](=[O:27])[O:24][CH:23]3[OH:28])[C:16](=[O:32])[CH:15]([NH:33][C:34]([C:36]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:39]=[CH:38][N:37]=3)=[O:35])[CH2:14][CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC1OC(=O)CC1NC(=O)CN1CC(CNS(=O)(=O)c2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(CN1CC(CNS(=O)(=O)c2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O)NC1CC(=O)OC1O
Yield: 65 %

Procedure:
A solution of isoquinoline-1-carboxylic acid {6-(benzenesulfonylamino-methyl)-1-[(2-ethoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide, 35, as prepared in the above example, in CH3CN/H2O is treated with excess trifluoroacetic acid. The solution is stirred several hours then purified by preparative reverse phase HPLC to afford 150 mg (65% yield) of the desired product. 1H NMR (CD3OD) δ 9.14–9.11 (d, J=8.7 Hz, 1H), 8.55–8.53 (d, J=5.4 Hz, 1H), 8.07–8.03 (m, 2H), 7.93–7.85 (m, 3H), 7.81–7.76 (m, 1H), 7.68–7.60 (m, 3H), 5.68 (bs, 1H), 5.49–5.43 (d, d, J=12.3, 3.9 Hz, 1H), 4.68–4.62 (m, 2H), 4.41–4.32 (m, 1H), 4.30–4.01 (m, 2H), 3.55–3.48 (m, 3H), 2.81–2.67 (m, 2H), 2.57–2.49 (d, d, d, J=16.2, 8.4, 1.2 Hz, 1H), 2.46–2.36 (d, d, J=15.0, 15.0 Hz, 1H); MS 608 (M+H).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C(=O)C.C(N(CC)CC)C.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][C:27]1=[O:35]>CN(C=O)C>[C:5]([O:4][CH:1]([N:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)/[C:26](=[CH:25]/[C:20]2[NH:21][C:22]([CH3:24])=[CH:23][C:19]=2[CH3:18])/[C:27]1=[O:35])[CH3:2])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Agent: CC=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OC(C)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.7 %

Procedure:
A mixture of acetic anhydride (2.1 g, 20 mmol), acetaldehyde (4.4 g, 100 mmol), triethylamine (2.0 g, 20 mmol) and 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one (2.38 g, 10 mmol) in DMF (30 mL) was stirred at room temperature for 3 days. The solvents were removed and the residual oil was chromatographed on silica gel to give, as the first product eluted from the column, 2.5 g of product, which was crystallized from ether to give 2.1 g of the title compound, mp 107-110° C. HPLC Rt 6.78 min. 1H NMR (CDCl3) δ1.81 (d, 3H), 2.09 (s, 3H), 2.33 (s, 3H), 2.38 (s, 3H), 5.98 (s, 2H), 7.00-7.20 (m, 3H), 7.25 (dd, 1H), 7.39 (s, 1H), 7.51 (dd, 1H) and 13.0 (br s, 1H). Anal. Calcd for C19H20N2O3: C, 70.35; H, 6.21; N, 8.64. Found: C, 70.33; H, 6.18; N, 8.60.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[Br:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]([NH2:23])=O)=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[Br:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]#[N:23])=[C:17]2[C:13]=1[C:14]([CH:4]=[O:5])=[CH:15][NH:16]2
Reactant: NC(=O)c1ccc(Br)c2cc[nH]c12
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(Br)c2c(C=O)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
A solution of DMF (8.42 mL, 109 mmol) in CH2Cl2(105 mL) stirred on a salt-ice bath was treated dropwise with phosphorus oxychloride (2.57 mL, 27.6 mmol). After 15 min, 4-bromo-1H-indole-7-carboxamide (2 g, 8.37 mmol) was added in one portion while maintaining the temperature below −10° C. After addition, the mixture was stirred at room temperature overnight. After 16 h, ice was added, followed by NaHCO3 and 1 M aqueous NaOH added in portions to make the mixture basic. The mixture was extracted with dichloromethane (3 times), and the combined organic phases were washed with brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (80 g), eluting with a gradient from 100% CH2Cl2 to 15% Methanol-85% CH2Cl2, to provide the desired product as a pale solid (1.36 g, 65% yield). LCMS (M+H)+ m/z 248.9, 250.9.
Reaction SMILES: CO[C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]N(C2C=CC(CO)=CC=2)C)=[CH:6][CH:5]=1.CNC.B(Cl)(Cl)Cl.[Na+].[Cl-].O.S(=O)(=O)(O)O>C(Cl)Cl>[CH:3]1[C:4]2[CH2:5][C:6]3[C:7](=[CH:10][CH:6]=[CH:7][CH:8]=3)[CH2:8][C:9]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CN(C)c2ccc(CO)cc2)cc1
Agent: CNC
Agent: ClB(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: c1ccc2c(c1)Cc1ccccc1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cold solution of 4-{[(4-hydroxymethyl-phenyl)-methyl-amino]-methyl}-benzoic acid methyl ester (0.5 g, 1.8 mmol) and 3-isopropenyl-phenyl)-dimethyl-amine (0.31 g, 1.9 mmol) in methylene chloride (CH2Cl2, 25 mL)) is added dropwise a solution of boron trichloride (1 M BCl3 in CH2Cl2, 2 mL). The reaction mixture is allowed to stir overnight at room temperature cooled to −15° C. (NaCl/water) followed by dropwise addition of concentrated sulfuric acid (12 mL). Methylene chloride is removed and the mixture is allowed to stand at 40° C. over a period of 16 h. The resulting solution is poured into crushed ice and neutralized with 2 N sodium hydroxide. The aqueous solution is extracted with methylene chloride (2×75 ml), dried (Na2SO4) and concentrated giving the 9,10-dihydro-anthracene as a residue.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[CH2:8][C:9](=[CH:12]N(C)C)[C:10](=O)[C:4]=2[CH:3]=1.[NH:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[C:20]([NH2:22])=[NH:21]>>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[CH2:8][C:9]3[CH:12]=[N:22][C:20]([NH:19][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:21][C:10]=3[C:4]=2[CH:3]=1
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Br)cc2C1=O
Product: O=C1Cc2cnc(Nc3ccc(C(=O)O)cc3)nc2-c2cc(Br)ccc2N1

Procedure:
In a manner similar to method I, 7-bromo-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-k) and 4-guanidinobenzoic acid were converted to I-25 (22%): HRMS Calcd. for C19H13BrN4O3: 425.0249, Found 425.0269.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.CC(O)=O>[CH2:9]([NH:1][C@@H:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCC[C@@H](C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCC[C@@H](C)NCc1ccccc1
Temperature: 0 °C
Reaction time: 28 h

Procedure:
A sample of 0.65 mL (4.4 mmol) of (R)-(−)-2-aminoheptane (R-44) 0.44 mL (4.4 mmol) of benzaldehyde and 0.1 mL of HOAc were combined in 40 mL of CH2Cl2 and then cooled to 0° C. To the reaction mixture was added 2.75 mg (13 mmol) of sodium triacetoxyborohydride in one portion, which was stirred under argon at room temperature for 28 hours. The reaction mixture was diluted with 30 mL of CH2Cl2, cooled in an ice bath and 80 mL of 5% NaOH (in water) was added. Fractions were separated, organics (Na2SO4) dried and evaporated to 638 mg (71%) of (R)-15. 1H NMR (CDCl3) δ 0.88 (m, 3H), 1.08 (d, 3H J=6.6 Hz), 1.20-1.39 (m, 6H), 1.41-1.67 (m, 2H), 3.62-3.77 (m, 1H), 3.75 (p, 2H, J=12 Hz), 7.17-7.41 (m, 5H); MS (APCI+) m/z (rel): 206 (100); [α]D=+6.9° (c=1.0, MeOH).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH:21]([NH2:23])[CH3:22])[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>C1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:23][CH:21]([CH3:22])[CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COc1cccc(CC(C)N)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(CC(C)NS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of p-toluenesulfonyl chloride (28.8 gm., 0.15 M) in benzene (100 ml.) was added dropwise to a solution of 2-(3-methoxyphenyl)-1-methylethylamine (23 gm., 0.139 M) and triethylamine (13 gm., 0.15 M) in benzene (200 ml.) during 30 minutes. The reaction was stirred at room temperature for 4 hours. The precipitated triethylamine hydrochloride was filtered off and the benzene solution was washed with hydrochloric acid (3 N), water and saturated brine. The benzene solution was dried over magnesium sulfate. Evaporation of the solvent afforded N-toluene-p-sulfonyl-2-(3-methoxyphenyl)-1-methylethylamine as an oil. Wt=42 gm.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH:14]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[CH2:15][CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[N:17]1([CH:14]([C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)[CH2:15][CH3:16])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CCC(c1ccc(-c2ccc(OC)cc2)s1)n1ccnc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(c1ccc(-c2ccc(O)cc2)s1)n1ccnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(1-(5-(4-methoxyphenyl)thiophen-2-yl)propyl)-1H-imidazole (45 mg, 0.15 mmol; prepared as described in Example 3) in DCM (4 mL) was added BBr3 (0.02 mL, 0.22 mmol) at 0° C. The reaction was stirred at 0° C. for about 2 h, quenched with saturated NaHCO3 solution (10 mL), and extracted with DCM (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), the organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was washed with pentane (10 mL) afforded 4-(5-(1-(1H-imidazol-1-yl)propyl)thiophen-2-yl)phenol as off white solid (42 mg, 81.3% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.59 (s, 1H), 7.78 (s, 1H), 7.37 (d, 2H), 7.25 (s, 1H), 7.14 (d, 1H), 7.01 (d, 1H), 6.90 (s, 1H), 6.75 (d, 2H), 5.47 (t, 1H), 2.31-2.16 (m, 2H), 0.80 (t, 3H), LC-MS m/z calcd for [M−H]+ 285.10. found 217.2 [M-imidazole]+.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].Cl.Cl[CH2:7][CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(O)C.[OH-].[Na+]>[CH2:1]([NH:4][CH:8]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH3:7])[CH:2]=[CH2:3]
Reactant: CCN(CC)CCCl
Reactant: C=CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=CCNC(C)N(CC)CC

Procedure:
To a solution of 49.7 g (0.87 moles) of allylamine in 500 ml of ethanol, add in several portions 50 g (0.29 moles) of 2-chloro-N,N-diethylethanamine hydrochloride, then add 80.2 g (0.58 moles) of potassium carbonate. Stir the reaction at room temperature for 1 hr, then heat to reflux. Follow the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile:ammonium hydroxide, 9:1). At the completion of the reaction dilute the mixture with 500 ml of 20% sodium hydroxide solution. Extract the aqueous mixture with 4×200 ml of diethyl ether. Dry the combined ether extracts over anhydrous sodium sulfate. Remove the drying agent by filtration and evaporate the solvent in vacuo. Distill the residue at reduced pressure and collect the fraction distilling at 81° C. (20 mm Hg) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(F)cc2)C1Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a solution of 1,1-dimethylethyl (4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate (4.0 g, 9.10 mmol) in methanol (22 ml) was gradually added a solution of sodium hydroxide (0.44 g, 10.92 mmol) in methanol (22 ml) under ice-cooling. The reaction solution was stirred for 3 hrs., diluted with 1N hydrochloric acid (12 ml) and water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the title compound (2.90 g, 77%).