Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:26][CH:27]=1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2)cc1

Procedure:
77.6 mg of solid white 3-{4-[3-(4-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 4-trifluoromethylphenyl isocyanate.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])[CH:5]=1.Cl.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl>CN(C=O)C.CCOC(C)=O.O>[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])=[CH:17][CH:18]=2)([CH3:11])[CH3:12])[CH:5]=1
Reactant: CN(C)CCCCl
Reactant: CC(C)(c1ccc(O)cc1)c1cc(Br)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccc(C(C)(C)c2cc(Br)ccn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
Sodium hydroxide (pellets are finely grinded, 0.488 g, 12.2 mmol, 5 eq) is added to a solution of 4-[1-(4-bromo-pyridin-2-yl)-1-methyl-ethyl]-phenol (Step 31.2) (0.714 g, 2.44 mmol) in DMF (5 mL). The mixture is stirred for 20 min at rt. 3-Dimethylamino-1-propylchloride hydrochloride (0.611 g, 3.87 mmol, 1.6 eq) is added. The reaction mixture is heated to 90° C., stirred for 10 h, allowed to cool, diluted with EtOAc/H2O and extracted with EtOAc. The organic phase is washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) to afford 0.398 g of the title compound as an impure brown oil which is used without further purification: ESI-MS: 377.1/379.0 [M+H]+; TLC: Rf=0.22 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[N:7]=[C:6]([NH:14][C@H:15]([CH2:17][CH3:18])[CH3:16])[CH:5]=1.[OH-].[Li+].Cl>C1COCC1>[C@@H:15]([NH:14][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[N:7]=1)[C:3]([OH:19])=[O:2])([CH2:17][CH3:18])[CH3:16]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(S(C)(=O)=O)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Chill a solution of (S)-2-sec-butylamino-6-methanesulfonyl-isonicotinic acid methyl ester (1.02 g, 3.57 mmol) in THF (10 mL) in an ice bath. Add 1 N lithium hydroxide (5.4 mL, 5.4 mmol) and stir the solution at room temperature for 3 h. Add 1 N HCl until about pH=2. Concentrate and partition the residue between ethyl acetate and water. Separate the layers and extract the aqueous layer with ethyl acetate (2×30 mL). Wash the combined extract with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:26]COC)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[CH2:30][CH2:31][CH3:32])[CH2:7][C@H:6]1[CH3:33])=[O:4].[O:34]1[CH2:39][CH2:38][O:37][C:36]2[CH:40]=[C:41]([C:44]3([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]3=[O:50])[CH:42]=[CH:43][C:35]1=2>>[O:34]1[CH2:39][CH2:38][O:37][C:36]2[CH:40]=[C:41]([C:44]3([CH3:51])[NH:48][C:47](=[O:49])[N:46]([CH2:2][C:3]([N:5]4[CH2:10][CH2:9][N:8]([C:11]5[CH:16]=[CH:15][C:14]([C:17]([OH:26])([C:22]([F:25])([F:23])[F:24])[C:18]([F:21])([F:19])[F:20])=[CH:13][C:12]=5[CH2:30][CH2:31][CH3:32])[CH2:7][C@H:6]4[CH3:33])=[O:4])[C:45]3=[O:50])[CH:42]=[CH:43][C:35]1=2
Reactant: CC1(c2ccc3c(c2)OCCO3)NC(=O)NC1=O
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)[C@H](C)C1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)OCCO4)C2=O)[C@H](C)C1

Procedure:
(R)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-2-methylpiperazin-1-yl)ethanone and 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]([C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:13][CH:14]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[K+]>CO.O>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[N:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]3=[CH:14][N:13]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cccn2c(-c3ccc(F)cc3)ncc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccn2c(-c3ccc(F)cc3)ncc12
Temperature: 25 °C

Procedure:
To a solution of 3-(4-fluorophenyl)-imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester (290 mg, 1.0 mmol) in methanol (20 mL) is added a solution of 85% potassium hydroxide pellets (0.300 g, 3.92 mmol) in water (5.0 mL). The reaction mixture is warmed at reflux for 5 minutes, cooled to room temperature and concentrated in vacuo to remove excess methanol. The mixture is acidified to pH 4 with 1 N aqueous HCl and the resulting precipitate is collected by filtration, washed with water and dried to afford the title product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:9][C:10]1[C:11]([NH:16][C:17]([NH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[S:18])=[N:12][CH:13]=[CH:14][CH:15]=1>>[OH:9][C:10]1[C:11]([NH:16][C:17]([NH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[S:18])=[N:12][CH:13]=[CH:14][CH:15]=1.[NH2:16][C:11]1[N:1]=[C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]2[N:12]=1
Reactant: Nc1ncccc1O
Agent: CCOC(=O)NC(=S)Nc1ncccc1O
Product: Nc1nc2c(O)cccn2n1

Procedure:
260 a)N-(3-Hydroxy-2-pyridinyl)-N′-carboethoxy-thiourea was prepared from 2-amino-pyridin-3-ol (4.00 g, 0.0363 mol) in a manner analogous to Example 2a. The product of the reaction was isolated as a yellow solid. 260 b) 2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-ol was prepared from N-(3-hydroxy-2-pyridinyl)-N′-carboethoxy-thiourea (1.8 g, 5.9 mmol) in a manner analogous to Example 2b. Product was isolated as a beige solid (3.17 g, 58%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.18 (bs, 1H), 8.02 (dd, J=6.41 Hz, 1.2 Hz, 1H), 6.71-6.64 (m, 2H), 5.79 (bs, 2H). MS=151.0 (MH)+. 260 c) 2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-ol (0.200 g, 1.33 mmol) was suspended in acetone (1.9 mL). 1-(bromomethyl)-3-chloro-benzene (0.184 mL, 1.40 mmol) and potassium carbonate (193 mg, 1.40 mmol) were added and the reaction mixture was heated to 80° C. for 1 hour. Reaction mixture was cooled to room temperature, diluted with water, extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated. Resulting oil was taken up in dichloromethane and purified via chromatography (silica gel 0-100% ethyl acetate in hexanes). 8-(3-Chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was isolated as an oil which solidified on standing. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.17 (d, J=6.6 Hz, 1H), 7.56 (s, 1H), 7.44-7.42 (m, 3H), 6.99 (d, J=7.9 Hz, 1H), 6.79-6.75 (m, 1H), 5.94 (bs, 2H), 5.30 (s, 2H). MS=275 (MH)+. 260 d) [8-(3-Chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(3-chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (95.0 mg, 0.346 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (102 mg, 0.399 mmol in a manner analogous to Example 2d. Product was isolated as a pale orange solid (0.073 g, 47%). MP=135-138° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.33 (s, 1H), 8.37 (d, J=6.7 Hz, 1H), 7.58 (s, 1H), 7.51-7.44 (m, 5H), 7.09 (d, J=7.9 Hz, 1H), 6.91-6.86 (m, 3H), 5.35 (s, 2H), 3.04-3.01 (m, 4H), 2.46-2.44 (m, 4H), 2.22 (s, 3H). MS=449 (MH)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Br[CH:7]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[C:8](=[O:14])[C:9]([O:12][CH3:13])([CH3:11])[CH3:10].N12CCCCC1C=NCCC2>CC(C)=O>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[O:15][CH:7]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[C:8](=[O:14])[C:9]([O:12][CH3:13])([CH3:11])[CH3:10]
Reactant: COC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1Cl
Reactant: c1nc[nH]n1
Agent: C1=NCCCN2CCCCC12
Solvent: CC(C)=O
Product: COC(C)(C)C(=O)C(Oc1ccc(Cl)cc1Cl)n1cncn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
1H-1,2,4-Triazole (2.83 g, 0.041 mole) was added to a stirred solution of 14.6 g (0.041 mole) of 1-bromo-1-(2,4-dichlorophenoxy)-3-methoxy-3-methyl-2-butanone in 100 ml. of acetone at -10° C. To the resulting mixture, 6.09 g (0.041 mole) of 1,5-diazabicyclo[5.4.0]-undec-5-ene was added at a rate to maintain the temperature of the mixture below -5° C. After the addition was complete, the mixture was stirred an additional 30 minutes at 0° C. Then the solvent was evaporated off, the residue taken up in 300 ml. diethyl ether, and the resulting mixture extracted with water. The organic phase was dried using MgSO4 and the solvent evaporated. The residual yellow oil (13 g) was stirred for several minutes with boiling hexane, then filtered to remove insoluble material. Upon cooling the filtrate, 9.0 g (63.8% yield) of 1-(2,4-dichlorophenoxy)-1-(1H- 1,2,4-triazol-1-yl)-3-methoxy-3-methyl-2-butanone, m.p. 53°-54° C., was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:23]1([NH:26][C:27]([C:29]2[S:42][C:32]3=[N:33][C:34](S(C)=O)=[C:35]([Cl:38])[C:36]([CH3:37])=[C:31]3[C:30]=2[NH2:43])=[O:28])[CH2:25][CH2:24]1>C1COCC1>[CH:23]1([NH:26][C:27]([C:29]2[S:42][C:32]3=[N:33][C:34]([O:1][CH2:2][CH2:3][NH:4][C:5]([C:6]4[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=4)=[O:12])=[C:35]([Cl:38])[C:36]([CH3:37])=[C:31]3[C:30]=2[NH2:43])=[O:28])[CH2:25][CH2:24]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: O=C(NCCO)c1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCNC(=O)c2ccncc2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 10.3 %

Procedure:
To a solution of N-(2-hydroxyethyl)-isonicotinamide (0.831 g, 5.00 mmol) in THF (2.5 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl) amide (1.0 M in hexanes)(2.50 ml, 2.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 80° C. in a sealed tube for 2 hours, cooled to room temperature, and then quenched by the addition of water (15 ml). The mixture is diluted to 100 ml with water and then cooled to 0° C. and stirred. A yellow precipitate is formed. This solid is collected by filtration, slurried in EtOAc, and filtered again to give a yellow solid which is placed in the vacuum oven to dry (50° C. for 3 hours). This affords the title compound as a yellow solid (0.046 g, 10%). Mass (m/z): 446.3 (M++1), 444.2 (M+−1).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[C@@H:17]([CH3:18])[CH2:16][CH2:15][C@H:14]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]3[CH2:30][O:31][C:32]4[CH:57]=[C:56]5[C:35]([CH2:36][CH2:37][C:38]6[N:42]=[C:41]([C@@H:43]7[CH2:47][CH2:46][C@H:45]([CH3:48])[N:44]7[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[NH:40][C:39]=65)=[CH:34][C:33]=4[C:27]3=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:12])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4]>ClCCl.O=[Mn]=O>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[C@@H:17]([CH3:18])[CH2:16][CH2:15][C@H:14]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]3[CH2:30][O:31][C:32]4[CH:57]=[C:56]5[C:35]([CH:36]=[CH:37][C:38]6[N:42]=[C:41]([C@@H:43]7[CH2:47][CH2:46][C@H:45]([CH3:48])[N:44]7[C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])[NH:40][C:39]=65)=[CH:34][C:33]=4[C:27]3=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:12])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@@H](C)CC[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(cc2-3)CCc2nc([C@@H]3CC[C@H](C)N3C(=O)OC(C)(C)C)[nH]c2-4)[nH]1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@@H](C)CC[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6CC[C@H](C)N6C(=O)OC(C)(C)C)[nH]c54)cc2-3)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.5 %

Procedure:
To a solution of tert-butyl (2S,5S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-isoleucyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-5-methylpyrrolidine-1-carboxylate (2.77 g, 3.5 mmol) in dichloromethane (25 mL) was added MnO2 (9.00 g, 103 mmol). The resulting slurry was stirred at room temperature for 20 h. The solution was diluted with dichloromethane, filtered through celite, and concentrated. The crude oil was purified by column chromatography (SiO2, 0-5-10% EtOAc/MeOH) to provide tert-butyl (2S,5S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-isoleucyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-5-methylpyrrolidine-1-carboxylate (1.10 g, 40% over 2 steps) as a brown foam. LCMS-ESI+: calc'd for C44H53N7O6: 775.41 (M+). Found: 776.37 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:21][OH:22])=[N:14][C:15]=1[O:16][CH2:17][CH:18]([CH3:20])[CH3:19].[CH:23]1([CH:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34](O)[CH:33]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:25][CH2:24]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH:23]1([CH:26]([C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([O:22][CH2:21][C:13]3[CH:12]=[CH:11][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:15]([O:16][CH2:17][CH:18]([CH3:19])[CH3:20])[N:14]=3)[CH:37]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:25]1
Reactant: COC(=O)CC(c1cccc(O)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2OCC(C)C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)CC(c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)c1)C1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
Under a nitrogen atmosphere, to a solution of (5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methanol (100 mg) and methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propanoate (72 mg) in toluene (4.7 mL) were added 1,1′-(azodicarbonyl)dipiperidine (132 mg) and tributylphosphine (131 μL), and the mixture was stirred at room temperature for 14 hr. To the reaction mixture was added hexane/ethyl acetate (1:1), and the resulting precipitate was removed by filtration. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (131 mg) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:31]=[CH:30][C:25]([C:26](=[O:29])[CH2:27]Br)=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:27][C:26]([C:25]2[CH:30]=[CH:31][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:29])[CH:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:3]1
Reactant: CN1CCNC(c2ccccc2)C1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CCN(CC(=O)c2ccc(Cl)cc2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 95 %

Procedure:
To a stirred mixture of 14.0 g (0.08 mol) of 1-methyl-3-phenylpiperazine and 20 g (0.2 mol) of triethylamine in 160 ml of tetrahydrofuran was added dropwise a solution of 18.2 g (0.08 mol) of 4-chlorophenacyl bromide in 55 ml of chloroform. The resulting mixture was stirred at ambient temperature for 3.5 hours, poured into 50% aqueous sodium bicarbonate and extracted with chloroform. The organic extracts were combined, washed with water and saturated sodium chloride and dried over sodium sulfate. The filtrate was concentrated to dryness to give 25 g of crude 1-methyl-3-phenyl-4-(4-chlorophenacyl) piperazine. This material was used as such in the next step of the process.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH3:16])=[CH:4][CH:3]=1.[CH2:19]=[O:20]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:16][CH2:19][OH:20])=[CH:17][CH:18]=1
Reactant: Cc1ccc(Cn2c(C)nc3ccccc32)cc1
Reactant: C=O
Solvent: c1ccncc1
Product: Cc1ccc(Cn2c(CCO)nc3ccccc32)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Next, 1-(4-methylbenzyl)-2-(2-hydroxyethyl)benzimidazole was prepared. A mixture of 1-(4-methylbenzyl)-2-methylbenzimidazole (5.1 g, 21 mmol), formaldehyde (82 mmol as 6.7 g of the 37% aqueous solution), and 6.5 g of pyridine were stirred magnetically and heated to 90° C. After 24 h, the mixture was cooled to ambient and concentrated at reduced pressure to deposit a tan oil. The product was purified by flash chromatography (silica gel, 75% dichloromcthane/25% ether), followed by recrystallization from a mixture of 15 mL of methanol plus 10 mL of water. The product was obtained as 1.5 g (41%) of a white solid. 1H NMR (CDCl3)δ 2.31 (s, 3H), 2.99 (t, J=5.4, 2H), 4.12 (t, J=5.4, 2H), 4.4 (br s, 1H), 5.29 (s, 2H), 6.94 (d, J=8.0, 2H), 7.10 (d, J=7.9, 2H), 7.25 (m, 3H), 7.73 (m, 1H). ES−MS m/e 267+ (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48](=[O:50])[CH3:49])=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48](=[O:50])[CH3:49])=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 48 %

Procedure:
p-Methoxyaniline (0.046 g, 0.374 mmol), triethylamine (0.038 g, 0.374 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.063 g, 0.374 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.070 g, 0.187 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.043 g, 0.0897 mmol, 48%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([S:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:5]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][NH:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([S:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:5]=1
Reactant: CNC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CNC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Yield: 126.4 %

Procedure:
A mixture of N-methyl-3-(2,4-difluorophenylthio)-4-nitrobenzamide (0.68 g), iron powder (0.68 g) and ammonium chloride (68 mg) in ethanol (8 ml) and water (4 ml) was stirred and refluxed for 2 hours. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with water, dried and evaporated to give pale yellow crystals of N-methyl-4-amino-3-(2,4-difluorophenylthio)benzamide (0.78 g).
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])[CH3:14].[OH-].[Na+].CCCCCC.C(OCC)(=O)C>CO>[C:1]1([CH:11]=[CH:14][C:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CC(=O)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: O=C(C=Cc1cccc2ccccc12)c1cccs1
Yield: 80 %

Procedure:
3.12 g(20 mmol) of 1-naphthaldehyde and 2.52 g(20 mmol) of 2-acetylthiophene were dissolved in 20 ml of methanol and 800 mg(20 mmol) of sodium hydroxide was slowly added thereto. The mixture was reacted at room temperature for 8 hours and then the solid thus produced was filtered and dried. The filtrate was adjusted to pH 4-6 using 1N hydrochloric acid solution and extracted with ethyl acetate. The organic solvent was removed under reduced pressure and the residue was subjected to column chromatography(eluent: hexane/ethyl acetate=4/1, v/v) to give 4.23 g(16 mmol, Yield 80%) of the title compound together with the filtered solid.
Reaction SMILES: [ClH:1].C(OC([N:12]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:21])[CH3:20])[CH2:14][C@H:13]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=O)C1C=CC=CC=1>>[N+:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:13]2[CH2:14][C@@H:15]([NH:18][C:19](=[O:21])[CH3:20])[CH2:16][CH2:17][NH:12]2)=[CH:28][CH:27]=1)([O-:31])=[O:30].[ClH:1]
Reactant: CC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)[C@H](Cc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Product: CC(=O)N[C@H]1CCN[C@H](Cc2ccc([N+](=O)[O-])cc2)C1
Temperature: 55 °C

Procedure:
Concentrated hydrochloric acid is added to (2R*,4S*)-4-acetylamino-2-(4-nitro-benzyl)-piperidine-1-carboxylic acid benzyl ester (2.65 g, 6.45 mmol) and the mixture is heated at 55° C. for 2 hours, the evolution of gas occurring. The reaction mixture is washed twice with hexane and concentrated by evaporation under reduced pressure using a rotary evaporator. The title compound is obtained as a hydrochloride in the form of white crystals containing 3 molecules of water of crystallisation. M.p.: >250° C. TLC: methylene chloride/methanol/conc. ammonia (90:9:1) Rf =0.29. 1H-NMR (200 MHz, D2O): δ 8.26 (d, 2H), 7.59 (d, 2H), 4.26-4.17 (m,1H), 3.90-3.72 (m, 1H), 3.40-3.02(m, 4H), 1.99 (s, 3H), 2.06-1.75 (m, 4H).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[BrH:18].C(O)(=O)C.BrBr>C(O)(=O)C>[Br:18][CH2:16][C:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=1)=[O:17]
Reactant: Br
Reactant: CCCCCCCCc1ccc(C(C)=O)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: CCCCCCCCc1ccc(C(=O)CBr)cc1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
To a solution of 4′-octylacetophenone (18′) (23.9 g) in acetic acid (100 ml) is added hydrogen bromide-acetic acid solution (25%, 34 ml) under ice-cooling, which is followed by dropwise addition of bromine (5.3 ml). The mixture is heated to 30° C. and stirred for 3 hr. The solvent is distilled away and the mixture is purified by silica gel column chromatography to give 2-bromo-4′-octylacetophenone as colorless crystals.