Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:34]3[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][CH:42]=O)=[N:38][CH:39]=3)=[N:30][CH:31]=2)=[CH:22][CH:21]=1.[CH3:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:34]3[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][CH2:42][N:48]4[CH2:49][CH2:50][CH:45]([CH3:44])[CH2:46][CH2:47]4)=[N:38][CH:39]=3)=[N:30][CH:31]=2)=[CH:22][CH:21]=1
Reactant: O=CCCc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cn1
Reactant: CC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1CCN(CCCc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
74 mg (0.35 mmol) of sodium triacetoxyborohydride and 41 μL (0.73 mmol) of HOAc were added to a solution of 100 mg (0.288 mmol) of 3-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]pyridin-2-yl}propionaldehyde and 34 μL (0.288 mmol) of 4-methylpiperidine in 6 mL of THF and the mixture was stirred for 16 hours at RT. Saturated aqueous sodium bicarbonate solution was added and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over magnesium sulfate and evaporated down in vacuo. Yield: 44 mg (35% of theoretical); C27H28ClN3 (M=429.984); calc.: molpeak (M+H)+: 430/432 (Cl); found: molpeak (M+H)+: 430/432 (Cl); HPLC-MS: 7.65 minutes (method A).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+].[CH3:17][O:18][C:19]([C:21]1([CH:24]([OH:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH2:23][O:22]1)=[O:20]>C(Cl)Cl.C(OCC)C>[CH3:17][O:18][C:19]([C:21]1([C:24](=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH2:23][O:22]1)=[O:20]
Reactant: COC(=O)C1(C(O)CCCCCOc2ccc(Cl)cc2)CO1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C1(C(=O)CCCCCOc2ccc(Cl)cc2)CO1
Reaction time: 4 h
Yield: 56.4 %

Procedure:
To a suspension of 11.6 g (54 mmol) of pyridinium chlorochromate and 4.4 g (54 mmol) of sodium acetate in 200 ml of methylene chloride is added 2.95 g (9 mmol) of 2-[6-(4-chlorophenoxy)-1-hydroxyhexyl]-2-oxiranecarboxylic acid methyl ester (isomer A) prepared according to the procedure of Example 2, part 2, at room temperature under a nitrogen atmosphere. The mixture is stirred for 4 hours, is diluted with 600 ml of ethyl ether and is filtered through Florisil. Rotoevaporation gives 2.2 g of crude product. Preparative column chromatography (silica gel:ethyl ether (3:2)) affords 1.66 g (56.4%) of the title compound: IR (film) 1746, 1719 cm-1 ; NMR (CDCl3) δ 1.49 (2H, p, J=8 Hz), 1.62-1.86 (4H, mc), 2.62 (2H, m), 3.05 (1H, d, J=6 Hz), 3.36 (1H, d, J=6 Hz), 3.86 (3H, s), 3.94 (2H, t, J=6 Hz), 6.84 (2H, d, J=8 Hz) and 7.27 (2H, d, J=8 Hz).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=O)=O.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:9][CH:10]=1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(CCOS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(CCn2ccnc2)cc1
Reaction time: 18 h
Yield: 80 %

Procedure:
A mixture of 28.9 g of 2-(4-methylphenyl)ethanol methanesulfonate, 18.6 g of 1H-imidazole, 22.7 g of potassium carbonate and 600 ml of tetrahydrofuran was stirred for 18 hours at reflux temperature. After cooling, the reaction mixture was evaporated and the residue was taken up in water and extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated and the residue was destilled (13.3 Pa; 120° C.), yielding 20.1 g (83.0%) of 1-[2-(4-methylphenyl)ethyl]-1H-imidazole (interm. 6).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[O-:21].C([O-])(O)=O.[Na+]>C(O)(CC)(C)C.CCO>[C:4]([O:3][C:1]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[O-:21])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: [O-][n+]1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCC(C)(C)O
Product: CC(C)(C)OC(=O)NCCCNc1cccc[n+]1[O-]
Reaction time: 48 h

Procedure:
A mixture of N-Boc-1,3-diaminopropane (3.48 g, 20 mmol), 2-chloropyridine N-oxide hydrochloride (3.98 g, 24 mmol), and NaHCO3 (8.40 g, 100 mmol) in tert-amyl alcohol (50 mL) is heated at reflux under argon. After 48 h, the reaction is cooled, diluted with EtOH, filtered, and concentrated. The residue is reconcentrated from toluene and chromatographed (silica gel) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C[Si](Cl)(C)C.[Br:28]Br>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([Br:28])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: BrBr
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Br)c1ccc(F)cc1

Procedure:
4-Fluorophenylacetic acid methyl ester (3.0 g, 17.6 mmol) in THF (20 mL) under nitrogen at −78° was treated with 1M lithium hexamethyldisilazide (19.4 mL, 19.4 mmol) and stirred at −78° for fifteen minutes. Trimethyl silyl chloride was added (2.23 mL, 17.6 mmol) and the reaction stirred for a further fifteen minutes. Bromine (0.9 mL, 17.6 mmol) was added and the reaction stirred again for a further fifteen minutes then quenched with water and partitioned between DCM and sodium hydrogen carbonate solution. The organic phase was separated, dried (sodium sulphate) and concentrated in vacuo. Flash chromatography (diethylether-silica) yielded the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:22])[N:4]([CH3:21])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[Cl:23]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:23][C:7]1[N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][CH:13]=2)[N:4]([CH3:21])[C:3](=[O:22])[C:2]=1[OH:1]
Reactant: Cn1c(-c2ccc(Oc3ccccc3)cc2)ncc(O)c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cn1c(-c2ccc(Oc3ccccc3)cc2)nc(Cl)c(O)c1=O
Temperature: 50 °C
Yield: 17.9 %

Procedure:
To a solution of 50 mg (0.170 mmol) 5-hydroxy-3-methyl-2-(4-phenoxyphenyl)pyrimidin-4(3H)-one in 850 μl CH2Cl2 was added 23.8 mg (0.178 mmol)N-chlorosuccinimide. The reaction mixture was heated to 50° C. for 12 h, then cooled to rt, and concentrated in vacuo. Purification by HPLC gave 10.0 mg (18% yield) of 6-chloro-5-hydroxy-3-methyl-2-(4-phenoxyphenyl)pyrimidin-4(3H)-one. 1H NMR δ (ppm)(CDC3): 7.48-7.46 (2 H, m), 7.41-7.38 (2 H, m), 7.19 (1 H, d, 3=7.56 Hz), 7.09-7.05 (4 H, m), 6.43 (1 H, bs), 3.56 (3 H, s). FIRMS (ESI positive) calc (M+H)+=329.0687. Found 329.0693.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[NH:24][CH2:23][CH2:22][CH2:21]2>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:15])[CH2:21][CH2:22][CH2:23]1)=[O:14]
Reactant: Cc1cccc2c1NCCC2
Reactant: O=C(O)CSc1nc2ccccc2s1
Product: Cc1cccc2c1N(C(=O)CSc1nc3ccccc3s1)CCC2
Yield: 39 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 8-methyl-1,2,3,4-tetrahydroquinoline to yield 46 as a white solid (39%): MS m/z: 355 (M+H)+. Anal. Calcd. For, C19H18N2OS2: C, 64.38; H, 5.12; N, 7.90; S, 18.09. Found: C, 64.37; H, 5.02; N, 7.74; S, 18.10.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:21]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CS(C)=O>[F:9][C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=[C:2]([F:1])[C:7]=1[N:30]1[CH2:31][CH2:32][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:28][CH2:29]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(F)c(N2CCC(c3ccccc3)CC2)c(F)c1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
In a 100 mL round-bottom flask was mixed 3,4,5-trifluoronitrobenzene (1.751 mL, 15 mmol) and potassium phosphate, dibasic (5.23 g, 30.0 mmol) in DMSO (15.00 mL) to give a yellow suspension. 4-Phenylpiperidine (2.419 g, 15.00 mmol) was added portion-wise as a solid over 10 minutes to produce a deeper yellow suspension and a mild exotherm. The mixture was stirred for 1 hour and partitioned between EtOAc and water. The EtOAc layer was washed 2× by 50 mL each with water and brine, dried (Na2SO4), filtered and concentrated to give the title compound as a yellow solid (4.53 g, 95% yield).
Reaction SMILES: C(OC1C=CC(CCCl)=C([NH:18][C:19]([C:21]2[O:22][C:23]3C=CC(N)=C[C:24]=3[CH:25]=2)=[O:20])C=1)C1C=CC=CC=1.CC[N:33]=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:25]([CH2:21][C:19]([NH2:18])=[O:20])[CH2:24][C:23]([NH2:33])=[O:22]
Reactant: Nc1ccc2oc(C(=O)Nc3cc(OCc4ccccc4)ccc3CCCl)cc2c1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CCCC(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 524.9 %

Procedure:
To the 2-(4-benzyloxy-2-(5-aminobenzofuran-2-carboxamido)phenyl)ethyl chloride (0.243 mmol) was added the N-[(N-BOC-(4-aminobutyl)-N-methylpyrrole-4-(N-methylimidazole-2-carboxamido)-2-carboxamido)]glutaramide monocarboxylic acid (0.133 g, 0.258 mmol), EDCI (0.093 g, 0.486 mmol) and 1-hydroxybenzotriazole hydrate [HOBT] (0.033 g, 0.244 mmol) which was then dissolved in DMF (15 mL). Dissolution was aided by sonication and the suspension stirred under nitrogen at room temperature for two days with the flask covered with foil. At that time, the DMF was removed via kugelrohr apparatus (0.1 mm Hg, 60° C.). The resulting oil was dissolved in CHCl3, washed with water (1×75 mL), then with brine (1×75 mL) and dried over sodium sulfate. It was then filtered and concentrated under reduced pressure to yield the product N-[(N-BOC-(4-aminobutyl)-N-methylpyrrole-4-(N-methylimidazole-2-carboxamido)-2-carboxamido)]-N-[5-(3-benzyloxy-2-(2-chloroethyl)phenyl)benzofuran-2-carboxamido)]glutarodiamide as a brown oil (0.166 g, 68% yield). Rf=0.40 (10% MeOH/CHCl3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2=[CH:17][C:18]([Cl:21])=[C:19](Cl)[C:12]3=[C:13]2[N:8]([CH:9]([CH3:23])[CH2:10][C:11]3=[O:22])[CH:7]=1)=[O:5])[CH3:2].[CH3:24][CH:25]1[CH2:30][NH:29][CH2:28][CH2:27][NH:26]1>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2=[CH:17][C:18]([Cl:21])=[C:19]([N:29]3[CH2:28][CH2:27][NH:26][CH:25]([CH3:24])[CH2:30]3)[C:12]3=[C:13]2[N:8]([CH:9]([CH3:23])[CH2:10][C:11]3=[O:22])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC1CNCCN1
Reactant: CCOC(=O)c1cn2c3c(c(Cl)c(Cl)cc3c1=O)C(=O)CC2C
Solvent: CC#N
Product: CCOC(=O)c1cn2c3c(c(N4CCNC(C)C4)c(Cl)cc3c1=O)C(=O)CC2C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
14.17 g (0.04 mole) of 8,9-dichloro-5-methyl-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid ethyl ester was suspended in 250 ml of acetonitrile, 12.02 g (0.12 mole) of 2-methylpiperazine was added thereto, and this mixture was stirred at 50°-60° C. for 3 hours. The resulting reaction solution was concentrated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography [using a chloroform-methanol mixture (with a volume ratio of 10:1) as the developing solvent]. The fraction containing the desired product was evaporated to dryness under reduced pressure and the resulting residue was recrystallized from benzene to obtain 12.75 g (76.3% yield) of 9-chloro-5-methyl-8-(3-methyl-1-piperazinyl)-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid ethyl ester in the form of yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[NH:21][C:22]([C:24]1([CH3:27])[CH2:26][O:25]1)=[O:23]>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH2:27][C:24]([OH:25])([CH3:26])[C:22]([NH:21][C:13]2[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[CH3:11])=[O:23])=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)C1(C)CO1
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)C(C)(O)COc1ccc(C#N)c(F)c1

Procedure:
3-(4-Cyano-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1c starting from 2-fluoro-4-hydroxybenzonitrile and 2-methyloxirane-2-carboxylic acid (2-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1.3% methanol). 1H NMR (400 MHz, DMSO-d6): 1.46 (3H, s), 2.37 (3H, s), 4.13 (1H, d, J=10.1 Hz), 4.37 (1H, d, J=10.1 Hz), 6.51 (1H, s), 6.95-6.98 (1H, m), 7.17-7.21 (1H, m), 7.78-7.83 (1H, m), 8.05-8.12 (2H, m), 8.18 (1H, d, J=2.3 Hz), 9.57 (1H, s).
Reaction SMILES: CN.[C:3]([O:7][C:8]([N:10]1[C@@H:14]([C@H:15]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:12][C@H:11]1[CH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:40][N:41](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.C1COCC1>[Si:23]([O:22][C@H:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:14]1[CH2:13][CH2:12][C@@H:11]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:35](=[O:36])[NH:41][CH3:40])=[CH:38][CH:39]=2)[N:10]1[C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])([C:26]([CH3:28])([CH3:29])[CH3:27])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.6 %

Procedure:
Methylamine (5.71 mL of a 2M THF solution, 11.4 mmol) was added to a stirred, room temperature solution of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (2.00 g, 3.80 mmol), HATU (1.736 g, 4.56 mmol, 1.2 equivalents) and DIPEA (3.32 mL, 19.0 mmol, 5 equivalents) in DMF (7.8 mL). The reaction was stirred at room temperature for 12 hours, after which the mixture was diluted with EtOAc and partitioned with water. The aqueous layer was extracted with EtOAc (3×), and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by normal phase flash chromatography using silica gel (0-50% hexanes/ethyl acetate). The product fractions were collected and concentrated in vacuo to afford the title compound as a white solid (1.20 g, 59%). LC-MS=561.2 (M+Na)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:18]1([CH2:21][CH2:22][NH:23][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:4][CH2:3]2)[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: NCCc1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc(CCNC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
2 g of p-toluenesulfonic acid was added to a solution of 230 g of 4-oxo-1-benzylpiperidine and 221 g of 2-phenethylamine in 1 liter of toluene. The mixture was refluxed for 1 hour while removing the generated water using a Dean-Stark trap. The reaction mixture was concentrated under reduced pressure. To the residue was added 1 liter of ethanol. To the mixture being ice-cooled was slowly added 22 g of sodium boron hydride. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was ice-cooled, and then was made acidic by slow addition of concentrated hydrochloric acid. The resulting crystals were collected by filtration. The crystals were dissolved in water. The solution was made alkaline with a 25% aqueous sodium hydroxide solution and then extracted with methylene chloride. The extract was water-washed, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 222.2 g of 4-(2-phenylethylamino)-1-benzylpiperidine as a light yellow oily substance.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:16]=[C:15]2[C:8]([N:9]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=[C:11]2[CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH2:2][CH3:3].[F:27][C:28]([F:42])([CH:39]([F:41])[F:40])[CH2:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH:34]=O.[BH4-].[Na+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCO.C(Cl)(Cl)Cl.CO>[CH2:1]([O:4][C:5]1[CH:16]=[C:15]2[C:8](=[CH:7][CH:6]=1)[NH:9][CH:10]=[C:11]2[CH2:12][CH2:13][NH:14][CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH2:29][C:28]([F:27])([F:42])[CH:39]([F:40])[F:41])[CH:32]=1)[CH2:2][CH3:3]
Reactant: O=Cc1cccc(OCC(F)(F)C(F)F)c1
Reactant: CCCOc1ccc2c(c1)c(CCN)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Agent: [F-]
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCOc1ccc2[nH]cc(CCNCc3cccc(OCC(F)(F)C(F)F)c3)c2c1
Temperature: 0 °C

Procedure:
Combine 2-(5-propoxy-1-triisopropylsilanyltryptamine (138 mg, 0.37 mmol), 3-(2,2,3,3-tetrafluoropropoxy)benzaldehyde (87 mg, 1.8 mmol) and 1 g 3 Å molecular sieves in 25 mL EtOH and reflux overnight. Decant the liquid into a separate flask, cool to 0° C. and treat with 42 mg (1.1 mmol) NaBH4. Stir the reaction at ambient temperature for 1 hour, treat with 0.74 mmol of tetrabutylammonium fluoride and stir for an additional hour. Concentrate under vacuum to give a residue. Chromatograph the residue on silica gel eluting with 10% MeOH in CHCl3 to give the title compound. Treat the title compound with 10 mL EtOH with 0.25 mL 5 N HCl and 40 mL toluene then concentrating gives the hydrochloride of the title compound: ISMS 439 (M+1); 1H NMR (Free base-CDCl3) 7.89 (bs, 1H), 7.23-7.21 (m, 1H), 7.03-7.02 (d, 1H), 6.99-6.98 (d, 1H), 6.94-6.92 (m, 1H), 6.89-6.83 (m, 2H), 6.78-6.75 (m, 1H), 6.18-5.90 (m, 1H), 4.29-4.23 (m, 2H), 3.95-3.91 (m, 2H), 3.78 (s, 2H), 2.95 (s, 4H), 1.85-1.75 (m, 2H), 1.51 (bs, 1H), 1.06-1.03 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[N:17][C:18]1[CH:22]=[CH:21][NH:20][N:19]=1)[CH:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl>O>[CH2:1]([O:8][CH2:9][C:10]1[NH:17][C:18]2[N:19]([N:20]=[CH:21][CH:22]=2)[C:12](=[O:16])[C:11]=1[CH2:15][CH2:14][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OCCC1C(COCc1ccccc1)=Nc1cc[nH]n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1c(CCO)c(COCc2ccccc2)[nH]c2ccnn12
Reaction time: 0.67 h
Yield: 100 %

Procedure:
To 1.18 g of 3-{[2-(benzyloxy)-1-(tetrahydro-2-oxo-3-furyl)ethylidene]amino}pyrazole were added 600 μl of triethylamine and 2.0 ml of water, and the mixture was stirred for 40 minutes while heating under reflux. After the reaction system was allowed to coom to room temperature, 1N hydrochloric acid was added to adjust the pH of the reaction mixture to 4. After the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 1.18 g (yield: quantitative) of the intended product.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][N:27](S(C3C=CC(C)=CC=3)(=O)=O)[CH:26]=2)=[O:24])[CH:7]=[N:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:12][CH:11]=1.Cl>CO.O1CCCC1>[CH3:3][C:4]1[CH:5]=[C:6]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][NH:27][CH:26]=2)=[O:24])[CH:7]=[N:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)Nc3cnc(C4=CCC(N5CCOCC5)CC4)c(C)c3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)c2cc[nH]c2)cnc1C1=CCC(N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.4 %

Procedure:
1N Aqueous solution of sodium hydroxide (20 ml) was added to a suspension of N-{5-methyl-6-[4-(morpholin-4-yl)cyclohex-1-en-1-yl]pyridin-3-yl}-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carboxamide (2.07 g) in methanol (20 ml) and tetrahydrofuran (30 ml), and stirred at room temperature for 2.5 hours. 1N Hydrochloric acid aqueous solution was added at 0° C. to the reaction solution and concentrated in vacuo. The precipitated solid was washed with ethanol to give N-{5-methyl-6-[4-(morpholin-4-yl)cyclohex-1-en-1-yl]pyridin-3-yl}-1H-pyrrole-3-carboxamide (1.2 g) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:13]2[N:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([O-])=O>[Pd].CCO>[NH2:1][C:4]1[C:5]([C:13]2[N:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1
Reactant: CCOC(=O)Cn1c(-c2cc3c(cc2[N+](=O)[O-])OCO3)nc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cn1c(-c2cc3c(cc2N)OCO3)nc2ccccc21
Reaction time: 3.5 h
Yield: 10.1 %

Procedure:
A suspension of 1.0 g (2.71 mmol) of the ethyl 2-(6-nitro-1,3-benzodioxol-5-yl)-1H-benzimidazole-1-acetate from EXAMPLE 10 and 0.5 g of 10% palladium on carbon in 20 mL of absolute EtOH was agitated on a Parr apparatus under a hydrogen atmosphere at 32 psi for 3.5 h. The mixture was filtered through a pad of celite and concentrated to give the crude product mixture. Purification by silica gel chromatography gave 93 mg (9%) of ethyl 2-(6-amino-1,3-benzodioxol-5-yl)-1H-benzimidazole-1-acetate as a solid: mp 284.2-287° C.; 1H NMR (CDCl3) δ 1.29 (t, J=7.2 Hz, 3H), 4.27 (q, J=7.1 Hz, 2H), 4.85 (s, 2H), 5.93 (s, 2H), 6.38 (s, 1H), 6.79 (s, 1H), 7.26-7.40 (m, 3H), 7.73-7.83 (m, 1H); HRMS (FAB) Calc'd for M+H: 340.1297, found: 340.1255.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[NH:5][CH:6]=1.Br[CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:5]([CH:6]=1)[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2
Reactant: O=Cc1cc(Br)c[nH]1
Reactant: CCOC(=O)/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn2cc(Br)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
A mixture of 4-bromo-1H-pyrrole-2-carbaldehyde (1.00 g, 5.75 mmol), (E)-ethyl 4-bromobut-2-enoate (1.555 mL, 11.49 mmol), and potassium carbonate (1.74 g, 12.6 mmol) in DMF (20 mL) was stirred overnight at room temperature under a nitrogen atmosphere. Following reaction, the solution was extracted with ethyl acetate (2×100 mL) and water (100 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and purified via silica gel flash chromatography, eluting with a gradient of 10-30% EtOAc and hexane to give, upon removal of solvent, the title compound as a purple solid (350 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (t, J=7.40 Hz, 3H), 4.31 (q, J=5.40 Hz, 2H), 6.92 (s, 1H), 7.02-7.03 (m, 1H), 7.93 (s, 1H), 8.13 (s, 1H), 8.28-8.29 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C11H10BrNO2, 268. found, 268.