Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(/[CH:4]=[C:5]1\[CH2:6][CH2:7][CH2:8][C:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][N:11]([CH3:19])[C:10]=2[C:20]\1=O)C.CN(C=O)C.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH2:37])=[NH:36])=[C:30]([O:38][CH3:39])[CH:29]=1>>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]2[N:37]=[C:20]3[C:10]4[N:11]([CH3:19])[N:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]=4[CH2:8][CH2:7][CH2:6][C:5]3=[CH:4][N:36]=2)=[C:30]([O:38][CH3:39])[CH:29]=1
Reactant: COc1cc(Br)ccc1NC(=N)N
Reactant: CCOC(=O)c1nn(C)c2c1CCC/C(=C\N(C)C)C2=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(Br)cc3OC)nc1-2
Temperature: 120 °C
Reaction time: 4 h
Yield: 82.3 %

Procedure:
To a suspension of ethyl (7E)-7-[(dimethylamino)methylidene]-1-methyl-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxylate 1.72 g (5.92 mmol) in 20 mL of DMF N-(4-Bromo-2-methoxy-phenyl)-guanidine 1.60 g (6.511 mmol) was added. The mixture was stirred at 120° C. for 4 h. The resulting mixture was cooled at room temperature and dried to dryness. The crude solid was purified by flash chromatography on silica gel (eluant: AcOEt/hexane 4/6) to afford 2.30 g (82% yield) of the title compound as a yellow solid.
Reaction SMILES: [CH:1]1[C:10]2[C@@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(Cl)(Cl)Cl>[CH:1]1[C:10]2[C@@H:11]3[CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[O:22])[CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=C(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCC3)c1ccc(F)cc1
Temperature: 100 °C
Yield: 58.1 %

Procedure:
To a solution of (7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.21 g, 1.0 mmol)) in 1,4-dioxane (7.0 mL) were added 4-chloro-4′-fluorobutyrophenone (0.40 g, 2.0 mmol), KI (catalytic amount) and K2CO3 (0.28 g, 2.0 mmol). The reaction mixture was heated at 100° C. for 48 h. The reaction mixture was cooled to 20° C. then diluted with CHCl3. The solution was filtered to remove excess K2CO3 and the filtrate was concentrated in vacuo and chromatographed (silica gel, CHCl3:MeOH 98:2) to give the title compound (0.22 g, 58%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ1.75-2.20 (m, 7H), 2.20-2.35 (m, 1H), 2.35-2.48 (m, 2H), 2.48-2.60 (m, 1H), 2.60-2.78 (m, 3H), 2.78-2.90 (m, 1H), 2.99 (t, J=7.2 Hz, 2H), 3.05-3.15 (m, 1H), 3.18-3.32 (m, 2H), 6.62 (t, J=7.3 Hz, 1H), 6.86 (d, J=7.3 Hz, 1H), 7.12 (t, J=8.6 Hz, 2H), 7.90-8.08 (m, 2H) ppm.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][N:5]([C@H:15]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:16]([O:18]CC2C=CC=CC=2)=[O:17])[CH2:4]1)=O.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:35][CH:34]=1.Cl>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:43][CH2:44][N:45]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=4)[CH2:6][N:5]([C@H:15]([CH2:26][CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)[C:16]([OH:18])=[O:17])[CH2:4]3)[CH2:46][CH2:47]2)=[CH:37][CH:38]=1
Reactant: O=C[C@H]1CN([C@H](CC2CCCC2)C(=O)OCc2ccccc2)C[C@@H]1c1cccc(F)c1
Reactant: Fc1ccc(CCCC2CCNCC2)cc1
Agent: Cl
Product: O=C(O)[C@@H](CC1CCCC1)N1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2cccc(F)c2)C1
Yield: 102.7 %

Procedure:
The title compound was prepared from 20 mg (0.047 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-cyclopentylpropanoic acid, benzyl ester (from EXAMPLE 20, Step K) and 13 mg of 4-(3-(4-fluorophenyl)propyl)piperidine.HCl (from EXAMPLE 96, Step B) using a procedure analogous to that described in EXAMPLE 1, Step J to provide 26 mg (89%) of the title compound: RF: 0.20 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 1.01-1.83 (m, 22H), 2.21-2.88 (m, 10H), 3.12-3.19 (m, 2H), 3.37 (m, 1H), 5.16 (ABq, J=12.1 Hz, 2H), 6.83-7.39 (m, 13H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:9]1(O)[CH2:14][CH2:13]C[CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[C:1]([O:7][CH:8]1[CH2:13][CH2:14][CH2:9][CH2:10][CH2:11]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: COC(=O)CC(C)=O
Reactant: OC1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OC1CCCCC1
Yield: 84 %

Procedure:
A mixture of 1 equivalent of methyl acetoacetate, 1 equivalent of cyclohexanol and 100 mg of sulfated tin oxide catalyst prepared according to example 1 above, in 20 ml of toluene was heated to 110° C. in a two necked round bottom flask provided with a distillation condenser to remove methanol. The reaction was monitored by thin layer chromatography (TLC). After completion of the reaction (about 6 hours), the catalyst was filtered and the filtrate was concentrated and chromatographed on a silica gel column (95% petroleum ether and 5% ethyl acetate) to afford cyclohexyl acetoacetate as a viscous colorless liquid in 84% yield.
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]([CH3:10])[C:7](Cl)=[O:8])(=[O:4])=[O:3].[C:11]([OH:14])(=[O:13])[CH3:12]>>[CH3:1][S:2]([O:5][CH:6]([CH3:10])[C:7]([O:14][C:11](=[O:13])[CH3:12])=[O:8])(=[O:4])=[O:3]
Reactant: CC(=O)O
Reactant: CC(OS(C)(=O)=O)C(=O)Cl
Product: CC(=O)OC(=O)C(C)OS(C)(=O)=O

Procedure:
The acyl halides can be converted to the symmetrical or mixed acid anhydrides corresponding to the compounds of formula II when Y is acyloxy, by contacting the acyl halide with an appropriate acid. For example, 2-methanesulfonyloxypropionyl chloride is allowed to react with acetic acid to afford the mixed anhydride, acetic 2-methanesulfonyloxypropionic anhydride. Additionally, for example, 2-methanesulfonyloxypropionyl chloride is allowed to react with 2-methanesulfonylotypropionic acid to afford bis(2-methanesulfonyloxypropionic)anhydride, a symmetrical anhydride. Alternatively, the acid precursors of the acyl halides of formula II can be contacted with an appropriate acyl halide to afford the symmetrical or mixed acid anhydrides. For example, 2-methanesulfonyloxypropionic acid is allowed to react with acetyl chloride to afford the mixed anhydride, acetic 2-methanesulfonyloxypropionic anhydride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:2]1.[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][CH2:29][C:30](O)=[O:31])[CH:24]=[C:25]([F:27])[CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][CH2:29][C:30]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]3[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]4[NH:17][CH:18]=[CH:19][C:9]=34)[CH2:2]2)=[O:31])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: O=C(O)CNc1cc(F)cc(Cl)c1
Reactant: NC(=O)c1cnc2[nH]ccc2c1NC1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc2[nH]ccc2c1NC1CCCN(C(=O)CNc2cc(F)cc(Cl)c2)C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a solution of 4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (132 mg, 0.51 mmol, 1.0 eq) and 2-((3-chloro-5-fluorophenyl)amino)acetic acid (124 mg, 0.61 mmol, 1.2 eq) in DMF (3 mL) was added HBTU (387 mg, 1.02 mmol, 2.0 eq) and DIPEA (1 mL). The resulting mixture was stirred at 80° C. for 16 h and the solvent was concentrated in vacuo to afford a residue which was purified by prep-HPLC (MeOH/H2O with 0.05% TFA as mobile phase) to give afford the title compound as a light brown solid (110 mg, yield: 50%). 1H NMR (400 MHz, CD3OD) δ: 8.23 (s, 1H), 7.09-7.02 (m, 1H), 6.66-6.61 (m, 1H), 6.42-5.94 (m, 3H), 4.35-4.10 (m, 1H), 4.08-3.91 (m, 2H), 3.79-3.74 (m, 1H), 3.65-3.53 (m, 2H), 3.43-3.40 (m, 2H), 2.06-2.04 (m, 1H), 1.82-1.73 (m, 2H), 1.62-1.59 (m, 1H). ESI-MS (M+H)+: 445.15.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)C1C=CC=CC=1.[C:30]([O:35][CH3:36])(=[O:34])[C:31]([CH3:33])=[CH2:32]>>[CH3:36][O:35][C:30](=[O:34])[CH:31]([CH3:33])[CH2:32][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:29])[NH:19][S:20]2(=[O:21])=[O:22])=[C:9]([OH:8])[CH:14]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=C(C)C(=O)OC
Product: COC(=O)C(C)Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodo-phenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and methyl methacrylate analogous to Example 133. (M+1)+=343. HPLC retention time=0.99 min (Method 14).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:6]([N+:15]([O-])=O)=[CH:5][CH:4]=1.C1CCCCC=1>[Pd].C(O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[C:6]([NH2:15])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(N2CCOCC2)n1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COc1ccc(N)c(N2CCOCC2)n1

Procedure:
6.19 g (0.026 mol) of the product 4-(6-methoxy-3-nitropyrid-2-yl)morpholine synthesized according to the above procedure, 50 ml of ethanol, 20 ml of cyclohexene and 2 g of palladium-on-charcoal were placed in a fully equipped round-bottomed flask.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:16][CH:15]=2)=[CH:11][C:6]([C:7](OC)=[O:8])=[C:5]([CH:26]=O)[CH:4]=1)[CH3:2].[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][NH2:34].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:6](=[CH:11][C:12]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:16][CH:15]=1)[C:7](=[O:8])[N:34]([CH2:33][CH:29]1[CH2:30][CH2:31][CH2:32][O:28]1)[CH2:26]2)[CH3:2]
Reactant: CCc1cc(C=O)c(C(=O)OC)cc1Cc1ccc(-c2ccn(C)n2)cc1
Reactant: NCC1CCCO1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCc1cc2c(cc1Cc1ccc(-c3ccn(C)n3)cc1)C(=O)N(CC1CCCO1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
A mixture of methyl 4-ethyl-2-formyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)benzoate (0.11 g), (tetrahydrofuran-2-yl)methanamine (0.03 g) and anhydrous magnesium sulfate (0.07 g) in THF (3.00 mL) was stirred overnight at room temperature. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with acetic acid (3.00 mL), sodium triacetoxyborohydride (0.09 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (0.03 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[CH2:13]O.P(Br)(Br)[Br:17]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[CH2:13][Br:17]
Reactant: COC(=O)COc1ccc(Cl)cc1CO
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: COC(=O)COc1ccc(Cl)cc1CBr
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.) solution of (4-chloro-2-hydroxymethyl-phenoxy)-acetic acid methyl ester (5 g, 0.022 mmol) in DCM (50 mL) under an inert atmosphere of nitrogen is added phosphorus tribromide (1.03 mL, 0.011 mol) and the mixture is stirred at 0° C. for 90 minutes. The reaction mixture is diluted with water (15 mL) and allowed to warm to RT. The mixture is then washed with water (2×25 mL) and the organic portion is separated, washed with brine, dried (MgSO4) and concentrated in vacuo to yield the titled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH2:14])[CH2:5][CH2:4]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20](Cl)=[O:21]>>[CH3:1][O:2][CH:3]1[CH2:4][CH2:5][N:6]([C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:17]([O:16][CH3:15])[CH:18]=2)[CH2:7][CH2:8]1
Reactant: COC1CCN([C@@H]2CCC[C@H]2N)CC1
Reactant: COc1cc(C(=O)Cl)ccc1Cl
Product: COc1cc(C(=O)N[C@@H]2CCC[C@H]2N2CCC(OC)CC2)ccc1Cl

Procedure:
Following the procedure of Example 1b, using trans-N-[2-(4-methoxy-1-piperidinyl)cyclopentyl]amine and 3-methoxy-4-chlorobenzoyl chloride there is obtained as product trans-N-[2-(4-methoxy-1-piperidinyl)cyclopentyl]-3-methoxy-4-chlorobenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.CON(C)[C:13]([C:15]1[CH:19]=[CH:18][N:17]([S:20](=[O:25])(=[O:24])[N:21]([CH3:23])[CH3:22])[N:16]=1)=[O:14]>C1COCC1>[CH3:22][N:21]([CH3:23])[S:20]([N:17]1[CH:18]=[CH:19][C:15]([C:13](=[O:14])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:16]1)(=[O:24])=[O:25]
Reactant: CON(C)C(=O)c1ccn(S(=O)(=O)N(C)C)n1
Reactant: Clc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1ccc(C(=O)c2cccc(Cl)c2)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A solution of 3-chlorophenylmagnesium bromide (0.5 M in THF) (15.89 mL, 7.95 mmol) was added to a solution of 1-dimethylsulfamoyl-1H-pyrazole-3-carboxylic acid methoxy-methyl-amide (1.60 g, 6.11 mmol) in THF (20 mL) at −78° C. and under nitrogen. The mixture was stirred at −78° C. for 1 hour and then further stirred at room temperature for 5 hours. The mixture was quenched with NH4Cl (aq. sat. solution) and the product was extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 10/90). The desired fractions were collected and concentrated in vacuo to yield 3-(3-chloro-benzoyl)-1H-pyrazole-1-sulfonic acid dimethylamide (1.68 g, 88% yield) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:35][CH3:36])=[C:18]([CH:24]4[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[C:19]([F:23])=[C:20]([Cl:22])[CH:21]=3)[CH3:15])[N:9]=[C:10]([CH:11]([F:13])[F:12])[C:3]=12.[ClH:37].O1CCOCC1>C(Cl)Cl>[ClH:22].[ClH:37].[NH:26]1[CH2:27][CH:24]([C:18]2[C:17]([O:35][CH3:36])=[C:16]([CH:14]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([CH:11]([F:13])[F:12])=[N:9]3)[CH3:15])[CH:21]=[C:20]([Cl:22])[C:19]=2[F:23])[CH2:25]1
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Yield: 89 %

Procedure:
tert-Butyl 3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate (0.21 g, 0.40 mmol) was treated with 4.0 M hydrogen chloride in dioxane (1 mL, 4 mmol) in methylene chloride (4 mL) at room temperature for 2 h. The mixture was concentrated to give the desired product (0.177 g, 89%). LCMS calculated for C18H19ClF3N6O (M+H)+: m/z=427.1; Found: 427.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([NH2:26])[C:20]=2[N:19]=[CH:18]1>CC(O)=O.O>[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([N:26]3[CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:10](=[O:16])[CH:11]=[C:12]3[CH3:15])[C:20]=2[N:19]=[CH:18]1
Reactant: Nc1cccc2[nH]cnc12
Reactant: Cc1cc(=O)c(OCc2ccccc2)co1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(=O)c(OCc2ccccc2)cn1-c1cccc2[nH]cnc12
Temperature: 140 °C

Procedure:
5-(Benzyloxy)-2-methyl-4H-pyran-4-one (450 mg, 2.081 mmol) and 1H-benzimidazol-4-amine (279 mg, 2.095 mmol) were taken up in 40% HOAc/H2O (10 ml) in a microwave vial. The vial was sealed and the mixture heated to 140° C. for 30 min by microwave irradiation. The reaction was incomplete by LC/MS. The mixture was heated to 200° C. for 30 min by microwave irradiation. The reaction was incomplete by LC/MS. The mixture was heated to 170° C. for 1 h by microwave irradiation. The mixture was concentrated. The crude material was purified by preparative reversed-phase HPLC (30×150 mm Waters Sunfire (0.1% TFA), 5-35% ACN/water over 20 min at 50 mL/min, 2 injections). Fractions containing each compound were pooled separately then applied to separate Phenomenex Strata-X—C ion exchange columns (5 g). Each column was washed with H2O and MeOH (discard) then with 10% concentrated NH4OH in MeOH (collect). The collected fractions for each were concentrated separately to give the title compounds below: 1-(1H-benzimidazol-4-yl)-5-(benzyloxy)-2-methylpyridin-4(1H)-one: tan solid LC/MS rt=1.24 min, 1H NMR (500 MHz, d6-DMSO) δ 12.90 (bs, 1 H), 8.33 (s, 1 H), 7.72 (bs, 1 H), 7.49 (bs, 1 H), 7.41-7.25 (m, 7 H), 6.26 (s, 1 H), 4.94 (s, 2 H), 1.92 (s, 3 H). 1-(1H-benzimidazol-4-yl)-5-hydroxy-2-methylpyridin-4(1H)-one: tan solid, LC/MS rt=0.47 min, 1H NMR (500 MHz, d6-DMSO) δ 12.88 (bs, 1 H), 8.32 (s, 1 H), 7.70 (d, J=8.06 Hz, 1 H), 7.38-7.25 (m, 3 H), 6.25 (s, 1 H), 1.92 (s, 3 H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(OC(C)C)(=O)C.O>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: CC(=O)NNc1ccc(C)cc1
Temperature: 57.5 °C

Procedure:
104.8 g of 1-(4-methylphenyl)hydrazine hydrochloride are suspended in 525 ml of isopropyl acetate, a solution of 104.8 g of potassium carbonate in 300 ml of water is added and then the mixture is stirred until the solid has disappeared. 77.4 g of acetic anhydride are added while maintaining the temperature below 20° C. and then the mixture is left stirring at 20° C. A precipitate is observed to form, which precipitate disappears when the mixture is heated at approximately 55-60° C. The organic phase is washed twice with 200 ml of water and is then cooled at 0-5° C. overnight. The product formed is recovered by filtration and is then washed twice with 100 ml of MTBE.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH2:47][CH3:48])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH2:47][CH3:48])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1ccccn1
Reactant: CCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
A solution of triphenylphosphine (279 mg, 1.06 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (189 mg, 1.06 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid (prepared as in Example 77, 300 mg, 0.97 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminopyridine (200 mg, 2.13 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide (185 mg, 50%) as a pale orange solid: mp 144-145° C.; EI-HRMS m/e calcd for C21H26N2O3S (M+) 386.1664, found 386.1660.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][NH:20][C:21]([NH2:23])=[S:22].O>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[N:19][NH:20][C:21]([NH2:23])=[S:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NNC(N)=S
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=NNC(N)=S)c1ccccc1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
2-(tert-Butoxycarbonylamino)acetophenone (3.00 g) was dissolved in methanol (21.0 mL). To the solution was added an aqueous solution (water: 9.0 mL) of thiosemicarbazide hydrochloride (3.11 g, 24.4 mmol) at room temperature. After the mixture was stirred at the same temperature for 30 minutes, water (12.0 mL) was added, and the mixture was stirred at room temperature for 20 minutes and then at 0° C. for 1 hour. The deposited solid was collected by filtration and washed with cooled 50% aqueous methanol (20 mL). The resulting solid was dried at 40° C. under reduced pressure to give seed crystals of 2-(tert-butoxycarbonylamino)acetophenone thiosemicarbazone (3.56 g, yield: 95.1%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]([CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15](=O)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[CH2:15]([N:14]([C@H:11]1[CH2:10][CH2:9][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1)[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:16]
Reactant: CC(=O)N(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Reaction time: 18 h

Procedure:
To a stirred solution of trans-N-[4-(4-hydroxyphenyl)cyclohexyl]-N-(3-phenylpropyl)acetamide (282 mg, 0.80 mmol) in anhydrous THF (5 mL) was added LiAlH4 (1.2 mL of a 1M solution in Et2O, 1.2 mmol). After 18 hours, the reaction was quenched by addition of a mixture of H2O (2 mL), 2N NaOH (4 mL), and saturated NaCl (2 mL). The resulting mixture was diluted with Et2O (100 mL) and the resulting mixture was filtered. The filtrate was dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (90:9:1 CH2Cl2:MeOH:NH4OH) gave trans-4-{4-[N-ethyl-N-(3-phenylpropyl)-amino]cyclohexyl}phenol (130 mg, 48%) as a white solid: mp 192-194° C.; IR (KBr): 3197, 2939, 1614, 1516 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 9.16 (br s, 1H), 7.35-7.23 (m, 5H), 7.02 (d, J=8 Hz, 2H), 6.70 (d, J=8 Hz, 2H), 3.35-3.12 (m, 5H), 2.68 (q, J=5, 2 Hz, 2H), 2.42 (tt, J=9, 2 Hz, 1H), 2.12 (br d, J=9 Hz, 2H), 2.10 (m, 2H), 1.87 (br d, J=9 Hz, 2H), 1.63 (dddd, J=9, 9, 9, 2 Hz, 2H), 1.53 (dddd, J=9, 9, 9, 2 Hz, 2H), 1.27 (t, J=5 Hz, 3H); CI-MS (methane) (m/z): 338 [M+H]+; HPLC: method A, 8.80 minutes (97.8%); method B, 10.66 minutes (99.9%); Anal. Calcd for C23H31NO.HCl.0.125H2O: C, 73.43; H, 8.64; N, 3.72. Found: C, 73.36; H, 8.75; N, 3.56.