Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@:15]2(O)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@H:16]2[O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:11][CH:10]=1.C([N+](CC)(CC)S(NC(=O)OC)(=O)=O)C>C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C@H:16]([O:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@](O)(c2ccc(F)cc2)[C@H](OC(=O)C(C)(C)C)C1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)[C@H](OC(=O)C(C)(C)C)C1
Yield: 93.4 %

Procedure:
To a toluene solution (40 mL) of tert-butyl (3R,4R)-4-(4-fluorophenyl)-4-hydroxy-3-(pivaloyloxy)piperidine-1-carboxylate (2.04 g, 5.16 mmol) synthesized in Reference Synthesis Example 135, methyl N-(triethylammoniosulfonyl)carbamate (1.72 g, 7.22 mmol) was added and the resultant mixture was stirred at 60° C. for 3 hours. After completion of the reaction, ethyl acetate was added to the reaction solution and the resultant mixture was washed with each of saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1→3/1) to obtain the title compound (1.82 g, yield 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH3:35])(=[O:34])=[O:33])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH3:35])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(C)(=O)=O)n3)cc21

Procedure:
Title compound was prepared from 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-methanesulfonyl-phenyl)-amine in an analogous manner to Example 1221d. Product was isolated as a white solid (36 mg, 32%). MP=209-210, LCMS 514.09 (M+H), HPLC purity 91%, 1H-NMR (CDCl3, 400 MHz) δ 9.39 (s, 1H), 8.50 (d, J=8.4 Hz, 1H), 8.21 (s, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.63-7.58 (m, 2H), 7.32-7.25 (m, 3H), 7.05-7.03 (m, 1H), 3.75-3.65 (m, 2H), 3.10 (s, 3H), 2.37-2.27 (m, 2H), 2.08-2.04 (m, 2H), 1.35 (s, 6H), 1.20 (t, J=9.8 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[OH:16])=O)[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:27]>>[NH2:27]/[C:5](/[C:4]1[CH:17]=[CH:18][CH:19]=[CH:20][C:3]=1[CH2:1][CH3:2])=[C:7]1\[C:8](=[O:16])[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[S:11]\1
Reactant: CCc1ccccc1C(=O)c1sc2ccccc2c1O
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCc1ccccc1/C(N)=C1\Sc2ccccc2C1=O
Yield: 46 %

Procedure:
Prepared as in Example 1 from 2-(ethyl-benzoyl)benzo[b]-thiophen-3-ol, phosphorus(V) chloride and concentrated ammonia with a yield of 46% of theory. M.p. 132°-133° C. (ethyl acetate/petroleum ether 1:1).
Reaction SMILES: [CH2:1]([S:5][CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]#[CH:4].[OH:10][CH2:11][C:12]1([CH2:16][CH2:17][CH3:18])[CH2:15]O[CH2:13]1>>[CH2:1]([S:5][CH2:6][C:7]12[O:10][CH2:11][C:12]([CH2:16][CH2:17][CH3:18])([CH2:15][O:9]1)[CH2:13][O:8]2)[CH2:2][C:3]#[CH:4]
Reactant: CCCC1(CO)COC1
Reactant: C#CCCSCC(=O)O
Product: C#CCCSCC12OCC(CCC)(CO1)CO2

Procedure:
1-(But-3-ynylthiomethyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 2-(but-3-ynylthio)acetic acid and 3-hydroxymethyl-3-n-propyl-oxetane using the methodology described in Example I.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)ccc2C1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Fc1ccc2c(c1)CCC(N1CCCC1)=C2

Procedure:
16.7 g of 6-fluoro-3,4-dihydro-2(1H)-naphthalenone in 200 ml of benzene are boiled at reflux for 2.5 hours with 8.4 ml of pyrrolidine and 0.35 g of anhydrous p-toluenesulfonic acid. The 1-(6-fluoro-3,4-dihydro-2-naphthyl) pyrrolidine obtained is treated, without purification, with 10.8 g of acrylamide and 0.5 g of p-toluenesulfonic acid. The mixture is heated under nitrogen at 100° for 2 hours and at 150° for 2 hours. The mixture is dissolved in 180 ml of chloroform, washed with water and chromatoqraphed over 150 g of silica gel with chloroform. Recrystallization from ethyl acetate gives 8-fluoro -1,4,5,6-tetrahydrobenzo[f]quinolin-3(2H)-one with melting point 223-224°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][O:11][S:23]([CH3:22])(=[O:25])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
A solution of 22.0 gm (125.6 mMol) (R)-N-tert-butoxycarbonyl-2-amino-1-propanol and 19.5 gm (150.7 mmol) diisopropylethylamine in 450 mL dichloromethane was cooled to 0° C. To this solution was added dropwise 10.7 mL (138.2 mMol) methanesulfonyl chloride at a rate to maintain the temperature of the reaction mixture at from 0° C. to 10° C. Once the addition was complete the reaction mixture was stirred at 0° C. for about one hour. The reaction mixture was washed twice with 200 mL portions of water, once with 200 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 1:1 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from hexane and ethyl acetate to provide 19.4 gm (61%) of the desired compound in two crops (m.p.=65–68° C.)
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OCC)=O)[C@@H:6]([CH3:16])[CH2:5]1)[CH:2]=[CH2:3].[OH-].[K+].C(=O)=O.C1(C)C=CC=CC=1>C(O)C>[CH2:1]([N:4]1[CH2:5][C@@H:6]([CH3:16])[NH:7][CH2:8][C@@H:9]1[CH3:10])[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@H](C)N(C(=O)OCC)C[C@H]1C
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=CCN1C[C@@H](C)NC[C@@H]1C
Temperature: 5 °C
Yield: 69 %

Procedure:
Ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate (630 g, 2.78 mol) was added to a solution of 87% potassium hydroxide pellets (2970 g, 46 mol) in 4300 mL of 95% ethanol and heated at reflux for 1.5 hours. Carbon dioxide evolution was observed for the first 0.5-1 hour of heating. The reaction was cooled below reflux temperature and 2000 mL of toluene was carefully added. Ethanol was removed by azeotropic distillation at 105° C. while adding an additional 4000 mL of toluene to the reaction flask during the course of the distillation. After collection of 9000 mL of distillate, the reaction was cooled to 5° C. and 1000 mL of toluene was carefully added. The solution was slowly cooled to 5° C. and maintained at 5° C. for 30 minutes. The solution was filtered, and the filter cake was washed with an additional 1500 mL of toluene. The filtrate was washed with 1000 mL of water, dried over magnesium sulfate, and the solvent was removed to give 296 g (69%) of trans-1-allyl-2,5-dimethylpiperazine as a dark liquid. NMR (300 MHz, DMSO-d6): δ0.87 (d, J=6.3 Hz, 3H); 0.92 (d, J=6.3 Hz, 3H); 1.63 (t, J=11 Hz, 1H); 2.05 (m, 1H); 2.30 (t, J=11 Hz, 1H); 2.6-2.8 (m, 4H); 3.33 (dd, J1 =5 Hz, J2 =14Hz, 1H); 5.09 (d, J=8.7 Hz, 1H); 5.13 (d, J=14 Hz, 1H) 5.8 (m, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:28]3[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=3)[S:8][C:7]=2[CH:36]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]#[C:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)[S:8][C:7]=2[CH:36]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C#CCN3CCCCC3)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(C#CCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Step 4 (120 mg, 0.24 mmol) was dissolved in methylene chloride (0.5 mL), cooled to 0° C. and treated with boron tribromide (1.2 mL, 1 M, 1.2 mmol) and stirred for 30 minutes. The reaction was quenched with saturated sodium bicarbonate solution and extracted intochloroform. The combined organic layers was dried over anhydrous magnesium sulfate. After filtration, concentration and silica gel column chromatography with 2% methanol-methylene chloride as eluant the title compound (24 mg) was obtained.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1.[CH3:23][C@H:24]([NH2:28])[CH2:25][O:26][CH3:27].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(=O)(O)[O-].[Na+]>[CH3:23][C@H:24]([NH:28][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1)[CH2:25][O:26][CH3:27]
Reactant: N#Cc1nc(CCC=O)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: COC[C@H](C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC[C@H](C)NCCCc1cc(-c2cccc(C(F)(F)F)c2)nc(C#N)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(3-oxo-propyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (610 mg) in methanol (8 ml) was added 1-(s)-methyl-2-methoxyethylamine (0.85 mL), acetic acid (0.5 mL), and followed by sodium triacetoxyborohydride (0.82 g). The mixture was stirred at room temperature for 4 hours, then diluted with sodium bicarbonate aqueous solution (5%, 50 ml). The mixture was extracted with ethyl acetate (50 ml plus 3×20 ml). Combined organic layer was dried over sodium sulphate, filtered, solvent removed under vacuum. Residue was columned on silica gel using DCM-MeOH (20:1) as eluant to give 4-[3-(1-(s)-methyl-2-methoxyethylamino)-propyl]-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (250 mg). The above neutral product was dissolved in DCM and then HCl (1M in ether, 1 ml) added, 4-[3-(1-(s)-methyl-2-methoxyethylamino)-propyl]-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile HCl salt was collected by filtration (180 mg). 1H NMR (MeOD): δ 8.50 (s, 1H), 8.48 (d, 1H), 8.27 (s, 1H), 7.90 (d, 1H), 7.79 (t, 1H), 3.68 (m, 1H), 3.48 (m, 2H), 3.43 (s, 3H), 3.17 (m, 2H), 3.10 (t, 2H), 2.25 (m, 2H), 1.36 (d, 3H). MS m/z 379.5 (M+1), 80%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[C:7]2[C:12](=[O:13])[CH:11]3[CH2:14][CH2:15][N:8]2[CH2:9][CH2:10]3)=[CH:2]1>CO.[Pd]>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH:7]2[C:12](=[O:13])[CH:11]3[CH2:10][CH2:9][N:8]2[CH2:15][CH2:14]3)[CH2:2]1
Reactant: O=C1C(=Cc2ccoc2)N2CCC1CC2
Agent: [Pd]
Solvent: CO
Product: O=C1C2CCN(CC2)C1CC1CCOC1
Reaction time: 8 h

Procedure:
Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were dissolved in methanol (25 ml) and stirred for 15 mins. Furan-3-carboxaldehyde (2.83 g, 29.5 mmol) was then added in one portion and the mixture was stirred for an additional 20 hrs. The reaction mixture was then diluted with 40 ml water and cooled to 0° C. yielding 2-((3-furyl)methylene)-1-azabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was collected, washed with distilled water and dried under vacuum (5.16 g, 81.4%). 2-((3-Furyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (2.1 g, 100 mmol) was dissolved in methanol (100 ml) and 10% palladium on charcoal (0.2 g) was carefully added under nitrogen. The suspension was hydrogenated at 50 psig in a Parr hydrogenation apparatus for 8 hrs followed by quenching of the catalyst with a small amount of chloroform. The entire slurry was filtered through a pad of Celite filter aid followed by additional washing of the pad with methanol. Rotary evaporation of the pooled solvents gave the desired product, 2-((3-oxolanyl)methyl)-1-azabicyclo[2.2.2]octan-3-one, as a clear oil that solidified upon cooling (2.05 g, 96.7%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12](I)=[C:11]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][CH:34]([N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][C:45]#[CH:46])[CH2:38][CH2:37]1)[CH3:35]>CN(C)C=O.CS(C)=O.CO.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([C:46]#[C:45][CH2:44][CH2:43][CH2:42][N:39]2[CH2:40][CH2:41][N:36]([CH:34]([CH3:35])[CH3:33])[CH2:37][CH2:38]2)=[C:11]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCCCN1CCN(C(C)C)CC1
Reactant: CCCCc1nc(N)c2c(n1)c(I)c(C)n2COCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCCc1nc(N)c2c(n1)c(C#CCCCN1CCN(C(C)C)CC1)c(C)n2COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.4 %

Procedure:
To a degassed solution of 5-((benzyloxy)methyl)-2-butyl-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine (159 mg, 0.353 mmol) in anhydrous N,N-dimethylformamide (3 mL) under a nitrogen atmosphere at room temperature was added copper (I) iodide (19 mg, 0.100 mmol), bis(triphenylphosphine)palladium(II)dichloride (40 mg, 0.057 mmol) and finally triethylamine (0.088 mL, 0.636 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 10 minutes and then a solution of 1-(1-methylethyl)-4-(4-pentyn-1-yl)piperazine (110 mg, 0.565 mmol) in anhydrous degassed N,N-dimethylformamide (1 mL) was added. The reaction mixture was stirred at 55° C. for 40 minutes. Additional 1-(1-methylethyl)-4-(4-pentyn-1-yl)piperazine (110 mg, 0.565 mmol) was added and the reaction mixture was left to stir at 55° C. for 4 5 minutes. 1-(1-methylethyl)-4-(4-pentyn-1-yl)piperazine (110 mg, 0.565 mmol) was added and the reaction mixture was left to stir at 55° C. for 45 minutes. The reaction was evaporated in vacuo to yield a dark yellow oil. The oil was partitioned between water and dichloromethane. The organic layer was separated and the aqueous back extracted with dichloromethane. The combined organic extracts were passed through a hydrophobic frit and evaporated in vacuo to yield a dark yellow oil. The crude product was dissolved in 6 mL of 50:50 DMSO/MeOH and purified by MDAP (Method B). Fractions which contained product were concentrated to give the title compound as a yellow oil (61 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26](Br)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(OC(N1CCCC1C1NC(C2C=CC3C(=CC=C([C:60]4[CH:65]=[CH:64][C:63]([C:66]5[NH:67][C:68]([CH:71]6[CH:76]7[CH2:77][CH:73]([CH2:74][CH2:75]7)[N:72]6[C:78](=[O:88])[CH:79]([NH:83][C:84]([O:86][CH3:87])=[O:85])[CH:80]([CH3:82])[CH3:81])=[N:69][CH:70]=5)=[CH:62][CH:61]=4)C=3)C=2)=CN=1)=O)(C)(C)C>>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:60]4[CH:61]=[CH:62][C:63]([C:66]5[NH:67][C:68]([CH:71]6[CH:76]7[CH2:77][CH:73]([CH2:74][CH2:75]7)[N:72]6[C:78](=[O:88])[CH:79]([NH:83][C:84]([O:86][CH3:87])=[O:85])[CH:80]([CH3:82])[CH3:81])=[N:69][CH:70]=5)=[CH:64][CH:65]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 24 %

Procedure:
This compound was synthesized using the procedure used to make (1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester using 2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.154 g, 0.203 mmol) giving the title compound (0.041 g, 24% yield) as a white solid. LCMS-ESI+: calc'd for C46H54N8O6: 814.42 (M+); Found: 815.49 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][CH:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccncc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CNCCN1c1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
To a solution of tert-butyl 3-methyl-4-(3-nitropyridin-4-yl)piperazine-1-carboxylate (prepared according to methods similar to the one depicted in Step 1 of Preparation N-1) in DCM (5 mL) was added TFA (1.445 g, 976.4 μL, 12.67 mmol). The reaction mixture was stirred for 48 h at RT, then the solvent was removed under reduced pressure. The crude was redissolved in MeOH and loaded into a MeOH pre-washed SCX column, rinsed with MeOH and the product was released with methanolic ammonia. The ammonia extracts were concentrated under reduced pressure to yield 2-methyl-1-(3-nitro-4-pyridyl)piperazine (334 mg, 71%). MS (ES+) 223.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]1.O>CN(C)C=O>[CH3:23][CH:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:18][CH2:19]1
Reactant: CC1CCN(CCCCl)CC1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCN(CCCSc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C

Procedure:
Dissolve 8.50 g (55 mmol) of 4-nitrothiophenol in 40 mL of dimethylformamide and make basic with 13.7 mL of 4N potassium hydroxide. Add 10.60 g (60 mmol) of N-[3-chloropropyl]-4-methylpiperidine and heat this solution to 100° C. for 3 h. After this time cool the reaction to room temperature. Add 200 mL of water and extract with 2×150 mL of methylene chloride. Acidify the combined organic extracts to pH=1 with 1N hydrochloric acid and extract with 4×150 mL of water. Neutralize the combined aqueous extracts with saturated sodium bicarbonate solution and extract with 3×200 mL of methylene chloride. Dry the organic extracts over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo to provide the title compound.
Reaction SMILES: C(N[C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])(=O)C.[C:12](NC1C=C(C=CC=1)N)(=[O:15])CC.C(NC1C=C(C=CC=1)N)(=O)CCC.C(NC1C=C(C=CC=1)N)(=O)C1C=CC=CC=1>>[NH2:8][C:7]1[CH:6]=[C:5]([O:15][CH3:12])[CH:11]=[CH:10][CH:9]=1
Reactant: CCC(=O)Nc1cccc(N)c1
Reactant: CC(=O)Nc1cccc(N)c1
Agent: CCCC(=O)Nc1cccc(N)c1
Agent: Nc1cccc(NC(=O)c2ccccc2)c1
Product: COc1cccc(N)c1

Procedure:
m-acetylaminoaniline, m-propionylaminoaniline, m-butyrylaminoaniline or m-benzoylaminoaniline;
Reaction SMILES: C([NH:4][CH:5]([C:10]([OH:12])=[O:11])[CH2:6][CH2:7][S:8][CH3:9])(=O)C>O>[NH2:4][C@H:5]([C:10]([OH:12])=[O:11])[CH2:6][CH2:7][S:8][CH3:9]
Reactant: CSCCC(NC(C)=O)C(=O)O
Solvent: O
Product: CSCC[C@H](N)C(=O)O

Procedure:
100 g of the above catalyst was swelled in water for about one hour and packed into a jacketed glass column having 2.5 cm diameter and 80 cm height and kept at 50° C. Solution of N-acetyl-DL-methionine (0.2 mol, pH 7.0, added with 5.0×10-4 mol CoCl2) was continuously flown down from the top of the column at a flow rate of 1000 ml/hr. The reaction solution flown out of the bottom of the column was sampled on every certain interval of time and the amount of the L-methionine produced was determined by way of ninhydrine colorimetry. The results are shown in table 6.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([NH:9][C:10]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:8])(=[O:3])[CH3:2].[C:25]([O:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32])(=[O:27])[CH3:26].C(N(CC)CC)C>O1CCCC1>[C:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([NH:9][C:10]1[CH:19]=[C:18]([NH:20][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[O:28][C:25](=[O:27])[CH3:26])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(N)cc1NC(=O)c1ccccc1OC(C)=O
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)c2ccccc2OC(C)=O)cc1NC(=O)c1ccccc1OC(C)=O
Yield: 66.9 %

Procedure:
In 80 ml of tetrahydrofuran were dissolved 2 g of methyl 2-(2'-acetoxybenzamido)-4-aminobenzoate and 11.8 g of 2-acetoxybenzoylchloride, and to the solution was added dropwise a solution of 0.6 g of triethylamine in 5 ml of tetrahydrofuran while stirring under cooling with ice. Ten minutes after completion of the addition, the mixture was returned to room temperature, followed by stirring at that temperature for one hour. The reaction mixture was then poured into diluted hydrochloric acid-ice to precipitate crystals. The crystals were recovered by filtration and recrystallized from methanol to obtain 2.0 g of methyl 2,4-bis(2'-acetoxybenzamido)-benzoate having a melting point between 143° - 145°C. This product was confirmed to be identical to that obtained in Example 6.