Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:7]=[C:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[ClH:10].Cl.[CH2:12]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][SH:30])[CH2:23][CH2:22]1)[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:10].[ClH:10].[CH2:1]([NH:7][C:8](=[SH:30][CH2:29][CH2:28][CH2:27][N:24]1[CH2:23][CH2:22][N:21]([CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:26][CH2:25]1)[OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: SCCCN1CCN(CC=Cc2ccccc2)CC1
Reactant: CCCCCCN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCNC(O)=[SH]CCCN1CCN(CC=Cc2ccccc2)CC1
Yield: 64.2 %

Procedure:
The procedure described in Example 2 was followed, using 0.4 g of n-hexyl isocyanate, 1.0 g of 3-(4-cinnamylpiperazin-1-yl)propanethiol dihydrochloride, 0.6 g of triethylamine and 50 ml of methylene chloride, to give 0.44 g (31% of theory) of N-(n-hexyl)-S-[3-(4-cinnamylpiperazin-1-yl)propyl]thiocarbamate dihydrochloride as a white crystalline solid, M.p. 251°-253° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]([N:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1)([CH3:11])[CH3:10].[OH-].[K+].C(O)C1C=CC=CC=1>CCOCC>[CH:9]([NH:12][CH2:13][CH:14]([OH:16])[CH2:15][O:8][C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)([CH3:11])[CH3:10]
Reactant: CC(C)N1CC(O)C1
Reactant: Cc1ccc(O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: OCc1ccccc1
Product: Cc1ccc(OCC(O)CNC(C)C)cn1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
A mixture of 6.1 g of 6-methyl-3-pyridinol, 5.5 g of 1-isopropyl-3-azetidinol, 0.3 g of potassium hydroxide and 25 ml of benzyl alcohol is stirred for 16 hours under nitrogen in a bath at 150° C. After cooling, the reaction mixture is diluted with 50 ml of ether and extracted with 30 ml of 4 N hydrochloric acid. The aqueous phase is separated off, rendered alkaline with concentrated sodium hydroxide solution and extracted with 100 ml of methylene chloride. 3-(3'-Isopropylamino-2'-hydroxy-propoxy)-6-methyl-pyridine is isolated from the crude product thus obtained by bulb tube distillation at 130°-140° C. bath temperature and 0.04 mm Hg. It is identical in its properties with the product obtained in Example 19.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:38][N:13]2[C:14]3[C:19]([C:20]([C:21]4[C:22](=O)[O:23][C:24](=[O:36])[C:25]=4[C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]([CH3:35])[CH:27]=4)=[C:12]2[CH2:11][CH2:10]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:40](C)C=O>N>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:38][N:13]2[C:14]3[C:19]([C:20]([C:21]4[C:22](=[O:23])[NH:40][C:24](=[O:36])[C:25]=4[C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]([CH3:35])[CH:27]=4)=[C:12]2[CH2:11][CH2:10]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)C=O
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CC(NC(=O)OC(C)(C)C)CC4)C(=O)OC2=O)c2ccccc21
Agent: N
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CC(NC(=O)OC(C)(C)C)CC4)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 85 mg of 3-[7-t-butoxyformamido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 5 ml of dimethylformamide and 5 ml of 33% aqueous ammonia was heated to 100° C. for 1 hour. The cooled mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried and evaporated. Crystallization from ethyl acetate/n-hexane gave 70 mg of 3-[7-t-butoxyformamido-6,7,8,9-tetrahydro-pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 159°-163° C.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>S1(CCCC1)(=O)=O>[CH2:19]([O:8][C:7]1[CH:9]=[C:2]([C:1]([O:11][CH3:12])=[O:10])[C:3]([OH:4])=[CH:5][CH:6]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)ccc1O
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of methyl gentisate (16.8 g) and anhydrous potassium carbonate (7.0 g) in dry sulpholane (150 ml) was treated, with stirring, with benzyl chloride (12.7 g), and the mixture was stirred and heated at 100° C. for 4 hours. The mixture was then poured into water (800 ml) and the separated solid was filtered off and recrystallized from ethanol (with the aid of charcoal) to give methyl 5-benzyloxysalicylate (10.7 g), m.p. 108°-112° C. This ester (9.2 g) was heated at 150° C. for 3 hours with a mixture of anhydrous potassium carbonate (2.5 g) and benzyl chloride (4.52 g) in dry sulpholane (100 ml) and the mixture was then cooled and poured into a mixture of ice and water (700 ml), and the mixture was extracted with diethyl ether (2 × 300 ml). The ether extracts were combined and evaporated, the residual oil was triturated with water (100 ml), the oil was separated and the aqueous layer was extracted with diethyl ether (25 ml). The combined oil and extracts were washed with brine, dried over magnesium sulphate and evaporated to give crude methyl 2,5-dibenzyloxybenzoate (12.7 g). This ester (12.4 g) was heated at reflux with aqueous sodium hydroxide solution (2N; 400 ml) for 2 hours and allowed to cool. The separated sodium salt was filtered off and ground with hydrochloric acid (6N; 100 ml), the mixture was heated at reflux for 5 minutes and then cooled. The solid which separated was filtered off, washed with water and dried to give 2,5-dibenzyloxybenzoic acid (8.2 g), m.p. 107°-108.5° C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17][CH2:16]2.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].CO>C(OCC)(=O)C>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][CH:16]3[CH2:17][CH2:18][CH:19]4[CH2:22][CH2:23][N:15]3[CH2:21][CH2:20]4)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: C1CC2CCN(C1)CC2
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CC1CCC2CCN1CC2

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-azabicyclo[3.2.2]nonane. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 85% overall yield. FDMS m/e=314 (M+ of free base). α[D]589 =-20.39 c=0.48, methanol).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@@H:3]([OH:5])[CH3:4].[H-].[Na+].F[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].O>O1CCOCC1>[F:1][C:2]([F:7])([F:6])[C@H:3]([CH3:4])[O:5][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: C[C@H](O)C(F)(F)F
Reactant: O=C(O)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Oc1ccccc1C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
36.0 g (316 mmol) of (S)-1,1,1-trifluoro-propan-2-ol (CAS: 3539-97-7) was added to a cold (0 to 5° C.) suspension of 17.0 g (425 mmol) of NaH (pract., 60%) in 200 ml of dioxane. The suspension was stirred at room temperature during 0.5 h then cooled (0 to 5° C.) and a solution of 20.0 g (143 mmol) of 2-fluoro-benzoic acid in 100 ml of dioxane was added. The mixture was stirred during 0.5 h at room temperature and during 140 h under reflux. The mixture was poured into 800 ml of water, washed with 300 ml of MTBE, then acidified to pH 2 with hydrochloric acid and the product was extracted with MTBE. The solvent was concentrated in vacuo and the residue was crystallized from ethanol/water to provide 27.3 g (82%) of the title compound as a white solid. MS (m/e): 234.1 [M]+.
Reaction SMILES: [C:1]([O:14][CH2:15]Cl)([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[I-:17].[Na+].O>CC(C)=O>[C:1]([O:14][CH2:15][I:17])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)OCI

Procedure:
C4F9OCH2Cl (50 g, 0.175 mole, isomer ratio n/i=95:5) was combined with sodium iodide (52.5 g, 0.38 mole) in acetone (200 g) and heated to reflux overnight. Water was added and the acetone distilled from the reaction vessel using a Dean-Stark apparatus. The product was washed with water to remove residual acetone. Glc of the residue (52.6 g) revealed it to be 82.6 wt. % of the desired product C4F9OCH2I, which was further purified by distillation. The distillation fraction boiling at 110-115° C. was found to be 97.8 wt. % of the desired product with a 96/4 normal to iso ratio.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[CH2:27][CH:26]=[CH2:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCn1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc21
Reaction time: 48 h

Procedure:
A solution of 1-t-butoxycarbonyl-4-(1H-indol-4-yl)piperazine (prepared as described above) in tetrahydrofuran (50 mL) was added dropwise to a suspension of sodium hydride (0.7 g of a 60% mineral oil suspension) in tetrahydrofuran (150 mL) at room temperature. After stirring for further 30 min a solution of allyl bromide (3.5 mL) in tetrahydrofuran (50 mL) was added dropwise. After stirring for 48 h the mixture was poured onto ice-water followed by standard work-up with ethyl acetate giving an oil, which was purified by flash chromatography (eluent: heptane/ethyl acetate 85:15) giving 1-t-butoxycarbonyl-4-(1-allyl-1H-indol-4-yl)piperazine as an oil (3.2 g). The oil was dissolved in methanol (15 mL) and a saturated solution of HCl in diethyl ether (100 mL) was added. After stirring for 16 h at room temperature, the resulting colorless crystals consisting of the hydrochloride of the title compound (2.5 g) was collected by filtration and dried in vacuo.
Reaction SMILES: [I:1]C1C=C(C=C(OC)C=1)N.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)N>>[I:1][C:15]1[CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=[C:13]([O:12][CH3:11])[CH:14]=1
Reactant: COc1cc(N)cc(I)c1
Reactant: COc1cc(N)cc([N+](=O)[O-])c1
Product: COc1cc(I)cc([N+](=O)[O-])c1

Procedure:
Certain 5-alkoxy-3-aminophenyl substituted olefinic amine compounds, such as (E)-N-methyl-5-(5-methoxy-3-aminophenyl)-4-penten-2-amine, can be synthesized by coupling a 3-halo-5-alkoxyaniline such as 3-bromo-5-methoxyaniline or 3-iodo-5-methoxyaniline (protected by a phthaloyl functionality) with an olefin containing a secondary alcohol functionality, 4-penten-2-ol, under Heck reaction conditions. The resulting secondary alcohol intermediate can be converted to its p-toluenesulfonate ester, followed by treatment with methylamine (which also removes the protecting group). Alternatively, certain 5-alkoxy-3-aminophenyl substituted olefinic amine compounds can be synthesized by coupling a 3-halo-5-alkoxyaniline such as 3-bromo-5-methoxyaniline or 3-iodo-5-methoxyaniline (protected by a phthaloyl functionality) with an olefinic side chain compound, such as N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine, followed by removal of the protecting groups. The required 3-halo-5-alkoxyaniline compounds such as 3-bromo-5-methoxyaniline and 3-iodo-5-methoxyaniline can be prepared using the techniques of T. A. Emokpae et al., J. Chem. Soc., Perkin Trans 2 (1):14-17 (1977) and B. Liedholm, Acta Chem. Scand., Ser. B 38:877-884 (1984). In the former method, 3-bromo-5-methoxyaniline and 3-iodo-5-methoxyaniline can be prepared starting from commercially available 1,3,5-trinitrobenzene. Treatment of the latter compound with refluxing sodium methoxide produces 3,5-dinitroanisole. One of the nitro groups is then reduced to give 3-methoxy-5-nitroaniline. The latter compound can be diazotized and treated with copper(I) bromide to give 1-bromo-3-methoxy-5-nitrobenzene. Reduction with tin and hydrochloric acid gives 3-bromo-5-methoxyaniline. In a similar manner, 3-iodo-5-methoxyaniline can be prepared by diazotizing 3-methoxy-5-nitroaniline to give 1-iodo-3-methoxy-5-nitrobenzene. The latter compound can be reduced with iron filings and hydrochloric acid to give 3-iodo-5-methoxyaniline. Other 3-halo-5-alkoxyanilines such as 3-bromo-5-ethoxyaniline, 3-bromo-5-isopropoxyaniline, and 3-bromo-5-sec-butoxyaniline can be prepared using similar techniques. As such, compounds of the present invention such as (E)-N-methyl-5-(5-ethoxy-3-aminophenyl)-4-penten-2-amine, (E)-N-methyl-5-(5-isopropoxy-3-aminophenyl)-4-penten-2-amine, and (E)-N-methyl-5-(5-sec-butoxy-3-aminophenyl)-4-penten-2-amine can be similarly prepared.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CS(C)=O.CCOC(C)=O>[F:8][C:7]1[C:2]([CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([O:23][CH2:24][CH3:25])=[O:22])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1cccnc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ncccc1F
Temperature: 100 °C
Yield: 60.3 %

Procedure:
A mixture of 2,3-difluoropyridine (2.00 g, 17.4 mmol), Cs2CO3 (13.59 g, 41.7 mmol) and diethyl malonate (6.68 g, 41.7 mmol) in DMSO (19 mL) was heated at 100° C. for 4.5 h. The mixture was poured onto ice, diluted with EtOAc, and the organic phase was separated, washed sequentially with water and brine, and dried and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (sequentially 10%, 20% and 30%), to provide diethyl 2-(3-fluoropyridin-2-yl)malonate as a pale colored oil (2.68 g, 60% yield). 1H NMR (400 MHz, chloroform-d) δ 8.42 (dt, J=4.6, 1.3 Hz, 1H), 7.43 (ddd, J=9.4, 8.3, 1.4 Hz, 1H), 7.30 (dt, J=8.5, 4.3 Hz, 1H), 5.09 (d, J=1.1 Hz, 1H), 4.30 (q, J=7.0 Hz, 4H), 1.33-1.26 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12](=[O:15])[CH2:13]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20].[ClH:23].O>C(O)C>[ClH:23].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12](=[O:15])[CH2:13][NH:22][CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: O=C(CBr)c1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)NCC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.01 h

Procedure:
In 425 ml of ethanol, 64 g of 3-benzyloxyphenacyl bromide and 212 ml of iso-propylamine are stirred at 5° C. under N2 atmosphere, and the temperature is allowed to rise to 12° C. After 0.75 minutes, the clear solution is poured into 2 liters of crushed ice containing 500 ml of concentrated HCl and 1.5 liters of H2O. The mixture is stirred for 20 minutes, filtered and the solid is washed with water to afford 3'-(benzyloxy)-2-isopropylamino-acetophenone hydrochloride, mp 213°-215° C. dec. A 5 g.-sample of this material is stirred in 50 ml of methanol, and the mixture is cooled in ice and neutralized with 10% NaOH until a clear solution is obtained. To this solution, 2 g of NaBH4 is added and after 0.75 hours of stirring, the mixture is evaporated in vacuo, and the resulting solid is collected and washed with H2O. This gives, after drying, 4.4 g of m-(benzyloxy)-α-[(isopropylamino)methyl]benzyl alcohol, mp 83°-85° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.Cl.[N:9]1([CH:15](N2CCCCC2)[CH2:16]Cl)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[K+]>CO>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:16][CH2:15][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:5][N:6]=1
Reactant: ClCC(N1CCCCC1)N1CCCCC1
Reactant: Nc1nnc(S)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1nnc(SCCN2CCCCC2)s1
Yield: 111.2 %

Procedure:
2-Amino-5-mercapto-1,3,4-thiadiazole (4.0 g), dipiperidinoethylchloridehydrochloride (6.0 g), and potassium hydroxide (3.4 g) were stirred in methanol (100 ml) overnight at room temperature. The reaction mixture was concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 6.1 g of the aimed compound.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1C=CN=C1)=[O:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2C=CN=C(NN)[C:21]=2[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:16][CH:15]=1.O>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:11]=[CH:12][N:8]3[C:1](=[O:2])[NH:3][N:10]=[C:9]3[C:21]=2[C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)=[CH:18][CH:19]=1
Reactant: NNc1nccc(-c2ccc(Cl)cc2)c1-c1ccncc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To a stirring solution of 1,1′-carbonyldiimidazole (2.5 g, 15.4 mmol) in THF (15 mL) at room temperature under argon was added 4-(4-chlorophenyl)-2-hydrazinyl-3,4′-bipyridine (0.92 g, 3.1 mmol). The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was then concentrated under vacuum to produce a yellow solid. This solid was stirred in an ice bath and water (25 mL) was added. Solid was collected by filtration and further washed with water (15 mL×2). After drying in an oven at 50° C. under reduced pressure overnight, 960 mg of the title compound was obtained as a yellow solid. HPLC/MS: retention time=1.985 min, [M+H]+=323. 1H NMR (DMSO-d6, 500 MHz): δ 12.61 (s, 1H), 8.50 (d, J=6.05 Hz, 2H), 7.94 (d, J=7.15 Hz, 1H), 7.36 (d, J=8.2 Hz, 2H), 7.23 (d, J=6.05 Hz, 2H), 7.18 (d, J=8.2 Hz, 2H), 6.68 (d, J=7.15 Hz, 1H).
Reaction SMILES: C(C([N:7]([C:14]1[CH:19]=[CH:18][C:17](CC#N)=[C:16]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:15]=1)C(C(C)(C)C)=O)=O)(C)(C)C.C(C(NC1C=CC(CC#N)=C(OCC(F)(F)F)C=1)=O)(C)(C)C.[ClH:51].[C:52]([OH:55])(=[O:54])[CH3:53]>>[ClH:51].[NH2:7][C:14]1[CH:19]=[CH:18][C:17]([CH2:53][C:52]([OH:55])=[O:54])=[C:16]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])[CH:15]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)C(=O)N(C(=O)C(C)(C)C)c1ccc(CC#N)c(OCC(F)(F)F)c1
Agent: CC(C)(C)C(=O)Nc1ccc(CC#N)c(OCC(F)(F)F)c1
Agent: Cl
Product: Nc1ccc(CC(=O)O)c(OCC(F)(F)F)c1

Procedure:
A ~3:1 mixture of 4-(N,N-di-(tert-butylcarbonyl)-amino)-2-(2,2,2-trifluoroethoxy)phenylacetonitrile and 4-(tert-butylcarbonylamino)-2-(2,2,2-trifluoroethoxy)phenylacetonitrile (1.1 g) from Step 5 above was refluxed in a 1:1 mixture of acetic acid and concentrated aqueous HCl for 3 h. The solvents were removed under reduced pressure. The residue was dissolved in water and the solvent was evaporated under reduced pressure to remove residual acetic acid. 4-Amino-2-(2,2,2-trifluoroethoxy)phenylacetic acid hydrochloride was obtained as a colorless gum (HPLC retention time=4.2 min (method A)).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:22]([NH:24][N:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26]([N:28]1[CH2:32][CH2:31][CH2:30][N:29]1C(OC(C)(C)C)=O)=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[ClH:48]>O1CCOCC1.C(OCC)C>[ClH:48].[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:22]([NH:24][N:25]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:26]([N:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)N1CCCN1C(=O)OC(C)(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)N1CCCN1)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.267 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[(2-tert.butyloxycarbonyl-1-pyrazolidinyl)carbonyl]valerohydrazide was treated with 2 ml of 4M hydrogen chloride in dioxan and stirred for 2 hours at room temperature. The mixture was diluted with diethyl ether and the resulting solid was filtered off, washed with diethyl ether and dried to give 0.142 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[(1-pyrazolidinyl)carbonyl]valerohydrazide hydrochloride in the form of a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][CH2:8][Cl:9])[N:5]=[C:4]([CH3:10])[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:6]([CH2:7][CH2:8][Cl:9])[N:5]=[C:4]([CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1cc(Cl)n(CCCl)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1nn(CCCl)c(Cl)c1[N+](=O)[O-]
Reaction time: 0.67 h

Procedure:
3.6 g (0.02 mole) of 5-chloro-1(beta-chloroethyl)-3-methylpyrazole was added slowly to 10 ml of concentrated sulfuric acid with swirling. Thereafter 5 ml of fuming nitric acid was then added slowly also with swirling. During the addition, the mixture became quite warm. It was allowed to stand at room temperature for 40 minutes and then poured onto ice. A white solid was formed and was filtered off, washed well with water and dried in vacuo at 56° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[N:25]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: N#Cc1ccc(-c2ccc3oc(CCn4ccnc4)cc3c2)cc1

Procedure:
The product from Example 1C and imidazole were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 8.88 (s, 1H), 7.88 (m, 1H), 7.80 (m, 5H), 7.60 (m, 4H), 6.75 (s, 1H), 4.7 (t, J=6.3 Hz, 2H), 3.5 (t, J=6.3 Hz, 2H); MS (DCI) m/z 314 (M+H)+;
Reaction SMILES: [OH:1][CH2:2]C1CCCN1.CC1CCCN1.[CH3:14][O:15][CH2:16][CH:17]1C[CH2:20][CH2:19][NH:18]1.N1CCC[C@H]1C(O)=O.CC1NC(C)CNC1>>[CH3:2][O:1][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][O:15][CH3:14]
Reactant: COCC1CCCN1
Reactant: OCC1CCCN1
Agent: CC1CCCN1
Agent: CC1CNCC(C)N1
Agent: O=C(O)[C@@H]1CCCN1
Product: COCCNCCOC

Procedure:
Following the procedure described above, but substituting pyrrolidine with 2-hydroxymethylpyrrolidine, 2-methylpyrrolidine, 2-methoxymethylpyrrolidine, proline, 3,5-dimethylpiperazine, an bis-(2-methoxyethyl)amine provide: