Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[O:16])[NH:14][CH2:13][CH:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:11]3[CH:23]=2)[CH:5]=[CH:6][CH:7]=1.[Br:24]N1C(=O)CCC1=O>O1CCOCC1>[Br:24][C:23]1[N:11]2[CH:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][NH:14][C:15](=[O:16])[C:10]2=[CH:9][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: CCOC(=O)CC1CNC(=O)c2cc(-c3cccc(F)c3)cn21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Product: CCOC(=O)CC1CNC(=O)c2cc(-c3cccc(F)c3)c(Br)n21

Procedure:
Ethyl [7-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]acetate (116 mg, 0.36 mmol) was dissolved in dry dioxane (15 ml) and reacted with N-bromo succinimide (72 mg, 0.40 mmol) overnight at room temperature. The crude was dried under vacuo and purified on silica gel with Ethyl Acetate/Hexane 3/2 to give the wanted compound in quantitative yield.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH:10]=2)O1.[CH:21]([N:25]1[CH:29]=[C:28](I)[C:27]([C:31]2[S:32][CH:33]=[C:34]([Cl:36])[CH:35]=2)=[N:26]1)([CH2:23][CH3:24])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH:21]([N:25]1[CH:29]=[C:28]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH:10]=2)[C:27]([C:31]2[S:32][CH:33]=[C:34]([Cl:36])[CH:35]=2)=[N:26]1)([CH2:23][CH3:24])[CH3:22]
Reactant: CCC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: CCC(C)n1cc(I)c(-c2cc(Cl)cs2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(=O)Nc1cc(-c2cn(C(C)CC)nc2-c2cc(Cl)cs2)ccn1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]propanamide (0.48 mmol) and bis(tricyclohexylphosphine)palladium(II) chloride (0.04 mmol) were weighed into a microwave vial (reaction volume 2-5 mL). A solution of 1-sec-butyl-3-(4-chloro-2-thienyl)-4-iodo-1H-pyrazole (0.40 mmol) in 3.0 mL degassed dioxane and 1.0 mL of a degassed 2 M aqueous sodium carbonate solution were added. The reaction mixture was purged with argon, the microwave vial was capped with a septum and transferred to a laboratory microwave oven. The reaction mixture was irradiated to a reaction temperature of 120° C. for 12 min. After cooling to room temperature, the reaction mixture was diluted with dioxane and filtered through a short pad of silica. The filtered solid was washed thoroughly with dioxane, ethyl acetate and dichloromethane. The combined filtrates were concentrated in vacuum. The residue was purified by chromatography on silica gel (cyclohexane:ethyl acetate 97:3 to 0:100) to afford 155 mg N-{4-[1-sec-butyl-3-(4-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridin-2-yl}propanamide (99% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[C:19]1([C:25]([NH:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C.O.C(N(CC)CC)C>[C:14]([O:13][C:12](=[O:18])[NH:11][C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:31]([C:30]2[CH:34]=[CH:35][CH:36]=[C:28]([NH:27][C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:26])[CH:29]=2)=[O:32])=[CH:3][CH:4]=1)([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: O=C(O)c1cccc(NC(=O)c2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(NC(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (124 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (4 mL) were added 3-[(phenylcarbonyl)amino]benzoic acid (100 mg), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (95 mg), 1-hydroxybenzotriazole (67.2 mg) and triethylamine (69 μL). The mixture was stirred at room temperature overnight and water was added. Ethyl acetate was added to the mixture, and the resulting solid was collected by filtration to give the title compound (188 mg).
Reaction SMILES: [C:1]1([S:7][CH2:8][Cl:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N(Br)C(=[O:13])C1>CO.O>[C:1]1([S:7]([CH2:8][Cl:9])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCSc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CO
Product: O=S(CCl)c1ccccc1
Yield: 41.8 %

Procedure:
Chloromethyl phenyl sulfide (3 g, 18.9 mmol) was dissolved in a mixture of methanol (15 mL) and water (3 mL) The resulting mixture was cooled to a temperature between 0° C. and 5° C. NBS (4.04 g, 1.2 eq) was added in small portions, maintaining the same temperature range. The reaction mixture was stirred within the same temperature range until the reaction was complete. Thereafter, the reaction mixture was quenched by the addition of Na2SO3 solution (10%, 15 mL). The pH of the reaction mixture was adjusted to a value between 7 and 8, with saturated NaHCO3 solution. The resulting mixture was extracted with dichloromethane (3×50 mL). The combined organic layer was dried with anhydrous MgSO4 and concentrated. The crude product was purified by medium pressure chromatography (Ethyl Acetate/Hexane 2:8) to give 1.381 g (42%) of the desired product as a colourless liquid. 1H NMR (CDCl3, 400 MHz): δ 7.71-7.69 (2H, m), 7.57-7.56 (3H, m), 4.41 (2H, ABQ, J=10.8 Hz). 13C NMR (CDCl3, 100 MHz): δ 140.8, 132.1, 126.3, 124.8, 61.3. FT-IR (NaCl): 3058, 3004, 2935, 1472, 1444, 1384, 1218, 1085, 1052 cm−1.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:17]/[C:18](/[CH3:25])=[CH:19]/C(OCC)=O)C>CO>[CH:1]1([C:6]2[CH:11]=[CH:10][C:9](/[C:12](/[CH3:13])=[CH:19]/[C:18](=[O:17])[CH3:25])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(C2CCCC2)cc1
Reactant: CCOC(=O)/C=C(\C)OCC
Solvent: CO
Product: CC(=O)/C=C(\C)c1ccc(C2CCCC2)cc1
Yield: 51 %

Procedure:
(E)-4-(4-cyclopentyl-phenyl)-3-pentene-2-one was prepared analogous to Example 52 from 4'-cyclopentyl-acetophenone and ethyl (E)-3-ethoxy-crotonate with a yield of 51% of theory. B.p. 143°-147°C at 0.05 mm Hg. M.p. 33°-33.5°C (from methanol).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH3:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1>C1(C)C=CC=CC=1>[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:1][C:2]#[CH:3])[CH2:8][CH2:7]1
Reactant: CN1CCNCC1
Reactant: C#CCBr
Solvent: Cc1ccccc1
Product: C#CCN1CCN(C)CC1

Procedure:
11.1 ml (0.10 mol) of an 80% strength 2-propynyl bromide solution in toluene were added to a solution of 22.2 ml (0.20 mol) of N-methyl-piperazine in 100 ml of toluene while cooling in ice. After 30 minutes under reflux, the resulting N-methylpiperazine hydrobromide was filtered off with suction and washed with toluene, and the filtrate was washed twice each with 15% strength sodium hydroxide solution and saturated sodium chloride solution, concentrated and distilled in vacuo.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=O.N1C=CC=CC=1.[OH-].[Na+].[CH2:14]([N:16]=[C:17]=[S:18])[CH3:15]>O>[CH2:14]([N:16]1[C:3](=[O:5])[CH2:2][NH:1][C:17]1=[S:18])[CH3:15]
Reactant: CCN=C=S
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCN1C(=O)CNC1=S
Temperature: 40 °C
Yield: 90 %

Procedure:
Glycine 36 (150 mg, 2.0 mmol) was dissolved in H2O (5.0 mL) and pyridine (5.0 mL) solution. The pH of the solution was adjusted to about 9.0 as shown by an indicator paper by the addition of 1M NaOH. The solution was heated to 40° C. and kept at that temperature during the reaction. Ethyl isothiocyanate 35 (0.263 mL, 3.0 mmol) was added with vigorous stirring. Small portions of 1M NaOH was added to keep the pH at about 9.0. The reaction was completed when the alkali consumption ceased (1 h). Pyridine and excess alkyl isothiocyanates were then removed by repeated extraction with equal volumes of benzene. Subsequently, an amount of conc. HCl (0.75 mL) was added and the mixture was refluxed for 2 h. The residue was extracted with ethyl acetate (2×150 mL). The organic layer was dried with brine and MgSO4, then concentrated in vacuo. Flash column chromatography on silica gel (hexane:ethyl acetate=2:1) of the residue afforded the desired product 37 in 90% yield (258 mg, pale yellow solid). 1H NMR (400 MHz, CDCl3): 6.88 (br, 1H), 4.06 (d, J=1.2 Hz, 2H), 3.89 (q, J=7.2 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl.C(OC([N:12]1[CH2:16][CH:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:14][N:13]1[C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=O)C1C=CC=CC=1>CO.[Pd]>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:23]([N:13]2[CH2:14][CH:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:16][NH:12]2)=[O:32])=[CH:26][CH:27]=1
Reactant: O=C(Cc1ccc(F)cc1)N1CC(N2CCOCC2)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(Cc1ccc(F)cc1)N1CC(N2CCOCC2)CN1
Reaction time: 72 h
Yield: 81 %

Procedure:
2-[2-(4-Fluorophenyl)acetyl]-4-morpholin-4-yl-pyrazolidine-1-carboxylic acid benzyl ester HCl salt, 12, (100 mg, 0.2 mmol) is dissolved in methanol and Pd/C (5 mg) is added. The solution is then hydrogenated in a Parr® Hydrogenation Apparatus for 3 days after which time the catalyst is removed by filtration and the filtrate concentrated in vacuo to afford 55 mg (81% yield) of the desired product as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[N:5][N:6]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.O.[OH-].[Na+]>CN(C)C=O>[CH2:9]([N:8]([CH2:7][C:4]1[S:3][C:2]2=[N:1][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][N:6]2[N:5]=1)[CH2:11][CH3:12])[CH3:10]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCN(CC)Cc1nnc(N)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nn2cc(-c3ccccc3)nc2s1

Procedure:
18.6 g (0.1 mol) of 2-amino-5-diethylaminomethyl-1,3,4-thiadiazole and 19.9 g of ω-bromo-acetophenone in 70 mL of dimethylformamide are warmed at 150° C. for 3 hours. 150 ml of water are added to the cooled reaction mixture and the mixture is neutralised with 20% strength sodium hydroxide solution. The precipitate is filtered off with suction. After recrystallisation from acetonitrile, 11.5 g (40.2%) of melting point 138° C. remain.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH2:5][CH:6]([C:8](=[CH:10][CH:11]=1)[OH:9])[OH:7].N1C=C(C2CCCN2C)C=CC=1>>[NH2:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1
Reactant: NCCC1=CC=C(O)C(O)C1
Agent: CN1CCCC1c1cccnc1
Product: NCCc1ccc(O)c(O)c1
Reaction time: 0.17 h

Procedure:
The synaptosomal suspension was incubated for 10 min at 37° C. to restore metabolic activity. [3H]Dopamine ([3H]DA, specific activity=28.0 Ci/mmol, NEN Research Products) was added at a final concentration of 0.1 μM and the suspension was incubated at 37° C. for another 10 min. Aliquots of tissue (50 μL) and perfusion buffer (100 μL) were loaded into the suprafusion chambers of a Brandel Suprafusion System (series 2500, Gaithersburg, Md.). Perfusion buffer (room temperature) was pumped into the chambers at a rate of 3 mL/min for a wash period of 8 min. Test compound (10 μM) or nicotine (10 μM) was then applied in the perfusion stream for 40 sec. Fractions (12 sec each) were continuously collected from each chamber throughout the experiment to capture basal release and agonist-induced peak release and to re-establish the baseline after the agonist application. The perfusate was collected directly into scintillation vials, to which scintillation fluid was added. [3H]DA released was quantified by scintillation counting. For each chamber, the integrated area of the peak was normalized to its baseline.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:31])[C:14]([O:16][CH:17]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH2:18][CH3:19])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:31][CH:13]([CH3:12])[C:14]([O:16][CH:17]([O:20][C:21]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:22])[CH2:18][CH3:19])=[O:15]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCC(OC(=O)ON1C(=O)CCC1=O)OC(=O)C(C)C
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: CCC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)C(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]propyl 2-methylpropanoate (575 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 30 (651 mg, 99% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 5H), 1.06 (d, J=6.8 Hz, 3H), 1.07 (d, J=6.8 Hz, 3H), 1.17-1.39 (br. m, 3H), 1.64-1.76 (br. m, 4H), 1.83-1.91 (br. m, 2H), 2.09 (tt, J=12.4, 3.6 Hz, 1H), 2.50 (hept., J=6.8 Hz, 1H), 2.77-2.84 (br. m, 2H), 6.52 (t, J=5.6 Hz, 1H), 7.43 (t, J=6.0 Hz, 1H), 11.98 (br. s, 1H). MS (ESI) m/z 352.06 (M+Na)+; 328.02 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:11][C:12]1[O:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH:8][S:17]([C:15]2[O:16][C:12]([CH3:11])=[CH:13][CH:14]=2)(=[O:19])=[O:18])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)o1
Reactant: CSc1ccc(Cl)cc1N
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(C)o1
Yield: 61.2 %

Procedure:
Following General Procedure B, the title compound (212 mg, 48%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (189 mg, 1.09 mmol) and 5-methyl-furan-2-sulfonyl chloride (250 mg, 1.38 mmol).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH:5]1([Mg]Br)[CH2:7][CH2:6]1.C1COCC1.[CH3:15][C@H:16]1[C:20](=[O:21])[CH2:19][CH2:18][N:17]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>>[CH:5]1([C@:20]2([OH:21])[CH2:19][CH2:18][N:17]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[C@H:16]2[CH3:15])[CH2:7][CH2:6]1
Reactant: Br[Mg]C1CC1
Reactant: C[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C[C@@H]1N(C(=O)OCc2ccccc2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Reference Example 3 and using cerium chloride (11.1 g), 0.5 mol/L cyclopropylmagnesium bromide—THF solution (72.0 mL) and benzyl (2S)-2-methyl-3-oxopyrrolidine-1-carboxylate (3.0 g), the title compound was obtained as colorless oil (yield: 1.64 g, yield: 46%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[C:11]2[N:12]([CH3:17])[O:13][C:14](=[O:16])[N:15]=2)[N:6]=1.N1C=CC=CC=1.[O:30]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][CH2:32][CH:31]1[C:40](Cl)=[O:41]>ClCCl>[CH3:17][N:12]1[C:11](/[C:10](=[N:9]\[O:8][CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:40]([CH:31]3[O:30][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[O:33][CH2:32]3)=[O:41])[S:3][CH:4]=2)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14](=[O:16])[O:13]1
Reactant: O=C(Cl)C1COc2ccccc2O1
Reactant: Cn1oc(=O)nc1/C(=N\OCc1csc(N)n1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1oc(=O)nc1/C(=N\OCc1csc(NC(=O)C2COc3ccccc3O2)n1)c1ccccc1
Reaction time: 8 h
Yield: 106.4 %

Procedure:
To a solution of 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (120 mg, 0.362 mmol, 1 eq.) and pyridine (0.044 ml, 0.543 mmol, 1.5 eq) in dry dichloromethane (2.0 ml) at room temperature was added 2,3-dihydro-1,4-benzodioxine-2-carbonyl chloride (108 mg, 0.543 mmol, 1.5 eq) and stirring was allowed overnight. The reaction was quenched by addition of water and concentrated to dryness. The residue was taken in EtOAc and 0.5 ml of 1N NaOH was added. The solution was filtered through a chemelut pad and washed with EtOAc. After concentration, the residue was purified by chromatography on silica gel to give N-{4-[({[(Z)-(2-methyl-5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-yl}-2,3-dihydro-1,4-benzodioxine-2-carboxamide (190 mg, 99% yield).
Reaction SMILES: CO[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].[ClH:10].Cl.[NH2:12][CH2:13][CH2:14][SH:15]>C(O)(=O)C>[ClH:10].[ClH:10].[NH2:12][CH2:13][CH2:14][S:15][CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9]
Reactant: NCCS
Reactant: COCc1nc[nH]c1C
Agent: Cl
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CSCCN
Yield: 80 %

Procedure:
4-Methoxymethyl-5-methylimidazole as the hydrochloride (4.5 g, 0.03 mole) and 3.4 g (0.03 mole) of cysteamine hydrochloride were dissolved in a minimum amount of acetic acid and the mixture was refluxed for 18 hours. After cooling in an ice bath, the mixture was filtered to give 5.8 g (80%) of 4-(2-aminoethyl)thiomethyl-5-methylimidazole dihydrochloride salt (thioamine salt).
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2].[C:11](=O)([O-])[O-].[K+].[K+].CI>>[CH3:11][O:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ncccc1O
Agent: [K+]
Solvent: CI
Product: COc1cccnc1[N+](=O)[O-]
Yield: 97.4 %

Procedure:
The similar reaction as described in Reference Example 9 by using 2-nitro-3-hydroxypyridine (7.0 g), potassium carbonate (6.91 g) and methyl iodide (4.67 ml) gave the title compound (7.5 g) as crystalline powders.
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[CH:38][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][NH:23][C:24](=[O:37])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:27][CH:26]=3)=[CH:16][CH:15]=2)[C:8]([O:10]CC)=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][NH:23][C:24](=[O:37])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:27][CH:26]=3)=[CH:18][CH:19]=2)[C:8]([OH:10])=[O:9])=[CH:38][CH:39]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(OC(Cc2ccc(OCCNC(=O)c3ccc(-c4ccccn4)cc3)cc2)C(=O)O)cc1
Yield: 88.6 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(4-methylphenoxy)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (680 mg), which is the product of Example 114, was reacted with aqueous sodium hydroxide solution (1N, 2.60 ml) and the reaction mixture was treated to give the title compound (570 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.C([Li])CCC.CCCCCC.[CH3:24][C:25](=[C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)[CH3:26].[Cl-].[NH4+]>O1CCCC1>[CH2:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([C:25]([CH3:26])([CH3:24])[CH2:1][C:2]2[N:3]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:4]=[CH:5][N:6]=2)=[CH:28]1
Reactant: CC(C)=C1C=Cc2ccccc21
Reactant: Cc1nccn1-c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(Cc1nccn1-c1ccccc1)C1=CCc2ccccc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 1.58 g 2-methyl-1-phenyl-1H-imidazole (10 mmol) in 15 ml of tetrahydrofuran was cooled to −78° C. and 6.25 ml of 15% n-butyl-lithium in hexane (10 mmol) were added. The resulting mixture was stirred for an additional 20 min and then treated with a solution of 1.56 g 1-(1-methylethylidene)-1H-indene (10 mmol) in 5 ml tetrahydrofuran with vigorous stirring while the temperature was maintained at −78° C. The reaction mixture was allowed to reach room temperature, stirred for 14 h and hydrolyzed with saturated ammonium chloride solution. The organic layer was isolated and the aqueous layer was extracted three times with dichloromethane. The organic layers were dried over MgSO4, filtered and the solvent removed. The crude product was purified by column chromatography with silica as stationary phase. At the beginning a 5/1 hexane/ethyl acetate elution mixture was used (for the separation from 1-(1-methylethylidene)-1H-indene). Then, the elution mixture was changed to 1/1 hexane/ethyl acetate. After removal of the solvent 2.13 g (69%) of 2-[2-(1H-inden-3-yl)-2-methylpropyl]-1-phenyl-1H-imidazole was obtained as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]([C:13]([OH:15])=O)[CH2:11][N:10]([CH3:16])[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:20]([OH:24])[C:21]([NH2:23])=[O:22].O[NH-].O=[N-]>>[NH2:23][C:21](=[O:22])[C:20](=[O:24])[CH:19]([NH:18][C:13]([C@H:12]1[CH2:11][N:10]([CH3:16])[C:9](=[O:17])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:15])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: CN1C[C@H](C(=O)O)N(Cc2ccccc2)C1=O
Agent: [N-]=O
Agent: [NH-]O
Product: CN1C[C@H](C(=O)NC(Cc2ccccc2)C(=O)C(N)=O)N(Cc2ccccc2)C1=O

Procedure:
Coupling of (R)-3-Benzyl-1-methyl-2-oxo-imidazolidine-4-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [C:1]([S@@:5]([NH:7][C@H:8]([C:12]1([C:17]([O:19]CC)=O)[S:16][CH2:15][CH2:14][S:13]1)[CH2:9][CH2:10][CH3:11])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:22][NH2:23].C(O)C>>[C:1]([S@@:5]([NH:7][C@H:8]([C:12]1([C:17]([NH:23][CH3:22])=[O:19])[S:16][CH2:15][CH2:14][S:13]1)[CH2:9][CH2:10][CH3:11])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CCC[C@H](N[S@@](=O)C(C)(C)C)C1(C(=O)OCC)SCCS1
Solvent: CCO
Product: CCC[C@H](N[S@@](=O)C(C)(C)C)C1(C(=O)NC)SCCS1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
A heavy-walled glass tube was charged with ethyl (S,SS)-2-[1-(tert-butylsulfinylamino)butyl]-1,3-dithiolane-2-carboxylate (0.50 g, 1.4 mmol) and a chilled 8.0 M solution of methylamine in ethanol (5 mL, 40 mmol). The mixture was allowed to warm to room temperature and was allowed to stand for 72 hours. Distillation of the solvent at reduced pressure afforded (S,SS)-2-[1-(tert-butylsulfinylamino)butyl]-N-methyl-1,3-dithiolane-2-carboxamide (0.47 g, 98%) as a viscous amber-colored oil.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([C:4](=[O:16])[CH:5]=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8])[CH3:3].[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1>C1(C)C=CC=CC=1>[N:18]1([CH:5]([CH2:6][C:7]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[O:8])[C:4](=[O:16])[C:2]([CH3:17])([CH3:1])[CH3:3])[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: CC(C)(C)C(=O)C=CC(=O)c1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)C(CC(=O)c1ccc(Cl)cc1)n1cncn1
Temperature: 25 °C
Yield: 75 %

Procedure:
2,2-Dimethyl-6-p-chlorophenyl-hex-4-en-3,6-dione (0.05 mol) and 1,2,4-triazole (0.05 mol) were suspended in toluene (200 ml) and refluxed for 24 hours. After cooling to room temperature, the excess triazole was filtered off and the organic layer washed with water (2×150 ml) and dried over anhydrous sodium sulphate. Removal of the solvent gave a brown solid which on recrystallisation from petrol/chloroform gave 4-(1,2,4-triazol-1-yl)-2,2-dimethyl-6-p-chlorophenyl-hexan-3,6-dione (75% yield) as colourless needles m.p. 116°-119°.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:24][C:25]1[CH:26]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:28]=[CH:29][C:30]=1[Cl:31]>>[Cl:24][C:25]1[CH:26]=[C:27]([S:32]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:21])([F:22])[F:23])[CH2:12][CH2:13]2)(=[O:33])=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: FC(F)(F)c1ccccc1C1=CCN(Cc2ccccc2)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)N1CCC(c2ccccc2C(F)(F)F)CC1
Yield: 74.1 %

Procedure:
Using the procedure from Example 14A, 1-benzyl-4-[2-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (Example 14A, Step 14C, 150 mg, 0.65 mmol) was reacted with 3,4-dichlorobenzenesulfonyl chloride (191 mg, 0.12 mL, 0.78 mmol) to afford the title compound (211 mg), a white solid, in 74% yield.