Azzindani/Open_Reaction_Data huggingface dataset:
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])[NH:7][C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([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])[NH:7][C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared in an analogous manner to the preparation of example 381 by combining 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (48%). LCMS: m/z=483.24 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 8.08 (s, 1H), 8.01 (m, 2H), 7.45 (s, 1H), 7.33 (m, 3H), 7.23 (d, 1H, J=8.6 Hz), 6.92 (d, 1H, J=8.6 Hz), 6.57 (m, 1H), 2.93 (d, 3H, J=4.8 Hz), 2.37 (m, 2H), 2.07 (m, 2H), 1.35 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2ncc[nH]2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccnc1-c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a solution of 2-(4-chlorophenyl)-1H-imidazole (90 (20 mmol) in anhydrous THF (200 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.2 g, 30 mmol) and stirred for 30 min. Benzenesulfonyl chloride (2.82 mL, 22 mmol) was added and the reaction mixture was stirred overnight. After dilution by 100 mL of saturated NaHCO3 solution (aqueous), the reaction mixture was extracted by ethyl acetate (500 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 2:1) to give a pale solid. Yield: 54.9%. NMR (500 MHz, CDCl3) δ 7.65 (d, J=2.0 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.43 (d, J=8.5 Hz, 2H), 7.38 (t, J=8.0 Hz, 2H), 7.34-7.36 (m, 4H), 7.12 (d, J=1.5 Hz, 1H). MS (ESI): calculated for C15H11ClN2O2S, 318.0. found 341.0 [M+Na]+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:21][CH2:20]1
Reactant: ClCc1nc2cccnc2s1
Reactant: Fc1ccccc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-(2-fluorophenyl)piperazine (215 mg, 1.2 mmol), and DIEA (380 μL, 2.2 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.77 (m, 4H) 3.10 (m, 4H) 4.06 (s, 2H) 7.08 (m, 4H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.33 (dd, J=8.31, 1.53 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H); (ESI) m/z 329 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10](=[O:27])[N:11]([CH2:24][CH2:25]O)[N:12]=[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:14]=2[CH3:15])[CH:6]=[CH:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:47]NC(=O)CCC(N)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10](=[O:27])[N:11]([CH2:24][CH2:25][Br:47])[N:12]=[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:14]=2[CH3:15])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2c(C)c(Cc3ccccc3F)nn(CCO)c2=O)c1
Reactant: NC(=O)CCC(=O)NBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(-c2c(C)c(Cc3ccccc3F)nn(CCBr)c2=O)c1

Procedure:
A solution of 4-(3-methoxyphenyl)-5-methyl-6-(2-fluorobenzyl)-2-(2-hydroxyethyl)-pyridazin-3-one (from above) and triphenylphospine (570 mg, 22 mmol) in dichloromethane (8 mL) was treated with N-bromosuccinamide (400 mg, 22 mmol) at room temperature for 2 hours. The crude product was used for next step. MS: 431 (MH+).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([CH3:9])([CH3:8])[CH3:7])C.C[O-].[Na+].Cl.[NH2:23]O.Cl>CO>[C:6]([C:5]1[C:4]([OH:3])=[N:23][O:17][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C(=O)c1ccccc1)C(C)(C)C
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1c(O)noc1-c1ccccc1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
2-Benzoyl-3,3-dimethylbutyric acid ethyl ester (2.0 g) was dissolved in methanol (20 ml), and sodium methoxide (28% methanol solution, 1.6 ml) was added dropwise thereto at 5° C. under a nitrogen atmosphere, followed by stirring of the resulting mixture for 10 minutes. The reaction mixture was cooled to -30° C., and a suspension of hydroxylamine hydrochloride (1.1 g) and sodium methoxide (28% methanol solution, 6.2 ml) in methanol (10 ml) was added dropwise to the reaction mixture. The resulting mixture was stirred at the same temperature for 30 minutes, and 6N hydrochloric acid (14 ml) was added to the reaction mixture, followed by stirring of the resulting mixture at 80° C. for one hour. After the reaction, the solvent was evaporated under reduced pressure. After the residue was poured into ice-cold water and extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was crystallized from isopropyl ether to obtain the title compound (0.35 g, 20%) as colorless crystals.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1([Br:14])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:13].CC(O)(C)C>O>[Br:14][C:4]1([Br:3])[C:12]2[C:7](=[N:8][CH:9]=[C:10]([Br:1])[CH:11]=2)[NH:6][C:5]1=[O:13]
Reactant: BrBr
Reactant: O=C1Nc2ncccc2C1(Br)Br
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1Nc2ncc(Br)cc2C1(Br)Br
Temperature: 15 °C
Yield: 84.1 %

Procedure:
Bromine (13.4 mL, 0.262 mol) was added dropwise over a period of 30 min to a cooled (ice bath) and stirred suspension of 2 (37.86 g, 0.131 mol) in water:t-BuOH=1:1 (1500 mL). Cooling bath was removed and the mixture was stirred at r.t. overnight. Then the solution was cooled to 15° C. and saturated aqueous solution of NaHCO3 (278 mL) was added. A yellow suspension, which was formed, was concentrated in vacuum (bath temperature<32° C.) until about 1000 mL of condensate was collected. The solid was filtered off, washed with water (200 mL), and dried in vacuum to afford 3 (40.85 g, 85%) as tan powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[S:24]>C(#N)C>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]1[S:24][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:25]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: NC(=S)c1ccccc1Cl
Solvent: CC#N
Product: CSc1ccc(-c2sc(-c3ccccc3Cl)nc2-c2ccc(F)cc2)cc1
Temperature: 80 °C
Yield: 49.9 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethanone (2.03 g, 5.98 mmol) (Example 1, Step 3) in acetonitrile (60mL) in a 125 mL round bottom flask was added 2-chlorothiobenzamide (1.08 g, 6.28 mmol) and the suspension heated to 80° C. for 4 hours. The reaction was cooled to room temperature and the suspension filtered through a fritted funnel. The solid was recrystallized from hot acetonitrile (50 mL) and methanol (150 mL) yielding 2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylthiophenyl)thiazole as a tan solid (1.23 g, 50 %): mp 133°-134° C. 1H NMR (CDCl3) 300 mHz δ8.37 (d, J=6.17 Hz, 1H), 7.60 (dd, J=8.68, 5.28, 2H) 7.51 (d, J=9.44 Hz, 1H), 7.32-7.42 (m, 2H), 7.32 (d, J=8.68 Hz, 2H), 7.21 (d, J=8.68 Hz, 2H), 7.02 (t, J=8.68, 2H), 2.51 (s, 3H). MS (EI): m/z 412 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[C:17]([O:23][CH2:24][C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[N:16]=1>CN(C)C=O.[Cu]I>[CH3:22][S:21][C:19]1[CH:20]=[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:16]=[C:17]([O:23][CH2:24][C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[CH:18]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CSc1cc(Cl)nc(OCc2ccsc2)c1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(OCc2ccsc2)nc(Oc2cccc(C(F)(F)F)c2)c1

Procedure:
To a solution containing meta-trifluoromethylphenol (1.60 g, 0.0024×4.1 mol), sodium hydride (0.29 g, (ca.60% in mineral oil), 0.0024×3.0 mol) and CuI (0.22 g, 0.0024×0.5 mol) in dimethylformamide, 2-chloro-4-methylmercapto-6-(3-thienylmethyloxy)pyridine (0.64 g, 0. 0024 mol) was added and the resultant solution was refluxed for about 6 hours.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[OH-].[Na+:13].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Cl.Cl>O>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:18][NH:9][C:6]2[CH:5]=[CH:4][C:3]([S:1]([O-:11])(=[O:10])=[O:2])=[CH:8][CH:7]=2)[CH:20]=[CH:21][CH:22]=1.[Na+:13]
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: ClCc1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])c1ccc(NCc2cccc(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 120 h

Procedure:
A mixture of 17.2 g of sulfanilic acid, 100 ml of 5 Normal (N) sodium hydroxide solution, 100 ml of water and 16.1 g of 3-chlorobenzyl chloride was stirred in a 500-ml Erlenmeyer flask and heated to about 40°-50° C. After 5 days, a small portion of the reaction mixture was poured into dilute hydrochloric acid. A white precipitate formed which was insoluble in boiling water. The remaining portion of the reaction mixture was poured over 800 ml of ice-water, acidified with concentrated hydrochloric acid, and then filtered through a sintered glass funnel. After filtering, about 50 ml of slurry remained in the funnel. This slurry was put in a beaker, 200 ml of ethanol was added and the mixture was warmed to about 50° C. A solution of 5N sodium hydroxide was added dropwise until solution was achieved. The solution was carbon treated and filtered. Concentration of the filtrate gave a gummy semisolid which was recrystallized from 200 ml of acetic acid containing a small quantity of water. After vacuum oven drying, 5.4 g of the purified product, sodium 4-(((3-chlorophenyl)methyl)amino)benzenesulfonate, was obtained as an off-white solid having a melting point (mp) greater than 280° C.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:13][C:14]1[C:15]([F:25])=[C:16]([CH:20]=[C:21]([F:24])[C:22]=1F)[C:17]([OH:19])=[O:18].CC(C)([O-])C.[K+]>CS(C)=O.CCOC(C)=O>[C:1]12([CH2:11][O:12][C:22]3[C:21]([F:24])=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:25])[C:14]=3[Cl:13])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1F
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(F)c(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1F
Reaction time: 0.5 h
Yield: 150.9 %

Procedure:
To a solution of 1-adamantylmethanol (309 mg) and 3-chloro-2,4,5-trifluoro-benzoic acid (391 mg) in DMSO (5.6 mL) at 14° C. (bath) was added potassium tert-butoxide (458 mg) gradually. The mixture was stirred at that temp for 30 min. Diluted with EtOAc, the contents were washed with 1:4 mixture of 1M HCl and 1M NaH2PO4 (3×) and brine, and dried (Na2SO4). After filtration and concentration, the product was obtained as white solid (1.00 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1.O.O.[Sn](Cl)Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=3)[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reaction time: 4 h
Yield: 96.3 %

Procedure:
A mixture of the 6-methoxy-2-(4-nitropheyl)benzothiazoles 5 (22 mg, 0.077 mmol) and tin(II) chloride dihydrate (132 mg, 0.45 mmol) in boiling ethanol was stirred under nitrogen for 4 hrs. Ethanol was evaporated and the residue was dissolved in ethyl acetate (10 mL), washed with 1 N sodium hydroxide (2 mL) and water (5 mL), and dried over MgSO4. Evaporation of the solvent gave 19 mg (97%) of the product 6 as yellow solid.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)[CH3:33])=[O:30])([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29]([NH:31][C@H:32]([C:34]1[CH:40]=[CH:39][C:37]([NH:38]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:36][CH:35]=1)[CH3:33])=[O:30])([CH3:25])([CH3:26])[CH3:27]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and (S)-4-(1-tert.butoxycarbonylamino-ethyl)-aniline in DMF.
Reaction SMILES: C(O)C.[OH-].[K+].[CH2:6]([SH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1>O>[CH2:6]([S:13][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: SCc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccnc1SCc1ccccc1
Temperature: 55 °C
Reaction time: 0.42 h
Yield: 37.4 %

Procedure:
To a stirred solution of 35 ml of ethanol, 1 ml of water, and 2.0 g (0.025 mole) of 85% KOH pellets was added 3.2 g (0.025 mole) of benzyl mercaptan. To this mixture was added 4 g (0.025 mole) of 2-chloro-3-nitropyridine. After complete addition (20 minutes), the reaction mixture was warmed to 55° C. and held at that temperature for 25 minutes. It was then allowed to cool to room temperature over the next hour. The solid was filtered off (KCl) and the ethanol was removed from the filtrate. The residue was treated with 40 ml of acetone by warming, cooling and then filtering to remove more KCl. The filtrate was evaporated to leave an oil which solidified. The solid was recrystallized from 40 ml of ethanol to give 2.3 g of crystals, having a melting point of 57-59° C. The infrared spectrum was consistent with the structure. A second crop of 1.3 g of impure product was also obtained.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:27][CH:28]([CH3:32])[CH:29]([NH2:31])[CH3:30].C(N(CC)CC)C>C(#N)C>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=[C:3]([C:2]([F:1])([F:26])[F:25])[CH:4]=1)=[N:31][CH:29]([CH3:30])[CH:28]([CH3:32])[CH3:27])#[N:24]
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Reactant: CC(C)C(C)N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)C(C)N=C(NC#N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 48.8 %

Procedure:
A solution of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.8 mmol, 300 mg), 3-methyl-2-butylamine (0.88 mmol, 0.101 ml) and triethylamine (0.88 mmol, 0.123 ml) in acetonitrile (2 ml) was stirred for 7 h at 75° C. After concentration the residue was dissolved in ethyl acetate, washed with water, dried (Na2SO4) and concentrated. The residue was purified by column chromatography (heptane:ethyl acetate 4:1) to give the title compound (143 mg, 59%) as white crystals. Mp 134-136° C.; EI SP/MS: 366 (M+); 1H-NMR (CDCl3): δ 0.92 (d, 6H),1.15 (d, 3H), 1.78 (m, 1H), 3.78 (m, 1H), 4.85 (br, 1H), 7.73 (br s, 3H), 8.0 ppm (br, 1H); MA calc for C15H16F6N4 :C, 49.18%; H, 4.40%; N, 15.29%. Found: C, 48.95%; H, 4.38%; N 15.08%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].Cl.O.O.[C:13](O)(=[O:17])[C:14](O)=[O:15].[OH-].[Na+]>>[CH3:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[NH:1][C:13](=[O:17])[C:14](=[O:15])[NH:8]2
Reactant: Cc1cccc(N)c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Yield: 768.5 %

Procedure:
To a stirred solution of 2,3-diaminotoluene (0.498 g, 0.407 mmol, Aldrich) in 2 N HCl (6 mL, 12 mmol), oxalic acid dihydrate (0.520 g, 0.412 mmol, Fisher) was added in one portion. The resulting deep purple solution was refluxed for 13 h, to give a purple suspension. This was cooled to 25° C., filtered, washed with water (5 mL), and dried in vacuo (0.1 mm Hg) to give a purple powder. This was taken up in 2 N NaOH (25 mL, 50 mmol), giving a brown solution, which was filtered. The brown filtrate was acidified to pH 1.0 by addition of 2 N HCl (25 mL, 50 mmol), resulting in a tan suspension. Filtration of the suspension and washing of the filter cake with water (5 mL) gave the title compound as a tan powder (551 mg, 64%); mp 325° C. (the block was preheated to 320° C.); 1H NMR (DMSO-d6) δ 2.26 (s, 3H), 6.86-7.01 (m, 3H), 11.6 (broad, 2H).
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]([C:6]1[N:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)=[O:5].O>C1COCC1>[OH:5][CH:4]([C:6]1[N:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)[CH3:1]
Reactant: COC(=O)c1ccc(C=O)nc1
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
A solution of methyl magnesium bromide (1M in THF) (3.03 mL, 3.03 mmol) was added drop wise to a solution of methyl 6-formylpyridine-3-carboxylate (Intermediate 195, 0.50 g, 3.03 mmol) in THF (20 mL) at −78 C. The reaction mixture was stirred at −78 C for 1 h and water (20 mL) was added. The mixture was warmed to room temperature and extracted with EtOAc (3×20 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound as an off-white solid (0.407 g, 74%). Method B HPLC-MS: MH+ requires m/z=182 Found: m/z=182, Rt=1.11 min (98%).
Reaction SMILES: C[N:2](CC1C=CC=CC=1)[CH2:3][C:4]#C.O=[C:14]1O[C@H:19]([C@H:21]([CH2:23][OH:24])[OH:22])[C:17]([O-])=[C:15]1O.[Na+]>>[NH2:2][CH2:3][CH2:4][C:17]1[CH:15]=[CH:14][C:23]([OH:24])=[C:21]([OH:22])[CH:19]=1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: C#CCN(C)Cc1ccccc1
Agent: [Na+]
Product: NCCc1ccc(O)c(O)c1

Procedure:
The uptake reaction mixture was suspended in a final volume of 200 μl containing pargyline (final concentration of 10 μM) and sodium ascorbate (final concentration of 0.2 mg/ml) in each well of 96-well-round-bottom-plate.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[C:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[BH4-].[Na+].Cl>C(O)C>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:13][CH:14]=1
Reactant: N#CC(C#N)=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
First, 4.44 g of (4-(trifluoromethyl)benzylidene)malononitrile was dissolved in 20 ml of ethanol, and while stirring at room temperature, a suspension of 0.19 g of sodium borohydride in 5 ml of ethanol was added dropwise, followed by stirring at room temperature for 30 minutes. Then, 10% hydrochloride acid was added to the reaction mixture, which became acidic and was extracted with diethyl ether. The organic layer was successively washed with 10% hydrochloric acid, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.30 g of (4-(trifluoromethyl)benzyl)malononitrile (the intermediate (4)).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[I:14]N1C(=O)CCC1=O.P([O-])([O-])(O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[I:14][C:12]1[S:11][CH:10]=[C:9]([P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[CH:13]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOP(=O)(OCC)c1ccsc1
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)c1csc(I)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 73 %

Procedure:
In 5 ml of a mixed solvent of chloroform:acetic acid=1:1, 0.1101 g (0.5 mmols) of 3-(diethoxyphosphoryl)thiophene was dissolved, to which 0.2362 g (1.05 mmols) of commercially available N-iodosuccinimide was added at room temperature. Thereafter, the reaction mixture was stirred at room temperature for 4 days. After the reaction, a disodium hydrogen phosphate/sodium dihydrogen phosphate buffer solution, adjusted to pH=7, was added, followed by extraction with chloroform. The organic phase was washed with a 0.2N sodium hydroxide aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed, and the resulting crude product was purified with a PTLC plate (developed with ethyl acetate:hexane 1:1) to obtain the specified substance in the form of a yellow oil at a yield of 0.1263 g (yield: 73%). The thus obtained substance was used as it is for reaction in Example 12(9).
Reaction SMILES: [CH:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.C1C[O:20][CH2:19]C1>>[OH:20][CH2:19][C:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCC1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=C(O)C1(CO)CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Cyclopentanecarboxylic acid (1.10 g, 10.0 mmol) was placed in a round-bottomed bottomed flask, filled with nitrogen, and 30 mL of THF (30 mL) was added. The solution was cooled to −78° C., and LDA (8.8 mL, 2.5 m in hexane) was added dropwise. After being stirred for 30 min., the solution was bubbled by nitrogen stream containing formaldehyde gas (formaldehyde gas was in situ generated by thermal degradation of anhydrouse paraformaldehyde at 160° C.). When the reaction solution turned light yellow, the reaction mixture was quenched with a saturated aqueous NH4Cl solution at −78° C., and the organic material was extracted with EtOAc. The organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:12]1([C:15]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:16]=2[C:17](O)=[O:18])[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:16]=2[C:17]([NH:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:18])[CH2:14][CH2:13]1
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Product: O=C(N[C@@H]1CCC[C@@H]1N1CCCC1)c1ccc(C(F)(F)F)cc1C1CC1

Procedure:
The title compound, white solid, MS: m/e=367.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate K).