Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:27]=[C:26]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)[CH:25]=[CH:24][C:10]=1[O:11][C@H:12]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:13]1=[O:23].[Cl:34][C:35]1[CH:40]=[N:39][C:38](Cl)=[CH:37][N:36]=1.C(N(C(C)C)C(C)C)C>CS(C)=O.O>[Cl:34][C:35]1[N:36]=[CH:37][C:38]([N:20]2[CH2:19][CH2:18][CH:17]([N:14]3[CH2:15][CH2:16][C@H:12]([O:11][C:10]4[CH:24]=[CH:25][C:26]([C:28]5[O:29][C:30]([CH3:33])=[N:31][N:32]=5)=[CH:27][C:9]=4[F:8])[C:13]3=[O:23])[CH2:22][CH2:21]2)=[N:39][CH:40]=1
Reactant: Cc1nnc(-c2ccc(O[C@H]3CCN(C4CCNCC4)C3=O)c(F)c2)o1
Reactant: Clc1cnc(Cl)cn1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(-c2ccc(O[C@H]3CCN(C4CCN(c5cnc(Cl)cn5)CC4)C3=O)c(F)c2)o1
Temperature: 100 °C
Yield: 10.2 %

Procedure:
(S)-3-(2-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)-1-(piperidin-4-yl)pyrrolidin-2-one 2,2,2-trifluoroacetate (150 mg, 0.316 mmol) was dissolved in DMSO (3 mL) and 2,5-dichloropyrazine (70.7 mg, 0.474 mmol) and N-ethyl-N-isopropylpropan-2-amine (138 μL, 0.790 mmol) were added and the reaction heated to 100° C. overnight. The reaction was cooled and diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified twice over silica gel (100% EtOAc) to afford (S)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)pyrrolidin-2-one (15.2 mg, 0.0321 mmol, 10.2% yield) as a red solid. Mass spectrum (apci) m/z=473.1 (M+H).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:24])[C:6]1[CH:15]=[C:14]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:13]=[C:8]([C:9]([O:11]C)=[O:10])[CH:7]=1.Cl>O.CCO>[N:21]1[CH:20]=[CH:19][C:18]([CH:17]=[CH:16][C:14]2[CH:13]=[C:8]([C:9]([OH:11])=[O:10])[CH:7]=[C:6]([CH:15]=2)[C:5]([OH:24])=[O:4])=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(C=Cc2ccncc2)cc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(C=Cc2ccncc2)cc(C(=O)O)c1
Temperature: 25 °C

Procedure:
A solution of LiOH (2.5 mmol) in water (1 ml) was added to 5-(2-pyridin-4-yl-vinyl)-isophthalic acid dimethylester (297 mg, 1 mmol) suspended in 5 ml EtOH. The mixture was stirred at room temperature. The reaction was monitored by TLC until completion. 2.5 ml 1 M HCl solution was then added and the mixture was evaporated to dryness. The product was used in next step without further purification.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[C:21]([F:24])([F:23])[F:22].[OH-].[K+]>O1CCCC1>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH:3][C:1]#[N:2])=[CH:15][C:14]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#CC=Cc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 87.1 %

Procedure:
A solution of 10.6 g (0.06 mol) of diethyl cyanomethylphosphonate and 12.5 g (0.06 mol) of 4-chloro-3trifluoromethyl-benzaldehyde in 65 ml of tetrahydrofuran is added dropwise to a suspension of 6.7 g (0.12 mol) of pulverulent potassium hydroxide in 185 ml of tetrahydrofuran. During this process the temperature of the reaction mixture rises slightly. Stirring is subsequently continued at room temperature for 20 minutes, and the solid which separates out in this process is filtered off and washed with tetrahydrofuran. The filtrate is concentrated in vacuo and the residue which remains is dried. 12.1 g (87.0% of theory) of 4-chloro-3-trifluoromethyl-cinnamonitrile are obtained in the form of an E/Z isomer mixture.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[C:5]([CH2:8]O)=[N:4][CH:3]=1.BrC(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].[CH3:36][C:37]1[NH:38][CH:39]=[CH:40][N:41]=1>C1COCC1.CN(C=O)C>[Br:1][C:2]1[N:6]([CH3:7])[C:5]([CH2:8][N:38]2[CH:39]=[CH:40][N:41]=[C:37]2[CH3:36])=[N:4][CH:3]=1
Reactant: Cc1ncc[nH]1
Reactant: Cn1c(Br)cnc1CO
Agent: BrC(Br)(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nccn1Cc1ncc(Br)n1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
(5-Bromo-1-methyl-1H-imidazol-2-yl)-methanol (1.0 g, 5.24 mmol) and tetrabromomethane (2.48 g, 7.33 mmol) were dissolved in THF (10.0 ml) and cooled to 0° C. Triphenylphosphine (1.98 g, 7.33 mmol) was added portionwise over a period of 30 min. The reaction mixture was stirred at 0° C. for 1 h to provide a white suspension. In a second flask, NaH (1.05 g, 26.18 mmol, 60% in mineral oil) was suspended in DMF (20 ml) and cooled to 0° C. 2-Methylimidazole (2.15 g, 26.2 mmol) was added portionwise. The reaction mixture was stirred at 60° C. for 30 min, cooled to 0° C. and treated with the above suspension. After 2 h stirring at room temperature, the reaction mixture was quenched with aqueous saturated NaHCO3 solution (50 ml). The aqueous layer was extracted 3 times with AcOEt. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was chromatographed (silica, elution with CH2Cl2/MeOH=95:5) to provide the title compound (0.7 g, 52%) as a brown solid. MS: m/e=255.0 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.[CH2:18]=O>C(O)=O>[CH3:18][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: c1ccc2c(c1)CCC2CCC1CCCCN1
Reactant: C=O
Solvent: O=CO
Product: CN1CCCCC1CCC1CCc2ccccc21

Procedure:
45 g. of 1-[2-(2-piperidyl)ethyl]indane prepared as described above is mixed with 100 ml. of 37% formalin and 200 ml. of 98% formic acid is added while swirling and the solution is then heated overnight on a steam bath. The reaction mixture is worked up by concentrating in vacuo, dissolving in water, filtering, basification and extraction with ether. The ether extracts are dried over potassium hydroxide and after removal of the ether, the product is distilled collecting 42.6 g. (88%), N-methyl-1-[2-(2-piperidyl)ethyl]indane, boiling point 128°-130°C/0.2 mm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([O:11]C)=[O:10])=[N:3][CH:2]=1.[ClH:17]>C(O)(=O)C>[ClH:17].[ClH:17].[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([OH:11])=[O:10])=[N:3][CH:2]=1
Reactant: COC(=O)c1cccnc1-c1ccncn1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cccnc1-c1ccncn1

Procedure:
A mixture of methyl 2-(pyrimidin-4-yl)nicotinate (0.19 g), acetic acid (1.0 mL) and 6 N hydrochloric acid (5 mL) was heated under reflux for 5 hr. The solvent was evaporated under reduced pressure to give the title compound (0.26 g).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:12]([OH:14])=[O:13])=[CH:3]1>CC(O)=O.[Pd]>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH:4]1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(=O)c2ccccc2o1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)C1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 25 h
Yield: 72.2 %

Procedure:
A mixture of 4-oxochromene-2-carboxylic acid (20.0 g, 105 mmol) and Pd/C (3.0 g, w/w=10%) in AcOH (200 mL) was placed in Parr hydrogenation apparatus under H2 (50 psi) and stirred for 25 h at rt. It was then filtered and concentrated. The residue was suspended in water (300 mL), stirred for 10 min, filtered and dried to give 3,4-dihydro-2H-chromene-2-carboxylic acid (13.5 g, 72%) as a white solid. BH3 (57 mL, 114 mmol, 2.0 M in THF) was added slowly to a solution of this carboxylic acid in THF (120 mL) at 0° C. The reaction mixture was then warmed to rt and stirred for 5 h at this temperature. THF/H2O (30 mL, 1:1) was added drop wise while keeping the temperature between 0-5° C. and stirred for 20 min. K2CO3 (26.0 g, 189 mmol) was added and the reaction was vigorously stirred for 30 min. The THF layer was separated and concentrated to give the title compound (11.0 g, 89%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 7.10-7.03 (m, 2H), 6.86-6.81 (m, 2H), 4.14-4.08 (m, 1H), 3.85-3.68 (m, 2H), 2.92-2.84 (m, 1H), 2.80-2.73 (m, 1H), 1.98-1.92 (m, 1H), 1.90-1.79 (m, 1H). LCMS: 165 (M+1)+
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][C:5](=[CH2:20])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[CH:18]=[O:19]>CC(C)=O>[I:1][CH2:4][C:5](=[CH2:20])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[CH:18]=[O:19]
Reactant: [I-]
Reactant: C=C(CCl)COc1ccc(C(=O)OC)cc1C=O
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(CI)COc1ccc(C(=O)OC)cc1C=O
Reaction time: 5 h
Yield: 90.8 %

Procedure:
375 mg (2.5 mmol) of sodium iodide are added to 560 mg (2.08 mmol) of methyl 4-{[2-(chloromethyl)-2-propenyl]oxy}-3-formylbenzoate in solution in 20 ml of acetone. The solution is brought to reflux and is stirred for 5 hours with the exclusion of light. After the usual treatments, 680 mg (91%) of methyl 4-{[2-(iodomethyl)-2-propenyl]oxy}-3-formylbenzoate are obtained in the form of a white solid which turns yellow in light; 1H NMR (300 MHz, CDCl3): 10.48 (s, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.21 (dd, J=2.4 Hz and 8.7 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 5.54 (s, 1H), 5.35 (s, 1H), 4.87 (s, 2H), 4.04 (s, 2H), 3.89 (s, 3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:33]=[C:34]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:33]=[C:34](/[CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)\[CH3:35])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC(=CBr)C1CCCCC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)C1CCCCC1
Temperature: 85 °C

Procedure:
8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (110 mg, 0.5 mmol) was dissolved in DMF (3 mL) and potassium phosphate (212.4 mg, 1 mmol), copper(I) iodide (9.5 mg, 0.05 mmol) and L-proline (11.51 mg, 0.1 mmol) was added in to it. (1-bromoprop-1-en-2-yl)cyclohexane (121.8 mg, 0.6 mmol) was dissolved in DMF (2 mL) and added dropwise. Nitrogen was purged for 2 min and the reaction mixture was heated at 85° C. overnight (prolonged heating was required in some cases). DMF was evaporated and water was added. The precipitate obtained was filtered and purified by silica gel chromatography (100-200 mesh) using 0-3% MeOH:DCM as eluent. The compound was further purified through reverse phase purification. Yield: 35 mg. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.50 (s, 1H), 7.18 (m, 2H), 6.28 (s, 1H), 4.70 (m, 1H), 4.58 (m, 1H), 3.82 (m, 1H), 3.60 (m, 1H), 3.15 (s, 3H), 3.10 (m, 2H), 2.0 (m, 1H), 1.90 (s, 3H), 1.70 (m, 2H), 1.58 (m, 1H), 1.50 (m, 4H), 1.15 (m, 3H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=O)=[CH:5]1>>[CH2:1]([NH:3][CH2:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][CH:5]=1)[CH3:2]
Reactant: CCN
Reactant: O=Cc1c[nH]c2ccccc12
Product: CCNCc1c[nH]c2ccccc12

Procedure:
prepared by reaction of ethylamine with 1H-indole-3-carbaldehyde
Reaction SMILES: [F:1][CH:2]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:11]3[C:6](=[CH:7][C:8]([F:16])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[C:3]1=[O:17].[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O>C(O)(=O)C>[F:1][CH:2]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:11]3[C:6](=[CH:7][C:8]([F:16])=[CH:9][C:10]=3[N+:18]([O-:20])=[O:19])[CH2:5][C:4]=2[C:3]1=[O:17]
Reactant: CC1=CC(F)C(=O)C2=C1c1ccc(F)cc1C2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC1=CC(F)C(=O)C2=C1c1c(cc(F)cc1[N+](=O)[O-])C2

Procedure:
Treatment of 2,7-difluoro-4-methyl-9H-fluorenone in acetic acid with a mixture of nitric acid and sulfuric acid gave 2,7-difluoro-4-methyl-5-nitro-9H-fluorenone as the major product. 5-Amino-2,7-difluoro-4-methyl-9H-fluorenone was obtained by reduction using tin(II)chloride in a mixture of ethanol and aqueous hydrochloric acid. Thermal decomposition in hot xylene of the diazonium tetrafluoroborate, formed with sodium nitrite in aqueous fluoboric acid, provided 2,4,7-tri-fluoro-5-methyl-9H-fluorenone. Treatment of the ketone with potassium cyanide and ammonium carbonate in ethanol at 120° C. for 18 hours provided the title compound.
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.C([Li])CCC.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[F:26][C:27]1([F:51])[CH:31]([O:32][S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:30][N:29](C(OC(C)(C)C)=O)[C:28]1=O>O1CCCC1.O>[CH3:42][C:39]1[CH:38]=[CH:37][C:36]([S:33]([O:32][CH:31]2[C:27]([F:51])([F:26])[C:28]([C:25]3[C:20]([F:19])=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:29][CH2:30]2)(=[O:35])=[O:34])=[CH:41][CH:40]=1
Reactant: Fc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)OC2CN(C(=O)OC(C)(C)C)C(=O)C2(F)F)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)OC2CN=C(c3cccnc3F)C2(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of diisopropylamine (8.76 g) in tetrahydrofuran (230 mL) was added 1.6 mol/L n-butyllithium hexane solution (51 mL) at −78° C., and the mixture was stirred for 1 hr. 2-Fluoropyridine (11.2 g) was added dropwise thereto, and the mixture was stirred for 2 hr. To the resultant pale-yellow suspension was slowly added dropwise a solution of tert-butyl 3,3-difluoro-4-{[(4-methylphenyl)sulfonyl]oxy}-2-oxopyrrolidine-1-carboxylate (22.6 g) in tetrahydrofuran (50 mL), and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was heated to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with water. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained mixture was dissolved in dichloromethane (30 mL), trifluoroacetic acid (100 mL) was added dropwise under ice-cooling, and the mixture was stirred for 4 hr while allowing the mixture to warm to room temperature. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and a saturated aqueous sodium hydrogen carbonate solution was added until the mixture became neutral. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:1) to give the title compound as a colorless solid (yield 10.9 g, 51%).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]([CH:12]([CH2:15][CH:16]=[CH2:17])[CH:13]=O)[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:23][NH2:24].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.CO.ClCCl>[CH3:23][NH:24][CH2:13][CH:12]([CH:10]1[C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[CH2:7][O:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]1=2)[CH2:15][CH:16]=[CH2:17]
Reactant: C=CCC(C=O)C1c2ccccc2COc2ccccc21
Reactant: CN
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCC(CNC)C1c2ccccc2COc2ccccc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 72 %

Procedure:
Dissolved 2-[6,11 -dihydro-dibenzo[b,e]oxepin-11-yl]-pent-4-en-1-al (5.0 g, 18.0 mmol) in 20 mL of dry THF and 60 mL of dry MeOH. Added 3 A molecular sieves, methylamine hydrochloride (6.1 g, 89.8 mmol), and then sodium cyanoborohydride (1.13 g, 18.0 mmol). Stirred at room temperature for 23 hours. Evaporated reaction mixture. Added 80 mL of saturated NaHCO3 and 80 mL of dichloromethane. FIltered through celite. Separated layers. Extracted aqueous solution with dichloromethane. Dried combined organic extracts with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 5% MeOH--CH2Cl2. Combined appropriate fractions and evaporated to give 3.8 g (73% yield) of N-methyl-2-[6,11-dihydro-dibenzo[b,e]oxepin-11-yl]-pent-4-en-1-amine. Dissolved free base in ethyl acetate, and added one equivalent of maleic acid dissolved in ethanol. Evaporated to give maleate salt as a glass.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[CH:3]=1.Cl.[C:17]([O:21][C:22](=[O:27])[C:23]([NH2:26])([CH3:25])[CH3:24])([CH3:20])([CH3:19])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.O>[C:17]([O:21][C:22](=[O:27])[C:23]([NH:26][C:13]([C:4]1[CH:3]=[C:2]([Cl:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:12])=[O:15])([CH3:25])[CH3:24])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: O=C(O)c1cc(Cl)c2ccccc2c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1cc(Cl)c2ccccc2c1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
2.25 g of 4-chloro-1-hydroxy-naphthalene-2-carboxylic acid, 3.57 2-amino-2-methyl-propionic acid tert-butyl ester hydrochloride, 6.93 g HATU and 5.29 mL of N,N′diisopropylethylamine were dissolved in 100 mL of dimethylformamide. The reaction was heated at 60° C. for 1.5 hour followed by room temperature overnight. Water was added and the mixture was extracted with diethyl ether twice. The combined organic layers were dried with magnesium sulfate and concentrated in vacuo. Purification by flash chromatography on silica with heptanes/ethyl acetate afforded 1.016 g (28%) of 2-[(4-chloro-1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid tert-butyl ester as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[C:28]#[N:29])=[CH:4][C:5](=[O:20])[N:6]([CH:8]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:3]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[C:28]#[N:29])=[CH:4][C:5](=[O:20])[N:6]([CH:8]([CH2:16][CH:17]2[CH2:18][CH2:19]2)[C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)C(CC1CC1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Cl)cc1-c1cc(=O)n(C(CC2CC2)C(=O)O)cc1Cl

Procedure:
245 mg (0.57 mmol) of tert-butyl 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoate (racemate) were hydrolysed with 20 eq. of TFA according to General Method 6A. Yield: 268 mg (quant.)
Reaction SMILES: [NH2:1]/[C:2](=[N:28]\[OH:29])/[CH2:3][CH2:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)[N:9]=[N:8][C:7]=1[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23].[C:30](N1C=CN=C1)(N1C=CN=C1)=[O:31].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:25]1([NH:24][C:22]([C:7]2[N:8]=[N:9][N:10]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:16]=3)[C:6]=2[CH2:5][CH2:4][CH2:3][C:2]2[NH:1][C:30](=[O:31])[O:29][N:28]=2)=[O:23])[CH2:27][CH2:26]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC/C(N)=N/O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCc2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
To a solution of 5-[(4Z)-4-amino-4-(hydroxyimino)butyl]-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (240 mg, 0.6 mmol) obtained in Example 1209 and 1,1′-carbonyldiimidazole (97 mg, 0.6 mmol) in THF (5 ml) was added DBU (91 mg, 0.6 mmol) at room temperature and the mixture was stirred at 50° C. for 3 hr and concentrated. The residue was dissolved in water (10 ml), adjusted to pH 4-5 with 1N hydrochloric acid and liberated oil was extracted with ethyl acetate (30 ml×2). The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1) to give the title compound as a colorless powder (150 mg, 59%).
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:9]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:8]=2)=[CH:4][CH:3]=1.[CH3:31][N:32](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]1([N:9]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)=[CH:11][C:7]([CH2:6][C:5]3[CH:29]=[CH:30][C:2]([C:31]#[N:32])=[CH:3][CH:4]=3)=[N:8]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: FC(F)(F)Oc1ccc(-c2cc(Cc3ccc(Br)cc3)nn2C2CCCCC2)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(Cc2cc(-c3ccc(OC(F)(F)F)cc3)n(C3CCCCC3)n2)cc1
Temperature: 80 °C

Procedure:
A mixture of 526 mg 3-(4-bromobenzyl)-1-cyclohexyl-5-[4-(trifluoromethoxy)phenyl]-1H-pyrazole from Step C above, 79.9 mg zinc cyanide, 50.8 mg tetrakis(triphenylphosphine)palladium(0) in 2 mL DMF was heated under nitrogen in 80° C. oil bath for 20 hours. Evaporate most of DMF. The residue was purified on silica gel using 1 and 3% MeCN in methylene chloride to give the title compound as a yellowish solid. 1H NMR (CDCl3, 500 MHz) δ 7.61 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.35˜7.38 (m, 2H), 7.31 (d, J=8.3 Hz, 2H), 5.94 (s, 1H), 4.09 (s, 2H), 4.02 (tt, J=2.75 & 11.7 Hz, 1H), 2.03˜2.11 (m, 2H), 1.87˜1.94 (m, 4H), 1.69˜1.72 (m, 1H), 1.25˜1.35 (m, 3H). LC-MS: 2.55 min. (M+H=426.2).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:26](=[O:28])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCCCSc2ccncc2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(CCCSc1ccncc1)Cc1ccccc1
Yield: 84.3 %

Procedure:
To a solution of 1.0 g (3.87 mmol) of 4-[3-(N-benzylamino)propylthio)-pyridine and 0.65 ml (4.64 mmol) of triethylamine in 25 ml of methylene chloride, 0.49 ml (4.64 mmol) of acetyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: chloroform/methanol=25:l) to obtain 980 mg of the desired compound (yield: 84.2%, yellow oil).