Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[CH3:22])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:25]([N:27]4[CH2:32][CH2:31][S:30][CH2:29][CH2:28]4)=[O:26])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:41])C=1>>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[CH3:22])=[CH:19][CH:20]=4)[CH2:12][N:11]([C:25]([N:27]4[CH2:28][CH2:29][S:30](=[O:41])[CH2:31][CH2:32]4)=[O:26])[CH2:10]3)[O:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CC(F)(F)c1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCSCC3)C2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(F)(F)c1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCS(=O)CC3)C2)cc1

Procedure:
34.1 mg (0.074 mmol) of the compound from Example 54A were reacted according to General Method 1 with 22.9 mg (0.066 mmol) of meta-chloroperbenzoic acid. Yield: 39.7 mg (100% of theory).
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([OH:6])=[O:5].C(OC(=O)C)(=O)C.[N+](C1C=CC(O)=CC=1)([O-])=O.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1.CN(C)C=O.C(Cl)(Cl)Cl.O>[C:4]([OH:6])(=[O:5])[CH:3]=[CH:2][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCC(O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCC=CC(=O)O
Reaction time: 4 h
Yield: 49.3 %

Procedure:
To a solution of 3-hydroxyhexadecanoic acid (2 g) in pyridine was added acetic anhydride at 0° C., and the mixture was stirred for 4 hours. The reaction mixture was distributed into chloroform-water, and the chloroform layer was concentrated. The residue obtained was dissolved in N,N-dimethylformamide (DMF). Para-nitrophenol (1.02 g) and N,N'-dicyclohexylcarbodiimide (1.51 g) were added to the solution, and the mixture was stirred for 12 hours. The reaction mixture was filtered and concentrated, and the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 50:1) to give an active ester of 2-hexadecenoic acid (0.92 g) and an active ester of 3-acetoxyhexadecanoic acid (1.01 g).
Reaction SMILES: [O-2].[Nd+3:2].[O-2].[O-2].[Nd+3].[C:6]([OH:15])(=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>O>[OH2:14].[C:6]([O-:15])(=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Nd+3:2].[C:6]([O-:15])(=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:6]([O-:15])(=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCC(=O)O
Agent: [Nd+3]
Agent: [O-2]
Solvent: O
Product: CCCCCCCC(=O)[O-]
Temperature: 85 °C
Yield: 92 %

Procedure:
Forty (40) g of neodymium oxide, 220 g of octanoic acid and 220 g of water were mixed. The resultant mixture in the form of suspension was stireed as refluxed at 85° C. for three hours and cooled. The resultant reaction mixture was left standing at rest and separated into a water phase and an organic phase. The organic phase was poured into acetone of a volume about 20 times as large. The salt consequently precipitated therein was washed with acetone and was dried under a vacuum, to afford neodymium octanoate monohydrate. The yield was 92%.
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1O.[OH-].[Na+]>O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[O:6][CH3:7]
Reactant: COS(=O)(=O)OC
Reactant: Oc1cc(Cl)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethylsulfate (94.64 g) is added dropwise over a 40 minute period to a cooled stirred solution of 2,5-dichlorophenol (122.25 g) and sodium hydroxide (31.5 g) in water (300 ml). This mixture is stirred at room temperature for one hour, then at reflux for 2 hours, then cooled to room temperature. The organic layer is separated and combined with ether extracts of the remaining aqueous layer. The ether solution is dried (saturated NaCl, Na2SO4, K2CO3) and the ether removed to give 2,5-dichloroanisole. Distillation gives a colorless liquid (115° C. at aspirator vacuum).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:13][CH2:12]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCN1CCN(C)CC1
Yield: 95.1 %

Procedure:
A mixture of ethyl 4-bromobutanoate (5.75 g, 29.5 mmol; Aldrich No.167118) and 1-methylpiperazine (3.55 mL, 32.0 mmol; Aldrich No. 130001) and anhydrous K2CO3 (4.5 g, 32.5 mmol; Fisher No. P208) in acetonitrile (MeCN, 150 mL) was refluxed for 18 h before concentrated in vacuo. The organic layer was then separated and the aqueous layer was extracted with dichloromethane (DCM, 3×150 mL). The combined organic extracts were washed with water (150 mL), dried (Na2SO4), and concentrated in vacuo to give ethyl 4-(4-methylpiperzin-1-yl)butanoate (6.01 g, 96%) as a yellow oil.
Reaction SMILES: [OH-:1].[Na+].[O:3]1[C:14]2[C:10]3[NH:11][C:12](=[O:13])[C:9]=3[CH:8]=[CH:7][C:6]=2[O:5][CH2:4]1.OO.Cl>O>[NH2:11][C:10]1[C:14]2[O:3][CH2:4][O:5][C:6]=2[CH:7]=[CH:8][C:9]=1[C:12]([OH:1])=[O:13]
Reactant: O=C1Nc2c1ccc1c2OCO1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1c(C(=O)O)ccc2c1OCO2
Yield: 64.4 %

Procedure:
To a solution of sodium hydroxide (4.6 g, 115 mmol) in water (35 mL) was added the Intermediate from Step C (2.35 g, 14.4 mmol). A solution of hydrogen peroxide (30%, 21 mL) was then added over 30 minutes. The reaction was neutralized to pH 7 by the addition of diluted hydrochloric acid (1N). The precipitate was collected and dried to afford the product 4-aminobenzo[d][1,3]dioxole-5-carboxylic acid (1.68 g, yield 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.40-7.42 (d, 1H, J=8.4 Hz), 6.25-6.27 (d, 1H, J=8.4 Hz), 6.04 (s, 2H).
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[N:11](CC2C=CC(OC)=CC=2)[CH2:10][CH2:9]3)[CH2:5][CH2:4]1.C(OC(=O)C)C.CO>C(O)(C(F)(F)F)=O>[F:26][CH:2]([F:1])[C:3]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[NH:11][CH2:10][CH2:9]3)[CH2:5][CH2:4]1
Reactant: COc1ccc(CN2CCc3cc(C4(C(F)F)CC4)ccc3C2=O)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1NCCc2cc(C3(C(F)F)CC3)ccc21
Temperature: 70 °C
Yield: 66.6 %

Procedure:
Compound (VII) (0.068 g, 0.19 mmole) was dissolved in TFA 1 ml and heated to 70° C. for 1.5 hours. To the reaction mixture cooled to room temperature was added ethylacetate and the solution was washed with brine followed by sodium bicarbonate 5% solution, and again with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel prep TLC with 5% methanol in dichloromethylene affording compound (VIII) 0.030 g, 66% yield.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:4][CH2:3]1.Cl[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][N:28]=2)[N:25]=1>>[F:31][C:29]([F:30])([F:32])[C:26]1[N:24]2[N:25]=[C:20]([N:2]3[CH2:3][CH2:4][CH:5]([N:8]4[C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=5[CH2:11][O:10][C:9]4=[O:18])[CH2:6][CH2:7]3)[CH:21]=[CH:22][C:23]2=[N:28][N:27]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Agent: Cl
Product: O=C1OCc2ccccc2N1C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
A mixture of 1-piperidin-4-yl-4H-3,1-benzoxazin-2-one hydrochloride and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 4. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 1-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]-4H-3,1-benzoxazin-2-one.
Reaction SMILES: [NH2:1][C:2]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)P(=O)(N(C)C)N(C)C>[CH2:14]([NH:1][C:2]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])[CH3:15]
Reactant: CCI
Reactant: CCC(N)(C(=O)OC)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCNC(CC)(C(=O)OC)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
Methyl 2-amino-2-(2-thienyl)butyrate (11.94 g) is dissolved in hexamethylphosphoric triamide (200 ml), and ethyl iodide (28.7 g) and potassium carbonate (37.3 g) is added thereto. The mixture is stirred at room temperature for 4 hours and further stirred at 70° C. for one hour. Water is added to the reaction mixture and the mixture is extracted with ether. The extract is washed with water, dried and concentrated to remove solvent. The residue is purified by silica gel column chromatography, whereby methyl 2-ethylamino-2-(2-thienyl)butyrate (8.99 g) is obtained.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N=C=NC(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[NH2:48][C:49]1[CH:53]=[CH:52][N:51]([CH2:54][C:55]([CH3:58])([OH:57])[CH3:56])[N:50]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:26])([F:28])[F:27])[CH:13]=[N:12]2)[C:8]([NH:48][C:49]2[CH:53]=[CH:52][N:51]([CH2:54][C:55]([OH:57])([CH3:56])[CH3:58])[N:50]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(F)(F)F)cc1=O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C(F)(F)F)cc2=O)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 54.1 %

Procedure:
A solution of 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 21, 200.4 mg, 0.50 mmol) in methylene chloride (5.0 mL, 0.10 M) at 25° C. was treated with N,N′-diisopropylcarbodiimide (80 μL, 0.51 mmol) and 1-hydroxybenzotriazole (70.3 mg, 0.52 mmol). The solution was stirred at 25° C. for 45 min. After this time, the reaction was added to a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 95.3 mg, 0.61 mmol) in methylene chloride (2.0 mL) at 25° C. The reaction was stirred at 25° C. overnight. After this time, the reaction was diluted with methylene chloride (50 mL) and was washed with a 1N aqueous hydrochloric acid solution (2×50 mL), a saturated aqueous sodium bicarbonate solution (2×50 mL), water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 40 g, 1-4% methanol/methylene chloride) followed by silica gel column chromatography (AnaLogix 40 g, 1-3% methanol/methylene chloride) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide (144.2 mg, 53%) as a white solid; ES+-HRMS m/e calcd for C26H30N5O4F3 [M+H+] 534.2323, found 534.2321. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.07 (m, 1H), 1.27-1.77 (m, 8H), 1.92 (m, 1H), 2.25 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.47 (dd, J=4.4, J=10.8 Hz, 1H), 5.91 (d, J=2.8 Hz, 1H), 6.40 (d, J=2.2 Hz, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.53-7.63 (m, 2H), 7.83 (t, J=7.8 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 8.18 (d, J=2.8 Hz, 1H), 10.84 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:25][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCC1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Product: O=C(Nc1nc2cccc(NC3CCCC3)n2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for example 30, but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 44 mg; 0.16 mmol; 1.0 eq.) and cyclopentylamine (1.0 mL) as a white powder (23 mg, 44%). HPLC, Rt: 3.06 min. (purity 99.5%). LC/MS, M+(ESI): 322.1, M−(ESI): 320.1.
Reaction SMILES: C([O:8][C:9]1[C:14]([I:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=2)[N:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[OH:8][C:9]1[C:14]([I:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([NH2:23])=[O:22])=[CH:24][CH:25]=2)[N:10]=1
Reactant: NC(=O)c1ccc(Nc2ncc(I)c(OCc3ccccc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(Nc2ncc(I)c(O)n2)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To 4-((4-(benzyloxy)-5-iodopyrimidin-2-yl)amino)benzamide (J10, 2.84 g), trifluoroacetic acid (25 mL) was added at room temperature, and the mixture was stirred at 40 to 50° C. for 8 hours. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The obtained solid matter was washed with a mixed solvent of diisopropyl ether and chloroform, and then dried under reduced pressure to obtain 4-((4-hydroxy-5-iodopyrimidin-2-yl)amino)benzamide (J11, 1.35 g) as pale brown solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:10])[NH:5][C:6]([CH3:9])=[CH:7][CH:8]=1)[CH3:2].[Br:11]N1C(=O)CCC1=O>CO>[Br:11][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[C:4](=[O:10])[NH:5][C:6]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(C)[nH]c1=O
Solvent: CO
Product: CCc1cc(Br)c(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.3 %

Procedure:
A 2 neck round bottom flask, equipped with an overhead stirrer is charged with 3-ethyl-6-methyl-1H-pyridin-2-one (33.45 g, 0.26 mol) obtained from Step 1 as described above, N-bromosuccinimide (48.6 g, 0.273 mol) and methanol (867 mL) and the mixture stirred at ambient temperature for 17 hr. The mixture is then concentrated to a volume of 200 mL, diluted with water (600 mL) and the resulting suspension is chilled in an ice bath. The solids are collected by filtration, washed with water (300 mL) and dried in a vacuum oven at 64° C. for 24 hr to afford 5-bromo-3-ethyl-6-methyl-1H-pyridin-2-one (53.56 g, 95.3% yield) as an off white solid. LC/MS: MS m/e=215/217 (M+H), RT 2.64 min.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH:21]=[CH2:22]>CC(CC(C)C)=O>[C:20]([O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)(=[O:23])[CH:21]=[CH2:22]
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Product: C=CC(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 60 °C
Yield: 92 %

Procedure:
166 g of 2-Methyl-2-adamantanol, 303 g of triethylamine and 500 g of methylisobutyl ketone were mixed by stirring at 60° C. While stirring, 136 g of acrylic acid chloride was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred for six more hours. Then, extraction and distillation were conducted to obtain 2-methyl-2-adamantyl acrylate at the yield of 92%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14]C(=O)OC(C)(C)C)[CH2:9]2)=[CH:4][CH:3]=1.[ClH:22].O1CCOCC1>>[ClH:22].[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(F)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CCCN(c2ccc(F)cc2)C1

Procedure:
To tert-butyl (R)-[1-(4-fluorophenyl)piperidin-3-yl]carbamate (250 mg, 0.85 mmol) synthesized in Reference Synthesis Example 25, 4 M hydrogen chloride/1,4-dioxane solution (2.5 mL) was added and the resultant mixture was stirred at room temperature for 18 hours. After completion of the reaction, the resultant solid was collected by filtration to obtain the title compound (220 mg, quantitative).
Reaction SMILES: Cl[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:2]2[C:3]([C:9]#[N:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=2)=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#Cc1nc(Cl)cnc1Cl
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1nc(Cl)cnc1Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
In 25 mL of dimethylformamide was dissolved 2.5 g of 3,6-dichloro-2-pyrazinecarbonitrile. After adding 3.2 g of 4-(benzyloxy)phenol and 3.0 g of potassium carbonate, the mixture was stirred at room temperature for one hour. A mixture of 25 ml of ethyl acetate and 100 mL of water was added to the reaction mixture, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the residue, the insoluble matter was filtered off, and the filtrate was concentrated. The residue thus obtained was washed with n-hexane to obtain 3.84 g of 3-[(4-(benzyloxy)phenoxy)]-6-chloro-2-pyrazinecarbonitrile as a light brown-colored solid product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.C([Li])CCC.O1CCCC1.[C:19](=[O:21])=[O:20]>O1CCCC1>[F:1][C:2]1[C:7]([C:19]([OH:21])=[O:20])=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1
Reactant: Fc1cccc(F)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)nc1F
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Fifty (50) g of 2,6-difluoropyridine was dissolved in 200 ml of tetrahydrofuran, and into the solution 326 ml of 1.6M n-butyl lithium-tetrahydrofuran solution was added dropwise at -70° C., followed by an hour's stirring at the same temperature. To the reaction mixture 29 g of dry ice blocks were added little by little, followed by 30 minutes' stirring at the same temperature. Raising the temperature to about 5° C., 500 ml of ice water was added. The reaction mixture was washed twice with ethyl acetate, and the aqueous layer was adjusted to pH 3 with conc. hydrochloric acid. The aqueous layer was then extracted with chloroform. The extract was washed with saturated saline water, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The crystalline precipitate was collected by filtration, and recrystallized from diethyl ether-n-hexane to provide 63 g of 2,6-difluoro-3-pyridinecarboxylic acid (m.p. 170-171° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[C:18]([NH:26][C:27]1[CH:36]=[C:35](Br)[CH:34]=[CH:33][C:28]=1[C:29]([O:31]C)=[O:30])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C(=O)C>[C:18]([NH:26][C:27]1[CH:36]=[C:35]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:34]=[CH:33][C:28]=1[C:29]([OH:31])=[O:30])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: OB(O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cc(-c2ccc(F)cc2F)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 28.4 %

Procedure:
56 mg of 2,4-difluorophenylboronic acid, 63 mg of sodium carbonate and 34 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) were added to 2.5 mL of N,N-dimethylacetamide solution containing 80 mg of methyl 2-(benzamido)-4-bromobenzoate, and starred at 90° C. for 20 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 1.2 mol/L hydrochloric acid were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 1.0 mL of 1.0 mol/L aqueous sodium hydroxide and 4.0 mL of ethanol were added to the obtained residue and stirred at room temperature for 1 hour. 0.6 mol/L hydrochloric acid, was added to the reaction mixture and a solid substance was separated by filtration to obtain 24 mg of 2-(benzamido)-4-(2,4-difluorophenyl)benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]#[N:9])[C:3]=1[C:10]#[N:11].CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=O>C(O)(=O)C>[C:10]([C:3]1[C:4]([CH2:7][C:8]#[N:9])=[N:5][N:6]2[C:16]([C:18]3[CH:19]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[N:1][C:2]=12)#[N:11]
Reactant: N#CCc1n[nH]c(N)c1C#N
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: N#CCc1nn2c(-c3cccc(C(F)(F)F)c3)ccnc2c1C#N

Procedure:
A mixture of 2.94 g. of 5-amino-4-cyano-3-cyanomethyl pyrazole and 4.86 g. of 3-dimethylamino-3'-trifluoromethylacrylophenone in 25 ml. of glacial acetic acid is refluxed for 16 hours. The reaction mixture is evaporated to dryness and then extracted with methylene chloride. This solution is washed with a saturated sodium bicarbonate solution and dried with sodium sulfate. After passage of this solution through a short column of hydrous magnesium silicate, the effluent from this column is refluxed with gradual addition of hexane until the product crystallizes. Filtration gives crystals, m.p. 180°-181° C.
Reaction SMILES: [Br:1][C:2]1([Br:28])[CH2:4][CH:3]1[C:5]1[C:6]([CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24])=[N:7][N:8]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[CH:9]=1.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:28][C:2]1([Br:1])[CH2:4][CH:3]1[C:5]1[C:6]([C:22](=[O:27])[C:23]([F:24])([F:26])[F:25])=[N:7][N:8]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:18])[F:19])=[CH:12][C:11]=2[Cl:21])[CH:9]=1
Reactant: OC(c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC1(Br)Br)C(F)(F)F
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=C(c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC1(Br)Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Tetra-n-propylammonium perruthenate (50 mg) was added to a stirred solution of the title compound of Example 2 (0.15 g) and 4-methylmorpholine N-oxide (50 mg) in acetonitrile (5 ml) containing powdered 4 Å molecular sieves. The reaction mixture was stirred at room temperature for 24 hours and then evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel, using dichloromethane as eluant, followed by chromatographic reprocessing, using hexane and then a mixture of hexane: ethyl acetate (19:1) as eluants, gave the title compound as a colourless oil. δ (CDCl3): 1.83 (t,1H), 2.20 (dd,1H), 3.24 (dd,1H), 7.44 (s,1H), 7.79 (s,2H). IR (thin film): νmax 1722.9 cm-1.