Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][S-:14].[Na+]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([S:14][CH3:13])[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: C[S-]
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CSc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of the 2,4-dichloro-5-(trifluoromethyl)pyrimidine (2.50 g, 11.5 mmol) in THF (50 mL) in an ice bath under nitrogen was added zinc(II) chloride (1.0 M in ether, 13.8 mL, 13.8 mmol) dropwise. The mixture was stirred in the ice bath for two hours, then sodium methanethiolate (0.888 g, 12.7 mmol) was added. The mixture was stirred overnight, allowing the reaction to slowly come to room temperature. After 18 hours the reaction was quenched with 2 M HCl (15 mL), and the organics removed by evaporation under reduced pressure. The aqueous residue was diluted with brine (15 mL), and extracted with DCM (3×30 mL). The combined organic phases were dried (phase separator) and carefully evaporated to give a pale yellow oil. Chromatography (2×40 g silica cartridge, 0-20% DCM/n-hexane) followed by carefully evaporation of solvent (40° C.@400 mmHg then room temperature@200 mmHg) gave the title compound (I11) (2.149 g, 82% yield) as a colourless oil; 1H NMR (600 MHz, CDCl3) δ 8.66 (s, 1H), 2.61 (s, 3H). LCMS Method C: rt: 7.95 min; m/z 229.1 [M+H]+, Note: I11 is volatile.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[C:9]1=[O:18].[CH:19]([O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:21])[CH3:20].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[C:9]2=[O:18])=[CH:25][CH:24]=1)([CH3:21])[CH3:20]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccc(N2C(=O)C(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.7 %

Procedure:
A solution of triethylamine (28 g, 272 mmol) in CH2Cl2 (250 mL) was added to a mixture of 1H-indole-2,3-dione (10.0 g, 68 mmol), 4-isopropoxyphenylboronic acid (13.4 g, 75 mmol) and copper (II) acetate (5.0 g, 27 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The crude mixture was then treated with 1M HCl (3×350 mL), followed by aqueous saturated NaHCO3 solution (3×350 mL). The resulting organic faction was concentrated in vacuo and the residue was dissolved in CH2Cl2, dried over MgSO4, concentrated in vacuo, and re-suspended in CH2Cl2. The suspension was filtered and the filtrate was concentrated in vacuo. The crude product was recrystallized from a mixture of toluene/hexane (3:1), giving the desired product (7.6 g, 27 mmol).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[N+:12]([C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13].C[O-].[Na+]>C(O)C>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:20]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1]=2[OH:10])=[O:22])=[CH:23][CH:24]=1)([O-:14])=[O:13]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1ccccc1S
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(c1ccc([N+](=O)[O-])cc1)c1sc2ccccc2c1O

Procedure:
In a similar manner to Example 58, a mixture of methyl thiosalicylate (2.76 g), 4-nitrophenacyl bromide (4.0 g), sodium methoxide (1.94 g) and ethanol (200 ml) gave 2-(4-nitrobenzoyl)-3-hydroxybenzo[b]thiophene of which 2.25 g was reacted with hydrazine hydrate (6 ml) in a similar manner to Example 58, to give 3-(4-aminophenyl)-1H-[1]benzothieno[3,2-c]pyrazole, m.p. 113-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:24]=[C:25]([NH:30]C(OCC5C=CC=CC=5)=O)[CH:26]=[CH:27][C:28]=4[CH3:29])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH-].[K+].CCCCCC.CCOC(C)=O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:24]=[C:25]([NH2:30])[CH:26]=[CH:27][C:28]=4[CH3:29])[CH2:19][CH2:18]3)=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Sc2ccc(CN3CCC(c4cc(NC(=O)OCc5ccccc5)ccc4C)CC3)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: COc1ccc(Sc2ccc(CN3CCC(c4cc(N)ccc4C)CC3)cc2)cc1
Temperature: 100 °C
Yield: 98.2 %

Procedure:
N-[3-(1-{[4-(4-methoxyphenylthio)phenyl]methyl}(4-piperidyl))-4-methylphenyl] (phenylmethoxy)carboxamide (486 mg, 0.881 mmol) was dissolved in methanol (10.0 mL) and a KOH solution (40%, 1.20 mL) was added. The reaction mixture was heated at 100° C. for 10 h. After cooling to room temperature, the reaction mixture was poured into a separatory funnel. The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography (eluent: Hexane:EtOAc (1:1 then 1:4)) gave 3-(1-{[4-(4-methoxyphenylthio)phenyl]methyl}(4-piperidyl))-4-methylphenylamine (362 mg, 98.2% yield). 1H NMR (400 MHz; CDCl3) δ 7.43-7.35 (m, 4H), 7.24-7.11 (m, 3H), 6.93-6.85 (m, 2H), 6.63-6.58 (m, 1H), 6.48-6.42 (m, 1H), 3.82 (s, 3H), 3.48 (s, 2H), 3.03-2.91 (m, 2H), 2.68-2.54 (m, 1H), 2.20 (s, 3H), 2.13-1.98 (m, 2H), 1.79-1.64 (m, 4H). ESMS m/e: 419.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH2:9])[N:3]=1.[C:10]12([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2>C(O)C>[C:10]12([N:20]3[CH2:25][CH2:24][N:23]([C:6]4[CH:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH2:1])[N:7]=4)[CH2:22][CH2:21]3)[CH2:17][CH:16]3[CH2:15][CH:14]([CH2:13][CH:12]([CH2:18]3)[CH2:11]1)[CH2:19]2
Reactant: C1CN(C23CC4CC(CC(C4)C2)C3)CCN1
Reactant: Nc1cc(Cl)nc(N)n1
Solvent: CCO
Product: Nc1cc(N2CCN(C34CC5CC(CC(C5)C3)C4)CC2)nc(N)n1
Temperature: 170 °C
Yield: 80.2 %

Procedure:
A mixture of 2,6-diamino-4-chloropyrimidine (0.43 g, 3.0 mmol) and 1-(1-adamantyl)-piperazine (0.66 g, 3.0 mmol) in ethanol (30 ml) was heated in a sealed tube at 170° C. for 3 hours. After cooling the solvent was removed, the solid residue was dissolved in water (45 ml) and acidified to pH=3 with conc. HCl. The obtained mixture was heated to 50° C. the insolubles were filtered off and the clear solution was rendered alkaline with 10N NaOH under stirring and cooling. The precipitated crystals were collected, washed with water until neutral and dried. In this manner 0.79 g of the title compound was obtained in the form of its monohydrate, yield: 76.6%, mp. 265°-268° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][CH:20]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(Nc3cccc(C(F)(F)F)c3)c2cn1
Temperature: 195 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (234 mg, 1.22 mmol) (described in a previous experimental) and 3-aminobenzotrifluoride (2.00 mL, 16.0 mmol) is stirred under N2 at 190-200° C. for 2 h, and the resulting product is then chromatographed over silica gel (5-100. EtOH/EtOAc), and then over alumina (5-7%. EtOH/CHCl3) to give 7-amino-4-(3-trifluoromethylanilino)pyrido[4,3-d]pyrimidine (157 mg, 42%) as a cream solid. 1H NMR (DMSO) δ 10.04 (1H, s), 9.37 (1H, s), 8.46 (1H, s), 8.31 (1H, s), 8.19 (1H, d, J=8.2 Hz), 7.62 (1H, t, J=8.0 Hz), 7.45 (1H, d, J=7.7 Hz), 6.69 (2H, brs), 6.47 (1H, s).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH3:34][C@@H:35]1[NH:40][CH2:39][CH2:38][NH:37][C:36]1=[O:41].C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOC(C)=O>[CH3:34][C@@H:35]1[N:40]([CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=2)[CH2:39][CH2:38][NH:37][C:36]1=[O:41]
Reactant: C[C@@H]1NCCNC1=O
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@H]1C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 130 °C

Procedure:
((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (100 mg, 0.189 mmol, Intermediate B) was combined with (S)-3-methylpiperazin-2-one (21.59 mg, 0.189 mmol, Fluka, St. Louis, Mo.) potassium carbonate (78 mg, 0.568 mmol, Sigma-Aldrich, St. Louis, Mo., St. Louis, Mo.) and acetonitrile (1.26 mL). This mixture was heated at 130° C. for 30 min. After the reaction was allowed to cool to room temperature, the mixture was diluted with EtOAc and the solids were removed by filtering through a 0.2 μm millipore Millex-FG filter (Millipore, Billerica, Mass.). The filtrate was concentrated and purified by silica gel chromatography (10-100% EtOAc in hexanes) and then by reverse-phase HPLC purification (Phenomenex Gemini-NX 10μ, 110 Å, AXIA packed column, 100×50 mm, 60 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10 min gradient). The collected fractions were partitioned between CH2Cl2 and saturated aqueous NaHCO3, the organic layer was dried (Na2SO4), filtered and concentrated. The residue was taken up in MeOH and was passed through an AccuBond SPE SCX cartridge eluting with 2M ammonia/MeOH, to give (3S)-3-methyl-4-(((2S)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl)-2-piperazinone as a mixture of two diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]([OH:17])=O)[CH:6]=[CH:7][CH:8]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]2[N:34]3[C:30]([S:31][CH:32]=[CH:33]3)=[N:29][C:28]=2[CH3:35])=[O:26])[CH2:19]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]3[N:34]4[C:30]([S:31][CH:32]=[CH:33]4)=[N:29][C:28]=3[CH3:35])=[O:26])[CH2:19]2)=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Reactant: COc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: COc1cccc(-c2sc(C)nc2C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c1

Procedure:
prepared by reaction of 5-(3-methoxy-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [C:1]1([C:6]2[C:14]3[C:9](=[CH:10][N:11]=[C:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:13]=3)[N:8]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.C1CC=CCC=1>[Pd].C(O)C>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][N:11]=[C:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:13]=3)[N:8]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1=C(c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)CCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: c1cncc(-c2cc3c(C4CCCC4)nn(C4CCCCO4)c3cn2)c1
Yield: 74.1 %

Procedure:
A mixture of 42 mg (0.12 mmol) of 3-cyclopentenyl-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine, 2.0 ml (21 mmol) of 1,4-cyclohexadiene and 100 mg of 10% palladium on carbon in 10 ml of ethanol was heated to reflux for 48 hours, during which 1,4-cyclohexadiene was added incrementally. The mixture was filtered through celite, and the filtrate was concentrated to afford 31 mg (76%) of 3-Cyclopentyl-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine. ESI MS m/z 349.2 (M+1).
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH:12]=[N:11][C:10]([CH2:13][OH:14])=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33].[H-].[Na+]>C1COCC1>[C:21]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:8]2[CH:12]=[N:11][C:10]([CH2:13][O:14][CH2:28][C:29]3[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=3)[C:32]#[N:33])=[N:9]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: OCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cccc(COCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
A suspension of [1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]methanol obtained in Reference Example 36 (3.00 g, 8.79 mmol), 3-(bromomethyl)benzonitrile (1.89 g, 9.67 mmol) and 60% sodium hydride (oil dispersion, 0.316 g, 13.2 mmol) in THF (100 mL) was stirred at 70° C. for 15 hr. The reaction mixture was cooled to room temperature, and extracted with water and ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (10-30% ethyl acetate/hexane) to give the title compound as a colorless oil (3.50 g, 87%).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:14]1)=[O:11])=O)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of (R)-3-{N-(tert-butoxycarbonyl)glycyl}amino-1-(4-chlorobenzyl)pyrrolidine (5.39 g, 14.7 mmol) in methanol (60 mL) was added 4 N HCl in dioxane (38 mL). The solution was stirred at room temperature for 2 h. The reaction mixture was concentrated and 2 N NaOH solution (80 mL) was added. The mixture was extracted with dichloromethane (80 mL×3), and the combined extracts were dried over sodium sulfate and concentrated. Column chromatography (SiO2, AcOEt/EtOH/Et3N=90/5/5) gave (R)-3-(glycyl)amino-1-(4-chlorobenzyl)pyrrolidine (3.374 g, 86%): 1H NMR (CDCl3, 270 MHz) δ1.77 (dd, J=1.3 and 6.9 Hz, 1 H), 2.20-3.39 (m, 2 H), 2.53 (dd, J=3.3 and 9.6 Hz, 1 H), 2.62 (dd, J=6.6 and 9.6 Hz, 1 H), 2.78-2.87 (m, 1 H), 3.31 (s, 2 H), 3.57 (s, 2 H), 4.38-4.53 (br, 1 H), 7.18-7.32 (m, 4 H), 7.39 (br. s, 1 H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH3:9][O:10][CH2:11][C:12](Cl)=[O:13]>N1C=CC=CC=1>[CH3:9][O:10][CH2:11][C:12]([NH:7][C:3]1[CH:4]=[CH:5][CH:6]=[C:1]([NH:8][C:12](=[O:13])[CH2:11][O:10][CH3:9])[CH:2]=1)=[O:13]
Reactant: Nc1cccc(N)c1
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: COCC(=O)Nc1cccc(NC(=O)COC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of m-phenylenediamine (5.41 g) in pyridine (100 ml) is added dropwise methoxyacetyl chloride (10 ml). The mixture is stirred at room temperature for 2 hours, and thereafter, pyridine is distilled off under reduced pressure. To the residue is added water, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The resulting crude crystals are recrystallized from ethyl acetate-hexane to give the title compound (9.89 g) having the following physical properties.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[F:24])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[F:24][C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1cc(C(F)(F)F)ccc1N1CCNCC1
Yield: 94 %

Procedure:
A mixture of 3.11 g (9 mmol) 4-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester in 20 ml dioxane was treated with 8.93 ml 4N HCl in dioxane for 2 h at 80° C. The mixture was concentrated and treated with 20 ml water, 20 ml 2M Na2CO3 and extracted with 50 ml EtOAc. The organic phase was washed with 30 ml saturated NaCl. All aqueous phases were combined and extracted with 50 ml EtOAc. The combined organic phases were dried with MgSO4 and evaporated to yield 2.1 g (95%) of the title compound as brownish crystals; MS (m/e): 249.2 (MH+, 100%)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[C:10]([O:15][CH:16]2[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]2)=[N:11][CH:12]=[CH:13][CH:14]=1.FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:43](=[O:58])[C:44]1[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[C:46]([S:54]([CH3:57])(=[O:56])=[O:55])[CH:45]=1.CCN(C(C)C)C(C)C.CS(C1C=C(C=C(C(F)(F)F)C=1)C(Cl)=O)(=O)=O.[NH4+].[Cl-]>C(Cl)Cl>[C:23]([O:22][C:20]([N:18]1[CH2:19][CH:16]([O:15][C:10]2[C:9]([C:8]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:2]([C:43](=[O:58])[C:44]3[CH:49]=[C:48]([C:50]([F:53])([F:51])[F:52])[CH:47]=[C:46]([S:54]([CH3:57])(=[O:56])=[O:55])[CH:45]=3)[CH3:1])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:17]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: CNc1cnccc1-c1cccnc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: CS(=O)(=O)c1cc(C(=O)Cl)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1cccnc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 3-(3′-(methylamino)-3,4′-bipyridin-2-yloxy)azetidine-1-carboxylate (0.149 g, 418 μmol) in CH2Cl2 (4 mL) were added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (240 mg, 836 μmol, example 223, intermediate d) and DIPEA (216 mg, 292 μL, 1.67 mmol) and the light yellow solution was stirred at room temperature for 24 hours. Another batch of 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (164 mg, 573 μmol) and DIPEA (162 mg, 219 μL, 1.25 mmol) was added and stirring was continued at room temperature for 24 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted three times with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was twice purified by silica gel chromatography on a 20 g column using an MPLC system eluting with EtOAc. Light yellow gum (0.105 g; 41%). MS (ESI): m/z=607.18 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].S(Cl)([Cl:14])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C(=O)Cl)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
While 16.6 g of p-vinylbenzoic acid (manufactured by Wako Pure Chemical Industries, Ltd.), 80 ml of toluene, two drops of N,N-dimethylformamide were stirred at room temperature, 9.7 ml of thionyl chloride (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto, which was heated and stirred at 60° C. for 2 hours. The inside of the reaction system was cooled to 40° C., toluene and an excessive amount of thionyl chloride were removed under reduced pressure, and p-vinyl benzoic acid chloride was obtained. While 22.5 g of 2-aminoanthraquinone (manufactured by Tokyo Chemical Industry Co., Ltd.) and 110 ml of pyridine were stirred on ice, p-vinyl benzoic acid chloride was slowly added dropwise thereto. After stirring the mixture on ice for 30 minutes, the temperature was increased to 60° C. and the mixture was heat while stirring for 3 hours. Thereafter, the mixture was cooled to room temperature and water was added thereto. The resulting coarse crystals were filtrated and washed with water and methanol, and then 500 ml of methanol was added to the collected coarse crystals, and then heated while stirring at 60° C. Thereafter, the resultant crystals were separated by filtration, washed with methanol and dried. Thus, 20.1 g of M-19 was obtained (yield: 70%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[F:69][C:70]1[CH:75]=[CH:74][C:73](I)=[CH:72][CH:71]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O1CCOCC1>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][C:73]3[CH:74]=[CH:75][C:70]([F:69])=[CH:71][CH:72]=3)[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: Fc1ccc(I)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a dry 100 mL flask under a nitrogen atmosphere was added ethyl 3-amino-5-(4-fluorobenzyl)pyridine-2-carboxylate (200 mg, 0.73 mmol) described in example 1, Cs2CO3 (333 mg, 1.02 mmol), Pd2dba3 (20.1 mg, 0.022 mmol), and Xantphos (38.2 mg, 0.066 mmol). Dioxane (15 mL) and 1-fluoro-4-iodobenzene (0.25 mL, 2.19 mmol) were added and the resulting solution was refluxed for 3 hrs or until judged complete by TLC (7:3 hexanes:ethyl acetate). The mixture was allowed to cool to ambient temperature, filtered through Celite eluting with dichloromethane and concentrated under reduced pressure. Purification by silica gel chromatography (0-45% ethyl acetate/hexanes gradient elution) afforded ethyl 5-(4-fluorobenzyl)-3-[(4-fluorophenyl)amino]pyridine-2-carboxylate (193 mg, 72% yield) as a yellow solid. 1H NMR (CDCl3) δ 9.35 (s, 1 H), 7.95 (s, 1 H), 7.14 (, s, 1 H), 7.10-6.99 (m, 6 H), 6.96-6.93 (m, 2 H), 4.46 (q, J=7.2 Hz, 2 H), 3.83 (s, 2 H), 1.44 (t, J=7.2 Hz, 3 H); MS m/z 369 (M+1).