Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20](B4OC(C)(C)C(C)(C)O4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][N:34]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([C:33]4[CH:41]=[CH:40][C:36]([C:37](=[O:38])[NH2:39])=[CH:35][N:34]=4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Reactant: NC(=O)c1ccc(Br)nc1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C(N)=O)cn4)ccc3O2)CC1

Procedure:
The title compound is prepared from 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid tert-butyl ester and 6-bromonicotinamide following a procedure analogous to that described in Example 1. LC (method 6): tR=1.20 min; Mass spectrum (ESI+): m/z=424 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:4].C(O)C.[C-:16]#[N:17].[Na+]>O>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([CH2:2][C:16]#[N:17])=[O:4]
Reactant: COc1ccccc1C(=O)CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccccc1C(=O)CC#N

Procedure:
A 10.0 g. portion of α-bromo-o-methoxyacetophenone is suspended in 50 ml. of ethanol. A solution of 6.4 g. of sodium cyanide in 30 ml. of water is added as described in Example 8. Following the procedure of Example 8, there is obtained o-methoxybenzoylacetonitrile.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:17][CH2:16][C@H:15]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH:20]=[CH:19]2)[CH2:14][CH2:13]1.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:13][CH2:14][C@H:15]([CH:18]2[CH2:23][CH2:22][C:21]([CH2:4][CH2:3][CH2:2][CH2:7][CH3:6])([OH:24])[CH:20]=[CH:19]2)[CH2:16][CH2:17]1
Reactant: CCOc1ccc([C@H]2CC[C@H](C3C=CC(=O)CC3)CC2)c(F)c1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC1(O)C=CC([C@H]2CC[C@H](c3ccc(OCC)c(F)c3F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 4.00 g of 4-(trans-4-(2,3-difluoro-4-ethyloxyphenyl)cyclohexyl)-2-cyclohex enone (r-15) was dissolved into 60 mL of THF, 14.4 mL of pentylmagnesium bromide THF solution (1 M/L) was added dropwise thereto at room temperature, and the resultant mixture was stirred at 50° C. for 30 minutes, and then stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added dropwise under ice-cooling, the resultant mixture was subjected to extraction with ethyl acetate, and then organic layers were combined, the resultant organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. A solvent was evaporated under reduced pressure, and the resultant residue was purified by fractionation on silica gel column chromatography (eluate:heptane:ethyl acetate=6:4), and thus 3.45 g of 4-(trans-4-(2,3-difluoro-4-ethyloxyphenyl)cyclohexyl)-1-pentyl-2-cyclohexene-1-ol (compound (r-17)) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][O:18][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[N:31]([CH3:41])[N:32]=[C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:34]=3)=[O:29])=[C:23]([F:42])[CH:22]=2)[CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>O.C(#N)C>[F:42][C:23]1[CH:22]=[C:21]([C@H:17]2[O:18][CH2:19][CH2:20][NH:15][CH2:16]2)[CH:26]=[CH:25][C:24]=1[NH:27][C:28]([C:30]1[N:31]([CH3:41])[N:32]=[C:33]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:34]=1)=[O:29]
Reactant: Cn1nc(-c2ccccc2)cc1C(=O)Nc1ccc([C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2ccccc2)cc1C(=O)Nc1ccc([C@@H]2CNCCO2)cc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
To a stirred solution of trifluoroacetic acid (124 μl) in water (4 ml) was added a solution of (R)-2-{3-fluoro-4-[(2-methyl-5-phenyl-2H-pyrazole-3-carbonyl)-amino]-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (78 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 4 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis); gradient: EtOAc/heptane) to afford 2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid ((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amide (49 mg, 79%) as a white solid. MS (ISP): 381.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH2:32]([CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([CH:39]1[CH2:44][CH2:43][N:42]([C:22]([C:21]2[CH:25]=[CH:26][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:30])[F:29])[C:9]=4[CH:17]=3)=[CH:19][CH:20]=2)=[O:24])[CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC(Cc2ccccc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-benzylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=605.00 (M+H+); retention time=1.09 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.NO.Cl.CCN=C=NCCCN(C)C.C1C=CC2[N:63]([OH:64])N=NC=2C=1.CCN(CC)CC>CN(C)C=O>[OH:64][NH:63][C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:40])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[CH:32][CH:33]=1)=[O:36]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(=O)NO)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 80 °C
Yield: 44.3 %

Procedure:
To a solution of rac 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid prepared in Example 232 (50 mg, 0.09 mmol) in N,N-dimethylformamide (2 mL) was added. NH2OH.HCl (18 mg, 0.26 mmol), EDCI (33 mg, 0.17 mmol), HOBT (21 mg, 0.15 mmol) and NEt3 (0.036 mL, 0.26 mmol). The reaction mixture was heated at 80° C. for 48 h. The mixture was cooled to room temperature, and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by prep-HPLC to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydroxycarbamoyl-phenyl)-amide as a white solid (24 mg, 47%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH:9]=[C:10]([C:11](OCCCC)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH:9]=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCCCOC(=O)c1cc(-c2ccc(N)cc2)c2c(N)ncnn12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(CO)n3ncnc(N)c23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a cooled (0° C.) solution of the product of step 4 of Example 96 (220.0 mg, 0.68 mmol) in THF (23 mL) was added diisobutylaluminum hydride (1 M in THF, 7.4 mL, 7.4 mmol). The mixture was allowed to warm to rt and stirred for 30 min. The reaction was cooled (0° C.) and quenched with methanol (1 mL). The mixture was poured into a vigorously stirred 1.2 M aqueous Rochelle's salt solution (50 mL). The resultant mixture was stirred for 30 min and then extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated to dryness under reduced pressure. The crude material was purified by HPLC using a gradient of 50-90% MeCN in water to yield 170.0 mg (99%) of the desired product containing trace impurities. 1H-NMR (DMSO-d6) δ 8.14 (s, 1 H), 7.38 (d, J=8.0 Hz, 2 H), 7.07 (d, J=8.0 Hz, 2 H), 6.76 (s, 1 H), 4.75 (s, 2 H); MS [M+H]+=256.2; LCMS RT=1.05 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:9]=[C:10]([I:12])[CH:11]=1
Reactant: COC(=O)c1cc(F)cc(I)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCc1cc(F)cc(I)c1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
Methyl 3-fluoro-5-iodobenzoate (5.49 g, 19.60 mmol) was dissolved in DCM (100 mL) and cooled to −78° C. DIBAL-H (49.0 mL, 49.0 mmol) was added dropwise over 30 min and then after 1 h another portion of DIBAL-H (49.0 mL, 49.0 mmol) was added. Reaction mixture agitated at −78° C. for 4 h and poured carefully onto ice-cold 1N HCl. The mixture was agitated for 10 min and the layers separated and the aq. layer extracted with DCM and the combined organic extract was dried (magnesium sulfate), filtered and concentrated in vacuo to afford the desired product in quantitative yield. LCMS not conclusive.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=3[Cl:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=3[Cl:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:34])([F:35])[F:33]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cccc(C)c1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1Cl
Temperature: 25 °C
Yield: 6.4 %

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(2-chloro-3-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (58.6 mg, 1.03 mmol) in 4 N HCl in dioxane (4 mL) and water (1 mL) was stirred at 100° C. for overnight. The reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified via column chromatography (SiO2, 70% EtOAc in hexanes) to afford 4-chloro-N-[5-chloro-2-(2-chloro-3-methyl-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (34.5 mg) in 64% yield. 1H NMR (400 MHz, CDCl3) δ11.00 (s, 1H), 8.24 (d, 1H), 8.18 (m, 1H), 8.17 (d, 1H), 7.98 (dd, 1H), 7.63 (d, 1H), 7.35 (d, 1H), 7.24 (t, 1H), 7.1 (d, 1H), 2.37 (s, 3H); ESMS m/z (relative intensity): 522.9 (M+H)+ (100), 544.9 (M+Na)+ (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])[CH3:22].C[Si]([N:35]=[C:36]=[O:37])(C)C>C1COCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][CH:16]([NH:19][C:36]([NH2:35])=[O:37])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])[CH3:22]
Reactant: C[C@@H](Nc1cc(N2CCC(N3CCC(N)C3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](Nc1cc(N2CCC(N3CCC(NC(N)=O)C3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
To a stirred solution of 1-(1-(4-chloro-3-((R)-1-(2,4-dichlorophenyl)ethylamino)phenyl)piperidin-4-yl)pyrrolidin-3-amine (0.056 g, 0.12 mmol) in THF (1 mL) and acetic acid (1 drop) was added a solution of (trimethylsily)isocyanate (0.015 g, 0.13 mmol) in THF (0.5 mL). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with diluted with aqueous saturated sodium bicarbonate and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude was purified by flash chromatography (SiO2, 2-10% methanol in dichloromethane) to afford the desired product as a white solid (0.016 g, 0.031 mmol, 26%). 1H NMR (400 MHz, CDCl3) δ 7.36-7.32 (m, 2H), 7.16 (dd, J=2.2, 8.4 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.82 (br, 1H), 6.16 (dd, J=2.5, 8.8 Hz, 1H), 5.77 (br, 1H), 5.23 (br, 1H), 4.87 (q, J=6.6 Hz, 1H), 4.64 (d, J=5.2 Hz, 1H), 3.44-3.37 (m, 2H), 3.08-2.82 (m, 3H), 2.69-2.40 (m, 4H), 2.25-1.85 (m, 6H), 1.60-1.42 (m, 5H); MS: (ES) m/z calculated for C24H31Cl3N5O [M+H]+ 510.2. found 510.
Reaction SMILES: C[Si](C)(C)[N:3]1[CH:7]=[C:6](I)[CH:5]=[N:4]1.C([Mg]Cl)(C)C.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C.[Cl-].[NH4+]>[Cl-].[Na+].O.C1(C)C=CC=CC=1.C1COCC1>[CH3:27][C:22]1([CH3:28])[C:23]([CH3:26])([CH3:25])[O:24][B:20]([C:6]2[CH:5]=[N:4][NH:3][CH:7]=2)[O:21]1
Reactant: C[Si](C)(C)n1cc(I)cn1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.7 %

Procedure:
A flask equipped with a mechanical stirrer, a nitrogen inlet, an addition funnel and a thermowell was charged with 1-trimethylsilyl-4-iodopyrazole (225.1 g, 0.85 mol) and THF (2200 mL) at ambient temperature. This mixture was cooled to approximately −6° C. in an ice/salt/brine bath before a solution of isopropyl magnesium chloride in THF (2 M solution in THF, 510 mL, 1.02 mol, 1.2 equiv) was added at a rate such that the internal temperature did not exceed 0° C. The extent of metal/halogen exchange was monitored by GC and was found complete after about 10 min. To the orange brown solution was then added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (isopropylpinacolborate, 347 mL, 1.7 mol, 2.0 equiv) slowly at first keeping the temperature below 0° C. and then fairly rapidly after about half of the compound was added allowing the temperature to reach 5° C. (the reaction becomes quite thick and then thins out slowly). The reaction is then stirred at 0° C. for 10 min before being warmed to ambient temperature over 1 h and stirred at ambient temperature for an additional 1 h. The reaction mixture was cooled to approximately 6° C. and the saturated aqueous ammonium chloride solution (NH4Cl, 2.2 L) was added with a temperature increase to 25° C. The mixture was stirred for 5 minutes before being diluted with toluene (10 L). The layers were separated (a large amount of solid is present in the aqueous layer) and the organic layer was sequentially washed with water (6×2.2 L) and brine (2×2.2 L) before being dried over sodium sulfate (Na2SO4). The drying reagent, sodium sulfate (Na2SO4), was removed by filtration and the solution was concentrated under reduced pressure. Residual toluene was co-evaporated with n-heptane to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1, 90.3 g, 164.9 g theoretical, 54.8%) as a white solid. For 1: 1H NMR (400 MHz, DMSO-d6) δ 13.08 (bs, 1H), 7.94 (s, 1H), 7.62 (s, 1H), 1.23 (s, 12H) ppm; C9H15BN2O2 (MW, 194.04), LCMS (EI) m/e 195 (M++H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH2:3]1.Cl[C:18]1[N:23]([CH3:24])[C:22](=[O:25])[CH:21]=[C:20]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:19]=1.C(N(CC)CC)C>O1CCCC1>[CH3:24][N:23]1[C:22](=[O:25])[CH:21]=[C:20]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:19]=[C:18]1[N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH2:3]1
Reactant: O=C(Nc1ccccc1)C1CCCNC1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCCC(C(=O)Nc3ccccc3)C2)nc(-c2ccncc2)cc1=O
Yield: 91.6 %

Procedure:
A solution of 3-piperidinecarboxanilide hydrochloride (96.0 mg, 0.40 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (66.0 mg, 0.30 mmol) and triethylamine (0.33 ml, 2.50 mmol) in tetrahydrofuran (3 ml) was stirred at room temperature for 3 hours. The whole reaction mixture was evaporated in vacuo and the precipitate was washed with water and diethyl ether to give the title compound (107 mg, 92%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].Br[CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.O>CN(C)C=O>[CH2:7]([O:6][P:4]([CH:9]([CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: BrCCOC1CCCCO1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCOC1CCCCO1)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
856 mg of a sodium hydride dispersion (60% in oil) was washed three times with dry pentane under a nitrogen stream to separate the oil. After drying, the powder obtained was suspended in 7.2 ml of dry dimethylformamide under a nitrogen stream, and the suspension was cooled to 0° C. Then, 4.26 ml of ethyl diethylphosphonoacetate was dropwise added thereto over a period of one hour. The mixture was stirred at room temperature for 30 minutes and cooled to 0° C., and 5.4 g of 2-bromo-1-(2-tetrahydropyranyloxy)ethane was added thereto. The mixture was stirred at 65° C. overnight, and the reaction mixture was poured into 40 ml of water and extracted three times with 20 ml of ethyl acetate. The ethyl acetate layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (60 g of Kieselgel 60) by using a mixture of hexane/ethyl acetate (5/1 followed by 1/1). The product-containing fraction was again purified by silica gel column chromatography (110 g of Kieselgel 60) by using a mixture of hexane/acetone (4/1) to obtain 2.55 g of ethyl 2-diethylphosphono-4-(2-tetrahydropyranyloxy)butanoate as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:7]=1.[CH3:29][S:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].CCCC>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.C(O)C>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:6]2[CH:7]=[C:2]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([S:30][CH3:29])[CH:36]=3)[CH:3]=[CH:4][C:5]=2[F:28])[CH2:9][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:23])[F:24])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(Br)ccc2F)c(F)c1
Reactant: CSc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCC
Solvent: CCO
Product: CSc1cccc(-c2ccc(F)c(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)c1
Temperature: 88 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
5-(5-Bromo-2-fluoro-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Step 5 of Preparation 8, 3-(methylthio)phenylboronic acid (26.7 mg, 0.16 mmol), Pd(PPh3)4 (12.3 mg, cat.) and a 2N sodium carbonate solution (500.0 uL) were added to a mixed solvent of ethanol (500.0 uL) and 1,2-dimethylethane (2.0 mL). The reaction mixture was stirred at 88° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/15) to give 35.0 mg of the titled compound as a white liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=3[O-])[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[C:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])#[N:26]>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:27]([C:28]([O:30][CH3:31])=[O:29])[C:25]#[N:26])[N:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: COC(=O)CC#N
Reactant: CCOc1ccc(-c2nc(-c3cccc[n+]3[O-])cs2)cc1OCC
Solvent: CC(=O)OC(C)=O
Product: CCOc1ccc(-c2nc(-c3cccc(C(C#N)C(=O)OC)n3)cs2)cc1OCC
Temperature: 110 °C
Reaction time: 4 h
Yield: 56.6 %

Procedure:
A mixture of 3 g of 2-[2-(3,4-diethoxyphenyl)-4-thiazolyl]pyridine-1-oxide, 2.6 g of methyl cyanoacetate and 150 ml of acetic anhydride was stirred at 110° C. for 4 hours and then allowed to cool. The resulting crystals were collected by filtration and recrystallized from ethanol-dimethylformamide to obtain 2.1 g of 2-(3,4-diethoxyphenyl)-4-[6-(1-methoxycarbonyl-1-cyanomethyl)-2-pyridyl]thiazole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][CH:15]([O:24][CH2:25][CH3:26])[C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:13].N1CCCCC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:17]([C:16]([CH:15]([O:14][CH2:12][CH3:13])[O:24][CH2:25][CH3:26])=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)C(OCC)OCC
Yield: 113.7 %

Procedure:
A solution of 3-nitrobenzaldehyde (2.27 g), ethyl 4,4-diethoxyacetoacetate (3.28 g) and piperidine (0.2 ml) in benzene (15 ml) was refluxed under azeotropic dehydration for 3 hours. The resultant solution was washed three times with water and dried over magnesium sulfate. The solvent was removed from the reaction solution to give oily ethyl 2-(3-nitrobenzylidene)-4,4-diethoxyacetoacetate (6.0 g). The mixture of the compound obtained above and ethyl 3-aminocrotonate (1.94 g) was heated at about 95° to 100° C. for 7 hours and then at about 120° C. for 1.5 hours with stirring. After cooling, the resultant oil was extracted with ethyl acetate and the extract was washed with water and dried. The solvent was removed from the resultant solution to give an oil (7.8 g). The product was purified by column chromatography on silica gel with an eluent (benzene: ethyl acetate=20:1) to give the pure product of diethyl 2-methyl-4-(3-nitrophenyl)- 6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (4.65 g).