Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[CH:16]=[C:15]1[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:29])=[O:28])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][O:38][C:39](=[O:50])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH:48]=O)=[CH:42][CH:41]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][O:38][C:39](=[O:50])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][C:16]2[C:17]3[C:22](=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:14]([CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:15]=2[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:29])=[O:28])=[CH:42][CH:41]=1
Reactant: COC(=O)c1ccc(OCC=O)cc1
Reactant: O=S(=O)(Cc1ccccc1)NCCc1cc2ccc(Cl)cc2n1C(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3cc(Cl)ccc23)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
To N-[2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethyl]-C-phenyl-methanesulfonamide (0.033M, 1 equiv.) in DCM at 0° C. were added 4-(2-oxo-ethoxy)-benzoic acid methyl ester (3.3 equiv.), triethylsilane (6 equiv.), and TFA (5 equiv.). The reaction mixture was stirred at rt for 2 d 20 h before aqueous workup. Purification by silica gel chromatography followed by reverse phase HPLC gave 4-{2-[1-Benzhydryl-6-chloro-2-(2-phenylmethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester in 35% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH:10]([C:13]1[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=1)([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][C:15]2[CH:14]=[C:13]([CH:10]([CH3:12])[CH3:11])[NH:17][N:16]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CC(C)c1cc(N)n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(Nc2cc(Cl)nc(Cl)n2)n[nH]1
Temperature: 80 °C
Yield: 86.2 %

Procedure:
A mixture of 2,4,6-trichloropyrimidine (1.8 g, 9.8 mmol), 5-isopropyl-1H-pyrazol-3-ylamine (1.25 g, 10.0 mmol), diisopropylethylamine (3 mL, 18 mmol) and 1-butanol (10 mL) was heated to 80° C. for 2 h, at which point LC/MS indicated that the reaction was complete. The solvents were removed on a rotary evaporator and the paste was treated with ethyl acetate. The organic solution was washed with water and brine and dried over magnesium sulfate. The residue was concentrated on a rotary evaporator, and the pale yellow solid that remained was purified via flash chromatography to yield the desired product (2.3 g, 70%) as an off white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH2:14][CH3:15])([CH2:12][OH:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](OC=C)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(OC(C)C)(C)C>[C:1]([O:5][C:6]([NH:8][C@@:9]([CH2:14][CH3:15])([CH2:10][O:11][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(CO)(CO)NC(=O)OC(C)(C)C
Reactant: C=COC(=O)CCCCC
Solvent: CC(C)OC(C)C
Product: CCCCCC(=O)OC[C@@](CC)(CO)NC(=O)OC(C)(C)C
Yield: 87.3 %

Procedure:
To a suspension of 2-t-butoxycarbonylamino-2-ethylpropane-1,3-diol (52.9 g, 241 mmol) in isopropyl ether (1.0 1) were added successively vinyl hexanoate (41 ml, 254 mmol) and lipase [Immobilized lipase from Pseudomonas sp., TOYOBO, 0.67 U/mg] (2.1 g) with stirring, and the resulting mixture was stirred at room temperature for 4 hours. After stirring, the reaction mixture was filtered and evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (7:1–4:1–2:1) as the eluent to afford the title compound (66.8 g, yield: 87%)
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C([Li])CCC.B(OC)(OC)[O:19]C.OO>O1CCCC1>[CH3:10][N:6]1[CH2:7][CH2:8][O:9][C:4]2[CH:3]=[C:2]([OH:19])[CH:12]=[CH:11][C:5]1=2
Reactant: COB(OC)OC
Reactant: CN1CCOc2cc(Br)ccc21
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCOc2cc(O)ccc21
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 89.2 %

Procedure:
To a −78° C. solution of 7-bromo-4-methyl-3,4-dihydro-2H-1,4-benzoxazine (90%, 10.40 g, 41.0 mmol) in tetrahydrofuran (70 mL) under nitrogen was slowly added n-butyllithium solution (1.4 M in hexanes, 32 mL, 45 mmol) and the resulting suspension was stirred at −78° C. for 35 min. Trimethyl borate (6.0 mL, 54 mmol) was then added dropwise and the clear solution was stirred at −78° C. for 25 min and at ambient temperature for 16 h. The reaction was cooled to 0° C. and aqueous hydrogen peroxide (8.2 mL, 35%, 95 mmol) was slowly added. The resulting mixture was stirred at 0° C. for 10 min and at ambient temperature for 5 h. The insoluble material was removed by filtration and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was taken up into ethyl acetate (100 mL) and was acidified with hydrochloric acid (100 mL, 1 M). The layers were separated and the organic solution was extracted with water (2×50 mL). The combined aqueous solution was neutralized to pH˜6-7 with 5 M sodium hydroxide and extracted with ethyl acetate (3×100 mL). This organic solution was washed with brine (200 mL) and dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with hexanes/ethyl acetate (2:1) to afford 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol (6.04 g, 89%) as a light brown solid: mp 84-87° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ6.59 (d, J=9.0 Hz, 1H), 6.40-6.28 (m, 2H), 5.42 (br s, 1H), 4.30 (dd, J=4.2, 4.2 Hz, 2H), 3.19-3.09 (m, 2H), 2.80 (s, 3H); 13C NMR (75 MHz, CDCl3) δ149.1, 145.6, 130.5, 114.7, 108.0, 104.1, 65.3, 49.8, 40.1; MS (ES+) m/z 166.1 (M+1).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1.[CH3:37][C:38](=[O:41])[CH:39]=[CH2:40]>>[O:41]=[C:38]1[CH2:39][CH2:40][C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH:1]=[CH:37]1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C=CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Yield: 57.2 %

Procedure:
Benzyl 4-formylpiperidine-1-carboxylate (5.17 g, 20.907 mmol) and p-Toluenesulfonic acid monohydrate (0.398 g, 2.091 mmol) were stirred in Benzene (30.0 ml, 334.136 mmol) at 70° C. But-3-en-2-one (3.76 ml, 41.813 mmol) was added and the reaction mixture was refluxed o/n while removing water with dean-stark trap. After cooling the reaction mixture to rt, sat. NaHCO3 soln. was added and the organic layer was dried over Na2SO4 and evaporated. The resulting oil was purified by Biotage (SiO2, 250 g, EtOAc/Hep 10% to 50%) to afford the title compound (3.58 g, 11.96 mmol, 57.2% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19](O)=[O:20].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19](=[O:20])[CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)[CH2:6][CH2:5]2
Reactant: O=C(O)Cc1ccccn1
Reactant: Brc1ccc2c(c1)CCN2
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccn1)N1CCc2cc(Br)ccc21
Reaction time: 20 h
Yield: 65.3 %

Procedure:
To a solution of 5-bromoindoline (5.0 g), 2-pyridinylacetic acid hydrochloride (4.82 g) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (15.8 g) in N,N-dimethylformamide (100 mL) was added dropwise diisoprpylethylamine (6.53 g) at ambient temperature and the mixture was stirred at the same temperature for 20 hours. The mixture was poured into a mixture of ethyl acetate and water and the separated organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give 5-bromo-1-(2-pyridinylacetyl)indoline (5.23 g) as a light-brown powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[C:9]([O-])([O-])=O.[K+].[K+].C[CH:16]([SH:20])[C:17]([O-:19])=[O:18].O>CN(C=O)C>[CH3:9][O:19][C:17](=[O:18])[CH2:16][S:20][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc(Cl)nc1
Reactant: CC(S)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CSc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a solution of 2,5-dichloropyridine (13, 2.04 g, 13.8 mmol) in 40 mL of dry DMF was added K2CO3 (1.91 g, 13.8 mmol) and reaction mixture was stirred for 30 min at ambient temperature. Neat methylthioglycolate (1.26 mL, 14 mmol) was added via syringe and the reaction mixture was stirred overnight under N2. The reaction mixture was treated with H2O (120 mL) and the product was extracted into EtOAc (2×220 mL). Combined organic layers were washed with lot of water, brine, dried over Na2SO4, filtered and concentrated to give 2.3 g of crude material which was purified by column chromatography (hexanes/EtOAc). Obtained 1.1 g (5.0 mmol) of target 14, as a colorless oil, in 36% yield.
Reaction SMILES: O=[C:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[O:10].[C:12](C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13].[CH2:37](Cl)Cl>>[CH2:15]([O:14][C:12](=[O:13])[CH:11]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[O:10])[CH3:37])[CH3:16]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCCl
Reactant: CC(=O)CCCCCCC=O
Product: CCOC(=O)C=CCCCCCCC(C)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a cooled (−40° C.) solution of 28-2 (10.8 g, 69.2 mmol) in 150 mL CH2Cl2 was added (carbethoxymethylene)triphenylphosphorane (24.1 g, 69.2 mmol) in 100 mL CH2Cl2 gradually over 15 min. The reaction mixture was stirred for 12 hr while it was warmed up to room temperature. After solvent removal, the residue was purified using silica gel flash chromatography (EtOAc/hexanes: 1:8 to 1:6) to afford the desired product 28-3 as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([OH:12])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=2)[N:19]=1>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([OH:12])[CH2:7][CH2:8][N:9]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:23]([F:24])([F:26])[F:25])=[N:21][N:22]=3)[N:19]=2)[CH2:10][CH2:11]1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: OC1(c2nccs2)CCNCC1
Product: OC1(c2nccs2)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 65 %

Procedure:
A mixture of 4-(1,3-thiazol-2-yl)piperidin-4-ol and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by the method of Example 306 to give 4-(1,3-thiazol-2-yl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol in 65% yield.
Reaction SMILES: FC([P:8](=[O:23])([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])(F)C(F)(F)F.P(C(C(F)(F)F)(F)F)(C(C(F)(F)F)(F)F)C(C(F)(F)F)(F)F.[CH3:46][N:47]1[CH:51]=[CH:50][N:49]=[CH:48]1.[F:52][C:53]([F:64])([C:57]([F:63])([F:62])[C:58]([F:61])([F:60])[F:59])[CH2:54][CH2:55][OH:56]>C1C=CC=CC=1>[F:22][C:16]([P:8]([C:9]([F:14])([F:15])[C:10]([F:13])([F:12])[F:11])(=[O:56])[O-:23])([F:21])[C:17]([F:18])([F:19])[F:20].[F:52][C:53]([F:64])([C:57]([F:63])([F:62])[C:58]([F:61])([F:60])[F:59])[CH2:54][CH2:55][N+:49]1[CH:50]=[CH:51][N:47]([CH3:46])[CH:48]=1
Reactant: Cn1ccnc1
Reactant: O=P(C(F)(F)C(F)(F)F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)F
Agent: FC(F)(F)C(F)(F)P(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: c1ccccc1
Product: Cn1cc[n+](CCC(F)(F)C(F)(F)C(F)(F)F)c1
Product: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 100 °C
Yield: 98.1 %

Procedure:
8.27 g (20.5 mmol) of tris(pentafluoroethyl)phosphine oxide, (C2F5)3P═O, are mixed with 20 cm3 of dry benzene and 1.67 g (20.3 mmol) of N-methylimidazole in a flask fitted with a reflux condenser held at minus 25° C. 4.37 g (20.4 mmol) of 3,3,4,4,5,5,5-heptafluoropentan-1-ol are added to this mixture at room temperature while stirring using a magnetic stirrer. The reaction mixture is heated at an oil-bath temperature of 100° C. for 20 minutes. After cooling to room temperature, the phosphinate is separated from the benzene phase and washed twice with 10 cm3 of benzene. Drying at 60° C. (2 hours) under a vacuum of 13.3 Pa gives 11.55 g of 1-(3,3,4,4,5,5,5-heptafluoropentyl)-3-methylimidazolium bis(pentafluoroethyl)phosphinate as liquid. The yield is 97.5%.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([CH2:16][O:17][C:18]2[N:23]=[CH:22][C:21]([C:24]3[C:29](=[O:30])[N:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=5)=[CH:34][CH:33]=4)[C:27]([CH2:46][CH2:47][CH3:48])=[N:26][C:25]=3[CH2:49][CH3:50])=[CH:20][CH:19]=2)[CH2:15][CH2:14]1>C(OCC)(=O)C>[CH:13]1([CH2:16][O:17][C:18]2[N:23]=[CH:22][C:21]([C:24]3[C:29](=[O:30])[N:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[C:44]5[NH:3][C:4](=[O:7])[O:5][N:45]=5)=[CH:34][CH:33]=4)[C:27]([CH2:46][CH2:47][CH3:48])=[N:26][C:25]=3[CH2:49][CH3:50])=[CH:20][CH:19]=2)[CH2:15][CH2:14]1
Reactant: CCCc1nc(CC)c(-c2ccc(OCC3CC3)nc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(-c2ccc(OCC3CC3)nc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.58 g), sodium hydrogen carbonate (0.83 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.32 g, 57%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([NH:22][NH:23][C:24](=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>O1CCCC1>[Si:1]([O:18][CH2:19][C:20]1[S:40][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:23][N:22]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(=O)NNC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1nnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.8 %

Procedure:
To a solution of ethyl [2-({[tert-butyl(diphenyl)silyl]oxy}acetyl)hydrazino](oxo)acetate (3.20 g) in tetrahydrofuran (30 mL) was added Lawesson's reagent (3.02 g), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the title compound (3.05 g, yield 96%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[N:27]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH:28]1([C:31]([NH:1][C:2]2[N:27]=[C:5]3[CH:6]=[CH:7][C:8]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18]([C:20]5[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=5)=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:9][N:4]3[N:3]=2)=[O:32])[CH2:30][CH2:29]1
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.1 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (120 mg, 0.333 mmol) in N,N-dimethylacetamide (5 mL) was added cyclopropanecarbonyl chloride (30.5 μL, 0.336 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane) to give the title compound (110 mg, 77%) as a white solid.
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5]1.[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:9]1([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23])[N:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCn1ccc(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1ccc(-c2ccccc2)n1
Yield: 23.7 %

Procedure:
2.01 g of 1-(chloromethyl)-3-phenyl-1H-pyrazole hydrochloride and 1.42 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 27 ml of N,N-dimethylformamide. 2.43 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.66 g of [(3-phenyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl)malononitrile (referred as the compound of the present invention (10), hereinafter) shown by below formula.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].ClC(Cl)Cl.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O>[CH2:27]([O:26][C:24]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC1CCN(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred mixture of 175.4 parts of ethyl 4-piperidineacetate, 116.6 parts of sodium carbonate and 2250 parts of trichloromethane there were added dropwise 119.4 parts of ethyl chloroformate. After stirring for 4 hours at room temperature, the reaction mixture was diluted with 400 parts of water. The organic layer was separated, dried, filtered and evaporated, yielding 277 parts (100%) of ethyl 1-(ethoxycarbonyl)-4-piperidineacetate (interm 18).
Reaction SMILES: [CH3:1][C:2]1[C:3]([SH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]2[S:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:13][C:5](=[O:7])[C:4]=2[CH:8]=[CH:9][CH:10]=1
Reactant: N#Cc1ccccn1
Reactant: Cc1cccc(C(=O)O)c1S
Solvent: c1ccncc1
Product: Cc1cccc2c(=O)nc(-c3ccccn3)sc12
Yield: 52.9 %

Procedure:
A mixture of 3-methyl-2-mercaptobenzoic acid (2.40 g, 14.3 mmol), 2-cyanopyridine (1.20 g, 11.9 mmol) and pyridine (50.0 ml) was refluxed for 9 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.60 g, 52%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[N:16]([C:24]([O:26]C(C)(C)C)=[O:25])[S:17]([CH2:20]CCC)(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH2:35](OC1C=CC=CC=1N(C(OC(C)(C)C)=O)S(CCCC)(=O)=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[N:16]([C:24]([O:26][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:25])[S:17]([CH3:20])(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCS(=O)(=O)N(C(=O)OC(C)(C)C)c1ccccc1OCc1ccccc1
Reactant: CCCCS(=O)(=O)N(C(=O)OC(C)(C)C)c1cc(O)ccc1OCc1ccccc1
Solvent: CC(=O)O
Product: CS(=O)(=O)N(C(=O)OCc1ccccc1)c1cc(O)ccc1OCc1ccccc1

Procedure:
By carrying out the operation as described in preparation 13c but using the product from the preceding stage instead of the product from preparation 13b, the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][O:10][CH2:11]OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: COCOC
Reactant: Oc1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccccc1Cl
Reaction time: 72 h

Procedure:
2-Chlorophenol (96.4 g, 0.75 mol), dimethoxymethane (257.9 g, 3.39 mol) and 750 mg of p-toluenesulfonic acid were dissolved in 1.5 L of methylene chloride and the mixture heated at reflux with stirring under nitrogen for 72 hours in a flask equipped with a Soxhlet extraction apparatus containing 400 g of 3A molecular sieves. The mixture was allowed to cool and 3 ml of triethylamine was added. The mixture was then extracted with 2N sodium hydroxide and the organic phase was dried over magnesium sulfate. Evaporation of the volatiles under reduced pressure left 66.9 g of crude 1-chloro-2-methoxymethoxybenzene as a residue. This was distilled and the fraction boiling at 94° C. and 6.5 mm pressure was collected to obtain 51.3 g (40 percent of theory) of purified product. The proton nmr spectrum was consistent with the assigned structure.