Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:10]#[N:11])([CH3:13])[CH3:12])[CH:5]=[C:6]([F:8])[C:7]=1[C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28]
Reactant: CC(C)(C#N)c1cc(F)cc(Br)c1
Reactant: CC(C)(C)N=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1c(F)cc(C(C)(C)C#N)cc1Br
Temperature: -76 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of 2-(3-bromo-5-fluorophenyl)-2-methylpropanenitrile (30 g, 124 mmol, 1.0 equiv.) in 180 mL THF was added lithium diisopropylamide (82.6 ml of 1.8 M, 149 mmol, 1.2 equiv.) dropwise at −75° C. The reaction mixture was stirred at −76° C. for 2 hr. The tert-butylisocyanate (18.4 g, 21.8 ml, 186 mmol, 1.5 equiv.) was added dropwise at −75° C. and stirring was continued for 2 hr. An additional 0.5 equiv. of tert-butylisocyanate was added and the reaction mixture was allowed to warm gradually to room temperature and stirred overnight. The reaction mixture was quenched with 180 mL water and the THF was then removed under reduced pressure at 60° C. IPA was added at 60° C. and the product was crystallized out from 180 mL H2O and 120 mL IPA at 60° C. The mixture was cooled to room temperature slowly overnight. The crystals were collected by filtration, washed with H2O, H2O/IPA (1/1), and heptane, and dried overnight to afford 2-bromo-N-tert-butyl-4-(2-cyanopropan-2-yl)-6-fluorobenzamide (34.7 g, 102 mmol, 82.1% yield) as white crystalline solid with >99% HPLC purity. 1H NMR (300 MHz, DMSO-d6) 8 ppm 1.34 (s, 9 H) 1.70 (s, 6 H) 7.47 (dd, J=10.01, 1.70 Hz, 1 H) 7.60 (s, 1 H) 8.34 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1N=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[OH-:10].[Na+].Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[N:16]=[C:15]([NH:29][CH:30]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[N:14]=1>C1C=CC=CC=1>[Cl:28][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[N:16]=[C:15]([NH:29][CH:30]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[N:14]=[C:13]([O:9][CH2:8][CH:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[O:10]3)[N:18]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: [OH-]
Reactant: Cc1cccc(CO)n1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(OCC3C=CC=C(C)O3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 6-methyl-2-pyridylmethanol (145 mg, 1.17 mmol) and sodium hydroxide (63 mg, 1.57 mmol) in benzene (15 mL) was heated to reflux for 3 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.30 g, 0.785 mmol) at same temperature. The mixture was heated to reflux for 12 hours, concentrated under vacuum and diluted with water (20 mL). The mixture was then extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue thus obtained was purified by column chromatography (70–80% EtOAc-Hexane) to afford the title compound E30 as a hygroscopic solid (257 mg, 70%). HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B═CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 268 nm, Rt 23.93 min, 99.14% purity; MS (CI): m/z 469 (M+, 100).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([NH2:26])=[CH:21][CH:20]=2.Cl.O1CCOCC1.CCO.ClC(Cl)C>>[CH3:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([NH:26][C:2]1[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=1)=[CH:21][CH:20]=2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CCO
Solvent: CC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cc2cc(Nc3ccnc4cc(C(F)(F)F)ccc34)ccc2[nH]1
Temperature: 90 °C
Yield: 17.2 %

Procedure:
A suspension of 4-chloro-7-(trifluoromethyl)quinoline 1-A (158 mg, 0.68 mmol), 2-methyl-1H-indol-5-amine 1-B (100 mg, 0.68 mmol) and 4N HCl in dioxane (0.25 ml, 1.0 mmol) in a mix solvent (EtOH/dichloroethane, 1:1, 6 ml) was heated to 90° C. in a sealed tube overnight. The reaction mixture was concentrated and dissolved in 2 ml of DMSO. The solution was purified by HPLC (DionexSystem, 20-60% CH3CN/H2O over 30 minutes). 40 mg of N-(2-methyl-1H-indol-5-yl)-7-(trifluoromethyl)quinolin-4-amine 1 was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20]C(=O)C)[CH:15]=1)[CH3:2].[OH-].[Na+].O.C(OCC)(=O)C>CO>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=1)[CH3:2]
Reactant: CCOc1cc2[nH]ccc2cc1Oc1ccnc(NC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCOc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
N-(4-((6-ethoxy-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide described in Production Example 15-5 (7.16 g, 23.0 mmol) was dissolved in methanol (50 mL), a 2 M sodium hydroxide solution (50 mL) was added under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 75° C. for 2.5 hours. The reaction mixture was cooled to room temperature and then water and ethyl acetate were added for partition. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, then the resultant was filtered and concentrated under vacuum. A liquid mixture of diethyl ether and ethyl acetate was added to the residue, and the mixture was collected by filteration and washed to obtain the title compound (5.35 g, 86%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[Li]C1C=CC=CC=1.[Li]C(CC)C.CN([CH:38]=[O:39])C>C1COCC1>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]3[C:10]([C:2]([CH:38]=[O:39])=[N:3][NH:4]3)=[CH:9][CH:8]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH2:18][O:19][CH3:20]
Reactant: COCOc1ccc(-c2ccc3c(I)n[nH]c3c2)cc1OC
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: COCOc1ccc(-c2ccc3c(C=O)n[nH]c3c2)cc1OC
Temperature: -78 °C
Reaction time: 0.13 h
Yield: 71 %

Procedure:
In a 100-mL round-bottom flask, 3-iodo-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (921 mg, 2.245 mmol, 1.00 equiv) was dissolved in THF (36 mL) and cooled to −78° C. (allow 8 min at this scale). A solution of PhLi (2.5 mL, 1.8M, 4.49 mmol, 2.00 equiv) was added and the mixture was allowed to stir for 30 min. A solution of s-BuLi (3.63 mL, 4.71 mmol, 2.1 equiv) was added and the reaction mixture was allowed to stir for 1 h at −78° C. Neat DMF (1.4 mL, 18 mmol, 8.0 equiv) was added. The cold bath was removed and the reaction was allowed to slowly warm to 0° C. in the air. As the ice melted saturated sodium bicarbonate (20 mL) was added. The product was extracted into ethyl acetate (200 mL) from saturated sodium bicarbonate (75 mL more), dried over sodium sulfate, decanted and concentrated under reduced pressure. Purification by silica gel chromatography (450 mL silica, 4:6 ethyl acetate/hexane) gave 6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole-3-carbaldehyde (498 mg, 71%)): Rf sm 0.30, p 0.14 (ethyl acetate-hexane 4:6); 1H NMR (CDCl3) δ 10.85 (bs, 1H), 10.25 (s, 1H), 8.37 (d, 1H, J=8.4 Hz), 7.67 (s, 1H), 7.60 (d, 1H, J=8.4 Hz), 6.26 (d, 1H, J=8.7 Hz), 7.19 (m, 2H), 5.30 (s, 2H), 3.99 (s, 3H), 3.55 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[NH4+].[OH-].[CH2:18](O)[CH3:19]>>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:18][CH3:19])=[O:9]
Reactant: CCO
Reactant: Nc1cnccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCOC(=O)c1ccncc1N
Yield: 87 %

Procedure:
To a solution of 1 g (7.25 mmol) of 3-amino-4-pyridinecarboxylic acid in 5 mL of ethyl alcohol was added 2 mL of sulfuric acid. The mixture was warmed under reflux for 2 h. It was cooled and basified with conc. NH4OH solution to pH=8. The resulting solution was extracted with ethyl acetate and the organic layer was washed with brine and water, dried (MgSO4) and concentrated in vacuo to give 1.04 g of the title compound as a white solid (87%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:11][C:12]([O:15]C(OC(OC(C)(C)C)=O)=O)(C)C.CCN(CC)CC>CC#N.CN(C1C=CN=CC=1)C.O>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([C:12](=[O:15])[CH3:11])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Ic1ccc2[nH]ncc2c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 5-iodo-1H-indazole (1.00 g, 4.10 mmol) in CH3CN (20 ml) were added Boc2O (984 mg, 4.51 mmol), DMAP (125 mg, 1.02 mmol) and Et3N (0.64 ml, 4.6 mmol). The reaction mixture was stirred at room temperature for 5 hours, diluted with H2O and extracted with AcOEt. The organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound. This compound (>1.5 g) was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 1.72 (9H, s), 7.79 (1H, d, J=8.8 Hz), 7.98 (1H, d, J=8.8 Hz), 8.10 (2H, s). MS (ESI) m/z 345 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>CN(C)C=O.O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[N:8]2[CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1Nc2cc(Br)ccc2/C1=C/c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a solution of E/Z 6-Bromo-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one (5.3 g, 16 mmol) prepared in example 157a in N,N-dimethyl-formamide (50 mL) at 0° C. was added NaH (60% in mineral oil) (0.64 g, 16 mmol), followed by the dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (2.65 g, 16 mmol) in tetrahydrofuran (40 mL). The reaction mixture was stirred at 0° C. for 0.5 h, then poured into ice-water. The crude was extracted with ethyl acetate twice. The combined organic layer was dried over Na2SO4. The solvent was removed and the residue was purified by chromatography (hexanes) to give E/Z-6-Bromo-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one as a yellow oil (Yield 4.5 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([N:15]3[CH:19]=[N:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:23]N(C)C=O.S(OC)(OC)(=O)=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([N:15]3[CH:19]=[N:18][N:17]([CH3:23])[C:16]3=[O:20])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(N2CCN(n3cn[nH]c3=O)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COc1ccc(N2CCN(n3cnn(C)c3=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of 4.5 parts of 2,4-dihydro-4-[4-(4-methoxyphenyl)-1-piperazinyl]-3H-1,2,4-triazol-3-one, 0.8 parts of sodium hydride dispersion 78% and 27 parts of N,N-dimethylformamide is stirred for one hour at room temperature. Then there are added 2.5 parts of dimethyl sulfate and stirring at room temperature is continued for another hour. Water is added to the reaction mixture and the product is extracted twice with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 3.3 parts (71%) of 2,4-dihydro-4-[4-(4-methoxyphenyl)-1-piperazinyl]-2-methyl-3H-1,2,4-triazol-3-one; mp. 178.2° C.
Reaction SMILES: [CH3:1][O:2][C:3]([O:8][CH3:9])([CH2:6]C)[CH:4]=[CH2:5].[O:10]=[O+][O-]>CO>[CH3:9][O:8][C:3]([O:2][CH3:1])([CH2:4][CH3:5])[CH:6]=[O:10]
Reactant: O=[O+][O-]
Reactant: C=CC(CC)(OC)OC
Solvent: CO
Product: CCC(C=O)(OC)OC
Yield: 85.4 %

Procedure:
1 liter of a solution of 195 g (1.5 moles) of ethylacrolein dimethylacetal in methanol is reacted with ozone at -25° C. to -30° C. analogously to the procedure indicated in Example 1, and is then hydrogenated. The absorption of H2 is 29.55 standard liters (87.8% of theory). After working up, which is carried out analogously to the instructions in Example 2 by removing the catalyst, treating the reaction solution with an acid ion exchanger, distilling off the solvent and rectifying the reaction product, 169 g of ethylglyoxal dimethylacetal boiling at 52° C./15 are obtained, corresponding to a yield of 85.4% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH3:16])[C:11](=[O:17])[N:10]([CH2:18][C:19]([OH:21])=O)[N:9]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH3:16])[C:11](=[O:17])[N:10]([CH2:18][C:19]([NH:28][CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=3)=[O:21])[N:9]=2)=[CH:6][CH:7]=1
Reactant: COCCn1c(-c2ccc(Cl)cc2)nn(CC(=O)O)c1=O
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1c(-c2ccc(Cl)cc2)nn(CC(=O)NCc2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50.0 mg (0.160 mmol) of 2-[3-(4-chlorophenyl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 90A, 30.9 mg (0.176 mmol) of 3-trifluoromethylbenzyl-amine and 40.0 mg (0.209 mmol) of HOBt are placed in 2 ml of dimethylformamide and treated with 26.0 mg (0.192 mmol) of EDC hydrochloride. This is stirred overnight at room temperature, then stirred with 15 ml of water and the resulting precipitate recovered by filtration. The crude product is washed with water and dried in vacuo. 66.9 mg (89% of theory) of the target compound are thus obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14]([O:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)=[O:19])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:36])(S(F)(=O)=O)C(O)=O>CC#N.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH:28]([F:36])[F:27])[CH2:10][CH:9]1[C:14]([O:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)=[O:19])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1C(=O)OCC(=O)c1ccc(Br)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(OC(F)F)CC1C(=O)OCC(=O)c1ccc(Br)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester (500 mg) and Cu(I)I (45 mg) in MeCN (8 mL) at 45° C. was added 242 μl of difluoro-fluorosulfonyl-acetic acid in 2 mL of MeCN dropwise for 60 min. The reaction mixture was stirred at 45° C. for 60 min. and evaporated under reduced pressure, and resulting residue was taken up in ethyl acetate (100 mL). The organic phase was washed with brine (1×100 mL) and dried over sodium sulfate. After the solvent was removed, the resulting oil was subjected to silica gel chromatography using effluent of 10-50% ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 4-Difluoromethoxy-pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester (339 mg, 61%) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:7]C[C@@H:5](C(C)=C)[CH2:4][CH:3]=1.C([O-])([O-])=[O:12].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[C:29]([O:32][C:33](=O)[CH3:34])(=O)[CH3:30]>C(OCCCC)(=O)C>[CH3:30][C:29]12[O:32][CH:33]1[CH2:34][CH:3]([C:2]1([CH3:1])[O:12][CH2:7]1)[CH2:4][CH2:5]2
Reactant: O=C([O-])[O-]
Reactant: C=C(C)[C@H]1CC=C(C)CC1
Reactant: CC(=O)OC(C)=O
Agent: OO
Agent: [Na+]
Solvent: CCCCOC(C)=O
Product: CC1(C2CCC3(C)OC3C2)CO1
Temperature: 60 °C
Reaction time: 12 h
Yield: 96.9 %

Procedure:
Limonene (1.36 g, 10 mmol) was dissolved in butyl acetate (25 ml), and a composition containing sodium percarbonate (6.0 g, 38.1 mmol) and acetic anhydride (10.2 g, 100 mmol) was added thereto. The mixture was stirred at 60° C. After 12 hours, the reaction solution was washed with water to thereby completely remove acetic acid and sodium acetate, which were generated as by-products, and the remaining H2O2. Butyl acetate was distilled off from the organic phase by distillation, and as a result, 1.63 g (97% yields) of limonene diepoxide with a GC purity of 97% were obtained.
Reaction SMILES: [Cl-].[NH4+].[N-:3]=[N+:4]=[N-:5].[Na+].[CH:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:23]([CH2:30][C:31]#[N:32])=[CH:22][C:21]=3[C:33]([F:36])([F:35])[F:34])[CH:17]=2)[NH:12][CH:11]=1)([CH3:9])[CH3:8]>CN(C)C=O>[CH:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][C:20]3[C:25]([C:26]([F:27])([F:29])[F:28])=[CH:24][C:23]([CH2:30][C:31]4[NH:32][N:5]=[N:4][N:3]=4)=[CH:22][C:21]=3[C:33]([F:36])([F:34])[F:35])[CH:17]=2)[NH:12][CH:11]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CC#N)cc3C(F)(F)F)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(Cc4nnn[nH]4)cc3C(F)(F)F)cc12

Procedure:
251 mg (4.69 mmol) of ammonium chloride and 305 mg (4.69 mmol) of sodium azide are added to a solution of 200 mg (0.469 mmol) of nitrile derivative from Example VIII in 8 ml of dimethylformamide and the solution is boiled under reflux for 4 hours. The solution is then highly concentrated, treated with 6N hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases are dried, filtered and concentrated to an oil in vacuo. The crude product is dissolved in dichloromethane and chromatographed on silica gel 60 using dichloromethane with addition of methanol in the gradient mode (90:5 to 90:40).
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:1]1([O:9][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCCCCC1
Reactant: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OC1=CCCCCCC1
Reaction time: 15 h
Yield: 92.7 %

Procedure:
To a solution of cyclooctanone (40.0 g, 316 mmol) in 200 mL of anhydrous DMF were added triethylamine (TEA, 93.0 mL, 666 mmol) and chlorotrimethylsilane (84.0 mL, 666 mmol). The reaction was heated to reflux. After 15 h, the reaction was quenched with 20 mL of H2O and the DMF was removed on a rotary evaporator. The residue was diluted with hexanes (300 mL), washed with H2O (3×100 mL) and brine (1×50 mL), and dried over MgSO4. Distillation under reduced pressure (20 torr) yielded 58.1 g (93%) of the desired product as a colorless oil, bp 108° C. (20 torr) (lit. 106° C. at 25 torr). Nakamura, et al. J. Am. Chem. Soc. (1976) 98, 2346-2348. IR: 2926, 2851, 1661 cm−1. 1H NMR (CDCl3, 300 MHz): δ 0.20 (s, 9H), 1.39-1.58 (m, 8H), 2.02 (m, 2H), 2.19 (m, 2H), 4.75 (t, 1H, J=9.0 Hz). (Lit: 1H NMR (CDCl3, 600 MHz): δ 0.16 (s, 9H), 1.46 (m, 4H), 1.49 (m, 2H), 1.55 (m, 2H), 1.97 (m, 2H), 2.14 (m, 2H), 4.70 (t, 1H, J=8.0 Hz) (Frimer et al. J. Org. Chem. (2000) 65, 1807-1817.) 13C NMR (CDCl3, 75 MHz): δ 0.4, 25.5, 26.3, 26.4, 27.8, 30.9, 31.0, 105.41, 152.99. (Lit: 13C NMR (CDCl3, 150 MHz): δ 0.45, 25.52, 26.36, 26.40, 27.83, 30.98, 31.05, 105.45, 153.05) Frimer et al. (2000) supra) FAB-HRMS: Calcd. for C11H23OSi+ [M+H]+: 199.1518. found 199.1520.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].I[CH2:10][CH2:11][CH2:12][CH3:13]>[Ag]=O.CCOCC>[CH2:10]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH2:11][CH2:12][CH3:13]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CCCCI
Agent: O=[Ag]
Solvent: CCOCC
Product: CCCCO[C@@H](C)C(=O)OCC
Reaction time: 72 h
Yield: 44 %

Procedure:
Silver oxide (77.5 g, 0.3 mol) was added to a mixture of ethyl L-(+)-lactate (49.4 g, 0.4 mol) with 1-iodobutane (100 g, 0.5 mol) over 2 hours, followed by allowing the mixture to stand at room temperature for 3 days, adding ether (30 ml) to dilute it, filtering, distilling off ether, washing the residue with 2N-NaOH aqueous solution, drying it over anhydrous magnesium sulfate and distilling it to obtain ethyl (S)-2-butyloxypropionate (30.7 g) (b.p. 64° C./7 mmHg), adding to this product, 5N-NaOH aqueous solution (50 ml), agitating the mixture at room temperature for 5 hours, pouring it in 6N-HCl (75 ml), adding ether, agitating the mixture, washing the resulting organic layer with water and distilling off ether to obtain (S)-2-butyloxypropionic acid (21.4 g).
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH3:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[N:12]=[CH:11][C:10]=1[C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:31][CH:32]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][N:15]=2)[N:12]=[CH:11][C:10]=1[C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([CH:33]2[CH2:38][CH2:37][N:36]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1)=[O:25]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cc1c(C(=O)Nc2ccc(C3CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(C3CCN(S(=O)(=O)C(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Isopropylsulfonyl chloride (167 μl) was added at room temperature to a suspension of 5-methyl-N-[6-(piperidin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (215 mg) described in Reference Example 173 and potassium carbonate (237 mg) in N,N-dimethylformamide (1.7 ml), and stirred at room temperature for 4.5 hours. Water was added to the reaction solution, the precipitated solid was washed with ethyl acetate. The resulting solid was purified with a preparative HPLC (water:acetonitrile) to give the titled compound (44 mg) as a white solid.
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=2)[CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].Cl>C1COCC1.CO.O>[C:4]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)[CH2:13]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)c1ccc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(C(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 93.7 %

Procedure:
LiOH.H2O (1.14 g, 27.26 mmol) and water (5 mL) was added to a solution of 324 (4.36 g, 13.62 mmol) in THF (15 mL) and MeOH (15 mL). The reaction mixture was stirred at room temperature for 22 h, diluted with water and acidified with HCl (pH 4-5). The precipitate obtained was collected by filtration and rinsed with water to give the title compound 325 (3.91 g, 94% yield) as a white solid.