Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[C:17]([C:24]([F:27])([F:26])[F:25])[CH:18]=[CH:19][CH:20]=2)[N:15]=1.[CH:28](OCC)=[O:29]>C1COCC1>[Cl:13][C:14]1[C:23]([CH:28]=[O:29])=[CH:22][C:21]2[C:16](=[C:17]([C:24]([F:26])([F:25])[F:27])[CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: FC(F)(F)c1cccc2ccc(Cl)nc12
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cc2cccc(C(F)(F)F)c2nc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a cold solution of butyllithium (0.498 g, 1.7 mmol) in 2 mL dry THF at −20C. was added diisopropyl amine (0.192 g, 1.9 mmol) drop wise and reaction mixture was allowed to stir at 0° C. for 1 h. then reaction mixture was again cooled to −78° C. and a solution of 2-chloro-8-trifluoromethyl-quinoline (0.4 g, 1.70 mmol) in 4 mL dry THF was added drop wise continued stirring for 5-10 min then added ethyl formate (0.12 g, 1.7 mmol) drop wise, continued stirring for 0.5 h. n-Butyllithium was quenched with ammonium chloride solution and extracted with ether (3×10 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, concentrated under vacuum to get the crude compound. The crude residue was purified over silica gel (100-200 mesh) using 10% ethyl acetate: petroleum ether to afford the desired compound (0.15 g, 34%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:15]2[CH:16]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:18]=[C:13]([F:12])[CH:14]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1cc(F)cc(Oc2ccc(F)cc2)c1
Reactant: Cc1c(Br)cnc(N)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(Oc3ccc(F)cc3)c2)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 3.0 grams (0.012 mole) of 3-fluoro-5-(4-fluorophenoxy)phenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0)in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-[3-fluoro-5-(4-fluorophenoxy)phenyl]pyridine.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][NH:10][C@H:11]1[C@H:20]([O:21][CH3:22])[CH2:19][C:18]2[C:13](=[CH:14][C:15]([C:23](=[O:25])[NH2:24])=[CH:16][CH:17]=2)[C:12]1([CH3:27])[CH3:26])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:7][C@H:8]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:9][NH:10][C@@H:11]1[C:12]([CH3:27])([CH3:26])[C:13]2[CH:14]=[C:15]([C:23]([NH2:24])=[O:25])[CH:16]=[CH:17][C:18]=2[CH2:19][C@H:20]1[O:21][CH3:22]
Reactant: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1NC[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1NC[C@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 187.2 %

Procedure:
A solution of [(R)-1-benzyl-2-(trans-7-carbamoyl-3-methoxy-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-ethyl]-carbamic acid tert-butyl ester (2.20 g, 3.36 mmol) in DCM (20 mL) under an atmosphere of nitrogen was cooled to 0° C. and 4.0 M HCl in 1,4-dioxane (3.36 mL, 13.4 mmol) was added dropwise. The clear solution was stirred and allowed to warm to room temperature. After 3 h, the reaction flask was stored at −20° C. for 4 days. The reaction mixture was allowed to warm to room temperature and the solvents were evaporated under reduced pressure to give the title compound as an off-white solid (2.4 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[Cl:23][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(-c2cc(CO)ccn2)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine (18.15 g) was dissolved in chloroform (300 mL) , and to the solution thionyl chloride (19.2 mL) was added at 0° C.. After 30 minutes, the mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crystals were then recrystallized from chloroform-hexane to obtain the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7])=[CH2:2].[CH3:11][N:12]([CH3:30])[C:13]([C:15]1[O:16][C:17]2[C:23]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][CH:21]=[CH:20][C:18]=2[CH:19]=1)=[O:14].C(O)(=O)C>C(O)C>[C:6]([C:5]1[CH:8]=[CH:9][N:10]=[C:3]([CH2:1][CH2:2][N:27]2[CH2:28][CH2:29][N:24]([C:23]3[C:17]4[O:16][C:15]([C:13]([N:12]([CH3:30])[CH3:11])=[O:14])=[CH:19][C:18]=4[CH:20]=[CH:21][CH:22]=3)[CH2:25][CH2:26]2)[CH:4]=1)#[N:7]
Reactant: C=Cc1cc(C#N)ccn1
Reactant: CN(C)C(=O)c1cc2cccc(N3CCNCC3)c2o1
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)C(=O)c1cc2cccc(N3CCN(CCc4cc(C#N)ccn4)CC3)c2o1
Temperature: 90 °C

Procedure:
The compound was prepared according to the procedure disclosed in Example 39 starting from of 2-vinylisonicotinonitrile (0.076 g, 0.59 mmol), N,N-dimethyl-7-(piperazin-1-yl)benzofuran-2-carboxamide (0.080 g, 0.29 mmol) (Example 39d), and acetic acid (0.013 mL, 0.23 mmol). Ethanol was used as solvent and the reaction heated at 90° C. for two days. The crude product was purified by preparative HPLC to give the title compound. Yield: 0.061 g (52%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Agent: [Ni]
Solvent: CO
Product: Nc1cc(O)cc(C(F)(F)F)c1
Yield: 98.2 %

Procedure:
A mixture of 3-nitro-5-(trifluoromethyl)phenol (50 g, 241.42 mmol, 1.00 equiv) and Raney-Ni (6 g) in methanol (500 mL) was stirred under 1 atmosphere of hydrogen at 25° C. for 8 h. The catalyst was removed by filtration. The filtrate was concentrated under vacuum to give 42 g (98%) of 3-amino-5-(trifluoromethyl)phenol as a light yellow solid. LCMS (method D, ESI): RT=0.84 min, m/z=178.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].[N:15]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][NH2:15])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCc1ccc(NN)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-(4-aminophenyl)propionic acid ethyl ester (14 g, 72.5 mmol) in conc. HCl (200 mL) was added aqueous (10 mL) NaNO2 (5 g, 72.5 mmol) at 0° C. and the resulting mixture was stirred for 1 h. A solution of SnCl2.2H2O (33 g, 145 mmol) in conc. HCl (150 mL) was then added at 0° C. The reaction solution was stirred for an additional 2 h at RT. The precipitate was filtered and washed with EtOH and Et2O to yield 3-(4-hydrazinophenyl)propionic acid ethyl ester as a white solid, which was used for the next reaction without further purification. MS (ESI): m/z: 209 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:31][C:32]3[CH:41]=[CH:40][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=3)=[CH:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccc(O)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(COc2ccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)cc2)cc1
Reaction time: 1 h
Yield: 46.7 %

Procedure:
A solution of [4-(4-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl) methanone (0.5 g, 1.3 mmol), methyl 4-bromomethylbenzoate(0.30 g, 1.3 mmol) and K2CO3 (0.42 g, 3 mmol) in acetone (20 ml) was heated to reflux. After 1 hr, the reaction was cooled, filtered and concentrated. The resulting oil was dissolved in THF/MeOH (20 ml) and treated with 2N NaOH (2 ml) and heated to reflux. After 1 hr, the reaction was cooled, poured into 2N HCl and extracted with EtOAc. The organic layer was dried, concentrated to give a solid which was triturated with 10% EtOAc/hexane, filtered to give the desired compound (0.32 g, Yield=47%); MS (ESI) m/z 528 ([M+H]+); 1H NMR (DMSO) δ 12.98 (bs, 1H), 9.11 (s, 1H), 8.33 (d, 1H, J=6.8 Hz), 7.96-7.91 (m, 3H), 7.82-7.77 (m, 1H), 7.64-7.53 (m, 5H), 7.39-7.35 (m, 2H), 7.27 (d, 2H, J=7.8 Hz), 6.99 (d, 2H, J=7.8 Hz), 5.17 (s, 2H).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([CH:25]=[N:26][OH:27])[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[CH:29]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:33][CH:32]=1)=[CH2:30].C(=O)([O-])O.[K+].ClN1C(=O)CCC1=O>C(OCC)(=O)C.O>[F:28][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:30][CH:29]([C:31]5[CH:32]=[CH:33][C:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][CH:36]=5)[O:27][N:26]=4)[N:24]=3)[CH2:18][CH2:19]2)=[O:13])[N:4]=1
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C=NO)cs2)CC1
Reactant: C=Cc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(C2CC(c3csc(C4CCN(C(=O)Cn5nc(C(F)F)cc5C(F)F)CC4)n3)=NO2)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde oxime (1.50 g) and tert-butyl (4-vinylphenyl)carbamate (0.94 g) in ethyl acetate (140 ml) were added, at room temperature, potassium hydrogencarbonate (1.79 g) and N-chlorosuccinimide (0.50 g), and then one drop of water. After the reaction mixture had been stirred at 60° C. for 3 h, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl (4-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-O-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl)carbamate (0.90 g).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(N2CCCC2)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(N2CCCC2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(pyrrolidin-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.82 min.; [M+H]+: 395.20 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][NH:26][CH3:27]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][N:26]([CH3:27])[CH3:25])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Reactant: CNC
Solvent: CCO
Product: CN(C)CC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 16.1, Methanesulfonic acid 3-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester and Dimethylamine (10 equivalents of a 5.6 M EtOH solution) were converted to yield {3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-dimethyl-amine as light brown solid, MS: 327 (MH+, 1Cl).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH:8]=O)[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[O:23][C:24]=3[CH3:25])=[C:14]([O:31][CH3:32])[CH:13]=2)=[N:4]1)[CH3:2].[CH2:33]([P:42](=[O:49])([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([N:3]1[CH:7]=[C:6](/[CH:8]=[CH:33]/[P:42](=[O:49])([O:43][CH2:44][CH3:45])[O:46][CH2:47][CH3:48])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[O:23][C:24]=3[CH3:25])=[C:14]([O:31][CH3:32])[CH:13]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(C=O)c(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)n1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(CC)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 62.8 %

Procedure:
To a mixture of 1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carbaldehyde (0.50 g), tetraethyl methylenediphosphonate (0.35 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.050 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (9:1, v/v) to give diethyl (E)-2-{1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.41 g, yield 65%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 82-84° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:19][O:20][CH2:21]Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][O:9][CH2:19][O:20][CH3:21])[N:7]=1
Reactant: COCCl
Reactant: OCc1cccc(Br)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.4 %

Procedure:
Under a stream of argon, (6-bromopyridine-2-yl)methanol (10 g; 53.2 mmol) was dissolved in methylene chloride (50 mL). Diisopropylethylamine (9.6 g; 74.5 mmol) and chloromethyl methyl ether (5.35 g; 66.5 mmol) were added to the reaction mixture in an ice bath, and further, the reaction mixture was stirred at room temperature for 17 hours. The reaction solution was poured into ice water and extracted with chloroform. The organic layer was washed with water, dried over sodium sulfate, and then evaporated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (SiO2, 200 g) (toluene/ethyl acetate=10/1) to give 12.15 g (yield: 98%) of the title compound (11).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:10].[C:17]([O:21][C:22]([NH:24][C@H:25]1[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28][NH:27][C:26]1=[O:33])=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([O:21][C:22]([NH:24][C@H:25]1[CH2:31][CH2:30][C@@H:29]([O:32][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:10])[CH2:28][NH:27][C:26]1=[O:33])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCCCCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CNC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCOC(=O)O[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)C(=O)NC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
Triethylamine (2 mL, 15 mmol) is added to a solution of pentyl chloroformate (1.8 g, 12.2 mmol), (3S 6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one (1.5 g, 6.1 mmol) and 20 mL of CH2Cl2 at 5° C. The reaction mixture is stirred at room temperature overnight. The reaction mixture is then partitioned with water, and the organic layer is dried (Na2SO4), and concentrated by rotary evaporation. The resulting residue is chromatographed (5% EtOAc-CH2Cl2) to give 1.3 g (60%) of (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-([[pentyloxy]carbonyl]oxy)-2H-azepin-2-one as a pale yellow solid: 1H NMR (CDCl3): δ 5.90 (d, J=6 Hz, 1H), 5.77 (t, J=6 Hz, 1H), 4.79 (m, 1H), 4.30 (m, 1H), 4.12 (m, 3H), 3.53 (m, 2H), 2.24 (m, 1H), 1.92 (m, 2H), 1.66 (m, 1H), 1.44 (s, 9H), 1.34 (m, 5H), 0.91 (m, 3H).
Reaction SMILES: [CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[S:4][S:3][CH2:2]1.ClC(OCC)=O.[CH:19]([NH2:22])([CH3:21])[CH3:20].[Zn:23]>C(#N)C.C(N(CC)CC)C>[Zn:23].[SH:4][CH:5]([CH2:1][CH2:2][SH:3])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:22][CH:19]([CH3:21])[CH3:20])=[O:12]
Reactant: O=C(O)CCCCC1CCSS1
Reactant: CC(C)N
Agent: CCOC(=O)Cl
Agent: [Zn]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)CCCCC(S)CCS
Temperature: -65 °C
Reaction time: 1 h

Procedure:
4.2 g of DL-α-lipoic acid and 2.4 g of triethylamine were dissolved in 50 ml of acetonitrile and cooled down to −65° C. with stirring. To this was gradually added 2.4 g of ethyl chloroformate dropwise. Twenty minutes after the completion of the dropwise addition, 1.5 g of isopropylamine dissolved in 30 ml of acetonitrile was quickly added, and stirring was continued for 30 minutes and, further one hour at room temperature. The solvent was evaporated under reduced pressure, and water was added to the residue and the mixture then was cooled down. Precipitated pale yellow crystals were collected by filtration, dissolved in 60 ml of tetrahydrofuran (THF). To this were added 20 ml of 50% acetic acid aqueous solution and 2.0 g of zinc powder and reaction was allowed for two hours at 50° C. with stirring. Unreacted zinc was separated out by filtration, and the filtrate was concentrated. After addition of water to the residue, precipitated white crystals were collected by filtration. Recrystallized from THF/acetic acid/water gave 5.0 g of the aimed compound. mp. 271-273° C. TLC, Rf=0.89 (n-butanol/acetic acid/water=4/1/2).
Reaction SMILES: [H-].[Na+].CI.[CH2:5]([S:7][C:8]1[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1)=[O:11])[CH3:6].[C:27](=O)(O)[O-].[Na+]>C1COCC1>[CH2:5]([S:7][C:8]1[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=1[C:10]([N:12]([CH3:27])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][N:14]=1)=[O:11])[CH3:6]
Reactant: CCSc1ccccc1C(=O)Nc1ccc(C(F)(F)F)cn1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCSc1ccccc1C(=O)N(C)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.03 g of 60% sodium hydride (oil-based) and 0.14 g of methyl iodide were added to a mixture of 0.15 g of 2-ethylsulfanyl-N-(5-trifluoromethyl-pyridin-2-yl)-benzamide and 2 mL of THF, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium bicarbonate solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.10 g of 2-ethylsulfanyl-N-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-benzamide (hereinafter, referred to as Compound of Present Invention 1).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][N:12]([CH2:20][CH2:21][CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:15]([O:14][C:13](=[O:19])[N:12]([CH2:20][CH2:21][CH:22]([O:27][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]([CH3:10])[N:9]=1)[C:23]([F:26])([F:25])[F:24])[CH3:11])([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1ccc(C#N)c(Cl)n1
Reactant: CN(CCC(O)C(F)(F)F)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C#N)c(OC(CCN(C)C(=O)OC(C)(C)C)C(F)(F)F)n1
Reaction time: 96 h
Yield: 31.2 %

Procedure:
A mixture of 2-chloro-6-methylnicotinonitrile (0.215 g, 1.41 mmol) and tert-butyl N-methyl-N-(4,4,4-trifluoro-3-hydroxybutyl)carbamate (0.345 g, 1.34 mmol) in DMF (6 mL) was treated with caesium carbonate (0.875 g, 2.69 mmol) at ambient temperature. After stirring for 4 days, the mixture was diluted with water and extracted with diethyl ether. The combined organic extracts were washed (water, brine), dried, and evaporated to an orange oil/solid mixture. The crude material was purified by silica gel chromatography, eluting with 100% dichloromethane and 5% methanol/95% dichloromethane (v/v) to give the product as a yellow oil (0.156 g, 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[Cl:27][C:28]1[CH:29]=[C:30]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[CH:31]=[CH:32][CH:33]=1>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=1)[C:34]([NH:36][C:37]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[F:23])=[S:38])=[O:35]
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (76 mg, yield 93%).