Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[Br-].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Zn+].CCOC(C)=O>C1COCC1.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>[Cl:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[C:10]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: [Zn+]c1ccccn1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(-c2ccccn2)c2c(Cl)nc(Cl)nc21
Temperature: 65 °C
Reaction time: 3 h
Yield: 42.5 %

Procedure:
To a solution of 2,4-dichloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2.25 mmol), as prepared in Example 5, step 1, in THF (11 mL) was added tetrakis(triphenylphosphine)palladium(0) (131 mg, 0.113 mmol) and pyridin-2-ylzinc(II) bromide (9 mL, 4.5 mmol, 0.5 M solution in THF) which was then heated to 65° C. and stirred for 3 hrs. EtOAc (10 mL) was added and the resulting mixture was washed with water (20 mL). The aqueous layer was extracted with EtOAc (three×10 mL), and the combined organic layers were then washed with 1 M aqueous Na2SO3 (20 mL), sat. aqueous NaHCO3 (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was then purified via flash chromatography (20%-50% EtOAc/heptane) to give the title compound as a clear oil (378 mg, 43% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59-8.71 (m, 1H) 8.21 (s, 1H) 7.89 (td, J=7.77, 1.89 Hz, 1H) 7.70 (d, J=7.83 Hz, 1H) 7.39 (ddd, J=7.52, 4.86, 1.01 Hz, 1H) 5.67 (s, 2H) 3.50-3.67 (m, 2H) 0.79-0.95 (m, 2H) −0.17-0.00 (m, 9H). m/z (APCI+) for C17H20N4OCl2Si 395.00/397.00 (M+H)+.
Reaction SMILES: C([O:8][CH2:9][C:10]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][C:28]=3[Cl:29])[NH:25][CH:24]=[C:23]4[C:30]([O:32][CH3:33])=[O:31])=[CH:16][CH:15]=2)[CH2:13][O:12][CH2:11]1)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[Cl:29][C:28]1[CH:27]=[C:26]2[C:22]([C:23]([C:30]([O:32][CH3:33])=[O:31])=[CH:24][NH:25]2)=[CH:21][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([C:10]2([CH2:9][OH:8])[CH2:11][O:12][CH2:13]2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(COCc5ccccc5)COC4)cc3)cc12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(CO)COC4)cc3)cc12
Temperature: 25 °C
Yield: 24.8 %

Procedure:
To a 0° C. slurry of methyl 5-[4-(3-Benzyloxymethyl-oxetan-3-yl)-phenyl]-6-chloro-1H-indole-3-carboxylate (200 mg, 0.433 mmol) in DCM (5 mL) was added boron trichloride (1.73 mL, 1.0 M in DCM, 1.73 mmol) via syringe, and the mixture was allowed to warm to room temperature over five hours. The reaction mixture was concentrated to dryness, diluted with ethyl acetate (200 mL), washed with water (10 mL) and saturated brine (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford an orange film, which was purified by flash chromatography (12 g silica, 20-100% ethyl acetate/heptane, 38 column volumes). Product fractions were combined and concentrated in vacuo to afford the title compound as a colorless oil (40 mg, 25% yield). MS (ES+) 372 (M+H)+; 1H NMR (500 MHz, CD3OD) δ ppm 8.00-8.04 (m, 2 H), 7.60 (s, 1 H), 7.44-7.55 (m, 4 H), 4.10 (s, 2 H), 3.95-4.07 (m, 4 H), 3.88 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][N:7]=1.[C:20]1([NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26]>CN1C(=O)CCC1>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[NH:27][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N:26]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: Nc1ccccc1N
Reactant: CNC(=O)c1nc(-c2cccc(C=O)c2)cnc1N
Solvent: CN1CCCC1=O
Product: CNC(=O)c1nc(-c2cccc(-c3nc4ccccc4[nH]3)c2)cnc1N

Procedure:
A solution of 3-amino-6-(3-formylphenyl)-N-methylpyrazine-2-carboxamide (25.4 mg, 0.1 mmol) and 1,2-phenylendiamine in NMP (3 mL) was heated at 80° C. for 8 h. The solvent was removed and the residue was triturated with 0.1 M aquous hydrochloric acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)=[N:8][C:9]3[N:10]([N:12]=[CH:13][CH:14]=3)[CH:11]=2)=[CH:2]1.CC1NN=C(N)[N:25]=1>>[CH3:14][C:13]1[N:25]=[C:9]2[N:8]=[C:7]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:11][N:10]2[N:12]=1
Reactant: Cc1nc(N)n[nH]1
Reactant: O=Cc1ccc(-c2nc3ccnn3cc2-c2ccsc2)cc1
Product: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccsc3)cn2n1

Procedure:
This compound was prepared in a manner according to 4-(6-thiophen-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-benzaldehyde by using 5-methyl-1,2,4-triazol-3-amine in the first step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:18])=[C:11]([NH2:17])[C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19](O)=O>>[CH2:1]([O:8][C:9]1[C:10]2[N:18]=[CH:19][NH:17][C:11]=2[C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(OCc2ccccc2)c(N)c1N
Reactant: O=CO
Product: Cc1cc(C)c2[nH]cnc2c1OCc1ccccc1
Yield: 61 %

Procedure:
A mixture of 2.50 g (10.3 mmols) of 3-benzyloxy-4,6-dimethyl-1,2-phenylenediamine [J. Med. Chem., 30, 2216 (1987)]and 20 ml of formic acid was heated under reflux for 30 minutes. The mixture was concentrated under reduced pressure, and then an aqueous saturated sodium bicarbonate solution was added to the residue followed by extraction of the solution with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/ methanol =40/1) to afford 1.59 g (yield: 61%) of 7-benzyloxy-4,6-dimethylbenzimidazole.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6]CC.[C:9]([OH:13])(=[O:12])[CH2:10][CH3:11]>O>[C:9]([OH:13])(=[O:12])[CH2:10][CH2:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CCCCCCC
Reactant: CCC(=O)O
Solvent: O
Product: CCCCCCCCC(=O)O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
An autoclave was charged with 0.1 g of Rh(acac)(CO)2, 20 g of pyridineand 10 g of 1-octene in a mixture of 60 g of propionic acid and 10 g of water as solvent. A pressure of 30 bar was set using CO and the mixture was heated to 100° C. A reaction pressure of 100 bar was then set by injecting CO and was maintained by injection of further amounts (every 15 minutes). After 1 hour, the autoclave was depressurized and the reaction mixture produced was analyzed titrimetrically and by gas chromatography. Nonanoic acid (n/iso 2.6:1) was formed in an STY of 46 g/l/h (Sel.>95%). Nonanal (n/iso) could be detected in traces by gas chromatography. Hydrogenation products such as octane or nonanol were not found.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:14]3[O:15][CH2:16][CH2:17][CH2:18][C:13]3=[N:12][C:4]=1[CH:5]=[N+:6]2[O-].[NH4+:19].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:14]3[O:15][CH2:16][CH2:17][CH2:18][C:13]3=[N:12][C:4]=1[C:5]([NH2:19])=[N:6]2
Reactant: [NH4+]
Reactant: [O-][n+]1cc2nc3n(c2c2ccccc21)OCCC3
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc1n2OCCC1
Reaction time: 2 h

Procedure:
A solution of 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (0.364 g, 1.51 mmol) in 10 mL of dichloromethane was treated with 7 mL of concentrated aqueous NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (0.34 g, 1.78 mmol) was carefully added. Rapid stirring was continued for 2 hours. The reaction mixture was then diluted with more dichloromethane, washed successively with dilute aqueous K2CO3, H2O, and brine, dried over Na2SO4, and concentrated under reduced pressure. The solid was dissolved in hot CH3CN. The resulting crystals were filtered off and dried to give 0.0578 g of 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as a tan solid, dec. 229-234° C. MS (APCI) m/z 241 (M+H)+; Anal. calcd for C13H12N4O: C, 64.99; H, 5.03; N, 23.32. Found: C, 64.81; H, 4.74; N, 23.44.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:1]1(=[N:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: Nc1ccccc1
Product: c1ccc(N=C2CCCCC2)cc1

Procedure:
The dehydrated crude aniline via line 108 can be introduced to and reacted in the reactor 110 to produce a cyclohexanone-reduced product via line 112 that contains less cyclohexanone as compared to the dehydrated crude aniline in line 108. The reactor 110 can be a homogenous reactor where a portion of the cyclohexanone can react within the reactor 110 to produce an imine compound, e.g., cyclohexylidene aniline, as shown in Reaction 2. For example, the cyclohexanone can react with an amine, R—NH2 in the presence of a catalyst, e.g., sulfuric acid, to reduce the cyclohexanone concentration in the dehydrated crude aniline. For example, the concentration of the cyclohexanone in the dehydrated crude aniline can be reduced in an amount from a low of about 10%, and 20%, about 30%, or about 40% to a high of about 50%, about 60%, about 70%, about 80%, or about 90%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[N:9]([CH:10]=1)[CH2:8][CH2:7][S:6]2>C(#N)C.O.[O-2].[O-2].[Mn+4]>[S:6]1[CH2:7][CH2:8][N:9]2[CH:10]=[C:3]([CH:2]=[O:1])[N:4]=[C:5]12
Reactant: OCc1cn2c(n1)SCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: CC#N
Product: O=Cc1cn2c(n1)SCC2
Reaction time: 1.5 h

Procedure:
2,3-Dihydro-6-hydroxymethylimidazo[2,1-b]thiazole (1.47 g, 9.4 mmol) was dissolved in acetonitrile (30 ml) by addition of water (minimum volume). Manganese dioxide (4.41 g, 3 wt. equivalents) was added and the mixture stirred at ambient temperatures for 1.5 h. The mixture was filtered through Keiselguhr, the filter pad washed with water and the combined filtrate and washings evaporated to dryness under reduced pressure. The residue was triturated under diethyl ether, the solid collected by filtration and dried in air (1.33 g, 92%); nmax (CH2Cl2) 1685, 1528, 1272, 1260 and 1152 cm−1; dH (90 MHz; CD3OD) 3.84-4.10 (2H, m), 4.20-4.50 (2H, m), 7.97 (1H, s), 9.52 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[OH:15])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]#[N:26]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:7][C:6]=1[O:15][CH2:24][C:25]#[N:26])[CH3:2]
Reactant: CCOC(=O)c1ccc(S(C)(=O)=O)cc1O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(S(C)(=O)=O)cc1OCC#N
Temperature: 75 °C

Procedure:
A stirring solution of 11 (6.0 g) in DMF (200 mL) was treated with K2CO3 (6 g) and chloroacetonitrile (6 mL) and heated at 75° C. overnight. The mixture was cooled and partitioned between 1:1 EtOAc/hexanes and H2O. The organic layer was washed with 1 M NaOH, washed with brine, dried (MgSO4), filtered, and evaporated. The residue was triturated with Et2O/hexanes. The resulting solid was collected by filtration giving 6.6 g of 2-cyanomethoxy-4-methanesulfonyl-benzoic acid ethyl ester 12.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]([O:12][CH2:13][CH3:14])=[N:9]2)=[CH:4][C:3]=1[N:20]1[CH:24]=[C:23]([CH:25]=[O:26])[N:22]=[CH:21]1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]([O:12][CH2:13][CH3:14])=[N:9]2)=[CH:4][C:3]=1[N:20]1[CH:24]=[C:23]([CH2:25][OH:26])[N:22]=[CH:21]1
Reactant: CCOC(=O)c1cc2cc(-n3cnc(C=O)c3)c(Cl)cc2nc1OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(-n3cnc(CO)c3)c(Cl)cc2nc1OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 38.5 %

Procedure:
To a solution of the compound of Example 34 (1.91 g, 5.11 mmol) in ethanol (30 ml) was added sodium borohydride (96.8 mg, 2.56 mmol), and the mixture was stirred for 6 hours at room temperature. After concentrated the reaction mixture, the residue obtained was washed with water and then dried under reduced pressure, thereby obtaining 740 mg of title compound as light brown powder. Yield 39%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1OCCOCCOCCOCCOCCOC1.[K].Br[CH2:44][C:45]1[C:46]([C:53]2[C:58]([Cl:59])=[CH:57][CH:56]=[CH:55][C:54]=2[Cl:60])=[N:47][O:48][C:49]=1[CH:50]1[CH2:52][CH2:51]1>O1CCCC1.C(O)(C)(C)C>[CH:50]1([C:49]2[O:48][N:47]=[C:46]([C:53]3[C:58]([Cl:59])=[CH:57][CH:56]=[CH:55][C:54]=3[Cl:60])[C:45]=2[CH2:44][O:21][C@H:18]2[CH2:19][CH2:20][C@H:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=4)=[CH:10][CH:11]=3)[CH2:16][CH2:17]2)[CH2:52][CH2:51]1
Reactant: COc1ccc(COc2ccc(C3CCC(O)CC3)cc2)cc1
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COc1ccc(COc2ccc([C@H]3CC[C@H](OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)cc2)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
4-[4-(4-Methoxy-benzyloxy)-phenyl]-cyclohexanol (2.24 mmol, 700.00 mg) and 18-crown-6 (2.69 mmol, 710.70 mg) in tetrahydrofuran (10 mL) is treated with tert-butyl alcohol, potassium derivative (2.69 mmol, 2.69 mL; 1M in THF). The mixture is stirred for 30 minutes and 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (3.36 mmol, 1.17 g) is added. The mixture is stirred at room temperature for 5 minutes and heated to 40° C. for 1.5 h. Silica gel is added and the reaction mixture is concentrated under reduced pressure. The crude mixture is purified by silica gel flash chromatography eluting with a gradient of 10-60% EtOAc in hexanes. A second chromatography is performed on silica gel eluting with 0.5% EtOAc in DCM to yield the title compound (960 mg, 74%). MS m/z 577.9 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:22]1(Br)[CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[CH:22]1([O:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:14][CH:13]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(OC2CCC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41 %

Procedure:
To a stirred solution of 4-[N-(tert-butoxycarbonyl)amino]phenol (3.1 g, 14.81 mmol) in DMF (40 mL) was added cesium carbonate (12.1 g, 37.02 mmol) and cyclobutyl bromide (2.0 g, 14.81 mmol). The reaction mixture was stirred at r.t. for 3 days, and then at 60° C. for 19 h. The reaction mixture was cooled to r.t., filtered and partitioned between water (50 mL) and Et2O (100 mL). The layers were separated, and the aqueous fraction was further extracted with Et2O (3×50 mL). The combined organic fractions were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 5-8% EtOAc/hexanes) gave the title compound (1.6 g, 41%) as a white solid. δH (CDCl3) 7.24 (2H, d, J 8.9 Hz), 6.82-6.72 (2H, m), 6.31 (1H, br. s), 4.67-6.54 (1H, m), 2.52-2.36 (2H, m), 2.25-2.08 (2H, m), 1.94-1.78 (1H, m), 1.77-1.62 (1H, m), 1.53 (9H, s). LCMS (ES+) 208.0 ((M−tBu)+H)+, RT 3.10 minutes (Method 3).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:21]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[CH2:2][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:21]2)=[CH:37][CH:38]=1
Reactant: Cc1oc(-c2cccs2)nc1CCl
Reactant: COC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4cccs4)oc3C)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-(2-thienyl)oxazole (338 mg), methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (500 mg), potassium carbonate (397 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[1-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (715 mg, yield: 88%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH3:11][CH:12]([CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:14]Br.O>C(O)C>[CH3:11][CH:12]([CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:14][O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)CCCC(C)CCBr
Reactant: Oc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CCCC(C)CCOc1cccc(Br)c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 92 %

Procedure:
Under an inert atmosphere, 90 g of 3-bromophenol was dissolved in 600 ml of ethanol. Further, 39 g potassium hydroxide was added to this and the mixture was heated up to 70° C. for dissolution thereof. From a dropping funnel, 126 g of 3,7-dimethylbromooctane was dropped over 15 minutes. After completion of dropping, the mixture was heated to 84° C. and stirred for about 22 hours under heat. After completion of heating, the mixture was left to cool to room temperature. The reaction solution was bisected, 500 ml of water was added to respective portions, then, ethanol was distilled off by an evaporator. The solutions after distilling off of ethanol were combined and trisected, 300 ml of ethyl acetate was added to respective portions to cause liquid separation, and the organic layers were washed with 200 ml of water twice. The organic layers were combined and the solvent was distilled off by an evaporator, then, the residue was dried by heating at 90° C. for 5 hours under vacuum by a rotary pump. About 150 g of 3-(3,7-dimethyloctyloxy)-bromobenzene was obtained as an oily product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[Cl:14][C:15]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:17]2[C:18]([O:20][C:21](=O)[C:16]=12)=[O:19]>>[Cl:14][C:15]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:17]2[C:16]=1[C:21](=[O:20])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:18]2=[O:19]
Reactant: O=C1OC(=O)c2c(Cl)ccc(Cl)c21
Reactant: COC(=O)C(CN)C1(C)OCCO1
Product: COC(=O)C(CN1C(=O)c2c(Cl)ccc(Cl)c2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(4,7-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.23 g, 30%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.40 g, 2.30 mmol) and 3,6-dichlorophthalic anhydride (0.50 g, 2.30 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: C([O:5][P:6]([CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH:16]=1)[F:14])(=[O:12])[O:7]C(C)(C)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:26]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]([CH2:22][O:21][C:17]2[CH:16]=[C:15]([CH:13]([P:6](=[O:5])([OH:7])[OH:12])[F:14])[CH:20]=[CH:19][CH:18]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)c1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=P(O)(O)C(F)c1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6 %

Procedure:
The above fluoromethylphosphonic acid di-tert-butyl ester (1.29 g, 2-7 mmol) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (2.5 ml) was added and the mixture was stirred at room temperature for 16 h. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and water (50 ml) and a solid was formed in the aqueous phase. This was filtered off and dried in vacuo at 50° C. affording 55 mg (6%) of the title compound as a solid,
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]=2)[CH2:7][C:6]([OH:28])=[O:5])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 105.1 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (820 mg, 2.08 mmol) in dichloromethane (10 ml) was cooled to 0° C. and treated with trifluoroacetic acid (5 ml). The mixture was stirred for 2.5 hours being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue azeotroped with toluene (×2). The residue was then dissolved in ethyl acetate, washed sequentially with an aqueous solution of sodium dihydrogen citrate and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as an oil (740 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]#[N:25])[CH:6]=[CH:7][CH:8]=1.[C:26]([O-:29])(=[S:28])[CH3:27].[K+]>CN(C=O)C>[C:26]([S:28][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]#[N:25])[CH:6]=[CH:7][CH:8]=1)(=[O:29])[CH3:27]
Reactant: CC([O-])=S
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(CCl)c3)c2cc1OC
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3cccc(CSC(C)=O)c3)c2cc1OC
Yield: 40.5 %

Procedure:
To a stirred solution of 4-[3-(chloromethyl)phenylamino]-6,7-dimethoxy-3-quinolinecarbonitrile (0.97 g, 2.7 mmol) in 5.4 ml of DMF was added potassium thioacetate (0.93 g, 8.1 mmol) at 25° C. After 30 m the mixture was partitioned with methylene chloride and water. The organic layer was washed with water, dried, and concentrated. The residue was recrystallized from ethyl acetate to give 0.43 g of yellow solid, mp 172-177° C.