Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:11]2[CH:12]=[C:13]([C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:20](OCC)(=[O:26])[C:21]([O:23]CC)=[O:22].[O-]CC.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[O:26]=[C:20]([CH2:18][C:17](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH:12]=1)[C:21]([OH:23])=[O:22]
Reactant: CC(=O)c1cccc(C2CCCc3ccccc32)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Product: O=C(O)C(=O)CC(=O)c1cccc(C2CCCc3ccccc32)c1
Reaction time: 1.5 h

Procedure:
Isomer A: Into 1 mL distilled tetrahydrofuran was placed 0.046 g (0.18 mmol) of 1-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]-ethanone (isomer A), 0.054 g (0.37 mmol) diethyl oxalate, and 0.025 g (0.37 mmol) sodium ethoxide. After stirring for 1.5 hr, excess 10% citric acid solution was added and the THF removed in vacuo. The residue was partitioned between water and ethyl acetate and extracted. The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate, filtered, and the solvent removed in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[C:12]([NH:15][CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:14])[CH3:13]>>[C:12]([NH:15][C:16]([CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:14])[CH3:13]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: COC(=O)CCC/C=C\CBr
Product: CCOC(=O)C(CC=CCCCC(=O)OC)(NC(C)=O)C(=O)OCC

Procedure:
cis-Methyl 7-bromohept-5-enoate (prepared by the method of Brit. Pat. No. 1 355 991) and diethyl acetamidomalonate reacted under the conditions described in Example 1A to give diethyl acetamido-(6-methoxycarbonylhex-2-enyl)malonate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:12]1=[O:22].[C:23](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:23])[C:12]1=[O:22]
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-n1ccc2c(Cl)cccc21
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cn1c(C(F)(F)F)cc(=O)n(-n2ccc3c(Cl)cccc32)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
A mixture of 169B (0.88 g, 2.7 mmol), dry acetonitril (10 mL), potassium carbonate (0.41 g, 2.9 mmol) and methyl iodide (0.88 g, 6.2 mmol) is stirred overnight at room temperature. The solids are removed by filtration. The motherliquor is concentrated under reduced pressure. The residue obtained is purified by flash chromatography (ethyl acetate/petrol ether 2/8) to yield the product as a brown oil (0.23 g).
Reaction SMILES: [Br:1]Br.N[C:4]1[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[C:11]([Cl:20])[N:10]=2)[N:7]=[CH:6][C:5]=1[C:21]#[N:22].N(OC(C)(C)C)=O>C(Cl)(Cl)Cl>[Br:1][C:4]1[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[C:11]([Cl:20])[N:10]=2)[N:7]=[CH:6][C:5]=1[C:21]#[N:22]
Reactant: N#Cc1cnn(-c2nc(Cl)c(C(F)(F)F)cc2Cl)c1N
Reactant: BrBr
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cnn(-c2nc(Cl)c(C(F)(F)F)cc2Cl)c1Br
Temperature: 0 °C
Reaction time: 14 h

Procedure:
10.7 g (0.0667 mol) of bromine were added at 25° C. with stirring in the course of 10 minutes to 9.3 g (0.029 mol) of the compound from Example 3 in 200 ml of chloroform; 4.5 g [0.0435 mol] of tert-butyl nitrite were then added in the course of 5 minutes at the same temperature and the mixture was subsequently stirred for 14 hours. The reaction solution was stirred into 1 l of ice water and then extracted with methylene chloride. The organic extract was washed in the customary manner and dried, filtered off with suction through neutral alumina and concentrated under reduced pressure. After triturating in ether/pentane, filtering off with suction and drying, 4.0 9 (35.7% of theory) of the title compound of m.p. 121-122° C. were obtained (Active Compound Example No. 2a.022).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O.O>ClC(Cl)(Cl)Cl.ClC(Cl)Cl>[Br:15][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)NS(C)(=O)=O)cc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)NC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
To a solution of 4-methyl-N-(methylsulfonyl)benzamide (Preparation 55, 550 mg, 2.58 mmol) in tetrachloromethane (10 mL) was added N-bromosuccinimide (459 mg, 2.58 mmol) and diphenylperoxyanhydride (62.5 mg, 0.258 mmol) and the mixture was heated at reflux under nitrogen for 4 hours. The reaction mixture was cooled to room temperature, poured into water (100 mL) and extracted with DCM (50 mL). The organic layer was dried over magnesium sulphate and evaporated in vacuo to yield a cream solid. The solid was re-dissolved in trichloromethane (10 mL), diphenylperoxyanhydride (62 mg, 0.25 mmol) and N-bromosuccinimide (300 mg, 1.69 mmol) were added and the mixture heated at reflux for 6 hours then cooled to room temperature and evaporated in vacuo. The resulting residue was partitioned between DCM (50 mL) and water (50 mL), the aqueous further extracted with DCM (50 mL) and the combined organics dried over magnesium sulphate and concentrated in vacuo to yield a cream solid (625 mg). A portion of this material was purified by silica gel chromatography eluting with 0 to 30% EtOAc in heptane to yield the title compound as a white solid (25 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]5[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](=[O:28])[CH2:12][C:11]3=[O:29])=[CH:9][C:4]=2[N:3]=[CH:2]1.S(Cl)(Cl)=O.[C:34](O)(C(F)(F)F)=O>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:16]=[CH:17][C:18]([CH:21]5[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]5)=[CH:19][CH:20]=4)[C:13]([O:28][CH3:34])=[CH:12][C:11]3=[O:29])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1CCC(c2ccc(C3C(=O)CC(=O)N3c3ccc4[nH]cnc4c3)cc2)CC1
Solvent: O=S(Cl)Cl
Product: COC1=CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(C2CCC(=O)CC2)cc1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-5-(4-(4-oxocyclohexyl)phenyl)pyrrolidine-2,4-dione (1.5 g, 3.87 mmol) and thionyl chloride (1.1 g, 9.1 mmol) according to method 6 described above. The compound was further treated with TFA (5 ml) at room temperature for 1 h. The volatiles were evaporated and the residue was partitioned between sodium bicarbonate solution and MeOH/CHCl3 (5/95). The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[OH:27]>Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:27])[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1nc(NC2CCCCC2)nc2c1nc(Br)n2Cc1ccccc1
Reactant: CO
Agent: Cl
Product: Nc1nc(NC2CCCCC2)nc2c1nc(O)n2Cc1ccccc1
Yield: 23 %

Procedure:
6-Amino-9-benzyl-8-bromo-2-cyclohexylaminopurine (82 mg, 0.20 mmol) in concentrated hydrochloric acid (30 ml) and methanol (20 ml) were refluxed for 5 hours under heating. After removal of methanol, the reaction mixture was made basic with 28% aqueous ammonia. The resulting crystals were filtered, washed with water and dried to give the subject compound (7 mg, yield 23%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:11]([CH:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:15][C:16](O)=[O:17])[C:9](=[O:10])[C:8]2=[CH:30][CH:31]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:45][OH:46]>O1CCCC1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:11]([CH:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:15][C:16]([NH:45][OH:46])=[O:17])[C:9](=[O:10])[C:8]2=[CH:30][CH:31]=1)(=[O:3])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc(NC(C)=O)cc3C2=O)ccc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccc(NC(C)=O)cc3C2=O)ccc1OC
Yield: 43.4 %

Procedure:
3-(4-Acetoamidophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide was prepared by the procedure of Example 1 from 3-(4-acetoamidophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (2.0 g, 4.7 mmol), carbonyldiimidazole (836 mg, 5.16 mmol) and hydroxylamine hydrochloride (391 mg, 5.63 mmol) in tetrahydrofuran (8 mL) to afford 3-(4-acetoamidophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide as a yellow solid (0.9 g, 43% yield): mp, 138.0–140.0° C.; 1H NMR (DMSO-d6) δ 1.31 (t, J=6.9 Hz, 3H, CH3), 2.12 (s, 3H, CH3), 3.09 (d, J=7.9 Hz, 2H, CH2), 3.72 (s, 3H, CH3), 3.98 (q, J=6.9 Hz, 2H, CH2), 5.64 (t, J=7.8 Hz, 1H, NCH), 6.89 (br s, 2H, Ar), 7.01 (br s, 1H, Ar), 7.77–7.86 (m, 2H, Ar), 8.17 (br s, 1H, Ar), 8.80 (br s, 1H, OH), 10.58 (br s, 2H, 2NH); 13C NMR (DMSO-d6) δ 14.69, 24.18, 34.27, 50.15, 55.43, 63.69, 111.68, 112.26, 112.46, 119.63, 123.11, 124.37, 124.79, 131.26, 132.76, 114.87, 147.65, 148.48, 165.98, 167.26, 169.22; Anal Calcd for C22H23N3O7: C, 59.86; H, 5.25; N, 9.52. Found: C, 59.49; H, 5.24; N, 9.40.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[Na].[C:6]([C:8]1[CH:9]=[CH:10][C:11](I)=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])#[N:7]>[Cu]Br>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:4][CH:1]([CH3:3])[CH3:2])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])#[N:7]
Reactant: N#Cc1ccc(I)c(C(=O)O)c1
Reactant: CC(C)O
Agent: [Cu]Br
Agent: [Na]
Product: CC(C)Oc1ccc(C#N)cc1C(=O)O
Temperature: 120 °C
Yield: 55 %

Procedure:
To 198 mmol isopropanol was added 19.8 mmol sodium and the mixture was then heated at 100° C. until all the sodium was dissolved (30 min.). Susbsequently, 6.59 mmol 5-cyano-2-iodobenzoic acid [CAS: 219841-92-6; WO9901455] and 1.32 mmol copper (I) bromide were added and the reaction mixture heated at 120° C. for 2 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was suspended in 50 ml 1 M aq HCl and extracted 3× with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. Flash chromatography on silica gel (eluant: heptane/ethyl acetate) provided the title compound as a white solid (yield 55%). MS (m/e): 204.1 ([M−H]−, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:4]([O:16][CH:17]([F:19])[F:18])[CH:3]=1.C(O)CCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:36][CH2:37][CH:38]([OH:41])[CH2:39]O>C1(C)C=CC=CC=1>[F:18][CH:17]([F:19])[O:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1([CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[O:41][CH:38]([CH2:37][Cl:36])[CH2:39][O:15]1
Reactant: OCC(O)CCl
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1OC(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: FC(F)Oc1cc(Cl)ccc1C1(Cn2cncn2)OCC(CCl)O1
Temperature: 60 °C

Procedure:
14.2 parts of 1-(4-chloro-2-difluoromethoxyphenyl)-2-(1H-1,2,4-triazolyl)ethan-1-one and 100 ml of n-butanol in 450 ml of abs. toluene are heated in the presence of 9.4 parts of p-toluenesulfonic acid for 5 hours under reflux, while removing the water of reaction with a water separator. After cooling to 60° C., 33 parts of 3-chloro-1,2-propanediol and a further 18 parts of p-toluenesulfonic acid are added and the batch is refluxed for 80 hours while removing the water of reaction with a water separator. The reaction mixture is cooled to room temperature, washed twice with saturated aqueous sodium carbonate solution and with 2×200 ml of water, dried over sodium sulfate and filtered. The solvent is removed in a rotary evaporator and the oily residue is chromatographed through a 50 cm column of silica gel with a 1:1 mixture of methylene chloride/diethyl ether as eluant. The solvent mixture is removed by evaporation, affording the title compound in the form of a pale yellow oil with a refractive index nD22 : 1.5336.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[N:14]([CH3:30])[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl:31]([OH:35])(=[O:34])(=[O:33])=[O:32]>O>[Cl:31]([O-:35])(=[O:34])(=[O:33])=[O:32].[CH3:30][N+:14]1[N:13]([CH3:12])[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][C:15]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cn1c(-c2ccccc2)cc(-c2ccccc2)[n+]1C
Solvent: O
Product: [O-][Cl+3]([O-])([O-])[O-]

Procedure:
To a solution of 1,2-dimethyl-3,5-diphenylpyrazolium p-toluene sulfonate (10.0 g.) in 500 ml. of water is added a 20% aqueous solution of perchloric acid with vigorous stirring. The product separates immediately as a white solid. It is collected by filtration, washed with water and dried to give 8.3 g. of the desired product having a melting point of 183° C.-184° C., and the following elemental analysis:
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[N:9][CH:8]=[N:7][CH:6]=1.[CH2:11]([O:18][C:19]([N:21]1[CH:26]([CH3:27])[CH2:25][N:24]([CH2:28][C:29]2[CH:34]=C[C:32](C#N)=[C:31](N)[CH:30]=2)[C:23](=[O:38])[C@@H:22]1[CH3:39])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C>C(O)C>[CH2:11]([O:18][C:19]([N:21]1[CH:26]([CH3:27])[CH2:25][N:24]([CH2:28][C:29]2[CH:34]=[C:6]3[C:32]([C:10]([NH2:5])=[N:9][CH:8]=[N:7]3)=[CH:31][CH:30]=2)[C:23](=[O:38])[C@@H:22]1[CH3:39])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC1CN(Cc2ccc(C#N)c(N)c2)C(=O)[C@H](C)N1C(=O)OCc1ccccc1
Reactant: c1ncncn1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1C(=O)OCc1ccccc1
Yield: 85.1 %

Procedure:
Glacial acetic acid (0.9 ml, 15.54 mmol) and 1,3,5-triazine (840 mg, 10.36 mmol) is added to a solution of (2S,6RS)-4-(3-amino-4-cyano-benzyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (2.03 g, 5.18 mmol) in ethanol. The resulting mixture is heated to reflux overnight. Replaced the ethanol with ethyl acetate and washed with saturated sodium bicarbonate (5 mL). The ethyl acetate layer is dried with magnesium sulfate, filtered and condensed. The resulting residue is purified by flash colunm (SiO2, 20% methanol/methylene chloride) to give the product (2S,6RS)-4-(4-amino-quinazolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (1.85 g, 85%) as a yellow solid. C23H25N5O3 MS m/z: 420.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.N1C(C)=CC=CC=1C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:17](=[O:19])[CH3:18])=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1ncc(Br)cn1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(=O)Nc1ncc(Br)cn1
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 5-bromo-2-aminopyrimidine (2.0 g, 11.5 mmole) in CH2Cl2 (75 mL) at RT was added 2,6-lutidine (2.7 mL, 23.0 mmole) followed by acetyl chloride (0.99 g, 12.6 mmole). After stirring for 8 hours, the reaction solution was concentrated under vacuum. The remaining residue was dissolved EtOAc (200 mL), washed with H2O (100 mL) and brine, and dried over Na2SO4. Flash chromatography on silica gel (95:5 CHCl3/MeOH) and drying under high vacuum gave the title compound (1.74 g, 70%) as a yellow solid: MS (ES) m/e 217 (M+H)+.
Reaction SMILES: [C:1]([O:20]CCCC)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(OCCCC)(=O)CCCCCCCCCCC.C(O)(=O)CCCCCCCCCCC/C=C\CCCCCCCC>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCCCC
Agent: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCC(=O)OCCCC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O

Procedure:
Specific examples of the lubricants used in the present invention include (all trade names): NAA-102, castor oil hardened fatty acid, NAA-42, CATION SA, NIMINE L-201, NONION E-208, ANON BF, ANON LG, butyl stearate, butyl laurate, and erucic acid, all of which are produced by NOF Corp.; oleic acid produced by Kanto Kagaku; FAL-205 and FAL-123 produced by Takemoto Oil & Fat Co., Ltd.; NGELB OL produced by New Japan Chemical Co., Ltd.; TA-3 produced by Shin-Etsu Chemical Co., Ltd.; ARMIDE P produced by Lion-Armer Co., Ltd.; DUOMINE TDO produced by Lion Corp.; BA-41G produced by The Nisshin Oil Mills, Ltd.; PROFUAN 2012 E, NEW POLE PE61, and IONET MS-400 produced by Sanyo Chemical Industries, Ltd.
Reaction SMILES: [OH:1][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[N:4]([C:5](=[O:12])[CH2:6][CH2:7][CH2:8]2)[C@@H:3]1[C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=1.[CH3:22][C:23]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CN=C1.O>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[Si:26]([O:1][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[N:4]([C:5](=[O:12])[CH2:6][CH2:7][CH2:8]2)[C@@H:3]1[C:13]1[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=1)([C:23]([CH3:25])([CH3:24])[CH3:22])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC[C@@H]2CC[C@H](O)[C@@H](c3cc(F)c(F)c(F)c3)N12
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2CCCC(=O)N2[C@@H]1c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A solution of (6R*,7S*,9aR*)-7-hydroxy-6-(3,4,5-trifluorophenyl)octahydroquinolizin-4-one (164 mg), TBSCl (165 mg), imidazole (149 mg), and DMAP (6.7 mg) in DMF (5.0 mL) was stirred at room temperature overnight. To make the starting material disappear, TBSCl (165 mg) was added to the reaction solution, which was then stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 227 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Cl[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:17][CH:18]=1
Reactant: COC(=O)c1cccc(Cc2ccc(O)cc2)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1

Procedure:
A mixture of methyl 3-(4-hydroxybenzyl)benzoate (0.08 mol), 2-chloromethylquinoline (0.10 mol) and potassium carbonate (anhydrous, 0.10 mol) are heated at reflux in a 7:1 mixture of acetone:dimethylformamide (600 ml) until all the benzoate starting material is consumed. The reaction is then filtered, evaporated and the residue diluted with water and extracted with ethyl acetate. The ethyl acetate extracts are dried (magnesium sulfate), evaporated and then applied to a silica gel column. Elution with ethyl acetate:petroleum ethergives methyl 3-(4-(2-quinolinylmethyloxy)benzyl)benzoate.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20]C)[CH:14]=3)[CH:9]=2)[CH:4]=1.B(Br)(Br)Br>>[OH:20][C:15]1[CH:14]=[C:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]3)[CH:18]=[C:17]([CH3:19])[CH:16]=1
Reactant: COc1cc(C)cc(-c2ccc3cc(OC)ccc3c2)c1
Agent: BrB(Br)Br
Product: Cc1cc(O)cc(-c2ccc3cc(O)ccc3c2)c1

Procedure:
The compound is prepared by reaction of 2-methoxy-6-(3-methoxy-5-methylphenyl)naphthalene (26 mg, 0.10 mmol, 1 eq) with boron tribromide solution (1 ml, 1 mmol, 10 eq) according to method G. After the processing, the analytically pure compound was obtained (quantitative yield, 25 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1Cl)=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:15])[CH2:12][CH2:13][CH3:14]>O1CCOCC1>[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1[NH:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([OH:10])=[C:4]([CH3:9])[CH:5]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1cc(N)cc(C)c1O
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1cc(C)c(O)c(C)c1
Yield: 60.8 %

Procedure:
2,6-Dimethyl-4-aminophenol (0.78 g, 5.69 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (1.0 g, 3.79 mmol) in dioxan (35 ml) were refluxed under nitrogen for 2.5 hours. The solvent was evaporated, and the residue treated with saturated sodium bicarbonate solution and chloroform. The resulting solid was filtered, washed with chloroform and water, boiled in methanol and filtered again to give the title compound (0.84 g) m.p. 287°-9° (dec).
Reaction SMILES: [OH:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([O:25][CH:26]5[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]5)[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[NH:28]1[CH2:27][CH:26]([O:25][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH:18][C:13]3[CH:12]=[C:11]([C:8]4[S:7][C:6]([C:2]5([OH:1])[CH2:5][CH2:4][CH2:3]5)=[N:10][CH:9]=4)[CH:16]=[C:15]([CH3:17])[CH:14]=3)[N:24]=2)[CH2:29]1
Reactant: Cc1cc(Nc2nccc(OC3CN(C(=O)OC(C)(C)C)C3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(OC3CNC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of the product from Step 2 (200 mg, 0.39 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.49 mL). The mixture was stirred for 1 h at room temperature and then concentrated under reduced pressure. The resulting residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-[5-(3-{[4-(azetidin-3-yloxy)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]cyclobutanol (158 mg, 0.39 mmol, 98%) as a pale-yellow foam. MS ESI: [M+H]+ m/z 409.8. 1H NMR (500 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.23 (d, J=5.6, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 7.52 (s, 1H), 7.09 (s, 1H), 6.64-6.52 (m, 1H), 6.29 (d, J=5.6, 1H), 5.55-5.36 (m, 1H), 3.76 (dd, J=6.7, 9.7, 2H), 3.58-3.45 (m, 2H), 2.56-2.49 (m, 3H), 2.37-2.20 (m, 5H), 1.87 (dt, J=7.0, 10.0, 2H). rhSYK activity=+++