Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:14]([C:17]1[CH:37]=[CH:36][C:20]([CH2:21][O:22][C:23]([N:25]2[CH2:30][CH2:29][N:28]([N:31]=O)[CH:27]([C:33]([OH:35])=[O:34])[CH2:26]2)=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>C1COCC1>[N+:14]([C:17]1[CH:37]=[CH:36][C:20]([CH2:21][O:22][C:23]([N:25]2[CH2:30][CH2:29][N+:28]3[C-:27]([C:33](=[O:35])[O:34][N:31]=3)[CH2:26]2)=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=NN1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[n+]2noc(=O)[c-]2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
The THF (10 mL) solution of trifluoroacetic anhydride (24.0 g) was added to the THF (371 mL) solution of crude 4-nitrosopiperazine-1,3-dicarboxylic acid 1-(4-nitrobenzyl) ester under a nitrogen atmosphere at 0° C. for 15 min. The solution was stirred for 1.5 h at 0° C. and for 1 h at room temperature. The THF (5 mL) solution of trifluoroacetic anhydride (8.0 g) was added to the solution for 5 min and stirred for 20 h at room temperature. To the solution was added trifluoroacetic anhydride (8.0 g) for 5 min and the solution was stirred for 4 h. The precipitate was filtered and washed with THF and Et2O. The filtrate was concentrated under reduced pressure. The residue was triturated with THF, filtered and washed with Et2O. These materials were combined and dried under reduced pressure to afford the titled compound as colorless crystals (22.3 g, 91%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:27])[N:22]=[C:21]4C3C(C)=NC=CC=3)[S:17][C:13]=2[C:12]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH3:47][CH2:48]O>C1COCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:27])[N:22]=[C:21]4[C:48]3[CH:47]=[CH:16][N:15]=[CH:14][CH:13]=3)[S:17][C:13]=2[C:12]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(-c3cccnc3C)nn4C)sc2c1-c1ccc(Cl)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccc4c(c3)c(-c3ccncc3)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
In a vial was dissolved (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(2-methylpyridin-3-yl)-1H-indazol-5-yl)benzo[d]thiazol-6-yl)acetate (100 mg, 0.16 mmol) in THF (3 mL) and EtOH (1.5 mL). 1M NaOH (1.5 mL) was added, and the mixture was heated to 50° C. overnight. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting with 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C33H30ClN4O3S: 597.2 (M+H+); Found: 597.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.77 (d, J=6.1 Hz, 2H), 8.73 (s, 1H), 8.47 (d, J=6.3 Hz, 2H), 8.06 (d, J=8.9 Hz, 1H), 7.78-7.70 (m, 3H), 7.60 (dt, J=11.1, 7.5 Hz, 3H), 5.26 (s, 1H), 4.18 (s, 3H), 2.61 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[Cl:12].[SH-:13].[Na+].[OH-].[Na+].Cl>O.CN(C)C=O>[Cl:1][C:2]1[C:7]([SH:13])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[Cl:12]
Reactant: Clc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: [SH-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Sc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
Hexachlorobenzene (25.0 g, 0.088 mol) was added to 50 mL of dimethylformamide followed by the addition of 7.4 g (0.096 mol) of 73% sodium hydrosulfide and 7.9 mL (0.079 mol) of 40% aqueous sodium hydroxide. The stirred reaction mixture was heated to 85° C. for 3.0 hr, cooled to room temperature, and poured into 200 mL of water. After 10 min of stirring, the insoluble material was removed by filtration, and the filtrate acidified with 15 mL (0.18 mol) of concentrated aqueous hydrochloric acid. The resulting precipitate was collected by filtration, washed with 100 mL of water, and dried in vacuo giving 22.8 g, 92% of theoretical, of pentachlorothiophenol.
Reaction SMILES: Cl.[CH2:2]([NH:5][CH2:6][CH:7]=[CH2:8])[CH:3]=[CH2:4].[C:9](OC(=O)C)(=[O:11])[CH3:10].O>N1C=CC=CC=1>[C:9]([N:5]([CH2:6][CH:7]=[CH2:8])[CH2:2][CH:3]=[CH2:4])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCNCC=C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C=CCN(CC=C)C(C)=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 90.2 %

Procedure:
In 10 ml of pyridine was dissolved 0.5 g of diallylamine hydrochloride, and 1.0 g of acetic anhydride was added to the solution. The mixture was stirred at room temperature for 10 hours. Water was added to the mixture and the mixture was extracted with chloroform. The chloroform layer was washed with 0.01 N aqueous HCl solution, 1% aqueous sodium bicarbonate solution and finally with water, and concentrated to obtain 0.47 g of N-acetyldiallylamine [IR: 1640 cm-1, 1H-NMR δH 2.08 (3H), 3.94(4H), 5.16(4H), 5.76(2H)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[S:18]([CH3:17])(=[O:20])=[O:19]
Reactant: Clc1ccc(NCc2cccnc2)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccc(Cl)cc1Cl

Procedure:
A 2.7 g. portion of 3-(2,4-dichlorophenylaminomethyl)pyridine was dissolved in dichloromethane and reacted with 0.9 ml. of methanesulfonyl chloride in the presence of 1.4 g. of potassium carbonate at ambient temperature for several days. The reaction mixture was worked up as described in Example 4 to obtain 3.2 g. of oil, which was triturated with petroleum ether and then diethyl ether and filtered to obtain 2.8 g. of solid. The solid was triturated with chloroform, filtered and dried to obtain 0.9 g. of the desired product, m.p. 180°-186°. Its elemental analysis was as follows.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[H-].[Na+].Cl[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:10]=2)[O:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (770 mg) in DMF (10 mL) was added sodium hydride (60%, 114 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr. To the reaction mixture was added dropwise (2-(chloromethoxy)ethyl)(trimethyl)silane (990 mg) at room temperature, and the mixture was stirred for 15 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 5% aqueous lithium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.90 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:25]=[C:24]([C:26]2[O:30][N:29]=[C:28]([CH3:31])[N:27]=2)[CH:23]=[CH:22][C:21]=1[C:32]1[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][N:15]([C:38]([C:35]5[CH:34]=[CH:33][C:32]([C:21]6[CH:22]=[CH:23][C:24]([C:26]7[O:30][N:29]=[C:28]([CH3:31])[N:27]=7)=[CH:25][C:20]=6[CH3:19])=[CH:37][CH:36]=5)=[O:39])[C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:6][CH2:7]1
Reactant: Cc1noc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)n1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: Cc1noc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)n1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8) and 2'-methyl-4'-(3-methyl-1,2,4-oxadiazol-5-yl)biphenyl-4-carboxylic acid (D29) using a similar procedure to Example 1. This was converted to its oxalate salt, which was obtained as a yellow solid (3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[NH:23][C:22]([CH:24]=O)=[C:21]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])[CH:20]=1>C(O)C.N1CCCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:24][C:22]2[NH:23][C:19]([CH3:18])=[CH:20][C:21]=2[C:26]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)=[O:27])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)N2CCN(C)CC2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CCN(C)CC2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.7 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-methyl-3-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-fluoro-phenyl)-3-[5-methyl-3-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (44.1 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([NH2:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:20](OC)=O.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28]>CCOCC>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28].[CH3:20][NH:19][CH:12]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][CH2:11]1)[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: COCCCCC(N)C1(c2ccc(Cl)cc2)CCC1
Reactant: COC=O
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOCC
Product: CNC(CCCCOC)C1(c2ccc(Cl)cc2)CCC1
Temperature: 50 °C
Reaction time: 168 h

Procedure:
A mixture of 1-[1-(4-chlorophenyl)cyclobutyl]-5-methoxypentylamine [1.7 g prepared in a similar manner to that described in method D hereinbefore (X=Cl, R=3, S=1, T=0.67)] and methyl formate (20 ml) was allowed to stand at ambient temperature for 7 days. The mixture was then filtered to remove a colourless solid which was discarded. The filtrate was evaporated and the residue was dissolved in dry toluene (29 ml). The solution was added dropwise to a 70% solution of bis-(2-methoxyethoxy)aluminium hydride in toluene sold under the trade name Red-Al (4.3 ml) in dry toluene (11 ml) under nitrogen and then the reaction mixture was heated at 50° C. with stirring for 3 hours. The reaction mixture was cooled, and water (20 ml) and 5N sodium hydroxide (15 ml) were added. The aqueous layer was separated and extracted with ether and the extracts combined with the toluene solution, washed with water, dried, filtered and evaporated to give an oil which was dissolved in ether. A solution of maleic acid (0.33 g) in ether was added to give a solid which was recrystallised from propan-2-ol to give N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-5-methoxypentylamine maleate (m.p. 94°-95° C.).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C:16]1[S:17][C:18]2[CH2:19][NH:20][CH2:21][CH2:22][C:23]=2[N:24]=1)=[O:15]>CN(C=O)C>[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C:16]1[S:17][C:18]2[CH2:19][N:20]([C:2]([O:4][CH3:5])=[O:3])[CH2:21][CH2:22][C:23]=2[N:24]=1)=[O:15]
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Reactant: COC(=O)Cl
Solvent: CN(C)C=O
Product: COC(=O)N1CCc2nc(C(=O)Nc3ccccc3N)sc2C1
Reaction time: 3 h

Procedure:
Methyl chloroformate (1.0 mmol) was added drop wise to N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained from step VIII of example 1 (1.0 mmol) solution in 10 mL of dry DMF at 0° C. Reaction mixture was stirred for additional 3 h Reaction mixture was concentrated, diluted with water, extracted with dichloromethane, washed with brine solution, and dried over anhydrous Na2SO4. Concentrated and purified by column chromatography to get the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2([C:18]#[N:19])[CH2:17][CH2:16]2)=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][CH:9]2[C:11]([F:14])([F:13])[F:12])[CH:7]=1>CO.N.[Ni]>[Cl:1][C:2]1[C:3]([C:15]2([CH2:18][NH2:19])[CH2:17][CH2:16]2)=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][CH:9]2[C:11]([F:14])([F:12])[F:13])[CH:7]=1
Reactant: N#CC1(c2ncc(C3CC3C(F)(F)F)cc2Cl)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCC1(c2ncc(C3CC3C(F)(F)F)cc2Cl)CC1
Yield: 88.2 %

Procedure:
509 mg of 1-[3-chloro-5-[2-(trifluoromethyl)cyclopropyl]-2-pyridyl]cyclopropanecarbonitrile (step 2) was dissolved in 35 ml of methanol containing 2 ml of ammonia (7N in methanol). The solution was hydrogenated over Raney-nickel (flow: 1 mL/min, 50° C., 40 bar). Then the solvent was removed at reduced pressure to give 455 mg of [1-[3-chloro-5-[2-(trifluoromethyl)cyclopropyl]-2-pyridyl]cyclopropyl]methanamine as an orange oil. 1H-NMR (CDCl3): 8.30 ppm (s, 1H), 7.87 ppm (s, 1H), 2.94 ppm (s, 2H), 2.33 ppm (m, 1H), 1.85 ppm (m, 1H), 1.78 ppm (s, 2H, broad), 1.46 ppm (m, 1H), 1.22 ppm (m, 1H), 1.00 ppm (m, 2H), 0.90 ppm (m, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[NH:11][C:10]([C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=3)=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)[NH2:27].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[ClH:2].[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:3]2[C:4]3[NH:11][C:10]([C:12]4[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:21][CH:22]=4)=[CH:9][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CCOC(=O)c1ccc(-c2cc3ncnc(Cl)c3[nH]2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(-c2cc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3[nH]2)cc1
Temperature: 140 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
A mixture of ethyl 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate hydrochloride (517 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (462 mg) and 1-methyl-2-pyrrolidinone (8 mL) was stirred at 140° C. for 5 hrs, poured into water (40 mL), and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The precipitated solid was collected by filtration, washed with water and suspended in methanol (15 mL). After stirring at room temperature for 30 min, the solid was collected by filtration and dried under reduced pressure at 60° C. The obtained solid was suspended in ethanol (10 mL) and 1N aqueous sodium hydroxide solution (1.5 mL) was added. After stirring at room temperature for 6.5 hrs, and at 60° C. for 3.5 hrs, the mixture was cooled to room temperature. 1N Hydrochloric acid (155 mL) was added, and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure at 60° C. to give the title compound (498 mg).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2>C1COCC1>[CH:40]1[C:41]2[N:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:5]3([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]4[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=5[C:36]5[C:41]4=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:4]4[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]=4[C:11]4[C:6]3=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=4)[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]=2[CH:37]=[CH:38][CH:39]=1
Reactant: BrCCCCCCCCCCn1c2ccccc2c2ccccc21
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)C(CCCCCCCCCCn1c3ccccc3c3ccccc31)(CCCCCCCCCCn1c3ccccc3c3ccccc31)c1cc(Br)ccc1-2
Yield: 34.1 %

Procedure:
To a mixture of 5.2 g (16 mmol) 2,7-dibromofluorene in 300 mL THF was added 1.3 g (41 mmol) sodium hydride (75%) in several portions. A mixture of 15 g (39 mol) N-(10-bromodecyl)-carbazole (8) in 100 mL THF was added dropwisely at 70° C. and the mixture was refluxed for 48 h. After cooling, the solid was filtered and the filtrate was concentrated and dilute with water and extracted with CH2Cl2. The organic layer was collected and washed with brine and dried with anhydrous MgSO4. The crude product was further purified by silica column chromography to give 5.1 g (yield 34%, mp 94˜96° C.) title product. 1H NMR (CDCl3), δ (ppm): 8.10 (4H, d), 7.38˜7.48 (14 H, m), 7.23 (4H, t), 4.27 (4H, t), 0.88˜1.86 (36H, m). Anal. Calcd: C, 73.22; H, 6.68; N, 3.00. Found: C, 72.58; H, 6.59; N, 2.73.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3](=[O:10])[C@H:4]([C@@H:6]([CH3:9])[O:7][CH3:8])[NH2:5].S=[C:13]1[CH2:17][S:16][C:15](=[O:18])[NH:14]1>C(O)C>[CH3:11][N:2]([CH3:1])[C:3](=[O:10])[C@H:4]([C@@H:6]([CH3:9])[O:7][CH3:8])[NH:5][C:13]1[CH2:17][S:16][C:15](=[O:18])[N:14]=1
Reactant: O=C1NC(=S)CS1
Reactant: CO[C@H](C)[C@H](N)C(=O)N(C)C
Solvent: CCO
Product: CO[C@H](C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a solution of N,N,O-trimethyl-L-threoninamide (1198 mg) in ethanol (10 mL) was added 4-thioxothiazolidin-2-one (996 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (680 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(Cl)cc2)cc1
Yield: 68.2 %

Procedure:
A mixture of 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole from Example 1 (6.2 g, 15.4 mmol) and p-toluenesulfonic acid monohydrate (0.9 g, 4.7 mmol) in toluene (300 mL) was heated to reflux for 84 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentrating in vacuo, the crude mixture was purified by chromatography on silica gel using hexane/ethyl acetate (1/1) to give pure 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole (4.21 g, 71%) as a white solid: mp (DSC) 183° C. Anal. Calc'd. for C17H12N2SO2F3Cl: C, 50.94; H, 3.02; N, 6.99. Found: C, 50.64; H, 3.03; N, 6.85.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:19][CH2:20][CH3:21])[C@H:14]([OH:18])[C:15](O)=[O:16])=[O:11])([CH3:8])([CH3:7])[CH3:6].C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>C(OCC)(=O)C>[CH:1]1([NH:4][C:15](=[O:16])[C@@H:14]([OH:18])[C@@H:13]([NH:12][C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[CH2:19][CH2:20][CH3:21])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Product: CCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1

Procedure:
Cyclopropylamine (55 mg, 0.97 mmol) was dropwise added to an ethyl acetate (5 mL) solution of (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxyhexanoic acid (200 mg, 0.81 mmol), and the mixture was cooled by ice. HOBt monohydrate (130 mg, 0.85 mmol) and EDC hydrochloride (171 mg, 0.89 mmol) were added thereto, and the mixture was stirred with cooling by ice. As a result, the solid in the mixture aggregated to form a hard lump after about 5 minutes, and the mixture became impossible to be stirred.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:12][N:11]=2)=[CH:6][CH:5]=1)[CH3:3].[H-].[Na+].[C:29]1(C)[CH:34]=[CH:33][C:32](S(OCCCCCC)(=O)=O)=[CH:31][CH:30]=1>O>[CH2:33]([O:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:12][N:11]=2)=[CH:8][CH:9]=1)[CH3:3])[CH2:34][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(C)O)cc2)nc1
Reactant: CCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCOc1cnc(-c2ccc(C(C)OCCCCCC)cc2)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Into 20 ml of anhydrous dlmethylformamide were dissolved 1.78 g (5 millimole) of the (+)-2-{4-(1-hydroxyethyl)phenyl}-5-decyloxypyrimidine obtained in Preparation Example [starting material compound (VI)] 70, and then 0.24 g (6 millimole) of 60% sodium hydride was added thereto, followed by stirring at 40° C. for 1 hour. Subsequently, 1.79 g (7 millimole) of hexyl p-toluenesulfonate were added thereto, to subject to reaction at the same temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into 200 ml of water, extracted with 200 ml of toluene, followed by separation thereof, and the organic phase was washed with water sufficiently, followed by drying over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent; toluene: ethyl acetate) to obtain 1.81 g (yield: 82%) of (+)-2-{4-(1-hexyloxyethyl)phenyl}-5-decyloxypyrimidine.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([O:12][C:13]2[NH:14][C:15]([NH2:24])=[C:16]3[C:20]([N:21]=2)=[N:19][C:18]([O:22][CH3:23])=[N:17]3)[CH2:11][CH2:10][CH2:9]1.Br[CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]>>[Cl:30][CH2:29][CH2:28][CH2:27][CH2:26][N:19]1[C:18]([O:22][CH3:23])=[N:17][C:16]2[C:20]1=[N:21][C:13]([O:12][CH:8]1[CH2:9][CH2:10][CH2:11]1)=[N:14][C:15]=2[NH2:24]
Reactant: COc1nc2nc(OC3CCC3)[nH]c(N)c-2n1
Reactant: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OC3CCC3)nc2n1CCCCCl

Procedure:
Prepared similarly to Intermediate 44 from 2-(cyclobutyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.