Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:13])[C:8](=[O:9])[C:7](=[O:10])[C:6]([CH3:12])([CH3:11])[O:5]1.[N+](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-]>COC(C)(C)C.[Cl-].[Zn+2].[Cl-]>[CH2:20]([O:19][C:17]([CH:16]1[C:7](=[O:10])[C:6]([CH3:11])([CH3:12])[O:5][C:4]([CH2:3][O:2][CH3:1])([CH3:13])[C:8]1=[O:9])=[O:18])[CH3:21]
Reactant: COCC1(C)OC(C)(C)C(=O)C1=O
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: COC(C)(C)C
Product: CCOC(=O)C1C(=O)C(C)(C)OC(C)(COC)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of zinc chloride (11.80 ml, 11.80 mmol, 1M solution in diethyl ether) at 8° C. is carefully added a second solution of 2-methoxymethyl-2,5,5-trimethylfuran-3,4-dione (2.15 g, 11.56 mmol) in tert-butyl methyl ether (8 ml). This mixture is allowed to warm to 15° C. at which stage a solution of ethyl diazoacetate (1.35 g, 11.84 mmol) in tert-butyl methyl ether (6 ml) is added dropwise over 1 hour, maintaining an internal temperature below 21° C. with further stirring at room temperature overnight. The mixture is diluted with tert-butyl methyl ether (15 ml), washed with 1M hydrochloric acid (3×20 ml) and extracted with 1M sodium hydroxide (2×100 ml). To this aqueous phase is added solid sodium chloride, followed by acidification with concentrated hydrochloric acid then the mixture is extracted with dichloromethane. The organic extract is dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated in vacuo to afford 2-methoxymethyl-2,6,6-trimethyl-3,5-dioxo-tetrahydropyran-4-carboxylic acid ethyl ester (2.11 g) as a pink oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:11]#[N:12].[H-].[Na+].[CH2:20](I)[CH3:21]>CN(C)C=O>[CH2:20]([O:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:11]#[N:12])[CH3:21]
Reactant: COc1ccc(C#N)cc1OC1COCC1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC1COCC1Oc1cc(C#N)ccc1OC
Temperature: 40 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
1.0 g (4.2 mmol) of 3-(4-hydroxytetrahydrofuran-3-yloxy)-4-methoxybenzonitrile (A15) in 5 ml of dimethylformamide are added dropwise under a nitrogen atmosphere to a solution of 140 mg (4.6 mmol) of sodium hydride in 5 ml of dimethylformamide and the mixture is heated at 40° C. for 1 h. 600 μl (7.5 mmol) of ethyl iodide, dissolved in 1 ml of dimethylformamide, are then added dropwise at RT. The mixture is stirred at RT for 2 h, concentrated, treated with 25 ml of water and acidified with 2 N hydrochloric acid. After extraction with 3×25 ml of ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. For further purification, the product is chromatographed on silica gel [toluene/ethyl acetate=4:1]. The product-containing fractions are concentrated and the residue is crystallized from isopropanol. 660 mg of the title compound of m.p. 64-66° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:40]([CH3:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH:40]([CH3:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)N(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
To a solution of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile (1200 mg) in N,N-dimethylformamide (20 ml) were added potassium carbonate (1710 mg) and ethyl 2-bromopropionate (1.5 ml). The mixture was stirred at 100° C. for 12 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as an eluant to give the desired compound (882 mg, yield 60%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].[NH2:12][C:13]([NH2:15])=[S:14]>>[NH2:15][C:13]1[S:14][CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:12]=1
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: NC(N)=S
Product: Nc1nc(-c2ccc(Cl)cc2Cl)cs1
Yield: 97.1 %

Procedure:
Using 2′,4′-dichloroacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4](=[S:21])[NH:3]1.[NH2:22][CH2:23][C@H:24]([OH:33])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[OH:33][C@H:24]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][NH:22][CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:7]=[C:6]3[S:5][C:4](=[S:21])[NH:3][C:2]3=[O:1])=[CH:9][CH:10]=2)[CH2:15][CH2:16]1
Reactant: O=C1CCN(c2ccc(C=C3SC(=S)NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-[4-(4-Oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidine-4-one (which was obtained in Example 34) (0.16 g, 0.5 mmol) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) (0.12 g, 0.75 mmol) were mixed in 1,2-dichloroethane (10 mL) and then treated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and acetic acid (0.045 g, 0.75 mmol). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was quenched with 1N sodium hydroxide (NaOH) and then poured into a saturated aqueous sodium bicarbonate (NaHCO3). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried and concentrated. The residue was purified by preparative thin layer chromatography (16% MeOH/CH2CH2) to give the title compound as a pale yellowish solid; mp >220° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.50-1.70 (m, 2H), 1.90-2.10 (m, 2H), 2.60-3.40 (m, 7H), 3.90-4.20 (m, 3H), 6.70-7.15 (m, 6H), 7.30 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H); MS (ES) m/z: 470.0 (MH+); HRMS Calcd. for C24H27N3O3S2 (M+): 469.1494. Found: 469.1488.
Reaction SMILES: [C:1]1([N:7]2[C:12](=S)[C:11]([CH2:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:10][NH:9][C:8]2=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:24]O.Cl>[OH-].[K+].CO.O>[C:1]1([N:7]2[C:12](=[O:24])[C:11]([CH2:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:10][NH:9][C:8]2=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: O=c1[nH]nc(Cc2c(F)cccc2F)c(=S)n1-c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1[nH]nc(Cc2c(F)cccc2F)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
4-Phenyl-6-(2,6-difluorobenzyl)-5-thioxo-2H-(1,2,4)triazin-3-one (1.00 g, 3.02 mmol) was dissolved in a solution of KOH (643 mg) in MeOH (12 mL) and water (6 mL). A solution of H2O2 (1.2 mL, 30% in water) in water (5 mL) was added and the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was acidified with conc. HCl (1.1 mL) and a white solid precipitated. Filtered and washed with water to give a white solid (816 mg, 85.8%): MS (CI) m/z 380.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22](=[O:32])[NH:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:26]1([CH2:25][CH2:24][NH:23][C:22]([C:18]2([O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)[CH:17]=[CH:16][CH:21]=[CH:20][NH:19]2)=[O:32])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(NCCN1CCOCC1)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(OC2(C(=O)NCCN3CCOCC3)C=CC=CN2)cc1
Temperature: 75 °C
Yield: 64.2 %

Procedure:
A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53 g, 4.75 mmol) in DMF (8 mL) was stirred at room temp. for 2 h, then was sequentially treated with 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol) and K2CO3 (0.31 g, 2.26 mmol). The resulting mixture was heated at 75° C. overnight, cooled to room temp., and separated between EtOAc (25 mL) and a saturated NaCl solution (25 mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were washed with a saturated NaCl solution (3×25 mL) and concentrated under reduced pressure. The resulting brown solids were purified by column chromatography (58 g; gradient from 100% EtOAc to 25% MeOH/75% EtOAc) to afford 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC (10% MeOH/90% EtOAc) Rf 0.32.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([S:26][CH3:27])[CH:12]=3)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([S:26]([CH3:27])=[O:38])[CH:12]=3)=[CH:28][CH:29]=1
Reactant: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(SC)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(S(C)=O)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
To 498 mg of ethyl 9-p-chlorobenzyl-6-methylthio-1,2,3,4-tetrahydrocarbazol-1-yl-acetate from Example 23 in 10 cc of methylene chloride was added 300 mg of m-chloro perbenzoic acid. The resulting mixture was stirred for 1.5 hours at room temperature. The reaction mixture was diluted with ether and consecutively washed with a solution of sodium bicarbonate, water and brine. The crude product obtained after evaporation of the organic layer was purified on silica gel by flash chromatography eluting with 20% hexane/ethyl acetate and yielded 420 mg (82%) of the pure title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:13][CH3:14].[S:15]1[C:19]([CH:20]=O)=[CH:18][C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]1=2>>[S:15]1[C:19]([CH2:20][C:2]2[CH:11]=[C:10]([Br:12])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]=2[O:13][CH3:14])=[CH:18][C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]1=2
Reactant: COc1c(Br)cc(Br)c2ccccc12
Reactant: O=Cc1cc2ccccc2s1
Product: COc1c(Cc2cc3ccccc3s2)cc(Br)c2ccccc12

Procedure:
2,4-Dibromo-1-methoxynaphthalene (see J. Clayden, et al. Org. Lett., 5, (2003) 831) and benzo[b]thiophene-2-carboxaldehyde were treated in a manner similar to Reference Example 1 to give the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:33][CH3:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:41]1([CH2:47][C:48]([NH2:50])=[O:49])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:44]3[CH2:45][CH2:46][N:41]([CH2:47][C:48]([NH2:50])=[O:49])[CH2:42][CH2:43]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:33][CH3:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)OC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)OC)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, 4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-methoxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C36H44N5O4Cl2 [(M+H)+] 680.2765, observed 680.2767.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[C:17](Cl)=[O:18])([CH3:13])([CH3:12])[CH3:11]>>[CH2:1]([NH:9][C:17](=[O:18])[C:16]1[CH:20]=[C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:22]([OH:23])=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Product: CCCCCCCCNC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
In the manner of Example 1, n-octylamine was reacted with 3,5-di-t-butyl-4hydroxybenzoyl chloride to produce N-n-octyl-3,5-di-t-butyl-4-hydroxybenzamide; melting point 133°-135°C. When tested by the procedure of Example 2, the sample containing this compound lasted 1000 hours, about 3.3 times as long as the control.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]([Mg]Br)[CH2:12][CH:13]=[CH2:14]>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]([OH:5])[CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: C=CCC[Mg]Br
Reactant: O=Cc1cc(I)ccc1F
Solvent: C1CCOC1
Product: C=CCCC(O)c1cc(I)ccc1F
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A stirred solution of 2-fluoro-5-iodo-benzaldehyde (0.714 g, 2.86 mmol) in dry THF at −78° C. under nitrogen was treated over 10 min with 0.5 M 3-butenyl magnesium bromide in THF (6.85 mL, 3.43 mmol), stirred for 0.5 h, allowed to warm to −30° C. over 1 h, quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The extracts were combined, dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue by flash chromatography (5% to 10% ethyl acetate/petroleum ether) gave 1-(2-fluoro-5-iodo-phenyl)pent-4-en-1-ol as a clear oil, 565 mg (65% yield). A portion of this oil (0.25 g, 0.82 mmol) was dissolved in dry methylene chloride, cooled to 0° C., treated with boron triflouride etherate (0.1 mL, 0.81 mmol), stirred for 15 minutes under a nitrogen atmosphere, warmed to room temperature for 1 h, and quenched with saturated sodium bicarbonate. The reaction mixture was partitioned between methylene chloride and H2O; and the aqueous phase was extracted with methylene chloride. The organic phase and the extracts were combined, washed with brine, dried over MgSO4 and concentrated in vacuo to give 1-fluoro-4-iodo-2-pent-4-en-1-ylbenzene as a clear oil, 0.18 g (76% yield).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:30][CH:31]1[CH2:33][CH2:32]1)[CH2:27][CH2:28][CH3:29])[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=1.Br[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:30][CH:31]1[CH2:33][CH2:32]1)[CH2:27][CH2:28][CH3:29])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCBr
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-ol (300 mg) and ethyl 4-bromobutyrate (85%1) are dissolved in N,N-dimethylformamide (1 ml) and thereto is added potassium carbonate (82 mg) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=97:3% 17:3) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (296 mg). MS (m/z): 721 [M+H]+
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[CH2:15]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=[O:38])=[CH:32][CH:31]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:37](=[O:38])[CH2:36][C:33]2[CH:34]=[CH:35][C:30]([O:29][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:31][CH:32]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Reactant: Nc1cccc(I)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(I)c2)cc1
Reaction time: 8 h

Procedure:
To a solution of 14.29 g of m-iodoaniline and 15.52 g of pyridine in 150 ml of tetrahydrofuran is added at room temperature over 20 minutes a solution of p-tetradecyloxyphenylacetyl chloride in 150 ml of tetrahydrofuran. The mixture is stirred overnight and the solvent removed. The residue is partitioned between dilute hydrochloric acid and warm chloroform. The separated organic layer is washed with dilute hydrochloric acid, dried and evaporated to a residue which is crystallized from carbon tetrachloride:hexane to give 25.0 g of the desired product as a pink solid, m.p. 108°-110° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1([CH2:10]Br)[CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([CH2:10][NH:4][CH2:3][CH2:2][OH:1])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: BrCC1CCCC1
Reactant: NCCO
Product: OCCNCC1CCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2-(3,4-dichlorophenylimino)-3-(cyclopentylmethyl)-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH:47]=[O:48])=[C:7]([Cl:49])[N:6]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>CCO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([CH2:47][OH:48])=[C:7]([Cl:49])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To an EtOH (500 mL) solution of intermediate (11a) (41.0 g, 61.8 mmol) was added solid NaBH4 (2.8 g, 74.1 mmol). The mixture was stirred at room temperature for 1 hour. After cooling to 0° C., the reaction was quenched by dropwise addition of a 50/50 solution of acetic acid/water until no effervescence was observed. EtOAc (500 mL) was added and the organic was washed three times with saturated aqueous NaCl (100 mL). Solvent was removed and purification was achieved by silica gel chromatography (50:50 EtOAc:hexanes) using an isocratic gradient to provide intermediate (11b) as a white solid (37 g). MS m/z: [M+H+] calcd for C41H37ClN6O, 665.28. found 665.3. 1H-NMR (d4-MeOH): 0.79 (m, 3H), 1.20 (m, 2H), 1.46 (m, 2H), 2.45 (m, 2H), 4.30 (s, 2H), 5.19 (s, 2H), 6.83-6.90 (m, 8H), 7.05 (d, 2H), 7.23-7.33 (m, 10H), 7.53 (m, 2H), 7.81 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][CH:27]1[C:39](=[O:40])[C:38]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]=2[CH2:29][CH2:28]1.[H-].[Na+].C1(C)C=CC(S(O[CH2:53][CH:54]2[CH2:58][CH2:57][CH2:56][CH2:55]2)(=O)=O)=CC=1>>[CH:54]1([CH2:53][N:31]2[C:30]3[CH2:29][CH2:28][CH:27]([CH2:26][C:3]4[N:4]=[CH:5][N:6]([C:7]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:2]=4[CH3:1])[C:39](=[O:40])[C:38]=3[C:37]3[C:32]2=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: Cc1c(CC2CCc3[nH]c4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1c(CC2CCc3c(c4ccccc4n3CC3CCCC3)C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 48.9 %

Procedure:
Using the procedures described above for Intermediate 10, 1,2,3,9-tetrahydro-3-[[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]-4H-carbazol-4-one (500 mg) was treated with sodium hydride (73% dispersion in oil; 38 mg) and was then stirred with cyclopentanemethanol (p-toluenesulphonate) (292 mg) for 24 h. Work up and FCC as described above gave the title compound (283 mg), m.p. 177°-179°.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:22]([NH2:25])(=[S:24])[CH3:23].N1C=CC=CC=1>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:25]=[C:22]([CH3:23])[S:24][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: CC(N)=S
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Yield: 31.1 %

Procedure:
To 2-bromo-1-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)ethanone (1.10 g) in ethanol (15.0 mL) were added thioacetamide (0.266 g) and pyridine (0.300 mL). After refluxing for 2 h, the reaction mixture was extracted with EtOAc, 25% NH4OAc and purified by flash chromatography (50% EtOAc in hexane then 90% Et2O in hexane) to yield the title compound (0.320 g).