Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH2:9][Cl:10])=[O:6].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.O>CN(C=O)C>[Si:14]([O:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH2:9][Cl:10])=[O:6])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCCCl)c1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCCl)c1

Procedure:
A solution of 10 g (50 mmol) the ester from step (a), t-butyldimethylsilyl chloride (8.25 g, 55 mmol) and imidazole (4.76 g, 70 mmol) in 100 mL of DMF was stirred under argon for 1 h. The solution was poured into 100 mL of water and extracted with ether (3×50 mL). The combined ether solutions were extracted with 20 mL of water. The organic layer was dried and evaporated giving 18 g of an oil which was purified by column chromatography using 0-2% ethyl acetate in hexane yielding 14.4 g of the product as a colorless oil (91%); 1H NMR (CDCl3) δ0.218 (s,6H), 0.995 (s,9H), 3.81 (t,2H), 4.56 (t,2H), 7.05-7.65 (m,4H). ##STR13##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(Cl)[Cl:11].S(Cl)(Cl)=O>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([Cl:11])=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1cnccn1
Temperature: 30 °C

Procedure:
A mixture of 68.2 g (0.55 moles) 2-pyrazine carboxylic acid and methylene chloride (about 200 ml) containing a catalytic amount of pyridine was warmed (to about 30° C.). To that mixture, 78.5 g (0.66 mole) thionyl chloride was added dropwise. The reaction mixture was refluxed for 24 hours. The methylene chloride was removed under reduced pressure and heat to give the 2-pyrazine carboxylic acid chloride which was used in step (b) without further isolation.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:49]=[C:50]([CH:53]=[C:54]([CH3:56])[CH:55]=1)[CH2:51][NH2:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:52][CH2:51][C:50]4[CH:53]=[C:54]([CH3:56])[CH:55]=[C:48]([F:47])[CH:49]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Cc1cc(F)cc(CN)c1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2cc(C)cc(F)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3-fluoro-5-methylbenzylamine (Jrd-Fluoro) to give the title product. LC-MS (ES+) 786 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]1)=[O:23])[NH:6]2.[Cl:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]1)=[O:23])[N:6]2[C:37]1[CH:36]=[CH:35][N:34]=[C:33]([Cl:32])[CH:38]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2Cl)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(cc(C(=O)N4CCC(F)(F)CC4)n3-c3ccnc(Cl)c3)c2Cl)CC1
Yield: 34 %

Procedure:
The title compound was synthesized in analogy to example 66, from [4-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 228), 2-chloropyridine-4-boronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless foam (34%).
Reaction SMILES: [C:1]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][CH2:9][CH:10]2[CH2:37][CH2:36][C:13]3[N:14](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:15]=[N:16][C:12]=3[CH2:11]2)=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC(COCC2CCC3N=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3C2)=CC=1>C(O)(=O)C.O>[C:1]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][CH2:9][CH:10]2[CH2:37][CH2:36][C:13]3[NH:14][CH:15]=[N:16][C:12]=3[CH2:11]2)=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc(COCC3CCc4c(ncn4C(c4ccccc4)(c4ccccc4)c4ccccc4)C3)cc2)cc1
Agent: c1ccc(-c2ccc(COCC3CCc4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c4C3)cc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(-c2ccc(COCC3CCc4[nH]cnc4C3)cc2)cc1
Temperature: 90 °C

Procedure:
A solution of a mixture of 5-((biphenyl-4-yl)methoxymethyl)-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-((biphenyl-4-yl)methoxymethyl)-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole (440 mg, 0.78 mmol) in a mixture of acetic acid (5 ml) and water (0.6 ml) was heated to 90° C. for 2.25 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 220 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][C:7](=[O:13])[C:6]=2[CH:14]=1.[BH4-].[Na+].O>C(O)C>[Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH:7]([OH:13])[C:6]=2[CH:14]=1
Reactant: Cc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1Br)C(O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A stirred solution of the product of step c (26.9 g) in C2H5OH (200 ml) at 5° C. is treated with sodium borohydride (1.95 g) and stirred at room temperature for 12 h. The solvent is evaporated off under reduced pressure to give a residue which is treated with H2O (500 ml) and extracted with diethyl ether (3×200 ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product. This is purified by chromatography (silica gel, 10% acetone in hexane) and recrystallized from diethyl ether-pentane to give the title compound, m.p. 92°-93° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]CC.S(=O)(=O)(O)O>>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CCOC(=O)C(C)O
Reactant: CCCCCCCCO
Agent: O=S(=O)(O)O
Product: CCCCCCCCOC(=O)C(C)O
Yield: 43.8 %

Procedure:
A 500 mL one neck round bottom flask equipped with a distillation apparatus and nitrogen inlet/outlet was charged with 100.0 g (0.847 moles) of ethyl lactate, 220.49 g (1.69 moles) of octyl alcohol and 0.423 g of sulfuric acid (based on 0.5 g sulfuric acid/one mole ethyl lactate). The reaction was refluxed for 8 hours and ethanol was collected as formed. The acid was neutralized by washing three times with 100 mL saturated sodium bicarbonate solution. Approximately 50 mL ether was needed to break the emulsion. The organic layer was collected and dried over magnesium sulfate. Excess octyl alcohol was removed by high vacuum distillation, and three fractional distillations led to 75.0 g (44% yield) of clear colorless oil. According to GC, the product is 95% pure.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:16])CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][F:16])[N:7]=1
Reactant: OCc1cccc(Br)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FCc1cccc(Br)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A solution of (6-bromopyridin-2-yl)methanol (5 g, 27 mmol) in dry DCM (60 mL) was added dropwise at −78° C. to a cooled solution of DAST (13 g, 80 mmol) in dry DCM (50 mL). The reaction mixture was stirred 1 h at −78° C. then 1 h at room temperature. To complete the reaction, an additional 5 mL of DAST were slowly added at −60° C. and the reaction mixture was kept overnight at room temperature. The reaction was quenched with water and the organic layer extracted with DCM, dried over MgSO4 and evaporated. Purification over silicagel chromatography (prepacked 85 g silicagel column, Cyclohexane/AcOEt:90/10 as eluent) to afford 4.50 g of 2-bromo-6-(fluoromethyl)pyridine (Yield: 89%) as pale yellow oil which crystallized at 0° C.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][C:18]([O:20]C)=[O:19])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.[H][H].C(O)(=O)C>CO.[OH-].[Na+]>[C:18]([CH2:17][CH:6]([CH2:5][SH:4])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])([OH:20])=[O:19]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 4 h

Procedure:
To a solution of the product from Example 81 (3.0 g.) in methanol (60 ml.), 1N sodium hydroxide (60 ml.) is added. After 4 hours, the solution is applied to a column of Dowex 50 ion exchange resin in the hydrogen cycle, and the desired material is eluted with water to yield 2.3 g. of the named product Rf 0.2 (silica gel-benzene:acetic acid, 75:25).
Reaction SMILES: [Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:12])[CH:3]=1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2[CH2:19][CH2:20][CH2:21][CH2:22][C:14]1=2.O>C(O)(=O)C>[Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([N:6]2[C:16](=[O:17])[C:15]3[CH2:19][CH2:20][CH2:21][CH2:22][C:14]=3[C:13]2=[O:18])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Yield: 61.8 %

Procedure:
4-Chloro-2-fluoro-5-nitroaniline (19 g) and 3,4,5,6-tetrahydrophthalic anhydride (15.2 g) are dissolved in acetic acid (50 ml) and refluxed for 6 hours. After being allowed to cool, the resultant mixture is poured into water and extracted with toluene. The toluene layer is washed with water, an aqueous sodium hydrogen carbonate solution and water in order, dried and concentrated. The residue is crystallized from ethanol to give 20 g of N-(4-chloro-2-fluoro-5-nitrophenyl)-3,4,5,6-tetrahydrophthalimide. M.P., 157°-157.5° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][SH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:16][CH2:17][C:18]([OH:20])=[O:19].Cl>CN(C=O)C.O>[C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][S:12][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCCOCCc1ccccc1
Reactant: O=C(O)CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCSCCOCCc1ccccc1
Yield: 72.3 %

Procedure:
A solution of 2-[2-phenylethoxy]ethane thiol (2.13 g) in dry DMF (10 ml) was added dropwise to a cooled (0°) stirred suspension of sodium hydride (0.60 g, 80% in oil) in DMF (50 ml). The mixture was stirred at 0° for 90 min. A solution of 3-bromopropanoic acid (3.15 g) in dry DMF (10 ml) was then added dropwise and the reaction was stirred at room temperature for 16 hours. Water (250 ml) was added and the whole was acidified to pH 2/3 with concentrated hydrochloric acid. The aqueous solution was extracted several times with ether and the combined ethereal layers were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. This yielded the crude acid which was purified by flash chromatography over silica using 6:1 dichloromethane:ether (1 drop acetic acid/100 ml of eluant) to give the subtitled compound (2.15 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12](O)=[O:13])[CH:7]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].B.O1CCCC1.O>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][OH:13])[C@@H:7]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(CC(=O)O)CCN1C(=O)OCC
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H]1[C@@H](CCO)CCN1C(=O)OCC
Reaction time: 2 h

Procedure:
A solution of 10 g of 1-ethoxycarbonyl-2-ethoxycarbonyl-pyrrolidine-3-acetic acid in 50 ml tetrahydrofuran is cooled to 0° and 55 ml of borane/tetrahydrofuran (1 M) is added dropwise. After stirring 2 hours at 0°, 20 ml of water is added, the mixture is extracted with ethyl acetate, washed twice with water and dried over sodium sulfate. The solution is filtered, concentrated and purified by flash chromatography using ethyl acetate/hexane (1:1 to 7:3) to yield cis 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[CH:43]=[CH:42][N:41]=[CH:40]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[CH:43]=[CH:42][N:41]=[CH:40]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCCn3ccnc3)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(C)ccc(OCCCn3ccnc3)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-7-[3-(imidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C:16](=O)[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C/C(=[N:56]\[OH:57])/C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1>>[CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15](/[C:16](=[N:56]/[OH:57])/[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1
Reactant: C[C@]12CCCCC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCCCC1CC(=O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCCCC1C/C(=N\O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Yield: 95 %

Procedure:
17,17-Bis(ethylendioxy)-7(E)-hydroxyiminoandrostane was prepared in 95% yield from 3,3:17,17-bis(ethylendioxy)androstane-7-one by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6(E)-hydroxyiminoandrostane (Prepn. 20). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography (SiO2, CH2Cl2/MeOH 9/1). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 10.17 (s, 1H), 3.88-3.70 (m, 8H), 2.89 (m, 1H), 2.23-0.71 (m, 19H), 0.90 (s, 3H), 0.77 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:16].C(OOC(=O)C1C=CC=CC=1)(=[O:24])C1C=CC=CC=1.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[OH:24][CH:5]1[C:4]2[C:9](=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[C:8](=[O:16])[CH2:7][CH2:6]1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: COc1ccc([N+](=O)[O-])c2c1CCCC2=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc([N+](=O)[O-])c2c1C(O)CCC2=O
Temperature: 25 °C

Procedure:
2.0 gm of 5-methoxy-8-nitro-1-tetralone (described in Japanese Patent Laid-open (ko-kai) 279891/1989 and also in U.S. Pat. No. 4,939,255) and 2.05 gm of N-bromosuccinic imide were dissolved in 50 ml of carbon tetrachloride. After the addition of a catalytic amount of benzoyl peroxide, the mixture was heated under reflux for 4 hours and then cooled to room temperature, followed by the addition of 50 ml of chloroform. The mixture was washed with 10% aqueous solution of sodium hydroxide, water, and saturated brine in this order, and dried over anhydrous sodium sulfate. To the residue obtained by removing the solvent were added 5 ml of tetrahydrofuran, 5 ml of ethanol, 8 ml of water, and 250 mg of calcium carbonate, and the mixture was heated under reflux. A residue was obtained by removing the solvent from the reaction mixture, which, after the addition of 50 ml of water, was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography using chloroform-ethyl acetate (4:1) as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 1.49 gm of light yellow powder of the title compound.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:20]=[CH:19][C:12]3[NH:13][C:14]([CH2:16][CH2:17][CH3:18])=[N:15][C:11]=3[CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:27]Br>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:27][N:13]1[C:12]2[CH:19]=[CH:20][C:9]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])=[CH:10][C:11]=2[N:15]=[C:14]1[CH2:16][CH2:17][CH3:18]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CCCc1nc2cc(C(=O)c3ccccc3)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2cc(C(=O)c3ccccc3)ccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of phenyl-(2-propyl-1H-benzoimidazol-5-yl)methanone (5.28 g; 0.02 mol) in DMF (80 mL) was stirred under an atmosphere of nitrogen. Sodium hydride (60% dispersion in oil, 0.8 g; 0.02 mol) was added. The mixture was then stirred for 0.5 hour at ambient temperature. 3,4-dichlorobenzyl bromide (4.8 g; 0.02 mol) was then added in portions. The mixture was stirred at 80-90° C. for 3.5 hours, then at ambient temperature for 18 hours. The solvent was evaporated under vacuum. The residue was extracted with ethyl acetate (300 mL) and washed with water (2×200 mL). The organic phase was evaporated. Purification was achieved by flash chromatography on silica gel (EtOAc/Hexane; 1:9 to 1:3). Recrystallization from ethyl acetate affords the tide compound (4.2 g; 50% yield) as a white solid, m.p. 168-169° C. Anal. Calcd. for C24H20Cl2N2O: C, 68.09; H, 4.76; N, 6.62. Found: C, 67.70; H, 4.46; N, 6.49. Mass spectrum (DEI; M+) m/z 422, 424, 426. 1H-NMR (DMSO -d6; 400 MHz) δ7.94 (d, 1H), 7.73 (d, 2H), 7.64-7.72 (m, 3H), 7.59 (m, 1H), 7.56 (t, 2H), 7.47 (d, 1H), 6.98 (dd, 1H), 5.59 (s, 2H), 2.84 (t, 2H), 1.76 (m, 2H) and 0.94 ppm (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[Al](C)C.[I:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:30]=1)[C:20](=[O:29])[C:21]([C:24](OCC)=[O:25])=[CH:22][N:23]=2.Cl>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:24]([C:21]2[C:20](=[O:29])[N:19]3[CH:30]=[C:15]([I:14])[CH:16]=[CH:17][C:18]3=[N:23][CH:22]=2)=[O:25])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2ccc(I)cn2c1=O
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cn2c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 58 %

Procedure:
To a solution of 4-chlorobenzylamine (0.071 mL) in toluene (1.5 mL) at 0° C. is added trimethylaluminum (2M solution in toluene, 0.29 mL). After stirring the solution at 0° C. for 5 min, ethyl 7-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (Preparation 2, 200 mg) is added. The solution is stirred at 0° C. for an additional 10 min, then allowed to stir at room temperature overnight. The reaction mixture is poured into 3 N HCl (7.5 mL) and water, then extracted with CH2Cl2 (3×). The combined organic layers are dried (Na2SO4), filtered, and concentrated to afford a solid. The impurities are removed by dissolving the crude product in CH2Cl2 and filtering the insoluble solid. The filtrated is concentrated to afford 148 mg (58%) of title compound as a yellow solid. Physical characteristics: m.p. 191-194° C.; 1H NMR (300 MHz, DMSO-d6) δ9.36, 9.27, 9.03, 8.38, 7.68, 7.40, 4.57; IR (drift) 3319, 1683, 1637, 1612, 1560, 1541, 1507, 1478, 1347, 1339, 1295, 837, 792, 641, 625 cm−1; MS (ESI+) m/z 440 (M+H)+; Anal. found: C, 43.58; H, 2.48; N, 9.38.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(O)(C)C>[CH2:23]([N:15]([CH2:16][C:17]([F:19])([F:18])[F:20])[C:12]1[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:21])([F:22])[F:1])=[CH:14][CH:13]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: OC(c1ccc(NCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Solvent: CC(C)(C)O
Product: OC(c1ccc(N(Cc2ccccc2)CC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 100 °C
Reaction time: 10 h
Yield: 8 %

Procedure:
A solution of 100 mg (0.29 mmol) of 1,1,1,3,3,3-hexafluoro-2-[4-(2,2,2-trifluoro-ethylamino)-phenyl]-propan-2-ol in 0.5 mL tBuOH was treated with 0.1 mL (0.84 mmol) of benzylbromide and stirred at 100° C. for 10 hours in a sealed tube. Evaporation of the solvent and column chromatography on silicagel with n-heptane/EtOAc 8:1 yielded 10 mg (8%) of 2-{4-[benzyl-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, blue oil, MS: 432 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]12([NH2:16])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.C(N(CC)CC)C>C(OCC)C>[C:6]12([NH:16][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:13][CH:12]3[CH2:11][CH:10]([CH2:9][CH:8]([CH2:14]3)[CH2:7]1)[CH2:15]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: C=CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of acryloyl chloride (4.05 ml, 0.05 mole) in ethyl ether (25 ml) was added to a cold (+5° C.) solution of 1-adamantaneamine (7.65 g, 0.05 mole) and triethylamine (15.3 ml, 0.11 mole) in ethyl ether (300 ml) and the solution stirred for 72 hours at room temperature. The solvent was removed on a rotary evaporator. The residue was dissolved in ethyl acetate (100 ml), washed with 10 percent hydrochloric acid (100 ml) and water (50 ml), dried over sodium sulfate, filtered and the solvent removed in vacuo leaving an oily solid which was crystallized from methanol-ethyl acetate-hexane. The structure was confirmed by NMR.