Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13](Cl)[C:14](=[CH2:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.CN(C)C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[CH2:15][C:14](=[CH2:13])[CH3:16]
Reactant: C=C(C)CCl
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)c1ccccc1
Product: C=C(C)Cc1cc(C(=O)OCC)ccc1O
Yield: 89.3 %

Procedure:
Ethyl 4-hydroxybenzoate (50.0 g), methallyl chloride (32.6 g) and potassium carbonate (45.6 g) were refluxed with heating in acetone (150 ml) for 40 hours. The reaction mixture was filtrated and the filtrate was concentrated under a vacuum. The residue, after toluene (150 ml) was added thereto, was washed with 2% sodium hydroxide aqueous solution and water successively. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum, thereby yielding an oily compound. This compound was dissolved in N,N-dimethylaniline (80 ml) and refluxed with heating for about 10 hours. While being cooled with ice, the reaction mixture was acidified with concentrated hydrochloric acid and then extracted with toluene. The extract was extracted with 10% sodium hydroxide aqueous solution. The water layer was acidified with concentrated hydrochloric acid and then extracted with toluene. The extract was washed with water, dried over sodium sulfate anhydride and then concentrated under a vacuum, thereby yielding 59.2 g of ethyl 4-hydroxy-3-methallylbenzoate.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)=[O:6])[CH3:3].[OH:23]S([O-])(=O)=O.[K+].OO.[O-]Cl=O.[Na+]>CC#N.O.CCOC(C)=O>[CH3:3][C:2]([CH3:22])([O:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:23])=[O:19])=[CH:20][CH:21]=2)[CH:11]=[CH:10][N:9]=1)=[O:6])[CH3:1]
Reactant: O=S(=O)([O-])O
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2ccc(C=O)cc2)ccn1
Agent: OO
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cc(-c2ccc(C(=O)O)cc2)ccn1
Reaction time: 16 h

Procedure:
17-4 (1.0 g, 3.4 mmol) is slurried in CH3CN (40 mL). 10% KHSO4 (1.3 mL) and 30% H2O2 (0.957 mL) are added and the solution is cooled in an ice bath. NaClO2 (8.5 mmol, 770 mg) is added dropwise in 50 mL water over 20 min. The reaction is stirred for 16 hrs. The reaction mixture is diluted w/EtOAc and washed with saturated NaHCO3 (2×). The aqueous layers are combined, acidifed with 10% KHSO4, and extracted w/CH2Cl2 (2×) and EtOAc (2×) to give 17-5 as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.6-12.8 (bs, 1H), 9.9 (s, 1H), 8.3 (d, 1H), 8.0-8.1 (m, 3H), 7.9 (d, 2H), 7.3 (d, 1H), 1.5 (s, 9H). ##STR88## Ethyl 2-(4-(4-(2-(1,1-Dimethylethoxycarbonylamino)pyrid-4-yl)carbonylamino)phenoxy)acetate (17-6)
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[N:8]=1)=O.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[OH:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(O)c2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: O=c1ccn(-c2cccc(O)c2)nc1-c1ccnn1-c1ccccc1
Yield: 64.5 %

Procedure:
A mixture of 3-[3-(dimethylamino)prop-2-enoyl]-1-(3-hydroxyphenyl)pyridazin-4(1H)-one (0.481 g, 1.69 mmol) in methanol (10 mL) was treated with phenylhydrazine (0.462 g, 4.28 mmol) and the resulting mixture was stirred at reflux for 14 h. After this time, the reaction was directly concentrated to remove methanol and then dissolved in methylene chloride (60 mL). The solution was washed with water (60 mL), and brine (20 mL). After concentrated with silica gel, chromatography (silica, methylene chloride to 1:19 methanol/methylene chloride) afforded 1-(3-hydroxyphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (0.360 g, 65%) as a brown-yellow solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH:12](O)=[O:13]>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:12]=[O:13])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=CO
Product: O=CNc1ccc(C(F)(F)F)cc1

Procedure:
Was prepared according to Example 2 from 4-(trifluoromethyl)aniline and formic acid
Reaction SMILES: FC1C=C(CC(O)=O)C=CC=1.[N+:12]([O-:15])([OH:14])=O.[OH-].[Na+].[F:18][C:19]1[C:20]([N+]([O-])=O)=[C:21]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1.COC1C([N+]([O-])=O)=CC([N+]([O-])=O)=C(CC(OC)=O)C=1>S(=O)(=O)(O)O.CO>[CH3:32][O:31][C:29](=[O:30])[CH2:28][C:21]1[CH:20]=[C:19]([F:18])[C:24]([N+:12]([O-:15])=[O:14])=[CH:23][C:22]=1[N+:25]([O-:27])=[O:26]
Reactant: COC(=O)Cc1c([N+](=O)[O-])ccc(F)c1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: COC(=O)Cc1cc(OC)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C(O)Cc1cccc(F)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 27.5 °C
Reaction time: 20 h

Procedure:
m-Fluorophenyl acetic acid (15.00 gm) was dissolved in concentrated sulfuric acid (30 mL). A solution consisting of 90% nitric acid (18 mL) and concentrated sulfuric acid (22.5 mL) was added drop wise during 1 hour while maintaining the internal temperature between 20-35° C. After the addition, the solution was stirred for an additional 20 hours at 35° C. and the resultant yellow slurry was poured onto ice and filtered to give 21 gm of an off white solid. This solid obtained (mix of nitro acids) was dissolved in methanol (250 mL). Sulfuric acid (1 mL) was added and the solution was heated at reflux for 5 hours and then cooled in an ice bath. The pH was brought to ca 5 by dropwise addition of 2.5; N sodium hydroxide. Most of the methanol was removed by rotary evaporator and remainder solution was partitioned with ethyl acetate and water. After removing the aqueous phase the organic layer was dried with anhydrous sodium sulfate or magnesium sulfate, filtered over celite and concentrated to give light brown oil comprised of the following three compounds (listed in order of increasing polarity by tlc): methyl (3-fluoro-2,6-dinitrophenyl)acetate, methyl (5-fluoro-2,4-dinitrophenyl) acetate and methyl (5-methoxy-2,4-dinitrophenyl)acetate. The compounds were separated by flash chromatography (ethyl acetate/hexane 15-50%). (1) Methyl (3-fluoro-2,6-dinitrophenyl) acetate; 1H NMR (DMSO-d6) 400 MHz, δ: 3.645 (s, 3H), 4.056 (s, 2H), 7.909 (dd, J=8.8 & 9.2 Hz, 1H), 8.490 (dd, J=7.6 & 8.0 Hz, 1H). MS (ESI): m/z 256.8 [M−H]−. (2) Methyl (5-fluoro-2,4-dinitrophenyl) acetate; YD; 32%, Rf: 0.39 (EA:Hx: 3.0:7.0). 1H NMR (DMSO-d6) 400 MHz, δ: 3.637 (s, 3H), 4.223 (s, 2H), 7.923 (d, J=11.6 Hz, 1H), 8.832 (d, J=6.8 Hz, 1H). (C9H7FN2O6.1/9CH3COOC2H5) C, H, N. MS (ESI): m/z 256.8 [M−H]−. (3) Methyl (5-methoxy-2,4-dinitrophenyl) acetate; 1H NMR (DMSO-d6) 400 MHz, δ: 3.635 (s, 3H), 4.051 (s, 3H), 4.214 (s, 2H), 7.628 (s, 1H), 8.714 (s, 1H). MS (ESI); m/z 268.9 [M−H]−.
Reaction SMILES: [C:1]([O:6]C)(=O)[C@@H:2]([CH3:4])[OH:3].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>C(OCC)(=O)C>[OH:3][C@H:2]([CH3:4])[C:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:6]
Reactant: COC(=O)[C@@H](C)O
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Product: C[C@@H](O)C(=O)N1CCOCC1
Temperature: 85 °C
Yield: 87 %

Procedure:
A mixture of methyl (R)-lactate (175 g) and morpholine (440 ml, 3 eq) was heated at 85° C. for 40 h. The mixture was evaporated under reduced pressure. Purification of the residue by silica gel chromatography (using n-hexane:ethyl acetate=1:1 ˜ethyl acetate as an eluent) gave 4-[(R)-2-hydroxypropionyl]morpholine (232.4 g, 87% yield) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH2:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:21][CH3:22].[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:26]3[CH2:27][CH2:28][N:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25]3)=[N:10][C:4]=2[CH:3]=1
Reactant: CCCN1CCNCC1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCN1CCN(C2=Nc3cc(Br)ccc3N3CCc4cccc2c43)CC1
Temperature: 25 °C
Yield: 30.1 %

Procedure:
A stirred mixture of 7.88 g (0.0250 mole) of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one and 1200 ml of toluene was heated until a solution resulted. Then there was added 32.1 g (0.25 mole) of N-propylpiperazine, followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was refluxed for 3 hours, and then cooled to room temperature. The mixture was stirred with 500 ml of 2N sodium hydroxide solution for 15 minutes and the layers were separated. The aqueous phase was extracted with 300 ml of toluene. The toluene layers were combined, filtered, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, and concentrated to an oily solid. The oily solid was dissolved in 25 ml of hot ethyl acetate, filtered, and allowed to crystallize first at room temperature, then at 0° C. to yield 3.20 g (30%) of product, mp 134°-136° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[N:15]=1)[C:7]([O:9]C)=[O:8])([O-:3])=[O:2].[OH-].[Na+].Cl>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[N:15]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)no2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)no2)c([N+](=O)[O-])c1
Yield: 95.4 %

Procedure:
A mixture of methyl 3-nitro-4-[3-(4-trifluoromethylphenyl)-1,2,4-oxadiazol-5-yl]benzoate (2.00 g), 1 M aqueous sodium hydroxide solution (10.2 ml) and tetrahydrofuran (10 ml) was heated under reflux for 1 hr. After cooling, 1 M hydrochloric acid was added to acidify the reaction mixture. The crystals were collected by filtration to give 3-nitro-4-[3-(4-trifluoromethylphenyl)-1,2,4-oxadiazol-5-yl]benzoic acid (1.84 g, yield 95%). Recrystallization from hexane-tetrahydrofuran gave pale-yellow prism crystals. melting point: 233–234° C.
Reaction SMILES: [ClH:1].C([N:5]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH:13]([NH:19][CH2:20][CH2:21][CH3:22])[CH2:14]2)[CH2:6][C:7]#[CH:8])(=O)C.Cl>C(O)C>[ClH:1].[ClH:1].[CH2:6]([NH:5][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH:13]([NH:19][CH2:20][CH2:21][CH3:22])[CH2:14]2)[C:7]#[CH:8]
Reactant: C#CCN(C(C)=O)c1cccc2c1CCC(NCCC)C2
Agent: Cl
Solvent: CCO
Product: C#CCNc1cccc2c1CCC(NCCC)C2

Procedure:
0.48 g (0.0015 mol) of 5-(N-acetyl-N-propargyl-amino)-2-n-propylamino-tetraline-hydrochloride (Example 4.7.11) are refluxed in 10 ml of ethanol and 30 ml of 6 N hydrochloric acid for 16 hours. The mixture is then concentrated by rotary evaporation, finally at 80° C. under a complete water-jet vacuum. The residue is shaken with 50 ml of water, 50 ml of methylene chloride and excess ammonia. The aqueous phase separated off is extracted twice more with 15 ml of methylene chloride. The combined methylene chloride extracts are washed with 20 ml of water and concentrated by rotary evaporation as described above. The residue is crystallised analogously to Example 4.1.1 in the form of the dihydrochloride. Yield 0.12 g (25.2% of theory), melting point 198° C., unchanged after recrystallisation from ethanol/ether.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([CH3:17])[N:8]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:6][C:7]1[CH:12]=[C:11]([C:13]([OH:16])([CH3:14])[CH3:15])[CH:10]=[C:9]([CH3:17])[N:8]=1
Reactant: COc1ccc(CNc2cc(C(C)(C)O)cc(C)n2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(C)(C)O)cc(N)n1
Reaction time: 2 h

Procedure:
To a solution of 2-{2-[(2,4-dimethoxybenzyl)amino]-6-methylpyridin-4-yl}propan-2-ol (234 mg, 0.740 mmol) in dichloromethane (5 mL) was added TFA (1 mL) at 20° C. After 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (5-50% acetonitrile/water with 0.1% TFA, linear gradient) to afford 2-(2-amino-6-methylpyridin-4-yl)propan-2-ol. MS ESI calc'd. for C9H15N2O [M+H]+ 167. found 167.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][CH:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[CH3:27][O:28][C:29](=[O:36])[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([N:4]([CH2:8][C:9]1[S:13][C:12]([S:14]([N:33]2[CH2:34][CH2:35][CH:30]([C:29]([O:28][CH3:27])=[O:36])[CH2:31][CH2:32]2)(=[O:16])=[O:15])=[CH:11][CH:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: C=CCN(CC=C)Cc1ccc(S(=O)(=O)Cl)s1
Reactant: COC(=O)C1CCNCC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(CC=C)Cc1ccc(S(=O)(=O)N2CCC(C(=O)OC)CC2)s1
Reaction time: 3 h
Yield: 58.7 %

Procedure:
5-Diallylaminomethyl-thiophene-2-sulfonyl chloride 229b (270 mg, 1.88 mmol) and DIEA (0.88 mL, 5.13 mmol) were dissolved in 10 mL chloroform. This solution was added methylisonipecotate (269 mg, 1.88 mmol) in 1 mL chloroform. The reaction was stirred for 3 h, diluted with CH2Cl2 and extracted with HCl (0.1N), NaHCO3 sat. and brine. The organic layer was dried over MgSO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel using cyclohexane/EtOAc 1:1 as eluent to obtain 440 mg (65%) of 327a as colorless oil: H′ NMR (CDCl3) δ 7.30 (d, J=3.6 Hz, 1H), 6.83 (d, J=3.6 1H), 5.78 (m, 2H), 5.18 (m, 4H), 3.70 (s, 2H), 3.52 (m, 6H), 3.07 (m, 4H), 2.50 (m, 2H), 2.25 (m, 1H), 1.93 (m, 2H), 1.84 (m, 2H). M/Z APCI: 399.2 (M+1)
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)=O.[N+]([O-])(O)=O.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[NH:28][C:29]([NH2:31])=[NH:30].[OH-].[Na+]>C(O)(C)C>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[NH:28][C:29]1[N:31]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[N:11][CH:12]=2)[CH:4]=[CH:3][N:30]=1
Reactant: CN(C)/C=C/C(=O)c1cncnc1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cncnc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
(2E)-3-(Dimethylamino)-1-pyrimidin-5-ylprop-2-en-1-one (1 g, 5.6 mmol) and N-(2-methyl-5-nitrophenyl)guanidine nitrate (1.44 g, 5.6 mmol) (Z. Szakacs et al., J. Med. Chem. 2005, 48, 249) were suspended in 20 mL of isopropanol. Sodium hydroxide (0.28 g, 7 mmol) was then added. The mixture solution was stirred overnight and cooled to room temperature. The solid was collected by filtration and rinsed with isopropanol and diethyl ether. The filtrate was concentrated under reduced pressure and the residue was dissolved in 15 mL of isopropanol. The solution obtained was refluxed overnight and cooled to room temperature. The solid was collected by filtration and rinsed with isopropanol and diethyl ether. The pooled solid was rinsed with water and diethyl ether, and dried in vacuum to obtain 1.2 g (70% yield) of the title compound. MS (M+1)=309.10.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[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:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][C@@H:39]1[CH2:44][NH:43][CH2:42][CH2:41][NH:40]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:43]3[CH2:42][CH2:41][NH:40][C@H:39]([CH3:38])[CH2:44]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=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:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CNCCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN[C@H](C)C1

Procedure:
In a manner analogous to the method described in examples 8, (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 chloride (example 51) was coupled with (R)-2-methyl-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H42Cl2N5O2 [(M+H)+] 622.271, observed 622.2714.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[NH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>>[C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([NH:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][CH2:23]2)=[O:11])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: NN1CCN(Cc2ccccc2)CC1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NN1CCN(Cc2ccccc2)CC1
Reaction time: 6 h
Yield: 5.8 %

Procedure:
4-Acetylamino-5-chloro-methoxybenzoic acid (3.50 g, 0.144 mole) was treated with thionyl chloride (25 ml) at 50° for 1/2 hour. The mixture was evaporated in vacuo and the residue azeotroped twice with anhydrous benzene (100 ml) and redissolved in anhydrous benzene (100 ml). Triethylamine (1.45 g) was added followed by 1-amino-4-benzylpiperazine (2.75 g 0.144 mole) and the reaction left for 6 hours at room temperature. The mixture was evaporated in vacuo, taken up in water (50 ml) basified with dilute sodium hydroxide (10%) and extracted with chloroform. Evaporation of the dried (MgSO4) chloroform extract gave 4-acetylamino-5-chloro-2-methoxy-N-[4-benzyl-1-piperazinyl]benzamide (3.50 g; 58%) as colourless microcrystals m.p. 211°-213° C. A sample recrystallised from benzene gave m.p. 212° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:19]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:19]=2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)CCc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)c1
Product: CN(C)CCc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)c1
Yield: 91.9 %

Procedure:
Following general procedure F, {6-Bromo-4-[3-(2-(dimethylamino)ethyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (54 mg, 0.123 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (50 mg, 0.185 mmol) to afford the desired product (57 mg, 92%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.44 (s, 1H), 8.21 (dd, J=8.8, 1.9 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.92 (s, 1H), 7.66-7.57 (m, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.50 (s, 1H), 7.39 (dd, J=7.8, 2.2 Hz, 1H), 7.12 (d, J=11.5 Hz, 1H), 6.96 (s, 1H), 3.40-3.32 (m, 2H), 3.18-3.11 (m, 2H), 2.97-2.86 (m, 8H), 1.26-1.15 (m, 4H); ESI MS m/z 504 [C29H27ClFN3O2+H]+; HPLC 96.4% (AUC), tR=11.15 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH:17]3[CH2:22][CH2:21][Si:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(OC)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8].[AlH4-].[Li+].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([C@H:17]3[CH2:22][CH2:21][Si@H:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:19][CH2:18]3)[CH2:15][CH2:16]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCCC[Si]1(OC)CCC([C@H]2CC[C@H](CCc3ccc(F)c(F)c3)CC2)CC1
Agent: Cl
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(F)c(F)c3)CC2)CC1

Procedure:
Subsequently, the reaction mixture was concentrated, to which 200 ml of hexane was added thereby permitting secondarily produced triethylamine hydrochloride to be precipitated, followed by removal by filtration. The resultant filtrate was concentrated to obtain 34.6 g of 4-(trans-4-(2-(3,4-difluorophenyl)ethyl)cyclohexyl)-1-n-pentyl-1-methoxy-1-silacyclohexane. This silacyclohexane product was dissolved in 100 ml of THF and was added to 100 ml of a THF solution of 10.0 g of lithium aluminohydride, followed by agitation under reflux for 1 hour. The cis-trans isomer mixture was subjected to quantitative gas-chromatographic analysis in the same manner as set out hereinabove, revealing that a ratio of the cis isomer (retention time: 11.35 minutes) and the trans isomer (retention time: 11.61 minutes) was 12:88. The reaction mixture was poured into 200 ml of 5% hydrochloric acid and extracted with ethyl acetate. The extract was subjected to ordinary procedures of washing with brine, drying and concentration, followed by purification through silica gel chromatography to obtain 28.9 g of an intended product (yield: 86.3%). This product exhibited nematic liquid crystal properties at a temperature between 7.6° and 69.7° C. and was found to be very useful as a liquid crystal substance. The results of IR analysis of the product are shown below.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1.[C:16](Cl)(=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:16]([O:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1)(=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: OCCC#Cc1ccc(-c2cccs2)s1
Reactant: CC(C)CC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)CC(=O)OCCC#Cc1ccc(-c2cccs2)s1
Reaction time: 8 h

Procedure:
5-(4-Hydroxy-1-butynyl)-2,2'-bithiophene (1 g) was dissolved in pyridine (10 ml). Isovaleroyl chloride (1 ml) was added at room temperature, stirred for few minutes and kept overnight. The reaction mixture was treated as in example 21. Light yellowish oily product (1.06 g) was then obtained.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13](=[O:15])[CH3:14].B(Cl)(Cl)Cl>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:4]=1[C:13](=[O:15])[CH3:14]
Reactant: COc1ccc(C(F)(F)F)cc1C(C)=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1cc(C(F)(F)F)ccc1O
Temperature: 25 °C

Procedure:
2′-hydroxy-5′-trifluoromethyl-acetophenone was prepared using the following process (JACS, 2004, 126(3), 712-713). To a cooled solution of 2′-methoxy-5′-trifluoromethyl-acetophenone (650 mg, 2.98 mmol) at −78° C. in dry dichloromethane (40 ml) was slowly added a 1 M solution of boron trichloride in dichloromethane (7.5 ml, 7.5 mmol) keeping the internal temperature below −70° C. The brown-orange solution was slowly warmed up to room temperature within 2 hours.