Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl(O)(=O)(=O)=[O:2].[CH3:6][C:7]1[N:11]([CH2:12][CH:13]2[C:26](=[O:27])[C:17]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[N:24]([CH3:25])[C:16]=3[CH2:15][CH2:14]2)[CH:10]=[CH:9][N:8]=1.[C:28]([OH:31])(=[O:30])[CH3:29]>>[CH3:25][N:24]1[C:16]2[CH2:15][CH2:14][CH:13]([CH2:12][N:11]3[CH:10]=[CH:9][N:8]=[C:7]3[CH3:6])[C:26](=[O:27])[C:17]=2[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2.[C:28]([OH:31])(=[O:30])[CH:29]=[O:2]
Reactant: CC(=O)O
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Product: O=CC(=O)O

Procedure:
A mixture containing 2.83 g (0.01 mole) of 3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylic acid lactone [compound of the formula (Ic)] and 1.64 g (0.02 mole) of 2-methylimidazole in 6.0 ml of sulfolane (tetramethylenesulfone) is heated in an oil bath of 150 to 160° C. for 15 minutes while stirring. After cooling down and diluting with 60 ml of acetone the precipitate is filtered off, washed with acetone and dried to give 0.95 g of the title compound, m.p.: 190°-200° C. (with decomposition). The active agent content of this product measured by titration with perchloric acid in glacial acetic acid was found to be 96%. In the combined filtrate of the reaction, ondansetron could be detected by thin layer chromatography. The most important characteristics of the title product are as follows:
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>CO.O>[CH3:23][N:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1
Reactant: ClCCl
Reactant: Oc1ccc(CCN[C@H]2CC[C@H](c3ccccc3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CCc1ccc(O)cc1)[C@H]1CC[C@H](c2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a stirred solution of trans-4-[2-(4-phenylcyclohexylamino)ethyl]phenol (380 mg, 1.3 mmol) in MeOH (5 mL), H2O (0.5 mL), and CH2Cl2 (5 mL) was added ρformaldehyde (200 mg, 6.5 mmol). After stirring for 15 minutes NaBH(OAc)3 (340 mg, 1.6 mmol) was added, and the reaction mixture was stirred for 12 hours. Additional NaBH(OAc)3 (138 mg, 0.65 mmol) was added, and the mixture was stirred for 2 days. NaBH(OAc)3 (138 mg, 0.65 mmol) was added, and stirring was continued for 6 hours. Solid NaOH was added to give a clear solution, which was concentrated under reduced pressure. Purification by flash chromatography (silica, 89:10:1 CH2Cl2:MeOH:NH4OH) and formation of the HCl salt gave trans-4-{2-[methyl(4-phenylcyclohexyl)amino]ethyl}phenol (380 mg, 64%), as an off-white solid: mp 97-105° C.; IR (KBr): 2941, 1614, 1517 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.42 (s, 1H), 7.35-7.15 (m, 5H), 7.10 (br d, J=8 Hz, 2H), 6.77 (br d, J=8 Hz, 2H), 3.49-2.94 (m, 6H), 2.80-2.70 (m, 2H), 2.56-2.48 (m, 1H), 2.30-2.11 (m, 2H), 1.89 (br d, J=11.5 Hz, 2H), 1.75-1.50 (m, 4H); CI—MS (methane) (m/z): 310 [M+H]+; HPLC: method A, 5.99 minutes (99.4%); method B, 10.68 minutes (99.1%); Anal. Calcd for C21H27NO.HCl.0.25H2O: C, 71.98; H, 8.20; N, 4.00. Found: C, 71.60; H, 8.31; N, 3.86.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15]F.[F-].[Na+]>C(#N)C.ClC(Cl)(Cl)C(F)(F)F>[C:1]1([CH:7]([F:15])[C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=O)Cc1ccccc1
Reactant: FF
Agent: [F-]
Agent: [Na+]
Solvent: FC(F)(F)C(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C(=O)C(F)c1ccccc1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 40 %

Procedure:
Ethyl 3-phenylpyruvate (10 g; 0.052 mol) is dissolved in a mixture of acetonitrile (60 g) and trichlorotrifluoroethane (410 g), and the resulting solution is cooled to -10° C. Then, fluorine gas (0.067 mol) diluted with nitrogen to 10% concentration is introduced therein over a period of 2.5 hours while stirring vigorously. After addition of sodium fluoride (2 g), the solvent is distilled off under reduced pressure, and the residue is rectified to give ethyl 3-phenyl-3-fluoropyruvate (4.37 g). Boiling point, 90°-95° C./1 mmHg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]([OH:22])[CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:21][CH2:20][CH:19]([OH:22])[C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=2)[CH3:10])=[CH:4][CH:3]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)Cc1ccc(C)cc1
Solvent: c1ccccc1
Product: Cc1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1
Yield: 56.3 %

Procedure:
A mixture of 4-methylphenylacetone (1.56 g) and 2-(3-chlorophenyl)-2-hydroxyethanamine (1.81 g) was refluxed in benzene (70 ml) under Dean & Stark conditions for 4 h. The solvent was removed under reduced pressure, replaced with ethanol (100 ml) and the solution hydrogenated using Pt as catalyst. The filtered solution was evaported and the residual oil chromatographed on Kieselgel 60 (150 g). Elution with 1% methanol-chloroform gave the title compound (1.8 g) as an oil. Crystallisation from hexane gave 1.26 g as a 56:44 mixture of diastereoisomers, mp 76-78.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][OH:15])=[CH:10][CH:11]=2)[C:6]([CH3:22])([CH3:21])[CH2:5][CH2:4]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][O:15][C:43]3[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=3)=[CH:10][CH:11]=2)[C:6]([CH3:21])([CH3:22])[CH2:5][CH2:4]1)[CH3:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCN2CC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCN2CC
Yield: 46.5 %

Procedure:
1 g of (RS)-2-(N-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-heptanol dissolved in 20 ml THF were treated with 950 mg of triphenylphosphine, 550 mg of methyl 4-hydroxybenzoate and 0.57 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was diluted with 100 ml of ether and washed with two portions of 25 ml of water and one portion of 25 ml of sat. aq. sodium chloride solution. The organic phase was dried over MgSO4. The solvents were removed in vacuo and the resulting yellow oil was purified by flash chromatography (SiO2, 3% ethyl acetate/hexanes), giving 670 mg (RS)-methyl 4-[2-(N-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-heptyloxy]-benzoate as a pale yellow oil. The ester (670 mg), dissolved in 5 ml THF/5 ml H2O/5 ml methanol, was treated with 260 mg of lithium hydroxide hydrate. The mixture was stirred at 40° C. for 6 hours. The mixture was diluted with 5 ml water and acidified to pH 2 with 1N hydrochloric. The resulting suspension was taken in 20 ml ether and the phases were separated. The aqueous phase was extracted with three portions of 10 ml ether. The combined extracts were dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by preparative tlc (10% methanol/methylene chloride), yielding 320 mg of a pale yellow oil. 1H NMR (CDCl3): 8.01 (d, J=9.0 HZ, 2H), 6.98 (d, J=2.1 Hz, 1H), 6.95-6.85 (m, 3H), 6.52 (d, J=8.4 Hz, 1H), 4.64 (quint, J=5.8 Hz, 1H), 3.32 (q, J=7.1 Hz, 2H), 3.25-3.15 (m, 2H), 2.88 (dd, J=14.1, 5.9 Hz, 1H), 2.78 (dd, J=14.1, 5.9 Hz, 1H), 1.80-1.65 (m, 4H), 1.55-1.25 (m, 6H), 1.24 (s, 3H), 1.18 (s, 3H), 1.11 (t, J=7.1 Hz, 3H), 0.86 (t, J=6.7 Hz, 3H).
Reaction SMILES: ClC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.N1C2C(=CC=CC=2)C=C1.BrCCCCC[Cl:32]>>[Cl:32][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: ClCCCCCBr
Reactant: ClCCCCCCn1ccc2ccccc21
Agent: c1ccc2[nH]ccc2c1
Product: ClCCCCCn1ccc2ccccc21
Yield: 80 %

Procedure:
According to the procedure used for the synthesis of 1-(6-chlorohexyl)-1H-indole, 1-H-indole (0.585 g, 5.00 mmol) and 1-bromo-5-chloropentane (0.928 g, 5.00 mmol) gave the desired product (0.890 g, 80%). 1H NMR (CDCl3) δ 7.76–7.51 (m, 1H), 7.44–6.96 (m, 4H), 6.60–6.38 (m, 1H), 4.11 (t, 2H, J=6.8 Hz), 3.47 (t, 2H, J=6.4 Hz), 1.97–1.79 (m, 2H), 1.79–1.61 (m, 2H), 1.58–1.32 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1)#[N:24]>>[C:23]([C:25]1([C:28]([NH:20][C:19]2[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:22][CH:21]=2)=[O:29])[CH2:27][CH2:26]1)#[N:24]
Reactant: N#CC1(C(=O)O)CC1
Reactant: Nc1ccc(CCCCCCCCCc2ccccc2)cc1
Product: N#CC1(C(=O)Nc2ccc(CCCCCCCCCc3ccccc3)cc2)CC1
Yield: 93.7 %

Procedure:
General procedure E was used to convert 2.56 mmol of 17 and 3.84 mmol of 1-cyanocyclopropanecarboxylic acid to 2.40 mmol (94%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([CH2:18]P(=O)(OCC)OCC)#[N:17].[H-].[Na+].O>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:18]/[C:16]#[N:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#C/C=C/C1CCN(Cc2ccccc2)CC1
Yield: 109.8 %

Procedure:
A solution of 1-benzyl-4-formylpiperidine (4.5 g) in tetrahydrofuran (20 ml) was added dropwise to a suspension of diethyl cyanomethylphosphonate (4.31 g) and sodium hydride (0.97 g, 60% suspension in oil) in tetrahydrofuran (30 ml) at 0° C. under stirring. After stirring for 1 hour at ambient temperature, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine and dried over magnesium sulfate, and evaporated in vacuo to give (E)-3-(1-benzylpiperidin-4-yl)-2-propenenitrile (5.5 g) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:28]=[CH:27][C:15]2[CH2:16][CH:17]([CH2:22][C:23]([O:25]C)=[O:24])[C:18](=[O:21])[NH:19][CH2:20][C:14]=2[CH:13]=1.Cl.O1CCOCC1.[H][H]>[Pd].CO>[NH:3]1[CH2:4][CH2:5][CH2:6][N:1]=[C:2]1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:28]=[CH:27][C:15]2[CH2:16][CH:17]([CH2:22][C:23]([OH:25])=[O:24])[C:18](=[O:21])[NH:19][CH2:20][C:14]=2[CH:13]=1
Reactant: [H][H]
Reactant: COC(=O)CC1Cc2ccc(OCCCNc3ncccn3)cc2CNC1=O
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)CC1Cc2ccc(OCCCNC3=NCCCN3)cc2CNC1=O
Reaction time: 18 h

Procedure:
A mixture of methyl (±)-8-[3-(pyrimidin-2-ylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.36 g, 0.94 mmol), 4 M HCl in dioxane (0.25 mL, 1 mmol), 10% palladium on charcoal (0.24 g, 0.24 mmol), and MeOH (5 mL) was stirred under a balloon of hydrogen. After 18 hr, the mixture was filtered and the filtrate was concentrated. The residue was partitioned between EtOAc and aqueous K2CO3. A solid precipitated, which was collected by filtration and dried to give the title compound as a white solid: MS m/e 375.4 (M+H)+. Anal. Calcd for C19H26N4O4.2.5 H2O: C, 54.40; H, 7.45; N, 13.35. Found: C, 54.68; H, 7.12; N, 13.39.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[O:9][CH2:8]2.C=O.[C:17]([BH3-])#N.[Na+]>CC(O)=O.C(#N)C>[Cl:1][CH2:2][CH2:3][N:4]([CH3:17])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[O:9][CH2:8]2
Reactant: O=C1OCc2cc(NCCCl)ccc21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(CCCl)c1ccc2c(c1)COC2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A mixture of 5-(2-chloro-ethylamino)-3H-isobenzofuran-1-one (3.0 g, 14.2 mmol), 37% formaldehyde aqueous solution (10 ml, 134 mmol) and sodium cyanoborohydride (3.6 g, 56.8 mmol) in a mixture of 10% AcOH aqueous solution (40 ml) and acetonitrile (40 ml) was stirred at 0° C. for 30 minutes. The mixture was allowed to warm to room temperature and was continuously stirred for 2 hours. The mixture was concentrated under reduced pressure, basified with 1M NaOH aqueous solution, and extracted with EtOAc (3×100 ml). The combined organic layers were washed with 1M NaOH aqueous solution (100 ml) and then water (2×100 ml), dried over anhydrous Na2SO4. Removal of the solvent led to a light yellow oil, which was crystallized with diethyl ether to produce 5-[(2-chloro-ethyl)-methyl-amino]-3H-isobenzofuran-1-one as a yellow solid (2.5 g, 78%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@H:7]([OH:9])[CH3:8])=[CH:3][CH:2]=1.C([Li])CCC.[C:15]12([C:25](Cl)=[O:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>C1COCC1.CCCCCC>[C:15]12([C:25]([O:9][C@@H:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH3:8])=[O:26])[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: C[C@@H](O)c1ccncc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[C@@H](OC(=O)C12CC3CC(CC(C3)C1)C2)c1ccncc1
Yield: 88.1 %

Procedure:
The method followed that described in Example 1, but using (+)-(R)-1-(4-pyridyl)ethanol (369 mg, 3.0 mmol) in THF (12 ml), n-butyllithium (2.5 M, 1.2 ml, 3.0 mmol) in hexane, and 1-adamantanecarbonyl chloride (656 mg, 3.3 mmol) in THF (3 ml). Chromatography, on elution with petrol-ether-triethylamine 200:50:1, afforded the title compound (754 mg, 88%). [α]D +25.8° (c 1, CHCl3); IR νmax 1730 cm-1 ; 1H-NMR (CDCl3) δ1.50 (3H, d, J 6.6 Hz, CHCH3), 1.73 and 1.93 (12H, 2s, adamantyl CH2), 2.04 (3H, s, adamantyl CH), 5.80 (1H, q, J 6.6 Hz, OCH), 7.23 (2H, d, J 6.1 Hz, Py 3 and 5H), 8.58 (2H, d, J 6.1 Hz, Py 2 and 6H); MS m/z 285 (M+). By passing hydrogen chloride gas through a solution of the product in ether, the hydrochloride was obtained, m.p. 164°-166° C. Anal. Calcd: C, 67.17; H, 7.52; N, 4.35. Found: C, 67.58; H, 7.51; N, 4.36%.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH3:10][O-:11].[Na+]>CO>[F:9][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[O:11][CH3:10]
Reactant: C[O-]
Reactant: Nc1ccc(F)c(F)c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(N)ccc1F
Temperature: 110 °C

Procedure:
3,4-Difluoroaniline (2.6 g) was added to a 28% methanol solution of sodium methoxide, and the mixture was heated for 2 days at about 60° C. and for 4 days at 110° C. After distilled water (50 ml) was added to the reaction mixture, it was extracted with chloroform (50 ml). A chloroform layer was washed with distilled water (20 ml) and then dried over anhydrous magnesium sulfate. The dry chloroform layer was concentrated under reduced pressure to obtain the title compound (2.8 g) as a dark brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13](NC(=O)CC(F)(F)F)=[CH:12][CH:11]=2)[N:3]=1.ClC1C=C(NC2C=CC=CN=2)N=C(SC2C=CC(NC(=O)CC(F)(F)F)=CC=2)N=1.ClCS(C1C=C(S(CCl)(=O)=O)N=CN=1)(=O)=O.SC1C=CC([C:74]([NH:76][CH2:77][C:78]([F:81])([F:80])[F:79])=[O:75])=CC=1.C(N(CC)CC)C>C(#N)C>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([S:9][C:10]2[CH:11]=[CH:12][C:13]([C:74]([NH:76][CH2:77][C:78]([F:81])([F:80])[F:79])=[O:75])=[CH:14][CH:15]=2)[N:5]=1
Reactant: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1
Reactant: O=C(NCC(F)(F)F)c1ccc(S)cc1
Agent: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Cl)cc(Nc3ccccn3)n2)cc1
Agent: O=S(=O)(CCl)c1cc(S(=O)(=O)CCl)ncn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCC(F)(F)F)c1ccc(Sc2nc(Cl)cc(Cl)n2)cc1

Procedure:
4-(4,6-Dichloropyrimidin-2-ylthio)-N-(2,2,2-trifluoroethyl)benzamide was prepared according the procedure of 1a in Scheme 2 from 4,6-dichloromethylsulfonylpyrimidine (1.0 g, 4.4 mmol), 4-mercapto-N-(2,2,2-trifluoroethyl)benzamide (1.1 g, 4.7 mmol), and triethylamine (0.7 mL, 4.9 mmol) in acetonitrile (30 mL). Desired compound was purified by column chromatography (SiO2, ethyl acetate/heptanes=1:1-1:0, TLC: SiO2) to yield 210 mg (12%) (HPLC method A: Rf=8.508 minutes).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 87.7 %

Procedure:
To a 5 L 3 necked round bottomed flask with an overhead stirrer was added 4-chloroaniline (127.57 g, 1 mole), 1200 mL of CHCl3, and 1200 mL of saturated aqueous Na2CO3 solution. An addition funnel was attached to the flask and charged with 2,2-dimethylpropanoyl chloride (129 mL, 1.05 mole). The acid chloride was added dropwise to the vigorously stirred mixture over 1 h. The resulting mixture was stirred at ambient temperature for an additional 23 h. Some of the product separated from the mixture as white crystals. These crystals were collected by filtration. The filtrate was transferred to a separatory funnel and the layers were separated. The chloroform layer was washed with water and brine. Drying (MgSO4), filtration, and removal of the solvent in vacuo gave additional product. The two portions of product were combined and recrystallized from boiling EtOAc-hexanes to give 185.6 g of N-(4-chlorophenyl)-2,2-dimethylpropanamide as a white crystalline solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(#N)C.[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:3]([C:2]([F:1])([F:25])[F:26])[CH:4]=1)=[N:35][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)#[N:24]
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Reactant: NC1CCCC1
Solvent: CC#N
Product: N#CNC(=NC1CCCC1)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 85 °C
Reaction time: 3.5 h
Yield: 82 %

Procedure:
To a suspension of N-(3,5-bis(trifluoromethyl)phenyl)-N'-cyano-O-phenylisourea (0.400 g, 1.1 mmol) in dry acetonitrile (2.5 ml) triethylamine (0.164 ml, 1.2 mmol) and cyclopentylamine (0.116 ml, 1.2 mmol) was added. The homogenous solution was stirred at 85° C. under N2 for 3.5 h. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed with water twice. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography using ethyl acetate/heptane 1:2 to give the title compound. Yield 82% (0.320 g). mp 156-159° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].I[CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[CH2:12]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=1[CH:4]=[O:5])[CH3:13]
Reactant: CCI
Reactant: O=Cc1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cccc(F)c1C=O
Temperature: 80 °C

Procedure:
A mixture of commercially available 2-fluoro-6-hydroxybenzaldehyde (2.500 g; 17.80 mmol), iodoethane (5.566 g; 35.70 mmol), and K2CO3 (2.959 g; 21.40 mmol) in anh. DMF (50 ml) was heated to 80° C., under nitrogen, for 2 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-ethoxy-6-fluorobenzaldehyde as a yellow solid. LC-MS (conditions A): tR=0.66 min.; [M+H]+: 169.14 g/mol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([F:15])[CH:9]=1.[Cl-].[P:17]([O-])([S:22][CH2:23][CH2:24][CH3:25])([O:19][CH2:20][CH3:21])=[O:18]>C(#N)C>[P:17]([O:14][C:11]1[CH:12]=[CH:13][C:8]([Br:7])=[CH:9][C:10]=1[F:15])([S:22][CH2:23][CH2:24][CH3:25])([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Oc1ccc(Br)cc1F
Reactant: CCCSP(=O)([O-])OCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: CCCSP(=O)(OCC)Oc1ccc(Br)cc1F
Reaction time: 24 h
Yield: 61.2 %

Procedure:
5.5 g of potassium carbonate are added to 7.5 g of the resulting 4-bromo-2-fluorophenol in 100 ml of acetonitrile and the mixture is refluxed for one hour, with stirring. 7.5 g of O-ethyl S-n-propyl thiophosphate-chloride are then added dropwise at 50° C. and the mixture is stirred at this temperature for 3 hours and then at room temperature for 24 hours. The solvent is removed on a rotary evaporator, 400 ml of toluene and 100 ml of water are added, the phases are separated, the organic phase is washed with 2N sodium hydroxide solution and then with water and is dried with sodium sulfate, and the solvent and volatile impurities are stripped off under reduced pressure at 40° C./0.13 mbar. 7.5 g of O-ethyl S-n-propyl O-(4-bromo-2-fluorophenyl) thiophosphate are obtained as the residue; nD21 =1.5269.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:15])[CH2:13][CH3:14])[C:5](Cl)=[O:6].[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([CH2:11][CH:12]([CH3:15])[CH2:13][CH3:14])=[C:2]([Br:1])[CH:3]=3)=[CH:22][CH:21]=2)=[CH:24][CH:25]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCC(C)Cc1ccc(C(=O)Cl)cc1Br
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(-c2ccc(OC(=O)c3ccc(CC(C)CC)c(Br)c3)cc2)cc1
Reaction time: 2 h

Procedure:
This 3-bromo-4-(2'-methylbutyl)benzoic acid chloride (11.5 g, 0.04 mol) was dropwise added to a mixture of 4-hydroxy-4'-octyloxybiphenyl with anhydrous pyridine under ice cooling, followed by agitating the resulting mixture at 50°-60° C. for 2 hours, adding toluene (100 ml), sufficiently agitating the mixture, washing it with 6N-HCl, then with 2N-NaOH aqueous solution and further with water, further drying over anhydrous MgSO4, distilling off toluene and recrystallizing the residue from a mixture of ethanol (100 ml) with ethyl acetate (60 ml) to obtain 3-bromo-4-(2'-methylbutyl)benzoic acid 4'-octyloxy-4-biphenylyl ester (12.2 g), which exhibited liquid crystalline properties and had the following phase transistion points: ##STR45##
Reaction SMILES: [Cl-].[NH4+].[N-:3]=[N+:4]=[N-:5].[Na+].[C:7]([CH2:9][CH2:10][S:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][O:15][C:14]2[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:26][C:13]1=2)#[N:8]>CN(C)C=O>[N:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][C:29]=1[CH2:28][O:27][C:25]1[CH:24]=[CH:23][C:14]2[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:12]([S:11][CH2:10][CH2:9][C:7]3[NH:8][N:5]=[N:4][N:3]=3)[C:13]=2[CH:26]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCSC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)COc1ccc(OCc3ccc4ccccc4n3)cc1C2SCCc1nnn[nH]1
Temperature: 120 °C
Reaction time: 10 h
Yield: 20.7 %

Procedure:
0.6 g of ammonium chloride and 0.6 g of sodium azide were added to 1.32 g of 11-(2-cyanoethylthio)-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine dissolved in 10 ml of dimethylformamide and the mixture was stirred at 120° C. for 10 hours. After completion of the reaction, the solvent was removed and the residue was washed with water and then applied to silica gel column chromatography to obtain 0.3 g of the title compound as slightly brown powder.