Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](O)[CH:9]=[CH2:10].CCCCCC>O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:10][CH:9]=[CH2:8])=[O:6]
Reactant: O=C(O)CCCCl
Reactant: C=CCO
Solvent: CCCCCC
Solvent: O
Product: C=CCOC(=O)CCCCl
Temperature: 25 °C
Yield: 79 %

Procedure:
To a mixture of 4-chlorobutyric acid (48 ml; 0.48 mole), allyl alcohol (200 ml) and hexane (1.2 l) p-toluenesulfonic acid (16.0 g; 0.08 mole) was added. The obtained mixture was heated for 5 hours at reflux temperature in such a way that water was simultaneously removed with Dean-Stark apparatus (Vogel's Textbook of Practical Organic Chemistry, Fourth Ed., Longman, London, 1978, p. 411). The mixture was then cooled to room temperature and shaken with 7% aqueous sodium hydrogencarbonate solution (2×500 ml). The obtained solution was dried with magnesium sulfate and after the filtration of the drying agent hexane was evaporated. The crude residue was distilled under reduced pressure 10 mbar at the temperature of 95° C. and the title compound (61.2 g; 79%) was obtained in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.C(N(CC)CC)C.Cl.[CH3:21][C:22]([CH3:26])=[CH:23][CH2:24][NH2:25]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH2:24][CH:23]=[C:22]([CH3:26])[CH3:21])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: CC(C)=CCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)=CCNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To 10 ml of a solution of 438 mg (2.0 mmol) of 2,4-dichloro-7-metylthieno[3,2-d]pyrimidine and 445 mg (4.4 mmol) of triethylamine in DMF was added 243 mg (2.0 mmol) of 3-methyl-2-butenylamine hydrochloride under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 2 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 396 mg (yield: 74.0%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[C:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])[CH3:11]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:16]2[CH:17]=[CH:18][C:13]([C:10](=[O:12])[CH3:11])=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(-c2ccc(C(C)=O)cc2)cc1
Yield: 84 %

Procedure:
From 4-methoxy-bromobenzene and 4-acetylphenyl boronic acid, yield 84%; mp 150-151° C. (lit.,5 153-154° C.); IR: 1676, 1602, 1456 and 1236; 1H NMR (400 MHz; CDCl3): 8.01 (2H, d, J 8.4), 7.64 (2H, d, J 8.3), 7.58 (2H, d, J 8.8), 7 (2H, d, J 8.5), 3.86 (3H, s) and 2.62 (3H, s); 13C NMR (CDCl3): 197.6, 159.9, 145.3, 135.3, 132.2, 128.9, 128.3, 126.5, 114.4, 55.3 and 26.5; m/z (EI) 226 (80%, M+), 211 (100) and 69 (60)(Found: M+, 226.099. C15H14O2 requires M, 226.099).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Li+].[OH-].O>CO>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C(=O)OC)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.8 %

Procedure:
To a solution of methyl 4-[(4-butylphenyl)ethynyl]benzoate (23.0 g, 0.078 mol) in MeOH (200 ml) was added LiOH (3.6 g, 0.157 mol) followed by water (50 mL) and the reaction mixture was stirred for 5 hrs at rt. The solvents were removed under reduced pressure. The residue was acidified with an aqueous solution of HCl (1.5M) and a solid precipitated out. The precipitate was filtered and dried to yield 19.5 g (89%) of the title compound. 1H NMR (DMSO-d6) δ: 13.1 (brs, 1H), 7.96 (dd, J=1.6 and 6.7 Hz, 2H), 7.64 (d, J=6.8 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H), 1.55 (m, 2H), 1.29 (m, 2H), 0.88 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([OH:23])=[O:22].[CH2:24](O)[CH3:25].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reaction time: 8 h
Yield: 85 %

Procedure:
6.9 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid, 70 ml of ethanol and 4 g of concentrated sulfuric acid are heated at boiling for 8 hours. The liquid is reduced in volume, poured into water and ice, extracted with ether, washed with sodium carbonate solution, the organic solution is dried and reduced in volume. Ethyl 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate is obtained with a yield of 85%; F 51.5°-52.5°.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Li]C.Cl[Si:11]1([CH3:15])[CH2:14][CH2:13][CH2:12]1>CCOCC>[C:1]([Si:11]1([CH3:15])[CH2:14][CH2:13][CH2:12]1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C[Si]1(Cl)CCC1
Reactant: C#CCCCCC
Agent: [Li]C
Solvent: CCOCC
Product: CCCCCC#C[Si]1(C)CCC1
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 1-heptyne (1.31 mL, d=0.7238, 0.960 g, 10.0 mmol) in Et2O (10 mL) was added a solution of MeLi (9.43 mL, 1.06 M in Et2O, 1.0 equiv) at −78° C. After being stirred for 3 h, 1-chloro-1-methylsilacyclobutane (1.16 mL, 1.0 equiv) was added dropwise to the reaction solution at the same temperature, which was then stirred for another 5 h. The reaction mixture was quenched with H2O (10 mL) and then was extracted with pentane (3×25 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford the crude product, which was purified by column chromatography (SiO2, pentane) and Kugelrohr distillation to afford 1.66 g (92%) of 1-(1heptynyl)-1-methylsilacyclobutane as colorless oil
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.O[CH2:21]N1C2C=CC=CC=2N=N1.[BH4-].[Na+]>CCO.CN(C=O)C>[CH3:21][NH:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2
Reactant: OCn1nnc2ccccc21
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CNc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 70 °C

Procedure:
A mixture of (−)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (154 mg, 0.613 mmol, described in Intermediate 3) and 1-(hydroxymethyl)benzotriazole (93 mg, 0.625 mmol) in EtOH (2 mL) and DMF (0.2 mL) was heated at reflux for 4 h, then concentrated to dryness under reduced pressure. The residue was resuspended in THF (3 mL) and sodium borohydride (40 mg, 1.05 mmol) was added. The resulting mixture was heated to 70° C. for 6 h then quenched with H2O (50 mL) and extracted with EtOAc (50 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 80:20, to give the title compound, which was of sufficient purity for use in the next step. MS: m/z=266 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[CH2:7]([O:14][CH2:15][CH:16]1[CH2:21]CC(=O)C[CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]=[C:2]1[CH2:5][CH2:17][CH:16]([CH2:15][O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:21][CH2:3]1
Reactant: O=C1CCC(COCc2ccccc2)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCC(COCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A mixture of methyltriphenylphosphonium bromide (12.27 g) and anhydrous tetrahydrofuran (60.0 mL) was cooled to −78° C. A suspension of potassium t-butoxide (4.37 g) in tetrahydrofuran (60.0 mL) was added dropwise. The mixture was stirred at 0° C. for 1 hour and then for 1 hour as the reaction warmed to ambient temperature. The reaction mixture was cooled to −40° C. and a solution of EXAMPLE 341D (5 g,) in tetrahydrofuran (35 mL) was added dropwise. After stirring 18 hours at ambient temperature, the reaction was quenched by the careful addition of 33% brine (150 mL) and diluted with ether (150 mL). The layers were separated and the aqueous layer was extracted with ether (2×75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel and eluted with a 0, 10, 15, 25% ethyl acetate in hexane step gradient to provide the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:12]=[C:13]([CH:31]=[CH2:32])[C:14]2[O:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C(=O)C)=[C:21]([F:29])[CH:20]=3)=[N:16][C:15]=2[CH:30]=1)(=O)C.O1CCOCC1.Cl>O>[F:29][C:21]1[CH:20]=[C:19]([C:17]2[O:18][C:14]3[C:13]([CH:31]=[CH2:32])=[CH:12][C:11]([OH:10])=[CH:30][C:15]=3[N:16]=2)[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: C=Cc1cc(OC(C)=O)cc2nc(-c3ccc(OC(C)=O)c(F)c3)oc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
Potassium carbonate (55 mg) was added into a solution of 2-[4-(acetyloxy)-3-fluorophenyl]-7-vinyl-1,3-benzoxazol-5-yl acetate (0.14 g, 0.39 mmol) and 1,4-dioxane (3 mL). The mixture was stirred at 90° C. for 1 h, poured into water, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from EtOAc/hexanes, gave a white solid (0.06 g, 46% yield, m.p. 250–252° C.); MS m/e 272 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:12][C:11](=[O:13])[CH:10](O)[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[Br:20]Br>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:12][C:11](=[O:13])[CH:10]([Br:20])[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2Br
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 1.5 %

Procedure:
12.9 g (0.052 mol) of 5,7-di-tert-butyl-3-hydroxybenzofuranone are dissolved in 50 ml of toluene and treated with 2.9 ml (0.052 mol) of bromine at 30° C. The mixture is subsequently stirred at 60° C. for 30 minutes. The solvent is distilled off by means of a rotary evaporator. 1 g of the crude product is purified by flash chromatography over silica gel (Merck Silicagel 60, 70-230 mesh ASTM; mobile phase: 1:1 hexane/dichloromethane) to leave 0.26 g (36% of theory) of 5,7-di-tert-butyl-3-bromobenzofuranone (XLVII).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[CH2:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:19][CH2:20][C:21]#[CH:22]>CCCCCCC.CCOC(C)=O>[C:23]1([CH2:18][CH2:19][CH2:20][C:21]#[C:22][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccnc2)cc1
Reactant: C#CCCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C(#Cc1cccnc1)CCCc1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid pyridin-3-yl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (80 mg, 72%); 1H NMR δ (CDCl3): 8.62-8.63 (m, 1H), 8.48-8.46 (m, 1H), 7.68-7.64 (m, 1H), 7.21-7.17 (m, 6H), 2.76 (t, J=7.11 Hz, 2H), 2.4 (t, J=7.10 Hz, 2H), 1.91 (p, J=7.12 Hz, 2H); LCMS m/z: 221.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][O:19][C:20]4[CH:21]=[C:22]([C:34](=[O:36])[CH3:35])[CH:23]=[CH:24][C:25]=4[O:26]CC4C=CC=CC=4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[ClH:39]>C(O)(=O)C>[ClH:39].[F:1][C:2]1[CH:38]=[CH:37][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][O:19][C:20]4[CH:21]=[C:22]([C:34](=[O:36])[CH3:35])[CH:23]=[CH:24][C:25]=4[OH:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(OC/C=C/CN2CCC(c3noc4cc(F)ccc34)CC2)c1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)c1ccc(O)c(OC/C=C/CN2CCC(c3noc4cc(F)ccc34)CC2)c1
Temperature: 75 °C

Procedure:
The mixture of (E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-benzyloxyphenyl]ethanone (5.5 g, 10.7 mmol), acetic acid (50 ml), and hydrochloric acid (6 ml) was heated at 75° C. for 2 hours. At the end of reaction, the solvent was reduced to about 20 ml on a rotary evaporator. The solution was poured into ice water (350 ml) and extracted with dichloromethane (3×250 ml). The dichloromethane solution was washed with brine and dried over Na2SO4. A solid formed on concentration of the solvent. This was collected by filtration (3.4 g). Recrystallization from hot methanol (40 ml) gave 1.82 g of (E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-hydroxyphenyl]-ethanone hydrochloride as white crystals, 37.5%, m.p.=208°-210° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][O:18][CH2:19][CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:16][CH2:17][O:18][CH2:19][CH3:20])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOc1cccc(Br)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
In DMF (120 ml) was dissolved 3-bromophenol (12 g). To the mixture was added potassium carbonate (12.5 g) and then was added 2-bromoethylethyl ether (9.1 ml), and the mixture was stirred at 70° C. for 16 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-3-(2-ethoxyethoxy)benzene (12.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5]([N:7]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([NH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5]([N:7]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22](=[O:30])[C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:18][CH2:17]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:6])(=[O:36])[CH3:35]
Reactant: Nc1cccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2)c1
Yield: 74.1 %

Procedure:
Using 3-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(phenyl)benzamide (126.4 mg, 0.28 mmol) and acetic anhydride (0.03 ml, 0.32 mmol), the procedure of Inventive Example 94 was repeated to obtain 101.1 mg (73.1%) of the title compound in a colorless powder form.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[C:21]([F:24])([F:23])[F:22]>>[CH:2]([C:3]1[CH:11]=[CH:10][C:8]([O:9][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[C:21]([F:22])([F:24])[F:23])=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Product: COc1cc(C=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F

Procedure:
4-(4-Formyl-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile was prepared from vanillin and 4-fluoro-3-trifluoromethylbenzonitrile following General Procedure A. 1H NMR (400 Hz, CDCl3) δ 10.00 (s, 1H), 8.00 (m, 1H), 7.68 (dd, 1H), 7.58-7.53 (m, 2H), 7.29 (d, 1H), 6.75 (d, 1H), 3.83 (s, 3H); LC/MS (m/z) [M+1]+322.1 (calculated for C16H11F3NO3, 322.06).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([C:17]1[CH:18]=[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=[C:21]([CH2:23][CH2:24][CH3:25])[CH:22]=1)[CH2:15][CH3:16]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:29]2[CH2:30][CH2:31][N:26]([C:19]3[CH:20]=[C:21]([CH2:23][CH2:24][CH3:25])[CH:22]=[C:17]([CH2:14][CH2:15][CH3:16])[CH:18]=3)[CH2:27][CH2:28]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCc1cc(CCC)cc(N2CCNCC2)c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: CCCc1cc(CCC)cc(N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
In the manner given in Example 1A, p-nitrobenzenesulfonyl chloride, 1-(3,5-dipropylphenyl)-piperazine and triethylamine are stirred at reflux to give 1-[(p-nitrophenyl)sulfonyl]-4-(3,5-dipropylphenyl)piperazine.
Reaction SMILES: OO.[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([S:11]([CH2:13][CH3:14])=[O:12])[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:24])[C@:17]([OH:23])([CH3:22])[C:18]([F:21])([F:20])[F:19].CC[O:27]C(C)=O>O.C(O)(=O)C>[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([S:11]([CH2:13][CH3:14])(=[O:27])=[O:12])[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:24])[C@:17]([OH:23])([CH3:22])[C:18]([F:19])([F:20])[F:21]
Reactant: CCOC(C)=O
Reactant: CCS(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Temperature: 95 °C

Procedure:
Hydrogen peroxide (15 ml of a 30 wt. % solution in water) was added to a solution of (R)-N-[4-ethylsulphanyl-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 1) (1.88 g) in glacial acetic acid (26 ml) and the mixture was heated at 95° C. for 1.5 hours then cooled. EtOAc (200 ml) was added and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (4×200 ml) and brine (250 ml) then was dried. Volatile material was removed by evaporation and the residue was purified by chromatography eluting with 0-50% EtOAc/isohexane to give the title compound (1.71 g) as a white solid. NMR: 1.1 (t, 3H), 1.61 (s, 3H), 3.5 (q, 2H), 8.02 (d, 1H), 8.31 (d, 1H); m/z 392.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:11])[CH:3]=1.[Br:12][C:13]1[S:17][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:14]=1.CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][S:18]([C:16]2[S:17][C:13]([Br:12])=[CH:14][CH:15]=2)(=[O:20])=[O:19])=[O:8])=[C:4]([Cl:11])[CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(Br)s1)c1ccc(Br)cc1Cl
Reaction time: 72 h

Procedure:
An 8 mL reaction vial is charged with 4-bromo-2-chlorobenzoic acid (0.39 mmol, 1.5 eq) and 2.0 mL of dichloromethane. A stock solution (4.0 mL) containing 5-bromothiophene-2-sulfonamide (0.26 mmol, 1 eq) and N,N-[dimethyl]-4-aminopyridine (48 mg, 0.39 mmol, 1.5 eq) in dichloromethane is added, followed by 0.261 g carbodiimide polystyrene resin (2.0 mmol/g, 0.52 mmol, 2.0 eq, Novabiochem) and the vial is capped and shaken. After 72 hr, 0.77 g sulphonated polystyrene resin (MP-TsOH) is added (1.53 mmol/g, 1.17 mmol, Argonaut). After about 18 hr the reaction mixture is filtered and concentrated under reduced pressure. Chromatography was applied to the residue and fractions containing product were combined and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=2)[NH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:29](I)[CH3:30]>CN(C)C=O>[CH2:29]([N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=2)[NH:9][CH:8]=1)[CH3:30]
Reactant: CCI
Reactant: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCC[C@@H]1Cc1c[nH]c2ccc(CCS(=O)(=O)CC)cc12
Temperature: 120 °C
Yield: 35.9 %

Procedure:
To a solution of (R)-3-(pyrrolidin-2-ylmethyl)-5-(2-ethylsulphonylethyl)-1H-indole (0.27 g, 0.8 mmol) in dimethylformamide (dried over 4A sieves) (5 mls), was added sodium carbonate (90 mgs) and ethyl iodide (0.07 mls, 0.88 mmol) at room temperature. The mixture was heated at 120° C. under nitrogen for 16 hours. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate and water. The separated organic phase was washed with water (3×), dried (Na2SO4) and evaporated in vacuo to give an oil. Purification by column chromatography on silica gel, eluting with CH2Cl2 :EtOH:NH4OH (90:10:0.5) gave the title compound as a gum (100 mgs). Anal. Calcd for C19H28N2O2S· 1/4CH2Cl2. 1/2H2O: C,61.04; H,7.85; N,7.40. Found: C,60.80; H,7.69; N,7.48⟦alpha⟧sup.25D =+60° (c=0.1, MeOH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:31][C:32]([CH3:34])=O.[BH4-].[Na+]>C(O)(=O)C.O>[CH:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1)([CH3:34])[CH3:31]
Reactant: CC(C)=O
Reactant: CCOC(=O)CCCCCOc1cc(-c2ccc(N)cc2)cc(-c2ccccc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CCCCCOc1cc(-c2ccc(NC(C)C)cc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 6-{[4-(4-aminophenyl)-6-phenyl-2-pyridyl]oxy}hexanoate (3 g) and acetone (0.54 cc) in acetic acid (45 cc), brought to 15° C., is slowly added sodium borohydride (1.14 g) so as to maintain the temperature below 22° C. The mixture is then stirred at room temperature for 4 hours. The reaction mixture is then poured in distilled water (150 cc) and extracted with ethyl ether (2×100 cc). The combined organic phases are washed with distilled water until neutrality, dried over sodium sulphate and concentrated to dryness at 40° C. under reduced pressure. The oily residue obtained is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9-1 as a yellow oil).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]3[CH:15]=[C:16]([C:19]([O:21]CC)=O)[C:17]([OH:18])=[C:11]3[C:10]2=[O:24])=[CH:6][CH:5]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[F:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]3[CH:15]=[C:16]([C:19]([NH:2][CH3:1])=[O:21])[C:17]([OH:18])=[C:11]3[C:10]2=[O:24])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: CN
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2

Procedure:
Anhydrous methylamine gas was bubbled through a mixture of ethyl 2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (3.0 g, 9.0 mmol) and anhydrous aluminum chloride (3.0 g, 22.5 mmol) in anhydrous chloroform (45 mL) at 0° C. for 5 minutes. The resultant mixture was heated in a seal tube at 70° C. overnight and concentrated under vacuum. The residue partitioned between aqueous HCl and chloroform. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound.