Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Cl[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10].[Cl:11][C:12]1[C:13]([F:33])=[C:14]([CH:30]=[CH:31][CH:32]=1)[C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]>C1COCC1>[Cl:11][C:12]1[C:13]([F:33])=[C:14]([C@:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:18]2)([OH:16])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH:30]=[CH:31][CH:32]=1
Reactant: COCCCCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2F)C1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
A flame dried 250 mL three-necked flask was charged with magnesium turnings (7.02 g, 0.293 mol), a small crystal of iodine and THF (30 mL). The flask was evacuated and refilled with N2. A solution of 1-chloro-4-methoxybutane (28.69 g, 0.234 mol) in THF (120 mL) was added dropwise slowly to the mixture. The reaction mixture was stirred under reflux for 2.5 h and most of magnesium was consumed. The resulting Grignard reagent was used as follows To another 100 mL three-necked flask was added (R)-tert-butyl 3-(3-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (10 g, 0.0293 mol) and THF (100 mL). The flask was evacuated and refilled with N2. The mixture was cooled with dry ice-acetone bath and the Grignard reagent (250 mL) was added. The reaction mixture was allowed to warm slowly to rt while stirring overnight. The mixture was quenched with satd aq NH4Cl (50 mL), extracted with EtOAc (3×), and the combined organic layers were dried over Na2SO4. Evaporation of the solvent gave the crude product. The LC-MS analysis of the crude product indicated the presence of two isomers (95:5). Flash column chromatography, eluting with 10% EtOAc/PE afforded (R)-tert-butyl 3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (9.4 g, 75% yield). 1H NMR (400 MHz, DMSO): 0.68 (m, 1H), 1.50-1.01 (m, 7H), 1.37 (s, 9H), 1.75 (m, 2H), 2.01 (m, 1H), 3.11 (s, 3H), 3.17 (m, 2H), 3.85 (m, 1H), 7.2 (t, 1H), 7.45 (m, 2H). MS (E/Z): 430 (M+H+).
Reaction SMILES: [C:1]1([N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]([O-])=[O:15].[Na+]>Cl.O>[N:14]([C:4]1[CH:5]=[CH:6][C:1]([N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10])=[CH:2][CH:3]=1)=[O:15]
Reactant: O=N[O-]
Reactant: OCCN(CCO)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=Nc1ccc(N(CCO)CCO)cc1
Temperature: 0 °C

Procedure:
23.9 g of N-phenyldiethanol amine were ground in a mortar and dissolved in 50 ml conc. HCl. The solution was then cooled to 0°C and 10 g NaNO2 in 25 ml of water were added over a period of one hour with stirring. The temperature was maintained between 0°-5°C. After the addition was complete, the mixture was stirred one hour more and then filtered. The orange precipitate of 4-nitroso-N,N-bis-(β-hydroxyethyl) aniline formed was dried in a vacuum desiccator overnight. The dried product, amounting to 25.0 g was suspended in 150 ml. isopropanol and reduced on a Parr hydrogenator over Pt/C. When the loss in pressure approached theoretical, the mixture was filtered into a flask containing 200 ml. isopropanol saturated with HCl gas. A stream of HCl gas was passed through the filtrate during the filtration and for about 20 minutes after the filtration was complete. The white precipitate of N,N-bis-(β-hydroxyethyl)-p-phenylenediamine hydrochloride was collected and weighed. Yield 19.8 g.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9](NC1C=CC=CC=1)=[O:10].[Na].Cl>CO>[CH3:1][N:2]([CH:9]=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: O=CNc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CN(C=O)c1ccccc1
Temperature: 100 °C

Procedure:
To the reactor described in Example 1 is charged 107 grams (1.0 mole) of N-methyl aniline, 14 grams (0.1 mole) of sodium formanilide and 150 milliliters of methanol. The autoclave is closed, purged with carbon monoxide and the temperature raised to 100° C. with atmospheric steam. Carbon monoxide is then introduced at 28 kg/cm2 pressure for about 30 minutes. The basic reaction mixture is neutralized with hydrochloric acid and extracted with xylene. Gas liquid chromatographic analysis shows that a high conversion to N-methyl formanilide is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10](OC)=O)=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:20][NH:21][C:22]([NH2:24])=[NH:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[N:23]=[C:22]([NH2:24])[NH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCCOc1ccc(Cl)cc1
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: c1ccncc1
Product: Nc1nc(CCCOc2ccc(Cl)cc2)n[nH]1
Temperature: 125 °C
Yield: 72.3 %

Procedure:
A mixture of methyl 4-(4-chlorophenoxy)butanoate (1.4 g, 6.13 mmol), aminoguanidine bicarbonate (2.08 g, 15.3 mmol), and pyridine (12 mL) was added to a 100 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser, and heated to 125° C. using an oil bath. Progress of the reaction was monitored by analytical HPLC with UV detection at 215 nm. The mixture was heated for 20 hours, and an additional portion of aminoguanidine bicarbonate (0.60 g, 4.4 mmol) was added. After an additional 22 hours of heating, the reaction was complete. The reaction allowed to cool to ambient temperature, concentrated under reduced pressure and partitioned between ethyl acetate (50 mL) and water (20 mL). The aqueous layer was extracted once more with ethyl acetate (30 mL). The combined organic layers were washed with saturated aqueous NaCl (2×15 mL), dried (Na2SO4), filtered and concentrated. Dichloromethane (5 mL) was added and a precipitate that formed was isolated by filtration, rinsed with dichloromethane (5 mL), and then dried under reduced pressure to afford the title compound as a white powder (1.12 g, 72% yield).
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1>O>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[NH:18][C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: Cc1cccc(N)c1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Solvent: O
Product: Cc1cccc(Nc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)c1

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g), m-toluidine (32.2 g), and water (500 ml) was refluxed for 3 hours. After cooling and acidification with 2N hydrochloric acid, the precipitated 3-nitro-5-sulphamyl-4-(m-toluidino)-benzoic acid was collected by suction, washed with water, and recrystallized from isopropanol. After drying at 115°C in vacuo, the melting point was 256°-259°C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:20])=[C:4]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH2:17]Br)[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+]>C1COCC1.O>[Br:1][C:2]1[C:3]([CH3:20])=[C:4]([N:8]2[CH2:17][C:11]3[C:10](=[CH:15][C:14]([F:16])=[CH:13][CH:12]=3)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1NC(=O)c1cc(F)ccc1CBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1N1Cc2ccc(F)cc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
Step 3 A mixture of N-(3-bromo-2-methylphenyl)-2-(bromomethyl)-5-fluorobenzamide (2.54 g, 6.33 mmol) and sodium tert-butoxide (0.913 g, 9.50 mmol) in THF (80 mL) was stirred at rt for 30 min. The mixture was diluted with water and extracted with twice with DCM. The combined organic phases were washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)-6-fluoroisoindolin-1-one as a white solid (1.18 g, 58%). 1H NMR (400 MHz, chloroform-d) δ 7.59-7.65 (2 H, m), 7.45-7.50 (1 H, m), 7.33 (1 H, td, J=8.6, 2.5 Hz), 7.19-7.24 (1 H, m), 7.15 (1 H, t, J=7.9 Hz), 4.68 (2 H, s), 2.31 (3 H, s). Mass spectrum m/z 320, 322 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=2[O:23][CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH3:42])=[C:35]([O:43][CH3:44])[CH:34]=2)[CH:28]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=2[O:23][CH3:24])[CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]3[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH3:42])=[C:35]([O:43][CH3:44])[CH:34]=3)[CH:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN(c3cccc(OC)c3OC)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(2,3-dimethoxyphenyl)amino]piperidine (673 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:12]=[C:11]([NH2:13])[CH:10]=[CH:9][CH:8]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25]([NH:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:6][O:5][CH2:4][CH2:3][C:2]([F:1])([F:14])[F:15])[N:12]=1)(=[O:27])=[O:26]
Reactant: Nc1cccc(COCCC(F)(F)F)n1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1cccc(COCCC(F)(F)F)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(3,3,3-Trifluoro-propoxymethyl)-pyridin-2-ylamine (0.075 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.097 g) as a light yellow gum (0.08 g). MS (ESI−): 441.1 ([M−H]−).
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[C:10]([O:23]C)=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[N:16]=3)[CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CN1C(=O)CCC1>[CH3:22][NH:21][C:17]1[N:16]=[C:15]([C:13]2[CH:14]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:25]=[CH:26][C:2]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:3][CH:4]=3)[C:10](=[O:23])[NH:11][CH:12]=2)[CH:20]=[CH:19][N:18]=1
Reactant: CNc1nccc(-c2cnc(OC)c(NC(=O)c3ccc(Br)cc3)c2)n1
Reactant: C1CCNCC1
Solvent: CN1CCCC1=O
Product: CNc1nccc(-c2c[nH]c(=O)c(NC(=O)c3ccc(N4CCCCC4)cc3)c2)n1
Temperature: 160 °C
Yield: 45 %

Procedure:
4-Bromo-N-(2-methoxy-5-(2-(methylamino)pyrimidin-4-yl)pyridin-3-yl)benzamide (50 mg, 0.121 mmol) was placed in a microwave tube equipped with a stirrer bar. NMP (1.5 mL) was added, followed by piperidine (1.5 mL). The reaction vessel was heated at 160° C. for 2 hours in a microwave. After cooling, the solvent and excess piperidine were removed in vacuo. The crude compound was recrystallized from methanol to give the title compound as a white solid (22 mg, 45% yield). MS (ES+) m/e=405. 1H NMR (DMSO-d6) δH 1.54-1.61 (6H, m), 2.85 (3H, br s), 3.28-3.36 (4H, m), 6.95-7.12 (4H, m), 7.77 (2H, d), 8.00 (1H, s), 8.27 (1H, d), 9.02 (1H, br s), 9.09 (1H, s), 12.53 (1H, br s).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:20](OCC)=[O:21])=[CH:14][CH:13]=1.Cl>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][OH:21])=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(C(c1ccc(F)cc1)c1ccc(F)cc1)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)C(CO)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -10 °C
Reaction time: 18 h
Yield: 73.6 %

Procedure:
Diisobutylaluminum hydride (20 mL of 1M solution, 20 mmol) was added to a solution of ethyl 3,3-bis(4-fluorophenyl)-2-(1,1dimethylethyl)propionate (2.0 g, 5.8 mmol) in 20 mL of methylene chloride at -70° C. The solution was stirred at -70° C. for 4 hours and at -10° C. for 18 hours. The solution was hydrolyzed by addition of 2N hydrochloric acid. The aqueous layer was separated and extracted with methylene chloride. The combined organic portions were dried with magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 1.3 g of the title compound; m.p. =106°-108° C.
Reaction SMILES: C(OC(=O)C)C.[ClH:7].[CH3:8][O:9][C:10]([C:12]1[N:13]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([O:46]C(C)(C)C)=[O:45])=[CH:40][CH:39]=2)[C:14](=[O:36])[C:15]2[C:20]([C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][C:18]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:17][CH:16]=2)=[O:11]>>[ClH:7].[CH3:8][O:9][C:10]([C:12]1[N:13]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([C:44]([OH:46])=[O:45])=[CH:42][CH:43]=2)[C:14](=[O:36])[C:15]2[C:20]([C:21]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:19][C:18]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:17][CH:16]=2)=[O:11]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(NCc3ccccc3)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2ccccc2)c2cc(NCc3ccccc3)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 4N-hydrochloric acid ethyl acetate solution (6 ml) was added 6-benzylamino-2-(4-tert-butoxycarbonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), and the mixture was stirred at room temperature for 6 hrs. Crystals were collected by filtration to give the title compound (260 mg).
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]([C@@H:19]([OH:37])[CH2:20][NH:21][C:22]([CH3:36])([CH3:35])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)[C:9]2[S:13][C:12]([O:14]C(C)C)=[N:11][C:10]=2[CH:18]=1)(C)(C)C.Cl.[OH-].[Na+]>C(O)(C)C.O>[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:22]([NH:21][CH2:20][C@@H:19]([C:8]2[C:9]3[S:13][C:12](=[O:14])[NH:11][C:10]=3[CH:18]=[C:6]([OH:5])[CH:7]=2)[OH:37])([CH3:35])[CH3:36])=[CH:25][CH:26]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOc1ccc(CC(C)(C)NC[C@H](O)c2cc(OC(C)(C)C)cc3nc(OC(C)C)sc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCOc1ccc(CC(C)(C)NC[C@H](O)c2cc(O)cc3[nH]c(=O)sc23)cc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To (R)-1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)ethanol (7.5 g) in isopropanol (30 ml) and water (25 ml) was added 1M HCl aqueous solution (43 ml). The reaction mixture was then heated to 60° C. and stirred for 2.5 h. The mixture was cooled to 50° C., and then 2M NaOH aqueous solution (18 ml) was added slowly to adjust pH between 8.2-8.4. The reaction mixture was then cooled to 30° C., followed by extraction with TBME (first time with 40 ml, the second time with 25 ml). Two organic layers were combined and washed with water (38 ml for two times) before drying with anhydrous Na2SO4. After filtration, the filtrate was concentrated, and then dissolved in MeCN (145 ml). The solution was treated with active carbon (0.6 g) and heated to 60° C. After a second filtration, the cake was washed with MeCN (10 ml for two times), the filtrate was crystallized at 60° C. to gain (R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one (3.8 g). e.e.=97.6%.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[C:5]([CH3:10])[N:4]=1.[Cl:11][C:12]1[C:13]([O:35][CH3:36])=[CH:14][C:15]([O:33][CH3:34])=[C:16]([CH2:18][CH2:19][C:20]2([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[O:25][C:24](=[O:26])[CH2:23][C:22](=[O:27])[CH2:21]2)[CH:17]=1>>[Cl:11][C:12]1[C:13]([O:35][CH3:36])=[CH:14][C:15]([O:33][CH3:34])=[C:16]([CH2:18][CH2:19][C:20]2([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[O:25][C:24](=[O:26])[C:23]([CH2:2][C:3]3[NH:8][C:7](=[O:9])[CH:6]=[C:5]([CH3:10])[N:4]=3)=[C:22]([OH:27])[CH2:21]2)[CH:17]=1
Reactant: Cc1cc(=O)[nH]c(CCl)n1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc(C)cc(=O)[nH]3)C(=O)O2)cc1Cl
Yield: 19 %

Procedure:
The title compound was prepared as described in Example B(53), using 2-(chloromethyl)-6-methylpyrimidin-4(3H)-one (Example B(54), Step 1) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 19%. 1H NMR (300 MHz, DMSO-d6) δ 1.25-1.75 (m, 8H), 1.87 (s, m overlap, 4H), 2.05 (m, 1H), 2.36 (m, 1H), 2.43-2.50 (m, 2H, overlap with DMSO-d5), 2.56 (d, J=17.5 Hz, 1H), 2.67 (d, J=17.5 Hz, 1H), 3.48 (m, 2H, overlap with H2O), 3.77 (s, 3H), 3.84 (s, 3H), 5.98 (s, 1H), 6.71 (s, 1H), 7.09 (s, 1H). LC-MS (APCI) calcd for C26H31ClN2O6: 502.19; found (M+H+) 503.0 m/z.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)([CH3:6])[CH3:5].C(O)(=O)C.S(=O)(=O)(O)O>O>[CH3:6][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=1)([CH3:5])[C:3]([OH:17])=[O:2]
Reactant: COC(=O)C(C)(C)c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C(=O)O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.5 %

Procedure:
α,α-Dimethyl-(3-trifluoromethylphenyl)acetic acid methyl ester (24.6 g, 0.1 mol), acetic acid (150 ml), water (75ml) and sulfuric acid (36 g, 0.36 mol) are combined. The reaction is refluxed for 3 hours and stirred at room temperature for 3 days. The reaction is concentrated to half its original volume and added to ethyl acetate and washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 16.6 g α,α-dimethyl-(3-trifluoromethylphenyl)acetic acid as a white solid. 1H NMR CDCl3 1.63 (6H,s) 7.45-7.65 (4H, m)
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:27][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)[CH2:12][C:11](=O)[C:10]=2[CH:29]=1)(=[O:4])=[O:3].Cl.[NH2:31][OH:32].N1CCCCC1>>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:27][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)[CH2:12][C:11](=[N:31][OH:32])[C:10]=2[CH:29]=1)(=[O:4])=[O:3]
Reactant: NO
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)CC1)O2
Agent: Cl
Solvent: C1CCNCC1
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=NO)CC1(CCN(CCc3ccccc3)CC1)O2

Procedure:
In the manner of Example 427, 3,4-dihydro-6-methane-sulfonamido-1'-(2-phenylethyl)-spiro [(2H)-benzopyran-2,4'-piperidine]-4-one was treated with hydroxylamine hydrochloride to give, after chromatography, the piperidine as a solid, m.p. 95°-99° C.
Reaction SMILES: [Na].C[O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][N:7]=1)=[O:5].Br[CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[C:15]([O:17]C)=[O:16]>CO>[C:15]([CH:14]([S:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([OH:3])=[O:5])=[N:7][CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=1)([OH:17])=[O:16]
Reactant: COC(=O)C(Br)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(S)cn1
Agent: [Na]
Solvent: CO
Product: O=C(O)c1ccc(SC(C(=O)O)c2cccc(C(F)(F)F)c2)cn1
Reaction time: 8 h

Procedure:
To the solution prepared from 80 ml of methanol and 0.89 g of sodium, 6.53 g of 5-mercaptopyridine-2-carboxylic acid methyl ester are added, followed by the solution of 12.6 g of methyl α-bromo-m-trifluoromethylphenylacetate in 50 ml of methanol while stirring under nitrogen. The mixture is warmed for 1/2 hour on the steam bath and allowed to stand at room temperature overnight. It is evaporated, the residue taken up in water-diethyl ether, the organic phase washed with water, dried and evaporated. The residue is dissolved in the minimum amount of methanol-isopropanol (1:1), the solution mixed with 85 ml of N aqueous sodium hydroxide, warmed for 1/2 hour on the steam bath, and stored at room temperature overnight. The mixture is evaporated, the residue taken up in 2 N hydrochloric acid and the mixture extracted with diethyl ether-ethyl acetate (1:1). The extract is washed with water, dried and evaporated and the residue recrystalized from diethyl ether-ethyl acetate, to yield the 5-(α-carboxy-m-trifluoromethylbenzylmercapto)-pyridine-2-carboxylic acid melting at 190°-195°.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:29]3[CH:34]=[CH:33][C:32]([S:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]#[C:43][Si](C)(C)C)=[CH:38][CH:37]=4)=[CH:31][CH:30]=3)([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([S:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([C:29]3[CH:34]=[CH:33][C:32]([S:35][C:36]4[CH:37]=[CH:38][C:39]([C:42]#[CH:43])=[CH:40][CH:41]=4)=[CH:31][CH:30]=3)([C:21]([F:24])([F:23])[F:22])[C:25]([F:28])([F:26])[F:27])=[CH:18][CH:19]=2)=[CH:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(Sc2ccc(C(c3ccc(Sc4ccc(C#C[Si](C)(C)C)cc4)cc3)(C(F)(F)F)C(F)(F)F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#Cc1ccc(Sc2ccc(C(c3ccc(Sc4ccc(C#C)cc4)cc3)(C(F)(F)F)C(F)(F)F)cc2)cc1

Procedure:
The final desired product 2,2-bis[4-(4-ethynylphenylthio)phenyl]hexafluoropropane (Compound 11) was prepared by treating Compound 10 with anhydrous methanoltetrahydrofuran and anhydrous potassium carbonate according to the general procedure described in Example 1, Section E herein.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(#N)C>[Br:18][C:3]1[CH:4]=[CH:5][C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:7][C:2]=1[F:1]
Reactant: COc1ccc(CNc2cccc(F)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(CNc2ccc(Br)c(F)n2)cc1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To (6-fluoro-pyridin-2-yl)-(4-methoxy-benzyl)-amine (61, 151 g, 650 mmol) in 4 L of acetonitrile under an atmosphere of nitrogen, N-bromosuccinimide (116 g, 650 mmol) was added in portions. After reacting for 2 hours, the solvent was removed under vacuum and the residue taken up in ethyl acetate, then poured into aqueous sodium thiosulfate. The organic layer was washed with warm water, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was crystallized from heptane to provide the desired compound (62, 172 g, 553 mmol, 85% yield).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:15]=[N:16][C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=2[C:23]=1[CH3:24].C[Si]([N:29]=[C:30]=[S:31])(C)C>C1C=CC=CC=1>[CH3:13][C:14]1[CH:15]=[N:16][C:17]2[CH:18]([C:30](=[S:31])[NH2:29])[CH2:19][CH2:20][CH2:21][C:22]=2[C:23]=1[CH3:24]
Reactant: Cc1cnc2c(c1C)CCCC2
Reactant: C[Si](C)(C)N=C=S
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: CC(C)NC(C)C
Product: Cc1cnc2c(c1C)CCCC2C(N)=S
Yield: 5.3 %

Procedure:
By the method described in Example 11 using di-isopropylamine (4.9 ml 0.034 mol) in benzene (50 ml), n-butyl lithium solution (9% w/v, 25 ml, 0.034 mol), 3,4-dimethyl-5,6,7,8-tetrahydroquinoline (5.65g, 0.034 mol) and trimethylsilyl isothiocyanate (4.9 ml, 0.038 mol) was obtained 3,4-dimethyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (0.4 g, 5%) m.p. 163-5° C.