Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)C(C(=O)O)c1ccc(O)cc1
Solvent: CC(=O)O
Product: CC(C)C(C(=O)O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of α-isopropyl-4-hydroxyphenylacetic acid (18.2 g, 0.094 mol) in acetic acid (130 ml) is heated to 40° C. and nitric acid (70%, 9.56 g, 0.095 mol) is added at such a rate that the reaction temperature is maintained at 38°-40° and never exceeded 45° C. The reaction mixture is stirred at 40°-42° C. overnight and poured into ice-water. The yellow solid is collected by filtration, washed and dried (19.1 g); m.p. 103°-105°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH2:11][OH:12])[CH:8]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH2:11][OH:12])[CH:8]=1
Reactant: O=[N+]([O-])c1cnn(CCCO)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cnn(CCCO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.6 %

Procedure:
3-(4-Nitro-pyrazol-1-yl)-propan-1-ol (1.41 g, 8.23 mmol) was dissolved in MeOH (15 mL). Pd/C (0.532 g, 0.82 mmol) was added and the mixture was stirred under H2 at rt for 16 hours. The reaction mixture was filtered and the solvent evaporated in vacuo to afford the title compound as a red/brown oil (1.18 g, 100%); LCMS, Rt=0.31 min (MeOH-FA method), m/z 142 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](C(=O)C)=[CH:11][C:10]=1[CH3:20])([CH3:7])[CH3:6])[CH3:2].ClC1C=CC=[C:25]([C:29]([O:31]O)=[O:30])C=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:21])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:31][C:29](=[O:30])[CH3:25])=[CH:11][C:10]=1[CH3:20])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(OC)c(C(C)=O)cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1cc(OC)c(OC(C)=O)cc1C
Temperature: 25 °C
Yield: 44.4 %

Procedure:
A solution of 531 mg (1.8 mmol) 2-(4-acetyl-5-methoxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester, 545 mg (3.2 mmol) 3-chloroperbenzoic acid and 34 mg (0.2 mmol) 4-toluenesulfonic acid in 24 ml dichloromethane was heated under reflux conditions for 72 h. The mixture was cooled to room temperature and washed two times with ice water/sodium iodide solution and two times with ice water/aqueous NaHSO3 solution. The organic layer was dried over sodium sulfate, the solvent was removed under reduced pressure and the resulting brown solid was purified by column chromatography (silica gel, heptane/AcOEt) to give 235 mg (0.8 mmol, 42%) of the title compound as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[C:8]#[N:9].S(=O)(=O)(O)[OH:11]>>[Cl:7][C:4]1[C:3]([C:8]([NH2:9])=[O:11])=[C:2]([Cl:1])[S:6][N:5]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(Cl)nsc1Cl
Product: NC(=O)c1c(Cl)nsc1Cl
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed dichloro-1,2-thiazole-4-carbonitrile (3.7 g, 20.67 mmol, 1.00 equiv), sulfuric acid (15 mL). The resulting solution was stirred for 2 h at 110° C. The solution was used for the next step directly.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([C:8]1[CH:13]=[CH:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[C:10](=[O:26])[CH:9]=1)=O)C>O1CCCC1>[OH:5][CH2:6][C:8]1[CH:13]=[CH:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:22])[F:23])=[CH:16][C:15]=2[Cl:25])[C:10](=[O:26])[CH:9]=1
Reactant: CCOC(=O)c1ccn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(=O)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1cc(CO)ccn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 104.7 %

Procedure:
To lithium borohydride (0.32 g, 14.5 mmol) suspended in tetrahydrofuran (10 ml) was added a solution of 4-ethoxy carbonyl-1-2,6 dichloro-4-trifluoromethylphenyl)-2-pyridone (Compound 1, 10 g, 26 mmol) in tetrahydrofuran (30 ml). The mixture was heated under reflux for two hours, allowed to cool to room temperature and the solvent removed in vacuo. The residue was shaken with water and ethyl acetate, the layers separated, and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with water, then brine, dried over magnesium sulphate and evaporated in vacuo to give 4-hydroxymethyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-2-pyridone as a brown gum (9.2 g) (Compound 13).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Br:12]Br>C(Cl)(Cl)(Cl)Cl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([OH:1])=[C:3]2[C:8]=1[CH:7]=[N:6][CH:5]=[CH:4]2
Reactant: Oc1cccc2cnccc12
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(Br)c2cnccc12

Procedure:
For example, 5-hydroxyisoquinoline 66.7 is reacted with bromine in carbon tetrachloride to afford 8-bromo-5-hydroxyisoquinoline 66.8. The product is reacted with acetic anhydride in pyridine to give 5-acetoxy-8-bromoisoquinoline 66.9. The latter compound is coupled with a dialkyl propenyl phosphonate 66.10 (Aldrich) in the presence of ca. 3 mol % of bis(triphenylphosphine)palladium(II) chloride and triethylamine, in dimethylformamide at ca. 60°, to produce the coupled product 66.11. The acetyl protecting group is then removed by reaction with dilute aqueous methanolic ammonia, as described in J. Chem. Soc., 2137, 1964, to afford the phenol 66.12. The product is optionally reduced to yield the saturated analog 66.13. The reduction reaction is effected chemically, for example by the use of diimide or diborane, as described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 5, or catalytically.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:13]1[C:18](=[O:19])[CH:17]([CH3:20])[C:16](=O)[NH:15][C:14]1=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH2:6]([N:13]1[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([Cl:3])[NH:15][C:14]1=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC1C(=O)NC(=O)N(Cc2ccccc2)C1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: Cc1c(Cl)[nH]c(=O)n(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To 16.8 ml of 50% ethanol, 78.7 ml (844 mmol) of phosphorus oxychloride was added dropwise, with stirring under ice cooling conditions. To this solution, 23.22 g (100 mmol) of 3-benzyl-5-methylpyrimidine-2,4,6(1H,3H)-trione was added little by little. This mixture was stirred at 50° C. for 30 minutes and then at 100° C. for 90 minutes. After cooling, the reaction mixture was poured into ice water and stirred for 1 hour. The resulting precipitate was collected by filtration, washed with water and n-hexane and dried to yield 27.50 g (quant, light white crystal) of the desired product.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>O.[Fe]>[C:1]([O:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCC(=O)c1ccccc1[N+](=O)[O-])c1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1ccccc1C(=O)COC(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
A mixture of 2-(2-nitrophenyl)-2-oxoethyl benzoate (50 g) and ammonium chloride (1 0.75 g) in water (800 ml) was stirred at 90° for 20 minutes. Iron powder (80 g) was added gradually over a period of 20 minutes. The mixture was stirred at 95° for a further 3 hours and filtered hot through diatomaceous earth (sold under the trade name CELITE). The filter bed was washed with hot (80° ) water (100 ml) and then separately with hot (60° ) ethyl acetate (5×300 ml). The aqueous filtrate and aqueous washing were combined and extracted with ethyl acetate (4×400 ml) and the extracts combined with the ethyl acetate washings from above, which had been washed with aqueous sodium chloride (6M, 200 ml). The combined ethyl acetate extracts were dried over sodium sulphate and evaporated to give the novel compound 2-(2-aminophenyl)-2-oxoethyl benzoate, m.p. 125°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2>CC(O)=O.[Pd]>[OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: COC(=O)c1cc(O)cc2ccccc12
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1cc(O)cc2c1CCCC2
Reaction time: 21 h
Yield: 89.1 %

Procedure:
A mixture of methyl 3-hydroxy-1-naphthalenecarboxylate (5.77 g, 28.5 mmol) and 10% Pd/C (1.57 g) in HOAc (140 mL) was hydrogenated on a Parr apparatus at 60° C., and 50 psi for 21 h. After filtration through a pad of diatomaceous earth the solvent was removed in vacuo and the residue treated with water and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water, dried (MgSO4) and concentrated to yield product as a yellow oil (5.24 g, 89%). 1H NMR (CDCl3) δ 7.20 (d, 1H), 6.73 (d, 1H), 3.86 (s, 3H), 2.94 (d, 2H), 2.76 (d, 2H), 1.74 (m, 4H); MS m/z 205 (M−H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:35])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]4)=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:4].C1COCC1>[OH-].[Na+]>[O:34]=[S:30]1(=[O:33])[CH2:31][CH2:32][N:27]([CH2:26][C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:7]4[C:8]([CH3:11])=[CH:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=4)=[CH:17][CH:16]=3)=[O:35])=[CH:21][CH:22]=2)[CH2:28][CH2:29]1
Reactant: COC(=O)c1ccc(C)c(-c2ccc(C(=O)Nc3ccc(CN4CCS(=O)(=O)CC4)cc3)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1

Procedure:
4′-[4-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylcarbamoyl]-6-methyl-biphenyl-3-carboxylic acid methyl ester (1.09 g) was heated to reflux in 1M sodium hydroxide (20 ml) and THF (20 ml) for 3 h. The mixture was then allowed to cool, and the THF evaporated. The aqueous residue was extracted with dichloromethane, and was then acidified. The resultant white solid was collected by filtration and dried (950 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[CH:3]=1.Cl.[NH2:22][OH:23].C(N(CC)CC)C.O>O1CCOCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19](=[N:22][OH:23])[NH2:20])[CH:3]=1
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: NC(=NO)c1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
5-Amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (10.0 g, 31.1 mmol) was dissolved in 150 ml of dry dioxane, and then hydroxylamine hydrochloride (3.35 g, 46.8 mmol) and triethylamine (6.6 ml, 47.4 mmol) were added with stirring at room temperature. The mixture was stirred at room temperature for 74 hours and the reaction solution was poured into 300 ml of iced water. The solution was stirred for 30 minutes and the deposited crystal was filtered. The resulting crystal was washed with water and then dried under reduced pressure to obtain 8.30 g (23.4 mmol) of the title compound as a colorless crystal. The aqueous layer obtained by combining the above filtrate and wash was extracted three times with 150 ml of ethyl acetate. The extracted solution was washed three times with 500 ml of an aqueous saturated sodium chloride solution and the organic layer was dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the resulting crystal was washed with 50 ml of chloroform-hexane (1:1) and then filtered to obtain 1.19 g (3.36 mmol) of the title compound as a pale brown crystal. Yield 86%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[CH2:12][CH2:13][CH2:14][N:15]2[CH:19]=[C:18]([NH:20][C:21]([C:23]3[N:24]=[CH:25][O:26][C:27]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:22])[CH:17]=[N:16]2)=[CH:5][CH:4]=1>CC(C)=O.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH2:12][CH2:13][CH2:14][N:15]2[CH:19]=[C:18]([NH:20][C:21]([C:23]3[N:24]=[CH:25][O:26][C:27]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:22])[CH:17]=[N:16]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)N(CCCn1cc(NC(=O)c3ncoc3-c3cccc(C)c3)cn1)CC2
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: COc1ccc2ccn(CCCn3cc(NC(=O)c4ncoc4-c4cccc(C)c4)cn3)c2c1
Yield: 16.1 %

Procedure:
A solution of N-(1-(3-(6-methoxyindolin-1-yl)propyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (69 mg, 0.15 mmol) in acetone (1.0 mL) was added dropwise to a suspension of MnO2 (50 mg, 0.575 mmol) in acetone (0.5 mL). After stirring the dark reaction mixture for 18 h, the mixture was filtered over celite, rinsed with acetone and the solvent was removed under reduced pressure. Purification by prep. HPLC yielded the title compound (11 mg) as a redish solid. LC-MS conditions D: tR=1.14 min, [M+H]+=456.3.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH2:39][CH2:40][CH2:41]Cl)=[CH:34][CH:33]=1>CN(C=O)C>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:41][CH2:40][CH2:39][CH:38]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=3)[C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
N-Cyclopropyl-N-{1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide (34) was prepared by dissolving N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethylbenzenesulfonamide (110.6 mg, 0.318 mmol) in 10 mL of DMF and followed by the addition of triethylamine (48.3 mg, 0.477 mmol) and bis(4-fluorophenyl)butyl chloride (98.2 mg, 0.350 mmol). The reaction mixture was stirred overnight at 85° C. The crude compound was purified by column chromatography on silica gel (hexane/EtOAc, 7:3) to give the title compound 34 as a yellow sticky solid. 1H NMR (CDCl3): δ 8.12 (s, 1H), 8.04 (d, 1H), 7.84 (d, 1H), 7.61 (t, 1H), 7.13 (dd, 4H), 6.94 t, 4H), 3.84 t, 2H), 2.85 (d, 2H), 2.30 (t, 2H), 1.92 (m, 7H), 1.48 (m, 2H), 1.37 (m, 2H), 0.96 (m, 2H), 0.75 (m, 2H). LC: 100%. MS (M+H+): 593.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:27][CH3:28])[C:11]2[C:12]([CH3:26])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:14]3[O:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]=3[CH:21]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[CH2:27]([N:10]([C:11]1[C:12]([CH3:26])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:14]2[O:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]=2[CH:21]=1)[C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:29])=[O:2])=[CH:9][CH:8]=1)[CH3:28]
Reactant: CCN(c1ccc(C(=O)OC)cc1)c1cc2c(c(C(C)(C)C)c1C)OCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(c1ccc(C(=O)O)cc1)c1cc2c(c(C(C)(C)C)c1C)OCC2(C)C
Yield: 22.6 %

Procedure:
Following general procedure P and using 4-[ethyl-(7-t-butyl-3,3,6-trimethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid methyl ester (Compound 68, 0.11 g, 0.29 mmol) and 2 mL (7.5) of 5M sodium hydroxide in 5 mL of methanol, the title compound (0.025 g, 23%) was obtained as a pale yellow solid, after flash column chromatography using 25% ethyl acetate in hexanes as the eluent followed by recrystallization from hexanes. 1H NMR (300 MHz, CDCl3): δ 7.88 (d, 2H, J=9.0 Hz), 6.70 (s, 1H), 6.43 (d, 2H, J=9.0 Hz), 4.17 (s, 2H), 3.88-3.76 (m, 1H), 3.45-3.30 (m, 1H), 2.20 (s, 3H), 1.52 (s, 9H), 1.28-1.24 (m, 9H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[N:5]1([C:10]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[S:13](=[O:21])(=[O:20])[CH2:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[CH:29]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[C:31]([OH:38])[CH:30]=1>C1C=CC=CC=1.O1CCCC1>[N:5]1([C:10]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[S:13](=[O:21])(=[O:20])[CH2:12][C:11]=2[C:1]([O:38][C:31]2[CH:32]=[CH:33][C:34]([N+:35]([O-:37])=[O:36])=[CH:29][CH:30]=2)=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=S1(=O)CC=C(N2CCCC2)c2ccccc21
Reactant: O=C(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)C1=C(N2CCCC2)c2ccccc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
A solution of 6.0 g (0.06 mol) of phosgene in 55 ml of benzene was diluted with 30 ml of tetrahydrofuran and cooled to -10°. To this was added over a period of 30 min, a solution of 12.6 g (0.05 mol) of 4-(1-pyrrolidinyl)-2H-1-benzothiopyran 1,1-dioxide and 10 ml of triethylamine in 400 ml of tetrahydrofuran and the reaction mixture was stirred at room temperature for 3 hr. It was cooled to -40° and a solution of 7.7 g (0.055 mol) of p-nitrophenol and 12 ml of triethylamine in 50 ml of tetrahydrofuran was added. The mixture was stirred at room temperature for 16 hr, refluxed for 3 hr, and most of the solvent was evaporated. It was treated with ice-water and extracted ith dichloromethane. The dried dichloromethane phase was evaporated to an oily residue which became a gummy semisolid on trituration with several portions of ether. This gum was dissolved in dichloromethane. Slow distillation resulted in the crystallization of 13.0 g of product, mp 171°-174° dec. Recrystallization from a mixture of 250 ml of tetrahydrofuran and 250 ml of isopropyl ether gave 10.7 g of material, mp 175°-178° dec.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[NH:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C1COCC1.[Pd]>[F:1][C:2]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:3]=1[NH:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=[N+]([O-])c1ccc(NCCN2CCCCC2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(NCCN2CCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 2-fluoro-4-nitro-N-(2-(piperidin-1-yl)ethyl)aniline (1.87 g, 7.00 mmol) in THF (20 mL) was added catalyst Pd/C (0.50 g). The reaction mixture was stirred at rt under H2 overnight. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=15:1) to give the title compound as yellow oil (1.50 g, 90%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:16]1([CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH2:24]I)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:15])[CH2:10][CH2:11][N:12]([CH2:24][CH2:23][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: FC1(c2ccc(Cl)cc2)CCNCC1
Reactant: ICCC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC1(c2ccc(Cl)cc2)CCN(CCC(c2ccccc2)c2ccccc2)CC1
Temperature: 80 °C

Procedure:
A solution of 4-(4-chlorophenyl)-4-fluoropiperidine hydrochloride (100 mg, 0.40 mmol) and 3,3-diphenyl-1-iodopropane (145 mg, 0.45 mmol) in DMF (2.5 mL) was treated with potassium carbonate (560 mg, 4.05 mmol) and the resulting suspension heated at 80° C. for 14 hours. After this time the reaction was cooled to room temperature and quenched by pouring into 25% aqueous ammonium chloride solution (20 mL). The resulting suspension was then extracted with ethyl acetate (2×10 mL) and the combined extracts washed with water (10 mL) and brine (10 mL) then dried over magnesium sulfate. Subsequent filtration and concentration under reduced pressure afforded crude 4-(4-chlorophenyl)-1-(3,3-diphenyl-propyl)-4-fluoropiperidine as a yellow oil. This material was treated with 10% methanolic hydrogen chloride (10 mL) and the solution concentrated under reduced pressure. Trituration of the resulting oil with 1:1 ethyl acetate/2-butanone (10 mL) afforded a solid which was isolated by filtration and vacuum dried. This afforded a 41% yield of 4-(4-chlorophenyl)-1-(3,3-diphenylpropyl)-4-fluoropiperidine hydrochloride as an off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH2:30][CH3:31].[OH-].[Na+].Cl>C(O)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:14][CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])=[C:7]([CH2:30][CH3:31])[CH:8]=2)=[CH:28][CH:27]=1
Reactant: CCc1cc(SCC=C(c2ccc(F)cc2)c2ccc(F)cc2)ccc1OCC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(SCC=C(c2ccc(F)cc2)c2ccc(F)cc2)ccc1OCC(=O)O
Temperature: 5 °C
Reaction time: 18 h

Procedure:
{4-[3,3-Bis-(4-fluoro-phenyl)-allylsulfanyl]-2-ethyl-phenoxy}-acetic acid methyl ester (100 mg, 0.22 mmol, example 15) was dissolved in ethanol (10 ml). 1N NaOH (3 ml, 3 mmol) was added at room temperature and the reaction mixture was stirred for 18 h at 5° C. after which it was treated with 1 N HCl (15 ml) and extracted with dichloromethane (2×20 ml). The combined organic phases were dried and evaporated to give the title compound in 10 mg yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].O=[C:12]([CH2:17][CH3:18])[C:13]([O:15][CH3:16])=[O:14]>C(O)C>[CH3:16][O:15][C:13](=[O:14])/[C:12](=[N:10]\[NH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Br:1])/[CH2:17][CH3:18]
Reactant: CCC(=O)C(=O)OC
Reactant: NNc1ccc(Cl)cc1Br
Solvent: CCO
Product: CC/C(=N/Nc1ccc(Cl)cc1Br)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
A stirred solution of (2-bromo-4-chloro-phenyl)-hydrazine (step A) (1.98 g, 8.94 mmol) in ethanol (6.5 ml) was cooled to 0° C. and a solution of commercially available methyl 2-ketobutyrate (1.08 g, 1.04 ml, 9.3 mmol) in ethanol (2 ml) was added drop wise at 0° C. for 15 min. After the mixture was allowed to stir at room temperature for 3 h it was evaporated. The crude material (3.01 g) was purified by flash chromatography on silica gel (heptane/ethyl acetate 0-20%) to yield (Z)-2-[(2-bromo-4-chloro-phenyl)-hydrazono]-butyric acid methyl ester (2.67 g, 94%) as a light yellow solid, MS (ISP) m/z=321.3 [(M+H)+], mp 67° C.