Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][CH3:27].O>C(#N)C>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH3:27])[CH2:14][CH2:13]1
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution of 4-[2-fluoro-3-(methylsulfonyl)phenyl]piperidine (0.4 g, 1.55 mmol) in acetonitrile (40 ml) was added potassium carbonate (0.3 g, 2.17 mmol) and 1-iodopropane (0.151 ml, 1.55 mmol) and the mixture was heated at reflux for 15 h. The mixture was cooled to ambient temperature and water (50 ml) was added. The aqueous residue was extracted with ethylacetate (3×50 ml) and the combined organic phases was dried, concentrated, and purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (0.37 g, 79%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 255-257° C. MS m/z (relative intensity, 70 eV) 299 (M+, 2), 271 (16), 270 (bp), 147 (9) 133 (10).
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:3]=1[C:4]#[N:5].[CH3:14][NH2:15]>C(OCC)(=O)C>[Cl:13][C:6]1[C:3]([C:4]#[N:5])=[C:2]([NH:15][CH3:14])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: CN
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: CCOC(C)=O
Product: CNc1c([N+](=O)[O-])ccc(Cl)c1C#N
Temperature: 5 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a 1 L two-neck round bottom flask was added 2,6-dichloro-3-nitrobenzonitrile (11.1 g, 51.1 mmol) followed by ethyl acetate (102 mL). The flask was equipped with an internal thermometer and magnetic stir bar and cooled to 5° C. by immersion into an ice bath. Methylamine was added dropwise to the cooled reaction mixture as a 40% aqueous solution (8.9 mL, 115 mmol) with vigorous stirring. The reaction mixture was stirred for an additional 3 hours with cooling, after which more methylamine (1.8 mL, 23 mmol) was added. The reaction vessel was removed from the ice bath and stirred for an additional 1.5 hours. To the reaction mixture was added water (30 mL) followed immediately by hexane (45 mL) and the resulting slurry was stirred for 15 minutes. The solid was recovered by filtration and washed with water followed by methanol to provide 6-chloro-2-methylamino-3-nitro-benzonitrile (10.49 g, 96%) as a bright yellow solid, which was used directly without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.55-8.53 (m, 1H), 8.28 (d, 1H, J=9.0 Hz), 6.95 (d, 1H), J=9.0 Hz), 3.30 (d, 1H, J=5.5 Hz).
Reaction SMILES: [C:1]1(/[CH:7]=[C:8](\[C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])/[CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO.[OH-].[Na+]>[C:1]1(/[CH:7]=[C:8](\[C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])/[CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCCCCC#C/C(C=O)=C\c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCCCCC#C/C(=C\c1ccccc1)CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of Compound 2 (502 mg, 2.13 mmol) in methanol (20 mL) was added a solution of NaBH4 (80.4 mg, 2.13 mmol) in aqueous NaOH (0.5 N, 5 mL) followed by stirring at room temperature for 30 minutes. The reaction was then quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 20 percent EtOAc in hexane) to give 462.3 mg (91.4 percent) of Compound 3: yellow oil; Rf=0.19 (17 percent EtOAc in hexane); IR (neat) 3400 (br), 3296, 2942, 2862, 2210, 2116, 1072 cm−1; 1H NMR (300 MHz, CDCl3) δ7.84-7.81 (m, 2H), 7.37-7.26 (m, 3H), 6.71 (s, 1H), 4.25 (s, 2H), 2.49 (t, J=6.65 Hz, 2H), 2.24 (td, J=6.78, 2.37 Hz, 2H), 2.17 (br s, 1H), 1.98 (t, J=2.64 Hz, 1H), 1.79-1.60 (m, 4H); 13C NMR (75 MHz, CDCl3) δ136.7, 133.3, 129.1, 128.8, 128.7, 122.5, 98.8, 84.7, 79.3, 69.3, 68.1, 28.2, 28.1, 20.0, 18.6; MS (+CI) m/z (relative intensity) 239 (M+H+, 15), 221 (100); HRMS (+EI) calcd for C17H18O 238.1358 (M+), found 238.1316.
Reaction SMILES: [C:1]1([PH:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH3:20][C:21]([CH3:23])=[O:22]>>[C:1]1([P:7]([C:21]([OH:22])([CH3:23])[CH3:20])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[PH](c1ccccc1)c1ccccc1
Reactant: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)P(=O)(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
To a one liter four-inlet flask equipped with a temperature controller, a reflux condenser, a nitrogen feed and a mechanical stirrer, 1 mole (202 g) diphenyl phosphine oxide (DPPO) and 500 ml THF were added. The mixture was heated to 70° C. and then stirred. The stirring was continued until DPPO was dissolved completely. To this solution was added slowly 1.0 mole (58 g) acetone within two hours, and the temperature thereof was maintained at 70° C. for six hours after the addition of acetone was completed. The mixture was then cooled to room temperature to obtain solid, which was then filtered, and purified with THF to yield 2-(diphenyl phosphoryl) propan-2-ol [DPPP]. Yield, 96%; m.p. 96–98° C. Anal. Calcd. for C15H17PO2: C, 69.23; H, 6.53; O, 12.31; P, 11.93. Found: C, 69.11; H, 6.63; O, 12.18; P, 12.08. EIMS, m/z: 260 (96. M+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([OH:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[H-].[Na+].[CH3:26]I>C1COCC1>[CH3:26][O:21][C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:2]([F:1])([F:22])[F:23])=[N:4][N:5]=3)[CH:8]=2)=[CH:13][CH:14]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(O)c1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)c1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 10-mL cone-shaped flask equipped with a magnetic stir bar 2-(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)propan-2-ol (28 mg) was dissolved in dry THF (1 mL) and NaH (60% suspension in mineral oil, 20 eq.) and MeI (50 eq.) were added. The reaction mixture was stirred overnight at room temperature. Extracted with water and EtOAc, organic layer dried over MgSO4, concentrated, and purified by chromatography (3% MeOH in methylene chloride). The desired 6-(4-(2-methoxypropan-2-yl)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine was isolated.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=1.[Br:12]N1C(=O)CCC1=O>C(#N)C>[Br:12][C:8]1[CH:9]=[C:4]([O:3][CH:2]([F:1])[F:11])[C:5]([NH2:10])=[N:6][CH:7]=1
Reactant: Nc1ncccc1OC(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(Br)cc1OC(F)F
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
To a solution of 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 14.36 mmol) in acetonitrile (15 mL) was added N-bromosuccinimide (2.61 g, 14.65 mmol) over 3 min at 0° C. The reaction mixture was stirred at the same temperature for another 20 min and subsequently concentrated to dryness in vacuo. The resulting viscous mass was diluted with water and extracted with ethyl acetate (3×60 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 20% ethyl acetate in hexane) affording 5-bromo-3-(difluoromethoxy)pyridin-2-amine (3.2 g, 93%): 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.51 (s, 1H), 7.16 (t, J=73.6 Hz, 1H), 6.34 (s, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
Example 18 was prepared in accordance to a procedure described in Collins, et. al., Tetrahedron, 48, No. 37, pp 7887-7898, 1992. To a solution of 1-Fluoro-2-nitro-4-trifluoromethyl-benzene (1.0 g, 4.78 mmol) in dry THF (24 mL) was added 1-Methyl-piperazine (0.64 mL, 5.74 mmol). The solution turned bright yellow. NaHCO3 (1.1 g, 13 mmol) was added and the reaction was stirred at room temperature and monitored by LCMS: The reaction was filtered and concentrated before being taken up in CH2Cl2 and H2O. The organic layer was separated, dried with MgSO4, filtered, and concentrated to afford the title compound as an orange-brown oil.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[C:6]1([CH:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]([OH:5])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: O=C(O)C(Nc1ccccc1)c1ccccc1
Yield: 97 %

Procedure:
α-Bromophenylacetic acid (5.01 g, 23.2 mmol) was dissolved in aniline (25 ml, 274 mmol), and the mixture reacted in a closed vessel under microwave irradiation at 120° C. for 5 minutes (UPLC-MS monitoring: complete conversion). Dichloromethane (DCM) (100 ml) was added to the reaction mixture, and the resulting solid was filtered; 2M Na2CO3 (50 ml) was added to the solution, and the aqueous layer was washed with DCM (3×100 ml). The aqueous layer was acidified with 12N HCl (36 ml) and the title compound was recovered as racemic mixture by filtration (5.1 g, 97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[C:18]([CH3:19])=[CH:17][S:16][CH:15]=2)[N:11]([CH3:20])[N:10]=1.[Br:21]Br.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[C:18]([CH3:19])=[C:17]([Br:21])[S:16][CH:15]=2)[N:11]([CH3:20])[N:10]=1
Reactant: BrBr
Reactant: Cc1cscc1-c1nc(-c2c(F)cccc2Cl)nn1C
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)csc1Br
Temperature: 45 °C
Reaction time: 14 h

Procedure:
A suspension of 3-(2-chloro-6-fluorophenyl)-1-methyl-5-(4-methylthien-3-yl)-1H-1,2,4-triazole (2.35 g, 7.6 mmol) in glacial acetic acid (15 mL) was heated to 45° C. in order to effect solubilization. After cooling to 10° C., a solution of bromine (1.34 g, 0.43 mL, 8.4 mmol) in glacial acetic acid (4 mL) was added and the thick gel formed was stirred for 14 hours at room temperature. The reaction mixture was poured into cold water (100 mL) and extracted with ether (3×70 mL). The combined ethereal extracts were washed with water (100 mL), saturated aqueous sodium bicarbonate (2×100 mL), aqueous sodium bisulphite (10% solution, 300 mL) and brine (100 mL), dried over magnesium sulphate and concentrated under reduced pressure. Recrystallisation from ethyl acetate/hexane afforded yellow cubes. The mother liquor was chromatographed over silica gel to afford the product as colorless cubes (2.6 g, 89%): mp 133-134° C.; 1H NMR (CDCl3) δ 7.51 (s, 1H), 7.29-7.39 (m, 2H), 7.11 (t, 1H), 3.98 (s, 3H), 2.27 (s, 3H); EI/MS 386 m/e (M+).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([C:29]([F:32])([F:31])[F:30])=[C:21]3[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][C:22]=23)=[O:17])=[CH:9][C:8]=1[CH2:33][CH3:34])C>C1COCC1.CO.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:28][C:25]1([CH3:27])[CH2:24][CH2:23][C:22]2=[C:18]([C:16](=[O:17])[CH2:15][CH2:14][C:10]3[CH:11]=[C:12]([CH3:13])[C:7]([CH2:6][CH2:5][C:4]([OH:35])=[O:3])=[C:8]([CH2:33][CH3:34])[CH:9]=3)[S:19][C:20]([C:29]([F:32])([F:30])[F:31])=[C:21]2[CH2:26]1
Reactant: CCOC(=O)CCc1c(C)cc(CCC(=O)c2sc(C(F)(F)F)c3c2CCC(C)(C)C3)cc1CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(CCC(=O)c2sc(C(F)(F)F)c3c2CCC(C)(C)C3)cc(C)c1CCC(=O)O
Yield: 64.2 %

Procedure:
A solution of 3-{4-[3-(5,5-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-2-ethyl-6-methyl-phenyl}-propionic acid ethyl ester (340 mg, 0.668 mmol) in THF (5 mL), methanol (4 mL) and 2 N aq. LiOH (2 mL) is stirred at rt for 2 h before it is diluted with 10% aq. citric acid solution and extracted with DCM (3×75 mL). The combined organic extracts are dried over MgSO4, filtered and the solvent of the filtrate is evaporated. The crude product is purified on prep. TLC plates with heptane:EA 3:4 to give 3-{4-[3-(5,5-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-2-ethyl-6-methyl-phenyl}-propionic acid (206 mg) as a colourless glass; LC-MS: tR=1.17 min, [M+1]=481.36.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)[N:10]2[CH2:14][C@@H:13]3[O:15][C:16]4[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=4[O:18][C@H:12]3[CH2:11]2)=CC=1.Cl.O.C(Cl)(Cl)[Cl:37]>C(O)=O>[ClH:37].[N+:23]([C:22]1[C:16]2[O:15][C@@H:13]3[C@H:12]([CH2:11][NH:10][CH2:14]3)[O:18][C:17]=2[CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: ClC(Cl)Cl
Reactant: COc1ccc(C(c2ccc(OC)cc2)N2C[C@@H]3Oc4cccc([N+](=O)[O-])c4O[C@H]3C2)cc1
Agent: Cl
Solvent: O
Solvent: O=CO
Product: O=[N+]([O-])c1cccc2c1O[C@H]1CNC[C@@H]1O2

Procedure:
A solution of (±)-(trans)-2-[bis(4-methoxyphenyl)methyl]-2,3,3a,9a-tetrahydro-5-nitro-1H-[1,4]benzodioxino[2,3-c]pyrrole (1.12 g) in formic acid (10 ml) was heated under reflux with 10M hydrochloric acid (0.5 ml), water (1 ml) and chloroform (5 ml) for 70 minutes. The maroon mixture was cooled and partitioned between chloroform (20 ml) and water (10 ml). The chloroform layer was re-extracted with water (10 ml) and the aqueous solutions were sequentially washed with chloroform (20 ml), combined and evaporated to ca. 2 ml, when crystals formed. These were triturated with warm propan-1-ol (5 ml), cooled to 20° for 1 hour and harvested to give a first crop of the title compound (0.58 g). Concentration of the mother liquor gave a small second crop (0.03 g). Recrystallisation of the first crop from slightly aqueous propan-1-ol gave purer title compound (0.54 g) m.p. ca. 280° (dec.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][CH2:9][CH2:10]I.Cl>C1COCC1.CCOCC.[Zn]>[ClH:7].[Cl:7][CH2:8][CH2:9][CH2:10][N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: C1CSCCN1
Reactant: ClCCCI
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Product: ClCCCN1CCSCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
Step 1. To a solution of thiomorpholine (1.0 g, 9.7 mmol) and 1-chloro-3-iodopropane (1.98 g, 9.7 mmol) in dry THF (30 ml) was added activated zinc powder (0.64 g, 9.7 g atom). After the mixture was stirred at rt overnight, it was filtered, washed with EtOAc (20 ml), and concentrated. The residue was dissolved in EtOAc (50 ml), washed with 10% aq. NaHCO3 (10 ml), water (2×10 ml), dried over MgSO4, and concentrated. The residue was dissolved in ether (20 ml) before a 1 M ethereal HCl solution (9.7 ml, 9.7 mmol) was added dropwise at 0° C. The resulting precipitate was filtered, washed with ether (2×10 ml), and dried to afford 4-(3-chloropropyl)thiomorpholine hydrochloride (0.40 g, 19%) as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 2.20-2.25 (m, 2H), 2.78-2.81 (m, 2H), 3.09-3.27 (m, 6H), 3.68-3.71 (m, 2H), 3.74 (t, J=6.4 Hz, 2H), 11.20 (brs, 1H). Step 2. To a solution of OZ288 (0.38 g, 1.07 mmol) in dry acetonitrile (50 ml) were added powdered NaOH (0.09 g, 2.13 mmol) and tetrabutylammonium hydrogensulfate (0.07 g, 0.21 mmol). After the mixture was stirred at rt for 30 min, 4-(3-chloropropyl)thiomorpholine hydrochloride (0.23 g, 1.07 mmol) was added. The mixture was stirred at 60° C. overnight before the inorganic solid was filtered off and washed with EtOAc (2×25 ml). After removal of the solvents in vacuo, the residue was dissolved in EtOAc (50 ml). The organic layer was washed with water, brine, dried over MgSO4, and concentrated to afford OZ462 free base (0.433 g, 81%) as a colorless solid. To a solution of the above free base (0.41 g, 0.82 mmol) in EtOAc (10 ml) at 0° C. was added dropwise a solution of methanesulfonic acid (0.08 g, 0.82 mmol) in ether (10 ml). The resulting precipitate was filtered, washed with ether (25 ml), and dried under vacuum at 40° C. to afford trioxolane OZ462 (0.42 g, 86%) as a colorless solid. mp 156-158° C.; 1H NMR (500 MHz, CDCl3) δ 1.64-2.08 (m, 22H), 2.32-2.41 (m, 2H), 2.46-2.54 (m, 1H), 2.70 (d, J=14.7 Hz, 2H), 2.80 (s, 3H), 2.96-3.07 (m, 2H), 3.24-3.34 (m, 2H), 3.45-3.54 (m, 2H), 3.87 (d, J=11.8 Hz, 2H), 4.06 (t, J=5.4 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.3 Hz, 2H), 11.19 (brs, 1H); 13C NMR (125.7 MHz, CDCl3) δ 23.66, 24.86, 26.44, 26.84, 31.57, 34.66, 34.76, 36.37, 36.75, 39.42, 41.97, 54.35, 56.23, 64.61, 108.32, 111.36, 114.22, 127.74, 139.14, 156.40. Anal. Calcd for C30H45NO7S2: C, 60.48; H, 7.61; N, 2.35. Found: C, 60.60; H, 7.54; N, 2.17.
Reaction SMILES: C([O:8][C:9]1[CH:13]=[C:12](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)C1C=CC=CC=1>[Pd].O1CCCC1>[C:22]1([N:11]2[C:12](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:13][C:9]([OH:8])=[N:10]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C(=C/c1cc(OCc2ccccc2)nn1-c1ccccc1)\c1ccccn1
Agent: [Pd]
Solvent: C1CCOC1
Product: Oc1cc(/C=C/c2ccccn2)n(-c2ccccc2)n1
Yield: 79.9 %

Procedure:
2-[(E)-2-(3-Benzyloxy-1-phenyl-1H-pyrazol-5-yl)ethenyl]pyridine (2.52 g), 5% palladium on carbon (3.0 g) and tetrahydrofuran (200 mL) were subjected to catalytic reduction under a hydrogen atmosphere and atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated to give 1-phenyl-5-[(E)-2-pyridin-2-ylethenyl]-1H-pyrazol-3-ol as colorless crystals (1.50 g, yield 80%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 167-168° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2c(N)cnc3ccsc23)C1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A mixture of tert-butyl (3S)-3-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]piperidine-1-carboxylate (0.26 g, 0.69 mmol) and 10% palladium on carbon (80 mg) in methanol (5.0 mL) was stirred under an atmosphere of H2 (balloon) overnight. The mixture was filtered through a pad of Celite and concentrated to give 0.24 g of the desired product. LCMS calculated for C17H25N4O2S (M+H)+: m/z=349.2. Found: 349.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[OH-].[Na+].Cl[CH2:13][CH2:14][OH:15]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:13][CH2:14][OH:15]
Reactant: COc1ccccc1O
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1OCCO
Yield: 41.6 %

Procedure:
A solution of 43.2 g (0.35 mole) of 2-methoxyphenol (guaiacol, Aldrich) in 200 ml of ethanol was stirred and treated with 29 ml (0.36 mole) of 50% sodium hydroxide solution. To this solution was added a solution of 28.2 g (0.35 mole) of 2-chloroethanol (Aldrich) in 50 ml of ethanol and the reaction mixture was heated at reflux for 2 hr. The solids were removed by filtration. The filtrate was evaporeated under reduced pressure and the viscous residue was partitioned between 300 ml of 15% sodium hydroxide solution and 500 ml of ethyl ether. The organic layer was washed with 200 ml of 15% sodium hydroxide solution, 300 ml of water, dried (magnesium sulfate) and the solvent evaporated under reduced pressure to give 24.5 g (42%) of the title compound as a lightly colored, viscous oil.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:26]1([CH2:25][O:24][C:18]2[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:29])[CH2:27][CH2:28]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OCC2CC2)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1OCC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
The mixture of 2-(2-cyclopropylmethoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (10) (240 mg, 0.61 mmol) and KOH (500 mg, 8.93 mmol) is dissolved in EtOH (6 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (11) as white solid (223 mg, 100%).
Reaction SMILES: [C:1]1([CH:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([OH:21])=O)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:22]2[C@H:26]([OH:27])[C@H:25]([OH:28])[C@@H:24]([C:29]([NH:31][CH2:32][CH3:33])=[O:30])[O:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:40][C:41]([F:52])([F:51])[C:42]([NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:43].Cl.CN(C)CCCN=C=NCC>ClCCl>[C:1]1([CH:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([N:48]3[CH2:49][CH2:50][CH:45]([NH:44][C:42](=[O:43])[C:41]([F:51])([F:40])[F:52])[CH2:46][CH2:47]3)=[O:21])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:22]2[O:23][C@H:24]([C:29]([NH:31][CH2:32][CH3:33])=[O:30])[C@@H:25]([OH:28])[C@H:26]2[OH:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)O)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(NC1CCNCC1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)N4CCC(NC(=O)C(F)(F)F)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
A solution of 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxylic acid (Preparation 39) (0.2 g, 0.38 mmol), 2,2,2-trifluoro-N-(4-piperidinyl)acetamide (83 mg, 0.42 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (81 mg, 0.42 mmol) in dichloromethane (5 ml) was stirred at room temperature for 48 hours and then heated under reflux for a further 96 hours. The solution was allowed to cool to room temperature and then solvent removed by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:concentrated aqueous ammonia (95:5:1, by volume) changing to dichloromethane:methanol:concentrated aqueous ammonia (80:20:1, by volume). After evaporation of appropriate fractions the target compound was obtained as a white solid, (43 mg, 18%).