Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:6]1[C:10]([C:11]2[CH:12]=[C:13]([C:17]3[CH:18]=[CH:19][C:20]4[O:24][C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=4[CH:36]=3)[CH:14]=[CH:15][CH:16]=2)=[N:9][N:8]=[N:7]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[O:24][C:20]3[CH:19]=[CH:18][C:17]([C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([C:10]5[N:9]=[N:8][N:7]([CH2:2][CH:3]([CH3:5])[CH3:4])[N:6]=5)[CH:12]=4)=[CH:36][C:21]=3[C:22]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:26][CH:27]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn(CC(C)C)n4)c3)cc12
Reaction time: 8 h
Yield: 37.6 %

Procedure:
1-bromo-2-methylpropane (23 mg, 0.169 mmol) was added to a stirring solution of 5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (35 mg, 0.085 mmol) and Na2CO3 (18 mg, 0.169 mmol) in DMF (1 mL) at 100° C. It was allowed to stir overnight. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (15 mg, 38%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.49-8.56 (1 H, m), 8.34 (1 H, s), 8.08 (1 H, d, J=7.63 Hz), 7.99-8.04 (2 H, m), 7.87-7.94 (2 H, m), 7.79-7.84 (1 H, m), 7.73-7.78 (1 H, m), 7.70 (1H, t, J=7.63 Hz), 7.41 (2 H, t, J=8.70 Hz), 4.62 (2 H, d, J=7.32 Hz), 2.87 (3 H, d, J=4.27 Hz), 2.31-2.39 (1 H, m), 0.95 (6 H, d, J=6.71 Hz). LC-MS retention time: 2.09 min; m/z (MH+): 470. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=16.08 min, purity=99%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm, Rt=13.89 min, purity=99%.
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:8])[C:5]([CH3:7])=[CH2:6].[C:9]1([P:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([SH:17])=[S:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([P:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([S:17][CH2:2][NH:3][C:4](=[O:8])[CH:5]([CH3:7])[CH2:6][S:17][P:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[S:16])=[S:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=C(C)C(=O)NCO
Reactant: S=P(S)(c1ccccc1)c1ccccc1
Product: CC(CSP(=S)(c1ccccc1)c1ccccc1)C(=O)NCSP(=S)(c1ccccc1)c1ccccc1

Procedure:
Following the general procedure in Example 1, 0.4 mole N-hydroxymethylmethacrylamide is reacted with 0.8 mole of diphenylphosphinodithioic acid, to yield N-(diphenylphosphinothioylthiomethyl) 3-(diphenylphosphinothioylthio)-2-methylpropionamide.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([C:9]3[N:10]=[C:11]([O:21][CH:22]4[CH2:39][CH:38]5[CH:24]([C:25](=[O:45])[N:26]([CH3:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]6[C:35]([C:41](O)=[O:42])([NH:36][C:37]5=[O:40])[CH2:34]6)[CH2:23]4)[C:12]4[C:17]([CH:18]=3)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=4)[S:7][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]([C:9]3[N:10]=[C:11]([O:21][CH:22]4[CH2:39][CH:38]5[CH:24]([C:25](=[O:45])[N:26]([CH3:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]6[C:35]([C:41]([NH:64][S:61]([CH:58]7[CH2:60][CH2:59]7)(=[O:63])=[O:62])=[O:42])([NH:36][C:37]5=[O:40])[CH2:34]6)[CH2:23]4)[C:12]4[C:17]([CH:18]=3)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=4)[S:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3nc(C4CC4)cs3)cc2c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3nc(C4CC4)cs3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
A mixture of 29 (91 mg, 0.14 mmol) and 1,1′-carbonyldiimidazole (CDI) (47 mg, 0.29 mmol) in dry THF (7 mL) was heated at reflux for 2 h under nitrogen. LCMS analysis shows one peak of the intermediate (RT=5.37). Optionally, the azalactone derivative, if desired, can be isolated. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (52 mg, 0.43 mmol) was added. Then, DBU (50 μL, 0.33 mmol) was added and the reaction mixture was stirred at room temperature for 1 h, and then heated at 55° C. for 24 h. The solvent was evaporated, and the residue partitioned between AcOEt ethyl acetate and acidic water (pH=3). The crude material was purified by column chromatography (ethyl acetateAcOEt/CH2Cl2/pPetroleum ether, 1:1:1). The residue was crystallized in diethyl ether, filtered to give the target compound contaminated with the cyclopropylsulfonamide. This material was triturated in 3 mL of water, filtered, washed with water and dried overnight with the high vacuum pump to give 60 mg (57%) of the target compound 30 as a slightly yellow powder: m/z=734 (M+H)+, 1H-NMR (CDCl3): 10.94 (s, 1H), 8.08 (d, J=8.6 Hz, 1H), 8.00 (s, 1H), 7.12-7.15 (m, 2H), 6.91 (s, 1H), 6.35 (s, 1H), 5.74-5.77 (m, 1H), 5.63-5.69 (m, 1H), 5.06 (t, J=10.4 Hz, 1H), 4.60 (t, J=12.3 Hz, 1H), 3.93 (s, 3H), 3.35-3.42 (m, 2H), 3.04 (s, 3H), 2.89-2.96 (m, 2H), 2.52-2.52 (m, 2H), 2.37-2.45 (m, 2H), 2.10-2.32 (m, 2H), 1.61-1.93 (m, 4H), 1.3-1.51 (m, 4H), 0.90-1.30 (m, 8H).
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].[NH:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+]>C1COCC1>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: C1CSCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCSCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (7.00 g, 33.48 mmol) in THF (250 ml) at room temperature was added thiomorpholine (3.45 g, 33.48 mmol) and sodium bicarbonate (3.66 g, 43.52 mmol). The vessel was purged with nitrogen and stirred at room temperature for 48 hours. After removal of solvent under reduced pressure, the mixture was taken up in ethyl acetate and filtered. The organics were washed with water, then brine and dried with magnesium sulfate. Filtration and concentration provided the title compound as a bright orange solid. MS m/z: 293.1 (M+H+); calc MW=292.28.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].[OH-].[K+].[I-].[K+].O>CS(C)=O>[CH2:16]([C:7]1([CH2:7][CH2:8][CH2:9][CH3:10])[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:4][CH2:5][CH3:6]
Reactant: O=[N+]([O-])c1ccc2c(c1)Cc1ccccc1-2
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC1(CCCC)c2ccccc2-c2ccc([N+](=O)[O-])cc21
Temperature: 15 °C
Reaction time: 2 h
Yield: 158.7 %

Procedure:
12.66 g of 2-nitrofluorene (1) (60 mmol), 21.0 g of potassium hydroxide (0.3 mol, purity: 80%), and 1.01 g of potassium iodide (6 mmol) were dissolved in 200 ml of anhydrous dimethylsulfoxide under nitrogen atmosphere, and a reaction temperature was maintained at 15° C. Then, 33 ml of n-bromobutane (0.3 mol) was slowly added thereto for 2 hours, followed by stirring at 15° C. for 1 hour. Thereafter, 200 ml of distilled water was added to the reaction mixture and stirred for about 30 minutes, a product was extracted with 300 ml of dichloromethane, and the extracted organic layer was washed with 100 ml of distilled water three times. Then, the recovered organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure. The obtained product was purified using a silica gel column chromatography (eluent: dichloromethane:n-hexane=20:1), thereby obtaining 15.4 g of 9,9-di-n-butyl-2-nitrofluorene (5) (79.5%) as a light yellow product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH:13]=[CH2:14]>CO>[OH:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:14][CH2:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:10][CH:9]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: NCCCc1ccc(O)cc1
Solvent: CO
Product: CC(C)(C)OC(=O)CCNCCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a methanol solution (25 mL) of 4-(3-aminopropyl)phenol (1.83 g), tert-butyl acrylate (1.7 mL) was added dropwise thereto at room temperature, followed by stirring at room temperature overnight. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate→ethyl acetate:methanol=3:1) to give the title compound (1.55 g) having the following physical properties. TLC: Rf 0.24 (ethyl acetate:methanol 5:1);
Reaction SMILES: Cl.N[C:3]1[NH:8][C:7]2=[CH:9][CH:10]=[CH:11][C:6]2=[C:5]([OH:12])[N:4]=1.N([O-])=[O:14].[Na+]>>[OH:14][C:3]1[NH:8][C:7]2=[CH:9][CH:10]=[CH:11][C:6]2=[C:5]([OH:12])[N:4]=1
Reactant: Nc1nc(O)c2cccc-2[nH]1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1nc(O)c2cccc-2[nH]1
Temperature: 0 °C
Yield: 75.6 %

Procedure:
To a mixture solution of 20% HCl(62 ml) and 2-amino-4-hydroxycyclopenta[d]pyrimidine (20.6 g, 0.136 mol) prepared in the above Step 1 was added aqueous solution of sodium nitrite (19.4 g) for 4 hours while keeping the temperature of the reaction system at 70° C. The reaction mixture was cooled to 0° C. and the resulting solid was filtered, dried under reduced pressure to give 15.43 g of titled compound.
Reaction SMILES: C(O[C:6]([N:8]1[C@H:13]([C:14](=[O:25])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[CH2:12][C@:11]2([CH2:26][OH:27])[C@H:9]1[CH2:10]2)=[O:7])(C)(C)C.[C:28]([C:31]1[N:32]=[C:33]([CH2:40]C(O)=O)[N:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=12)(=[O:30])[CH3:29]>C(Cl)Cl.CO>[Cl:23][C:19]1[C:18]([F:24])=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][NH:15][C:14]([C@@H:13]1[CH2:12][C@:11]2([CH2:26][OH:27])[C@@H:9]([CH2:10]2)[N:8]1[C:6](=[O:7])[CH2:40][C:33]1[N:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]2=[C:31]([C:28](=[O:30])[CH3:29])[N:32]=1)=[O:25]
Reactant: CC(=O)c1nc(CC(=O)O)n2ccccc12
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)NCc2cccc(Cl)c2F)C[C@@]2(CO)C[C@@H]12
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1nc(CC(=O)N2[C@H](C(=O)NCc3cccc(Cl)c3F)C[C@@]3(CO)C[C@@H]23)n2ccccc12

Procedure:
was prepared using the protocols described for the preparation of Example 758 from (1R,3S,5S)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]-hexane-2-carboxylic acid tert-butyl ester (prepared as described in Scheme B28) and (1-acetyl-imidazo[1,5-a]pyridin-3-yl)-acetic acid (prepared as described in Scheme A19). Rf, TLC (CH2Cl2/MeOH 9:1)=0.40; MS (UPLC/MS): 499.4/501.4 [M+H]+, 521.4/523.4 [M+Na]+, 543.5/545.5 [M+HCOO]−; tR (HPLC conditions f): 1.66 min.
Reaction SMILES: [I-:1].[NH2:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[C:5]([CH3:10])[N+:4]=1[CH3:11].[C:12]1([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[I-:1].[NH2:2][C:3]1[N:8]=[C:7]([N:21]2[CH2:22][CH2:23][CH:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:19][CH2:20]2)[CH:6]=[C:5]([CH3:10])[N+:4]=1[CH3:11]
Reactant: Cc1cc(Cl)nc(N)[n+]1C
Reactant: c1ccc(C2CCNCC2)cc1
Agent: [I-]
Solvent: CCO
Product: Cc1cc(N2CCC(c3ccccc3)CC2)nc(N)[n+]1C
Yield: 50 %

Procedure:
A mixture of 2-amino-4-chloro-1,6-dimethylpyrimidinium iodide (0.571 g; 2 mM; described in Indian Research, 1976, 21 p. 96) and 4-phenylpiperidine (0.644 g; 4 mM) in ethanol (30 ml) was heated under reflux for 15 hours. The solvent was removed in vacuo and the residue was triturated with ether. The solid was removed by filtration and recrystallised from a mixture of methanol and ether to give 2-amino-1,6-dimethyl-4-(4-phenylpiperidino)pyrimidinium iodide as a solid (0.41 g, 50% yield), m.p. 248°-250° C. (decomp.); microanalysis, found: C,50.0; H,5.6; N,13.7%; C17H23N4I requires C,49.8; H,5.6; N,13.7%; NMR (220 MHz; d5): 1.4-1.75 (2H, b, piperidine 3-H axial and 5-H axial), 1.85-2.0 (2H, d, piperidine 3-H equatorial and 5-H equatorial), 2.4 (3H, s, CH3), 2.8-3.3 (3H, b, piperidine 4-H and piperidine 2-H axial and 6-H axial), 3.45 (3H, s, N--CH3), 4.2-4.4 (1H, broad d, piperidine 2-H equatorial or 6-H equatorial), 4.85-5.05 (1H, broad d, piperidine 6-H equatorial or 2-H equatorial), 6.7 (1H, s pyrimdine 5H), 7.1-7.4 (5H, complex, aromatic H), 7.85-8.0 (2H, br, NH2).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>C(#N)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(S([N-][C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.Cl[Ru+]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:12]([OH:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(=O)CS(C)(=O)=O)ccc1OC
Agent: Cl[Ru+]
Agent: Cc1ccc(S(=O)(=O)[N-][C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CC#N
Product: CCOc1cc([C@@H](O)CS(C)(=O)=O)ccc1OC
Temperature: 22.5 °C
Reaction time: 40 h
Yield: 87 %

Procedure:
A mixture of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (1.2 g, 4.4 mmol), RuCl(p-cymene)[(S,S)-Ts-DPEN] (28 mg, 0.044 mmol), and 5:2 formic acid-triethylamine complex (2.2 mL) in acetonitrile (7.2 mL) was stirred at 20-25° C. for 40 h. The mixture was evaporated to dryness and the residue was chromatographed on a silica gel column, using a hexanes-ethyl acetate gradient. The appropriate fractions were pooled and evaporated. The residue was triturated with heptane (25 mL) and the resulting slurry was filtered and dried under vacuum to provide (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol as a white solid (1.05 g, 87% yield); achiral HPLC (Hypersil BDS C8, 5.0 μm, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min): 12.37 (99.8%); chiral HPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 85:15 heptane-i-PrOH): 18.07 (0.51%), 20.43 (99.4%); 1H NMR(CHCl3-d) δ 1.48 (t, J=7.0 Hz, 3H), 2.77 (dd, J=1.1, 2.6 Hz, 1H), 3.05 (s, 3H), 3.17 (dd, J=0.9, 14.7 Hz, 1H), 3.46 (dd, J=10.1, 14.6 Hz, 1H), 3.88 (s, 3H), 4.11 (q, J=7.0 Hz, 2H), 5.27-5.32 (m, 1H), 6.82-6.95 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17]O)[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:53]I>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][I:53])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CI)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Yield: 688.4 %

Procedure:
To a mixture of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (500 mg, 0.98 mmole) (prepared according to procedure as described in J. Med. Chem. 2008; 51 (5); 1145-1149), PPh3 (3.0 g, 7.3 mmole) and imidazole (650 mg, 9.5 mmole) in 50 mL of dichloromethane (DCM) was added iodine (2.4 g, 9.5 mmole) at 0° C. and refluxed for 18 hrs. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (2×200 mL). The crude product obtained after the removal of solvent was purified using silica gel column chromatography (0.5% methanol in DCM) to furnish 3.5 g of (2S,3R,4R,5S,6S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-iodomethyl-tetrahydro-pyran-3,4,5-triol.
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH2:18].[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>ClCCl>[CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCC(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Yield: 82.7 %

Procedure:
Following the procedure in Example 1, Step 4, 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine (0.12 g, 0.50 mmol), hexanoyl chloride (0.072 mL, 0.52 mmol) and poly-(4-vinylpyridine) (700 mg) in dichloromethane (10 mL) provided 0.14 g of N-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-ylhexanamide. MS (ESI) m/z 339;
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:19]([C:20]([O:22]C)=[O:21])=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[O:17][C:14]2=[CH:15][N:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.CO.C(OCC)(=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:19]([C:20]([OH:22])=[O:21])=[C:18]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[O:17][C:14]2=[CH:15][N:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cnc(OCc3ccccc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(-c2ccc(F)cc2)oc2cnc(OCc3ccccc3)cc12
Yield: 100 %

Procedure:
NaOH (27.8 mL, 27.8 mmol, 1M aq.) was added to a stirring solution of methyl 5-(benzyloxy)-2-(4-fluorophenyl)furo[2,3-c]pyridine-3-carboxylate (2.62 g, 6.94 mmol) in THF (174 mL) and MeOH (174 mL) at 60° C. for 2 hours. The mixture was diluted with ethyl acetate and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 5-(benzyloxy)-2-(4-fluorophenyl)furo[2,3-c]pyridine-3-carboxylic acid (2.52 g, 6.94 mmol, 100% yield) consistent by LCMS. LC-MS retention time: 2.19 min; m/z (MH+): 364. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[H-].[Na+]>C1COCC1>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.9 %

Procedure:
To a solution of 4-fluoronitrobenzene (1.41 g, 10 mmol) in THF (50 mL) was added N-Boc-4-hydroxypiperidine (2.01 g, 10 mmol) and sodium hydride (60% in mineral oil, 583 mg, 14.5 mmol). The mixture was stirred at room temperature for 14 hrs. After purification through flash column chromatography, 4-(4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (2.51 g, 78% yield) was obtained as a solid. This nitro compound was hydrogenated to the corresponding amine and coupled with 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid to give 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester. LC-MS showed a single peak with a retention time of 4.08 min. LRMS calcd for C27H28F3N3O5 (M+1) 532.20, obsd 532.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:33]C)=[C:6]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([NH2:25])=[O:24])=[N:18]3)[CH:7]=1.B(Br)(Br)Br.CO>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]([CH3:31])([CH3:32])[CH2:9][C:10]([OH:30])([C:26]([F:28])([F:27])[F:29])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([NH2:25])=[O:24])=[N:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(C(N)=O)ccc12)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CC(O)(CNc1cccc2nc(C(N)=O)ccc12)C(F)(F)F)c1cc(F)ccc1O
Reaction time: 20 h

Procedure:
220 mg (0.46 mmol) of 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]quinoline-2-carboxylic acid amide is dissolved in 5.0 ml of dichloromethane and mixed with 9.2 ml of a 1N boron tribromide solution in dichloromethane. After 20 hours at room temperature, the reaction is halted by adding methanol. The solvent is removed in a vacuum, the residue is taken up in saturated sodium bicarbonate solution and ethyl acetate, extracted with ethyl acetate, and the combined organic phases are dried on sodium sulfate. After removal of the solvent and purification on silica gel with hexane-ethyl acetate (0–100%), 60 mg (28% of theory) of the product is obtained.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.O1CCOCC1>O>[N:19]1([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: C1CNCCN1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1c(N2CCNCC2)n(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A mixture of 2-chloro-1-phenyl-1H-indole-3-carboxaldehyde (2.0 g, 7.83 mmol), piperazine (6.73 g, 78.3 mmol) and dioxane (25 mL) is heated at reflux overnight. After cooling to room temperature, water (100 mL) is added and after 1 hr the solids are collected by filtration, washed with water and purified by flash chromatography eluting with chloroform-5% methanol. Product containing fractions are combined and concentrated to afford 2-(piperazin-1-yl)-1-phenyl-1H-indol-3-carboxaldehyde (0.87 g, 36%) as a beige solid. A sample, mp 175° C., is purified by flash chromatography eluting with dichloromethane-5% methanol. NMR (CDCl3) 10.29 (1H, s), 8.27 (1H, d), 7.60 (2H, m), 7.51 (1H, t), 7.40 (2H, d), 7.23 (1H, m), 7.15 (1H, t), 6.98 (1H, d), 3.27 (4H, m), 2.78 (4H, m).