Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([Cl:12])=[C:4]([NH2:13])[N:3]=1.Br[CH2:15][C:16](=O)[CH2:17][CH3:18]>>[NH2:13][C:4]1[N:3]2[CH:15]=[C:16]([CH2:17][CH3:18])[N:1]=[C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[Cl:12]
Reactant: COC(=O)c1cc(Cl)c(N)nc1N
Reactant: CCC(=O)CBr
Product: CCc1cn2c(N)c(Cl)cc(C(=O)OC)c2n1

Procedure:
The title compound was prepared according to the procedure described in the step 4 in EXAMPLE 1 from methyl 2,6-diamino-5-chloro-3-pyridinecarboxylate (EXAMPLE 1, Step 3) and 1-bromo-2-butanone.
Reaction SMILES: [BH4-].[Na+].Br[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([F:21])[CH:8]=1)=[O:6].[OH-].[Na+]>O1CCOCC1.CO.O>[F:21][C:9]1[CH:8]=[C:7]([CH:5]2[CH2:4][O:6]2)[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Fc1cc(C2CO2)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 100.4 %

Procedure:
Sodium borohydride (1.25 g) was added in portions to a stirred solution of 2-bromo-1-[3-fluoro-4-(phenylmethoxy)phenyl]ethanone (16.6 g) in dioxan (100 ml) and methanol (100 ml) at 0°. After 0.5 h a solution of sodium hydroxide (4.0 g) in water (20 ml) was added and the mixture stirred for a further 1 h at 0°. Water was added and the mixture extracted with EA. The extracts were dried and evaporated to give the title compound as a colourless oil (12.6 g) which partially solidified on standing, t.l.c. (PE-EA 6:4) Rf 0.40.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH2:44][C:45]6[CH:50]=[CH:49][C:48]([B:51]7[O:55]C(C)(C)C(C)(C)[O:52]7)=[CH:47][CH:46]=6)[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1>C1COCC1.O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH2:44][C:45]6[CH:46]=[CH:47][C:48]([B:51]([OH:55])[OH:52])=[CH:49][CH:50]=6)[S:40]([CH3:43])(=[O:41])=[O:42])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34](=[O:35])[NH:36][CH3:37])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(Cc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(Cc3ccc(B(O)O)cc3)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12

Procedure:
A solution of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)benzofuran-3-carboxamide (0.12 g, 0.15 mmol) and NaIO4 (0.16 g, 0.74 mmol) in THF/H2O (12 mL/4 mL) was stirred at room temperature for 24 hours. The mixture was filtered and extracted by EtOAc. The combined organic phases was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-HPLC to provide Compound 205. 1H-NMR (Methanol-d4, 400 MHz) δ 8.00 (s, 2H), 7.77˜7.79 (m, 2H), 7.53˜7.66 (m, 1H), 7.51˜7.52 (m, 1H), 7.22˜7.44 (m, 6H), 7.11˜7.14 (m, 1H), 6.99˜7.01 (m, 1H), 6.91˜6.93 (m, 1H), 6.82˜6.86 (m, 1H), 6.14 (s, 2H), 4.84˜4.86 (m, 1H), 4.50˜4.58 (m, 1H), 3.17˜3.20 (m, 3H), 2.93 (s, 3H). MS (M+H)+: 735.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:17]#[C:18][C:19]1[CH:20]=[CH:21][C:22]3[O:31][CH2:30][CH2:29][N:28]4[C:24](=[N:25][C:26]([C:32](=[O:34])[NH2:33])=[CH:27]4)[C:23]=3[CH:35]=1)([OH:16])[CH2:12]2)=O)(C)(C)C.[ClH:36].CCOC(C)=O>CO>[OH:16][C:11]1([C:17]#[C:18][C:19]2[CH:20]=[CH:21][C:22]3[O:31][CH2:30][CH2:29][N:28]4[CH:27]=[C:26]([C:32]([NH2:33])=[O:34])[N:25]=[C:24]4[C:23]=3[CH:35]=2)[CH2:10][C@H:9]2[NH:8][C@H:13]([CH2:14][CH2:15]2)[CH2:12]1.[ClH:36]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)(C#Cc1ccc3c(c1)-c1nc(C(N)=O)cn1CCO3)C2
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)C[C@H]4CC[C@@H](C3)N4)ccc1OCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a solution of 3-(2-Carbamoyl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-9-ylethynyl)-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.5 g, 1.1 mmol) in methanol (20 mL) was added HCl/EtOAc (4 M, 20 mL) at 0° C. The solution was stirred for 3 h at room temperature. The reaction mixture was filtered and washed with EtOAc to afford desired product as HCl salt (400 mg, 96%). 1H NMR: (DMSO-d6, 400 MHz): δ 9.44 (s, 1H), 9.10 (s, 1H), 8.52 (s, 1H), 8.02 (s, 1H), 7.46 (s, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 4.55 (s, 4H), 3.96 (s, 2H), 2.45-2.17 (m, 6H), 1.91-1.88 (m, 2H). LCMS [M+H]+=379.0.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[SH2:16].[Na]>>[S:16]1[CH:4]=[C:3]([C:4]2[C:5]([C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:7])=[CH:14][CH:15]=[CH:2][CH:3]=2)[CH:2]=[CH:15]1
Reactant: S
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: [Na]
Product: O=C(c1ccccc1)c1ccccc1-c1ccsc1

Procedure:
4-chlorobenzophenone and sodium hydrogen sulfide are reacted to produce 4-thiolbenzophenone. The thiol functionalities are then reacted with methyl acrylate or any other oligomeric diacrylate or polyacrylate. One product has the following formula:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[CH:15]1([CH:21]=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:21][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=CC1CCCCC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(CC2CCCCC2)CC1

Procedure:
The title compound was prepared (1.83 g, 83%) from tert-butyl piperidin-4-ylcarbamate (1.50 g, 7.48 mmol) and cyclohexanecarbaldehyde (0.84 g, 7.48 mmol) by following the general procedure described for Preparation 3. 1H NMR (400 MHz, CDCl3) δ 4.80 (bs, 1H), 3.71 (m, 1H), 3.63 (m, 2H), 2.53 (m, 2H), 2.43 (m, 2H), 2.00-1.61 (m, 9H), 1.44 (s, 9H), 1.23 (m, 4H), 0.95 (m, 2H); MS (ESI) m/z: Calculated for C17H33N2O2, 297.25; Observed: 297.1 (M++1).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].II.Br[C:23]1[CH:27]=[CH:26][S:25][CH:24]=1.C([Mg]Br)CCCCCCCCCCCCCCCCC>CCOCC.[Ni].[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[CH2:1]([C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Brc1ccsc1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: Cl[Ni]Cl
Agent: [Ni]
Agent: CCCCCCCCCCCCCCCCCC[Mg]Br
Solvent: CO
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCc1ccsc1
Temperature: 0 °C

Procedure:
3-n-octadecylthiophene was prepared as set forth in Kumda et al Bull. Chem Soc. Jpn. 1976, 49, 1958-1969 and Tetrahedron 1982, 38, 3347-3354. A dry 1000 mL 2 neck flask was charged with Mg ribbon (3.34 g, 137 mmol) under N2 followed by addition of ˜200 mL of anhydrous Et2O. The flask was cooled in an ice bath (0° C.). In a separate 500 mL flask 40 g (120 mmol) of n-C18H37Br was dissolved in ˜200 mL of anhydrous Et2O under N2. The Et2O solution of n-C18H37Br was slowly transfer into the flask containing the Mg ribbon, with sonication, stirring, and addition of I2 to initiate Grignard. After complete addition of n-C18H37Br to the Mg the reaction mixture was allowed to stir overnight to allow for complete formation of the Grignard reagent (n-C18H37MgBr). A dry 1000 mL 3-neck flask was charged with 0.540 g of 1,3-Bis(diphenylphosphino)propane nickel (II) chloride was added under nitrogen followed by ˜100 mL of anhydrous Et2O and 11.25 mL (120 mmol) of 3-bromothiphene. The flask was then cooled in an ice bath (0° C.). The Et2O solution of n-C18H37MgBr was slowly added to the flask containing the nickel catalyst and the 3-bromothiophene to prevent the generation of excessive heat and high concentrations of n-C18H37MgBr in the presence of the catalyst. The reaction mixture was allowed to stir overnight resulting in the formation of two layers. The top Et2O layer contained the product and the second small lower dark brown oily layer contained the Ni catalyst and the Mg salts. The primary side product of the reaction was the coupling product of two equivalents of n-C18H37MgBr to form C36H74, which was easily separated form the product since it had low solubility in Et2O. The product was purified via aqueous workup followed by filtration and removal of the Et2O by rotoevaporation to leave the impure low melting solid product. This solid was redissolved in a minimal amount of Et2O (˜30 mL) followed by addition of ˜250 mL of MeOH and placed into low temperature freezer (−80° C.) for recrystalization. The yield of this reaction is about 80-90%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[O:17]=[C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:18])[N:8]1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N+:6]=1[O-:27]
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-methylpyridin-2-yl)isoindoline-1,3-dione (1.62 g, 6.8 mmol) in DCM (32 ml) is added mCPBA (4.1 g, 18.2 mmol) in small portions at room temperature, and the solution is then stirred at room temperature overnight. The solution is diluted with dichloromethane, washed with aqueous Na2CO3 solution, dried over Na2SO4 and concentrated to afford 2-(1,3-dioxoisoindolin-2-yl)-5-methylpyridine 1-oxide as a brown solid. It is used without further purification in the next step. LC-MS m/z: 254.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][CH:10]=[C:11]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])[CH3:12])=[C:4]([CH3:21])[N:3]=1.P(Cl)(Cl)([Cl:24])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:24])[C:5]([CH2:9][CH:10]=[C:11]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])[CH3:12])=[C:4]([CH3:21])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=CCc1c(C)nc(N)nc1O)c1cc(Cl)ccc1Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CC(=CCc1c(C)nc(N)nc1Cl)c1cc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 2.0 grams (0.006 mole) of 2-amino-4-hydroxy-6-methyl-5-[3-(2,5-dichlorophenyl)-2-butenyl]pyrimidine, 16.5 grams (0.107 mole) of phosphorus oxychloride, and 1.5 grams (0.007 mole) of phosphorus pentachloride is heated at reflux for about 18 hours. After this time the reaction mixture is slowly pipetted into wet ice during a 20 minute period. The mixture is then stirred until the ice melted, and the resultant solid is collected by filtration. The solid is dissolved in methylene chloride, and the solution is dried with magnesium sulfate. The mixture is filtered and the filtrate is concentrated under reduced pressure, yielding 2.0 grams of 2-amino-4-chloro-6-methyl-5-[3-(2,5-dichlorophenyl)-2-butenyl]pyrimidine; mp 97°-100° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH:2]=[CH2:3].[Sn]>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[NH2:17])[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1ccc([N+](=O)[O-])c(OCC=C)c1
Agent: [Sn]
Product: C=CCOC(=O)c1ccc(N)c(OCC=C)c1
Yield: 73 %

Procedure:
Stannous chloride dihydrate (22.6 parts) was treated with industrial methylated spirits (70 parts) and heated to 60° to dissolve. The above ester (6.5 parts) was dissolved in industrial methylated spirits (2.8 parts) and run in to the hot solution of tin salt at such a rate as to maintain a gentle reflux (30 minutes). Finally the mixture was heated at reflux for 3 hours. After cooling, solvent was evaporated, and the residue treated with ethyl acetate (125 parts), and stirred in an ice bath. Ammonia (density 0.880 g/ml, 15 parts) was run in, keeping the temperature below 20°, and finally stirring at ambient temperature for 1 hour before filtering. The filtered tin salts were washed with two portions of ethyl acetate (each 45 parts), and the organic solvent evaporated. The oily residue was purified by chromatography on silica, eluting initially with dichloromethane:hexane 3:1, then 1:1, and finally with dichloromethane. Appropriate fractions were combined to give allyl 3-allyloxy-4-aminobenzoate (4.2 parts, 73%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH4+].[Cl-]>C1C=CC=CC=1>[CH2:16]([CH:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccccc1)C(C)=O
Yield: 74 %

Procedure:
0.1 Mol of ethyl acetoacetate, 0.1 mol of K2CO3, 0.1 mol of benzyl bromide, 0.01 mmol of PEG-400 (polyethylene glycol 400) and 100 ml of benzene were stirred at 75° C. for 7 hours. After cooling, 20 ml of saturated solution of NH4Cl was added to dissolve solid, and product was extracted with ethyl acetate. After removing the solvent, the residue was distilled under reduced pressure, and a cut fraction was collected at 116-118° C./20 Pa. Yield 74%.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12](OC)=[CH:11][CH:10]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:17]([NH:24][OH:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N+:24]([O-:25])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(C(=O)Cn2ccnc2)cc1
Reactant: ONCc1ccccc1
Product: [O-][N+](Cc1ccccc1)=C(Cn1ccnc1)c1ccccc1

Procedure:
2-(1H-Imidazol-1-yl)-1-phenyl-N-(phenylmethyl)ethanimine N-oxide (2, R1 =R2 =C6H5, X=CH) Compound 2 (R1 =R2 =C6H5, X=CH) was prepared by the procedure described in Example 1, Method B, by reacting 2-(1H-imidazol-1-yl)acetophenone (1, R1 =C6H5, X=CH) with N-benzylhydroxylamine. Compound 2 (R1 =R2 =C6H5, X=CH) was obtained as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([CH2:15]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:6][C:5]2=1.[C-:27]#[N:28].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([CH2:15][C:27]#[N:28])[CH2:6][C:5]2=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3[nH]c4ccc(F)cc4c3C2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: N#CCC1CCc2[nH]c3ccc(F)cc3c2C1
Reaction time: 2 h

Procedure:
To a suspension of the crude toluene-4-sulfonic acid 6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl-methyl ester (9.827 g, 0.0263 mol) in ethanol (70 mL) was added solid sodium cyanide (49.01 g, 0.0447 mol). The mixture was stirred at gentle reflux for 16 hours. Following TLC, a small amount of additional sodium cyanide was added and heating resumed for 2 hours. Most of the solvent was removed under reduced pressure (ca 55 mL). The residue was slurried in water (70 mL) and extracted with diethyl ether (3×). The extracts were washed with water and brine, and dried over anhydrous magnesium sulfate. Removal of the solvent provided a mustard colored solid which was purified by flash chromatography on silica gel Merck-60 using a gradient from 8:2 to 1:1 of ethyl acetate in hexane. The desired title compound was obtained as a yellow oil that solidifies in vacuo to yield light yellow crystals (5.2 g), m.p. 136-138° C. MS (ES): [M−H]− @m/z 227.1.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9]CC2C=CC=CC=2)[CH:5]=[CH:4][C:3]=1[N:17]1[C:25]2[C:20](=[C:21]([O:26]CC3C=CC=CC=3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[N:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:26])[C:20]=2[CH:19]=[CH:18]1
Reactant: Fc1c(OCc2ccccc2)ccc(-n2ccc3c(OCc4ccccc4)cccc32)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(-n2ccc3c(O)cccc32)c(F)c1F
Yield: 53.9 %

Procedure:
1-{2,3-difluoro-4-[(phenylmethyl)oxy]phenyl}-4-[(phenylmethyl)oxy]-1H-indole (D23) (141 mg, 0.319 mmoL) was dissolved in ethyl acetate (10 mL) and was hydrogenated at room temperature and atmospheric pressure in the presence of 10% palladium on charcoal (50% wet) (70 mg). After 22 hours the mixture was filtered and concentrated in vacuo. The crude product was purified by MDAP and the isolated material was partitioned between ethyl acetate and sat. NH4Cl. The phases were separated and the aqueous phase extracted with more ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound (E13), (45 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)([OH:7])[CH2:4][CH2:5][CH3:6].CN(C)[CH:20]=[O:21].C(C1NC=CN=1)(C1NC=CN=1)=O>O1CCCC1>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:3]2([CH2:4][CH2:5][CH3:6])[O:7][C:20](=[O:21])[NH:1][CH2:2]2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: CCCC(O)(CN)c1ccc(OC)c(OC)c1
Reactant: CN(C)C=O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCCC1(c2ccc(OC)c(OC)c2)CNC(=O)O1

Procedure:
17.35 mmol of 5-amino-4-(3,4-dimethoxyphenyl)-4-pentanol is dissolved in 10 ml. of absolute dimethylformamide and reacted with 18.3 mmol of 98% strength carbonyl diimidazole in 100 ml. of absolute tetrahydrofuran for 4 days at room temperature under the exclusion of moisture. After the solvent has been distilled off, the residue is taken up in ethyl acetate, extracted twice with 1 N hydrochloric acid, and washed neutral with saturated sodium chloride solution. The thus-obtained oil is purified by way of a silica gel column (350 g.) in a chloroform/methanol system 30:1. The product is 5-(3,4-dimethoxyphenyl)-5-propyl-2-oxazolidinone in an 81.7% yield in the form of an oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O1CCCC1>[Cl:3][C:4]1[C:9]([N:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CCCCCCBr
Reactant: O=C(Nc1cccnc1Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCN(C(=O)c1ccccc1)c1cccnc1Cl
Temperature: 25 °C
Yield: 58 %

Procedure:
0.63 g sodium hydride (NaH) (26 mmol) and 50 mL tetrahydrofuran (THF) were added in an ice bath with stirring. 3.01 g N-(2-chloro-pyridin-3-yl)-benzamide (13 mmol) and 40 mL THF were then added and reacted for 30 min. Next, 3.28 g 1-bromo-hexane (20 mmol) was added and reacted for 24 hr. After cooling to room temperature, the reaction was quenched by water. After extraction three times by ethyl acetate, removal of water by magnesium sulphate (MgSO4), concentration, and purification by column, 2.39 g white solid was obtained, with a yield of 58%.
Reaction SMILES: [Li+].[OH-].C([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:14][C:15]([C:18]2[C:23]([NH2:24])=[N:22][CH:21]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[N:19]=2)=[N:16][N:17]=1)(=O)C.Cl>C1COCC1>[NH2:24][C:23]1[C:18]([C:15]2[O:14][C:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[OH:6])=[N:17][N:16]=2)=[N:19][C:20]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:21][N:22]=1
Reactant: CC(=O)Oc1ccccc1-c1nnc(-c2nc(-c3ccc(S(=O)(=O)C(C)C)cc3)cnc2N)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4O)o3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
LiOH (292.0 μL of 1 M, 0.2920 mmol) was added to a suspension of 2-(5-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl acetate (14 mg, 0.02920 mmol) in THF (5 mL) at ambient temperature. After 3 h, a further portion of LiOH (292.0 μL of 1 M, 0.2920 mmol) was added and the reaction continued to stir at room temperature for 1 h. 1M HCl was added dropwise until the reaction mixture was acidic and the resultant precipitate isolated by filtration. The solid residue was dissolved in a mixture of MeCN and water and lypholised to give the product as a green solid (5.1 mg, 38% yield); 1H NMR (400 MHz, DMSO) d 1.20 (d, 6H), 3.46 (m, 1H), 6.98-7.22 (m, 2H), 7.36-7.59 (m, 1H), 7.75-8.16 (m, 5H), 8.37 (d, 2H), 9.06 (s, 1H) and 10.43 (s, 1H) ppm; MS (ES+) 438.2
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19](S(C2C=CC=CC=2)(=O)=O)[CH:18]=[C:17]3[C:32]#[N:33])[CH:10]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[C:32]#[N:33])[CH:10]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)c(C#N)cn3S(=O)(=O)c2ccccc2)C(Cc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3[nH]cc(C#N)c3c2)C(Cc2ccccc2)C1
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
To a suspension of 4-(1-benzenesulfonyl-3-cyano-1H-indol-5-yl)-3-benzyl-piperazine-1-carboxylic acid tert-butyl ester (0.37 g, 0.7 mmol) in 10 mL MeOH was added K2CO3 (0.27 g, 2.0 mmol) in 2 mL H2O. The reaction mixture was stirred for 30 minutes and then solution was concentrated under reduced pressure and extracted with EtOAc. The combine organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification via flash chromatography (25% EtOAc in hexane) afforded 3-benzyl-4-(3-cyano-1H-indol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.23 g, 85%) as a white foam; MS (M+H)=417.
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[O:28][CH2:29][CH2:30][O:31]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][NH:51][C:52](=[O:54])[CH3:53])=[C:45](O)[CH:44]=1>>[C:52]([NH:51][CH2:50][CH2:49][C:46]1[CH:47]=[CH:48][C:43]([F:42])=[CH:44][C:45]=1[O:31][CH2:30][CH2:29][O:28][CH:16]1[CH:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:15][C:12]3[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=3)=[CH:14][CH:13]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17]1)(=[O:54])[CH3:53]
Reactant: CC(=O)NCCc1ccc(F)cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCc3ccccc3)cc2)cc1
Product: CC(=O)NCCc1ccc(F)cc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(Cc2ccccc2)cc1

Procedure:
Analogously to Method G, 6.7 g of tert-butyl 4-(4-benzyloxyphenyl)-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate and 4.54 g of N-[2-(4-fluoro-2-hydroxyphenyl)ethyl]acetamide (Example 112b) are reacted. The title compound is obtained as a yellowish oil. Rf=0.16 (2:1 EtOAc-heptane); Rt=5.44.