Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH2:7][C@@H:8]3[C@H:11]([CH:12]=2)[C:10](=[CH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.P([O-])(O)(O)=O.[K+].[N+:38]([CH3:41])([O-:40])=[O:39]>>[N+:38]([CH2:41][C@@:10]1([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][C@H:8]2[C@@H:11]1[CH:12]=[C:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:7]2)([O-:40])=[O:39]
Reactant: CC(C)(C)OC(=O)C=C1C[C@@H]2CC(C3CCCC3)=C[C@H]12
Reactant: C[N+](=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C[C@]1(C[N+](=O)[O-])C[C@@H]2CC(C3CCCC3)=C[C@@H]21
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Tert-butyl(±)-[(1S,5R)-3-cyclopentylbicyclo[3.2.0]hept-3-en-6-ylidene]acetate (3.30 g, 12.0 mmol) was dissolved in nitromethane (30 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.20 g, 14.5 mmol) was added, and the mixture was stirred at 60° C. for 5 hours. The mixture was allowed to cool, and a saturated aqueous solution of potassium dihydrogen phosphate was then added thereto, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain the compound of interest as a yellow oil substance (3.50 g, 87%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[CH:25][N:24]=[CH:23][N:22]=1>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[C:27]([C:26]1[C:21]([NH:20][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:22][CH:23]=[N:24][CH:25]=1)#[N:28]
Reactant: N#Cc1cncnc1N
Reactant: O=C(O)CCCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cncnc1NC(=O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Under an atmosphere of nitrogen, oxalyl chloride (961 mg) was added dropwise to a solution of 5-phenylvaleric acid (Fluka, 1.00 g) in CH2Cl2 (8 ml) and DMF (0.4 ml). After stirring at ambient temperature overnight, the mixture was slowly added at 0° C. to a solution of 4-aminopyrimidine-5-carbonitrile (Aldrich, 505 mg) in pyridine (8 ml). The mixture was stirred overnight at r.t., taken up in CH2Cl2, washed with water, and dried (Na2SO4). After filtration, the solvent was evaporated, and the title compound (1.00 g, 64%) was obtained from the residue by column chromatography (silica gel, eluent gradient n-heptane/ethyl acetate=100:0-60:40). MS: m/e=281.3 [M+H+]. 1H NMR (d6-DMSO): δ 1.60-1.80 (m, 4H), 2.55-2.60 (m, 2H), 3.14 (t, 2H), 7.14-7.29 (m, 5H), 9.17 (d, 2H), 11.34 (bs, 1H).
Reaction SMILES: [NH:1]([CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([CH2:20][CH3:21])[S:19][C:13]=2[NH:12][C:11]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]=[C:40](C(Cl)(Cl)Cl)[O:39][N:38]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-:47].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[NH:1]([CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([CH2:20][CH3:21])[S:19][C:13]=2[N:12]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:47])[O:39][N:38]=3)=[CH:27][CH:26]=2)[C:11]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCc1cc2c(=O)n(CCNc3ccccc3)c(=O)[nH]c2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CCNc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
A mixture of 3-(2-anilinoethyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.33 g), potassium carbonate (0.11 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and methanol (5 mL). 1N Aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 7 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from acetone-hexane to give the title compound as colorless crystals (0.2 g, 56%).
Reaction SMILES: [I:1]I.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl.ClCCl.FC(F)(F)C([O-])=O.[Ag+]>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][C:12]=1[I:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(OCc2ccccc2)cc1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: FC(F)(F)Oc1ccc(OCc2ccccc2)c(I)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
Iodine (71.96 g, 0.28 mol) in chloroform was added dropwise to a mixture of 2-benzyloxy-5-(trifluoromethoxy)benzene (Preparation 12, 73.06 g, 0.27 mol) and silver trifluoroacetate (71.57 g, 0.32 mol) in dichloromethane and the mixture was stirred at room temperature for 18 hours. The mixture was filtered through celite, washed with aqueous sodium thiosulfate (5%, 2×2 l), dried MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate, to give the title compound as a colorless oil (108.03 g), containing 11% unreacted 2-benzyloxy-5-(trifluoromethoxy)iodobenzene. 1H NMR (360 MHz, CDCl3) δ 7.67 (1H, d, J=2.8 Hz), 7.40 (5H, m), 7.16 (1H, dd, J=8.9, 2.8 Hz), 6.82 (1H, d, J=8.9 Hz), and 5.14 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([O:21]C(=O)C)=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:25]=1)=[O:4].[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:25]=1)=[O:4]
Reactant: COC(=O)Nc1cn2cc(Sc3ccc(OC(C)=O)cc3)ccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)Nc1cn2cc(Sc3ccc(O)cc3)ccc2n1

Procedure:
1.0 Gm. of the acetate derivative obtained in Example 15 is heated with a 10 ml. 50% methanol-water solution of .5 g. of potassium hydroxide for one hour. After evaporation of the methanol in vacuo the reaction mixture is acidified with glacial acetic acid. The resultant solids are removed by filtration, washed with water and dried to yield 2-(methoxycarbonylamino) 6-(p-hydroxyphenylthio) imidazo [1,2-a] pyridine.
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][C:28]([F:31])([F:30])[F:29])(=O)OC.O.[NH2:34][NH2:35]>>[CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4]1[C:3]2=[N:34][N:35]=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][C:28]([F:31])([F:30])[F:29])[CH:19]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: COP(=O)(CC(=O)c1ccccc1OC(F)(F)F)OC
Reactant: NN
Solvent: O
Product: CC1(C)[C@H]2CC[C@]1(C)c1nnc(-c3ccccc3OC(F)(F)F)cc12

Procedure:
light yellow solid. MS (EI): 348.0 (M+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [2-Oxo-2-(2-trifluoromethoxy-phenyl)-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=3)=[N:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O>[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([C:34]2[NH:21][C:16]3[CH:15]=[C:14]([C:12]4[O:13][C:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=5)=[N:10][N:11]=4)[CH:19]=[CH:18][C:17]=3[N:20]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: Nc1ccc(-c2nnc(Nc3cccc(Cl)c3)o2)cc1N
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCc1cc(C)c(-c2nc3ccc(-c4nnc(Nc5cccc(Cl)c5)o4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-[5-(3-chlorophenylamino)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diamine (210 mg, 0.7 mmol) and 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester (169 mg, 0.77 mmol) (from step D) in DMSO (2.5 mL) was added Yb(OTf)3 (86 mg, 0.14 mmol) and the mixture was stirred at RT for 72 h. The mixture was poured into water and the resulting precipitate was filtered and washed with water. The solid was purified by flash chromatography using 10% MeOH/CH2Cl2 as eluent to give the title compound as a tan solid. MS: m/z 502.0 (M+1). H1-NMR (DMSO-d6): δ ppm 12.91 (m, 0.6H), 10.93 (s, 0.3H), 10.48 (dd, 0.3H), 8.33 (s, 0.4H), 8.13 (s, 0.6H), 7.89-7.73 (M, 2.3H), 7.68 (d, 0.3H), 7.59 (d, 0.4H), 7.52 (m, 1H), 7.46-7.35 (m, 1H), 7.08 (s, 3H), 3.61 (s, 3H), 2.87 (t, 2H), 2.69 (t, 2H), 2.10 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:32][C:33]1N=[C:37]([CH2:39][N:40]2CCNCC2)[CH:36]=[CH:35][CH:34]=1.CC1[N:52]=C(C=O)C=CC=1>>[NH:52]1[C:32]2[C:37](=[C:36]([C:2]3[N:3]=[C:4]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=6)[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:39]=[N:40]1
Reactant: Cc1cccc(CN2CCN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2)n1
Reactant: Cc1cccc(C=O)n1
Reactant: Cc1cccc(CN2CCNCC2)n1
Product: Cc1cccc(CN2CCN(Cc3cc4nc(-c5cccc6[nH]ncc56)nc(N5CCOCC5)c4s3)CC2)n1

Procedure:
Via 2-chloro-6-[4-(6-methyl-pyridin-2-ylmethyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared from 1-(6-methyl-pyridin-2-ylmethyl)-piperazine. The amine, 1-(6-methyl-pyridin-2-ylmethyl)-piperazine, was prepared using 6-methyl-2-pyridinecarboxaldehyde, analogous to 124.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:10]([C:12]1[S:13][C:14]([CH2:18][CH2:19]O)=[C:15]([CH3:17])[N:16]=1)[CH3:11].[OH-].[Na+]>CCCCCC.O>[CH2:10]([C:12]1[S:13][C:14]([CH2:18][CH2:19][O:2][N+:1]([O-:4])=[O:3])=[C:15]([CH3:17])[N:16]=1)[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: CCc1nc(C)c(CCO)s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Product: CCc1nc(C)c(CCO[N+](=O)[O-])s1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
Fifteen (15) ml of nitric acid of (85-90%) were added dropwise to 15 ml of sulfuric acid (95-98%) over a time period of 20 minutes while keeping the temperature at 0-5° C. After 2 hours, 14.3 grams (83.60 mmol) of 2-ethyl-4-methyl-5-thiazoleethanol, prepared as described above, were added, while the temperature was still maintained at 0-5° C., the reaction mixture was stirred for 2 hours at the same temperature, and was then poured carefully onto 125 ml of cold water. The water solution was made basic with a 20% aqueous solution of sodium hydroxide and the aqueous phase was extracted with three portions of 75 grams of dichloromethane. The extracts were combined and dried over sodium sulfate, filtered and evaporated to dryness. Chromatography of the crude product on silica gel (using a mixture of 75:25 ethyl acetate:hexane as an eluent) yielded 10.5 grams (58% yield) of colorless liquid having a purity of 98%, as determined by gas chromatography.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(N(CC)CC)C.[C:35]1([CH2:41][CH2:42][S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[O:15][C:45](=[O:46])[C:44]([S:43][CH2:42][CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:48]([OH:49])[CH:14]=2)[CH:8]=1
Reactant: CC(=O)c1cccc(-c2ccccc2)c1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1oc(-c2cccc(-c3ccccc3)c2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3'-phenylacetophenone (2.00 g, 10.21 mmol), trimethylsilyltriflate (2.36 mL, 12.24 mmol), triethylamine (2.84 mL, 20.40 mmol), methylene chloride (26 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 93-94° C.; 1H NMR (400 MHz, DMSO-d6) δ2.79 (t, 2 H), 3.01 (t, 2 H), 6.92 (s, 1 H), 7.21 (m, 5 H), 7.42 (t, 1 H), 7.52 (t, 2 H), 7.64 (t, 1 H), 7.75 (d, 2 H), 7.82 (t, 2 H), 8.02 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(O)[CH2:3]1.O=P(Cl)(Cl)Cl.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5][C:4]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:3]1
Reactant: CC1(C)CC(C)(C)CC(O)(C#Cc2ccccn2)C1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)C=C(C#Cc2ccccn2)CC(C)(C)C1
Yield: 79.3 %

Procedure:
3,3,5,5-Tetramethyl-1-(2-pyridinylethynyl)cyclohexanol (200 mg, 0.78 mmol) was dissolved in pyridine. POCl3 (153 mg, 1.0 mmol) was added, and the mixture was heated to reflux for 6 h. After cooling, the POCl3 and pyridine were removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 2:1 hexane:ethyl acetate to afford 2-[(3,3,5,5-tetramethyl-1-cyclohexen-1-yl)-ethynyl]pyridine (148 mg, 80% yield) as a light tan solid. M.p. 55-56° C. 1H NMR (CDCl3, 300 MHz) Δ8.56 (m, 1H), 7.62 (m, 1H), 7.40 (d, J=7 Hz, 1H), 7.18 (m 1H), 6.09 (s, 1H), 2.00 (s, 2H), 1.35 (s, 2H), 1.05 (s, 6H), 0.99 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][CH:28]=[N:29][CH:30]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[N:29][CH:30]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3cncnc3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (133 mg, 0.75 mmol) and 3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (223 mg, 0.75 mmol) in xylene (15 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light red solid (250 mg, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](O)([CH3:19])[CH3:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C(O)(=[O:23])C.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[Cl:35][CH2:36][C:37]#[N:38]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]([C:17]([NH:38][C:37](=[O:23])[CH2:36][Cl:35])([CH3:19])[CH3:18])=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)O
Reactant: N#CCCl
Reactant: Cn1cc(Br)cc(Nc2ccc(C(C)(C)O)cn2)c1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cn1cc(Br)cc(Nc2ccc(C(C)(C)NC(=O)CCl)cn2)c1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
5-Bromo-3-[5-(1-hydroxy-1-methyl-ethyl)-pyridin-2-ylamino]-1-methyl-1H-pyridin-2-one (4.7 g, 13.9 mmol) was suspended in chloro acetonitrile (28 ml). Acetic acid (2.4 ml) was added to the suspension at ambient temperature and cooled to 0° C. Sulfuric acid, concentrated solution (2.4 ml) was added slowly to the cooled suspension. The reaction mixture was stirred 4 hr at room temperature then poured into ice. Ethyl acetate was added. Sodium bicarbonate was slowly added to neutralize the acidic mixture. A white precipitate was collected to give N-{1-[6-(5-Bromo-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino)-pyridin-3-yl]-1-methyl-ethyl}-2-chloro-acetamide (4 g, 70%) as a off-white solid. MS (H+)=415.0
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:34]=[CH:35][CH:36]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][O:17][C:18]3[CH:31]=[CH:30][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:20][CH:19]=3)[N:13]([CH3:32])[C:12]=2[CH:33]=1.[CH2:37]([N:43]=[C:44]=[O:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C(N(CC)CC)C>CN(C)C=O>[O:28]=[C:26]1[NH:25][C:24](=[O:29])[CH:23]([CH2:22][C:21]2[CH:30]=[CH:31][C:18]([O:17][CH2:16][C:14]3[N:13]([CH3:32])[C:12]4[CH:33]=[C:8]([O:7][C:6]5[CH:5]=[C:4]([NH:3][C:44]([NH:43][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:45])[CH:36]=[CH:35][CH:34]=5)[CH:9]=[CH:10][C:11]=4[N:15]=3)=[CH:19][CH:20]=2)[S:27]1
Reactant: CCCCCCN=C=O
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(N)c3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCNC(=O)Nc1cccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 67.8 %

Procedure:
A mixture of 5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), n-hexyl isocyanate (280 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 7 hours and then allowed to stand overnight. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate/n-hexane=3:1→4:1→ethyl acetate→ethyl acetate:methanol=15:1 as the eluant. The product was recrystallized from ethyl acetate to afford the title compound (298 mg, mp 143.7-146.9° C.).
Reaction SMILES: [NH2-].[Na+].[Br-].[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:6][CH2:7][CH3:8])=[O:5].[N+:39]([C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH:45]=O)([O-:41])=[O:40].CCOCC>O1CCCC1.O>[CH2:7]([O:6][C:4](=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:45][C:44]1[CH:47]=[CH:48][CH:49]=[C:42]([N+:39]([O-:41])=[O:40])[CH:43]=1)[CH3:8]
Reactant: CCOC(=O)CCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCCCCCCCCC=Cc1cccc([N+](=O)[O-])c1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
Sodium amide (0.40 g, 9.74 mmol) was weighed directly into a flame-dried 50 ml round-bottomed flask filled with argon. 11-Carbethoxyundecyltriphenylphosphonium bromide (5.00 g, 9.0 mmol) was added followed by anhydrous tetrahydrofuran (THF, 15 ml). The mixture was cooled to -30° C. After the reaction mixture had stirred for 30 minutes at -30° C., a solution of m-nitrobenzaldehyde (1.4 g, 9.30 mmol) in anhydrous THF (5 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred for 4 hours. Ether was added. The reaction mixture was cooled to 0° C., and H2O was cautiously added to destroy residual base. The ether layer was removed, washed with H2O, 2% NaHSO4 and brine, and dried (MgSO4). The solvent was evaporated under reduced pressure to yield an oily residue. Purification by column chromatography (150 g silica gel, hexanes:ethyl acetate, 15:1) gave the pure compound 4, ethyl-12-(m-nitrophenyl)-11-dodecenoate (1.323 g, 42% yield).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[C:13](O)(C)[CH2:12][CH2:11][CH2:10]N1S(C1C=CC(O)=CC=1)(=O)=O)=O)([CH3:4])([CH3:3])C.[C:26](=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[CH:6]([O:5][CH:1]([CH3:3])[CH3:4])([CH3:8])[CH3:26].[CH3:10][CH2:11][CH2:12][CH2:13][CH2:8][CH3:6]
Reactant: CC(C)(C)OC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCCC1(C)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)OC(C)C
Product: CCCCCC

Procedure:
A mixture of 3-hydroxy-1-(4-hydroxy-benzenesulfonyl)-3-methyl-piperidine-2-carboxylic acid tert-butyl ester (XIX, 0.20 g, 0.54 mmol), the appropriate alkyl halide (0.81 mmol), cesium carbonate (0.35 g, 1.1 mmol) and dimethylformamide (1 ml) was stirred at about 23° C. for about 24 hours. The mixture was diluted with ethyl acetate, washed 5 times with water, dried over sodium sulfate, filtered and concentrated. Trituration of the residue from isopropyl ether-hexane afforded the corresponding 3-hydroxy-1-(4-arylmethoxy-benzenesulfonyl)-3-methyl-piperidine-2-carboxylic acid tert-butyl ester (compound of formula XX) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:16]=1.[CH3:17][I:18]>CO>[I-:18].[CH3:17][N+:13]1[CH:14]=[CH:15][C:10]([C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:16][C:6]=3[CH:7]=2)=[CH:11][CH:12]=1
Reactant: Fc1ccc2oc(-c3ccncc3)cc2c1
Reactant: CI
Solvent: CO
Product: C[n+]1ccc(-c2cc3cc(F)ccc3o2)cc1
Product: [I-]

Procedure:
18.5 g (0.087 mole) of 4-(5-fluoro-2-benzofuranyl)-pyridine is dissolved in 170 ml of methanol, and the solution is stirred with 57 ml of methyl iodide for 15 hours at 40°-45°. The solution is thereupon cooled to -10°, and the precipitated salt is filtered off with suction. The filter residue is subsequently washed with 100 ml of cold isopropanol. The 1-methyl-4-(5-fluoro-2-benzofuranyl)-pyridinium-iodide thus obtained can be directly further processed.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][OH:5].[Cr](O)(O)(=O)=[O:23].S(OS([O-])=O)([O-])=O.[Na+].[Na+]>CC(C)=O.C(O)(=O)C.O>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][C:4]([OH:23])=[O:5]
Reactant: O=[Cr](=O)(O)O
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
3,7,11,15-Tetramethyl-hexadecan-1-ol (8.96 g, 30.0 mmol) was dissolved in a mixed solvent of acetone (360 ml) and acetic acid (180 ml), a solution of anhydrous chromic acid (7.27 g, 72.7 mmol) in water (9.0 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. A solution of sodium disulfite (100 g, 526 mmol) in water (450 ml) was added to the reaction mixture after completion of the reaction, the mixture was stirred at room temperature overnight and extracted 6 times with diethyl ether (135 ml). The solvent of the obtained organic layer was evaporated under reduced pressure. Diethylether (450 ml) and water (150 ml) were added to the oil after concentration to allow partitioning, and the aqueous layer was extracted 3 times with ethyl acetate (150 ml). The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The oil (10.1 g) after concentration was purified by chromatography (silica gel; 250 g, eluate; 50:1→3:1 hexane-ethyl acetate) to give the title compound (6.78 g, 72.3%) as a pale-blue oil.