Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH2:12])=[O:11].[Cl:13][CH2:14][C:15]([CH2:17]Cl)=O>>[Cl:13][CH2:14][C:15]1[N:12]=[C:10]([C:2]2[S:1][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=3[CH:3]=2)[O:11][CH:17]=1
Reactant: NC(=O)c1cc2c(s1)CCCC2
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2cc3c(s2)CCCC3)n1
Yield: 53 %

Procedure:
In substantially the same manner as in Reference Example 47, 4,5,6,7-tetrahydro-2-benzothiophene carboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(4,5,6,7-tetrahydro-2-benzothienyl)oxazole. The yield was 53%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 102-103° C.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].CCCCCCCCCCCCCC(NCC(N[C@H](C(N[C@H](C(N[C@H](C(N1[C@H](C(N2[C@H](C(N[C@H](C(N3[C@H](C(N4[C@H](C(N[C@H](C(N[C@H](C(N5[C@H](C(N)=O)CCC5)=O)C[O:100][P:101](O)([OH:103])=[O:102])=O)CCC(N)=O)=O)CCC4)=O)CCC3)=O)C)=O)CCC2)=O)CCC1)=O)C)=O)CCC(O)=O)=O)CCCCN)=O)=O>>[CH2:11]([O:12][P:101]([OH:103])([OH:102])=[O:100])[C@H:9]1[O:10][C@@H:2]([OH:1])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCCC(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](COP(=O)(O)O)C(=O)N1CCC[C@H]1C(N)=O
Product: O=P(O)(O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
HEK 293 cells were grown in 10 cm plates with Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal calf serum (FCS). On the day of the experiment, cells were incubated with low glucose medium supplemented with 0.5% FCS for 1 hour, followed by the addition of the conjugate L803-mts or its respective controls LE803-mts and LS803-mts at various concentrations, for additional 2.5 hours. A vehicle control of DMSO (0.1% DMSO) was also tested. Cells were thereafter washed twice with ice-cold GS buffer (50 mM Tris, pH=7.8, 100 mM NaF, 10 mM EDTA with protease inhibitors: 20 μg/ml leupeptine, 10 μg/ml aprotinine, 10 mg/ml pepstatin A, 1 mM benzamidine), scraped with the same buffer, and frozen in liquid nitrogen (as described in Eldar-Finkelman et al., 1996). Glycogen synthase activity was assayed according to the method of Thomas et al. (1968), based on the incorporation of uridine 5-diphosphate [14C] glucose (UDPG) into glycogen. Aliquots of cell lysates (15 μl) were incubated with 15 μl reaction mixture (66.6 mM Tris, pH=7.8, 32.5 mM KF, 0.8 μCi/μl [14C]-UDPG (400 μM), 13 mg/ml glycogen rabbit liver, Sigma) for 20 minutes at 30° C. (as described in Eldar-Finkelman et al., 1996). The reactions were then spotted on ET31 (Whatman) papers, washed with 66% ice-cold ethanol, and counted for radioactivity. Glycogen synthase assays were measured in the presence of 0.1 mM glucose-6-phosphate (G6P). Similar results were obtained when G6P was absent in the assays (data not shown).
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.N1C=CC=CC=1.[C:32]1([CH3:42])[CH:37]=[CH:36]C(S(Cl)(=O)=O)=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:21][S:22]([C:25]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:24])=[O:23])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: COC(=O)c1cn2c3c(c(OS(C)(=O)=O)c(F)cc3c1=O)CCN2C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cn2c3c(c(OS(=O)(=O)c4ccc(C)cc4)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
304 mg of the compound (168) obtained in Example 45 was added to 2 ml of pyridine, and 260 mg of p-toluene-sulfonyl chloride was added to the solution. The solution was stirred for 2 hours at room temperature. 50 ml of chloroform was added to the solution, and the solution was washed with water and aqueous 5% citric acid solution. The organic layer was separated, and after drying over magnesium sulfate, the solvent was removed by distillation. To the residue, ethanol was added, and the solid matter was filtered off and washed with isopropyl ether to obtain 220 mg of the subject compound (169).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([NH:13][C:14]([C:16]3[CH:32]=[CH:31][C:19]([O:20][C@@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([O:29]C)=[O:28])[CH2:23][CH2:22]4)=[CH:18][CH:17]=3)=[O:15])=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([NH:13][C:14]([C:16]3[CH:32]=[CH:31][C:19]([O:20][C@@H:21]4[CH2:22][CH2:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]4)=[CH:18][CH:17]=3)=[O:15])=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Nc3nnc(-c4cccc(Cl)c4)s3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1nnc(-c2cccc(Cl)c2)s1)c1ccc(O[C@H]2CC[C@@H](C(=O)O)CC2)cc1
Reaction time: 18 h
Yield: 65.5 %

Procedure:
150 mg of methyl cis-4-{4-[5-(3-chlorophenyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenoxy}-cyclohexanecarboxylate (0.32 mmol, 1 eq.) is placed in 1 mL of tetrahydrofuran. 27 mg of lithium hydroxide monohydrate (0.64 mmol, 2 eq.) dissolved in 1 mL are added and stirring is continued for 18 hours. The reaction medium is diluted with water, washed with ethyl acetate and acidified with aqueous 6% sulfur dioxide solution. The solid obtained is filtered off by suction and washed successively with water, ethanol and diethyl ether. 96 mg of cis-4-{4-[5-(3-chlorophenyl)[1.3.4]thiadiazol-2-ylcarbamoyl]-phenoxy}cyclohexanecarboxylic acid are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31](=[O:36])[CH2:30][N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)C(C)(C)C)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1 g), 1-bromo-3,3-dimethylbutan-2-one (0.4 mL), potassium carbonate (0.75 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.4 g, 32%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[NH:17][C:16]3[CH2:15][CH2:14][NH:13][C:12](=[O:18])[C:11]=3[CH:10]=2)O1.Br[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([N:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:32])[N:27]=[CH:26]2>>[C:33]([N:31]([CH3:32])[C:28]1[N:27]=[CH:26][C:25]2[C:30](=[C:21]([C:9]3[NH:17][C:16]4[CH2:15][CH2:14][NH:13][C:12](=[O:18])[C:11]=4[CH:10]=3)[CH:22]=[CH:23][CH:24]=2)[N:29]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Reactant: CN(c1ncc2cccc(Br)c2n1)C(C)(C)C
Product: CN(c1ncc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1)C(C)(C)C
Yield: 22.9 %

Procedure:
2-(2-(tert-butyl(methyl)amino)quinazolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (8 mg, 22% yield) as a yellow crystalline solid was prepared according to the procedure described for Example 370, using 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (609) (146 mg, 0.56 mmol), and 8-bromo-N-(tert-butyl)-N-methylquinazolin-2-amine (377a) (30 mg, 0.10 mmol) as the starting materials. 1H NMR (400 MHz, CDCl3) δ ppm 12.87 (1H, br. s.), 9.04 (1H, s), 8.07 (1H, dd, J=7.5, 1.3 Hz), 7.52 (1H, dd, J=7.8, 1.2 Hz), 7.23-7.30 (1H, m), 7.11 (1H, d, J=2.0 Hz), 5.40 (1H, br. s.), 3.66 (2H, td, J=6.8, 2.5 Hz), 3.37 (3H, s), 2.98 (2H, t, J=6.8 Hz), 1.67 (9H, s). m/z (ESI, +ve ion) 350.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[C:14]1([C:20]2[C:21]([O:23][C:24](=O)[CH:25]=2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:22]=[C:21]1[C:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:25][C:24](=[O:23])[N:1]1[CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Product: COC(=O)C(CN1C(=O)C=C(c2ccccc2)C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(2,5-dioxo-3-phenyl-2,5-dihydro-pyrrol-1-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (1.0 g, 56%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (1.00 g, 5.29 mmol) and phenylmaleic anhydride (1.10 g, 6.34 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[C:4]([CH3:12])[CH:3]=1.[CH:13]([Sn](CCCC)(CCCC)CCCC)=[CH2:14]>O1CCOCC1>[CH3:12][C:4]1[CH:3]=[C:2]([CH:13]=[CH2:14])[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=1
Reactant: CC(=O)Nc1cc(C)cc(Br)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Product: C=Cc1cc(C)cc(NC(C)=O)n1
Temperature: 100 °C

Procedure:
37.5 g of N-(6-bromo-4-methyl-pyridin-2-yl)-acetamide (compound G4) is dissolved in 750 ml anoxic dioxane under a nitrogen atmosphere. Subsequently, 70.3 ml of vinyl tributylstannane and 11.5 g trans-dichloro-bis(triphenylphosphane)palladium-(II) are added. The reaction mixture is heated to 100° C. for 65 h. Thereafter, the volatile components are removed in vacuo and the remaining residue is purified by chromatography on silica gel (eluent: toluene/ethyl acetate 6:1) to afford 21.0 g of the title compound. M.p. 140° C. GC-MS: 176.2 (M+). TLC: Rf=0.40 (toluene/ethyl acetate 4:1).
Reaction SMILES: [C:1](OC=O)(=[O:3])C.[CH2:7]([O:14][NH:15][CH2:16][C@@H:17]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:18]([OH:20])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([O:14][N:15]([CH2:16][C@@H:17]([CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1)[C:18]([OH:20])=[O:19])[CH:1]=[O:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)OC=O
Reactant: O=C(O)[C@@H](CNOCc1ccccc1)CC1CCCC1
Solvent: C1CCOC1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Formic acetic anhydride (27.78 g, 0.32 mol) followed by TEA (52.7 mL, 0.38 mol) were added to a cooled (0° C.) solution of 2(R)-(benzyloxyamino-methyl)-3-cyclopentyl-propionic acid in THF (180 mL). The reaction mixture was stirred for 1 hour at 0° C. and then at room temperature for 1 hour before the solvent was removed in vacuo. The residue was purified by column chromatography (SiO2, 25-100% EtOAc in hexanes) to give the title compound as a colourless oil (36.10 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:21][O:22][CH3:25])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(Cl)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
440 mg tert-butyl 4-(4-chlorophenyl)-4-hydroxymethylpiperidine-1-carboxylate are placed in 2.5 ml dimethylformamide and 92 mg sodium hydride (60% in mineral oil) are added. The reaction mixture is stirred for 30 min at ambient temperature, then 95 μl methyl iodide are added. After 1 h the reaction mixture is poured onto ice and the product is extracted with diethyl ether. 370 mg product are obtained as an oil.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH:5]([CH:7]=O)=O>>[NH:3]1[CH:5]2[CH:7]([NH:3][CH2:2][CH2:1][NH:4]2)[NH:4][CH2:1][CH2:2]1
Reactant: NCCN
Reactant: O=CC=O
Product: C1CNC2NCCNC2N1
Temperature: 80 °C

Procedure:
In a 250-ml round bottom flask was placed 24.0 g of ethylene diamine (0.40 mole). This was cooled to 0° C. by a salt/ice bath and 14.5 g of 40% aqueous glyoxal solution (0.10 mole) was added dropwise during the next 30 minutes. This solution was then heated at 80° C. for 5 hours. During the heating period of crystals formed in the solution. The solution was allowed to slowly cool to room temperature, then cooled to 0° C. The product was then collected by vacuum filtration and washed with cold 50% ethanol. The yield of product m.p. 162°-170° C. (decomposition) is 12.0 g (0.085 mole, 85%). ##STR2##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[N:15]O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:26][C:25]([C:24]3[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=3)=[N:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(F)cc1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(F)cc1
Yield: 24.3 %

Procedure:
Ethyl 3-(4-fluorophenyl)-2-hydroxyimino-3-oxopropionate (33.5 g) and 4-nitrobenzylamine (23.7 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-fluorophenyl)-2-(4-nitrophenyl)imidazole-4-carboxylate (12.1 g),whichwasdissolvedinethylalcohol. 1MSodiumhydroxidesolution was added and the mixture was reacted and treated in the same manner as in.Starting Material Synthetic Example 2 to give 5-(4-fluorophenyl)-2-(4-nitrophenyl)imidazole-4-carboxylic acid (10.3 g), melting point 173-178° C. (decomposition).
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]([N:10]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:26][CH3:27])[C:16]=3[OH:25])[CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Cl)=[CH:38][C:37]=1[CH3:44]>>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([N:10]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:26][CH3:27])[C:16]=3[O:25][CH2:40][C:39]3[CH:42]=[CH:43][C:36]([O:35][CH3:34])=[C:37]([CH3:44])[CH:38]=3)[CH2:11]2)=[O:9])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)C1Cc2c(ccc(OC)c2O)CN1C(=O)C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CCl)cc1C
Product: CCOC(=O)C1Cc2c(ccc(OC)c2OCc2ccc(OC)c(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
This compound is prepared from the phenol derivative of Example 31 and 4-methoxy-3-methyl benzyl chloride by a procedure similar to that in Example 32. The product is purified by silica gel chromatography; tlc (1:1 ethyl-acetate/hexane), one spot, Rf 0.7.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([CH3:31])=[C:25]([CH3:32])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH:44]=O)[CH3:43])[CH3:34]>>[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH3:44])[CH:43]=[CH:5][C:4]1[C:25]([CH3:32])=[C:26]([CH3:31])[C:27]([O:29][CH3:30])=[CH:28][C:3]=1[Cl:2])[CH3:34]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: COc1cc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(Cl)cc(OC)c(C)c1C

Procedure:
By the procedure of Example 1, 2-chloro-4-methoxy-5,6-dimethyl-benzyltriphenylphosphonium chloride is reacted with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to obtain 9-(2-chloro-4-methoxy-5,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester, a yellow-red oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:30][C:31]1[C:32]([F:50])=[CH:33][C:34]([OH:49])=[C:35]([C:37]2[CH:38]=[N:39][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:41]=2)[CH:36]=1>>[Cl:30][C:31]1[C:32]([F:50])=[CH:33][C:34]([O:49][C:8]2[CH:7]=[CH:6][C:5]([S:10]([N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH3:29])[C:14]3[S:18][N:17]=[CH:16][N:15]=3)(=[O:11])=[O:12])=[CH:4][C:3]=2[C:1]#[N:2])=[C:35]([C:37]2[CH:38]=[N:39][N:40]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH:41]=2)[CH:36]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc(Cl)c(F)cc2O)cn1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3cc(F)c(Cl)cc3-c3cnn(C(=O)OC(C)(C)C)c3)c(C#N)c2)c(OC)c1

Procedure:
The title compound was prepared using a method analogous to that for Preparation 733 below, using 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 68) and tert-butyl 4-(5-chloro-4-fluoro-2-hydroxyphenyl)-1H-pyrazole-1-carboxylate (Preparation 743). Purification was by column chromatography (silica, heptane-ethyl acetate 10-60% v/v).
Reaction SMILES: Cl[CH2:2][C:3](=[O:25])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[C:26]([O-:29])(=[O:28])[CH3:27].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:26]([O:29][CH2:2][C:3](=[O:25])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)(=[O:28])[CH3:27]
Reactant: CC(=O)[O-]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CCl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
1.0 g of 21-chloro-17-hydroxy-4-pregnene-3,20-dione in 20 ml of dimethylformamide is agitated at 80° C. with 1.0 g of potassium acetate. After 30 minutes, the reaction mixture is introduced into ice water, the precipitated product is suctioned off, dissolved in ethyl acetate, and dried over sodium sulfate, thus obtaining 940 mg of 21-acetoxy-17-hydroxy-4-pregnene-3,20-dione; mp 236.5° C.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15][OH:16])=[O:11])[CH2:5][CH2:4]1)[CH3:2].C[C@H]1CC[C@H](NC([C@@H]2C[C@H]2C[O:31][S:32]([CH3:35])(=O)=[O:33])=O)CC1>>[CH2:1]([C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15][O:16][S:32]([CH3:35])(=[O:33])=[O:31])=[O:11])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H]1C(=O)N[C@H]1CC[C@H](C)CC1
Reactant: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CO)CC1
Product: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2COS(C)(=O)=O)CC1

Procedure:
Follow the procedure of Example 11d, and substitute trans-2-hydroxymethyl-cyclopropanecarboxylic acid trans-(4-ethylcyclohexyl)-amide, Example 13c for methane sulfonic acid 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester therein, to obtain the title compound, m/z=304 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: COc1cccc(-c2ccccc2)c1
Temperature: 130 °C

Procedure:
190 mg 3-bromoanisole, 183 mg phenyl boronic acid and 275 mg potassium carbonate are mixed in 2 ml xylene. To this is added 27 mg of the catalyst from example 5a (corresponds to 0.5 mol % palladium). The reaction mixture is stirred and heated, under an atmosphere of nitrogen, to a temperature of 130° C. for a period of 2 hours. A GC analysis showed that all starting material is consumed and 3-methoxy biphenyl is formed selectively (100% conversion).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH3:16])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([N:15]([CH3:16])[C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][NH:1][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=2)=[O:33])=[CH:22][CH:21]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CN(C(=O)CN(C(=O)CN)c1ccccc1)c1ccc(Cl)cc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccc(Cl)cc2)c2ccccc2)c1
Yield: 32.9 %

Procedure:
The procedure is analogous to that described in Example 1, but 2.2 g of 2-(2-amino-N-phenylacetamido)-N-(4-chlorophenyl)-N-methylacetamide and 0.87 g of 3-methylphenyl isocyanate are used as the starting material. The product obtained is purified by chromatography on 60 g of silica (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: methylene chloride/methanol (99-1 by volume)], collecting 20 cm3 fractions. Fractions 30 to 43 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from acetonitrile, 1.0 g of N-(4-chlorophenyl)-N-methyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 160° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl.[NH2:21][OH:22]>CCO>[OH:22][NH:21][C:7](=[NH:8])[C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=N)NO)cc1
Temperature: 70 °C
Yield: 97.8 %

Procedure:
To a mixture of 4-Methoxy-benzonitrile (1.07 g, 8 mmol) and DIEA (4.11 ml, 24 mmol) in EtOH (12.5 ml) was added 1.7 g of Hydroxylamine hydrochloride (24 mmol) and the reaction was heated at 70° C. for 48 h. Half of the solvent was removed under reduced pressure. The mixture was poured in DCM (100 ml) and water (30 ml). 2.5 ml of NaOH 1N was added until pH=9-10. The organic layer was separated and the aqueous phase was extracted with DCM. The organics layers were combined, washed with water, dried over MgSO4, filtered and evaporated under reduced pressure to afford 1.3 g (98%) of N-Hydroxy-4-methoxy-benzamidine as a colorless oil which can be used without further purification.