Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([N:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:18]([O:20][CH3:21])=[O:19])[N:11]=[C:10]1[CH2:22][O:23][CH3:24])C1C=CC=CC=1>O1CCOCC1.CO.[Pd]>[CH3:24][O:23][CH2:22][C:10]1[NH:11][C:12]([C:18]([O:20][CH3:21])=[O:19])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[N:9]=1
Reactant: COCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
650 mg of 10% w/w palladium-on-carbon and 6.1 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 6.5 g of dimethyl 1-benzyl-2-methoxymethylimidazole-4,5-dicarboxylate [prepared as described in step (iii) above] in 65 ml of methanol. The mixture was then stirred at room temperature for 1.5 hours under a hydrogen atmosphere. At the end of this time, the catalyst was filtered off and the filtrate was concentrated by evaporation under reduced pressure, to give a crystalline compound. This crystalline compound was washed with ethyl acetate, no give 5.13 g of the hydrochloride of the title compound, melting at 108°-111° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([C:16](=[CH:22]OCC)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:15])[CH2:12][CH2:13][CH3:14]>>[C:11]([C:16](=[CH:22][NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Reactant: COc1cc(O)ccc1N
Product: CCCC(=O)C(=CNc1ccc(O)cc1OC)C(=O)OCC
Yield: 99.4 %

Procedure:
4-Amino-3-methoxyphenol (21 g) and ethyl 2-butyryl-3-ethoxyacrylate (36 g) were heated together at 90°-110° for 30 minutes to afford ethyl 2-butyryl-3-(4-hydroxy-2-methoxyphenylamino)acrylate (46.1 g, 77%) as a brown solid, m.p. 140°-142°.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH:14]([CH3:18])[C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[O:28][CH3:29]>>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:15](=[O:17])[CH:14]([C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH3:18])=[CH:23][C:22]=1[O:28][CH3:29]
Reactant: COc1cc(N)ccc1F
Reactant: CC(C(=O)[O-])c1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: COc1cc(NC(=O)C(C)c2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Yield: 21.9 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 100 mg of sodium 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]propanoate and 195 mg of 4-fluoro-3-methoxyaniline in place of the 2,4-difluoroaniline. 30 mg of N-(4-fluoro-3-methoxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]propanamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:37])=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]3[CH:36]=[CH:35][C:26]4[C@H:27]([CH2:30][C:31]([O:33]C)=[O:32])[CH2:28][O:29][C:25]=4[CH:24]=3)[CH:16]=2)[C:5]([CH3:14])=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][O:11][CH2:10]1.[OH-].[Li+]>CO.O1CCCC1>[F:1][C:2]1[C:3]([CH3:37])=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]3[CH:36]=[CH:35][C:26]4[C@H:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][O:29][C:25]=4[CH:24]=3)[CH:16]=2)[C:5]([CH3:14])=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCOC5)c(F)c4C)c3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(O[C@H]2CCOC2)c(F)c(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 2 h
Yield: 57.5 %

Procedure:
Methyl 2-((S)-6-((3′-fluoro-2′,6′-dimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy) biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 19d (150 mg, 0.30 mmol) was dissolved in 4 mL of a mixture of the solvents of methanol and tetrahydrofuran (V/V=1:1), followed by addition of 1M aqueous lithium hydroxide solution (1.5 mL, 1.50 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure, mixed with 10 mL of water, 1M hydrochloric acid was added dropwise to adjust the pH to 2˜3, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by TLC with elution system A to obtain the title compound 2-((S)-6-((3′-fluoro-2′,6′-dimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 19 (85 mg, yield 57.8%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22]CC(OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.[C:38]([O:42]C(=O)CN)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][NH:22][C:20]([C@H:19]([NH:18][C:16]([N:13]1[C:14](=[O:15])[CH:8]([CH2:7][C:6]2[CH:34]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:35][CH3:36])[CH2:9][NH:10][C:11](=[O:33])[CH2:12]1)=[O:17])[CH2:31][CH3:32])=[O:21])([CH3:41])([CH3:40])[CH3:39]
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NOC(C)(C)C

Procedure:
Instead of the starting material compound of Example 220, that is, glycine tert-butyl ester hydrochloride, O-(tert-butyl)hydroxylaminehydrochloride was used for the similar procedure as in Example 220 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([C:18]([N:15]3[CH2:16][CH2:17][CH:12]([CH3:11])[CH2:13][CH2:14]3)=[O:19])[N:9]=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2nn[nH]c2c1
Reactant: CC1CCN(C(=O)Cl)CC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1CCN(C(=O)n2nnc3ncc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-Chloro-1H-[1,2,3]triazolo[4,5-b]pyridine (200 mg, 1.29 mmol) and 4-methyl-piperidin-1-carbonyl chloride (418 mg, 2.56 mmol) were dissolved in 10 ml of pyridine. Then triethylamine (180 μl, 3.88 mmol) was added and stirred at room temperature for 4 h and left to stand overnight. The reaction mixture was concentrated and the residue was mixed with water and ethyl acetate. The organic phase was separated off, the aqueous phase was extracted once more, and the combined organic phases were washed with water and concentrated. The crude product was purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 106 mg (29%) of (6-chloro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-(4-methyl-piperidin-1-yl)-methanone, M+H+: 280.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:17][CH2:18][C:19](OC)=[O:20])[C:13](OC)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>C1COCC1.[Cl-].[Na+].O.O>[OH:20][CH2:19][CH2:18][CH2:17][C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][OH:14]
Reactant: COC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)OC
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H](CO)CCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
A solution of dimethyl (2R)-2-{[(benzyloxy)carbonyl]amino}pentanedioate (22.4 g) in dry THF (74 ml) was added dropwise over 1 h to a stirred mixture of lithium borohydride (4.5 g) in THF (200 ml) at room temperature, under nitrogen. Stirring at room temperature was continued for 3 days. The reaction mixture was diluted with brine and water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (16.5 g) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1.S(Cl)([Cl:18])(=O)=O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:18])=[O:11])=[CH:8][CH:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(O)c1ccc(-c2cccs2)cc1
Product: O=C(Cl)c1ccc(-c2cccs2)cc1

Procedure:
A mixture of 3 g of 4-(2-thienyl)benzoic acid and 30 ml of sulfonyl chloride is refluxed for 45 minutes and the solvent removed. The residue is dissolved in carbon tetrachloride and the solvent removed under vacuum (2-times) to give 4-(2-thienyl) benzoyl chloride. To a cooled (0° C.) solution of 2.0 g of 5,11-dihydro-10H-dibenz[b,e][1,4]diazepine and 7 ml of N,N-diisopropylethylamine in 30 ml of dichloromethane is added dropwise a solution of 3.15 g of 4-(2-thienyl)benzoyl chloride in 30 ml of dichloromethane. The mixture is stirred at room temperature for 16 hours and diluted with 50 ml of chloroform. The solution is washed with 30 ml each of water, 2N HCl, saturated NaHCO3, water and dried (Na2 SO4). The solvent is removed under vacuum and the residue (3.1 g) chromatographed on silica gel (column) with hexane-ethyl acetate (2:1) as eluent to give 1.8 g of solid, m.p. 114° C.-116° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1nc[nH]n1
Reactant: Ic1ccccc1
Product: c1ccc(-n2cncn2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-[1,2,4]triazole (104 mg, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 120 mg (83% isolated yield) of the desired product as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[N:8][N:9]=1
Reactant: COc1ccc2c(-c3cccs3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(-c3cccs3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-(thiophen-2-yl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:8])=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(Br)c(OCC(F)(F)F)c1
Product: O=C(c1ccc(Br)c(OCC(F)(F)F)c1)N1CCCC1

Procedure:
Starting with 4-bromo-3-(2,2,2-trifluoroethoxy)benzoic acid and pyrrolidin, Int06.06 was prepared analogously to the procedure for the preparation of Int02.05.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.C([O-])(=O)C.[K+].C(OC([N:41]1[CH:45]=[CH:44][CH:43]=[CH:42]1)=O)(C)(C)C>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][C:8]=2[C:7](=[O:27])[N:6]([CH3:28])[C:5]2[CH:4]=[CH:3][C:2]([C:42]3[NH:41][CH:45]=[CH:44][CH:43]=3)=[N:12][C:11]1=2)[CH3:14]
Reactant: CCN1c2ncc(CCc3ccccc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: CC(C)(C)OC(=O)n1cccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1c2ncc(CCc3ccccc3)cc2C(=O)N(C)c2ccc(-c3ccc[nH]3)nc21
Temperature: 125 °C
Yield: 18.2 %

Procedure:
A mixture containing 2-chloro-5,11-dihydro-11-ethyl-5-methyl-8-(2-phenylethyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.10 g, 0.26 mmol), potassium acetate (0.05 g, 0.51 mmol), N-(tert-butyloxycarbonyl)pyrrole (0.078 g, 0.47 mmol), and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol) in 2 mL of N,N-dimethylformamide was heated in a sealed tube at 125° C. for 10 hours. Additional potassium acetate (50 mg), N-(tert-butyloxycarbonyl)pyrrole (0.08 g), and tetrakis(triphenylphosphine)palladium(0) (15 mg) were added, and the reaction mixture was heated at 140° C. for an additional 8 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated. Purification by flash chromatography, eluting with ethyl acetate/hexanes, provided 20 mg of the title compound, as a foam.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-:16])[CH:5]=[CH:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-:16])=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(CSc2cccc[n+]2[O-])c1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(CS(=O)c2cccc[n+]2[O-])c1

Procedure:
The procedure employed is identical with that of Example 68 using 4.6 gm (0.02 mol) 2-(3-Methylphenylmethylthio)pyridine N-oxide in 50 ml of chloroform and 4 gm (0.02 mol) MCPBA in 100 ml chloroform.
Reaction SMILES: [CH2:1]([CH:5]1[CH:13]2[C:9]([CH2:10][CH2:11][CH2:12]2)=[CH:8][C:7](=[O:14])[CH2:6]1)[CH:2]([CH3:4])[CH3:3]>[Pd]>[CH2:1]([CH:5]1[CH:13]2[CH:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8][C:7](=[O:14])[CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1CC(=O)C=C2CCCC21
Agent: [Pd]
Product: CC(C)CC1CC(=O)CC2CCCC21
Yield: 95 %

Procedure:
5-Isobutylbicyclo [4.3.0] non-1-en-3-one (25.4 g, 0.13 mol) is treated according to the procedure of Example 8 with 0.5 g of 5% palladium on carbon. Distillation gives 24 g (bp 90°-92° C. at 0.5 mm) of pure 5-isobutylbicyclo [4.3.0] nonan-3-one represented by the structure: ##STR11##
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>O1CCCC1.CO>[F:18][C:17]([F:19])([F:20])[C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 50 °C
Yield: 89.2 %

Procedure:
A mixture of 3.56 g (12 mmol) of 4-(3-trifluoromethyl-phenoxy)-benzoic acid methyl ester, and 15 mL (60 mmol) of 4 N sodium hydroxide (NaOH) solution in 45 mL of tetrahydrofuran (THF) and 15 mL of methanol (MeOH) was heated at 50° C. for 25 h, when analysis by thin layer chromatography revealed complete conversion of starting material to product. The reaction mixture was concentrated and acidified with 2N HCl solution while keeping the flask in an ice bath, when a white precipitate formed. The solid was filtered and dried to give 3.02 g (89%) of desired 4-(3-trifluoromethyl-phenoxy)-benzoic acid as a white solid as indicated by 1H NMR and 19F-NMR.
Reaction SMILES: [C:1]([N:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[CH:11]=2)[CH:8]=[C:7]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[C:1]([N:4]1[CH2:5][CH2:6][C:7]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])=[CH:8][CH:9]1[C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: COc1cccc(C2C=C(c3cc(F)ccc3F)CCN2C(C)=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)N1CCC(c2cc(F)ccc2F)=CC1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-Acetyl-4-(2,5-difluorophenyl)-6-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (1-6,20 mg, 0.06 mmol) was dissolved in CH2Cl2 (1 mL) and treated with BBr3 (0.58 mL, 1M in CH2Cl2, 0.6 mmol). The reaction was stirred 6 h at 25° C. until completion. The reaction solution was washed with 5% NH4Cl (aq.), dried with MgSO4 and filtered. Following concentration under reduced pressure, the crude was purified via reverse phase column chromatography (CH3CN/H2O/0.1% TFA gradient) to provide 3-[1-Acetyl-4-(2,5-difluorophenyl)-1,2,5,6-tetrahydropyridin-2-yl]phenol (1-7). δ 7.26 (m, 2H), 6.96 (m, 5H), 6.38 (s, 1H); 6.15 (m, 1H), 3.79 (dd, J=13.7, 4.9 Hz, 1H), 3.42 (dt, J=11.0, 3.7 Hz, 1H); 2.75 (m, 1H); 2.42 (dd, J=16.0, 1.0 Hz, 1H), 2.21 (s, 3H); MS 330.0 found, 330.4 (M+H+) required.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].C[C:28]1[CH:33]=[CH:32][C:31](B(O)OOCC)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:28]2[CH:29]=[CH:30][C:31]([O:4][CH:5]([CH3:18])[CH3:6])=[CH:32][CH:33]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CCOOB(O)c1ccc(C)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(OC(C)C)cc2)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-methylethoxy-phenylboronic acid, 5-[4-(1-methylethoxy)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=55%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[NH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:14][CH2:13]1.C(Cl)Cl>CCOCC>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][N:12]([NH:11][C:8]([NH:7][C:4]3[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=3)=[O:9])[CH2:13][CH2:14]2)=[CH:21]1
Reactant: NN1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)NN2CCN(CCc3c[nH]c4ccccc34)CC2)cc1
Reaction time: 3 h

Procedure:
4.0 g of p-tolylisocyanate are added dropwise to a stirred solution of 6.13 g of 3-[2-(4-aminopiperazin-1-yl)-ethyl]indole in 100 ml. of dry methylene chloride while maintaining the reaction temperature below 35° C. After three hours at ambient temperature, ether is added to promote precipitation. The precipitate is filtered, washed with ether, and dried. The resulting solid is recrystallized twice from a methanol and water mixture to give 1-[1-(indol-3-ylethyl)piperazin-4-yl]-3-p-tolylurea, m.p. 201°-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH2:13][CH2:12]1)=[O:10].[I-].[CH3:20]CCCCCCCCCCCCC[N+](C)(C)C.[OH-].[Na+]>ClC(Cl)(Cl)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:11]2([N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[CH2:12][CH2:13]2)[CH2:20][O:10]1
Reactant: O=C(c1ccc(Cl)cc1Cl)C1(n2cncn2)CC1
Reactant: CCCCCCCCCCCCCC[N+](C)(C)C
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)(Cl)Cl
Product: Clc1ccc(C2(C3(n4cncn4)CC3)CO2)c(Cl)c1

Procedure:
1-(1-H-1,2,4-Triazol-1-yl)cyclopropyl 2,4-dichlorophenyl ketone (0.5 g, 1.8 mMole) was added to trimethylsulfphoxonium iodide (0.57 g, 2.6 mMole), cetrimide (0.02 g), 1,1,1-trichloroethane (10 ml) and aqueous sodium hydroxide solution (5 ml of 20%). The mixture was refluxed for twenty hours.
Reaction SMILES: [C:1]1([S:7][C@@H:8]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C@H:25]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C@H:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:9]2[O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:51])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]1([S:7]([C@@H:8]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C@H:25]([O:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:30])[CH3:31])[C@H:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:21])[CH3:22])[C@H:9]2[O:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15])=[O:51])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](S(=O)c2ccccc2)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H]1OC(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of thioglycoside 40 (0.62 g, 1.0 mmol) in 20 mL of CH2Cl2 at -78° C. is added 67% m-CPBA (0.26 g, 1.0 mmol). The reaction mixture is stirred at -78° C. for 2 h and then allowed to slowly warm up to room temperature. Saturated NaHCO3 is added until the solution is basic. The reaction mixture is diluted with 100 mL of CH2Cl2 and washed with H2O (100 mL), saturated NaCl (100 mL), dried over Na2SO4, filtered, concentrated and purified by flash chromatography (15% EtOAc/hexane) to give 0.59 g (92%) of the title compound 41 as a mixture of diastereomers: Rf 0.38, 0.19 (20% EtOAc/hexane). FABMS C32H48O10S (MNa+) calcd 647.2866, found 647.2868.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:14]=[C:13]([O:15][CH:16]([CH3:18])[CH3:17])[N:12]=[C:11](O)[N:10]=1)[CH2:2]2.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:11]1[N:10]=[C:9]([N:3]2[CH2:4][CH:5]3[O:8][CH:1]([CH2:7][CH2:6]3)[CH2:2]2)[CH:14]=[C:13]([O:15][CH:16]([CH3:18])[CH3:17])[N:12]=1
Reactant: CC(C)Oc1cc(N2CC3CCC(C2)O3)nc(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)Oc1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
In a 25 mL round-bottomed flask was placed 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-isopropoxypyrimidin-2-ol (31, 215 mg, 0.810 mmol) in POCl3 (20 ml) to give a fine off-white suspension. The mixture was stirred at 100° C. for 16 h. The mixture was cooled to room temperature, concentrated, diluted with dichloromethane, and washed with saturated NaHCO3. The aqueous phase was made basic with NaOH (5N) to pH 10 and extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered and concentrated to give the title compound (106 mg, 46%). Aryl chloride 32 could be transformed into aniline 19 as described in scheme 2 for the conversion of 5 into 6. Aniline 19 could be transformed into urea or carbamate compounds as described in scheme 2 (and illustrated in the experimental section for scheme 8).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(OCC)C>[O:13]1[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:11][CH2:12]1
Reactant: NCCN1CCOCC1
Reactant: C=C1CC(=O)O1
Solvent: CCOCC
Product: CC(=O)CC(=O)NCCN1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of diketene (23.0 ml) in diethyl ether (115 ml) was added dropwise a solution of N-(2aminoethyl)morpholine (34.7 g) in diethyl ether (300 ml) at -40° C. After stirring for 2 hours at the same condition, the resulting precipitates were collected by filtration and dried in vacuo to give N-(2morpholinoethyl)acetoacetamide (41.1 g).