Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[I-:2].[F:3][CH2:4][C:5]([N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])([CH2:8][CH2:9][CH2:10]OCC1C=CC=CC=1)[C:6]#[N:7].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC#N.O>[F:3][CH2:4][C:5]([N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])([CH2:8][CH2:9][CH2:10][I:2])[C:6]#[N:7]
Reactant: N#CC(CF)(CCCOCc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: [I-]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#CC(CF)(CCCI)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
Chlorotrimethylsilyl (22 g) is added dropwise over 20 minutes to a suspension of NaI (30 g) in CH3CN (300 ml) cooled to 0° C. Stirring is continued for 30 minutes at room temperature. 2-Fluoromethyl2-phthalimido-5-benzyloxypentanenitrile (25 g) in CH3CN (50 ml) is added, and the mixture is stirred overnight at room temperature. This mixture is then poured into cold water containing sodium bicarbonate and sodium thiosulfate, and extracted with diethyl ether. The organic layer is dried over MgSO4 and concentrated in vacuo. The residue is taken up in THF (200 l) and triethylamine (7 g) is added. After stirring for 1 hour, the mixture is poured into water and extracted with diethyl ether. The organic layer is washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue, a mixture of 2-fluoromethyl-2-phthalimido-5-hydroxypentanenitrile and 2-fluoromethyl-2-phthalimido-5-iodopentanenitrile is taken up in CH3CN (50 ml) and added to a solution of iodotrimethylsilyl prepared as described above from TMS Cl (22 g) and NaI (30 g) in CH3CH (300 ml). The mixture is stirred overnight at room temperature. Then it is poured into cold water containing sodium bicarbonate and sodium thiosulfate, and extracted with diethyl ether. The residue obtained after concentration of the organic layer in vacuo is filtered on a florisil column (30 g). Elution with diethyl ether and removal of the solvent under reduced pressure gives 22 g of 2-fluoromethyl-2-phthalimido-5-iodopentanenitrile as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+].O.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:23]=1[C:24](Cl)=[O:25]>O1CCOCC1>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:23]=1[C:24]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:25]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: NCCc1ccc(-c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 43 gm (20.1 millimols) of 4-[2-Aminoethyl]-4'-hydroxy-biphenyl in a mixture of 8.5 gm (21.3 millimols) of sodium hydroxide, 270 ml of water and 100 ml of dioxane, was acylated with 41.5 gm (20.1 millimols) of 2-methoxy-5-chloro-benzoyl chloride at 0° C. After stirring at room temperature for 2 hours, the mixture was extracted with chloroform, and the organic phase was dried over sodium sulfate. After distilling off the extracting agent, 72 gm (94% of theory) of a light yellow oil were obtained. This oil crystallized slowly and was uniform in the thin-layer chromatogram (silicagel; eluant: benzene/ethyl acetate = 7:2). After purification by column chromatography on silicagel with benzene/ethyl acetate as the eluant, the oil crystallized slowly. M.p. 169° C
Reaction SMILES: O.O.[Sn](Cl)Cl.Cl.[Cl:7][C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)(O)[C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=2)[N:16]([CH3:37])[C:15](=[O:38])[CH:14]=1>CC(O)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=2)[N:16]([CH3:37])[C:15](=[O:38])[CH:14]=1
Reactant: Cn1c(=O)cc(CCc2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(=O)cc(CCc2cccc(Cl)c2)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc21
Temperature: 110 °C

Procedure:
To a solution of tin(II) chloride dihydrate (268 mg, 1.189 mmol, 4 equip) and concentrated HCl (0.373 ml) in AcOH (4 ml) was added 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(hydroxy)(thiazol-2-yl)methyl)-1-methylquinolin-2(1H)-one (160 mg, 0.307 mmol, 1 equip). The resulting solution was heated to 110° C. for 45 minutes. The reaction was cooled to room temperature and concentrated. The residue was purified by MPLC using dichloromethane-methanol as the eluent to yield 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1-methylquinolin-2(1H)-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([OH:10])[CH3:9].Cl[C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=3)=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([O:10][C:13]1[C:14]2[C:21]([C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=3)=[C:20]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1)[CH3:9]
Reactant: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: COC(=O)CCCCC(C)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC(C)CCCCC(=O)OC)c23)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Put 717 mg (4.48 mmol) (+/−)-6-hydroxyheptanoic acid methyl ester under argon in 10 ml THF and cool to 0° C. Add 2.25 ml (4.48 mmol) of a 2 M solution of phosphazene base P2-tert.-butyl in THF and stir for a further 10 min at RT. Then cool to 0° C. again. Add 1.0 g (2.99 mmol) 4-chloro-5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidine and continue stirring overnight at RT. Dilute with water, acidify with 10% aqueous citric acid solution and extract twice with ethyl acetate. Combine the ethyl acetate phases and wash once with satd. sodium chloride solution. Dry over magnesium sulphate, concentrate by evaporation and purify the residue by column chromatography on silica gel (solvent: cyclohexane/ethyl acetate 9:1). 640 mg (46.7% of theor.) of the target compound is obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][NH:15]CC2C=CC=CC=2)[C@H:10]([OH:23])[CH2:9]1.[H][H]>CO.[Pd]>[NH2:15][CH2:14][C@@H:11]1[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH:2]2[O:1][CH2:5][CH2:4][O:3]2)[CH2:9][C@H:10]1[OH:23]
Reactant: O[C@@H]1CN(CCC2OCCO2)CC[C@H]1CNCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC[C@@H]1CCN(CCC2OCCO2)C[C@H]1O
Yield: 91.4 %

Procedure:
A mixture of intermediate (43) (0.019 mol) in methanol (150 ml) was hydrogenated with palladium-on-carbon (10%, 2g) as a catalyst. After uptake of 1 equivalent hydrogen, the catalyst was filtered off and the filtrate was evaporated, yielding 4 g of (trans)-4-(aminomethyl)-1-[2-(1,3-dioxolan-2-yl)ethyl]-3-piperidinol (intermediate 44).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](I)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:18])[O:4][N:3]=1.[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:28]=[CH:29][C:20]=3[CH3:19])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: Cc1ccc2ccccc2c1B(O)O
Reactant: Cc1noc(C)c1-c1cc(I)c2[nH]c(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc2ccccc2c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 150 °C

Procedure:
In a 2-5 mL Smith Process Vial, 6-(3,5-dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one (100.0 mg 0.282 mmol), (2-methylnaphthalen-1-yl)boronic acid (176.0 mg, 0.946 mmol, 3.36 equiv), PEPPSI-iPr (19.2 mg, 0.028 mmol, 0.1 equiv) and Cs2CO3 (337.0 mg, 1.126 mmol, 4 equiv) were placed. The mixture was suspended in 1,4-dioxane (1.5 mL) and water (0.5 mL) under N2. The mixture was heated at 150° C. for 75 min using microwave reactor (Biotage Optimizer). After an aqueous work up, the crude product was purified by a silica-gel column chromatography (hexane/EtOAc 20:80) to give 6-(3,5-dimethylisoxazol-4-yl)-4-(2-methylnaphthalen-1-yl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(N(CC)CC)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:15][C:11]2[CH:10]=[C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:14]=[CH:13][CH:12]=2)=[CH:20][CH:19]=1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2cccc(Oc3ccc(Cl)cc3)c2)OC1(C)C

Procedure:
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.23 g), copper(II) acetate (0.19 g), triethylamine (0.218 g) and 4-chlorophenylboronic acid (0.237 g) were stirred at room temperature overnight. The solid was filtered off, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (Varian, Superflash SF25-40 g column), eluting with 0-25% ethyl acetate/hexane, to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[O:33])=[CH:30][C:29]=1[O:37][CH3:38]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[O:33])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(N)=O)ccc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(N)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 64.3 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10.0 mmol), K2CO3 (2.0 g) and 4-(3-bromopropoxy)-3-methoxybenzamide (2.32 g, 8.0 mmol) in acetonitrile (80 ml) was heated at reflux for 5 hours. At the end of the reaction the solvent was evaporated. The residue was extracted into dichloromethane. The inorganic insolubles were filtered off. The dichloromethane was concentrated again. The crude residue was purified by flash chromatography over a silica gel column (55 g, SiO2 ; eluted with 1% methanol in dichloromethane, 1 l; 2% methanol in dichloromethane, 1 l). The material thus obtained weighed 2.93 g (84%) as white crystals. Recrystallization from hot ethanol (60 ml) gave 2.2 g of 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide as white crystals, m.p.=163°-164° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:17])[C:12](Br)=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:17])[C:12]([B:29]([OH:34])[OH:30])=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCc2ccccc2)cc(C)c1B(O)O
Temperature: -78 °C
Yield: 60.1 %

Procedure:
To a solution (100 mL) of 5-(benzyloxy)-2-bromo-1,3-dimethylbenzene (8.78 g, 30.2 mmol) in tetrahydrofuran was added n-butyllithium hexane solution (1.6 M, 22.6 mL, 36.2 mmol) under stirring at −78° C. The reaction mixture was stirred at the same temperature for 1.5 hr, and triisopropyl borate (20.9 mL, 90.6 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added 2 M hydrochloric acid (150 mL) and the mixture was stirred for 2.5 hr. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Cold hexane was added to the residue to allow crystallization. The precipitated crystals were collected by filtration, washed with cold hexane and dried to give the title compound (4.65 g, yield 60%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:34][C@H:35]([OH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=[O:25])=[C:19]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:55][S:56]([NH2:59])(=[O:58])=[O:57].C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O>[CH:28]1([O:27][C:19]2[CH:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:8]([CH2:34][C@H:35]([OH:42])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][CH:13]=3)[CH:22]=[CH:21][C:20]=2[CH2:23][C:24]([NH:59][S:56]([CH3:55])(=[O:58])=[O:57])=[O:25])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(CC(=O)O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccccc1
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(CC(=O)NS(C)(=O)=O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccccc1
Reaction time: 1.5 h
Yield: 23.6 %

Procedure:
To a solution of [4′-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenylyl]acetic acid (228 mg) in N,N-dimethylformamide (2.5 ml) was added 1,1′-carbonyldiimidazole (77 mg) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 1.5 hours. To this one were added methanesulfonamide (76 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (91 mg) at 5° C., and the mixture was stirred at the same temperature for 5 hours. The resulting mixture was poured into 1N hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid (twice) and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/ethyl acetate=10:1 to 5:1) to give tert-butyl [2-(3′-(cyclohexyloxy)-4′-[2-[(methylsulfonyl)amino]-2-oxoethyl]-4-biphenylyl]ethyl]-[(2R)-2-hydroxy-2-phenylethyl]carbamate (61 mg).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CC(C)=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
A mixture containing 2-(chloromethyl)quinoline hydrochloride (15 g), 4-hydroxybenzaldehyde (8.56 g) and anhydrous potassium carbonate (29 g) was heated under reflux in acetone (300 mL) for 86 h. After cooling to room temperature, ether (400 mL) was added and the mixture was filtered on celite. The filtrate was evaporated to dryness under reduced pressure and purified by flash chromatography using 15% ethyl acetate/hexane. The title compound was obtained after recrystallization from ethyl acetate/hexane m.p. 89°-90°.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:4][OH:5].[C:16]([N:20]=[C:21]=[S:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(O)C>[C:16]([NH:20][C:21]([NH:2][C@@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:4][OH:5])=[S:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N=C=S
Reactant: N[C@H](CO)Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)NC(=S)N[C@H](CO)Cc1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
The process is performed as in Example 2, starting with 5.65 g of (2S)-2-amino-3-(3-nitrophenyl)-1-propanol hydrochloride, 3.7 cm3 of tert-butyl isothiocyanate and 3.41 cm3 of triethylamine in 60 cm3 of ethanol, After stirring for 3 days at a temperature in the region of 20° C. and then heating for 30 minutes at a temperature in the region of 60° C., 3.7 cm3 of tert-butyl isothiocyanate are added to the reaction medium and heating is then continued for a further 3 hours at the same temperature. After an identical work-up, 6.45 g of N-(tert-butyl)-N′-[(1S)-2-hydroxy-1-(3-nitrobenzyl)ethyl]thiourea are obtained in the form of a yellow foam. (Rf=0.61 in a 40/5/0.5 by volume mixture of dichloromethane/methanol/aqueous ammonia, on a Merck 60F254R silica plate).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CNc1ccc(F)cc1
Agent: Br
Product: CC(c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1ccc(F)cc1
Yield: 51.6 %

Procedure:
4-fluoro-N-methylaniline (204 mg, 1.63 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (200 mg, 0.41 mmol, as described in Example 3.03), using an analgous procedure to that described in Example 3.00, to afford 8-(1-((4-fluorophenyl)(methyl)amino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (96 mg, 51.9%) as a white solid. Mass Spectrum: M+H+ 454. NMR Spectrum: (DMSOd6) 1.55 (d, 3H), 2.65 (s, 3H), 2.89 (s, 3H), 3.00 (s, 3H), 3.20-3.27 (m, 2H), 3.27-3.33 (m partially hidden by H2O, 2H), 3.42-3.48 (ms, 2H), 3.48-3.56 (m, 2H), 5.48 (q, 1H), 5.54 (s, 1H), 6.83 (dd, 2H), 7.04 (dd, 1H), 7.65 (d, 2H), 7.86 (d, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]1>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]2)=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)C1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 31.1 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.43 g, 3 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.5 g, 3 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.49 g, 31%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][C:12]2[S:13][C:14]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[O:10])[CH:6]=[CH:5][N:4]=1.O.[CH3:31][NH:32][CH3:33]>CO>[C:22]([C:14]1[S:13][C:12]([NH:11][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][N:32]([CH3:33])[CH3:31])[CH:8]=2)=[O:10])=[N:16][C:15]=1[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1)c1ccnc(CCl)c1
Reactant: CNC
Solvent: CO
Solvent: O
Product: CN(C)Cc1cc(C(=O)Nc2nc(-c3ccco3)c(C(=O)c3ccccc3)s2)ccn1
Reaction time: 8 h
Yield: 41 %

Procedure:
Compound 140 (100 mg, 0.236 mmol) was dissolved in a methanol solution (2 mL) of 2.0 mol/L dimethylamine, followed by stirring overnight. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford the entitled Compound 141 (42.0 mg, 41%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](N3CCN(CC)CC3)[C:11]3[CH:22]=[CH:23][S:24][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.C(N(CC)CC)C.CC([OH:62])(C#C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:62])[C:11]3[CH:22]=[CH:23][S:24][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCN1CCN(c2nc(-c3ccc(Br)cc3)cc3sccc23)CC1
Reactant: C#CC(C)(C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=c1[nH]c(-c2ccc(Br)cc2)cc2sccc12
Yield: 109.5 %

Procedure:
6-(4-Bromophenyl)-4-(4-ethylpiperazin-1-yl)thieno[3,2-c]pyridine (0.96 g) was heated under reflux in the presence of bistriphenylphosphine dichloride (48 mg), triphenylphosphine (174 mg) and cuprous iodide (46 mg), in 2-methyl-3-butyn-2-ol (0.26 g), pyridine (15 ml) and triethylamine (30 ml) for 1.5 hr. The reaction solution was evaporated, and the resulting residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane system), to give 0.80 g of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]3)=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1ccc2cc(OCCCCSc3ccc(Cl)c(Cl)c3)ccc2[nH]1
Reactant: OO
Product: O=c1ccc2cc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)ccc2[nH]1

Procedure:
Prepared analogous to Example 123 from 6-[4-(3,4-dichloro-phenyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: O=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:3]12[CH2:14][CH2:15][C:16](=[O:17])[O:18][C:2]=1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2
Reactant: O=C(O)CCC1CCCCCCCCCCC1=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCC2=C(CCCCCCCCCC2)O1

Procedure:
One part of β-(2-oxocyclododecyl)propionic acid, 1 part of acetic anhydride, 10 parts of glacial acetic acid, and 0.5 part of Amberlyst 15 were allowed to react at 50° C for 4 hours and the reaction solution was withdrawn and analyzed by gas chromatography to find that β-(2-oxocyclododecyl)propionic acid was not present and 13-oxabicyclo(10.4.0)hexadec-1(12)-en-14-one was produced in 99% selectivity.